JP2002167327A - Solid formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a granulation powder containing a higher amount of slightly water soluble, highly water repellent biologically active substance as well as a solid formulation containing the granulation powder having excellent disintegration and dissolution of the biologically active substance. SOLUTION: This invention relates to 1) a granulation powder including a biologically active substance and a cellulose disintegrator, 2) a granulation powder including a biologically active substance, a cellulose disintegrator and a binder, 3) a solid formulation containing the granulation powder of 1) and 2), a cellulose disintegrator, a stearic acid lubricant and 4) a solid formulation of 3) as an elliptical tablet.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a granulated powder, a solid preparation and a method for producing the same.

[0002]

2. Description of the Related Art In a granulation process of a high-content preparation of a poorly water-soluble and highly water-repellent physiologically active substance, granulation does not proceed in a binder solution in which a binder is dissolved or partially dispersed in ordinary water,
In addition, operability is poor in the steps up to the tableting step, and the uniformity of the content of the physiologically active substance in the uncoated tablet obtained by tableting is also a concern. In general, tablets are selected as the dosage form of the solid preparation, and the tablet shape is selected to be circular from the viewpoint of ingestibility and manufacturability. However, when it is necessary to increase the tablet weight from the viewpoint of the content and content of the physiologically active substance in the tablet, the ingestibility is poor and the dissolution of the drug is delayed.

[0003]

A granulated powder having a uniform and high content of a poorly water-soluble and highly water-repellent physiologically active substance has not been obtained. Conventionally, a solid preparation having good disintegration properties and a solid preparation having a high content of a physiologically active substance have not yet been obtained from known granulated powder.

[0004]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and have studied cellulosic disintegrants (for example, calcium carboxymethylcellulose (hereinafter sometimes abbreviated as CMC-Ca). ), Etc.) to provide a poorly water-soluble and / or water-repellent physiologically active substance (for example, gonadotropin GnRH).
(Gonadotropinreleasing hormone) even if it is a physiologically active substance having an antagonistic action), the operability up to the tableting step is good, and the granulated powder containing the biologically active substance uniformly and at a high content, and thus the biologically active substance Obtaining a solid preparation containing a uniform and high content, especially a solution (or suspension) containing the physiologically active substance, a cellulosic disintegrant and a binder (for example, hydroxymethylcellulose (hereinafter sometimes abbreviated as HPC) and the like). Turbidity), a granulated powder having good operability up to the tableting step can be obtained, and the granulated powder containing a high content of the bioactive substance, and thus the bioactive substance, It has been found that a solid preparation containing a high content can be obtained. Further, they have found that a solid preparation containing the granulated powder can be a solid preparation having excellent disintegration properties. It has also been found that dissolution is unexpectedly improved by forming the solid preparation into a tablet, particularly an oval tablet. It has also been found that when the physiologically active substance is unstable due to color change due to light, it can be stably stored for a long period of time even under non-shading by making a film-coated tablet. As a result of further research on the above matters, the present invention has been completed.

(1) Granulated powder containing a physiologically active substance and a cellulosic disintegrant; (3) The granulated powder according to the above (1), which is a disintegrant obtained by combining a selected compound or two or more compounds; (3) The granulated powder according to the above (1), wherein the cellulosic disintegrant is carboxymethylcellulose calcium; 4) the granulated powder according to the above (1), wherein the physiologically active substance is poorly water-soluble; (5) the granulated powder according to the above (1), wherein the physiologically active substance is water-repellent; (7) The granulated powder according to the above (1), which is water-soluble and water-repellent; End; (8) a physiologically active substance, wherein

Embedded image Wherein, X is a carbon atom or a nitrogen atom, - - - indicates a single bond or a double bond], or a salt thereof having a partial structure represented by [hereinafter, may be abbreviated as compound (X) The granulated powder according to the above (1), wherein (9) the compound (X) has the formula

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

Embedded image (Wherein R ⁵ represents a hydrogen atom or R ⁴ and R ⁵ may be linked to form a heterocyclic ring), and n represents an integer of 0 to 5 The granulated powder according to the above (8), which is a compound represented by the following formula (I): -N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4- (3-methoxyureido) phenyl]
-3-phenylthieno [2,3-d] pyrimidine-2,
The granulated powder according to the above (8), which is 4 (1H, 3H) -dione or a salt thereof; (11) a compound of the formula (X)

Embedded image[Wherein, R⁹Is optionally substituted C_1-7Alkyl group,
Optionally substituted C _3-7Cycloalkyl group, substituted
C that may be_1-6Alkoxyamino group or substituted
An optionally substituted hydroxyamino group is represented by R^TenIs replaced
May be C_1-7Alkyl group or substituted
Each represents a good phenyl group;⁹Is unsubstituted C_1-7A
When it is a alkyl group, R^TenIs the substituted C_1-7Alkyl
Represents a group or substituted phenyl]
Or a salt thereof [hereinafter, may be abbreviated as compound (VIII).
(12) the compound (X) is 3- (N-benzyl-N-meth);
(Tylaminomethyl) -4,7-dihydro-5-isobutyi
Ryl-7- (2,6-difluorobenzyl) -2- [4
-[(1-hydroxycyclopropyl) carbonylamido
No] phenyl] -4-oxothieno [2,3-b] pyri
Gin or granulated powder according to (8), a salt thereof; (13) a physiologically active substance, a cellulose-based disintegrant and binding
The solution according to the above (1), wherein the solution containing the agent is mixed and dried.
Granulated powder; (14) hydroxypropyl cellulose as binder, pregelatinized
Starch, sucrose, gelatin, gum arabic powder, meth
Cellulose, hydroxypropyl methylcellulose,
Polyvinylpyrrolidone, dextrin and pullulan?
Or a combination of two or more compounds selected from
(15) The granulated powder according to the above (13), wherein the binder is hydroxypropylcellulose.
(16) The granulated powder according to (13) above, wherein (16) the solution containing a binder is an alcohol solution.
(13) The granulated powder according to the above (13); (17) The alcohol is an alcohol having 1 to 3 carbon atoms.
(18) The granulated powder according to (16) above, wherein (18) the alcohol is ethanol.
(19) Granulated powder according to the above (1) for tableting; (20) Bioactive substance, cellulosic disintegrant and binding
Granulation characterized by mixing a solution containing an agent and drying
(21) Compounding granulated powder described in (1) to (18) above
(22) Granulated powder or cell according to any one of the above (1) to (18)
Combined with loin disintegrant and stearic acid lubricant
(23) The cellulosic disintegrant is carboxymethyl cellulose.
Over scan calcium, carboxymethylcellulose, cross
Carmellose sodium or low-substituted hydroxypro
Compounds selected from pill cellulose or two or more compounds
(22) The disintegrant according to (22) above,
(24) Cellulose-based disintegrant is carboxymethylcellulo
(22) the solid preparation according to the above (22), wherein the stearic acid-based lubricant is magnesium stearate;
(26) The solid preparation according to the above (22), wherein the solid preparation is a film-coated tablet.
(27) The solid preparation according to the above (21), which is an oval tablet.
(28) A solid product according to the above (21), which is a capsule.
(29) The solid product according to the above (21), which is a granule / fine granule
(30) granulated powder containing compound (I); (31) 5- (N-benzyl-N-methylaminomethyl)
L) -1- (2,6-difluorobenzyl) -6- [4
-(3-methoxyureido) phenyl] -3-phenyl
Thieno [2,3-d] pyrimidine-2,4 (1H, 3
(30) The above (30) comprising H) -dione or a salt thereof.
(32) mixing the compound (I) with a solution containing a binder,
The granulated powder according to the above (30), which is dried; (33) the binder is hydroxypropylcellulose,
Starch, sucrose, gelatin, gum arabic powder, meth
Cellulose, hydroxypropyl methylcellulose,
Polyvinylpyrrolidone, dextrin and pullulan?
Or a combination of two or more compounds selected from
(32) The granulated powder according to the above (32), wherein the solution containing the binder is an alcohol solution.
(32) the granulated powder according to (32), wherein the alcohol is an alcohol having 1 to 3 carbon atoms
(36) The granulated powder according to (34) above, wherein (36) the alcohol is ethanol.
(37) Granulated powder according to the above (30) for tableting; (38) Mixing compound (I) with a solution containing a binder
(39) dispersing the granulated powder according to the above (30) to (36);
A solid preparation that is combined. (40) The granulated powder according to (30) to (36),
Contains a lurose disintegrant and a stearic acid lubricant
(41) the cellulosic disintegrant is carboxymethyl cellulose
Sucrose, carboxymethylcellulose, cloth
Carmellose sodium or low-substituted hydroxypro
Compounds selected from pill cellulose or two or more compounds
The disintegrant according to the above (40), which is a disintegrant obtained by combining
(42) Cellulose-based disintegrant is carboxymethylcellulo
(43) the stearic acid-based lubricant is magnesium stearate;
(44) The solid preparation according to the above (40), wherein the solid preparation is a film-coated tablet.
(45) The solid preparation according to the above (39), which is an oval tablet.
(46) The solid product according to the above (39), which is a capsule.
(47) The solid product according to the above (39), which is a granule / fine granule
(48) Gonadotropin-releasing hormone antagonist
(39) The solid preparation according to (39) above, which is an agent for preventing or treating sex hormone-dependent diseases.
It relates to the solid preparation as described in (39).

[0006] The "bioactive substance" used in the present invention is preferably a substance having a molecular weight of about 1000 or less, preferably about 900 or less, more preferably about 800 or less, and particularly preferably about 700 or less. In the present invention, the effect of a “bioactive” substance is remarkably exhibited when it is poorly water-soluble or / and water-repellent. The solubility of the "poorly water-soluble physiologically active substance" used in the present invention is, for example, 0.1
% (W / V) or less, preferably 0.01% (W / V) or less. Here, the solubility refers to the second solution [0.2 M phosphate buffer (about pH 6.8)] described in the 14th revised Japanese Pharmacopoeia.
After adding the drug in excess, for example, Recipro Sh
aker (Model SR-I, Taiyo Kagaku Kogyo Co., Ltd.), shake 100 times or more per minute at room temperature (about 15 to
(Approximately 25 ° C.) for 30 minutes or more, and shows the drug concentration in the supernatant obtained by centrifuging the undissolved drug.

[0007] The "water-repellent physiologically active substance" used in the present invention includes substances that are hardly wetted, that is, substances having a large contact angle. As a specific example, the diameter of the physiologically active substance is 13 m with a load of 1 ton / cm ² using a Shimadzu Autograph (AG-5000B type) (manufactured by Shimadzu Corporation).
m of a compression molded product (300 mg), a drop of purified water was dropped on the surface thereof using a syringe, and the contact angle of the water droplet 15 seconds after the drop was measured using an automatic contact angle meter (CA-Z type) (Kyowa Substances whose value measured by Interfacial Science) is 40 degrees or more, preferably 60 degrees or more, and more preferably 80 degrees or more. Magnesium stearate, a typical example of a substance having high water repellency, a compound A (5- (N-benzyl-
N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4- (3-methoxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H , 3H) -dione) and the compound B (3- (N-benzyl-N-methylaminomethyl) described below)
-4,7-dihydro-5-isobutyryl-7- (2,6
-Difluorobenzyl) -2- [4-[(1-hydroxycyclopropyl) carbonylamino] phenyl] -4
-Oxothieno [2,3-b] pyridine) was measured by the above method, and as a result, it was found to be about 96 degrees, about 90 degrees and about 88 degrees, respectively.

[0008] Examples of the "physiologically active substance" used in the present invention include GnRH antagonists, GnRH agonists and antibiotics. Of these, GnR
H antagonists are preferred. The “GnRH antagonist” may be any compound having a GnRH antagonistic action.

Embedded image Wherein, X is a carbon atom or a nitrogen atom, - - - indicates a single bond or a double bond], or a salt thereof having a partial structure represented by (basic skeleton), and more specifically, the Compound (I), compound (VIII) or a salt thereof and the like.

The definition of each substituent in the above formula (I) is described below. “C _1-4 alkoxy group” represented by R ¹ or R ²
As, for example, methoxy, ethoxy, propoxy,
Isopropoxy, butoxy, tert-butoxy and the like. Of these, a C _1-3 alkoxy group is preferred. More preferably, it is methoxy. The “C _1-4 alkoxy-carbonyl group” represented by R ¹ or R ² includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl and the like. Of these, a C _1-3 alkoxy-carbonyl group is preferred. More preferably, it is methoxycarbonyl. R
¹ or an optionally substituted C represented by R ²
_As the “C _1-4 alkyl group” of the “ _1-4 alkyl group”, for example, a linear C _1-4 alkyl group (eg, methyl, ethyl, propyl, butyl, etc.), a branched C _3-4 alkyl group (Eg, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.). Of these, a C _1-3 alkyl group is preferred. Especially, ethyl is preferable.

The “substituent” of the “optionally substituted C _1-4 alkyl group” represented by R ¹ or R ² includes:
For example, (i) hydroxy, (ii) C _1-7 acyloxy (eg, C _1-6 alkyl-carbonyloxy such as acetoxy, propionyloxy), (iii) benzoyloxy, (iv) C _1-6 alkoxy-carbonyl ( examples include methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl), benzyloxycarbonyl, C _1-4 acyl (e.g., acetyl, C _1-3 alkyl, such as propionyl - carbonyl), C _1-4 alkyl (e.g., Methyl,
An amino group (eg, amino, dimethylamino, methoxycarbonyl) which may have one or two substituents selected from ethyl, propyl, butyl, etc.) and C _1-3 alkylsulfonyl (eg, methanesulfonyl) Amino, ethoxycarbonylamino, tert-butoxycarbonylamino, benzyloxycarbonylamino, acetylamino, methanesulfonylamino, etc.), (v) C
_1-10 alkoxy (eg, methoxy, ethoxy, propoxy, tert-butoxy, etc.), (vi) C _3-7 cycloalkyloxycarbonyloxy-C _1-3 alkoxy (eg, cyclohexyloxycarbonyloxy-1-ethoxy, etc.) , (Vii) C _1-3 alkoxy-C _1-3 alkoxy (eg, methoxymethoxy, methoxyethoxy, etc.). Of these, hydroxy is preferred. R ¹
Or a “C _1-4 optionally having substituent (s)” for R ²
The “C _1-4 alkyl group” of the “alkyl group” includes, for example, 1 to 5, preferably 1 to 5,
It may have from 3 to 3, and when the number of substituents is 2 or more, each substituent may be the same or different. One of R ¹ and R ² is preferably a hydrogen atom, and the other is preferably a C _1-3 alkoxy group.

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

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

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

Embedded image As the group represented by, for example,

Embedded image And the like. Of these, the formula

Embedded image The group represented by is preferred.

R ⁶ is represented by the formula

Embedded image [Wherein, R ⁵ has the same meaning as described above]. R ⁴ is preferably a C _1-3 alkyl group and R ⁵ is preferably a hydrogen atom. n is preferably an integer of 0 to 2.

[0015] In compound (I), preferred compounds, R ¹ is hydroxy group, a methoxy group or a C _1-3 alkyl group; R ² is a hydrogen atom or a C _1-3 alkyl group; R ⁴ is C
_A compound wherein R ⁶ is a benzyl group; and n is 0, or a salt thereof. Among them, preferably, R ¹ is a methoxy group; and the like, or a salt thereof is a and n are 0; R ² and R ⁵ are each a hydrogen atom; R ⁴ is C _1-3 alkyl group; R ⁶ is a benzyl group . Specific examples of compound (I) include 5- (N-benzyl-N
-Methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4- (3-methoxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-
2,4 (1H, 3H) -dione, 5- (N-benzyl-N
-Methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4- (3-hydroxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, 5- (N-benzyl-)
N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4- (3-methylureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-
2,4 (1H, 3H) -dione, 5- (N-benzyl-N
- methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4- (3-ethylureido) phenyl] -3-phenyl-thieno [2,3-d] pyrimidine -
2,4 (1H, 3H) -dione or a salt thereof. Among them, 5- (N-benzyl-N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6
-[4- (3-methoxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H,
3H) -dione or a salt thereof is preferred.

The definition of each substituent in the above formula (VIII) is described below. Examples of the “C _1-7 alkyl group” of the “ _optionally substituted C _1-7 alkyl group” for R ⁹ include, for example, a linear C _1-7 alkyl group (eg, methyl, ethyl, propyl,
Butyl, pentyl, hexyl, heptyl, etc.), branched C
_3-7 alkyl group (eg, isopropyl, isobutyl, sec-
Butyl, tert-butyl, isopentyl, neopentyl and the like). Of these, a branched C _3-7 alkyl group is preferred. Especially, isopropyl is preferable. R
Indicated by ⁹ "optionally substituted C _1-7 alkyl group"
Examples of the “substituent” include (i) a hydroxy group and (i)
i) C _1-7 acyloxy (eg, C _1-6 alkyl-carbonyloxy such as acetoxy, propionyloxy; benzoyloxy, etc.); (iii) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl,
tert-butoxycarbonyl, etc.), benzyloxycarbonyl, C _1-3 acyl (eg, C _1-2 alkyl-carbonyl such as acetyl, propionyl, etc.), C _1-3 alkylsulfonyl (eg, methanesulfonyl, etc.) and C _{1 -3}
Amino (eg, amino, methoxycarbonylamino, ethoxycarbonylamino, tert-butoxycarbonylbenzyloxycarbonylamino, Acetylamino, methanesulfonylamino, methylamino, dimethylamino, etc.), (i
v) C _3-7 cycloalkyloxycarbonyloxy (eg,
Cyclohexyloxycarbonyloxy) and C
C which may have 1 to 3 substituents selected from _1-3 alkoxy (eg, methoxy, ethoxy, etc.)
_1-10 (preferably C _1-4 ) alkoxy (eg, methoxy,
Ethoxy, propoxy, tert- butoxy, cyclohexyloxycarbonyloxy-1-ethoxy, methoxymethoxy, etc. ethoxymethoxy), (v) C _1-6 alkoxy - and carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.) No. Of these, a hydroxy group is preferred. The “C _1-7 alkyl group” is, for example, one of the above substituents at a substitutable position.
It may have from 5 to 5, preferably 1 to 3, and when the number of substituents is 2 or more, each substituent may be the same or different.

The optionally substituted C represented by R ⁹
_As the “C _3-7 cycloalkyl group” of the “ _3-7 cycloalkyl group”, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like can be mentioned. Of these, cyclopropyl is preferred. “Optionally substituted C _{3-7 represented} by R ⁹
Examples of the “substituent” of the “cycloalkyl group” include one to three same substituents as the “substituent” of the “optionally substituted C _1-7 alkyl group” for R ⁹ . When the number of the substituents is 2 or more, respective substituents may be the same or different. Represented by R ⁹ in the "optionally substituted C _1-6 alkoxy group" as "C _1-6 alkoxy group" is, for example, mono- - or di -C _1-6 alkoxy group (eg, methoxyamino, ethoxyamino,
Dimethoxyamino, diethoxyamino, ethoxymethoxyamino, etc.). Among them, Mono-C _1-3
An alkoxyamino group (eg, methoxyamino, etc.) is preferred. Represented by R ⁹ "substituent" of the "optionally substituted C _1-6 alkoxy group" is represented by R ⁹ in the "optionally substituted C _1-7 alkyl group", " And the same number as the “substituent”. When the number of substituents is two or more, each substituent may be the same or different. The "substituent", "C _1-6 alkoxy group" of the C _1-6 alkoxy amino or "nitrogen atom of the amino group"
May be substituted. The "optionally substituted C
Specific examples of " _1-6 alkoxyamino group" include methoxyamino, N-methyl-N-methoxyamino, N-ethyl-N-methoxyamino, ethoxyamino, dimethoxyamino, diethoxyamino, ethoxymethoxyamino and the like. Can be Preferred examples include a C _1-3 alkoxyamino group and an NC _1-3 alkyl-NC _1-3 alkoxyamino group.

R⁹The “optionally substituted
As the “substituent” for the “droxyamino group”, hydroxy
Substitute "hydroxy group" or "amino group" for amino group
As a substituent on the “hydroxy group”
Is (i) C_1-7Acyl group (eg, acetyl, propionyl)
Such as C_1-6Alkyl-carbonyl; benzoyl
Etc.), (ii) C_1-6Alkoxy-carbonyl (eg, meth
Xoxycarbonyl, ethoxycarbonyl, tert-butoxy
Carbonyl), benzyloxycarbonyl, C _1-3
Acyl (eg, C such as acetyl, propionyl, etc.)_1-2Al
Kill-carbonyl, etc.), C_1-3Alkylsulfonyl
(Eg, methanesulfonyl, etc.) and C_1-3Alkyl
(Eg, methyl, ethyl, etc.)
An amino group optionally having one or two amino groups (specific examples:
, Methoxycarbonylamino, ethoxycarbonyla
Mino, tert-butoxycarbonylbenzyloxycarbo
Nilamino, acetylamino, methanesulfonylami
, Methylamino, dimethylamino, etc.), (iii) C
_3-7Cycloalkyloxycarbonyloxy (eg,
Rohexyloxycarbonyloxy) and C_1-3
Selected from alkoxy (eg, methoxy, ethoxy, etc.)
Which may have 1 to 3 substituents_1-10(Preferred
Or C_1-4) Alkyl group (eg, methyl, ethyl, pro
Pill, tert-butyl, cyclohexyloxycarbonyl
Oxy-1-ethyl, methoxymethyl, ethoxymethyl
And the like as a substituent on the “amino group”.
And the groups described in the above (i) to (iii).
"Hydroxy group" or "amino"
Each substituent of "group" may be the same or different. "Place
Preferred Examples of "Hydroxyamino Group which may be Replaced"
As N-C _1-6Alkyl-N-hydroxyamino
Groups (eg, N-methyl-N-hydroxyamino, N-ethyl
And N-hydroxyamino). Sa
More preferably N-C_1-3Alkyl-N-hydroxyl
And a mino group.

The optionally substituted C represented by R ¹⁰
_As the “C _1-7 alkyl group” of the “ _1-7 alkyl group”, for example, a linear or branched C _1-7 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
c-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and the like). Among them, a C _1-3 alkyl group (eg, methyl, ethyl,
Propyl, isopropyl, etc.). Particularly preferred is isopropyl. As the “substituent” of the “optionally substituted C _1-7 alkyl group” for R ¹⁰ ,
The same number as the “substituent” of the “optionally substituted C _1-7 alkyl group” for R ⁹ is mentioned.
When the number of substituents is two or more, each substituent may be the same or different. Examples of the “substituent” of the “optionally substituted phenyl group” represented by R ¹⁰ include halogen (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-3 alkyl group (eg, methyl, ethyl , Propyl, isopropyl, etc.) and C _1-3 alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.). Among them, halogen (preferably fluorine) is preferable.
The "phenyl group" may have, for example, 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions. When the number of the substituents is 2 or more, the respective substituents are the same. Or they may be different.

R⁹Is preferably a substituted branch C_3-7
Alkyl group or substituted C_3-7Cycloalkyl group,
More preferably, a branched C substituted with a hydroxy group
_3-7C substituted with an alkyl group or a hydroxy group_3-7Shi
A cycloalkyl group. Of these, substituted with hydroxy group
Done C_3-7Cycloalkyl groups are preferred. Also Hyde
C optionally substituted with a roxy group_1-3Alkyl group, ar
C optionally substituted with a droxy group_3-7Cycloalkyl
Group, mono-C_1-3Alkoxyamino group, N-C _1-3Al
A kill-N-hydroxyamino group or a hydroxyamino group
Are preferred. R⁹Is particularly preferably a hydroxy group
A cyclopropyl group or methoxy which may be substituted with
And a cyamino group. Most preferably, a hydroxy group
Is a cyclopropyl group substituted with R^TenIs preferred
Or optionally substituted C_1-7It is an alkyl group.
More preferably, it may be substituted with a hydroxy group.
C_1-3And an alkyl group. Particularly preferably isop
Ropil. Also, phenyl is preferable. Compound (VI
Preferred examples of II) include R⁹Is replaced by a hydroxy group
C which may be replaced_1-3Alkyl and hydroxy groups
Optionally substituted C_3-7Cycloalkyl group or
No-C_1-3Alkoxyamino group; R^TenBut C_1-3Alkyl
Group or a phenyl group or a salt thereof.
I can do it. More preferably, R⁹But (1) 1 or 2
Substituted with a hydroxy group of_1-3Alkyl group, (2)
C substituted with a droxy group_3-7A cycloalkyl group, or
Is (3) C_1-3Alkoxyamino group; R^TenIs isopropyl
Group or a phenyl group or a salt thereof.
I can do it.

[0021] Specific examples of the compound (VIII) is 3-
(N-benzyl-N-methylaminomethyl) -4,7-
Dihydro-5-isobutyryl-7- (2,6-difluorobenzyl) -2- (4-cyclopropanecarbonylaminophenyl) -4-oxothieno [2,3-b] pyridine, 5-benzoyl-3- (N- Benzyl-N-methylaminomethyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-4-oxo-2- [4- (3
- hydroxy-2-methyl-propionylamino) phenyl] thieno [2,3-b] pyridine, 5- (4-fluorobenzoyl)-3-(N-benzyl -N- methylaminomethyl) -7- (2,6 -Difluorobenzyl)-
4,7-dihydro-4-oxo-2- (4-cyclopropanecarbonylaminophenyl) thieno [2,3-b]
Pyridine, 3- (N-benzyl--N- methylaminomethyl) -4,7-dihydro-5- isobutyryl-7-
(2,6-difluorobenzyl) -2- [4- (3-hydroxy-2-methylpropionylamino) phenyl]
-4-oxothieno [2,3-b] pyridine, 3- (N
-Benzyl-N-methylaminomethyl) -4,7-dihydro-5-isobutyryl-7- (2,6-difluorobenzyl) -2- (4-N'-methoxyureidophenyl) -4-oxothieno [2 3-b] pyridine, 3-
(N-benzyl-N-methylaminomethyl) -4,7-
Dihydro-5-isobutyryl-7- (2,6-difluorobenzyl) -2- [4-[(1-hydroxycyclopropyl) carbonylamino] phenyl] -4-oxothieno [2,3-b] pyridine, (R ) -4,7-Dihydro-2- [4- (3-hydroxy-2-methylpropionylamino) phenyl] -7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl ) -5-Isobutyryl-4-oxothieno [2,3-
b] pyridine, 4,7-dihydro-2- [4- (2-hydroxy-2-methylpropionylamino) phenyl]
7- (2,6-difluorobenzyl)-3-(N-benzyl -N- methylaminomethyl) -5-isobutyryl-4-oxothieno [2,3-b] pyridine, 4,7
Dihydro-2- [4- (3-hydroxy-3-methylbutyrylamino) phenyl] -7- (2,6-difluorobenzyl) -3- (N-benzyl-N-methylaminomethyl) -5-isobutyryl -4-oxothieno [2, 3
-B] pyridine, (R) -4,7-dihydro-2- [4
-(2,3-dihydroxypropionylamino) phenyl] -7- (2,6-difluorobenzyl) -3- (N
- benzyl -N- methylaminomethyl) -5-isobutyryl-4-oxothieno [2,3-b] pyridine, 3-
(N- Benzyl -N- methylamino) -5- benzoyl-7- (2,6-difluorobenzyl) 4,7
-Dihydro-2- [4-[(1-hydroxycyclopropyl) carbonylamino] phenyl] -4-oxothieno [2,3-b] pyridine or a salt thereof. Among them, 3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-5-isobutyryl-
7- (2,6-difluorobenzyl) -2- [4-
[(1-Hydroxycyclopropyl) carbonylamino] phenyl] -4-oxothieno [2,3-b] pyridine or a salt thereof is preferred.

The salts of compound (I) and compound (VIII) are preferably physiologically acceptable acid addition salts. Examples of such a salt include salts with inorganic acids (eg, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.) and organic acids (eg, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, etc.). Acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-
For example, a salt with toluenesulfonic acid or the like is used. When the compound (I) has an acidic group, an inorganic base (eg, an alkali metal salt or an alkaline earth metal such as sodium, potassium, calcium, magnesium or the like, ammonia or the like) or an organic base (eg, trimethylamine,
Physiologically acceptable salts may be formed with triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like.

Compound (I) can be prepared by a method known per se, for example, JP-A-9-169768, WO 96/24
No. 597, or a method analogous thereto. Specific examples include the following production methods 1 and Production Method 2. The compounds in the reaction formulas may include those forming salts, and examples of the salts include those similar to the salts of compound (I).

Embedded image In the above formula, L represents a leaving group, and other symbols have the same meanings as described above. As the "leaving group" represented by L, for example, 1
-Imidazolyl, a halogen atom, an alkoxy group which may have a substituent, and the like. The “alkoxy group optionally having substituent (s)” includes a C _1-4 alkoxy group optionally having 1 to 3 halogen atoms (eg, chlorine, bromine, etc.) (eg, 2, 2,2-trichloroethoxy group).

Compound (II) is disclosed in JP-A-9-169768.
The method can be obtained by a method described in Japanese Patent Application Laid-Open Publication No. H10-205 or a method analogous thereto. Compound (II) and carbonyldiimidazole (N,
Reaction with N'-carbonyldiimidazole; CDI) or phosgene (including dimers and trimers) to give compound (IV), then react with compound (III) to give compound (I) . The compound (IV) may be allowed to continue the reaction without isolation, or may be isolated and used in the next step.
Compound (IV) can also be obtained by reacting compound (II) with a chloroformate compound (eg, 2,2,2-trichloroethyl chloroformate, 1-chloroethyl chloroformate, etc.). .

[0025] In the reaction of the compound (II) with carbonyldiimidazole or phosgene, etc., the amount of such carbonyldiimidazole or phosgene, compound (II) 1
It is about 1 to 3 moles per mole. The reaction is
The reaction is usually performed in a suitable solvent that does not adversely influence the reaction. Examples of the solvent include ethers (eg, ethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, dimethylformamide,
Dimethylacetamide, etc., halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.) and the like. The reaction temperature is usually about 0 to about 150 ° C, preferably at room temperature (about 15 to about 25 ° C). The reaction time is usually about 1 to about 36 hours. This reaction is performed, if necessary, in the presence of a base. As the "base", for example,
Sodium carbonate, sodium bicarbonate, potassium carbonate,
An inorganic base such as potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and thallium hydroxide, or an organic base such as triethylamine and pyridine is used. The amount of the “base” to be used is about 2 to 1 mol of the compound (II).
Mol to 20 mol, preferably about 5 mol to 12 mol. The subsequent reaction conditions with compound (III) may be the same as those for reacting compound (II) with carbonyldiimidazole or phosgene. Compound (II
The amount of I) to be used is about 2 to 20 mol, preferably about 5 to 10 mol, per 1 mol of compound (II) or compound (IV). The reaction temperature is usually about 0 to 150 ° C,
Preferably at room temperature (about 15 to 25 ° C). The reaction time is generally about 1 to 6 hours. Further, a carbonyldiimidazole or phosgene compound (III), may be reacted simultaneously with the compound (II).

[0026]

Embedded image In the above formulas, the R ⁷ is a hydrogen atom or an alkyl group, R ⁸ is an alkyl group, and other symbols are as defined above. R
⁷ or as "alkyl group" represented by R ^8, similar to the "C _1-4 alkyl group" of the "optionally substituted C _1-4 alkyl group" represented by R ¹ or R ² include those of.

The compound (V) is reacted with a method known per se, for example, by reacting p-nitrophenylacetone, a cyanoacetate derivative and sulfur (eg, Chem. Ber., Vol. 99, 94-1).
00, 1966), the resulting 2-amino-4-methyl-
5- (4-nitrophenyl) thiophene, JP 9-
169768, WO 96/24597 and the like or a method analogous thereto.

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

Embedded image Wherein each symbol is as defined above, or a salt thereof (hereinafter abbreviated as compound (VI)) to obtain compound (VII), which is then subjected to a ring closure reaction. ,
Compound (I) is obtained. Examples of the "condensing reagent" include benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (benz
otriazol-1-yloxytripyrrolidinophosphonium hexafluo
rophosphate: PyBOP). The amount of the “condensing reagent” to be used is about 1 to 3 with respect to 1 mol of compound (V).
Is a mole. This reaction is generally performed in a suitable solvent that does not adversely influence the reaction. Examples of the solvent include alcohols (eg, ethanol, methanol, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons (Eg, chloroform, dichloromethane, etc.). The reaction temperature is usually about 0 to about 150 ° C, preferably at room temperature (about 15 to about 150 ° C).
About 25 ° C). The reaction time is usually about 1 to about 36 hours. The product can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method.

Compound (VII) is subjected to a ring closure reaction in the presence of a base. Examples of the "base" include an inorganic base such as sodium methoxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and thallium hydroxide; and an organic base such as triethylamine and pyridine. A base is used. The amount of the “base” to be used is about 2 to 20 mol, preferably about 5 to 12 mol, per 1 mol of compound (VII).
Is a mole. This reaction is generally performed in a suitable solvent that does not adversely influence the reaction. Examples of the solvent include alcohols (eg, ethanol, methanol, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, dimethylformamide, dimethylacetamide, etc.), halogenated hydrocarbons (Eg, chloroform, dichloromethane, etc.). The reaction temperature is usually about 0 to about 150 ° C, preferably at room temperature (about 15 to about 150 ° C).
About 25 ° C). The reaction time is usually about 1 to about 36 hours.

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

[0031] Compound (I), per se known separation means, for example, recrystallization, distillation, can be isolated by chromatography and the like, and purified. When the compound (I) is obtained in a free form, it can be converted into the salt of interest by a method known per se or a method based it, when obtained as a salt Conversely, a method known per se Alternatively, it can be converted into a free form or another desired salt by a method analogous thereto. Compound (I) may be a hydrate or a non-hydrate. Examples of the hydrate include monohydrate, 1.5-hydrate and dihydrate. When the compound (I) is obtained as a mixture of optically active compounds, it can be separated into the desired (R) -form or (S) -form by a known optical resolution means. Compound (I) is an isotope (eg, ³ H, ¹⁴ C, ³⁵ S)
It may be labeled with, for example.

Compound (VIII) or a salt thereof can be prepared by a method known per se, for example, WO 95/28405, WO
It can be produced by the method described in JP 00/00493 or a method analogous thereto.

As described above, the granulated powder of the present invention requires a physiologically active substance and a cellulosic disintegrant in a first embodiment, and a combination of a physiologically active substance and a cellulosic disintegrant in a second embodiment. In the third embodiment, a cellulosic disintegrant and a binder are not essential for the compound (I). First, items common to the production of the granulated powder of the first to third aspects will be described. A physiologically active substance and a cellulosic disintegrant (e.g., a disintegrant obtained by combining a compound selected from CMC-Ca, carboxymethylcellulose, croscarmellose sodium or low-substituted hydroxypropylcellulose or two or more compounds, preferably CMC Mixtures and binders such as HPC, pregelatinized starch, sucrose, gelatin, acacia powder, methylcellulose, etc.
Hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, crystalline cellulose, dextrin, pullulan, etc., preferably HPC, etc.) are mixed, granulated, and a granulated powder is obtained, and dried if necessary. Mixing and granulation are performed using a commonly used granulator. For example, a solution containing a mixture (premix) obtained by previously mixing a physiologically active substance, an excipient (preferably lactose, starch or the like) and a cellulosic disintegrant (preferably CMC-Ca), and a binder. (Preferably HP
C solution etc.) and granulate. The solution containing the binder used here includes an aqueous solution and an alcohol solution. Among them, aqueous solutions and those having 1 to 3 carbon atoms
The alcohol solution is particularly preferably an aqueous solution and an ethanol solution. The alcohol solution refers to a (water-alcohol) solution, and the alcohol ratio in the solution is:
It is usually 5 to 99.5%, preferably 10 to 50%.

The binder is selected from, for example, HPC, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, crystalline cellulose, dextrin, pullulan and the like. Any of the compounds described above or a binder obtained by combining two or more compounds can be used. Also, the granulated powder of the present invention can be obtained by using a suspension containing a binder instead of a solution containing a binder. In addition, excipients (preferably lactose, starch and the like), disintegrants (preferably CMC-Ca and the like), lubricants (preferably
Stearic acid, calcium stearate, etc.), coloring agents (preferably, yellow iron sesquioxide, iron sesquioxide, etc.), fragrances (preferably lemon flavors, lime flavors, etc.), sunscreens (preferably, titanium oxide, talc, etc.) (preferably, ascorbic acid, sodium metabisulfite, inorganic salts (magnesium carbonate and calcium carbonate), etc.) a stabilizer (preferably, hydroxyethyl cellulose, ethyl cellulose, acrylic resin or the like) functional polymer dissolved or the like, by mixing with premix was suspended, it is also possible to manufacture the granules.

The granulated powder according to the first embodiment of the present invention must contain a physiologically active substance and a cellulosic disintegrant. When the physiologically active substance is the compound (I), ie, the third powder, In the embodiment, good granulated powder can be obtained without containing a cellulosic disintegrant.

Mixing and granulation of a physiologically active substance and a binder such as HPC are preferably carried out at about 20 to 45 ° C. The content of the physiologically active substance in the granulated powder in the present invention,
It is not particularly limited as long as the object of the present invention is achieved, for example, 0.1 to 30% by weight, preferably 0.2 to 20 wt%. The amount of the “binder” to be used is not particularly limited as long as the object of the present invention is achieved. And 50 parts by weight. The amount of the “excipient” used is not particularly limited as long as the object of the present invention is achieved.
About 0.25 to 1000 parts by weight, preferably about 0.3 to 6
00 parts by weight, more preferably about 0.5 to 150 parts by weight. The use amount of the “disintegrant” such as the cellulosic disintegrant is not particularly limited as long as the object of the present invention is achieved.
0.01 to 300 parts by weight, preferably about 0.05 to 250 parts by weight. However, when the physiologically active substance is the compound (I), it is possible to produce granulated powder without using a disintegrant as well as a cellulosic disintegrant. The blending ratio of the cellulosic disintegrant and the binder in the second embodiment is also the same as that of the disintegrant and the binder.

The content of which may be further dissolved or suspended in a solution or suspension containing a binder "excipient" is not particularly limited as long as the object of the present invention is achieved, for example, about 1% to 50%, and the like. The content ratio of the “disintegrant” that may be further dissolved and suspended in the solution or suspension containing the binder is not particularly limited as long as the object of the present invention is achieved, for example, about 1 to 50% And so on. The content ratio of the “lubricant” which may be further dissolved and suspended in the solution or suspension containing the binder is not particularly limited as long as the object of the present invention is achieved. ~ 20%
And so on. The content ratio of the “colorant” that may be further dissolved and suspended in the solution or suspension containing the binder is not particularly limited as long as the object of the present invention is achieved. For example, 10%.

[0038] The content ratio of the "flavor" which may be further dissolved and suspended in the solution or suspension containing the binder is not particularly limited as long as the object of the present invention is achieved.
About 0.01% to 10%, and the like. "Light shielding agent" that may be further dissolved and suspended in a solution or suspension containing a binder
Is not particularly limited as long as the object of the present invention is achieved, and is, for example, about 0.05 to 20%.
Content of which may be further dissolved or suspended not in a solution or suspension containing a binder "stabilizing agent" is not particularly limited as long as the object of the present invention is achieved, for example, about 0.0
1 to 30%. The content ratio of the “functional polymer” which may be further dissolved and suspended in the solution or suspension containing the binder is not particularly limited as long as the object of the present invention is achieved. For example, 90%.

[0039] As the particle size of the granulated powder obtained (diameter), preferably about 50 to 1000 [mu] m. When a solution containing a binder is used, the obtained granulated powder is usually about 30 to remove the solvent and moisture in the granulated powder.
To 60 ° C., dried for about 0.5 to 30 minutes. The granulated powder of the present invention is excellent in tableting and is preferably used for tableting.

The granulated powder can be prepared by mixing and drying a solution or suspension containing a binder and other components by a conventional wet granulation method, but is preferably obtained by fluidized bed granulation. Physiologically active substance, spraying the solution or suspension containing a binder as necessary to the cellulose-based disintegrant premixed obtained mixture (premix) such as CMC-Ca optionally excipients and need While mixing and drying, granulate. The conditions are as follows. Flowing (air supply) air volume: 1 to 10 m ³ / min Spraying temperature: 25 to 100 ° C Spraying speed: 10 to 800 g / min Drying speed: 30 to 90 ° C Drying time: 0.5 to 30 minutes

The solid preparation of the present invention contains the above granulated powder. Preferably, the above granulated powder, cellulosic disintegrant (for example, CMC-Ca, croscarmellose sodium or low-substituted hydroxypropyl, etc., preferably CMC-Ca, etc.) CMC-Ca and stearic acid-based lubricant (Eg, stearic acid, sodium stearate or magnesium stearate, preferably magnesium stearate, etc.). The content of the physiologically active substance in the solid preparation of the present invention is not particularly limited as long as the object of the present invention is achieved.
40 wt%, preferably from about 0.3 to 35 wt%, more preferably such as about 1-30 wt%. The content of the cellulosic disintegrant in the solid preparation of the present invention (total amount including the one in the granulated powder) is not particularly limited as long as the object of the present invention is achieved. %, Preferably about 1 to 12% by weight, more preferably about 3 to 10% by weight.
And so on. The content of the stearic acid-based lubricant in the solid preparation of the present invention is not particularly limited as long as the object of the present invention is achieved, for example, about 0.3 to 1.5% by weight, preferably about 0.5 to 1.5% by weight. 1.2% by weight.

The solid preparation of the present invention may further comprise a conventional excipient, disintegrant, binder, lubricant, colorant,
It may contain a fragrance, a light-blocking agent and the like. The "excipient"
Examples thereof include lactose, starch, sucrose, mannitol, crystalline cellulose, light anhydrous silicic acid, magnesium carbonate, calcium carbonate, calcium phosphate, calcium sulfate, aluminum silicate, aluminum metasilicate and the like. As the "disintegrant", for example, CMC-
Ca, croscarmellose sodium, sodium carboxymethyl starch, starch, low substituted hydroxypropylcellulose, and cross-linked in Sol Bull polyvinylpyrrolidone. Examples of the "binder" include HPC, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, crystalline cellulose, dextrin, pullulan and the like. Can be Of these, HPC is preferred. When HPC is used as the binder, a solution of HPC (eg, an aqueous solution, an alcohol solution, etc.) may be used. Among them, an alcohol solution of HPC is preferred. Specific examples include those obtained by diluting HPC or an aqueous HPC solution with alcohols (eg, ethanol, isopropyl alcohol, n-propyl alcohol, methanol, etc.) about 1 to 100 times. When HPC is used, a suspension of HPC may be used. Examples of the "lubricant" include stearic acid, calcium stearate, magnesium stearate, talc, colloidal silica and the like. Examples of the “colorant” include yellow iron sesquioxide, iron sesquioxide and the like. Of these, yellow iron sesquioxide is preferred. The “flavor” may be any of synthetic and natural products, and includes, for example, lemon flavor, lime flavor, orange flavor, strawberry flavor, menthol and the like. Examples of the "light-shielding agent", for example titanium oxide, talc, calcium carbonate, magnesium carbonate, and the like. Of these, titanium oxide is preferred.

The content of the excipient in the solid preparation of the present invention is not particularly limited as long as the object of the present invention is achieved. It is. The content of the disintegrant in the solid preparation of the present invention is not particularly limited as long as the object of the present invention is achieved. For example, about 0.1 to 30% by weight, preferably about 3 to 2
5% by weight, and the like. Although the content of the binder in the solid preparation of the present invention is not particularly limited as long as the object of the present invention is achieved, for example, 1 to 10% by weight, preferably about 2 to 5% by weight
And so on. The content of the lubricant in the solid preparation of the present invention is not particularly limited as long as the object of the present invention is achieved. For example, about 0.1 to 3% by weight, preferably about 0.2 to 2% by weight
And so on. The content of the colorant in the solid preparation of the present invention is an object of the present invention is not particularly limited as long as it is achieved, for example, from about 0.0001 to 0.4 wt%, preferably from about 0.0
01 to 0.2% by weight, and the like. The content of the fragrance in the solid preparation of the present invention is not particularly limited as long as the object of the present invention is achieved, for example, about 0.0001 to 0.4% by weight, preferably about 0.001 to 0.2% by weight. and the like. The content of the light-blocking agent in the solid preparation of the present invention is not particularly limited as long as the object of the present invention is achieved.
4% by weight, preferably about 0.003 to 3% by weight.

Preferred specific examples of the solid preparation of the present invention include (1) a solid preparation containing granulated powder containing compound (I), (2) a compound (I) and HP
A solid preparation comprising granulated powder containing C,
(3) granulated powder containing compound (I) and HPC, solid preparation containing CMC-Ca and magnesium stearate, (4) compound (I) and HPC
Granules comprising a, CMC-Ca, magnesium stearate, solid preparation obtained by blending the lactose and starch, (5) granules comprising the compound (I) and HPC, CMC-Ca, magnesium stearate, lactose, solid preparation obtained by blending starch and hydroxypropyl methylcellulose, (6) compound (I) granules comprising a and HPC, CMC-Ca, magnesium stearate, lactose, starch, hydroxypropyl Solid formulation comprising propylmethylcellulose and titanium oxide, (7) granulated powder containing compound (I) and HPC, CMC-Ca, magnesium stearate,
A solid preparation containing HPC, lactose, starch, hydroxypropyl methylcellulose, titanium oxide and yellow iron sesquioxide, and (8) a granulated powder containing compound (I) or compound (VIII) and CMC-Ca. (9) Compound (I) or Compound (VIII),
Granulated powder containing CMC-Ca and HPC, CM
Solid preparation obtained by mixing the C-Ca and magnesium stearate, (10) Compound (I) or compound (VII
I), a granulated powder containing CMC-Ca and HPC, a solid preparation comprising CMC-Ca, magnesium stearate, lactose and starch, (11) compound (I) or compound (VIII), CMC -Ca and HP
A solid preparation comprising granulated powder containing C, CMC-Ca, magnesium stearate, lactose, starch and hydroxypropylmethylcellulose, (12)
A granulated powder comprising compound (I) or compound (VIII), CMC-Ca and HPC, a solid preparation comprising CMC-Ca, magnesium stearate, lactose, starch, hydroxypropylmethylcellulose and titanium oxide, (13) Compound (I) or compound (VII
I), granulated powder containing CMC-Ca and HPC, CMC-Ca, magnesium stearate, lactose,
Solid preparations containing starch, hydroxypropylmethylcellulose, titanium oxide and yellow iron sesquioxide are included.

The solid preparation of the present invention is produced, for example, by the following method. 1) The particle size of granulated powder described above, to obtain a sized powder. The sizing typically can be used a commercial particle sizer, such as a power mill. 2) the 1) obtained in sized powder, the CMC-Ca, and magnesium stearate, optionally disintegrants, binders, mixed lubricants, coloring agents, perfumes, together with the light-shielding agent, to obtain a mixed powder . 3) The mixed powder obtained in 2) is molded to obtain a solid preparation. The mixed powder obtained above is (i) granules or fine granules as they are, (ii) filled into capsules (eg, gelatin capsules, hydroxypropylmethylcellulose capsules, etc.) as capsules, and (iii) suspensions for use. It may be used as a cloudy dry syrup or (iv) a caplet. Usually, the mixed powder is formed into pills, tablets and the like. Among them, tablets are preferable, round tablets, oval tablets and the like are more preferable, and oval tablets are particularly preferable. The circular tablet, horizontal cross-section refers to a tablet of round in the width direction, tablets edges are corners may be any of Sumimaru. The oval tablets, horizontal cross-section in the width direction refers to one of the oval tablet edges are corners may be any of Sumimaru. Generally, a circular tablet has a diameter of about 5 to 13 mm and a thickness of about 3 to 8 mm at a portion where the cross-sectional area in the width direction is maximized. Oval tablets, usually at the site where the cross-sectional area of the width direction is maximum, its diameter is about 8～17Mm, minor axis about 5 to 9 mm, a thickness of about 3~8m
m, and the tablet edge may be rounded or rounded. For molding, a commercially available molding machine such as a tablet machine may be used. The tableting pressure at the time of molding into tablets is usually 0.5 to 2.5 ton /
cm ² .

[0046] 4) The solid preparation obtained in the above 3), if necessary, a film-coated tablets. Specifically, the resulting solid preparation (preferably above 3) tablets, more preferably oval tablet) was sprayed a film coating solution and optionally dried. The “film coating liquid” is prepared, for example, by dissolving or suspending a polymer for film coating in a solvent. The said film coating solution, further, for example (preferably yellow ferric oxide) colorants, sunscreens (preferably, titanium oxide) may be added and the like. Examples of the "film coating polymer", such as hydroxypropyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose acetate succinate, acrylic resin (methacrylic acid, acrylic acid copolymers, such as aminoalkyl methacrylate copolymer) , Shellac, polyvinyl acetate phthalate, gum arabic, cellulose acetate phthalate,
Hydroxypropyl methylcellulose phthalate, carboxymethylethylcellulose and the like can be mentioned. As the "solvent", for example, water, alcohols (e.g., ethanol, isopropyl alcohol, n- propyl alcohol, methanol, etc.), acetone, ethyl acetate, dichloromethane, chloroform, hexane, toluene, heptane, and the like. The amount of the “polymer for film coating” may be selected according to the type of the solid preparation. For example, when the solid preparation is a tablet, about 0.5 to 1 part
0% by weight. The spray temperature is usually from 25 to 80C. The spraying time is usually 5 minutes to 24 hours. The drying temperature is usually 30 to 80C. The drying time is usually 1 minute to 24 hours. The present invention also provides film-coated tablets containing compound A or compound B described below. The “film-coated tablet containing compound A or compound B” is produced by the same method as described above.

The solid preparation of the present invention can increase the content of a physiologically active substance, is excellent in disintegration, and is excellent in dissolution of a physiologically active substance. In particular film-coated tablets can long-term stably preserved in a non-light-shielding pressure. In addition, by performing granulation using a mixture of a physiologically active substance and an alcohol solution of a binder, granulation properties are improved, and granulated powder having a predetermined particle size can be easily prepared. it can.

Since the solid preparation of the present invention has low toxicity,
It can be used as a safe drug for mammals (eg, human, cow, pig, dog, cat, mouse, rat, rabbit, etc.). The solid preparation of the present invention can be used as a prophylactic / therapeutic agent for various diseases depending on the type of the physiologically active substance contained. For example, bioactive agent GnR
In the case of an H antagonist, it inhibits the secretion of gonadotropin and controls the concentration of sex hormones in the blood to prevent and treat male or female hormone-dependent diseases, and diseases caused by excess of these hormones. Can be used for the prevention and treatment of Specifically, sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), bone metastasis of sex hormone-dependent cancer,
Benign prostatic hyperplasia, uterine fibroids, endometriosis, precocious puberty,
Amenorrhea, premenstrual syndrome, multilocular ovary syndrome, acne,
It is useful for the prophylaxis and / or treatment of baldness, Alzheimer's disease (Alzheimer's disease, Alzheimer's senile dementia, and a combination thereof). The solid preparation of the present invention is also useful for regulating reproduction in males and females (eg, pregnancy regulators, menstrual cycle regulators, etc.). The solid preparation of the present invention can be further used as a contraceptive for men and women and as an ovulation inducer for women. The solid preparation of the present invention can be used for the treatment of infertility by utilizing the rebound effect after drug withdrawal. It can also be used as a prophylactic or therapeutic agent for benign or malignant tumors which are LH-RH sensitive in sex hormone-independent. Moreover, the solid preparation of the present invention is the regulation of animal estrus in livestock areas, improvement of meat quality for meat, also useful in such animal growth promotion. The solid preparation of the present invention is also useful as a spawning promoter for fish.

The solid preparation of the present invention is intended to suppress the transient increase in blood testosterone (in the case of male) concentration (flare phenomenon) which is observed when a GnRH superagonist such as leuprorelin acetate is administered. Can be used. The solid preparation of the present invention comprises leuprorelin acetate (Leuproreli acetate).
n), Gonadrelin, Buserelin
GnRH super agonists (preferably leuprorelin acetate) such as elin), triptrelin, triperelin, goserelin, nafarellin, histrelin, deslorelin, meterelin, lecirelin, etc. ) and it can be used in combination. Moreover, the solid preparation of the present invention, steroidal or nonsteroidal antiandrogen agent or antiestrogen, chemotherapeutic agent, GnRH antagonistic peptide, 5.alpha.-reductase inhibitors,
α- receptor inhibitors, aromatase inhibitors, 17.beta.-hydroxysteroid dehydrogenase inhibitor, adrenal androgen production inhibitor, phosphorylase inhibitor, hormonal therapy agents,
It is also effective to use in combination with at least one kind of drug that inhibits the action of cell growth factor or its receptor.

The "chemotherapeutic agent" includes Ifosfamide, UFT, Adriamycin (Adriam
ycin), peplomycin, cisplatin, cyclophosphamide
ide), 5-FU, UFT, methotrexate (Methotrex
ate), mitomycin C, mitoxantrone, taxotere and the like. Examples of the “peptidic GnRH antagonist” include parenterally administered peptidic GnRH antagonists such as Cetrorelix, Ganirelix, and Abarelix. Examples of the "adrenal androgen production inhibitor" include lyase (C _17,20- lyase) inhibitors. Examples of the "phosphorase inhibitor" include tyrosine phosphorylase. Examples of the "hormonal therapeutic agents", antiestrogens, progesterone preparations (e.g., MPA, etc.), androgens, estrogens, anti-androgens and the like.

[0051] The "cell growth factor (growth Factors)" may be any as long as the substances that promote cell proliferation, typically, a molecular weight of 20,000 or less of peptides binding to a receptor Factors that exert their effects at low concentrations are mentioned, specifically, (1) EGF (epidermal g
Rowth factor) or substances possessing substantially the same activity (e.g., EGF, heregulin (HER2 ligand)
(2) insulin or a substance having substantially the same activity as insulin (eg, insulin, IGF (insul)
in-like growth factor) -1, IGF-2, etc.),
(3) FGF (fibroblast growth factor) or a substance having substantially the same activity as that (eg, αFGF, β
FGF, KGF (Keratinocyte Growth Factor), HG
F (Hepatocyte Growth Factor), FGF-10, etc.), (4) Other cell growth factors (eg, CSF (colon
y stimulating factor), EPO (erythropoietin),
IL-2 (interleukin-2), NGF (nerve growth fac)
tor), platelet-derived growth factor (PDGF),
TGFβ (transforming growth factor β) and the like. As the “cell growth factor receptor”,
Any receptor may be used as long as it has the ability to bind to the above-mentioned cell growth factor. Specifically, EGF receptor, heregulin receptor (HER2), insulin receptor-1, insulin receptor-2 , IGF receptor, FG
F receptor-1 or FGF receptor-2 and the like. Examples of the drug that inhibits the action of the cell growth factor include:
Herceptin (HER2 receptor antibody) and the like. Examples of the drug that inhibits the action of the cell growth factor or its receptor include herbimycin, PD15
3035 (Science 265 (5175) p1093, (1994)).

[0052] HER2 inhibitors are also examples of agents that inhibit the action of cell growth factors or their receptors.
As a HER2 inhibitor, if it is a substance that inhibits HER2 activity (eg, phosphorylation activity), an antibody, a low molecular compound (synthetic compound, natural product), an antisense, a HER2 ligand, heregulin, or a structure thereof may be used. Any of modified or modified parts may be used. Also, material (e.g., HER2 receptor antibody) which inhibits HER2 activity by inhibiting HER2 receptor may be. HE
The low molecular compound having an R2 inhibitory activity, for example,
Compounds described in WO98 / 03505, specifically 1
-[3- [4- [2-((E) -2-phenylethenyl) -4-oxazolylmethoxy] phenyl] propyl] -1,2,4-triazole and the like. For prostatic hypertrophy, GnRH super agonists, antiandrogens, antiestrogens, peptidic GnRH antagonists, 5α-reductase inhibitors, α-receptor inhibitors, aromatase inhibitors, 17β-hydroxysteroid dehydrogenation Combinations of drugs such as enzyme inhibitors, adrenal androgen production inhibitors, and phosphorylase inhibitors with the solid preparations of the present invention are also included.

For prostate cancer, GnRH super agonist,
Antiandrogens, antiestrogens, chemotherapeutic agents [eg, ifosfamide (ifosfamide), UFT, adriamycin (Adriamycin), peplomycin (Peplomyc
in), cisplatin, etc.], peptidic GnRH antagonists, aromatase inhibitors, 17β-hydroxysteroid dehydrogenase inhibitors, adrenal androgen production inhibitors, phosphorylase inhibitors, hormone therapy agents [eg, estrogens Agents (eg, DSB, EMP, etc.), anti-androgen agents (eg, CMA, etc.)], agents that inhibit the action of cell growth factor or its receptor and the solid preparation of the present invention. . For breast cancer, GnRH super agonists, antiestrogens, chemotherapeutic agents [eg, cyclophosphamide,
5-FU, UFT, methotrexate,
Adriamycin, Mitomycin C
(Mitomycin C), Mitoxantron
e) etc.), peptidic GnRH antagonists, aromatase inhibitors, adrenal androgen production inhibitors, phosphorylase inhibitors, hormonal therapeutic agents [eg, anti-estrogenic agents [eg,
Tamoxifen, etc.), progestin (eg, MPA, etc.), androgen, estrogen, etc.), a drug such as a drug inhibiting the action of cell growth factor or its receptor, and the solid preparation of the present invention. Combination is mentioned. The above agents may be administered to the same subject at a time or time difference between the solid preparation of the present invention. Alternatively, the above drugs (1 to 3 drugs) may be blended in the solid preparation of the present invention. Furthermore, the solid preparation of the present invention can be administered before administration of a GnRH superagonist such as leuprorelin acetate to perform treatment without causing flare.

[0054] The solid preparation of the present invention are usually administered orally. The dosage of the solid preparation of the present invention varies depending on the type and content of the physiologically active substance, the dosage form, the duration of release of the physiologically active substance, the target disease, the target animal, etc., but may be any effective amount of the physiologically active substance. . For example, when compound (I) or compound (VIII) is used as the physiologically active substance, the dose of the compound per administration is about 0.01 to 10 mg / kg body weight per adult (body weight 60 kg). The frequency of administration is once every two days or 1 to 4 times a day.

[0055]

DETAILED DESCRIPTION OF THE INVENTION Hereinafter, Reference Examples, Examples and is by way of experimental examples further illustrate the present invention, which are not intended to limit the present invention.

[0056]

EXAMPLES Reference Example 1 2-Amino-4-methyl-5- (4-nitrophenyl)
Thiophene-3-carboxylic acid ethyl ester 4-nitrophenyl acetone (35.0 g, 195 mm
ol), ethyl cyanoacetate (23.8 g, 195 mmol)
l), a mixture of ammonium acetate (3.1 g, 40 mmol) and acetic acid (9.1 ml, 159 mmol)
While removing the water generated by the Dean-Stark apparatus, 24
Heated to reflux for an hour. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer was washed with brine dried (MgSO _4), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography. The obtained oil was dissolved in ethanol, sulfur (5.0 g, 160 mmol) and diethylamine (16.0 ml, 160 mmol) were added, and the mixture was added at 60-70 ° C.
In was stirred for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure,
The residue was partitioned with dichloromethane and aqueous sodium bicarbonate. The organic layer was washed with brine, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from ether-hexane to give the title compound as red plate crystals (22.2 g, 52%). mp: 168-170 ° C (recrystallized from ether-hexane). As Elemental analysis _{C 14 H 14 N 2 O 4} S ^{1 H-NMR (200MHz, CDCl} 3) δ: 1.39
(3H, t, J = 7.1Hz), 2.40 (3H,
s), 4.34 (2H, q, J = 7.1 Hz), 6.2
7 (2H, br), 7.48 (2H, d, J = 8.7H)
z), 8.23 (2H, d, J = 8.7 Hz). IR (KBr): 3446, 3324, 1667, 15
80,1545,1506,1491,1475,14
10,1332 cm ^-1 .

Reference Example 2 5-methyl-6- (4-nitrophenyl) -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3
H) -dione The compound obtained in Reference Example 1 (5.00 g, 16.32 m)
phenylisocyanate (2.66 ml, 24.48 mmol) was added to a pyridine (30 ml) solution, stirred at 45 ° C. for 6 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in ethanol (6 ml) And 28% sodium methoxide (7.86 g, 4
0.80 mmol) was added and the reaction solution was stirred at room temperature for 2 hours, 2N hydrochloric acid (25 ml, 50 mmol) was added, and the ethanol solvent was distilled off under reduced pressure. Obtained by filtering the residue water - washed with ethanol, and recrystallized from dried ethanol under reduced pressure to give the title compound as a yellow powder (6.0
9g, 98%). mp:> 300 ℃. Elemental analysis value As C ₁₉ H ₁₃ N ₃ O ₄ S.0.3H ₂ O ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.
50 (3H, s), 7.31-7.46 (5H, m),
7.78 (2H, d, J = 8.8 Hz), 8.32 (2
H, d, J = 8.8 Hz), 12.50 (1H, s). IR (KBr): 1715,1657,1593,15
10cm ^-1.

[0058] Reference Example 3 1- (2,6-difluorophenyl) -5- methyl-6
-(4-nitrophenyl) -3-phenylthieno [2,
3-d] pyrimidine-2,4 (1H, 3H) -dione The compound obtained in Reference Example 2 (52.54 g, 0.131
mol) in dimethylformamide (1.0 l),
Potassium carbonate (19.00g, 0.138mol), potassium iodide (22.90g, 0.138mol),
2,6-difluorobenzyl chloride (22.40 g,
0.138 mol) and stirred at room temperature for 2 hours.
The residue obtained by concentrating the reaction solution was partitioned between chloroform and brine. The aqueous layer was extracted with chloroform, the extract washed and dried with brine combined (MgSO _4), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (6) as pale yellow crystals.
1.50 g, 93%). mp: 280-282 [deg.] C. Elemental analysis value C ₂₆ H ₁₇ N ₃ O ₄ SF ₂ ^{1 H-NMR (300MHz, CDCl} 3) δ: 2.57
(3H, s), 5.38 (2H, s), 6.94 (2
H, d, J = 8.1Hz), 7.42-7.58 (8
H, m), 8.29 (2H, d, J = 8.8 Hz). IR (KBr): 1719, 1669, 1524, 14
73 cm ^-1 .

Reference Example 4 5-bromomethyl-1- (2,6-difluorobenzyl) -6- (4-nitrophenyl) -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H ) -
Dione The compound obtained in Reference Example 3 (30.34 g, 0.060
mol), N-bromosuccinimide (12.81 g,
0.072 mol), a mixture of α, α′-azobisisobutyronitrile (1.15 g, 0.007 mol) and chlorobenzene (450 ml) was stirred at 85 ° C. for 3 hours. After cooling the reaction mixture was washed with brine dried (MgSO
₄ ) After that, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound as yellow needles (80.
21 g, 100%). mp: 228-229 ° C. ^{1 H-NMR (300MHz, CDCl} 3) δ: 4.77
(2H, s), 5.38 (2H, s), 6.96 (2
H, t, J = 8.1Hz), 7.29-7.58 (6
H, m), 7.79 (2H, d, J = 8.5 Hz),
8.35 (2H, d, J = 8.5Hz). IR (KBr): 1721, 1680, 1524, 14
73,1348 cm ^-1 . FAB-Mass m / z 5
84 (MH) ⁺

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

Reference Example 6 6- (4-aminophenyl) -5- (N-benzyl-N
-Methylaminomethyl) -1- (2,6-difluorobenzyl) -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione Compound (3) obtained in Reference Example 5 .00g, 4.80mm
ol) in formic acid (30 ml), under ice cooling, 1M hydrogen chloride-ether (14.4 ml, 14.4 mmol) and 10% palladium on carbon powder (300 mg) were added, and the mixture was stirred with hydrogen at room temperature and pressure for 2 hours. It was added. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried (Mg
After SO ₄ ), the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as white crystals (2.41 g, 84%). mp: 205-207 ° C. Elemental analysis _{C 34 H 28 N 4 O 2} SF 2 · 0.1AcOEt · 1.2H 2 O as C (%) H (%) N (%) Calculated: 66.09; 5.03; 8.96 Found: 66.93; 4.94; 8.67 ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.05
(3H, s), 3.56 (2H, s), 3.83 (2
H, br), 3.88 (2H, s), 5.36 (2H,
s), 6.70 (2H, d, J = 8.8 Hz), 6.8
8-6.94 (2H, m), 7.21-7.31 (8
H, m), 7.41-7.53 (5H, m). IR (KBr): 1715, 1657, 1628, 15
37cm ^-1.

[0062] Reference Example 7 5-(N-benzyl--N- methylaminomethyl) -1
(2,6-difluorobenzyl) -6- [4- (3-methoxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione In Reference Example 6, The obtained compound (5.0 g, 8.41 mmol)
l) in dichloromethane (120 ml) solution under ice-cooling,
Triethylamine (2.34 ml, 16.82 mmol)
l) was added and stirred. The reaction solution was added with N,
N'-carbonyldiimidazole (2.73 g, 16.
82 mmol), and the mixture was returned to room temperature from under ice-cooling and stirred for 42 hours. Back under ice cooling again, O- methylhydroxylamine hydrochloride (7.02g, 84.08mmo
l) and triethylamine (11.7 ml, 84.0).
8 mmol) was added. The reaction solution was returned from ice cooling to room temperature and stirred for 3 hours. The reaction was partitioned with chloroform and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with chloroform, extracts were washed with brine combined, dried (MgSO _4), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a pale yellow solid, which was recrystallized from chloroform-ether to give white crystals (4.52).
g, 80%). mp: 204-205 ° C. As Elemental analysis _{C 36 H 31 N 5 O 4} SF 2 ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.05
(3H, s), 3.57 (2H, s), 3.82 (3
H, s), 3.90 (2H, s), 5.37 (2H,
s), 6.92 (2H, d, J = 8.2Hz), 7.1
6-7.31 (9H, m), 7.42-7.57 (5
H, m), 7.63 (1H, s), 7.73 (2H,
d, J = 8.8 Hz). IR (KBr): 3338,3064,1717,16
69, 1628, 1591, 1531, 1470c
m ^-1 .

[0063] Reference Example 8 3- (N-benzyl--N- methylaminomethyl) -4,
7-dihydro-5-isobutyryl-7- (2,6-difluorobenzyl) -2- [4-[(1-hydroxycyclopropyl) carbonylamino] phenyl] -4-oxothieno [2,3-b] pyridine 2 - (4-aminophenyl) -7- (2,6-difluorobenzyl) -4,7-dihydro-5-isobutyryl -
3- (N- Benzyl -N- methylaminomethyl) -4-
Oxothieno [2,3-b] pyridine (0.57 g,
1.0 mmol) in dichloromethane (10 ml) solution, diisopropylethylamine (0.52 g, 4 mm
ol) and 2-hydroxycyclopropanecarboxylic acid (0.204 g, 2 mmol), and the mixture was stirred under ice-cooling.
The solution benzotriazol-1-yloxytris dimethylamino phosphonium hexafluorophosphate (BOP reagent) (1.76g, 4mmol) was added. The mixture was stirred for 1 hour under ice cooling, and further stirred at room temperature for 4 days.
The reaction solution was dried under reduced pressure, and the obtained residue was partitioned between water (50 ml) and chloroform (50 ml). The aqueous layer was again extracted with chloroform (10 ml). The extracts were combined, washed with brine, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain yellow powdery crystals were recrystallized from ether (0.27g, 41%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.16
-1.20 (2H, m), 1.18 (6H, d), 1.
48-1.51 (2H, m), 2.09 (3H, s),
3.64 (2H, s), 3.95 (1H, br s),
4.14 (2H, s), 4.12-4.19 (1H,
m), 5.20 (2H, s), 6.99 (2H, t),
7.10-7.25 (5H, m), 7.34-7.46
(1H, m), 7.57 (2H, d), 7.70 (2
H, d), 8.21 (1H, s), 8.82 (1H,
s).

Example 1 5- (N-benzyl-N-methylaminomethyl) -1-
(2,6-difluorobenzyl) -6- [4- (3-methoxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (hereinafter referred to as compound A) (Abbreviated as A) -Containing Solid Preparation A preparation having the formulation shown in Table 1 was produced as follows. (1) 400.5 g of hydroxypropyl methylcellulose 2910 (TC-5) was dissolved in 4050 g of purified water. The resulting solution of titanium oxide 45 g, is dispersed yellow ferric 4.5 g, to obtain a coating agent. (2) 730 g of compound A obtained in Reference Example 7, lactose 20
81 g of corn starch, 365 g of corn starch and 182.5 g of carboxymethylcellulose calcium (carmellose calcium) were fluidized and granulated by a dryer (Powrex).
Placed in, preheated mixing, hydroxypropyl cellulose 1
2920 g of a 20% ethanol solution in which 46 g was dissolved was sprayed to obtain a granulated powder. The production conditions in the granulation step are shown in [Table 2].

[0065] (3) (2) above obtained granulated powder 314
4 g was sized using a power mill (manufactured by Showa Chemical Machinery Co., Ltd.). 2976 g of the obtained sized powder, 93 g of carmellose calcium and magnesium stearate 31
g was used as a mixed powder using tumbling mixer (produced by Showa Kagaku Kikai Kosakusho), and tableting the mixed powder 2900g by a tableting machine (Kikusui Seisakusho Ltd.) to give naked tablets. Sizing, indicating the production conditions in the mixing and tableting steps in Table 2. (4) The coating agent obtained in the above (1) is sprayed on the naked tablet obtained in the above (3) in a film coating machine (manufactured by Powrex), and 100 mg of the compound A is contained per tablet. 5,000 film-coated tablets having the formulation shown in Table 1 were obtained. The production conditions in the film coating process shown in Table 2.

[0066]

[Table 1]

[0067]

[Table 2]

Example 2 3- (N-benzyl-N-methylaminomethyl) -4,
7-dihydro-5-isobutyryl-7- (2,6-difluorobenzyl) -2- [4-[(1-hydroxycyclopropyl) carbonylamino] phenyl] -4-oxothieno [2,3-b] pyridine ( hereinafter, the formulation of the formulation shown in compound B hereinafter) containing a solid preparation Table 3 were prepared as follows. (1) 405.8 g of hydroxypropyl methylcellulose 2910 (TC-5) was dissolved in 4104 g of purified water. 45.6 g of titanium oxide and 4.56 g of yellow iron sesquioxide were dispersed in the obtained solution to obtain a coating agent. (2) 1100 g of compound B obtained in Reference Example 8, lactose 2
119 g, corn starch 418 g and carboxymethylcellulose calcium (carmellose calcium) 209 g were put into a fluidized-granulation dryer (manufactured by Powrex Co., Ltd.), mixed by preheating, and mixed with hydroxypropylcellulose 16.
Spray 3344 g of an aqueous solution in which 7.2 g is dissolved,
To obtain a granule.

(3) Granulated powder 368 obtained in (2) above
4 g was sized using a power mill (manufactured by Showa Chemical Machinery Co., Ltd.). 3539 g of the obtained sized powder, 110.6 g of carmellose calcium, and 36.86 g of magnesium stearate were mixed with a tumbler mixer (manufactured by Showa Chemical Machinery Co., Ltd.), and 3496 g of the mixed powder was converted into a tableting machine (Kikusui). (Manufactured by Seisakusho) to obtain a bare tablet. (4) The coating agent obtained in the above (1) is sprayed on the naked tablet obtained in the above (3) in a film coating machine (manufactured by Powrex), and 100 mg of the compound B is contained per tablet. 7,000 film-coated tablets having the formulations shown in Table 3 were obtained. Table 4 shows the manufacturing conditions in each step.

[0070]

[Table 3]

[0071]

[Table 4]

Example 3 100 g of Compound A, 116 g of lactose and 60 g of corn starch were placed in a fluidized-granulation dryer (manufactured by Powrex), preheated and mixed, and sprayed with 150 g of an aqueous solution in which 9 g of hydroxypropylcellulose was dissolved. ] Was obtained.

[0073] Example 4 Compound A1000g, placed lactose 1070g and corn starch 600g in a fluidized granulating dryer (Powrex Corp.), followed by mixing at the preheating temperature and spraying an aqueous solution 2500g prepared by dissolving hydroxypropyl cellulose 150 g, Table 5 ] Was obtained.

Example 5 Compound A (200 g), lactose (560 g), corn starch (100 g) and carboxymethylcellulose calcium (carmellose calcium) (50 g) were placed in a fluidized-granulation dryer (manufactured by Powrex), preheated and mixed to dissolve 50 g of hydroxypropylcellulose. by spraying an aqueous solution 834 g, to obtain a granule formulation shown in Table 5].

[0075]

[Table 5]

Experimental Example 1 The evaluation of the productivity (granulation) of the granulated powder in Example 1- (2) and Examples 3 to 5 is shown in [Table 6]. In Examples 3 to 5, since granulation was insufficient, the obtained granulated powder was poor in handling and tableting was difficult, but formulation was possible. On the other hand, since the granulated powder obtained in Example 1- (2) was sufficiently granulated, there was no problem in the tableting step.

[0077]

[Table 6]

Experimental Example 2 The production scale in Example 1 was changed from 5,000 tablets to 60
The results are shown in Table 7 below. The results are shown in Table 7.
Further, the production scale in Example 2 was changed from 7,000 tablets to 580 tablets, and the light resistance test of bare tablets and film-coated tablets containing 25 mg per compound B produced according to the method described in Example 2 The results are shown in [Table 8]. In each case, the irradiated surface of the uncoated tablet turned yellow upon irradiation with light, and a remarkable increase in related substances was observed as compared with the control (light-shielded tablet). On the other hand, the film-coated tablet did not show any change in appearance due to light irradiation, and the related substances hardly increased as compared with the control (tablet shaded).

[0079]

[Table 7]

[0080]

[Table 8]

Example 6 Compound A (600 g), lactose (1710 g), corn starch (300 g) and carboxymethylcellulose calcium (carmellose calcium) (150 g) were placed in a fluidized-granulation dryer (manufactured by Powrex Co., Ltd.) and mixed by preheating to dissolve 120 g of hydroxypropylcellulose. 2400 g of a 20% ethanol solution was sprayed to obtain a granulated powder. 2500 g of the obtained granulated powder was sized using a power mill (manufactured by Showa Kagaku Kikai Kosakusho). The obtained sized powder 192
0 g, carmellose calcium 60 g and magnesium stearate 20 g were made into a mixed powder using a tumbler mixer (manufactured by Showa Kagaku Kikai Kosakusho), and the mixed powder was tableted with a tableting machine (manufactured by Shimadzu Corporation). ] In the formula given above. Tableting conditions are shown in Table 10.

[0082]

[Table 9]

[0083]

[Table 10]

Experimental Example 3 The dissolution properties of the uncoated tablets obtained in Example 1- (3) and Example 6 were compared. As a test solution, Tween 80 was added at 0.
The dissolution rate was measured according to the Japanese Pharmacopoeia second method (paddle method, 50 rpm) using a citrate buffer solution containing 1% of pH 3.0. The results are shown in Figure 1]. Than this, in Example 1-
Oval tablets (3), round tablets of Examples 6 to, it can be seen that the dissolution rate is high.

Example 7 1) 5 mg tablets (1) 445 g of hydroxypropylmethylcellulose 2910 (TC-5) was dissolved in 4500 g of purified water. 50 g of titanium oxide and 5 g of yellow iron sesquioxide were dispersed in the obtained solution to obtain a coating agent. (2) 42 g of compound A obtained in Reference Example 7, lactose 319
2 g, 420 g of corn starch and 210 g of carboxymethylcellulose calcium (carmellose calcium) were put into a fluidized-granulation dryer (manufactured by Powrex), preheated and mixed, and hydroxypropylcellulose 168 was added.
Spray 20% ethanol solution 3360g obtained by dissolving g, to obtain a granule. The production conditions in the granulation step are the same as in [Table 2]. (3) to give a sized powder using the above (manufactured by Showa Chemical Machinery) using a power mill to granulated powder 3528g obtained in (2).
3168 g of the obtained sized powder, carmellose calcium 9
9 g and 33 g of magnesium stearate were mixed with a tumbler mixer (manufactured by Showa Kagaku Kikai Kosakusho) to obtain a mixed powder, and 3000 g of the mixed powder was tableted with a tableting machine (manufactured by Kikusui Seisakusho) to obtain a bare tablet. Sizing, production conditions in the mixing and tableting process are the same as Table 2. (4) The coating agent obtained in the above (1) is sprayed on the naked tablet obtained in the above (3) in a film coating machine (manufactured by Powrex), and 5 mg of the compound A is contained per tablet. 5,000 film-coated tablets having the formulation shown in Table 11 were obtained. The production conditions in the film coating step are the same as in [Table 2]. 2) 50 mg tablet (1) 1780 g of hydroxypropyl methylcellulose 2910 (TC-5) was dissolved in 18000 g of purified water. 200 g of titanium oxide and 20 g of yellow iron sesquioxide were dispersed in the obtained solution to obtain a coating agent. (2) 1500 g of compound A obtained in Reference Example 7, lactose 1
0050G, corn starch 1500g and carboxymethylcellulose calcium (carmellose calcium) 750 g placed in a fluidized granulating dryer (Powrex Corp.), preheated mixing, hydroxypropyl 20% ethanol by dissolving cellulose 600g solution 12000
g was sprayed to obtain a granulated powder. Manufacturing conditions in the granulation step are the same as Table 2. (3) 12960 g of the granulated powder obtained in the above (2) was sized using a power mill (manufactured by Showa Kagaku Kikai Kosakusho). 36000 g of the obtained sized powder, 1125 g of carmellose calcium and 375 magnesium stearate
g was made into a mixed powder using a tumbler mixer (manufactured by Showa Kagaku Kikai Kosakusho), and 36500 g of the mixed powder was tableted with a tableting machine (manufactured by Kikusui Seisakusho) to obtain a bare tablet. The production conditions in the sizing, mixing and tableting steps are the same as in Table 2. (4) The coating obtained in the above (1) is sprayed onto the naked tablet obtained in the above (3) in a film coating machine (manufactured by Powrex), and the tablet contains 50 mg of compound A per tablet. Film-coated tablet 6 having the formulation shown in Table 11
6,000 tablets were obtained. The production conditions in the film coating step are the same as in [Table 2].

[Table 11]

Example 8 (1) Compound A (8.4 g), lactose (3226 g), corn starch (420 g) and carboxymethylcellulose calcium (carmellose calcium) (210 g) were placed in a fluidized granulation dryer (manufactured by Powrex), preheated and mixed. 3360 g of an aqueous solution in which 168 g of cellulose was dissolved was sprayed to obtain a granulated powder. The production conditions in the granulation process are shown in [Table 1
3]. (2) 3528 g of the granulated powder obtained in the above (1) was sized using a power mill (manufactured by Showa Kagaku Kikai Kosakusho). 3168 g of the obtained sized powder, 99 g of carmellose calcium and 33 g of magnesium stearate were mixed using a tumbler mixer (manufactured by Showa Kagaku Kikai Kosakusho) to obtain a mixed powder shown in [Table 12]. Table 13 shows the production conditions in the sizing and mixing steps. (3) The mixed powder obtained in the above (2) is tableted with a tableting machine (manufactured by Kikusui Seisakusho), and the obtained bare tablet is coated with a coating agent (purified water) in a film coating machine (manufactured by Powrex). To hydroxypropyl methylcellulose 2910 (TC-
5) is dissolved in a solution containing titanium oxide and yellow iron sesquioxide suspended therein, and sprayed with a coating solution containing 1 mg of compound A per tablet, as shown in Table 12. Formulated film-coated tablets can be obtained.

[0087]

[Table 12]

[0088]

[Table 13]

Example 9 Compound A 25 g, lactose 167.5 g, corn starch 25 g
And 12.5 g of carboxymethylcellulose calcium (carmellose calcium) was placed in a fluidized-granulation dryer (manufactured by Powrex), preheated and mixed, and sprayed with 200 g of an aqueous solution in which 10 g of hydroxypropylcellulose was dissolved. Grain powder was obtained. The obtained granulated powder was sufficiently granulated, and there was no problem in the tableting process.

[0090]

[Table 14]

Example 10 (1) 700 g of compound A, 2576 g of lactose, 420 g of corn starch and 210 g of carboxymethylcellulose calcium (carmellose calcium) were placed in a fluidized granulation dryer (manufactured by Powrex), preheated and mixed, and hydroxypropyl cellulose was added. 1974 g of an aqueous solution in which 126 g was dissolved was sprayed to obtain a granulated powder. The production conditions in the granulation process are shown in [Table 1
6]. The obtained granulated powder was sufficiently granulated, and there was no problem in the tableting process. (2) 3950 g of the granulated powder obtained in the above (1) was sized using a power mill (manufactured by Showa Kagaku Kikai Kosakusho). The obtained sized powder (3168 g), carmellose calcium (99 g) and magnesium stearate (33 g) were mixed with a tumbler mixer (manufactured by Showa Kagaku Kikai Kosakusho) to obtain a mixed powder.
00g was tableted with a tableting machine (manufactured by Kikusui Seisakusho), and [Table 1
Give plain tablets shown in 5]. The production conditions in the sizing, mixing and tableting steps are shown in [Table 16]. (3) A solution obtained by dissolving hydroxypropylmethylcellulose 2910 (TC-5) in purified water was separately added to the naked tablet obtained in (2) above using a film coating machine (manufactured by Powrex), and titanium oxide and Spraying a coating solution prepared by mixing a suspension of yellow iron sesquioxide), a film-coated tablet having the formulation shown in [Table 15] containing 50 mg of compound A per tablet can be obtained.

[0092]

[Table 15]

[0093]

[Table 16]

Example 11 1) 5 mg tablets (1) 210 g of compound A, 3066 g of lactose, 420 g of corn starch and 210 g of calcium carboxymethylcellulose (carmellose calcium) were placed in a fluidized granulating dryer (manufactured by Powrex Co.), and preheated and mixed. Then, 1974 g of an aqueous solution in which 126 g of hydroxypropylcellulose is dissolved is sprayed to obtain a granulated powder. (2) 3528 g of the granulated powder obtained in the above (1) is sized using a power mill (manufactured by Showa Kagaku Kikai Kosakusho). 3168 g of the obtained sized powder, 99 g of carmellose calcium and 33 g of magnesium stearate were mixed into a mixed powder using a tumbler mixer (manufactured by Showa Kagaku Kikai Kosakusho Co., Ltd.).
3000g was tableted with a tableting machine (manufactured by Kikusui Seisakusho) and [Table 1
7] is obtained. (3) Titanium oxide and yellow solution were separately added to the solution obtained by dissolving hydroxypropylmethylcellulose 2910 (TC-5) in purified water in a film coating machine (manufactured by Powrex) on the naked tablet obtained in (2) above. By spraying a coating agent obtained by mixing a suspension of iron sesquioxide, a film-coated tablet having the formulation shown in [Table 17] containing 5 mg of compound A per tablet can be obtained. 2) 25 mg tablets (1) 420 g of compound A, 2856 g of lactose, 420 g of corn starch and 210 g of carboxymethylcellulose calcium (carmellose calcium) were placed in a fluidized-granulation dryer (manufactured by Powrex), preheated and mixed, and 126 g of hydroxypropyl cellulose was added. 1974 g of the dissolved aqueous solution is sprayed to obtain a granulated powder. (2) 3528 g of the granulated powder obtained in the above (1) is sized using a power mill (manufactured by Showa Kagaku Kikai Kosakusho). The obtained sized powder (3168 g), carmellose calcium (99 g) and magnesium stearate (33 g) were mixed with a tumbler mixer (manufactured by Showa Kagaku Kikai Kosakusho) to obtain a mixed powder.
00g was tableted with a tableting machine (manufactured by Kikusui Seisakusho), and [Table 1
7] is obtained. (3) the plain tablets obtained in the above (2), a film coating machine (Powrex Co., Ltd.) in a coating agent (a was dissolved hydroxypropylmethylcellulose 2910 (TC-5) solution, apart from titanium oxide and yellow By spraying a coating agent prepared by mixing a suspension of iron sesquioxide, film-coated tablets having the formulation shown in [Table 17] containing 25 mg of compound A per tablet can be obtained.

[0095]

[Table 17]

Example 12 (1) 405.8 g of hydroxypropyl methylcellulose 2910 (TC-5) was dissolved in 4104 g of purified water. 45.6 g of titanium oxide and 4.56 g of yellow iron sesquioxide were dispersed in the obtained solution to obtain a coating agent. (2) 55 g of compound B obtained in Reference Example 8, lactose 316
3 g, 418 g of corn starch and 209 g of carboxymethylcellulose calcium (carmellose calcium) were placed in a fluidized-granulation dryer (manufactured by Powrex), and preheated and mixed.
Spray 3344 g of an aqueous solution in which 7.2 g is dissolved,
To obtain a granule. (3) 3539 g of the granulated powder obtained in the above (2) was sized using a power mill (manufactured by Showa Kagaku Kikai Kosakusho).
3101 g of the obtained sized powder and carmellose calcium 9
6.9 g and 32.3 g of magnesium stearate were mixed with a tumbler mixer (manufactured by Showa Kagaku Kikai Kosakusho) to obtain a powder mixture. Obtained. The plain tablets obtained in (4) above (3), in a film coating machine (Powrex Co., Ltd.), sprayed with the coating agent obtained in the above (1), to 5mg contain per tablet Compound B, 6,580 film-coated tablets having the formulation shown in Table 18 were obtained. The manufacturing conditions in each step are the same as in [Table 4].

[0097]

[Table 18]

[0098]

According to the present invention, by mixing a solution containing a physiologically active substance, a cellulosic disintegrant and a binder, a granulated powder having a predetermined particle size and improved granulation properties can be easily adjusted. be able to. Further, a solid preparation comprising the granulated powder of the present invention, particularly a granulated powder of the present invention, a solid preparation comprising a cellulose-based disintegrant and a stearic acid-based lubricant, has a content of a physiologically active substance. It can be made high, has excellent disintegration properties, and is excellent in dissolving physiologically active substances. Particularly when film-coated tablets are used, they can be stably stored for a long period of time even under non-light shielding.

[Brief description of the drawings]

FIG. 1 shows the dissolution rates of the uncoated tablets obtained in Example 1- (3) and Example 6. In the figure, - ● - it is a elution curve of Compound A from the elliptical tablet, - □ - shows the elution curves of Compound A from a round tablet, respectively.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/12 A61K 47/12 47/26 47/26 47/32 47/32 47/36 47/36 47 / 38 47/38 47/42 47/42 A61P 5/24 A61P 5/24 13/08 13/08 15/00 15/00 171 171 15/08 15/08 15/16 15/16 15/18 15 / 18 17/10 17/10 17/14 17/14 25/28 25/28 35/00 35/00 35/04 35/04 43/00 111 43/00 111 B01J 2/28 B01J 2/28 F-term ( (Reference) 4C076 AA29 AA30 AA31 AA44 AA53 CC30 DD41 DD67 EE31 EE32 EE33 EE38 FF05 FF06 FF07 FF09 FF21 FF36 4C086 AA01 AA02 CB22 MA02 MA03 MA05 MA35 MA37 MA41 NA03 ZA16 ZA81 ZA86 ZB01 Z92 ZA92 ZA92

Claims (49)

[Claims] A granulated powder comprising a physiologically active substance and a cellulosic disintegrant. 2. The disintegrant according to claim 1, wherein the cellulosic disintegrant is a compound selected from calcium carboxymethylcellulose, carboxymethylcellulose, croscarmellose sodium or low-substituted hydroxypropylcellulose, or a combination of two or more compounds. granulated powder. 3. The granulated powder according to claim 1, wherein the cellulosic disintegrant is calcium carboxymethylcellulose. 4. The granulated powder according to claim 1, wherein the physiologically active substance is poorly water-soluble. 5. The granulated powder according to claim 1, wherein the physiologically active substance is water repellent. 6. The granulated powder according to claim 1, wherein the physiologically active substance has poor water solubility and water repellency. 7. The granulated powder according to claim 1, wherein the contact angle of the physiologically active substance is 80 degrees or more. 8. The biologically active substance has the formula: Wherein, X is a carbon atom or a nitrogen atom, - - - is a single bond or a double bond shown] compound having a partial structure represented by or granulated powder according to claim 1, wherein a salt thereof. 9. A compound of the formula Wherein, X is a carbon atom or a nitrogen atom, - - - indicates a single bond or a double bond], or a salt thereof having a partial structure represented by the formula ## STR3 ## Wherein R ¹ and R ² each represent a hydrogen atom, a hydroxy group, a C _1-4 alkoxy group, a C _1-4 alkoxy-carbonyl group or a C _1-4 alkyl group which may have a substituent. , R ³ represents a hydrogen atom, a halogen atom, a hydroxy group or a C _1-4 alkoxy group which may have a substituent, or two adjacent R ³ are linked to form a C _1-4 alkylenedioxy. R ⁴ may be a hydrogen atom or a C _1-4 alkyl group, and R ⁶ may be an optionally substituted C
_1-4 alkyl group or formula (Wherein R ⁵ represents a hydrogen atom or R ⁴ and R ⁵ may be linked to form a heterocyclic ring), and n represents an integer of 0 to 5 The granulated powder according to claim 8, which is a compound represented by the formula: or a salt thereof. 10. A compound of the formula Wherein, X is a carbon atom or a nitrogen atom, - - - indicates a single bond or a double bond], or a salt thereof having a partial structure represented by the, 5-(N-benzyl -N- methyl Aminomethyl) -1- (2,6-difluorobenzyl) -6- [4- (3-methoxyureido) phenyl]
-3-phenylthieno [2,3-d] pyrimidine-2,
9. The composition according to claim 8, which is 4 (1H, 3H) -dione or a salt thereof.
Granulated powder as described. 11. A compound of the formula[Wherein X represents a carbon atom or a nitrogen atom,--- Is simple
Or a double bond).
The compound or a salt thereof has the formula:[Wherein, R⁹Is optionally substituted C_1-7Alkyl group,
Optionally substituted C _3-7Cycloalkyl group, substituted
C that may be_1-6Alkoxyamino group or substituted
An optionally substituted hydroxyamino group is represented by R^TenIs replaced
May be C_1-7Alkyl group or substituted
Each represents a good phenyl group;⁹Is unsubstituted C_1-7A
When it is a alkyl group, R^TenIs the substituted C_1-7Alkyl
Represents a group or substituted phenyl]
9. The granulated powder according to claim 8, which is a salt thereof. 12. A compound of the formula Wherein, X is a carbon atom or a nitrogen atom, - - - indicates a single bond or a double bond], or a salt thereof having a partial structure represented by the, 3- (N-benzyl -N- methyl Aminomethyl) -4,7-dihydro-5-isobutyryl-7- (2,6-difluorobenzyl) -2- [4-
The granulated powder according to claim 8, which is [(1-hydroxycyclopropyl) carbonylamino] phenyl] -4-oxothieno [2,3-b] pyridine or a salt thereof. 13. The granulated powder according to claim 1, wherein a solution containing a physiologically active substance, a cellulosic disintegrant and a binder is mixed and dried. 14. A binder comprising a compound selected from hydroxypropylcellulose, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, dextrin and pullulan, or a combination of two or more compounds. The granulated powder according to claim 13, which is a binder. 15. The granulated powder according to claim 13, wherein the binder is hydroxypropyl cellulose. 16. The granulated powder according to claim 13, wherein the solution containing the binder is an alcohol solution. 17. The granulated powder according to claim 16, wherein the alcohol is an alcohol having 1 to 3 carbon atoms. 18. The method according to claim 1, wherein the alcohol is ethanol.
6. Granulated powder according to 6. 19. The granulated powder according to claim 1, which is for tableting. 20. A method for producing a granulated powder, comprising mixing a solution containing a physiologically active substance, a cellulosic disintegrant and a binder and drying. 21. A solid preparation comprising the granulated powder according to claim 1 blended. 22. The solid preparation according to claim 21, comprising the granulated powder according to any one of claims 1 to 18, a cellulose disintegrant and a stearic acid lubricant. 23. A disintegrant for cellulosic substances comprising calcium carboxymethylcellulose, carboxymethylcellulose,
23. The solid preparation according to claim 22, which is a disintegrant comprising a compound selected from croscarmellose sodium or low-substituted hydroxypropylcellulose or a combination of two or more compounds. 24. The solid preparation according to claim 22, wherein the cellulosic disintegrant is calcium carboxymethylcellulose. 25. The solid preparation according to claim 22, wherein the stearic acid-based lubricant is magnesium stearate. 26. The tablet according to claim 2, which is a film-coated tablet.
The solid preparation according to 1. 27. The solid preparation according to claim 21, which is an oval tablet. 28. The solid preparation according to claim 21, which is a capsule. 29. The solid preparation according to claim 21, which is a granule / fine granule. 30. The formula Wherein R ¹ and R ² each represent a hydrogen atom, a hydroxy group, a C _1-4 alkoxy group, a C _1-4 alkoxy-carbonyl group or a C _1-4 alkyl group which may have a substituent. , R ³ represents a hydrogen atom, a halogen atom, a hydroxy group or a C _1-4 alkoxy group which may have a substituent, or two adjacent R ³ are linked to form a C _1-4 alkylenedioxy. R ⁴ may be a hydrogen atom or a C _1-4 alkyl group, and R ⁶ may be an optionally substituted C
_1-4 alkyl group or formula (Wherein R ⁵ represents a hydrogen atom or R ⁴ and R ⁵ may be linked to form a heterocyclic ring), and n represents an integer of 0 to 5 ] The granulated powder which contains the compound represented by these, or its salt. 31. 5- (N-benzyl-N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6
[4- (3-Methoxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H,
31. 3H) -dione or a salt thereof.
Granulated powder as described. 32. The formula Wherein R ¹ and R ² each represent a hydrogen atom, a hydroxy group, a C _1-4 alkoxy group, a C _1-4 alkoxy-carbonyl group or a C _1-4 alkyl group which may have a substituent. , R ³ represents a hydrogen atom, a halogen atom, a hydroxy group or a C _1-4 alkoxy group which may have a substituent, or two adjacent R ³ are linked to form a C _1-4 alkylenedioxy. R ⁴ may be a hydrogen atom or a C _1-4 alkyl group, and R ⁶ may be an optionally substituted C
_1-4 alkyl group or formula (Wherein R ⁵ represents a hydrogen atom or R ⁴ and R ⁵ may be linked to form a heterocyclic ring), and n represents an integer of 0 to 5 31. The granulated powder according to claim 30, wherein the compound or a salt thereof is mixed with a solution containing a binder and dried. 33. A binder comprising a compound selected from hydroxypropylcellulose, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, dextrin and pullulan, or a combination of two or more compounds. 33. The granulated powder according to claim 32, which is a binder. 34. The granulated powder according to claim 32, wherein the solution containing a binder is an alcohol solution. 35. The granulated powder according to claim 34, wherein the alcohol is an alcohol having 1 to 3 carbon atoms. 36. The method according to claim 3, wherein the alcohol is ethanol.
4. Granulated powder according to 4. 37. The granulated powder according to claim 30, which is for tableting. 38. The formula Wherein R ¹ and R ² each represent a hydrogen atom, a hydroxy group, a C _1-4 alkoxy group, a C _1-4 alkoxy-carbonyl group or a C _1-4 alkyl group which may have a substituent. , R ³ represents a hydrogen atom, a halogen atom, a hydroxy group or a C _1-4 alkoxy group which may have a substituent, or two adjacent R ³ are linked to form a C _1-4 alkylenedioxy. R ⁴ may be a hydrogen atom or a C _1-4 alkyl group, and R ⁶ may be an optionally substituted C
_1-4 alkyl group or formula (Wherein R ⁵ represents a hydrogen atom or R ⁴ and R ⁵ may be linked to form a heterocyclic ring), and n represents an integer of 0 to 5 ] A method for producing granulated powder, comprising mixing a compound represented by the formula (I) or a salt thereof with a solution containing a binder and drying the mixture. 39. A solid preparation comprising the granulated powder according to claim 30. (40) A solid preparation according to the above (39), which comprises the granulated powder according to the above (30) to (36), a cellulose disintegrant and a stearic acid lubricant. 41. The cellulosic disintegrant is calcium carboxymethyl cellulose, carboxymethyl cellulose,
41. The solid preparation according to claim 40, which is a disintegrant comprising a compound selected from croscarmellose sodium or low-substituted hydroxypropylcellulose or a combination of two or more compounds. 42. The solid preparation according to claim 40, wherein the cellulosic disintegrant is carboxymethylcellulose calcium. 43. The solid preparation according to claim 40, wherein the stearic acid-based lubricant is magnesium stearate. 44. A film-coated tablet according to claim 3.
9. The solid preparation according to 9. 45. The solid preparation according to claim 39, which is an oval tablet. 46. The solid preparation according to claim 39, which is a capsule. 47. The solid preparation according to claim 39, which is a granule / fine granule. 48. The solid preparation according to claim 39, which is a gonadotropin releasing hormone antagonist. 49. The solid preparation according to claim 39, which is an agent for preventing or treating sex hormone-dependent diseases.