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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
  • A61P5/12—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/14—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems

Definitions

• the present invention relates to novel thiazolidin-4-one derivatives having the following formula(I), which inhibit platelet-activating factor and/or 5-lipoxygenase for the prevention or treatment of inflammatory and allergic disorders mediated by platelet-activating factor and/or leukotrienes, and to pharmaceutical compositions containing these compounds, and to the use thereof to inhibit PAF and/or leukotriene.
• a process for preparing these compounds is also included in the present invention.
• n, T, Q, R 1 , R 2 , R ⁇ R 4 , R 5 , R 6 , R 7 and R s are respectively defined as the below.
• PAF-antagonistic activity-possessing compounds are very useful for treating various PAF-induced diseases, such as inflammatory diseases, allergic diseases, anaphylatic shocks, septic shocks, vascular diseases as DIC, myocardinal diseases, asthma, pulmonary edema, and adult respiratory diseases.
• Leukotrienes like PAF, are potent lipid mediators of a variety of topical and systemic diseases and disorders.
• a 5-lipoxygenase in cytoplasm catalyzes the conversion of arachidonic acid to leukotriene A4 which is the precursor of leukotriene B4 and C4.
• Leukotriene B4 and C4 are oxygenated metabolites that contribute to the pathogenosis of such inflammatory disorders as arthritis, asthma, psoriasis, and thrombotic disease.
• Leukotrienes are released concomitantly from leukocytes with PAF from a common phospholipid precursor upon cellular activation and act synergistically with PAF in many biological models.
• JV-(phenyl, pyridyl)-2-pyridyl-thiazoUdin-4-one derivatives for agricultural chemicals Japanese Patent Kokai No. 145679/79]
• JV-(phenyl, benzyl, cycloalkyl)-2-pyridyl-thiazolidin-4- one derivatives for agricultural chemicals Japanese Patent Kokai No. 55184/80]
• N- (carboxycyclohexylmethyl)-2-pyridyl-thiazolidin-4-one derivatives for anticomplementary acitvity Japanese Patent Application Kokai No.
• N- (carboxymethylphenyl)-2-pyridyl-thiazolidin-4-one derivatives having anti- inflammatory and analgesic activity Japanese Patent Kokai No. 88170/82]
• N- (pyrazinyl)-2-pyridyl-thiazolidin-4-one derivatives for agricultural chemicals Japanese Patent Kokai No. 183689/83
• N-(phenyl)-2-pyridyl-thiazolidin-4-one derivatives for intermediates in synthesis U.S. Patent No.
• PAF and leukotrienes synthesis of new compounds which possess leukotriene or PAF inhibitory activity, and preferably compounds which possess both inhibitory activity will be very useful as active ingredients in the prevention and/or treatement of those diseases and disorders. Accordingly, the present inventors have conducted long term investigations and studies on thiazolidin-4-one derivatives which have PAF antagonistic acitvity and/ or leukotrienes inhibitory activity. The present invention has been accomplished based on these findings.
• the present invention relates to the novel thiazolidin-4-one derivatives having the following formula(I), which act as PAF antagonists and/or inhibit biosynthesis of leukotrienes via the 5-lipoxygenase pathway.
• n is (), 1, 2 or 3;
• Q is C, - C l alkyl group, phenyl group that is optionally substituted with one or more suitable substituents selected from methoxy group and nitro group, or pyridiyl group that is optionally substituted with one or more methyl group;
• R 1 , R 2 and R 3 are independently hydrogen atom, C, ⁇ C 10 alkyl group, C 3 - C 6 cycloalkyl group, or phenyl group that is optionally substituted with one or more methoxy group;
• R 4 , R 5 , R 6 , R 7 and R" are independently hydrogen atom, hydroxyl group, halogen atom, C, - C l0 alkyl group, C, - C 10 alkoxy group, nitro group,
• T is hydrogen atom, hydroxyl group, C, ⁇ C, 0 alkyl group,
• R 9 is hydrogen atom, phenyl group that is optionally substituted with one or more suitable substituents selected from C, ⁇ C 6 alkyl group and C, ⁇ C 6 alkoxy group, or a pyridyl group
• R 10 is hydrogen atom, C, ⁇ C ]0 alkyl group, or C, - C 4 alkanoyl group
• R n is C, ⁇ C, 0 alkyl group, C, - C 10 alkoxy group, or amino group that is optionally substituted with one or more suitable substituents selected from C, ⁇ C , (1 alkyl group and C 3 ⁇ C 6 cycloalkyl group
• R 12 is C, ⁇ C 1(1 alkyl group or phenyl group
• R 13 is hydrogen atom, C,
• R 14 is hydrogen atom or C, ⁇ C, 0 alkyl group or when taken together, connecting R 13 and R 14 , a substituted or unsubstituted four- to seven-membered cycloamino group, or a cycloamino group having another hetero atoms; and R 16 is hydrogen atom or C, - C 10 alkyl group.
• the present invention also includes pharmaceutically acceptable salts of the formula(I), including, for example, salts with mineral acids such as, e.g., hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic acid such as, e.g., formic acid, acetic acid, malic acid, citric acid, maleinic acid, fumalic acid or tartaric acid.
• mineral acids such as, e.g., hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid
• organic carboxylic acid such as, e.g., formic acid, acetic acid, malic acid, citric acid, maleinic acid, fumalic acid or tartaric acid.
• the compounds according to the invention may be existed geometrical or optical isomerism.
• the present invention includes isomer in each case the isomerism and hydrate of the compounds.
• Novel compounds(I) of the present invention can be prepared by reacting compound of formula(II)
• T and Q are defined as in the formula(I); with compound of formula(III)
• n, R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R" are defined as in the formual(I); in the presence of base and solvent at -78 "C to reflux temperature, via the formula (I- 1 ) as an intermidate
• n, T, Q, R 1 , R 2 , R 3 , R 4 , R ⁇ R fi , R 7 and R' are defined as in formula(I).
• reaction of compound(II) with compound(III) is preferably carried out in a suitable solvent which at least one selected from inert organic solvents such as, e.g., tetrahydrofuran, benzene, toluene, dichloromethane or dichloroethane, and polar organic solvents such as, e.g., methanol, ethanol, dimethylsulfoxide, N,N- dimethylformamide or acetic acid.
• inert organic solvents such as, e.g., tetrahydrofuran, benzene, toluene, dichloromethane or dichloroethane
• polar organic solvents such as, e.g., methanol, ethanol, dimethylsulfoxide, N,N- dimethylformamide or acetic acid.
• the basic medium for the reaction of compound (II) and (III) is preferably metal hydride such as, e.g., sodium hydride, potassium hydride or calcium hydride, lithium diisopropylamide, methyl lithium, butyl lithium, phenyl lithium, sodium methoxide, sodium ethoxide, sodium acetate, sodium hydroxide, potassium hydroxide, or organic base such as, e.g., trie thy 1 amine, piperidine or morpholine, etc.
• metal hydride such as, e.g., sodium hydride, potassium hydride or calcium hydride, lithium diisopropylamide, methyl lithium, butyl lithium, phenyl lithium, sodium methoxide, sodium ethoxide, sodium acetate, sodium hydroxide, potassium hydroxide, or organic base such as, e.g., trie thy 1 amine, piperidine or morpholine, etc.
• reaction mixture can be reacted with an acid or alkali to immediately obtain compound of the formula(I).
• n, T, Q, R 1 , R 2 , R 3 , R 4 , R s , R ⁇ R 7 and R s are defined as the above.
• Suitable preferred acids are inorganic acid such as, e.g., hydrochloric acid, hydrochloric acid methanol or hydrochloric acid/ethanol, or organic acid such as, e.g., acetic acid or p-toluenesulfonic acid, etc..
• suitable preferred alkalis are sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, etc..
• the formula(I-l) as intermidate may be isolated from the reaction mixture in a high yield.
• the compound of formula(I) can be prepared by reacting compound of formula(II-l)
• T and Q are defined as in the formula(I), and X is halogen atom; with compound of formula( ⁇ i)
• n, R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R* are defined as in the formula(I); in the presence of zinc and an organic solvent in which tetrahydrofuran, benzene, toluene or trimethoxyborane at -78 * C to reflux temperature, to obtain the formula (1-1) as intermidate
• n, T, Q, R 1 , R 2 , R ⁇ R 4 , R R ⁇ R 7 and R" are defined as in the formulaQ); and reacting the compound of formula(I-l) with the said acid or alkali.
• the present invention relates to process for preparing compound of formula(II-l)
• T and Q are as defined in formula(I), and X is halogen atom; reacting compound of formula(H)
• T and Q are defined as in formula(I); with halide such as, e.g., bromine, iodine, chlorine, iVbromosuccinimide, N- bromophthalimide, -chlorosuccinimide or JV-chlorophthalimide in an organic solvents such as, e.g., ether, tetrahydrofuran, chloroform, carbon tetrachloride, dichloromethane, benzene, toluene, dimethyl form amide or etc. at 0 * C to reflux temperature.
• halide such as, e.g., bromine, iodine, chlorine, iVbromosuccinimide, N- bromophthalimide, -chlorosuccinimide or JV-chlorophthalimide in an organic solvents such as, e.g., ether, tetrahydrofuran, chloroform, carbon tetrachloride, dichloromethan
• T and Q are defined as in formula(I); by dehydrating the compound of Q-CHO( where in, Q is defined as in the formula(I)) with compound of T-NH 2 ( wherein, T is defined in the formula(I)) and mercaptoacetic acid(HSCH 2 CO 2 H) in an organic solvent uch as, e.g., benzene, toluene, xylene and etc..
• reaction mixture was cooled to 0 "C and added methanol (10 mL). When no more evolution of hydrogen gas the reaction mixture was warmed to room temperature added water(2() L) and extracted with ethyl acetate(2 x 100 mL).
• reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate(3 x 30 mL).
• the combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness.
• the residue was dissolved in 30% HCl-ethanol solution(5 mL), stirred for 3 h and then neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate
• reaction mixture was cooled to 0 "C and added methanol(4 mL). When no more evolution of hydrogen gas the reaction mixture was warmed to room temperature added watei lO mL), and extracted with ethyl acetate(2 x 50 mL).
• the present invention further relates to pharmaceutical compositions containing these compounds or acceptable salts thereof and the use of these compounds as antagonist of the PAF and/or inhibitor of the leukotriene.
• compounds of the present invention possess activity of PAF-antagonist and/or leukotriene-inhibition.
• compounds of the invention may be used for the treatment and prophylaxis of diseases mediated or effected by PAF and leukotriene.
• the typical diseases for which the compounds of the present invention may be used as a therapeutic and propylactic agent include inflammation (for example, arthritis, nephritis), circulatory diseases(for example, shock, thrombosis, transplant rejection, cerebral anemia, etc.) and allergic diseases (for example, asthma, psoriasis).
• the compounds according to the invention, as well as the pharmaceutically acceptable salts thereof, have potent PAF-antagonistic and leukotriene-inhibitory activity.
• the novel compounds may be used in pharmaceutical composition comprising a phar aceutically effective amount of one of the compounds defined above and a pharmaceutically acceptable carrier.
• the inventive compounds are particularly useful as anti-allergic agents, anti-asthmatic agents, anti-psoriasis agents, anti-anaphylact ⁇ c shock agents, anti-septic shock agents, anti-arthritic agents, anti-nephritic agents, anti-thromboplastic agents, anti-transplant rejection agents and anti-cerebral anemic agents.
• Solid or liquid pharmaceutically acceptable carriers may also be employed.
• Solid carriers include starch, lactose, calcium sulphate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid.
• Liquid carriers include syrup, peanut oil, olive oil, saline solution and water.
• the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with wax.
• a liquid carrier When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid(e.g. solution) or a nonaqueous or aqueous liquid suspension.
• the pharmaceutical preparations are prepared conventional techniques of the pharmaceutical chemist.
• Compounds according to the present invention may be administrated orally topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
• parenteral as used herein includes subcutaneous injections, intravenous injection, intramuscular injection, intrasternal injection or infusion techniques.
• An examplary daily dosage employed depends on the type of disease, the degree of symptom and age.
• the dosage levels of the compound in the above- indicated compositions may, of course, be varied and may conveniently be between about 0.0 lmg to about 200 mg per kilogram of the weight.
• compositions containing compounds according to the invention may be in any form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispensable powders or granules, emulsion, hard or soft capsules, syrups or elixirs.
• the tablets, capsules and the like may also contain a binder such as, e.g., lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; excipients such as, e.g., dicalcium phosphate; a disintegrating agent such as, e.g., co starch or potato starch; a lubricant such as, e.g., magnesium stearate, calcium stearate, sodium stearylfumalate or polyethylene glycol wax.
• a liquid carrier such as e.g., a fatty oil.
• active compounds according to the present invention may also be administered parenterally.
• a solution or suspension of the active compounds may be prepared in water, optionally mixed with stabilizer or buffering agents.
• the dosages for parenteral administration are preferably as ampule or vial type.
• active compounds according to the invention may also be administered by any known process of administrating the dose including topically, for example, an ointment, cream, jelly, solution, suspension or pachydematous patch; rectally, for example, suppository; intranasally or intrathoracally by inhalation spray.
• the present invention provides pharmaceutical compositions comprising a pharmaceutically effective amount of thiazolidin-4-one derivatives and a pharmaceutically acceptable salt thereof.
• the present invention also provides the pharmaceutical uses of these compounds and compositions, especially for the prevent or treatment of various PAF- and/or leukotriene- induced diseases, [pharmaceutical compositions] Orally administration(Tablet) :
• Sterile water may be added to the above composition for intravenous injection.
• Pharmacology Example 1 PAF-induced rabbit platelet aggregation.
• Platelet rich plasma was obtained by centrifugation of blood at 150 g for 10 min at room temperature. The number of platelets was adjusted to 3 x 10* platelets/mL with platelet poor plasma. Platelet aggregation was monitored by continuous recording of light transmission in a dual-channel aggregometer(Chrono-Log 560-VS) coupled with a two channel recorder(Chrono-Log 707). Stirred PRP was treated with various concentration of test compounds or vehicle(0.5 % DMSO) for 2 min and then PAF(5 x l() 'y M) was added to induce platelet aggregation.
• Inhibition values were calculated by comparing the extent of aggregation obtainted in the presence of the vehicle alone(0.5 % DMSO) and in the presence of a test compound. Log concentration-response curves were generated and the IC ⁇ values were determined by regression analysis.
• Pharmacology Example 2 Inhibitory activity for LTB spirit biosynthesis
• a suspension of rat basophillic leukemia- 1 cell in phosphoric acid buffer solution with a concentration of 5 x 10 r '/mL was allowed at 37'C for 5 min and added the compound of thiazolidin-4-one.
• a ter allowed for 5 min, to the mixture was added arachidonic acid(25 l/mL) and calcium ionophoie A23187(1 / /mL).
• the reaction mixture was quenched with 0.1N cooled hydrochloric acid and centrifuged with 3,3(X) rpm for 5 min. The supernatant solution was extracted with ethyl acetate and concentrated under nitrogen gas.

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• 1995
  • 1995-12-28 KR KR1019950061220A patent/KR960022486A/ko not_active Application Discontinuation
  • 1995-12-29 CA CA002184174A patent/CA2184174A1/en not_active Abandoned
  • 1995-12-29 WO PCT/KR1995/000183 patent/WO1996020936A1/en not_active Application Discontinuation
  • 1995-12-29 EP EP95941921A patent/EP0748317A1/de not_active Withdrawn
  • 1995-12-29 AU AU43173/96A patent/AU4317396A/en not_active Abandoned
  • 1995-12-29 CN CN95191872A patent/CN1142227A/zh active Pending
  • 1995-12-29 JP JP8520863A patent/JPH09503792A/ja active Pending
• 1996
  • 1996-08-16 HU HU9602263A patent/HU9602263D0/hu unknown

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