WO1994007865A1 - Compose d'ester carboxylique - Google Patents

Compose d'ester carboxylique Download PDF

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Publication number
WO1994007865A1
WO1994007865A1 PCT/JP1993/001350 JP9301350W WO9407865A1 WO 1994007865 A1 WO1994007865 A1 WO 1994007865A1 JP 9301350 W JP9301350 W JP 9301350W WO 9407865 A1 WO9407865 A1 WO 9407865A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
phenyl
dimethylamino
methylethoxy
acetate
Prior art date
Application number
PCT/JP1993/001350
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English (en)
Japanese (ja)
Inventor
Takanori Oe
Ryuhei Ikezawa
Haruhito Kobayashi
Masao Hisadome
Noriyuki ARIMA
Original Assignee
Yoshitomi Pharmaceutical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yoshitomi Pharmaceutical Industries, Ltd. filed Critical Yoshitomi Pharmaceutical Industries, Ltd.
Publication of WO1994007865A1 publication Critical patent/WO1994007865A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel and pharmaceutically useful carboxylic ester compound.
  • the present inventors have found a condensed pyrazole compound having a leukocyte phagocytosis-enhancing action, a macrophage phagocytosis-enhancing action, a leukocyte count recovery action, an infection resistance activating action, an antitumor action, an immunopotency improving action, and the like ( Japanese Unexamined Patent Publication No. 2-85252).
  • the free-potency ruponic acid compound had low absorption and bioavailability (bioavai labiliter: BA) when administered orally, and had problems as an oral preparation.
  • an object of the present invention is to provide a compound having a good absorption rate by oral administration and a good bioavailability.
  • the present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, have found that a novel carbonate compound has a good absorption rate by oral administration and a higher bioavailability can be obtained.
  • the present invention has been completed.
  • the present invention provides the following.
  • a 3 represents alkylene, Y represents a single bond, —CO— or one CH (OH) one, and R 7 and R 8 may be the same or different and represent hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, Anru, Ariru, phenylalanine alkyl or is 1 to 3 halogen, hydroxyl, carboxy, alkoxycarbonyl, phenylene Le alkyl O alkoxycarbonyl, one 0- R 9 (wherein, R s is 1 3 represents a halogen or an alkyl or Ariru optionally substituted by a hydroxyl group.) in one Ji 0NR] ° RH (wherein, R, R 11 represents hydrogen or alkyl Le identical or different.) one NR ′ 2 R 13 (where R 12 and R 13 are the same or different and represent hydrogen or alkyl, or R 12 and R 13 represent a group that forms a heterocyclic ring with an adjacent nitrogen
  • R 15 and R ′ 6 are the same or different and each represent hydrogen, halogen, hydroxyl, nitro, amino, alkyl, alkoxy, cycloalkyl or cycloalkylalkyl, or R 15 and R 16 together with a benzene ring
  • a group forming a condensed ring a group represented by:
  • R '7 iii) (In the formula, A 4 represents alkylene, A 5 represents a single bond or — ⁇ , and R 17 represents an alkyl, cycloalkyl, cycloalkylalkyl, which may be substituted with 1 to 3 halogen or hydroxyl groups. Represents a phenyl or phenylalkyl group.
  • a 6 represents a single bond or alkylene, and R "and R” may be the same or different and represent hydrogen, halogen, hydroxyl, nitro, amino, alkyl, alkoxy, cycloalkyl or cycloalkylalkyl.
  • a 7 represents a single bond or alkylene
  • R 2 ° represents hydrogen or alkyl, cycloalkyl, cycloalkylalkyl, aryl or phenyl optionally substituted by 1 to 3 halogen or hydroxyl groups.
  • R 21 represents hydrogen or alkyl, cycloalkyl, cycloalkylalkyl, aryl or phenylalkyl optionally substituted by 1 to 3 halogens or hydroxyl groups).
  • n represents 0 or 1.
  • R 7 and R 8 may be the same or different and represent hydrogen, alkyl, alkenyl, cycloalkyl, cyclo cycloalkylalkyl, Ashiru, Ariru, phenylalanine alkyl or is 1-3 halogens, hydroxyl, carboxy, alkoxycarbonyl, phenylene Le alkyl O alkoxycarbonyl, one 0- R s (where, R 9 is 1 to 3 pieces of a halogen or alkyl or Ariru be substituted with a hydroxyl group.), -CONR] 0 R I !
  • R '° represents hydrogen or alkyl le R 1 Lima same or different.
  • — NR 12 R 13 where R 12 and R 13 are the same or different and represent hydrogen or alkyl, or R 12 and R 13 represent a group that forms a heterocyclic ring with an adjacent nitrogen atom
  • RH represents alkyl, aryl or phenylalkyl which may be substituted by 1 to 3 halogens or hydroxyl groups.
  • R 15 and R 16 are the same or different and represent hydrogen, halogen, hydroxyl, nitro, amino, alkyl, alkoxy, cycloalkyl or cycloalkylalkyl, or R 15 and R 16 are condensed with a benzene ring
  • a 4 represents alkylene
  • a 5 represents a single bond or — ⁇
  • R 17 is an alkyl optionally substituted with 1 to 3 halogens or hydroxyl groups, cycloalkyl Alkyl, cycloalkylalkyl, aryl and aralkyl.
  • the carboxylic acid ester compound or the pharmaceutically acceptable salt thereof according to the above (1) which is a group represented by the following formula:
  • R 6 is the formula
  • R 7 and R 8 may be the same or different and represent hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkyl cycloalkylalkyl, Ashiru, Ariru, phenylalanine alkyl or is 1-3 halogens, hydroxyl, carboxy, alkoxycarbonyl, phenylene Le alkyl O alkoxycarbonyl, - 0- R 9 (wherein, R 9 is 1 to 3 Alkyl or aryl which may be substituted by one or more halogens or hydroxyl groups.), -CONR ⁇ R 11 (where R "and R 11 are the same or different and represent hydrogen or alkyl), and one NR 12 R 13 (where R ′ 2 and R 13 are the same or different and represent hydrogen or alkyl, or R 12 and R 13 represent a group that forms a heterocyclic ring with an adjacent nitrogen
  • R 1 represents hydrogen, halogen, alkyl or alkoxy;
  • R 2 , R 3 represents hydrogen;
  • Z represents 10-;
  • a 'and A 2 represent alkylene
  • R 4 and R 5 are the same or different and each represents hydrogen, alkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl or acyloxyalkyl;
  • R 6 is the formula
  • a 3 represents alkylene, Y represents a single bond or one C ⁇ —, R 7 , R 8 is the same or different and represents hydrogen, alkyl, cycloalkyl or aryl, or R 7 and R 8 each represent a group which forms a heterocyclic ring with an adjacent nitrogen atom.
  • R 15 and R 16 are the same or different and represent hydrogen, halogen, hydroxyl, nitro, amino, alkyl, or alkoxy, or R 15 and R 16 represent a group forming a condensed ring with a benzene ring. ), A group represented by the formula
  • a 4 represents alkylene, A 5 represents a single bond, and R 17 represents alkyl, aryl, phenylalkyl which may be substituted by 1 to 3 halogen or hydroxyl groups.
  • R 1 represents hydrogen, halogen, alkyl or alkoxy;
  • R 2 and R 3 represent hydrogen;
  • Z represents — ⁇ ;
  • a ′ and A 2 represent alkylene
  • R 4 and R 5 are the same or different and each represents hydrogen, alkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl or acyloxyalkyl;
  • R 6 is the formula
  • a 3 represents alkylene, Y represents a single bond or a CO—, R 7 R 8 are the same or different and represent hydrogen, alkyl, cycloalkyl, aryl, or R 7 , R 8 are adjacent
  • a pharmaceutical composition comprising the carboxylic acid ester compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (7) as an active ingredient.
  • a therapeutic agent for pancytopenia comprising as an active ingredient the carboxylic acid ester compound or the pharmaceutically acceptable salt thereof according to any of (1) to (7).
  • halogen means chlorine, bromine, fluorine or iodine
  • alkyl means a straight-chain or branched-chain alkyl having 1 to 8 carbon atoms, methyl, ethyl, propyl, isopropyl, butyl , Isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, octyl and the like.
  • alkyl in the formula is preferably a linear or branched alkyl having 1 to 3 carbon atoms.
  • Alkoxy means linear or branched alkoxy having 1 to 8 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyne, tertiary butoxy, pentyloxy, isopentyloxy, and hexyloxy. And octyloxy.
  • Alkylene means straight or branched chain alkylene having 1 to 8 carbon atoms, and includes methylene, ethylene, 1,1-dimethylethylene, trimethylene, propylene, 2-methyltrimethylene, and 2-ethyltrimethylene. , Tetramethylene, pentamethylene, heptamethylene, octamethylene and the like.
  • the alkylene in A 1 is preferably a straight-chain or branched-chain alkylene having 1 to 3 carbon atoms.
  • the alkylene in A 2 is preferably a straight-chain or branched-chain alkylene having 1 to 5 carbon atoms, and more preferably methylene.
  • the cycloalkyl is a cycloalkyl having 3 to 7 carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, and preferably cyclohexyl.
  • Alkenyl means a straight-chain or branched alkenyl having 2 to 8 carbon atoms, and includes vinyl, aryl, 1-proenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and the like.
  • Diaminoalkyl is a straight chain or branched chain alkyl having 1 to 4 carbon atoms, such as aminomethyl, 2-aminoethyl, 3-aminopropyl, and 4-aminobutyl.
  • Monoalkylaminoalkyl is a straight-chain or branched-chain alkyl having 1 to 4 carbon atoms in the alkyl part, and includes methylaminomethyl, 2-methylaminoethyl, 2-ethylaminoethyl, and 3-methylaminobutyl. Mouth pill, 3-ethylaminobu mouth pill, 4-methylaminobutyl and the like.
  • Dialkylaminoalkyl is a straight-chain or branched alkyl having 1 to 4 carbon atoms in each alkyl moiety, and includes dimethylaminomethyl, 2-dimethylaminoethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 3-getyl aminobutyral pill, 4-dimethylaminobutyl and the like.
  • Hydroxyalkyl is a straight-chain or branched-chain alkyl having 1 to 4 carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-1-methylethyl, 2, 3-dihydro Xypropyl and the like.
  • Cycloalkylalkyl is a cycloalkyl moiety having 3 to 7 carbon atoms, and the alkyl moiety is a linear or branched alkyl having 1 to 4 carbon atoms, such as cyclopropylmethyl and cyclobutyl.
  • Aryl includes phenyl and naphthyl.
  • Phenylalkyl is a linear or branched alkyl having 1 to 4 carbon atoms in the alkyl portion, and is benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl. And so on.
  • the acyloxyalkyl is an alkanol, benzoyl, or substituted benzoyl having 2 to 6 carbon atoms (substituents include halogen, alkyl, alkoxy, nitro, etc.), and the alkyl moiety has 1 to 4 carbon atoms.
  • acyl refers to an alkanol having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, petyryl, valeryl, pivaloyl, or aroyl such as benzoyl, tolyl, and naphthoyl.
  • Alkoxycarbonyl is an alkoxydialkyl having 1 to 4 carbon atoms in the form of a straight or branched chain, and includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, and third-class butoxy. Cicarbonyl and the like.
  • Phenylalkyloxycarbonyl is a straight-chain or branched-chain alkyl having an alkyl moiety of 1 to 4 carbon atoms, such as benzyloxycarbonyl, phenylethoxyquincarbonyl, or phenylpropoxycarbonyl. , Examples thereof include 1-phenylethoxyquincarbonyl and phenylbutoxycarbonyl.
  • R 7 and hetero atoms as heterocyclic rings R 8 and R 12 and R 13 are formed by combining with the adjacent nitrogen atom, it may be substituted with an alkyl group or hydroxyalkyl group 5- to 7-membered ring which may have at least one nitrogen, oxygen or sulfur, 1-pyrrolidinyl, piperidino, 1-piperazinyl, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4- (2-hydr) (1) -piperazinyl, 1-homopiperazinyl, 4-methyl-11-homopiperazinyl, 2-oxo-11-pyrrolidinyl, morpholino, thiomorpholino and the like.
  • R 15 and R 16 the group forming a condensed ring together with the benzene ring is bicyclo [4.2.0] octa-1,3,5-triene, indane, 1,2,3,4-tetrahydro Examples include naphthalene and 6,7,8,9-tetrahydric-5H-benzocycloheptene.
  • salts are also included in the present invention.
  • Pharmaceutically acceptable salts include, for example, hydrochloride, hydrobromide, sulfate, phosphate, formate, acetate, fumarate, maleate, benzoate, tartrate, quine Salts, malates, mandelates, methanesulfonates, benzenesulfonates, and the like.
  • hydrates monohydrate, 1Z dihydrate, 3-dihydrate, etc.
  • other solvates are also included in the present invention.
  • the compound of the present invention has an asymmetric carbon in the molecule, various optical isomers are present. In addition, when the compound has at least two asymmetric carbons, various diastereomers are present. Exists.
  • the present invention also includes those optical isomers and individual isomers. The present invention also includes stereoisomers.
  • the compound of the general formula (I) can be produced by the following method.
  • L represents an appropriate leaving group such as halogen (chlorine, iodine, bromine, etc.), hydroxyl group, methanesulfonyloxy, toluenesulfonyloxy, and other symbols are as defined above. Is synonymous with )
  • a free carboxylic acid compound of the general formula (II) or a metal salt thereof (sodium salt, potassium salt, etc.) and L in the formulas vi i;) to xi i) are halogen, methanesulfonyloxy, toluenesulfonyl Reaction conditions for reacting with a compound exhibiting a leaving group such as xy are appropriately selected depending on the type of substituent in the starting compound used, but are preferably benzene, toluene, xylene, dimethylformamide, and pyridine.
  • reaction inert to the reaction, such as sodium chloride, chloroform, dichloromethane, dichloroethane, etc., if necessary, sodium hydroxide, hydroxide hydroxide, sodium carbonate, carbonate carbonate, triethylamine, 1,8-diazabicyclo [1,8-diazabicyclo] 5.4.0]
  • a deoxidizing agent such as Ndeco 7-ene.
  • the carboxylic acid of the general formula (II) is an acid halide (acid chloride, acid bromide, etc.), symmetrical acid anhydride or mixed acid anhydride (alkyl carbonic acid mixed anhydride, alkyl phosphoric acid mixed acid)
  • a reactive derivative such as an anhydride with a compound in which L in formulas vi i) and ix
  • a deoxidizing agent such as potassium oxide, sodium carbonate, potassium carbonate, and triethylamine.
  • a tertiary base such as triethylamine, pyridine, and N, N-dimethylaniline is used. It is performed in the presence of
  • the reaction conditions are appropriately selected depending on the type of the substituent in the starting compound to be used, but are preferably inert to the reaction of benzene, toluene, xylene, dimethylformamide, pyridine, chloroform, dichloromethane, dichloroethane and the like.
  • the reaction is carried out at 120 to 100 eC in a solvent.
  • reaction conditions are appropriately selected depending on the type of the substituent in the starting compound to be used, but are preferably inert to the reaction of benzene, toluene, xylene, dimethylformamide, pyridine, chloroform, dichloromethane, dichloroethane and the like.
  • a solvent in the presence of a base such as sodium hydride or sodium alkoxide, or using a deoxidizing agent such as sodium hydroxide, sodium hydroxide, sodium carbonate, sodium carbonate, triethylamine, etc. Proceed at ⁇ 10 o e c.
  • the compound obtained by the above method 1 or 2 is converted to hydrogen peroxide, formic acid, peracetic acid, trifluoroperacetic acid, It is obtained by reacting with peroxides such as perbenzoic acid, perbenzoic acid and monoperfluoric acid.
  • peroxides such as perbenzoic acid, perbenzoic acid and monoperfluoric acid.
  • Compounds of the general formula (I) thus obtained include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, fumaric acid, maleic acid, benzoic acid, tartaric acid, cunic acid, lingoic acid, mandel
  • a pharmaceutically acceptable salt can be obtained by treating the compound with an inorganic or organic acid such as an acid, methanesulfonic acid or benzenesulfonic acid in a conventional manner.
  • the asymmetric carbon is usually produced as a racemate. These are usually obtained by a conventional method such as fractional recrystallization, chromatography and the like. Can be optically resolved into optical isomers. Further, an optical isomer can also be produced using an optically active starting compound. Further, compounds having two or more asymmetric carbons can be obtained as individual diastereomers or mixtures thereof, and the individual diastereomers can be separated by a conventional method such as fractional recrystallization, chromatography, and the like.
  • the method is performed according to the method of Stosssel et al. [Journal of Clinical Investigation, Vol. 51, pp. 615, 1972].
  • Glycogen was intraperitoneally administered to ICR mice (body weight: 30 to 35 g). Two hours later, ascites leukocytes were collected to prepare a 5 ⁇ 10 6 / m1 leukocyte suspension.
  • the compound of the present invention is added to 20 Om1, 100 ⁇ l of mouse serum and 1001 of killed yeast cells (1 ⁇ 10 8 cells / m 1) are added, and the mixture is incubated at 37 ° C. for 20 minutes. . Then, about 200 leukocytes in the reaction solution are observed under a microscope (magnification: X400), and the number of leukocytes that have phagocytosed one or more killed yeast cells is calculated. The relative ratio of 0.1 M of the compound of the present invention to the phagocytosis rate of the control leukocyte is calculated.
  • ICR mice (body weight 20 to 25 g) are intraperitoneally administered with 200 mg / kg of cyclophosphamide, and on the day after administration, 0.3 mg / kg of the compound of the present invention is orally administered or 0.1 mg of the compound of the present invention is intravenously administered.
  • blood of the ICR mouse is collected, and the white blood cell count is measured by a call-evening counter.
  • the relative ratio to the peripheral leukocyte count of the mice administered with cyclophosphamide is calculated as a percentage.
  • the compound of the present invention is intravenously administered for four days on days 8, 9, 10, and 14.
  • heparinized blood is collected from the tail of the rat, and the platelet count is measured using an automatic hemocytometer. The experiment is performed with 4 to 6 animals per group.
  • mice Four to five week old BALBZc mice are whole-body irradiated with 4.0 Gy of radiation. Administer the compound of the present invention intravenously for 3 days from 3 days before to the day before X-ray irradiation. On days 19 and 22 after X-ray irradiation, blood is collected from the mouse orbital venous plexus, and the number of red blood cells is measured using an automatic hemocytometer. The experiment was performed with 8 animals per group, and the results are shown as the mean standard deviation. Experimental Example 7 Recovery effect of red blood cell count in X-ray irradiated mice (Therapeutic effect)
  • mice Four to five week old BALBZc mice are whole-body irradiated with 4.0 Gy of radiation. Administer the compound of the present invention intravenously for 9 consecutive days from the next day to the 9th day after X-ray irradiation. On day 14 after X-ray irradiation, blood is collected from the mouse orbital venous plexus, and the number of red blood cells is measured using an automatic hemocytometer. The experiment was carried out with 6 animals per group, and the results are shown as the mean soil standard deviation.
  • Intravenous and oral administration of the control compound and oral administration of the compound of Example 3 are performed using male SD rats and male beagle dogs. Animals are fasted for 24 hours prior to dosing. However, water is available ad libitum. Intravenous administration is performed by dissolving the control compound in physiological saline, and oral administration is performed by dissolving the control compound and the compound of Example 3 in 0.5% methylcellulose solution. After administration, blood is collected over time and immediately centrifuged, and the obtained plasma is stored frozen at 18 ° C until measurement.
  • Plasma is deproteinized with peranil acetate, acetic acid and sodium lauryl sulfate are added to the supernatant, and the mixture is extracted with a mixed solution of formoacetonitrile. After separating the organic layer, the solution is back-extracted with an aqueous ammonia solution and measured by high performance reversed-phase liquid chromatography with fluorescence detection.
  • the bioavailability (B A) of the control compound and the compound of Example 3 was calculated using the area under the plasma concentration-time curve after administration of rats and dogs, respectively.
  • the absorption rate in dogs was calculated by measuring the amount of rubonic acid released from feces of the control compound and the compound of Example 3 in feces.
  • the compound of Example 6 did not show any death at 100 mg / kg / kg after single oral administration to a rat.
  • the compound of the present invention Since the compound of the present invention has a high absorption rate by oral administration and a high bioavailability, it can be a good oral preparation.
  • the compound of the present invention based on the above experimental examples and various pharmacological experiments, has a platelet count together with a leukocyte phagocytosis-enhancing action, a macrophage phagocytosis-enhancing action, a leukocyte count recovery action, an infection resistance activating action, an antitumor action, an immune function improving action, etc. It has a recovery effect and a red blood cell count recovery effect, and is useful for comprehensive treatments such as activation of infection defense effects in the treatment of infectious diseases and cancer treatment and reduction of bone marrow disorders.
  • Various diseases caused by bone marrow disorders such as regenerative ⁇ benign anemia, myelodysplastic syndrome, myeloid anemia, congenital anemia, renal anemia, congenital and idiopathic neutropenia, and idiopathic thrombocytopenia It is useful for treating purpura.
  • the compound of the present invention is useful as an orally administrable therapeutic agent for pancytopenia.
  • Omg of the compound of the present invention is sufficiently kneaded with 98 mg of lactose, 45 mg of corn starch and 3 mg of hydroxypropylcellulose in a kneading machine.
  • the kneaded product is passed through a 200-mesh sieve, dried at 50 ° C., and then passed through a 24-mesh sieve. Furthermore, it is mixed with 3 mg of talc and 1 mg of magnesium stearate, and a tablet weighing 20 Omg is obtained using a 9 mm diameter punch.
  • This preparation can be sugar-coated or film-coated if necessary.

Abstract

L'invention concerne un composé, ou un de ses sels pharmaceutiquement acceptables, et un remède contre la pancytopénie qui le contient comme ingrédient actif. Ce composé a la formule générale (I) dans laquelle X représente =N- ou =C-; R1 à R3 représentent chacun hydrogène, halogène, alkyle ou alcoxy; Z représente -O-, -S- ou -NR- (R représentant hydrogène ou alkyle); R4 et R5 représentent chacun hydrogène, alkyle, aminoalkyle, mono- ou dialkylaminoalkyle, hydroxyalkyle ou acyloxyalkyle, ou bien R4 et R5 se combinent pour représenter un groupe cyclique; R6 représente (a), (b), (c), (d), (e) ou (f), A?1, A2, A6 et A7¿ représentent chacun une liaison simple ou alkylène; A?3, A4 et A8¿ représentent chacun alkylène; A5 représente une liaison unique ou -O-; R?7, R8, R17, R20 et R21¿ représentent chacun alkyle, cycloalkyle, cycloalkylalkyle, aryle ou phénylalkyle éventuellement substitués à condition que R7 et R8 puissent aussi représenter chacun hydrogène, alcényle ou acyle et que R20 ainsi que R21 puissent aussi représenter chacun hydrogène; et R?15, R16, R18 et R19¿ représentent chacun hydrogène, halogène, OH, NO¿2?, NH2, alkyle, alcoxy, cyclalkyle ou cycloalkylalkyle, à condition que R?15 et R16¿ puissent se combiner pour représenter un groupe cyclique.
PCT/JP1993/001350 1992-09-29 1993-09-20 Compose d'ester carboxylique WO1994007865A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP28534492 1992-09-29
JP4/285344 1992-09-29
JP4578793 1993-02-10
JP5/45787 1993-02-10

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WO1994007865A1 true WO1994007865A1 (fr) 1994-04-14

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0641564A1 (fr) * 1992-05-21 1995-03-08 Yoshitomi Pharmaceutical Industries, Ltd. Compose de pyrazole condense optiquement actif, pour le traitement de la thrombocytopenie et de l'erythropenie
US7241791B2 (en) 2002-09-25 2007-07-10 Wyeth Substituted 4-(indazol-3-yl)phenols

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989003385A1 (fr) * 1987-10-13 1989-04-20 Yoshitomi Pharmaceutical Industries, Ltd. Composes de pyrazole fusionnes, procede de preparation et utilisation en medecine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989003385A1 (fr) * 1987-10-13 1989-04-20 Yoshitomi Pharmaceutical Industries, Ltd. Composes de pyrazole fusionnes, procede de preparation et utilisation en medecine

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0641564A1 (fr) * 1992-05-21 1995-03-08 Yoshitomi Pharmaceutical Industries, Ltd. Compose de pyrazole condense optiquement actif, pour le traitement de la thrombocytopenie et de l'erythropenie
EP0641564A4 (fr) * 1992-05-21 1995-05-03 Yoshitomi Pharmaceutical Compose de pyrazole condense optiquement actif, pour le traitement de la thrombocytopenie et de l'erythropenie.
US7241791B2 (en) 2002-09-25 2007-07-10 Wyeth Substituted 4-(indazol-3-yl)phenols

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