WO2003097064A1 - Agent de traitement du diabète - Google Patents

Agent de traitement du diabète Download PDF

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Publication number
WO2003097064A1
WO2003097064A1 PCT/JP2003/006136 JP0306136W WO03097064A1 WO 2003097064 A1 WO2003097064 A1 WO 2003097064A1 JP 0306136 W JP0306136 W JP 0306136W WO 03097064 A1 WO03097064 A1 WO 03097064A1
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Prior art keywords
substituted
unsubstituted
lower alkyl
heterocyclic group
hydrogen atom
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PCT/JP2003/006136
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English (en)
Japanese (ja)
Inventor
Satoshi Nakanishi
Hiroshi Yano
Kiyotoshi Mori
Fumiko Ogino
Hideaki Kusaka
Kimihisa Ueno
Yuji Nomoto
Yuzuru Matsuda
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Kyowa Hakko Kogyo Co., Ltd.
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Priority to AU2003234929A priority Critical patent/AU2003234929A1/en
Priority to JP2004505062A priority patent/JPWO2003097064A1/ja
Publication of WO2003097064A1 publication Critical patent/WO2003097064A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a therapeutic agent for diabetes containing a condensed purine derivative.
  • Diabetes is a major feature of hyperglycemia caused by metabolic abnormalities centering on glucose metabolism based on insulin secretion deficiency and decreased sensitivity of target cells. If hyperglycemia persists for a long time, serious complications occur in various organs and nerves, such as retinopathy, nephropathy, and neuropathy, mainly due to vascular disorders. Therefore, in the treatment of diabetes, it is extremely important to control and maintain a normal blood glucose level, and the means for that have been studied for a long time.
  • a type of diabetes whose onset is slow and does not necessarily require insulin treatment for life support (type 2 diabetes)
  • treatment to control blood sugar levels by combining exercise therapy, dietary therapy, and drugs is used.
  • a sulfonylurea insulin secretagogue a type of oral hypoglycemic agent
  • insulin secretagogues such as nateglinide peripaglinide, which are non-sulfonylurea K + ATP channel blockers, are also commercially available.
  • all of the currently available insulin secretagogues promote insulin secretion independent of blood glucose levels, so incorrect doses can cause severe hypoglycemia or There is a problem that it cannot be controlled, and it is not always satisfactory.
  • a condensed purine derivative having a structure different from that of a sulfonylurea insulin secretion enhancer can be a hypoglycemic agent capable of promoting insulin secretion in accordance with a blood glucose level (WO 00/01388, International Publication W001 / 47931).
  • Combining multiple conventional hypoglycemic agents involves using short-acting insulin secretagogues with long-lasting hypoglycemic agents to enhance meal-related insulin secretion and treat postprandial hyperglycemia (WO 098/56378).
  • Short-acting insulin secretagogues include sulphonylurine insulin secretagogue darikidone and non-sulfonylurea K + ATP
  • Yanenel blockers repaglinide and nateglinide are not limited to insulin secretagogues as long-acting hypoglycemic agents, but compounds containing sulfonylurea insulin secretagogues such as dalibenclamide and daliclazide have been shown. I have. Also, a combination of repaglinide and metformin, which is not an insulin secretagogue, is known.
  • An object of the present invention is to provide a therapeutic agent for diabetes, which comprises one or more selected from a sulfonylurea antidiabetic agent and a non-sulfonylurea K + ATP channel blocker antidiabetic agent, and a condensed purine derivative.
  • the present invention relates to the following (1) to (18).
  • R la represents a hydrogen atom, lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aromatic heterocyclic group
  • R 2a represents a hydrogen atom, lower alkyl, substituted or unsubstituted aralkyl
  • R 3a represents a hydrogen atom, lower alkyl or substituted or unsubstituted aralkyl
  • X 1 and X 2 are each independently Represents a hydrogen atom, a lower alkyl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted aryl
  • na represents an integer of 0 to 3.
  • Sulfonylurea antidiabetic drugs are dalibenclamide, glipizide, daliclazide, dalimepiride, tolazamide, tolptamide, acetohexamide, carpamide, kokulpropamide, glibornuride, gliquidone, glicentolide, dalisoxamide
  • the therapeutic agent for diabetes according to the above (1) which is one or more antidiabetic agents selected from the group consisting of glicloviramide, glyccyclamide and glibusol.
  • the antidiabetic agent is one or more antidiabetic agents selected from lipaglid, nateglinide and migulinide. Diabetes treatment.
  • R la represents a hydrogen atom, lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aromatic heterocyclic group
  • R 2a represents a hydrogen atom, lower alkyl, substituted or unsubstituted aralkyl
  • R 3a represents a hydrogen atom, lower alkyl or substituted or unsubstituted aralkyl
  • X 1 and X 2 are each independently Represents a hydrogen atom, a lower alkyl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted aryl
  • na represents an integer of 0 to 3.
  • R 6a has the same meaning as R 6 above, represents a substituted or unsubstituted lower alkyl or cyano] and R 2b represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted Aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, halogen, low Lower alkylthio, -NR 7 R 8 (wherein R 7 and R 8 have the same meanings as R 4 and R 5 , respectively), -CO 2 H, lower alkoxyl propylonyl, -COHal (where Hal is halogen Represents —C0NR 9 R 10 (wherein R 9 and R 1D have the same meanings as above and R 5 ), or —CH 0, and R 3b represents a hydrogen atom, lower alkyl, substituted or unsubstituted lower
  • nb represents an integer of 0 to 3
  • V 1 represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted aryl.
  • V 2 represents a substituted lower alkyl or a substituted or unsubstituted aromatic heterocyclic group
  • R 2b is substituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alicyclic heterocyclic group, halogen, lower alkylthio, -NR3 ⁇ 4 8 (wherein R 7 and R 8 are as defined above, respectively) der Ru), - C0 2 H, lower alkoxycarbonyl, -COHal (in the formula, Hal is
  • sulfonylurea antidiabetic agent is glibenclamide, glibizide, daliclazide, glimepiride, tolazamide, tolptamide, acetohexamide, carpamide, kokunorepropamide, glipornulide, glicidone, glicentamide, glisoramide.
  • the preventive and / or therapeutic agent for diabetic complications according to the above (5) which is one or more antidiabetic agents selected from glyoxepide, glicloviramide, glyciclamide and glybusol.
  • non-sulfoelurea K + ATP channel blocker antidiabetic agent is one or more antidiabetic agents selected from lipaglinide, nateglinide and miglinide. And / or therapeutic agents.
  • R la represents a hydrogen atom, lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aromatic heterocyclic group
  • R 2a represents a hydrogen atom, lower alkyl, substituted or unsubstituted aralkyl
  • Substituted or substituted represents an unsubstituted aryl or substituted or unsubstituted aromatic heterocyclic group
  • R 3a represents a hydrogen atom, lower alkyl or substituted or unsubstituted aralkyl
  • X 1 and X 2 represent Each independently represents a hydrogen atom, a lower alkyl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted aryl
  • na represents an integer of 0 to 3
  • R 6a has the same meaning as R 6 above), represents a substituted or unsubstituted lower alkyl or cyano]
  • R 2b represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted Aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, halogen, lower alkylthio, _NR 7 R 8 (wherein R 7 and R 8 is as defined above for R 4 and R 5 ), -CO 2 H, lower alkoxycarbonyl, -COHal (where Hal represents a halogen), -C0NR 9 R 10 (wherein R 9 And R ie have the same meanings as R 4 and, respectively, or -CH0, R 3b represents a hydrogen atom, lower alkyl, substituted or unsubstituted aral
  • Sulfur-urea antidiabetic or non-sulfonylurea K + ATP channel containing as active ingredient at least one selected from condensed purine derivatives represented by the formula: Blocker An anti-diabetic agent effect enhancer.
  • Sulfonylurea antidiabetic agents are dalibenclamide, glipizide, daliclazide, glimepiride, tolazamide, tolptamide, acetohexamide, carbbutamide, chlorpronomide, glibornuride, glicidone, glicentamide, griseolamide Enhanced effect of the anti-diabetic agent for sulfonylurea or non-sulfonylurea K + ATP channel blocker according to the above (9), which is one or more antidiabetic agents selected from glyoxepide, glicloviramide, and glycicamide glibusol. Agent.
  • non-sulfonylurea K + ATP channel blocker antidiabetic agent is one or more antidiabetic agents selected from lipaglid, nateglinide and miglidide.
  • antidiabetic agents selected from lipaglid, nateglinide and miglidide.
  • Condensed purine derivative is (i?)-8-benzyl-2-cyclopentyl-7, 8-dihydro-4-propyl-1 ⁇ imidazo [2, purine-5 (4 / force-one, 0?
  • R la represents a hydrogen atom, lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted aromatic heterocyclic group
  • R 2a represents a hydrogen atom, lower alkyl, substituted or unsubstituted aralkyl
  • R 3a represents a hydrogen atom, lower alkyl or substituted or unsubstituted aralkyl
  • X 1 and X 2 are each independently Represents a hydrogen atom, a lower alkyl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted aryl
  • na represents an integer of 0 to 3.
  • R 3b is a hydrogen atom, a lower alkyl, represents Araruki Le or lower alkoxyalkyl substituted or unsubstituted, nb represents an integer of 0 3
  • V 1 represents hydrogen atom, a substituted Or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted aromatic heterocyclic group
  • V 2 represents substituted lower alkyl or substituted or unsubstituted aromatic heterocyclic group.
  • V 1 represents a hydrogen atom, lower alkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aryl
  • R lba is the R lb Represents the definition, a represents) a group other than substituted lower alkyl
  • R 2b is substituted lower alkyl, substituted or unsubstituted Ararukiru, substituted or unsubstituted alicyclic heterocyclic group, a halo gen, lower alkylthio, - NR 7 R 8 (wherein, R 7 and R 8 Ru each as defined above der), - C0 2 H, lower alkoxycarbonyl - le, -COHal (in the formula, Hal is Ru as defined above der), -C0NR 9 R 10 (wherein, R 9 and R ie
  • a sulfonylurea antidiabetic or non-sulfonylurea K + ATP channel characterized by containing, as an active ingredient, at least one selected from a condensed purine derivative represented by the formula: and a pharmacologically acceptable salt thereof. Reduction of side effects of blocker antidiabetic agent Agent.
  • sulfourea antidiabetic agent is dalibenclamide, glipizide, daliclazide, glimepiride, tolazamide, tolptamide, acetohexamide, carbutamid, chlorpropamide, glipornulide, glicidone, glicentide, glisoramidide, glisoramidide.
  • non-sulfonylurea K + ATP channel blocker antidiabetic agent is one or more antidiabetic agents selected from lipag, linid, nateglinide and migulinide.
  • a sulfonylurea antidiabetic agent one or more selected from non-sulfonylurea K + ATP channel blocker antidiabetic agents, and a condensed purine derivative represented by the formula (I);
  • compound (I) the compound represented by the formula (I) is referred to as compound (I).
  • compound (I) the compound represented by the formula (I).
  • the lower alkyl includes, for example, an alkyl having 1 to 10 carbon atoms which is linear, branched, cyclic or a combination thereof.
  • Examples of the straight-chain or branched lower alkyl include, for example, methyl, ethyl, 1-pinopenole, isopropyl,? "Butinole, isobutinole, butynole, tert-butylinole, pentinole, neopentinole, /?- Hexyl, heptinol, / ⁇ -otatinole, -nonyl, 77 "decyl and the like.
  • the cyclic lower alkyl may have one or more rings, and more specifically, cyclopropyl, cyclobutyl, cyclopentinole, cyclohexinole, cycloheptinole, cyclopentinole, nonoleda 'Mantyl, Ryo Damantinole and the like. Of these, tert-butyl / le or pentyls are preferred.
  • Examples of the lower alkyl represented by R la include a linear or branched lower alkyl or a cyclic lower alkyl having 1 to 3 rings (for example, cyclopropynole, cyclopentinole, cyclopentinole, cyclohexinole, 3-
  • a lower alkyl represented by R 2a is preferably a linear or branched lower alkyl or a monocyclic lower alkyl.
  • aryl examples include monoaryl or two or more fused rings having 6 to 14 carbon atoms, more specifically, phenyl, naphthyl, indul, anthraenole and the like.
  • Aralkyl includes, for example, a monocyclic or two or more fused rings And aralkyl having 7 to 15 carbon atoms, more specifically, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like.
  • aromatic heterocyclic group examples include a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring.
  • aromatic heterocyclic groups are preferred, and more specifically, furyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolinole, tetrazolyl, oxazolyl, thiazoli / re, pyridyl, pyrazyl, pyrimidinyl, pyridazi-nore, Triadinole, indolinole, indazolinole, benzimidazolinole, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, phthalazini , Nafuchiri Jiniru, quinoxalinyl, quinazolinyl, Shin'norieru and purinyl is like et be.
  • Substituents of substituted aryl, substituted aralkyl and substituted aromatic heterocyclic groups may be the same or different, and may be substituted or unsubstituted lower alkyl having 1 to 3 substituents, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkyl, Unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aralkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted Arylo, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted lower alkylthio, substituted or unsubstituted lower alkylsulfur, carboxy, substituted or unsubstituted rubamoy
  • the lower alkyl portion of lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkylthio, lower alkylsulfonyl, lower alkanol, and mono- or di-lower alkyl-substituted amino has the same meaning as the above lower alkyl.
  • the two lower alkyls may be the same or different.
  • Lower alkenyl includes, for example, linear or branched Examples thereof include chain-like alkenyl having 2 to 6 carbon atoms, more specifically, butyl, aryl, topropropenyl, methacryl, butenyl, crotyl, pentenyl, hexenyl and the like.
  • the lower alkynyl includes, for example, linear or branched alkynyl having 2 to 6 carbon atoms, and more specifically, ethynyl, propynyl, petinole, pentynyl, hexyl and the like.
  • the number of unsaturated bonds in lower alkenyl and lower alkynyl is not particularly limited, but is preferably one.
  • the aralkyl part of the aralkyl is the same as the above-mentioned aralkyl, and the aryl part of the aralkyl and the aralkyl is the same as the above.
  • the halogen include fluorine, chlorine, bromine, and iodine atoms.
  • substituents of the substituted lower alkylthio, the substituted lower alkylsulfonyl, the substituents rubamoyl and the substituted lower alkanoyl include, for example, the same or different, hydroxy, halogen, canolepoxy, snorejo, phosphono having 1 to 3 substituents.
  • ester groups derived from acidic groups lower alkyl esters, aralkyl esters, aryl esters, etc.
  • halogen is as defined above
  • the lower alkyl portion of the lower alkyl ester is the same as the lower alkyl
  • the aryl portion of the ester is the same as the aryl.
  • examples of the alkyl having a substituent include hydroxyxetil, trifluoromethyi / re, and the like.
  • the substitution position of X 1 or X 2 is not particularly limited, and each can be substituted at any position on the ring.
  • X 1 or X 2 is a substituent other than a hydrogen atom
  • the configuration of the carbon atom to which they are bonded may be either 5 or;?.
  • na is preferably 0.
  • the alkyl portion of lower alkyl, lower alkylthio, lower alkoxycarbyl and lower alkoxyalkyl includes, for example, a straight-chain, branched-chain, From the combination of these Alkyl.
  • the linear or branched lower alkyl include, for example, methinole, ethinole, propinole, isopropinole, ⁇ "putinole, isoptinole, sec-petitinole, ieri-putinole, pentinole, neopentinole, 7T" hexinole,?
  • cyclic lower alkyl may have one or more rings, e.g., cyclopropyl propyl, cyclobutyl, cyclopentinole, cyclohexinole, cycloheptinole, cyclooctinole, nonoleada mantyl, Adamanchinole, bicyclo [2.2.1] heptinole, bicyclo [2.2.2] octynole, bisik [3. 3.0] octyl, bisik [3.3.1] nonyl, and the like.
  • rings e.g., cyclopropyl propyl, cyclobutyl, cyclopentinole, cyclohexinole, cycloheptinole, cyclooctinole, nonoleada mantyl, Adamanchinole, bicyclo [2.2.1] heptinole, bicyclo [2.2.2] octyn
  • the aryl and the aryl moiety of the aralkyl include, for example, aryl having 6 to 14 carbon atoms, which is monocyclic or has 2 or more fused rings, and more specifically, phenyl, naphthyl, indul, anthranyl and the like.
  • the aralkyl includes, for example, aralkyl having 7 to 15 carbon atoms, the aralkyl part of which is a monocyclic or two or more fused rings, more specifically, benzyl, phenethylenol, benzhydryl, naphthylmethyl and the like.
  • aromatic heterocyclic group for example, a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a 3- to 8-membered ring is fused. And a condensed aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and the like, and having 5 to 14 ring atoms.
  • Group is preferred, and more specifically, furyl, chelyl, pyrrolyl, imidazolyl, vilazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, indazolyl, benzimidyl, benzimidyl Benzoxazolyl, Benzothiazolyl, Quinolinole, Isoquinolinole, Phthalazur, Naph Tilidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, purinyl and the like.
  • alicyclic heterocyclic group examples include a 5- or 6-membered monocyclic alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring
  • a condensed alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom which is condensed with Specifically, pyrrolidinyl, 2,5-dioxopyrrolidinyl, thiazolidinyl, oxosazolidinyl, 2-oxooxazolidinyl, piperidinyl, piperazel, homopiperazinyl, morpholinyl, thiomorpholininole, Tetrahydroviranyl, tetrahydrofurothiopyral, tetrahydrofuryl, tetrahydroquinolyl, tetrahydroisoquinolyl,
  • heterocyclic group formed together with an adjacent nitrogen atom for example, a 5- or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom
  • the monocyclic heterocyclic group is A condensed heterocyclic group containing at least one nitrogen atom, which is a bicyclic or tricyclic condensed 3- to 8-membered ring, which may contain another nitrogen atom, an oxygen atom or a sulfur atom;
  • the condensed heterocyclic group may contain another nitrogen atom, oxygen atom or sulfur atom).
  • halogen examples include fluorine, chlorine, bromine, and iodine atoms.
  • Examples of the substituent of the substituted aryl, the substituted aralkyl, the substituted aromatic heterocyclic group and the substituted alicyclic heterocyclic group may be the same or different, and may be a substituted or unsubstituted lower alkyl having 1 to 3 substituents, substituted or unsubstituted.
  • Aryl substituted or unsubstituted aryloxy, substituted or unsubstituted arylo, substituted or unsubstituted aralkyl, substituted or unsubstituted aralkyloxy, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, Substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted lower alkylthio, substituted or unsubstituted lower alkylsulfol, substituted or unsubstituted lower alcohol, mono Or di-lower alkyl-substituted rubamoyl, mono Shikuwaji lower alkyl-substituted amino, halogen, carboxy, hydroxy, Examples thereof include nitro, amino, and cyano.
  • the lower alkenyl includes, for example, a linear or branched alkenyl having 2 to 6 carbon atoms, more specifically, butyl, aryl, 1-propenyl, methacryl, butenyl, crotinol
  • the lower alkynyl include a linear or branched alkynyl having 2 to 6 carbon atoms, more specifically, ethynyl, propynyl, butyr, pentul, and the like. Hexinyl and the like.
  • the number of unsaturated bonds in lower alkenyl and lower alkynyl is not particularly limited, but is preferably one.
  • the lower alkyl portion of lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkylthio, lower alkylsulfonyl, lower alkanoyl, mono- or di-lower alkyl-substituent rubamoyl and mono- or di-lower alkyl-substituted amino is as defined for the lower alkyl.
  • the aralkyl portion of aralkyl and aralkyl is the same as the above-mentioned aralkyl.
  • Aryl, atrox and the aryl part of Aroil are synonymous with the above-mentioned aryl.
  • Halogen has the same meaning as the above-mentioned halogen.
  • substituent of the alkanoyl include the same or different hydroxy having 1 to 3 substituents, halogen, carboxy, sulfo, phosphono as defined above, and esters derived from these acidic groups (lower alkyl esters, a Aralkyl esters, aryl esters and the like; the lower alkyl portion, the aralkyl portion and the aryl portion of these esters are as defined above), and the like.
  • the two lower alkyls bonded to carbamoyl and amino, respectively may be the same or different.
  • substituent of the substituted lower alkyl include the same or different and substituted with 1 to 3 lower alkoxy, hydroxy, cyano, azide, carboxy, phosphono, or esters derived from these acidic groups (lower alkyl esters, aralkyls).
  • the lower alkyl moiety has the same meaning as the lower alkyl.
  • the aryl part of the aryl and arylsulfonyloxy has the same meaning as the above aryl.
  • the aralkyl portion of aralkyl and aralkyloxy has the same meaning as the above-mentioned aralkyl.
  • the halogen, the aromatic heterocyclic group, the alicyclic heterocyclic group, and the heterocyclic group formed together with the adjacent nitrogen atom are as defined above.
  • the substituents of the substituted aromatic heterocyclic group and the substituted alicyclic heterocyclic group are as defined above.
  • the substitution position of V 1 or V 2 is not particularly limited, and each can be substituted at any position on the ring.
  • V 1 or V 2 is a substituent other than a hydrogen atom
  • the configuration of the carbon atom to which they are bonded may be either s or scale.
  • nb is preferably 0.
  • the sulfonylurea antidiabetic agent means an insulin secretagogue having a sulfolurea structure or a sulfonamide structure.
  • dalibenclamide, gliclazide or glimepiride is mentioned, and particularly preferably, glipenclamide is mentioned.
  • Non-sulfonylurea K + ATP channel blocker does not have sulfonyl urea structure or sulfonamide structure, but is known to inhibit K + ATP channel like sulfonylurea anti-diabetic agent It means an insulin secretagogue.
  • Specific examples include lipaglinide, nateglinide, and migulinide.
  • the compound (I) and pharmacologically acceptable salts of the compound (II) include base addition salts such as acid addition salts, metal salts, ammonium salts and organic amine addition salts, and amino acid addition salts.
  • Pharmaceutically acceptable acid addition salts include, for example, inorganic acid salts such as hydrochloride, sulfate, phosphate, etc., drunkate, maleate, fumarate, tartrate, citrate, etc.
  • Organic acid salts can be mentioned.
  • Examples of pharmacologically acceptable metal salts include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, as well as aluminum salts and zinc salts.
  • the pharmacologically acceptable organic amine addition salts include, for example, organic amine addition salts such as morpholine and piperidine.
  • examples of pharmacologically acceptable amino acid addition salts include addition salts such as lysine, glycine, and phenylalanine.
  • Sulfonylurea anti-diabetic agents and non-sulfonyl urea K + ATP channel blocking agents-anti-diabetic agents can also be used in the form of their pharmacologically acceptable salts.
  • the salt is defined as the pharmacologically acceptable salt of compound (I).
  • Compound (1), compound (11), a sulfonylurea antidiabetic agent and a non-sulfonylurea K + ATP channel pro-diabetic agent, and a pharmaceutically acceptable salt thereof are hydrates or solvates. In some cases, these adducts can be used in the present invention.
  • the type of the solvent that forms the solvate is not particularly limited as long as it is pharmacologically acceptable, and includes, for example, ethanol and acetone.
  • Some of compound (1), compound (11), sulfonylurea antidiabetic agent and non-sulfonylurea K + ATP channel blocker antidiabetic agent have one or more asymmetric carbon atoms.
  • the intermediate compound and the target compound obtained in these production methods are purified by a purification method commonly used in organic synthetic chemistry, for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc. Isolation can be purified. Further, the intermediate compound can be subjected to the next reaction without purification.
  • a pharmacologically acceptable salt of the compound (I) or the compound (II) when the salt of the compound (I) or the compound (II) is obtained, it may be purified as it is, When it is obtained in the form of, it may be dissolved or suspended in an appropriate solvent, and an acid or a base may be added to form a salt. It is also possible to convert the target substance obtained in the form of a salt to a free form and then to the desired salt.
  • R 2a is lower alkyl or a substituted or unsubstituted aralkyl
  • R 3a is a hydrogen atom or a substituted or unsubstituted aralkyl
  • X 2 is Compounds which are a hydrogen atom and na is 0 are preferable.
  • R 3b is a hydrogen atom or lower alkyl
  • V 1 is a hydrogen atom
  • V 2 is substituted lower alkyl
  • nb is 0.
  • R la is hydrogen, propyl, cyclopentyl or iar-butyl and R 2a is? Propyl, ethyl or benzyl, R 3a is hydrogen, methyl or benzyl, X 1 is hydrogen, lower alkyl or substituted or unsubstituted aralkyl, X 2 is hydrogen, na
  • R 3b is a hydrogen atom
  • V 1 is a hydrogen atom
  • V 2 is picolyl
  • compound (1) compound (II) or a pharmaceutically acceptable salt thereof.
  • compound 16 compound 18-20, compound 23, compound 31, compound 35, compound 37, compound 43, compound 55, compound 98, compound 104, compound 106, compound 1 10 and compound 1 12 is particularly preferred.
  • compounds in free form or other pharmacologically acceptable salts of these compounds are particularly preferred.
  • compound (1), compound (II) or a pharmacologically acceptable salt thereof is not limited to these compounds.
  • the compounds specifically described in JP-A-3-204880 or WO098 / 15555 or pharmacologically acceptable salts thereof may also be used as the compound (1), the compound (II) or a compound thereof. Preferred as a pharmacologically acceptable salt.
  • the combination with at least one is not particularly limited, but preferable combinations include, for example, 1 Glibenclamide and compound 16 ;
  • glibenclamide and compound 16 a combination of (1) glibenclamide and compound 16; (2) glibenclamide and compound 98; (3) glibenclamide and compound 106 is preferred.
  • One or more selected from sulferurea anti-diabetic agents and non-sulfonyl urea K + ATP channel blocker anti-diabetic agents and selected from compound (1), compound (II) and pharmaceutically acceptable salts thereof
  • a synergistic insulin secretion-promoting effect in cultured cells / 3 cells and a high hypoglycemic effect in rats are indicated, so that diabetes therapeutics, diabetic complications (eg, retinopathy, renal disease) And / or neurosis) are useful as preventive and / or therapeutic agents.
  • At least one selected from the compound (1), the compound (II) and a pharmaceutically acceptable salt thereof is a sulfonylurea antidiabetic agent or a non-sulfonylurea K + ATP channel blocker antidiabetic. It is also useful as an active ingredient of a drug effect enhancer or a side effect reducing agent.
  • the therapeutic agent for diabetes or the prevention or treatment of diabetic complications of the present invention includes at least one selected from a sulfolurea antidiabetic agent and a non-sulfururea K + ATP channel blocker antidiabetic agent,
  • the compound (1), the compound (II) and one or more selected from pharmacologically acceptable salts thereof are used in combination.
  • the sulfonylurea antidiabetic agent of the present invention or the non-sulfonylurea K + AT Compound (1), compound (II), and their pharmacological agents include those that enhance the effects of locker antidiabetic drugs or those that reduce the side effects of sulfonylurea antidiabetic drugs or nonsulfonylurea K + ATP channel blocker antidiabetic drugs. It is possible to administer only one or more selected from salts acceptable for the above, but usually, the active compounds (1), (II), and their pharmacologically acceptable It is desirable to provide in the form of a pharmaceutical composition containing one or more selected from salts and one or more pharmaceutical additives.
  • Anti-diabetic agent of the present invention agent for preventing and / or treating diabetic complications, sulfonyl urea anti-diabetic agent or non-sulfonylurea K + ATP channel blocker anti-diabetic agent effect enhancer and sulfonylurea anti-diabetic agent or non-sulfonylurea anti-diabetic agent Sulfururea K + ATP channel blocker
  • the anti-diabetic agent side-effect reducing agent can be administered to humans and other mammals.
  • Anti-diabetic agent of the present invention prevention of diabetic complications Z or therapeutic agent, sulfonyl urea anti-diabetic agent or non-sulfonylurea K + ATP channel blocker anti-glycemic effect enhancer and sulfonylurea anti-diabetic agent Drug or non-sulfonylurea K + ATP channel blocker
  • the form of the drug for reducing the side effects of antidiabetic drugs is not particularly limited, and it can be selected from oral or parenteral dosage forms that are most suitable for the purpose of treatment or prevention. It is possible to select the form.
  • compositions suitable for oral administration include, for example, tablets, capsules, powders, granules, fine granules, syrups, solutions, emulsions, suspensions, chewing agents, and the like.
  • Formulations suitable for administration include, for example, injections (for subcutaneous injection, intramuscular injection, intravenous injection, etc.), infusions, inhalants, nebulizers, suppositories, gels or ointments Examples thereof include, but are not limited to, transdermal absorbents, transmucosal absorbents, transdermal absorbents in the form of patches, tapes and the like.
  • Liquid preparations suitable for oral administration include water, sucrose, sorbitol, fructose, and other sugars, polyethylene glycol, propylene glycol, and other daricols, sesame oil, olive oil, and soybean oil. It can be produced by using oils such as oils, preservatives such as hydroxybenzoic acid esters, and flavors such as strawberry flavor and peppermint.
  • capsule For the manufacture of solid preparations such as tablets, tablets, powders and granules, excipients such as lactose, glucose, sucrose and mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc Agents, binders such as polyvinyl alcohol, hydroxypropyl cellulose and gelatin, surfactants such as fatty acid esters, and plasticizers such as glycerin.
  • excipients such as lactose, glucose, sucrose and mannitol
  • disintegrants such as starch and sodium alginate
  • lubricants such as magnesium stearate and talc Agents
  • binders such as polyvinyl alcohol, hydroxypropyl cellulose and gelatin
  • surfactants such as fatty acid esters
  • plasticizers such as glycerin.
  • Formulations for injection or infusion suitable for parenteral administration preferably contain the above-mentioned substances, which are the active ingredient, dissolved or suspended in a sterile aqueous medium isotonic with the blood of the recipient.
  • a solution can be prepared using a saline solution, a pudose solution, or an aqueous medium composed of a mixture of a saline solution and a glucose solution.
  • Formulations for enteral administration can be prepared using carriers such as cocoa butter, hydrogenated fats and hydrogenated carboxylic acids, and are provided as suppositories.
  • the above-mentioned substance as an active ingredient can be dispersed as fine particles, and it does not irritate the oral and respiratory tract mucous membranes of the recipient and facilitates absorption of the active ingredient.
  • Specific examples of the carrier include lactose and glycerin.
  • Preparations in the form of an aerosol or dry powder can be prepared depending on the nature of the substance used as the active ingredient and the carrier used. These preparations for parenteral administration include one or more selected from glycols, oils, flavors, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc. Alternatively, two or more auxiliary components can be added.
  • the form of administration of the therapeutic agent for diabetes and the prevention of diabetic complications of the present invention and the Z or therapeutic agent is not particularly limited, and at the time of administration, a sulfourea antidiabetic agent and a non-sulfonyl urea K + ATP channel blocker antidiabetic agent At least one selected from the group consisting of the compound (1), the compound (II) and a pharmacologically acceptable salt thereof.
  • Such administration forms include, for example, (1) one or more selected from sulfonylurea antidiabetic agents and non-sulfonylurea K + ATP channel blocker antidiabetic agents, compound U), compound (II) and their pharmacology.
  • Simultaneous administration of the two formulations via different routes of administration 5 At least one selected from a rufonylurea antidiabetic agent and a non-sulfonylurea K + ATP channel blocker antidiabetic agent, and selected from compound (1), compound (II) and a pharmaceutically acceptable salt thereof 1 And two or more preparations obtained by separately preparing two or more preparations at different time points by different administration routes. Above all, the above 1 and 3 are preferred.
  • one or more compounds selected from a sulfonylurea antidiabetic agent and a non-sulfolurea K + ATP channel blocker antidiabetic agent are combined with a compound (1), a compound (II), and a pharmacological agent thereof. It is preferable to separately prepare one or more selected from salts acceptable in the form of an oral preparation such as a tablet, and to administer the two oral preparations simultaneously or with a time lag.
  • the dosage and frequency of administration of the therapeutic agent for diabetes or the preventive and / or therapeutic agent for diabetic complications of the present invention depends on the type and severity of the disease, the dosage form, conditions such as the age and weight of the patient, and the presence or absence of complications. Can be appropriately increased or decreased depending on the various factors described above.
  • the dose of the sulfonylurea antidiabetic agent or the non-sulfonylurea K + ATP channel blocker antidiabetic agent can also be appropriately selected based on the dose used clinically.
  • the daily dose is usually 0.01 to 50000 mg, Preferably, the dose is 0.1 to 5000 mg, which can be administered once or several times a day.
  • the dose per dose is usually 0. The dose is 1 to 100 mg, preferably 0.5 to 50 mg, and this amount can be administered in one or several divided doses.
  • the dose is usually 0.01 to 50000 mg per day. Preferably, 0.:! It can be administered once or several times a day. ,
  • compound (1), compound (II) or a pharmacologically acceptable salt thereof is usually added to 1 part by weight of a sulfonylurea antidiabetic or non-sulfonylurea K + ATP channel blocker antidiabetic. It can be used in an amount of about 0.000001 to 100,000 parts by weight, preferably about 0.000001 to 10,000 parts by weight.
  • One or more selected from the sulfonylurea antidiabetic agent and the non-sulfonylurea K + ATP channel blocker antidiabetic agent used in the present invention, compound (1), compound (II) and their pharmacologically With one or more selected from acceptable salts Combinations include, for example, prophylaxis of diabetes (eg, type 2 diabetes, gestational diabetes, etc.); therapeutic agents; prevention and treatment of glucose intolerance; inhibitors of the transition from glucose intolerance to diabetes; hyperlipidemia (eg, high Prevention of triglycerideemia, hypercholesterolemia, hypo-HD Lemia, etc .; therapeutic agent; prevention of hyperinsulinemia; therapeutic agent; diabetic complications (eg, retinopathy, nephropathy, neuropathy, macrovascular disorder) Prevention and treatment of coronary artery and cerebrovascular disorders; Prevention and treatment of hyperammonemia; Treatment and treatment of obesity Prevention and treatment of obesity; Hypertension that causes syndrome X, visceral obesity, insulin resistance diabetes It
  • the therapeutic effect of diabetes (eg, hypoglycemic effect, etc.) possessed by a combination with at least one selected from physiologically acceptable salts is, for example, glucose before and after administration of the combination, glucose in venous blood plasma of the administration subject, Alternatively, the concentration can be evaluated by measuring the concentration of insulin and comparing the obtained concentration before and after administration.
  • Combination with one or more selected from physically acceptable salts has excellent insulin secretion promoting action and hypoglycemic action.
  • the combination with one or more salts selected from the group consisting of the following active ingredients has superior pharmaceutical properties (e.g., enhanced insulin secretion promoting action, enhanced hypoglycemic action, Reduction of the use of each active ingredient, reduction of side effects such as hypoglycemia, reduction of secondary ineffectiveness, improvement of stability, improvement of bioavailability, improvement of in vivo absorption).
  • one or more compounds selected from the group consisting of the sulfoelurea antidiabetic agent and the non-sulfonylurea K + ATP channel blocker antidiabetic agent used in the present invention compound (1), compound (II) and their pharmacologically Combination with one or more selected from acceptable salts
  • the insulin secretion effect is greater than the additive insulin secretion promoting effect predicted from the effect of each active ingredient alone.
  • this combination provides a high hypoglycemic effect.
  • sulfonylurea antidiabetic drugs currently used in the treatment of mammals, including humans, and nonsulfonylurea K + ATP channel blocker antidiabetic drugs provides such a synergistic insulin secretion effect. Because of this, this new combination is extremely useful as an antidiabetic agent. In addition, by reducing the amount of sulfonylurea antidiabetic used, it is possible to delay the onset of secondary ineffectiveness often observed when a sulfonylurea antidiabetic is used for a long period of time, or to reduce the onset itself. Can be.
  • Test Example 1 Insulin secretion promoting action
  • ⁇ 6 cells have an elevated insulin content and glucose-stimulated insulin secretion in vivo. ] It is close to 3 cells and well preserves the properties of knee cells in vivo in that insulin secretion increases in response to glucose concentration [The above literature and Diabetologia, 36, 1139-1145 (1993)] ].
  • ⁇ 6 cells promote insulin secretion in response to a sulfonylurea agent used as a therapeutic agent for diabetes, for example, dalibenclamide [Cellular 'signaling, Vol. 5, pp. 777-786 (1993)].
  • ⁇ ⁇ 6 cells and the insulin secretion test using ⁇ 6 cells were performed basically according to the method described in Diabetologia, Vol. 36, pp. 1399-1145 (1993).
  • the effect of the compound on insulin secretion activity in the presence of 14.5 ramol / l glucose was determined by measuring the amount of insulin in the cell culture supernatant collected as follows. MIN6 cells cultured in a 24-well plate were mixed with buffer A containing 2 mmol / l dalcos (119 mmol / l sodium chloride, 4.74 mmol / l lithium chloride, 2.54 mraol / l calcium chloride, 1.19 ml).
  • Antibody-reactive insulin secreted into the culture supernatant is replaced with 1% bovine serum albumin, 0.1% Tween 20, 0.12% ethylenediaminetetraacetic acid (EDTA) '2Na, 0.1% sodium azide
  • quantification was performed by radioimmunoassay.
  • a standard curve was prepared using human insulin as a standard substance, and each insulin value was calculated from the curve.
  • the relative amount (%) of each measured value was calculated, with the insulin value obtained when dimethyl sulfoxide as a solvent was added instead of the test compound as 100%.
  • Table 1 The results are shown in Table 1 as the average of 4-8 cases.
  • An oral glucose tolerance test for grouping was performed two days before the efficacy evaluation. Actually, after measuring the blood glucose level of the rats fasted for 24 hours, 2 g / kg of darcose was orally loaded, and the blood glucose levels were measured 30, 60 and 120 minutes after the darcose loading. The animals were divided into groups so that the area under the blood glucose curve (AUC) of the change in blood glucose over time and the average value of the blood glucose at each time point were equal in each group (6 animals in each group).
  • AUC area under the blood glucose curve
  • the drug efficacy was evaluated using rats fasted for 24 hours two days after grouping. After measuring the blood glucose level, the test compound was orally administered. Thereafter, the blood glucose level was measured immediately before glucose loading, and then 2 g / kg glucose was orally loaded. The blood glucose level was measured 60 minutes after the glucose load. The test compound was orally administered 15 minutes before the glucose load.
  • Example 1 Tablet Prepare tablets of the following composition in the usual manner, Formulation compound 9 8 18 mg dalibenclamide 2 mg lactose 143.4 rag
  • a tablet having the following composition is prepared by a conventional method.
  • Prescription Compound 9 8 18 mg Nateglinide 2 mg Lactose 143.4 rag Potato starch 30 mg Hydroxypropinoresenolerose 6 mg Magnesium stearate 0.6 mg
  • a tablet having the following composition is prepared by a conventional method.
  • an antidiabetic agent comprising a sulfonylurea antidiabetic agent or a non-sulfonylurea K + ATP channel blocker antidiabetic agent and a condensed purine derivative can be provided.

Abstract

L'invention a trait à un agent de traitement du diabète, caractérisé en ce qu'il contient au moins un élément sélectionné entre des agents antidiabétiques de sulfonylurée et des agents antidiabétiques bloquant le canal K+ ATP exempts de sulfonylurée, et au moins un élément sélectionné entre un dérivé de purine condensé représenté par la formule (I), et un dérivé de purine condensé représenté par la formule (II) ; et à des sels pharmaceutiquement acceptables de tels composés.
PCT/JP2003/006136 2002-05-17 2003-05-16 Agent de traitement du diabète WO2003097064A1 (fr)

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WO2004096812A1 (fr) * 2003-04-25 2004-11-11 Kyowa Hakko Kogyo Co., Ltd. Derive de pyrimidine fusionne
WO2008017381A1 (fr) 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituée, son procédé de fabrication, médicament contenant ce composé et son utilisation
DE102007005045A1 (de) 2007-01-26 2008-08-07 Sanofi-Aventis Phenothiazin Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
DE102007063671A1 (de) 2007-11-13 2009-06-25 Sanofi-Aventis Deutschland Gmbh Neue kristalline Diphenylazetidinonhydrate, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2010003624A2 (fr) 2008-07-09 2010-01-14 Sanofi-Aventis Composés hétérocycliques, leurs procédés de préparation, médicaments comprenant lesdits composés et leur utilisation
WO2010068601A1 (fr) 2008-12-08 2010-06-17 Sanofi-Aventis Hydrate de fluoroglycoside hétéroaromatique cristallin, ses procédés de fabrication, ses procédés d'utilisation et compositions pharmaceutiques le contenant
WO2011023754A1 (fr) 2009-08-26 2011-03-03 Sanofi-Aventis Nouveaux hydrates de fluoroglycoside hétéroaromatiques cristallins, substances pharmaceutiques comprenant ces composés et leur utilisation
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120050A1 (fr) 2011-03-08 2012-09-13 Sanofi Nouveaux dérivés phényl-oxathiazine substitués, procédé pour leur préparation, médicaments contenant ces composés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120051A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés benzyl-oxathiazine substitués avec adamantane ou noradamantane, médicaments contenant ces composés et leur utilisation
WO2012120058A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des groupes benzyle ou hétérométhylène, leur procédé de production, leur utilisation comme médicament ainsi que produits pharmaceutiques les contenant et leur utilisation
WO2012120057A1 (fr) 2011-03-08 2012-09-13 Sanofi Nouveaux dérivés phényl-oxathiazine substitués, procédé pour leur préparation, agent pharmaceutique contenant ces composés et leur utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase

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WO2000001388A1 (fr) * 1998-07-02 2000-01-13 Kyowa Hakko Kogyo Co., Ltd. Medicaments antidiabetiques
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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004096812A1 (fr) * 2003-04-25 2004-11-11 Kyowa Hakko Kogyo Co., Ltd. Derive de pyrimidine fusionne
WO2008017381A1 (fr) 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituée, son procédé de fabrication, médicament contenant ce composé et son utilisation
DE102007005045A1 (de) 2007-01-26 2008-08-07 Sanofi-Aventis Phenothiazin Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
DE102007063671A1 (de) 2007-11-13 2009-06-25 Sanofi-Aventis Deutschland Gmbh Neue kristalline Diphenylazetidinonhydrate, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2010003624A2 (fr) 2008-07-09 2010-01-14 Sanofi-Aventis Composés hétérocycliques, leurs procédés de préparation, médicaments comprenant lesdits composés et leur utilisation
WO2010068601A1 (fr) 2008-12-08 2010-06-17 Sanofi-Aventis Hydrate de fluoroglycoside hétéroaromatique cristallin, ses procédés de fabrication, ses procédés d'utilisation et compositions pharmaceutiques le contenant
WO2011023754A1 (fr) 2009-08-26 2011-03-03 Sanofi-Aventis Nouveaux hydrates de fluoroglycoside hétéroaromatiques cristallins, substances pharmaceutiques comprenant ces composés et leur utilisation
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120050A1 (fr) 2011-03-08 2012-09-13 Sanofi Nouveaux dérivés phényl-oxathiazine substitués, procédé pour leur préparation, médicaments contenant ces composés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120051A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés benzyl-oxathiazine substitués avec adamantane ou noradamantane, médicaments contenant ces composés et leur utilisation
WO2012120058A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des groupes benzyle ou hétérométhylène, leur procédé de production, leur utilisation comme médicament ainsi que produits pharmaceutiques les contenant et leur utilisation
WO2012120057A1 (fr) 2011-03-08 2012-09-13 Sanofi Nouveaux dérivés phényl-oxathiazine substitués, procédé pour leur préparation, agent pharmaceutique contenant ces composés et leur utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase

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