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WO2006070385A1 - Esters/amides de l'acide 2-alkyl- ou 2-arylsulfonyl-1,2,3,4-tétrahydro-9h-pyrido(3,4-b)indole-3-carboxylique employés en tant qu'agents antithrombotiques - Google Patents

Esters/amides de l'acide 2-alkyl- ou 2-arylsulfonyl-1,2,3,4-tétrahydro-9h-pyrido(3,4-b)indole-3-carboxylique employés en tant qu'agents antithrombotiques Download PDF

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WO2006070385A1
WO2006070385A1 PCT/IN2004/000417 IN2004000417W WO2006070385A1 WO 2006070385 A1 WO2006070385 A1 WO 2006070385A1 IN 2004000417 W IN2004000417 W IN 2004000417W WO 2006070385 A1 WO2006070385 A1 WO 2006070385A1
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pyrido
indole
carboxylic acid
alkyl
tetra hydro
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PCT/IN2004/000417
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English (en)
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Stuti Gaur
Zeeshan Fatima
Anshuman Dixit
Zahid Ali
William Rasican Surin Surin
Kapil Kapoor
Kanta Bhutani
Mohd. Salim Ansari
Madhu Dikshit
Anil Kumar Saxena
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Council Of Scientific And Industrial Research
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Priority to PCT/IN2004/000417 priority Critical patent/WO2006070385A1/fr
Publication of WO2006070385A1 publication Critical patent/WO2006070385A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to antithrombotic compounds 2-alkyl aryl sulphonyl- 1,2,3, 4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic acid esters/amides, pharmaceutically acceptable salts and compositions thereof useful in treatment of intravascular thrombosis such as myocardial ischemia and stroke.
  • the compound has the following general structure
  • R represents methyl ester or amide and ⁇ represents alkyl, aryl and heteroaryl moiety.
  • the present invention particularly relates to novel compounds 2-alkyl/ aryl sulphonyl-l, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole -3- carboxylic acid esters/ amides, which are potent antithrombotic agents and can be useful in treatment of intravascular thrombosis, such as myocardial ischemia and stroke.
  • the present invention also relates to processes for preparing the said novel compounds.
  • the present invention relates to 2-alkyl/ aryl sulphonyl-l, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole -3- carboxylic acid esters/ amides, processes for preparing the said compounds and to their use in medicine.
  • Cardiovascular diseases associated with intravascular thrombosis are the most common cause of death in both developed and developing countries.
  • Arterial and venous thromboses are the principal causes for the evolution of myocardial infarction, thromboembolic stroke and deep vein thrombosis.
  • thromboembolic stroke Approximately three million individuals die each year in the United States only from venous (deep vein thrombosis and pulmonary embolism) or arterial thrombosis (acute myocardial infarction and unstable angina).
  • Initiation of thrombosis is a complex process.
  • the final event i.e. the thrombus formation is primarily due to the activation of platelets and coagulation cascade.
  • Clinical and experimental studies indicate that abnormalities in the normal blood flow, activation of platelets, coagulation cascade or fibrinolysis contribute to the pathogenesis of intravascular thrombosis/thromboembolism.
  • the treatment strategy for thrombosis has improved with newer diagnostic and surgical tools but effective antithrombotic therapy with minimal side effects still poses a challenge to scientists around the globe.
  • Antithrombotic agents have been researched and developed for use in treating cardiovascular and other diseases. Presently established antithrombotic agents include heparin, coumarin, and aspirin.
  • both heparin 1 and coumarin 2 have a highly-variable dose-related response, and their anticoagulant effects must be closely monitored to avoid a risk of serious bleeding.
  • the erratic anticoagulant response of heparin is likely due to its propensity to bind non- specifically to plasma proteins.
  • Aspirin has a limited efficacy and at high doses presents a risk of gastrointestinal bleeding.
  • Tissue plasminogen activators 3 ' 4 , platelet GPIIb/IIIa antagonists 5 , ADP receptor antagonists 6 are also being currently used to treat thrombosis, however, these drugs have some inherent problems and limitations. Therefore, new search is taken up to develop next generation anti-thrombotic agents such as direct thrombin inhibitors 7 , tissue factor pathway inhibitors 8 , Factor Xa inhibitors 9 , collagen antagonists 10 and gene therapy. The search of a potent orally active and specific anti-thrombotic agent with minimal danger of bleeding or unrelated side effects is thus an area of interest. Moreover, the high cost of anticoagulant and antithrombotic therapy necessitates the search for efficacious new chemical entities.
  • the main object of the invention is to provide novel molecules 2-alkyl/ aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole -3- carboxylic acid esters/ amides that exhibit better therapeutic efficacy to treat intravascular thrombosis, myocardial ischemia and stroke over the existing antithrombotic agents.
  • It is another object of the invention to provide a pharmaceutical composition comprising 2-alkyl/ aryl sulphonyl- 1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole -3- carboxylic acid esters/ amides and pharmaceutically acceptable additive(s) and a process for preparing such composition.
  • cardiopulmonary bypass prevention of microthromboembolism
  • prevention of mechanically-induced platelet activation in vitro such as the use of the compounds in the preservation of blood products, e.g. platelet concentrates
  • prevention of shunt occlusion such as renal dialysis and plasmapheresis
  • thrombosis secondary to vascular damage/inflammation such as vasculitis, arteritis,
  • a diffuse thrombotic/platelet consumption component such as disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, heparin-induced thrombocytopenia and pre-eclampsia/eclampsia.
  • DIC disseminated intravascular coagulation
  • septicemia surgical or infectious shock
  • postoperative and post-partum trauma CAD
  • cardiopulmonary bypass surgery incompatible blood transfusion
  • abruptio placenta thrombotic thrombocytopenic purpura
  • snake venom and immune diseases
  • the present invention provides novel pharmacologically active compounds, specifically new 2-alkyl aryl sulphonyl-1, 2,3,4- tetrahydro-9H-pyrido(3,4-b) indole -3- carboxylic acid esters /amides which are used as potential therapeutic agents for intravascular thrombosis, myocardial ischemia and stroke and other disorders as mentioned above.
  • the present invention relates to 2-alkyl/aryl sulphonyl-1, 2,3,4-tetrahydro- 9H-pyrido (3,4-b) indole-3 -carboxylic acid esters/ amides having formula 1 :
  • R is selected from methyl ester and amide; and Rj is selected from the group consisting of alkyl, aryl, and heteroaryl moiety.
  • the compound comprises at least one of: a. 2[-2,5 dichlorobenzene sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido [3,4-b] indole-3- carboxylic acid ester b. 2[2,4,6, trimethyl benzene sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3- carboxylic acid ester c. 2[2,nitrobenzene sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3 -carboxylic acid ester d.
  • the compound includes at least one of: o. 2[-2,5 dichlorobenzene sulfonyl]- 1,2,3, 4, -tetra hydro-9H-pyrido[3,4-b] indole-3- carboxylic acid amide p. 2[-4-methoxy benzene sulfonyl]- 1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3- carboxylic acid amide q. 2[-l-napthylsulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide r.
  • the present invention also provides a process for synthesis of 2-alkyl/aryl sulphonyl- l,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid esters/amides of formula 1:
  • R is selected from methyl ester and amide; and R 1 is selected from the group consisting of alkyl, aryl, and heteroaryl moiety, the process comprising condensing an alkyl or aryl sulphonyl chloride wherein aryl includes substituted phenyl substituted by group selected from the group consisting of hydrogen, halogens, alkyl and alkoxy, substituted napthyl substituted by group selected from the group consisting of hydrogen and dimethyl amino; and heteroaryl like quinoline with dimethyl- 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole -3- carboxylate Formula 2 in the presence of a base and an organic solvent at temperature ranging from 30°C to 12O 0 C for 8 to 24 hours to produce the corresponding 2- alkyl/ aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole -3- carboxylic acid
  • the invention relates to a process for the synthesis of the above compounds by condensing an alkyl or aryl sulphonyl chloride where in aryl includes, substituted phenyl by groups like hydrogens, halogens, alkyl, alkoxy etc., substituted napthyl by hydrogen, di methyl amino, and heteroaryl like quinoline with dl 1, 2, 3, 4-tetrahydro-9H- pyrido (3, 4-b) indole -3-amide formula 3 in the presence of a base and an organic solvent at temperature ranging from 30°C to 120°C for 8 to 24 hours to produce the corresponding 2- alkyl/ aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole -3- carboxylic acid amides.
  • the invention relates to a process for the synthesis of the above compounds wherein 2-alkyl/ aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole -3- carboxylic acid esters is treated with methanolic ammonia for 24 to 48 hours hrs to obtain the corresponding 2-alkyl/ aryl sulphonyl-1, 2, 3, 4-tetrahydro ⁇ 9H-pyrido (3,4-b) indole -3- carboxylic acid amides.
  • the synthesis of 2-alkyl/ aryl sulphonyl-1, 2, 3, 4- tetrahydro-9H-pyrido (3,4-b) indole -3- carboxylic acid esters/amide of formula 1 includes the presence of one of the organic solvent selected from a group of acetone, DMF, THF, dioxane, a base including at least one of TEA, K 2 CO 3 , Na 2 CO 3 , pyridine and a temperature of about 30°C to 12O 0 C for 8 to 24 hours.
  • the molar ratios of the substituted sulphonyl chloride to dl methyl- 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole -3-carboxylate/ dl 1, 2, 3, 4-tetrahydro- 9H-pyrido (3, 4-b) indole-3-amide is about 1:2.
  • the organic solvents include acetone, DMF, THF, dioxane and the organic solvent is present about 0.8-2.2 ml per mmol.
  • the molar ratio of the base to the dl methyl- 1, 2, 3, 4- tetrahydro-9H-pyrido (3, 4-b) indole -3-carboxylate / dl 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4- b) indole -3-amide is about 1 :4.
  • the invention also relates to pharmaceutical compositions having the compound of formulal described above in a mixture with a pharmaceutically acceptable carrier.
  • the invention further relates to a process for preparing the pharmaceutical composition by bringing the compound into association with a pharmaceutically acceptable additive.
  • the invention also relates to method of treating various diseases with the pharmaceutical compositions of the present invention.
  • the method involves treating intravascular thrombosis in mammals by administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition.
  • the method involves treating myocardial ischemia in mammals, by administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition
  • the method involves treating stroke in mammals, by administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition.
  • the diseases treated are selected to be intravascular thrombosis, myocardial ischemia and stroke or a combination thereof
  • the intravascular diseases are selected to include as mentioned above.
  • halogen of the compound is selected from the group of chlorine, bromine fluorine and iodine, and mixtures thereof
  • the alkoxy is selected to be a C 1 -Ci 0 oxy
  • the alkyl is selected to be Ci-Ci 0 alkyl
  • the heteroaryl is selected to be a C 4 -Ci 0 heteroaryl.
  • Figure 1 is a graphical representation of the effect of compound (i) on human platelet aggregation.
  • the compound of the present invention achieves the following objects: i) providing novel molecules 2-alkyl/ aryl sulphonyl- 1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole -3- carboxylic acid esters/ amides that may exhibit better therapeutic efficacy to treat intravascular thrombosis, myocardial ischemia and stroke over the existing antithrombotic agents.
  • v) providing a pharmaceutical composition comprising 2-alkyl/ aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole -3- carboxylic acid esters/ amides. And pharmaceutically acceptable additive (s) and a process for preparing such composition. vi) providing for use of the compounds in the treatment or prevention of primary arterial thrombotic complications of atherosclerosis such as thrombotic stroke, peripheral vascular disease, and myocardial infarction without thrombolysis.
  • vii) providing for the use of the compounds of the invention for the treatment or prevention of arterial thrombotic complications due to interventions in atherosclerotic disease such as angioplasty, endarterectomy, stent placement, coronary and other vascular graft surgery.
  • viii) providing for the use of the compounds of the invention for the treatment or prevention of thrombotic complications of surgical or mechanical damage such as tissue salvage following surgical or accidental trauma, reconstructive surgery including skin flaps, and "reductive" surgery such as breast reduction.
  • ix providing for the use of the compounds of the invention for the prevention of mechanically-induced platelet activation in vivo such as cardiopulmonary bypass (prevention of microthromboembolism), prevention of mechanically-induced platelet activation in vitro such as the use of the compounds in the preservation of blood products, e.g. platelet concentrates, prevention of shunt occlusion such as renal dialysis and plasmapheresis, thrombosis secondary to vascular damage/inflammation such as vasculitis, arteritis, glomerulonephritis and organ graft rejection.
  • cardiopulmonary bypass prevention of microthromboembolism
  • prevention of mechanically-induced platelet activation in vitro such as the use of the compounds in the preservation of blood products, e.g. platelet concentrates
  • prevention of shunt occlusion such as renal dialysis and plasmapheresis
  • thrombosis secondary to vascular damage/inflammation such as vasculitis, arteritis, glomeruloneph
  • x) providing for the use of the compounds of the invention as indicators with a diffuse thrombotic/platelet consumption component such as disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, heparin-induced thrombocytopenia and pre- eclampsia/eclampsia.
  • xi) providing for the use of the compounds of the invention for the treatment or prevention of venous thrombosis such as deep vein thrombosis, veno-occlusive disease, hematological conditions such as thrombocythemia and polycythemia, and migraine.
  • xii) providing for the use of the compounds of the invention for the treatment of unstable angina, coronary angioplasty and myocardial infarction.
  • xiii) providing for the use of the compounds of the invention for the adjunctive therapy in the prevention of coronary arterial thrombosis during the management of unstable angina, coronary angioplasty and acute myocardial infarction, i.e. perithrombolysis.
  • Agents commonJy used for adjunctive therapy in the treatment of thrombotic disorders can be used, for example heparin and/or aspirin, just to mention a few.
  • xiv) providing for the use of the compounds of the invention for a method of treating mammals to alleviate the pathological effects of atherosclerosis and arteriosclerosis, acute MI, chronic stable angina, unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis or abrupt closure following angioplasty, carotid endarterectomy, and anastomosis of vascular grafts.
  • xv) providing for the use of the compounds of the invention for the in vitro to inhibit the aggregation of platelets in blood and blood products, e.g. for storage, or for ex vivo manipulations such as in diagnostic or research use.
  • This invention also provides a method of inhibiting platelet aggregation and clot formation in a mammal, especially a human, which comprises the internal administration.
  • xvi) providing for the use of the compounds of the invention for treatment of chronic or acute states of hyperaggregability, such as disseminated intravascular coagulation (DIC), septicemia, surgical or infectious shock, post-operative and post-partum trauma, cardiopulmonary bypass surgery, incompatible blood transfusion, abruptio placenta, thrombotic thrombocytopenic purpura (TTP), snake venom and immune diseases, which are likely to be responsive to these compounds.
  • DIC disseminated intravascular coagulation
  • septicemia surgical or infectious shock
  • post-operative and post-partum trauma such as cardiopulmonary bypass surgery, incompatible blood transfusion, abruptio placenta, thrombotic thrombocytopenic purpura (TTP), snake venom and immune diseases, which are likely to be responsive to these compounds.
  • TTP
  • fibrinolytic agent is intended to mean any compound, whether a natural or synthetic product, which directly or indirectly causes the lysis of a fibrin clot.
  • Plasminogen activators are a well known group of fibrinolytic agents.
  • Useful plasminogen activators include, for example, anistreplase, urokinase (UK), pro-urokinase (pUK), streptokinase (SK), tissue plasminogen activator (tPA) and mutants, or variants thereof, which retain plasminogen activator activity, such as variants which have been chemically modified or in which one or more amino acids have been added, deleted or substituted or in which one or more functional domains have been added, deleted or altered such as by combining the active site of one plasminogen activator or fibrin binding domain of another plasminogen activator or fibrin binding molecule.
  • xviii) providing for use of the compounds of the invention for extracorporeal circulation, which is routinely used for cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Platelets released from artificial surfaces show impaired hemostatic function. Compounds of the invention can be administered to prevent adhesion.
  • xix) providing for the use of the compounds of the invention for other applications including prevention of platelet thrombosis, thromboembolism and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty of coronary and other arteries and after coronary artery bypass procedures.
  • the present invention provides novel pharmacologically active compounds, specifically new 2-alkyl aryl sulphonyl-1, 2,3,4- tetrahydro-9H-pyrido(3,4-b) indole -3- carboxylic acid esters /amides which are used as potential therapeutic agents for intravascular thrombosis, myocardial ischemia and stroke and other disorders as mentioned above.
  • the compound of the invention has the formula 1
  • R represents methyl ester or amide and Ri represents alkyl, aryl and heteroaryl moiety.
  • Representative compounds include: a. 2[-2,5 dichlorobenzene sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3- carboxylic acid ester b. 2[2,4,6, trimethyl benzene sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3- carboxylic acid ester c.
  • R designates methylester and amide
  • amide designates alkyl group includes methyl, aryl group includes naphthyl and phenyl group substituted by alky, alkoxy, halogen groups and heteroaryl group includes quinoline.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula 1 in a mixture with a pharmaceutically acceptable conventional carriers and a process for the preparation of a pharmaceutical composition which comprises bringing a compound of the formula 1 into association with a pharmaceutically acceptable conventional carrier.
  • the invention provides a method of treating intravascular thrombosis and myocardial ischemia and stroke in mammals, that comprises administering to a subject in need thereof an effective amount of a compound of formula 1.
  • the compounds of the invention are useful in therapy, particularly in the prevention of platelet aggregation.
  • the compounds of the invention have shown to possess antithrombotic activity in different test models.
  • the compounds of the present invention are thus useful as anti-thrombotic agents, and are thus useful in the treatment or prevention of unstable angina, coronary angioplasty and myocardial infarction.
  • the compounds prevent intravascular thrombosis, its progression or recurrence. They may be useful as additive or synergistic therapy to reduce the incidence of myocardial ischemia, acute myocardial infarction, unstable angina, during and after angioplasty or stent replacement, prevent cerebrovascular events, secondary prevention of stroke and pulmonary thromboembolism.
  • These agents may also be used in combination with antithrombotic drugs and anticoagulants in patients undergoing angioplasty or stenting for coronary artery disease and also in conjunction with fibrinolysis protocols.
  • Diseases or conditions associated with platelet aggregation are disorders or procedures characterized by thrombosis, primary arterial thrombotic complications of atherosclerotic disease, thrombotic complications of interventions of atherosclerotic disease, thrombotic complications of surgical or mechanical damage, mechanically-induced platelet activation, shunt occlusion, thrombosis secondary to vascular damage and inflammation, indications with a diffuse thrombotic/platelet consumption component, venous thrombosis, coronary arterial thrombosis, pathological effects of atherosclerosis and arteriosclerosis, platelet aggregation and clot formation in blood and blood products during storage, chronic or acute states of hyper-aggregability, reocclusion of an artery or vein following fibrinolytic therapy, platelet adhesion associated with extracorporeal circulation, thrombotic complications associated with thrombolytic therapy, thrombotic complications associated with coronary and other angioplasty, or thrombotic complications associated with coronary artery bypass procedures.
  • thrombosis disorders or procedures associated with thrombosis are unstable angina, coronary angioplasty, or myocardial infarction; said primary arterial thrombotic complications of atherosclerosis are thrombotic stroke, peripheral vascular disease, or myocardial infarction without thrombolysis; said thrombotic complications of interventions of atherosclerotic disease are angioplasty, endarterectomy, stent placement, coronary or other vascular graft surgery; said thrombotic complications of surgical or mechanical damage are associated with tissue salvage following surgical or accidental trauma, reconstructive surgery including skin flaps, or reductive surgery; said mechanically-induced platelet activation is caused by cardiopulmonary bypass resulting in microthromboembolism and storage of blood products; said shunt occlusion is renal dialysis and plasmapheresis; said thromboses secondary to vascular damage and inflammation are vasculitis, arteritis, glomerulonephritis or organ graft rejection; said indications with a diffuse thrombotic
  • arteriosclerosis pathological effects of atherosclerosis and arteriosclerosis are arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks, strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis or abrupt closure following angioplasty, carotid endarterectomy, or anastomosis of vascular grafts; said chronic or acute states of hyper-aggregability is caused by DIC, septicemia, surgical or infectious shock, post-operative trauma, post-partum trauma, cardiopulmonary bypass surgery, incompatible blood transfusion, abruptio placenta, thrombotic thrombocytopenic purpura, snake venom or immune diseases.
  • a method of preparation of the inventive compounds consists of the condensation of different alkyl/aryl sulphonyl chlorides with dl methyl- 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4- b) indole -3- carboxylate /dl -1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole -3- amide to get the compounds of formula 1 (2-alkyl/ aryl sulphonyl- 1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole -3- carboxylic acid esters/ amides) as shown in scheme 1 of the accompanying drawings.
  • the compounds of the present invention can be used as pharmaceutical compositions comprising compounds of the present invention with a suitable pharmaceutical career.
  • these compositions are used to produce intravascular antithrombotic activity and contain an effective amount of the compounds useful in the method of the invention.
  • the most preferred compounds of the invention are
  • the method involves in the synthesis of the compounds of formula 1 wherein R is methyl ester comprises of condensation of an alkyl or aryl sulphonyl chloride with dimethyl- 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole -3- carboxylate of formula 2 in the presence of a base selected from trimethylamine, potassium carbonate, pyridine in organic solvent selected from THF, DMF, acetone, dioxane at a temperature ranging from 30 0 C to 120°C for 8 to 24 hours to produce the corresponding 2-alkyl/ aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H- pyrido (3,4-b) indole -3- carboxylic acid esters.
  • Two methods were used for the synthesis of 2-alkyl/ aryl sulphonyl- 1, 2, 3, 4- tetrahydro-9H-pyrido (3,4-b) indole -3- carboxy
  • the second method involves 2-alkyl/ aryl sulphonyl- 1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole -3- carboxylic acid esters synthesized as described previously, treated with methanolic ammonia for 24-32 hours at 32°C to obtain 2-alkyl/ aryl sulphonyl-1, 2, 3, 4- tetrahydro-9H-pyrido (3,4-b) indole -3- carboxylic acid amide.
  • the compounds of the invention show marked antithrombotic activity and can be used as therapeutic agents for the treatment of intravascular thrombosis, myocardial ischemia and stroke as shown for instance by the following data of the compounds
  • Pulmonary thromboembolism was induced by following a method of Diminno and Silver (1) .
  • Test compounds (30 ⁇ M/Kg) or vehicle were administered orally 60 min prior to the thrombotic challenge.
  • % Protection was expressed as: OO
  • P te st is the number of animals paralyzed/dead in the test compound-treated group
  • mice tail bleeding time was performed by method of Dejna et al, (2) .
  • the tail 2mm from tip was incised and the blood oozed was soaked with filter paper till the bleeding stops.
  • the time elapsed from the tip incision to the stoppage of bleeding was determined as the bleeding time.
  • Test compound (30 ⁇ M/kg), aspirin or vehicle was given orally 60 min prior to the tail incision.
  • Each group consisted of 5 mice.
  • Platelet aggregation was monitored according to the protocol described earlier (3) .
  • Sprague Dawley rats (wt 250-300 gm) were anaesthetized with ether and blood (9 mL) was drawn from the heart into a plastic syringe containing 1 ml of 1.9% tri-
  • Sodium citrate The blood was centrifuged at 275xg for 20 min and the platelet rich plasma (PRP) was collected. The remaining blood was further centrifuged at 1500g for 15 min at 20 0 C to obtain platelet poor plasma (PPP). The platelet count in the PRP was adjusted to 2X10 8 cells/ml by using PPP. Adenosine-5 '-diphosphate (ADP), thrombin, collagen, calcium ionophore A23187 or phorbol myristate ester (PMA) induced aggregation was monitored on a dual channel aggregometer (Chrono-log, USA). The test compound was incubated with PRP for 5 min before the addition of aggregation inducing agent. Percent inhibition of the test compounds at various concentrations was calculated as follows:
  • thromboplastin time TT
  • PT prothrombin time
  • aPTT activated partial thromboplastin time
  • Rabbit venous thrombosis model Experiments were performed on New Zealand white strain rabbits (2-3kg) either sex. Escherichia coli LPS strain 1055:B5 (Sigma Chemicals, USA) was injected intravenously via ear vein (l ⁇ g/kg) (5 ' 6 ⁇ Jugular veins on both sides were exposed and dissected free from surrounding tissue. Two loose sutures were placed 1.5 cm apart and all collateral veins were ligated. Four hours after E. Coli endotoxin injection (animal is watched for any signs of hypersensitivity reaction during this period), stasis was established and maintained for 45 min by tightening the two sutures. Ligated segments were removed and opened longitudinally and the thrombus was carefully removed and weighed.
  • Heparin sodium (Beparine from beef intestinal mucosa > 140 USP units/mg; Biological E. Limited, India) was given in doses of (0.5, 0.25, 0.1 mg/kg Lv., via ear vein) 5 min before stasis.
  • mice Effect of test compounds is indicated in the following table (1) against collagen and epinephrine induced thrombosis in mice, which is a primary screening model to detect antithrombotic efficacy of the test agents. At the same dose these compounds were also evaluated for their effect on the bleeding time in mouse (Table 1).
  • Ex vivo effect of selective compounds on rat platelet aggregation Blood was collected in sodium citrate to obtain PRP and evaluate the ex vivo effect of selective compounds ((i), (ii) ,(iii) at 30 ⁇ M/kg administered by the ip route) against ADP, collagen, phorbol myristate ester (PMA) calcium ionophore (A23187), or thrombin induced aggregation. It was observed that all these compounds were consistent against collagen-induced platelet aggregation (Table 3).
  • Compound(i) inhibited ADP (lOuM), collagen (lO ⁇ g/ml), and A23187 (2.5 ⁇ g/ml) induced platelet aggregation but had no inhibitory effect against thrombin (0.64LVmI) and PMA (1.5 ⁇ M) induced platelet aggregation.
  • Effect on clotting parameters The selected compounds were also tested in vitro for their effect on thrombin time (TT), prothrombin time (PT) and activated partial thromboplastin time (aPTT) at lOO ⁇ g/ml and 200 ⁇ g/ml in vitro (Table 4). The test compounds at 100 ⁇ g/ml had no significant effect of on these parameters. Some effect was though seen on PT at 200 ⁇ g/ml concentration, but the concentration seems to be quite high.
  • n number of groups
  • mice used for AT testing were 10 in each group, while 5 mice were used in each group to evaluate BT. Values are mean ⁇ SEM Table 2: Effect of Test compounds on venous thrombosis model in rabbits:
  • n number of experiments which consists of at least 6 or more observations
  • Table 4 Effect of test substances against clotting parameters
  • Example 1 Preparation of 2-[-2,5 dichlorobenzene sulfonyl]-l,2,3,4,-tetra hydro-9H- pyrido[3,4-b] indole-3-carboxylic acid ester.
  • Example 2 Preparation of 2-[2,4,6, trimethyl benzenesulfonyl]-l,2,3,4,-tetra hydro-9H- pyrido[3,4-b] indole-3-carboxylic acid ester.
  • Example 3 Preparation of 2[2, nitrobenzenesulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester.
  • 2-nitrobenzenesulphonyl chloride 0.486 gm, 2.2 mmol
  • dry acetone 5ml
  • Example 4 Preparation of 2[l-napthyl sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3 -carboxylic acid ester.
  • 1-napthylsulphonyl chloride (0.497 gm, 2.2 mmol) in dry acetone (5ml) was added to a stirred solution of dl methyl- 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole -3- carboxylate (0.46gm, 2.0 mmol) and dry triethylamine (0.56 ml, 4.0 mmol) in dry acetone (8ml).
  • Example 5 Preparation of 2-[4-methoxy benzene sulfonyl]-l,2,3,4,-tetra hydro-9H- pyrido[3,4-b] indole-3-carboxylic acid ester.
  • Example 7 Preparation of 2-[dansyl sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole- 3-carboxylic acid ester.
  • 2-dansyl sulphonyl chloride 0.592gm,2.2mmol
  • dry acetone 5ml
  • 2-dansyl sulphonyl chloride 0.592gm,2.2mmol
  • dl methyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole -3- carboxylate (0.46gm,2.0mmol)
  • dry triethylamine (0.56ml ,4.0mmol
  • Example 8 Preparation of 2-[2,4,6 tri isopropyl benzene sulfonyl]-l, 2,3,4, -tetra hydro-9H- pyrido[3,4-b] indole-3-carboxylic acid ester.
  • Example 9 Preparation of 2-[4-floro benzene sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4- b] indole-3-carboxylic acid ester.
  • 4-floro benzene sulphonyl chloride (0.427gm,2.2mmol) in dry acetone (5ml) was added to a stirred solution of dl methyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole -3- carboxylate (0.46gm,2.0mmol) and dry triethylamine (0.56ml ,4.0mmol) in dry acetone (8ml).
  • Example 10 Preparation of 2-[2-tri floro methyl benzene sulfonyl]-l,2,3,4,-tetra hydro-9H- pyrido[3,4-b] indole-3-carboxylic acid ester.
  • Example 11 Preparation of 2-[methane sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester.
  • Methane sulphonyl chloride (0.18 ml,2.4 mmol) in dry acetone (5ml) was added to a stirred solution of dl methyl- 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole -3- carboxylate (0.46 gm, 2.0 mmol) and dry triethylamine (0.56 ml, 4.0 mmol) in dry acetone (8ml).
  • Example 12 Preparation of 2-[2-napthalene sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester .
  • 2-naphthyl sulphonyl chloride (0.497 gm, 2.2 mmol) in dry acetone (5ml) was added to a stirred solution of dl methyl- 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole -3- carboxylate (0.46 gm,2.0 mmol ) and dry triethylamine (0.56ml, 4.0 mmol) in dry acetone (10ml) during 15 min and was allowed to stirr for 12 hours at room temperature 32 0 C.
  • Example 13 2[benzene sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester i) Benzene sulphonyl chloride (0.388gm, 2.2mmol) in dry acetone (5ml) was added to a stirred solution of dl methyl- 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole -3- carboxylate (0.46 gm, 2.0 mmol) and dry triethylamine (0.56 ml, 4.0 mmol) in dry acetone (8ml). during 15 min and was allowed to stirr for 8hrs.
  • Example 15 Preparation of 2-[2, 5 dichlorobenzene sulfonyl]-l,2,3,4,-tetra hydro-9H- pyrido[3,4-b] indole-3-carboxylic acid amide.
  • Example 16 Preparation of 2-[4-methoxy benzene sulfonyl]-l,2,3,4,-tetra hydro-9H- pyrido[3,4-b] indole-3-carboxylic acid amide.
  • 4-methoxy benzene sulphonyl chloride (.495gm,2.4mmol) in dry acetone(5ml) was added to a stirred solution of dl 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole -3-amide (0.430gm, 1.0 mmol) and dry triethylamine (0.56ml, 4.0 mmol) in dry DMF(5 ml).
  • Example 17 Preparation of 2-[l-napthyl sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide. i) 2-[l-napthylsulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester (0.210gm, 0.5mmol) was kept at room temperature (32°C) in methanolic ammonia(30ml) for 24 hrs.
  • Example 18 Preparation of 2-[8-quinoline sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.
  • 2-[8-quinoline sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester (0.21 lgm, 0.5mmol) was kept at room temperature(32°C) in methanolic ammonia(30ml) for 48 hrs The reaction mixture was then evaporated under vaccum to obtain 2-[8-quinoline sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indoie-3-carboxylic acid amide .
  • This was purified by column chromatography over silica gel using 2% methanol chloroform as eluent.Yield 0.130g
  • Example 19 Preparation of 2-[4-floro benzene sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4- b] indole-3-carboxylic acid amide.
  • Example 20 Preparation of 2-[ methane sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.
  • Methane sulphonyl chloride (0.18ml,2.4mmol) was added to a stirred solution of dl 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole -3-amide (0.430gm,2.0mmol) and dry triethylamine (0.56ml ,4.0mmol) in dry DMF (8ml). during 15 min at room temperature 30°C. The reaction mixture was allowed to stirr for 8hrs. at room temperature.
  • Example21 Preparation of 2-[3-nitro benzene sulfonyl]-l,2,3,4,-tetra hydro-9H-pyrido[3,4- b] indole-3-carboxylic acid amide.
  • 3-nitro benzene sulphonyl chloride (0.53 lgm,2.4mmol) in dry acetone was added to a stirred solution of dl 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole -3-amide (0.430gm,2.0mmol) and dry triethylamine (0.56ml, 4.0mmol) in dry DMF (8ml) during 15 min and was allowed to stirr for 8hrs. at room temperature.
  • Example 22 Preparation of 2-[2, 4, 6 trimethyl benzene sulfonyl]-l,2,3,4,-tetra hydro-9H- pyrido[3,4-b] indole-3-carboxylic acid amide.
  • 2,4,6 trimethyl benzene sulphonyl chloride 0.524gm,2.4mmol
  • dl 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole -3-amide 0.430gm,2.0mmol
  • dry triethylamine (0.56 ml, 4.0mmol
  • Example 23 Preparation of 2-[2-napthyl sulfonyl]-l, 2,3,4, -tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne des composés antithrombotiques de type esters/amides de l'acide 2-alkyl- ou 2-arylsulfonyl-1,2,3,4-tétrahydro-9H-pyrido(3,4-b)indole -3-carboxylique, des sels de qualité pharmaceutique de ces composés et des préparations élaborées à partir de ces composés, et pouvant être employés dans le traitement de thromboses intravasculaires telles que l’ischémie myocardique et les accidents cérébrovasculaires. Les composés présentent la structure générale (I) suivante où R représente un ester méthylique ou un amide, et R1 représente un groupement alkyle, aryl ou hétéroaryle.
PCT/IN2004/000417 2004-12-27 2004-12-27 Esters/amides de l'acide 2-alkyl- ou 2-arylsulfonyl-1,2,3,4-tétrahydro-9h-pyrido(3,4-b)indole-3-carboxylique employés en tant qu'agents antithrombotiques WO2006070385A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19612298A1 (de) * 1996-03-28 1997-10-02 Hoechst Ag Heterocyclische N-substituierte alpha-Iminohydroxamsäuren
WO1997037658A1 (fr) * 1996-04-04 1997-10-16 F.Hoffmann-La Roche Ag Utilisation de derives de tetrahydro-beta-carbolines en tant qu'agents antimetastatiques
WO1998051301A1 (fr) * 1997-05-14 1998-11-19 Pierre Fabre Medicament Utilisation d'amines indoliques comme medicaments antithrombotiques
WO2001087883A1 (fr) * 2000-05-15 2001-11-22 Darwin Discovery Limited Derives d'acides hydroxamique et carboxylique possedant une activite inhibitrice des metalloproteinases et du facteur de necrose tumorale
WO2004000842A1 (fr) * 2002-06-19 2003-12-31 Janssen Pharmaceutica, N.V. Derives substitues de 2,4-dihydro-pyrrolo (3, 4-b) -quinolin-9-one utilises comme inhibiteurs de la phosphodiesterase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19612298A1 (de) * 1996-03-28 1997-10-02 Hoechst Ag Heterocyclische N-substituierte alpha-Iminohydroxamsäuren
WO1997037658A1 (fr) * 1996-04-04 1997-10-16 F.Hoffmann-La Roche Ag Utilisation de derives de tetrahydro-beta-carbolines en tant qu'agents antimetastatiques
WO1998051301A1 (fr) * 1997-05-14 1998-11-19 Pierre Fabre Medicament Utilisation d'amines indoliques comme medicaments antithrombotiques
WO2001087883A1 (fr) * 2000-05-15 2001-11-22 Darwin Discovery Limited Derives d'acides hydroxamique et carboxylique possedant une activite inhibitrice des metalloproteinases et du facteur de necrose tumorale
WO2004000842A1 (fr) * 2002-06-19 2003-12-31 Janssen Pharmaceutica, N.V. Derives substitues de 2,4-dihydro-pyrrolo (3, 4-b) -quinolin-9-one utilises comme inhibiteurs de la phosphodiesterase

Non-Patent Citations (2)

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Title
MATTER ET AL: "Affinity and Selectivity of Matrix Metalloproteinase Inhibitors: A Chemometrical Study from the Perspective of Ligands and Proteins", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 42, no. 22, 1999, pages 4506 - 4523, XP002162629, ISSN: 0022-2623 *
TRIPATHI, RAVISH C. ET AL: "Synthesis and SAR studies in 2-substituted 1,2,3,4-tetrahydro-9H- pyrido[3,4-b]indole-3-carboxylic acids - a new class of potent antiulcer agents", INDIAN JOURNAL OF CHEMISTRY, SECTION B: ORGANIC CHEMISTRY INCLUDING MEDICINAL CHEMISTRY , 28B(4), 333-7 CODEN: IJSBDB; ISSN: 0376-4699, 1989, XP009052431 *

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