WO2003080060A1 - Substituted piperazine antithrombotic pai-1 inhibitors - Google Patents

Substituted piperazine antithrombotic pai-1 inhibitors Download PDF

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WO2003080060A1
WO2003080060A1 PCT/US2003/007508 US0307508W WO03080060A1 WO 2003080060 A1 WO2003080060 A1 WO 2003080060A1 US 0307508 W US0307508 W US 0307508W WO 03080060 A1 WO03080060 A1 WO 03080060A1
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carboxylic acid
substituted
optionally substituted
nitro
trifluoromethyl
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PCT/US2003/007508
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French (fr)
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Yuo-Ling Chou
Ameen Ghannam
Monica J. Kochanny
Wheeseong Lee
Shou-Fu Lu
Kenneth J. Shaw
Bin Ye
Zuchun Zhao
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Schering Aktiengesellschaft
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Priority to AU2003220184A priority Critical patent/AU2003220184A1/en
Publication of WO2003080060A1 publication Critical patent/WO2003080060A1/en

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Definitions

  • the present invention relates to substituted piperazine compounds and their pharmaceutically acceptable salts which 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 substituted piperazine compounds, derivatives of the substituted piperazine 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 fibrino lysis 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 uPA convert plasminogen to plasmin which in turn degrades fibrin, as follows:
  • 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 endothelial 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 it 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 benzothiophenobenzofuran- 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 IC 50 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 PAIL-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 fibrino lysis and are therefore useful as pharmacological agents for the treatment of disease states characterized by thrombotic activity.
  • the present invention relates to substituted piperazine 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:
  • RI represents one or more substituents and is selected from the group consisting of hydrogen, haloalkyl, halo, and nitro;
  • X, Y and Z are each independently either C or N;
  • A is absent or present and is selected from the group consisting of methylene, carbonyl, and alkylaminocarbonyl
  • B is either absent or present and is selected from the group consisting of alkylaminocarbonyl, methylene and carbonylalkylester
  • R2 represents one or more substituents and is selected from the group consisting halo, nitro, carboxylic acid, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, carboxamide,
  • 10 D is either N or O
  • R3 is selected from the group consisting of optionally substituted aryl (optionally substituted by carboxylic acid, nitro, carboxylic acid substituted aralkoxy, carboxylic acid substituted alkoxy, optionally substituted aryloxyalkanyl (optionally substituted by carboxylic acid, alkoxy and nitro)), substituted aralkyl (optionally substituted by hydroxy, alkoxy, nitro,
  • carboxylic acid substituted pyrrolidinyl optionally substituted by carboxylic acid
  • carboxylic acid substituted piperidinyl optionally substituted by carboxylic acid
  • carboxylic acid substituted pyradinyloxy optionally substituted by carboxylic acid
  • R4 is present when D is N and further is selected from the group consisting of halo, nitro, carboxylic acid, alkyl, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, menthoxy alkyl 5 carbonyl amino, alkoxy, carbonyl amino, optionally substituted aralkylamino (optionally substituted by phenoxy (optionally substituted by nitro, and/or carboxylic acid), alkyl ester, alkoxy, optionally substituted aralkyl (optionally substituted by carboxylic acid and/or nitro), alkylaminocarbonyl, carboxylic acid substituted pyridinyloxy, and alkyl phosphonic acid; or R3 and R4 form an optionally substituted piperydinyl or pyrrolidinyl (optionally
  • R2 and R3 form a dioxo-substituted heterocyclic ring with the phenyl group (when Y and Z are C) wherein said heterocylic ring is substituted by methylphosphonic acid; 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 R b 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.
  • Halo 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, 3-bromo-2-fluoropropyl, and the like.
  • Haloalkoxy refers to a radical of the formula -OR f , where R f is haloalkyl as defined above, e.g., 2-trifiuoromethoxy, difiuoromethoxy, trichloromethoxy, 2-trifiuoroethoxy, 3- bromo-2-fiuoropropoxy, and the like.
  • “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.
  • 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, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N- ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine,
  • “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: (i) preventing the disease-state from occurring in a human, in particular, when such human is predisposed to the disease-state but has not yet been diagnosed as having it; (ii) inhibiting the disease-state, i.e., arresting its development; or (iii) relieving the disease-state, i.e., causing regression of the disease-state.
  • the disease state may comprise, for example, unstable angina, myocardial infarction, cerebral thromboembolism, transient ischemic attack, stroke, DVT, and coronory reocclusion after thrombolytic therapy, among others related to thrombotic activity.
  • 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 fibrosis.
  • fibrosis such as, but not limited to, idiopathic and drug-induced pulmonary fibrosis, hepatic fibrosis and systemic fibrosis.
  • 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.
  • Each compound listed herein has been demonstrated to inhibit the activity of PAI-1 5 either by an in vitro or an in vivo assay or both. Specifically, the present compounds have been demonstrated to have IC 50 values of less than about 15 ⁇ M.
  • PAI-1 inhibitors of the present invention To screen small molecule PAI-1 inhibitors of the present invention, a chromogenic in vitro assay was developed in which human PAI-1 activity is measured by inhibition of uPA-
  • 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).
  • 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 lOmg 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 a substituted piperazine base molecule. More specifically, the present invention relates to a disubstituted piperazine base molecule, as shown below:
  • a preferred group of compounds having the general substituted piperazine structure as noted above is that group wherein the compounds are selected from formula (I), as shown below:
  • RI represents one or more substituents and is selected from the group consisting of hydrogen, haloalkyl, halo, and nitro;
  • X, Y and Z are each independently either C or N;
  • A is absent or present and is selected from the group consisting of methylene, carbonyl, and alkylaminocarbonyl;
  • B is either absent or present and is selected from the group consisting of alkylaminocarbonyl, methylene and carbonylalkylester;
  • R2 represents one or more substituents and is selected from the group consisting halo, nitro, carboxylic acid, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, carboxamide, carbamoyl, alkoxyaminocarbonyl, substituted aralkylamino (optionally substituted by substituted phenoxy (optionally substituted by nitro, carboxylic acid or alkyl ester), carboxylic acid substituted pyridinyloxy, or alkoxy), substituted aryloxy (substituted by pyridinyl), substituted piperazinyl (optionally substituted by substituted aryl (optionally substituted by haloalkyl)), imidazolyl, and pyridinyloxy;
  • D is either N or O;
  • R3 is selected from the group consisting of optionally substituted aryl (optionally substituted by carboxylic acid, nitro, carboxylic acid substituted aralkoxy, carboxylic acid substituted alkoxy, optionally substituted aryloxyalkanyl (optionally substituted by carboxylic acid, alkoxy and nitro)), substituted aralkyl (optionally substituted by hydroxy, alkoxy, nitro, carboxylic acid, carboxylic acid substituted aryloxy, nicotonic acid, optionally substituted aryloxy (optionally substituted by nitro and/or carboxylic acid), and carboxylic acid substituted alkyl ester), carboxylic acid substituted cyclohexanyl, carboxylic acid substituted alkyl, optionally substituted piperazinyl (optionally substituted by carboxylic acid substituted aralkyl), alkoxy (optionally substituted by carboxylic acid), optionally substituted aralkyloxy (optionally substituted by carboxylic acid), carb
  • R4 is present when D is N and further is selected from the group consisting of halo, nitro, carboxylic acid, alkyl, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, menthoxy alkyl carbonyl amino, alkoxy, carbonyl amino, optionally substituted aralkylamino (optionally substituted by phenoxy (optionally substituted by nitro, and/or carboxylic acid), alkyl ester, alkoxy, optionally substituted aralkyl (optionally substituted by carboxylic acid and/or nitro), alkylaminocarbonyl, carboxylic acid substituted pyridinyloxy, and alkyl phosphonic acid; or R3 and R4 form an optionally substituted piperydinyl or pyrrolidinyl (optionally substituted by carboxylic acid, carboxylic acid ester, nitro, and aminocarbonyl alkyl carboxylic acid) when D is N; or R2 and R3
  • a preferred subgroup of compounds is that subgroup of compounds of Formula I wherein D is N and is substituted at the meta position of the phenyl or heteroaromatic ring structure.
  • This preferred subgroup of compounds is, therefore, selected from compounds of the following Formula IA:
  • RI represents one or more substituents and further is selected from the group consisting of haloalkyl, halo, and nitro;
  • A is either aminocarbonyl, methylene or carbonyl; 5 B is absent;
  • X, Y and Z are each independently either C or N;
  • R2 is selected from the group consisting of halo, nitro, carboxylic acid, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, carbamoyl, carboxamide, alkoxyaminocarbonyl, optionally substituted aralkylamino (optionally substituted by optionally substituted phenoxy i 0 (optionally substituted by nitro or carboxylic acid), alkyl ester, alkoxy, or optionally substituted pyridinyloxy (optionally substituted by carboxylic acid);
  • R3 is hydrogen, or optionally substituted aralkyl (optionally substituted by carboxylic acid or nitro);
  • R4 is present when D is N and further is selected from the group consisting of 15 substituted aralkyl (optionally substituted by alkoxy, nitro, carboxylic acid or carboxylic acid substituted aryloxy), carboxylic acid substituted cyclohexanyl, carboxylic acid substituted alkyl, optionally substituted piperazinyl (substituted by carboxylic acid substituted aralkyl), and alkylphosphonic acid; or R3 and R4 form an optionally substituted piperidinyl or pyrrolidinyl (optionally .0 substituted by carboxylic acid, carboxylic acid ester, nitro, and aminocarbonyl alkyl carboxylic acid) when D is N; or R2 and R3 form a dioxo-substituted heterocyclic ring with the phenyl group (when Y and Z are C) wherein said heterocylic ring is substituted by methylphosphonic acid.
  • Particularly preferred compounds of this subgroup of compounds are selected from the 5 following:
  • Another preferred subgroup of Formula I is that group of compounds wherein D is N and R3 and R4 form a substituted piperidinyl, as follows:
  • A is either aminocarbonyl, methylene or carbonyl; B is absent;
  • X, Y and Z are each independently either C or N;
  • R2 is selected from the group consisting of halo, nitro, carboxylic acid, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, carboxamide, alkoxyaminocarbonyl, optionally substituted aralkylamino (optionally substituted by optionally substituted phenoxy (optionally substituted by nitro or carboxylic acid), alkyl ester, alkoxy, or optionally substituted pyridinyloxy (optionally substituted by carboxylic acid); and
  • R5 is substituted one or more times by carboxylic acid, carboxylic acid ester, nitro, and/or carbonyl amino alkyl carboxylic acid.
  • Particularly preferred compounds of this subgroup of compounds are selected from the following:
  • Another preferred subgroup of Formula I is that group of compounds wherein D is N and R3 and R4 form an optionally substituted pyrrolidinyl, as shown below as Formula IC:
  • RI is hydrogen or haloalkyl
  • X, Y and Z are each independently either C or N;
  • R2 is substituted one or more times and is selected from the group consisting of nitro and haloalkyl; and R6 is carboxylic acid.
  • Particularly preferred compounds of this subgroup of compounds are selected from the following:
  • Another preferred subgroup of Formula I is that group of compounds of Formula ID, as shown below:
  • B is absent or present and when present is carbonylmethylether
  • X, Y and Z are each independently either C or N;
  • R2 is substituted one or more time and is selected from the group consisting of pyrrolidinyl, nitro, haloalkyl, aralkylamino, optionally substituted aryloxy (optionally substituted by pyridinyl), optionally substituted piperazinyl (optionally substituted by haloalkyl substituted aryl), imidazolyl, and pyridinyloxy;
  • R3 is selected from the group consisting of optionally substituted aralkyl (optionally substituted by hydroxy, haloalkyl, carboxylic acid, halo, nitro, optionally substituted aryloxy (optionally substituted by carboxylic acid, halo and/or nitro)), alkoxy, carboxylic acid substituted aralkoxy, carboxylic acid substituted pyrrolidinyl, carboxylic acid substituted piperidinyl, carboxylic acid substituted alkoxy, and carboxylic acid substituted pyridinyloxy; and
  • R4 is selected from the group consisting of optionally substituted aralkyl (optionally substituted by carboxylic acid and/or nitro), alkyl, and alkyl amino carbonyl.
  • Particularly preferred compounds of this subgroup of compounds are selected from the following: 2- ⁇ 4-[Bis-(2-hydroxy-5-nitro-benzyl)-amino]-phenoxy ⁇ -l-[4-(3-trifluoromethyl-phenyl)- piperazin- 1 -yl]-ethanone; 2-[4-Nitro-2-( ⁇ 3 -trifluoromethyl -4- [4-(3 -trifluoromethyl-pheny l)-piperazin- 1 -yl] - phenylamino ⁇ -methyl)-phenoxy] -benzoic acid; 6-[2-Methoxy-6-( ⁇ 3-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino ⁇ -methyl)-phenoxy] -nicotinic acid; 2- [2-Methoxy-6-( ⁇ 3 -trifluoromethyl-4-[4-(3
  • Formula IE wherein RI is substituted one or more times and is selected from the group consisting of haloalkyl, halo, and nitro; A is absent or present and when present is aminocarbonyl, methylene and carbonyl;
  • B is absent or present and when present is alkylaminocarbonyl;
  • X, Y and Z are each independently either C or N;
  • R2 is substituted one or more times and is selected from the group consisting of alkyl ester, haloalkyl, alkylaminocarbonyl, and nitro; and R3 is selected from the group consisting of optionally substituted aralkyl (optionally substituted by carboxylic acid and/or nitro), optionally substituted aryl (optionally substituted by carboxylic acid, nitro, carboxylic acid substituted aralkoxy, carboxylic acid substituted alkoxy, optionally substituted aryloxyalkyl (optionally substituted by carboxylic acid, alkoxy and/or nitro), and carboxylic acid substituted pyridinyl.
  • Preferred compounds having the generic formula IE are shown as follows:
  • A preferably N-(3 -trifluoromethy lphenyl)piperazine (from Aldrich) was subjected to react with an equimolar amount of substituted fluoro-nitrobenzene B, in the presence of base, e. g., triethylamine, at 0 °C to 40 °C, preferably at ambient temperature, to obtain C.
  • base e. g., triethylamine
  • R' 3 -CH 2 Br direct alkylation
  • R' 3 -CHO reductive amination
  • A (preferably N-(3-trifluoromethylphenyl)piperazine) (from Aldrich) was subjected to react with an equimolar amount of substituted benzene or substituted pyridine G, in the presence of base, e. g., triethylamine, at 0 °C to 40 °C, preferably at ambient temperature, to obtain H.
  • base e. g., triethylamine
  • A (preferably N-(3-trifluoromethylphenyl)piperazine) (from Aldrich) was subjected to react with an equimolar amount of substituted fluorobenzene K, in the presence of base, e. g., triethylamine, at 0 °C to 40 °C, preferably at ambient temperature, to obtain M.
  • base e. g., triethylamine
  • compound A preferably N-(3-trifluoromethylphenyl)piperazine (from Aldrich) was subjected to react with an equimolar amount of substituted benzene or heteroaromatic L, in the presence of base, e. g., triethylamine, at 0 °C to 40 °C, preferably at ambient temperature, to obtain M.
  • base e. g., triethylamine
  • Scheme 5 Select compounds from Formulas IA, IB, ID and IE: Select compounds of Formulas IA, IB, ID and IE may be made by the synthesis method described below as Scheme 5. Although Scheme 5 is specific to compounds of Formula IB, select compounds of Formulas I A, ID and IE may also be made using this synthetic scheme: Scheme 5.
  • n is either 1 or 2.
  • Example 1 Preparation of 4-( ⁇ 2,4-Dinitro-5-[4-(3-trifluoromethyl-phenyl -piperazin-l-yl1- phenylaminol-methvD-benzoic acid
  • compositions for oral administration containing a compound of the present invention, or a pharmaceutically acceptable salt thereof, e.g, l- ⁇ 4-nitro-2-trifluoromethyl-5-[4-(2-trifluoromethyl- phenylcarbamoyl)-piperazin- 1 -yl] -phenyl ⁇ -piperidine-4-carboxylic acid:
  • 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 400 and polysorbate 80. A sufficient quantity of water is then added with stirring to provide 100 mL of the solution which is filtered and bottled.
  • the above ingredients are melted, mixed and filled into soft elastic capsules.
  • the compound of the invention is dissolved in the cellulose/saline solution, filtered and bottled for use.
  • 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, l- ⁇ 4-nitro-2- trifluoromethyl-5-[4-(2-trifluoromethyl- pheny lcarbamoyl)-piperazin- 1 -y 1] -phenyl ⁇ -piperidine-4-carboxylic acid :
  • Polyethylene glycol 400 20.0 g
  • 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.
  • Example 10 Preparation of Representative Pharmaceutical Compositions in Suppository Form
  • a representative pharmaceutical composition in suppository form containing a compound of the invention, or a pharmaceutically acceptable salt thereof, e.g, l- ⁇ 4-nitro-2-trifluoromethyl-5-[4-(2-trifluoromethyl-phenylcarbamoyl)- piperazin- 1 -yl] -phenyl ⁇ -piperidine-4-carboxylic acid : Ingredients % wt./wt.
  • the ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight.
  • Example 11 Preparation of Representative Pharmaceutical Compositions for Insufflation 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, 1 - ⁇ 4- ⁇ itro-2-trifluoromethyl-5-[4-(2-trifluoromethyl-phenylcarbamoyl)- piperazin- 1 -yl] -phenyl ⁇ -piperidine-4-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, l- ⁇ 4-nitro-2-trifluoromethyl-5-[4-(2-trifluoromethyl-phenylcarbamoyl)- piperazin-l-yl]-phenyl ⁇ -piperidine-4-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, l- ⁇ 4-nitro-2-trifluoromethyl-5-[4-(2-trifluoromethyl-phenylcarbamoyl)-piperazin- 1-yl] -phenyl ⁇ -piperidine-4-carboxylic acid:

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Abstract

This invention is directed to substituted piperazine compounds of formula (I) and their pharmaceutically acceptable salts which are useful as antithrombotic agents by inhibiting plasminogen activator inhibitor-1 (PAI-1). In addition, the present invention relates to pharmaceutical compositions and their pharmaceutically acceptable salts, containing the substituted piperazine compounds, derivatives of the substituted piperazine compounds, and methods of using the compounds to treat disease-states characterized by thrombotic activity.

Description

SUBSTITUTED PIPERAZINE ANTITHROMBOTIC PAI-1 INHIBITORS
Field of the Invention
The present invention relates to substituted piperazine compounds and their pharmaceutically acceptable salts which are useful as antithrombotic agents by inhibiting plasminogen activator inhibitor- 1 (PAI-1). In addition, the present invention relates to pharmaceutical compositions and their pharmaceutically acceptable salts containing the substituted piperazine compounds, derivatives of the substituted piperazine compounds, and methods of use. Background of the Invention
Thrombotic 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.
Generally, 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. Currently marketed 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 fibrino lysis 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 uPA convert plasminogen to plasmin which in turn degrades fibrin, as follows:
PAI-1 inhibitors
PAI-1
Plasminogen
Figure imgf000003_0001
Plasmin
Fibrin
Figure imgf000003_0002
Fibrin degradation products
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. As a member of the serine protease inhibitor (serpin) superfamily, 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. In patients with recent onset unstable angina, subsequent cardiovascular events such as acute myocardial infarction and severe recurrent angina correlated closely with increased plasma PAI-1 activity. In addition, 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. Further, PAI-1 is also implicated in cancer progression and invasion. 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, such as antiplatelet and anticoagulant drugs, have presented a major challenge in reducing angiographic reocclusion. In fact, 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.
The anti-thrombotic effects of 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.
In addition, several drugs have been reported that inhibit PAI-1 secretion or production in endothelial cells. Fibrates, for example, are a class of compounds widely used to lower plasma cholesterol and triglycerides in hyperlipidemic patients. In addition, 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 endothelial 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 it 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.
To date, several small molecules have been identified that directly inhibit human PAI-1 activity. For example, compounds derived from microbial metabolites, such as diketopiperazine-based compounds, were found to inhibit PAI-1 activity. In amidolytic assays, these compounds inhibited PAI-1 activity with IC50 values ranging from 3.5 to 80 μM. However, it is not clear whether these compounds directly block PAI-1 binding to tPA or convert active PAI-1 to latent PAI-1.
In addition, another small molecule PAI-1 inhibitor has been developed from flufenamic acid. Further, a series of benzothiophenobenzofuran- 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.
In addition to small molecules that directly inhibit PAI-1 activity, other molecules were reported to inhibit PAI-1 production. In general, these molecules are neither potent nor specific. For example, in tissue culture, gemfibrozil (lOOμM) 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 PAIL-1 synthesis by cultured hepatocytes (HepG2), although effective concentrations required for gemfibrozil were much higher (750μM). When administered in rabbits, both gemfibrozil and niacin inhibited PAI-1 mRNA expression in the liver and reduced plasma PAI-1 concentrations in the animals. In other studies, attempts were made to use antisens oligonucleotides to block PAI-1 production in human endothelial cells or smooth muscle cells. It is very unlikely that an anti-PAI-1 drug for chronic use could be developed based on an antisens strategy.
More recently, Vingradsky et al. reported another compound, (3E, 4E)-3-benzylidene-4- (3,4,5-trimethoxy-benzylidene)-pyrrolidine-2,5-dione (T-686), as a novel PAI-1 inhibitor. In cultured human umbilical vein endothelial cells, T-686 (lOμM) reduced basal production of PAI-1 by 32%. T-686 also attenuated TGF-B induced PAI-1 expression in these cells. In hypercholesterolemic rabbits, oral administration of T-686 (30mg/kg/day) lowered plasma PAI- 1 levels and reduced atherosclerotic lesion area by 19%. These studies support the concept that inhibition of PAI-1 is a useful therapeutic strategy for prevention of atherothrombotic diseases. Therefore, 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. In addition, 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. Summary of the Invention
The present invention relates to antithrombotic molecules that act as PAI-1 inhibitors in fibrino lysis and are therefore useful as pharmacological agents for the treatment of disease states characterized by thrombotic activity. Specifically, the present invention relates to substituted piperazine compounds and their pharmaceutically acceptable salts that are useful as antithrombotic agents that inhibit PAI-1 in fibrinolysis.
To this end, in an embodiment of the present invention, the invention provides compounds selected from the group consisting of the following formula:
Figure imgf000006_0001
Formula I wherein:
RI represents one or more substituents and is selected from the group consisting of hydrogen, haloalkyl, halo, and nitro;
X, Y and Z are each independently either C or N;
A is absent or present and is selected from the group consisting of methylene, carbonyl, and alkylaminocarbonyl; B is either absent or present and is selected from the group consisting of alkylaminocarbonyl, methylene and carbonylalkylester;
R2 represents one or more substituents and is selected from the group consisting halo, nitro, carboxylic acid, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, carboxamide,
5 carbamoyl, alkoxyaminocarbonyl, substituted aralkylamino (optionally substituted by substituted phenoxy (optionally substituted by nitro, carboxylic acid or alkyl ester), carboxylic acid substituted pyridinyloxy, or alkoxy), substituted aryloxy (substituted by pyridinyl), substituted piperazinyl (optionally substituted by substituted aryl (optionally substituted by haloalkyl)), imidazolyl, and pyridinyloxy;
10 D is either N or O;
R3 is selected from the group consisting of optionally substituted aryl (optionally substituted by carboxylic acid, nitro, carboxylic acid substituted aralkoxy, carboxylic acid substituted alkoxy, optionally substituted aryloxyalkanyl (optionally substituted by carboxylic acid, alkoxy and nitro)), substituted aralkyl (optionally substituted by hydroxy, alkoxy, nitro,
[ 5 carboxylic acid, carboxylic acid substituted aryloxy, nicotonic acid, optionally substituted aryloxy (optionally substituted by nitro and/or carboxylic acid), and carboxylic acid substituted alkyl ester), carboxylic acid substituted cyclohexanyl, carboxylic acid substituted alkyl, optionally substituted piperazinyl (optionally substituted by carboxylic acid substituted aralkyl), alkoxy (optionally substituted by carboxylic acid), optionally substituted aralkyloxy
.0 (optionally substituted by carboxylic acid), carboxylic acid substituted pyrrolidinyl, carboxylic acid substituted piperidinyl, carboxylic acid substituted pyradinyloxy, and carboxylic acid substituted pyradinyl; and
R4 is present when D is N and further is selected from the group consisting of halo, nitro, carboxylic acid, alkyl, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, menthoxy alkyl 5 carbonyl amino, alkoxy, carbonyl amino, optionally substituted aralkylamino (optionally substituted by phenoxy (optionally substituted by nitro, and/or carboxylic acid), alkyl ester, alkoxy, optionally substituted aralkyl (optionally substituted by carboxylic acid and/or nitro), alkylaminocarbonyl, carboxylic acid substituted pyridinyloxy, and alkyl phosphonic acid; or R3 and R4 form an optionally substituted piperydinyl or pyrrolidinyl (optionally
30 substituted by carboxylic acid, carboxylic acid ester, nitro, and aminocarbonyl alkyl carboxylic acid) when D is N; or R2 and R3 form a dioxo-substituted heterocyclic ring with the phenyl group (when Y and Z are C) wherein said heterocylic ring is substituted by methylphosphonic acid; as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In another aspect, 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.
In another aspect, 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.
In another aspect, 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.
In another aspect, 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. Detailed Description of the Presently Preferred Embodiments A. Definitions As used in the specification and/or the appended claims, unless specified to the contrary, the following terms have the meaning indicated:
"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 -ORa, where Ra 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 -RaRb where Ra 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. "Halo" 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, 3-bromo-2-fluoropropyl, and the like.
"Haloalkoxy" refers to a radical of the formula -ORf, where Rf is haloalkyl as defined above, e.g., 2-trifiuoromethoxy, difiuoromethoxy, trichloromethoxy, 2-trifiuoroethoxy, 3- bromo-2-fiuoropropoxy, and the like.
"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.
"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, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N- ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline and caffeine. "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: (i) preventing the disease-state from occurring in a human, in particular, when such human is predisposed to the disease-state but has not yet been diagnosed as having it; (ii) inhibiting the disease-state, i.e., arresting its development; or (iii) relieving the disease-state, i.e., causing regression of the disease-state. The disease state may comprise, for example, unstable angina, myocardial infarction, cerebral thromboembolism, transient ischemic attack, stroke, DVT, and coronory reocclusion after thrombolytic therapy, among others related to thrombotic activity.
The yield of each of the reactions described herein is expressed as a percentage of the theoretical yield.
The compounds of the invention, or their pharmaceutically acceptable salts, 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 nomenclature used herein is a modified form of the I.U.P.A.C. system wherein the compounds of the invention are named as derivatives of piperazine, as defined above. For example, a compound of the invention selected from formula I wherein RI is trifluoromethyl; A is absent; B is absent; R2 is nitro; D is N; R3 is carboxylic acid substituted cyclohexanyl; and R4 is hydrogen, i.e.:
Figure imgf000011_0001
is 4- { 4-nitro-3 - [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenylamino } - cyclohexanecarboxylic acid. B. Utility
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 fibrosis. 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.
Each compound listed herein has been demonstrated to inhibit the activity of PAI-1 5 either by an in vitro or an in vivo assay or both. Specifically, the present compounds have been demonstrated to have IC50 values of less than about 15μM.
C. Testing
To screen small molecule PAI-1 inhibitors of the present invention, a chromogenic in vitro assay was developed in which human PAI-1 activity is measured by inhibition of uPA-
[ 0 dependent substrate hydrolysis. In this assay, human uPA (30nM), and human recombinant PAI-1 (8nm) were incubated in a reaction mixture containing 50nM Tris-HCl (pH=7.5), 140 nM NaCl, 2.5 nM CaCl2 and 0.1% polyethylene glycol (PEG). 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
15 at 405 nm.
Additionally, an in vivo fibrin clot lysis assay was developed. The fibrin clot lysis assay was used to evaluate the potency of small molecule PAI-1 inhibitors. In this assay, pooled human plasma was diluted (1 :3) in a buffer containing 150 nM NaCl, 2 nM CaCl2, 20 mM Hepes, pH 7.4. Fibrin clot formation was initiated by the addition of human thrombin (30 nM).
10 The newly formed fibrin clot remained stable at 37°C for at least two hours. If exogenous human tPA (4 nM) was included in the assay, the clot would be lysed within 20 minutes at 37°C, which has a monitored optical absorbance at 405 ran. In the presence of recombinant human or rat PAI-1 (4.3 nM), the activity of tPA was reduced and clot lysis time was delayed. When both PAI-1 and PAI-1 inhibitors were added, the PAI-1 activity was significantly
.5 inhibited, as demonstrated by shorted clot lysis times. The inhibition of PAI-1 by small molecule compounds was dose dependent. The IC50 values were determined for each compound. In control studies, PAI-1 inhibitors did not affect the tPA-dependent clot lysis in the absence of PAI-1 under the same experimental conditions.
D. General Administration
30 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. Thus, 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.
Generally, depending on the intended mode of administration, 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.
Preferably, 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.
The preferred route of administration is oral, using a convenient daily dosage regimen which can be adjusted according to the degree of severity of the disease state to be treated. For such oral administration, 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. 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.
Preferably, such 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.
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. For example, 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.
If desired, 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.
Actual methods of preparing such dosage forms are known and are apparent, to those skilled in the art. For example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Co., Easton, Pennsylvania, 1990). The 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. Generally, 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. Preferably, the pharmaceutical composition includes from about 0.7 mg to about 10 mg/kg of body weight per day. For example, for administration to a 70 kg person, the dosage would be about lOmg to about 1.0 gram per day of a compound of the invention. More preferably, 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. E. Compounds as PAI-1 inhibitors Preferred Embodiments
The present invention relates to compounds having a substituted piperazine base molecule. More specifically, the present invention relates to a disubstituted piperazine base molecule, as shown below:
Figure imgf000015_0001
A preferred group of compounds having the general substituted piperazine structure as noted above is that group wherein the compounds are selected from formula (I), as shown below:
Figure imgf000015_0002
Formula I wherein:
RI represents one or more substituents and is selected from the group consisting of hydrogen, haloalkyl, halo, and nitro; X, Y and Z are each independently either C or N;
A is absent or present and is selected from the group consisting of methylene, carbonyl, and alkylaminocarbonyl;
B is either absent or present and is selected from the group consisting of alkylaminocarbonyl, methylene and carbonylalkylester; R2 represents one or more substituents and is selected from the group consisting halo, nitro, carboxylic acid, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, carboxamide, carbamoyl, alkoxyaminocarbonyl, substituted aralkylamino (optionally substituted by substituted phenoxy (optionally substituted by nitro, carboxylic acid or alkyl ester), carboxylic acid substituted pyridinyloxy, or alkoxy), substituted aryloxy (substituted by pyridinyl), substituted piperazinyl (optionally substituted by substituted aryl (optionally substituted by haloalkyl)), imidazolyl, and pyridinyloxy; D is either N or O;
R3 is selected from the group consisting of optionally substituted aryl (optionally substituted by carboxylic acid, nitro, carboxylic acid substituted aralkoxy, carboxylic acid substituted alkoxy, optionally substituted aryloxyalkanyl (optionally substituted by carboxylic acid, alkoxy and nitro)), substituted aralkyl (optionally substituted by hydroxy, alkoxy, nitro, carboxylic acid, carboxylic acid substituted aryloxy, nicotonic acid, optionally substituted aryloxy (optionally substituted by nitro and/or carboxylic acid), and carboxylic acid substituted alkyl ester), carboxylic acid substituted cyclohexanyl, carboxylic acid substituted alkyl, optionally substituted piperazinyl (optionally substituted by carboxylic acid substituted aralkyl), alkoxy (optionally substituted by carboxylic acid), optionally substituted aralkyloxy (optionally substituted by carboxylic acid), carboxylic acid substituted pyrrolidinyl, carboxylic acid substituted piperidinyl, carboxylic acid substituted pyradinyloxy, and carboxylic acid substituted pyradinyl; and
R4 is present when D is N and further is selected from the group consisting of halo, nitro, carboxylic acid, alkyl, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, menthoxy alkyl carbonyl amino, alkoxy, carbonyl amino, optionally substituted aralkylamino (optionally substituted by phenoxy (optionally substituted by nitro, and/or carboxylic acid), alkyl ester, alkoxy, optionally substituted aralkyl (optionally substituted by carboxylic acid and/or nitro), alkylaminocarbonyl, carboxylic acid substituted pyridinyloxy, and alkyl phosphonic acid; or R3 and R4 form an optionally substituted piperydinyl or pyrrolidinyl (optionally substituted by carboxylic acid, carboxylic acid ester, nitro, and aminocarbonyl alkyl carboxylic acid) when D is N; or R2 and R3 form a dioxo-substituted heterocyclic ring with the phenyl group (when Y and Z are C) wherein said heterocylic ring is substituted by methylphosphonic acid; as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof.
A preferred subgroup of compounds is that subgroup of compounds of Formula I wherein D is N and is substituted at the meta position of the phenyl or heteroaromatic ring structure. This preferred subgroup of compounds is, therefore, selected from compounds of the following Formula IA:
Figure imgf000016_0001
Formula IA wherein:
RI represents one or more substituents and further is selected from the group consisting of haloalkyl, halo, and nitro;
A is either aminocarbonyl, methylene or carbonyl; 5 B is absent;
X, Y and Z are each independently either C or N;
R2 is selected from the group consisting of halo, nitro, carboxylic acid, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, carbamoyl, carboxamide, alkoxyaminocarbonyl, optionally substituted aralkylamino (optionally substituted by optionally substituted phenoxy i 0 (optionally substituted by nitro or carboxylic acid), alkyl ester, alkoxy, or optionally substituted pyridinyloxy (optionally substituted by carboxylic acid);
R3 is hydrogen, or optionally substituted aralkyl (optionally substituted by carboxylic acid or nitro); and
R4 is present when D is N and further is selected from the group consisting of 15 substituted aralkyl (optionally substituted by alkoxy, nitro, carboxylic acid or carboxylic acid substituted aryloxy), carboxylic acid substituted cyclohexanyl, carboxylic acid substituted alkyl, optionally substituted piperazinyl (substituted by carboxylic acid substituted aralkyl), and alkylphosphonic acid; or R3 and R4 form an optionally substituted piperidinyl or pyrrolidinyl (optionally .0 substituted by carboxylic acid, carboxylic acid ester, nitro, and aminocarbonyl alkyl carboxylic acid) when D is N; or R2 and R3 form a dioxo-substituted heterocyclic ring with the phenyl group (when Y and Z are C) wherein said heterocylic ring is substituted by methylphosphonic acid.
Particularly preferred compounds of this subgroup of compounds are selected from the 5 following:
( { 2-Nitro-4-trifluoromethyl-5- [4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenylamino } - methyl)-phosphonic acid; {7-[4-(3-Chloro-phenyl)-piperazin-l-yl]-2,3-dioxo-6-trifluoromethyl-3,4-dihydro-2H- quinoxalin- 1 -ylmethyl} -phosphonic acid; 30 {7- [4-(4-Fluoro-phenyl)-piperazin- 1 -yl]-2,3 -dioxo-6-trifluoromethyl-3 ,4-dihydro-2H- quinoxalin- 1 -ylmethyl } -phosphonic acid; 6-(4-Carboxy-benzylamino)-3-nitro-2-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-benzoic acid; -(4-Carboxy-benzylamino)-3-nitro-2-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-benzoic acid methyl ester; -{4-Nitro-3-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenylamino}- cyclohexanecarboxylic acid; -({4-Nitro-3-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenylamino}-methyl)-benzoic acid; -({4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenylamino } - methyl)-benzoic acid; -({2-Carbamoyl-4-nitro-3-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenylamino}- methyl)-benzoic acid; -(4-Carboxy-benzylamino)-3-nitro-2-[4-(4-trifluoromethyl-phenyl)-piperazin-l-yl]-benzoic acid methyl ester; -( { 4-Trifluoromethyl-3 - [4-(3 -trifluoromethy l-phenyl)-piperazin- 1 -yl] -phenylamino } -methy 1)- benzoic acid; -({2-Dimethylcarbamoyl-4-nitro-3-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino}-methyl)-benzoic acid; -( { 2-Formyl-4-nitro-3 - [4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenylamino } -methyl)- benzoic acid; -({2,4-Dinitro-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenylamino}-methyl)-benzoic acid; -( { 5 -Nitro-6- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -pyridin-2-ylamino } -methyl)- benzoic acid; 4-({3-Nitro-6-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-pyridin-2-ylamino}-methyl)- benzoic acid;
3-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenylamino}- propionic acid.
Another preferred subgroup of Formula I is that group of compounds wherein D is N and R3 and R4 form a substituted piperidinyl, as follows:
Figure imgf000019_0001
Formula IB wherein RI is haloalkyl, halo, and nitro;
A is either aminocarbonyl, methylene or carbonyl; B is absent;
X, Y and Z are each independently either C or N;
R2 is selected from the group consisting of halo, nitro, carboxylic acid, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, carboxamide, alkoxyaminocarbonyl, optionally substituted aralkylamino (optionally substituted by optionally substituted phenoxy (optionally substituted by nitro or carboxylic acid), alkyl ester, alkoxy, or optionally substituted pyridinyloxy (optionally substituted by carboxylic acid); and
R5 is substituted one or more times by carboxylic acid, carboxylic acid ester, nitro, and/or carbonyl amino alkyl carboxylic acid.
Particularly preferred compounds of this subgroup of compounds are selected from the following:
1 - {4-Nitro-3 - [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenyl } -piperidine-4-carboxylic acid; l-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenyl}- piperidine-4-carboxylic acid; l-{2-Formyl-4-nitro-3-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenyl}-piperidine-4- carboxylic acid; 5 '-Nitro-6'-[4-(3 -trifluoromethyl -phenyl)-piperazin- 1 -yl] -3 ,4,5 ,6-tetrahydro-2H-
[1 ,2']bipyridinyl-4-carboxylic acid; 1 - { 2,4-Dinitro-5- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenyl } -piperidine-4- carboxylic acid;
1 - { 4-Nitro-2-trifluoromethyl-5 -[4-(3 -trifluoromethyl -phenyl)-piperazin- 1 -yl] -phenyl } - piperidine-3-carboxylic acid; - {4- [2-(2-Isopropyl-5 -methyl-cyclohexyloxy)-acetylamino] -2-trifluoromethyl-5- [4-(3 - trifluoromethyl-phenyl)-piperazin-l-yl]-phenyl}-piperidine-4-carboxylic acid; ',5'-Difluoro-6'- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -3 ,4,5 ,6-tetrahydro-2H- [l,2']bipyridinyl-4-carboxylic acid; -(4-Carboxy-piperidin-l-yl)-5-nitro-6-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- pyrimidine-4-carboxylic acid methyl ester; ',3',5,-Trifluoro-6'-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-3,4,5,6-tetrahydro-2H-
[1 ,4']bipyridinyl-4-carboxylic acid; 1 - { 5 - [4-(4-Chloro-3 -trifluoromethyl-phenylcarbamoyl)-piperazin- 1 -yl]-4-nitro-2- trifluoromethyl-phenyl} -piperidine-4-carboxylic acid; 1 - { 5 - [4-(2-Chloro-5-trifluoromethyl-phenylcarbamoyl)-piperazin- 1 -yl] -4-nitro-2- trifluoromethyl -phenyl } -piperidine-4-carboxylic acid; 1 - { 5 - [4-(5-Chloro-2-nitro-4-trifluoromethyl-phenyl)-piperazin- 1 -yl] -4-nitro-2-trifluoromethyl- phenyl }-piperidine-4-carboxylic acid ethyl ester; l-{5-[4-(2,6-Dinitro-3-trifluoromethyl-phenyl)-piperazin-l-yl]-4-nitro-2-trifluoromethyl- phenyl}-piperidine-4-carboxylic acid ethyl ester; l-{5-[4-(2,4-Bis-trifluoromethyl-benzyl)-piperazin-l-yl]-4-nitro-2-trifluoromethyl-phenyl}- piperidine-4-carboxylic acid; 1 - {4-Nitro-2-trifluoromethyl-5-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin- 1 -yl]-phenyl } - piperidine-4-carboxylic acid; 6-(4-Carboxy-piperidin- 1 -yl)-5-nitro-2-[4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl]- pyrimidine-4-carboxylic acid methyl ester; l-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenylcarbamoyl)-piperazin-l-yl]- phenyl }-piperidine-4-carboxylic acid;
1 - {4-Nitro-2-trifluoromethyl-5-[4-(2-trifluoromethyl-phenylcarbamoyl)-piperazin- 1 -yl] - phenyl } -piperidine-4-carboxylic acid; 3-Nitro-l-{4-trifluoromethyl-3-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenyl}- piperidine-4-carboxylic acid; l-{2-Nitro-4-trifluoromethyl-5-[4-(4-trifluoromethyl-phenyl)-piperazin-l-yl]-phenyl}- piperidine-4-carboxylic acid; l-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-benzyl)-piperazin-l-yl]-phenyl}- piperidine-4-carboxylic acid; l-{4-Nitro-2-trifluoromethyl-5-[4-(4-trifluoromethyl-benzyl)-piperazin-l-yl]-phenyl}- piperidine-4-carboxylic acid; 1 - { 4-Nitro-2-trifluoromethyl-5- [4-(4-trifluoromethyl-benzoyl)-piperazin- 1 -yl] -phenyl } - piperidine-4-carboxylic acid; l-{4-Isopropoxycarbonylamino-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l- yl]-phenyl } -piperidine-4-carboxylic acid; l-{4-[2-(2-Carboxy-4-nitro-phenoxy)-3-methoxy-benzylamino]-2-trifluoromethyl-5-[4-(3- trifluoromethyl-phenyl)-piperazin- 1 -yl]-phenyl } -piperidine-4-carboxylic acid tert-butyl ester;
6-[2-({4-(4-tert-Butoxycarbonyl-piperidin-l-yl)-5-trifluoromethyl-2-[4-(3-trifluoromethyl- phenyl)-piperazin-l-yl]-phenylamino}-methyl)-6-methoxy-phenoxy]-nicotinic acid; 1 - {4- [3 -Methoxy-2-(2-methoxycarbonyl-4-nitro-phenoxy)-benzylamino] -2-trifluoromethyl-5 -
[4-(3 -trifluoromethyl -phenyl)-piperazin- 1 -yl] -phenyl } -piperidine-4-carboxylic acid; [(l-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenyl}- piperidine-4-carbonyl)-amino]-acetic acid; 6-[2-({4-(4-Carboxy-piperidin-l-yl)-5-trifluoromethyl-2-[4-(3-trifluoromethyl-phenyl)- piperazin- 1 -yl] -phenylamino } -methyl)-6-methoxy-phenoxy] -nicotinic acid methyl ester; 3 -(4- {4-Nitro-2-trifluoromethyl-5 -[4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenyl } - piperazin- 1 -ylmethyl)-benzoic acid.
Another preferred subgroup of Formula I is that group of compounds wherein D is N and R3 and R4 form an optionally substituted pyrrolidinyl, as shown below as Formula IC:
Figure imgf000021_0001
Formula IC wherein RI is hydrogen or haloalkyl; A is absent; B is absent;
X, Y and Z are each independently either C or N;
R2 is substituted one or more times and is selected from the group consisting of nitro and haloalkyl; and R6 is carboxylic acid.
Particularly preferred compounds of this subgroup of compounds are selected from the following:
1 - {4-Nitro-3- [4-(3 -trifluorornethyl-phenyl)-piperazin- 1 -yl] -phenyl } -pyrrolidine-2-carboxylic acid; 1 - { 2,4-Dinitro-5 - [4-(3 -trifluoromethyl -phenyl)-piperazin- 1 -yl]-phenyl } -pyrrolidine-2- carboxylic acid; 1 - {4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl]-phenyl} - pyrrolidine-2-carboxylic acid.
Another preferred subgroup of Formula I is that group of compounds of Formula ID, as shown below:
Figure imgf000022_0001
Formula ID wherein RI is substituted one or more times and is selected from the group consisting of haloalkyl, halo, and nitro; A is absent or present and when present is aminocarbonyl, methylene and carbonyl;
B is absent or present and when present is carbonylmethylether;
X, Y and Z are each independently either C or N;
R2 is substituted one or more time and is selected from the group consisting of pyrrolidinyl, nitro, haloalkyl, aralkylamino, optionally substituted aryloxy (optionally substituted by pyridinyl), optionally substituted piperazinyl (optionally substituted by haloalkyl substituted aryl), imidazolyl, and pyridinyloxy;
R3 is selected from the group consisting of optionally substituted aralkyl (optionally substituted by hydroxy, haloalkyl, carboxylic acid, halo, nitro, optionally substituted aryloxy (optionally substituted by carboxylic acid, halo and/or nitro)), alkoxy, carboxylic acid substituted aralkoxy, carboxylic acid substituted pyrrolidinyl, carboxylic acid substituted piperidinyl, carboxylic acid substituted alkoxy, and carboxylic acid substituted pyridinyloxy; and
R4 is selected from the group consisting of optionally substituted aralkyl (optionally substituted by carboxylic acid and/or nitro), alkyl, and alkyl amino carbonyl.
Particularly preferred compounds of this subgroup of compounds are selected from the following: 2-{4-[Bis-(2-hydroxy-5-nitro-benzyl)-amino]-phenoxy}-l-[4-(3-trifluoromethyl-phenyl)- piperazin- 1 -yl]-ethanone; 2-[4-Nitro-2-( { 3 -trifluoromethyl -4- [4-(3 -trifluoromethyl-pheny l)-piperazin- 1 -yl] - phenylamino } -methyl)-phenoxy] -benzoic acid; 6-[2-Methoxy-6-({3-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino } -methyl)-phenoxy] -nicotinic acid; 2- [2-Methoxy-6-( { 3 -trifluoromethyl-4-[4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] - phenylamino}-methyl)-phenoxy]-5-nitro-benzoic acid;
4-[4-Nitro-2-({3-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino}-methyl)-phenoxymethyl]-benzoic acid; 5-Bromo-2-[3-fluoro-2-({3-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino } -methyl)-phenoxy] -benzoic acid; l-[3-Fluoro-6-nitro-2-({3-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino } -methyl)-phenyl] -pyrrolidine-2-carboxylic acid; 1 - [3 -Fluoro-6-nitro-2-( { 3-trifluoromethyl-4- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] - phenylamino}-methyl)-phenyl]-piperidine-4-carboxylic acid; 2-Hydroxy-5-( { 3 -trifluoromethyl-4- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] - phenylamino } -methyl)-benzoic acid;
[3 -Methoxy-4-( { 3 -trifluoromethyl-4- [4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl] - phenylamino } -methyl)-phenoxy] -acetic acid; l-[3-Trifluoromethyl-2-({3-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino } -methyl)-phenyl] -piperidine-4-carboxylic acid ; 1 - [3 -Fluoro-2-( { 3 -trifluoromethyl-4-[4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] - phenylamino } -methyl)-phenyl] -piperidine-4-carboxylic acid; 5 -Chloro-2- [2-methoxy-6-( { 3 -trifluoromethyl-4- [4-(3 -trifluoromethyl-pheny l)-piperazin- 1 -yl] - phenylamino}-methyl)-phenoxy]-3-nitro-benzoic acid; 6- [3 -( { 3 -Trifluoromethyl-4- [4-(3 -trifluoromethy 1-pheny l)-piperazin- 1 -yl] -phenylamino } - methyl)-phenoxy]-nicotinic acid; 2-[5-Methoxy-2-({4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenylamino}-methyl)- 5 phenoxy]-5-nitro-benzoic acid;
2-[2-Methoxy-6-({2-pyrrolidin-l-yl-5-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)- piperazin- 1 -yl] -phenylamino } -methyl)-phenoxy] -5-nitro-benzoic acid; 2- [2-Methoxy-6-( { 2-trifluoromethyl-4-[4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] - phenylamino}-methyl)-phenoxy]-5-nitro-benzoic acid; [0 6-[2-Methoxy-6-({2-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino } -methyl)-phenoxy] -nicotinic acid; 4-[4-Trifluoromethyl-2-({2-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino } -methyl)-phenoxy] -benzoic acid; 2- [2-Methoxy-6-( { 3 -trifluoromethyl-4- [4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl] - 15 phenylamino}-methyl)-phenoxy]-5-nitro-benzoic acid;
5 -Nitro-2- { 3 -trifluoromethyl-4- [4-(3 -trifluoromethyl-pheny l)-piperazin- 1 -yl] -phenylamino } - benzoic acid; 2- [2-(3 -Ethyl- 1 - { 3 -trifluoromethyl-4- [4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenyl } - ureidomethyl)-6-methoxy-phenoxy]-5-nitro-benzoic acid; .0 4-{2-[(Methyl-{3-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenyl}- amino)-methyl]-4-trifluoromethyl-phenoxy}-benzoic acid; 4- {2- [(Ethyl- { 3 -trifluoromethyl-4- [4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenyl } - amino)-methyl]-4-trifluoromethyl-phenoxy}-benzoic acid; l-{2-[(Methyl-{3-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenyl}- .5 amino)-methyl]-4-trifluoromethyl-phenyl}-piperidine-4-carboxylic acid;
1 - {2- [(Ethyl- { 3 -trifluoromethyl-4- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenyl } - amino)-methyl]-4-trifluoromethyl-phenyl}-piperidine-4-carboxylic acid; 4- [2-( { 2-(4-Pyridin-4-yl-phenoxy)-5-trifluoromethyl-4- [4-(3 -trifluoromethyl-phenyl)- piperazin- 1 -yl] -phenylamino } -methy l)-4-trifluoromethy 1-phenoxy] -benzoic acid ; 30 2-[2-Methoxy-6-({2-(4-pyridin-4-yl-phenoxy)-5-trifluoromethyl-4-[4-(3-trifluoromethyl- phenyl)-piperazin-l-yl]-phenylamino}-methyl)-phenoxy]-5-nitro-benzoic acid; 4-[4-Nitro-2-({2-(4-pyridin-4-yl-phenoxy)-5-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)- piperazin- 1 -yl]-phenylamino } -methyl)-phenoxymethyl]-benzoic acid; - [4-Trifluoromethyl-2-( { 5-trifluoromethyl-2,4-bis- [4-(3 -trifluoromethyl -phenyl)-piperazin- 1 - yl] -phenylamino } -methyl)-phenoxy] -benzoic acid; - [2-Methoxy-6-( { 5-trifluoromethyl-2,4-bis- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] - phenylamino}-methyl)-phenoxy]-5-nitro-benzoic acid; -[4-Nitro-2-({5-trifluoromethyl-2,4-bis-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino } -methyl)-phenoxymethyl] -benzoic acid; - [2-( { 2-Imidazol- 1 -yl-5-trifluoromethyl-4-[4-(3 -trifluoromethyl -phenyl)-piperazin- 1 -yl] - phenylamino } -methyl)-4-trifluoromethyl-phenoxy] -benzoic acid; - [2-( { 2-(Pyridin-3 -yloxy)-5-trifluoromethyl-4- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] - phenylamino}-methyl)-4-trifluoromethyl-phenoxy]-benzoic acid; - {2- [2-(2-Carboxy-4-nitro-phenoxy)-3 -methoxy-benzylamino]-4-trifluoromethyl-5 - [4-(3 - trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenyl} -piperazine- 1 -carboxylic acid tert-butyl ester; l-[2-({2-Imidazol-l-yl-5-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino}-methyl)-3-trifluoromethyl-phenyl]-piperidine-4-carboxylic acid; l-[2-({2-Imidazol-l-yl-5-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino } -methyl)-4-trifluoromethyl-phenyl] -piperidine-4-carboxylic acid; l-[4-Trifluoromethyl-2-({5-trifluoromethyl-2,4-bis-[4-(3-trifluoromethyl-phenyl)-piperazin-l- yl] -phenylamino }-methyl)-phenyl]-piperidine-4-carboxylic acid; l-[2-({2-(4-Pyridin-4-yl-phenoxy)-5-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)- piperazin-l-yl]-phenylamino}-methyl)-4-trifluoromethyl-phenyl]-piperidine-4- carboxylic acid; 5-Bromo-2-[3-fluoro-2-({5-trifluoromethyl-2,4-bis-[4-(3-trifluoromethyl-phenyl)-piperazin-l- yl]-phenylamino}-methyl)-phenoxy]-benzoic acid;
5-Bromo-2-[3-fluoro-2-({2-(4-pyridin-4-yl-phenoxy)-5-trifluoromethyl-4-[4-(3- trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenylamino } -methyl)-phenoxy]-benzoic acid; 6-[2-Methoxy-6-({5-trifluoromethyl-2,4-bis-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino } -methyl)-phenoxy] -nicotinic acid; 4-({5-Trifluoromethyl-2,4-bis-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenylamino}- methyl)-benzoic acid. Another preferred subgroup of Formula I is that group of compounds as follows:
Figure imgf000026_0001
Formula IE wherein RI is substituted one or more times and is selected from the group consisting of haloalkyl, halo, and nitro; A is absent or present and when present is aminocarbonyl, methylene and carbonyl;
B is absent or present and when present is alkylaminocarbonyl; X, Y and Z are each independently either C or N;
R2 is substituted one or more times and is selected from the group consisting of alkyl ester, haloalkyl, alkylaminocarbonyl, and nitro; and R3 is selected from the group consisting of optionally substituted aralkyl (optionally substituted by carboxylic acid and/or nitro), optionally substituted aryl (optionally substituted by carboxylic acid, nitro, carboxylic acid substituted aralkoxy, carboxylic acid substituted alkoxy, optionally substituted aryloxyalkyl (optionally substituted by carboxylic acid, alkoxy and/or nitro), and carboxylic acid substituted pyridinyl. Preferred compounds having the generic formula IE, are shown as follows:
4-(3 - { 2- [4-(3 -Trifluoromethyl-phenyl)-piperazin- 1 -yl] -acetylamino } -phenoxymethyl)-benzoic acid; 6-(4-Carboxy-phenoxy)-3 -nitro-2- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -benzoic acid methyl ester; 6- { 2-Methoxycarbonyl-4-nitro-3 -[4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenoxy } - nicotinic acid; 3-{4-Nitro-3-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}-benzoic acid; 4-{4-Nitro-3-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}-benzoic acid; 4-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}- benzoic acid;
4-{4-Nitro-3-[4-(3-trifluoromethyl-phenyl)-piperazin-l-ylmethyl]-phenoxy}-benzoic acid; 5-Nitro-2-(2-{4-nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenoxy}-phenoxy)-benzoic acid; -(2-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}- phenoxymethyl)-benzoic acid; -Nitro-4-(2- {4-nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl]- phenoxy}-phenoxy)-benzoic acid; -(3- {4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl]-phenoxy} - phenoxymethyl)-benzoic acid; -(4- {4-Nitro-2-trifluoromethyl-5 - [4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenoxy } - benzyloxy)-benzoic acid; -(4- {4-Nitro-2-trifluoromethyl-5 - [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenoxy } - benzyloxy)-benzoic acid; -(4-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}- benzyloxy)-benzoic acid; 3 - { 4-Nitro-2-trifluoromethyl-5 - [4-(3 -trifluoromethyl -phenyl)-piperazin- 1 -yl] -phenoxy } - benzoic acid; 3-(2-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}- benzyloxy)-benzoic acid; 2-(2-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}- benzyloxy)-benzoic acid; 3-Methoxy-2-(2-{4-nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenoxy} -benzyloxy)-benzoic acid;
4-(3- {4-Benzylamino-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl]- phenoxy } -phenoxymethyl)-benzoic acid; 4-(3- {4-Heptanoylamino-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl]- phenoxy } -phenoxymethyl)-benzoic acid.
F. Preparation of Compounds
1. Scheme 1 (Formulas I A and ID):
Compounds of the Formulas IA and ID, as described above, may be synthesized via the following reaction scheme: Scheme 1.
Figure imgf000028_0001
Compounds of formula E and F, where Rl5 R2, and Ri are as defined for formulas I A and ID, and R3 is R'3-CH2-, where R3 is defined for formulas IA and ID, were prepared as depicted in Scheme 1. Compounds of formula A and B can be prepared according to methods known to those of ordinary skill in the art or are commercially available, for example, from Aldrich Chemical Company, Inc. ("Aldrich") or from Maybridge Co. ("Maybridge"). In general, A, preferably N-(3 -trifluoromethy lphenyl)piperazine (from Aldrich) was subjected to react with an equimolar amount of substituted fluoro-nitrobenzene B, in the presence of base, e. g., triethylamine, at 0 °C to 40 °C, preferably at ambient temperature, to obtain C. Hydrogenation of C, followed by either direct alkylation (R'3-CH2Br) or reductive amination (R'3-CHO), afforded E in excellent yields. Further alkylation of E with an equimolar amount R4-Br gave F. 2. Scheme 2 (Formulas IB and IC):
Compounds of the Formulas IB and IC may be synthesized via the following scheme 2: Scheme 2.
Figure imgf000029_0001
Compounds of formula J or K, where Rl5 R2, R5 and Re are as defined for formulas IB and IC, were prepared as depicted in Scheme 2. Compounds of formula A and G can be prepared according to methods known to those of ordinary skill in the art or are commercially available, for example, from Aldrich Chemical Company, Inc. or from Maybridge Co.
In general, A (preferably N-(3-trifluoromethylphenyl)piperazine) (from Aldrich) was subjected to react with an equimolar amount of substituted benzene or substituted pyridine G, in the presence of base, e. g., triethylamine, at 0 °C to 40 °C, preferably at ambient temperature, to obtain H. Second addition of substituted piperidine to H or pyrrolidine to H, afforded product J or K, respectively.
3. Scheme 3 (Select compounds from Formulas IA):
Selected Compounds of Formulas IA, as described above, may be synthesized via the following Scheme 3 : Scheme 3.
Figure imgf000030_0001
Select compounds of formula P, where R\ and R2 are as defined for Formula IA, were prepared as depicted in Scheme 3. Compounds of formula A and L can be prepared according to methods known to those of ordinary skill in the art or are commercially available, for example, from Aldrich Chemical Company, Inc. or from Maybridge Co.
In general, A (preferably N-(3-trifluoromethylphenyl)piperazine) (from Aldrich) was subjected to react with an equimolar amount of substituted fluorobenzene K, in the presence of base, e. g., triethylamine, at 0 °C to 40 °C, preferably at ambient temperature, to obtain M. Second addition of aminophosphate N to M afforded O, followed by de-protection afforded product P in moderate yields.
4. Scheme 4 (Select compounds of Formula IE):
Compounds of Formula IE, as described above, may be synthesized via the following:
Scheme 4.
Figure imgf000031_0001
Compounds of formula R, where Ri, R2, and R3 are as defined for formula IE, were prepared as depicted in Scheme 4. Compounds of formula A and L can be prepared according to methods known to those of ordinary skill in the art or are commercially available, for example, from Aldrich Chemical Company, Inc. or from Maybridge Co.
In general, compound A (preferably N-(3-trifluoromethylphenyl)piperazine) (from Aldrich) was subjected to react with an equimolar amount of substituted benzene or heteroaromatic L, in the presence of base, e. g., triethylamine, at 0 °C to 40 °C, preferably at ambient temperature, to obtain M. Second addition of hydroxy substituted-R3 (Q) afforded product R.
5. Scheme 5 (Select compounds from Formulas IA, IB, ID and IE): Select compounds of Formulas IA, IB, ID and IE may be made by the synthesis method described below as Scheme 5. Although Scheme 5 is specific to compounds of Formula IB, select compounds of Formulas I A, ID and IE may also be made using this synthetic scheme: Scheme 5.
Figure imgf000032_0001
Compounds of formula V, W, and X, where Rl5 R2, and R are as defined for Formulas IA, IB, ID and IE, were prepared as depicted in Scheme 5. Compounds of formulas S and L can be prepared according to methods known to those of ordinary skill in the art or are commercially available, for example, from Aldrich Chemical Company, Inc. or from Maybridge Co.
In general, 4-N-Boc-piperazine S (from Aldrich) was subjected to react with an equimolar amount of substituted benzene or heteroaromatic L, in the presence of base, e. g., triethylamine, at 0 °C to 40 °C, preferably at ambient temperature, to obtain T. Second addition of substituted piperidine to T, afforded product U. De-protection of U with TFA and further reaction with phenylisocyanate, benzoyl chloride, or benzyl bromide afforded V, W, and X, respectively. 6. Scheme 6 (Preparation of intermediates-substituted benzaldehydes)
Select intermediates that may be useful in synthesizing contemplated derivatives of the present invention are as follows in Scheme 6: Scheme 6.
Figure imgf000033_0001
wherein n is either 1 or 2.
Intermediates, such as substituted benzaldehydes, can be prepared in two different methods. First, replacement of fluorine of substituted fluorobenzaldehyde with an equimolar amount of substituted cyclic amine in the presence of base, for example, K2CO3, affords N- substituted benzaldehyde.
Second, replacement of the fluorine of substituted fluorobenzaldehyde with an equimolar amount substituted phenol or substituted hydroxypyridine in the presence of base, for example, K2CO3, afforded O-substituted benzaldehyde.
Examples
The following examples illustrate particularly preferred compounds of the present invention, methods of making the particularly preferred compounds of the present invention, assay methods, and methods of making representative pharmaceutical compositions of the compounds of the present invention. Example 1. Preparation of 4-({2,4-Dinitro-5-[4-(3-trifluoromethyl-phenyl -piperazin-l-yl1- phenylaminol-methvD-benzoic acid
1) Diisopropylethyl amine (9.5g, 73.5mmol) was added to a stirred solution of N-(3- trifluoromethyl)-piperazine (11.84 g, 51.4 mmol) and 2,4-difluoro-l ,5-dinitro-benzene (10.0 g, 49 mmol) in acetonitrile (200 mL) for 1.5h at 0°C. The solvent was removed under vacuo and the reaction mixture was diluted with EtOAc (300 mL), washed with 0.1 N HCl (100 mL), NaHCO3 (Sat., 100 mL) and brine (2x100 mL) successively. The organic layer was dried over Na2SO4, and concentrated to afford l-(5-fluoro-2,4-dinitro-phenyl)-4-(3-trifluoromethyl- phenyl)-piperazine (20.0 g, 100%) as a yellow solid.
2) A stirred mixture of l-(5-fluoro-2,4-dinitro-phenyl)-4-(3-trifluoromethyl-phenyl)- piperazine (1.2 g, 2.9 mmol), 4-carboxy-benzyl amine (460 mg, 3.04 mmol), and diisopropylethyl amine (1.12 g, 8.7 mmol) in DMSO (10 mL) was kept at 110°C for 2h. The mixture was cooled to rt, and was purified by HPLC directly to afford 4-({2,4-dinitro-5-[4-(3- trifluoromethyl-phenyl)-piperazin-l-yl]-phenylamino}-methyl)-benzoic acid (600 mg).
3) 1H NMR (300 MHz, DMSO): 9.21 (m, 1), 8.72 (s, 10), 7.93 (d,2), 7.64 (d,2), 7.38 (m, 1), 7.19 (m,2), 7.06 (m,l), 6.11 (s, 1), 4.78 (m,2), 3.37 (br.s, 4), 3.19 (br.s, 4).
4) Other compounds of the present invention synthesized in a similar fashion are as follows: ( {2-Nitro-4-trifluoromethyl-5 - [4-(3 -trifluoromethyl -phenyl)-piperazin- 1 -yl] -phenylamino } - methyl)-phosphonic acid; {7-[4-(3-Chloro-phenyl)-piperazin-l-yl]-2,3-dioxo-6-trifluoromethyl-3,4-dihydro-2H- quinoxalin- 1 -ylmethyl } -phosphonic acid; {7-[4-(4-Fluoro-phenyl)-piperazin-l-yl]-2,3-dioxo-6-trifluoromethyl-3,4-dihydro-2H- quinoxalin-1 -ylmethyl} -phosphonic acid;
6-(4-Carboxy-benzylamino)-3-nitro-2-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-benzoic acid; 6-(4-Carboxy-benzylamino)-3-nitro-2-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-benzoic acid methyl ester; 4- {4-Nitro-3 -[4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenylamino } - cyclohexanecarboxylic acid; 4-({4-Nitro-3-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenylamino}-methyl)-benzoic acid; -( {4-Nitro-2-trifluoromethyl-5- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenylamino } - methyl)-benzoic acid; -({2-Carbamoyl-4-nitro-3-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenylamino}- methyl)-benzoic acid; 6-(4-Carboxy-benzylamino)-3-nitro-2-[4-(4-trifluoromethyl-phenyl)-piperazin-l-yl]-benzoic acid methyl ester; 4-( {4-Trifluoromethyl-3 -[4-(3 -trifluoromethyl -phenyl)-piperazin- 1 -yl] -phenylamino } -methyl)- benzoic acid; 4-( { 2-Dimethylcarbamoyl-4-nitro-3 -[4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] - phenylamino }-methyl)-benzoic acid; 4-( { 2-Formyl-4-nitro-3 - [4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenylamino } -methyl)- benzoic acid; 4-( { 5-Nitro-6- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -pyridin-2-ylamino } -methyl)- benzoic acid; 4-( { 3 -Nitro-6- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -pyridin-2-ylamino } -methyl)- benzoic acid; 3-{4-NiuO-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenylamino}- propionic acid.
Example 2. Preparation of 5'-Nitro-6'-[4-(3-trifluoromethyl-phenyl -piperazin-l-vn-3,4.5,6- tetrahydro-2H-r 1 ,2']bipyridinyl-4-carboxylic acid
1) To a stirred solution of N-(3 -trifluoromethy l)-piperazine (4 g, 17.4 mmol) and 2, 6- dichloro-3-nitropyridine (3.35 g, 17.4 mmol) in DMSO (300 mL) was added Cs2CO3 (6.79 g, 20.85 mmol) at rt. The mixture was stirred for 2h at rt, then poured into water (500 mL). The reaction mixture was extracted by ethyl ether (4x500 mL) and washed with brine (2x100 mL).
The organic layer was dried over Na2SO4, and concentrated to afford crude product.
Purification by flash chromatography afforded l-(6-chloro-3-nitro-pyridin-2-yl)-4-(3- trifluoromethyl-phenyl)-piperazine (4.56 g, 68%). 2) To a stirred solution of l-(6-chloro-3-nitro-pyridin-2-yl)-4-(3-trifluoromethyl- phenyl)-piperazine (0.5 g, 1.29 mmol) in DMSO (30 mL) was added isonipecotic acid (0.17 g,
1.29 mmol) and Cs CO3 (0.51 g, 1.55 mmol) at rt. The mixture was stirred at rt overnight, then 60 °C for 3h. The reaction mixture was cooled to rt, then poured into water (50 mL), and neutralized with 1 N HCl to pH 5-6. The reaction mixture was extracted with CH2C12 (3x30 mL), washed with brine (2x100 mL). The organic layer was dried over Na2SO4, and concentrated to afford crude product. Purification by flash chromatography afforded 5'-nitro-6'- [4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-3,4,5,6-tetrahydro-2H-[l,2']bipyridinyl-4- carboxylic acid (0.32 g).
3) 1H NMR (300 MHz, CDC13): 8.26 (d, 1), 7.38 (m, 1), 7.04-7.2 (m, 3), 6.14 (d, 1), 4.37 (m, 2), 3.63 (m, 4), 3.39 (m, 4), 3.24 (m, 2), 2.71 (m, 1), 2.06 (m, 2), 1.77 (m, 2).
4) Other compounds of the present invention synthesized in a similar fashion are as follows: l-{4-Nitro-3-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenyl}-piperidine-4-carboxylic acid; l-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenyl}- piperidine-4-carboxylic acid; 1 - {2-Formyl-4-nitro-3-[4-(3 -trifluoromethyl -phenyl)-piperazin- 1 -yl] -phenyl }-piperidine-4- carboxylic acid; l-{2,4-Dinitro-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenyl}-piperidine-4- carboxylic acid; 1 - { 4-Nitro-2-trifluoromethyl-5 - [4-(3 -trifluoromethyl -phenyl)-piperazin- 1 -yl] -phenyl } - piperidine-3 -carboxylic acid; l-{4-[2-(2-Isopropyl-5-methyl-cyclohexyloxy)-acetylamino]-2-trifluoromethyl-5-[4-(3- trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenyl } -piperidine-4-carboxylic acid; 3',5'-Difluoro-6'-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-3,4,5,6-tetrahydro-2H-
[1 ,2']bipyridinyl-4-carboxylic acid; 2-(4-Carboxy-piperidin- 1 -yl)-5-nitro-6-[4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl]- pyrimidine-4-carboxylic acid methyl ester; 2',3,,5,-Trifluoro-6'-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-3,4,5,6-tetrahydro-2H-
[1 ,4']bipyridinyl-4-carboxylic acid; l.{5-[4-(5-Chloro-2-nitro-4-trifluoromethyl-phenyl)-piperazin-l-yl]-4-nitro-2-trifluoromethyl- phenyl }-piperidine-4-carboxylic acid ethyl ester;
1 - { 5 -[4-(2,6-Dinitro-3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -4-nitro-2 -trifluoromethyl- pheny l}-ρiperidine-4-carboxylic acid ethyl ester; 1 - { 5- [4-(2,4-Bis-trifluoromethyl-benzyl)-piperazin- 1 -yl] -4-nitro-2-trifluoromethyl-phenyl } - piperidine-4-carboxylic acid; l-{4-Nitro-2-trifluoromethyl-5-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-l-yl]-phenyl}- piperidine-4-carboxylic acid; 6-(4-Carboxy-piperidin- 1 -yl)-5-nitro-2- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] - pyrimidine-4-carboxylic acid methyl ester; 3 -Nitro- 1 - {4-trifluoromethyl-3 -[4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenyl } - piperidine-4-carboxylic acid; l-{2-Nitro-4-trifluoromethyl-5-[4-(4-trifluoromethyl-phenyl)-piperazin-l-yl]-phenyl}- piperidine-4-carboxylic acid; l-{4-Isopropoxycarbonylamino-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l- yl]-phenyl}-piperidine-4-carboxylic acid; 1 - {4- [2-(2-Carboxy-4-nitro-phenoxy)-3 -methoxy-benzylamino] -2-trifluoromethyl-5- [4-(3 - trifluoromethyl-phenyl)-piperazin-l-yl]-phenyl}-piperidine-4-carboxylic acid tert-butyl ester;
6-[2-({4-(4-tert-Butoxycarbonyl-piperidin-l-yl)-5-trifluoromethyl-2-[4-(3-trifluoromethyl- phenyl)-piperazin-l-yl]-phenylamino}-methyl)-6-methoxy-phenoxy]-nicotinic acid; l-{4-[3-Methoxy-2-(2-methoxycarbonyl-4-nitro-phenoxy)-benzylamino]-2-trifluoromethyl-5-
[4-(3 -trifluoromethyl -phenyl)-piperazin- 1 -yl] -phenyl } -piperidine-4-carboxylic acid; [(l-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenyl}- piperidine-4-carbonyl)-amino] -acetic acid; 6-[2-({4-(4-Carboxy-piperidin-l-yl)-5-trifluoromethyl-2-[4-(3-trifluoromethyl-phenyl)- piperazin- 1 -yl] -phenylamino } -methyl)-6-methoxy-phenoxy] -nicotinic acid methyl ester. 1 -{4-Nitro-3-[4-(3-trifluoromethyl-phenyl)-piperazin-l -yl] -phenyl }-pyrrolidine-2-carboxylic acid; 1 - {2,4-Dinitro-5 - [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenyl } -pyrrolidine-2- carboxylic acid; l-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenyl}- pyrrolidine-2-carboxylic acid. Example 3. Preparation of l-(4-Nitro-2-trifluoromethyl-5-[4-(2-trifluoromethyl- phenylcarbamov -piperazin- 1 -yll-phenyl) -piperidine-4-carboxylic acid
1) Diisopropylethyl amine (3.1 g, 24 mmol) was added to a stirred solution of N-boc- piperazine (3.6 g, 19.23 mmol) and 2,4-dichloro-5-nitrobenzotrifluoride (5 g, 19.23 mmol) in acetonitrile (150 mL) at rt. The mixture was kept at reflux for 5h, then cooled to rt. After removal of solvent, the reaction mixture was diluted with EtOAc (300 mL) and washed with 0.1 N HCl (2x50 mL), NaHCO3 (sat. 1x50 mL), and brine (2x100 mL) successively. The organic layer was dried over Na2SO4, and concentrated to afford crude l-boc-4-(5-chloro-2- nitro-4-trifluoromethyl-phenyl)-piperazine as a yellow solid. 2) A stirred mixture of crude l-boc-4-(5-chloro-2-nitro-4-trifluoromethyl-phenyl)-piperazine, ethyl isonipecotic ester (3.0 g, 19.23 mmol), and diisopropylethyl amine (3.1 g, 24 mmol) in DMSO (50 mL) was kept at 110°C for 10 h, then cooled to rt. The mixture was diluted with EtOAc (300 mL), and washed with brine (2x100 mL). The organic layer was dried over Na SO4, and concentrated to afford crude product. Further purification by flash chromatography afforded l-[5-(4-boc-piperazin-l-yl)-4-nitro-2-trifluoromethyl-phenyl]- piperidine-4-carboxylic acid ethyl ester (9 g).
3) To a stirred solution of l-[5-(4-boc-piperazin-l-yl)-4-nitro-2-trifluoromethyl- phenyl]-piperidine-4-carboxylic acid ethyl ester (711 mg, 1 mmol) in CH2C1 (5 mL) was added TFA (2 mL) at rt. The reaction mixture was stirred for 1 h, then was stripped down to dryness to give a de-protected product. To a stirred solution of this de-protected product in CH2C12 (5 mL) was added N-(2-trifluoromethylphenyl)isocyanate (188 mg, 1 mmol) and triethyl amine (121 mg, 1.2 mmol). After 2 h at rt, the solvent was removed, and the resulting residue was purified directly by flash chromatography to afford l-{4-nitro-2-trifluoromethyl-5- [4-(2-trifluoromethyl-phenylcarbamoyl)-piperazin- 1 -yl] -phenyl } -piperidine-4-carboxylic acid ethyl ester (620 mg).
4) To a stirred solution of l-{4-nitro-2-trifluoromethyl-5-[4-(2-trifluoromethyl- phenylcarbamoyl)-piperazin-l-yl] -phenyl }-piperidine-4-carboxylic acid ethyl ester (220 mg) in THF (5mL), MeOH (5 mL) was added LiOH (120 mg) in water (5 mL) at rt. The reaction mixture was stirred at rt for 30 min, then quenched with 0.1 N HCl to pH 4-5. The mixture was extracted with EtOAc (2x25 mL), washed with brine (2x10 mL). The organic layer was dried over Na2SO4, and concentrated to afford crude product. Further purification by HPLC afforded l-{4-nitro-2-trifluoromethyl-5-[4-(2-trifluoromethyl-phenylcarbamoyl)-piperazin-l-yl]- phenyl}-piperidine-4-carboxylic acid (210 mg).
5) 1H NMR (300 MHz, DMSO): 8.17 (s, 1), 7.6 (m, 2), 7.43 (m, 2), 6.93 (s, 1), 3.58 (br., 4), 3.49 (br., 2), 3.27 (br., 4), 2.85 (m, 2), 2.4 (m, 1), 1.93 (m, 2), 1.78 (m, 2).
6) Other compounds of the present invention synthesized in a similar fashion are as follows:
1 - { 5 - [4-(4-Chloro-3 -trifluoromethyl-phenylcarbamoyl)-piperazin- 1 -yl] -4-nitro-2- trifluoromethyl -phenyl } -piperidine-4-carboxylic acid; l-{5-[4-(2-Chloro-5-trifluoromethyl-phenylcarbamoyl)-piperazin-l-yl]-4-nitro-2- trifluoromethyl-phenyl } -piperidine-4-carboxylic acid; l-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenylcarbamoyl)-piperazin-l-yl]- phenyl } -piperidine-4-carboxylic acid; 1 - { 4-Nitro-2-trifluoromethy 1-5 - [4-(3 -trifluoromethyl-benzy l)-piperazin- 1 -yl] -phenyl } - piperidine-4-carboxylic acid; 1 - { 4-Nitro-2-trifluoromethyl-5- [4-(4-trifluoromethyl-benzyl)-piperazin- 1 -yl] -phenyl } - piperidine-4-carboxylic acid; l-{4-Nitro-2-trifluoromethyl-5-[4-(4-trifluoromethyl-benzoyl)-piperazin-l-yl]-phenyl}- piperidine-4-carboxylic acid.
Example 4. Preparation of 2-[2-Methoxy-6-({3-trifluoromethyl-4-[4-(3-trifluoromethyl- phenyD-piperazin- 1 -vπ-phenylamino}-methvD-phenoxy1-5-nitro-benzoic acid
1) To a stirred solution of N-(3-trifluoromethyl)-piperazine (10 g, 47.8 mmol) and 4- fluoro-3-trifluoromethyl-nitrobenzene (11.56 g, 50.2 mmol) in acetonitrile (150 mL) was added triethyl amine (5.81 g, 57.4 mmol) at rt. The mixture was kept at reflux for 4 h, then was cooled to rt. After removal of solvent, the reaction mixture was diluted with EtOAc (300 mL) and washed with brine (2x100 mL). The organic layer was dried over Na2SO4, and concentrated to afford l-(4-nitro-2-trifluoromethyl-phenyl)-4-(3-trifluoromethyl-phenyl)-piperazine (20.0 g, 100%)) as a yellow oil.
2) A solution of compound l-(4-nitro-2 -trifluoromethyl -phenyl)-4-(3-trifluoromethyl- phenyl)-piperazine (20.0 g) in EtOAc (150 mL) and MeOH (150 mL) containing 10% Pd C (2 g) was put under a 50 psi hydrogen atmosphere for 2 h. Pd/C was filtered off and the filtrate was concentrated to afford 3-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamine (19.1 g, 100%). 3) A mixture of 3-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamine (1.0 g, 2.57 mmol) and phenylether benzaldehyde (893 mg, 2.7 mmol) in MeOH (10 mL), CH2C12 (10 mL), and HOAc (1 mL) was stirred for 1 h at rt, then NaBH3CN (333 mg, 5.14 mmol) was added in one portion. After 3 h at rt, the solvent was removed under vacuum,
5 and the resulting residue was diluted with EtOAc (50 mL) and washed with brine (2x 10 mL). The organic layer was dried over Na2SO4, and concentrated to afford crude 2-[2-methoxy-6- ( { 3 -trifluoromethyl-4- [4-(3 -trifluoromethyl-pheny l)-piperazin- 1 -yl] -phenylamino } -methyl)- phenoxy]-5-nitro-benzoic acid methyl ester. 4) LiOH (400 mg) in water (10 mL) was added to a solution of crude 2-[2-methoxy-6-({3-
[ 0 trifluoromethyl-4- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenylamino } -methyl)- phenoxy]-5-nitro-benzoic acid methyl ester in THF (10 mL) and MeOH (10 mL). The mixture was kept at reflux for lh, then cooled to 0°C, and quenched with 1 N HCl to pH 5-6. The reaction mixture was extracted with EtOAc (3x30 mL), washed with brine (2x20 mL), dried over Na2SO4, and concentrated to afford crude product. Purification by HPLC using
15 acetonitrile-water (20-80%) as eluting solvent afforded 2-[2-Methoxy-6-({3-trifluoromethyl-4- [4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenylamino}-methyl)-phenoxy]-5-nitro-benzoic acid (1.56 g).
5) 1H NMR (300 MHz, DMSO): 8.58 (s, 1), 8.21 (d, 1), 6.95-7.42 (m, 9), 6.5-6.8 (m, 3), 4.23 (br., 2), 3.67 (s, 3), 3.26 (br, 4), 2.81 (br, 4).
10 6) Other compounds of the present invention synthesized in a similar fashion are as follows: 2-{4-[Bis-(2-hydroxy-5-nitro-benzyl)-amino]-phenoxy}-l-[4-(3-trifluoromethyl-phenyl)- piperazin- 1 -yl]-ethanone; 2- [4-Nitro-2-( { 3 -trifluoromethyl -4-[4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] - 5 phenylamino }-methyl)-phenoxy] -benzoic acid;
6- [2-Methoxy-6-( { 3 -trifluoromethyl-4- [4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl] - phenylamino}-methyl)-phenoxy]-nicotinic acid; 4- [4-Nitro-2-( { 3 -trifluoromethyl -4-[4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] - phenylamino } -methyl)-phenoxymethyl]-benzoic acid;
30 5-Bromo-2-[3-fluoro-2-({3-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l -yl]- phenylamino } -methyl)-phenoxy] -benzoic acid; 1 - [3 -Fluoro-6-nitro-2-( { 3 -trifluoromethyl-4- [4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl] - phenylamino } -methyl)-phenyl]-pyrrolidine-2-carboxylic acid; -(2- {4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl]-phenoxy } - phenoxymethyl)-benzoic acid; -Nitro-4-(2-{4-nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenoxy }-phenoxy)-benzoic acid; -Chloro-2-[2-methoxy-6-({3-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino}-methyl)-phenoxy]-3-nitro-benzoic acid; - [3 -( { 3 -Trifluoromethyl-4- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenylamino } - methyl)-phenoxy]-nicotinic acid; - [5-Methoxy-2-( { 4-[4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenylamino } -methyl)- phenoxy]-5-nitro-benzoic acid; - [2-Methoxy-6-( {2-trifluoromethyl-4- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] - phenylamino } -methyl)-phenoxy] -5 -nitro-benzoic acid; -[2-Methoxy-6-({2-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino } -methyl)-phenoxy] -nicotinic acid; -[4-Trifluoromethyl-2-({2-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino } -methyl)-phenoxy] -benzoic acid; -[2-Methoxy-6-( { 3 -trifluoromethyl-4- [4-(3 -trifluoromethyl -phenyl)-piperazin- 1 -yl] - phenylamino}-methyl)-phenoxy]-5-nitro-benzoic acid; -Nitro-2- { 3 -trifluoromethyl-4- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenylamino } - benzoic acid; - [2-(3 -Ethyl- 1 - { 3 -trifluoromethyl-4-[4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenyl } - ureidomethyl)-6-methoxy-phenoxy]-5-nitro-benzoic acid; - { 2- [(Methyl- { 3 -trifluoromethyl-4- [4-(3 -trifluoromethyl-pheny l)-piperazin- 1 -yl] -phenyl } - amino)-methyl]-4-trifluoromethyl-phenoxy} -benzoic acid; - { 2- [(Ethyl- { 3 -trifluoromethyl-4- [4-(3 -trifluoromethyl -phenyl)-piperazin- 1 -yl] -phenyl } - amino)-methyl]-4-trifluoromethyl-phenoxy } -benzoic acid; - [2-( {2-(4-Pyridin-4-yl-phenoxy)-5 -trifluoromethyl-4- [4-(3 -trifluoromethyl-phenyl)- piperazin- 1 -yl] -phenylamino } -methyl)-4-trifluoromethyl-phenoxy] -benzoic acid. Example 5. Preparation of l-[2-({2-Imidazol-l-yl-5-trifluoromethyl-4-[4-(3-trifluoromethyl- phenvπ-piperazin- 1 -yl] -phenylamino } -methvD-3 -trifluoromethyl-phenyl] -piperidine-4- carboxylic acid
1) To a stirred solution of 2,4-dichloro-5-nitrobenzotrifluoride (13.0 g, 50 mmol) in acetonitrile (200 mL) was added imidazole (3.74 g, 55 mmol) and triethyl amine (10.1 g, 100 mmol) at rt. After mixing for 28 h at 50 °C, the reaction mixture was cooled to rt, and the solvent was removed under vacuo. The resulting residue was diluted with EtOAc (300 mL) and washed with brine (2x50 mL). The organic layer was dried over Na2SO4, and concentrated to afford crude product, which was purified further by flash chromatography to give l-(5-chloro- 2-nitro-4-trifluoromethyl-phenyl)-lH-imidazole (8.36 g) as a yellow solid.
2) A stirred mixture of l-(5-chloro-2-nitro-4-trifluoromethyl-phenyl)-lH-imidazole (6.36 g, 21.8 mmol), N-(3-trifluoromethylphenyl)-piperazine (6.02 g, 26.2 mmol), diisopropylethyl amine (5.64 g, 43.6 mmol) in DMSO (80 mL) was kept at 115 °C for 16 h. After cooling to rt, the reaction mixture was diluted with EtOAc (250 mL), and washed with 0.1 N HCl (1x50 mL), NaHCO3 (sat. 30 mL), and brine (2x40 mL). The organic layer was dried over Na2SO4, and concentrated to give crude product, which was purified further by flash chromatography to afford l-(5-imidazol-l-yl-4-nitro-2-trifluoromethyl-phenyl)-4-(3- trifluoromethyl-phenyl)-piperazine (6.0 g).
3) A solution of l-(5-imidazol-l-yl-4-nitro-2-trifluoromethyl-phenyl)-4-(3- trifluoromethyl-phenyl)-piperazine (3.8 g) in EtOAc (50 mL) and MeOH (50 mL) containing 10%) Pd/C (0.6 g) was put under 50 psi hydrogen atmosphere for 2 h. Pd/C was filtered off and the filtrate was concentrated to afford 2-imidazol-l-yl-5-trifluoromethyl-4-[4-(3- trifluoromethyl-phenyl)-piperazin-l-yl]-phenylamine (3.8 g, 100%).
4) A mixture of compound 2-imidazol-l-yl-5-trifluoromethyl-4-[4-(3-trifluoromethyl- phenyl)-piperazin-l-yl]-phenylamine (200 mg, 0.44 mmol) and phenylether benzaldehyde (172 mg, 0.48 mmol) in MeOH (5 mL), CH2C12 (5 mL), and HO Ac (1 mL) was stirred for 1 h at rt, then NaBH3CN (50 mg) was added in one portion. After 3 h at rt, the solvent was removed under vacuo, and the resulting residue was diluted with EtOAc (50 mL) and washed with brine (2x 10 mL). The organic layer was dried over Na2SO , and concentrated to afford crude product. To a solution of this crude product in dichloromethane (5 mL) was added TFA (2 mL) at rt, and stirred for 1 h. After removal of TFA and solvent, the crude product was purified by HPLC to afford l-[2-({2-imidazol-l-yl-5- trifluoromethyl-4-[4-(3-trifluoromethyl- pheny l)-piperazin- 1 -yl] -phenylamino } -methyl)-3 -trifluoromethyl-phenyl] -piperidine-4- carboxylic acid (130 mg).
5) 1H NMR (300 MHz, DMSO): 9.23 (s, 1), 7.86 (s, 1), 7.64 9s, 1), 7.61 (s, 1), 7.37-7.52 (m, 4), 7.21 (m, 1), 7.16 (s, 1), 7.03 (m, 1), 6.86 (s, 1), 6.11 (br, 1), 4.47 (m, 2), 3.36
5 (br, 4), 3.04 (d, 2), 2.84 (br, 4), 2.71 (t, 2), 2.4 (m, 1), 1.91 (m, 2), 1.62 (m, 2).
6) Other compounds of the present invention synthesized in similar fashion are as follows:
1 - [3 -Fluoro-6-nitro-2-( { 3 -trifluoromethyl -4-[4-(3 -trifluoromethyl -phenyl)-piperazin- 1 -yl] - phenylamino}-methyl)-phenyl]-piperidine-4-carboxylic acid; [ 0 1 - [3 -Trifluoromethyl-2-( { 3 -trifluoromethyl-4- [4-(3 -trifluoromethyl -phenyl)-piperazin- 1 -yl] - phenylamino } -methyl)-phenyl] -piperidine-4-carboxylic acid; 1 - [3 -Fluoro-2-( { 3 -trifluoromethyl-4- [4-(3 -trifluoromethyl-pheny l)-piperazin- 1 -yl] - phenylamino } -methyl)-phenyl] -piperidine-4-carboxylic acid; 2-[2-Methoxy-6-({2-pyrrolidin-l-yl-5-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)- [ 5 piperazin- 1 -yl] -phenylamino } -methyl)-phenoxy] -5-nitro-benzoic acid;
1 - { 2- [(Methyl- { 3 -trifluoromethyl-4- [4-(3 -trifluoromethyl-phenyl) -piperazin- 1 -yl] -phenyl } - amino)-methyl] -4-trifluoromethyl-phenyl } -piperidine-4-carboxylic acid; 1 - { 2- [(Ethyl- { 3 -trifluoromethyl-4- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenyl } - amino)-methyl]-4-trifluoromethyl-phenyl}-piperidine-4-carboxylic acid; .0 4-[4-Nitro-2-({2-(4-pyridin-4-yl-phenoxy)-5-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)- piperazin- 1 -yl] -phenylamino } -methyl)-phenoxymethyl] -benzoic acid; 4-[4-Trifluoromethyl-2-({5-trifluoromethyl-2,4-bis-[4-(3-trifluoromethyl-phenyl)-piperazin-l- yl] -phenylamino }-methyl)-phenoxy] -benzoic acid; 2-[2-Methoxy-6-({5-trifluoromethyl-2,4-bis-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- 5 phenylamino}-methyl)-phenoxy]-5-nitro-benzoic acid;
4-[4-Nitro-2-({5-trifluoromethyl-2,4-bis-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino } -methyl)-phenoxymethyl] -benzoic acid; 4-[2-({2-Imidazol-l-yl-5-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino}-methyl)-4-trifluoromethyl-phenoxy]-benzoic acid; 30 4-[2-({2-(Pyridin-3-yloxy)-5-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino } -methyl)-4-trifluoromethyl-phenoxy] -benzoic acid; 4-{2-[2-(2-Carboxy-4-nitro-phenoxy)-3-methoxy-benzylamino]-4-trifluoromethyl-5-[4-(3- trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenyl} -piperazine- 1 -carboxylic acid tert-butyl ester; 1 -[2-({2-Imidazol- 1 -yl-5-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl]- phenylamino}-methyl)-4-trifluoromethyl-phenyl]-piperidine-4-carboxylic acid; 1 -[4-Trifluoromethyl-2-({5-trifluoromethyl-2,4-bis-[4-(3-trifluoromethyl-phenyl)-piperazin- 1 - yl]-phenylamino}-methyl)-phenyl]-piperidine-4-carboxylic acid; l-[2-({2-(4-Pyridin-4-yl-phenoxy)-5-trifluoromethyl-4-[4-(3-trifluoromethyl-phenyl)- piperazin-l-yl]-phenylamino}-methyl)-4-trifluoromethyl-phenyl]-piperidine-4- carboxylic acid; 5-Bromo-2-[3-fluoro-2-({5-trifluoromethyl-2,4-bis-[4-(3-trifluoromethyl-phenyl)-piperazin-l- yl]-phenylamino}-methyl)-phenoxy]-benzoic acid; 5-Bromo-2- [3 -fluoro-2-( { 2-(4-pyridin-4-yl-phenoxy)-5-trifluoromethyl-4- [4-(3 - trifluoromethyl-phenyl)-piperazin- 1 -yl]-phenylamino}-methyl)-phenoxy]-benzoic acid; 6-[2-Methoxy-6-({5-trifluoromethyl-2,4-bis-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenylamino} -methyl)-phenoxy]-nicotinic acid;
4-( { 5-Trifluoromethyl-2,4-bis-[4-(3 -trifluoromethyl -phenyl)-piperazin- 1 -yl] -phenylamino } - methyl)-benzoic acid.
Example 6. Preparation of 6-{2-Methoxycarbonyl-4-nitro-3-[4-(3-trifluoromethyl-phenylV piperazin- 1 -yl] -phenoxy} -nicotinic acid
1) To a stirred solution of N-(3-trifluoromethyl)-piperazine (12 g, 52 mmol) and methyl 2, 6- difluoro-3-nitrobenzoate (10 g, 49.5 mmol) in acetonitrile (150 mL) was added triethyl amine (5.81 g, 57.4 mmol) at 0°C. The mixture was then kept at rt overnight. After removal of solvent, the reaction mixture was diluted with EtOAc (300 mL), washed with 0.1 N HCl (2x50 mL), NaHCO3 (sat. 1x50 mL), and brine (2x100 mL) successively. The organic layer was dried over Na2SO4, and concentrated to afford 6-fluoro-3 -nitro-2- [4-(3 -trifluoromethyl -phenyl)-piperazin- l-yl]-benzoic acid methyl ester (20.0 g, 100%) as a yellow oil.
2) To a stirred solution of compound 6-fluoro-3-nitro-2-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl] -benzoic acid methyl ester (300 mg, 0.7 mmol) in DMSO (10 mL) was added 2- hydroxy-5-carboxylpyridine (117 mg, 0.84 mmol), and K2CO3 (291 mg, 2.11 mmol). The mixture was kept at 120°C for about 2 h, then cooled to rt, and quenched with 0,1 N HCl to pH 4-5. The mixture was extracted with EtOAc (2x25 mL) and washed with brine (2x 10 mL). The organic layer was dried over Na2SO4, and concentrated to afford crude product, which was purified by HPLC using acetonitrile-water (20-80%) as eluting solvent system to afford 6-{2- methoxycarbonyl-4-nitro-3 -[4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenoxy } -nicotinic acid (240 mg). 3) 1H NMR (300 MHz, DMSO): 8.22 (d, 1), 7.86 (d, 2), 7.4 (t, 1), 7.12-7.28 (m, 3),7.06
(d, 1), 6.9 (d, 2), 3.61 (s, 3), 3.54 (br, 4), 3.37 (br, 4).
4) Other compounds of the present invention synthesized in a similar fashion are as follows:
4-(3 - { 2- [4-(3 -Trifluoromethyl-phenyl)-piperazin- 1 -yl] -acetylamino } -phenoxymethyl)-benzoic acid;
6-(4-Carboxy-phenoxy)-3 -nitro-2- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -benzoic acid methyl ester;
3 - { 4-Nitro-3 - [4-(3 -trifluoromethy l-phenyl)-piperazin- 1 -yl] -phenoxy } -benzoic acid;
4-{4-Nitro-3-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}-benzoic acid; 4-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}- benzoic acid;
4-{4-Nitro-3-[4-(3-trifluoromethyl-phenyl)-piperazin-l-ylmethyl]-phenoxy}-benzoic acid;
3-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}- benzoic acid.
Example 7. Preparation of 3-Nitro-4-(2-{4-nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl- phenvD-piperazin-l-vπ-phenoxy)-phenoxy -benzoic acid
1) To a stirred solution of 2,4-dichloro-5-nitrobenzotrifluoride (5 g, 19.23 mmol) in
DMSO (100 mL) was added 1 ,2-dihydroxybenzene (4.23 g, 38.44 mmol) and K2CO3 (5.3 g, 38.44 mmol) at rt. After mixing for 10 h at 50 °C, the reaction mixture was cooled to rt, and poured into ice water (100 mL). The reaction mixture was extracted with EtOAc (3x100 mL), and washed with brine (2x50 mL). The organic layer was dried over Na SO4, and concentrated to afford crude product, which was purified further by flash chromatography to give 2-(5- chloro-2-nitro-4-trifluoromethyl-phenoxy)-phenol (5.7 g, 89%) as a yellow solid. 2) A stirred mixture of 2-(5-chloro-2-nitro-4-trifluoromethyl-phenoxy)-phenol (4.7 g,
14.1 mmol), N-(3-trifluoromethylphenyl)-piperazine (3.24 g, 14.1 mmol), and diisopropylethyl amine (2.18 g, 16.9 mmol) in DMSO (80 mL) was kept at 115 °C for 16 h. After cooling to rt, the reaction mixture was diluted with EtOAc (250 mL), and washed with 0.1 N HCl (1x50 m), NaHCO3 (sat. 30 mL), and brine (2x40 mL). The organic layer was dried over Na2SO4, and concentrated to give crude product, which was purified further by flash chromatography to afford 2-{2-nitro-4-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}- phenol (6.1 g, 82%).
3) To a stirred solution of 2- {2-nitro-4-trifluoromethyl-5-[4-(3 -trifluoromethyl -phenyl)- piperazin-1-yl] -phenoxy} -phenol (4 g, 7.58 mmol) in DMSO (100 mL) was added methyl 4- chloro-3-nitrobenzoate (1.64 g, 7.58 mmol) and KO-tBu (0.94 g, 8.34 mmol) at rt. After keeping 2 h at 110 °C, the reaction mixture was cooled to rt, and poured into ice water (100 mL). The reaction mixture was extracted with EtOAc (3x120 mL), and washed with brine (2x50 mL). The organic layer was dried over Na2SO4, and concentrated to afford crude product, which was purified further by flash chromatography to give product 3-nitro-4-(2-{2- nitro-4-trifluoromethyl-5- [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenoxy} -phenoxy)- benzoic acid methyl ester (4.7 g, 88%) as a yellow solid. 4) To a stirred solution of 3-nitro-4-(2- {2-nitro-4-trifluoromethyl-5-[4-(3- trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}-phenoxy)-benzoic acid methyl ester (600mg, 0.85 mol) in THF (10 mL) and MeOH (10 mL) was added LiOH (200 mg) in water (10 mL). The reaction mixture was stirred at rt overnight, then quenched with 0.5 N HCl to pH 5-6. The reaction mixture was extracted with EtOAc (3x30 mL), and washed with brine (2x20 mL). The organic layer was dried over Na2SO4, and concentrated to afford crude product, which was purified further by HPLC to give 3-nitro-4-(2-{4-nitro-2-trifluoromethyl-5-[4-(3- trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}-phenoxy)-benzoic acid (500 mg) as a yellow solid.
5) Η NMR (300 MHz, DMSO):8.39 s, 1), 8.09 (d, 2), 7.35-7.6 (m, 5), 6.94-7.22 (m, 4), 6.44 (s, 1), 3.38 (br.s, 4), 3.12 (br. s, 4).
6) Other compounds of the present invention synthesized in similar fashion are as follows: 5-Nitro-2-(2-{4-nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenoxy}-phenoxy)-benzoic acid; 4-(2-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}- phenoxymethyl)-benzoic acid; 4.(3- {4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenoxy} - phenoxymethyl)-benzoic acid;
2-(4-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}- benzyloxy)-benzoic acid;
3-(4-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}- benzyloxy)-benzoic acid;
4-(4- {4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl]-phenoxy } - benzyloxy)-benzoic acid; 3-(2-{4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]-phenoxy}- benzyloxy)-benzoic acid; 2-(2- {4-Nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin- 1 -yl] -phenoxy }- benzyloxy)-benzoic acid; 3-Methoxy-2-(2-{4-nitro-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenoxy}-benzyloxy)-benzoic acid; 4-(3 - { 4-Benzylamino-2-trifluoromethyl-5 - [4-(3 -trifluoromethyl-phenyl)-piperazin- 1 -yl] - phenoxy} -phenoxymethyl)-benzoic acid;
4-(3-{4-Heptanoylamino-2-trifluoromethyl-5-[4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- phenoxy } -phenoxymethyl)-benzoic acid.
Example 8 Preparation of Representative Pharmaceutical Compositions for Oral Administration
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, l-{4-nitro-2-trifluoromethyl-5-[4-(2-trifluoromethyl- phenylcarbamoyl)-piperazin- 1 -yl] -phenyl } -piperidine-4-carboxylic acid:
Ingredients % wt./wt.
Compound of the invention 20.0% Lactose 79.5% Magnesium stearate 0.5%
The above ingredients are mixed and dispensed into hard-shell gelatin capsules containing 100 mg each, one capsule would approximate a total daily dosage.
2. Ingredients % wt./wt.
Compound of the invention 20.0% Magnesium stearate 0.9% Starch 8.6%
Lactose 69.6%
PVP (polyvinylpyrrolidine) 0.9%
The above ingredients, with the exception of the magnesium stearate, 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.
3. Ingredients % wt./wt.
Compound of the invention 0.1 g
Propylene glycol 20.0 g
Polyethylene glycol 400 20.0 g
Polysorbate 80 1.0 g
Water q.s. 100 mL
The compound of the invention is dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80. A sufficient quantity of water is then added with stirring to provide 100 mL of the solution which is filtered and bottled.
4. Ingredients % wt./wt.
Compound of the invention 20.0% Peanut oil 78.0%
Span 60 2.0%
The above ingredients are melted, mixed and filled into soft elastic capsules.
5. Ingredients % wt./wt.
Compound of the invention 1.0%
Methyl or carboxymethyl 2.0% cellulose
0.9%) saline q.s. 100 mL
The compound of the invention is dissolved in the cellulose/saline solution, filtered and bottled for use.
Example 9 Preparation of Representative Pharmaceutical Compositions for Parenteral Administration
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, l-{4-nitro-2- trifluoromethyl-5-[4-(2-trifluoromethyl- pheny lcarbamoyl)-piperazin- 1 -y 1] -phenyl } -piperidine-4-carboxylic acid :
Ingredients % wt./wt.
Compound of the invention 0.02 g
Propylene glycol 20.0 g
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 0.2μ membrane filter and packaged under sterile conditions.
Example 10 Preparation of Representative Pharmaceutical Compositions in Suppository Form 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, l-{4-nitro-2-trifluoromethyl-5-[4-(2-trifluoromethyl-phenylcarbamoyl)- piperazin- 1 -yl] -phenyl } -piperidine-4-carboxylic acid : Ingredients % wt./wt.
Compound of the invention 1.0% Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%
The ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight.
Example 11 Preparation of Representative Pharmaceutical Compositions for Insufflation 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, 1 -{4-Νitro-2-trifluoromethyl-5-[4-(2-trifluoromethyl-phenylcarbamoyl)- piperazin- 1 -yl] -phenyl } -piperidine-4-carboxylic acid:
Ingredients % wt./wt. Micronized compound of 1.0% the invention
Micronized lactose 99.0%
The ingredients are milled, mixed, and packaged in an insufflator equipped with a dosing pump.
Example 12
Preparation of Representative Pharmaceutical Compositions in Nebulized Form
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, l-{4-nitro-2-trifluoromethyl-5-[4-(2-trifluoromethyl-phenylcarbamoyl)- piperazin-l-yl]-phenyl}-piperidine-4-carboxylic acid:
Ingredients % wt./wt.
Compound of the invention 0.005% Water 89.995%
Ethanol 10.000%
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.
Example 13
Preparation of Representative Pharmaceutical Compositions in Aerosol Form
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, l-{4-nitro-2-trifluoromethyl-5-[4-(2-trifluoromethyl-phenylcarbamoyl)-piperazin- 1-yl] -phenyl }-piperidine-4-carboxylic acid:
Ingredients % wt./wt.
Compound of the invention 0.10%) Propellent 11/12 98.90%
Oleic acid 1.00%
The compound of the invention is dispersed in oleic acid and the propellants. The resulting mixture is then poured into an aerosol container fitted with a metering valve. While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes and modifications may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims as appended hereto.

Claims

Claims What is claimed is: 1. A compound of the following formula:
Figure imgf000052_0001
wherein:
RI represents one or more substituents and is selected from the group consisting of hydrogen, haloalkyl, halo, and nitro;
X, Y and Z are each independently either C or N;
A is absent or present and is selected from the group consisting of methylene, carbonyl, and alkylaminocarbonyl;
B is either absent or present and is selected from the group consisting of alkylaminocarbonyl, methylene and carbonylalkylester;
R2 represents one or more substituents and is selected from the group consisting halo, nitro, carboxylic acid, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, carboxamide, carbamoyl, alkoxyaminocarbonyl, substituted aralkylamino (optionally substituted by substituted phenoxy (optionally substituted by nitro, carboxylic acid or alkyl ester), carboxylic acid substituted pyridinyloxy, or alkoxy), substituted aryloxy (substituted by pyridinyl), substituted piperazinyl (optionally substituted by substituted aryl (optionally substituted by haloalkyl)), imidazolyl, and pyridinyloxy; D is either N or O;
R3 is selected from the group consisting of optionally substituted aryl (optionally substituted by carboxylic acid, nitro, carboxylic acid substituted aralkoxy, carboxylic acid substituted alkoxy, optionally substituted aryloxyalkanyl (optionally substituted by carboxylic acid, alkoxy and nitro)), substituted aralkyl (optionally substituted by hydroxy, alkoxy, nitro, carboxylic acid, carboxylic acid substituted aryloxy, nicotonic acid, optionally substituted aryloxy (optionally substituted by nitro and/or carboxylic acid), and carboxylic acid substituted alkyl ester), carboxylic acid substituted cyclohexanyl, carboxylic acid substituted alkyl, optionally substituted piperazinyl (optionally substituted by carboxylic acid substituted aralkyl), alkoxy (optionally substituted by carboxylic acid), optionally substituted aralkyloxy (optionally substituted by carboxylic acid), carboxylic acid substituted pyrrolidinyl, carboxylic acid substituted piperidinyl, carboxylic acid substituted pyradinyloxy, and carboxylic acid substituted pyradinyl; and R4 is present when D is N and further is selected from the group consisting of halo, nitro, carboxylic acid, alkyl, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, menthoxy alkyl carbonyl amino, alkoxy, carbonyl amino, optionally substituted aralkylamino (optionally substituted by phenoxy (optionally substituted by nitro, and/or carboxylic acid), alkyl ester, alkoxy, optionally substituted aralkyl (optionally substituted by carboxylic acid and/or nitro), alkylaminocarbonyl, carboxylic acid substituted pyridinyloxy, and alkyl phosphonic acid; or R3 and R4 form an optionally substituted piperydinyl or optionally substituted pyrrolidinyl (optionally substituted by carboxylic acid, carboxylic acid ester, nitro, and aminocarbonyl alkyl carboxylic acid) when D is N; or R2 and R3 form a dioxo-substituted heterocyclic ring with the phenyl group (when Y and Z are C) wherein said heterocylic ring is substituted by methylphosphonic acid; as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
2. A pharmaceutical composition 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 following formula:
Figure imgf000053_0001
wherein:
RI represents one or more substituents and is selected from the group consisting of hydrogen, haloalkyl, halo, and nitro;
X, Y and Z are each independently either C or N;
A is absent or present and is selected from the group consisting of methylene, carbonyl, and alkylaminocarbonyl; B is either absent or present and is selected from the group consisting of alkylaminocarbonyl, methylene and carbonylalkylester;
R2 represents one or more substituents and is selected from the group consisting halo, nitro, carboxylic acid, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, carboxamide, carbamoyl, alkoxyaminocarbonyl, substituted aralkylamino (optionally substituted by substituted phenoxy (optionally substituted by nitro, carboxylic acid or alkyl ester), carboxylic acid substituted pyridinyloxy, or alkoxy), substituted aryloxy (substituted by pyridinyl), substituted piperazinyl (optionally substituted by substituted aryl (optionally substituted by haloalkyl)), imidazolyl, and pyridinyloxy; D is either N or O;
R3 is selected from the group consisting of optionally substituted aryl (optionally substituted by carboxylic acid, nitro, carboxylic acid substituted aralkoxy, carboxylic acid substituted alkoxy, optionally substituted aryloxyalkanyl (optionally substituted by carboxylic acid, alkoxy and nitro)), substituted aralkyl (optionally substituted by hydroxy, alkoxy, nitro, carboxylic acid, carboxylic acid substituted aryloxy, nicotonic acid, optionally substituted aryloxy (optionally substituted by nitro and/or carboxylic acid), and carboxylic acid substituted alkyl ester), carboxylic acid substituted cyclohexanyl, carboxylic acid substituted alkyl, optionally substituted piperazinyl (optionally substituted by carboxylic acid substituted aralkyl), alkoxy (optionally substituted by carboxylic acid), optionally substituted aralkyloxy (optionally substituted by carboxylic acid), carboxylic acid substituted pyrrolidinyl, carboxylic acid substituted piperidinyl, carboxylic acid substituted pyradinyloxy, and carboxylic acid substituted pyradinyl; and
R4 is present when D is N and further is selected from the group consisting of halo, nitro, carboxylic acid, alkyl, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, menthoxy alkyl carbonyl amino, alkoxy, carbonyl amino, optionally substituted aralkylamino (optionally substituted by phenoxy (optionally substituted by nitro, and/or carboxylic acid), alkyl ester, alkoxy, optionally substituted aralkyl (optionally substituted by carboxylic acid and/or nitro), alkylaminocarbonyl, carboxylic acid substituted pyridinyloxy, and alkyl phosphonic acid; or R3 and R4 form an optionally substituted piperydinyl or pyrrolidinyl (optionally substituted by carboxylic acid, carboxylic acid ester, nitro, and aminocarbonyl alkyl carboxylic acid) when D is N; or R2 and R3 form a dioxo-substituted heterocyclic ring with the phenyl group (when Y and Z are C) wherein said heterocylic ring is substituted by methylphosphonic acid; as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
3. The pharmaceutical composition of claim 2 wherein the disease-state is selected from the group consisting of unstable angina, myocardial infarction, cerebral thromboembolism, transient ischemic attack, stroke, DVT, and coronory reocclusion after thrombolytic therapy.
4. 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 following formula:
Figure imgf000055_0001
wherein: RI represents one or more substituents and is selected from the group consisting of hydrogen, haloalkyl, halo, and nitro;
X, Y and Z are each independently either C or N;
A is absent or present and is selected from the group consisting of methylene, carbonyl, and alkylaminocarbonyl; B is either absent or present and is selected from the group consisting of alkylaminocarbonyl, methylene and carbonylalkylester;
R2 represents one or more substituents and is selected from the group consisting halo, nitro, carboxylic acid, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, carboxamide, carbamoyl, alkoxyaminocarbonyl, substituted aralkylamino (optionally substituted by substituted phenoxy (optionally substituted by nitro, carboxylic acid or alkyl ester), carboxylic acid substituted pyridinyloxy, or alkoxy), substituted aryloxy (substituted by pyridinyl), substituted piperazinyl (optionally substituted by substituted aryl (optionally substituted by haloalkyl)), imidazolyl, and pyridinyloxy; D is either N or O;
R3 is selected from the group consisting of optionally substituted aryl (optionally substituted by carboxylic acid, nitro, carboxylic acid substituted aralkoxy, carboxylic acid substituted alkoxy, optionally substituted aryloxyalkanyl (optionally substituted by carboxylic acid, alkoxy and nitro)), substituted aralkyl (optionally substituted by hydroxy, alkoxy, nitro, carboxylic acid, carboxylic acid substituted aryloxy, nicotonic acid, optionally substituted aryloxy (optionally substituted by nitro and/or carboxylic acid), and carboxylic acid substituted alkyl ester), carboxylic acid substituted cyclohexanyl, carboxylic acid substituted alkyl, optionally substituted piperazinyl (optionally substituted by carboxylic acid substituted aralkyl), alkoxy (optionally substituted by carboxylic acid), optionally substituted aralkyloxy (optionally substituted by carboxylic acid), carboxylic acid substituted pyrrolidinyl, carboxylic acid substituted piperidinyl, carboxylic acid substituted pyradinyloxy, and carboxylic acid substituted pyradinyl; and
R4 is present when D is N and further is selected from the group consisting of halo, nitro, carboxylic acid, alkyl, alkyl ester, haloalkyl, dialkylamide, acetaldehyde, menthoxy alkyl carbonyl amino, alkoxy, carbonyl amino, optionally substituted aralkylamino (optionally substituted by phenoxy (optionally substituted by nitro, and/or carboxylic acid), alkyl ester, alkoxy, optionally substituted aralkyl (optionally substituted by carboxylic acid and/or nitro), alkylaminocarbonyl, carboxylic acid substituted pyridinyloxy, and alkyl phosphonic acid; or R3 and R4 form an optionally substituted piperydinyl or pyrrolidinyl (optionally substituted by carboxylic acid, carboxylic acid ester, nitro, and aminocarbonyl alkyl carboxylic acid) when D is N; or R2 and R3 form a dioxo-substituted heterocyclic ring with the phenyl group (when Y and Z are C) wherein said heterocylic ring is substituted by methylphosphonic acid; as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
5. The method of claim 4 wherein the disease-state is selected from the group consisting of unstable angina, myocardial infarction, cerebral thromboembolism, transient ischemic attack, stroke, DVT, and coronary reocclusion after thrombolytic therapy.
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US8026360B2 (en) 2004-09-20 2011-09-27 Xenon Pharmaceuticals Inc. Substituted pyridazines as stearoyl-CoA desaturase inhibitors
US7829712B2 (en) 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
US7767677B2 (en) 2004-09-20 2010-08-03 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US7777036B2 (en) 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
US8071603B2 (en) 2004-09-20 2011-12-06 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
US7919496B2 (en) 2004-09-20 2011-04-05 Xenon Pharmaceuticals Inc. Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-CoA desaturase enzymes
US7951805B2 (en) 2004-09-20 2011-05-31 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
US7968538B2 (en) * 2005-01-25 2011-06-28 Galenea Corp. Substituted arylamine compounds and methods of treatment
US8604021B2 (en) 2005-01-25 2013-12-10 Oren Becker Substituted arylamine compounds and methods of treatment
US8541457B2 (en) 2005-06-03 2013-09-24 Xenon Pharmaceuticals Inc. Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors
US7812025B2 (en) 2005-08-12 2010-10-12 Takeda Pharmaceutical Company Limited Brain/neuronal cell-protecting agent and therapeutic agent for sleep disorder
WO2007020888A1 (en) * 2005-08-12 2007-02-22 Takeda Pharmaceutical Company Limited Brain/neuronal cell-protecting agent, and therapeutic agent for sleep disorder
US8044052B2 (en) 2006-10-18 2011-10-25 Pfizer Inc. Biaryl ether urea compounds
US20160024022A1 (en) * 2011-09-02 2016-01-28 Purdue Pharma L.P. Pyrimidines as sodium channel blockers
US9656968B2 (en) * 2011-09-02 2017-05-23 Purdue Pharma L.P Pyrimidines as sodium channel blockers
US10059675B2 (en) 2011-09-02 2018-08-28 Purdue Pharma L.P. Pyrimidines as sodium channel blockers
WO2020257734A1 (en) * 2019-06-20 2020-12-24 Baylor College Of Medicine Compounds, compositions, and methods for treating, ameliorating, or preventing bacterial infections

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