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WO1998033777A1 - Composes ayant une activite inhibant la metalloprotease - Google Patents

Composes ayant une activite inhibant la metalloprotease Download PDF

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Publication number
WO1998033777A1
WO1998033777A1 PCT/JP1998/000306 JP9800306W WO9833777A1 WO 1998033777 A1 WO1998033777 A1 WO 1998033777A1 JP 9800306 W JP9800306 W JP 9800306W WO 9833777 A1 WO9833777 A1 WO 9833777A1
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Prior art keywords
formula
hydrogen atom
optionally substituted
lower alkyl
compound
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PCT/JP1998/000306
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English (en)
Japanese (ja)
Inventor
Hiroshige Tsuzuki
Sadao Miyazaki
Tsunetoshi Honma
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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Priority to AU55774/98A priority Critical patent/AU5577498A/en
Publication of WO1998033777A1 publication Critical patent/WO1998033777A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members

Definitions

  • the present invention relates to a compound having a protease inhibitory activity at the mouth and its use. Background art.
  • the extracellular matrix is composed of collagen, proteodalican, etc., and has a role of maintaining cell functions such as cell growth, differentiation, and adhesion, as well as a tissue support function.
  • the degradation of extracellular matrix involves the protease, which contains a metal ion in the active center, and especially the matrix metaprotease (MMP).
  • MMP matrix metaprotease
  • Matrix Messenger proteases are currently MMP-1 (type I collagenase; produced by osteoclasts, chondrocytes, tumor cells, fibroblasts, inflammatory cells, etc.), MMP-2, MMP-9 (type IV 18 types are known, including collagenase; produced by tumor cells, fibroblasts, vascular endothelial cells, blood cells, inflammatory cells, epithelial cells, etc.), MMP-3 (stromelysin), etc. In a strategic situation, it is operating due to growth and organizational reform.
  • MMP-1 type I collagenase; produced by osteoclasts, chondrocytes, tumor cells, fibroblasts, inflammatory cells, etc.
  • MMP-2 type IV 18 types are known, including collagenase; produced by tumor cells, fibroblasts, vascular endothelial cells, blood cells, inflammatory cells, epithelial cells, etc.
  • MMP-3 stromelysin
  • the present inventors have conducted research to develop compounds having strong meta-oral protease inhibitory activity.
  • X and Y are each independently an oxygen atom or a sulfur atom
  • Z is one N (R A )-(R A is a hydrogen atom or lower alkyl)
  • R 1 is optionally substituted —
  • R 2 is the same or different and is a hydrogen atom, an optionally substituted lower alkyl, a compound represented by the formula (A):
  • R 3 represents alkyl or lower alkyloxy
  • R B represents a hydrogen atom or lower alkyl
  • R 4 is an optionally substituted amino, carbonyl, or alkyloxycarbonyl
  • m is an integer of 1 to 3
  • R B is as defined above, and a group represented by the formula (C):
  • the present invention relates to a pharmaceutical composition containing a compound represented by the formula (1) as an active ingredient, and more specifically to the following inventions a) to c).
  • composition as described above which is a female protease inhibitor.
  • composition as described above which is a therapeutic or prophylactic agent for rheumatoid arthritis.
  • the compound of the present invention relates to a compound represented by the following 1) to 6).
  • X and Y are each independently an oxygen atom or a sulfur atom, ⁇ is one N (RA) — (RA is a hydrogen atom or lower alkyl), R 1 is an optionally substituted aryl or Optionally substituted heteroaryl, wherein R 2 is the same or different Elemental atom, optionally substituted lower alkyl, formula (A)
  • R 3 represents alkyl or lower alkyloxy
  • R B represents a hydrogen atom or lower alkyl
  • R 4 is an optionally substituted amino, carboxy, or alkyloxycarbonyl, m is an integer of 1-3, and RB is as defined above), and a formula (C):
  • R 5 and R B have the same meanings as described above, and q represents an integer of 1 to 3).
  • R 1 is not an unsubstituted phenyl, and when R 1 is p_bromophenyl, R 2 is not a hydrogen atom.
  • R 1 is not an unsubstituted phenyl
  • R 1 is p_bromophenyl
  • R 2 is not a hydrogen atom.
  • R 6 and R 7 each independently represent a hydrogen atom, an optionally substituted lower alkyl, a halogen, or a substituted Represents amino, nitro, cyano, formyl, carbonyl, lower alkyloxy, lower alkyloxy, lower alkyloxy, mercapto, or lower alkylthio, provided that R 6 and R 7 are not hydrogen atoms at the same time but R 6 and R 7 When either one is p-bromo and the other is a hydrogen atom, then R 2 is not a hydrogen atom.) Or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 8 and R 9 each independently represent a hydrogen atom, an optionally substituted lower alkyl, a halogen, an optionally substituted amino, Represents nitro, cyano, formyl, carboxy, lower alkyloxycarbonyl, hydroxy, lower alkyloxy, mercapto, or lower alkylthio, provided that R 8 is a promoter, R 9 is a hydrogen atom, and R 2 is not a hydrogen atom And R 8 and R 9 are not both hydrogen atoms at the same time. Is a pharmacologically acceptable salt or hydrate thereof,
  • R 1 represents a fluorine atom, a chlorine atom, an iodine atom, an optionally substituted lower alkyl, an optionally substituted amino, nitro, cyano, formyl, carboxy Or a lower alkyloxycarbonyl, hydroxy, lower alkyloxy, mercapto, or lower alkylthio), or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • R 11 is the same or differently substituted lower alkyl, and formula (A)
  • R 3 represents alkyl or lower alkyloxy
  • R B represents a hydrogen atom or lower alkyl
  • R 5 and R B are as defined above, and Q is an integer of 1 to 3).
  • Q is an integer of 1 to 3.
  • R 2 and R 11 are not limited to the above definitions, and are compounds that are groups that are converted to hydrogen atoms in a living body, or pharmacologically acceptable thereof. Salts or hydrates thereof are useful as prodrugs.
  • the present invention relates to the following A) to D).
  • a pharmaceutical composition comprising the compound according to any one of the above 1) to 6) as an active ingredient.
  • a meta-oral protease inhibitor comprising the compound according to any one of the above 1) to 6) as an active ingredient.
  • Lagenase inhibitor-D A therapeutic or prophylactic agent for rheumatoid arthritis, comprising the compound according to any one of the above 1) to 6) as an active ingredient.
  • the compounds of the present invention all have excellent meta-oral protease activity, and particularly preferred are compounds in which R 2 and R 11 are hydrogen atoms and prodrug derivatives which are converted to hydrogen atoms in vivo.
  • both R 2 are a) a hydrogen atom, b) a group represented by the formula (A), c) a group represented by the formula (B), d) a formula (C) Group, e) a group represented by the formula (D), and when the substituent in R 1 Q is f) halogen, g) cyano, h) trioctaalkyl, a compound represented by the following combination is preferable.
  • New (R 2, R 1 °) (a, f) (a, g) (a, h) (b, f) (b, g) (b, h) (c, f) (c, g) ( c, h) (d, f) (d, g) (d, h) (e, f) (e, g) (e, h).
  • R B is preferably a hydrogen atom.
  • halogen means fluorine, chlorine, bromine, and iodine. Of these, fluorine, chlorine and bromine are preferred.
  • alkyl refers to a straight-chain or branched C- ⁇ 2 .
  • lower alkyl refers to straight or branched C i Ce alkyl. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl and the like. Preferably, methyl, ethyl, n-propyl, i-propyl are used.
  • the “optionally substituted lower alkyl” for R 2 includes: lower alkyloxy (eg, methyloxy, ethyloxy), hydroxy, mercapto, lower alkylthio (eg, methylthio), carboxy, lower alkyloxy.
  • Lower alkyl, hydroxy lower alkyl, carboxy lower alkyl and alkyloxycarbonyl lower alkyl are preferred. Particularly, hydroxymethyl, 1-hydroxyl, and 1-hydroxypropyl are preferred.
  • the “optionally substituted lower alkyl” in R 6 , R 7 , R 8 , R 9 , and R 1 Q includes lower alkyloxy (eg, methyloxy, ethyloxy), hydroxy, mercapto , Lower alkylthio (eg, methylthio), methoxyl, lower alkyloxycarbonyl (methyloxycarbonyl), mono-lower alkyl-substituted amino (eg, N-methyl'amino), di-lower alkyl-substituted amino (eg, N , N-dimethylamino), morpholino, halogen (eg, chloro, promo, trifluoro, trichloro), and the like, which means the above-mentioned "lower alkyl”.
  • lower alkyloxy eg, methyloxy, ethyloxy
  • hydroxy mercapto
  • Lower alkylthio eg, methylthio
  • methoxyl e
  • Lower alkyl, halo lower alkyl and hydroxy lower alkyl are preferred.
  • methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, chloromethyl, chloroethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoro Romethyl, trifluoromethyl and hydroxymethyl are preferred. More preferably, trifluoromethyl is exemplified.
  • aryl means a monocyclic or condensed cyclic aromatic hydrocarbon.
  • phenyl, naphthyl and the like can be mentioned. Phenyl is preferred.
  • heteroaryl means a 5- to 6-membered aromatic ring arbitrarily selected containing one or more oxygen, sulfur, or nitrogen atoms in the ring, which is a carbon ring or a carbon ring. It may be condensed with another heterocycle, and these may be bonded at all substitutable positions.
  • pyrrolyl eg, 1-pyrrolyl
  • indolyl eg, 2-indolyl
  • carbazolyl eg, 3-carbazolyl
  • imidazolyl eg, 4-imidazolyl
  • pyrazolyl eg, 1-pyrazolyl
  • benzimidazolyl Eg, 2-benzimidazolyl
  • indazolyl eg, 3-indazolyl
  • indolizinyl eg, 6-indolizinyl
  • pyridyl eg, 4-pyridyl
  • quinolyl eg, 5-quinolyl
  • isoquinolyl eg, 3-isoquinolyl
  • acridyl eg, 1-acrylidyl
  • phenanthridinyl eg, 2-phenanthridinyl
  • pyridazinyl eg, 3_pyridazinyl
  • aryl refers to hydroxy, lower alkyloxy (eg, methyloxy, ethyloxy), mercapto, lower alkylthio (eg, methylthio), cycloalkyl (eg, cyclopropyl, cyclopropyl, Croptyl, cyclopentyl), halogen (eg, fluorine, chlorine, bromine, iodine), carboxy, lower alkyloxycarbonyl (eg, methyloxycarbonyl, ethyloxycarbonyl), nitro, cyano, aryloxy (eg, phenyloxy), Optionally substituted amino (eg, amino, methylamino, dimethylamino, acetylamino, benzylideneamino, acetylamino), guanidino, optionally substituted lower alkyl (eg, , Methyl, ethyl, n-
  • hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, carboxy, lower alkyloxycarbonyl, nitro, cyano, optionally substituted amino, optionally substituted lower alkyl Alkanoyl is preferred.
  • hydroxy, methyloxy, fluoro, black, promo, carboxy, methyloxycarbonyl, Cyano, amino, dimethylamino, acetylamino, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl and trifluoromethyl are preferred. More preferred are hydroxy, alkyloxy, cyano, methyloxycarbonyl, and trifluoromethyl.
  • optionally substituted heteroaryl refers to hydroxy, lower alkyloxy (eg, methyloxy, ethyloxy), mercapto, lower alkylthio (eg, methylthio), cycloalkyl (eg, cyclopropyl, cyclobutyl, etc.).
  • Cyclopentyl halogen (eg, fluorine, chlorine, bromine, iodine), carboxy, lower alkyloxycarbonyl (eg, methyloxycarbonyl, ethyloxyl ponyl), nitro, cyano, aryloxy (eg, phenyloxy), substituted
  • Optionally amino eg, amino, methylamino, dimethylamino, getylamino, benzylideneamino, acetylamino
  • guanidino optionally substituted lower alkyl
  • heteroaryl which may be substituted by 2 or more is meant.
  • substituents mentioned above hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, carboxyl, lower alkyloxycarbonyl, cyano, optionally substituted amino, Lower alkyl, which may be substituted, is preferred.
  • lower alkyloxy means a lower alkyloxy in which the alkyl moiety is a straight-chain or branched C 6 alkyl.
  • methyloxy, ethyloxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, sec-butyloxy, tert-butyloxy and the like can be mentioned.
  • Methyloxy, ethyloxy and n-propyloxy are preferred.
  • alkyloxycarbonyl means an alkyloxycarbonyl in which the alkyl portion is the above-mentioned “alkyl” having a straight or branched chain.
  • lower alkyloxycarbonyl means an alkyloxycarbonyl in which the alkyl moiety is the above “lower alkyl”.
  • methyloxycarbonyl, ethyloxycarbonyl, ⁇ -propyloxycarbonyl, i-propyloxycarbonyl, n_butyloxycarbonyl and the like can be mentioned.
  • Methyloxycarbonyl and ethyloxycarbonyl are preferred.
  • acyl means an alkylcarbonyl in which the alkyl portion is the above “alkyl”.
  • alkyl For example, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl, n-octylcarbonyl, n-nonanylcarbonyl, n-deca Nilcarponyl, n — ndecanylcarbonyl, n — Dodecylcarbonyl, n — tridecanylcarbonyl, n-tetradecanylcarbonyl, n —pendecanylcarbonyl, n —hexadecanylcarbonyl, n-heptadecanylcarbonyl, n —octadecanyl Carbonyl, n-nona
  • lower alkylthio the alkyl moiety means a lower alkylthio is linear or branched C i to C 6 alkyl.
  • methylthio, ethylthio and the like can be mentioned.
  • the “optionally substituted amino” refers to an amino in which a nitrogen atom may be substituted by one or two of the above “lower alkyl” or lower alkanol, that is, unsubstituted amino, monosubstituted Means amino or disubstituted amino.
  • methylamino, dimethylamino, ethylamino, getylamino, methylethylamino, propylamino, N-methylpropylamino, ethylpropylamino, dipropylamino, dibutylamino, acetylamino and the like can be mentioned.
  • amino, methylamino, dimethylamino, and acetylamino are preferable.
  • the compound of the present invention can be synthesized, for example, by the method shown by the following formula. However, these are merely examples of the method for producing the compound represented by the general formula (I), and compounds produced by other methods are also included in the scope of the present invention.
  • This production method is a general method for synthesizing a dimer of a 2,4-imidazolidinedione derivative. That is, as a starting material, a benzaldehyde derivative represented by the general formula (VI) (otherwise, 3-thiophencarbaldehyde, 4-pyridinecarbaldehyde, etc.) or an amino acid derivative represented by the general formula (VII) is used. This is a method for producing the desired compounds represented by the general formulas (IX), (X) and (XI).
  • a benzaldehyde derivative (VI) is used as a starting material, and in the first step, an amino acid derivative is used as a starting material, and the step is performed to convert to a 2,4_imidazolidinedione derivative represented by the general formula (VIII).
  • VIII 2,4_imidazolidinedione derivative represented by the general formula (VIII).
  • the second step is a step of converting the compound represented by the general formula (VIII) into a dimer represented by the general formula (IX).
  • the 3-position nitrogen atom is In this step, the compound is converted into a compound represented by the general formula (X) by chilling (an alkylation or the like can be similarly performed).
  • the fourth step is a step in which various side chains are further introduced by using hydroxymethyl at the 3-position as a foothold, thereby leading to a target compound represented by the general formula (XI).
  • the starting compound has a substituent that hinders the reaction in each step, the starting compound should be protected in advance by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), etc. To remove the protecting group.
  • the details of each step are as follows.
  • This step is performed using a Bucherer-Bergs reaction.
  • the benzaldehyde derivative represented by the general formula (VI), which is a starting material, is dissolved in an alcohol solvent such as ethanol and propanol.
  • an aqueous solution of a cyanating agent such as sodium cyanide and cyanogen amide at room temperature under ice-cooling to room temperature, and the mixture is stirred for 3 to 30 minutes, preferably 5 to 10 minutes.
  • an aqueous solution of ammonium carbonate is added, and after 10 to 40 minutes, preferably 20 to 30 minutes, the reaction temperature is raised to 50 to 80 ° (preferably 60 to 70 ° C).
  • This step can be performed by using a modification of the first step.
  • An aqueous solution of a cyanating agent such as sodium cyanate and potassium cyanate is added to an aqueous solution of the amino acid derivative represented by the general formula (VII), which is a starting material, at 90 to 100 ° C, preferably 94 to 100 ° C. Stir at 98 ° C for 1-3 hours, preferably 1.5-2 hours.
  • reaction After adding an acid such as concentrated hydrochloric acid to the liquid under ice cooling, the mixture is stirred at 90 to 100 ° C, preferably 94 to 98 ° C for 1 to 3 hours, preferably 1.5 to 2 hours. I do.
  • it can be converted to the desired 2,4-imidazolidinedione derivative represented by the general formula (VIII).
  • the 2,4-imidazolidinedione derivative (VIII) obtained in the previous step is converted to a dimer.
  • VIII 2,4-imidazolidinedione derivative obtained in the previous step
  • it can be produced by the following two methods, Method a and Method b (Kenneth H. Dudley and Daniel L. Bius., The Journal of Organic Chemistry, 34, (4), 1133-1136 (1969) ), Karl E. Schulte, Volker von Weissenborn and Soon K. Kwon., Arch. Pharm., 309, 1066-1019 (1976)).
  • the compound represented by the general formula (VIII) obtained in the first step is suspended in water, and dissolved by adding an aqueous sodium hydroxide solution (preferably 1 to 2N). After stirring for 3 to 10 hours, preferably 5 to 8 hours while passing air under ice-cooling to 50 ° C, preferably 15 to 30 ° C, 3 to 20 hours, preferably 8 to 10 hours Leave for 15 hours.
  • an aqueous sodium hydroxide solution preferably 1 to 2N
  • Glacial acetic acid is added to the compound represented by the general formula (VIII) obtained in the first step, and the mixture is dissolved by heating to 80 to 110 ° C, preferably 90 to 100 ° C.
  • a solution of bromine in glacial acetic acid is added and the mixture is stirred with 80-: L10 :, preferably SOIOOO, for 30 minutes to 3 hours, preferably 1-2 hours.
  • 80-: L10 preferably SOIOOO
  • the filtrate is cooled with ice to 50 t: preferably 15 to 30 ° C.
  • the pH of the reaction solution is adjusted to 3 to 3 by adding an acid such as concentrated hydrochloric acid. 4, and normal post-processing can be performed.
  • the dimer represented by the general formula (IX) is converted into an N-hydroxymethyl derivative.
  • the reaction can be carried out under the conditions of N-hydroxymethylation which is usually carried out, for example, by the following method (SA Varia, S. Schuller, KB Sloan, and VJ Stella, Journal of Pharmaceutical Sciences, 78, (8), 1068-1073 (1984))
  • aqueous formalin solution and a base such as potassium carbonate or sodium carbonate are added to the compound represented by the general formula (IX) obtained in the second step to form a suspension, which is then cooled to ⁇ 60 ° C under ice-cooling. Stir at preferably 20 to 40 ° C for 5 to 50 hours, preferably 10 to 30 hours. After usual post-treatment, the compound can be converted into the desired compound represented by the general formula (X).
  • Esterification reaction of the compound represented by the general formula (X) obtained in the third step (a method using a dehydrating condensing agent such as N, N-dicyclohexylcarpoimide (DCC), an azide method) , An acid chloride method, an acid anhydride method, an active ester method, etc.) to obtain a compound represented by the general formula (II) having a side chain R 2 .
  • a compound having a target side chain R 2 can be obtained in this step (Jounal of Pharmaceutical Sciences Vol. 72, No. 4, 1983, 400-405). , Jounal of Pharmaceutical Sciences Vol. 73, No. 8, 1984, 1068-1073, Jounal of Pharmaceutical Sciences Vol.
  • the compound of the present invention also includes pharmacologically acceptable salts or hydrates thereof.
  • pharmacologically acceptable salts or hydrates thereof for example, alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (magnesium, calcium, etc.), ammonium, salts with organic bases and amino acids, or inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid) Etc.), and salts with organic acids (acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.).
  • These salts can be formed by a commonly used method. When forming a hydrate, it may be coordinated with any number of water molecules.
  • the compounds of the present invention are not limited to specific isomers, but include all possible isomers, racemates, and meso isomers. Particularly, a meso form is preferable.
  • the compound of the present invention exhibits excellent meta-oral protease inhibitory activity, especially MMP inhibitory activity, and inhibits matrix degradation, as described in Experimental Examples described later. Therefore, the compound of the present invention is effective for diseases caused by MMP and its related enzyme, TNF-a convertase.
  • osteoarthritis rheumatoid arthritis, corneal ulcers, periodontal disease, tumor metastasis or invasion, progression of viral infections (eg, HIV infection), atherosclerosis obliterans, atherosclerosis Aneurysm, atherosclerosis, restenosis, sepsis, septic shock, coronary thrombosis, abnormal angiogenesis, scleritis, multiple sclerosis, open-angle glaucoma, retinopathy, proliferative network Membranosis, neovascular glaucoma, pterygium, keratitis, bullous epidermis, psoriasis, diabetes, nephritis, neurological disease, gingivitis, tumor growth, tumor angiogenesis, ocular tumors, hemangiofibromas, hemangiomas, It can be used as a prophylactic or therapeutic agent for fever, bleeding, coagulation, cachexia, anorexia, acute infection, shock, autoimmune
  • the compound of the present invention When the compound of the present invention is administered to a human for the purpose of treating or preventing the above-mentioned diseases, the compound is orally administered as a powder, granules, tablets, capsules, pills, liquids, or the like, or as an injection or suppository. It can be administered parenterally as a transdermal absorbent, an inhalant, and the like.
  • a pharmaceutical formulation can be prepared by mixing an effective amount of the compound with excipients, binders, wetting agents, disintegrating agents, lubricants, and other pharmaceutical additives suitable for the dosage form, if necessary. it can. In the case of injections, they should be sterilized with a suitable carrier to produce the preparation.
  • Dosage will also vary depending on the condition of the disease, the route of administration, the age or weight of the patient, and will ultimately be at the discretion of a physician, but for oral administration to adults, 0.1 to 100 mgZkg Daily, preferably 1 to 20 mgZkgZ days, when administered parenterally, usually 0.01 to; L 0 mgZkgZ days, preferably 0.1 to 1 mgZkg / day. This may be administered once or in several divided doses.
  • the precipitated crystals were collected by filtration to obtain a mixed crystal of the compound (IX-1) and the compound (IX-2). To this, IN-sodium hydroxide (2 ml) was added and stirred to obtain a sodium hydroxide-insoluble compound (IX-2) (114 mg, 26%).
  • Test example 1 Table 1
  • Type I collagenase (MMP-1) was purchased and used from Kagai Co., Ltd. (8, Tomijindai, Yamagata Prefecture). The activity of type I collagenase (MMP-1) against type I collagen, which is a natural substrate, was measured using type I collagenase atskit, sold by Yagai Co., Ltd. (8 Tomijindai, Yamagata City, Yamagata Prefecture). .
  • type I collagenase (MMP-1) The effect of type I collagenase (MMP-1) on synthetic substrates was measured by the method of Harold Weingarten et al. (Analytical Biochemistry, 147, 437-440 (1985)). That is, HS-Leu produced by the action of type I collagenase (MMP-1) using Ac-Pro-Leu-Gly- (2-mercapto-4-methyl-pentanoyl) -Leu-Gly-OEt as a substrate -Leu-Gly-OEt was labeled with ABD-F (7-Fluoro-4-sulfanyl-2, l, 3-benzoxadiazole) and the fluorescence intensity was measured. Assays for inhibitors perform the following four assays for one compound (inhibitor).
  • substrate type I collagen or synthetic substrate
  • enzyme type I collagenase (MM P-1)
  • inhibitor type I collagenase (MM P-1)
  • Substrate type I collagen or synthetic substrate
  • enzyme type I collagenase (MMP-1)
  • Inhibition (%) ⁇ 1-(A- B) / (C-D) ⁇ X 100
  • type IV collagenase (MMP-9) was purified.
  • MMP_9 is secreted into the culture medium by stimulating human fibroblast sarcoma ATCCHT180 strain with 12-tetradecanoylphorpol-13-acetate (TPA).
  • TPA 12-tetradecanoylphorpol-13-acetate
  • MMP was prepared by gelatin-zymography (HidekazuTanaka et al, (1993) Biochem. Biophys. Res. Commun., 190, 732-740, molecular cloning and expression of mouse 105-kDa gelatinase cDNA). — 9 was produced.
  • the culture supernatant of the HT180 strain was concentrated and purified with Gelatin Sepharose 4B, Concanavalin A Sepharose and Cefacryl S-200. This purified pro-MMP-9 (92 kDa, gelatinase B) showed a single active band by gelatin zymography. Then, activation with trypsin was performed to obtain activated MMP-9.
  • Collagenase uses the above-mentioned MMP-9, the substrate and the measurement kit use the type IV collagenase activity measurement kit of Yagai Co., Ltd. (Yamagata 8 Tomijindai, Yamagata Prefecture). Yagai Co., Ltd. (Yamagata ⁇ 8, Fujindai, Yamagata Prefecture). The following four assays are performed for one compound (inhibitor).
  • the fluorescence intensity was measured in accordance with the Atsusei method of Kagay Co., Ltd. (Yamagata, No. 8 Tomijindai, Yamagata Prefecture), and the inhibition (%) was determined by the following equation.
  • IC 5 Indicates the concentration of the inhibitor at which the inhibition (%) becomes 50%.
  • a granule containing the following ingredients is produced.
  • the compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed with a V-type mixer. An aqueous solution of HP C-L (low viscosity hydroxypropyl cell mouth) is added to the mixed powder, kneaded, granulated (extrusion granulated with a pore size of 0.5 to 1 mm), and dried. The obtained dried granules are combed through a vibrating sieve (12 to 60 mesh) to obtain granules.
  • HP C-L low viscosity hydroxypropyl cell mouth
  • a powder for capsule filling containing the following ingredients is produced.
  • lactose compound represented by the formula (I) is passed through a 60-mesh sieve. Cornstarch is passed through a 120 mesh sieve. These and magnesium stearate are mixed with a V-type mixer. Fill the No. 5 hard gelatin capsules with 10 times powder.
  • a tablet is prepared containing the following ingredients:
  • the compound represented by the formula (I), lactose, microcrystalline cellulose, and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60-mesh sieve and mixed.
  • the mixed powder is mixed with magnesium stearate to obtain a mixed powder for tablet making.
  • the mixed powder is hit directly to obtain 15 Omg tablets.
  • the compound of the present invention has excellent meta-oral protease inhibitory activity, especially MMP inhibitory activity Inhibits matrix degradation. Therefore, the compound of the present invention is effective for diseases caused by MMP and its related enzyme TNF- ⁇ convertase and the like.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés représentés par la formule générale (I), des sels pharmacologiquement acceptables de ceux-ci, ou bien des hydrates de ceux-ci, et une composition pharmaceutique et un inhibiteur de métalloprotéase contenant lesdits composés, sels ou hydrates comme principe actif.
PCT/JP1998/000306 1997-01-31 1998-01-27 Composes ayant une activite inhibant la metalloprotease Ceased WO1998033777A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55774/98A AU5577498A (en) 1997-01-31 1998-01-27 Compounds having metalloprotease inhibitory activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP1796397 1997-01-31
JP9/17963 1997-01-31

Publications (1)

Publication Number Publication Date
WO1998033777A1 true WO1998033777A1 (fr) 1998-08-06

Family

ID=11958408

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/000306 Ceased WO1998033777A1 (fr) 1997-01-31 1998-01-27 Composes ayant une activite inhibant la metalloprotease

Country Status (2)

Country Link
AU (1) AU5577498A (fr)
WO (1) WO1998033777A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04297461A (ja) * 1991-03-27 1992-10-21 Otsuka Pharmaceut Factory Inc ２−チオヒダントイン誘導体
JPH05331148A (ja) * 1990-04-27 1993-12-14 Orion Yhtymae Oy カテコール誘導体、その薬学的に許容しうる塩およびエステルならびにそれらを含有する医薬組成物
JPH0665196A (ja) * 1992-06-11 1994-03-08 F Hoffmann La Roche Ag ヒドロキサム酸誘導体
JPH06256293A (ja) * 1993-01-06 1994-09-13 Ciba Geigy Ag アリールスルホンアミド置換化ヒドロキサム酸
JPH07291938A (ja) * 1994-04-25 1995-11-07 F Hoffmann La Roche Ag 三環式置換基を有するヒドロキサム酸誘導体

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05331148A (ja) * 1990-04-27 1993-12-14 Orion Yhtymae Oy カテコール誘導体、その薬学的に許容しうる塩およびエステルならびにそれらを含有する医薬組成物
JPH04297461A (ja) * 1991-03-27 1992-10-21 Otsuka Pharmaceut Factory Inc ２−チオヒダントイン誘導体
JPH0665196A (ja) * 1992-06-11 1994-03-08 F Hoffmann La Roche Ag ヒドロキサム酸誘導体
JPH06256293A (ja) * 1993-01-06 1994-09-13 Ciba Geigy Ag アリールスルホンアミド置換化ヒドロキサム酸
JPH07291938A (ja) * 1994-04-25 1995-11-07 F Hoffmann La Roche Ag 三環式置換基を有するヒドロキサム酸誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts Service (C A S); 1 January 1900 (1900-01-01), XP002912598, Database accession no. 86-155575R *

Also Published As

Publication number Publication date
AU5577498A (en) 1998-08-25

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