WO2001089521A1 - Medicinal compositions containing thiophene derivatives - Google Patents

Abstract

Medicinal compositions allowing a physiologically active substance (drug), which has an effect of promoting osteogenesis and chondrogenesis, to stably act over a long time at an affected part. These medicinal compositions contain compounds represented by the following general formula (Ia) or salts thereof together with a biodegradable polymer compound: (Ia)

Description

 Description Technical composition containing thiophene derivative

 The present invention relates to a novel pharmaceutical composition containing a thiophene derivative and a biodegradable polymer compound, particularly to a medicament or composition for preventing or treating bone disease or cartilage disease. Background art

It is known that the incidence of osteoarthritis and rheumatoid arthritis due to articular cartilage degeneration has a strong correlation with age, and the number of patients is increasing due to the recent aging of the population. Despite clinical symptoms such as marked pain, lameness, and limited range of motion when these articular cartilage diseases progress, pain relief with anti-inflammatory drugs such as steroids, protection of articular cartilage with hyaluronic acid, etc. Is conservatively treated and is not intended to regenerate damaged cartilage (Latest Department of Internal Medicine, Nakayama Shoten, Vol. 74, 77-94, 265-272, 1995) . In addition, like these articular cartilage diseases, osteoporosis is increasing toward an aging society, and the frequency of occurrence of osteoporosis-related limb fractures is increasing remarkably. It is known that in vivo, peptide bioactive substances such as bone morphophogetic protein (BMP) promote the healing of bone fractures (Procedureing National Academia Science, USA (Proceeding National Academy Science USA), Vol. 87, pp. 2220-2224, 1990). However, such peptidic substances are rapidly metabolized in vivo and are physicochemically or biologically unstable. In recent years, various non-peptidic bone and cartilage formation promoting substances which are expected to be able to overcome these points have been proposed. In addition, since these disease sites are limited to a local site such as a fracture site or a joint, a physiologically active substance (drug) having a bone and cartilage formation promoting effect is stably applied to the disease site for a long period of time. A pharmaceutical composition is required. Furthermore, by using such a non-peptide bone / chondrogenesis promoting substance together with a biodegradable polymer as a pharmaceutical composition, especially a sustained-release agent, a long-lasting effect of the medicinal component can be expected. Japanese Patent Application Laid-Open No. 9-263545 (WO 96/39134) discloses an attempt to use a non-peptide bone / chondrogenesis promoting substance together with a biodegradable polymer as a pharmaceutical composition, especially a sustained release agent. A pharmaceutical composition comprising a non-peptide bone promoting substance and a biodegradable polymer compound is described. Further, Japanese Patent Application Laid-Open No. 2000-72678 (WO 99/65474) describes a sustained-release preparation for preventing and treating cartilage diseases, comprising a benzozopine derivative or the like and a biodegradable polymer compound. On the other hand, examples of the drug used in the pharmaceutical composition of the present invention include a condensed benzothiophene derivative represented by the general formula (I) .A compound having a condensed benzothiophene derivative as a basic skeleton is described in the following literature. ing.

 Maybridge, Inc. (Trevillett, Tintagel, North

4,5-Dihydro-8- (methylthio) isoxazo mouth [5,4-d] based on the company's product catalog (Vol. 241, published October 1991) distributed by Cornwall, PL34 OHW, UK ] Benzo [c] thiophene-6-carboxamide [4,5-dihydro-8-Unethy 丄 thiono isoxazolo [5,4 ~ d] benzo [c] thienophene-6-carboxami de] is available.

 JP-A-8-245386 discloses 4,5-dihydro-8_ (methylthio) isoxosazolo [5,4-d] benzo [c] thiophene-6-carboxamide [4,5_dihydro-8-unethylthio) isoxazolo [5 , 4-d] benzo [cj thienophene-6-carboxamide] A cell differentiation-inducing factor action enhancer comprising a representative compound is described.

 Japanese Patent Application Laid-Open No. 10-130271 (WO 98/09958) discloses that osteoporosis, bone fracture, osteoarthritis, osteoarthritis, Fused thiophene compounds useful for the prophylactic treatment of bone diseases such as rheumatoid arthritis, arteriosclerosis, cancer metastasis and diseases based on neurodegeneration are described.

Furthermore, GB-A-2336589, WO 99/6425 and Condensed thiophene derivatives are described in Liebigs Ann. 1996, pp. 239-245. Disclosure of the invention

 The present invention provides a pharmaceutical composition, a production method, and a use thereof, in which a physiologically active substance such as a substance for promoting bone cartilage formation, for example, is locally applied, and the effect is maintained for a long period of time. The present inventors have conducted various studies to solve the above-mentioned problems and the like. As a result, a thiophene derivative or a salt thereof represented by the following general formula (la) having a characteristic of ring A, It has been found that a pharmaceutical composition containing a molecular compound is a very useful pharmaceutical composition from the viewpoint of sustained release and controlled release of the thiophene derivative, and as a result of further studies, the present invention has been completed. Reached. That is, the present invention

 (1) General formula (la)

[Wherein, R ¹ 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, and R ² represents a cyano group, a formyl group. , A thioformyl group or a formula: one Z ¹ —? ² (wherein, Z represents —CO—, —CS—, —SO— or one S 0 ₂ —, and Z ² is each independently substituted Represents a good hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group.) Represents a group represented by), ring A a represents an optionally substituted 5- to 7-membered ring, R represents a hydrogen atom or a halogen Atom, cyano group or amino group, each optionally substituted, acyl And R represents a thiophene ring or a ring-constituting atom of the ring Aa, and may form a hydrocarbon or heterocyclic ring. ] A pharmaceutical composition comprising a compound represented by the formula or a salt thereof and a biodegradable polymer compound.

 (2) — the general formula (I a) is

General formula (I)

 [Wherein ring A is

(In the formula, R ³ represents a hydrogen atom, a hydrocarbon residue which may be substituted, a heterocyclic group, a hydroxyl group, an amino group, a sulfonolene group or an acyl group.) Group 5 represents a 5-membered heterocyclic ring; ring B represents a 5- to 7-membered hydrocarbon ring which may have a substituent; ).

 (3) The pharmaceutical composition according to the above (1), wherein the biodegradable polymer conjugate is an aliphatic polyester.

 (4) The pharmaceutical composition according to the above (3), wherein the aliphatic polyester is a lactic acid-glycolic acid copolymer.

(5) The lactic acid-glycolic acid copolymer is a lactic acid-glycolic acid copolymer having a composition ratio of lactic acid / glycolic acid of about 100/0 to 4060 (molar ratio). The pharmaceutical composition according to any one of the preceding claims. (6) The pharmaceutical composition according to the above (13), wherein the weight average molecular weight of the lactic acid-glycolic acid copolymer is about 3,000 to 50,000.

 (7) The pharmaceutical composition according to the above (1), which is a preparation for topical administration.

 (8) The pharmaceutical composition according to the above (1), which is a preparation for intra-articular administration.

 (9) The pharmaceutical composition according to the above (1), which is a sustained-release preparation.

 (10) The pharmaceutical composition according to the above (1), which is an agent for preventing or treating bone disease or cartilage disease.

 (11) The pharmaceutical composition according to the above (10), wherein the bone disease is a fracture or a bone defect.

(12) The pharmaceutical composition according to the above (10), wherein the cartilage disease is osteoarthritis.

(13) The pharmaceutical composition according to the above (9), wherein the sustained-release preparation is a microcapsule.

(14) The compound according to the above (1), wherein the compound represented by the general formula (Ia) or a salt thereof is removed from the organic solvent solution containing the biodegradable polymer compound. A method for producing a pharmaceutical composition.

 (15) The above-mentioned (14), wherein the organic solvent is one or a combination of two or more selected from halogenated hydrocarbons, ethers, fatty acid esters, aromatic hydrocarbons, alcohols, acetonitrile and lower fatty acids. Manufacturing method.

 (16) The method according to the above (14), wherein the organic solvent is a halogenated hydrocarbon and a lower fatty acid. (1) If the above general formula is (1), explanations of various definitions included in the scope of the present invention and preferable examples thereof will be described below.

R ¹ 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.

May be substituted in R ¹ ! Examples of the hydrocarbon residue in the hydrocarbon residue include an optionally substituted aliphatic hydrocarbon residue, an alicyclic hydrocarbon residue, an alicyclic monoaliphatic hydrocarbon residue, and an aromatic And a hydrocarbon residue or an aromatic monoaliphatic hydrocarbon residue (an aralkyl group). Examples of the aliphatic hydrocarbon residue include methyl, ethyl, propyl, isopropylinole, puynole, isobutynole, sec-pentinole, tert-butynole, pentinole, isopentinole, neopentyl, tert-pentinole, hexyl, isohexyl, C 1-8 saturated aliphatic hydrocarbon residues (eg, alkyl group) such as heptyl and octyl, for example, vinyl, aryl (allyl), 1-propenyl, 2-methyl-1-propenyl, 1 —Petinore, 2—Betini / le, 3—Betinore, 3—Methinore 21—Putnore, 1—Pentinore, 2—Pentinole, 3—Pentenigre, 4—Pentenole , 4-1 Mechinore 1-Penteninole, 1-Hexeninole, 2-Hexeninole, 3-Hexeninole, 4-1 Hexeninole, 5-Hexeninole, 2, 4-1 Hexeninole, 1 _Hepter, 1-octeninole, Echininole, 1—Propiel, 2-Propininole, 1-Petinole,

2-Petinole, 3-Petinole, 1-Pentinyl, 2-Pentinole, 3-Pentinole, 4-Pentinole, 1-Hexnorre, 2_Hex / Le, 3-Hexnole , 4-hexyne, 5-hexyne, 2,4-hexazininole, 1-heptininole, 1-octynyl and other unsaturated aliphatic hydrocarbons having 2 to 8 carbon atoms (eg, alkenyl group, alkynyl group , An alkadiyl group, an alkadiyl group, etc.). Examples of the alicyclic hydrocarbon residue include a saturated alicyclic hydrocarbon residue having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Alkyl group, etc.), 1-cyclopentenyl, 2-cyclopenteninole, 3-cyclopenteninole, 1-cyclohexeninole, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2 —Cycloheptur,

C3-C7 unsaturated alicyclic hydrocarbon residues (e.g., cycloalkenyl group, cycloalkadiele group, etc.) such as 3-cycloheptur, 2,4-cyclohexheptageninole, 1-indenyl, 2-Indul, 1-Indanole, 2-Indanyl, 1,2,3,4-Tetrahydro-1-naphthyl, 1,2,3,4-Tetrahydro-2-naphthyl, 1,2-Dihydro-1-naphthyl, 1 Partial saturation of 1,2-dihydro-1-naphthyl, 1,4-dihydro-1-naphthinole, 1,4-dihydro-12-naphthinole, 3,4-dihydro 1-naphthyl, 3,4-dihydro-2-naphthyl Fused bicyclic. Hydrocarbon residue [preferably C. - Partially saturated condensation Bicyclic hydrocarbon residue, etc. (5 And a 6-membered non-aromatic cyclic hydrocarbon group to which a benzene ring is bonded)]. Examples of the alicyclic monoaliphatic hydrocarbon residue include those in which the above alicyclic hydrocarbon residue is bonded to an aliphatic hydrocarbon residue, for example, cyclopropylmethyl, cyclopropylethyl, cyclopeptinolemethy. Nole, Cyclobutylethyl, Pennopenmethyl methyl, 2-cyclopenteninolemethinole, 3-pennopeninolemethinole, Pennopenetinole, Cycopeninolemethinole, 2-cyclohexeninole Methynole, 3-cyclohexeninolemethyl, siky hexylethyl, siky heptylmethinole, siky heptylethyl, 2- (3,4-dihydro_2-naphthyl) ethyl, 2-(1,2,3, 4 Tetorahi chondroitinase 2 Nafuchinore) Echiru, 2 - (3, 4-dihydro-2-naphthyl) Hetu Le such as those with carbon number 4-1 4 (eg, C ₃ _ ₇ cycloalkyl group C ₃ - ₇ consequent opening alkenyl primary alkyl group, C ₃ - ₇ consequent opening alkyl one C ₂ - ₄ alkenyl group, C ₃ _ ₇ consequent opening alkenyl one C ₂ -. ₄ alkenyl, C _M partially saturated fused bicyclic hydrocarbon one CH alkyl group, C ₉ -, etc. ₁₀ partially saturated fused bicyclic hydrocarbon one C ₂ _ ₄ alkenyl group). Examples of the aromatic hydrocarbon residue include phenyl, 1-naphthyl, β-naphthyl, 4-indeninole, 5-indur, 41-indaninole, 5-indaninole, 5,6,7,8-tetrahydro-1-naphthyl , 5,6,7,8-tetrahydro-1-naphthyl, 5,6-dihydro-11-naphthyl, 5,6-dihydro-12-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro 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 14-naphthyl. Examples of the aromatic monoaliphatic hydrocarbon residue include benzyl, phenethyl, 1-phenylenoletinol, 1-phenylinolepropizole, 2-phenylinolepropinole, and phenyl CHalkyl such as 3-phenylinolepropyl. Aralkyl groups having 7 to 14 carbon atoms, such as naphthinolealkyl groups such as naphthylmethyl, naphthylethyl, β-naphthylmethyl, and β-naphthylethyl; Ali-Lu C Archi ), For example, styryl, cinnamyl and the like C ₂ _ ₄ alkenyl groups. Aryl C ₂ _ ₄ alkyl group and the like.

The heterocyclic group of the optionally substituted heterocyclic group for R ¹ includes, for example, (i) a 5- to 7-membered heterocyclic ring containing l sulfur atoms, one nitrogen atom or one oxygen atom. A group, (ii) a 5- to 6-membered heterocyclic group containing 2 to 4 nitrogen atoms, or (iii) a 5- to 6-membered atom containing 1 to 2 nitrogen atoms and one sulfur or oxygen atom (Iv) these heterocyclic groups are condensed with a 5- to 6-membered ring containing 2 or less nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom, and . The heterocyclic groups exemplified in (i) to (iv) may each be a saturated or unsaturated heterocyclic group, and the unsaturated heterocyclic group may be either aromatic or non-aromatic. You may.

Examples of the heterocyclic group in the optionally substituted heterocyclic group for R ¹ 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 ¹ include: (i) an aromatic monocyclic heterocyclic group (eg, furyl, cheel, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl) , Imidazolyl, virazolinol, 1,2,3-oxadiazolyl, 1,2,4 monooxadiazolyl, 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, pyragel, triazinyl, etc.), (ii) fused aromatic heterocyclic group (eg, Benzofuranyl, isobenzofuranyl, benzo [b] thenyl, indolyl, isoindolyl, 1H-indazo Ril, benzimidazolyl, benzoxazolyl, 1,2-benzothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolyel, quinoxalinyl, phthalazinole, naphthyridinyl, prinyl, pteridinyl, kyrpazolinyl Hi-Ripolininole, β-Ruporinil, γ-Carbolyl, Athalidinyl, Phenoxazinyl, Phenothiazinyl, Phenazil, Phenoxatiinyl, Thiantreel, Phenoanthrinyl, Phenoantorinil, Indolidinyl, Pyro [1,2-b] pyridazinyl, Pyrazo [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] pyridazi-nore, imidazo [1,2-a] pyrimidinyl, 1,2, 4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl, etc.) and (iii) non-aromatic heterocyclic groups (eg, oxilanyl, azetidul, oxetanyl) , Cetanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazyl and the like.

In R ^1, as the Surufieru group in substituted optionally Surufieru may be based, "hydrocarbon residue" in "each optionally substituted hydrocarbon residue or heterocyclic group" as R ¹ mentioned above or " Heterocyclic group ”and one SO— bonded to each other.

 Preferably, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butynole, tert-petitinole, pentinole, isopentinole, neopentinole, tert-pentinole, hexinole, isohexinole, heptyl, octyl, etc.

- 8 alkyl and Surufieru group bonded to C i _ ₈ alkyl sulfides El; Fueyu Le, shed one naphthyl, / 3-naphthyl, 4-indenyl, 5-Indeyuru, 4 one ^ emissions Daninore, 5-indanyl, 5, 6 , 7,8-Tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 5,6-dihydro_1-naphthyl, 5,6—Dihydro-1-naphthyl, 5,6-dihydro _ 3-naphthyl, 5, C _6, such as 6-dihydro eleven naphthyl - i 0 Ariru group and Sunorefi - C ₆ _ i where Le group is bonded. Aromatic monocyclic heterocyclic group (eg, furyl, cheel, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, virazolyl, 1,2,3-oxoxadiazolyl, 1,2,4- Oxadiazolyl, 1,3,4-thiaxazolyl, furazal, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolinole, 1,2,4— Triazolyl, tetrazolyl, pyridyl, pyrimidur, pyridazyl, A group in which a sulfinyl group is bonded to a pyrazinyl or triazinyl group; an aromatic condensed heterocyclic group (eg, benzofuranyl, isobenofurael, benzo [b] chenyl, indolinole, isoindolinole, 1H-indazolyl, benzimidazolinole, benzoin Oxazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalininole, phthalazinyl, naphthyridinyl, prill, pteridinyl, carbazolyl, α-caprolitolinole , Β-force vorinore, _γ- force vorinore, atarigenore, fenoxazinyl, phenothiazinyl, fenazinyl, fenoxathiinyl, thianthrenyl, phenanthrezinole, fenant mouth-lininole, indolizinino Pyro [1,2—b] pyridazinyl, pyrazo [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, etc.) and a sulfinyl group.

More preferably, methyl, ethyl, propyl, isopropyl, butyl, isobutynole, sec-butyl, tert-butynole, pentynole, isopentyl, neopent chinole, tert-pentyl, hexinole, isohexynole, heptinole, octynole, etc. Bok ₈ alkyl and sulfinyl group bonded C ^ 8 alkylsulfinyl can be mentioned up.

In R ^1, it is a sulfonyl group in the optionally sulfonyl group which may be substituted, the above-mentioned as R ¹ of the "each substituted or substituted hydrocarbon residue which may have heterocyclic group", "hydrocarbon residue" Or those in which a “heterocyclic group” and one so ₂ — are bonded.

 Preferably, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butylinole, tert-pentinole, pentyl, isopenpentole, neopentinole, tert-pentyl, hexinole, isohexyl / heptyl, octynole, etc.

_ ₈ C i _ with alkyl and sulfonyl groups bonded. Alkylsulfonyl; fuel, a-Naphthyl, β-Naphthyl, 4-Indeninole, 5-Indeninole, 4_indanil, 5-Indanyl, 5,6,7,8-Tetrahydro-1-naphthinole, 5,6,7,8-Tetrahydro-2-naphthinole, 5, 6-dihydro-1 one Nafuchinore, 5, 6 dihydric draw 2-naphthyl, 5, 6-dihydro-one 3-naphthyl, 5, 6- dihydro 4-naphthyl C ₆ _ i such. C ₆ — i 0 arylsulfoyl bonded with aryl and sulfonyl groups; aromatic monocyclic heterocyclic group (eg, furyl, chenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, villa Zolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4 A group in which a thiadiazolyl, 1,2,3_triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidiel, pyridazinyl, pyrazyl, triazinyl, etc.) are bonded to a sulfonyl group; an aromatic fused heterocyclic group (eg, Benzofurur, Isobenzofural, Benzo [b] Chenyl, Indolyl, Isoindolyl, 1H-Indazolyl, Benzoimidazolyl, benzoxazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalininole, phthalazinyl, naphthyridinyl, prinyl, pteridininole, carbazolyl, carbazolyl , Β-carbinole, γ-carborenole, ataridinil, phenoxazinyl, phenothiazinyl, fenazidinole, fenoxathiinyl, thianthrenyl, phenanth resinyl, phenanthine linyl, indolinidinyl, pyrrodine [1,2-b] pyridinyl , Pyrazo mouth [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridaziel, imidazo [1,2_a] pyridi Le, imidazo [1,5—a] pyridi , 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, etc.) and a sulfo group.

More preferably, methyl, ethyl, propyl, isopropyl, butyl, isobutynole, sec-butyl, tert-butyl, pentynole, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc. C E _ ₈ alkylsulfonyl C _ ₈ alkyl and sulfonyl group is bonded in the cited et it is.

In R ^1, as the hydroxy group which may be substituted, hydroxyl group and optional substituents on the hydroxyl group, for example, "respectively optionally substituted carbon hydrocarbon residue or heterocyclic group represented by R ¹ And a hydroxyl group substituted by ".

Preferably, substituted with C- ₈ alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butynole, tert-butylinole, pentyl, isopentyl, neopentinole, tert-pentyl, hexinole, isohexyl, heptyl, octyl and the like. _8- alkyloxy; phenyl, α-naphthyl, 1-naphthyl, 4-indur, 5-indenyl, 4-indanyl, 5-indanil, 5,6,7,8-tetrahydro-l-naphthyl, 5,6, 7,8-tetrahydro-1-naphthinole, 5,6-dihydro-1-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-1 41 C ₆ _i, such as Nafchinore. Substituted with an aryl group. Aryloxy; aromatic monocyclic heterocyclic group

(E.g., furyl, chenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadazolyl, 1,3,4-oxadiazolyl, frazanil, 1 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolinole, tetrazolinole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinole, triazinyl Hydroxyl group substituted with an aromatic fused heterocyclic group (eg, benzofuranyl, isobenzofuryl, benzo [b] thenyl, indolyl, isoindolyl, 1H-indazolinole, benzoimidazolyl, benzoxazolyl, 1, 2 —Benzisothiazolyl, 1 H-benzotriazo Ril, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prynyl, pteridinyl, rubazolyl, α-caprolporinyl, 8-carporyl, γ-carboryl, ataridinini ^^, fenoxinieni ^ /, Phenazidinore, phenoxathiinyl, thianthrenyl, phenanthryl, phenanthrinyl, indolidine Nil, Pyro mouth [1,2—b] pyridazinyl, Birazolo [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- Hydroxyl groups substituted with triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl, etc. can be generated.

More preferably, C ₆ —e. A hydroxyl group substituted with aryloxy (particularly preferably phenyl) or an aromatic monocyclic heterocyclic group (particularly preferably pyridyl) or an aromatic fused heterocyclic group (particularly preferably quinolyl) is exemplified.

 "Hydrocarbon residue" as a substituent of the substituted hydroxyl group exemplified here or

The “heterocyclic group” is the same substituent as the “hydrocarbon residue” or the “heterocyclic group” in the “optionally substituted hydrocarbon residue or heterocyclic group” as R ¹ described above. You may have each. In R ^1, as the thiol group that may be substituted, an appropriate substituent, for example, represented by R ¹ 'may be substituted hydrocarbon residue or heterocyclic group to a thiol group and a thiol group And a thiol group substituted with Preferably, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butylinole, tert-butylinole, pentinole, isopenpentole, neopentinole, tert-pentinole, hexyl, isohexyl, heptyl, octyl and the like. E

- C ₈ substituted by ₈ alkyl alkylthio; phenyl, alpha-naphthyl, beta-naphthyl, 4 one Indeyuru, 5 _ Indeyuru, 4 one indanyl, 5-indanyl, 5, 6, 7, 8-tetrahydro-one 1-naphthyl , 5,6,7,8-tetrahydro-1-naphthyl, 5,6-dihydro-1-naphthinole, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro-4-naphthyl, etc. Noje

C ₆ — i substituted with 0 aryl group. Arylthio; aromatic monocyclic heterocyclic group (eg, furyl, cyenyl, pyrrolyl, oxazolinole, isoxoxolinole, thiazolinole, isotizazolyl, imidazolyl, pyrazolyl, 1,2,3-oxaziazolyl, 1,2,4-oxaziazolyl , 1,3,4_oxadizazolyl, frazanil, 1,2, 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolinole, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazil, triazinyl, etc. Thiol group; aromatic fused heterocyclic group (eg, benzofurayl, isobenzofuranyl, benzo [b] chenyl, indolinole, isoindolyl, 1H-indazolinole, benzoimidazolinole, benzoxazolyl, 1,2-benzoisothiol Azolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalininole, phthalazinyl, naphthyridinole, prenyl, pteridinyl, rubazolyl, a-only rupolynil, β-ylpolylinyl, y-ylpolylinyl, atalyline Zinyl, phenoxazininole, phenothiazinyl, phenazidinore, fenoxathiinyl, thiantreninole, phenanthrezinole, phenanthrinyl, indolizyl, pyro [1,2—b] pyridazyl, virazolo [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] pyrimidel, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4, 3-b] pyridazinyl etc.).

The “hydrocarbon residue” or “heterocyclic group” as the substituent of the substituted thiol group exemplified here is the above-mentioned “optionally substituted hydrocarbon residue or heterocyclic group” as R ^1. It may have the same substituent as the “hydrocarbon residue” or the “heterocyclic group” in the “group”.

More preferably, methyl, ethyl, propyl, isopropyl, butyl, isobutynole, sec butynole, tert-butyl, pentynole, isopenpentole, neopentyl, tert-pentyl, hexyl, isohexyl, heptinole, octynole, etc. include C i _ ₈ alkylthio substituted with ₈ alkyl.

Examples of the amino group which may be substituted in R ¹ include an amino group, an N-monosubstituted amino group and an N, N-disubstituted amino group. The location is a substituted amino group, for example, be optionally substituted hydrocarbon group substituted (e.g., represented by R ¹ Those similar to the conversion to hydrocarbons may be residues, more specifically, C _M alkyl group, c ₃ _ ₇ cycloalkyl, c ₂ _ ₈ alkenyl, c ₂ _ ₈ alkynyl group, c ₃ — ₇ may have a cycloalkenyl group or a CH alkyl group. Aryl), an optionally substituted heterocyclic group (for example, the same as the optionally substituted heterocyclic group represented by R ¹ ), or a compound represented by the formula: R ′ represents a hydrogen atom or a hydrocarbon residue or a heterocyclic group which may be substituted, respectively, wherein “a hydrocarbon residue or a heterocyclic group which may be respectively substituted” as R ′ Has the same substituent as the “hydrocarbon residue” or “heterocyclic group” in the above-mentioned “hydrocarbon residue or complex ring group which may be substituted” as R, respectively. ), Preferably c _w . Ashiru group (e.g., c ₂ _ ₇ Arukanoiru, Benzoiru, Nikochinoiru etc.), amino group (e.g. having a one or two substituents, Mechiruamino, Jimechiruamino, Echiruamino, Jechiruamino, dipropionate Piruamino, Jibuchiruamino, Jiariruamino, the consequent opening Xylamino, phenylamino, N-methyl-1-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinylamino and the like.

 Further, two groups in the substituted amino group may combine to form a nitrogen-containing 5- to 7-membered ring (for example, piperidino, morpholino, thiomorpholino, etc.).

“Hydrocarbon residue”, “heterocyclic group”, “sulfur group” in “hydrocarbon residue, heterocyclic group, sulfier group, sulfol group, which may be substituted” represented by R ¹ Group "and" sulfonyl group "are:! May be substituted with up to three substituents. Examples of the substituent include a lower (C alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl) , pentyl, isopentyl, neopentyl, hexyl, etc.), lower (C ₂ - ₆₎ alkenyl [e.g., Bulle, Ariru (allyl), 1-propenyl, 2 one methyl one 1 one propenyl - le, 1 - 2-butenyl, 2-butenyl, 3-methyl-2-butul, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenole, 4-methynole , 1-hexeninole, 2-hexene-nore, _3- hexenyl, 4-hexenyl, 5-hexenyl, etc.], lower (C ₂ _ ₆ ) alk Nyl groups (eg, ethur, 1-probul, 2-probul, 1-butynyl, 2-butul, 3-butynyl, 1-pentul, 2-pentul, 3-pentul, 4-pentinole, 1-hexynole, 2 to Kishunore, 3- to carboxymethyl two Honoré, key shell to 4, such as hexynyl to 5-), C ₃ _ ₇ cycloalkyl group (e.g., cyclopropyl, cyclohexyl Shikuropuchinore, consequent opening pentyl, consequent opening, cyclo the like heptyl), C ₆ _ ₁₀ Ariru group (e.g., phenyl, alpha-naphthyl, such as single-naphthyl), aromatic Hajime Tamaki [e.g., furyl, thienyl, pyrrolyl, Okisazoriru, isoxazolyl, thiazole Lil, isothiazolyl, imidazolyl, Pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazadinore, 1 2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazur, triazir -Benyl, benzofuranyl, isobenzofuranyl, benzo [b] thenyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothi Azolyl, 1H—benzotriazolyl, quinolyl, isoquinolinole, cinnolinyl, quinazolinyl, quinoxalinyl, phthalagel, naphthyridinyl, prenyl, pteridyl, carpazolinole, CK—norevolyl, nitrocarolinolyl, _γ -arenopolyribonyl , Phenoxazininole, phenothiazinole, fenajur, phenoxatiinyl, thiantreninole, pentanitole-le, phenatrolinyl, indolininole, pyro [1,2-b] pyridaziel, pyrazo [1,5-a] pyridyl, Imidazo [1,2—a] pyridinole, imidazo [1,5—a] pyridyl, imidazo [1,2—b] pyridazinyl, imidazo [1,2—a] pyrimidinyl, 1,2,4-triazo mouth [4 , 3—a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazi-nore, etc. (i) Aroma with 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur A 5- or 6-membered heterocyclic group, (ii) an aromatic 5- or 6-membered heterocyclic ring having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a benzene ring or a nitrogen atom; Oxygen atom Fused bicyclic heterocyclic group in which an aromatic 5- or 6-membered heterocyclic 瘃 having 1-3 hetero atoms selected from sulfur atom to form condensed, (iii) ①Aromatic 5- or 6-membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, ②benzene ring and ③selected from nitrogen atom, oxygen atom and sulfur atom Condensed tricyclic heterocyclic group formed by condensing an aromatic 5- or 6-membered heterocyclic or benzene ring having 1 to 3 heteroatoms], a non-aromatic heterocyclic group (eg, oxilael, azetidur, oxetanyl) A 4- to 7-membered member having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur such as cetanyl, pyrrolidyl, tetrahydrofuryl, thiolaninole, piperidinyl, tetrahydropyrael, morpholinyl, thiomorpholinyl, and piperazil. non-aromatic heterocyclic group, etc.), C ₇ _ ₁₄ Ararukiru group (example, benzyl, phenethyl, 1 one Fueniruechiru, 1 one Hue - Propyl, 2-phenylpropyl, 3 _ phenylpropyl, alpha-Na Fuchirumechiru one Nafuchiruechiru, beta one naphthylmethyl, etc.. Ariru one C _W alkyl groups such as beta one naphthylene Honoré ethyl Honoré), amino group, N- monosubstituted amino group [e.g., Mechiruamino, Echiruamino, Ariru (allyl) amino, cyclohexyl amino, N- (C ^ ₆ alkyl) amino groups such as Fueniruamino, N- (C ₂ _ ₆ Al Keninore) amino group, N _ (C ₃ - ₇ Shikuroanorekiru) amino group, N-- like (〇 _{6 10} Ari) amino groups], N, N-disubstituted amino group [e.g., Jimechiruamino, Jechiru amino, Jibuchiruamino, Jiariru (allyl) amino, such as N- methyl-one N- Fueyu Ruamino, C alkyl, C ₂ _ ₆ alkenyl, C ₃ _ ₇ cycloalkyl Contact and C ₆ - _1. An amino group substituted with two substituents selected from an aryl group, etc.), an amidino group, an acyl group (e.g., formyl, acetyl, propioyl, butyryl, isobutyryl, valeryl, isopaparyl, pino) Roinore to, Kisanoiru, Heputanoinore, Okutanoiru, cyclopropanecarboxamide two Honoré, cyclobutanecarbonyl, cyclopentyl emissions tanker Honoré Boni Honoré, hexane Kano levo Nino les to consequent opening, Kurotonoinore, key sensor carbonyl to 2-cyclopropyl, Benzoiru, C ₂ such Nikochinoiru _ ₈ Arukanoiru group, C ₃ one ₈ § Rukenoiru group, C ₃ _ ₇ cycloalkyl one carbo - group, C _{3 "7} Shikuroaruke - Lou force Lupo group, Ariru -. carbo - group, nitrogen atom, oxygen 5- or 6-membered aromatic or aromatic having 1 to 3 heteroatoms selected from atoms and sulfur HiKaoru such aromatic heterocyclic ring-carbonyl heterocyclic one carbonyl group group formed by combining), the force Rubamoiru group, N- monosubstituted force Rubamoiru group [e.g., methyl Scarpa moil, Echiru Power Rubamoiru, alkoxy carbamoyl cyclohexane, such as such as phenylene carbamoyl N - alkyl) force Rubamoiru group, N- (C _{2 "6} Aruke - Le) force Rubamoiru group, N- (C ₃ - ₇ cycloalkyl) force Rubamoiru group , N— (C.aryl) carbamoyl group, etc.], N, N—disubstituted rubamoyl group [eg, dimethylcarbamoyl, dimethylcarbamoyl, dibutylcarbamoyl, diallylcarbamoyl,

N- methyl-one N- Hue - such as carbamoyl, C ^ ₆ alkyl group, C ₂ _ ₆ alkenyl Le group, C ₃ _ ₇ consequent opening alkyl Contact Yopi C _M. A sulfamoyl group substituted with two substituents selected from aryl groups, a sulfamoyl group, an N-monosubstituted sulfamoyl group [eg, methylsulfamoinole, ethylsulfamoinole, cyclohexylsulfamoyl, Hue - N- alkyl) sulfa carbamoyl groups such Rusurufamoiru, N- (C ₂ - ₆ alkenyl) sulfamoyl, N- (C ₃ - ₇ cycloalkyl Honoré) sulfamoyl group, N - (C ₆ - ₁₀ Ariru) sulfamoyl group, etc. ], N, N over-disubstituted sulfamoyl group [e.g., dimethylsulfamoyl, Jefferies chill sul Famo I le, dibutylsulfamoyl, Jiariru (allyl) sulphamoyl, such as N- methylcarbamoyl Lou N- Hue acylsulfamoyl, ₆ alkyl group, C ₂ _ ₆ Arukeeru group,

C ₃ _ ₇ cycloalkyl group and C ^. Sulfamoyl group substituted with two substituents selected from aryl groups, etc.), carboxyl group, lower (C) alkoxy-unrebonyl group (eg, methoxycarbol, ethoxycarbonyl, propoxycarbinole, isopropoxyca ^^ bon / le, putoxycanolevone, isobutoxyka ^^ boninole, sec-butoxycarbonyl, tert-butoxycanoleboninole, pentinoleoxycarbonyl, hexyloxycarbonyl, etc.), hydroxyl group, lower ( C, _ ₆ ) Alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, ΐert-butoxy, pentinoreoxy, hexyloxy, etc.), lower (C ₂ _ ₆₎ ) Arke-loxy group [eg, allyl oxy, 2-butyroxy, 2-pente / Reokishi, to 3 such as Kiseninoreokishi],

C ₃ _ ₇ cycloalkyl O alkoxy group (e.g., cyclopropyl O alkoxy, cyclobutyl O alkoxy, cyclopentyloxy Ruo alkoxy, cyclohexane Kishiruokishi, cyclohexylene, etc. Puchiruokishi)

C ₆ — K) aryloxy group (eg, phenoxy, naphthyloxy, etc.), C ₇ _ ₁₄ 7 ral cheloxy group (eg, phenyl alkyloxy, naphthyl-CM alkylo C ₆ _i such as shore. Aryl, CM alkyloxy, etc.), mercapto, lower

(C ^) alkylthio group (e.g., methylthio, Echiruchio, propylthio, isopropoxy port Pinorechio, Puchinorechio, Isobuchinorechio, sec Buchinorechio, tert- flop Chiruchio, pentylthio, Isopenchiruchio, neopentylthio, the like cyclohexylthio), C _M4 Ararukiruchio group (e.g. Phenyl-CH alkylthio, naphthyl-cw alkylthio, etc. cw. Aryl-cw alkylthio group, etc.), cw. Arylthio group (e.g., phenylthio, naphthylthio, etc.), lower (c ^) alkyl sulfier group (e.g., methylsulfinyl, ethylsulfinyl, propylsulfyl, isopropylsulfiel, butylsulfiel, etc.) Sopuchirusurufi cycloalkenyl, sec- Petit Rusuru sulfinyl, tert- Petit Luz Honoré Fi El, Penchinore Sunorefininore, isopentyl Roh less Honoré Fini Honoré, neopentyl zone less Honoré Fi two Honoré, the like carboxymethyl Rusurufieru), C ₇ _ ₁₄ § Lal kill sulfinyl group (e.g., phenylene Lou CH § Ruki Angeles sulfide El, etc. 〇 _{6-1 10} § Li one Le one C _W alkylsulfinyl group such Nafuchiru CH alkylsulfide El), C ₆ _ _1Q § reel sulfide El group (e.g., Hue Nils sulfide El and naphthylsulfinyl), lower (C preparative ₆₎ alkyl Snorrehoninole group (eg, methinoresinolehoninole, ethylsulfur, propylsnolehoninole, isopropylsnolephonyl, butylsulfoninole, isobutylszolephonyl, sec-butylsulfoninole, tert-butylsulfonyl, tert-butylsulfonyl, pentino Resunorehoninore, isopentyl Nchirusuruhoniru, neopentyl sulfonyl, the like hexyl Sno Reho sulfonyl), C ₇ _ ₁₄ § Lal kill sulfonyl group (e.g., phenyl one CH alkylsulfonyl, C ₆ _ _1Q such Nafuchiru alkylsulfonyl C ₆ _i. Arylsulfonyl group (eg, phenylsulfonyl, naphthinolesulfoninole, etc.), sulfo group, cyano group, azide group, halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), nitro group, nitroso group, esterification A phosphono group [eg, a ( _6- alkoxy) phosphoryl group such as a phosphono group or ethoxyphosphoryl, a di (Cw alkoxy) phosphoryl group such as a diethoxyphosphoryl group], an esterified phosphono group Lower (C ^) alkyl group substituted with a di (C ^ ₆ alkoxy) phosphoryl C w alkyl group such as a phosphonoalkyl group, an alkoxyphosphorylalkyl group, and a diethoxyphosphorylmethyl group Etc.).

When a hydroxyl group and a lower (C ^) alkoxy group are adjacent to each other as a substituent, c J- ₆ alkylenedioxy such as methylenedioxy and ethylenedioxy may be formed. C _{6 →} above. The same as a substituent of an aryl group, an aromatic heterocyclic group, or an N-monosubstituted amino group. C _6-1 as a substituent of an aryl group or an N, N-disubstituted amino group. Aryl group and N-monosubstituent. Aryl group, a, N-disubstituted carbamoyl group as a substituent. As a substituent of an aryl group or an N-monosubstituted sulfamoyl group. Aryl, the same as a substituent of an N, N-disubstituted sulfamoyl group. Aryl group, c ₆ — i. In aryloxy group. Ariru group, in 〇 ₇ _ ₁₄ § Rarukiruokishi group. Aryl group, C ₇ — C ₆ _i in ₁₄ Aralkyl group. Free radical group,. C ^ in arylthio group. Ariru group, c ₇ - ₁₄ § Lal kills sulfinyl in Le group. Ariel group,. In the arylsulfinyl group. Ariru group, C ₇ _ _½ § Lal kills in sulfonyl group. Aryl group, and C. C ₆ — i in arylsulfonyl group. The aryl group may be further substituted with 1 to 3 substituents. Examples of the substituent include a lower (C ^) alkyl group, an amino group, an N- (Cwalkyl) amino group, , N- di (Cw alkyl) amino group, amidino group, a force Luba moil group, N- _(C-6 alkyl) force Rubamoiru group, N, N- di (〇 DOO ₆ alkyl) force Rubamoiru group, a sulfamoyl group, N -Alkyl) sulfamoyl group,

N, N-di (〇 DOO ₆ alkyl) sulfamoyl group, a carboxyl group, a lower (C ₂ - ₇₎ alkoxycarbonyl group, a hydroxyl group, a lower alkoxy group, a mercapto group, a lower (C ^) alkylthio group, a sulfo group, Shiano group An azido group, a halogen atom, a nitro group, a nitroso group, an optionally esterified phosphono group [eg, a phosphono group, a _6- alkoxyphosphoryl group, a di (Cw alkoxy) phosphoryl group, etc.]; (Cw) alkyl group substituted with a good phosphono group

[Example, phosphono primary alkyl group, alkoxy phosphoryl primary alkyl group, and di (C ^ ₆ alkoxy) phosphoryl one Cw al kill groups such as jet alkoxy phosphoryl methyl], and the like. Among the above substituents, a hydroxyl group and a lower (CJ alkoxy group as a substituent, when the contact may form a cw § Rukirenjiokishi such Mechirenjiokishi Oyopi Echirenjiokishi. R ¹ is preferably Represents an optionally substituted sulfier group, sulfel group, hydroxyl group or thiol group, that is, R ¹ is a group represented by the formula: _SR ¹⁴ , -SOR ¹⁴ , —SO ₂ R ¹⁴ or one OR ¹⁴ (wherein R ¹⁴ represent, respectively, an optionally substituted hydrocarbon residue or heterocyclic group.) in the group represented by the formula. here in substituted "may be substituted respectively represented by R ¹⁴ even good charcoal hydrocarbon residue "is configured as a force R ¹⁴ which are the same as those for" each optionally substituted hydrocarbon Motozanmoto or heterocyclic group "represented by R ¹ TansoHara A group having 2 or more is preferable, and a cyclic group which may be substituted is more preferable, and an aromatic group which may be substituted (more preferably, a nitrogen-containing heterocyclic ring which may be substituted ) Is preferred.

R ¹ ′ is, among the optionally substituted hydrocarbon residue, heterocyclic group, sulfyl group, sulfonyl group, hydroxyl group, thiol group or amino group, a formula: 1 X, 1 W (wherein, X ′ represents a bond, an optionally substituted carbon atom, an optionally substituted nitrogen atom, an oxygen atom or an optionally sulfur atom, and W ′ may be substituted A cyclic group or a carbon atom or a nitrogen atom having two or more substituents.).

In R ¹ ′, an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group may be an optionally substituted hydrocarbon residue as R ^1. Group, heterocyclic group, sulfinyl group, sulfonyl group, hydroxyl group, thiol group or amino group.

In R ¹ ′, the formula: 10Χ, 1 W, (wherein X is a bond, an optionally substituted carbon atom, an optionally substituted nitrogen atom, an oxygen atom or an oxidized Represents a sulfur atom, may be substituted, and represents a cyclic group or a carbon atom or a nitrogen atom having two or more substituents.) In the group represented by Carbon atom "means two carbon atoms and one hydrogen atom A divalent group having an atom and one substituent or two substituents, and "optionally substituted nitrogen atom" represented by X 'is a hydrogen atom or a substituted nitrogen atom Shows a divalent group having a group. The substituent may be a substituent that the “hydrocarbon residue” or “heterocyclic group” in the above “optionally substituted hydrocarbon residue or heterocyclic group” as R ¹ has And R ¹ include the same groups as the “optionally substituted hydrocarbon residue or heterocyclic group”.

The “sulfur atom which may be oxidized” represented by X ′ is one s _, S O— or one

It represents a divalent sulfur atom represented by S 0 ₂ —.

As the "cyclic group" in the "carbon atom or a nitrogen atom to have a substituted cyclic group or may have two or more substituents" represented, even "substituted respectively by the R ¹ described above A cyclic group in the `` good hydrocarbon residue or heterocyclic group '', for example, an optionally substituted alicyclic hydrocarbon residue, an optionally substituted aromatic hydrocarbon residue, and an optionally substituted And a heterocyclic group (aromatic monocyclic heterocyclic group, aromatic condensed heterocyclic group, non-aromatic heterocyclic group). The substituent which the “cyclic group” may have is R. ^{The same} substituents as the “hydrocarbon residue” or “heterocyclic group” in the “hydrocarbon residue or heterocyclic group which may be substituted” as 1 may be mentioned. .

The “carbon atom having two or more substituents” in the “optionally substituted cyclic group or carbon atom or nitrogen atom having two or more substituents” represented by W is, for example, tert-butyl, isopropyl And the same or different 2 to 3 substituents are bonded to the carbon atom as described above (in other words, those having 0 to 1 hydrogen atom on the atom are mentioned. as "hydrocarbon residue" or "heterocyclic group" substituent Contact Yopi R ¹ which may have the in "each optionally substituted by hydrocarbon residue or heterocyclic group" as R ¹ which is And the same groups as those described above for “a hydrogen residue or a heterocyclic group which may be substituted”.

The nitrogen atom having two or more substituents is an N, N-disubstituted amino group. Examples of the substituent in the “N, N-disubstituted amino group” include the same substituents as the “amino group I” in the “optionally substituted amino group” for R ¹ described above. No.

R ¹ ′ is, among the optionally substituted hydrocarbon residue, heterocyclic group, sulfinyl group, sulfonyl group, hydroxyl group, thiol group or amino group, a formula: one X, one W (wherein, X 'Represents an oxygen atom or a sulfur atom which may be oxidized, and represents a cyclic group which may be substituted.) Is a group represented by the following formula:

R ² is a cyano group, a formyl group, a thioformyl group or a formula: one Z ¹ —? ² (wherein Z ¹ represents one CO—, one CS—, one SO— or one S0 ₂ —, and Z ² represents Represents an optionally substituted hydrocarbon residue, a heterocyclic group, an amino group or a hydroxyl group.

Z ¹ in R ² is preferably one CO— or one CS—, more preferably one CO—.

R ² is represented by one CO—Z ² ′ (wherein, Z ² ′ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, an amino group, or a hydroxyl group). The group is preferred.

The optionally substituted hydrocarbon group which may be substituted in Z ^2, for example, are you Keru substituted R ¹ Les, be good Le, the same as the hydrocarbon residue. The optionally substituted hydrocarbon residue in Z ² is preferably an aliphatic hydrocarbon residue, more preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isopti / re, sec And saturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms (eg, alkyl) such as -butyl, tert-butyl, pentyl, isopenpentyl, neopentynole, tert-pentyl, hexyl, isohexynole, heptinole, and octyl. . .

Examples of the optionally substituted heterocyclic group for Z ² include the same as the optionally substituted heterocyclic group for R ¹ . Examples of the optionally substituted amino group for Z ² include, for example, the same as the optionally substituted amino group for R ¹ . Of substitution at Z ² Examples of the optionally substituted amino group preferably include an amino group and an amino group having one or two C w alkyl groups as substituents (eg, methylamino, dimethinorealamino, ethylamino, getylamino, dibutylamino, etc.). .

The hydroxy group which may be substituted in Z ^2, for example, those similar to the even better hydroxyl optionally be substitution in R ^1. The optionally substituted hydroxyl group in Z ² is preferably a hydroxyl group, and methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butylinole, pentinole, isopentyl, neopentyl, neopentyl, tert-pentyl , Kishinore, hexyl I Seo, heptyl, is C _i-8 alkyl Ruokishi substituted with 〇 ^ ₈ alkyl such Okuchiru like to.

It may also be Z ² is is a an amino group or substituted or optionally substituted in R ² les is preferably a hydroxyl group. In R ² Z ² is amino group which may be substituted more preferred. Especially, Z ² in R ² is Amino group or an amino group having a C i_ ₈ Arukinore group as one or two substituents, (e.g., Mechiruamino, Jimechiruamino, Echiruamino, Jechiruamino, Jibuchiruamino etc.) are preferable.

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

Examples of the optionally substituted hydrocarbon residue in R ³ include, for example, the same as the optionally substituted hydrocarbon residue in R ¹ . The hydrocarbon residue which may be substituted in R ³ is preferably an aliphatic hydrocarbon residue, more preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isoptizle, sec-butyl, tert-butyl, Examples thereof include saturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms (eg, alkyl group) such as pentinole, isopentinole, neopentinole, tert-pentyl, hexinole, isohexinole, heptinole, and octyl.

The heterocyclic group which may be substituted in R ^3, for example, in R ¹ The same thing as the heterocyclic group which may be substituted is mentioned.

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

Examples of the optionally substituted amino group for R ³ include the same as the optionally substituted amino group for R ¹ .

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

The optionally substituted acyl group for R ³ is preferably, for example, a group in which the `` optionally substituted hydrocarbon residue or heterocyclic group '' represented by R ¹ is bonded to a carbonyl group. the hydrocarbon residue represented by R ^1, heterocyclic group, sulfinyl group, those similar to the Ashiru group as a substituent of the sulfonyl group levator only ^ is.

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

As the hydrogen atom of R ³ ′, an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfonyl group or an acyl group, the hydrogen atom of R ³ , an optionally substituted hydrocarbon residue, Examples include the same as a ring group, a sulfonyl group or an acyl group.

R ³ ″ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfol group or an acyl group.

R ³ 'each optionally substituted hydrocarbon group which may be substituted ", a heterocyclic group, the Sunorehoniru group or Ashiru group, each optionally substituted hydrocarbon group which may be substituted R ^3, a heterocyclic group, sulfonyl And the same as the above-mentioned groups or acyl groups.

R ⁴ represents a substituted hydroxyl group.

The substituted hydroxyl group for R ⁴ may be a substituted hydroxyl group represented by R ¹ A substituted hydroxyl group in an optionally substituted hydroxyl group, e.g., an appropriate substituent for the hydroxyl group, e.g., a `` substituted hydrocarbon residue or heterocyclic group which may be substituted '' represented by R ¹ Hydroxyl group.

Preferably, methyl, Echiru, propyl, isopropyl, heptyl, Isopuchiru, sec- heptyl, tert- Puchinore, Penchinore, Isopenchinore, neopentyl, tert one Penchinore to, Kishinore, the I Soviet Kishinore, to Puchinore, old Kuchinore etc. - ₈ C ^ ₈ alkyloxy substituted with alkyl; phenyl, α-naphthyl, β-naphthinole, 4-indur, 5-indur, 4-indanole, 5-indanil, 5,6,7,8-tetrahydro-11-naphthyl , 5,6,7,8-tetrahydro-1-naphthinole, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-13-naphthyl, 5,6-dihydro C such as one 41 naphthyl

₆ _ E. C ₆ — substituted with an aryl group. Aryloxy; aromatic monocyclic heterocyclic groups (eg, furyl, phenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isotizazolyl, imidazolyl, pyrazolyl, 1,2,3-oxazidiazolyl, 1,2,4- Oxaziaziolinole, 1, 3, 4 Oxaziaziolinole, Frazanil,

1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, Hydroxyl group substituted with pyrazur, triazinyl, etc.); aromatic condensed heterocyclic group (eg, benzofurayl, isobenzofuranyl, benzo [b] phenyl, indolyl, isoindolyl, 1H-indazolyl, benzoimidazolyl, benzoxazolyl) , 1,2-Benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolyl, quinazolyl, quinoxalinyl, phthalazinole, naphthyridinole, purinyl, pteridinyl, lipazolyl, a-caprolitol , Β-Riporinil, Ippiruperiel, Atari Phenoxazinyl, phenothiazinyl, fenadur, fenoxathiinyl, thianthrenyl, phenanthrininole, phenanthrinyl, indolidyl, pyrol [1,2-b] pyridazyl, virazolo [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] pyrimidyl, 1,2,4-triazolo [4,3-1a] pyridyl, 1,2,4-triazolo [4,3-1b ] Pyridazinyl, etc.).

 More preferably, alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptinole, octinole, etc. Substituted alkyloxy; more preferably substituted with methyl, ethyl, propyl, isopropyl. ^ 3 alkynoleoxy.

 "Hydrocarbon residue" as a substituent of the substituted hydroxyl group exemplified here or

The “heterocyclic group” may be the “hydrocarbon residue” or the “heterocyclic group” in the aforementioned “optionally substituted hydrocarbon residue or heterocyclic group” as R ^1. V, each of which may have the same substituent as the substituent. R ⁵ represents the optionally substituted sulfinyl group or snorlefur group in R ¹ .

R ⁶ has the same meaning as the substituted or substituted thiol group in R ¹ .

R ⁷ has the same meaning as the substituent of the optionally substituted amino group in R ¹ . R ⁸ has the same meaning as R ² .

R ⁹ has the same meaning as Z ² above.

R ^1G represents a protecting group for a lipoxyl group. The carboxyl protecting group represented by R ^{1 0,} for example, include substituted similar such as substituted hydrocarbon residue which may have groups shown in R ^1. R ¹¹ represents an amino group which may be substituted.

The amino group which may be substituted in R ^{1 1,} the same amino group which may be substituted represented by R ^1, for example, an amino group, N- mono-substituted amino group Contact and New, Nyu- Disubstituted amino groups. 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 ¹ , more specifically, ₈ alkyl group, C._ ₇ consequent opening Anorekiru group, C ₂ _ _s alkenyl, C ₂ _ ₈ alkynyl group, C ₃ _ ₇ cycloalkenyl group, which may have an alkyl group C _{6 →.} An aryl group), an optionally substituted heterocyclic group (for example, the same as the optionally substituted heterocyclic group represented by R ¹ ), or a compound represented by the formula: Represents a hydrogen atom or a hydrocarbon residue or a heterocyclic group which may be substituted, respectively, wherein the “hydrocarbon residue or heterocyclic group which may be respectively substituted” as R ′ is as defined above. R ′ has the same substituent as the “hydrocarbon residue” or “heterocyclic group” in the “optionally substituted hydrocarbon residue or heterocyclic group” as R ′ or.), preferably C _H0 Ashiru group (e.g., C ₂ _ ₇ Arukanoiru, Benzoiru, two Kochinoiru etc.), an amino group (e.g. having a one or two substituents, Mechirua amino, Jimechiruamino, Echiruamino, Jechiruami , Puropiruamino, Jipu port Piruamino, Jibuchiruamino, Jiariruamino, Kishiruamino cyclohexane, Hue Niruamino, N- methyl-N- Fueniruamino, Asechiruamino, propionyl Amino, Benzoiruamino, nicotinyl Noi Rua amino, etc.). More preferably, an N, N-disubstituted amino group (eg, dimethylamino, getylamino, dipropylamino, dibutylamino, diarylamino, N-methyl-1-N-phenylamino, etc.) is more preferable, and N, N-diC ^ is more preferable. ₃ alkylamino groups (eg, dimethylamino, getylamino, dipropylamino, 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, monoreholino, thiomorpholino, etc.).

R ¹³ represents an optionally substituted amino group or a substituted hydroxyl group. The R ^{1 3,} include the same groups as the R ⁴ or the R ^{1 1.} R ¹³ ′ represents an optionally substituted amino group or hydroxyl group. R ¹³ ′ includes a 7k acid group, R ⁴ and the same groups as R ¹¹ .

X represents a halogen atom such as fluorine, chlorine, bromine, and iodine

Z ⁵ indicates one CO—.

Z ⁶ has the same meaning as the optionally substituted amino group in Z ² . Z ⁷ indicates one CO—.

z ⁸ has the same meaning as the optionally substituted hydrogen residue or heterocyclic group in z ² . Ring Aa represents a 5- to 7-membered ring which may be substituted.

 The optionally substituted 5- to 7-membered 5- to 7-membered ring in ring Aa 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. As the alicyclic ring, C ₅ - ₇ saturated alicyclic hydrocarbon ring (e.g., cyclopentane, hexane cyclo, c ₅ _ ₇ cycloalkane such as cycloheptane) and C ₅ _ ₇ unsaturated alicyclic Aromatic hydrocarbon ring (eg, 1-cyclopentene, 2-cyclopentene, 3-cyclopentene, 1-cyclohexene, 2-cyclohexene, 3-cyclohexene, 1-cycloheptene, 2-cycloheptene, 3-cycloheptene , 2, C ₅ _ ₇ consequent opening alkenes such Putajen like to 4 consequent opening, and a C ₅ _ ₇ cycloalkadienes). Examples of the aromatic ring include a benzene ring.

Examples of the 5- to 7-membered heterocyclic ring include (i) a 5- to 7-membered heterocyclic ring containing one sulfur atom, one nitrogen atom or one oxygen atom, and (ii) two to four-membered heterocyclic ring. A 5- to 7-membered heterocyclic ring containing a nitrogen atom, or (iii) a 5- to 7-membered heterocyclic ring containing one or two nitrogen atoms and one sulfur or oxygen atom is exemplified. Further, the heterocyclic rings exemplified in (i) to (iii) may be saturated or unsaturated heterocyclic groups, respectively. The unsaturated heterocyclic ring may be any of aromatic and non-aromatic. Is also good. Particularly preferred as the ring Aa is an aromatic 5-membered heterocyclic ring represented by the following ring A. As the optionally substituted 5- to 7-membered ring substituent in ring Aa, an optionally substituted hydrocarbon residue represented by R ³ , a heterocyclic group, a hydroxyl group, an amino group, Examples are the same as the sulfonyl group or the acyl group. Ring A is

(Wherein, R ³ 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.) Is shown. Ring A is

(Wherein, R ³ has the same meaning as described above.)

R 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 which may be substituted, R may be substituted together with the ring-constituting atoms of the thiophene ring and the ring Aa! / May form a hydrocarbon ring or a heterocyclic ring.

Examples of the optionally substituted amino group for R include, for example, the same as the optionally substituted amino group for R ¹ .

Examples of the optionally substituted acyl group for R include the same as the optionally substituted acyl group for R ³ . Examples of the optionally substituted hydrocarbon residue in R include, for example, the same as the optionally substituted hydrocarbon residue in R ¹ .

The heterocyclic group which may be substituted in R, for example, location for R ¹ The same thing as the heterocyclic group which may be substituted is mentioned.

The optionally substituted hydrocarbon ring formed by R together with the thiophene ring and the ring-constituting atoms (preferably ring-constituting carbon atoms) of ring Aa may be alicyclic or aromatic. Further, the hydrocarbon ring is preferably a 5- to 14-membered ring, and more preferably a 5- to 7-membered ring. The hydrocarbon ring is preferably a hydrocarbon ring represented by the following ring B. Ring B represents a 5- to 7-membered hydrocarbon ring which may have a substituent.

The 5- to 7-membered hydrocarbon ring of the 5- to 7-membered hydrocarbon ring which may have a substituent in ring B is an alicyclic or aromatic 5- to 7-membered hydrocarbon ring, Is also good. The alicyclic 5-7 membered hydrocarbon ring, C ₅ - ₇ saturated alicyclic hydrocarbon ring (e.g., cyclopentane, hexane consequent opening, C ₅ _ ₇ Shikuroaruka emissions such Sik port heptane) and C ₅ _ ₇ unsaturated alicyclic hydrocarbon ring (for example, 1-cyclopentene, 2-cyclopentene, 3-cyclopentene, 1-cyclohexene, 2-cyclohexene,

Cyclohexene 3-cyclopropyl, 1 Shiku port heptene, 2-sik port heptene, heptene to 3 consequent opening, 2, 4- C ₅ _ ₇ cycloalkene such as butadiene cyclohexane, C ₅ _ ₇ consequent opening Anorekajien) etc. Is mentioned.

 Examples of the aromatic hydrocarbon residue include a benzene ring.

Preferably, C ₅ _ ₇ saturated alicyclic hydrocarbon ring, or more preferably C ₆ saturated alicyclic hydrocarbon ring (cyclohexane).

R is preferably a 5- to 14-membered heterocyclic ring which may be substituted with a thiophene ring and a ring-constituting atom of ring Aa (preferably, a ring-constituting carbon atom), and more preferably It is 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; To 7-membered heterocyclic ring, or (iii):! To 5 to 7-membered heterocyclic ring containing two nitrogen atoms and one sulfur or oxygen atom. The heterocyclic rings exemplified in (i) to (iii) may be either saturated or unsaturated, and the unsaturated heterocyclic groups may be aromatic or non-aromatic. It may be. Having substituents on rings B, B-1, C, D, D-2, D-3, D-4, D, D, -1, D'-2, D, -3 Examples of the substituent of the 5- to 7-membered hydrocarbon ring include those similar to the substituent of the “optionally substituted hydrocarbon residue” in R ¹ . As the substituent of the 5- to 7-membered hydrocarbon ring which may have a substituent in ring B, preferably an aliphatic hydrocarbon residue is used, and more preferably, for example, methyl, ethanol, propyl, isopropyl , Butyl, isoptyl, sec-butyl, tert-butynole, pentynole, isopenpentole, pentosepentinole, tert-pentyl, hexyl, isohexyl, heptyl, octyl and other saturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms (Eg, an alkyl group). Rings B, B—1, C, D, D-2, D—3, D—4, D, D, —1, D, one 2, D, —3, even if they have ^ ¾ It represents a good 5- to 7-membered hydrocarbon ring, preferably a 5- to 7-membered hydrocarbon ring having no substituent. 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 exemplified. In the above formula (Ia), a compound represented by the formula (I) is preferable.

In the above formula (I), R ¹ is an optionally substituted sulfinyl group, sulfonyl group, hydroxyl group or thiol group; R ² is one Z i — Z ² (where Z ¹ is

Represents CO— or one CS—, and Z ² represents a substituted or unsubstituted hydroxyl group or an amino group. ); Ring A is

[Wherein, R ³ has the same meaning as described above. A compound or a salt thereof, in which ring B is a 5- to 7-membered hydrocarbon ring which may have a substituent. In the above formula (I), R ¹ is each substituted with an alkyl-bound sulfier group or sulfonyl group, a thiol group optionally substituted with Ci-s alkyl, or substituted with 1 to 3 substituents, respectively. May be C ₆ — i. Ariru (particularly preferably phenyl), an aromatic monocyclic Hajime Tamaki (particularly preferably pyridyl) or an aromatic fused Hajime Tamaki (particularly preferably quinolyl) optionally hydroxyl group which may be substituted with; is R ² , -Τ ^χ -ζ ² (wherein ζ ¹ represents one co—, and z ² represents an optionally substituted hydroxyl group or an amino group, respectively); Ring A:

[Wherein, R ³ has the same meaning as described above. Wherein R ³ is a saturated aliphatic hydrocarbon residue having 1 to 8 carbon atoms (eg, an alkyl group); and a compound or a salt thereof, wherein ring B is a C ₅ _ ₇ saturated alicyclic hydrocarbon ring, preferable. As the compound represented by the general formula (I),

4, 5 - dihydro - ⁸ - ^(2, 3 - dimethyl phenoxyethanol) -1- (2, 2, 2-triflate Ruo Roe chill)-1H-Cheno [3, 4-g] Indazo Ichiru - 6- Colepoxamide;

 4,5-dihydro-1-methyl-8- (3,4-methylenedioxyphenoxy) -1H-thieno [3,4-g] indazoinole-6-carboxamide;

 8- (4-benzyloxyphenoxy) -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazol-6-propanolamide;

4-{[6- (aminocarbonyl) -2-methyl-4,5-dihydro-1H-thieno [3,4-g] indazo mono-8-inole] 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-caprolupoxamide; 4,5-dihydro-: l-methyl-8-phenoxy-1H-thieno [3,4-g] indazonole-6-carboxamide;

 4-{[6- (aminocarbonyl) -1-methyl-4,5-dihydro-1H-thieno [3,4-g] indazole-8-inole] oxy} benzylphosphonic acid ethyl ester;

4,5-dihydromethyl-8-phenylsulfanyl-1H-thieno [3,4-g] indazole-6-carboxamide;

4,5-dihydro-8- (3,4-methylenedioxyphenoxy) -1- (2,2,2-trifluoroethyl)-1H-cheno [3,4-g] indazole- ⁶ -carboxami Do;

4,5-dihydroxymethyl-8- (4-trifluoromethoxyphenoxy) -1H-thieno [3,4-g] indazole-6-carboxamide; or

N-Ethyl-4,5-dihydro-trimethyl_8_ (3,4-methylenedioxyphenoxy) -1H-thieno [3,4-g] indazole-6-carboxamide is preferred. In the formula (II), R ¹ is an optionally substituted sulfiel group, sulfonyl group, hydroxyl group or thiol group; R ² is one Z i— Z ² (where Z ¹ is one CO— or One CS—, Z ² each represents a substituted or unsubstituted hydroxyl group or an amino group.); R ⁴ is an alkyloxy; and ring C may have a substituent. Compounds that are hydrocarbon rings or salts thereof are preferred. In the formula (II), R ¹ is a sulfiel group or a sulfonyl group bonded with alkyl, a thiol group optionally substituted with alkyl, or 1 to 3 substituents, respectively. May be C ₆ — i. Ariru (especially rather preferably phenyl), an aromatic monocyclic Hajime Tamaki (particularly preferably pyridyl) or aromatic Zokuchijimigo Hajime Tamaki (particularly preferably quinolyl) hydroxyl group which may be substituted with; is R ^2, One Z ¹ —Z ² (wherein, Z ¹ represents one CO—, and Z ² each represents an optionally substituted hydroxyl group or an amino group); R ⁴ is C alkyloxy; C ₅ _ ₇ is a saturated compound is alicyclic hydrocarbon ring, or a salt thereof is more preferable. In the present invention, a compound represented by the formula (Ia) [hereinafter referred to as compound (Ia). ] Or The salt of the raw material compound for producing the salt 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, basic or And salts with acidic amino acids. Preferred examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salts, ammonium salts and the like. . Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, jetanolamine, triethanolamine, dicyclohexylamine, Ν, Ν′-dibenzylethylenediamine and the like. And salts thereof. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, triflic acid / leoacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include salts with sulfonic acid, ρ-toluenesulfonic acid, and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin and the like. Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, glutamic acid, and the like. Salts. Compound (Ia) or a salt thereof may be a prodrug thereof. A prodrug of compound (I) or a salt thereof is a compound that is converted into compound (Ia) or a salt thereof by a reaction with an enzyme or stomach acid under physiological conditions in a living body, that is, (1) enzymatic oxidation, reduction, or hydrolysis. A compound that undergoes decomposition or the like to change to compound (la) or a salt thereof, and (2) a compound that undergoes hydrolysis or the like by gastric acid or the like to change to compound (la) or a salt thereof. As a prodrug of the compound (la) or a salt thereof, a compound or a salt thereof (for example, a compound in which a hydroxyl group of the ligate compound (la) or a salt thereof is acylated, alkylated, phosphorylated, or borated) , A compound or a salt thereof in which the hydroxyl group of the compound (la) or a salt thereof is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarponinole, or the like. ), A compound in which the carboxyl group of the compound (la) or a salt thereof is esterified or amidated (for example, the compound (la) or the salt thereof Ethyl esterification, phenyl esterification, carboxyoxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyshethyl esteranol, phthalidyl ester (5-Methyl-1-oxo-1,3-dioxolen-1-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound or its salt, etc. Can be These prodrugs can be produced according to a method known per se or a method analogous thereto. .

Further, the prodrug of compound (Ia) or a salt thereof can be prepared under the physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs,” Vol. It may change to its salt. The compound (la) or a salt thereof in the present invention may be labeled with an isotope (eg, ² H, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.). When the compound used in the present invention or a salt thereof has a double bond in the molecule and has a Z or E configuration, each of them or a mixture thereof is included in the compound used in the present invention. included.

 When the compound used in the present invention or a salt thereof has a stereoisomer due to having an asymmetric carbon in the molecule or the like, the positional deviation of each of them or a mixture thereof is also included in the compound used in the present invention. It is. Hereinafter, the method for producing the compound used in the present invention will be described.

 The compound (la) or a salt thereof can be prepared by a method known per se (for example, see JP-A-2000-3).

09591, the method described in JP-A-2000-239280, the method described in WO 98Z09958, the method described in JP-A-2000-169470, and the method described in JP-A-2000-169471. The method described in JP-A-2000-

169472, etc.) or a method analogous thereto. R is a compound (la). As in the case of a compound (I), R represents a thiophene ring and a ring A a. In the case of a compound forming a hydrocarbon ring or a heterocyclic ring which may be substituted together with a ring-constituting carbon atom, the compound (Ia) or a salt thereof is, for example, a method A to F shown below or a method analogous thereto. Can be manufactured.

[Method A]

[Wherein, compound (III) represents hydroxylamine or monosubstituted hydrazine (R ³ 'NHNH ₂ ) or a salt thereof, and other symbols have the same meanings as described above. In this reaction, compound (I) is produced by reacting compound (II) with compound (III).

 This reaction is carried out according to a conventional method, 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 hydrides such as sodium hydride, sodium hydroxide, and hydrogenation hydride, potassium t-toxide, sodium acetate, triethylamine, pyridine, 1,8-diazabicyclo [5.4.0] -7 — Organic bases such as pendecene and sodium methoxide.

 The amount of the acid compound (III) to be used is preferably about 1 to about 5 molar equivalents relative to the compound (II).

Solvents that do not adversely affect the reaction include, for example, water, methanol, ethanol, propanol, and other alcohols; ethers such as getyl ether, tetrahydrofuran, and dioxane; halogenated carbons such as chloroform and dichloromethane. Hydrogenated hydrocarbons; 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 used in a mixture at an appropriate ratio.

 The reaction temperature is generally about _50 to about 150 ° C, preferably about 0 to about 100 ° C.

 The reaction time is generally about 0.5 to about 20 hours.

R ³ ′ on ring A generated by this reaction can be converted to an optionally substituted hydroxyl group or an optionally substituted amino group described as R ³ using a method known per se. .

 The compound (I) 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. The compound (II) used as a starting compound in the above-mentioned method A is a novel compound, and the compound (IV):

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

And orthoformate. That is, for compound (IV), a known method, for example, Indian Journal of Chem. Sec. B, Vol. 35, pp. 49-51 (1996) ), 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 orthoformate used is preferably about 1 to about 10 molar equivalents.

 Examples of the acid include boron trifluoride monoethenole complex.

 The amount of the acid to be used is preferably about 1 to about 10 molar equivalents relative to compound (IV).

 Examples of the base include triethylamine, disoptylethylamine, 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 used in a mixture at an appropriate ratio.

 The reaction temperature is generally about 1100 to about 150 ° C, preferably about 170 to about 0.

 The reaction time is usually about 0.5 to about 20 hours.

 The compound (II) 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 the starting compounds, for example, the compound (I

V-1):

 H)

Is a known compound and is described in Liebigs Ann. 1996, pp. 239-245, or Synthetic Communications (Synth. Commun.) 1995, pages 2449-2455. Further, the compound (IV-2, 3) used as a starting compound of the compound represented by the amino group which may be substituted for R ¹ of the compound (I) in the above method A is produced by the following synthesis method. You.

 (Step 1) ''

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

 In this reaction, compound (V) is produced by reacting 1,3-cycloalkanedione with alkyl isothiocyanate or arylaryl 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

—Dimethylamines, 1,8-diazabicyclo [5.4.0] amides such as 7-diene; metal hydrides such as lithium hydride and sodium hydride; sodium methoxide; Alkyl metal alkoxides such as sodium methoxide and t-butoxy potassium.

 The amount of the reactant used is preferably about 1 to 3,3-cycloalkanedione.

From about 10 molar equivalents.

 The amount of the base used is preferably about 1 to about 1 based on 1,3-cycloalkanedione.

10 molar equivalents.

 The reaction temperature is usually about 150 to about 150 ° C, preferably about 0 to about 100 ° C.

 The reaction time is usually about 0.5 to about 20 hours.

Compound (V) thus obtained can be obtained by a known separation and purification means, for example, concentration, It can be isolated and purified by vacuum concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

(Process 2)

(V) (VI)

(V) (VI)

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

 In this reaction, compound (VI) is produced by reacting compound (V) with compound (VI I). This method is carried out according to a conventional method 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 ethyl acetate, ethyl bromoacetate, t-butyl bromoacetate, and the like.

 The amount of compound (VII) to be used is preferably about 1 to about 10 molar equivalents relative to compound (V).

 Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, and potassium carbonate; pyridine, triethylamine, N, N

—Dimethylaerin, 1,8-diazabicyclo [5.4.0] Amines such as vinyl chloride; metal hydrides such as hydrogen hydride and sodium hydride; sodium methoxide, sodium ethoxy And alkali metal alkoxides such as 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 getyl ether; halogenated hydrocarbons such as chlorophonolem and dichloromethane. Amides such as N, N-dimethylformamide;

Sulfoxides and the like. These solvents may be used in a mixture at an appropriate ratio.

 The reaction temperature is usually about 150 to about 150 ° C, preferably about 110 to about 100 ° C.

 The reaction time is generally about 0.5 to about 20 hours.

 The compound (VI) 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.

(Process 3)

 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 according to a conventional method, in the presence of a base, in a solvent that does not adversely influence the reaction.

 Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, and potassium carbonate; pyridine, triethynoleamine, N, N-dimethinorea diline, 1,8-diazabicyclo [5.4] [0] Amines such as amide 7-ene; metal hydrides such as hydrogen hydride and sodium hydride; metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide No.

 The amount of the base to be used is preferably about 1 to about 5 molar equivalents relative to compound (VI).

Solvents that do not adversely affect the reaction include, for example, benzene, toluene, xylene Aromatic hydrocarbons such as methane; ethers such as tetrahydrofuran, dioxane, and getyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide; and sulfoxides such as dimethinoresulfoxide And the like. These solvents may be used in a mixture at an appropriate ratio.

 The reaction temperature is usually about 150 to about 150 ° C, preferably about 110 to about 100 ° C.

 The reaction time is usually from about 0.5 to about 20 hours.

 The compound (IV-2) 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. it can.

(Process 4)

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

 In this reaction, the compound (IV-2) is acylated to produce the compound (IV-3). This method is performed using a method of appropriately reacting compound (IV-2) with an acylating agent.

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, isobutyl carbonate, and the like). Is mentioned. The amount of these acylating agents to be used is preferably about 1 to about 5 molar equivalents relative to the compound (VI-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 getyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; Amides such as N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; and the like. These solvents may be used in a mixture at an appropriate ratio.

 The reaction temperature is generally about -50 to about 150C, preferably about -10 to about 100C.

 The reaction time is usually 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. it can.

[Method B]

 (1-2) (1-1)

 [Wherein ring A is

R

を示し、 各記号は前記と同意義を有する。 〕 本法では、 ィ匕合物 (1-2) と求核試剤との反応により化合物 (1 -1) を製 造する。 本反応は、 自体公知の方法、 例えば、 W098Z18792号公報に記載の方 法、 あるいはそれに準じた方法により行われる。

And each symbol has the same meaning as described above. In this method, the compound (1-1) is produced by reacting the compound (1-2) with a nucleophilic reagent. This reaction is carried out by a method known per se, for example, the method described in W098Z18792 or a method analogous thereto.

 Examples of the nucleophilic reagent include a metal phenolate, a metal alcoholate, a Grignard reagent, an alkyl metal reagent, an aryl metal reagent, and a thioalcolate.

 The amount of the nucleophilic reagent to be used is preferably about 1 to about 5 molar equivalents relative to compound (1-2).

 Solvents that do not adversely affect the reaction include, for example, ethers such as getyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; Examples include amides such as N, N-dimethylformamide and 1-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; These solvents can be used by mixing at an appropriate ratio! / You may.

 The reaction temperature is usually about 150 to about 150 ° C, preferably about 110 to about 100 ° C.

 The reaction time is usually about 0.5 to about 20 hours.

 The compound (1-1) 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 (I 2) used as a starting compound in the above-mentioned Method B can be produced by the following method.

 (1-3) (1-2)

Wherein each symbol has the same meaning as described above. ] In this method, compound (1-2) is produced using compound (I-13) and an oxidizing agent. This reaction is carried out by a method known per se, for example, as an oxidizing agent, manganese diacid, permanganic acid, chromic acid, lead tetraacetate, halogen, ozone, hydrogen peroxide, organic peroxide, organic peracid , Sodium hydrogen monotungstate, oxygen, N-halocarboxylic acid amide, hypohalous acid ester, odosyl compound, nitric acid, dinitrogen tetroxide, dimethyl sulfoxide, ethyl azodicarboxylate, black base (III) acid, etc. This is performed by the method used, 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 influence the reaction. As the oxidizing agent, for example, m-chloroperbenzoic acid, peracetic acid and the like are preferable.

Solvents which do not adversely affect the reaction include, for example, ethers such as getyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chlorophonolem and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene. Amides such as N, N-dimethylformamide and 1-methylpyrrolidone; These solvents may be used in a mixture at an appropriate ratio.

 The reaction temperature is usually about -50 to about 150 ° C, preferably about 110 to about 100 ° C.

 The reaction time is generally about 0.5 to about 20 hours.

 The compound (1-2) 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. .

[Method C]

(1 -5) Wherein each symbol has the same meaning as described above. In this method, compound (1-5) is produced by the elimination reaction of the carboxyl protecting group. For this reaction, all conventional methods used for elimination reaction of carboxyl protecting group, for example, hydrolysis, reduction, elimination using Lewis acid and the like can be applied. When the carboxyl protecting group is an ester, it can be removed by hydrolysis or elimination with a Lewis acid. The hydrolysis can be eliminated by elimination using a base or a Lewis acid. The hydrolysis is preferably carried out in the presence of a base or an acid. Suitable bases include, for example, alkali metal hydroxide (Eg, sodium hydroxide, calcium hydroxide, etc.), alkaline earth metal hydroxides (eg, magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonates (eg, sodium carbonate, potassium carbonate, etc.) ), Alkaline earth metal carbonates (eg, magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonates (sodium bicarbonate, potassium bicarbonate, etc.), alkaline metal acetates (eg, sodium acetate, potassium acetate, etc.) ), Alkaline earth metal phosphate (eg magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate Inorganic bases such as (for example, disodium hydrogen phosphate and diammonium hydrogen phosphate), trialkylamines (eg, trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 5-Diazabicyclo [4.3.2] non-1-ene, 1,4-diazabicyclo [2.2.2] non_5-ene, 1,8-diazabicyclo [4.3.0] — Organic bases such as 7-indene. The hydrolysis using a base is often performed in water, a hydrophilic organic solvent, or a mixed solvent. Suitable acids include organic acids (eg, formic acid, hydrobromic acid, sulfuric acid, and the like).

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 carboxyl protecting group and the elimination method. The elimination using a Lewis acid can be carried out by reacting compound (1-4) or a salt thereof with a Lewis acid, Boron halide (eg, boron trichloride, boron trifluoride, etc.), titanium tetrahalide (eg, titanium tetrachloride, titanium tetrabromide, etc.), aluminum halide (eg, aluminum chloride, bromide, etc.) Aluminum And trihaloacetic acid (for example, trichloroacetic acid, trifluoroacetic acid, etc.). This elimination reaction is preferably performed in the presence of a cation scavenger (eg, anisol, phenol, etc.), and usually, nitroalkyl (eg, nitromethane, nitroethane, etc.), alkylene / , Ethyl chloride, etc.), getyl ether, carbon disulfide, and other solvents that do 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 halogenated alkyl (for example, 2-odoethyl, 2,2,2-trichloroethyl) ester and aralkyl (for example, benzyl) ester. The reduction method used in the present elimination reaction includes, for example, a metal (eg, zinc, zinc amalgam, etc.) or a salt of a chromium compound (eg, chromium (I), organic or inorganic). Combination with a salt (eg, acetic acid, propionic acid, 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 (1-5) 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 ² is represented by the formula: Z ⁵ — Z ⁶ (wherein, Z ^ S—CO—, Z ⁶ represents an optionally substituted amino group). The compound (1-6) is produced, for example, by the following Method D.

[Method D]

(1-5) (1-6)

[In the formula, the compound (VI II) represents Z ⁶ H, and the other symbols have the same meanings as described above. ]

In this method, the compound (1-5) or its reactive derivative at the carboxyl group or its salt is reacted with the compound (VIII) or its reactive derivative at its amino group or its salt to form the compound (1-5). 1-6) is manufactured. Suitable reactive derivatives in the amino group of the compound (VI II) include a Schiff base imino or an enamine tautomer thereof formed by the reaction of the compound (VIII) with a carbonyl compound such as an aldehyde or a ketone. Living organisms; silyl derivatives formed by the reaction of compound (VI II) with silyl compounds such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea; compound (VIII) and trisalt Derivatives formed by the reaction with phosphorus or phosgene. Suitable reactive derivatives at the carboxyl group of the compound (I-15) include, specifically, acid nodogenates, acid anhydrides, activated amides, activated esters and the like. Preferable 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, and nodogen phosphoric acid. , Dialkyl phosphorous acid, 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, isovabutyric acid, vivalic acid, pentanoic acid, isopentanoic acid, and trichloroacetic acid Acids or mixed acid anhydrides with acids such as aromatic carboxylic acids such as benzoic acid; symmetric acid anhydrides; imidazole, 4-substituted imidazole, dimethylpyrazole Activated amides with triazole, tetrazole or tetrazole; or, for example, cyanomethinole ester, methoxymethyl ester, dimethyliminomethinole ester, vinyl ester, propargyl ester, p-two-port phenyl estenole, trichlorophenylenole Estenolle, Pentaco mouth mouth feninole estenore, mesinole feninole estenore, phenylazozo phenyl estenolle, feninole thioestenole, p-nitro pheno-noestelastol, p-cresino retino estenolle, carboxymethylthioeste Activated ester such as nore, bilanyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, or N, N-dimethylhydroxyamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysk Shinimid N - hydroxycarboxylic phthalimide, 1-hydroxy -1H- benzotriazole of N - ester of a non Dorokishi compounds. These reactive derivatives can be arbitrarily selected depending on the type of the compound (1-5) to be used. Suitable salts of the reactive derivative of the compound (1-5) include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt, for example, trimethylamine And base salts such as organic salts such as salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N, N-dibenzylethylenediamine salts and the like. The reaction is usually carried out in water, for example, alcohols such as methanol, ethanol, etc., as well as common use such as acetone, dioxane, acetonitrile, chloroform, methylene chloride, chlorinated ethylene, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine. The reaction can be carried out in any other solvent as long as it does not adversely affect the reaction. These conventional solvents may be used as a mixture with water. In this reaction, when the compound (1-5) is used in the form of a free acid or a salt thereof, N, -hexylhexylcarbodiimide; N-cyclohexylcarbodiimide; N'-morpholinoethyl carbodiimide; N-cyclohexyl-N '-(4-ethylethylaminohexyl) carbodiimide; Ν, Ν'-getyl carbodiimide, Ν, Ν'-disopropylpyrucarbodiimide, Ν-ethyl-N '-(3-dimethylaminopropyl) carbodiimide; Ν, N'-carbo-bis (2-methylimidazole); pentamethyleneketene-Ν- Cyclohexylimine; Diphenylketylene-N-cyclohexylimine; Ethoxyacetylene; 1-Alkoxy-1-cycloethylene; Trialkyl phosphite; Ethyl polyphosphate; Isopropyl polyphosphate; Diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; for example, ethyl ethyl formate; lower alkyl haplate such as isopropyl chloroformate; triphenylphosphine; 2-ethyl-

7-Hydroxybenzisoxazolidum salt, 2-ethynole-5- (m-sulfophenyl) isoxazolidium hydroxide inner salt; N-hydroxybenzotriazole; l- (p-c Oral benzene snolephoninole)-6-cotyl-1H-benzotriazole; prepared by reaction of Ν, Ν'-dimethylformamide with thiol chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc. It is desirable to carry out the reaction in the presence of a conventional condensing agent such as a so-called Vilsmeier reagent. The reaction can also be carried out with inorganic or organic bases such as alkali metal bicarbonate tri (lower) alkylamine, pyridine, Ν- (lower) alkylmorpholine, Ν, Ν-di (lower) alkylbenzylamine, etc. It may be performed in the presence. The reaction temperature is not particularly limited, but the reaction is usually carried out under cooling or heating. The amount of the compound (VIII) to be used is 0:! To 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (1-5).

 The reaction temperature is usually 30 ° C to 100 ° C.

 The reaction time is usually 0.5 to 20 hours. When a mixed acid anhydride is used, the compound (1-5) and a carbonic acid ester (eg, methyl methyl carbonate, ethyl methyl carbonate, isoptyl carbonic acid carbonate, etc.) are converted to a base (eg, triethylamine, N— The reaction is carried out in the presence of methyl morpholine, N, N-dimethinorea diphosphorus, sodium hydrogen carbonate, sodium carbonate, carbonated carbonate, etc.), and further reacted with compound (VI II).

 The amount of the compound (VIII) to be used is generally:! 110 molar equivalents, preferably 0.3-3 molar equivalents.

 The reaction temperature is usually from 30 ° C to 100 ° C.

The reaction time is usually 0.5 to 20 hours. The compound (1-6) 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-15) used as a starting compound in the above method D is produced by the above method C.

[Method E]

 (1-7) (1-8)

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

 In this method, compound (1-8) is produced from compound (I-17) in the presence of a dehydrating agent. This reaction is performed using a method of appropriately reacting compound (1-7)) with a dehydrating agent. Here, examples of the dehydrating agent include acetic anhydride, trifluoroacetic anhydride, hydric pentate, and thiol chloride.

 The amount of the dehydrating agent to be used is from 0.1 to: L 00 molar equivalents based on the compound (1-7), preferably:! ~ 10 molar equivalents.

 The reaction temperature is usually from 30 ° C to 100 ° C.

The reaction time is usually 0.5 to 20 hours.

 The compound (1-8) thus obtained should 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. Can be.

The compound (I-17) used as a starting compound in the above method E is produced by the above method D or B. For example, when an acid halide is used, the reaction adversely affects the reaction in the presence of a base. It is performed in a solvent that does not. Examples of solvents that do not adversely affect the reaction include ethers such as ethyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chlorophonolene and dichloromethane; and 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 used in a mixture at an appropriate ratio.

[Method F]

[式中、 各記号は前記と同意義を有する。 ]

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

 In this method, compound (1-10) is produced by reacting nucleophilic reagent with compound (1-9). As the nucleophilic reagent, for example, metal phenolate, metal alcoholate, Grignard reagent, alkyl metal reagent, aryl metal reagent, thioalcolate 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 the compound (1-9).

This reaction is usually 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 getyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; and aromatic hydrocarbons such as benzene, toluene, and xylene. Amides such as N, N-dimethylformamide and 1-methylpyrrolidone; and sulfoxides such as dimethylsulfoxide. These solvents are mixed at an appropriate ratio. They may be used in combination.

 The reaction temperature is usually about 170 to about 150 ° C, preferably about -70 to about 0 ° C.

 The reaction time is generally about 0.5 to about 20 hours.

 The compound (1-10) thus obtained should be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc. Can be. The compound (1-9) used as a starting compound in the above Method F can be produced by the Method D. Compound (I) can also be obtained by the following production method other than the above production method.

 (I X-1)

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

(IX-1) is produced by reacting compound (IV) with an amide acetal. Examples of the amide acetal include an active acetal form of N, N-dialkylformamide, preferably N, N-dimethylformamide dimethyl acetal, N, N-dimethylformamide dodecyl acetal, Butoxybisdimethylaminomethane, Trisdimethylaminomethane, N, N-Dimethinoleformamidodipropylacetate, N, N-Dimethylformamidobis (2-trimethylsilylethyl) acetal, N, N-Dimethylformamid Dojibenzyl acetal, N, N-dimethylformamide -1-Butyl acetal, N, N-Dimethinolehonorem, N, N-N-dimethylformamide N, N-Dimethylformamide The active acetal is used, more preferably N, N-dimethylformamide dimethyl acetal, N, N-dimethylformamide dodecyl acetal, trisdimethylamino methane or the like.

 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).

Any solvent may be used for this reaction as long as it does not inhibit the reaction. Examples thereof include hydrocarbons (eg, n-hexane, N-heptane, benzene, toluene, xylene, etc.), halogenated carbon Hydrogens (eg, dichloromethane, etc.), ethers (diethylenoate, diisopropinoleate, ethylene glycolone resin methinolate, tetrahydrofuran, dioxane, etc.), amides (eg, N, N-dimethyl) N, N-diC, _3- alkylformamides such as formamide, Ν, Ν-dimethylacetamide, Ν-methylpyrrolidone, etc.), esters (eg, ethyl acetate, methyl acetate, etc.), (Eg, acetonitrile, etc.), sulfoxides (eg, dimethylsulfoxide, etc.) alone, or a mixture of two or more thereof.

 This reaction is carried out at a reaction temperature of 0 to 150 ° C, preferably 50 to 120 ° C, for about 30 minutes to 24 hours, preferably 1 to 6 hours. Any of the amide acetal described herein is known per se and can be easily obtained as a commercial product. Compound (IV) can be prepared by a known method, for example, the article of D. Prim et al.

 (Synth. Commun., Vol. 25, p. 2449, 1995) or a method analogous thereto.

[Η 法]

 (I X-2)

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

 Compound (IX-2) is produced by a dealcoholation reaction of compound (II). This reaction is performed using an acid or a base. 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.The base is hydrogenated Hydride metal or alkaline earth metal hydrides, such as sodium, lithium metal hydride, lithium hexamethyl disilazide, lithium hexamethyl disilazide, sodium hexamethyl disilazide, etc. Metal amides, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.Alkali metals or alkaline earth metal lower alkoxides, such as potassium hydroxide, sodium hydroxide, etc. Metal or alkaline earth metal hydroxides, carbonated lime, sodium carbonate, cesium carbonate, etc. Carbonates, potassium hydrogencarbonate, sodium hydrogencarbonate and other alkaline metal or alkaline earth metal bicarbonates, triethylamine, diisopropylamine, pyridine, dimethylaminopyridine, 1,8-diazabisik mouth [5 , 4,0] -7-Pendecene and the like. Of these, 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 are preferable, and 1 mole of compound (II) Is used in an amount of 0.1 to 100 mol, preferably 1 to 30 mol.

In this reaction, if necessary, any solvent can be used as long as it does not inhibit the reaction. Among them, alcohols (e.g., methanol, ethanol, d _ ₃ alcohols, such as-propanol) and the like 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 ° (preferably 0 to 30 ° C) for about 10 minutes to 6 hours, preferably 30 minutes to 3 hours. Can be produced by a method known in the art of compound (IV), for example, a method described in a paper by A. Nangia et al. (Indian J. Chem., Vol. 35, p.

[Method I]

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

The compound represented by the general formula (I) is obtained by converting the compound (VII) to hydroxylamine or a salt thereof, or hydra represented by R ³ 'NHNH ₂ (R ³ ' has the same meaning as described above). It is produced by ring closure with gins or salts thereof.

 In this reaction, 1 mol to 10 mol, preferably 1 mol to 5 mol of hydroxylamine or hydrazine is used per 1 mol of compound (IX).

 As a solvent used in this reaction, any solvent may be used as long as it does not inhibit the reaction. Preferably, alcohols (eg, C ^ s alcohols such as methanol, ethanol, and propanol) and alcohols are suitable. 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. It is used in an amount of 0.1 mol to 100 mol, preferably 1 mol to 30 mol, per 1 mol. Further, it may be used also as a solvent. This reaction is carried out at a reaction temperature of 0 to 120 ° C, preferably 50 to 100 ° C, for about 10 minutes. The reaction is carried out for 6 hours, preferably for 1 to 3 hours.

In addition, R ³ ′ on Ring A generated by this reaction can be converted to an optionally substituted hydroxyl group or an optionally substituted amino group described as R ³ using a method known per se. it can.

[J method]

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

In the reaction for cyclizing compound (IX-3) with a hydrazine represented by R ³ ′ NHNH ₂ in the presence of an acid to produce i-conjugate (1-11), i-conjugate (1-11) VII-2) 1 mol to 10 mol, preferably 1 mol to 5 monoles of hydrazine is used per 1 mol.

 As a solvent used in this reaction, any solvent may be used as long as it does not inhibit the reaction, but alcohols (eg, alcohols such as methanol, ethanol, and propanol) are preferably used.

 The anhydrous conditions in this reaction are substantially anhydrous conditions, specifically, do not actively add water to the solvent, 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 the compound (IX-3). Further, it may be used also as a solvent. This reaction is carried out at a reaction temperature of 0 to 120 ° C, preferably 40 to 70 ° C, for about 10 minutes to 6 hours, preferably 1 hour to 3 hours. In the general formula (IX-3), a compound having a hydroxyl group in which R ¹³ ′ is substituted with a cyclic group can be obtained by a known method from the compound (IV), for example, a paper by D. Prim et al. (Synth. Coface un. , 25 volumes, 2449 pages,

1995) or a method analogous thereto, but the compound (IX) is subjected to a general acid hydrolysis reaction (for example, a mixed solvent of an alcohol or amide and water as a solvent). Using 0.1 to 10 moles of the same acid as above with respect to 1 mole of compound (K), react at 0 ° C at 120 ° C for 10 minutes and react for 6 hours. ).

Further, by using an “optionally substituted amino group” as R ¹³ ′ in the general formula (IX-3), the corrosiveness is considered to be a problem during the production of the compound (IX-3). The target compound can be industrially and advantageously produced without using a compound such as a boron trifluoride etherate complex.

[K method]

(1-12) (1-13) (Table ¹⁴ ) The compound (1-12) which is a thiol in which R ¹ may be substituted in the general formula (I) is a compound (1-13) as follows. Leading to.

 First, compound (1-12) is subjected to an oxidation reaction to obtain compound (1-13). Examples of the oxidizing agent include peroxy acids such as metabenzo-perbenzoic acid, peracetic acid, formic acid, and trifluoroperacetic acid, peroxides such as dioxysilane, hydrogen peroxide in the presence of a metal catalyst, and oxone (trade name). It can be used in an amount of 2 to 10 mol per 1 mol of compound (1-12).

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 (1-12) to promote the reaction. Is desirable.

Any solvent may be used for this reaction as long as it does not hinder the reaction. Examples of the solvent include hydrocarbons (eg, n-hexane, N-heptane, benzene, toluene, xylene, etc.), and halogenated compounds. hydrocarbons (e.g., dichloromethane, etc.), ethers (di-Echiruetenore, diisopropyl ether Honoré, ethylene glycol dimethyl ether Honoré, as tetrahydrofuran, Jiokisan etc.), alcohols (e.g., methanol, E ethanol, C _ _Q alcohols propanol ), Ami earth (eg, N, N -. dimethyl formamide, etc. N, N- di preparative ₃ alkyl formamidine de, N, N- dimethyl § Seto Ami de, N- Mechirupirori dong, etc.), esters ( Eg, ethyl acetate, methyl acetate, etc.), nitriles (eg, acetonitrile, etc.), sulfoxides (eg, Such as methylsulfoxide, ketones (acetone, 2-butanone, 4-methyl-2-pentanone, cyclohexone), carboxylic acids (eg, formic acid, acetic acid, trifluoroacetic acid, etc.), or two or more kinds A mixed system is mentioned.

 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, 1 to 24 hours, preferably 2 to 5 hours. It is performed by reacting for a time.

 The compound (1-13) obtained as described above is subjected to a substitution reaction to produce a compound (1-14). In this reaction, 1 to 2 mol, preferably 1 to 1.5 mol of R ,, _ 0H is used per 1 mol of compound (1-13).

Incidentally, 1 "over 0« [1 "-0 moiety corresponds to hydroxy group which may be substituted R ^1.

 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, hydrogen carbonate carbonate, Sodium hydrogen carbonate and the like are preferred, and 1 to 3 mol, preferably 1 to 2 mol, is used per 1 mol of compound (1-13).

Any solvent may be used for this reaction as long as it does not inhibit the reaction. Examples thereof include hydrocarbons (eg, n-hexane, N-heptane, benzene, toluene, xylene, etc.), halogenated carbon Hydrogens (eg, dichloromethane, etc.), ethers (di Ethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc., amides (eg, Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, Ν-methylpyrrolidone, etc.), esters ( Eg, ethyl acetate, methyl acetate, etc.), nitriles (eg, acetonitrile, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), ketones (acetone, 2-butanone, 4-methynole-1-pentanone, cyclohexone) Etc.), among which hydrocarbons (eg, η-hexane, Ν-heptane, benzene, tonolen, xylene, etc.), amides (eg, Ν, Ν-dimethylformamide, Ν, Ν) -Dimethylacetamide, Ν-methylpyrrolidone, etc.), esters (eg, ethyl acetate, Methyl ketones), ketones (aceton, 2-butanone, 4-methyl-2-pentanone, cyclohexone, etc.), ethers (getyl ether, diisopropylpropionate ether, ethylene glycolone methyl ether, tetrahydrofuran) , Dioxane, etc.) are preferred. 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, for 1 to 24 hours, preferably 2 to 6 hours.

[L method]

The compound (1-4) in which R ^{1 Q} represents a carboxyl-protecting group can be converted to the compound (1-7) in a single step by reacting with formamide in the presence of a base. Formamide is usually used also as a solvent, and is used in an amount of 1 to 30 milliliters, preferably 2 to 10 milliliters per gram of compound (1-4).

Examples of the base used in this reaction include the bases described in [Method H]. Thorium methoxide, sodium ethoxide, potassium t-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like are preferred. To 10 mol, preferably 1 to 5 mol.

When a solvent is used in this reaction, any solvent may be used as long as it does not inhibit the reaction, but alcohols (eg, ₃ alcohols such as methanol, ethanol, propanol, etc.), amides (eg, N, N-dimethylform) Amide, 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 to 100 ° C, for 1 to 12 hours, preferably 1 to 3 hours. Compound (la) The force R may be substituted together with the ring-forming carbon atoms of the thiophene ring and ring Aa! / If the compound does not form a hydrocarbon ring or a heterocyclic ring, or a compound, the compound (la) or a salt thereof may be produced by, for example, the A 'method to the L' method shown below or a method analogous thereto. Can be.

[Α 'method]

 (5) (2)

 When Q = NH

 (4-1) (4-2)

 (2-1) © -2)

[In the formula, R ¹⁶ represents an optionally substituted hydrocarbon residue corresponding to R, and R ¹⁷ and R ¹⁸ each represent a hydrogen atom or each of the same substituted as exemplified for R ¹ A good hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group, and A ¹ and A ² are each a hydrogen atom or an optionally substituted hydrocarbon residue as exemplified for R ¹ ; Hal represents a heterocyclic group, Hal represents a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), and Q represents a sulfur atom, an oxygen atom or an NH group. R ¹⁵ is 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 have the same meaning as above. ]

In this method, first, compound (A) is halogenated by a method known per se to give compound (2), and then compound (A) is produced by reacting compound (2) with amide, thioamide or amidine. . The reaction between compound () and compound (3) is performed in an appropriate solvent in the presence or absence of a base. Examples of the solvent include aromatic hydrocarbons such as benzene, benzene, and xylene; dichloromethane, chloroform; carbon tetrachloride; 1,2-dichloroethane; 1,1,2,2-tetrachloroethane; Hydrogenated hydrocarbons, ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, ethylene glycol Examples include alcohols such as coal, Ν, Ν-dimethylformamide, dimethylsulfoxide, acetoetrile, 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. Alkali metal alkoxides such as tert-butoxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, alkali metal salts such as sodium hydrogen carbonate, sodium acetate, sodium acetate acetate, disodium hydrogen phosphate, dihydrogen hydrogen phosphate Alkali metal hydrogen phosphates such as sodium hydride, alkali metal hydrides such as hydrogen hydride, trimethinoleamine, triethylamine, pyridine, picoline, N-methinolevine lysine, N-methylmorpholine, N, N—amines such as dimethylaniline, etc. A base is appropriately selected and used. The amount of the base used is preferably about 1 to about 5 molar equivalents relative to compound (2), and the amount of amide, thioamide or amidine () used is about 1 to 1 relative to compound (). ~ 5 molar equivalents are preferred. This reaction is generally carried out at about 0 ° C. to about + 180 ° C., preferably about + 30 ° C. to about + 120 ° C., for about 30 minutes to about 50 hours. The compound (A) thus obtained can be obtained by a known separation and purification method, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography. It can be isolated and purified by one method.

The compound (A) wherein R ^{2 is} —COOR ¹⁶ [ie, the compound (4,)] is subjected to a known acid or hydrolysis reaction to give the corresponding carboxylic acid.

(5.), and subjecting the compound (5.) to an amidation reaction [reaction with compound (6.)] known per se to produce compound (7). Can be done. 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 with the conjugate (6). The reaction between the compound (5.) and the halogenating agent is usually carried out in a solvent. Examples of the solvent include aromatic hydrocarbons such as benzene and toluene, and ethers such as getyl ether and tetrahydrofuran. Can be For example, pyridine, N, N-dimethylformamide and 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 about:! ~ 2 molar equivalents are preferred. The obtained acid halide may be subjected to a reaction with the compound (6) after being separated by a usual separation and purification means, or the reaction mixture containing the acid halide may be subjected to a reaction with the compound () without separation. It can also be attached. The reaction between the acid halide and the compound (0) is usually performed in a solvent. Examples of the solvent include halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachloroethane and the like, ethers such as getyl ether, dioxane, tetrahydrofuran, etc., acetone, acetonitrile, Ethyl acetate, N, N-dimethylformamide and the like. The reaction can also be carried out using an excess amount of the compound 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, triethynoleamine, pyridine, N, N-dimethinoleaniline, for example, sodium hydrogen carbonate, Examples include inorganic bases such as potassium carbonate. The amount of the compound () to be used is preferably about 1 to 2 mol equivalent to the acid halide, but an excessive amount of the compound (6.) can be used as a 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 (±), compounds in which Q is an NH group can undergo isomerism like compound (A-1) and compound (4-2). ) Compounds (-1) and (-2) are produced by subjecting the compound to a reaction with an element. This reaction is carried out in an appropriate 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 dimethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and the like. Mixed solvents and the like can be 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, potassium Alkali metal alkoxides such as tert-butoxide, sodium carbonate, carbonate carbonate, sodium hydrogen carbonate, sodium hydrogen carbonate, sodium acetate, alkali metal salts such as potassium acetate, disodium hydrogen phosphate, dihydrogen phosphate Al-metal hydrogen phosphates such as potassium, alkali metal hydrides such as sodium hydride and potassium hydrogen, trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, N, N—Bases such as amines such as dimethyla-line The amount of these bases used is preferably about 1 to about 5 molar equivalents relative to compound (A), and the amount of halogenated hydrocarbon (_§_) used is different from compound (A). About 1 to about 5 molar equivalents are preferred. This reaction is generally carried out at about 0 ° C to about + 180 ° C, preferably about + 30 ° C to about + 120 ° C, for about 30 minutes to about 50 hours. The thus obtained conjugates (9.1-1) and (-2) are obtained by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Each can be isolated and purified.

[Β 'method]

 (Each symbol in the formula has the same meaning as above.)

In this method, after the above compound (2.) is azido-formed to a compound (10) by a method known per se, a carboxylic acid anhydride (11) (e.g., acetic anhydride, propionic anhydride, butyric anhydride) , Isobutyric anhydride, etc.) to produce compound (12). 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 affect the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane; N, N-dimethylformamide; Carboxylic acid (eg, acetic acid, propionic acid, butyric acid, isobutyric acid, etc.) corresponding to the substance (11) or a mixed solvent thereof. The reaction temperature is usually about 120 ° C. to about + 150 ° C., preferably about 0 ° C. to about + 100 ° C., and the reaction time is about 1 hour to about 24 hours. The compound (12) 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 (13) is produced by subjecting compound (12) to a reaction with phosphorus oxychloride in an appropriate solvent or without a solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, chloroform, Halogenated hydrocarbons such as tetrachlorosilane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, ethers such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, dimethyl sulfoxide, Examples include acetonitrile or a mixed solvent thereof. The amount of phosphorus used for the compound

About 1 to about 5 molar equivalents to (12) are preferred. The reaction temperature is usually 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 (13) 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.

The compound (1 3) in which R ² is --COOH can be produced by subjecting the compound (1 3) in which R ² is one COOR ¹⁶ to an acid or alkali hydrolysis known per se, and wherein R ² is The compound (1 3) in which R ² is _CONR ¹⁷ R ¹⁸ is produced by subjecting the i-OHOH compound (13), which is one COOH, to a known amidation reaction [reaction with the compound (6.)]. You can also. In this reaction, compound (')

The reaction leading to compound (7) from the compound (5) can be carried out under the same conditions as the reaction leading to (5.).

[Method C]

(16) (In the formula, R ¹⁹ 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). 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 aromatic hydrocarbons such as benzene, toluene and xylene, ethenoles such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxetane, methanol, ethanol, propylene glycol, isopropanol, and the like. Alcohols such as butanol, 2-methoxyethanol, ethylene glycol, N, N-dimethylformamide, ethyl acetate, or a mixed solvent thereof. The reaction temperature is usually about 120 ° C to about + 150 ° C, preferably about 0 ° C to about + 100 ° C, and the reaction time is about 1 hour to about 24 hours. The compound (14) 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.

 The compound (16) is produced by subjecting the compound (14) to a reaction with a dithioester represented by the general formula (15) in an appropriate solvent or without a solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2,2.

—Halogenated hydrocarbons such as tetrachloroethane, ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and mixed solvents thereof. Can be The dithioester (15) is preferably used in an amount of about 1 to about 5 molar equivalents relative to the compound (14)! The reaction temperature is usually 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. The compound (JD) is produced by reacting the compound (16) with phosphorus oxychloride in the same manner as in the method B ′.

R ² is able to produce the compound (1 7) is an R ² gar COOH by subjecting to an COOR ^16, compound (1-7) per se known acid or alkali hydrolysis reaction, also, R ² A compound (17) in which R ^{2 is} --CONR ¹⁷ R ¹⁸ by subjecting the compound ( ¹⁷ ) in which is —COOH to an amidation reaction [reaction with the compound (6.)] known per se. Can also. This reaction can be carried out under the same conditions as in the reaction for deriving the compound (7 ′) from the compound (Α ′) and the compound (7_) from the compound.

(In the formula, Q ′ represents an oxygen atom or NA ^1. Other symbols are as defined above.)

In this method, compound (18) is produced by subjecting compound (II) to a reaction with oxychloride phosphorus in the presence of N, N-dimethylformamide. Examples of solvents include dichloromethane, chloroform, carbon tetrachloride, halogenated carbons such as 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, getyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc. May be used, or a mixed solvent thereof. N, N-dimethylformamide The amount of the salt used is preferably about 1 to about 5 molar equivalents relative to the compound (ヒ). The reaction temperature is usually about 120 ° C. to about + 180 ° C., preferably about 0 ° C. to about + 120 ° C., and the reaction time is about 1 hour to about 24 hours. . The compound (丄 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 (20) is produced by reacting the compound (18) with a hydroxylamine derivative or a hydrazine derivative of the compound (19). 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; halogenated compounds such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and 1,1,2,2-tetrachloroethane. Examples include hydrocarbons, ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and a mixed solvent thereof. Examples of the base include alkali metal hydroxides such as sodium hydroxide and hydroxylating power, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium methoxide, and the like. Alkali metal alkoxides such as sodium methoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, hydrogencarbonate, aluminum acetate, sodium acetate, etc. Metal phosphates such as disodium and dibasic hydrogen phosphate metal phosphates such as sodium hydride and lithium hydride metal hydrides, trimethylamine, triethylamine, pyridine, picoline, N-methyl Amines such as pyrrolidine, N-methylmorpholine, N, N-dimethylaniline A base is appropriately selected and used. The amount of the base used is preferably about 1 to about 5 molar equivalents relative to the compound (丄 8), and the amount of hydroxylamine or hydrazine (19) is About 1 to about 5 molar equivalents to 8) are preferred. This reaction is generally carried out at about 0 ° C. to about + 180 ° C., preferably about + 30 ° C. to about + 120 ° C., for about 30 minutes to about 50 hours. The compound {2_0) 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. By subjecting the compound (20) in which R ² is one COOR ¹⁶ to an acid or alkali hydrolysis reaction known per se, a compound (20) in which R ² is one COOH can be produced. Compound (20) wherein R ^{2 is} --CONR ¹⁷ R ¹⁸ can also be produced by subjecting compound (20) wherein ² is --COOH to an amidation reaction [reaction with compound (6.)] known per se. it can. This reaction can be carried out under the same conditions as those for the reaction for deriving the compound (A,) compound (5.) and for deriving the compound (!) From the compound (J_).

[Ε 'method]

 (Each symbol in the formula has the same meaning as above.)

In this method, compound (21) is produced by subjecting compound (18) to a reaction with sulfur and sodium sulfate in an appropriate solvent, and then treating with sulfuricfuryl chloride. Examples of the solvent include ethers such as gethyle ether, tetrahydrofuran, dioxane, and dimethoxetane; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, and ethylene glycol; , N-dimethylformamide, dimethyl sulfoxide, acetonitrile, or a mixed solvent thereof. The amount of sulfur and sodium sulfate used is preferably about 1 to about 3 mol equivalent to compound (18), respectively. The reaction temperature is usually about 0 ° C to about + 180 ° C, especially about + 30 ° C to about + 30 ° C. + 120 ° C is preferred and the reaction time is 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, 1,1,2,2-tetrachloroethane and the like. Examples thereof include halogenated hydrocarbons, ethenoleatenole, ethers such as tetrahydrofuran, dioxane, and dimethoxetane, and a mixed solvent thereof. The amount of the salted sulfuryl to be used is preferably about 1 to about 3 molar equivalents relative to compound (18). The reaction temperature is usually about 120 ° C to about + 150 ° C, preferably 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 (22) is produced by reacting compound (21) with a large excess of ammonia. This reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include alcohols such as ethenole ethers, tetrahydrofuran, dioxane, dimethoxyethane, etc., methanol, ethanol, propanol, isopropanol, butanol, 2-methoxyethanol, ethylene glycol and the like. And the like. This reaction is generally carried out at about 120 ° C. to about + 180 ° C., preferably about 0 ° C. to about + 120 ° C., for about 1 hour to about 50 hours. The compound (22) 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 ² Gar COOR ^16, compound (22) can be prepared compound is R ² gar COOH (22) by subjecting the known acid or alkali hydrolysis reaction, also, R ² is one Compound (22) wherein R ^{2 is} --CONR ¹⁷ R ¹⁸ can also be produced by subjecting compound (22) which is COOH to an amidation reaction [reaction with compound] known per se. This reaction can be carried out under the same conditions as those for deriving compound () from compound (Α ') and for deriving compound (JL) from compound (5.). [F, Law]

(In the formula, R ² represents an ethoxycarbol group or a p-toluenesulfonyl group. Other symbols have the same meanings as described above.) 'In the present method, the above compound (丄) The compound (23) is subjected to a reaction with ethyl carbazinate or p-toluenesulfol-hydrazide in a solvent to produce a compound (24). Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene, dichloromethane, chloroform, tetrachlorosilane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and the like. Alcohols such as halogenated hydrocarbons, ethynoles such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, methanol, ethanol, propanolone, isopropanol, pptanolone, 2-methoxyethanol, and ethylene glycol; Examples include N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, ethyl acetate, or a mixed solvent thereof. Ethyl carpazate or p-toluenesulfonyl hydrazide (23) is preferably used in an amount of about 1 to about 2 molar equivalents with respect to the hydric compound (丄). 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 thus-obtained compound (24) is a known separation and purification means, for example, It can be isolated and purified by concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

 The compound (25) is produced by treating the compound (24) with a salted zionyl. This reaction is performed in an appropriate solvent or without a solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated compounds such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and 1,1,2,2-tetrachloroethane. Examples include hydrocarbons, ethers such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, and mixed solvents thereof. This reaction is generally carried out at about 120 ° C. to about + 180 ° C., preferably about 0 ° C. to about + 120 ° C., for about 1 hour to about 50 hours. The compound (25) 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.

R ² Gar COOR ^16, compound (25) can be prepared compound is R ² gar CO OH (25) by the subjected to per se known acid or alkali hydrolysis reaction, also, R ² is Compound (25) wherein R ^{2 is} --CONR ¹⁷ R ¹⁸ can also be produced by subjecting compound (25) which is one COOH to an amidation reaction [reaction with compound (6.)] known per se. This reaction can be performed under the same conditions as the reaction for deriving compound () from compound (± ') and the reaction for deriving compound (7) from compound (5).

[G 'method]

Dehydration

 (Each symbol in the formula has the same meaning as above.)

In this 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 a compound (27). Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated compounds such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and 1,1,2,2-tetrachloroethane. Examples include hydrocarbons, ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, N, N-dimethinoleformamide, dimethyl sulfoxide, acetonitrile, ethyl acetate, and 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, potassium tert. —Alkali metal alkoxides such as butoxide, sodium carbonate, sodium carbonate, hydrogencarbonate, sodium hydrogencarbonate, sodium acetate, sodium acetate, sodium metal phosphate, sodium phosphate, dihydrogen phosphate, dihydrogen phosphate Alkali metal hydrogen phosphates such as potassium hydride, sodium hydride, alkaline metal hydrides such as lithium hydride, trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, N Salts such as amines such as N, N-dimethylaniline There are used appropriately selected, the amount of these bases to I 匕合 product (1 8) from about 1 to about 5 molar equivalents to the preferred thiol (2. The amount of 6_) to be used is preferably 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 at about + 30 ° C to about + 120 ° C, for about 1 hour to about 50 hours. The compound (27) 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.

 In the above reaction, the compound (28) may be partially produced, 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. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, chloroform, tetrachloride, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, and the like. Halogenated hydrocarbons, ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane, methanol, ethanol, prono-nore, isopropanol, butanol, 2-methoxyethanol, ethylene glycol, etc. Alcohol, acetonitrile, ethyl acetate or 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. And mixtures of carboxylic acids (acetic acid, benzoic acid, etc.) and the like (eg, pyrrolidine, piperidine). The amount of the dehydrating reagent used is a catalyst amount or a large excess with respect to the conjugate (2JL), and the reaction temperature is usually about 0 ° C to about + 180 ° C, particularly about + 30 ° C to about + 120 ° C is preferred and the reaction time is from about 1 hour to about 50 hours. The compound (2_8) 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.

R ² is able to R ² to produce a compound of one CO OH (28) by subjecting to an COOR ^16, compound (28) per se known acid or alkali hydrolysis reaction, also, R ² is compound which is over COOH (28) known per se amidation reaction [compound (6) and reaction] 1 ² gar I Nyo be subjected to. Compound (28) which is 0 ^^ 1 ¹⁷ 1 ¹⁸ can also be produced. In this reaction, the compound (4 ') The reaction can be carried out under the same conditions as those for the reaction leading to the compound (5.) and the reaction leading to the compound (!) From the compound.

 (Each symbol in the formula has the same meaning as above.)

 In this method, the above compound (2.) is subjected to a reaction of compound (29) with imine in an appropriate solvent in the presence of a base to produce compound (30). Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; and a mixed solvent thereof. As the base, for example, a base such as lithium getylamide or lithium diisopropylamide is appropriately selected and used. The amount of the base to be used is preferably about 1 to about 2 molar equivalents relative to compound (2.). The amount of (29) to be used is preferably about 1 to about 2 molar equivalents relative to compound (2.). This reaction is advantageously performed by first treating the imine (29) with a base, and then adding the compound (). The reaction temperature is usually about 80 ° C to about + 100 ° C, preferably about -80 ° C to about + 30 ° C, and the reaction time is about 30 minutes to about 24 hours. The compound (30) 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.

R ² Gar COOR ^16, compound (30) R ² by subjecting the known acid or alkali hydrolysis reaction can produce a compound of one COOH (30). In addition, R ² gar The compound (30) wherein R ² is one CONR ¹⁷ R ¹⁸ can also be produced by subjecting the compound (30) which is COOH to an amidation reaction [reaction with the compound ()] known per se. This reaction is performed from the compound ('). The reaction can be carried out under the same conditions as the reaction for deriving compound (A) and the reaction for deriving compound (!) From compound (5). For example, compound (la) can also be produced according to the following I ′ method _c

 [Ι 'method]

(In the formula, n represents 1 or 2, and each of the other symbols has the same meaning as described above.) In this method, first, 1,3-diketone is converted to a base, carbon disulfide, and a halogenated hydrocarbon (3 By treating in the order of 1), a dithioester of the compound (32) is produced. This reaction 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; ethers such as dimethyl ether, tetrahydrofuran, dioxane, and dimethoxetane; N, N-dimethylformamide, dimethylsulfoxide; Examples include acetonitrile and 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 the like. Alkali metal alkoxides such as potassium tert-butoxide, sodium carbonate, sodium carbonate, sodium bicarbonate, sodium bicarbonate, sodium acetate, sodium acetate, sodium acetate, etc., disodium hydrogen phosphate, Hydrogen phosphate Alkali metal hydrogen phosphates such as dipotassium, sodium hydride, alkali metal hydrides such as hydrogen hydride, trimethylamine, triethylamine, pyridin, picoline, N-methinolepyrrolidine, N- Bases such as amines such as methyl monoreforin 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 hydride (31) to be used is about 1 to about 2 molar equivalents, preferably about 1 molar equivalent, based on 1,3-diketone. This reaction is carried out usually at about 180 ° C. to about + 150 ° C., preferably about −20 ° C. to about + 100 ° C., for about 1 hour to about 24 hours. The thus obtained compound (32) may 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. Can be.

Compound (34) is produced by subjecting compound (32) to a reaction with a halogenated hydrocarbon represented by general formula (33) in an appropriate solvent in the presence of a base. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as gethyle ether, tetrahydrofuran, dioxane, and dimethoxyethane, methanol, ethanolanol, propanol, isopropanol, butanol, and the like. Alcohols such as 2-methoxyethanol and ethylene glycol; ketones such as cetone and methyl ethyl ketone; N, N-dimethylformamide, dimethyl snolefoxide, acetonitrile, ethyl acetate, and mixtures thereof. No. Examples of the base include alkali metal hydroxides such as sodium hydroxide and hydroxylating lime; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; sodium methoxide; sodium methoxide Alkali metal alkoxides such as sid, potassium tert-butoxide, sodium carbonate, lithium carbonate, sodium bicarbonate, aluminum chloride metal salts such as sodium hydrogen carbonate, sodium acetate, potassium acetate, disodium hydrogen phosphate, Metal hydrogen phosphates such as dihydrogen phosphate and alkali metal hydrides such as sodium hydride and hydrogen hydride, trimethylamine, triethylamine, pyridine, picolin, N-methinolepyrrolidine, N-methylmorpholine, N, N-dimethinorea Bases such as amines such as amines are appropriately selected and used, and the amount of these bases used is preferably about 1 to about 10 molar equivalents, particularly preferably about 1 to about 5 molar equivalents, based on compound (32). The amount of the halogenated hydrocarbon (33) to be used is preferably about 1 to about 2 molar equivalents relative to the compound (32). 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 (丄) 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. The compound (35) is produced by subjecting the compound (34) to an oxidation reaction. As the oxidizing agent used in this reaction, peracids such as peracetic acid, pertrifluoroacetic acid, and m-chlorobenzoic acid, oxidized metals such as potassium permanganate and oxidized chromium, and hydrogen peroxide are used. . In this reaction, the oxidizing agent is used in 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (34). ■

 Any solvent can be used for this reaction as long as it does not hinder the reaction. For example, hydrocarbons such as n-hexane, N-heptane, benzene, toluene, xylene, etc .; Halogenated hydrocarbons such as carbon chloride, diethyl ether, diisopropyl ether, ethylene glycolone resin, ethers such as tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide And amides such as N-methylpyrrolidone, esters such as ethyl acetate and methyl acetate, ketones such as acetone, 2-butanone, 4-methyl-2-pentanone, and cyclohexaquinone. Mouth form, halogenated hydrocarbons such as Shishidani carbon, getyl ether, Propyl ether, ethylene glycol / regimen Chino Les ether Honoré, as tetrahydrofuran, ethers such as Jioki acid. These solvents are used alone or as a mixture of two or more.

This reaction is carried out 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 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. Next, the compound is subjected to a reaction with various nucleophilic reagents to produce a compound (II). As the nucleophilic reagent, for example, metal phenolate, metal alcoholate, Grignard reagent, alkyl metal reagent, aryl metal reagent, thioalcoholate, amine and the like are used. In this reaction, it is preferable to add a base in some cases. Examples of the base to be used include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium carbonate, and the like. Alkali metal salts such as potassium carbonate, sodium hydrogen carbonate, cesium fluoride, sodium acetate and potassium acetate; metal hydrogen phosphates such as disodium hydrogen phosphate and dihydrogen phosphate; sodium hydroxide Metal hydroxides such as oxidizing rims, triethylamine, pyridine,

Amines such as N-methylmorpholine are exemplified.

 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 to be used is preferably about 1 to about 5 molar equivalents relative to compound (35).

 This reaction is usually 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 chlorophonolem 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 used in a mixture at an appropriate ratio. The reaction temperature is usually about 170 to about 150 ° C, preferably about −20 to about 100 ° C.

 The reaction time is usually about 0.5 to about 24 hours.

 The compound (II) 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 (1) in which R ^{2 is} --COOR ¹⁶ is converted to a known acid or alkali hydrolyzate. Solution by subjecting the reaction can be prepared compound is R ² gar COOH and (丄) The compound wherein R ² is an COOH (丄) known per se amidation reaction [Compound () and To produce the compound (11) wherein R ² is one of CONR ^{17 and} R ¹⁸ .

[J 'method]

 Compound (20) can also be synthesized by the following method.

[Wherein R ¹⁹ and R ² . Represents a hydrogen atom or an optionally substituted hydrocarbon residue or a heterocyclic group, respectively, as exemplified for R ¹ , and the other symbols have the same meanings as described above. ]

In this method, the compound (3) is produced by subjecting the above compound (1) to a reaction with a trialkyl orthoformate and a boron trifluoride-ethyl ether complex in the presence of a base. As the base, an organic base such as triethylamine or diisopropylethylamine is used. As the solvent, for example, halogenated carbons such as dichloromethane, chloroform and tetrachlorocarbon are preferable. The amount of the trialkyl orthoformate, boron trifluoride-ethyl ether complex and base used is preferably about 1 to about 10 molar equivalents relative to the compound (II)! The reaction temperature is usually about 170 ° C. to about 60 ° C., preferably 150 ° C. to 30 ° C., and the reaction time is about 1 hour to about 24 hours. The compound (31) thus obtained can be obtained by a known separation and purification means, for example, concentration, reduction, etc. Isolation and purification can be performed by pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

 The compound (III) is reacted with N, N-dimethylformamide dialkyl acetal or trisdialkylaminomethane to produce the compound (32). 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.

 The compound (31) and the compound (32) thus obtained are reacted with a hydroxylamine derivative or a hydrazine derivative of the compound (19) to produce a compound (20). The reaction may be accelerated 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. Examples of the solvent include alcohols such as methanol, ethanol and the like, aromatic hydrocarbons such as benzene, toluene and xylene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like. Amides are preferred. The amount of the acid used is preferably about 0.1 to about 10 molar equivalents based on the compound (1)! / ,. The reaction temperature is usually about 0 ° C. to about 120 ° C., preferably 50 ° C. to 100 ° C., 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.

[Κ 'method]

 (36) (38)

[The symbols in the formula are as defined above. Y is boronic acid, boronic ester, Indicates lead halide, copper halide, trialkyltin or triflate. The starting material compound (36) of the present method is known from the literature [W02000047578, EP 676395, and Monatshef tefur Chemie, 120, 65 (1987)]. Can be produced by the method described in the above or a method analogous thereto.

 The compound (37) in which 丫 (boronic acid, boronic ester or triflate) is bonded to a 5- to 7-membered ring is reacted with the compound (36) in the presence of a metal catalyst to form a compound. Manufacture goods (^ _8).

Examples of the metal catalyst used in this reaction include metal catalysts generally used in aryl coupling. For example, tetrakis (triphenylphosphine) palladium (0), dichloropalladium (11), diacetoxypalladium (11), tetrakis (triphenylphosphine) nickel (0), dichloronickel (11), diacetoxy -Hackel (11), copper (I) chloride, copper (II) chloride, etc. are used. In some cases, it is preferable to further add phosphine (for example, triphenylphosphine, tributylphosphine, etc.).

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 getyl ether, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; N, N-dimethylformamide; N, N-dimethylacetamide; Amides such as N-methylpyrrolidone are preferred. It is preferable that the amount of the compound (37) used is about 1 to about 5 molar equivalents with respect to the compound (36). The amount of the metal catalyst to be used is preferably about 0.1 to about 1 molar equivalent with respect to the compound (36). The reaction temperature is usually about 170 ° 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 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. The conversion of R ¹ of compound (la) can also be performed by the following method.

[L, law] In the general formula (Ia), a compound in which R ¹ may be substituted with a hydrocarbon residue, a heterocyclic group, a hydroxyl group, or an amino group is produced by the following method.

 [Wherein, R ′ represents an optionally substituted hydrocarbon residue, and other symbols have the same meanings as described above. ]

 That is, the sulfidyl compound or the sulfonyl compound (40) is obtained by subjecting the sulfanyl group of the compound (3_9), which can be produced by the method K to the kappa A 'method by the K, method, to oxidation conditions. To manufacture. Examples of the oxidizing agent used in the acid reaction include hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, pertrifluoroacetic acid, potassium permanganate, and chromium acid. 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 jeti / ether, tetrahydrofuran, and dioxane, and halogenated carbons such as dichloromethane, chlorophonolem, 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 (3-9). The reaction temperature is usually about 0 ° C. to about 100 ° C., preferably 0 ° C. to 50 ° C., and the reaction time is about 1 hour to about 24 hours. The compound (40) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

 Next, the compound (丄) is produced by reacting the conjugated product (40) with a nucleophilic agent in the presence of a base, if 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. Examples of the solvent include ethers such as getyl ether, tetrahydrofuran and dioxane; halogenated carbons such as dichloromethane, chloroform and carbon tetrachloride; Aromatic hydrocarbons such as butane, toluene and xylene, and amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone are preferred. The nucleophile and the base are preferably used in an amount of about 1 to about 10 molar equivalents relative to compound (39). The reaction temperature is usually about 170 ° C. to about 100 ° C., preferably −20 ° C. to 50 ° C., and the reaction time is about 1 hour to about 24 hours. The compound (丄) 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. All compounds used or obtained in the above-mentioned production methods are intended to include the corresponding salts, even if not 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, it can be separated into a d-isomer and a single isomer by ordinary optical resolution means. The conjugate or a salt thereof used in the present invention can be isolated and purified by means of, 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 is used in the next step without any purification or as a reaction solution. The term “biodegradable” in the biodegradable polymer compound used in the present invention refers to the body, that is, hard tissues such as soft tissues and osseous bones, such as subcutaneous and intramuscular, and in particular, fibers other than the digestive tract. It means that it has the property of being completely or partially degraded or metabolized by the bodily fluid in the tissue within the intended treatment period.

In the biodegradable polymer compound (preferably, biodegradable polymer) used in the present invention, the “polymer compound” generally has a weight average molecular weight of about 3,000 to about 5, 0, 000, preferably from about 4, 000 to about, 4, 000, more preferably from about 5, 000 to about 3, 000. Also, the degree of dispersion (weight Average molecular weight Z number average molecular weight) Force Usually, a polymer compound having about 1.2 to about 4.0, more preferably about 1.5 to 3.5 is preferable.

 The biodegradable polymer compound used in the present invention is, for example, a biodegradable polymer that is hardly soluble or insoluble in water. Examples of the biodegradable polymer compound used in the present invention include, for example, fatty acid polyesters [eg, polyhydroxycarboxylic acids (eg, glycolic acid, diacid, 2-hydroxybutyric acid, 2-hydroxyvaleric acid] , 2-hydroxy-3-methinobutyric acid, 2-hydroxycaproic acid, 2-hydroxyisocaproic acid, 2-hydroxycaprylic acid, etc., hydroxydicarboxylic acids (eg, malic acid, etc.), hydroxy Tricarboxylic acids (eg, citric acid, etc.), one or more polymers such as lactic acid prolactone, parerolactone, copolymers, or mixtures thereof]; and derivatives thereof (eg, polylactic acid, polyglycolic acid, and the like) {Polyethylene glycol block polymer, etc.); Poly-α-cyano acrylate; Poly-1] 3-hydroxy Butyric acid; polyalkylene oxalates (eg, polytrimethylene oxalate, polytetramethylene oxalate, etc.); polyorthoesters; polyamino acids (eg, poly-γ-benzyl-L-glutamic acid, Poly-L-alanine, Poly-γ-methyl-L-glutamic acid, etc.); Hyaluronic acid esters; Dekinstearate; Collagen; Gelatin; Fibrin; Hydroxyapatite; Dioxanone; Polymers, copolymers, or mixtures thereof having a free carboxyl group, synthesized from at least one kind of lysine and the like are used. In addition, the biodegradable polymer of the present invention includes the drug “delivery”, a company report, 2000 (The drug delivery companies report 2000), (Pharmaventures Ltd., Magdalen Centre, Oxford Science Park Oxford, 0X4 4GA, UK))

 (Synthetic polymers) can also be used.

One of these biodegradable polymer conjugates may be used, or two or more copolymers or a simple mixture may be used. The type of polymerization may be any of random, block, and graft. Preferred examples of the biodegradable polymer conjugate are, for example, aliphatic polyesters. In particular, for example, synthesized from one or more _α -hydroxycarbonic acids Polymers and copolymers are preferred from the viewpoint of biodegradability and biocompatibility, and specifically synthesized from one or more of lactic acid, glycolic acid, 2-hydroxybutyric acid, 2-hydroxyvaleric acid, and the like. The used copolymer or a mixture thereof is used.

 The biodegradable polymer compound in the present invention is produced by a method known per se, for example, a method described in JP-A-61-28521 or a method analogous thereto. The α-hydroxycarboxylic acids may be any of a D-form, an L-form, and 0- and L-forms, but the D- and L-forms are preferred. Examples of the homopolymers of monohydroxycarboxylic acids include homopolymers such as lactic acid, glycolic acid and 2-hydroxybutyric acid. As the hydroxycarboxylic acids, lactic acid is preferred. Examples of copolymers of α-hydroxycarboxylic acids include copolymers of glycolic acid and other α-hydroxycarboxylic acids. Examples of monohydroxycarboxylic acids include lactic acid and 2-hydroxybutyric acid. preferable. Specifically, for example, lactic acid-glycolic acid copolymer, 2-hydroxybutyric acid-glycolic acid copolymer and the like, preferably lactic acid-glycolic acid copolymer and the like are used.

If Rereru use lactic one glycated Ichiru acid copolymer as the biodegradable polymer compound, the composition ratio (mol _^0/0) is preferably 100 / 0-40 Bruno 60, 100 / 0-50 / 50 Is particularly preferred.

The weight average molecular weight of the above lactic acid-glycolic acid copolymer is usually from about 3,000 to about 50,000, preferably from about 4,000 to about, 40,000, more preferably from about 5,000 to about 4,000. It is about 30,000. The dispersity (weight average molecular weight / number average molecular weight) is usually preferably about 1.2 to about 4.0, more preferably about 1.5 to 3.5. The weight-average molecular weight, number-average molecular weight and dispersity in the present specification mean that the weight-average molecular weight is 1, 110,000, 707,000, 354,000, 189, 000, 156,000, 98, 900, 66. , 437, 37, 200, 17, 100, 9, 830, 5, 870, 2, 500, 1, 303, 500 Measured by gel permeation chromatography (GPC) using 14 kinds of polystyrene as reference materials Means the calculated molecular weight in terms of polystyrene and the calculated degree of dispersion. For measurement Was used with a GPC column KF804LX2 (manufactured by Showa Denko) and Kuguchiguchi form as the mobile phase. In addition, biodegradable 'I' raw polymer is dissolved in a mixed solvent of acetone and methanol, and phenolphthalein is used as an indicator. This solution is titrated with an alcoholic solution of sodium hydroxide and potassium hydroxide, and the carboxy group is titrated. The number average molecular weight obtained by quantification was calculated as the number average molecular weight obtained by quantification of the terminal group, while the number average molecular weight obtained by quantification of the terminal group was an absolute value. Since relative values vary depending on the analysis conditions (eg, mobile phase type, column type, reference material, slice width selection, baseline selection, etc.), it is difficult to make a unique numerical value, but for example, , A polymer synthesized from lactic acid and glycolic acid by a noncatalytic dehydration polycondensation method and having a free hydroxyl group at the terminal has a number average molecular weight determined by GPC The number average molecular weight determined by the terminal group is almost the same as that of the lactic acid-glycolic acid copolymer when the number average molecular weight determined by the terminal group is about 0.2 of the number average molecular weight determined by the GPC measurement. It is referred to as being within a range of about 1.5 to about 1.5 times, preferably within a range of about 0.3 to about 1.2 times. Non-catalytic dehydration polycondensation from acid (Japanese Patent Application Laid-Open No. 61-28521) or ring-opening polymerization using a catalyst from a cyclic substance such as lactide and glycolide (Encyclopedic Handbook of Biomaterials and Bioengineering Part A: Materials, Volume 2, Marcel Dekker, Inc., 1995.

 The polymer synthesized by ring-opening polymerization is a polymer having no carboxyl group, but a polymer in which the polymer is chemically treated to have a free carboxyl group at its end (Journal Reb Control Releases (J. Controlled Release), Vol. 41, pp. 249-257, pp. 1996 can also be used.

The above-mentioned lactic acid-dalicholic acid copolymer having a free carboxyl group at its terminal can be prepared by a known production method (for example, a non-catalytic dehydration polycondensation method, see Japanese Patent Application Laid-Open No. 61-28521). A polymer having a free carboxyl group which is not specified at the terminal can be produced by a known production method (for example, see WO94 / 15587). In addition, a lactate-glycolic acid copolymer whose terminal has been converted into a free carboxyl group by a chemical treatment after ring-opening polymerization is, for example, Behringer-zingerheim

 (Boehringer Ingelheim KG) may be used.

 These biodegradable polymer compounds may be used alone or as a mixture of two or more. The form of the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include sustained-release agents that maintain its effects over a long period of time. The form of the sustained-release preparation is not particularly limited, but a parenteral preparation is preferable, and a transdermal preparation, a transmucosal preparation, an implant, a microcapsule injection, and the like can be considered. Injectable preparations using microcapsules, which place little burden on patients, are preferred. Preferred methods for producing the pharmaceutical composition of the present invention include a method of removing a solvent from a liquid containing compound (I) or a salt thereof and a biodegradable polymer compound. The liquid containing compound (I) or a salt thereof may be a suspension.

 In the pharmaceutical composition of the present invention, a method for producing a sustained-release preparation, in particular, a microcapsule (hereinafter sometimes referred to as a microsphere) is illustrated below.

 (I) Underwater drying method

 An organic solvent solution of a biodegradable polymer compound is heated with an organic compound solution (I) or a salt thereof to prepare an organic solvent solution. At this time, the compound (I) or a salt thereof may not be completely or partially dissolved in the organic solvent solution of the biodegradable polymer compound and may be dispersed, and may be a known compound such as a homogenizer or an ultrasonic wave. It is preferable to disperse finely in a short time by the above method. Also, depending on the solubility of the drug, water may be added to the organic solvent.

Examples of the organic solvent include halogenated hydrocarbons (eg, dichloromethane, chlorophonolem, dichloroethane, trichloroethane, carbon tetrachloride, etc.), ethers (eg, ethyl ether, isopropyl ether, etc.), fatty acid esters (eg, 齚Ethyl acid, butyl acetate, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), alcohols (eg, ethanol, methanol, etc.), acetonitrile, lower fatty acids (eg, acetic acid, propionic acid, etc.) are used. Can be These are appropriate May be used as a mixture. Of these, dichloromethane is preferred as the halogenated hydrocarbon, ethanol and methanol as the alcohol, and acetic acid as the lower fatty acid. These may be used in a mixture at an appropriate ratio (for example, a mixed solvent of a halogenated hydrocarbon and a lower fatty acid (for example, acetic acid)). An additive may be added to the above organic solvent solution. Examples of the additives include acetic acid, carbonic acid, oxalic acid, citric acid, phosphoric acid, phosphoric acid, hydrochloric acid, benzoic acid, ascorbic acid, tartaric acid, etc., as solubilizing agents for maintaining the stability and solubility of the drug. Sodium hydroxide, arginine, lysine, aspartic acid or salts thereof may be added. Further, as a drug stabilizing agent, a polyol compound such as albumin, gelatin, cunic acid, sodium ethylenediaminetetraacetate, dextrin, sodium bisulfite, polyethylene glycol, etc., or paraoxybenzoic acid, which is generally used as a preservative, is used. Estenoles (eg, methylparaben, propylparaben, etc.), benzyl alcohol, octabutanol, thimerosal, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like may be added.

The concentration of the biodegradable polymer compound in the organic solvent solution varies depending on the molecular weight of the biodegradable polymer and the type of the organic solvent.For example, when dichloromethane is used as the organic solvent, generally, It is selected from about 0.5 to about 70% by weight, more preferably about 1 to about 60% by weight, and particularly preferably about 2 to about 50% by weight. Next, an organic solvent solution of the biodegradable polymer compound containing the obtained compound (I) or a salt thereof was added to the aqueous phase to form an o (oil phase) / W (aqueous phase) emulsion. Thereafter, the solvent in the oil phase is evaporated to prepare microcapsules. The volume of the aqueous phase at this time is generally about 1 to about 100,000 times the volume of the oil phase, more preferably about 5 to about 5,000 times, and particularly preferably about 10 to 100 times. It is selected from double to about 2000 times. An emulsifier may be added to the above external water phase. In general, the emulsifier may be any one that can form a stable oZw emulsion. Specifically, for example, anionic surfactants (sodium oleate, sodium stearate, sodium lauryl sulfate, etc.), nonionic surfactants (polyoxyethylene sorbitan fatty acid ester (Tween _OVeen ) 80, Tween (IVeen) 60, Atlas powder One company), polyoxyethylene castor oil derivatives (HC0-60, HC0_50, Nikko Chemicals, etc.), polybutylpyrrolidone, polybutyl alcohol, carboxymethyl cellulose, lecithin, gelatin, hyaluronic acid and the like. You may use one of these or a combination of two or more. The concentration at the time of use is preferably in the range of about 0.01 to 10% by weight, more preferably in the range of about 0.05 to about 5% by weight. An osmotic pressure regulator may be added to the above external aqueous phase. The osmotic pressure adjusting agent may be any as long as it exhibits an osmotic pressure when used as an aqueous solution.

 Examples of the osmotic pressure adjusting agent include polyhydric alcohols, monohydric alcohols, monosaccharides, disaccharides, oligosaccharides, amino acids, and derivatives thereof.

 Examples of the above-mentioned polyhydric alcohols include dihydric alcohols such as glycerin, pentahydric alcohols such as arabitol, xylitol and adtol, and hexahydric alcohols such as mannitol, sorbitol and dulcito tonle. . Of these, hexahydric alcohols are preferred, and mannitol is particularly preferred.

 Examples of the above monohydric alcohols include methanol, ethanol, and isopropyl alcohol, and among them, methanol is preferable.

 Examples of the above monosaccharides include pentoses such as arabinose, xylose, lipose, and 2-deoxyribose, and hexoses such as pudose, fructose, galactose, manose, sorbose, rhamnose, and fucose. Carbohydrates are preferred.

 As the oligosaccharide, for example, trisaccharides such as maltotriose and raffinose sugars, and tetrasaccharides such as stachyose are used, and among them, trisaccharides are preferable. As the derivatives of the above monosaccharides, disaccharides and oligosaccharides, for example, dalcosamine, galactosamine, glucuronic acid, galacturonic acid and the like are used.

As the above amino acids, any L-form amino acid can be used, and examples thereof include glycine, leucine, arginine and the like. Of these, L-arginine is preferred. These osmotic pressure regulators may be used alone or as a mixture.

 These osmotic pressure adjusting agents are used at a concentration such that the osmotic pressure of the external aqueous phase is about 1 Z50 to about 5 times, preferably about 1 to 25 to about 3 times the osmotic pressure of physiological saline. As a method for removing the organic solvent, a method known per se or a method analogous thereto is used. For example, a method in which the organic solvent is evaporated at normal pressure or gradually reduced pressure while stirring with a propeller-type stirrer or a magnetic stirrer, etc., and the organic solvent is evaporated while adjusting the degree of vacuum using a rotary vaporizer. The method of making it do.

The micro force cell obtained in this way is separated by centrifugation or filtration, and then the physiologically active compound, drug-retaining substance, lactating agent, etc. adhering to the surface of the microcapsule are distilled water several times. Wash repeatedly, disperse again in distilled water and freeze-dry. During the manufacturing process, an anti-aggregation agent may be added to prevent aggregation of the particles. Examples of the aggregation inhibitor include water-soluble polysaccharides such as mannitol, ratatose, glucose, starches (eg, corn starch), amino acids such as glycine, and proteins such as fibrin and collagen. Among them, mannitol is preferred. After freeze-drying, if necessary, the microcapsules may be heated under reduced pressure so that the microcapsules do not fuse with each other to remove water and organic solvents in the microforce capsule. Preferably, the polymer is heated at a temperature slightly higher than the midpoint glass transition temperature of the biodegradable polymer determined by a differential scanning calorimeter under a condition of a heating rate of 10 to 20 ° C per minute. . More preferably, the polymer is heated within a temperature range of about 30 ° C. higher than the midpoint glass transition temperature of the biodegradable polymer. In particular, when a lactic acid-dalicholic acid copolymer is used as the biodegradable polymer, the temperature range is preferably higher than the midpoint glass transition temperature and 10 ° C higher than the midpoint glass transition temperature, and more preferably, medium. Heat in the temperature range above the midpoint glass transition temperature and 5 ° C above the midpoint glass transition temperature. The heating time varies depending on the amount of microcapsules, etc. After the black capsule itself reaches a predetermined temperature, about 12 hours to about 168 hours, preferably about 24 hours to about 120 hours, particularly preferably about 48 hours to about 96 hours It is. The heating method is not particularly limited as long as the assembly of micro force cells can be uniformly heated.

 As the heating and drying method, for example, a method of heating and drying in a constant temperature bath, a fluidized bath, a moving tank or a kiln, a method of heating and drying with a microwave, and the like are used. Of these, the method of heating and drying in a thermostat is preferred.

(I I) Phase separation method

 When microcapsules are produced by this method, a coacervation agent is added to an organic solvent solution of the biodegradable polymer compound containing the compound (I) or a salt thereof described in the above (I) in water drying method. Is added slowly with stirring to precipitate a micro force plate, which is then solidified. The coacervation agent is used in an amount of about 0.01 to 1.0 times, preferably about 0.05 to 500 times, particularly preferably about 0.001 to! 200 times the oil phase volume. To be elected.

 The coacervation agent is a polymer-based, mineral oil-based or vegetable oil-based compound which is miscible with an organic solvent and does not dissolve both the bioactive compound and the biodegradable polymer. If it is, there is no particular limitation. Specifically, for example, silicone oil, sesame oil, soybean oil, corn oil, cottonseed oil, coconut oil, linseed oil, mineral oil, n-hexane, n-heptane and the like are used. These may be used as a mixture of two or more.

 After fractionating the micro forceps obtained in this manner, washing is repeated with heptane or the like to remove bioactive compounds and coacervation agents other than the biodegradable polymer, and then dried under reduced pressure. I do. Alternatively, washing may be performed in the same manner as described in the underwater drying method (I), followed by freeze-drying, and further, desolvation by heating and drying.

(I I I) Spray drying method

In the case of producing microcapsules by this method, the organic solvent solution of the biodegradable polymer conjugate containing the compound (I) or the salt thereof described in the above-mentioned (I) in water drying method is sprayed with a nozzle. Spray into the drying room of a spray dryer (spray dryer) Then, the organic solvent in the atomized droplets is volatilized in a very short time to prepare microcapsules. Examples of the nozzle include a two-fluid nozzle type, a pressure nozzle type, and a rotating disk type. After that, if necessary, washing may be carried out in the same manner as described in the above-mentioned in-water drying method (I), followed by freeze-drying, and further, desolvation by heating and drying.

 As a dosage form other than the above-mentioned microcapsules, an organic solvent solution of the biodegradable polymer compound containing the compound (I) or a salt thereof described in the in-water drying method of the microcapsule production method (I) may be used, for example, by rotary. After evaporating the organic solvent and water to dryness while adjusting the degree of vacuum using an evaporator or the like, the powder may be ground into fine powder by a jet mill or the like.

 Further, the pulverized fine powder may be washed in the same manner as described in the in-water drying method of the microcapsule production method (I), followed by freeze-drying, and further, desolvation by heating and drying.

 In the microphone mouth capsule or fine powder obtained here, the drug release can be controlled in accordance with the decomposition rate of the biodegradable high molecular compound to be used and the type and amount of the compound (I) or its salt. The sustained-release preparations thus obtained can be formulated as such or as a raw material in various dosage forms, and can be used in the periosteum, subperiosteum, near the bone, in the knee joint, in the shoulder joint, in the finger joint. Injection or implant for intramuscular, subcutaneous, organ, etc., transmucosal agent for nasal cavity, rectum, child, etc., inhalant, oral (eg, capsule (eg, hard capsule, soft capsule, etc.) ), Solid preparations such as granules and powders, and liquid preparations such as syrups, emulsions and suspensions). It can also be administered with a needleless syringe. When administered intra-articularly, it can be administered suspended in an aqueous solution of hyaluronic acid. When administered as an implant for fractures, etc., it can be administered in combination with implanted bone, hydroxyapatite or artificial bone. It can also be administered by mixing it with bone cement such as polymethyl methacrylate / calcium phosphate.

For example, in order to make the pharmaceutical composition of the present invention an injection, it is necessary to use a dispersant (eg, aniline). On-surfactants (sodium oleate, sodium stearate, sodium lauryl sulfate, etc.), non-ionic surfactants (polyoxyethylene sorbitan fatty acid ester (Tween 80, Tween 60, Atlas powder) Co., Ltd.), polyoxyethylene castor oil derivatives [HC0_60, HC0-50, Nikko Chemicals] etc.), stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, benzalkonium chloride, chloridenebenzetonium, monostearic acid Surfactants such as glycerin; lecithin; gelatin; polybulpyridone; polybutyl alcohol; hyaluronic acid or a salt thereof (such as sodium salt); polysaccharides such as carboxymethylcellulose and sodium alginate; Examples: Esters of paraoxybenzoic acid such as methylparaben or propylparaben, chlorobutanol, pentinoleanolechol, methylosal, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc., tonicity agents (eg, sodium chloride, mannitol, sorbitol) , Pudose, proline, glycerin, etc.), buffers

(Eg, buffers such as phosphates, acetates, carbonates, citrates), soothing agents (eg, benzyl alcohol), etc. Aqueous suspensions Dispersed with vegetable oils such as sesame oil and corn oil Thus, a sustained-release injection that can be actually used as an oily suspension can be obtained.

 When used as a suspension injection, the particle size of the sustained-release preparation in the pharmaceutical composition of the present invention may be within a range that satisfies the dispersibility and the needle penetration property. For example, the average particle diameter About 0.01 to 300 μπι, preferably about 0.05 to 150 μm, and more preferably about 0.1 to 100 μπη.

In order to make the sustained-release preparation in the pharmaceutical composition of the present invention into a sterile preparation, a method for sterilizing the production process, a method for sterilizing with gamma rays, a method for combining these, or a method for adding a preservative, etc. However, there is no particular limitation. The compound (I) or a salt thereof used in the present invention has excellent alkaline phosphatase inducing activity and chondromodulin production promoting activity and / or expression enhancing activity. Inducing osteoblast differentiation including progenitor osteoblasts, promoting differentiation induction, promoting chondrogenesis, including precursor chondrocytes In addition, it is expected to have a chondrocyte differentiation-inducing and differentiation-inducing promoting action, and also a BMP action enhancing action. If such differentiation is induced, the differentiation induction promoting action acts on not only osteoblast and chondrocyte differentiation but also differentiation induction of various cells. Compound (I) or a salt thereof is expected to have a neurotrophic factor action-enhancing activity. Further, compound (I) or a salt thereof is expected to have anti-matrix meta-oral protease (anti-MMP) activity. It is caloric and has excellent clinically useful properties such as stability and bioavailability. Compound (I) or a salt thereof, which is used in the present invention, has a strong osteogenesis promoting action, osteoblast differentiation induction and differentiation induction promoting action including precursor osteoblasts, chondrogenesis promoting action, cartilage including precursor chondrocytes Since the cell differentiation-inducing and differentiation-inducing action and the BMP action-enhancing action are expected, the pharmaceutical composition of the present invention may be used for, for example, an osteogenesis-promoting agent, an agent for preventing and treating bone disease, an agent for preventing and treating bone fracture, and cartilage. As a formation promoting agent and a therapeutic agent for preventing cartilage diseases, specifically, in the field of orthopedics, simple fractures, intractable fractures, incomplete bone fusion, false joints, refractures, bone deformities and osteoarthritis, osteosarcoma, myeloma, bone Non-metabolic bone diseases such as dysplasia, scoliosis, etc .; bone defects, osteoporosis, osteomalacia, rickets,, wein's [[osteomyelitis, renal osteodystrophy, bone Behcet's disease, rigid myelitis] Metabolic bone diseases such as; As a prophylactic / therapeutic agent for osteoarthritis and similar diseases, and for joint diseases represented by cartilage diseases such as rheumatoid arthritis, as a bone tissue repair agent after surgery for multiple myeloma, lung cancer, breast cancer, etc. In the dental field, which can be used in combination with autologous bone grafting and artificial bone grafting in order to promote bone formation after bone resection, treatment of periodontal disease, tooth in periodontal disease It is also expected to be applicable to repair of peripheral tissue defects, stabilization of artificial dental roots, ridge formation, and repair of cleft lip.

 In addition, since compound (I) or a salt thereof used in the present invention is expected to have a neurotrophic factor action-enhancing activity, Alzheimer's disease and general senile dementia, motor-Euron's disorder Treatment and prevention of various neurodegenerative diseases such as (amyotrophic lateral sclerosis) and diabetic peripheral neuropathy can be expected.

Furthermore, since the pharmaceutical composition containing the compound (I) of the present invention or a salt thereof is expected to have anti-MMP activity, it can be used for osteoarthritis, rheumatoid arthritis, arteriosclerosis, cancer Treatment and prevention of MMP-related diseases such as metastasis can be expected. Since the pharmaceutical composition of the present invention has low toxicity, it can be safely administered to mammals (eg, human, rat, mouse, dog, rabbit, cat, cat, pig, pig, etc.). You.

 The dose of the pharmaceutical composition of the present invention depends on the type and content of the bioactive compound as the main drug, dosage form, administration route, duration of release of the bioactive compound, target disease, target animal, and subject to be treated. It varies depending on the condition of the animal and the like, but may be any effective amount of the physiologically active compound. The daily dose of the pharmaceutical composition is, for example, about 0.1 mg to about 50 Omg, preferably in the case of oral administration per adult (body weight 50 kg) as a compound (I) or a salt thereof. Is in the range of about 1 mg to about 100 mg, for parenteral administration, for example, in the range of about 0.01 mg to about 100 mg, preferably about 0.1 mg to about 10 mg. Can be administered.

 When the pharmaceutical composition of the present invention is a sustained release preparation, Compound (I) or a salt thereof is released per adult (body weight 50 kg) per day, for example, about 0.0 Img to about 100 mg. As described above.

 The frequency of administration of the pharmaceutical composition of the present invention depends on the type and content of the biologically active compound as the active ingredient, dosage form, administration route, duration of release of the biologically active compound, target disease, target animal, target animal to be treated, etc. Can be selected as appropriate, for example, once a week, once a few weeks, once a month, or once a few months (eg, 3 months, 4 months, 6 months, etc.) The times can be selected as appropriate.

The duration of release of the physiologically active compound can be obtained by appropriately selecting the type, composition and blending amount of the biodegradable polymer compound to obtain the required duration of release of the biologically active compound. The pharmaceutical composition of the present invention comprises a cartilage disease healing promoting substance (eg, chondroitin, chondroitin sulfate, dextran sulfate, dalcosamine, dalcosamine darican, bone formation protein (BMP), transforming growth factor (TGF- / 3) ), An anti-inflammatory agent (such as cortisol palmitate) or a lubricating substance (such as hyaluronan), or as a single preparation, or at the same time or at intervals of time. it can. Further, the pharmaceutical composition of the present invention includes, for example, (1) a cyclooxygenase inhibitor (Cox-I, Cox-II inhibitor), (2) a disease-modifying antirheumatic drug and an immunosuppressant, and (3) a biologic. It can be administered simultaneously or at intervals with ④ analgesics and anti-inflammatory agents or ⑤ other prophylactic or therapeutic agents for bone or joint diseases. The route of administration can be appropriately selected, and may be, for example, oral, topical or transdermal administration.

 (1) Examples of cyclooxygenase inhibitors (CoX-I, Cox-II inhibitors) include salicylic acid derivatives such as celecoxib, oral fuecoxib, and aspirin, diclofenac, indomethacin, loxoprofen, and the like. The dosage of these oral preparations is, for example, about 100 to 20 Omg / day for celecoxib, about 10 to 30 mg / day for oral fuecoxib, about 1000 to 4500 mg / day for salicylic acid derivatives such as aspirin, and about 25 to 50 mg for diclofenac. 75 mg / day, indomethacin is about 50 to 15 Omg / day, and loxoprofen is about 60 to 180 mg / day.

 (2) Examples of disease-modifying antirheumatic drugs and immunosuppressants include methotrexate, leflunomide, prograf, sulfasalazine, D-penicillamine, and oral gold preparations. The dosage of these oral preparations is, for example, about 2.5 to 7.5 mg / week for methotrexate, about 20 to: leflunomide: about L0 Omg / day, about 1 to 5 mg / day for prograf, and about sulfasalazine for About 500-200 Omg / day, D

— Penicillamine is about 100 to 600 mg / day, and oral gold is about 3 to 6 mg / day.

③ Examples of biologics include monoclonal antibodies (eg, anti-TNF-α antibody, anti-IL-12 antibody, anti-IL-16 antibody, anti-ICAM-I antibody, anti-CD4 antibody, etc.), soluble receptors (eg, , Soluble TNF-receptors, etc.) and proteinaceous ligands (IL-I receptor antagonists, etc.). The dose of these oral preparations is, for example, about 0.1 to 5 Omg / kg / day, preferably 0.5 to 20 mg / kg / day.

④ Painkillers Antiphlogistics include, for example, central analgesics (eg, morphine, codine, pentadisine, etc.), steroids (eg, prednisolone, dexamethazo) , Betamethasone, etc.), and anti-inflammatory enzyme agents (eg, promersin, lysozyme, proctase, etc.). The dosage of these oral preparations is, for example, about 1 to 100 Omg / day for central analgesics, preferably about 5 to 30 Omg / day, and about 0 to 40 Omg / day for steroids. Days, preferably about 0.5 to: 10 Omg / day, the anti-inflammatory enzyme agent is about 1 to 10 Omg / day, preferably about 5 to 4 Omg / day.

⑤Other bone or joint diseases [For example, if bone fracture, refracture, bone defect, osteoporosis, osteoarthritis, bone Behcet's disease, stiff myelitis, rheumatoid arthritis, osteoarthritis, etc.] Prophylactic and / or therapeutic agents for destruction of joint tissue and bone tissue repair after surgery for multiple myeloma, lung cancer, breast cancer, etc.], for example, calcium preparations (eg, calcium carbonate, etc.), calcitonin preparations (eg, , © Nagi calcitonin, salmon calcitonin, porcine calcitonin, Abikatonin etc.), vitamin D ₃ compounds (e.g., 1 Fei - hydroxycarboxylic vitamin D _3, 1 a, 25-dihydrazide mud carboxymethyl vitamin D _3, Furoka Rushitorioru, Sekarushifuヱ roll, etc.), sex hormone-related compounds (eg, tipolone, estrogen, estradione, saturon, raloxifene, Droloxifene, virgin melomeroxifene, tamoxifen, mieveristone, etc., prostaglandin A or bisphosphonic acids (eg, etidronate, simadronate, alendronate, tinoledronate, risedronate, clodronate, etc.), ipriflavones, fluorine compounds (eg, sodium fluoride, etc.), vitamin K _2, platelet-derived growth factor (PDGF), insulin-like growth factor one 1 and 2 (I GF-1, one 2), parathyroid hormone (Rotauita) compound (e.g., Rotauita ( 1-34), ΡΤΗ (1-84), ΡΤΗ (1-36), etc.). Hereinafter, the present invention will be described more specifically with reference to Reference Examples, Examples, and Experimental Examples, but these do not limit the present invention. Reference example 1

Preparation of 4,5-dihydro-1-methyl-8-phenoxy-1H-thieno [3,4-g] indazole-6-carboxamide: a) 4,5,6,7-Tetrahydro-3-methylsulfonyl-4-oxobenzo [c] thiophene-1 -force

To a dichloromethane solution (150 ml) of 4,5,6,7-tetrahydro-3-methylsulfanyl-4-oxobenzo [c] thiophene-to-carboxylic acid ethyl ester (5.0 g) under ice-cooling, _m -c Benzoic acid (16.0 g) was added, and the mixture was stirred at room temperature for 24 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 solution of sodium hydrogencarbonate and water, and further washed with ethyl acetate-hexane to obtain the title compound (5.5 g, 98%) as pale yellow crystals. Recrystallization from ethyl acetate-THF yielded a pale yellow prism. Melting point: 199-200 ° C. b) 4,5,6,7-Tetrahydro-4-oxo-3 -phenoxybenzo [c] thiophene-tricarboxylic acid ester:

4,5,6,7-Tetrahydro-3-methylsulfoninole-4-oxobenzo [c] thiophene-1-force To a solution of ethyl ester of rubonate (6.0 g) and phenol (2.2 g) in tetrahydrofuran (50 ml) Sodium hydride (1.0 g) was added, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added an aqueous solution of taenoic acid, and the mixture was concentrated under reduced pressure. The residual oil was poured into water and extracted with ethyl acetate. The organic layer was dried (MgSO _4), the solvent was obtained was evaporated under reduced pressure 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 -Jetoxymethinole-4,5,6,7-tetrahydro-4-oxo-3-phenoxybenzo [c] thinphen-1-forcenolevonic acid ethinole ester ':

A solution of boron trifluoride aetezole complex (4.54 ml) in dichloromethane (20 ml) was added dropwise to triethyl orthoformate (5.0 g) cooled to -40 ° C. The solution was stirred under ice-cooling for 15 minutes, and then cooled to -70 ° C. To the solution was added a solution of 4,5,6,7-tetrahydro-4-oxo-3-phenoquinbenzo [c] thiophene-1-carboxylic acid ethyl ester (4.78 g) in dichloromethane (25 ml), followed by disodium terephthalate. Propylethylamine (7.44 ml) was added dropwise. After stirring at -70 ° C for 1 hour, the reaction solution was poured into an aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The organic layer was washed with water, dilute hydrochloric acid and saturated brine, dried (MgSO _4), vacuum Shimono ' Shrank. The obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound

(6.3 g, 100%) as colorless needles, mp: 73-73 ° C. d) 4,5-Dihydro-1-methyl-8-phenoxy-1H-thieno [3,4_g] indazol_1-force ethyl ester of ribonate and 4,5-dihydro-2-methyl-8-phenoxy-2H-ceno [3,4-g] Indazole-1-potassium ethyl ester:

5-Jetoxymethyl-4,5,6,7-tetrahydro-4-oxo-3- 3-phenoxybenzo [c] thiophene-1-carboxylic acid ethyl ester (6.32 g), methylhydrazine monohydrate (6.32 g) A mixed solution of 0.7 g) and 2N hydrochloric acid (23raL) in 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 with water, aqueous sodium hydrogen carbonate solution, washed successively with saturated brine, dried (MgSO _4), and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (1: 2), the title compound was obtained as colorless prism crystals. 4,5-dihydro-1-methyl-8-phenoxy-1H-thieno [3,4_g] indazole-1-force ethyl ester of rubonate (2.38 g, 44 ° /.), Melting point: 91-93 ° C (re- Crystallizing solvent: AcOEt-hexane). 4,5-Dihydro-2-methyl-8-phenoxy-2H-cheno [3,4-g] indazomono-1-carboxylate 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-force rubonic acid:

4,5-dihydro-:!-Methyl-8-phenoxy-1H-thieno [3,4-g] indazol-1-carbonate ethyl ester (2.03 g), ethanol (50 mL) and 0.6N water A mixture of aqueous potassium oxide solutions (20 mL) was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, acidified with 2 N hydrochloric acid, and extracted with a mixture of ethyl acetate and THF. After the organic layer is successively washed with water, saturated Japanese brine, dried (MgSO _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-tomethyl-8-phenoxy-1H-cheno [3,4-g] indazole-6-force lipoxamide:

4, 5 - dihydro - 1-methyl - 8 - phenoxy - 1H-thieno [3, 4_g] Indazo one Roux 6 - Power Honoré Pont acid (0. 50g), H0Bt-NH 3 (0. 26g), WSC (0 36 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 the mixture was extracted with a mixed solution of ethyl acetate-THF. The organic layer was washed successively with water and saturated brine, dried (M _g S0 _4), and reduced pressure concentrated. 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

 Preparation of 8-benzyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: a) 3-benzyl-4,5,6,7-tetrahydro- 4-oxobenzo [c] thiophene-1-potassium ethinolate

4,5,6,7-Tetrahydro-3-methylsulfoninole-4-oxobenzo [c] thiophene-1_force 1M benzylmagnesium bromide ether solution (300 ml) in anhydrous THF solution (6.0 g) 21 ml) was added dropwise. After the mixture was stirred at room temperature for 2 hours, an aqueous solution of citric acid was added to the reaction solution. The THF was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried (MgSO _4), and concentrated under reduced pressure. The obtained residual oil was subjected to silica gel gel chromatography. The title compound (1.3 g, 21%) was obtained as pale yellow ff "crystals from the 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-ethoxymethyl-4,5,6,7-tetrahydro-4-oxobenzo [c] thiophene-1-potassium olevonate Esthenore:

In the same manner as in Reference Example lc), the title compound (yield: 100%) was pale yellow from 3-benzyl-4,5,6,7-tetrahydro-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester. Obtained as an oil. ¾-NMR (δ ppm in CDC1 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. OHz), 3.5-3.9 (5H, m), 4.28 (2H, q, J = 7.4Hz) , 4.59 (2H, s), 5.11 (1H, d, J = 3.6 Hz), 7.2-7.4 (5H, m). C) 8-benzyl-4,5-dihydro- 1-Methyl-1H-thieno [3,4-g] indazole-6-force ethyl benzoate and 8-benzyl-4,5-dihydro-2-methyl-2H-thieno [3,4-g] indazole -6-Carboxylic acid ethyl ester:

 In the same manner as in Reference Example Id), 8-benzyl-5-ethoxymethyl-4,5,6,7-tetrahydrido-4-oxobenzo [c] thiophene-1-carboxylic acid ethynoleate was used to give 8-butane. Benzyl-4,5-dihydro-trimethyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (yield: 79%) as a pale yellow oil and 8_benzyl-4,5 2-Diethyl mouth-2-methyl-2H-thieno [3,4_g] indazole-6-potassium ethyl ester (yield: 20%) was obtained as a pale yellow oil.

8_ benzyl - 4, 5 - dihydro - 1 - methyl - 1H-Cheno [3, 4-g] Indazoru - 6-carbonitrile phosphate Echiruesuteru: W-NMI S ppm in CDC1 3): 1. 33 (3H, t , J = 7.2 Hz),

2.64 (2H, t, J = 6.8 Hz), 3.20 (2H, t, J = 6.8 Hz), 3.97 (3H, s), 4.30 (2H, q, J = 7 2Hz), 4.38 (2H, s), 7.2.7.4 (5H, ra), 7.44 (1H, s).

8-benzyl - 4, 5-dihydro - 2 - methyl - 2H - thieno [3, 4_g] indazole-6-phosphate Echiruesuteru:. ΝΜ (δ ppm in CDC1 3): l "32 (3H, t, J = 7. OHz),

 2.75 (2H, t, J = 7.2 Hz), 3.30 (2H, t, J = 7.2 Hz), 3.92 (3H, s), 4.27 (2H, q, J = 7 OHz), 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] indazol-6-carboxylic acid:

In the same manner as in Reference Example le), the title compound (yield: 84%) was prepared from 8-benzyl-4,5-dihydro-1-methinole-1H-thieno [3,4-g] indazole-6-carboxylate. ) 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:

In the same manner as in Reference Example If), the title compound (yield: 94%) was obtained from 8-benzyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid. ) Was obtained as pale yellow prism crystals. Melting point: 126-127 ° C (recrystallization solvent: AcOEt). Reference example 3

 Preparation of 4,5-dihydro-1-methyl-8-phenylsulfanyl-1H-cheno [3,4_g] indazole-6-carboxamide: a) 5-Jetoxymethyl-4,5,6,7-tetrahid Dro-3-methylsulfanyl-4-oxobenzo [c] thiophene-1-carboxylic acid ethyl ester:

In the same manner as in Reference Example lc), the title compound (yield: 100%) was prepared from 4,5,6,7-tetrahydro-3-methylsulfal-4-oxobenzo [c] thiophene-to-carboxylic acid ethyl ester. Obtained as colorless needles. Melting point: 115-116 ° C b) 4,5-Dihydro-1-methyl-8-methylsulfal-1H-thieno [3,4-g] indazo mono- 6-carboxylate

In the same manner as in Reference Example Id), the title compound (yield: 5-ethyloxymethyl-4,5,6,7-tetrahydro-3-methylsnorephanyl-4-oxobenzo [c] thiophen-1-carboxylate) : 77%) as pale yellow prism crystals. Melting point: 113-114 ° C (recrystallization solvent: AcOEt-hexane). c) 4,5-Dihydro-1-methyl-8-methinolesulfonyl-1H-thieno [3,4-g] indazole-6-carboxylate ethenoleestenole:

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 This gave the title compound (79 g, 90%) as yellow needles. Melting point: 140-141 ° C d) 4,5-Dihydromethyl-8-phenylsulfanyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester:

 4,5-Dihydromethyl-8-methylsulfol-1H-thieno [3,4-g] indazole-

To a solution of 6-carboxylic acid ethyl ester (2.0 g) and thiophenol (0.60 ml) in THF (70 ml) was added 60% sodium hydride (0.26 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was stirred at room temperature for 5 hours. The reaction solution was poured into an aqueous solution of citrate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried (M _g S0 _4). The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. The title compound (0.90 g, 41%) was obtained as a pale yellow oil from the fraction eluted with ethyl acetate-hexane (1: 2). Ή-賺_{(δ ppm in CDC1 3):} 1. 35 (. 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 E) 4,5-Dihydro-1-methyl-8-phenylsulfa-nore-1H-thieno [3,4-g] indazole-6. -carboxylic acid:

In the same manner as in Reference Example le), the title compound (yield: 4,5-dihydro-1-methyl-8-phenylsulfaninole-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester was obtained. : 92%) as colorless prisms. Melting point: 286-287 ° C. f) 4,5-Dihydro-1-methyl-8-phenylsulfanyl-1H-thieno [3,4_g] indazole-6-carboxamide:

In the same manner as in Reference Example If), the title compound (yield: 95) was obtained from 4,5-dihydro-1-methyl-8-phenylsulfonyl-1H-thieno [3,4-g] indazole-6-carboxylic acid. %) As colorless prisms. Melting point: 205-206. C. The compounds of Reference Examples 4 to 9 were synthesized by the method according to Reference Example 1. Reference example 4 4,5-Dihydro-1-methyl-8- (3,4-methylenedioxyphenoxy) -1H-cheno [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-force / repoxamide

 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-caproloxamide

 Melting point: 212-213 ° C Reference Example 8

4,5-dihydro-8_ (3,4-dioxyphenoxy) -1- (2,2,2-trifluoroethyl) -1H-thieno [3,4- _§ : urel-6-carboxamide

 Melting point: 216—218 ° C Reference Example 9

 4,5-Dihydro-8- (2,3-dimethylphenoxy) -1- (2,2,2-trifluoroethyl) -1H-Ceno [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] indazo 1-yl-8-yl] benzyl benzoic acid ester Melting point: 92-93 ° C

4-[{6- (aminocarbonyl) -2-methyl-4,5-dihydro-1H-thieno [3,4-g] indazole-8-yl] oxy} benzylphosphonic acid ethyl ester

 Melting point: 180-181. C Reference example 1 2

Production of N-ethyl-4,5-dihydro "!-Methyl-8- (3,4-methylenedioxyphenoxy) -1H-thieno [3,4_g] indazole-6-carboxamide:

N-Ethyl-4,5-dihydro-methyl-8- (3,4-methylenedioxyphenoxy) obtained in Reference Example 4-1H-thieno [3,4-g] indazole-6-caprolufonic acid ( To a suspension (1.5 g) of THF (50 ml) was added oxalyl chloride (0.7 ml) and N, N-dimethylformamide (3 drops) under ice-cooling. After stirring at room temperature for 30 minutes, the mixture was 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 is water, after aqueous sodium bicarbonate solution, washed and dried with saturated Japanese brine (MgSO _4), and evaporated. The residual oil was subjected to column chromatography. From the fraction eluted from ethyl acetate-hexane (3: 2), the title compound (1.36 g, 84%) was obtained as colorless needles. Melting point: 138-139 ° C. Reference Example 1 3

 4,5-Dihydro-1-methyl-8- [4- (2-quinolylmethyloxy) phenoxy] -1H-Ceno [3,4-g] indazole-6-hexylboxamide a) 8- (4- Benzyloxyphenoxy) -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazono-6-carboxylic acid ethyl ester:

The title compound was obtained as pale yellow crystals from the compound obtained in Reference Example 1a) in the same manner as in Reference Example 1b). The crystals were recrystallized from tetrahydrofuran-ethyl acetate to obtain pale yellow prism crystals. 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 at normal pressure in a stream of hydrogen for 2 hours. The insolubles were removed by filtration, and the filtrate was concentrated to obtain pale yellow crystals. Recrystallize from tetrahydrofuran-ethyl acetate to give the title compound

(5.6 g, 94%) was obtained as pale yellow needles. Melting point: 245-246 ° C. c) 4,5-Dihydro-1_methyl _8_ [4- (2-quinolylmethyloxy) phenoxy] -1Η-thieno [3,4-g] indazol-6-ethyl ethyl ester:

4,5-Dihydro-8- (4-hydroxyphenoxy) -1_methyl-1H-thieno [3,4-g] indazole- _6- ethyl ester of rubonic acid. A DMF solution (50 ml) of methylquinoline hydrochloride (1.7 g) and potassium carbonate (1.7 g) 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 Kuen acid solution, water, washed successively with saturated brine, dried (MgSO _4), and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The title compound (1.9 g, 92%) was obtained as colorless prisms from the portion eluted with ethyl acetate: hexane (2: 1). Melting point: 12 to 122. C. d) 4,5-dihydro-1-methyl-8- [4- (2-quinolylmethyloxy) phenoxy] -1H-thieno [3,4-g] indazole-6-capillonic acid:

 Reference Example 1 In the same manner as in e), 4,5-dihydro-1-methyl-8- [4- (2-quinolylmethyl-loxy) phenoxy] -1H-thieno [3,4-g] indazole-6-force The title compound (yield: 98%) was obtained as colorless prisms from ethyl ester rubonate. Melting point: 269-

e) 4,5-Dihydro-1-methyl-8_ [4- (2-quinolylmethyloxy) phenoxy] -1H-thio Eno [3,4_g] indazole-6-carboxamide:

 Reference Example I 4,5-Dihydro-1-methyl-8- [4- (2-quinolylmethyloxy) phenoxy] -1H-thieno [3,4-g] indazol-6- The title compound (yield: 95%) was obtained as colorless prism crystals from carboxylic acid. Melting point: 214-215 ° C. The compounds of Reference Examples 14 to 15 were synthesized by a method according to Reference Example 13. Reference example 1 4

 4,5-dihydro-tomethyl-8- [4- (4-pyridylmethyloxy) phenoxy] -1H-cheno [3,4-g] indazole-6-carpoxamide

Melting point: 249-250 ° C Reference example 15

 4,5-dihydro-1-methyl-8- (4-fluorophenoxy) -1H-cheno [3,4-g] indazoyl-6-caproloxamide

Melting point: 188-189 ° C Reference Example 16

 4,5-dihydro-methyl-8- (3-pyridinyloxy) -1H-cheno [3,4-g] indazole-6-carboxamide a) 4,5-dihydro-1-methyl-8- (3- Pyridinyloxy) -1H-thieno [3,4-g] indinazono 1-6-force / Ethinoleestenole reponic acid:

3,4-Dimethoxyphenol (l.OOg) was dissolved in N-methylpyrrolidone (50 ml), and 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. The mixture was stirred at room temperature for 30 minutes and at 70 ° C for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer Kuen acid solution, water, washed successively with 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 fraction eluted with ethyl acetate: hexane (2: 1). Melting point: 74-75 ° C (recrystallization solvent: ethyl acetate-hexane). b) 4,5-Dihydro-trimethyl-8- (3-pyridinyloxy) -1H-cheno [3,4-g] indazole-6-carboxylic acid:

 In the same manner as in Reference Example le), the title compound was obtained from 4,5-dihydro-1-methyl-8- (3-pyridinyloxy) -1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester. (Yield: 99%) was obtained as colorless prism crystals. Melting point: 247-248 ° C (recrystallization solvent: tetrahydrofuran). c) 4,5-Dihydric mouth-1-methyl-8- (3-pyridinyloxy) -1H-cheno [3,4-g] indazole-6-carboxamide:

 In the same manner as in Reference Example 1f), the title compound was obtained from 4,5-dihydro-1-methyl-8- (3-pyridininoleoxy) -1H-thieno [3,4-g] indazole-6-carboxylic acid. The compound (yield: 91%) was obtained as colorless prism crystals. Melting point: 124-125 ° C (recrystallization solvent: tetrahydrofuran-isopropyl ether). Example 1

Lactic acid-glycolic acid copolymer [hereinafter may be referred to as PLGA in the formulation shown in Table 1. Lactic acid-glycolic acid composition ratio (mol./.) 75/25, weight average molecular weight 11300, number average molecular weight 6.430 by GPC measurement, number average molecular weight 3,530 by terminal group determination, Wako Pure Chemical Industries] After preparing a dichloromethane solution or suspension with the compound obtained in Reference Example, a 0.1% aqueous solution of polybutyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Co., Ltd.) (hereinafter referred to as PVA) in the volume shown in Table 1 The solution was sometimes referred to as a solution), and it was converted to 0 / W emulsion at 7, OOOrpm using a turbine type homomixer. The 0 / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane, solidify the oil phase, and collected using a centrifuge (05PR-22, Hitachi, Ltd.) at 3, OOOrpm. This was dispersed again in distilled water and then centrifuged to wash the free drug. The collected microforce was re-dispersed by adding a small amount of distilled water, and then freeze-dried. The incorporation rates of the compounds into the obtained micro force cells are as shown in Table 1. [table 1]

 Micro PLGA, chloro compound Compound PVA uptake rate

 Cuff. Cell Methane M (g / h quantity (mJL) (%)

 ヽ

 () (ml)

 BU01 1.9 4.0 Reference example 9 0.1 1600 86

 BU02 1.9 8.0 Reference example 4 0.1 1600 88

 BU03 1.9 4.0 Reference example 5 0.1 1600 95

 BU04 1.9 4.0 Reference example 1 1 0.1 1600 88

 BU05 1.9 9.0 Reference example 2 0.1 400 100

 BUOD 1.9 7.0 Reference example 6 0.1 400 100

 BU07 3.8 15.0 Reference example 1 0.2 800 100

 BU08 1.9 3.5 Reference example 1 0 0.1 400 98

 BU09 1.9 10 Reference example 3 0.1 800 100

 BU10 3.8 18 Reference example 8 0.2 1600 100

 BU11 3.8 10 Reference example 7 0.2 800 100

 BU13 5.7 6 Reference example 1 2 0.3 800 100

Example 2

The formulation shown in Table 2, also shown an uptake rate of microcapsules obtained in _c Table 2 prepared micro power capsule through the same process as in Example 1.

 [Table 2]

実施例 3

Example 3

According to the formulation shown in Table 3, the same procedure as in Example 1 was carried out to prepare a microphone mouth capsule of the compound of Reference Example 4. Table 3 also shows the rate of incorporation into the obtained microcapsules _c [Table 3]

実験例 1

Experimental example 1

 Using the microcapsules obtained in Example 1 as ligation products, lmg was dissolved in a dispersing medium [carboxymethylcellulose (1.25mg), Posisorbate 20 (0.25mg), and mann-tolu (12.5mg) were dissolved. Water] 0.25 mL, and administered subcutaneously to the head of 7-week-old male SD rats (n = 4) under ether anesthesia using a 23G injection needle. The rats were sacrificed at regular intervals after administration and the microcapsules remaining at the administration site were extracted. The results of quantifying the amount of compound X in the extracts by HPLC are shown in Table 4.

 [Table 4]

実験例 4

Experiment 4

Using the microphone-mouth capsules obtained in Examples 2 and 3, the amount of the compound remaining at the administration site was quantified in the same manner as in Experimental Example 1, and the results of calculating the residual ratio are shown in Table 5 as average values (n = 4 ). In experiments other than BU14, 15, 19, and 20, 20 mg of microcapsules were dispersed in 0.1 mL of the same dispersion medium as in Experimental Example 1 and administered. [Table 5]

 ： Not implemented Possibility of industrial use

 INDUSTRIAL APPLICABILITY The pharmaceutical composition of the present invention contains a high content of a physiologically active substance such as a substance promoting bone and cartilage formation and can control the release rate thereof, so that the desired pharmacological action of the physiologically active compound can be maintained for a long period of time. Can be expected. Thus, for example, bone disorders in mammals, such as bone fractures, refractures, intractable fractures, bone malunion, pseudoarthritis, osteomalacia, bone Behcet's disease, ankylosing spondylitis, autologous bone grafting, artificial bone grafting, deformity As a preventive or therapeutic agent for the destruction of bone and cartilage in osteoarthritis and similar diseases, as a bone tissue repair material after surgery for multiple myeloma, lung cancer, breast cancer, etc., and periodontal disease It can be used safely as an agent for promoting regeneration of periodontal tissue, etc.

 Furthermore, since the pharmaceutical composition of the present invention can maintain a constant blood concentration regardless of day and night, the dose and the number of doses can be reduced, and furthermore, the local concentration and the blood drug concentration can be reduced. It is expected that the treatment effect will be more clear because there is little change in the condition and there will be no change in the condition due to discontinuation of taking the drug.

Claims

 Scope of request General formula (l a)

[Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfol group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, Honolemil group, thioformyl group or formula: Z ¹ — Z ² (where Z ¹ is CO—, one CS SO—or one SO. And Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. Aa represents a 5- to 7-membered ring which may be substituted, and R represents a hydrogen atom, a halogen atom, a cyano group or an amino group or an acyl group which may be respectively substituted. And R represents a hydrocarbon residue or a heterocyclic group, and R may be substituted with a thiophene ring or a ring-constituting atom of the ring Aa to form a hydrocarbon ring or a heterocyclic ring. ] A pharmaceutical composition comprising a compound represented by the formula or a salt thereof and a biodegradable polymer compound. 2. General formula (la) Force S General formula (I) ''

[Wherein ring A is

(In the formula, R ³ 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.) A ring having a 5- to 7-membered hydrocarbon ring which may have a substituent; and the other symbols have the same meanings as in claim 1. The pharmaceutical composition according to claim 1, which is:  3. The pharmaceutical composition according to claim 1, wherein the biodegradable polymer compound is an aliphatic polyester.  4. The pharmaceutical composition according to claim 3, wherein the aliphatic polyester is a lactic acid-glycolic acid copolymer. 5. The lactic acid-glycolic acid copolymer has a composition ratio of lactic acid / glycolic acid of about 100 5. The pharmaceutical composition according to claim 4, which is a seasoning acid-glycolic acid copolymer having a molar ratio of 0 to 400.  6. The pharmaceutical composition according to claim 13, wherein the lactic acid-glycolic acid copolymer has a weight average molecular weight of about 3,000 to 500,000. 7. The pharmaceutical composition according to claim 1, which is a preparation for topical administration.  8. The pharmaceutical composition according to claim 1, which is a preparation for intra-articular administration.  9. The pharmaceutical composition according to claim 1, which is a sustained-release preparation.  10. The pharmaceutical composition according to claim 1, which is an agent for preventing or treating bone disease or cartilage disease.  11. The pharmaceutical composition according to claim 10, wherein the bone disease is a fracture or a bone defect. 12. The pharmaceutical composition according to claim 10, wherein the cartilage disease is osteoarthritis.  13. The pharmaceutical composition according to claim 9, wherein the sustained-release preparation is a microcapsule. 14. The pharmaceutical composition according to claim 1, wherein the organic solvent is removed from the organic solvent solution containing the compound represented by the general formula (la) or a salt thereof and a biodegradable polymer compound. Manufacturing method. 15. The organic solvent according to claim 14, wherein the organic solvent is one or a combination of two or more selected from halogenated hydrocarbons, ethers, fatty acid esters, aromatic hydrocarbons, alcohols, acetate and lower fatty acids. Manufacturing method.  16. The method according to claim 14, wherein the organic solvent is a halogenated hydrocarbon and a lower fatty acid.