+

WO1998030541A1 - Inhibiteurs a base d'acide hydroxamique et de cetone a terminaison c permettant de lutter contre les metalloproteinases matricielles et la secretion de fnta - Google Patents

Inhibiteurs a base d'acide hydroxamique et de cetone a terminaison c permettant de lutter contre les metalloproteinases matricielles et la secretion de fnta Download PDF

Info

Publication number
WO1998030541A1
WO1998030541A1 PCT/US1998/000142 US9800142W WO9830541A1 WO 1998030541 A1 WO1998030541 A1 WO 1998030541A1 US 9800142 W US9800142 W US 9800142W WO 9830541 A1 WO9830541 A1 WO 9830541A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbon atoms
alkyl
substituted
halogen
haloalkyl
Prior art date
Application number
PCT/US1998/000142
Other languages
English (en)
Inventor
Steven K. Davidsen
Alan Scott Florjancic
George S. Sheppard
Jamie R. Giesler
Lianhong Xu
Yan Guo
Michael L. Curtin
Michael R. Michaelides
Carol K. Wada
James H. Holms
Original Assignee
Abbott Laboratories
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
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to JP53103098A priority Critical patent/JP2002503216A/ja
Priority to AU59582/98A priority patent/AU5958298A/en
Priority to CA002277105A priority patent/CA2277105A1/fr
Priority to EP98902771A priority patent/EP0964851A1/fr
Publication of WO1998030541A1 publication Critical patent/WO1998030541A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/32—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/24—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
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • TNF ⁇ secretion to pharmaceutical compositions comprising these compounds, and to a medical method of treatment. More particularly, this invention concerns C-terminal ketone compounds which inhibit matrix metalloproteinases and TNF ⁇ secretion, pharmaceutical compositions comprising these compounds and a method of inhibiting matrix metalloproteinases and TNF ⁇ secretion.
  • MMP's matrix metalloproteinases
  • collagenase stromelysin
  • gelatinase a class of extracellular enzymes including collagenase, stromelysin, and gelatinase which are believed to be involved in the tissue destruction which accompanies a large number of disease states varying from arthritis to cancer.
  • Typical connective tissue cells are embedded within an extracellular matrix of high molecular weight proteins and glycoproteins.
  • processes which include cell division, matrix synthesis, and matrix degradation.
  • an imbalance of these three processes can lead to improper tissue restructuring.
  • joint mobility can be lost when there is improper remodelling of load-bearing joint cartilage.
  • lack of coordination of cell division and the two processes of matrix synthesis and degradation can lead to conversion of transformed cells to invasive phenotypes in which increased matrix turnover permits tumor cells to penetrate basement membranes surrounding capillaries leading to subsequent metastasis.
  • TNF ⁇ Tumor Necrosis Factor ⁇
  • TNF ⁇ is originally expressed as a membrane- bound protein of about 26 kD, which is proteolytically cleaved to release a soluble 17 kD fragment (TNF ⁇ processing) which combines with two other secreted TNF ⁇ molecules to form a circulating 51 kD homotrimer.
  • TNF ⁇ processing proteolytically cleaved to release a soluble 17 kD fragment
  • MMP inhibitors were found to inhibit TNF ⁇ processing (see Mohler, et al., Nature, 1994, 370, 218; Gearing, et al., Nature, 1994, 370, 555; and McGeehan, et al., Nature, 1994, 370, 558), leading to the hypothesis that TNF ⁇ processing is caused by an as yet uncharacterized metalloproteinase residing in the plasma membrane of cells producing Tj ⁇ . Inhibitors of this metalloproteinase would therefore be useful as therapeutics to treat disease states involving TNF ⁇ secretion.
  • TGF ⁇ Transforming growth factor alpha
  • EGF epidermal growth factor
  • TGF ⁇ is a potent mitogen which ellicites its biological activity by binding to cell surface receptors, in particular epidermal growth factor (EGF) receptor. It is known to promote angiogenesis and to stimulate epithelial cell migration and therefore has been implicated in a number of malignant disorders such as breast cancer and ovarian carcinoma.
  • EGF ⁇ is produced by proteolytic cleavage of a 160 amino acid membrane bound precursor.
  • the present invention provides a novel class of C-terminal ketone inhibitors of matrix metalloproteinases and/or TNF ⁇ secretion.
  • the present invention provides a macrocyclic compound of formula I
  • W is NHOH or -OH.
  • R 1 and R 4 are independently selected at each occurrence from hydrogen or alkyl of one to four carbon atoms.
  • V is O or NOR 1 .
  • R 2 is selected from the group consisting of
  • alkanoyloxy wherein the alkyl portion is of one to four carbon atoms
  • phenoxy wherein the phenyl ring is unsubstituted or substitued with 1, 2 or 3 substituents independently selected from (8a) alkyl of one to four carbon atoms, (8b)hydroxy, (8c) alkoxy of one to four carbon atoms, (8d) halogen, (8e) haloalkyl of one to four carbon atoms, (8f) cyano, (8g) cyanoalkyl, (8h) -CO2R 7 wherein R 7 is hydrogen or alkyl of one to four carbon atoms, (8i) - CONR7R 8 wherein R 7 is defined above and R 8 is selected from hydrogen, alkyl of one to four carbon atoms, alkanoyl of one to four carbon atoms, phenyl, and phenyl substituted with 1, 2, or 3 substutuents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloal
  • (10) -S O ⁇ 11 wherein n is 0, 1 or 2 and R 11 is selected from (10a) alkyl of one to six carbon atoms, (10b) phenyl, (10c) phenyl substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R 7 , -CONR 7 R 8 , (lOd) thienyl, (10e) thienyl substituted with alkyl of one to four carbon atoms, (lOf) phenylalkyl wherein the alkyl portion is of one to four carbon atoms, (lOg) phenylalkyl wherein the alkyl portion is of one to four carbon atoms, and the phenyl ring is substituted with 1, 2 or 3 substituents independently selected from
  • R 12 is hydrogen or alkyl of one to four carbon atoms and R 13 is selected from (1 la) hydrogen, (l ib) alkyl of one to four carbon atoms, (1 lc) -CO2R 14 wherein R 14 is independently selected at each occurrence from (i) alkyl of one to four carbon atoms, (ii) haloalkyl of one to four carbon atoms, (iii) phenyl, (iv) phenyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, nitro, cyano, cyanoalkyl, -SO2NH2, - CO2R 7 , and -COJNR 7 R 8 , (v) phenylalkyl wherein the alkylene portion is of one to four carbon 5 atoms, (vi)
  • alkanoyloxy wherein the alkyl portion is of one to four carbon atoms, 5 (6) pyridyl,
  • phenoxy wherein the phenyl ring is unsubstituted or substitued with 1, 2 or 3 substituents independently selected from (8a) alkyl of one to four carbon atoms, (8b) hydroxy, (8c) alkoxy of one to four carbon atoms, (8d) halogen, (8e) haloalkyl of one to four carbon atoms, (8f) cyano, 0 (8g) cyanoalkyl, (8h) -CO 2 R 7 , (8i) -CONR 7 R 8 , (8j) phenyl, and (8k) phenyl substituted with 1 , 2, or 3 substutuents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO 2 R 9 , and -CONR ⁇ RlO,
  • R 3 is selected from the group consisting of
  • R 6 is selected from the group consisting of
  • indolyl substituted with (gl) alkyl of one to four carbon atoms, (g2) halogen, (g3) haloalkyl of one to four carbon atoms, (g4) alkoxy of one to four carbon atoms, (g5) -SO2NR 7 R 8 , (g6) -CO2R 7 , (g7) alkylsulfonyl of one to four carbon atoms, and (g8) phenyl, wherein the phenyl ring may be substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, and alkoxy of one to four carbon atoms,
  • the present invention provides pharmaceutical compositions which comprise a therapeutically effective amount of compound of formula I in combination with a pharmaceutically acceptable carrier.
  • the present invention provides a method of inhibiting matrix metalloproteinases and/or TNF ⁇ secretion in a host mammal in need of such treatment comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I.
  • alkyl refers to a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single hydrogen atom.
  • Alkyl groups are exemplified by methyl, ethyl, n- and wo-propyl, n-, sec-, iso- and tert-butyl, and the like.
  • alkylsulfonyl represents an alkyl group, as defined above, attached to the parent molecular group through a SO2 group.
  • alkanoyl represents an alkyl group, as defined above, attached to the parent molecular moiety through a carbonyl group.
  • Alkanoyl groups are exemplified by formyl, acetyl, propionyl, butanoyl and the like.
  • alkoxy and alkoxyl denote an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, butoxy, and the like.
  • alkoxycarbonyl represents an ester group; i.e. an alkoxy group, attached to the parent molecular moiety through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like.
  • alkenyl refers to monovalent straight or branched chain groups of 2 to 6 carbon atoms containing a carbon-carbon double bond, derived from an alkene by the removal of one hydrogen atom and include, but are not limited to groups such as ethenyl, 1-propenyl, 2- propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl and the like.
  • alkylene denotes a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon containing by the removal of two hydrogen atoms, for example -CH2-, -CH2CH2-, -CH(CH3)CH2- and the like.
  • alkenylene denotes a divalent group derived from a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond.
  • alkynylene refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing at least one carbon- carbon triple bond.
  • alkynylene include -CH ⁇ CH-, -CH ⁇ C-CH2-, -CH ⁇ CH- CH(CH 3 )- and the like.
  • cycloalkyl refers to a monovalent saturated cyclic hydrocarbon group.
  • Representative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2. ljheptane and the like.
  • Cycloalkylene denotes a divalent radical derived from a cycloalkane by the removal of two hydrogen atoms.
  • (cycloalkyl)alkyl and "(cycloalkenylene)alkyl” refer, respectively, to a cycloalkyl group or cycloalkenylene group as defined above attached to the parent molecular moiety through an alkylene group.
  • cyanoalkyl denotes an alkyl group, as defined above, substituted by a cyano group and includes, for example, cyanomethyl, cyanoethyl, cyanopropyl and the like.
  • haloalkyl denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.
  • hydroxyalkyl represents an alkyl group, as defined above, substituted by one to three hydroxyl groups with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group.
  • phenoxy refers to a phenyl group attached to the parent molecular moiety through an oxygen atom.
  • salt By pharmaceutically acceptable salt is meant those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art . For example, S. M Berge, et al. describe pharmaceutically acceptable salts in detail in J.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable ahphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • Examples of particular esters includes formates, acetates, propionates, butyates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • Asymmetric centers may exist in the compounds of the present invention.
  • the present invention contemplates the various stereoisomers and mixtures thereof.
  • Individual stereoisomers of compounds of the present invention are made by synthesis from starting materials containing the chiral centers or by preparation of mixtures of enantiomeric products follwed by separation as, for example, by conversion to a mixture of diastereomers followed by separation by recrystallization or chromatographic techniques, or by direct separation of the optical enantiomers on chiral chromatographic columns.
  • Starting compounds of particular stereochemistry are either commercially available or are made by the methods detailed below and resolved by techniques well known in the organic chemical arts.
  • Preferred Embodiments Preferred compounds of the present invention have formula I wherein R ⁇ is defined therein; R 1 and R 4 are hydrogen; R 2 is selected from the group consisting of
  • R 11 is selected from (2a) phenyl, (2b) phenyl substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R 7 , and -CONR 7 R 8 , (2c) thienyl and (2d) thienyl substituted with alkyl of one to four carbon atoms and (3) -NR 12 R 13 wherein R 12 and R 13 are independently selected from hydrogen and alkyl of one to four carbon with the N atoms to which they are attached define a
  • R 3 is selected from the group consisting of
  • More preferred compounds have the structure immediately above wherein W is -NHOH and V is O. Still more preferred compounds have the structure immediately above wherein R 2 is selected from the group consisting of hydrogen, hydroxy and alkenyl of two to six carbon atoms; R 3 is selected from the group consisting of isobutyl, cyclohexyl, 3-phenylpropyl, 3-(4- tolyl)propyl and biphenyloxy; R 5 is selected from the group consisting of alkyl of one to six carbon atoms, and alkyl of one to six carbon atoms substituted with cycloalkyl of three to eight carbon atoms, carboxy, phenyl, and hydroxyphenyl; and R 6 is selected from
  • Still yet more preferred compounds have the structure immediately above wherein R 6 is selected from the group consisting of
  • R 6 is selected from the group consisting of phenyl and phenyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, hydroxy, hydroxyalkyl of one to four carbon atoms, haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, -NR 7 R 8 , cyano, -SO NR 7 R 8 , -SO 2 R 16 , -CH 2 NRl 8 Rl 9 , -CONR 7 R 8 , -CO 2 R 7 , and phenyl, wherein the phenyl ring may be substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms.
  • the efficacy of the compounds of this invention as matrix metalloproteinase inhibitors was determined by measuring the inhibition of stromelysin.
  • the inhibition of stromelysin by the compounds of this invention was determined as follows: Recombinant truncated stromelysin (human sequence) produced in E. coli was prepared by expression and purification of the protein as described by Ye et al., Biochemistry , 1992, 31, 11231-11235.
  • the enzyme was assayed by its cleavage of the thiopeptide ester substrate Ac-Pro-Leu-Gly-[2-mercapto-4-methyl-pentanoyl]- Leu-Gly-OEt described by Weingarten and Feder, Anal. Biochem. , 1985, 147, 437-440 (1985), as a substrate of vertebrate collagenase.
  • the reported conditions were modified to allow assays to be carried out in a microtiter plate.
  • DTNB 5,5'-dithio-bis(2-nitrobenzoic acid)
  • the rates of cleavage of the substrate by stromelysin in the presence or absence of inhibitors are measured in a 30 min assay at ambient temperature. Solutions of the compounds in DMSO are prepared, and these are diluted at various concentrations into the assay buffer (50 mM MES/NaOH pH 6.5 with 10 mM CaCl2 and 0.2% Pluronic F-68), which is also used for dilution of the enzyme and substrate.
  • the potency of the compounds [IC50] are calculated from the inhibition/inhibitor concentration data.
  • the compounds of this invention inhibit stromelysin as shown by the data for representative examples in Table 1.
  • the present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally , intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
  • parenteral administration refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifier
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • dosage levels of about 1 to about 50, more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally to a mammalian patient.
  • the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
  • THF for tetrahydrofuran
  • DMF for NN-dimethylformamide
  • ETOAc for ethyl acetate
  • Et2 ⁇ for diethyl ether
  • IPA for isopropanol
  • ETOH for ethanol
  • MeOH for methanol
  • AcOH for acetic acid
  • HOBT for 1-hydroxybenzotriazole hydrdate
  • EDC for l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride
  • NMM for N-methylmorpholine
  • Bu 3 P for tributylphosphine
  • ADDP for l,l'-(azodicarbonyl)dipiperidine
  • DMPU for l,3-dimethyl-3,4,5,6-tetrahydro- 2( lH)-pyrimidinone.
  • keto amine 2 is accomplished as shown in Scheme 2. Conversion of the protected amino acid 6 to the methyl ester or N,O-dimethylamide is accomplished by known methods. Reaction of 7 with R 6 MgX wherein X is Br, Cl or I, or R 6 Li generates ketone 8. Acidic removal of the tert-butyl protecting groups gives amino ketone 2. Alternatively, 6 can be treated with a carbon anion such as phenyllithium which gives 8 directly. Scheme 2
  • n 92.9 g, 96%), bp 154-156 °C / 0.15 mm.
  • the filtrate was extracted with dichloromethane (3x) to remove the balance of the chiral oxazolidinone.
  • the combined organic extracts were washed with aqueous 0.5 N sodium hydroxide.
  • the base layers were acidified with IM sulfuric acid to pH 3 and extracted with ethyl acetate. After washing with water and brine, drying over sodium sulfate, and evaporation of solvents the residue amounted to 64.9 g (98%) of R-2-( -butyl)-succinic acid-4-t-butyl ester.
  • hthium diisopropylamide prepared by the addition of n- butyllithium (7.8 ml, 19.5 mmol, 2.5M in hexanes) to a solution of diisopropylamine (2.6 ml, 19.5 mmol) in 30 ml THF at -78 °C, was added a solution of epimeric isobutyl succinate y (2.3 g, 8.1 mmol) in THF (10 mL) at -78 °C by cannula in a stream. The resulting clear, yellow solution was stirred at -78 °C for 1 hour, warmed to 0 °C and recooled to -78 °C.
  • the desired compound was prepared according to the method used to prepare succinate ester 1, except substituting allyl bromide for 4-bromo-l-butene.
  • the desired compound was prepared according to the method used to prepare succinate ester 1, except substituting 5-bromo-l-pentene for 4-bromo-l-butene.
  • the filtrate was concentrated to a small volume and the residue was partitioned between aqueous 1 M sodium carbonate and ether.
  • the aqueous phase was extracted with ether.
  • the combined ether layers were extracted with aqueous 1 M sodium carbonate.
  • the basic solution was treated with charcoal and filtered.
  • the filtrate was acidified with 3 M hydrochloric acid. After cooling in an ice bath, the soft solid was filtered, washed with ice water, and dried over sodium hydroxide to give yn (45 g) as a mixture of isomers which was used without further purification.
  • the mixtureof isomers y ⁇ was hydrogenated in 600 mL THF over 9 g of 10% palladium on carbon at 4 atmospheres of hydrogen for 18 hours. After filtration and concentration of the solution, the residue was crystalhzed from hexane to yield 5-(4-tolyl)pentanoic acid (viii, 33 g, mp 77-78 °C).
  • the desired compound was prepared using Step 4 of the preparation of succinate ester 1, except substituting x for ni.
  • the desired compound was prepared using steps 5 and 6 of the preparation of succinate ester 1 , except substituting succinate ester 4 for jy.
  • succinate ester 2 (0.79g, 3mmol) in 10 mL methylene chloride was added pentaflurophenol (0.65g, 3.5mmol) and EDCI (0.69g, 3.5mmol). The resulting solution was stirred for 16 hours while warming to ambient temperature. The reaction mixture was quenched with 2N Na2CO 3 . The organic layer was washed with 2N HCl and brine, dried (sodium sulfate) and concentrated to give succinate ester .8 (0.8 g) as a crude yellow oil, which was used without further purification.
  • the desired compound was prepared using steps 1-4 of the preparation of succinate ester 1, except substituting 4-pentenoic acid for 4-methyl valeric acid in step 1.
  • the desired compound was prepared from the succinate ester 7 using the Suzuki coupling conditions described in Example 4 IB.
  • the desired compound was prepared from succinate ester 8, using step 5 of the preparation of succinate ester 1, except substituting allyl iodide for butenyl iodide.
  • the desired compound was prepared using steps 1 -4 of the preparation of succinate ester 1, except substituting 6-benzyloxyhexanoic acid for 4-methyl valeric acid in step 1.
  • the desired compound was prepared using steps 1 -4 of the preparation of succinate ester 1, except substituting 6-(trimethylsilyl)-5-hexynoic acid for 4-methyl valeric acid in step 1.
  • A1C1 (5.5g, 50mmol) was then added over a period of 5 minutes, during which time the solution became a blood-red color, and the reaction mixture was allowed to warm to ambient temperature and stir for 16 hours.
  • the reaction mixture was poured into cold water and extracted with methylene chloride. The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo to give 7.5g of a crude red solid.
  • Hash chromatography hexane-ethyl acetate, gradient elution 3:1 to 1:1) gave 2.6 g of a product lb containing ⁇ 60% of the desired acylation product which was carried on without further purification.
  • Ester id (0.5 g, 1.0 mmol) was dissolved in cold (0°) TFA and stirred for 5 hours while warming to ambient temperature. Solvent was removed under a stream of nitrogen and the residue was azeotroped with methylene chloride and dried on high vacuum for 16 hours to give le (250 mg) as a 1 : 1 mixture of epimers at the Phe center.
  • the desired compound was prepared by coupling of 2 ⁇ andR-2-( -butyl)-succinic acid-4-t- butyl ester according to the method of Example 2C, followed by hydrolysis of the tert-butyl ester using the method of Example IE. mp 110 °C (dec).
  • the desired compound was prepared by coupling of 2c and succinate ester 5 according to the method of Example 2C, followed by hydrolysis of the tert-butyl ester using the method of Example IE, and conversion of the acid to the hydroxamate according to the method of Example 5. mp 185 °C.
  • the desired compound was prepared by coupling of 2c and succinate ester 6 according to the method of Example 2C, followed by hydrolysis of the tert-butyl ester using the method of Example IE.
  • the desired compound was prepared according to the method of Examples 1A-C, except substituting L-tert-leucine for L-phenylalanine.
  • Pentafluorophenol ester Qa (0.605 g, 1.53 mmol), prepared as described in WO94/02446, and ic (0.448 g, 1.70 mmol) were combined in dry DMF (6 mL). The solution was heated at 30 °C for 24 hours, then reduced in volume by rotary evaporation under high vacuum. The residue was diluted with ethyl acetate, then washed successiveively with brine, pH3 buffer, aqueous Na2CO3, pH7 buffer and brine. The organics were dried over Na2SO4 and evaporated to give 10b (0.764 g) as a tan solid which was carried forward without purification.
  • the desired compound was prepared according to the method of Examples 3A-E, except substituting phenyllithium for ethylmagnesium bromide.
  • the desired compound was prepared according to the method of Example 1, except substituting 1 -methylindole for indole.
  • the desired compound was prepared according to the method of Example 1 A, except substituting N-Boc-O-tBu-L-tyrosine for N-BOC-1-phenylalanine.
  • reaction mixture was poured onto water, extracted with CH2CI2 (3x), dried over Na2SO4, filtered and concentrated in vacuo to give an orange oil which was purified by flash chromatography (30% ethyl acetate-hexanes) to give 22a (1.2 g) as a yellow oil.
  • the desired compound was prepared according to the method of Examples 21B-E except substituting 2ia for 2ia.
  • 1H NMR(300 MHz, DMSO-d6) ⁇ 0.54-0.87 ( , 7H), 0.95-1.35 (m, 2H ),1.68-2.11 (m, 2.5H), 2.32-2.47 (m, 0.5H), 2.83-3.15 (m, 2H), 4.63-4.85 (m, 2H), 5.29- 5.52 (m, 2H), 7.11-7.40 (m, 6H), 8.02-8.20 (2H), 8.58-8.75 (IH), 8.73 (s, IH).
  • the desired compound was prepared according to the method of Example 25B, except substituting 22e for 25_a.
  • the desired compound was prepared according to the method of Examples 5A and B, except substituting 30b for the compound of Example 4.
  • the desired compound was prepared according to the method of Examples 2A and B, except substituting 3_la for 212 and substituting for R-2-(/-butyl)-succinic acid-4-t-butyl estersuccinate ester 4.
  • Example 31 C
  • the desired compound was prepared according to the method of Example 5, except substituting lib for the compound of Example 4.
  • the desired compound was prepared according to the method of Example 19C, except substituting 32_c for succinate ester 3.
  • the desired compound was prepared by adding 4-bromo-tert-butylbenzene to a 0 °C solution of nBuLi in diethyl ether .
  • the resulting 4-tert-butylphenyllithium solution was added to a -78 °C solution of N-BOC-tBu(OH) tyrosine in diethyl ether.
  • the solution was stirred at -78 °C for 30 minutes, warmed to 0° over 1 hour and quenched with an aqueous solution of NH4CI.
  • the aqueous layer was extracted twice with diether ether and the combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo.
  • the desired compound was prepared according to the method of Examples IE and F, except substituting 36e for Id. mp 126-129 °C. l H NMR (300 MHz, DMSO-d6) ⁇ 0.6-1.0 (m, 8H), 1.1-1.4 (m, 2H), 1.8-2.2 (m, 2H), 2.6-3.2 (m, 6H), 4.2-4.6 (m, 3H), 5.2-5.4 (m, 2H), 5.8-6.0 (m, IH), 7.1-7.3 (m, 5H), 8.4-8.6 (m, IH), 8.45-8.55 (m, IH), 8.70 and 8.73 (two s, IH), 10.36 and 10.40 (two s, IH). MS (DCI/NH3) m/e 433 (M+H)+ 450 (M+NH4)+.
  • the desired compounds was prepared according to the method of Example 27B, except substituting allyl bromide for cinnamyl bromide.
  • Example 41D The desired compound was prepared according to the methods of Example 41, except substituting 2c for 10a in Example 41D.
  • IH NMR 300 MHz, DMSO-d 6 ) ⁇ 1.236-1.377 (m, 4H), 2.274- 2.441 (m, 2H), 2.918-2.988 (dd, IH), 3.111-3.183 (dd, IH), 3.570 (s, 3H), 3.638 (s, 6H), 3.826 (t, IH), 5.222 (d, IH), 5.387 (q, IH), 6.343 (s, 2H), 7.118-7.276 (m, 9H), 7.439 (d, IH), 8.125 (d, IH), 8.297 (s, IH), 8.435 (d, IH).
  • the desired compound was prepared according to the method of Examples 41D-F, except substituting ketone 43b for 10a.
  • IH NMR 300 MHz, DMSO-d 6 ) ⁇ 0.883 (s, 9H), 1.171-1.399 (m, 4H), 2.291-2.515 (m, 2H), 2.728-2.833 (m, IH), 3.575 (s, 3H), 3.635 (s, 6H), 3.797 (s, 3H),3.772-3.813 (m, IH), 5.199 (d, IH), 5.304 (d, IH), 6.388 (s, 2H), 6.960-7.009 (t, IH), 7.104 (d, IH), 7.449-7.501 (t, IH), 7.550-7.588 (dd, IH), 7.929 (d, IH), 8.852 (s, IH), 10.645 (s, IH).
  • the desired compound was prepared according to the method of Example 2C, except coupling succinate 7 instead of 4 with ketone 2c.
  • MS (ESI) m/e 461 (M + H) + .
  • the desired compound was prepared according to the method of Example 4 IB, except using 45_a instead of 41a.
  • Example 45A-45C The desired compound was prepared according to the method of Example 45A-45C, except substituting ketone 9a for 2c in Example 45A.
  • the desired compound was prepared according to the method of Example 43A and 43B, except using phenyl lithium in place of 3-lithioanisole.
  • Example 45A-45C The desired compound was prepared according to the method of Example 45A-45C, except substituting ketone 47a for 2c in Example 45A. mp 146 °C.
  • the desired compound was prepared according to the method of Example 2C and 2D, except coupling succinate IQ instead of 4 with ketone 9a instead of 2£.
  • the desired compound was prepared according to the methods of Examples 18A and B. except substituting N-Boc-alpha-cyclohexyl alanine for N-Boc-phenylalanine.
  • the desired compound was prepared according to the method of Example 27B, except substituting 1,3-dibromo-l-propene for cinnamyl bromide.
  • Example 52_a A solution of Example 52_a (3.0 g, 8.9 mmol) in DMF (100 mL) at room temperature was treated with [l,l'-bis(diphenylphosphino)-fe ⁇ ocene] dichloropalladium (363 mg, 0.445 mmol), 3- acetimidobenzenoboronic acid (2.39 g, 13.35 mmol) and cesium carbonate (8.7 g, 26.7 mmol), stirred at 60°C for 7 hours, cooled to room temperature and diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with water and brine, dried (Na2SO4) and concentrated to an oil. The oil was purified on silica gel with 50% ethyl acetate/hexane to provide 716.9 mg (20%) of 52b as a yellow oil. MS (ESI) m/e 392 (M+H) + .
  • the olefin 52b was converted to the desired compound 52c following the procedure of

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pyrrole Compounds (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Cette invention concerne des composés à terminaison C qui correspondent à la formule (I). Ces composés consistent en de puissants inhibiteurs de métalloprotéinase matricielle, et peuvent être utilisés dans le traitement de maladies où la métalloprotéinase matricielle joue un rôle. Cette invention concerne également des compositions inhibant la métalloprotéinase matricielle, ainsi qu'un procédé d'inhibition de métalloprotéinase matricielle chez un mammifère.
PCT/US1998/000142 1997-01-07 1998-01-07 Inhibiteurs a base d'acide hydroxamique et de cetone a terminaison c permettant de lutter contre les metalloproteinases matricielles et la secretion de fnta WO1998030541A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP53103098A JP2002503216A (ja) 1997-01-07 1998-01-07 マトリックスメタロプロテイナーゼおよびｔｎｆａ分泌の、ｃ末端ケトンヒドロキシアミド酸阻害剤
AU59582/98A AU5958298A (en) 1997-01-07 1998-01-07 C-terminal ketone hydroxamic acid inhibitors of matrix metalloproteinases and tnfa secretion
CA002277105A CA2277105A1 (fr) 1997-01-07 1998-01-07 Inhibiteurs a base d'acide hydroxamique et de cetone a terminaison c permettant de lutter contre les metalloproteinases matricielles et la secretion de fnta
EP98902771A EP0964851A1 (fr) 1997-01-07 1998-01-07 Inhibiteurs a base d'acide hydroxamique et de cetone a terminaison c permettant de lutter contre les metalloproteinases matricielles et la secretion de fnta

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US77977897A 1997-01-07 1997-01-07
US08/779,778 1997-01-07

Publications (1)

Publication Number Publication Date
WO1998030541A1 true WO1998030541A1 (fr) 1998-07-16

Family

ID=25117535

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/000142 WO1998030541A1 (fr) 1997-01-07 1998-01-07 Inhibiteurs a base d'acide hydroxamique et de cetone a terminaison c permettant de lutter contre les metalloproteinases matricielles et la secretion de fnta

Country Status (9)

Country Link
EP (1) EP0964851A1 (fr)
JP (1) JP2002503216A (fr)
AR (1) AR011061A1 (fr)
AU (1) AU5958298A (fr)
CA (1) CA2277105A1 (fr)
CO (1) CO4920222A1 (fr)
TW (1) TW399042B (fr)
WO (1) WO1998030541A1 (fr)
ZA (1) ZA9818B (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999061412A1 (fr) * 1998-05-22 1999-12-02 Welfide Corporation Derives d'acide hydroxamique et utilisation medicinale de ces derives
EP1169031A1 (fr) * 1999-04-09 2002-01-09 British Biotech Pharmaceuticals Limited Agents antimicrobiens
US6838466B2 (en) 2001-12-20 2005-01-04 Schering Corporation Compounds for the treatment of inflammatory disorders
US7364736B2 (en) 2001-06-26 2008-04-29 Amgen Inc. Antibodies to OPGL
EP1992636A2 (fr) 1999-11-12 2008-11-19 Amgen Inc. Procédé pour la correction d'un mauvais repliement de bisulfure dans les molécules Fc
WO2020070239A1 (fr) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de l'egfr pour traiter les kératodermies
WO2022005943A3 (fr) * 2020-06-30 2022-02-17 Genentech, Inc. Procédés de fabrication de composés tricycliques serd ayant un fragment phényle ou pyridinyle substitué

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004071384A2 (fr) * 2003-02-11 2004-08-26 Boehringer Ingelheim International Gmbh Nouvelles compositions pharmaceutiques a base d'anticholinergiques et d'inhibiteurs de l'enzyme tace

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0489577A1 (fr) * 1990-12-03 1992-06-10 Celltech Limited Dérivés peptidyliques
EP0498665A1 (fr) * 1991-02-07 1992-08-12 British Biotech Pharmaceuticals Limited Dérivés de l'acide hydroxamique, procédé pour leur préparation et leur utilisation
WO1993024449A1 (fr) * 1992-06-03 1993-12-09 Celltech Limited Derives de peptidyle et leur utilisation comme inhibiteurs de metalloproteinases
EP0575844A2 (fr) * 1992-06-25 1993-12-29 F. Hoffmann-La Roche Ag Composés d'acides hydroxamic et compositions pharmaceutiques de ceux-ci
WO1994025435A1 (fr) * 1993-04-27 1994-11-10 Celltech Limited Derives peptidiques et leur utilisation comme inhibiteurs de metalloproteases
WO1995006031A1 (fr) * 1993-08-23 1995-03-02 Immunex Corporation Inhibiteurs de la secretion de facteur alpha de necrose tumorale
WO1995019956A1 (fr) * 1994-01-20 1995-07-27 British Biotech Pharmaceuticals Limited Inhibiteurs de metalloproteinase
WO1995019961A1 (fr) * 1994-01-22 1995-07-27 British Biotech Pharmaceuticals Limited Inhibiteurs de metalloproteinase
WO1995032944A1 (fr) * 1994-05-28 1995-12-07 British Biotech Pharmaceuticals Limited Acide succinyle hydroxamique, acide n-formyl-n-hydroxy amino carboxylique et derives amides de l'acide succinique en tant qu'inhibiteurs des metalloproteases
WO1996033161A1 (fr) * 1995-04-18 1996-10-24 British Biotech Pharmaceuticals Limited Derives de succinamides et leur emploi comme inhibiteurs de la metalloproteinase

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0489577A1 (fr) * 1990-12-03 1992-06-10 Celltech Limited Dérivés peptidyliques
US5300501A (en) * 1990-12-03 1994-04-05 Celltech Limited Peptidyl derivatives
EP0498665A1 (fr) * 1991-02-07 1992-08-12 British Biotech Pharmaceuticals Limited Dérivés de l'acide hydroxamique, procédé pour leur préparation et leur utilisation
WO1993024449A1 (fr) * 1992-06-03 1993-12-09 Celltech Limited Derives de peptidyle et leur utilisation comme inhibiteurs de metalloproteinases
EP0575844A2 (fr) * 1992-06-25 1993-12-29 F. Hoffmann-La Roche Ag Composés d'acides hydroxamic et compositions pharmaceutiques de ceux-ci
WO1994025435A1 (fr) * 1993-04-27 1994-11-10 Celltech Limited Derives peptidiques et leur utilisation comme inhibiteurs de metalloproteases
WO1995006031A1 (fr) * 1993-08-23 1995-03-02 Immunex Corporation Inhibiteurs de la secretion de facteur alpha de necrose tumorale
WO1995019956A1 (fr) * 1994-01-20 1995-07-27 British Biotech Pharmaceuticals Limited Inhibiteurs de metalloproteinase
WO1995019961A1 (fr) * 1994-01-22 1995-07-27 British Biotech Pharmaceuticals Limited Inhibiteurs de metalloproteinase
WO1995032944A1 (fr) * 1994-05-28 1995-12-07 British Biotech Pharmaceuticals Limited Acide succinyle hydroxamique, acide n-formyl-n-hydroxy amino carboxylique et derives amides de l'acide succinique en tant qu'inhibiteurs des metalloproteases
WO1996033161A1 (fr) * 1995-04-18 1996-10-24 British Biotech Pharmaceuticals Limited Derives de succinamides et leur emploi comme inhibiteurs de la metalloproteinase

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6610729B1 (en) 1998-05-22 2003-08-26 Mitsubishi Pharma Corporation Hydroxamic acid derivatives and medicinal utilization thereof
WO1999061412A1 (fr) * 1998-05-22 1999-12-02 Welfide Corporation Derives d'acide hydroxamique et utilisation medicinale de ces derives
EP1169031A1 (fr) * 1999-04-09 2002-01-09 British Biotech Pharmaceuticals Limited Agents antimicrobiens
EP1992636A2 (fr) 1999-11-12 2008-11-19 Amgen Inc. Procédé pour la correction d'un mauvais repliement de bisulfure dans les molécules Fc
EP3492100A1 (fr) 2001-06-26 2019-06-05 Amgen Inc. Anticorps pour opgl
US7364736B2 (en) 2001-06-26 2008-04-29 Amgen Inc. Antibodies to OPGL
EP2087908A1 (fr) 2001-06-26 2009-08-12 Amgen, Inc. Anticorps opgl
US7034057B2 (en) 2001-12-20 2006-04-25 Schering Corporation Compounds for the treatment of inflammatory disorders
US7598242B2 (en) 2001-12-20 2009-10-06 Schering Corporation Compounds for the treatment of inflammatory disorders
US6838466B2 (en) 2001-12-20 2005-01-04 Schering Corporation Compounds for the treatment of inflammatory disorders
WO2020070239A1 (fr) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de l'egfr pour traiter les kératodermies
WO2022005943A3 (fr) * 2020-06-30 2022-02-17 Genentech, Inc. Procédés de fabrication de composés tricycliques serd ayant un fragment phényle ou pyridinyle substitué
US11873305B2 (en) 2020-06-30 2024-01-16 Genentech, Inc. Processes for synthesis of substituted indole intermediates for the synthesis of serd compounds

Also Published As

Publication number Publication date
TW399042B (en) 2000-07-21
ZA9818B (en) 1998-07-02
EP0964851A1 (fr) 1999-12-22
AU5958298A (en) 1998-08-03
CO4920222A1 (es) 2000-05-29
CA2277105A1 (fr) 1998-07-16
AR011061A1 (es) 2000-08-02
JP2002503216A (ja) 2002-01-29

Similar Documents

Publication Publication Date Title
AU735194B2 (en) Heteroaryl succinamides and their use as metalloproteinase inhibitors
JP2951527B2 (ja) アリールスルホンアミド置換化ヒドロキサム酸
AU710666B2 (en) Biphenyl hydroxamate inhibitors of matrix metalloproteinases
RU2072986C1 (ru) Способ получения амидов карбоновых или сульфоновых кислот или их физиологически совместимых солей
KR20090033912A (ko) 화학적 화합물
JPH04352757A (ja) アミノ酸誘導体
EP0630366B1 (fr) Derives heterocycliques substitues utilises comme agents inhibiteurs de l'agregation plaquettaire
JPH10509719A (ja) マトリックスメタロプロテアーゼ阻害因子
KR20000075681A (ko) 메탈로프로테아제 억제제로서의 후위 히드록사메이트 유도체
US5478856A (en) Styrene derivatives and salts thereof
US5952320A (en) Macrocyclic inhibitors of matrix metalloproteinases and TNFα secretion
TW200825056A (en) New compounds
US5985911A (en) C-terminal ketone inhibitors of matrix metalloproteinases and TNFα secretion
EP0964851A1 (fr) Inhibiteurs a base d'acide hydroxamique et de cetone a terminaison c permettant de lutter contre les metalloproteinases matricielles et la secretion de fnta
US6812237B2 (en) N-substituted peptidyl nitriles as cysteine cathepsin inhibitors
US6174915B1 (en) Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses
EP1283825B1 (fr) Utilisation de peptidyl nitriles a substitution- n comme inhibiteurs des cathepsines de cysteine
JP2001509151A (ja) マトリックス金属プロテイナーゼおよびＴＮＦα分泌の大環状阻害剤
HUP0102776A2 (hu) Hidroxámsavszármazékok mint a humán CD23 termelés és a TNF felszabadítás inhibitorai
US5962438A (en) Estrogen derivative having carriers to bone
KR100402561B1 (ko) 하이드라진 유도체
AU763835B2 (en) Heteroaryl succinamides and their use as metalloproteinase inhibitors
CA2277121A1 (fr) Inhibiteurs macrocycliques de metalloproteinases matricielles et de secretion de fnt.alpha.
JPH1067737A (ja) メルカプトケトンおよびメルカプトアルコールならびにそれらの製造方法
WO2001047836A1 (fr) Nouveaux agents de desacetlylation selective

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 2277105

Country of ref document: CA

Ref country code: CA

Ref document number: 2277105

Kind code of ref document: A

Format of ref document f/p: F

Ref country code: JP

Ref document number: 1998 531030

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: PA/a/1999/006337

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 1998902771

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1998902771

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1998902771

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载