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WO1997031910A1 - Antagonistes des recepteurs de fibrinogenes - Google Patents

Antagonistes des recepteurs de fibrinogenes Download PDF

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Publication number
WO1997031910A1
WO1997031910A1 PCT/US1997/002712 US9702712W WO9731910A1 WO 1997031910 A1 WO1997031910 A1 WO 1997031910A1 US 9702712 W US9702712 W US 9702712W WO 9731910 A1 WO9731910 A1 WO 9731910A1
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Prior art keywords
alkyl
substituted
mono
aryl
unsusbstituted
Prior art date
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PCT/US1997/002712
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English (en)
Inventor
John Wai
Mark E. Duggan
Thorsten E. Fisher
George D. Hartman
James J. Perkins
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Merck and Co Inc
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Merck and Co Inc
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Priority claimed from GBGB9606489.4A external-priority patent/GB9606489D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to EP97906712A priority Critical patent/EP0885205A4/fr
Priority to JP9531013A priority patent/JP2000505471A/ja
Priority to AU21332/97A priority patent/AU712082B2/en
Publication of WO1997031910A1 publication Critical patent/WO1997031910A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates generally to modulating cell adhesion and to inhibiting the binding of fibrinogen and other proteins to blood platelets, and inhibiting the aggregation of blood platelets specifically to the gp Ilb/IIIa fibrinogen receptor site.
  • Fibrinogen is a glycoprotein present in blood plasma that participates in platelet aggregation and in fibrin formation. Platelets are cell-like anucleated fragments, found in the blood of all mammals, that also participate in blood coagulation. Interaction of fibrinogen with the Ilb/IIIa receptor site is known to be essential for normal platelet function.
  • platelets When a blood vessel is damaged by an injury or other causative factor, platelets adhere to the disrupted subendothethial surface. The adherent platelets subsequently release biologically active constituents and aggregate. Aggregation is initiated by the binding of agonists, such as thrombin, epinephrine, or ADP to specific platelet membrane receptors. Stimulation by agonists results in exposure of latent fibrinogen receptors on the platelet surface, and binding of fibrinogen to the glycoprotein Ilb/IIIa receptor complex.
  • agonists such as thrombin, epinephrine, or ADP
  • arginine- glycine-aspartic acid containing tripeptides are recognized by at least one member of a family of structurally related receptors, integrins, which are heterodimeric proteins with two membrane-spanning subunits.
  • integrins which are heterodimeric proteins with two membrane-spanning subunits. The authors state that the conformation of the tripeptide sequence in the individual proteins may be critical to recognition specificity.
  • Ruggeri et al. Proc. Nat'l Acad. Sci. U.S.A., 83, 5708- 5712 ( 1986) explore a series of synthetic peptides designed in lengths to 16 residues, that contain RGD and a valine attached to the aspartic acid residue of RGD that inhibit fibrinogen binding to platelets. See also Koczewiak et al., Biochem. 23, 1767-1774 (1984); Ginsberg et al., J. Biol. Chem. 260(7), 3931-3936 (1985); and Haverstick et al., Blood 66(4), 946-952 (1985). Other inhibitors are disclosed in Eur. Pat. App. Nos. 275,748 and 298,820.
  • Ilb/IIIa complex This polypeptide contains 49 amino acids and has the RGD subunit and various disulfide bridges.
  • Gan et al. J. Biol. Chem., 263, 19827-19832 (1988).
  • Dennis et ai Proc. Nat'l Acad. Sci. USA, 87, 2471-2475 (1989).
  • these snake venom factors also have high affinity for other members of the adhesive protein receptor family including the vitronectin and fibronectin receptors so are not selective for the gp Ilb/IIIa complex.
  • 5,037,808 discloses the use of indolyl platelet-aggregation inhibitors which are believed to act by antagonizing interactions between fibrinogen and/or extracellular matrix proteins and the platelet gp Ilb/IIIa receptor.
  • U.S. Patent No. 5,037,808 discloses guanidino peptide mimetic compounds that retain an Asp residue which inhibit platelet aggregation.
  • WO9014103 describes the use of antibody-poly-peptide conjugates wherein said polypeptides contain the Arg-Gly-Asp (RGD) sequence.
  • W091 11458 discloses the use of large cyclic peptides containing RGD flanked by proline residues which are platelet
  • WO9101331 discloses small cyclic platelet aggregation inhibitors which are synthetic cyclic pentapeptides
  • U.S. Patent No. 5,051,405 also discloses the use of peptides and pseudopeptides such as N-amidino-piperidine-3-carboxylglycyl-L- aspartyl-L-valine that inhibit platelet aggregation and thrombus formation in mammalian blood.
  • EP 445 796 discloses linear compounds which can include internal piperazinyl or piperidinyl derivatives.
  • EP437 367 discloses linear polypeptide fibrinogen receptor antagonists.
  • U.S. Patent No. 5,256,812 discloses compounds of the R 1 -A-(W) a -X- (CH 2 ) b -(Y) c -B-Z-COOR wherein R 1 is a guandidino or amidino moiety and A and B are chosen from specific monosubstituted aryl or
  • a number of very serious diseases and disorders involve hyperthrombotic complications which lead to intravascular thrombi and emboli.
  • Myocardial infarction, stroke, phlebitis and a number of other serious conditions create the need for novel and effective fibrinogen receptor antagonists.
  • Fibrinogen receptor antagonists of this invention have the general formula:
  • variable groups are defined in detail below.
  • Compounds of the invention are useful for inhibiting the binding of fibrinogen to blood platelets and for inhibiting the
  • Combination therapies are also described which employ the instant compounds with other active agents such as a thrombolytic agent, an anticoagulant agent, and/or an antiplatelet agent.
  • a further object of this invention is to provide pharmaceutical compositions which are useful in the above-described methods. Further objects of this invention will be apparent from the disclosure herein.
  • the present invention provides compounds having the formula I
  • X is heterocycle
  • heterocycle is selected from:
  • ( 1 ) a five or six membered saturated, partially unsaturated or aromatic ring which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(R 1 )- and -S-, wherein one of the carbon atoms may be substituted with a member selected from R 1 a and -NHR 1 , (2) an eight to ten membered bicyclic ring system which is saturated, or completely or partially unsaturated, and which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(R 1 )- and -S-, wherein one of the carbon atoms may be substituted with a member selected from R 1a and -NHR 1 ,
  • A is a bond between X and Y or is selected from:
  • Y is selected from:
  • Z is selected from aryl and heterocycle; aryl is a 5- or 6-membered aromatic ring system which is unsubstituted or mono-, di- or tri-substituted with R 2 ;
  • n is an integer selected from 0 and 1;
  • R 1 and R 3 are independently selected at each occurrence from:
  • R 1a is independently selected at each occurrence from:
  • R 2 is independently selected at each occurrence from:
  • R 4 is selected from
  • D is selected from -SO 2 - and -C(O)-;
  • R 5 is selected from:
  • R 6 is selected from:
  • X-A- together represent a group selected from:
  • n is an integer selected from 2, 3, 4, and 5;
  • Q is selected from -N(R 1 )-, -S- and -O-;
  • Y is selected from:
  • R 1 a which consists of carbon atoms and one, two or three heteroatoms selected from the group -O-, -N-, -N(R 1 )- and -S-, and which may be fused to a benzene ring to form a bicyclic structure, for example,
  • aryl is a 5- or 6-membered aromatic carbon ring which is unsubstituted or mono-, di- or tri-substituted with R 2 ;
  • R 1 is independently selected at each occurrence from -H, C 1 - 10 alkyl, C 3-8 cycloalkyl-, aryl-C 0-8 alkyl- and hydroxy-C 0 -6 alkyl-;
  • R 1 a is independently selected at each occurrence from -H, halogen,
  • R 2 is independently selected at each occurrence from -H, halogen,
  • R 3 is independently selected at each occurrence from -H, -C 1 -10 alkyl
  • R 5 is selected from:
  • D is selected from -SO 2 - and -C(O)-;
  • R 6 is selected from:
  • heterocycle is selected from a five or six membered saturated, partially unsaturated or aromatic ring which is unsubstituted, or
  • R 1 a monosubstituted or disubstituted with R 1 a , and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R 1 )- and -S-; and wherein the remaining variables are as defined above in formula I.
  • R 1 a monosubstituted or disubstituted with R 1 a , and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R 1 )- and -S-; and wherein the remaining variables are as defined above in formula I.
  • Q is selected form -NH-, -O- and -S-;
  • Y is selected from:
  • Z is selected from:
  • R 1 is independently selected at each occurrence from -H and
  • R 1 a is independently selected at each occurrence from -H, halogen and -C 1 - 10 alkyl;
  • R 2 is independently selected at each occurrence from -H, halogen and -C 1 -10 alkyl
  • R 3 is independently selected at each occurrence from -H and
  • R 5 is selected from:
  • D is selected from -SO 2 - and -C(O)-; and R 6 is selected from:
  • heterocycle is selected from a five or six membered saturated, partially unsaturated or aromatic ring which is unsubstituted, or
  • R 1 a monosubstituted or disubstituted with R 1 a , and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R 1 )- and -S-; and any remaining variables are as defined in formula II.
  • Y is selected from:
  • Z is selected from:
  • R 1 is independently selected at each occurrence from -H and
  • R 1a is independently selected at each occurrence from -H, halogen and -C 1-10 alkyl
  • R 2 is independently selected at each occurrence from -H, halogen and
  • R 3 is independently selected at each occurrence from -H and
  • R 5 is selected from:
  • D is selected from -SO 2 - and -C(O)-;
  • R 6 is selected from:
  • heterocycle is selected from a five or six membered saturated, partially unsaturated or aromatic ring which is unsubstituted, or
  • R 1 a monosubstituted or disubstituted with R 1 a , and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R 1 )- and -S-; and the remaining variables are as defined in formula II.
  • Y is selected from -C(O)-N(R 1 )- and -N(R 1 )-C(O)-;
  • R 1 is independently selected at each occurrence from -H and
  • R 1a is independently selected at each occurrence from -H, halogen and -C 1-10 alkyl
  • R 2 is independently selected at each occurrence from -H, halogen and
  • R 3 is independently selected at each occurrence from -H and
  • R 5 is selected from:
  • D is selected from -SO 2 - and -C(O)-;
  • R 6 is selected from:
  • heterocycle is selected from a five or six membered saturated, partially unsaturated or aromatic ring which is unsubstituted, or
  • R 1 a monosubstituted or disubstituted with R 1 a , and which consists of carbon atoms and one or two heteroatoms selected from the group -O-, -N-, -N(R 1 )- and -S-;
  • Y is selected from -C(O)-NH- and -NH-C(O)-; and R 6 is selected from (1) unsubstituted, mono and disubstituted phenyl, (2) methyl, (3) benzyl wherein the aryl portion may be unsubstituted, mono or di-substituted, and (4) thienyl; and any remaining variables are as defined in formula IV.
  • a second class of the instant embodiments are compounds of formulas I, II, III , and IV wherein Y is -NH-C(O)-.
  • Compounds in this class are exemplified, but not limited to, those of formula VI as defined in Table II .
  • any substituent e.g., R 1 , R 2 , etc.
  • its definition on each occurrence is independent of its definition at any other occurrence.
  • combinations of substitutents and/or variables are permissible only if such combinations result in stable compounds.
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, heptyl, octyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), secbutyl (s-Bu), tertbutyl (t-Bu), isopentyl, isohexyl and the like.
  • cycloalkyl is intended to include cyclized alkyl chains having the specified number of carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Alkoxy or "alkyloxy” represents an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge, e.g., methoxy, ethoxy, propyloxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and the like.
  • the specified number of carbon atoms in the appropriate groups described herein may include a zero in the range, e.g., C 0 -6 or C 0-8 When a zero is in the specified range, it means that a bond is present in place of that carbon group.
  • halo or halogen is meant to include fluoro, chloro, bromo and iodo.
  • oxy means an oxygen (O) atom.
  • aryl is defined above in the definition of Formula I; unsubstituted, mono-, di- and tri-substituted phenyl (Ph) is preferred.
  • heteroaryl is defined above in the definition of Formula I.
  • the term heteroaryl encompasses a five or six- membered heteroaryl ring as defined in formula I fused to a benzene, pyridine or pyrimidine ring.
  • heteroaryl groups include pyrrolyl, triazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, furanyl, pyranyl, thienyl, oxazolyl, isooxazolyl, thiazolyl, indolyl, benzimidazolyl, benzofuranyl, benzopyranyl, benzothienyl, quinolyl, isoquinolyl and the like.
  • heteroaryl ring may be attached within structural Formula I at any heteroatom or a carbon atom in the ring which results in the creation of a stable structure.
  • Preferred heteroaryl groups include pyridyl, thiazolyl, oxazolyl, thienyl, indolyl, benzofuranyl, and benzothienyl.
  • C 0 -6 alkylaryl as used herein includes an alkyl group as defined above bonded to an aryl group as defined above.
  • the C 0 -6 designation refers to the alkyl component of the alkylaryl unit.
  • Examples of C 0-8 alkylaryl include phenyl-, benzyl-, fluorobenzyl-, chlorobenzyl-, phenylethyl-, phenylpropyl-, fluorophenylethyl-, and chlorophenylethyl-.
  • C 0 -6 alkylheterocycle as used herein includes an alkyl group as defined above bonded to a heterocycle group as defined above.
  • the C 0-8 designation refers to the alkyl component of the alkylheterocycle unit.
  • Examples of C 0 -6 alkylheterocycle include thienyl-, thienylmethyl-, thienylethyl-, and thienylpropyl-.
  • Amino acids suitable for compounds of the present invention include naturally occurring L- or D-amino acids, for example, those naturally occurring L-amino acids present in humans, e.g., protein amino acids, including L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamine, L-glutamic acid, L-glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L- proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine, and those naturally occurring D-amino acids which are non-protein amino acids, such as those found, for example, in antibiotic substances produced by bacteria and fungi, including D-valine, D-asparagine, D- glutamate, D-ornithine, D-phenylalan
  • salts shall mean non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methyl
  • Prodrugs such as ester derivatives of described compounds, are compound derivatives which, when absorbed into the bloodstream of a warm-blooded animal, anabolize or cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
  • the compounds of the present invention are chiral and the present compounds may occur as racemates, racemic mixtures and as individual diasteriomers or enantiomers with all such isomeric forms being included within the scope of this invention.
  • crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates and hydrates, as well as anhydrous compositions, are encompassed within the scope of this invention.
  • terapéuticaally effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
  • mamal includes humans.
  • anti-coagulant shall include heparin, and warfarin.
  • thrombolytic agent shall include agents such as streptokinase and tissue plasminogen activator.
  • platelet anti- aggregation agent shall include agents such as aspirin and
  • the compounds of the present invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • intravenous bolus or infusion
  • intraperitoneal subcutaneous
  • intramusculsar form all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • An effective but non-toxic amount of the compound desired can be any effective but non-toxic amount of the compound desired.
  • Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex Ilb/II Ia receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption.
  • the aggregated platelets may form thrombi and
  • thromboemboli Compounds of this invention may be administered to these surgical patients to prevent the formation of thrombi and
  • Extracorporeal circulation is routinely used for cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between gp Ilb/IIIa on the platelet membranes and
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • Oral dosages of the present invention when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day and preferably 0.01-100 mg/kg/day and most preferably 0.01 -20 mg/kg/day.
  • oral dosages for an adult patient are, for example, 1 mg, 10 mg or 100 mg.
  • the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
  • compounds of the present invention may be
  • preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, or course, be continuous rather that intermittent throughout the dosage regime.
  • the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as
  • carrier materials suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with convention pharmaceutical practices.
  • a therapuetically effective amount of a compound of formula I can be used for the preparation of a medicament useful for inhibiting the binding of fibrinogen to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a mammal.
  • the medicament may be comprised of from 1 mg to 100 mgs of a compound of formula I, or more particularly, it may contain 1 mg, 10 mgs, 50 mgs, or 100 mgs of said compound.
  • Therapeutically effective amounts of a compound of formula I together with another active agent such as an anticoagulation agent or a thrombolytic agent can be used for the preparation of a medicament useful for inhibiting the binding of fibrinogen to blood platelets, inhibiting the aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a mammal.
  • active agents include plasminogen activators or streptokinase, heparin, aspirin, warfarin, ticlopidine and/or clopidogrel.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture.
  • suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhy droxy- ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • the compounds of the present invention can also be co- administered with suitable anticoagulation agents or thrombolytic agents such as plasminogen activators or streptokinase in the treatment of various vascular pathologies. They may also be combined with heparin, aspirin, warfarin, ticlopidine and/or clopidogrel. Coadministration includes administration together at essentially the same time in a single dosage form or in separate dosage forms, or each agent administered at separately staggered times in order to achieve beneficial thrombosis prevention or thrombolysis.
  • the compounds of the present invention can be prepared readily according to the following Schemes and Examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures.
  • TBAF tetrabutylammonium fluoride
  • DEAD diethyl azodicarboxylate
  • PPh3 triphenyl phosphine
  • BOP Benzotriazol-1 -yloxytris(dimethylamino)phosphonium, hexafluorophosphate
  • NMM N-methyl morpholine
  • NMP N-methyl pyrrolidine
  • Oxone potassium peroxymonosulfate
  • Step 1 4-[3-(N-Boc-Piperidin-4-yl)propyloxylbenzaldehyde (1-3)
  • Step 2 N-[(3-(N-Boc-Piperidin-4-yl)propyloxy)phen-4-yl- methyl]glycine methyl ester ( 1 -5)
  • Step 3 N-[(3-(N-Boc-Piperidin-4-yl)pro ⁇ yloxy)phen-4-yl)- methyl]-N'-phenylsulfonyl glycine methyl ester (1 -6)
  • Step 4 N-[(3-(N-Boc-Piperidin-4-yl)propyloxy)phen-4-yl-methyl]- N'-phenylsulfonyl glycine (1-7)
  • ester 1-6 900 mg, 1.61 mmol
  • 1N NaOH (2 ml) and EtOH 5 ml
  • the reaction mixture was then acidified with 10% KHSO 4 , followed by extraction with EtOAc.
  • the organic portion was washed with brine, dried (MgSO 4 ) and concentrated to give the carboxylic acid 1-7 as a white solid.
  • Step 5 N-[(3-(Piperidin-4-yl)propyloxy)phen-4-yl-methyl]-N'- phenylsulfonyl glycine (1 -8)
  • Step 3 6-Formyl-N-[(N-Boc-piperidin-4-yl)ethyI]-3,4- dihydroisoquinolin-1 -one (2-5)
  • Step 4 N-(N-[(N-Boc-Piperidin-4-yl)ethyl]-3,4-dihydro- isoquinolin-1-one-6-yl-methyl)glycine methyl ester (2-6)
  • 4A molecular sieves (3.60 g)
  • Step 5 N-(N-[(N-Boc-Piperidin-4-yl)ethyl]3,4-dihydro- isoquinolin-1 -one-6-yl-methyl)-N'-phenylsulfonyI glycine methyl ester (2-7)
  • Step 6 N-(N-[(N-Boc-Piperidin-4-yl)ethyl]-3,4-dihydro- isoquinolin-1-one-6-yl-methyl)-N'-phenylsulfonyl glycine
  • ester 2-7 600 mg, 1.00 mmol
  • 1 N NaOH 2.0 ml
  • EtOH 5 ml
  • the reaction mixture was then acidified with 10% KHSO 4 followed by extraction with EtOAc.
  • the organic portion was washed with brine, dried (MgSO 4 ) and concentrated to give acid 2-8 as a white solid.
  • Step 7 N-(N-[(Piperidin-4-yl)ethyl]-3,4-dihydroisoquinolin-1-one-
  • the yellow solid was dissolved ethanol (200 mL) and shaken under an atmosphere of hydrogen gas at 50 psi in the presence of 0.8 g of 5% Pd/C for 18 h at RT.
  • the product solution was filtered through a pad of Celite, and the filtrate was concentrated under vacuum to give 2 as pink solid.
  • Step 2 4-[4-(4-tert-Butyloxycarbonyl-piperazin-1 -yl)phenylamino- carbonyl]-nitrobenze (3-4)
  • the resultant 4-nitrobenzoyl chloride (3-3) was dissolved in dichloro- methane (25 mL) and was added dropwisely to a cold (0°C) solution of aniline 3-2 (6.12 g, 22.1 mmol) and DMAP (135 mg) in a mixture of dichloromethane (30 mL) and pyridine (4.5 mL) over a period of 30 min.
  • the resultant slurry was diluted with dichloromethane (60 mL) and stirred at 0°C for 1 h.
  • the product mixture was further diluted with dichloromethane (600 mL), washed successively with sat. aq.
  • Step 4 N- ⁇ 4-14-(Piperazin-1-yl)phenylaminocarbonyl]phenyl ⁇ -N- phenyl-sulfonylglycine (3-6a)
  • Step 1 N-Benzylsulfonyl-4-[4-(4-tert-butyloxycarbonyl-piperazin-
  • Step 2 N- ⁇ 4-[4-(Piperazin-1 -yl)phenylaminocarbonyl]phenyl ⁇ -N- benzyl-sulfonylglvcine (3-6b)
  • Step 2 N- ⁇ 4-[4-(Piperazin-1-yl)phenylaminocarbonyl]phenyl ⁇ -N- methylsulfonylglycine (3-6c)
  • Step 1 N-4-bromo-phenylsulfonyl-4-[4-(4-tert-butyloxycarbonyl- piperazin-1-yl)-phenylamino-carbonyl]-aniline (3-5d)
  • Step 2 N- ⁇ 4-[4-(piperazin-1-yl)phenylaminocarbonyllphenyl ⁇ -N- 4-bromo-phenyl-sulfonylglycine (3-6d)
  • Step 1 N-4-nitrophenyl-N-phenylsulfonylglycine ethyl ester (4-8a)
  • Step 2 N- ⁇ 4-[4-(4-tert-Butyloxycarbonylpiperazin-1 - yl)phenylcarbonyl-amino]phenyl ⁇ -N-phenylsulfonylglycine ethyl ester (4-10a)
  • dichloromethane 25 mL and DMF (3 drops) at RT was treated with oxalyl chloride (0.43 mL, 4.9 mmol) over a period of 10 min.
  • the resultant solution was stirred at RT for 1 h, and concentrated under vacuum. The residue was dissolved in toluene and concentrated to remove residual oxalyl chloride.
  • the resultant acid chloride 4-9 was redissolved in dichloromethane (5 mL), and added to a cold (0°C) solution the above aniline (1.1 g, 3.3 mmol) and DMAP (0.48 g, 3.9 mmol) in dichloromethane (25 mL).
  • Step 3 N- ⁇ 4-[4-(Piperazin-1-yl)phenylcarbonylamino]phenyl ⁇ -N- phenyl-sulfonylglvcine (4-11a)
  • aq. sodium hydroxide (0.85 mL, 1 M, 1.7 mmol) was added.
  • the resultant mixture was stirred at RT for 2 h.
  • the product mixture was concentrated, acidified, and extracted into dichloromethane. The combined organic extract were dried over sodium sulfate, filtered and concentrated under vacuum.
  • This product was prepared using 2-thiophene sulfonyl chloride in place of phenylsulfonyl chloride in Step 1.
  • This product was prepared using 3-fluorophenylsulfonyl chloride in place of phenylsulfonyl chloride in Step 1.
  • This product was prepared using 4-fluorophenylsulfonyI chloride in place of phenylsulfonyl chloride in Step 1..
  • This product was prepared using trifluoromethanesulfonic anhydride and tert-butyl bromoacetate in place of phenylsulfonyl chloride and ethylbromo acetate, respectively, in Step 1.
  • This product was prepared using (1S)-(-)-10- camphorsulfonyl chloride in place of phenylsulfonyl chloride in Step 1..
  • Step 1 N-4-Nitrophenyl-N-benzoylglycine ethyl ester (5- 13a)
  • Step 2 N- ⁇ 4-[4-(4-tert-Butyloxycarbonyl-piperazin-1 -yl)- phenylcarbonyl-amino]phenyl ⁇ -N-benzoylglycine ethyl ester (5 -14a)
  • Step 3 N- ⁇ 4-[4-(Piperazin-1-yl)phenylcarbonylamino]phenyl ⁇ -N- benzoyl-glycine (5-15a)
  • Step 1 N-4-Nitrophenyl-N-2-fluorobenzoyl-glycine ethyl ester (5- 13b)
  • Step 2 N- ⁇ 4-[4-(4-tert-Butyloxycarbonyl-piperazin-1-yl)- phenylcarbonyl-amino]phenyl ⁇ -N-2-fluorobenzoylglycine ethyl ester (5-14b)
  • Step 3 N- ⁇ 4-[4-(Piperazin-1-yl)phenyIcarbonylaminolphenyl ⁇ -N-
  • Step 1 N-4-Nitrophenyl-N-3-fluorobenzoylglycine ethyl ester (5-13c)
  • Step 2 N- ⁇ 4-[4-(4-tert-Butyloxycarbonyl-piperazin-1 -yl)- phenylcarbonyl-amino]phenyl ⁇ -N-3-fluorobenzoylglycine ethyl ester (5-14c)
  • Step 3 N- ⁇ 4-[4-(piperazin-1-yl)phenylcarbonylamino]phenyl ⁇ -N-
  • Step 1 N-4-Nitrophenyl-N-4-fluorobenzoylglvcine ethyl ester (5-13d) Following the procedure described for 5-13a, but
  • Step 2 N- ⁇ 4-[ 4-(4-tert -Butyloxycarbonyl-piperazin-1-yl)- phenylcarbonyl-aminolphenyl ⁇ -N-4-fluorobenzoylglycine ethyl ester (5-14d)
  • Step 3 N- ⁇ 4-[4-(Piperazin-1 -yl)phenylcarbonylamino]phenyl ⁇
  • N-4-fluoro-benzoylglycine Following the procedure described for 4-1 1a. but substituting N- ⁇ 4-[4-(4-tert -butyloxycarbonyl-piperazin-1 -yl)- phenylcarbonylamino]phenyl ⁇ -N-4-fluorobenzoyl-glycine ethyl ester (5-14d) for N- ⁇ 4-[4-(4-tert -butyloxycarbonyl-piperazin- 1-yl)- phenylcarbonylamino]phenyl ⁇ -N-phenylsulfonylglycine ethyl ester (4-10a), 5-15d was prepared.
  • Step 1 N-4-Nitrophenyl-N-picolinoyl-glycine ethyl ester (5-13d)
  • Step 2 N- ⁇ 4-[4-(4-tert-Butyloxycarbonyl-piperazin-1-yl)- phenylcarbonyl-amino]phenyl ⁇ -N-picolinoylglycine ethyl ester (5-14e)
  • Step 3 N- ⁇ 4-[4-(Piperazin-1 -yl)phenylcarbonylaminojphenyl ⁇ -
  • Step 1 N-4-Nitrophenyl-N-nicotinoyl-glycine ethyl ester (5-13f)
  • Step 2 N- ⁇ 4-[4-(4-tert- Butyloxycarbonyl-piperazin-1-yl)- phenylcarbonyl aminojphenyl ⁇ -N-nicotinoylglycine ethyl ester (5-14f)
  • Step 3 N- ⁇ 4-[4-(Piperazin-1-yl)phenylcarbonylamino]phenyl ⁇ -N- nicotinoyl-glycine (5-15f)
  • Step 1 N-4-Nitrophenyl-N-isonicotinoyl-glycine ethyl ester (5- 13g) Following the procedure described for 5-13a, but substituting isonicotinoyl chloride hydrochloride for benzoyl chloride, 5-13g was prepared.
  • Step 2 N-(4-[4-(4-tert -Butyloxycarbonyl-piperazin-1-yl)- phenylcarbonyl-amino]phenyl ⁇ -N-isonicotinoylglycine ethyl ester (5-14 g)
  • Step 3 N- ⁇ 4-[4-(Piperazin-1 -yl)phenylcarbonylaminolphenyl ⁇ -N- isonicotin-oyl-glycine (5-15g)
  • Step 1 N-4-Nitrophenyl-N-acetyl-glycine ethyl ester (5-13h)
  • Step 2 N- ⁇ 4-[4-(4-tert -Butyloxycarbonyl-piperazin-1 -yl)- phenylcarbonyl-amino]phenyl ⁇ -N-acetylglycine ethyl ester
  • Step 3 N- ⁇ 4-[4-(Piperazin-1-yl)phenylcarbonyl mino]phenyl ⁇ -N- acetyl-glycine (5-15h)
  • Step 1 N-4-Nitrophenyl-N-cyclopropanecarboxylglycine ethyl ester (5-13i)
  • Step 2 N- ⁇ 4-[4-(4-tert-Butyloxycarbonyl-piperazin-1 -yl)- phenyIcarbonyl-amino]phenyl ⁇ -N-cyclopropane- carboxylglycine ethyl ester (5-14i)
  • Step 3 N- ⁇ 4-[4-(Piperazin-1-yl)phenylcarbonylamino]phenyl ⁇ -N- cyclopropanecarboxylglycine (5-15i)
  • Step 1 N-4-Nitrophenyl-N-benzyloxyacetyl-glycine ethyl ester (5-13j)
  • Step 2 N- ⁇ 4-[4-(4-tert -Butyloxycarbonyl-piperazin-1 -yl)- phenylcarbonyl-aminolphenyl ⁇ -N-benzyloxyacetylglycine ethyl ester (5-14j)
  • Step 3 N- ⁇ 4-[4-(Piperazin-1-yl)phenyIcarbonylamino]phenyl ⁇ -N- benzyloxy-acetylglycine (5-15j)
  • Step 1 N-3-Methyl-4-nitrophenyl-N-benzoyl-glycine ethyl ester (5-131)
  • Step 2 N- ⁇ 4-[4-(4-tert-Butyloxycarbonyl-piperazin- 1 -yl)- phenylcarbonyl-aminol-3-methyl-phenyl ⁇ -N- benzoylglycine ethyl ester (5-141)
  • Step 3 N- ⁇ 4-[4-(Piperazin-1 -yl)phenylcarbonylamino]-3-methyl- phenyl ⁇ -N-2-benzoylglycine (5-151)
  • Step 1 N-2-Methyl-4-nitrophenyl-N-benzoyl-glycine ethyl ester (5-13m)
  • Step 2 N- ⁇ 4-[4-(4-tert-Butyloxycarbonyl-piperazin-1 -yl)- phenylcarbonyl-amino]-2-methyl-phenyl ⁇ -N- benzoylglycine ethyl ester (5-14m)
  • Step 3 N- ⁇ 4-[4-(Piperazin-1-yl)phenyIcarbonyla mino]-2-memy phenyl ⁇ -N-2-benzoylglycine (5- 15m)
  • Step 1 N- ⁇ 4-[4-(4-tert-Butyloxycarbonyl-piperazin-1-yl)-3- methylphenyl-carbonylaminol-phenyl ⁇ -N-benzoylglycine ethyl ester (5-14n)
  • Step 2 N- ⁇ 4-[4-(Piperazin-1-yl)-3-methyl-phenylcarbonylaminol- phenyl )-N-benzoylglycine (5-15n)
  • Step 1 N- ⁇ 4-[4-(4-tert -Butyloxycarbonyl-piperazin-1-yl)-2- methylphenyl-carbonylamino]-phenyl ⁇ -N-benzoylglycine ethyl ester (5-14o)
  • Step 2 N- ⁇ 4-[4-(Piperazin-1 -yl)-2-methylphenylcarbonylamino]- phenyl ⁇ -N-benzoylglycine (5-15o)
  • Step 1 9-H-2-(1 ,1-Dimethylethoxycarbonyl)-7-bromo ⁇ -carboline
  • Step 2 9-H-2-(1 ,1-Dimethylethoxycarbonyl)- ⁇ -carbolin-7-yl
  • Step 3 N- ⁇ 4-[9-Boc- ⁇ -carbolme-7-yl)carbonylamino]phenyl ⁇ -N- phenyl-sulfonyl glycine (6-4)
  • Step 1 4-(4-Pyridyl)phenylcarboxylate (7-2)
  • HOAc/MeOH was treated with 250 mg PtO 2 and hydrogenated at 50 psi for 4 hr.
  • the solution was filtered through Solka Floe, evaporated and azeotroped with heptane to remove excess HOAc.
  • the intermediate amino acid acetic acid salt was obtained as a white solid.
  • Step 3 Ethyl 2-(1 -phenylsulfonamido-4-(4-(N-(1,1- dimethylethoxycarbonyl)-piperidin-4-yl)phenyl- carboxamide)-phenyl)acetate (7-4)
  • Step 4 N- ⁇ 4-[4-N-Boc-piperidin-4-yl)phenylcarboxylamino]- phenyl ⁇ -N-phenylsulfonylglycine (7-5)
  • Step 5 N- ⁇ 4-[4-Piperidm-4-yl)phenylcarbonylamino]phenyl ⁇ -N- phenyl-sulfonylglycine (7-6)
  • Step 1 4-(Pyridyl)piperidin-4-yl-carboxylic acid (8-1 )
  • Ethyl isonipecotate (6.0 g, 38.66 mmol), 4-chloropyridine hydrochloride (5.9 g, 38.66 mmol) and N-methylmorpholine (9.3 mL, 85.0 mmol) were dissolved in N-methylpyrrolidinone (50 mL) and the resulting solution heated at 100° for 48 h.
  • the solution was
  • Step 2 N- ⁇ 4-[N-(4-Pyridyl)-piperidinyl-4-carbonylamino ⁇ phenyl ⁇ - N-phenyl-sulfonyl-glycine methyl ester (8-2)
  • Step 1 N-4-(4-tert-Butyloxycarbonylpiperaziny-1-y)-benzoyl]-5- nitro-indoline (9-2)
  • Step 2 N-[4-(1 -tert-Butyloxycarbonylpiperaziny-1 -y)benzoyl]-5- phenyl-sulfonylamino-indoline (9-3)
  • Step 3 N- ⁇ N-[4-(4-tert-Butyloxycarbonylpiperaziny-1-yl)- benzoyn-5-indolinyl ⁇ -N-phenylsufonyl-glycine (9-4)
  • Step 3 N- ⁇ 2-[4-(4-tert-Butyloxycarbonylpiperazin-yl)- phenylamino-carbonyl]thien-5-yl ⁇ -N-phenylsulfonyl- glvcine methyl ester (10-4)
  • Step 1 6-Nitro-3,4-dihydroquinolin-2-(1H)-one (1 1 -2)
  • Step 3 6-[4-(4-tert-Butyloxycarbonyl-piperazin-1 -yl)- phenylcarbonylaminol-1-carbomethoxymethyI-3,4- dihydroquinolin-2-(1H)-one (11 -4)
  • Step 4 6-[4-(4-Piperazin-1-yl)-phenylcarbonylamino]-1 - carbohydroxymethyl-3.4-dihvdroquinolin-2-(l H)-one (1 1 -5) Following the procedure described for 4-11 a, but substituting 6-[4-(4-tert -butyloxycarbonyl-piperazin-1 -yl)- pheny Icarbony lamino]- 1 -carbomethoxy-methyl-3 , 4-dihydroquinolin-2- (1H)-one (1 1-4) for 4- 10a, 1 1-5 was prepared.
  • Tablet Preparation Tablets containing 25.0, 50.0, and 100.0 mg., respectively, of the active compound p) from Table I are prepared as illustrated below:
  • Intravenous formulations An intravenous dosage form of the above-indicated active compound is prepared as follows:
  • the active compound is dissolved at room temperature in a previously prepared solution of sodium chloride, citric acid, and sodium citrate in Water for Injection (USP, see page 1636 of United States Pharmacopeia/National Formulary for 1995, published by United States Pharmacopeial Convention, Inc., Rockville, Maryland, copyright 1994.
  • Compounds of the invention may be administered to patients where inhibition of human or mammalian platelet aggregation or adhesion is desired.
  • Compounds of the invention are useful in inhibiting platelet aggregation and thus, they may find utility in surgery on peripheral arteries (arterial grafts, carotid endaterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interation of platelets with artificial surfaces, leads to platelet aggregation and consumption.
  • the aggregated platelets may form thrombi and
  • thromboemboli Compounds of the invention may be administered to these surgical patients to prevent the formation of thrombi and

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Abstract

Antagoniste des récepteurs de fibrinogènes de la formule générale: X-A-Y-Z-B (I), incluant, par exemple, des composés de la formule (IV), utiles pour inhiber la liaison d'un fibrinogène aux plaquettes sanguines ou l'agrégation des plaquettes sanguines, et pour traiter ou prévenir la formation d'un thrombus ou d'un embole.
PCT/US1997/002712 1996-02-28 1997-02-24 Antagonistes des recepteurs de fibrinogenes Ceased WO1997031910A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP97906712A EP0885205A4 (fr) 1996-02-28 1997-02-24 Antagonistes des recepteurs de fibrinogenes
JP9531013A JP2000505471A (ja) 1996-02-28 1997-02-24 フィブリノーゲン受容体拮抗物質
AU21332/97A AU712082B2 (en) 1996-02-28 1997-02-24 Fibrinogen receptor antagonists

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US1238096P 1996-02-28 1996-02-28
US60/012,380 1996-02-28
GB9606489.4 1996-03-27
GBGB9606489.4A GB9606489D0 (en) 1996-03-27 1996-03-27 Fibrinogen receptor antagonists

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WO1997031910A1 true WO1997031910A1 (fr) 1997-09-04

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EP (1) EP0885205A4 (fr)
JP (1) JP2000505471A (fr)
AU (1) AU712082B2 (fr)
CA (1) CA2246756A1 (fr)
WO (1) WO1997031910A1 (fr)

Cited By (24)

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EP0912175A4 (fr) * 1996-06-28 1999-09-08 Merck & Co Inc Antagonistes du recepteur de fibrinogene
JP2001026506A (ja) * 1999-04-28 2001-01-30 Takeda Chem Ind Ltd スルホンアミド誘導体
WO2001016119A1 (fr) * 1999-08-27 2001-03-08 Eli Lilly And Company Composes n,n-arylsulfonylglycine hypoglycemiques
EP1174028A4 (fr) * 1999-04-28 2002-11-06 Takeda Chemical Industries Ltd Derives de sulfamide
WO2002102780A1 (fr) * 2001-06-18 2002-12-27 Ono Pharmaceutical Co., Ltd. Compose derive de tetrahydroquinoline et medicament contenant ledit compose comme principe actif
US6642252B2 (en) 2000-11-07 2003-11-04 Bristol-Myers Squibb Company Acid derivatives useful as serine protease inhibitors
US6713467B2 (en) 2000-11-07 2004-03-30 Bristol-Myers Squibb Company Acid derivatives useful as serine protease inhibitors
US6906192B2 (en) 2000-11-07 2005-06-14 Bristol Myers Squibb Company Processes for the preparation of acid derivatives useful as serine protease inhibitors
WO2005049589A3 (fr) * 2003-10-14 2005-09-15 Cadila Healthcare Ltd Nouveaux composes heterocycliques
US7786155B2 (en) 2007-10-16 2010-08-31 Novartis Ag Organic compounds
US8012982B2 (en) 2004-10-01 2011-09-06 Istituto Di Ricerche Biologia Molecolare P. Angeletti Spa Modulators of HCV replication
US8618299B2 (en) 2009-07-01 2013-12-31 Albany Molecular Research, Inc. Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof
US8629158B2 (en) 2009-07-01 2014-01-14 Albany Molecular Research, Inc. Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8637501B2 (en) 2009-07-01 2014-01-28 Albany Molecular Research, Inc. Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof
US8697700B2 (en) 2010-12-21 2014-04-15 Albany Molecular Research, Inc. Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof
US8716308B2 (en) 2008-01-11 2014-05-06 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US8993765B2 (en) 2010-12-21 2015-03-31 Albany Molecular Research, Inc. Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof
US9073925B2 (en) 2009-07-01 2015-07-07 Albany Molecular Research, Inc. Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US10562912B2 (en) 2013-06-05 2020-02-18 C&C Research Laboratories Heterocyclic derivatives and use thereof
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10752640B2 (en) 2014-08-01 2020-08-25 Nuevolution A/S Compounds active towards bromodomains
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors

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WO2011027888A1 (fr) * 2009-09-07 2011-03-10 大日本住友製薬株式会社 Dérivé diamide-phényle et son sel pharmaceutiquement acceptable

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US5183810A (en) * 1990-02-13 1993-02-02 Merck & Co., Inc. Imidazole angiotensin II antagonists incorporating a substituted benzyl element
US5464833A (en) * 1992-08-19 1995-11-07 Otsuka Pharmaceutical Co., Ltd. Apoptosis regulating composition
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Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0912175A4 (fr) * 1996-06-28 1999-09-08 Merck & Co Inc Antagonistes du recepteur de fibrinogene
US6586617B1 (en) 1999-04-28 2003-07-01 Sumitomo Chemical Takeda Agro Company, Limited Sulfonamide derivatives
JP2001026506A (ja) * 1999-04-28 2001-01-30 Takeda Chem Ind Ltd スルホンアミド誘導体
EP1174028A4 (fr) * 1999-04-28 2002-11-06 Takeda Chemical Industries Ltd Derives de sulfamide
US6617343B1 (en) 1999-08-27 2003-09-09 Eli Lilly And Company Hypoglycemic N,N-arylsulfonylglycine compounds
WO2001016119A1 (fr) * 1999-08-27 2001-03-08 Eli Lilly And Company Composes n,n-arylsulfonylglycine hypoglycemiques
US6642252B2 (en) 2000-11-07 2003-11-04 Bristol-Myers Squibb Company Acid derivatives useful as serine protease inhibitors
US6713467B2 (en) 2000-11-07 2004-03-30 Bristol-Myers Squibb Company Acid derivatives useful as serine protease inhibitors
US6906192B2 (en) 2000-11-07 2005-06-14 Bristol Myers Squibb Company Processes for the preparation of acid derivatives useful as serine protease inhibitors
WO2002102780A1 (fr) * 2001-06-18 2002-12-27 Ono Pharmaceutical Co., Ltd. Compose derive de tetrahydroquinoline et medicament contenant ledit compose comme principe actif
WO2005049589A3 (fr) * 2003-10-14 2005-09-15 Cadila Healthcare Ltd Nouveaux composes heterocycliques
US8012982B2 (en) 2004-10-01 2011-09-06 Istituto Di Ricerche Biologia Molecolare P. Angeletti Spa Modulators of HCV replication
US7786155B2 (en) 2007-10-16 2010-08-31 Novartis Ag Organic compounds
US9650378B2 (en) 2008-01-11 2017-05-16 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US8716308B2 (en) 2008-01-11 2014-05-06 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US9296743B2 (en) 2008-01-11 2016-03-29 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
US8629158B2 (en) 2009-07-01 2014-01-14 Albany Molecular Research, Inc. Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8637501B2 (en) 2009-07-01 2014-01-28 Albany Molecular Research, Inc. Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof
US9073925B2 (en) 2009-07-01 2015-07-07 Albany Molecular Research, Inc. Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8618299B2 (en) 2009-07-01 2013-12-31 Albany Molecular Research, Inc. Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof
US8697700B2 (en) 2010-12-21 2014-04-15 Albany Molecular Research, Inc. Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof
US8993765B2 (en) 2010-12-21 2015-03-31 Albany Molecular Research, Inc. Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof
US10562912B2 (en) 2013-06-05 2020-02-18 C&C Research Laboratories Heterocyclic derivatives and use thereof
US10752640B2 (en) 2014-08-01 2020-08-25 Nuevolution A/S Compounds active towards bromodomains
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US12338233B2 (en) 2018-02-13 2025-06-24 Gilead Sciences, Inc. PD-1/Pd-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US12269812B2 (en) 2018-07-13 2025-04-08 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors

Also Published As

Publication number Publication date
EP0885205A1 (fr) 1998-12-23
AU712082B2 (en) 1999-10-28
JP2000505471A (ja) 2000-05-09
CA2246756A1 (fr) 1997-09-04
AU2133297A (en) 1997-09-16
EP0885205A4 (fr) 2002-11-27

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