JPH09208496A - Composition containing lh-rh antagonist - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine having heightened solubility in water, cutaneous absorption and drug stability, particularly a composition containing a luteinizing hormone releasing hormone (LH-RH) antagonist useful as a LH-RH antagonist. SOLUTION: This composition contains a nonpeptide-based LH-RH antagonist of formula I (R<1> and R<2> are each H or a group through C, N, O or S; R<3> is a homocyclic or a heterocyclic ring; R<4> is H, formyl, carbonyl, etc.; R<5> is H or a group through C; (n) is 0-3) or formula II (R<6> is H, an alkyl, etc.; R<7> is H, an alkyl, an aryl, etc.; R<8> is an amino; R<9> is an aryl, (r) is 0-3) and a branched cyclodextrin-carbonic acid. For 1 mole of the LH-RH antagonist, 0.1-20 moles of the branched cyclodextrin-carbonic acid are included. This composition suppresses secretion of a gonadotropic hormone, controls concentration of a sex hormone in blood and is useful for prostato-tumor, gynecological tumor, leukemia, large intestine tumor, gastiritis, Hodgkin's disease, malignant melanoma, peptic ulcer, etc., and oestrous control of an animal, flesh improvement for an edible meat, growth promotion, etc., in a field of stockbreeding.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a LH-RH antagonist-containing composition having improved water solubility, and more specifically,
By the branched cyclodextrin-carboxylic acid which is a cyclodextrin derivative, pharmaceuticals, veterinary drugs, especially LH-RH
It relates to a composition having improved water solubility containing a non-peptide LH-RH antagonist useful as an antagonist.

[0002]

BACKGROUND OF THE INVENTION Improving the solubility of water-insoluble or sparingly soluble drugs in water is the most common and important problem in the field of medicine and the like, and the use of cyclodextrins is often used. It is an effective means to solve this problem. Cyclodextrins are used for improving drug solubility and stability, as well as drug absorption, drug stabilization in blood, volatility, taste masking, flavoring, emulsification, powderization and stabilization. All of these are considered to be effects due to cyclodextrin forming a complex in which an active ingredient such as a target drug is included. As such cyclodextrins, various homologues are known, and the solubility in water varies depending on the type.
For example, α-cyclodextrin in which 6 glucoses are bound in a ring has a solubility in water of about 15%, β-cyclodextrin in which 7 glucoses are bound in a ring is about 2%, and 8 glucoses are bound in a ring. Bound γ-cyclodextrin is reported to be about 23%.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have aimed to improve the solubility of non-peptide LH-RH antagonists by various cyclodextrins in water, oral absorption and stability of drugs. As a result of earnest studies, it was found that the above-mentioned object can be achieved by using a branched cyclodextrin-carboxylic acid having certain improved properties, and the present invention has been completed. That is, the present invention is:

(1) A composition comprising a non-peptide LH-RH antagonist and a branched cyclodextrin-carboxylic acid, (2) a non-peptide LH-RH antagonist is a thienopyridine or thienopyrimidine LH- The composition according to (1) above, which is an RH antagonist, and (3) the thienopyridine LH-RH antagonist has the formula:

Embedded image [In the formula, R ¹ and R ² are each hydrogen, carbon, nitrogen,
R ³ is an optionally substituted homologous or heterocyclic group, R ⁴ is hydrogen, a formyl group, a sulfur atom-containing group or an optionally substituted hydrocarbon residue. A carbonyl group optionally substituted with or an esterified or amidated carboxyl group, R ⁵ is a group through a hydrogen atom or a carbon atom, and n is 0 to 0.
A compound represented by the formula [3] or a salt thereof: (4) Thienopyrimidine L
The H-RH antagonist has the formula

Embedded image {In the formula, R ⁶ is hydrogen, an alkyl group or a formula- (CH ₂ ) p
Q wherein, p is an integer of 0 to 3, Q is halogen, nitro, cyano, amino, optionally substituted carboxyl group, alkylenedioxy group, or a group of the formula -A-R ¹⁰ (wherein, A is A chemical bond or an intervening group, R ¹⁰ represents an aryl group which may be substituted with a group represented by), an optionally substituted cycloalkyl group or an optionally substituted heterocyclic group. The group represented by
⁷ is hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group or an optionally substituted cycloalkyl group, and R ⁸ is optionally substituted A good amino group, R ⁹ is an optionally substituted aryl group, and r is an integer of 0 to 3} or a salt thereof, wherein the composition is (5). The composition according to (1) above, wherein the branched cyclodextrin-carboxylic acid is contained in an amount of 0.1 to 20 mol per mol of the LH-RH antagonist, (6) the branched cyclodextrin-carboxylic acid is at least one carboxyl group. The composition according to (1) above, which is a cyclodextrin having an organic group containing at 6-O position of at least one glucose unit of the cyclodextrin ring,
(7) The composition according to (1) above, wherein the cyclodextrin ring is a cyclodextrin ring having 6 to 8 glucose units, (8) branched cyclodextrin-
The carboxylic acid is 6-O-cyclomaltoheptaosyl- (6
→ 1) -α-D-glucosyl- (4 → 1) -O-α-D-
The composition according to (1) above, which is glucuronic acid, (9) the composition according to (1) above, which is a medicine, (10) LH-RH.
The composition according to (1) above, which is an antagonist, (11) LH-
The composition according to (1) above, wherein the RH antagonist is a water-insoluble or sparingly soluble substance, and (12) the composition according to 1 above for oral use. About.

The branched cyclodextrin-carboxylic acid used in the present invention includes not only its free carboxylic acid but also its alkali metal (eg, lithium, sodium, potassium, etc.), alkaline earth metal (eg, calcium, magnesium, etc.). And the like are included. These branched cyclodextrin-carboxylic acids may be used alone or in combination of two or more kinds, or may be used in a state where a free carboxylic acid and a salt thereof are mixed. The branched cyclodextrin
A carboxylic acid is a cyclodextrin having an organic group containing at least one carboxyl group at the 6-O position of at least one glucose unit of the cyclodextrin ring. The cyclodextrin ring of the branched cyclodextrin-carboxylic acid has, for example, 6, 7 or 8 glucose units. Preferably, the cyclodextrin ring has 7 glucose units. Examples of the cyclodextrin include α-cyclodextrin and β
-Cyclodextrin, γ-cyclodextrin and the like. The organic group containing at least one carboxyl group has 1 to 3 glucose units,
Moreover, it is preferable that at least one of the hydroxymethyl groups of the glucose unit in the organic group is oxidized to a carboxyl group.

Specific examples of the branched cyclodextrin-carboxylic acid include 6-O-cyclomaltohexaosyl- (6 → 1) -α-D-glucosyl- (4 → 1) -O-α-.
D-glucuronic acid (cyclomaltohexaosyl- (6 →
1) -α-D-glucopyranosyl- (4 → 1) -O-α-
D-glucopyranoside uronic acid) (hereinafter, α-CyD-G ₂
-COOH may be abbreviated; the abbreviations of the following compounds are also shown in parentheses), 6-O-cyclomaltoheptaosyl- (6 → 1) -α-D-glucosyl- (4
→ 1) -O-α-D-glucuronic acid (cyclomaltoheptaosyl- (6 → 1) -O-α-D-glucopyranosyl-
(4 → 1) -O-α-D-glucopyranoside uronic acid) (β
_{-CyD-G 2 -COOH), 6} -O- cycloalkyl maltooctaose O Sil - (6 → 1) -α- D- glucosyl - (4 → 1) -
O-α-D-glucuronic acid (cyclomaltooctaosyl- (6 → 1) -O-α-D-glucopyranosyl- (4 → 1)
-O-α-D-glucopyranoside uronic acid (γ-CyD-
G ₂ -COOH), 6-O- cycloalkyl maltohexaose O Sil -
(6 → 1) -α-D-glucuronic acid (cyclomaltohexaosyl- (6 → 1) -O-α-D-glucopyranosideuronic acid) (α-CyD-G ₁ -COOH), 6-O- Cyclomaltoheptaosyl- (6 → 1) -α-D-glucuronic acid
(Cyclomaltoheptaosyl- (6 → 1) -O-α-D-
Glucopyranosiduronic acid) (β-CyD-G ₁ -COO
H), 6-O-cyclomaltooctaosyl- (6 → 1)-
α-D-Glucuronic acid (Cyclomaltooctaosyl- (6
→ 1) -O-α-D-glucopyranoside uronic acid) (γ-
CyD-G ₁ -COOH), 2-O- (6-cyclomaltohexaosyl) -acetic acid (α-CyD-CH ₂ COOH), 2-
O- (6-cyclomaltoheptaosyl) -acetic acid (β-CyD
_{-CH 2 COOH), 2-O-} (6- cyclo maltooctaose O Sil) - acetic acid _{(γ-CyD-CH 2 COOH} ), 3-O-
(6-Cyclomaltoheptaosyl) -propionic acid (β-
_{CyD-CH 2 CH 2 COOH)} , 2- hydroxy -3-O
-(6-Cyclomaltoheptaosyl) -propionic acid (3
-O- (6-cyclomaltoheptaosyl) -2-hydroxy-propionic acid) (β-CyD-CH ₂ CH (OH) -C
OOH), 7 ^A , 7 ^C -di-O- [α-D-glucuronyl-
(1 → 4) -O-α-D-Glucosyl]-(1 → 6) -maltoheptaose (β-CyD- (G ₂ COOH) ₂ ), 6-O
-Cyclomaltoheptaosyl-O-α-D-maltosyl- (4 → 1) -O-α-D-glucuronic acid (cyclomaltoheptaosyl- (6 → 1) -O-α-D-glucopyranosyl- (4 → 1) -O-α-D-glucopyranosyl- (4 →
1) -O-α-D-glucopyranoside uronic acid) (β-Cy
D-G ₃ -COOH), and their aforementioned salts (eg, beta-
CyD-G ₂ -COOH sodium salt (cyclomaltoheptaosyl- (6 → 1) -O-α-D-glucopyranosyl- (4 → 1) -O-α-D-glucopyranoside uronate sodium (also β -CyD-G ₂ abbreviated as -COONa))) and the like.

More specifically, 6-O-cyclomaltohexaosyl- (6 → 1) -α-D-glucosyl- (4 →
1) -O-α-D-glucuronic acid (α-CyD-G ₂ -C
OOH), 6-O-cyclomaltoheptaosyl- (6 →
1) -α-D-glucosyl- (4 → 1) -O-α-D-
Glucuronic acid (β-CyD-G ₂ -COOH), and 6-O-cyclomaltooctaosyl-α-D-glucosyl- (4 → 1) -O-α-D-glucuronic acid (γ-Cy).
D-G ₂ -COOH), respectively α- cyclodextrin (glucose units number 6), beta-cyclodextrin (glucose units 7) and γ- cyclodextrin (branched cyclodextrin containing glucose units 8) - carboxylic It is an acid, and maltose is α- (1 → 6) -bonded to one glucose unit of its cyclodextrin ring, and the 6-hydroxymethyl group of terminal glucose of the maltose is oxidized to a carboxyl group to form glucuronic acid. ing.

Further, 6-O-cyclomaltohexaosyl- (6 → 1) -α-D-glucuronic acid (α-CyD-G _1-
COOH), 6-O-cyclomaltoheptaosyl- (6 →
1) -α-D-glucuronic acid (β-CyD-G ₁ -COO
H), and 6-O-cyclomaltooctaosyl- (6 →
1) -α-D-glucuronic acid (γ-CyD-G ₁ -COO
In H), glucose is α- (1 → 6) -bonded to one glucose unit of the cyclodextrin ring, and the hydroxymethyl group at 6-position of the branched glucose is oxidized to a carboxyl group to form glucuronic acid. It is a branched cyclodextrin-carboxylic acid. And 2-O-
(6-Cyclomaltohexaosyl) -acetic acid (α-CyD-C
H ₂ COOH), 2-O- (6-cyclomaltoheptaosyl) -acetic acid (β-CyD-CH ₂ COOH), 2-O- (6-
Cyclomalto octaosyl) -acetic acid (γ-CyD-CH ₂ C
OOH) is a branched cyclodextrin-carboxylic acid that is branched into one glucose unit of its cyclodextrin ring to which a carboxymethyl group is attached. Such branched cyclodextrin-carboxylic acid or salts thereof,
It is described in JP-A-7-76594, and it can be produced, for example, by the method described in the publication.

Examples of the non-peptide LH-RH antagonist used in the composition of the present invention include (a) WO 9
Formula described in Japanese Patent Publication No. 5/28405

Embedded image [In the formula, R ¹ and R ² are each hydrogen, carbon, nitrogen,
R ³ is an optionally substituted homologous or heterocyclic group, R ⁴ is hydrogen, a formyl group, a sulfur atom-containing group or an optionally substituted hydrocarbon residue. A carbonyl group optionally substituted with or an esterified or amidated carboxyl group, R ⁵ is a group through a hydrogen atom or a carbon atom, and n is 0 to 0.
Represents an integer of 3] or a salt thereof,
(B) Formula described in Japanese Patent Application No. 7-271638

[Chemical 6] {In the formula, R ⁶ is hydrogen, an alkyl group or a formula- (CH ₂ ) p
Q wherein, p is an integer of 0 to 3, Q is halogen, nitro, cyano, amino, optionally substituted carboxyl group, alkylenedioxy group, or a group of the formula -A-R ¹⁰ (wherein, A is A chemical bond or an intervening group, R ¹⁰ represents an aryl group which may be substituted with a group represented by), an optionally substituted cycloalkyl group or an optionally substituted heterocyclic group. The group represented by
⁷ is hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group or an optionally substituted cycloalkyl group, and R ⁸ is optionally substituted A good amino group, R ⁴ is an optionally substituted aryl group, and r is an integer of 0 to 3} or a salt thereof, (c) described in European Patent Application No. 679642. ,formula

Embedded image [Wherein, the ring A is a benzene ring which may have a substituent,
Ar is an aromatic group which may have a substituent, R ¹ and R ² are a nitrogen-containing heterocyclic group together with an adjacent nitrogen atom, m is an integer of 1 to 6, and n is 1 to 3 integer,

Embedded image Showing a nitrogen atom] or a salt thereof,
(D) The formula described in WO 95/29900.

Embedded image [Wherein, the ring A is a benzene ring which may have a substituent,
Ar is an aromatic group which may have a substituent, and R ¹ , R ² and R ³ each have a hydrogen atom, an acyl group, a hydrocarbon group which may have a substituent or a substituent. Optionally a heterocyclic group, or R ² and R ³ may be combined to form a non-aromatic cyclic hydrocarbon group, X is a methylene group or a carbonyl group,

Embedded image A heterocyclic group which may have a substituent or -Z- (CH
₂ ) A compound represented by _m- W (Z is a methylene group or a carbonyl group, W is an optionally substituted amino group, and m is an integer of 0 to 5) or a salt thereof, and (e) Japanese Patent Application Formula described in No. 7-300330

Embedded image [In the formula, Ar ¹ and Ar ² are each an aromatic group which may have a substituent, and P and Q are each an aromatic group which may contain an etheric oxygen or sulfur in the carbon chain and which has 2 or more carbon atoms. A divalent aliphatic hydrocarbon group, R ¹ and R ² are each i) an acyl represented by —CO—R or —CONH—R (R represents a heterocyclic group which may have a substituent). Or ii) a hydrocarbon group which may have a substituent, R ² and R ⁴ each represent a hydrogen atom or an alkyl group which may have a substituent, R ¹ and R ² or R ³ and R ⁴ May form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom, and j represents 0 or 1] or a salt thereof or the like is used.

Non-peptide LH- used in the present invention
The RH antagonist is preferably WO 95/284.
Compound (I) described in Japanese Patent Publication No. 05 and Japanese Patent Application No. 7-271
Compound (II) described in No. 638 is used. The non-peptidic LH-RH antagonist is preferably, for example, 3- (N- described in WO 95/28405.
Benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2,6-difluorobenzyl) -5-isobutyryl-2- (4-propionylaminophenyl) -4
-Oxothieno [2,3-b] pyridine (Compound 1), 3- (N-benzyl-N-methylaminomethyl)
-4,7-Dihydro-7- (2,6-difluorobenzyl) -5-benzoyl-2- (4-isobutyrylaminophenyl) -4-oxothieno [2,3-b] pyridine (Compound 2) and 3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2,6-difluorobenzyl) -5-isobutyryl-2- (4-isobutyrylaminophenyl) -4-oxothieno [2,3-
b] Pyridine (Compound C) or salts thereof, etc. 2,4 (1H, 3H) -described in Japanese Patent Application No. 7-271638.
Dioxo-1- (2,6-difluorobenzyl) -5-
(N-benzyl-N-methylaminomethyl) -6- (4
-Isobutyrylaminophenyl) -3- (3-methoxyphenyl) thieno [2,3-d] pyrimidine (Compound 3) or a salt thereof or the like is used.

In the compound (I), examples of the group represented by R ¹ , R ² and R ⁵ via the carbon atom include, for example, optionally substituted aliphatic hydrocarbon groups [eg, alkyl (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl), cycloalkyl (eg C _3-6 silloalkyl such as cyclopropyl, cyclopentyl, cyclohexyl),
Alkoxyalkyl (eg, C _1-3 alkoxy C _1-6 alkyl such as methoxymethyl, ethoxymethyl, ethoxybutyl, propoxymethyl, propoxyhexyl), hydroxyalkyl (eg, hydroxymethyl, hydroxyethyl, hydroxybutyl, hydroxypropyl, etc.) C _1-6
Alkyl), alkenyl (eg vinyl, butadienyl,
C _2-6 alkenyl such as hexatrienyl), formyl, carboxyl, alkoxycarbonyl (eg C _1-6 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl), etc.], cyano, amide, mono, dialkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, hexylcarbamoyl, dimethylcarbamoyl, mono- and methyl ethylcarbamoyl, di-C _1-6 alkylcarbamoyl), amidino, aliphatic aromatic group [eg, aryl (e.g., phenyl,
C _6-14 aryl such as naphthyl and anthracenyl), aralkyl (eg, C _7-20 aralkyl such as benzyl, benzhydryl, trityl and the like), heterocyclic group having a bond at a carbon atom (eg, 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl,
2-, 4- or 5-thiazolyl, 3-, 4- or 5
-Pyrazolyl, 2-, 4- or 5-imidazolyl, 3
-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3-
Or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3- Triazolyl, 1,2,4-triazolyl, 1H- or 2H-
In addition to carbon atoms such as tetrazolyl, oxygen atoms, sulfur atoms,
5-membered ring group containing 1 to 4 heteroatoms selected from nitrogen atom and the like; N-oxide-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxide-2- , 4- or 5-pyrimidinyl, 2- or 3-
Thiomorpholinyl, 2- or 3-morpholinyl, oxoimidazolinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-
Carbon such as oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, 2- or 3-piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl, N-oxide-3- or 4-pyridazinyl 6-membered ring group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like in addition to atoms; benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [ 4,5
-B] pyridazinyl, benzimidazolyl, quinolyl,
Isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolidinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl,
Bicyclic or tricyclic containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atoms such as phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl. Besides a carbon atom such as a cyclic condensed ring group, for example, an oxygen atom,
And a 5- to 8-membered ring containing 1 to 4 heteroatoms such as a sulfur atom and a nitrogen atom or a condensed ring thereof) and the like.

Examples of the substituent include (a) hydroxyl, (b) amino, (c) mono- or di-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino). Etc.), (d) C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, hexyloxy, etc.) and (e) 1 to 4 selected from halogen (fluorine, chlorine, bromine, iodine), etc. C _6-14 aryl (eg, phenyl, naphthyl, etc.); mono- or di-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.); C _1-4 acylamino (eg, formylamino, acetylamino, etc.); hydroxyl; carboxyl; nitro; C _1-6 alkoxy (eg,
Methoxy, ethoxy, propoxy, isopropoxy, butoxy etc.); C _1-6 alkyl-carbonyloxy (eg acetoxy, ethylcarbonyloxy etc.) and halogen (eg fluorine, chlorine, bromine, iodine), substituted as described below And a group via a nitrogen atom which may be present. The number of substitutions is 1 to 6, preferably 1 to 3.

The group represented by R ¹ and R ² via the nitrogen atom is, for example, amino, which may be each substituted, -NR ^a R ^b [wherein R ^a is hydrogen, alkyl, cycloalkyl, Aryl, heterocyclic group, -SOp- (p is 1 to
R ^b represents hydrogen or alkyl], or a heterocyclic group having a bond at the nitrogen atom (eg,
1H-1-pyrrolyl, 1-imidazolyl, pyrazolyl,
Indolyl, 1H-1-indazolyl, 7-purinyl,
1-pyrrolidinyl, 1-pyrrolinyl, 1-imidazolidinyl, pyrazolidinyl, piperazinyl, pyrazolinyl,
1-piperidinyl, 4-morpholinyl, 4-thiomorpholinyl, etc.) and the like. The alkyl, cycloalkyl, aryl and heterocyclic groups have the same meanings as described above.

Examples of the substituent include C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl etc.), C _2-6
Alkenyl (eg, vinyl, 1-methylvinyl, 1-propenyl, allyl, etc.), C _2-6 alkynyl (eg, ethynyl, 1-
Propynyl, propargyl, etc.), C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _5-7 cycloalkenyl (eg, cyclopentenyl, cyclohexenyl, etc.), C
_7-11 Aralkyl (eg, benzyl, α-methylbenzyl,
Phenethyl etc.), C _6-14 aryl (eg phenyl, naphthyl etc.), C _1-6 alkoxy (eg methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert- Butoxy etc.), C _6-14 aryloxy (eg phenoxy etc.), C _1-6 alkanoyl (eg formyl, acetyl, propionyl, n-butyryl, iso-butyryl etc.), C _6-14 aryl-carbonyl (eg , Benzoyl etc.), C _1-6 alkanoyloxy (eg formyloxy, acetyloxy, propionyloxy, n-butyryloxy, iso-butyryloxy etc.),
C _6-14 aryl-carbonyloxy (eg, benzoyloxy etc.), carboxyl, C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl, iso Butoxycarbonyl, tert-butoxycarbonyl, etc.), carbamoyl group, N-mono-C
_1-4 alkylcarbamoyl (eg, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,
N-isopropylcarbamoyl, N-butylcarbamoyl, etc.), N, N-di-C _1-4 alkylcarbamoyl (eg,
N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-dibutylcarbamoyl, etc.), cyclic aminocarbonyl (eg, 1-aziridinylcarbonyl, 1-azetidinyl) Carbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl, morpholinocarbonyl, etc.),
Halogen (fluorine, chlorine, bromine, iodine), mono-, di- or tri-halogeno-C _1-4 alkyl (eg, chloromethyl, dichloromethyl, trifluoromethyl, trifluoroethyl, etc.), oxo group, amidino , Imino group, amino, mono- or di-C _1-4 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, etc.) , In addition to carbon atom and one nitrogen atom, 1 hetero atom selected from oxygen atom, sulfur atom, nitrogen atom, etc.
To 3 to 6 membered cyclic amino groups which may contain 3 to 3 (eg, aziridinyl, azetidinyl, pyrrolidinyl,
Pyrrolinyl, pyrrolyl, imidazolyl, birazolyl, imidazolidinyl, piperidino, morpholino, dihydropyridyl, pyridyl, N-methylpiperazinyl, N-ethylpiperazinyl, etc., C _1-6 alkanoylamino (eg, formamide, acetamide, trifluoroa) Cetamide, propionylamide, butyrylamide, isobutyrylamide, etc.), benzamide, carbamoylamino, N-C _1-4
Alkylcarbamoylamino (eg, N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylamino, N-isopropylcarbamoylamino, N-butylcarbamoylamino, etc.), N, N-di-C
_1-4 alkylcarbamoylamino (eg, N, N-dimethylcarbamoylamino, N, N-diethylcarbamoylamino,
N, N-dipropylcarbamoylamino, N, N-dibutylcarbamoylamino, etc.), C _1-3 alkylenedioxy (eg,
Methylenedioxy, ethylenedioxy, etc.), -B (O
H) _2, hydroxyl, epoxy (-O-), nitro, cyano, mercapto, sulfo, Surufuino, phosphono, dihydroxy ball reel, sulfamoyl, C _1-6 alkylsulfamoyl (e.g., N- methylsulfamoyl, N -Ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.), DiC _1-6 alkylsulfamoyl (eg, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N,
N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, etc.), C _1-6 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, etc.), phenylthio , C _1-6 alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl,
Butylsulfinyl, etc.), phenylsulfinyl, C
_1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.), phenylsulfonyl and the like can be mentioned. The number of substitutions is 1 to 6, preferably 1 to 3.

Examples of the group via the oxygen atom represented by R ¹ and R ² include hydroxyl and optionally substituted alkoxy, cycloalkoxy, aryloxy, aralkyloxy, and heterocyclic oxy groups. . Said each optionally substituted alkoxy,
The alkyl, cycloalkyl, aryl, aralkyl and heterocyclic groups in the cycloalkoxy, aryloxy, aralkyloxy and heterocyclic oxy groups have the same meanings as described above. The substituent has the same meaning as the substituent in the group via the nitrogen atom.

Examples of the group having a sulfur atom represented by R ¹ and R ² include mercapto, and optionally substituted alkylthio, cycloalkylthio, arylthio, aralkylthio, and heterocyclic thio groups. Said each optionally substituted alkylthio,
Cycloalkylthio, arylthio, aralkylthio,
The alkyl, cycloalkyl, aryl, aralkyl and heterocyclic group in the heterocyclic thio group have the same meaning as described above.
The substituent has the same meaning as the substituent in the group via the nitrogen atom.

The homocyclic group in the optionally substituted homocyclic group represented by R ³ is, for example, benzene, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane or the like having 3 to 7 carbon atoms. A cycloalkane of 3 to 7 members such as cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and the like, which has only 3 to 7 carbon atoms, and a cycloalkene having 3 to 7 carbon atoms.

The substituent which the homocycle may have is, for example, C _1-15 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, Hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, etc.), C _3-10 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _2-10 alkenyl (eg, Vinyl, allyl, 2-methylallyl, 2-butenyl, 3-butenyl, 3-octenyl, etc., C _2-10 alkynyl (eg, ethynyl, 2-propynyl, 3-hexynyl etc.), C _3-10 cycloalkyl (eg , Cyclopropenyl,
Cyclopentenyl, cyclohexenyl, etc.), C _6-10 aryl (eg, phenyl, naphthyl, etc.), C _1-19 aralkyl (eg, benzyl, phenylethyl, trityl, etc.), nitro, hydroxyl, mercapto, oxo, thioxo, cyano , Carbamoyl, carboxyl, C _1-5 alkoxy-
Carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), sulfo, halogen (fluorine, chlorine, bromine, iodine), C _1-6 alkoxy (eg, methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, etc.), C _6-10 aryloxy (eg, phenoxy etc.), C _1-6 alkylthio (eg, methylthio, ethylthio, n-propylthio, isopropylthio) , N-butylthio, t-butylthio, etc.), C _6-10 arylthio (eg, phenylthio, etc.), C
_1-6 alkylsulfinyl (eg, methylsulfinyl,
Ethylsulfinyl etc.), C _6-10 arylsulfinyl (eg phenylsulfinyl etc.), C _1-6 alkylsulfonyl (eg methylsulfonyl, ethylsulfonyl etc.), C _6-10 arylsulfonyl (eg phenylsulfonyl etc.), Amino, C _1-6 acylamino (eg, acetylamino, propionylamino, etc.), mono- or di-C
_1-4 alkylamino (eg, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, dimethylamino, diethylamino, etc.), C
_3-8 cycloalkylamino (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.), C _6-10 arylamino (eg, anilino, etc.), C _1-6 aralkyl (eg, formyl, acetyl, Hexanoyl, etc.), C _6-10 aryl-carbonyl (eg, benzoyl, etc.), and a 5- to 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen, etc. in addition to carbon atoms (eg, 2- or 3-thienyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 2
-, 4- or 5-thiazolyl, 3-, 4- or 5-
Isothiazolyl, 2-, 4- or 5-oxazolyl,
3-, 4- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 1,2,3- or 1,2,4-triazolyl, 1H or 2H-tetrazolyl, 2-3
-Or 4-pyridyl, 2-, 4- or 5-pyrimidyl, 3- or 4-pyridanidyl, quinolyl, isoquinolyl, indolyl, etc.) and the like. The number of substitutions is 1
6 to 6, preferably 1 to 3. Examples of the optionally substituted heterocyclic group represented by R ³ include 2-
Or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2
-, 4- or 5-oxazolyl, 2-, 4- or 5
-Thiazolyl, 3-, 4- or 5-pyrazolyl, 2
-, 4- or 5-imidazolyl, 3-, 4- or 5
-Isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl),
1,3,4-oxadiazolyl, 3- or 5- (1,2,
4-thiadiazolyl), 1,3,4-thiadiazolyl, 4
-Or 5- (1,2,3-thiadiazolyl), 1,2,5-
Thiadiazolyl, 1,2,3-triazolyl, 1,2,4-
A 5-membered ring group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atom such as triazolyl, 1H- or 2H-tetrazolyl, for example, N
-Oxide-2-, 3- or 4-pyridyl, 2-, 4
-Or 5-pyrimidinyl, N-oxide-2-, 4-
Or 5-pyrimidinyl, thiomorpholinyl, morpholinyl, oxoimidazolinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl,
1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl, N
6-membered ring group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atom such as -oxide-3- or 4-pyridazinyl, for example, benzofuryl, benzothiazolyl, benzoxazolyl , Tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b]
Pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,
Quinoxalinyl, indolizinyl, quinolidinyl, 1,
In addition to carbon atoms such as 8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl and phenoxazinyl, oxygen atom, sulfur atom, nitrogen atom, etc. 5 to 8 containing 1 to 4 heteroatoms such as oxygen atom, sulfur atom and nitrogen atom in addition to carbon atoms such as bicyclic or tricyclic fused ring group containing 1 to 4 selected heteroatoms
A membered ring or a condensed ring thereof and the like can be mentioned.

Examples of the substituent that the heterocyclic group may have include C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), C _2-6 alkenyl (eg vinyl,
1-methylvinyl, 1-propenyl, allyl, etc.), C _2-6 alkynyl (eg, ethynyl, 1-propynyl, propargyl, etc.), C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) , C
_5-7 cycloalkenyl (eg, cyclopentenyl, cyclohexenyl, etc.), C _7-11 aralkyl (eg, benzyl, α
-Methylbenzyl, phenethyl etc.), C _6-14 aryl (eg phenyl, naphthyl etc.), C _1-6 alkoxy (eg methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec- Butoxy, tert-
Butoxy etc.), C _6-14 aryloxy (eg phenoxy etc.), C _1-6 alkanoyl (eg formyl, acetyl,
Propionyl, n-butyryl, iso-butyryl, etc.), C _6-14
Aryl-carbonyl (eg, benzoyl etc.), C _1-6 alkanoyloxy (eg, formyloxy, acetyloxy, propionyloxy, n-butyryloxy, iso-butyryloxy etc.), C _6-14 aryl-carbonyloxy (eg, benzoyl) Oxy), carboxyl, C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), carbamoyl group , N-mono-C _1-4 alkylcarbamoyl (eg, N
-Methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, etc.), N, N-di-C _1-4 alkylcarbamoyl (eg, N, N-dimethylcarbamoyl, N , N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N,
N-dibutylcarbamoyl etc.), cyclic aminocarbonyl (eg, 1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl, morpholino Carbonyl, etc.), halogen (fluorine, chlorine, bromine, iodine), mono-, di- or tri-halogeno-C _1-4 alkyl (eg, chloromethyl, dichloromethyl, trifluoromethyl, trifluoroethyl, etc.), Oxo group, amidino, imino group, amino, mono- or di C _1-4 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, Dibutylamino, etc.), carbon atom and one nitrogen atom, as well as oxygen atom, sulfur Atoms, nitrogen atoms, etc., 3 to 6-membered cyclic amino groups which may contain 1 to 3 hetero atoms (eg, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, virazolyl, imidazolidinyl, piperidino, Morpholino, dihydropyridyl, pyridyl, N-methylpiperazinyl, N-ethylpiperazinyl, etc.), C _1-6 alkanoylamino (eg, formamide, acetamide, trifluoroacetamide, propionylamide, butyrylamide,
Isobutyrylamide, etc.), benzamide, carbamoylamino, N—C _1-4 alkylcarbamoylamino (eg, N
-Methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylamino, N-isopropylcarbamoylamino, N-butylcarbamoylamino, etc.), N, N-di-C _1-4 alkylcarbamoylamino (eg, N, N -Dimethylcarbamoylamino, N, N-diethylcarbamoylamino, N, N-dipropylcarbamoylamino, N, N-dibutylcarbamoylamino, etc., C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.) ), -B (OH) ₂ , hydroxyl, epoxy (-O
-), Nitro, cyano, mercapto, sulfo, sulfino, phosphono, dihydroxyboryl, sulfamoyl, C _1-6 alkylsulfamoyl (eg, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfyl) Famoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.), diC _1-6 alkylsulfamoyl (eg, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N , N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, etc.), C _1-6 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, etc.), phenylthio, C _1-6 alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl, propyl sulfinyl, butylsulfinyl, etc.) Phenylsulfinyl, C _1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl,
Butylsulfonyl etc.), phenylsulfonyl and the like. The number of substitutions is 1 to 6, preferably 1 to 3
It is.

R^FourAn etherified carboxy represented by
Examples of the ester group in the alkyl group include alkyl and silane.
Examples include chloroalkyl, aryl, aralkyl, and heterocyclic groups.
These have the same meanings as described above. R^FourRepresented by
Examples of the amidated carboxyl group include —C
ONR^aR ^b(Where R^aAnd R^bHas the same meaning as above
Group). R^FourIs replaced by
Optionally substituted lower alkyl group with a hydroxyl group, R
^FourA lower alkyl substituted with a group through the sulfur atom represented by
Examples of the lower alkyl group in the kill group include methyl.
Ru, ethyl, propyl, isopropyl, butyl, isobu
C such as tyl, S-butyl, pentyl, hexyl_1-6Archi
Group. In the hydroxyl group which may be substituted
Examples of the substituent include halogen (eg, chlorine, odor
Element, fluorine, etc.), C_6-10Aryl (eg, phenyl, naphth
Chill), C_7-12Aralkyl (eg, benzyl, phenyl
1 to 4 units selected from ethyl etc.) and nitro etc.
C which may have a substituent_1-6Alkyl (eg methyl,
Ethyl, n-propyl, i-propyl, n-butyl, te
rt-butyl etc.), halogen (eg chlorine, bromine, fluorine)
Etc.), C_1-6Alkyl (eg, methyl, ethyl, n-pro
Pills, etc., C_1-10Aryl (eg, phenyl, naphthyl
Etc.), C_7-12Aralkyl (eg, benzyl, phenylethyl)
1 to 4 substituents selected from the group such as
C which may have_6-10Aryl (eg, phenyl, na
Futyl etc.); halogen (eg chlorine, bromine, fluorine etc.),
C_1-6Alkyl (eg, methyl, ethyl, n-propyl
Etc.), C_6-10Aryl (eg, phenyl, naphthyl, etc.),
C_7-12Aralkyl (eg, benzyl, phenylethyl, etc.)
And 1 to 4 substituents selected from nitro and the like
May be C_7-12Aralkyl (eg, benzyl, pheny
Ruethyl, naphthylmethyl, etc.); formyl, halogen
(Eg chlorine, bromine, fluorine, etc.), C_1-6Alkyl (eg,
Methyl, ethyl, n-propyl, etc.), C_6-10Aryl
(Eg, phenyl, naphthyl, etc.), C_7-12Aralkyl
(Eg benzyl, phenylethyl etc.) and nitro etc.
C optionally having 1 to 3 substituents
_1-6Alkyl-carbonyl (eg, acetyl, propioni
Etc.); halogen (eg chlorine, bromine, fluorine etc.), C
_1-6Alkyl (eg, methyl, ethyl, n-propyl
Etc.), C_6-10Aryl (eg, phenyl, naphthyl, etc.),
C_7-12Aralkyl (eg, benzyl, phenylethyl, etc.)
And 1 to 4 substituents selected from nitro and the like
May be C_6-10Aryloxy-carbonyl (eg,
Phenyloxycarbonyl, naphthyloxycarbonyl
Etc.); halogen (eg, chlorine, bromine, fluorine, etc.), C_1-6
Alkyl (eg, methyl, ethyl, n-propyl, etc.), C
_6-10Aryl (eg, phenyl, naphthyl, etc.), C_7-12A
Ralalkyl (eg, benzyl, phenylethyl, etc.) and nit
Even if it has 1 to 4 substituents selected from
Good C_6-10Aryl-carbonyl (eg, benzoyl, na
Futylcarbonyl, etc.); halogen (eg chlorine, bromine, fluorine)
C, etc., C_1-6Alkyl (eg, methyl, ethyl, n-
Propyl), C_6-10Aryl (eg, phenyl, naphthi
Le), C_7-12Aralkyl (eg benzyl, phenyle
1 to 4 substituents selected from til etc.) and nitro etc.
C optionally having a group_7-12Aralkyl-carbonyl
(Eg benzylcarbonyl, phenethylcarbonyl
Etc.); halogen (eg, chlorine, bromine, fluorine, etc.), C_1-6
Alkyl (eg, methyl, ethyl, n-propyl, etc.), C
_6-10Aryl (eg, phenyl, naphthyl, etc.), C_7-12A
Ralalkyl (eg, benzyl, phenylethyl, etc.) and nit
Even if it has 1 to 4 substituents selected from
Good pyranyl or furanyl, tri (C_1-4Alkyl)
Silyl (eg, trimethylsilyl, triethylsilyl, etc.)
Are used. The group via the sulfur atom is as defined above.
Have righteousness.

The hydrocarbon residue in the carbonyl group optionally substituted by an optionally substituted hydrocarbon residue represented by R ⁴ is, for example, a saturated or unsaturated hydrocarbon residue having up to 25 carbon atoms. Groups. Preferred specific examples include, for example, alkyl (eg, methyl, ethyl,
C _1-8 alkyl such as propyl, isopropyl, butyl, t-butyl, pentyl and hexyl), cycloalkyl (eg C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclohexyl), alkoxyalkyl (eg methoxymethyl) , Ethoxymethyl, ethoxybutyl, propoxyhexyl, etc., C _1-3 alkoxy C _1-6 alkyl), alkenyl (eg, vinyl, butenyl, butadienyl, hexatrienyl, etc. C _2-6 alkenyl), aryl (eg, phenyl) , Naphthyl, anthracenyl, etc. C
_6-14 aryl), aralkyl (eg, C _7-20 aralkyl such as benzyl, benzhydryl, trityl, etc.) and the like. The substituent has the same meaning as the substituent in the group via the carbon atom.

^One of R ¹ and R ² has the general formula R ^c- (CH ₂ ) m- [wherein R ^c is a group through a nitrogen atom which may be substituted, and m is an integer of 0 to 3]. a group represented by the shown] and the other in the general formula R ^d -A- [wherein the R ^d is optionally substituted phenyl group, a
Represents an intervening group].
The group represented by R ^c via an optionally substituted nitrogen atom has the same meaning as described above.

The substituent in the optionally substituted phenyl group represented by R ^d is, for example, halogen (fluorine, chlorine, bromine, iodine), halogen (fluorine,
C _1-8 alkyl _optionally substituted by 1 to 3 with chlorine, bromine, iodine (eg, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, ter
t-butyl, pentyl, isopentyl, neopentyl, etc.), and C _1-8 alkoxy optionally substituted by 1 to 3 halogens (fluorine, chlorine, bromine, iodine) (eg,
Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, etc.), halogen (fluorine, chlorine,
C optionally substituted by 1 to 3 bromine, iodine)
_1-8 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, etc.), C
_1-6 aralkyloxy (eg, formyloxy, acetoxy, propionyloxy, etc.), hydroxyl, carboxyl, C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), cyano, nitro, amide , Mono- or di-C _1-6
Examples thereof include alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, etc.). The number of substitutions is 1 to 5, preferably 1 to 3
It is.

Examples of the intervening group represented by A include C _1-4 alkylene (eg, methylene, ethylene, etc.), C _1-6
Alkenylene (eg, vinylene, butadienylene, etc.),-
A group represented by (CH ₂ ) cNR ^e- [wherein c represents an integer of 0 to 3 and R ^e represents hydrogen or C _1-6 alkyl (eg, methyl, ethyl, butyl, etc.)], CO-, -CONR ^a
A group represented by-(in the formula, R ^a has the same meaning as described above), -O-, -S-, -NR ^a S (O) e- (in the formula, e is an integer of 0 to 2) And R ^a has the same meaning as described above).

R ³ is a general formula

Embedded image [Wherein R ^f is hydrogen, halogen, or a group through a carbon, nitrogen, oxygen, or sulfur atom, and R ^g is hydrogen, halogen, nitro, cyano, or is substituted through an oxygen, nitrogen, or sulfur atom. It represents a good aliphatic hydrocarbon residue]. The optionally substituted carbon, nitrogen, oxygen or sulfur atom-containing group represented by R ^f has the same meaning as R ¹ .

The aliphatic hydrocarbon residue which may be substituted in the aliphatic hydrocarbon residue which may be substituted through an oxygen, nitrogen or sulfur atom represented by R ^g is, for example, C _{1 -15} alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s
-Butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, etc.), C
_3-8 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _2-10 alkenyl (eg, vinyl, allyl, 2-methylallyl, 2-
Butenyl, 3-butenyl, 3-octenyl, etc.), C _2-10
Examples include alkynyl (eg, ethynyl, 2-propynyl, 3-hexynyl, etc.) and C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, etc.). Examples of the substituent which the hydrocarbon group may have include, for example, nitro, hydroxyl, oxo, thioxo, cyano, carbamoyl, carboxyl, C _1-4 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.),
Sulfo, halogen (fluorine, chlorine, bromine, iodine), C
_1-4 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, etc.), C _1-4 alkylthio (eg, methylthio, ethylthio, n-propylthio, isopropylthio, n) -Butylthio, t-butylthio, etc.), amino, C _1-6 alkanoylamino (eg, acetylamino,
Propionylamino, etc.), mono- or di-C _1-4 alkylamino (eg, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, dimethylamino, diethylamino, etc.), C _1-4 alkanoyl (Eg, formyl, acetyl, propionyl, etc.), (a) halogen (eg, fluorine, chlorine, bromine, iodine); (b) C _1-4 alkyl (eg, methyl, ethyl, propyl, isopropyl, etc.), etc. It may have 1 to 4 selected substituents, for example, 2- or 3-thienyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5- Thiazolyl, 3-, 4-
Or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2
-, 4- or 5-imidazolyl, 1,2,3- or 1,2,4-triazolyl, 1H or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidyl, In addition to carbon atoms such as 3- or 4-pyridanidyl, quinolyl, isoquinolyl, and indolyl, 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen, etc.
5 or 6-membered heterocyclic groups containing C _1-6 haloalkyl (eg, difluoromethyl, trifluoromethyl, trifluoroethyl, trichloroethyl, etc.) and the like. The number of substitutions is 1-4, preferably 1-3.

In the compound (II), R ⁶ , R ⁷ and R
Examples of the alkyl group represented by ¹⁰ include those having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl and the like,
Of these, those having 1 to 3 carbon atoms are preferable. Examples of the aryl group in Q and the optionally substituted aryl group represented by R ⁷ and R ⁹ include a monocyclic or condensed polycyclic aromatic hydrocarbon group. Preferred specific examples include C such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like.
_6-14 aryl groups and the like, among which phenyl, 1
-Naphthyl, 2-naphthyl and the like are preferable.

The number of substitutions on the aryl group is 1 or more, preferably 1 to 3. Examples of the substituent include an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.) (the alkyl group may be substituted with alkyl-carbonyl or alkoxy-carbonyl). ), An alkenyl group substituted with an alkylacyl group or an alkoxycarbonyl group having 2 to 4 carbon atoms (eg, vinyl group, allyl, 2-butenyl, etc.), an alkynyl group having 3 to 4 carbon atoms (eg, propargyl, 2 -Butynyl, etc.), cycloalkyl groups having 3 to 7 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _6-14 aryl groups (eg,
Phenyl, naphthyl, etc. The aryl group has a substituent such as halogen, alkyl, alkoxy, or a group of formula —S (O) n.
It may have a group represented by —R ¹¹ (in the formula, n is an integer of 0 to 2 and R ¹¹ is alkyl or amino), or nitro or cyano. ), A heterocyclic group [eg, a 5- to 9-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom (eg, furyl, thienyl, pyrrolyl, thiazolyl, Imidazolyl,
Pyrazolyl, pyridyl, etc.), a 5- to 9-membered non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom (eg, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl) , Tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.). The heterocyclic group may have halogen or lower alkyl as a substituent. ], An aralkyl group having 7 to 10 carbon atoms (eg, benzyl, phenylethyl, etc.), a formula

Embedded image [In the formula, R ¹² is hydrogen, C _1-6 alkyl _optionally substituted with hydroxy, C _1-6 alkyl-carbonyl, C _1-3
Alkoxy-C _1-3 alkyl-carbonyl, formyl,
Benzoyl, C _{3-6 optionally} substituted with hydroxy
Indicates cycloalkyl. R ¹³ represents hydrogen or C _1-6 alkyl. ], Amidino group, acyl group (for example, acetyl, propionyl, butyryl, etc., having 1 to 8 carbon atoms)
Alkylcarbonyl groups, for example benzoyl, etc., having 6 to 14 carbon atoms, arylcarbonyl groups, for example, methoxycarbonyl, ethoxycarbonyl, etc., having 7 to 8 carbon atoms
Aralkylcarbonyl groups), carbamoyl groups,
N-monosubstituted carbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, and other alkylcarbamoyl groups having 1 to 6 carbon atoms), N, N-disubstituted carbamoyl group (eg, dimethylcarbamoyl, diethylcarbamoyl, etc.) , N-, substituted with an alkyl group having 1 to 6 carbon atoms
Di-substituted carbamoyl group), sulfamoyl group, N-
Mono-substituted sulfamoyl group (for example, N-alkylsulfamoyl group having an alkyl group having 1 to 6 carbon atoms such as methylsulfamoyl, ethylsulfamoyl, propylsulfamoyl group), N, N-disubstituted Sulfamoyl group (eg, N, N-disubstituted sulfamoyl group substituted with an alkyl group having 1 to 6 carbon atoms such as dimethylsulfamoyl and diethylsulfamoyl), carboxyl group, alkoxycarbonyl having 1 to 3 carbon atoms Group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), hydroxyl group, substituent (eg, alkyl-carbonyl group having 2 to 4 carbon atoms, alkyl group having 1 to 3 carbon atoms, halogen, alkylthio having 1 to 3 carbon atoms, Alkoxy group having 1 to 3 carbon atoms (eg, methoxy), which may have alkoxy group having 1 to 3 carbon atoms, hydroxyl group, etc. Ethoxy, propoxy), alkenyloxy group having 2 to 4 carbon atoms (e.g., vinyloxy,
Allyloxy, etc.), cycloalkyloxy groups (eg, cyclopropyloxy, cycloethyloxy, etc., aralkyloxy groups having 3 to 7 carbon atoms), aralkyloxy groups (eg, benzyloxy, etc., aralkyloxy groups having 7 to 10 carbon atoms) Etc.), aryloxy groups (eg, phenyloxy, naphthyloxy, etc.), mercapto groups,
An alkylthio group having 1 to 3 carbon atoms (eg, methylthio, ethylthio, propylthio, etc.), an aralkylthio group (eg, an aralkylthio group having 7 to 10 carbon atoms such as benzylthio), an arylthio group (eg, phenylthio, naphthylthio, etc.), An alkylsulfinyl group having 1 to 3 carbon atoms (eg, methylsulfinyl, ethylsulfinyl,
Propylsulfinyl), an alkylsulfonyl group having 1 to 3 carbon atoms (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.), a lower alkylenedioxy having 1 to 3 carbon atoms (eg, methylenedioxy, ethylenedioxy, propylene) Dioxy, etc.), sulfo group, cyano group, azido group, nitro group, nitroso group, halogen (eg,
Fluorine, chlorine, bromine, iodine) and the like.

The alkyl in the above definition of the group is preferably an alkyl having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, Examples thereof include pentyl, isopentyl, neopentyl, hexyl and the like, and among them, those having 1 to 3 carbon atoms are preferable. As the acyl in the definition of the above group, alkylcarbonyl is preferable, and as the “alkyl”, the same as those mentioned above can be mentioned. The alkoxy in the definition of the above group is preferably one having 1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy,
Examples thereof include isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, and hexyloxy. Of these, those having 1 to 3 carbon atoms are preferable.

The cycloalkyl group in the optionally substituted cycloalkyl group represented by R ⁶ and R ⁷ is, for example, a cycloalkyl group having 3 to 10 carbon atoms or a bicycloalkyl group having 3 to 10 carbon atoms. Is mentioned. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2,2,1] heptyl, bicyclo [2,2,2] octyl, bicyclo [3.
2,1] octyl, bicyclo [3,2,1] nonyl, bicyclo [4,2,1] nonyl, bicyclo [4,3,1]
Decyl and the like. Among them, cyclopentyl,
Cyclohexyl is preferred. Examples of the substituent of the cycloalkyl group include the same as the above-mentioned substituents in the aryl group represented by R ⁷ .

The heterocyclic group in the optionally substituted heterocyclic group represented by R ⁶ includes, for example, oxygen (O), sulfur (S), and nitrogen (ring atoms) as ring-constituting atoms (ring atoms). Examples thereof include a 5- to 13-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from N), a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group), and the like. Preferred examples of the aromatic heterocyclic group include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
Imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl, 1,
2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,
Aromatic monocyclic heterocyclic groups such as 2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl; for example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, Indolyl, isoindolyl, 1H-
Indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl , Purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl , Pyrazolo [1,5-a]
Pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-
Examples thereof include aromatic condensed heterocyclic groups such as triazolo [4,3-a] pyridyl and 1,2,4-triazolo [4,3-b] pyridazinyl.

Preferred examples of the above non-aromatic heterocyclic group include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. Further, the heterocyclic group may have one or more, preferably 1 to 3 appropriate substituents, and the substituents are the same as the above-mentioned substituents in the optionally substituted aryl group. Is mentioned.

Examples of the substituent in the optionally substituted alkyl group represented by R ⁷ include the same as the above-mentioned substituents in the aryl group. Examples of the aralkyl group in the optionally substituted aralkyl group represented by R ⁷ include an aryl-alkyl group. The aryl has the same meaning as the aryl group in the optionally substituted aryl group represented by R ⁷ . Examples of the alkyl include C _1-6 such as methyl, ethyl, propyl, butyl, pentyl and hexyl.
And an alkyl group. Examples of the substituent are the same as those of the optionally substituted aryl group represented by R ⁷ .

The halogen represented by Q is fluorine,
Examples include chlorine, bromine, and iodine. Examples of the substituent of the carboxyl group which may have a substituent in Q include alkyl, cycloalkyl, aryl, aralkyl, and heterocyclic groups, which have the same meanings as described above. Examples of the alkylenedioxy in Q include C _1-6 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, propylenedioxy, 2,2-
Dimethylmethylenedioxy).

The intervening group represented by A is, for example, C
_1-4 alkylene (eg, methylene, ethylene, etc.), C _1-6 alkenylene (eg, vinylene, butadienylene, etc.), −
(CH ₂ ) aNR ¹⁴ — [In the formula, a is an integer of 0 to 3, R ¹⁴
_Represents hydrogen or C _1-6 alkyl (specific examples are the same as those mentioned above), —CO—, —C
ONR ¹⁵ - wherein, R ¹⁵ is hydrogen, C _1-6 alkyl (. Specific examples of the indicating those similar to the), C _3-6 cycloalkyl (example shows the same as the ), C _6-14
A group represented by aryl (specific examples are the same as those described above) and a heterocyclic group (specific examples are the same as those described above), -S (O) p- (p is Indicates an integer of 0 to 2.)
A group represented ^{by, -O -, - NR 15 S} (O) e- ( wherein, e
Represents an integer of 0 to 2, and R ¹⁵ has the same meaning as above)
And the like.

The optionally substituted amino group represented by R ⁸ is, for example, one represented by the formula:

Embedded image (In the formula, R ¹⁶ represents an alkyl group, a cycloalkyl group, an aryl group or a heterocyclic group which may be substituted,
¹⁷ represents hydrogen or an optionally substituted alkyl group. r
Represents an integer of 0 to 3. And a group represented by), hexamethylenetetraamino. The optionally substituted alkyl group, the optionally substituted cycloalkyl group, the optionally substituted aryl group, and the optionally substituted heterocyclic group have the same meanings as described above.

In the compound (II), preferred examples of R ⁶ include, for example, hydrogen or formula-(CH ₂ ) pQ '[wherein Q'is halogen, nitro, cyano, amino or formula -A'-R. ¹⁰ '(wherein A'is -O- or -S-, R
¹⁰ 'represents an aryl group which may be substituted with a group represented by). and p has the same meaning as defined above. Preferable examples of R ^7, for example, (1) C _1-3 alkoxy or C _6-14 aryl optionally substituted by a C _1-6 alkyl group, (2) amino, acyl, carbamoyl, carboxy, nitro , Hydroxy, C _1-3 alkoxy, formula —S (O) n—R
¹⁸ (in the formula, n is an integer of 0 to 2 and R ¹⁸ is C _1-3 alkyl), an aryl group optionally substituted with sulfo or halogen, (3) C _{3 -10} cycloalkyl groups.

Preferred examples of the substituent in the optionally substituted amino group represented by R ⁸ include, for example,
formula

Embedded image [Wherein R ¹⁶ 'is (1) alkyl, (2) halogen, nitro,
Alkyl or the formula -S (O) m-R ¹⁹ (wherein, m is 0 to
An integer of 2 and R ¹⁹ represents alkyl or amino. Represents a phenyl optionally substituted by a group represented by (4), (3) a heterocyclic group optionally substituted by halogen or alkyl, and (4) N-monosubstituted lower alkylcarbamoyl. R ¹⁷ 'represents hydrogen or an alkyl group. ] The group represented by these, or hexamethylene tetraammonium is mentioned.

A preferable example of aryl in the optionally substituted aryl group represented by R ⁹ is phenyl. Preferred examples of the substituents include amino, acyl, carbamoyl, N-monosubstituted alkylcarbamoyl, carboxy, nitro, hydroxy, C _1-3 alkoxy optionally substituted by C _1-3 alkoxy, and a formula

Embedded image (In the formula, R ¹² ′ represents C _1-6 alkyl, C _1-3 alkoxy optionally substituted by C _1-3 alkoxy, formyl, and R ¹³ ′ represents hydrogen, C _1-6 alkyl. And a C _2-4 alkenyl group substituted with a lower alkoxycarbonyl or a lower alkylcarbonyl. In any of the above cases, the number of substituents is from 1 to
Three is preferable. r preferably represents 1.

In the compound (II), R ⁶ is more preferably, for example, halogen or the formula —A ″ —R ¹⁰ ″.
(In the formula, A ″ is —O— or —S— and R ¹⁰ ″ is alkyl) is an aryl group which may be substituted. R ⁷ is more preferably, for example, (1) C
_1-3 alkoxy or C _1-6 alkyl group optionally substituted by C _6-14 aryl, (2) C _1-3 alkoxy or formula —S (O) n—R ¹⁸ (wherein n is 0 ~ 2 is an integer
¹⁸ represents C _1-3 alkyl. (3) C _3-10 cycloalkyl group, which may be substituted with a group represented by (4).

R ⁸ is more preferably, for example, of the formula

Embedded image [In the formula, R ¹⁶ ″ is the formula —S (O) m—R ¹⁹ ′ (where m is 0.
An integer of ˜2 and R ¹⁹ ′ represents alkyl. ) Represents phenyl or pyridyl which may be substituted with a group represented by. R ¹⁷ ″ represents hydrogen or an alkyl group.] More preferred examples of the aryl in the optionally substituted aryl group represented by R ⁹ include phenyl. More preferred examples are amino, acyl, N-monosubstituted alkylcarbamoyl, nitro, C _1-3 alkoxy optionally substituted by C _1-3 alkoxy, and a formula

Embedded image (Wherein, R ¹² "is C _1-6 alkyl, C _1-3 acyl optionally substituted with alkoxy, C _1-4 acyl with optionally substituted C _1-3 alkoxy, benzoyl, formyl R ¹³ ″ represents hydrogen or C _1-6 alkyl), and a C _2-4 alkenyl group substituted with lower alkoxycarbonyl or lower alkylcarbonyl.

The compound (I) can be easily produced by a method known per se. Examples of the method include WO 95/2
The method described in Japanese Patent No. 8405 may be used. The salt of compound (I) is preferably a physiologically acceptable acid addition salt. Such salts include, for example, inorganic acids (eg,
With hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.),
Or organic acids (eg formic acid, acetic acid, trifluoroacetic acid,
Fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and salts thereof are used. Further, when the compound of the present invention has an acidic group such as —COOH, the compound of the present invention is an inorganic base (eg, an alkali metal salt such as sodium, potassium, calcium, magnesium or an alkaline earth metal, ammonia, etc.). Or an organic base (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, etc.).

The compound (II) can be produced, for example, by the method shown below. A urea derivative (iii) is produced from the 2-aminothiophene derivative (i), for example, by the following method A or B. 1. Method A: A suitable ketone or aldehyde (i) having an active methylene group is added by the method of Karl Gevaert et al. [KG
ewald, E.Schinke and H.Bφttcher, Chem. Ber., 99 ,
94-100 (1966)], the cyanoacetic acid ester derivative is reacted with sulfur to convert it into a 2-aminothiophene derivative (ii). That is, in the case of a ketone (R ⁸ ′ ≠ H), it is heated under reflux in the presence of acetic acid and ammonium acetate in a cyanoacetic acid ester derivative and a suitable solvent, for example, toluene to once give an alkylidene cyanoacetic acid ester derivative, and then sulfur. By heating in the presence of a base and a suitable solvent such as ethanol, a 2-aminothiophene derivative (ii) is obtained. In the case of aldehyde (R ⁸ ′ = H), the 2-aminothiophene derivative (ii) is obtained by heating in the presence of a cyanoacetic acid ester derivative, sulfur and a base in a suitable solvent such as dimethylformamide. See [Equation 1].

[Equation 1] The 2-aminothiophene derivative (ii) produced by the above method or a salt thereof is reacted with an isocyanate derivative. The isocyanate derivative has, for example, the formula R ⁷ -N
Examples thereof include derivatives represented by CO (in the formula, R ⁷ has the same meaning as described above). The reaction of the compound (ii) and a salt thereof with an isocyanate derivative is carried out in a solvent that does not adversely influence the reaction (eg, tetrahydrofuran, pyridine, dioxane, benzene, dichloromethane, 1,2-dichloroethane, toluene, xylene) in about 15 ~ 130 ℃
Done in The isocyanate derivative is the compound (ii) 1
About 1 to 5 equivalents, preferably about 1.1 to 2.5, relative to equivalents
Use equivalents. The reaction time ranges from a few minutes to several days, preferably from about 15 minutes to about 2 days.

2. Method B: produced by reacting a 2-aminothiophene derivative (ii) or a salt thereof with phosgene or its equivalent [eg, diphosgene such as bis (trichloromethyl) carbonate, triphosgene such as trichloromethylchloroformate] An amine [eg, a compound represented by the formula R ⁷ —NH ₂ (wherein R ⁷ has the same meaning as described above)] is added to the isocyanate derivative. The reaction of the compound (ii) or a salt thereof with phosgene or an equivalent thereof is carried out in a solvent which does not adversely influence the reaction (eg, dioxane, tetrahydrofuran, benzene, toluene, xylene, 1,2-dichloroethane, chloroform) in about 40%. It is carried out at ~ 120 ° C. Phosgene or an equivalent thereof is about 0.1 for 1 equivalent of the compound (ii).
5 to 2 equivalents, preferably about 0.9 to 1.1 equivalents are used.
The reaction time is a few minutes to a few days, preferably about 15 minutes to about 2
Day. The amine addition reaction is carried out in a solvent that does not adversely influence the reaction (eg, pyridine, tetrahydrofuran, dioxane, benzene, dichloromethane, 1,2-dichloroethane, toluene, xylene) at about 15 to 130 ° C. The amine is about 1 to 1 equivalent of the compound (ii).
5 equivalents, preferably about 1.1 to 3 equivalents, are used. The reaction time ranges from a few minutes to several days, preferably from about 15 minutes to about 2 days.

The obtained compound (iii) or its salt is
The ring closure reaction is carried out by treating with a base to obtain a thieno [2,3-d] pyrimidine derivative (iv). The ring closure reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include alcohols such as methanol, ethanol and isopropanol, and ethers such as dioxane and tetrahydrofuran. As the base, for example, alkali metal alkoxides such as sodium methylate, sodium ethylate, and sodium isopropoxide, and alkali metal hydrides such as sodium hydride are used. The amount of base used is about 1.1-5 equivalents, preferably about 1.5-3 equivalents, relative to 1 equivalent of compound (iii). The reaction temperature is about 10 ° C to the boiling point of the working solvent, preferably about 25 ° C to the boiling point of the working solvent. The reaction time is a few minutes to a few days, preferably about 10 minutes to 2 days.

In the presence of a compound (iv) and a halogenated aralkyl derivative in the presence of a base (eg, an organic base such as pyridine or triethylamine), a solvent (eg, an organic base such as pyridine or triethylamine) which does not adversely affect the reaction.
(2,4-dioxothieno [2,3-d] pyrimidine derivative (IIa) by stirring in amides such as dimethylformamide and dimethylacetamide) at about 10 to 100 ° C. Then, the compound (IIa) is subjected to N-bromo in a solvent that does not adversely influence the reaction (eg, halogenated hydrocarbons such as carbon tetrachloride and chloroform) in the presence of α, α′-azobisisobutyronitrile. About 3 with succinimide (NBS)
Stir at 0-100 ° C to obtain compound (IIb). Furthermore, in the presence of a base (eg, a tertiary organic amine (eg, triethylamine, diisopropylamine)), the compound (IIb) is reacted with various amines (eg, R ³ —H) in a solvent that does not adversely affect the reaction (eg, Amides such as dimethylformamide, dimethylacetamide, nitriles such as acetonitrile, alcohols such as ethanol) in about 10 to 100
Compound (II ′) is produced by stirring at 0.5 ° C. for 0.5 to 8 hours. If necessary, the compound is salified with a suitable acid (eg, hydrochloric acid, oxalic acid).

The above manufacturing method is shown in [Equation 2].

[Equation 2] In the formula of [Formula 2], each symbol has the same meaning as described above. R ²⁰
And R ²¹ represent a substituent of the aryl group, and X represents a leaving group. Examples of the leaving group represented by X include a nucleophile [eg,
Negatively charged heteroatoms (eg oxygen, sulfur,
A hydrocarbon residue having a nitrogen atom or the like), which can easily undergo a substitution reaction. In particular,
For example, halogen atom (iodine, bromine, chlorine, etc.), alkanoyloxy (eg, acetoxy), alkylsulfonyloxy (eg, methanesulfonyloxy, etc.), alkyl-
Arylsulfonyloxy (eg, p-toluenesulfonyloxy and the like) and the like.

The salt of compound (II) thus obtained is preferably a physiologically acceptable acid addition salt.
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.). For example, salts with acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. are used. Further, when the compound (II) has an acidic group such as —COOH, an inorganic base (eg, an alkali metal salt such as sodium, potassium, calcium, magnesium or an alkaline earth metal, ammonia etc.) or an organic base (eg. Examples: trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,
(N, N′-dibenzylethylenediamine, etc.) to form a salt. The thus-obtained compound (II) or a salt thereof can be isolated and purified by a usual separation means such as recrystallization, distillation and chromatography. When compound (II) is obtained in a free form, it can be converted into a salt by a method known per se or a method analogous thereto, and conversely, when it is obtained as a salt, a method known per se or a method similar thereto Depending on the method, it can be converted into an educt or other salt. When compound (II) or a salt thereof is an optically active substance, it can be converted into the d-form, l-form by a usual optical resolution means.
Can be separated into the body.

In the composition of the present invention, a branched cyclodextrin-carboxylic acid is added together with a water-insoluble or sparingly soluble non-peptide LH-RH antagonist as an active ingredient to improve its water solubility. The term "water-insoluble or sparingly soluble" as used herein means that the solubility in water at room temperature is about 1 mg / ml or less. Specific examples of the water-insoluble or sparingly soluble non-peptide LH-RH antagonist used include:
For example, the above compounds 1, 2, C and 3 and the like can be mentioned.

In the present invention, the mixing ratio of the branched cyclodextrin-carboxylic acid and the non-peptide LH-RH antagonist is not particularly limited and can be selected from a wide range, but the water solubility of these substances can be selected. Considering this, the branched cyclodextrin-carboxylic acid is contained in an amount of 0.1 to 20 mol, preferably 0.1 to 10, more preferably 0.2 to 5 mol, and particularly preferably 1 mol of the non-peptide LH-RH antagonist. Preferably, it is mixed in the range of 1 to 3 mol.

The composition of the present invention can be produced by a known method by mixing the branched cyclodextrin-carboxylic acid with the desired non-peptide LH-RH antagonist. The composition of the branched cyclodextrin-carboxylic acid and the substance can be prepared, for example, by the following four methods. (1) Coprecipitation method [Crassons et al., No. 5
Annual Conference of Pharmaceutical Technology (5th lnt. Conf. Pharmaceutical Te
chnology), Paris, 30 May 1989-6
Month 1], (2) Freeze-drying or spray-drying method [Kurozumi et al., Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), 23, 3]
062 (1975); Kata et al., Pharmasy (P
harmazie) 39,856 (1984)], (3) Phase-solution diagram crystallization method [Uekama et al., International Journal of Pharmaceuticals (In.
t. J. Pharmac. 10, 1 (1982)], (4) Kneading method [J. Szejtli et al., “Cyclodextrin and its inclusion complex (Cyclodextrins an
d their inclusion complexes) ", Akadeimial Kiado, Budapest
est) (1982), P. 109-114; Kyowa Ja
p. Prov. Pat. Pubin. No. 106 698 (198
2)].

More specifically, (1) the desired antagonist is added to an aqueous solution of branched cyclodextrin-carboxylic acid (hereinafter, simply referred to as CD-carboxylic acid), and the mixture is heated if necessary. Stirring
(Shake). The composition is obtained by removing the remaining unreacted antagonist by filtration, centrifugation, or the like. (2) A method in which CD-carboxylic acid is dissolved in water, the target antagonist is added thereto, mixed for 10 minutes to several hours, and then freeze-dried [M. Kurozumi]
Chem. Pharm. Bull., 23,142 (197).
5)] to obtain powder. When this is dissolved in water and the unreacted antagonist is removed, an aqueous solution of the composition is obtained. (3) The antagonist is dissolved in a suitable water-compatible organic solvent in advance, and this is brought into contact with the CD-carboxylic acid in the aqueous solution, and then the organic solvent and water are distilled off under vacuum or freeze-dried. [EP-A-5194428, JP-A 5
-178765 (JP-A-5-178765)],
Water is added to the residue to dissolve it, and unreacted antagonist is removed to obtain an aqueous solution of the composition. (4) Acidic antagonists are dissolved in aqueous ammonia, added with CD-carboxylic acid, and lyophilized. Excess ammonia is removed in the process of lyophilization, and a composition of the ammonium salt of the antagonist is obtained. (5) An antagonist is dissolved in a lipophilic organic solvent (eg, ethyl ether), mixed with a saturated aqueous solution of CD-carboxylic acid, shaken vigorously for 10 minutes to several hours, and then allowed to stand in a cool place overnight. Then, the composition is deposited and then separated by centrifugation and filtration. The obtained powder is dissolved in water to obtain an aqueous solution of the composition. (6) Both powders of the antagonist and CD-carboxylic acid are mixed, and a small amount of water is added thereto and kneaded [Wai Nakai (Y.
Nakai) et al., Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), 26, 241.
9 (1978), or thereafter freeze-dried. (7) Regarding the antagonist, an aqueous solution of the inclusion compound is obtained by mixing the aqueous solution of CD-carboxylic acid and the aqueous solution of the antagonist. Among the above methods (1) to (7), the above method (3) is particularly effective for solubilizing the non-peptide LH-RH antagonist.

The composition or the aqueous solution of the composition thus obtained according to the known method is often an inclusion body or forms a complex by electrostatic or hydrophobic interaction or hydrogen bond. Is forming. Therefore, in the present specification, the composition is not only the clathrate, the complex itself,
It also means a mixture of inclusion complex, complex, free inclusion compound and / or free CD-carboxylic acid. That is, the obtained powder and aqueous solution may contain a water-insoluble or sparingly soluble compound and / or free CD-carboxylic acid, which is an uninclusion body or an uncomplex, in addition to the inclusion complex and the complex. Such powders and aqueous solutions, including the contact bodies themselves, are extremely water-soluble and have the property of being instantly soluble in water.

The composition of the present invention has LH-RH antagonism and has low toxicity, so that it can be used in warm-blooded mammals (for example, human,
In monkeys, cows, horses, dogs, cats, rabbits, rats, mice, etc.), by suppressing the secretion of gonadotropins by LH-RH receptor antagonism and controlling the concentration of sex hormones in the blood, Alternatively, it can be safely used for the prevention / treatment of female hormone-dependent diseases and the treatment of diseases caused by excess of these hormones. That is, the composition of the present invention comprises prostate cancer, benign prostatic hyperplasia, endometriosis, uterine fibroids, uterine fibroids, precocious puberty, breast cancer,
Bladder cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, gastritis, Hodgkin's disease, malignant melanoma, metastasis, multiple myeloma, non-Hodgkin's lymphoma, non-small cell lung cancer, ovarian cancer, digestion Ulcer, systemic fungal infection, small cell lung cancer, valvular heart disease, mastopathy, polycystic ovary, infertility, proper ovulation induction in women with chronic anovulation, acne, amenorrhea (eg, secondary Amenorrhea), ovarian and breast cystic disease (including polycystic ovary), gynecologic cancer, ovarian hyperandrogenemia and hirsutism, AIDS due to T cell production through thymogenic It is effective for treatment of hormone-dependent diseases and contraception, reduction of symptoms of premenstrual syndrome (PMS), and male contraception for treatment of in vitro fertilization (IVF) male offenders. Furthermore, the composition of the present invention is useful in the field of animal husbandry for controlling estrus of animals, improving meat quality for meat, and promoting animal growth. The composition of the present invention is also useful as a fish spawning promoter. The composition of the present invention can be used alone, but it is also effective to use it in combination with a steroidal or nonsteroidal antiandrogen or antiestrogen. Further, the composition of the present invention can be used for suppressing the transient increase in blood testosterone concentration (flare phenomenon) which is observed upon administration of a hyperagonist such as leuprorelin acetate. Further, the composition of the present invention may be used in combination with a chemotherapeutic agent for cancer. Specific preferred examples of the combination include Ifosfamide, UTF, and adriamycin (Adr) for prostate cancer.
iamycin), Peplomycin, Cisplatin
A chemotherapeutic agent such as (Cisplatin) can be used in combination with the composition of the present invention. For breast cancer, cyclophospamide, 5-FU, UFT,
Methotrexate, Adriamycin (Adr
A chemotherapeutic agent such as iamycin), mitomycin C, or mitoxantrone can be used in combination with the composition of the present invention.

When the composition of the present invention is used as a prophylactic / therapeutic agent for the above-mentioned diseases or in the field of livestock or fisheries, either oral administration or parenteral administration is possible according to a method known per se, The aqueous solution or powder itself obtained as described above, or mixed with a pharmaceutically acceptable carrier, is usually orally administered as a solid preparation such as tablets, capsules, granules and powders, or intravenously or subcutaneously. , Parenteral administration such as injection, suppository or sublingual tablet intramuscularly. Further, it may be administered sublingually, subcutaneously, intramuscularly, etc. as a sustained release preparation such as sublingual tablets and microcapsules. The daily dose varies depending on the degree of symptoms; age, sex, weight, sensitivity difference of administration subject; timing of administration, interval, properties of pharmaceutical preparation, preparation, type; type of active ingredient, etc., but is not particularly limited. Usually a warm-blooded mammal 1k
About 0.01 to 500 mg, preferably about 0.1 to 100 m as a non-peptide LH-RH antagonist per g body weight.
g, more preferably about 1 to 100 mg, which is usually administered in 1 to 4 divided doses per day. When used in the field of livestock or fisheries, the dose is also based on the above, but about 0.1 to 500 mg, preferably about 1 to 200 mg, per 1 kg body weight of the subject organism is usually administered in 1 to 3 divided doses per day. . The above pharmaceutically acceptable carrier,
Various conventional organic or inorganic carrier substances are used as formulation materials, and excipients, lubricants, binders in solid formulations,
Disintegrant: It is added as a solvent, a solubilizing agent, a suspending agent, a tonicity agent, a buffering agent, a soothing agent, etc. in a liquid preparation. If necessary, formulation additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used.

Preferable examples of the above-mentioned excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose and light anhydrous silicic acid. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Preferred examples of the disintegrant include, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium,
And sodium carboxymethyl starch. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Suitable examples of the solubilizer include, for example, polyethylene glycol,
Examples include propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferred examples of the suspending agent include, for example, stearyltriethanolamine,
Surfactants such as sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxy And hydrophilic polymers such as propylcellulose. Preferable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-
Mannitol and the like. Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Preferred examples of the soothing agent include benzyl alcohol and the like. Preferable examples of the above preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the above antioxidant include sulfite, ascorbic acid and the like.

Suspending agents, solubilizing agents, stabilizing agents, isotonic agents, preservatives and the like are added to the composition of the present invention to prepare intravenous, subcutaneous and intramuscular injections by a method known per se. . At that time, if necessary, a freeze-dried product can be prepared by a method known per se. When the composition of the present invention is administered to, for example, a human, it is orally or parenterally safe as a pharmaceutical composition by mixing itself or with an appropriate pharmacologically acceptable carrier, excipient, or diluent. Can be administered to. Examples of the pharmaceutical composition include oral agents (eg, powders, granules, capsules, tablets), injections, drip infusions, external preparations (eg, nasal preparations, transdermal preparations, etc.), suppositories (eg, Rectal suppositories, vaginal suppositories) and the like. These preparations can be produced by a method known per se, which is generally used in the preparation process.

The composition of the present invention comprises a dispersant (eg, Tween 80 (Atlas Powder, USA), HOC 6).
0 (manufactured by Nikko Chemicals) polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.), preservative (eg, methylparaben, propylparaben, benzyl alcohol, etc.), tonicity agent (eg, sodium chloride, mannitol, sorbitol, glucose, etc.), etc. Aqueous injections, or soluble, suspended or emulsified in olive oil, sesame oil, cottonseed oil, corn oil or other vegetable oils, propylene glycol, etc., can be molded into oily injections to give injections.

To prepare a preparation for oral administration, the composition of the present invention can be prepared by a method known per se, for example, an excipient (eg, lactose,
Sucrose, starch, etc.), disintegrants (eg, starch, calcium carbonate, etc.), binders (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricants (eg, talc, stearin Magnesium oxide, polyethylene glycol 6000, etc.), and compression-molded, and if necessary, coated with a method known per se for the purpose of taste masking, enteric coating or long-lasting to obtain a preparation for oral administration. it can. Examples of the coating agent include hydroxypropyl methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, and Bluronic.
F 68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, copolymerization of methacrylic acid / acrylic acid) and coloring matter (eg, bengara, titanium dioxide, etc.)
Are used. In the case of an enteric-coated preparation, it is preferable to provide an intermediate phase between the enteric phase and the drug-containing phase by a method known per se for the purpose of separating both phases.

To prepare an external preparation, the composition of the present invention can be made into a solid, semi-solid or liquid external preparation according to a method known per se. For example, as the above solid, the composition of the present invention may be used as it is, or an excipient (eg, glycol, mannitol, starch, microcrystalline cellulose, etc.), a thickener (eg, natural gums, cellulose derivative, Acrylic acid polymer, etc.) is added and mixed to obtain a powdery composition. The liquid is almost the same as the injection, and is an oily or aqueous suspension. In the case of semi-solid, an aqueous or oily gel or ointment is preferred. In addition, these are all pH
Regulators (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoic acid esters, chlorobutanol, benzalkonium chloride, etc.) and the like may be added.

For example, in the case of a suppository, the composition of the present invention can be made into an oily or aqueous solid, semisolid or liquid suppository according to a method known per se. Examples of the oily base used in the above composition include glycerides of higher fatty acids [eg, cacao butter, witepsols (Dynamite Nobel, Germany), etc.], intermediate fatty acids [eg, miglyols (Dynamite Nobel, Germany) Etc.] or vegetable oil (eg, sesame oil, soybean oil, cottonseed oil, etc.) and the like. Examples of the aqueous base include polyethylene glycols, propylene glycol,
Examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers and the like.

[0062]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below with reference to Examples, Experimental Examples and Reference Examples, but these do not limit the present invention. ¹ H-NMR spectrum is using Varian GEMINI 200 (200 MHz) type spectrometer, using tetramethylsilane as an internal standard,
JEOL LAMBDA300 (300MHz) type spectrum meter or Brooker AM500 (500M
(Hz) type spectrometer and all δ values are shown in ppm. The symbols used in this specification have the following meanings. s: singlet, d: doublet, t: triplet, dt: double triplet, m: multiplet, br: wide range

[0063]

【Example】

Example 1 Compound 2 (19 mg) was dissolved in 10 ml of ethanol,
Separately from this solution, 6-O-cyclomaltoheptaosyl-
(6 → 1) -α-D-glucosyl- (4 → 1) -O-α-D
-Sodium glucuronate (β-CyD-G ₂ -COON
a) 41.5 mg was dissolved in 10 ml water. The aqueous solution was added to and mixed with the ethanol solution with stirring, and the mixture was stirred at room temperature for 3 hours.
The solvent was distilled off from the resulting solution under reduced pressure, and the residue was mixed with 10 ml of water.
And was filtered through a membrane filter (0.22 μm) (aqueous solution A). On the other hand, only compound 2 (2 mg) was added to 10 ml of water and shaken at room temperature for 3 hours, and then 0.2
It was filtered through a 2 μm membrane filter (aqueous solution B). Compound 2 in the above aqueous solution A and aqueous solution B is
It was quantified from the absorption intensity of the ultraviolet absorption spectrum (320 nm). The results of the dissolved concentration (as compound 2) are as follows. Comparative solubility of non-peptide LH-RH antagonists Compound 2 and β-CyD-G ₂ -COONa 2 0.5 mg / ml Compound 2 only 0.5 mg / ml Non-peptide LH-RH antagonists alone as described above In contrast, the addition of β-CyD-G ₂ -COONa resulted in an extremely high improvement in solubility.

Example 2 Compound 2 (300 mg) was dissolved in 10 ml of ethanol, and 6-O-cyclomaltoheptaosyl- (6 → 1) -α-D-glucosyl- (4 → 1) was dissolved separately from this solution. -O-α
-D-Glucuronate sodium (β-CyD-G ₂ -CO
622 mg of ONa) was dissolved in 10 ml of water. The aqueous solution was added to and mixed with the ethanol solution with stirring, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the resulting solution under reduced pressure, and the residue was treated with water 60
Dissolve in ml, and membrane filter (0.22μm)
After filtration, and vacuum freeze-drying, 770 mg of powder was obtained.
770 mg of the powder was completely dissolved in 15 ml of water. Also, β-C
The composition of the present invention consisting of yD-G ₂ -COONa and compound 2 gives a stable complex at room temperature, and compound 2
No decomposition was observed.

Example 3 Compound C (289 mg) was dissolved in 20 ml of methanol, and separately from this solution, 6-O-cyclomaltoheptaosyl- (6 → 1) -α-D-glucosyl- (4 → 1). -O-α
-D-Glucuronate sodium (β-CyD-G ₂ -CO
1866 mg of ONa) was dissolved in 20 ml of water. Compound C
An aqueous solution of β-CyD-G ₂ -COONa was added to and mixed with the methanol solution of 1 under stirring, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the resulting solution under reduced pressure, the residue was dissolved in 60 ml of water, filtered through a membrane filter (0.22 μm), and freeze-dried under vacuum to obtain 1820 mg of powder. The content of compound C was measured from the absorption intensity of the ultraviolet absorption spectrum (320 nm) of a 50% aqueous methanol solution of the obtained powder. As a result, the content of compound C was 15.6%.

Example 4 In the same manner as in Example 1, the dissolved concentrations of the composition of the present invention containing Compound C and Compound C alone were measured. The results of the dissolved concentration (as compound C) are as follows. Comparative solubility of non-peptide LH-RH antagonist Compound C and β-CyD-G ₂ -COONa 30.0 mg / ml Compound C only 0.9 mg / ml Non-peptide LH-RH antagonist alone as above In contrast, the addition of β-CyD-G ₂ -COONa resulted in an extremely high improvement in solubility.

Reference Example 1 Preparation of 2-amino-5-phenylthiophene-3-carboxylic acid ethyl ester: ethyl cyanoacetate (6.1 g, 5
0 mmol), sulfur (1.61 g, 50 mmol), triethylamine
(3.5 ml, 25 mmol), dimethylformamide (10 ml)
Phenylacetaldehyde (50% diethyl phthalate solution; 12.05 g, with stirring at 45 ° C.).
50 mmol) was added dropwise over 20 minutes. After stirring at 45 ° C. for 9 hours, the reaction solution was concentrated and the resulting residue was extracted with ethyl acetate. After the extract was washed with brine dried (MgSO _4),
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from ether-hexane to give pale yellow plate crystals (5.55 g, 45%). mp 124.5-125.5 ° C (literature value; 123-12
4 ° C). ¹ H-NMR (200MHz, CDCl ₃ ) δ: 1.37 (3H, t, J = 7.1Hz),
4.30 (2H, d, J = 7.1Hz), 5.97 (2H, br), 7.17-7.46 (6
H, m). IR (KBr): 3448, 3320, 1667, 1590, 1549 cm ^-1 .

Reference Example 2 2-amino-4-methyl-5- (4-methoxyphenyl)
Production of thiophene-3-carboxylic acid ethyl ester: 4
-Methoxyphenylacetone (16.5 g, 0.10 mol),
Ethyl cyanoacetate (12.2g, 0.10mol), ammonium acetate (1.55g, 20mmol), acetic acid (4.6ml, 80mmo
A mixture of l) and benzene (20 ml) was heated to reflux for 24 hours while removing water produced by the Dean Stark apparatus. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was partitioned between dichloromethane and aqueous sodium hydrogen carbonate. The organic layer was washed with brine and dried (M
After gSO ₄ ), the solvent was distilled off under reduced pressure. To the resulting residue in ethanol (30 ml) was added sulfur (3.21 g, 0.10 mol)
And diethylamine (10.4 ml, 0.10 mol) were added and 5
After stirring at 0 to 60 ° C. for 2 hours, the reaction solution was concentrated and the resulting residue was extracted with ethyl acetate. The extract was washed and dried with brine (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 pale yellow plate crystals (1
(1.5 g, 40%) was obtained. mp 79-80 ° C. ¹ H-NMR (200MHz, CDCl ₃ ) δ: 1.37 (3H, t, J = 7.1Hz),
2.28 (3H, s), 3.83 (3H, s), 4.31 (2H, q, J = 7.1Hz),
6.05 (2H, brs), 6.91 (2H, d, J = 8.8Hz), 7.27 (2H, d,
J = 8.8Hz). IR (KBr): 3426, 3328, 1651, 1586, 1550, 1505, 1485
cm ^-1 .FAB-MS m / z: 291 (M ⁺ ).

Reference Example 3 Preparation of 2-amino-4-methyl-5- (4-nitrophenyl) thiophene-3-carboxylic acid ethyl ester: 4-methoxyphenylacetone was prepared in the same manner as in Reference Example 2. Instead of 4-nitrophenylacetone (3
5.0 g, 195 mmol) were used and ethyl cyanoacetate (23.
8g, 195mmol), ammonium acetate (3.1g, 40mmo
l), acetic acid (9.1 ml, 159 mmol), sulfur (5.0 g, 160)
colorless crystals (22.2 g, 52%) from diethyl amine (16.0 ml, 160 mmol). mp 168-170 ° C (recrystallized from ether-hexane). ¹ H-NMR (200MHz, CDCl ₃ ) δ: 1.39 (3H, t, J = 7.1Hz),
2.40 (3H, s), 4.34 (2H, q, J = 7.1Hz), 6.27 (2H, br
s), 7.48 (2H, d, J = 8.7Hz), 8.23 (2H, d, J = 8.7Hz). IR (KBr): 3446, 3324, 1667, 1580, 1545, 1506, 149
1, 1475, 1410, 1332 cm ^-1 .

Reference Example 4 3-isobutyl-2,4 (1H, 3H) -dioxo-5-
Methyl-6- (4-methoxyphenyl) -thieno [2,
Preparation of 3-d] pyrimidine: isovaleric acid (1.15 ml,
10.03 mmol), diphenylphosphoryl azide (2.8
3g, 10.30mmol) triethylamine (1.45ml,
A solution of 10.03 mmol) in benzene (15 ml) was heated and stirred for 1 hour and a half to generate isobutyl isocyanate, and the compound synthesized in Reference Example 2 (2.00 g, 6.8 g).
5 mmol) and benzene (5 ml) were added and the mixture was heated under reflux for 4 days.
The reaction solution was partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate, The extract was 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 a white powder (2.64 g, 99%). The obtained urea derivative was made into a solution of ethanol (30 ml) and 28
% Sodium methoxide (3.93 g, 20.37 mmol)
Was added, the reaction mixture was stirred at room temperature for 16 hours, 1N hydrochloric acid (22 ml, 22 mmol) was added, and the ethanol solvent was evaporated under reduced pressure. The obtained residue was filtered, washed with water-ethanol, dried under reduced pressure, and recrystallized from ethanol to give white needle crystals (1.61 g, 70%). mp 215-216 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.96 (6H, d, J = 6.
8Hz), 2.20 (1H, sept, J = 6.8Hz), 2.50 (3H, s), 3.85-
3.87 (5H, m), 6.96 (2H, d, J = 8.8Hz), 7.33 (2H, d, J =
8.8Hz), 9.50 (1H, s). IR (KBr): 1711, 1657, 1537, 1499, 1458 cm ^-1 .

Reference Example 5 Preparation of 2,4 (1H) -dioxo-5-methyl-3- (3-methoxyphenyl) -6- (4-nitrophenyl) -thieno [2,3-d] pyrimidine: Reference The title compound was produced in the same manner as in Reference Example 4 using the compound obtained in Example 3 as a starting material. mp> 300 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.50 (3H, s), 3.78
(3H, s), 6.87 (1H, d, J = 8.1Hz), 6.92 (1H, s), 7.00 (1
H, d, J = 8.1Hz), 7.38 (1H, t, J = 8.1Hz), 7.77 (1H, d,
J = 8.7Hz), 8.31 (2H, d, J = 8.7Hz), 12.48 (1H, s). IR (KBr): 1717, 1661, 1593, 1510, 1429 cm ^-1 .

Reference Example 6 2-Amino-4-methyl-5- (4-methoxyphenyl)
Production of thiophene-3-carboxylic acid: ethanol (60 m) of the compound (3.0 g, 10.3 mmol) synthesized in Reference Example 2
l) solution, 2N sodium hydroxide (20.0 ml, 40.
(0 mmol) was added and the mixture was heated under reflux for 1.5 hours. After cooling, 2N hydrochloric acid (20.0 ml, 40.0 mmol) was added to the reaction solution to neutralize it,
It was extracted with ethyl acetate. The organic layer was washed with brine dried (MgSO _4), and the solvent was distilled off under reduced pressure. The obtained residue was washed with ether-hexane to give a pale yellow powder (2.
2 g, 91%). mp 142-145 ° C. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ: 2.22 (3H, s), 3.7
9 (3H, s), 6.98 (2H, d, J = 8.8Hz), 7.25 (2H, d, J =
8.8Hz), 7.39 (2H, s). IR (KBr): 3470, 1647, 1576, 1508, 1475 cm ^-1 .

Reference Example 7 Preparation of 2,4 (1H) -dioxo-6- (4-methoxyphenyl) -5-methylthieno [2,3-d] oxazine: Compound synthesized in Reference Example 6 (6.00 g, 22.8 mmo
triphosgene (6.76 g, 22.8 mmol) was added to a solution of l) in dioxane (100 ml), the mixture was stirred at 100 ° C. for 4 hours, and the reaction mixture was concentrated, and the resulting residue was filtered and washed with ether, Pale yellow powder (596g, 90
%) Was obtained. mp 209-210 ° C. ¹ H-NMR (200MHz, DMSO-d ₆ ) δ: 2.36 (3H, s), 3.
82 (3H, s), 7.06 (2H, d, J = 8.8Hz), 7.41 (2H, d, J = 8.
8Hz), 10.50 (1H, s). IR (KBr): 1779, 1709, 1533, 1497 cm ^-1 .

Reference Example 8 Preparation of 2,4 (1H) -dioxo-1- (2-fluorobenzyl) -6- (4-methoxyphenyl) -5-methylthieno [2,3-d] oxazine: Reference Example 7 To a solution of the compound (4.80 g, 16.59 mmol) obtained in 1. above in dimethylformamide (300 ml) was added potassium carbonate (3.43).
g, 24.88 mmol), potassium iodide (2.75 g, 1
6.59 mmol), 2-fluorobenzyl chloride (2.9
6 ml, 24.88 mmol) was added and the mixture was stirred at room temperature for 2 hours.
The residue obtained by concentrating the reaction solution was partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate, The extract was 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 white crystals (4.87 g, 74%). mp 162-163 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.43 (3H, s), 3.84
(3H, s), 5.21 (2H, s), 6.95 (2H, d, J = 8.8Hz), 7.0
5-7.44 (6H, m). IR (KBr): 1769, 1719, 1562, 1531, 1493 cm ^-1 . FAB-MS m / z: 398.1 (MH ^<+> ).

Reference Example 9 2,4 (1H, 3H) -Dioxo-1- (2-fluorobenzyl) -6- (4-methoxyphenyl) -3- (3-
Methoxypropyl) -5-methylthieno [2,3-d]
Production of pyrimidine: Compound obtained in Reference Example 8 (600
mg, 1.51 mmol) in dichloromethane (12 ml) under ice-cooling 3-methoxypropylmine (0.17 ml, 1.17 ml).
67 mmol) was added and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction solution was partitioned between dichloromethane and brine. The aqueous layer was extracted with dichloromethane, extract was 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 a white powder (524 mg, 78%). The obtained amine derivative was made into a THF (20 ml) solution, and triphosgene (351 mg, 1.18 mmo was added to this solution.
l) and triethylamine (0.15 ml, 2.37 mmol) were added and the mixture was heated under reflux for 1.5 hours. After cooling, the reaction solution was extracted with ethyl acetate, the organic layer was washed with brine dried (MgSO ₄
After that, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography, dried and recrystallized from ethyl acetate-hexane to give white plate crystals (398 m
g, 72%). mp 113-115 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.00 (2H, quint,
J = 6.7Hz), 2.50 (3H, s), 3.34 (3H, s), 3.50 (2H, t,
J = 6.7Hz), 3.83 (3H, s), 4.18 (2H, t, J = 6.7Hz), 5.
26 (2H, s), 6.93 (2H, d, J = 8.8Hz), 7.07-7.12 (2H,
m), 7.24-7.29 (4H, m). IR (KBr): 1700, 1659, 1473 cm ^-1 .

Reference Example 10 Using the compound obtained in Reference Example 5 as a starting material, the following compound was prepared by the same method as described in Reference Example 8.

Embedded image mp 231-234 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.57 (3H, s), 3.8
3 (3H, s), 5.38 (2H, s), 6.80-7.01 (5H, m), 7.29-
7.46 (2H, m), 7.56 (2H, d, J = 8.8Hz), 8.29 (2H, d,
J = 8.8Hz). IR (KBr): 1719 cm ^-1 .

Reference Example 11 2,4 (1H, 3H) -Dioxo-1- (2-fluorobenzil) -5-bromomethyl-6- (4-methoxyphenyl) -3- (3-methoxypropyl) thieno [2,
Preparation of 3-d] pyrimidine: the compound (270 mg, 0.576 mmol) obtained in Reference Example 9, N-bromosuccinimide (103 mg, 0.576 mmol), α, α′-azobisisobutyronitrile ( A mixture of 10 mg, 0.058 mmol) and carbon tetrachloride (10 ml) was heated to reflux for 2 hours.
After cooling, the insoluble matter was removed by filtration, and the filtrate was diluted with chloroform.
The organic layer was washed with brine dried (MgSO _4), and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give a colorless powder (294 mg, 93%). mp 105-107 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.01 (2H, quint, J
= 6.7Hz), 3.33 (3H, s), 3.50 (2H, t, J = 6.7Hz), 3.85
(3H, s), 4.21 (2H, t, J = 6.7Hz), 4.81 (2H, s) 5.27
(2H, s), 6.98 (2H, d, J = 8.8Hz), 7.09-7.34 (4H, m),
7.49 (2H, d, J = 8.8Hz). IR (KBr): 1713, 1661, 1628, 1541 cm ^-1 . FAB-MS m / z: 548.1 (MH ^<+> ).

Reference Example 12 Using the compound obtained in Reference Example 10 as a starting material, Reference Example 11
The following compounds were produced by a method similar to that described in.

Embedded image mp 253-254 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.83 (3H, s), 4.77
(2H, S), 5.38 (2H, s), 6.82-7.02 (4H, m), 7.32-7.
46 (2H, m), 7.79 (2H, d, J = 8.8Hz), 8.35 (2H, s, J =
8.8Hz). IR (KBr): 1725, 1678, 1599, 1533, 1473 cm ^-1 . FAB-MS m / z: 613.9 (MH ^<+> ).

Reference Example 13 2,4 (1H, 3H) -Dioxo-1- (2-fluorobenzil) -5- (N-benzyl-N-methylaminomethyl) -6- (4-methoxyphenyl) Production of 3- (3-methoxypropyl) thieno [2,3-d] pyrimidine hydrochloride: Compound obtained in Reference Example 11 (284 mg,
0.519 mmol) in dimethylformamide (10 ml) was added to ethyl diisopropylamine (0.14 ml) under ice cooling.
0 ml, 0.780 mmol) and methylbenzylamine (0.0
80 ml, 0.620 mmol) was added. After stirring at room temperature for 2 hours, the reaction mixture was concentrated and the resulting residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate, the organic layers were combined and dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a colorless oil (280 mg, 9
2%). To a solution of this oily substance in ethyl acetate (4 ml) was added 1N ethereal hydrochloric acid (0.3 ml) under ice cooling,
It was stirred at the same temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure and the obtained residue was crystallized from ethyl acetate-ether to give hydrochloride (220 mg) as white crystals. mp 95-100 ° C. IR (KBr): 1702, 1657, 1562, 1543, 1489 cm ^-1 .

Reference Example 14 Using the compound obtained in Reference Example 12 as a starting material, Reference Example 13
The following compounds were produced by a method similar to that described in.

[Chemical 21] mp 163-164 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.15 (3H, s), 3.60
(2H, S), 3.84 (3H, s), 3.95 (2H, s), 5.38 (2H,
s), 6.81-6.97 (5H, m), 7.17-7.33 (6H, m), 7.45 (1H,
t, J = 8.2Hz), 8.02 (2H, d, J = 8.8Hz), 8.25 (2H, d,
J (8.8Hz). IR (KBr): 1719, 1671, 1597, 1522, 1473 cm ^-1 .

Reference Example 15 6- (4-Aminophenyl) -2,4 (1H, 3H) -dioxo-1- (2,6-difluorobenzil) -5-
(N-benzyl-N-methylaminomethyl) -3- (3
Production of -methoxyphenyl) thieno [2,3-d] pyrimidine hydrochloride: Compound obtained in Reference Example 14 (9.00
50% palladium-carbon powder (0.90 g) was added to a formic acid (200 ml) solution (g, 13.75 mmol) under ice cooling, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours, and then the reaction solution was concentrated. The resulting residue was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with dichloromethane, the organic layers were combined and dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a colorless powder (5.13 g, 60%). To a solution of this compound (100 mg) in ethyl acetate (4 ml) was added 1N ethereal hydrochloric acid (0.3 ml) under ice cooling,
It was stirred at the same temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-ether to give hydrochloride (95 mg) as white crystals. mp 162-165 ° C. IR (KBr): 1715, 1659, 1537, 1473 cm ^-1 .

Reference Example 16 2,4 (1H, 3H) -Dioxo-1- (2,6-difluorobenzyl) -6- (4-propionylaminophenyl) -5- (N-benzyl-N-methylaminomethyl) )
-3- (3-Methoxyphenyl) thieno [2,3-d]
Preparation of pyrimidine hydrochloride: Compound (250 mg, 0.38 mmol) obtained in Reference Example 15 in dichloromethane (10 m
l) solution, triethylamine (0.053 ml,
0.38 mmol), propionyl chloride (0.033 ml, 0.03 mmol).
38 mmol) was added and stirred for 1 hour. The reaction mixture was partitioned with dichloromethane and saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with dichloromethane, the extracts were combined, washed with brine and dried (Mg
After SO ₄ ) the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a colorless oil (220 mg, 82%). To a solution of the obtained acyl derivative in ethyl acetate (4 ml) was added 1N ethereal hydrochloric acid (0.3 ml) under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure and the obtained residue was crystallized from ethyl acetate-ether to give the hydrochloride (213 mg) as white crystals. mp 218-224 ° C. IR (KBr): 1713, 1665, 1601, 1543, 1475 cm ^-1 .

Reference Example 17 2,4 (1H, 3H) -Dioxo-1- (2,6-difluorobenzyl) -5- (N-benzyl-N-methylaminomethyl) -6- (4-isobutyryl) Aminophenyl) -3- (3-methoxyphenyl) thieno [2,3-
d] Production of Pyrimidine (Compound 3) The title compound was produced by the same method as that described in Reference Example 16 except that isobutyryl chloride was used in place of propionyl chloride, using the compound obtained in Reference Example 15 as a starting material ( Yield 85%, melting point 170-173 ° C).

Embedded image

Test Example 1 Measurement of Oral Absorption in Rats The freeze-dried powder containing the compound C obtained in Example 3 was dissolved in distilled water for injection so that the concentration of the compound C was 1.5 mg / ml. did. The solution was applied to SD rats (male), which had been raised for 3 weeks after removing the testis at 6 weeks of age, at a weight of 1
Oral administration was performed at a rate of 15 mg / kg (n = 5).
In addition, Compound C was suspended in a suspension (0.5% methylcellulose / 99.5% distilled water) at a concentration of 1.5 mg / ml, and orally administered animals were used as a control group (n = 4). Using. 2, 4, 6, 8, 12, and 24 hours after administration, blood was collected from the jugular vein under ether anesthesia, and the final concentration was 3 mg.
/ Ml EDTA (ethylenediamine tetraacetic acid) and aprotinin at a final concentration of 300 KIU / ml were immediately added. After centrifugation at 3000 × g for 15 minutes, the concentration of the compound in the obtained plasma was calculated from the ¹²⁵ I-leuprorelin binding inhibition rate (specific experimental methods are shown in Test Examples 2, 3 and 4). As a result, the rats to which the freeze-dried powder containing Compound C was administered showed a blood concentration of Compound C which was about 2 to 4 times that of the control group.

Test Example 2 Preparation of ¹²⁵ I-leuprorelin 10 μl of a 3 × 10 ⁻⁴ M aqueous solution of leuprorelin and 0.
10 μl of 01 mg / ml lactoperoxidase was placed in a tube, 10 μl of 37 MBq of Na ¹²⁵ I solution was added, and after stirring, 10 μl of 0.01% H ₂ O ₂ was added and reacted at room temperature for 20 minutes. 700 with 0.05% TFA solution
The reaction was stopped by adding μl and purified by reverse phase HPLC. The conditions of HPLC are shown below. ¹²⁵ I-Luprorelin was eluted at a retention time of 26-27 minutes. Column: TSKgel ODS-80TMCTR (4.6mmx10cm) Eluent: Solvent A (0.05% TFA) solvent _{B (40% CH 3 CN-} 0.05% TFA) 0 minute (100% Solvent A) -3 minutes ( 100% solvent A) -7 minutes (50% solvent A + 50% solvent B) -40 minutes (100% solvent B) Elution temperature: room temperature Elution rate: 1 ml / min

Test Example 3 Preparation of CHO (Chinese Hamster Ovary) Cell Membrane Fraction Containing Human GnRH Receptor Human GnRH receptor-expressing CHO cells (10 ⁹ cells) were added with 5 mM EDTA in phosphate buffered saline (P
BS-EDTA) and centrifuged at 100 xg for 5 minutes. The cell pellet was added to the cell homogenate buffer (10 mM NaHCO ₃ , 5 mM EDTA, pH =
7.5 ml) was added and homogenized using a Polytron homogenizer. 40 of the obtained homogenate
After centrifugation at 0 × g for 15 minutes, the supernatant was subjected to ultracentrifugation at 100,000 × g for 1 hour to obtain a precipitate of a membrane fraction. The precipitate was suspended in 2 ml of assay buffer and 100,000
It was centrifuged at × g for 1 hour. The membrane fraction recovered as a precipitate was suspended again in 20 ml of assay buffer, dispensed, stored at −80 ° C., and thawed each time before use.

Test Example 4 Measurement of ¹²⁵ I-Luprorelin Binding Inhibition Rate The membrane fraction prepared in Test Example 3 was diluted with assay buffer to 200 μg / ml, and 188 μl was dispensed into each tube. 2 μl plasma and 38 nM collected from rat
10 .mu.l of ^.sup.125 I-leuprorelin was simultaneously added. The standard curve of the compound is that compound C dissolved in 100% DMSO was diluted 1,000 times with 60% DMSO and then diluted with control rat plasma.
10 μl of M ¹²⁵ I-leuprorelin was added at the same time. To determine maximal binding, 2 μl of control rat plasma and 10 μl of 38 nM ¹²⁵ I-leuprorelin.
and 1 were added to prepare a reaction solution. In addition, in order to measure the amount of non-specific binding, 100% dissolved in 60% DMSO was used.
A reaction solution containing 2 μl of μM leuprorelin and 10 μl of 38 nM ¹²⁵ I-leuprorelin was also prepared at the same time. After reacting at 25 ° C. for 60 minutes, the reaction solution was suction-filtered using a polyethyleneimine-treated Whatman glass filter (GF-F). After filtration, the radioactivity of ¹²⁵ I-leuprorelin remaining on the filter paper was measured using a γ-counter. (Maximum bound radioactivity-radioactivity when sample plasma was added) / (maximum bound radioactivity-nonspecific bound radioactivity) was calculated to determine the binding inhibition rate (%) of each test plasma. Further, the inhibition rate was obtained by changing the concentration of the test substance, and the concentration of the sample plasma was calculated from the Hill plot.

[0088]

According to the present invention, by using a branched cyclodextrin-carboxylic acid, non-peptide LH
-The water solubility, oral absorbability, and drug stability of the RH antagonist are significantly improved as compared with the case of the compound alone, and the action on the living body, for example, the action of destroying red blood cells is smaller than that of β-cyclodextrin. , Shows high safety for blood. Moreover, β-CyD-G ₂ -COOH is extremely little decomposed by acid or enzyme. Therefore, also in this respect, the composition of the present invention is highly safe for animals including the human body.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/505 ACV A61K 31/505 ACV 45/06 45/06 // C07D 495/04 105 C07D 495 / 04 105A 105Z

Claims (12)

[Claims] 1. A composition comprising a non-peptide LH-RH antagonist and a branched cyclodextrin-carboxylic acid. 2. The composition according to claim 1, wherein the non-peptide LH-RH antagonist is a thienopyridine or thienopyrimidine LH-RH antagonist. 3. A thienopyridine LH-RH antagonist,
Formula 1 [In the formula, R ¹ and R ² are each hydrogen, carbon, nitrogen,
R ³ is an optionally substituted homologous or heterocyclic group, R ⁴ is hydrogen, a formyl group, a sulfur atom-containing group or an optionally substituted hydrocarbon residue. A carbonyl group optionally substituted with or an esterified or amidated carboxyl group, R ⁵ is a group through a hydrogen atom or a carbon atom, and n is 0 to 0.
The compound according to claim 1, which is an integer of 3, or a salt thereof. 4. A thienopyrimidine LH-RH antagonist is represented by the formula: {In the formula, R ⁶ is hydrogen, an alkyl group or a formula- (CH ₂ ) p
Q wherein, p is an integer of 0 to 3, Q is halogen, nitro, cyano, amino, optionally substituted carboxyl group, alkylenedioxy group, or a group of the formula -A-R ¹⁰ (wherein, A is A chemical bond or an intervening group, R ¹⁰ represents an aryl group which may be substituted with a group represented by), an optionally substituted cycloalkyl group or an optionally substituted heterocyclic group. The group represented by
⁷ is hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group or an optionally substituted cycloalkyl group, and R ⁸ is optionally substituted A good amino group, R ⁹ is an optionally substituted aryl group, and r is an integer of 0 to 3} or a salt thereof. 5. The composition according to claim 1, which contains 0.1 to 20 mol of branched cyclodextrin-carboxylic acid with respect to 1 mol of the LH-RH antagonist. 6. A branched cyclodextrin-carboxylic acid is
The composition according to claim 1, which is a cyclodextrin having an organic group containing at least one carboxyl group at the 6-O position of at least one glucose unit of the cyclodextrin ring. 7. The composition according to claim 1, wherein the cyclodextrin ring is a cyclodextrin ring having 6 to 8 glucose units. 8. A branched cyclodextrin-carboxylic acid is 6
-O-cyclomaltoheptaosyl- (6 → 1) -α-D-
The composition according to claim 1, which is glucosyl- (4 → 1) -O-α-D-glucuronic acid. 9. The composition according to claim 1, which is a medicine. 10. The composition according to claim 1, which is an LH-RH antagonist. 11. The composition according to claim 1, wherein the LH-RH antagonist is a water-insoluble or sparingly soluble substance. 12. The composition according to claim 1, which is for oral use.