WO2000023443A1 - Derives de tetrahydropyridopyridine, et produits intermediaires permettant de produire lesdits derives - Google Patents

Derives de tetrahydropyridopyridine, et produits intermediaires permettant de produire lesdits derives Download PDF

Info

Publication number
WO2000023443A1
WO2000023443A1 PCT/JP1999/005831 JP9905831W WO0023443A1 WO 2000023443 A1 WO2000023443 A1 WO 2000023443A1 JP 9905831 W JP9905831 W JP 9905831W WO 0023443 A1 WO0023443 A1 WO 0023443A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyrazine
tetrahydropyrido
compound
solvent
carboxamide
Prior art date
Application number
PCT/JP1999/005831
Other languages
English (en)
Japanese (ja)
Inventor
Kazuya Yoshiizumi
Minoru Yamamoto
Fumio Nakajima
Yasuko Itoh
Shoji Ikeda
Kei Naruse
Kohichiro Yoshino
Original Assignee
Akzo Nobel N.V.
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 Akzo Nobel N.V. filed Critical Akzo Nobel N.V.
Priority to AU62284/99A priority Critical patent/AU6228499A/en
Publication of WO2000023443A1 publication Critical patent/WO2000023443A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel tetrahydropyridopyrazine derivative having an inhibitory effect on the production of tumor necrosis factor (hereinafter, referred to as TNF- ⁇ ), an intermediate for producing the same, and a pharmaceutical composition containing the tetrahydropyridopyrazine derivative as an active ingredient.
  • TNF- ⁇ tumor necrosis factor
  • TNF- ⁇ is a type of cytokine produced by active macrophages, and works locally at inflammation as an inflammatory mediator.
  • TNF- ⁇ is an important cytokine by nature, but when it is produced in excess, it can be used, for example, in non-insulin-dependent diabetes, rheumatoid arthritis, osteoarthritis, sepsis, congenital immunodeficiency syndrome ( ⁇ I DS), which is thought to cause diseases such as graft-versus-host reaction (GVHD), asthma, atopic dermatitis, and ulcerative colitis. May be a prophylactic or therapeutic agent for these diseases.
  • GVHD graft-versus-host reaction
  • asthma graft-versus-host reaction
  • atopic dermatitis atopic dermatitis
  • ulcerative colitis May be a prophylactic or therapeutic agent for these diseases.
  • TNF- ⁇ is secreted on the membrane surface as a membrane-bound precursor consisting of 233 amino acids with a molecular weight of 26 kDa, and is extracellularly cleaved enzymatically between amino acids Ala-76 and Val-77. To be liberated.
  • the enzyme involved in this cleavage is TNF- ⁇ converting enzyme
  • TACE TNF- ⁇ production inhibitor
  • TACE is an enzyme similar to extracellular matrix-degrading enzyme (hereinafter abbreviated as ⁇ )
  • hydroxamic acid compounds with ⁇ inhibitory activity found TAC ⁇ inhibitory activity and used as TNF- ⁇ production inhibitor Attempts have been proposed (USP 5691382).
  • a compound having a strong MMP inhibitory activity has no TACE inhibitory activity [J. Med. Chem., 40, 1026-1040 (1997)]. Does not always show a TNF-ct production inhibitory effect.
  • An object of the present invention is to provide a novel compound having an inhibitory effect on TNF- ⁇ production and an intermediate for producing the same.
  • the present inventors have conducted various studies and found that the following formula (I)
  • R 1 represents an atomic group selected from the group consisting of a Ci Ce alkyl group, a phenyl group and a heteroaryl group, which may have a substituent.
  • the heteroaryl group means a 6-membered aromatic ring group containing one or two nitrogen atoms, and both the heteroaryl group and the phenyl group are substituted with a substituent, for example, an amino group or a phenoxy group. May be.
  • the alkyl group means a straight or branched alkyl group of from 1 to 6 carbon atoms, a substituted group, e.g. Ci Cg alkoxy, Ci Cs alkylthio group Wakashi Ku is fluorine atom It may be.
  • Pharmaceutically acceptable salts include, for example, inorganic base salts such as sodium salt, potassium salt and calcium salt and organic base salts such as arginine salt and lysine salt.
  • the compound represented by the formula (I) has one or more asymmetric carbon atoms, and a racemate, a stereoisomer or a mixture thereof based on these asymmetric carbons is all included in the compound of the present invention. Included. Formula (II) useful as an intermediate for production
  • A represents a hydrogen atom, a tert-butoxycarbonyl group or a benzyloxycarbonyl group.
  • a salt thereof is also included in the compound of the present invention.
  • salts of the intermediates for production include, for example, inorganic base salts such as sodium salt, potassium salt, calcium salt and the like, and organic base salts such as dicyclohexylamine salt, and hydrochloride salts which can be formed when A is a hydrogen atom. , Sulfate, and P-toluenesulfonate.
  • the compound represented by the formula (II) includes optically active substances and racemic forms, all of which are included in the compounds of the present invention.
  • R 1 represents a Ci Ce alkyl group (which may be substituted with a methoxy group, an ethoxy group or a methylthio group), a phenyl group (which is substituted with an amino group or a phenoxy group). Or a heteroaryl group such as pyridyl or virazyl is preferred! /.
  • the following compounds can be exemplified as the compound of the present invention.
  • the compound (I) of the present invention and a pharmaceutically acceptable salt thereof can be produced from the compound (III) or the compound (IV) according to the following scheme 1.
  • B z 1 represents a benzyl group.
  • R 1 is the same as described above.
  • the compound (I) of the present invention is obtained by converting the compound (IV) into an acid chloride using 1.0 to 5.0 mol of oxalyl chloride with respect to 1 mol of the compound (IV) in a solvent such as dichloromethane. Later, it can be produced by reacting with an appropriate amount of hydroxylamine.
  • the compound (I) of the present invention is prepared by converting compound (III) into a lower alcohol such as methanol or ethanol, if necessary, with water, hydrochloric acid, acetic acid, or N, N-dimethylformamide (hereinafter abbreviated as DMF). It can also be produced by hydrogenolysis at room temperature to 60 ° C under a hydrogen stream or under pressure in the presence of a catalyst such as palladium carbon (hereinafter abbreviated as Pd-C). be able to.
  • a catalyst such as palladium carbon
  • the target compound in the case of producing a compound (I) having an amino substituent in the R 1 portion, the target compound can be suitably obtained from the corresponding nitro compound according to the present method. That is, if the reaction in the same manner substituted nitro compounds of the nitro group instead of those the Amino group of the [compound (III) to corresponds] as a precursor, reduction of deprotection and nitro group of B Z 1 hydroxamic acid moiety The reaction proceeds simultaneously, and the desired compound (I) can be obtained. Therefore, as long as this method is used, the nitro-substituted product is considered to be an equivalent of the amino-substituted product. In the following reactions, the amino-substituted product will be replaced with the nitro-substituted product unless otherwise specified.
  • Compound (III) is used for peptide synthesis in Scheme 1 above by using compound (IV) in an aprotic solvent such as DMF, THF or dichloromethane.
  • aprotic solvent such as DMF, THF or dichloromethane.
  • Ordinary condensing agents for example, dicyclohexyl carpoimide (hereinafter abbreviated as DCC), 1-ethyl-13- (3-dimethylaminopropyl) carboimide 'hydrochloride (hereinafter abbreviated as WSC) It is produced by reacting with 0-benzylhydroxylamine using, for example. The reaction is usually performed at 0 ° C.
  • the molar ratio of the compound to be subjected to the reaction is generally 1.0 to 1.5 for O-benzylhydroxylamine per 1 mol of compound (IV).
  • Mole, condensing agent 1.0 to 1.5 mole.
  • B c represents a tert-butoxycarbonyl group.
  • B z 1 and R 1 are the same as described above.
  • Compound (IIa) is reacted with di-tert-butyl dicarbonate in a solvent such as dioxane or water using alkali such as sodium hydroxide to give compound (IIb) [where A is Bo in general formula (II). Compound which is c group] can be synthesized. reaction The molar ratio of the compound to be used is 1.0 to 3.0 moles of sodium hydroxide and 1.0 to 2.0 monoles of di-tert-butynole dicarbonate with respect to 1 mole of the compound (IIa).
  • Compound (V) can be synthesized by reacting compound (lib) with O-benzylhydroxylamine by the above-mentioned method using a condensing agent such as DCC or WSC.
  • a condensing agent such as DCC or WSC.
  • Compound (VI) can be synthesized by stirring compound (V) at 0 ° C. to room temperature using a solution containing an excess of acid, for example, a 4N hydrochloric acid / ethyl acetate solution.
  • the compound (II) can be synthesized by reacting the compound (VI) with the corresponding sulfo-ercide lid (XVI) using a base such as dimethylaminopyridine or triethylamine in a solvent such as DMF or water or dioxane.
  • a base such as dimethylaminopyridine or triethylamine
  • a solvent such as DMF or water or dioxane.
  • the molar ratio of the compound to be subjected to the reaction is such that 2.0 to 3.0 mol of the base and 1.0 to 2.0 mol of (XVI) are required per 1 mol of the compound (VI).
  • the reaction time is 1-18 hours.
  • Compound (IV) can be produced from compound (IIa) by the following method.
  • Compound (VIII) can be obtained by reacting the methyl ester (VII) with the corresponding sulfoyl chloride (XVI) in a solvent such as DMF or dioxane or water using a base such as dimethylaminopyridine or triethylamine. .
  • the molar ratio of the compound used in the reaction is 2.0 to 3.0 mol of the base and 1.0 to 3.0 mol of the compound (XVI) per 1 mol of the methyl ester (VII).
  • Compound (VIII) is stirred in a solvent such as dioxane or water with an alkali such as sodium hydroxide at 0 ° C to room temperature for 30 minutes to 5 hours to give compound (I). V) is obtained.
  • t Bu represents a tert-butyl group
  • Z group represents a benzyloxycarbonyl group
  • R 1 is the same as described above.
  • Compound (IIc) (general) is prepared by stirring compound (IIa) with Z-chloride in a solvent such as water or dioxane with alkali such as sodium hydroxide at 0 ° C. to room temperature for 1 to 5 hours.
  • a compound in which A is a Z group in the formula (II)] The molar ratio of the compound to be reacted is 2.0 to 3.0 monoles of sodium hydroxide and 1.0 to 2.0 monoles of Z-chloride per 1 mol of the compound (IIa).
  • the tert-butyl ester (IX) can be obtained by reacting the compound (lie) with an excess of isobutene at 140 ° C. to room temperature for 5 to 48 hours in a solvent such as dichloromethane using an acid catalyst such as sulfuric acid.
  • the compound (XI) can be obtained by reacting the compound (X) with the corresponding sulfo-uric chloride (XVI) in a solvent such as DMF or dioxane or water using a base such as dimethylaminopyridine or triethylamine.
  • a solvent such as DMF or dioxane or water
  • a base such as dimethylaminopyridine or triethylamine.
  • the molar ratio of the compound to be subjected to the reaction is 1.0 to 2.0 mol for the base and 1.0 to 2.0 mol for the compound (XVI) per 1 mol of the compound (X).
  • the compound (IV) can be obtained by stirring the compound (XI) in a solvent such as dichloromethane with an acid such as trifluoroacetic acid or formic acid at 0 ° C to room temperature.
  • compound (IV) can be obtained by directly reacting compound (IIa) with sulfoyl chloride (XVI) in a water-containing solvent in the presence of a base.
  • Compound (IIa) is synthesized by the following method.
  • optically active form of the compound of the present invention can be obtained by optically resolving an intermediate by a conventional method and then deriving the final product according to the above-mentioned scheme, or by optically resolving the final product by a conventional method.
  • optical resolution of the intermediate can be performed, for example, in the case of the compound (lib) as follows.
  • the racemic compound (IIb) is added to a solvent such as ethyl acetate, and an equivalent amount of (1-)- ⁇ -methylbenzylamine is added to recrystallize the precipitated salt.
  • the obtained salt is dissolved in an acidic aqueous solution.
  • a solvent such as ethyl acetate
  • the (+)-form of the compound (Ilb) can be obtained by using (+)- ⁇ -methylbenzyl / amine.
  • the sulfonyl chloride (XVI) can be converted to the corresponding phenyl —Can be synthesized by the reaction of ter (XV) with chlorosulfonic acid.
  • compound (XV) is mixed with chlorosulfonate in a solvent such as 1,2-dichloroethane at a temperature of 20 ° C to 50 ° C :!
  • the compound (XVI) is obtained by stirring for ⁇ 48 hours.
  • the molar ratio for the reaction is 1 mol to 10 mol of chlorosulfonic acid per 1 mol of compound (XV).
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof is orally or parenterally administered to a human.
  • the dosage form for oral administration includes tablets, granules, powders, fine granules; solid preparations such as hard capsules, and liquid preparations such as syrups and soft capsules.
  • Such a preparation can be produced by a conventional method, and tablets, granules, powders, or fine granules can
  • Hard capsules are prepared by filling the above fine granules or powders into appropriate capsules.
  • the syrup is prepared by dissolving or suspending the compound (I) of the present invention or a pharmaceutically acceptable salt thereof in an aqueous solution containing sucrose, carboxycellulose, and the like.
  • it is produced by dissolving or suspending the compound (I) of the present invention or a pharmaceutically acceptable salt thereof in vegetable oil, oily emulsion, glycol or the like, and filling in a soft capsule.
  • Examples of dosage forms for parenteral administration include injections, suppositories such as suppositories and vaginal suppositories, and nasal administration such as sprays. These preparations can be produced by a conventional method.
  • an injection can be prepared by adding compound (I) of the present invention or a pharmaceutically acceptable salt thereof to a physiological saline or lipid excipient, for example, vegetable oil, oily emulsion, It can be produced by dissolving or emulsifying in glycol or the like and aseptically enclosing in ampules or vials.
  • a physiological saline or lipid excipient for example, vegetable oil, oily emulsion
  • the invention's effect Since the compound of the present invention has a strong TNF- ⁇ production inhibitory activity (see Test Examples), the compound of the present invention or a pharmaceutically acceptable salt thereof is suitably used as a TNF-o; production inhibitor.
  • the TNF- ⁇ concentration in the culture supernatant was quantified using a human TNF- ⁇ measurement ELI S ⁇ kit (Amersham).
  • the TNF- ⁇ concentration in the culture supernatant without the test compound (A) was used as a control, and the TNF- ⁇ concentration in the culture supernatant with the test compound was added (X).
  • TNF— ⁇ secretion inhibition rate (%) (1 - ⁇ / ⁇ ) XI 00
  • O-benzylhydroxylamine hydrochloride (12.4 g) and triethylamine (7.9 g) were added, and the mixture was stirred overnight at room temperature.
  • Ethyl acetate and water were added to the residue obtained by distilling off the solvent, and the organic layer was washed with aqueous sodium hydrogen carbonate solution, diluted hydrochloric acid, water, and saturated saline, and then dried over magnesium sulfate. After removing magnesium sulfate, the solvent was distilled off to obtain 21.7 g of the title compound.
  • the reaction mixture was poured into 500 ml of water and extracted with ethyl acetate.
  • the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, 10% aqueous solution of citric acid and water, and dried over magnesium sulfate.
  • the residue obtained by distilling off the ethyl acetate was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 1.80 g of the title compound.
  • (+) _N-benzyloxy-N-tert-butoxycanoleboninole-5,6,7,8-tetrahydropyrido [3,4-b] pyrazine-17-carboxamide 1.80 g to 4 N under ice-cooling Hydrochloric acid and ethyl acetate solution (15 ml) were added, and the mixture was stirred for 1.5 hours. The precipitated solid was collected by filtration to obtain 1.4 g of the title compound as a light brown powder.
  • DMF 1 Om 1 was added to 0.46 g of 5,6,7,8-tetrahydropyrido [3,4-b] virazine-17-carboxylic acid methyl ester hydrochloride obtained in Reference Example 3, and 4 0.70 g of -dimethylaminopyridine and 0.60 g of 4-methoxybenzenesulfonyl chloride were added, and the mixture was stirred overnight at room temperature. Add aqueous citric acid to make it acidic After that, it was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate.
  • the organic layer was washed with water, an aqueous solution of sodium hydrogencarbonate, water, and saturated saline, and then dried over magnesium sulfate. After removing magnesium sulfate, the solvent is distilled off to obtain the target.
  • the title compound (0.19 g) was obtained as a pale yellow solid.
  • the reaction mixture was diluted with 50 ml of a stomal form, and washed with 0.5 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluate; ethyl acetate) to give 0.40 g of the title compound as a colorless powder.
  • (+)-N-benzyloxy-5,6,7,8-tetrahydropyrido [3,4-b] pyrazine-17-carboxamide hydrochloride obtained in Reference Example 2 (2) Dissolve in a mixed solvent of 15 ml of water and 10 ml of dioxane, and add 0.63 g of triethylamine and 0.85 g of 4-propoxybenzenesulfoyl chloride in 5 ml of dioxane under ice cooling. And stirred at room temperature for 7.5 hours. After the solvent was distilled off, ethyl acetate was added.
  • the Torifunoreorome Tokishibenzen 5.0 8 1 was dissolved in 1,2-dichloroethane 10 Om 1, by adding a click every mouth acid 10. 8 g under ice-cooling, followed by stirring at room temperature for 2 days. After adding iced water and extracting with black-mouthed form, the organic layer was washed with water and dried over magnesium sulfate. After removing magnesium sulfate, the solvent was distilled off to obtain 6.3 g of the title compound.
  • (+) —N-benzyloxy-1,5,6,7,8-tetrahydropyrido [3,4-b] pyrazine-17-potassium lipoxamide hydrochloride 0.50 g in dioxane 1 Om 1 and water 10 m 1 The mixture was dissolved in a mixed solvent, and a solution of 0.40 g of triethylamine and 0.49 g of 4-trifluoromethylbenzenesnorefoninolechloride in 2 ml of dioxane was added under ice cooling, followed by stirring at room temperature for 2 days.
  • 2-Fluoroethoxybenzene 0.87 was dissolved in 1,2-dichloroethane 2 Om 1, 2.1 g of chlorosulfonic acid was added under ice cooling, and the temperature was raised to room temperature over 5 hours. After adding 10 Om 1 of ice water, the organic layer was dried over sodium sulfate. After removal of sodium sulfate, the solvent was distilled off to obtain 0.99 g of the title compound.
  • Hydrochloride 0.50 g mixed with dioxane 1 Om 1 and water 10 ml After dissolving in a solvent, 0.40 g of triethylamine and 0.45 g of 4- (2-fluoroethoxy) benzenesulfonyl chloride were added under ice-cooling, and the mixture was stirred overnight at room temperature.
  • the reaction solution was acidified by adding dilute hydrochloric acid, and then extracted with ethyl acetate.
  • the organic layer was washed with water and saturated saline, and then dried over magnesium sulfate.
  • the residue obtained by removing magnesium sulfate is subjected to silica gel column chromatography.
  • the residue obtained by distilling off the solvent was acidified by adding dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over magnesium sulfate. After removing magnesium sulfate, the solvent was distilled off to obtain 16 g of the title compound.
  • HP LC exhibited the following retention times.
  • (+)-N-benzyloxy-6- (4-methoxybenzenes-norefoninole) obtained in Reference Example 18-1,6,7,8-tetrahydropyrido [3,4-1b] virazine 0.58 g of 7-carboxamide was dissolved in a mixed solvent of 8 ml of methanol and 8 ml of dioxane, and stirred overnight at room temperature under a hydrogen atmosphere using 29 g of 10% Pd—CO. After removing Pd-C, the residue obtained by distilling off the solvent was purified by silica gel column chromatography (mobile phase; chloroform / methanol 1 OZl), and 0.34 g of the title compound was purified. Obtained as a yellow powder.
  • (+) — N-benzyloxy-1 6— [4- (3-methoxypropoxy) benzenesulfonyl] obtained in Reference Example 19—5, 6, 7, 8-tetrahydropyrido [3,4-b 0.57 g of pyrazine-17-carboxamide is dissolved in a mixed solvent of 1 Om 1 of methanol and 15 ml of dioxane, and 30 g of 10% Pd—C O. Stirred. After removing Pd—C, the solvent was distilled off, and the residue obtained was purified by silica gel column chromatography (mobile phase; chloroform-form methanol 10/1) to give the title compound 0 .19 g were obtained as a pale yellow solid.
  • the above acid solution was added to a mixed solvent of 1.5 ml of a 50% aqueous hydroxylamine solution and 5 ml of 1,2-dimethoxetane, and the mixture was stirred overnight for 2.5 hours.
  • the tetrahydropyridopyrazine derivative (I) of the present invention or a pharmaceutically acceptable salt thereof has an excellent TNF-a production inhibitory action and is useful as a TNF-a production inhibitor.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés représentés par la formule générale (I) ci-après, ou leurs sels pharmaceutiquement acceptables, formule dans laquelle R1 représente un groupe sélectionné dans le groupe constitué de alkyle C¿1-6?, phényle et hétéroaryle éventuellement substitués. Du fait de leur puissant effet d'inhibition vis-à-vis de la production du TNF-α, les composés (I) ou leurs sels pharmaceutiquement acceptables sont utiles en tant que médicaments, notamment comme inhibiteurs de la production du TNF-α.
PCT/JP1999/005831 1998-10-22 1999-10-22 Derives de tetrahydropyridopyridine, et produits intermediaires permettant de produire lesdits derives WO2000023443A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU62284/99A AU6228499A (en) 1998-10-22 1999-10-22 Tetrahydropyridopyridine derivatives and intermediates for producing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP30078298 1998-10-22
JP10/300782 1998-10-22

Publications (1)

Publication Number Publication Date
WO2000023443A1 true WO2000023443A1 (fr) 2000-04-27

Family

ID=17889038

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1999/005831 WO2000023443A1 (fr) 1998-10-22 1999-10-22 Derives de tetrahydropyridopyridine, et produits intermediaires permettant de produire lesdits derives

Country Status (2)

Country Link
AU (1) AU6228499A (fr)
WO (1) WO2000023443A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6770647B2 (en) 2001-08-17 2004-08-03 Bristol-Myers Squibb Pharma Company Bicyclic hydroxamates as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme (TACE)
JP2006515319A (ja) * 2002-12-19 2006-05-25 バーテックス　ファーマシューティカルズ　インコーポレイテッド Ｔａｃｅのインヒビター
JP2008506752A (ja) * 2004-07-21 2008-03-06 アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ オクタヒドロピロロ［２，３，ｃ］ピリジン誘導体と、その医薬としての利用法

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0652218A1 (fr) * 1993-11-10 1995-05-10 Takeda Chemical Industries, Ltd. Composés hétérocycliques, leur préparation et utilisation
WO1996033172A1 (fr) * 1995-04-20 1996-10-24 Pfizer Inc. Derives d'acide hydroxamique arylsufonyle en tant qu'inhibiteurs de mmp et de tnf
JPH08337583A (ja) * 1995-04-13 1996-12-24 Takeda Chem Ind Ltd 複素環化合物およびその製造法
WO1997018194A1 (fr) * 1995-11-13 1997-05-22 Hoechst Aktiengesellschaft ACIDES α-IMINOHYDROXAMIQUES ET CARBOXILIQUES CYCLIQUES ET HETEROCYCLIQUES SUBSTITUES EN POSITION N
WO1998034918A1 (fr) * 1997-02-11 1998-08-13 Pfizer Inc. Derives de l'acide arylsulfonylhydroxamique
WO1998050348A1 (fr) * 1997-05-09 1998-11-12 Agouron Pharmaceuticals, Inc. Inhibiteurs de metalloproteases, compositions pharmaceutiques les contenant et leurs utilisations pharmaceutiques
WO1999006410A1 (fr) * 1997-08-04 1999-02-11 Amgen Inc. Inhibiteurs de metalloproteases heterocycliques hybrides et substitues par de l'acide hydroxamique
JPH11147876A (ja) * 1997-09-12 1999-06-02 Kanebo Ltd テトラヒドロイソキノリン誘導体およびそれを有効成分とする薬剤

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0652218A1 (fr) * 1993-11-10 1995-05-10 Takeda Chemical Industries, Ltd. Composés hétérocycliques, leur préparation et utilisation
JPH08337583A (ja) * 1995-04-13 1996-12-24 Takeda Chem Ind Ltd 複素環化合物およびその製造法
WO1996033172A1 (fr) * 1995-04-20 1996-10-24 Pfizer Inc. Derives d'acide hydroxamique arylsufonyle en tant qu'inhibiteurs de mmp et de tnf
WO1997018194A1 (fr) * 1995-11-13 1997-05-22 Hoechst Aktiengesellschaft ACIDES α-IMINOHYDROXAMIQUES ET CARBOXILIQUES CYCLIQUES ET HETEROCYCLIQUES SUBSTITUES EN POSITION N
WO1998034918A1 (fr) * 1997-02-11 1998-08-13 Pfizer Inc. Derives de l'acide arylsulfonylhydroxamique
WO1998050348A1 (fr) * 1997-05-09 1998-11-12 Agouron Pharmaceuticals, Inc. Inhibiteurs de metalloproteases, compositions pharmaceutiques les contenant et leurs utilisations pharmaceutiques
WO1999006410A1 (fr) * 1997-08-04 1999-02-11 Amgen Inc. Inhibiteurs de metalloproteases heterocycliques hybrides et substitues par de l'acide hydroxamique
JPH11147876A (ja) * 1997-09-12 1999-06-02 Kanebo Ltd テトラヒドロイソキノリン誘導体およびそれを有効成分とする薬剤

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6770647B2 (en) 2001-08-17 2004-08-03 Bristol-Myers Squibb Pharma Company Bicyclic hydroxamates as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme (TACE)
JP2006515319A (ja) * 2002-12-19 2006-05-25 バーテックス　ファーマシューティカルズ　インコーポレイテッド Ｔａｃｅのインヒビター
JP2008506752A (ja) * 2004-07-21 2008-03-06 アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ オクタヒドロピロロ［２，３，ｃ］ピリジン誘導体と、その医薬としての利用法

Also Published As

Publication number Publication date
AU6228499A (en) 2000-05-08

Similar Documents

Publication Publication Date Title
RU2764243C2 (ru) Гетероциклические соединения в качестве ингибиторов PAD
CA2425440C (fr) Aza- et polyaza-naphthalenyl carboxamides utiles comme inhibiteurs de l'integrase du vih
CA2733247C (fr) Derives d'amides heterocycliques en tant qu'antagonistes du recepteur ep4
EP1491543B1 (fr) Produits intermédiaires pour la préparation des dérivés d'imidazo-pyridine
RU2366659C2 (ru) Новые производные пиридина, способ их получения и содержащая их фармацевтическая композиция
US20100179137A1 (en) Pyridone compound
WO2007032466A1 (fr) Composé hétérocyclique et procédé de production et utilisation de celui-ci
JP6793658B2 (ja) Ｔｎｆ阻害剤として有用な三環式ヘテロ環式化合物
WO2007134986A1 (fr) Dérivés de pyridopyrimidinone
WO2003086400A1 (fr) Derives de pyridinone et de pyrimidinone substitues en n a utiliser en tant qu'inhibiteurs de lp-pla2 dans le traitement de l'atherosclerose
JP2008524210A (ja) メタロプロテイナーゼ阻害剤としての新規ヒダントイン誘導体
CN101932584A (zh) 作为pi3k阻滞剂的吡咯并嘧啶衍生物及其用途
CZ374692A3 (en) Proteolytic enzymes inhibitors based on saccharin derivatives
US7102008B2 (en) Hydantoin derivatives as inhibitors of matrix metalloproteinases and/or TNF-α converting enzyme
JP2003533525A (ja) Ｍｍｐおよびｔｎｆ阻害活性を有するヒドロキサム酸およびカルボン酸誘導体
JPH01500834A (ja) アザインドール及びインドリジン誘導体、その製造方法及び薬剤としてのその用途
WO1995005374A1 (fr) Derive de cyclopentene heteroaromatique fusionne ayant une activite antagoniste de l'endotheline
JP2007513120A (ja) ピロール化合物
US6407112B1 (en) Optically active tetrahydrobenzindole derivative
JP2955332B2 (ja) アンチ葉酸の不斉合成
JP2009543837A (ja) Ｅｐ１受容体に対して親和性を有するインドール化合物
JP3111321B2 (ja) 縮合チアゾール化合物
JP2018538355A (ja) ベンズアミド誘導体
WO2000023443A1 (fr) Derives de tetrahydropyridopyridine, et produits intermediaires permettant de produire lesdits derives
WO2001036420A1 (fr) Derives d'aza-indolizine tricyclique ayant un effet inhibiteur sur spla¿2?

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

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

AL Designated countries for regional patents

Kind code of ref document: A1

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

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

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase