JP2000154137A - Sustained release oral formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject sustained release oral formulation that can sustain the release of the medicines from the pharmaceutical preparation, smoothen its level in the blood after oral administration and can develop sufficient action and is useful as an antiinflammatory agent, an antirheumatics or the like by admixing quinoline derivative or the like and a gel-forming substance thereto. SOLUTION: This sustained release oral formulation includes (A) a quinoline or quinazoline derivative [preferably ethyl 4-(3,4-dimethoxyphenyl)-6, 7- dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate or a thienopyridine or thienopyrimidine derivative and (B) a gel-forming substance, preferably a water-soluble polymeric compound (preferably hydroxypropylmethyl-cellulose), preferably at a weight ratio A/B of about 1/(0.1-100), where the amount of the component B is more than 10 wt.% based on the total composition. In an preferred embodiment, a disintegrator (preferably a sugar alcohol) is admixed thereto.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 6-293634 (Japanese Patent Publication No. 2647338) discloses a plain tablet containing a low-melting oily substance and having improved abrasion resistance. This uncoated tablet has the above-mentioned 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 contained drug is released in the gastrointestinal tract at a time, and depending on the drug, a high blood concentration may be exhibited.

[0003]

[0004] Drugs such as anti-inflammatory agents such as therapeutic agents for arthritis, anti-rheumatic agents, bone formation promoting agents, and agents for preventing or treating diseases considered to be involved in immunity,
It is required to work for a long time. By sustaining release from the preparation and smoothing the blood concentration after oral administration, it is possible to exert sufficient effects with few side effects.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies to achieve sustained release from the preparation and to smooth the blood concentration after oral administration. As a result, quinoline or quinazoline derivatives or thienopyridine or thienoline have been studied. The pyrimidine derivative contains a gel-forming substance and, if necessary, a disintegration aid, especially a saccharide, thereby making it possible to control the release of the quinoline or quinazoline derivative or the thienopyridine or the thienopyrimidine derivative. The present inventors have found that they can have release properties, and have further studied based on this finding. As a result, the present invention has been completed.

The present invention relates to a sustained release oral preparation comprising (1) (i) a quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative and (ii) a gel-forming substance, (2) a quinoline or a quinazoline derivative or a thienopyridine. Alternatively, the preparation according to the above (1), wherein the thienopyrimidine derivative is a compound having an anti-inflammatory action or an anti-rheumatic action, (3) the preparation according to the above (1), further comprising a disintegration aid, (4) The above-mentioned (1), wherein the gel-forming substance is a water-soluble polymer compound, and (5) the above-mentioned (4), wherein the water-soluble polymer compound is a cellulose derivative, a polyvinyl polymer or a polyhydric alcohol. (6) The preparation according to (4), wherein the water-soluble polymer compound is hydroxypropylmethylcellulose. (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) (i) a quinoline or quinazoline derivative Or the thienopyridine or thienopyrimidine derivative: (ii) the preparation according to the above (1), wherein the gel-forming substance is about 1: about 0.1 to 100 by weight, (10) (i) the quinoline or quinazoline derivative or Thienopyridine or thienopyrimidine derivatives:
The above (3), wherein (ii) the gel-forming substance: (iii) the disintegration aid is about 1: about 0.1 to 50: about 0.01 to 50 by weight.
(11) The preparation according to (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

Embedded image [In the formula, Y represents a nitrogen atom or CG (G represents a carboxyl group which may be esterified or amidated, an acyl group which may be substituted, a hydroxyalkyl group which may be protected or a halogen atom. Is shown).
¹ is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X ¹ is an oxygen atom or an optionally oxidized sulfur atom, n is 0 or 1, k is 0 or 1 is shown. 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 (I) or a salt thereof:

(13) Y is CG '' (G '' represents a carboxyl group which may be esterified), and R ¹
The C _1-4 alkyl group in but a C _1-4 alkyl group substituted with a good nitrogen-containing unsaturated optionally substituted heterocyclic group (provided that constituting nitrogen atom of a nitrogen-containing unsaturated heterocyclic group And (14) the quinoline derivative or quinazoline derivative is ethyl 4- (3,4-dimethoxyphenyl)-
6,7-dimethoxy-2- (1,2,4-triazole-1
(13) The preparation according to the above (13), which is -ylmethyl) quinoline-3-carboxylate.

(15) Thienopyridine or a thienopyrimidine derivative has the formula

Embedded image [Wherein, R ² and R ³ are the same or different and each represent a hydrogen atom, a halogen atom or an optionally substituted alkyl group, and R ² and R ³ may be bonded to each other and may be substituted with 5 to 5; It may form a 7-membered ring. W is a nitrogen atom,
X ² represents an oxygen atom, an optionally oxidized sulfur atom or a group represented by CG ′ (wherein, G ′ represents a carboxyl group which may be esterified or a halogen atom). 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 an optionally substituted amino group. , Respectively. Ring D may be substituted. The preparation according to the above (1), which is a compound represented by the formula (I) or a salt thereof:
(16) In the thienopyridine or thienopyrimidine derivative, R ² and R ³ are bonded to form an optionally substituted 5- to 7-membered ring, and W is CG ′ (where G ′ is
Represents a carboxyl group which may be esterified, or a halogen atom. Wherein R ⁴ is a heterocyclic ring which may be substituted; (17) an oral preparation comprising a quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative; A method for controlling the release of a quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative obtained by mixing a gel-forming substance with a preparation;
8) use of a gel-forming substance for producing a sustained-release preparation containing a quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative;
9) The above (1) wherein the quinoline or quinazoline derivative or the thienopyridine or the thienopyrimidine derivative is a compound having an anti-inflammatory effect or an anti-rheumatic effect.
(7) The method described in (7), (20) a quinoline or quinazoline derivative or a thienopyridine or thieno 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 a thienopyrimidine derivative. (21) The method according to (17) above, 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, and (23) the above-mentioned method, wherein the water-soluble polymer compound is hydroxypropylmethylcellulose ( (21) The method according to (20), wherein the disintegration aid is a saccharide, (25) the method according to (24), wherein the saccharide is a sugar alcohol, (26) (i) ) The quinoline or quinazoline derivative or the thienopyridine or thienopyrimidine derivative: (ii) the gel-forming substance is in a weight ratio of about 1: about 0.1 to 100 (1).
7) The method according to the above, (27) (i) a quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative: (ii) a gel-forming substance: (iii) a disintegration aid,
The method according to the above (20), wherein the weight ratio is about 1: about 0.1 to 50: about 0.01 to 50, and the gel-forming substance is blended in an amount of about 10% by weight or more based on the whole preparation. (29) The method according to the above (17), wherein the quinoline or quinazoline derivative has the formula

Embedded image [In the formula, Y represents a nitrogen atom or CG (G represents a carboxyl group which may be esterified or amidated, an acyl group which may be substituted, a hydroxyalkyl group which may be protected or a halogen atom. Is shown).
¹ is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X ¹ is an oxygen atom or an optionally oxidized sulfur atom, n is 0 or 1, k is 0 or 1 is shown. G and R ¹ may combine with each other to form a ring. Ring A and ring B may each have a substituent. (17) The method according to the above (17), wherein Y is CG ''
(G ″ represents a carboxyl group which may be esterified), and R ¹ is a C _1-4 alkyl group substituted with a nitrogen-containing unsaturated heterocyclic group which may have a substituent. (However, when the nitrogen atom constituting the nitrogen-containing unsaturated heterocyclic group is
_1-4 alkyl group is bonded to), a method of n is above (29) above, wherein 0, (31) quinoline derivative or quinazoline derivative, ethyl 4- (3,4-dimethoxyphenyl) - 6,7-dimethoxy-2- (1,2,4-
(32) The preparation according to the above (30), which is (triazol-1-ylmethyl) quinoline-3-carboxylate.
Thienopyridine or thienopyrimidine derivative has the formula

Embedded image [Wherein, R ² and R ³ are the same or different and each represent a hydrogen atom, a halogen atom or an optionally substituted alkyl group, and R ² and R ³ may be bonded to each other and may be substituted with 5 to 5; It may form a 7-membered ring. W is a nitrogen atom,
X ² represents an oxygen atom, an optionally oxidized sulfur atom or a group represented by CG ′ (wherein, G ′ represents a carboxyl group which may be esterified or a halogen atom). 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 an optionally substituted amino group. , Respectively. 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 a thienopyridine or thienopyrimidine derivative, R ² and R ³ are bonded to each other to form a 5- to 7-membered ring which may be substituted, and W is CG ′ (in the formula, G ′
Represents a carboxyl group which may be esterified, or a halogen atom. Wherein R ⁴ is an optionally substituted heterocycle, (34) a quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative,
Use according to the above (18), which is a compound having an anti-inflammatory effect or an anti-rheumatic effect, (35) gel formation for producing a sustained-release preparation containing a quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative Use of substances and disintegration aids, (36)
The above-mentioned (1), wherein the gel-forming substance is a water-soluble polymer compound.
Use according to item 8), (37) Use according to item (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 hydroxypropyl methylcellulose, (39) the use according to the above (35), wherein the disintegration aid is a saccharide, (4)
0) Use according to item (39), wherein the saccharide is a sugar alcohol, (41) (i) a quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative:
(ii) the gel-forming substance is in a weight ratio of about 1: about 0.1-100;
(42) (i) a quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative: (ii) a gel-forming substance: (ii)
i) The disintegration aid is about 1: about 0.1 to 50: about 0.1 by weight.
(43) the use according to the above (18), which is from 01 to 50;
The use according to the above (18), 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

Embedded image [In the formula, Y represents a nitrogen atom or CG (G represents a carboxyl group which may be esterified or amidated, an acyl group which may be substituted, a hydroxyalkyl group which may be protected or a halogen atom. Is shown).
¹ is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X ¹ is an oxygen atom or an optionally oxidized sulfur atom, n is 0 or 1, k is 0 or 1 is shown. G and R ¹ may combine with each other to form a ring. Ring A and ring B may each have a substituent. And (45) Y is CG ''.
(G ″ represents a carboxyl group which may be esterified), and R ¹ is a C _1-4 alkyl group substituted with a nitrogen-containing unsaturated heterocyclic group which may have a substituent. (However, when the nitrogen atom constituting the nitrogen-containing unsaturated heterocyclic group is
_1-4 alkyl group is bonded to) the use of n is above (14) above, wherein a 0, (46) quinoline derivative or quinazoline derivative, ethyl 4- (3,4-dimethoxyphenyl) - 6,7-dimethoxy-2- (1,2,4-
Use according to the above (45), which is (triazol-1-ylmethyl) quinoline-3-carboxylate, (47)
Thienopyridine or thienopyrimidine derivative has the formula

Embedded image [Wherein, R ² and R ³ are the same or different and each represent a hydrogen atom, a halogen atom or an optionally substituted alkyl group, and R ² and R ³ may be bonded to each other and may be substituted with 5 to 5; It may form a 7-membered ring. W is a nitrogen atom,
X ² represents an oxygen atom, an optionally oxidized sulfur atom or a group represented by CG ′ (wherein, G ′ represents a carboxyl group which may be esterified or a halogen atom). 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 an optionally substituted amino group. , Respectively. 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 thienopyridine or thienopyrimidine derivative, R ² and R ³ are bonded to form an optionally substituted 5- to 7-membered ring, and W is CG ′ (where G ′ is Represents a carboxyl group which may be esterified, or a halogen atom.), And R ⁴ represents a heterocyclic ring which may be substituted (1)
8) The use described in the item.

[0009]

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 (particularly anti-arthritic effects), anti-rheumatic effects, bone resorption inhibiting effects, immunomodulatory effects, and / or immune cytokines [eg,
Interleukin-2 (IL-2), Interferon-γ (IFN-γ), etc.] are preferred.

Specific examples of the quinoline or quinazoline derivative contained in the sustained-release oral preparation of the present invention include, for example,

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

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

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

In the above formula [I], the hydrocarbon residue in the optionally substituted hydrocarbon residue represented by R ¹ includes an aliphatic hydrocarbon residue, an alicyclic hydrocarbon residue, Examples thereof include an alicyclic-aliphatic hydrocarbon residue, an aromatic carbon ring-aliphatic hydrocarbon residue, and an aromatic hydrocarbon residue. As the aliphatic hydrocarbon residue, a saturated aliphatic hydrocarbon residue having 1 to 10 carbon atoms (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl) Tert-pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, etc.), an unsaturated aliphatic hydrocarbon residue having 2 to 10 carbon atoms (for example, C _2-10 alkenyl group, C 2
_2-10 alkynyl groups include, for example, vinyl (ethenyl), allyl, 1-propenyl, 2
-Propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl,
1-pentenyl, 2-pentenyl, 3-pentenyl, 4
-Pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 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-hexynyl, 2,4-hexadiynyl, 5
-Hexynyl, 1-heptynyl, 1-octynyl and the like)).

The alicyclic hydrocarbon residue has 3 carbon atoms.
To 8 saturated alicyclic hydrocarbon residues (eg, C _3-8 cycloalkyl groups, specific examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.). ) And also a C _7-10 bicycloalkyl group (eg,
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 the like, and an unsaturated alicyclic hydrocarbon residue having 5 to 8 carbon atoms (eg, C _5-8 cycloalkenyl group, C _5-8
Examples thereof include a cycloalkadienyl group. Specific examples thereof include 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, and 2-cyclopentenyl.
-Cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cyclopentadienyl, 2,4-cyclohexadienyl, 2,5-cyclohexadienyl, 2,4
-Cycloheptadienyl and the like. ). As the alicyclic-aliphatic hydrocarbon residue, those in which the alicyclic hydrocarbon residue and the aliphatic hydrocarbon residue are bonded to each other have 4 to 9 carbon atoms (for example, cyclopropylmethyl, cyclopropylethyl). , Cyclobutylmethyl,
Cyclopentylmethyl, 2-cyclopentenylmethyl,
3-cyclopentenylmethyl, cyclohexylmethyl,
2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl, etc.). Examples of the aromatic carbocyclic-aliphatic hydrocarbon residue include phenylalkyl having 7 to 9 carbon atoms (eg, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, etc.), Naphthylalkyl having 11 to 13 carbon atoms (for example, α-naphthylmethyl, α-naphthylethyl, β
-Naphthylmethyl, β-naphthylethyl and the like). Examples of the aromatic hydrocarbon residue include phenyl, naphthyl (eg, α-naphthyl, β-naphthyl),
An aryl group having 6 to 14 carbon atoms such as anthryl, phenanthryl, acenaphthylenyl and the like can be mentioned.

In the above-mentioned formula [I], the heterocyclic group in the optionally substituted heterocyclic group represented by R ¹ includes, for example, (i) 5 to 5 containing one sulfur, nitrogen or oxygen atom. 7
Membered heterocyclic group, (ii) 5-6 membered heterocyclic group containing 2-4 nitrogen atoms, (iii) 5-6 membered heterocyclic group containing 1-2 nitrogen atoms and one sulfur or oxygen atom Ring group, (i
v) 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, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,4-oxadiazolyl,
1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, flazanil, 1,2,4-thiadiazolyl, 1,3,
4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,
2,5-thiadiazolyl, 1,2,3-triazolyl, 1,
A 5-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen and the like in addition to carbon atoms such as 2,4-triazolyl, 1H- or 2H-tetrazolyl, (2) Pyridyl, pyrimidinyl, thiomorpholinyl, morpholinyl, oxoimidazinyl, triazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl,
1,3-thiazinyl, piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl, 3- or 4-pyridazinyl, and other heteroatoms selected from oxygen, sulfur, nitrogen, etc. 6-membered heterocyclic group containing 1 to 4 atoms, (3) for example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, benzothiazolyl, benzoisothiazolyl, benzooxazolyl, benzoisoxazolyl, benzo Triazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolyl, isoindolyl, indolizinyl, quinolidinyl, 1,8
-Naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, α-, β- or γ-carbolinyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenoxazinyl, phenothiazinyl, phenoxathiinyl, thianthrenyl , Phenathridinyl, phenatrolinyl, 1H
-Indazol-3-yl, 1H-indazol-1-
Yl, 1H-pyrrolo [2,3-b] pyrazin-2-yl,
1H-pyrrolo [2,3-b] pyridin-6-yl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, 1H-imidazo [4,5-b] pyridin-2- Yl, 1H-imidazo [4,5-c] pyridin-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] pyrazin-2-yl, 1H-pyrrolo [1,
2-a] Imidazol-1-yl, 1H-pyrrolo [1,
2-b] [1,2,4] triazol-1-yl, 1.8
a-Dihydroimidazo [1,2-a] pyridin-1-yl, 7-purinyl, 3,3a-dihydro [1,2,4] triazolo [1,5-a] pyrimidin-3-yl, 1H-
Pyrazolo [4,3-d] oxazol-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-
1-yl, 3,3a-dihydro [1,2,4] triazolo [1,5-a] pyrimidin-3-yl, 1,8a-dihydroimidazo [1,2-a] pyrimidin-1-yl, 1H
-Pyrazolo [4,3-d] oxazol-1-yl, 4
Bicyclic or tricyclic condensation containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen and the like in addition to carbon atoms such as H-imidazo [4,5-d] thiazol-4-yl And heterocyclic groups. Preferred examples of the non-aromatic heterocyclic group include a 3 to 7-membered heterocyclic group containing 1 to 4 sulfur, nitrogen or oxygen atoms, and oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, Thiolanyl, piperidinyl,
Examples include tetrahydropyranyl, morpholinyl, 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 ring. It may be. As such a substituent, for example, 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, Good amino group, optionally substituted acyl group, optionally substituted hydroxyl group, optionally substituted thiol group, optionally esterified carboxyl group, amidino group, carbamoyl group, sulfamoyl group, sulfo group Group, cyano group, azide group, nitroso group, oxo group and the like. As the aliphatic chain hydrocarbon group as the substituent, a linear or branched aliphatic hydrocarbon group, for example, an alkyl group (preferably having 1 to 1 carbon atoms)
0 alkyl group), alkenyl group (preferably having 2 carbon atoms)
And an alkynyl group (preferably an alkynyl group having 2 to 10 carbon atoms). Preferred examples of the alkyl group include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se.
c-butyl, tert-butyl, pentyl, isopentyl,
Neopentyl, tert-pentyl, 1-ethylpropyl,
Hexyl, isohexyl, 1,1-dimethylbutyl, 2,
2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl,
Decyl and the like. Preferred examples of the alkenyl group include, for example, vinyl, allyl, isopropenyl, 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,
-Hexenyl, 3-hexenyl, 4-hexenyl, 5-
Hexenyl and the like. Preferred examples of the alkynyl group include, for example, ethynyl, 1-propynyl, 2-
Propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like Is mentioned.

The alicyclic hydrocarbon group as the substituent includes a saturated or unsaturated C _3-10 alicyclic hydrocarbon group (for example, C _3-10 cycloalkyl group, C _3-8 cycloalkenyl group). , A C _4-8 cycloalkadienyl group). Preferred examples of the C _3-10 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] nonyl, bicyclo [4.3.1] decyl and the like can be mentioned. Preferred examples of the C _3-8 cycloalkenyl group include, for example, 2-cyclopentene-1-
Examples thereof include yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, and 3-cyclohexen-1-yl, and among them, a cycloalkenyl group having 5 to 7 carbon atoms is preferable. Preferred examples of the C _4-8 cycloalkadienyl group include, for example, 2,4-cyclopentadiene-
1-yl, 2,4-cyclohexadien-1-yl, 2,
5-cyclohexadien-1-yl and the like, among which a cycloalkadienyl group having 5 to 7 carbon atoms is preferable. The aryl group as the substituent has 6 carbon atoms.
To 14 monocyclic or condensed polycyclic aromatic hydrocarbon groups are preferred, and preferred examples include, for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like, among which phenyl, 1-naphthyl, 2-
Naphthyl and the like are preferred.

Preferred examples of the aromatic heterocyclic group as the substituent include (i) a 5- to 7-membered heterocyclic group containing one sulfur, nitrogen or oxygen atom, and (ii) 2 to 4 heterocyclic groups. 5 containing nitrogen atom
And (iii) a 5- to 6-membered heterocyclic group containing one or two nitrogen atoms and one sulfur or oxygen atom. Examples of the aromatic monocyclic heterocyclic group include: Frills,
Thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furzanil, 1,2,3-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, ) As an aromatic condensed heterocyclic group fused to a 6-membered ring containing 2 or less nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom, for example, benzofuranyl, isobenzofuranyl, benzo [ b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, Zookisazoriru, 1, 2
-Benzisoxazolyl, benzothiazolyl, 1,2
-Benzoisothiazolyl, 1H-benzotriazolyl,
Quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,
Purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl Pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,
5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [ 4,3-b] pyridazinyl and the like.

Preferred 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, and include oxiranyl, azetidinyl, oxetanyl , Thietanyl, pyrrolidinyl,
Tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl,
And piperazinyl. Examples of halogen as the substituent include fluorine, chlorine, bromine and iodine, and fluorine and chlorine are particularly preferred. As the optionally substituted amino group as the substituent,
(i) an amino group, and (ii) a substituted amino group (having 1 to 1 carbon atoms)
1 or 2 substituted alkyl, alkenyl having 2 to 10 carbons, alkynyl having 2 to 10 carbons, acyl having 1 to 10 carbons, aromatic or heterocyclic having 6 to 12 carbons Amino group (eg, methylamino,
Dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino,
Phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino, etc.)].

The acyl group which may be substituted as the substituent includes (i) formyl and (ii) a carbon atom having 1 carbon atom.
-10, alkyl, alkenyl or aromatic group having 2-10 carbon atoms and a carbonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclo Pentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, etc.). The hydroxyl group which may be substituted as the substituent includes (i) a hydroxyl group, and (ii) an appropriate substituent,
In particular, a hydroxyl group having a hydroxyl group-protecting group (for example, alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyloxy, aryloxy, etc.) is exemplified. Examples of the alkoxy include alkoxy having 1 to 10 carbons (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.) are preferred. As the alkenyloxy, alkenyloxy having 2 to 10 carbon atoms (eg, allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy, etc.) is preferable. . As the alkynyloxy, alkynyloxy having 2 to 10 carbon atoms (eg, ethynyloxy, 2-propynyloxy, etc.) is preferable. Examples of the aralkyloxy include phenyl-C _1-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.). Examples of the acyloxy include alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, butyryloxy,
Isobutyryloxy) are preferred. 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, particularly a thiol group having a substituent used as a protecting group for the thiol group (for example, alkylthio, Alkenylthio, alkynylthio, aralkylthio, acylthio, arylthio, etc.). Examples of the alkylthio include alkylthio having 1 to 10 carbon atoms (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, t-
ert-butylthio, pentylthio, isopentylthio,
Neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.) are preferred. As the alkenylthio, alkenylthio having 2 to 10 carbon atoms (eg, allyl)
(allyl) thio, crotylthio, 2-pentenylthio, 3
-Hexenylthio, 2-cyclopentenylmethylthio,
2-cyclohexenylmethylthio) is preferred. As the alkynylthio, alkynylthio having 2 to 10 carbon atoms (eg, ethynylthio, 2-propynylthio, etc.) is preferable. Examples of the aralkylthio include phenyl -C _1-4 alkylthio (e.g., benzylthio, etc. phenethylthio) and the like. Examples of the acylthio include alkanoylthio having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.)
Is preferred. As the arylthio, phenylthio, 4
-Chlorophenylthio and the like.

The carboxyl group which may be esterified and which is shown as the substituent includes (i) a carboxyl group, (ii) a carboxyl group bonded to an alkyl group having 1 to 6 carbon atoms (ie, alkoxycarbonyl, For example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), (iii) a carboxyl group and 3 carbon atoms ~ 6 alkenyl groups attached (i.e. alkenyloxycarbonyl, e.g. allyl (all
yl) oxycarbonyl, crotyloxycarbonyl, 2
-Pentenyloxycarbonyl, 3-hexenyloxycarbonyl, etc.), and (iv) one in which a carbonyl group and an aralkyl group are bonded (that is, aralkyloxycarbonyl, for example, benzyloxycarbonyl, phenethyloxycarbonyl, etc.).

In the above formula [I], the substituent on the hydrocarbon residue or the heterocyclic group represented by R ¹ may be one or more, preferably one or more, suitable substituents at any substitutable positions. You may have up to three. Examples of such a substituent include a C _1-10 alkyl group, a C _2-10 alkenyl group,
C _2-10 alkynyl group, C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, C _4-8 cycloalkadienyl group, aryl group, aromatic heterocyclic group, non-aromatic heterocyclic group, aralkyl Groups (eg, aryl C _1-6 alkyl groups), amino groups, N-monosubstituted amino groups, N, N-disubstituted amino groups,
Amidino group, acyl group, carbamoyl group, N-monosubstituted carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, phenylcarbamoyl, etc.), N, N-disubstituted carbamoyl group (N, N-dimethylcarbamoyl, N,
N-diethylcarbamoyl, piperidinocarbamoyl,
Morpholinocarbamoyl, etc.), sulfamoyl group, N
A monosubstituted sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, phenylsulfamoyl,
p-toluenesulfamoyl), N, N-disubstituted sulfamoyl group (eg, N, N-dimethylsulfamoyl, N-methyl-N-phenylsulfamoyl, piperidinosulfamoyl, morpholinosulfamoyl) Etc.), carboxyl group, _C1-10 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-
Butoxycarbonyl), hydroxyl group, C _1-10 alkoxy group, C _2-10 alkenyloxy group, C _3-7 cycloalkyloxy group, aralkyloxy group, aryloxy group, mercapto group, C _1-10 lower alkylthio group , Aralkylthio, arylthio, sulfo, cyano,
Examples include an azide group, a halogen atom, a nitro group, a nitroso group, and an oxo group. Specific examples of such substituents include, for example, the same substituents as those described above on the hydrocarbon residue, the heterocyclic group and the amino group.

In the above formula [I], the optionally substituted hydrocarbon residue represented by R ¹ is preferably a group 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), and Z ¹ represents an optionally substituted hydrocarbon residue or a ring-constituting atom. X ³ represents an optionally substituted heterocyclic group bonded to X ³ ]. 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
Preferably is - (wherein, x is an integer of 0 to 2, more preferably x is _{0) - (CH 2) x} . Examples of the optionally substituted hydrocarbon residue represented by Z ¹ include the same as those exemplified as the aforementioned optionally substituted hydrocarbon residue represented by R ¹ . Examples of the optionally substituted heterocyclic group bonded to X ³ by a ring-constituting atom represented by Z ¹ include those exemplified as the aforementioned optionally substituted heterocyclic group represented by R ¹ And those bonded to X ³ by a ring-constituting atom. Among them, aromatic 5 containing 2 to 3 hetero atoms (eg, oxygen atom, nitrogen atom, sulfur atom)
Membered heterocyclic groups are preferred.

In the above formula [I], a preferable example of the optionally substituted hydrocarbon residue represented by R ¹ is a group represented by the formula — (CH ₂ ) _y —Z ² (where y is 1 to An integer of 4, Z ² is a nitrogen-containing unsaturated heterocyclic group which may be substituted,
Each of the constituent nitrogen atoms is shown below. )
And the group represented by 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,
Pyrazol-1-yl, 1,2,4-triazol-1-
Yl, 1,2,4-triazol-4-yl, 1,2,3-
Triazol-1-yl, 1,2,3-triazole-2
-Yl, pyrrol-1-yl, tetrazol-1-yl, 2-pyrrolin-1-yl, 3-pyrrolin-1-yl, 2-imidazolin-1-yl, 2-pyrazolin-1
-Yl, 3-pyrazolin-1-yl and the like are preferably 5-membered nitrogen-containing unsaturated heterocyclic groups, and these may form a condensed ring (eg, benzimidazole-1-yl, indo- 1-yl, 1H-indazol-1-yl, benzotriazol-1-yl, benzotriazol-2-yl
Yl, isoindol-2-yl, 7-purinyl, 1H
-Pyrrolo [1,2-a] imidazol-1-yl, 1H
-Pyrrolo [1,2-b] [1,2,4] triazole-1
-Yl, 1,8a-dihydroimidazo [1,2-a] pyridin-1-yl, 1,8a-dihydro [1,2,4] triazolo [1,5-a] pyridin-1-yl, 3a-dihydro [1,2,4] triazolo [1,5-a] pyrimidin-3-yl, 1,8a-dihydroimidazo [1,2-
a] Pyrimidin-1-yl, 1H-pyrazolo [4,3-
d] Oxazol-1-yl, 4H-imidazo [4.5
-D] thiazol-4-yl and the like). In addition to these 5-membered nitrogen-containing unsaturated heterocyclic groups, 6-membered nitrogen-containing unsaturated heterocyclic groups such as 1,4-dihydropyridin-1-yl and 1,2-dihydropyridin-1-yl Are also mentioned.

In the above formula [I], a preferable example of the optionally substituted hydrocarbon residue represented by R ¹ is a group represented by the formula — (CH ₂ ) _z —Z ^3. . In the formula, z is an integer of 1 to 4, and Z ³ is a formula —N (R ⁵ ) (R ⁶ )
[Wherein, R ⁵ and R ⁶ are the same or different and each represent hydrogen, an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group, or R ⁵ and R ⁶ are bonded to each other; To form an optionally substituted heterocyclic group]
And an optionally substituted amino group represented by Examples of 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 include the substituents exemplified for R ¹ above. And the same as the hydrocarbon residue in the optionally substituted hydrocarbon residue or the heterocyclic group in the optionally substituted heterocyclic group. 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,
-Piperidyl, piperazinyl, 4-morpholinyl, 4-
Thiomorpholinyl, homopiperazin-1-yl, 1,2,
4-triazol-1-yl, 1,3,4-triazol-1-yl, pyrazol-1-yl, imidazole-1
-Yl, 1,2,3-triazol-1-yl, 1,2,3
-Triazol-2-yl, tetrazol-1-yl,
Benzimidazol-1-yl, indol-1-yl, 1H-indazol-1-yl and the like. These rings may have 1 to 3 substituents at any substitutable position on the ring. Such substituents 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 can be mentioned. 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.

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 substituents 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], specific examples of the optionally substituted heterocyclic group represented by R ⁴ include the specific examples of the optionally substituted heterocyclic group represented by R ¹ described above. And the same. In the above formula [II], R ⁴
Specific examples of the optionally substituted amino group represented by the formula: -N (R ⁵ ) (R ⁶ ) wherein R ⁵ and R ⁶ have the same meaning as described above. And an optionally substituted amino group.

In the above formulas [I] and [II], the optionally oxidized sulfur atom represented by X ¹ or X ² includes a thio group, a sulfinyl group and a sulfonyl group. Groups are preferred. The above formula [I],
In [II], the carboxyl group which may be esterified and represented by G or G ′ includes (i) a carboxyl group, and (ii) a carboxyl group bonded to an alkyl group having 1 to 6 carbon atoms ( That is, alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), (iii) carboxyl Bonded to an alkenyl group having 3 to 6 carbon atoms (ie, alkenyloxycarbonyl, for example, allyl (a
llyl) oxycarbonyl, crotyloxycarbonyl,
2-pentenyloxycarbonyl, 3-hexenyloxycarbonyl, etc.), and (iv) those in which a carbonyl group and an aralkyloxy group are bonded (that is, aralkyloxycarbonyl, for example, benzyloxycarbonyl, phenethyloxycarbonyl, etc.). . The aralkyl group in the aralkyloxycarbonyl group means an alkyl group (arylalkyl group) having an aryl group as a substituent. As the aryl group,
For example, phenyl, naphthyl and the like may be mentioned, and these may have the same substituent as the substituent of the optionally substituted heterocyclic group represented by R ¹ . As the alkyl group, a lower alkyl group having 1 to 6 carbon atoms is preferable. Preferred 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 -CON (R ⁷ ) (R ⁸ ) (wherein R ⁷ and R ⁸ have the same meanings as R ⁵ and R ⁶ above) It is represented by In the above formula [I], the acyl group represented by G is a formyl group or a formula —CO—R ⁹ (wherein R ⁹ is an alkyl group having 1 to 10 carbon atoms or an alkenyl having 2 to 10 carbon atoms) Or an aryl group having 6 to 14 carbon atoms). An alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or 6 carbon atoms represented by R ^9;
Specific examples of the aryl groups of Nos. To 14 include the same as those described above.

When G is a hydroxyalkyl group, examples of the alkyl group of the hydroxyalkyl group include the alkyl groups having 1 to 8 carbon atoms among the hydrocarbon groups represented by R ¹ above. . The hydroxyalkyl group is preferably, -CH ₂ OH or -CH (O
H) -R ¹⁰ (R ¹⁰ is an alkyl group having 1 to 7 carbon atoms among shown as examples of the hydrocarbon residue represented by R ¹ are represented by like is.). R ^{10 in} this formula is preferably
Methyl, ethyl and the like. When G is a protected hydroxyalkyl group, protected hydroxy in the groups of the formula -CH ₂ OCOR ¹¹ or -CH (OCOR ¹²⁾
—R ¹⁰ (R ¹⁰ has the same meaning as described above, and R ¹¹ and R ¹² each represent an alkyl group, an aralkyl group, or an aryl group which may have a substituent). Examples of the alkyl group represented by R ¹¹ and R ¹² include an alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
Butyl and the like. The aralkyl group represented by R ¹¹ and R ¹² means an alkyl group having 1 to 4 carbon atoms (C _6-10 aryl-alkyl group) having a C _6-14 aryl group as a substituent. Examples of the C _6-10 aryl group include phenyl, naphthyl and the like, and examples of the aralkyl group include benzyl, phenethyl,
3-phenylpropyl, (1-naphthyl) methyl, (2
-Naphthyl) methyl and the like. R ¹¹ and R
Examples of the C _6-10 aryl group represented by ¹² include phenyl, naphthyl and the like. When G ′ is a halogen atom, the halogen atom includes chlorine, bromine,
Iodine, fluorine, preferably chlorine or bromine. In the above formula (I), when Y is CG, R ¹ and G
May combine with each other to form a 5-membered ring. Such a structure is represented by the following formulas [III] and [IV].

[0030]

Embedded image

Wherein R ¹² is hydrogen, an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic group, Z ⁴ is an optionally substituted hydrocarbon residue, Represents an optionally substituted heterocyclic group or an optionally substituted amino group, and the 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 like. Specific examples of the optionally substituted amino group represented by Z ⁴ include the same as those described above for the optionally substituted amino group represented by Z ³ .

R ² and R ³ may be bonded to each other to form a 5- to 7-membered ring formed together with a carbon atom on an adjacent thiophene ring (ie, a vinylene group). R ² and R ³
Are bonded to each other to form the 5- to 7-membered ring,
(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 optionally substituted C _Examples thereof include a 5- to 7-membered heterocyclic group containing one nitrogen atom which may be substituted with _1-10 alkyl (preferably C _1-4 alkyl). R ² and R ³
R ² and R ³ moiety of but the 5-7 membered ring formed bond to each other, -R ² -R ³ - is represented by, in particular, for _{example, - (CH 2) 3 -} , - ( CH ₂ ) ₄ -,-(CH ₂ ) _5- , -C
_{H 2 -N (M) -CH 2} -CH 2 -, - CH = N-CH 2 -C
_{H 2 -, - CH = N} -CH = CH -, - N = CH-CH
= CH-, -CH = CH-N = CH-, -N (M) -CH
_{2 -CH 2 -CH 2 -, -} CH 2 -CH 2 -N (M) -CH
_{2 -, - CH 2 -S-} CH 2 -CH 2 -, - CH 2 -SO-
_{CH 2 -CH 2 -, - CH} 2 -SO 2 -CH 2 -CH 2 -, -
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 — and —CH ＝ N—CH ＝ CH—. In the above formula (I), M is a hydrogen atom, an optionally substituted hydrocarbon residue, an optionally substituted acyl group,
It represents a carbamoyl group which may be substituted, a thiocarbamoyl group which may be substituted or a sulfonyl group which may be substituted. 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 residue represented by M, an optionally substituted C _1-4 alkyl group (eg,
Methyl, ethyl, isopropyl, propyl, butyl, benzyl, phenethyl, 2-, 3- or 4-pyridylmethyl, a C _1-4 alkyl group which may be substituted by a phenyl group, etc.). Examples of the optionally substituted acyl group represented by M include the same acyl groups as those exemplified as the acyl group as the substituent for the optionally substituted hydrocarbon residue and heterocyclic group represented by R ¹ above. Groups. Examples of the optionally substituted carbamoyl group represented by M include those represented by R ¹³ NHCO— (R ¹³ has the same meaning as R ¹ above). Examples of the optionally substituted thiocarbamoyl group represented by M include R ¹ NH
And those represented by CS- (R ¹³ is as defined above for R ¹ ). Examples of the optionally substituted sulfonyl group represented by M include those represented by R ¹ SO ₂ — (R ¹³ has the same meaning as R ¹ above).

Examples of the optionally substituted hydrocarbon residue represented by M include a C _1-10 alkyl group [
_1-3 alkyl (eg, methyl, ethyl, propyl, isopropyl, etc.)] or a C _1-4 alkyl group optionally substituted with a phenyl group is preferable. The phenyl group as a substituent on the chain of the optionally substituted C _1-4 alkyl group represented by M further comprises one or more substituents at any substitutable position, preferably 1 to 3 The substituent may be the same as the substituent shown on the hydrocarbon residue and the heterocyclic group represented by R ¹ .
C _1-10 lower alkyl group, C _2-10 lower alkenyl group, C
_2-10 lower alkynyl group, C _3-7 cycloalkyl group, C _3-7
Cycloalkenyl group, C _4-7 cycloalkadienyl group,
An aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, an aralkyl group (eg, an aryl C _1-6 alkyl group), an amino group, an N-monosubstituted amino group, an N, N-disubstituted amino group, Amidino group, acyl group, carbamoyl group, N-monosubstituted carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, phenylcarbamoyl, etc.), N, N-disubstituted carbamoyl group (eg, N, N-dimethylcarbamoyl, N, N -Diethylcarbamoyl, piperidinocarbamoyl, morpholinocarbamoyl, etc.), sulfamoyl group, N-monosubstituted sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, phenylsulfamoyl, p-toluenesulfamoyl, etc.), N, N-disubstituted sulfamoyl groups (eg, N, N-dimethylsulfamoyl, N-methyl-N-phenyls Famoiru, piperidinylmethyl ɽ sulfamoyl, morpholinosulfamoyl sulfamoyl, etc.), a carboxyl group, C _1-10 lower alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,
Isopropoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), hydroxyl group, C _1-10 lower alkoxy group,
C _2-10 lower alkenyloxy group, C _3-7 cycloalkyloxy group, aralkyloxy group, aryloxy group, mercapto group, C _1-10 lower alkylthio group, aralkylthio group, arylthio group, sulfo group, cyano group, Examples include an azide group, a nitro group, a nitroso group, an oxo group, and a halogen. As a substituted or substituted hydrocarbon residue represented by M, phenyl C _1-3 alkyl (eg, benzyl, phenethyl, 4-methoxybenzyl, etc.) is more preferred. The optionally substituted 5- to 7-membered ring (—R ² —R ³ —) formed by bonding R ² and R ³ to each other includes:
_{-CH 2 -N (CH 3) -CH} 2 -CH 2 -, - CH 2 -N
_{(-CH 2 -C 6 H 5)} -CH 2 -CH 2 -, - CH 2 -N
_{(-CH 2 -B-OCH 3)} -CH 2 -CH 2 - (B is p-
Shows a phenylene _{group), - CH 2 -NH-CH} 2 -CH 2
-And the like are preferable.

[0034] As particularly preferable in R ² and R ^3, or R ² and R ³ are both methyl groups, R ² and R ³ are combined with each other -R ² -R ³ - is -CH ₂ - N (M)-
A 6-membered ring containing a nitrogen atom that is CH ₂ —CH ₂ — (M is a hydrogen atom, C _1-3 alkyl or benzyl) is exemplified.

In the above formula [I], ring A and ring B may have a substituent. Examples of such a substituent include:
Halogen atom, nitro group, optionally substituted C _1-10
An alkyl group, an _optionally substituted C _2-10 alkenyl group, an _optionally substituted C _2-10 alkynyl group, an _optionally substituted hydroxyl group, an optionally substituted thiol group, Amino group, optionally substituted acyl group (eg, C _1-10 alkanoyl group, C _2-10 alkenoyl group, C _2-10 alkynoyl group), optionally esterified carboxyl group or substituted An aromatic ring group which may be used is 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. The optionally substituted C _1-10 alkyl group shown as a substituent on ring A and ring B may have 1 to 1 carbon atoms.
0 straight-chain alkyl, branched alkyl having 3 to 10 carbon atoms, cyclic alkyl having 3 to 10 carbon atoms,
For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. No. These C _1-10 alkyl groups, C
_{The 2-10} alkenyl group and the C _2-10 alkynyl group may be the same substituents as those described above for the hydrocarbon residue and the heterocyclic group represented by R or Z ¹ at any substitutable position. May be provided for 1 to 3.

The optionally substituted hydroxyl group shown as a substituent on ring A and ring B includes (i) a hydroxyl group, and (ii) an appropriate substituent for the hydroxyl group, particularly those used as a protective group for the hydroxyl group. (E.g., 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, ter
t-butoxy, pentyloxy, isopentyloxy,
Neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.) are preferred. Examples of the alkenyloxy include alkenyloxy having 2 to 10 carbon atoms (eg, allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy,
-Cyclopentenylmethoxy, 2-cyclohexenylmethoxy, etc.). Examples of the alkynyloxy include alkynyloxy having 2 to 10 carbon atoms (eg, propynyloxy and the like). Examples of the aralkyloxy include phenyl-C _1-4 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 group shown as a substituent on ring A and ring B includes (i) a thiol group and (ii) an appropriate substituent on the thiol group, particularly a protecting group for the thiol group. Examples thereof include alkylthio, alkenylthio, alkynylthio, aralkylthio, acylthio, and arylthio. 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, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.). Examples of the alkenylthio include alkenylthio having 2 to 10 carbon atoms (eg, allyl thio, crotylthio, 2-pentenylthio, 3-hexenylthio, 2-cyclopentenylmethylthio, 2-cyclohexenylmethylthio, etc.).
Is mentioned. The alkynylthio has 2 to 2 carbon atoms.
And 10 alkynylthios (eg, ethynylthio, 2-propynylthio, etc.). Examples of the aralkylthio include phenyl -C _1-4 alkylthio (e.g., benzylthio, etc. phenethylthio) and the like. Examples of the acylthio include alkanoylthio having 2 to 4 carbon atoms (eg,
Acetylthio, propionylthio, butyrylthio, isobutyrylthio, etc.) are preferred. Examples of the arylthio include phenylthio, 4-chlorophenylthio and the like.

The optionally substituted amino group shown as a substituent on ring A and ring B includes (i) an amino group, (ii) alkyl having 1 to 10 carbon atoms, and 2 to 10 carbon atoms.
Alkenyl, alkynyl having 2 to 10 carbon atoms, 1 carbon atom
An amino group having one or two substituents having 1 to 10 acyl groups, 6 to 12 aromatic groups or heterocyclic groups (eg, methylamino, dimethylamino, ethylamino,
Diethylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N
-Phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino, etc.). Examples of the optionally substituted acyl group shown as a substituent on ring A and ring B include (i) formyl, and (ii) alkyl having 1 to 10 carbons, alkenyl having 2 to 10 carbons, and carbon number. Those having 2 to 10 alkynyl or an aromatic group having 6 to 12 carbon atoms bonded to a carbonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentane) Carbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-
Cyclohexenecarbonyl, benzoyl, nicotinoyl and the like).

Examples of the carboxy which may be esterified as a substituent on ring A and ring B include (i) a carboxyl group and (ii) a carboxyl group bonded to an alkyl group having 1 to 6 carbon atoms ( That is, alkoxycarbonyl,
For example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), (ii)
i) those in which a carboxyl group is bonded to an alkenyl group having 3 to 6 carbon atoms (that is, alkenyloxycarbonyl, for example, allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl, 3-hexenyloxycarbonyl, etc.) And (iv) those in which a carbonyl group and an aralkyloxy group are bonded (that is, aralkyloxycarbonyl, for example, benzyloxycarbonyl, phenethyloxycarbonyl and the like). Examples of the _optionally substituted aromatic ring group shown as a substituent on ring A and ring B include C _6-14 aromatic hydrocarbon residues (eg, phenyl, naphthyl, anthryl, etc.) and heteroaromatic residues (Eg, pyridyl, furyl, thienyl, imidazolyl, thiazolyl, etc.).

The 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 substituents. When substituents on ring A or ring B are adjacent to each other, linked substituents adjacent, - (CH _{2) t}
— Or —O— (CH ₂ ) ₁ —O— (where t represents an integer of 3 to 5, and 1 represents an integer of 1 to 3), and such a ring may be , A 5- to 7-membered ring formed together with carbon atoms of a benzene ring. Preferably, ring A is substituted with at least one alkoxy group (preferably a C _1-3 alkoxy group), more preferably at least one methoxy. More preferably, ring A is substituted with two identical or different alkoxy groups (preferably C _1-3 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 a C _1-3 alkoxy group), more preferably at least one methoxy or isopropoxy. More preferably, ring B is substituted with two identical or different alkoxy groups (preferably C _1-3 alkoxy groups). Specifically, for example, it is particularly preferable that ring B is substituted at the 3-position with a methoxy group or an isopropoxy group, and at the 4-position with a methoxy group. Ring D of the compound represented by the above formula [II] is substituted with at least one alkoxy group (preferably C _1-3 alkoxy group), more preferably at least one methoxy or isopropoxy. More preferably, ring D is substituted with one alkoxy group (preferably a C _1-3 alkoxy group). Specifically, for example, the case where ring D is substituted with a methoxy group at the 4-position is particularly preferred. Among the compounds represented by the above formula [I], particularly preferred is Y
Is CG ″ (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. A compound in which n is 0, which is a C _1-4 alkyl group (however, bonded to the C _1-4 alkyl group at a constituent nitrogen atom of the nitrogen-containing unsaturated heterocyclic group). In the compound represented by the formula [II], it is particularly preferable that R ² and R ³ are bonded to form an optionally substituted 5- to 7-membered ring, and specifically, R ² and R ³ are Bond with each other to form a 5- to 7-membered ring formed together with a hydrogen atom on an adjacent thiophene ring (that is, a vinylene group);
Compounds in which G ′ of G ′ represents a halogen atom are exemplified. For example, 3-chloro-5,6,7,8-tetrahydro-4-
(4-methoxyphenyl) -2- (succinimidomethyl) thieno [2,3-b: 5,4-c ′] dipyridine, 3-
Chloro-4- (3,4-dimethoxyphenyl) -5,6,
7,8-tetrahydro-2- (succinimidomethyl)
Thieno [2,3-b: 5,4-c '] dipyridine, 3-chloro-4- (4-ethoxyphenyl) -5,6,7,8-tetrahydro-2- (succinimidomethyl) thieno [2, 3-b: 5,4-c '] dipyridine, 3-bromo-
5,6,7,8-Tetrahydro-4- (4-methoxyphenyl) -2- (succinimidomethyl) thieno [2,3
-B: 5,4-c '] dipyridine, 7-acetyl-3-chloro-5,6,7,8-tetrahydro-4- (4-hydroxy-3-methoxyphenyl) -2- (succinimidomethyl) thieno [2,3-b: 5,4-c ′] dipyridine,
7-acetyl-3-chloro-5,6,7,8-tetrahydro-4- (4-hydroxyphenyl) -2- (succinimidomethyl) thieno [2,3-b: 5,4-c '] dipyridine, 7-acetyl-3-chloro-5,6,7,8-tetrahydro-4- (4-methoxyphenyl) -2- (succinimidomethyl) thieno [2,3-b: 5,4-c '] dipyridine, 7-acetyl-3-chloro-4- (4-ethoxyphenyl) -5,6,7,8-tetrahydro-2-
(Succinimidomethyl) thieno [2,3-b: 5,4-
c '] dipyridine, 7-acetyl-3-chloro-4-
(3,4-dimethoxyphenyl) -5,6,7,8-tetrahydro-2- (succinimidomethyl) thieno [2,3
-B: 5,4-c '] dipyridine or a salt thereof.

As the salt of the quinoline or quinazoline derivative or thienopyridine or 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, Examples thereof include salts with acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferred examples of the salt with the inorganic base include alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), aluminum salt, ammonium salt and the like. No. Preferred examples of the salt with the organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like.

Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid,
Tartaric acid, maleic acid, citric acid, succinic acid, malic acid,
Salts with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned. Preferred examples of the salt with a basic amino acid include, for example, arginine, lysine,
Salts with ornithine and the like can be mentioned, and preferable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid. Among these salts, sodium salts and potassium salts are most preferred. Further, the quinoline or quinazoline derivative, the thienopyridine or the thienopyrimidine derivative or a salt thereof in the present invention may be a hydrate.

The quinoline or quinazoline derivative or the thienopyridine or the thienopyrimidine derivative in the present invention are described in, for example, JP-A-6-306052 (EP-A-567107) and JP-A-7-118266 (EP). -A-60
8870), JP-A-7-69890 (EP
-A-634169), JP-A-8-53419 (EP-A-686630), JP-A-8-2
No. 25531 (International Patent Application Publication WO 95/243)
No. 94) and JP-A-8-225577 (WO 9).
6/14319), JP-A-10-36374 and 10-59977 (WO97 / 4050) or the like 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 preferable.
The water-soluble polymer compound is preferably about 2 to 3
6000 mPa · s, more preferably about 2 to 4000
Compounds having a viscosity of 2 mPa · s, more preferably 2 to 1500 mPa · s (measured under conditions of 20 ° C. ± 0.1 ° C. in a 2% (W / W) aqueous solution in terms of dry matter) are 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, for example, hydroxypropyl methylcellulose [eg, grade TC-5E
W (viscosity: 2 to 4 mPa · s), TC-5MW (viscosity:
3-6 mPa · s), TC-5R (viscosity: 4-8 mPa)
· S), TC-5S (viscosity 12 to 18 mPa · s), 60
SH-50 (viscosity: 40 to 60 mPa · s), 65SH
-50 (viscosity: 40 to 60 mPa · s), 65SH-4
00 (viscosity: 320 to 480 mPa · s), 90-SH
400 (viscosity: 320 to 480 mPa · s), 90SH
-30000F (viscosity: 24000-36000mP
a.s), etc.], 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, in the present specification, 2
A polyhydric alcohol that is solid at 5 ° C., for example, polyethylene glycol (preferably having an average molecular weight of about 8,000
To 70000 polyethylene glycol), polypropylene alcohol, polyglycerin and the like.
As the gel-forming substance, preferably a cellulose derivative,
More preferably, hydroxypropylmethylcellulose or hydroxypropylcellulose is more preferably 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 palatinose, etc.), monosaccharides (eg, glucose, mannose, xylose, galactose, talose, etc.) and polysaccharides (eg, maltose, lactose (lactose), sucrose, etc.) No. Erythritol or sorbitol is more preferably used as the saccharide.

(1) Quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative:
(2) The gel-forming substance is about 1: about 0.1-100 by weight.
It is preferable to use them in a mixture such that The ratio is preferably about 1: about 0.1 to 50, and about 1: about 0.1.
2-20 are more preferred. 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 50: about 0.01 to 50 by weight, and about 1: about 0.1 by weight.
More preferably, an amount of about 50 to about 0.05 to 30 is used, and the weight ratio is about 1: about 0.2 to 20: about 0.1.
-20 is most preferred. In the oral sustained release preparation of the present invention, the gel-forming substance is preferably about 10% by weight or more, more preferably about 10 to 99.
9% by weight, more preferably about 15-95% by weight,
Particularly preferably, about 20 to 90% by weight is blended. 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, still more preferably about 3 to 70% by weight, based on the whole preparation. %, Particularly preferably about 5 to 50%, optimally about 5 to 23% by weight
Be blended.

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 may be 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 and then granulating and pressing (tableting). You can also get. In addition, after granulating a mixture containing an active ingredient and an excipient into granulated powder, other formulation materials 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 20.
The thickness is about 00 μm, and more preferably about 10 to 500 μm.

The tablet of the present invention can be prepared 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 substances 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, sweeteners and the like can also be used. When these pharmaceutically acceptable carriers are compounds having an action as the above-mentioned gel-forming substance or disintegration aid, the compounding ratio and the compounding ratio in the oral preparation of the present invention are Is calculated by adding the blending amount. Suitable examples of the excipient include lactose, sucrose, D-mannitol, erythritol, starch, crystalline cellulose, light anhydrous silicic acid, 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, for example, crystalline cellulose, pregelatinized starch,
Partially pregelatinized starch, sucrose, D-mannitol, trehalose, dextrin, hydroxypropylcellulose,
Hydroxypropyl methylcellulose, polyvinylpyrrolidone and the like can be mentioned. Preferably, crystalline cellulose is used. Preferred examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, low-substituted hydroxypropylcellulose and the like. If necessary, a preparation for oral administration can be prepared by coating with a method known per se for the purpose of taste masking, enteric coating or sustainability. As the coating agent, for example, hydroxypropyl methylcellulose,
Ethyl cellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Bruronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohm, Germany, methacrylic acid / acrylic acid Polymerization) and the like. Preferable examples of the preservative include, for example, p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Suitable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like. Examples of the coloring agent include titanium oxide, iron sesquioxide (red iron), and food coloring. Sweeteners include aspartame, sodium saccharin, dipotassium glycyrrhizinate, stevia and the like.

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) gel-forming substance, and if necessary, (3) After mixing the disintegration aid, the mixture is kneaded, granulated, dried and sized by a conventional method using a binding solution dissolved in an appropriate solvent to produce granules. The granules can be filled into capsules to form capsules.

In the sustained-release oral preparation of the present invention, the release period of the drug can be appropriately controlled by the amount of the gel-forming substance and the like, or the amount of the gel-forming substance and the disintegration aid. The sustained-release oral preparation of the present invention usually contains about 1 to 1
A sustained release time of 48 hours, preferably about 1 to 24 hours, more preferably about 3 to 24 hours. In the present invention,
For example, when a quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative or a salt thereof has an anti-inflammatory effect and further has an anti-arthritic effect, the sustained-release oral preparation of the present invention can be used for all of the inflammatory symptoms in joints. For preventing or treating arthritis. Examples of the arthritis include rheumatoid arthritis. Further, for example, when the quinoline or quinazoline derivative or the thienopyridine or the thienopyrimidine derivative or a salt thereof has an antirheumatic effect, the sustained-release oral preparation of the present invention can be used as a preventive or therapeutic agent for rheumatism and the like. Further, for example, when the quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative or a salt thereof has a bone resorption inhibiting action, the sustained-release oral preparation of the present invention can be used as a bone destruction accompanying arthritis, a bone resorption inhibitor, osteoporosis and the like. Can be used as a prophylactic / therapeutic agent. Further, for example, when a quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative or a salt thereof has an immune cytokine production inhibitory action, the sustained-release oral preparation of the present invention is useful for preventing or preventing diseases in which immunity is involved. It can be used as a therapeutic agent and / or an agent for preventing or treating rejection after organ transplantation. A quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative or a salt thereof suppresses an immunomodulatory effect or production of an immune cytokine [eg, interleukin-2 (IL-2), interferon-γ (IFN-γ) and the like]. When it has an effect, the sustained-release oral preparation of the present invention can be used as a prophylactic or therapeutic agent for diseases in which immunity including autoimmune diseases is considered to be involved. 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 lymphocytic leukocytes, chronic lymphocytic leukocytes, chronic Myeloid leukemia, colon cancer, colon cancer, rectal cancer, Helicobacter pylori infection, Hodgkin's disease, insulin-dependent diabetes, malignant melanoma, multiple myeloma, non-Hodgkin's lymphoma, non-small cell lung cancer, ovarian cancer, digestion Ulcers, prostate cancer, septic shock, tuberculosis,
Infertility, arteriosclerosis, Behcet's disease, asthma, atopic dermatitis, nephritis, systemic fungal infection, acute bacterial meningitis, acute myocardial infarction, acute pancreatitis, acute viral encephalitis, adult respiratory distress syndrome, bacterial pneumonia, chronic Pancreatitis, herpes simplex virus infection, varicella-zoster virus infection,
AIDS, human papillomavirus infection, influenza, invasive staphylococcal infection, peripheral vascular disease, sepsis, interstitial liver disease, localized ileitis, and the like. In particular, the sustained-release oral preparation of the present invention can prevent or prevent systemic lupus erythematosus, chronic hepatitis, interstitial liver disease, asthma, psoriasis, ulcerative colitis, Crohn's disease, localized ileitis or multiple sclerosis. It is used as a therapeutic agent. Since the oral preparation of the present invention has low toxicity, it can be used in mammals (eg, humans,
Cow, horse, pig, dog, cat, mouse, rat, rabbit, etc.)
Can be used safely against The sustained-release oral preparation of the present invention releases a drug over a long period of time,
Since stable drug efficacy is obtained, it is used as a highly efficacious preparation. The dosage of the sustained-release oral preparation of the present invention is the type, content of the contained quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative,
Although it depends on the dosage form, the animal to be administered, etc., the effective amount of these drugs may be sufficient. Good.

[0050]

The present invention will be described in more detail with reference to the following Examples, Reference Examples and Experimental Examples, but the present invention is not limited thereto. Compound A used in the following Examples 1 to 16 and Reference Example 1 was ethyl 4-
(3,4-dimethoxyphenyl) -6,7-dimethoxy-2
-(1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate;
No. 6 or a compound produced by the method described in JP-A-8-67679 was used.

Example 1 Compound A (400 g), hydroxypropyl methylcellulose (grade TC-5MW, manufactured by Shin-Etsu Chemical Co., Ltd.) 3
24 g of erythritol and 40 g of a tumbling fluidized granulator (MP
-10, manufactured by Powrex), and the supply air temperature is 65 ° C.
Fluid granulation was performed while spraying 400 g of 10% by weight hydroxypropylmethylcellulose under the condition of a spraying speed of 19 g / min. After granulation, the product is dried to a temperature of 32 ° C., 600 g of the granulated powder is weighed, and 15 g of crystalline cellulose (Grade Avicel PH101, manufactured by Asahi Kasei Corporation) and light anhydrous silicic acid (Grade Sylysia 320, YK FF Co., Ltd.) 6g) and 6 g of magnesium stearate were added and mixed. This mixture was converted into a tableting machine (Correct 19K).
AWC (manufactured by Kikusui Seisakusho) was used to make tablets with a 10 mmφ corner punch (tablet pressure: 0.2 ton / punch). The tablets were sized using a power mill (Showa Giken Co., Ltd., P-3) with a punching size of 1.5 mmφ. The obtained rectified powder is again tableted (Correct 19K AWC, manufactured by Kikusui Seisakusho)
Was used to produce 429 mg tablets per tablet with a 10 mmφ corner punch (tablet pressure: 1.0 ton / punch).

Example 2 400 g of compound A, hydroxypropylmethylcellulose (grade TC-5EW, manufactured by Shin-Etsu Chemical Co., Ltd.) 3
24 g were charged into a tumbling fluidized-granulator (MP-10, manufactured by Powrex), the supply air temperature was 60 ° C., and the spray speed was 19 g / mi.
Under the conditions of n, fluid 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., and 600 g of the granulated powder is weighed.
15 g of crystalline cellulose (grade Avicel PH101, manufactured by Asahi Kasei Corporation), light anhydrous silicic acid (grade thyricia 320, manufactured by YK KK) 6.1
g and 6.1 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 using a 10 mmφ corner punch (tablet pressure: about 0.2 ton / punch). The tablets were sized using a power mill (Showa Giken Co., Ltd., P-3) with a punching size of 1.5 mmφ. The obtained rectified powder was again used with a tableting machine (Correct 19K AWC, manufactured by Kikusui Seisakusho) to obtain 400 mg tablets per tablet with a 10 mmφ corner punch (tablet pressure: 1.0 ton / punch).

Examples 3 to 6 2 g of compound A, 1.9 g of hydroxypropylmethylcellulose [grade TC-5EW (Example 3), grade TC-5MW (Example 4), grade TC-5]
R (Example 5), grade TC-5S (Example 6)], crystalline cellulose (grade Avicel PH10
1, manufactured by Asahi Kasei Corporation) was weighed and mixed in a mortar. 400 mg of the mixed powder was weighed, and tableted with a 10 mmφ corner punch at a tableting pressure of 1.0 ton / cm ² using a universal testing machine (Shimadzu Corporation) to produce tablets.

Examples 7 to 8 2 g of compound A, hydroxypropylmethylcellulose 9
25 mg [grade TC-5EW (Example 7), grade TC-5MW (Example 8)], crystalline cellulose (grade Avicel PH101, manufactured by Asahi Kasei Corporation) 75
mg was weighed and mixed in a mortar. 300mg of this mixed powder
Is weighed and measured using a universal testing machine (Shimadzu) at 10 mm.
Tablets were produced with a φ-corner punch at a tableting pressure of 1.0 ton / cm ² to produce tablets.

Example 9 2 g of compound A, hydroxypropylmethylcellulose 6
30 mg (grade TC-5MW), crystalline cellulose (grade Avicel PH101, manufactured by Asahi Kasei Corporation)
70 mg was weighed and mixed in a mortar. This mixed powder 270
mg and weighed using a universal testing machine (Shimadzu Corporation).
Tablets were produced with a tablet having a corner diameter of mmφ at a tableting pressure of 1.0 ton / cm ² to produce tablets.

Example 10 2 g of compound A, 3.85 g of hydroxypropylmethylcellulose (grade TC-5EW), crystalline cellulose (grade Avicel PH101, manufactured by Asahi Kasei Corporation)
150 mg was weighed and mixed in a mortar. This mixed powder 60
Weigh 0 mg, and use a universal testing machine (Shimadzu Corporation)
Tablets were produced using a punch having a 0 mmφ corner at a tableting pressure of 1.0 ton / cm ² to produce tablets.

Example 11 2 g of compound A, 1.8 g of hydroxypropylmethylcellulose (grade TC-5EW), crystalline cellulose (grade Avicel PH101, manufactured by Asahi Kasei Corporation)
100 mg, 1 g of erythritol, 50 mg of light anhydrous silicic acid (grade thyricia 320, manufactured by YK F. Co., Ltd.), and 50 mg of magnesium stearate were weighed and mixed in a mortar. 500 mg of the mixed powder was weighed and tableted with a universal testing machine (Shimadzu Corporation) with a 10 mmφ corner punch at a tableting pressure of 1.0 ton / cm ² to produce a tablet.

Example 12 2 g of compound A, 1.8 g of hydroxypropylmethylcellulose (grade TC-5EW), crystalline cellulose (grade Avicel PH101, manufactured by Asahi Kasei Corporation)
100 mg, 1 g of sorbitol, 50 mg of light anhydrous silicic acid (grade thyricia 320, manufactured by YK KK) and 50 mg of magnesium stearate were weighed and mixed in a mortar. 500 mg of the mixed powder was weighed and tableted with a universal testing machine (Shimadzu Corporation) with a 10 mmφ corner punch at a tableting pressure of 1.0 ton / cm ² to produce a tablet.

Examples 13 to 16 2 g of compound A, 1.42 g of hydroxypropylmethylcellulose (grade TC-5MW), crystalline cellulose (grade Avicel PH101, manufactured by Asahi Kasei Corporation)
100 mg, light anhydrous silicic acid (grade thyricia 3
20, YK F Co., Ltd.) 40 mg, magnesium stearate 40 mg, additive 400 mg [lactose (Example 13), croscarmellose sodium (Acdizol, manufactured by Asahi Kasei Corporation) (Example 14), low degree of substitution Hydroxypropylcellulose (grade LH-3
1) (Example 15) and carmellose calcium (grade ECG-505) (Example 16)] were weighed and mixed in a mortar. 400 mg of the mixed powder was weighed, and tableted with a 10 mmφ corner punch at a tableting pressure of 1.0 ton / cm ² using a universal testing machine (Shimadzu Corporation) to produce tablets.

Reference Example 1 478.9 g of compound A, 218.5 g of lactose and 127.9 g of corn starch were charged into a tumbling fluidized-granulator (MP-10, manufactured by Powrex), and the air supply temperature was 70 ° C. and the spraying speed was 10 g.
The fluidized granulation was performed while spraying 520 g of a 6% by weight aqueous solution of hydroxypropylcellulose under the conditions of / min. After granulation, the product is dried to a product temperature of 45 ° C., and the dried product is power milled (Showa Giken Co., Ltd., P-3, punching size 1.2).
mmφ) to obtain a sized powder. Then, using 853 g of the sized powder, 45.5 g of croscarmellose sodium (Acdizol, Asahi Kasei Corporation), 2.7 g of magnesium stearate, polyethylene glycol 600
9.1 g of the mixture (Sanyo Chemical Co., Ltd.). Using a tableting machine (Correct 19K AWC, manufactured by Kikusui Seisakusho), the mixed powder was crushed with a 7 mmφ corner punch at a rate of 190 per tablet.
mg tablets (tableting pressure 1.0 ton / cm ² ).

Experimental Example 1 The disintegration time of the tablets produced in Examples 4, 13, 14, 15, and 16 was examined using a disintegration tester (Toyama Sangyo Co., Ltd.) without a disc according to the Japanese Pharmacopoeia disintegration test method. As a result, the tablet obtained in Example 4 was 160 minutes,
It is 130 minutes for the tablet of Example 13, 90 to 120 minutes for the tablet of Example 14, and 1 for the tablet of Example 15.
40 minutes, that 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 900 rpm of 0.6% sodium lauryl sulfate (SLS) aqueous solution was used. Was tested. A 2 ml sample was taken over time, filtered through a 0.45 μm membrane filter, accurately weighed 1 ml, and accurately weighed and diluted 8 ml of the mobile phase to obtain a sample solution. Separately, 20 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. Sample solution and standard solution 1
0 μl was measured by liquid chromatography. The elution rate was calculated by the following equation using the peak areas of compound A as QT and QS. Dissolution rate (%) = QT / QSx0.9 × WSx content × theoretical formulation / WT / 20 The results are shown in [Table 1] and [Table 2].

[0063]

[Table 1]

[0064]

[Table 2]

As is clear from the above [Table 1] and [Table 2], the tablet of Reference Example 1 elutes 100% in 0.75 hours, whereas the tablets of Examples 1 to 12 exhibit a sustained release. It can be seen that it has.

Compound B used in the following Examples 17 to 19 and Reference Example 2 was 3-chloro-5,6,7,
8-tetrahydro-4- (4-methoxyphenyl) -2
-(Succinimidomethyl) thieno [2,3-b: 5.4
-C '] dipyridine, and a compound produced by a method similar to the method described in Synthesis Example 1-5 below was used.

Preparation of 3-chloro-5,6,7,8-tetrahydro-4- (4-methoxyphenyl) -2- (succinimidomethyl) thieno [2,3-b: 5,4-c '] dipyridine :

Synthesis Example 1 Acetonitrile (48 g) was dissolved in 1.6 M n-butyllithium in hexane (728 ml) and tetrahydrofuran (9 g).
00 ml) at -70 ° C. 20 at -70 ° C
After stirring for 4 minutes, 4-methoxybenzoyl chloride (10
0 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. The mixture was stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration to obtain ω-cyano-4-methoxyacetophenone (69.5 g, 68%). Recrystallized from ethanol. Colorless prism crystals. 127-128 ° C.

Synthesis Example 2 The compound (40 g) obtained in Synthesis Example 1, sulfur (8 g), 1-
Benzyl-4-piperidone (43.2 g), morpholine (19.
9 g) and 2-propanol (1000 ml) are mixed with 70
Stirred at C for 5 hours. The reaction mixture was left at room temperature overnight. The precipitated crystals are collected by filtration, washed with 2-propanol,
-Amino-6-benzyl-3- (4-methoxybenzoyl) -4,5,6,7-tetrahydrothieno [2,3-c] pyridine (52.4 g, 61%) was obtained. Recrystallized from ethyl acetate-hexane. Yellow prism crystals. Melting point 164-16
5 ° 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 (140 ml) under ice-cooling. rear,
Refluxed for 2.5 hours. The reaction mixture was diluted with toluene (100 ml)
It was poured into water (100 ml) with stirring. After the toluene layer was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure. 7
-Benzyl-3-chloro-2-chloromethyl-5,6,
7,8-tetrahydro-4- (4-methoxyphenyl)
Thieno [2,3-b: 5,4-c '] dipyridine (8.2 g, 8
3%). 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 mixed at 70 ° C. After stirring for an hour, the mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and 7-benzyl-3-chloro-5,6,7,8-tetrahydro-4- ( 4-methoxyphenyl) -2- (succinimidomethyl) thieno [2,3-b: 5,4-c ']
Dipyridine (21 g, 58%) was obtained. Recrystallized from tetrahydrofuran-isopropyl ether. Colorless prism crystals. 241-243 ° C.

Synthesis Example 5 The compound obtained in Synthesis Example 4 (14.5 g) and formic acid (29.1 m
l), 10% palladium on carbon (50% hydrate, 14.5)
g) and a mixture of methanol (500 ml) was stirred at room temperature for 21 hours. 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. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), and the solvent was distilled off. The residue was subjected to silica gel column chromatography. Ethyl acetate-methanol (10: 1, v /
From the portion eluted in v), Compound B (5.0 g, 42%)
I got Recrystallized from ethyl acetate-methanol. Colorless prism crystals. 225-226 ° C.

Example 17 160 mg of compound B, hydroxypropyl methylcellulose (grade TC-5MW, manufactured by Shin-Etsu Chemical Co., Ltd.)
689.6 mg, crystalline cellulose (grade Avicel P
H101, manufactured by Asahi Kasei Corporation) 96 mg, light anhydrous silicic acid 4.8 mg, and magnesium stearate 9.6 m
g was weighed and mixed in a mortar. 300 mg of the mixed powder was weighed and 9.5 mm using a universal testing machine (Shimadzu Corporation).
A tablet was produced by tableting with a φ punch at a tableting pressure of 1.0 ton / cm ² .

Examples 18 to 19 160 mg of compound B, hydroxypropylmethylcellulose (grade TC-5EW, manufactured by Shin-Etsu Chemical Co., Ltd.)
497.6 mg, crystalline cellulose (grade Avicel P
96 mg of H101 (manufactured by Asahi Kasei Corporation), 4.8 mg of light anhydrous silicic acid, 9.6 mg of magnesium stearate and 192 mg of lactose (Example 18) or sorbitol (Example 19) were weighed and mixed in a mortar. 300 mg of this mixed powder was weighed, and a tableting pressure of 1.0 ton / cm ^{2 was} applied with a 9.5 mmφ punch using a universal testing machine (Shimadzu Corporation).
To produce tablets.

Reference Example 2 After 0.5 g of compound B, 2.21 g of lactose and 0.4 g of corn starch were mixed in a mortar, 0.7 g of an aqueous solution containing 0.1 g of hydroxypropyl cellulose was added and kneaded. The kneaded product subjected to vacuum drying at 40 ° C. for 16 hours was pulverized in a mortar to give a sized powder. 0.16 g of croscarmellose sodium and 0.016 g of magnesium stearate were mixed with 2.96 g of the sized powder. 170 mg of this mixed powder
Is weighed and measured using a universal testing machine (Shimadzu) at 7.5 m
Tablets were produced with a mφ punch at a tableting pressure of 1.0 ton / cm ² to produce tablets.

Experimental Example 3 One tablet obtained in Reference Example 2 and Examples 17 to 19 was precisely weighed, and a test was conducted at 50 rpm by a paddle method using 900 ml of a 0.3% aqueous sodium lauryl sulfate solution. . Sample 1 ml over time,
Filtration through a 45 μm membrane filter, 0.2 ml
Was diluted with 0.8 ml of a mobile phase to obtain a sample solution. Separately, Compound B was accurately weighed, a solution of 0 to 62 μg / ml was prepared, diluted in the same manner as the sample solution, and used as a standard solution. 20 μl of the standard solution and the sample solution were measured by liquid chromatography. 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].

[0077]

[Table 3]

[0078]

The oral preparation of the present invention has an excellent sustained-release property, so that 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. Can be. In addition, the tableting property of the oral preparation of the present invention is improved because the granulated product has good flowability during the production. 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.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/30 A61K 47/30 A61P 27/00 A61P 27/00 29/00 101 29/00 101 // C07D 215/58 C07D 215/58 239/76 239/76 403/06 403/06 495/04 105 495/04 105Z

Claims (18)

[Claims] 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 thienopyridine or thienopyrimidine derivative is a compound having an anti-inflammatory or 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 preparation according to claim 4, wherein the water-soluble polymer compound is hydroxypropylmethylcellulose. 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. A quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative.
(2) The gel-forming substance is about 1: about 0.1-100 by weight.
The preparation according to claim 1, which is: 10. A weight ratio of (1) quinoline or quinazoline derivative or thienopyridine or thienopyrimidine derivative: (2) gel-forming substance: (3) disintegration aid in a weight ratio of about 1: about 0.1 to 50: about 0. The formulation according to claim 3, wherein the formulation is from 0.01 to 50. 11. The method according to claim 1, wherein the gel-forming substance is present in an amount of about 1 to the whole preparation.
The preparation according to claim 1, which is contained in an amount of 0% by weight or more. 12. A quinoline or quinazoline derivative represented by the formula: [In the formula, Y represents a nitrogen atom or CG (G represents a carboxyl group which may be esterified or amidated, an acyl group which may be substituted, a hydroxyalkyl group which may be protected or a halogen atom. Is shown).
¹ is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, X ¹ is an oxygen atom or an optionally oxidized sulfur atom, n is 0 or 1, k is 0 or 1 is shown. 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. 13. A nitrogen-containing unsaturated heterocyclic ring wherein Y is CG ″ (G ″ represents a carboxyl group which may be esterified) and R ¹ may have a substituent. A C _1-4 alkyl group substituted by a group (provided that it is bonded to the C _1-4 alkyl group at a nitrogen atom constituting the nitrogen-containing unsaturated heterocyclic group), and n is 0. 13. The formulation according to 12. 14. The quinoline derivative or quinazoline derivative is ethyl 4- (3,4-dimethoxyphenyl) -6,
7-dimethoxy-2- (1,2,4-triazole-1-
14. The formulation according to claim 13, which is (ylmethyl) quinoline-3-carboxylate. 15. A thienopyridine or thienopyrimidine derivative having the formula: [Wherein, R ² and R ³ are the same or different and each represent a hydrogen atom, a halogen atom or an optionally substituted alkyl group, and R ² and R ³ may be bonded to each other and may be substituted with 5 to 5; It may form a 7-membered ring. W is a nitrogen atom,
X ² represents an oxygen atom, an optionally oxidized sulfur atom or a group represented by CG ′ (wherein, G ′ represents a carboxyl group which may be esterified or a halogen atom). 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 an optionally substituted amino group. , Respectively. 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 a thienopyridine or thienopyrimidine derivative, R ² and R ³ are bonded to form a 5- to 7-membered ring which may be substituted, and W is CG ′ (G 'Represents a carboxyl group which may be esterified or a halogen atom.) And R ⁴ is a heterocyclic ring which may be substituted.
5. The formulation according to 5. 17. A method for controlling the release of a quinoline or quinazoline derivative or a thienopyridine or a thienopyrimidine derivative obtained by mixing a gel-forming substance in an oral preparation containing a quinoline or a 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 thienopyridine or a thienopyrimidine derivative.