Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

• the present invention relates to substituted benzenesulfonamide derivatives having thromboxane A 2 receptor antagonistic activity, thromboxane A 2 synthesis inhibitory activity, etc., and useful as platelet aggregation inhibitors, antithrombotic agents, and antiasthmatic agents, and their derivatives.
• thromboxane A 2 receptor antagonistic activity thromboxane A 2 synthesis inhibitory activity, etc.
• platelet aggregation inhibitors antithrombotic agents, and antiasthmatic agents, and their derivatives.
• Thromboxane A 2 is a powerful physiological active substance biosynthesized from Arakidon acid in vivo.
• the substance has a smooth muscle contraction effect on the bronchi, coronary arteries, etc. Although it has physiological effects such as plate agglutination, it is thought that when produced excessively in vivo, it may cause various disorders such as thrombus and asthma.
• Agents that antagonize thromboxane A 2 relative to the thromboxane A 2 receptor, drug there have is to inhibit the synthesis of thromboxane A 2 is excessive production of thromboxane A 2 as described above is a cause It is expected to be useful as a prophylactic or therapeutic agent for certain diseases.
• diseases include, for example, cardiovascular diseases such as angina pectoris and myocardial infarction, cerebrovascular disorders, thrombosis, and asthma.
• Clinical trials have been conducted on so far, some of thromboxane A 2 receptor ⁇ anti agent or thromboxane A 2 synthesis inhibitors.
• the only drug actually used in clinical practice is Ozadarrell (The Merck Index, 11th edition, 6935).
• Japanese Patent Application Laid-Open Nos. 3-22 and 9-27972 and 3-227972 disclose if compounds that combine the action of the toxin boxane A 2 receptor with the action of inhibiting the synthesis of thromboxane 2 . Such compounds may exert more certain effects by enhancing or complementing the rain action.
• the present invention has both antithromboxane A 2 receptor anti-thrombotic activity and thromboxane A 2 synthesis inhibitory activity, and is useful for the prophylaxis or treatment of diseases caused by thromboxane A 2. It is intended to be useful as an agent.
• Another object of the present invention is to provide a method for producing the above compound and a medicinal product containing the above compound. Disclosure of the invention
• the present invention provides the following general formula (I):
• R 1 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom
• R 2 represents a phenyl group, a phenyl group, or a furyl group which may have a substituent
• R 3 represents a hydrogen atom.
• R 1 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom
• R 2 represents a phenyl group, a phenyl group, or a furyl group which may have a substituent
• R 3 represents a hydrogen atom.
• n represents an integer of 1 to 5
• the present invention provides a method for producing the above compound and a pharmaceutical composition containing the above compound.
• the pharmaceutical composition provided by the present invention is useful as a platelet aggregation inhibitor, an antithrombotic agent, and an antiasthmatic agent.
• the lower alkyl group represented by R 1 and R 3 includes, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group. Group, isobutyl group, sec-butyl group, tert-butyl group and the like.
• Examples of the lower alkoxy group represented by R 1 include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group.
• halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
• substituent which may be substituted with a phenyl group, a phenyl group, a phenyl group and a furyl group represented by R 2 include, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group and an isobutyl group.
• Lower alkynole groups such as tert-butyl, sec-butyl and tert-butyl; methoxy, ethoxy, n-propoxy and isopropoxy Groups, lower alkoxy groups such as n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group; halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; fluoromethyl group, difluoromethino And a lower alkyl group substituted by a no-ring gen atom such as a tri group or a trinoleolomethyl group.
• the compound represented by the formula (I) of the present invention is preferably the following compound:
• the present invention is not limited to these examples.
• those in which R 3 is a hydrogen atom are converted, if necessary, into pharmacologically acceptable salts. It can also be converted to an acid.
• Examples of the pharmacologically acceptable salt of the compound represented by the general formula (I) of the present invention include alkali addition salts.
• Examples thereof include inorganic alkali salts such as sodium, potassium, calcium, and ammonium; and salts of organic bases such as trimethylamine, triethylamine, pyrrolidine, piperidine, piperazine, and N-methylmorpholine. .
• the compound represented by the general formula (I) of the present invention has a power that optical isomers based on asymmetric carbon can exist, and the scope of the present invention includes these optical isomers and a mixture of any ratio thereof , And racemates are also included.
• the compound of the present invention represented by the general formula (I) can be produced by the method of the present invention described below, but the production method of the compound of the present invention is not limited to these methods. .
• the compound represented by the general formula (I) has the following general formula (II):
• R 1 is as defined above
• a sulfonyl chloride derivative as described above, in a solvent in the presence of a base, and further, if necessary, hydrolyzing the ester.
• the solvent used when reacting the compound of (11) with the compound of (III) is not particularly limited as long as the reaction is not inhibited.
• ether solvents such as getyl ether, tetrahydrofuran and 1,4-dioxane
• halogenated hydrocarbon solvents such as chloroform, chloride methylene and 1,2-dichloroethane
• aromatic hydrocarbons such as benzene and toluene.
• Aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, etc. are used for O o
• Examples of the base used in this reaction include organic bases such as triethylamine, diisopropylpropylethylamine, 1,8-diazabicyclo [5,4,0] -17-indene, pyridine, and the like; or sodium carbonate, Examples of such groups include carbon dioxide lime, sodium hydrogen carbonate, and hydrogen carbonate lime.
• the reaction may be carried out in a range from 0 ° C to the reflux of the solvent used.
• a base or acid in water or a water-containing solvent can be performed.
• the aqueous solvent used in the hydrolysis reaction include, for example, water in a solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, tetrahydrofuran, or 1,4-dioxane in an arbitrary ratio. What is added and mixed may be used.
• the base for example, sodium hydroxide, sodium hydroxide, sodium carbonate, carbonated carbonate, or the like may be used
• the acid for example, hydrochloric acid, hydrobromic acid, sulfuric acid, or the like may be used.
• the reaction may be carried out in the range from 0 ° C to the temperature of the solvent.
• the amine derivative represented by the general formula (II) used as a starting material is a novel compound and can be produced as follows (in the following scheme, R 2 , R 3 and n is as described above). More specifically, this compound can be produced by the method described in Examples.
• the compound of the present invention represented by the formula (I) and a pharmacologically acceptable salt thereof may be directly administered to a patient, but is preferably administered as a drug containing the above compound as an active ingredient.
• the medicament include oral preparations such as capsules, mi, fine granules, granules, powders, and syrups; These pharmaceutical products can be manufactured by a conventional method by adding a pharmacologically or pharmaceutically acceptable additive to the compound of the present invention.
• excipients such as lactose, D-mannitol, corn starch, microcrystalline cellulose, etc .; disintegrants such as canoleboxy methoxy cellulose, carboxymethyl cellulose calcium, etc .; hydroxypropyl cellulose Binders such as hydroxypropylmethylcellulose and polyvinylpyrrolidone; lubricating agents such as magnesium stearate and talc; and pharmaceutical ingredients such as coating agents such as hydroxypropylmethinorescellulose, sucrose and titanium oxide. .
• solubilizers or solubilizers which can constitute aqueous or ready-to-use dosage forms such as propylene glycol; inorganic or organic acids or A pH adjusting agent such as a base; an isotonic agent such as ⁇ , glucose, and glycerin; or a formulation component such as a stabilizer may be used.
• the dose of the compound of the present invention to a treated patient is usually 1 to 50 mg per day for oral administration and 1 to 50 mg for parenteral administration as a daily dose for adults. It may be increased or decreased as necessary depending on the symptoms and age.
• thromboxane A 2 receptor antagonistic action thromboxane A 2 receptor antagonistic action
• thromboxane A 2 synthase inhibitory action thromboxane A 2 synthase inhibitory action
• platelet aggregation inhibitory action thromboxane A 2 synthase inhibitory action
• airway constriction inhibitory action thromboxane A 2 synthase inhibitory action
• leukotriene D 4 antagonistic action The test results of the prostaglandin F 2 antagonism and the ameliorating effect of the immunoglobulin E-related asthma model and the results of acute toxicity are shown below. During the above test, danoretrovan was used as a control drug.
• Test Example 1 Thromboxane A 2 receptor antagonism
• Guinea pig (approximately 400 g) 1/10 volume 3.8% sodium citrate was collected from the abdominal vein, and the blood was centrifuged to obtain platelet-rich plasma (PRP: 6 x 10 5 ⁇ 1) was. Put the above PRP 190-1 in a cuvette, set it in an aggregometer (Hematotracer I; Nikko Bioscience), add dimethylsulfoxide solution 1a1 of the test compound, and add 37 ° C. Incubated at C for 2 minutes.
• PRP platelet-rich plasma
• Example 3 5 0.7. 9
• Example 5 0.16
• Example 46 0.4 Control drug 2.0
• the compounds of the present invention exhibited superior thromboxane receptor antagonism as compared with the control drug.
• Test Example 2 thromboxane A 2 synthase inhibitory activity
• a 2 synthase was prepared by adding a test compound in dimethyl sulfoxide solution 101 and prostaglandin. It was mixed with H 2 (Caymann) 100 ⁇ g / ml (51) and reacted at 25 ° C for 3 minutes. Generated by the thromboxane A 2 stable variants thromboxane B 2 RIA method; was determined by (TXB 2 assay kit NEN Co.). The enzyme activity 50% inhibiting concentration (IC 5. Values) shown in Table 2. Table 2 Thromboxane A 2 synthase inhibitory action
• Test Example 3 Platelet aggregation inhibitory action
• test compound was orally administered to male Hartley guinea pigs (about 400 g), and one hour later, blood was collected from the abdomen: »pulse under ether anesthesia.
• treatment was performed according to the method of Test Example 1.
• Table 3 shows the results.
• Table 3 Platelet aggregation inhibitory action
• Test compound 4 airway constriction inhibitory effect of compound of the present invention showing superior platelet aggregation inhibitory effect as compared with control drug
• the compound of the present invention showed an excellent airway constriction inhibitory effect as compared with the control drug.
• Test Example 5 Roikotoryen D 4 antagonism
• the dog (8-lllig) was anesthetized with pentobarbital and killed by Ml from the Mill vein, and a spiral specimen of the mesenteric vein was prepared without removing the endothelium.
• the specimen was isometrically suspended in Krebs-Henseleit's solution at 37 ° C with a load of 0.5 g.
• Prostaglandin F 2 a to sustained contraction caused by (3xi0- 6 M Ono), and the test of calculated cumulatively added to 50% inhibitory concentration (IC 5 values.).
• Table 6 shows the results.
• Table 6 Prostaglandin F 2 ⁇ 3 ⁇ 4 ⁇ action Test compound ( ⁇ )
• the compound of the present invention showed a superior prostaglandin F 2 antagonism as compared with the control drug.
• Test Example 7 Imnoglobulin
• Hartley male guinea pigs (about 400 g) were sensitized by injecting 0.8 mg / kg of anti-benzyl penicilloyl bovine serum agrupulin (BP0-BGG) into the femoral artery. Approximately 48 hours later, the guinea pigs were anesthetized with urea (1.5 g / kg, ip :), and then, while ventilating with a respirator (Model 683; Harvard), the air volume was measured with a sensor (Model 7020; The measurement was performed according to the method of Konzett-Rossler.
• test compound is orally administered 2 hours before the stimulation with the antigen [benzyl penicilloyl bovine serum albumin (BP0-BSA), 0.2 mg / kg, iv]. Assuming 0%, a 50 % inhibition value (ED50 value) was calculated from the obtained effect. Table 7 shows the results. Table 7 Improving effect of immunoglobulin E-related asthma model
• Test compound ED 5 o (mg / kg, po)
• Test Example 8 Acute toxicity
• Example 3 4- (4- (3-phenolic phenyl) phenyl) methyl butyrate Properties Light yellow-brown liquid
• Example 11 1 Methyl 4- [4- (2-furoyl) phenyl] butyrate
• Example 11 4-C4- (Hydroxyphenylmethyl) phenyl) Butyrate Methyl 4- (4-benzoylphenyl) butyrate 14.0 g of methanol in 15 Oml To the suspension, under continuous cooling, 1.88 g of sodium borohydride was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The ether layer was washed successively with dilute hydrochloric acid and water and dried. The solvent was distilled off under reduced pressure to obtain 12.7 g of a colorless liquid.
• Example 3 2 4— [4-[[Mouth (4-methylphenyl) methyl]] phenyl] Methyl butyrate
• Example 66 4-C4- (azidophenylmethyl) phenyl] butyric acid and 4-C4- (azi) recovered from the mother liquor after salt formation with L- (1-1) phenylphenylethylamine Dophenylmethyl) phenyl] butyric acid 36.8 g, and T)-(+) — 1-phenyl Crystals extracted from a solution of 15.1 g of tilamine in 11 mL of ethyl acetate were recrystallized six times from ethyl acetate to obtain 11.1 g of colorless needles having a melting point of 117 to 120 ° C. .
• Negation R scan Bae spectrum 5 (CDC1 3) ppm: 2.59 (2H, br), 3.59 (2H, s), 3.67 (3H, s), 5.22 (lH, s), 7.11-7.42 (9H, m)
• (+)-4- [4- (Azidophenylmethinole) phenyl] 96 mg of platinum oxide was added to a solution of 4.79 g of methyl butyrate in 5 ml of methanol, and hydrogenated at room temperature and normal pressure for 2 hours. After filtering off the catalyst, the filtrate was distilled off under reduced pressure. The residue was dissolved in ether and acidified with dilute hydrochloric acid. The precipitated crystals were collected by filtration to obtain 4.44 g of colorless crystals of hydrochloride. Recrystallization from 7 gave colorless needles with a melting point of 208-212 ° C.
• Example 8 4- [4-[(4-cyclophenylphenylsulfonylamino) (2-fluorophenyl) methyl] funinyl] methyl butyrate
• Example 11 1 4-C4-[(4-chlorophenyl) (4-chlorophenylsulfonylamino) methyl] phenyl] methyl butyrate
• Example 12 4-C4-C (4-chlorophenylsulfonylamino) (4-methylphenyl) methyl] phenyl] methyl butyrate
• Example 14 4: 4- (4-C (4-cyclophenylphenylsulfonylamino) (4-trifluoromethylphenyl) methyl] phenyl] methyl butyrate
• (+)-4-[4- (Aminophenylmethinole) phenyl] Methyl butyrate (4.28 g) and triethylamine (2.53 ml) in methylene chloride (25 ml) were added under ice-cooling to give 4-benzene benzenesulfonyl. 3.51 g of chloride was added, and the mixture was stirred at room temperature for 1 hour.
• the reaction solution was washed sequentially with dilute hydrochloric acid, aqueous potassium carbonate solution and water. After dehydrating the methylene chloride layer, The solvent was distilled off under reduced pressure. The residue was purified by silica gel gel chromatography (methylene chloride) to obtain 5.73 g of crystals. Recrystallization from a mixture of ether and isopropyl ether gave colorless prisms having a melting point of 66.5 to 68 ° C.
• Example 18 4-C4-[((4-fluorophenylsulfonylamino) phenylmethyl] phenyl] methyl severe acid
• Example 19 4- [4-C (4-fluorophenyl) (4-fluorophenylsulfonylamino) methyl] phenyl] methyl butyrate
• Example 20 4- (4-C (4-chlorophenyl) (4-fluorophenylsulfonylamino) methyl] phenyl] methyl butyrate
• Example 21 1 4-([4-[(4-bromophenylsulfonylamino) phenylmethyl] phenyl] methyl butyrate
• Example 22 4- [4-[(4-bromophenylsulfonibreamino) (4-fluorophenylinyl) methinole] phenyl] methyl butyrate
• Example 25 4- (4-[(4-Methoxyphenylsulfonylamino) phenylmethyl] phenyl] methyl butyrate
• Example 26 4- [4-[(4-fluorophenyl) (4-methoxyphenylsulfonylamino) methinole] phenyl] methyl butyrate
• Example 27 4-C4-C (4-cyclophenylphenylsulfonylamino) (2-phenyl) methyl] phenyl] methyl butyrate
• Example 28 4-C4-C (4-chlorophenylsulfonylamino) (2-furyl) methyl] phenyl] methyl butyrate
• Example 35 4-C4- [phenyl (phenylsulfonylamino) methinole] phenyl] acrylic acid
• Example 37 4- [4-1-((4-chlorophenylsulfonylamino) (3-fluorophenyl) methyl] phenyl] butyric acid
• Example 38 4- [4-[(4-chlorophenylsulfonylamino) (4-fluorophenyl) methyl] phenyl] butyric acid
• Example 39 4-C4-C (4-chlorophenyl) (4-chlorophenylsulfonylamino) methyl] phenyl] butyric acid
• Example 41 1 4- [4-[(4-chlorophenylsulfonylamino) (2-methoxyphenyl) methizole] phenyl] butyric acid
• Example 42 4-C4-C (4-chlorophenylsulfonylamino) (4-trifluoromethylphenyl) methyl] phenyl] butyric acid
• Example 44 4- [4-[[(4-fuzoreo mouth feninole)] (4-funorelolophenylsulfonylamino) methyl] phenyl] butyric acid
• Example 48 4-C4-C (4-methylphenylsulfonylamino) phenylmethyl] phenyl] butyric acid
• Example 50 4- [4-([4- (methoxyphenylsulfonylamino) phenylmethyl] phenyl] butyric acid
• Example 51 -C4-C (4-monofluorophenyl) (4-methoxyphenylsulfonylamino) methyl] phenyl] butyric acid
• Difficult example 53 (1) -4- [4-1 [(4-chlorophenylsulfoninoleamino) phenylmethyl] phenylbutyric acid '
• the reaction solvent was distilled off under reduced pressure, water was added to the residue, acidified with dilute hydrochloric acid, and extracted with methylene chloride.
• Example 2 Compound of 9 5 Omg Lactose qs Maize starch 3 4 mg Magnesium stearate 2 mg Hydroxypropyl methylcellulose 8 mg Polyethylene glycol 6 0 0 0 .5 mg Titanium oxide 0.5 mg
• a capsule is produced by the following method, Example 2 9 Compound 5 Omg Lactose Appropriate amount Carboxymethylcellulose calcium 15 mg Hydroxypropylcellulose 2 mg Magnesium stearate 2 mg
• the agent is manufactured by the following method.
• the substituted benzenesulfonamide derivative represented by (I) and the physiologically acceptable salt thereof of the present invention are useful as a platelet aggregation inhibitor, a detoxifying agent and an antiasthmatic agent.

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• Chemical & Material Sciences (AREA)
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• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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• 1992
  • 1992-12-01 TW TW81109597A patent/TW219358B/zh active
  • 1992-12-17 WO PCT/JP1992/001643 patent/WO1993013057A1/ja active Application Filing
  • 1992-12-17 AU AU31709/93A patent/AU3170993A/en not_active Abandoned

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