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WO1999024429A1 - Nouveaux composes thiazolidine et utilisation de ceux-ci en medecine - Google Patents

Nouveaux composes thiazolidine et utilisation de ceux-ci en medecine Download PDF

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Publication number
WO1999024429A1
WO1999024429A1 PCT/JP1998/005026 JP9805026W WO9924429A1 WO 1999024429 A1 WO1999024429 A1 WO 1999024429A1 JP 9805026 W JP9805026 W JP 9805026W WO 9924429 A1 WO9924429 A1 WO 9924429A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
benzyl
dione
pharmaceutically acceptable
Prior art date
Application number
PCT/JP1998/005026
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English (en)
Japanese (ja)
Inventor
Shoji Kamiya
Masayasu Kasai
Akihisa Yoshimi
Hiroaki Shirahase
Hiroshi Matsui
Original Assignee
Kyoto Pharmaceutical Industries, 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 Kyoto Pharmaceutical Industries, Ltd. filed Critical Kyoto Pharmaceutical Industries, Ltd.
Priority to AU97627/98A priority Critical patent/AU9762798A/en
Publication of WO1999024429A1 publication Critical patent/WO1999024429A1/fr

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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
    • C07D417/12—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 chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel thiazolidine compound having a blood glucose and blood lipid lowering effect, and a pharmaceutical use thereof.
  • Therapeutic agents for diabetes include biguanide compounds whose main function is to suppress the absorption of intestinal glucose and release of glucose from the liver, and sulfonylprea compounds and insulin which have a main effect of promoting insulin secretion. Has been used. However, great care must be taken when using biguanides, such as those that cause lactic acidosis, and sulfonylprea compounds, which often have severe hypoglycemia because of their potent hypoglycemic effects. In recent years, research and development of therapeutic agents for diabetes that do not have these disadvantages have been actively conducted, and various compounds having an insulin resistance improving effect have been found.
  • Insulin resistance plays an important role as one of the causes of non-insulin-dependent resistant diabetes mellitus (NIDDM) together with decreased insulin secretion, and there is a strong demand for the development of drugs that improve insulin resistance. It is getting rare.
  • NIDDM non-insulin-dependent resistant diabetes mellitus
  • a drug for improving the insulin resistance for example, a thiazolidine compound as disclosed in WO 91/203 is known.
  • the present invention provides a compound represented by the general formula (I):
  • (J) represents a didol ring group which may be substituted with a lower alkyl group or a lower alkoxy group or an indoline ring group which may be substituted with a lower alkyl group or a lower alkoxy group
  • Y is
  • W represents a lower alkylene group
  • 777 "represents a single bond
  • a 1 and A 2 are the same or different and represent a single bond or an oxygen atom, provided that Y—A 1 — at the 1-position of the indole ring group or the indoline ring group, or
  • a ′ and A 2 represent a single bond.
  • a pharmaceutically acceptable salt represented by the formula:
  • the present invention also relates to a pharmaceutical composition, an antihyperglycemic agent, an antihyperlipidemic agent, an insulin resistance improving agent, and an antidiabetic complication agent comprising the above thiazolidine compound or a pharmaceutically acceptable salt.
  • the lower alkyl group has 1 to 6 carbon atoms and may be linear or branched, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, isopentyl, neopentyl, hexyl and the like.
  • the lower alkoxy group has 1 to 6 carbon atoms and may be linear or branched.
  • the lower alkylene group preferably has 1 to 6 carbon atoms and may be linear or branched, and includes, for example, methylene, ethylene, trimethylene and tetramethyl.
  • Tylene pentamethylene, hexamethylene, methylmethylene, 2,2-dimethyltrimethylene, 2-ethyltrimethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene and the like.
  • alkoxycarbonyl group examples include a straight-chain or branched-chain alkoxy moiety having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, and the like. Isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like.
  • Examples of the acidic group include a carboxyl group, a sulfonic acid group, and a phosphoric acid group.
  • Preferred examples of the thiazolidine compound represented by the general formula (I) and a pharmaceutically acceptable salt include the following thiazolidine compounds (1) to (4) And the salts acceptable above.
  • the compound (I) of the present invention may be in the form of a pharmaceutically acceptable salt.
  • an acid addition salt can be formed, but as an acid for forming the acid addition salt, a salt can be formed with a basic moiety, and a pharmaceutically acceptable salt can be formed.
  • acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid, and toluenesulfonic acid.
  • the compound (I) of the present invention has an acidic group such as a carboxyl group
  • examples thereof include alkali metal salts (eg, sodium salt, magnesium salt, etc.) and alkaline earth metal salts.
  • Salts such as salts (eg, calcium salts, magnesium salts, etc.) and organic base salts (eg, triethylamine salts, dicyclohexylamine salts, pyridine salts, etc.) can be used.
  • the compound (I) of the present invention can be produced, for example, by the following production method.
  • Y 1 is an acidic group, a protected acidic group, an alkoxycarbonyl group, a hydroxyl group, a protected hydroxyl group, or an acidic group, a protected acidic group, an alkoxycarbonyl group, a hydroxyl group or a protected Indicates a lower alkylene group substituted with a hydroxyl group.
  • the carboxyl group may be protected by, for example, tert-butyl, tert-amyl, benzyl, p-methoxybenzyl, p-methoxybenzyl, benzhydryl, p—Difluorophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, methylthiomethyl, trityl, 2,2,2-trichloroethyl, trimethylsilyl, diphenylmethoxybenzenesulfonylmethyl, dimethylaminoethyl, etc. No.
  • Respect protected human Dorokishiru group in Y 1 as a group for protecting the human Dorokishiru groups, such as formyl, Asechiru, monochloro acetyl, dichloro acetyl Le, triflumizole Ruo b acetyl, main butoxycarbonyl, ethoxycarbonyl, benzyl Roxycarbonyl, 2,2,2-trichloromouth ethoxycarbonyl, benzoyl, trityl, tetrahydroviranyl, trimethylsilyl and the like.
  • formyl, Asechiru monochloro acetyl, dichloro acetyl Le, triflumizole Ruo b acetyl, main butoxycarbonyl, ethoxycarbonyl, benzyl Roxycarbonyl, 2,2,2-trichloromouth ethoxycarbonyl, benzoyl, trityl, tetrahydroviranyl, trimethyl
  • the compound (I) is subjected to a dehydration reaction as exemplified by the Mitsunobu reaction (“Reagents for Organic Synthesis by Fieser & Fieser, Vol 6, 6 ⁇ 5”) to give the compound (I) of the present invention. a).
  • This reaction is carried out in a solvent that does not inhibit the reaction, such as dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, toluene, xylene, ethyl acetate, N, N'-dimethylformamide, It is carried out in N, N'-dimethylacetamide, dimethylsulfoxide and the like, and a mixture thereof in the presence of azo compounds and phosphines.
  • the azo compounds to be used include getyl azodicarboxylate, 1 .— (azodicarbonyl) dipiperidine and the like.
  • the phosphines include triphenylphosphine and tributylphosphine compounds.
  • the molar ratio of the compound ( ⁇ ) to the compound (m) is not particularly limited, but 1 to 5 mol, preferably 1 to 3 mol of the compound (m) is used per 1 mol of the compound ((). It is preferably used.
  • the azo compound and the phosphine are used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, per 1 mol of compound (II).
  • the reaction conditions such as the reaction temperature and the reaction time vary depending on the used reaction reagents, reaction solvents and the like, but are usually from ⁇ 30 to 50, and from 30 minutes to 10 hours.
  • the elimination means may be, for example, decomposition with an acid (for example, formyl, tert-butoxycarbonyl, tritoxy) depending on the type of the protective group. Lityl, Tetrahidrobiranil, etc. Decomposition with an acid such as trifluoroacetic acid), decomposition with a base (for example, acetyl, dichloroacetyl, trifluoroacetyl, etc., decomposition with a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate), contact Reduction (for example, benzyl, benzyloxycarbonyl and the like are decomposed with palladium monocarbon and the like).
  • an acid for example, formyl, tert-butoxycarbonyl, tritoxy
  • a base for example, acetyl, dichloroacetyl, trifluoroacetyl, etc.
  • contact Reduction for example, benzyl, benzyloxycarbony
  • a ', A 2, W, Y 1 and - are each as defined above.
  • X is a halogen atom such as chlorine, bromine, iodine and fluorine, an alkylsulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, phenylsulfonyloxy and trisulfonyloxy And a leaving group such as an arylsulfonyloxy group.
  • This production method is a method for producing the compound (Ia) of the present invention by converting the compound ( ⁇ ) described in Production Method 1 into a compound (IV) by a method known per se and reacting with the compound (m). It is.
  • reaction between compound (m) and compound (W) is carried out in a solvent that does not inhibit the reaction, for example, dioxane, acetate nitrile, tetrahydrofuran, chloroform, methylene chloride-
  • a solvent that does not inhibit the reaction for example, dioxane, acetate nitrile, tetrahydrofuran, chloroform, methylene chloride-
  • the reaction is carried out in the presence of a base in ethylene benzene, toluene, xylene, ethyl acetate, N, N'-dimethylformamide, N, N'-dimethylacetamide, dimethylsulfoxide and the like, and a mixture thereof.
  • the molar ratio used with (IV) is not particularly limited.
  • the base used in this reaction is not particularly limited, but may be an alkali metal carbonate such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, etc., or an alkali metal hydroxide such as sodium hydroxide or hydroxylating lime.
  • Inorganic bases such as potassium metal salts, alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, hydrogen hydrides such as hydrogen hydride, calcium hydride, etc.
  • Compounds or organic bases such as triethylamine, diisopropylethylamine and the like.
  • the molar ratio of the compound (m) to the base used is not particularly limited, but 1 to 5 mol, preferably 1 to 3 mol of the base is used per 1 mol of the compound (m).
  • the reaction conditions such as the reaction temperature and the reaction time vary depending on the used reaction reagent, reaction solvent and the like, but are usually from ⁇ 30 to 150 ° C. and from 30 minutes to 10 hours.
  • the protecting group can be removed by the method described in Production Method 1 if necessary.
  • reaction between compound (VI) and 2,4-thiazolidinedione [compound (W)] is carried out in a solvent that does not inhibit the reaction, such as dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, Performed in the presence or absence of a catalyst in toluene, xylene, ethyl acetate, N, N'-dimethylformamide, N, N'-dimethylacetamide, dimethylsulfoxide, etc., and a mixture thereof .
  • a solvent that does not inhibit the reaction such as dioxane, acetonitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, Performed in the presence or absence of a catalyst in toluene, xylene, ethyl acetate, N, N'-dimethylformamide, N,
  • the molar ratio of the compound (VI) to the compound (YE) is not particularly limited, but 1 to 5 mol, preferably 1 to 3 mol of the compound (W) is used per 1 mol of the compound (VI). I have.
  • the catalyst used includes, for example, sodium acetate, piperidinum acetate or pyridinium benzoate.
  • the reaction conditions such as the reaction temperature and the reaction time vary depending on the used reaction reagent, reaction solvent and the like, but are usually from 10 to 150, and from 30 minutes to 10 to several hours.
  • the protecting group can be removed by the method described in Production Method 1 if necessary.
  • This production method is a method for producing the compound (Ic) of the present invention by subjecting the compound (lb) to reduction by catalytic hydrogenation or the like.
  • This reaction is carried out in a solvent that does not hinder the reaction, for example, dioxane, acetate nitrile, tetrahydrofuran, chloroform, methylene chloride, ethylene chloride, benzene, toluene, xylene, acid ethyl, N, N'-dimethyl.
  • the reaction is performed in the presence of a catalyst in formamide, N, N'-dimethylacetamide, dimethylsulfoxide, and the like, and a mixture thereof.
  • the catalyst used is, for example, palladium monocarbon, palladium black or the like, preferably palladium monocarbon. This reaction is usually carried out under atmospheric pressure or under pressure, but is preferably carried out under pressure.
  • reaction conditions such as the reaction temperature and the reaction time vary depending on the catalyst, the reaction solvent and the pressure used, but are usually from 10 to 50, and are from several hours to one day.
  • the reaction can also be achieved by reacting a metal hydride according to the method disclosed in W093Z1309A.
  • the protecting group can be removed by the method described in Production Method 1 if necessary. (Method 5) HO /
  • R 1 is a carboxyl group, an alkoxycarbonyl group (for example, a methoxycarbonyl group, an ethoxyquin carbonyl group, an isopropoxycarbonyl group, etc.), a carbamoyl group and one C 02 ⁇ (where ⁇ is sodium, potassium And a metal atom such as calcium or an equivalent cation such as an ammonium group, etc.), and Ha1 ⁇ represents a halogen atom such as chlorine, bromine or iodine.
  • a compound (IV) is reacted with a nitrobenzene compound (compound (VDI)) according to the reaction between compound (m) and compound (w) described in production method 2.
  • the reaction between compound (XI) and thiourea is a solvent that does not inhibit the reaction, for example, dioxane, acetonitril, tetrahydrofuran, methanol, ethanol, propanol, butanol, ethylene glycol monomethyl.
  • Ether chloroform, methylene chloride, ethylene chloride, benzene, toluene, xylene, ethyl acetate, N, N'-dimethylformamide, N, N'-dimethylacetamide, dimethylsulfoxide, etc., and mixtures thereof Done.
  • the molar ratio of compound (XI) to thiourea is not particularly limited, but 1 to 3 mol, preferably 1 to 2 mol of thiourea is used per 1 mol of compound (XI).
  • the reaction conditions such as the reaction temperature and the reaction time vary depending on the used reaction reagents, reaction solvents and the like, but are usually 50 to 150 ° C and 30 minutes to 10 hours.
  • the hydrolysis step is carried out in a solvent which does not inhibit the reaction of the compound ( ⁇ ), for example, dioxane, acetonitrinole, tetrahydrofuran, methanol, ethanol, propanol, butanol, ethylene glycol monomethyl ether, sulfolane, Heating in N, N'-dimethylformamide, N, N'-dimethylacetamide, dimethyl sulfoxide, etc., and mixtures thereof in the presence of water, organic acids such as acetic acid, or mineral acids such as sulfuric acid, hydrochloric acid, etc. It is done by doing.
  • a solvent which does not inhibit the reaction of the compound ( ⁇ ) for example, dioxane, acetonitrinole, tetrahydrofuran, methanol, ethanol, propanol, butanol, ethylene glycol monomethyl ether, sulfolane, Heating in N, N'-dimethylformamide, N
  • the amount of the acid to be added is generally 0.1 to 10 mol, preferably 0.2 to 3 mol, per 1 mol of compound ( ⁇ ).
  • the reaction conditions such as the reaction temperature and the reaction time vary depending on the used reaction reagent, reaction solvent and the like, but are usually 50 to 100, and 30 to 10 to several hours.
  • the protecting group can be removed by the method described in Production Method 1 if necessary.
  • the compound (I) of the present invention obtained as described above can be purified by a conventionally known method (for example, chromatography, recrystallization, reprecipitation, etc.).
  • the compound (I) of the present invention in the form of a pharmaceutically acceptable salt can be produced by a method known per se.
  • the dose of the compound (I) of the present invention varies depending on the administration subject, symptoms, and the like. For example, in the case of oral administration to an adult to a patient with diabetes, diabetic complications, or hyperlipidemia, one day is required. A dose of 1 mg to 200 mg may be administered.
  • N-Acetyl-1 6-hydroxymethylindolin 8 Dissolve Og in acetonitrile 8 and add 13.2 g of triflatylphosphine and 20.
  • KK- Ay mice Male, 12- to 15-week-old, CLEA Japan
  • TALA Japan genetically exhibiting obesity, hyperglycemia, and hyperlipidemia
  • Plasma glucose glucose (glucose CII—Test Co., Wako Pure Chemical Industries) was measured and divided into groups (3-5 animals per group) so that there was no difference in average body weight and average plasma glucose level. All test compounds were added to the powdered feed at 0.1 (wZw)%, and the mixture was administered for 4 days.
  • the control group was kept on a powder diet for 4 days. On day 5, a blood sample was collected from the tail vein under anesthesia and the plasma glucose was measured.
  • the plasma glucose lowering rate of the test compound-administered group was determined by the following formula from the average plasma Darcos values of the control group and the test compound-administered group.
  • Plasma glucose decrease rate (%) 100 X
  • Plasma triglycerides (triglyceride G-Test Pico, Wako Pure Chemical) were measured and divided into groups (3-5 animals per group) so that there was no difference in average body weight and average plasma triglyceride level. All test compounds were added to the powdered feed at 0.1 (wZw)%, and administered as a feed for 4 days. The control group was fed on a powder feed for 4 days. On day 5, a blood sample was collected from the tail vein under anesthesia, and plasma triglyceride was measured. The plasma triglyceride lowering rate of the test compound administration group was determined by the following formula from the average plasma triglyceride values of the control group and the test compound administration group.
  • Plasma triglyceride reduction rate (%) 100 X
  • the compound (I) of the present invention has a blood sugar and blood lipid lowering effect on mammals such as dogs, rats, mice, pomace, and pests including humans. Accordingly, the present invention compound (I) diabetes mellitus, complications of diabetes are useful in the treatment and prevention of hyperlipidemia such as c
  • This application is based on patent application No. 31063/1997 filed in Japan, the contents of which are incorporated in full herein.

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

Abstract

L'invention concerne des nouveaux composés thiazolidine, représentés par la formule générale (I), ou des sels de ceux-ci, acceptables sur le plan pharmacologique. Dans cette formule, (a) représente un noyau indole ou indoline, éventuellement substitué par alkyle inférieur ou alcoxy inférieur; Y représente un groupe acide, alcoxycarbonyle, hydroxy, etc.; W représente alkylène inférieur; ----- représente une liaison simple ou double, et A1 et A2 sont semblables ou différents et représentent chacun une liaison simple ou oxygène, à condition que lorsque Y-A1- ou (b) se fixe en position 1 du noyau indole ou indoline, A1 et A2 représentent chacun une liaison simple. Ces composés (I) sont utiles dans le traitement et la prévention du diabète, des complications du diabète, de l'hyperlipémie, etc.
PCT/JP1998/005026 1997-11-12 1998-11-09 Nouveaux composes thiazolidine et utilisation de ceux-ci en medecine WO1999024429A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU97627/98A AU9762798A (en) 1997-11-12 1998-11-09 Novel thiazolidine compounds and medicinal utilization thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP31063397 1997-11-12
JP9/310633 1997-11-12

Publications (1)

Publication Number Publication Date
WO1999024429A1 true WO1999024429A1 (fr) 1999-05-20

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Application Number Title Priority Date Filing Date
PCT/JP1998/005026 WO1999024429A1 (fr) 1997-11-12 1998-11-09 Nouveaux composes thiazolidine et utilisation de ceux-ci en medecine

Country Status (2)

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AU (1) AU9762798A (fr)
WO (1) WO1999024429A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05506430A (ja) * 1990-02-09 1993-09-22 ファルマシア・アンド・アップジョン・カンパニー インスリン感性化剤類の高血圧治療のための使用
JPH07330728A (ja) * 1994-04-11 1995-12-19 Sankyo Co Ltd 複素環化合物
JPH09165371A (ja) * 1995-10-09 1997-06-24 Sankyo Co Ltd 複素環化合物を含有する医薬

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05506430A (ja) * 1990-02-09 1993-09-22 ファルマシア・アンド・アップジョン・カンパニー インスリン感性化剤類の高血圧治療のための使用
JPH07330728A (ja) * 1994-04-11 1995-12-19 Sankyo Co Ltd 複素環化合物
JPH09165371A (ja) * 1995-10-09 1997-06-24 Sankyo Co Ltd 複素環化合物を含有する医薬

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LOHRAY BRAJ B. et al., "Novel Euglycemic and Hypolipidemic Agents. 1", J. MED. CHEM., Vol. 41, No. 10, (1998), p. 1619-1630. *
LOHRAY BRAJ B. et al., "Novel Indole Containing Thioazolidinedione Derivatives as Potent Euglycemic and Hypolipidemic Agents", BIOORG. MED. CHEM. LETT., Vol. 7, No. 7, (1997), p. 785-788. *

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