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WO1998000134A1 - Fibrinogen receptor antagonists - Google Patents

Fibrinogen receptor antagonists Download PDF

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Publication number
WO1998000134A1
WO1998000134A1 PCT/US1997/011133 US9711133W WO9800134A1 WO 1998000134 A1 WO1998000134 A1 WO 1998000134A1 US 9711133 W US9711133 W US 9711133W WO 9800134 A1 WO9800134 A1 WO 9800134A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
mmol
etoac
aryl
nmr
Prior art date
Application number
PCT/US1997/011133
Other languages
French (fr)
Inventor
Mark E. Duggan
Melissa S. Egbertson
George D. Hartman
Steven D. Young
Nathan C. Ihle
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9700893.2A external-priority patent/GB9700893D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU35798/97A priority Critical patent/AU721130B2/en
Priority to EP97932307A priority patent/EP0912175A4/en
Priority to JP10504291A priority patent/JP2000514061A/en
Publication of WO1998000134A1 publication Critical patent/WO1998000134A1/en

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
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    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the invention relates generally to modulating cell adhesion and to inhibiting the binding of fibrinogen and other proteins to blood platelets, and inhibiting the aggregation of blood platelets specifically to the gp Ilb/LIIa fibrinogen receptor site.
  • Fibrinogen is a glycoprotein present in blood plasma that participates in platelet aggregation and in fibrin formation. Platelets are cell-like anucleated fragments, found in the blood of all mammals, that also participate in blood coagulation. Interaction of fibrinogen with the Ilb/IIIa receptor site is known to be essential for normal platelet function.
  • platelets When a blood vessel is damaged by an injury or other causative factor, platelets adhere to the disrupted subendothethial surface. The adherent platelets subsequently release biologically active constituents and aggregate. Aggregation is initiated by the binding of agonists, such as thrombin, epinephrine, or ADP to specific platelet membrane receptors. Stimulation by agonists results in exposure of latent fibrinogen receptors on the platelet surface, and binding of fibrinogen to the glycoprotein Ilb/IIIa receptor complex.
  • agonists such as thrombin, epinephrine, or ADP
  • arginine- glycine-aspartic acid containing tripeptides are recognized by at least one member of a family of structurally related receptors, integrins, which are heterodimeric proteins with two membrane-spanning subunits.
  • integrins which are heterodimeric proteins with two membrane-spanning subunits. The authors state that the conformation of the tripeptide sequence in the individual proteins may be critical to recognition specificity.
  • Ruggeri et al. Proc. Nat'l Acad. Sci. U.S.A., 83, 5708- 5712 (1986) explore a series of synthetic peptides designed in lengths to 16 residues, that contain RGD and a valine attached to the aspartic acid residue of RGD that inhibit fibrinogen binding to platelets. See also Koczewiak et al., Biochem. 23, 1767-1774 (1984); Ginsberg et al., J. Biol. Chem. 260(1), 3931-3936 (1985); and Haverstick et ai, Blood 66(4), 946-952 (1985). Other inhibitors are disclosed in Eur. Pat. App. Nos. 275,748 and 298,820.
  • Ilb/LIIa complex This polypeptide contains 49 amino acids and has the RGD subunit and various disulfide bridges.
  • these snake venom factors also have high affinity for other members of the adhesive protein receptor family including the vitronectin and fibronectin receptors so are not selective for the gp Hb/LIIa complex.
  • 5,037,808 discloses the use of indolyl platelet-aggregation inhibitors which are believed to act by antagonizing interactions between fibrinogen and/or extracellular matrix proteins and the platelet gp Ilb/IIIa receptor.
  • U.S. Pat. No. 5,037,808 discloses guanidino peptide mimetic compounds that retain an Asp residue which inhibit platelet aggregation.
  • WO9014103 describes the use of antibody-polypeptide conjugates wherein said polypeptides contain the Arg-Gly-Asp (RGD) sequence.
  • W091 11458 discloses the use of large cyclic peptides containing RGD flanked by proline residues which are platelet aggregation inhibitors.
  • WO9101331 discloses small cyclic platelet aggregation inhibitors which are synthetic cyclic pentapeptides containing the tripeptide sequence Arg-Gly-Asp and a thioether linkage in the cycle.
  • U.S. Patent No. 5,051,405 also discloses the use of peptides and pseudopeptides such as N-amidino-piperidine-3-carboxylglycyl-L- aspartyl-L-valine that inhibit platelet aggregation and thrombus formation in mammalian blood.
  • EP 445 796 discloses linear compounds which can include internal piperazinyl or piperidinyl derivatives.
  • EP437 367 discloses linear polypeptide fibrinogen receptor antagonists.
  • U.S. Patent No. 5,256,812 discloses compounds of the formula Rl-A- (W) a -X-(CH2)b-OOc-B-Z-COOR wherein Rl is a guandidino or amidino moiety and A and B are chosen from specific monosubstituted aryl or heterocyclic moieties.
  • a number of very serious diseases and disorders involve hyperthrombotic complications which lead to intravascular thrombi and emboli.
  • Myocardial infarction, stroke, phlebitis and a number of other serious conditions create the need for novel and effective fibrinogen receptor antagonists.
  • X is a 5, 6 or 7 membered aromatic or nonaromatic ring, having 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on the carbon and nitrogen atoms with Rl , or disubstituted on the carbon and nitrogen atoms with Rl and R ⁇ , where R and R ⁇ are independently selected from the group consisting of hydrogen, halogen, Cl -10 alkyl,
  • Ci-6 alkylamino Ci-8 alkyl Ci-6 alkylamino Ci-8 alkyl
  • a 9 or 10 membered fused aromatic or nonaromatic ring having 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on the carbon and nitrogen atoms with R 1 , or disubstituted on the carbon and nitrogen atoms with Rl and R2, where Rl and R ⁇ are independently selected from the group consisting of hydrogen, halogen,
  • Y is a 5 or 6 membered aromatic or nonaromatic ring, having 0, 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or substituted on carbon and nitrogen atoms with R ⁇ selected from the group consisting of hydrogen, halogen,
  • R4 is hydrogen, Ci-4 alkyl, or
  • A is a 5 or 6 membered aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R ⁇ , disubstituted on carbon and nitrogen atoms with R 5 and R 6 , or trisubstituted on carbon and nitrogen atoms with R5, R6 and R7 ; where R ⁇ , R6 and R?
  • A is a 9 or 10 membered fused aromatic ring, having 0, 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R5, disubstituted on carbon and nitrogen atoms with R5 and R6, or trisubstituted on carbon and nitrogen atoms with R5, R6 and R7, where R5, R and R? are each independently selected from the group consisting of hydrogen, halogen,
  • R8 is selected from the group consisting of hydrogen, Ci -io alkyl,
  • the invention also includes the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the aggregation of blood platelets, preventing platelet thrombosis, preventing thromboembolism or preventing reocclusion, in a mammal.
  • the invention includes compounds of the formula X-Y-Z-A-B
  • X is a 5, 6 or 7 membered aromatic or nonaromatic ring, having 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on the carbon and nitrogen atoms with Rl , or disubstituted on the carbon and nitrogen atoms with Rl and R ⁇ , where Rl and R2 are independently selected from the group consisting of hydrogen, halogen, Ci-10 alkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl, Cl-3 acylamino, Cl-3 acylamino Cl-8 alkyl, Cl -6 alkylamino Cl-8 alkyl,
  • Cl-3 alkoxycarbonyl Cl-3 alkoxycarbonyl Cl-6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl-6 alkyl, or
  • a 9 or 10 membered fused aromatic or nonaromatic ring having 1, 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on the carbon and nitrogen atoms with Rl , or disubstituted on the carbon and nitrogen atoms with Rl and R2, where Rl and R ⁇ are independently selected from the group consisting of hydrogen, halogen,
  • Y is a 5 or 6 membered aromatic ring or non-aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or substituted on the carbons and nitrogens with R3 selected from the group consisting of hydrogen, halogen, Ci- 10 alkyl,
  • R4 is hydrogen, Ci-4 alkyl, or C3-6 cycloalkyl
  • A is a 5 or 6 membered aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on the carbons or nitrogen with R5, disubstituted with R5 and R6, or trisubstituted with R 5 , R 6 and R 7 , where R 5 , R6 and R 7 are independently selected from the group consisting of hydrogen, halogen, C l -io alkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, arylsulfonylamino, amino, amino Cl-8 alkyl, nitro,
  • a 9 or 10 membered fused aromatic ring having 0, 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on the carbons or nitrogen with R5, disubstituted with R ⁇ and R6, or trisubstituted with R ⁇ , R6 and R 7 , where R ⁇ , R6 and R 7 are independently selected from the group consisting of hydrogen, halogen,
  • R° " is selected from the group consisting of hydrogen, Cl-10 alkyl,
  • R9 is hydrogen
  • Cl-8 alkyl aryl, aryl Cl -6 alkyl, Cl -8 alkylcarbonyloxy -6 alkyl aryl carbonyloxy -6 alkyl, aryl Cl-6 alkylcarbonyloxy Cl-6 alkyl, Cl-8 alkylaminocarbonyl Cl-6 alkyl, or Cl-8 dialkylamino carbonyl Cl-6 alkyl.
  • the compounds have the structure
  • X is a 5, 6 or 7 membered aromatic or nonaromatic ring having 1 , 2 or 3 nitrogen atoms and unsubstituted or substituted with NH2;
  • Y is a 5 or 6 membered aromatic or nonaromatic ring having 0,
  • A is a 5 or 6 membered aromatic ring, having 0, 1, 2, or 3 nitrogen atoms and unsubstituted or monosubstituted on the carbons or nitrogen with R ⁇ , disubstituted with R ⁇ and R6, same or different, or trisubstituted with R ⁇ , R6 and R 7 , same or different, wherein R$, R6 and R 7 are selected from the group consisting of arylsulfonylamino, Ci-3 alkylsulfonylamino, Cl-3 alkyl, -CF3, C ⁇ _3aIkyloxy, halogen, nitro,
  • A is a 9 membered fused aromatic ring system having 0, 1 , 2 or
  • A is isoindolinone or indolinone
  • R ⁇ is hydrogen or Cl-3alkyl
  • R is hydrogen or -(CH2)l-3C(O)NH(CH2)0-2CH3 or -(CH2)l-3 C(O)N((CH2)0-2CH3)2-
  • the compounds have the structure
  • X is a 5 or 6 membered aromatic or nonaromatic ring having 1 or 2 nitrogen atoms and unsubstituted or substituted with NH2;
  • Y is a 6 membered aromatic or nonaromatic ring having 0 or 1 nitrogen atoms and unsubstituted or substituted with CH3; or X and Y form the fused ring systems:
  • A is phenyl unsubstituted, monosubstituted with R5, disubstituted with R ⁇ and R6, or trisubstituted with R 5 , R 6 , or R 7 , where R5, R6, 0 r R 7 are selected from
  • A is a 9 membered fused aromatic ring system having 1 nitrogen atom
  • A is isoindolinone or indolinone
  • R° " is* hydrogen or Ci-3alkyl
  • R9 is hydrogen, -(CH2)l-3C(0)NH(CH 2 ) ⁇ - 2 CH3, or
  • the compounds have the structure
  • Exemplary compounds of the group include
  • fibrinogen receptor antagonist activity is based on evaluation of inhibition of ADP- stimulated platelets. Aggregation requires that fibrinogen bind to and occupy the platelet fibrinogen receptor site. Inhibitors of fibrinogen binding inhibit aggregation.
  • human platelets are isolated from fresh blood, collected into acid citrate/dextrose by differential centrifugation followed by gel filtration on Sepharose 2B in divalent ion-free Tyrode's buffer (pH 7.4) containing 2% bovine serum albumin.
  • Platelet aggregation is measured at 37°C in a Chronolog aggregometer.
  • the reaction mixture contains gel-filtered human platelets (2 x 108 per ml), fibrinogen (100 micrograms per ml (ug/ml)), Ca2+ (1 mM), and the compound to be tested.
  • the aggregation is initiated by adding 10 mM ADP 1 minute after the other components are added.
  • the reaction is then allowed to proceed for at least 2 minutes.
  • the extent of inhibition of aggregation is expressed as the percentage of the rate of aggregation observed in the absence of inhibitor.
  • the IC50 is the dose of a particular compound inhibiting aggregation by 50% relative to a control lacking the compound. The following compounds were tested and found to have IC50 values in the range between 10 nM and 50 mM:
  • these compounds are useful for treating mammals suffering from a bone condition caused or mediated by increased bone resorption, who are in need of such therapy.
  • Pharmacologically effective amounts of the compounds, including pharamaceutically acceptable salts thereof, are administered to the mammal, to inhibit the activity of mammalian osteoclasts.
  • these compounds are useful for treating angiogenesis (formation of new blood vessels). It has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor.
  • Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate
  • Compounds of the present invention may be chiral; included within the scope of the present invention are racemic mixtures and separated enantiomers of the general formula. Furthermore, all diastereomers, including E, Z isomers, of the general formula are included in the present scope. Furthermore, hydrates as well as anhydrous compositions and polymorphs of the general formula are within the present invention.
  • Prodrugs such as ester derivatives of described compounds, are compound derivatives which, when absorbed into the bloodstream of a warm-blooded animal, cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
  • pharmaceutically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.
  • anti-coagulant shall include heparin, and warfarin.
  • thrombolytic agent shall include agents such as streptokinase and tissue plasminogen activator.
  • platelet anti-aggregation agent shall include agents such as aspirin and dipyridamole.
  • alkyl means straight or branched alkane containing 1 to about 10 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexy, octyl radicals and the like;
  • alkenyl means straight or branched alkene containing 2 to about 10 carbon atoms, e.g., propylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2,2-methylbuten- 1 - yl, 3-methylbuten-l-yl, hexen- 1-yl, hepten-1-yl, and octen-1-yl radicals and the like; alkynyl means straight or branched alkyne containing 2 to about 10 carbon atoms, e
  • aryl means a 5- or 6-membered aromatic ring containing 0, 1 , or 2 heteroatoms selected from O, N, and S, e.g. phenyl, pyridine, pyrimidine, imidazole, thiophene, oxazole, isoxazole, thiazoie, and amino- and halogen- substituted derivatives thereof.
  • alkyloxy or “alkoxy” include an alkyl portion where alkyl is as defined above, e.g., methyloxy, propyloxy, and butyloxy.
  • arylalkyl and “alkylaryl” include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above.
  • arylalkyl examples include benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl.
  • alkylaryl examples include toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine, butylpyridine, butenylpyridine, and pentenylpyridine.
  • halogen includes fluorine, chlorine, iodine and bromine.
  • oxy means an oxygen (O) atom.
  • thio means a sulfur (S) atom.
  • Oxone potassium peroxymonosulfate
  • the compounds of the present invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • intravenous bolus or infusion
  • intraperitoneal subcutaneous
  • intramusculsar form all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • An effective but non-toxic amount of the compound desired can be employed as an anti-aggregation agent.
  • Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex Ilb/IIIa receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption. The aggregated platelets may form thrombi and thromboemboli. Compounds of this invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.
  • Extracorporeal circulation is routinely used for cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between gp Ilb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the circuit. (Gluszko et al., Amer. J. Physioi, 252(H), 615-621 (1987)). Platelets released from artificial surfaces show impaired hemostatic function. Compounds of the invention may be administered to prevent adhesion.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • Oral dosages of the present invention when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day and preferably 0.01-100 mg/kg/day and most preferably 0.01-20 mg/kg/day.
  • a typical 90 kg patient would receive oral dosages ranging between about 0.9 mg/day and about 9 g/day, most preferably between about 0.9 mg/day and 1.8 g/day.
  • Suitable pharmaceutical oral compositions such as tablets or capsules may contain between 10-500 mg of active drug, for example, 10 mg, 100 mg, 200 mg and 500 mg.
  • the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
  • compounds of the present invention may be administered in divided doses of two, three, or four times daily.
  • preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, or course, be continuous rather that intermittent throughout the dosage regime.
  • the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with convention pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture.
  • suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium. alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.
  • ester _ 9 A mixture of ester (260 mg, 0.56 mmol), 10% Pd/C (100 mg) and EtOH (10 ml) was stirred under I atm H2 for 18 h. The reaction mixture was filtered through a celite pad and concentrated to furnish ester _ 9 as a brown solid.
  • ester 9 250 mg, 0.53 mmol
  • 1 N NaOH 1 ml, 1.00 mmol
  • EtOH 3 ml
  • the solution was acidified with 10% KHSO4 and then extracted with EtOAc.
  • the EtOAc phase was washed with brine, dried (MgS04) and concentrated to furnish acid 1-10 as a tan solid.
  • ester 5 ⁇ 2 250 mg, 0.4678 mmol
  • anisole 203 ⁇ l, 1.87 mmol
  • CH2CI2 3 ml
  • ester 63 300 mg, 0.64 mmol
  • 10% Pd/C 100 mg
  • EtOH 10 ml
  • the reaction mixture was filtered through a celite pad and concentrated to furnish ester 6 as a yellow oil.
  • ester £ (260 mg, 0.5563 mmol), 1 N NaOH (1 ml, 1 mmol) and EtOH (3 ml) was stirred at ambient temperature for 1.0 h.
  • the solution was acidified with 10% KHSO4 and then extracted with EtOAc.
  • the EtOAc phase was washed with brine, dried (MgS04) and concentrated to furnish acid 63 as a white solid.
  • Ethyl 6-chloronicotinate 8-1. Maybridge Chemical Co., 2.0 g, 10.8 mmol
  • piperazine 1.4 g, 15 mmol
  • Boc 2 0 2.6 g, 11.9 mmol
  • the reaction mixture was stirred overnight then diluted with EtOAc, washed with water, sat NaHC03 and brine, dried (MgS ⁇ 4), filtered and concentrated.
  • Acid M 500 mg, 1.6 mmol
  • NMM 720 ⁇ L, 6.5 mmol
  • BOP reagent 793 mg, 1.8 mmol
  • 4-aminophenol 260 mg, 1.8 mmol
  • the reaction mixture was diluted with EtOAc, washed with water (5x), sat. NaHC03 and brine, dried (MgS04), filtered and concentrated.
  • Phenol 84 (374 mg, 0.94 mmol), t-butyl bromoacetate (151 ⁇ L, 0.94 mmol) and CS2CO3 (761 mg, 2.3 mmol) were combined in 5 mL DMF. After 90 min. the reaction mixture was diluted with EtOAc, washed with water (4x) and brine, dried (MgS04), filtered and concentrated. Flash chromatography (silica, 50% EtOAc/hexane) provided ⁇ 5 as a brown solid.
  • Ester 83 (290 mg, 0.57 mmol) was dissolved in 5 mL 1 : 1 TFA/CH2CI2. After 1 h the reaction was concentrated and azeotroped with toluene. Flash chromatography (silica, 10: 1 :1 EtOH/H2 ⁇ /NH4 ⁇ H) and trituration with Et 2 0 provided % as a light brown solid.
  • sulfanilic acid 14.38 g, 83 mmol
  • .sodium carbonate 4.29 g, 40.5 mmol
  • distilled H2 ⁇ 83 mL
  • sodium nitrite 6.16 g, 89.3 mmol
  • H2O 15 mL
  • the reaction mixture was poured onto a mixture of ice (100 g) and 12N HCI (17.4 mL). The ice was allowed to melt and the solid diazonium salt was collected by suction filtration on a scintered glass frit.
  • O-cresol (9.10 g, 84.1 mmol) was dissolved in a solution of NaOH (1.21 g, 30.25 mmol) in H2O (100 mL). This solution was cooled to 0°C and the solid diazonium salt was added in one portion. This well stirred mixture was maintained at +15°C for 4 h. The temperature of the mixture was raised to +60°C and sodium dithionite (35 g, 1.03 mol) was added portionwise.
  • the EtOAc extract was dried (MgS ⁇ 4), filitered and cooled to 0°C in an ice bath. This solution was saturated with dry HCI gas and aged 30 min. at 0°C. The excess HCI was removed with a stream of argon and the solvent was removed in vacuo.
  • the product was purified by preparative reverse phase HPLC using a H2O-CH3CN gradient on a Waters C-18 column. Obtained 105 mg of 2-(4-(4-(3-methyl-4-(l-piperazinyl)phenylcarbonyl- amino)phenoxy)acetic acid as a white solid.
  • HOAc/MeOH was treated with 250 mg Pt ⁇ 2 and hydrogenated at 50 psi for 4 hr.
  • the solution was filtered through Solka Floe, evaporated and azeotroped with heptane to remove excess HOAc.
  • the intermediate amino acid acetic acid salt was obtained as a white solid.
  • lH NMR 400 MHz, CD3OD) ⁇ 8.96 (m, 2H), 7.35 (m, 2H), 3.5 (bd, 2h), 3.4 (m, 2H), 3.2 (m, 2H), 3.0 (m, 2H).
  • NaNH2 (142 mmol) was prepared in situ as described in Leffler, M.T. Organic Reactions 1942 Vol. I.
  • Dimethylaniline (20 ml) was added dropwise to the freshly prepared NaNH2- 16-1 (8.0 g, 47.3 mmol) was dissolved in a small amount of dimethylaniline and added to the mixture.
  • the slurry was heated to 160° for 2 hours.
  • the reaction mixture is cooled and diluted with 10% KHSO4 and water.
  • the layers are separated, and the dimethylaniline layer is washed with 10% KHSO4.
  • the aqueous layers are combined, basified with saturated NaHC03, and extracted with EtOAC (3x).
  • the combined organic layers are washed w/brine and concentrated to yield an oily solid.
  • 17-1 is dissolved in dichloroethane (30 mL) and added dropwise, rapidly to a refluxing solution of Boc2 ⁇ in dichloroethane (10 mL). After the addition, the reaction is refluxed for 30 min, then stirred at RT overnight. The reaction mixture is cooled and concentrated to yield a yellow solid, which is purified by chromatography (silica, 30% EtOAc/Hexane) to give 17-2 as a white solid. Rf (50% EtOAc/Hex) 0.73.
  • 17-4 (1.0 g, 3.4 mmol) is slurried in CH3CN (40 mL). 10% KHSO4 (1.3 mL) and 30% H2O2 (0.957 mL) are added and the solution is cooled in an ice bath. NaC102 (8.5 mmol, 770 mg) is added dropwise in 50 mL water over 20 min. The reaction is stirred for 16 hrs. The reaction mixture is diluted w/EtOAc and washed with saturated NaHC03 (2x). The aqueous layers are combined, acidifed with 10% KHSO4, and extracted W/CH2CI2 (2x) and EtOAc (2x) to give 17-5 as a yellow solid.
  • CD3OD ⁇ 8.3 (d, IH), 8.1 (bd, 3H), 7.9 (d, 2H), 7.5 (bs, IH), 7.2 (s, IH), 6.9 (s, IH), 6.8 (d, IH), 4.7 (s, 2H), 2.3 (s, 3H), 1.5 (s, 9H).
  • Methyl 4-(3(R)-((N-benzyl)pyrrolidinyl)amino)benzoate (18-2) A solution of (0.52 g, 1.87 mmol) in dioxane (10 mL) and 1 : 1 H2 ⁇ /concentrated H2SO4 (10 mL) was heated to 100°C for 18 hours. The solvent was removed in vacuo and the residue dissolved in MeOH (30 mL) and stirred for 4 days. The solvent was removed and the residue taken up in saturated NaHC03 and IN NaOH to give a pH of 10, then extracted with chloroform.
  • N-benzyl-3-(R)-(( 1.1 -dimethylethoxycarbonyl)amino)pyrrolidine (19-1)
  • TCI N-benzyl-3-(R)-aminopyrrolidine
  • Boc2 ⁇ 6.80 g, 31.2 mmol
  • Et3N 7.9 ml, 57 mmol
  • the reaction was stirred at room temperature for 15 h, then solvent was removed.
  • the residue was purified by flash chromatography on silica gel eluting with EtOAc (3)/hexane (2) to give 19-1 as an oil.
  • 21 -3 was prepared in two steps from 4'-hydroxy-2'methyl- acetophenone, 21 -1. (Aldrich, 18.0 g, 0.120 mol).
  • the first step employed the procedure found in Merck Process Patent US 852870-92031 , which resulted in a 70/30 mix of 21 -3 and 3-iodo-4-hydroxy-6-methyl benzoic acid (21-2)
  • Methyl 4-hydroxy-2-methylbenzoate (21-4) 2P3 (5.0 g, 32.9 mmol) was redissolved in MeOH (150 mL) and cooled to 0°. HCI (g) was bubbled through for a few minutes, the cooling bath was removed and the reaction was stirred at RT for 16 hours. The reaction mixture was then concentrated to yield pure 21 -4 as a tan solid.

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Abstract

Fibrinogen receptor antagonists having the structure X-Y-Z-A-B and pharmaceutically acceptable salts, wherein X is a 5, 6 or 7 membered aromatic or nonaromatic ring, and Y is a 5 or 6 membered aromatic ring, e.g., formula (I).

Description

TITLE OF THE INVENTION FIBRINOGEN RECEPTOR ANTAGONISTS
BACKGROUND OF THE INVENTION The invention relates generally to modulating cell adhesion and to inhibiting the binding of fibrinogen and other proteins to blood platelets, and inhibiting the aggregation of blood platelets specifically to the gp Ilb/LIIa fibrinogen receptor site. Fibrinogen is a glycoprotein present in blood plasma that participates in platelet aggregation and in fibrin formation. Platelets are cell-like anucleated fragments, found in the blood of all mammals, that also participate in blood coagulation. Interaction of fibrinogen with the Ilb/IIIa receptor site is known to be essential for normal platelet function.
When a blood vessel is damaged by an injury or other causative factor, platelets adhere to the disrupted subendothethial surface. The adherent platelets subsequently release biologically active constituents and aggregate. Aggregation is initiated by the binding of agonists, such as thrombin, epinephrine, or ADP to specific platelet membrane receptors. Stimulation by agonists results in exposure of latent fibrinogen receptors on the platelet surface, and binding of fibrinogen to the glycoprotein Ilb/IIIa receptor complex.
Attempts have been made to use natural products and synthetic peptides to determine the mechanism of adhesion and platelet aggregation. For example, Rouslahti and Pierschbacher in Science, 238, 491-497 (1987), describe adhesive proteins such as fibronectin, vitronectin, osteopontin, collagens, thrombospondin, fibrinogen, and von Willebrand factor that are present in extracellular matrices and in blood. The proteins contain the tripeptide arginine-glycine-aspartic acid (RGD) as their glycoprotein Ilb/IIIa recognition site. These arginine- glycine-aspartic acid containing tripeptides are recognized by at least one member of a family of structurally related receptors, integrins, which are heterodimeric proteins with two membrane-spanning subunits. The authors state that the conformation of the tripeptide sequence in the individual proteins may be critical to recognition specificity.
Cheresh-in Proc. Nat'l Acad. Sci. U.S. A., 84, 6471-6475, (1987), describes an Arg-Gly-Asp directed adhesion receptor expressed by human endothethial cells that is structurally similar to the LTb/IIIa complex on platelets but is antigenically and functionally distinct. This receptor is directly involved in endothelial cell attachment to fibrinogen, von Willebrand factor, and vitronectin.
Pierschbacher and Rouslahti, in J. ofBiol. Chem., 262, (36), 17294-17298 (1987) hypothesized that the Arg-Gly-Asp sequence alone would be a sufficient signal for receptor recognition and binding and that, therefore, the conformation of the tri-peptide sequence would be determinative. Various synthetic peptides were produced and the authors concluded that the stereochemical conformation of Arg-Gly-Asp as influenced by enantiomeric substitutions or additions to this sequence significantly influenced receptor-ligand interaction. The authors further showed that cyclization of a decapeptide by forming a disulfide bridge between non-terminal residues Pen and Cys, rendered the peptide much less effective at inhibiting attachment to fibronectin. In Proc. Nat'l Acad. Sci. U.S.A., 81 , 5985-5988 (1984), the same authors describe tetrapeptide variants of the cell recognition site of fibronectin that retain attachment-promoting activity. Peptides having a tetrapeptide recognition site are described in U.S. Pat. Nos. 4,589,881 and 4,614,517. A number of large polypeptide fragments in the cell- binding domain of fibronectin have cell-attachment activity. For example, see U.S. Pat. Nos. 4,517,686, 4,661,1 11 and U.S. Pat. No. 4,578,079.
Ruggeri et al., Proc. Nat'l Acad. Sci. U.S.A., 83, 5708- 5712 (1986) explore a series of synthetic peptides designed in lengths to 16 residues, that contain RGD and a valine attached to the aspartic acid residue of RGD that inhibit fibrinogen binding to platelets. See also Koczewiak et al., Biochem. 23, 1767-1774 (1984); Ginsberg et al., J. Biol. Chem. 260(1), 3931-3936 (1985); and Haverstick et ai, Blood 66(4), 946-952 (1985). Other inhibitors are disclosed in Eur. Pat. App. Nos. 275,748 and 298,820.
A number of low molecular weight polypeptide factors have been isolated from snake venom. These factors apparently have high affinity for the gp LTb/IIIa complex. For example, Huang et al., J. Biol Chem., 262, 16157-16163 (1987); Huang et al., Biochemistry, 28, 661-666 (1989) describe the primary structure of the venom trigramin which is a 72 amino acid polypeptide that contains the RGD subunit. Echistatin is another compound which has high affinity for the gp
Ilb/LIIa complex. This polypeptide contains 49 amino acids and has the RGD subunit and various disulfide bridges. Gan et al., J. Biol. Chem., 263, 19827-19832 (1988). See also, Dennis et al., Proc. Nat'l Acad. Sci. USA, 87, 2471-2475 (1989). However, these snake venom factors also have high affinity for other members of the adhesive protein receptor family including the vitronectin and fibronectin receptors so are not selective for the gp Hb/LIIa complex.
While it is known that the tripeptide sequence Arg-Gly-Asp is present in certain polypeptides that can duplicate or inhibit the cell attachment-promoting effects of fibronectin and vitronectin, the tripeptide Arg-Gly-Asp has low activity. At present, there is little understanding of how other amino acids coupled to this sequence influence binding specificity. U.S. Pat. No 5,023,233 discloses small cyclic hexapeptides which contain the sequence Arg-Gly-Asp and are useful platelet aggregation inhibitors. U.S. Pat. No. 5,037,808 discloses the use of indolyl platelet-aggregation inhibitors which are believed to act by antagonizing interactions between fibrinogen and/or extracellular matrix proteins and the platelet gp Ilb/IIIa receptor. U.S. Pat. No. 5,037,808 discloses guanidino peptide mimetic compounds that retain an Asp residue which inhibit platelet aggregation. WO9014103 describes the use of antibody-polypeptide conjugates wherein said polypeptides contain the Arg-Gly-Asp (RGD) sequence.
W091 11458 discloses the use of large cyclic peptides containing RGD flanked by proline residues which are platelet aggregation inhibitors. WO9101331 discloses small cyclic platelet aggregation inhibitors which are synthetic cyclic pentapeptides containing the tripeptide sequence Arg-Gly-Asp and a thioether linkage in the cycle. U.S. Patent No. 5,051,405 also discloses the use of peptides and pseudopeptides such as N-amidino-piperidine-3-carboxylglycyl-L- aspartyl-L-valine that inhibit platelet aggregation and thrombus formation in mammalian blood. EP 445 796 discloses linear compounds which can include internal piperazinyl or piperidinyl derivatives. EP437 367 discloses linear polypeptide fibrinogen receptor antagonists. U.S. Patent No. 5,256,812 discloses compounds of the formula Rl-A- (W)a-X-(CH2)b-OOc-B-Z-COOR wherein Rl is a guandidino or amidino moiety and A and B are chosen from specific monosubstituted aryl or heterocyclic moieties.
While a multitude of compounds or peptide analogs believed to inhibit platelet aggregation by inhibiting binding to a blood platelet by fibrinogen are known, the present invention provides novel fibrinogen receptor antagonists that have significant binding activity and are, therefore, useful for the reasons stated herein. A number of very serious diseases and disorders involve hyperthrombotic complications which lead to intravascular thrombi and emboli. Myocardial infarction, stroke, phlebitis and a number of other serious conditions create the need for novel and effective fibrinogen receptor antagonists.
SUMMARY OF THE INVENTION The invention includes compounds of the formula
X-Y-Z-A-B
and pharmaceutically acceptable salts,
wherein X is a 5, 6 or 7 membered aromatic or nonaromatic ring, having 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on the carbon and nitrogen atoms with Rl , or disubstituted on the carbon and nitrogen atoms with Rl and R^, where R and R^ are independently selected from the group consisting of hydrogen, halogen, Cl -10 alkyl,
C3-8 cycloalkyl, aryl, aryl Ci-8 alkyl, amino, amino C 1-8 alkyl,
Ci-3 acylamino,
Cl-3 acylamino Ci-8 alkyl,
Ci-6 alkylamino Ci-8 alkyl,
Ci -6 alkylamino, Ci -6 dialkylamino Cl-8 alkyl,
Cl-6 alkoxy,
Ci -6 alkoxy Cl-6 alkyl, aryl Cl-6 alkyloxy, aryl Cl-6 alkyloxy Cl -6 alkyl, carboxy, carboxy Cl-6 alkyl,
Cl-3 alkoxycarbonyl,
Cl-3 alkoxycarbonyl Cl -6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl-6 alkyl, or
a 9 or 10 membered fused aromatic or nonaromatic ring, having 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on the carbon and nitrogen atoms with R 1 , or disubstituted on the carbon and nitrogen atoms with Rl and R2, where Rl and R^ are independently selected from the group consisting of hydrogen, halogen,
Cl-10 alkyl,
C3-8 cycloalkyl, aryl, aryl C 1-8 alkyl, amino, amino Ci-8 alkyl,
Cl-3 acylamino,
Cl-3 acylamino Cl-8 alkyl, Cl-6 alkylamino C 1 -8 alky 1 ,
Cl -6 alkylamino,
Cl-6 dialkylamino Cl-8 alkyl,
Cι_6 alkoxy,
Cl-6 alkoxy Cl-6 alkyl, aryl Cl-6 alkyloxy, aryl Cl -6 alkyloxy Cl -6 alkyl, carboxy, carboxy Cl-6 alkyl,
Cl-3 alkoxycarbonyl, Cl-3 alkoxycarbonyl Cl -6 alkyl , carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl-6 alkyl;
Y is a 5 or 6 membered aromatic or nonaromatic ring, having 0, 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or substituted on carbon and nitrogen atoms with R^ selected from the group consisting of hydrogen, halogen,
Ci-io alkyl,
C3-8 cycloalkyl, aryl, aryl Cl -8 alkyl, amino, amino Cl-8 alkyl,
Cl-3 acylamino, Cl-3 acylamino Cl-8 alkyl,
Cl-6 alkylamino,
Cl -6 alkylamino Cl-8 alkyl,
Cl -6 dialkylamino,
Cl-6 dialkylamino Cl-8 alkyl, Cl-6 alkoxy,
Cl-6 alkoxy Cl-6 alkyl, aryl Cl-6 alkyloxy, aryl Cl -6 alkyloxy Cl-6 alkyl, carboxy, carboxy Cl-6 alkyl,
Cl-3 alkoxycarbonyl,
Cl-3 alkoxycarbonyl Cl-6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl-6 alkyl; or
X and Y combined together form the structures
Figure imgf000009_0001
Figure imgf000010_0001
Z is
O R4
II i — C-N—
R40
I II
—N-C—
— CH CH2~ "
— CH=CH—
-CH2-O—
— O— CH2 —
O II — C-CH2—
0
II
— CH2-C —
— CH2NR
•NR4CH2—
OH I
■CH- ■CH;
OH I
•CH2-CH- ,or Z representes a bond;
R4 is hydrogen, Ci-4 alkyl, or
C3-6 cycloalkyl; A is a 5 or 6 membered aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, 0, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R^, disubstituted on carbon and nitrogen atoms with R5 and R6, or trisubstituted on carbon and nitrogen atoms with R5, R6 and R7; where R^, R6 and R? are each independently selected from the group consisting of hydrogen, halogen, Cl-10 alkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, arylsulfonylamino, amino, amino Cl-8 alkyl, nitro, Cl -3 acylamino,
Cl-3 acylamino Cι _8 alkyl,
Cl -6 alkylamino,
Cl-3 alkylsulfonylamino,
Cl-6 alkylamino Cl-8 alkyl, Cl-6 dialkylamino,
Cl -6 dialkylamino Cl-8 alkyl,
Cl -6 alkoxy,
Cl -6 alkoxy Cl -6 alkyl, trihaloalkyl, aryl Cl-6 alkyloxy, aryl Cl-6 alkyloxy Cl-6 alkyl, carboxy, carboxy Cl-6 alkyl,
Cl-3 alkoxycarbonyl,
Cl-3 alkoxycarbonyl Cl-6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl-6 alkyl, or
A is a 9 or 10 membered fused aromatic ring, having 0, 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on carbon and nitrogen atoms with R5, disubstituted on carbon and nitrogen atoms with R5 and R6, or trisubstituted on carbon and nitrogen atoms with R5, R6 and R7, where R5, R and R? are each independently selected from the group consisting of hydrogen, halogen,
Cl-10 alkyl,
C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl,
Cl-3 acylamino,
Cl -3 acylamino Cl -8 alkyl,
Cl -6 alkylamino, Cl-6 alkylamino C l -8 alkyl,
Cl-6 dialkylamino,
Cl -6 dialkylamino Cl-8 alkyl,
Cl -6 alkoxy,
Cl -6 alkoxy Cl -6 alkyl, aryl Cl-6 alkyloxy, aryl Cl-6 alkyloxy Cl-6 alkyl, carboxy, carboxy Cl-6 alkyl,
Cl-3 alkoxycarbonyl,
Cl-3 alkoxycarbonyl Cl-6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl-6 alkyl;
Bis
-0(CH2)mC02R9 ι
-(CH2)nC02R9,
Figure imgf000013_0001
-OCH(R8)(CH2)pC02R£ wherein m is 1, 2, or 3, n is 0, 1, 2, or 3, and p is 0, 1, 2, or 3;
R8 is selected from the group consisting of hydrogen, Ci -io alkyl,
C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl,
Cl-3 acylamino,
Ci-3 acylamino - alkyl,
Cl-6 alkylamino, Cl-6 alkylamino Cl-8 alkyl, Cl-6 dialkylamino, Cl-6 dialkylamino Cl -8 alkyl, Cl-6 alkoxy, Cl-6 alkoxy C 1 -6 alkyl, aryl Cl-6 alkyloxy, aryl Cl-6 alkyloxy Cl-6 alkyl, carboxy, carboxy Cl-6 alkyl, Cl-3 alkoxycarbonyl,
Cl-3 alkoxycarbonyl Cl-6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, hydroxy Cl-6 alkyl; and
hydrogen,
Cl-8 alkyl, aryl, aryl Cl-6 alkyl,
Cl-8 alkylcarbonyloxy Cl-6 alkyl aryl carbonyloxy Cl-6 alkyl, aryl Cl-6 alkylcarbonyloxy Cl-6 alkyl,
Cl-8 alkylaminocarbonyl Cl-6 alkyl, or Cl-8 dialkylamino carbonyl Cl-6 alkyl.
The invention also includes the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the aggregation of blood platelets, preventing platelet thrombosis, preventing thromboembolism or preventing reocclusion, in a mammal. DETAILED DESCRIPTION OF THE INVENTION
The invention includes compounds of the formula X-Y-Z-A-B
and pharmaceutically acceptable salts,
wherein X is a 5, 6 or 7 membered aromatic or nonaromatic ring, having 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on the carbon and nitrogen atoms with Rl , or disubstituted on the carbon and nitrogen atoms with Rl and R^, where Rl and R2 are independently selected from the group consisting of hydrogen, halogen, Ci-10 alkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl, Cl-3 acylamino, Cl-3 acylamino Cl-8 alkyl, Cl -6 alkylamino Cl-8 alkyl,
Cl-6 alkylamino, Cl -6 dialkylamino Cl-8 alkyl, Cl-6 alkoxy, Cl-6 alkoxy Cl-6 alkyl, aryl Cl -6 alkyloxy, aryl Cl -6 alkyloxy Cl-6 alkyl, carboxy, carboxy Cl-6 alkyl,
Cl-3 alkoxycarbonyl, Cl-3 alkoxycarbonyl Cl-6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl-6 alkyl, or
a 9 or 10 membered fused aromatic or nonaromatic ring, having 1, 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on the carbon and nitrogen atoms with Rl , or disubstituted on the carbon and nitrogen atoms with Rl and R2, where Rl and R^ are independently selected from the group consisting of hydrogen, halogen,
Cl -10 alkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl, Cl -3 acylamino,
Cl -3 acylamino Cl-8 alkyl,
Cl -6 alkylamino Cl-8 alkyl,
Cl-6 alkylamino,
Cl -6 dialkylamino Cl-8 alkyl, Cl-6 alkoxy,
Cl-6 alkoxy Cl-6 alkyl, aryl Cl-6 alkyloxy, aryl Cl -6 alkyloxy Cl-6 alkyl, carboxy, carboxy Cl-6 alkyl,
C l-3 alkoxycarbonyl,
C l -3 alkoxycarbonyl Cl -6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl-6 alkyl;
Y is a 5 or 6 membered aromatic ring or non-aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or substituted on the carbons and nitrogens with R3 selected from the group consisting of hydrogen, halogen, Ci- 10 alkyl,
C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl,
Cl -3 acylamino,
Cl-3 acylamino Cl-8 alkyl,
Cl-6 alkylamino,
Cl-6 alkylamino Cl-8 alkyl, Cl-6 dialkylamino,
Cl -6 dialkylamino Cl-8 alkyl,
Cl-6 alkoxy,
Cl-6 alkoxy Cl-6 alkyl, aryl Cl-6 alkyloxy, aryl Cl-6 alkyloxy Cl-6 alkyl, carboxy, carboxy Cl-6 alkyl,
C l-3 alkoxycarbonyl,
Cl-3 alkoxycarbonyl Cl-6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl-6 alkyl; X and Y combined together form the structures
Figure imgf000018_0001
Z is
O R4
II T C-N-
R40
I ii
-N-C-
_CH CH2
-CH=CH—
CH2-0—
-O— CH2 —
O II -C-CH2—
O
II ■CH2-C —
— CH2NR
— NR4CH2— , OH
I
CH — CH2 — i
OH I
— CH2-CH — , or
Z represents a bond;
R4 is hydrogen, Ci-4 alkyl, or C3-6 cycloalkyl; A is a 5 or 6 membered aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on the carbons or nitrogen with R5, disubstituted with R5 and R6, or trisubstituted with R5, R6 and R7, where R5, R6 and R7 are independently selected from the group consisting of hydrogen, halogen, C l -io alkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, arylsulfonylamino, amino, amino Cl-8 alkyl, nitro,
Cl-3 acylamino,
Cl-3 acylamino Cl -8 alkyl,
Cl-6 alkylamino,
Cl-3 alkylsulfonylamino, Cl -6 alkylamino Cl-8 alkyl,
Cl-6 dialkylamino,
Cl-6 dialkylamino Cl-8 alkyl,
Cl-6 alkoxy,
Cl-6 alkoxy -6 alkyl, trihaloalkyl, aryl Cl-6 alkyloxy, aryl Cl-6 alkyloxy Cl-6 alkyl, carboxy, carboxy Cl-6 alkyl, Cl-3 alkoxycarbonyl,
Cl-3 alkoxycarbonyl Cl -6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl-6 alkyl, or
a 9 or 10 membered fused aromatic ring, having 0, 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on the carbons or nitrogen with R5, disubstituted with R^ and R6, or trisubstituted with R^, R6 and R7, where R^, R6 and R7 are independently selected from the group consisting of hydrogen, halogen,
Cl -10 alkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl -8 alkyl,
Cl-3 acylamino,
Cl-3 acylamino Cl -8 alkyl,
Cl -6 alkylamino,
Ci-6 alkylamino Cl-8 alkyl, Cl -6 dialkylamino,
Cl -6 dialkylamino Cl-8 alkyl,
Cl -6 alkoxy,
Cl-6 alkoxy Cl-6 alkyl, aryl Cl-6 alkyloxy, aryl C 1 -6 alkyloxy C 1 -6 alky 1 , carboxy, carboxy Cl-6 alkyl,
Cl-3 alkoxycarbonyl,
Cl-3 alkoxycarbonyl Cl-6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl-6 alkyl;
-0(CH2)mC02R9 >
- (CH2)nC02R9 , or
Figure imgf000021_0001
-0CH(R8)(CH2)pCO2R£ wherein m is 1, 2, or 3, n is 0, 1 , 2, or 3, and p is 0, 1, 2, or 3;
R°" is selected from the group consisting of hydrogen, Cl-10 alkyl,
C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl,
Cl -3 acylamino,
Cl-3 acylamino Cl -8 alkyl,
Cl-6 alkylamino,
Cl -6 alkylamino Cl-8 alkyl, Cl-6 dialkylamino,
Cl-6 dialkylamino Cl-8 alkyl,
Cl-6 alkoxy,
Cl-6 alkoxy Cl-6 alkyl, aryl Cl-6 alkyloxy, ary 1 C 1 -6 alky loxy C 1 -6 alkyl , carboxy, carboxy Cl-6 alkyl,
Ci-3 alkoxycarbonyl,
Cl-3 alkoxycarbonyl Cl-6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, hydroxy Cl -6 alkyl; and
R9 is hydrogen,
Cl-8 alkyl, aryl, aryl Cl -6 alkyl, Cl -8 alkylcarbonyloxy -6 alkyl aryl carbonyloxy -6 alkyl, aryl Cl-6 alkylcarbonyloxy Cl-6 alkyl, Cl-8 alkylaminocarbonyl Cl-6 alkyl, or Cl-8 dialkylamino carbonyl Cl-6 alkyl.
In one class, the compounds have the structure
X-Y-Z-A-B
and pharmaceutically acceptable salts,
wherein
X is a 5, 6 or 7 membered aromatic or nonaromatic ring having 1 , 2 or 3 nitrogen atoms and unsubstituted or substituted with NH2;
Y is a 5 or 6 membered aromatic or nonaromatic ring having 0,
1 , 2 or 3 nitrogen atoms and unsubstituted or substituted with Ci-3alkyl; or X and Y together form the fused ring systems:
Figure imgf000023_0001
Z is
O O II II
•CNH- -NH- -c- 'CH2CH2
— CH=CH— , - — , or
Figure imgf000024_0001
CH3
Z represents a bond;
A is a 5 or 6 membered aromatic ring, having 0, 1, 2, or 3 nitrogen atoms and unsubstituted or monosubstituted on the carbons or nitrogen with R^, disubstituted with R^ and R6, same or different, or trisubstituted with R^, R6 and R7, same or different, wherein R$, R6 and R7 are selected from the group consisting of arylsulfonylamino, Ci-3 alkylsulfonylamino, Cl-3 alkyl, -CF3, Cι_3aIkyloxy, halogen, nitro,
or A is a 9 membered fused aromatic ring system having 0, 1 , 2 or
3 nitrogen atoms,
or
A is isoindolinone or indolinone;
B is -0CH(R8)(CH2)pC02R9,
(CH2)nC02R9, n = 0, 1, 2, 3, p = 0, 1 , 2, 3, wherein-
R^ is hydrogen or Cl-3alkyl and
R is hydrogen or -(CH2)l-3C(O)NH(CH2)0-2CH3 or -(CH2)l-3 C(O)N((CH2)0-2CH3)2-
In a subclass of the class, the compounds have the structure
X-Y-Z-A-B
and pharmaceutically acceptable salts,
wherein
X is a 5 or 6 membered aromatic or nonaromatic ring having 1 or 2 nitrogen atoms and unsubstituted or substituted with NH2;
Y is a 6 membered aromatic or nonaromatic ring having 0 or 1 nitrogen atoms and unsubstituted or substituted with CH3; or X and Y form the fused ring systems:
Figure imgf000025_0001
Z is
O O
II II
•CNH— , -NH— , -C- ■CH2CH2
ii II
— CH=CH— , -C-N— . -NHC- , or
I CH3
Z represents a bond;
A is phenyl unsubstituted, monosubstituted with R5, disubstituted with R^ and R6, or trisubstituted with R5, R6, or R7, where R5, R6, 0r R7 are selected from
-NHSO2C6H5,
-NHSO2CH3
Figure imgf000026_0001
-CH3, -CF3, -OCH3, -Cl, -Nθ2, and
-Br,
or
A is a 9 membered fused aromatic ring system having 1 nitrogen atom,
or
A is isoindolinone or indolinone;
B is -OCH(RS)Cθ2R9,
Figure imgf000027_0001
wherein n = 1 or 2
R°" is* hydrogen or Ci-3alkyl and
R9 is hydrogen, -(CH2)l-3C(0)NH(CH2)θ-2CH3, or
-(CH2) 1 -3 C(O)N((CH2)0- CH )2.
In a group of the subclass, the compounds have the structure
X-Y-Z-A-B
and pharmaceutically acceptable salts,
wherein
Xis
Figure imgf000027_0002
"sNχ χ
Figure imgf000027_0004
H
Figure imgf000027_0003
Yis
Figure imgf000027_0005
or X and Y form the fused ring systems:
Figure imgf000028_0001
Figure imgf000028_0002
Z is
O O
II II
■CNH— -NH — ■c— -CH2CH2
O O II II CH=CH— , -C-N— -NHC" or
I CH3
Z represents a bond; A is
Figure imgf000029_0001
Figure imgf000029_0002
and
Bis
-OCH2C02H,
-OCH2C02CH2C(0)NHCH3,
-OCH2C02CH C(0)N(CH2CH3)2,
-OCH C02CH2CH3,
-CH CH2C0 H, -CH2COOH, -OCH(CH3)C02H, or -OCH(CH3)C02CH2CH3.
Exemplary compounds of the group include
3-(4-(4-piperazin- 1 -ylphenylcarbonylamino)ρhenyl) propanoic acid,
2-(4-(4-Piperaziny 1- 1 -y l)pheny lcarbonylamino)phenoxy) acetic acid,
Ethyl 2-(4-(4-(l -piperazinyl)phenylcarbonylamino)phenoxy)acetate, hydrochloride,
2-(5-(4-( 1 -Piperaziny l)pheny lcarbony lamino)indol- 1 -y 1) acetic acid,
3-(3-(4-Piperazin- 1 -ylphenyl)carbonylamino)phenyl) propanoic acid,
Ethyl 2-(4-(4-(piperazin-l -yl)phenylcarbonylamino) phenoxy)propanoate
2-(4-(4-(Piperazin- 1 -y phenylcarbony lamino)phenoxy ) propionic acid,
2-(4-(((2-Piperazin-l-yl)pyridin-5-yl)carbonylamino)phenoxy)acetic acid,
3-Methyl-4-((l ,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-7- yl)carbonylamino)phenoxyacetic acid, • 2-(4-(5-(4-( 1 , 1 -Dimethylethoxycarbonyl)-piperazin- 1 -yl)-2- thienylcarbonylamino)-3-methylphenoxy)-acetic acid,
4-(2-(l , 1 -dimethylethoxycarbonyl)-l ,2,3,4-tetrahydro-9H-pyrido[3,4- b]benzofuran-7-yl)carbonylamino)-3-methylphenoxy acetic acid,
4-((2,3,4,5-tetrahydropyrazino-[l ,2-a]indole-8-yl)carbonylamino)-3- methylphenoxyacetic acid, and
(+ /-) 4-((3-(l ,l-Dimethylethoxycarbonyl)-l ,la,2,3,4,5-hexahydro- pyrazino-[ 1 ,2-a]indole-8-yl)carbonyIamino)-3-methylphenoxyacetic acid.
One test which is used to evaluate fibrinogen receptor antagonist activity is based on evaluation of inhibition of ADP- stimulated platelets. Aggregation requires that fibrinogen bind to and occupy the platelet fibrinogen receptor site. Inhibitors of fibrinogen binding inhibit aggregation. In the ADP-stimulated platelet aggregation assay used to determine inhibition associated with the compounds claimed in the instant invention, human platelets are isolated from fresh blood, collected into acid citrate/dextrose by differential centrifugation followed by gel filtration on Sepharose 2B in divalent ion-free Tyrode's buffer (pH 7.4) containing 2% bovine serum albumin.
Platelet aggregation is measured at 37°C in a Chronolog aggregometer. The reaction mixture contains gel-filtered human platelets (2 x 108 per ml), fibrinogen (100 micrograms per ml (ug/ml)), Ca2+ (1 mM), and the compound to be tested. The aggregation is initiated by adding 10 mM ADP 1 minute after the other components are added. The reaction is then allowed to proceed for at least 2 minutes. The extent of inhibition of aggregation is expressed as the percentage of the rate of aggregation observed in the absence of inhibitor. The IC50 is the dose of a particular compound inhibiting aggregation by 50% relative to a control lacking the compound. The following compounds were tested and found to have IC50 values in the range between 10 nM and 50 mM:
3 -(4-(4-piperazin-l-ylpheny Icarbony lamino)phenyl) propanoic acid,
2-(4-(4-Piperaziny 1- 1 -yl)phenylcarbonylamino)phenoxy) acetic acid,
Ethyl 2-(4-(4-(l -piperazinyl)pheny Icarbony lamino)phenoxy)acetate, hydrochloride,
2-(5-(4-( 1 -Piperaziny l)pheny Icarbony lamino)indol- 1 -y 1) acetic acid,
3-(3-(4-Piperazin-l-ylphenyl)carbonylamino)phenyl) propanoic acid,
Ethyl 2-(4-(4-(piperazin- 1 -y l)phenylcarbony lamino) phenoxy)propanoate
2-(4-(4-(Piperazin- 1 -yl)phenylcarbonylamino)phenoxy ) propionic acid,
2-(4-(((2-Piperazin- 1 -yl)pyridin-5-yl)carbonylamino)phenoxy)acetic acid,
3-Methyl-4-((l ,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-7- yl)carbonylamino)phenoxyacetic acid,
2-(4-(5-(4-( 1 , 1 -DimethylethoxycarbonyI)-piperazin- 1 -y l)-2- thieny Icarbony lamino)-3 -methy lphenoxy )-acetic acid 4-(2-( 1 , 1 -dimethylethoxycarbonyl)- 1 ,2,3,4-tetrahydro-9H-pyrido[3 ,4- b]benzofuran-7-yl)carbonylamino)-3-methylphenoxy acetic acid,
4-((2,3,4,5-tetrahydropyrazino-[l,2-a]indole-8-yl)carbonylamino)-3- methylphenoxyacetic acid, and
(+ /-) 4-((3-( 1 ,1 -Dimethylethoxycarbonyl)- 1 ,1 a,2,3,4,5-hexahy dro- pyrazino-[ 1 ,2-a]indole-8-yl)carbonylamino)-3-methylphenoxyacetic acid.
Additionally, these compounds are useful for treating mammals suffering from a bone condition caused or mediated by increased bone resorption, who are in need of such therapy. Pharmacologically effective amounts of the compounds, including pharamaceutically acceptable salts thereof, are administered to the mammal, to inhibit the activity of mammalian osteoclasts.
Additionally, these compounds are useful for treating angiogenesis (formation of new blood vessels). It has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor.
Inhibition of angiogenesis can cause tumor regression in animal models. (See. Harrison's Principles of Internal Medicine. 12th ed., 1991). These compounds are therefore useful in the treatment of cancer by inhibiting tumor growth. (See e.g., Brooks et al., Cell, 79:1157-1164 (1994)). The term "pharmaceutically acceptable salts" shall mean non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothen-ate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, valerate.
Compounds of the present invention may be chiral; included within the scope of the present invention are racemic mixtures and separated enantiomers of the general formula. Furthermore, all diastereomers, including E, Z isomers, of the general formula are included in the present scope. Furthermore, hydrates as well as anhydrous compositions and polymorphs of the general formula are within the present invention.
Prodrugs, such as ester derivatives of described compounds, are compound derivatives which, when absorbed into the bloodstream of a warm-blooded animal, cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
The term "pharmaceutically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician. The term "anti-coagulant" shall include heparin, and warfarin. The term "thrombolytic agent" shall include agents such as streptokinase and tissue plasminogen activator. The term "platelet anti-aggregation agent" shall include agents such as aspirin and dipyridamole.
The term "alkyl" means straight or branched alkane containing 1 to about 10 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexy, octyl radicals and the like; the term alkenyl means straight or branched alkene containing 2 to about 10 carbon atoms, e.g., propylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2,2-methylbuten- 1 - yl, 3-methylbuten-l-yl, hexen- 1-yl, hepten-1-yl, and octen-1-yl radicals and the like; alkynyl means straight or branched alkyne containing 2 to about 10 carbon atoms, e.g., ethynyl, propynyl, butyn- 1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-l-yl radicals and the like.
The term "aryl" means a 5- or 6-membered aromatic ring containing 0, 1 , or 2 heteroatoms selected from O, N, and S, e.g. phenyl, pyridine, pyrimidine, imidazole, thiophene, oxazole, isoxazole, thiazoie, and amino- and halogen- substituted derivatives thereof.
The terms "alkyloxy" or "alkoxy" include an alkyl portion where alkyl is as defined above, e.g., methyloxy, propyloxy, and butyloxy. The terms "arylalkyl" and "alkylaryl" include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above. The )-n or Cl-n designation where n may be an integer from 1-10 or 2-10 respectively refers to the alkyl component of the arylalkyl or alkylaryl unit. Examples of arylalkyl include benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl. Examples of alkylaryl include toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine, butylpyridine, butenylpyridine, and pentenylpyridine. The term "halogen" includes fluorine, chlorine, iodine and bromine.
The term "oxy" means an oxygen (O) atom. The term "thio" means a sulfur (S) atom. Under standard nonmenclature used throughout this disclosure, the terminal portion of the designated side chain is described first followed by the adjacent functionality toward the point of attachment. For example, a Cl -6 alkyl substituted with Cl-5 alkyl-carbonylamino is equivalent to
H O I II C l -6-alkyl-N-C-C 1 -5-alkyl
In the schemes and examples below, various reagent symbols have the following meanings: BOC
(or Boc): t-butyloxycarbonyl Pd-C: palladium on activated carbon catalyst
DMF: dimethylformamide DMSO: dimethylsulfoxide CBZ: carbobenzyloxy
CH2C12: methylene chloride CHCI3: chloroform EtOH: ethanol MeOH: methanol EtOAc: ethyl acetate HOAc: acetic acid
BOP: benzotriazol- 1 -yloxytris(dimethylamino)phosphonium, hexafluorophosphate EDC: l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Oxone: potassium peroxymonosulfate
LDA: lithium diisopropylamide
PYCLU: Chloro-N,N,N',N'-bis(pentamethylene)formamidinium hexafluorophosphate
NMM: N-methylmorpholine
The compounds of the present invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
Likewise, they may be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramusculsar form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an anti-aggregation agent.
Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex Ilb/IIIa receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption. The aggregated platelets may form thrombi and thromboemboli. Compounds of this invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.
Extracorporeal circulation is routinely used for cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between gp Ilb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the circuit. (Gluszko et al., Amer. J. Physioi, 252(H), 615-621 (1987)). Platelets released from artificial surfaces show impaired hemostatic function. Compounds of the invention may be administered to prevent adhesion.
Other applications of these compounds include prevention of platelet thrombosis, thromboembolism and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty or coronary artery bypass procedures. They may also be used to prevent myocardial infarction.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day and preferably 0.01-100 mg/kg/day and most preferably 0.01-20 mg/kg/day. For example, a typical 90 kg patient would receive oral dosages ranging between about 0.9 mg/day and about 9 g/day, most preferably between about 0.9 mg/day and 1.8 g/day. Suitable pharmaceutical oral compositions such as tablets or capsules may contain between 10-500 mg of active drug, for example, 10 mg, 100 mg, 200 mg and 500 mg. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
Advantageously, compounds of the present invention may be administered in divided doses of two, three, or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, or course, be continuous rather that intermittent throughout the dosage regime.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with convention pharmaceutical practices. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium. alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.
SCHEME1
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000040_0003
SCHEME 1. CONTINUED
Figure imgf000041_0001
Ifi
Figure imgf000041_0002
1 .
1 N NaOH EtOH
Figure imgf000041_0003
HI.
TFA, CH2CI2
Figure imgf000041_0004
1-11
Figure imgf000042_0001
1 .
Methyl 4-(l -piperazinyDbenzoate (1-3)
A solution of amine U. (20.0 g, 132 mmol), amine 2 (23.6 g, 132 mmol) and n-butanol (500 ml) was refluxed for 168 h. The solution was allowed to cool to ambient temperature. The crystals were collected, washed with Et2θ and dried in vac o to give ester 3 as a white solid. lH NMR (CD3OD): δ 7.86 (d, J=9Hz, 2H), 7.98 (d, J=9Hz, 2H), 3.78 (s, 3H), 3.53 (m, 4H), 3.31 (m, 4H).
Figure imgf000042_0002
1 -4
Methyl 4-(4-(l .1 -dimethylethoxycarbonyDpiperazin- 1 -vDbenzoate ( 1 -4) To a stirred solution of amine θ (15.0 g, 61.1 mmol),
NEt3 (7.42 g, 73.4 mmol) and DMF (150 ml) was added Boc20 (14.7 g, 67.2 mmol). After 1.0 h, the solution was diluted with EtOAc and then washed with H20, 10% KHSO4, brine, dried (MgS04) and concentrated to furnish ester bA as a yellow solid. TLC Rf = 0.63 (silica, 40% EtOAc/hexanes) l H NMR (CD3OD): δ 7.91 (d, J=9Hz, 2H), 7.01 (d, J=9Hz, 2H), 3.88
(s, 3H), 3.59 (m, 4H), 3.38 (m, 4H).
Figure imgf000043_0001
1£
4-f4-( 1.1 -Dimethylethoxycarbony Ppiperazin- 1 -vPbenzoic acid ( 1 -5)
A solution of ester 1=4 (21.1 g, 61.1 mmol) 1 N NaOH (100 ml, 100 mmol) and EtOH (200 ml) was heated to 60°C for 2.0 h. The solution was acidifed with 10% KHSO4 and then extracted with EtOAc. The EtOAc phase was washed with brine, dried (MgSθ4) and concentrated to furnish acid 1^5 as a white solid. iH NMR (CD3OD): δ 7.81 (d, J=9Hz, 2H), 6.88 (d, J=9Hz, 2H), 3.49 (m, 4H), 3.24 (m, 4H), 1.40 (s, 9H).
Figure imgf000043_0002
N-(4-bromophenyl)-4-(4-( 1 , 1 -dimethylethoxycarbony Ppiperazin- 1 - yPbenzamide ( 1 -7) A solution of acid i^. (400 mg, 1.31 mmol), amine 1^6
(248 mg, 1.44 mmol), BOP reagent (867 mg, 1.97 mmol), NMM (575 μl, 5.24 mmol) and DMF was heated at 60°C for 72 h. The solution was diluted with EtOAc and then washed with H2O, sat. NaHC03, 10% KHSO4 brine, dried (MgSθ4) and concentrated. Flash chromatography (silica, 20% EtOAc/hexanes) furnished amide 7 as a yellow solid. TLC Rf = 0.36 (silica, 20% EtOAc/hexanes) iH NMR (CDCI3): δ 7.78 (d, J=9Hz, 2H), 7.70 (s, IH), 7.54 (d, J=9Hz, 2H), 7.46 (d, J=9Hz, 2H), 6.92 (d, J=9Hz, 2H), 3.58 (m, 4H), 3.30 (m, 4H), 1.49 (s, 9H).
Figure imgf000044_0001
(E)-Methyl 3-(4-(4-(4-( 1 , 1 -dimethylethoxycarbony piperazin- 1 - yPphenylcarbonylaminophenvPprop-3-enoate (1-8) A solution of amide \J_ (300 mg, 0.6519 mmol), methyl acrylate (587 μl, 6.52 mmol), 0(tolyl)3P (120 mg, 0.311 mmol), NEt3 (184 μl, 1.30 mmol), Pd (OAc)2 (15 mg, 0.0512 mmol) and CH3CN (5 ml) was heated to 100°C in a sealed tube for 18 h. The solution was diluted with EtOAc and then washed with H2O, sat. NaHCθ3, 10% KHSO4, brine, dried (MgS04) and concentrated. Flash chromatography (silica, 25% — > 40% EtOAc/hexanes) furnished olefin
1 -8 as a yellow solid.
TLC Rf = 0.36 (silica, 50% EtOAc/hexanes) iH NMR (CDCI3): δ 7.87 (s, IH), 7.81 (d, J=9Hz, 2H), 7.68 (m, 3H), 7.53 (d, J=9Hz, 2H), 6.94 (d, J=9Hz, 2H), 6.39 (d, J=16Hz, IH), 3.81 (s, 3H), 3.61 (m, 4H), 3.30 (m, 4H), 1.50 (s, 9H).
Figure imgf000044_0003
Figure imgf000044_0002
Methyl 3 -(4-(4-(4-( 1,1 -dimethylethoxycarbony piperazin- 1- vPphenylcarbonylaminopheny Ppropanoate (1-9)
A mixture of ester (260 mg, 0.56 mmol), 10% Pd/C (100 mg) and EtOH (10 ml) was stirred under I atm H2 for 18 h. The reaction mixture was filtered through a celite pad and concentrated to furnish ester _ 9 as a brown solid. iH NMR (CDC13): δ 7.79 (d, J=9Hz, 2H), 7.67 (s, IH), 7.54 (d, J=8Hz, 2H), 7.19 (d, J=8Hz, 2H), 6.92 (d, J=9Hz, 2H), 3.67 (s, 3H), 3.60 (m, 4H), 3.29 (m, 4H), 2.94 (t, J=8Hz, 2H), 2.63 (t, J=8Hz, 2H), 1.49 (s, 9H).
Figure imgf000045_0001
1 -10
3-(4-(4-(4-( 1 , 1 -dimethylethoxycarbonyPpiperazin- 1 - vPphenylcarbonylaminophenyPpropanoic acid (1-10
A solution of ester 9 (250 mg, 0.53 mmol), 1 N NaOH (1 ml, 1.00 mmol) and EtOH (3 ml) was stirred at ambient temperature for 1.5 h. The solution was acidified with 10% KHSO4 and then extracted with EtOAc. The EtOAc phase was washed with brine, dried (MgS04) and concentrated to furnish acid 1-10 as a tan solid. TLC Rf = 0.11 (silica, 10:0.2:0.2 CH2Cl2/MeOH/AcOH) iH NMR (CD3OD): δ 7.86 (d, J=9Hz, 2H), 7.55 (d, J=8Hz, 2H), 7.20 (d, J=9Hz, 2H), 7.08 (d, J=8Hz, 2H), 3.60 (bs, 4H) 3.45 (m, 4H), 2.89 (t, J=8Hz, 2H), 2.59 (t, J=8Hz, 2H), 1.48 (s, 9H).
Figure imgf000045_0002
1 -1 1
3-(4-(4-piperazin-l-ylphenylcarbonylamino)phenyl) propanoic acid (1-1 1
To a solution of acid PT0 (215 mg, 0.4743 mmol), TFA
(3.0 ml) and CH2CI2 (3.0 ml) was stirred at ambient temperature for
1.5 h. The solution was concentrated and then azeotroped with toluene.
The residue was trituated with 10:0.2:0.2 EtOH/NH4θH/H20, filtered, washed with Et2θ and dried in vacuo to furnish acid 1 -1 1 as a tan solid. TLC Rf = 0.55 (silica, 10:1 :1 EtOH/NH4θH/H2θ) iH NMR (D20): δ 7.83 (d, J=9Hz, 2H), 7.42 (d, J=8Hz, 2H), 7.31 (d, J=8Hz, 2H), 7.16 (d,-J=9Hz, 2H), 3.25 (m, 4H), 2.96 (m, 4H, 2.89 (t, J=8Hz, 2H), 2.49 (t, J=8Hz, 2H).
SCHEME 2
Figure imgf000047_0001
1-5 2-2
BOP, NMM DMF 60°
Figure imgf000047_0002
3
Br CO2tBu
Cs2C03, DMF
Figure imgf000047_0003
2-5
TFA, CH2CI2
Figure imgf000047_0004
23.
Figure imgf000048_0001
2£
N-(4-Hydroxyphenyl)-4-(4-( 1 , 1 -dimethylethoxycarbonyPpiperaziny 1-
1 -yDbenzamide (2-3) A solution of carboxylic acid 2d. (400 mg, 1.31 mmole), 4- aminophenyl M (210 mg, 1.44 mmol), BOP reagent (867 mg, 1.97 mmole), NMM (575 μl, 5.24 mmol) and DMF (10 ml) was heated to 60°C for 72 h. The reaction mixture was diluted with EtOAc and then washed with H2θ, sat NaHC03, 10% KHSO4, dried (MgSθ4) and then concentrated. Flash chromatography (silica, 50% EtOAc/hexanes) furnished the amide 2^3. as a white solid. TLC Rf = 0.25 (silica, 50% EtOAc/hexanes) iH NMR (CD3OD): δ 7.82 (d, J=9Hz, 2H), 7.40 (d, J=9Hz, 2H), 7.0 (d, J=9Hz, 2H), 6.75 (d, J=9Hz, 2H), 3.57 (bs, 4H), 3.30 (bs, 4S), 1.47 (s, 9H).
Figure imgf000048_0002
2 ≥
tert-Butyl 2-(4-(4-(4-( 1 , 1 -dimethylethoxycarbonyPpiperazinyl- 1 - yPphenylcarbonylamino)phenoxy)acetate (2-5)
To a stirred solution of amide 2 3. (400 mg, 1.01 mmol) and DMF (5 ml) was added cesium carbonate (820 mg, 2.53 mmole) followed by t-butyl bromoacetate (195 μl, 1.21 mmol). After 20 h, the reaction mixture was diluted with EtOAc and then washed with H2O, 10% KHSO4, brine, dried (MgS04) and concentrated. Flash chromatography (silica, 25% EtOAc/hexanes) furnished ester 2^5. as a white solid. TLC Rf = 0.40 (silica, 50% EtOAc/hexanes) iH NMR (CDC13): δ 7.79 (d, J=9Hz, 2H), 7.63 (s, IH), 7.54 (d, J=9Hz,
2H), 6.92 (m, 4H), 4.51 (s, 2H), 3.60 (m, 4H), 3.30 (m, 4H), 1.50 (s,
18H).
O
HN / N \0/ C~~NH \0/ OCH2c°2H 3
2-(4-(4-Piperazinyl-l -yl)phenylcarbonylamino)phenoxy) acetic acid (2-6) A solution of ester 2=1 (275 mg, 0.5378 mmol), TFA (5 ml) and CH2C12 (5 ml) was stirred at ambient temperature for 2.0 h. The solution was concentrated and then azeotroped with toluene. The residue was trituated with 10:0.5:0.5 EtOH/NH4θH/H20, filtered, washed with EtOH and then washed with EtOH to furnish acid 2^6 as a white solid.
TLC Rf = 0.34 (silica, 10:0.5:0.5 EtOH/NH4θH/H20) iH NMR (CD3OD): δ 7.83 (d, J=9Hz, 2H), 7.50 (d, J=9Hz, 2H), 7.00 (d, J=9Hz, 2H), 6.92 (d, J=9Hz, 2H), 4.36 (s, 2H), 3.30 (m, 4H), 2.96 (m, 4H).
SCHEME3
BOC -- -O' >C02tBu
Figure imgf000050_0001
23.
CH3I, Cs2C03 DMF, 60°C
Figure imgf000050_0002
TFA, CH2CI2
Figure imgf000050_0003
Figure imgf000051_0001
tert-Buty 1 2-(4-(4-(4-( 1 , 1 -dimethylethoxycarbony Ppiperazin- 1 - yl)phenylcarbonyl(N-methvPamino)phenox v)acetate (3- 1 ) To a stirred solution of ester 2d (200 mg, 0.3911 mmol) was added cesium carbonate (318 mg, 0.9778 mmole) followed by CH3I (29 μl, 0.47 mmol). After heating at 60° for 2.0 h, the reaction mixture was diluted with EtOAc and then washed with H20, 10% KHSO4, brine, dried (MgSθ4) and concentrated. Flash chromatography (silica, 40% EtOAc/hexanes) furnished ester 3d. as a yellow solid. TLC Rf = 0.45 (silica, 50% EtOAc/hexanes) iH NMR (CDCI3): δ 7.21 (d, J=9Hz, 2H), 6.97 (d, J=9Hz, 2H), 6.75 (d, J=9Hz, 2H), 6.63 (d, J=9Hz, 2H), 4.45 (s, 2H), 3.52 (bt, 4H), 3.43 (s, 3H), 3.13 (bt, 4H), 1.47 (s, 18H).
Figure imgf000051_0002
2-(4-(4-(l -PiperazinyPpheny Icarbony 1(N -me thy l)amino)phenoxy)-acetic acid (3-2) A solution of ester 3d. ( 190 mg, 0.3617 mmole), TFA (3 ml) and CH2CI2 (3 ml) was stirred at ambient temperature for 30 minutes. The solution was concentrated and then azeotroped with toluene. Flash chromatography (silica, 10:0.2:0.2 EtOH/NH4θH/H20) furnished acid 3 2 as a white solid. TLC Rf = 0.42 (silica, 10:0.2:0.2 EtOH/NH4θH/H20) iH NMR (CD3OD): δ 7.25 (d, J=9Hz, 2H), 7.06 (d, J=9Hz, 2H), 6.91 (d, J=9Hz, 2H), 6.82 (d, J=9Hz, 2H), 4.66 (s, 2H), 3.50 (m, 4H), 3.41 (s, 3H), 3.35 (m, 4H).
SCHEME 4
Figure imgf000052_0001
23
HCI (g) EtOH, 0°C RT
HOHN H- x>- C- NH -rs- O C02CH2CH3
4-1
Ethyl 2-(4-(4-( 1 -piperaziny l)pheny lcarbonylamino)phenoxy)acetate hydrochloride (4-1 )
To a stirred solution of acid 23 (40 mg, 0.1125 mmol) and
EtOH (2 ml) at 0°C was bubbled HCI gas for 3 minutes. After 24 h at ambient temperature, the solution was concentrated to give ethyl ester 4^
1 as a white solid. iH NMR (D2θ): δ 7.87 (d, J=9Hz, 2H), 7.44 (d, J=9Hz, 2H), 7.19 (d,
J=9Hz, 2H), 7.05 (d, J=9Hz, 2H), 4.80 (s, 2H), 4.31 (q, J=7Hz, 2H) 3.62
(m, 4H), 3.43 (m, 4H), 1.30 (t, J=7Hz, 3H). SCHEME 5
Figure imgf000053_0001
Figure imgf000054_0001
N-(5-lndolyl)-4-(4-( 1 , 1 -dimethylethoxycarbonyPpiperazin- 1 - vDbenzamide (5-2) To a stirred solution of acid 2d. (500 mg, 1.63 mmol),
NMM (715 μl, 6.52 mmol) and DMF (5 ml) was added BOP reagent (1.08 g, 2.45 mmol). After 30 minutes, amine 5_d. (Aldrich 260 mg, 1.96 mmole) was added. After 18 h at 60°C, the solution was diluted with EtOAc and then washed with H 0, brine, dried (MgSθ4) and concentrated. Flash chromatography (silica, 20% EtOAc/CHCl3) afforded amide 5^2 as a yellow solid. TLC Rf = 0.13 (silica, 20% EtOAc/CHCl3) iH NMR (10% CD3OD/CDCI3): δ 7.90 (s, IH), 7.83 (d, J=9Hz, 2H), 7.63 (m, 2H), 7.22 (9s, IH), 6.94 (d, J=9Hz, 2H), 6.52 (d, J=3Hz, IH), 3.59 (m, 4H), 3.28 (m, 4H), 1.49 (s, 9H).
Figure imgf000054_0002
tert-Butyl 2-(5-(4-(4-( 1 , 1 -dimethy lethoxycarbonyPpiperazin- 1 - yl)phenylcarbonylamino)indol- 1 -vPacetate (5-4)
To a stirred solution of amide 5^2 (300 mg, 0.71 mmol) and THF (5 ml) was added NaH (60% dispersion in mineral oil; 29 mg, 0.7137 mmol). After 10 minutes, bromide 5^ . (115 μl, 0.71 mmol) was added. After 30 minutes, the solution was diluted with EtOAc and then washed with H20, brine, dried (MgS04) and concentrated. Flash chromatography (silica, 40% EtOAc/hexanes) afforded ester 5^4 as a yellow solid.
TLC Rf = 0.18 (silica, 40% EtOAc/hexanes) iH NMR: δ 7.92 (s, IH), 7.83 (d, J=9Hz, 2H), 7.77 (s, IH), 7.39 (dd,
J=9Hz, 2Hz, IH), 6.93 (d, J=9Hz, 2H), 6.52 (d, J=3Hz, IH), 4.72 (s,
2H), 3.60 (m, 4H), 3.28 (m, 4H), 1.49 (s, 9H), 1.43 (s, 9H).
Figure imgf000055_0001
2-(5-(4-( 1 -Piperaziny pheny Icarbony lamino)indol- 1 -y 1) acetic acid (5-5)
To a stirred solution of ester 5^2 (250 mg, 0.4678 mmol), anisole (203 μl, 1.87 mmol) and CH2CI2 (3 ml) at 0°C was added TFA.
After 30 min., the solution was concentrated and then azeotroped with toluene. Flash chromatography (silica, 10:0.1 :0.1 E1OH/NΗ4O/H2O) afforded crude acid. The crude material was purified by prep HPLC to furnish acid 5-5.
TLC Rf = 0.31 (silica, 10:0.5:0.5 E1OH/NH4OH/H2O) H NMR (50:50 d6- DMSO/D2O, 2 drops IN NaOD): δ 7.87 (d, J=9Hz, 2H), 7.71 (s, IH), 7.24 (m, 3H), 7.07 (d, J=9Hz, 2H), 6.47 (d,
J=3Hz, IH), 4.63 (s, 2H), 3.25 (m, 4H), 2.89 (m, 4H).
SCHEME6
Figure imgf000056_0001
BOP, NMM, DMF, 60°C
Figure imgf000056_0002
^^C02Me, NEt3, o(tolyl)3P, CH3CN, Pd(OAc)2 sealed tube 100°C
Figure imgf000056_0003
fi=3
10%Pd/C EtOH, H2
Figure imgf000056_0004
6-4
INNaOH EtOH SCHEME 6 CONTINUED
Figure imgf000057_0001
5=5
TFA, CH2CI2
Figure imgf000057_0002
03
Figure imgf000057_0003
N-(3-bromophenyl)-4-(4-( 1 , 1 -dimethylethoxycarbonyPpiperazin- 1 - yl))benzamide (6-2)
A solution of acid ! > (400 mg, 1.31 mmol), amine 6d, (248 mg, 1.44 mmol), BOP reagent (867 mg, 1.97 mmol), NMM (575 μl, 5.24 mmol) and DMF (10 ml) was heated to 60°C for 72 h. The solution was diluted with EtOAc and then washed with H20, sat. NaHC03, 10% KHSO4, brine, dried (MgSθ4) and concentrated. Flash chromatography (silica, 25% EtOAc/hexanes) furnished amide 6^2 as a yellow solid.
TLC Rf = 0.31 (silica, 25% EtOAc/hexanes) i H NMR (CD3OD): δ 7.99 (s, IH), 7.84 (d, J=9Hz, 2H), 7.60 (m, IH),
7.25 (m, 2H), 7.02 (d, J=9Hz, 2H), 3.57 (m, 4H), 3.31 (m, 4H), 1.47 (s,
9H).
Figure imgf000058_0003
Figure imgf000058_0001
(E)-Methyl (3-(3-(4-(4-(l ,l-dimethylethoxycarbonyl)piperazin-l - yl))phenyl)carbonylaminophenyl)prop-3-enoate (6-3)
A solution of amide X2 (400 mg, 0.86 mmol), methyl acrylate (783 μl, 8.69 mmole), 0(tolyl)3P (159 mg, 0.415 mmol), NE13 (245 μl, 1.74 mmole), Pd(OAc)2 (20 mg, 0.069 mmole) and CH3CN (5 ml) was heated to 100°C in a sealed tube for 18 h. The solution was diluted with EtOAc and then washed with H20, sat. NaHCθ3, 10% KHSO4, brine, dried (MgS04) and concentrated. Flash chromatography (silica, 20% — » 30% EtOAc/hexanes) furnished olefin 6-3 as a yellow solid. TLC Rf = 0.47 (silica, 50% EtOAc/hexanes) iH NMR (CD3OD): δ 7.94 (s, IH), 7.87 (dd, J=2Hz, 9Hz, 2H), 7.71 (m, 2H), 7.36 (m, 2H), 7.03 (dd, J=2Hz, 9Hz, 2H), 6.52 (d, J=16Hz, IH), 3.78 (s, 3H), 3.57 (m, 4H), 3.29 (m, 4H), 1.47 (s, 9H).
Figure imgf000058_0004
Figure imgf000058_0002
Methyl (3-(3-(4-(4-( 1 , 1 -dimethy lethoxycarbonyPpiperazin- 1 - yl))phenyl)carbonylaminophenyl)propanoate (6-4)
A mixture of ester 63 (300 mg, 0.64 mmol), 10% Pd/C (100 mg) and EtOH (10 ml) was stirred under 1 atm H2 for 18 h. The reaction mixture was filtered through a celite pad and concentrated to furnish ester 6 as a yellow oil. iH NMR (CDC13): 7.80 (m, 3H), 7.54 (s, IH), 7.47 (d, J=8Hz, IH),
7.27 (m, IH), 6.96 (d, 8Hz, IH), 6.92 (d, J=9Hz, 2H), 3.68 (s, 3H), 3.60
(m, 4H), 3.29 (m, 4H), 2.96 (t, J=8Hz, 2H), 2.66 (t, J=8Hz, 2H), 1.50 (s,
9H).
Figure imgf000059_0001
β=5
3-(3-(4-.(4-(l ,l-Dimethylethoxycarbonyl)piperazin-l -yl))phenyl)- carbonylaminophenvDpropanoic acid C6-5)
A solution of ester £ (260 mg, 0.5563 mmol), 1 N NaOH (1 ml, 1 mmol) and EtOH (3 ml) was stirred at ambient temperature for 1.0 h. The solution was acidified with 10% KHSO4 and then extracted with EtOAc. The EtOAc phase was washed with brine, dried (MgS04) and concentrated to furnish acid 63 as a white solid. TLC Rf = 0.08 (silica, 10:0.2:0.2 CH Cl2/MeOH/AcOH) iH NMR (CD3OD): δ 7.84 (d, J=9Hz, 2H), 7.51 (m, 2H), 7.25 (t, J=8Hz, IH), 7.03 (m, 3H), 3.57 (m, 4H), 3.29 (m, 4H), 2.91 (t, J=8Hz, 2H), 2.60 (t, J=8Hz, 2H), 1.47 (s, 9H).
Figure imgf000060_0002
Figure imgf000060_0001
3-(3-(4-Piperazin- 1 -ylphenyl)carbonylamino)phenyl) propanoic acid (6-6) A solution of acid M (210 mg, 0.4633 mmol), TFA (3 ml) and CH2CI2 (3 ml) was stirred at ambient temperature for 1.0 h. The solution was concentrated and then azeotroped with toluene. Flash chromatography (silica, 10:0.1:0.1 → 10:0.5:0.5 EtOH/NH4θH/H2θ) furnished acid §3 as a tan solid. TLC Rf = 0.59 (silica, 10: 1 :1 EtOH/NH4θH/H2θ) i H NMR (D20): δ 7.82 (d, J=9Hz, 2H), 7.38 (m, 2H), 7.34 (s, IH), 7.15 (d, J=9Hz, 3H), 3.25 (m, 4H), 2.96 (m, 4H), 2.90 (t, J=8Hz, 2H), 2.50 (t, J=8Hz, 2H).
SCHEME7
Figure imgf000061_0004
Figure imgf000061_0001
TFA, CH2CI2
Figure imgf000061_0005
Figure imgf000061_0002
NaOH, EtOH
Figure imgf000061_0006
Figure imgf000061_0003
Figure imgf000062_0001
Ethy 1 2-[4-(4-(4-( 1 , 1 -Dimethylethoxycarbony Ppiperazin- 1 - yl)phenylcarbonylamino)phenoxypropanoate (7-2) Phenol 2=1 (381 mg, 0.993 mmol), ethyl 2-bromopro- pionate (2=1, 129 μL, 0.99 mmol), and Cs2C03 (807 mg, 2.5 mmol) were combined in 5 mL DMF. After stirring overnight the reaction was diluted with EtOAc, washed with water (3x), 10% KHSO4 (3x) and brine, dried (MgS04), filtered and concentrated. Flash chromato- graphy (silica, 40% EtOAc/hexane) provided 2=2. as a white solid. TLC Rf = 0.41 (silica, 50% EtOAc/hexane) iH NMR (400 MHz, CDCI3): δ 7.78 (d, J=9Hz, 2H), 7.60 (s, IH), 7.52 (d, J=9Hz, 2H), 6.92 (d, J=9Hz, 2H), 6.89 (d, J=9Hz, 2H), 4.72 (q, J=7Hz, IH), 4.22 (q, J=7Hz, 2H), 3.59 (m, 4H), 3.28 (m, 4H), 1.61 (d, J=7Hz, 3H), 1.49 (s, 9H), 1.26 (t, J=7Hz, 3H).
Figure imgf000062_0002
Ethyl 2-(4-(4-(piperazin- 1 -y Pphenylcarbonylamino) phenoxy)propanoate(7-3)
A solution of 2=2 (266 mg, 0.53 mmol) and anisole (200 μL, 1.8 mmol) in 5 mL 1 : 1 CH2CI2 TFA was stirred for 20 min. After concentration and azeotroping with toluene, flash chromatography (silica, 33: 1 : 1 EtOH/H20/NH4θH) provided 2=1 as a white solid. TLC Rf = 0.37 (silica, 20: 1 : 1 EtOH/H2θ/NH4θH iH NMR (400 MHz, CD3OD): δ 7.84 (d, J=9Hz, 2H), 7.54 (d, J=9Hz, 2H), 7.01 (d, J=9Hz, 2H), 6.88 (d, J=9Hz, 2H), 4.21 (q, J=7Hz, 2H), 3.31 (m, 4H), 2.98 (m, 4H), 1.57 (d, J=7Hz, 3H), 1.26 (t, J=Hz, 3H).
Figure imgf000063_0001
2-(4-(4-(Piperazin- 1 -yPphenylcarbony lamino)phenoxy) propionic acid (7-4)
Ester 7^3. (44 mg, 0.11 mmol) was dissolved in 1 mL EtOH, then 1 M NaOH (122 μL, 0.12 mmol) was added. After 3 h the reaction was neutralized with 1 N HCI, concentrated, then purified by flash chromatography (silica, 50:1 :1 EtOH/H20/NH4θH) providing 74 as a white solid.
TLC Rf = 0.15 (silica, 50:1 :1 EtOH/H20/NH4θH) iH NMR (400 MHz, D20): δ 7.69 (d, J=9Hz, 2H), 7.22 (d, J=9H, 2H),
7.01 (d, J=9Hz, 2H), 6.80 (d, J=9Hz, 2H), 4.48 (q, J=7Hz, IH), 3.10 (m,
4H), 2.82 (m, 4H), 1.40 (d, J=7Hz, 3H).
SCHEME8
Figure imgf000064_0001
3=3
1) BOP Reagent, DMF
2) 4-aminophenoi, 60°C
Figure imgf000064_0002
t-Butyl bromoacetate Cs2C03, DMF
Figure imgf000064_0003
TFA, CH2CI2
Figure imgf000064_0004
Figure imgf000065_0001
3=2
Eth yl 6-f4-( 1.1 -dimethylethoxycarbonvPpiperazin- 1 - yllnicotinate C8-2) Ethyl 6-chloronicotinate (8-1. Maybridge Chemical Co., 2.0 g, 10.8 mmol) and piperazine (1.4 g, 15 mmol) were combined in 54 mL NMP and heated at 50°C overnight. After cooling, Boc20 (2.6 g, 11.9 mmol) was added. The reaction mixture was stirred overnight then diluted with EtOAc, washed with water, sat NaHC03 and brine, dried (MgSθ4), filtered and concentrated. Flash chromatography (silica, 25% EtOAc/hexane) provided $Xλ as a white solid. TLC Rf = 0.63 (silica, 40% EtOAc/hexane) iH NMR (400 MHz, CDCI3): δ 8.80 (d, J=2Hz, IH), 8.04 (dd, J=9, 2Hz, IH), 6.58 (d, J=9Hz, IH), 4.34 (q, J=7Hz, 2H), 3.68 (m, 4H), 3.54 (m, 4H), 1.49 (s, 9H), 1.37 (t, J=7Hz, 3H).
Figure imgf000065_0003
Figure imgf000065_0002
6-r4-(Ll-Dimethylethoxycarbonyl)piperazin-l -yllnicotinic acid (8-3) Ester & (3.0 g, 9.3 mmol) was dissolved in 93 mL EtOH, 1 M NaOH (23 mL, 23 mmol) was added, and the reaction mixture was stirred overnight. After concentrating, the residue was dissolved in water, washed with EtOAc, and the aqueous layer was acidified with 10% KHSO4. After extracting with EtOAc, the organic layer was washed with brine, dried (MgS04), filtered and concentrated providing ^3 as a white solid. H NMR (400 MHz, CD3OD): δ 8.71 (d, J=2Hz, IH), 8.08 (dd, J=9, 2Hz, IH), 6.77 (d, J=9Hz, IH), 3.61 (m, 4H), 3.53 (m, 4H), 1.49 (s, 9H).
Figure imgf000066_0001
N-(4-Hydroxyphenyl)-6-(4-(l , 1 -dimethy lethoxycarbonyPpiperazin- 1 - yPnicotinamide (8-4) Acid M (500 mg, 1.6 mmol), NMM (720 μL, 6.5 mmol) and BOP reagent (793 mg, 1.8 mmol) were combined in 8 mL DMF. After 1.5 h, 4-aminophenol (260 mg, 1.8 mmol) was added and the reaction was heated to 60°C overnight. The reaction mixture was diluted with EtOAc, washed with water (5x), sat. NaHC03 and brine, dried (MgS04), filtered and concentrated. Flash chromatography (silica, 50-60% EtOAc/hexane) provided 84 as a brown solid. TLC Rf = 0.40 (silica, 70% EtOAc/hexane) i H NMR (400 MHz, CDC13): δ 8.66 (d, J=2Hz, IH), 7.98-7.95 (m, 2H), 7.33 (d, J=9Hz, 2H), 6.75 (d, J=9Hz, 2H), 6.58 (d, J=9Hz, IH), 3.61 (m, 4H), 3.52 (m, 4H), 1.48 (m, 9H).
Figure imgf000066_0002
tert-Buty 1 2-((4-(2-(4-( 1 , 1 -dimethy lethoxycarbonyPpiperazin- 1 - yl)pyridin-5-yl)carbonylamino)phenoxy)acetate (8-5)
Phenol 84 (374 mg, 0.94 mmol), t-butyl bromoacetate (151 μL, 0.94 mmol) and CS2CO3 (761 mg, 2.3 mmol) were combined in 5 mL DMF. After 90 min. the reaction mixture was diluted with EtOAc, washed with water (4x) and brine, dried (MgS04), filtered and concentrated. Flash chromatography (silica, 50% EtOAc/hexane) provided ^5 as a brown solid. TLC Rf = 0.53 (silica, 70% EtOAc/hexane) i H NMR (400 MHz, CDCI3): δ 8.66 (d, J=2Hz, IH), 7.99 (dd, J=9, 2Hz, I H), 7.56 (s, IH), 7.52 (d, J=8Hz, 2H), 6.90 (d, J=8Hz, 2H), 6.65 (d, J=9Hz, IH), 4.5 Ks, 2H), 3.68 (m, 4H), 3.56 (m, 4H), 1.49 (s, 18H).
Figure imgf000067_0002
-
Figure imgf000067_0001
jU-χ) — OCH2C02H
2-(4-(((2-Piperazin-l-yl)pyridin-5-yl)carbonylamino)phenoxy)acetic acid (8-6)
Ester 83 (290 mg, 0.57 mmol) was dissolved in 5 mL 1 : 1 TFA/CH2CI2. After 1 h the reaction was concentrated and azeotroped with toluene. Flash chromatography (silica, 10: 1 :1 EtOH/H2θ/NH4θH) and trituration with Et20 provided % as a light brown solid. iH NMR (400 MHz, D 0): δ 8.42 (d, J=2Hz, IH), 7.89 (dd, J=9, 2Hz, IH), 7.04 (d, J=8 Hz, 2H), 6.78 (d, J=9Hz, 2H), 6.76 (d, J=10 Hz, IH), 4.32 (s, 2H), 3.37 (m, 4H), 2.74 (m, 4H).
SCHEME9
Figure imgf000068_0001
NaH/DMF CICHoCN
Figure imgf000068_0002
SCHEME 9 rCONT'D)
Figure imgf000069_0001
BOC20 / TEA
Figure imgf000069_0002
Pd(OAc)2 / dppp/ DMF CO(g) CH3OH
Figure imgf000069_0003
LiOH THF/H20/MeOH
Figure imgf000069_0004
PYCLU/i-Pr2NEt
HCI • CH3 104 SCHEME 9 rCONT'D)
Figure imgf000070_0001
LiOH THF/H20/MeOH
9-9
Figure imgf000070_0002
SCHEME 9 (CONT'D)
COoCH3 2=3
Figure imgf000071_0001
NaBH3CN / EtOAc
Figure imgf000071_0002
SCHEME 9 (CONT'D)
PYCLU/i-Pr2NEt
Figure imgf000072_0001
Figure imgf000072_0002
LiOH THF/H20/MeOH
HCI/EtOAC
(+/ -) 2=12
Figure imgf000072_0003
Figure imgf000073_0001
Ethyl 2-(4-bromo-l -hvdrazinimine)propanoate 9-1
A mixture of 4-bromophenylhydrazine (Aldrich, 0.5 g, 2.2 mmol) and ethyl acetoacetate (Aldrich, 0.24 mL, 2.2 mmol) in pyridine (0.6 mL) was heated to reflux overnight. The reaction was cooled, diluted with water and the precipitate that resulted was collected and washed with water, dried under vacuum to give 9-1. Rf(10% MeOH/CHCl3 saturated with NH3)=0.86 iH NMR (400 MHz, CDCI3) δ 7.64 (s, IH), 7.41 (d, 2H), 7.39 (d, 2H), 4.304.34 (q, 2H), 2.10 (s, 3H), 1.36 (t, 3H).
Figure imgf000073_0002
5-Bromo-2-ethoxycarbonyl indole 9-2
A mixture of 94, (0.54 g, 1.9 mmol) and polyphosphoric acid (1.6 mL) was heated to 115°C for 10 minutes, then diluted with cold water and extracted with EtOAc. The layers were separated and the aqueous layer extracted with EtOAc. The organic layers were combined, washed with brine, dried with MgS04, filtered and concentrated to give 9^2 as a brown solid. Rf(30% EtOAc/hexanes)=0.45 i H NMR (400 MHz, CDCI3) δ 8.95(bs, IH), 7.82 (s, IH), 7.41 (d, IH), 7.30 (d, IH), 7.15 (s, IH), 4.44 (q, 2H), 1.40 (t, 3H).
Figure imgf000074_0001
-fCvanomethyl)-2-ethoxycarbonyl-5-bromo-indole 9-3
A solution of 9^2 (11.2 g, 44.4 mmol) in DMF (400 mL) was treated with NaH (3.2 g of 60% dispersion in oil, 66.6 mmol) for 0.5 hour and then chloroacetonitrile (Aldrich, 5.6 mL, 88.8 mmol) was added and the reaction was stirred overnight. The solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The water layer was extracted with EtOAc, the organic layers were combined, washed with water, brine, dried with MgSθ4, filtered and evaporated to give 93 as a brown solid. Rf(30% EtOAc/hexanes)=046 iH NMR (400 MHz, CDCI3) δ 7.82-7.83 (bs, IH), 7.51-7.54 (dd, IH), 7.30-7.32 (bd, 2H), 5.60 (s, 2H), 4.414.43 (q, 2H), 1.41-1.43 (t, 3H).
Figure imgf000074_0002
8-Bromo-2.3.4.5-tetrahvdropyrazino-r 1 ,2-alindole 9-4
A slurry of 9^3 (12.2 g, 39.7 mmol) in diethyl ether (400 mL) was added via dropping funnel to a solution of LAH in ether (79.4 mL, 1 M in ether, 79.4 mmol) and stirred at room temperature overnight. The slurry was diluted with saturated sodium potassium tartrate (Rochelle's salt) and stirred for 15 minutes, then transferred to a separatory funnel containing EtOAc and the layers separated. The aqueous layer was extracted with EtOAc, the organic layers were combined, washed with water, brine, dried with MgS04, filtered and evaporated to give 94 as a brown solid. Rf(10% MeOH/CHCl3 saturated with NH3)=042 iH NMR (400 MHz, CDCI3) δ 8.38-8.41 (bs, IH), 7.66 (s, IH), 7.21- 7.22 (dd, 2H), 7.14 (d, 2H), 6.14 (s, IH), 4.22 (s, 2H), 3.99 (t, 2H), 3.36-3.37 (t, 2H).
Figure imgf000075_0001
8-Bromo-3-(l ,l -dimethylethoxycarbonyl)-2,3,4,5-tetrahydro- pyrazino-[ 1.2-alindole 9-5 A solution of 94^(10 g, 40 mmol) in CH2C12 (200 mL) was cooled to 0°C and treated with di-tertbutyldicarbonate (8.7 g, 40 mmol) and triethylamine (5.6 mL, 40 mmol). The solution was allowed to warm slowly and after 48 hours was concentrated and the residue dissolved in EtOAc, washed with water and brine, dried over Na2Sθ4, filtered and evaporated. The residue was chromatographed (30% EtOAc/hexanes) to give 9-5 as a solid. Rf(30% EtOAc/hexanes)=0.22 H NMR (400 MHz, CDCI3) δ 7.67 (d, IH), 7.23 (d, IH), 7.13 (d, IH), 6.21 (s, IH), 4.80 (s, 2H), 4.04 (t, 2H), 3.93 (t, 2H), 1.50 (s, 9H).
Figure imgf000075_0002
8-Methoxycarbonyl-3-( 1,1 -dimethylethoxycarbony tetrahydropyrazino-f 1 ,2-alindole 9-6 A solution of M (3.0 g, 8.5 mmol) in MeOH (60 mL) and
DMSO (20 mL) was treated with triethylamine (3.55 mL, 25.5 mmol), l ,3-Bis(diphenylphosphino)propane (1.75 g, 4.25 mmol) and palladium (II) acetate (0.952 g, 4.25 mmol). Carbon monoxide was bubbled through the solution while it was heated to reflux for 2 hours. The reaction was heated at reflux overnight under a balloon atmosphere of carbon monoxide. Additional l ,3-Bis(diphenylphosphino)propane (0.8 g, 2.12 mmol) and palladium acetate (0.476 g, 2.12 mmol) were added and the reaction was heated at reflux for 48 hours under a balloon atmosphere of carbon monoxide. The reaction was cooled to room temperature, the residue was partitioned between water and EtOAc. The water layer was extracted with EtOAc, the organic layers were combined, washed with water, brine, dried with MgSθ4, filtered and evaporated. The residue was chromatographed (25% EtOAc/hexanes) to give 93 as a yellow solid. Rf(30% EtOAc/hexanes)=0.21 iH NMR (400 MHz, CDCI3) δ 8.32 (s, IH), 7.90 (d, IH), 7.26 (d, IH), 6.38 (s, IH), 4.83 (s, 2H), 4.12 (t, 2H), 3.96-3.93 (m, 5H), 1.50 (s, 9H).
Figure imgf000076_0001
3-(l ,l -dimethylethoxycarbonyl)-2,3,4,5-tetrahydropyrazino-[l,2- alindole-8-carboxyhc acid 9-7 A slurry of 9 (150 mg, 0.454 mmol) in THF/H2θ/MeOH was treated with LiOH (38.2 mg, 0.91 mmol) and stirred for 1 hour. TLC indicated no reaction. LiOH (38.2 mg.) was added and the reaction mixture (still a slurry) was stirred for an additional hour with no reaction. The reaction mixture was concentrated to dryness and dissolved in MeOH and H2O. LiOH (114 mg) was added and the reaction mixture was stirred and heated to 75° for 3 hours and stirred at RT for 16 hours resulting in a complete reaction. The reaction mixture is diluted with EtOAc and 10% citric acid. The layers are separated and the organic layer is washed with water and brine, dried, filtered and concentrated to give 9-7 as a white solid. lH NMR (400 MHz; CDCI3) δ 8.40 (s, IH), 7.95(d, IH), 7.32 (d, IH), 6.41 (s, IH), 4.84 (s, 2H), 4.144.1 1 (m, 2H), 3.96 (m, 2H), 1.50 (s, 9H).
Figure imgf000077_0001
Ethyl 4-((3-(l ,l -dimethylethoxycarbonyl)-2,3,4,5-tetrahydrop
11.2-alindole-8-yl)carbonylamino)-3-methylphenoxyacetate 9-8
A solution of M (1 10 mg, 0.35 mmol) and 10-4 (85.7 mg, 0.35 mmol) in CH2C12 were treated with diisopropylethylamine and
PYCLU as described for 23-5 to give 9-8 as a white solid after chromatography in 50% EtOAC/Hexane.
Rf (50% EtOAc/Hexane) 0.34 iH NMR (400 MHz, CDCI3) δ 8.12 (s, IH), 7.8-7.65 (m, 2H), 7.59 (s, IH), 7.36 (d, IH), 6.84 (m, 2H), 6.39 (s, IH), 4.85 (s, 2H), 4.62 (s, 2H),
4.294.27 (q, 2H), 4.154.13 (t, 2H), 3.96 (t, 2H), 2.33 (s, 3H), 1.50 (s,
9H), 1.33- 1.31 (t, 3H).
Figure imgf000077_0002
4-((2,3,4,5-tetrahydropyrazino-[l ,2-a] dole-8-yl)carbonylamino)-3- methylphenoxyacetic acid 9-9
A slurry of (0.15 mmol, 75 mg) and THF/H 0/MeOH was treated with LiOH (13 mg, 0.30 mmol) and stirred for 1 hour. The reaction mixture was diluted with EtOAC and 10% citric acid. The layers were separated and the organic layer was washed with H2θ and brine. The organic layer was dried, filtered and concentrated to give desired acid as a white solid. This solid is slurried in EtOAc, cooled to -78° and saturated with HCI. The reaction mixture is warmed to 0° and stirred for 15 min. The reaction mixture was concentrated to yield a white solid which was taken up in a EtOAc/hexane/ether mixture and filtered. The solids were washed with ether to give 9^9 as a white solid. Rf 10/1/1 EtOH/NH4θH/H2θ) 0.16 iH NMR (400 MHz; D2O) δ 8.09 (s, IH), 7.62-7.60 (d, IH), 7.45 (d, IH), 7.14-7.12 (d, IH), 6.84 (d, IH), 6.79-6.76 (dd, IH), 6.35 (s, IH), 4.40 (s, 2H), 4.074.02 (m, 4H), 3.23-3.22 (t, 2H), 2.15 (s, 3H).
Figure imgf000078_0001
(+ /-) 8-Methoxycarbonyl-3-( 1 ,1 -dimethy lethoxycarbonyl)- l ,la,2,
3.4.5-hexahydropyrazino-lT .2-a]indole 9-10
9-6 (0.091 mmol, 30 mg) was dissolved in EtOAc and cooled to 0°C. NaBH3CN (0.45 mmol, 28 mg) was added portion-wise and the reaction was warmed to room temperature for 15 min. The reaction mixture was basified with saturated NaHCθ3 and extracted into EtOAc. The organic layer was washed with brine, dried (MgSθ4), filtered and concentrated to yield 9- 10 as a colorless oil. Rf (2: 1 hexane/ EtOAc)=0.4 i H NMR (400 MHz; CDCI3) δ 7.83-7.82 (d, IH), 7.73 (s, IH), 6.40- 6.38 (d, IH), 4.154.0 (bs, 2H), 3.85 (s, 3H), 3.60-3.56 (m, 2H), .305- 2.65 (m, 4H), 2.60-2.58 (dd, IH), 1.50 (s, 9H).
Figure imgf000079_0001
(+ /-) 3-( 1 , 1 -Dimethylethoxycarbonyl)- 1 , 1 a,2,3,4,5-hexahydro- pyrazino-IT .2-a1indole-8-carboxylic acid 9- 1 1 940 (0.90 mmol, 300 mg) was slurried in THF/H20/MeOH
(2mL/2/2). LiOH (1.8 mmol, 76 mg) was added and the reaction mixture was heated to 50°C. After 0.5 hours, the reaction mixture became homogeneous, and was then stirred at room temperature for an additional 2 hours. The reaction mixture was diluted with 10% citric acid and EtOAc. The layers were separated, and the organic layer was washed with H20 and brine. Drying (MgSθ4), filtering and concentrating gave 9-1 1 as a yellow solid. Rf (97/3/1 CHCl3/MeOH/HOAC)=0.70 iH NMR (400 MHz; CDCI3) δ 7.90 (d, IH), 7.87 (s, IH), 6.41-6.39 (d, IH), 4.25-4.0 (bs, 2H), 3.65-3.57 (m, 2H), 3.10-3.0 (dd, IH), 3.02-2.98 d, IH), 2.98-2.91 (bs, IH), 2.69-2.66 (bs, IH), 2.62-2.60 (dd, IH), 1.50 (s, 9H).
(+ /-) Ethyl 4-((3 -(1 ,1 -Dimethylethoxycarbonyl)- 1 ,1 a,2,3, 4,5 - hexahydro-pyrazino-[ 1 ,2-a]indole-8-yl)carbonylamino)-3- methylphenoxyacetate 9- 12
A solution of 941 (250 mg, 0.79 mmol) and 104 (193 mg, 0.79 mmol) in CH C12 were treated with diisopropylethylamine and PYCLU as described for 23-5 to give 9-12 as a white solid after chromatography in 50% EtOAC/Hexane.
Rf (50% EtOAc/Hexane) 0.35 iH NMR (400 MHz, CDCI3) δ 7.70-7.63 (m, 3H), 7.36 (s, IH), 6.82-
6.76 (m, 2H), 6.45-6.43 (d, IH), 4.60 (s, 2H), 4.304.25 (q, 2H), 4.21 -
4.09 (bs, 2H), 3.59-3.57 (m, 2H), 3.10-3.09 (m, IH), 3.05-2.51 (m, 3H),
2.78-2.60 (m, IH), 2.29 (s, 3H), 1.50 (s, 9H), 1.32-1.29 (t,3H).
Figure imgf000080_0001
(+ /-) 4-((3-(l ,l -Dimethylethoxycarbonyl)-l ,la,2,3,4,5-hexahydro- pyrazino-[ 1 ,2-a]indole-8-yI)carbonylamino)-3-methylphenoxyacetic acid
9- 13
A slurry of 9-12 (0.25 mmol, 125 mg) and THF/H 0/MeOH was treated with LiOH (21 mg, 0.50 mmol) and heated to 80° for 1 hour. The reaction mixture was diluted with EtOAC and 10% citric acid. The layers were separated and the organic layer was washed with H20 and brine. The organic layer was dried, filtered and concentrated to give desired acid as a white solid. This solid is slurried in EtOAc, cooled to -78° and saturated with HCI. The reaction mixture is warmed to 0° and stirred for 15 min. The reaction mixture was concentrated and the white solid triturated with ether to give 9-13 as a white solid.
Rf 10/1/1 EtOH/NH4θH/H20) 0.3 i H NMR (400 MHz, D20) δ 7.70-7.67 (d, IH), 7.63 (s, IH), 7.1 1-7.09
(d, IH), 6.86 (d, IH), 6.78-6.76 (dd, IH), 6.69-6.68 (d, IH), 4.57 (s,
2H), 3.93-3.90 (bd, 2H), 3.39-3.31 (m, 3H), 3.19-3.07 (m, 3H), 2.74-
2.68 (dd, IH). SCHEME 10
Br COOEt
Cs C°3- DMF
Figure imgf000081_0001
NH; NHBoc
IfH 10-2
Figure imgf000081_0002
NHBoc NHc
103 10-4
Figure imgf000081_0003
Boc
13 SCHEME 10 CONTINUED
Figure imgf000082_0001
Figure imgf000082_0002
1Ω3
Figure imgf000082_0003
4-(l .l -Dimethylethoxycarbonyl)amino-3-methylphenol (10-2)
To a 1 L round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added 4-amino-3-methylphenol (15.00 g, 121.79 mmol), di-f -butylpyrocarbonate (27.25 g, 124.84 mmol) and CHC13 (300 mL). This heterogeneous mixture was heated at reflux for 24 h during which time all of the solids dissolved. The mixture was cooled to room temperature and the solid product was collected by filtration. The material was triturated with a mixture of Et2θ-hexanes (1 : 1), collected on a frit and dried in vacuo to give 21.25 g (92%) of 4- (l,l -dimethylethoxycarbonyl)amino-3-methylphenol (10-2). mp: 143- 144°C. iH NMR (CDCI3): δ 1.51 (s, 9H), 2.14 (s, 3H), 6.08 (br s, IH), 6.48 (m, 2H), 6.60 (br s, IH), 7.20 (d, j=8.5Hz, IH).
Ethyl 4-( 1 , 1 -DimethylethoxycarbonyI)amino-3-methylphenoxyacetate πo-3)
To a 200 mL round bottomed flask with a stirring bar, and an argon inlet was added 4-(l,l-dimethylethoxycarbonyl)amino-3- methylphenol (5.00 g, 22.39 mmol), CS2CO3 (14.59 g, 44.78 mmol), DMF (50 mL), and ethyl bromoacetate (2.61 mL, 23.51 mmol). This mixture was stirred vigorously at ambient temperature for 24 h. The mixture was filtered through a frit and the DMF was removed under high vacuum. The residue was dissolved in EtOAc (300 mL) and washed with H2θ (2x) and brine (lx). Drying (MgS04), filtration, and removal of the solvent in vacuo gave a solid. This material was triturated with 5% Et2θ-hexane, the solid was collected by filtration and dried in vacuo to give 5.40 g (78%) of ethyl 4-( 1,1 -dimethy 1- ethoxycarbonyl)amino-3-methylphenoxyacetate as a white, crystalline solid. iH NMR (CDCI3): δ 1.29 (t, j=7.2Hz, 3H), 1.51 (s, 9H), 2.22 (s, 3H), 4.26 (q, j=7.2Hz, 2H), 4.57 (s, 2H), 6.08 (br s, IH), 6.72 (m, 2H), 7.56 (s, IH).
Ethyl 4-amino-3-methylphenoxyacetate. hydrochloride (10-4)
To a 500 mL round bottomed flask with a gas dispersion tube was added a solution of ethyl 4-( 1 ,1 -dimethy lethoxycarbonyl)- amino-3-methylphenoxyacetate (5.31 g, 17.13 mmol) in EtOAc (200 mL). This solution was cooled in an ice bath and dry HCI gas was sparged through the solution, vigorously, for 10 min. The resulting mixture was aged for 15 min. at 0°C. The excess HCI gas was removed with a stream of argon and the solvent was removed in vacuo. The product was triturated with 50 mL of EtOAc and collected on a frit. The crystals were washed with additional EtOAc and dried in vacuo to give 4.21 g (100%) of ethyl 4-amino-3-methylphenoxy acetate, hydrochloride as white crystals, mp: 198-200°C. iH NMR (DMSO-d6): δ 1.21 (t, j=7.1Hz, 3H), 2.33 (s, 3H), 4.17 (q, j=7.1Hz, 2H), 4.78 (s, 2H), 6.82 (dd, j=3,9Hz, IH), 6.92 (d, j=3Hz, IH), 7.39 (d, j=9Hz, IH), 10.21 (br s, 3H).
Ethyl 2-(4-(4-(4-( 1 , 1 -dimethy lethoxycarbonyPpiperazin- 1 -y Ppheny 1- carbonylamino)-3-methylphenoxy)acetate ( 10-5)
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(4-( 1,1 -dimethylethoxycarbony I) piperazinyPbenzoic acid (0.75 g, 2.45 mmol), ethyl 4-amino-3- methylphenoxyacetate hydrochloride (0.60 g, 2.45 mmol), chloro- N,N,N',N',-bis(pentamethylene)formamidinium hexafluorophosphate (0.97 g, 2.69 mmol), and CH2CI2 (30 mL). This mixture was cooled in an ice bath and diisopropylethylamine (1.74 mL, 10.0 mmol) was added. The ice bath was allowed to expire and the solution was stirred at ambient temperature for 48 h. The solution was diluted with CHCI3 and washed with 10% aqueous citric acid, saturated aqueous NaHCθ3, and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on 75 g of silica gel using 50% EtOAc-hexane as eluant. There was obtained 1.22 g (100%) of ethyl 2-(4-(4-(4-( 1 ,1 -dimethylethoxycarbony piperazin- 1- yl)phenylcarbonylamino)-3-methylphenoxy)acetate as a crystalline solid. iH NMR (CDCI3): δ 1.30 (t, j=7.1Hz, 3H), 1.49 (s, 9H), 2.27 (s, 3H), 3.27 (m, 4H), 3.59 (m, 4H), 4.26 (q, j=7.1Hz, 2H), 4.59 (s, 2H), 6.75 (m, 2H), 6.90 (d, j=8.8Hz, 2H), 7.54 (br s, IH), 7.65 (m, IH), 7.79 (d, j=8.8Hz, 2H).
2-(4-(4-(4-( 1 , 1 -Dimethylethoxycarbony Ppiperazin- 1 -yPpheny 1- carbonylamino)-3-methylphenoxy)acetic acid (10-6)
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added ethyl 2-(4-(4-(4-( 1 ,1 -dimethy lethoxycarbonyPpiperazin- 1 -yPpheny lcarbonylamino)-3 -methy Iphenoxy)- acetate (1.22 g, 2.45 mmol) and 20 mL of CH3OH. To this solution was added aqueous NaOH (10 mL of a IN solution). The mixture was stirred at ambient temperature for 18 h. The mixture was neutralized with 10 mL of IN HCI and diluted with H2θ. The product was collected on a frit and washed with a little H2θ. This material was dried in vacuo to give 0.953 g (83%) of 2-(4-(4-(4-(l ,l-dimethyl- ethoxycarbonyPpiperazin- 1 -yl)phenylcarbonylamino)-3-methyl- phenoxy)acetic acid as a white solid. iH NMR (CDCI3): δ 1.49 (s, 9H), 2.26 (s, 3H), 3.27 (m, 4H), 3.58 (m, 4H), 4.57 (s, 2H), 6.74 (m, 2H), 6.90 (d, j=8.5 Hz, 2H), 7.60 (m, IH), 7.65 (m, IH), 7.79 (d, j=8.5 Hz, 2H).
2-(4-(4-(l-Piperazinyl)phenylcarbonylamino)-3-methylphenoxy)acetic acid, dihvdrochloride (10-7)
To a 200 mL round bottomed flask equipped with a stirring bar and a gas dispersion tube was added 2-(4-(4-(4-( 1 ,1 -dimethylethoxycarbony Ppiperazin- 1 -yl)phenylcarbonylamino)-3-methyl- phenoxy)acetic acid (0.95 g, 2.03 mmol) and 100 mL of dry EtOAc. This well stirred suspension was cooled in an ice bath and HCI gas was sparged through the solution for 15 min. This mixture was aged 30 min. at 0°C then the excess HCI was removed with a stream of argon and the EtOAc was removed in vacuo. The product was triturated with EtOAc, collected on a frit and dried in vacuo to give 895 mg of 2-(4-(4- (l-piperazinyl)phenylcarbonylamino)-3-methylphenoxy)acetic acid, dihvdrochloride, mp: >250°C. iH NMR (DMSO-d6): δ 2.16 (s, 3H), 3.20 (m, 4H), 3.54 (m, 4H), 4.66 (s, 2H), 6.72 (d, j=3Hz, IH), 6.75 (s, IH), 7.06 (d, j=9.0Hz, 2H), 7.15 (d, j=3.0Hz, IH), 7.90 (d, j=9.0Hz, 2H), 9.43 (br s, IH), 9.56 (s, IH). SCHEME11
Figure imgf000086_0001
SOCI2 /MeOH
Figure imgf000086_0002
Figure imgf000086_0003
Figure imgf000086_0005
Figure imgf000086_0004
SCHEME 1 1 (CONT'D)
NaOH / EtOH reflux
Figure imgf000087_0001
NaOH HCOEt
113
Figure imgf000087_0002
SCHEME 1 1 (CONT'D)
Figure imgf000088_0001
SCHEME 1 1 (CONT'D)
1. oxalyl chloride / DMF cat.
Figure imgf000089_0002
Figure imgf000089_0001
Figure imgf000089_0003
1. LiOH
2. HCI
Figure imgf000090_0001
Methyl 4-bromo-2-hvdroxy benzoate 1 1 -2
200 mL of MeOH was cooled to 0°C and treated dropwise with thionyl chloride (30 mL, 0.4 mole) so that the reaction temperature was kept below 15°C throughout the addition. A solution of 11-1 (12.7g, prepared by the method of R. Glannon et al., J. Med. Chem. 1992 35, 734, 0.0585 mol) in 50 mL MeOH was added to the reaction and the mixture was warmed to room temperature and stirred for 48 hours, then heated to 60°C for 7 hours. The volatile components were removed under high vacuum and the residue chromatographed (silica, gradient straight hexanes to 10% EtOAc/Hexanes) to give 1 1-2 as a bright yellow oil that solidified on standing. Rf (5% EtOAc/Hexanes) 0.6 iH NMR (400 MHz, CDCI3) δ 10.8 (s, IH), 7.68 (d, IH), 7.19 (s, IH), 7.03 (d, IH), 3.95 (s, 3H).
Figure imgf000090_0002
Methyl 4-Bromo-2-(ethyl acet-2-yloxy)-benzoate 1 1-3
A solution of 1 1 -2 (26.6 g, 0.1 15 mole) in acetone (80 mL) was treated with chloroethylacetate (14 g, 0.1 15 mole), potassium iodide (3 g, 0.018 mole), and potassium carbonate (31.7 g, 0.23 mole) and heated to 50°C with vigorous stirring for 2 hours. The suspension was filtered, evaporated to dryness, resuspended in ether, re-filtered and concentrated to give 1 1 -3 as a golden-brown oil. Rf (10% EtOAc/Hexanes) 0.11 iH NMR (400 MHz, CDCI3) δ 7.7 (d, IH), 7.2 (d, IH), 7.04 (s, IH), 4.7
(s, 2H), 4.3 (q, 2H), 3.9 (s, 3H), 1.3 (t, 3H).
Figure imgf000091_0001
6-Bromo-benzofuran-3-one 1 1-5
Sodium hydride (5.52 g, 60% dispersion in oil, 0.138 mole) was placed in a 3L vessel equipped with an overhead stirrer, argon line, reflux condenser and addition funnel. Toluene (215 mL) was added and the solution heated to reflux. A solution of 1 1 -3 (36.3 g, 0.115 mole) in 100 mL toluene was added dropwise over 1.5 hours to give an orange suspension. The reaction was heated for an additional 3 hours, then cooled to room temperature and filtered through a glass-fiber filter. The cake was washed with 500 mL Et2θ and dried under vacuum to give 1 1-4 as a sandy orange solid (streaks from baseline in 30% EtOAc/ Hexanes). A suspension of 1 14 (5 g, 0.016 mol) in EtOH (20 mL) was added to a solution of NaOH (4 g, 0.1 mole) in H2O (35 mL). The reaction was heated to reflux for 1.25 hours, then cooled and the volatile components removed under vacuum. The residue was suspended in 200 mL 6N HCI and 200 mL CHCI3 and stirred vigorously for 0.5 hours. The layers were separated and the aqueous layer was washed with CHCI3. The organic layers were combined, dried with MgS04, filtered and evaporated to give 1 1 -5 as a deep red solid. Rf (20% EtOAc/Hexanes) 0.61 iH NMR (400 MHz, CDCI3) δ 7.53 (d, IH), 7.35 (s, IH), 7.24 (d, IH), 4.64 (s, 2H).
Figure imgf000092_0001
f6-Bromo-benzofuran-3-yl)-acetonitrile 11-6
Sodium hydride (0.7 g, 0.0173 mol) was washed with hexanes then suspended in THF (8 mL). Diethyl cyanomethylphosphonate (3.07 g, 0.0173 mol) was added dropwise and stirred 10 minutes to give clear yellow solution. A solution of 1 1-5 (3.38 g, 0.0158 mol) in THF (20 mL) was added dropwise, the solution stirred for 0.5 hour, then heated to reflux for 0.5 hour. A solution of 6N HCL (3.4 mL) was added and the THF was removed under vacuum. The concentrated solution was diluted with Et2θ and washed with 4 X 30 mL 6N HCI, the ether layer was dried (MgS04), filtered and evaporated. The residue was chromatographed (20% EtOAc/Hexanes) to give 11-6 as an orange solid. Rf (20% EtOAc/Hexanes) 0.45 iH NMR (400 MHz, CDCI3) δ 7.7 (s, IH), 7.65 (s, IH), 7.45 (s, 2H), 3.75 (s, 2H).
Figure imgf000092_0002
2-(6-Bromo-benzofuran-3-yl)-ethylamine 11-7
A solution of LP6 (10.9 g, 0.0462 mol) in THF (100 mL) was cooled to 0°C and treated dropwise with BH3/THF solution (1 Molar, 110.8 mL, 0.11 mol). The cold bath was removed and the reaction stirred overnight. MeOH was carefully added (20 mL) and the solvent removed under vacuum.. The residue was dissolved in 50 mL MeOH and 400 mL MeOH saturated with HCI and heated to reflux for 3 hours. The volatile components were removed under vacuum and the residue was suspended in Et2θ. A bright yellow solid percipitated and was collected and washed five times with Et2θ, then dried under vacuum to give 11-7 as a tan solid.
Rf (5% MeOH/ CHCI3 saturated with NH3) 0.23 iH NMR (400 MHz, CD3OD) δ 7.72 (s, 2H), 7.6 (d, IH), 7.45 (d,
IH), 3.25 (m, 2H), 3.06 (m, 2H).
Figure imgf000093_0001
7-bromo-2-( 1 , 1 -dimethylethoxycarbonyl)- 1 ,2,3 ,4-tetrahy dro-9H- pyridor3.4-b1benzofuran 1 1 -10
A solution of IL7 (11.8 g, 0.043 mol) in MeOH (150 mL) was diluted with CHCI3 (400 mL) and washed with 75 mL IN NaOH. The aqueous layer was backwashed with CHCI3, the organic layers were combined, evaporated, and the residue azeotroped with toluene to remove residual water. The resulting brown oil was treated with 200 mL ethyl formate and brought to reflux for 1.5 hours until the solution was homogenous. The solvent was removed, the residue was dissolved in 200 mL CHCI3, washed with 30 mL IN HCI, brine, dried over MgS04, filtered and evaporated to give 1 1-8 as a solid that was used without further purification. Rf (5% MeOH/ CHCI3 saturated with NH3) 0.47 iH NMR (400 MHz, CD3OD) δ 8.04 (s, IH), 7.67 (s, IH), 7.63 (s, IH), 7.55 (d, IH), 7.4 (d, IH), 3.53 (m, 2H), 2.4 (m, 2H). Solid 1 1 -8 was crushed and placed in a flask equipped with an overhead stirrer. Polyphosphoric acid (20 mL) and CHCI3 (5 mL) was added and the reaction heated to 80°C for 1.5 hours. The reaction was removed from the oil bath and 250 mL H2O, 30 mL NH4OH, and 200 mL CHCI3 was added and stirred vigorously. The resulting opaque mixture was transferred to a separatory funnel, the layers separated, and the aqueous layer was extracted repeatedly with CHCI3. The organic layers were combined, filtered through a pad of SolkaFloc, dried over Na2Sθ4, filtered and evaporated to give the intermediate cyclic imine (1 1-9) as a pale yellow foam. A 5g sample of this material (0.02 mol) was dissolved in 200 mL MeOH and 20 mL IN HCI. Sodium borohydride (1.5g, 0.04 mol) was added in portions. After 0.5 hours the solvent was removed and the residue was partitioned between saturated NaHC03 and CHCI3. The aqueous layer was extracted with CHCI3, the organic layers were combined, dried (Na2Sθ3) and filtered to give a clear yellow solution. (Rf amine (5% MeOH/ CHCI3 saturated with NH3) 0.45). Di-tert-butyl dicarbonate (4.5 g, 0.02 mol) and TEA (2.8 mL, 0.02 mol) were added and the solution stirred overnight, then washed with 10% KHSO4. The organic layer was evaporated and the residue was chromatographed in 10% EtOAc/Hexanes to give 1 1-10 as a white solid.
Rf (20% EtOAc/Hexanes) 0.60 iH NMR (400 MHz, CDCI3) δ 7.6 (s, IH), 7.35 (d, IH), 7.3 (d, IH), 4.56 (bs, 2H), 3.75 (bs, 2H), 2.7 (bs, 2H), 1.5 (s, 9H).
Figure imgf000094_0001
Methyl 2-(l ,1 -dimethylethoxycarbonyl)- 1 ,2,3,4-tetrahydro-9H- pyridol"3.4-b1benzofuran-7-yl carboxylate 1 1 -1 1 A solution of 1 1-10 (l g. 2.84 mmol), 1 ,3 di-phenyl phosphino propane (0.35 g, 0.852 mmol) in DMSO/MeOH (1 : 1, 15 mL) was treated with TEA (1.5 mL, 10.7 mmol) and thouroughly purged with carbon monoxide, then treated with Pd(OAc)2 (0.191g, 0.852 mmol) and warmed to 80°C. After heating overnight, the reaction was cooled, treated with an additional amount of 1 ,3 di-phenyl phosphino propane (0.35g, 0.852 mmol), re-purged with carbon monoxide and treated with an additional amount of Pd(OAc)2 (0.191 g, 0.852 mmol). After heating for three days the reaction was evaporated, partitioned between water and CHCI3, and the water layer washed with CHCI3. The organic layers were combined, dried over MgSθ4, filtered through a sintered glass filter and concentrated. The residue was chromatographed (silica, gradient 5% EtOAc/Hexanes to 10% EtOAc/Hexanes) to give 1 1-11 as a yellow oil. Rf (20% EtOAc/Hexanes) 0.5 iH NMR (400 MHz, CDCI3) δ 8.13 (s, IH), 7.96 (d, IH), 7.48 (d, IH), 4.6 (bs, 2H), 3.95 (s, 3H), 3.75 (bs, 2H), 2.75 (bs, 2H), 1.5 (s, 9H).
Figure imgf000095_0001
2-( 1 , 1 -dimethylethoxycarbonyl)- 1 ,2,3 ,4-tetrahydro-9H-pyrido [3 ,4- blbenzofuran-7-yl carboxylic acid 1 1-12
A solution of 11-11 (0.79 g, 2.38 mmol) in 1 : 1 THF/MeOH (30 mL) was treated with LiOH (0.95 g, 23.8 mmol) in 10 mL of H2O and heated to 30°C overnight. The solvents were removed under vacuum and the residue was dissolved in H2O and acidified with 10% KHSO4 and extracted with EtOAc. The organic layer was dried over MgSθ4, filtered and evaporated to give 1 1-12 as an off-white solid. Rf (97:3:1 CHCl3/MeOH/HOAc) 0.27 i H NMR (400 MHz, CDCI3) δ 8.2 (s, IH), 8.0 (d, IH), 7.50 (d, IH), 4.65 (bs, 2H), 3.8 (bs, 2H), 2.75 (bs, 2H), 1.52 (s, 9H).
Figure imgf000096_0001
Ethyl 4-(2-( 1 , 1 -dimethylethoxycarbonyl)- 1 ,2,3 ,4-tetrahy dro-9H- pyrido[3,4-b]benzofuran-7-yl)carbonylamino)-3-methyIphenoxy- acetate 1 1 -13
A solution of 1 1-12 (0.1 g, 0.321 mmol) in CH2CI2 (10 mL) was treated with oxalyl chloride (0.06 mL, 0.7 mmol) and two drops of DMF. After stirring at room temperature for 0.5 hours, the reaction was diluted with benzene and evaporated. The resulting acid chloride was dissolved in CHCI3 (5 mL) and treated with 104 (0.075 g,
0.26 mmol), then cooled to 0°C and treated with diisopropylethylamine (0.167 mL, 0.3 mmol). The reaction was warmed to room temperature and stirred overnight, then evaporated, partitioned between EtOAc and 10% KHSO4, and the EtOAc layer was washed again with 10% KHSO4. The EtOAc layer was washed with brine, dried over MgSθ4, filtered and evaporated to give 1 1-13. Rf (60% EtOAc/Hexanes) 0.64 iH NMR (400 MHz, CDCI3) δ 8.0 (s, IH), 7.73 (m, 2H), 7.62 (s, IH),
7.53 (d, IH), 6.85 (s, IH), 6.8 (m, IH), 4.62 (d, 2H), 4.61 (s, 2H), 4.29 (q, 2H), 3.68 (bs, 2H), 2.75 (bs, 2H), 2.30 (s, 3H), 1.5 (s, 9H), 1.3 (t, 3H).
Figure imgf000097_0001
4-(2-(l , l-dimethylethoxycarbonyl)-l,2,3,4-tetrahydro-9H-pyrido[3,4- blbenzofuran-7-yl)carbonylamino)-3-methylphenoxy acetic acid 1 1-14 A solution of 1 1 -13 (0.145 g, 0.285 mmol) in 1 :1 THF/MeOH (6 mL) was treated with LiOH (0.114 g, 28.5 mmol) dissolved in 6 mL of H2θ. After stirring for 1 hour at room temperature the solvents were removed, the residue dissolved in H2θ/EtO Ac/10% KHSO4 and the layers separted. The water layer was washed with EtOAc, the organic layers were combined, dried, and filtered to give the intermediate acid as a yellow oil. This material was dissolved in EtOAc (10 mL), cooled to -78°C, the solution saturated with HCI gas and warmed to 0°C for 0.5 hours, then concentrated and dried under vacuum to give 1 1 -14 as fluffy solid. Rf (9: 1 : 1 EtOH/H2θ/NH4θH) 0.78 iH NMR (400 MHz, D2O) δ 7.84 (s, IH), 7.65 (d, IH), 7.5 (d, IH), 7.1 (d, IH), 6.81 (s, IH), 6.72 (d, IH), 4.28 (s, 2H), 3.8 (bs, 2H), 2.96 (m, 2H), 2.6 (bs, 2H), 2.13 (s, 3H).
SCHEME 12
Figure imgf000098_0001
12=1 12-2
Boc20 , CHCI3 reflux
Figure imgf000098_0002
NHBoc
12-3
Figure imgf000098_0003
NHBoc
12-4
SCHEME 12 CONTINUED
Figure imgf000099_0001
Figure imgf000099_0002
Figure imgf000099_0003
.HCI
Figure imgf000099_0004
12-8 2-Methyl-3-aminophenol (12-2)
To a 500 mL erlenmeyer flask was added sulfanilic acid (14.38 g, 83 mmol), .sodium carbonate (4.29 g, 40.5 mmol) and distilled H2θ (83 mL), when all of the sulfanilic acid dissolved, the solution was cooled in an ice bath to 0°C and a solution of sodium nitrite (6.16 g, 89.3 mmol) in H2O (15 mL) was added in one portion. The ice bath was allowed to warm to +15°C and the mixture was stirred at this temperature 1 h. The reaction mixture was poured onto a mixture of ice (100 g) and 12N HCI (17.4 mL). The ice was allowed to melt and the solid diazonium salt was collected by suction filtration on a scintered glass frit. O-cresol (9.10 g, 84.1 mmol) was dissolved in a solution of NaOH (1.21 g, 30.25 mmol) in H2O (100 mL). This solution was cooled to 0°C and the solid diazonium salt was added in one portion. This well stirred mixture was maintained at +15°C for 4 h. The temperature of the mixture was raised to +60°C and sodium dithionite (35 g, 1.03 mol) was added portionwise. The reaction was allowed to proceed at +60°C for 15 min. The mixture was cooled to room temperature, diluted with saturated aqueous NaHCθ3 and extracted with EtOAc. The EtOAc extract was dried (MgSθ4), filtered, concentrated in vacuo and chromatographed on 100 g of silica gel using 1 :3 EtOAc- hexane as eluant. There was obtained 2-methyl-3-amino-phenol as a tan solid. iH NMR (CDCI3) δ 2.18 (s, 3H), 3.35 (br s, 2H), 4.24 (br s, IH), 6.42 (m, IH), 6.50 (m, IH), 6.61 (d, j=9Hz, IH).
4-( 1.1 -DimethylethoxycarbonvI)amino-2-methylphenol (124)
Using a method similar to that described for compound 10-2. 4-( 1 ,1 -dimethylethoxycarbony l)amino-2-methylphenol was prepared. i H NMR (CDCI3): δ 1.51 (s, 9H), 2.21 (s, 3H), 4.62 (br s, IH), 6.22 (br s, IH), 6.62 (m, IH), 6.98 (m, IH), 7.08 (br s, IH). Ethy 1 4-( 1 , 1 -dimethylethoxycarbonyl)amino-2-methylphenoxyacetate
( 124)
Using a method similar to that described for compound 10-3. ethyl 4-(l ,l -dimethylethoxycarbonyl)amino-2-methylphenoxy- acetate was prepared. iH NMR (CDC13): δ 1.29 (t, j=7.2Hz, 3H), 1.52 (s, 9H), 2.28 (s, 3H), 4.25 (q, j=7.2Hz, 2H), 4.58 (s, 2H), 6.25 (br s, IH), 6.65 (d, j=8.5Hz, IH), 7.08 (br d, j=8.5Hz, IH), 7.17 (br s, IH).
Ethyl 4-amino-2-methylphenoxyacetate. hydrochloride (12-5)
Using a method similar to that described for compound
10-4. ethyl 4-amino-2-methylphenoxyacetate, hydrochloride was prepared. iH NMR (CD3OD): δ 1.21 (t, j=7.1Hz, 3H), 2.35 (s, 3H), 4.25 (q, j=7.1Hz, 2H), 4.81 (s, 2H), 6.95 (d, j=,9Hz, IH), 7.21 (m, 2H).
Ethyl 2-(4-(4-(4-( 1 , 1 -dimethy lethoxycarbonyPpiperazin- 1 -y Ppheny 1- carbonylamino)-2-methylphenoxy)acetate ( 12-6)
Using a method similar to that described for compound 10-5. ethyl 2-(4-(4-(4-( 1,1 -dimethylethoxycarbony piperazin- 1- yl)phenylcarbonylamino)-2-methylphenoxy)acetate was prepared. H NMR (DMSO-d6): δ 1.41 (t, j=7Hz, 3H), 1.42 (s, 9H), 2.20 (s, 3H), 2.50 (m, 4H), 3.29 (m, 4H), 4.29 (q, j=7Hz, 2H), 4.78 (s, 2H), 6.80 (d, j=8.5 Hz, IH), 7.01 (d, j=8.8Hz, 2H), 7.50 (m, 2H), 7.86 (d, j=8.8Hz, 2H), 9.68 (s, IH).
2-(4-(4-(4-(l ,1 -dimethylethoxycarbonyl)piperazin-l -y pheny 1- carbonylamino)-2-methylphenoxy)acetic acid (12-7)
Using a method similar to that described for compound 10-6. 2-(4-(4-(4-( 1 , 1 -dimethylethoxycarbony piperazin- 1 -yl)phenyl- carbonylamino)-2-methylphenoxy)acetic acid was prepared and used in the next step without purification. 2-(4-(4-(l -Piperazinyl)phenylcarbonylamino)-2-methylphenoxy)acetic acid, dihvdrochloride (12-8)
Using a method similar to that described for compound 10-7, 2-(4-(4-( 1 -piperazinyl)phenylcarbonylamino)-2-methyl- phenoxy)acetic acid, dihydrochloride was prepared, mp: >250°C. i H NMR (D20): δ 2.15 (s, 3H), 3.29 (m, 4H), 3.48 (m, 4H), 4.65 (s, 2H), 6.76 (d, j=8.5Hz, IH), 7.04 (d, j=8.6, 2H), 7.17 (m, 2H), 7.69 (d, j=8.6Hz, 2H).
SCHEME 13
COOH COOCH3
MeOH , HCI (g) , RT
Figure imgf000103_0001
NH NH
13=1 13-2
Figure imgf000103_0002
13-3
Figure imgf000103_0003
Figure imgf000103_0005
13-4
Figure imgf000103_0004
13-5 SCHEME 13 CONTINUED
BrCH2COOEt
Cs2C03 , DMF c
COOEt
•HCI
Figure imgf000104_0001
Figure imgf000105_0001
13-5 + uta i-Pr2NEt, CH2CI2
Figure imgf000105_0002
LiOH HCI
Figure imgf000105_0003
Methyl 3-methyl-4-aminobenzoate (13-2)
To a 500 mL round bottomed flask equipped with a stirring bar, reflux condenser and a drying tube was added 3-methyl4- aminobenzoic acid (8.00 g, 52.92 mmol) and anhydrous methanol (300 mL). This solution was saturated with anhydrous HCI gas and the mixture was stirred at ambient temperature for 26 h. The methanol and HCI were removed in vacuo and the solid product was suspended in 400 mL of EtOAc. This mixture was made basic by careful addition of aqueous NaHC03 solution. The layers were separated and the organic phase was washed with brine, dried (MgS04), filtered and concentrated in vacuo to give methyl 3-methyl-4-aminobenzoate as a yellow solid. iH NMR (CDC13): δ 2.18 (s, 3H), 3.85 (s, 3H), 3.99 (br s, 2H), 6.63 (d, j=8.3 Hz, IH), 7.75 (m, 3H). Methyl and n-Butyl 3-methyl4-(l-piperazinyl)benzoate (13-3)
To a 1L round bottomed flask with a stirring bar, reflux condenser, and an argon inlet was added methyl 3-methyl-4- aminobenzoate (8.74 g, 52.74 mmol), bis 2-chloroethylamine hydrochloride (9.81 g, 55.0 mmol) and n-BuOH (175 mL). This mixture was heated at reflux for 8 days. The n-BuOH was removed in vacuo and the residue was partitioned between EtOAc (200 mL) and 0.2N HCI (300 mL). The layers were separated and the organic phase was extracted with another 100 mL portion of 0.2 N HCI. The aqueous phases were combined and made basic with solid NaHC03. This mixture was extracted with EtOAc (2 x 200 mL) and the combined EtOAc extracts were washed with brine, dried (Na2S04), filtered and concentrated in vacuo to give 10.39 g of a mixture of ethyl and n-butyl 3-methyl4-(l-piperazinyl)benzoates. This material was used in the next step without further purification.
Methyl and n-Butyl 3-memyI4-(l-(4-(l ,l -dimemylemoxy)carbonyl)- piperazinyPbenzoates (13-4)
To a 1L round bottomed flask equipped with a stirring bar and an argon inlet was added a mixture of ethyl and n-butyl 3-methyl-4- ( 1 -piperazinyPbenzoates (10.39 g, 44.35 mmol based on the mw of the methyl ester only; vide supra), di- rt-butyldicarbonate (14.67 g, 67.22 mmol) and dry CHCI3 (100 mL). This solution was heated at reflux for 19 h. The cooled reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel (300 g) using 40% EtOAc- hexane as eluant to give 5.0 g of a mixture of methyl and n-butyl 3- methy 14-( 1 -(4-( 1 , 1 -dimethy lethoxy)carbonyl)piperazinyl)benzoates. This material was used in the next step without further purification.
3-Methyl-4-( 1 -(4-( 1 , 1 -dimethylethoxy)carbonyl)piperaziny Pbenzoic acid ( 13-5)
The product from the preceding step, a mixture of methyl and n-butyl 3-methyl-4-(l-(4-(l , l-dimethylethoxy)carbonyl)piper- azinyPbenzoates (5.00 g) was dissolved in 95% EtOH (100 mL) and NaOH (10 g, 250 mmol) was added. This solution was heated at reflux for 2 h. The mixture was cooled to room temperature and the EtOH was removed in vacuo. The residue was dissolved in 300 mL of H2O. This solution was washed with Et2θ (200 mL) then acidified with 10% aqueous citric acid. This mixture was extracted with EtOAc (2 x 250 mL). The combined EtOAc extracts were washed with H2O and brine. Drying (MgSθ4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on 75 g of silica gel using 40% EtOAc-hexane as eluant. The chromatographed product was recrystallized from 15 mL of 20% EtOAc-hexane to give 228 mg of 3- methyl-4-(l-(4-(l,l -dimethylethoxy)carbonyl)piperazinyl)benzoic acid as white crystals. iH NMR (CDCI3): δ 1.49 (s, 9H), 2.35 (s, 3H), 2.94 (m, 4H), 3.59 (m, 4H), 6.99 (d, j=8Hz, IH), 7.92 (m, 2H), 11.65 (br s, IH).
4-0.1 -Dimethy lethox vcarbonylamino)phenol (13-7)
To a 500 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added 4-aminophenol (10.00 g, 91.63 mmol), di-terY-butyldicarbonate (20.00 g, 91.63 mmol) and dry CHCI3 (250 mL). This solution was heated at reflux for 6 h. The mixture was cooled in an ice bath and the product was collected by filtration. The product was washed with a little cold CHCI3 and dried in vacuo to give 16.43 (86%) of 4-(l,l-dimethylethoxycarbonyl- amino)phenol as white crystals, mp: 142-143°C. iH NMR (CDCI3): δ 1.51 (s, 9H), 5.27 (br s, IH), 6.34 (br s, IH), 6.72 (d, j=8Hz, 2H), 7.16 (d, j=8Hz, 2H).
Ethyl (4-( 1.1 -dimethylethox vcarbonylamino)phenoxy)acetate (1 -8)
To a 500 mL round bottomed flask with a stirring bar and an argon inlet was added 4-( 1 ,1 -dimethy Iethoxycarbonylamino)phenol (8.20 g, 39.19 mmol), CS2CO3 (25.54 g, 78.38 mmol), DMF (75 mL), and ethyl bromoacetate (4.78 mL, 43.1 1 mmol). This heterogeneous mixture was stirred at ambient temperature for 3.5 h. The mixture was diluted with a little CHCI3 and filtered through a frit to remove the salts. The DMF was removed under high vacuum and the residue was suspended in 500 mL of EtOAc. This mixture was washed with H2θ (3x), and brine. Drying (MgSθ4), filtration and removal of the solvent in vacuo, gave an oil. This material was chromatographed on 400g of silica gel using 20% EtOAc-hexane as eluant. There was obtained 1 1.9 g (100%) of ethyl (4-( 1,1 -dimethy lethoxycarbonyl- amino)phenoxy)acetate as an oil. iH NMR (CDC13): δ 1.29 (t, j=6.4Hz, 3H), 1.50 (s, 9H), 4.25 (q, j=6.4Hz, 2H), 4.57 (s, 2H), 6.36 (br s , IH), 6.84 (d, j=8Hz, 2H), 7.26 (d, j=8Hz, 2H).
Ethyl 4-aminophenoxyacetate. hydrochloride (13-9)
To a 500 mL round bottomed flask with a stirring bar and a gas dispersion tube was added ethyl (4-(l ,l -dimethylethoxycarbony 1- amino)phenoxy)acetate (1 1.9 g, 40.29 mmol) and dry EtOAc. This solution was cooled in an ice bath and saturated with anhydrous HCI gas over 15 min. The resulting suspension was aged 30 min. at 0°C. The excess HCI was removed with a stream of argon and the EtOAc was removed in vacuo. The solid product was triturated with EtOAc, collected on a frit, and dried in vacuo at room temperature to give 7.33 g (78%) of ethyl 4-aminophenoxyacetate, hydrochloride as a white crystalline soild. iH NMR (DMSO-d6): δ 1.21 1 (t, j=6.4Hz, 3H), 4.16 (q, j=6.4Hz, 2H), 4.82 (s, 2H), 7.05 (d, j=8Hz, 2H), 7.34 (d, j=8Hz, 2H), 10.27 (br s, 3H). Ethyl 2-(4-(4-(3-methyl-4-( 1,1 -dimethylethoxycarbony Ppiperazin- 1 - vPphenylcarbon ylamino)phenoxy)acetate (13-10)
In a manner similar to that described for compound 10-5. using acid 13-5 and aniline 13-8, ethyl 2-(4-(4-(3-methyl-4-( 1 ,1- dimethylethoxycarbonyPpiperazin- 1 -yPpheny 1-carbonylamino)- phenoxy)acetate was prepared. i H NMR (CDC13): δ 1.29 (t, j=7.0Hz, 3H), 1.48 (s, 9H), 2.37 (s, 3H), 2.95 (m, 4H), 3.59 (m, 4H), 4.25 (q, j= 7.Hz, 2H), 4.61 (s, 2H), 6.95 (d, j=8.5Hz, 2H), 7.03 (d, j=8.5Hz, IH), 7.55 (d, j=8.5Hz, 2H), 7.62 (m, 2H). 2-(4-(4-(3-Methyl-4-( 1 -piperazinyI)phenylcarbonylamino)phen- oxy)acetic acid (13- 1 1 )
To a 100 mL round bottomed flask with a stirring bar was added ethyl 2-(4-(4-(3-methyl-4-(l ,l-dimethylethoxycarbonyl)piper- azin- 1 -yl)phenylcarbonylamino)phenoxy)acetate (31 1 mg, 0.63 mmol), MeOH (5 mL), THF (20 mL), and IN LiOH (20 mL). This solution was stirred at ambient temperature for 24 h. The solvents were removed in vacuo and the residue was acidified with 10% aqueous citric acid. This mixture was extracted with EtOAc. The EtOAc extract was dried (MgSθ4), filitered and cooled to 0°C in an ice bath. This solution was saturated with dry HCI gas and aged 30 min. at 0°C. The excess HCI was removed with a stream of argon and the solvent was removed in vacuo. The product was purified by preparative reverse phase HPLC using a H2O-CH3CN gradient on a Waters C-18 column. Obtained 105 mg of 2-(4-(4-(3-methyl-4-(l-piperazinyl)phenylcarbonyl- amino)phenoxy)acetic acid as a white solid. iH NMR (D20): δ 2.28 (s, 3H), 3.17 (m, 4H), 3.35 (m, 4H), 4.55 (s, 2H), 6.94 (d, j=7.5Hz, 2H), 7.12 (d, j=8.2Hz, IH), 7.33 (d, j=7.5Hz, 2H), 7.63 (m, 2H).
SCHEME 14
Figure imgf000110_0001
14-1 14-2
Figure imgf000110_0002
Figure imgf000110_0003
14-4
Figure imgf000110_0004
14-6 l -Nitrophenyl4-(l .l-dimethylethoxycarbonyl)piperazine (14-2)
To a 200 mL round bottomed flask was added 1 -nitro- phenylpiperazine (5.01 g, 24.2 mmol), di-/erf-butyldicarbonate (5.85 g, 26.8 mmol), triethylamine (3.87 mL, 27.8 mmol), and dry THF (100 mL). This solution was heated at reflux for 18 h. The mixture was cooled to room temperature and the solvents were removed in vacuo. The residue was dissolved in EtOAc and washed with 10% aqueous citric acid, H2θ, and brine. Drying (MgS04), filtration, and removal of the solvent in vacuo gave 7.7 g of l-nitrophenyl-4-(l,l-dimethyl- ethoxycarbonyPpiperazine as a yellow solid. H NMR (CDC13): δ 1.42 (s, 9H), 3.41 (m, 4H), 3.62 (m, 4H), 6.81 (d, j=8.5Hz, 2H), 8.16 (d, j=8.5Hz, 2H).
4-(4-( 1.1 -Dimethylethoxycarbonv piperazin- 1 -vPaniline (14-3) To a 250 mL Parr haydrogenation bottle was added 1 - nitrophenyl-4-( 1 ,1 -dimethylethoxycarbony Ppiperazine (4.5 g, 16.34 mmol), EtOAc (81 mL), MeOH (27 mL), and 5% Pd-C (0.18 g). This mixture was hydrogenated under 45 psig H2 at ambient temperature for 24 h. The mixture was filtered through a celite pad and the solvents were removed in vacuo. The residue was chromatographed on 250 g of silica gel using 70% EtOAc-hexane as eluant. There was obtained 3.43 g of 4-(4-(l ,l-dimethylethoxycarbonyl)piperazin-l-yl)aniline as a yellow solid. iH NMR (CDCI3): δ 1.49 (s, 9H), 2.98 (m, 4H), 3.49 (br s, 2H), 3.57 (m, 4H), 6.66 (d, j=9Hz, 2H), 6.82 (d, j=9Hz, 2H).
N-(4-(4-( 1 ,1 -dimethylethoxycarbony Ppiperazin- l-yl)phenyl)4- hvdroxybenzamide ( 14-4)
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(4-( 1 ,1 -dimethy lethoxycarbonyPpiperazin- 1- yPaniline (0.868 g, 3.13 mmol), 4-hydroxybenzoic acid (0.525 g, 3.80 mmol), chloro-N,N,N',N',-bis(pentamethylene)formamidinium hexafluorophosphate (1.35 g, 3.74 mmol), and CH2CI2 (45 mL). This mixture was cooled in an ice bath and diisopropylethylamine (0.96 mL, 5.52 mmol) was added. The ice bath was allowed to expire and the mixture was stirred at ambient temperature 18 h. The mixture was diluted with EtOAc and washed with 10% aqueous citric acid, water and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on 100 g of silica gel using 70% EtOAc-hexane as eluant to give 0.57 g of N-(4-(4-(l ,l- dimethylethoxycarbonyl)piperazin-l -yl)phenyl)4-hydroxybenzamide as a grey solid. iH NMR (CDC13): δ 1.48 (s, 9H), 3.01 (m, 4H), 3.48 (m, 4H), 6.82 (d, J=9Hz, 2H), 6.85 (d, j=9Hz, 2H), 7.58 (d, j=8Hz, 2H), 7.81 (d, j=8Hz, 2H), 9.80 (br s, IH), 10.01 (br s, IH).
Figure imgf000112_0001
4-(4-(4-( 1 , 1 -dimethylethoxycarbony Ppiperazin- 1 - yPpheny laminocarbonvDphenox vacetate (14-5) To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added N-(4-(4-(l ,l -dimethylethoxycarbony piperazin- 1 -yPpheny l)4-hydroxybenzamide (0.56 g, 1.41 mmol) DMF (35 mL), Cs2C03 (0.49 g, 1.51 mmol) and rf -butyl bromoacetate (0.28 mL, 1.75 mmol). This mixture was stirred at ambient temperature for 18 h. The mixture was diluted with EtOAc and washed with H2θ and brine. Drying (MgSθ4), filtration and removal of the solvent in vacuo gave 0.78 g of terf-butyl 4-(4-(4-( 1 ,1 -dimethylethoxycarbony piperazin- 1 -yPpheny laminocarbonyPphenoxyacetate which was used in the next step without purification. iH NMR (DMSO-d6): δ 1.48 (s, 9H), 1.49 (s, 9H), 3.02 (m, 4H), 3.39 (m, 4H), 4.78 (s, 2H), 6.88 (d, j=9Hz, 2H), 7.02 (d, j=9Hz, 2H), 7.62 (d, j=8Hz, 2H), 7.82 (d, j=8Hz, 2H), 9.82 (br s, IH).
4-(4-(Piperazin- 1 -yPphenylaminocarbony phenoxyacetic acid ( 14-6) To a 100 mL round bottomed flask with a stirring bar and a gas dispersion tube was added ferf-butyl 4-(4-(4-( 1 ,1 -dimethy lethoxycarbonyPpiperazin- 1 -yPphenylaminocarbonyPphenoxyacetate (0.78 g, 1.52 mmol) and EtOAc (40 mL). This solution was cooled in an ice bath and HCI gas was sparged through the solution for 15 min. The - I l l -
resulting mixture was aged 90 min. The excess HCI and EtOAc were removed in vacuo and the crude product was purified by preparative reverse phase HPLC* There was obtained 0.218 g of 4-(4-(piperazin- 1 • yPphenylaminocarbonyPphenoxyacetic acid as a crystalline solid. iH NMR (0.1N NaOD-D2θ): δ 2.99 (m, 4H), 3.15 (m, 4H), 4.59 (s, 2H), 7.03 (d, j=9Hz, 2H), 7.16 (d, j=9Hz, 2H), 7.7.37 (d, j=8Hz, 2H), 7.88 (d, j=8Hz, 2H).
SCHEME 15
Figure imgf000114_0001
5=1
Figure imgf000114_0002
15-2
Figure imgf000114_0003
NHBoc
15=2
O COOEt
'CH3
Figure imgf000114_0004
NHBoc NH2
154 15=5 SCHEME 15 CONTINUED
Figure imgf000115_0001
Figure imgf000115_0002
2-(4-(4-( 1 -Piperazinyl)phenylcarbonylamino)-3 ,5-dimethyl- phenoxy)acetic acid, dihvdrochloride (15-8)
Using a -sequence essentially the same as described for compound 12-8. but starting with 3,5-dimethyIphenol (15-1). 2-(4-(4- ( 1 -piperazinyl)phenylcarbonylamino)-3,5-dimethylphenoxy)acetic acid, dihydrochloride was prepared, mp: >250°C. i H NMR (D20): δ 2.15 (s, 6H), 3.32 (m, 4H), 3.54 (m, 4H), 4.64 (s, 2H), 6.72 (s, 2H), 7.12 (d, j=8.6, 2H), 7.17 (m, 2H), 7.83 (d, j=8.6Hz, 2H).
SCHEME 16
Figure imgf000117_0001
KMn04/H20
Figure imgf000117_0002
1. LiOH
2. HCI / EtOAc
Figure imgf000117_0003
Figure imgf000118_0001
Figure imgf000118_0002
Figure imgf000119_0001
16-2
4-(4-Pyridinyl)benzoic acid (16-2)
A slurry of 16-1 (5 g, 29.6 mmol, prepared as described in Chambron, J.C; Sauvage, J.P., Tetrahedron, 1987, 895 and Comins, D.L.; Abdullah, A.H., J. Org. Chem., 1982, 47, 4315 method B) in 200 mL H2θ was treated with 10% HCI until the solids dissolved. The solution was treated with solid KMnθ4 in portions (1 1.2 g, 888 mmol), stirred until the KMnθ4 hjad dissolved and heated to 90°C for 18hr. An additional 2 g of KMnθ4 was added and the reaction was again heated to 90°C for 2 hr. The reaction was cooled to ~60°C, filtered and the solids were washed with warm water. The filtrate was evaporated and the residue chromatographed (Silica gel, 10: 1 :1 EtOH/H2θ/NH4θH) to give 16-2 as an off-white solid. iH NMR (400 MHz, DMSO) δ 8.61 (m, 2H), 8.0 (m, 2H), 7.72 (m, 4H).
Figure imgf000119_0002
16-3
4-( 1 -( 1.1 -Dimethylethoxycarbonyl)piperidin-4-yl)benzoic acid ( 16-3) A solution of \6X1 (0.5 g, 2.5 mmol) in 20 mL 20%
HOAc/MeOH was treated with 250 mg Ptθ2 and hydrogenated at 50 psi for 4 hr. The solution was filtered through Solka Floe, evaporated and azeotroped with heptane to remove excess HOAc. The intermediate amino acid acetic acid salt was obtained as a white solid. Rf (10: 1 :1 EtOH/H2θ/NH4θH) 0.3. lH NMR (400 MHz, CD3OD) δ 8.96 (m, 2H), 7.35 (m, 2H), 3.5 (bd, 2h), 3.4 (m, 2H), 3.2 (m, 2H), 3.0 (m, 2H).
A slurryof the amino acid (0.5 g, 1.9 mmol) in 30% H2θ/dioxane (12 mL) was treated with 1 N NaOH (4.8 mL) and ditertbutyldicarbonate (0.564 g, 2.58 mmol) at room temperature for 6 hr. The reaction was acidified to pH 5 with 10% KHSO4 and extracted several times with EtOAc. The EtOAc layers were combined and evaporated to give 16-3 as a white solid. Rf (97:3:1 CHCl3/MeOH/HOAc) 0.39. iH NMR (400 MHz, CD3OD) δ 7.95 (d, 2H), 7.33 (d, 2H), 4.2 (bd, 2H), 2.85 (b, 3H), 1.8 (bd, 2H), 1.6 (m, 2H), 1.48 (s, 9H).
Figure imgf000120_0001
Ethyl 2-(4-(4-(l-(l ,l -DimemylethoxycarbonyPpiperidin-4- v phenylcarbonyl amino)-3-methylphenoxy)acetate H6-4)
A slurry of ^3 (0.15g, 0.49 mmol) and 0 (0.12g, 0.49 mmol) in CH2CI2 was treated with chloro-N,N,N',N',- bis(pentamethylene)formamidinium hexafluorophosphate (0.194g, 0.54 mmol) and diisopropylethyl amine (0.34 mL, 1.96 mmol) and stirred at room temperature for 24 hours. The solution was diluted with EtOAc and washed with H2θ, 10% citric acid, saturated NaHCθ3 and brine, dried over MgS04, filtered and evaporated. The residue was chromatographed (silica gel 50% EtOAc/Hexanes) then triturated with ether/hexanes to give 16-4. Rf(50% EtOAc/Hexanes) 0.33.
IH NMR (400 MHz,CDCl3)δ 7.81 (2s,2H), 7.70(d,lH), 7.50 (s, IH), 7.31 (2s, 2H), 6.8 (m, 2H), 4.6 (s, 2H), 4.28 (q, 2H), 2.8 (m, 2H), 2.72 (m, IH), 2.30 (s, 3H), 1.85 (bd, 2H), 1.75 (m,2H), 1.48 (s, 9H) 1.3 (t, 3H).
Figure imgf000121_0001
2-(4-(4-(Piperidin-4-yl)phenylcarbonylamino)-3-methylphenoxy) acetate (16-5) A solution of 16-4 (0. lg, 0.2 mmol) in 1 : 1 : 1
THF/MeOH/H2θ was treated with LiOH (0.084g, 2 mmol) at room temperature. After 1 hour the reaction was diluted with EtOAc and 10% KHSO4 and the layers were separated. The organic layer was washed with H2O, brine, dried with MgSθ4, filtered and evaporated to give the acid as a clear oil.
Rf(9:l:l CH2Cl2/MeOH/HOAc) 0.57.
IH NMR (400 MHz,CD30D) δ 7.94 (2s,2H), 7.44(2s,2H), 7.2 (d, IH), 6.90 (m, IH), 6.8 (m, IH), 4.62 (s, 2H), 4.24 (bd, 2H), 2.9 (b, 2H), 2.83 (m, IH), 2.28 (s, 3H), 1.86 (bd, 2H), 1.7-1.6 (m, 2H), 1.5 (s, 9H). A slurry of the intermediate acid (0.9 g, 1.19 mmol) was cooled to -78°C and saturated with HCI gas. The reaction was warmed to 0°C, then concentrated in vacuo to give 16-5 as the HCI salt. Rf (10:1: 1 EtOH/H2θ/NH4θH) 0.81. iH NMR (400 MHz, CD3OD) δ 7.94 (2s, 2H), 7.44 (2s, 2H), 7.2 (d, IH), 6.90 (m, IH), 6.8 (m, IH), 4.65 (s, 2H), 3.52 (bd, 2h), 3.15 (bt, 2H), 3.05 (m, IH), 2.12 (bd, 2H), 1.97 (m, 2H).
Figure imgf000122_0001
16-6
Ethyl 2-(4-(4-(Pyridin-4-yl)phenylcarbonylamino)-3-methyl- phenoxy)acetate (16-6) 16-2 (0.5 g, 2.5 mmol) and Ethyl 2-acetoxy-4-amino benzene hydrochloride (13-9) (0.579 g, 2.5 mmol) were coupled as described for 16-4 to give 16-6 after chromatography (silica gel, 5% MeOH/EtOAc) followed by reverse phase preparative HPLC. iH NMR (400 MHz, CD3OD) δ 8.82 (d, 2H), 8.30 (d, 2H), 8.15 (d, 2H), 8.05 (d, 2H), 7.60 (d, 2H), 6.98 (d, 2H), 4.70 (s, 2H), 4.23 (q, 2H), 1.30 (t, 3H).
Figure imgf000122_0002
15=Z
2-(4-(4-(Pyridin-4-yl)phenylcarbonylaminophenoxy)acetic acid (16-7) 16-6 was treated with LiOH as described for 16-5 to give
16-7 after chromatography (silica gel, 10:1 : 1 EtOH/H2θ/NH4θH) followed by preparative reverse phase HPLC.
Rf (10:1 :1 EtOH/H2θ/NH4θH) 0.76. iH NMR (400 MHz, DMSO) δ 8.65 (d, 2H), 8.10 (d, 2H), 7.96 (d, 2H),
7.8 (d, 2H), 7.65 (d, 2H), 6.90 (d, 2H), 4.58 (bs, 2H). SCHEME 17
Figure imgf000123_0001
NaNH2
Dimethylaniline
160°
Figure imgf000123_0002
Figure imgf000123_0003
Figure imgf000123_0004
SCHEME 17 (CONT'D)
-
Figure imgf000124_0002
Figure imgf000124_0001
SCHEME 17 (CONT'D)
Figure imgf000125_0001
HCI/EtOAc
Figure imgf000125_0002
Figure imgf000125_0003
Figure imgf000126_0001
11=1
2- Amino-4-(4-meth ylphen vPpyridine ( 17- 1 )
NaNH2 (142 mmol) was prepared in situ as described in Leffler, M.T. Organic Reactions 1942 Vol. I. Dimethylaniline (20 ml) was added dropwise to the freshly prepared NaNH2- 16-1 (8.0 g, 47.3 mmol) was dissolved in a small amount of dimethylaniline and added to the mixture. The slurry was heated to 160° for 2 hours. The reaction mixture is cooled and diluted with 10% KHSO4 and water. The layers are separated, and the dimethylaniline layer is washed with 10% KHSO4. The aqueous layers are combined, basified with saturated NaHC03, and extracted with EtOAC (3x). The combined organic layers are washed w/brine and concentrated to yield an oily solid. This oily solid was purified by flash chromatography (5% MeOH/EtOAc) to give \1=1 as a tan solid. Rf (5% MeOH/EtOAc) 0.36. *H NMR (400 MHz, DMSO-d6) δ 7.9 (d, IH), 7.5 (d, 2H), 7.3 (d, 2H), 6.7 (d, IH), 6.6 (s, IH), 5.9 (d, IH), 2.3 (s, 3H).
Figure imgf000126_0002
17-2
2-( 1 , 1 -Dimethylethoxycarbonylamino-4-(4-methy lphenyl) pyridine ( 17-2)
17-1 is dissolved in dichloroethane (30 mL) and added dropwise, rapidly to a refluxing solution of Boc2θ in dichloroethane (10 mL). After the addition, the reaction is refluxed for 30 min, then stirred at RT overnight. The reaction mixture is cooled and concentrated to yield a yellow solid, which is purified by chromatography (silica, 30% EtOAc/Hexane) to give 17-2 as a white solid. Rf (50% EtOAc/Hex) 0.73. *H NMR (400 MHz, CDCI3) δ 8.3 (d, IH), 8.2 (s, IH), 7.5-7.6 (m, 4H), 7.3 (bs, IH), 7.1 (d, IH), 2.3 (s, 3H), 1.5 (s, 9H)
Figure imgf000127_0001
113
2-( 1 , 1 -Dimethylethoxycarbonylamino-4-(4-dibromomethylpheny 1) pyridine ( 17-3) U=2 (LO g, 3.5 mmol) is dissolved in CCI4. NBS (1.3 g;
7.3 mmol) is added, followed by AlBN (28.7 mg, 0.18 mmol). The reaction is heated to reflux while shining a white light directly on the flask. After 2 hours, AlBN (28.7 mg) is added, the light is turned off, and the reacion is stirred overnight to effect completion to product. The reaction mixture is cooled and the succinimide is filtered off, washing the solids with CCI4. The filtrate is concentrated to give 17-3 as a brown solid which is used in the next step without further purification. Rf (50% EtO Ac/Hex) 0.70. iH NMR (400 MHZ, CDCI3) δ 8.3 (d, IH), 8.2 (S, IH), 7.7 (m, 3H), 7.2 (bs, IH), 7.1 (d, IH), 6.7 (s, IH), 1.5 (s,9H).
Figure imgf000128_0001
4-(2-( 1 , 1 -Dimethylethoxycarbonylamino)pyrid-4-yl) benzaldehvde (17-4) 12=1 (1.5 g, 34 mmol) is dissolved in waterTHF (15 mL/45 mL). AgN03 (1.1 g, 6.8 mmol) is added and stirred for 1/2 hour. The reaction mixture is diluted w/EtOAc and water. The layers are separated and the organic layer is filtered to remove the solids. The filtrate is washed w/brine, dried (MgSθ4), filtered and concentrated to yield a brown solid. The solid is purified on a "plug" of silica, eluting first w/50% EtOAC/hexane, then 100% EtOAc to elute all of the product. The fractions are concentrated to give 17-4 as a brown solid. Rf (50% EtOAc/Hexane)0.62. iH NMR (400 MHz, CDCI3) δ 10.1 (s, IH), 8.29 (d,lH), 8.26 (s,lH), 8.0 (d,2H), 7.8 (d, 2H), 7.5 (bs, IH), 7.2 (d,lH), 1.5 (s, 9H).
Figure imgf000128_0002
4-(2-( 1 , 1 -Dimethylethoxycarbony lamino)pyrid-4-yl) benzoic acid (17-5)
17-4 (1.0 g, 3.4 mmol) is slurried in CH3CN (40 mL). 10% KHSO4 (1.3 mL) and 30% H2O2 (0.957 mL) are added and the solution is cooled in an ice bath. NaC102 (8.5 mmol, 770 mg) is added dropwise in 50 mL water over 20 min. The reaction is stirred for 16 hrs. The reaction mixture is diluted w/EtOAc and washed with saturated NaHC03 (2x). The aqueous layers are combined, acidifed with 10% KHSO4, and extracted W/CH2CI2 (2x) and EtOAc (2x) to give 17-5 as a yellow solid. *H NMR (400MHz, DMSO-d6) δ 12.6-12.8 (bs, IH), 9.9 (s, IH), 8.3 d, IH), 8.0-8.1 (m, 3H), 7.9 (d, 2H), 7.3 (d, IH), 1.5 (s, 9H).
Figure imgf000129_0001
23
Ethyl 2-(4-(4-(2-( 1 , 1 -Dimethylethoxycarbony lamino)pyrid-4- yl)carbonylamino)phenoxy)acetate (17-6) A mixture of 173 (300 mg, 0.956 mmol), H-9 (0.956 mmol, 236 mg), diisopropylethylamine (3.8 mmol, 0.66 mL), PYCLU (1.05 mmol, 378 mg), and CH2CI2 (10 ml) is stirred at RT for 16 hours. The reaction mixture is diluted with EtOAc and washed with saturated NaHC03 and Brine. The Organic layer is dried (MgS04), filtered and concentrated to yield a pink solid. Triturations with hexanes followed by flash chromatography (silica, 30% EtOAc/Hex) affored 17-6 as a white solid. Rf (30% EtOAc/Hexanes) 0.24. *H NMR (400 MHz, CDCI3) δ 8.3 (d, IH), 8.2 (s, IH), 7.9 (d, 2H), 7.8 (2d, 3H), 7.4 (bs, IH), 7.6 (bs, IH), 7.2 (d, IH), 6.8 (s, IH), 6.7 (d, IH), 4.6 (s, 2H), 4.3 (q, 2H), 2.3 (s, 3H), 1.5 (s, 9H), 0.9 (t, 3H).
Figure imgf000130_0001
12=1
2-(4-(4-(2-(l ,1 -Dimethylethoxycarbonylamino)pyrid-4- yl)carbonylamino)phenoxy)acetic acid H7-7) A mixture of U3 (0.17 mmol, 90 mg), LiOH (0.60 mmol,
25 mg), and THF/H2θ/MeOH/ (1 mL/1 mL/1 mL) is stirred for 2 hours. The reaction mixture is diluted with EtOAc and 10% KHSO4. The aqueous layer is back-extracted with EtOAc. The organic layers are combined, washed with brine, dried (MgSθ4), filtered and concentrated to yield 17-7 as a white solid. lH NMR (400 MHz,
CD3OD) δ 8.3 (d, IH), 8.1 (bd, 3H), 7.9 (d, 2H), 7.5 (bs, IH), 7.2 (s, IH), 6.9 (s, IH), 6.8 (d, IH), 4.7 (s, 2H), 2.3 (s, 3H), 1.5 (s, 9H).
Figure imgf000130_0002
2-(4-(4-r2-Aminopyrid-4-yl)carbonylamino)phenoxy)acetic acid (17-8)
17-7 (0.14 mmol, 70 mg) is dissolved in EtOAC (3 mL) and cooled to -78°. HCI (g) is bubbled through until the solution is saturated. The reaction is stirred at 0° for 3 hours, then at 35° for 16 hours. The reaction mixture is concentrated to yield a tan solid, which is purified by flash chromatography (10/0.25/0.25 EtOH/NH4θH/H2θ) to yield 17-8 as an off white solid. Rf (10/0.5/0.5/0.5 EtOH/NH4θH/H2θ) 0.86. *H NMR (400MHz, DMSO-d6) δ 9.8 (s, IH), 8.0 (d, 2H), 7.9 (d, IH), 7.7 (d, 2H), 7.2 (d, IH), 6.9 (m, 2H), 6.8 (m, 2H), 6.0 (d, IH), 2.2 (s, 3H). SCHEME 18
Figure imgf000131_0001
SCHEME 18 (CONT'D)
18-2
Figure imgf000132_0001
1.) HCI(g) 2.) LiOH
Figure imgf000132_0002
Figure imgf000133_0001
4-G(R)-((N-benzyl)pyrrolidinyl)amino)phenylnitrile (18-1 )
A solution of N-benzyl-3-(R)-aminopyrrolidine (TCI, 0.45 g, 2.27 mmol) in 1 mL acetonitrile was treated with 4-fluoro- phenylcyanide (Aldrich, 3 g, 25.5 mmol) and heated to 100°C. The acetonitrile was allowed to evaporate and the slurry was heated for 18 hours. Additional 4-fluorophenylcyanide (1 g) was added and the reaction heated for 18 hours. The oily mixture was absorbed onto silica gel and eluted first with 20% EtOAc/Hexanes, then with 5% MeOH/CHCl3 saturated with NH3 to give 18-1. Rf (5% MeOH/CHCl3 saturated with NH3) 0.55. ΪH NMR (400 MHz, CDCI3) δ 7.4 (d, 2H), 7.3 (m, 5H), 6.5 (d, 2H), 4.45 (bd, IH), 4.0 (m, IH), 3.64 (s, 2H), 2.83 (m, IH), 2.75 (dd, IH), 2.6 (dd, IH), 2.43(m, IH), 2.34 (m, IH), 1.6 (m, IH).
Figure imgf000133_0002
Methyl 4-(3(R)-((N-benzyl)pyrrolidinyl)amino)benzoate (18-2) A solution of (0.52 g, 1.87 mmol) in dioxane (10 mL) and 1 : 1 H2θ/concentrated H2SO4 (10 mL) was heated to 100°C for 18 hours. The solvent was removed in vacuo and the residue dissolved in MeOH (30 mL) and stirred for 4 days. The solvent was removed and the residue taken up in saturated NaHC03 and IN NaOH to give a pH of 10, then extracted with chloroform. The organic extracts were combined, evaporated and the residue chromatographed in a gradient of 20-30% EtOAc/Hexanes to give 18-2 as a clear oil. Rf=(50% EtOAc/Hexanes) 0.31. i H NMR (400 MHz, CDCI3) δ 7.45 (d, 2H), 7.30 (m, 5H), 4.35 (bd, IH), 4.05 (m, IH), 3.34 (s, 3H), 3.63 (s, 2H), 2.8 (m, 2H), 2.58 (dd, IH), 2.45 (dd, IH), 2.84 (m, IH), 1.65 (m, IH).
Figure imgf000134_0001
Methyl 4-(3-(R)-( 1 -(1 ,1 -dimethy lethoxycarbonyl)pyrrolidinyl) amino)benzoate (18-3)
A suspension of 1&2 (0.29 g, 0.93 mmol) and 10% Pd/C (0.068 g, 23% by weight) in CH3OH (7 ml) was stirred under hydrogen atmosphere for 48 hours. The mixture was filtered through Solka Floe, and solvent removed. The residue was dissolved in CH2CI2 (5 ml) and treated with Et3N (0.65 ml, 4.7 mmol) and BOC2O (0.45 g, 2.1 mmol). The reaction mixture was stirred 1 h at room temperature, then diluted with EtOAc and washed with 10% KHSO4 and brine, dried (Na2Sθ4), and the solvent removed. The residue was purified by flash chromatography on silica gel, eluting with EtOAc (l)/hexane (1) to provide 18-3 as an oil. Rf=0.3 (silica gel, EtOAc (3)/hexane (2)). iH NMR (400 MHz, CDCI3) δ 1.47 (9H, s), 1.92 (IH, s), 2.20 (IH, q), 3.25 (3H, s), 4.11 (IH, m), 4.19 (IH, m), 6.55 (2H, d), 7.87 (2H, d).
Figure imgf000135_0001
Ethyl 2-(3-methyl-4-(4-(3-(R)-(( 1 -( 1 , 1 -dimethylethoxycarbonyPpyrro- lidinyl)amino)phenylcarbonylamino)phenyloxy)acetic acid (18-4) A solution of 18-3 (0.245 g, 0.76 mmol) in dioxane (4 ml) was treated with IN NaOH (3.0 ml, 3.0 mmol) at room temperature for 1 h. A second portion of IN NaOH (3.0 ml, 3.0 mmol) was then added, and the reaction mixture was stirred for 15 h. The solution was then adjusted to pH 7 with IN HCI and the solvent removed. The residue was suspended in CH2CI2 (6 ml) and treated with I (0.19 g, 0.77 mmol), diisopropylethylamine (0.53 mmol, 3.0 mmol), and PYCLU (Fluka, 0.30 g, 0.83 mmol). The reaction mixture was stirred for 48 h at room temperature, then solvent was removed and the residue was purified by flash chromatography on silica gel, eluting with EtOAc (3)/hexane (2) to give 18-4 as an oil.
Rf=0.2 (silica gel, EtOAc (3)/hexane (2)). iH NMR (400 MHz, CDCI3) δ 1.30 (3H, t), 1.47 (9H, s), 1.93 (IH, s), 2.24 (IH, m), 2.28 (3H, s), 3.27 (IH, m), 3.49 (2H, m), 3.73 (IH, m), 4.1 1 (2H, m), 4.16 (IH, m), 4.29 (2H, q), 4.60 (2H, s), 6.62 (2H, d), 6.77 (IH, d), 6.81 (IH, s), 7.41 (IH, s), 7.68 (IH, d), 7.73 (2H, d).
Figure imgf000136_0001
2-(3-Methyl-4-(4-(3(R)-(pyrrolidinyl)amino)phenylcarbonylamino) phenyloxy)acetic acid (18-5)
A solution of M (0.216 g, 0.434 mmol) in EtOAc (10 ml) was cooled to -78°C and treated with HCI (g) for 1.5 min. The reaction mixture was stirred at 0°C for 1 h and then solvent was removed. The residue taken up in THF ( /CH3OH (l)/H2θ (1) (6 ml) and treated with LiOH«H2θ (0.1 lg, 2.6 mmol) at room temperature for 2.5 h. The solvent was removed and the residue was purified by flash chromatography on silical gel eluting with EtOH (18) l2θ (O/NH4OH (1) to afford 18-5 as a white solid. Rf=0.2 (silica gel, EtOH (18)/H2θ (O/NH4OH (1)). iH NMR (400 MHz, D2O) δ 1.57 (IH, m), 2.06 (IH, m), 2.08 (3H, s), 2.60 (IH, m), 2.76 (IH, m), 2.86 (IH, m), 3.03 (IH, m), 3.93 (IH, m), 4.38 (2H, s), 6.71 (3H, m), 6.80 (IH, s), 7.05 (IH, d), 7.66 (2H, d).
SCHEME 19
Figure imgf000137_0001
SCHEME 19fCONT'D)
12=2
Figure imgf000138_0001
Figure imgf000139_0001
N-benzyl-3-(R)-(( 1.1 -dimethylethoxycarbonyl)amino)pyrrolidine (19-1) A solution of N-benzyl-3-(R)-aminopyrrolidine (TCI, 5.00 g, 28.4 mmol) in CH2CI2 (100 ml) was treated with Boc2θ (6.80 g, 31.2 mmol) and Et3N (7.9 ml, 57 mmol). The reaction was stirred at room temperature for 15 h, then solvent was removed. The residue was purified by flash chromatography on silica gel eluting with EtOAc (3)/hexane (2) to give 19-1 as an oil. Rf=0.4 (silica gel, EtOAc (1)/ hexane (1)). iH NMR (400 MHz, CDCI3) δ 1.43 (9H, s), 1.60 (IH, m), 2.27 (2H, m), 2.51 (IH, m), 2.62 (IH, m), 2.76 (IH, m), 3.58 (2H, s), 4.13 (IH, m), 4.89 (IH, m), 7.29 (5H, m).
Figure imgf000139_0002
19-2
4-((3-(R)-( 1 , 1 -Dimethylethoxycarbony I)amino)pyrrolidin- 1 - v phenylnitrile (19-2)
A suspension of I (7.43 g, 26.9 mmol) and 10% Pd/C (2.45 g, 33% by weight) in CH3OH (150 ml) was stirred under H2 (g) atmosphere for 5 h. The reaction mixture was filtered through a pad of Solka Floe, and the solvent was removed. The residue was dissolved in CH3CN (20 ml) and treated with 4-fluorobenzonitrile (16.1 g, 133 mmol) at 70°C for 18 h. The reaction mixture was then cooled to room temperature and the solvent was removed. The residue was purified by flash chromatography on silica gel eluting with EtOAc (l)/hexane (1) to afford 19-2 as a white solid.
Rf=0.4 (silica gel, EtOAc (2)/hexane (3)). iH NMR (400 MHz, CDC13) δ 1.45 (9H, s), 1.99 (IH, m), 2.30 (IH, m),
3.18 (IH, m), 3.46 (2H, m), 3.62 (IH, m), 4.36 (IH, b), 4.67 (IH, b),
6.52 (2H, d), 7.47 (2H, d).
Figure imgf000140_0001
19-3
Methyl 4-((3-(R)-( 1,1 -dimethylethoxycarbony l)amino)pyrrolidin-l- yl)-benzoate (19-3)
A solution of 19-2 (1.48 g) in dioxane (25 ml) and H2SO4 (l)/H2θ (1) (25 ml) was heated at 70°C for 15 h. The reaction mixture was then concentrated to remove the dioxane, diluted with CH3OH (100 ml), heated at 60°C for 2 h, and stirred at room temperature for 48 h. The reaction mixture was concentrated to remove the CH3OH, and the residue adjusted to pH 10 with 6N NaOH and sat. NaHCθ3. The aqueous mixture was then extracted with CH2CI2, and the organic extracts concentrated to afford an oil. This residue was dissolved in CH2CI2 (25 ml) and treated with Boc2θ (2.96 g, 13.6 mmol) and Et3N (2.2 ml, 16 mmol). The reaction mixture was stirred at room temperature for 15 h. The solvent was then removed and the residue purified by flash chromatography on silica gel eluting with EtOAc (2)/hexane (3) to yield 19-3 as an oil. Rf=0.5 (silica gel, EtOAc (2), hexane (3)). iH NMR (400 MHz, CDC13) δ 1.27 (9H, s), 1.99 (IH, m), 2.30 (I H, m), 3.22 (IH, m), 3.42 (2H, m), 3.85 (3H, s), 4.37 (IH, b), 4.69 (IH, b), 6.51 (2H, d), 7.91 (2H, d).
Figure imgf000141_0001
Ethyl 2-(4-((3-(R)-( 1 ,1 -dimethylethoxycarbony l)amino)pyrrolidin- l -yl)phenylcarbonylamino)-3-methylphenoxy)acetic acid (19-4) A solution of 19^ (0.418 g, 1.30 mmol) in dioxane (10 ml) was treated with IN NaOH (7.0 ml, 7.0 mmol), and the reaction mixture was stirred at room temperature for 15 h. A second portion of IN NaOH (3.0 ml, 3.0 mmol) was then added and the reaction mixture was stirred an additional 15 h. Solvent was removed, and the residue was taken up in H2θ, adjusted to pH 6-7 with 10% KHSO4 and extracted with EtOAc. The combined organic extracts were dried (Na2Sθ4) and the solvent was removed. The residue was taken up in CH2CI2 (7 ml) and treated with 10-4 (0.33 g, 1.3 mmol), DIPEA (0.81 mmol, 4.6 mmol) and PYCLU (Fluka, 0.53 g, 1.5 mmol). The reaction mixture was stirred at room temperature for 48 h. The solvent was then removed and the residue was purified by flash chromatography on silica gel eluting with EtOAc (l)/hexane (1) to afford 19-4 as a white solid. Rf=0.3 (silica gel, EtOAc (l)/hexane (1)). iH NMR (400 MHz, CDCI3) δ 1.30 (3H, t), 1.46 (9H, s), 2.04 (IH, m), 2.29 (3H, s), 2.31 (IH, m), 3.23 (IH, m), 3.45 (2H, m), 3.65 (IH, m), 4.27 (2H, q), 4.38 (IH, b), 4.60 (2H, s), 4.72 (1 H, b), 6.57 (2H, d), 6.77 (IH, d), 7.67 (IH, s), 7.41 (IH, s), 7.72 (IH, d), 7.77 (2H, d).
Figure imgf000142_0001
2-(4-((3(R)-amino)pyrrolidin-l-yl)phenylcarbonylamino)-3- methylphenoxy)acetic acid (19-5) A solution of I (0.306 g, 0.615 mmol) in EtOAc (15 ml) at -78°C was treated with HCI (g) for 1.5 min. The reaction mixture was then stirred at 0°C for 1 h, and the solvent was removed.
The residue was taken up in THF (l)/CH3θH(l)/H2θ (1) (6 ml) and treated with LiOH»H2θ at room temperature for 1 h. The solvent was removed, and the residue was purified by flash chromatography on silica gel eluting with EtOH (18)/H2θ (O/NΗ4OH (1) to give IM as a white solid.
Rf=0.4 (silica gel, EtOH (18)/H2θ (D/NH4OH. iH NMR (400 MHz, D2O) δ 1.74 (IH, m), 2.10 (3H, s), 2.12 (IH, m), 3.00 (IH, m), 3.28 (IH, m), 3.39 (IH, m), 3.47 (IH, m), 3.59 (IH, m),
4.39 (2H, s), 6.61 (2H, d), 6.71 (IH, d), 6.81 (IH, s), 7.07 (IH, d), 7.79
(2H, d).
SCHEME 20
Figure imgf000143_0001
MeOH/HOAC cone. HCI H20/Pt02/H2
Figure imgf000143_0002
BOC20
1 N NaOH/H20/Dioxane
Figure imgf000143_0003
CH3 SCHEME 20 (CONT'D)
20-3
Figure imgf000144_0001
HCI (g) EtOAc
Figure imgf000144_0002
Figure imgf000145_0001
20-1
4-(Piperidin-4-vPpiperidinyl carboxylic acid, acetic acid salt (20-1) A suspension of the lithium salt of N-(pyridin-4-yl)-4- piperidine carboxylic acid (prepared as described in Tetrahedron, 1988 44(23) 7095-7108, 1 g, 5.55 mmol) in 50 mL 20% HOAc/MeOH, 10 mL H2θ and 10 mL concentrated HCI was treated with Ptθ2 (1.7 g) and hydrogenated at 65 psi for 24 hrs. The solution was filtered, evaporated and the residue azeotroped with heptane to yield 20-1 as a white solid. Rf(9: 1 : 1 EtOH/H2θ/NH4θH)=0.39. iH NMR (400 MHz, D2O) δ 3.6-3.5 (m, 4H), 3.9 (m, IH), 3.1-3.0 (m, 4H), 2.65 (m, IH), 2.32 (d, 2H), 2.25 (d, 2H), 2.0-1.7 (m, 4H).
Figure imgf000145_0002
20-2
4-(( 1 , 1 -Dimethy lethoxycarbonyl)piperidin-4-y Ppiperidiny 1 carboxylic acid (20-2)
A solution of 20-1 (1.7 g, 5.55 mmol) in H2O (10 mL) was treated with sufficient IN NaOH to bring the solution to pH 11. Dioxane (20 mL) was added followed by BOC anhydride (1.33 g, 6.2 mmol) dissolved in 5 mL dioxane. After 1 hr the solvents were removed and the residue was triturated with acetonitrile and n-butanol, filtered and the filtrate concentrated. The residue was chromatographed (silica gel, 9:1:1 EtOH/H2θ/NH4θH) to give 20^2 as a white solid. Rf(9: 1 : 1 EtOH/H2θ/NH4θH)=0.70 lH NMR (400 MHz, D2O) δ 4.12 (bd, 2H), 3.5 (bd, 2H), 3.32 (m, IH), 2.95 (bt, 2H), 2.75 (bt, 2H), 2.9 (m, IH), 2.15 (bd, 2H), 2.0 (bd, 2H), 1.7 (m, 2H), 1.55 (m, 2H), 1.35 (s, 9H).
Figure imgf000146_0001
Ethyl 2-(4-(4-(( 1 , 1 -dimethylethoxycarbony l)piperidin-4- yl)piperidinylcarboxamido)3-methylphenoxy)acetic acid (20-3)
20-2 (486 mg; 1.6 mmol) and K (250 mg, 1.6 mmol) were dissolved in CH2CI2. PYCLU (1.8 mmol, 634 mg) was added, followed by diisopropylethylamine (6.4 mmol, 1.1 mL). The reaction is stirred for 2 days. The reaction mixture is diluted with EtOAc and washed with H2O, 10% KHSO4, sat NaHC03 and brine. The organic layer is dried (MgS04), filtered and concentrated to yield a tan oil. Flash chromatography (10% MeOH/CHCl3 sat NH3) yielded desired product (20-3) plus bis piperidine urea by-product. This material is triturated with hexane to remove most of the by-product. Rf (10% MeOH/ CHCI3 sat. NH3)=0.20 iH NMR (400 MHz, CdCl3) δ 7.55-7.57 (d, IH), 6.88 (s, IH), 6.74 (s, IH) 6.71-6.72 (d, IH), 4.6 (s, IH), 4.27-4.29 (q, 2H), 4.23-4.25 (bs, 2H), 2.9-3.0 (d, 2H), 2.6-2.7 (t, 2H), 2.35-2.45 (t, 2H).
Figure imgf000147_0001
2-(-4-(4-(( 1 , 1 -Dimethylethoxycarbonyl)piperidin-4-yl)piperidiny 1- carboxamido)3-rnethylphenoxy)acetic acid (20-4)
20-3 (300 mg) was dissolved in THF/H2θ/MeOH (2 mL/2 mL/2 mL). LiOH (50 mg) was added and the reaction is stirred for 2 hours. IN HCI was added (0.50 mL) and the reaction mixture was concentrated to yield 20-4 as a tan solid. Rf(9/1/1 CH2Cl2/MeOH/HOAc)=0.16 iH NMR (400 MHz, CD3OD) δ 7.06-7.08 (d,lH), 6.81 (s, IH), 6.75 (d, IH), 4.88 (s, 2H), 4.12-4.15 (bd, 2H), 3.04-3.07 (bd, 2H), 2.6-2.8 (vbs, 2H), 2.25-2.45 (m, 4H), 2.17 (s, 3H), 1.46-1.56 (m, 6H), 1.45 (9H).
Figure imgf000147_0002
20-5
2-(4-(4-(Piperidin-4-yl)piperidinylcarboxamido)3-methylphenoxy) acetic acid (20-5)
20-4 (0.08 mmol) is dissolved in EtOAc and cooled to -78°. HCI (g) is bubbled through until the solution is saturated. The reaction is warmed to 0°, and stirred for five minutes. The reaction mixture is concentrated to yield a tan solid. The material was purified by flash chromatography using 10/1/1 EtOH/NH4θH/H2θ as an eluent, resulting in pure 20-5 as a white solid. Rf( 10/1/1 EtOH/NH4θH/H2θ)=0.15 iH NMR (400 MHz, D2O) 7.0 (d, IH), 6.8 (s, IH), 6.7 (dd, IH), 4.7 (s, IH), 3.4 (d, 2H), 3.1 (bd, 2H), 2.9 (t, 2H), 2.8 (bt, IH), 2.5 (bs, 3H), 2.10-2.13 (d, 2H), 2.06 (s, 3H), 1.96-1.99 (d, 2H), 1.65-1.75 (m, 4H).
SCHEME 21
Figure imgf000149_0001
21-1
Figure imgf000149_0002
10% Pd/C
H2
MeOH
Figure imgf000149_0003
21-3
Figure imgf000149_0004
21A SCHEME 21 (CONT'D)
Figure imgf000150_0001
21-5
NBS CCI4 Δ
Figure imgf000150_0002
2 . COoEt SCHEME 21 (CONT'D)
21-7
Figure imgf000151_0001
- EtOAc C02H -78°-0°
preparitive 1 HPLC
Figure imgf000151_0002
C02H
Figure imgf000152_0001
213
4-Hvdroxy-2-methyl benzoic acid (21-3)
21 -3 was prepared in two steps from 4'-hydroxy-2'methyl- acetophenone, 21 -1. (Aldrich, 18.0 g, 0.120 mol).
The first step employed the procedure found in Merck Process Patent US 852870-92031 , which resulted in a 70/30 mix of 21 -3 and 3-iodo-4-hydroxy-6-methyl benzoic acid (21-2)
For the second step, the mixture (7.0 g) of 21 -2 and 21 -3 was reduced in MeOH (200 mL) using 10% Pd/C (700 mg) under a hydrogen balloon. After 16 hours of stirring, the reaction mixture was filtered through celite, the celite pad was washed with MeOH and the filtrate was concentrated to yield pure 21 -3 as a tan solid. iH NMR (400 MHz, CDCI3) δ 7.8 (d, IH), 6.6 (m, 2H), 2.5 (s, 3H). Rf (90 % Ethyl Acetate/Hexane)=0.34
Figure imgf000152_0002
Methyl 4-hydroxy-2-methylbenzoate (21-4) 2P3 (5.0 g, 32.9 mmol) was redissolved in MeOH (150 mL) and cooled to 0°. HCI (g) was bubbled through for a few minutes, the cooling bath was removed and the reaction was stirred at RT for 16 hours. The reaction mixture was then concentrated to yield pure 21 -4 as a tan solid.
Rf (50% Ethyl Acetaje/Hexane)=0.83 iH NMR (400 MHz, CDCI3) δ 7.9 (d, IH), 6.7 (m, 2H), 3.85 (s, 3H),
2.57 (s, 3H).
Figure imgf000153_0001
2P5_
Ethyl 2-(3-methyl-4-methoxycarbonylphenoxy)acetate (21-5) 2P4 (1.5 g; 9.0 mmol) was dissolved in DMF (150 mL).
Ethyl bromoacetate (9.0 mmol, 1.0 mL) was added followed by Cs2C03
(9.0 mmol, 2.9 g). The slurry was stirred vigorously for 16 hours.
The reaction mixture was diluted with EtOAc and washed twice with water, 10% KHSO4 and brine. The organic layer was dried (MgS04), filtered and concentrated to yield 21-5 which will be used in the next step without any further purification.
Rf (30 % Ethyl Acetate/Hexane)=0.40 iH NMR (400 MHz, CDCI3) δ 7.9 (d, IH), 6.7-6.8 (m, 2H), 4.6 (s, 2H),
4.3-4.3 (q, 2H), 3.9 (s, 3H), 2.6 (s, 3H), 1.3 (t, 3H).
Figure imgf000154_0001
213
Ethyl 2-(3-bromomethyl-4-methoxycarbonylphenoxy)acetate (21-6) 21 -5 (2.1 g; 8.3 mmol) was dissoved in CCU (40 mL). NBS (10.3 mmol, 1.9 g) was added followed by dibenzoyl peroxide (1.66 mmol, 400 mg). The reaction mixture was heated to reflux for 16 hours. The reaction mixture was cooled and filtered through a celite pad to remove excess succinimide. The filtrate was concentrated to yield 21 -6 as a tan oil, which was used in the next step without any further purification. Rf (30% Ethyl Acetate/Hexane)=0.52
Figure imgf000154_0002
Ethyl 1 -(4-( 1 , 1 -Dimethylethoxycarbonylpiperazin- 1 -y pheny I)-2-oxo- isoindolin-5-oxy)acetate (21-7)
21-6 (8.3 mmol) was dissolved in benzene (100 mL), followed by 14-3. The mixture was heated to reflux for 32 hours. Triethylamine (8.3 mmol) was added and the reaction was refluxed for 2 more days. The reaction mixture was then concentrated to yield a brown solid which was absorbed on silica and purified by flash chromatography. A small amount of the product was eluted with 50% EtOAC/Hex. Most of the material was then flushed off the column with 10% MeOH/CHCl3 saturated with NH3. These flushings yielded a brown solid which was repurified on a column of silica using 10%
MeOH/CHCl3 as a eluent to yield 21-7 as a brown solid.
Rf (50% EtOAc/Hex)=0.48 iH NMR (400 MHz, CDCI3) δ 7.8 (d, IH), 7.7 (d, 2H), 7.0 (m, 4H),
4.77 (s, 2H), 4.72 (s, 2H), 4.3 (q, 2H), 3.6 (m, 4H), 3.1 (m, 4H), 1.5 (s,
9H), 1.3 (t, 3H).
Figure imgf000155_0001
21-8
1 -(4-( 1 , 1 -Dimethylethoxycarbonylpiperazin- 1 -yl)phenyl)-2-oxo- isoindolin-5-oxy)acetic acid (21 -8)
21 -7 (1.3 g; 2.6 mmol) was dissolved in THF/H2θ/MeOH
(5 mL/5/5). LiOH (5.2 mmol, 218 mg) was added and the reaction mixture was stirred for 2 hours. 1 N HCI was added (2.6 mL), and the reaction mixture was concentrated to yield 21 -8 and excess LiCl as a brown solid.
Rf(9/1/1 CH2CH2/MeOH/HOAc)=0.80 iH NMR (400 MHz, CD3OD) δ 7.7 (m, 3H), 7.0-7.1 (m, 4H), 3.3 (bm, 4H), 3.1 (bm, 4H), 1.5 (s, 9H).
Figure imgf000156_0001
l -(((4-Piperazin-l-yl)phenvP-2-oxo-isoindolin-5-oxy)acetic acid (21 -9) 21-8 (2.6 mmol) was dissolved in EtOAc and cooled to -78°. HCI was bubbled through until the solution was saturated. The reaction mixture was then stirred at 0° for 10 min and concentrated to yield a brown solid. Flash chromatography (10/0.8/0.8 EtOH/NH4θH/ H2θ) yielded 21-9 as a brown solid. This material was further purified by preparative HPLC to yield pure 21-9 (TFA salt) as an off-white solid.
RftlO/1/1 EtOH/NH4θH/H2θ)=0.72 iH NMR (400 MHz, DMSO- d6) δ 7.8 (d, 2H), 7.7 (d, IH), 7.2 (s, IH),
7.1 (d, 3H), 4.9 (s, 2H), 4.8 (s, 2H), 3.2-3.3 (bd, 8H).
SCHEME 22
Figure imgf000157_0001
SCHEME 22 (CONT'D)
NaOH
Figure imgf000158_0001
SCHEME 22 (CONT'D)
Figure imgf000159_0001
SCHEME 22 (CONT'D)
22-7
CLU
Figure imgf000160_0001
SCHEME 22 (CONT'D)
Figure imgf000161_0001
o
SCHEME 22 (CONT'D)
22-11
Figure imgf000162_0001
Figure imgf000162_0002
Figure imgf000163_0001
1 -Chloro-2-(2-methyl-4-acetamidophenyl)ethanone (22-2)
A suspension of 3-acetamido toluene (Aldrich) (33.45 g, 0.224 mole) in nitromethane (100 mL) was treated with chloracetylchloride (69.3 mL, 0.739 mole). The solution became homogenous. Aluminum trichloride (92.3 g, 0.694 mol) was added in 10 g portions over 40 minutes. The temperature rose to 50°C and the solution became dark brown. The reaction was heated to 80°C for 2 hours, then cooled to room temperature and concentrated to give a thick green oil that was added to crushed ice and stirred with a overhead stirrer. The resulting tan solid was collected in a sintered glass funnel and washed with water and dried to give 22-2 as a tan solid. Rf (40% EtOAc/Hexanes)=0.14. iH NMR (300 MHz, CDCI3) δ 7.66 (d, IH), 7.58 (m, IH), 7.43 (s, IH), 7.28 (s, IH), 4.62 (s, 2H), 2.55 (s, 3H), 2.2 (s, 3H).
Figure imgf000163_0002
1 -( 1 -Py ridinium)-2-(2-methy 1-4-acetamidopheny 1) ethanone. chloride (22-3)
A solution of 22-2 (21.8 g, 0.098 mol) in refluxing ethanol (110 mL) was treated with pyridine (28 mL). A salmon-pink percipitate formed and after 2 hours of reflux the mixture was cooled to room temperature, filtered and rinsed with cold (-20°C) EtOH and dried to give 22-3 as an off-white solid.
Rf (9: 1 : 1 EtOH/H2θZNH4θH) 0.12 iH NMR (400 MHz, D2O) δ 8.66 (d, 2H), 8.5 (m, IH), 8.08 (d, 2H),
7.92 (d, IH), 7.5 (d, IH), 7.33 (s, IH), 2.4 (s, 3H), 2.1 (s, 3H).
Figure imgf000164_0001
2-Methyl-4-amino-benzoic acid 22-4 To a 60°C solution of 22^3 (23.5 g, 0.077 mol) in H2O
(155 mL) was added 2.5 M NaOH solution (160 mL). An orange percipitate formed. The reaction was heated to reflux for 2.5 hours, then the homogenous solution was cooled to room temperature and treated with 2.5 M HCI (160 mL) and stirred overnight. The pH of the solution was adjusted to pH 4-5 with NaOH solution and the yellow percipitate that formed was washed with water and dried to give 22-4 as a gummy yellow solid.
Rf(9: l : l EtOH/H2θ/NH4θH)=0.76. iH NMR (300 MHz, CD3OD) δ 7.75 (d, IH), 6.43 (m, 2H), 2.42 (s, 3H).
Figure imgf000165_0001
n-Butyl 2-methyl-4-amino-benzoate. hydrochloride (22-5)
A suspension of 22-4 (8.8 g, 58 mmol) in n-butanol (200 mL) was cooled to 0°C under argon and saturated with HCI gas. A salmon-pink percipitate formed. The solution was heated to reflux for 18 hours then evaporated. The residue was dissolved in EtOAc and saturated NaHCθ3 and the layers were separated. The aqueous layer was washed repeatedly with EtOAc, the EtOAc layers were combined, dried with brine and MgS04, filtered and evaporated. The oily residue was dissolved in CHCI3 and evaporated to give 22-5 as a brown solid. Rf (20% EtOAc/Hexanes) 0.5
*H NMR (300 MHz, CDCI3) δ 7.83 (d, IH), 6.48 (m, 2H), 4.23 (t, 2H), 3.9 (bs, 2H), 2.53 (s, 3H), 1.7 (m, 2H), 1.48 (m, 3H), 0.95 (t, 3H).
Figure imgf000165_0002
n-Butyl 2-methyl-4-piperizin-l-yl-benzoate. hydrochloride (22-6) A solution of 22-5 (10.7 g, 52 mmol) in n-butanol (285 mL) was treated with bis chloroethylamine hydrochloride (9.22 g, 52 mmol) and refluxed for one week. The ethanol was removed in vacuo and the residue was diluted with EtOAc. A percipitate formed and was collected and washed with EtOAc and dried to give 22-6 as tan solid. Rf (2.5% MeOH/CHCl3 saturated with NH3)=0.31 lH NMR (400 MHz, CD3OD) δ 7.88 (d, IH), 6.88 (m, 2H), 4.24 (t, 2H), 3.55 (m, 4H), 3.36 (m, 4H), 2.56 (s, 3H), 1.73 (m, 2H), 1.5 (m, 2H), 1.0 (t, 3H).
Figure imgf000166_0001
n-Buty 1 2-methy l-4-(4-( 1 , 1 -dimethylethoxycarbony lpiperizin- 1 -y 1)- benzoate acid (22-7)
A solution of 223 (10.5 g, 33.3 mmol) in CH2CI2 (100 mL) was cooled to 0°C and treated with triethylamine (18.8 mL, 0.133 mol) and di-tert-butyldicarbonate (14.75 g, 66 mmol). The solution was allowed to warm to room temperature and after 1 hour was washed with
10% KHSO4, brine, dried over MgS04, filtered and evaporated to give
22-7 as brown oil.
Rf (5% EtOAc/Hexanes)=0.4 iH NMR (300 MHz, CDCI3) δ 7.9 (d, 2H), 6.68 (m, 2H), 4.23 (t, 2H),
3.55 (m, 4H), 3.38 (m, 4H), 2.6 (s, 3H), 1.75 (m, 2H), 1.5 (m, 1 1H),
0.95 (t, 3H).
Figure imgf000166_0002
2-Methyl-4-(4-( 1 , 1 -dimethy lethoxycarbonylpiperizin- 1 -yl) benzoic acid (22-8)
A solution of 22^7 (2.55 g, 6.78 mmol) in 4:1 EtOH/H2θ (125 mL) was treated with NaOH (2.7 g, 67.8 mmol) and refluxed overnight. The solvents were removed and the residue was partitioned between EtOAc and 10% KHSO4. The layers were separated and the aqeous layer was washed with EtOAc several times. The organic layers were combined, washed with brine, dried over MgS04, filtered and evaporated to give 22-8 as a white solid. iH NMR (400 MHz,-CDCl3) δ 8.0 (d, IH), 6.7 (m, 2H), 3.6 (m, 4H), 3.34 (m, 4H), 2.6 (s, 3H), 1.5 (s, 9H).
Figure imgf000167_0001
N-(4-Benzyloxyphenyl)-2-methyl-4-(4-( 1 , 1 -dimethylethoxycarbonyl) piperizin- l -yl)benzamide (22-9) A solution of 22=8 (2.06 g, 6.43 mmol) in CH2CI2 (50 mL) was treated with p-benzyloxy analine hydrochloride (Aldrich, 1.66 g, 7.08 mmol), diisopropyl amine (5.6 mL, 32 mmol) and PYCLU 93.47 g, 9.6 mmol). After stirring for 24 hours the volatile components were removed in vacuo and the residue was dissolved in EtOAc and washed with 10% KHSO4, water, saturated NaHC03, water and brine, dried over MgSθ4, filtered and evaporated. The residue was chromatographed in a gradient of 20 to 50% EtOAc/Hexanes to give 22-9 as an oil. Rf (50% EtOAc/Hexanes)=0.57 iH NMR (400 MHz, CDCI3) δ 7.4 (m, 8H), 7.0 (d, 2H), 6.76 (m, 2H), 4.08 (s, 2H), 3.6 (s, 4H), 3.22 (bs, 4H), 2.53 (s, 3H), 1.5 (s, 9H).
Figure imgf000168_0001
1 -(4-Benzyloxyphenyl)-5-(4-( 1 , 1 -dimethylethoxycarbonyPpiperizin- 1 - yl)isoindolin-2-one (22-10) A solution of 22-9 (0.66 g, 1.31 mmol) in THF (65 mL) was cooled to -78°C under argon. n-Butyllithium (2.2M in hexanes, 2.4 mL) was added dropwise to give a deep red solution. The reaction was stirred for 20 minutes, then rapidly transferred via wide bore canulla to a -78°C THF solution of cyanogen bromide (2.77 g, 26.2 mmol in 65 mL). The resulting colorless solution was stirred for 25 minutes, then quenched with methanol. The solution was diluted with water, the volatile solvents were removed in vacuo and the remaining water layer was extracted with EtOAc. The EtOAc layer was washed with brine, dried over MgSθ4, filtered and evaporated. The residue was chromatographed in a gradient of 20 to 30% EtOAc/Hexanes to give 22-10 as an oil.
Rf (40% EtOAc/Hexanes)=0.25 iH NMR (400 MHz, CDCI3) δ 7.77 (s, IH), 7.7 (d, 2H), 7.44 (m, 2H), 7.4 (m, 2H), 7.34 (m, IH), 7.0 (m, 3H), 6.9 (s, IH), 5.1 (s, 2H), 4.73 (s, 2H), 3.6 (m, 4H), 3.3 (m, 4H), 1.5 (s, 9H).
Figure imgf000169_0001
1 -(4-Hydroxyphenyl)-5-(4-( 1 , 1 -dimethylethoxycarbony Ppiperizin- 1 - yl)isoindohn-2-one (22- 1 1 )
A solution of 22-10 (0.155 g, 0.31 mmol) in 10 mL glacial acetic acid was treated with 10% Pd/C (0.3 g) and hydrogenated at 60 psi for 5 hours. The solution was decanted from the catalyst, concentrated and the residue chromatographed using a gradient of 60 to 90% EtOAc/Hexanes to give 22-1 1 as an oil. Rf(50% EtOAc/Hexanes)=0.19
*H NMR (300 MHz, CDCI3) δ 7.79 (d, IH), 7.55 (d, 2H), 7.0 (m, IH), 6.92 (bs, IH), 6.86 (m, 2H), 4.72 (s, 2H), 3.6 (m, 4H), 3.3 (m, 4H), 1.5 (s, 9H).
Figure imgf000170_0001
Ethyl 4-(2-oxo-5-(4-( 1 ,1 -dimethy lethoxycarbonyl)piperizin-l-yl)iso- indolin- 1 -vPphenox vacetate (22- 12) A solution of 22-11 (0.045 g, 0.11 mmol) in DMF (5 mL) was treated with cesium carbonate (23 mg, 0.07 mmol) and ethyl bromoacetate (15 uL, 0.011 mmol). After 3 hours the solvents were removed in vacuo and the residue was dissolved in EtOAc and washed with water, brine, dried over MgS04, filtered and evaporated. The residue was chromatographed in a gradient of 30 to 50% EtOAc/Hexanes to give 22-12 as an oil. Rf(40% EtOAc/Hexanes)=0.36 iH NMR (400 MHz, CDCI3) δ 7.74 (m, 3H), 7.0 (m, 2H), 6.95 (m, 2H), 4.73 (s, 2H), 4.62 (s, 2H), 4.28 (q, 2H), 3.6 (m, 4H), 3.3 (m, 4H), 1.5 (s, 9H).
Figure imgf000171_0001
Ethyl 4-(2-oxo-5-piperizin-l -yl)isoindolin-l -yl)phenoxyacetate, hydrochloride (22-13)
A solution of 22-12 (0.04 g, 0.08 mmol) in EtOAc (10 mL) was cooled to -78°C, saturated with HCI gas, warmed to 0°C and evaporated at ambient temperature to give 22- 13 as a white solid. iH NMR (300 MHz, D2O) δ 7.54 (d, IH), 7.4 (d, 2H), 7.03 (m, 3H), 6.89 (d, 2H), 4.6 (s, 2H), 4.15 (q, 2H), 3.43 (m, 4H), 3.23 (m, 4H), 1.15 (t, 3H).
Figure imgf000171_0002
4-(2-Oxo-5-piperizin- 1 -v isoindolin- 1 -vPphenox vacetic acid (22-14) A solution of 22-13 (0.04 g, 0.08 mmol) in 1 : 1 THF/H2O
(6 mL) was treated with IN NaOH solution (0.4 mL). The reaction was concentrated and the residue chromatographed in 9: 1 :1
EtOH/H2θ/NH4θH to give 22-14 as a white solid.
Rf(9: l :l EtOH/H2θ/NH4θH)=0.62 iH NMR (400 MHz, D2O + deutero trifluoroacetic acid) δ 7.49 (d, IH),
7.44 (d, 2H), 6.95 (m, 3H), 6.74 (d, 2H), 4.33 (bs, 4H), 3.42 (bs, 4H),
3.25 (bs, 4H). SCHEME 23
Figure imgf000172_0001
BOCoO
Figure imgf000172_0002
Cs2CO3/BrCH2C02Et
Figure imgf000172_0003
1. H2 Pd/C
2. CH3S02CI
Figure imgf000172_0004
233 HCI /EtOAc 2233.
Figure imgf000172_0005
SCHEME 23 (CONT'D)
23-4
Figure imgf000173_0001
SCHEME 23 (CONT'D)
Figure imgf000174_0001
23-2
Figure imgf000174_0002
Figure imgf000174_0003
Figure imgf000174_0004
Figure imgf000175_0001
1. H2 Pd/C
2. 3-pyridylS02CI
Figure imgf000175_0002
Figure imgf000176_0001
23=1
2-Nitro-4-( 1.1 -dimethylethoxycarbonylamino)phenol (23- 1 )
A solution of 2-nitro-4-amino phenol (Aldrich) (20 g, 130 mmol) in THF (500 mL) was cooled to 0°C and treated with ditertbutyldicarbonate (64 g, 293 mmol) and triethylamine (37 mL, 265 mmol). After 24 hours the solution was concentrated and the residue dissolved in EtOAc, washed with 10% KHSO4, saturated NaHCθ3, and brine, dried over Na2Sθ4, filtered and evaporated. The crude bis- protedted material (Rf (40% EtOAc/Hexanes) 0.69) was then dissolved in 400 mL 1 :1 THF/H2O and treated with LiOH«H2θ (38 g, 1.3 mol). After stirring at room temperature overnight the solvent was removed and the residue was dissolved in EtOAc and washed with brine, dried with Na2Sθ4, filtered and concentrated to give 23-1 as a reddish oily solid.
Rf(20% EtOAc/Hexanes)=0.41 iH NMR (400 MHz, CDCI3) δ 10.35 (s, IH), 8.18 (s, IH), 7.58 (d, IH),
7.13 (d, IH), 6.45 (bs, IH), 1.55 (s, 9H).
Figure imgf000176_0002
22-2
Ethyl 2-(2-nitro-4-( 1 , 1 -dimethylethoxycarbony lamino)phenoxy)acetic acid (23-2)
A solution of 23JL (5 g, 19.7 mmol) in DMF (125 mL) was treated with cesium carbonate (3.17 g, 9.73 mmol), stirred for 10 minutes and treated with ethyl bromoacetate (2.2 mL, 19.8 mmol) at room temperature. After 1.5 hours the solution was concentrated under high vacuum and the-residue was absorbed to silica gel and chromatographed in a gradient of 20 to 30% EtOAc/Hexanes to give 23-2 as a bright yellow solid. Rf(30% EtOAc/Hexanes)=0.26 i H NMR (400 MHz, CDCI3) δ 7.95 (s, IH), 7.5 (d, IH), 6.97 (d, IH), 6.62 (bs, IH), 4.72 (s, 2H), 4.25 (q, 2H), 1.5 (s, 9H), 1.28 (t, 3H).
Figure imgf000177_0001
23,4
Ethyl 2-(2-methanesulfonamido-4-aminophenoxy)acetic acid hydrochloride (23-4)
A solution of 23-2 (2 g, 5.88 mmol) in EtOAc (25 mL) was treated with 10% Pd/C (0.67 g), and hydrogenated under balloon pressure for 1.5 hours. The solution was filtered through SolkaFloc, and the cake rinsed with EtOAc. The filtrate was not concentrated but was treated directly with methanesulfonyl chloride (3.0 mL, 39 mmol) and pyridine (5.0 mL, 62 mmol) and stirred overnight. The solution was concentrated and the residue was dissolved in EtOAc and washed with 10% KHSO4, saturated Na2C03, and brine, dried with Na2S04, filtered and concentrated to give a yellow oil that was chromatographed (40% EtOAc/Hexanes) to give 23,3 (Rf 30% EtOAc/Hexanes) 0.19) contaminated with 23-3a. The mixture (1.7 g) was dissolved in EtOAc (75 mL), cooled to -78°C and saturated with HCI gas, warmed to 0°C for 1 hour and concentrated. The residue was partitioned between CH2CI2 and saturated NaC03, the layers separated and the aqueous layer extracted with CH2CI2. The organic layer was dried over Na2S04, filtered and evaporated and the residue chromatographed
(60% EtOAc/Hexanes) to give 23-4 as an off-white solid.
Rf(60% EtOAc/Hexanes) 0.3 iH NMR (400 MHz, CDCI3) δ 7.7 (bs, IH), 6.95 (s, IH), 6.74 (d, IH),
6.4 (d, IH), 4.6 (s, 2H), 4.33 (q, 2H), 2.98 (s, 3H), 1.3 (t, 3H).
Figure imgf000178_0001
Ethyl 2-(4-(4-(4-( 1 , 1 -dimethy lethoxycarbonyPpiperazin- 1 -y Ppheny 1- carbonylamino)-2-methanesulfonamidophenoxy)acetate (23-5)
A suspension of 23^4 (0.125 g, 0.433 mmol) and 1 -5 (0.136 g, 0.444 mmol) in CH2CI2 (4 mL) was treated with diisopropylamine (0.3 mL, 1.7 mmol) and PYCLU (0.173 g, 0.48 mmol) and stirred at room temperature for three days. The solution was concentrated and the residue was absorbed to silica gel and chromatographed in a gradient of 20 to 60% EtOAc/Hexanes to give 23-5 as a pale yellow oil. Rf (60% EtOAc/Hexanes)=0.27 iH NMR (400 MHz, CDCI3) δ 7.82 (dd, IH), 7.79 (s, IH), 7.77 (s, IH), 7.54 (bs, IH), 7.48 (s, IH), 6.90 (m, 3H), 4.7 (s, 2H), 4.25 (q, 2H), 3.6 (m, 4H), 3.3 (m, 4H), 3.03 (s, 3H), 1.5 (s, 9H), 1.3 (t, 3H).
Figure imgf000179_0001
2-(4-(4-(Piperazin- 1 -yl)phenylcarbonylamino)-2-methane- sulfonamidophenoxy)acetic acid (23-6)
A solution of 23-5 (0.093 g, 0.16 mmol) was dissolved in
EtOAc (10 mL), cooled to -78°C and saturated with HCI gas, warmed to
0°C for 1 hour and concentrated. The resulting white solid was dissolved in 1:1:1 H2θ/THF/MeOH, treated with LiOH-H2θ (0.038 g, 0.9 mmol) and stirred at room temperature for 1 hour. The reaction was concentrated and chromatographed (18: 1:1 EtOH/H2θ/NH4θH) to give a yellow oil that was diluted with CH2CI2 and evaporated to give
23-6 as white solid.
Rf(9:l :l EtOH/H2θ/NH4θH)=0.48 iH NMR (400 MHz, D2O + NaOD) δ 7.74 (s, IH), 7.72 (s, IH), 7.21 (s,
IH), 7.07 (s, IH), 7.05 (s, IH), 6.9 (d, IH), 6.74 (d, IH), 4.38 (s, 2H),
3.15 (m, 4H), 2.85 (m, 7H).
Figure imgf000180_0001
Ethy 1 2-(4-(4-(4-( 1 , 1 -dimethy lethoxycarbonyPpiperazin- 1 - yl)phenylcarbonylamino)-2-nitrophenoxy)acetate (23-7)
A solution of 23-2 (0.3 g, 0.88 mmol) was dissolved in EtOAc (10 mL), cooled to -78°C and saturated with HCI gas, warmed to 0°C for 1 hour and concentrated to give Ethyl 2-(2-nitro-4- aminophenoxy)acetic acid as a white solid that was coupled immediately (0.26 g, 0.88 mmol) to 1^5 (0.29 g, 0.95 mmol) as described for 23-5 to give 23-7 as a yellow solid after chromatography in a gradient of 40 to 100% EtOAc/Hexanes. Rf(50% EtOAc/Hexanes)=0.22
Figure imgf000180_0002
2-(4-(4-(Piperazin- 1 -yl)phenylcarbonylamino)-2-nitrophenoxy)- acetic acid (23-8)
A solution of 23-7 (0.186 g, 0.352 mmol) in EtOAc was treated first with HCI gas then with LiOH«H2θ as described for 23-6 to give 23-8 as a yellow solid after chromatography in 18:1 :1
EtOH/H2θ/NH4θH).
Rf(18: l :l EtOH/H2θ/NH4θH)=0.47 iH NMR (400 MHz, D2θ) δ 8.0 (s, IH), 7.68 (2s, 2H), 7.52 (d, IH), 7.0 (m, 2H), 3.12 (bs, 4H), 2.85 (bs, 4H).
Figure imgf000181_0001
NHS023-pyridyl
23=2
Ethyl 2-(2-(3-pyridyl)sulfonamido-4-( 1 , 1 -dimethylethoxycarbonyl)- aminophenoxy)acetate (23-9)
A solution of 23-2 (2 g, 5.88 mmol) in EtOAc (25 mL) was treated with 10% Pd/C and 3-pyridylsulfonyl chloride (JOC, 1989, 54, 389-393) as described for 23-3 to give 23-9 after chromatography in a gradient of 30 to 50% EtOAc/Hexanes as a white solid. Rf(40% EtO Ac/Hexanes)=0.11 iH NMR (400 MHz, CDCI3) δ 9.02 (s, IH), 8.71 (d, IH), 8.1 (m, 2H), 7.4 (s, IH), 7.33 (m, 2H), 6.69 (d, IH), 6.58 (s, IH), 4.4 (s, 2H), 4.23 (q, 2H), 1.5 (s, 9H), 1.25 (t, 3H).
Figure imgf000181_0002
23.^ NHS023-pyridyl
Ethyl 2-(4-(4-(4-( 1 , 1 -dimethy lethoxycarbonyPpiperazin- 1 -y Pphenyl- carbonylamino)-2-(3-pyridylsulfonamido)phenoχy)acetate (23-1 1) A solution of 23^9 (0.318 g, 0.704 mmol) in EtOAc (10 mL) was treated with HCI gas as described for 23-4 to give 23- 10 as a white solid that was coupled directly with 5 as described for 23-5 to give 23- 1 1 as a oily yellow solid after chromatography in a gradient of 20 to 40% acetone/Hexanes. Rf(50% EtOAc/Hexanes)=0.41 iH NMR (400 MHz, CDCI3) δ
Figure imgf000182_0001
23-12
2-(4-(4-(Piperazin- 1 -yl)phenylcarbonylamino)-2-(2-(3-pyridyl- sulfonamido)phenoxy)acetic acid (23-12)
A solution of 23-11 (0.047 g, 0.087 mmol) in EtOAc was treated first with HCI gas then with LiOH»H2θ as described for 23-6 to give 23-12 as a yellow solid after chromatography in 18:1 :1 EtOH/H20/NH40H).
Rf(18:l:l EtOH/H2θ/NH4θH)=0.38 iH NMR (400 MHz, D2O + NaOD) δ 8.76 (s, IH), 8.5 (m, IH), 8.13 (m, IH), 7.7 (m, 2H), 7.45 (m, IH), 7.12 (s, IH), 7.08 (m, 2H), 6.84 (m, IH), 6.67 (d, IH), 4.13 (s, 2H), 3.25 (m, 4H), 2.87 (m, 4H).
Figure imgf000182_0002
23-13
Ethyl 2-(2-methoxy-4-nitrophenoxy)acetic acid (23-13)
2-methoxy-4-nitro phenol (Aldrich) (1.0 g, 5.9 mmol) was treated with cesium carbonate and ethylbromoacetate as described for 23-2 to give crude 23-13 after removal of DMF. The crude material was partitioned between water and EtOAc, the organic layer was dried with brine and MgS04, filtered and evaporated to give 23-13 as a yellow solid. Rf(50% EtOAc/Hexanes)=0.54 iH NMR (400 MHz, CDC13) δ 7.8 (d, IH), 7.76 (s, IH), 6.75 (d, IH),
4.71 (s, 2H), 4.2 (q, 2H), 3.9 (s, 3H), 1.21 (t, 3H).
Figure imgf000183_0001
23-14
Ethyl 2-(2-methoxy-4-aminophenoxy)acetic acid (23-14)
A solution of 23-13 (0.7 g, 2.7 mmol) in EtOH (10 mL) was treated with 10% Pd/C (0.14 g) and hydrogenated at balloon pressure. The solution was filtered through Solka-Floc and evaporated to give 23-14 as a tan oil. iH NMR (400 MHz, CDCI3) δ 6.78 (d, IH), 6.33 (s, IH), 6.21 (d, IH), 4.59 (s, 2H), 4.21 (q, 2H), 3.8 (s, 3H), 3.45 (bs, 2H), 1.28 (t, 3H).
Figure imgf000183_0002
Ethyl 2-(4-(4-(4-( 1 , 1 -dimethy lethoxycarbony piperazin- 1 - yPphenylcarbonylamino)-2-methoxyphenoxy)acetate (23-15)
Acid 13 and amine 23-14 were coupled as described for
23-5 to give 23-15 as brown solid after chromatography in 50% EtOAc/Hexanes.
Rf(50% EtOAc/Hexanes)=0.13 iH NMR (400 MHz, CDCI3) δ 7.8 (d, 2H), 7.6 (d, IH), 6.92 (d, 2H),
6.86 (m, 2H), 4.64 (s, 2H), 4.24 (q, 2H), 3.9 (s, 3H), 3.6 (m, 4H), 3.3
(m, 4H), 1.5 (s, 9H), 1.25 (t, 3H).
Figure imgf000184_0001
2-(4-(4-(4-Piperazin- 1 -yl)phenylcarbonylamino)-2-methoxy- phenoxy)acetic acid (23-16) Compound 23-15 was treated with LiOH and HCI gas as described for 23-6 to give 23-16 as a white solid after chromatography in 10:1 :1 EtOH/H2θ/NH4θH. Rf (10:1 :1 EtOH/H2θ/NH4θH)=0.15 iH NMR (400 MHz, D2θ) δ 7.78 (d, 2H), 7.15 (s, IH), 7.08 (d, 2H), 6.9 (m, IH), 6.78 (d, IH), 4.4 (s, 2H), 3.8 (s, 3H), 3.18 (bs, 4H), 2.88 (bs, 4H).
SCHEME 24
t
Figure imgf000185_0001
Figure imgf000186_0001
2-(l ,1 -Dimethylethoxycarbonyl)-7-bromo-l ,2,3,4-tetrahydro-9H- ρyridor3.4-b1indole (24-2) A suspension of 24-1. prepared by the method of Rinehard et al. (J. Am. Chem. Soc, 1987, 109, p 3378-3387) (0.366 g, 1.46 mmol) in CH2CI2 (8 mL) was treated with triethylamine (0.61 mL, 4.4 mmol) followed by di-tert-butyldicarbonate (0.38 g 1.7 mmol) for 1 hour at room temperature. The solution was concentrated and the residue chromatographed (20% EtOAc/Hexanes) to give 24-2 as a white solid.
Rf (20% EtOAc/Hexanes)=0.28. iH NMR (400 MHz, CDCI3) δ 8.0-7.6 (m, IH), 7.46 (s, IH), 7.33 (d, IH), 7.2 (d, IH), 4.6 (bs, 2H), 3.78 (bs, 2H), 2.76 (bs, 2H), 1.5 (s, 9H).
*
Figure imgf000186_0002
2-( 1,1 -Dimethylethoxycarbonyl)- 1 ,2,3, 4-tetrahydro-9H-pyrido [3,4- blindol-7-yl carboxylic acid (24-3) A solution of 24^2 (0.26 g, 0.734 mmol) in THF ( 10 mL) was cooled to 0°C and treated with methylmagnesium chloride (3.0 M in THF, 0.29 mL, 0.87 mmol) to give a pale yellow solution. After 15 minutes the solution was cooled to -78°C and treated with tBuLi (1.7M in pentane, 4.35 mL, 7.39 mmol) to give a bright yellow solution. After 10 minutes C02 gas was bubbled vigorously through the solution for 10 minutes. Saturated NH4CI, water and enough 6N NaOH to reach pH12 were added and the solution extracted with EtOAc. The EtOAc layer was back extracted with 0.5 NaOH and the aqueous layers combined, acidified to pH 7 and extracted with EtOAc, the EtOAc layer was dried (Na2S04) filtered and concentrated to give 24-3 as an off- white solid.
Rf(75:25:l CHCl3/MeOH HOAc)=0.48. iH NMR (400 MHz, DMSO-d6) δ 12.0 bs, I H), 1 1.2 (s, IH), 7.93 (s, IH), 7.6 (d, IH), 7.45 (d, IH), 4.6 (s, 2H), 3.68 (m, 2H), 2.7 (m, 2H), 1.4 (s, 9H).
Figure imgf000187_0001
Ethyl 4-(2-( 1 , 1 -dimethylethoxycarbonyl)- 1 ,2,3,4-tetrahydro-9H- pyridor3.4-blindol-7-yl)carbonylamino)-3-methylphenoxyacetate (24-4) A solution of 24^3 (0.078 g, 0.25 mmol) and K (0.303 g,
1.23 mmol) in CH2CI2 were treated with diisopropylamine and PYCLU as described for 23-5 to give 24-4 as a white solid after chromatography in a gradient of 40 to 60% EtOAc/Hexanes. Rf (40% EtOAc/Hexanes)=0.1 1 iH NMR (400 MHz, CDCI3) δ 8.5-8.2 (m, IH), 8.0 (s, IH), 7.75 (d, IH), 7.63 (s, IH), 7.52 (s, 2H), 6.83 (s, IH), 6.80 (d, IH), 4.7 (bs, 2H), 4.6 (s, 2H), 4.28 (q, 2H), 3.8 (bs, 2H), 2.83 (bs, 2H), 2.82 (s, 3H), 1.5 (s, 9H), 1.3 (t, 3H).
Figure imgf000188_0001
3-Methyl-4-((l,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-7- yl)carbonylamino)phenoxyacetic acid (24-5)
A solution of 244 (0.082 g, 0.16 mmol) in EtOAc (10 mL) was treated first with HCI gas, then with LiOH»H2θ as described for 23^
6 to give 24-5 as a white solid after chromatography in 18: 1 :1 EtOH/H2θ/NH4θH. Rf (18: 1 : 1 EtOH/H2θ/NH4θH)=0.48 iH NMR (400 MHz, D2θ) δ 7.9 (s, IH), 7.54 (m, 2H), 7.13 (d, IH), 6.84 (s, IH), 6.75 (d, IH), 4.40 (s, 2H), 3.8 (s, 2H), 3.0 (m, 2H), 2.7 (m, 2H), 2.15 (s, 3H).
SCHEME 25
Figure imgf000189_0001
NBS THF
Figure imgf000189_0002
Cs2C03/BrCH2C02Et
Figure imgf000189_0003
HCI/EtOAc
SCHEME 25 (CONT'D)
Figure imgf000190_0001
Figure imgf000190_0002
SCHEME 25 (CONT'D)
25-4 25-4a
LiOH
Figure imgf000191_0001
Figure imgf000192_0001
2,6-Dibromo-3-methyl-4-(l ,1 -dimethylethoxycarbonyPamino- phenol (25-1 ) A solution of 10-2 (1.0 g, 450 mmol) in 20 mL THF under argon was treated with N-Bromosuccinimide (1.6 g, 9 mmol) for 2 hr. The solution was concentrated and the residue was resuspended in carbontetrachloride and filtered. The filtrate was concentrated and chromatographed (15% EtOAc/Hexanes) to give 25-1 as a white solid. Rf(20% EtOAc/Hexanes)=0.56 iH NMR (400 MHz, CDCI3) δ 7.79 (bs, IH), 6.08 (bs, IH), 5.8 (s, IH), 2.33 (s, 3H), 1.43 (s, 9H).
Figure imgf000192_0002
Ethyl 2-(2,6-dibromo-3-methyl-4-(l , 1 -dimethylethoxycarbonyl)- aminophenoxy)acetate (25-2)
A solution of 25- 1 (0.6 g, 1.57 mmol) in DMF was treated with cesium carbonate and ethyl bromo acetate as described for 10-3 to give 25-2 as a tan solid
Rf(20% EtOAc/Hexanes)=0.56 U NMR (400 MHz, CDCI3) δ 8.0 (bs, IH), 6.21(bs, IH), 4.56 (s, 2H),
4.3 (q, 2H), 2.35 (s, 3H), 1.5 (s, 9H), 1.33 (t, 3H).
Figure imgf000193_0001
Ethyl 2-(2.6-dibromo-3-methyl-4-aminophenoxy)acetate (25-3)
A solution of 21=2 (0.6 g, 1.29 mmol) in EtOAc (10 mL) was treated with HCI gas as described for 16-10 to give 25-3 as a tan solid. iH NMR (400 MHz, DMSO) δ 7.0 (s, IH), 4.8-4.4 (b, 2H), 4.41 (s, 2H), 4.2 (q, 2H), 2.18 (s, 3H), 1.2 (t, 3H).
Figure imgf000193_0002
Ethyl 2-(2,6-dibromo-3-methyl-4-(4-(N-( 1 , 1 -dimethylethoxycar- bonyl)piperizin-4-yl)phenylcarboxamide)phenoxy) acetate (25-4)
A solution of 25;3 (0.520 g, 1.29 mmol) and i (0.395 g, 1.29 mmol) in CH2CI2 was treated with chloro-N,N,N'N',-bis(penta- methylene)formamidinium hexafluorophosphate (0.504 g, 0.1.4 mmol) and diisopropylethyl amine (0.9 mL, 5.16 mmol) and stirred at room temperature for 24 hours. The solution was diluted with EtOAc and washed with H2θ, 10% KHSO4, saturated NaHCθ3 and brine, dried over MgSθ4, filtered and evaporated. The residue was chromatographed (silica gel 30% EtOAc/Hexanes) to give a mixture of
25-4 and 25-4a.
R 25-4a(50% EtOAc/Hexanes)=0.45. lH NMR (400 MHz, CDCI3) δ 8.0 (m, 2H), 7.8 (d, 2H), 7.5 (s, IH),
6.93 (d, 2H), 6.85 (d, IH), 4.6 (s, 2H), 4.3 (q, 2H), 3.6 (bs, 8H), 3.35
(m, 8H), 2.4 (s, 3H),-1.45 (s, 9H), 1.35 (t, 3H).
R 25-4(50% EtOAc/Hexanes)=0.37. iH NMR (400 MHz, CDCI3) δ 7.6 (d, 2H), 6.7 (d, 2H), 4.6 (s, 2H), 4.3
(q, 2H), 3.55 (bs, 4H), 3.3 (bs, 4H), 2.38 (s, 3H), 1.45 (s, 9H), 1.33 (t,
3H).
Figure imgf000194_0001
2-(2,6-Dibromo-3-methyl-4-(4-(4-(l,l-dimethylethoxycarbonyl)- piperizin-4-yl)phenylcarbonylamino)phenoxy) acetic acid (25-5)
A solution of 25-4 and 25 -4a (0.3 g) in 1 : 1 : 1 THF/MeOH/H2θ was treated with LiOH (0.084 g, 2 mmol) at 60°C. After 1 hour the reaction was diluted with EtOAc and 10% KHSO4 and the layers were separated. The organic layer was washed with H2O, brine, dried with MgS04, filtered and evaporated to give 25-5 as a clear oil after chromatography in 9:0.5:0.5 CH2Cl2/MeOH/HOAc. Rf(9:0.5:0.5 CHCl3/MeOH/HOAc)=0.6. iH NMR (400 MHz, CD3OD) δ 7.90 (d, 2H), 7.6 (s, 2H), 7.05 (d, 2H), 4.55 (s, 2H), 3.6 (bs, 4H), 3.3 (bs, 4H), 2.35 (s, 3H), 1.5 (s, 9H).
Figure imgf000195_0001
2-(2,6-Dibromo-3-methyl-4-(4-piperizin-4-yl)phenylcarbonylamino) phenoxy) acetic acid, hydrochloride (25-6)
A slurry of the intermediate acid (0.4 g, 0.6 mmol) in EtOAc was cooled to -78°C and saturated with HCI gas. The reaction was warmed to 0°C, then concentrated in vacuo to give 25-6 as the HCI salt. Rf(10:0.5:0.5 EtOH/H2θ/NH4θH) 0.18. iH NMR (400 MHz, D2θ) δ 7.73 (d, 2H), 7.23 (s, IH), 7.02 (d, 2H), 4.3 (s, 2H), 3.1 (bs, 4H), 2.82 (bs, 4H), 2.1 (s, 3H).
SCHEME 26
Figure imgf000196_0001
1. BOC20/DMAP
2. LiOH
Figure imgf000196_0002
HCI/EtOAc
Figure imgf000196_0003
SCHEME 26 (CONT'D)
PYCLU
Figure imgf000197_0001
Figure imgf000197_0002
Figure imgf000197_0003
10% Pd/C H2
SCHEME 26 (CONT'D)
Figure imgf000198_0001
CIS02C6H5
Figure imgf000198_0002
1. LiOH
2. HCI/EtOAc
Figure imgf000198_0003
NHS02 C6H5
Figure imgf000199_0001
1-0.1 -dimethylethox vcarbonyloxy)-3-nitro-4-aminophenol (26- 1 )
A solution of 3-nitro-4-amino phenol (Aldrich) (8 g, 52.6 mmol) in THF (250 mL) was cooled to 0°C and treated with ditertbutyldicarbonate (24 g, 110 mmol) and triethylamine (14 mL, 105 mmol). The solution was allowed to warm slowly and after 24 hours was concentrated and the residue dissolved in EtOAc, washed with 10% KHS04, saturated NaHC03, and brine, dried over Na2Sθ4, filtered and evaporated to give 26-1 as a brown oil. iH NMR (400 MHz, CDCI3) δ 7.94 (s, IH), 7.21 (dd, IH), 6.8 (d, IH), 6.04 (bs, 2H), 1.5 (s, 9H).
Figure imgf000199_0002
3-Nitro-4-( 1.1 -dimethylethoxycarbonylamino)ρhenol (26-2)
A solution of 26- 1 (52.6 mmol) in dichloroethane (150 mL) was added at a rapid drip to a refluxing solution of di-tert- butyldicarbonate (12 g, 52.6 mmol) in dicloroethane (100 mL) and the resulting mixture was refluxed for 20 minutes, then cooled to room temperature and stirred overnight. Triethylamine (52.6 mmol) and 2,6- dimethylaminopyridine (1.3 g, 10.5 mmol) were added and the solution refluxed for 2 hours and stirred at room temperature overnight. The solvents were removed and the residue was dissolved in 240 mL 1: 1:1 THF/MeOH/H2θ and treated with LiOH«H2θ (22 g, 526 mmol) for 48 hours. The solution was diluted with water, 10% KHSO4 and EtOAc and the layers separated. The organic layer was washed with water and brine, dried over MgS04, filtered and evaporated. The residue was chromatographed (20% EtOAc/Hexanes) to give 26-2 as a yellow solid. Rf (20% EtOAc/Hexanes)=0.26 iH NMR (400 MHz, CDCI3) δ 9.5 (bs, IH), 8.35 (d, IH), 7.61 (s, IH), 7.13 (d, IH), 5.33 (s, IH), 1.55 (s, 9H).
Figure imgf000200_0001
Ethyl 2-(3-nitro-4-(l , 1 -dime thy lethoxycarbonylamino)phenoxy) acetate (26-3)
A solution of 26-2 (2 g, 7.87 mmol) in DMF (75 mL) treated with cesium carbonate (1.28 g, 3.93 mmol), stirred for 10 minutes and treated with ethyl bromoacetate (0.8 mL, 7.92 mmol) at room temperature. After 1.5 hours the solution was concentrated under high vacuum and the residue was absorbed to silica gel and chromatographed in 10% EtOAc/Hexanes to give 26-3 as a yellow solid. Rf(30% EtOAc/Hexanes) 0.18 iH NMR (400 MHz, CDCI3) δ 9.4 (bs, IH), 8.44 (d, IH), 7.65 (s, IH), 7.26 (m, IH), 4.63 (s, 2H), 4.24 (q, 2H), 1.55 (s, 9H), 1.3 (t, 3H).
Figure imgf000201_0001
Ethyl 2-(3-nitro-4-aminophenoxy)acetate. hydrochloride (26-4)
A solution of 26-3 (0.5 g, 0.2.5 mmol) was dissolved in EtOAc (15 mL), cooled to -78°C and saturated with HCI gas, warmed to 0°C for 1 hour and concentrated to give 26-4 as an orange solid. Rf (10% MeOH/CHCl3 saturated with NH3)=0.13 iH NMR (400 MHz, CD3OD) δ 7.51 (d, IH), 7.18 (dd, IH), 7.0 (d, IH), 4.68 (s, 2H), 4.24 (q, 2H), 1.15 (t, 3H).
Figure imgf000201_0002
Ethyl 2-(3-nitro-4-(4-(4-( 1 ,1 -dimethylethoxycarbony Ppiperazin- 1- yl)phenylcarbonylamino)phenoxy)acetate (26-5) A solution of 26-4 (0.65 g, 2.46 mmol) and i (1 -5 g, 4.9 mmol) were treated with PYCLU and diisopropylamine as described for
23-5 to give 26-5 and 26-5a after chromatography in 30%
EtOAc/Hexanes.
Rf(30% EtOAc/Hexanes)=0.16 i H NMR 26 5 (400 MHz, CDCI3) δ 8.95 (d, IH), 7.9 (d, 2H), 7.75 (s,
IH), 6.95 (d, 2H), 4.65 (s, 2H), 4.28 (q, 2H), 3.6 (m, 4H), 3.35 (m, 4H),
1.5 (s, 9H), 1.3 (t, 3H).
Figure imgf000202_0001
Ethyl 2-(3-phenylsuIfonamido-4-(4-(4-( 1 , 1 -dimethy lethoxycar- bonv piperazin- 1 -yl)phenylcarbonylamino)phenoxy)acetate (26-7) A solution of 26-5 (0.4 g, 0.76 mmol) in EtOH (10 mL) was treated with 10% Pd/C (0.070 g), and hydrogenated under balloon pressure for 1.5 hours. The solution was filtered through SolkaFloc, and the cake rinsed with EtOAc. The filtrate was concentrated to give 26-6. Rf( 10% MeOH/CHCl3 saturated with NH3)=0.72
The crude amine was dissolved in pyridine (3 mL) and treated with phenylsulfonyl chloride (0.10 mL, 0.83 mmol) and stirred for four hours. The solution was diluted with EtOAc and washed with water and brine, dried with MgSθ4, filtered and concentrated to give a yellow oil that was chromatographed (gradient 30% EtOAc/Hexanes to 100% EtOAc) to give 26-7 as an oil. (Rf 30% EtOAc/Hexanes) 0.85)
*H NMR 26-5(400 MHz, CDCI3) δ 8.04 (s, IH), 7.7 (d, 2H), 7.65 (d, 2H), 7.5 (s, 2H), 7.42 (d, IH), 7.38 (m, 2H), 6.9 (m, 2H), 6.8 (d, IH), 6.6 (s, IH), 4.46 (s, 2H), 4.25 (q, 2H), 3.6 (m, 4H), 3.3 (m, 4H), 1.5 (s, 9H), 1.28 (t, 3H).
Figure imgf000203_0001
NHS02 C6H5
2-(3-Phenylsulfonamido-4-(4-(4-piperazin-l -yPpheny lcarbonyl- amino )phenoxy)acetic acid (26-8)
A solution of 26-7 (0.18 g, 0.28 mmol) was treated with LiOH and HCI gas as described for 23-6 to give 26-8 as a white solid after chromatography (10:0.5:0.5 EtOH/NH4θH/H2θ) and further purification via reverse phase HPLC. iH NMR (400 MHz, D2O) δ 7.6 (m, 3H), 7.48 (d, 2H), 7.23 (m, IH),
7.18 (m, 2H), 7.1 (d, 2H), 6.59 (s, IH), 6.5 (d, IH), 4.23 (s, 2H), 3.2 (m, 4H), 2.9 (m, 4H).
SCHEME 27
Figure imgf000204_0001
Cs2C03) DMF, Nal, 60°C
Figure imgf000204_0002
EtOAc, 0°C
Figure imgf000204_0003
Cs2C03, DMF, Nal, 60°C SCHEME 27 (CONT'D)
HCI (g)
EtOAc, 0°C
Figure imgf000205_0002
4-[4-(4-(l , 1 -dimethylethoxycarbonyPpiperazin- 1 -yl)phenyl- carbonylamino]-3-methylphenoxyacetic acid; N,N-diethylglycolamide ester (27-2)
A solution of carboxylic acid 10-6 (500 mg, 1.07 mmol), N,N-diethyl chloroacetamide 27-1 (0.154 mL, 1.12 mmol), Nal (5 mg, 0.03 mmol), CS2CO3, (173 mg, 0.535 mmol) and DMF (5 mL) was heated at 60°C for 20 h. The reaction mixture was diluted with EtOAc and washed with water, 10% aqueous KHSO4 and brine. Drying (MgS04), filtration, removal of the solvent in vacuo, and chromatography on silica gel using a gradient of 50 to 90% EtOAc in hexane as eluant gave 4-[4-(4-(l,l-dimethylethoxycarbonyl)piperazin-l- yl)phenylcarbonylamino]-3-methylphenoxy acetic acid N,N-diethyl- glycolamide ester (27-2) as a white solid. iH NMR (CD3OD): δ 1.23 (t, J=7Hz, 6H), 1.48 (s, 9H), 2.25 (s, 3H), 3.32 (m, 8H), 3.58 (m, 2H), 4.83 (s, 2H), 4.92 (s, 2H), 6.83 (dd, J=3Hz, 9Hz, IH), 6.90 (s, IH), 7.03 (d, J=9Hz, 2H), 7.19 (d, J=(Hz, IH), 7.78 (d, J=9Hz, 2H). 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino]-3-methylphenoxyacetic acid: N.N-diethylglycolamide ester, hydrochloride (27-3)
To a stir ed solution of EtOAc (7 mL) saturated with HCI gas was added ester 27-2 (500 mg, 0.86 mmol), suspended in EtOAc (3 mL). The mixture was stirred for 1 h at ambient temperature, purged with dry argon for 30 min and concentrated in vacuo to give 4-[4- (piperazin- 1 -yl)phenylcarbonylamino]-3-methylphenoxyacetic acid N,N- diethylglycolamide ester, hydrochloride (27-3) as a white solid. H NMR (D20): δ 1.11 (t, J=7Hz, 3H), 1.21 (t, J=7Hz, 3H), 2.23 (s, 3H), 3.37 (t, J=7Hz, 4H), 3.44 (m, 4H), 3.62 (m, 4H), 4.96 (s, 2H), 5.01 (s, 2H), 6.92 (d, J=9Hz, IH), 7.00 (s, IH), 7.21 (m, 3H), 7.90 (d, J=9Hz, 2H).
4-[4-(4-( 1 , 1 -DimethylethoxycarbonyPpiperazin- 1 -yPpheny lcarbonyl- aminol-3-methylphenoxyacetic acid: N-methylglvcolamide ester (27-5) A solution of carboxylic acid 10-6 (500 mg, 1.07 mmol), N-methyl chloroacetamide 27-4 (0.121 mg, 1.12 mmol), Nal (5 mg, 0.03 mmol), CS2CO3, (173 mg, 0.535 mmol) and DMF (5 mL) was heated at 60°C for 20 h. The reaction mixture was diluted with EtOAc and washed with water, 10% aqueous KHSO4 and brine. Drying (MgS04), filtration, removal of the solvent in vacuo, and chromatography on silica gel using EtOAc as eluant gave 4-[4-(4-(l ,l- dimethy lethoxycarbony Ppiperazin- 1 -yPpheny lcarbonylamino] -3- methylphenoxyacetic acid N-methylglycolamide ester (27-5) as a white solid. iH NMR (CD3OD): δ 1.49 (s, 9H), 2.31 (s, 3H), 2.77 (d, J=5Hz, 3H), 3.29 (m, 4H), 3.61 (m, 4H), 4.67 (s, 2H), 4.75 (s, 2H), 5.85 (br s, IH), 6.87 (m, 2H), 6.95 (d, J=(Hz, 2H), 7.47 (s, IH), 7.78 (m, IH), 7.79 (d, J=9Hz, 2H).
4-[4-(Piperazin- 1 -yl)phenylcarbonylamino]-3-methylphenoxyacetic acid: N-methylglvcolamide ester, hydrochloride (27-6)
HCI gas was rapidly bubbled through a solution of 4-[4-(4- (1, 1 -dimethylethoxycarbonyPpiperazin- 1 -y l)phenylcarbonylamino]-3- methylphenoxyacetic acid N-methylglycolamide ester (27-5) (325 mg, 0.60 mmol) in EtOAc (30 mL) at 0°C for 20 min. The mixture was aged 40 min., purged wityh argon and concentrated in vacuo. The solid was triturated with EtOAc and Et2θ to give 4-[4-(piperazin-l - yl)phenylcarbonylamino]-3-methylphenoxyacetic acid N- methylglycolamide ester, hydrochloride (27-6) as a white solid. ^H NMR (D2θ): δ 2.23 (s, 3H), 2.78 (s, 3H), 3.43 (m, 4H), 3.62 (m, 4H), 4.75 (s, 2H), 4.95 (s, 2H), 6.90 (d, J=8Hz, IH), 6.99 (s, IH), 7.21 (m, 3H), 7.90 (d, J=9Hz, 2H).
SCHEME 28
Figure imgf000208_0001
OH
BOCPO , CHCI, Br COOEt
reflux -OCH3 Cs2C03 , DMF
NHBoc
28-3
t
Figure imgf000208_0002
28-4 28-5 SCHEME 28 (CONT'D)
Figure imgf000209_0001
Figure imgf000209_0002
Figure imgf000209_0003
Figure imgf000209_0004
Figure imgf000209_0005
4- [4 -( 1 -PiperazinyPphenylcarbony lamino] - 3 -methoxyphenoxyacetic acid, hydrochloride (28-8)
Using a .sequence essentially the same as described for compound 15-8. but starting with 3-methoxyphenol (28-1). 4-[4-(l- piperazinyl)phenylcarbonylamino]-3-methoxyphenoxyacetic acid, hydrochloride (28-8) as prepared. *H NMR (D2θ): δ 3.33 (d, J=3.9Hz, 4H), 3.51 (t, J=3.9Hz, 4H), 3.75 (s, 3H), 4.62 (s, 2H), 6.51 (d, J=8.6Hz, IH), 6.64 (s, IH), 7.05 (d, J=7.4Hz, 2H), 7.32 (d, J=8.6Hz, IH), 7.75 (d, J= 7.4Hz, 2H).
SCHEME 29
l2, pyridine, 100°C
Figure imgf000211_0001
OH 29-1
Figure imgf000211_0002
22=2
Figure imgf000211_0003
Cl PFfi
'N- N- i-Pr2NEt, CH2CI2
Figure imgf000211_0004
BrCHgCOOBu1, Cs2C03, DMF SCHEME 29 (CONT'D)
COOBu1
Figure imgf000212_0001
HCI (gas)
EtOAc, 0°C
Figure imgf000212_0002
4-Hydroxy-2-methylbenzoic acid (29-2)
Following the procedure described in US 92-852870 920317, 4-hydroxy-2-methylbenzoic acid was prepared from 4- hydroxy-2-methylacetophenone 29-1. ^H NMR (CD3OD): δ 2.52 (s, 3H), 6.64 (m, 2H), 7.84 (d, J=8.4 Hz, IH).
4-[4-( 1 -PiperazinyPpheny laminocarbonyl]-3-methylphenoxyacetic acid, hydrochloride (29-5)
Using a sequence essentially the same as described for compound 14-6. but starting with 4-hydroxy-3-methylbenzoic acid (29-2). 4-[4-(l-piperazinyl)phenylaminocarbonyl]-3- methylphenoxyacetic acid, hydrochloride (29-5) was prepared. ^H NMR (DMSO-D6): δ 2.36 (s, 3H), 3,26 (d, J=7.3Hz, 8H), 3.80 (br s, 4H), 4.73, (s, 2H), 6.81 (dd, J= 2.4, 8.4 Hz, 2H), 6.84 (d, J=2.4Hz, IH), 6.97 (d, J=8.7Hz, 2H), 7.39 (d, J=8.4 Hz, IH), 7.62 (d, J=8.7Hz, 2H), 8.72 (br s, IH), 9.99 (s, IH). SCHEME 30
Figure imgf000213_0001
30-1 2. Na2S204
OH
Boc20 , CHCI3
CF reflux
NH,
30-2
Figure imgf000213_0002
20
SCHEME 30 (CONT'D)
t
Figure imgf000214_0001
NHBoc
Figure imgf000214_0002
2ΩA 30-5
Figure imgf000214_0003
i-Pr2NEt, CH2CI2
Figure imgf000214_0004
SCHEME 30 (CONT'D)
Figure imgf000215_0001
Figure imgf000215_0002
HCI (gas)
Figure imgf000215_0003
30-8
4-0.1 -Dimethylethoxycarbonyl)amino-3-trifluoromethylphenol (30-3) Using a method similar to that described for compound 15-3. starting with 3-trifluorophenol, 4-( 1 , 1 -dimethylethoxycarbony 1)- amino-3-trifluoromethylphenol (30-3) was prepared. *H NMR (CDC13): δ 1.55 (s, 9H), 4.12 (m, 2H), 6.72 (d, IH), 7.12 (m, IH), 7.26 (m, IH). Ethyl 4-( 1,1 -dimethylethoxycarbonyl amino-3-trifluoromethyl- phenoxyacetate (30-5)
To a 200 mL round bottomed flask with a stirring bar and an argon inlet was added 4-( 1,1 -dimethy lethoxycarbonyl)amino-3- trifluorophenol (4.80 g, 17.3 mmol), 18-crown-6 (4.63 g, 17.5 mmol), and THF (69 mL). This mixture was cooled to 0°C in an ice-water bath, then a solution of potassium hexamethyl disilylazide in toluene (34.7 mL, 17.4 mmol) was added followed by ethyl bromoacetate (1.93 mL, 17.4 mmol). This mixture was stirred under argon for 16 h, allowing the cooling bath to expire. This mixture was transferred to a separatory funnel, acidified with 10% aqueous citric acid and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgS04), filyered and concentrated in vacuo. The BOC group was removed as described for 29-9. This material was chromatographed on silica gel to give ethyl 4-( 1 ,1 -dimethy lethoxy-carbonyl amino-3- trifluoromethylphenoxyacetate (30-5) as an oil. *H NMR (CDCI3): δ 1.58 (t, 3H), 3.93 (br s, 2H), 4.27 (q, 2H), 4.56 (s, 2H), 6.69 (d, IH), 6.95 (dd, IH), 7.00 (d, IH).
4-[4-(l-Piperazinyl)phenylcarbonylamino]-3-trifluoromethylphenoxy- acetic acid (30-8)
Using a sequence similar to that described for compound 12-8 but starting with ethyl 4-( 1 , 1 -dimethylethoxycarbonyl amino-3- trifluoromethylphenoxyacetate (30-5). 4-[4-(l -piperazinyl)phenyl- carbonylamino]-3-trifluoromethylphenoxyacetic acid (30-8) was prepared. iH NMR (DMSO-d6): δ 3.25 (s, 4H), 3.50 (s, 4H), 4.84 (s, 2H), 7.09 (d, J=8.0 Hz, 2H), 7.25 (m, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.88 (d, J= 8.0 Hz, 2H), 8.82 (br s, IH), 9.72 (s, IH). SCHEME31
Figure imgf000217_0001
51=1 31-3
Et3N,CH2CI2
SCHEME31 (CONT'D)
Figure imgf000218_0001
31-5
HC! (gas) EtOAc, 0°
Figure imgf000218_0002
Ethyl 4-(4-nitrophenylcarbamate)-3-methylphenoxyacetate (31-1) A solution of ethyl 4-amino-3-methylphenoxyacetate hydrochloride (10-4) (300 mg, 1.22 mmol) in CH2CI2 (30 mL) was placed in a 50 mL flask. To this solution 4-nitrophenyl chloroformate (246 mg, 1.22 mmol) and pyridine (0.22 mL) were added at room temperature. The reaction was stirred at ambient temperature 18 h, then concentrated in vacuo to yield ethyl 4-(4-nitrophenylcarbamate)-3- methylphenoxyacetate (32-1). iH NMR (CDCI3): δ 1.30 (t, j=7.0 Hz, 3H), 2.34 (s, 3H), 4.28 (q, j=7.0 Hz, 2H), 4.59 (s, 2H), 6.70 (dd, j=8.3, 2.0 Hz, IH), 6.7 (d, j=2.0 Hz, IH), 7.40 (d, j=8.3 Hz, IH), 8.05 (d, j=7.0 Hz, IH), 8.28 (d, j=7.0 Hz, 2H).
4-0.1 -Dimethylethoxycarbonyl)-4.4'-bipiperidine (31-3)
A solution of bipiperidine dihydrochloride (Aldrich 31 -2) (25 g, 0.1 mol) in H2O (100 mL) was placed in a 2L round bottomed flask. A solution of 6N NaOH was added dropwise to adjust the pH to 8-9. The solution was diluted with EtOH (1200 mL) and stirred vigorously at ambient temperature. The resulting mixture was treated with a solution of di-t-butyl dicarbonate (24 g, 0.1 1 mol) in EtOH (800 mL). Periodically, 6N NaOH was added to maintain pH 8-9. After stirring at ambient temperature 18 h, the reaction was concentrated in vacuo. The residue was dissolved in 1 :1 ether:H2θ (1000 mL) and the pH adjusted to 12 with 6N NaOH. The aqueous phase was separated and extracted again with ether. The ether phases were combined and washed with brine, 10% citric acid, and H2O. The citric acid and H2O washes were combined and the pH adjusted to 12-13 with 6N NaOH, then extracted in 3 portions with ether (600 mL). The ether extract was washed (brine), dried (Na2Sθ4) and concentrated in vacuo to a clear oil which solidified on standing to yield 4-( 1,1 -dimethylethoxycarbony l)- 4,4'-bipiperidine (31 -3). *H NMR (CDCI3): δ 1.25 (br m, 7H), 1.45 (s, 9H), 1.66 (br d, 4H), 2.60 (dd, 4H), 3.1(d, j=12 Hz, 2H), 4.21(br s, 2H). Ethy 1-4- [(4-( 1 , 1 -dimethy lethoxycarbonyl)-4,4'-bipiperidiny 1- 1 - carbonyl)aminol-3-methylphenoxyacetate (31 -4)
A solution of ethyl 4-(4-nitrophenylcarbamate)-3- methylphenoxyacetate (31- 1). (457 mg, 1.22 mmol), 4-( 1 ,1 -dimethy 1- ethoxycarbonyl)-4,4'-bipiperidine (31-3) 327 mg, 1.22 mmol), and triethylamine (0.34 mL, 2.44 mmol) in CH2CI2 (20 mL). The solution was refluxed 4 h, cooled and diluted with CH2CI2 (10 mL). The reaction was extracted with H2O (15 mL). The CH2CI2 extract was washed (1% NaOH, H2O, 10% KHSO4, brine), dried (Na2Sθ4), filtered, then concentrated in vacuo to an oil. The oil was chromatographed on silica using 50% EtOAc/hexane to obtain ethyl-4- [(4-(l ,l -dimethylethoxycarbonyl)-4,4'-bipiperidinyl-l-carbonyl)amino]- 3-methylphenoxyacetate (31 -4) iH NMR (CDCI3): δ 1.27 (br m, 7H), 1.30 (t, j= 7.0 Hz, 3H), 1.46 (s, 9H), 1.68 (d, j=12 Hz, 2H), 1.75 (d, j=10 Hz, 2H), 2.22 (s, 3H), 2.65 (t, j=12 Hz, 2H), 2.83 (t, j=12 Hz, 2H), 4.08 (d, j=12 Hz, IH), 4.25 (br s, 2H), 4.27 (q, j=7 Hz, 2H), 4.58 (s, 2H), 5.97 (s, IH), 6.70 (dd, j=8.3, 2 Hz, IH), 6.73 (d, j=2 Hz, IH), 7.40 (d, j=8.3 Hz, IH),
4-[(4-(l ,l -Dimethylethoxycarbonyl)-4,4'-bipiperidinyl-l-carbonyP- aminol-3-methylphenoxyacetic acid (31 -5)
In a 25 mL round bottomed flask a solution of ethyl-4-[(4- (1,1 -dimethylethoxycarbonyl)-4,4'-bipiperidiny 1- 1 -carbony l)amino] -3- methylphenoxyacetate (31-4) (100 mg, 0.2 mmol), IM LiOH, (0.6 mL, 0.6 mmol), H2θ (5 mL), THF (5 mL), and MeOH (5 mL) was stirred at ambient temperature 3 h. The reaction was concentrated in vacuo, then dissolved in CHCI3 (20 mL). The CHCI3 extract was washed (IN HCI, H2O, and brine), dried (NaS04), filtered, and concentrated to yield 4- [(4-( 1 ,1 -dimethy lethoxycarbonyl)-4,4'-bipiperidiny I- 1 -carbony l)amino]- 3-methylphenoxyacetic acid (31-5). ^ NMR (CDCI3): δ 1.22 (br m, 6H), 1.46 (s, 9H), 1.6 (br m, 4H), 2.2 (s, 3H), 2.6 (br t, 2H), 2.79 (t, j=l l Hz, 2H), 4.0 (br m, 5H), 4.58 (s, 2H), 6.1 (dd, j=9, 2 Hz, IH), 6.75 (d, j=2 Hz, IH), 7.21 (d, j=9Hz, IH), 8.1 (s, IH). 4-[(4-[4,4']-Bipiperidinyl-l-carbonyl)aminol-3-methylphenoxyacetic acid, hydrochloride (31 -6)
In a 35 mL round bottomed flask 4-[(4-( 1 , 1 -dimethy 1- ethoxycarbonyl)-4,4'-bipiperidinyI-l -carbony l)amino] -3 -methylphen- oxyacetic acid (31-5) (83 mg, 0.17 mmol) was dissolved in CH2CI2 (10 mL) and cooled to 0°. Anhydrous HCI was bubbled through the solution for 5 min. The reaction was stirred at 0° 4 h, then concentrated in vacuo to yield 4-[(4-[4,4']-bipiperidinyl-l-carbonyl)amino]-3- methylphenoxyacetic acid, hydrochloride (31-6). H NMR (DMSO-d6): δ 1.04 (br d, j=l l Hz, 3H), 1.3 (br s, 3H), 1.62 (d, j=12 Hz, 2H), 1.79 (d, j=l 1 Hz, 2H), 2.07 (s, 3H), 2.67 (t, j=12 Hz, 2H), 2.74 (br m, 2H), 4.07 (d, j=12 Hz, 2H), 4.59 (s, 2H), 6.62 (dd, j=9, 2 Hz, IH), 6.70 (d, j=2 Hz, IH), 6.95 (d, j=9 Hz, IH), 7.87 (s, IH), 8.2 (br s, IH), 8.5 (br s, IH).
SCHEME 32
Figure imgf000222_0001
213
32-1 a (n=0) 32-1 b m=1)
Figure imgf000222_0002
32-3a n=0) 32-3bm=1)
TFA, CH2CI2, 0C
•
Figure imgf000222_0003
4-(2-(4-Dimethoxyethoxycarbonyl)-(4,4')-bipiperidinyl- 1 - carbonvPphenol (32-2a)
In a 50 L round bottomed flask a solution of 4-(l ,l- dimethylethoxcarbonyl)-4,4'-bipiperidine (31-3) (400 mg, 1.49 mm), 4- hydroxybenzoic acid (206 mg, 1.49 mm), (32-la). chloro-N,N,N',N'- bis(pentamethyl)formamidinium hexafluorophosphate (537 mg, 1.49 mm) and diisopropylethylamine (0.52 mL, 2.98 mm) in 25 mL DMF was stirred at ambient temperature 48 h. The reaction was concentrated in vacuo, then partitioned between EtOAc and H2θ. The EtOAc extract was washed (H2O, sat'd NaHCθ3, H2O, 10% KHSO4 and brine), dried (Na2Sθ4), filtered and concentrated in vacuo. The resulting oil was chromatographed on silica using 5% MeOH/CHCl3 as eluent to yield 4- (2-(4-dimethoxyethoxycarbonyl)-(4,4')-bipiperidinyl)-l -carbonyl)- phenol (32-2a). *H NMR (CDCI3): δ 1.2 (br m, 6H), 1.4 (s, 9H), 1.58 (br m, 4H), 4.1 (m, 2H), 4.3 (m, IH), 6.83 (d, j=8.5 Hz, 2H), 7.31 (d, j=8.5 Hz, 2H).
4-(2-(4-Dimethoxyethoxycarbonyl)-(4,4')-bipiperidinyl- l -yl-2-oxo- ethv phenol (32-2b) In a manner similar to the preparation of compound 32-2a.
4-(2-(4-dimethoxyethoxycarbonyI)-(4,4')-bipiperidinyl-l -yl-2-oxo- ethyl)-phenol 2=M was prepared. *H NMR (CDCI3): δ 0.89 (m, IH), 1.1 (m, 3H), 1.45 (s, 9H), 1.5 (br m, 6H) 2.49 (t, j=12 Hz, IH), 2.62 (m, 2H), 2.91 (t, j=12 Hz, IH), 3.64 (s, 2H). 3.90 (d, j=12 Hz, IH), 4.1 (m, 2H), 4.68 (d, j=12 Hz, IH), 6.12 (br m, IH), 6.77 (d, j=8 Hz, 2H), 7.07 (d, j=8 Hz, 2H).
t-Butyl-4-(2-(4-Dimethoxyethoxycarbonyl)-(4,4')-bipiperidinyl-l - carbonv phenoxyacetate (32-3a) In a 50 mL round bottomed flask a mixture of 4-(2-(4- dimethoxyethoxy carbony l)-(4,4')-bipiperidiny 1-1 -carbony l)-phenol (32- 2a) (378 mg, 0.97 mm), t-butyl bromoacetate (0.16 mL, 1.067 mm) and cesium carbonate (348 mg, 1.067 mm) in 50 mL DMF was stirred at ambient temperature 18 h. The reaction was concentrated in vacua, then partitioned between CHCI3 and H2O. The CHCI3 extract was washed (10% KHSO4, H2θ, NaHCθ3 and brine), dried (Na2S04), filtered and concentrated in vacuo to yield t-butyl-4-(2-(4-dimethoxy- ethoxycarbonyl)-(4,4')-bipiperidiny I- 1 -carbonyl)-phenoxyacetate (32- la}. iH NMR (CDCI3): δ 1.2 (m, 6H), 1.42 (s, 9H), 1.45 (s, 9H), 2.68 (m, 4H), 2.61 (t, 2H), 2.8 (m, 2H), 4.18 (m, 4H), 4.5 (s, 2H), 6.9 (d, j=8 Hz, 2H), 7.35 (d, j=8 Hz, 2H).
t-Butyl-4-(2-(4-dimethoxyethoxycarbonyl)-(4,4')-biρiperidinyl-l-yl- 2-oxo-ethyl)phenoxyacetate (32-3b)
In a manner similar to the preparation of 32-3a. t-butyl-4- (2-(4-dimethoxyethoxycarbonyl)-(4,4')-bipiperidinyl-l-yl-2-oxo-ethyl)- phenoxyacetate (32-3b) was prepared. lH NMR (CDCI3): δ 0.88 (m, IH), 1.11 (m, 5H), 1.45 (s, 9H) 1.48 (s, 9H), 1.61 (m, 4H), 2.48 (t, j=12Hz, IH), 2.61 (br t, 2H), 2.88 (t, j=13 Hz, IH), 3.66 (s, 2H), 3.88 (d, j=13 Hz, IH) 4.1 (m, 2H), 4.49 (s, 2H), 4.68 (d, j=13 Hz, IH), 6.84 (d, j=8.8 Hz, 2H), 7.15 (d, j=8.8 Hz, 2H).
r4-(r4.4'-1-Bipiperidinyl-l -carbonvPphenoxylacetic acid (32-4a) In a round bottomed flask, t-butyI-4-(2-(4-dimethoxy- ethoxycarbonyl)-(4,4')-bipiperidinyl-l-carbonyl)-ρhenoxyacetate (32-3a) (56 mg, 0.11 mm) was stirred with trifluoracetic acid (2.5 mL) and CH2CI2 (5 mL) at 0° 18 h. The reaction was concentrated in vacuo to yield [4-([4,4'-]-bipiperidinyl-l-carbonyl)phenoxy] -acetic acid (35- 4a). iH NMR (DMSO-d6) δ 1.11 (m, 2H), 1.32 (m, 4H), 1.78 (m, 2H), 1.80 (d, j=12 Hz, 2H), 2.81 (dd, j=l 1 Hz, 4H), 3.28 (d, j=l 1 Hz, 2H), 4.73 (s, 2H), 6.94 (d, j=8.5 Hz, 2H), 7.32, J=8.5, 2H), 8.16 (br s, IH), 8.47 (br s, IH).
[4-(2-[4,4']-Bipiperidinyl- 1 -yl-2-oxo-ethyl)phenoxy]acetic acid
(32-4b)
In a manner similar to the preparation of (32-4a). 4-(2- [4,4']-bipiperidinyl-l -yl-2-oxo-ethyl)-phenoxy]-acetic acid (32-4b) was prepared. *H NMR (CDCI3): δ 0.81 (m, IH), 1.07 (m, IH), 1.36 (br s, 2H), 1.62(d,j=13Hz, IH), 1.74 (d, j=12 Hz, IH), 1.87 (br s, 2H), 2.56 (t, j=l 1 Hz, IH), 2.94 (m, 3H), 3.36 (d, j=12 Hz, 2H), 3.70 (m, 3H), 4.0 (d, j=13 Hz, IH), 4.57 (d, j=13 Hz, IH), 4.64 (s, 2H), 6.89 (d, j=8.5 Hz, 2H),7.17(d,j=8.5Hz, 2H).
SCHEME 33
Figure imgf000226_0001
33-1
o-o- C02H
33-2
Figure imgf000226_0002
SCHEME 33 (CONT'D)
Figure imgf000227_0001
COoEt
Figure imgf000227_0002
23=1
Ethyl 4-pyridylpiperidin-4-ylcarboxylate (33-1)
Ethyl isonipecotate (6.0 g 38.66 mmol), 4-chloropyridine hydrochloride (5.9 g, 38.66 mmol) and N-methylmoφholine (9.3 g mL, 85.00 mmol), were dissolved in N-methylpyrrolidine (50 mL) and the resulting solution was heated at 100°C for 48 h. The solution was concentrated in vacuo and the residue was dissolved in EtOAc and washed with water and brine (2 x 100 mL), then dried (Na2Sθ4) and evaporated. The resulting residue was purified by flash chromatography (5% MeOH/CHCl3) to afford 33-1 as a crystalline solid. iH NMR (CDCI3) δ 8.21 (d, J=6.8 Hz, 2H), 6.78 (d, J=6.8 Hz, 2H), 4.18 (q, J=7.0 Hz, 2H), 3.85 (m, 2H), 3.10 (m, 2H), 2.61 (m, IH), 2.05 (m, 2H), 1.85 (m, 2H), 1.23 (t, J=7.0 Hz, 3H).
Figure imgf000228_0001
233 4-Pyridylρiperidin-4-ylcarboxylic acid (33-2)
A solution of 33J, (10 g, 42.7 mmol) in THF (50 mL) was treated with IN LiOH (47 mL, 47.0 mmol) and water (50 mL). The resulting solution was stirred at ambient temperature for 12 h. The solution was concentrated and the aqueous residue was cooled to 0°C, then adjusted to pH = 6 with IN HCI. The resulting solid was collected by filtration and dried in vacuo to afford 33-2 as a white solid. H NMR (D2θ) δ 7.95 (d, J=6.8 Hz, 2H0, 6.73 (d, J=6.8 Hz, 2h), 3.76 (d, J=12.8 Hz, 2H0, 2.81 (m, 2H), 2.20 (m, IH), 1.85 (d, J=12.9 Hz, 2H), 1.55 (m, 2H).
Figure imgf000228_0002
233 Ethyl 4-(Pyridyl)(piperidin-4-yl)-carbonylamino-3-methylphenoxy- acetate (33-3)
Ethyl 4-amino-3-methylphenoxyacetate hydrochloride (10-4) (0.35 g, 1.41 mmol), 4-(PyridyI)(piperidin-4-yl)-carboxylic acid (0.30 g, 1.41 mmol), chloro-N, N, N, N'-bis(pentamethylene)form- amidinium hexafluorophosphate (0.50 g, 1.41 mmol), and diisopropylethylamine (0.25 mL, 1.41 mmol) were dissolved in dimethylformamide (15 mL). The solution was stirred at ambient temperature for 48 h and the solvent removed in vacuo to give an oil. This material was chromatographed on silica gel using 5:95 methanol- ammonia saturated chloroform as eluant to afford 33-3 as a beige solid. iH NMR (CDC13): δ 8.27 (d, j=5.6 Hz, 2H), 7.53 (d, j=8.8 Hz, IH), 7.03 (s, IH), 6.78 (s, IH), 6.73 (d, j=8.8 Hz, IH) k, 6.68 (d, j=6.1 Hz, 2H), 4.59 (s, 2H), 4.27 (q, j=7.1 Hz, 2H), 3.97 (d, j=13.2 Hz, 2H), 2.95 (t, j=l 1.7 Hz, 2H), 2.53 (m, IH), 2.06 (d, j=10.7 Hz, 2H), 1.92 (m, 2H), 1.73 (s, 3H), 1.30 (t, j=7.1 Hz, 3H).
Figure imgf000229_0001
33-4
4-(Pyridyl)(piperidin-4-yl)-carbonylamino-3-methylphenoxyacetate
(33-4)
A solution of Ethyl 4-(Pyridyl)(piperidin-4-yl)-carbonyl- amino-3-methyIphenoxyacetate (33-3) (0.05 g, 0.126 mmol) in tetrahydrofuran (10 mL) was treated with 1 N lithium hydroxide (0.13 mL, 0.132 mmol) and H2θ (10 mL). The resulting solution was stirred at ambient temperature and the solvent removed in vacuo to give 33-4 as a colorless glass. *H NMR (CD3OD) δ 8.09 (d, j=6.6 Hz, 2H), 7.09 (d, j=8.6 Hz, 2H), 6.87 (d, 6.8 Hz, IH), 6.81 (s, IH), 6.75 (d, j=8.6 Hz, IH), 4.34 (s, 2H), 4.10 (d, j=13.2 Hz, 2H), 3.02 (t, 10.0 Hz, 2H), 2.82 (m, IH), 2.18 (s, 3H), 1.98 (d, J=10.3 Hz, 2H), 1.83 (m, 2H).
SCHEME 34
Br COOEt
l 1/2 eq Cs2C03 DMF
Figure imgf000230_0001
Figure imgf000230_0002
SCHEME 34 (CONT'D)
Figure imgf000231_0001
Figure imgf000231_0002
Figure imgf000231_0003
Figure imgf000231_0004
Figure imgf000231_0005
3-Chloro-4-aminophenol (34-2)
Using a procedure similar to that described for compound 12-2 but starting with 3-chlorophenol (34-1). 3-chloro-4-aminophenol (34-2) was prepared. *H NMR (CDC13): δ 6.57 (dd, J= 2.8, 8.6 Hz, IH), 6.73 (m, 2H).
4-( 1.1 -Dimethylethoxycarbonyl)amino-3-chlorophenol (34-3)
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(l ,l -dimethylethoxycarbonyl)amino-3- chlorophenol (1.91 g, 13.3 mmol), di-tert-butyldicarbonate (3.14 g, 14.4 mmol) and THF (50 mL). To this mixture was added triethylamine (2.23 mL, 16.0 mmol) and the mixture was stirred at room temperature for 98 h. The solvent was removed in vacuo. The residue was acidified with 10% aqueous citric acid and extracted with EtOAc. The EtOAc extract was washed with water and brine. Drying (MgS04), filtration, removal of the solvent in vacuo and chromatography on silica gel using EtOAc-hexane as eluant gave an oil. This material was dissolved in THF (25 mL) and MeOH (8 mL) and IN LiOH (25 mL) were added. This solution was stirred at ambient temperature 4 h. This mixture was acidified with 10% citric acid and extracted with EtOAc. The organic layer was dried (MgS04), filtered and concentrated in vacuo to give 34-3 as an oil. H NMR (CDCI3): δ 1.53 (s, 9H), 6.69 (dd, J= 2.8, 8.9 Hz, 2H), 6.85 (d, J= 2.8 Hz, IH), 7.80 (d, J= 8.9 Hz, IH).
Ethyl 4-(l , 1 -dimethylethoxycarbonyl)amino-3-chlorophenoxyacetate
(34-4)
To a 50 mL round bottomed flask with a stirring bar and an argon inlet was added 4-( 1,1 -dimethy lethoxy carbony l)amino-3- chlorophenol (0.831 g, 3.41 mmol) and DMF (16 mL). This mixture was cooled in an ice bath then C 2CO3 (0.552 g, 1.69 mmol) and ethyl bromoacetate (0.37 mL, 3.34 mmol) were added. The resulting mixture was stirred for 6 h, during which time the cooling bath was allowed to expire. The mixture was filtered through a frit and the DMF was removed in vacuo. The residue was dissolved in EtOAc and washed with water (12X) and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave an oil which was purified by silica gel chromatography (EtOAc-hexane) to give ethyl 4-(l ,l-dimethyl- ethoxycarbonyl)amino-3 -chlorophenoxy acetate (34_ ) as an oil. ^H NMR (CDC13): δ 1.30 (m, 3H), 1.53 (s, 9H), 4.27 (m, 2H), 4.57 (s, 2H), 6.78 (br s, IH), 6.83 (dd, J= 2.8, 8.8 Hz, IH), 6.96 (d, J=2.8 Hz, IH), 8.02 (br d, J= 8.8 Hz, IH).
4-[4-(l-Piperazinyl)phenylcarbonyiamino]-3-chlorophenoxyacetic acid (34-8)
Using a sequence similar to that described for compound 12-8. but starting with ethyl 4-( 1 ,1 -dimethy lethoxycarbonyl)amino-3- chlorophenoxyacetate (34-4). 4-[4-(l-piperazinyl)phenylcarbonyl- amino] -3 -chlorophenoxy acetic acid was prepared. H NMR (DMSO-d6,
HCI salt): δ 3.22 (t, J= 5.0 Hz, 4H), 3.53 (t, J= 5.0 Hz, 4H), 4.75 (s,
2H), 6.94 (dd, J= 2.9, 8.8 Hz, IH), 7.08 (d, J= 8.9 Hz, 2H), 7.11 (d,
J=2.9 Hz, IH), 7.40 (d, J=8.8 Hz, IH), 7.91 (d, J= 8.9 Hz, 2H), 9.12 (br s, lH), 9.69 (s, IH).
SCHEME 35
Figure imgf000234_0001
1 -5
Figure imgf000234_0002
23=1
Figure imgf000234_0003
35-2
O COOEt
BrCH2COOEt
Cs2C03 / DMF
Figure imgf000234_0004
SCHEME 35 (CONT'D)
23A
Ph3P/CBr4 CH2CI2/0°C
Figure imgf000235_0001
25=1 SCHEME 35 (CONT'D)
Figure imgf000236_0001
35-9
1 -Hydroxymethy l-4-(4-( 1 , 1 -dimethylethoxycarbonyl )piperaziny 1)- benzene (35- 1 )
To an oven dried 500 mL round bottomed flask with a stirring bar and an argon inlet was added acid lι5 (5.00 g, 16.32 mmol) and distilled, dry, THF (80 mL). This solution was cooled in an ice bath and borane»THF complex (125 mL of a IM solution in THF, 125 mmol) was added with a syringe. The resulting solution was maintained at 0°C for 3.5 h. The reaction was quenched by addition of MeOH (50 mL), slowly, with a syringe over 5 min. This mixture was stirred at ambient temperature for 18 h. The solvents were removed in vacuo and the residue was dissolved in EtOAc (300 mL). This solution was washed with saturated aqueous NaHC03 and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave 4.86 g of 1 -hydroxymethy 1-4- (4-( 1 , 1 -dimethy lethoxycarbonyPpiperazinyPbenzene, 35- 1. as a white solid. iH NMR (CDCI3): δ 1.48 (s, 9H), 3.11 (m, 4H), 3.59 (m, 4H), 4.61 (s, 2H), 6.91 (d, J=7 Hz, 2H), 7.27 (d, J=7 Hz, 2H).
4-(4-( 1.1 -Dimethylethox vcarbonvPpiperazinvPbenzaldehvde (35-2) To a 50 mL round bottomed flask with a stirring bar and an argon inlet was added 1 -hydroxymethyl-4-(4-( 1,1 -dimethy lethoxy- carbonyl)piperazinyl)benzene, 35-1 (2.15 g, 7.35 mmol), CHCI3 (100 mL), and Mnθ2 (12.0 g, 138 mmol). This mixture was stirred at ambient temperature for 24 h. The salts were removed by filtration and the solvent was removed in vacuo. The residue was chromatographed on 90 g of silica gel using 30/70 EtOAc-hexane as eluant. There was obtained 4-(4-(l , 1 -dimethy lethoxycarbonyl)piperazinyl)benzaldehyde 35-2 (2.10 g, 99%) as a crystalline solid. *H NMR (CDCI3): δ 1.49 (s, 9H), 3.39 (m, 4H), 3.59 (m, 4H), 6.89 (d, J=9 Hz, 2H), 7.75 (d, J=9 Hz, 2H), 9.79 (s, IH).
Ethyl 2-(4-hydroxymethylphenoxy)acetate (35-4)
To a 500 mL round bottomed flask with a stirring bar and an argon inlet was added 4-hydroxybenzyl alcohol (7.50 g, 60.42 mmol), CS2CO3 (29.53 g, 90.63 mmol), DMF (100 mL), and ethyl bromoacetate (1 1.09 g, 66.46 mmol). This mixture was stirred at ambient temperature for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and water. The layers were separated and the organic phase was washed with two additional portions of water. Drying (MgSθ4), filtration and removal of the solvent in vacuo, gave an oil. This material was chromatographed on 250 g of silica gel using 1 : 1 EtOAc-hexane as eluant. There was obtained ethyl 2-(4-hydroxymethyl-phenoxy)acetate 35-4 (7.47 g, 59%) as an oil. *H NMR (CDCI3): δ 1.29 (t, J=7 Hz, 3H), 2.07 (br s, IH), 4.26 (q, J=7 Hz, 2H), 4.58 (s, 2H), 4.60 (s, 2H), 6.88 (d, J=9 Hz, 2H), 7.27 (d, J=9 Hz, 2H). Ethyl 2-(4-bromomethylphenoxy)acetate (35-5)
To a 1L round bottomed flask with a stirring bar, addition funnel and an argon inlet was added ethyl 2-(4-hydroxymethyl- phenoxy)acetate 35 (7.47 g, 35.53 mmol), CBr4 (13.26 g, 39.97 mmol) and dry CH2CI2 (300 mL). This solution was cooled in an ice bath and and a solution of triphenyl phosphine (10.48 g, 39.97 mmol) in CH2CI2 (100 mL) was added dropwise over 1 h. The ice bath was allowed to expire and and the mixture was stirred at ambient temperature 18 h. The solvent was removed in vacuo and the residue was chromatographed directly on 200 g of silica gel useing 15% EtOAc- hexane as eluant. There was obtained ethyl 2-(4-bromomethyl- phenoxy)acetate 35-5 (7.2 g, 74%) as a low melting solid, mp.: 44- 45°C. *H NMR (CDCI3): δ 1.29 (t, J=7 Hz, 3H), 4.26 (q, J=7 Hz, 2H), 4.48 (s, 2H), 4.61 (s, 2H), 6.86 (d, J=9 Hz, 2H), 7.32 (d, J=9 HZ, 2H).
4-(Ethoxycarbonylmethoxy)benzyltriphenylphosphonium bromide (35-6)
To a 100 mL round bottomed flask with a stirring bar and a reflux condenser topped with an argon inlet was added ethyl 2-(4- bromomethylphenoxy)acetate 35-5 (2.73 g, 10 mmol), triphenyl- phosphine (2.62 g, 10 mmol) and dry benzene (50 mL). This solution was warmed to 50°C for 20 h. The mixture was cooled to room temperature and the product was collected by filtration. The white solid was washed with a little benzene and dried in vacuo to give 4-(ethoxy- carbonylmethoxy)benzyltriphenyl-phosphonium bromide 35-6 as a white, crystalline solid (4.79 g, 89%). H NMR (CDCI3): δ 1.28 (t, J=7 Hz, 3H), 4.27 (q, J=7 Hz, 2H), 4.53 (s, 2H), 5.38 (d, J=14 Hz, 2H), 6.66 (d, J=9 Hz, 2H), 7.06 (d, J=9 Hz, 2H), 7. 62 (m, 6H), 7.76 (m, 9H).
(E) Ethyl 4-(2-(4-(4-( 1, 1 -dimethylethoxycarbony PpiperazinyP ethenyPphenoxyacetate (35-7)
To an oven dried 100 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(ethoxy carbony 1- methoxy)benzyltriphenyl-phosphonium bromide ( 1.106 g, 2.07 mmol) and dry THF (50 mL). To this well stirred mixture was added a solution of lithium hexamethyldisilylazide (2.20 mL of a IM solution in THF). The deep red-solution was stirred 1 h at ambient temperature then cooled in an ice bath to 0°C. To this mixture was added a solution of 4-(4-(l ,l-dimethylethoxycarbonyl)piperazinyl)benzaldehyde (0.60 g, 2.07 mmol) in 10 mL of THF. The ice bath was removed and the solution was stirred at ambient temperature for 3 h. The reaction mixture was diluted with EtOAc and washed with water and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave 1 g of an oil. This material was chromatographed on 80 g of silica gel using 25% EtOAc-hexane as eluant. There was obtained (E)-ethyl 4-(2- (4-(4-( 1 , 1 -dimethylethoxycarbonyPpiperazinyPpheny 1)- ethenyPphenoxyacetate 35-7 as an oil. H NMR (CDCI3): δ 1.26 (t, j=7 Hz, 3H), 1.49 (s, 9H), 3.16 (m, 4H), 3.57 (m, 4H), 4.27 (q, j=7 Hz, 2H), 4.60 (s, 2H), 6.90 (m, 6H), 7.40 (m, 4H), and 175 mg of a mixture of E,Z isomers.
4-(2-(4-(l-PiperazinyPphenyl)ethyl)phenoxyacetic acid (35-8)
To a 25 mL round bottomed flask with a stirring bar and a balloon hydrogenation adaptor was added (E,Z) ethyl 4-(2-(4-(4-(l,l - dimethylethoxycarbonyl)piperazinyl)phenyl)ethenyl)phenoxyacetate (175 mg, 0.36 mmol), absolute EtOH (10 mL) and 10% Pd-C. This mixture was hydrogenated at 1 atmosphere at ambient temperature for 18 h. The cataylst was removed by filtration and the filtrate was concentrated in vacuo. The residue was chromatographed on 40 g of silica gel using 20% EtOAc-hexane as eluant. The purified hydrogenation product was hydrolyzed in THF (2 mL) with IN NaOH (1 mL) for 3 h at ambient temperature. The reaction mixture was diluted with EtOAc and washed with 10% aqueous citric acid, water, and brine. Drying (MgS04), filtration and removel of the solvent in vacuo gave the corresponding acid as a white solid. This material was dissolved in EtOAc (20 mL) and cooled to 0°C in an ice bath. The solution was saturated with dry HCI gas for 15 min. The resulting suspension was aged 30 min at 0°C, then the solvent and excess HCI were removed in vacuo. The solid product was triturated with fresh EtOAC and collected on a frit. After drying at 60°C/0.05 torr there was obtained 103 mg- of 4-(2-(4-(l-piperazinyl)phenyl)ethyl)phenoxy- acetic acid 213 as the hydrochloride salt, mp > 250°C. lH NMR (DMSO-D6): δ 2.76 (s, 4H), 3.20 (m, 4H), 3.33 (m, 4H), 4.61 (s, 2H), 6.80 (d, J=8 Hz, 2H), 6.90 (d, J=8 Hz, 2H), 7.12 (m, 4H), 9.21 (br s, 2H).
(E) 4-(2-(4-(l -PiperazinyPpheny PethenyPphenoxyacetic acid (35-9) To a 25 mL round bottomed flask with a stirring bar and an argon inlet was added (E) ethyl 4-(2-(4-(4-(l ,l-dimethylethoxy- carbonyl)piperazinyl)phenyl)ethenyl)phenoxyacetate (57 mg, 0.12 mmol), THF (2.0 mL) and IN NaOH (1.00 mL). This mixture was stirred at ambient temperature 18 h. The reaction was neutralized with IN HCI (1.00 mL) and extracted with several portions of EtOAc. The combined EtOAc extracts were washed with water and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave 45 mg of a solid. This solid was dissolved in 4N HCI- 1,4-dioxane. The mixture was stirred 18 h at ambient temperature. The milky suspension was concentrated in vacuo. The crude product was triturated with a little EtOAc and collected on a frit. This material was dried in vacuo to provide 24 mg of (E) 4-(2-(4-(l-piperazinyl)phenyl)ethenyl)phenoxy- acetic acid 35-9 as the hydrochloride salt, mp > 250°C. *H NMR (DMSO-D6): δ 3.2 (m, 4H), 3.45 (m, 4H), 4.69 (s, 2H), 6.89 (d, J=9 Hz, 2H), 6.98 (d, J=9 Hz, 2H), 7.02 (s, 2H), 7.48 (m, 4H), 9.15 (br s, 2H), 13.02 (br s, IH). SCHEME 36
Figure imgf000241_0001
Figure imgf000241_0002
2. BOC20, Et3N, CH2CI2 ^^
SCHEME 36 (CONT'D)
dine,
Figure imgf000242_0001
Figure imgf000242_0002
23=1
Figure imgf000242_0003
36-8
Figure imgf000243_0001
5
5-Nitrothiophene-2-carboxylic acid (36-2)
To a 500 mL round bottomed flask with a stirring bar, was added 5-nitrothiophene-2-carboxaldehyde (7.86 g, 50.00 mmol) in CH- 3CN (50 mL), NaH2Pθ4 (1.86 g, 13.50 mmol) in water (20 mL), and 30% H2O2 (aq) (6 mL). To this mixture, cooled in an ice bath, was added NaClθ2 (8 g, 70.80 mmol) in water (70 mL) dropwise over a period of an hour. The reaction was stirred at room temperature for 5 hours. It was worked up by addition of Na2S03 (500 mg), acidified with IM HCI, and then extracted with ethyl acetate (3X). The combined organic layers were washed with water (IX), and brine (IX). Drying (MgS04), filtration and removal of the solvents in vacuo yielded 5- Nitrothiophene-2-carboxylic acid as a yellow powder. iH NMR (300 MHz, CDCI3) δ 7.91(d, J= 4.4 Hz, IH), 7.80(d, J= 4.4 Hz, IH)
Figure imgf000243_0002
233
Methyl 5-nitrothiophene-2-carboxylate (36-3)
To a 500 mL round bottomed flask with a stirring bar, was added 5-nitrothiophene-2-carboxylic acid (4.62 g, 26.68 mmol) and MeOH (100 mL). This solution was cooled in an ice bath and dry HCI gas was bubbled through the solution till saturated. The reaction was equipped with a condensor and a drying tube and refluxed overnight. The solvent was then removed in vacuo to a yellow solid, which was then dissolved in EtOAc. This solution was washed with NaHC03 (sat, aq) (3X), and brine (2X), dried (MgSθ4), and filtered. Removal of the solvents in vacuo and drying of the product in vacuo yielded methyl 5- nitrothiophene-2-carboxylate as a tan solid. iH NMR (300 MHz, CDCI3) δ 7.88(d, J= 4.4 Hz, IH), 7.70(d, J= 4.4 Hz, IH), 3.96(s, 3H)
Figure imgf000244_0001
Methyl 5-aminothiophene-2-carboxylate (36-4)
To a Parr flask was added methyl 5-nitrothiophene-2- carboxylate (5.00 g, 26.71 mmol) and MeOH (100 mL). The solution was purged with a stream of Ar, and 5% platinum on sulfide carbon
(2.00 g) was added. The mixture was hydrogenated on a Parr apparatus set at 50 psi for 6.5 hours. The reaction was then filtered through celite and the solvents removed in vacuo to yield methyl 5-aminothiophene-2- carboxylate as an olive green oil. iH NMR (300 MHz, CDCI3) δ 7.45(d, J= 4.0 Hz, IH), 6.09(d, J= 4.0
Hz, IH), 4.31(br s, 2H), 3.81(s, 3H)
Figure imgf000244_0002
36-5
5-(4-( 1 , 1 -DimethylethoxycarbonyP-piperazin- 1 -y l)-thiophene-2- carboxylate. (36-5) To a 500 mL round bottomed flask equipped with a condenser, stirring bar, and argon inlet was added methyl 5- aminothiophene-2-carboxylate (4.27 g, 27.16 mmol), bis(2- chloroethyPamine, hydrochloride (5.82 g, 32.59 mmol) and n-BuOH (90 mL, previously purged with Ar). This solution was reluxed for 7 days under Ar, and the reaction was followed by HPLC. The solvents were then removed in vacuo, and the residue partitioned between EtOAc and NaHC03 (aq). Extracted aqueous with EtOAc (3X), and then washed the combined organics with brine (IX), dried (Na2S04), filtered, and concentrated in vacuo. The residue was azeotroped with toluene (3X), and dried in vacuo overnight.
The dried product was dissolved in CH2CI2 (80 mL), and triethylamine (4.2 mL, 30.13 mmol), di- rf-butylpyrocarbonate (6.53 g, 29.90 mmol), and CH2CI2 (20 mL) were added and the reaction was stirred at room temperature for 2 hours. The reaction was then concentrated in vacuo. This yielded 490 mg of n-butyl 5-(4-(l,l- dimethylethoxycarbony l)-piperazin- 1 -yl)-thiophene-2-carboxy late and 700 mg of 5-(4-( 1 ,1 -dimethylethoxycarbony l)-piperazin- 1 -y 1)- thiophene-2-carboxylate as a mixture of the methyl and n-butyl esters. iH NMR of n-butyl ester (300 MHz, CDCI3) δ 7.55(d, J= 4.4 Hz, IH), 6.06(d, J= 4.4 Hz, IH), 4.24(t, 2H), 3.58(t, 4H), 3.22(t, 4H), 1.69(m, 2H), 1.48(s, 9H), 1.42(m, 2H), 0.95(t, 3H)
Figure imgf000245_0001
36-6
5-(4-( 1 , 1 -DimethylethoxycarbonyP-piperazin- 1 -yl)-thiophene-2- carboxylic acid, (36-6) To a 50 ml round bottomed flask with a stirring bar was added n-butyl 5-(4-( 1,1 -dimethy lethoxycarbonyl)-piperazin-l-yl)- thiophene-2-carboxylate (490 mg, 1.33 mmol) and 4.2 mL of a 2.5M NaOH solution in 3:1 MeOH/H2θ. THF (2 mL) was added to keep the reaction homogeneous. The reaction was stirred at room temperature and followed by HPLC. After 2 days, the reaction was concentrated in vacuo , acidified with 10% citric acid and extracted with EtOAc (3X). The combined organics were washed with water (IX), brine (IX), dried (Na2S04), filtered, and the solvents removed in vacuo. The product was azeotroped with benzene (3X) and dried in vacuo over 2 days to yield 5-(4-( 1 , 1 -dimethylethoxycarbonyl)-piperazin- 1 -y l)-thiophene-2- carboxylic acid as a dark green solid. iH NMR (300 MHz, CD3OD) δ 7.5 l(d, J= 4.4 Hz, IH), 6.19(d, J= 4.4 Hz, IH), 3.57(t, 4H), 3.24(t, 4H), 1.47(s, 9H)
Figure imgf000246_0001
23=1
Ethyl 2-(4-(5-(4-( 1 , 1 -dimethylethoxycarbonyl)-piperazin- 1 -yl)-2- thienylcarbonylamino)-3-methylphenoxy)-acetate (36-7)
To a 100 ml round bottomed flask with a stirring bar and an argon inlet was added 5-(4-(l ,l-dimethylethoxycarbonyl)-piperazin- l-yl)-thiophene-2-carboxylic acid (428 mg, 1.370 mmol), anhydrous CH2CI2 (10 mL), DMF (.05 mL), and distilled oxalyl chloride (.180 mL, 2.06 mmol). It was stirred 1.5 hours at room temperature. The acid chloride was concentrated in vacuo , azeotroped with benzene (3X), and stored under a blanket of Ar.
To another 100 mL round bottomed flask with a stirring bar and an argon inlet was added ethyl 4-amino-3-methylphenoxyacetate hydrochloride, anhydrous pyridine (7 mL), and dimethylaminopyridine (34 mg, 0.278 mmol). Cooled in an ice bath. A solution of the acid chloride in pyridine (3 mL) was added. The ice bath was removed and the reaction was stirred at 80°C overnight. The reaction was concentrated in vacuo , dissolved in EtOAc, washed with aq. KHSO4 (3X), aq. NaHCθ3 (2X), brine (IX), dried (Na2Sθ4), filtered, and the solvents removed in vacuo. This material was chromatographed on silica gel in 18% EtOAc-hexane as eluant yielding ethyl 2-(4-(5-(4-(l,l-dimethylethoxycarbonyl)- piperazin-l-yl)-2-thienylcarbonylamino)-3-methylphenoxy)-acetate. iH NMR (300 MHz, DMSO-d6) δ 9.42(s, IH), 7.67(d, J= 4.3 Hz, IH), 7.13(d, J= 8.8 Hz, IH), 6.83(d, J=2.7 Hz, IH), 6.74(dd, J= 8.8, 2.7 Hz, IH), 6.24(d, J= 4.3 Hz, IH), 4.76(s, 2H), 4.17(q, J= 7.1 , 2H), 3.47(t, 4H), 3.16(t, 4H), 2.15(s, 3H), 1.42(s, 9H), 1.22(t, J= 7.1 Hz, 3H)
Figure imgf000247_0001
2-(4-(5-(4-( 1 , 1 -Dimethylethoxycarbony P-piperazin- 1 -y l)-2- thienylcarbonylamino)-3-methylphenoχy)-acetic acid (36-8)
To a 100 mL round bottomed flask with a stirring bar was added ethyl 2-(4-(5-(4-(l ,1 -dimethy lethoxy carbony l)-piperazin-l -yl)-2- thienylcarbonylamino)-3-methylphenoxy)-acetate (250mg, 0.496 mmol), MeOH (8 mL), and IM NaOH (1 mL). The reaction was stirred overnight at room temperature.
The reaction was concentrated in vacuo, acidified with aq. KHSO4 and extracted with EtOAc (2X). The organic extracts were washed with brine (IX), dried (Na2S04), filtered, and the solvents removed in vacuo. This product was dissolved in CH2CI2 (8 mL)> and trifluoroacetic acid (2 mL) was added. The reaction was stirred for 2 hours at room temperature and then concentrated in vacuo. The residue was subjected to HPLC on a C- 18 reverse-phase column eluting with 100% H20 -50% H2O/CH3CN (with 0.1 % TFA) over 40 minutes. Collection and lyophilization of the appropriate fractions yielded 2-(4- (5-(4-( 1 , 1 -Dimethylethoxycarbony l)-piperazin- 1 -y l)-2- thieny Icarbony lamino)-3-methylphenoxy)-acetic acid as a white fluffy solid. iH NMR (300 MHz, CD3OD) δ 7.62(d, J= 4.1 Hz, IH), 7.16(d, J= 8.5 Hz, IH), 6.86(d, J=2.7 Hz, IH), 6.79(dd, J= 8.5, 2.7 Hz, IH), 6.34(d, J= 4.1 Hz, IH), 4.65(s, 2H), 3.50(m, 4H), 3.40(m, 4H), 2.24(s, 3H)
EXAMPLE 37
Tablet Preparation
Tablets containing 25.0, 50.0, and 100.0 mg., respectively, of the active compound 3-(4-(4-piperazin-l -yIpheny Icarbony lamino)- phenyl)-propanoic acid are prepared as illustrated below:
TABLE FOR DOSES CONTAINING FROM 25-100MG OF THE ACTIVE COMPOUND
Figure imgf000248_0001
All of the active compound, cellulose, and a portion of the com starch are mixed and granulated to 10% com starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet. EXAMPLE 38
Intravenous formulations
An intravenous dosage form of the above-indicated active compound is prepared as follows:
Active Compound 0.5-10.0mg
Sodium Citrate 5-50mg
Citric Acid l-15mg
Sodium Chloride 1 -8mg
Water for Injection (USP) q.s. to 1 L
Utilizing the above quantities, the active compound is dissolved at room temperature in a previously prepared solution of sodium chloride, citric acid, and sodium citrate in Water for Injection (USP, see page 1636 of United States Pharmacopeia/National Formulary for 1995, published by United States Pharmacopeial Convention, Inc., Rockville, Maryland, copyright 1994.
EXAMPLE 39
Intravenous formulation
A pharmaceutical composition was prepared at room temperature using 3-(4-(4-piperazin-l -ylphenylcarbonylamino)phenyl) propanoic acid, a citrate buffer, and sodium chloride, to obtain a concentration of of 0.25 mg/ml.
800 grams of water was introduced into a standard pharmaceutical mixing vessel. 0.25 grams of 4-(N-piperazine)benzoyl- N-(aminophen-4-yl)propionic acid was dissolved in the water. 2.7 grams sodium citrate and 0.16 grams citric acid were added to obtain a finished citrate concentration of 10 mM. 8 grams of sodium chloride was added. 200 grams of water was then added to achieve the desired final concentrations of ingredients. The resulting aqueous formulation had the following concentrations:
Ingredient Amount 3-(4-(4-piperazin- 1 -ylphenylcarbonylamino)phenyl) propanoic acid 0.25 mg/ml
citrate buffer 10 mM
sodium chloride 8 mg/ml
The finished concentrated formulation is stored in a standard USP Type I borosilicate glass container at 30-40 degrees C. Prior to compound administration, the concentrated formulation is diluted in a 4:1 ratio resulting in a finished concentration of 0.05 mg/ml and transfered to an infusion bag.
Therapeutic Treatment
Compounds of the invention may be administered to patients where inhibition of human or mammalian platelet aggregation or adhesion is desired.
Compounds of the invention are useful in inhibiting platelet aggregation and thus, they may find utility in surgery on peripheral arteries (arterial grafts, carotid endaterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interation of platelets with artificial surfaces, leads to platelet aggregation and consumption. The aggregated platelets may form thrombi and thromboemboli. Compounds of the invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.

Claims

WHAT IS CLAIMED IS:
1. A-compound of the formula
X-Y-Z-A-B
and pharmaceutically acceptable salts,
wherein
X is a 5, 6 or 7 membered aromatic or nonaromatic ring, having 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on the carbon and nitrogen atoms with Rl , or disubstituted on the carbon and nitrogen atoms with Rl and R2, where R and R^ are independently selected from the group consisting of hydrogen, halogen, Cl-10 alkyl,
C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl,
Cl-3 acylamino, Ci -3 acylamino Cl-8 alkyl, Cl-6 alkylamino Cl-8 alkyl, Cl-6 alkylamino, Cl -6 dialkylamino Cl-8 alkyl,
Cl -6 alkoxy, Cl-6 alkoxy Cl -6 alkyl, aryl Cl -6 alkyloxy, aryl Cl-6 alkyloxy Cl -6 alkyl, carboxy, carboxy Cl-6 alkyl, Cl-3 alkoxycarbonyl, Cl-3 alkoxycarbonyl Cl-6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl-6 alkyl, or
a 9 or 10 membered fused aromatic or nonaromatic ring, having 1, 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on the carbon and nitrogen atoms with Rl, or disubstituted on the carbon and nitrogen atoms with Rl and R^, where R* and R^ are independently selected from the group consisting of hydrogen, halogen,
Cl -10 alkyl,
C3-8 cycloalkyl, aryl, aryl Cl -8 alkyl, amino, amino Cl-8 alkyl,
Cl-3 acylamino,
Cl-3 acylamino Cl-8 alkyl, Cl-6 alkylamino Cl-8 alkyl,
Cl-6 alkylamino,
Cl-6 dialkylamino Cl-8 alkyl,
Cl-6 alkoxy,
Cl-6 alkoxy Cl-6 alkyl, aryl Cl -6 alkyloxy, aryl Cl-6 alkyloxy Cl -6 alkyl, carboxy, carboxy Cl-6 alkyl,
C l-3 alkoxycarbonyl, Cl-3 alkoxycarbonyl Cl-6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl-6 alkyl;
Y is a 5 or 6 membered aromatic ring or non-aromatic ring, having 0, 1, 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or substituted on the carbons and nitrogens with R3 selected from the group consisting of hydrogen, halogen,
Cl-10 alkyl,
C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl,
Cl-3 acylamino, Cl -3 acylamino C 1 -8 alkyl,
Cl -6 alkylamino,
Cl-6 alkylamino Cl-8 alkyl,
C l -6 dialkylamino,
Cl-6 dialkylamino Cl-8 alkyl, Cl-6 alkoxy,
Cl-6 alkoxy Cl-6 alkyl, aryl Cl-6 alkyloxy, aryl Cl-6 alkyloxy Cl-6 alkyl, carboxy, carboxy Cl-6 alkyl,
Cl-3 alkoxycarbonyl,
Cl-3 alkoxycarbonyl Cl-6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl-6 alkyl;
X and Y combined together form the structures
Figure imgf000254_0001
Z is
O R4 ii r
-C-N-
R40
N-C —
"CH2CH2
-CH=CH—
CH2-0—
-O— CH2 -
Figure imgf000255_0001
■CH2NR
— NR4CH2— >
OH I
CH CH >
OH
I
— CH2-CH — , or
Z represents a bond;
R^ is hydrogen, Cl-4 alkyl, or C3-6 cycloalkyl; A is a 5 or 6 membered aromatic ring, having 0, 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on the carbons or nitrogen with R5, disubstituted with R5 and R6, or trisubstituted with R5, R6 and R7, where R5, R6 and R are independently selected from the group consisting of hydrogen, halogen, Cl -10 alkyl, C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, arylsulfonylamino, amino, amino Cl-8 alkyl, nitro,
Cl -3 acylamino,
Cl-3 acylamino Cl-8 alkyl,
Cl-6 alkylamino,
Cl-3 alkylsulfonylamino, Cl-6 alkylamino Cl - alkyl ,
Cl -6 dialkylamino,
Cl-6 dialkylamino Cl-8 alkyl,
Cl -6 alkoxy,
Ci -6 alkoxy Cl -6 alkyl, trihaloalkyl, aryl Cl-6 alkyloxy, aryl Cl -6 alkyloxy Cl-6 alkyl, carboxy, carboxy Cl-6 alkyl, Ci-3 alkoxycarbonyl,
Cl-3 alkoxycarbonyl Cl-6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl -6 alkyl, or
a 9 or 10 membered fused aromatic ring, having 0, 1 , 2 or 3 heteroatoms selected from N, O, and S, and either unsubstituted or monosubstituted on the carbons or nitrogen with R5, disubstituted with R5 and R6, or trisubstituted with R5, R and R7, where R^, R6 and R? are independently selected from the group consisting of hydrogen, halogen,
Cl - 10 alkyl, C3-8 cycloalkyl, aryl, aryl Cl -8 alkyl, amino, amino Cl -8 alkyl,
Cl-3 acylamino,
Cl -3 acylamino Cl -8 alkyl,
Cl -6 alkylamino,
Cl-6 alkylamino Cl-8 alkyl, Cl -6 dialkylamino,
Cl-6 dialkylamino Cl-8 alkyl,
Cl-6 alkoxy,
Cl -6 alkoxy Cl -6 alkyl, aryl Cl-6 alkyloxy, ary 1 C l -6 alkyloxy C 1 -6 alkyl , carboxy, carboxy Cl-6 alkyl,
Cl-3 alkoxycarbonyl,
Cl-3 alkoxycarbonyl Cl-6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, and hydroxy Cl-6 alkyl;
-0(CH2)mC02R9 ?
*~(CH2)nC02R , or
Figure imgf000257_0001
— OCH(R8)(CH2)pC02Rε wherein m is 1 , 2, or 3, n is 0, 1 , 2, or 3, and p is 0, 1 , 2, or 3;
R8 is selected from the group consisting of hydrogen,
Cl-10 alkyl,
C3-8 cycloalkyl, aryl, aryl Cl-8 alkyl, amino, amino Cl-8 alkyl,
Cl-3 acylamino,
Cl-3 acylamino Cl -8 alkyl,
Cl-6 alkylamino, Cl -6 alkylamino Cl-8 alkyl,
Cl-6 dialkylamino,
Cl -6 dialkylamino Cl-8 alkyl,
Cl-6 alkoxy,
Cl -6 alkoxy Cl -6 alkyl, aryl Cl-6 alkyloxy, aryl Cl-6 alkyloxy Cl-6 alkyl, carboxy, carboxy Cl-6 alkyl,
Cl-3 alkoxycarbonyl, Cl-3 alkoxycarbonyl Cl-6 alkyl, carboxy Cl-6 alkyloxy, hydroxy, hydroxy Cl-6 alkyl; and
R9 IS hydrogen,
Cl-8 alkyl, aryl, aryl Cl-6 alkyl, Cl -8 alkylcarbonyloxy Cl-6 alkyl aryl carbonyloxy Cl-6 alkyl, aryl Cl-6 alkylcarbonyloxy Cl-6 alkyl, Cl-8 alkylaminocarbonyl Cl-6 alkyl, or Cl-8 dialkylamino carbony 1 Cl-6 alkyl.
2. A compound of claim 1 having the formula
X-Y-Z-A-B
and pharmaceutically acceptable salts,
wherein
X is a 5, 6 or 7 membered aromatic or nonaromatic ring having 1 , 2 or 3 nitrogen atoms and unsubstituted or substituted with NH2;
Y is a 5 or 6 membered aromatic or nonaromatic ring having 0, 1, 2 or 3 nitrogen atoms and unsubstituted or substituted with Cl_3alkyl;
or X and Y together form the fused ring systems:
Figure imgf000259_0001
Z is
Figure imgf000260_0001
Z represents a bond;
A is a 5 or 6 membered aromatic ring, having 0, 1, 2, or 3 nitrogen atoms and unsubstituted or monosubstituted on the carbons or nitrogen with R^, disubstituted with R^ and R6, same or different, or trisubstituted with R^, R and R7, same or different, wherein R^, R6 and R? are selected from the group consisting of arylsulfonylamino, Cl-3 alkylsulfonylamino, Ci-3 alkyl, -CF3, Ci-3alkyloxy, halogen, nitro,
or A is a 9 membered fused aromatic ring system having 0, 1, 2 or
3 nitrogen atoms,
or
A is isoindolinone or indolinone;
B is -OCH(R8)(CH2)pCθ2R9,
(CH2)nC0 R9, n = 0, 1 , 2, 3, p = 0, 1, 2, 3, wherein-
R8 is hydrogen or Cl-3alkyl and
R9 is hydrogen or -(CH2)l-3C(O)NH(CH2)0-2CH3 or -(CH2)l -3 C(O)N((CH2)0-2CH3)2-
3. A compound of claim 2 having the formula
X-Y-Z-A-B
and pharmaceutically acceptable salts,
wherein
X is a 5 or 6 membered aromatic or nonaromatic ring having 1 or 2 nitrogen atoms and unsubstituted or substituted with
NH2;
Y is a 6 membered aromatic or nonaromatic ring having 0 or 1 nitrogen atoms and unsubstituted or substituted with CH3;
or X and Y form the fused ring systems:
Figure imgf000261_0001
Z is
O O
II II
-CNH— NH- -c- i GH2CH
Figure imgf000262_0001
Z represents a bond;
A is phenyl unsubstituted, monosubstituted with R^, disubstituted with R^ and R6, or trisubstituted with R^, R6, or R7, where R^, R6, or R^ are selected from
-NHSO2C6H5,
-NHSO2CH3
Figure imgf000262_0002
-CH3, -CF3, -OCH3, -Cl, -Nθ2, and
-Br,
or
A is a 9 membered fused aromatic ring system having 1 nitrogen atom,
or
A is isoindolinone or indolinone;
B is -OCH(R8)C02R9, -(CH2)nC02R9 wherein n = 1 or 2
R8 is- hydrogen or Cl-3alkyl and
R9 is hydrogen, -(CH2)l -3C(O)NH(CH2)0-2CH3, or
-(CH2)1 -3 C(O)N((CH2)0-2CH3)2.
4. A compound of claim 3 having the formula
X-Y-Z-A-B
and pharmaceutically acceptable salts,
wherein
X is
Figure imgf000263_0001
Figure imgf000263_0002
Y is
Figure imgf000263_0003
or X and Y form the fused ring systems:
Figure imgf000264_0001
Figure imgf000264_0002
Z is
O O II II CNH- NH— "C , ^CH CH2
o O
II I! •CH=CH— , -C-N— NHC- or
I CH3
Z represents a bond; A is
Figure imgf000265_0001
Figure imgf000265_0002
Figure imgf000265_0003
and
B is
-OCH2C02H,
-OCH2C02CH2C(0)NHCH3,
-0CH2CO2CH2C(0)N(CH2CH3)2,
-OCH2CO2CH2CH3,
-CH2CH2CO2H, -CH2COOH, -OCH(CH3)C02H, or -OCH(CH3)C02CH2CH3.
5. A compound of claim 4 selected from the group consisting of
3-(4-(4-piperazin- 1 -ylphenylcarbonylamino)phenyl) propanoic acid,
2-(4-(4-Piperazinyl- 1 -y l)pheny lcarbonylamino)phenoxy ) acetic acid,
Ethyl 2-(4-(4-(l-piperazinyI)phenylcarbonylamino)phenoxy)acetate, hydrochloride,
2-(5-(4-(l -PiperazinyPpheny Icarbony lamino)indol-l-yl) acetic acid,
3-(3-(4-Piperazin-l -ylphenyl)carbonylamino)phenyl) propanoic acid,
Ethyl 2-(4-(4-(piperazin- 1 -y phenylcarbony lamino) phenoxy)propanoate
2-(4-(4-(Piperazin- 1 -yl)phenylcarbonylamino)phenoxy) propionic acid,
2-(4-(((2-Piperazin-l-yl)pyridin-5-yl)carbonylamino)phenoxy)acetic acid,
3-Methyl-4-((l ,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-7- yl)carbonylaminθ)phenoxyacetic acid, 2-(4-(5-(4-( 1 , 1 -Dimethylethoxycarbony l)-piperazin- 1 -y l)-2- thienylcarbonylamino)-3-methylphenoxy)-acetic acid,
4-(2-( 1 , 1 -dimethylethoxycarbonyl)- 1 ,2,3 ,4-tetrahydro-9H-pyrido[3 ,4- b]benzofuran-7-yl)carbonylamino)-3-methylphenoxy acetic acid,
4-((2,3,4,5-tetrahydropyrazino-[l ,2-a]indole-8-yl)carbonylamino)-3- methylphenoxyacetic acid, and
(+ /-) 4-((3-(l ,l-Dimethylethoxycarbonyl)-l ,la,2,3,4,5-hexahydro- pyrazino-[ 1 ,2-a]indole-8-yl)carbonylamino)-3-methylphenoxyacetic acid,
and pharmaceutically acceptable salts thereof.
6. A compound of Claim 1 for use in inhibiting the binding of fibrinogen to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a mammal.
7. A composition comprising a compound of Claim 1 and a pharmaceutically acceptable carrier.
8. A method for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising treating the mammal with a composition of Claim 7.
9. A method for inhibiting the aggregation of blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising treating the mammal with a composition of Claim 7.
10. A composition for inhibiting the aggregation of blood platelets in a mammal, comprising an efficacious amount of a compound of Claim 1 in combination with one or more agents selected from a thrombolytic agent, an anticoagulant agent, and an antiplatelet agent and a pharmaceutically acceptable carrier.
11. A method for inhibiting the aggregation of blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising treating the mammal with a composition of Claim 10.
12. A method for inhibiting the binding of fibrinogen to blood platelets in a mammal, by blocking fibrinogen from acting at its receptor site, comprising treating the mammal with a composition of Claim 10.
13. A method for inhibiting osteoclast mediated bone resorption, comprising treating the mammal with a composition of Claim 7.
14. A method for inhibiting angiogenesis in a mammal comprising treating the mammal with a composition of Claim 7.
15. A method for inhibiting tumor growth in a mammal comprising treating the mammal with a composition of Claim 7.
16. The use of a compound of Claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the aggregation of blood platelets, preventing platelet thrombosis, preventing thromboembolism or preventing reocclusion, in a mammal.
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Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998054135A1 (en) * 1997-05-30 1998-12-03 Meiji Seika Kaisha, Ltd. Nitrogenous heterocyclic compounds and hyperlipemia remedy containing the same
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US9073931B2 (en) 2012-03-16 2015-07-07 Vitae Pharmaceuticals, Inc. Liver X receptor modulators
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Families Citing this family (5)

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Publication number Priority date Publication date Assignee Title
GB0209715D0 (en) * 2002-04-27 2002-06-05 Astrazeneca Ab Chemical compounds
DE10342570A1 (en) * 2003-09-15 2005-04-14 Bayer Healthcare Ag Process for the preparation of 4- (4-aminophenyl) -3-morpholinone
MX2007014927A (en) * 2005-06-06 2008-02-15 Hoffmann La Roche SULFONAMIDE DERIVATIVES USEFUL AS LIVER CARNITINE PALMITOYL TRANSFERASE (L-CPTl) INHIBITORS.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994022834A1 (en) * 1993-03-29 1994-10-13 Zeneca Limited Heterocyclic derivatives as platelet aggregation inhibitors
EP0659743A1 (en) * 1993-12-27 1995-06-28 Hoechst Aktiengesellschaft Piperidine derivatives as inhibitors of platelet aggregation and their preparation
EP0718287A2 (en) * 1994-12-23 1996-06-26 Dr. Karl Thomae GmbH Piperazine derivatives, medicaments containing them, their use, and processes for their preparation
DE4446301A1 (en) * 1994-12-23 1996-06-27 Thomae Gmbh Dr K Piperazine derivatives, pharmaceutical compositions containing them, their use and processes for their preparation

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08504194A (en) * 1992-12-01 1996-05-07 メルク エンド カンパニー インコーポレーテッド Fibrinogen receptor antagonist
IL116893A (en) * 1995-02-10 2000-02-29 Yamanouchi Pharma Co Ltd Piperazine derivatives and pharmaceutical compositions containing them
JP2000505471A (en) * 1996-02-28 2000-05-09 メルク エンド カンパニー インコーポレーテッド Fibrinogen receptor antagonist
AU719102B2 (en) * 1996-06-28 2000-05-04 Merck & Co., Inc. Fibrinogen receptor antagonist prodrugs
AU709631B2 (en) * 1996-06-28 1999-09-02 Merck & Co., Inc. Fibrinogen receptor antagonist prodrugs

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994022834A1 (en) * 1993-03-29 1994-10-13 Zeneca Limited Heterocyclic derivatives as platelet aggregation inhibitors
EP0659743A1 (en) * 1993-12-27 1995-06-28 Hoechst Aktiengesellschaft Piperidine derivatives as inhibitors of platelet aggregation and their preparation
EP0718287A2 (en) * 1994-12-23 1996-06-26 Dr. Karl Thomae GmbH Piperazine derivatives, medicaments containing them, their use, and processes for their preparation
DE4446301A1 (en) * 1994-12-23 1996-06-27 Thomae Gmbh Dr K Piperazine derivatives, pharmaceutical compositions containing them, their use and processes for their preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0912175A4 *

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Publication number Priority date Publication date Assignee Title
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CN114933538A (en) * 2022-06-27 2022-08-23 八叶草健康产业研究院(厦门)有限公司 Method for producing 2-methyl-4-aminophenol, and method for producing 2-methyl-4- (Boc-amino) -phenol

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CA2258093A1 (en) 1998-01-08
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JP2000514061A (en) 2000-10-24
EP0912175A1 (en) 1999-05-06
AU721130B2 (en) 2000-06-22

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