WO1996019483A1 - Inhibiteurs de la thrombine bicyclique a faible poids moleculaire - Google Patents

Inhibiteurs de la thrombine bicyclique a faible poids moleculaire Download PDF

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Publication number
WO1996019483A1
WO1996019483A1 PCT/CA1995/000708 CA9500708W WO9619483A1 WO 1996019483 A1 WO1996019483 A1 WO 1996019483A1 CA 9500708 W CA9500708 W CA 9500708W WO 9619483 A1 WO9619483 A1 WO 9619483A1
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Prior art keywords
alkyl
compound according
aryl
oxo
cycloalkyl
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PCT/CA1995/000708
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English (en)
Inventor
John Dimaio
Annette Marian Doherty
M. Arshad Siddiqui
Jeremy John Edmonds
John W. Gillard
Yves St-Denis
Micheline Tarazi
Patrice Preville
Sophie Levesque
Benoit Bachand
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Biochem Pharma Inc.
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Publication date
Priority claimed from GBGB9426038.7A external-priority patent/GB9426038D0/en
Priority claimed from GBGB9510266.1A external-priority patent/GB9510266D0/en
Priority claimed from GBGB9510267.9A external-priority patent/GB9510267D0/en
Priority claimed from GBGB9510265.3A external-priority patent/GB9510265D0/en
Priority to SK838-97A priority Critical patent/SK83897A3/sk
Priority to JP8519383A priority patent/JPH11508535A/ja
Priority to EP95940923A priority patent/EP0802916A1/fr
Priority to BR9510433A priority patent/BR9510433A/pt
Priority to EE9700113A priority patent/EE9700113A/xx
Application filed by Biochem Pharma Inc. filed Critical Biochem Pharma Inc.
Priority to APAP/P/1997/001004A priority patent/AP9701004A0/en
Priority to AU42505/96A priority patent/AU4250596A/en
Priority to NZ297360A priority patent/NZ297360A/xx
Priority to MD97-0253A priority patent/MD970253A/ro
Publication of WO1996019483A1 publication Critical patent/WO1996019483A1/fr
Priority to IS4504A priority patent/IS4504A/is
Priority to FI972466A priority patent/FI972466A/fi
Priority to BG101647A priority patent/BG101647A/xx
Priority to NO972892A priority patent/NO972892L/no
Priority to US08/880,885 priority patent/US6057314A/en
Priority to LVP-97-141A priority patent/LV12019B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to compounds useful for the
  • 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
  • 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 (eg. ADP TXA 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
  • 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. However, heparin also catalyzes inhibition of other proteases in the coagulation cascade and its
  • thrombocytopenia, osteoporosis and triglyceridemia have been observed following prolonged treatment with heparin.
  • Hirudin derived from the glandular secretions of the leech hirid ⁇ medicinalis is one of the high molecular weight natural anticoagulant protein inhibitors of
  • 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.,
  • Thrombin activity can also be inhibited by low molecular weight compounds that compete with fibrinogen for
  • Blomback et al first designed a thrombin inhibitor that was modeled upon the partial sequence of the fibrinogen A(LBi)0c chain comprising its proteolytically susceptible region (Blomback, et al., J. Clin. Lab. Invest., 24 , 59, 1969). This region of fibrinogen minimally includes the residues commencing with phenylalanine: Ala-Asp-Ser-Gly-Glu-Gly-Asp-Phe-Leu-Ala-Glu-Gly
  • aldehyde group is presumed to contribute strongly to inhibitory activity in view of its chemical reactivity toward thrombin's catalytic Ser residue, generating a hemiacetal intermediate.
  • thrombin inhibitors bearing the (D)Phe-Pro-Arg general motif are those incorporating COOH- terminal boroarginine variants such as boronic acids or boronates (Kettner, C. et al., J. Biol. Chem., 268, 4734, 1993). Still other congeners of this motif are those bearing phosphonates (Wang, C-L J., Tetrahedron Letters, ll, 7667, 1992) and ⁇ -Keto esters (Iwanowicz, E.J. et al., Bioorganic and Medicinal Chemistry Letters, 12, 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, 32, 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.
  • One object of the present invention is to provide thrombin inhibitors that display inhibitory activity towards the target enzyme, thrombin.
  • a further object of the present invention is to provide thrombin inhibitors that display inhibitory activity towards the target enzyme thrombin and are provided for in s pnarmacologically acceptable state.
  • Still a further object of the present invention is to provide for the use of heterocyclic thrombin inhibitors and formulations thereof as anticoagulant and thrombin inhibitory agents.
  • Yet a further object of the present invention is to provide for the use of heterocyclic thrombin inhibitors and formulations thereof for therapeutic treatment of various thrombotic maladies .
  • a further object of the present invention is a process for the synthesis of these low molecular weight thrombin inhibitors.
  • the enzyme inhibitors of the present invention are encompassed by the structure of general Formula I.
  • the present invention provides for novel compounds that display thrombin inhibitory activity as reflected in formula I :
  • A is selected from (CH-R 8 ) , S, SO, SO , O and NR wherein R 8 is hydrogen, C alkyl optionally interupted with 1 or 2 heteroatoms; C aryl, C _ cycloalkyl or heterocyclic ring or a hydrophobic group;
  • R 6 and R 7 are independently selected from
  • D is selected from (CH-R 5 ) wherein R is hydrogen, C
  • E is selected from CH and CH substituted with the -C ( O ) F. provided that only one of D and E is substituted with with -C (O)R ;
  • X is selected from O, N-R , or CH-R ;
  • Y is selected from O, S, SO, SO , N-R and CH-R provided that when X is N-R then Y is CH-R or O, and when X is O then Y is CH-R ;
  • Z is selected from O, S and H ;
  • R is a polar amino acid residuearginyl moiety or an analog or derivative thereof optionally substituted with an amino acid, a peptide or a heterocycle ;
  • R 2 is selected from H and C alkyl optionally substituted with C aryl, a 6 member heterocycle or a C _ cycloalkyl ring;
  • R 3 is selected from H, NRR- and C alkyl
  • R 4 and R 5 are independently selected from H; NR,R, ; C, , aryl or C cycloalkyl optionally substituted with C . alkyl; C alkyl optionally interrupted by one or more
  • heteroatom or carbonyl group and optionally substituted with OH, SH, NRR or a C aryl, heterocycle or C cycloalkyl group optionally substituted with halogen, hydroxyl , C alkyl; an amino acid side chain; and a hydrophobic group.
  • the molecules, compositions and methods of this invention are useful as anti-coagulants, or in the treatment and
  • the present invention relates to molecules 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 alkyl, C alkenyl (e.g. vinyl, allyl) or C alkynyl (e.g. propargyl) optionally interrupted by a carbonyl group, (e.g. forming an acyl group); C aryl, C
  • hydrophobic groups include cyclohexyl, benzyl, benzoyl, phenylmethyl ,
  • arginyl moiety represents an arginine amino acid residue or an analogue or derivative thereof.
  • 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);
  • ns trained group i.e. an aryl, cycloalkyl or
  • 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 R ) halogen or C alkyl.
  • Aromatic rings include benzene, napththalene, phenanthrene and anthracene.
  • Preferred aromatic rings are benzene and naphthalene.
  • cycloalkyl represents a saturated carbocyclic ring of 3 to 7 carbon atoms which is optionally mono- or di-substituted with OH, SH, amino (i.e. NR.R ) halogen or C alkyl.
  • Cycloalkyl groups 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 disubstituted with OH, SH, amino (i.e. NR R ) halogen or C alkyl
  • heteroatom represents oxygen, nitrogen or sulfur (O, N or S) as well as sulfoxyl or sulfonyl (SO or SO ) 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 Freferrably, 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
  • a heterocycle is optionally mono- or di-substituted with OH, SH, amino (i.e. NR R- ) , halogen, CF , oxo or C alkyl.
  • suitable monocyclic heterocycles include but are not limited to pyridine, piperidine, pyrazine, piperazine, pyrimidine, imidazole, thiazole, oxazole, furan, pyran and thiophene .
  • suitable bicyclic heterocycles include but are not limited to indole, quinoline,
  • 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 include natural amino acid residues such as alanine; isoleucine; leucine;
  • Vellaccio Suitable non-naturally ocurring amino acids include cyclohexylalanine and 1-aminocyclohexanecarboxylic.
  • amino acid side chain is meant the substituent attached to the carbon which is ⁇ to the amino group.
  • R 2 is H or C alkyl. More preferably R is H methyl or ethyl and most preferably R is H.
  • R 3 is H or C alkyl. More preferably, R is K methyl or ethyl, and most preferably R is H.
  • one of R 4 or R 5 is 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 alkyl optionally substituted by NP. P. or carboxy.
  • the hydrophobic moiety may be linked via a spacer such as a C . alkyl chain optionally interrupted with 1 or more (i.e. 1-4) heteroatoms, carbonyl or sulfonyl (SO ) groups.
  • one of R 4 and R 5 is phenyl , cyclohexyl, indole, thienyl, quinoline,
  • A is absent or CH .
  • B is S or CH .
  • D is CH .
  • E is CH substituted with -C(O)R wherein R is as previously defined.
  • X is CH-R or N-R .
  • Y is CH-R or S.
  • R 1 is represented by one of formula Via to VId:
  • R 11 is hydrogen or C alkyl
  • K is a bond or -NH- ;
  • G is C alkoxy; cyano ; -NH ; -CH -NH ; -CINH.-NH; -NHC(NH)-NH; -CH -NH-C (NH) -NH ; a C cycloalkyl or aryl substituted with cyano, -NH , -CH -NH , -C(NH)-NH , -NH C(NH)-NH or -CH -NH-C (NH) -NH ; or a 5 or 6 member, saturated or unsaturated heterocycle optionally
  • U is cyano, -NH , -C(NH)-NH or -NH-C (NH) -NH ;
  • P is a bond, -C(O)- or a bivalent group:
  • J is C alkylene optionally substituted with OH, NH and C alkyl and optionally interrupted by a heteroatom selected from O, S and N;
  • n 0 or 1 ;
  • T is H, OH, amino, a peptide chain, C alkyl, C alkoxy, C aralkyl, or heterocycle optionally substituted.
  • R 11 is H or methyl and most preferably H.
  • K is a bond
  • G is -NH-C(NH)-NH attached via a methylene chain of 3-7 carbons or phenyl substituted with -C(NH)-NH attached via a methylene chain of 0 to 3 carbons. More preferably G -NH-C(NH)-NH attached via a methylene chain of 3 atoms .
  • P is -C(O)-.
  • J is selected from: -CH -S-CH -CH - ; -CH -O-CH CH - ; -CH -NH-CH -CH - ; and a bond when n is 0. More preferably, J is a bond while n is 0.
  • R is selected from the following amino acid derivatives prepared
  • 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:
  • R' is hydrogen, C _ alkyl optionally carboxyl substituted, carboxyl, -C . alkyl-CO -C alkyl, C aralkyl, C
  • 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 as defined above.
  • T is or
  • R' is H or C alkyl such as methyl, ethyl, propyl or butyl and most preferably wherein R' is hydrogen, .
  • T is a 1,2 thiazole optionally
  • compounds of the invention are represented by formulas II, III, IV and V, wherein X, Y, B, R to R and R are as previously defined.
  • compounds of the invention are represented by one of formulas VII, VIII, IX and X:
  • B is O, S, -CH-, or -NH- ;
  • Y is selected from O, S, SO, SO , N-R and CH-R tenu;
  • R j is an arginyl moiety or an analog or derivative thereof optionally substituted with an amino acid, a peptide or a heterocycle;
  • R 2 is H or C alkyl
  • R 3 is selected from H, NR R 7 and C alkyl
  • R 4 and R 5 are independently selected from H; NRR ; C aryl or C cycloalkyl optionally substituted with C alkyl C alkyl optionally interrupted by one or more
  • heteroatom or carbonyl group and optionally substitute:! with OH, SH, NRR, or a C aryl, heterocycle or C cycloalkyl group optionally substituted with halogen, hydroxyl , C . alkyl; an amino acid side chain; and a hydrophobic group;
  • R ⁇ is hydrogen, C . alkyl optionally interupted with 1 or 2 heteroatoms; C aryl, C, - cycloalkyl or heterocyclic ring or a hydrophobic group; and
  • n 1 or 2.
  • Preferred compounds according to formula VII include: 0005 6S-benzylhexahydro-5-oxo-5H- thiazolo[3,2-a] pyridine-3R- carboxamido (propyl
  • 0275 8a-Methyl-5-oxo-6-(3- phenyl-propyl)-hexahydrothiazolo[3,2-a]pyridine-3- carboxylic acid [4- guanidino-1-(thiazole-2- carbonyl)-butyl]-amide
  • 0280 8a-Methyl-5-oxo-6-(3- phenyl-propyl)-hexahydrothiazolo[3,2-a]pyridine-3- carboxylic acid [4- guanidino-1-(thiazole-2- carbonyl)-butyl]-amide
  • More preferred compounds according to formula (VII) include:
  • 0220 6-Benzyl-8a-methyl-5-oxo-hexahydro-thiazolo[3,2- a]pyridine-3-carboxylic acid [1-(benzothiazole-2- carbonyl)-4-guanidino-butyl]-amide; 0240 8a-Methyl-5- oxo-6-(2-trifluoromethyl-quinolin-6-ylmethyl)- hexahydro-thiazolo[3,2-a]pyridine-3-carboxylic acid [1- (benzothiazole-2-carbonyl)-4-guanidino-butyl]-amide; 0245 6-Benzyl-5-oxo-hexahydro-thiazolo[3,2-a]pyridine-3- carboxylic acid [4-guanidino-1-(thiazole-2- carbonyl)butyl]-amide; 0260 6-Benzyl-8a-methyl-5-oxo-hexahydro-thiazolo[3,2- a]pyridine
  • thiazolo[3,2-a]pyridine-3-carboxylic acid [4-guanidino- 1-(thiazole-2-carbonyl)-butyl]-amide.
  • Most preferred compounds according to formula VII include: 0085 6S-cyclohexylmethylhexahydro-5-oxo-5H-thiazolo[3,2- a]pyridine-3R-carboxamido (propylcarbo methoxy
  • Preferred compounds according to formula VIII include:
  • 0670 4-Oxo-2-(3-phenyl-propionyl)- octahydro-pyrrolo[1,2-a]pyrazine- 6-carboxylic acid [3-(2-amino-6- chloro-pyrimidin-4-yl)-1- (thiazole-2-carbonyl)-propyl]- amide
  • 0675 4-Oxo-2-(3-phenyl-propionyl)- octahydro-pyrrolo[1,2-a]pyrazine- 6-carboxylic acid [3-(6-amino- pyridin-2-yl)-1-(thiazole-2- carbonyl)-propyl]-amide
  • 0745 4-Oxo-2-(3-phenyl-propionyl)- octahydro-pyrrolo[1,2-a]pyrazine- 6-carboxylic acid [1-(3guanidino-cyclohexylmethyl)-2- oxo-2-thiazol-2-yl-ethyl]-amide
  • 0750 4-Oxo-2-(3-phenyl-propionyl)- octahydro-pyrrolo[1,2-a]pyrazine- 6-carboxylic acid [1-(4- guanidino-cyclohexylmethyl)-2- oxo-2-thiazol-2-yl-ethyl]-amide
  • Preferred compounds according to formula (VIII) include: 0325 3-Aminomethyl-2-benzoyl-4-oxo-octahydro-pyrrolo[1,2- a]pyridine-6-carboxylic acid [1-(benzothiazole-2- carbonyl)-4-guanidino-butyl]-amide
  • 0750 4-Oxo-2-(3-phenyl-propionyl)-octahydro-pyrrolo[1,2- a]pyrazine-6-carboxylic acid [1-(4-guanidinocyclohexylmethyl)-2-oxo-2-thiazol-2-yl-ethyl]-amide
  • 0760 4-Oxo-2-(3-phenyl-propionyl)-octahydro-pyrrolo[1,2- a]pyrazine-6-carboxylic acid [1-(5-benzyl-thiazole-2- carbonyl)-4-guanidino-butyl]-amide
  • Preferred compounds according to formula IX include:
  • Preferred compounds according to formula X include
  • More preferred compounds according to formula X include: 925 7-Benzyl-6-oxo-octahydro-pyrido[2,1-c][1,4]thiazine-4- carboxylic acid [4-guanidino-1-(thiazole-2- carbonyl)butyl]-amide; and940 6-Oxo-7-phenethyloctahydro-pyrido[2,1-c][1,4]thiazine-4-carboxylic acid [4-guanidino-1-(thiazole-2-carbonyl)-butyl)-amide .
  • Preferred compounds according to formula III include:
  • Step 2
  • Step 3
  • adduct e. from aldehyde c with d is done by stirring the reactant in aromatic solvents e.g. benzene or toluene in presence of catalytic amount of suitable acid e.g, p-toluenesulfonic acid.
  • aldehyde c to aldehyde g is readily achieved by appropriate protection deprotection protocals found in T. Greene, Protective Groups In Organic Synthesis, (John Wiley & Sons, 1981).
  • Step 4
  • Tne cylization of adduct e to f may readily be achieved by appropriate Lewis acids e.g, trimethyl aluminum in suitable solvents e.g. dichloromethane, the methodology found in T. Greene, supra. Step 4':
  • the compound f can be derived from the treatment of aldehyde g with d in presence of suitable aromatic solvents e.g, benzene.
  • Pg is a nitrogen protecting group
  • each of R 20 ; and R 21 is independently a C alkyl; and X, R 1 , R 3 , R 4 and R 5 are as previously defined.
  • the amino and carboxylic functions of the unsaturated compound of formula (a) are protected with appropriate protecting groups.
  • a variety of protecting groups known for reactive functional groups and suitable protection and deprotection protocols may be found in T. Greene,
  • 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 unsaturated compound of formula is easily obtained by methods and protocols known to chemist skill on the art.
  • the protected unsaturated compound of formula (a) is subjected to appropriate conditions to allow cyclisation using an appropriate reagent such as mercuric acetate in an inert solvent such as tetrahydrofuran (THF) to yield to a protected amino alcohol of formula (b) .
  • the protected amino alcohol of formula (b) is oxidized using an appropriate oxidizing agent such as sulfur trioxide pyridine complex in an appropriate solvent such as diclhoromethane or dimethylformamide to yield to a protected amino aldehyde of formula (c) .
  • an appropriate oxidizing agent such as sulfur trioxide pyridine complex
  • an appropriate solvent such as diclhoromethane or dimethylformamide
  • intermediate (C) can be made by the ozonolysis of a compound of formula (a') prepared according to Collado et al, J. Org. Chem.,1995, 60:5011.
  • the protected amino aldehyde of formula (c) is coupled with an amino acid alkyl ester of formula (d) by first forming the imine followed by contacting the obtained imine with an appropriate reagent such as sodium
  • the cyclic intermediate of formula (e) is functionalized at the amino position to yield to the amino substituted cyclic intermediate of formula (f).
  • Conditions appropriate for such reactions are well known in the art and will depend on the nature of the R 5 substituent.
  • the amino protecting group of the cyclic intermediate of formula (f) is removed under appropriate conditions and the resulting compound is then subjected to appropriate condition for internal ring closure such as low heat in an inert solvent or as a raw compound to yield to a bicyclic intermediate of formula (g).
  • the bicyclic intermediate of formula (g) can also be obtained by hydrolysing the ester function (-C(O)O-R 20 ) of the cyclic intermediate of formula (g) to the free carboxylic acid followed by standard peptide coupling using an appropriate coupling reagent such as benzotriazole-1-yloxy-tris- (dimethylamino)phosphonium hexafluorophosphate (BOP) in an inert solvent such as dimethyl formamide (DMF).
  • an appropriate coupling reagent such as benzotriazole-1-yloxy-tris- (dimethylamino)phosphonium hexafluorophosphate (BOP) in an inert solvent such as dimethyl formamide (DMF).
  • Pg is a sulfur or amino protecting group
  • L is a leaving group
  • each of R 20 ; and R 21 is independently a C alkyl; and R 1 , R,
  • R 4 and R 5 are as previously defined.
  • the carboxylic acid compound (a) is coupled to the cyclic amine compound (b) with a peptide coupling agent such as benzotriazol-1-yloxy-tris- (dimethylamino) phosphonium hexafluorophosphate (BOP reagent) in the presence of a base such as n-methylmorpholine in an appropriate solvent such as dimethylformamide (DMF) or dichloromethane (DCM) to yield to an amido compound of formula (c) .
  • a peptide coupling agent such as benzotriazol-1-yloxy-tris- (dimethylamino) phosphonium hexafluorophosphate (BOP reagent) in the presence of a base such as n-methylmorpholine in an appropriate solvent such as dimethylformamide (DMF) or dichloromethane (DCM) to yield to an amido compound of formula (c) .
  • a peptide coupling agent such as benzotriazol
  • the compound of formula (c) is subjected to appropriate conditions to allow internal cyclisation to yield to a bicyclic intermediate of formula (d).
  • appropriate conditions for example, acid mediated cyclisation using p-toluenesulfonic acid or TFA in an appropriate solvent such as dichloroethane.
  • each of R 20 and R 21 is independently a C alkyl; and B, R 1 , R 3 , R 4 , and R 5 are as previously defined.
  • the process depicted in scheme 4 is briefly described as follows:
  • the halogenated compound of formula (a) is converted to a halomethyl ketone of formula (b) using an appropriate reagent, such as diazomethane in an inert solvent such as diethyl ether at a temperature of about -25°C to about 0°C.
  • an appropriate reagent such as diazomethane in an inert solvent such as diethyl ether at a temperature of about -25°C to about 0°C.
  • the resulting mixture is then treated under acidic
  • halomethyl ketone of formula (b) is coupled with an amino acid alkyl ester of formula (c) with an appropriate base such as sodium cyanoborohydride in an organic solvent such as methanol (MeOH) to yield to a cyclic intermediate of formula (d).
  • an appropriate base such as sodium cyanoborohydride in an organic solvent such as methanol (MeOH)
  • the cyclic intermediate of formula (d) is treated under acidic conditions using an appropriate acid such as camphorsulfonic acid in an appropriate solvent such as toluene ti yield to a bicyclic intermediate of formula (e).
  • an appropriate acid such as camphorsulfonic acid
  • an appropriate solvent such as toluene ti yield to a bicyclic intermediate of formula (e).
  • Suitable conditions for peptide bond formation are well known in th 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.
  • Compounds of the present invention may be prepared for assay by dissolving them in buffer to give solutions ranging in concentrations from 1 to 100 ⁇ M. In an assay to determine the inhibitory dissociation
  • 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 assay is well known to those skilled in the art.
  • 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 thrombogenic 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.
  • the proportion of each carrier 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.
  • parenteral for parenteral
  • the compound may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution
  • 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.
  • 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 .
  • Physicians will determine the dosage of the present therapeutic agents which will be most suitable. Dosages may vary with the mode of administration and the
  • the dosage may vary with the particular patient under treatment.
  • composition When the composition is administered orally, a larger quantity cf the active agent will typically be required to produce the same effect as caused with a smaller quantity-given parenterally.
  • the preferred compounds as of the present invention are synthesized using conventional preparative steps and recovery methods known to those skilled in the art of organic and bio-organic synthesis, while providing a new a unique combination for the overall synthesis of each compound.
  • 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), HCl (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.
  • 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), HCl (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.
  • 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), HCl (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 ⁇ 50 mL), brine (50 mL), dried with MgSO 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 at room temperature (40 psi). The solution was filtered through celite, and concentrated under reduced pressure toe yield a clear residue.
  • tert-Butyloxycarbonyl-ortho-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 at room temperature (40 psi). The solution was filtered through celite, and concentrated under reduced pressure to yield a clear residue.
  • tert-Butyloxycarbonyl-para-aminomethyl-phenylalanine-N,O-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 (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.
  • tert-Butyloxycarbonyl-meta-aminomethyl-phenylalanine-N,O- 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.! mmol), and HgCl (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.
  • tert-Butyloxycarbonyl-ortho-aminomethyl-phenylalanine-N,O-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 (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.
  • the mixture was diluted with ethyl acetate (150 mL), and the organic layer washed with saturated aqueous ammonium chloride (2 ⁇ 50 mL), brine (50 mL), dried with MgSO 4 , filtered, and concentrated under reduced pressure.
  • the crude material was purified on silica gel (ethyl acetate/hexane), and
  • the mixture was diluted with ethyl acetate (150 mL), and the organic layer washed with saturated aqueous ammonium chloride (2 ⁇ 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 reaction was quenched with saturated aqueous ammonium chlcride.
  • the mixture was diluted with ethyl acetate (150 mL), and the organic layer washed with saturated aqueous ammonium chloride (2 ⁇ 50 mL), brine (50 mL), dried with MgSO 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 ⁇ 50 mL), brine (50 mL), dried with MgSO4, 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-(4-pyridyl)alanine-N,O-dimethylamide (4.50 g, 14.4 mmol) was dissolved in acetic acid (100 mL), and PtO (100 mg) added. The solution was shaken under H until gas uptake ceased. The solution was filtered through celite, and concentrated under reduced pressure yielding tert-butyloxycarbonyl-3-(4-piperidyl)alanine-N,O-dimethylamide.
  • tert-Butyloxycarbonyl-3-(3-pyridyl)alanine-N,O-dimethylamide (4.50 g, 14.4 mmol) was dissolved in acetic acid (100 mL), and PtO (100 mg) added. The solution was shaken under H 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 PtO (100 mg) added. The solution was shaken under H 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-(4-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 (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.
  • 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 (0.95 g, 3.5 mmol) added. The solution was
  • the mixture was diluted with ethyl acetate (150 mL), and the organic layer washed with saturated aqueous ammonium chloride (2 ⁇ 50 mL), brine (50 mL), dried with MgSO 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 ⁇ 50 mL), brine (50 mL), dried with MgSO 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 ⁇ 50 mL), brine (50 mL), dried with MgSO 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 PtO (100 mg) added. The solution was shaken under H until gas uptake ceased. The solution was filtered through celite, concentrated under reduced pressure, taken up in HO (150 mL), and lyophilized. The semi-solid was dissolved in ethyl acetate (350 mL), washed with 1 N NaOH (3 ⁇ 50 mL) and brine (3 ⁇ 50 mL). The solution was dried with MgSI filtered, and concentrated under reduced pressure yielding the title compound.
  • tert-Butyloxycarbonyl-meta-nitro-phenylalanine-N,O-dimethylamide 13.88 g, 39.3 mmol was dissolved in acetic acid (100 mL), and PtO (100 mg) added. The solution was shaken under H until gas uptake ceased. The solution was filtered through celite, concentrated under reduced pressure, taken up in HO (150 mL), and lyophilized. The semi-solid was dissolved in ethyl acetate (350 mL), washed with 1 N NaOH (3 ⁇ 50 mL), and brine (3 ⁇ 50 mL). The solution was dried with MgSO 4 , filtered, and concentrated under reduced pressure yielding the title compound.
  • tert-Butyloxycarbonyl-ortho-nitro-phenylalanine-N,O-dimethylamide 13.88 g, 39.3 mmol was dissolved in acetic acid (100 mL), and PtO (100 mg) added. The solution was shaken under H until gas uptake ceased. The solution was filtered through celite, concentrated under reduced pressure, taken up in H 2 O (150 mL), and lyophilized. The semi-solid was dissolved in ethyl acetate (350 mL), washed with 1 N NaOH (3 ⁇ 50 mL), and brine (3 ⁇ 50 mL). The solution was dried with MgSO 4 , filtered, and concentrated under reduced pressure yielding the title compound.
  • tert-Butyloxycarbonyl-3-(cis/trans-4-aminocyclohexyl)alanine-N,O-dimethylamide (1.00 g, 3.0 mmol) was dissolved in saturated aqvieous 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 ⁇ 50 mL), and brine (2 ⁇ 50 mL).
  • the solution was dried with MgSO 4 , filtered, and concentrated under reduced pressure.
  • the semi-solid was chromatographed on silica gel (ethyl acetate/ hexane).
  • tert-Butyloxycarbonyl-3-(cis/ trans-3 - aminocyclohexyl)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 ⁇ 50 mL), and brine (2 ⁇ 50 mL).
  • the solution was dried with MgSO 4 , filtered, and concentrated under reduced pressure.
  • the semi-solid was chromatographed on silica gel (ethyl acetate hexane).
  • the semi-solid was chromatographed on silica gel (ethyl acetate' hexane).
  • guanidylated amino acid (3.88 g, 6.1 mmol) in THF (15 mL) was added dropwise, and the resulting mixture stirred. The reaction was quenched with saturated aqueous ammonium
  • guanidylated amino acid (3.88 g, 6.1 mmol) in THF (15 mL) was added dropwise, and the resulting mixture stirred. The reaction was quenched with saturated aqueous ammonium
  • guanidylated amino acid (3.88 g, 6.1 mmol) in THF (15 mL ; was added dropwise, and the resulting mixture stirred. The reaction was quenched with saturated aqueous ammonium
  • Oxidation of the organoborane was achieved by the addition of 4.7 g (2.0 equiv., 27.2 mmol) of 3-chloroperoxybenzoic acid at 0°C, with warming to ambient temperature and stirring for an additional hour.
  • the organic phase was washed with 5% Na 2 CO 3 , ddH 2 O, and dried over sodium sulfate. Due to the instability of the alcohol, a quick column was performed to remove the extreme polar and nonpolar material which originated from the 3-chloroperoxybenzoic acid.
  • the alcohol (4) was obtained in a yield of 65%.
  • the aldehyde, (5), (2.6 g, 7.10 mmol) was dissolved in benzene (70 mL) and a catalytic amount of ptoluenesulfonic acid was added, followed by 1.58 g (1.2 equiv., 8.52 mmol) of L-cysteine ethyl ester and 4 A molecular sieves .
  • the reaction was allowed to stir overnight at ambient temperature followed be removal of solvent in vacuo .
  • the residue was dissolved in
  • Oxalyl chloride (9) (25 g, 0.197 mol) was cooled to 0oC and cyclohexane propionic acid (20 ml, 0.14 mol) was added. This was left to stir overnight. The resultant mixture was distilled to give an 84% yield of the
  • the chiral auxiliary (11) (13.6g, 76.7 mmol, 1 eq) was dissolved in dry THF and cooled to -78oC. Then n-BuLi ⁇ 52.8 mL, 84.4 mmol, 1.2 equiv.) was added and left for 2 mins (dark orange solution). The acid chloride (10) (13.4 g, 76.6 mmol, 1 eq) was then added and left to stir overnight. Work-up was done by quenching with saturated NH 4 Cl extracting with ethyl acetate, washing the extracts with water and brine, drying over sodium sulphate and concentration.
  • the starting material (12)(9.13g, 29 mmol, leq) was dissolved in dry THF and cooled to -78oC, after which LiHMDS (31.9 mL, 31.9 mmol, 1.1 eq) was added dropwise over 40 mins. Then, 30 minutes later, allyl bromide (7.5 mL, 86.9 mmol, 3 eq) was added slowly over 10 mins. The mixture was left to warm overnight. Work-up included quenching with sat. ammonium chloride, extraction with ethyl acetate, washing with 10% sodium thiosulphate, decolourising with charcoal, drying over sodium sulphate and concentration in vacuo. The product was obtained as a yellow oil (13) in 96% yield.
  • the starting material (1.97 g, 3.9 mmol, 1 equiv.) was dissolved in 20 mL of dry dichloromethane and cooled to 0oC. Trimethylaluminum (5.9 mL, 11.8 mmol, 3 equiv.), was added dropwise and the mixture was left stirring overnight. After complete reaction as evidenced by HPLC, methanol was added until a yellow t>olid mass was formed. Dichloromethane was added to dissolve the solid and the whole mixture was stirred for 15-30 minutes and then filtered.
  • the starting material (16) (0.95 g, 2.9 mmol, 1 equiv.) was dissolved in 10 mL of dioxane. The solution was cooled to 10oC, and to it was added LiOH H 2 O(0.123 g, 2.9 mmol, 1 eq.) dissolved in 10 mL of water. The bath was removed and the mixture was stirred at room temperature for 1 hour. TLC showed complete reaction and the solvent was evaporated under vacuum. The remaining aqueous layer was washed with ether (2X), acidified with 10% citric acid, and extracted with dichloromethane (3X). The combined extracts were dried over sodium sulphate and concentrated to give a white solid which was
  • BOC-DiCbz Arg (7.6 g, 14.0 mmol) was dissolved in anhydrous THF (40 mL) and cooled to 0oC. Triethylamine (2. mL) was added followed by 14.5 mmol of a 1M toluene solution of isopropyl chloroformate via a syringe. The reaction was allowed to stir at 0oC for 30 minutes then quickly filtered. The white solid was discarded. To the filtrate was bubbled freshly prepared diazomethane until the color of the solution turned yellow. The reaction mixture was allowed to stand overnight in a well
  • the products of the reactions described above can be isolated in the free form or in the form of salts.
  • the products can be obtained as pharmaceutically acceptable acid addition salts by reacting one of the free bases with an acid.
  • the product can be obtained as pharmaceutically acceptable salts by reacting one of the free bases with an acid.
  • the pyrrolidine-aldehyde (6) is coupled with the protected diamino-propionic acid (7) by first forming the imine (8) (MgSO 4 , CH 2 Cl 2 ). Isolation of the imine (8) is done by filtration of the MgSO ⁇ and evaporation of the solvent. The crude imine is then treated with NaBH(OAc) and actic acid (AcOH) in THF for 15 hours to obtain the amine (8) after extrative work-up .
  • imine (8) MgSO 4 , CH 2 Cl 2
  • the CB7 (7) protecting group of the amine (8) is removed by hydrogenation with palladium on charcoal 10% as a catalyst in methanol (MeOH).
  • the catalyst is filtered and the MeOH evaporated to give the crude diamine (9) that can be used without any purification.
  • the cyclisation is done by heating the crude oil (9) from step 7, neat slightly above the boiling point of methanol.
  • the bicyclic lactam (10) is purified by flash
  • the carboxylic acid (13) is coupled with benzothiazole ketoarginine (14) in DMF using BOP as the coupling agent in the presence of diisopropylethylamine (EtNiPr ).
  • the two CBZ(Z) protecting groups of compound (15) are removed by catalytic hydrogenation with Pd/C 10% as a catalyst.
  • the catalyst is filtered and the solvent is evaporated to give the amino-guanidine (16).
  • the enamine (5) (1.0eq) is treated with mercuric acetate (1.1 eq) in THF. The solvent is evaporated to dryness and the residue dissolved in methanol. The resulting organomercurial is reductivly cleaved with sodium borohydride (1.3eq). The resulting crude lactam thioether is purified by flash chromatography on silica gel affording compound (6).
  • the isolated bicyclic lactam (8) is hydrolysed with one equivalent of lithium hydroxyde in a 1:1 mixture of THF and water. The mixture is stirred at room temperature for 1 hour. The crude mixture is extracted with ether and the resulting solution is poured into 10% citric acic aqueous solution and extracted with dichloromethane to yield the corresponding carboxylic acid (9).
  • STEP 6
  • the crude carboxylic acid (9) is coupled with
  • Cyclic compound (3) (913mg, 3.32 mmol) was disolved in 5' ml of dry Toluene.
  • ( IS) - (+ ) -10-Camphorsulfonic acid 91 mg, 0.39 mmol was added and the mixture was left to reflux for 4 days.
  • the mixture was worked up byevaporation of solvent, dissolving residue in ethyl acetate and washing with 2 x 5 % NaHCO 3 .
  • the Ethyl acetate layer was dried over Na 2 SO4 and evaporated.
  • the crude residue was purified by silica gel flash column chromatography using 60 % ETOAC / 40 %Hexane followed by 70 % ETOAC / 30 % Hexane giving 62.5% of Bicyclic compound (4).
  • Benzyl bromide (0.26 ml, 2.22 mmol) is then added and the mixture is allowed to reach room temperature and stirred for 15 hours. The mixture is then poured into 10% HCl (50 ml and extracted wiht diclhoromethane (4 ⁇ 60ml). The combined organic phases are dried over MgSO and the solvent remove by evaporation to yield to the crude alkylated amide (6).
  • the steady-state was achieved within 3 min and measured for a few min.
  • the kinetic data (the steady-state velocity at various
  • the fibrin clotting assay was performed in 50 mM Tris HCl buffer (pH 7.52 at 37 °C) containing 0.1 M NaCl and 0.1% poly (ethylene glycol) 8000 with 9.0 ⁇ 10-10 M (0.1 NIH unit/mL) and 0.03 % (w/v) of the final concentrations of human thrombin and bovine fibrinogen, respectively, as reported elsewhere (Szewczuk et al., supra).
  • the clotting time was plotted against the inhibitor concentrations and the IC 50 was estimated as the inhibitor concentration required to double the clotting time relative to the control. Results are summarized in Tables 1 and 2 below.
  • the fibrin clot assay was performed essentially as
  • a serial dilution of the inhibitor was prepared in 50 mM tris HCl buffer (pH7.8 at 23 oC) containing 0. IM NaCl and 0.1% (w/v) polyethylene glycol 8000.
  • Human plasma 60uL, collected in 3.8% sodium citrate, blood/anticoagulant 9:1 was added to microtiter wells (microtiter plate, Falcon) containing 100 ⁇ L of various inhibitor dilutions. The solution was mixed after which 50 ⁇ L of human thrombin (InM final cone.) was added and mixed for 15 seconds. The turbidity of the clot was immediately monitored by
  • microplate autoreader (Dynateck MR 5000) at 405nm and recorded every 3 min. The maximal turbidity in the absence of inhibitors was reached within a 60 min. IC values were calculated at 30 minutes as the inhibitor concentration that gave half the optical density of the control.
  • Rat blood was collected into ACD (6/1 v/v) by cardiac puncture.
  • Suspensions of washed platelets were prepared as described by Ardlie et al, (Br. J. Haematol. 1970, 19:7 and Proc. Soc. Exp. Biol. Med., 1971, 136:1021).
  • the final suspending medium was a modified Tyrode solution (NaCl 138mM, KCl 2.9mM, HEPES 20mM, NaH.PO. 0.42mM, NaHCO 12mM, CaCl ImM, MgCl 2mM, 0.1% glucose, 0.35% albumin, apyrase l ⁇ L/mL pH 7.4). Platelet counts were adjusted to 5000,000/uL.
  • IC 50 values represent the concentration that was necessary to inhibit platelet aggregation or secretion to 50% of the control
  • the FeCl induced injury to the carotid artery in rats was induced according to the method described by Kurz, K.D., Main, R.W., Sandusky, G.E., Thrombosis Research 60; 269-280, 1990 and Schumacher, W.A. et al. J. Pharmacology and Experimental Therapeutics 267; 1237-1242, 1993.
  • Male, Sprague-Dawley rats ( 375-410 g) were anesthetized with urethane ( 1500 mg ⁇ kg ip). Animals were laid on a 37°C heating pad.
  • the carotid artery was exposed through a midline cervical incision. Careful blunt dissection was used to isolate the vessel from the carotid sheath. Using forceps, the artery was lifted to provide sufficient clearance to insert two small pieces of polyethylene tubing (PE-205 ) underneath it.
  • a temperature probe PE-205
  • Inhibitor compounds were given as an iv bolus (mg/kg) followed immediately by an iv infusion ( ⁇ g/kg/min. via femoral vein) .

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Abstract

L'invention a pour objet la découverte d' inhibiteurs compétitifs hétérocycliques de l'enzyme thrombine, ayant la formule (I); leur préparation, et les compositions pharmaceutiques de ces derniers. De même, l'invention traite de l'utilisation de ces composés et de ces compositions in vitro comme anticoagulants et in vivo comme agents pour le traitement et la prophylaxie des troubles thrombotiques tels que la thrombose veineuse, l'embolisme pulmonaire et la thrombose artérielle provenant de cas d'ischémie aigüe tels que l'infarctus du myocarde ou l'infarctus cérébral. De plus, ces composés et ses compositions présentent une utilité thérapeutique pour la prévention et le traitement des coagulopathies associées au pontage coronarien, ainsi qu'aux cas de resténose suivant les actes d'angioplastie transluminale.
PCT/CA1995/000708 1994-12-22 1995-12-21 Inhibiteurs de la thrombine bicyclique a faible poids moleculaire WO1996019483A1 (fr)

Priority Applications (15)

Application Number Priority Date Filing Date Title
MD97-0253A MD970253A (ro) 1994-12-22 1995-12-21 Inhibitori biciclici micromoleculari ai trombinei
NZ297360A NZ297360A (en) 1994-12-22 1995-12-21 5-oxo-5H-thiazolo[3,2-a]pyridine, 5-oxo-2-thia-4a,7-diaza-naphthalene, 4-oxo-octahydro-pyrrolo[1,2-a]pyrazine or 6-oxo-octahydro-pyrido-[2,1-c][1,4]thiazine derivatives and medicaments
AU42505/96A AU4250596A (en) 1994-12-22 1995-12-21 Low molecular weight bicyclic thrombin inhibitors
APAP/P/1997/001004A AP9701004A0 (en) 1994-12-22 1995-12-21 Low molecular weight bicyclic thrombin inhibitors.
JP8519383A JPH11508535A (ja) 1994-12-22 1995-12-21 低分子量２環式トロンビン阻害剤
SK838-97A SK83897A3 (en) 1994-12-22 1995-12-21 Low molecular weight bicyclic thrombin inhibitors
EP95940923A EP0802916A1 (fr) 1994-12-22 1995-12-21 Inhibiteurs de la thrombine bicyclique a faible poids moleculaire
BR9510433A BR9510433A (pt) 1994-12-22 1995-12-21 Compostos de inibidores de trombina cicíclicos de baixo peso molecular método para o seu tratamento e processo para a sua produção
EE9700113A EE9700113A (et) 1994-12-22 1995-12-21 Madala molekulmassiga bitsüklilised trombiini inhibiitorid
IS4504A IS4504A (is) 1994-12-22 1997-06-11 Tvíhringja þrombín efnahemlar með lítinn sameindaþunga
FI972466A FI972466A (fi) 1994-12-22 1997-06-11 Pienen molekyylipainon bisyklisiä trombiini-inhibiittoreita
NO972892A NO972892L (no) 1994-12-22 1997-06-20 Bicykliske lavmolekylvekts-trombin-inhibitorer
BG101647A BG101647A (en) 1994-12-22 1997-06-20 Low molecular weight bicyclic thrombin inhibitors
US08/880,885 US6057314A (en) 1995-12-21 1997-06-23 Low molecular weight bicyclic thrombin inhibitors
LVP-97-141A LV12019B (en) 1994-12-22 1997-07-15 BULK CYCLIC FIBERS INHIBITORS

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
GBGB9426038.7A GB9426038D0 (en) 1994-12-22 1994-12-22 Low molecular weight bicyclic thrombin inhibitors
GBGB9503136.5A GB9503136D0 (en) 1994-12-22 1995-02-17 Low molecular weight bicyclic thrombin inhibitors
GB9426038.7 1995-03-06
GB9503136.5 1995-03-06
GBGB9510267.9A GB9510267D0 (en) 1995-05-22 1995-05-22 Low molecular weight thiobicyclic thrombin inhibitors
GB9510267.9 1995-05-22
GBGB9510265.3A GB9510265D0 (en) 1995-05-22 1995-05-22 Low molecular weight diaminobicyclic thrombin inhibitors
GB9510265.3 1995-05-22
GB9510266.1 1995-05-22
GBGB9510266.1A GB9510266D0 (en) 1995-05-22 1995-05-22 Low molecular weight bicyclic thrombin inhibitors

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US08/880,885 Continuation US6057314A (en) 1995-12-21 1997-06-23 Low molecular weight bicyclic thrombin inhibitors

Publications (1)

Publication Number Publication Date
WO1996019483A1 true WO1996019483A1 (fr) 1996-06-27

Family

ID=27517273

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA1995/000708 WO1996019483A1 (fr) 1994-12-22 1995-12-21 Inhibiteurs de la thrombine bicyclique a faible poids moleculaire

Country Status (22)

Country Link
EP (1) EP0802916A1 (fr)
JP (1) JPH11508535A (fr)
CN (1) CN1175259A (fr)
AP (1) AP9701004A0 (fr)
AU (2) AU4250596A (fr)
BG (1) BG101647A (fr)
CA (1) CA2208772A1 (fr)
CZ (1) CZ189997A3 (fr)
EE (1) EE9700113A (fr)
FI (1) FI972466A (fr)
HU (1) HUT77651A (fr)
IL (1) IL116503A0 (fr)
IS (1) IS4504A (fr)
LV (1) LV12019B (fr)
MD (1) MD970253A (fr)
MX (1) MX9704718A (fr)
NO (1) NO972892L (fr)
NZ (1) NZ297360A (fr)
OA (1) OA10493A (fr)
PL (1) PL320965A1 (fr)
SK (1) SK83897A3 (fr)
WO (1) WO1996019483A1 (fr)

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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
US10208048B2 (en) 2015-04-28 2019-02-19 Janssen Sciences Ireland Uc RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
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
US11339165B2 (en) 2017-11-29 2022-05-24 Janssen Sciences Ireland Unlimited Company Pyrazolopyrimidines having activity against the respiratory syncytial virus (RSV)
US11491157B2 (en) 2018-01-31 2022-11-08 Janssen Sciences Ireland Unlimited Company Co Cork, IE Cycloalkyl substituted pyrazolopyrimidines having activity against RSV
US11708369B2 (en) 2018-04-23 2023-07-25 Janssen Sciences Ireland Unlimited Company Heteroaromatic compounds having activity against RSV

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US6020331A (en) * 1995-03-24 2000-02-01 Molecumetics, Ltd. β-sheet mimetics and use thereof as protease inhibitors
US6245764B1 (en) 1995-03-24 2001-06-12 Molecumetics Ltd. β-sheet mimetics and use thereof as inhibitors of biologically active peptides or proteins
US7511039B2 (en) 1995-03-24 2009-03-31 Myriad Genetics, Inc. β-sheet mimetics and use thereof as inhibitors of biologically active peptides or proteins
US6586426B1 (en) 1995-03-24 2003-07-01 Molecumetics Ltd. β-sheet mimetics and use thereof as protease inhibitors
US6699869B1 (en) 1995-03-24 2004-03-02 Myriad Genetics Inc. β-sheet mimetics and use thereof as inhibitors of biologically active peptides or proteins
US7125872B2 (en) 1995-03-24 2006-10-24 Myriad Genetics, Inc. β-sheet mimetics and use thereof as inhibitors of biologically active peptides or proteins
WO1997005160A1 (fr) * 1995-08-01 1997-02-13 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Derives lactames bicycliques utilises comme inhibiteurs de thrombine
WO1997017363A1 (fr) * 1995-11-03 1997-05-15 Akzo Nobel N.V. Inhibiteurs de la thrombine
US6432921B2 (en) 1995-11-03 2002-08-13 Akzo Nobel N.V. Thrombin inhibitors
US6034067A (en) * 1996-02-13 2000-03-07 Akzo Nobel, N.V. Serine protease inhibitors
WO1997030073A1 (fr) * 1996-02-13 1997-08-21 Akzo Nobel N.V. Inhibiteurs de la serine protease
US6218365B1 (en) * 1996-03-01 2001-04-17 Akzo Nobel N.V. Serine protease inhibitors
WO1997031939A1 (fr) * 1996-03-01 1997-09-04 Akzo Nobel N.V. Inhibiteurs de la serine-protease
US6410684B1 (en) 1996-03-01 2002-06-25 Akzo Nobel N.V. Serine protease inhibitors
WO1997031937A1 (fr) * 1996-03-01 1997-09-04 Akzo Nobel N.V. Inhibiteur de la serine-protease
US6124291A (en) * 1996-06-18 2000-09-26 Warner-Lambert Company Pyrrolo[1,2-a]pyrazine-1,4-dione serine protease inhibitors
WO1997048706A1 (fr) * 1996-06-18 1997-12-24 Warner-Lambert Company Pyrrolo(1,2-a)pyrazine 1,4-diones servant d'inhibiteurs des serines proteases
WO1998005333A1 (fr) * 1996-08-05 1998-02-12 Molecumetics Ltd. Utilisation de mimetiques de feuillets beta comme inhibiteurs de protease et de kinase ou comme inhibiteurs de facteurs de transcription
EP1661566A3 (fr) * 1996-08-05 2008-04-16 Myriad Genetics, Inc. Utilisation de mimétiques de feuillets beta comme inhibiteurs de protéase et de kinase ou comme inhibiteurs de facteurs de transcription
EP1661566A2 (fr) * 1996-08-05 2006-05-31 Myriad Genetics, Inc. Utilisation de mimétiques de feuillets beta comme inhibiteurs de protéase et de kinase ou comme inhibiteurs de facteurs de transcription
WO1998009987A1 (fr) * 1996-09-06 1998-03-12 Biochem Pharma, Inc. Inhibiteurs lactame de la thrombine
US6262047B1 (en) 1996-10-11 2001-07-17 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6525076B1 (en) 1996-10-11 2003-02-25 Millennium Pharmaceuticals, Inc. Selective factor Xa inhibitors
US6194435B1 (en) 1996-10-11 2001-02-27 Cor Therapeutics, Inc. Lactams as selective factor Xa inhibitors
US6369080B2 (en) 1996-10-11 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
WO1998028326A1 (fr) * 1996-12-23 1998-07-02 Biochem Pharma Inc. Inhibiteurs bicycliques de thrombine
US6117896A (en) * 1997-02-10 2000-09-12 Molecumetics Ltd. Methods for regulating transcription factors
US6372744B1 (en) 1997-02-10 2002-04-16 Molecumetics Ltd. β-sheet mimetics and methods relating to the use thereof
US6369063B1 (en) 1997-04-14 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6204268B1 (en) 1997-04-14 2001-03-20 Cor Therapeutics, Inc Selective factor Xa inhibitors
US6133256A (en) * 1997-04-14 2000-10-17 Cor Therapeutics Inc Selective factor Xa inhibitors
US6228854B1 (en) 1997-08-11 2001-05-08 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6333321B1 (en) 1997-08-11 2001-12-25 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6218382B1 (en) 1997-08-11 2001-04-17 Cor Therapeutics, Inc Selective factor Xa inhibitors
EP1017383A1 (fr) * 1997-09-23 2000-07-12 Merck & Co., Inc. Inhibiteurs de thrombine
EP1017383A4 (fr) * 1997-09-23 2001-11-28 Merck & Co Inc Inhibiteurs de thrombine
JP2002503674A (ja) * 1998-02-12 2002-02-05 モレキュメティックス リミテッド βシート模倣物およびその使用に関する方法
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
EP1058549A1 (fr) * 1998-12-23 2000-12-13 Du Pont Pharmaceuticals Company INHIBITEURS DU FACTEUR Xa OU DE LA THROMBINE
US6602871B2 (en) 1998-12-23 2003-08-05 Bristol-Myers Squibb Pharma Company Thrombin or factor Xa inhibitors
EP1058549A4 (fr) * 1998-12-23 2003-11-12 Bristol Myers Squibb Pharma Co INHIBITEURS DU FACTEUR Xa OU DE LA THROMBINE
US6403583B1 (en) 1998-12-23 2002-06-11 Patrick Y. S. Lam Thrombin or factor Xa inhibitors
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
FR2795072A1 (fr) * 1999-06-15 2000-12-22 Adir Nouveaux derives bicycliques d'amino-pyrazinones, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
EP1069132A1 (fr) * 1999-06-15 2001-01-17 Adir Et Compagnie Dérivés bicycliques d'amino-pyrazinones, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
US7030239B2 (en) * 2000-03-23 2006-04-18 Elan Pharmaceuticals, Inc. Compounds to treat Alzheimer's disease
WO2002002519A3 (fr) * 2000-06-29 2002-07-25 Bristol Myers Squibb Pharma Co Inhibiteurs de la thrombine ou du facteur xa
US6586418B2 (en) 2000-06-29 2003-07-01 Bristol-Myers Squibb Company Thrombin or factor Xa inhibitors
WO2002002519A2 (fr) * 2000-06-29 2002-01-10 Bristol-Myers Squibb Pharma Company Inhibiteurs de la thrombine ou du facteur xa
US8431550B2 (en) 2000-10-27 2013-04-30 Johnson & Johnson Consumer Companies, Inc. Topical anti-cancer compositions and methods of use thereof
EP1215213A3 (fr) * 2000-12-14 2002-09-25 Les Laboratoires Servier Dérivés bicycliques d'amino-pyrazones, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
FR2818277A1 (fr) * 2000-12-14 2002-06-21 Servier Lab Nouveaux derives bicycliques d'amino-pyrazinones, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
EP1215213A2 (fr) * 2000-12-14 2002-06-19 Les Laboratoires Servier Dérivés bicycliques d'amino-pyrazones, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
US7897144B2 (en) 2001-02-28 2011-03-01 Johnson & Johnson Comsumer Companies, Inc. Compositions containing legume products
US7053214B2 (en) 2002-02-14 2006-05-30 Myriad Genetics, Inc. β-sheet mimetics and composition and methods relating thereto
US7629318B2 (en) 2002-03-22 2009-12-08 Gpc Biotech Ag Immunosuppressant compounds, methods and uses related thereto
US9988375B2 (en) 2014-10-06 2018-06-05 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
US10301301B2 (en) 2014-10-06 2019-05-28 Cortexyme, Inc. Inhibitors of lysine gingipain
US9758473B2 (en) 2014-10-06 2017-09-12 Cortexyme, Inc. Inhibitors of lysine gingipain
US10611769B2 (en) 2015-04-28 2020-04-07 Janssen Sciences Ireland Unlimited Company RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
US11084826B2 (en) 2015-04-28 2021-08-10 Janssen Sciences Ireland Unlimited Company RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
US10208048B2 (en) 2015-04-28 2019-02-19 Janssen Sciences Ireland Uc RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
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
US11339165B2 (en) 2017-11-29 2022-05-24 Janssen Sciences Ireland Unlimited Company Pyrazolopyrimidines having activity against the respiratory syncytial virus (RSV)
US11491157B2 (en) 2018-01-31 2022-11-08 Janssen Sciences Ireland Unlimited Company Co Cork, IE Cycloalkyl substituted pyrazolopyrimidines having activity against RSV
US11708369B2 (en) 2018-04-23 2023-07-25 Janssen Sciences Ireland Unlimited Company Heteroaromatic compounds having activity against RSV

Also Published As

Publication number Publication date
CZ189997A3 (cs) 1998-09-16
HUT77651A (hu) 1998-07-28
FI972466A0 (fi) 1997-06-11
LV12019A (lv) 1998-04-20
NO972892L (no) 1997-08-20
AU715378B2 (en) 2000-02-03
BG101647A (en) 1998-03-31
CN1175259A (zh) 1998-03-04
LV12019B (en) 1998-07-20
NO972892D0 (no) 1997-06-20
OA10493A (en) 2002-04-10
EE9700113A (et) 1997-12-15
SK83897A3 (en) 1998-05-06
MX9704718A (es) 1998-06-28
AU4250596A (en) 1996-07-10
AU4062895A (en) 1996-07-04
MD970253A (ro) 1999-05-31
JPH11508535A (ja) 1999-07-27
CA2208772A1 (fr) 1996-06-27
EP0802916A1 (fr) 1997-10-29
IS4504A (is) 1997-06-11
AP9701004A0 (en) 1997-07-31
PL320965A1 (en) 1997-11-24
IL116503A0 (en) 1996-03-31
NZ297360A (en) 2000-03-27
FI972466A (fi) 1997-08-19

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