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WO1996020186A1 - Derives d'acide carboxylique, leur procede de fabrication et composition medicale contenant ces derives - Google Patents

Derives d'acide carboxylique, leur procede de fabrication et composition medicale contenant ces derives Download PDF

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Publication number
WO1996020186A1
WO1996020186A1 PCT/JP1995/002686 JP9502686W WO9620186A1 WO 1996020186 A1 WO1996020186 A1 WO 1996020186A1 JP 9502686 W JP9502686 W JP 9502686W WO 9620186 A1 WO9620186 A1 WO 9620186A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
methyl
physiologically acceptable
group
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/JP1995/002686
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English (en)
Japanese (ja)
Inventor
Makoto Murata
Toshiyuki Negoro
Shozo Ueda
Buichi Fujitani
Yoshiyuki Ono
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.)
Sumitomo Pharma Co Ltd
Original Assignee
Dainippon Pharmaceutical 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 Dainippon Pharmaceutical Co Ltd filed Critical Dainippon Pharmaceutical Co Ltd
Priority to AU43159/96A priority Critical patent/AU4315996A/en
Publication of WO1996020186A1 publication Critical patent/WO1996020186A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans

Definitions

  • the present invention relates to a novel carboxylic acid derivative having an aldose reductase (aldose reductase) inhibitory action, and more particularly to a benzyl group.
  • Japanese Unexamined Patent Publication No. Hei 2 — 2 6 4 7 18 discloses 3— (3,4—dihydroxybenzyl) 1 7—hydroquinine represented by the following formula: It discloses that 2,3-dihydro-14H-1-benzopyran-4-one has an aldose reductase inhibitory action.
  • Japanese Unexamined Patent Publication (Kokai) No. 63-079771 U.S. Pat. No. 4,8,076 discloses a 4H-1 monobenzopyran-14-one derivative represented by the following general formula. Disclosed as having uric acid excretion, diuretic and antihypertensive effects Is
  • R 2 are the same or different and each represents a hydrogen atom, a lower alkyl group, an aryl group optionally having one or more substituents, or an aryl group having one or more substituents.
  • a good aralkyl group, etc., Y and Y 2 are the same or different and are a hydrogen atom, a lower alkyl group, a halogen atom, etc., ⁇ is a carboxyl group, a lower alkoxycarbonyl group, etc., and ⁇ is an integer of 1 to 6.
  • the dashed line means an optionally present double bond.
  • the basic structure of the compound of the present invention is a structure common to natural substances known as homoisoflavonoids. Many homoisoflavonoids have been isolated [see, for example, Chem. Pharm. Bull., 28. 1477-1484 (1980)]. Also, Bull. So Chim. Fr., 128, 976-978 (1991) discloses a compound having a 3—benzyl-4H-1-1-benzothiopyran-14-one skeleton which is a basic structure of the compound of the present invention. Have been reported. However, none of these compounds has a hydroxyl group as a substituent in the benzyl moiety.
  • Japanese Unexamined Patent Publication No. Hei 5-310719 discloses that thiazolidin-2,4-dione derivatives represented by the following general formula are aldose redak. It discloses that it has a protease inhibitory action and a hypoglycemic action.
  • R, R 2 and R 3 are each independently a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, an alkoxycarbonyloxy group, and A is a methylene group or an oxygen atom )
  • R represents a hydrogen atom or a chlorine atom.
  • aldose reductase is a key enzyme in the pathway of polyol metabolism and is an enzyme that converts glucose to sorbitol.
  • the uptake of glucose into tissues such as blood vessels, peripheral nerves, lenses, retina, and kidneys increases as blood glucose levels rise, as compared to healthy individuals.
  • polyol metabolism by aldose reductase becomes active, sorbitol production increases, and sorbitol accumulation in tissues progresses.
  • the present invention provides a compound represented by the general formula (I):
  • R represents a group represented by the following formula (A) or (B)
  • the present invention also provides a compound represented by the general formula (H), which is useful as an intermediate of a compound represented by the formula (I) wherein R is a group represented by the formula [A]:
  • R ′ represents a carboxyl-protecting group
  • X represents the same as described above
  • a wavy line represents an E configuration or a Z configuration.
  • physiologically acceptable salts of the compound represented by the formula (I) include salts with inorganic bases such as sodium salt, potassium salt and ammonium salt, and isopropylamine.
  • Salts with organic bases such as getylamine, ethanolamine, triethanolamine, piperidine, and salts with lysine.
  • “Compound that can be converted into a compound of formula (I) in vivo” refers to a compound of formula (I) in which a carboxyl group of the compound is modified.
  • acetomethyl ester, propionyloxymethyl ester, bivaloyloxymethyl ester, 2- (ethoxyquinoxy) ethyl ester, and phthalidyl ester for example, a 2-hydroxycarbonyl group at a carboxyl group.
  • protecting group for carboxyl group means a protecting group which can be eliminated by hydrolysis or hydrogenolysis.
  • Specific examples of the former include lower alkyl groups such as methyl, ethyl and propyl.
  • Specific examples of the latter group include benzyl, 4-methoxybenzyl, and 4-nitrobenzyl.
  • the scope of the compounds of the present invention includes the following compounds, physiologically acceptable salts thereof, and compounds which can be converted into the compounds in vivo.
  • the compound of the present invention can be produced, for example, by the following method.
  • Examples include alkaline bicarbonate such as tritium and calcium bicarbonate.
  • Specific examples of the solvent to be used include lower alcohols such as methanol and ethanol, dioxane, water and a mixture thereof.
  • the reaction temperature is usually about 0 to about 100 ° C, preferably about 50 ° C to about 90 ° C.
  • R 1 is a protecting group which can be eliminated by hydrogenolysis
  • the hydrogenolysis is carried out according to a method known per se, and usually in a suitable solvent, palladium monocarbon, Raney nickel, etc.
  • the reaction is carried out by reacting with hydrogen in the presence of the above catalyst.
  • Specific examples of the solvent to be used include water, methanol, ethanol, acetic acid, dioxane, and tetrahydrofuran. These solvents may be used alone or
  • the reaction temperature is usually about 25 "C to about 80 ° C, and the reaction is carried out under normal pressure or under pressure.
  • the starting compound represented by the formula (H) can be produced, for example, by a method shown in the following reaction scheme.
  • the compound of the formula (H), which is an intermediate of the present invention, can be produced by reacting the compound of the formula (IV) with the compound of the formula (V).
  • This reaction is carried out under usual aldol condensation conditions, for example, by reacting a compound of the formula (IV) with a compound of the formula (V) in a suitable solvent in the presence of an acid or a base.
  • the acid used include hydrochloric acid, sulfuric acid, and acetic acid.
  • Specific examples of the base include alkaline hydroxides such as sodium hydroxide and potassium hydroxide, and the like. Piperidine and liposome.
  • Specific examples of the solvent to be used include lower alcohols such as methanol and ethanol, aromatic hydrocarbons such as toluene and xylene, or a mixture thereof.
  • the reaction temperature is usually about 0 ° C to about 140 ° C.
  • the starting compound represented by the formula (IV) can be produced according to a method known per se, using commercially available 4-chloro-3-methylphenol as a starting material. For example, after reacting acrylonitrile in the presence of benzyltrimethylammonium hydroxide with chloro-3-methylphenol, the product is hydrolyzed to 3— (4 One 3 -methylphenoxy).
  • the compound can be converted to a compound of the formula (IV) by subjecting it to a ring closure under the conditions of a Friedel-Crafts reaction, for example, using trifluoroacetic anhydride and trifluoroborane etherate.
  • 3- (4-chloro-3-methylphenoxy) punic acid also reacts with 4-chloro-3-methylphenol and ethyl 3-bromopropanoate in the presence of a suitable base to give the product Can also be produced by hydrolysis of
  • the starting compound in which X is an oxygen atom can be obtained by, for example, using a commercially available sodium salt of 2-hydroxybenzaldehyde with a low-alkyl alkyl bromoacetate according to a conventional method. It can be produced by alkylation or esterification of a commercially available 2-formyloxyacetic acid with a suitable esterifying agent in the presence of an acid or a base according to a conventional method.
  • the starting compound in which X is a methylene group in the formula (V) is disclosed in No. 1,810,039 (Chem. Abstr., 98, 125429b (1983)) or a method analogous thereto, or subjecting the product to a transesterification reaction by a conventional method. It can be manufactured by attaching.
  • the conversion of the compound of the formula (E) to the compound of the formula ( ⁇ ) can be carried out, for example, by the method described in J. Chem. So, Perkin I, 1977, 359-363. That is, the compound of the formula (H) can be led to the compound of the formula ( ⁇ ⁇ ⁇ ) by making the compound of the formula (H) differentiate in the presence of rhodium trichloride.
  • the solvent to be used for example, halogenated hydrocarbons such as dichloromethane and black form, lower alcohols such as methanol and ethanol, water, or a mixture thereof. Is mentioned.
  • the reaction temperature is usually about 25 ° C to about 80 ° C.
  • R 11 represents a hydrogen atom or a carboxyl-protecting group.
  • R 11 is a protecting group which can be eliminated by hydrogenolysis, it can be produced by hydrogenolysis of the product.
  • the reaction of the compound of the formula (VI) with the compound of the formula (V ') is usually carried out in a suitable aqueous solvent in the presence of a base.
  • a base include sodium hydroxide and alkali hydroxide such as sodium hydroxide.
  • the solvent to be used include lower alcohols such as methanol and ethanol, dioxane, and a mixture thereof.
  • the reaction temperature is usually about 0 ° C to about 100 ° C, preferably about 50 ° C to about 90 ° C.
  • the starting compound represented by the above formula (V [) can be prepared by a known method [for example, SR Sandler and W. Rikichichi, “Organic Functional Group Preparations”, Academic Press, New York and London , pp. 484-485 (1968)], and can be produced according to a method known per se using 3 -fluorothiol enol as a starting material. For example, in the presence of a suitable base, 3-fluorothiophenol is reacted with 3-bromoethyl ether, and the product is hydrolyzed to 3-(3 -fluorodithio) propanoic acid.
  • the propanoic acid compound Can be converted to a compound of the formula (VI) by subjecting the ring to ring closure under the conditions of Free-Draeff-Crafuch reaction using, for example, trifluoroacetic anhydride and trifluoroborane etherate.
  • the product obtained by each of the above production methods can be isolated and purified by a conventional method such as chromatography, recrystallization, reprecipitation and the like.
  • the prodrug of the compound of the formula (I) can be produced according to a conventional method, and can be obtained, for example, by the following method.
  • Prodrugs which do not have a hydroxy group in the ester moiety can be prepared by adding a compound of formula (I) to a compound of the formula (I) in a suitable solvent in the presence of a base in the presence of It can be produced by reacting a suitable alkylating agent such as chloromethyl pivalate.
  • a suitable solvent such as chloromethyl pivalate.
  • the solvent to be used include acetonitrile, dioxane, toluene, acetone, dimethylformamide, and a mixture thereof.
  • Specific examples of the base include heavy solvents. Alkaline bicarbonate, such as sodium carbonate and potassium bicarbonate, and triethylamine.
  • the reaction temperature is usually about 0 ° C to about 100 ° C.
  • Such prodrugs may also be used in the absence of solvents or in acetonitrile, dioxane, toluene, acetone, dimethylformamide, or mixtures thereof, with the appropriate acid (eg, sulfuric acid, hydrochloric acid, In the presence of p-toluenesulfonic acid), a dihydric alcohol having one hydroxy group protected (for example, 2- (benzyloxy) ethanol) and a compound of formula (I) are reacted with each other for about 0 hours. After the reaction at a temperature of about 150 ° C. to about 150 ° C., the protecting group in the product can be produced by a conventional method, for example, by deprotection by hydrogenolysis.
  • the appropriate acid eg, sulfuric acid, hydrochloric acid, In the presence of p-toluenesulfonic acid
  • a dihydric alcohol having one hydroxy group protected for example, 2- (benzyloxy) ethanol
  • the 2- (hydroxy) ethyl ester of the compound wherein R is a group represented by the formula [A] is also a compound wherein R 1 is a lower alkyl group (eg, methyl, ethyl) in the formula (m).
  • R 1 is a lower alkyl group (eg, methyl, ethyl) in the formula (m).
  • a catalyst eg, sodium hydride, sodium hydroxide, sodium alkoxide
  • the compound of the present invention represented by the above formula (I) can be converted into a physiologically acceptable salt by treating it with an inorganic or organic base.
  • the inorganic and organic bases include hydroxides, carbonates or bicarbonates of alkali metals (for example, sodium and potassium), ammonium hydroxide, and isopropylamine. , Getylamine, ethanolamine, pyridin and lysine. Salt formation is carried out in a conventional manner, for example, in water, lower alcohols (eg, methanol, ethanol, isopropyl alcohol), ethyl acetate, acetonitril, dioxane, toluene or a mixture thereof.
  • Diabetes was induced by administering streptozotocin (40 mgZkg) dissolved in physiological saline to the tail vein of four male Wistar rats (body weight 200-250 g) per group.
  • T sorbitol content in sciatic nerve of streptozotocin-treated diabetic rat administered test compound
  • N sorbitol content in the sciatic nerve of a normal rat (a rat treated with no streptozotocin and no test compound).
  • Table 1 the compounds of Examples 1, 2 and 3 have a significantly lower sorbitol accumulation-inhibitory effect than that of epallesstatt and stronger than that of the torres sunset.
  • the compound represented by the formula (I), a physiologically acceptable salt thereof, and a compound capable of being converted into a compound of the formula (I) in vivo (hereinafter, also referred to as “the compound of the present invention”) has excellent aldose reductase inhibitory activity and low toxicity, and as a therapeutic agent for diabetic complications, various diabetic complications in humans including mammals (eg, It can be used for the treatment and prevention of retinopathy, cataract, keratopathy, neuropathy, and sickness. Further, since the compound of the present invention is excellent in solubility, it is particularly useful as an eye drop for treatment and prevention of retinopathy, cataract, keratosis and the like.
  • the administration route of the compound of the present invention may be any of oral administration, parenteral administration, rectal administration and topical administration, but oral administration and topical administration as eye drops are preferred.
  • the dose of the compound of the present invention varies depending on the type of the compound, the administration method, the condition of the patient and the age, etc. Usually 0.01 to 20 mg / kg / day, preferably 0.05 to 10 mg / kg. / Day.
  • the compounds of the present invention are usually administered in the form of a pharmaceutical composition prepared by mixing with a pharmaceutical carrier.
  • a pharmaceutical carrier a substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used.
  • the pharmaceutical carrier a substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used.
  • compositions are prepared according to a conventional method. When used, liquid preparations may be dissolved or suspended in water or other appropriate medium. Tablets and granules may be coated by well-known methods. Solubilizing agents, buffers, pH adjusters, tonicity agents, soothing agents, preservatives, etc. can be added to injections and eye drops as needed.
  • compositions can usually contain the compound of the present invention as an active ingredient in an amount of 0.01% or more, preferably 0.03 to 70%.
  • pharmaceutical compositions may also contain other therapeutically active ingredients, such as oral hypoglycemic agents.
  • a pharmaceutical composition comprising the compound of the present invention as an active ingredient is used for the treatment of diabetic complications.
  • insulin or oral hypoglycemic agents such as gliclazide, glibenclamide, troubyumid, acetatehexamide, and glymidine sodium.
  • gliclazide glibenclamide
  • troubyumid acetatehexamide
  • glymidine sodium can also be used together.
  • Example 5 The same reaction and treatment as in Example 5 were carried out in the same manner as in Example 5 except that ethyl 2- (2-formylphenyl) propanoate was used in place of ethyl (2-formyloxy) acetate in Example 5. Get things.
  • the starting compounds used in the above examples are produced as follows.
  • Methyl 3- (2-formylphenyl) propanoate 8.0 produced according to the method described in JP-A-57-181039 (Chem. Abstr., 98, 125429b (1983)) g is added to a mixture of 60 ml of dioxane and 60 ml of 1N aqueous sodium hydroxide solution, and the mixture is stirred at 70 ° C for 1 hour. After completion of the reaction, the solvent is distilled off under reduced pressure, water is added to the residue, and diluted hydrochloric acid is added under ice-cooling to make it acidic.
  • the precipitated crystals are collected by filtration, washed with water, applied to a silica gel column chromatograph, and eluted with a chromatophore // metanol (20: 1).
  • the fractions containing the desired product are collected and concentrated under reduced pressure to obtain 3.6 g of the desired product.
  • Compound 2 200 g Corn starch 160 g Lactose 600 g Hydroquinine propylcellulose 30 g Light gay anhydride 10 g The above components are mixed and granulated according to a conventional method. Prepare 20% powder O
  • the total amount was 100 ml.
  • An eye drop was prepared according to the above-mentioned formulation according to a conventional method. Industrial applicability
  • the compound of the present invention has a potent aldose reductase inhibitory activity and low toxicity, and thus is useful as a therapeutic agent for glycemic complications in mammals including humans It is.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé d'acide carboxylique représenté par la formule générale (I): R-CH2COOH, les sels de ce dérivé, un composé susceptible d'être transformé pour former le composé sus-mentionné (I) in vivo, un procédé de fabrication du dérivé en question et une composition médicale à base de ce dérivé. Dans ladite formule, R est un groupe représenté par la formule [A] ou [B]. Dans la formule [A], X est oxygène ou méthylène. Etant donné qu'ils ont un effet inhibiteur puissant sur le processus aldose réductase, ces composés sont utiles pour le traitement des complications diabétiques.
PCT/JP1995/002686 1994-12-28 1995-12-26 Derives d'acide carboxylique, leur procede de fabrication et composition medicale contenant ces derives Ceased WO1996020186A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU43159/96A AU4315996A (en) 1994-12-28 1995-12-26 Carboxylic acid derivatives, process for producing the same, and medicinal composition containing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP6/340596 1994-12-28
JP34059694 1994-12-28

Publications (1)

Publication Number Publication Date
WO1996020186A1 true WO1996020186A1 (fr) 1996-07-04

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PCT/JP1995/002686 Ceased WO1996020186A1 (fr) 1994-12-28 1995-12-26 Derives d'acide carboxylique, leur procede de fabrication et composition medicale contenant ces derives

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AU (1) AU4315996A (fr)
WO (1) WO1996020186A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110172052A (zh) * 2019-05-25 2019-08-27 扬州工业职业技术学院 一种苯并吡喃酮衍生物的制备工艺与应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63107971A (ja) * 1986-06-04 1988-05-12 Dai Ichi Seiyaku Co Ltd ベンゾピラン誘導体
JPH02264718A (ja) * 1989-04-04 1990-10-29 Tsumura & Co アルドースリダクターゼ阻害剤
JPH05310719A (ja) * 1992-04-28 1993-11-22 Terumo Corp チアゾリジン−２，４−ジオン誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63107971A (ja) * 1986-06-04 1988-05-12 Dai Ichi Seiyaku Co Ltd ベンゾピラン誘導体
JPH02264718A (ja) * 1989-04-04 1990-10-29 Tsumura & Co アルドースリダクターゼ阻害剤
JPH05310719A (ja) * 1992-04-28 1993-11-22 Terumo Corp チアゾリジン−２，４−ジオン誘導体

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110172052A (zh) * 2019-05-25 2019-08-27 扬州工业职业技术学院 一种苯并吡喃酮衍生物的制备工艺与应用

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