WO2003080564A1 - Inhibiteurs de facteur pai-1 antithrombotique a base de menthol substitue - Google Patents

Inhibiteurs de facteur pai-1 antithrombotique a base de menthol substitue Download PDF

Info

Publication number
WO2003080564A1
WO2003080564A1 PCT/US2003/007506 US0307506W WO03080564A1 WO 2003080564 A1 WO2003080564 A1 WO 2003080564A1 US 0307506 W US0307506 W US 0307506W WO 03080564 A1 WO03080564 A1 WO 03080564A1
Authority
WO
WIPO (PCT)
Prior art keywords
carboxylic acid
optionally substituted
menthoxy
substituted
nitro
Prior art date
Application number
PCT/US2003/007506
Other languages
English (en)
Inventor
Shawn Bauer
Raju Mohan
Kenneth J. Shaw
Qingyu Wu
Bin Ye
Brad O. Buckman
Ameen Ghannam
Brian D. Griedel
Seock-Kyu Khim
Zuchun Zhao
Original Assignee
Schering Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to AU2003222278A priority Critical patent/AU2003222278A1/en
Publication of WO2003080564A1 publication Critical patent/WO2003080564A1/fr

Links

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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D213/60—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
    • C07D213/79—Acids; Esters
    • 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
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to menthol-substituted compounds and their pharmaceutically acceptable salts that are useful as antithrombotic agents by inhibiting plasminogen activator inhibitor- 1 (PAI-1).
  • PAI-1 plasminogen activator inhibitor- 1
  • the present invention relates to pharmaceutical compositions and their pharmaceutically acceptable salts containing the menthol substituted compounds, derivatives of the menthol substituted compounds, and methods of use. Background of the Invention
  • thrombootic diseases remain a major health care problem despite the tremendous progress made in understanding the molecular mechanisms of blood coagulation and pathogenesis of thrombosis and atherosclerosis. In fact, each year in the United States, approximately 1.5 million patients experience acute myocardial infarction and 5 million patients develop angina.
  • thrombosis occurs from an imbalance between prothrombotic and antithrombotic mechanisms. In principle, either enhanced platelet activation and blood coagulation or reduced fibrinolytic activity could lead to thrombosis.
  • antithrombotic drugs and the majority in development are designed to inhibit platelets or blood coagulation factors.
  • Thrombolytic agents such as streptokinase, and recombinant tissue-type plasminogen activator (tPA) and urokinase (uPA) are used mostly for acute myocardial infarction. These protein-based drugs are designed to be administered intravenously for rapid onset of action.
  • PAI-1 is the major negative regulator of tPA and uPA in the fibrinolytic system. High levels of PAI-1 reduce fibrinolytic potential and contribute to the development of thrombosis. Recent studies have demonstrated the feasibility of using small molecular weight nonpeptide compounds to inhibit PAI-1 activity and promote fibrinolysis in vivo. In addition to thrombosis, PAI-1 may also play a role in other pathological settings such as chemotherapy- induced pulmonary fibrosis and cancer progression.
  • Fibrinolysis is a physiological mechanism designed to remove intravascular thrombus maintaining vascular patency. After a blood clot is formed in an injured vessel, the fibrinolytic system degrades the fibrin clot, restoring blood flow to vital organs and tissues.
  • the fibrinolytic system consists of several proteases, namely tPA and uPA and plasminogen, which form a enzymatic cascade in which tPA and uP A convert plasminogen to plasmin which in turn degrades fibrin, as follows:
  • PAI-1 inhibitors tPA PAI-1 inhibitors
  • the fibrinolytic enzymes of the fibrinolytic system are not only physiologically important in vascular homeostasis but can also cause unwanted effects such as bleeding and excessive vascular proteolysis. Therefore, tight regulation of the fibrinolytic system is of homeostatic importance. Under physiological conditions, regulation is typically achieved by activation of zymogens through limited proteolysis, controlled binding of plasminogen or plasmin to fibrin, and inactivation of proteases by serine protease inhibitors, as shown above.
  • PAI-1 is the principal negative regulator of tPA and uPA in the fibrinolytic system.
  • the PAI-1 gene is located on chromosome 7q21.3-q22.
  • the protein consists of 379 amino acids and has a molecular weight of 52kDa.
  • serpin serine protease inhibitor
  • PAI-1 protein folds into a conserved tertiary structure consisting of three beta- sheets, nine alpha-helices and a reactive center loop.
  • PAI-1 inhibits tPA and uPA through its reactive center loop that mimics the substrate sequence of the target proteases. The reaction results in the formation of an irreversible complex of the protease and inhibitor, thereby inhibiting the activities of the enzymes.
  • PAI-1 is synthesized by vascular endothelial cells, hepatocytes and smooth muscle cells and can range in concentration in human plasma between about 0.5 to 1.5 nmol/L. Functionally, there are two forms of PAI-1 : an active form and an inactive or latent form. Only the active form binds to tPA and uPA, and inhibits their activities. PAI-1 is typically released from cells in active form, but is rapidly converted to the latent form through a conformational change. This conformational change prevents the interaction of PAI-1 with tPA or uPA. PAI-1 as a thrombotic risk factor is well documented in several studies.
  • Elevated levels of plasma PAI-1 are associated with a variety of thrombotic diseases including deep vein thrombosis, disseminated intravascular coagulation (DIC), unstable angina, premature myocardial infarction, coronary artery disease, and atherosclerosis.
  • DIC disseminated intravascular coagulation
  • unstable angina premature myocardial infarction
  • coronary artery disease and atherosclerosis.
  • subsequent cardiovascular events such as acute myocardial infarction and severe recurrent angina correlated closely with increased plasma PAI-1 activity.
  • high levels of plasma PAI-1 are also reported in other metabolic diseases that are associated with increased thrombotic risk, such as obesity, noninsulin-dependent diabetes, hyperinsulinemia, and hypertriglyceridemia.
  • PAI-1 is also implicated in cancer progression and invasion.
  • PAI-1 PAI-1-specific neoplasmic sarcoma
  • ovarian cancer High levels of PAI-1 have been reported in a variety of human tumors including neuroblastoma, colorectal carcinoma, head and neck squamous cell carcinoma, breast carcinoma, gastric cancer, and ovarian cancer. The expression was often associated with large, invasive tumors, metastatic tumors, and drug resistant tumors.
  • Thrombolytic therapy using known agents have presented a major challenge in reducing angiographic reocclusion.
  • angiographic reocclusion is observed in about 30% of patients three months after successful thrombolysis for acute myocardial infarction.
  • Reocclusion significantly affects recovery of left ventricular function and leads to a poorer long-term clinical outcome.
  • Other approaches are therefore necessary to reduce coronary reocclusion.
  • a number of polyclonal and monoclonal antibodies against PAI-1 have been developed.
  • anti-PAI-1 antibodies are well documented in various animal models. For example, infusion of anti -human PAI-1 antibody reduced plasma PAI-1 activity and inhibited intravascular thrombus formation, as demonstrated by a dose-dependent decrease in fibrin deposition in the lungs of rats having endotoxin induced thrombosis. Studies with PAI-1 antibodies suggest the PAI-1 inhibitors could be used in combination with antiplatelet and anticoagulant drugs to prevent coronary reocclusion after thrombolytic therapy.
  • Fibrates are a class of compounds widely used to lower plasma cholesterol and triglycerides in hyperlipidemic patients.
  • Raloxifene and Tamoxifen estrogen derived compounds developed to treat osteoporosis and breast cancer, were shown to inhibit PAI-1 secretion induced by IL-1 in estrogen-activated human umbilical vein endothilial cells.
  • a major drawback to the above-identified drugs is that they inhibit PAI-1 production or secretion by endothelial cells.
  • the molecular mechanism controlling PAI-1 synthesis and secretion may vary in different cells, and therefore would be difficult to develop a specific drug that directly inhibits the production of PAI-1 in the variety of cells.
  • An alternative approach is to develop a drug that directly inhibits PAI-1 activity, instead.
  • a drug that inhibits PAI-1 activity has immediate antithrombotic effects once present in the blood.
  • PAI-1 inhibitor has been developed from flufenamic acid. Further, a series of benzothiophenobenzofiiran- and indole-based small molecules have been identified that inhibit PAI-1 activity. Although recent progress has demonstrated the feasibility of developing a small molecule PAI-1 inhibitor, most reported PAI-1 inhibitor compounds have an IC50 value in the micromolar range. Further chemical modifications are clearly needed to improve the potency of these compounds.
  • gemfibrozil (lOO ⁇ M) suppressed basal PAI-1 production from human umbilical vein endothelial cells by 15% and attenuated the augmentation of PAI-1 synthesis induced by growth factors, such as EGF, TGF-B and platelet lysates. Similar effects of gemfibrozil were also observed on PAI-1 synthesis by cultured hepatocytes (HepG2), although effective concentrations required for gemfibrozil were much higher (750 ⁇ M).
  • T-686 3E, 4E-3-benzylidene-4- (3,4,5-trimethoxy-benzylidene)-pyrrolidine-2,5-dione
  • T-686 3E, 4E-3-benzylidene-4- (3,4,5-trimethoxy-benzylidene)-pyrrolidine-2,5-dione
  • T-686 reduced basal production of PAI-1 by 32%.
  • T-686 also attenuated TGF-B induced PAI-1 expression in these cells.
  • oral administration of T-686 (30mg/kg/day) lowered plasma PAI- 1 levels and reduced atherosclerotic lesion area by 19%.
  • a class of compounds is needed in pharmaceutical mixtures that inhibits the activity of PAI-1 in vivo that overcomes the problems associated with prior compounds.
  • a class of compounds is necessary that has increased potency at smaller dosages than the compounds known in the prior art to prevent thrombosis, atherosclerosis, fibrosis, such as, but not limited to, idiopathic and drug-induced pulmonary fibrosis, hepatic fibrosis and systemic sclerosis, and may further be utilized to prevent cancer invasion and chemotherapy- induced fibrosis.
  • the present invention relates to antithrombotic molecules that act as PAI-1 inhibitors in fibrinolysis and are therefore useful as pharmacological agents for the treatment of disease states characterized by thrombotic activity.
  • the present invention relates to menthol substituted compounds and their pharmaceutically acceptable salts that are useful as antithrombotic agents that inhibit PAI-1 in fibrinolysis.
  • the invention provides compounds selected from the group consisting of the following formula:
  • a, b, and c is 0 to 2;
  • A is either absent or present and is either carbonyl or forms a heterocyclic ring system with B (if B is N) and the phenyl group;
  • B is either absent or present and is selected from the group consisting of N or O;
  • Rl is either absent or present and is selected from the group consisting of hydrogen, alkyl, alkylene, aryl, haloalkyl, menthoxy alkyl, or forms a heterocyclic ring system with the B (if B is N) and the phenyl (preferably forming an optionally substituted indole);
  • R2 is selected from the group consisting of hydrogen, alkoxy, amino, monoalkylaminocarbonyl, monoalkylaminocarbonyl carboxylic acid, nitro, alkyl, haloalkyl, substituted aralkoxy (substituted with carboxylic acid), alkoxy substituted phenyl amido, cyclohexyloxybenzoylamino, or a fused [l,3]dioxinyl ring system;
  • X is either C or N
  • D is either absent or present and is either O or N;
  • Y is either absent or present and is selected from alkylene, optionally substituted aryl, carbonyl, or forms a heterocyclic ring system with D (if D is N) and the phenyl ring;
  • Z is either absent or present and is selected from the group consisting of alkylene, aryl, sulfonyl, aminocarbonyl, or carbonyl;
  • R3 is either absent or present and is selected from the group consisting of optionally substituted phenyl (optionally substituted by hydrogen, nitro, hydroxy, and/or alkoxy), carboxylic acid, alkoxy, alkyl or carbamate ester; and
  • R4 is either absent or present and is selected from the group consisting of optionally substituted dibenzo[b,e][l,4]dioxepin-l 1-one (wherein said phenyl groups of said dioxepinone are optionally substituted by hydroxy, alkyl, carboxylic acid, and alkoxy), optionally substituted pyridinyl (optionally substituted by carboxylic acid and/or alkylene), naphthalene, optionally substituted phenyl (optionally substituted by one or more of hydroxy, carboxylic acid, nitro, alkyl, alkoxy, carboxylic acid substituted alkoxy, alkyl ester, acetic acid, acetic acid ether, amido, amino, alkoxyamido, methanesulfonyl amino, halo, tetrazolyl, optionally substituted aralkoxy (optionally substituted by hydroxy, carboxylic acid, nitro, alkyl, alkoxy, te
  • R3 and R4 form a carboxylic acid substituted fully saturated monocyclic aza ring with up to 6 carbon atoms, as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • this invention provides compositions useful in treating a human having a disease-state characterized by thrombotic activity, which composition comprises a therapeutically effective amount of a compound of the invention as described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • this invention provides a method of treating a human having a disease-state characterized by thrombotic activity, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of the invention as described above.
  • this invention provides a method of treating a human having a disease-state alleviated by the inhibition of plasminogen activator inhibitor- 1 (PAI-1), which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of the invention as described above.
  • PAI-1 plasminogen activator inhibitor- 1
  • this invention provides a method of inhibiting plasminogen activator inhibitor- 1 (PAI-1) in vitro or in vivo by the administration of a compound of the invention.
  • PAI-1 plasminogen activator inhibitor- 1
  • Alkyl refers to a straight or branched chain monovalent or divalent radical consisting solely of carbon and hydrogen, containing no unsaturation and having from one to six carbon atoms, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1- dimethylethyl (t-butyl), and the like.
  • Alkoxy refers to a radical of the formula -OR a , where R a is alkyl as defined above, e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, n-pentoxy, 1,1- dimethylethoxy (t-butoxy), and the like.
  • Alkylene refers to a straight or branched chain divalent radical consisting of carbonyl and hydrogen, containing no unsaturation and having from one to six carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and the like.
  • Aryl refers to a phenyl or naphthyl radical.
  • Aralkyl refers to a radical of the formula -R a Rb where R a is alkyl as defined above, and Rb is aryl as defined above, e.g., benzyl.
  • Aryloxy refers to a radical of the formula -ORb where Rb is aryl as defined above, e.g., benzyloxy, and the like.
  • Dialkylamino refers to a radical of the formula -NRaRa where each Ra is independently an alkyl radical as defined above, e.g., diethylamino, methylethylamino, diethylamino, dipropylamino, ethylpropylamino, and the like.
  • Dialkylaminocarbonyl refers to a radical of the formula -C(O)NRaRa where each Ra is independently an alkyl radical as defined above, e.g., diethylaminocarbonyl, dipropylaminocarbonyl, ethylpropylaminocarbonyl, and the like.
  • Hydro refers to bromo, chloro, iodo or fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difiuoromethyl, trichloromethyl, 2- trifluoroethyl, 1 -fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1 -bromomethyl-2- bromoethyl, and the like.
  • Haloalkoxy refers to a radical of the formula -OR f , where R f is haloalkyl as defined above, e.g., 2-trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2-trifluoroethoxy, 1- fluoromethyl-2-fluoroethoxy, 3-bromo-2-fluoropropoxy, 1 -bromomethyl-2-bromoethoxy, and the like.
  • Heterocyclic ring system refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur.
  • the heterocyclic ring system may be monocyclic, bicyclic, or tricyclic ring systems, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclic ring system radical may be optionally oxidized; the nitrogen atom may be optionally quatermized; and the ring system may be partially or fully saturated or aromatic.
  • the heterocyclic ring system radical may be attached to the main structure at any heteroatom or carbon which results in the creation of a stable structure.
  • heterocyclic ring system radicals include, but are not limited to, aziridinyl, azetidinyl, piperidinyl, piperazinyl, 2-oxo-piperazinyl, 2-oxopiperidinyl, 2-oxo- pyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolinyl, pyrrolidinyl, imidazolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, is
  • Methoxy refers to a radical of 2-isopropyl-5-methyl-cyclohexyloxy. Menthoxy may be in any of two forms: (+)-menthoxy, or (-)-menthoxy. Compounds of the present invention preferably utilize (-)-menthoxy, although (+)-menthoxy should not be excluded from the present invention.
  • “Monoalkylamino” refers to a radical of the formula -NHRa where Ra is an alkyl radical as defined above, e.g., methylamino, ethylamino, propylamino, and the like.
  • “Monoalkylaminocarbonyl” refers to a radical of the formula -C(O)NHRa where Ra is an alkyl radical as defined above, e.g., methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and the like. "Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitutions. “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are 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, trifluoroacetic 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, salicylic 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, tri
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, 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- dimethylaminoethanol, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betamine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N- ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexyl
  • Rt refers to room temperature.
  • “Therapeutically effective amount” refers to that amount of a compound of formula (I) which, when administered to a human in need thereof, is sufficient to effect treatment, as defined below, for disease-states characterized by thrombotic activity.
  • the amount of a compound of formula (I) which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease-state and its severity, and the age of the human to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • Treating or “treatment” as used herein cover the treatment of a disease-state in a human, which disease-state is characterized by thrombotic activity, and include:
  • the disease state may comprise unstable angina, myocardial infarction, cerebral thromboembolism, transient ischemic attack, stroke, DVT, and coronory reocclusion after thrombolytic therapy, as well as others.
  • the compounds of the invention may have asymmetric carbon atoms, oxidized sulfur atoms or quaternized nitrogen atoms in their structure.
  • the compounds of the invention and their pharmaceutically acceptable salts may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of this invention.
  • the compounds of the present invention are inhibitors of PAI-1 and therefore useful in disease-states characterized by thrombotic activity based on PAI-l's role in inhibiting fibrinolysis (see Background of the Invention above).
  • a primary indication for the compounds is prophylaxis of deep vein thrombosis (DVT), disseminated intravascular coagulation (DIC), unstable angina, premature myocardial infarction, subsequent cardiovascular events such as acute myocardial infarction, coronary artery disease, and atherosclerosis.
  • the compounds of the present invention may also be useful for indications of increased thrombotic risk, such as obesity, noninsulin-dependent diabetes, hyperinsulinemia, and hypertriglyceridemia.
  • the compounds of the present invention may also be used in treating diseases characterized by fibrosis, such as, but not limited to, idiopathic and drug-induced pulmonary fibrosis, hepatic fibrosis and systemic sclerosis.
  • fibrosis such as, but not limited to, idiopathic and drug-induced pulmonary fibrosis, hepatic fibrosis and systemic sclerosis.
  • the compounds of the present invention may also be useful in treating cancer progression and invasions, such as neuroblastoma, colorectal carcinoma, head and neck squamous cell carcinoma, breast carcinoma, gastric cancer and ovarian cancer.
  • a chromogenic in vitro assay was developed in which human PAI-1 activity is measured by inhibition of uPA- dependent substrate hydrolysis.
  • human uPA (30nM), and human recombinant PAI-1 (8nm)
  • PEG polyethylene glycol
  • the activity of uPA was determined by the initial rate of cleavage of a peptide substrate (S2444, Glu-Gly-Arg-pNA; Diapharma).
  • the cleavage product, p-nitroaniline was measured by monitoring IR absorbance at 405 nm.
  • fibrin clot lysis assay was developed.
  • the fibrin clot lysis assay was used to evaluate the potency of small molecule PAI-1 inhibitors.
  • pooled human plasma was diluted (1:3) in a buffer containing 150 nM NaCl, 2 nM CaCl 2 , 20 mM Hepes, pH 7.4.
  • Fibrin clot formation was initiated by the addition of human thrombin (30 nM). The newly formed fibrin clot remained stable at 37°C for at least two hours.
  • Administration of the compounds of the present invention in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be administered, for example, orally, nasally, parenterally, topically, transdermally, or rectally, in the form of a solid, semi-solid, lyophilized powder or liquid dosage forms, such as via tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • the compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention and 99% to about 1% by weight of a suitable pharmaceutical excipient.
  • the composition will be about 5% to about 75% by weight of a compound(s) of the invention with the rest being suitable pharmaceutical excipients.
  • a pharmaceutically acceptable composition containing a compound(s) of the invention is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, pregelatinized starch, magnesium stearate, sodium saccharine, talcum, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate, and the like.
  • excipients such as, for example, pharmaceutical grades of mannitol, lactose, starch, pregelatinized starch, magnesium stearate, sodium saccharine, talcum, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate, and the like.
  • Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations, and any other like excipient that may be apparent to one having ordinary skill in the art.
  • compositions will take the form of capsule, caplet, or tablet and therefore will also contain a diluent such as lactose, sucrose, dicalcium phosphate, and other like diluents; a disintegrant such as croscarmellose sodium or derivatives thereof; a lubricant such as magnesium stearate and other like lubricants; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose ether derivatives, and other like lubricants.
  • a diluent such as lactose, sucrose, dicalcium phosphate, and other like diluents
  • a disintegrant such as croscarmellose sodium or derivatives thereof
  • a lubricant such as magnesium stearate and other like lubricants
  • a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose ether derivatives, and other like lubricants
  • the compounds of the present invention may also be formulated into a suppository using, for example, about 0.5% to about 50% active ingredient disposed in a carrier that slowly dissolves within the body.
  • typical carrier materials may be polyethylene glycol (PEG), PEG 1000 (96%) and PEG 4000 (4%).
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. a compound(s) of the invention (about 5% to about 20%), and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and other like carriers, to form a solution or suspension.
  • a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and other like carriers, to form a solution or suspension.
  • a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and antioxidants, such as citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and antioxidants, such as citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • composition to be administered will contain a therapeutically effective amount of a compound of the invention for treatment of a disease state alleviated by the inhibition of PAI-1 in fibrinolysis, in accordance with the teachings of this invention.
  • the compounds of the present invention are administered in a therapeutically effective amount which will vary depending upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states and the host undergoing therapy.
  • a therapeutically effective daily does is from about 0.14 mg to about 14.3 mg/kg of body weight per day of a compound of the present invention.
  • the pharmaceutical composition includes from about 0.7 mg to about 10 mg/kg of body weight per day.
  • the dosage would be about 1 Omg to about 1.0 gram per day of a compound of the invention.
  • the pharmaceutical composition includes about 50 mg to about 700 mg per day of a compound of the present invention. Most preferably, the pharmaceutical composition includes about 100 mg to about 500 mg per day of a compound of the present invention.
  • the present invention relates to compounds having substituted menthoxy groups. More specifically, the present invention relates to substituted menthoxy groups as shown below:
  • a preferred group of compounds having the general substituted menthoxy structure as noted above is that group wherein the compounds are selected from formula (I), as shown below:
  • Formula I as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof.
  • a preferred subgroup of this group is that subgroup of compounds wherein a, b, and c is 0 to 2;
  • A is either absent or present and is either carbonyl or forms a heterocyclic ring system with the B (if B is N) and the phenyl (preferably forming benzimidazolyl);
  • B is either absent or present and is selected from the group consisting of N or O;
  • Rl is absent or present and is selected from the group consisting of hydrogen, alkyl, alkylene, aryl, haloalkyl, menthoxy alkyl, or forms a heterocyclic ring system with B (if B is N) and the phenyl (preferably forming an optionally substituted indole);
  • R2 is selected from the group consisting of hydrogen, alkoxy, amino, monoalkylaminocarbonyl, monoalkylaminocarbonyl carboxylic acid, nitro, alkyl, haloalkyl, substituted aralkoxy (substituted with carboxylic acid), cyclohexyloxybenzoylamino, or a fused [l,3]dioxinyl ring system or [l,4]dioxinyl ring system with the phenyl;
  • X is either C or N;
  • D is absent or present and is either O or N;
  • Y is either absent or present and is selected from alkylene, aryl, carbonyl, or forms a heterocyclic ring system with D and the phenyl ring (preferably forming an optionally substituted benzimidazolyl or an optionally substituted indole);
  • Z is either absent or present and is selected from the group consisting of alkylene, aryl, sulfonyl, aminocarbonyl, or carbonyl;
  • R3 is either absent or present and is selected from the group consisting of hydrogen, optionally substituted phenyl (optionally substituted by nitro, hydroxy, and/or alkoxy), optionally substituted aralkyl (optionally substituted by nitro and hydroxy), carboxylic acid, alkoxy, or alkyl; and
  • R4 is either absent or present and is selected from the group consisting of optionally substituted dibenzo[b,e][l,4]dioxepin-l 1-one (wherein said phenyl groups of said dioxepinone are optionally substituted by hydroxy, alkyl, carboxylic acid, and alkoxy), optionally substituted pyridinyl (optionally substituted by carboxylic acid and/or alkylene), naphthalene, optionally substituted phenyl (optionally substituted by one or more of hydroxy, carboxylic acid, nitro, alkyl, alkoxy, carboxylic acid substituted alkoxy, alkyl ester, acetic acid, acetic acid ether, amido, amino, alkoxyamido, methanesulfonylamino, halo, tetrazolyl, optionally substituted aralkoxy (optionally substituted by hydroxy, carboxylic acid, nitro, alkyl, alkoxy, t
  • a preferred subgroup of compounds is that subgroup of compounds of Formula I wherein a is 0 or 1; b is 1, c is 0; A is carbonyl; B is N; X is C; and Rl, R2, R3, R4, D, Y and Z are as described above.
  • This preferred subgroup of compounds is, therefore, selected from compounds of the following Formula IA:
  • a preferred subclass of Formula IA is that group of compounds of Formula I A wherein R2 is hydrogen and D is N, as shown below in Formula IA1 :
  • Rl is hydrogen, alkyl, alkylene, or forms a five member ring structure with the nitrogen and the phenyl to form a substituted indole;
  • Y is absent or present and is selected from the group consisting of hydrogen or methylene
  • R3 is absent or present and is selected from the group consisting of hydrogen, alkyl, optionally substituted aralkyl (optionally substituted by one or more of hydroxy or nitro), and carboxylic acid;
  • Z is either absent or present and is selected from the group consisting of methylene, sulfonyl, aminocarbonyl, and carbonyl;
  • R4 is either absent or present and is selected from the group consisting of optionally substituted dibenzo[b,e][l,4]dioxepin-l 1-one (wherein said phenyl groups of said dioxepinone are optionally substituted by hydroxy, alkyl, carboxylic acid, and alkoxy), optionally substituted pyridinyl (optionally substituted by carboxylic acid and/or alkylene), naphthalene, optionally substituted phenyl (optionally substituted by one or more of hydroxy, carboxylic acid, nitro, alkyl, alkoxy, carboxylic acid substituted alkoxy, alkyl ester, acetic acid, acetic acid ether, amido, amino, alkoxyamido, methanesulfonyl amino, halo, tetrazolyl, optionally substituted aralkoxy (optionally substituted by hydroxy, carboxylic acid, nitro, alkyl, alkoxy, te
  • Particularly preferred compounds of this class of compounds are selected from the following:
  • Another preferred subclass of Formula IA is that group of compounds of the following Formula IA1, as follows:
  • R2 is hydrogen or carboxylic acid substituted benzyloxy, or a fused [l,3]dioxinyl ring system or [l,4]dioxinyl ring system with the phenyl ;
  • Y is absent or present and is selected from the group consisting of hydrogen or methylene;
  • R3 is absent or present and is selected from the group consisting of hydrogen, and optionally substituted aryl (optionally substituted by one or more of hydroxy, nitro, and carboxylic acid);
  • Z is either absent or present and when present is methylene;
  • R4 is either absent or present and is selected from the group consisting of optionally substituted dibenzo[b,e][l,4]dioxepin-l 1-one (wherein said phenyl groups of said dioxepinone are optionally substituted by hydroxy, alkyl, carboxylic acid, and alkoxy), and optionally substituted phenyl (optionally substituted by one or more of hydroxy, carboxylic acid, nitro, alkoxy and optionally substituted aryloxy (optionally substituted by hydroxy and nitro).
  • Particularly preferred compounds of this class of compounds are selected from the following: 3 -Hydroxy-4- [(3 - ⁇ [2-menthoxy-acetylamino] -methyl ⁇ -pheny lamino)-methy 1] - 8 -methoxy- 1,9- dimethyl-11-oxo-l lH-dibenzo[b,e][l,4]dioxepine-6-carboxylic acid; N- ⁇ 6-[Bis-(2-hydroxy-5-nitro-benzyl)-amino]-4H-benzo[l,3]dioxin-8-ylmethyl ⁇ -2-menthoxy- acetamide;
  • Another preferred subgroup of Formula I is that group of compounds wherein a is 1, b and c are 0, and D, X, Y, Z, Rl, R2, R3 and R4 are as described above, as follows:
  • Formula IB A preferred subclass of Formula IB is that subclass of compounds wherein D is N, having the following formula:
  • Rl is hydrogen or forms a five member ring structure with the nitrogen and the phenyl to form a substituted indole;
  • X is either C or N;
  • R2 is selected from the group consisting of hydrogen, alkoxy, amino, monoalkylaminocarbonyl, monoalkylaminocarbonyl carboxylic acid, nitro, alkyl, and optionally substituted aralkoxy (optionally substituted with carboxylic acid);
  • Y is either absent or present and is selected from the group consisting of hydrogen, methylene, carbonyl or forms a 5 member heterocyclic ring system with the N and the phenyl ring to form a substituted indole or substituted benzoimidazole;
  • R3 is absent or present and is selected from the group consisting of hydrogen, alkyl, optionally substituted aryl (optionally substituted by one or more of hydroxy or nitro), carboxylic acid and alkyl ether;
  • Z is either absent or present and is selected from the group consisting of alkylene, optionally substituted aryl, and carbonyl;
  • R4 is either absent or present and is selected from the group consisting of hydrogen, optionally substituted pyridinyl (optionally substituted by carboxylic acid, alkylene), naphthalene, optionally substituted phenyl (optionally substituted by one or more of hydrogen, hydroxy, carboxylic acid, nitro, alkyl, alkoxy, carboxylic acid substituted alkoxy, alkyl ester, acetic acid, acetic acid ether, amido, amino, alkoxy amido, methanesulfonylamino, halo, tetrazolyl, optionally substituted aralkoxy (optionally substituted by hydroxy, carboxylic acid, nitro, alkyl, alkoxy, tetrazole), optionally substituted aryloxy (optionally substituted by hydrogen, hydroxy, carboxylic acid, nitro, alkyl, alkoxy, tetrazolyl, carboxylic acid substituted alkoxy, alkyl ester, amino,
  • Another preferred subclass of Formula IB is that group of compounds wherein D is oxygen, and Z, Rl, R2 and R4 are as described above.
  • This preferred subclass can generally be represented by formula IB2, as follows:
  • Rl is hydrogen, X is either C or N, R2 is hydrogen, amine, alkoxy, and/or haloalkyl; Z is either absent or present and when present is methylene; and R4 is either absent or present and when present is optionally substituted aryl (optionally substituted by carboxylic acid).
  • Preferred compounds having the generic formula IB2 are shown as follows: 4- ⁇ 5-[2-Menthoxy-acetylamino]-2-methoxy-phenoxymethyl ⁇ -benzoic acid; 4- ⁇ 4-[2-Menthoxy-acetylamino]-phenoxymethyl ⁇ -benzoic acid; 4- ⁇ 2-Amino-5-[2-menthoxy-acetylamino]-phenoxy ⁇ -benzoic acid; 4- ⁇ 5-[2-Menthoxy-acetylamino]-2-nitro-phenoxy ⁇ -benzoic acid; 4- ⁇ 4-[2-Menthoxy-acetylamino]-3-trifluoromethyl-phenoxymethyl ⁇ -benzoic acid; 4- ⁇ 4-[2-Menthoxy-acetylamino]-3-trifluoromethyl-phenoxymethyl ⁇ -benzoic acid;
  • Another preferred subclass of Formula IB is that group of compounds wherein X is C; D is N; Rl is H; and the amino group is substituted at the meta position of the phenyl ring.
  • This preferred subclass can generally be represented by Formula IB3, as follows:
  • R2 is selected from the group consisting of hydrogen, nitro, monoalkylcarbonylalkoxy, optionally substituted arylamido (optionally substituted by hydrogen or haloalkyl), and aralkylamido;
  • Y is either absent or present and when present is methylene
  • R3 is either absent or present and when present is optionally substituted aryl (optionally substituted by hydrogen, hydroxy, and nitro);
  • Z is either absent or present and when present is selected from the group consisting of methylene and amido;
  • R4 is either absent or present and when present is selected from the group consisting of optionally substituted aryl (optionally substituted by hydroxy, nitro, tetrazole, optionally substituted aryloxy (optionally substituted by tetrazole), optionally substituted pyridinyloxy (optionally substituted by carboxylic acid, cyano, and tetrazolyl), and optionally substituted pyrrolidine (optionally substituted by hydrogen and carboxylic acid)), optionally substituted piperidinyl (optionally substituted by carboxylic acid), optionally substituted cyclohexane (optionally substituted by carboxylic acid) and carboxylic acid.
  • Preferred compounds having the generic formula IB3 are as shown as follows: N- ⁇ 3-[Bis-(2-hydroxy-5-nitro-benzyl)-amino]-phenyl ⁇ -2-menthoxy-acetamide; 3 -Hydroxy-4-(3 - ⁇ 3 - [2-menthoxy-acetylamino]-phenyl ⁇ -ureido)-benzoic acid; 2-Menthoxy-N- ⁇ 3 - [4-( 1 H-tetrazol-5-yl)-benzylamino] -phenyl ⁇ -acetamide; N-(3- ⁇ 2,6-Bis-[2-(2H-tetrazol-5-yl)-phenoxy]-benzylamino ⁇ -phenyl)-2-menthoxy-acetamide; N-(3 - ⁇ 2-Fluoro-6- [2-(2H-tetrazol-5 -yl)-phenoxy]-benzylamino ⁇
  • a still further preferred subclass of Formula IB is that group of compounds wherein Rl is H, X is C, D is O and is substituted at the meta position of the phenyl ring, and Z is absent.
  • This preferred subclass can generally be represented by Formula IB4, as follows:
  • R2 is one or more of hydrogen, alkylamido, alkylamido carboxylic acid, alkyl ester amido, nitro, menthoxyacetylamino, and akloxyarylamido;
  • Z is absent or present and when present is methylene
  • R4 is optionally substituted phenyl (optionally substituted by carboxylic acid, hydroxy, nitro, alkoxy, tetrazole, and alkyl ester), optionally substituted pyridinyl (optionally substituted by carboxylic acid).
  • Another preferred subgroup of Formula I is that group of compounds wherein a is 2; b and c are 0; and Y, R3 and Z are absent.
  • the preferred subgroup is represented by Formula IC, as follows:
  • Rl is absent when B is O, and is hydrogen when B is N;
  • X is either C or N
  • R2 is selected from the group consisting of hydrogen and nitro; D is O or N; and
  • R4 is selected from the group consisting of optionally substituted aryl (optionally substituted with carboxylic acid, morpholinyl alkyl, and optionally substituted arylester (optionally substituted by alkoxy and/or carboxylic acid)), optionally substituted piperidinyl (optionally substituted by carboxylic acid), optionally substituted pyridinyl (optionally substituted by alkenyl), and carboxylic acid substituted cyclohexane; or R3 and R4 form a carboxylic acid substituted fully saturated monocyclic aza ring with up to 6 carbon atoms.
  • Particularly preferred compounds of Formula IC are as follows: 4- ⁇ 5-[2-Menthoxy-ethoxy]-2-nitro-phenoxy ⁇ -benzoic acid; l- ⁇ 6-[2-Menthoxy-ethylamino]-5-nitro-pyridin-2-yl ⁇ -pyrrolidine-2-carboxylic acid; l-[6-[2-Menthoxy-ethylamino]-5-nitro-pyridin-2-yl]-piperidine-4-carboxylic acid; 4- ⁇ 6-[2-Menthoxy-ethylamino]-5-nitro-pyridin-2-yloxy ⁇ -3-morpholin-4-ylmethyl-benzoic acid; 4- ⁇ 6-[2-Menthoxy-ethylamino]-5-nitro-pyridin-2-yloxy ⁇ -benzoic acid; 1 -[6-[2-Menthoxy-ethylamino]-5-nitro-pyridin-2-yl]-piperidine-3-carboxylic acid
  • Another preferred subgroup of Formula I is that group of compounds wherein a is 1, b and c are 0, B is N, and A forms benzimidazole with B and the phenyl group.
  • D is O; and R2 is hydrogen.
  • This subgroup of compounds is generally represented as Formula ID, as shown below:
  • Rl is selected from the group consisting of hydrogen, haloaralkyl and menthoxy- alkyl; and R4 is carboxylic substituted phenyl.
  • Preferred compounds of Formula ID are as follows:
  • E was achieved either by its direct alkylation with equimolar alkyl bromide (R ⁇ Z-Br), in the presence of a base, e. g., potassium carbonate, or by its reductive-amination (Rj-Z'-CHO, wherein Z is Z'-CH 2 -) using a borohydride as reducing reagents, for example, NaBH 3 CN, with equimolar aldehydes.
  • a base e. g., potassium carbonate
  • Rj-Z'-CHO reductive-amination
  • Compounds F were obtained by dialkylation of D (I ⁇ -Z-Br, or R - Y-Br), or further alkylation (R 3 - Y-Br) and/or reductive- amination (R 3 -Y'-CHO, wherein Y is Y'-CH 2 -) of E.
  • Preparation of J was achieved either by its direct alkylation of I with equimolar alkyl bromide (R*.-Z-Br), in the presence of a base, e. g., potassium carbonate, or by its reductive- amination (I ⁇ t-Z'-CHO, wherein Z is Z'-CH 2 -) using a borohydride as reducing reagents, for example, NaBH CN, with equimolar aldehydes.
  • a base e. g., potassium carbonate
  • I ⁇ t-Z'-CHO wherein Z is Z'-CH 2 -
  • Compounds K were obtained by dialkylation of I (R-j-Z-Br, or R 3 -Y-Br), or further alkylation (I-Lj-Z-Br) and/or reductive-amination (R 3 -Y'- CHO, wherein Y is Y'-CH 2 -) of J.
  • substituted 4-nitrophenol L was subjected to standard alkylation, in the presence of base, e. g., potassium carbonate, with an equimolar amount of alkyl bromide (R 3 - Y-Br) at 0 °C to 80 °C, preferably at ambient temperature to obtain M. Reduction of M was achieved by tin chloride to afford N.
  • Menthoxy-acetyl chloride A (from Aldrich) was subjected to standard amidation, in the presence of base, e. g., triethylamine, with an equimolar amount of the substituted aniline N, at 0 °C to 40 °C, preferably at ambient temperature, to give product O.
  • compound HH was prepare in a similar synthetic route as in Scheme 4.
  • base e.g., sodium hydride
  • R4-O- alkoxy group
  • Scheme 8 illustrates methods of making intermediates that are used throughout the present invention. Specifically, Scheme 8 illustrates methods of making substituted benzaldehydes, as follows: Scheme 8
  • Example 1 Preparation of 2-Hydroxy-3 - [(4- ⁇ [2-menthoxy-acetylamino] -methyl ⁇ -phenylamino methyll - benzoic acid
  • Example 5 Other compounds made using similar methods as described in Example 1 are as follows: 3-[4-( ⁇ Allyl-[2-menthoxy-acetyl]-amino ⁇ -methyl)-phenylsulfamoyl]-benzoic acid; N- [4-(2 -Hydroxy- 5 -nitro-benzylamino)-benzy 1] -2-menthoxy-acetamide ;
  • Example 5 Other compounds made using similar methods as described in Example 5 are as follows: 4- ⁇ 5-[2-Menthoxy-acetylamino]-2-methoxy-phenoxymethyl ⁇ -benzoic acid; 4- ⁇ 4-[2-Menthoxy-acetylamino]-phenoxymethyl ⁇ -benzoic acid; 4- ⁇ 2-Amino-5-[2-menthoxyacetylamino] -phenoxy ⁇ -benzoic acid; 4- ⁇ 5-[2-Menthoxy-acetylamino]-2-nitro-phenoxy ⁇ -benzoic acid; 4- ⁇ 4- [2-Menthoxy-acetylamino] -3 -trifluoromethyl-phenoxymethyl ⁇ -benzoic acid; 4- ⁇ 4-[2-Menthoxy-acetylamino]-3-trifluoromethyl-phenoxymethyl ⁇ -benzoic acid.
  • DMSO-d 6 9.2 (d, 2), 7.4 (m, 2), 7.0 (d, 1), 4.0 (m, 6), 3.5 (d, 2), 3.2 (t, 2), 3.0 (t, 2),
  • This example illustrates the preparation of representative pharmaceutical compositions for oral administration containing a compound of the present invention, or a pharmaceutically acceptable salt thereof, e.g., 3 -Hydroxy-4-[(4- ⁇ [2-menthoxy-acetylamino] methyl ⁇ - phenylamino)-methyl] -8-methoxy- 1 ,9-dimethyl- 11 -oxo- 11 H-dibenzo [b,e] [ 1 ,4] dioxepine-6- carboxylic acid: 1. Ingredients % wt./wt.
  • the above ingredients are combined and granulated using water as a granulating liquid, the formulation is then dried, mixed with the magnesium stearate and formed into tablets with an appropriate tableting machine.
  • Polyethylene glycol 400 20.0 g
  • the compound of the invention is dissolved in propylene glycol, polyethylene glycol
  • the above ingredients are melted, mixed and filled into soft elastic capsules.
  • This example illustrates the preparation of a representative pharmaceutical formulation for parenteral administration containing a compound of the invention, or a pharmaceutically acceptable salt thereof, e.g., 3 -Hydroxy-4- [(4- ⁇ [2-menthoxy-acetylamino] methyl ⁇ - phenylamino)-methyl] -8-methoxy- 1 ,9-dimethyl- 11 -oxo- 11 H-dibenzo [b,e] [ 1 ,4] dioxepine-6- carboxylic acid: Ingredients % wt./wt.
  • Polyethylene glycol 400 20.0 g
  • Polysorbate 80 1.0 g 0.9% saline solution q.s. 100 mL
  • the compound of the invention is dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80. A sufficient quantity of 0.9% saline solution is then added with stirring to provide 100 mL of the I.N. solution which is filtered through a 0.2 ⁇ membrane filter and packaged under sterile conditions.
  • This example illustrates the preparation of a representative pharmaceutical composition in suppository form containing a compound of the invention, or a pharmaceutically acceptable salt thereof, e.g., 3 -Hydroxy-4- [(4- ⁇ [2-menthoxy-acetylamino] methyl ⁇ -phenylamino)-methyl]- 8-methoxy-l,9-dimethyl-l 1-oxo-l 1 H-dibenzo [b,e][l, 4] dioxepine-6-carboxy lie acid: Ingredients % wt./wt.
  • This example illustrates the preparation of a representative pharmaceutical formulation for insufflation containing a compound of the invention, or a pharmaceutically acceptable salt thereof, e.g., 3-Hydroxy-4-[(4- ⁇ [2-menthoxy-acetylamino] methyl ⁇ -phenylamino)-methyl] -8- methoxy-l,9-dimethyl-l 1-oxo-l lH-dibenzo[b,e][l,4]dioxepine-6-carboxylic acid:
  • the ingredients are milled, mixed, and packaged in an insufflator equipped with a dosing pump.
  • This example illustrates the preparation of a representative pharmaceutical formulation in nebulized form containing a compound of the invention, or a pharmaceutically acceptable salt thereof, e.g., 3-Hydroxy-4-[(4- ⁇ [2-menthoxy-acetylamino] methyl ⁇ -phenylamino)-methyl] - 8-methoxy-l,9-dimethyl-l 1-oxo-l lH-dibenzo[b,e][l,4]dioxepine-6-carboxylic acid:
  • the compound of the invention is dissolved in ethanol and blended with water.
  • the formulation is then packaged in a nebulizer equipped with a dosing pump.
  • This example illustrates the preparation of a representative pharmaceutical formulation in aerosol form containing a compound of the invention, or a pharmaceutically acceptable salt thereof, e.g., 3 -Hydroxy-4- [(4- ⁇ [2-menthoxy-acetylamino] methyl ⁇ -phenylamino)-methyl]-8- methoxy-l,9-dimethyl-l 1-oxo-l 1 H-dibenzo [b,e][l, 4] dioxepine-6-carboxylic acid: Ingredients % wt./wt.

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)

Abstract

L'invention concerne des composés de menthol substitué et leurs sels, acceptables sur le plan pharmaceutique, utiles en tant qu'agents antithrombotiques par inhibition de l'inhibiteur 1 de l'activateur du plasminogène (PAI-1). Elle concerne, en outre, des compositions pharmaceutiques et leurs sels, acceptables sur le plan pharmaceutique, contenant des composés de menthol substitué, des dérivés des composés de menthol substitué, ainsi que des méthodes d'utilisation des composés de menthol substitué afin de traiter des états maladifs caractérisés par une activité thrombotique.
PCT/US2003/007506 2002-03-20 2003-03-12 Inhibiteurs de facteur pai-1 antithrombotique a base de menthol substitue WO2003080564A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003222278A AU2003222278A1 (en) 2002-03-20 2003-03-12 Menthol substituted antithrombotic pai-1 inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US36593202P 2002-03-20 2002-03-20
US60/365,932 2002-03-20

Publications (1)

Publication Number Publication Date
WO2003080564A1 true WO2003080564A1 (fr) 2003-10-02

Family

ID=28454727

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/007506 WO2003080564A1 (fr) 2002-03-20 2003-03-12 Inhibiteurs de facteur pai-1 antithrombotique a base de menthol substitue

Country Status (2)

Country Link
AU (1) AU2003222278A1 (fr)
WO (1) WO2003080564A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058683A2 (fr) * 2002-12-20 2004-07-15 Migenix Corp. Ligands d'adenine nucleotide translocase (ant) et compositions et methodes associees
US6936638B2 (en) 2002-12-20 2005-08-30 Migenix Corp. Ligands of adenine nucleotide translocase (ANT) and compositions and methods related thereto
WO2008144982A1 (fr) * 2007-05-29 2008-12-04 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Composés constitués d'un cycle de 7 chaînons et son utilisation pharmaceutique pour la prévention et le traitement du diabète et d'un syndrome métabolique
WO2011106273A1 (fr) * 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
CN105111118A (zh) * 2015-08-14 2015-12-02 天津小新医药科技有限公司 L-薄荷醇类p2y12受体拮抗剂、制备方法及其用途
CN105111119A (zh) * 2015-08-14 2015-12-02 天津小新医药科技有限公司 一类卤代苯l-薄荷醇类p2y12受体拮抗剂及其用途
CN105152996A (zh) * 2015-08-14 2015-12-16 天津小新医药科技有限公司 一类l-薄荷醇类p2y12受体拮抗剂及其用途
CN107935858A (zh) * 2016-10-12 2018-04-20 利尔化学股份有限公司 5‑氟‑2‑硝基苯酚的制备方法
WO2022178030A1 (fr) * 2021-02-17 2022-08-25 Concentric Analgesics, Inc. Agonistes de trpm8 utilisés en tant qu'agents de refroidissement et pour le traitement d'une maladie

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5494921A (en) * 1994-09-16 1996-02-27 Merck & Co., Inc. Fibrinogen receptor antagonists
US6121308A (en) * 1998-08-01 2000-09-19 Boehringer Ingelheim Kg Disubstituted bicyclic heterocycles, the preparation thereof and their use as pharmaceutical compositions
WO2001079193A2 (fr) * 2000-04-14 2001-10-25 Corvas International, Inc. Inhibiteurs heteroaromatiques hydrazinyl-substitues de la thrombine
WO2003002519A1 (fr) * 2001-06-29 2003-01-09 Bayer Aktiengesellschaft Derives phenoles et leur utilisation dans des medicaments

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5494921A (en) * 1994-09-16 1996-02-27 Merck & Co., Inc. Fibrinogen receptor antagonists
US6121308A (en) * 1998-08-01 2000-09-19 Boehringer Ingelheim Kg Disubstituted bicyclic heterocycles, the preparation thereof and their use as pharmaceutical compositions
WO2001079193A2 (fr) * 2000-04-14 2001-10-25 Corvas International, Inc. Inhibiteurs heteroaromatiques hydrazinyl-substitues de la thrombine
WO2003002519A1 (fr) * 2001-06-29 2003-01-09 Bayer Aktiengesellschaft Derives phenoles et leur utilisation dans des medicaments

Non-Patent Citations (19)

* Cited by examiner, † Cited by third party
Title
BRIMBLE M A ET AL: "Addition of Cyclopentadiene and 2-Trimethylsilyloxyfuran to Quinones Bearing a Menthyl Ester Chiral Auxiliary", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 54, no. 20, 14 May 1998 (1998-05-14), pages 5363 - 5374, XP004116437, ISSN: 0040-4020 *
CHONG, J. M. ET AL, JOURNAL OF ORGANIC CHEMISTRY., vol. 58, no. 25, 1993, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC., US, pages 7300 - 7303, ISSN: 0022-3263 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002250240, Database accession no. 4745018 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002250241, Database accession no. 17185 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002250242, Database accession no. 6656515 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002250243, Database accession no. 3206656 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002250244, Database accession no. 3200940 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002250245, Database accession no. 3143538 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002250246, Database accession no. 3750786 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002250247, Database accession no. 3175857 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002250248, Database accession no. 3156332 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002250249, retrieved from 3147711 *
FORSTER ET AL, JOURNAL OF THE CHEMICAL SOCIETY., vol. 99, 1911, CHEMICAL SOCIETY, LONDON, GB, pages 1339, ISSN: 0368-1769 *
HOLMES; ADAMS, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 56, 1934, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC., US, pages 2093, ISSN: 0002-7863 *
HUECKEL, K ET AL, CHEMISCHE BERICHTE., vol. 91, 1958, VERLAG CHEMIE GMBH. WEINHEIM., DE, pages 311 - 319, ISSN: 0009-2940 *
KISSMAN, T, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 74, 1952, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC., US, pages 4317, ISSN: 0002-7863 *
RULE ET AL, JOURNAL OF THE CHEMICAL SOCIETY., 1931, CHEMICAL SOCIETY, LONDON, GB, pages 1478 - 1481, ISSN: 0368-1769 *
RULE, T, JOURNAL OF THE CHEMICAL SOCIETY., 1931, CHEMICAL SOCIETY, LONDON, GB, pages 1929 - 1933, ISSN: 0368-1769 *
UMEMOTO, T ET AL, BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN., vol. 64, no. 4, 1991, JAPAN PUBLICATIONS TRADING CO. TOKYO., JP, pages 1081 - 1092, ISSN: 0009-2673 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058683A2 (fr) * 2002-12-20 2004-07-15 Migenix Corp. Ligands d'adenine nucleotide translocase (ant) et compositions et methodes associees
WO2004058683A3 (fr) * 2002-12-20 2004-09-30 Mitokor Inc Ligands d'adenine nucleotide translocase (ant) et compositions et methodes associees
US6936638B2 (en) 2002-12-20 2005-08-30 Migenix Corp. Ligands of adenine nucleotide translocase (ANT) and compositions and methods related thereto
WO2008144982A1 (fr) * 2007-05-29 2008-12-04 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Composés constitués d'un cycle de 7 chaînons et son utilisation pharmaceutique pour la prévention et le traitement du diabète et d'un syndrome métabolique
US8158623B2 (en) 2007-05-29 2012-04-17 Shanghai Institute Of Materia Medica Chinese Academy Of Sciences Heptacyclic compounds and the pharmaceutical uses thereof for preventing and treating diabetes and metabolic syndrome
EA018657B1 (ru) * 2007-05-29 2013-09-30 Шангхай Инститьют Оф Матириа Медика, Чайниз Акэдеми Оф Сайнсиз Соединения с семичленным кольцом и их применение для предупреждения и лечения диабета и метаболического синдрома
WO2011106273A1 (fr) * 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
CN105111118A (zh) * 2015-08-14 2015-12-02 天津小新医药科技有限公司 L-薄荷醇类p2y12受体拮抗剂、制备方法及其用途
CN105111119A (zh) * 2015-08-14 2015-12-02 天津小新医药科技有限公司 一类卤代苯l-薄荷醇类p2y12受体拮抗剂及其用途
CN105152996A (zh) * 2015-08-14 2015-12-16 天津小新医药科技有限公司 一类l-薄荷醇类p2y12受体拮抗剂及其用途
CN107935858A (zh) * 2016-10-12 2018-04-20 利尔化学股份有限公司 5‑氟‑2‑硝基苯酚的制备方法
WO2022178030A1 (fr) * 2021-02-17 2022-08-25 Concentric Analgesics, Inc. Agonistes de trpm8 utilisés en tant qu'agents de refroidissement et pour le traitement d'une maladie

Also Published As

Publication number Publication date
AU2003222278A1 (en) 2003-10-08

Similar Documents

Publication Publication Date Title
US7858645B2 (en) Indazole derivatives
US7700628B2 (en) Aromatic ether derivatives useful as thrombin inhibitors
US8222248B2 (en) Organic compounds
US5451677A (en) Substituted phenyl sulfonamides as selective β 3 agonists for the treatment of diabetes and obesity
ES2375522T3 (es) Nuevo derivado de n-(2-aminofenil)benzamida con estructura urea.
US20090062294A1 (en) Heteroaryl-substituted urea modulators of fatty acid amide hydrolase
US20060116410A1 (en) 4-Aminomethyl benzamidine derivatives
US20060035939A1 (en) 3-Aminobenzamide compounds and inhibitors of vanilloid receptor subtype 1 (VR1) activity
US8012972B2 (en) Pyridinecarboxylic acid (2-aminophenyl) amide derivative having urea structure
KR20000070568A (ko) 당뇨병 및 비만 치료를 위한 β3 효능제로서의 티아졸 벤젠설폰아미드
KR20010031557A (ko) 치환 아닐리드
FR2884516A1 (fr) Antagonistes npy, preparation et utilisations
CZ187397A3 (en) Derivative of arylsulfonamide and heteroarylsulfonamide, process of its preparation and use
US20070276011A1 (en) Plasminogen Activator Inhibitor-1 Inhibitor
JP2008266322A (ja) ヒストン脱アセチル化酵素阻害作用を有する化合物を有効成分として含有する眼圧下降剤
WO2003080060A1 (fr) Inhibiteurs antithrombotiques de pai-1, a base de piperazine substituee
WO2003080564A1 (fr) Inhibiteurs de facteur pai-1 antithrombotique a base de menthol substitue
JPWO2002046161A1 (ja) 置換カルボン酸誘導体
RU2655170C2 (ru) Производные 1-фенил-2-пиридинилалкиловых спиртов в качестве ингибиторов фосфодиэстеразы
JP2009137997A (ja) Ｍｍｐ阻害剤として使用するためのアザシクロアルキル置換酢酸誘導体
JP2005517641A (ja) ムスカリン受容体アンタゴニストとしての４−ピペリジニルアルキルアミン誘導体
US7999000B2 (en) N-(2-amino-phenyl)-acrylamides
WO1999024395A1 (fr) Composes inhibant l'activite de la tryptase
MX2007015867A (es) Derivados del acido antranilico.
US20050043304A1 (en) Novel amine derivative having human beta-tryptase inhibitory activity and drugs containing the same

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP