WO1994007865A1

WO1994007865A1 - Carboxylic ester compound

Info

Publication number: WO1994007865A1
Application number: PCT/JP1993/001350
Authority: WO
Inventors: Takanori Oe; Ryuhei Ikezawa; Haruhito Kobayashi; Masao Hisadome; Noriyuki ARIMA
Original assignee: Yoshitomi Pharmaceutical Industries, Ltd.
Priority date: 1992-09-29
Filing date: 1993-09-20
Publication date: 1994-04-14

Abstract

A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, and a pancytopenia remedy containing the same as the active ingredient, wherein X represents =N- or =C-; R1 to R3 represent each hydrogen, halogen, alkyl or alkoxy; Z represents -O-, -S- or -NR- (R being hydrogen or alkyl); R?4 and R5¿ represent each hydrogen, alkyl, aminoalkyl, mono- or dialkylaminoalkyl, hydroxyalkyl or acyloxyalkyl, or alternatively R?4 and R5¿ are combined together to represent a cyclic group; R6 represents (a), (b), (c), (d), (e) or (f); A?1, A2, A6 and A7¿ represent each a single bond or alkylene; A?3, A4 and A8¿ represent each alkylene; A5 represents a single bond or -O-; R?7, R8, R17, R20 and R21¿ represent each optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, aryl or phenylalkyl, provided that R?7 and R8¿ may further represent each hydrogen, alkenyl or acyl, and R?20 and R21¿ may further represent each hydrogen; and R?15, R16, R18 and R19¿ represent each hydrogen, halogen, OH, NO¿2?, NH2, alkyl, alkoxy, cycloalkyl or cycloalkylalkyl, provided that R?15 and R16¿ may be combined together to represent a cyclic group.

Description

Memorandum

Carboxylic acid ester compounds

`` Technical field J

The present invention relates to a novel and pharmaceutically useful carboxylic ester compound.

"Background technology"

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). Among these, the free-potency ruponic acid compound had low absorption and bioavailability (bioavai labiliter: BA) when administered orally, and had problems as an oral preparation.

Therefore, an object of the present invention is to provide a compound having a good absorption rate by oral administration and a good bioavailability.

"Disclosure of the invention"

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.

That is, the present invention provides the following.

(1) General formula

[In the formula, X represents = N— or = CH—; R ′, R ² , and R ³ are the same or different and represent hydrogen, halogen, alkyl, or alkoxy; and Z represents 100—, 1 S— Represents one NR— (where R represents hydrogen or alkyl); A ¹ and A ² are the same or different and represent a single bond or alkylene; R ⁴ ′ and R ⁵ are the same or different and represent hydrogen, Alkyl, aminoalkyl, monoalkylaminoalkyl, dia R ⁶ represents a group which is a heteroalkylalkyl, a hydroxyalkyl or an acyloxyalkyl, or a group in which R ⁴ and R ⁵ form a heterocyclic ring with an adjacent nitrogen atom;

A ³ -Y-NR ⁷ R ⁸ i)

(In the formula, 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 atom.) Or one 0C0R ¹⁴ (here And R ¹⁴ represents alkyl, aryl or phenylalkyl optionally substituted by 1 to 3 halogens or hydroxyl groups.) Alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, acyl substituted by , Aryl or phenylalkyl, or a group in which R ⁷ and R ⁸ form a heterocyclic ring with an adjacent nitrogen atom.

(Wherein, 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:

- A ⁴ -0C0-A ⁵ one 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.

(In the formula, 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.) Group represented, formula

(In the formula, A ⁷ represents a single bond or alkylene, and R ² ° represents hydrogen or alkyl, cycloalkyl, cycloalkylalkyl, aryl or phenyl optionally substituted by 1 to 3 halogen or hydroxyl groups. Represents an alkyl group) or a group represented by the formula:

One A ⁸ -〇 one R ²¹ vi)

(Wherein A ⁸ represents alkylene, R ²¹ represents hydrogen or alkyl, cycloalkyl, cycloalkylalkyl, aryl or phenylalkyl optionally substituted by 1 to 3 halogens or hydroxyl groups). And n represents 0 or 1. ]

Or a pharmaceutically acceptable salt thereof. (2) ^Re is the formula

A ³ -Y-NR ⁷ R ⁸ i)

(Wherein, A ³ represents alkylene, Y represents a single bond, —CO— or —CH (OH) —, and 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}} ! ( wherein, 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) ) Or one OCORH (here , RH represents alkyl, aryl or phenylalkyl which may be substituted by 1 to 3 halogens or hydroxyl groups.) Represents an alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, acyl, aryl or phenylalkyl substituted by Or a group in which R ⁷ and R ⁸ form a heterocyclic ring together with an adjacent nitrogen atom.)

(Wherein 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 group forming a ring, a group represented by:

A ⁴ -OCO-A ⁵ — R ¹⁷ iii)

(In the formula, A ⁴ represents alkylene, A ⁵ represents a single bond or —〇, 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:

(3) R ⁶ is the formula

-A ³ -Y-NR ⁷ R ⁸ i)

(Where A ³ represents alkylene, Y represents a single bond, one CO— or one CH (0H) one, and 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 atom) or One 0C0R "(where R ¹⁴ represents alkyl, aryl or phenylalkyl which may be substituted by 1 to 3 halogens or hydroxyl groups; alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, acyl, substituted by A carboxylate compound according to any one of the above (1) to (2), which represents a reel or phenylalkyl, or a group in which R ⁷ and R ⁸ form a heterocyclic ring together with an adjacent nitrogen atom. Its pharmaceutically acceptable salts.

(4) X represents -N =; 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 -Y-NR ⁷ R ⁸ i)

(Wherein, A ³ represents alkylene, Y represents a single bond or one C〇—, 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. ), A group represented by the formula

(In the formula, 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 -OCO-A ⁵ — R ¹⁷ iii)

(Wherein 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.) The carboxylic acid ester compound or a pharmaceutically acceptable salt thereof according to the above (1) to (2), which is a represented group.

(5) X represents —N =; R ¹ represents hydrogen, halogen, alkyl or alkoxy; R ² and R ³ represent hydrogen; Z represents —〇; 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 -Y-NR ⁷ R ⁸ i)

(Wherein, 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 carboxylate compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (4), which is a group represented by the following formula:

(6) ◎ (Sat) Ichiban rubamoylmethyl 3- (4- (2-dimethylamino- 1-Methylethoxy) phenyl) 1 H-Pyrazo mouth [3,4-b] pyridine 1 1 acetate

◎ (Sat) 1-N-methylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 H-pyrazo-mouth [3,4-b] Pyridine-11-acetate

◎ '(Sat) 1 N, N-dimethylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1 H-pyrabro [3,4-b] pyridin-1ase

◎ (Sat) 1 N, N-Jetylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1 H-Pyrazo mouth [3,4-b] Pyridin-1 1 Asset

◎ (Sat) 1-indan-1-yl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1-1H-pyrazo-mouth [3,4-b] pyridine-11-acetate

◎ (Sat) 1 2— (N, N-dimethylamino) ethyl 3— (4- (2-dimethylamino 1-methylethoxy) phenyl) 1 1 H—Pyrazo mouth [3, 4-b] pyridin-1 1— Acetate

◎ (Sat) -Pivaloyloxymethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) -1H-Pyrazo-mouth [3,4-b] Pyridine-11-acetate

◎ (Sat) 1-Piberidylcarbamoylmethyl 3- (4- (2-dimethylamino 1-methylethoxy) phenyl) 1 1-H-pyrabro [3,4-b] pyridin G

◎ (Sat) N, N-diisopropyl rubamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) -1H-pyrabro [3,4-b] pyridin-1 1-acetate

◎ (Sat) 1 N, N-dibutylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1H-pyrabro [3,4-b) pyridin-11-acete One ◎ (Sat) 1-N-cyclohexylcarbamoylmethyl 3- (4- (2-dimethylamino-1-1-methylethoxy) phenyl) 1 H-pyrabro [3,4-b] pyridin-1-1-acetate

◎ S (+) —N, N—dimethylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1 H-pyrazo mouth [3,4-b] pyridin-11-acete-1 G

◎ S (+) — N, N—Jetylcarbamoylmethyl 3- (4- (2-dimethylamino-1-1-methylethoxy) phenyl) 1 1 H-Pyrazo-mouth [3,4-b] Pyridine-11 Acetate

◎ S (+)-N, N-diisopropyl rubamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl-1H-pyrazo mouth [3,4-b] pyridine-11-acetate

The carboxylic acid ester compound or a pharmaceutically acceptable salt thereof according to the above (1) to (2) and (4), which is selected from the group consisting of:

(7) ◎ (Sat) Rubamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 H-pyrabro [3,4-b] Pyridine-1 1-acetate

◎ (Sat) 1-N-methylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1H-pyrabro [3,4-1b] pyridine-1 1-acetate

◎ (Sat) 1 N, N-Dimethylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1H-Pyrazo mouth [3, 4-b] Pyridin-1-acetate

◎ (Earth) — N, N—Jetylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1 H-pyrabro [3,4-b) pyridin-1 1-acetate

◎ (Sat) 1-piberidylcarbamoylmethyl 3- (4- (2- (dimethylamino-1-1-methylethoxy) phenyl) -1H-pyrabro [—3,4-b] pyridin-1-acetate ◎ (Sat) i-N, N-diisopropyl rubamoylmethyl 3- (4- (2-dimethylamine 1-methylethoxy) phenyl) 1 1H-pyrazo mouth [3,4-b] pyridine-1 1-acetate

◎ (Sat) 1 N, N-dibutylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 H-pyrazo-mouth [3, 4-b] pyridin

◎ (Sat) 1-N-cyclohexylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1H-Pyrazo mouth [3,4-b] Pyridine-11-acetate

◎ S (+) — N, N—dimethylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1 H-pyrazo-mouth [3, 4-b] pyridin-11-acete-1 G

◎ S (+) — N, N—Jetylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1 H-Pyrazo mouth [3,4-b] Pyridine-11-acete One

◎ S (+)-N, N-diisopropyl rubamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1 H-pyrazo mouth [3,4-b] pyridine-11-acetate G

The carboxylic acid ester compound according to any one of (1) to (6) or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

(8) 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.

(9) 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). In the present specification, halogen means chlorine, bromine, fluorine or iodine, and 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. In particular, - preferably 1-4 straight-chain or branched TECHNICAL chain alkyl carbon atoms and alkyl Le in R ^1, the R ^7, R ⁸ The 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. In particular, 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. Methyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclobutyl pyrethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclobutyl pyrpropyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclopropyl Butyl, cyclopentylbutyl, cyclohexylbutyl, cycloheptylbutyl and the like. 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. Straight-chain or branched-chain alkyl of the formula: Examples thereof include halogen, alkyl, alkyloxy, and nitro), 2-acetoxityl, 3-acetoxoxypropyl, and 4-acetoxoxybutyl.

The term "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.

As R ⁴ and R ^5, 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. In 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.

If the compounds of the present invention can form salts, these 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. In addition, hydrates (monohydrate, 1Z dihydrate, 3-dihydrate, etc.) and other solvates are also included in the present invention.

When 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.

Method 1

General formula

(In the formula, each symbol is as defined above.)

And a reactive derivative thereof represented by the formula:

LA ³ -Y-NR ⁷ R ⁸ vii)

LA ⁴ one 0- CO- A one R ix)

LA ⁸ 1 0-R ² 〗 xii)

(In the formula, 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 ) By reacting with the compound represented by

(1) 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. In a solvent 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] The reaction is performed at a temperature of 0 ° C to 250 ° C using a deoxidizing agent such as Ndeco 7-ene.

(2) — 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) When reacting a reactive derivative such as an anhydride with a compound in which L in formulas vi i) and ix) represents a hydroxyl group, particularly when an acid halide is used, sodium hydroxide, water This is performed using a deoxidizing agent such as potassium oxide, sodium carbonate, potassium carbonate, and triethylamine. When using a mixed acid anhydride, 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.

Method 2

General formula (III)

(In the formula, each symbol is as defined above.)

And a condensed pyrazole compound represented by

L'-A ² -COO-A ³ -Y-NR ⁷ R ⁸ xiii)

L 'one A ² — COO— A ⁴ —〇 one CO— A ⁵ — R ¹⁷ xv)

A "COO

xvn

L 'I A ² — COO— A ⁸ —〇R ² ' xviii)

(Wherein L ′ represents a suitable leaving group other than the hydroxyl group of L, and the other symbols are as defined above.) A method for producing by reacting a compound represented by the following formula:

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. In 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.

Further, the compounds of the general formulas (II) and (III), which are starting compounds, can be synthesized by the method described in JP-A-2-82558.

When the compound of the general formula (I) of the present invention is a compound that forms N-methyl oxide, 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. The reaction black port Holm, Jikurorome Tan, Jechirue one ether, benzene, acetone, Jiokisan, in a solvent inert to the reaction such as Asetonitoriru, carried out at a temperature of O ^e C~ l 0 0 Hand.

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.

When an asymmetric carbon is present in the compound of the general formula (I) of the present invention and a pharmaceutically acceptable salt thereof, 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.

When a compound of general formula (I) or a pharmaceutically acceptable salt thereof is used as a medicine

, By itself or mixed with suitable pharmacologically acceptable carriers, excipients, etc. It can be administered orally in the form of capsules, powders and the like. The dosage may vary depending on the target disease, symptoms, age, administration method, etc., but is usually about 10 to 50 mg / day for an adult, and is administered once or divided into several doses. be able to.

Next, the specific action of the compound of the present invention will be specifically described.

Experimental example 1 Leukocyte phagocytic activity

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 μl 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.

Experimental Example 2 Recovery of white blood cell count

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. On day 4 after cyclophosphamide administration, 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.

Experimental Example 3 Antitumor experiment

Male CDF, mice 1 0 ⁶ IMC cancer cells (derived from a microorganism Chemical Laboratory) to (8 weeks old) were implanted intraperitoneally, the compound of the present invention once a day from the day after transplantation, administered within 5 consecutive days ip . Observe the survival or death of 3 or 6 mice per group and calculate TZC (%) = (MST of NS TZ control group of treatment group) x 100 from M'ST Mean Survival Time). to.

Experimental example 4 Recovery effect of platelet count in bone marrow transplant mice

Radiation 8. 0 Gy in I CR mice 6-8 weeks old were whole body irradiation, and then port 1 0 ⁷ syngeneic mouse bone marrow cells. The compound of the present invention is administered intravenously continuously for 9 days from the day after bone marrow transplantation. On day 1 after bone marrow transplantation, heparinized blood is collected from the abdominal aorta of the mouse, and the platelet count is measured using an automatic hemocytometer. The experiment is performed with 5 animals per group. Experimental Example 5 Recovery-promoting action of platelet count reduction in rats treated with anticancer drugs

Administer 3 mg of dimustine hydrochloride intravenously to a 6-week-old SD rat, and intravenously administer 15 mg of Zkg the next day. After the first administration of dimustine hydrochloride, the compound of the present invention is intravenously administered for four days on days 8, 9, 10, and 14. On a certain day after administration, 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.

Experimental Example 6 Recovery effect of red blood cell count in X-ray irradiated mice (preventive effect)

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)

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.

Experimental Example 8 Recovery action of red blood cell count in bone marrow transplanted mice

6-8 radiation 8. 0 Gy in I CR mice age and body irradiation and then port 1 0 ⁷ syngeneic mouse bone marrow cells. The compound of the present invention is administered intravenously continuously for 9 days from the day after bone marrow transplantation. On day 1 after bone marrow transplantation, heparinized blood is collected from the abdominal aorta of the mouse, and the number of red blood cells is measured using an automatic hemocytometer. The experiment is performed with 5 animals per group. Further, the high bioavailability of the compound of the present invention is revealed by the following experimental methods. Example 9 Bioavailability test

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.

Reference compound: (Sat) 13- (4-1 (2-dimethylamino-11-methylethoxy) phenyl 2-H-pyrazo-mouth [3,4-b] Pyridine-11-acetic acid Table 1: Bioavailability And absorption rate Rat dog Compound of Example 3 Control compound Compound of Example 3 Control compound

(2mg / kg) (2mg / kg) (2mg / kg) (2mg / kg)

BA 4 1 4 2 6 1 3 (%) Absorption rate 7 0 1 5 (%) Experimental Example 10 Acute toxicity

The compound of Example 6 did not show any death at 100 mg / kg / kg after single oral administration to a rat.

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.

Therefore, the compound of the present invention is useful as an orally administrable therapeutic agent for pancytopenia.

Hereinafter, the present invention will be described specifically with reference to Production Examples and Examples, but the present invention is not limited thereto.

Production Example 1

(1) Suspend 27 g of 60% sodium hydride in 15 Om1 of toluene, and add a mixture of 200 ml of toluene containing 75 g of (+)-1-dimethylamino-2-brovanol to 50 ml. It was added dropwise at 60 ° C. After cooling, add dimethylformamide 20 Om1, and add 10 2 g of 2-chloro-1- (4-fluorobenzoyl) pyridine at 10 10 ^ ^ -5 ° C. It was put into the batch. It took 3 hours, gradually raising the temperature to 4 O ^e C, an additional 2 hours heating at 4 O ^e C, to complete the reaction by stirring. Water was added, the toluene layer was separated, washed with water, and the toluene layer was extracted with dilute hydrochloric acid. The extract was made alkaline with potassium carbonate, and the liberated oil was extracted with toluene. By distilling off toluene, 190 g of crude 2-chloro-3-C4- (2-dimethylamino-1-methylethoxy) benvyl] pyridine was obtained as an oil.

(2) Above crude product 190 g, pyridine 60 Om1 and hydrazine hydrate 92 g The mixture was refluxed and stirred for 12 hours. Pyridine was distilled off, and toluene (500 ml) was added to the residue, and the mixture was dissolved by heating to 40 to 50 ° C. After washing with warm water, toluene was distilled off. The residue was crystallized by adding isopropyl ether, collected by filtration, and recrystallized from a mixture of isopropyl ether and isopropyl alcohol to obtain a melting point.

(25) to 127 ° C (+) — 3— (4- (2-dimethylamino-1-methylethoxy phenyl.) Phenyl) -1 1-H-pyrazo-mouth [3,4-b] Pyridine 10.7 g O [] D ²³ = + 15.3 ° (c = l, methanol)

(3) Suspend 2.7 g of 60% sodium hydride in 46 ml of toluene, add 31 ml of dimethylformamide under ice-cooling, and then add (+) — 3—C4-(2 —Dimethylylminnow 1-methylethoxy) phenyl) -11H-pyrabro [3,4-1b] Pyri'din 18 g was added in 2-3 divided doses. After stirring for 15 minutes, a mixed solution of 8.2 g of ethyl acetate and 16 ml of toluene was added dropwise, and the mixture was reacted at room temperature for 1 hour and at 40 ° C. for 1 hour. After cooling, water was added, the toluene layer was separated, washed with water and dried. By removing the toluene, the crude ethyl (+) — 3— [4- (2-dimethylamino 1-methylethoxy) phenyl] 1 1H-pyrazo mouth [3,4-b] pyridine 1 1 1 20.8 g of acetate were obtained as an oil.

(4) 20.8 g of the above crude product was dissolved in 43 ml of methanol, a solution of 2.4 g of sodium hydroxide and 21 ml of water was added, and the mixture was stirred at room temperature for 1 hour. After adjusting the pH to 7 with dilute hydrochloric acid and distilling off methanol, the residue was purified using a synthetic adsorbent (trade name: Diaion HP-20). After recrystallization from water-containing isopropyl alcohol (including water of crystallization), ethanol was added and the mixture was heated to a melting point of 21-2 to 13 ° C.

(+)-3 -C4-(2-Dimethylamino-11-methylethoxy) phenyl] -1H-pyrabro [3,4-1b] Pyridine-11-acetic acid was obtained. (CO _D ²² = +25

7 ° (c = 1, methanol)

Production Example 2

(1) (1) A reaction treatment using 1-dimethylamino-12-propanol in the same manner as in (1) and (2) of Production Example 1 yields (1) -3-3 having a melting point of 125 to 127. [4- (2-Dimethylamino-1-methylethoxy) phenyl] -11H-pilabro [3,4-b] pyridine was obtained. [H] _D ²³ = —15.0. (C = l, Evening Nord)

(2) (1-)-3- (4- (2-Dimethylamino-11-methylethoxy) phenyl) -1H-pyrazo-mouth [3,4-b] Using pyridine, ) (by reaction treatment in the same manner as 4), mp 2 1 2 to 2 1 4 ^e C of (1) one 3- [4 one (2-dimethylamino § plasminogen 1 one-methylethoxy) phenyl] one 1 H —Pyrabro [3,4-b] Pyridine-1-monoacetic acid was obtained. []. ²³ = — 25.0. (C = l, methanol)

Example 1

(Earth) 1 S- (4- (2-dimethylamino-1-methylethoxyquin) phenyl) 1 1 H-pyrazo mouth [3,4-b] Pyridine-11-acetic acid 3. Og and potassium carbonate 1.1 g 0.9 ml of 2-chloroacetamide was added to 10 ml of a dimethylformamide suspension of the above, and the mixture was stirred at 45'C for 2 hours. Under ice-cooling, 50 Oml of water was added to the reaction solution, and the mixture was extracted with 50 ml of chloroform. After the extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1.6 g of a pale yellow oil. Crystals obtained by treating this oily substance with 20% ethanol-hydrochloride were recrystallized from ethanol to give (soil) one-piece rubamoylmethyl 3- (4- (2- Dimethylamino-1 monomethylethoxyquin) phenyl) 1H-pyrazo-mouth [3,4-b] pyridine-11-acetate hydrochloride monohydrate 0.7 g was obtained.

Example 2

(Earth) 3- (4- (2- (1-dimethylamino-1-methylethoxy) phenyl) -11-H-pyrazo [3,4-b] 3.5 g of pyridine-11-monoacetic acid and 1.4 g of potassium carbonate the dimethylformamidine de suspension 1 0 m 1 2-chloro-N- Mechiruase evening Mi de 2 g, and the mixture was stirred for 2 hours at 4 5 ^e C. Under ice-cooling, 50 ml of water was added to the reaction solution, and the mixture was extracted with 5 mL of chloroform. After the extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 3.O g of a pale yellow oil. The crystals obtained by treating this oil with 20% ethanol-chloride were recrystallized from ethyl acetate-ethanol to give (E) -N-methylcarbamoylmethyl with a melting point of 170-172. 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1-1H-villazolo [3,4-b] pyridine-11-acetate hydrochloride 1 / 2-hydrate 0.6 g Was.

Example 3

(Earth) 1- (4- (2-Dimethylamino-1-methylethoxy) phenyl)-1 H-Pyrazo-mouth [3,4-b] Pyridine-1-1-acetic acid 3.5 g of dichloromethane

To a suspension of 15 ml, 1.2 g of thionyl chloride and 2-3 drops of dimethylformamide were added, and the mixture was stirred at room temperature for 1 hour. Under ice-cooling, add 1.2 g of N-methylmorpholine and 1.0 g of 2-hydroxy-1-N, N-dimethylacetamide to dichloroethane solution.

1 Oml was added. The mixture was stirred at the same temperature for 1 hour and further at room temperature for 2 hours. The reaction solution was washed with water, washed with a saturated aqueous solution of sodium hydrogen carbonate, and further washed with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 2.5 g of a yellow oil. Crystals obtained by treating this oily substance with 20% monoisopropyl alcohol hydrochloride were recrystallized from isopropyl alcohol to give (Sat) 1N, N-dimethylcarbamoylmethyl 3- (melting point: 104 to 105). 4- (2-Dimethylamino-1-methylethoxy) phenyl) 1 H-Pyrazo mouth [3,4-1b] Pyridine-11-acetate

1.6 g were obtained.

Example 4

(Sat) 1-3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1-1H-pyrazo [3,4-b] pyridine-11-monoacetic acid 5. Og and triethylamine 1.5 g ethyl acetate solution 1 in 25 ml 5. In C, 10 ml of a solution of 1.9 g of isobutyl chloroformate in ethyl acetate was added dropwise, and the mixture was stirred at the same temperature for 15 minutes. A solution of 2.5 g of 2-hydroxy-N, N-getylacetamide in 10 ml of ethyl acetate was added dropwise with a pressure of −5, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was washed with water, washed with an aqueous solution of potassium carbonate, and further washed with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a brown oily substance. Crystals obtained by treating this oily substance with 20% hydrochloric acid-ethanol were recrystallized from ethyl acetate-ethanol to give (Sat) -N, N-getylcarbamoyl having a melting point of 165-166. Methyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) -1H-pyrazo-mouth [3,4-b] pyridine-11-acetate hydrochloride 1 Z2 hydrate 2.9 g was obtained. .

Example 5 (Sat) 13- (4- (2-Dimethylamino-1-methylethoxy) phenyl) -11H-Pyrabro [3,4-b] pyridine 5.0 g of dimethylformamide solution 0.68 g of 60% sodium hydride was added, and the mixture was stirred for 1 hour. 20 mL of a dimethylformamide solution of 4.3 g of 2-bromoacetic acid 5-indanyl ester was added at 0 ° C, and the mixture was stirred for 2 hours. Under ice-cooling, 50 ml of water was added to the reaction solution, and extracted with 50 ml of chloroform. After the extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1.6 g of a pale yellow oil. The oily substance was treated with 20% hydrochloric acid-ethanol, and the resulting crystals were recrystallized from isopropyl ether-ethanol to give a melting point of 205-207. C (Sat) 1-Indane-5-yl 3- (4- (2-Dimethylamino-1-methylethoxy) phenyl) 1-1H-Pyrazo mouth [3,4-b] Pyridine-11-acetate hydrochloride 2.0 g were obtained.

Example 6

(10)-3-(4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1H-pyrazo-mouth [3,4-b] pyridine-11-monoacetic acid 20 g and potassium carbonate 5.4 g dimethyl To 40 ml of the formamide suspension, 7.2 g of 2-chloro-N, N-dimethylacetamide was added, and the mixture was stirred with 45 and 2 hours. Under ice-cooling, add 20 ml of 15% aqueous sodium chloride solution to the reaction solution, extract twice with 100 ml of toluene, dry with magnesium sulfate, evaporate the solvent under reduced pressure, and colorless and transparent oil. 13 g were obtained. The oil was crystallized from isopropyl ether and recrystallized from ether to give a melting point of 69-71. S (+)-N, N-dimethylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) of C-1H-pyrabro [3,4-b] pyridine-11-acetate was obtained. . [H] _D = + 9.2 ° (c = 1, methanol)

Corresponding hydrochloride monohydrate: Melting point 102-104 ^e C, [H] _D = + 14.7 ° (c = 1, water)

-NMRCCDsOD) d: 1.3 (3H.d) .2.92 (3H.s), 2.97 (6H.s), 2.98 (3H, s). 3.45 (1H.dd), 3.54C1H, dd), 4.92 (2H .s). 4.96-5.07 (1H.m), 5.5K2H.s), 7.22C2H, d), 7.30 (1H, dd), 7.98 (2H.d), 8.49 (1H.d), 8.55 (1H, d)

Hereinafter, the following compounds can be similarly synthesized. Example 7

(Earth)-2-(N, N-dimethylamino) ethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1 H-pyrabro [3, 4-b] pyridin-1-acetate G dihydrochloride, mp 2 4 5 ^e C

Example 8

(Sat) 1-Vivaloyloxymethyl 3- (4- (2-dimethylamino 1-methylethoxy) phenyl) 1 1 H-Pyrazo mouth [3,4-b] Pyridine-1-acetate hydrochloride, melting point 1 9 7 ° C

Example 9

(Sat) 1-1-Piberidylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1-1H-Pyrazo-mouth [3,4-1b] Pyridine-11-acetate, melting point 9 2 ~ 94 ° C

Example 10

(Earth) 1 N, N-diisopropyl rubamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1-H-pyrazo mouth [3,4-b] pyridine-11-acetate, melting point 9 6 ~ 9 8. C

Example 1 1

(Earth) — N, N-dibutylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1H-pyrazo-mouth [3,4-b] pyridin-1-acetate, melting point 6 2-6 Four. C

Example 1 2

S (+)-N, N-Jetylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1H-Pyrazo-mouth [3,4-b] pyridin-111 acetate, [N] _D = + 8.9 ° (c = methanol)

H-NMRCCDCh) δ: 0.92-1.28 (6H, m), 1.29C3H.d). 2.36C6H.s), 2.57 (2H.dd), 2.96-3.52C4H.m) .4.42-4.72 (1H.m) ). 4.80 (2H, s), 5.50 (2H.s) .7.03 (2H, d), 7.06-7.27 (2H.m), 7.86 (2H.d). 8.30 (1H.dd) .8.54C1H , dd)

Corresponding hydrobromide salt: Melting point 141-143 ° C, [H] _D = + 14.0 ° (c = 1, water) Example 13

S (+) — N, N-diisopropyl rubamoyl methyl 3- (4- (2-dimethylamino 1-methylethoxy) phenyl) -11H-pyrazo mouth [3,4-b] pyridine-11-acetate, [ a] _D = +8.0. (C = l, methanol)

'HN RCCDCh) (5: 0.80-1.56 (15H.m), 2.36C6H, s) .2.57C2H, dd), 3.42-3.82 (2H, m) .4.42-4.72C1H, m), 4.78 (2H, s ) .5.50 (2H, s), 7.03 (2H.d) .7.06-7.32 (2H, m), 7.85 (2H.d), 8.3K1H, dd), 8.55C1H, dd)

Example 14

(Sat) 1-morpholinocarbonylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1-H-pyrazo [3,4-b] pyridine-11-acetate

Example 15-

(Earth) 1 2- (N, N-Getylcarbamoyl) ethyl 3- (4-1 (2-Dimethylamino-1-methylethoxy) phenyl) 1-1H-Pyrabro [3,4-b] Pyridine-1-1-acete G

Example 16

(Sat) 1-N-cyclohexylcarbamoylmethyl 3- (4- (2-dimethylamino-11-methylethoxy) phenyl) -11H-Pyrabro [3,4-b] pyridin-11-acetate, melting point 1 30 ~ 1 32 ° C

Example 17

(±) — 1,2,3,4-tetrahydrodronaphthalene-1-yl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1 H-pyrazo [3,4-1! )] Pyridine 1-11 acetate

Example 18

(Sat) 1-Benzoyloxymethyl 3- (4- (2-dimethylamino 1-methylethoxy) phenyl) -1H-Pyrazo mouth [3,4-b) pyridin-1-acetate

Example 19

(Earth) 1 N-phenylcarbamoylmethyl 3- (4-(2-dimethylamino 11-Methylethoxy) phenyl) 1-H-pyrazo mouth [3,4-b] pyridine 1-acetate

Example 20

(Sat) 1-4-Methylphenyl 3- (4- (2-dimethylamino 1-methylethoxy) phenyl) 1-1H-Pyrabro [3,4-b) pyridine-11-acete

Example 2 1

(Sat) 1-Diacetylaminoethyl 3- (4- (2-Dimethylamino 1-methylethoxy) phenyl) 1-1H-Pyrazo mouth [3,4-b] Pyridin-1

Example 22

(Sat) 12- (N, N-dimethylcarbamoylamino) ethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1H-pyrazo [3,4-1b] pyridine One 11 One

Example 23

N, N-Dimethylcarbamoylmethyl 3- (4- (3-dimethylaminopropoxy) phenyl) 1-1H-pyrabro [3,4-b] pyridine-11-acetate Example 24-

N, N-Dimethylcarbamoylmethyl 3- (4- (3-dimethylaminopropoxy) phenyl) 1-6-isopropyl-1H-pyrabro [3,4-b] pyridin-1-acetate

Example 2 5

N, N-Dimethylcarbamoylmethyl 3- (4- (3-dimethylaminopropoquine) phenyl) 1-6-methyl-1H-pyrabro [3,4-b] pyridine-11-acetate

Example 26

(Sat) 1-N, N-dimethylcarbamoylmethyl 2-methyl-1- (3- (4- (3-dimethylaminobroboxyl) phenyl) -1H-Py'razolo [3,4-b] pyridin-1 Le) Probionet Example 2 7

N, N-dimethylcarbamoylmethyl 3- [3- (4- (3-dimethylaminopropoxydi) phenyl) 1 1H-pyrazo port [3,4-b) pyridin-1-yl] propionate

Example 2 8

N, N-Dimethylcarbamoylmethyl 6- [3- (4- (3-dimethylaminobromoboxyl) phenyl) -1-H-pyrazo [3,4-b] pyridin-1-yl] hexanoet

Example 2 9

N, N-Dimethylcarbamoylmethyl 3- (4- (2-dimethylaminoethylamino) phenyl) 1 1 H-Pyrazo [3,4-b) Pyridine 1-l-acetate 1 h

Example 30

(Earth) 1 N, N-dimethylcarbamoylmethyl 3- (4- (2-dimethylamino 1-methylethoxy) phenyl) 1-6-isopropyl-1 H-pyrabro [3,4-1b] pyridine-11-acetate G

Example 3 1

S (Earth) 1 N, N-dimethylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1-6-isopropyl-1 H-pyrazo

[3,4-b] Pyridine-1 1-acetate

Example 3 2

(Earth) 1 N, N-dimethylcarbamoylmethyl 3- (4- (2-dimethylamino 1-methylethoxyphenyl) -16-methyl-1 H-pyrazo-mouth [3,4-b] pyridine-11-acete One

Example 3 3

(Earth) 1 N, N-dimethylcarbamoylmethyl 3- (4- (2-dimethylamino 1-methylethoxy) phenyl)-6-tertiary butyl-1 H-pyrazo [3,4-b) pyridine One 1—Acetate-Example 3 4 (Earth) 1 N, N-dimethylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) -1,4,6-dimethyl-1 H-pyrabro [3,4-1b] pyridine-11-acetate

Example 35

N, N-Dimethylcarbamoylmethyl 3- (4- (2-dimethylaminoethylthio) phenyl) 1-1H-pyrabro [3,4-b] pyridine-11-acetate Example 36

(Sat) 11-ethoxycarbonyloxetyl 3- (4- (2-dimethylamino-1-methylethoxyquin) phenyl) 1-1H-pyrabro [3,4-1b] pyridin-1-yl acetate

Example 37

(Sat) 1-phthalidyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1-1H-pyrazo-mouth [3,4-b] pyridine-11-acetate Example 38

(Sat) -Methoxymethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) -11H-pyrazo-mouth [3,4-1b] Pyridine-11-acetate Example 3 9

(±) — 5-Methyl-1,3-dioxolene 2-one- 4-methyl 4- (4- (2-dimethylamino-1-methylethoxyquin) phenyl) 1 1-Hylazolo [3,4-b] Pyridine 1 acetate

Formulation example 1

5 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.

Although the present invention has been described in detail with reference to the specification including production examples and examples, various changes and modifications can be made without departing from the spirit and scope of the present invention.

Claims

The scope of the claims

(1) — General formula

[Wherein, X represents = N— or = CH—; R ¹ , R ² , and R ³ are the same or different and represent hydrogen, halogen, alkyl, or alkoxy; and Z represents —0—, —S— or Represents one NR— (where R represents hydrogen or alkyl); A ¹ and A ² are the same or different and represent a single bond or alkylene; R ⁴ and R ⁵ are the same or different and represent hydrogen, alkyl R ⁶ , aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl or acyloxyalkyl, or a group in which R ⁴ and R ⁵ form a heterocyclic ring with an adjacent nitrogen atom; Is the expression

.- A ³ -Y-NR ⁷ R ⁸ i)

(Wherein A ³ represents alkylene, Y represents a single bond, —C〇— or one CH (0H) one, and R ⁷ and R ⁸ may be the same or different and represent hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, Ryo sills, Ariru, phenylalanine alkyl or 1 to 3 halogens, hydroxy, carboxy, alkoxycarbonyl, phenylene Le alkyl O alkoxycarbonyl, one 0- R ⁹ (wherein, R ³ is 1 be substituted by to 3 halogens or hydroxyl group represents an alkyl or Ariru.), with -CONR ¹⁰ R ⁿ (wherein, R ^ie, RH is a hydrogen or alkyl Le identical or different.) one 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 which forms a heterocyclic ring with an adjacent nitrogen atom) or - OCOR ¹⁴ (here , R "is optionally substituted by 1-3 halogens or hydroxyl alkyl, Ariru or Fuwenirua Indicate the kill. Represents alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, acyl, aryl or phenylalkyl substituted by

, R ⁷ and R ⁸ represent a group which forms a heterocyclic ring with an adjacent nitrogen atom. ) A group represented by the formula

(Wherein 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 , R ^{] 6} together with a benzene ring A group forming a condensed ring, a group represented by:

A ⁴ -OCO-A ⁵ R ¹⁷ iii)

(Wherein, A ⁴ represents alkylene, A ⁵ represents a single bond or 10-, R ¹⁷ is alkyl optionally substituted with 1 to 3 halogens or hydroxyl groups, cycloalkyl, cycloalkylalkyl , Aryl, and phenylalkyl).

(In the formula, A ⁶ represents a single bond or alkylene, and R ¹⁸ and R ″ may be the same or different and represent hydrogen, halogen, hydroxyl, nitro, amino, alkyl, alkoxy, cycloalkyl or cycloalkylalkyl.) Represents a group represented by the formula R 20

— ^A7 7 =

.0

'丫

0

(In the formula, A ⁷ represents a single bond or alkylene; R ² ° represents hydrogen or alkyl, cycloalkyl, cycloalkylalkyl, aryl or phenylalkyl which may be substituted by 1 to 3 halogen or hydroxyl groups. A) or a group represented by the formula

-A ⁸ -0-R ^2] vi)

Or a pharmaceutically acceptable salt thereof.

(2) R ⁶ is the formula

A ³ -Y-NR ⁷ R ⁸ i)

(Wherein 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, cyclo cycloalkylalkyl, Ashiru, Ariru, the phenylalanine alkyl or 1 to 3 halogens, hydroxy, carboxy, alkoxycarbonyl, phenylene Le alkyl O alkoxycarbonyl, one 0- R ³ (wherein, R ⁹ is 1 to 3 pieces of a halogen or an alkyl or Ariru optionally substituted by a hydroxyl ^{^{group.), -CONR, 0 R]}} 1 ( wherein, R '°, R' ¹ represents a hydrogen or alkyl Le identical or different. ), One NR ¹² R] ³ (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 which forms a heterocyclic ring with an adjacent nitrogen atom) shown.) or single 0C0R ¹⁴ ( In this, the alkyl R ¹⁴ is substituted by.) Showing the 1-3 halogens or alkyl optionally substituted by hydroxyl, Ariru or Fuwenirua alkyl, alkenyl, cycloalkyl , Cycloalkylalkyl, acyl, aryl or phenylalkyl

(Wherein, 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 fused with a benzene ring A group forming a ring, a group represented by:

A ⁴ -OCO-A ⁵ R ¹⁷ iii)

(In the formula, A ⁴ represents alkylene, A ⁵ represents a single bond or 10-, R ¹⁷ is alkyl, cycloalkyl, cycloalkylalkyl optionally substituted by 1 to 3 halogens or hydroxyl groups, 2. The carboxylate compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a group represented by aryl or phenylalkyl.

(3) R ⁶ is the formula

— A ³ -Y-NR ⁷ R ⁸ i)

(In the formula, A ³ represents alkylene, Y represents a single bond, one CO— or one CH (0H) one, and R ⁷ and R ⁸ may be the same or different and represent hydrogen, alkyl, alkenyl, cycloalkyl, cyclo Alkylalkyl, acyl, aryl, phenylalkyl or 1-3 halogens, hydroxyl, carboxy, alkoxycarbonyl, phenylalkyloxycarbonyl, 110 R ⁹ (where R ^s is be substituted by 1-3 halogens or hydroxyl group represents an alkyl or Ariru.), ^{-CONR, 0} R (where, R ", R ¹ 'is hydrogen or alkyl Le identical 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 form a heterocyclic ring with an adjacent nitrogen atom. The group to be formed is shown. Or —OCOR ^14, wherein R ¹⁴ represents alkyl, aryl or phenylalkyl optionally substituted by 1 to 3 halogens or hydroxyl groups.) Or alkyl, alkenyl, cycloalkyl, cyclo It represents an alkylalkyl, an acyl, an aryl or a phenylalkyl, or a group in which R ⁷ and R ⁸ form a heterocyclic ring with an adjacent nitrogen atom. 3. The carboxylic acid ester compound according to claim 1, which is a group represented by the formula: or a pharmaceutically acceptable salt thereof.

(4) X represents -N =; R ¹ represents hydrogen, halogen, alkyl or alkoxy; R ² and R ³ represent 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 -Y-NR ⁷ R ⁸ i)

(Wherein A ³ represents alkylene, Y represents a single bond or a CO—, R ⁷ and R ⁸ are the same or different and represent hydrogen, alkyl, cycloalkyl, aryl, or R ⁷ , R ⁸ And a group forming a heterocyclic ring with an adjacent nitrogen atom.

— A ⁴ -0C0-A ⁵一 R〗 ⁷ iii)

(In the formula, A ⁴ represents alkylene, A ⁵ represents a single bond, R ¹⁷ represents alkyl, aryl, phenyloxy which may be substituted by 1 to 3 halogen or hydroxyl groups. Indicate the kill. 3. The compound according to claim 1, which is a group represented by the formula: or a pharmaceutically acceptable salt thereof.

(5) X represents -N =; R ¹ represents hydrogen, halogen, alkyl or alkoxy; R ² and R ³ represent hydrogen; Z represents 1-11; A ¹ and A ² represent alkylene R ⁴ and R ⁵ are the same or different and represent hydrogen, alkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl or acyloxyalkyl;

R ⁶ is the formula

A ³ -Y-NR ⁷ R ⁸ i)

(Wherein, A ³ represents alkylene, Y represents a single bond or one CO—, R ⁷ R 8 are the same or different and represent hydrogen, alkyl, cycloalkyl, aryl, or R ⁷ , R ⁸ are adjacent 5. The carboxylic acid ester compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a group represented by the following formula:

(6) ◎ (Sat) Rubamoyl Methyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 H-Pyrazo Mouth [3,4-b] Pyridine 1-acetate

◎ (Sat) 1-N-methylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1-H-pyrazo-mouth [3,4-b] Pyridine-1

◎ (Sat) 1 N, N-Dimethylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1H-Pyrazo mouth [3, 4-b] Pyridin-11-acetate

◎ (Sat) 1 N, N-Jetylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1H-Pyrabro [3,4-b] pyridin-11-acetate

◎ (Sat) 1-indan-5-yl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1H-pyrabro [3,4-b] pi'lysine-11-acetate ◎ (Sat) 1 2— (N, N-dimethylamino) ethyl 3- (4— (2-dimethylamino-1-methylethoxy) phenyl) 1 1 H—Pyrazo mouth [3, 4—b] pyridin-1 1-acetate

◎ (Sat) -Pivaloyloxymethyl 3- (4- (2-dimethylamino-11-methylethoxy) phenyl) -1H-Pyrazo-mouth [3,4-b] Pyridine-1-1-acetate

◎ (Sat) 1-1-Piberidylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1-1H-pyrabro [3,4-b] pyridin-11 acetate

◎ (Sat) 1 N, N-diisopropyl rubamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1H-pyrabro [3,4-b] pyridine-11-acetate

◎ (Sat) — N, N-dibutylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1-H-pyrazo [3,4-b] pyridin-1-acetate

◎ (Sat) 1-N-cyclohexylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1-1H-Pyrazo mouth [3,4-b] Pyridine-11-acetate

◎ S (+) — N, N-dimethylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxyquin) phenyl) 1 1 H-pyrazo mouth [3, 4-b] pyridin-11-acetate

◎ S (+) — N, N-Getylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1 H-Pyrazo mouth [3,4-b] pyridin-1 1-acetate

◎ S (+) — N, N-diisopropyl rubamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxyquin) phenyl-1H-pyrazo mouth [3,4-b] pyridine-11-acetate

The carboxylic ester compound according to claims 1 to 2 or 4, which is selected from the group consisting of: and a pharmaceutically acceptable salt thereof.

(7) ◎ (Earth) Rubamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1-1H-pyrabro [3,4-b] Pyridine-1-acetate

◎ (Sat) 1-N-methylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1-H-pyrazo mouth [3,4-b] Pyridine-11-acetate

◎ (Sat) 1 N, N-dimethylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1H-pyrazo [3,4-1b] pyridin-11-acetate

◎ (Sat) 1 N, N-Jetylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1-H-pyrazo mouth [3, 4-b] pyridin-1-acetate

◎ (±) — 1-Piberidylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1-1H-pyrazo-mouth [3,4-b] pyridin-1-acetate

◎ (Sat) i-N, N-diisopropyl rubamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) -1 1-H-pyrazo mouth [3,4-b] pyridine-11-acetate

◎ (Sat) 1 N, N-dibutylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1H-pyrabro [3, 41-b] pyridine 11-acetate

◎ (Sat) 1-N-cyclohexylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1-H-pyrazo [3,4-b] pyridine 11-acetate

◎ S (+)-N, N-dimethylcarbamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1-H-pyrabro [3,4-b] pyridine-11-acetate

◎ S (+) — N, N—Jetylcarbamoylmethyl 3- (4- (2-dimethylaminoamine 1-methylethoxy) phenyl) 1 1H-pyrabro [3,4-b) Lysine 1 11

◎ S (+)-N, N-diisopropyl rubamoylmethyl 3- (4- (2-dimethylamino-1-methylethoxy) phenyl) 1 1H-pyrabro [3,4-b] pyridine-11-acetate

The carboxylate compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which is selected from the group consisting of:

(8) A pharmaceutical composition comprising, as an active ingredient, the carboxylic acid ester compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

(9) A therapeutic agent for pancytopenia, comprising as an active ingredient the carboxylic acid ester compound according to claims 1 to 7 or a pharmaceutically acceptable salt thereof.