WO2000016776A1 - Sustained release oral preparations - Google Patents

Abstract

Oral preparations with sustained release which can be prepared by mixing (1) a quinoline or quinazoline derivative or a thienopyridine or thienopyrimidine derivative with (2) a gelling substance optionally together with (3) a disintegration aid.

Description

 Description Sustained-release oral preparation Technical field

 The present invention relates to a sustained release preparation for oral administration containing quinoline or a quinazoline derivative or a thienopyridine or a thienopyrimidine derivative. Background art

 Japanese Unexamined Patent Publication No. Hei 6—2 9 3 6 3 4 discloses a plain tablet containing a low-melting oily substance and having improved abrasion resistance. It has been. This uncoated tablet has the above-described excellent properties of improved abrasion resistance, but also has the properties of high disintegration and high dissolution. However, when a plain tablet containing a drug is administered orally, the drug is released into the gastrointestinal tract at one time, and some drugs may show high blood levels.

 Drugs such as anti-inflammatory drugs such as arthritis drugs, anti-rheumatic drugs, bone formation promoters, and drugs that prevent or treat immunity-related diseases are required to act over a long period of time . By sustaining release from the formulation and smoothing the blood concentration after oral administration, sufficient side effects can be achieved with less side effects. Disclosure of the invention

The present inventors have conducted intensive studies to achieve sustained release from the preparation and to smoothen the blood concentration after oral administration.As a result, quinoline or a quinazoline derivative or a chenopyridine or a thienopyrimidine derivative had a gel-forming substance. And, if necessary, a disintegration aid, especially a saccharide, to control the release of quinoline or quinazoline derivatives or thienopyridine or chenopyrimidine derivatives. After finding that it can be provided, further research based on this finding The present invention has been completed.

 The present invention

 (1) a sustained-release oral preparation comprising (i) a quinoline or quinazoline derivative or a chenoviridine or a thienopyrimidine derivative and (ii) a gel-forming substance,

 (2) The preparation according to the above (1), wherein the quinoline or quinazoline derivative or the chenoviridine or thienopyrimidine derivative is a compound having an anti-inflammatory effect or an anti-rheumatic effect.

 (3) The preparation according to (1), further comprising a disintegration aid,

 (4) The preparation according to the above (1), wherein the gel-forming substance is a water-soluble polymer compound.

(5) The preparation according to the above (4), wherein the water-soluble polymer compound is a cellulose derivative, a polyvinyl polymer compound or a polyhydric alcohol.

 (6) The preparation according to the above (4), wherein the water-soluble polymer compound is hydroxypropylmethyl cellulose.

 (7) The preparation according to the above (3), wherein the disintegration aid is a saccharide,

 (8) The preparation according to the above (7), wherein the saccharide is a sugar alcohol,

 (9) (0) The preparation according to the above (1), wherein the quinoline or quinazoline derivative or thienopyridine or chenobilimidine derivative: (ii) the gel-forming substance is about 1: about 0.1 to 100 by weight,

 (10) (i) quinoline or quinazoline derivative or thienopyridine or chenobilimidine derivative: (ii) gel-forming substance: (iii) disintegration aid in a weight ratio of about 1: about 0.1 to 50: about 0 The formulation according to the above (3), which is 0.1 to 50,

(11) The preparation according to the above (1), wherein the gel-forming substance is blended in an amount of about 10% by weight or more based on the whole preparation.

(12) The quinoline or quinazoline derivative has the formula (x) _n- one R

[I]

[In the formula, Y is a nitrogen atom or C—G (G is an esterified or amidated propyloxyl group, an optionally substituted acyl group, an optionally protected hydroxyalkyl group, or a halogen atom. R ¹ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X ¹ represents an oxygen atom or an optionally oxidized sulfur atom, and n represents 0 or 1 and k represent 0 or 1. G and R ¹ may combine with each other to form a ring. Ring A and ring B may each have a substituent. The preparation according to the above (1), which is a compound represented by the formula or a salt thereof,

(13) Y is C_G ″ (G ′ ″ represents a carboxyl group which may be esterified), and R ¹ is substituted with a nitrogen-containing unsaturated heterocyclic group which may have a substituent. and has CI_ ₄ alkyl group (provided that the constituting nitrogen atom of a nitrogen-containing unsaturated heterocyclic group is bound to the <3 i ₄ alkyl group), preparation of (12) above, wherein n is 0 ,

 (14) When the quinoline or quinazoline derivative is ethyl 4- (3,4-dimethoxyphenyl)-6,7-dimethoxy-12- (1,2,4-triazolyl-1-ylmethyl) quinoline-3 A formulation according to the above (13), which is a carboxylate;

(15) Chenoviridine or a chenobilimidine derivative has the formula

Wherein R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom, or an optionally substituted alkyl group, and R ² and R ³ may be bonded and replaced It may form a 5- to 7-membered ring. W is a nitrogen atom, C—G ′ (wherein, G ′ represents an optionally esterified propyloxyl group or a halogen atom), X ² is an oxygen atom, Or a group represented by the formula: (CH ₂ ) _Q — (wherein Q is an integer of 0 to 5), and R ⁴ is a heterocyclic group which may be substituted Or a substituted or unsubstituted amino group, respectively. Ring D may be substituted. The preparation according to the above (1), which is a compound represented by the formula or a salt thereof,

(16) In a chenopyridine or chenobilimidine derivative, R ² and R ³ are combined to form an optionally substituted 5- to 7-membered ring, and W is C — G ′ (where G ′ is an ester Wherein R ⁴ is a heterocyclic ring which may be substituted, wherein R ⁴ is an optionally substituted heterocyclic group or a halogen atom.

 (17) a method for controlling the release of quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative obtained by mixing a gel-forming substance with an oral preparation containing quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative,

 (18) use of a gel forming substance for producing a sustained-release preparation containing a quinoline or quinazoline derivative or a chenopyridine or a thienopyrimidine derivative;

(19) A compound in which a quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative has an anti-inflammatory effect or an anti-rheumatic effect. The method according to the above (17), which is a compound,

 (20) Controlling release of quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative obtained by mixing a gel-forming substance and a disintegration aid with an oral preparation containing a quinoline or quinazoline derivative or a thienopyridine or thienopyrimidine derivative Method,

 (21) The method according to the above (17), wherein the gel-forming substance is a water-soluble polymer compound.

 (22) The method according to the above (21), wherein the water-soluble polymer compound is a cellulose derivative, a polyvinyl polymer compound or a polyhydric alcohol.

 (23) The method according to the above (21), wherein the water-soluble polymer compound is hydroxypropyl methylcellulose,

 (24) The method according to the above (20), wherein the disintegration aid is a saccharide,

 (25) The method according to the above (24), wherein the saccharide is a sugar alcohol,

 (26) The method according to the above (17), wherein (i) quinoline or a quinazoline derivative or a thienopyridine or thienopyrimidine derivative: (ii) the gel-forming substance is about 1: 1: about 0.1 to 100 by weight ratio. ,

 (27) (i) quinoline or quinazoline derivative or thienopyridine or chenobilimidine derivative: (ii) gel-forming substance: (iii) disintegration aid in a weight ratio of about 1: about 0 ::! (50) The method according to the above (20), which is about 0.01 to 50, (28) The gel-forming substance is blended in an amount of about 10% by weight or more based on the whole preparation, (17). The method described,

 (29) The quinoline or quinazoline derivative has the formula 1, J

[I]

Wherein Y is a nitrogen atom or C-G (G is a carboxyl group which may be esterified or amidated, an optionally substituted acyl group, a hydroxyalkyl group which may be protected or a halogen atom. R ¹ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X ¹ represents an oxygen atom or an optionally oxidized sulfur atom, and n represents 0 or 1. And k represents 0 or 1. G and R ¹ may combine with each other to form a ring. Ring A and ring B may each have a substituent. The method according to the above (17), which is a compound represented by the formula or a salt thereof,

(30) Y is C_G ″ (G ′ ″ represents a carboxyl group which may be esterified), and R ¹ is substituted with a nitrogen-containing unsaturated heterocyclic group which may have a substituent. — Alkyl group (provided that the nitrogen atom constituting the nitrogen-containing unsaturated heterocyclic group is

Wherein n is 0.

(29) The method described in paragraph (2),

 (31) The quinoline derivative or quinazoline derivative is ethyl 4- (3,4-dimethoxyphenyl) —6,7-dimethoxy-2- (1,2,4-triazol-1-ylmethyl) quinoline-1- The preparation according to the above (30), which is a carboxylate;

 (32) Chenoviridine or thienopyrimidine derivative has the formula

Wherein R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom, or an optionally substituted alkyl group, and R ² and R ³ may be bonded and replaced It may form a 5- to 7-membered ring. W is a nitrogen atom, C-G '(wherein G' represents a propyloxyl group or a halogen atom which may be esterified), X ² is an oxygen atom, May be A sulfur atom or a formula — (CH ₂ ) _q — (wherein Q is an integer of 0 to 5); and R ⁴ is an optionally substituted heterocyclic group or a substituted And each represents a diamino group. Ring D may be substituted. The method according to the above (17), which is a compound represented by the formula or a salt thereof,

(33) In the chenobilizine or chenobilimidine derivative, R ² and R ³ are combined to form an optionally substituted 5- to 7-membered ring, and W is C-G ′ (where G ′ is an ester A carboxyl group or a halogen atom which may be optionally substituted.) Wherein R ⁴ is a heterocyclic ring which may be substituted,

 (34) The use according to the above (18), wherein the quinoline or quinazoline derivative or the chenopyridine or thienopyrimidine derivative is a compound having an anti-inflammatory effect or an anti-rheumatic effect,

 (35) use of a gel former and a disintegration aid for producing a sustained-release preparation containing a quinoline or quinazoline derivative or a chenopyridine or a thienopyrimidine derivative;

 (36) The use according to the above (18), wherein the gel-forming substance is a water-soluble polymer compound.

 (37) The use according to the above (36), wherein the water-soluble polymer compound is a cellulose derivative, a polyvinyl polymer compound or a polyhydric alcohol.

 (38) The use according to the above (36), wherein the water-soluble polymer compound is hydroxypropylmethylcellulose,

 (39) The use according to the above (35), wherein the disintegration aid is a saccharide,

 (40) The use according to the above (39), wherein the saccharide is a sugar alcohol,

 (41) The use according to the above (18), wherein (i) a quinoline or a quinazoline derivative or a thienopyridine or a chenobilimidine derivative: (ii) the gel-forming substance is about 1: 1: about 0.1 to 100 by weight,

(42) (i) Quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative: (ii) gel-forming substance: (iii) disintegration aid in a weight ratio of about 1: about 0.1 to 50: about 0 The use according to the above (18), which is 0.1 to 50; (43) The use according to the above (8), wherein the gel-forming substance is at least about 10% by weight based on the whole preparation,

 (44) The quinoline or quinazoline derivative has the formula

(In the formula, Y represents a nitrogen atom or C_G (G represents an esterified or amidated propyloxyl group, an optionally substituted acyl group, an optionally protected hydroxyalkyl group, or a halogen atom. R ¹ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X ¹ represents an oxygen atom or an optionally oxidized sulfur atom, and n represents 0 or 1. , K represents 0 or 1. G and R ¹ may combine with each other to form a ring. Ring A and ring B may each have a substituent. The use according to the above (18), which is a compound represented by the formula or a salt thereof,

(45) Y is C-G '' (G '' represents a carboxyl group which may be esterified), and R ¹ is a nitrogen-containing unsaturated heterocyclic group which may have a substituent. is substituted CI- ₄ alkyl group (provided that the constituting nitrogen atom of a nitrogen-containing unsaturated heterocyclic group is bound to the C i_ ₄ alkyl group), (14) above, wherein n is 0 Use of,

 (46) When the quinoline or quinazoline derivative is ethyl 4- (3,4-dimethoxyphenyl) -1,6,7-dimethoxy-2- (1,2,4-triazolyl-1-ylmethyl) quinoline-3 Use of the above (45) which is a carboxylate,

(47) Chenopyridine or chenobilimidine derivative has the formula

Wherein R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom, or an optionally substituted alkyl group, and R ² and R ³ may be bonded and replaced It may form a 5- to 7-membered ring. W is nitrogen atom, one G C a group represented by '(wherein, G' is. Showing the esterified carboxyl group which may or halo gen atom,), X ² is an oxygen atom, optionally oxidized A sulfur atom or a group represented by the formula — (CH ₂ ) _Q — (wherein q represents an integer of 0 to 5), and R ⁴ represents an optionally substituted heterocyclic group or The amino groups that may be substituted are respectively shown. Ring D may be substituted. The use according to the above (18), which is a compound represented by the formula or a salt thereof, and

(48) In the chenobilizine or thienopyrimidine derivative, R ² and R ³ are combined to form an optionally substituted 5- to 7-membered ring, and W is C-G '(where G' is A carboxyl group which may be esterified, or a halogen atom.) Wherein R ⁴ is a heterocyclic ring which may be substituted; About. BEST MODE FOR CARRYING OUT THE INVENTION

The quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative contained in the sustained-release oral preparation of the present invention may be any as long as it can be used as a medicament. These derivatives include anti-inflammatory effects (especially anti-arthritic effects), anti-rheumatic effects, bone resorption inhibiting effects, immunomodulatory effects, and / or immune site forces [eg, interleukin-2 (IL-2), Interferonase (IFN-r) and the like] Compounds having an effect on production suppression are preferred. Specific examples of the quinoline or quinazoline derivative contained in the sustained-release oral preparation of the present invention include:

[Each group in the formula has the same meaning as described above. [I] or a salt thereof.

 Specific examples of the thienopyridine or thienopyri 'derivative contained in the sustained release oral preparation of the present invention include, for example,

[Each group in the formula has the same meaning as described above. [II] or a salt thereof.

In the above formula [I], examples of the hydrocarbon residue in the optionally substituted hydrocarbon residue represented by R ¹ include an aliphatic hydrocarbon residue, an alicyclic hydrocarbon residue, and an alicyclic ring. And aliphatic hydrocarbon residues, aromatic carbocycle-aliphatic hydrocarbon residues, aromatic hydrocarbon residues and the like.

Examples of the aliphatic hydrocarbon residue include a saturated aliphatic hydrocarbon residue having 1 to 10 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, pentyl, isopentyl) , Neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, deci Le etc.), unsaturated aliphatic hydrocarbon residues from 2 to 1 0 carbon atoms (e.g., C ₂ - _{1 0} alkenyl group, C ₂ - ₁₀ alkynyl group, and specific examples thereof, For example, vinyl (Ethenyl), aryl, 1-probenyl, 2-probenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1 1-propenyl, 1-pentenyl 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexagenenyl, 5-hexenyl, 1-heptenyl, 1 _Octenyl, ethynyl, 1_propynyl, 2_propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3_to Xynyl, 2,4-hexadinyl, 5-hexynyl, 11- heptynyl, 11-year-old cutinyl, etc.).

The alicyclic hydrocarbon residue, a saturated alicyclic hydrocarbon residues (e.g. carbon number 3~ _8, C ₃ - 8 cycloalkyl group, and specific examples thereof include e.g. consequent opening, cyclobutyl , cyclopentyl, cyclohexyl, Shikurohepu chill, and the like Shikurookuchiru) and, furthermore, C ₇ -. ₁₀ bicyclo alkyl group (e.g., bicyclo [2, 2, 1] heptyl, bicyclo [2, 2, 2] Octyl, bicyclo [3,2,1] octyl, bicyclo [3,2,2] nonyl, bicyclo [3,3,1] nonyl, bicyclo [4,2,1] nonyl, bicyclo [4,3, 1] decyl, etc.) and an unsaturated alicyclic hydrocarbon residue having 5 to 8 carbon atoms (eg, a C ₅ _ ₈ cycloalkenyl group, a C ₅ _ ₈ cycloalkadienyl group). Specific examples thereof include 1-cyclopentenyl, 2- Cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cyclopentenyl, 2,4-cyclohexenyl, 2,5-cyclohexenyl, 2,4-cyclohexenyl, etc.).

The alicyclic monoaliphatic hydrocarbon residue has 4 to 9 carbon atoms (e.g., cyclobutane) among the above-mentioned alicyclic hydrocarbon residue and aliphatic hydrocarbon residue bonded. Mouth pillmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclo Hexylpropyl, cycloheptylmethyl, cycloheptylethyl, etc.).

 Examples of the aromatic carbocyclic monoaliphatic hydrocarbon residue include phenylalkyl having 7 to 9 carbon atoms (eg, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, and 1-phenylpropyl). , Carbon number 1 :! To 13 naphthylalkyl (for example, α-naphthylmethyl, α-naphthylethyl, 3-naphthylmethyl, / 3-naphthylethyl) and the like. Examples of the aromatic hydrocarbon residue include a C6-C14 aryl group such as phenyl, naphthyl (eg, hinaphthyl, 3-naphthyl), anthryl, phenanthryl, and acenaphthylenyl.

In the above formula [I], the heterocyclic group in the optionally substituted heterocyclic group represented by R ¹ includes, for example, (i) 5 to 7 containing one sulfur, nitrogen or oxygen atom. Membered heterocyclic group, (ii) 5- to 6-membered heterocyclic group containing 2 to 4 nitrogen atoms, (iii): 5 to 6-membered containing! To 2 nitrogen atoms and one sulfur or oxygen atom And (iv) these heterocyclic groups may be fused to a 6-membered ring containing up to 2 nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom. Further, it may be a non-aromatic heterocyclic group.

 Specific examples of the heterocyclic group include, for example, (1) for example, chenyl, furyl, pyrazole, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,4-oxaziazolyl, 1,2, 3-oxosaziazolyl, 1,3,4-oxaxazolyl, furazanil, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,

Hetero selected from oxygen, sulfur, nitrogen, etc. in addition to carbon atoms such as 2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl A 5-membered heterocyclic group containing 1 to 4 atoms,

(2) For example, pyridyl, pyrimidinyl, thiomorpholinyl, morpholinyl, o Xoimidazinyl, triazinyl, pyrrolidinyl, piberidinyl, pyraryl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl, 3 — Or a 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen, etc., in addition to carbon atoms such as 4-pyridazinyl,

(3) For example, benzofuranyl, isobenzofuranyl, benzo [b] chenyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoy soxazolyl, benzotriazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolyl, isoindolyl, indolizinyl, quinolidinyl, 1,8-naphthyridinyl, prinyl, pteridinyl, dibenzofuranyl , Carbazolyl, a-,) 3_ or erupirporinyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, fenazinyl, fenoxazinyl, phenothiazinyl, fenoxathiinyl, titanyl Entrenyl, phenatridinyl, phenatrolinyl, 1H-indazole-3-yl, 1H-indazole-1-yl, 1H-pyrro [2,3-b] pyrazin-2-yl, 1H-pyr Mouth [2,3-b] Pyridine 6-yl, Pyro Mouth [1,2-b] Pyridazinyl, Pyrazo Mouth [1,5-a] pyridyl, 1 H-Imidazo [4,5-b] Pyridine 2-yl, 1H-imidazo [4,5-c] pyridine- 2-yl, imidazo [1,2_a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2— b] Pyridazinyl, imidazo [1, 2-a] Pyrimidinyl, 1H-imidazo [4, 5-b] pyrazine-2-yl, 1H-pyro-mouth [1, 2-a] imidazole-1-yl , 1 H-pyrrolo [1,2-b] [1,2,43 triazole-11-yl, 1,8a-dihydroleumidazo [1,2-a] pyridine- 1-yl, 7-purinyl, 3,3a-dihydro [1,2,4] triazolo [1,5-a] pyrimidine-13-yl, 1H-pyrazo mouth [4,3_d] oxazo 1-yl 1-yl, 4H-imidazo [4,5-d] thiazol 4-yl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4—triazolo [4,3-b] pyridazinyl, 1,8a-dihydro [1,2,4] triazolo [1,5-a] pyridine-11-yl, 3,3a-dihydro [1,2,4] triazolo [1,5—a] pyrimidine—3—yl, 1,8a—dihydroimidazo [1,2—a] pyrimidine—1yl, 1H—pyrazo mouth [4 , 3 — d] Oxazole— 1-yl, 4 H-imidazo [4, 5- d] Hetero selected from oxygen, sulfur, nitrogen, etc. in addition to carbon atoms such as thiazo-l- 4-yl A bicyclic or tricyclic fused heterocyclic group containing 1 to 4 atoms is exemplified. Preferable examples of the non-aromatic heterocyclic group include a 3 to 7-membered heterocyclic group containing 1 to 4 sulfur, nitrogen or oxygen atoms, oxilanyl, azetidinyl, oxedinyl, cesinyl, Pyrrolidinyl, tetrahydrofuryl, thiolanyl, piberidinyl, tetrahydropyranyl, morpholiel, thiomorpholinyl, piperazinyl and the like.

The hydrocarbon residue or heterocyclic group represented by R ¹ in the above formula [I] has 1 to 3 substituents at any substitutable position on the chain or the ring. Is also good. Examples of such a substituent include an aliphatic chain hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, a halogen atom, a nitro group, and a substituted group. Good amino group, optionally substituted acyl group, optionally substituted hydroxyl group, optionally substituted thiol group, optionally esterified lipoxyl group, amidino group, sorbamoyl group, sulfamoyl Group, sulfo group, cyano group, azido group, nitroso group, oxo group and the like.

 Examples of the aliphatic chain hydrocarbon group as the substituent include a linear or branched aliphatic hydrocarbon group, for example, an alkyl group (preferably an alkyl group having 1 to 10 carbon atoms), alkenyl Groups (preferably an alkenyl group having 2 to 10 carbon atoms), an alkynyl group (preferably an alkynyl group having 2 to 10 carbon atoms) and the like.

Preferred examples of the alkyl group include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, Crest Examples include syl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl, and decyl.

 Preferred examples of the alkenyl group include, for example, vinyl, aryl, isopropyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1 Butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4 —Hexenyl, 5-hexenyl and the like.

 Preferred examples of the alkynyl group include, for example, ethynyl, 1-propyl,

2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- Hexynyl, 5-hexynyl and the like.

The alicyclic hydrocarbon group as the substituent, C ₃ saturated or unsaturated - _1Q alicyclic hydrocarbon group (e.g., c ₃ - ₁₀ cycloalkyl group, c ₃ _ ₈ Shikuroaruke sulfonyl group, c ₄ _ ₈ such cycloalkadienyl group).

 The Cg-i. Preferred examples of the cycloalkyl group include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, Bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.

3.1] nonyl, bicyclo [4.2.1] noel and bicyclo [4.3.1] decyl.

Preferable examples of the C ₃ _ _s cycloalkenyl group, e.g., 2-Shikurobe pentene _ 1 _ I le, 3-cyclopentene - 1 _ I le, hexene one to 2-cyclopropyl

Examples thereof include 1-yl and 3-cyclohexene-11-yl, and among them, a cycloalkenyl group having 5 to 7 carbon atoms is preferable.

Preferable examples of the C ₄ _ ₈ cycloalkadienyl group include, for example, 2,4-cyclopentene-1-yl, 2,4-cyclohexadiene-1-yl, 5-cyclohexadene-1-yl; and among them, a cycloalkadienyl group having 5 to 7 carbon atoms is preferable.

 The aryl group as the substituent is preferably a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, and preferable examples thereof include, for example, phenyl, naphthyl, anthryl, Examples thereof include phenanthryl and acenaphthylenyl, and among them, phenyl, 1-naphthyl and 2-naphthyl are preferable.

 Preferable examples of the aromatic heterocyclic group as the substituent include (01) a 5- to 7-membered heterocyclic group containing one sulfur, nitrogen or oxygen atom, and (ii) 2 to 4 nitrogen atoms. A 5- to 6-membered heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur or oxygen atom, and (iii) an aromatic monocyclic heterocyclic group, For example, furyl, chenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4, oxazazolyl , 2,3 —thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3 —triazolyl, 1,2,4 —triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl , Pyrazinyl, triazinyl and the like,

(iv) As a fused aromatic heterocyclic group fused to a 6-membered ring containing 2 or less nitrogen atoms, a benzene ring or a 5-membered ring containing 1 sulfur atom, for example, benzofuranyl, isobenzofuranyl , Benzo [b] chenyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl , Quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, α-carporinyl, i3-carbolinyl, α-carbolinyl, acridinin, phenoxazinyl, phenothininyl, phenothininyl H Ntoreniru, Fuenatorijiniru, Hue Natororiniru, indolizinyl, pyrosulfate port [! 1, 2)] pyridazinyl, pyrazole port [1, 5 _ a] pyridyl, 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-!)] Pyridazinyl and the like.

 Preferable examples of the non-aromatic heterocyclic group as the substituent include a 3 to 7-membered heterocyclic group containing 1 to 4 sulfur, nitrogen or oxygen atoms, oxilanyl, azetidinyl, oxedynyl. , Quinyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piberidinyl, tetrahydroviranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like.

 Examples of halogen as the substituent include fluorine, chlorine, bromine and iodine, and fluorine and chlorine are particularly preferred.

 Examples of the amino group which may be substituted as the substituent include (i) an amino group, and (ii) a substituted amino group [alkyl having 1 to 10 carbons, alkenyl having 2 to 10 carbons, carbon An amino group having one or two substituents of an alkynyl having 2 to 10 carbon atoms, an acyl group having 1 to 10 carbon atoms, or an aromatic group or a heterocyclic group having 6 to 12 carbon atoms (eg, methylamino Dimethylamino, ethylamino, methylamino, dibutylamino, diarylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinylamino, etc.).

 Examples of the optionally substituted acyl group as the substituent include (i) formyl, and (ii) alkyl having 1 to 10 carbons, alkenyl or aromatic having 2 to 10 carbons. With a carbonyl group bonded (eg, acetyl, propionyl, butyryl, isoptyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentane luponyl, cyclohexanecarbonyl, cycloheptanecarbonyl, cycloheptanylcarbonyl) , 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, etc.).

Examples of the optionally substituted hydroxyl group as the substituent include (i) a hydroxyl group, and (ii) an appropriate substituent, particularly one used as a protecting group for a hydroxyl group. And a hydroxyl group (for example, alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyloxy, aryloxy, etc.).

 Examples of the alkoxy include alkoxy having 1 to 10 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy). , Isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.).

 Examples of the alkenyloxy include alkenyloxy having 2 to 10 carbon atoms (eg, allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy, etc.). Is preferred.

 As the alkynyloxy, an alkynyloxy having 2 to 10 carbon atoms (eg, ethynyloxy, 2-propynyloxy, etc.) is preferable.

As the aralkyloxy, for example, phenyl- _2- alkyloxy (eg, benzyloxy, phenethyloxy, etc.) can be mentioned.

 Preferred as the acyloxy are alkanoyloxys having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, petyriloxy, isobutyryloxy, etc.).

 Examples of the aryloxy include phenoxy, 4-chlorophenoxy and the like.

 Examples of the thiol group which may be substituted as the substituent include a thiol group and a thiol group having an appropriate substituent on the thiol group, in particular, a thiol group having a thiol group used as a protective group (for example, alkylthio, alkenylthio, Alkynylthio, aralkylthio, acylthio, arylthio, etc.).

Examples of the alkylthio include alkylthio having 1 to 10 carbon atoms (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, Hexylthio, heptylthio, nonylthio, cyclobutyl Ruthio, cyclopentylthio, cyclohexylthio, etc.) are preferred.

 Examples of the alkenylthio include alkenylthio having 2 to 1.0 carbon atoms (eg, allylthio, crotylthio, 2-pentenylthio, 3-hexenylthio, 2-cyclopentenylmethylthio, 2-cyclohexenyl And methylthio).

 As the alkynylthio, alkynylthio having 2 to 10 carbon atoms (eg, ethylthio, 2-propynylthio, etc.) is preferable.

 Examples of the aralkylthio include phenyl C alkylthio (eg, benzylthio, phenethylthio, etc.).

 As the acylthio, an alkanolthio having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.) is preferable.

 Examples of the arylthio include phenylthio and 41-chlorophenylthio.

 Examples of the carboxyl group which may be esterified as the substituent include (i) a carboxyl group, and (ii) a carboxyl group bonded to an alkyl group having 1 to 6 carbon atoms (that is, an alkoxy group such as methoxycarbonyl). (Iii) carboxyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.) Those having an alkenyl group having 3 to 6 carbon atoms bonded (ie, alkenyloxycarbonyl, for example, allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl, 3-hexenyloxy) (Xycarbonyl, etc.), and (iv ) Bonded carbonyl and aralkyl groups (ie, aralkyloxycarbonyl, such as benzyloxycarbonyl, phenethyloxycarbonyl, etc.).

In the above formula [I], the substituent in the hydrocarbon residue or the heterocyclic group represented by R ¹ may further have one or more, preferably 1 to 3 suitable substituents at any substitutable positions. You may have. Such substituents include, for example, ₁₀ alkyl group, C ₂ _ ₁₀ alkenyl, C 0 alkynyl group, C ₃ - ₈ cycloalkyl group, C ₃ _ ₈ cycloalkenyl group, C ₄ - ₈ cycloalkadienyl group, Ariru group, an aromatic heterocyclic group , Non-aromatic heterocyclic group, aralkyl group (eg, aryl

—Ci—6 alkyl group, etc.), amino group, N-monosubstituted amino group, Ν, ア ミ ノ -disubstituted amino group, amidino group, acyl group, carbamoyl group, Ν_monosubstituted carbamoyl group (eg, Methylcarbamoyl, ethylcarbamoyl, phenylcarbamoyl, etc.), Ν, Ν-disubstituted rubamoyl group (Ν, ジ メ チ ル _dimethylcarbamoyl, Ν, ジ ェ -getylcarbamoyl, piperidinocarbamoyl, morpholino carbamoyl, etc.) , Sulfamoyl groups, Ν_monosubstituted sulfamoyl groups (eg, methylsulfamoyl, ethylsulfamoyl, phenylsulfamoyl, ρ-toluenesulfamoyl, etc.), Ν, Ν-disubstituted sulfamoyl groups (eg, Ν, Ν_dimethylsulfamoyl, Ν-methyl_Ν-phenylsulfamoyl, piberidinosulfamoyl, morpholine Sulfamoyl, etc.), Karupokishi Le group, C. Alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, etc.), hydroxyl group, (: trialkoxy group, C ₂ _ ₁₀ Arukeniruokishi group, C ₃ one ₇ cycloalkyl O alkoxy group, Ararukiruokishi group, Ariruokishi group, mercapto group,. a lower alkylthio group, Ararukiruchio group, Ariruchio group, a sulfo group, Shiano group, azide group, a halogen atom, Examples of the substituent include a nitro group, a nitroso group, an oxo group, etc. Specific examples of such a substituent include the same as those described above as the substituent on the hydrocarbon residue, the heterocyclic group and the amino group. One.

In the above formula [I], the optionally substituted hydrocarbon residue represented by R ¹ is preferably a compound represented by the formula —CH ₂ —X ³ —Z ^{1 wherein} X ³ is An oxygen atom, an optionally oxidized sulfur atom or — (CH ₂ ) _X — (wherein X represents an integer of 0 to 5), Z ¹ represents an optionally substituted hydrocarbon residue, And a heterocyclic group which may be substituted with X ³ by a ring-constituting atom.]. Examples of the optionally oxidized sulfur atom represented by X ³ include a thio group, a sulfinyl group, and a sulfonyl group, and a thio group is particularly preferable.

X ³ is preferably 1 (CH ₂ ) _X _ (where X is an integer of 0 to 2, and more preferably X is 0).

The hydrocarbon residue may be substituted represented by Z ^1, include the same ones as exemplified as an optionally substituted hydrocarbon residue which may be substituted represented by the aforementioned R ^1.

As good double heterocyclic group optionally substituted by ring-constituting atoms represented by Z ¹ binds to X ^3, which is illustrated as a optionally substituted heterocyclic group represented by the aforementioned R ¹ Among them, the same as those bonded to X ³ via a ring-constituting atom can be mentioned. Among them, an aromatic 5-membered heterocyclic group containing 2 to 3 hetero atoms (eg, an oxygen atom, a nitrogen atom, and a sulfur atom) is preferable.

In the above formula [I], as a preferable example of the optionally substituted hydrocarbon residue represented by R ¹ , a compound represented by the formula _ (CH ₂ ) _y — Z ² (where y is an integer of 1 to 4) And Z ² represents a nitrogen-containing unsaturated heterocyclic group which may be substituted, which is bonded at a constituent nitrogen atom.). Examples of the nitrogen-containing unsaturated heterocyclic group of the optionally substituted nitrogen-containing unsaturated heterocyclic group include unsaturated heterocycles containing one or more nitrogen atoms as ring-constituting atoms. Specific examples of such an unsaturated heterocyclic group include, for example, imidazole-1-yl, pyrazole-11-yl, 1,2,4-triazole-11-yl, 1,2,2 4-triazole-4-yl, 1, 2, 3-triazole-1-yl, 1, 2, 3-triazo-l 2-yl, pyro-l-l-yl, tetrazo-l-l 1-yl, 2-pyrroline-1-yl, 3-pyrroline-1-yl, 2-imidazoline-111-yl, 2-pyrazolin-1-1-yl, 3-pyrazolin-l-yl, etc. 5 A membered nitrogen-containing unsaturated heterocyclic group is preferable, and these may form a condensed ring (eg, benzimidazole-1-yl, indole-1-yl, 1H-indazole-1 —Yl, benzotriazole— 1-yl, benzotriazole—2-yl, isoindoyl 2-yl, 7-purinyl, 1H-pyrro [1 , 2—a] Imidazole—11-yl, 1 H—pyro mouth [1, 2— b] [1,2,4] triazo-1-yl, 1,8a-dihydroimidazo [1,2-a] pyridine-1-yl, 1,8a-dihydro [1,2,4 ] Triazolo [1,5-a] pyridine-1-yl, 3,3a-dihydro [1,2,4] triazolo [1,5-a] pyrimidine_3-yl, 1,8a-dihydro Imidazo [1, 2-a] pyrimidine-1-yl, 1H-pyrazo opening [4, 3- d] oxazolyl-1-yl, 4H-imidazo [4, 5- d] thiazole _ 4 —E.g.) In addition to these 5-membered nitrogen-containing unsaturated heterocyclic groups, 6-membered nitrogen-containing unsaturated heterocyclic groups such as 1,4-dihydropyridine-11-yl and 1,2-dihydropyridine-1-yl Are also mentioned.

In the above formula [I], as the optionally substituted hydrocarbon residue represented by R ¹

A group represented by the formula — (CH ₂ ) _Z — Z ³ is a preferred example. In the formula, z is an integer of 1 to 4, Z ³ is a formula —N (R ⁵ ) (R ⁶ ) wherein R ⁵ and R ⁶ are the same or different, and are hydrogen or substituted Or an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group, or R ⁵ and R ⁶ may be bonded to each other to form an optionally substituted heterocyclic group.] And an optionally substituted amino group.

As the heterocyclic group of the hydrocarbon residue or the optionally substituted heterocyclic group in the optionally substituted hydrocarbon residue represented by R ⁵ and R ⁶ , each of those exemplified for R ¹ described above is exemplified. The same as the hydrocarbon residue in the optionally substituted hydrocarbon residue or the heterocyclic group in the optionally substituted heterocyclic group can be mentioned.

R ⁵ and R ⁶ may combine with each other to form a ring. Examples of such _N (R ⁵ ) (R ⁶ ) include, for example, 1-pyrrolidinyl, 1 _imidazolidinyl, 1-pyrazolidinyl , 1-piperidyl, piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, homopyrazine-111, 1,2,4-triazole- 1-yl, 1,3,4-triazole — 1-yl, 1-pyrazol, 1-yl, imidazole-1-yl, 1, 2, 3 _triazo-1-yl, 1,2,3-triazol 2-yl, tetrazol-1 _ Yl, benzimidazo 1-ruil, India, 1-ruil, 1H-indazol-11-yl and the like. These rings may have 1 to 3 substituents at any substitutable position on the ring. Examples of such a substituent include the same ones as those exemplified as the substituent on the optionally substituted hydrocarbon residue and the optionally substituted heterocyclic group represented by R ¹ . The substituent may further have a substituent, and the substituent which may further have a substituent may further have a substituent in the above-described substituent of the hydrocarbon residue or the heterocyclic group. The same substituents as those described above may be used.

The hydrocarbon residue and the heterocyclic group represented by R ⁵ and R ⁶ may have 1 to 3 substituents at any substitutable position on the chain or the ring. Examples of such a substituent include the same as those exemplified as the substituent on the optionally substituted hydrocarbon residue and the optionally substituted heterocyclic group represented by R ¹ . The substituent may further have a substituent, and as the substituent which may further have a substituent, the substituent of the above-mentioned hydrocarbon residue or heterocyclic group further has a substituent. And the same substituents as those described above. In the above formula [II], examples of the optionally substituted heterocyclic group represented by R ⁴ are the same as the examples of the optionally substituted heterocyclic group represented by R ¹ described above. Things.

In the above formula [II], specific examples of the optionally substituted amino group represented by R ⁴ include the formula: N (R ⁵ ) (R ⁶ ) wherein R ⁵ and R ⁶ are as defined above. And having the same meaning as above].

In the above formulas [I] and [II], examples of the optionally oxidized sulfur atom represented by X ¹ or X ² include a thio group, a sulfinyl group and a sulfonyl group, and a thio group is particularly preferable. .

In the above formulas [I] and [II], the carboxyl group which may be esterified and represented by G or G ′ includes (i) a carbonyl group, (ii) a carboxyl group and 1 to 6 carbon atoms. (Ie, alkoxyl propyl, such as methoxycarbonyl, ethoxycarbonyl, propoxyl propyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), (iii) those in which a carboxyl group is bonded to an alkenyl group having 3 to 6 carbon atoms (ie, alkenyloxycarbonyl, For example, allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl, 3-hexenyloxycarbonyl, etc.), and (iv) a carbonyl group bonded to an aralkyloxy group (ie, Aralkyloxycarbonyl, for example, benzyloxycarbonyl, phenyloxycarbonyl, etc.). The aralkyl group in the aralkyloxycarbonyl group means an alkyl group having an aryl group as a substituent (arylalkyl group). As the Ariru group, e.g., phenyl, etc. naphthyl and the like, even if they have a same substituents having good multi heterocyclic group optionally substituted represented by R ¹ Good. As the alkyl group, a lower alkyl group having 1 to 6 carbon atoms is preferable. Preferable examples of the aralkyl group include, for example, benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl) methyl, (2-naphthyl) methyl and the like, among which benzyl, phenethyl and the like are preferable. .

In the above formula [I], the amidated carboxyl group represented by G is one C ON (R ⁷ ) (R ⁸ ) (wherein R ⁷ and R ⁸ have the same meanings as R ⁵ and R ⁶ above) ).

 In the above formula [I], the acyl group represented by G is a formyl group or a formula

CO—R ⁹ (wherein, R ⁹ represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an aryl group having 6 to 14 carbon atoms). Groups. Specific examples of the alkyl group having 1 to 10 carbon atoms, the alkenyl group having 2 to 10 carbon atoms or the aryl group having 6 to 14 carbon atoms represented by R ⁹ are the same as those described above. Is mentioned.

When G is a hydroxyalkyl group, as the § alkyl group of such hydroxyalkyl group, an alkyl group having 1 to 8 carbon atoms include among shown as examples of the hydrocarbon residue represented by R ^1. The hydroxyalkyl group is preferably —CH ₇ OH or —CH (OH) —R ¹⁰ (R ¹⁰ is represented by R ¹ above. Examples of the hydrocarbon residue include an alkyl group having 1 to 7 carbon atoms. ). R ^{1 Q in} this formula is preferably methyl, ethyl and the like.

When G is a protected hydroxyalkyl group, the protected hydroxy in this group has the formula —CHzOCOR ¹¹ or 1 CH (OC〇R ¹² ) —R ¹⁰ (where R ¹⁰ is as defined above, R ¹¹ and R ¹² each represent an alkyl group, an aralkyl group or an aryl group which may have a substituent. The alkyl group represented by R ¹¹ and R ^12, an alkyl group having 1 to 6 carbon atoms, e.g., methyl, Echiru, propyl, isopropyl, butyl, isobutyl, sec- heptyl, tert- butyl and the like. The § aralkyl group represented by R ¹¹ and R ^12, means such as Ce-i ₄ Ariru alkyl group having 1 to 4 carbon atoms group as a substituent (Ce ^. § Li one Roux alkyl group). The C ₆ - The ₁₀ Ariru group, e.g., phenyl, naphthyl and the like. As the § La alkyl group, e.g., benzyl, phenethyl, 3-phenylpropyl, (1 one-naphthyl) methyl, (2- Naphthyl) methyl and the like. The C ₆ _ ₁₀ Ariru group represented by R ^{1 1} and R ^12, for example, phenyl, naphthyl and the like.

 When G ′ is a halogen atom, examples of such a halogen atom include chlorine, bromine, iodine, and fluorine, preferably chlorine or bromine.

In the above formula (I), when Y is C-G, R ¹ and G may combine with each other to form a 5-membered ring. Such structure is represented by the following formula [III] and [IV] _c

[III] [IV]

Wherein R ¹² is hydrogen, an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group, and z ⁴ is an optionally substituted hydrocarbon residue. A heterocyclic group which may be substituted or an amino group which may be substituted, and other symbols have the same meanings as described above. ]

In the formulas [III] and [IV], examples of the optionally substituted hydrocarbon residue and the optionally substituted heterocyclic group represented by R ¹² and Z ⁴ include those exemplified as R ¹ described above. And the same. Specific examples of the optionally substituted amino group represented by z ^4, can be mentioned those similar to those of the optionally substituted amino group represented by Z ³ described above.

R ² and R ³ may be bonded to each other to form a 5- to 7-membered ring formed with a carbon atom on the adjacent thiophene ring (that is, a vinylene group). The 5- to 7-membered ring formed by bonding R ² and R ³ to each other includes (i) a C ₅ _ ₇ alicyclic hydrocarbon group, or (ii) 1 to 4 oxygen atoms, 1 to 4 sulfur atoms which may be oxidized or C which may be substituted. Examples thereof include a 5- to 7-membered heterocyclic group containing one nitrogen atom which may be substituted with alkyl (preferably Ci- ₄ alkyl).

R ² and R ³ moiety of the 5-7 membered ring to which R ² and R ³ are bonded to each other to form the

—R ² — R ³ —, for example, — (CH ₂ ) ₃ —, — (CHJ 2 ^ 4

(CH 2J Bruno _{5 CH 9 -N (M) -CH} 9 -CH 9 -, - CH = N- CH 9 - 7

CH ₂ —, one CH = N-CH = CH-, _ N = CH-CH = CH-, one CH = CH-N = CH-,-N (M)-CH ₂ -CH ₂ _CH ₂ -,- CH ₂ - CH ₂ one _{N (M) _CH 2 -,} - CH 2 - S _CH 2 _CH 2 -, one _{CH 2 -SO - CH 2- CH 2} -, - CH 2 - S0 2 - CH 2 - CH 2 -, One CH ₂ — O— CH ₂ — CH ₂ — and the like. , Preferably _CH ₂ —N (M) —CH ₂ _CH ₂ (M is methyl, ethyl, propyl, benzyl, etc.), —CH = N—CH 2—CH ₂ —, —CH = N—CH = CH—.

 In the above formula (I), M is a hydrogen atom, an optionally substituted hydrocarbon residue, an optionally substituted acyl group, an optionally substituted sorbamoyl group, an optionally substituted It represents a thiocarbamoyl group or an optionally substituted sulfonyl group.

Examples of the optionally substituted hydrocarbon residue represented by M include the same as the optionally substituted hydrocarbon residue represented by R ¹ . For example, as the optionally substituted hydrocarbon group which may be substituted represented by M, Ji optionally substituted E - ₄ alkyl group (e.g., methyl, Echiru, isopropyl, propyl, heptyl, benzyl, phenethyl, 2- , 3- or 4-pyridylmethyl, a C alkyl group which may be substituted with a phenyl group, etc.).

Examples of the optionally substituted acyl group represented by M include those exemplified as the acyl group as a substituent of the optionally substituted hydrocarbon residue and heterocyclic group represented by R ¹ above. And the same acyl group.

Examples of the optionally substituted carbamoyl group represented by M include those represented by R ¹³ NHC 0— (R ¹³ is as defined above for R ¹ ).

Examples of the optionally substituted thiocarbamoyl group represented by M include those represented by RNHCS— (R ¹³ has the same meaning as R ¹ above).

As the optionally substituted sulfonyl group represented by M,

Embedded image (R ¹³ is as defined above for R ¹ ).

Examples of the optionally substituted hydrocarbon residue represented by M include a (: toe. Alkyl group [especially, alkyl (eg, methyl, ethyl, propyl, isopropyl, etc.)] or a phenyl group. Good C Kill groups are preferred.

The phenyl group as a substituent on the chain of the optionally substituted C ₄ alkyl group represented by M further has one or more, preferably 13 substituents at any substitutable position. The substituent may be the same as the substituents on the hydrocarbon residue and the heterocyclic group represented by R ^1.

_{1 0-lower} alkyl group, c ₂ - _{1 Q} lower alkenyl group, c ₂ - _{1 Q} lower alkynyl group,

C ₃ _ ₇ cycloalkyl, C ₃ - ₇ cycloalkenyl group, C ₄ - ₇ Shikuroarukaji Eniru group, Ariru group, an aromatic heterocyclic group, non-aromatic heterocyclic group, Ararukiru group

(Eg, aryl C ₆ alkyl group), amino group, N-monosubstituted amino group, N, N-disubstituted amino group, amidino group, acyl group, rubamoyl group, N-monosubstitution rubamoyl group (eg, Methylcarbamoyl, ethylcarbamoyl, phenylcarbamoyl, etc.), N, N-disubstituted rubamoyl group (eg, N, N-dimethyl dirubamoyl, N, N-getylcarbamoyl, piperidinocarbamoyl, morpholino dirubamoyl) ), Sulfamoyl group, N-monosubstituted sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, phenylsulfamoyl, p-toluenesulfamoyl, etc.), N, N-disubstituted sulfamoyl group (eg, N , N-dimethylsulfamoyl, N_methyl-N-phenylsulfamoyl, piberidinosulfamoyl, morpholino Sulfamoyl), carboxyl group,. Lower alkoxycarbonyl groups (eg, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), hydroxyl group,

. A lower alkoxy group, Cs-i. Lower Arukeniruokishi group, C ₃ - ₇ cycloalkyl Arukiruokishi group, Ararukiruokishi group, Ariruokishi group, a mercapto group,. And lower alkylthio, aralkylthio, arylthio, sulfo, cyano, azido, nitro, nitroso, oxo, and halogen.

As the substituted hydrocarbon residue represented by M, phenyl C ^ alkyl (eg, benzyl, phenethyl, 4-methoxybenzyl, etc.) is more preferable. As the optionally substituted 5- to 7-membered ring (—R ² —R ³ —) formed by bonding R ² and R ³ to each other, one CH ₂ —N (CH ₃ ) —CH ₂ —CH ₂ —, — CH ₂ -N (one CH ₂ _C ₆ H ₅ ) _CH ₂ — CH _2- , one CH ₂ — N (-CH ₂ -B-OCH3) one CH ₂ — CH ₂ _ (B is p— shows a phenylene _{group), - CH 2 - NH- CH} 2 _CH 2 - and the like are preferable.

As particularly preferable in R ² and R ^3, or R ² and R ³ are both methyltransferase group, R ² and R ³ are each other Ini bonded to over R ² - R ³ _ is _CH ₂ - N (M) —CH ₂ —CH ₂ — (M is a hydrogen atom, C i_ ₃ alkyl or benzyl) and a 6-membered ring containing a nitrogen atom.

In the above formula [I], ring A and ring B may have a substituent, and examples of such a substituent include a halogen atom, a nitro group, and an optionally substituted C i. An alkyl group may be substituted. Alkenyl group, optionally substituted C ₂ — i. Alkynyl group, a hydroxy group which may be substituted, an optionally substituted thiol group, an optionally substituted amino group, optionally substituted Ashiru group (for example, C physician ₁₀ Arukanoiru groups, C ₂ - ₀ Arukenoiru group, C ₂ - ₁₀ Arukinoiru group), is optionally esterified carboxyl group or replacement even though which may be aromatic ring group used.

Examples of the halogen shown as a substituent on ring A and ring B include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being particularly preferred. Optionally substituted C i shown as a substituent on ring A and ring B. The alkyl group may be any of linear alkyl having 1 to 10 carbons, branched alkyl having 3 to 10 carbons, and cyclic alkyl having 3 to 10 carbons, such as methyl, ethyl, propyl, and the like. Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. These (: ₁₀ alkyl groups, C ₂ —. Alkenyl groups, C ₂ — i. The alkynyl group may be a hydrocarbon residue represented by R or Z ¹ and a heterocyclic ring at any substitutable position. The group may have 1 to 3 substituents similar to the substituents described above. Examples of the optionally substituted hydroxyl group shown as the substituent for ring A and ring B include (Π) a hydroxyl group, and (ii) an appropriate substituent for the hydroxyl group, particularly one used as a protective group for the hydroxyl group. Hydroxyl groups (for example, alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acysiloxy, aryloxy, etc.).

 Examples of the alkoxy include alkoxy having 1 to 10 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, Pentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.). Examples of the alkenyloxy include alkenyloxy having 2 to 10 carbon atoms (eg, allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexyl). Xenilmethoxy).

 The alkynyloxy includes alkynyloxy having 2 to 10 carbon atoms.

 (Eg, propieroxy, etc.).

Examples of the aralkyloxy include phenyl Ci- ₄ alkoxy (eg, benzyloxy, phenethyloxy, etc.).

 As the acyloxy, an alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.) is preferable.

 Examples of the aryloxy include phenoxy, 4-chlorophenoxy and the like.

 The optionally substituted thiol groups shown as the substituents on ring A and ring B include (i) a thiol group, and (ii) an appropriate substituent for the thiol group, in particular, protection of the thiol group. For example, alkylthio, alkenylthio, alkynylthio, aralkylthio, acetylsilthio, arylthio and the like having the one used as a group can be mentioned.

Examples of the alkylthio include alkylthio having 1 to 10 carbon atoms (eg, methylthio). O, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio Are preferred. Examples of the alkenylthio include alkenylthio having 2 to 10 carbon atoms (eg, allylthio, crotylthio, 2-pentenylthio, 3-hexenylthio, 2-cyclopentenylmethylthio, and 2-cycloalkyl). Hexenylmethylthio).

 Examples of the alkynylthio include alkynylthio having 2 to 10 carbon atoms (eg, ethylthio, 2-propynylthio, etc.).

As the Ararukiruchio, for example phenylene Lou C Bok ₄ alkylthio (e.g., benzylthio, etc. Fuenechiruchio) and the like.

 As the acylthio, an alkanolthio having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.) is preferable.

 Examples of the arylthio include phenylthio, 41-cloth phenylthio and the like.

The optionally substituted amino group shown as a substituent on ring A and ring B includes (i) an amino group, and (ii) an alkyl having 1 to 10 carbons, and an alkyl having 2 to 10 carbons. Alkenyl, alkynyl having 2 to 10 carbon atoms, acryl group having 1 to 10 carbon atoms, amino group having 1 to 2 aromatic or heterocyclic groups having 6 to 12 carbon atoms (eg, Methylamino, dimethylamino, ethylamino, acetylamino, dibutylamino, diarylamino, cyclohexylamino, phenylamino, N-methyl-1-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinylamino, etc.). The optionally substituted sacyl groups shown as substituents for ring A and ring B include (i) formyl, and (ii) alkyl having 1 to 10 carbons and alkenyl having 2 to 10 carbons. Alkynyl having 2 to 10 carbon atoms or aromatic group having 6 to 12 carbon atoms bonded to a carbonyl group (eg, acetyl, propionyl, petite) Ryl, isobutyryl, valeryl, isovaleryl, bivaloyl, hexanoyl, heptanyl, octanoyl, cyclobutanecarbonyl, cyclopentane, luponyl, cyclohexane, luponyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinyl, etc. Are listed.

 Examples of the optionally esterified carbonyl represented by the substituents of ring A and ring B include (i) a carboxyl group, and (ii) a carbonyl group having 1 to 6 carbon atoms. (I.e., alkoxycarbonyl, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec_butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl (Iii) a carboxyl group bonded to an alkenyl group having 3 to 6 carbon atoms (ie, alkenyloxycarbonyl, for example, allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxy) Carbonyl, 3-hexenyloxycarbonyl And (iv) those in which a carbonyl group and an aralkyloxy group are bonded (that is, aralkyloxycarbonyl, for example, benzyloxycarbonyl, phenethyloxycarbonyl, etc.).

Is the ring A and optionally substituted aromatic cyclic group shown as substituents of the ring B, C ₆ - _{1 4} aromatic hydrocarbon residues (e.g., phenyl, naphthyl, anthryl, etc.) and a heterocyclic aromatic Group residues (eg, pyridyl, furyl, chenyl, imidazolyl, thiazolyl, etc.) and the like.

Such substituents on ring A and ring B may be substituted at any substitutable position on each ring, and may be substituted with 1 to 4 identical or different groups. When the substituents on ring A or ring B are adjacent to each other, the adjacent substituents are linked to form one (CH ₂ ) _t — or — O— (CH ₂ ), — O— (where And t is an integer of 3 to 5, and 1 is an integer of 1 to 3), and such a ring may be formed together with a carbon atom of a benzene ring.

Including 7-membered ring. Preferably, ring A is substituted with at least one alkoxy group (preferably a -3alkoxy group), more preferably at least one methoxy. More preferably, ring A is substituted with two identical or different alkoxy groups (preferably Ci ₃ alkoxy groups), preferably methoxy. Specifically, for example, it is particularly preferable that ring A is substituted with two methoxy groups at the 6-position and the 7-position of the quinoline ring or the quinazoline ring.

Preferably, ring B is substituted with at least one alkoxy group (preferably (3 ^ 3 alkoxy group), more preferably at least one methoxy or isopropoxy. More preferably, ring B is the same or It is substituted by two different alkoxy groups (preferably c ^ ₃ alkoxy groups), for example, ring B is replaced by a methoxy or isopropoxy group at position 3 and at position 4 Particularly preferred is a case where the compound represented by the above formula [II] has at least one alkoxy group (preferably an alkoxy group), more preferably at least one methoxy or isopropoxy group. More preferably, ring D is

It is substituted by one alkoxy group (preferably C ^ 3 alkoxy group). Specifically, for example, it is particularly preferable that ring D is substituted at the 4-position with a methoxy group.

In the compound represented by the above formula [I], particularly preferably, Y is C—G ′ ″ (G ′ ″ represents a carboxyl group which may be esterified), and R ¹ has a substituent. be ₄ are substituted in good nitrogen-containing unsaturated heterocyclic group optionally alkyl group (provided that is bound to the C Bok ₄ alkyl group Te constituting nitrogen atom smell of nitrogen-containing unsaturated heterocyclic group) And a compound in which n is 0.

In the compound represented by the formula [II], R ² and R ³ are particularly preferably bonded to form an optionally substituted 5- to 7-membered ring. Specifically, R ² and R ³ are Bond with each other to form a 5- to 7-membered ring formed with a hydrogen atom on the adjacent thiophene ring (that is, a vinylene group), and G 'of C-G' represented by W represents a Haguchigen atom Compounds. For example, 3-chloro-1,5,6,7,8-tetrahydro-4-1 (4-methoxyphenyl)

2- (Succinimidmethyl) thieno [2,3-b: 5,4-c '] dipyridine, 3-chloro-4- (3,4-dimethoxyphenyl) -1,5,6,7,8-tetrahi Draw 2— (succinimidomethyl) thieno [2,3_b: 5,4_c '] dipyridine,

 3-chloro-1,4- (4-ethoxyphenyl) -1,5,6,7,8-tetrahydro-12- (succinimidomethyl) thieno [2,3-b: 5,4-c '] dipyridine,

3-bromo-5,6,7,8-tetrahydro-4- (4-methoxyphenyl)

2- (Succinimidmethyl) thieno [2,3-b: 5,4-c '] dipyridine, 7-acetyl-13-chloro-5,6,7,8-tetrahydro-1- (4-hydroxy-3-methyl) Xyphenyl) 1 2— (succinimidomethyl) thieno [2,

3—b: 5, 41 c,] dipyridine,

 7,6-acetyl-3,6-chloro-5,6,7,8-tetrahydro-4- (4-hydroxyphenyl) 1-2_ (succinimidmethyl) thieno [2,3-b: 5,4-C] dipyridine,

 7-acetyl-1-3-chloro-5,6,7,8-tetrahydro-4- (4-methoxyphenyl) 1-2_ (succinimidomethyl) thieno [2,3-b: 5,4_c '] dipyridine,

 7-acetyl-3 _cloth— 4- (4-ethoxyphenyl) -1,5,6,7,8-tetrahydro-1- (succinimidmethyl) thieno [2,3-b: 5,4-c '] dipyridine,

 7 _Acetyl-3 _clo mouth— 4 _ (3,4-dimethoxyphenyl) — 5,6,7,8-tetrahydro-2- (succinimidomethyl) thieno [2,3—b: 5, 4 -c '] Dipyridine, or salts thereof.

As the salt of the quinoline or quinazoline derivative or the thienopyridine or the thienopyrimidine derivative that can be used in the present invention, a pharmaceutically acceptable salt is preferable, for example, a salt with an inorganic base, a salt with an organic base, and an inorganic acid. And salts with organic acids, salts with basic or acidic amino acids, and the like. Preferable examples of the salt with the inorganic base include alkali metal salts (eg, sodium Salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), aluminum salts, ammonium salts and the like.

 Preferred examples of the salt with the organic base include, for example, trimethylamine, tritylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, Ν′-dibenzylethylenediamine and the like. And salts thereof.

 Preferable examples of salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

 Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, Ρ— And salts with 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, salts with aspartic acid, glutamic acid, etc. Is mentioned.

 Among these salts, sodium salts and potassium salts are most preferred.

 Further, the quinoline or quinazoline derivative, thienopyridine or chenobilimidine derivative or a salt thereof in the present invention may be a hydrate.

The quinoline or quinazoline derivative or the thienopyridine or chenobilimidine derivative in the present invention is described in, for example, Japanese Patent Application Laid-Open No. Hei 6-30652 (European Patent Application Publication No. 5- 5-56771). Kaihei 7—1 1 8 2 6 6 Publication (Ε Ρ—Α-6 880 7 0 Publication), Japanese Unexamined Patent Publication No. 7-69890 (公報 Ρ—A— 6 3 4 1 6 9 ), Japanese Patent Application Laid-Open No. 8-535419 (Japanese Patent Application Laid-Open No. 6-86630), Japanese Patent Application Laid-Open No. 8-225531 (International Patent Application Publication) WO95 / 243943, Japanese Patent Application Laid-open No. Hei 8-2255707 (WO96 / 14319), Japanese Patent Application Laid-Open No. Hei10-366734 And can be easily produced according to the production method described in, for example, Japanese Patent Application Laid-Open No. 10-59997 (WO 97/45050) or a method analogous thereto. As the gel-forming substance contained in the sustained-release oral preparation of the present invention, a water-soluble polymer compound is suitable. The water-soluble polymer compound is preferably about 2 to 360 mPa's, more preferably about 2 to 400 mPa's, and still more preferably 2 to 150 mPa-s. A compound having a viscosity of 2% (W / W) aqueous solution in terms of dry matter (measured under conditions of 20 ° C. ± 0.1 ° C.) is preferred. Specific examples of the water-soluble polymer compound include a cellulose derivative, a polyvinyl polymer compound, and a polyhydric alcohol.

 Examples of the cellulose derivative include hydroxypropyl methylcellulose (eg, grade TC-5EW (viscosity: 2-4 mPa's), TC-5 MW (viscosity: 3-6 mPa-s), TC-5 (Viscosity: 4 to 8 iPa-s), TC-5S (viscosity 12 to 18 mPa-s), 60 SH—50 (viscosity: 40 to 60 mPa's), 65 SH-50 ( Viscosity: 40 to 60 mPa's), 65 SH—400 (viscosity: 320 to 480 mPa's), 90—SH400 (viscosity: 320 to 480 mPa-s), 90 SH-30 00F (viscosity: 2400 to 360 000 mPa's)], hydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, croscarmellose sodium, carmellose calcium and the like.

 Examples of the polyvinyl polymer include polyvinylpyrrolidone and carboxyvinyl polymer.

 As the polyhydric alcohol, a polyhydric alcohol which is solid at 25 ° C. is used herein, and examples thereof include polyethylene glycol (preferably a polyhydric alcohol having an average molecular weight of about 8,000 to 700,000). Tylene glycol), polypropylene alcohol, polyglycerin and the like.

 As the gel-forming substance, preferably a cellulose derivative, more preferably hydroxypropylmethylcellulose or hydroxypropylcellulose, more preferably hydroxypropylmethylcellulose is used.

As the disintegration aid contained in the sustained-release oral preparation of the present invention, saccharides are preferable. Examples of the saccharides include sugar alcohols (eg, erythritol, sorbitol) , Mannitol, maltitol, xylitol, reduced starch saccharified product, reduced paratinose, etc.), monosaccharides (eg, glucose, mannose, xylose, galactose, evening lose, etc.), polysaccharides (eg, maltose) , Lactose (lactose). Sucrose and the like.

 Erythritol or sorbitol is more preferably used as the saccharide.

 (1) Quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative: (2) It is preferable to use a mixture of gel-forming substances in a weight ratio of about 1: about 0.1 to about 100. The ratio is preferably about 1: about 0.1 to 50, and more preferably about 1: about 0.2 to 20.

 When the oral sustained-release preparation of the present invention further comprises (3) a disintegration aid, (1) quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative: (2) gel-forming substance: (3) disintegration aid It is preferable to use an amount of about 1: about 0.1 to about 50: about 0.01 to about 50 by weight, and about 1: about 0.1 to about 50: about 0 by weight. It is more preferable to use an amount of from about 0.5 to about 30, and most preferably from about 1: about 0.2 to about 20: about 0.:! To 20 by weight.

 In the sustained-release oral preparation of the present invention, the gel-forming substance is preferably at least about 10% by weight, more preferably about 10 to 99.9% by weight, more preferably about 10% by weight, based on the whole preparation. 15 to 95% by weight, particularly preferably about 20 to 90% by weight.

 When a disintegration aid is further added to the oral preparation of the present invention, the disintegration aid is preferably about 1% by weight or more, more preferably about 1 to 90% by weight, and still more preferably about 3 to 90% by weight, based on the whole preparation. 70% by weight, particularly preferably about 5 to 50% by weight, and most preferably about 5 to 23% by weight.

The sustained release oral preparation of the present invention is formed into, for example, tablets, granules and the like. Capsules containing granules may also be used. At that time, the gel-forming substance and the disintegration aid may be blended inside the preparation or coated on the preparation surface. Sustained-release oral tablets are prepared by mixing the active ingredient and other pharmaceutical additives and then directly pressing (tableting), or once pressing, granulating and granulating and pressing. Tablets) can also be obtained. Alternatively, after granulating a mixture containing the active ingredient and the excipient into a sized powder, other pharmaceutical ingredients may be mixed and tableted.

 The granulated powder can be prepared by a conventional method such as a wet granulation method and a dry granulation method using a binder. Preferred granulated powder is obtained by a wet granulation method, for example, a stirring granulation method, a fluidized granulation method and the like. The average particle size of the granulated powder is, for example, about 0.1 to 200 m, and more preferably about 10 to 500 m.

 The tablet of the present invention can be formulated according to a generally used method known per se. For example, a pharmaceutically acceptable carrier can be blended with the drug used in the present invention and formed into a tablet.

 As the pharmaceutically acceptable carrier, various organic or inorganic carrier materials commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants and the like are compounded. If necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used. When these pharmaceutically acceptable carriers are the aforementioned gel-forming substances or compounds having an action as a disintegration aid, the compounding ratio and the compounding ratio in the oral preparation of the present invention are as follows: It shall be calculated by adding the compounding amount of the compound.

 Preferable examples of the excipient include lactose, sucrose, D-mannitol, erythritol, starch, crystalline cellulose, light caffeic anhydride and the like. Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like.

 Preferred examples of the binder include crystalline cellulose, arsenic starch, partially pregelatinized starch, sucrose, D-mannitol, trehalose, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and the like. Is mentioned. Preferably, crystalline cellulose is used.

Preferred examples of the disintegrant include, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethylstarch, and low-substituted hydroxypropylcellulose. Lulose and the like.

 If necessary, a preparation for oral administration can be prepared by coating in a manner known per se for the purpose of taste masking, enteric coating or sustaining. Examples of the coating agent include hydroxypropyl methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Bull Mouth Nick F68, cellulose acetate phthalate, and hydroxypropylmethylcellulose. Evening rate, hydroxymethyl cellulose acetate succinate, Eudragit (manufactured by ROHM, Germany, methacrylic acid / acrylic acid copolymer) and the like.

 Preferred examples of preservatives include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

 Preferable examples of the antioxidant include, for example, sulfite and ascorbic acid. Examples of the coloring agent include titanium oxide, iron sesquioxide (red iron), and edible pigments. Sweetening agents include aspartame, saccharin sodium, dipotassium glycyrrhizinate, stevia and the like.

 Further, for example, when the sustained release oral preparation of the present invention is produced as a granule, (1) quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative and (2) a gel-forming substance, and if necessary, (3) a disintegration aid After mixing, the mixture is kneaded, granulated, dried and sized using a binding solution dissolved in an appropriate solvent in a conventional manner to produce granules. The granules can be filled into capsules to make capsules.

In the sustained-release oral preparation of the present invention, the release period of the drug can be appropriately adjusted by the amount of the gel-forming substance and the like, or the amount of the gel-forming substance and the disintegration aid and the like. The sustained release oral preparation of the present invention usually exhibits a sustained release time of about 1 to 48 hours, preferably about 1 to 24 hours, more preferably about 3 to 24 hours. In the present invention, for example, quinoline or a quinazoline derivative, a cynopyridine or a thienopyrimidine derivative or a salt thereof has an anti-inflammatory effect. If it has, and further has an anti-arthritic effect, the sustained-release oral preparation of the present invention can be used as an agent for preventing or treating all arthritis exhibiting inflammatory symptoms in joints. Examples of the arthritis include rheumatoid arthritis. Further, for example, when quinoline or a quinazoline derivative or chenobilizine or a chenobilimidine derivative or a salt thereof has an antirheumatic effect, the sustained-release oral preparation of the present invention can be used as a prophylactic or therapeutic agent for rheumatism or the like.

 Further, for example, when quinoline or a quinazoline derivative or a chenopyridine or a thienopyrimidine derivative or a salt thereof has a bone resorption inhibitory action, the sustained-release oral preparation of the present invention provides a bone destruction associated with arthritis, a bone resorption inhibitor, and a bone coarser. It can be used as a prophylactic and therapeutic agent for porosis and the like.

 Further, for example, when the quinoline or quinazoline derivative or the chenobilizine or the thienopyrimidine derivative or a salt thereof has an inhibitory effect on the production of an immune cytokine, the sustained-release oral preparation of the present invention can be used to prevent diseases that are considered to be involved in immunity. It can be used as a therapeutic agent or as a preventive and therapeutic agent for rejection after Z and organ transplantation.

 A quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative or a salt thereof produces an immunomodulatory effect or an immune cytokine [eg, interleukin-12 (IL-2), inferon-feron-a (IFN-τ), etc.). In the case of having an action of suppressing thyroid, the sustained-release oral preparation of the present invention can be used as a prophylactic or therapeutic agent for diseases considered to be involved in immunity including autoimmune diseases.

Such target diseases include, for example, systemic erythematosus, inflammatory bowel disease (ulcerative colitis, Crohn's disease), multiple sclerosis, psoriasis, chronic hepatitis, bladder cancer, breast cancer, cervical cancer, chronic lymphoid disease Leukocytes, chronic myelogenous leukemia, colorectal cancer, colon cancer, rectal cancer, Helicobacter pylori infection, Hodgkin's disease, insulin-dependent diabetes mellitus, malignant melanoma, multiple myeloma, non-Hodgkin's lymphoma, non-small cell Lung cancer, ovarian cancer, peptic ulcer, prostate cancer, septic shock, tuberculosis, infertility, atherosclerosis, Behcet's disease, asthma, atopic dermatitis, nephritis, whole body Sexually transmitted fungal infection, acute bacterial meningitis, acute myocardial infarction, acute inflammation, acute viral encephalitis, adult respiratory distress syndrome, bacterial pneumonia, chronic inflammation, simple herpes virus infection, varicella-zoster virus Infectious diseases, AIDS, human papillomavirus infection, influenza, invasive staphylococcal infections, peripheral vascular disease, sepsis, interstitial liver disease, and localized ileitis. In particular, the sustained-release oral preparation of the present invention includes systemic erythematosus, chronic hepatitis, interstitial liver disease, asthma, psoriasis, ulcerative colitis, Crohn's disease, localized ileitis or multiple sclerosis, etc. It is used as a prophylactic or therapeutic agent.

 Since the oral preparation of the present invention has low toxicity, it can be safely used for mammals (eg, humans, cows, peas, pigs, dogs, cats, mice, rats, rabbits, etc.).

 The sustained-release oral preparation of the present invention is used as a highly efficacious preparation because it releases a fixed amount of a drug over a long period of time and thus provides stable drug efficacy.

 The dosage of the sustained-release oral preparation of the present invention varies depending on the type, content, dosage form, administration target animal, etc. of the quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative contained therein. Adults (assuming a body weight of 50 Kg) can administer about 10 to 50 Omg per person 3 times a day or once a day. Hereinafter, the present invention will be described more specifically with reference to Examples, Reference Examples, and Experimental Examples, but the present invention is not limited thereto.

 Compound A used in Examples 1 to 16 and Reference Example 1 below was ethyl 4- (3,4-dimethoxyphenyl) -16,7-dimethoxy-2- (1,2,

4-triazo-1-ylmethyl) quinoline-3-potassium lipoxylate, manufactured by the method described in JP-A-7-1118266 or JP-A-8-67679. The compound used was used. Example 1

Compound A 400 g, hydroxypropyl methylcellulose (grade T C- 5MW, Shin-Etsu Chemical Co., Ltd.) 324 g and erythritol 40 g were tumbled into a fluidized granulator (MP-10, manufactured by PALEC), supply air temperature 65 ° C, atomization speed 19 g Under the conditions of / min, fluidized granulation was performed while spraying 400 g of 10% by weight of hydroxypropylmethylcellulose. After granulation, dry to a product temperature of 32 ° C, weigh 600 g of the granulated powder, and add 15 g of crystalline cellulose (Grade Avicel PH101, manufactured by Asahi Kasei Corporation) and light anhydrous kaic anhydride (Grade Silica). 320, manufactured by YK F. Co., Ltd.) and 6 g of magnesium stearate were added and mixed. Using a tableting machine (Correct 19K AWC, manufactured by Kikusui Seisakusho), this mixture was formed into tablets (tabletting pressure: 0.2 ton, punch) with a punch having a 1 Ommci angle. The tablets were sized using a power mill (Showa Giken Co., Ltd., P-3) with a panning size of 1.5 mmφ. The rectified powder thus obtained was again used with a tableting machine (Correct 19 K AWC, manufactured by Kikusui Seisakusho) to produce 429 mg tablets per tablet with a 1 Ommci) corner punch (tableting pressure 1.0 tonZ Pestle) Example 2

400 g of compound A, 324 g of hydroxypropylmethylcellulose (grade TC-5EW, manufactured by Shin-Etsu Chemical Co., Ltd.) were charged into a tumbling fluidized granulator (MP-10, manufactured by Baurek), and the air supply temperature was 60 ° C and the spray speed Under the condition of 19 g / min, fluidized granulation was performed while spraying 400 g of 10% by weight of hydroxypropylmethylcellulose. After granulation, the product is dried to a product temperature of 33 ° C, 600 g of the granulated powder is weighed, and 15 g of crystalline cellulose (grade Avicel PHI 01, manufactured by Asahi Kasei Corporation), light gay anhydride (grade Silica 320, grade) 6.1 g of YK F) and 6.1 g of magnesium stearate were added and mixed. Using a tableting machine (Correct 19 K AWC, manufactured by Kikusui Seisakusho), this mixture was formed into tablets (tablet pressure: about 0.2 to nZ punch) with a 10 mm φ corner punch. The tablets were sized using a paper mill (Showa Giken Co., Ltd., P-3) with a punching size of 1.5 mm <i). The obtained rectified powder was again used with a tableting machine (Correct 19K AWC, manufactured by Kikusui Seisakusho) to obtain a tablet of 400 mg per tablet with a 10 mm φ corner punch. to nZ punch). Examples 3 to 6

Compound A2 g, hydroxypropyl methylcellulose 1.9 g [Grade TC-5 EW (Example 3), Grade TC-5MW (Example 4), Grade TC-5R (Example 5), Grade TC-15S (Example 6)], 100 mg of crystalline cellulose (grade Avicel PH101, manufactured by Asahi Kasei Corporation) was weighed and mixed in a mortar. The mixed powder (40 Omg) was weighed and tableted with a punch having a corner angle of 1 1ηιπιφ at a tableting pressure of 1.0 ton / cm ² using a universal testing machine (Shimadzu Corporation) to produce tablets. Examples 7 to 8

Compound A 2 g, hydroxypropyl methylcellulose 925 mg [grade TC-5EW (Example 7), grade TC-5MW (example 8)], crystalline cellulose (grade Avicel PH101, manufactured by Asahi Kasei Corporation) 75 mg Weighed and mixed in a mortar. 30 Omg of the mixed powder was weighed and tableted with a punch with a 10 mm φ corner at a tableting pressure of 1.0 tonZcm ² using a universal testing machine (Shimadzu Corporation). Example 9

2 g of Compound A, 63 Omg of hydroxypropylmethylcellulose (grade TC-5 MW), and 7 Omg of crystalline cellulose (grade Avicel PH101, manufactured by Asahi Kasei Corporation) were weighed and mixed in a mortar. 270 mg of this mixed powder was weighed and tableted with a 1 Omm i) corner punch at a tableting pressure of 1.0 to nZcm ² using a universal testing machine (Shimadzu Corporation). Example 10

2 g of Compound A, 3.85 g of hydroxypropylmethylcellulose (grade TC-5 EW), and 15 Omg of crystalline cellulose (grade Avicel PH101, manufactured by Asahi Kasei Corporation) were weighed and mixed in a mortar. This mixed powder 60 Omg Was weighed and tableted with a punch with a corner pressure of 1 ton / cm ² using a universal testing machine (Shimadzu) at a tableting pressure of 1.0 ton / cm ² . Example 1 1

 Compound A 2 g, hydroxypropyl methylcellulose 1.8 g (grade

TC-5EW), microcrystalline cellulose (Grade Avicel PH101, manufactured by Asahi Kasei Corporation) 10 Omg, erythritol 1 g, light caffeic anhydride (grade Silica 320, manufactured by YK F Co., Ltd.) 5) Omg and Magnesium Stearate 5 Omg were weighed and mixed in a mortar. The mixed powder (50 Omg) was weighed, and tableted with a punch having a corner of 1ηηηπιφ at a tableting pressure of 1.0 to nZcm ² using a universal testing machine (Shimadzu Corporation). Example 1 2

Compound A 2 g, hydroxypropylmethylcellulose 1.8 g (Grade TC-1 EW), crystalline cellulose (Grade Avicel PH 101, manufactured by Asahi Kasei Corporation) 10 Omg, sorbitol 1 g, light gay anhydride (Grade Sa) Irish 320, manufactured by Y'K EF Co., Ltd.) 5 Omg, and magnesium stearate 5 Omg were weighed and mixed in a mortar. The mixed powder (50 Omg) was weighed and tableted with a punch of 1Ο Ο Φ at a tableting pressure of 1.0 ton / cm ² using a universal testing machine (Shimadzu Corporation). . Example 13: 16

Compound A 2 g, Hydroxypropylmethylcellulose 1.42 g (grade TC-5 MW), crystalline cellulose (grade Avicel PH 101, manufactured by Asahi Kasei Corporation) 10 Omg, light silicic anhydride (grade Silica 320) , YK F Co., Ltd.) 40 mg, magnesium stearate 4 Omg, additive 40 mg [lactose (Example 13), croscarmellose sodium (Axidisol, Asahi Kasei Corporation) (Example 14) ), Low-substituted hydroxypropyl cellulose (grade LH-31) (Example 15), carmellose calcium Pum (grade ECG-505) (Example 16) was weighed and mixed in a mortar. The mixed powder (40 Omg) was weighed and tableted using a universal testing machine (Shimazu Seisakusho) with a 10 mm Φ corner punch at a tableting pressure of 1.0 to nZcm ² to produce tablets. Reference example 1

 Compound A: 478.9 g, lactose, 21.8 g, and corn starch, 127.9 g, were charged into a tumbling fluidized-granulator (MP-10, manufactured by PALEK), and the air supply temperature was 70 ° C and the spray rate Under the condition of 10 gZmin, fluid granulation was performed while spraying 520 g of a 6% by weight aqueous solution of hydroxypropyl cell mouth. After granulation, the product was dried to a product temperature of 45 ° C, and the dried product was pulverized with a power mill (Showa Giken Co., Ltd., P-3, punch size 1.2 ηιιηφ) to obtain sized powder. Then, using 853 g of the sized powder, croscarmellose sodium (Axidisol, Asahi Kasei Co., Ltd.) 45.5 g, magnesium stearate 2.7 g, polyethylene glycol 600,000 (Sanyo Chemical Co., Ltd.) 9 lg mixed. This mixed powder is used in a tableting machine

(Correct 19 K AWC, manufactured by Kikusui Seisakusho) was used to produce a tablet of 19 Omg per tablet with a 7 mmci) angle punch (tablet pressure: 1.0 to nZcm ² ). Experimental example 1

 The disintegration time of the tablets produced in Examples 4, 13, 14, 14, 15 and 16 was examined using a disintegration tester (Toyama Sangyo Co., Ltd.) without a disc according to the Japanese Pharmacopoeia collapse test method. The tablet obtained in Example 4 has 160 minutes, the Example 13 tablet has 130 minutes, the Example 14 tablet has 90 to 120 minutes, and the Example 15 tablet has 140 minutes. The time of the tablet of Example 16 was 130 minutes. Experimental example 2

Each tablet obtained in Reference Example 1 and Examples 1 to 12 was precisely weighed (WT), and a 0.6% aqueous sodium lauryl sulfate (SLS) solution (900 ml) was used. The test was conducted at 50 rpm according to the paddle method. Over time, 2 ml of the sample was sampled, filtered through a 0.45 m membrane filter, 1 ml was accurately measured, and 8 ml of the mobile phase was accurately measured and diluted to obtain a sample solution. Separately, 0 mg of Compound A was precisely weighed (WS), and the mobile phase was added to make exactly 100 ml. 1 ml of this solution was accurately measured, and 8 ml of the mobile phase was accurately measured and diluted to obtain a standard solution. The sample solution and the standard solution were measured by liquid chromatography. The elution rate was calculated by the following formula using the peak areas of compound A as QT and QS. Dissolution rate (%) = QT / QS 0.9 xWS x content x theoretical formulation WTZ20 The results are shown in [Table 1] and [Table 2]. 1]

Tablet of Reference Example 1

 Time (hr) 0 0.083 0.25 0.5 0.75

 Dissolution rate) 0 16.6 41.9 78.6 101 Tablet of Example 1

 Time (hr) 0 1 2 3 4 5 6 Dissolution rate) 0 9.8 27 45.2 61.7 75.1 84.3 Tablet of Example 2

 Time (hr) 0 1 2 3 4 5 6 Dissolution rate) 0 11.7 31.6 50.5 65.8 77.1 86.1 Tablet of Example 3

Time (hr) 0 1 2 3 4 6 8 Elution rate) 0 19.8 42.7 65.3 79.3 93.8 95.2 Tablet of Example 4

 Time (hr) 0 1 2 3 .4 6 8 Dissolution rate (%) 0 9.0 0 21.2 40.8 55 77.9 90.7 Tablet of Example 5

 Time (hr) 0 1 2 3 4 6 8 dissolution rate) 0 7. 4 19.6 36.3 50.2 75.4 92.6 2]

Example 6 tablets

 Time (hr) 0 1 2 3 4 6 8 Elution rate ^) 0 4.6 1 1 20.1 30.3 49.5 67.7 Tablet of Example 7

 Time (hr) 0 1 2 3 4 5 6 Dissolution rate (%) 0 35. 8 72. 7 86. 1 1 12 104 106 Tablet of Example 8

 Time (hr) 0 1 2 3 4 5 6 Dissolution rate) 0 13.7 37. 4 54. 8 77 88. 3 88. 9 Tablet of Example 9

 Time (hr) 0 1 2 3 4 5 6 Elution rate (%) 0 16. 8 38. 9 57. 7 84. 6 86. 8 92.6 Tablet of Example 10

Time (hr) 0 1 2 3 4 5 6 Elution rate ^) 0 19.1 35. 6 45. 9 59. 2 60. 9 65.2 Four

Example 11 Tablet of 1

As is clear from the above [Table 1] and [Table 2], the tablet of Reference Example 1 elutes 100% in 0.75 hours, while the tablets of Examples 1 to 12 release sustained release. It can be seen that Compound B used in Examples 17 to 19 and Reference Example 2 below is 3-chloro-5,6,7,8-tetrahydro-4-1 (4-methoxyphenyl) 1-2- (succinimidomethyl) thieno [ 2,3-b: 5,4-c ′] dipyridine, and a compound produced by the same method as that described in Synthesis Example 15 below was used.

Preparation of 3,6-chloro-1,5-tetrahydro-4- (4-methoxyphenyl) -12- (succinimidomethyl) thieno [2,3-b: 5,4-c '] dipyridin : Synthesis example 1

Acetonitrile (48 g) was added dropwise to a mixture of a 1.6 M solution of n-butyllithium in hexane (728 ml) and tetrahydrofuran (900 ml) at 170 ° C. After stirring at 170 for 20 minutes, a solution of 4-methoxybenzoyl chloride (100 g) in tetrahydrofuran (200 ml) was added dropwise at the same temperature. The reaction mixture was further stirred at the same temperature for 30 minutes, and then acidified with 4N hydrochloric acid. 30 minutes at room temperature The mixture was stirred, and the precipitated crystals were collected by filtration to obtain ω-cyano_4-methoxyacetophenone (69.5 g, 68%). Recrystallized from ethanol. Colorless prism crystal. Melting point 1 2 7— 1 2 8 ° C. Synthesis example 2

 A mixture of the compound (40 g) obtained in Synthesis Example 1, sulfur (8 g), 1-benzylidyl 4-piperidone (43 · 2 g), morpholine (19.9 g) and 2-propanol (1000 ml) was mixed with 70%. The mixture was stirred at ° C for 5 hours. The reaction mixture was allowed to stand at room temperature. The precipitated crystals are collected by filtration, washed with 2-propanol, and then treated with 2-amino-6-benzyl-3- (4-methoxybenzoyl) -1,4,5,6,7-tetrahydrocheno [2,3_ c] pyridine (52.4 g, 61%) was obtained. It was recrystallized from ethyl acetate-hexane. Yellow prism crystals. Mp 164-165 ° C. Synthesis example 3

Aluminum chloride (6.5 g) was added to a mixture of the compound (8 g) obtained in Synthesis Example 2, 1,3-dichloroacetone (5.4 g) and tetrahydrofuran (HOml) under ice-cooling, followed by 2.5 hours. Refluxed. The reaction mixture was poured into toluene (100 ml) -water (100 ml) with stirring. Washing the toluene layer, and the solvent was distilled off under reduced pressure after drying (Mg S_〇 _4). 7-Benzyl-3-cyclomethyl-2-chloromethyl-5,6,7,8-tetrahydro-4- (4-methoxyphenyl) thieno [2,3-b: 5,4-c '] dipyridine (8.2 g, 83%). Recrystallized from ethanol. Melting point 194-195 ° C. Synthesis example 4

A mixture of the compound (13.9 g) obtained in Synthesis Example 3, succinimide (4.4 g), potassium carbonate (6.2 g) and N, N-dimethylformamide (140 ml) was stirred at 70 ° C. for 2 hours. After that, the mixture was poured into water and extracted with ethyl acetate. Concentrated acetic acid Echiru layer Washing, drying (Mg S_〇 ₄₎ was followed under reduced pressure. The residue was subjected to silica gel column chromatography, and dissolved with ethyl acetate-hexane (1: 1, vZv). 7-Benzyl-3-cyclopenta-5,6,7,8-tetrahydro-4- (4-methoxyphenyl) -1- (succinimidomethyl) thieno [2,3-b: 5,4- c ′] dipyridine (21 g, 58%) was obtained. Recrystallized from tetrahydrofuran monoisopropyl ether. Colorless prism crystal. Mp 24 1—243 ° C. Synthesis example 5

A mixture of the compound obtained in Synthesis Example 4 (14.5 g), formic acid (29.1 ml), 10% palladium carbon (50% water content, 14.5 g) and methanol (500 ml) was added at room temperature. The mixture was stirred for 1 hour. After filtering off the catalyst, the filtrate was concentrated under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. Acetate Echiru layer was washed with water, evaporated and dried (Mg S_〇 ₄₎ and the solvent, residue was subjected to silica gel column chroma Togurafi scratch. Compound B (5.0 g, 42%) was obtained from the portion eluted with ethyl acetate-methanol (10: 1, vZv). Recrystallized from ethyl acetate-methanol. Colorless prism crystal. 225-226 ° C. Example 17

Compound B 16 Omg, hydroxypropyl methylcellulose (Daredo TC_5MW, manufactured by Shin-Etsu Chemical Co., Ltd.) 689.6 mg, crystalline cellulose (Grade Avicel PH101, manufactured by Asahi Kasei Corporation) 96 mg, light gay anhydride 4.8 mg and 9.6 mg of magnesium stearate were weighed and mixed in a mortar. 30 Omg of this mixed powder was weighed and tableted with a 9.5 mmd) punch at a tableting pressure of 1.0 to nZ cm ² using a universal testing machine (Shimadzu Corporation). Examples 18 to; L 9

Compound B 16 Omg, hydroxypropyl methylcellulose (grade TC-5EW, manufactured by Shin-Etsu Chemical Co., Ltd.) 497.6 mg, crystalline cellulose (Daredo Avicel PH 101, manufactured by Asahi Kasei Corporation) 96 mg, light caffeic anhydride 4.8 mg, magnesium stearate 9.6 mg and lactose (Example 18) or sorbitol (Example 19) 192 mg were weighed and mixed in a mortar. The mixed powder 3 0 Omg weighed, using a universal testing machine (Shimadzu Corporation), 9. mallet 5 ΙΏΠΙ Φ, and tableted with a tableting pressure of 1. 0 to nZc m ^2, tablets were prepared. Reference example 2

5 g of Compound B O, 2.21 g of lactose, and 0.4 g of corn starch were mixed in a mortar, and 0.7 g of an aqueous solution containing 0.4 lg of hydroxypropylcellulose was added for kneading. The kneaded material, which had been vacuum-dried at 40 ° C for 16 hours, was pulverized in a mortar to obtain sized powder. To 9.6 g of the sized powder, 0.16 g of croscarmellose sodium and 0.016 g of magnesium stearate were mixed. 17 Omg of this mixed powder was weighed and tableted with a 7.5 mm </ i> punch at a tableting pressure of 1.0 to nZcm ² using a universal testing machine (Shimadzu Corporation). Experiment 3

 One tablet obtained in Reference Example 2 and Examples 17 to 19 was precisely weighed, and tested at 50 rpm by a paddle method using 0.3% sodium lauryl sulfate aqueous solution 90 Om 1. Was done. 1 ml was sampled over time, filtered through a 0.45 membrane filter, and 0.2 ml was diluted with 0.8 ml of the mobile phase to obtain a sample solution. Separately, Compound B was accurately weighed, and a solution of 0 to 62 ^ g / ml was prepared and diluted in the same manner as the sample solution to obtain a standard solution. The measurement was performed by liquid chromatography using the standard solution and the sample solution at 201. The concentration of the sample solution was determined from the standard solution, and the elution rate was calculated. The results are shown in [Table 3]. [Table 3]

Tablet of Reference Example 2

 Time (hr) 0 0.25 0.5 0.75 1

Elution rate) 0 55.5 88.6 97.9 100.6 Example 17 Tablets

Industrial applicability

 Since the oral preparation of the present invention has excellent sustained-release properties, it can be advantageously used as a sustained-release oral preparation in terms of smoothing the blood concentration, maintaining the effect, and preventing side effects.

 In addition, since the oral preparation of the present invention has good flowability of the granulated product during its production, tableting properties are improved.

 Furthermore, by incorporating a gel-forming substance and, if necessary, a disintegration aid into the preparation, the release of the drug can be controlled, in particular, controlled release.

Claims

The scope of the claims

 I. A sustained-release oral preparation comprising (1) a quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative and (2) a gel-forming substance.

2. The preparation according to claim 1, wherein the quinoline or quinazoline derivative or the chenobiridin or chenobilimidine derivative is a compound having an anti-inflammatory effect or an anti-rheumatic effect.

 3. The preparation according to claim 1, further comprising a disintegration aid.

 4. The preparation according to claim 1, wherein the gel-forming substance is a water-soluble polymer compound. 5. The preparation according to claim 4, wherein the water-soluble polymer compound is a cellulose derivative, a polyvinyl polymer compound or a polyhydric alcohol.

 6. The formulation according to claim 4, wherein the water-soluble polymer compound is hydroxypropyl methylcellulose.

 7. The preparation according to claim 3, wherein the disintegration aid is a saccharide.

8. The preparation according to claim 7, wherein the saccharide is a sugar alcohol.

 9. The preparation according to claim 1, wherein the (1) quinoline or quinazoline derivative or the thienopyridine or the thienopyrimidine derivative: (2) the gel-forming substance is about 1: about 0.1 to about 100 by weight.

 1 0. (1) Quinoline or quinazoline derivative or thienopyridine or chenobilimidine derivative: (2) Gel-forming substance: (3) Disintegration aid is approximately

4. The preparation according to claim 3, wherein 1: ^ 0. 1 -50: ^ 0.01 50.

 2. The preparation according to claim 1, wherein the gel-forming substance is incorporated in an amount of about 10% by weight or more based on the whole preparation.

1 2. The quinoline or quinazoline derivative has the formula

Wherein Y is a nitrogen atom or C-G (G is a carboxyl group which may be esterified or amidated, an optionally substituted acyl group, a hydroxyalkyl group which may be protected or a halogen atom. R ¹ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X ¹ represents an oxygen atom or an optionally oxidized sulfur atom, and n represents 0 or 1. And k represents 0 or 1. G and R ¹ may combine with each other to form a ring. Ring A and ring B may each have a substituent. The preparation according to claim 1, which is a compound represented by the formula or a salt thereof.

1 3. Y is C_G '' (G '' represents a carboxyl group which may be esterified), and R ¹ is substituted by a nitrogen-containing unsaturated heterocyclic group which may have a substituent. has been that d_ ₄ alkyl group (provided that the constituting nitrogen atom of the nitrogen-containing unsaturated heterocyclic group is bonded to the C ₄ alkyl group), formulation of claim 1 wherein n is 0.

14. When the quinoline derivative or quinazoline derivative is ethyl 4- (3,4-dimethyloxy) -1,6,7-dimethyloxy 2- (1,2,4-triazol-1-ylmethyl) quinoline-3 14. The preparation according to claim 13, which is lipoxylate.

1 5. Chenoviridine or thienopyrimidine derivative has the formula

Wherein R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom, or an optionally substituted alkyl group, and R ² and R ³ may be bonded and replaced It may form a 5- to 7-membered ring. W represents a nitrogen atom, C—G ′ (wherein, G ′ represents a carboxyl group or a halogen atom which may be esterified), X ² represents an oxygen atom, and an oxidized group. R ⁴ represents an optionally substituted heterocyclic group or a group represented by a sulfur atom or a group represented by formula (CH ₂ ) _Q — (wherein Q represents an integer of 0 to 5). The amino groups that may be substituted are respectively shown. Ring D may be substituted. The preparation according to claim 1, which is a compound represented by the formula or a salt thereof.

16. In Chenoviridine or Chenovirimidine Derivatives, Shaku ² and Shaku ³ are combined to form an optionally substituted 5- to 7-membered ring, and W is C-G '

(Wherein, G 'is esterified which may be force Rupokishiru group or a halogen atom.) In a group represented by claim 1 5 R ⁴ is heterocyclic ring which may be substituted A formulation as described.

 17. A method for controlling the release of a quinoline or quinazoline derivative or a chenoviridine or a thienopyrimidine derivative comprising a gel-forming substance in an oral preparation containing a quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative.

18. Use of a gel-forming substance for producing a sustained-release preparation containing a quinoline or quinazoline derivative or a chenoviridine or a thienopyrimidine derivative.