WO1996029307A1 - Composes de diphenylmethyle-azetidinone et inhibiteur d'elastase - Google Patents

Composes de diphenylmethyle-azetidinone et inhibiteur d'elastase Download PDF

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Publication number
WO1996029307A1
WO1996029307A1 PCT/JP1996/000743 JP9600743W WO9629307A1 WO 1996029307 A1 WO1996029307 A1 WO 1996029307A1 JP 9600743 W JP9600743 W JP 9600743W WO 9629307 A1 WO9629307 A1 WO 9629307A1
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Prior art keywords
acetyl
methoxy
carbonyl methoxy
diphenylacetyl
carbonyl
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PCT/JP1996/000743
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English (en)
Japanese (ja)
Inventor
Kazuhiro Tsutsumi
Takashi Inaba
Toshizo Tanaka
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Japan Tobacco Inc.
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Priority to AU50144/96A priority Critical patent/AU5014496A/en
Publication of WO1996029307A1 publication Critical patent/WO1996029307A1/fr

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    • 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
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/12—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is an anti-inflammatory action, it relates to a novel Azechijinon derivative having elastase inhibitory activity and cytokine production inhibitory action, c background art utilized in the field of medicine
  • Is deeply involved in Diseases that may be associated with immune abnormalities in the progression of these inflammatory symptoms include rheumatoid arthritis, bronchitis due to chronic respiratory tract infections, adult respiratory distress syndrome, and bronchioles classified as type II asthma.
  • respiratory diseases such as obstructive asthma, and nonspecific inflammatory diseases such as inflammatory bowel disease (Coulomb's disease and lupus colitis) and one of the skin diseases such as psoriasis.
  • elastin and collagen are the fibrous proteins that make up the stroma of in vivo connective tissues such as lungs, cartilage, vascular walls, and skin. It is thought to play an important role. Therefore, as a prophylactic and therapeutic agent for the above-mentioned diseases caused by tissue destruction and deterioration by elastase and cell injury, and also for various diseases such as ophthalmitis, nephritis and arteriosclerosis, and diseases of multiple organs and sepsis, Elastase inhibitors have been considered to be effective.
  • non-peptide inhibitors include, for example, The Journal of Biological Chemistry, Vol. 257, pp. 508-5, pp. 91 (1982) [Biol. Chem., 257_. 5085-5091 (1982)] discloses benzoxazidinone derivatives and quinazoline derivatives.
  • the journal Rub Medinnal Chemistry, Vol. 30, pp. 107-102 (1989) [ed. Chem .. 30, 1017-1023 (1987)] contains a pyrone derivative, Pp. 31, 105-106 pp. (1988) [J. Med. Chem .. 31.
  • R and R 1 are alkyl groups and the like; R 2 and R 3 are hydrogen atoms, OB (B represents a heteroarylalkyl group and the like), etc .; A is (CO) NB, B 2 and the like. ⁇ Are disclosed, and WO 9 3Z0 0 3 32
  • R is d -C e alkyl group; R 1 is an alkyl group or the like; R 2, R 3 is hydroxyl, Al kill group, a halogen atom, a carboxyl group or the like; M is a hydrogen atom, an alkyl group, are alkenyl Le group ) Is disclosed. However, there is no disclosure of an azetidinone derivative having a diphenyl group.
  • the inventors of the present invention have conducted intensive studies to solve the above problems, and as a result, have a strong elastase inhibitory activity, are orally administrable, have excellent safety, and have a cytokine production inhibitory activity.
  • the present inventors have found a novel diphenylmethylazetidinone derivative represented by the general formula [I], and have completed the present invention.
  • the present invention relates to novel diphenylmethyl-azetidinone derivatives shown in the following (1) to (9) and pharmaceutical uses thereof.
  • R 1 and R 2 are the same or different and each is an alkyl group or R 1 and R 2
  • A represents a hydroxyl group or a group selected from the following:
  • R 3 and R e are the same or different and each represent a hydrogen atom, an alkyl group, a cycloalkyl group or an aralkyl group which may be substituted with a hydroxyl group, and R 4 and R 5 are the same or different, respectively. Hydrogen atom, alkyl group or and R 5 together One (CH 2 ) r -or
  • R 7 represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group or an alkynyl group
  • R 8 represents an alkyl group or a cycloalkyl group
  • s represents 0 or an integer of 1 to 3
  • t represents an integer of 1 to 5
  • u represents 0 or an integer of 1 or 2.
  • m represents 0 or an integer of 1 to 5.
  • a pharmaceutical composition comprising the diphenylmethylazetidinone compound of (1) to (6) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • An elastase inhibitor comprising the diphenylmethylazetidinone compound of (1) to (6) or a pharmacologically acceptable salt thereof.
  • An anti-inflammatory agent comprising the diphenylmethylazetidinone compound of (1) to (6) or a pharmacologically acceptable salt thereof.
  • B 2 is a single bond, which means that D and one (CH 2 ) severelyare directly bonded
  • D is a single bond, which means that B 1 and B 2 are directly bonded.
  • both B 2 and D are single bonds, it means that B 1 and one (CH 2 ) precedeare directly bonded ⁇
  • the compounds of the present invention include stereoisomers and optical isomers, and the present invention covers all of them.
  • the alkyl group J is a linear or branched alkyl group having 1 to 8 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an ibb-open-bil group, an n-butyl group, Isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, tert-pentyl group, neopentyl group, 2-pentyl group, 3-bentyl group, n-hexyl group, isohexyl group, R 1 or R 2 is preferably a methyl group having 1 to 4 carbon atoms, an ethyl group, an n-propyl group, an isopropyl group, a 2-hexyl group, an n-hexyl group or an n-octyl group.
  • R 3 , R 4 , R s , R as a e is preferably a methyl group, Echiru group, n- flop A pill group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group or an n-hexyl group, and particularly preferably a methyl group , Ethyl, n-propyl, isopropyl, n-butyl or isobutyl, etc.
  • R 7 or R 8 is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group or an n- And a butyl group, and particularly preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an n-pentyl group or an n-heptyl group.
  • the “cycloalkyl group” is a cyclic alkyl group having 3 to 7 carbon atoms, and examples thereof include a propyl group, a cyclobutyl group, a cyclobentyl group, a cyclohexyl group, a cyclohexyl group, and the like, preferably a cyclobutyl group.
  • aralkyl group refers to an aryl group comprising an aryl group such as a phenyl group, a naphthyl group or a biphenyl group and an alkyl group having 1 to 6 carbon atoms, such as a benzyl group, A phenyl group, a phenyl propyl group, a phenyl butyl group or a phenyl hexyl group, and preferably a benzyl group or a phenyl group;
  • ⁇ Alkenyl group j represents a linear or branched alkenyl group having 2 to 6 carbon atoms, such as an ethyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-brodinyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 2-methyl-1-butenyl group, 3-methyl-1-butenyl group, 1 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 2-methyl-1-pentenyl group, 3-methyl-11-pentenyl group, 4-methyl- 1 It is a monopentyl group, a 2,3-dimethyl-1-butenyl group or a 3,3-dimethyl-1-butenyl group.
  • it is an ethenyl group having 2 to 4 carbon atoms, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group or 2-methyl-1-propenyl group.
  • Alkynyl group means alkynyl having 2 to 6 carbon atoms which may be straight or divided Represents an ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 1-benthinyl group, 2-pentynyl group, 3-pentynyl group, 1-methyl-2-butynyl group, 1-methyl-3-butynyl group, 2-methyl-3-butynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-methyl-1-pentynyl, 4-methyl-11-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl- 4 One pentynyl group, 1,1 dimethyl
  • the “pharmacologically acceptable salt” may be any salt that forms a nontoxic salt with the diph Xnylmethylazetidinone compound represented by the above general formula [I], such as hydrochloric acid, sulfuric acid, phosphoric acid, and odor.
  • Salts of inorganic acids such as hydrofluoric acid and nitric acid; acetic acid, propionic acid, malonic acid, citric acid, lactic acid, malic acid, succinic acid, tartaric acid, fumaric acid, maleic acid, glycolic acid, methanesulfonic acid, P- Examples thereof include salts of organic acids such as toluenesulfonic acid, gluconic acid, ascorbic acid, aspartic acid, and glutamic acid. In some cases, it may be a hydrate or a hydrate. Particularly preferred are hydrochlorides and nitrates.
  • the “carboxy protecting group” may be any protecting group that is usually used to protect a carboxy group, such as a methyl group, an ethyl group, an n-butyl group, an isopropyl group, an n-butyl group, alkyl groups such as tert-butyl group or isobutyl group; halogen-substituted alkyl groups such as 2,2,2-trichloroethyl group or 2,2,2-trifluoroethyl group; benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, 0-nitrobenzyl group, p-nitrobenzyl group, an aralkyl group such as a p-bromobenzyl group, a diphenylmethyl group or a trityl group; a trimethylsilyl group, a triethylsilyl group, an ippdimethylpyrylsilyl group, a
  • the "amino protecting group” may be any protecting group which is usually used as a protecting group for an amino group, such as methoxycarbonyl, ethoxyquincarbonyl, propoxycarbonyl, isopropoxycarbonyl, n —Butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxypropyl, tert-amyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, Alkoxycarbonyl group such as benzyloxycarbonyl group or 9-fluorenylmethoxycarbonyl group or aralkyloxycarbonyl group; formyl group, acetyl group, propionyl group, butyryl group, valeryl group, bivaloyl group, chloroacetyl group, trichloroacetyl group The trifluoroacetyl group An alkyl group such as a methyl group, a tert-butyl group or
  • the compound represented by the general formula (3) obtained in the first step is reacted with a sulfonyl isocyanate such as chlorosulfonyl isocyanate under cooling, preferably under ice cooling.
  • a sulfonyl isocyanate such as chlorosulfonyl isocyanate under cooling, preferably under ice cooling.
  • This reaction can be carried out in a solvent such as toluene, dichloromethane, nitromethane, hexane, heptane, diisopropyl ether or without a solvent.
  • a sulfite such as sodium sulfite or sulfurous acid lime or thiophenol, the general formula (4) (wherein R 1 , R 2 , and Ac each have the same meaning as described above).
  • a compound is obtained.
  • This reaction can be carried out in a solvent such as toluene, dichloromethane, nitromethane, hexane, h
  • the one-branched acetoxy lanthanate represented by formula (6) is converted to methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, water, or a mixture thereof.
  • a base such as sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide or potassium tert-butoxide
  • Rc is A hydroxy I ⁇ acid ester represented by the following formula is obtained.
  • Step 5 In a solvent such as benzene, toluene, acetone, methyl ethyl ketone or N, N-dimethylformamide, the compound represented by the general formula (4) obtained in the second step is ice-cooled or heated.
  • the compound represented by the general formula (8) (R 1 , R 2 , R c ) is reacted with the compound represented by the general formula (7) obtained in the fourth step preferably at room temperature in the presence of palladium acetate or zinc oxide.
  • E Part 1 is a carboxy group or a carboxy group protected with a carboxy protecting group (R c 0 2 C), a compound represented by the general formula (9) wherein E 2 part is a group selected from a halogen atom or an amino group, wherein R c , X and s each have the same meaning as described above; E wherein 3 parts are a group selected from an amino group or a halogen atom (10) (R 7 ′ represents an alkyl group, a cycloalkyl group, an alkenyl group or an alkynyl group, and X has the same meaning as described above. Is condensed with a compound represented by the general formula (11) (where m represents the same meaning as described above).
  • the order of condensation is arbitrary.
  • the compound represented by the general formula (9) is not used, and the compound represented by the general formula (9) and the compound represented by the general formula (11) are not used. It is only necessary to react the compound to be reacted.
  • the amino compound or a salt thereof is converted into dichloromethane, chloroform, dimethyl ether, React with halogen compounds in ice-cooled or heated to reflux in ethyl dithioate, butyl stylate, diisopropyl ether, tetrahydrofuran, 4-dioxane, methanol, benzene, toluene or a mixed solvent thereof.
  • a base such as triethylamine or N, N-diisopropylethylamine.
  • the carboxy compound When condensing a carboxy compound (11) with an amino compound (9, 10 or 9 + 10), the carboxy compound is converted to dichloromethane, chloroform, toluene, ethyl acetate, butyl acetate, 1,2-dichloroethane, tetrahydrofuran 1-Ethyl-3- (3-dimethylaminobutyryl) -carbodiimide hydrochloride in a solvent such as dioxane or N, N-dimethylformamide at room temperature or under heating, preferably at room temperature.
  • a solvent such as dioxane or N, N-dimethylformamide
  • WSC ⁇ HC 1 react with an amino compound in the presence of a box mixture such as dicyclohexylcarbodiimide (DCC) or diisopropylcarpoimide, or prepare from carboxy compounds from thionyl chloride or oxalyl chloride did In the presence of a base such as triethylamine, N, N-diisopropylethylamine, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, etc.
  • a box mixture such as dicyclohexylcarbodiimide (DCC) or diisopropylcarpoimide
  • a base such as triethylamine, N, N-diisopropylethylamine, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, etc.
  • a carboquin compound activated with N ,, '-carbonyldiimidavour, ethyl chlorocarbonate, isobutyl chlorocarbonate or bivaloyl chloride is reacted with an amino compound in the above solvent.
  • a condensing agent such as WSC ⁇ HC1, DCC or disopropyl carbopimidide, 1-hydroxybenbutriabulium, ⁇ -hydroxysuccinic acid imid or 4-dimethylaminopyridine, etc.
  • reaction auxiliary such as triethylamine, ⁇ ⁇ , ⁇ ⁇ diisopropylpyrethylamine or lithium when the carboxy group is activated by introducing an acid halide or by using another activating agent.
  • a base such as hexamethyldisilazide, sodium bicarbonate, sodium bicarbonate, sodium carbonate or sodium carbonate during the reaction.
  • one part is a carboxine group protected by a carboxy protecting group
  • a method usually used for removing the protecting group can be used.
  • the protecting group is a group that can be removed under acidic conditions such as a tert-butyl group are as follows.
  • tert-Butyl protected compound (9 + 11 or 9 + 10 + 11) was converted to methanol, ethanol, n-propanol, isopropanol, dichloromethane, chloroform, getyl ether, tetrahydrofuran, 1,4-dioxane, drunk In an acid, water or the like, or a mixed solvent thereof, or without using a solvent, hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, formic acid, By performing a deprotection reaction in the presence of an acid such as trifluoroacetic acid or trifluoromethanesulfonic acid, the compound is represented by the general formula (12) (where R 7 , m, and s have the same meanings as described above). Is obtained.
  • the protecting group is, for example, a benzyl group
  • Benzyl protected compound (9 + 11 or 9 + 10 + 11) was converted to methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, diacid, dichloromethane, N, N-dimethylform.
  • a catalyst such as palladium carbon, palladium black or palladium hydroxide carbon at room temperature to 60, preferably at room temperature, in an amide or the like or a mixed solvent thereof.
  • E 1 is an alkyl group such as a methyl group and an ethyl group is as follows.
  • the compound represented by the general formula (12) is obtained by performing a reaction using a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate under the temperature or under reflux. Is received. In the case where another protecting group is used, deprotection may be carried out by a method usually used for removing the protecting group. Manufacturing method A-3
  • a method for producing a difluoromethyl compound represented by the general formula (14) (R 7 , ⁇ , and s each have the same meaning as described above) is shown.
  • the general formula (1 3) E 1 part instead is an amino group or a protected Amino group (R N NH or R N 2 N) of the general formula shown in Process ⁇ - 2 (9) ( R N Habe Nji Ruo propoxycarbonyl sulfonyl group, tert- butoxycarbonyl group, an amino protecting group such as Futaruimi de group, in particular R N NH Habe Nji Ruo alkoxycarbonyl group or a tert- butoxy aryloxycarbonyl group in represents a protected amino group, R N 2 N represents an amino group protected with Futaruimi de group, X, s have the same meanings as defined above, respectively.) in may be used table the compound . This is shown in FIG. Reaction process diagram 3
  • E 1 part is R N NH, it can be performed according to conventional method performed to remove the protecting group R N.
  • An example in which the protecting group is, for example, a benzyloxycarbonyl group is as follows.
  • the benzyloxycarbonyl protected compound (13 + 11 or 13 + 10 + 11) was converted to methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetic acid, dichloromethane, N, N
  • a catalyst such as palladium carbon, palladium black or palladium hydroxide carbon at room temperature to 60, preferably at room temperature, in dimethylformamide or a mixed solvent thereof.
  • a compound represented by the general formula (14) (where R 7 , m and s each have the same meaning as described above) is obtained.
  • the tert-butoxycarbonyl protected compound (13 + 11 or 13 + 10 + 11) was converted to methanol, ethanol, n-propanol, isopropanol, dichloromethane, chloroform, dimethyl ether, tetrahydrofuran, 4 In dioxane, diacid, water, etc., or a mixed solvent thereof, or without using a solvent, One 2 Te 0 e C to 8 0, preferably under ice-cooling to room temperature, hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, formic acid, Torifuruoro acetate, the presence of an acid such as triflate Ruo b methanesulfonic acid, deprotection reaction
  • a phthalimid-protected compound (13 + 11 or 13 + 10 + 11) is converted to methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 1,4-dioxane, etc., or a mixed solvent thereof with water.
  • the compound represented by the single-arm formula (14) can be obtained by performing a deprotection reaction in the presence of hydrazine or a hydrate thereof at a medium temperature, under ice cooling or heating, preferably at room temperature. When another protecting group is used, deprotection may be carried out by a method usually used for removing the protecting group. Production method A-4
  • a diphene represented by the general formula (18) (t represents an integer of 1 to 5, u represents 0 or an integer of 1 to 2, and s and m each have the same meaning as described above)
  • the method for producing a dimethyl compound will be described.
  • the compound represented by the general formula (10) shown in the production method A-2 was not used, and instead of the general formula (9), the general formula (17) (R c , s, t, u Represents the same meaning as described above, and may be a compound represented by the formula: This is shown in FIG.
  • a compound represented by the following general formula (19) (R 1 , R 2 , R c , D, B 1 , B 2 , and m each have the same meaning as described above) is obtained.
  • a condensing agent such as WSC ⁇ HC1, DCC or diisopropylcarbodiimide
  • 1-hydroxyquinbenebutriabule, N-hydroxysuccinic acid imide or 4-dimethylamidate is used.
  • a reaction auxiliary such as minopyridine.
  • a compound represented by the general formula (14) is dissolved in a solvent such as dichloromethane, chloroform, 1,2-dichloroethane or tetrahydrofuran, in the form of triethylamine, N, N-diisopropyrethylamine or N-methyl.
  • a carbonylating agent such as phosgene, trichloromethyl chloroformate, bistrichloromethyl carbonate, or 1,1'-carbonyldiimidazole in the presence of a base such as morpholine.
  • the compound represented by the general formula (8) is added, and if necessary, the base is added, whereby B 1 is obtained.
  • a compound represented by the general formula (19) is obtained.
  • the compound represented by the general formula (19) can also be obtained by reacting the compound represented by the general formula (8) with the carbonylating agent and then reacting the compound represented by the general formula (14). The compound represented by is obtained.
  • the carboxy-protecting group R c of the general formula (19) is deprotected, and the compound represented by the general formula [I], wherein A is a hydroxyl group [ ⁇ ] (R 1 , R 2 , ⁇ 1, beta 2, D, m is a process for obtaining a representative.) as defined above, may be performed a method similar to deprotect the cull Bokishi protecting group. When another protecting group is used, deprotection may be carried out by a method usually used for removing the protecting group.
  • the compound represented by the general formula [1 '] When the compound represented by the general formula [1 '] is converted into a pharmacologically acceptable salt, the compound represented by the general formula [ ⁇ ] is converted into methanol, ethanol, ⁇ -propanol, isopropanol, tetrahydrofuran, Some solvents such as 4-dioxane and water are dissolved in these mixed solvents, and sodium hydroxide, hydroxide hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, etc.
  • the base addition salt of the compound represented by the general formula [1 '] can be obtained by adding the base without solvent or by dissolving it in the above solvent.
  • R 3 and R e are the same or different and each represents a hydrogen atom, an alkyl group, a cycloalkyl group or an aralkyl group which may be substituted with a hydroxyl group;
  • B 1 is produced by a method different from the method shown in Production method A.
  • the amino acid is obtained by a usual method.
  • a protecting group or after introducing an amino protecting group by a method usually used for a compound represented by the general formula (9) or (10) in which E 2 or E 3 is an amino group.
  • E 2 or E 3 is an amino group.
  • it may be condensed compounds 3 or E 2 parts E is represented by the general formula is a halogen atom (1 0) or the general formula (9).
  • a method usually used for deprotecting the protecting group may be used.
  • a compound represented by the general formula (21) when a compound represented by the general formula (21) is desired, a compound represented by the general formula (15) may be used instead of the general formula (9), and the compound represented by the general formula (22) may be used.
  • the amino group of the general formula (17) may be protected by a commonly used method.
  • This process is general formula Amino protecting group R N (23) is a step of deprotecting, it is possible to use a method to be performed normally.
  • the protecting group is, for example, a benzyloxycarbonyl group
  • the method shown in 3 ′ of the sixth step can be used.
  • deprotection may be performed using a method usually used for removing the protecting group.
  • This step is a step of condensing the compound represented by the general formula (24) and the general formula (11).
  • the general formula (25) R 1 , R 2 , R c , D, and m each have the same meaning as described above.
  • the compound represented by is obtained. ).
  • the compound represented by the one-branch formula (25) obtained in the first and second steps is represented by the general formula [I] by performing a method similar to that shown in the eighth and ninth steps.
  • B 1 of the compounds is
  • the thus-obtained compound of the present invention represented by the general formula [I] is elastase It is useful as a therapeutic or prophylactic agent for inflammation based on its inhibitory activity
  • the compound of the present invention is usually administered orally or parenterally, systemically or locally.
  • Dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually in the range of 0.0 lmg to 1 g per adult once or several times daily or parenterally. Is done.
  • the one or more active substances may include at least one inert diluent, dispersant or adsorbent, such as lactose, mannitol, grape, hydroxybutyral cellulose, micronized It is mixed with crystalline cellulose, starch, poly (vinylhydrin), magnesium aluminate metasilicate or powdered maleic anhydride.
  • the composition may be mixed with additives other than the diluent according to a conventional method.
  • gastric-soluble or sucrose such as sucrose, gelatin, hydroxybutyl cellulose or hydroxymethylcellulose phthalate as necessary. It may be coated with a film of an enteric substance, or may be coated with two or more layers. 'In addition, capsules of substances such as gelatin or ethylcellulose may be used.
  • a liquid composition for oral administration it can be in the form of pharmaceutically acceptable emulsions, solubilizers, suspensions, syrups or elixirs.
  • the diluent used includes, for example, purified water, ethanol, vegetable oil or emulsifier.
  • this composition may be mixed with an auxiliary agent such as a wetting agent, a suspending agent, a sweetening agent, a flavoring agent, a fragrance or a preservative in addition to the diluent.
  • solubilizing agents When preparing parenteral injections, use sterile aqueous or non-aqueous solutions, solubilizing agents, suspending agents, or emulsifying agents.
  • water-soluble solutions, solubilizing agents, and suspending agents include distilled water for injection, physiological saline, cyclodextrin and its derivatives, triethanolamine, diethanolamine, and monoethanolamine.
  • organic amines such as triethylamine and inorganic solution.
  • a water-soluble solution for example, vegetable oils such as propylene glycol, polyethylene glycol or olive oil, and alcohols such as ethanol may be used.
  • solubilizing agent for example, surfactants (formation of mixed micelles) such as boroxyethylene hydrogenated castor oil and sucrose fatty acid ester, or lecithin or hydrogenated lecithin (formation of ribosome) are also used.
  • an emulsion preparation comprising a water-insoluble dissolving agent such as vegetable oil and lecithin, borooxyethylene hydrogenated castor oil or polyoxyethylene polyoxypropylene glycol can be used.
  • Other compositions for parenteral administration include one or more active substances, topical solutions, ointments or suppositories, suppositories or vesicles, formulated in a manner known per se. It may be.
  • Me is a methyl group
  • Et is an ethyl group
  • Pr is a propyl group
  • i-Pr is an isopropyl group
  • Bu is a butyl group
  • t-Bu is a tert-butyl group
  • Bn represents a benzyl group
  • Ac represents an acetyl group.
  • Chlorosulfonyl isocyanate (48.Oml) was added dropwise to the cyclohexylidenemethyl acetate (58.54 g) obtained in Reference Example 1 under ice-cooling, and the mixture was stirred overnight at the same temperature under a nitrogen atmosphere. After completion of the reaction, toluene (120 ml) was added to the reaction solution, and this was poured into a mixture of sodium hydrogencarbonate (296.2 g), sodium sulfite (170.5 g), ice (450 g), and water (1.371). And stirred for 4 hours.
  • tert-butyl hydroquinacetate The tert-butyl acetoacetate acetate (91.46 g) obtained in Reference Example 4 was dissolved in a mixed solvent of methanol (300 ml) and water (200 ml), and potassium carbonate (72.56 g) was added, followed by stirring at room temperature for 1 hour. did. After the completion of the reaction, the reaction solution was cooled with ice, concentrated hydrochloric acid was added to adjust the pH to about 8, and the mixture was concentrated under reduced pressure. Water (800ral) was added to the obtained residue, and extracted three times with getyl ether. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (37.66 g) as a pale yellow oil.
  • Methyl 4,4-diphenylbutanoate (1.4.25 g) obtained in Reference Example 9 was dissolved in methanol (65.3 ml), and 2N aqueous sodium hydroxide solution was added at room temperature.
  • the solution was washed successively with an acid (120 ml), water (100 ml), a saturated aqueous sodium hydrogen carbonate solution (120 ml) and a saturated aqueous sodium chloride solution.
  • the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain ethyl (N-methyl-N-diphenylacetylamino) acetate.
  • This was dissolved in ethanol (150 ml), and a 1 N aqueous sodium hydroxide solution was added dropwise. After stirring at room temperature overnight, water (100 ml) was added to the residue obtained by concentration under reduced pressure, and the residue was washed with ethyl acetate.
  • the aqueous layer was ice-cooled, acidified with concentrated hydrochloric acid, extracted twice with St-ethyl, and the organic layer was washed with a saturated aqueous sodium chloride solution (150 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (9.10 g) as a white amorphous solid.
  • Ethyl (N-diphenylacetyl-N-ethylamino) acetate (6.30 g) obtained in Reference Example 12 was dissolved in a mixed solvent of methanol (13 ml) and tetrahydrofuran (13ral), and 1N hydroxide was added. Lithium (25 ml) was added and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, ethyl acetate was added to the residue obtained by concentration under reduced pressure, and the residue was washed with 10% citric acid and a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (5.76 g) as white crystals.
  • Ethyl (N-butyl-N-diphenylacetylamino) acetate was obtained from ethyl propimate (3.88 ml) in the same manner as in Reference Example 12. This was treated in the same manner as in Reference Example 13 to obtain the title compound (8.22 g). However, n-butylamine was used instead of the 70% ethylethylamine aqueous solution, sodium hydroxide was used instead of lithium hydroxide, and ethanol was used instead of the mixed solvent of methanol and tetrahydrofuran.
  • n-Pentylamine (4.64 ml) was dissolved in benzene (10 ml), a solution of ethyl bromosulfate (2.22 ml) in benzene (5 ml) was added, and the mixture was heated under reflux for 2 hours. After the completion of the reaction, the insolubles were separated and the solution was decompressed to obtain the title compound (4.45 g).
  • the title compound (4.67 g) was obtained from ethyl (N-diphenylacetyl-N-pentylamino) acetate (6.81 g) obtained in Reference Example 16 by performing the same method as in Reference Example 13.
  • sodium hydroxide was used instead of lithium hydroxide
  • methanol was used instead of a mixed solvent of methanol and tetrahydrofuran.
  • ethyl (N-diphenylacetyl-N-butylamino) acetate was obtained in the same manner as in Reference Example 12. This was treated in the same manner as in Reference Example 13 to obtain the title compound (5.15 g).
  • n-heptylamine was used instead of the 70% aqueous ethylethylamine solution
  • sodium hydroxide was used instead of lithium hydroxide
  • methanol was used instead of the mixed solvent of methanol and tetrahydrofuran.
  • Ethyl (N-diphenylacetyl-N-isopropylamino) acetate was obtained from ethyl bromosuccinate (3.34 g) in the same manner as in Reference Example 12. This was treated in the same manner as in Reference Example 13 to obtain the title compound (2.31 g).
  • isopropylamine is used instead of the 70% aqueous solution of ethylamine
  • sodium hydroxide is used instead of lithium hydroxide
  • methanol and tetrahydrofuran are used.
  • Ethanol was used instead of the mixed solvent.
  • Diphenylenediic acid (10.60 g) was dissolved in chloroform (200 ml), and 1-ethyl-3- (3-dimethylaminobutyl) carbodiimide hydrochloride (WSC ⁇ HC1) (10.54 g) and 1-Hydroxybenzotriabule (8.42 g) was added, the mixture was stirred at room temperature and stirred for 5 hours.
  • Glycineethyl ester hydrochloride (6.90 g) and triethylamine (7.7 ml) were added to this solution, and the mixture was stirred at room temperature for 2 days.
  • reaction solution was washed sequentially with water and an aqueous solution of potassium carbonate, dried over magnesium sulfate, and concentrated under reduced pressure to obtain ethyl (N-diphenylacetylamino) acetate.
  • ethyl (N-diphenylacetylamino) acetate This was dissolved in methanol (200ral), sodium hydroxide (6 g) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, 1N hydrochloric acid was added to the residue obtained by decompressing the solvent under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (9.39 g).
  • n-Propylamine (2.lral) was dissolved in benzene (5 ml), a solution of ethyl 2-bromopropionate (2.3 g) in benzene (1 Oml) was added, and the mixture was stirred at 55 for 16 hours. After concentration under reduced pressure, add getyl ether to the residue, remove insolubles, concentrate the concentrate, dissolve the resulting residue in chloroform (30 ml), and add triethylamine (1.8 ml). Then, diphenylacetyl chloride (3.0 g) was added little by little, and the mixture was stirred at room temperature for 4 hours.
  • reaction solution was poured into ice water, and the aqueous solution was washed with ethyl acetate, acidified with 1N hydrochloric acid, and extracted with ethyl ester.
  • the organic extract is washed with water and a saturated aqueous solution of sodium chloride in that order, dried over magnesium sulfate, and concentrated under reduced pressure.
  • the title compound (2.24 g) was obtained from the elution part of n-hexane: ethyl acetate: ⁇ acid 2: 1: 0.01.
  • the title compound (7.20 g) was obtained as white crystals by performing the same method as in Reference Example 35 from difluoroacetic acid (8.50 g) and N-aminophthalimide (6.49 g). However, triethylamine was not used.
  • N-diphenylacetylaminophthalimide (7.20 g), n -Brobanol (1.66 ml) and triphenylphosphine (5.82 g) obtained in Reference Example 40 were added to tetrahydrofuran (70 ml).
  • the mixture was cooled on ice, and a solution of disopropyl carboxycarboxylate (4.38 ml) in tetrahydrofuran (30 ml) was added, followed by stirring at the same temperature for 1 hour.
  • D-Proline (5.0 g) was dissolved in a mixed solvent of N, N-dimethylformamide ( ⁇ ), 1,4-dioxane (100 ml), and water (10 ml), and potassium carbonate (6.23 g) and diphthene chloride were dissolved.
  • ethyl acetate and water were added to the residue obtained by vacuum concentration to separate an aqueous layer.
  • the aqueous layer was adjusted to pH 1 by adding concentrated hydrochloric acid, and extracted with ethyl acetate.
  • the organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (13.44 g).
  • the title compound (19.21 g) was obtained from isodipecotic acid (lO.Og) in the same manner as in Reference Example 44. However, a mixed solvent of 1,4-dioxane and water was used instead of a mixed solvent of N, N-dimethylformamide, 1,4-dioxane and water.
  • Reference Examples 56 and 57 can be produced by the method described in the specification of WO 93/00332.
  • Benzyl (3,3-getyl-2-oxoazetidine-141-yloxy) acetate (1.43 g) was dissolved in tetrahydrofuran (20 ml), and the solution was dissolved in an argon atmosphere at 160. After cooling to C, 1N lithium hexamethyldisilazide tetrahydrofuran solution (5.84 ml) was added, and the mixture was stirred at the same temperature for 15 minutes. Then, a solution of difuenylacetyl chloride (1.54 g) in tetrahydrofuran (5 ml) was added, and the mixture was stirred at the same temperature for 15 minutes and at 0'C for 30 minutes.
  • Difluorocarboxylic acid (5.43 g) was dissolved in N, N-dimethylformamide (30 ml), triethylamine (3.57 ml) and diphenylphosphoryl azide (5.52 ml) were added, and the mixture was heated at room temperature for 2 hours. The mixture was stirred at 50'C for 1.5 hours. Then base Njiru (3, 3 Jechi Lou 2- Okisoazechijin one 4 one Iruokishi) acetate (2.91 g), added sequentially catalytic amount of 4-dimethyl ⁇ amino pyridine and Toriechiruamin (3.82 ml), at 5 0 e C Stirred for 1 hour at room temperature overnight.
  • the tert-butyl (3,3-getyl-2-oxazetidine-4-yloxy) acetate (2.65 g) obtained in Reference Example 6 was dissolved in tetrahydrofuran (100 ml), and triethylamine (5.74 ml) was added. After cooling on ice, bistrichloromethyl carbonate (1.02 g) and 4-dimethylaminopyridine (377 mg) were added, and the mixture was stirred at room temperature for 40 minutes. Next, the reaction solution was cooled with ice, and the diphene obtained in Reference Example 39 was obtained. Lucetylhydrazine (1.17 g) was added, and the mixture was stirred at room temperature for 2 hours.
  • Example 1 [11- (N-diphenylacetyl-N-methylamino) acetyl-3,3-diethyl-2-oxoazetidine-14-yloxy] ⁇ acid
  • Reference Example 50 tert-butyl [111- (N-diphenylacetyl-N-ethylamino) acetyl-3,3-dimethyl-2-oxoazetidine-14-yloxy] acetate (790 mg) obtained in Reference Example 50 was added to chloroform (1.5 mg). acetic acid (3 ml), and the mixture was stirred at 0 for 30 minutes and at room temperature for 1 hour. After the reaction, The liquid was concentrated under reduced pressure to give the title compound (707 mg) as a white amorphous solid.
  • Example 5 6 'NMR of the sodium salt of Example 23 (300 MHz.dpprn.CDC) 80-0.99 (9H.m) .1.13-1.33 (8H.m) .1.45-1.8K6H, m), 3.33 (2H.t).
  • Example 58 ' ⁇ NMR of 8 (the sodium salt of Example 27) (300 MHz, (Jppm.CDCh) 79-0.98 (6H, m), 1.48-1.98 (8H.m), 3.29-3.78 (3H, m) 4.00-4.05 (1H, broad s), 95 (0.5H.s) .5.03 (0.5H, s). 5.17 (0.5H, s) .5.3K0.5H.s). 5.76C1H.broad s). 03-7.38 (11H.m)
  • Example 60 sodium salt of Example 29 (300 MHz. ⁇ .CDCh) 80-0.88 (3 ⁇ .m) .0.93-0.99 (3H, m), 1.42-1.95 (8H, m), 3.28 ( 1H. Broad s).
  • Example 61 NMR (300 °, ⁇ .CDCU) 79-0.98 (6 °, m). 1.48-1.98C8H, m), 3.29-3.78 (3H.m) of the sodium salt of Example 30. -4.05 (1H.broad s), 95 (0.5H.s) .5.03 (0.5H.s). 5.17 (0.5H, s) .5.31 (0.5H.s), 5.76 (1H.broad s). 0 ⁇ ⁇
  • Example 1 [1- (N-diphenylacetyl-N-methylamino) acetyl] —3,3-diethyl-2-oxoazetidine-14-yloquine] obtained in Example 1 was converted to N, N-dimethyl After dissolving in formamide (4 ml) and cooling on ice, add N-methylpiperazine (78 ⁇ 1), then add WSC-HC1 (136 rag) and 1-hydroquinbezotriazole (96 mg) and cool to ice. The mixture was stirred for 19 hours under cooling to room temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate.
  • Example 7 1 to 18 (9th step) By performing the same method as in Example 70, the compounds of Examples 71 to 185 were obtained. The results are shown in Tables 19 to 38.
  • Example 7NR of Example 7 1 (300 MHz, (5 ppm.CDCh) 0.95-1.06C6H, m), 1.68-1.93 (4H, m), 2.26 (6H, s), 2.42-2.46 (2H.m). 3H, s), 3.06 (3H, s), 3.20-3.53 (2H, m), 4.30-4.81 (4H.m). 5.16 (lH.s). 5.29 (lH, s),

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne des composés de diphénylméthyle-azétidinone représentés par la formule générale (I) ou des sels pharmaceutiquement acceptables de ces composés, et des compositions médicinales, un inhibiteur de l'élastase et un agent anti-inflammatoire à base de ces composés. Dans ladite formule, R1 et R2 représentent alkyle ou alkylène; A représente un amino substitué; B1 représente -CO- ou -CONH-; B2 représente une liaison unique ou -CO-; et D représente une liaison unique ou alkylamino. Les composés de la formule (I) ont un effet inhibiteur de l'élastase et sont utiles en tant qu'agent anti-inflammatoire.
PCT/JP1996/000743 1995-03-23 1996-03-21 Composes de diphenylmethyle-azetidinone et inhibiteur d'elastase WO1996029307A1 (fr)

Priority Applications (1)

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JP9126495 1995-03-23
JP7/91264 1995-03-23
JP8/30003 1996-01-23
JP3000396 1996-01-23

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997021675A1 (fr) * 1995-12-08 1997-06-19 Smithkline Beecham Plc Derives de beta-lactame monocycliques utilises dans le traitement de l'atherosclerose
WO1997041098A1 (fr) * 1996-04-26 1997-11-06 Smithkline Beecham Plc Derives azetidinones destines au traitement de l'atherosclerose
US6673829B2 (en) 2001-09-14 2004-01-06 Novo Nordisk A/S Aminoazetidine,-pyrrolidine and -piperidine derivatives
JP2005538060A (ja) * 2002-06-12 2005-12-15 ケモセントリックス， インコーポレイテッド 抗炎症性組成物および使用の方法
US7767695B2 (en) 2001-09-14 2010-08-03 High Point Pharmaceuticals, Llc Substituted piperidines

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH026471A (ja) * 1988-04-11 1990-01-10 Merck & Co Inc 抗炎症及び抗変性剤としての新規置換アゼチジノン類
JPH05132458A (ja) * 1990-10-15 1993-05-28 Merck & Co Inc 抗炎症及び抗変性剤としての新規な置換アゼチジノン類
JPH06263723A (ja) * 1992-10-27 1994-09-20 Merck & Co Inc 抗炎症剤及び抗変性剤としての新規置換アゼチジノン類
JPH06329625A (ja) * 1991-06-25 1994-11-29 Merck & Co Inc 抗炎症薬及び抗変性薬として有用な新規な置換アゼチジノン
JPH07242624A (ja) * 1994-02-28 1995-09-19 Japan Tobacco Inc 新規なアゼチジノン誘導体

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH026471A (ja) * 1988-04-11 1990-01-10 Merck & Co Inc 抗炎症及び抗変性剤としての新規置換アゼチジノン類
JPH05132458A (ja) * 1990-10-15 1993-05-28 Merck & Co Inc 抗炎症及び抗変性剤としての新規な置換アゼチジノン類
JPH06329625A (ja) * 1991-06-25 1994-11-29 Merck & Co Inc 抗炎症薬及び抗変性薬として有用な新規な置換アゼチジノン
JPH06263723A (ja) * 1992-10-27 1994-09-20 Merck & Co Inc 抗炎症剤及び抗変性剤としての新規置換アゼチジノン類
JPH07242624A (ja) * 1994-02-28 1995-09-19 Japan Tobacco Inc 新規なアゼチジノン誘導体

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997021675A1 (fr) * 1995-12-08 1997-06-19 Smithkline Beecham Plc Derives de beta-lactame monocycliques utilises dans le traitement de l'atherosclerose
WO1997041098A1 (fr) * 1996-04-26 1997-11-06 Smithkline Beecham Plc Derives azetidinones destines au traitement de l'atherosclerose
US6673829B2 (en) 2001-09-14 2004-01-06 Novo Nordisk A/S Aminoazetidine,-pyrrolidine and -piperidine derivatives
US7767695B2 (en) 2001-09-14 2010-08-03 High Point Pharmaceuticals, Llc Substituted piperidines
JP2005538060A (ja) * 2002-06-12 2005-12-15 ケモセントリックス， インコーポレイテッド 抗炎症性組成物および使用の方法

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