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WO1994021612A1 - Derives de carbostyrile employes comme inhibiteurs de metalloproteinases de la matrice extracellulaire - Google Patents

Derives de carbostyrile employes comme inhibiteurs de metalloproteinases de la matrice extracellulaire Download PDF

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Publication number
WO1994021612A1
WO1994021612A1 PCT/JP1994/000434 JP9400434W WO9421612A1 WO 1994021612 A1 WO1994021612 A1 WO 1994021612A1 JP 9400434 W JP9400434 W JP 9400434W WO 9421612 A1 WO9421612 A1 WO 9421612A1
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Prior art keywords
group
compound
reaction
dihydrocarbostyril
amino
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PCT/JP1994/000434
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English (en)
Inventor
Makoto Sakamoto
Takeshi Imaoka
Masaaki Motoyama
Yoshihito Yamamoto
Hideki Takasu
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Otsuka Pharmaceutical Co Ltd
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Otsuka Pharmaceutical Co Ltd
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Priority to EP94910035A priority Critical patent/EP0641323A1/fr
Priority to AU62637/94A priority patent/AU672888B2/en
Publication of WO1994021612A1 publication Critical patent/WO1994021612A1/fr
Priority to KR1019940704126A priority patent/KR950704257A/ko
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen 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
    • C07D215/38—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to carbostyril
  • the extracellular matrix metalloproteinases are secreted from mammal animal cells, and decomposes
  • extracellular matrix (collagen, type IV collagen, laminin proteoglican, fibronectin, elastin, gelatin, etc.).
  • Abnormal promotion of secretion and activity of extracellular matrix metalloproteinases are considered to induce various diseases, including metastasis, infiltration and proliferation of cancer cells, rheumatoid arthritis, peridontal diseases, corneal ulcer, osteoporosis, other bone absorption diseases, multiple sclerosis, and the like.
  • Substances showing inhibitory actions of extracellular matrix metalloproteinases include natural products such as TIMP-1, TIMP-2, and ⁇ 2 -macroglobulin. Compounds possessing such inhibitory action are disclosed in the Japanese Patent Laid-open Publication No. 62-230757, WO- 905716 and WO-9217460. More specifically, the Japanese Patent Laid-open Publication No. 62-230757 discloses a compound expressed in a formula:
  • R A denotes a group HN(OH)-CO- or HCO-N0H-;
  • R A is an alkyl group with C 2 to C 5 ;
  • R B is a characteristic group of a natural ⁇ -amino acid of which any existing functional group may be protected, any existing amino group may be acylated, or any existing carboxylic group may be formed into amide
  • R C is hydrogen atom, amino, hydroxy, mercapto, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 alkylamino, C 1 to C 6 alkylthio or aryl- ( C 1 to C 6 alkyl) group, or amino- ( C 1 to C 6 alkyl), hydroxy- (C 1 to C 6 alkyl), mercapto- ( C 1 to C 6 alkyl) or carboxyl- ( C 1 to C 6 alkyl) of which amino, hydroxy, mercapto or carboxyl group may be protected, amino group may be acylated, or carboxyl group may be formed into amide;
  • R D is hydrogen atom or methyl group
  • R E is hydrogen atom, or C 1 to C 6 alkyl, C 1 to
  • R F is hydrogen atom or methyl group
  • R B and R D may be combined together to form -(CH 2 )m- group wherein p is 4 to 11; and R D and R F may be combined together to form trimethylene group].
  • WO-905716 discloses a compound expressed in a formula:
  • R G is hydrogen atom, C 1 to C 6 alkyl, C 1 to C 6 alkenyl, phenyl, phenyl (C 1 to C 6 ) alkyl, C 1 to C 6 alkylthiomethyl, phenylthiomethyl, substituted phenylthiomethyl, phenyl(C 1 to C 6 )alkylthiomethyl, or hexacyclic thiomethyl group; or R G denotes -SR X , where R X denotes as follows:
  • R H is hydrogen atom, C 1 to C 6 alkyl, C 1 to C 6 alkenyl, phenyl ( C 1 to C 6 ) alkyl, cycloalkyl (C 1 to C 6 ) alkyl, or cycloalkenyl (C 1 to C 6 ) alkyl group
  • R I is amino acid side chain, C 1 to C 6 alkyl, benzyl, (C 1 to C 6 ) alkoxybenzyl, benzyloxy (C 1 to C 6 ) alkyl or benzyloxybenzyl group
  • R J is hydrogen atom or methyl group
  • q is an integer of 1 to 6
  • B is -NH 2 group, substituted noncyclic amine or heterocyclic base.
  • WO-9217460 discloses a compound expressed in a formula:
  • R K is hydrogen atom, C 1 to C 6 alkyl or -(CH 2 ) r -D-R N , group; r is 0 or an integer of 1 to 6; D is single bond, or oxygen or sulfur atom; R N is aryl which may be substituted or heteroaryl which may be substituted; R L is an alkyl group with C 3 to C 6 ; R M is -(CH 2 ) s -E-(CH 2 ) t - group; s is an integer of 1 to 9; t is an integer of 2 to 10; E is -NR O - group (R O is hydrogen atom, C 1 to C 6 alkyl, C 2 to C 6 alkanoyl, C 1 to C 6 alkoxycarbonyl, aryl, aralkyl, or aralkyloxycarbonyl, in which each aryl group may possess a substituent); and -(CH 2 ) S - is bonded to a carbon atom indicated by * in formula
  • R 1 denotes hydrogen atom or group -A-R 1a (A shows a lower alkylene group, R 1a is hydrogen atom, amino group, phthalimido group, thienylthio group, lower alkanoylthio group, mercapto group, phenyl group which may possess one to three groups selected from the group consisting of halogen atom, hydroxyl group, lower alkyl group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group and lower
  • alkylenedioxy group as substituent, carboxy group, lower alkoxy carbonyl group, phenylthio group or lower alkylthio group);
  • R 2 is hydrogen atom or lower alkyl group
  • R 3 is hydrogen atom, hydroxyl group, lower alkoxy group, lower alkoxy-lower alkoxy group, lower alkoxy-lower alkoxy-lower alkoxy group, lower alkoxy-lower alkoxy-lower alkoxy group or group: -B-R 3a ⁇ B is lower
  • R 3a is hydrogen atom, hydroxy group, lower alkoxy group, lower alkoxy-lower alkoxy group, phenyl group which may possess one to three groups selected from the group consisting of halogen atom, cyano group, hydroxy group, lower alkyl group, lower alkoxy group, carboxy group and lower
  • alkoxycarbonyl group as substituent thienyl group which may possess halogen atom as substituent, phthalimido group, carboxy group, lower alkoxycarbonyl group or group:
  • R 3b is hydrogen atom or lower alkyl group
  • R 3c is hydrogen atom, lower alkyl group or lower alkoxy group
  • group -N(R 3b )-R 3c may form a saturated heterocyclic ring with five or six members which may further possess one hetero atom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom) ⁇ ;
  • R 4 is hydrogen atom, halogen atom, hydroxyl group, lower alkyl group, lower alkoxy group, or lower alkylenedioxy group;
  • R 5 is hydrogen atom, benzoyl group, lower alkanoyl group, or phenyl-lower alkyl group;
  • R 6 is alkyl group with 1 to 12 carbon atoms, lower alkoxy-lower alkyl group, or phenyl-lower alkyl group which may possess lower alkylenedioxy group as substituent on the phenyl ring;
  • n 1 or 2], and its salt.
  • the carbostyril derivative and its salt of the invention possess an excellent extracellular matrix
  • inhibitory action in particular, the inhibitory action on Stromelysin purified from the culture supernatant of mouse colon cancer cell (Colon 26 Cell), inhibitory action on interstitial collagenase purified from the culture supernatant of human fibroblast cell (Detroit 551 Cell), and inhibitory action on type IV collagenase purified from the culture supernatant of human pulmonary fibrosarcoma cell (HT-1080 Cell), and are low in toxicity and superior in oral absorption.
  • carbostyril derivative expressed in formula (1) of the invention and its salts are useful in clinical fields as prophylactic and therapeutic agents for diseases and episodes related with extracellular matrix metalloproteinases
  • interstitial collagenase type IV collagenase, Stromelysin, etc.
  • metastasis infiltration or proliferation of various cancer cells
  • rheumatoid arthritis periodontal diseases
  • corneal ulcer osteoporosis
  • other bone absorption diseases multiple sclerosis
  • hypomyelination diseases accompanied by vascularization
  • dermal and gastrointestinal ulceration and wound healing and postoperative symptoms, for example, colon anastomosis characterized by elevation of collagenase level, increase of collagen destruction caused in relation with diabetes mellitus, atherosclerosis, proliferation due to suture of blood vessels, nephritis, and others.
  • lower alkylene group examples include methylene, methylmethylene, ethylene, dimethylmethylene, trimethylene, 1- methyltrimethylene, 2-methyltrimethylene, 2,2-dimethyl- trimethylene, tetramethylene, pentamethylene, hexamethylene groups, and other alkylene groups of straight chain or
  • thienylthio group examples include 2-thienylthio, 3-thienylthio and other thienylthio groups.
  • lower alkanoylthio group examples include formyl ⁇
  • alkanoyl portion is an alkanoyl group of straight chain or branched chain with 1 to 6 carbon atoms.
  • lower alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl groups, and other alkyl groups of straight chain or branched chain with 1 to 6 carbon atoms.
  • lower alkoxy group examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy,
  • lower alkenylene group examples include vinylene, allylene, isopropenylene, 2-butenylene, 3-pentenylene, 4- hexenylene, 2-methyl-butenylene groups, and other alkenylene groups of straight chain or branched chain with 2 to 6 carbon atoms.
  • lower alkynylene group examples include ethynylene, 1-propynylene, 2-propynylene, 2-butynylene, 3-pentynylene, 4- hexynylene, 2-methyl-2-butynylene groups, and other alkynylene groups of straight chain or branched chain with 2 to 6 carbon atoms.
  • halogen atom examples include fluorine atom, bromine atom, chlorine atom, and iodine atom.
  • lower alkoxycarbonyl group examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy- carbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxy- carbonyl, hexyloxycarbonyl groups, and other alkoxycarbonyl group of which alkoxy portion is an alkoxy group of straight chain or branched chain with 1 to 6 carbon atoms.
  • Examples of thienyl group which may possess a halogen atom as a substituent include 5-fluoro-2-thienyl, 5-bromo-2- thienyl, 3-bromo-2-thienyl, 5-chloro-2-thienyl, 5-chloro-3- thienyl, 4-chloro-2-thienyl, 4-chloro-3-thienyl, 5-iodo-2- thienyl groups, and other thienyl group which may possess a halogen atom as a substituent.
  • saturated heterocyclic group of five members or six members that may further possess one hetero atom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom include 1-pyrrolidinyl, 1- piperidinyl, 1-imidazolidinyl, 1-piperadinyl, morpholino, and thiomorpholino groups.
  • lower alkanoyl group examples include formyl, acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, hexanoyl groups, and other alkanoyl groups of straight chain or branched chain with 1 to 6 carbon atoms.
  • phenyl-lower alkyl group examples include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, 2- phenylpropyl groups, and other phenyl-lower alkyl groups of which alkyl portion is an alkyl group of straight chain or branched chain with 1 to 6 carbon atoms.
  • lower alkylenedioxy group examples include methylenedioxy, ethylenedioxy, trimethylenedioxy groups, and other alkylenedioxy groups with 1 to 3 carbon atoms.
  • phenyl-lower alkyl group which may possess a lower alkylenedioxy group as a substituent on the phenyl ring include, aside from the phenyl-lower alkyl group
  • lower alkylthio group examples include methylthio, ethylthio, isopropylthio, butylthio, tertiary butylthio, pentylthio, hexylthio group and other alkylthio groups of straight chain or branched chain with 1 to 6 carbon atoms.
  • lower alkoxy-lower alkoxy group examples include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, methoxypropoxy, propoxymethoxy, butoxymethoxy, t- butoxypropoxy, butoxyethoxy, isopropoxypropoxy, propoxyethoxy, t-butoxymethoxy, pentyloxymethoxy, methoxypentyloxy,
  • each alkoxy portion is alkoxy group of straight chain or branched chain with 1 to 6 carbon atoms.
  • lower alkoxy-lower alkoxy-lower alkoxy group examples include methoxymethoxymethoxy, methoxymethoxyethoxy, methoxyethoxyethoxy, ethoxyethoxymethoxy, ethoxyethoxyethoxy, methoxyethoxypropoxy, propoxymethoxyethoxy,
  • each alkoxy portion is alkoxy group of straight chain or branced chain with 1 to 6 carbon atoms.
  • lower alkoxy-lower alkoxy-lower alkoxy-lower alkoxy- lower alkoxy group examples include methoxymethoxymethoxymethoxy, methoxyethoxymethoxyethoxy, methoxyethoxypropoxyethoxy, ethoxyethoxymethoxymethoxy, methoxyethoxyethoxyethoxy,
  • methoxyethoxypropoxyporopoxy propoxymethoxyethoxyethoxy, isopropoxy(2-methyl)propoxyethoxypropoxy, butoxyethoxyethoxymethoxy, t-butoxyethoxymethoxypropoxy, butoxyethoxymethoxybutoxy, isopropoxymethoxypropoxyethoxy, propoxyethoxyethoxyethoxy, t-butoxymethoxymethoxymethoxymethoxy, pentyloxyethoxyethoxyethoxy, methoxypentyloxypentyloxymethoxy, hexyloxymethoxyethoxyhexyloxy, methoxymethoxyhexyloxymethoxy, hexyloxyhexyloxyethoxyethoxy, and other alkoxy-alkoxy-alkoxy- alkoxy group of which each alkoxy portion is alkoxy group of straight chain or branched chain with 1 to 6 carbon atoms.
  • alkyl group with 1 to 12 carbon atoms examples include methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, 2,4-dimethylpentyl, hexyl, 3-methylhexyl,
  • lower alkoxy-lower alkyl group examples include methoxymethyl, ethoxymethyl, isopropoxyethyl, methoxyethyl, 3-ethoxypropyl, 2-methoxybutyl, tertiary butoxyethyl,
  • R 4 indicates a similar group or a different group.
  • Compounds expressed in formula (1) include all of stereoisomer, optical isomer, and geometrical isomer.
  • the compounds and material compounds of the invention may be manufactured in various methods, and for example, the compounds of the invention may be manufactured by the method shown in reaction scheme 1 or reaction scheme 2 below.
  • reaction scheme 1 is a method of reaction between the amine compound of formula (3) and the carboxylic acid of formula (2) by ordinary amide bond
  • a mixed acid anhydride method that is, a method of reaction of carboxylic acid (2) with alkyl- halocarboxylic acid to form a mixed acid anhydride, which is allowed to react with amine (3)
  • an active ester method that is, a method of changing carboxylic acid (2) into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, and 1-hydroxybenzotriazole ester which is allowed to react with amine (3)
  • a carbodiimide method that is, a method of condensation reaction of carboxylic acid (2) with amine (3) in the presence of activator such as
  • the mixed acid anhydride used in the mixed acid anhydride method (i) is obtained by an ordinary Schotten- Baumann reaction, and by reacting with amine (3) without isolating, usually, the compound in formula (1) is obtained.
  • the Schotten-Baumann reaction is conducted in the presence of an basic compound.
  • Usable basic compounds are conventional compounds used in Schotten-Baumann reaction, including
  • the reaction is performed generally at about -20 to 100 °C, preferably 0 to 50 °C, and the reaction time is about 5 minutes to 10 hours, preferably 5 minutes to 2 hours.
  • the reaction between the obtained mixed acid anhydride and amine (3) is usually
  • the mixed acid anhydride method is generally conducted in a solvent.
  • the usable solvents are all conventional solvents used in mixed acid anhydride, and specific examples include chloroform, dichloromethane,
  • dichloroethane and other halogenated hydrocarbons benzene, toluene, xylene and other aromatic hydrocarbons; diethyl ether, diisopropyl ether, tetrahydrofurane, dimethoxy ethane and other ethers; methyl acetate, ethyl acetate, other esters; N,N-dimethyl formamide, dimethyl sulfoxide, acetonitrile, hexamethylphosphoric acid triamide and other non-protonic polar solvent; and their mixed solvents.
  • alkyl- halocarboxylic acid examples include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate.
  • the blending rate of the carboxylic acid (2) and alkyl- halocarboxylic acid (3) used in this method equal mols should be used generally, but the alkylhalocarboxylic acid and carboxylic acid (2) may be used in a range of 0.5 to 1 mol to amine (3).
  • this reaction is carried out in the presence of a basic compound, in a proper solvent.
  • a basic compound known compounds may be widely used, and for example, aside from the basic compound used in the Schotten-Baumann reaction, sodium
  • hydroxide potassium hydroxide, sodium hydride, and potassium hydride may be used.
  • solvent aside from the solvent used in the mixed acid anhydride method, for example,
  • the blending rate of amine (3) and carboxylic acid halide is not particularly limited, and may be selected in a wide range, and the latter should be used at least by equal mol to the former, preferably 0.5 to equal mol.
  • the reaction is usually conducted at about -20 to 180 °C, preferably 0 to 150 °C, and the reaction is generally terminated in about 5 minutes to 30 hours.
  • the reaction is conducted in a proper solvent, in the presence of a basic compound.
  • the basic compound include sodium hydroxide, potassium hydroxide, sodium
  • alcoholate and potassium alcoholate.
  • solvent examples include methanol, ethanol and other alcohols
  • the blending rate of amine (3) and carboxylic acid ether is not particularly limited, and may be selected in a wide range, but usually the former should be used at least an equal mol of the latter, preferably 2 to 5 times mol.
  • the quantity of use of the basic compound may be about 1 to 3 times mol of the carboxylic acid ester.
  • the reaction is conducted usually at about -20 to 180 °C, preferably about 0 to 40 °C, and the reaction is usually terminated in about 5 minutes to 30 hours.
  • the amide bond formation reaction shown in reaction scheme 1 may be also executed by a method of reaction between carboxylic acid (2) and amine (3) in the presence of
  • condensation agent such as triphenylphosphine, diphenyl phosphinyl chloride, phenyl-N-phenyl phosphoramide chloridate, diethyl chlorophosphenite, diethyl cyanophosphate, azide diphenyl phosphate, bis (2-oxo-3-oxazolidinyl) phosphinic chloride, and other phosphorus compounds.
  • This reaction is conducted in the presence of the solvent and basic compound used in the method of reaction of carboxylic acid halide with amine (3), usually at about -20 to 150 °C, preferably about 0 to 100 °C, and the reaction is usually terminated in about 5 minutes to 30 hours.
  • the content of the condensation agent and carboxylic acid (2) may be at least about an equal mol of amine (3), preferably about equal mol to double mol.
  • R 5' denotes benzoyl group, lower alkanoyl group or phenyl- lower alkyl group; and X is a halogen atom.
  • reaction of transforming the compound of formula (1-A) into the compound of formula (1-B) is effected by presenting the compound of formula (1-A) for ordinary
  • a catalytic reduction can be conducted in a proper solvent, in the presence of a catalyst.
  • Ordinary solvents can be widely used, for example, methanol, ethanol, isopropanol and other alcohols; hexane, cyclohexane, other hydrocarbons; diethylene glycol dimethyl ether, dioxane, tetrahydrofurane, diethyl ether and other ethers; methyl acetate, ethyl acetate and other esters; N,N-dimethyl formamide and other polar solvents; water; acetic acid; and their mixed solvents.
  • Examples of reducing catalyst include palladium, palladium-black,
  • the reaction may be conducted under pressure, but when performing at ordinary pressure, the reaction
  • reaction temperature may be about 10 to 60 °C, preferably 20 to 40 °C, and the reaction is terminated generally in about 1 hour to 5 days.
  • a hydrogen supply source such as
  • cyclohexene, cyclohexadiene, formic acid, ammonium formate, and isopropyl alcohol is used, it may be conducted in a proper solvent, in the presence of a catalyst.
  • a catalyst the same solvent as in the catalytic reduction may be used.
  • catalyst examples include palladium, palladium-black, and palladium-carbon.
  • the quantity of use of the catalyst may be about 0.01 to 2 times of the weight of the compound of formula (1-A), the reaction temperature is about 10 to 100 oC and the reaction is generally terminated in about 1 minute to 3 days.
  • the conditions of ordinary saponification may be widely applied.
  • the reaction may be conducted.
  • Examples of basic compound include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and other inorganic bases.
  • the quantity of use of such basic compound may be about 1 to 6 mols in 1 mol of the compound in formula (1-A).
  • the reaction is usually conducted at about -10 to 50 °C and the reaction is generally terminated in about 30 minutes to 24 hours.
  • the reaction for transforming the compound in formula (1-B) into the compound in formula (1-A) is conducted in a proper solvent, in the presence of a basic compound, by reaction between the compound expressed in a formula R 5' -X or (R 5' ) 2 O [where R 5' and X are same as defined above] and the compound in formula (1-B).
  • solvent include polar solvents such as N,N-dimethyl formamide, and halogenated hydrocarbons such as dichloromethane.
  • Examples of basic compound include pyridine, triethylamine, N-methylmorpholine, and other organic bases. The quantity of use of such basic compound may be about 1 to 3 times mol in 1 mol of the
  • the reaction temperature may be -10 to 50 °C and the reaction is generally terminated in about 10 minutes to 24 hours.
  • ⁇ he compound in formula (2) which is a starting material in reaction scheme 1 may be manufactured in various methods. For example, it may be manufactured in the methods shown in the reaction schemes 4, 6, 7, 8, and 9.
  • R 2 , R 3 , R 4 , R 6 , and n are same as defined above; and R 9 and R 10 denote selectively eliminatable ester groups such as phenyl-lower alkoxycarbonyl group and lower alkoxycarbonyl group.
  • the compound in formula (5) is manufactured by eliminating the protective group of carboxyl group of the compound in formula (4).
  • the method of eliminating the protective group of ordinary carboxyl group may be widely applied, for example, the method of treating with acid, the method of using catalytic
  • the compound in formula (5) may be manufactured by treating the compound in formula (4) in the presence of the acid, in a proper solvent or without using solvent.
  • acid may include organic acid such as trifluoroacetic acid, and
  • inorganic acid such as hydrogen fluoride and hydrogen
  • the acid may be used excessively to 1 mol of the compound in formula (4).
  • Ordinary solvents may be widely used, including halogenated hydrocarbons such as
  • dichloromethane ethers such as dioxane, esters such as ethyl acetate, acetic acid, and others.
  • the reaction proceeds usually around -40 to 60 °C, preferably -20 to 40 °C, and the reaction is generally terminated in about 1 minute to 5 hours.
  • the conditions of known reduction reaction may be widely applied.
  • the reaction may be conducted in the same condition as in the reduction reaction shown in reaction scheme 2.
  • an ordinary basic compound may be used.
  • basic compound include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and other inorganic bases.
  • the quantity of use of such basic compound may be about 1 to 3 mols in 1 mol of the compound in formula (4).
  • the reaction is generally conducted at about -10 to 50 °C and the reaction is generally terminated in about 30 minutes to 24 hours.
  • the compound in formula (7) may be prepared by reaction between the compound in formula (5) and the compound in formula (6) by ordinary amide bond formation reaction.
  • the amide bond formation reaction can be conducted in the same manner as in the method of reaction scheme 1.
  • the compound in formula (2-A) is manufactured by presenting the reaction in formula (7) for elimination
  • reaction of carboxyl protective group may be widely applied.
  • aromatic hydrocarbons such as toluene and benzene may be used.
  • the reaction temperature is about 50 to 120 °C and it is preferred to react while refluxing. Generally, the reaction is
  • the compound in formula (9) is manufactured by presenting the compound in formula (7) to elimination
  • reaction of carboxyl protective group may be widely applied.
  • the elimination reaction is conducted in the same manner as the elimination reaction of carboxyl protective group shown in reaction scheme 3.
  • reaction product after the elimination reaction of carboxyl protective group to Mannich reaction as the solvent, for example, water, methanol, ethanol, isopropanol and other alcohols may be used, and as the aliphatic secondary amine, for example, dimethylamine, diethylamine, and piperidine may be used.
  • the quantity of use of the aliphatic secondary amine may be about 1 to 2 times mol of the compound in formula (7).
  • the quantity of use of formaldehyde is about 1 to 2 times mol of the compound in formula (7).
  • the reaction temperature is 10 to 60 °C, preferably about 20 to 40 °C, and the reaction is generally terminated in about 1 hour to 3 days.
  • reaction solution finishing the Mannich reaction may be heated or refluxed at reaction temperature of about 50 to 120°C. Generally, the reaction is terminated in about 1 minute to 1 day.
  • R 2 , R 3 , R 4 , R 6 , and n are same as defined above; and R 11 denotes thienyl group, lower alkanoyl group, phenyl group, or lower alkyl group.
  • the compound in formula (2-B) is manufactured by reaction between the compound in formula (9) and the compound in formula (10) in a proper solvent or without using solvent.
  • solvent include methanol, ethanol, and other alcohols.
  • the quantity of use of the compound in formula (10) is excessive to 1 mol of the compound in formula (9) or equivalent to the solvent amount.
  • the reaction is usually conducted at 10 to 120 °C, preferably 20 to 100 °C, and the reaction is generally terminated in about 1 hour to 10 days in a dark place.
  • the compound of which R 1 denotes a lower alkyl group in the compound in formula (2) is obtained by presenting the compound in formula (9) to ordinary reduction reaction.
  • the reaction conditions of ordinary reduction reaction may be widely employed, for example, same as in the reduction condition shown in reaction scheme 2.
  • R 2 , R 3 , R 4 , R 6 , X, and n are same as defined above; and R 12 denotes lower alkanoyl group or lower alkyl group.
  • amine examples include methanol, ethanol, and other alcohols.
  • examples of amine include methylamine, ethylamine, and other aliphatic amines.
  • the quantity of use of amine may be excessive to' 1 mol of the compound shown in formula (2-C).
  • the reaction is usually conducted at about -20 to 100 °C and the reaction is generally terminated in about 1 minute to 24 hours.
  • the reaction to obtain the compound in formula (2-C) from the compound in formula (2-D) is effected by the reaction between the compound expressed in a formula R 12 -X or (R 12 ) 2 O [where R 12 and X are same as defined above] and the compound in formula (2-D) in a proper solvent, in the presence of a basic compound.
  • the solvent include halogenated hydrocarbons such as chloroform, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofurane, esters such as ethyl acetate, and polar solvents such as N,N-dimethyl formamide.
  • Examples of the basic compound include organic bases such as triethyl amine, and inorganic bases such as potassium carbonate and sodium carbonate.
  • the quantity of use of the basic compound is about 2 to 5 mols in 1 mol of the compound in formula (2-D).
  • the reaction is conducted usually at about 0 to 100 °C and the reaction is generally terminated in about 1 minute to 24 hours.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 9 , R 10 , X, and n are same as defined above;
  • R 3 denotes a group -A-R 1a (A and R 1a same as defined above); and R 19 shows lower alkyl group or phenyl- lower alkyl group.
  • the compound in formula (14) is manufactured by reaction between the compound in formula (12) and the compound in formula (13) in a proper solvent, in the presence of a basic compound.
  • a basic compound include sodium hydride, potassium hydride, lithium hydride, sodium methylate, and potassium ethylate.
  • the solvent include ethers such as tetrahydrofurane, and polar solvents such as dimethyl formamide.
  • the quantity of use of the basic compound is 1 to 3 times mol in 1 mol of the compound in formula (12), preferably an equivalent mol.
  • the quantity of use of the compound in formula (13) is 1 to 3 times mol in 1 mol of the compound in formula (12), preferably an equivalent mol.
  • the reaction temperature is usually about 0 to 120°C, preferably about 20 to 60°C. Generally, the reaction is terminated in about 1 hour to 5 days.
  • the compound in formula (15) is manufactured by presenting the compound in formula (12) or the compound in formula (14) for elimination reaction of carboxyl protective group in a proper solvent, and heating the reaction product after the elimination reaction in a proper solvent.
  • the elimination reaction of carboxyl protective group the conditions of known elimination reaction of carboxyl
  • reaction protective group may be widely applied, and the elimination reaction may be conducted same as in the reaction shown in, for example, reaction scheme 3.
  • the heating reaction of the reaction product after elimination reaction of carboxyl protective group may be conducted same as in the reaction shown in reaction scheme 4.
  • the compound in formula (16) is manufactured by reaction between the compound in formula (15) and the compound in formula (6) by an ordinary amide bond formation reaction.
  • the amide bond formation reaction may be performed same as in the method of reaction scheme 1.
  • the compound in formula (2-E) is manufactured by presenting the reaction in formula (16) for elimination reaction of carboxyl protective group in a proper solvent.
  • the compound in formula (15) used in reaction scheme 8 may be manufactured in various methods. For example, by the method shown below, it is manufactured in the same reaction conditions as in the reactions corresponding to those
  • R 6 CH 2 COOH is first treated by halogenating reagent to obtain an acid halide, which is caused to react with an optically active oxazolidine-2-on in the presence of n-butyl lithium to obtain R 6 CH 2 COZ, which is then caused to react with ⁇ -haloacetate XCH 2 R 10 to obtain R 10 CH 2 CH(R 6 )COZ, and this compound is hydrolyzed to remove an optically active oxazolidine-2-on, thereby obtaining R 10 CH 2 CH(R 6 )COOH [where R 6 , R 10 , and X are same as defined above; and Z denotes an optically active 2-oxo-oxazolidyl group].
  • R 2 , R 3 , R 4 , R 6 , and n are same as defined above;
  • R 14 denotes a lower alkoxycarbonyl group;
  • R 15 is alkylidene group with 1 to 12 carbon atoms, lower alkoxy-lower alkylidene group, or phenyl-lower alkylidene group which may possess lower alkylenedioxy group on a phenyl ring as a substituent; and
  • R 16 is a lower alkyl group.
  • the compound in formula (20) is obtained by reaction between the compound in formula (18) and the compound in formula (19) in a proper solvent in the presence of a basic compound, and subsequent saponification (alkaline hydrolysis).
  • Proper solvents may include methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, and other alcohols.
  • Examples of the basic compound include sodium hydride, potassium hydride, lithium hydride, sodium methylate, and potassium ethylate.
  • the quantity of use of the compound in formula (19) is about 1 to 1.5 mol in 1 mol of the compound in formula (18).
  • the quantity of use of the basic compound is about 1 to 1.5 mol in 1 mol of the compound in formula (18).
  • the reaction is conducted usually at about 10 to 120 °C and the reaction is generally terminated in about 1 minute to 24 hours.
  • the subsequent saponification is performed by using, for example, an ordinary basic compound.
  • the basic compound include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and other inorganic bases.
  • the quantity of use of the basic compound may be 2 to 6 mols in 1 mol of the compound in formula (18).
  • the reaction is usually conducted at about 0 to 100 °C and the reaction is generally terminated in about 1 to 24 hours.
  • the compound in formula (22) is manufactured by causing the compound in formula (20) to react with dehydration condensation agent such as acetic anhydride and N,N'- dicyclohexyl carbodiimide (DCC), and presenting the reaction product for reaction with the compound in formula (21).
  • dehydration condensation agent such as acetic anhydride and N,N'- dicyclohexyl carbodiimide (DCC)
  • the quantity of use of acetic anhydride or DCC may be 1 mol or excessive to 1 mol of the compound in formula (20).
  • the reaction proceeds at about 20 to 120°C, and the reaction is generally terminated in about 1 minute to 10 hours.
  • the quantity of use of the compound in formula (21) may be excessive to 1 mol of the compound in formula (20).
  • the reaction is usually conducted at 10 to 100 °C and the reaction is generally terminated in about 1 to 24 hours.
  • the compound in formula (23) is obtained by presenting the compound in formula (22) to an ordinary reduction
  • reaction In this reduction reaction, the conditions of the known reduction reaction may be widely applied.
  • the reaction may be conducted in the same manner as in
  • reaction scheme 2 The compound in formula (24) is obtained by the reaction between the compound in formula (23) and the compound in formula (6) by ordinary amide bond formation reaction.
  • the amide bond formation reaction is done in the same manner as in reaction scheme 1.
  • the compound in formula (2-A) is manufactured by treating the compound in formula (24) in a proper solvent, in the presence of a basic compound.
  • a proper solvent include methanol, ethanol, and other alcohols.
  • Examples of the basic compound include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as triethyl amine.
  • the quantity of use of the basic compound may be about 1 to 3 mols of 1 mol of the compound in formula (24).
  • the reaction is usually performed at about 0 to 40 °C and the reaction is generally terminated in about 1 to 24 hours.
  • the compound in formula (4) used as a starting material in reaction scheme 3 is manufactured in various methods. For example, it may be manufactured in the method shown in reaction scheme 10.
  • R 6 , R 9 and R 10 are same as defined above; R 17 is an alkaline metal such as sodium, potassium or the like; and Y denotes a halogen atom.
  • the compound in formula (28) is manufactured by presenting the compound in formula (26) and the compound in formula (27) for an ordinary diazo coupling reaction in a proper solvent in the presence of a nitrite.
  • nitride examples include sodium nitrite and potassium nitrite.
  • the quantity of use of the nitride is about 1 to 1.5 mol in 1 mol of the compound in formula (26), and the quantity of use of the compound in formula (27) is about 1 to 1.5 mol in 1 mol of the compound in formula (26).
  • the solvent may include water, hydrochloric acid, sulfuric acid, other acidic solvents, and their mixed
  • the reaction is usually conducted at about -10 to 100 °C and the reaction is generally terminated in about 1 minute to 1 day.
  • the compound in formula (29) is manufactured by presenting the compound in formula (18) for an ordinary esterification reaction in a proper solvent.
  • the compound in formula (4) is manufactured by reaction between the compound in formula (29) and the compound in formula(30) in a proper solvent, in the presence of a basic compound.
  • a basic compound examples include polar solvents such as dimethylformamide, and halogenated hydrocarbons such as dichloromethane.
  • the basic compound examples include sodium hydride and potassium t-butoxide.
  • the quantity of use of the basic compound is about 1 to 3 mols in 1 mol of the compound in formula (29).
  • the reaction is conducted usually at about -20 to 70 °C and the reaction is generally terminated in about 1 hour to 10 days.
  • reaction scheme 8 The compound in formula (12) used as a starting material in reaction scheme 8 is manufactured in various methods. For example, it is manufactured in the method shown in reaction scheme 11 below. Reaction scheme 11
  • the compound in formula (32) is manufactured by presenting the compound in formula (26) for an ordinary diazo coupling reaction in a proper solvent in the presence of a nitrite.
  • the diazo coupling reaction is conducted in the same reaction conditions as in manufacture of the compound in formula (28) in reaction scheme 10.
  • the compound in formula (34) is manufactured by reaction between the compound in formula (32) and the compound in formula (33) in a proper solvent, in the presence of a basic compound.
  • a basic compound examples include ethers such as tetrahydrofurane, and aromatic hydrocarbons such as benzene and toluene.
  • the basic compound include organic bases such as triethyl amine and N-methylmorpholine.
  • the quantity of use of the basic compound is about 1 to 2 mols of 1 mol of the compound in formula (32), and the quantity of use of the compound in formula (33) is about 1 to 2 mols of 1 mol of the compound in formula (32).
  • the reaction temperature is about 0 to 100 °C and the reaction is generally terminated in about 1 to 24 hours.
  • the compound in formula (34) may be also manufactured by presenting for an ordinary esterification reaction in a proper solvent.
  • the compound in formula (12) is manufactured by transforming the compound in formula (34) into sulfonate ester, and reacting with the compound in formula (35) in the presence of a basic compound.
  • the reaction of transforming the compound in formula (34) into sulfonate ester is realized by reaction with acid anhydride such as sulfonic anhydride and acid halide such as sulfonyl halide, in a proper solvent, in the presence of a basic compound.
  • the solvent include halogenated hydrocarbons such as dichloromethane, and ethers such as tetrahydrofurane.
  • the basic compound such as sulfonic anhydride
  • acid halide such as sulfonyl halide
  • organic bases such as pyridine
  • the quantity of use of the basic compound is about 1 to 1.5 mol of 1 mol of the compound in formula (34).
  • the quantity of use of acid is about 1 to 1.5 mol of 1 mol of the compound in formula (34).
  • anhydride or acid halide is about 1 to 1.5 mol of 1 mol of the compound in formula (34).
  • the reaction temperature is about -50 to 50 °C and the reaction is generally terminated in about 1 minute to 1 day.
  • the reaction between the sulfonate ester of the compound in formula (34) and the compound in formula (35) is conducted in a proper solvent, in the presence of a basic compound.
  • a basic compound examples include polar solvent such as dimethyl formamide and halogenated hydrocarbons such as dichloromethane.
  • the basic compound examples include sodium hydride, potassium hydride, lithium hydride, sodium methylate, and potassium ethylate.
  • the quantity of use of the basic compound is about 1 to 2 mols in 1 mol of the compound in formula (34), and the quantity of use of the compound (35) is about 1 to 2 mols in 1 mol of the compound in formula (34).
  • the reaction temperature is about -10 to 50 °C and the
  • reaction is generally terminated in about 1 hour to 10 days.
  • the compound in formula (6) used in reaction schemes 3, 8 and 9 is a novel or known compound, which may be easily manufactured in a method disclosed, for example, in J. Med. Chem., 1972, 15, 325, or J. Org. Chem., 1989, 54, 3394.
  • the compound in formula (6) is manufactured in methods shown in the following reaction schemes 12 and 13. Reaction scheme 12
  • R 2 , R 4 , R 3a , B, X, and n are same as defined above; and R 20 denotes acyl group or amino group protective group.
  • the reaction between the compound in formula (36) and the compound in formula (37) is conducted in a proper solvent, in the presence of a basic compound.
  • a basic compound examples include sodium hydride, potassium hydride, lithium hydride, sodium methylate, potassium ethylate, and other inorganic bases.
  • the quantity of use of such basic compound is usually about 0.5 to 2 times mol of the compound in formula (36), preferably an equivalent mol.
  • the blending rate of the compound in formula (36) and the compound in formula (37) is 1 to 3 times the mol of the latter to the former, preferably about an equivalent mol.
  • the reaction temperature is usually about -20 to 120 °C,
  • reaction is generally terminated in about 10 minutes to 5 days.
  • R 16a denotes lower alkyl group, lower alkoxy-lower alkyl group, lower alkoxy-lower alkoxy-lower alkyl group, or
  • reaction between the compound in formula (39) and the compound in formula (40) can be conducted in the same reaction conditions as in the reaction between the compound in formula (36) and the compound in formula (37) in reaction scheme 12.
  • the compound in formula (38-A) and the compound in formula (38-B) are transformed into the compound in formula (6) by an ordinary de-protection reaction.
  • the compound in formula (15) used in reaction scheme 8 is manufactured in various methods. For example, it is manufactured in the method shown in the following reaction scheme 14.
  • the de-protection of the compound in formula (12) can be effected in the same conditions as in the reaction for obtaining the compound in formula (5) from the compound in formula (4) in reaction scheme 3.
  • the subsequent Mannich reaction can be effected in the reaction conditions same as the reaction for obtaining the compound in formula (9) from the compound in formula (7) in reaction scheme 5.
  • hydrogenation of the compound in formula (41) can be effected in the same conditions as in the reaction for reducing the compound in formula (1-A) to transform into the compound in formula (1-B) in reaction scheme 2.
  • the amino group, hydroxyl group or other substituent in the intermediate compound shown in the foregoing reaction schemes can be properly protected by an ordinary method not affecting the reaction, and the protective group may be properly eliminated in an ordinary method after reaction.
  • the compound in formula (1) of the invention, and the intermediate compounds shown in the reaction schemes for its manufacture may be variously changed in the types of R 1 , R 3 , R 5 , and others contained therein, but they are not limited to them alone, and various changes as effected ordinarily may be applicable.
  • reaction scheme 15 For example, as the elimination reaction of the protective group of the hydroxyl group, there is an example of de-silylation reaction for obtaining the compound in formula (1-B) from the compound in formula (42) in reaction scheme 15. Reaction scheme 15
  • R 1 , R 2 , R 3 , R 4 , R 6 and n are same as defined above; and R 21 , R 22 , and R 23 are lower alkyl groups.
  • reaction between the compound in formula (2) and the compound in formula (3') can be effected in the same reaction conditions as in the reaction between the compound in formula (2) and the compound in formula (3) in reaction scheme 1.
  • the reaction conditions in ordinary de-silylation may be applied.
  • this de-silylation reaction is effected by using a proper catalyst customarily used in this kind of de-silylation reaction, for example, a proper amount of hydrochloric acid, sulfuric acid, perchloric acid and other inorganic acids;
  • inert solvents such as water, methanol, ethanol, isopropanol and other lower alcohols; acetone, methyl ethyl ketone and other ketones; dioxane, tetrahydrofurane, diethyl ether, ethylene glycol dimethyl ether and other ethers;
  • the catalyst may be used in the range from an ordinary catalyst amount to excessive amount, preferably an excessive amount.
  • temperature is usually about 0 to 100 °C, preferably from room temperature to about 80 °C and the reaction is terminated in about 3 minutes to 20 hours.
  • R 1 is a phthalimido-lower alkyl group
  • R 1 is a phthalimido-lower alkyl group
  • R 1 may be transformed into an amino-lower alkyl group.
  • the inert solvent used in this reaction for example,
  • hydrazine derivative examples include methyl hydrazine, ethyl hydrazine, other lower alkyl-substituted hydrazines, phenyl hydrazine and other aryl-substituted hydrazines.
  • the quantity of use of hydrazine or hydrazine derivative to the starting material compound of which R 1 corresponds to a phthalimido-lower alkyl group is usually at least equivalent mol, or preferably equivalent mol to 10 times mol.
  • the reaction is conducted usually at 0 to 100 °C, preferably 0 to 80 °C, and the reaction is generally terminated in about 1 to 40 hours.
  • the compound of the formula (13) used as starting material in reaction scheme 8 is a known compound disclosed, for example, in J. Gen. Chem., 22, 267-269 (1952), and Khim. Geterotsikl. Soedin., 3, 344-345 (1975), among others, and can be easily manufactured according to the method mentioned in these literatures.
  • the compound of the invention may contain an
  • additional salt of a pharmaceutically permitted acid or base compound may be easily formed by acting the acid or the base.
  • the acid used in salt formation include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and, if
  • organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid.
  • the base compound used in the salt formation may include, among others, sodium hydroxide, potassium
  • hydroxide calcium hydroxide, sodium carbonate, and potassium hydrogencarbonate.
  • the extracellular matrix metalloproteinases inhibitor of the invention is used generally in a form of an ordinary
  • the pharmaceutical preparation is adjusted by ordinary filler, thickener, binder, humidifier, disintegrating agent, surface active agent, lubricant, and other diluents and vehicles.
  • the pharmaceutical preparation is adjusted by ordinary filler, thickener, binder, humidifier, disintegrating agent, surface active agent, lubricant, and other diluents and vehicles.
  • preparations various forms can be selected depending on the purpose of treatment, and representative examples include tablets, pills, powders, liquid, suspension, emulsion,
  • carriers are used, for example, lactose, sucrose, sodium
  • Tablets may be manufactured in ordinary coated tables as required, for example, sugar coated tablet, gelatin coated tablet, enteric coated tablet, film coated tablet, double tablet, or multilayer tablet.
  • carriers When forming into pills, carriers are used, such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc and other vehicles; arable gum powder, tragacanth powder, gelatin, ethanol and other binder; laminaran, agar and other
  • disintegrating agents When forming into suppositories, carriers are used, such as polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, and semisynthetic glyceride. Capsules are manufactured according to the conventional manner, and various carriers listed above and the compound of the invention are blended, and put into hard gelatin capsule, hard capsule, etc. When prepared as injections, liquids, emulsions, and suspensions should be sterilized, and isotonic with the blood.
  • carriers such as polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, and semisynthetic glyceride.
  • Capsules are manufactured according to the conventional manner, and various carriers listed above and the compound of the invention are blended, and put into hard gelatin capsule, hard capsule, etc.
  • liquids, emulsions, and suspensions should be sterilized, and isotonic with the blood.
  • diluents such as water, aqueous solution of lactic acid, ethyl alcohol, propylene glycol, ethoxy isostearyl alcohol, and polyoxyethylene sorbitan fatty acid ester.
  • salt, glucose or glycerin enough for preparing an isotonic solution may be contained in the pharmaceutical preparations, or ordinary dissolution aid, desiccant, soothing agent or the like may be added.
  • coloring matter, preservative, perfume, flavor, sweetener, and other medicines may be contained in the pharmaceutical preparations.
  • diluents are used, for example, white vaseline, paraffin, glycerin, cellulose derivative, polyethylene glycol, silicon, and bentonite.
  • the quantity of the compound of the invention to be contained in the pharmaceutical preparation of the invention is not particularly defined, but may be selected from a wide range, and it may be usually in a range of 1 to 70 % by weight of the pharmaceutical preparation.
  • the method of administration of the pharmaceutical preparation of the invention is not particularly limited, and determined properly depending on the age, sex and other conditions of the patients, severity of disease, and dosage forms, and usually it is administered systematically or locally, orally or parenterally.
  • tablets, pills, liquid, suspensions, emulsions, granules, and capsules are administered orally, injections are administered
  • the dose of the pharmaceutical preparation of the invention may be properly selected depending on the age, body weight, symptom, therapeutic effect, route of administration, treating time and others, and it is usually administered in a range of about 0.1 to 100 mg per 1 kg of body weight, and the daily dose may be administered once daily or in several divided portions. Since the dose varies with various parameters.
  • the reaction solution was concentrated in vacuo, and 10 ml of ethyl acetate was added to the residue, and the mixture was heated and dissolved, and 2 ml of hexane was added, and after letting stand at room temperature for a day, the precipitating crystals were
  • reaction solution was concentrated in vacuo, dissolved in 200 ml of saturated aqueous solution of potassium carbonate, and washed with chloroform (20 ml x 3 times). The water layer was cooled in an ice bath, and the pH was adjusted to 1 by
  • reaction solution was washed once with water, and one with saturated brine sequentially, and dried with sodium sulfate anhydride. Filtering off the sodium sulfate anhydride, the filtrate was dripped in 30 minutes on the N,N-dimethyl
  • the obtained oily residue was extracted in 100 ml of ethyl acetate, and the ethyl acetate layer was washed once with water and twice with saturated brine, and dried with sodium sulfate anhydride, and concentrated in vacuo.
  • the obtained oily residue was purified by silica gel column chromatography, and eluted in chloroform, and the captioned compound was obtained in an oily form. Yield: 4.00 g.
  • the obtained oily residue was dissolved by 181.4 g in 350 ml of ethanol, and 400 ml of 5N sodium hydroxide was added to stir overnight at room temperature.
  • the reaction solution was concentrated in vacuo, and the residue was washed with 200 ml of diethyl ether.
  • the water layer was stirred in ice, adjusted to pH 1 by concentrated hydrochloric acid, and extracted with 400 ml of ethyl acetate.
  • the ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate anhydride, and concentrated in vacuo.
  • 300 ml of diethyl ether was added to solidify, and the captioned compound was obtained. Yield: 67.34 g.
  • the catalyst was filtered off from the reaction solution by using celite. To the obtained filtrate, 23.72 ml of
  • the obtained compound (8.20 g) was suspended in 200 ml of ethyl acetate, and the ethyl acetate layer was washed sequentially with 0.5M sulfuric acid (100 ml x 2 times) and saturated brine ( 100 ml x 3 times), and dried over magnesium sulfate anhydride, and concentrated in vacuo. The obtained residue was dried, and the captioned compound was obtained in an oily form. Yield: 4.60 g.
  • the reaction solution was concentrated in vacuo, and 300 ml of ethyl acetate was added to the residue, and the insoluble matter was filtered off, and the filtrate was sequentially washed with 1N hydrochloric acid (100 ml x 2 times), aqueous solution of saturated sodium hydrogencarbonate ( 100 ml x 2 times), and saturated brine ( 100 ml), and dried over magnesium sulfate anhydride.
  • the organic layer was evaporated in vacuum, and 5 ml of ethyl acetate was added to the obtained oily residue, and further 50 ml of hexane was added, and the precipitating crystals were filtered, and the captioned compound was obtained. Yield: 7.2 g.
  • 3S-methylsuccinate was added, and 130 ⁇ l of triethylamine and 377 mg of dicyclohexylcarbodiimide were added, and the mixture was stirred for 2 hours in ice-cooling and overnight at room temperature.
  • the formed insoluble matter was filterated off from the .reaction solution, and the filtrate was concentrated in vacuo. The obtained oily residue was dissolved and
  • the obtained oily residue was dried, and dissolved in 10 ml of dimethyl formamide, and while stirring in ice-cooling, a 5 ml dimethyl formamide solution of 306 mg of 1-hydroxybenzotriazole and 362 mg of benzyloxyamine hydrochloride with 231 ⁇ l of N-methyl morpholine was added, and further 120 ⁇ l of N-methyl morpholine and 434 mg of 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was stirred for 2 hours in ice-cooling and overnight at room temperature.
  • the reaction solution was concentrated in vacuo, and 50 ml of ethyl acetate was added to the obtained oily residue to extract.
  • the ethyl acetate layer was washed sequentially twice with saturated aqueous solution of sodium hydrogencarbonate, twice with IN hydrochloric acid, and twice with saturated brine, and dried over magnesium sulfate anhydride, and concentrated in vacuo. Adding diethyl ether to the obtained crystalline residue, it was filtered and dried, and the captioned compound was obtained. Yield: 430 mg.
  • reaction solution was evaporated in vacuum, and 40 ml of ethyl acetate was added to the residue, which was sequentially washed with 15 ml of 1N hydrochloric acid, 15 ml of aqueous solution of saturated sodium hydrogencarbonate, and 10 ml of saturated brine, and dried over magnesium sulfate, and evaporated in vacuum, and the captioned compound was obtained in a colorless oil form. Yield: 600 mg.
  • reaction solution was concentrated in vacuo, and 100 ml of ethyl acetate was added, and it was washed sequentially with 1N hydrochloric acid (80 ml), aqueous solution of saturated sodium hydrogencarbonate (50 ml x 2 times), and saturated brine (50 ml x 2 times), and dried over magnesium sulfate anhydride, and evaporated in vacuum. To the residue, n-hexane was added, precipitates were filtered, and the captioned compound was obtained. Yield: 5.34 g.
  • Tetrahydrofurane (2.5 ml) was added to diisopropyl- amine (1.38 ml, 9.85 mmol), being ice-cooling, n-butyl lithium (1.63 M hexane solution) (5.50 ml, 8.97 mmol) was dripped, and the solution was stirred for 15 minutes, and cooled to -78°C, and tetrahydrofurane (5 ml) solution of 4S-isopropyl-3-(1- oxononyl)-2-oxazolidinone (2.30 g, 8.54 mmol) was dripped, and the solution was stirred for 30 minutes at -78°C.
  • N-methylmorpholine was added by 190 ⁇ l while cooling and stirring in ice-salt, and 240 ⁇ l of isobutyl chloroformate was added and stirred for 5 minutes.

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Abstract

Dérivé de carbostyrile de la formule (1), dans laquelle R?1, R2, R3, R4, R5, R6¿ et n sont tels que définis, ou son sel. Ce dérivé de carbostyrile ou son sel possède d'excellentes propriétés de neutralisation des métalloprotéinases de la matrice extracellulaire.
PCT/JP1994/000434 1993-03-18 1994-03-17 Derives de carbostyrile employes comme inhibiteurs de metalloproteinases de la matrice extracellulaire Ceased WO1994021612A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP94910035A EP0641323A1 (fr) 1993-03-18 1994-03-17 Derives de carbostyrile employes comme inhibiteurs de metalloproteinases de la matrice extracellulaire
AU62637/94A AU672888B2 (en) 1993-03-18 1994-03-17 Carbostyril derivatives as matrix metalloproteinases inhibitors
KR1019940704126A KR950704257A (ko) 1993-03-18 1994-11-18 매트릭스 메탈로프로테이나제 억제제로서의 카보스티릴 유도체(Carbostyril derivatives as matrix metalloproteinases inhibitors)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP5826493 1993-03-18
JP5/58264 1993-03-18
JP25687393 1993-10-14
JP5/256873 1993-10-14

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Publication Number Publication Date
WO1994021612A1 true WO1994021612A1 (fr) 1994-09-29

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EP (1) EP0641323A1 (fr)
KR (1) KR950704257A (fr)
CN (1) CN1105799A (fr)
AU (1) AU672888B2 (fr)
CA (1) CA2136108A1 (fr)
TW (1) TW290541B (fr)
WO (1) WO1994021612A1 (fr)

Cited By (17)

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WO1996029313A1 (fr) * 1995-03-21 1996-09-26 The Procter & Gamble Company Acides hydroxamiques contenant du lactame
WO1997013515A1 (fr) * 1995-10-12 1997-04-17 Otsuka Pharmaceutical Co., Ltd. Derive carbostyrylique pour le traitement de maladies oculaires
WO1997019053A1 (fr) 1995-11-23 1997-05-29 British Biotech Pharmaceuticals Limited Inhibiteurs de metaloproteinases
US5866717A (en) * 1994-11-26 1999-02-02 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
US5917090A (en) * 1995-06-30 1999-06-29 British Biotech Pharmaceuticals Ltd. Matrix metalloproteinase inhibitors
EP0871439A4 (fr) * 1996-01-02 1999-07-21 Rhone Poulenc Rorer Pharma Composes d'acide (aryle, heteroaryle, arylmethyle ou heteroarylmethyle) hydroxamique substitues
US5952320A (en) * 1997-01-07 1999-09-14 Abbott Laboratories Macrocyclic inhibitors of matrix metalloproteinases and TNFα secretion
US5985911A (en) * 1997-01-07 1999-11-16 Abbott Laboratories C-terminal ketone inhibitors of matrix metalloproteinases and TNFα secretion
US6169075B1 (en) 1996-09-10 2001-01-02 British Biotech Pharmaceuticals Limited Cytostatic agents
US6288261B1 (en) 1998-12-18 2001-09-11 Abbott Laboratories Inhibitors of matrix metalloproteinases
US6462023B1 (en) 1996-09-10 2002-10-08 British Biotech Pharmaceuticals, Ltd. Cytostatic agents
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6838466B2 (en) 2001-12-20 2005-01-04 Schering Corporation Compounds for the treatment of inflammatory disorders
US6858598B1 (en) 1998-12-23 2005-02-22 G. D. Searle & Co. Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6987104B2 (en) 2001-06-15 2006-01-17 Vicuron Pharmaceuticals Inc. Pyrrolidine bicyclic compounds and its derivatives, compositions and methods of use
US7148242B2 (en) 2001-06-15 2006-12-12 Novartis Ag N-formyl hydroxylamine compounds, compositions and methods of use
US7879877B2 (en) 2003-07-30 2011-02-01 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives for accelerating salivation

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ATE212549T1 (de) * 1996-04-04 2002-02-15 Hoffmann La Roche Verwendung von tetrahydrobetacarbolin-derivaten zur vorbeugung der metastasenbildung
CN108285469B (zh) * 2018-03-15 2020-07-24 遵义医学院 一种抗菌类喹诺酮衍生物及其制备方法和应用

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WO1990005716A1 (fr) * 1988-11-23 1990-05-31 British Bio-Technology Limited Inhibiteurs de collagenase a base d'acide hydroxamique
WO1992017460A1 (fr) * 1991-04-08 1992-10-15 Smithkline Beecham Plc Nouveaux composes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990005716A1 (fr) * 1988-11-23 1990-05-31 British Bio-Technology Limited Inhibiteurs de collagenase a base d'acide hydroxamique
WO1992017460A1 (fr) * 1991-04-08 1992-10-15 Smithkline Beecham Plc Nouveaux composes

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5866717A (en) * 1994-11-26 1999-02-02 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
WO1996029313A1 (fr) * 1995-03-21 1996-09-26 The Procter & Gamble Company Acides hydroxamiques contenant du lactame
US5917090A (en) * 1995-06-30 1999-06-29 British Biotech Pharmaceuticals Ltd. Matrix metalloproteinase inhibitors
WO1997013515A1 (fr) * 1995-10-12 1997-04-17 Otsuka Pharmaceutical Co., Ltd. Derive carbostyrylique pour le traitement de maladies oculaires
US6060486A (en) * 1995-10-12 2000-05-09 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivative for curing ophthalmological diseases
WO1997019053A1 (fr) 1995-11-23 1997-05-29 British Biotech Pharmaceuticals Limited Inhibiteurs de metaloproteinases
EP0871439A4 (fr) * 1996-01-02 1999-07-21 Rhone Poulenc Rorer Pharma Composes d'acide (aryle, heteroaryle, arylmethyle ou heteroarylmethyle) hydroxamique substitues
US6462023B1 (en) 1996-09-10 2002-10-08 British Biotech Pharmaceuticals, Ltd. Cytostatic agents
US6169075B1 (en) 1996-09-10 2001-01-02 British Biotech Pharmaceuticals Limited Cytostatic agents
US5952320A (en) * 1997-01-07 1999-09-14 Abbott Laboratories Macrocyclic inhibitors of matrix metalloproteinases and TNFα secretion
US5985911A (en) * 1997-01-07 1999-11-16 Abbott Laboratories C-terminal ketone inhibitors of matrix metalloproteinases and TNFα secretion
US6288261B1 (en) 1998-12-18 2001-09-11 Abbott Laboratories Inhibitors of matrix metalloproteinases
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6858598B1 (en) 1998-12-23 2005-02-22 G. D. Searle & Co. Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6987104B2 (en) 2001-06-15 2006-01-17 Vicuron Pharmaceuticals Inc. Pyrrolidine bicyclic compounds and its derivatives, compositions and methods of use
US7148242B2 (en) 2001-06-15 2006-12-12 Novartis Ag N-formyl hydroxylamine compounds, compositions and methods of use
US7612059B2 (en) 2001-06-15 2009-11-03 Vicuron Pharmaceuticals, Inc. Pyrrolidine bicyclic compounds and its derivatives, compositions and methods of use
US6838466B2 (en) 2001-12-20 2005-01-04 Schering Corporation Compounds for the treatment of inflammatory disorders
US7034057B2 (en) 2001-12-20 2006-04-25 Schering Corporation Compounds for the treatment of inflammatory disorders
US7598242B2 (en) 2001-12-20 2009-10-06 Schering Corporation Compounds for the treatment of inflammatory disorders
US7879877B2 (en) 2003-07-30 2011-02-01 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives for accelerating salivation

Also Published As

Publication number Publication date
CA2136108A1 (fr) 1994-09-29
AU672888B2 (en) 1996-10-17
TW290541B (fr) 1996-11-11
EP0641323A1 (fr) 1995-03-08
CN1105799A (zh) 1995-07-26
AU6263794A (en) 1994-10-11
KR950704257A (ko) 1995-11-17

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