EP0641323A1 - Carbostyril derivatives as matrix metalloproteinases inhibitors - Google Patents

Carbostyril derivatives as matrix metalloproteinases inhibitors

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Publication number
EP0641323A1
EP0641323A1 EP94910035A EP94910035A EP0641323A1 EP 0641323 A1 EP0641323 A1 EP 0641323A1 EP 94910035 A EP94910035 A EP 94910035A EP 94910035 A EP94910035 A EP 94910035A EP 0641323 A1 EP0641323 A1 EP 0641323A1
Authority
EP
European Patent Office
Prior art keywords
group
compound
reaction
dihydrocarbostyril
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP94910035A
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German (de)
English (en)
French (fr)
Inventor
Makoto Sakamoto
Takeshi Imaoka
Masaaki Motoyama
Yoshihito Yamamoto
Hideki Takasu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Otsuka Pharmaceutical Co Ltd
Original Assignee
Otsuka Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by Otsuka Pharmaceutical Co Ltd filed Critical Otsuka Pharmaceutical Co Ltd
Publication of EP0641323A1 publication Critical patent/EP0641323A1/en
Ceased legal-status Critical Current

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Classifications

    • 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 derivatives, method of preparing the same, and extracellular matrix metalloproteinases inhibitor.
  • 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, TI P-2, and ⁇ 2 -macroglobulin.
  • R A denotes a group HN(0H)-C0- or HC0-N0H-;
  • R A is an alkyl group with C 2 to C5;
  • 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 (however, excluding hydrogen atom or methyl group);
  • R c is hydrogen atom, amino, hydroxy, mercapto, C ⁇ to Cg alkyl, C- j _ to Cg alkoxy, C- to Cg alkylamino, C-L to Cg alkylthio or aryl- ( C 1 to Cg alkyl) group, or amino- ( C- ⁇ to Cg alkyl), hydroxy- (C-L to Cg alkyl), mercapto- ( C 1 to Cg alkyl) or carboxyl- ( C 1 to Cg alkyl) of which amino,
  • R F is hydrogen atom or methyl group
  • R B and R D may be combined together to form -(CH 2 )m- group
  • ⁇ 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 H is hydrogen atom, C*-_ to Cg alkyl, C- j _ to Cg alkenyl, phenyl ⁇ C to Cg) alkyl, cycloalkyl (C-*_ to Cg) alkyl, or cycloalkenyl (C- ⁇ to C ) alkyl group;
  • R 1 is amino acid side chain, C to Cg alkyl, benzyl, (C- ⁇ to C ) alkoxybenzyl, benzyloxy (C* j _ to Cg) alkyl or benzyloxybenzyl group;
  • R J is hydrogen atom or methyl group;
  • q is an integer of 1 to 6; and B is -NH 2 group, substituted noncyclic amine or heterocyclic base] .
  • WO-9217460 discloses a compound expressed in a formula:
  • R ⁇ is hydrogen atom, C- ⁇ to Cg alkyl or -(CH 2 ) r -D-R Iv . 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 to Cg; R M is -(CH 2 ) s -E-(CH ) t - group; s is an integer of 1 to 9; t is an integer of 2 to 10; E is -NR°- group (R° is hydrogen atom, C to Cg alkyl, C 2 to Cg alkanoyl, C ⁇ to Cg 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 (53)
  • R 1 denotes hydrogen atom or group -A-R la (A shows a lower alkylene group, R la 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, phenyl hio group or lower alkylthio group); R ⁇ 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 alkylene group, lower alkenylene group or lower alkynylene group, 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: -C0-N(R 3b )R 3c (where R
  • R 5 is hydrogen atom, benzoyl group, lower alkanoyl group, or phenyl-lower alkyl group;
  • R° 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; and
  • n is 1 or 2] , and its salt.
  • the carbostyril derivative and its salt of the invention possess an excellent extracellular matrix metalloproteinases 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.
  • the compound of the invention is characterized by high inhibitory actions, low toxicity, excellent oral absorption, long duration of effect, high safety, and stability of pharmaceutical preparations.
  • the 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 corneal ulcer
  • osteoporosis other bone absorption diseases
  • multiple sclerosis hypomyelination
  • diseases accompanied by vascularization dermal and gastrointestinal ulceration
  • 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, prolif ⁇ eration 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 branched chain with 1 to 6 carbon atoms.
  • thienylthio group examples include 2-thienylthio, 3-thienylthio and other thienylthio groups.
  • lower alkanoylthio group examples include formyl- thio, acetylthio, propanoylthio, butanoylthio, isobutanoyl- thio, pentanoylthio, hexanoylthio groups, and other alkanoyl ⁇ thio groups of which 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, pentyloxy, hexyloxy groups, and other alkoxy groups of straight chain or branched chain with 1 to 6 carbon atoms.
  • 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.
  • 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, hexyloxymethoxy, methoxyhexyloxy, hexyloxyexyloxy, and other alkoxy-alkoxy group of which 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 methoxy ethoxymethoxy, methoxymethoxyethoxy, methoxyethoxyethoxy, ethoxyethoxymethoxy, ethoxyethoxyethoxy, methoxyethoxypropoxy, propoxymethoxyethoxy, isopropoxypropoxypropoxy, butoxyethoxymethoxy, t- butoxymethoxypropoxy, butoxyethoxymethoxy, isopropoxymethoxypropoxy, propoxyethoxyethoxy, t- butoxymethoxymethoxy, pentyloxyethoxyethoxy, methoxypentyloxypentyloxy, hexyloxymethoxyethoxy, methoxymethoxyhexyloxy, hexyloxyhexyloxyethoxy, and other alkoxy-alkoxy-alkoxy group of which each alkoxy portion is alkoxy group of straight chain
  • lower alkoxy-lower alkoxy-lower alkoxy-lower alkoxy- lower alkoxy group examples include methoxymethoxymethoxymethoxy, methoxyethoxymethoxyethoxy, methoxyethoxypropoxyethoxy, ethoxyethoxymethoxymethoxy, methoxyethoxyethoxyethoxy, methoxyethoxypropoxyporopoxy, propoxymethoxyethoxyethox , isopropoxy(2-methyl )propoxyethoxypropoxy, butoxyethoxyethoxymethoxy, t-butoxyethoxymethoxypropoxy, butoxyethoxymethoxybutoxy, isopropoxy ethoxypropoxyethox , propoxyethoxyethoxyethoxy, t-butoxymethoxymethoxymethoxy, pentyloxyethoxyethoxy, methoxypentyloxypentyloxymethox , hexy
  • alkyl group with 1 to 12 carbon atoms examples include methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, 2,4-dimethylpentyl, hexyl, 3-methylhexyl, 2,3,6-trimethylhexyl, heptyl, 4-isobutylheptyl, octyl, 2- ethyloctyl, nonyl, decyl, undecyl, dodecyl, and other alkyl groups of straight chain or branched chain with 1 to 12 carbon atoms.
  • lower alkoxy-lower alkyl group examples include methoxymethyl, ethoxymethyl, isopropoxyethyl, methoxyethyl, 3-ethoxypropyl, 2-methoxybutyl, tertiary butoxyethyl, 5-methoxypentyloxy, 3-methoxypentyloxy, 4-methoxyhexyloxy, 2-propoxyexyloxy, and other alkoxy-alkyl groups wherein each of alkoxy group and alkyl group is straight chain or branched chain with 1 to 6 carbon atoms.
  • 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.
  • the method shown in 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 formation reaction.
  • the condition of the known amide bond formation reaction can be easily applied.
  • 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 dicyclohexylcarbodiimide and carbonyldiimid
  • 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 triethylamine, trimethylamine, pyridine, dimethyl aniline, N- methyl morpholine, 1,5-diazabicyclo[4,3,0]nonene-5 (DBN), 1.8- dizaibicyclo[5,4,0]undecene-7 (DBU), 1,4-diazabicyclo [2,2,2]- octane (DABCO), other organic bases, potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, and other inorganic bases.
  • 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 conducted at about -20 to 150 ⁇ C, preferably 10 to 50 ⁇ C, and the reaction time is about 5 minutes to 10 hours, preferably 5 minutes to 5 hours.
  • 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.
  • the solvent aside from the solvent used in the mixed acid anhydride method, for example, methanol, ethanol, propanol, butanol, 3-methoxy-l-butanol, ethyl cellosolve, methyl cellosolve and other alcohols; pyridine; acetone; and water may be used.
  • 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 include methanol, ethanol and other alcohols; tetrahydrofurane, dioxane and other ethers; and dimethyl formamide and other polar solvents.
  • 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 - 20 -
  • diphenyl phosphate bis (2-oxo-3-oxazolidinyl) phosphinic chloride, and other phosphorus compounds.
  • This reaction is conducted in the presence of t h e solvent and basic compound used in the method of reaction o f 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 J denotes benzoyl group, lower alkanoyl group or phenyl- lower alkyl group; and X is a halogen atom.
  • the 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 reduction reaction or saponification reaction.
  • 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.
  • reducing catalyst examples include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, and Raney nickel.
  • the quantity of use of such catalyst may be about 0.001 to 2 times of the weight of the compound of formula (1-A).
  • the reaction may be conducted under pressure, but when performing at ordinary pressure, the 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.
  • the solvent the same solvent as in the catalytic reduction may be used.
  • Examples of catalyst 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 ⁇ C and the reaction is generally terminated in about 1 minute to 3 days.
  • saponification reaction 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 J -X or (R ⁇ ) 2 0 [where R ⁇ 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, triethy1amine, 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 compound in formula (1-B).
  • 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. Reaction scheme 3 R 5 R 6
  • R 2 , R 3 , R , R , and n are same as defined above; and R 9 and R 1 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 reduction, and the method by saponification.
  • 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 chloride.
  • 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.
  • the conditions of the ordinary saponification may be widely applied.
  • 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 in a proper solvent, and heating the reaction product after elimination reaction in a proper solvent.
  • the elimination reaction of the carboxyl protective group the conditions of known elimination reaction of carboxyl protective group may be widely applied.
  • the elimination reaction of the carboxyl protective group is conducted in the same manner as the elimination reaction of the carboxyl protective group shown in reaction scheme 3.
  • aromatic hydrocarbons such as toluene and benzene may be used.
  • the reaction temperature is about 50 to 120 °C and it is preferre d to react while refluxing. Generally, the reaction is terminated in about 1 minute to 3 days.
  • the compound in formula (9) is manufactured by presenting the compound in formula (7) to elimination reaction of carboxyl protective group in a proper solvent, subjecting the reaction product after the elimination reaction to Mannich reaction with aliphatic secondary amine in a proper solvent, in the presence of formaldehyde, and heating the reaction product after the Mannich reaction.
  • the elimination reaction of the carboxyl protective group the conditions of known 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.
  • the solvent for example, water, methanol, ethanol, isopropanol and other alcohols
  • the aliphatic secondary amine for example, dimethylamine, diethylamine, and piperidine
  • 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 - 29 -
  • R 2 , R 3 , R 4 , R , 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 t h e 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 , R , R , R , X, and n are same as defined above; and R 12 denotes lower alkanoyl group or lower alkyl group.
  • the reaction to obtain the compound in formula (2-D) from the compound in formula (2-C) is effected by saponification or in the presence of amine in a proper solvent.
  • the reaction conditions of ordinary saponification reaction may be widely applied, and it may be performed same as in the saponification reaction in, for example, reaction scheme 3.
  • usable solvents 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 0 [where R 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.
  • 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.
  • the basic compound include sodium hydride, potassium hydride, lithium hydride, sodium methylate, and potassium ethylate.
  • the solvent examples 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 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 disclosed in WO-9309097.
  • R°CH 2 C00H 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°CH 2 COZ, which is then caused to react with ⁇ -haloacetate XCH R 1 X 0 U to obtain R .1 J -0 U ,CH CH(R°)C0Z, and this compound is hydrolyzed to remove an optically active oxazolidine-2-on, thereby obtaining R 10 CH 2 CH(R 6 )C00H [where R ⁇ , R 1 ⁇ , and X are same as defined above; and Z denotes an optically active 2-oxo-oxazolidyl group] .
  • R , R 3 , R , R , and n are same as defined above;
  • R 14 denotes a lower alkoxycarbonyl group;
  • R 1 ⁇ 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)
  • DCC N,N'- dicyclohexyl carbodiimide
  • 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.
  • 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 , 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 solvents.
  • 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 include organic bases such as pyridine, triethylamine, and N-methylmorpholine.
  • 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 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 dioxane, tetrahydrofurane, diethyl ether, ethylene glycol dimethyl ether and other ethers; dimethyl formamide, dimethyl sulfoxide, hexamethylene phosphoric acid triamide and other polar solvents.
  • the basic compound 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.
  • T h e reaction temperature is usually about -20 to 120 °C, preferably about 0 to 60 °C, and the 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 lower alkoxy-lower alkoxy-lower alkoxy-lower alkyl group.
  • 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 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.
  • 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.
  • R 1 , R , R 3 , R , R 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; formic acid, acetic, acid, propionic acid and other lower alkane acids; benzoic acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, 4-methylbenzene sulfonic acid and other organic sulfonic acid; and other organic acids, usually in a solvent.
  • 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; formic acid, acetic, acid, propionic acid and other lower alkane acids; benzoic acid, methane sulfonic
  • the solvent examples include ordinary 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; benzene, toluene, xylene, chlorobenzene and aromatic hydrocarbons; acetic acid, propionic acid, and lower alkane acid; and their mixed solvents.
  • the catalyst may be used in the range from an ordinary catalyst amount to excessive amount, preferably an excessive amount.
  • the reaction 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.
  • the following hydrazine decomposition reaction may be presented.
  • 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, dichloromethane, dichloroethane, chloroform, carbon tetrachloride and halogenated hydrocarbons; methanol, ethanol, and other alcohols may be known.
  • 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.
  • the salt 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 necessary, 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 compound of formula (1 ) manufactured in the foregoing methods and its salt are easily isolated and refined from the reaction system by ordinary separation means, such as distillation method, recrystallization method, column chromatography, preparative thin layer chromatography, and solvent extraction method.
  • the extracellular matrix metalloproteinases inhibitor of the invention is used generally in a form of an ordinary pharmaceutical preparation.
  • the pharmaceutical preparation is adjusted by ordinary filler, thickener, binder, humidifier, disintegrating agent, surface active agent, lubricant, and other diluents and vehicles.
  • various forms can be selected depending on the purpose of treatment, and representative examples include tablets, pills, powders, liquid, suspension, emulsion, granules, capsules, suppositories, injections (liquid, suspension, etc.), and ointment.
  • carriers are used, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystal cellulose, silicic acid and other vehicles; water, ethanol, propanol, single syrup, glucose liquid, starch liquid, gelatin solution, carboxy methyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinyl pyrrolidone and other binders; dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, polyoxy ethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose and other disintegrating agent; sucrose, stearin, cacao butter, hydrogenated oil and other disintegration suppressors; quaternary ammonium base, sodium lauryl sulfate and other absorption promoters; glycerin, starch and other moisture retainers; starch
  • 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 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.
  • 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.
  • 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 may be contained in the pharmaceutical preparations.
  • diluents 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 intravenously, intramuscularly, intradermally, subcutaneously, or intraperitoneally by mixing with ordinary fluid replacement if necessary.
  • Suppositories are administered intrarectally, and ointments are applied externally.
  • 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 conditions, it may be enough at a smaller dose or a larger dose beyond the specified range may be needed, depending on the individual cases.
  • the obtained residue was dissolved in 15 ml of dimethyl formamide, 1.45 g of 3S-amino-3,4-dihydrocarbostyril was added, and while cooling in a water bath, 1.21 g of 1-hydroxybenzotriazole and 1.84 g of N,N'-dicyclohexyl carbodiimide were added, and the pH was adjusted to 8 by N-methylmorpholine, and the solution was stirred for 20 hours at room temperature. After filtering off the sediment, the solution was evaporated in vacuum.
  • 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 Q filtered, and the captioned compound was obtained in a white solid form. Yield: 500 mg.
  • the 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 concentrated hydrochloric acid, and after extracting with chloroform (50 ml x 2 times), it was washed with brine (20 ml), dried over magnesium sulfate, and evaporated in vacuum, and the captioned compound was obtained in a white solid form. Yield: 1.98 g.
  • the 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 formamide solution above prepared while stirring in ice. After dripping, the solution was stirred overnight at room temperature. The reaction solution was concentrated in vacuo, and dripped in 30 minutes. After dripping, the solution was stirred overnight at room temperature. The reaction solution was concentrated in vacuo, and the obtained residue was extracted in 300 ml of ethyl acetate.
  • 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 ethyl acetate layer was washed sequentially with IN hydrochloric acid (300 ml x 1 time and 200 ml x 1 time) and twice with saturated brine, and dried over sodium sulfate anhydride, and concentrated in vacuo.
  • the obtained oily residue was purified by silica gel column chromatography (eluted in 2% methanol/chloroform), and the captioned compound was obtained in an oily form. Yield: 13.81 g.
  • 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 mixture was washed sequentially with IN 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, and evaporated in vacuum.
  • the oily residue was purified by column chromatography (silica gel 200 g, eluted in 33% ethyl acetate/hexane), and the obtained oily matter was dried in vacuum, and crystallized, and the captioned compound was obtained. Yield: 14.38 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 IN 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 extracted with 50 ml of ethyl acetate.
  • 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.
  • the obtained oily residue was purified by the silica gel column chromatography, and eluted in chloroform, and the captioned compound was obtained. Yield: 740 mg.
  • 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 IN 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 IN 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.
  • the reaction solution was concentrated in vacuo, and 50 ml of ethyl acetate was added to the residue, and it was washed by 10 ml of water, 10 ml of IN hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate (10 ml x 3 times), and 10 ml of brine, and dried over magnesium sulfate, and evaporated in vacuum.
  • the obtained residue was dried (790 mg).
  • a 10 ml solution of tetrahydrofurane of 390 mg of the obtained compound while cooling and stirring in ice/salt, 126 ⁇ l of N-methyl ⁇ morpholine and 111 ⁇ l of isobutyl chloroformate were added, and the mixture was stirred for 15 minutes.
  • 195 mg of 0-(t-butyldimethylsilyl)hydroxyamine was added, and stirred overnight at room temperature.
  • the insoluble matter was filtered off from the reaction solution, and 4 ml of acetic acid and 4 ml of water were added to the filtrate, and stirred for 3 hours at room temperature.
  • the reaction solution was concentrated in vacuo, and the obtained residue was dissolved and extracted in 50 ml of ethyl acetate.
  • the ethyl acetate layer was washed three times in saturated brine and two times in water, and concentrated in vacuo.
  • the obtained residue was purified by silica gel column chromatography (eluted in 3% methanol/chloroform), and the captioned compound was obtained in a white solid form. Yield: 170 mg.
  • Example 62 After conducting a reaction between a corresponding starting material and the compound obtained by catalytic reduction treatment of the compound of Reference Example 61, the captioned compound was obtained in the same manner as in Example 62.

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EP94910035A 1993-03-18 1994-03-17 Carbostyril derivatives as matrix metalloproteinases inhibitors Ceased EP0641323A1 (en)

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JP5826493 1993-03-18
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US6838466B2 (en) 2001-12-20 2005-01-04 Schering Corporation Compounds for the treatment of inflammatory disorders

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GB9423914D0 (en) * 1994-11-26 1995-01-11 British Biotech Pharm Polyether derivatives as metalloproteinase inhibitors
US5672598A (en) * 1995-03-21 1997-09-30 The Procter & Gamble Company Lactam-containing hydroxamic acids
US5917090A (en) * 1995-06-30 1999-06-29 British Biotech Pharmaceuticals Ltd. Matrix metalloproteinase inhibitors
AR004214A1 (es) * 1995-10-12 1998-11-04 Otsuka Pharma Co Ltd Una preparación de gotas oftálmicas para la cura de enfermedades oftálmicas
AU711804B2 (en) 1995-11-23 1999-10-21 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
DE69728375T2 (de) * 1996-01-02 2005-02-10 Aventis Pharmaceuticals Inc. Substituierte (aryl, heteroaryl, arylmethyl oder heteroarylmethyl) hydroxamisaeureverbindungen
CN1113648C (zh) * 1996-04-04 2003-07-09 弗·哈夫曼-拉罗切有限公司 四氢－β－咔啉衍生物作为抗转移瘤剂的用途
IL128337A0 (en) 1996-09-10 2000-01-31 British Biotech Pharm Cytostatic hydroxamic acid derivatives
US6462023B1 (en) 1996-09-10 2002-10-08 British Biotech Pharmaceuticals, Ltd. 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
WO2002102791A1 (en) 2001-06-15 2002-12-27 Vicuron Pharmaceuticals Inc. Pyrrolidine bicyclic compounds
AR036053A1 (es) 2001-06-15 2004-08-04 Versicor Inc Compuestos de n-formil-hidroxilamina, un proceso para su preparacion y composiciones farmaceuticas
US7879877B2 (en) 2003-07-30 2011-02-01 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives for accelerating salivation
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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GB9107368D0 (en) * 1991-04-08 1991-05-22 Smithkline Beecham Plc Novel compounds

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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

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AU672888B2 (en) 1996-10-17
AU6263794A (en) 1994-10-11

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