WO2001085722A1 - Sulfonamides heterobicycliques et utilisation de celles-ci comme inhibiteurs de recepteur adp des plaquettes - Google Patents

Sulfonamides heterobicycliques et utilisation de celles-ci comme inhibiteurs de recepteur adp des plaquettes Download PDF

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WO2001085722A1
WO2001085722A1 PCT/US2001/014441 US0114441W WO0185722A1 WO 2001085722 A1 WO2001085722 A1 WO 2001085722A1 US 0114441 W US0114441 W US 0114441W WO 0185722 A1 WO0185722 A1 WO 0185722A1
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alkyl
group
aryl
substituted
heteroaryl
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PCT/US2001/014441
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English (en)
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Robert M. Scarborough
Charles K. Marlowe
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Cor Therapeutics, Inc.
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Priority to JP2001582323A priority Critical patent/JP2003532728A/ja
Priority to EP01938998A priority patent/EP1278744A1/fr
Priority to AU2001264566A priority patent/AU2001264566A1/en
Priority to CA002408156A priority patent/CA2408156A1/fr
Priority to US10/275,154 priority patent/US20040029867A1/en
Publication of WO2001085722A1 publication Critical patent/WO2001085722A1/fr
Priority to HK03102259.9A priority patent/HK1050008A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to novel benzofused heterocyclic sulfonamide derivatives which are effective platelet ADP receptor inhibitors. These derivatives may be used in various pharmaceutical compositions. In particular, the derivatives may be used in pharmaceutical compositions effective for the prevention and/or treatment of cardiovascular diseases, particularly those diseases related to thrombosis.
  • Thrombotic complications are a major cause of death in the industrialized world. Examples of these complications include acute myocardial infarction, unstable angina, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular disease, preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminated intravascular coagulation and thrombotic cytopenic purpura. Thrombotic and restenotic complications also occur following invasive procedures, e.g., angioplasty, carotid endarterectomy, post CABG (coronary artery bypass graft) surgery, vascular graft surgery, stent placements and insertion of endovascular devices and protheses.
  • CABG coronary artery bypass graft
  • Platelet aggregates play a critical role in these events. Blood platelets, which normally circulate freely in the vasculature, become activated and aggregate to form a thrombus with disturbed blood flow caused by ruptured atherosclerotic lesions or by invasive treatments such as angioplasty, resulting in vascular occlusion. Platelet activation can be initiated by a variety of agents, e.g., exposed subendothelial matrix molecules such as collagen, or by thrombin which is formed in the coagulation cascade.
  • agents e.g., exposed subendothelial matrix molecules such as collagen, or by thrombin which is formed in the coagulation cascade.
  • ADP adenosine 5'- diphosphate
  • ATP adenosine 5'-triphosphate
  • platelet ADP receptors are members of the family of P2 receptors activated by purine and/or pyrimidine nucleotides (King, B.F., Townsend-Nicholson, A. & Burnstock, G. (1998) Trends Pharmacol. Sci. 19:506-514).
  • ADP-dependent platelet aggregation requires activation of at least two ADP receptors (Kunapuli, S.P. (1998), Trends Pharmacol. Sci. 19:391-394; Kunapuli, S.P. & Daniel, J.L. (1998) Biochem. J. 336:513-523; Jantzen, H.M. et al. (1999) Thromb. Hemost. 81 :111-117).
  • One receptor appears to be identical to the cloned P2Yj receptor, mediates phospholipase C activation and intracellular calcium mobilization and is required for platelet shape change.
  • Some purine derivatives of the endogenous antagonist ATP are selective platelet ADP receptor antagonists which inhibit ADP-dependent platelet aggregation and are effective in animal thrombosis models (Humphries et al. (1995), Trends Pharmacol. Sci. 16, 179; Ingall, A.H. et al. (1999) J. Med. Chem. 42, 213-230).
  • Novel triazolo [4,5-d] pyrimidine compounds have been disclosed as P 2T - antagonists ( WO 99/05144).
  • Tricyclic compounds as platelet ADP receptor inhibitors have also been disclosed in WO 99/36425.
  • the target of these antithrombotic compounds appears to be the platelet ADP receptor mediating inhibition of adenylyl cyclase.
  • platelet ADP receptor inhibitors having antithrombotic activity that are useful in the prevention and/or treatment of cardiovascular diseases, particularly those related to thrombosis.
  • the invention provides compounds of formula (I):
  • A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, and alkylheteroaryl;
  • R 2 is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 1 and R 2 can be direct linked or can be indirectly linked through a carbon chain that is from 1 to 8 carbon atoms in length, or W is selected from the group consisting of:
  • K is independently selected from the group consisting of C and N, with the proviso that when K is a ring carbon atom, each ring carbon atom is either bound to W or independenty substituted by L;
  • Q is independently selected from the group consisting of C and N, with the proviso that when Q is a ring carbon atom, each ring carbon atom is independenty substituted by L, wherein
  • L in each instance, is independently selected from the group consisting of:
  • R 3 and R 4 are each independently selected from the group consisting of: hydrogen, halogen, -CN, -NO 2 , -C, .10 alkyl, C 3.8 -cycloalkyl, aryl, amino, amino-C,. 8 -alkyl, C,. 3 -acylamino, C,. 3 -acylamino-C, .8 -alkyl, C,. 6 -alkylamino, C L g-alkylamino C,. 8 alkyl, C]_ 6 dialkylamino, C,.
  • D is selected from the group consisting of S, O and N-R 5 wherein R 5 is selected from the group consisting of:
  • the invention provides pharmaceutical compositions for preventing or ' treating thrombosis in a mammal containing a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the invention further provides a method for preventing or treating thrombosis in a mammal by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • alkenyl refers to a trivalent straight chain or branched chain unsaturated aliphatic radical.
  • alkinyl (or “alkynyl”) refers to a straight or branched chain aliphatic radical that includes at least two carbons joined by a triple bond. If no number of carbons is specified alkenyl and alkinyl each refer to radicals having from 2-12 carbon atoms.
  • alkyl refers to saturated aliphatic groups including straight-chain, branched-chain and cyclic groups having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms.
  • cycloalkyl refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms and preferably 3 to 7 carbon atoms.
  • C,-C 6 alkoxy refers to an ether moiety whereby the oxygen is connected to a straight or branched chain of carbon atoms of the number indicated.
  • mono-C,-C 6 alkylamino refers to an amino moiety whereby the nitrogen is substituted with one H and one C,-C 6 alkyl substituent, the latter being defined as above.
  • di-C,-C 6 alkylamino refers to an amino moiety whereby the nitrogen is substituted with two C,-C 6 alkyl substituents as defined above.
  • monoarylamino refers to an amino moiety whereby the nitrogen is substituted with one H and one aryl substituent, such as a phenyl, the latter being defined as above.
  • diarylamino refers to an amino moiety whereby the nitrogen is substituted with two aryl substituents, such as phenyl, the latter being defined as above.
  • C r C 6 alkylsulfonyl refers to a dioxosulfur moiety with the sulfur atom also connected to one C,-C 6 alkyl substituent, the latter being defined as above.
  • C,-C 6 alkoxycarbonyl refers to a hydroxycarbonyl moiety whereby the hydrogen is replaced by a C,-C 6 alkyl substituent, the latter being defined as above.
  • the terms "carbocyclic ring structure " and " C 3 . 16 carbocyclic mono, bicyclic or tricyclic ring structure” or the like are each intended to mean stable ring structures having only carbon atoms as ring atoms wherein the ring structure is a substituted or unsubstituted member selected from the group consisting of: a stable monocyclic ring which is aromatic ring ("aryl") having six ring atoms ("phenyl”); a stable monocyclic non-aromatic ring having from 3 to 7 ring atoms in the ring; a stable bicyclic ring structure having a total of from 7 to 12 ring atoms in the two rings wherein the bicyclic ring structure is selected from the group consisting of ring structures in which both of the rings are aromatic, ring structures in which one of the rings is aromatic and ring structures in which both of the rings are non-aromatic; and a stable tricyclic ring structure having a total of from 10 to 16 atom
  • non-aromatic rings when present in the monocyclic, bicyclic or tricyclic ring structure may independently be saturated, partially saturated or fully saturated.
  • carbocyclic ring structures include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), 2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
  • the ring structures described herein may be attached to one or more indicated pendant groups via any carbon atom which results in a stable structure.
  • substituted as used in conjunction with carbocyclic ring structures means that hydrogen atoms attached to the ring carbon atoms of ring structures described herein may be substituted by one or more of the substituents indicated for that structure if such substitution(s) would result in a stable compound.
  • aryl which is included with the term “carbocyclic ring structure” refers to an unsubstituted or substituted aromatic ring, substituted with one, two or three substituents selected from loweralkoxy, loweralkyl, loweralkylamino, hydroxy, halogen, cyano, hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl, carboalkoxy and carboxamide, including but not limited to carbocyclic aryl, heterocyclic aryl, and biaryl groups and the like, all of which may be optionally substituted.
  • Preferred aryl groups include phenyl, halophenyl, loweralkylphenyl, napthyl, biphenyl, phenanthrenyl and naphthacenyl.
  • arylalkyl which is included with the term “carbocyclic aryl” refers to one, two, or three aryl groups having the number of carbon atoms designated, appended to an alkyl group having the number of carbon atoms designated. Suitable arylalkyl groups include, but are not limited to, benzyl, picolyl, naphthylmethyl, phenethyl, benzyhydryl, trityl, and the like, all of which may be optionally substituted.
  • phenyl refers to a six carbon containing aromatic ring which can be variously mono- or poly-substituted with H, C,-C 6 alkyl, hydroxyl, C,-C 6 alkoxy, amino, mono-C,-C 6 alkylamino, di-C C 6 alkylamino, nitro, fluoro, chloro, bromo, iodo, hydroxycarbonyl, or C j -C 6 alkoxycarbonyl.
  • heterocyclic ring or “heterocyclic ring system” is intended to mean a substituted or unsubstituted member selected from the group consisting of stable monocyclic ring having from 5-7 members in the ring itself and having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S; a stable bicyclic ring structure having a total of from 7 to 12 atoms in the two rings wherein at least one of the two rings has from 1 to 4 hetero atoms selected from N, O and S, including bicyclic ring structures wherein any of the described stable monocyclic heterocyclic rings is fused to a hexane or benzene ring; and a stable tricyclic heterocyclic ring structure having a total of from 10 to 16 atoms in the three rings wherein at least one of the three rings has from 1 to 4 hetero atoms selected from the group consisting of N, O and S.
  • heterocyclic ring or “heterocyclic ring system” include aromatic rings, as well as non-aromatic rings which can be saturated, partially saturated or fully saturated non-aromatic rings.
  • heterocyclic ring system includes ring structures wherein all of the rings contain at least one hetero atom as well as structures having less than all of the rings in the ring structure containing at least one hetero atom, for example bicyclic ring structures wherein one ring is a benzene ring and one of the rings has one or more hetero atoms are included within the term "heterocyclic ring systems” as well as bicyclic ring structures wherein each of the two rings has at least one hetero atom.
  • the ring structures described herein may be attached to one or more indicated pendant groups via any hetero atom or carbon atom which results in a stable structure.
  • substituted means that one or more of the hydrogen atoms on the ring carbon atom(s) or nitrogen atom(s) of the each of the rings in the ring structures described herein may be replaced by one or more of the indicated substituents if such replacement(s) would result in a stable compound.
  • Nitrogen atoms in a ring structure may be quaternized, but such compounds are specifically indicated or are included within the term "a pharmaceutically acceptable salt” for a particular compound.
  • the total number of O and S atoms in a single heterocyclic ring is greater than 1, it is preferred that such atoms not be adjacent to one another. Preferably, there are no more that 1 O or S ring atoms in the same ring of a given heterocyclic ring structure.
  • Examples of monocylic and bicyclic heterocylic ring systems, in alphabetical order, are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3- b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl
  • Preferred heterocyclic ring structures include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocylic ring structures.
  • aromatic heterocyclic ring system has essentially the same definition as for the monocyclic and bicyclic ring systems except that at least one ring of the ring system is an aromatic heterocyclic ring or the bicyclic ring has an aromatic or non-aromatic heterocyclic ring fused to an aromatic carbocyclic ring structure.
  • halo or halogen as used herein refer to Cl, Br, F or I substituents.
  • haloalkyl refers to an aliphatic carbon radicals having at least one hydrogen atom replaced by a Cl, Br, F or I atom, including mixtures of different halo atoms.
  • Trihaloalkyl includes trifluoromethyl and the like as preferred radicals, for example.
  • methylene refers to -CH2-.
  • salts includes salts of compounds derived from the combination of a compound and an organic or inorganic acid. These compounds are useful in both free base and salt form. In practice, the use of the salt form amounts to use of the base form; both pharmaceutically acceptable acid and base addition salts are within the scope of the present invention.
  • “Pharmaceutically acceptable acid addition salt” refers to salts retaining the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.
  • Bio property for the purposes herein means an in vivo effector or antigenic function or activity that is directly or indirectly performed by a compound of this invention that are often shown by in vitro assays. Effector functions include receptor or ligand binding, any enzyme activity or enzyme modulatory activity, any carrier binding activity, any hormonal activity, any activity in promoting or inhibiting adhesion of cells to an extracellular matrix or cell surface molecules, or any structural role. Antigenic functions include possession of an epitope or antigenic site that is capable of reacting with antibodies raised against it.
  • carbon atoms bonded to four non-identical substituents are asymmetric. Accordingly, the compounds may exist as diastereoisomers, enantiomers or mixtures thereof.
  • the syntheses described herein may employ racemates, enantiomers or diastereomers as starting materials or intermediates. Diastereomeric products resulting from such syntheses may be separated by chromatographic or crystallization methods, or by other methods known in the art. Likewise, enantiomeric product mixtures may be separated using the same techniques or by other methods known in the art.
  • Each of the asymmetric carbon atoms when present in the compounds of this invention, may be in one of two configurations (R or S) and both are within the scope of the present invention.
  • A is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, and alkylheteroaryl;
  • R 2 is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 1 and R 2 can be direct linked or can be indirectly linked through a carbon chain that is from 1 to 8 carbon atoms in length, or W is selected from the group consisting of:
  • K is independently selected from the group consisting of C and N, with the proviso that when K is a ring carbon atom, each ring carbon atom is either bound to W or independenty substituted by L;
  • Q is independently selected from the group consisting of C and N, with the proviso that when Q is a ring carbon atom, each ring carbon atom is independenty substituted by L, wherein
  • L in each instance, is independently selected from the group consisting of:
  • R 3 and R ⁇ in each instance are each independently selected from the group consisting of: hydrogen, halogen, -CN, -NO 2 , -C 0 alkyl, C 3 . 8 -cycloalkyl, aryl, amino, amino-C,. 8 -alkyl, C, .3 -acylamino, C,. 3 -acylamino-C,. 8 -alkyl, C,. 6 -alkylamino, C,. 6 -a ⁇ kylamino C,. g alkyl, C,_ 6 dialkylamino, C,. 6 dialkylamino C, .8 alkyl, C, .6 alkoxy, C L6 alkoxy-C,.
  • D is selected from the group consisting of S, O and N-R 5 wherein R 5 is selected from the group consisting of:
  • Another preferred embodiment of the compound of formula (I) includes the compound set forth below in Table 1 :
  • a compound of formula (I) may be prepared by various methods as outlined in the following documents: Tetrahedron Lett. 40: 1103-1106 (1999); Synthesis 861, (1983); J. Med. Chem. 28: 1925 (1985);U.S. Patent 2,332,906 (1943), U.S. Patent 2,809,966 (1957); U.S. Patent 2,712,012 (1955); U.S. 2,790,798 (1957); and U.S. Patent 2,362,087 (1944), which are incorporated herein in their entirety by reference.
  • Other well-known heterocyclic and carbocyclic synthetic procedures as well as modification of the procedures that are incorporated above may be utilized.
  • a compound of formula (I) may exist as enantiomers, diastereomers or a mixture thereof.
  • the enantiomers and diastereomers may be separated by chromatographic or crystallization methods, or by other methods known in the art.
  • the asymmetric carbon atom when present in a compound of formula (I) of the invention may be in one of two configurations (R or S) and both are within the scope of the invention.
  • the presence of small amounts of the opposing enantiomer or diastereomer in the final purified product does not affect the therapeutic or diagnostic application of such compounds.
  • compounds of formula (I) may be further treated to form pharmaceutically acceptable salts.
  • Treatment of a compound of the invention with an acid or base may form, respectively, a pharmaceutically acceptable acid addition salt and a pharmaceutically acceptable base addition salt, each as defined above.
  • a pharmaceutically acceptable acid addition salt and a pharmaceutically acceptable base addition salt each as defined above.
  • Various inorganic and organic acids and bases known in the art including those defined herein may be used to effect the conversion to the salt.
  • the invention also relates to pharmaceutically acceptable isomers, hydrates, and solvates of compounds of formula (I).
  • Compounds of formula (I) may also exist in various isomeric and tautomeric forms including pharmaceutically acceptable salts, hydrates and solvates of such isomers and tautomers.
  • prodrug derivatives of the compounds of formula (I) refers to a pharmacologically inactive derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug.
  • Prodrugs are variations or derivatives of the compounds of formula (I) of this invention which have groups cleavable under metabolic conditions. Prodrugs become the compounds of the invention which are pharmaceutically active in vivo when they undergo solvolysis under physiological conditions or undergo enzymatic degradation.
  • Prodrug compounds of this invention may be called single, double, triple, etc., depending on the number of biotransformation steps required to release the active drug within the organism, and indicating the number of functionalities present in a precursor-type form.
  • Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam (1985); Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, CA (1992)).
  • Prodrugs commonly known in the art include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, or amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative.
  • the prodrug derivatives of this invention may be combined with other features herein taught to enhance bioavailability.
  • a compound of formula (I) according to the invention may be formulated into pharmaceutical compositions. Accordingly, the invention also relates to a pharmaceutical composition for preventing or treating thrombosis in a mammal, particularly those pathological conditions involving platelet aggregation, containing a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, each as described above, and a pharmaceutically acceptable carrier or agent.
  • a pharmaceutical composition of the invention contains a compound of formula (I), or a salt thereof, in an amount effective to inhibit platelet aggregation, more preferably, ADP-dependent aggregation, in a mammal, in particular, a human.
  • Pharmaceutically acceptable carriers or agents include those known in the art and are described below.
  • Pharmaceutical compositions of the invention may be prepared by mixing the compound of formula (I) with a physiologically acceptable carrier or agent.
  • Pharmaceutical compositions of the invention may further include excipients, stabilizers, diluents and the like and may be provided in sustained release or timed release formulations.
  • Acceptable carriers, agents, excipients, stablilizers, diluents and the like for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., ed. A.R. Gennaro (1985).
  • Such materials are nontoxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium and/or nonionic surfactants such as TWEEN, or polyethyleneglycol.
  • buffers such as phosphate, citrate, acetate and other organic acid salts
  • antioxidants such as ascorbic acid,
  • Methods for preventing or treating thrombosis in a mammal embraced by the invention administer a therapeutically effective amount of a compound of formula (I) alone or as part of a pharmaceutical composition of the invention as described above to a mammal, in particular, a human.
  • Compounds of formula (I) and pharmaceutical compositions of the invention containing a compound of formula (I) of the invention are suitable for use alone or as part of a multi-component treatment regimen for the prevention or treatment of cardiovascular diseases, particularly those related to thrombosis.
  • a compound or pharmaceutical composition of the invention may be used as a drug or therapeutic agent for any thrombosis, particularly a platelet-dependent thrombotic indication, including, but not limited to, acute myocardial infarction, unstable angina, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular disease, preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminated intravascular coagulation and thrombotic cytopenic purpura, thrombotic and restenotic complications following invasive procedures, e.g., angioplasty, carotid endarterectomy, post CABG (coronary artery bypass graft) surgery, vascular graft surgery, stent placements and insertion of endovascular devices and protheses.
  • invasive procedures e.g., angioplasty, carotid endarterectomy, post CABG (coronary artery bypass graft) surgery, vascular graft surgery
  • Compounds and pharmaceutical compositions of the invention may also be used as part of a multi-component treatment regimen in combination with other therapeutic or diagnostic agents in the prevention or treatment of thrombosis in a mammal.
  • compounds or pharmaceutical compositions of the invention may be coadministered along with other compounds typically prescribed for these conditions according to generally accepted medical practice such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin.
  • Coadministration may also allow for application of reduced doses of the thrombolytic agents and therefore minimize potential hemorrhagic side-effects.
  • Compounds and pharmaceutical compositions of the invention may also act in a synergistic fashion to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to reperfusion.
  • the compounds and pharmaceutical compositions of the invention may be utilized in vivo, ordinarily in mammals such as primates, (e.g., humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
  • mammals such as primates, (e.g., humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
  • the biological properties, as defined above, of a compound or a pharmaceutical composition of the invention can be readily characterized by methods that are well known in the art such as, for example, by in vivo studies to evaluate antithrombotic efficacy, and effects on hemostasis and hematological parameters.
  • Compounds and pharmaceutical compositions of the invention may be in the form of solutions or suspensions.
  • the compounds or pharmaceutical compositions of the invention may also be in such forms as, for example, tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions or injectable administration, and the like, or incorporated into shaped articles.
  • Subjects (typically mammalian) in need of treatment using the compounds or pharmaceutical compositions of the invention may be administered dosages that will provide optimal efficacy.
  • the dose and method of administration will vary from subject to subject and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet, concurrent medication, overall clinical condition, the particular compound of formula (I) employed, the specific use for which the compound or pharmaceutical composition is employed, and other factors which those skilled in the medical arts will recognize.
  • Dosage formulations of compounds of formula (I), or pharmaceutical compositions contain a compound of the invention, to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods. Formulations typically will be stored in a solid form, preferably in a lyophilized form. While the preferred route of administration is orally, the dosage formulations of compounds of formula (I) or pharmaceutical compositions of the invention may also be administered by injection, intravenously (bolus and/or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally, transdermally or intraperitoneally.
  • a variety of dosage forms may be employed as well including, but not limited to, suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches.
  • the compounds of formula (I) and pharmaceutical compositions of the invention may also be incorporated into shapes and articles such as implants which may employ inert materials such biodegradable polymers or synthetic silicones as, for example, SILASTIC, silicone rubber or other polymers commercially available.
  • the compounds and pharmaceutical compositions of the invention may 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 lipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular compound or pharmaceutical composition of the invention, individual determinations may be made to determine the optimal dosage required.
  • the range of therapeutically effective dosages will be influenced by the route of administration, the therapeutic objectives and the condition of the patient. For injection by hypodermic needle, it may be assumed the dosage is delivered into the bodily fluids. For other routes of administration, the absorption efficiency must be individually determined for each compound by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect.
  • effective dosage levels that is, the dosage levels necessary to achieve the desired result, i.e., platelet ADP receptor inhibition
  • applications of a compound or pharmaceutical composition of the invention are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved.
  • the compounds and compositions of the invention may be administered orally in an effective amount within the dosage range of about 0.01 to 1000 mg/kg in a regimen of single or several divided daily doses.
  • a pharmaceutically acceptable carrier typically, about 5 to 500 mg of a compound of formula (I) is compounded with a pharmaceutically acceptable carrier as called for by accepted pharmaceutical practice including, but not limited to, a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor, etc.
  • a pharmaceutically acceptable carrier as called for by accepted pharmaceutical practice including, but not limited to, a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor, etc.
  • the amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained.
  • Typical adjuvants which may be incorporated into tablets, capsules and the like include, but are not limited to, binders such as acacia, corn starch or gelatin, and excipients such as microcrystalline cellulose, disintegrating agents like corn starch or alginic acid, lubricants such as magnesium stearate, sweetening agents such as sucrose or lactose, or flavoring agents.
  • binders such as acacia, corn starch or gelatin
  • excipients such as microcrystalline cellulose
  • disintegrating agents like corn starch or alginic acid
  • lubricants such as magnesium stearate
  • sweetening agents such as sucrose or lactose
  • flavoring agents such as sucrose or lactose
  • a dosage form is a capsule, in addition to the above materials it may also contain liquid carriers such as water, saline, or a fatty oil.
  • Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit.
  • dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired.
  • a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate
  • Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.
  • the effect of testing the compound according to the invention on ADP-induced human platelet aggregation is preferably assessed in 96-well microtiter assay (see generally the procedures in Jantzen, H.M. et al. (1999) Thromb. Hemost. 81:111-117).
  • Human venous blood is collected from healthy, drug-free volunteers into ACD (85 mM sodium citrate, 111 mM glucose, 71.4 mM citric acid) containing PGI 2 (1.25 ml ACD containing 1.6 M PGI 2 /10 ml blood; PGI 2 was from Sigma, St. Louis, MO).
  • ACD 85 mM sodium citrate, 111 mM glucose, 71.4 mM citric acid
  • PGI 2 (1.25 ml ACD containing 1.6 M PGI 2 /10 ml blood; PGI 2 was from Sigma, St. Louis, MO).
  • Platelet-rich plasma (PRP) is prepared by centrifugation at 160 x g for 20 minutes at
  • Washed platelets are prepared by centrifuging PRP for 10 minutes at 730 x g and resuspending the platelet pellet in CGS (13 mM sodium citrate, 30 mM glucose, 120 mM NaCl; 2 ml CGS/10 ml original blood volume) containing lU/ml apyrase (grade V, Sigma, St. Louis, MO).
  • CGS 13 mM sodium citrate, 30 mM glucose, 120 mM NaCl; 2 ml CGS/10 ml original blood volume
  • lU/ml apyrase grade V, Sigma, St. Louis, MO
  • the platelets are collected by centrifugation at 730 x g for 10 minutes and resuspended at a concentration of 3xl0 8 platelets/ml in Hepes-Tyrode's buffer (10 mM Hepes, 138 mM NaCl, 5.5 mM glucose, 2.9 mM KC1, 12 mM NaHCO 3 , pH 7.4) containing 0.1% bovine serum albumin, 1 mM CaCl 2 and 1 mM MgCl 2 . This platelet suspension is kept >45 minutes at 37°C before use in aggregation assays.
  • Inhibition of ADP-dependent aggregation is preferably determined in 96-well flat- bottom microtiter plates using a microtiter plate shaker and plate reader similar to the procedure described by Frantantoni et al., Am. J. Clin. Pathol. 94, 613 (1990). All steps are performed at room temperature.
  • the total reaction volume of 0.2 ml/well includes in Hepes-Tyrodes buffer/0.1% BSA: 4.5 x 10 7 apyrase-washed platelets, 0.5 mg/ml human fibrinogen (American Diagnostica, Inc., Greenwich, CT), serial dilutions of test compounds (buffer for control wells ) in 0.6% DMSO.
  • ADP is added to a final concentration of 2 M which induces submaximal aggregation. Buffer is added instead of ADP to one set of control wells (ADP " control). The OD of the samples is then determined at 490 nm using a microtiter plate reader (Softmax, Molecular
  • a second assay is used to determine whether such inhibition is mediated by interaction with platelet ADP receptors. Utilizing the second assay the potency of inhibition of such compounds with respect to [ 3 H]2-MeS-ADP binding to whole platelets is determined.
  • [ 3 H]2-MeS-ADP binding experiments are routinely performed with outdated human platelets collected by standard procedures at hospital blood banks. Apyrase-washed outdated platelets are prepared as follows (all steps at room temperature, if not indicated otherwise):
  • Outdated platelet suspensions are diluted with 1 volume of CGS and platelets pelleted by centrifugation at 1900 x g for 45 minutes. Platelet pellets are resuspended at 3- 6xl0 9 platelets /ml in CGS containing 1 U/ml apyrase (grade N, Sigma, St. Louis, MO) and incubated for 15 minutes at 37°C. After centrifugation at 730 x g for 20 minutes, pellets are resuspended in Hepes-Tyrode's buffer containing 0.1% BSA (Sigma, St. Louis, MO) at a concentration of 6.66x10 8 platelets/ml. Binding experiments are performed after > 45 minutes resting of the platelets.
  • binding experiments are performed with fresh human platelets prepared as described in I.(Inhibition of ADP -Mediated Platelet Aggregation in vitro), except that platelets are resuspended in Hepes-Tyrode's buffer containing 0.1 % BSA (Sigma , St. Louis, MO) at a concentration of 6.66x10 8 platelets/ml. Nery similar results are obtained with fresh and outdated platelets.
  • a platelet ADP receptor binding assay using the tritiated potent agonist ligand [ 3 H]2-MeS-ADP has been adapted to the 96-well microtiter format.
  • lxlO 8 apyrase-washed platelets are preincubated in 96-well flat bottom microtiter plates for 5 minutes with serial dilutions of test compounds before addition of InM [ 3 H]2-MeS-ADP ([ 3 H]2-methylthioadenosine-5'- diphosphate, ammonium salt; specific activity 48-49 Ci/mmole, obtained by custom synthesis from Amersham Life Science, Inc., Arlington Heights, IL, or ⁇ E ⁇ Life Science Products, Boston, MA). Total binding is determined in the absence of test compounds.
  • Samples for nonspecific binding may contain 10 "5 M unlabelled 2-MeS-ADP (RBI, ⁇ atick, MA). After incubation for 15 minutes at room temperature, unbound radioligand is separated by rapid filtration and two washes with cold (4-8°C) Binding Wash Buffer (10 mM Hepes pH 7.4, 138 mM ⁇ aCl) using a 96-well cell harvester (Minidisc 96, Skatron Instruments, Sterling, NA) and 8x12 GF/C glassfiber filtermats (Printed Filtermat A, for 1450 Microbeta, Wallac Inc., Gaithersburg, MD).
  • the platelet-bound radioactivity on the filtermats is determined in a scintillation counter (Microbeta 1450, Wallac Inc., Gaithersburg, MD). Specific binding is determined by subtraction of non-specific binding from total binding, and specific binding in the presence of test compounds is expressed as % of specific binding in the absence of test compounds dilutions.

Abstract

La présente invention concerne de nouveaux composés représentés par la formule (I), contenant des dérivés de sulfonamides hétérobicycliques benzocondensés qui sont des inhibiteurs de récepteur ADP des plaquettes efficaces. Ces composés comprenant des sels pharmaceutiquement acceptables conviennent dans diverses compositions pharmaceutiques destinées à la prévention et au traitement de maladies cardio-vasculaires et en particulier de celles qui sont liées aux thromboses.
PCT/US2001/014441 2000-05-05 2001-05-04 Sulfonamides heterobicycliques et utilisation de celles-ci comme inhibiteurs de recepteur adp des plaquettes WO2001085722A1 (fr)

Priority Applications (6)

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JP2001582323A JP2003532728A (ja) 2000-05-05 2001-05-04 ヘテロ二環式スルホンアミドおよび血小板ａｄｐレセプターインヒビターとしてのそれらの使用
EP01938998A EP1278744A1 (fr) 2000-05-05 2001-05-04 Sulfonamides heterobicycliques et utilisation de celles-ci comme inhibiteurs de recepteur adp des plaquettes
AU2001264566A AU2001264566A1 (en) 2000-05-05 2001-05-04 Heterobicyclic sulfonamides and their use as platelet adp receptor inhibitors
CA002408156A CA2408156A1 (fr) 2000-05-05 2001-05-04 Sulfonamides heterobicycliques et utilisation de celles-ci comme inhibiteurs de recepteur adp des plaquettes
US10/275,154 US20040029867A1 (en) 2001-05-04 2001-05-04 Heterobicyclic sulfonamides and their use as platelet adp receptor inhibitors
HK03102259.9A HK1050008A1 (zh) 2000-05-05 2003-03-28 雜雙環磺胺劑及以其作為血小板腺苷二磷酸(adp)受體抑制劑

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