JP2002080400A - Method for producing drug containing phospholipid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a safe formulation having slight irritation to an object of administration and further having a high content of a water-insoluble drug or a slightly water-soluble drug and to provide a simple method for producing the formulation. SOLUTION: This method for producing the water-insoluble drug or the slightly water-soluble drug coated with a phospholipid is characterized by mixing a solution containing the water-insoluble drug or the slightly water-soluble drug and the phospholipid in an organic solvent with an aqueous solvent, then emulsifying the resultant mixture, removing the organic solvent from the obtained emulsion and thereby forming a phopspholipid film on the surface of the water-insoluble or the slightly water-soluble drug.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a water-insoluble or poorly water-soluble drug having a surface coated with a phospholipid and a method for producing the same.

[0002]

2. Description of the Related Art A water-soluble drug can be easily injected as an aqueous solution, whereas a water-insoluble or poorly water-soluble drug by itself is difficult to make an injection as an aqueous solution.
When formulating such a water-insoluble or poorly water-soluble drug as an injection, there are roughly two approaches. 1
One is a method of solubilizing to form a solution.For example, a method of ionizing using a non-physiological pH, a method of using a non-aqueous solvent, a method of using a surfactant, a water-soluble clathrate compound such as cyclodextrin And a method of forming a complex. The other is a method of preparing a suspension, and specific formulations include, for example, emulsions, liposomes, nanocapsules, microcapsules, nanocrystals, microcrystals, and phospholipid-coated drugs.

[0003] Emulsion preparations are obtained by dispersing oil droplets in which a drug is dissolved in water, and are effective for lipophilic drugs. The oil is liquid at normal temperature, metabolized in the body,
It is not limited to those that do not irritate living tissues, and usually vegetable oils (eg, olive oil, sesame oil, soybean oil, camellia oil, rapeseed oil, corn oil, peanut oil, menzite oil, etc.) are used. In order to obtain a stable emulsion, additional surfactants (eg polysorbate, poloxamer, lecithin, polyethoxylated castor oil)
oil), bile acids, etc.] are used. As the surfactant, those having an HLB value of about 8 to 18 are generally used.
This enables stable O / W type emulsification. Liposomes are vesicles composed of phospholipid bilayer membranes, and can incorporate poorly soluble drugs into hydrophobic lipid bilayer membranes. Phospholipids are components of biological membranes and have excellent biocompatibility. In addition, the liposome preparation is effective as a drug carrier in blood, and depending on the drug, sustained release is possible.
Microcapsule preparations and nanocapsule preparations are prepared by encapsulating a drug in a base material to form fine particles through which needles can pass, and can be made into an aqueous suspension. The base herein refers to a biocompatible and biodegradable polymer. Specific examples include polylactic acid (PLA) or lactic acid-glycolic acid copolymer (PLGA). The base is gradually metabolized into water and carbon dioxide by hydrolysis in the body. These formulations are capable of sustained and long term release of the drug. At that time, the release period can be arbitrarily changed by changing the molecular weight of the polymer or the composition ratio of lactic acid / glycolic acid. These formulations have low irritation and are widely used clinically.

[0004] In recent years, a phospholipid film has been formed by utilizing a technique for increasing the dissolution rate of water-insoluble or poorly water-soluble drugs into fine submicron-sized fine particles (nanocrystals), or utilizing the physicochemical properties of water-insoluble or poorly water-soluble drugs. Technology has been developed. As a specific method for producing nanocrystals, for example, a poorly water-soluble drug is suspended in an aqueous solution of a surfactant, and this is suspended using zirconium oxide or zirconium silicate beads having a diameter of about 0.6 mm to 0.8 mm. By performing wet grinding for 4 days, fine crystals having a particle size of 400 nm or less can be obtained [Pharmaceutical Research, Vol. 13, No. 2,
No. 272-278 (1996); Pharmaceutical Research, Vol. 16, No. 4,
569-574 (1996)]. As a method for producing a phospholipid-coated drug, there is known a method of coating a phospholipid on a micron-sized or submicron-sized drug surface by applying ultrasonic waves to an aqueous suspension of drug microparticles and an amphipathic phospholipid. [WO91 / 16068 International Publication;
US Patent No. 5,091,187; International Journal of Pharmashtics
Journal of Pharmaceutics) Volume 200, pp. 27-39 (2000
Year); Controlled Release Newsletter (C
ONTROLLED RELEASE NEWSLETTER) Volume 17 Issue 2 21-31
Page (2000)]. By making the surface of the drug fine particles hydrophilic by this method, both the dispersibility and the needle passing property of the drug are improved. Further, the phospholipid constituting the surface of the phospholipid-coated drug has excellent biocompatibility as described above.

[0005]

PROBLEM TO BE SOLVED BY THE INVENTION It is intended to provide a preparation which is safe, has little irritation to a subject to be administered, and has a high content of a water-insoluble or poorly water-soluble drug, and a simple production method of the preparation.

[0006]

Means for Solving the Problems In order to solve the above problems, the present inventors have conducted intensive studies focusing on coating phospholipids on the surfaces of fine particles of a water-insoluble or poorly water-soluble drug. By dissolving a water-insoluble or poorly water-soluble drug and a phospholipid in an organic solvent, and removing the organic solvent from the obtained organic solvent solution, a phospholipid film can be formed on the surface of the water-insoluble or poorly water-soluble drug. I found it. Furthermore, it has been found that the thus produced phospholipid-coated water-insoluble or poorly water-soluble drug has excellent stability, excellent dispersibility in a dispersion medium, and sustained release. As a result of further studies based on these findings, the present invention has been completed.

That is, the present invention relates to (1) mixing and emulsifying an organic solvent solution containing a water-insoluble or poorly water-soluble drug and a phospholipid with an aqueous solvent, and removing the organic solvent from the obtained emulsion. (2) a method for producing a pharmaceutical composition comprising a water-insoluble or poorly water-soluble drug and a phospholipid; and (2) a phospholipid in an amount of about 0.1 to about 100 parts by weight based on 100 parts by weight of the water-insoluble or poorly water-soluble drug. (1) The production method according to (1), wherein the aqueous solvent is water; (4) the organic solvent is a halogenated hydrocarbon. (5) The method according to (1), wherein the water-insoluble or poorly water-soluble drug has a solubility in water at 20 ° C. of about 0 to about 1 mg / mL; (6) an aqueous solvent Volume is insoluble or poorly soluble in water (1) The production method according to the above (1), which is about 1 to about 1000 times the volume of the organic solvent solution containing the drug and the phospholipid; (7) the pharmaceutical composition produced by the production method according to the above (1); 8) The pharmaceutical composition according to the above (7), which is an injection; (9) the pharmaceutical composition according to the above (8), which is a non-injectable injection; (10) a water-insoluble or poorly water-soluble drug and a phospholipid. A phospholipid-coated water-insoluble or poorly water-soluble drug having a weight ratio of about 100: 1 to about 10 and an average particle diameter of about 1 to about 150 μm; (11) the phospholipid-coated water according to the above (10), which is used for joint administration. (12) a water-insoluble or poorly water-soluble drug represented by the formula (I):

Embedded image [Wherein ring A represents an optionally substituted benzene ring, R
Represents a hydrogen atom or a hydrocarbon group which may be substituted,
B represents a carboxy group which may be esterified or amidated, X represents -CH (OH)-or -CO-, k represents 0 or 1, and k 'represents 0, 1 or 2. And (13) a water-insoluble or poorly water-soluble drug represented by the general formula (I):
a):

Embedded image[Wherein, R^1aIs an optionally substituted hydrocarbon
Elemental residue, heterocyclic group, sulfinyl group, sulfonyl group, water
Represents an acid group, a thiol group or an amino group;^2aIs sheer
Group, formyl group, thioformyl group or formula: -Z^1a
-Z^2a(Where Z ^1aIs -CO-, -CS-, -SO
-Or -SO_Two-, Z^2aAre replaced respectively
A hydrocarbon residue, a heterocyclic group, a hydroxyl group or an
Shows a mino group. ) Represents a group represented by the following formula:
An optionally substituted 5- to 7-membered ring,^aIs a hydrogen atom,
Or a halogen atom, a cyano group or each substituted
Good amino group, acyl group, hydrocarbon residue or heterocyclic ring
A group represented by R^aIs the ring constituent of the thiophene ring and the ring Ca
Hydrocarbon ring or heterocyclic optionally substituted with
A ring may be formed. Or a salt thereof
And the like.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The water-insoluble or poorly water-soluble drug used in the present invention has a solubility in water at 20 ° C. of preferably about 0 to 1 mg / mL, more preferably about 0 to 1 mg / mL.
Examples include, but are not limited to, 0.1 mg / mL drug. When the aqueous solution is charged at physiological pH, a method of changing the pH to a molecular form by changing the pH; a method of complexing with a counter ion having a fat-soluble chemical structure; Applying the production method of the present invention by converting to a water-insoluble or poorly water-soluble drug using a method known per se such as a method of chemically modifying a hydrophobic group in a site that does not contribute to pharmacological activity in the structure of Can be. By converting a water-soluble drug into a water-insoluble or poorly water-soluble drug, sustained release of the drug is expected. The water-insoluble or sparingly water-soluble drug used in the present invention is water-insoluble or sparingly water-soluble, but is preferably soluble in body fluids (eg, synovial fluid, subcutaneous or intramuscular interstitial fluid, etc.). Specifically, the solubility in the body fluid at the administration site (for example, in the joint) is preferably about 10 times or more, more preferably about 100 to 10 times, the solubility in water at 20 ° C.
Preference is given to a drug with a factor of 10,000, more preferably a factor of 1000 to 100,000.

[0009] The types of drugs used in the present invention include:
For example, antitumor agents, antibiotics, anti-inflammatory agents, analgesics, osteoarthritis prophylactic and therapeutic agents, antihyperlipidemic agents, antibacterial agents, sedatives,
Examples include tranquilizers, antiepileptics, antidepressants, digestive tract disorders, allergic disorders, hypertension, diabetes, hormones, fat-soluble vitamins and the like. Antitumor agents include, for example, taxol, anthracycline-based antineoplastic agents such as doxorubicin hydrochloride, methotrexate, etoposide, 5-fluorouracil,
Mitoxantrone, mesna, dimesna, aminoglutethimide, tamoxifen, acroline, cisplatin,
Examples include carboplatin, cyclophosphamide, lomustine (CCNU), carmustine (BCNU), and the like, and derivatives thereof. Examples of the antibiotic include aminoglycoside antibiotics such as amikacin, dibekacin, gentamicin, and derivatives thereof. Examples of anti-inflammatory substances include salicylic acid anti-inflammatory drugs such as aspirin, pyrazolone anti-inflammatory drugs such as aminopyrine, aniline anti-inflammatory drugs such as phenacetin and acetaminophenone, phenylbutazone, ketophenylbutazone and the like. Pyrazolidinedione anti-inflammatory drugs,
Anthranilic acid anti-inflammatory drugs such as mefenamic acid, acetic acid anti-inflammatory drugs such as indomitacin, trioxopyrimidine anti-inflammatory drugs such as bucolome, benzidamine, mepyrizole,
Examples include basic anti-inflammatory drugs such as tiaramid and tinolidine, anti-inflammatory enzyme agents, non-steroidal anti-inflammatory drugs and the like. Analgesics include xylocaine, pentazocine, aspirin and the like.

[0010] Bone disease prevention and therapeutic agent, for example, prostaglandin A1 derivative, vitamin D derivative, vitamin K ₂ derivative, eicosapentaenoic acid derivative, benzylphosphonic acid, bisphosphonic acid derivative, sex hormone derivative, phenol sulfonium lid Non-peptidic bone formation promoting substances, such as a rain derivative, a benzothiopyran or benzothiepine derivative, a thienoindazole derivative, a menatetrenone derivative, and a helioxanthin derivative, and a poorly soluble peptide bone formation promoting substance. Examples of the therapeutic agent for joint diseases include matrix metalloprotease inhibitors (MMPI), anti-inflammatory steroids such as prednisolone, hydrocortisone, methylprednisolone, dexbetamethasone, and betamethasone, indomethacin, diclofenac, loxoprofen, ibuprofen, piroxicam, sulindac and the like. Non-steroidal anti-inflammatory analgesics.

Examples of the antihyperlipidemic agent include clinofibrate, clofibrate, cholestyramine, soysterol, tocopherol nicotinate, nicomol,
Niceritrol, probucol, elastase and the like. Examples of the tranquilizer include benzodiazepines such as diazepam, lorazepam and oxazolam. Examples of the antiepileptic include phenytoin, phenobarbital, carbamazepine, primidone and the like. Examples of the antidepressant include imiplanin, noxiptiline, phenelzine and the like.
Examples of the therapeutic agent for gastrointestinal diseases include metoclopramide, famotidine, omeprazole, sulpiride, trepibutone and the like. Examples of the therapeutic agent for allergic diseases include clemastine fumarate, cyproheptadine hydrochloride, diphenhydramine, methdilamine, clemizole, methoxyphenamine and the like. As antihypertensive agents, calcium antagonists such as nicardipine hydrochloride,
Angiotensin converting enzyme inhibitors such as delapril hydrochloride and captopril; alpha1-receptor blockers such as prazosin hydrochloride; and reserpines. Examples of the therapeutic agent for diabetes include glymidine, glipzide, glibenclamide, buformin, metformin and the like. Hormonal agents mainly include steroid hormones, for example, dexamethasone, betamethasone, prednisolone, hydrocortisone, triamcinolone, triamcinolone acetonide, fluocinolone acetonide,
Hexestrol, methimazole, estriol and the like. Examples of fat-soluble vitamins include vitamin A, vitamin D, vitamin E, vitamin K
, Folic acid (vitamin Ms), and various derivatives.

The water-insoluble or poorly water-soluble drug used in the present invention preferably includes a benzothiopyran or benzothiepine derivative or a thiophene derivative. Examples of the benzothiopyran or benzothiepine derivative include, for example, JP-A-3-232880 (European Patent Application Publication No. 376197), JP-A-4-364179 (European Patent Application Publication No. 460488) and JP-A-Hei. 8-
No. 231569 (European Patent Application Publication No. 7)
19782) and JP-A-2000-72678.
Or a salt thereof described in, for example, WO 00/09100, and among others, a compound represented by the formula (I):

Embedded image [Wherein ring A represents an optionally substituted benzene ring, R
Represents a hydrogen atom or a hydrocarbon group which may be substituted,
B represents a carboxy group which may be esterified or amidated, X represents -CH (OH)-or -CO-, k represents 0 or 1, and k 'represents 0, 1 or 2. [Compound (I)] or a salt thereof is preferred.

In the above formula (I), examples of the substituent on the optionally substituted benzene ring represented by ring A include a halogen atom, a nitro group, an optionally substituted alkyl group and a substituted A hydroxyl group, an optionally substituted mercapto group, an optionally substituted amino group, an acyl group, a mono- or di-alkoxyphosphoryl group, a phosphono group, an optionally substituted aryl group, And an optionally substituted aralkyl group or an optionally substituted aromatic heterocyclic group. These substituents may be the same or different, and may have 1 to 4, preferably 1 or 2 substituents on the benzene ring. Good.

As the "halogen atom", for example, fluorine, chlorine, bromine, iodine and the like are used. The alkyl group in the “optionally substituted alkyl group” is preferably an alkyl group having 1 to 10 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl) , Isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), a cycloalkyl group having 3 to 7 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, etc.), and these are, for example, halogen atoms. (Eg, fluorine, chlorine, bromine, iodine, etc.), hydroxyl group, alkoxy group having 1 to 6 carbon atoms
(Eg, methoxy, ethoxy, propoxy, butoxy, hexyloxy, etc.), a mono- or di-C _1-6 alkoxyphosphoryl group (eg, methoxyphosphoryl, ethoxyphosphoryl, dimethoxyphosphoryl, diethoxyphosphoryl, etc.), a phosphono group, etc. 1-3 may be substituted. Specific examples of the substituted alkyl group include, for example, trifluoromethyl, trifluoroethyl, trichloromethyl, hydroxymethyl, 2-hydroxyethyl,
Examples include methoxyethyl, 1-methoxyethyl, 2-methoxyethyl, 2,2-diethoxyethyl, 2-diethoxyphosphorylethyl, phosphonomethyl and the like.

As the substituted hydroxyl group in the "optionally substituted hydroxyl group", for example, an alkoxy group, an alkenyloxy group, an aralkyloxy group, an acyloxy group, an aryloxy group and the like are used. The “alkoxy group” is preferably an alkoxy group having 1 to 10 carbon atoms (eg, methoxy, ethoxy, propoxy, butoxy,
Examples thereof include tert-butoxy, pentyloxy, hexyloxy, heptyloxy, nonyloxy, and the like, and a C 4-6 cycloalkoxy group (eg, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like). The “alkenyloxy group” is preferably an alkenyloxy group having 2 to 10 carbon atoms, for example, allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy or 2
-Cyclohexenylmethoxy and the like are used. The “aralkyloxy group” preferably has 6 to 19 carbon atoms.
Aralkyloxy group, more preferably 7-1 carbon atoms
4 aryl-C 1-4 alkyloxy groups (eg,
Benzyloxy, phenethyloxy, etc.). The “acyloxy group” is preferably an alkanoyloxy group, for example, an alkanoyloxy group having 2 to 10 carbon atoms (eg, acetyloxy, propionyloxy,
n-butyryloxy, hexanoyloxy, etc.). As the “aryloxy group”, an aryloxy group having 6 to 14 carbon atoms (eg, phenoxy, biphenyloxy, etc.) is preferably used. These groups further
For example, 1 to 3 halogen atoms, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a mono- or di-C _1-6 alkoxyphosphoryl group, a phosphono group and the like as described above may be substituted. Specific examples of the substituted hydroxyl group include, for example, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-methoxyethoxy,
4-chlorobenzyloxy, 2- (3,4-dimethoxyphenyl) ethoxy and the like.

The “optionally substituted mercapto group”
As the substituted mercapto group in the above, for example, an alkylthio group, an aralkylthio group, an acylthio group and the like are used. The “alkylthio group” is preferably an alkylthio group having 1 to 10 carbon atoms (eg, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, nonylthio, etc.),
To 6 cycloalkylthio groups (eg, cyclobutylthio,
Cyclopentylthio, cyclohexylthio, etc.). As the "aralkylthio group", preferably an aralkylthio group having 7 to 19 carbon atoms, more preferably an aryl having 6 to 14 carbon atoms-an alkylthio group having 1 to 4 carbon atoms, for example, benzylthio or phenethylthio is used. . The “acylthio group” is preferably an alkanoylthio group, for example, an alkanoylthio group having 2 to 10 carbon atoms (eg, acetylthio, propionylthio, n-
Butyrylthio, hexanorthio, etc.). These groups are further substituted with 1 to 3 halogen atoms, hydroxyl groups, alkoxy groups having 1 to 6 carbon atoms, mono- or di-C _1-6 alkoxyphosphoryl groups, phosphono groups and the like as described above. You may. Specific examples of the substituted mercapto group include, for example, trifluoromethylthio, 2,2,2-trifluoroethylthio, 2-methoxyethylthio, 4-chlorobenzylthio, 3,4-dichlorobenzylthio, 4-fluoro Benzylthio, 2- (3,
4-dimethoxyphenyl) ethylthio and the like.

Examples of the substituent of the substituted amino group in the "optionally substituted amino group" include the same alkyl group having 1 to 10 carbon atoms and alkenyl group having 2 to 10 carbon atoms as described above (eg, , Allyl, vinyl, 2-pentene-1
-Yl, 3-penten-1-yl, 2-hexen-1-
Yl, 3-hexen-1-yl, 2-cyclohexenyl, 2-cyclopentenyl, 2-methyl-2-propen-1-yl, 3-methyl-2-buten-1-yl, etc.),
An aryl group having 6 to 14 carbon atoms (e.g., phenyl, naphthyl, etc.) or an aralkyl group having 7 to 19 carbon atoms (e.g., benzyl, phenethyl, etc.) is used singly or two times the same or different. same halogen atom and groups mentioned above, an alkoxy group having 1 to 6 carbon atoms, mono- - or di -C _1-6 alkoxy phosphoryl group, may be substituted by a phosphono group or the like. Specific examples of the substituted amino group include, for example, methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino or N
-Methyl-N-phenylamino, N-methyl-N- (4
-Chlorobenzyl) amino, N, N-di (2-methoxyethyl) amino and the like.

The "acyl group" includes an organic carboxylic acid acyl group or a hydrocarbon group having 1 to 6 carbon atoms [eg, C
An acyl sulfonate group having _1-6 alkyl (eg, methyl, ethyl, n-propyl, hexyl, etc.), phenyl, etc.] is used. Examples of the "organic carboxylic acyl group" include formyl, an alkyl-carbonyl group having 1 to 10 carbon atoms (eg, acetyl, propionyl, butyryl, valeryl, pivaloyl, hexanoyl, octanoyl, cyclobutanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl) Alkenyl-carbonyl group having 2 to 10 carbon atoms (eg, crotonyl, 2-cyclohexenecarbonyl, etc.), aryl-carbonyl group having 6 to 14 carbon atoms (eg, benzoyl, etc.), aralkyl having 7 to 19 carbon atoms. Carbonyl group (eg, benzylcarbonyl, benzhydrylcarbonyl, etc.), 5- or 6-membered aromatic heterocyclic carbonyl group (eg, nicotinoyl, 4-thiazolylcarbonyl, etc.), 5- or 6-membered aromatic heterocyclic acetyl Groups (eg, 3-pyridylacetyl, 4-thia Zolylacetyl). As the “acyl sulfonic acid group having a hydrocarbon group having 1 to 6 carbon atoms”, for example, methanesulfonyl, ethanesulfonyl and the like are used. These groups may be further substituted with 1 to 3 substituents, for example, the same halogen atoms, hydroxyl groups, alkoxy groups having 1 to 6 carbon atoms, amino groups and the like as described above. Specific examples of the acyl group include, for example, trifluoroacetyl, trichloroacetyl, 4-methoxybutyryl, 3-cyclohexyloxypropionyl, 4-chlorobenzoyl, 3,4-dimethoxybenzoyl and the like.

The "mono- or di-alkoxyphosphoryl group" includes, for example, mono-C _1-6 alkoxy such as methoxyphosphoryl, ethoxyphosphoryl, propoxyphosphoryl, isopropoxyphosphoryl, butoxyphosphoryl, pentyloxyphosphoryl, hexyloxyphosphoryl and the like. A phosphoryl group, such as dimethoxyphosphoryl,
Di-C _1-6 alkoxyphosphoryl groups such as diethoxyphosphoryl, dipropoxyphosphoryl, diisopropoxyphosphoryl, dibutoxyphosphoryl, dipentyloxyphosphoryl, dihexyloxyphosphoryl and the like are used. Preferably, a di-C _1-6 alkoxy group such as dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxyphosphoryl, diisopropoxyphosphoryl, ethylenedioxyphosphoryl, dibutoxyphosphoryl and the like are used. As the aryl group in the “aryl group which may be substituted”, an aryl group having 6 to 14 carbon atoms, for example, phenyl, naphthyl, anthryl and the like are preferably used. It may be substituted with 1 to 3 alkyl groups, halogen atoms, hydroxyl groups, alkoxy groups having 1 to 6 carbon atoms and the like. Specific examples of the substituted aryl group include, for example, 4-chlorophenyl, 3,4-dimethoxyphenyl, 4-cyclohexylphenyl, 5,6,7,8-tetrahydro-2-naphthyl, and the like.

The "aralkyl group which may be substituted"
The aralkyl group in preferably has 7 to 7 carbon atoms.
Nineteen aralkyl groups, for example, benzyl, naphthylethyl, trityl and the like are used. May be substituted. Specific examples of the substituted aralkyl group include, for example, 4-chlorobenzyl, 3,4-dimethoxybenzyl,
-Cyclohexylbenzyl, 5,6,7,8-tetrahydro-2-naphthylethyl and the like. The aromatic heterocyclic group in the “optionally substituted aromatic heterocyclic group” is preferably a 5- to 6-membered aromatic heterocyclic group having 1 to 4 nitrogen atoms, oxygen atoms and / or sulfur atoms. For example, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl and the like are used. May be substituted.

When two alkyl groups are substituted adjacent to each other on the benzene ring A, they are linked to each other to form a group represented by the formula:
An alkylene group represented by (CH ₂ ) m-(where m represents an integer of 3 to 5) (eg, trimethylene, tetramethylene, pentamethylene, etc.) may be formed, and two alkoxy groups may be formed. When substituted adjacent to each other, the formula:
O- (CH ₂₎ n-O- [wherein, n represents an integer of 1 to 3] alkylenedioxy group represented by (e.g., methylenedioxy, ethylenedioxy, trimethylenedioxy, etc.)
May be formed. In such a case, a 5- to 7-membered ring is formed together with the carbon atoms of the benzene ring.

In the above formula (I), R represents a hydrogen atom or a hydrocarbon group which may be substituted. As the hydrocarbon group in the “optionally substituted hydrocarbon group” for R, an alkyl group (preferably having 1 to 1 carbon atoms)
An alkyl group of 0, such as methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, ter
t-butyl, pentyl, isopentyl, neopentyl, hexyl and the like. ), The same alkenyl group as described above (preferably an alkenyl group having 2 to 10 carbon atoms), and further, as described above, the same aryl group (preferably an aryl group having 6 to 14 carbon atoms) and an aralkyl group (preferably Is an aralkyl having 7 to 19 carbon atoms). Examples of the substituent on the hydrocarbon group include a 5- to 6-membered aromatic heterocyclic group (eg, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, etc.), the same halogen atom as described above, and the same divalent as described above. —C _1-6 alkoxyphosphoryl group, phosphono group and the like are used.

In the above formula (I), B represents a carboxyl group which may be esterified or amidated.
Examples of the esterified carboxyl group in the “optionally esterified carboxyl group” for B include an alkoxycarbonyl group, preferably
_{A 1-10} alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), an aryloxycarbonyl group,
Preferably, a C _6-14 aryloxycarbonyl group (eg, phenoxycarbonyl), an aralkyloxycarbonyl group, preferably a C _7-19 aralkyloxycarbonyl group (eg, benzyloxycarbonyl) is used.

The amidated carboxyl group in the “carboxyl group which may be amidated” represented by B is preferably a group represented by the formula: —CON (R ¹ ) (R ² )
R ¹ and R ² each represent a hydrogen atom, a hydrocarbon group which may be substituted, or a 5- to 7-membered heterocyclic group which may be substituted. A carbamoyl group which may be substituted. Examples of the hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R ¹ and R ² include an alkyl group, preferably an alkyl group having 1 to 10 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), an alkenyl group, preferably an alkenyl group having 2 to 10 carbon atoms (eg, allyl,
Vinyl, 2-penten-1-yl, 3-penten-1-
Yl, 2-hexen-1-yl, 3-hexen-1-yl, 2-cyclohexenyl, 2-cyclopentenyl, 2
-Methyl-2-propen-1-yl, 3-methyl-2-
Buten-1-yl, etc.), an aryl group, preferably an aryl group having 6 to 14 carbon atoms (eg, phenyl, naphthyl, anthryl, etc.), an aralkyl group, preferably 7 to 19 carbon atoms.
Aralkyl groups (eg, benzyl, naphthylethyl, trityl, etc.) and the like, and these hydrocarbon groups are, for example,
(i) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (ii) a hydroxyl group, (iii) an alkoxy group having 1 to 6 carbon atoms (eg, methoxy, ethoxy, propoxy, butoxy, te
rt-butoxy, pentyloxy, hexyloxy, etc.),
(iv) one or two identical or different carbon atoms having 1 to 1 carbon atoms;
6 amino groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.)
Methylamino, ethylamino, dimethylamino, diethylamino, dipropylamino, etc.), (v) one or two identical or different acyl groups (e.g.
(Vi) an amino group substituted with an alkanoyl group (e.g., acetylamino, propionylamino, benzoylamino, etc.); (vi) one or two identical or different alkyl groups having 1 to 6 carbon atoms A carbamoyl group (e.g., carbamoyl, methylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.), (vii) C
_1-6 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.),
(viii) a mono- or di-alkoxyphosphoryl group (e.g.,
Mono- or di-C _1-6 alkoxyphosphoryl groups (eg, dimethoxyphosphoryl, diethoxyphosphoryl,
Ethylenedioxy phosphoryl, etc.), etc.], (ix) mono- - or di - alkoxy phosphoryl alkyl group [eg, mono- - or di -C _1-6 alkoxy phosphoryl -C _1-3 alkyl group (e.g., methoxy phosphoryl methyl, ethoxy Phosphorylmethyl, methoxyphosphorylethyl, ethoxyphosphorylethyl, dimethoxyphosphorylmethyl, diethoxyphosphorylmethyl, dimethoxyphosphorylethyl,
Diethoxyphosphorylethyl, etc.), formula (x)

Embedded image [Wherein, p represents an integer of 2 to 4. And (xi) a phosphono group, (xii) an aromatic heterocyclic group (as defined above), and the like.
Three may be substituted.

Examples of the 5- to 7-membered heterocyclic group in the "optionally substituted 5- to 7-membered heterocyclic group" for R ¹ and R ² include one sulfur atom, nitrogen atom or oxygen atom. 5 to 7 membered heterocyclic group containing, 5 containing 2 to 4 nitrogen atoms
5-6 membered heterocyclic groups containing 複 素 6-membered heterocyclic groups, 1-2 nitrogen atoms and one sulfur or oxygen atom are used, and these heterocyclic groups contain no more than 2 nitrogen atoms It may be condensed with a 6-membered ring, a benzene ring or a 5-membered ring containing one sulfur atom. Examples of the substituent which the “optionally substituted 5- to 7-membered heterocyclic group” may have include the aforementioned R
¹ to 4 substituents which are the same as the substituents which the hydrocarbon group of the “optionally substituted hydrocarbon group” represented by ¹ and R ² may have are used. Preferred examples of the 5- to 7-membered heterocyclic group represented by R ¹ and R ² include, for example, 2-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, triazinyl, triazolyl, Thienyl, pyrrolyl, pyrrolinyl, furyl, pyrrolidinyl, benzothienyl, indolyl, imidazolidinyl, piperidyl, piperidino, piperazinyl, morpholinyl, morpholino, pyrido [2,3
-D] pyrimidyl, benzopyranyl, 1,8-naphthyridyl, quinolyl, thieno [2,3-b] pyridyl and the like.

R ¹ and R ² are linked together to form
(R ¹ ) (R ² ) may form a 5- to 7-membered ring, and examples of such a ring include morpholine, thiomorpholine, piperidine, homopiperazine, piperazine, pyrrolidine, pyrroline, pyrazoline, imidazoline, Imidazolidine, thiazolidine, azepine and the like. R ¹
Specific examples of the substituted alkyl group which is a preferable example of the “optionally substituted hydrocarbon group” for R ² include trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, 2-chloromethyl, Hydroxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2,2-dimethoxyethyl, 2,2-diethoxyethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2- (2-thienyl) Ethyl, 3- (3-
Furyl) propyl, 2-morpholinoethyl, 3-pyrrolylbutyl, 2-piperidinoethyl, 2- (N, N-dimethylamino) ethyl, 2- (N-methyl-N-ethylamino) ethyl, 2- (N, N- Diisopropylamino) ethyl, 5- (N, N-dimethylamino) pentyl, N, N-dimethylcarbamoylethyl, N, N-dimethylcarbamoylpentyl, ethoxycarbonylmethyl, isopropoxycarbonylethyl, tert-butoxycarbonylpropyl, 2- Specific examples of substituted aralkyl groups such as diethoxyphosphorylethyl, 3-dipropoxyphosphorylpropyl, 4-dibutoxyphosphorylbutyl, ethylenedioxyphosphorylmethyl, 2-phosphonoethyl, and 3-phosphonopropyl include, for example, 4- Chlorobenzyl,
3- (2-fluorophenyl) propyl, 3-methoxybenzyl, 3,4-dimethoxyphenethyl, 4-ethylbenzyl, 4- (3-trifluoromethylphenyl) butyl, 4-acetylaminobenzyl, 4-dimethylaminophenethyl , 4-diethoxyphosphorylbenzyl, 2-
Specific examples of substituted aryl groups such as (4-dipropoxyphosphorylmethylphenyl) ethyl include, for example, 4
-Chlorophenyl, 4-cyclohexylphenyl, 5,
6,7,8-tetrahydro-2-naphthyl, 3-trifluoromethylphenyl, 4-hydroxyphenyl, 3,4,
5-trimethoxyphenyl, 6-methoxy-2-naphthyl, 4- (4-chlorobenzyloxy) phenyl, 3,4
-Methylenedioxyphenyl, 4- (2,2,2-trifluoroethoxy) phenyl, 4-propionylphenyl, 4-cyclohexanecarbonylphenyl, 4-dimethylaminophenyl, 4-benzoylaminophenyl,
4-diethoxycarbamoylphenyl, 4-tert-butoxycarbonylphenyl, 4-diethoxyphosphorylphenyl, 4-diethoxyphosphorylmethylphenyl,
-(2-diethoxyphosphorylethyl) phenyl, 2-diethoxyphosphorylmethylphenyl, 3-diethoxyphosphorylmethylphenyl, 4-dipropoxyphosphorylphenyl, 4- (2-phosphonoethyl) phenyl, 4-phosphonomethylphenyl, Specific examples of the substituted 5- to 7-membered heterocyclic group such as 4-phosphonophenyl include, for example, 5-
Chloro-2-pyridyl, 3-methoxy-2-pyridyl,
5-methyl-2-benzothiazolyl, 5-methyl-4-
Phenyl-2-thiazolyl, 3-phenyl-5-isoxazolyl, 4- (4-chlorophenyl) -5-methyl-
2-oxazolyl, 3-phenyl-1,2,4-thiadiazol-5-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-acetylamino-2-pyrimidyl, 3-methyl -2-thienyl, 4,5-dimethyl-2
-Furanyl, 4-methyl-2-morpholinyl and the like.

Among the above, ring A is preferably the same or different and is preferably a halogen atom, an optionally substituted alkyl group, an optionally substituted hydroxyl group, an optionally substituted mercapto group or / and a substituted or unsubstituted mercapto group. A benzene ring which may be substituted with one or more, more preferably one or two, amino groups which may be substituted. More preferred ring A is the same or different and is a halogen atom, having 1 to 10 carbon atoms (more preferably 1 to 5 carbon atoms).
An alkoxy group having 1 to 10 carbon atoms (more preferably 1 to 5 carbon atoms), a formula: —O— (CH ₂ ) n —O
An alkylenedioxy group represented by the formula [where n represents an integer of 1 to 3] and / or 1 or 2 alkylthio groups having 1 to 10 carbon atoms (more preferably 1 to 5 carbon atoms); It is a benzene ring which may be substituted. Particularly preferred examples of the ring A include a compound represented by the formula: —O— (CH ₂ ) n —O—
[Wherein, n represents an integer of 1 to 3], which is a benzene ring in which adjacent carbon atoms are substituted with an alkylenedioxy group. R is preferably a hydrogen atom, a C _1-6 alkyl group (eg, methyl, ethyl, etc.) or a phenyl group.

B is, for example, an alkoxy-carbonyl group and a formula: -CON (R ¹ ) (R ² ) wherein R ¹ and R ² are each a hydrogen atom, an optionally substituted hydrocarbon group or a substituted Or a 5- to 7-membered heterocyclic group which may be represented by the following formula: Preferred examples of R ¹ and R ² are that R ¹ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms (eg, methyl, ethyl, propyl, etc.) and R ² is a halogen (eg, fluorine, chlorine, bromine, etc.) , C _1-6 alkoxy (eg, methoxy, ethoxy, etc.), mono- or di-alkoxyphosphoryl (eg, mono- or di-C _1-6 alkoxyphosphoryl, such as dimethoxyphosphoryl, diethoxyphosphoryl, etc.), mono- or Di-alkoxyphosphorylalkyl (eg, dimethoxyphosphorylmethyl,
Mono- or di-C such as diethoxyphosphorylmethyl
_1-6 alkoxyphosphoryl-C _1-6 alkyl, etc.)
(Dialkyls in di-C _1-6 alkoxy may be taken together to form a C _1-6 alkylene group) or substituted with C _1-6 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.). A phenyl or phenyl-C _1-3 alkyl group, or a 5- or 6-membered ring having one or two nitrogen atoms or one nitrogen atom and one sulfur atom optionally substituted with a phenyl group It is a heterocyclic group (eg, pyridyl and the like).
More preferred examples of R ¹ and R ² include a phenyl group in which R ¹ is a hydrogen atom and R ² is substituted by mono- or di-C _1-6 alkoxyphosphoryl-C _1-3 alkyl (eg, 4- Diethoxyphosphorylmethylphenyl).

In the above formula (I), X is -CH (OH)
-Or -CO-, preferably -CO-. In the above formula (I), k represents 0 or 1, k ′ represents 0, 1 or 2, and preferably k is 1 and k ′ is 0.
Is the case.

More preferred examples of the compound (I) include, for example, those represented by the formula (II)

Embedded image [Wherein, R ³ represents a C _1-6 alkyl group, and R ⁴ and R ⁵ each represent a C _1-6 alkyl group, or together represent a C _1-6 alkylene group]. Optically active benzothiepine derivatives.

In the above formula (II), the “C _1-6 alkyl group” represented by R ³ , R ⁴ and R ⁵ includes, for example, methyl, ethyl, propyl, isopropyl, butyl,
Isobutyl, sec-butyl, tert-butyl, pentyl,
Examples thereof include an alkyl group such as isopentyl, neopentyl, and hexyl, and preferably an alkyl group having 1 to 4 carbon atoms. R ⁴ and R ⁵ together form C
_{A 1-6} alkylene group may be formed, in which case, for example,

Embedded image [Wherein, p represents an integer of 2 to 4. ]. As R ³ , R ⁴ and R ⁵ , for example, an alkyl group having 1 to 4 carbon atoms such as methyl and ethyl is preferable. Compound (II) is an (2R, 4S) -coordinated optically active compound, and substantially contains no (2S, 4R) -coordinated compound, and is more preferable as the optical purity approaches 100%.

Particularly preferred examples of the compound (II) include:
For example, (2R, 4S)-(-)-N- [4- (diethoxyphosphorylmethyl) phenyl] -1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo -3-benzothiepine-2-carboxamide (hereinafter sometimes referred to as compound A) or a salt thereof. The structure of compound A is represented by the following formula.

Embedded image

As the salt of the benzothiopyran or benzothiepine derivative used in the present invention, a pharmacologically acceptable salt is preferably used. As the pharmacologically acceptable salt, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like is used. Examples of salts that can form salts of benzothiopyran or benzothiepine derivatives include inorganic bases such as alkali metals (eg, sodium and potassium) and alkaline earth metals (eg, calcium and magnesium), and organic bases such as Trimethylamine, triethylamine, pyridine, picoline, N, N-
Dibenzylethylenediamine, diethanolamine, etc., as inorganic acids, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, etc., as organic acids, formic acid,
Acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid and the like, as basic or acidic amino acids, for example, arginine, lysine, asparagine Acid, glutamic acid and the like are used.

The benzothiopyran or benzothiepine derivative or a salt thereof used in the present invention is described in, for example, JP-A-3-232880 (EP-A-376197) and JP-A-4-364.
No. 179 (European Patent Application Publication No. 4604)
No. 88), the same method as the method described in JP-A-8-231569 (European Patent Application Publication No. 719782), a method similar thereto, or a method analogous thereto. .

As the thiophene derivative, compounds having a condensed benzothiophene derivative as a basic skeleton are described in the following documents and the like. Maybridge (Trevillett, Tintagel, North Cornwall, PL34)
0HW, UK) based on the company's product catalog (Vol.241, published October 1991).
(Methylthio) isoxazolo [5,4-d] benzo [c] thiophene-6-carboxamide [4,5-dihydro-8- (methylthi
o) isoxazolo [5,4-d] benzo [c] thienophene-6-carboxamid
e] can be obtained. JP-A-8-245386
In the publication, 4,5-dihydro-8- (methylthio) isoxazolo [5,4-d] benzo [c] thiophene-6-carboxamide [4,5-dihydro-8- (methylthio) isoxazolo [5,4 -d] benz
o [c] thienophene-6-carboxamide] is described. JP-A-10-130271 (WO98 / 099)
No. 58) has a cell differentiation inducing factor action enhancing action and an anti-matrix metalloprotease action, and has bone diseases such as osteoporosis, fracture, osteoarthritis, rheumatoid arthritis, arteriosclerosis, cancer metastasis and neurodegeneration. Condensed thiophene compounds useful for the prevention and treatment of diseases based on thiophene are described. Furthermore, GB-A-2336589 publication,
WO 99/6425 and Liebigs Ann. 1996, pages 239-245, describe fused thiophene derivatives.

The thiophene derivative used in the present invention is preferably a compound represented by the general formula (Ia)

Embedded image[Wherein, R^1aIs an optionally substituted hydrocarbon
Elemental residue, heterocyclic group, sulfinyl group, sulfonyl group, water
Represents an acid group, a thiol group or an amino group;^2aIs sheer
Group, formyl group, thioformyl group or formula: -Z^1a
-Z^2a(Where Z ^1aIs -CO-, -CS-, -SO
-Or -SO_Two-, Z^2aAre replaced respectively
A hydrocarbon residue, a heterocyclic group, a hydroxyl group or an
Shows a mino group. ) Represents a group represented by the following formula:
An optionally substituted 5- to 7-membered ring,^aIs a hydrogen atom,
Or a halogen atom, a cyano group or each substituted
Good amino group, acyl group, hydrocarbon residue or heterocyclic ring
A group represented by R^aIs the ring constituent of the thiophene ring and the ring Ca
Hydrocarbon ring or heterocyclic optionally substituted with
A ring may be formed. Or a salt thereof
It is.

R ^1a represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group.

Examples of the hydrocarbon residue in the optionally substituted hydrocarbon residue in R ^1a include an optionally substituted aliphatic hydrocarbon residue, an alicyclic hydrocarbon residue and an aliphatic hydrocarbon residue. A cyclic-aliphatic hydrocarbon residue, an aromatic hydrocarbon residue, or an aromatic-aliphatic hydrocarbon residue (aralkyl group);

Examples of the aliphatic hydrocarbon residue include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, A saturated aliphatic hydrocarbon residue having 1 to 8 carbon atoms such as octyl (eg, an alkyl group), for example, vinyl, allyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-
Butenyl, 3-butenyl, 3-methyl-2-butenyl,
1-pentenyl, 2-pentenyl, 3-pentenyl, 4
-Pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4-hexadienyl, 1-
Heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3
-Butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2,4-hexadynyl, 1-heptynyl, 1 −
Examples thereof include an unsaturated aliphatic hydrocarbon residue having 2 to 8 carbon atoms such as octynyl (eg, alkenyl group, alkynyl group, alkadienyl group, alkadiynyl group and the like).

The alicyclic hydrocarbon residue is, for example, a saturated alicyclic hydrocarbon residue having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl (eg, cycloalkyl group, etc.). , 1-
Cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl,
2-cycloheptenyl, 3-cycloheptenyl, 2,4
-An unsaturated alicyclic hydrocarbon residue having 3 to 7 carbon atoms such as cycloheptadienyl (e.g., cycloalkenyl group, cycloalkadienyl group, etc.), 1-indenyl, 2-indenyl, 1-indanyl, -Indanyl, 1,2,3,4-
Tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl, 1,2-dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl, 1,4-dihydro-1-naphthyl, 1,4-dihydro-2-naphthyl, 3,
4-dihydro-1-naphthyl, 3,4-dihydro-2-
Partially saturated condensed bicyclic hydrocarbon residue such as naphthyl [preferably C _9-10 partially saturated condensed bicyclic hydrocarbon residue or the like (a benzene ring is bonded to a 5- to 6-membered non-aromatic cyclic hydrocarbon group) And the like))].

The alicyclic-aliphatic hydrocarbon residue includes
Those in which the alicyclic hydrocarbon residue and the aliphatic hydrocarbon residue are bonded, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3
-Cyclopentenylmethyl, cyclopentylethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3
-Cyclohexenylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl, 2-
(3,4-dihydro-2-naphthyl) ethyl, 2- (1,
2,3,4-tetrahydro-2-naphthyl) ethyl, 2-
Those having 4 to 14 carbon atoms such as (3,4-dihydro-2-naphthyl) ethenyl (eg, C _3-7 cycloalkyl-C _1-4)
Alkyl group, C _3-7 cycloalkenyl-C _1-4 alkyl group, C _3-7 cycloalkyl-C _2-4 alkenyl group, C _3-7
Cycloalkenyl-C _2-4 alkenyl group, C _9-10 partially saturated condensed bicyclic hydrocarbon-C _1-4 alkyl group, C _9-10 partially saturated condensed bicyclic hydrocarbon-C _2-4 alkenyl group, etc. ).

Examples of the aromatic hydrocarbon residue include phenyl, α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8-tetrahydro- 1-naphthyl, 5,
6,7,8-tetrahydro-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro-4- And aryl groups having 6 to 10 carbon atoms (including those in which a 5- to 6-membered non-aromatic hydrocarbon ring is fused to a phenyl group) such as naphthyl.

The aromatic-aliphatic hydrocarbon residue includes:
For example, benzyl, phenethyl, 1-phenylethyl, 1
-Phenylpropyl, 2-phenylpropyl, 3-phenyl
Phenyl-C such as nilpropyl_1-4Alkyl group, for example
Α-naphthylmethyl, α-naphthylethyl, β-naphthyl
Naphthyl-C such as tylmethyl and β-naphthylethyl
_1-4C7-14 aralkyl groups such as alkyl groups
(C_6-10Aryl-C_1-4Alkyl group), for example, still
Phenyl-C such as cinnamyl_2-4Alkenyl group
Which C_6-10Aryl-C_2-4Alkenyl groups, etc.
It is.

The heterocyclic group of the heterocyclic group which may be substituted in R ^1a includes, for example, (i) 5 to 5 carbon atoms containing one sulfur atom, one nitrogen atom or one oxygen atom.
A 7-membered heterocyclic group, (ii) a 5- to 6-membered heterocyclic group containing 2 to 4 nitrogen atoms, or (iii) 1 to 2 nitrogen atoms and 1
And (iv) a 5- to 6-membered ring containing not more than 2 nitrogen atoms, a benzene ring or one sulfur-containing 5 to 6-membered heterocyclic group containing 2 or less nitrogen atoms. It may be condensed with a 5-membered ring containing an atom. The heterocyclic groups exemplified in (i) to (iv) may each be a saturated or unsaturated heterocyclic group, and the unsaturated heterocyclic group may be any of aromatic and non-aromatic. Is also good.

Examples of the heterocyclic group in the optionally substituted heterocyclic group for R ^1a include an aromatic monocyclic heterocyclic group, an aromatic fused heterocyclic group and a non-aromatic heterocyclic group. Specific examples of the heterocyclic group in the optionally substituted heterocyclic group for R ^1a include (i) an aromatic monocyclic heterocyclic group (eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, Imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.), (ii) aromatic fused heterocyclic group (eg, benzofuranyl, isobenzoyl) Furanyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, Benzoxazolyl, 1,2-benzisothiazolyl, 1H-
Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothinyl, phenazinyl Thiantrenyl, phenanthrinyl, phenanthrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl,
Pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-
b] pyridazinyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4- Triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,
3-b] pyridazinyl) and (iii) a non-aromatic heterocyclic group (eg, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,
Thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like).

R^1aThe optionally substituted
The sulfinyl group in the rufinyl group is as described above.
R^1aAs the carbonized carbon which may be substituted
Hydrocarbon residue or heterocyclic group ''
Or a compound in which a “heterocyclic group” and —SO— are bonded,
It is. Preferably, methyl, ethyl, propyl, isop
Propyl, butyl, isobutyl, sec-butyl, ter
t-butyl, pentyl, isopentyl, neopentyl,
tert-pentyl, hexyl, isohexyl, hepti
C, such as le and octyl _1-8Alkyl and sulfinyl groups
C is_1-8Alkylsulfinyl; phenyl,
α-naphthyl, β-naphthyl, 4-indenyl, 5-a
Ndenyl, 4-indanyl, 5-indanyl, 5,6,
7,8-tetrahydro-1-naphthyl, 5,6,7,8-te
Trahydro-2-naphthyl, 5,6-dihydro-1-na
Futyl, 5,6-dihydro-2-naphthyl, 5,6-dihi
Dro-3-naphthyl, 5,6-dihydro-4-naphthyl
Such as C_6-10Aryl and sulfinyl groups are linked
C_6-10Arylsulfinyl; aromatic monocyclic compound
Elementary ring groups (eg, furyl, thienyl, pyrrolyl, oxazoly
, Isoxazolyl, thiazolyl, isothiazolyl,
Imidazolyl, pyrazolyl, 1,2,3-oxadiazoli
1,2,4-oxadiazolyl, 1,3,4-oxadi
Azolyl, flazanil, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazol
1,2,3-triazolyl, 1,2,4-triazolyl
, Tetrazolyl, pyridyl, pyrimidinyl, pyridazi
Nil, pyrazinyl, triazinyl, etc.) and sulfinyl
A group to which a group is bonded; an aromatic fused heterocyclic group (eg,
Ranyl, isobenzofuranyl, benzo [b] thienyl,
Drill, isoindolyl, 1H-indazolyl, ben
Zoimidazolyl, benzoxazolyl, 1,2-benzo
Isothiazolyl, 1H-benzotriazolyl, quinori
, Isoquinolyl, cinnolinyl, quinazolinyl, quino
Xalinyl, phthalazinyl, naphthyridinyl, purini
, Pteridinyl, carbazolyl, α-carbolinyl,
β-carbolinyl, γ-carbolinyl, acridinyl,
Phenoxazinyl, phenothiazinyl, phenazinyl,
Phenoxathiinyl, thianthrenyl, phenanthredge
Nil, phenanthrolinyl, indolizinyl, pyrrolo
[1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridi
Le, imidazo [1,2-a] pyridyl, imidazo [1,5-a]
Pyridyl, imidazo [1,2-b] pyridazinyl, imidazo
[1,2-a] pyridyl, imidazo [1,5-a] pyridyl, i
Midazo [1,2-b] pyridazinyl, imidazo [1,2-a] pi
Limidinyl, 1,2,4-triazolo [4,3-a] pyridi
1,2,4-triazolo [4,3-b] pyridazinyl, etc.)
And a group in which a sulfinyl group is bonded. More preferred
Or methyl, ethyl, propyl, isopropyl,
Chill, isobutyl, sec-butyl, tert-butyl
, Pentyl, isopentyl, neopentyl, tert
-Pentyl, hexyl, isohexyl, heptyl, octyl
C such as chill_1-8Alkyl and sulfinyl groups are linked
C_1-8Alkylsulfinyl.

R^1aThe optionally substituted
As the sulfonyl group in the sulfonyl group, the above-mentioned R
^1aHydrocarbons each of which may be substituted
"Hydrocarbon residue" or "heterocyclic residue"
Ring group ”and -SO₂And-are bonded. Good
Preferably, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl
, Pentyl, isopentyl, neopentyl, tert
-Pentyl, hexyl, isohexyl, heptyl, octyl
C such as chill _1-8Alkyl and sulfonyl groups bonded
C_1-8Alkylsulfonyl; phenyl, α-naphthy
, Β-naphthyl, 4-indenyl, 5-indenyl,
4-indanyl, 5-indanyl, 5,6,7,8-tetra
Lahydro-1-naphthyl, 5,6,7,8-tetrahydro
-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,
6-dihydro-2-naphthyl, 5,6-dihydro-3-
C such as naphthyl, 5,6-dihydro-4-naphthyl
_6-10C having an aryl group and a sulfonyl group bonded_6-1
0Arylsulfonyl; aromatic monocyclic heterocyclic group (eg,
Furyl, thienyl, pyrrolyl, oxazolyl, isooxo
Sazolyl, thiazolyl, isothiazolyl, imidazoly
, Pyrazolyl, 1,2,3-oxadiazolyl, 1,2,
4-oxadiazolyl, 1,3,4-oxadiazolyl,
Frazanil, 1,2,3-thiadiazolyl, 1,2,4-thio
Asiazolyl, 1,3,4-thiadiazolyl, 1,2,3-
Triazolyl, 1,2,4-triazolyl, tetrazolyl
, Pyridyl, pyrimidinyl, pyridazinyl, pyrazini
, Triazinyl, etc.) and a sulfonyl group;
 Aromatic fused heterocyclic group (eg, benzofuranyl, isoben
Zofuranyl, benzo [b] thienyl, indolyl, isoi
Ondolyl, 1H-indazolyl, benzimidazolyl,
Benzoxazolyl, 1,2-benzoisothiazolyl,
1H-benzotriazolyl, quinolyl, isoquinolyl,
Cinnolinyl, quinazolinyl, quinoxalinyl, phthala
Zinyl, naphthyridinyl, prenyl, pteridinyl, ka
Rubazolyl, α-carbolinyl, β-carbolinyl, γ
-Carbolinyl, acridinyl, phenoxazinyl,
Enothiazinyl, phenazinyl, phenoxathiinyl,
Thiantrenyl, phenanthrinyl, phenanthroli
Nil, indolizinyl, pyrrolo [1,2-b] pyridazini
, Pyrazolo [1,5-a] pyridyl, imidazo [1,2-a]
Pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,
2-b] pyridazinyl, imidazo [1,2-a] pyridyl, i
Midazo [1,5-a] pyridyl, imidazo [1,2-b] pyrida
Dinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-
Triazolo [4,3-a] pyridyl, 1,2,4-triazolo
[4,3-b] pyridazinyl) and sulfonyl group
Groups. More preferably, methyl, ethyl,
Ropyl, isopropyl, butyl, isobutyl, sec-
Butyl, tert-butyl, pentyl, isopentyl,
Neopentyl, tert-pentyl, hexyl, isohe
C for xyl, heptyl, octyl, etc._1-8With alkyl
C to which a sulfonyl group is bonded_1-8Alkylsulfonyl is
No.

R^1aOptionally substituted water
As the acid group, a hydroxyl group and an appropriate substitution for this hydroxyl group
A group, for example, R¹"
Substituted with a hydrocarbon residue or a heterocyclic group "
Groups. Preferably, methyl, ethyl, propyl
, Isopropyl, butyl, isobutyl, sec-butyl
Tert-butyl, pentyl, isopentyl, neo
Pentyl, tert-pentyl, hexyl, isohexyl
C such as le, heptyl, octyl, etc. _1-8Substitute with alkyl
Done C_1-8Alkyloxy; phenyl, α-naph
Tyl, β-naphthyl, 4-indenyl, 5-indenyl
4-Indanyl, 5-Indanyl, 5,6,7,8-
Tetrahydro-1-naphthyl, 5,6,7,8-tetrahi
Dro-2-naphthyl, 5,6-dihydro-1-naphthy
5,6-dihydro-2-naphthyl, 5,6-dihydro
-3-naphthyl, 5,6-dihydro-4-naphthyl, etc.
C_6-10C substituted with an aryl group_6-10Ally
Roxy; aromatic monocyclic heterocyclic group (eg, furyl, thie
Nil, pyrrolyl, oxazolyl, isoxazolyl, thi
Azolyl, isothiazolyl, imidazolyl, pyrazoly
1,2,3-oxadiazolyl, 1,2,4-oxadi
Azolyl, 1,3,4-oxadiazolyl, furazanil,
1,2,3-thiadiazolyl, 1,2,4-thiadiazol
1,3,4-thiadiazolyl, 1,2,3-triazolyl
1,2,4-triazolyl, tetrazolyl, pyridi
, Pyrimidinyl, pyridazinyl, pyrazinyl, tria
A hydroxyl group substituted with a dilinyl or the like); condensed aromatic heterocycle
Groups (eg, benzofuranyl, isobenzofuranyl, benzo
[b] thienyl, indolyl, isoindolyl, 1H-a
Ndazolyl, benzimidazolyl, benzoxazoly
1,2-benzoisothiazolyl, 1H-benzotri
Azolyl, quinolyl, isoquinolyl, cinnolinyl,
Nazolinyl, quinoxalinyl, phthalazinyl, naphthyl
Dinyl, purinyl, pteridinyl, carbazolyl, α-
Carbolinyl, β-carbolinyl, γ-carbolinyl,
Acridinyl, phenoxazinyl, phenothiazinyl,
Phenazinyl, phenoxathiinyl, thianthrenyl,
Phenanthrinil, phenanthrolinyl, indolizy
Nil, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5
-A] pyridyl, imidazo [1,2-a] pyridyl, imidazo
[1,5-a] pyridyl, imidazo [1,2-b] pyridazini
Le, imidazo [1,2-a] pyridyl, imidazo [1,5-a]
Pyridyl, imidazo [1,2-b] pyridazinyl, imidazo
[1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3
-A] pyridyl, 1,2,4-triazolo [4,3-b] pyrida
And a hydroxyl group substituted with dilinyl or the like. More preferred
Or C_6-10Aryloxy (particularly preferably
Phenyl) or an aromatic monocyclic heterocyclic group (particularly preferred
Is pyridyl) or a fused aromatic heterocyclic group (particularly preferred
Or quinolyl). here
"Hydrocarbon as a substituent of the substituted hydroxyl group exemplified in
The “primary residue” or the “heterocyclic group” is the same as the above R^1aAs
Of `` each optionally substituted hydrocarbon residue or
"Hydrocarbon residue" or "heterocycle" in "heterocyclic group"
May have the same substituents as the “group”.

R^1a, Optionally substituted
As the all group, a thiol group and this thiol group
Optional substituents, such as R^1a"
An optionally substituted hydrocarbon residue or heterocyclic group ''
Substituted thiol groups. Preferably, meth
, Ethyl, propyl, isopropyl, butyl, isobu
Chill, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, tert-pentyl, f
C such as xyl, isohexyl, heptyl, octyl, etc.
_1-8C substituted with alkyl_1-8Alkylthio;
Phenyl, α-naphthyl, β-naphthyl, 4-indenyl
5-Indenyl, 4-Indanyl, 5-Indani
5,6,7,8-tetrahydro-1-naphthyl, 5,
6,7,8-tetrahydro-2-naphthyl, 5,6-dihi
Dro-1-naphthyl, 5,6-dihydro-2-naphthy
5,6-dihydro-3-naphthyl, 5,6-dihydro
C such as -4-naphthyl_6-10Substituted with an aryl group
C_6-10Arylthio; aromatic monocyclic heterocyclic group
(E.g., furyl, thienyl, pyrrolyl, oxazolyl, i
Soxazolyl, thiazolyl, isothiazolyl, imida
Zolyl, pyrazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazo
Ryl, Frazanil, 1,2,3-thiadiazolyl, 1,2,
4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,
2,3-triazolyl, 1,2,4-triazolyl, tet
Lazolyl, pyridyl, pyrimidinyl, pyridazinyl, pi
Thiol substituted with radinyl, triazinyl, etc.)
Group; aromatic fused heterocyclic group (eg, benzofuranyl, iso
Benzofuranyl, benzo [b] thienyl, indolyl, a
Soindrill, 1H-indazolyl, benzimidazoli
Benzoxazolyl, 1,2-benzoisothiazolyl
1H-benzotriazolyl, quinolyl, isoquinolyl
, Cinnolinyl, quinazolinyl, quinoxalinyl,
Tarazinil, naphthyridinyl, purinyl, pteridini
, Carbazolyl, α-carbolinyl, β-carbolinyl
, Γ-carbolinyl, acridinyl, phenoxazini
Le, phenothiazinyl, phenazinyl, phenoxathii
Nil, thianthrenyl, phenanthrinil, phenan
Tolorinyl, indolizinyl, pyrrolo [1,2-b] pyrida
Dinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2
-A] pyridyl, imidazo [1,5-a] pyridyl, imidazo
[1,2-b] pyridazinyl, imidazo [1,2-a] pyridin
Le, imidazo [1,5-a] pyridyl, imidazo [1,2-b]
Pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,
2,4-triazolo [4,3-a] pyridyl, 1,2,4-to
Thiol substituted with liazolo [4,3-b] pyridazinyl, etc.
And a thiol group. The substituted thiol exemplified here
Hydrocarbon group or heterocycle as a substituent of
The group is a group represented by R^1aAs "each replaced
Hydrocarbon residue or heterocyclic group "
A substituent similar to the `` hydrogen residue '' or `` heterocyclic group ''
Each may have. More preferably, methyl, ethi
Propyl, isopropyl, butyl, isobutyl, s
ec-butyl, tert-butyl, pentyl, isopene
Chill, neopentyl, tert-pentyl, hexyl,
C such as isohexyl, heptyl and octyl_1-8Al
C replaced by kill_1-8And alkylthio.

The amino group which may be substituted in R ^1a includes an amino group, an N-monosubstituted amino group and an N, N-disubstituted amino group. Examples of the substituted amino group include, for example, an optionally substituted hydrocarbon residue (for example, the same as the ^optionally substituted hydrocarbon residue represented by R ^1a , more specifically, C _{1 -8} alkyl group, C _3-7 cycloalkyl group, C _2-8 alkenyl group,
C _2-8 alkynyl group, C _3-7 cycloalkenyl group, C _1-4
A C _6-10 aryl group which may have an alkyl group), an _optionally substituted heterocyclic group (for example, R ^1a
Or the same as the optionally substituted heterocyclic group represented by the formula: or a formula: -COR ^a ′ (wherein, R ^a ′ is a hydrogen atom or a hydrocarbon residue or a heterocyclic group, each of which may be optionally substituted) shows a ring group. Note that, R a ^' "each optionally substituted hydrocarbon residue or heterocyclic group" as the above-mentioned R ^a' "each optionally substituted hydrocarbon residue as Or a substituent similar to the "hydrocarbon residue" or "heterocyclic group" in the "heterocyclic group"), preferably a C _1-10 acyl group (eg, C _2-7 alkanoyl) , Benzoyl, nicotinoyl, etc.) as one or two substituents (eg, methylamino, dimethylamino, ethylamino, diethylamino, dipropylamino, dibutylamino, diallylamino, cycloalkyl) Hexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino, etc.). Further, two groups in the substituted amino group may be bonded to form a nitrogen-containing 5- to 7-membered ring (for example, piperidino, morpholino, thiomorpholino, etc.).

R^1a''
A hydrocarbon residue, a heterocyclic group, a sulfinyl group,
"Hydrocarbon residue" and "heterocycle"
Group "," sulfinyl group "and" sulfonyl group "
Each may be substituted with 1 to 3 substituents,
As the substituent, for example, lower (C_1-6) Alkyl group
(Eg, methyl, ethyl, propyl, isopropyl,
, Isobutyl, sec-butyl, tert-butyl,
Pentyl, isopentyl, neopentyl, hexyl
Etc.), low grade (C_2-6) Alkenyl group [eg, vinyl, allyl
(Allyl), 1-propenyl, 2-methyl-1-propenyl
1-butenyl, 2-butenyl, 3-butenyl, 3-
Methyl-2-butenyl, 1-pentenyl, 2-pentenyl
3-pentenyl, 4-pentenyl, 4-methyl-3
-Pentenyl, 1-hexenyl, 2-hexenyl, 3-
Hexenyl, 4-hexenyl, 5-hexenyl, etc.],
Low grade (C_2-6) Alkynyl group (eg, ethynyl, 1-pro
Pinyl, 2-propynyl, 1-butynyl, 2-butynyl
, 3-butynyl, 1-pentynyl, 2-pentynyl,
3-pentynyl, 4-pentynyl, 1-hexynyl, 2
-Hexynyl, 3-hexynyl, 4-hexynyl, 5-
Hexynyl), C_3-7Cycloalkyl group (eg, cyclo
Propyl, cyclobutyl, cyclopentyl, cyclohexyl
Sil, cycloheptyl, etc.), C_6-10Aryl group (eg,
Phenyl, α-naphthyl, β-naphthyl, etc.), aromatic
Heterocyclic group [eg, furyl, thienyl, pyrrolyl, oxazo
Ryl, isoxazolyl, thiazolyl, isothiazolyl,
Imidazolyl, pyrazolyl, 1,2,3-oxadiazoli
1,2,4-oxadiazolyl, 1,3,4-oxadi
Azolyl, flazanil, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazol
1,2,3-triazolyl, 1,2,4-triazolyl
, Tetrazolyl, pyridyl, pyridazinyl, pyrimidi
Nil, pyrazinyl, triazinyl, benzofuranyl, i
Sobenzofuranyl, benzo [b] thienyl, indori
, Isoindolyl, 1H-indazolyl, benzimi
Dazolyl, benzoxazolyl, 1,2-benzisoxa
Zolyl, benzothiazolyl, 1,2-benzisothiazo
Ryl, 1H-benzotriazolyl, quinolyl, isoquino
Ril, cinnolinyl, quinazolinyl, quinoxalinyl,
Phthalazinyl, naphthyridinyl, purinyl, pteridini
, Carbazolyl, α-carbolinyl, β-carbolinyl
, Γ-carbolinyl, acridinyl, phenoxazini
Le, phenothiazinyl, phenazinyl, phenoxathii
Nil, thianthrenyl, phenathridinyl, phenatro
Linyl, indolizinyl, pyrrolo [1,2-b] pyrida
Dinyl, pyrazolo [1,5-a] pyridyl, imidazo
[1,2-a] pyridyl, imidazo [1,5-a] pyridi
Le, imidazo [1,2-b] pyridazinyl, imidazo
[1,2-a] pyrimidinyl, 1,2,4-triazolo
[4,3-a] pyridyl, 1,2,4-triazolo [4,3
-B] pyridazinyl and the like, (i) nitrogen atom, oxygen atom
Having 1 to 4 heteroatoms selected from
An aromatic 5- or 6-membered heterocyclic group, (ii) a nitrogen atom,
1-3 heteroatoms selected from oxygen and sulfur atoms
Aromatic 5- or 6-membered heterocycle and benzene ring
Is a heteroatom selected from nitrogen, oxygen and sulfur
Aromatic 5- or 6-membered heterocyclic ring having 1 to 3
A fused bicyclic heterocyclic group formed by combining (iii) nitrogen
One heteroatom selected from an atom, an oxygen atom and a sulfur atom
Aromatic 5- or 6-membered heterocyclic ring having 3 to 3 rings
Ring, nitrogen atom, oxygen atom, sulfur atom
5- or 6-membered aromatic having 1-3 heteroatoms
Condensed tricyclic formed by condensing a heterocyclic ring or a benzene ring
Heterocyclic group], non-aromatic heterocyclic group (eg, oxiranyl,
Zetidinyl, oxetanyl, thietanyl, pyrrolidini
, Tetrahydrofuryl, thiolanyl, piperidinyl,
Tetrahydropyranyl, morpholinyl, thiomorpholini
Nitrogen, oxygen, sulfur, etc.
A 4- to 7-membered non-metal having 1 to 3 heteroatoms selected from
An aromatic heterocyclic group), C_7-14Aralkyl groups (eg, ben
Jill, phenethyl, 1-phenylethyl, 1-phenyl
Propyl, 2-phenylpropyl, 3-phenylpropyl
, Α-naphthylmethyl, α-naphthylethyl, β-na
C such as fthylmethyl and β-naphthylethyl_6-10Ally
Le-C_1-4Alkyl group, etc.), amino group, N-monosubstituted
Amino group [eg, methylamino, ethylamino, allyl (al
lyl) amino, cyclohexylamino, phenylamino
N- (C_1-6Alkyl) amino group, N- (C_2-6A
Lucenyl) amino group, N- (C_3-7Cycloalkyl) a
Amino group, N- (C_6-10Aryl) amino group etc.], N,
N-disubstituted amino group [eg, dimethylamino, diethyla
Mino, dibutylamino, diallyl (allyl) amino, N
-Methyl-N-phenylamino,_1-6Alkyl
Group, C_2-6Alkenyl group, C_3-7A cycloalkyl group and
C_6-10Substituted with two substituents selected from an aryl group
Amino group, etc.), amidino group, acyl group (eg,
Acetyl, propionyl, butyryl, isobutylyl
, Valeryl, isovaleryl, pivaloyl, hexanoy
, Heptanoyl, octanoyl, cyclopropanecal
Bonyl, cyclobutanecarbonyl, cyclopentanecar
Bonyl, cyclohexanecarbonyl, crotonoyl, 2
-Cyclohexenecarbonyl, benzoyl, nicotine
C such as_2-8Alkanoyl group, C_3-8Alkenoyl group,
C_3-7Cycloalkyl-carbonyl group, C_3-7Cycloal
Kenyl-carbonyl group, C_6-10Aryl-carbonyl
Hetero group selected from group, nitrogen atom, oxygen atom and sulfur atom
5- or 6-membered aromatic or aromatic having 1 to 3 atoms
Is a complex formed by combining a non-aromatic heterocycle with a carbonyl group.
A carbamoyl group, N-mono)
Substituted carbamoyl group [eg, methylcarbamoyl, ethyl
Carbamoyl, cyclohexylcarbamoyl, phenyl
N- (C such as carbamoyl_1-6Alkyl) carb
Moyl group, N- (C_2-6Alkenyl) carbamoyl group,
N- (C_3-7Cycloalkyl) carbamoyl group, N-
(C_6-10Aryl) carbamoyl group and the like, N, N-di
Substituted carbamoyl groups [eg dimethylcarbamoyl, die
Tylcarbamoyl, dibutylcarbamoyl, diallyl
(allyl) carbamoyl, N-methyl-N-phenylcar
C, such as Bamoyl_1-6Alkyl group, C_2-6Alkenyl
Group, C_3-7Cycloalkyl group and C_6-10Aryl group
A carbamoyl group substituted with two substituents selected from
Etc.], sulfamoyl group, N-monosubstituted sulfamoyl
Groups [eg, methylsulfamoyl, ethylsulfamoi
, Cyclohexylsulfamoyl, phenylsulfa
N- (C_1-6Alkyl) sulfamoyl
Group, N- (C_2-6Alkenyl) sulfamoyl group, N-
(C_3-7Cycloalkyl) sulfamoyl group, N- (C
_6-10Aryl) sulfamoyl group, etc., N, N-di configuration
Substituted sulfamoyl groups [eg, dimethylsulfamoyl, di
Ethyl sulfamoyl, dibutyl sulfamoyl, dia
Allyl sulfamoyl, N-methyl-N-fe
C, such as Nilsulfamoyl_1-6Alkyl group, C_2-6A
Lucenyl group, C_3-7Cycloalkyl group and C_6-10Ants
Substituted with two substituents selected from a sulfur group
Moyl group, etc.), carboxyl group, lower (C_1-6) Arco
Xy-carbonyl group (eg, methoxycarbonyl, ethoxy
Cicarbonyl, propoxycarbonyl, isopropoxy
Carbonyl, butoxycarbonyl, isobutoxycarbo
Nil, sec-butoxycarbonyl, tert-butoxy
Cicarbonyl, pentyloxycarbonyl, hexylo
Hydroxyl group, lower (C_1-6) Alkoki
Cy groups (eg, methoxy, ethoxy, propoxy, isopro
Poxy, butoxy, isobutoxy, sec-butoxy,
tert-butoxy, pentyloxy, hexyloxy
), Low grade (C_2-6) Alkenyloxy group [eg, allyl
(Allyl) oxy, 2-butenyloxy, 2-pentenyl
Ruoxy, 3-hexenyloxy, etc.], C_3-7Cycloa
Alkyloxy group (eg, cyclopropyloxy, cyclobutyl
Tyloxy, cyclopentyloxy, cyclohexylo
Xy, cycloheptyloxy, etc.), C_6-10Arlio
Xy group (eg, phenoxy, naphthyloxy, etc.), C
_7-14An aralkyloxy group (eg, phenyl-C_1-4Archi
Ruoxy, naphthyl-C_1-4C such as alkyloxy
_6-10Aryl-C_1-4Alkyloxy group), merka
Pt group, lower (C_{1 -6}) Alkylthio group (eg, methylthio
E, ethylthio, propylthio, isopropylthio, bu
Tylthio, isobutylthio, sec-butylthio, te
rt-butylthio, pentylthio, isopentylthio,
Neopentylthio, hexylthio, etc.), C_7-14Aral
Kirthio group (eg, phenyl-C_1-4Alkylthio, naph
Chill-C _1-4C such as alkylthio_6-10Aryl-C_1-4
Alkylthio group), C_6-10Arylthio group (eg,
Enylthio, naphthylthio, etc.), lower (C_1-6) Al
Killsulfinyl group (eg, methylsulfinyl, ethyl
Sulfinyl, propylsulfinyl, isopropyls
Rufinyl, butylsulfinyl, isobutylsulfy
Nil, sec-butylsulfinyl, tert-butyl
Sulfinyl, pentylsulfinyl, isopentyls
Rufinil, neopentyl sulfinyl, hexyl sulf
Finyl), C_7-14Aralkylsulfinyl group
(Eg, phenyl-C_1-4Alkylsulfinyl, nafti
Le-C_1-4C such as alkylsulfinyl_{6- Ten}Aryl
-C_1-4Alkylsulfinyl group), C_6-10Ally
Rusulfinyl group (eg, phenylsulfinyl, naphthy
Rusulfinyl, etc.), lower (C_1-6) Alkylsulfo
Group (eg, methylsulfonyl, ethylsulfonyl,
Ropylsulfonyl, isopropylsulfonyl, butyls
Ruphonyl, isobutylsulfonyl, sec-butylsulfur
Honyl, tert-butylsulfonyl, pentylsulfo
Nil, isopentylsulfonyl, neopentylsulfonyl
, Hexylsulfonyl, etc.), C_7-14Aralkyl Sul
Honyl group (eg, phenyl-C_1-4Alkylsulfonyl,
Naphthyl-C_1-4C such as alkylsulfonyl_6-10Ants
RU-C_1-4Alkylsulfonyl group), C_6-10Ants
Sulfonyl group (eg, phenylsulfonyl, naphthyl
Sulfonyl), sulfo group, cyano group, azide group,
Logen atoms (eg, fluorine, chlorine, bromine, iodine, etc.),
Nitro group, nitroso group, and optionally esterified
Suphono groups [eg, phosphono groups, ethoxyphosphoryl, etc.
(C_1-6Alkoxy) phosphoryl group, diethoxyphospho
Di (C_1-6Alkoxy) phosphoryl group
Etc.), which may be substituted with an optionally esterified phosphono group.
Low grade (C_1-6) Alkyl group (eg, phosphono-C_1-6A
Alkyl group, C_1-6Alkoxyphosphoryl-C_1-6Alkyl
Group, di (C) such as diethoxyphosphorylmethyl_1-6Al
Coxy) phosphoryl-C_1-6Alkyl groups, etc.)
I can do it. Among the above substituents, a hydroxyl group and a lower group
(C_1-6) When the alkoxy group is adjacent as a substituent
Is a C such as methylenedioxy and ethylenedioxy
_{1 -6}An alkylenedioxy may be formed.

The above C _6-10 aryl group, aromatic heterocyclic group,
A C _6-10 aryl group as a substituent of an N-monosubstituted amino group, a C _6-10 aryl group as a substituent of an N, N-disubstituted amino group, and a C _6-10 aryl group as a substituent of an N-monosubstituted carbamoyl group _6-10 aryl group, N, N- C _6-10 aryl group as a substituent of di-substituted carbamoyl group, C _6-10 aryl as a substituent of the N- mono-substituted sulfamoyl group, N, N-
A C _6-10 aryl group as a substituent of a disubstituted sulfamoyl group, a C _6-10 aryl group in a C _6-10 aryloxy group,
A C _6-10 aryl group in a C _7-14 aralkyloxy group,
_7-14 aralkylthio C _6-10 aryl group in the group, C _6-10 aryl groups in C _6-10 arylthio group, C _{7- 14} aralkyl sulfinyl C _6-10 aryl group in the Le group, C _6-10 C _6-10 aryl groups in the aryl sulfinyl group, C _6-10 aryl groups C _6-10 aryl groups, and C _6-10 during arylsulfonyl groups in C _7-14 aralkylsulfonyl groups, further 1
May be substituted with up to 3 substituents, such as a lower (C _1-6 ) alkyl group, an amino group,
N- (C _1-6 alkyl) amino group, N, N-di (C _1-6 alkyl) amino group, amidino group, carbamoyl group, N-
(C _1-6 alkyl) carbamoyl group, N, N-di (C _1-6
Alkyl) carbamoyl group, sulfamoyl group, N-
(C _1-6 alkyl) sulfamoyl group, N, N-di (C
_1-6 alkyl) sulfamoyl group, carboxyl group, lower (C _2-7 ) alkoxycarbonyl group, hydroxyl group, lower (C _1-6 ) alkoxy group, mercapto group, lower (C _1-6 )
Alkylthio group, sulfo group, cyano group, azido group, halogen atom, nitro group, nitroso group, phosphono group which may be esterified [eg, phosphono group, C _1-6 alkoxyphosphoryl group, di (C _1-6 Alkoxy) phosphoryl group, etc., and a lower (C _1-6 ) alkyl group substituted with an optionally esterified phosphono group [eg, phosphono-C _1-6
Alkyl group, C _1-6 alkoxyphosphoryl-C _1-6 alkyl group, di (C _1-6 alkoxy) phosphoryl-C _1-6 alkyl group such as diethoxyphosphorylmethyl, etc.]. Among the above substituents, when hydroxyl group and lower the (C _1-6) alkoxy groups are adjacent as substituents form a C _1-6 alkylenedioxy, such as methylenedioxy and ethylenedioxy Is also good.

R^1aAre preferably each substituted
Sulfinyl group, sulfonyl group, hydroxyl group or
Is a thiol group. That is, R^1aIs the formula:
SR ^14a, -SOR^14a, -SO₂R^14aOr
-OR^14a(Where R^{14 a}Are each replaced
And a hydrocarbon residue or a heterocyclic group which may be present. )
Are preferred. Where R^14a"Each
Optionally substituted hydrocarbons which may be substituted
The residue is R^1aIs replaced by
A hydrocarbon residue or a heterocyclic group which may be
But R^14aAs a constituent carbon atom
A group having two or more groups is preferable, and a cyclic group which may be substituted;
Is more preferably a group of
An optionally substituted aromatic group (more preferably,
Nitrogen-containing heterocycle) are preferred.

R^{1a '}May be substituted
Hydrocarbon residues, heterocyclic groups, sulfinyl groups, sulfonyl groups
A hydroxyl group, a thiol group or an amino group,
-X ^a'-W^a'(Where X^a'Is a bond, substituted
Carbon atom, nitrogen atom which may be substituted, acid
A hydrogen atom or a sulfur atom which may be oxidized;
^a'Is an optionally substituted cyclic group or two or more substituents
Represents a carbon atom or a nitrogen atom having a group. )
Group. R^{1a '}, Each of which is
A hydrocarbon residue, a heterocyclic group, a sulfinyl group,
The ruphonyl, hydroxyl, thiol or amino group is represented by R
^1aEach optionally substituted hydrocarbon residue as
Group, heterocyclic group, sulfinyl group, sulfonyl group, hydroxyl
Group, thiol group or amino group. R
^{1a '}In the formula: -X^a'-W^a'(Where X^a'Is the end
Joint, optionally substituted carbon atom, substituted
May be nitrogen atom, oxygen atom or oxidized
Represents a sulfur atom, W^a'Is an optionally substituted cyclic group
Or a carbon or nitrogen atom having two or more substituents
Indicates a child. )), X ^aIs indicated by '
"Optionally substituted carbon atom" means two carbon atoms
Hydrogen atom, one hydrogen atom and one substituent or two
A divalent group having a substituent of^aIs indicated by '
`` Optionally substituted nitrogen atom '' means one nitrogen atom
Represents a hydrogen atom or a divalent group having a substituent. The place
As the substituent, the above-mentioned R<sup>1a</sup>As "each replaced
A hydrocarbon residue or a heterocyclic group which may be
"Hydrocarbon residue" or "heterocyclic group" may have
Substituents and R<sup>1a</sup>As "each has been replaced
A hydrocarbon residue or a heterocyclic group which may be
I can do it. X<sup>a</sup>'Sulfur which may be oxidized
"Yellow atom" means -S-, SO- or -SO<sub>2</sub>-
A divalent sulfur atom. W<sup>a</sup>'Replacement shown as'
Having an optionally substituted cyclic group or two or more substituents
Carbon or nitrogen atom "as a" cyclic group "
Is R<sup>1a</sup>As "each has been replaced
A hydrocarbon group or a heterocyclic group ''
For example, an optionally substituted alicyclic hydrocarbon residue,
Aromatic hydrocarbon residue which may be substituted,
Heterocyclic group (aromatic monocyclic heterocyclic group, aromatic condensed
Heterocyclic group and non-aromatic heterocyclic group).
The substituent which the “group” may have is R.<sup>1a</sup>As
Of `` each optionally substituted hydrocarbon residue or
"Hydrocarbon residue" or "heterocycle" in "heterocyclic group"
The same as the substituent which the group may have
You. W^a'Optionally substituted ring shown as'
Group or carbon atom having two or more substituents or nitrogen
"Atoms" and "carbon atoms having two or more substituents"
Is used, for example, tert-butyl, isopropyl.
Two or three identical or different substituents are bonded to the carbon atom.
Combined (in other words, 0-1 water on the atom
And those having an elemental atom.
R^1aAs the "optionally substituted charcoal
"Hydrocarbon residue" in "hydrogen residue or heterocyclic group"
Or a substituent which the “heterocyclic group” may have and R
^1aHydrocarbons each of which may be substituted
Residues or heterocyclic groups ". Said 2
A nitrogen atom having at least two substituents includes N, N-di
Shows a substituted amino group. The "N, N-disubstituted amino group"
The substituent in the above-mentioned R^1aReplace as
Same as "amino group" in "optionally substituted amino group".
Such substituents are exemplified. R^{1a '}Are each replaced
Optionally substituted hydrocarbon residue, heterocyclic group, sulfinyl
Group, sulfonyl group, hydroxyl group, thiol group or amino group
Of the formula: -X ^a'-W^a'(Where X^a'Is an oxygen atom
Or W represents an optionally oxidized sulfur atom;
It represents a cyclic group which may be substituted. ) Is preferred.
Good.

R^2aIs cyano, formyl, thiophor
Mill group or formula: -Z^1a-Z^2a(Where Z^1aIs
-CO-, -CS-, -SO- or -SO₂Indicates-
Then Z ^2aIs an optionally substituted hydrocarbon
Indicates a residue, a heterocyclic group, an amino group or a hydroxyl group. )
Is done.

Z ^1a in R ^2a is preferably —CO— or —CS—, more preferably —CO—. R ^2a
A group represented by —CO—Z ^{2a ′} (wherein, Z ^{2a ′} represents a hydrogen atom, a hydrocarbon residue which may be substituted, a heterocyclic group, an amino group or a hydroxyl group). preferable.

The optionally substituted hydrocarbon residue in Z ^2a includes, for example, the same as the ^optionally substituted hydrocarbon residue in R ^1a . Z
^{The optionally} substituted hydrocarbon residue in ^2a is preferably an aliphatic hydrocarbon residue, more preferably, for example, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert
-A saturated aliphatic hydrocarbon residue having 1 to 8 carbon atoms (eg, alkyl) such as pentyl, hexyl, isohexyl, heptyl, and octyl.

Examples of the ^optionally substituted heterocyclic group for Z ^2a include the same as the ^optionally substituted heterocyclic group for R ^1a .

The optionally substituted amino group for Z ^2a includes, for example, the same as the ^optionally substituted amino group for R ^1a . The optionally substituted amino group for Z ^2a is preferably an amino group and an amino group having one or two C _1-8 alkyl groups as a substituent (eg, methylamino, dimethylamino, ethylamino, Diethylamino, dibutylamino, etc.).

The optionally substituted hydroxyl group for Z ^2a includes, for example, the same as the ^optionally substituted hydroxyl group for R ^1a . The ^optionally substituted hydroxyl group for Z ^2a is preferably a hydroxyl group, and methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert
- pentyl, hexyl, isohexyl, heptyl, _{C 1-8 C 1 -8} alkyloxy substituted with alkyl such as octyl.

[0061] Z ^2a is a hydroxyl group may be a substituted amino group or substituted or optionally substituted are preferable in R ^2a. Z ^2a is amino group which may be substituted and more preferably in the R ^2a. In particular, Z in R ^2a
2a is an amino group or an amino group having one or two C _1-8 alkyl groups as a substituent (eg, methylamino,
Dimethylamino, ethylamino, diethylamino, dibutylamino, etc.) are preferred.

R ^3a represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group.

Examples of the ^optionally substituted hydrocarbon residue for R ^3a include, for example, the same as the ^optionally substituted hydrocarbon residue for R ^1a . R
^{As the optionally} substituted hydrocarbon residue in ^3a , preferably an aliphatic hydrocarbon residue, more preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
Examples thereof include saturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms (eg, alkyl groups) such as pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, and octyl.

Examples of the optionally substituted heterocyclic group for R ^3a include the same as the ^optionally substituted heterocyclic group for R ^1a .

Examples of the ^optionally substituted hydroxyl group for R ^3a include, for example, the same as the ^optionally substituted hydroxyl group for R ^1a .

The optionally substituted amino group for R ^3a includes, for example, the same as the ^optionally substituted amino group for R ^1a .

The optionally substituted sulfonyl group for R ^3a includes, for example, the same as the optionally substituted sulfonyl group for R ^1a .

Examples of the optionally substituted acyl group for R ^3a include, for example, those wherein the “optionally substituted hydrocarbon residue or heterocyclic group” for R ^1a is bonded to a carbonyl group. Preferred are those similar to the acyl group as a substituent for the hydrocarbon residue, heterocyclic group, sulfinyl group, or sulfonyl group represented by R ^1a .

R ^{3a ′} represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfonyl group or an acyl group. Examples of the hydrogen atom of R ^{3a ′,} an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfonyl group, and an acyl group include a hydrogen atom of R ^3a , an optionally substituted hydrocarbon residue, The same as the ring group, the sulfonyl group or the acyl group can be mentioned.

R ^{3a ″} represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfonyl group or an acyl group. Each substituted optionally substituted hydrocarbon residue which may of R ^{3a '',} a heterocyclic group, a sulfonyl group or an acyl group, each optionally substituted hydrocarbon residue R ^3a, a heterocyclic group, a sulfonyl group Or the same thing as an acyl group is mentioned.

R^4aRepresents a substituted hydroxyl group. R
^4aAs the substituted hydroxyl group for^1aIndicated by
Substituted or unsubstituted hydroxyl group
Substituted hydroxyl groups in, for example, appropriate substitution for hydroxyl groups
A group, for example, R^1a''
Substituted with a hydrocarbon residue or a heterocyclic group which may be
Acid groups. Preferably, methyl, ethyl, pro
Pill, isopropyl, butyl, isobutyl, sec-butyl
Chill, tert-butyl, pentyl, isopentyl, ne
Pentyl, tert-pentyl, hexyl, isohexyl
C such as sill, heptyl, octyl, etc. _1-8Alkyl
Transformed C_1-8Alkyloxy; phenyl, α-na
Futyl, β-naphthyl, 4-indenyl, 5-indenyl
4-Indanyl, 5-Indanyl, 5,6,7,8-
Tetrahydro-1-naphthyl, 5,6,7,8-tetrahi
Dro-2-naphthyl, 5,6-dihydro-1-naphthy
5,6-dihydro-2-naphthyl, 5,6-dihydro
-3-naphthyl, 5,6-dihydro-4-naphthyl, etc.
C_6-10C substituted with an aryl group_6-10Ally
Roxy; aromatic monocyclic heterocyclic group (eg, furyl, thie
Nil, pyrrolyl, oxazolyl, isoxazolyl, thi
Azolyl, isothiazolyl, imidazolyl, pyrazoly
1,2,3-oxadiazolyl, 1,2,4-oxadi
Azolyl, 1,3,4-oxadiazolyl, furazanil,
1,2,3-thiadiazolyl, 1,2,4-thiadiazol
1,3,4-thiadiazolyl, 1,2,3-triazolyl
1,2,4-triazolyl, tetrazolyl, pyridi
, Pyrimidinyl, pyridazinyl, pyrazinyl, tria
A hydroxyl group substituted with a dilinyl or the like); condensed aromatic heterocycle
Groups (eg, benzofuranyl, isobenzofuranyl, benzo
[b] thienyl, indolyl, isoindolyl, 1H-a
Ndazolyl, benzimidazolyl, benzoxazoly
1,2-benzoisothiazolyl, 1H-benzotri
Azolyl, quinolyl, isoquinolyl, cinnolinyl,
Nazolinyl, quinoxalinyl, phthalazinyl, naphthyl
Dinyl, purinyl, pteridinyl, carbazolyl, α-
Carbolinyl, β-carbolinyl, γ-carbolinyl,
Acridinyl, phenoxazinyl, phenothiazinyl,
Phenazinyl, phenoxathiinyl, thianthrenyl,
Phenanthrinil, phenanthrolinyl, indolizy
Nil, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5
-A] pyridyl, imidazo [1,2-a] pyridyl, imidazo
[1,5-a] pyridyl, imidazo [1,2-b] pyridazini
Le, imidazo [1,2-a] pyridyl, imidazo [1,5-a]
Pyridyl, imidazo [1,2-b] pyridazinyl, imidazo
[1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3
-A] pyridyl, 1,2,4-triazolo [4,3-b] pyrida
And a hydroxyl group substituted with dilinyl or the like. More preferred
Or methyl, ethyl, propyl, isopropyl,
Chill, isobutyl, sec-butyl, tert-butyl
, Pentyl, isopentyl, neopentyl, tert
-Pentyl, hexyl, isohexyl, heptyl, octyl
C such as chill_1-8C substituted with alkyl_1-8Al
Kiloxy; more preferably methyl, ethyl, pro
Pill, C substituted with isopropyl_1-3Alkyloxy
Shi. Placement of the substituted hydroxyl group exemplified here
A “hydrocarbon residue” or “heterocyclic group” as a substituent is
R mentioned above^1aAs "each may be substituted
Hydrocarbon residue or heterocyclic group "
Group or a substituent which the "heterocyclic group" may have
May have such substituents.

R ^5a represents an optionally substituted sulfinyl or sulfonyl group in R ^1a . R ^6a has the same meaning as the optionally substituted thiol group in R ^1a . R ^7a has the same meaning as the substituent of the optionally substituted amino group in R ^1a . R ^8a has the same meaning as R ^2a . R ^9a has the same meaning as Z ^2a described above. R ^10a represents a protecting group for a carboxyl group. Examples of the carboxyl protecting group represented by R ^10a include the same groups as the ^optionally substituted hydrocarbon residue represented by R ^1a .

R ^11a represents an amino group which may be substituted. Examples of the optionally substituted amino group for R ^11a include the same as the ^optionally substituted amino group for R ^1a , for example, amino group, N-monosubstituted amino group and N, N-disubstituted amino group. Groups. Examples of the substituted amino group include, for example, a hydrocarbon residue which may be substituted (for example, the same as the ^optionally substituted hydrocarbon residue represented by R ^1a , more specifically,
It may have a C _1-8 alkyl group, C _3-7 cycloalkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-7 cycloalkenyl group, C _1-4 alkyl group. A C _6-10 aryl group and the like, an _optionally substituted heterocyclic group (for example,
Or the same as the optionally substituted heterocyclic group represented by R ^1a ) or a compound of the formula: —COR ^a ′ (wherein, R ^a ′ is a hydrogen atom or a hydrocarbon residue each of which may be substituted) or showing a heterocyclic group. Incidentally, R a ^' "each optionally substituted hydrocarbon residue or heterocyclic group" as the above-mentioned R ^a' as the "each optionally substituted hydrocarbon at residue or heterocyclic group, "" hydrocarbon residue "or" heterocyclic group "and the same substituents may be, respectively.), preferably C _1-10 acyl groups (e.g., C _{2- 7} alkanoyl, benzoyl, and nicotinoyl, etc.), an amino group (e.g. having a one or two substituents, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, dibutylamino, Allylamino, cyclohexylamino, phenylamino, N- methyl -N- phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino amino, etc.). More preferably, an N, N-disubstituted amino group (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, diallylamino, N-methyl-N-phenylamino, etc.), still more preferably, N, N-diamino A _C1-3 alkylamino group (eg, dimethylamino, diethylamino, dipropylamino, etc.) is exemplified. Further, two groups in the substituted amino group may be bonded to form a nitrogen-containing 5- to 7-membered ring (for example, piperidino, morpholino, thiomorpholino, etc.).

R ^13a represents an amino group which may be substituted or a substituted hydroxyl group. As R ^13a ,
The same groups as those for R ^4a or R ^11a can be mentioned.

R ^{13a ′} represents an optionally substituted amino group or hydroxyl group. ^{Examples of} R ^{13a ′} include a hydroxyl group, and groups similar to R ^4a or R ^11a .

[0076] Hal is fluorine, chlorine, bromine, the ^{Z 5a} of a halogen atom iodine -CO-. Z
^6a has the same meaning as the optionally substituted amino group in Z ^2a . Z ^7a represents -CO-. Z ^8a
Has the same meaning as the optionally substituted hydrocarbon residue or heterocyclic group in Z ^2a .

Ring Ca is an optionally substituted 5- to 7-membered ring. 5 which may be substituted in ring Ca
The 5- to 7-membered ring of the 7-membered ring may be any of a 5- to 7-membered hydrocarbon ring or a 5- to 7-membered heterocyclic ring. The 5- to 7-membered hydrocarbon ring may be either an alicyclic ring or an aromatic ring. Examples of the alicyclic ring include C _5-7 saturated alicyclic hydrocarbon ring (for example, C _5-7 cycloalkane such as cyclopentane, cyclohexane, cycloheptane) and C _5-7.
Unsaturated alicyclic hydrocarbon ring (for example, 1-cyclopentene, 2-cyclopentene, 3-cyclopentene, 1-cyclohexene, 2-cyclohexene, 3-cyclohexene, 1-cycloheptene, 2-cycloheptene, 3-cycloheptene, 2,4 C such as cycloheptadiene, etc.
_5-7 cycloalkene, C _5-7 cycloalkadiene) and the like. Examples of the aromatic ring include a benzene ring. As the 5- to 7-membered heterocyclic ring, for example, (i)
A 5- to 7-membered heterocyclic ring containing one sulfur atom, one nitrogen atom or one oxygen atom, (ii) a 5- to 7-membered heterocyclic ring containing 2 to 4 nitrogen atoms, or (iii) 5- to 7-membered heterocycles containing 1-2 nitrogen atoms and one sulfur or oxygen atom, and the like. Further, the heterocycles exemplified in (i) to (iii) may each be a saturated or unsaturated heterocyclic group, and the unsaturated heterocycle may be any of aromatic and non-aromatic. . The ring Ca is particularly preferably an aromatic 5-membered heterocyclic ring represented by the following ring C.

Optionally substituted 5 in ring Ca
Examples of the substituent of the 7-membered ring include the same as the optionally substituted hydrocarbon residue, heterocyclic group, hydroxyl group, amino group, amino group, sulfonyl group and acyl group represented by R ^3a .

Ring C is

Embedded image (In the formula, R ^3a represents a hydrogen atom, a hydrocarbon residue which may be substituted, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group.)
Represents a membered heterocyclic ring. Ring C is

Embedded image (Wherein, R ^3a has the same meaning as described above.).

R ^a represents a hydrogen atom, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a cyano group, or an amino group, an acyl group, a hydrocarbon residue or a heterocyclic group, each of which may be substituted. In the formula, Ra may form a hydrocarbon ring or a heterocyclic ring which may be substituted together with ^a thiophene ring and a ring-constituting atom of the ring Ca.

[0081] As the amino group which may be substituted in R ^a, for example, those similar to the amino group which may be substituted in R ^1a.

[0082] As the acyl group which may be substituted in R ^a, for example, those similar to the acyl group which may be substituted in R ^3a.

[0083] As the optionally substituted hydrocarbon group which may be substituted in R ^a, for example, it includes the same hydrocarbon residue may be substituted at R ^1a.

[0084] The heterocyclic group which may be substituted in R ^a, for example, those similar to the heterocyclic group which may be substituted in R ^1a.

The optionally substituted hydrocarbon ring formed by ^Ra with the thiophene ring and the ring-constituting atoms of ring Ca (preferably ring-constituting carbon atoms) may be alicyclic or aromatic. Is also good. The hydrocarbon ring is preferably a 5- to 14-membered ring, more preferably a 5- to 7-membered ring. The hydrocarbon ring is preferably a hydrocarbon ring represented by the following ring D.

Ring D is optionally substituted with 5 to 7
A membered hydrocarbon ring. The 5- to 7-membered hydrocarbon ring of the optionally substituted 5- to 7-membered hydrocarbon ring in ring D may be any of an alicyclic or aromatic 5- to 7-membered hydrocarbon ring. Good. As the alicyclic 5- to 7-membered hydrocarbon ring,
C _5-7 saturated alicyclic hydrocarbon ring (eg, C _5-7 cycloalkane such as cyclopentane, cyclohexane, cycloheptane) and C _5-7 unsaturated alicyclic hydrocarbon ring (eg, 1-cyclopentene, 2-cyclopentene, 3-
Cyclopentene, 1-cyclohexene, 2-cyclohexene, 3-cyclohexene, 1-cycloheptene, 2-
C _5-7 cycloalkene, such as cycloheptene, 3-cycloheptene, and 2,4-cycloheptadiene, and C _5-7 cycloalkadiene). Examples of the aromatic hydrocarbon residue include a benzene ring. Preferably, a C _5-7 saturated alicyclic hydrocarbon ring, more preferably a C ₆ saturated alicyclic hydrocarbon ring (cyclohexane) is used.

R ^a is preferably a heterocyclic ring which may be substituted with ^a thiophene ring and a ring-constituting atom of ring Ca (preferably a ring-constituting carbon atom).
It is a 4-membered heterocyclic ring, more preferably a 5- to 7-membered heterocyclic ring. The heterocyclic ring is preferably, for example, (i) a 5- to 7-membered heterocyclic ring containing one sulfur atom, one nitrogen atom or one oxygen atom, and (ii) a five-membered heterocyclic ring containing 2 to 4 nitrogen atoms. ~ 7
Membered heterocycle, or (iii) 1-2 nitrogen atoms and 1
And a 5- to 7-membered heterocycle containing one sulfur or oxygen atom. Further, the heterocyclic ring exemplified in (i) to (iii) may be either saturated or unsaturated, and the unsaturated heterocyclic group may be either aromatic or non-aromatic.

Rings D, D-1, E, F, F-2, F-3, F-4,
Examples of the substituent of the 5- to 7-membered hydrocarbon ring which may have a substituent in F ', F'-1, F'-2, and F'-3 include, for example, R
Examples include the same substituents as the “optionally substituted hydrocarbon residue” in ^1a . As the substituent of the 5- to 7-membered hydrocarbon ring which may have a substituent in ring D, preferably an aliphatic hydrocarbon residue, more preferably, for example, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert
-A saturated aliphatic hydrocarbon residue having 1 to 8 carbon atoms (eg, an alkyl group) such as pentyl, hexyl, isohexyl, heptyl, and octyl.

Rings D, D-1, E, F, F-2, F-3, F-4,
F ', F'-1, F'-2, F'-3, each represent an optionally substituted 5- to 7-membered hydrocarbon ring, preferably an unsubstituted 5- to 5-membered hydrocarbon ring. And 7-membered hydrocarbon rings. More preferably, a 5- to 7-membered saturated hydrocarbon ring having no substituent is exemplified. More preferably, a 6-membered saturated hydrocarbon ring having no substituent is used.

In the above formula (Ia), the formula (Ia ')

Embedded image The compound represented by is preferred. Formula (Ia ′)
Wherein R ^1a is an optionally substituted sulfinyl group, sulfonyl group, hydroxyl group or thiol group;
^2a is ^-Z 1a ^{-Z 2a (wherein, Z 1a} represents a -CO- or ^{-CS-, Z 2a} represent, respectively, the optionally substituted hydroxyl group or an amino group.); Ring C is,

Embedded image [Wherein, R ^3a has the same meaning as described above. A compound wherein Ring D is a 5- to 7-membered hydrocarbon ring which may have a substituent, or a salt thereof is preferred.

[0091] In the above formulas (Ia ^{'), R 1a} is a sulfinyl group or a sulfonyl group attached at _{C 1-8} alkyl, _{respectively, C 1-8} alkyl optionally substituted thiol group, or 1, respectively, C _6-10 aryl (particularly preferably phenyl), aromatic monocyclic heterocyclic group (particularly preferred pyridyl) or aromatic fused heterocyclic group (particularly preferred quinolyl) which may be substituted by three substituents ) hydroxy group which may be substituted by; ^{R 2a} is -
Z ^1a -Z ^2a (wherein, Z ^1a represents -CO-;
^2a represents a hydroxyl group or an amino group which may be substituted. ); Ring C:

Embedded image [Wherein, R ^3a has the same meaning as described above. R
^3a is a saturated aliphatic hydrocarbon residue having 1 to 8 carbon atoms (eg, an alkyl group); a compound wherein Ring D is a _C5-7 saturated alicyclic hydrocarbon ring or a salt thereof is more preferred.

As the compound represented by the general formula (Ia '), 4,5-dihydro-8- (2,3-dimethylphenoxy) -1- (2,
2,2-trifluoroethyl) -1H-thieno [3,4-g] indazole-6-carboxamide; 4,5-dihydro-1-methyl-8- (3,4-
Methylenedioxyphenoxy) -1H-thieno [3,4-g] indazole-6-carboxamide; 8- (4-benzyloxyphenoxy) -4,5-dihydro-1-methyl-1H-thieno [3,4- g] indazole-6-carboxamide; 4-{[6- (aminocarbonyl)-
2-methyl-4,5-dihydro-1H-thieno [3,4-g] indazole
-8-yl] oxy} benzylphosphonic acid ethyl ester; 8-benzyl-4,5-dihydro-1-methyl-1H-thieno [3,4
-g] indazole-6-carboxamide; 4,5-dihydro-1-
Methyl-8- (4-methoxyphenoxy) -1H-thieno [3,4-g] indazole-6-carboxamide; 4,5-dihydro-1-methyl
-8-phenoxy-1H-thieno [3,4-g] indazole-6-carboxamide; 4-{[6- (aminocarbonyl) -1-methyl-4,5-
Dihydro-1H-thieno [3,4-g] indazol-8-yl] oxy} benzylphosphonic acid ethyl ester; 4,5-dihydro-1-methyl-8-phenylsulfanyl-1H-thieno [3,4-
g] indazole-6-carboxamide; 4,5-dihydro-8-
(3,4-methylenedioxyphenoxy) -1- (2,2,2-trifluoroethyl) -1H-thieno [3,4-g] indazole-6-carboxamide; 4,5-dihydro-1-methyl -8- (4-trifluoromethoxyphenoxy) -1H-thieno [3,4-g] indazole-6
-Carboxamide; or N-ethyl-4,5-dihydro-1-methyl-8- (3,4-methylenedioxyphenoxy) -1H-thieno
[3,4-g] indazole-6-carboxamide and the like are preferred.

In the formula (IIa '), R^1aAre replaced by
Sulfinyl group, sulfonyl group, hydroxyl group which may be
Or a thiol group; R^2aIs -Z^1a-Z^2a(formula
Medium, Z ^1aRepresents -CO- or -CS-, and Z represents^2a
Is an optionally substituted hydroxyl group or amino group
Is shown. ); R^4aBut C_1-8Alkyloxy; ring
E is an optionally substituted 5- to 7-membered hydrocarbon ring
Or a salt thereof is preferred.

In the formula (IIa ′), R^1aBut C
_1-8Sulfinyl group or sulfo linked by alkyl
Nyl group, C_1-8Thio optionally substituted with alkyl
Or substituted with 1 to 3 substituents, respectively.
May be C_6-10Aryl (particularly preferably phenyl
), An aromatic monocyclic heterocyclic group (particularly preferably
) Or an aromatic fused heterocyclic group (particularly preferably
A hydroxyl group optionally substituted with^2aIs -Z
^1a-Z^2a(Where Z^1aRepresents -CO-; Z represents
^2aRepresents an optionally substituted hydroxyl group or amino group, respectively.
And a no group. ); R^{4 a}But C_1-3Alkyloxy;
Ring C is C_5-7Compounds that are saturated alicyclic hydrocarbon rings
Or a salt thereof is more preferred.

In the present invention, the compound represented by the formula (Ia) [compound (Ia) is referred to. Or a salt of a raw material compound for producing the salt thereof, is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a base And salts with acidic or acidic amino acids. Preferred examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferred examples of salts with organic bases include:
For example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,
Salts with N, N'-dibenzylethylenediamine and the like can be mentioned. Preferred examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred 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,
Salts with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned. Preferred examples of salts with basic amino acids include, for example, arginine, lysine,
Salts with ornithine and the like are mentioned, and preferable examples of the salts with acidic amino acids include salts with aspartic acid and glutamic acid.

Compound (Ia) or a salt thereof may be a prodrug thereof. A prodrug of compound (Ia) or a salt thereof is a compound that is converted into compound (Ia) or a salt thereof by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, that is, enzymatic oxidation, reduction, hydrolysis, or the like. And a compound that changes to the compound (Ia) or a salt thereof by causing hydrolysis or the like by gastric acid or the like. As a prodrug of compound (Ia) or a salt thereof, a compound or a salt thereof (for example, compound (Ia) or a salt thereof) in which a hydroxyl group of compound (Ia) or a salt thereof is acylated, alkylated, phosphorylated, or borated A compound in which the hydroxyl group of a salt is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumalylated, alanylated, dimethylaminomethylcarbonylated, or a salt thereof), the carboxyl group of compound (Ia) or a salt thereof is , Esterified or amidated compounds (for example, when the carboxyl group of compound (Ia) or a salt thereof is ethyl-esterified, phenyl-esterified, carboxyoxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified) , Ethoxycarbonyloxyethyl ester , Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)
Methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound or a salt thereof, and the like are used. These prodrugs can be produced according to a method known per se or a method analogous thereto. The prodrug of compound (Ia) or a salt thereof can be prepared under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, Molecular Design, pp. 163-198. May be changed.

The compounds of the present invention (Ia) or a salt thereof isotope ^{(eg, 2 H, 3 H, 1} 4 C, 35 S,
¹²⁵ I).

When the compound used in the present invention or a salt thereof has a double bond in the molecule and Z or E configuration is present, each of them or a mixture thereof is a compound used in the present invention. include. When the compound used in the present invention or a salt thereof has a stereoisomer such as having an asymmetric carbon in the molecule, each of them or a mixture thereof is included in the compound used in the present invention.

The method for producing the compound used in the present invention will be described below. Compound (Ia) or a salt thereof is
A method known per se (for example, JP-A-2000-309591)
JP-A-2000-239280, the method described in WO98 / 09958,
The method described in JP-A-2000-169470, the method described in JP-A-2000-169471, and the method described in JP-A-2000-169471
Etc.) or a method analogous thereto.

Compound (Ia) is a compound in which R forms a hydrocarbon ring or a heterocyclic ring which may be substituted with a thiophene ring and a ring-constituting carbon atom of ring Ca, like compound (Ia ′). In some cases, compound (Ia) or a salt thereof can be produced, for example, by the following Method A to Method F or a method analogous thereto.

[Method A]

Embedded image [In the formula, compound (III) represents hydroxylamine or monosubstituted hydrazine (R ^{3 a ′} NHNH ₂ ) or a salt thereof, and other symbols have the same meanings as described above. ]

In this reaction, compound (Ia ′) is produced by reacting compound (IIa ′) with compound (III). This reaction is carried out in a conventional manner in a neutral or in the presence of an acid or a base in a solvent that does not adversely influence the reaction. Examples of the acid include mineral acids such as hydrochloric acid and sulfuric acid; and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, acetic acid, and trifluoroacetic acid. Examples of the base include inorganic bases such as sodium hydride, sodium hydroxide, potassium hydride, etc., t-butoxy potassium, sodium acetate, triethylamine, pyridine, 1,8-diazabicyclo [5.4.0] -7-undecene, sodium Organic bases such as methoxide are exemplified. The amount of the acid and compound (III) to be used is preferably about 1 to about 5 molar equivalents relative to compound (IIa ′). Solvents that do not adversely affect the reaction include, for example, alcohols such as water, methanol, ethanol and propanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; benzene, toluene and xylene. Aromatic hydrocarbons; amides such as N, N-dimethylformamide and 1-methylpyrrolidone; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is
Usually, about -50 to about 150C, preferably about 0 to about 10
0 ° C. The reaction time is generally about 0.5 to about 20 hours. R ^{3a ′} on ring C produced by this reaction is
^The compound can be converted to an optionally substituted hydroxyl group or an optionally substituted amino group described as ^3a using a method known per se. The compound (Ia ′) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Compound (IIa ′) used as a starting compound in the above-mentioned Method A is a novel compound, and compound (IV):

Embedded image Wherein each symbol has the same meaning as described above. And orthoformic acid ester. That is, Compound (IV) can be prepared by a known method, for example, Indian Journal of Chemistry Section B (Indian.
J. Chem. Sec. B) 35: 49-51 (1996)
Year) or a method analogous thereto. That is, this reaction is usually performed in the presence of an acid and a base in a solvent that does not adversely influence the reaction. The amount of the orthoformate to be used is preferably about 1 to about 10 molar equivalents relative to compound (IV). Examples of the acid include a boron trifluoride-ether complex. The amount of the acid to be used is preferably about 1 to about 1 relative to compound (IV).
0 molar equivalent. As the base, triethylamine,
Diisobutylethylamine, 1,8-diazabicyclo
[5.4.0] -7-undecene and the like. The amount of the base to be used is preferably about 1 to about 10 molar equivalents relative to compound (IV). Examples of the solvent that does not adversely affect the reaction include halogenated hydrocarbons such as chloroform and dichloromethane; and aromatic hydrocarbons such as benzene, toluene, and xylene. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is
Usually, about -100 to about 150C, preferably about -70 to
About 0 ° C. The reaction time is generally about 0.5 to about 20 hours. Compound (IIa ′) thus obtained
Can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Among the compounds (IV) used as starting compounds, for example, compound (IV-1):

Embedded image Is a known compound and is a known compound.
igs Ann.) 1996, pp. 239-245, or Synthetic Communications (Synth. Commu.
n.) 1995, pp. 2449-2455.

In the above method A, compound (Ia ′)
Used as a raw material compound of a compound represented by R ^{1a of} which may be an amino group which may be substituted (IV-2,
3) is produced by the following synthesis method. (Step 1)

Embedded image Wherein each symbol has the same meaning as described above. In this reaction, compound (V) is produced by reacting 1,3-cycloalkanedione with an alkyl isothiocyanate or an aryl isothiocyanate in the presence of a base. Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, and potassium carbonate; pyridine, triethylamine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undeca- Amines such as 7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The amount of the reaction reagent used is preferably about 1 to about 10 molar equivalents based on 1,3-cycloalkanedione. The amount of the base used is preferably about 1 to about 10 molar equivalents based on 1,3-cycloalkanedione.
The reaction temperature is generally about -50 to about 150C, preferably about 0 to about 100C. The reaction time is usually about 0.5
~ 20 hours. The compound (V) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

(Step 2)

Embedded image Wherein each symbol has the same meaning as described above. In this reaction, compound (VI) is produced by reacting compound (V) with compound (VII). This method is carried out in a conventional manner in the presence of a base in a solvent that does not adversely influence the reaction. Examples of the compound (VII) include haloacetic esters, specifically, ethyl chloroacetate, ethyl bromoacetate, t-butyl bromoacetate and the like. Compound (V
The amount of II) to be used is preferably about 1 to about 10 molar equivalents relative to compound (V). As the base, for example, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate,
Alkali metal salts such as potassium carbonate; amines such as pyridine, triethylamine, N, N-dimethylaniline and 1,8-diazabicyclo [5.4.0] undec-7-ene; potassium hydride and sodium hydride Metal hydrides; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t.-butoxide. The amount of the base to be used is preferably about 1 to about 5 molar equivalents relative to compound (V).
Solvents that do not adversely affect the reaction include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; Examples include amides such as dimethylformamide; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is generally about -50 to about 150C, preferably about -10 to about 100C. The reaction time is generally about 0.5 to about 20 hours. Compound (VI) thus obtained can be obtained by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

(Step 3)

Embedded image Wherein each symbol has the same meaning as described above. In this reaction, compound (IV-2) is produced from compound (VI). This method is carried out in a conventional manner in the presence of a base in a solvent that does not adversely influence the reaction. As the base,
Alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-dimethylaniline,
1,8-diazabicyclo [5.4.0] undec-7-
Amines such as ene; metal hydrides such as potassium hydride and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The amount of these bases used is
The amount is preferably about 1 to about 5 molar equivalents relative to compound (VI). Solvents that do not adversely affect the reaction include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; Examples include amides such as dimethylformamide; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is usually about-
50 to about 150C, preferably about -10 to about 100C. The reaction time is generally about 0.5 to about 20 hours. Compound (IV-2) thus obtained can be obtained by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction,
It can be isolated and purified by crystallization, recrystallization, phase transfer, chromatography and the like.

(Step 4)

Embedded image Wherein each symbol has the same meaning as described above. In this reaction, compound (IV-2) is acylated to produce compound (IV-3). The present method relates to the compound (IV-2)
And an acylating agent are appropriately reacted. Here, examples of the acylating agent include acid anhydrides, acid halides (acid chlorides, acid bromides), imidazolides, and mixed acid anhydrides (eg, anhydrides with methyl carbonate, ethyl carbonate, and isobutyl carbonate). Can be The amount of these acylating agents to be used depends on the amount of the compound (VI-
It is preferably about 1 to about 5 molar equivalents relative to 2). Solvents that do not adversely affect the reaction include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; Examples include amides such as dimethylformamide; sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is generally about -50 to about 150C, preferably about -10 to about 100C. The reaction time is generally about 0.5 to about 20 hours. The compound (IV-3) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

[Method B]

Embedded image Wherein ring C ′ is

Embedded image And each symbol has the same meaning as described above. ]

In this method, compound (I-1) is produced by reacting compound (I-2) with a nucleophilic reagent. The reaction is
It is carried out by a method known per se, for example, the method described in WO98 / 18792 or a method analogous thereto. Examples of the nucleophilic reagent include metal phenolates, metal alcoholates, Grignard reagents, alkyl metal reagents,
Aryl metal reagents, thioalcoholates and the like. The amount of the nucleophilic reagent to be used is preferably about 1 to about 5 molar equivalents relative to compound (I-2). Examples of the solvent that does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane;
Aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N, N-dimethylformamide and 1-methylpyrrolidone; and sulfoxides such as dimethylsulfoxide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is usually about-
50 to about 150C, preferably about -10 to about 100C. The reaction time is generally about 0.5 to about 20 hours. The compound (I-1) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The compound (I-2) used as a starting compound in the above-mentioned Method B can be produced by the following method.

Embedded image Wherein each symbol has the same meaning as described above. In this method, compound (I-2) is produced from compound (I-3) using an oxidizing agent. This reaction is carried out by a method known per se, for example, as an oxidizing agent, manganese dioxide, permanganate,
Chromic acid, lead tetraacetate, halogen, ozone, hydrogen peroxide,
Organic peroxides, organic peroxy acids, hydrogen peroxide-sodium tungstate, oxygen, N-halocarboxylic amides, hypohalous esters, iodosyl compounds, nitric acid, nitrous oxide, dimethyl sulfoxide, ethyl azodicarboxylate, chloro It is performed by a method using gold (III) acid or the like, or by anodic oxidation or a method analogous thereto. That is, this reaction is usually performed in the presence of an oxidizing agent in a solvent that does not adversely affect the reaction. As the oxidizing agent, for example, m-chloroperbenzoic acid, peracetic acid and the like are preferable. Examples of the solvent that does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene, and xylene; Amides such as dimethylformamide and 1-methylpyrrolidone are exemplified. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is usually about -50 to about 150C, preferably about-
10 to about 100 ° C. The reaction time is usually about 0.5
~ 20 hours. The compound (I-2) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

[Method C]

Embedded image Wherein each symbol has the same meaning as described above. ]

In this method, compound (I-5) is produced by an elimination reaction of a carboxyl protecting group. This reaction includes all the conventional methods used for the elimination reaction of a carboxyl protecting group. For example, hydrolysis, reduction, elimination using a Lewis acid, and the like can be applied. When the carboxyl protecting group is an ester, it can be eliminated by hydrolysis or elimination with a Lewis acid. Hydrolysis can be eliminated by elimination with a base or Lewis acid. The hydrolysis is
It is preferable to carry out in the presence of a base or an acid. Suitable bases include, for example, alkali metal hydroxides (e.g., sodium hydroxide, calcium hydroxide, etc.), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonates (e.g., carbonate Sodium, potassium carbonate, etc.), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetates (e.g., sodium acetate, potassium acetate Inorganic bases such as alkaline earth metal phosphates (e.g., magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphates (e.g., disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), and trialkylamines (e.g., For example, trimethylamine, triethylamine, etc.), picoline, N-methyl Roridins, N- methylmorpholine, 1,5-diazabicyclo [4.3.2] non -
5-ene, 1,4-diazabicyclo [2.2.2] non-
5-ene, 1,8-diazabicyclo [4.3.0] -7-
Organic bases such as undecene are exemplified. The hydrolysis using a base is often performed in water, a hydrophilic organic solvent or a mixed solvent. Suitable acids include organic acids
(For example, formic acid, hydrobromic acid, sulfuric acid, etc.). This hydrolysis reaction is usually performed in an organic solvent, water or a mixed solvent composed of these. The reaction temperature is not particularly limited, and is appropriately selected depending on the type of the carboxyl protecting group and the elimination method. The elimination using a Lewis acid can be carried out by subjecting compound (I-4) or a salt thereof to a Lewis acid such as boron trihalide (eg, boron trichloride, boron trifluoride, etc.), titanium tetrahalide (eg, titanium tetrachloride, Titanium tetrabromide, etc.), aluminum halide
(Eg, aluminum chloride, aluminum bromide, etc.), and trihaloacetic acid (eg, trichloroacetic acid, trifluoroacetic acid, etc.). This elimination reaction is preferably performed in the presence of a cation scavenger (e.g., anisole, phenol, etc.), and is usually nitroalkane (e.g., nitromethane, nitroethane, etc.), alkylene halide (e.g., methylene chloride, ethylene chloride, etc.), The reaction is performed in a solvent such as diethyl ether, carbon disulfide, or a solvent that does not adversely affect the reaction. These solvents may be used as a mixture thereof. The elimination by reduction is preferably applied to the elimination of protecting groups such as alkyl halide (eg, 2-iodoethyl, 2,2,2-trichloroethyl and the like) esters and aralkyl (eg benzyl and the like) esters. As the reduction method used in the present elimination reaction, for example, a metal (e.g., zinc, zinc amalgam, etc.) or a salt of a chromium compound (e.g., chromic chloride, chromium acetate, etc.) and an organic or inorganic salt (e.g., acetic acid, propionic acid, etc.) , Hydrochloric acid, etc.); conventional catalytic reduction in the presence of a conventional metal catalyst (eg, palladium carbon, Raney nickel, etc.). The reaction temperature is not particularly limited, and the reaction is usually performed under cooling, at room temperature, or under heating. The compound (I-5) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

In the general formula (I), R ^2a is represented by the formula: -Z ^5a-
Z ^{6a (wherein, Z 5a} is ^{-CO-, Z 6a} shows an amino group which may be substituted.) The compound represented by (I-
6) is produced, for example, by the following Method D. [Method D]

Embedded image [In the formula, compound (VIII) represents Z ^6a H, and other symbols have the same meanings as described above. In this method, compound (I-5) or a reactive derivative at the carboxyl group or a salt thereof is reacted with compound (VIII) or a reactive derivative at the amino group or a salt thereof to obtain compound (I-6). )
To manufacture. Suitable reactive derivatives at the amino group of compound (VIII) include Schiff base imino or its enamine tautomer, which is formed by the reaction of compound (VIII) with a carbonyl compound such as an aldehyde or ketone; VIII) a silyl derivative produced by the reaction of a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea; etc .; produced by the reaction of compound (VIII) with phosphorus trichloride or phosgene Derivatives.

Examples of suitable reactive derivatives at the carboxyl group of compound (I-5) include acid halides, acid anhydrides, activated amides and activated esters. Preferred examples of the reactive derivative include acid chloride; acid azide; substituted phosphoric acid such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, and dialkyl phosphite. ,
Sulfurous acid, thiosulfuric acid, sulfuric acid, for example, sulfonic acid such as methanesulfonic acid, for example, carboxylic acid such as acetic acid, propionic acid, butyric acid, pivalic acid isobutyrate, pentanoic acid, isopentanoic acid, and trichloroacetic acid, or aromatic compound such as benzoic acid Mixed anhydrides with acids such as aromatic carboxylic acids; symmetric anhydrides; activated amides with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or, for example, cyano Methyl ester, methoxy methyl ester, dimethyl imino methyl ester,
Vinyl ester, propargyl ester, p-nitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-
Activated esters such as nitrophenyl ester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, or, for example, N, N-dimethylhydroxyamine, 1-hydroxy-2- (1H) -pyridone,
Examples include esters with N-hydroxy compounds such as N-hydroxysuccinimide, N-hydroxyphthalimide, and 1-hydroxy-1H-benzotriazole. These reactive derivatives can be arbitrarily selected depending on the type of the compound (I-5) to be used. Suitable salts of the reactive derivative of the compound (I-5) include, for example, alkali metal salts such as sodium salt and potassium salt, for example, alkaline earth metal salts such as calcium salt and magnesium salt, and ammonium salts such as trimethylamine salt. Triethylamine salt,
Pyridine salt, picoline salt, dicyclohexylamine salt,
Base salts such as organic base salts such as N, N-dibenzylethylenediamine salt are exemplified. The reaction is generally carried out with water, for example, alcohols such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, and the like.
The reaction is carried out in a conventional solvent such as N, N-dimethylformamide or pyridine, but the reaction can be carried out in any other organic solvent that does not adversely influence the reaction. These conventional solvents may be used as a mixture with water.

In this reaction, when the compound (I-5) is used in the form of a free acid or a salt thereof, N, N'-
Dicyclohexylcarbodiimide; N-cyclohexyl-
N'-morpholinoethylcarbodiimide; N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylamino Propyl) carbodiimide; N, N'-carbonylbis (2-
Methyl imidazole); Pentamethyleneketene-N-cyclohexylimine; Diphenylketene-N-cyclohexylimine; Ethoxyacetylene; 1-alkoxy-1-chloroethylene; Trialkyl phosphite; Ethyl polyphosphate; Phosphorus chloride; diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; ethyl chloroformate; lower alkyl haloformate such as isopropyl chloroformate;
2-ethyl-7-hydroxybenzisoxazolium salt, 2
-Ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt; N-hydroxybenzotriazo-
1- (p-chlorobenzenesulfonyloxy) -6-chloro
-1H-benzotriazole; in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent prepared by the reaction of N, N'-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc. It is desirable to carry out the reaction. The reaction also involves alkali metal bicarbonate tri (lower) alkylamine, pyridine, N-
It may be carried out in the presence of an inorganic or organic base such as (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine and the like. The reaction temperature is not particularly limited,
Usually, the reaction is carried out under cooling or heating.

The amount of compound (VIII) to be used is 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (I-5). The reaction temperature is usually -30
C. to 100C. The reaction time is usually 0.5 to 20
Time.

When a mixed acid anhydride is used, compound (I-5) and a chlorocarbonate (eg, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate) are used as bases (eg, triethylamine, N-methylmorpholine). ,
(N, N-dimethylaniline, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, etc.) and further react with compound (VIII). Compound (VII
The amount of I) to be used is generally 0. 1 relative to compound (I-5).
It is 1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents. The reaction temperature is usually -30C to 100C. The reaction time is usually 0.5 to 20 hours. Compound (I-6) thus obtained can be obtained by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like. The compound (I-5) used as a starting compound in the above method D is produced by the above method C.

[Method E]

Embedded image Wherein each symbol has the same meaning as described above. In this method, compound (I-8) is produced from compound (I-7) in the presence of a dehydrating agent. This reaction is carried out with compound (I-7))
And a dehydrating agent are appropriately reacted.
Here, examples of the dehydrating agent include acetic anhydride, trifluoroacetic anhydride, phosphorus pentoxide, thionyl chloride and the like. The amount of the dehydrating agent to be used is 0.1 to 100 molar equivalents, preferably 1 to 10 molar equivalents, relative to compound (I-7). The reaction temperature is usually -30C to 100C. The reaction time is usually 0.5 to 20 hours. The compound (I-8) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. . The compound (I-7) used as a starting compound in the above method E is produced by the above method D or method B.

For example, when an acid halide is used, the reaction is carried out in the presence of a base in a solvent that does not adversely influence the reaction. Solvents that do not adversely affect the reaction include, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; Examples include amides such as dimethylformamide and 1-methylpyrrolidone; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.

[Method F]

Embedded image [Wherein the symbols have the same meanings as described above. In this method, compound (I-10) is produced by reacting nucleophilic reagent with compound (I-9). As the nucleophilic reagent,
For example, metal phenolates, metal alcoholates, Grignard reagents, alkyl metal reagents, aryl metal reagents, thioalcoholates and the like are used. The amount of the nucleophilic reagent to be used is preferably about 1 to about 5 molar equivalents relative to compound (I-9). This reaction is generally performed in a solvent that does not adversely influence the reaction. Solvents that do not adversely affect the reaction include, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; Examples include amides such as dimethylformamide and 1-methylpyrrolidone; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is generally about -70 to about 150
° C, preferably from about -70 to about 0 ° C. The reaction time is
Usually, about 0.5 to about 20 hours. Compound (I-10) thus obtained can be obtained by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer,
It can be isolated and purified by chromatography and the like.

The compound (I-9) used as a starting compound in the above-mentioned Method F can be produced by a Method D.

Compound (Ia ') can be prepared by the above-mentioned process.
It can also be obtained by the following production method.

[Method G]

Embedded image Wherein each symbol has the same meaning as described above. (IX-1) is produced by reacting the compound (IV) with an amide acetal. Examples of the amide acetal include, for example, an active acetal form of N, N-dialkylformamide,
Preferably N, N-dimethylformamide dimethyl acetal, N, N-dimethylformamide diethyl acetal, t
-Butoxybisdimethylaminomethane, trisdimethylaminomethane, N, N-dimethylformamide dipropyl acetal, N, N-dimethylformamide bis (2-trimethylsilylethyl) acetal, N, N-dimethylformamide dibenzyl acetal, N, N Active acetal form of dimethylformamide such as -dimethylformamide di-t-butyl acetal, N, N-dimethylformamide dineopentyl acetal, N, N-dimethylformamide dicyclohexyl acetal, N, N-dimethylformamide diisopropyl acetal is used, More preferably, N, N-dimethylformamide dimethyl acetal, N, N-dimethylformamide diethyl acetal, trisdimethylaminomethane and the like are used. The amount of the amide acetal to be used is 1 mol to 50 mol, preferably 1 mol to 30 mol, per 1 mol of compound (IV). The solvent used in this reaction may be any solvent as long as it does not inhibit the reaction.
Heptane, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, etc.), ethers (diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran,
Dioxane), amides (eg, N, N-diC _1-3 alkylformamide such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), esters (eg, ethyl acetate) , Methyl acetate, etc.), nitriles (eg, acetonitrile, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.) alone, or a mixture of two or more thereof. The reaction is carried out at a reaction temperature of 0 to 150.
C., preferably at 50 to 120.degree. C., for about 30 minutes to 24 hours, preferably 1 to 6 hours.

The amide acetals described here are known per se and can be easily obtained as commercial products. Compound (IV) can be prepared by a known method, for example, the article of D. Prim et al.
nth.Commun., 25, 2449, 1995),
Alternatively, it is manufactured by a method equivalent thereto.

[Method H]

Embedded image Wherein each symbol has the same meaning as described above. Compound (IX-2) is produced by a dealcoholation reaction of compound (IIa ′). This reaction is performed using an acid or a base. Acids include hydrochloric acid, hydrobromic acid, sulfuric acid,
Inorganic acids such as phosphoric acid, and organic acids such as trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.Examples of the base include alkali metal or alkaline earth metal Compounds, lithium diisopropylamide, lithium hexamethyldisilazide, alkali metal or alkaline earth metal amides such as sodium hexamethyldisilazide,
Lower alkoxides of alkali metals or alkaline earth metals such as sodium methoxide, sodium ethoxide and potassium t-butoxide; hydroxides of alkali metals or alkaline earth metals such as potassium hydroxide and sodium hydroxide; potassium carbonate , Sodium carbonate, cesium carbonate and other carbonates, potassium hydrogen carbonate, sodium hydrogen carbonate and other alkali metal or alkaline earth metal hydrogen carbonates, triethylamine, diisopropylamine, pyridine, dimethylaminopyridine, 1,8-diazabicyclo [5 , 4,0] -7-undecene and the like. Among these, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid,
Organic acids such as benzenesulfonic acid and p-toluenesulfonic acid are preferred, and are used in an amount of 0.1 mol to 100 mol, preferably 1 mol to 30 mol, per 1 mol of compound (IIa '). In this reaction, if necessary, any solvent can be used as long as it does not inhibit the reaction. Among them, alcohols (eg, _C1-3 alcohols such as methanol, ethanol, and propanol) are preferable. Further, the above-mentioned acid or base may be used also as a solvent. This reaction is carried out at a reaction temperature of 0 to 50 ° C., preferably 0 to 30 ° C., for about 10 minutes to 6 hours, preferably 30 minutes to 3 hours.
It is performed by reacting for a time.

Compound (IIa ') can be prepared from compound (IV) by a known method, for example, a paper by A. Nangia et al. (Indian J. Che.
m., 35B, 49, 1996) or a method analogous thereto.

[Method I]

Embedded image Wherein each symbol has the same meaning as described above. The compound represented by the general formula (Ia ′) is a compound (VII)
Hydroxylamine or a salt thereof, or R ^{3a ′} N
It is produced by cyclization with a hydrazine represented by HNH ₂ (R ^{3a ′} has the same meaning as described above) or a salt thereof.
In this reaction, 1 mol to 10 mol of hydroxylamine or hydrazine is added to 1 mol of compound (IX),
Preferably, it is used in an amount of 1 mol to 5 mol. The solvent used in this reaction may be any solvent as long as it does not inhibit the reaction, but is preferably an alcohol (eg, a _C1-3 alcohol such as methanol, ethanol, propanol, etc.) or an alcohol. A mixed system with another solvent or water is used. In this reaction, an acid may be present in order to adjust the reaction rate, regioselectivity, solubility and the like. Examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. 0.1 mole to 1 mole
It is used in an amount of 100 mol, preferably 1 mol to 30 mol. Moreover, you may use also as a solvent. In this reaction, the reaction temperature was 0
The reaction is carried out at a temperature of from 120 to 120 ° C., preferably from 50 to 100 ° C., for about 10 minutes to 6 hours, preferably 1 to 3 hours. In addition, R on ring C generated by this reaction
^{3a ′} can be converted to an optionally substituted hydroxyl group or an optionally substituted amino group described as R ^3a using a method known per se.

[J method]

Embedded image Wherein each symbol has the same meaning as described above. Compound (IX-3) is reacted with R ^{3a ″} NHNH _{2 in} the presence of an acid.
In the reaction for producing the compound (I-11) by ring closure with the hydrazine represented by the formula, 1 mol to 10 mol, preferably 1 mol to 10 mol, per 1 mol of the compound (VII-2).
5 moles are used. As the solvent used in this reaction, any solvent may be used as long as it does not inhibit the reaction, but alcohols (eg, _C1-3 alcohols such as methanol, ethanol and propanol) are preferably used. The anhydrous condition in this reaction means a substantially anhydrous condition, specifically, a solvent in which water is not positively added, for example, a solvent having a water content of about 5% or less, preferably a water content of about 3% or less. This means that the reaction is carried out using a solvent, more preferably a solvent having a water content of 1% or less. Examples of the acid used in this reaction include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Particularly, methanesulfonic acid is preferred, and it is used in an amount of 0.1 mol to 100 mol, preferably 1 mol to 30 mol, per 1 mol of compound (IX-3). Moreover, you may use also as a solvent. In this reaction, the reaction temperature is 0 to 120 ° C,
The reaction is carried out preferably at 40 to 70 ° C. for about 10 minutes to 6 hours, preferably for 1 hour to 3 hours.

In the formula (IX-3), a compound having a hydroxyl group in which R ^{13a ′} is substituted with a cyclic group can be prepared from the compound (IV) by a known method, for example, the article of D. Prim et al. (Synth. , 2
449, 1995) or a method analogous thereto. Compound (IX) can be produced by a general acid hydrolysis reaction (for example, using a mixed system of alcohols or amides and water as a solvent). And the reaction is carried out at a reaction temperature of 0 to 120 ° C. for 10 minutes to 6 hours using the same acid as described above in an amount of 0.1 mol to 10 mol per 1 mol of compound (IX). In addition, R in the general formula (IX-3)
By using an “optionally substituted amino group” as ^{13a ′} , the compound (IX-3) can be prepared without using a compound such as a boron trifluoride etherate complex, which has a problem of corrosiveness in the production. The compounds can be produced industrially advantageously.

[Method K]

Embedded image The compound (I-12) in which R ^1a is a thiol which may be substituted in the general formula (I) is obtained as follows.
It is led to. First, compound (I-12) is subjected to an oxidation reaction to give compound (I-13). As the oxidizing agent, a peracid such as metachloroperbenzoic acid, peracetic acid, formic acid, and trifluoroperacetic acid, a peroxide such as dioxirane, hydrogen peroxide in the presence of a metal catalyst, and oxone (trade name) are used. Can be used in an amount of 2 to 10 mol per 1 mol of compound (I-12). When oxidizing with peracetic acid or the like, an acid such as hydrochloric acid or sulfuric acid is added in an amount of 1 to 10 mol, preferably 2 to 5 mol, per 1 mol of compound (I-12) to promote the reaction. . As the solvent used in this reaction, any solvent may be used as long as it does not inhibit the reaction, and examples thereof include hydrocarbons (eg, n-hexane, N-heptane, benzene, toluene, xylene, etc.), halogenated hydrocarbons ( eg dichloromethane), ethers (diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), alcohols (e.g., methanol, ethanol, C _1-3 alcohols propanol), amides (e.g., N N, N-diC _1-3 alkylformamides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc., esters (eg, ethyl acetate, methyl acetate, etc.),
Nitriles (eg, acetonitrile, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), ketones (acetone, 2-butanone, 4-methyl-2-pentanone, cyclohexone, etc.), carboxylic acids (eg, formic acid, acetic acid, Trifluoroacetic acid) or a mixture of two or more. The temperature and time in this reaction vary depending on the oxidizing agent used.For example, when the reaction is performed with peracetic acid, the reaction temperature is 0 to 100 ° C, preferably 30 to 60 ° C.
For 1 to 24 hours, preferably 2 to 5 hours. The compound (I-13) obtained as described above is subjected to a substitution reaction to produce a compound (I-14). In this reaction, R ″ -OH was used per 1 mol of compound (I-13).
Is used in an amount of 1 to 2 mol, preferably 1 to 1.5 mol. Note that the R ^a ″ -O portion of R ^a ″ -OH corresponds to the optionally substituted hydroxyl group of R ^1a . Examples of the base used in this reaction include the bases described in [Method H]. Among them, sodium methoxide, sodium ethoxide, potassium t-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate And the like are preferably used in an amount of 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (I-13). As the solvent used in this reaction, any solvent may be used as long as it does not inhibit the reaction, and examples thereof include hydrocarbons (eg, n-hexane, N-heptane, benzene, toluene, xylene, etc.), halogenated hydrocarbons ( For example, dichloromethane and the like), ethers (diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran,
Dioxane), amides (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), esters (eg, ethyl acetate, methyl acetate, etc.),
Nitriles (eg, acetonitrile, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), ketones (acetone, 2-butanone, 4-methyl-2-pentanone, cyclohexynone, etc.), among which hydrocarbons ( For example, n-hexane, N-heptane, benzene, toluene,
Xylene, etc.), amides (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), esters (eg, ethyl acetate, methyl acetate, etc.),
Ketones (acetone, 2-butanone, 4-methyl-2-
Preferred are pentanone, cyclohexone, etc.) and ethers (diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.). These solvents are used alone or as a mixture of two or more. This reaction is carried out at a reaction temperature of 20
To 120 ° C, preferably 70 to 100 ° C, 1 to 24
The reaction is carried out for a time, preferably 2 to 6 hours.

[L method]

Embedded image Compounds in which R ^10a represents a carboxyl-protecting group (I-
4) can be converted to compound (I-7) in one step by reacting with formamide in the presence of a base. Formamide is usually used also as a solvent, and 1 to 30 ml per gram of compound (I-4), preferably 2 to 30 ml.
Use 10 ml. As the base used in this reaction,
Examples of the base described in [Method H] include sodium methoxide, sodium ethoxide, potassium t-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. -4) 1 to 10 mol, preferably 1 to 5 mol, per 1 mol. When a solvent is used in this reaction, any solvent may be used as long as it does not hinder the reaction, but alcohols (eg, _C1-3 alcohols such as methanol, ethanol, propanol, etc.), amides (eg, N,
N-dimethylformamide, N, N-dimethylacetamide,
N-methylpyrrolidone, formamide, etc.) are preferred. This reaction is carried out at a reaction temperature of 20 to 120 ° C, preferably 70
The reaction is carried out at 1 to 100 ° C for 1 to 12 hours, preferably 1 to 3 hours.

When the compound (Ia) is a compound in which ^Ra does not form a hydrocarbon ring or a hetero ring which may be substituted together with ^a thiophene ring and a ring-constituting carbon atom of the ring Ca, the compound (Ia) or The salt can be produced, for example, by the following methods A ′ to L ′ or a method analogous thereto. [Method A ']

Embedded image [In the formula, R ^16a represents an optionally substituted hydrocarbon residue corresponding to R ^a , and R ^17a and R ^18a are each independently a hydrogen atom or a substituted same as exemplified for R ^1a. A represents a hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group, and A ^1a and A ^2a each represent
H represents a hydrogen atom or an optionally substituted hydrocarbon residue or a heterocyclic group as exemplified for R ^1a , Hal represents a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), and Q represents sulfur Represents an atom, oxygen atom or NH group. R
^15a represents a hydrogen atom or an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an acyl group, a sulfonyl group or an amino group. Other symbols are as defined above. In this method, first, compound ( 1 ) is halogenated by a method known per se to give compound ( 2 ), and then compound ( 4 ) is produced by reacting compound ( 3 ) with amide, thioamide or amidine. The reaction between compound ( 2 ) and compound ( 3 ) is performed in an appropriate solvent in the presence or absence of a base. Examples of the solvent include benzene, toluene,
Aromatic hydrocarbons such as xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane,
Halogenated hydrocarbons such as 1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, and ethylene glycol , N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, ethyl acetate or a mixed solvent thereof. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium methoxide, sodium ethoxide and potassium te.
alkali metal alkoxides such as rt-butoxide, alkali metal salts such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate and potassium acetate; alkali metal hydrogens such as disodium hydrogen phosphate and dipotassium hydrogen phosphate Phosphates, sodium hydride, alkali metal hydrides such as potassium hydride, trimethylamine, triethylamine, pyridine,
Bases such as amines such as picoline, N-methylpyrrolidine, N-methylmorpholine and N, N-dimethylaniline are appropriately selected and used, and the amount of these bases to be used is about 1 to about 5 based on compound ( 2 ). The molar equivalent is preferred, and the amount of amide, thioamide or amidine ( 3 ) used is preferably about 1 to about 5 molar equivalents relative to compound ( 2 ). This reaction is generally carried out at about 0 ° C to about + 180 ° C, preferably at about + 30 ° C to
The reaction is performed at about + 120 ° C. for about 30 minutes to about 50 hours. The compound ( 4 ) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound R ^2a is ^{-COOR 16a} (4) [i.e., compound (4 ')] can produce the corresponding carboxylic acid (5) by subjecting the known acid or alkali hydrolysis reaction, also By subjecting compound ( 5 ) to an amidation reaction [reaction with compound ( 6 )] known per se, compound ( 7 ) can be produced. The amidation reaction can be carried out, for example, by introducing the compound ( 5 ) into an acid halide with a halogenating agent such as oxalyl chloride or thionyl chloride, and then reacting the compound ( 6 ) with the compound ( 6 ). The reaction between the compound ( 5 ) and the halogenating agent is usually performed in a solvent, and examples of the solvent include aromatic hydrocarbons such as benzene and toluene, and ethers such as diethyl ether and tetrahydrofuran. For example, pyridine, N, N-dimethylformamide or the like may be used as the reaction accelerator. This reaction is generally performed at about 0 ° C. to about + 120 ° C. for about 30 minutes to about 24 hours. The amount of the halogenating agent to be used is preferably about 1 to 2 molar equivalents relative to compound ( 5 ). The reaction of the acid halide obtained compound was separated by conventional separation and purification means may be subjected to reaction with (6), and the reaction mixture a compound containing the acid halide without separation (6) It can also be attached. The reaction between the acid halide and the compound ( 6 ) is usually performed in a solvent. Examples of the solvent include halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, dioxane and tetrahydrofuran, acetone, acetonitrile, ethyl acetate, N, N -Dimethylformamide and the like.
The reaction can also be carried out using an excess amount of the compound ( 6 ) as a solvent. This reaction can be carried out in the presence or absence of a base. Examples of the base include organic bases such as trimethylamine, triethylamine, pyridine and N, N-dimethylaniline, and inorganic bases such as sodium hydrogencarbonate and potassium carbonate. Bases and the like. The amount of the compound (6) is preferably about 1-2 molar equivalents relative to the acid halide can be used an excess amount of the compound (6) as the solvent. This reaction is generally carried out at about 0 ° C. to about +120.
C. for about 30 minutes to about 24 hours. Among the compounds ( 4 ), the compound wherein Q is an NH group is the compound ( 4)
-1) and the compound (4 -2) is capable of isomerization as, Compound by subjecting to reaction with a halogenated hydrocarbon of the compound (8) (9 -1) and (9 -2) I do. This reaction is carried out in a suitable solvent in the presence or absence of a base. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and a mixed solvent thereof. Is mentioned. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium methoxide, sodium ethoxide and potassium tert-butoxide. Alkali metal alkoxides, such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, alkali metal salts such as sodium acetate and potassium acetate, and alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate , Sodium hydride,
Alkali metal hydrides such as potassium hydride, trimethylamine, triethylamine, pyridine, picoline, N
-Methylpyrrolidine, N-methylmorpholine, N, N-
Bases such as amines such as dimethylaniline are appropriately selected and used, and the amount of these bases used is preferably about 1 to about 5 molar equivalents relative to compound ( 4 ), and the amount of halogenated hydrocarbon ( 8 ) used is preferably About 1 to about 5 molar equivalents relative to compound ( 4 ) are preferred. This reaction is carried out usually at about 0 ° C. to about + 180 ° C., preferably at about + 30 ° C. to about + 120 ° C., for about 30 minutes to about 50 hours. Thus obtained compound (9 -1) and (9 -2) known separation and purification means,
For example, they can be isolated and purified by concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

[B 'method]

Embedded image(Each symbol in the formula has the same meaning as described above.) In the present method, the above compound (2) By a method known per se
Azide compound10) And then carboxylic anhydride
object(11) (Eg, acetic anhydride, propionic anhydride, butyric acid)
Anhydride, isobutyric anhydride, etc.)
By the compound (12) To manufacture. As the reduction reaction
Is a transition metal catalyst (eg, palladium, platinum, rhodium
) And hydrogen are preferred.
The reaction is performed in a solvent that does not adversely influence the reaction. The
Examples of the solvent include benzene, toluene, and xylene.
Which aromatic hydrocarbons, diethyl ether, tetrahydric
Ethers such as lofuran, dioxane and dimethoxyethane
, N, N-dimethylformamide, ethyl acetate
Or acid anhydride (11) Corresponding carboxylic acid (eg, vinegar
Acid, propionic acid, butyric acid, isobutyric acid) or this
And the like. The reaction temperature is usually about -2.
0 ° C to about + 150 ° C, particularly preferably about 0 ° C to about + 100 ° C
And the reaction time is from about 1 hour to about 24 hours. this
The compound thus obtained (12) Is a known separation and purification method
Stages, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
Isolation and purification by phase transfer, chromatography, etc.
Can be. Compound(12) In a suitable solvent or insoluble
The compound is subjected to a reaction with phosphorus oxychloride
object(13) To manufacture. As the solvent, for example, benze
Aromatic hydrocarbons such as toluene, xylene,
Chloromethane, chloroform, carbon tetrachloride, 1,2-dic
Loroethane, 1,1,2,2-tetrachloroethane
Halogenated hydrocarbons, diethyl ether, tetrahydride
Ethers such as lofuran, dioxane and dimethoxyethane
Dimethyl sulfoxide, acetonitrile or
These include mixed solvents. Phosphorus oxychloride
The amount used should be the compound (12) To about 1 to about 5 molar equivalents
preferable. The reaction temperature is usually about 0 ° C to about + 150 ° C, preferably
Or about + 30 ° C. to about + 120 ° C., and the reaction time is about
1 hour to about 24 hours. Conversion obtained in this way
Compound (13) Is a known separation and purification means, for example, concentration, reduced pressure
Concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography
Can be isolated and purified. R^2aBut-
COOR^16aIs a compound (13) Is replaced by a known acid
Or alkali hydrolysis to give R^2aIs -C
Compounds that are OOH (13) Can be manufactured
R^2aIs -COOH (13Public)
Knowledge of amidation reaction [compound (6Reaction)
By R^2aIs -CONR ^17aR^18aIs a compound
object(13) Can also be produced. The reaction
(4’) To the compound (5), The compound (5) Or
Compound (7Under the same conditions as the reaction leading to
it can.

[C 'method]

Embedded image (In the formula, R ^19a represents a methyl group or an ethyl group. Other symbols have the same meanings as described above.) In this method, compound ( 14 ) is produced by reducing compound ( 10 ) described above. . As the reduction reaction, catalytic reduction using a transition metal catalyst (eg, palladium, platinum, rhodium, etc.) and hydrogen is preferable, and this reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include benzene, toluene, aromatic hydrocarbons such as xylene, diethyl ether, tetrahydrofuran, dioxane, ethers such as dimethoxyethane,
Examples thereof include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, and ethylene glycol, N, N-dimethylformamide, ethyl acetate, and a mixed solvent thereof. The reaction temperature is usually about -20 ° C to about +150.
C., especially from about 0.degree. C. to about + 100.degree. C., and the reaction time is from about 1 hour to about 24 hours. The compound ( 14 ) thus obtained can be obtained by known separation and purification means, for example, concentration,
It can be isolated and purified by concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound ( 14 ) was prepared by reacting the compound of the general formula ( 1)
Compound ( 16 ) is produced by subjecting the compound to the reaction with the dithioester represented by 5 ). Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 2-dichloroethane, 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile and the like A mixed solvent and the like can be mentioned. The amount of the dithioester ( 15 ) to be used is preferably about 1 to about 5 molar equivalents relative to compound ( 14 ). The reaction temperature is generally about 0 ° C. to about + 150 ° C., preferably about + 30 ° C. to about + 120 ° C., and the reaction time is about 1 hour to about 24 hours. The compound ( 16 ) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound ( 1
Compound ( 17 ) is produced by reacting 6 ) with phosphorus oxychloride in the same manner as in Method B '. R ^2a is -CO
The compound ( 17 ) which is OR ^16a is subjected to an acid or alkali hydrolysis reaction known per se, whereby R ^2a is -C
OOH, Compound (17) can be produced, ^{also, R 2a} by subjecting the compound ^{R 2a} is -COOH (17) in the reaction of the compound (6)] per se known amidation reaction Compound ( 17 ), which is -CONR ^17a R ^18a , can also be produced. This reaction leads to compounds (4 ') (5) the reaction can be carried out from the compound (5) under the same conditions as in the reaction leading to compound (7).

[D 'method]

Embedded image (In the formula, Q ′ represents an oxygen atom or NA ^1a . The other symbols have the same meanings as described above.) In the present method, the above compound ( 1 ) is treated with an oxy group in the presence of N, N-dimethylformamide. Compound ( 18 ) is produced by subjecting it to a reaction with phosphorus chloride. As the solvent, for example, halogenated carbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane or the like; A mixed solvent may be used. N, N-
The amount of dimethylformamide and phosphorus oxychloride to be used is preferably about 1 to about 5 molar equivalents relative to compound ( 1 ). The reaction temperature is usually about -20 ° C to about + 180 ° C, particularly about 0 ° C to about + 120 ° C, and the reaction time is about 1 hour to about 24 hours. The compound ( 18 ) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound ( 1
8 ) is reacted with a hydroxylamine derivative or hydrazine derivative of compound ( 19 ) to give compound ( 2)
0 ). This reaction is advantageously performed in a solvent that does not adversely influence the reaction, in the presence of a base. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane. , Diethyl ether, tetrahydrofuran, dioxane, ethers such as dimethoxyethane, N, N-dimethylformamide,
Examples thereof include dimethyl sulfoxide, acetonitrile, and a mixed solvent thereof. Examples of the base include sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, magnesium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, sodium methoxide,
Sodium ethoxide, alkali metal alkoxides such as potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate,
Alkali metal salts such as sodium acetate and potassium acetate,
Alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, alkali metal hydrides such as sodium hydride and potassium hydride, trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methyl Bases such as amines such as morpholine and N, N-dimethylaniline are appropriately selected and used. The amount of these bases used is preferably about 1 to about 5 molar equivalents relative to compound ( 18 ), and hydroxylamine or hydrazine ( The amount of ( 19 ) is preferably about 1 to about 5 molar equivalents relative to compound ( 18 ). This reaction is usually performed at about 0 ° C.
To about + 180 ° C, preferably from about + 30 ° C to about + 120 ° C
For about 30 minutes to about 50 hours. The compound ( 20 ) thus obtained is obtained by a known separation and purification means,
For example, they can be isolated and purified by concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound R ^2a is ^{-COOR 16a} (20) to be able ^{to R 2a} by subjecting the known acid or alkali hydrolysis reaction to produce the compound (20) is -COOH, ^{also, R 2a} is - CO
OH, compound (20) and ^{R 2a} by subjecting to the reaction with the compound (6)] per se known amidation reaction can also be prepared compounds is ^-CONR 17a ^{R 18a} (20). This reaction leads to compounds (4 ') (5) the reaction can be carried out from the compound (5) under the same conditions as in the reaction leading to compound (7).

[E 'method]

Embedded image (In the formula, each symbol has the same meaning as described above.) In this method, the above compound ( 18 ) is subjected to a reaction with sulfur and sodium sulfide in an appropriate solvent, and then treated with sulfuryl chloride. Thus, compound ( 21 ) is produced. Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, and ethylene glycol;
Examples thereof include dimethylformamide, dimethylsulfoxide, acetonitrile, and a mixed solvent thereof.
The amount of sulfur and sodium sulfide used is determined by the amount of compound ( 18 )
About 1 to about 3 molar equivalents are preferred. The reaction temperature is usually about 0 ° C to about + 180 ° C, especially about + 30 ° C to about +
120 ° C is preferred and the reaction time is from about 1 hour to about 24 hours. The sulfuryl chloride treatment of the intermediate thus obtained is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,
Examples include halogenated hydrocarbons such as 2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, and a mixed solvent thereof. The amount of sulfuryl chloride to be used is preferably about 1 to about 3 molar equivalents relative to compound ( 18 ). The reaction temperature is usually about -20 ° C to about + 150 ° C, particularly about 0 ° C to about + 100 ° C, and the reaction time is about 1 hour to about 24 hours. The compound ( 21 ) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound ( 2
1 ) reacts with a large excess of ammonia to give compound ( 2)
2 ) is manufactured. This reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, and ethylene glycol; and mixed solvents thereof. . This reaction is generally carried out at about -20 ° C to about + 180 ° C, preferably at about 0 ° C to
The reaction is performed at about + 120 ° C. for about 1 hour to about 50 hours. The compound ( 22 ) thus obtained is separated and purified by a known means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization,
It can be isolated and purified by recrystallization, phase transfer, chromatography and the like. R ^2a is -COOR ^16a
In it ^{R 2a} by subjecting the compound (22) per se known acid or alkali hydrolysis reaction it is possible to produce a compound that is -COOH (22), ^{also, R 2a}
R by but subjecting the compound is -COOH (22) in a per se known amidation reaction [compound (6) reaction with]
Compound ( 22 ), wherein ^2a is —CONR ^17a R ^18a
Can also be manufactured. This reaction leads to compounds (4 ') (5) the reaction can be carried out from the compound (5) under the same conditions as in the reaction leading to compound (7).

[F 'method]

Embedded image (In the formula, R ^20a represents an ethoxycarbonyl group or a p-toluenesulfonyl group. Other symbols have the same meanings as described above.) In this method, the compound ( 1 ) is prepared by reacting the compound ( 1 ) in an appropriate solvent subjected to reaction with carbazate ethyl or p- toluenesulfonyl hydrazide (23), compound (24)
To manufacture. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane. , Diethyl ether, tetrahydrofuran, dioxane, ethers such as dimethoxyethane,
Examples thereof include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, and ethylene glycol, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, ethyl acetate, and a mixed solvent thereof.
The amount of ethyl carbazate or p-toluenesulfonylhydrazide ( 23 ) to be used is preferably about 1 to about 2 molar equivalents relative to compound ( 1 ). The reaction temperature is usually about 0 ° C. to about + 180 ° C., preferably about + 30 ° C. to about + 120 ° C., and the reaction time is about 1 hour to about 24 hours.
The compound ( 24 ) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound ( 25 ) is produced by treating compound ( 24 ) with thionyl chloride. The reaction is
The reaction is performed in an appropriate solvent or without a solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane. And ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, and a mixed solvent thereof. This reaction is carried out usually at about -20 ° C to about + 180 ° C, preferably at about 0 ° C to about + 120 ° C, for about 1 hour to about 50 hours. The compound ( 2 ) thus obtained
5 ) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. R ^{2a is-}
COOR ^16a, compound can ^{be R 2a} by subjecting the known acid or alkali hydrolysis reaction (25) to produce a compound (25) is -COOH, ^A compound ^{R 2a} is -COOH (25) the ^{R 2a} by subjecting to the reaction with the compound (6)] per se known amidation reaction can also be prepared compounds is ^-CONR 17a ^{R 18a} (25). The reaction is
The reaction for deriving compound ( 5 ) from compound ( 4 ') and the reaction for deriving compound ( 7 ) from compound ( 5 ) can be carried out under the same conditions.

[G 'method]

Embedded image (In the formula, each symbol has the same meaning as described above.) In the present method, the compound ( 18 ) is subjected to a reaction of the compound ( 26 ) with a thiol in an appropriate solvent in the presence of a base. To produce the compound ( 27 ). Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 2-dichloroethane, 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, ethyl acetate Alternatively, a mixed solvent thereof may be used. As the base,
For example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide Alkali metal salts such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate and potassium acetate; alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; sodium hydride;
Alkali metal hydrides such as potassium hydride, trimethylamine, triethylamine, pyridine, picoline, N
-Methylpyrrolidine, N-methylmorpholine, N, N-
Bases such as amines such as dimethylaniline are appropriately selected and used, and the amount of these bases used is preferably about 1 to about 5 molar equivalents relative to compound ( 18 ), and thiol ( 26 )
Is preferably used in an amount of about 1 to about 3 molar equivalents relative to compound ( 18 ). This reaction is carried out usually at about 0 ° C. to about + 180 ° C., preferably about + 30 ° C. to about + 120 ° C., for about 1 hour to about 50 hours. The compound ( 2 ) thus obtained
7 ) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. In the above reaction, the compound ( 28 ) may be partially generated, but usually, the compound ( 27 ) is subjected to an aldol-type dehydration condensation reaction to produce the compound ( 28 ). This reaction is performed in a solvent that does not adversely influence the reaction. As the solvent, for example, benzene, toluene, aromatic hydrocarbons such as xylene,
Dichloromethane, chloroform, carbon tetrachloride, 1,2-
Halogenated hydrocarbons such as dichloroethane, 1,1,2,2-tetrachloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, ethylene Examples thereof include alcohols such as glycol, acetonitrile, ethyl acetate, and a mixed solvent thereof. Examples of the dehydration reagent include lower carboxylic anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride, and isobutyric anhydride; sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid; and amines ( A mixture of pyrrolidine, piperidine, etc.) and carboxylic acids (acetic acid, benzoic acid, etc.) is appropriately selected and used. The amount of the dehydrating reagent to be used is a catalytic amount or a large excess with respect to compound ( 27 ), the reaction temperature is generally about 0 ° C to about + 180 ° C, particularly preferably about + 30 ° C to about + 120 ° C, and the reaction time is about 1 hour to about 50 hours. The compound ( 28 ) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
Compound R ^2a is ^{-COOR 16a} (28) to be able ^{to R 2a} by subjecting the known acid or alkali hydrolysis reaction to produce the compound (28) is -COOH, ^{also, R 2a} is - By subjecting the compound ( 28 ) which is COOH to an amidation reaction [reaction with the compound ( 6 )] known per se, R ^2a is -CONR ^17a R
Compound ( 28 ), which is ^18a , can also be produced.
This reaction leads to compounds (4 ') (5) the reaction can be carried out from the compound (5) under the same conditions as in the reaction leading to compound (7).

[H 'method]

Embedded image (Each symbol in the formula has the same meaning as described above.) In this method, the compound ( 2 ) is subjected to a reaction of the compound ( 29 ) with an imine in an appropriate solvent in the presence of a base. And
Compound ( 30 ) is produced. As the solvent, for example, benzene, toluene, aromatic hydrocarbons such as xylene,
Diethyl ether, tetrahydrofuran, dioxane,
Examples thereof include ethers such as dimethoxyethane, and a mixed solvent thereof. As the base, for example, a base such as lithium diethylamide and lithium diisopropylamide is appropriately selected and used, and the amount of the base to be used is preferably about 1 to about 2 molar equivalents relative to compound ( 2 ),
The amount of imine ( 29 ) to be used is preferably about 1 to about 2 molar equivalents relative to compound ( 2 ). In this reaction, first, imine ( 29 )
Is advantageously treated by adding compound ( 2 ) after treating with a base. The reaction temperature is usually about -80 ° C to about +10
At 0 ° C, preferably from about -80 ° C to about + 30 ° C, the reaction time is from about 30 minutes to about 24 hours. The compound ( 30 ) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. R
^The compound ( 30 ) in which R ^2a is -COOH can be produced by subjecting the compound ( 30 ) in which ^2a is -COOR ^16a to an acid or alkali hydrolysis reaction known per se, and wherein R ^2a is -COOH. Is a compound ( 3
0 ) is subjected to an amidation reaction known per se [reaction with compound ( 6 )], whereby R ^2a is -CONR ^17a R
Compound ( 30 ), which is ^18a , can also be produced.
This reaction leads to compounds (4 ') (5) the reaction can be carried out from the compound (5) under the same conditions as in the reaction leading to compound (7).

For example, compound (Ia) can also be produced according to the following method I ′. [Method I ']

Embedded image (In the formula, n represents 1 or 2, and other symbols have the same meanings as described above.) In the present method, first, a 1,3-diketone is converted to a base, carbon disulfide and a halogenated hydrocarbon ( 31 ). To produce a dithioester of the compound ( 32 ). This reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include benzene, toluene, aromatic hydrocarbons such as xylene, diethyl ether, tetrahydrofuran, dioxane, ethers such as dimethoxyethane,
Examples thereof include N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and a mixed solvent thereof. As the base, for example, sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, carbonate Alkali metal salts such as potassium, sodium bicarbonate, potassium bicarbonate, sodium acetate and potassium acetate; alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; sodium hydride and potassium hydride Alkali metal hydride, trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-
Bases such as amines such as methylmorpholine and N, N-dimethylaniline are appropriately selected and used. The amount of these bases used is preferably about 1 to about 2 molar equivalents based on 1,3-diketone, and the amount of carbon disulfide used is preferably about 1 to about 2 molar equivalents based on 1,3-diketone. The amount of hydrogen ( 31 ) used is about 1 to 1,3-diketone.
About 2 molar equivalents, especially about 1 molar equivalent, are preferred. This reaction is usually carried out at about -80 ° C to about + 150 ° C, preferably at about -20 ° C.
To about + 100 ° C. for about 1 hour to about 24 hours. The compound ( 32 ) thus obtained can be obtained by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization,
It can be isolated and purified by recrystallization, phase transfer, chromatography and the like. Compound ( 32 ) was dissolved in a suitable solvent,
Compound ( 34 ) is produced by reacting with a halogenated hydrocarbon represented by the general formula ( 33 ) in the presence of a base. Examples of the solvent include benzene, toluene,
Aromatic hydrocarbons such as xylene, diethyl ether,
Ethers such as tetrahydrofuran, dioxane, dimethoxyethane, etc., alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, ethylene glycol, ketones such as acetone and methyl ethyl ketone, N, N-dimethylformamide, dimethyl sulfoxide , Acetonitrile, ethyl acetate or a mixed solvent thereof. As the base, for example, sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, carbonate Alkali metal salts such as potassium, sodium bicarbonate, potassium bicarbonate, sodium acetate and potassium acetate; alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; sodium hydride and potassium hydride Alkali metal hydride, trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-
Bases such as amines such as methylmorpholine and N, N-dimethylaniline are appropriately selected and used, and the amount of these bases to be used is about 1 to about 10 molar equivalents, particularly about 1 to about 5 molar equivalents to compound ( 32 ). The molar equivalent is preferred, and the amount of the halogenated hydrocarbon ( 33 ) to be used is about 1 to about the compound ( 32 ).
About 2 molar equivalents are preferred. The reaction temperature is usually about 0 ° C. to about +
180 ° C., preferably about + 30 ° C. to about + 120 ° C., and the reaction time is about 1 hour to about 24 hours. The compound ( 1 ) thus obtained is separated and purified by known means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer,
It can be isolated and purified by chromatography and the like. Compound ( 35 ) is produced by subjecting compound ( 34 ) to an oxidation reaction. Examples of the oxidizing agent used in this reaction include peracids such as peracetic acid, pertrifluoroacetic acid, and m-chlorobenzoic acid; metal oxides such as potassium permanganate and chromium oxide; and hydrogen peroxide. In this reaction, the oxidizing agent is used at 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound ( 34 ). As the solvent used in this reaction, any solvent may be used as long as it does not inhibit the reaction, and examples thereof include hydrocarbons such as n-hexane, N-heptane, benzene, toluene, and xylene; Hydrocarbons, ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-
Dimethylacetamide, amides such as N-methylpyrrolidone, ethyl acetate, esters such as methyl acetate, acetone, 2-butanone, 4-methyl-2-pentanone, ketones such as cyclohexone and the like, dichloromethane chloroform, Halogenated hydrocarbons such as carbon tetrachloride and ethers such as diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran and dioxane are preferred. These solvents are used alone or as a mixture of two or more. This reaction is carried out by reacting at a reaction temperature of 0 ° C to 120 ° C, preferably 20 to 80 ° C for 1 to 24 hours, preferably 2 to 6 hours. The compound ( 35 ) thus obtained can be obtained by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

Next, the compound ( 1 ) is produced by subjecting the compound ( 35 ) to a reaction with various nucleophilic reagents. As the nucleophilic reagent, for example, metal phenolates, metal alcoholates, Grignard reagents, alkyl metal reagents, aryl metal reagents, thioalcoholates, amines and the like are used. In this reaction, it is preferable to add a base in some cases. As the base to be used, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, magnesium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, sodium carbonate, potassium carbonate,
Alkali metal salts such as sodium hydrogen carbonate, cesium fluoride, sodium acetate and potassium acetate; metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; metal hydroxides such as sodium hydroxide and potassium hydroxide And amines such as triethylamine, pyridine and N-methylmorpholine. The amount of the nucleophilic reagent to be used is preferably about 1 to about 5 molar equivalents relative to compound ( 35 ). When a base is used, the amount is preferably about 1 to about 5 molar equivalents relative to compound ( 35 ). This reaction is generally performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene, and xylene; Examples include amides such as dimethylformamide and 1-methylpyrrolidone, and sulfoxides such as dimethylsulfoxide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is generally about -70 to about 150C, preferably about -20 to about 100C. The reaction time is usually about 0.
5 to about 24 hours. The compound ( 1 ) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. R ^2a is -CO
By subjecting the compound ( 1 ) which is OR ^16a to an acid or alkali hydrolysis reaction known per se, R ^2a is -CO
A compound ( 1 ) which is OH,
Compound R ^2a is -COOH (1) to produce compound ^{R 2a} is -CONR ^{1 7a} R ^18a (1) is by the subjecting to the reaction with the compound (6)] amidation reaction known per se You can also.

[Method J '] Compound ( 20 ) can also be synthesized by the following method.

Embedded image [Wherein, R ^19a and R ^20a each represent a hydrogen atom or an optionally substituted hydrocarbon residue or a heterocyclic group as exemplified for R ^1a , and other symbols are as defined above. It has the same meaning. In this method, compound ( 31 ) is produced by subjecting compound ( 1 ) to a reaction with trialkyl orthoformate and boron trifluoride-diethyl ether complex in the presence of a base. As the base, an organic base such as triethylamine and diisopropylethylamine is used. As the solvent, for example, halogenated carbons such as dichloromethane, chloroform and carbon tetrachloride are preferable. The amount of the trialkyl orthoformate, boron trifluoride-diethyl ether complex and base to be used is preferably about 1 to about 10 molar equivalents relative to compound ( 1 ). The reaction temperature is usually about -70 ° C to about 60
C., especially −50 ° C. to 30 ° C., and the reaction time is about
1 hour to about 24 hours. The compound ( 31 ) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Compound ( 32 ) is produced by reacting compound ( 1 ) with N, N-dimethylformamide dialkyl acetal or trisdialkylaminomethane. This reaction is performed in a solvent that does not adversely influence the reaction, or in the absence of a solvent.
As the solvent, aromatic hydrocarbons such as benzene, toluene and xylene, and amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone are preferable. By reacting thus obtained compound (31) and the compound (32) with hydroxylamine derivatives or hydrazine derivatives of the compound (19) to produce the compound (20). The reaction may be promoted by adding an acid to the reaction system. As the acid to be used, the above-mentioned inorganic acids and organic acids are used. This reaction is performed in a solvent that does not adversely influence the reaction.
As the solvent, alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene, toluene and xylene, N, N-dimethylformamide, N, N-dimethylacetamide, and amides such as N-methylpyrrolidone are preferable. . The amount of the acid to be used is about 0.1 to about 1 based on the compound ( 1 ).
0 molar equivalents are preferred. The reaction temperature is usually about 0 ° C to about 12 ° C.
0 ° C., especially 50 ° C. to 100 ° C., is preferred, and the reaction time is about 1 hour to about 24 hours. The compound ( 20 ) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Compound (Ia) can also be synthesized by the following method. [K 'method]

Embedded image [The symbols in the formula are as defined above. Y represents boronic acid, boronic ester, zinc halide, copper halide, trialkyltin or triflate. The starting compound ( 36 ) of this method is described in literature [WO2000047578, EP6
76395, and Monash Eft Fühl Chemich (Mo
natshefte fur Chemie), volume 120, page 65 (1987)] can be used as it is, or can be produced by the method described therein or a method analogous thereto. Compound ( 3
6 ) is reacted with a compound ( 37 ) in which Y (boronic acid, boronic ester, or triflate) is bonded to a 5- to 7-membered ring in the presence of a metal catalyst to give compound ( 3).
8 ) is manufactured. As the metal catalyst used in this reaction,
Metal catalysts generally used in aryl coupling are exemplified. For example, tetrakis (triphenylphosphine) palladium (0), dichloropalladium (II), diacetoxypalladium (II), tetrakis (triphenylphosphine) nickel (0), dichloronickel (II), diacetoxynickel (II), Copper (I) chloride, copper (II) chloride and the like are used. In some cases, it is preferable to further add phosphine (for example, triphenylphosphine, tributylphosphine, or the like). This reaction is performed in a solvent that does not adversely influence the reaction, or in the absence of a solvent. Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and xylene; N, N-dimethylformamide;
Amides such as dimethylacetamide and N-methylpyrrolidone are preferred. The amount of compound ( 37 ) to be used is preferably about 1 to about 5 molar equivalents relative to compound ( 36 ), respectively. The amount of the metal catalyst to be used is preferably about 0.1 to about 1 molar equivalent relative to compound ( 36 ). The reaction temperature is generally about -70 ° C to about 150 ° C, preferably 20 ° C to 80 ° C, and the reaction time is about 1 hour to about 24 hours. The compound ( 38 ) thus obtained is separated and purified by a known means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

The conversion of R ^{1a in} compound (Ia) can also be carried out by the following method. [Method L '] In the general formula (Ia), a compound of a hydrocarbon residue, a heterocyclic group, a hydroxyl group, or an amino group in which R ^1a may be substituted is produced by the following method.

Embedded image [Wherein, R ^{1a ″} represents an optionally substituted hydrocarbon residue, and other symbols have the same meanings as described above. That is, the sulfinyl compound or the sulfonyl compound ( 40 ) is produced by subjecting the sulfanyl group of the compound ( 39 ) which can be produced from the compound ( 34 ) by the A 'method to the K' method to oxidation conditions. As the oxidizing agent used in the present oxidation reaction, hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, pertrifluoroacetic acid, potassium permanganate,
Chromium oxide or the like is used. This reaction is performed in a solvent that does not adversely influence the reaction, or in the absence of a solvent. As the solvent, for example, ethers such as diethyl ether, tetrahydrofuran, and dioxane, and halogenated carbons such as dichloromethane, chloroform, and carbon tetrachloride are preferable. The amount of the oxidizing agent to be used is preferably about 1 to about 10 molar equivalents relative to compound ( 39 ). The reaction temperature is usually about 0 ° C to about 100 ° C,
In particular, 0 ° C to 50 ° C is suitable, and the reaction time is about 1 hour to
About 24 hours. The compound thus obtained ( 4
0 ) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Next, the compound ( 4
Compound ( 1 ) is produced by reacting nucleophile with 0 ) in the presence of a base as necessary. As the nucleophile, organic metal reagents such as Grignard reagents and organic lithium reagents, alcohols such as aromatic alcohols and aliphatic alcohols, and amines such as aromatic amines and aliphatic amines can be used. As the base, the above-mentioned inorganic bases and organic bases can be used. This reaction is performed in a solvent that does not adversely influence the reaction, or in the absence of a solvent.
As the solvent, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane, dichloromethane,
Halogenated carbons such as chloroform and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and xylene; N, N
Amides such as -dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone are preferred. The amount of the nucleophile and the amount of the base to be used is preferably about 1 to about 10 molar equivalents relative to compound ( 39 ). The reaction temperature is usually about -70 ° C to about 100 ° C, particularly -20 ° C to 50 ° C, and the reaction time is about 1 hour to about 24 hours. The compound ( 1 ) thus obtained is separated and purified by a known means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

All the compounds used or obtained in the above-mentioned production methods are intended to include the corresponding salts, unless otherwise specified, and can be converted into each other by a method known per se or a method analogous thereto.

When the compound used in the present invention or a salt thereof is an asymmetric molecule, d is obtained by ordinary optical resolution means.
Body, l-body.

The compound or a salt thereof used in the present invention can be isolated and purified by, for example, solvent extraction, concentration under reduced pressure, crystallization, recrystallization, distillation, chromatography and the like.

In the production of the compound or its salt used in the present invention, the obtained compound or its salt may be used in the next step without any purification or as a reaction solution.

The phospholipid used in the present invention may be any pharmacologically acceptable substance, for example, lecithin, phosphatidylcholine, phosphatidylethanol derived from the composition of egg yolk, soybean or other animals and plants. Amines, phosphatidic acid, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, sphingomyelin and the like, or hydrogenated products thereof; high-purity phosphatidylcholine obtained by total synthesis or semisynthesis, Phosphatidylethanolamine, phosphatidic acid, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, sphingomyelin and the like; and phosphatid modified with derivatives of these phospholipids such as polyethylene glycol Ethanolamine, and the like.

[0151] Examples of the phosphatidylcholine, preferably C _12-26 diacyl phosphatidylcholine, more preferably C _14-18 diacyl phosphatidylcholine (e.g., distearoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine Choline, dimyristoylphosphatidylcholine, dilauroylphosphatidylcholine, dioleoylphosphatidylcholine, 1-myristoyl-2-palmitoylphosphatidylcholine, 1-palmitoyl-2-myristoylphosphatidylcholine, 1- Palmitoyl-2-stearoylphosphatidylcholine, 1-stearoyl-2
-Palmitoyl phosphatidyl choline). As the phosphatidylethanolamine,
Preferably C _12-26 diacyl phosphatidyl ethanolamine, more preferably C _14-18 diacyl phosphatidyl ethanolamine (e.g., dipalmitoyl phosphatidyl ethanolamine, Jimi Riruto yl phosphatidylethanolamine, etc.) are used . The phosphatidic acid is preferably C
_12-26 diacyl phosphatidic acids, more preferably _{C 14-18} diacyl phosphatidic acids (e.g.,
Dipalmitoylphosphatidic acid, dimyristoylphosphatidic acid, etc.). The phosphatidyl glycerol is preferably C _12-26 diacyl phosphatidyl glycerol, more preferably C _14-18 diacyl phosphatidyl glycerol (for example, distearoyl phosphatidyl glycerol, dipalmitoyl phosphatidyl glycerol, Myristoyl phosphatidyl glycerol, dilauroyl phosphatidyl glycerol, dioleoyl phosphatidyl glycerol, etc.) are used. The phosphatidylinositol is not limited to phosphatidylinositol, and may be mono- and di-phosphates thereof.
Preferably _{C 12-26} diacyl phosphatidylinositol, more preferably _{C 14-18} diacyl phosphatidylinositol used. The phosphatidylserine is preferably _{C12-26 diacylphosphatidylserine} , more preferably C12-26diacylphosphatidylserine.
_14-18 diacylphosphatidylserine (e.g.,
Dipalmitoyl phosphatidylserine, dimyristoyl phosphatidylserine, brainfosfatidylserine, etc.). Examples of the sphingomyelin, preferably C _12-26 diacyl sphingomyelin, more preferably C _14-18 diacyl sphingomyelin (e.g., brain sphingomyelin, dipalmitoyl sphingomyelin, distearoyl sphingomyelin, and the like).

In obtaining a hydrogenated product of lecithin, hydrogenation can be performed by a method known per se. The phospholipid used in the present invention may be used alone or in a mixture of two or more.

The phospholipids used in the present invention include
Phospholipids not modified with ethylene glycol are preferred.
Good. The phospholipid used in the present invention is preferably
Kuha C_12-26Phospholipids having an acyl group, more preferred
Or C_14-18Phospholipids having an acyl group, further
Preferably C_12-26Phosphorous fat having two acyl groups
Quality, particularly preferably C _14-18Has two acyl groups
Phospholipids are used. Among them, preferably C
_12-26Diacylphosphatidylcholine, more preferred
Or C_14-18Diacylphosphatidylcholine
(For example, distearoylphosphatidylcholine,
Palmitoyl phosphatidylcholine, dimyristoyl
Phosphatidylcholine, dilauroylphosphatidyl
Lucolin, dioleoylphosphatidylcholine, 1-
Myristoyl-2-palmitoyl phosphatidyl coli
, 1-palmitoyl-2-myristoyl phosphatid
Zircholine, 1-palmitoyl-2-stearoylfo
Sphatidylcholine, 1-stearoyl-2-palmit
Ilphosphatidylcholine).

The organic solvent used in the present invention is not particularly limited as long as it is immiscible with an aqueous solvent. The organic solvent that is immiscible in such an aqueous solvent varies depending on the type of the aqueous solvent, and includes, for example, a halogenated hydrocarbon (eg, dichloromethane, chloroform,
Carbon tetrachloride, etc.), ethers (eg, diethyl ether,
Aliphatic esters (eg, ethyl acetate, butyl acetate, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), preferably halogenated hydrocarbons (eg, dichloromethane, chloroform, And the like. These may be mixed and used at an appropriate ratio. The aqueous solvent may be mixed as long as the organic solvent after mixing is immiscible with the aqueous solvent. For example, a mixed solvent of a halogenated hydrocarbon and a lower fatty acid (eg, acetic acid or the like) is suitably used. The organic solvent used in the present invention has a boiling point of about 3
Organic solvents at 0 ° C to 90 ° C are preferred. When a phospholipid-coated water-insoluble or poorly water-soluble drug is produced by using a spray drying method described later, the organic solvent is not particularly limited as long as it dissolves the water-insoluble or poorly water-soluble drug and the phospholipid. Examples of the organic solvent include halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride, etc.), ethers (eg, diethyl ether, isopropyl ether, etc.), aliphatic esters (eg, ethyl acetate, butyl acetate, etc.) ), Aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), alcohols (eg, methanol, ethanol, propanol, butanol, etc.),
Acetonitrile and the like, preferably halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride, etc.)
Are used. These may be mixed and used at an appropriate ratio.

The aqueous solvent used in the present invention is not particularly limited as long as it is immiscible in an organic solvent solution containing a water-insoluble or poorly water-soluble drug and a phospholipid. Examples of the aqueous solvent include water and a mixture of water and a hydrophilic organic solvent. As the hydrophilic organic solvent,
For example, C _1-3 alcohols (methanol, ethanol, propanol, etc.); acetonitrile and the like. Such a hydrophilic organic solvent may be preferably added in an amount of about 0 to 50 parts by weight, more preferably about 0 to 10 parts by weight, based on 100 parts by weight of water. In addition, an aggregation inhibitor may be added to the water used as the aqueous solvent in order to prevent aggregation of the water-insoluble or poorly water-soluble drugs coated with the phospholipid in the emulsion or suspension. Examples of the coagulation inhibitor include water-soluble polysaccharides such as mannitol, lactose, glucose, starches (eg, corn starch), hyaluronic acid and alkali metal salts thereof, glycine,
Proteins such as fibrin and collagen, sodium chloride,
Inorganic salts such as sodium hydrogen phosphate are appropriately used. As the aqueous solvent used in the present invention, water is preferably used.

In the present invention, an organic solvent containing a water-insoluble or poorly water-soluble drug and a phospholipid and an aqueous solvent are mixed and emulsified by the following method, and the organic solvent is removed from the obtained emulsion by the following method. By doing so, a pharmaceutical composition containing a water-insoluble or poorly water-soluble drug and a phospholipid can be produced. The pharmaceutical composition produced by the production method of the present invention may have a water-insoluble or poorly water-soluble drug and a phospholipid coexistent.Specifically, a phospholipid coating is formed on the surface of a water-insoluble or poorly water-soluble drug. Both those formed and those in which the water-insoluble or poorly water-soluble drug is uniformly dispersed and present inside the aggregate composed of the phospholipid. As the "pharmaceutical composition comprising a water-insoluble or poorly water-soluble drug and a phospholipid" in the present invention, "a phospholipid-coated water-insoluble or poorly water-soluble drug having a phospholipid film formed on the surface of a water-insoluble or poorly water-soluble drug" Is preferred.

The phospholipid-coated water-insoluble or poorly water-soluble drug is prepared by dissolving the water-insoluble or poorly water-soluble drug and the phospholipid in an organic solvent and removing the organic solvent from the obtained organic solvent solution to obtain the water-insoluble or poorly water-soluble drug. It can be obtained by forming a phospholipid coating on the surface. The formation of a phospholipid coating on the surface of a water-insoluble or poorly water-soluble drug means that one or more aggregates of one or more molecules of the water-insoluble or poorly water-soluble drug are completely enclosed by the phospholipid, and a part of the hydrophobic group of the phospholipid. Alternatively, it indicates that all are in direct contact (interact) with the molecule of the drug. In the production method of the present invention, the phospholipid is a water-insoluble or poorly water-soluble drug.
For example, about 0.1 to 1000 parts by weight, preferably about 0.1 to 200 parts by weight, more preferably about 1 to 55 parts by weight, and still more preferably about 1 to 15 parts by weight with respect to 0 parts by weight. The concentration of the water-insoluble or poorly water-soluble drug in the organic solvent is preferably about 1 to 100.
0 mg / mL, more preferably about 10 to 500 mg / m
L, more preferably about 50 to 250 mg / mL. Hereinafter, (a) an emulsification method and (b) a spray drying method will be described in detail as examples of a method for producing a phospholipid-coated water-insoluble or poorly water-soluble drug.

(A) Emulsification method In this method, an organic solvent solution containing a water-insoluble or poorly water-soluble drug and a phospholipid is mixed with an aqueous solvent.
Stir to obtain an O / W emulsion. The step of mixing the organic solvent solution and the aqueous solvent may be any method, for example, a method of adding an aqueous solvent to the organic solvent solution, a method of adding the organic solvent solution to the aqueous solvent, or the method of adding the organic solvent solution and the aqueous solvent Includes a method of simultaneously transferring to another container. The temperature of the organic solvent solution and the aqueous solvent may be any temperature as long as the insoluble or poorly water-soluble drug can be decomposed and dissolved. In order to simplify the production, for example, the reaction may be performed at room temperature (1 to 30 ° C) or normal temperature (15 to 25 ° C). The stirring is carried out, for example, by vigorous shaking (shaking stirring) for about 1 to 60 minutes, preferably about 5 to 30 minutes in a closed system, or by ultrasonic irradiation, a turbine-type stirrer, a homogenizer [eg, Polytron (Kinematica)]. And a propeller type stirrer. For example, when using a homogenizer, the mixture is stirred at about 20,000 rpm for about 30 seconds to 1 minute. The volume of the aqueous solvent at this time is, for example, about 1 to 1000 times, more preferably about 3 to 500 times, particularly preferably about 5 to 5 times the volume of the organic solvent solution containing the water-insoluble or poorly water-soluble drug and the phospholipid. 100
Fold, particularly preferably about 10 to 50 fold.
The concentration of the water-insoluble or poorly water-soluble drug in the O / W emulsion is preferably about 0.1 to 500 mg / m2.
L), more preferably about 0.2 to 100 mg / mL, even more preferably about 1 to 20 mg / mL. An emulsifier may be added to the aqueous solvent. The emulsifier is not particularly limited as long as it can form a generally stable O / W emulsion. Examples of the emulsifier include an anionic surfactant, a nonionic surfactant,
Polyoxyethylene castor oil derivatives, polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, lecithin, gelatin, hyaluronic acid and the like. These may be used in appropriate combination. The concentration of the emulsifier in the aqueous solvent is preferably about 0.001%.
To 20% (w / w). More preferably, about 0.5.
01% to 10% (w / w), particularly preferably about 0.
05% to 5% (w / w). After diluting the obtained O / W emulsion by further adding an aqueous solvent as necessary, the organic solvent is removed. For the removal of the organic solvent, a commonly used method is employed. Examples of the method include, for example, a method in which the organic solvent is removed while adjusting the degree of vacuum using a propeller-type stirrer, a magnetic stirrer, or the like, while gradually reducing the pressure while stirring or using a rotary evaporator. Can be Thus, the organic solvent is removed, and the organic solvent solution containing the phospholipid and the water-insoluble or poorly water-soluble drug is solidified. The suspension thus obtained is optionally sieved (mesh size: about 10 to 500 μm, preferably about 20 to 150 μm).
After that, the precipitate is collected by centrifugation with a centrifuge. The resulting precipitate is resuspended in a small amount of distilled water and freeze-dried to obtain a phospholipid-coated water-insoluble or poorly water-soluble drug. Thereafter, if necessary, the organic solvent or the aqueous solvent remaining in the phospholipid-coated water-insoluble or poorly water-soluble drug is further removed by heating (if necessary under reduced pressure).

(B) Spray drying method In this method, an organic solvent solution containing a water-insoluble or poorly water-soluble drug and a phospholipid is sprayed into a drying chamber of a spray dryer (spray dryer) using a nozzle. The organic solvent in the atomized droplets is removed in a short time to produce a phospholipid-coated water-insoluble or poorly water-soluble drug. As the nozzle, for example, a two-fluid nozzle type, a pressure nozzle type,
There is a rotating disk type and the like. At this time, if desired, it is also effective to spray an aqueous solution of the anticoagulant from another nozzle simultaneously with the above organic solvent solution, for the purpose of preventing coagulation of the phospholipid-coated water-insoluble or poorly water-soluble drug. The thus obtained phospholipid-coated water-insoluble or poorly water-soluble drug is preferably freeze-dried after resuspension in a small amount of distilled water. Thereafter, the organic solvent or aqueous solvent in the phospholipid-coated water-insoluble or poorly water-soluble drug is further removed by heating (if necessary under reduced pressure) if necessary.

The phospholipid-coated water-insoluble or poorly water-soluble drug has the following properties. The thickness of the phospholipid coating is preferably about 1 nm to about 50 μm, more preferably about 2 nm to about 10 μm, and more preferably about 1 nm to about 10 μm.
It is 0 nm to 5 μm. The average particle size of the drug in the phospholipid-coated water-insoluble or poorly water-soluble drug is preferably about 0.095 to 149.5 μm, more preferably about 0.45 to 75 μm, more preferably about 1 to 45 μm, and particularly preferably About 5 to 25 μm
It is. The average particle size of the phospholipid-coated water-insoluble or poorly water-soluble drug is preferably about 0.1 to 150 μm, more preferably about 0.5 to 50 μm, more preferably about 5 to 50 μm, and particularly preferably more than 10 μm and 50 μm or less. (For example, 11μ to 50μ
m). Further, it may be about 1 μm to about 150 μm, or more than 10 μm and 150 μm or less (for example, 11 μm to 150 μm, 11 μm to 50 μm). The phospholipid-coated water-insoluble or poorly water-soluble drug is preferably used in an amount of about 0.1 to 200 parts by weight, more preferably about 1 to 55 parts by weight, more preferably about 1 to 100 parts by weight of the water-insoluble or poorly water-soluble drug. To 20 parts by weight, particularly preferably about 1 to 10 parts by weight of phospholipid. The molar ratio of the water-insoluble or poorly water-soluble drug: phospholipid in the phospholipid-coated water-insoluble or poorly water-soluble drug is, for example, about 100: 0.5 to 150,
Preferably about 100: 0.5-50, more preferably about 100: 0.5-15, even more preferably about 100: 0.5.
0.5-10, particularly preferably about 100: 0.5-
7 The drug release period of the phospholipid-coated water-insoluble or poorly water-soluble drug is, for example, about 1 day or more, preferably about 2 days to 3 months, more preferably about 3 days to 3 months, and still more preferably about 1 week to 1 month. is there. The phospholipid-coated water-insoluble or poorly water-soluble drug preferably has sustained release and / or sustainability, but is not particularly limited thereto. The average particle size of the phospholipid-coated water-insoluble or poorly water-soluble drug is measured using a Coulter counter.

The form of the pharmaceutical composition produced by the production method of the present invention is not particularly limited. For example, a water-insoluble or poorly water-soluble drug coated with a phospholipid, or a water-insoluble or poorly water-soluble drug coated with a phospholipid is used as a raw material. By being formulated into various dosage forms, parenteral preparations [injections into non-vessels (for example, injections or implants into joints, intramuscularly, subcutaneously, organs, etc.); injections into blood vessels Or infusions;
Transmucosal preparations for the nasal cavity, rectum, uterus, etc.], oral preparations (for example, capsules (for example, hard capsules, soft capsules, etc.), solid preparations such as granules and powders, liquid preparations such as suspensions, etc.) ]
Etc. can be administered.

The pharmaceutical composition produced by the production method of the present invention is preferably used as an injection. For example,
Aqueous suspensions or oil suspensions can be prepared using a dispersion medium such as water; vegetable oil; medium-chain fatty acid triglyceride.
For example, a phospholipid-coated water-insoluble or poorly water-soluble drug is
Dispersants (for example, surfactants such as Tween 80, HCO-60, and rheodol; polysaccharides such as carmellose sodium (sodium carboxymethylcellulose), sodium alginate, and hyaluronic acid); preservatives (for example, methyl paraben, propyl paraben, etc.) ) And / or an isotonic agent (eg, sodium chloride, sodium hydrogen phosphate, disodium phosphate, mannitol, sorbitol, glucose, etc.) to give an aqueous suspension. In addition, a phospholipid-coated water-insoluble or poorly water-soluble drug is dispersed together with a vegetable oil such as sesame oil or corn oil or a mixture thereof with a phospholipid such as lecithin, or a medium-chain fatty acid triglyceride (eg, Miglyol 812) to form an oily suspension. An injection is obtained by making the suspension turbid. Among the injections, injections into non-vessels are preferable, and injections into joints are particularly preferable.

In order to make various preparations obtained from the phospholipid-coated water-insoluble or sparingly water-soluble drug and / or the phospholipid-coated water-insoluble or sparingly water-soluble drug as raw materials, aseptic preparations, a method of sterilizing all the production steps, Examples include a method of sterilizing with high-pressure steam, a method of sterilizing with gamma rays, and a method of adding a preservative, but are not particularly limited.

Various preparations obtained from a phospholipid-coated water-insoluble or sparingly water-soluble drug and / or a phospholipid-coated water-insoluble or sparingly water-soluble drug as raw materials have low toxicity. Therefore, depending on the water-insoluble or poorly water-soluble drug to be used, it is used as a preventive or remedy for various diseases in mammals including humans (eg, human, horse, cow, pig, dog, cat, rat, mouse, rabbit, etc.). be able to.

For example, when the compound (I) or a salt thereof is used, the compound may be used as a bone formation promoting agent, a bone disease preventing / treating agent, a bone fracture preventing / treating agent, a cartilage formation promoting agent, a cartilage disease preventing / treating agent, etc. Non-metabolic bone diseases such as bone fracture, refracture, bone deformity / osteomyelosis, osteosarcoma, myeloma, osteogenesis imperfecta, and scoliosis in the field of orthopedic surgery; bone loss, osteoporosis,
Metabolic bone diseases such as osteomalacia, rickets, fibrous osteomyelitis, renal osteodystrophy, bone Pechet disease, ankylosing myelitis; or cartilage such as osteoarthritis, rheumatoid arthritis, cartilage defect It can be used as a preventive or remedy for joint diseases represented by diseases, as a bone tissue repair agent after surgery for multiple myeloma, lung cancer, breast cancer and the like. In the field of dentistry, it can be expected to be applied to treatment of periodontal disease, repair of periodontal tissue defects in periodontal disease, stabilization of artificial dental roots, repair of ridges and cleft palate.

The dose of the pharmaceutical composition produced by the production method of the present invention varies depending on the type and content of the water-insoluble or poorly water-soluble drug used, the release time of the drug, the animal to be administered, and the like. Any effective amount may be used. For example,
When the compound (I) or a salt thereof is administered into the joint as an aqueous suspension injection using the compound (I) or a salt thereof as a water-insoluble or sparingly water-soluble drug, the dose of water-insoluble or As the amount of poorly water-soluble drug,
For example, about 0.1 mg or more, preferably about 0.2 mg to about 500 mg, more preferably about 0.5 mg to about 200 m
g is used. For example, when the above compound (I) or a salt thereof is used as a water-insoluble or poorly water-soluble drug and administered intraarticularly as an aqueous suspension injection, an adult (body weight 50)
kg) One dose per person is preferably about 0.1 to 50 mL, more preferably about 0.2 to 50, as the administration volume of the phospholipid-coated water-insoluble or poorly water-soluble drug dispersed in the aqueous medium. 10 mL, more preferably about 0.5 to
5 mL. For example, when the compound (I) or a salt thereof is used as a water-insoluble or poorly water-soluble drug and administered intra-articularly as an aqueous suspension injection, an adult (body weight 50 k
g) The concentration of the active ingredient in a single administration per person may be, for example, about 0.1 mg / mL or more, preferably about 0.1 mg / mL or more, as the concentration of the phospholipid-coated water-insoluble or poorly water-soluble drug dispersed in an aqueous medium. About 0.1-300m
g / mL, more preferably about 0.2 to 200 mg / m
L, more preferably about 0.5-50 mg / mL (eg,
20 mg / mL, etc.). For example, when the above compound (I) or a salt thereof is used as a water-insoluble or poorly water-soluble drug and administered intra-articularly as an aqueous suspension injection, the administration frequency per adult (body weight 50 kg) is, for example, about 1%.
Once a day or more, preferably once every two to three months,
More preferably, the interval is about once every three days to about three months, even more preferably about once a week to once a month. The pharmaceutical composition produced by the production method of the present invention can be stably stored in a dry state in a cold place (for example, in a refrigerator) or at room temperature for a long time without aggregation.

[0167]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited thereto. Compound A, that is, (2
R, 4S)-(-)-N- [4- (diethoxyphosphorylmethyl) phenyl] -1,2,4,5-tetrahydro-4
-Methyl-7,8-methylenedioxy-5-oxo-3
-Benzothiepine-2-carboxamide is disclosed in
No. 231569 (European Patent Application Publication No. 719)
No. 782) manufactured by the same method as that described in Example 1 was used.

Reference Example 1 4,5-dihydro-1-methyl-8-phenoxy-1H-thieno [3,4-
g] Production of indazole-6-carboxamide: a) 4,5,6,7-tetrahydro-3-methylsulfonyl-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester: 4,5,6,7- M-Chloroperbenzoic acid (16.0 g) was added to a dichloromethane solution (150 ml) of tetrahydro-3-methylsulfanyl-4-oxobenzo [c] thiophene-1-carboxylic acid ethyl ester (5.0 g) under ice-cooling, and 24 Stirred at room temperature for hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The precipitated crystals were collected by filtration, washed with an aqueous sodium hydrogen carbonate solution and water, and further washed with ethyl acetate-hexane to give the title compound (5.5 g, 98%) as pale-yellow crystals.
Recrystallization from ethyl acetate-THF gave pale yellow prism crystals. Melting point: 199-200 [deg.] C. b) 4,5,6,7-tetrahydro-4-oxo-3-phenoxybenzo [c] thiophen-1-carboxylic acid ethyl ester: 4,5,
6,7-tetrahydro-3-methylsulfonyl-4-oxobenzo
[c] Sodium hydride (1.0 g) was added to a solution of thiophene-1-carboxylic acid ethyl ester (6.0 g) and phenol (2.2 g) in tetrahydrofuran (50 ml), and the mixture was stirred at room temperature for 14 hours.
An aqueous citric acid solution was added to the reaction solution, and the mixture was concentrated under reduced pressure. The residual oil was poured into water and extracted with ethyl acetate. After drying the organic layer (MgSO ₄ ), the solvent was distilled off under reduced pressure to obtain crude crystals. Recrystallization from ethyl acetate-diisopropyl ether gave the title compound (5.0 g, 80%) as colorless prisms. Melting point:
125-127 ° C. c) 5-Diethoxymethyl-4,5,6,7-tetrahydro-4-oxo-3-phenoxybenzo [c] thiophen-1-carboxylic acid
Ethyl ester: boron trifluoride ether complex (4.54ml)
Was added dropwise to triethyl orthoformate (5.0 g) cooled to -40 ° C. Cool the solution on ice 15
After stirring for minutes, the mixture was cooled to -70 ° C. A solution of 4,5,6,7-tetrahydro-4-oxo-3-phenoxybenzo [c] thiophen-1-carboxylic acid ethyl ester (4.78 g) in dichloromethane (25 ml) was added to the solution, and then diisopropylethylamine
(7.44 ml) was added dropwise. After stirring at -70 ° C for 1 hour, the reaction solution was poured into aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with water, diluted hydrochloric acid, and saturated saline in this order,
It was dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (6.3 g, 100%) as colorless needles, melting point: 73-73 ° C. d) 4,5-dihydro-1-methyl-8-phenoxy-1H-thieno [3,4-g] indazole-1-carboxylic acid ethyl ester and 4,5-dihydro-2-methyl-8-phenoxy-2H -Thieno [3,4-g] indazole-1-carboxylic acid ethyl ester: 5-diethoxymethyl-4,5,6,7-tetrahydro-4-oxo-3-phenoxybenzo [c] thiophene-1-carboxylic acid Acid ethyl ester (6.3
2g), methylhydrazine monohydrate (0.7g), 2N hydrochloric acid (23mL)
And a mixed solution of ethanol (50 mL) was heated to reflux for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution and saturated saline, dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The title compound was obtained as colorless prism crystals from the portion eluted with ethyl acetate-hexane (1: 2). 4,5-
Dihydro-1-methyl-8-phenoxy-1H-thieno [3,4-g] indazole-1-carboxylic acid ethyl ester (2.38 g, 44
%), Melting point: 91-93 ° C (recrystallization solvent: AcOEt-hexane). 4,5-
Dihydro-2-methyl-8-phenoxy-2H-thieno [3,4-g] indazole-1-carboxylic acid ethyl ester (0.87 g, 16
%), Melting point: 89-90 ° C (recrystallization solvent: AcOEt-hexane). e) 4,5-dihydro-1-methyl-8-phenoxy-1H-thieno
[3,4-g] indazole-1-carboxylic acid: 4,5-dihydro-1-
Methyl-8-phenoxy-1H-thieno [3,4-g] indazole-1
-Carboxylic acid ethyl ester (2.03g), ethanol (50m
A mixture of L) and a 0.6 N aqueous potassium hydroxide solution (20 mL) was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, acidified with 2N hydrochloric acid, and extracted with a mixed solution of ethyl acetate-THF. The organic layer is washed successively with water and saturated saline, and then dried (MgS
O ₄ ) and concentrated under reduced pressure. The obtained crude crystals were recrystallized from tetrahydrofuran to give the title compound (1.87 g, 100%) as colorless needles. Melting point: 259-261 ° C f) 4,5-dihydro-1-methyl-8-phenoxy-1H-thieno
[3,4-g] indazole-6-carboxamide: 4,5-dihydro
1-methyl-8-phenoxy-1H-thieno [3,4-g] indazole-6-carboxylic acid (0.50 g), HOBt-NH ₃ (0.26 g), WSC (0.36 g)
g) and DMF (10 ml) were stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, water was poured into the residual oil, and ethyl acetate was added.
Extracted with a mixture of THF. The organic layer was washed sequentially with water and saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate to give the title compound (0.49 g, 99%)
Was obtained as colorless prism crystals. Melting point: 200-202 ° C

Reference Example 2 8-benzyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g]
Preparation of indazole-6-carboxamide: a) 3-benzyl-4,5,6,7-tetrahydro-4-oxobenzo
[c] thiophene-1-carboxylic acid ethyl ester: 4,5,6,
7-tetrahydro-3-methylsulfonyl-4-oxobenzo
To a solution of [c] thiophene-1-carboxylic acid ethyl ester (6.0 g) in anhydrous THF (300 ml) was added dropwise a 1M benzylmagnesium bromide ether solution (21 ml). After the mixture was stirred at room temperature for 2 hours, aqueous citric acid solution was added to the reaction solution. T
HF was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The obtained residual oil was subjected to silica gel column chromatography. The title compound (1.3 g, 21%) was obtained as pale yellow needles from a portion eluted with ethyl acetate-hexane (1: 5). Recrystallization from ethyl acetate-hexane gave colorless crystals. Melting point: 96-97 ° C. b) 3-Benzyl-5-diethoxymethyl-4,5,6,7-tetrahydro-4-oxobenzo [c] thiophene-1-carboxylic acid ethyl ester: In the same manner as in Reference Example 1c), 3-benzyl- Four,
5,6,7-tetrahydro-4-oxobenzo [c] thiophen-1-
The title compound was obtained from carboxylic acid ethyl ester (yield: 100
%) As a pale yellow oil. ¹ H-NMR (δ ppm in CDCl ₃ ): 1.14 (3H, t, J = 7.4Hz), 1.25
(3H, t, J = 7.4Hz), 1.28 (3H, t, J = 7.4Hz), 2.0-2.4 (2H, m),
2.74 (1H, dt, J = 4.4,9.8Hz), 2.92 (1H, ddd, J = 5.6,10.4,
18.0Hz), 3.5-3.9 (5H, m), 4.28 (2H, q, J = 7.4Hz), 4.59
(2H, s), 5.11 (1H, d, J = 3.6Hz), 7.2-7.4 (5H, m) .c) 8-benzyl-4,5-dihydro-1-methyl-1H-thieno [3,4
-g] indazole-6-carboxylic acid ethyl ester and 8-
Benzyl-4,5-dihydro-2-methyl-2H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: Reference Example 1d)
In the same manner as above, 3-benzyl-5-diethoxymethyl-4,5,6,
7-tetrahydro-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester to 8-benzyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid Ethyl ester (yield: 79%) as pale yellow oil and 8-benzyl-4,5-dihydro-2-methyl-2H-thieno
[3,4-g] indazole-6-carboxylic acid ethyl ester (yield: 20%) was obtained as a pale yellow oil. 8-benzyl-4,5-
Dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-
Carboxylic acid ethyl ester: ¹ H-NMR (δ ppm in CDC
l ₃ ): 1.33 (3H, t, J = 7.2Hz), 2.64 (2H, t, J = 6.8Hz), 3.20
(2H, t, J = 6.8Hz), 3.97 (3H, s), 4.30 (2H, q, J = 7.2Hz), 4.
38 (2H, s), 7.2-7.4 (5H, m), 7.44 (1H, s) .8-benzyl-4,
5-dihydro-2-methyl-2H-thieno [3,4-g] indazole-6
-Carboxylic acid ethyl ester: ¹ H-NMR (δ ppm in CDCl
₃ ): 1.32 (3H, t, J = 7.0Hz), 2.75 (2H, t, J = 7.2Hz), 3.30 (2H, t, J = 7.2Hz)
(H, t, J = 7.2Hz), 3.92 (3H, s), 4.27 (2H, q, J = 7.0Hz), 4.62
(2H, s), 7.18 (1H, s), 7.2-7.5 (5H, m) .d) 8-benzyl-4,5-dihydro-1-methyl-1H-thieno [3,4
-g] indazole-6-carboxylic acid: 8-benzyl-4,5-dihydro-1-methyl-1H-thieno [3,4
-g] indazole-6-carboxylic acid ethyl ester,
The title compound (yield: 84%) was obtained as pale yellow crystals. Melting point: 300 ° C. or higher (recrystallization solvent: THF-MeOH). e) 8-benzyl-4,5-dihydro-1-methyl-1H-thieno [3,4
-g] indazole-6-carboxamide: 8-benzyl-4,5-dihydro-1-methyl-1H-thieno in the same manner as in Reference Example 1f).
From [3,4-g] indazole-6-carboxylic acid, the title compound
(Yield: 94%) was obtained as pale yellow prism crystals. Melting point: 126
-127 ° C (recrystallization solvent: AcOEt).

Reference Example 3 Production of 4,5-dihydro-1-methyl-8-phenylsulfanyl-1H-thieno [3,4-g] indazole-6-carboxamide: a) 5-Diethoxymethyl-4,5 , 6,7-Tetrahydro-3-methylsulfanyl-4-oxobenzo [c] thiophene-1-carboxylic acid ethyl ester: In the same manner as in Reference Example 1c), 4,5,
From 6,7-tetrahydro-3-methylsulfanyl-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester,
The title compound (yield: 100%) was obtained as colorless needles. Melting point: 115-116 ° C b) 4,5-dihydro-1-methyl-8-methylsulfanyl-1H-
Thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: In the same manner as in Reference Example 1d), 5-diethoxymethyl-4,
The title compound (yield: 77%) was obtained as pale yellow prism crystals from 5,6,7-tetrahydro-3-methylsulfanyl-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester. Melting point: 113-114 ° C (recrystallization solvent: AcOEt-hexane). c) 4,5-dihydro-1-methyl-8-methylsulfonyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 4,5-dihydro-1-methyl-8-methylsulfanyl -1H-
Thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (80 g) was dissolved in trifluoroacetic acid (240 ml). Under ice-cooling, 30% aqueous hydrogen peroxide (80 ml) was added dropwise, and the mixture was stirred at room temperature for 6 hours. The reaction solution was neutralized with an aqueous sodium hydroxide solution, and the precipitated crystals were collected by filtration. Recrystallization from ethyl acetate gave the title compound (79 g, 90%) as yellow needles. Melting point: 14
0-141 ° C d) 4,5-dihydro-1-methyl-8-phenylsulfanyl-1
H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 4,5-dihydro-1-methyl-8-methylsulfonyl-1
H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (2.0 g) and thiophenol (0.60 ml) in THF solution (70
To the resulting mixture was added 60% sodium hydride (0.26 g) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes and further at room temperature for 5 hours. The reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and then dried (MgSO ₄ ).
The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. Ethyl acetate-hexane
From the part eluted with (1: 2), the title compound (0.90 g, 41%) was obtained as a pale yellow oil. ¹ H-NMR (δ ppm in CDCl ₃ ): 1.3
5 (3H, t, J = 7.4Hz), 2.65 (2H, t, J = 6.8Hz), 3.26 (2H, t, J =
6.8Hz), 4.16 (3H, s), 4.32 (2H, q, J = 7.4Hz), 7.1-7.3 (5
H, m) .e) 4,5-dihydro-1-methyl-8-phenylsulfanyl-1
H-thieno [3,4-g] indazole-6-carboxylic acid: Reference Example 1
In the same manner as in e), the title compound (yield: 92%) was obtained from 4,5-dihydro-1-methyl-8-phenylsulfanyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester. ) Was obtained as colorless prism crystals. Melting point: 286-287 ° C. f) 4,5-dihydro-1-methyl-8-phenylsulfanyl-1
H-thieno [3,4-g] indazole-6-carboxamide: 4,5-dihydro-1-methyl-8-phenylsulfanyl-1H-thieno [3,4-g] in the same manner as in Reference Example 1f). The title compound (yield: 95%) was obtained as colorless prisms from indazole-6-carboxylic acid. Melting point: 205-206 [deg.] C.

The compounds of Reference Examples 4 to 9 were synthesized in the same manner as in Reference Example 1.

Reference Example 4 4,5-dihydro-1-methyl-8- (3,4-methylenedioxyphenoxy) -1H-thieno [3,4-g] indazole-6-carboxamide Melting point: 204-205 ° C.

Reference Example 5 8- (4-benzyloxyphenoxy) -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide Melting point: 200-201 ° C.

Reference Example 6 4,5-dihydro-1-methyl-8- (4-methoxyphenoxy) -1H-
Thieno [3,4-g] indazole-6-carboxamide Melting point: 203-205 ° C

Reference Example 7 4,5-dihydro-1-methyl-8- (4-trifluoromethoxyphenoxy) -1H-thieno [3,4-g] indazole-6-carboxamide Melting point: 212-213 ° C.

Reference Example 8 4,5-dihydro-8- (3,4-methylenedioxyphenoxy) -1-
(2,2,2-trifluoroethyl) -1H-thieno [3,4-g] indazole-6-carboxamide Melting point: 216-218 ° C

Reference Example 9 4,5-dihydro-8- (2,3-dimethylphenoxy) -1- (2,2,2-
(Trifluoroethyl) -1H-thieno [3,4-g] indazole-6
-Carboxamide Melting point: 190-191 ° C

Reference Example 10 4-{[6- (aminocarbonyl) -1-methyl-4,5-dihydro-1H-
Thieno [3,4-g] indazol-8-yl] oxy} benzylphosphonic acid ethyl ester Melting point: 92-93 ° C

Reference Example 11 4-{[6- (aminocarbonyl) -2-methyl-4,5-dihydro-1H-
Thieno [3,4-g] indazol-8-yl] oxy} benzylphosphonic acid ethyl ester Melting point: 180-181 ° C

Reference Example 12 Production of N-ethyl-4,5-dihydro-1-methyl-8- (3,4-methylenedioxyphenoxy) -1H-thieno [3,4-g] indazole-6-carboxamide : N-ethyl-4,5-dihydro-1-methyl-8- obtained in Reference Example 4
(3,4-methylenedioxyphenoxy) -1H-thieno [3,4-g]
Indazole-6-carboxylic acid (1.50 g) in THF suspension (50 ml)
Oxalyl chloride (0.7 ml) and N, N-dimethylformamide (3 drops) were added to the mixture under ice-cooling, stirred at room temperature for 30 minutes, and concentrated under reduced pressure. To a solution obtained by adding THF (50 ml) to the residue was added a 70% ethylamine solution (2 ml) under ice-cooling, followed by stirring for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water, an aqueous solution of sodium hydrogen carbonate and saturated saline, dried (MgSO ₄ ), and the solvent was distilled off. The residual oil was subjected to column chromatography. Ethyl acetate-hexane
From the portion eluted from (3: 2), the title compound (1.36 g, 84%) was obtained as colorless needles. Melting point: 138-139 ° C.

Reference Example 13 4,5-Dihydro-1-methyl-8- [4- (2-quinolylmethyloxy) phenoxy] -1H-thieno [3,4-g] indazole-6-carboxamide a) 8 -(4-benzyloxyphenoxy) -4,5-dihydro-1-
Methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid
Ethyl ester: Reference Example 1a) in the same manner as Reference Example 1b)
The title compound was obtained as pale yellow crystals from the compound obtained in. Recrystallized from tetrahydrofuran-ethyl acetate,
A pale yellow prism crystal was obtained. Melting point: 139-140 ° C. b) 4,5-dihydro-8- (4-hydroxyphenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 8- (4-benzyloxyphenoxy)- 4,5-
Dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-
Carboxylic acid ethyl ester (7.4 g) and 10% palladium
-Carbon (3.0 g) was added to a mixed solvent of tetrahydrofuran (100 ml) and methanol (50 ml), and the mixture was stirred in a hydrogen stream at normal pressure for 2 hours. The insolubles were removed by filtration, and the filtrate was concentrated to obtain pale yellow crystals. Recrystallization from tetrahydrofuran-ethyl acetate gave the title compound (5.6 g, 94%) as pale yellow needles. Melting point: 245-246 ° C. c) 4,5-dihydro-1-methyl-8- [4- (2-quinolylmethyloxy) phenoxy] -1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 4,5 -Dihydro-8- (4-hydroxyphenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (1.5 g), 2-chloromethylquinoline hydrochloride (1.7 g) , And potassium carbonate (1.7
A solution of g) in DMF (50 ml) was stirred at 70 ° C. for 10 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed sequentially with a citric acid aqueous solution, water, and saturated saline, and then dried (MgS
O ₄ ) and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. Ethyl acetate: hexane
From the portion eluted with (2: 1), the title compound (1.9 g, 92%) was obtained as colorless prism crystals. Melting point: 121-122 ° C. d) 4,5-dihydro-1-methyl-8- [4- (2-quinolylmethyloxy) phenoxy] -1H-thieno [3,4-g] indazole-6-carboxylic acid: Reference Example 1e) 4,5-dihydro-1-
Methyl-8- [4- (2-quinolylmethyloxy) phenoxy] -1H
The title compound (yield: 98%) was obtained as colorless prisms from -thieno [3,4-g] indazole-6-carboxylic acid ethyl ester. Melting point: 269-270 ° C. e) 4,5-dihydro-1-methyl-8- [4- (2-quinolylmethyloxy) phenoxy] -1H-
Thieno [3,4-g] indazole-6-carboxamide: 4,5-dihydro-1-methyl-8- [4- (2-quinolylmethyloxy) phenoxy] -1H in the same manner as in Reference Example 1f). Title compound (yield: 95%) from -thieno [3,4-g] indazole-6-carboxylic acid
Was obtained as colorless prism crystals. Melting point: 214-215 ° C.

Reference Example 1 was obtained in the same manner as in Reference Example 13.
4 to 15 compounds were synthesized.

Reference Example 14 4,5-Dihydro-1-methyl-8- [4- (4-pyridylmethyloxy) phenoxy] -1H-thieno [3,4-g] indazole-6-carboxamide Melting point: 249- 250 ℃

Reference Example 15 4,5-dihydro-1-methyl-8- (4-fluorophenoxy) -1H-
Thieno [3,4-g] indazole-6-carboxamide Melting point: 188-189 ° C

Reference Example 16 4,5-dihydro-1-methyl-8- (3-pyridinyloxy) -1H-thieno [3,4-g] indazole-6-carboxamide a) 4,5-dihydro-1-methyl -8- (3-pyridinyloxy)-
1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: Dissolve 3,4-dimethoxyphenol (1.00 g) in N-methylpyrrolidone (50 ml) and add potassium t-butoxide
(1.29 g) was added. After stirring at room temperature for 30 minutes, the compound (3.00 g) obtained in Reference Example 3c) was added. Stir for 30 minutes at room temperature, 7
Stirred at 0 ° C. for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with an aqueous citric acid solution, water and saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography.
The title compound (1.06 g, 38%) was obtained as pale-yellow prism crystals from a portion eluted with ethyl acetate: hexane (2: 1). Melting point: 74-75 ° C (recrystallization solvent: ethyl acetate-hexane). b) 4,5-dihydro-1-methyl-8- (3-pyridinyloxy)-
1H-thieno [3,4-g] indazole-6-carboxylic acid: Reference Example 1
In the same manner as in e), the title compound (yield: 4,5-dihydro-1-methyl-8- (3-pyridinyloxy) -1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester was obtained. : 99%) as colorless prisms. Melting point: 247-248 ° C (recrystallization solvent: tetrahydrofuran). c) 4,5-dihydro-1-methyl-8- (3-pyridinyloxy)-
1H-thieno [3,4-g] indazole-6-carboxamide: In the same manner as in Reference Example 1f), 4,5-dihydro-1-methyl-8- (3-
Pyridinyloxy) -1H-thieno [3,4-g] indazole-6-
The title compound (yield: 91%) was obtained as colorless prism crystals from the carboxylic acid. Melting point: 124-125 ° C (recrystallization solvent: tetrahydrofuran-isopropyl ether).

Example 1 240 mg of Compound A and 60 mg of dipalmitoylphosphatidylcholine (manufactured by Wako Pure Chemical Industries) were dissolved in 3 mL of chloroform. 75 mL of distilled water was added thereto, and the mixture was vigorously shaken and stirred for 10 minutes in a closed system to obtain an O / W emulsion. 225 mL for this O / W emulsion
Of distilled water was added thereto, and the mixture was shaken lightly by hand. Then, chloroform was distilled off under reduced pressure using a rotary evaporator for about 1 hour to solidify. The obtained suspension was wet-sieved with a mesh having a size of 75 μm. The resulting suspension was sieved and centrifuged by a centrifuge to collect the precipitate. The collected precipitate was suspended in a small amount of distilled water, and the resulting suspension was freeze-dried to obtain spherical fine particles coated with compound A by a phospholipid. The result of observing the morphology with a scanning electron microscope (SEM) is shown in FIG. The average particle size of the obtained fine particles measured by a Coulter counter was 15 μm. The content of Compound A was measured by high performance liquid chromatography to be 97%.

Example 2 160 mg of Compound A and 40 mg of dipalmitoylphosphatidylcholine (manufactured by Wako Pure Chemical Industries) were dissolved in 2 mL of chloroform. To this, 50 mL of distilled water was added, and the mixture was vigorously shaken and stirred for 10 minutes in a closed system to obtain an O / W emulsion. 150 mL for this O / W emulsion
Of distilled water was added thereto, and the mixture was shaken lightly by hand. Then, chloroform was distilled off under reduced pressure using a rotary evaporator for about 1 hour to solidify. The obtained suspension was wet-sieved with a mesh having a size of 75 μm. 24 mg of mannitol was added to the suspension obtained by sieving and dissolved, and the mixture was freeze-dried to obtain a mixture of spherical fine particles coated with phospholipid of compound A and mannitol. The result of observing the morphology with a scanning electron microscope (SEM) is shown in FIG. The average particle size of the obtained fine particles measured by a Coulter counter was 12 μm. The content of Compound A was measured by high performance liquid chromatography and found to be 70%.

Test Example 1 The phospholipid-coated fine particles obtained in Example 1 were evaluated for their kinetics in blood. 0.52 spherical fine particles obtained in Example 1
mg (0.5 mg as compound A) and 2.59 mg
(2.5 mg as compound A) in a dispersion medium [2.5% (w
/ V) sorbit, 0.9% (w / v) sodium chloride, 0.1% (w / v) rheodol, 0.5% (w / v)
v) Carmellose sodium and 0.0715% (w
/ V) Distilled water containing disodium phosphate] were suspended in 10 µL and 50 µL, respectively, and injected into the knee joint of the left leg of a 6-week-old male SD rat under diethyl ether anesthesia (n = 5 each). Thereafter, blood was collected over time from the tail vein, serum was separated, and the concentration of Compound A in the serum was determined by enzyme immunoassay (EI
Measured in A). The change in serum concentration is shown in [FIG. 3], and the kinetic parameters in blood are shown in [Table 1]. As is clear from FIG. 3, it was confirmed that Compound A was continuously released from the phospholipid-coated fine particles. As is evident from Table 1, C _max and AUC showed linearity between the two doses, and the release did not change with the dose.

[0189]

[Table 1] Tmax: Time to reach maximum blood concentration Cmax: Maximum blood concentration AUC: Area under blood concentration BA = (AUC of coated fine particles) / (AUC of solution)

Example 3 285 mg of Compound A and 15 mg of dipalmitoylphosphatidylcholine (manufactured by Wako Pure Chemical Industries) were dissolved in 3 mL of chloroform. 75 mL of distilled water was added thereto, and the mixture was vigorously shaken and stirred for 10 minutes in a closed system to obtain an O / W emulsion. This O / W type emulsion is 150m
An aqueous solution in which 480 mg of mannitol was dissolved in L of distilled water was added, and the mixture was slightly shaken by hand. Then, chloroform was distilled off under reduced pressure using a rotary evaporator over about 1 hour. The obtained suspension was wet-sieved with a mesh having a size of 75 μm. The suspension obtained by sieving is freeze-dried,
A mixture of spherical fine particles coated with compound A with a phospholipid and mannitol was obtained. The average particle size of the obtained fine particles measured by a Coulter counter was 11 μm.

Example 4 100 mg of the compound of Reference Example 4 and 25 mg of distearoylphosphatidylcholine (Nippon Seika) were dissolved in 10 mL of chloroform. 25
0 mL of distilled water was added, and the mixture was vigorously shaken and stirred in a closed system for 10 minutes to obtain an O / W emulsion. A 50 mg / 250 mL mannitol aqueous solution was added to the O / W emulsion, and the mixture was lightly shaken by hand. Then, chloroform was distilled off under reduced pressure using a rotary evaporator over about 1 hour.
This suspension was wet-sieved with a mesh having a size of 75 μm. The suspension obtained by sieving was further evaporated under reduced pressure to dryness. Water was added to this to redisperse to 2 mL. The suspension was subjected to high-pressure steam sterilization (121 ° C., 20 minutes) in a sealed container to obtain rod-shaped phospholipid-coated fine particles.
The content of the compound of Reference Example 4 was 42 mg / mL as measured by high performance liquid chromatography.

Example 5 A powder of 100 mg of the compound of Reference Example 13 was prepared.
25 mg of distearoyl phosphatidylcholine was dispersed in 1 mL of chloroform solution. To this, 25 mL of distilled water was added, and the mixture was vigorously shaken and stirred for 10 minutes in a closed system to obtain an S / O / W emulsion. This S / O
After adding a 50 mg / 25 mL aqueous solution of mannitol to the / W emulsion and shaking lightly by hand, chloroform was distilled off under reduced pressure over about 1 hour using a rotary evaporator. This suspension was wet-sieved with a mesh having a size of 75 μm. The suspension obtained by sieving was further evaporated under reduced pressure to dryness. Water was added to this to redisperse to 2 mL. The suspension is autoclaved in a sealed container (121
(C, 20 minutes) to obtain rod-shaped phospholipid-coated fine particles. The content of the compound of Reference Example 13 was measured by high performance liquid chromatography and found to be 33 mg / mL.

Example 6 90 mg of the compound of Reference Example 13 and 10 mg of distearoylphosphatidylcholine were dissolved in 1 mL of a mixed solvent of chloroform and acetic acid (9/1 (v / v)). This is 2
5 mL of distilled water was added, and the mixture was vigorously shaken and stirred for 10 minutes in a closed system to obtain an O / W emulsion. A 250 mg / 25 mL mannitol aqueous solution was added to the O / W emulsion, and the mixture was slightly shaken by hand. Then, chloroform was distilled off under reduced pressure using a rotary evaporator over about 1 hour.
This suspension was wet-sieved with a mesh having a size of 75 μm. The suspension obtained by sieving was further evaporated under reduced pressure to dryness. Water was added to this to redisperse it to 5 mL. This suspension was subjected to high-pressure steam sterilization (121 ° C., 20 minutes) in a sealed container to obtain polygonal plate-shaped phospholipid-coated fine particles. The content of the compound of Reference Example 13 was measured by high performance liquid chromatography and found to be 21 mg / mL.

Example 7 Phospholipid-coated fine particles were obtained in the same manner as in Example 4 except that the compounds of Reference Examples 1 to 3, 5 to 12 or 14 to 16 were used instead of the compound of Reference Example 4.

[0195]

EFFECT OF THE INVENTION The production method of the present invention is simple and has a high yield (the loss of the drug as a raw material and the phospholipid is small, and the incorporation rate into the final product, a phospholipid-coated water-insoluble or poorly water-soluble drug, is high). Therefore, it can be produced industrially advantageously. Furthermore, the phospholipid-coated water-insoluble or poorly water-soluble drug obtained by the production method of the present invention and the phospholipid-coated water-insoluble or poorly water-soluble drug of the present invention are safe, less irritating to administration subjects, and are water-insoluble or poorly water-soluble. Since the content of the soluble drug is high, the stability is excellent, the dispersibility in the dispersion medium is excellent, and the drug has a sustained release effect, an excellent pharmaceutical preparation can be provided.

[0196]

[Brief description of the drawings]

FIG. 1 shows a view of a spherical fine particle of compound A coated with a phospholipid obtained in Example 1 by a scanning electron microscope.

FIG. 2 shows a diagram obtained by a scanning electron microscope of a mixture of spherical fine particles of compound A coated with phospholipid and mannitol, obtained in Example 2.

FIG. 3 shows a phospholipid-coated compound A obtained in Test Example 1.
5 shows the results of measurement of changes in the serum concentration of fine particles. -○-is 0.
The change in serum concentration of Compound A at a dose of 5 mg / rat is shown, and-●-shows the change in serum concentration of Compound A at a dose of 2.5 mg / rat.

Claims (13)

[Claims] An aqueous solvent containing a water-insoluble or poorly water-soluble drug and a phospholipid and an aqueous solvent are mixed and emulsified, and the organic solvent is removed from the obtained emulsion. A method for producing a pharmaceutical composition comprising a poorly water-soluble drug and a phospholipid. 2. The method according to claim 1, wherein the phospholipid is used in an amount of about 0.1 to about 1000 parts by weight based on 100 parts by weight of the water-insoluble or poorly water-soluble drug. 3. The method according to claim 1, wherein the aqueous solvent is water. 4. The method according to claim 1, wherein the organic solvent is a halogenated hydrocarbon. 5. The method according to claim 1, wherein the water-insoluble or poorly water-soluble drug has a solubility in water at 20 ° C. of about 0 to about 1 mg / mL. 6. The method according to claim 1, wherein the volume of the aqueous solvent is about 1 to about 1000 times the volume of the organic solvent solution containing the water-insoluble or poorly water-soluble drug and the phospholipid. 7. A pharmaceutical composition produced by the production method according to claim 1. 8. The pharmaceutical composition according to claim 7, which is an injection. 9. The pharmaceutical composition according to claim 8, which is a non-intravascular injection. 10. A phospholipid-coated water-insoluble or poorly water-soluble drug having an average particle diameter of about 1 to about 150 μm, wherein the weight ratio of the water-insoluble or poorly water-soluble drug to the phospholipid is about 100: 1 to about 10. 11. The phospholipid-coated water-insoluble or poorly water-soluble drug according to claim 10, which is used for joint administration. 12. The method according to claim 12, wherein the water-insoluble or poorly water-soluble drug is of the formula (I): [Wherein ring A represents an optionally substituted benzene ring, R
Represents a hydrogen atom or a hydrocarbon group which may be substituted,
B represents a carboxy group which may be esterified or amidated, X represents -CH (OH)-or -CO-, k represents 0 or 1, and k 'represents 0, 1 or 2. Or a salt thereof. 13. A water-insoluble or sparingly water-soluble drug,
Formula (Ia):[Wherein, R^1aIs an optionally substituted hydrocarbon
Elemental residue, heterocyclic group, sulfinyl group, sulfonyl group, water
Represents an acid group, a thiol group or an amino group;^2aIs sheer
Group, formyl group, thioformyl group or formula: -Z^1a
-Z^2a(Where Z ^1aIs -CO-, -CS-, -SO
-Or -SO_Two-, Z^2aAre replaced respectively
A hydrocarbon residue, a heterocyclic group, a hydroxyl group or an
Shows a mino group. ) Represents a group represented by the following formula:
An optionally substituted 5- to 7-membered ring,^aIs a hydrogen atom,
Or a halogen atom, a cyano group or each substituted
Good amino group, acyl group, hydrocarbon residue or heterocyclic ring
A group represented by R^aIs the ring constituent of the thiophene ring and the ring Ca
Hydrocarbon ring or heterocyclic optionally substituted with
A ring may be formed. Or a salt thereof
The method according to claim 1, wherein