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WO1996037497A1 - Inhibiteurs de thrombine bicycliques de type uree et de faible poids moleculaire - Google Patents

Inhibiteurs de thrombine bicycliques de type uree et de faible poids moleculaire Download PDF

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Publication number
WO1996037497A1
WO1996037497A1 PCT/CA1996/000318 CA9600318W WO9637497A1 WO 1996037497 A1 WO1996037497 A1 WO 1996037497A1 CA 9600318 W CA9600318 W CA 9600318W WO 9637497 A1 WO9637497 A1 WO 9637497A1
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alkyl
mmol
solution
compound according
carbonyl
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PCT/CA1996/000318
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English (en)
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John Dimaio
John W. Gillard
M. Arshad Siddiqui
Benoit Bachand
Annette Marian Doherty
Jeremy John Edmunds
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Biochem Pharma Inc.
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Priority to JP8535221A priority Critical patent/JPH11505260A/ja
Priority to AU56825/96A priority patent/AU5682596A/en
Priority to EP96914817A priority patent/EP0846120A1/fr
Publication of WO1996037497A1 publication Critical patent/WO1996037497A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

Definitions

  • This invention relates to compounds useful for the treatment of thrombotic disorders, and more particularly to novel heterocyclic inhibitors of the enzyme thrombin.
  • thrombus formation on blood vessel walls precipitates acute cardiovascular disease states that are the chief cause of death in economically developed societies.
  • Plasma proteins such as fibrinogen, proteases and cellular receptors participating in hemostasis have emerged as important factors that play a role in acute and chronic coronary disease as well as cerebral artery disease by contributing to the formation of thrombus or blood clots that effectively diminish normal blood flow and supply.
  • Vascular aberrations stemming from primary pathologic states such as hypertension, rupture of atherosclerotic plaques or denuded endothelium, activate biochemical cascades that serve to respond and repair the injury site.
  • Thrombin is a key regulatory enzyme in the coagulation cascade; it serves a pluralistic role as both a positive and negative feedback regulator. However, in pathologic conditions the former is amplified through catalytic activation of cofactors required for thrombin generation as well as activation of factor XIII necessary for fibrin cross-linking and stabilization.
  • thrombin In addition to its direct effect on hemostasis, thrombin exerts direct effects on diverse cell types that support and amplify pathogenesis of arterial thrombus disease.
  • the enzyme is the strongest activator of platelets causing them to aggregate and release substances (e.g. ADP TXA 2 NE) that further propagate the thrombotic cycle. Platelets in a fibrin mesh comprise the principal framework of a white thrombus.
  • Thrombin also exerts direct effects on endothelial cells causing release of vasoconstrictor substances and translocation of adhesion molecules that become sites for attachment of immune cells.
  • the enzyme causes mitogenesis of smooth muscle cells and proliferation of fibroblasts. From this analysis, it is apparent that inhibition of thrombin activity constitutes a viable therapeutic approach towards the attenuation of proliferative events associated with thrombosis.
  • ATIII antithrombin III
  • heparin exerts clinical efficacy in venous thrombosis by enhancing ATIII/thrombin binding through catalysis.
  • heparin also catalyzes inhibition of other proteases in the coagulation cascade and its efficacy in platelet-dependent thrombosis is largely reduced or abrogated due to inaccessibility of thrombus-bound enzyme.
  • Adverse side effects such as thrombocytopenia, osteoporosis and triglyceridemia have been observed following prolonged treatment with heparin.
  • Hirudin derived from the glandular secretions of the leech hirido medicinalis is one of the high molecular weight natural anticoagulant protein inhibitors of thrombin activity
  • Hirudin as a therapeutic agent is likely antigenicity and lack of an effective method of neutralization, especially in view of its extremely tight binding characteristics toward thrombin.
  • the exceedingly high affinity for thrombin is unique and is attributed to a simultaneous interaction with the catalytic site as well as a distal "anion binding exosite" on the enzyme.
  • Thrombin activity can also be abrogated by Hirudin-like molecules such as hirulog (Maraganore, J.M. et al . , Biochemistry, 2__, 7095, 1990) or hirutonin peptides (Di aio, J. et al., J. Med. Chem., ___., 3331, 1992) .
  • Hirudin-like molecules such as hirulog (Maraganore, J.M. et al . , Biochemistry, 2__, 7095, 1990) or hirutonin peptides (Di aio, J. et al., J. Med. Chem., ___., 3331, 1992) .
  • Thrombin activity can also be inhibited by low molecular weight compounds that compete with fibrinogen for thrombin's catalytic site, thereby inhibiting proteolysis of that protein or other protein substrates such as the thrombin receptor.
  • a common strategy for designing enzyme inhibitory compounds relies on mimicking the specificity inherent in the primary and secondary structure of the enzyme' s natural substrate.
  • Blomback et al. first designed a thrombin inhibitor that was modeled upon the partial sequence of the fibrinogen A ⁇ chain comprising its proteolytically susceptible region (Blomback, et al . , J. Clin. Lab. Invest., ___, 59, 1969) . This region of fibrinogen minimally includes the residues commencing with phenylalanine:
  • the aldehyde group is presumed to contribute strongly to inhibitory activity in view of its chemical reactivity toward thrombin' s catalytic Ser 195 residue, generating a hemiacetal intermediate.
  • Still other congeners of this motif are those bearing phosphonates (Wang, C-L J. , Tetrahedron Letters, 3_3_, 7667, 1992) and ⁇ -Keto esters (Iwanowicz, E.J. et al .,Bioorganic and Medicinal Chemistry Letters, __2_, 1607, 1992) .
  • Neises, B. et al . have described a trichloromethyl ketone thrombin inhibitor (MDL-73756) and Attenburger, J.M. et al . have revealed a related difluoro alkyl amide ketone (Tetrahedron Letters, 22, 7255, 1991) .
  • Maraganore et al. disclose a series of thrombin inhibitors that incorporate the D-Phe-Pro- moiety and hypothesize that this preferred structure fits well within the groove adjacent to the active site of thrombin. Variations on these inhibitors are essentially linear or cyclic peptides built upon the D- Phe-Pro moiety.
  • thrombin inhibitors that display inhibitory activity towards the target enzyme, thrombin.
  • the present invention provides for novel compounds that display thrombin inhibitory activity as represented by formula (I) :
  • X is selected from CH-R 5 , 0, S, SO, S0 2 and NR 9 wherein R 5 is hydrogen, C 1-6 alkyl optionally interrupted with 1 or 2 heteroatoms; C 6 . 16 aryl, C 3 . 7 cycloalkyl or heterocyclic ring or a hydrophobic group; R 2 is selected from H, NH 2 and __ alkyl optionally substituted with C e aryl, a 6 member heterocycle or a C 3 . 7 cycloalkyl ring; R 3 and R 4 are independently selected from H; NR e R 7 ; C 6-16 aryl or
  • C__._ e alkyl optionally interrupted by one or more heteroatom or carbonyl group and optionally substituted with OH, SH, NR ⁇ R 7 or a C 6 . 16 aryl, heterocycle or C 3 . 7 cycloalkyl group optionally substituted with halogen, hydroxyl, C_. e alkyl; an amino acid side chain; and a hydrophobic group
  • R 6 is a polar amino acid residue, arginyl moiety or an analog or derivative thereof optionally substituted with an amino acid, a peptide or a heterocycle
  • R 7 and R 8 are independently hydrogen or C_.
  • compositions comprising compounds of the formula (I) in combination with pharmaceutically acceptable carriers, diluents or adjuvants.
  • a method for the treatment or prophylaxis of thrombotic disorders in a mammal comprising administering to said mammal an effective amount of a compound according to formula (I) .
  • the present invention relates to compounds which inhibit the enzyme, thrombin. These molecules are characterized by a heterobicyclic moiety as illustrated in formula (I) :
  • hydrophobic group refers to any group which lacks affinity for, or displaces water.
  • Hydrophobic groups include but are not limited to C ⁇ Q alkyl, C 2 . 20 alkenyl (e.g. vinyl, allyl) or C 2 . 20 alkynyl (e.g. propargyl) optionally interrupted by a carbonyl group, (e.g. forming an acyl group) ; C 6 . 16 aryl, C 3 . 7 cycloalkyl, C 6 .
  • aralkyl C 6 _ 20 cycloalkyl substituted C ⁇ Q alkyl, wherein the aliphatic portion is optionally interrupted by a carbonyl group (e.g. forming an acyl group) and the ring portion is optionally substituted with C__ 6 alkyl such as methyl ethyl or t-butyl; or a hydrophobic amino acid side chain.
  • Preferred hydrophobic groups include cyclohexyl, benzyl, benzoyl, phenylmethyl, phenethyl and para-t-butyl-phenylmethyl .
  • an analogue or derivative of the natural residue may incorporate a longer or shorter methylene chain from the alpha carbon (i.e. ethylene or butylene chain) ; replacement of the guanidino group with a hydrogen bond donating or accepting group (i.e. amino, amidino or methoxy) ; replacement of the methylene chain with a constrained group (i.e. an aryl, cycloalkyl or heterocyclic ring) ; elimination of the terminal carboxyl (i.e. des-carboxy) or hydroxyl (i.e. an aldehyde) ; or a combination thereof.
  • alkyl represents a straight or branched, saturated or unsaturated chain having a specified total number of carbon atoms.
  • aromatic or aryl represents an unsaturated carbocyclic ring(s) of 6 to 16 carbon atoms which is optionally mono- or di-substituted with OH, SH, amino (i.e. NR e R 7 ) halogen or C ⁇ g alkyl.
  • Aromatic rings include benzene, napththalene, phenanthrene and anthracene. Preferred aromatic rings are benzene and naphthalene.
  • cycloalkyl represents a carbocyclic ring of 3 to 7 carbon atoms which is optionally mono- or di-substituted with OH, SH, amino (i.e. NR 6 R 7 ) halogen or C ⁇ g alkyl.
  • Cycloalkyl groups are generally saturated but may be partially unsaturated and include cyclo-propyl, butyl, pentyl, hexyl and heptyl .
  • a preferred cycloalkyl group is cyclohexyl.
  • aralkyl represents a substituent comprising an aryl moiety attached via an alkyl chain (e.g. benzyl, phenethyl) wherein the sum total of carbon atoms for the aryl moiety and the alkyl chain is as specified.
  • the aryl or chain portion of the group is optionally mono- or di-substituted with OH, SH, amino (i.e. NR 6 R 7 ) halogen or C_. 6 alkyl
  • heteroato as used herein represents oxygen, nitrogen or sulfur (O, N or S) as well as sulfoxyl or sulfonyl (SO or S0 2 ) unless otherwise indicated. It is understood that alkyl chains interrupted by one or more heteroatoms means that a carbon atom of the chain is replaced with a heteroatom having the appropriate valency. Preferably, an alkyl chain is interrupted by 0 to 4 heteroatoms and that two adjacent carbon atoms are not both replaced.
  • heterocycle represents a saturated or unsaturated mono- or polycyclic (i.e. bicyclic) ring incorporating 1 or more (i.e. 1-4) heteroatoms selected from N, O and S. It is understood that a heterocycle is optionally mono- or di- substituted with OH, SH, amino (i.e. NR 6 R 7 ) , halogen, CF 3 , oxo or C__ 6 alkyl .
  • suitable monocyclic heterocycles include but are not limited to pyridine, piperidine, pyrazine, piperazine, pyrimidine, imidazole, thiazole, oxazole, furan, pyran and thiophene.
  • bicyclic heterocycles include but are not limited to indole, quinoline, isoquinoline, purine, and carbazole.
  • hydrophobic amino acid represents an amino acid residue that bears an alkyl or aryl group attached to the ⁇ - carbon atom.
  • glycine which has no such group attached to the ⁇ -carbon atom is not a hydrophobic amino acid.
  • the alkyl or aryl group can be substituted, provided that the substituent or substituents do not detract from the overall hydrophobic character of the amino acid.
  • hydrophobic amino acids examples include natural amino acid residues such as alanine; isoleucine; leucine; phenylalanine; and non-naturally occurring amino acids such as those described in "The Peptides", vol. 5, 1983, Academic Press, Chapter 6 by D.C. Roberts and F. Vellaccio.
  • Suitable non-naturally occurring amino acids include cyclohexylalanine and 1- aminocyclohexane-carboxylic.
  • amino acid side chain is meant the substituent attached to the carbon which is ⁇ to the amino group.
  • side chain of the amino acid alanine is a methyl group and while benzyl is the side chain for phenylalanine.
  • X is CH-R 5 , S or O wherein R 5 is preferably H or C- L . 4 alkyl and most preferably H. More preferably, X is S.
  • R 2 is H, methyl or ethyl. Most preferably, R 2 is H.
  • one of R 3 or R 4 is a carboxyl group or a hydrophobic group such as a saturated or unsaturated carbocycle of 5 or 6 members optionally fused to another carbocyclic group while the other is H, C- ⁇ g alkyl optionally substituted by NR 6 R 7 or carboxy.
  • the carboxy group or hydrophobic group may be linked via a spacer such as a C- ⁇ g alkyl chain optionally interrupted with 1 or more (i.e. 1-4) heteroatoms, carbonyl or sulfonyl (S0 2 ) groups.
  • one of R 3 and R 4 is an optionally substituted aromatic ring such as phenyl, cyclohexyl, indole, thienyl, quinoline, tetrahydroisoquinoline, naphthyl or benzodioxolane linked via C__ 16 alkyl optionally interrupted with a heteroatom or a carbonyl while the other is H, carboxymethyl or carboxyethyl .
  • Optional aromatic ring substituents include OH, carboxy, C 1-4 alkyl and halogen.
  • one of R 3 and R 4 is optionally substituted phenyl or cyclohexyl linked via a C 1-4 alkyl optionally interrupted with carbonyl while the other is H, carboxymethyl or carboxyethyl.
  • R 3 is benzyl, phenylethyl, phenylpropyl or cyclohexyl-methyl and R 4 is H.
  • R 7 and R 8 are independently hydrogen, methyl or ethyl . More preferably R 7 and R 8 are independently hydrogen or methyl. Most preferably R 7 and R 8 are both hydrogen.
  • n is 0 or 1. More preferably, m is 0.
  • n is 0 or 1. More preferably, n is 1.
  • R 6 is represented by one of formula Via to VId:
  • R x _ is hydrogen or C- L .g alkyl
  • K is a bond or -NH- ;
  • G is Ci. 4 alkoxy; cyano; -NH 2 ; -CH 2 -NH 2 ; -C(NH)-NH 2 ; -NH-C(NH)- NH 2 ; -CH 2 -NH-C(NH) -NH 2 ; a C 6 cycloalkyl or aryl substituted with cyano, -NH 2 , -CH 2 -NH 2 , -C(NH)-NH 2 , -NH-C (NH) -NH 2 or -CH 2 - NH-C (NH) -NH 2 ; or a 5 or 6 member, saturated or unsaturated heterocycle optionally substituted with cyano, -NH 2 , -CH 2 - NH 2 , -C(NH)-NH 2 , -NH-C(NH) -NH 2 or -CH 2 -NH-C (NH) -NH 2 ;
  • U is cyano, -NH 2 , -C(NH)-NH 2 or -NH-C (NH) -NH 2 ;
  • P is a bond, -C(O)- or a bivalent group:
  • J is C- j ⁇ .g alkylene optionally substituted with OH, NH 2 and C 1-6 alkyl and optionally interrupted by a heteroatom selected from O, S and N; n is 0 or 1; and
  • T is H, OH, amino, a peptide chain, C- ⁇ g alkyl, C_. 16 alkoxy, C 6- 20 aralkyl, or heterocycle optionally substituted.
  • R X1 is H or methyl and most preferably H.
  • K is a bond.
  • G is -NH-C(NH) -NH 2 attached via a methylene chain of 3-7 carbons or phenyl substituted with -C(NH)-NH 2 attached via a methylene chain of 0 to 3 carbons. More preferably G is -NH-C (NH) -NH 2 attached via a methylene chain of 3 atoms.
  • P is -C(0)-.
  • J is selected from: -CH 2 -S-CH 2 -CH 2 - ; -CH 2 -0-CH 2 -CH 2 - ; -CH 2 -NH-CH 2 -CH 2 - ; and a bond when n is 0. More preferably, J is a bond while n is 0.
  • R 6 is selected from the following amino acid derivatives prepared according to the procedures described in Bioorg. Med. Chem., 1995, 3:1145 :
  • T is a peptide of 1 to 4 amino acid residues in length and preferably fibrinogen' s A or B chain or fragment or derivative thereof.
  • T is a heterocycle selected from the group consisting of:
  • X 5 , X 10 , X ⁇ and X 12 are each independently selected from the group consisting of N, or C-X 7 where X 7 is hydrogen, C 1-4 alkyl, or C 6-16 aryl;
  • X 6 and X 13 are each independently selected from the group consisting of C, O, N, S, N-X 7 , or CH-X 7 ;
  • R' is hydrogen, C ⁇ alkyl optionally carboxyl substituted, carboxyl, -C 0 . 16 alkyl-C0 2 -C 1 . 16 alkyl, C e . 20 aralkyl, C 3 . 7 cycloalkyl, aryl or an aromatic heterocycle.
  • T is selected from the group consisting of
  • R' is as defined above.
  • T is selected from the group consisting of
  • R' is as defined above.
  • T is selected from the group consisting of
  • R' is H or ⁇ alkyl such as methyl, ethyl, propyl or butyl and most preferably wherein R' is hydrogen, .
  • T is a 1,2 thiazole optionally substituted with R' and/or is attached to J at the 2, 3, 4 or 5 position of the ring.
  • a more preferred embodiment of the present invention is illustrated by compounds having Formulae II, III, IV, and V wherein R 3 , R 4 , R 6 , R 7 and R 8 are as defined in each of the above embodiments.
  • the compounds of formulae (I) to (V) may contain one or more chiral centers and thus exist in the form of many different isomers, optical isomers (i.e. enantiomers) and mixtures thereof including racemic mixtures. All such isomers, enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention.
  • Preferred compounds of the invention include:
  • Compounds of the present invention are further characterized by their ability to inhibit the catalytic activity of thrombin, which can be demonstrated in the assay as follows.
  • Compounds of the present invention may be prepared for assay by dissolving them in buffer to give solutions ranging in concentrations from 0 to lOO ⁇ M.
  • Ki inhibitory dissociation constant
  • a chromogenic or fluorogenic substrate of thrombin would be added to a solution containing a test compound and thrombin; the resulting catalytic activity of the enzyme would be spectrophotometrically determined. This type of assays is well known to those skilled in the art .
  • compounds of the invention may be used in the treatment and/or prophylaxis of thrombotic disorders mediated by the activity of thrombin.
  • thrombotic disorders include venous thrombosis, pulmonary embolism, arterial thrombosis, myocardial infarction and cerebral infarction.
  • Methods of treatment or prophylaxis according to the invention comprise administering to a mammal, more particularly human, an effective amount of compounds of the present invention.
  • effective is meant an amount of the compound sufficient to alleviate or reduce the severity of the disorder as measured by parameters established for the particular indication i.e. blood flow (patency) , clot size or density.
  • the compounds of the present invention may be used as anti ⁇ coagulants in vi tro or ex vivo as in the case of contact activation with foreign thrombogenic surfaces such as is found in tubing used in extracorporeal shunts .
  • the compounds of the invention may also be used to coat the surface of such conduits.
  • the compounds of the invention are obtained as lyophilized powders, redissolved in isotonic saline and added in an amount sufficient to maintain blood in an anticoagulated state.
  • the therapeutic agents of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or adjuvants.
  • the proportion of each carrier, diluent or adjuvant is determined by the solubility and chemical nature of the compound, the route of administration, and standard pharmaceutical practice.
  • the compounds may be injected parenterally; this being intramuscularly, intravenously, or subcutaneously.
  • the compound may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic.
  • the compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like.
  • the compounds may also be administered sublingually in the form of troches or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavouring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form.
  • the compounds may be administered orally in the form of solutions which may contain colouring and/or flavouring agents.
  • Dosages may vary with the mode of administration and the particular compound chosen.
  • the dosage may vary with the particular patient under treatment.
  • typical dosage is about 0.1 to 500 mg/kg body weight per day, and preferably about 0.5 to 10 mg/kg body weight per day.
  • compositions When the composition is administered orally, a larger quantity of the active agent will typically be required to produce the same effect as caused with a smaller quantity given parenterally.
  • various methods can be employed depending upon the particular starting materials and/or intermediates involved.
  • Pg is a nitrogen protecting group
  • R 20 is a C_. e alkyl; and X, n, m, R 3 , R 4 , R 6 R 7 , and R 8 are as defined above .
  • the amino function of the alkylaminoalcohol of formula (X) is protected with an appropriate amino protecting group.
  • a variety of protecting groups known for reactive functional groups and suitable protection and deprotection protocols may be found in T. Greene, Protective Groups In Organic Synthesis. (John Wiley & Sons, 1981) .
  • the appropriate protecting group to use in a particular synthetic scheme will depend on many factors, including the presence of other reactive functional groups and the reaction conditions desired for removal.
  • the protected aminoalkylalcohol is then subjected to oxidation, using an appropriate oxidizing agent, such as a catalytic amount of tetrapropylammonium perruthenate (TPAP) along with N-methylmorpholine oxide (NMO) in an inert solvent such as dichloromethane (CH 2 C1 2 ) to yield to a protected amino alkyl aldehyde of formula (XI) .
  • an appropriate oxidizing agent such as a catalytic amount of tetrapropylammonium perruthenate (TPAP) along with N-methylmorpholine oxide (NMO) in an inert solvent such as dichloromethane (CH 2 C1 2 ) to yield to a protected amino alkyl aldehyde of formula (XI) .
  • TPAP tetrapropylammonium perruthenate
  • NMO N-methylmorpholine oxide
  • XI dichloromethane
  • the protected amino alkyl aldehyde of formula (XI) is coupled with an amino acid alkyl ester of formula (XII) with an appropriate base such as potassium carbonate in an inert solvent such as dichloromethane to yield to a cyclic intermediate of formula (XIII) .
  • the ester function (-C(O)O-R 20 ) of the bicyclic intermediate of formula (XIV) is subjected to hydrolysis using an appropriate reagent such as LiOH to yield to the free carboxylic acid.
  • the resulting compound is then coupled to R 6 H with a peptide coupling agent such as BOP in an appropriate solvent such as dimethylformamide to yield to a coupled bicyclic compound of formula (XV) .
  • a peptide coupling agent such as BOP in an appropriate solvent such as dimethylformamide
  • Suitable conditions for peptide bond formation are well known in the art of peptide chemistry. For example see Principles of Peptide Synthesis. Bodanszky M. , Springer- Verlag, Berlin, Heidelberg, New York, Tokyo 1984; and The Peptides. Analysis. Synthesis. Biology, Vol. 1.edited by Gross E., and Meienhofer J. , Academic Press , New York, San Francisco, London, 1979.
  • the compounds of this invention may be purified during their synthesis and/or after their preparation by standard techniques well known to the skilled artisan.
  • One preferred purification technique is silica gel chromatography.
  • the flash chromatographic technique may be used.
  • other chromatographic methods, including HPLC may be used for purification of the compounds. Crystallization may also be used to purify the products, as may washing procedures with appropriate organic solvents.
  • the compound of formula (I) is desired as a single isomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from isomerically pure starting material or any convenient intermediate. Resolution of the final product, or an intermediate or starting material therefor, may be effected by any suitable method known in the art: see for example, “Stereochemistry of Carbon Compounds", by E.L. Eliel (McGraw Hill, 1962) , and “Tables of Resolving Agents", by S.H. Wilen. Resolution of the final compound can also be achieved using chiral HPLC techniques .
  • the semi-solid was suspended in a mixture of acetic acid (20 mL) , and dry ethanol (40 mL) with warming. Subsequently, Pd/C catalyst (0.30 g, 10% Pd) was added, and hydrogen was bubbled through the mixture with warming. The hydrogenation was continued until no starting material could be detected as judged by TLC. The catalyst was removed by filtration, the solution was concentrated under reduced pressure (50 mL) , HCI (50 mL, 1 N) was added, and the mixture was concentrated once again to 50 mL. The solution was chilled overnight yielding the title compound.
  • the semi-solid was suspended in a mixture of acetic acid (20 mL) , and dry ethanol (40 mL) with warming. Subsequently, Pd/C catalyst (0.30 g, 10% Pd) was added, and hydrogen was bubbled through the mixture with warming. The hydrogenation was continued until no starting material could be detected as judged by TLC. The catalyst was removed by filtration, the solution was concentrated under reduced pressure (50 mL) , HCI (50 mL, 1 N) was added, and the mixture was concentrated once again to 50 mL. The solution was chilled overnight yielding the title compound.
  • the semi-solid was suspended in a mixture of acetic acid (20 mL) , and dry ethanol (40 mL) with warming. Subsequently, Pd/C catalyst (0.30 g, 10% Pd) was added, and hydrogen was bubbled through the mixture with warming. The hydrogenation was continued until no starting material could be detected as judged by TLC. The catalyst was removed by filtration, the solution was concentrated under reduced pressure (50 mL) , HCI (50 mL, 1 N) was added, and the mixture was concentrated once again to 50 mL. The solution was chilled overnight yielding the title compound.
  • Butyloxycarbonyl-para-amidino-phenylalanine-N,0-dimethylamide (1.15 g, 3.3 mmol) in THF (15 mL) was then added dropwise, and the resulting mixture stirred. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was diluted with ethyl acetate (150 mL) , and the organic layer washed with saturated aqueous ammonium chloride (2 x 50 mL) , brine (50 mL) , dried with MgS0 4 , filtered, and concentrated under reduced pressure. The crude material was purified on silica gel (ethyl acetate/hexane) , and concentrated under reduced pressure.
  • the mixture was diluted with ethyl acetate (150 mL) , and the organic layer washed with saturated aqueous ammonium chloride (2 x 50 mL) , brine (50 mL) , dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • the crude material was purified on silica gel (ethyl acetate/hexane) , and concentrated under reduced pressure.
  • the mixture was diluted with ethyl acetate (150 mL) and the organic layer washed with saturated aqueous ammonium chloride (2 x 50 mL) , brine (50 mL) , dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • the crude material was purified on silica gel (ethyl acetate/hexane) , and concentrated under reduced pressure.
  • tert-Butyloxycarbonyl -para-cyano-phenylalanine-N,O- dimethylamide (1.33 g, 4.0 mmol) was dissolved in ethanol saturated with ammonia (30 mL) , and sponge Raney Ni (100 mg) added. The solution was shaken under H 2 at room temperature (40 psi) . The solution was filtered through celite, and concentrated under reduced pressure to yield a clear residue. The residue was dissolved in ethyl acetate (250 mL) , and washed with 1 N NaOH (2 x 50 mL) , and brine (2 x 50 mL) . The solution was dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • tert-Butyloxycarbonyl-ineta-cyano-phenylalanine-N,0- dimethylamide (1.33 g, 4.0 mmol) was dissolved in ethanol saturated with ammonia (30 mL) , and sponge Raney Ni (100 mg) added. The solution was shaken under H 2 at room temperature (40 psi) . The solution was filtered through celite, and concentrated under reduced pressure to yield a clear residue. The residue was dissolved in ethyl acetate (250 mL) , and washed with 1 N NaOH (2 x 50 mL) , and brine (2 x 50 mL) . The solution was dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • tert-Butyloxycarbonyl -ortho-cyano-phenylalanine-N,0- dimethylamide (1.33 g, 4.0 mmol) was dissolved in ethanol saturated with ammonia (30 mL) , and sponge Raney Ni (100 mg) added. The solution was shaken under H 2 at room temperature (40 psi) . The solution was filtered through celite, and concentrated under reduced pressure to yield a clear residue. The residue was dissolved in ethyl acetate (250 mL) , and washed with 1 N NaOH (2 x 50 mL) , and brine (2 x 50 mL) . The solution was dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • tert-Butyloxycarbonyl-para-aminomethyl-phenylalanine-N,0- dimethylamide (1.00 g, 3.1 mmol) was dissolved in dry THF (10 mL) under nitrogen with stirring. The solution was cooled, N,N' -bis- (benzyloxycarbonyl) -S-methyl-isothiourea (1.14 g, 3.2 mmol) , and HgCl 2 (0.95 g, 3.5 mmol) added. The solution was concentrated under reduced pressure, the remaining residue was suspended in ethyl acetate (200 mL) , and filtered through celite. The filtrate was concentrated under reduced pressure. Flash chromatography over silica gel (hexane/ethyl acetate gradient) afforded the purified compound.
  • the mixture was diluted with ethyl acetate (150 mL) , and the organic layer washed with saturated aqueous ammonium chloride (2 x 50 mL) , brine (50 mL) , dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • the crude material was purified on silica gel (ethyl acetate/hexane) , and concentrated under reduced pressure.
  • the mixture was diluted with ethyl acetate (150 mL) , and the organic layer washed with saturated aqueous ammonium chloride (2 x 50 mL) , brine (50 mL) , dried with magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the crude material was purified on silica gel (ethyl acetate/hexane) , and concentrated under reduced pressure.
  • the mixture was diluted with ethyl acetate (150 mL) , and the organic layer washed with saturated aqueous ammonium chloride (2 x 50 mL) , brine (50 mL) , dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • the crude material was purified on silica gel (ethyl acetate/hexane) , and concentrated under reduced pressure.
  • the semi-solid was suspended in a mixture of acetic acid (20 mL) , and dry ethanol (40 mL) with warming. Subsequently, Pd/C catalyst (0.30 g, 10% Pd) was added, and hydrogen was bubbled through the mixture with warming. The hydrogenation was continued until no starting material could be detected as judged by TLC. The catalyst was removed by filtration, and the solution was concentrated under reduced pressure (50 mL) , HCI (50 mL, 1 N) was added, and the mixture was concentrated once again to 50 mL. The solution was chilled overnight yielding the title compound.
  • the mixture was diluted with ethyl acetate (150 mL) , and the organic layer washed with saturated aqueous ammonium chloride (2 x 50 mL) , brine (50 mL) , dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • the crude material was purified on silica gel ethyl acetate/hexane) , and concentrated under reduced pressure.
  • tert-Butyloxycarbonyl-3- (3-pyridyl) alanine-N,O-dimethylamide (4.50 g, 14.4 mmol) was dissolved in acetic acid (100 mL) , and Pt0 2 (100 mg) added. The solution was shaken under H 2 until gas uptake ceased. The solution was filtered through celite, and concentrated under reduced pressure yielding tert- butyloxycarbonyl-3- (3-piperidyl) alanine-N,O-dimethylamide.
  • tert-Butyloxycarbonyl-3- (2-pyridyl) alanine-N,O-dimethylamide (4.50 g, 14.4 mmol) was dissolved in acetic acid (100 mL) , and Pt0 2 (100 mg) added. The solution was shaken under H 2 until gas uptake ceased. The solution was filtered through celite, and concentrated under reduced pressure yielding tert- butyloxycarbonyl-3- (2-piperidyl) alanine-N,O-dimethylamide.
  • tert-Butyloxycarbonyl-3- (3-piperidyl) alanine-N,O-dimethylamide (1.00 g, 3.2 mmol) was dissolved in dry THF (10 mL) under nitrogen with stirring. The solution was cooled, N,N'-bis- (benzyloxycarbonyl) -S-methyl-isothiourea (1.14 g, 3.2 mmol) , and HgCl 2 (0.95 g, 3.5 mmol) added. The solution was concentrated under reduced pressure, the remaining residue was suspended in ethyl acetate (200 mL) , and filtered through celite. The filtrate was concentrated under reduced pressure. Flash chromatography over silica gel (hexane/ethyl acetate gradient) afforded the title compound.
  • tert-Butyloxycarbonyl-3- (2-piperidyl) alanine-N,O-dimethylamide (1.00 g, 3.2 mmol) was dissolved in dry THF (10 mL) under nitrogen with stirring. The solution was cooled, N,N'-bis- (benzyloxycarbonyl) -S-methyl-isothiourea (1.14 g, 3.2 mmol) , and HgCl 2 (0.95 g, 3.5 mmol) added. The solution was concentrated under reduced pressure, the remaining residue was suspended in ethyl acetate (200 mL) , and filtered through celite. The filtrate was concentrated under reduced pressure. Flash chromatography over silica gel (hexane/ethyl acetate gradient) afforded the title compound.
  • the mixture was diluted with ethyl acetate (150 mL) , and the organic layer washed with saturated aqueous ammonium chloride (2 x 50 mL) , brine (50 L) , dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • the mixture was diluted with ethyl acetate (150 mL) , and the organic layer washed with saturated aqueous ammonium chloride (2 x 50 mL) , brine (50 mL) , dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • the mixture was diluted with ethyl acetate (150 mL) , and the organic layer washed with saturated aqueous ammonium chloride (2 x 50 mL) , brine (50 mL) , dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • tert-Butyloxycarbonyl-para-nitro-phenylalanine-N,O- dimethylamide 13.88 g, 39.3 mmol was dissolved in acetic acid (100 mL) , and Pt0 2 (100 mg) added. The solution was shaken under H 2 until gas uptake ceased. The solution was filtered through celite, concentrated under reduced pressure, taken up in H 2 0 (150 mL) , and lyophilized. The semi-solid was dissolved in ethyl acetate (350 mL) , washed with 1 N NaOH (3 x 50 mL) , and brine (3 x 50 mL) . The solution was dried with MgS0 4 , filtered, and concentrated under reduced pressure yielding the title compound.
  • the mixture was diluted with ethyl acetate (150 mL) , and the organic layer washed with saturated aqueous ammonium chloride (2 x 50 mL) , brine (50 mL) , dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • the crude material was purified on silica gel (ethyl acetate/hexane) , and concentrated under reduced pressure.
  • the mixture was diluted with ethyl acetate (150 mL) , and the organic layer washed with saturated aqueous ammonium chloride (2 x 50 mL) , brine (50 mL) , dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • the crude material was purified on silica gel (ethyl acetate/hexane) , and concentrated under reduced pressure.
  • ter ⁇ -Butyloxycarbonyl-3- (cis/t a ⁇ s-2- aminocyclohe yl) alanine-N,O-dimethylamide (1.00 g, 3.0 mmol) was dissolved in saturated aqueous sodium bicarbonate, and THF [60 mL, (1:1)] with stirring. The solution was cooled and a solution of benzyl chloroformate (0.43 mL, 3.0 mmol) in THF (10 mL) was added dropwise. Excess solid sodium bicarbonate was added, the THF was removed under reduced pressure, and the remaining aqueous phase was poured into ethyl acetate (250 mL) , and mixed thoroughly.
  • the aqueous phase was discarded and the remaining solution was washed with saturated aqueous sodium bicarbonate (2 50 mL) , 4 N aqueous sodium bisulfate (2 x 50 mL) , and brine (2 x 50 mL) .
  • the solution was dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • the semi-solid was chromatographed on silica gel (ethyl acetate/ hexane) .
  • the mixture was diluted with ethyl acetate (150 mL) , and the organic layer washed with saturated aqueous ammonium chloride (2 x 50 mL) , brine (50 mL) , dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • the crude material was purified on silica gel (ethyl acetate/hexane) , and concentrated under reduced pressure.
  • the mixture was diluted with ethyl acetate (150 mL) , and the organic layer washed with saturated aqueous ammonium chloride (2 x 50 mL) , brine (50 mL) , dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • the crude material was purified on silica gel (ethyl acetate/hexane) , and concentrated under reduced pressure.
  • the mixture was diluted with ethyl acetate (150 mL) , and the organic layer washed with saturated aqueous ammonium chloride (2 x 50 mL) , brine (50 mL) , dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • the crude material was purified on silica gel (ethyl acetate/hexane) , and concentrated under reduced pressure.
  • the mixture was diluted with ethyl acetate (150 mL) , and the organic layer washed with saturated aqueous ammonium chloride (2 x 50 mL) , brine (50 mL) , dried with MgS0 4 , filtered, and concentrated under reduced pressure.
  • the crude material was purified on silica gel (ethyl acetate/hexane) , and concentrated under reduced pressure.
  • Tetrapropylammonium perruthenate (67 mg; 4.23 mmoles) was added to a well stirred mixture of the alcohol (2) (608 mg; 4.23 mmols) and powdered 4A molecular sieves (1.5 g) in dichloromethane (10 ml) . After being stirred for 20 minutes, the mixture was filtered through celiteTM. Evaporation of the solvent gave a black oil which was then purified on silica gel
  • the isolated urea (5a) is hydrolyzed with one equivalent of LiOH»H 2 0 in a 1:1 mixture of THF and H 2 0. The mixture is stirred at room temperature for 1 hour and the resulting solution is poured into 10% citric acid and extracted with dichloromethane to yield the crude carboxylic acid.
  • the crude carboxylic acid is coupled with benzothiazole keto arginine in DMF using BOP as the coupling reagent in the presence of diisopropylethylamine. Extraction with EtOAc gives a solid that is purified on silica gel to give the protected amide.
  • the CBZ protecting group is removed with BBr 3 in dichloromethane at room temperature finally gives the bicyclic benzothiazole keto arginine inhibitors (6) .
  • the urea of formula (7) is produced according to the same method as for the bicyclic benzothiazole keto arginine inhibitors (6) with the difference that the N- benzylethanolamine (1) is substituted by N-Benzyl-3-amino- propanol.
  • the amide was dissolved in CH 2 C1 2 (10 ml) and treated at -78°C with BC1 3 IM (2.8 ml) . The solution was stirred at room temperature for 2 hours and quenched with dry methanol (3.0 ml) at -78°C. The solution was stirred at room temperature for one hour, then volatiles were evaporated. Purification by HPLC afforded the pure compound A (59.8 mg, fast moving component, one pure isomer) and B (37.4 mg, slow moving component, one pure isomer) . *Stereochemistry arbitrarily assigned.
  • the reaction reached a steady-state within 3 minutes after mixing thrombin with the substrate and an inhibitor. The steady-state velocity was then measured for a few minutes.
  • the compounds of this invention were also pre-incubated with thrombin for 20 minutes at room temperature before adding the substrate.
  • the steady-state was achieved within 3 min and measured for a few min.
  • the kinetic data (the steady-state velocity at various concentrations of the substrate and the inhibitors) of the competitive inhibition was analyzed using the methods described by Segel (1975) .
  • a non-linear regression program, RNLIN in the IMSL library (IMSL, 1987) , LMDER in MINPACK library (More et al., 1980) or MicrosoftTM ExcellTM was used to estimate the kinetic parameters (K,,, V max and K_) .

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Abstract

Inhibiteurs hétérocycliques de l'enzyme thrombine, leur préparation et compositions pharmaceutiques contenant lesdits inhibiteurs de formule générale (I) dans laquelle X, R2, R3, R4, R6, R7 et R8 sont tels que définis dans la présente demande. La présente invention concerne en outre l'utilisation de ces composés et compositions en tant qu'anticoagulants et en tant qu'agents pour le traitement et la prophylaxie des troubles thrombotiques telle que la thrombose veineuse, l'embolie pulmonaire et la thrombose artérielle entraînant des accidents ischémiques aigus tels que l'infarctus du myocarde ou l'infarctus cérébral.
PCT/CA1996/000318 1995-05-22 1996-05-22 Inhibiteurs de thrombine bicycliques de type uree et de faible poids moleculaire WO1996037497A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP8535221A JPH11505260A (ja) 1995-05-22 1996-05-22 低分子量２環式尿素型トロンビン阻害剤
AU56825/96A AU5682596A (en) 1995-05-22 1996-05-22 Low molecular weight bicyclic-area type thrombin inhibitors
EP96914817A EP0846120A1 (fr) 1995-05-22 1996-05-22 Inhibiteurs de thrombine bicycliques de type uree et de faible poids moleculaire

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9510264.6 1995-05-22
GBGB9510264.6A GB9510264D0 (en) 1995-05-22 1995-05-22 Low molecular weight bicyclic-urea type thrombin inhibitors

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998028326A1 (fr) * 1996-12-23 1998-07-02 Biochem Pharma Inc. Inhibiteurs bicycliques de thrombine
US6323219B1 (en) 1998-04-02 2001-11-27 Ortho-Mcneil Pharmaceutical, Inc. Methods for treating immunomediated inflammatory disorders
US6469036B1 (en) 1999-01-27 2002-10-22 Ortho-Mcneil Pharmaceutical, Inc. Peptidyl heterocyclic ketones useful as tryptase inhibitors
US7192615B2 (en) 2001-02-28 2007-03-20 J&J Consumer Companies, Inc. Compositions containing legume products
US7309688B2 (en) 2000-10-27 2007-12-18 Johnson & Johnson Consumer Companies Topical anti-cancer compositions and methods of use thereof
US7629318B2 (en) 2002-03-22 2009-12-08 Gpc Biotech Ag Immunosuppressant compounds, methods and uses related thereto
US8093293B2 (en) 1998-07-06 2012-01-10 Johnson & Johnson Consumer Companies, Inc. Methods for treating skin conditions
US8106094B2 (en) 1998-07-06 2012-01-31 Johnson & Johnson Consumer Companies, Inc. Compositions and methods for treating skin conditions
US8431550B2 (en) 2000-10-27 2013-04-30 Johnson & Johnson Consumer Companies, Inc. Topical anti-cancer compositions and methods of use thereof
US9758473B2 (en) 2014-10-06 2017-09-12 Cortexyme, Inc. Inhibitors of lysine gingipain
US10730826B2 (en) 2016-09-16 2020-08-04 Cortexyme, Inc. Ketone inhibitors of lysine gingipain
US10906881B2 (en) 2015-11-09 2021-02-02 Cortexyme, Inc. Inhibitors of arginine gingipain

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 108, no. 9, 29 February 1988, Columbus, Ohio, US; abstract no. 75817d, UKON NAGAI ET AL: "Synthesis of an LH-RH analog with restricted conformation by incorporation of a bicyclic beta-turn dipeptide unit" page 728; XP002008859 *
K. KAWASAKI ET AL: "Amino acids and peptides. XIII. Synthesis studies on N-terminal tripeptide amide analogs of fibrin alpha-chain", CHEMICAL AND PHARMACEUTICAL BULLETIN., vol. 39, no. 3, March 1991 (1991-03-01), TOKYO JP, pages 584 - 589, XP000576123 *
PEPT. CHEM., vol. 24, 1987, pages 295 - 298 *
U. NAGAI ET AL: "Bicyclic turned dipeptide (BTD) as a beta-turn mimetic; its design, synthesis and incorporation into bioactive peptides", TETRAHEDRON, vol. 49, no. 17, 1993, OXFORD GB, pages 3577 - 3592, XP000576111 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998028326A1 (fr) * 1996-12-23 1998-07-02 Biochem Pharma Inc. Inhibiteurs bicycliques de thrombine
US6323219B1 (en) 1998-04-02 2001-11-27 Ortho-Mcneil Pharmaceutical, Inc. Methods for treating immunomediated inflammatory disorders
US8093293B2 (en) 1998-07-06 2012-01-10 Johnson & Johnson Consumer Companies, Inc. Methods for treating skin conditions
US8106094B2 (en) 1998-07-06 2012-01-31 Johnson & Johnson Consumer Companies, Inc. Compositions and methods for treating skin conditions
US6469036B1 (en) 1999-01-27 2002-10-22 Ortho-Mcneil Pharmaceutical, Inc. Peptidyl heterocyclic ketones useful as tryptase inhibitors
US7132418B2 (en) 1999-01-27 2006-11-07 Ortho-Mcneil Pharmaceutical, Inc. Peptidyl heterocyclic ketones useful as tryptase inhibitors
US8431550B2 (en) 2000-10-27 2013-04-30 Johnson & Johnson Consumer Companies, Inc. Topical anti-cancer compositions and methods of use thereof
US7309688B2 (en) 2000-10-27 2007-12-18 Johnson & Johnson Consumer Companies Topical anti-cancer compositions and methods of use thereof
US7897144B2 (en) 2001-02-28 2011-03-01 Johnson & Johnson Comsumer Companies, Inc. Compositions containing legume products
US7192615B2 (en) 2001-02-28 2007-03-20 J&J Consumer Companies, Inc. Compositions containing legume products
US7629318B2 (en) 2002-03-22 2009-12-08 Gpc Biotech Ag Immunosuppressant compounds, methods and uses related thereto
US10301301B2 (en) 2014-10-06 2019-05-28 Cortexyme, Inc. Inhibitors of lysine gingipain
US9988375B2 (en) 2014-10-06 2018-06-05 Cortexyme, Inc. Inhibitors of lysine gingipain
US9758473B2 (en) 2014-10-06 2017-09-12 Cortexyme, Inc. Inhibitors of lysine gingipain
US10676470B2 (en) 2014-10-06 2020-06-09 Cortexyme, Inc. Inhibitors of lysine gingipain
US11332464B2 (en) 2014-10-06 2022-05-17 Cortexyme, Inc. Inhibitors of lysine gingipain
US10906881B2 (en) 2015-11-09 2021-02-02 Cortexyme, Inc. Inhibitors of arginine gingipain
US10730826B2 (en) 2016-09-16 2020-08-04 Cortexyme, Inc. Ketone inhibitors of lysine gingipain
US11325884B2 (en) 2016-09-16 2022-05-10 Cortexyme, Inc. Ketone inhibitors of lysine gingipain
US12110263B2 (en) 2016-09-16 2024-10-08 Lighthouse Pharmaceuticals, Inc. Ketone inhibitors of lysine gingipain

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GB9510264D0 (en) 1995-07-19
ZA964090B (en) 1997-05-13
AU5682596A (en) 1996-12-11
EP0846120A1 (fr) 1998-06-10
CA2218816A1 (fr) 1996-11-28
JPH11505260A (ja) 1999-05-18

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