Classifications

• • 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
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/70—Sulfur atoms
• • 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
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/14—Nitrogen atoms not forming part of a nitro radical
• • 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
  • 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
  • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
  • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
• • 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
  • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
• • 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
  • C07D211/36—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 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
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
  • C07D213/53—Nitrogen atoms
• • 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
  • C07D213/72—Nitrogen atoms
  • C07D213/73—Unsubstituted amino or imino 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
  • 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
  • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
  • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
  • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
• • C—CHEMISTRY; METALLURGY
  • 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
  • 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
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems

Definitions

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

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Diabetes (AREA)
• Hematology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (5)

Publications (2)

Family

ID=26310811

Family Applications (1)

Country Status (5)

Families Citing this family (43)

Citations (5)

Family Cites Families (4)

• 1997
  • 1997-06-25 EP EP97932307A patent/EP0912175A4/de not_active Withdrawn
  • 1997-06-25 CA CA002258093A patent/CA2258093A1/en not_active Abandoned
  • 1997-06-25 JP JP10504291A patent/JP2000514061A/ja active Pending
  • 1997-06-25 WO PCT/US1997/011133 patent/WO1998000134A1/en not_active Application Discontinuation
  • 1997-06-25 AU AU35798/97A patent/AU721130B2/en not_active Ceased

Patent Citations (5)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events