JP2002356446A - Medicinal solution - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicinal solution in which non-peptide physiologically active substance is dissolved in high concentration. SOLUTION: The medicinal solution comprises non-peptide physiologically active substance, organic acid and an biocompatible organic solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical solution containing a non-peptide physiologically active substance, an organic acid and a biocompatible organic solvent.

[0002]

2. Description of the Related Art As a non-peptidic pharmaceutical solution of a physiologically active non-peptidic substance, for example, a solution injection solution prepared by dissolving testosterone enanthate in a solvent composed of chlorobutanol and sesame oil (Delatestril, Beatty Pharmaceutical) Or Haloperidol decanoate in a solvent consisting of benzyl alcohol and sesame oil (Haldor, Ort McNail Pharmaceuticals, USA). Japanese Patent Application Laid-Open No. 05-017356 discloses a liquid composition in which nifedipine is dissolved in a solvent composed of polyvinylpyrrolidone and polyethylene glycol.

[0003]

Although water-free pharmaceutical solutions of the above non-peptidic physiologically active substances have been studied, non-peptidic physiologically active substances have to be reduced in size to be administered. No technique has been reported for dissolving the non-peptidic physiologically active substance at a higher concentration in a solvent in which the active substance is dissolved.

[0004]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and produced for the first time a pharmaceutical solution comprising a non-peptidic physiologically active substance, an organic acid and a biocompatible organic solvent. However, surprisingly, the non-peptidic physiologically active substance dissolves more than the solubility of the non-peptidic physiologically active substance in the biocompatible organic solvent, and has excellent effects in formulation such as miniaturization of the preparation. I found something to give. Further, based on these findings, as a result of further intensive studies, the present invention has been completed. That is, the present invention provides (1) a pharmaceutical solution comprising a non-peptidic physiologically active substance, an organic acid and a biocompatible organic solvent, and (2) an organic acid comprising a lower fatty acid, an aliphatic hydroxycarboxylic acid and an aromatic organic acid. The pharmaceutical solution according to the above (1), which is one or more organic acids selected, (3) the pharmaceutical solution according to the above (2), wherein the aliphatic hydroxycarboxylic acid is lactic acid,
(4) The pharmaceutical solution according to the above (2), wherein the aromatic organic acid is an aromatic hydroxycarboxylic acid, (5) the pharmaceutical solution according to the above (4), wherein the aromatic hydroxycarboxylic acid is salicylic acid, (6) The pharmaceutical solution according to the above (4), wherein the aromatic hydroxycarboxylic acid is 1-hydroxy-2-naphthoic acid or 3-hydroxy-2-naphthoic acid; The pharmaceutical solution according to 4), wherein (8) the aromatic hydroxycarboxylic acid is selected from salicylic acid, 1-hydroxy-2-naphthoic acid, 3-hydroxy-2-naphthoic acid and pamoic acid
A pharmaceutical solution according to the above (4), which is a mixture of
(9) The pharmaceutical solution according to the above (1), wherein the non-peptide physiologically active substance is a basic substance, and (10) the pharmaceutical solution according to the above (1), wherein the molecular weight of the non-peptide physiologically active substance is about 1,000 or less. (11) The pharmaceutical solution according to the above (1), wherein the biocompatible organic solvent is polyethylene glycol or a fatty acid ester thereof, or dimethyl sulfoxide, (12) a pharmaceutical solution according to the above (12), further comprising a hydrophilic polymer. (14) the pharmaceutical solution according to (1), wherein the content of the non-peptidic physiologically active substance is about 5% by weight or more based on the total weight of the solution;
The pharmaceutical solution according to the above (1), wherein the content of the organic acid is about 1% by weight to about 40% by weight based on the total weight of the solution, (1)
5) The pharmaceutical solution according to the above (1), which contains about 1/20 to about 100 mol of an organic acid per 1 mol of the non-peptidic physiologically active substance;
The pharmaceutical solution according to the above (1), which contains the non-peptide physiologically active substance at a concentration higher than the solubility in a biocompatible organic solvent, and (17) the pharmaceutical solution according to the above (1), which is a preparation for parenteral administration. (18) The pharmaceutical solution according to the above (17), which is an injection preparation, (19) the implantable preparation containing the pharmaceutical solution according to the above (1), (20) the above-mentioned (1) which is a preparation for oral administration And (21) a capsule containing the pharmaceutical solution according to (1).

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The "non-peptide physiologically active substance" used in the present invention may be a free form or a salt. Examples of the "salt" include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids,
And salts with basic or acidic amino acids. Preferable examples of the metal salt include an alkali metal salt such as a sodium salt and a potassium salt; an alkaline earth metal salt such as a calcium salt, a magnesium salt and a barium salt; an aluminum salt. Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, arginine,
Salts with lysine, ornithine and the like are mentioned. Preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid and the like.

The "non-peptide physiologically active substance" may be any pharmacologically useful substance, and is preferably a synthetic organic compound. The “non-peptidic physiologically active substance” peptide is a peptide consisting of only essential amino acids. Examples of the "synthetic organic compound" include a compound having a hydrophilic portion mainly having a tertiary amine and a highly hydrophobic portion such as a chain or cyclic alkyl and an aromatic group, or a salt thereof. . Specific examples include basic and amphiphilic drugs [CAD (cationic amphiphilic
drug); Pharmacological Reviews (Pharmacolo)
gical Reviews), Vol. 42, No. 4, pp. 327-354]. "Non-peptide bioactive substance"
The basic substance which is preferable as the acid dissociation constant (pK
a) wherein 3) to 8 are used. The pKa can be measured, for example, by the “potentiometry method” described in “The 4th Edition, Experimental Chemistry Lecture 9 Electric and Magnetic”, edited by The Chemical Society of Japan, Maruzen Co., Ltd. (1991), pp. 288-289. Examples of the “non-peptidic physiologically active substance” include substances having a receptor action or antagonistic action, an enzyme inhibitory action, a carrier promoting or suppressing action, and the like. The receptor on which the “non-peptidic physiologically active substance” exerts an agonistic or antagonistic action may be on the cell surface or inside the cell. Such cell surface receptors include, for example, ion channel-linked, G protein-linked and enzyme-linked.
Types of ligands for the receptor include small peptides, proteins, amino acids, nucleotides, steroids, fatty acid derivatives, nitric oxide, carbon monoxide and the like. Examples of the receptor include, for example, luteinizing hormone releasing hormone (LH-R
H) receptor, thyroid stimulating hormone secreting hormone (TR
H) Receptor, corticotropin secreting hormone (CRF)
Receptor, endorphin receptor, substance P receptor, neurotensin receptor, thyroid stimulating hormone (T
SH) receptor, lactating hormone (PRL) receptor, follicle stimulating hormone (FSH) receptor, luteinizing hormone (LH) receptor, adrenocorticotropic hormone (ACTH) receptor and the like.

[0007] Examples of enzymes which the "non-peptide physiologically active substance" exhibits an inhibitory action include blood coagulation enzymes, fibrinolytic enzymes, digestive enzymes, phosphorylases, metabolic enzymes, antioxidant enzymes and the like. Examples of the enzyme include monoamine oxidase (MAO), angiotensin converting enzyme, HMG-
CoA reductase, cholesterol esterification enzyme (AC
AT), cyclooxygenase (COX), trypsin, α-chymotrypsin, kallikrein, β-galactosidase, elastase, thrombomodulin, thrombin, blood coagulation factors (factor I-X), protein C, protein S, plasmin, plus Minogen activator, urokinase, protein kinase C, tyrosine kinase, cytochrome p450s (3
A4, 1A, 2C, 2D, etc.) and superoxide dismutase (SOD). Examples of the enzyme whose CAD exhibits an inhibitory action include those derived from human cells, bacteria, phages or viruses. CAD exhibiting the inhibitory effect is expected to have an antibacterial or antiviral effect. Examples of the enzyme include a cross-linking enzyme transpeptidase, penicillin-binding proteins (PBP-1A, PBP-1B, PBP-2, PBP-2).
-3, PBP-4, PBP-5, PBP-6), neuraminidase, aminopeptidase A, aminopeptidase B, α-amylase, β-lactamase, reverse transcriptase inhibitor and the like.

[0008] Carriers in which the "non-peptidic physiologically active substance" exhibits promotion or suppression include, for example, passive or active ion channels, glucose transporters, peptide transporters, p-glycoprotein and the like. Examples of the carrier include voltage-gated sodium channels, calcium-gated sodium channels, potassium-gated calcium channels, potassium channels,
Chloride ion channel, gastric mucosal proton pump (H ⁺ ,
K ⁺ -ATPase), glucose transporters (GLUT1, GLUT2, GLUT3, GLUT
4), PEPT1, MDR1, MDR2, MRP, cM
OAT, ACT1 and the like.

The "non-peptidic physiologically active substance" is not particularly limited as long as it has the above-mentioned activity. , Indomethacin, atropine, scopolamine, morphine, pethidine or a salt thereof, as those having a tranquilizing action, diazepam, lorazepam, etc., as those having an antibacterial action, griseofulvin, etc., as those having an action as an antibiotic , Dibekacin, canendomycin, ribidomycin, tobramycin, amikacin, fradiomycin, sisomycin, tetracycline, oxytetracycline, lolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin, cephalothin Lysine, cefotiam, cefotiam hexetil, cefsulodin, cefmenoxime, cefmetazole, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazesin, azuleonal or a salt thereof, as those having antitumor activity, fumegillin, tomycin, tomycin, tomemycin, tofumycin Fluorouracil and the like have an anti-hyperlipidemic effect; Clofibrate and the like have an antitussive and expectorant effect; ephedrine, methylephedrine, noscapine, codeine, dihydrocodeine, cloperastine, protokyrol, and isoproterenol , Salbutamol, terbutaline or a salt thereof, etc., have a muscle relaxing action, and pridinol, pancuronium, etc. As phenytoin, acetazolamide, chlordiazepoxide, etc., as those having an anti-ulcer effect, metoclopramide, etc., as those having an antidepressant effect, clomipramine, etc., as those having an anti-allergic effect, diphenhydramine, triperenamine, Diphenylpyraline,
Methoxyphenamine, etc., has a cardiotonic effect,
Ethylephrine, etc., as an arrhythmia therapeutic effect,
Alprenolol, bufetrol, oxprenolol, etc., as those having a vasodilatory effect, oxyfedrine, bamethane, etc., as those having a hypotensive diuretic effect,
Pentolinium, mecamyl aluminate, clonidine, etc.
As those having a therapeutic effect on diabetes, glybuzole and the like have antitubercular activity, ethambutol, paraaminosalicylic acid, etc. Including estrogens, luteinizing hormones (LH), dexamethasone, hexestrol, betamethasone, triamcinolone, triamcinolone setonide, fluocinolone acetonide,
Prednisolone, hydrocortisone and the like. Further, as fat-soluble vitamins, vitamins A, vitamin D
, Vitamin E, vitamin K, folic acid (vitamin M)
And the like.

[0010] The "non-peptidic physiologically active substance" is CAD
Examples of such properties include, for example, amilodarone, promethazine, those showing a receptor antagonism such as propranolol, chloramphenicol, those showing an enzyme inhibitory action such as gentamicin, amitriptyline,
Those exhibiting a carrier antagonism such as imipramine and trimiprosine are exemplified.

[0011] As the "non-peptide physiologically active substance",
For example, gonadotropin releasing hormone (GnRH (Go
nadotropin releasing hormone)) agonists (agonists) or antagonists (antagonists), more preferably GnRH antagonists. Such GnR
H is luteinizing hormone releasing hormone: LH-RH (Lu
It has a teinizing hormone-releasing hormone) -like effect. The “GnRH antagonist” includes GnRH
Any compound having an antagonistic action may be used. For example, the following [I] (compound (I) or a salt thereof), [I
Embodiments of [I], [III] and [IV] are exemplified.
[I]

[0012]

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[Wherein R ¹ and R ² each represent a hydrogen atom, a hydroxy group, a C _1-4 alkoxy group, a C _1-4 alkoxy-carbonyl group or a C
_1-4 alkyl group, R ³ is a hydrogen atom, a halogen atom, or a hydroxy group or an optionally substituted C _1-4 alkoxy group, or linked two adjacent R ³ C May form a _1-4 alkylenedioxy group, R ⁴ represents a hydrogen atom or a C _1-4 alkyl group, and R ⁶ represents a C _1-4 alkyl group which may have a substituent or a formula

[0014]

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Wherein R ⁵ represents a hydrogen atom or R ⁴ and R ⁵ may be linked to each other to form a heterocyclic ring, and n is 0 to 5 Or a salt thereof. The definition of each substituent in the above formula is described below. The “C _1-4 alkoxy group” represented by R ¹ and R ² includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like. Of these, a C _1-3 alkoxy group is preferred. More preferably, it is methoxy. The “C _1-4 alkoxy-carbonyl group” represented by R ¹ and R ² includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl and the like. Of these, a C _1-3 alkoxy-carbonyl group is preferred. More preferred is methoxycarbonyl. Examples of the “C _1-4 alkyl group” of the “ _optionally substituted C _1-4 alkyl group” represented by R ¹ and R ² include, for example, a linear C _1-4 alkyl group (eg, , Methyl,
Ethyl, propyl, butyl, etc.), a branched C _3-4 alkyl group (eg, isopropyl, isobutyl, sec-butyl, te)
rt-butyl and the like). Among, C _{1 -3} alkyl group. Especially, ethyl is preferable.

The “substituent” of the “optionally substituted C _1-4 alkyl group” represented by R ¹ and R ² includes:
For example, (i) hydroxy, (ii) C _1-7 acyloxy (eg, C _1-6 alkyl-carbonyloxy such as acetoxy, propionyloxy), (iii) benzoyloxy, (iv) C _1-6 alkoxy-carbonyl ( Eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), benzyloxycarbonyl, C _1-4 acyl (eg, C _1-3 alkyl-carbonyl such as acetyl, propionyl), C _1-4 alkyl (eg, methyl) , Ethyl, propyl, butyl and the like) and C _1-3 alkylsulfonyl (eg, methanesulfonyl and the like) and an amino group which may have one or two substituents (eg,
Amino, dimethylamino, methoxycarbonylamino,
Ethoxycarbonylamino, tert-butoxycarbonylamino, benzyloxycarbonylamino, acetylamino, methanesulfonylamino, etc.), (v) C _1-10 alkoxy (eg, methoxy, ethoxy, propoxy, tert.
-Butoxy, etc.), (vi) C _3-7 cycloalkyloxycarbonyloxy-C _1-3 alkoxy (eg, cyclohexyloxycarbonyloxy-1-ethoxy, etc.), (vi
i) C _1-3 alkoxy-C _1-3 alkoxy (eg, methoxymethoxy, methoxyethoxy, etc.) and the like.
Of these, hydroxy is preferred. The “C _1-4 alkyl group” of the “C _1-4 alkyl group _optionally having substituent (s)” represented by R ¹ and R ² may be, for example, 1 to 5 at the substitutable position. , Preferably 1 to 3, and when the number of substituents is 2 or more, each substituent may be the same or different. One of R ¹ and R ² is preferably a hydrogen atom and the other is a C _1-3 alkoxy group.

The "halogen atom" for R ³ includes, for example, fluorine, chlorine, bromine and iodine. Of these, chlorine is preferred. As the "C _1-4 alkoxy group" of the "optionally C _1-4 alkoxy group which may have a substituent" represented by R ^3, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert- butoxy And the like. Of these, methoxy is preferred. R
^3, as the "substituent" of the "optionally having substituent optionally C _1-4 alkoxy group" represented, the R ¹ and R ² "which may have a substituent C ₁ represented by And the same as the "substituent" of the " _-4 alkyl group". C _1-10
Alkoxy is preferred, especially C _1-4 alkoxy such as methoxy, ethoxy, propoxy, tert-butoxy. The C _1-4 alkoxy group may have, for example, 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions, and when the number of substituents is 2 or more, each substituent May be the same or different. Two adjacent R
Examples of the “C _1-4 alkylenedioxy group” formed by linking ³ include methylenedioxy, ethylenedioxy and the like. R ³ is preferably a hydrogen atom.

The "C _1-4 alkyl group" for R ⁴ includes, for example, a linear C _1-4 alkyl group (eg, methyl, ethyl, propyl, butyl, etc.), a branched C _3-4 alkyl group. Groups (eg, isopropyl, isobutyl, sec-butyl, tert-
Butyl, etc.). Among them, a C _1-3 alkyl group is preferred. Especially, methyl is preferable. Represented by R ⁶ As the "C _1-4 alkyl group optionally having a substituent" represented by R ¹ and R ² "which may have a substituent C _1-4 alkyl group" And the same.

The "heterocycle" formed by linking R ⁴ and R ⁵ includes a 5- or 6-membered nitrogen-containing heterocyclic group. When R ⁴ and R ⁵ are linked, the formula

[0020]

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The group represented by the formula:

[0022]

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And the like. Of these, the formula

[0024]

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A group represented by the following formula is preferred.

R ⁶ is represented by the formula

[0027]

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In the formula, R ⁵ has the same meaning as described above. R ⁴ is a C _1-3 alkyl group and R ⁵
Is preferably a hydrogen atom. n is preferably an integer of 0 to 2.

[0029] In compound (I), preferred compounds, R ¹ is hydroxy group, a methoxy group or a C _1-3 alkyl group; R ² is a hydrogen atom or a C _1-3 alkyl group; R ⁴ is C
_A compound wherein R ⁶ is a benzyl group; and n is 0, or a salt thereof. Of these, preferred are compounds in which R ¹ is a methoxy group; R ² is a hydrogen atom; R ⁴ is a C _1-3 alkyl group; R ⁶ is a benzyl group; Specific examples of compound (I) include 5- (N-benzyl-N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4
-(3-Methoxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H)
-Dione, 5- (N-benzyl-N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4
-(3-hydroxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3
H) -dione, 5- (N-benzyl-N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6
[4- (3-methylureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3
H) -dione, 5- (N-benzyl-N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6
[4- (3-ethylureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3
H) -dione or a salt thereof. Among them, 5- (N-benzyl-N-methylaminomethyl)-
1- (2,6-difluorobenzyl) -6- [4- (3
-Methoxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione or a salt thereof is preferred.

The salt of compound (I) is preferably a physiologically acceptable acid addition salt. Such salts include:
For example, inorganic acids (eg, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,
Phosphoric acid, etc.) or organic acids (eg, formic acid, acetic acid,
Salts with trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. When the compound (I) has an acidic group, an inorganic base (eg, an alkali metal salt such as sodium, potassium, calcium, magnesium, or an alkaline earth metal, ammonia, etc.) or an organic base (eg, trimethylamine, triethylamine , Pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,
And N, N′-dibenzylethylenediamine) to form physiologically acceptable salts.

The compound (I) is not particularly limited, but may be any of known methods, for example, JP-A-9-169768.
JP-A-2001-278, a method described in WO 96/24597, a method analogous thereto, or JP-A-2001-278.
It can be produced by the method described in JP-A-884 or WO00 / 56739 or a method analogous thereto. In detail, the following production method 1 and production method 2 are mentioned. The compounds in the reaction schemes include those forming salts, and examples of the salts include the same as the salts of compound (I).

[0032]

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In the above formula, L is a leaving group, and other symbols are as defined above. As the "leaving group" for L, for example, 1-imidazolyl, a halogen atom, an alkoxy group which may have a substituent and the like are mentioned. As the "optionally substituted alkoxy group",
A C _1-4 alkoxy group optionally having 1 to 3 halogen atoms (eg, chlorine, bromine, etc.) (eg, 2,2,2-
Trichloroethoxy group).

Compound (II) is described, for example, in JP-A-9-169.
No. 768, WO96 / 24597, or a method analogous thereto. Compound (II
I) can be obtained by a known method. The compound (II) is reacted with carbonyldiimidazole (N, N'-carbonyldiimidazole; CDI) or phosgene (including dimers and trimers) to obtain a compound (IV) and then a compound (III) ) To give compound (I). The compound (IV) may be allowed to continue the reaction without isolation, or may be isolated and used in the next step. Compound (IV) can also be obtained by reacting compound (II) with a chloroformate compound (eg, 2,2,2-trichloroethyl chloroformate, 1-chloroethyl chloroformate, etc.).

In the reaction of compound (II) with carbonyldiimidazole or phosgene, the amount of carbonyldiimidazole or phosgene used is the same as that of compound (II) 1
It is about 1 to 3 moles per mole. This reaction is generally performed in a suitable solvent that does not adversely influence the reaction. Examples of the solvent include ethers (eg, ethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg, benzene,
Examples thereof include toluene, etc., amides (eg, dimethylformamide, dimethylacetamide, etc.), and halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.). The reaction temperature is generally about 0 to about 150 ° C, preferably at room temperature (about 15 to about 25 ° C). The reaction time is usually about 1 to about 36 hours. The reaction is
If necessary, the reaction is performed in the presence of a base. Examples of the “base” include sodium carbonate, sodium hydrogen carbonate,
Potassium carbonate, potassium bicarbonate, sodium hydroxide,
An inorganic base such as potassium hydroxide or thallium hydroxide, or an organic base such as triethylamine or pyridine is used. The amount of the “base” to be used is about 2 mol to about 20 mol, preferably about 5 mol to about 12 mol, per 1 mol of compound (II). The subsequent compound (II
The reaction conditions with I) may be the same as those for reacting compound (II) with carbonyldiimidazole or phosgene. The amount of compound (III) to be used is about 2 to about 20 mol, preferably about 5 to about 10 mol, per 1 mol of compound (II) or compound (IV). The reaction temperature is generally about 0 to about 150 ° C, preferably at room temperature (about 15 to about 25 ° C). The reaction time is
Usually about 1 to about 6 hours. Further, carbonyldiimidazole or phosgene and compound (III) may be simultaneously reacted with compound (II).

[0036]

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In the above formula, R ⁷ is a hydrogen atom or an alkyl group, R ⁸ is an alkyl group, and other symbols are as defined above. Represented by R ⁷ and R ⁸ as "alkyl group", "C _1-4 alkyl group" of the "optionally substituted C _1-4 alkyl group" represented by R ¹ and R ² Similar ones can be mentioned.

Compound (V) can be prepared by a known method, for example, p-
Reaction of nitrophenylacetone, a cyanoacetate derivative and sulfur (eg, Chem. Ber., Vol. 99, 94-100)
P. 1966), the resulting 2-amino-4-methyl-5.
-(4-Nitrophenyl) thiophene is disclosed in
No. 69768, WO 96/24597 and the like or by a method analogous thereto.

When R ⁷ is a hydrogen atom, compound (V) is
In the presence of a condensing reagent, the formula

[0040]

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Wherein each symbol is as defined above, or a salt thereof (hereinafter abbreviated as compound (VI)) to give compound (VII), followed by a ring closure reaction To give compound (I). Examples of the “condensation reagent” include, for example, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (benzotriazol-1-yloxytripyrrolidinophosphonium)
hexafluorophosphate: PyBOP). The amount of the "condensing reagent" used is 1 mole of the compound (V),
About 1 to about 3 moles. This reaction is generally performed in a suitable solvent that does not adversely influence the reaction. Examples of the solvent include alcohols (eg, ethanol, methanol, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons (Eg, chloroform, dichloromethane, etc.). The reaction temperature is generally about 0 to about 150 ° C., preferably,
At room temperature (about 15 to about 25 ° C.). The reaction time is
Usually, from about 1 to about 36 hours. The product can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method.

Compound (I) can be obtained by subjecting compound (VII) to a ring closure reaction in the presence of a base. Examples of the “base” include sodium methoxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide,
An inorganic base such as thallium hydroxide or an organic base such as triethylamine or pyridine is used. The amount of the “base” to be used is about 2 mol to about 20 mol, preferably about 5 mol to about 1 mol, per 1 mol of compound (VII).
2 moles. This reaction is generally performed in a suitable solvent that does not adversely influence the reaction. As the solvent, for example,
Alcohols (eg, ethanol, methanol, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons (eg, chloroform,
Dichloromethane and the like are used. The reaction temperature is generally about 0 to about 150 ° C., preferably at room temperature (about 1 ° C.).
5 to about 25 ° C). The reaction time is generally about 1 to about 36 hours.

When R ⁷ is an alkyl group, compound (V)
Is reacted with the activated compound (VI) to obtain a compound (I). The activated compound (VI) can be produced according to a known method, and is obtained, for example, by reacting an organoaluminum reagent with compound (VI) in a suitable solvent that does not adversely influence the reaction. As the “organoaluminum reagent”, for example, trimethylaluminum, dimethylaluminum chloride and the like, or a solution containing these and the like can be mentioned. The amount of the “organoaluminum reagent” to be used is about 1 to about 5 mol, preferably 1 mol, per 1 mol of compound (VI). Examples of the solvent include halogenated hydrocarbons (eg, chloroform,
Dichloromethane) is preferred. The reaction temperature is usually
It is at about 0 to about 150 ° C, preferably at room temperature (about 15 to about 25 ° C). The reaction time is usually about 1 to about 6 hours. Compound (V) is activated compound (V
By reacting with (I), a ring-closing reaction is performed to obtain compound (I). The amount of the "compound (V)" to be used is preferably about 1/5 of the mixture of the compound (VI) and the organoaluminum reagent. This reaction is generally performed in a suitable solvent that does not adversely influence the reaction. As the solvent, the solvent used in the reaction for obtaining the activated compound (VI) is preferable. The reaction temperature is generally about 0 to about 15
0 ° C., preferably at room temperature (about 15 to about 25 ° C.). The reaction time is generally about 1 to about 48 hours.

Compound (I) can be isolated and purified by a known separation means, for example, recrystallization, distillation, chromatography and the like. When the compound (I) is obtained in a free form, it can be converted to a target salt by a known method or a method analogous thereto. It can be converted into a free form or another desired salt by an analogous method. Compound (I) may be a hydrate or a non-hydrate. Examples of the hydrate include monohydrate, 1.5-hydrate and dihydrate. When the compound (I) is obtained as a mixture of optically active substances, it can be separated into the desired (R) -form or (S) -form by known optical resolution means. Compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, etc.).

[II] Formula (VIII)

[0046]

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[Wherein, R⁹May have a substituent
C_1-7Alkyl group, optionally substituted C_3-7Shiku
Loalkyl group, optionally substituted C_1-6Arco
Hydroxy optionally having a xyamino group or a substituent
A cyamino group is represented by R^TenIs an optionally substituted C_1-7
Phenyl group which may have an alkyl group or a substituent
And R⁹Is unsubstituted C_1-7Is an alkyl group
If R^TenIs the substituted C _1-7Alkyl group or substituted
Or a salt thereof.
[Hereinafter, it may be abbreviated as compound (VIII)]. the above
The definition of each substituent in the formula is described below. R⁹Indicated by
"C optionally having substituent (s)_1-7Alkyl group "
_1-7Examples of the “alkyl group” include a straight-chain C_1-7Alkyl group
(E.g., methyl, ethyl, propyl, butyl, pentyl,
Hexyl, heptyl, etc.), branched C_3-7Alkyl group
(Eg, isopropyl, isobutyl, sec-butyl, tert-
Butyl, isopentyl, neopentyl, etc.)
Can be Among them, branch C_3-7Alkyl groups are preferred.
Especially, isopropyl is preferable. R⁹Indicated by
"C optionally having substituent (s)_1-7Alkyl group
Examples of the “substituent” include (i) hydroxy, (ii) C_1-7
Acyloxy (eg, acetoxy, propionyloxy
Which C_1-6Alkyl-carbonyloxy; benzoylo
(Iii) C)_1-6Alkoxy-carbonyl
(E.g., methoxycarbonyl, ethoxycarbonyl, tert
-Butoxycarbonyl, etc.), benzyloxycarbonyl
Le, C_1-3Acyl (eg, acetyl, propionyl, etc.)
C_1-2Alkyl-carbonyl, etc.), C_1-3Alkylsul
Honyl (eg, methanesulfonyl, etc.) and C_1-3Al
Substitutions selected from kills (eg, methyl, ethyl, etc.)
Amino which may have one or two groups (eg,
, Methoxycarbonylamino, ethoxycarbonyla
Mino, tert-butoxycarbonylamino, benzyloxy
Cicarbonylamino, acetylamino, methanesulfoni
Amino, methylamino, dimethylamino, etc.), (i
v) C_3-7Cycloalkyloxycarbonyloxy (eg,
Cyclohexyloxycarbonyloxy) and C
_1-3Select from alkoxy (eg, methoxy, ethoxy, etc.)
C which may have 1 to 3 substituents
_1-10(Preferably C_1-4) Alkoxy (eg, methoxy,
Ethoxy, propoxy, tert-butoxy, cyclohexyl
Leoxycarbonyloxy-1-ethoxy, methoxymeth
Toxi, ethoxymethoxy, etc.), (v) C_1-6Alkoki
C-carbonyl (eg, methoxycarbonyl, ethoxyca
Rubonyl, propoxycarbonyl, etc.)
You. Of these, hydroxy is preferred. The "C_1-7Archi
Is, for example, one of the above substituents at a substitutable position.
May have five, preferably one to three,
When the number of substituents is 2 or more, each substituent is the same or different
It may be.

R⁹Represented by `` may have a substituent
C<sub>3-7</sub>"C" in the "cycloalkyl group"<sub>3- 7</sub>Cycloalkyl
As the `` group '', for example, cyclopropyl, cyclobutyi
, Cyclopentyl, cyclohexyl, cycloheptyl
And the like. Among them, preferably, cyclopro
Pills. R⁹Having a substituent
May be C_3-7"Substituent" of "cycloalkyl group"
Is the above R⁹"C optionally having substituent (s)
_1-7The same as the “substituent” of the “alkyl group”
There are three. When the number of substituents is 2 or more, each substituent
May be the same or different. R⁹"
C optionally having a substituent_1-6Alkoxyamino group "
"C _1-6Examples of the “alkoxyamino group” include, for example, mono
-Or di-C_1-6Alkoxyamino group (eg, methoxy
Amino, ethoxyamino, dimethoxyamino, diethoxy
Ciamino, ethoxymethoxyamino, etc.)
It is. Of these, Mono-C_1-3Alkoxyamino group
(Eg, methoxyamino, etc.) are preferred. R⁹Indicated by
C which may have a substituent_1-6Alkoxyamino
The “substituent” of the “group” includes the above R⁹Replace with
C optionally having a group_1-7"Substituent" of "alkyl group"
And the same number is the same. 2 or more substituents
In the case, each substituent may be the same or different. The
"Substituents" are C_1-6"C" of the alkoxyamino group_1-6Al
The “Coxy group” or the “amino group” may be substituted.
The "C which may have a substituent"_1-6Alkoxyamino
Specific examples of `` group '' include methoxyamino, ethoxyamino
No, dimethoxyamino, diethoxyamino, ethoxyme
Toxamino and the like.

The “substituent” of the “optionally substituted hydroxyamino group” for R ⁹ may be substituted for the “hydroxy group” or the “amino group” of the hydroxyamino group. Examples of the substituent on the “hydroxy group” include (i) a C _1-7 acyl group (eg, C _1-6 alkyl-carbonyl such as acetyl and propionyl; benzoyl and the like); (ii) C _1-6 alkoxy- Carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), benzyloxycarbonyl, C _1-3
Selected from acyl (eg, C _1-2 alkyl-carbonyl such as acetyl, propionyl, etc.), C _1-3 alkylsulfonyl (eg, methanesulfonyl, etc.) and C _1-3 alkyl (eg, methyl, ethyl, etc.) An amino group optionally having one or two substituents (specific examples: amino, methoxycarbonylamino, ethoxycarbonylamino, tert-butoxycarbonylamino, benzyloxycarbonylamino, acetylamino, methanesulfonylamino, methylamino, Dimethylamino), (ii
i) C _3-7 cycloalkyloxycarbonyloxy (eg,
Cyclohexyloxycarbonyloxy) and C
C which may have 1 to 3 substituents selected from _1-3 alkoxy (eg, methoxy, ethoxy, etc.)
_1-10 (preferably C _1-4 ) alkyl groups (eg, methyl, ethyl, propyl, tert-butyl, cyclohexyloxycarbonyloxy-1-ethyl, methoxymethyl, ethoxymethyl, etc.) and the like; Examples of the substituent on the "nitrogen atom of the group" include the groups described in the above (i) to (iii). Each substituent of the “hydroxy group” or “amino group” of the hydroxyamino group may be the same or different. Preferred examples of the “hydroxyamino group optionally having a substituent” include an N—C _1-6 alkyl-N-hydroxyamino group (eg, N-methyl-N-hydroxyamino, N-ethyl-N -Hydroxyamino), an NC _1-3 alkyl-NC _1-3 alkoxyamino group (eg, N-methyl-N-methoxyamino, N-ethyl-N-methoxyamino, etc.) and the like. More preferably, it is an NC _1-3 alkyl-N-hydroxyamino group.

The “C _1-7 alkyl group” of the “C _1-7 alkyl group _optionally having substituent (s)” for R ¹⁰ includes:
For example, a linear or branched C _1-7 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, etc.) and the like can be mentioned. Can be Of these, a C _1-3 alkyl group (eg, methyl,
Ethyl, propyl, isopropyl, etc.) are preferred. Particularly preferred is isopropyl. Represented by R ¹⁰ in the "optionally substituted C _1-7 alkyl group" as "substituent" which may have a "substituent represented by the R ⁹ C _1-7 The same number as the “substituent” of the “alkyl group” is exemplified. When the number of substituents is two or more, each substituent may be the same or different. “Substituent” of the “optionally substituted phenyl group” represented by R ¹⁰
As, for example, halogen (eg, fluorine, chlorine, bromine,
Examples thereof include iodine), a C _1-3 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.) and a C _1-3 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.). Among them, halogen (preferably fluorine) is preferable. The "phenyl group" may have, for example, 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions. When the number of the substituents is 2 or more, each substituent is the same. Or they may be different.

R ⁹ is preferably a substituted branched C _3-7
An alkyl group or a substituted C _3-7 cycloalkyl group,
More preferably, branched C _3-7 substituted with hydroxy.
It is a C _3-7 cycloalkyl group substituted with an alkyl group or hydroxy. Of these, a C _3-7 cycloalkyl group substituted with hydroxy is preferred. Also, a C _1-3 alkyl group optionally substituted with hydroxy, a C _3-7 cycloalkyl group optionally substituted with hydroxy, mono-C _1-3 alkoxyamino, N—C _1-3 alkyl- An N-hydroxyamino group, a hydroxyamino group and the like are also preferable. R ⁹ is particularly preferably a cyclopropyl group or a methoxyamino group which may be substituted with hydroxy. Most preferred is a cyclopropyl group substituted with hydroxy. R ¹⁰ is preferably a C _1-7 alkyl group which may have a substituent. More preferably, C which may be substituted by hydroxy
_{And 1-3} alkyl groups. Particularly preferred is isopropyl. Also, phenyl is preferable. Compound (VIII)
Preferred examples of R ⁹ are a C _1-3 alkyl group optionally substituted with hydroxy, a C _3-7 cycloalkyl group optionally substituted with hydroxy or mono-C _1-3
An alkoxyamino group; a compound in which R ¹⁰ is a C _1-3 alkyl group, or a salt thereof. More preferably, R ⁹ is (1) a C _1-3 alkyl group substituted with one or two hydroxy, and (2) a C _3-7 alkyl group substituted with hydroxy.
A cycloalkyl group, or (3) a C _1-3 alkoxyamino group; a compound in which R ¹⁰ is an isopropyl group or a phenyl group, or a salt thereof. R ⁹ is (1) hydroxy, C _1-3 alkyl-carbonyloxy, amino, benzyloxycarbonylamino, C _1-3 alkoxy, C _1-3 alkoxy-C _1-3 alkoxy and C _1-3 alkoxy- 1 to 2 substituents selected from carbonyl
An optionally substituted C _1-7 alkyl group, (2) a C _3-7 cycloalkyl group optionally substituted with hydroxy or C _1-3 alkyl-carbonyloxy, or (3) a C _1-3 alkyl group.
Alkoxyamino group; R ¹⁰ is (1) Good isopropyl or optionally substituted by hydroxy (2) compounds wherein a phenyl group or a salt thereof is also preferred.

Preferred specific examples of compound (VIII) include 3- (N-benzyl-N-methylaminomethyl)-
4,7-dihydro-5-isobutyryl-7- (2,6-
Difluorobenzyl) -2- (4-cyclopropanecarbonylaminophenyl) -4-oxothieno [2,3-
b] pyridine, 5-benzoyl-3- (N-benzyl-
N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-4-oxo-2- [4
-(3-hydroxy-2-methylpropionylamino)
Phenyl] thieno [2,3-b] pyridine, 5- (4-
Fluorobenzoyl) -3- (N-benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-4-oxo-2- (4-cyclopropanecarbonylaminophenyl) Thieno [2,3
-B] pyridine, 3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-5-isobutyryl-7
-(2,6-difluorobenzyl) -2- [4- (3-
(Hydroxy-2-methylpropionylamino) phenyl] -4-oxothieno [2,3-b] pyridine, 3-
(N-benzyl-N-methylaminomethyl) -4,7-
Dihydro-5-isobutyryl-7- (2,6-difluorobenzyl) -2- (4-N'-methoxyureidophenyl) -4-oxothieno [2,3-b] pyridine;
-(N-benzyl-N-methylaminomethyl) -4,7
-Dihydro-5-isobutyryl-7- (2,6-difluorobenzyl) -2- [4-[(1-hydroxycyclopropyl) carbonylamino] phenyl] -4-oxothieno [2,3-b] pyridine, ( R) -4,7-Dihydro-2- [4- (3-hydroxy-2-methylpropionylamino) phenyl] -7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylamino Methyl) -5-isobutyryl-4-oxothieno [2,3
-B] pyridine, 4,7-dihydro-2- [4- (2-
Hydroxy-2-methylpropionylamino) phenyl] -7- (2,6-difluorobenzyl) -3- (N
-Benzyl-N-methylaminomethyl) -5-isobutyryl-4-oxothieno [2,3-b] pyridine, 4,
7-dihydro-2- [4- (3-hydroxy-3-methylbutyrylamino) phenyl] -7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -5 -Isobutyryl-4-oxothieno [2,3-b] pyridine, (R) -4,7-dihydro-
2- [4- (2,3-dihydroxypropionylamino) phenyl] -7- (2,6-difluorobenzyl)
-3- (N-benzyl-N-methylaminomethyl) -5
-Isobutyryl-4-oxothieno [2,3-b] pyridine, 3- (N-benzyl-N-methylaminomethyl)
-5-benzoyl-7- (2,6-difluorobenzyl) -4,7-dihydro-2- [4-[(1-hydroxycyclopropyl) carbonylamino] phenyl] -4
-Oxothieno [2,3-b] pyridine or a salt thereof.

As the salt of compound (VIII), those similar to the salts of compound (I) can be mentioned. Compound (VIII)
May be a hydrate or a non-hydrate.
Examples of the hydrate include monohydrate, 1.5 hydrate and dihydrate. Compound (VIII) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, etc.).

Compound (VIII) can be prepared by a known method, for example, JP-A-2000-219690, WO00 / 0049.
It can be produced by the method described in Japanese Patent Publication No. 3 or a method analogous thereto.

[III] Formula (IX)

[0056]

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[In the formula, R ¹¹ is a hydrogen atom or a C _1-3 alkyl group, R ¹² is a hydrogen atom, a hydroxy group or a C _1-3 alkoxy group, and R ¹³ is a C ₃ which may have a substituent. _{-7 represents a} branched alkyl group or a C _3-7 cycloalkyl group optionally having substituent (s)] (hereinafter sometimes abbreviated as compound (IX)) or a salt thereof.

The definition of each substituent in the formula (IX) is described below. As the “C _1-3 alkyl group” represented by R ¹¹ ,
Methyl, ethyl, propyl, isopropyl. Of these, methyl and ethyl are preferred. More preferably, it is methyl. The “C _1-3 alkoxy group” represented by R ¹² includes methoxy, ethoxy, propoxy, and isopropoxy. Of these, methoxy and ethoxy are preferred. More preferably, it is methoxy. R
Examples of the “C _3-7 branched alkyl group” of the “ _optionally substituted C _3-7 branched alkyl group” represented by ¹³ include isopropyl, isobutyl, 1-methylpentyl,
-Methylpentyl, 5-methylhexyl, sec-butyl, tert-butyl, isopentyl, neopentyl,
tert-pentyl, isohexyl, 2,4-dimethyl-3-pentyl and the like. Among them, isopropyl, isobutyl, 2,4-dimethyl-3-pentyl and the like are preferable. More preferably, it is isopropyl.

The “substituent” of the “C _3-7 branched alkyl group _optionally having substituent (s)” for R ¹³ includes, for example, (i) hydroxy, (ii) C _1-7 acyloxy group (E.g.,
C _1-6 alkyl-carbonyloxy such as acetoxy and propionyloxy; benzoyloxy and the like, (ii
i) a C _1-10 alkoxy group (eg, methoxy, ethoxy, propoxy, tert-butoxy, etc.) and the like. The “C _3-7 branched alkyl group” may have, for example, one to three of the above substituents at substitutable positions,
When the number of substituents is two or more, each substituent may be the same or different. Represented by R ¹³ in the "optionally substituted C _3-7 cycloalkyl group" as the "C _{3 -7} cycloalkyl group", for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Is mentioned. Of these, cyclohexyl is preferred. As the “substituent” of the “C _3-7 cycloalkyl group _optionally having substituent (s)” represented by R ¹³ , the same number as the above “substituent” can be mentioned.
When the number of substituents is two or more, each substituent may be the same or different. Preferred specific examples of compound (IX) include isopropyl {3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2,6-difluorobenzyl) -2- [4- ( 3-methylureido) phenyl] -4-oxothieno [2,3-b] pyridine-5-carboxylic acid ester} or a salt thereof.

As the salt of compound (IX), compound (I)
And the like.

Compound (IX) can be prepared by a known method, for example, W
It can be produced by the method described in O95 / 28405, a method analogous thereto, or the method described in JP-A-2002-030087. As a specific example, the formula (X)

[0062]

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Wherein R ¹³ is as defined above, or a salt thereof (hereinafter may be abbreviated as compound (X)) and carbonyldiimidazole (N,
N′-carbonyldiimidazole; CDI) or phosgene (including dimers and trimers) and the like, and then the compound of formula (XI)

[0064]

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Wherein each symbol is as defined above, to obtain a compound (IX). Examples of the salts of compounds (X) and (XI) include the same as the salts of compound (IX). Compound (X) can be produced by the method described in WO95 / 28405 or a method analogous thereto. As the compound (XI), a commercially available product can be used. The amount of carbonyldiimidazole or phosgene to be used is about 1 to about 5 mol, respectively, per 1 mol of compound (X). The reaction of compound (X) with carbonyldiimidazole, phosgene, or the like is usually performed in a suitable solvent that does not adversely influence the reaction. Examples of the solvent include ethers (eg, ethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, dimethylformamide, dimethylacetamide, etc.) And halogenated hydrocarbons (eg, chloroform, dichloromethane, and the like). The reaction temperature is generally about 0 to about 50 ° C, preferably about 0 to about 25 ° C. The reaction time is usually about 1 to about 12 hours.

This reaction is carried out, if necessary, in the presence of a base. As the "base", for example, an inorganic base such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, thallium hydroxide, or an organic base such as triethylamine or pyridine is used. . The amount of the “base” to be used is about 1 to about 5 mol, per 1 mol of compound (X),
Preferably, it is about 1 to about 3 moles. The subsequent reaction conditions with compound (XI) may be the same as those for reacting compound (X) with carbonyldiimidazole, phosgene, or the like. The amount of compound (XI) to be used is about 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (X). The reaction temperature is usually
About 0 to about 50 ° C., preferably about 0 to about 2 ° C.
5 ° C. The reaction time is usually about 1 to about 12 hours. Further, carbonyldiimidazole or phosgene and compound (XI) may be simultaneously reacted with compound (X).

Compound (IX) can be isolated and purified by known separation means, for example, recrystallization, distillation, chromatography and the like. When the compound (IX) is obtained in a free form, it can be converted to a target salt by a known method or a method analogous thereto. It can be converted into a free form or another desired salt by an analogous method. Compound (IX) may be a hydrate or a non-hydrate. Examples of the hydrate include monohydrate, 1.5 hydrate and dihydrate.
Compound (IX) is an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, etc.)
It may be labeled with, for example.

[IV] Formula (XII)

[0069]

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[Wherein A or D is a nitrogen atom and the other is a carbon atom or both are nitrogen atoms, B is a nitrogen atom or a carbon atom, m is an integer of 0 to 3, R
¹⁴ , R ¹⁵ and R ¹⁶ are the same or different and are (i) a hydrogen atom or (ii) a group bonded via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, and R ¹⁷ is bonded via a carbon atom R ¹⁸ is a group bonded via a hydrogen atom, a halogen (eg, fluorine, chlorine, bromine, iodine, etc.) or a carbon atom or an oxygen atom, and R ¹⁹ is a group bonded via a hydrogen atom or a carbon atom R ²⁰ represents a homocyclic group or a heterocyclic group which may have a substituent, and the broken line represents a single bond or a double bond, respectively.
Or a salt thereof (hereinafter, compound (XII)
Or its salt).

The definition of each substituent in the formula (XII) is described below. In the formula, the “group bonded via a carbon atom” includes (1) a hydrocarbon group optionally having a substituent, (2) an acyl group optionally having a substituent, (3) Examples include a heterocyclic group having a bond at a carbon atom which may have a substituent, (4) a carboxyl group which may be esterified or amidated, and (5) a cyano group. In the formula, the “group bonded via a nitrogen atom” includes (1) a nitro group, (2)
Wherein -NR ²¹ R ²² [wherein, R ²¹ is hydrogen, may be an optionally substituted hydrocarbon group, an optionally substituted acyl group which may have a substituent hydroxy A heterocyclic group which may have a substituent, a substituent or a group represented by the formula -S (O) t-R
²⁵ is a group represented by the formula: wherein t is an integer of 0 to 2, R ²⁵ is a hydrogen atom or a C _1-10 hydrocarbon group which may have a substituent, and R ²² is hydrogen. A hydrocarbon group which may have a substituent or an acyl group which may have a substituent, or R ²¹ and R ²² are bonded to each other and have a substituent together with an adjacent nitrogen atom. May form a cyclic amino group which may be substituted]. Where:
Examples of the “group bonded via an oxygen atom” include a hydroxy group which may have a substituent. The hydroxy group which may have a substituent includes a group represented by the formula -OR
²⁶ (wherein R ²⁶ is a hydrogen atom or a C _1-10 hydrocarbon group which may have a substituent, a C _1-20 acyl group,
_1-20 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl,
sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl, nonylsulfonyl, decylsulfonyl, undecylsulfonyl, dodecylsulfonyl, tridecylsulfonyl, tetradecylsulfonyl, pentadecylsulfonyl, etc.), And a C _6-14 arylsulfonyl group (eg, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.) or a heterocyclic group. In the formula, the “group bonded via a sulfur atom” includes a group represented by the formula —S (O) t—R ²⁷ (wherein
t represents an integer of 0 to 2, and R ²⁷ represents a hydrogen atom or a hydrocarbon group or a heterocyclic group which may have a substituent.

[0072] As the "which may carboxyl group optionally esterified", the formula -COO-R ^{3 4} (wherein, R ³⁴ is a hydrogen atom or an optionally substituted C _1-10 hydrocarbon group Is shown.). "Carboxyl group which may be amidated" includes a compound represented by the formula -CO
-NR ²⁸ R ²⁹ [wherein, R ²⁸ represents a hydrogen atom, a hydrocarbon group which may have a substituent or an alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy) shows tert- butoxy, pentyloxy, a C _1-6 alkoxy, etc.) such as hexyloxy. R ²⁹ represents a hydrogen atom or a hydrocarbon group which may have a substituent. R ²⁸ and R ²⁹ may combine to form an optionally substituted cyclic amino group together with the adjacent nitrogen atom. ] The group represented by this is mentioned. Examples of the carboxyl group which may be amidated include, for example, a group represented by -CONH ₂ , or a mono- or di-C _1-15 alkylcarbamoyl group, preferably a mono- or di-C _1-10 alkylcarbamoyl group (Eg, methylcarbamoyl, ethylcarbamoyl,
Hexylcarbamoyl, dimethylcarbamoyl, methylethylcarbamoyl, etc.) are preferred.

"Hydrocarbon group optionally having substituent (s)"
Is a C _1-20 hydrocarbon group (preferably a C _1-10 hydrocarbon group), for example. Examples of the C _1-20 hydrocarbon group, for example, (1) as C _1-15 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, tert- butyl, pentyl, hexyl, Heptyl, octyl, nonyl, decyl,
And undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and the like. Among them, C _1-10 alkyl is preferable, and C _1-6 alkyl group is particularly preferable.), (2) C
_3-10 cycloalkyl group (examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like and among them a C _3-6 cycloalkyl group is preferred), (3)
C _2-10 alkenyl groups (for example, vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, butadienyl, 2-methylallyl, hexatrienyl, 3-octenyl and the like; _2-4 alkenyl groups are preferred), (4) _C2-10 alkynyl groups (examples include ethynyl, 2-propynyl, butynyl, 3-hexynyl and the like, among which _C2-6 alkynyl groups are preferred), (5) C _3-10 cycloalkenyl (for example,
Examples include cyclopropenyl, cyclopentenyl, cyclohexenyl and the like, among which a C _3-6 cycloalkenyl group is preferable, and (6) a C _6-14 aryl group (for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl and the like) Among them, phenyl and naphthyl are preferable, and (7) C _7-20 aralkyl group (for example,
Benzyl, phenethyl, include C _6-14 aryl -C _1-6 alkyl group such as benzhydryl, among others benzyl, phenyl -C _1-6 alkyl group such as phenethyl are preferred) and the like.

The hydrocarbon group may have 1 at any substitutable position.
To 6, preferably 1 to 5, more preferably
May have 1 to 3 substituents. The substituent
As, for example, (1) halogen (eg, fluorine, chlorine,
Bromine, iodine, etc.), (2) nitro, (3) nitroso, (4) shea
No., (5) Substituent [eg, (i) C_1-6Alkyl (the C_1-6Archi
Is hydroxy, C_1-6Alkoxy, C_1-3Alkoxy
-C_1-3Alkoxy, C_{1 -3}Alkylthio, hydroxy-
C_1-3Alkoxy, C_1-6Alkyl-carbonyl, carbo
Xy, carbamoyl, C_1-6Alkyl-carbamoyl,
5- to 8-membered heterocyclic group (referred to as "
One heteroatom selected from the group consisting of
The same as "5- to 8-membered heterocyclic group containing 4 to 4")
Or halogen (eg, fluorine, chlorine, bromine, iodine, etc.)
May have 1 to 3 substituents), (ii)
C_1-4Acyl (eg, C_1-4Alkanoyl (eg, formyl,
Acetyl, propionyl, butyryl, isobutyryl
Etc.), C_3-4Alkenoyl (eg, vinylcarbonyl, 1
-Propenylcarbonyl, 2-propenylcarbonyl
Etc.), (iii) C_7-20Aralkyl (C_7-20Aralki
The radical is C_6-14Aryl-C_1-6Alkyl and halogen
N, C_1-3Alkoxy or C_1-41 to 3 alkyl
, Preferably one, as a substituent
I), (iv) C_6-14Aryl (the C_6-14Aryl is halo
Gen (eg, fluorine, chlorine, bromine, iodine, etc.)
Three, preferably one, may have as a substituent
I), (v) C_2-6Alkenyl, (vi) C_3-7Cycloalkyl
Ru, (vii) C_1-3Alkoxy-carbonyl, (viii) mono-
Or di-C_1-6Alkylamino, (ix) C_2-6Alkenyl
Amino, (x) C_1-3Alkoxy-carbonyl, (xi) C_1-6
Alkyl-carbonyl, or (xii) C_3-6Cycloalkyl
Hydroxy-carbonyl)
(6) Formula -S (O) t-R³⁰Wherein t is 0 to 2
Integer, R³⁰Is a hydrogen atom or any substitutable position
1 to 3, preferably 1 substituent (eg halogen
(Eg, fluorine, chlorine, bromine, iodine, etc.), nitro, shear
No, hydroxy, oxo, thioxo, carboxy, shea
No-C_6-14Aryl, halogeno C_6-14Aryl etc.)
Represents a hydrocarbon group which may be
Is C_1-20Hydrocarbon groups, especially C_1-6Alkyl, C_6-14
Aryl, C_7-20Aralkyl is preferred)
Group, (7) an amino group which may have a substituent (e.g., formula-
NR³¹R³²[Wherein, R ³¹And R³²Are the same or different
Is a hydrogen atom, C_1-6Alkyl, C_1-6Alkylamino
-C_1-6Alkyl, C_1-6Alkoxy, C_2-6Alkene
Le, C_3-7Cycloalkyl, phenyl, phenyl-C_1-6
Alkyl, C_1-6Alkanoyl, C_3-6Alkenoyl, C
_3-7Cycloalkyl-carbonyl, phenyl-C_1-6Al
Kill-carbonyl, C_1-6Alkoxy-carbonyl,
Enyl-C_1-6Alkoxy-carbonyl or 5 to
8-membered heterocyclic group (the following “oxygen atom, sulfur,
1 to 4 heteroatoms selected from atoms, nitrogen atoms, etc.
5 to 8-membered heterocyclic group ").
A group represented by the formula:³³[Wherein, R³³Is
(i) hydrogen atom, (ii) hydroxy, (iii) C_1-10Alkyl,
(iv) C_1-6Alkoxy (this alkoxy is halogen or
1 to any position where a substituent such as nitro can be substituted
C which may have three, preferably one_6-14Aryl
), (V) C_3-6Cycloalkyl,
(vi) C_6-14Aryl, (vii) C_6-14Aryloxy, (vi
ii) C_7-20Aralkyl, formula (ix) -NR^{twenty three}R^{twenty four}(Where R
^{twenty three}Is hydrogen or C which may each have a substituent
_1-10Hydrocarbon group, C_1-20Acyl, hydroxy, hetero
A cyclic group or a formula -S (O) t-R^{twenty five}(Where t is not 0
The integer of 2 is represented by R^{twenty five}Is a hydrogen atom, even if it has a substituent
Good C_1-10Represents a hydrocarbon group or a heterocyclic group)
Group^{twenty four}Is hydrogen or C_1-10Indicates a hydrocarbon group,
R^{twenty three}And R^{twenty four}Binds and is replaced with an adjacent nitrogen atom
May form a cyclic amino group which may have a group
An) an optionally substituted amino group represented by
Is (x) a 5- to 8-membered heterocyclic group ("below carbon atom"
Heterogen selected from oxygen, sulfur, nitrogen, etc.
5- to 8-membered heterocyclic group containing 1 to 4 children "
))] (For example, C_1-6Alkano
Il, C_3-6Alkenoyl, C_1-6Alkoxy-carboni
(9) nitrogen atom, oxygen atom and sulfur
Contains 1 to 4 heteroatoms selected from atoms
5- to 8-membered heterocyclic group, (10) sulfo, (11) C_6-14Ants
, (12) C_3-7Cycloalkyl, (13) C_1-6Alkylene
Dioxy (eg, methylenedioxy, ethylenedioxy,
Propylenedioxy, 2,2-dimethylenedioxy
Etc.), (14) oxo, (15) thioxo, (16) C_2-4Alkini
Le, (17) C_3-10Cycloalkyl, (18) C_2-10Alkenyl
(Preferably C_2-6Alkenyl group), (19) C_7-20Ara
Ruquil (ie, C_6-14Aryl-C_1-6Archi
), (20) amidino and (21) azide
You.

Each group used in the description of the "substituent" of the "hydrocarbon group" is exemplified below. C _1-10 alkyl includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (ie, C _1-4 alkyl), pentyl, hexyl (ie, C _1-6 alkyl) ), Heptyl, octyl, nonyl, decyl and the like. C _3-10 cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (ie, C _3-10 cycloalkyl)
_3-6 cycloalkyl), cycloheptyl (ie, C
_3-7 cycloalkyl), cyclooctyl, cyclononyl, cyclodecyl and the like. Examples of C _2-10 alkenyl include vinyl, allyl, isopropenyl, 1
-Butenyl, 2-butenyl, 3-butenyl, butadienyl, 2-methylallyl, hexatrienyl (i.e.
C _2-6 alkenyl), 3-octenyl and the like.
Examples of C _2-4 alkynyl include ethynyl, 2-propynyl, butynyl and the like. As C _1-6 alkoxy, for example, methoxy, ethoxy, propoxy,
Isopropoxy (ie, C _1-3 alkoxy), butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like. Examples of the C _1-3 alkoxy-C _1-3 alkoxy include methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxymethoxy, ethoxyethoxy, ethoxypropoxy, propoxymethoxy, propoxyethoxy, propoxypropoxy and the like. As C _1-3 alkylthio, for example, methylthio, ethylthio, propylthio, isopropylthio and the like can be mentioned.
Examples of hydroxy-C _1-3 alkoxy include hydroxymethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy and the like. C _1-6 alkyl-carbonyl includes, for example, acetyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, tert.
-Butylcarbonyl, pentylcarbonyl, hexylcarbonyl and the like. As C _3-7 cycloalkyl-carbonyl, for example, cyclopropylcarbonyl,
Cyclobutylcarbonyl, cyclopentylcarbonyl,
Cyclohexylcarbonyl, cycloheptylcarbonyl and the like can be mentioned. Examples of the C _1-6 alkoxy-carbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl (that is, C _1-3 alkoxy-carbonyl), butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxy Carbonyl and the like. Examples of C _3-6 cycloalkyloxy-carbonyl include cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, and the like. Examples of phenyl-C _1-6 alkyl-carbonyl include benzylcarbonyl, phenethylcarbonyl and the like. As phenyl-C _1-6 alkoxy-carbonyl, for example, benzyloxycarbonyl,
Phenethyloxycarbonyl and the like. As C _1-6 alkyl-carbamoyl, for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,
Isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, sec-butylcarbamoyl, t
tert-butylcarbamoyl, pentylcarbamoyl,
Hexylcarbamoyl and the like. Examples of the C _1-6 alkanoyl include formyl, acetyl, propionyl, butyryl, isobutyryl and the like. C _3-6
Alkenoyl includes, for example, vinyl carbonyl, 1
-Propenylcarbonyl, 2-propenylcarbonyl,
1-butenylcarbonyl, 1-pentenylcarbonyl and the like can be mentioned. Examples of the C _6-14 aryl include phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl and the like. Examples of the cyano C _6-14 aryl include 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl and the like. Halogeno C
_{As 6-14} aryl, for example, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2
-Chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl,
-Bromophenyl, 2,6-difluorophenyl, 2,
3-dichlorophenyl, 2,4-dichlorophenyl,
Examples thereof include 2,5-dichlorophenyl and 2,6-dichlorophenyl. C _7-20 aralkyl, ie C _6-14 aryl-C _1-6 alkyl, includes, for example, benzyl,
Phenethyl and the like. As C _6-14 aryloxy, for example, phenoxy, 1-naphthyloxy, 2-
Naphthyloxy and the like. Mono- or di-C
_{As 1-6} alkylamino, for example, methylamino,
Ethylamino, propylamino, isopropylamino,
Butylamino, dimethylamino, diethylamino and the like. As C _2-6 alkenylamino, for example,
Vinylamino, allylamino, isopropenylamino,
Examples thereof include 1-butenylamino, 2-butenylamino, 3-butenylamino, butadienylamino, and 2-methylallylamino. Examples of the C _1-6 alkylamino-C _1-6 alkyl include methylaminomethyl, ethylaminomethyl, propylaminomethyl, methylaminoethyl, ethylaminoethyl and the like. Phenyl-C
Examples of _1-6 alkyl include benzyl, phenethyl and the like.

Substituent on hydrocarbon group having substituent
Of which, (9) selected from nitrogen atom, oxygen atom and sulfur atom
5 to 8 members containing 1 to 4 heteroatoms
A heterocyclic group of (11) C_6-14Aryl, (12) C_3-7Cycloa
Lequil, (16) C_2-4Alkynyl, (17) C_3-10Cycloal
Kill group, (18) C_2-10An alkenyl group, and (19) C_7-20A
Aralkyl or the like is located at any substitutable position of the substituent.
Furthermore, 1 to 4, preferably 1 to 3 substituents are
May have. As the substituent which may further have
Are, for example, (1) hydroxy, (2) amino, (3) mono-
Or Di-C_1-4Alkylamino (eg, methylamino, d
Tylamino, propylamino, dimethylamino, diethyl
Ruamino, etc.), (4) C_1-4Alkoxy (eg, methoxy, d
Toxic, propoxy, isopropoxy, butoxy, iso
Butoxy, sec-butoxy, tert-butoxy
Etc.), (5) halogen (eg, fluorine, chlorine, bromine, iodine)
Etc.), (6) Nitro and (7) C_1-6Alkyl (eg, meth
, Ethyl, propyl, isopropyl, butyl, isobu
Chill, sec-butyl, tert-butyl, pentyl,
1 to 3 groups selected from hexyl, etc.)
Preferably one or two groups are mentioned. Also, the charcoal
Hydrogen group is C_3-10Cycloalkyl, C_3-10Cycloalkene
Nil, C_{6-1 Four}Aryl or C_7-20If you are an aralkyl group
In the case where_1-6Alkyl (eg, methyl, ethi
Propyl, isopropyl, butyl, isobutyl, s
ec-butyl, tert-butyl, pentyl, hexyl
Etc.) may have 1 to 3_1-6Al
Kills can also include one to three hydroxy, oxo,
C_1-6Alkoxy (eg, methoxy, ethoxy, propoxy
Si, isopropoxy, butoxy, isobutoxy, sec
-Butoxy, tert-butoxy, pentyloxy, to
Xyloxy, etc.), C_1-3Alkylthio (eg, methylthio
E, ethylthio, propylthio, isopropylthio
Etc.), halogen (eg, fluorine, chlorine, bromine, iodine)
Etc.), may be substituted with carbamoyl or the like. The replacement
C_1-6As alkyl, for example, formyl
(Where methyl is replaced by oxo), carboxy
(Methyl substituted by oxo and hydroxy
Stuff), C_1-6Alkoxycarbonyl (methyl is oxo
And those substituted by alkoxy) (eg, methoxy
Cicarbonyl, ethoxycarbonyl, tert-butoxyca
C such as rubonil_1-6Alkoxycarbonyl, etc.), hydro
Kishi C _1-6Alkyl (eg, hydroxymethyl, hydroxy
Siethyl, hydroxybutyl, hydroxypropyl
Etc.), C_1-3Alkoxy-C_1-6Alkyl (eg, methoxy
Methyl, ethoxymethyl, ethoxybutyl, propoxy
Methyl, propoxyhexyl, etc.). Up
The number of the substituents in the above is 1 to 6, but not 1
And 5 are preferable, and 1 to 3 are particularly preferable.
One or two are most preferred. The substituent further has
The number of substituents which may be optionally present is preferably 1 to 4.
And preferably 1 to 3 and more preferably 1 or 2
Most preferred.

A group linked via a carbon atom, R ²¹ ,
The R ^22, R ²³ and acyl groups in the exemplified substituents described above acyl group which may have as an example of R ^26, include C _1-20 acyl group, e.g., formyl, C
_1-6 alkyl-carbonyl (eg, acetyl, ethylcarbonyl, propylcarbonyl, tert-butylcarbonyl, etc.), C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), C _{6- 14} aryl-carbonyl (eg, benzoyl, naphthoyl, etc.), C _6-14 aryloxy-carbonyl (eg, phenoxycarbonyl, etc.), C _7-20 aralkyl-carbonyl (eg, C _6-14 aryl-C such as benzylcarbonyl, etc.) _1-6 alkyl-carbonyl, etc.), C _7-20 aralkyloxy-carbonyl (eg, C _6-14 aryl-C _1-6 alkoxy-carbonyl such as benzyloxycarbonyl), C _2-4 alkenyl-carbonyl (eg, , 2-propenylcarbonyl etc.), C _3-6 cycloalkyl - carbonyl (e.g., cyclopropylcarbonyl and the like , Tricyclic C _9-10
A bridged cyclic hydrocarbon-carbonyl (eg, adamantyl carbonyl, etc.); Examples of the substituent in the optionally substituted acyl group include the same substituents as those exemplified above as the substituent in the optionally substituted hydrocarbon group.

In the formula, the heterocyclic group in the heterocyclic group or the heterocyclic group which may have a substituent is, in addition to a carbon atom, a heteroatom selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like. A 5- to 8-membered heterocyclic group containing four, a bicyclic or tricyclic fused heterocyclic group formed by condensing two or three of the same or different heterocyclic groups,
And a bicyclic or tricyclic fused heterocyclic group formed by condensing one or two benzene rings with the heterocyclic group. Specific examples of the heterocyclic group include, for example,
(1) thienyl, furyl, pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanil, 1,2,4-thiadiazolyl, 1,2,
3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,
In addition to carbon atoms such as 2,3-triazolyl, 1,2,4-triazolyl, triazinyl, triazolidinyl, 1H- or 2H-tetrazolyl, containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen, etc. 5-membered heterocyclic group; (2) pyridyl, pyrimidinyl, thiomorpholinyl, morpholinyl, triazinyl, pyrrolidinyl,
In addition to carbon atoms such as piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, oxotriazinyl, pyridazinyl, and pyrazinyl, oxygen, sulfur, and nitrogen atoms A 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of: benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-
b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl,
Cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, indolyl, quinolidinyl,
Other than carbon atoms such as 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like, an oxygen atom, a sulfur atom, a nitrogen atom And a bicyclic or tricyclic fused heterocyclic group containing 1 to 4 heteroatoms selected from the above.

The substituent of the substituent which may be substituted on the heterocyclic group
For example, (1) C_1-6Alkyl (eg, methyl, d
Chill, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hex
Etc.), (2) C_2-6Alkenyl (eg, vinyl, allyl, i
Sopropenyl, 1-butenyl, 2-butenyl, 3-butene
Nil, butadienyl, 2-methylallyl, hexatrie
Nyl, etc.), (3) C_2-6Alkynyl (eg, ethynyl, 2-p
Lopinyl, butynyl, 3-hexynyl, etc.), (4) C_3-6Shi
Chloroalkyl (eg, cyclopropyl, cyclobutyl,
Clopentyl, cyclohexyl, etc.), (5) C_5-7Cycloa
Lucenyl (eg, cyclopentenyl, cyclohexenyl,
Cycloheptenyl, etc.), (6) C_7-15Aralkyl (e.g.
C, such as benzyl and phenethyl_6-10Aryl-C_1-5Al
And benzyl), (7) C_6-14Aryl
(E.g., phenyl, naphthyl, anthryl, phenantri
, Acenaphthyl, anthracenyl and the like,
Enyl), (8) C_1-6Alkoxy, (9) C_6-14Arlio
Kishi (eg, phenoxy, etc.), (10) C_1-6Alkanoyl
(E.g., formyl, acetyl, propionyl, butyryl,
Isobutyryl, etc.), (11) C_6-14Aryl-carbonyl
(Eg, benzoyl, etc.), (12) C_1-6Alkanoyloxy
(Eg, formyloxy, acetyloxy, propionyl
Oxy, butyryloxy, isobutyryloxy, etc.), (1
3) C_6-14Aryl-carbonyloxy (eg, benzoyl
Oxy, etc.), (14) carboxyl, (15) C_1-6Alkoxy
-Carbonyl (eg, methoxycarbonyl, ethoxycal
Bonyl, propoxycarbonyl, isopropoxycarbo
Nil, butoxycarbonyl, isobutoxycarbonyl,
tert-butoxycarbonyl, etc.), (16) carbamoyl, (1
7) N-mono-C_1-4Alkyl carbamoyl (eg, N-methyl
Rucarbamoyl, N-ethylcarbamoyl, N-propylca
Rubamoyl, N-isopropylcarbamoyl, N-butylca
Lubamoyl, etc.), (18) N, N-di-C_1-4Alkyl carba
Moyl (eg, N, N-dimethylcarbamoyl, N, N-diethyl
Carbamoyl, N, N-dipropylcarbamoyl, N, N-dib
(19) 3- to 6-membered cyclic amino group
Rubonyl (eg, 1-aziridinylcarbonyl, 1-azetidi
Nylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperi
Dinylcarbonyl, N-methylpiperazinylcarbonyl,
Morpholinocarbonyl), (20) halogen (eg,
Element, chlorine, bromine, iodine, etc.), (21) mono-, di- or
Tri-halogeno-C_1-4Alkyl (eg, chloromethyl,
Dichloromethyl, trifluoromethyl, trifluoroethyl
Chill, etc.), (22) oxo, (23) amidino, (24) imino, (2
5) amino, (26) mono- or di-C_1-4Alkylamino
(Eg, methylamino, ethylamino, propylamino,
Isopropylamino, butylamino, dimethylamino,
Diethylamino, dipropylamino, diisopropyla
Mino, dibutylamino, etc.), (27) carbon atom and one nitrogen
Selected from oxygen, sulfur, nitrogen, etc.
3 to 3 heteroatoms which may contain 1 to 3 heteroatoms
6-membered cyclic amino group (eg, aziridinyl, azetidiny
, Pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazoly
, Pyrazolyl, imidazolidinyl, piperidino, mol
Holino, dihydropyridyl, N-methylpiperazinyl, N-
Ethyl piperazinyl, etc.), (28) C_1-6Alkanoylami
No (eg, formylamino, acetylamino, trifluoro
Roacetylamino, propionylamino, butyrylamino
, Isobutyrylamino, etc.), (29) benzamide, (30)
Carbamoylamino, (31) NC_1-4Alkyl carbamo
Ilamino (eg, N-methylcarbamoylamino, N-ethyl
Rucarbamoylamino, N-propylcarbamoylami
No, N-isopropylcarbamoylamino, N-butyl carb
Bamoylamino, etc.), (32) N, N-di-C_1-4Alkylka
Rubamoylamino (eg, N, N-dimethylcarbamoylamino
No, N, N-diethylcarbamoylamino, N, N-dipropyl
Carbamoylamino, N, N-dibutylcarbamoylamino
Etc.), (33) C_1-3Alkylenedioxy (eg, methylenedioxy
Oxy, ethylenedioxy, etc.), (34) -B (OH)_Two, (3
5) hydroxy, (36) epoxy (-O-), (37) nitro,
(38) cyano, (39) mercapto, (40) sulfo, (41) sulf
Ino, (42) phosphono, (43) sulfamoyl, (44) C_1-6
Alkylsulfamoyl (eg, N-methylsulfamoi
, N-ethylsulfamoyl, N-propylsulfamoy
, N-isopropylsulfamoyl, N-butylsulfa
Moir etc.), (45) di C_1-6Alkylsulfamoyl
(Example: N, N-dimethylsulfamoyl, N, N-diethylsulfur
Famoyl, N, N-dipropylsulfamoyl, N, N-dib
Tilsulfamoyl, etc.), (46) C_1-6Alkylthio
(Eg, methylthio, ethylthio, propylthio, isop
Ropirthio, butylthio, sec-butylthio, tert-butyl
Ruthio, etc.), (47) phenylthio, (48) C_1-6Alkyls
Rufinyl (eg, methylsulfinyl, ethylsulfinyl
Nil, propylsulfinyl, butylsulfinyl
Etc.), (49) phenylsulfinyl, (50) C _1-6Alkyl
Sulfonyl (eg, methylsulfonyl, ethylsulfonyl
, Propylsulfonyl, butylsulfonyl, etc.) and
(51) phenylsulfonyl and the like. The heterocyclic group
The number of the substituents which may be substituted on 1 to 6 is preferably
Or 1 to 3, more preferably 1 or 2
is there.

The heterocyclic group in the heterocyclic group which may have a substituent and has a bond at a carbon atom includes, in addition to the carbon atom, a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom. A 5- to 8-membered heterocyclic group containing 1 to 4, a bicyclic or tricyclic fused heterocyclic group formed by condensing two or three heterocyclic groups which are the same or different from each other, and a heterocyclic group thereof A bicyclic or tricyclic fused heterocyclic group or the like formed by condensing one or two benzene rings with a cyclic group, wherein the heterocyclic group having a bond at a carbon atom constituting the heterocyclic ring is No. Specific examples of the heterocyclic group having a bond at the carbon atom include, for example, (1) thienyl (eg, 2- or 3-thienyl), furyl (eg, 2
-Or 3-furyl, etc.), pyrrolyl (eg, 2- or 3
-Pyrrolyl), oxazolyl (eg, 2-, 4- or 5-oxazolyl), thiazolyl (eg, 2-, 4- or 5-thiazolyl), pyrazolyl (eg, 3-, 4-
Or 5-pyrazolyl), pyrrolidinyl (eg, 2- or 3-pyrrolidinyl, etc.), imidazolyl (eg, 2-,
4- or 5-imidazolyl, etc.), imidazolinyl (eg, 2-imidazolinyl, 4-imidazolidinyl, etc.), isoxazolyl (eg, 3-, 4- or 5-isoxazolyl, etc.), isothiazolyl (eg, 3-, 4-
Or 5-isothiazolyl), oxadiazolyl [eg, 3- or 5- (1,2,4-oxadiazolyl),
2-, 5- or 6- (1,3,4-oxadiazolyl)
Etc.], thiadiazolyl [e.g., 3- or 5- (1,2,4
-Thiadiazolyl), 2- or 5- (1,3,4-thiadiazolyl), 4- or 5- (1,2,3-thiadiazolyl), 3- or 4- (1,2,5-thiadiazolyl)
Etc.), triazolyl [e.g., 2- or 5- (1,2,3-
Triazolyl), 3- or 5- (1,2,4-triazolyl), etc.), tetrazolyl [eg, 5- (1H- or 2H-
Tetrazolyl) etc., and 1 to 4 hetero atoms selected from oxygen, sulfur, nitrogen and the like.
(2) pyridyl (eg, 2-, 3-
Or 4-pyridyl, etc.), pyrimidinyl (eg, 2-, 4
-Or 5-pyrimidinyl), thiomorpholinyl (eg, 2- or 3-thiomorpholinyl), morpholinyl (eg, 2- or 3-morpholinyl), triazinyl (eg, 3- or 6-triazinyl), piperidinyl (eg, , 2-, 3- or 4-piperidinyl), pyranyl (eg, 2- or 3-pyranyl), thiopyranyl (eg, 2- or 3-thiopyranyl), oxazinyl [eg, 2- or 3- (1 , 4-oxazinyl), etc.),
Thiazinyl (eg, 2- or 3- (1,4-thiazinyl), 1- or 4- (1,3-thiazinyl), etc.), piperazinyl (eg, 2- or 3-piperazinyl, etc.), triazinyl (eg, 3 Carbon atoms such as-or 6-triazinyl, etc., pyridazinyl (eg, 3- or 4-pyridazinyl), pyrazinyl (eg, 2- or 3-pyrazinyl, etc.), pyridazinyl (eg, 3- or 4-pyridazinyl, etc.) A 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like; (3) benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, Triazolo [4,
5-b] pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, indolyl, quinolizinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl,
Bicyclic or 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen, etc., in addition to carbon such as acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like. Groups having a bond at a carbon atom of the tricyclic fused heterocyclic group. Examples of the group which may be substituted on the heterocyclic group having a bond at a carbon atom include the same substituents as those exemplified above for the heterocyclic group which may have a substituent.

The cyclic amino group in the cyclic amino group and the cyclic amino group which may have a substituent may further have one atom selected from an oxygen atom, a sulfur atom and a nitrogen atom. And a 7-membered nitrogen-containing cyclic group. Examples include, for example, pyrrolidinyl,
Pyrrolinyl, pyrrolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, imidazolidinyl, imidazolinyl,
Imidazolyl, 1,2,3-triazinyl, 1,2,3-triazolidinyl, 1,2,3-triazolyl, 1,2,3,
4-tetrazolyl, piperidinyl, piperazinyl, azepinyl, hexamethyleneimino, oxazolidino, morpholino, thiazolidino or thiomorpholino. Among them, those having 5 or 6 members are preferable, and for example, pyrrolidinyl, pyrazolinyl, pyrazolyl, piperidinyl, piperazinyl, morpholino, and thiomorpholino are preferable. The cyclic amino group may have 1 to 3 substituents at any substitutable position. Examples of the substituent include (1) C _1-6 alkyl (eg, methyl, ethyl , Propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl (ie, C _1-4
Alkyl), pentane, hexane, etc.), (2) C _6-14 aryl (eg, phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, etc.), (3) C _7-10 aralkyl (phenyl-C _1-4 alkyl (eg, phenyl-C _1-4 alkyl) , Benzyl, phenethyl, etc.)), (4) benzhydryl, (5) C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), (6) C _6-14
Aryl-carbonyl (eg, benzoyl, etc.), and
(7) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, te
rt-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.).
Preferred substituents include C _1-6 alkyl,
Among them, C _1-3 alkyl is more preferred.

In the homocyclic group which may have a substituent
Examples of the homocyclic group include C_6-10Aryl group (eg,
Enyl, naphthyl, etc.), C_3-7Cycloalkyl group
(Eg, cyclopropyl, cyclobutyl, cyclopent
, Cyclohexyl, cycloheptyl, etc.), C_3-7Shiku
Roalkenyl (eg, cyclopropenyl, cyclobutenyl
, Cyclopentenyl, cyclohexenyl, cyclohep
3- to 7-membered carbocyclic ring which may be condensed such as
A group or the like is used. The homocyclic group may be any substitutable
1 to 6, preferably 1 to 3, and more
Preferably it may have one or two substituents.
As the substituent, for example, (1) 1 to 3, preferably
Represents one or two halogens (eg, fluorine, chlorine, bromine,
Optionally substituted with iodine, etc.)_1-15Alkyl
(Eg, methyl, ethyl, propyl, isopropyl,
, Isobutyl, sec-butyl, tert-butyl,
Pentyl, hexyl (ie C_1-6Alkyl), to
Butyl, octyl, nonyl, decyl, undecyl, dode
Syl, tridecyl, tetradecyl, pentadecyl, etc.)
(Preferably, C may be substituted with halogen._1-6
Alkyl), (2) C_3-10Cycloalkyl (eg, cyclopropyl
Ropyl, cyclobutyl, cyclopentyl, cyclohexyl
, Cycloheptyl, cyclooctyl, cyclononyl,
Cyclodecyl, etc.), (3) C_2-10Alkenyl (eg, vinyl
, Allyl, isopropenyl, 1-butenyl, 2-butene
Nil, 3-butenyl, butadienyl, 2-methylali
, Hexatrienyl, 3-octenyl, etc.), (4) C
_2-10Alkynyl (eg, ethynyl, 2-propynyl, butyric)
Nyl, 3-hexynyl, etc.), (5) C_3-10Cycloalkenyl
(Eg, cyclopropenyl, cyclopentenyl, cyclo
Hexenyl, etc.), (6) C_6-10Aryl (eg, phenyl,
Naphthyl, etc.), (7) C_7-20Aralkyl (eg, benzyl,
Phenethyl, etc.), (8) nitro, (9) hydroxy, (10) mel
Capto, (11) oxo, (12) thioxo, (13) cyano, (14)
Carbamoyl, (15) carboxyl, (16) C_1-6Alkoki
C-carbonyl (eg, methoxycarbonyl, ethoxyca
Rubonyl, etc.), (17) sulfo, (18) halogen (eg, fluorine)
Element, chlorine, bromine, iodine, etc.), (19) C_1-6Alkoxy
(Eg, methoxy, ethoxy, propoxy, isopropoxy
Si, butoxy, isobutoxy, sec-butoxy, te
rt-butoxy, pentyloxy, hexyloxy
Etc.), (20) C_6-10Aryloxy (eg, phenoxy
Etc.), (21) C_1-6Acyloxy (eg, acetoxy, pro
C such as pionyloxy_1-6Alkanoyloxy, etc.), (2
2) C_1-6Alkylthio (eg, methylthio, ethylthio,
Propylthio, isopropylthio, butylthio, ter
t-butylthio, etc.), (23) C_6-10Arylthio (e.g.,
Enylthio, etc.), (24) C_1-6Alkylsulfinyl
(Eg, methylsulfinyl, ethylsulfinyl, etc.),
(25) C_6-10Arylsulfinyl (eg, phenylsulfin
), (26) C_1-6Alkylsulfonyl (eg, methyl
Rusulfonyl, ethylsulfonyl, etc.), (27) C_6-10Ants
Arylsulfonyl (eg, phenylsulfonyl, etc.), (28)
Mino, (29) C_1-6Acylamino (eg, acetylamino,
C such as propionylamino_1-6Alkanoylamino
Etc.), (30) mono- or di-C_1-4Alkylamino
(Eg, methylamino, ethylamino, propylamino,
Isopropylamino, butylamino, dimethylamino,
Diethylamino, etc.), (31) C_3-8Cycloalkylamino
(Eg, cyclopropylamino, cyclobutylamino,
Clopentylamino, cyclohexylamino, etc.), (32)
C _6-10Arylamino (eg, anilino, etc.), (33) C_1-6
Alkanoyl (eg, formyl, acetyl, hexanoyl
Etc.), (34) C_6-10Aryl-carbonyl (eg, benzoy
Oxygen, sulfur, nitrogen, etc. in addition to (35) carbon atoms
5 to 6 containing 1 to 4 heteroatoms selected from
Membered heterocyclic group [eg, thienyl (eg, 2- or 3-thienyl)
Frills (eg, 2- or 3-furyl etc.)
Zolyl (eg, 3-, 4- or 5-pyrazolyl, etc.),
Azolyl (eg, 2-, 4- or 5-thiazolyl, etc.),
Isothiazolyl (eg, 3-, 4- or 5-isothiazo
Ryl, etc.), oxazolyl (eg, 2-, 4- or 5-
Xazolyl, etc.), isoxazolyl (eg, 3-, 4-
Or 5-isoxazolyl), imidazolyl (eg, 2
-, 4- or 5-imidazolyl), triazolyl
(Eg, 1,2,3- or 1,2,4-triazolyl),
Tetrazolyl (eg, 1H or 2H-tetrazolyl
Etc.), pyridyl (eg, 2-, 3- or 4-pyridyl)
Etc.), pyrimidinyl (eg, 2-, 4- or 5-pyrimidyl)
Jill, etc.), pyridazinyl (eg, 3- or 4-pyridazi)
Nil, etc.), quinolyl, isoquinolyl, indolyl, etc.)
And so on. R^{twenty one}Or R^{twenty three}Having a substituent represented by
The hydroxy group which may be represented by the above formula -O
R²⁶[Wherein, R²⁶Is as defined above)
Is mentioned.

Where R¹⁴, R¹⁵And R¹⁶As
Same or different (i) hydrogen or (ii) above
Bonds through a carbon, nitrogen or oxygen atom of
Groups are preferred. Particularly preferably, R¹⁴But each
C which may have a substituent _1-15Alkyl group, C_3-10Shi
Chloroalkyl group, C_2-10Alkenyl group, C_2-10Alkini
Group, C_3-10Cycloalkenyl group, C_6-14Aryl group,
C_7-20Aralkyl group or C_1-20Acyl group, nitro
Group, formula -NR^{twenty three}R^{twenty four}(Where R^{twenty three}And R^{twenty four}Is the above
A group represented by the same meaning), or a formula -OR²⁶ (In the formula,
R²⁶Is a hydrogen atom or even if each has a substituent
Good C_1-10Hydrocarbon group, C_1-20Acyl group, C_1-20Archi
Rusulfonyl group, C_6-14Arylsulfonyl group or
5- to 8-membered heterocyclic group (as described above, except for an oxygen atom
One heteroatom selected from the group consisting of
The same as "5- to 8-membered heterocyclic group containing 4 to 4")
Represents a group represented by the formula:¹⁵Or R¹⁶Less of
One is hydrogen and the other is a carbon atom, nitrogen atom or
Is a group bonded through an oxygen atom (preferably R¹⁵and
R¹⁶Are both hydrogen). R¹⁴Is preferably 1
Substituted with three, preferably one hydroxy group
May be C_1-10Alkyl group (preferably C_1-6Al
Kill group), nitro group, amino group, formula -NR^{twenty three}R^{twenty four} (T
But R^{twenty three}Is hydrogen, R^{twenty four}Is one to three, preferably one
C which may be substituted with two hydroxy groups_1-6Archi
Ru-carbonyl, one to three, preferably one C
_1-6Alkoxy group (eg, methoxy, ethoxy, propoxy
Si, isopropoxy, butoxy, isobutoxy, sec
-Butoxy, tert-butoxy, pentyloxy, f
C which may be substituted with xyloxy or the like)_1-6Archi
Ruamino-carbonyl, C_6-14Arylamino-carbo
) Or a formula -OR.²⁶(However, R²⁶Is
Replaced with hydrogen, 1 to 3, preferably 1 hydroxy
C which may be replaced_1-10Alkyl, C_3-10Cycloal
Kill or 1 to 3, preferably 1 hydroxy
C optionally substituted with_1-6Alkyl-carboni
Le, C_1-6Alkylsulfonyl group, C_6-10Arylsul
Honyl group).

Where R¹⁷(1) having a substituent
May be C_1-10Hydrocarbon group, (2) having substituents
May be C_1-20An acyl group, having (3) a substituent
A heterocyclic group having a bond at a good carbon atom;
A carboxyl group which may be
Or (5) a cyano group is preferred. Among them, preferably, R
¹⁷Is C which may have a substituent_1-15Archi
Group, C_3-10Cycloalkyl group, C_2-10Alkenyl group,
C_2-10Alkynyl group, C_3-10Cycloalkenyl group, C
_6-14Aryl group or C_7-20It is an aralkyl group. Further
Preferably a C which may have a substituent_1-6Alkyl
Group (for example, optionally substituted aminoalkyl
Group). R¹⁷As a preferred example of the formula,
− (CH_Two) r-NR^{twenty three}R^{twenty four} Wherein r is an integer of 1 to 3
The number, R^{twenty three}Is hydrogen, C which may have a substituent_1-10Charcoal
A hydride group, an optionally substituted C_1-20Acyl group,
A hydroxy group which may have a substituent (the above formula-
OR²⁶A group represented by), a group which may have a substituent
A ring group or a formula -S (O) t-R^{twenty five}(Where t is not 0
The integer of 2 is represented by R^{twenty five}Has a hydrogen atom or a substituent
May be C_1-10A group represented by a hydrocarbon group) is represented by R
^{twenty four}Is hydrogen or C_1-10Represents a hydrocarbon group or R^{twenty three}And R^{twenty four}
Has a substituent with an adjacent nitrogen atom
May form a cyclic amino group which may be present)
Can be R¹⁷Is more preferably a halogen atom, C
_1-20A hydroxy group which may be substituted with an acyl group,
Or C_1-10Alkyl and / or C_6-14Aryl-C
_1-10Substituted with an amino group optionally substituted with alkyl
C that may be_1-3It is an alkyl group. Particularly preferred
Is N-C_1-6With alkyl-N-benzylaminomethyl
is there.

In the formula, as the halogen represented by R ¹⁸ ,
Examples include fluorine, chlorine, bromine and iodine. R
Preferred as ¹⁸ are hydrogen, a C _1-15 alkyl group which may have a substituent, a C _3-10 cycloalkyl group which may have a substituent, and a C which may have a substituent. _2-10 alkenyl group, C _2-10 alkynyl group _optionally having substituent (s), C _3-10 cycloalkenyl group _optionally having substituent (s), C _{6 optionally} having substituent (s) _-14 aryl group, a C _7-20 aralkyl group which may have a substituent, a C _1-20 acyl group which may have a substituent, a carboxyl group which may be esterified or amidated, Or the formula -O
-R ²⁶ (wherein, R ²⁶ is a hydrogen atom or a C _1-15 alkyl group, a C _3-10 cycloalkyl group, a C _2-10 alkenyl group, a C _2-10 Alkynyl group, C _3-10 cycloalkenyl group, C _6-14 aryl group, C
_7-20 aralkyl group, C _1-20 acyl group, C _1-20 alkylsulfonyl group, C _6-14 arylsulfonyl group or heterocyclic group). Among them, R ¹⁸ is preferably hydrogen or 1 to 3, preferably 1 C
_6-14 aryl or C _1-6 alkoxy group optionally substituted C _1-15 alkyl group, 1 to 3, preferably one hydroxy group in the optionally substituted C _1-6 alkyl - carbonyl, C _1-6 alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert- butoxycarbonyl, etc.), C _{6-1 4} aryl - carbonyl (e.g., benzoyl, etc.), C _6-14 aryloxy - Carbonyl (eg, phenoxycarbonyl, etc.), C _7-15 aralkyl-carbonyl (eg, benzylcarbonyl, etc.), C _7-19 aralkyloxy-carbonyl (eg, benzyloxycarbonyl, etc.),
N—C _1-10 alkyl-N- (C _1-10 alkoxy) amino-carbonyl (eg, N-methyl-N-methoxyamino-
Carbonyl, etc.), C _1-15 alkyloxy and C _1-20 arylsulfonyl groups. More preferably, R ¹⁸ is (1) a C _1-6 alkoxy-carbonyl group,
(2) a C _6-14 aryl group optionally substituted by halogen or C _1-6 alkoxy or (3) a phenyl-C _1-3 alkyl group. In the formula, R ¹⁹ is hydrogen or
Which may have a substituent, respectively C _1-15 alkyl group,
C _3-10 cycloalkyl group, C _2-10 alkenyl group, C _2-10
An alkynyl group, a C _3-10 cycloalkenyl group, a C _6-14 aryl group or a C _7-20 aralkyl group is preferred. Among them, R ¹⁹ is preferably hydrogen or a C _1-10 alkyl group,
More preferably, hydrogen or a C _1-6 alkyl group is used.

Where R²⁰Has a substituent
An optionally substituted homocyclic or heterocyclic group, preferably
C optionally having a substituent_6-14Aryl groups
You. R ²⁰And more preferably 1 to 3,
Or one or two halogen atoms or C_1-6Arco
A phenyl group which may be substituted with an xy group;
You. Particularly preferably substituted with one or two halogen atoms
A phenyl group which may be Formula (XII) above
In the formula, m is an integer of 0 to 3, preferably m is 0
An integer of from 2 to 2, more preferably m is 0 or 1
is there. In the above formula, r is an integer of 1 to 3, preferably
Preferably, r is 1 or 2, more preferably, r is 1.
is there.

In the above formula (XII), one of A and D is a nitrogen atom, the other is a carbon atom or both are nitrogen atoms, and B is a nitrogen atom or carbon atom. Accordingly, as the compound represented by the formula (XII), for example,

[0088]

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[0089]

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[0090]

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[0091]

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Wherein each symbol is as defined above. (Preferably, formulas (a), (b),
(c), (d), (e) or (g). Among them, preferred are compounds in which B in the formula (XII) is a nitrogen atom, particularly compounds represented by the formula (c) or (e), most preferably compounds represented by the formula (e). In the compound (XII), the general formula

[0093]

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A compound represented by the formula: wherein each symbol is as defined above is preferred. Among them, R ¹⁴ is (1) (i)
Carbamoyl optionally substituted with C _1-6 alkyl or C _1-6 alkoxy, or (ii) amino group optionally substituted with C _1-6 alkyl-carbonyl, or (2) C 2
_3-6 may be substituted with a cycloalkyl C _1-6 alkoxy group; R ¹⁷ is N-C _1-6 alkyl -N- benzylamino methyl group; R ¹⁸ is (1) C _1-6 alkoxy - carbonyl Group, (2) C _6-14 aryl group optionally substituted with halogen or C _1-6 alkoxy or (3) phenyl-C
Further preferred are compounds wherein a _1-3 alkyl group; and R ¹⁹ is a hydrogen atom. R ¹⁴ is (1) a nitro group, (2)
(I) C _1-6 alkyl optionally substituted with hydroxy, (ii) C _1-6 alkyl-carbonyl optionally substituted with hydroxy, halogen or thienyl, (iii)
C _6-10 aryl-carbonyl optionally substituted with C _1-6 alkyl, C _1-6 alkoxy or halogen, (iv)
C _3-6 cycloalkyl-carbonyl, (v) C _2-4 alkenyl-carbonyl, (vi) C _1-6 alkoxy-carbonyl, (vii) C _1-6 alkylamino-carbonyl, (vii
i) each having one or two substituents selected from C _1-6 alkoxyamino-carbonyl, (ix) phenylaminocarbonyl, (x) C _1-6 alkyl, nitro and C _1-6 alkoxy Good isoxazolylcarbonyl, thienylcarbonyl, thiazolylcarbonyl, pyrazolylcarbonyl or furylcarbonyl, (xi) pyridylcarbonyl, (xii) C _1-6 alkylsulfonyl,
(Xiii) an amino group optionally having one or two substituents selected from thienylsulfonyl and (xiv) phenylsulfonyl optionally substituted with C _1-6 alkyl,
(3) a pyrrolyl group, or (4) a hydroxy group optionally substituted with C _1-6 alkyl, C _3-6 cycloalkyl-C _1-3 alkyl or C _1-6 alkyl-carbonyl; R
¹⁷ represents (1) halogen, (2) hydroxy and (3) C
_1-6 alkyl, phenyl-C _1-3 alkyl and di-C
_1-6 alkylamino -C _1-3 substituents one or two have a substituent which is selected from an amino optionally one or two optionally having C _1-6 alkyl group selected from alkyl R ¹⁸ is (1) halogen, (2) halogen or C
_1-6 alkyl optionally substituted by a phenyl group or, (3) (i) C 1-6 -alkyl, (ii) C _1-6-alkyl and C _1-6 amino or substituted alkoxy (iii) C
A carbonyl group substituted with _1-6 alkoxy; and R ¹⁹
Is preferably a hydrogen atom or a C _1-3 alkyl group. Specific examples of compound (XII) include 8- (2,6-
Difluorobenzyl) -5,8-dihydro-2- [4-
(Ethylaminocarbonylamino) phenyl] -3-
(N-methyl-N-benzylaminomethyl) -5-oxoimidazo [1,2-a] pyrimidine-6-carboxylic acid ethyl ester, 8- (2,6-difluorobenzyl)
-5,8-Dihydro-2- [4- (methoxyaminocarbonylamino) phenyl] -3- (N-methyl-N-benzylaminomethyl) -5-oxoimidazo [1,2-
a] Pyrimidine-6-carboxylic acid isopropyl ester, 8- (2,6-difluorobenzyl) -5,8-dihydro-2- [4- (ethylaminocarbonylamino)
Phenyl] -3- (N-methyl-N-benzylaminomethyl) -5-oxoimidazo [1,2-a] pyrimidine-6-carboxylic acid isopropyl ester or a salt thereof.

Compound (XII) or a salt thereof can be prepared by a known method, for example, JP-A-11-315079, WO99
/ 33831, or a method analogous thereto.

Among the embodiments of the compounds shown in the above [I] to [IV], the compound (I) shown in [I] or a salt thereof is preferable.

As the “non-peptide physiologically active substance”,
Somatostatin receptor (SSTR)
r)) Agonists (agonists) or antagonists (antagonists), preferably also SSTR agonists. Furthermore, SSTRs have subtypes of types 1, 2, 3, 4, and 5, and preferably include type 2 SSTR (SSTR2) agonists. The “SSTR2 agonist” may be any compound having an SSTR2 agonistic action, and includes, for example, the embodiment of compound (XIII).

[0098]

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Compound (XIII) is prepared by treating (2S) -6-amino-2-{[(2R, 3S) -3- (1H-indole-
3-yl) -2-({[4- (2-oxo-2,3-dihydro-1H-benzimidazol-3-yl) -1-)
Tert-butyl piperidinyl] carbonyl {amino) butanoyl] amino} hexanoate. Compound (XII
I) is based on the National Academy of Sciences (1998), 95th
Vol. 10836-10841.

The “non-peptidic physiologically active substance” has a molecular weight of about 1,000 or less, preferably about 10 or more and about 900 or less, more preferably about 50 or more and about 9 or less.
A substance having a value of not more than 00, more preferably not less than about 50 and not more than about 800, even more preferably not less than about 100 and not more than about 800, particularly preferably not less than about 100 and not more than about 700 is preferred.

The “organic acid” used in the present invention includes:
For example, in addition to adipic acid and fumaric acid, lower fatty acids, aliphatic sulfonic acids, aliphatic hydroxycarboxylic acids, aromatic organic acids (eg, aromatic carboxylic acids, aromatic hydroxycarboxylic acids, aromatic sulfonic acids, etc.) and the like can be used. No. Examples of the lower fatty acid include acetic acid, propionic acid, and butyric acid. As the aliphatic sulfonic acid, for example,
Methanesulfonic acid and the like can be mentioned. As the aliphatic hydroxycarboxylic acid, for example, lactic acid, tartaric acid, malic acid,
Alternatively, citric acid and the like can be mentioned. Examples of the aromatic carboxylic acid include benzoic acid and phthalic acid. Examples of the aromatic hydroxycarboxylic acid include salicylic acid, hydroxynaphthoic acid (eg, 1-hydroxy-2-naphthoic acid, 3-hydroxy-2-naphthoic acid), and pamoic acid. Examples of the aromatic sulfonic acid include benzene sulfonic acid. Among the above organic acids, lower fatty acids, aliphatic hydroxycarboxylic acids and aromatic organic acids are preferred.
The “organic acid” is produced by a known method or a method analogous thereto.

Hydroxynaphthoic acid used in the present invention
Represents one hydroxy group and one hydroxy group on different carbons of naphthalene.
One carboxyl group is bonded. Therefore,
The position of the ruboxyl group is the 1st and 2nd position of the naphthalene ring
14 different positions of hydroxy groups for each
There are species of isomers. And any of the isomers
May be used, and mixtures of these in any proportion
Is also good. As described later, those having a large acid dissociation constant
PKa (pKa = -log _Ten Ka and Ka are acid dissociation constants
Is preferable. And slightly water-soluble
Is preferred. P of the above hydroxynaphthoic acid isomer
As Ka, the value of 3-hydroxy-2-naphthoic acid
(PKa = 2.708, Chemical Handbook Basics II, Japanization
Society, published only September 25, 1969) is known
Compares pKa of three isomers of hydroxybenzoic acid
By doing so, useful knowledge can be obtained. That is, m-
PKa of hydroxybenzoic acid and p-hydroxybenzoic acid
Is 4 or more, whereas o-hydroxybenzoic acid (sa)
The pKa (= 2.754) of lylic acid is extremely small.
Therefore, among the above 14 isomers, the naphthalene ring
Carboxyl and hydroxy groups on adjacent carbon atoms of
Bound, 3-hydroxy-2-naphthoic acid, 1-hydrido
Roxy-2-naphthoic acid and 2-hydroxy-1-na
Futheic acid is preferred.

The "aromatic hydroxycarboxylic acid" used in the present invention may be a mixture of various aromatic hydroxycarboxylic acids. For example, salicylic acid and 3-
Hydroxy-2-naphthoic acid, salicylic acid and pamoic acid, 3
-Hydroxy-2-naphthoic acid and pamoic acid, 1-hydroxy-2-naphthoic acid and pamoic acid, 2-hydroxy-1-naphthoic acid and pamoic acid, or salicylic acid, 3-hydroxy-2-naphthoic acid and pamoic acid, etc. There are combinations of
Preferred are 3-hydroxy-2-naphthoic acid and pamoic acid, and 1-hydroxy-2-naphthoic acid and pamoic acid.

The “biocompatible organic solvent” used in the present invention may be any one which can be generally added to a drug (see “Drug Additives Dictionary 2000” edited by Yakuji Nippo, Japan Pharmaceutical Excipients Association). The organic solvents described and any similar ones may be used. As the organic solvent, those which can easily dissolve the non-peptidic substance are preferable. The biocompatible organic solvent used in the present invention is listed below, but is not limited thereto. Examples of biocompatible organic solvents include α-thioglycerin, dimethyl sulfoxide,
Glycerol, lower alcohols (eg, methanol, ethanol, anhydrous ethanol, isopropanol, etc.), lauric acid, ethylene glycol, polyethylene glycol (eg, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600), ethylenediamine, m-
Cresol, diethanolamine oleate, N, N-
Dimethylacetamide, thioglycolic acid, caproic acid, triethanolamine, propylene glycol, monoethanolamine, caprylic acid, 2-ethylhexyl acrylate / vinyl pyrrolidone copolymer solution, capric acid, 2-ethylhexyl acrylate / methacrylic acid 2-
Ethylhexyl / dodecyl methacrylate copolymer solution,
Linoleic acid isostearyl alcohol, isostearic acid, allyl isothiocyanate, 2-ethyl-1,3-hexanediol, oleyl alcohol, cretamiton,
Geraniol, dipropylene glycol, ethers (eg, diethylene glycol monoethyl ether, dimethyl ether, polyoxyethylene octyl phenyl ether, α-monoisostearyl glyceryl ether, etc.), dimethyl polysiloxane, cinnamaldehyde,
Petroleum benzine, tocopherol, triethylene glycol, trichloroethane, nicotinic acid benzyl ester,
Butylphthalylbutyl glycolate, 1,3-butylene glycol, hexdecanol, ketones (eg, methyl isobutyl ketone, methyl ethyl ketone, etc.), N-methyl-2-pyrrolidone, lauryl alcohol, lauromacrogol, lanolin alcohol and the like. . Alternatively, ethyl acetate, benzyl acetate, hexyl laurate,
Isopropyl myristate, octyl dodecyl myristate, decyl oleate, isostearyl palmitate, hexadecyl isostearate, ethyl linoleate, diisobutyl adipate, diisopropyl adipate, isoamyl isovalerate, diisopropyl sebacate, cetyl 2-ethylhexanoate, etc. Fatty acid esters of
Aromatic fatty acid esters such as benzyl benzoate, diethyl phthalate, dioctyl phthalate and the like can be mentioned. Alternatively, vegetable oils, triacetin, medium-chain fatty acid triglycerides, glycerin dioleate, glyceryl monoisostearate, glycerin fatty acid esters such as glyceryl monooleate, propylene glycol monocaprylate,
Examples include propylene glycol fatty acid esters such as propylene glycol monostearate, propylene glycol dicaprate, propylene glycol dicaprylate, and propylene glycol caprylate.
Alternatively, diglyceryl monooleate, diglyceryl dioleate, diglyceryl monoisostearate, diglyceryl monooleate, tetraglyceryl monooleate, tetraglyceryl pentaoleate, hexaglyceryl monolaurate, hexaglyceryl monomyristate, monoolein Hexaglyceryl acid, hexaglyceryl pentaoleate, hexaglyceryl polyricinoleate, decaglyceryl monolaurate, decaglyceryl monooleate, decaglyceryl monolinoleate, decaglyceryl trioleate, decaglyceryl pentaoleate, decaglyceryl heptaoleate , Polyglycerol fatty acid esters such as decaglyceryl decaoleate, glycerin caprylic acid polyethylene glycol, Ethylene glycerin fatty acid ester, polyethylene glycol monooleate, dioleate polyethylene glycol, polyethylene glycol fatty acid esters such as dilinoleate polyethylene glycol, polyoxyethylene castor oil, polyoxyethylene hardened castor oil, and the like. Alternatively, sorbitan monolaurate, sorbitan monooleate, sorbitan fatty acid esters such as sorbitan sesquioleate trisorbate, polysorbate 20, polysorbate 40, polysorbate 60, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate, And polyoxyethylene sorbite fatty acid esters such as polyoxyethylene sorbite monolaurate and polyoxyethylene sorbite tetraoleate. Among the above, polyethylene glycol or its fatty acid ester, or dimethyl sulfoxide is preferred. The biocompatible organic solvent may be used as a mixture of two or more of the above (preferably 1 to 5, more preferably 1 to 3).

Examples of the hydrophilic polymer (hydrophilic polymer) used in the present invention include hydroxyalkylcellulose such as hydroxypropylcellulose and hydroxypropylmethylcellulose, alkylcellulose such as methylcellulose and ethylcellulose, and polyalkenylpyrrolidone such as polyvinylpyrrolidone. And aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, and the like. Alternatively, hydrophilic polymers such as carboxyvinyl polymer, polyvinyl alcohol, gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, and chitosan can be mentioned. The hydrophilic polymer may be used as a mixture of two or more (preferably 1 to 5, more preferably 1 to 3).

The content of the “non-peptidic physiologically active substance” in the “pharmaceutical solution” of the present invention is preferably about 5% by weight or more, for example, about 5% by weight to about 90% by weight, Preferably from about 10% to about 80% by weight, more preferably from about 20% to about 70% by weight. The content of the "organic acid" in the "pharmaceutical solution" of the present invention is, for example, about 0.1% to about 50% by weight, preferably about 1% to about 40% by weight based on the total weight of the solution. , More preferably from about 5% to about 30% by weight. The content of the "biocompatible organic solvent" in the "pharmaceutical solution" of the present invention is, for example, about 30% to about 94.9% by weight, preferably about 40% by weight, based on the total weight of the solution.
To about 89% by weight, more preferably from about 50% to about 75% by weight. The amount ratio of the non-peptidic bioactive substance to the organic acid is, for example, about 1/20 to about 100 mol, preferably about 1/10 to about 20 mol per 1 mol of the non-peptidic bioactive substance. Mole, more preferably about 1/5 to about 10 mole.

The solubility of the “non-peptidic physiologically active substance” in a biocompatible organic solvent refers to the solubility in a biocompatible organic solvent.
After adding the drug in excess, for example, Recipro Shak
er (Model SR-I, Taiyo Kagaku Kogyo Co., Ltd.), shaking 100 times or more per minute at room temperature (about 15 ° C. to about 25 ° C.) for 30 minutes or more, followed by filtration. 5 shows the drug concentration in the filtrate obtained by the above method. In the present invention, "contains a non-peptidic bioactive substance at a concentration higher than the solubility of the non-peptidic bioactive substance in a biocompatible organic solvent" means that the non-peptidic bioactive substance in the present pharmaceutical solution is It means that the concentration is higher than the solubility. For example, the concentration is preferably about 1.2 times or more the solubility, more preferably about 1.5 times or more the solubility, and still more preferably about 2 times or more the solubility. It is.

The “pharmaceutical solution” of the present invention can be prepared by a known method by mixing a non-peptidic physiologically active substance, an organic acid and a biocompatible organic solvent. In this mixing, the order of the non-peptidic physiologically active substance, the organic acid and the biocompatible organic solvent does not matter. That is, the order in which the non-peptidic physiologically active substance and the organic acid are mixed and then the biocompatible organic solvent is added, the order in which the non-peptidic physiologically active substance is added to the biocompatible organic solvent and mixed, and then the organic acid is further added and mixed. For example, an organic acid may be added to a biocompatible organic solvent, mixed, and then added to a non-peptide physiologically active substance and mixed.
The mixing may be performed under any conditions such as standing, shaking, rotation, stirring, and the like, and may be performed under heating if necessary.

The “pharmaceutical solution” of the present invention may contain additives generally used for pharmaceuticals. Examples include stabilizers, preservatives, antioxidants, lubricants, surfactants, anticoagulants, thickeners, and the like. In the pharmaceutical solution of the present invention, as long as the non-peptidic physiologically active substance is dissolved, the organic acid or additives to be added as necessary may be in a dispersed state or a suspended state. It is preferable that the "medical solution" of the present invention does not contain a biodegradable polymer.

The “pharmaceutical solution” of the present invention can be formulated into various dosage forms as it is or as a raw material,
Formulation for injection or implantation into subcutaneous, organ, etc.
As a preparation for parenteral administration such as a transmucosal absorbent or transdermal agent to the nasal cavity, rectum, uterus, etc., or a capsule (eg,
Hard capsules, soft capsules, etc.), syrups, emulsions,
It can be administered as a formulation for oral administration such as a liquid such as a suspension.

The “pharmaceutical solution” of the present invention may be prepared by using only a non-peptidic physiologically active substance, an organic acid and a biocompatible organic solvent, or may be in the form of a liquid or a candy by adding additives as required. It can be manufactured into a shape, a gel or a paste. In the case of a liquid, it can be manufactured as a sustained release agent by filling in a sustained release pump.

[0112] As a sustained release pump, for oral use, there is Oros ^TM of Alza. This is a system comprising a drug reservoir portion and a polymer portion which swells due to osmotic pressure, and the drug gradually releases from the reservoir portion as the polymer gradually swells. As a pump for injection, there is Duros ^™ of Alza for injection. This also releases the drug at the injection site by osmotic pressure, similar to Oros. In addition to these, a pump using an electric dynamic motor, a spring-type motor, a motor utilizing external energy (electromagnetic field, ultrasonic wave, microwave, etc.), a heat swelling polymer, a photo-reactive polymer, a pH-reactive polymer, etc. as a driving force. Can also be used.

A preferable size of the sustained-release pump is 15 mL or less, more preferably 0.1 mL or more and 7 mL or less for oral administration as a volume. The preferred size of the sustained-release pump for injection administration is 8 mL or less, more preferably 0.1 mL or more and 6 mL or less. The preferable volume of the reservoir in the sustained-release pump is 7 mL or less, more preferably 0.01 mL or more 3 for oral administration.
mL or less. In the case of injection administration, the reservoir volume in the sustained-release pump is preferably 4 mL or less, more preferably 0.01 mL or more and 2 mL or less.

The release period of the sustained-release pump is 1 hour to 48 hours, preferably 2 hours to 36 hours, more preferably 3 hours to 24 hours for oral use. When the sustained release pump is for injection, the period is 1 day or more and 2 years or less, preferably 1 week or more and 1.5 years or less, more preferably 2 weeks or more and 1 year or less.

Since the pharmaceutical solution of the present invention has low toxicity, it can be used for mammals (eg, humans, cows, pigs, dogs, cats, mice,
Rat, rabbit, etc.). The pharmaceutical solution of the present invention can be used as a prophylactic / therapeutic agent for various diseases depending on the type of the physiologically active substance contained. For example, if the bioactive substance is Gn
When it is an RH antagonist, for example, sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), bone metastasis of sex hormone-dependent cancer, prostatic hypertrophy, uterine fibroids, endometriosis , Uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polyatrial ovary syndrome, polycystic ovary syndrome, acne, baldness, Alzheimer's disease (Alzheimer's disease, Alzheimer's senile dementia And / or a combination thereof). The pharmaceutical solution of the present invention is also useful for regulating reproduction in males and females (eg, pregnancy regulators, menstrual cycle regulators, etc.). The pharmaceutical solution of the present invention can be further used as a contraceptive for men and women, and as an ovulation inducer for women. The pharmaceutical solution of the present invention can be used for treatment of infertility by utilizing the rebound effect (restoration of hormone secretion) after drug withdrawal. In addition, sex hormone-independent and LH-R
It can also be used as a prophylactic / therapeutic agent for H-sensitive benign or malignant tumors. In addition, the pharmaceutical solution of the present invention can be used as a preventive / therapeutic agent for irritable bowel syndrome and a preventive agent for postoperative recurrence of sex hormone-dependent cancer (prostate cancer postoperative recurrence preventive agent, breast cancer or ovarian cancer surgery before and after menopause). Post-recurrence preventive agent). Furthermore, the pharmaceutical solution of the present invention is useful in the field of animal husbandry for regulating estrus in animals, improving meat quality for meat, promoting animal growth, and the like. The pharmaceutical solution of the present invention is also useful as a spawning promoter for fish.

The pharmaceutical solution of the present invention suppresses the transient increase in blood testosterone (in the case of male) concentration (flare phenomenon), which is observed when a GnRH superagonist such as leuprorelin acetate is administered. Can be used. The pharmaceutical solution of the present invention comprises leuprorelin acetate (Le
uprorelin acetate), Gonadorelin,
Buserelin, Triptorel
in), Goserelin, Nafarelin
elin), Histrelin, Deslorelin (D
It can be used in combination with a GnRH super agonist (preferably leuprorelin acetate) such as eslorelin, meterelin, lecirelin and the like.
Further, the pharmaceutical solution of the present invention may be a steroidal or non-steroidal antiandrogen or antiestrogen, a chemotherapeutic agent, a peptide GnRH antagonist, a 5α-reductase inhibitor, an α-receptor inhibitor, an aromatase inhibitor. To be used in combination with at least one of a drug, a 17β-hydroxysteroid dehydrogenase inhibitor, an adrenal androgen production inhibitor, a phosphorylase inhibitor, a hormonal therapy agent, a drug that inhibits the action of a cell growth factor or its receptor, etc. Is also effective.

The “chemotherapeutic agent” includes Ifosfamide, UFT, Adriamycin (Adriam
ycin), peplomycin, cisplatin, cyclophosphamide
ide), 5-FU, Methotrexate,
Mitomycin C, Mitoxantrone, Taxotere and the like.

Examples of the “peptidic GnRH antagonist” include Cetrorelix and Ganirelix.
parenterally administered peptidic GnRH antagonists such as nirelix) and Abarelix. The “adrenal androgen production inhibitor” includes, for example, a lyase (C _17,20- lyase) inhibitor. Examples of the "phosphorase inhibitor" include tyrosine phosphorylase. As the "hormone therapy agent",
Examples include antiestrogens, progestin (eg, MPA), androgens, estrogens, antiandrogens, and the like.

The "cell growth factors" may be any substance that promotes cell growth, and is usually a peptide having a molecular weight of 20,000 or less, which binds to a receptor. Factors that exert their effects at low concentrations are mentioned, specifically, (1) EGF (epidermal g
rowth factor) or a substance having substantially the same activity as that (eg, EGF, halegulin (HER2 ligand))
(2) insulin or a substance having substantially the same activity as insulin (eg, insulin, IGF (insul)
in-like growth factor) -1, IGF-2, etc.),
(3) FGF (fibroblast growth factor) or a substance having substantially the same activity as that (eg, aFGF, bF
GF, KGF (Keratinocyte Growth Factor), HGF
(Hepatocyte Growth Factor), FGF-10, etc.)
(4) Other cell growth factors (eg, CSF (colony stimulus)
ulating factor), EPO (erythropoietin), IL-
2 (interleukin-2), NGF (nerve growth factor),
PDGF (platelet-derived growth factor), TGF
β (transforming growth factor β) and the like. The “cell growth factor receptor” may be any receptor as long as it has the ability to bind to the above-mentioned cell growth factor, and specifically, EGF receptor, hallegulin receptor (HER2) , Insulin receptor-1,
Examples include insulin receptor-2, IGF receptor, FGF receptor-1 or FGF receptor-2. Examples of the drug that inhibits the action of the cell growth factor include Herceptin (HER2 receptor antibody). Examples of the drug that inhibits the action of the above-mentioned cell growth factor or its receptor include herbimycin, PD153030
(Science 265 (5175), p1093, (1994)).

[0120] HER2 inhibitors are also examples of agents that inhibit the action of cell growth factors or their receptors.
As a HER2 inhibitor, any substance that inhibits HER2 activity (eg, phosphorylation activity) can be used as an antibody, a low-molecular compound (synthetic compound, natural product), antisense, HER2 ligand, hallegulin, or one of these structures. Any of modified or modified parts may be used. Further, it may be a substance that inhibits HER2 activity by inhibiting HER2 receptor (eg, HER2 receptor antibody). HE
Examples of the low-molecular compound having an R2 inhibitory action include:
Compounds described in WO98 / 03505, specifically 1- [3- [4- [2-((E) -2-phenylethenyl) -4-oxazolylmethoxy] phenyl] propyl] -1 , 2,4-triazole and the like. For benign prostatic hyperplasia, GnRH super agonists, antiandrogens, antiestrogens, peptidic GnRH antagonists, 5α-reductase inhibitors, α-receptor inhibitors, aromatase inhibitors, 17β-hydroxysteroid dehydrogenation A combination use of a drug such as an enzyme inhibitor, an adrenal androgen production inhibitor, a phosphorylase inhibitor and the pharmaceutical solution of the present invention is also included.

For prostate cancer, GnRH super agonists,
Anti-androgens, anti-estrogens, chemotherapeutic agents [eg, Ifosfamide, UFT, Adriamycin, Peplomyc
in), cisplatin, etc.], peptidic GnRH antagonists, aromatase inhibitors, 17β-hydroxysteroid dehydrogenase inhibitors, adrenal androgen production inhibitors, phosphorylase inhibitors, hormone therapy agents [eg, estrogens Agents (eg, DSB, EMP, etc.), antiandrogen agents (eg, CMA, etc.), agents that inhibit the action of cell growth factor or its receptor, and the pharmaceutical solution of the present invention. No. For breast cancer, GnRH super agonists, antiestrogen agents, chemotherapeutic agents [eg, cyclophosphamid
e), 5-FU, UFT, methotrexate
e), Adriamycin, Mitomycin C, Mitoxantrone
one), peptidic GnRH antagonist, aromatase inhibitor, adrenal androgen production inhibitor, phosphorylase inhibitor, hormonal therapy [eg, anti-estrogen [eg, tamoxifen, etc.], luteinizing hormone, etc. (Eg, MPA, etc.), androgenic agents, estrogenic agents, etc.], agents that inhibit the action of cell growth factors or their receptors, and the pharmaceutical solutions of the present invention. The above-mentioned drugs may be administered to the same subject simultaneously with the pharmaceutical solution of the present invention or at a time interval. Furthermore, the pharmaceutical solution of the present invention can be administered before administration of a GnRH superagonist such as leuprorelin acetate to perform treatment without causing flare.

The dosage of the pharmaceutical solution of the present invention varies depending on the type and content of the physiologically active substance, the dosage form, the duration of release of the physiologically active substance, the target disease, the target animal, and the like. Should be fine. The dose of the physiologically active substance per dose is, for example, when the pharmaceutical solution is a sustained release formulation for 24 hours, about 0.01 mg to 20 mg / kg body weight per adult (body weight 60 kg), preferably about 0.05 mg to 10 mg / kg body weight. In the case of a one-month formulation, an adult (body weight 60 k
g) about 0.01 mg to 40 mg / kg per person
Body weight, preferably about 0.05-10 mg / kg
Weight. The dose of the pharmaceutical solution of the present invention per administration is about 0.05 mg per adult (body weight 60 kg).
To 50 mg / kg, preferably about 0.1 mg to 30 mg / kg. The frequency of administration is once every few weeks,
Kind and content of bioactive substance, dosage form, duration of bioactive substance release, target disease, target, such as once a month or once every several months (eg, once every 3 months, 4 months, 6 months, etc.) It can be appropriately selected depending on the animal or the like.

[0123]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Experimental Examples, but these are not intended to limit the present invention. “Room temperature” in the following Reference Examples and Examples indicates about 15 ° C. to about 25 ° C.

Reference Example 1 2-amino-4-methyl-5- (4-nitrophenyl)
Thiophene-3-carboxylic acid ethyl ester 4-nitrophenylacetone (35.0 g, 195 mm
ol), ethyl cyanoacetate (23.8 g, 195 mmol)
l), a mixture of ammonium acetate (3.1 g, 40 mmol) and acetic acid (9.1 ml, 159 mmol)
While removing the water generated by the Dean-Stark apparatus, 24
Heated to reflux for an hour. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer was washed with brine, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography. The obtained oil was dissolved in ethanol, and sulfur (5.0 g, 160 mmol) and diethylamine (16.0 ml, 160 mmol) were added.
Stirred at C for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure,
The residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer was washed with brine, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from ether-hexane to give the title compound (22.2 g, 52%) as red plate-like crystals. mp: 168-170 ° C (recrystallized from ether-hexane). As Elemental analysis _{C 14 H 14 N 2 O 4} S ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.39
(3H, t, J = 7.1 Hz), 2.40 (3H,
s), 4.34 (2H, q, J = 7.1 Hz), 6.2
7 (2H, br), 7.48 (2H, d, J = 8.7H)
z), 8.23 (2H, d, J = 8.7 Hz). IR (KBr): 3446, 3324, 1667, 15
80, 1545, 1506, 1491, 1475, 14
10,1332 cm ^-1 .

Reference Example 2 5-methyl-6- (4-nitrophenyl) -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3
H) -dione The compound obtained in Reference Example 1 (5.00 g, 16.32 m)
phenylisocyanate (2.66 ml, 24.48 mmol) was added to a pyridine (30 ml) solution, and the mixture was stirred at 45 ° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in ethanol (6 ml). And 28% sodium methoxide (7.86 g, 40.
80 mmol), and the reaction solution was stirred at room temperature for 2 hours. Then, 2N hydrochloric acid (25 ml, 50 mmol) was added, and the ethanol solvent was distilled off under reduced pressure. The obtained residue was filtered, washed with water-ethanol, dried under reduced pressure and recrystallized from ethanol to give the title compound as a yellow powder (6.09 g, 9
8%). mp:> 300 ° C. Elemental analysis value As C ₁₉ H ₁₃ N ₃ O ₄ S.0.3H ₂ O ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.
50 (3H, s), 7.31-7.46 (5H, m),
7.78 (2H, d, J = 8.8 Hz), 8.32 (2
H, d, J = 8.8 Hz), 12.50 (1H, s). IR (KBr): 1715, 1657, 1593, 15
10 cm ^-1 .

Reference Example 3 1- (2,6-difluorobenzyl) -5-methyl-6
-(4-nitrophenyl) -3-phenylthieno [2,
3-d] pyrimidine-2,4 (1H, 3H) -dione The compound obtained in Reference Example 2 (52.54 g, 0.131
mol) in dimethylformamide (1.0 l),
Potassium carbonate (19.00 g, 0.138 mol), potassium iodide (22.90 g, 0.138 mol),
2,6-difluorobenzyl chloride (22.40 g,
0.138 mol), and the mixture was stirred at room temperature for 2 hours. The residue obtained by concentrating the reaction solution was partitioned between chloroform and brine. The aqueous layer was extracted with chloroform, the combined extracts were washed with brine, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (6) as pale yellow crystals.
1.50 g, 93%). mp: 280-282 [deg.] C. Elemental analysis value C ₂₆ H ₁₇ N ₃ O ₄ SF ₂ ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.57
(3H, s), 5.38 (2H, s), 6.94 (2
H, d, J = 8.1 Hz), 7.42-7.58 (8
H, m), 8.29 (2H, d, J = 8.8 Hz). IR (KBr): 1719, 1669, 1524, 14
73 cm ^-1 .

Reference Example 4 5-bromomethyl-1- (2,6-difluorobenzyl) -6- (4-nitrophenyl) -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H )-
Dione The compound obtained in Reference Example 3 (30.34 g, 0.060
mol), N-bromosuccinimide (12.81 g,
0.072 mol), a mixture of α, α′-azobisisobutyronitrile (1.15 g, 0.007 mol) and chlorobenzene (450 ml) was stirred at 85 ° C. for 3 hours. After cooling, the reaction solution is washed with brine and dried (MgSO ₄ )
Thereafter, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (80.21) as yellow needles.
g, 100%). mp: 228-229 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.77
(2H, s), 5.38 (2H, s), 6.96 (2
H, t, J = 8.1 Hz), 7.29-7.58 (6
H, m), 7.79 (2H, d, J = 8.5 Hz),
8.35 (2H, d, J = 8.5 Hz). IR (KBr): 1721, 1680, 1524, 14
73,1348 cm ^-1 . FAB-Mass m / z 5
84 (MH) ⁺

Reference Example 5 5- (N-benzyl-N-methylaminomethyl) -1-
(2,6-difluorobenzyl) -6- (4-nitrophenyl) -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione The compound obtained in Reference Example 4 ( 80.00g, 0.119
mol) of dimethylformamide (600 ml) under ice-cooling.
ml, 0.155 mol) and benzylmethylamine (18.45 ml, 0.143 mol). After stirring at room temperature for 2 hours, the residue obtained by concentrating the reaction solution was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a yellow oil (74.90).
g, 100%) and recrystallized from ethyl acetate to give the title compound as yellow needles. mp: 173-174 ° C. Elemental analysis value As C ₃₄ H ₂₆ N ₄ O ₄ SF ₂ .0.5H ₂ O ¹ H-NMR (300 MHz, CDCl ₃ ) [free amine] δ: 1.31 (3H, s), 3.60 (2H,
s), 3.96 (2H, s), 5.39 (2H, s),
6.95 (2H, t, J = 8.2 Hz), 7.18-
7.55 (11H, m), 8.02 (2H, d, J =
9.0Hz), 8.26 (2H, d, J = 9.0H)
z). IR (KBr) [hydrochloride]: 1719, 1678, 15
97, 1520 cm ^-1 .

Reference Example 6 6- (4-aminophenyl) -5- (N-benzyl-N
-Methylaminomethyl) -1- (2,6-difluorobenzyl) -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione Compound (3) obtained in Reference Example 5 .00g, 4.80mm
ol) in formic acid (30 ml), under ice-cooling, 1M hydrogen chloride-ether (14.4 ml, 14.4 mmol) and 10% palladium on carbon powder (300 mg) were added, and the mixture was stirred at room temperature and pressure for 2 hours. Hydrogenated. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with dichloromethane, and the organic layers were combined and dried (MgS
After O ₄ ), the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as white crystals (2.41 g, 84%). mp: 205-207 ° C. Elemental analysis value C ₃₄ H ₂₈ N ₄ O ₂ SF ₂ 0.1AcOEt
・ As 1.2H ₂ O ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.05
(3H, s), 3.56 (2H, s), 3.83 (2
H, br), 3.88 (2H, s), 5.36 (2H,
s), 6.70 (2H, d, J = 8.8 Hz), 6.8
8-6.94 (2H, m), 7.21-7.31 (8
H, m), 7.41-7.53 (5H, m). IR (K
Br): 1715, 1657, 1628, 1537 cm
^-1 .

Reference Example 7 5- (N-benzyl-N-methylaminomethyl) -1-
(2,6-difluorobenzyl) -6- [4- (3-methoxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione In Reference Example 6, The obtained compound (5.0 g, 8.41 mmol)
l) in dichloromethane (120 ml) solution under ice-cooling,
Triethylamine (2.34 ml, 16.82 mmol)
l) was added and stirred. The reaction solution was added with N,
N'-carbonyldiimidazole (2.73 g, 16.
82 mmol), and the mixture was returned to room temperature from ice-cooling and stirred for 42 hours. Return to ice-cooling again, and add O-methylhydroxylamine hydrochloride (7.02 g, 84.08 mmol) and triethylamine (11.7 ml, 84.08 mm).
ol) was added. The reaction solution was returned to room temperature from ice cooling and stirred for 3 hours. The reaction solution was partitioned between chloroform and saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with chloroform, the combined extracts were washed with brine, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a pale yellow solid,
Recrystallization from ether gave white crystals (4.52 g, 80
%) Of the title compound. mp: 204-205 ° C. Elemental analysis value: C ₃₆ H ₃₁ N ₅ O ₄ SF ₂ ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.05
(3H, s), 3.57 (2H, s), 3.82 (3
H, s), 3.90 (2H, s), 5.37 (2H,
s), 6.92 (2H, d, J = 8.2 Hz), 7.1
6-7.31 (9H, m), 7.42-7.57 (5
H, m), 7.63 (1H, s), 7.73 (2H,
d, J = 8.8 Hz). IR (KBr): 3338, 3064, 1717, 16
69, 1628, 1591, 1531, 1470c
m ^-1 .

Reference Example 8 3- (N-benzyl-N-methylaminomethyl) -4,
7-dihydro-5-isobutyryl-7- (2,6-difluorobenzyl) -2- [4-[(1-hydroxycyclopropyl) carbonylamino] phenyl] -4-oxothieno [2,3-b] pyridine 2 -(4-aminophenyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-5-isobutyryl-
3- (N-benzyl-N-methylaminomethyl) -4-
Oxothieno [2,3-b] pyridine (0.57 g,
1.0 mmol) in dichloromethane (10 ml) solution, diisopropylethylamine (0.52 g, 4 mm
ol) and 1-hydroxycyclopropanecarboxylic acid (0.204 g, 2 mmol), and the mixture was stirred under ice-cooling. To this solution was added benzotriazol-1-yloxytrisdimethylaminophosphonium hexafluorophosphate (BOP reagent) (1.76 g, 4 mmol). The mixture was stirred for 1 hour under ice-cooling and further for 4 days at room temperature. The reaction solution was evaporated to dryness under reduced pressure, and the resulting residue was washed with water (50 m
1) and chloroform (50 ml). The aqueous layer was extracted again with chloroform (10 ml). The extracts were combined, washed with brine, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography, and recrystallized from ether to obtain yellow powdery crystals (0.27 g, 41%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.16
-1.20 (2H, m), 1.18 (6H, d), 1.
48-1.51 (2H, m), 2.09 (3H, s),
3.64 (2H, s), 3.95 (1H, br s),
4.14 (2H, s), 4.12-4.19 (1H,
m), 5.20 (2H, s), 6.99 (2H, t),
7.10-7.25 (5H, m), 7.34-7.46
(1H, m), 7.57 (2H, d), 7.70 (2
H, d), 8.21 (1H, s), 8.82 (1H,
s).

Reference Example 9 Compound (XIII) was prepared according to the American Academy of Sciences outline (199
8), vol. 95, pp. 10836-10841.

Example 1 The compound (200 mg) obtained in Reference Example 7 and salicylic acid (62.1 mg) were treated with dimethyl sulfoxide (2 m
L), mixed with a vortex mixer, and allowed to stand at room temperature overnight to dissolve.

Example 2 The compound (1200 mg) obtained in Reference Example 7 and salicylic acid (372.6 mg) were treated with dimethyl sulfoxide (22.6 mg).
mL), mixed with a vortex mixer, and allowed to stand at room temperature overnight to dissolve.

Example 3 The compound (200 mg) obtained in Reference Example 8 and salicylic acid (42.1 mg) were treated with dimethyl sulfoxide (2 m
L), mixed with a vortex mixer, and allowed to stand at room temperature overnight to dissolve.

Example 4 The compound (XIII) (25 mg) synthesized in Reference Example 9 and 3-hydroxy-2-naphthoic acid (14.6 mg) were added to polyethylene glycol 300 (2.0 mL).
After mixing with a vortex mixer, the mixture was allowed to stand at room temperature overnight to dissolve.

Example 5 The compound (XIII) (75 mg) synthesized in Reference Example 9 and 3-hydroxy-2-naphthoic acid (43.7 mg) were added to polyethylene glycol 300 (1.9 mL).
After mixing with a vortex mixer, the mixture was allowed to stand at room temperature overnight to dissolve.

Example 6 A subcutaneously implantable minipump (Model 2004, manufactured by Alza) was filled with 200 μL of the solution prepared in Example 2.

Example 7 A subcutaneously implantable minipump (Model 2001, manufactured by Alza) was filled with 200 μL of the solution prepared in Example 5.

Experimental Example 1 The subcutaneously implantable mini-pump prepared in Example 6 was implanted subcutaneously on the back of a 7-week-old male SD rat. A predetermined time after the transplantation, blood was collected from the tail vein of the rat, and the serum was collected. The time course of the obtained drug concentration in serum is shown in [Table 1] (n = 4
Average).

[0141]

[Table 1]

From the results shown in Table 1, it was confirmed that the compound obtained in Reference Example 7 was continuously released over 21 days.

Experimental Example 2 The subcutaneously implantable mini-pump prepared in Example 7 was subcutaneously implanted into the back of a 26-week-old male Wistar fatty rat. A predetermined time after the transplantation, blood was collected from the tail vein of the rat, and the serum was collected. The time course of the obtained drug concentration in serum is shown in Table 2 (average value of n = 5).

[0144]

[Table 2]

The results in Table 2 show that the concentration of compound (XIII) in the serum was maintained high for almost 7 days by the one-week pump.

[0146]

The pharmaceutical solution of the present invention comprises a non-peptidic physiologically active substance, an organic acid and a biocompatible organic solvent. It can be contained at a concentration higher than the solubility of the substance in the biocompatible organic solvent, and as a result, the content of the non-peptide physiologically active substance in the preparation can be increased. As a result, the preparation can be made into a size that can be administered to a living body, and the burden on the patient can be reduced by downsizing the preparation.

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Yoko Akiyama 4-803, 1-3, Takakaicho, Omihachiman-shi, Shiga F-term (reference) 4C076 AA13 AA54 BB01 BB11 BB32 DD41E DD43E DD55E FF12 FF15 GG46

Claims (21)

[Claims] 1. A pharmaceutical solution comprising a non-peptide physiologically active substance, an organic acid and a biocompatible organic solvent. 2. The pharmaceutical solution according to claim 1, wherein the organic acid is one or more organic acids selected from lower fatty acids, aliphatic hydroxycarboxylic acids and aromatic organic acids. 3. The pharmaceutical solution according to claim 2, wherein the aliphatic hydroxycarboxylic acid is lactic acid. 4. The pharmaceutical solution according to claim 2, wherein the aromatic organic acid is an aromatic hydroxycarboxylic acid. 5. The pharmaceutical solution according to claim 4, wherein the aromatic hydroxycarboxylic acid is salicylic acid. 6. The pharmaceutical solution according to claim 4, wherein the aromatic hydroxycarboxylic acid is 1-hydroxy-2-naphthoic acid or 3-hydroxy-2-naphthoic acid. 7. The pharmaceutical solution according to claim 4, wherein the aromatic hydroxycarboxylic acid is pamoic acid. 8. The pharmaceutical composition according to claim 4, wherein the aromatic hydroxycarboxylic acid is a mixture of two or more kinds selected from salicylic acid, 1-hydroxy-2-naphthoic acid, 3-hydroxy-2-naphthoic acid and pamoic acid. solution. 9. The pharmaceutical solution according to claim 1, wherein the non-peptide physiologically active substance is a basic substance. 10. The pharmaceutical solution according to claim 1, wherein the non-peptide physiologically active substance has a molecular weight of about 1,000 or less. 11. The pharmaceutical solution according to claim 1, wherein the biocompatible organic solvent is polyethylene glycol or a fatty acid ester thereof, or dimethyl sulfoxide. 12. The pharmaceutical solution according to claim 1, further comprising a hydrophilic polymer. 13. The pharmaceutical solution according to claim 1, wherein the content of the non-peptide physiologically active substance is about 5% by weight or more based on the total weight of the solution. 14. The pharmaceutical solution according to claim 1, wherein the content of the organic acid is about 1% to about 40% by weight based on the total weight of the solution. 15. The pharmaceutical solution according to claim 1, comprising an organic acid in an amount of about 1/20 to about 100 mol per 1 mol of the non-peptide physiologically active substance. 16. The pharmaceutical solution according to claim 1, wherein the non-peptidic physiologically active substance is contained in a concentration higher than the solubility of the non-peptidic physiologically active substance in a biocompatible organic solvent. 17. The pharmaceutical solution according to claim 1, which is a preparation for parenteral administration. 18. The pharmaceutical solution according to claim 17, which is a preparation for injection. 19. An implantable preparation comprising the pharmaceutical solution according to claim 1. 20. The pharmaceutical solution according to claim 1, which is a preparation for oral administration. 21. A capsule containing the pharmaceutical solution according to claim 1.