WO2002030873A1 - Inhibiteur des mmp - Google Patents

Inhibiteur des mmp Download PDF

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Publication number
WO2002030873A1
WO2002030873A1 PCT/JP2001/008325 JP0108325W WO0230873A1 WO 2002030873 A1 WO2002030873 A1 WO 2002030873A1 JP 0108325 W JP0108325 W JP 0108325W WO 0230873 A1 WO0230873 A1 WO 0230873A1
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group
lower alkyl
salt
formula
aryl
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PCT/JP2001/008325
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English (en)
Japanese (ja)
Inventor
Akihiko Sawada
Masahiro Neya
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Fujisawa Pharmaceutical Co., Ltd.
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Publication of WO2002030873A1 publication Critical patent/WO2002030873A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel compounds and their pharmaceutically acceptable salts.
  • the present invention relates to novel compounds useful as inhibitors of matrix metaoral protease (hereinafter referred to as MMP) or tumor necrosis factor ⁇ (hereinafter referred to as TNF) production, and pharmaceutically acceptable salts thereof.
  • MMP matrix metaoral protease
  • TNF tumor necrosis factor ⁇
  • the present invention also relates to pharmaceutical compositions containing them, their use as medicaments, and methods of using them for the treatment or prevention of ⁇ - or TNF ⁇ -mediated diseases.
  • An object of the present invention is to provide a novel and useful compound having a pharmacological activity such as an inhibitory activity against MM- or TNF production, a pharmaceutically acceptable salt thereof, and the novel compound and a salt thereof. Is to provide a method of manufacturing the same.
  • Another object of the present invention is to provide a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound of the present invention has inhibitory activity on MMP or TNFa production, and has seizures, arthritis, cancer, tissue ulcer, decubitus ulcer, restenosis, periodontal disease, epidermolysis bullosa, scleritis, psoriasis and matrix meta Other diseases characterized by oral protease activity It is useful for treating and / or preventing diseases such as AIDS, sepsis, septic shock, and other diseases caused by production of TNF ⁇ .
  • Matrix-degrading meta-oral proteases such as gelatinases ( ⁇ __2, ⁇ ⁇ -9), stomalisine ( ⁇ ⁇ -3) and collagenases (MMP-1, MMP-8, MMP- 13) is involved in tissue matrix degradation and involves many pathologies involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (eg, osteoarthritis and rheumatoid arthritis), cerebral disease (Eg, seizures), tissue ulcers (eg, corneal, epidermal and stomach ulcers), abnormal wound healing, periodontal disease, bone disease (eg, Paget's disease, osteoporosis), tumor metastasis or invasion and It has been linked to HIV infection.
  • arthritis eg, osteoarthritis and rheumatoid arthritis
  • cerebral disease Eg, seizures
  • tissue ulcers eg, corneal, epidermal and stomach ulcers
  • abnormal wound healing eg, periodontal disease, bone disease (eg, Paget's disease, osteoporos
  • Tumor necrosis factor is recognized to be involved in many infectious and autoimmune diseases. Furthermore, TNF has been shown to be a major mediator of the inflammatory response seen in sepsis and septic shock.
  • the target compound of the present invention is novel and can be represented by the following formula (I).
  • R 1 and R 2 each represent an optionally substituted aryl group, an optionally substituted aryl lower alkyl group, an aryl lower alkenyl group, an aryloxy lower alkyl group, or an optionally substituted aryl group. Or a salt thereof.
  • the target compound of the present invention can be produced by the following steps. -OH ⁇ -Cl
  • Trityl Linker Crown made by Chiron Technologies Pty: Ltd
  • 50 ml of a 20% acetyl chloride / methylene chloride solution was added.
  • the reaction mixture was allowed to stand for 3 hours.
  • the crown was separated by filtration, and the crown was washed with methylene chloride (50 ml x 5 minutes x 2).
  • N-Hydroxyphthalimide (660 mg) was placed in a 100-ml wide-bottle or bottle, and N, N-diisopropylethylamine (2.8 ml) was added to a mixture suspended in 20 ml of methylene chloride. .
  • the crown (100 pieces) prepared in Production Method 1 was added to the reaction mixture, allowed to stand for 18 hours, and then the crown was filtered off. The crown was washed with methylene chloride (50 ml ⁇ 5 minutes ⁇ 3 times). The obtained crown was dried.
  • N-a-Fmoc- ⁇ -1 (4,4_dimethinole_2,6-dioxo- 1-cyclohexylidene) ethyl-L-diaminopropionic acid (1.47 g)
  • HOBt (1-hydroxybenzotriazole)
  • diisopropylcarbodiimide 450 / iL
  • Carboxylic acid (VIII) was added to a 100 ml wide dome bottle. 1.5% HOB tZN, N-dimethylformamide solution (20 ml) and diisopropylcarbodiimide (300 L) were mixed and left for 20 minutes. Crown with Transtem obtained in Production Method 5 ⁇ ⁇ ⁇ Divided by 10 minutes using a TranSort system manufactured by Chiron Technologies Pty Ltd., 10 crowns with Transtem were added to each reaction mixture, and the mixture was allowed to stand for 18 hours.
  • the carboxylic acid (XI) was added to a 100 ml wide-mouthed medium bottle. 1. 5% HOBt / N, N-dimethylformamide solution (20 ml) and diisopropylcarbodiimide (300 iL) were added.
  • the crown with Transtem obtained in Production Method 7 was divided into 10 pieces by the TranSort system, and the crown with Transtem (10 pieces) was added to each reaction mixture and allowed to stand for 18 hours. After filtering and mixing 0 kinds of crowns with Transtem, they were washed with N, N-dimethylformamide (50 ml x 5 minutes x 3 times) and methylene chloride (50 ml x 5 minutes x 3 times), and obtained.
  • the Transtem-equipped crown obtained in Production Method 8 was placed at a specified position on a pin holder made by Chiron Technologies Pty Ltd. using the ranSort system.
  • each target compound was immersed in a 5% trifluoroacetic acid Z methylene chloride solution (1.5 ml) for 1 hour, and the target compound was cut out from the crown with Transtem. The obtained solution was dried in a stream of nitrogen to obtain the target compound. The structure of each target compound was determined using an LCZMS apparatus (ESI + or ESI).
  • R 1 and R 2 have the same meaning as described above, Fmoc means 9-fluorenylmethoxycarbonyl, and DDE means 1- (4,4-dimethynole-1,2,6-dioxo-1-1-cyclohexylidene) ethyl.”
  • the salt of the object compound of the present invention or a pharmaceutically acceptable salt may be a conventional non-toxic salt, and may be an organic acid salt (for example, acetate, trifluoroacetate, maleate, tartrate, fumarate) , Methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), inorganic acid (eg, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphoric acid) Salts, etc.), amino acids (eg, arginine, aspartic acid, glutamic acid, etc.), alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, etc.) Magnesium salt, etc., ammonium salt, organic base salt (for example, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexyl
  • the target compounds and their pharmaceutically acceptable salts include solvates such as clathrates (eg, hydrates).
  • solvates such as clathrates (eg, hydrates).
  • Suitable "aryl” in the terms “aryl group” and “optionally substituted aryl group” are, for example, aryl having 6 to 10 carbon atoms such as phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, etc. Preferably it is phenyl, which may have one or more substituents.
  • substituted aryl groups include halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, aryloxy, arylo lower alkyl, and preferably aryloxy (eg, phenoxy, etc.). ), Nitro oxaloyl (for example, benzoyl).
  • Suitable aroyls include aroyl having 6 to 10 carbon atoms, particularly preferably benzoyl.
  • heterocyclic group in the term “optionally substituted heterocyclic group” is a saturated or unsaturated group containing at least one heteroatom such as an oxygen atom, a sulfur atom, a nitrogen atom and the like. It means a 3- to 8-membered monocyclic or polycyclic heterocyclic group.
  • heterocyclic groups are:
  • An unsaturated 3- to 8-membered, preferably 5- or 6-membered monocyclic monocyclic group containing up to 4 nitrogen atoms such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl; Pyridazinyl, triazolyl (for example, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (for example, 1H-tetratolyl) Lazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (for example, 4,5-dihydro-1,2,4_triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.);
  • a saturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing up to 4 nitrogen atoms for example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperidino, birazolidinyl, piperazinyl and the like;
  • Unsaturated condensed 7 to 13 membered, preferably 9 or 10 membered bicyclic heterocyclic group containing one to five nitrogen atoms e.g., indolyl, isoindolyl, indolizinyl, Benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazopyridyl, tetrazolopyridazinyl (eg, tetrazolo [1,5-b] pyridazinyl, etc.), dihydrotriazolopyridazinyl and the like;
  • Unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing one or two oxygen atoms and one to three nitrogen atoms for example, oxazolyl, isoxazolyl, oxaziazolyl (for example, 2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.);
  • An unsaturated 3- to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing one or two sulfur atoms and one to three nitrogen atoms for example, thiazolyl, 1,2-thiazolyl, thiazolinyl, Thiadiazolyl (for example, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.);
  • the most preferred heterocyclic group is an unsaturated 5- or 6-membered heterocyclic monocyclic group containing a sulfur atom.
  • heterocyclic groups may have one or more substituents.
  • substituents of the substituted heterocyclic group include halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, aryloxy, lower alkyl, aryl, and optionally substituted.
  • Heterocyclic group haloaryl, hydroxyaryl, lower alkoxyaryl, lower alkylaryl, nitroarylole, biphenyl, aryloxyaryl, trihaloalkylaryl, cyano (lower) alkoxyaryl, cyanoaryl, cyano (lower) Alkylaryl, lower alkanoyloxyl, lower alkanoyloxy (lower) alkylaryl, di (lower) alkylaminosulfonylaryl, hydroxy (lower) alkylaryl, lower alkoxycarbonyl Aryl, lower alkoxycarbonyl (lower) alkoxyl, lower alkoxysulfoninoleoxyl, aryl substituted with halogen and hydroxy, aryl and halogen substituted alkoxy, halogen and lower alkoxy Aryl, a lower alkyl-heterocyclic group and an aryl substituted with a lower alkoxy, a lower alkyl-he
  • a suitable "aryl lower alkyl” in the term “substituted or more aryl lower alkyl” is a straight-chain or branched alkyl having 1 to 6 carbon atoms, which is substituted by the above aryl, and is methyl, ethynole, propyl. Isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like. Preferred aryl lower alkyls are phenylmethyl and naphthylmethyl.
  • the aryl group may be substituted by one or more substituents, and examples of the substituent include halogen, cyano, nitro, acylamino, carbamoyl, hydroxy, lower alkoxy, lower alkenyl carbamoyl, and carboxy.
  • substituents include halogen, cyano, nitro, acylamino, carbamoyl, hydroxy, lower alkoxy, lower alkenyl carbamoyl, and carboxy.
  • it includes naphthylmethyl or chloro off We methylpropenylmethyl group as a 1 1 or 1 ⁇ 2.
  • aryl lower alkenyl in the term “aryl lower alkenyl” is a straight-chain or branched alkenyl having 2 to 6 carbon atoms, which is substituted by aryl, and is selected from the group consisting of bier, 1-propenyl, and 2-propane. Nyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl and the like are exemplified, and preferably a butyl.
  • Preferred examples of lower alkenyl include phenylbutyl.
  • aryloxy lower alkyl include phenoxymethyl, phenoxethyl, naphthoxymethyl, naphthoxethyl, and preferably phenoxethyl.
  • lower means 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise specified.
  • Suitable "norogens” include fluorine, bromine, and chlorine iodine.
  • R 1 and R 2 are an aryloxyaryl group, an aryloylyl group, a nitroaryl group, an aryl lower alkyl group, a haloaryl lower alkyl group, an aryl lower alkenyl group, an aryloxy lower alkyl group, Or an unsaturated 3- to 8-membered heteromonocyclic group containing 1 or 2 sulfur atoms.
  • R 1 and R 2 are each a phenoxyphenyl group, a benzoylphenyl group, a ditrophenyl group, a naphthyl lower alkyl group, a halophenyl lower alkyl group, a phenyl lower alkenyl group, a phenoxy lower alkyl group, or a phenyl group; 'The compound according to the above (1),
  • R 1 and R 2 are each, 3- or 4-Fuenokishifue two Honoré group, 4-Benzo Irufueniru group, 4-nitrophenyl group, 1-naphthylmethyl group, 2-chlorophyll Enirumechiru group, 2-phenylene Rubiniru group, 1- Or the compound according to the above (2), which is a 2-phenoxethyl group or a 2-phenyl group.
  • the compound obtained by the above-mentioned production method can be separated and purified by a conventional method, for example, pulverization, recrystallization, column chromatography, reprecipitation and the like.
  • the target compound can be converted to a salt thereof by a conventional method.
  • the target compound may include one or more stereoisomers due to asymmetric carbon, and all such isomers and mixtures thereof are included in the scope of the present invention.
  • Collagenase initiates the degradation of vertebrate collagen and, in addition to their normal function in connective tissue metabolism and wound healing, a number of pathologies, such as joint rupture in rheumatoid arthritis, periodontal disease, corneal ulcers , Tumor metastasis, osteoarthritis, pressure ulcer, restenosis after percutaneous coronary lumen dilatation, osteoporosis, psoriasis, active chronic hepatitis, self
  • the compounds of the present invention are useful for the treatment and Z or prevention of such conditions, as they have been implicated in autoimmune keratitis and the like.
  • the compounds of the present invention and their pharmaceutically acceptable salts are suitable for oral, parenteral or topical administration of a pharmaceutically acceptable carrier, for example, an organic or inorganic solid or liquid.
  • a pharmaceutically acceptable carrier for example, an organic or inorganic solid or liquid.
  • the compound can be used in the form of a preparation containing one of the compounds as an active ingredient by mixing with an excipient.
  • Formulations may include capsules, tablets, dragees, granules, solutions, suspensions, emulsifiers, sublingual tablets, suppositories, ointments and the like. If necessary, these preparations may contain auxiliary substances, stabilizers, wetting agents, emulsifiers, buffers and other commonly used additives.
  • the dose of the compound varies depending on the age and condition of the patient, but the daily dose is 0.01 to 100 mg per kg of human body weight for intravenous administration, and human for intramuscular administration.
  • the inhibitory activity of MMP-13 was measured using Arthrogen-CIA MMP-13 Kit (Chondrex) according to the prescription of Chondrex according to the following procedure.
  • the amount of Substrate released by the enzymatic reaction was measured using a fluorometer (SPECTRAFLUOR PLUS: TECA) at an excitation wavelength of 360 nm and a fluorescence wavelength of 465 nm. IC 5. Values are shown as the concentration of each sample required for 50% inhibition. 2. Test compound
  • the target compound having the following structural formula was synthesized by the method shown in the above-mentioned Production method 9.

Abstract

L'invention concerne un nouvel inhibiteur des MMP. Cet inhibiteur est un composé représenté par la formule (I), dans laquelle R1 et R2 représentent chacun l'aryle éventuellement substitué, l'arylalkyle inférieur éventuellement substitué, l'arylalcényle inférieur, l'aryloxyalkyle inférieur ou un groupe hétérocyclique éventuellement substitué. Ce composé est utile en tant qu'inhibiteur des MMP.
PCT/JP2001/008325 2000-10-10 2001-09-25 Inhibiteur des mmp WO2002030873A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1577302A1 (fr) * 2002-12-24 2005-09-21 Daiichi Pharmaceutical Co., Ltd. Nouveaux derives d'ethylenediamine
US7348437B2 (en) * 2004-06-01 2008-03-25 The Scripps Research Institute Proteomic analysis
FR2950056A1 (fr) * 2009-09-17 2011-03-18 Galderma Res & Dev Nouveaux composes benzene-carboxylamides, leur procede de synthese et leur utilisation en medecine ainsi qu'en cosmetique
FR2950057A1 (fr) * 2009-09-17 2011-03-18 Galderma Res & Dev Nouveaux composes benzene-carboxylamides, leur procede de synthese et leur utilisation en medecine ainsi qu'en cosmetique
EP2295402A3 (fr) * 2003-01-08 2011-08-03 The University of Washington Agents anti-bactériens
WO2011132712A1 (fr) * 2010-04-20 2011-10-27 大正製薬株式会社 Nouveau dérivé d'acide hydroxamique
US9403758B2 (en) 2012-05-10 2016-08-02 Achaogen, Inc. Antibacterial agents
US9617256B2 (en) 2007-06-12 2017-04-11 Achaogen, Inc. Antibacterial agents

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998015525A1 (fr) * 1996-10-07 1998-04-16 Sumitomo Pharmaceuticals Co., Ltd. Acides hydroxamiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998015525A1 (fr) * 1996-10-07 1998-04-16 Sumitomo Pharmaceuticals Co., Ltd. Acides hydroxamiques

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1577302A4 (fr) * 2002-12-24 2010-09-01 Daiichi Seiyaku Co Nouveaux derives d'ethylenediamine
EP1577302A1 (fr) * 2002-12-24 2005-09-21 Daiichi Pharmaceutical Co., Ltd. Nouveaux derives d'ethylenediamine
CN102267924A (zh) * 2003-01-08 2011-12-07 诺华疫苗和诊断公司 抗菌剂
US8153843B2 (en) 2003-01-08 2012-04-10 University Of Washington Antibacterial agents
US8101640B2 (en) 2003-01-08 2012-01-24 Novartis Vaccines And Diagnostics, Inc. Antibacterial agents
EP2295402A3 (fr) * 2003-01-08 2011-08-03 The University of Washington Agents anti-bactériens
US8084615B2 (en) 2003-01-08 2011-12-27 University Of Washington Antibacterial agents
US7348437B2 (en) * 2004-06-01 2008-03-25 The Scripps Research Institute Proteomic analysis
AU2005260111B2 (en) * 2004-06-01 2011-06-16 The Scripps Research Institute Proteomic analysis
US9617256B2 (en) 2007-06-12 2017-04-11 Achaogen, Inc. Antibacterial agents
WO2011033009A1 (fr) 2009-09-17 2011-03-24 Galderma Research & Development Composés de n-[2-hydroxycarbamoyl-2-(pipérazinyl)éthyl]benzamide, leur préparation et utilisation à titre d'inhibiteurs de tace
US9115102B2 (en) 2009-09-17 2015-08-25 Galderma Research & Development N-[2-hydroxycarbamoyl-2-(piperazinyl) ethyl] benzamide compounds, their preparation and their use as TACE inhibitors
WO2011033010A1 (fr) 2009-09-17 2011-03-24 Galderma Research & Development Composés de 4-alcoxy-n-(2-hydroxycarbamoyl-2-pipéridinyléthyl)benzamide en tant qu'inhibiteurs de tace sélectifs destinés au traitement de maladies inflammatoires
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JP2013505216A (ja) * 2009-09-17 2013-02-14 ガルデルマ・リサーチ・アンド・デヴェロップメント 炎症性疾患治療用の選択的ｔａｃｅ阻害剤としての４−アルコキシ−ｎ−（２−ヒドロキシカルバモイル−２−ピペリジニル−エチル）ベンズアミド化合物
JP2013505215A (ja) * 2009-09-17 2013-02-14 ガルデルマ・リサーチ・アンド・デヴェロップメント Ｎ−［２−ヒドロキシカルバモイル−２−（ピペラジニル）エチル］ベンズアミド化合物、それらの製法及びｔａｃｅ阻害剤としてのそれらの使用
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