WO1997011946A1 - Analgesiques - Google Patents
Analgesiques Download PDFInfo
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- WO1997011946A1 WO1997011946A1 PCT/JP1996/002759 JP9602759W WO9711946A1 WO 1997011946 A1 WO1997011946 A1 WO 1997011946A1 JP 9602759 W JP9602759 W JP 9602759W WO 9711946 A1 WO9711946 A1 WO 9711946A1
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- lower alkyl
- hydrogen atom
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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
-
- 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
- C07D487/12—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 three hetero rings
- C07D487/14—Ortho-condensed systems
Definitions
- the present invention relates to a novel analgesic containing a specific pyrazo [1,5-a] pyrimidine derivative as an ingredient.
- the present invention provides a new analgesic which has a strong analgesic action and is useful for alleviating pain symptoms such as postoperative pain, migraine, gout, neuropathic pain, cancer pain, chronic pain and the like.
- Ri us analgesic as an active ingredient pin Li Mi di emissions derivatives of particular represented by the following general formula (1) to (3).
- R 11 is a hydrogen atom, a lower alkyl group, a pyridyl group; a furyl group, a phenyl group, a phenyl group which may have a lower alkyl group or a phenylthio group as a substituent.
- R 12 is a hydrogen atom, a halogen atom, a phenyl group, or a substituent;
- a phenyl group having a group selected from a gen atom, a phenylthio group and a trifluoromethyl group, and a phenyl group having a trifluoromethyl group and a nitro group as substituents A phenyl group having a lower alkoxy group and a phenylthio group as substituents, a hydrogen atom, R 13 as a substituent, an oxo group, an ethylenedioxy group, Lower alkanoyloxy group; lower alkoxy group, lower alkylthio group, carboxyl group, lower alkyl group which may have a halogen atom or cesyl group, lower alkenyl group, cycloalkyl group, and substituent; Te lower alkyl group, halogen atom and this Tonoa Ru off Weniru group with 1 to 3 groups
- a phenyl group which may have 1 to 3 groups selected from alkoxy groups, a pyridyl group which may have a lower alkyl group or a halogen atom as a substituent, quinolyl Group, isoquinolyl group A represents a single bond or a lower alkylene group, respectively.
- R 2 1 is hydrogen atom, phenylalanine group, an N- lower alkyl Rupiro Li group or pin lysyl group
- the R 22 is a hydrogen atom
- R 23 is a hydrogen atom, a lower alkyl group or a hydroxyl group
- R 24 represents a hydrogen atom or a cyano group, respectively, and R 23 and R 24 are bonded to each other to form a lower alkylene group or a group;
- R 31 is a hydrogen atom or N-lower alkylpyrrolyl
- R 32 represents a hydrogen atom
- R 33 represents a lower alkyl group
- R 34 represents a cyano group
- R 36 represents a hydrogen atom or a lower alkyl group.
- the analgesic provided by the present invention has a particularly strong analgesic effect, and is effective in alleviating pain symptoms such as postoperative pain, migraine, gout, neuropathic pain, and cancer pain.
- there are no side effects that are common to conventional analgesics and there is no danger of causing hallucinations, confusion, or being addictive or addictive.
- examples of the lower alkyl group include a linear or branched lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. Can be exemplified.
- pyridyl group 2-pyridyl, 3-pyridyl, 4-pyridyl group ⁇
- furinole group 2-furyl, 3-furinole base
- chenyl group Includes a 2-phenyl and a 3-phenyl group.
- a phenyl group which may have a lower alkyl group or a phenylthio group as a substituent includes, in addition to a phenyl group, 2 — methylphenyl, 3 — methylinophenyl, 4-methylphenyl, 2 — ethylphenyl, 4-ethylphenyl, 4 — butylphenyl, 4 hexanoylphenyl, 2 — phenylthiophene, 3 — phenyl Examples thereof include benzylthiophenyl, and 4-phenylthiophenyl group.
- N—lower alkylpyrrolyl group is N—methyl
- the villazinyl group includes 2-vinylazinyl and 3-pyrazinyl groups.
- the halogen atoms include fluorine, chlorine, bromine and iodine atoms.
- Examples of the phenyl group having a substituent selected from a halogen atom, a phenylthio group and a trifluoromethyl group include 2-phenylphenol, 3-phenylphenol, 4-phenylphenol, and 4-phenylphenol. 2-phenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-chlorophenyl, 2-phenyl
- a phenyl group having a trifluoromethyl group and a dihydroxy group as a substituent 4—nitro-13-triphenylolemethylinolephenyl, 4—nitrite (B) 2—trifnorolelomethynolephenyl, 2—2ftro4—triphneolelomethynolefenyl group, and the like.
- phenyl group having a lower alkoxy group and a phenylylthio group as a substituent examples include 3 -methoxy-4-phenylthiophenyl, and 3 -ethoxy-14-phenyl.
- Lower having a oxo group, an ethylenedioxy group, a lower alkanoyloxy group, a lower alkoxy group, a lower alkylthio group, a carboxyl group, a halogen atom or a phenyl group as a substituent.
- alkyl group include, in addition to the unsubstituted lower alkyl group exemplified above, acetyl, 1-year-old Oxopropyl, 2-oxopropyl, 2-oxobutyl.
- Lower alkenyl groups include vinyl, aryl, and isoprene. Examples include lodenyl, 3-butenyl, 4-penteninole, and 5-hexenyl groups.
- cycloalkyl group examples include cyclopropyl, cyclobutynole, cyclopentinole, cyclohexynole, cycloheptyl, and cyclooctyl groups.
- phenyl group which may have 1 to 3 groups selected from a lower alkyl group, a halogen atom and a lower alkoxy group as a substituent, in addition to the phenyl group, 2— Methyl phenyl, 3—Methynolefenyl, 4—Methynolefenyl, 4—Ethynolephane, 41-Propylphenyl, 4—Butylphenyl, 4—T—Butynolepenyl, 4P 2,4-dimethinolephenyl, 2,3-dimethinolephenyl, 2,5—dimethinolephenyl, 2,6—dimethinolephenyl, 3, 4 — dimethyl phenyl, 3, 5 — dimethyl phenyl, 2 — phenol phenyl, 3 — phenol phenol, 4- phenol phenol, 2 — bromo phenol Ninore, 3 — Bu Mofu
- Examples of the lower alkoxy group include methoxy, ethoxy, proboxy, isopropoxy, butoxy, pentyloxyhexyloxy and the like.
- lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, and hexyloxycarbonyl. And the like.
- Examples of the calcium metal include sodium, potassium, and lithium.
- lower alkylene groups include methylene, ethylene, methylethylene, trimethylene, tetramethylene, penmethylen, and hexamethylene. Examples include a len group.
- a lower alkyl group or a lower alkoxy group examples include phenyl, 2-methylinophenyl, 3-methylinophenyl, 4-methylinophenyl, and 4-amino.
- Etinolev phenyl 4-propynolef, 4-butynolef, 4-t-butynolef, 4-pentynolefenyl, 4-hexinolefenyl, 2,3-dimethinolef Zinyl, 2,4-Dimethyl norethenyl, 2,5—Dimethyl norfenyl, 2,6—Dimethyl phenyl, 3,4—Dimethinolevenyl, 3,5—Dimethynolephenyl, 2—Me Triphenyl, 3—methoxyphenyl, 4—methoxyphenyl, 41-ethoxyphenyl, 41-propoxyphenyl, 4-butoxy Sienil,
- pyridyl group which may have a lower alkyl group or a halogen atom as a substituent, in addition to the above-mentioned unsubstituted pyridyl group, 6-methyl-1-2- Pyridyl, 6—ethyl 1—pyridyl, 6—propyl 2—pyridyl, 6—butynole 1—pyridyl, 6—pentinole 1 2—pyridyl, 6—hexyl 1 2 — pyridyl, 6 — methylil 3 — pyridyl, 2 — methinolay 4 — pyridyl, 5 — methinolay 2 — pyridyl, 4 — methinolay 2 — pyridyl, 6 — ku Roll 2 — pyridyl, 6 — Bromo 2 — pyridyl, 6 — Funoleo Roll 2 — pyridino
- the quinolinol groups include 2-quinolinyl, 3-quinolinol, 4-quinolinyl, 5-quinolinyl, 6-quinolinole, 7-quinolinole, and 8-quinolinyl groups. Included.
- the isoquinoline groups include 1-isoquinoline, 3—isoquinoyl, 41-isoquinoyl, 5—isoquinoline, 6—isoquinoyl, and 7—isoquinoyl , 8- basically included.
- R 11 is a hydrogen atom or a lower alkyl group
- R 1 2 and R 1 4 is hydrogen atom
- R 1 3 is a lower alkyl group
- R 1 5 is hydrogen atom, full Eniru group having three pin lysyl group or substituent and to lower an alkoxy group
- compound a is a single bond or a main switch les emission group
- R 1 2 Gaha Rogge emissions atom R 1 1 and R 1 4 is hydrogen atom
- R 1 3 is a lower alkyl group
- a compound in which a lower alkenyl group, R 15 is a pyridyl group, and A is a methylene group
- R 12 is a hydrogen atom are particularly preferred.
- R 1 1 is a lower alkyl group, R 1 3 the n - butyl group, off having 3 lower alkoxy groups and R 14 is a hydrogen atom, a R 1 5 Gapi lysyl group or substituent Weniru A group wherein A and A are a methylene group,
- R 11 is a hydrogen atom
- R 13 and R 14 are bonded to each other to form a tetramethylene group
- R 15 is a pyridyl group
- R 11 and R 14 are hydrogen atoms
- R 13 is cycloalkyl group A compound in which R 15 is a pyridyl group and A is a methylene group, a lower alkoxy lower alkyl group, a lower alkylthio lower alkyl group or a phenyl group,
- R 11 and R 14 are a hydrogen atom, R 13 is an n-butyl group,
- R 15 is a hydrogen atom, a lower alkyl group, a pyridyl group, a quinolyl group or an isoquinolyl group which may have a lower alkyl group or a halogen atom as a substituent, and A is a single bond A compound, and
- R 11 and R 14 are a hydrogen atom, R 13 is an n-butyl group,
- phenylalanine groups have a, Pi lysyl group or keno Li Le group and A is a lower alkylene les emissions groups der Ru compounds of lower alkoxy groups R 15 is a substituent.
- preferred active ingredient compounds of the present invention divided into the above five groups, particularly preferred compounds include the following compound groups, respectively.
- R 11 is a lower alkyl group
- R 13 is an n-butyl group
- R 14 is a hydrogen atom
- R 15 is a pyridyl group
- A is a methylene group
- R 11 is a hydrogen atom
- R 13 and R 14 are bonded to each other to form a tetramethylene group
- R 15 is a pyridyl group
- R 11 and R 14 are hydrogen atoms
- R 13 is cyclohexyl group, Or a phenyl group, a compound wherein R 15 is a pyridyl group and A is a methylene group,
- R 11 and R 14 are hydrogen atoms, R 13 is n-butyl group,
- R 15 is a hydrogen atom, a lower alkyl group, a halogen-substituted pyridyl group or an isoquinolyl group, and A is a single bond, and
- R 11 and R 14 are hydrogen atoms, R 13 is n-butyl group,
- R 15 is a phenyl or pyridyl group having 2 to 3 lower alkoxy groups as substituents and A is a lower alkylene group.
- R 11 and R 14 are a hydrogen atom
- R 13 is an n-butyl group
- R 15 is a hydrogen atom or a pyridyl group
- A is a single bond or a lower alkyl group.
- Compounds that are thiol groups are more preferred.
- the active ingredient compounds of the present invention are 5-n-butyl-7- (4-pyridylmethoxy) pyrazolo [1,5-a] pyrimidine and 5— n — Butinore 1 7-hydroxypyrazolo [1,5 — a] pyrimidine power.
- the active ingredient compounds of the present invention are generally known compounds, and can be produced, for example, by using appropriate starting material compounds shown below.
- the method is represented by the general formulas (1) to (3). Each compound will be described below with reference to the reaction scheme. [Reaction scheme 11]
- R 2a is a hydrogen atom, a phenyl group, a phenyl group having a substituent selected from a halogen atom, a phenyloxy group and a trifluoromethyl group, and a thiol group as a substituent.
- R 3a is a phenyl group having a trifluoromethyl group and a nitro group, or a phenyl group having a lower alkoxy group and a phenylthio group as a substituent, and R 3a is a lower alkoxy group as a substituent.
- R 5 a is a lower alkyl group, there off Weniru group of this with 1 to 3 groups selected from lower alkyl groups and lower alkoxy groups as a substituent, a lower alkyl group or a halogen atom as a substituent
- the condensation reaction of the compound (2) with the 3-aminopyrazole derivative (3) is carried out in a suitable inert solvent at a temperature in the range from room temperature to the boiling point of the solvent. Is done.
- suitable inert solvent include acetic acid, ethanol, benzene, tonolenene, xylene, and tetrahydrofuran (THF).
- the ratio of the compound (2) to the 3—aminovirazole derivative (3) is preferably approximately equimolar, and the reaction is completed in about 2 to 5 hours.
- the desired compound (1a) can be obtained.
- halogenation reaction of compound (1a) is carried out by using a suitable deoxidizing agent such as N, N-dimethylylaniline, N, N-getylalanine, triethylamine, etc.
- a suitable halogenating agent such as phosphorus oxychloride, odor It will be implemented by using synthetic phosphorus. Since the halogenating agent also functions as a solvent, it is not necessary to use a solvent in the reaction. Other inert solvents such as benzene, toluene, and xylene can also be used.
- the amount of the deoxidizing agent used is usually about 1 to 10 times the weight of the compound (1a), and the reaction is carried out at a temperature of about room temperature to about 150 ° C. It can be performed in 5 to 12 hours.
- the halogenated compound (4) obtained by the above reaction can be converted into the compound (1b) by reacting the halogenated compound (4) with the alcohol derivative (5).
- This reaction can be generally performed in a suitable solvent in the presence of a deoxidizing agent.
- the deoxidizing agent includes alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, and potassium carbonate, lithium hydride, and hydrogen.
- Alkali metal hydrides such as sodium hydride and potassium hydride, inorganic bases such as bicarbonate and carbonate, and triethylamine, N, N-Jetylaniline, N-methylmonorefo
- tertiary amines such as phosphorus, pyridin, and 4-—dimethylaminopyridine.
- the solvent include lower alcohols such as methanol and ethanol, and chains such as tetrahydrofuran (THF) and 1,4-dioxane.
- THF tetrahydrofuran
- DFS 0 dimethylsulfoxide Inert solvents
- the amounts of the alcohol derivative (5) and the deoxidizing agent to be used in the above reaction with respect to the halide (4) are not particularly limited, but are usually about equimolar to excess molar for both.
- the reaction often proceeds under cooling, at room temperature, and under heating, and is usually completed in about 0.5 to 15 hours under a temperature condition of 0 ° C. to the reflux temperature of the solvent.
- the condensation reaction between the compound (6) and the 3 -aminovirazole derivative (3) in the above reaction scheme 1-2 is carried out by the compound (2) and the 3 -aminovirazole derivative (3) in the above reaction scheme 11.
- the reaction can be carried out in the same manner as in the reaction with 3).
- the compound (6) is a lower alkyl group having protected carboxy two Le group as defined R 3 b, Example Ebajime Chiruaseta Lumpur, main Chiruechiruaseta Lumpur, di Echinoreaseta Lumpur, A lower alkyl group having, as a protected carbonyl group, a di-lower alkyl acetal residue such as dipropinoleacetanole, dibutinoleacetanole, dipentinolecetone nore, dihexinolecetal, etc. And cyclic acetal residues such as ethylene acetal, trimethylenacetal, tetramethylenacetal, etc. Examples thereof include a lower alkyl group possessed as a carbonyl group.
- the hydrolysis reaction of the compound (1c) according to the above reaction scheme -2 can be carried out using an organic acid such as acetic acid, propionic acid or p-toluenesulfonic acid.
- organic acids such as acetic acid, propionic acid or p-toluenesulfonic acid.
- carboxylic acids such as acetic acid and propionic acid also serve as a solvent, and therefore, when these are used, there is no particular need to use other solvents, but even in this case, other organic solvents may be used.
- other suitable inert solvents such as, for example, benzene, toluene and xylene can be used.
- the reaction can be carried out at room temperature to around the reflux temperature of the solvent in about 10 to 80 hours, and thus the compound (1d) can be obtained.
- the compound in (1 d) are a lower alkyl group having a carbonylation Le groups defined R 3 c, a "protected carbonylation Le groups defined the corresponding R 3 b
- a protective alkyl group having a lower alkyl group for example, formyl, forminolemethyl, acetyl, 2-formylletyl, 2-oxopropyl, propionyl, 3-honoleminolepropyl , 3-oxobutyl, 2-oxobutyl-butyryl, 4-forminolebutyl, 4-oxopentyl, 3-oxo-pentyl, 2-oxopentyl, valeryl, 5-formylpentyl, 5-oxohexyl, 4- Oki Examples include sohexyl, 3-oxohexyl, and 2-oxohexylhexanoyl groups.
- the subsequent reduction reaction of compound (1d) can be carried out using an appropriate reducing agent in an inert solvent.
- the reducing agent include sodium borohydride and potassium borohydride. Lithium borohydride, sodium borohydride and sodium borohydride. Examples include boron hydride compounds such as lithium, aluminum lithium hydride, aluminum lithium hydride such as tributoxy aluminum hydride, and the like. You. When a borohydride compound is used as the reducing agent as the inert solvent, an alcohol-based solvent such as methanol or ethanol, or an alcohol-based solvent and dichlorometh- anol are used.
- the amount of the reducing agent to be used is preferably at least about equimolar to the compound (Id).
- the reaction can be performed at a temperature of about 0 ° C. to about room temperature for about 30 minutes to about 3 hours.
- the alkanolization of the thus obtained compound (7) is carried out using an alkanolizing agent without solvent or in an inert solvent such as pyridin, norethidine, DMF or DMA.
- an alkanolizing agent for example, acid anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, hexanoic anhydride, and anhydrous heptanoic acid can be used. They can be used in 1 to 10 times the equivalent of the normal compound (7).
- the reaction conditions are appropriately set at a temperature of about 0 ° C to about 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 (7) is not converted to alkanol. It is preferable to choose.
- R 13 , R 14 , R 15 and A are as defined above.
- R 2 b represents a halogen atom.
- the halogenation reaction of the compound (1f) shown in Reaction Scheme-3 is performed in an inert solvent such as dimethoxetane, dimethoxetane monohydrate, benzene, carbon tetrachloride, etc.
- Imide (NBS), N-chlorosuccinic acid imide N-chlorosuccinic acid imide
- halogenating agent such as (NCS) or bromine.
- the amount of the halogenating agent used is 1 equivalent to the compound (1f). 7/11946
- the reaction is generally performed in an amount of about 25 to a small excess, and the reaction can be carried out at about 0.5 V to about room temperature in about 0.5 to 5 hours.
- compound (9) can be obtained by reacting compound (8) with ethyl formate (the reaction is carried out in methanol and ethanol). , T-butanol, benzene, xylene, tonolenene, dichloromethan, macroporous form, acetic acid, methanol-water mixture and other inert solvents.
- equimolar amount to a small excess of Na with respect to the compound (8)
- using an equimolar amount to a small excess of ethyl formate with respect to the compound (8) usually at a temperature around room temperature. It can take about 0.5 to 20 hours.
- the ratio of (10) to be used is generally equimolar to a small excess with respect to compound (9), and the reaction is completed in about 5 hours at the reflux temperature of the solvent.
- n represents an integer of 3 to 6 ⁇
- reaction between the compound (11) and the compound (12) shown in Reaction Scheme 15 is carried out in an inert solvent such as acetic acid or toluene.
- the reaction was carried out by reacting the compound (12) in an equimolar amount to a small excess with respect to (11) at a temperature of about 100 ° C for about 3 to 10 hours. And thus the desired compound
- R 2 1, R 22 and R 26 are the same above.
- the compound (14) is reacted with the compound (15) to obtain a compound (16), and the compound (17) is reacted with the compound (1). and 8), this compound is reacted with MCPBA and (1 9), Ri by the further thereto in the this reaction of M e NHNH 2, the desired compound (1 1) and the compound (lm) You can get each.
- reaction between compound (16) and compound (17) is as described above.
- the reaction can be carried out in the same manner as in the reaction of the compound (1j) with the compound (13) shown in Reaction Scheme 16 below.
- reaction is carried out in a suitable solvent such as methylene chloride or macropore form at around 0 ° C. for about 3 hours using an equimolar amount of MCPBA to (18).
- a suitable solvent such as methylene chloride or macropore form
- the reaction at a temperature of 60 ° C. for about 30 minutes the compound (11) is selectively obtained, and the reaction at a temperature of 100 ° C. (: about 20 minutes) is carried out.
- the compound (1 m) is mainly obtained.
- the reaction is carried out by reacting the compound (21) in an equimolar amount to a small excess with respect to (20) at a temperature near room temperature for about 48 hours, and thus the desired Compound (I n) can be obtained.
- Some of the active ingredient compounds of the present invention can be converted into pharmaceutically acceptable acid addition salts, and such salts are also included in the present invention.
- the acid capable of forming the above-mentioned acid addition salt include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, 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 (for the isolation means, various commonly used isolation means can be used). Any of the following methods can be employed, including, for example: adsorption chromatography, preparative thin-layer chromatography, recrystallization, and solvent extraction. And the like.
- the active ingredient compounds of the present invention represented by the above general formulas (1) to (3) include optical isomers having a carbon atom as an asymmetric center. It can be in any of the isomeric forms (racemic, R- and S-isomers). Further, the active ingredient compound of the present invention Some of them include those having a cis or trans isomer structure, and the analgesic of the present invention can naturally use such isomers as an active ingredient.
- the analgesic of the present invention is usually used in the form of a general pharmaceutical composition using a pharmaceutical carrier together with the above-mentioned active ingredient compound.
- the preparation carrier may be a diluent or a diluent such as a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant, a lubricant, etc. Excipients 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, capsules, suppositories, injections (solutions, suspensions, etc.), ointments and the like.
- the above-mentioned pharmaceutical carriers include, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose.
- Excipients such as glucose, gay acid and potassium phosphate, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, Carboxy Mesinoresorenolose, Hydroxypropinoresorenolose, Mesinoresenorose, Polyvininole 11 27
- Binders such as pyrrolidone, carboxymethylcellulose sodium, canoleboximetyl senoreroscanoresum, low-substituted hydroxypropylcellulose, dried starch, sodium alginate, container powder, lamellar starch Disintegrators such as mint powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sonolebitan fatty acid esters, sodium laurinoleate, and stearic acid Surfactants such as monoglycerides, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, quaternary ammonium base, sodium raurylsulfate, etc.
- Disintegrators such as mint powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sonolebitan fatty acid esters, sodium laurinoleate, and stearic acid
- Surfactants such as monoglycerides, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, quaternary
- Absorption enhancer such as glycerin and starch
- adsorbent such as starch, lactose, kaolin, bentonite, colloidal gay acid, refined tar Lubricants such as oils, stearic acid salts, powdered boric acid, polyethylene glycol, and the like can be used.
- tablets are coated with ordinary skin as required, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double-coated tablets, or multi-layer tablets. It can be done.
- a pharmaceutical carrier for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, Binders such as powdered lagunates, gelatin and ethanol, and disintegrants such as laminarancanthene can be used.
- excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder
- Binders such as powdered lagunates, gelatin and ethanol, and disintegrants such as laminarancanthene
- pharmaceutical carriers such as polyethylene glycol, cocoa butter, higher alcohol, higher alcohol esters, gelatin, and semi-synthetic Glyceride etc. can be used.
- 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.
- the drug of the present invention is prepared as an injection, such as a solution, emulsion, or suspension
- diluents include, for example, water, ethyl alcohol, macro alcohol, propylene glycol, ethoxylated isostearinoleanol, polyoxylated Isostearinole alcohol, polyoxyethylene sorbitan fatty acid esters and the like 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, or the normal solution may be used.
- Auxiliaries, buffers, soothing agents and the like may be added.
- the present agent may contain a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent, and other pharmaceuticals as necessary.
- ointment such as paste, cream, gel, etc.
- diluents such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, and vent Nights can be used.
- the amount of the active compound represented by any of the general formulas (1) to (3) to be contained in the drug of the present invention is not particularly limited and may be appropriately selected from a wide range.
- the content is preferably about 1 to 70% 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 in admixture with normal replenishers such as glucose and amino acids.
- the dosage of c above pharmaceutical preparations suppositories are administered rectally, the usage, patient's age, sex
- the amount of the compound of the present invention, which is usually an active ingredient, is about 0.5 to 20 mg per 1 kg of body weight per day, preferably depending on other conditions, the degree of disease, etc. 1 or more: L is preferably about 0 mg, and the preparation can be administered in 1 to 4 times a day.
- Table 1 shows the structure and melting point or NMR data of each compound obtained.
- step (2) Dissolve 5.7 g of the compound obtained in step (2) in 120 ml of methanol, add 0.53 g of sodium borohydride under ice cooling, and add The mixture was stirred at ° C for 2 hours. After the completion of the reaction, diluted hydrochloric acid was added dropwise to make the solution acidic, and the mixture was extracted with black hole form. The organic layer was collected, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol-n-hexane to give 7-hydroxy 5- (3 4.16 g of colorless crystals of pyroxy mouth [1,5-a] pyrimidine were obtained.
- step (4) The compound obtained in step (4) was treated in the same manner as in step (2) of Reference Example 1 to obtain the target compound as a pale yellow oil.
- 6-ethoxycanoleponinoleme 7-7-hydroxyl 5-methinole 1-phenylvinyl zolo [1,5-a] pyrimidine 3.2 g of ethanol 6 O
- a solution of 1.3 g of sodium hydroxide in 25 ml of water was added, and the mixture was stirred at room temperature for 3 hours.
- the solvent is distilled off, the remaining water is distilled off azeotropically with ethanol, and the precipitated crystals are washed with hot ethanol and collected by filtration to obtain 2.7 g of the target compound as gray-white crystals. Obtained.
- Table 1 shows the structure and melting point of the obtained compound.
- 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 SD male rats per group.
- Celit method (Randall, -shi.0 and Sellitto, J. J Arch. Int.
- 0.1 ml of a 20% yeast suspension was subcutaneously injected subcutaneously into the left hind leg of each rat, and the experimental group was further treated with the compound of the present invention.
- a 5% Arabic gum suspension (without the compound of the present invention) was added at a rate of 10 ml Z kg. It was administered orally.
- the pain threshold of the left hind foot and foot of each rat group was measured in the same manner as described above, and this was defined as the “post-value”.
- the pain threshold recovery rate (%) was calculated from the measured value (post-value) and the pre-value of each group according to the following formula.
- Pain threshold recovery rate (%) [(average value after average in experimental group) 1 (average value after average in control group)] Z [(average value before average in control group) 1 (average value after average in control group)] X 100
- the value obtained 0 determined according to Pharmacodyn., 111, 409 (1957) 3 is defined as the “previous value”.
- the experimental group further received a 5% gum arabic suspension of the compound of the present invention, and the control group received a 5% gum arabic gum suspension (without the compound of the present invention).
- a predetermined time after the Substance P injection the pain threshold of the left hind foot and foot of each rat group was measured in the same manner as described above, and this was defined as the “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.
- Pain threshold recovery rate (%) [(mean mean value of experimental group)-(mean mean value of control group)] / [(mean mean value before control group)-(mean mean value after control group)] X 100
- Preparation of 100 tablets for oral use containing 5 mg of each of the compound obtained in Production Example 66 was prepared according to the following formulation ( 5 g lactose of the compound obtained in Production Example 66 (Japanese Pharmacopoeia) ) 50 g contact cellulose (Japanese Pharmacopoeia) 25 g crystalline cellulose (Japanese Pharmacopoeia) 25 g methyl cellulose (Japanese Pharmacopoeia) 1.5 g magnesium stearate 1 g of um (Japanese Pharmacopoeia) That is, the compound obtained in Production Example 66, lactose, corn starch, and the resulting cellulose are sufficiently mixed, and the mixture is mixed with methyl cellulose. Granulated with a 5% aqueous solution of nollose and carefully dried through a 200 mesh sieve. The dried granules were passed through a 200 mesh sieve, mixed with magnesium stearate and pressed into tablets.
- a sterilized aqueous solution containing the compound obtained in Production Example 66 and suitable for parenteral administration was prepared according to the following formulation.
- Japanese Pharmacopoeia 0.4 g sodium metabisulfite (Japanese Pharmacopoeia) 0.1 g methyl-paraben (Japanese Pharmacopoeia) 0.18 g propirno. Laben (Japanese Pharmacopoeia) 0.02 g distilled water for injection 100 ml That is, the above parabens, sodium metabisulfite and sodium chloride are stirred at 80 ° C while stirring. Was dissolved in about half the volume of distilled water, and the resulting solution was cooled to 40 ° C., and the compound obtained in Production Example 66 and polyoxyethylene sorbitan monooleate were dissolved therein. . Next, distilled water for injection is added to the obtained solution to adjust to the final volume, and an appropriate finolator is used. The mixture was sterilized and filtered to prepare an injection.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1019970703534A KR100260292B1 (ko) | 1995-09-28 | 1996-09-24 | 진통제 |
EP96931299A EP0795555A4 (en) | 1995-09-28 | 1996-09-24 | ANALGETICS |
US08/836,822 US5843951A (en) | 1995-09-28 | 1996-09-24 | Analgesic composition of pyrazolo(1,5-A) pyrimidines |
AU70022/96A AU707530B2 (en) | 1995-09-28 | 1996-09-24 | Analgesic composition |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7/289096 | 1995-09-28 | ||
JP28909695 | 1995-09-28 |
Publications (1)
Publication Number | Publication Date |
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WO1997011946A1 true WO1997011946A1 (fr) | 1997-04-03 |
Family
ID=17738755
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1996/002759 WO1997011946A1 (fr) | 1995-09-28 | 1996-09-24 | Analgesiques |
Country Status (8)
Country | Link |
---|---|
US (1) | US5843951A (ja) |
EP (1) | EP0795555A4 (ja) |
KR (1) | KR100260292B1 (ja) |
CN (1) | CN1169149A (ja) |
AU (1) | AU707530B2 (ja) |
CA (1) | CA2206080A1 (ja) |
TW (1) | TW492970B (ja) |
WO (1) | WO1997011946A1 (ja) |
Cited By (6)
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WO1999059998A1 (fr) * | 1998-05-19 | 1999-11-25 | Otsuka Pharmaceutical Factory, Inc. | DERIVES DE PYRAZOLO[1,5-a]PYRIMIDINE |
WO2002053565A1 (fr) * | 2000-12-28 | 2002-07-11 | Ono Pharmaceutical Co., Ltd. | Composes de derives tricycliques et heterocycliques et medicaments renfermant ces composes comme principe actif |
JP2002540155A (ja) * | 1999-03-26 | 2002-11-26 | ユーロ−セルティック エス. ア. | アリール置換ピラゾール、イミダゾール、オキサゾール、チアゾールおよびピロール、ならびにそれらの使用 |
WO2004083211A1 (ja) * | 2003-03-19 | 2004-09-30 | Sanwa Kagaku Kenkyusho Co. Ltd. | ピラゾロピリミジン化合物及びその用途 |
WO2004113344A1 (ja) * | 2003-06-25 | 2004-12-29 | Ono Pharmaceutical Co., Ltd. | ピラゾロピリミジン化合物のメタンスルホン酸塩、その結晶およびその製造方法 |
JP2021500380A (ja) * | 2017-10-27 | 2021-01-07 | バイエル アクチェンゲゼルシャフトBayer Aktiengesellschaft | P2x3阻害剤としての新規なピラゾロ−ピロロ−ピリミジン−ジオン誘導体 |
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US6664261B2 (en) * | 1996-02-07 | 2003-12-16 | Neurocrine Biosciences, Inc. | Pyrazolopyrimidines as CRF receptor antagonists |
AU731838B2 (en) * | 1997-03-14 | 2001-04-05 | Otsuka Pharmaceutical Co., Ltd. | Novel pyrimidine derivative |
US6235741B1 (en) | 1997-05-30 | 2001-05-22 | Merck & Co., Inc. | Angiogenesis inhibitors |
JP2002501532A (ja) * | 1997-05-30 | 2002-01-15 | メルク エンド カンパニー インコーポレーテッド | 新規血管形成阻害薬 |
US6245759B1 (en) | 1999-03-11 | 2001-06-12 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
DE10050661A1 (de) * | 2000-10-13 | 2002-04-18 | Gruenenthal Gmbh | Substituierte 3,4-Dihydro-pyrimido[1,2-a]pyrimidine und 3,4-Dihydro-pyrazino[1,2-a]pyrimidine |
ATE345344T1 (de) | 2001-03-27 | 2006-12-15 | Neurogen Corp | (oxopyrazolo 1,5aöpyrimidin-2-yl) alkylcarbonsäureamide |
EP1506196B1 (en) * | 2001-11-01 | 2012-01-18 | Icagen, Inc. | Pyrazolopyrimidines as sodium channel inhibitors |
US7176210B2 (en) * | 2003-02-10 | 2007-02-13 | Pfizer Inc. | Cannabinoid receptor ligands and uses thereof |
TW200639163A (en) | 2005-02-04 | 2006-11-16 | Genentech Inc | RAF inhibitor compounds and methods |
GB0908394D0 (en) | 2009-05-15 | 2009-06-24 | Univ Leuven Kath | Novel viral replication inhibitors |
EP2640705A2 (en) | 2010-11-15 | 2013-09-25 | Katholieke Universiteit Leuven | Novel antiviral compounds |
WO2012149157A2 (en) | 2011-04-26 | 2012-11-01 | Bioenergenix | Heterocyclic compounds for the inhibition of pask |
US10392389B2 (en) | 2012-10-25 | 2019-08-27 | Bioenergenix Llc | Heterocyclic compounds for the inhibition of PASK |
WO2014066743A1 (en) | 2012-10-25 | 2014-05-01 | Bioenergenix | Heterocyclic compounds for the inhibition of pask |
CN107033149B (zh) * | 2017-06-12 | 2020-01-03 | 上海交通大学 | 一种dpp-4酶抑制剂及其制备和应用 |
MA50256A (fr) | 2017-09-15 | 2020-07-22 | Aduro Biotech Inc | Composés de pyrazolopyrimidinone et leurs utilisations |
WO2020264084A1 (en) | 2019-06-27 | 2020-12-30 | Boston Scientific Scimed, Inc. | Detection of an endoscope to a fluid management system |
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JPH05125079A (ja) * | 1991-11-05 | 1993-05-21 | Otsuka Pharmaceut Factory Inc | ピラゾロ[1,5−aピリミジン誘導体 |
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CH420182A (de) * | 1962-05-18 | 1966-09-15 | Shionogi & Co | Verfahren zur Herstellung eines neuen Pyrazolo-pyrimidin-Derivates |
GB1011048A (en) * | 1962-09-10 | 1965-11-24 | Shionogi & Co | Pyrazolopyrimidine derivative and the production thereof |
BE786611A (fr) * | 1971-08-16 | 1973-01-22 | Int Chem & Nuclear Corp | Nouveaux inhibiteurs de xanthine-oxydase et leur procede de preparatio |
BE792533A (fr) * | 1971-12-09 | 1973-06-08 | Int Chem & Nuclear Corp | Nouvelles pyrazolo (1,5a) pyrimidines et leur procede de preparation |
JP2753659B2 (ja) * | 1990-09-03 | 1998-05-20 | 株式会社大塚製薬工場 | ピラゾール誘導体 |
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US5707997A (en) * | 1994-06-21 | 1998-01-13 | Otsuka Pharmaceutical Factory, Inc. | Pyrazolo 1,5-a!pyrimidine derivative |
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1996
- 1996-09-24 WO PCT/JP1996/002759 patent/WO1997011946A1/ja not_active Application Discontinuation
- 1996-09-24 US US08/836,822 patent/US5843951A/en not_active Expired - Fee Related
- 1996-09-24 CA CA002206080A patent/CA2206080A1/en not_active Abandoned
- 1996-09-24 AU AU70022/96A patent/AU707530B2/en not_active Ceased
- 1996-09-24 EP EP96931299A patent/EP0795555A4/en not_active Withdrawn
- 1996-09-24 CN CN96191570A patent/CN1169149A/zh active Pending
- 1996-09-24 KR KR1019970703534A patent/KR100260292B1/ko not_active IP Right Cessation
- 1996-09-26 TW TW085111836A patent/TW492970B/zh active
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JPH05125079A (ja) * | 1991-11-05 | 1993-05-21 | Otsuka Pharmaceut Factory Inc | ピラゾロ[1,5−aピリミジン誘導体 |
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JOURNAL OF MEDICINAL CHEMISTRY, Vol. 26, No. 12, pp. 1706-1709, 1983 (USA), GABRIELLA AUZZI et al., "2-Phenylpyrazolo(1,5-a) Pyrimidin-7-Ones. A New Class of Nonsteroidal Anti-inflammatory Drugs Devoid of Ulcerogenic Activity". * |
JOURNAL OF PHARMACEUTICAL SCIENCES, Vol. 82, No. 5, pp. 580-586, 1993 (USA), FABRIZIO BRUNI et al., "Synthesis and Study of Anti-Inflammatory Properties of Some Pyrazolo(1,5-a)Pyrimidine Derivatives". * |
PHARMACOLOGICAL RESEARCH COMMUNICATIONS, Vol. 18, No. 3, pp. 241-256, 1986, PIRISINO-VETTORRI, L., "Pharmacological Activity of 2-Phenylpyrazolo-4-Ethyl-Anti-Inflammatory Agent". * |
See also references of EP0795555A4 * |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1999059998A1 (fr) * | 1998-05-19 | 1999-11-25 | Otsuka Pharmaceutical Factory, Inc. | DERIVES DE PYRAZOLO[1,5-a]PYRIMIDINE |
US6372749B1 (en) | 1998-05-19 | 2002-04-16 | Otsuka Pharmaceutical Factory, Inc. | Pyrazolo[1,5-a]pyrimidine derivatives |
JP2002540155A (ja) * | 1999-03-26 | 2002-11-26 | ユーロ−セルティック エス. ア. | アリール置換ピラゾール、イミダゾール、オキサゾール、チアゾールおよびピロール、ならびにそれらの使用 |
JP4832647B2 (ja) * | 1999-03-26 | 2011-12-07 | ユーロ−セルティック エス. ア. | アリール置換ピラゾール、イミダゾール、オキサゾール、チアゾールおよびピロール、ならびにそれらの使用 |
WO2002053565A1 (fr) * | 2000-12-28 | 2002-07-11 | Ono Pharmaceutical Co., Ltd. | Composes de derives tricycliques et heterocycliques et medicaments renfermant ces composes comme principe actif |
US7034153B2 (en) | 2000-12-28 | 2006-04-25 | Ono Pharmaceutical Co., Ltd. | Tricyclic and heterocyclic derivative compounds and drugs containing these compounds as the active ingredient |
US7459459B2 (en) | 2000-12-28 | 2008-12-02 | Ono Pharmaceutical Co., Ltd. | Tri-heterocyclic compounds and a pharmaceutical comprising them as an active ingredient |
US7807688B2 (en) | 2000-12-28 | 2010-10-05 | Ono Pharmaceutical Co., Ltd. | Tri-heterocyclic compounds and a pharmaceutical comprising them as an active ingredient |
WO2004083211A1 (ja) * | 2003-03-19 | 2004-09-30 | Sanwa Kagaku Kenkyusho Co. Ltd. | ピラゾロピリミジン化合物及びその用途 |
WO2004113344A1 (ja) * | 2003-06-25 | 2004-12-29 | Ono Pharmaceutical Co., Ltd. | ピラゾロピリミジン化合物のメタンスルホン酸塩、その結晶およびその製造方法 |
US7947697B1 (en) | 2003-06-25 | 2011-05-24 | Ono Pharmaceutical Co., Ltd. | 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[d] pyrazolo[1,5-a]pyrimidine methanesulfonate as a CRF antagonist |
JP2021500380A (ja) * | 2017-10-27 | 2021-01-07 | バイエル アクチェンゲゼルシャフトBayer Aktiengesellschaft | P2x3阻害剤としての新規なピラゾロ−ピロロ−ピリミジン−ジオン誘導体 |
Also Published As
Publication number | Publication date |
---|---|
CA2206080A1 (en) | 1997-04-03 |
EP0795555A1 (en) | 1997-09-17 |
CN1169149A (zh) | 1997-12-31 |
AU7002296A (en) | 1997-04-17 |
AU707530B2 (en) | 1999-07-15 |
US5843951A (en) | 1998-12-01 |
KR100260292B1 (ko) | 2000-07-01 |
TW492970B (en) | 2002-07-01 |
EP0795555A4 (en) | 1998-01-07 |
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