[go: up one dir, main page]

WO1999021554A1 - Agent anti-ulcereux - Google Patents

Agent anti-ulcereux Download PDF

Info

Publication number
WO1999021554A1
WO1999021554A1 PCT/JP1998/004775 JP9804775W WO9921554A1 WO 1999021554 A1 WO1999021554 A1 WO 1999021554A1 JP 9804775 W JP9804775 W JP 9804775W WO 9921554 A1 WO9921554 A1 WO 9921554A1
Authority
WO
WIPO (PCT)
Prior art keywords
lower alkyl
hydroxy
compound
mmol
production example
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1998/004775
Other languages
English (en)
Japanese (ja)
Inventor
Saichi Matsumoto
Hirokuni Jyoyama
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shionogi and Co Ltd
Original Assignee
Shionogi and Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shionogi and Co Ltd filed Critical Shionogi and Co Ltd
Priority to AU96457/98A priority Critical patent/AU9645798A/en
Publication of WO1999021554A1 publication Critical patent/WO1999021554A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • 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
    • 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
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings

Definitions

  • the present invention relates to a novel benzylidene derivative, an anti-ulcer agent and an anti-gastrointestinal disorder agent comprising the benzylidene derivative as an active ingredient.
  • the present invention further provides the benzylidene-derived yarn.
  • drugs commonly referred to as disease-modifying antirheumatic drugs are often used in combination with non-steroid anti-inflammatory drugs.
  • Conventional nonsteroidal anti-inflammatory drugs have had problems with side effects such as gastrointestinal disorders and induction of ulcers caused by long-term administration in the treatment of such chronic inflammatory diseases.
  • non-steroidal anti-inflammatory agent itself further has a preventive effect against gastrointestinal disorders and ulcers, the above-mentioned problem of side effects can be avoided and clinical value will be increased.
  • it can be used in combination with other existing non-steroidal anti-inflammatory drugs, so that early treatment of chronic inflammatory diseases can be effectively performed. No such non-steroidal anti-inflammatory drug has ever been known to have a potent and preventive effect on gastrointestinal disorders and ulcers. Summary of the Invention
  • R 1 and R 4 are the forces wherein R 1 is hydrogen, lower alkyl, lower alkoxy, hydroxy lower alkyl or carboxy lower alkyl and R 4 is hydroxy or R 1 and R 4 are Together form one CR 5 R 6 — (CH 2 ) m — ⁇ one or one CR5R 6 — (CH 2 ) p CH (OH) one O— (where m is an integer from 1 to 3 P is an integer from 0 to 2; R 5 and R 6 each independently represent hydrogen, lower alkyl, lower alkoxy or hydroxy lower alkyl);
  • R 2 is hydrogen, lower alkyl, lower alkoxy, hydroxy lower alkyl or carboxy lower alkyl;
  • R : i is hydrogen, lower alkyl, cycloalkyl, lower alkoxy, arylalkyloxy, heteroarylalkyloxy, lower alkylcarbonyl, arylcarbonyl, substituted or unsubstituted rubamoyl, or a compound represented by the formula:
  • the present invention provides a novel use of such a derivative as an anti-ulcer agent and an anti-gastrointestinal disorder agent.
  • the present invention provides an anti-ulcer agent comprising a compound represented by the formula (I), a pharmaceutically acceptable salt or a hydrate thereof as an active ingredient.
  • the present invention provides an anti-gastrointestinal disorder containing the compound represented by the formula (I) or a pharmaceutically acceptable salt or a hydrate thereof as an active ingredient.
  • a preparation containing a compound comprising R and H is a preferred anti-ulcer and anti-gastrointestinal disorder.
  • the present invention provides the use of a compound represented by the formula (I) for the manufacture of an anti-ulcer agent.
  • the present invention also provides use of the compound represented by the formula (I) for the manufacture of an anti-digestive tract disorder agent.
  • the present invention provides a method for preventing and / or treating ulcer, which comprises administering an effective amount of a compound represented by the formula (I) to a mammal in need thereof.
  • the present invention also provides a method for preventing and / or treating a gastrointestinal tract disorder, which comprises administering an effective amount of a compound represented by the formula (I) to a mammal in need thereof.
  • a part of the benzylidene derivatives of the present invention represented by the above formula (I) has been disclosed as a PG production inhibitor in Japanese Unexamined Patent Publication No. 6-21819 (published on August 2, 1994). .
  • the present invention further provides a novel compound of the formula ():
  • R 1 ′ and R 4 ′ are the forces where R 1 ′ is hydroxy lower alkyl or carboxyl lower alkyl and R 4 ′ is hydroxy or when R 1 ′ and R 4 ′ are To form one CR 5 R i; _ (CH 2 ) m — O— or one CR 5 R fi — (CH 2 ) p CH (OH) —O— (where m is an integer from 1 to 3 P is an integer from 0 to 2; R 5 and R 6 are each independently hydrogen, lower alkyl, Represents lower alkoxy or hydroxy lower alkyl);
  • R 2 ′ is hydrogen, lower alkyl, lower alkoxy, hydroxy lower alkyl or carboxy lower alkyl;
  • R 3 ′ is hydrogen, lower alkyl, cycloalkyl, lower alkoxy, arylalkyloxy, heteroarylalkynoleoxy, lower alkylcarbonyl, arylcarbonyl, substituted or unsubstituted rubamoyl, or a formula:
  • FIG. 1 is a graph showing the effect of suppressing indomethacin-induced gastric damage in rats.
  • the experimental results are expressed as the mean soil standard error, and the significance test is performed using the Dimnett t-test (* p
  • compound (I) of the present invention has a (E) -type steric structure, as is clear from the structural formulas described above.
  • compound (I) herein refers to stereoisomers of the (E) — type.
  • “Lower alkyl” means a linear or branched alkyl group of Ci—Cs, methinole, ethynole, n-propynole, i-propynole, n-butynole, i-butynole, s-butynole, t-butynole.
  • N-pentinole, i-pentinole, nesenti pentinole, s-pentinole, t-pentinole, n-hexyl, neohexyl, i_hexinole, s-hexyl, t-hexinole, heptinole, octyl Is exemplified.
  • C 4 , —C 4 linear or branched alkyl is preferred.
  • Most preferred groups are methyl or ethyl.
  • Lower alkoxy j means straight or branched alkyloxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, S -Butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, neopentinoleoxy, S-pentyloxy, t-pentinoleoxy, n-hexyloxy, neohexyloxy, i-hexyloxy, s-hexyloxy And t-hexoxy, etc.
  • C j _C 3 alkoxy is preferred, and the most preferred group is methoxy.
  • “Hydroxy lower alkyl” is the above-mentioned lower alkyl group substituted with a hydroxyl group, and exemplifies hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 1,1-dimethyl-12-hydroxyethyl and the like. Can be done.
  • Carboxy lower alkyl means a lower alkyl group substituted with a carboxyl group, and examples thereof include carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, 1,1-dimethyl-2-carboxyethyl and the like. Power S can.
  • Cycloalkyl means cycloalkyl having 3 to 7 carbon atoms, and examples include cyclopropynole, cyclopentinole, cyclopentinole, cyclohexinole, cycloheptinole and the like. Among them, C 3 -C 5 cycloalkyl is preferred.
  • Aryl means unsubstituted or substituted phenyl or naphthyl, and examples of the substituent include a halogen, a lower alkoxy, a lower alkyl and a nitro group, which may have one or more of these.
  • substituent include a halogen, a lower alkoxy, a lower alkyl and a nitro group, which may have one or more of these.
  • phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-nitrophenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 3,4-dinitrophenyl, 1-naphthinole, 2-naphthyl and the like can be mentioned.
  • Arylalkyloxy is the above-mentioned lower alkoxy group substituted with the above-mentioned aryl group, and is benzyloxy, 4-chlorobenzyloxy, 4-methoxybenziloxy, 3,4-dichlorobenzyloxy.
  • Heteroaryl is a group having 1 to 4 hetero atoms, and examples thereof include pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, and tetrazolyl.
  • Preferred heterocyclic rings for the present invention are pyridyl, thiazolyl, oxazolyl, imidazolyl. The most preferred group is pyridyl.
  • Heteroarylalkyloxy is the above-mentioned lower alkoxy group substituted with the above-mentioned heteroaryl group.
  • lower alkylcarbonyl is exemplified by acetyl, propionyl, butyryl, valeryl, hexyl, heptanoyl, octanoyl and the like.
  • Arylcarbonyl means benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl, 4-nitrobenzoyl, 3,4-dichlorobenzoyl, 3,4-dimethoxybenzoyl, 3,4-dinitrobenzoyl , 1-naphthoyl, 2-naphthoyl and the like.
  • the substituent may be lower alkyl, lower alkoxy, hydroxy, cycloalkyl, arylalkyl, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, cycloalkyloxy, arylalkyl. And one or more of these may be substituted on the N atom.
  • lower alkyl, lower alkoxy and hydroxy are preferred.
  • Halogen includes fluorine, chlorine, bromine, and iodine.
  • lower alkyloxycarbonyl examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl and the like.
  • Substituted amino means mono- or di-substituted amino, and the substituent includes the lower alkyl and arylalkyl.
  • “Pharmaceutically acceptable salt or hydrate thereof” means a salt of a compound represented by the formula (I) or a hydrate thereof, which is substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those formed by reaction of a compound of formula (I) with an inorganic or organic acid or base. Such salts are known as acid addition and base addition salts.
  • Acids commonly used to form acid addition salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and p-toluenesulfonic acid, methanesulfonic acid, Organic acids such as oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and p-toluenesulfonic acid, methanesulfonic acid
  • Organic acids such as oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid.
  • Bases commonly used to form base addition salts include inorganic bases such as ammonium hydroxide, ammonium carbonate, ammonium hydrogen carbonate, hydroxides and carbonates of alkali or alkaline earth metals, and Organic bases such as aliphatic, primary, secondary and tertiary amines, aliphatic diamines and the like can be mentioned.
  • the above-mentioned pharmaceutically acceptable acid or base addition salts are usually obtained by reacting the compound of the formula (I) with an equimolar or excess acid or base.
  • the compound of the present invention can be produced essentially by the method described in JP-A-6-218119 which forms a part of the description of the present invention, but the production method itself is not limited in any sense. Nor is it intended to limit the invention.
  • One production method of the compound of the present invention is exemplified in the following production examples. Reaction formula I
  • RR 2 and R 3 are as defined above, and R 7 is hydrogen or a hydroxy protecting group.
  • R 7 of the compound represents a hydroxy protecting group
  • examples of the protecting group include methoxymethyl, methoxetoxymethyl, trimethylsilyl and tert-butyldimethylsilyl.
  • R 7 is preferably a hydroxy protecting group, especially a methoxymethyl group.
  • the sulfur-containing heterocyclic compound 1 can be produced, for example, according to the following reaction formula.
  • the reaction may be carried out in the presence of a base (A), if necessary, using a solvent such as ether, chloroform, methylene chloride, dichloroethane, tetrahydrofuran, dimethoxetane, jetoxetane, benzene, tonolene, xylene, ethylenol acetate, methylenol acetate, etc. And using these aqueous solvents.
  • the amine (R 3 NH 2 ) may be a hydrochloride.
  • a phase transfer catalyst As the phase transfer catalyst, quaternary ammonium salts such as N-benzyltrimethylammonium salt and tetrabutylammonium salt are preferable.
  • the reaction from the sulfone amide intermediate A to the sulfur-containing heterocyclic compound A can be carried out in the same solvent as described above in the presence of the base (B), but the reaction is carried out in an anhydrous solvent such as dimethyl sulfoxide or dimethylformamide. Solvents are preferred.
  • the base (B) in addition to the above bases, sodium hydride and lithium hydride can be used.
  • the sulfur-containing heterocyclic compound A can be obtained at once without isolating the sulfonamide intermediate _ from the compound II.
  • the reaction between the compound I and the amine is carried out in a suitable solvent in the presence of 2 equivalents of a base.
  • the solvent and the base are selected from the above examples, but it is particularly preferable to use sodium hydride as the base and dimethylformamide as the solvent.
  • the desired sulfur-containing heterocyclic compound A can be obtained from commercially available ⁇ -sanoleton (see Production Examples). That is, the compound A is reacted with an amine (R 3 NH 2 ), and then a dehydrating agent is allowed to act. The reaction operation can be carried out without using a solvent, but may be carried out in the above-mentioned solvent if necessary.
  • a commonly used reagent such as phosphorus oxychloride, thionyl chloride, phosphorus pentachloride or phosphorus pentoxide can be used, and phosphorus oxychloride is particularly preferred.
  • the aldol reaction of the compound with the compound obtained above is carried out in the presence of a base (C) in a suitable solvent.
  • a base (C) an organic lithium salt such as n-butyllithium, sec-butyllithium, tert-butyllithium, phenyllithium, lithium diisopropylamide, lithium getylamide, lithium hexamethyldisilazane, and hydrogenation are used.
  • alkali metal bases such as sodium and tert-butoxycalime. Particularly, lithium diisopropylamide or lithium hexamethyldisilazane is preferred.
  • reaction solvent examples include ether solvents such as getyl ether, tetrahydrofuran (THF), dimethoxyxetane, and diethoxyxetane, and hydrocarbon solvents such as n-hexane and cyclohexane. If necessary, it is desirable to carry out the reaction in the presence of a reagent serving as a ligand for metal lithium, for example, tetramethylethylenediamine, hexamethylphosphoramide and the like.
  • ether solvents such as getyl ether, tetrahydrofuran (THF), dimethoxyxetane, and diethoxyxetane
  • hydrocarbon solvents such as n-hexane and cyclohexane. If necessary, it is desirable to carry out the reaction in the presence of a reagent serving as a ligand for metal lithium, for example, tetramethylethylenediamine, hexamethylphosphoramide and the like.
  • the reaction is carried out at a temperature of 180 ° C. to + 50 ° C., preferably at a lower temperature.
  • the aldol adduct ⁇ is converted to compound (I) in the presence of an acid.
  • the acid include organic acids such as trifluoroacetic acid, p-toluenesulfonic acid, and camphorsulfonic acid, and inorganic acids such as sulfuric acid and hydrochloric acid.
  • ordinary dehydrating reagents such as thionyl chloride, methanesulfonyl chloride, aluminum chloride, phosphorus oxychloride and phosphorus pentachloride may be used.
  • reaction formula II The reaction is carried out in an aromatic hydrocarbon such as benzene, toluene and xylene, a halogenated hydrocarbon such as chloroform, dichloromethane and dichloroethane, and a ether-based solvent such as tetrahydrofuran, dimethyloxetane and dietoxetane under heating. Is desirable. Reaction formula II
  • the base (C) in the above formula has the same meaning as defined above.
  • Y represents an N-protecting group, such as tert-butoxycanoleboninole, penzinoleoxycanoleboninole, benzinole, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 4-nitrobenzyl, etc. .
  • the conditions for the aldol reaction are the same as those in the above Reaction Scheme I.
  • Dehydration and deprotection reagents used for conversion of caro-form with aldol to 10 include p-toluenesulfonic acid, trifluoroacetic acid, aluminum chloride, titanium tetrachloride and the like.
  • the conditions such as the reaction solvent and the temperature are the same as in the case of Reaction Formula I.
  • Compound 10 is deprotected to give compound 10 of formula (I) wherein R : i is hydrogen.
  • R 3 is an alkylidene
  • the base (D) to be used is sodium hydroxide
  • alkali metal salts such as lime, sodium carbonate, carbonated lime, sodium hydrogencarbonate, hydrogenated limestone, lithium hydroxide, and the like
  • organic bases such as pyridine, triethylamine, and disopropylethylamine.
  • the alkylation is preferably carried out using sodium hydroxide or carbonic acid lime and sharing an appropriate quaternary ammonium salt as a phase transfer catalyst.
  • R 3 X is an acylating agent
  • an organic base such as pyridine, 4-dimethylaminoviridine, triethylamine or diisopropylethylamine as the base (D).
  • R 3 X is a carbamoylating agent or an alkoxycarbonylating agent
  • an organic lithium base such as n-butyllithium, lithium hexamethyldisilazane, and lithium diisopropylamide is preferably used as the base (D).
  • organic bases such as pyridine, triethylamine and diisopropylethylamine or the above-mentioned alkali metal salts can also be used.
  • the compound 11 is debenzylated to obtain a compound of the formula (I) wherein R 3 is a hydroxyl group.
  • Debenzylation is performed using a deprotecting agent. Deprotection is carried out by hydrogenation in the presence of a palladium carbon or platinum oxide catalyst or by using a Lewis acid such as aluminum chloride and titanium tetrachloride in the presence of anisol and 2,6-di-tert-butylphenol as required. Can be implemented.
  • halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, nitromethane, benzene, toluene, xylene and the like can be used.
  • the methods described in the above Reaction Schemes I, II and III can be generally applied to the production of the compound (I) of the present invention, and specific examples are shown in Production Examples 1-43 described below.
  • the compound (I) of the present invention can be administered orally or parenterally as an anti-inflammatory agent.
  • the compound of the present invention can be used in the usual preparations, for example, solid preparations such as tablets, powders, granules and capsules; liquid preparations; oily suspensions; or liquid preparations such as syrups or elixirs. It can also be used as a dosage form.
  • the compound of the present invention can be used as an aqueous or oily suspension for injection or an external preparation.
  • any of conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, etc. can be used, and other additives such as preservatives, It may contain a stabilizer or the like.
  • the dose of the compound of the present invention varies depending on the method of administration, the age, body weight, condition and type of disease of the patient, but is usually orally 10 to 50 per day for adults.
  • Omg preferably 50-100 mg, or parenterally 1-250 Omg per day, preferably 5-1 Omg, divided into 1-5 doses Administration.
  • parenterally 1-250 Omg per day preferably 5-1 Omg, divided into 1-5 doses Administration.
  • Li HMD S Lithium hexamethyldisilazane
  • DI BAL Diisobutyl aluminum hydride
  • Ethylamine (70% aqueous solution, 4.4 gr, 68.3 t) was added to a solution of 3-chloropropylsulfonyl chloride (6.1 g, 34.5 kol) in ethanol solution (25 ml), and cooled with ice. The mixture was added dropwise with stirring. After the addition was completed in about 15 minutes, the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, benzene (10 Oml) was added to the residue, and the solvent was distilled off under reduced pressure.Ethanol (15 Oml) was added to the residue, the insoluble material was filtered off, and the ether was removed under reduced pressure.
  • This intermediate 3f (6.25 gr, 33.3 t ol) was reacted with sodium hydride (60% oily, 1.47 gr, 36.7 butyl ol) in the same manner as in Production Example 1 to obtain the desired product.
  • the compound was obtained as a colorless oil. Yield 3.70 g (73%).
  • N-benzyloxy 1,2-isothiazolidine-1-1,1-dioxide (4 g) 3-chloronolepropylsnolephonyl chloride ⁇ ⁇ (30.28gr, 0.17mol), ⁇ benzylbenzylhydroxyamine hydrochloride 27.3 g (0.17 mol), lithium carbonate (50 gr, 0.36 mol) and tetrabutylammonium sulfate (about 50 Omg) in a mixture of ether (11) and water (100 ml) at room temperature for 24 hours After the reaction, Extracted with ethyl acetate.
  • I RCCHC ⁇ ) ⁇ -1 3018, 1 516, 1 307, 1 262, 1 225, 1 1 55, 1 138, 1027
  • I RCKBr ⁇ -1 : 3010, 2960, 1595, 1493, 1300, 1 267, 1 1 31.
  • N- (2-pyridyl) -11,2-isothiazolidine-11,1-dioxide (41) By reacting 3-chloropropylsulfonyl chloride and 21-aminopyridine in the same manner as in Production Example 10. N- (2-Pyridyl) -13-chloropropylsulfonamide intermediate 31 was obtained as a pale yellow solid. Yield 54%. Then, to a DMF solution (30 ml) of this intermediate (2.138 gr, 9.11 mol) was added sodium hydride (60% oily, 401 mg, 10 mmol) under ice-cooling, and the mixture was heated to 85 ° C. After stirring for 30 minutes under reduced pressure, the solvent was distilled off under reduced pressure.
  • the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the target compound 4n was obtained as a yellow solid from a fraction eluted with a methylene chloride-methanol (10: 1) mixed solution. Yield 1.2 94gr (27%).
  • reaction mixture was cooled to 78 ° C, 100 ml of THF was added, and N-ethyl-1,2-isothiazolidine-l, l-dioxide 4a (15gr, 100.5mmol), 3,5-di-tert- Butynolee 4-Methoxymethoxybenzyl aldehyde A solution of K6a (25 g, 90.5 mmol) and HMP A (30 ml) in THF (70 ml) was added dropwise with stirring for 15 minutes, and then stirring was continued for 30 minutes at the same temperature. did.
  • the reaction product was subjected to silica gel column chromatography, and the target compound was obtained from the fraction eluted from a mixed solution of n-hexane monoethyl acetate (6: 1). Yield: 2.40 gr (41%).
  • reaction product was subjected to silica gel column chromatography, and the target compound was obtained from the fraction eluted from a mixed solution of n-hexane monoethyl acetate (2: 1). Yield 8.5%. mp 233-234 ° C
  • the reaction mixture was poured into a 1N aqueous hydrochloric acid solution (2 Oml), extracted with ethyl acetate (30 ml), and the ethyl acetate layer was washed with water (3 Oml) and saturated saline (3 Oml), and then dried over anhydrous sodium sulfate. did.
  • the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and the target compound Iu was obtained from the fraction eluted with a mixture of n-hexane monoethyl acetate (7: 3). Yield 230 mg (41%).
  • Titanium tetrachloride (500 ⁇ l, 4.56 mmol) was added to a methylene chloride solution (8 ml) of the compound IV (60 Omg, 1.13 mmol) obtained in Production Example 38 under ice cooling, and the mixture was stirred for 1.5 hours.
  • a 2N hydrochloric acid aqueous solution (10 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes.
  • the reaction mixture was extracted with methylene chloride (20 ml), and the organic layer was washed with saturated saline (20 ml). And dried. The solvent is distilled off under reduced pressure.
  • the target compound Iw was obtained from the fraction which was subjected to chromatography and eluted with n-hexane monoethyl acetate (1) mixed solution. Yield 150 mg (33%).
  • the aldol adduct Jjl (6.27 gr) was dissolved in toluene (120 ml), p-toluenesulfonic acid hydrate (600 mg) was added, and the mixture was heated under reflux for 30 minutes. 100 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The crystalline residue was recrystallized from methanol to obtain the target compound_I2L as colorless columnar crystals. Yield 2.16 gr (30%).
  • novel compounds of the present invention can be produced according to the following examples, but the production method itself does not limit the present invention in any way.
  • One method for producing the novel compound of the present invention is illustrated below.
  • Ozone gas was passed through a solution of 25 (3.90 g, 7.65 mmol) in dichloromethane (100 ml) and methanol (20 ml) at 178 ° C until the solution turned blue.
  • Triethylphosphine (3.94 ml, 23 mmol) was added to the reaction solution, and the temperature was slowly raised to room temperature.
  • the reaction solution was concentrated, the residue t- butanol (40 ml), H 2 0 (10 ml), 2 - methyl - 2-butene (8.1 ml, 76.5 mmol), NaH 2 P0 4 (2.31 g, 15.3 hide ol) And NaC10 2 (3.50 g, 30.6 mmol) was added slowly at room temperature.
  • DIBAL (0.93 M) (0.64 ml, 0.595 mmol) was slowly added to a solution of 29 (56 mg, 0.133 mmol) in hexane (1 ml) and dichloromethane (1 ml) at -78 ° C. Further, stirring was continued for 1 hour under the same conditions. Dilute hydrochloric acid was added to the reaction solution, the temperature was raised to room temperature, and the mixture was further stirred at room temperature for 15 minutes. The product was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate and saturated saline, dried and concentrated. The residue was purified by silica gel chromatography to give 31 mg (59%) of 31. Amorphous solid.
  • reaction solution is returned to room temperature, poured into dilute aqueous sodium hydrogen carbonate solution (60 ml), and the organic layer is separated and washed with saturated saline (60 ml). After drying, the solvent was distilled off, and the residue was purified by column chromatography to obtain 1.02 g (37%) of 44.
  • reaction solution is returned to room temperature, adsorbed on a small amount of silica gel, and eluted with ethyl acetate (150 ml).
  • residue obtained by distilling off the solvent was purified by column chromatography to obtain 556 mg (90%) of 51 as colorless crystals. mp. 152-155 ° C
  • IR (KBr) cnf ' 3411, 3140, 2965, 1642, 1594, 1436, 1291, 1266, 1143.
  • IR (KBr) cm— 1 3436, 2963, 2871, 1642, 1602, 1453, 1288, 1151.
  • compound (la) was administered to 6 rats per group. Oral administration, and 2 hours later, indomethacin 3 Omg / kg was orally administered.
  • the animals were exsanguinated and killed under anesthesia, the stomach was removed, and fixed by immersion in 1% formalin solution. The occurrence and degree of stomach dysfunction was determined by observing the stomach mucosal dysfunction using a stereomicroscope and expressing the cumulative value of bleeding plaques as a lesion index.
  • the compound of the present invention has an effect of suppressing indomethacin-induced gastric damage and the like, it is useful as an anti-gastrointestinal disorder agent and an anti-ulcer agent by a non-steroid anti-inflammatory agent.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Nouvel agent anti-ulcéreux contenant un composé représenté par la formule générale (I), un de ses sels acceptables sur le plan pharmaceutique, ou un hydrate de ce composé ou de ce sel en tant qu'ingrédient actif.
PCT/JP1998/004775 1997-10-24 1998-10-22 Agent anti-ulcereux Ceased WO1999021554A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU96457/98A AU9645798A (en) 1997-10-24 1998-10-22 Antiulcerative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/292358 1997-10-24
JP29235897 1997-10-24

Publications (1)

Publication Number Publication Date
WO1999021554A1 true WO1999021554A1 (fr) 1999-05-06

Family

ID=17780777

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/004775 Ceased WO1999021554A1 (fr) 1997-10-24 1998-10-22 Agent anti-ulcereux

Country Status (2)

Country Link
AU (1) AU9645798A (fr)
WO (1) WO1999021554A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1026162A4 (fr) * 1997-10-24 2001-01-17 Shionogi & Co Agent anti-rhumatismal
JP2017057190A (ja) * 2006-03-17 2017-03-23 ザ ジョンズ ホプキンス ユニバーシティ 新規で生理学的に有用なニトロキシル供与体としてのｎ−ヒドロキシルスルホンアミド誘導体

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06211819A (ja) * 1992-10-28 1994-08-02 Shionogi & Co Ltd ベンジリデン誘導体

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06211819A (ja) * 1992-10-28 1994-08-02 Shionogi & Co Ltd ベンジリデン誘導体

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1026162A4 (fr) * 1997-10-24 2001-01-17 Shionogi & Co Agent anti-rhumatismal
US6525081B1 (en) 1997-10-24 2003-02-25 Shionogi & Co., Ltd. Antirheumatic
US6743923B2 (en) 1997-10-24 2004-06-01 Shionogi & Co., Ltd. Antirheumatic agent
JP2017057190A (ja) * 2006-03-17 2017-03-23 ザ ジョンズ ホプキンス ユニバーシティ 新規で生理学的に有用なニトロキシル供与体としてのｎ−ヒドロキシルスルホンアミド誘導体
US9969684B2 (en) 2006-03-17 2018-05-15 Cardioxyl Pharmaceuticals, Inc. N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors

Also Published As

Publication number Publication date
AU9645798A (en) 1999-05-17

Similar Documents

Publication Publication Date Title
ES2483992T3 (es) Compuesto oxazol y composición farmacéutica
TWI482761B (zh) 製備１，２，４-二唑苯甲酸之方法
CN109942505B (zh) 异噻唑啉酮类化合物及相应用途
FR2569404A1 (fr) Nouveaux derives de 1,2-benzisothiazol-3-ylpiperazine, compositions pharmaceutiques contenant de tels composes et leurs procedes de preparation
CA2942871A1 (fr) Modulateurs de ror-gamma et leurs utilisations
EP1341761A1 (fr) Indoles substituees, compositions pharmaceutiques contenant ces indoles et leur utilisation comme agent de fixation de ppar-$g(g)
JP2005529855A (ja) Ｃｂ１−アンタゴニスト作用、アゴニスト作用または部分アゴニスト作用を有するチアゾール誘導体
WO2008038768A1 (fr) Composé ayant une structure de pyrimidine bicyclique et composition pharmaceutique comprenant le composé
JPH0471073B2 (fr)
US5418230A (en) Benzylidene derivatives
JP3507124B2 (ja) ベンジリデン誘導体の製造法
TW475928B (en) Antirheumatic agent comprising a benzylidene derivative as an active ingredient
RU2370488C2 (ru) Ингибиторы матриксных металлопротеиназ
WO1999021554A1 (fr) Agent anti-ulcereux
JP2728357B2 (ja) ベンジリデン誘導体
ES2348838T3 (es) Compuestos de cicloalquilideno como moduladores slectivos del receptor de estrã“genos.
JP3134097B2 (ja) オキサゾール化合物
KR20030041168A (ko) 비페닐 이속사졸 술폰아미드의 제조 방법
JP2011502119A (ja) Ｃｂ−１アンタゴニスト／逆アゴニストの合成及び結晶体
JPWO1999021554A1 (ja) 抗潰瘍剤
JP3618815B2 (ja) クロロアルキルスルホニルクロリドの製造方法
MXPA00003693A (en) Antirheumatic
WO1995018121A1 (fr) Nouveau derive de benzylamine
CN114634503A (zh) 含吲哚生物碱杂环取代-1,3-噻唑烷酮类衍生物及其制备方法和用途
BE895076R (fr) 1-oxydes et 1, 1-dioxydes de 1,2,5-thiadiazoles 3,4-disubstitues

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IS JP KE KG KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

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

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: KR

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase