WO1995035298A1 - DERIVE DE PYRAZOLO[1,5-a]PYRIMIDINE - Google Patents
DERIVE DE PYRAZOLO[1,5-a]PYRIMIDINE Download PDFInfo
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- WO1995035298A1 WO1995035298A1 PCT/JP1995/001104 JP9501104W WO9535298A1 WO 1995035298 A1 WO1995035298 A1 WO 1995035298A1 JP 9501104 W JP9501104 W JP 9501104W WO 9535298 A1 WO9535298 A1 WO 9535298A1
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- lower alkyl
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- pyrimidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
Definitions
- the present invention relates to a novel pyrazo port [1,5-a] pyrimidine derivative.
- the pyrazo [1,5-a] pyrimidine derivative of the present invention is a novel compound which has not been published in any literature.
- An object of the present invention is to provide a compound useful as a pharmaceutical as described below.
- R 1 is a hydrogen atom, a lower alkyl group which may have a phenyl group, a lower alkoxy group, a lower alkylthio group, an oxo group or a hydroxy group as a substituent;
- Loalkyl ⁇ , Chenil, Frill R 2 is a naphthyl group; a lower alkenyl group or a phenyl group which may have 1 to 3 groups selected from a lower alkyl group, a lower alkoxy group, a phenylthio group and a halogen atom as a substituent;
- Examples of each group in the above general formula (1) include the following groups. That is, examples of the lower alkyl group include linear or branched lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl groups. .
- cycloalkyl group examples include cyclopropyl, cyclobutynole, cyclopentinole, cyclohexynole, cycloheptyl, cyclooctyl and the like.
- Examples of the lower alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy-hexyloxy and the like.
- Examples of the lower alkylthio group include a methylthio, ethylthio, propylthio, butylthio, pentylthio, and hexylthio group.
- Halogen atoms include fluorine, chlorine, bromine and iodine atoms.
- halogen-substituted lower alkyl group examples include trifluoromethyl, pentafluoroethyl, and heptafluoropropyl. Hexyl, nonafluorobutyl, pendecafluoropentyl, tridecafluorohexyl and the like.
- halogen-substituted lower alkoxy group examples include trifluoromethoxy, pentaphenylenoethoxy, heptanefluoropropoxy, nonafluorobutoxy, pendecafluoropentyloxy, tridecafluorohexyloxy and the like.
- Examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl group.
- di-lower alkoxyphosphoryl lower alkyl group examples include dimethoxyphosphorylmethyl, ethoxyphosphorylmethyl, dipropoxyphosphorylmethyl, diisopropoxyphosphorinolemethyl, dibutoxyphosphorylmethyl, and dipentoxyloxy.
- Examples include phosphorylmethyl, dihexyloxyphosphorinolemethyl, 2_ (dimethoxyphosphorinole) ethyl, and 2— (diethoxyphosphorinole) ethyl, and 3— (jetoxyphosphoryl) propyl. .
- the naphthyl group includes 1-naphthyl and 2-naphthyl groups.
- Lower alkylene groups include methylene, ethylene,
- Examples of the lower alkenylene group include a vinylene group and a propenylene group.
- Examples of the pyridyl group that may be substituted with a halogen atom include 2—pyridyl, 3—pyridyl, 4-1pyridyl, 61-cyclo mouth, 1 _2_pyridyl, and 5—cyclo mouth.
- Phenoxy groups that may be substituted with a halogen atom include phenoxy, 2-chlorophenoxy, 3-chlorophenoxy, and 4-chlorophenyl. Examples thereof include enoxy, 4-phenolenooxy, 4-bromophenoxy, 4-hydroxyenoxy, and the like.
- the phenyl group includes a 2-phenyl and a 3-phenyl group
- the furyl group includes a 2-furyl and a 3-furyl group.
- lower alkenyl groups include vinyl, aryl, isopropeninole, 1-buteninole, 2-buteninole, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, and 1-pentenyl.
- Hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like can be exemplified.
- phenyl-lower alkyl group examples include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylinolebutyl, 5-phenylenopentyl, and 6-phenylhexyl. it can.
- Phenyl lower alkoxy groups include benzyloxy
- Examples thereof include 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, and 6-phenylhexyloxy.
- Examples of the lower alkanoyloxy group include an acetoxyl group, a pionyloxy group, a butyryloxy group, a pa, a relyloxy group, a vivaloyloxy group, a hexanoyloxy group, and a heptanyloxy group.
- lower alkyl group which may have a phenyl group, a lower alkoxy group, a lower alkylthio group, an oxo group or a hydroxyl group as a substituent
- Examples thereof include 5—honolemilpentyl, 5-oxohexyl, 4-oxohexyl, 3-oxohexyl, 2-oxohexyl, and hexanoyl group.
- phenyl group which may have 1 to 3 groups selected from a lower alkyl group, a lower alkoxy group, a phenylthio group and a halogen atom as a substituent include phenyl and 2-methylinophenyl.
- a phenyl group which may have from 1 to 3 groups selected from a group selected from the group consisting of a quinoleoxy group, an amino group, a cyano group, a lower alkanoyloxy group, a phenyl group and a di-lower alkoxyphosphoryl lower alkyl group.
- the following groups can be exemplified.
- phenyl group and the like can be exemplified.
- Examples of the benzoyl group having 1 to 3 groups selected from a lower alkoxy group, a halogen-substituted lower alkyl group, and a halogen atom as a substituent include 2—cyclobenzoyl and 3—cyclobenzoyl.
- the pyrazo [1: 5-a] pyrimidine derivative of the present invention represented by the above general formula (1) has a strong analgesic effect.
- an analgesic it is useful for relieving pain symptoms such as postoperative pain, migraine, gout, cancer pain, chronic pain, and neuropathic pain.
- the derivative does not have side effects that are common to conventional analgesics, does not cause hallucinations and confusion, and does not cause addiction or addiction.
- the pyrazo opening [1,5—a] pyrimidine derivative of the present invention which is preferable as the above-mentioned analgesic, is a compound in which Q is a carbonyl group and n is 0 in the aforementioned general formula (1).
- a carbonyl group wherein n is 1 and R 1 is a lower alkyl group or a phenyl group, and R 2 is one to three of a group selected from a lower alkoxy group and a halogen-substituted lower alkyl group as a substituent;
- R 2 is a phenyl group which may have 1 to 3 halogen atoms
- R 3 , R 4 , R 5 and R 6 are each selected from a hydrogen atom and a compound in which A represents a single bond.
- R 1 is a lower alkyl group which may have a lower alkylthio group as a substituent or a phenyl group which may have a phenylthio group as a substituent
- R 2 is a substituent
- R 5 is a hydrogen atom
- R 6 is a hydrogen atom or a benzoyl group having a halogen-substituted lower alkyl group as a substituent
- Q is a carbonyl group
- A is a single bond
- R 3 , R 4 and R 6 are each a hydrogen atom, n is 0, R 1 is an n-butyl group, and R 2 is a phenyl group having 2 to 3 lower alkoxy groups or A phenyl group having 1 to 2 halogen-substituted lower alkyl groups, or a compound wherein R 1 is a phenyl group and R 2 is a phenyl group having 3 lower alkoxy groups; and
- R 2 is a 2,4-dimethoxyphenyl group, 3,4,5—trimethoxyphenyl group, 2—trifluoromethylphenyl group, or 2,5—bis (trifluoromethyl) phenyl group Compound.
- pyrazo opening [1,5—a] pyrimidine derivative of the present invention include 5—n—butyl—7— (3,4,5—trimethoxybenzoinoleamido. No.) Pyrazo mouth [1,5—a] pyrimidine and 5—n—butynole 7— (2—trifluorometylbenzoylamino) pyrazo mouth [1,5 PGT / JP95 / 01104
- R 2 , R 3 , R 5 , n, Q and A are the same as above, R is a hydrogen atom, and a substituent is a phenyl group, a lower alkoxy group or a lower alkylthio group.
- R la may represent a lower alkylene group by combining with R 5, and R 4a may represent a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, An enyl lower alkyl group or a phenyl group which may have a phenylthio group as a substituent, X and Y each represent a halogen atom, and Z represents a lower alkyl group.
- the condensation reaction of the compound (2) with the compound (3) is carried out in a suitable inert solvent at a temperature ranging from room temperature to the boiling point of the solvent.
- suitable inert solvent examples include acetic acid, ethanol, benzene, toluene, xylene, tetrahydrofuran (THF) and the like.
- the proportion of compound (2) to compound (3) used is preferably about equimolar, and the reaction is completed in about 2 to 5 hours, and thus the desired compound is obtained.
- the subsequent halogenation reaction of compound (4) is carried out in the presence of a suitable deoxidizing agent, for example, N, N-dimethylylaniline, N, N-getylaniline, triethylamine, etc.
- a suitable deoxidizing agent for example, N, N-dimethylylaniline, N, N-getylaniline, triethylamine, etc.
- the reaction is carried out using an appropriate halogenating agent, such as phosphorus oxychloride or phosphorus oxybromide. Since the halogenating agent also functions as a solvent, it is not necessary to use a solvent in the reaction, but other inactive solvents such as benzene, toluene, and xylene can be used.
- the amount of the above-mentioned deoxidizing agent is usually about 1 to 10 times the amount of the compound (4), and the reaction is carried out at about 0.5 to about 150 ° C. at room temperature. It takes about 12 hours.
- the halide (5) obtained by the above reaction can be converted to the compound (6) by treating it with ammonia water or hydrazine. This treatment does not require a solvent, and usually the compound (5) is heated together with an excess amount of aqueous ammonia at about 100 to 150 ° C for about 1 to 12 hours, or This can be achieved by treating (5) with an excess amount of hydrazine at about 0 ° C to room temperature for about 5 to 30 hours.
- the compound (6) thus obtained can be converted into the compound (1) of the present invention by reacting it with the acid halide (7).
- This reaction can be carried out in a suitable solvent in the presence of a deoxidizing agent.
- the solvent include aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene, and petroleum ether, dimethyl ether, and dimethyl alcohol.
- Linear or cyclic ethers such as shetan, tetrahydrofuran (THF) and 1,4-dioxane; ketones such as acetone, ethylmethylketon, and acetophenonone; Examples include halogenated hydrocarbons such as dichloromethane, chloroform-form, carbon tetrachloride, and 1,2-dichloroethane.
- the deoxidizing agent include tertiary amines such as triethylamine, N, N-getylaniline, N-methylmorpholine, pyridine, and 4-methylaminopyridin.
- the amount of the acid halide (7) and the deoxidizer to be used for the compound (6) in the above reaction is not particularly limited, but the amount of the acid halide is usually about equimolar, deoxidant rather good to be about an equimolar amount to an excess molar amount, the reaction is completed in about 0.5 5 to about 2 0 hours under room temperature and the reflux temperature of the solvent (Incidentally, the compound (6 ) Is a compound wherein n is 0
- (6 ′) can also be produced by the method described in the following reaction step formula-1 ′.
- R 2 , R 3 , R 5 , X, Y, A, Q, Z and n are as defined above.
- ⁇ is a lower alkyl group having a protected oxo group
- ⁇ is a lower alkyl group having an oxo group
- ⁇ is a lower alkyl group having an acyloxy group
- ⁇ is a lower alkyl group having a tri-lower alkylsilyloxy group.
- R lb represents a hydroxy lower alkyl group
- R 4b represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, or a phenyl group which may have a phenylthio group as a substituent.
- the condensation reaction between the compound (8) and the compound (9) in the above reaction scheme 12 can be carried out in the same manner as the reaction between the compound (2) and the compound (3) in the above reaction scheme 11. You.
- examples of the lower alkyl group having a protected oxo group defined by ⁇ include, for example, dinoreacetol, methylthiolereacetanole, and jetinole.
- a lower alkyl group having a cyclic acetal residue such as ethylene acetal, trimethylene acetal, and tetramethylene acetal as the protected oxo group.
- the hydrolysis reaction of the compound (10) according to the above reaction scheme-2 can be carried out using an organic acid such as acetic acid, propionic acid, p-toluenesulfonic acid and the like.
- organic acids such as acetic acid, propionic acid, p-toluenesulfonic acid and the like.
- carboxylic acids such as acetic acid and propionic acid also serve as a solvent, and therefore, when such a solvent is used, it is not necessary to use another solvent.
- other suitable inert solvents such as benzene, toluene, xylene and the like can be used.
- the subsequent reduction reaction of compound (11) can be carried out using an appropriate reducing agent in an inert solvent.
- the reducing agent include sodium borohydride, potassium borohydride, lithium borohydride, sodium borohydride, sodium borohydride, and the like.
- Borohydride compounds, and lithium aluminum hydrides such as lithium aluminum hydride and tributoxy aluminum hydride.
- an alcohol-based solvent such as methanol or ethanol, or an alcohol-based solvent and dichloromethane or dimethyl ether are used. It is preferable to use a mixed solvent with, for example, lithium aluminum hydride as the reducing agent.
- ethers such as THF.
- the amount of the reducing agent used should be at least equal to that of compound (11). It is better to set the amount to about
- the reaction can be performed at a temperature of about 0 ° C. to about room temperature, and requires about 30 minutes to 3 hours.
- the acylation reaction of the compound (12) thus obtained is carried out without solvent or with pyridine, lutidine, N, N-dimethylformamide (DMF), N, N-dimethylacetamide.
- acylating agent for example, acid anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, hexanoic anhydride, and heptanoic anhydride can be used. These compounds can be used usually in 1 to 10 equivalents to the compound (12).
- the reaction conditions are preferably appropriately selected from a temperature of about 0 ° C. to room temperature and a time of about 30 minutes to about 2 hours so that the hydroxyl group at the 7-position of the compound (12) is not acylated. No.
- the halogenation reaction of the compound (13) obtained above can be carried out in the same manner as in the halogenation reaction of the compound (4) in the reaction step formula 11.
- the conversion reaction of the obtained compound (14) into the compound (15) can be carried out under the same conditions as in the conversion reaction of the compound (5) into the compound (6) in the reaction process formula-1. .
- the lower alkyl group having an acyloxy group defined by ⁇ in the compound (14) It is decomposed and converted to a hydroxy lower alkyl group.
- the silylation reaction of the compound (15) obtained above can be carried out using a trialkylsilane halide in a suitable inert solvent such as THF or dichloromethane in the presence of a deoxidizing agent.
- a deoxidizing agent include sodium carbonate, potassium carbonate, triethylamine, N, N-dimethylaminopyridin and the like.
- the trialkylsilane halide include, for example, trimethylsilyl chloride, triethylsilyl chloride, tripropylsilan chloride, triptylsilyl chloride, and butylethylsilyl chloride. These compounds can be used generally in an equimolar amount to an excess molar amount with respect to the compound (15), and the reaction is completed in about 5 to 30 hours under a temperature condition near room temperature.
- the desired compound (lb) of the present invention can be obtained by reacting the compound (16) obtained above with an acid halide (7).
- This reaction can also be carried out in the same manner as the reaction using the acid halide (7) in Reaction Scheme 11.
- the substituent ⁇ at the 5-position of the compound (16) can be easily converted into the corresponding R lb group (hydroxy lower alkyl group) during this reaction and by hydrolysis treatment thereafter. (Reaction process formula 1 3)
- R 2 , R 3 , R ′′, R 5 , X, Y, Z, Q, A, n and ⁇ ⁇ are the same as above.
- R represents a lower alkyl group having an oxo group.
- reaction of the compound (17) with the nitrile derivative (18) is carried out in an inert solvent such as DMF, DMA, dimethyl sulfoxide (DMSO), and the like.
- the reaction can be carried out in the presence of a base such as potassium hydride.
- Amount of trinyl derivative (18) and base used is usually carried out in an amount of 1 to excess equivalent to the compound (17), respectively, and the reaction is carried out at a temperature of 0 ° C. to near room temperature for 2 to 10 hours.
- the condensation reaction between the compound (2 ⁇ ) and the compound (3) can be carried out in the same manner as in the reaction in the reaction scheme 1 ′.
- C The hydrolysis reaction of the compound (19) is carried out in the reaction scheme It can be carried out in the same manner as in the same reaction in 1-2.
- reaction of compound (20) with compound (7) can be carried out in the same manner as in the reaction step formula 11.
- the halogenation reaction can be carried out according to a commonly used method.
- the compound (21) can be prepared without solvent or in an inert solvent such as culoform form and methyl ether.
- examples include a method of reacting with a halogenating agent such as thionyl chloride or thionyl bromide in a solvent.
- the halogenating agent is generally used in an excess amount, and the reaction can usually be carried out at a temperature of about room temperature to about 150 ° C. for about 0.5 to 5 hours. (Reaction process formula 1-5)
- R 2 , R 3 , R 5 , A and n are the same as above.
- R ld represents a hydrogen atom, a lower alkyl group which may have a lower alkoxy group or a lower alkylthio group as a substituent, a cycloalkyl group, a cyenyl group, a furyl group or a lower alkyl group as a substituent, A phenyl group which may have 1 to 3 groups selected from an alkoxy group, a phenylthio group and a halogen atom, and R ld and R 5 may be bonded to each other to form a lower alkylene group.
- R 4 e represents a halogen atom.
- the halogenation reaction of the compound (1d) shown in Reaction Scheme 15 can be carried out in an inert solvent such as benzene, carbon tetrachloride, or chloroform, by immobilizing N-bromosuccinic acid imide (NBS :), N — Using halogenating agents such as chlorosuccinic acid.imide (NCS) Can be implemented.
- NBS N-bromosuccinic acid imide
- NCS chlorosuccinic acid.imide
- the amount of the halogenating agent to be used is generally 1 equivalent to a small excess with respect to the compound (1d), and the reaction is carried out under a temperature condition of about room temperature to the reflux temperature of the solvent.
- R le is a hydrogen atom, a lower alkyl group which may have a phenyl group, a lower alkoxy group, a lower alkylthio group or an oxo group as a substituent, a cycloalkyl group, a chenyl group, a furyl group, a lower alkenyl group.
- a phenyl group which may have from 1 to 3 substituents selected from a lower alkyl group, a lower alkoxy group, a chlorodithio group and a halogen atom; and R le and R 5 May combine with each other to form a lower alkylene group, and R 2a represents a naphthyl group, a cycloalkyl group, a furyl group, a phenyl group, a pyridyl group which may be substituted with a halogen atom, Substituted with a halogen atom Phenoxy groups or substituents that may be present include lower alkyl groups, lower alkoxy groups, halogen atoms, nitro groups, halogen-substituted lower alkyl groups, halogen-substituted lower alkoxy groups, lower alkoxycarbonyl groups, and phenyl lower groups.
- R 6 a is phenyl lower alkyl
- a benzoyl group having 1 to 3 groups selected from a lower alkoxy group, a halogen-substituted lower alkyl group and a halogen atom as a group or a substituent is shown.
- compound (1 g) can be obtained by reacting compound (1f) with compound (22) in an inert solvent in the presence of a base.
- a base if R 6 a is a phenyl-lower alkyl group, in the above inert solvent medium, DMF, DMA. Is the DMSO and the like, also with bases, hydrogen Kana Application Benefits um, hydrogenated Examples thereof include calcium.
- R "is a benzoyl group having 1 to 3 groups selected from a lower alkoxy group, a halogen-substituted lower alkyl group and a halogen atom as a substituent the inert solvent may be chloro.
- Mouth form, dichloromethan, etc., as bases, triethylamine, N, N-dimethy Luaniline and the like can be exemplified.
- the amount of compound (22) to be used is generally 1 to a small excess, and the amount of the base used is preferably 1 to an excess.
- the reaction is carried out at a temperature of about 0 ° C. to about room temperature for 3 to 30 hours.
- R la , R 2 , R 3 , R 48 , R 5 , X, Y, Q and A are as defined above.
- R 6b represents a lower alkyl group or a phenyl lower alkyl group.
- the reaction of the compound (5) with the compound (23) in the reaction scheme 17 is carried out in an inert solvent such as methanol or ethanol in a sodium hydrogencarbonate, sodium carbonate, calcium carbonate solution.
- an inert solvent such as methanol or ethanol in a sodium hydrogencarbonate, sodium carbonate, calcium carbonate solution.
- R le , R 3 , R 4 ⁇ R 5 and Y are the same as described above.
- R 2 b is lower alkoxy groups as a substituent, a phenylalanine group with 1 to 3 groups selected from halogen atoms ⁇ beauty halogen-substituted lower alkyl group
- R 6 e is lower alkoxy as a substituent
- the compound of the present invention can be a pharmaceutically acceptable acid addition salt, and these salts are also included in the compound of the present invention.
- the acids capable of forming the above-mentioned acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, tartaric acid, and citric acid.
- the reaction for forming the acid addition salt can be carried out according to a conventional method.
- the target compound obtained by each of the above steps can be easily isolated by ordinary separation and purification means.c
- the isolation means may be any of various commonly used means. Either can be used, for example, adsorption chromatography, preha. Examples thereof include thin-layer thin-layer chromatography, recrystallization, and solvent extraction.
- some of the compounds represented by the general formula (1) of the present invention have optical isomers having a carbon atom as an asymmetric center, and the present invention relates to both optically active isomers and racemic isomers. People.
- the compound of the present invention is generally used in the form of a general pharmaceutical composition using a suitable nontoxic pharmaceutical carrier, and the present invention also provides such a pharmaceutical composition, particularly an analgesic.
- the above-mentioned pharmaceutical carriers used in the pharmaceutical preparation of the present invention include, as fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants, which are usually used depending on the use form of the preparation.
- diluents or excipients such as preparations can be exemplified, and these are appropriately selected and used depending on the dosage unit form of the obtained preparation.
- various forms can be selected according to the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, turnips Cell preparations, suppositories, injections (solutions, suspensions, etc.), ointments and the like can be mentioned.
- the above-mentioned pharmaceutical carriers include, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, gay acid, and phosphorus.
- Excipients such as acid potassium, water, ethanol, propanol, simple syrup, sugar solution of sugar, starch solution, gelatin solution, phenolic nitrocellulose, hydroxypropyl pircenorelose, methinoresenorrero , Polyvinyl Binders such as pyrrolidone, sodium carboxymethylcellulose, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, dried starch, sodium alginate, powdered agar, powdered laminar powder, Disintegrators such as sodium hydrogen carbonate and calcium carbonate; surfactants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate and monoglyceride stearate; Disintegration inhibitors such as sucrose,
- pharmaceutical carriers such as glucose, lactose, starch, cocoa butter, and hydrogenated vegetable oils; excipients such as kaolin and talc; arabic gum powder, tragacanth powder; Binders such as gelatin and ethanol, and disintegrants such as lamina lanthanum can be used.
- pharmaceutical carriers such as glucose, lactose, starch, cocoa butter, and hydrogenated vegetable oils
- excipients such as kaolin and talc
- arabic gum powder such as tragacanth powder
- Binders such as gelatin and ethanol, and disintegrants such as lamina lanthanum
- disintegrants such as lamina lanthanum
- Capsules are usually prepared by mixing the active ingredient compound of the present invention with the various pharmaceutical carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like according to a conventional method.
- a liquid, emulsion, or suspension When prepared as an injection, such as a liquid, emulsion, or suspension, it is preferable that these are sterilized and are isotonic with blood, and when formed into such a form, they are used as diluents.
- diluents For example, water, ethynoleanol, macro gonorre, propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene disosteryl alcohol, polyoxyethylene sorbitan fatty acid ester Can be used.
- a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the drug of the present invention, and a usual solubilizing agent, buffer, etc. Agents, soothing agents and the like may be added.
- the drug of the present invention may contain a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent, and the like, and other pharmaceuticals, if necessary.
- Mold into an ointment such as paste, cream, gel, etc.
- white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite, etc. can be used as a diluent.
- the amount of the active ingredient compound of the present invention represented by the general formula (1) to be contained in the drug of the present invention is not particularly limited and may be appropriately selected from a wide range, but is usually about 1 to 70 in a pharmaceutical preparation. It is preferred that the content be about 10% by weight.
- the administration method of the above pharmaceutical preparation is not particularly limited, and is determined according to various preparation forms, patient age, gender and other conditions, degree of disease, and the like.
- tablets, pills, solutions, suspensions, emulsions, granules, and capsules are administered orally, and injections are administered intravenously either alone or as a mixture with normal replenishers such as glucose and amino acids.
- injections are administered intravenously either alone or as a mixture with normal replenishers such as glucose and amino acids.
- the dosage of c above pharmaceutical preparations suppositories are administered rectally, the usage, the age of the patient, gender and other
- the amount of the compound of the present invention, which is usually the active ingredient is preferably about 0.5 to 20 mg per 1 kg of body weight per day.
- the drug can be administered 1 to 4 times daily.
- Table 1 Each compound shown in Table 1 was obtained in the same manner as in Example 1. Table 1 shows the structure and melting point of each compound obtained. Note that 1 H-NMR spectrum data is shown for the oil.
- Example 101 Example 101 and Example 102
- Example 104 to Example 106
- Example 1 In the same manner as in Example 1, each compound shown in Table 4 was obtained. Table 4 shows the structure and melting point of each compound obtained. Example 1 2 9
- the target compound was obtained in the same manner as in Example 1 using the obtained crystals and 3,4,5-trimethoxybenzoyl chloride.
- Table 5 shows the structure and melting point of the obtained compound.
- Example 1 In the same manner as in Example 12 29, the compounds shown in Table 5 were obtained. Table 5 also shows the structure and melting point of the obtained compound. Example 1 3 1
- Table 5 also shows the structure and melting point of the obtained compound.
- Example 23 the previous fraction of silica gel column chromatography was purified again by silica gel column chromatography (eluate: dichloromethane), and further recrystallized. Colorless crystals of the compound were obtained. Table 5 also shows the structure and melting point of the obtained compound.
- each compound shown in Table 5 was obtained from the preceding fraction of silica gel column chromatography in Examples 32 and 52.
- Table 5 shows the structure and melting point of each compound obtained.
- M e methyl group
- E t ethyl group
- n Pr n-propyl group
- Mouth (Jetil ⁇ 1 ter 1 n — hexane)
- Mouth ethyl acetate n-hexane T / P95 / 01104
- M e methyl group
- E t ethyl group
- n Pr n-propyl group
- nBu n-butyl group
- tBu t-butyl group
- nPe n-pentyl group
- the pain threshold of the left hind paw of each rat was measured using a pressure-stimulated analgesic effect measuring device (manufactured by Unicom) using seven 6-week-old male male rats per group.
- Celit method [Randall, L.0. And Sellitto, JJ, Arch. Int.
- the pain threshold of hind limb ⁇ was measured in the same manner as above, and this was defined as “post-value”.
- the pain threshold recovery rate (%) was calculated from the measured value (after value) and the before value of each group according to the following formula.
- the pain threshold of the left hind paw of each rat was measured using a pressure-stimulated analgesic effect measuring device (manufactured by Unicom) using seven 6-week-old male Wistar rats per group. Tut method C Randall, L.0. And Sellitto, JJ, Arch. Int. Pharmacodyn .. Ill, 409 (1957)). The obtained value is referred to as “previous value”.
- the experimental group further received a 5% arabic gum suspension of the compound of the present invention, and the control group received a 5% arabic gum suspension (not containing the compound of the present invention).
- Oral administration was performed so that the dose would be 1 mg Z kg, and 1 hour after that, a physiological saline solution of substance P (25 ng Z 0. Lm) was injected subcutaneously into the left hind paw of each rat.
- a physiological saline solution of substance P 25 ng Z 0. Lm
- the pain threshold value of the left hind paw of each rat group was measured in the same manner as described above, and this was defined as “post-value”.
- the pain threshold recovery rate (%) was calculated from the measured value (after value) and the before value of each group according to the following formula.
- tablets 2000 tablets containing 300 mg per tablet were prepared according to the following formulation.
- Example 1 Compound of the present invention obtained in Example 1 600 g Lactose (Japanese Pharmacopoeia product) 67 g Corn starch (Japanese Pharmacopoeia product) 33 g Carboxymethylcellulose calcium (Japanese Pharmacopoeia product)
- Tin capsules 2000 tablets were prepared according to the following formulation.
- Example 32 Compound of the present invention obtained in Example 32 400 g Microcrystalline cellulose (Japanese Pharmacopoeia) 60 g Corn starch (Japanese Pharmacopoeia) 34 g Talc (Japanese Pharmacopoeia) 4 g Magnesium stearate (Japanese Pharmacopoeia product) 2 g That is, according to the above-mentioned prescription, each component is finely powdered, mixed to form a uniform mixture, and then filled into a gelatin capsule for oral administration having desired dimensions. The desired capsule was obtained.
- the pyrazo [1,5-a] pyrimidine derivative according to the present invention has a strong analgesic action and is useful as an analgesic.
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Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95920260A EP0714898B1 (en) | 1994-06-21 | 1995-06-05 | PYRAZOLO [1,5-a]PYRIMIDINE DERIVATIVE |
KR1019960700854A KR100315837B1 (ko) | 1994-06-21 | 1995-06-05 | 피라졸로[1,5-a]피리미딘유도체 |
US08/602,824 US5707997A (en) | 1994-06-21 | 1995-06-05 | Pyrazolo 1,5-a!pyrimidine derivative |
DK95920260T DK0714898T3 (da) | 1994-06-21 | 1995-06-05 | Pyrazolo[1,5-a]primidinderivat |
AU25765/95A AU680370B2 (en) | 1994-06-21 | 1995-06-05 | Pyrazolo(1,5-a)pyrimidine derivative |
CA002169719A CA2169719C (en) | 1994-06-21 | 1995-06-05 | Pyrazolo[1,5-a]pyrimidine derivative |
AT95920260T ATE208776T1 (de) | 1994-06-21 | 1995-06-05 | Pyrazolo(1,5-a) pyrimidin-derivate |
DE69523864T DE69523864T2 (de) | 1994-06-21 | 1995-06-05 | PYRAZOLO[1,5-a] PYRIMIDIN-DERIVATE |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP13863594 | 1994-06-21 | ||
JP6/138635 | 1994-06-21 | ||
JP7/53997 | 1995-03-14 | ||
JP5399795 | 1995-03-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995035298A1 true WO1995035298A1 (fr) | 1995-12-28 |
Family
ID=26394734
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1995/001104 WO1995035298A1 (fr) | 1994-06-21 | 1995-06-05 | DERIVE DE PYRAZOLO[1,5-a]PYRIMIDINE |
Country Status (13)
Country | Link |
---|---|
US (1) | US5707997A (ja) |
EP (1) | EP0714898B1 (ja) |
KR (1) | KR100315837B1 (ja) |
CN (1) | CN1046730C (ja) |
AT (1) | ATE208776T1 (ja) |
AU (1) | AU680370B2 (ja) |
CA (1) | CA2169719C (ja) |
DE (1) | DE69523864T2 (ja) |
DK (1) | DK0714898T3 (ja) |
ES (1) | ES2164153T3 (ja) |
PT (1) | PT714898E (ja) |
TW (1) | TW307767B (ja) |
WO (1) | WO1995035298A1 (ja) |
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US6060478A (en) * | 1996-07-24 | 2000-05-09 | Dupont Pharmaceuticals | Azolo triazines and pyrimidines |
US6124289A (en) * | 1996-07-24 | 2000-09-26 | Dupont Pharmaceuticals Co. | Azolo triazines and pyrimidines |
US6191131B1 (en) | 1997-07-23 | 2001-02-20 | Dupont Pharmaceuticals Company | Azolo triazines and pyrimidines |
US6313124B1 (en) | 1997-07-23 | 2001-11-06 | Dupont Pharmaceuticals Company | Tetrazine bicyclic compounds |
US6630476B2 (en) | 2000-07-07 | 2003-10-07 | Bristol-Myers Squibb Pharma Company | Pyrrolo [3,4-d] pyrimidines as corticotropin releasing factor (CRF) antagonists |
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US6958341B2 (en) | 1999-04-06 | 2005-10-25 | Bristol-Myers Squibb Pharma Company | Pyrazolopyrimidines as CRF antagonists |
US6960583B2 (en) | 1999-04-06 | 2005-11-01 | Bristol-Myers Squibb Company | Pyrazolotriazines as CRF antagonists |
WO2006044958A1 (en) | 2004-10-19 | 2006-04-27 | Sb Pharmco Puerto Rico Inc. | Pyrazolo [1,5-alpha] pyrimidinyl derivatives useful as corticotropin-releasing factor (crf) receptor antagonists |
US7067661B2 (en) | 2002-09-04 | 2006-06-27 | Schering Corporation | Pyrazolopyrimidines as cyclin dependent kinase inhibitors |
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1995
- 1995-06-05 AU AU25765/95A patent/AU680370B2/en not_active Ceased
- 1995-06-05 WO PCT/JP1995/001104 patent/WO1995035298A1/ja active IP Right Grant
- 1995-06-05 DK DK95920260T patent/DK0714898T3/da active
- 1995-06-05 CA CA002169719A patent/CA2169719C/en not_active Expired - Fee Related
- 1995-06-05 ES ES95920260T patent/ES2164153T3/es not_active Expired - Lifetime
- 1995-06-05 KR KR1019960700854A patent/KR100315837B1/ko not_active IP Right Cessation
- 1995-06-05 DE DE69523864T patent/DE69523864T2/de not_active Expired - Fee Related
- 1995-06-05 CN CN95190760A patent/CN1046730C/zh not_active Expired - Fee Related
- 1995-06-05 US US08/602,824 patent/US5707997A/en not_active Expired - Lifetime
- 1995-06-05 AT AT95920260T patent/ATE208776T1/de not_active IP Right Cessation
- 1995-06-05 PT PT95920260T patent/PT714898E/pt unknown
- 1995-06-05 EP EP95920260A patent/EP0714898B1/en not_active Expired - Lifetime
- 1995-06-16 TW TW084106201A patent/TW307767B/zh active
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JPS4864097A (ja) * | 1971-12-09 | 1973-09-05 | ||
JPS6157587A (ja) * | 1984-08-29 | 1986-03-24 | Shionogi & Co Ltd | 縮合複素環誘導体および抗潰瘍剤 |
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Cited By (36)
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US7678793B2 (en) | 1996-07-24 | 2010-03-16 | Bristol-Myers Squibb Pharma Company | Azolo triazines and pyrimidines |
US6124289A (en) * | 1996-07-24 | 2000-09-26 | Dupont Pharmaceuticals Co. | Azolo triazines and pyrimidines |
US6136809A (en) * | 1996-07-24 | 2000-10-24 | Dupont Pharmaceuticals | Azolo triazines and pyrimidines |
US6358950B1 (en) | 1996-07-24 | 2002-03-19 | Bristol-Myers Squibb Pharma Company | Azolo triazines and pyrimidines |
US6060478A (en) * | 1996-07-24 | 2000-05-09 | Dupont Pharmaceuticals | Azolo triazines and pyrimidines |
US6191131B1 (en) | 1997-07-23 | 2001-02-20 | Dupont Pharmaceuticals Company | Azolo triazines and pyrimidines |
US6313124B1 (en) | 1997-07-23 | 2001-11-06 | Dupont Pharmaceuticals Company | Tetrazine bicyclic compounds |
US6958341B2 (en) | 1999-04-06 | 2005-10-25 | Bristol-Myers Squibb Pharma Company | Pyrazolopyrimidines as CRF antagonists |
US6960583B2 (en) | 1999-04-06 | 2005-11-01 | Bristol-Myers Squibb Company | Pyrazolotriazines as CRF antagonists |
US7026317B2 (en) | 1999-04-06 | 2006-04-11 | Bristol-Myers Squibb Pharma Company | Pyrazolotriazines as CRF antagonists |
US6734185B2 (en) | 2000-07-07 | 2004-05-11 | Bristol-Myers Squibb Pharma Company | Pyrrolo[3,4-d]pyrimidines as corticotropin releasing factor (CRF) antagonists |
US6630476B2 (en) | 2000-07-07 | 2003-10-07 | Bristol-Myers Squibb Pharma Company | Pyrrolo [3,4-d] pyrimidines as corticotropin releasing factor (CRF) antagonists |
US7390908B2 (en) | 2001-08-17 | 2008-06-24 | Astrazeneca Ab | Compounds effecting glucokinase |
US7161003B1 (en) | 2002-09-04 | 2007-01-09 | Schering Corporation | Pyrazolopyrimidines as cyclin dependent kinase inhibitors |
US7468372B2 (en) | 2002-09-04 | 2008-12-23 | Schering Corporation | Trisubstituted 4-aminopyrazolopyrimidines as cyclin dependent kinase inhibitors |
US7078525B2 (en) | 2002-09-04 | 2006-07-18 | Schering Corporation | Pyrazolopyrimidines as cyclin dependent kinase inhibitors |
US7084271B2 (en) | 2002-09-04 | 2006-08-01 | Schering Corporation | Pyrazolopyrimidines as cyclin dependent kinase inhibitors |
US7119200B2 (en) | 2002-09-04 | 2006-10-10 | Schering Corporation | Pyrazolopyrimidines as cyclin dependent kinase inhibitors |
US7067661B2 (en) | 2002-09-04 | 2006-06-27 | Schering Corporation | Pyrazolopyrimidines as cyclin dependent kinase inhibitors |
US7196078B2 (en) | 2002-09-04 | 2007-03-27 | Schering Corpoartion | Trisubstituted and tetrasubstituted pyrazolopyrimidines as cyclin dependent kinase inhibitors |
US8673924B2 (en) | 2002-09-04 | 2014-03-18 | Merck Sharp & Dohme Corp. | Substituted pyrazolo[1,5-a]pyrimidines as cyclin dependent kinase inhibitors |
US7205308B2 (en) | 2002-09-04 | 2007-04-17 | Schering Corporation | Trisubstituted 7-aminopyrazolopyrimidines as cyclin dependent kinase inhibitors |
US7309705B2 (en) | 2002-09-04 | 2007-12-18 | Schering Corporation | Pyrazolopyrimidines as cyclin dependent kinase inhibitors |
US8586576B2 (en) | 2002-09-04 | 2013-11-19 | Merck Sharp & Dohme Corp. | Substituted pyrazolo[1,5-a]pyrimidines as cyclin dependent kinase inhibitors |
US7074924B2 (en) | 2002-09-04 | 2006-07-11 | Schering Corporation | Pyrazolopyrimidines as cyclin dependent kinase inhibitors |
US7470695B2 (en) | 2002-09-04 | 2008-12-30 | Schering Corporation | N-heteroaryl pyrazolopyrimidines as cyclin dependent kinase inhibitors |
US7511049B2 (en) | 2002-09-04 | 2009-03-31 | Schering Corporation | Pyrazolopyrimidines as cyclin dependent kinase inhibitors |
US7514442B2 (en) | 2002-09-04 | 2009-04-07 | Schering Corporation | Trisubstituted 4-aminopyrazolopyrimidines as cyclin dependent kinase inhibitors |
WO2004022062A1 (en) | 2002-09-04 | 2004-03-18 | Schering Corporation | Pyrazolopyrimidines as cyclin dependent kinase inhibitors |
US8580782B2 (en) | 2002-09-04 | 2013-11-12 | Merck Sharp & Dohme Corp. | Substituted pyrazolo[1,5-a]pyrimidines as cyclin dependent kinase inhibitors |
EP2194058A1 (en) | 2002-09-04 | 2010-06-09 | Schering Corporation | Pyrazolopyrimidines suitable for the treatment of cancer diseases |
WO2006044958A1 (en) | 2004-10-19 | 2006-04-27 | Sb Pharmco Puerto Rico Inc. | Pyrazolo [1,5-alpha] pyrimidinyl derivatives useful as corticotropin-releasing factor (crf) receptor antagonists |
US7700773B2 (en) | 2005-09-09 | 2010-04-20 | Schering Corporation | 4-cyano, 4-amino, and 4-aminomethyl derivatives of pyrazolo[1,5-a]pyridines, pyrazolo[1,5-c]pyrimidines and 2H-indazole compounds and 5-cyano, 5-amino, and 5-aminomethyl derivatives of imidazo[1,2-a]pyridines, and imidazo[1,5-a]pyrazines as cyclin dependent kinase inhibitors |
WO2007041712A1 (en) | 2005-10-06 | 2007-04-12 | Schering Corporation | Pyrazolopyrimidines as protein kinase inhibitors |
US8071608B2 (en) | 2009-04-09 | 2011-12-06 | Astrazeneca Ab | Therapeutic agents |
US9969687B2 (en) | 2013-12-23 | 2018-05-15 | Norgine B.V. | Compounds useful as CCR9 modulators |
Also Published As
Publication number | Publication date |
---|---|
DK0714898T3 (da) | 2002-03-18 |
AU2576595A (en) | 1996-01-15 |
PT714898E (pt) | 2002-04-29 |
EP0714898A1 (en) | 1996-06-05 |
CA2169719A1 (en) | 1995-12-28 |
EP0714898A4 (en) | 1997-04-02 |
DE69523864D1 (de) | 2001-12-20 |
DE69523864T2 (de) | 2002-06-13 |
ES2164153T3 (es) | 2002-02-16 |
ATE208776T1 (de) | 2001-11-15 |
US5707997A (en) | 1998-01-13 |
CN1046730C (zh) | 1999-11-24 |
AU680370B2 (en) | 1997-07-24 |
CA2169719C (en) | 2002-04-16 |
EP0714898B1 (en) | 2001-11-14 |
TW307767B (ja) | 1997-06-11 |
KR100315837B1 (ko) | 2002-02-28 |
CN1131948A (zh) | 1996-09-25 |
KR960703919A (ko) | 1996-08-31 |
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