JP2003183284A - Nitrogen-containing heterocyclic compound and application of the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a bicyclic nitrogen-containing heterocyclic compound having gonadotropin releasing hormone antagonism, and to provide a pharmaceutical composition containing the same. <P>SOLUTION: This compound (a salt thereof) is shown by the formula [wherein, A and D are such that either one of them is N and the other C, or both of them being N atoms; B is N or C; R is a halogenobenzyl; R<SP>1</SP>is a (substituted) alkyl, (substituted) heterocyclic group, (substituted) amino or the like; R<SP>2</SP>is a (substituted) alkyl or the like; R<SP>3</SP>is a (substituted) alkyl or the like; and R<SP>4</SP>is a group of the formula (a) (wherein, R<SP>5</SP>is a halogen atom, alkyl, alkoxy or the like; and ring E is a benzene ring optionally having substituent(s) in addition to R<SP>5</SP>) or the like]. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to gonadotropin releasing hormone (GnRH).
one)) A nitrogen-containing heterocyclic compound having an antagonistic effect, a method for producing the same, and a pharmaceutical composition containing the same.

[0002]

BACKGROUND OF THE INVENTION Secretion of the anterior pituitary gland is related to the secretion of peripheral hormones secreted from the target organs of the respective hormones and secretory promoters or secretion suppressor hormones secreted from the hypothalamus, which is the upper center of the anterior pituitary gland. In the specification, these hormone groups are collectively referred to as hypothalamic hormones). To date, hypothalamic hormones such as thyrotropin-releasing hormone (TRH) or gonadotropin-releasing hormone {G
nRH (Gonadotropin releasing hormone): Luteinizing hormone (LH-RH)
Also known as one releasing hormone)]}. As a compound having GnRH antagonistic action, a linear peptide that is a derivative of GnRH
(U.S. Pat. No. 5,140,009, U.S. Pat. No. 5,171,835), cyclic hexapeptide derivatives (JP-A-61-191698) and 2
Cyclic peptide derivatives [Journal of Medicinal
Chemistry (Journal of Medicinal Chemistry), 36
Vol., 3265-3273, 1993] and the like. Gn
As the non-peptidic compound having RH antagonistic action,
PCT International Publication WO95 / 28405, WO97
/ 14697 gazette, WO97 / 14682 gazette, W
O99 / 33831, WO00 / 00493, WO00 / 56739, WO01 / 2904
The compounds described in Japanese Patent Publication No. 4 and the like are mentioned.

[0003]

[Problems to be Solved by the Invention] Hypothalamic hormones are mediated by receptors that are thought to exist in the anterior pituitary gland,
It is presumed that the hormone action and the like are expressed, and analysis of receptor genes specific to these is being promoted, including that in humans. Therefore, a specific and selective antagonist or agonist for these receptors regulates the action of hypothalamic hormone and controls the secretion of anterior pituitary hormone. As a result, prevention or treatment of such an anterior pituitary hormone-dependent disease can be expected. However, peptidic compounds have problems in many aspects such as oral absorbability, dosage form, dose, drug stability, duration of action, and stability against metabolism. Oral GnRH having excellent therapeutic effects on hormone-dependent cancers such as prostate cancer, endometriosis and precocious puberty, and not causing transient pituitary-gonadotropic action (acute action) There is a strong demand for antagonists, especially non-peptidic antagonists.

[0004]

The inventors of the present invention produced various nitrogen-containing heterocyclic derivatives and investigated the action thereof. As a result, some of the nitrogen-containing heterocyclic compounds showed excellent GnRH.
It has been found that it has an antagonistic action and is useful as a medicine. The present inventors have completed the present invention based on this finding.

That is, the present invention is based on the formula [1]

[Chemical 7] [In the formula, either A or D is a nitrogen atom and the other is
Carbon atom or both are nitrogen atoms, B is nitrogen atom or
Carbon atom, R is a halogenobenzyl group, R¹Is hydrogen
Child, an alkyl group which may have a substituent, a substituent
Optionally having an aralkyl group, optionally having a substituent
An aryl group, a heterocyclic group which may have a substituent, or
Is an amino group which may have a substituent, R²Is a substituent
Optionally having an alkyl group or a substituent
The aralkyl group which may be ³Is a hydrogen atom or a substituent
An alkyl group which may have R^FourIs an expression

[Chemical 8] (In the formula, R ⁵ is halogen, an alkyl group, an acyl group, an optionally esterified or amidated carboxyl group, a hydroxy group, an alkoxy group, a thiol group, an alkylthio group, an amino group, a monoalkylamino group, a dialkylamino group. A group, a monoacylamino group or a diacylamino group, and ring E represents a benzene ring which may further have a substituent in addition to R ⁵ ) or a heterocyclic group which may have a substituent. Represents a ring group] (hereinafter, may be abbreviated as compound (I)) or a salt thereof,
[2] R ¹ is (1) hydrogen atom, (2) (i) hydroxy, (ii)
C _1-7 acyloxy, (iii) benzoyloxy, (iv) C
_1-6 alkoxycarbonyl, benzyloxycarbonyl, C _1-4 acyl, C _1-4 alkyl and amino optionally having 1 or 2 substituents selected from C _1-3 alkylsulfonyl, (v) C _1-10 alkoxy and (vi) C
_1-3 alkoxy -C _{1 -3} 1 without a substituent selected from alkoxy to 5 optionally having C _1-6 alkyl group, (3)
(i) hydroxy, (ii) C _1-7 acyloxy, (iii) benzoyloxy, (iv) C _1-6 alkoxycarbonyl, benzyloxycarbonyl, C _1-4 acyl, C _1-4 alkyl and C _1-3 Substituent selected from alkylsulfonyl is 1
Or two may have amino, which may have five to 1 substituent selected from (v) C _1-10 alkoxy and (vi) C _1-3 alkoxy -C _{1 -3} alkoxy C _7-12
Aralkyl group, (4) (i) hydroxy, (ii) C _1-7 acyloxy, (iii) benzoyloxy, (iv) C _1-6 alkoxycarbonyl, benzyloxycarbonyl, C _1-4 acyl, C _1-4 alkyl and C _1-3 alkyl substituents selected from alkylsulfonyl which may have one or two amino, from (v) C _1-10 alkoxy and (vi) C _1-3 alkoxy -C _{1 -3} alkoxy A C _6-12 aryl group which may have 1 to 5 selected substituents, (5) (i) hydroxy, (ii) C _1-7 acyloxy, (iii) benzoyloxy, (iv) C _{1 -6} alkoxycarbonyl, benzyloxycarbonyl, C _1-4 acyl, C _1-4 alkyl and C _1-3
An amino optionally having 1 or 2 substituents selected from alkylsulfonyl, (v) C _1-10 alkoxy and
(vi) C _1-3 alkoxy -C _{1 -3} 5 which may have 1-5 amino acids a substituent selected from alkoxy to 7-membered heterocyclic group, or ^{(6) -NR 6 R 7 (} R 6 Is a hydrogen atom, a hydroxy group, a C _1-6 alkyl group or a C _1-6 alkoxy group,
R ⁷ represents a hydrogen atom or a C _1-6 alkyl group), and R ² is
(1) (i) hydroxy, (ii) C _1-7 acyloxy, (iii)
Benzoyloxy, (iv) C _1-6 alkoxycarbonyl,
Amino optionally having 1 or 2 substituents selected from benzyloxycarbonyl, C _1-4 acyl, C _1-4 alkyl and C _1-3 alkylsulfonyl, (v) C _1-10 alkoxy, ( vi) C _1-3 alkoxy-C _1-3 alkoxy and (vii) a C _1-6 alkyl group which may have 1 to 5 substituents selected from 5 to 6-membered aromatic heterocyclic groups, (2) (i) hydroxy, (ii) C _1-7 acyloxy, (i
ii) having 1 or 2 substituents selected from benzoyloxy, (iv) C _1-6 alkoxycarbonyl, benzyloxycarbonyl, C _1-4 acyl, C _1-4 alkyl and C _1-3 alkylsulfonyl. May amino, (v) C
_1-10 alkoxy and (vi) C _1-3 alkoxy -C _{1 -3} 1 without a substituent selected from alkoxy to 5 optionally having C _7-12 aralkyl group, R ³ is (1) a hydrogen atom Or (2)
(i) hydroxy, (ii) C _1-7 acyloxy, (iii) benzoyloxy, (iv) C _1-6 alkoxycarbonyl, benzyloxycarbonyl, C _1-4 acyl, C _1-4 alkyl and C _1-3 Substituent selected from alkylsulfonyl is 1
Or two may have amino, which may have five to 1 substituent selected from (v) C _1-10 alkoxy and (vi) C _1-3 alkoxy -C _{1 -3} alkoxy C _1-6
Alkyl group, R ⁴ is of formula (i)

[Chemical 9] (In the formula, R ⁵ is halogen, C _1-6 alkyl group, C _1-6 acyl group, carboxyl group, C _1-6 alkoxycarbonyl group, carbamoyl group, N-mono C _1-6 alkylcarbamoyl group, N, N-diC _1-6 alkylcarbamoyl group, hydroxy group, C _1-6 alkoxy group, thiol group, C _1-6 alkylthio group, amino group, mono C _1-6 alkylamino group, di C _1-6 alkylamino group group, a mono C _1-6 acylamino group or a di C _1-6 acylamino group, ring E may further halogen, hydroxy, may have a substituent group selected from C _1-6 alkyl or C _{1 -6} alkoxy A group represented by benzene ring), (ii) halogen, C _1-6 alkyl,
C _1-6 acyl, carboxyl, C _1-6 alkoxycarbonyl, carbamoyl, N-mono C _1-6 alkylcarbamoyl, N, N-diC _1-6 alkylcarbamoyl, hydroxy, C _1-6 alkoxy, thiol, C _1-6 alkylthio,
5- or 6-membered aromatic optionally having a substituent selected from amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, mono-C _1-6 acylamino and di-C _1-6 acylamino A heterocyclic group or (iii) C _1-6 alkyl, C _1-6 acyl, carboxyl, C _1-6 alkoxycarbonyl, carbamoyl, N-mono C _1-6 alkylcarbamoyl,
N, N-diC _1-6 alkylcarbamoyl, hydroxy,
C _1-6 alkoxy, thiol, C _1-6 alkylthio, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, substituent selected from mono C _1-6 acylamino and di C _1-6 acylamino A compound of the above-mentioned [1] which is a 5- to 6-membered non-aromatic heterocyclic group which may have
[3] The compound described in [1] above, wherein A is a nitrogen atom,
[4] The compound according to the above [1], wherein B is a nitrogen atom,
[5] The compound according to the above [1], wherein D is a nitrogen atom,
[6] Expression

[Chemical 10] [In the formula, R represents a halogenobenzyl group, R ¹ represents a hydrogen atom,
An alkyl group which may have a substituent, an aralkyl group which may have a substituent, an aryl group which may have a substituent, a heterocyclic group which may have a substituent or a substituent R ² is an optionally substituted amino group, R ² is an optionally substituted alkyl group or an optionally substituted aralkyl group, and R ³ is a hydrogen atom or a substituent. R ⁴ is an alkyl group which may be

[Chemical 11] (In the formula, R ⁵ is halogen, an alkyl group, an acyl group, a carboxyl group which may be esterified or amidated, a hydroxy group, an alkoxy group, a thiol group, an alkylthio group, an amino group, a monoalkylamino group, a dialkylamino group. A group, a monoacylamino group or a diacylamino group, and ring E represents a benzene ring which may further have a substituent in addition to R ⁵ ) or a heterocyclic group which may have a substituent. A cyclic group] or a salt thereof, [7] R ¹ is (1) a 5- to 7-membered heterocyclic group, or
(2) —NR ⁶ R ⁷ (R ⁶ is a hydrogen atom, a hydroxy group, C _1-6
An alkyl group or a C _1-6 alkoxy group, R ⁷ represents a hydrogen atom or a C _1-6 alkyl group), R ² represents a C _7-12 aralkyl group, R ³ represents a C _1-6 alkyl group, and R ⁴ represents formula

[Chemical 12] [Wherein R ^5a represents a C _1-6 alkoxy group] or a 5-membered aromatic heterocyclic group, [8] 5-membered aromatic heterocycle The compound according to the above [7], wherein the group is a nitrogen-containing heterocyclic group,

[9] The compound according to the above [7], wherein the 5-membered aromatic heterocyclic group is pyrrolyl, [1.
0] 3- (N-benzyl-N-methylaminomethyl)-
8- (2,6-difluorobenzyl) -5,8-dihydro-2- {4- (3-furylcarbonylamino) phenyl} -6- (4-methoxyphenyl) -5-oxoimidazo [1,2- a] pyrimidine, 3- (N-benzyl-N
-Methylaminomethyl) -8- (2,6-difluorobenzyl) -5,8-dihydro-2- {4- (ethylaminocarbonylamino) phenyl} -6- (4-methoxyphenyl) -5-oxoimidazo [1,2-a] pyrimidine, 3- (N-benzyl-N-methylaminomethyl)-
8- (2,6-difluorobenzyl) -5,8-dihydro-2- {4- (methoxyaminocarbonylamino) phenyl} -6- (4-methoxyphenyl) -5-oxoimidazo [1,2-a ] Pyrimidine, 3- (N-benzyl-N-methylaminomethyl) -8- (2,6-difluorobenzyl) -5,8-dihydro-2- {4- (ethylaminocarbonylamino) phenyl} -5 Oxo-6
-(1-pyrrolyl) imidazo [1,2-a] pyrimidine or a salt thereof, the compound according to [1], [1]
1] A prodrug of the compound according to [1] or a salt thereof, [12] A pharmaceutical composition comprising the compound according to [1] or a salt thereof, or a prodrug thereof, [1]
[3] The pharmaceutical composition according to the above [12], which is a gonadotropin-releasing hormone antagonist, [14] The pharmaceutical composition according to the above [12], which is a prophylactic / therapeutic agent for sex hormone-dependent diseases, and [15] sex. Hormone-dependent cancer, sex hormone-dependent cancer bone metastasis, benign prostatic hyperplasia, uterine fibroids, endometriosis,
Uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome,
Dysmenorrhea, multilocular ovary syndrome, polycystic ovary syndrome,
Acne, baldness, Alzheimer's disease, infertility, irritable bowel syndrome or hormone-independent and GnRH-sensitive benign or malignant tumor preventive / therapeutic agent, reproductive regulator, contraceptive, ovulation inducer or sex hormone-dependent [12] The pharmaceutical composition according to [12], which is an agent for preventing recurrence of cancer, and [16] a gonadotropin, which is administered to a mammal with an effective amount of the compound according to [1] or a salt thereof. The present invention relates to a method for antagonizing a release hormone, [17] use of the compound according to the above [1] or a salt thereof for producing a gonadotropin-releasing hormone antagonist, and the like.

The halogenobenzyl group represented by R includes, for example, a benzyl group in which a substitutable position on the benzene ring is mono- or di-substituted with a halogen atom (fluorine, chlorine, bromine, iodine). Preferred are 2-fluorobenzyl, 2,6-difluorobenzyl, 2-chloro-6-fluorobenzyl and the like, and more preferred is 2,6-difluorobenzyl.

The alkyl group of the "optionally substituted alkyl group" represented by R ¹ is, for example, a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, n -Butyl, isobutyl, sec-butyl, ter
t-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,
3,3-dimethylbutyl, 3,3-dimethylpropyl, 2
-Ethylbutyl etc.) and the like. Examples of the substituent of the “alkyl group which may have a substituent (s)” include (i) hydroxy, (ii) C _1-7 acyloxy (eg, acetoxy, propionyloxy, butyryloxy, etc.), (iii) Benzoyloxy, (iv) C _1-6 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), benzyloxycarbonyl, C _1-4 acyl (eg, formyl, acetyl, propionyl, butyryl, etc.), C _{1 -4} alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.) and C _1-3 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl,
A substituent selected from isopropylsulfonyl, etc.)
Or amino optionally having 2 units, (v) C _1-10 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, hexyloxy, heptoxy, octyloxy, etc.) , (Vi) C _1-3 alkoxy-C _1-3 alkoxy (for example, methoxymethoxy, ethoxymethoxy, propoxymethoxy, isopropoxymethoxy, 1-methoxyethoxy, 1-ethoxyethoxy, 1-propoxyethoxy, 1-isopropoxy. Ethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-propoxyethoxy, 2-isopropoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 3-propoxypropoxy and the like) and the like. It may have 1 to 5 of these substituents at substitutable positions.

The aralkyl group of the "aralkyl group which may have a substituent" represented by R ¹ is, for example, C _7-12.
Aralkyl groups (eg, benzyl, phenethyl, 1-naphthylmethyl, 2-naphthylmethyl, 1-naphthylethyl, 2-naphthylethyl, etc.) and the like can be mentioned. Examples of the substituent of the “aralkyl group which may have a substituent” include the same number of substituents as the substituent of the “alkyl group which may have a substituent”.

Examples of the aryl group of the "aryl group which may have a substituent" represented by R ¹ include a C _6-12 aryl group (eg, phenyl, naphthyl, etc.) and the like. As the substituent of the "aryl group which may have a substituent", the same number of substituents as those of the "alkyl group which may have a substituent" can be mentioned.

The heterocyclic group of the "optionally substituted heterocyclic group" represented by R ¹ is, for example, a hetero atom selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atom. And a 5- to 7-membered heterocyclic group containing 1 to 4 groups. Specific examples of the heterocyclic group include (1) thienyl, furyl, pyrrolyl, pyrrolinyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl, 1,2,4.
-Oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4 -Triazolyl, triazinyl,
5-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atom such as triazolidinyl, 1H- or 2H-tetrazolyl; (2) pyridyl, pyrimidinyl, thiomorpholinyl, morpholinyl , Triazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, oxotriazinyl, pyridazinyl, pyrazinyl and the like, an oxygen atom, Examples thereof include a 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from sulfur atom, nitrogen atom and the like. As the substituent of the “heterocyclic group which may have a substituent (s)”, the same number of substituents as those of the “alkyl group which may have a substituent (s)” can be mentioned.

The "optionally substituted amino group" represented by R ¹ is, for example, --NR ⁶ R ⁷ (R ⁶ is a hydrogen atom, hydroxy, a C _1-6 alkyl group or C _{1 -6} alkoxy group, R ⁷ represents a hydrogen atom or a C _1-6 alkyl group)
And so on. The C _1-6 alkyl group represented by R ⁶ and R ⁷ includes, for example, methyl, ethyl, n-propyl,
Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3 Examples include 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl and the like. Examples of the C _1-6 alkoxy group represented by R ⁶ include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, hexyloxy and the like.

The alkyl group of the "optionally substituted alkyl group" represented by R ² is, for example, a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, n -Butyl, isobutyl, sec-butyl, ter
t-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,
3,3-dimethylbutyl, 3,3-dimethylpropyl, 2
-Ethylbutyl etc.) and the like. Examples of the substituent of the “alkyl group which may have a substituent (s)” include (i) hydroxy, (ii) C _1-7 acyloxy (eg, acetoxy, propionyloxy, butyryloxy, etc.), (iii) Benzoyloxy, (iv) C _1-6 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), benzyloxycarbonyl, C _1-4 acyl (eg, formyl, acetyl, propionyl, butyryl, etc.), C _{1 -4} alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.) and C _1-3 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl,
A substituent selected from isopropylsulfonyl, etc.)
Or amino optionally having 2 units, (v) C _1-10 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, hexyloxy, heptoxy, octyloxy, etc.) , (Vi) C _1-3 alkoxy-C _1-3 alkoxy (for example, methoxymethoxy, ethoxymethoxy, propoxymethoxy, isopropoxymethoxy, 1-methoxyethoxy, 1-ethoxyethoxy, 1-propoxyethoxy, 1-isopropoxy. Ethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-propoxyethoxy, 2-isopropoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 3-propoxypropoxy, etc.), (vii) 5- or 6-membered aromatic Heterocyclic groups (eg thienyl, furyl, pyrro , Oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, triazinyl, triazolidinyl, 1H- or 2H-tetrazolyl, pyridyl, pyrimidinyl, triazinyl, pyranyl, thiopyranyl, 1,4-oxazinyl 1,4-thiazinyl,
1,3-thiazinyl, triazinyl, oxotriazinyl, pyridazinyl, pyrazinyl, etc.) and the like. It may have 1 to 5 of these substituents at substitutable positions.

Examples of the "aralkyl group which may have a substituent" represented by R ² include the same ones as the "aralkyl group which may have a substituent" represented by R ^1. To be

The "optionally substituted alkyl group" represented by R ³ is the same as the "optionally substituted alkyl group" represented by R ^1. To be

R ⁴ is

[Chemical 13] (In the formula, R ⁵ is halogen, an alkyl group, an acyl group, an optionally esterified or amidated carboxyl group, a hydroxy group, an alkoxy group, a thiol group, an alkylthio group, an amino group, a monoalkylamino group, a dialkylamino group. A group, a monoacylamino group or a diacylamino group, and ring E represents a benzene ring which may further have a substituent in addition to R ⁵ ) or a heterocyclic group which may have a substituent. Indicates a ring group.

The alkyl group represented by R ⁵ is, for example,
C _1-6 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-
Butyl, tert-butyl, n-pentyl, isopentyl,
Neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl etc.) and the like. . R ⁵
Examples of the acyl group represented by include C _1-4 acyl (eg, formyl, acetyl, propionyl, butyryl, etc.) and the like. As the optionally esterified or amidated carboxyl group represented by R ⁵ ,
For example, carboxyl, C _1-6 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl,
Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, etc.), carbamoyl, N-monoalkylcarbamoyl (eg, N
-Methylcarbamoyl, N-ethylcarbamoyl, N-
Propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-tert-butylcarbamoyl, etc.), N, N-dialkylcarbamoyl (eg, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, etc.) and the like. .

Examples of the alkoxy group represented by R ⁵ include C _1-6 alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, hexyloxy). Is mentioned. Examples of the alkylthio group represented by R ⁵ include C _1-6 alkylthio groups (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio,
Pentylthio, hexylthio, etc.) and the like.
Examples of the monoalkylamino group represented by R ⁵ include mono C _1-6 alkylamino groups (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino). , Pentylamino, hexylamino, etc.) and the like. Examples of the dialkylamino group represented by R ⁵ include diC _1-6 alkylamino groups (eg, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, disec-butylamino, ditert-butyl). Amino etc.) and the like.

Examples of the monoacylamino group represented by R ⁵ include mono C _1-6 acylamino groups (eg, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, etc.) and the like. Examples of the diacylamino group represented by R ⁵ include a diC _1-6 acylamino group (eg, diformylamino, diacetylamino, etc.) and the like.

Substituents which ring E may further have include halogen (eg, fluorine, chlorine, bromine and iodine), hydroxy, C _1-6 alkyl (eg, methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3 , 3-Dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, etc.), C _1-6 alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, hexyloxy). Etc.) and the like.

The "heterocyclic group" of the "optionally substituted heterocyclic group" represented by R ⁴ is a 5- to 6-membered aromatic heterocyclic group (eg, thienyl, furyl, pyrrolyl). , Oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,4-thiadiazolyl,
1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, triazinyl, triazolidinyl, 1H- or 2
H-tetrazolyl, pyridyl, pyrimidinyl, triazinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, triazinyl, oxotriazinyl, pyridazinyl, pyrazinyl, etc.) Examples thereof include a non-aromatic heterocyclic group (for example, a heterocyclic ring in which a part or all of the above aromatic heterocycle is reduced). Among them, a 5-membered aromatic heterocyclic group is preferable, and pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, imidazolinyl, isoxazolyl, isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl,
5-membered 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl The nitrogen-containing heterocyclic group of is preferable. Particularly, pyrrolyl is preferable.

The substituent which the “heterocyclic group optionally having substituent (s)” represented by R ⁴ may have is halogen, C _1-6 alkyl, C _1-6 acyl, carboxyl. , C
_1-6 alkoxycarbonyl, carbamoyl, N-mono C
_1-6 alkylcarbamoyl, N, N-diC _1-6 alkylcarbamoyl, hydroxy, C _1-6 alkoxy, thiol, C _1-6 alkylthio, amino, mono C _1-6 alkylamino, di C _1-6 alkyl Amino, mono C _1-6 acylamino, di C _1-6 acylamino and the like can be mentioned. “C _1-6 alkyl”, “C _1-6 acyl”, “C ₁ ” as the substituent which the “heterocyclic group which may have a substituent” represented by R ⁴ may have; _-6 alkoxycarbonyl "," N-mono C _1-6 alkylcarbamoyl "," N, N-diC _1-6 alkylcarbamoyl "," C _1-6 alkoxy "," C _1-6 alkylthio "," mono " C _1-6 alkylamino ”,“ di-C
" _1-6 alkylamino", "mono C _1-6 acylamino" and "di C _1-6 acylamino" mean "C represented by R ^5.
“ _1-6 alkyl”, “C _1-6 acyl”, “C _1-6 alkoxycarbonyl”, “N-mono C _1-6 alkylcarbamoyl”, “N, N-diC _1-6 alkylcarbamoyl”,
"C _1-6 alkoxy", "C _1-6 alkylthio", "mono C _1-6 alkylamino", "di C _1-6 alkylamino",
The same thing as "mono C _1-6 acylamino" and "di C _1-6 acylamino" is shown.

R is 2-fluorobenzyl, 2,6
-Difluorobenzyl or 2-chloro-6-fluorobenzyl are preferred. The R ^1, 5 to 7-membered heterocyclic group or -NR ⁶ R ⁷ (R ⁶ is a hydrogen atom, a hydroxy group, a C _1-6 alkyl group or a C _1-6 alkoxy group, R ⁷
Is preferably a hydrogen atom or a C _1-6 alkyl group). R ² is preferably a C _7-12 aralkyl group. R ³ is preferably a C _1-6 alkyl group. R ⁴ is an expression

[Chemical 14] A group represented by (in the formula, R ^5a represents a C _1-6 alkoxy group) or a 5-membered nitrogen-containing aromatic heterocyclic group is preferable.

One of A and D represents a nitrogen atom and the other represents a carbon atom, and B represents a nitrogen atom or a carbon atom. Therefore, as the compound represented by the compound (I),

[Chemical 15] [Wherein each symbol has the same meaning as above], and a compound represented by the formula (a), (c), (d), (e) or (f) is preferable. It is a compound. Among them, the compound (I) is preferably a compound in which B is a nitrogen atom, particularly a compound represented by the formula (c) or (e), and most preferably the formula (c).
Examples thereof include compounds represented by (e).

Among them, in the compound (I), the compound of the formula

[Chemical 16] In the compound represented by, R is 2-fluorobenzyl
2,6-difluorobenzyl or 2-chloro-6
-Fluorobenzyl, R¹Is a 5- to 7-membered heterocyclic group
Or-NR⁶R⁷(R⁶Is a hydrogen atom, a hydroxy group, C_1-6
Alkyl group or C _1-6R is an alkoxy group⁷Is a hydrogen atom
Or C_1-6Alkyl group), R²Is C_{7- 12}Aralchi
Lu group, R³Is C_1-6Alkyl group, R^FourIs the expression

[Chemical 17] A group represented by (in the formula, R ^5a represents a C _1-6 alkoxy group) or a 5-membered nitrogen-containing aromatic heterocyclic group is preferable.

Particularly in compound (I)

[Chemical 18] In the compound represented by, R is 2-fluorobenzyl
2,6-difluorobenzyl or 2-chloro-6
-Fluorobenzyl, R¹Is a 5- to 7-membered heterocyclic group
Or-NR⁶R⁷(R⁶Is a hydrogen atom, a hydroxy group, C_1-6
Alkyl group or C _1-6R is an alkoxy group⁷Is a hydrogen atom
Or C_1-6Alkyl group), R²Is C_{7- 12}Aralchi
Lu group, R³Is C_1-6Alkyl group, R^FourIs the expression

[Chemical 19] A group represented by (in the formula, R ^5a represents a C _1-6 alkoxy group) or a 5-membered nitrogen-containing aromatic heterocyclic group is preferable.

More specifically, 3- (N-benzyl-N)
-Methylaminomethyl) -8- (2,6-difluorobenzyl) -5,8-dihydro-2- {4- (3-furylcarbonylamino) phenyl} -6- (4-methoxyphenyl) -5-oxo Imidazo [1,2-a] pyrimidine, 3- (N-benzyl-N-methylaminomethyl)-
8- (2,6-Difluorobenzyl) -5,8-dihydro-2- {4- (ethylaminocarbonylamino) phenyl} -6- (4-methoxyphenyl) -5-oxoimidazo [1,2-a ] Pyrimidine, 3- (N-benzyl-
N-methylaminomethyl) -8- (2,6-difluorobenzyl) -5,8-dihydro-2- {4- (methoxyaminocarbonylamino) phenyl} -6- (4-methoxyphenyl) -5-oxo Imidazo [1,2-a] pyrimidine or 3- (N-benzyl-N-methylaminomethyl) -8- (2,6-difluorobenzyl) -5,8
-Dihydro-2- {4- (ethylaminocarbonylamino) phenyl} -5-oxo-6- (1-pyrrolyl) imidazo [1,2-a] pyrimidine or salts thereof and the like can be mentioned.

The compound of the present invention (compound (I) or a salt thereof) can be prepared by the methods described below and their modifications,
Further, it can be produced by a known method. For example, a method for producing the compounds represented by the above formulas (e) and (c) is shown below.

Method for producing compound represented by formula (e) or salt thereof

[Chemical 20] [Wherein L represents a leaving group and each symbol has the same meaning as described above]

A suitable solvent which does not adversely affect the reaction of the 2-aminopyrimidine derivative (ii) (for example, ethers such as ethyl ether, dioxane, dimethoxyethane and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, dimethyl). Formamide, amides such as dimethylacetamide, alcohols such as methanol and ethanol, dichloromethane, acetone, etc.) and add an equal amount to a small excess (about 1 to 3 mol) of the α-haloketone derivative (i), The ring-closed derivative (iii) is obtained by stirring at -10 to 40 ° C for about 1 to 24 hours. This is added to a suitable solvent (eg, acetic acid, etc.), and a suitable metal (eg, zinc dust) is added with stirring at about 0 to 100 ° C. to produce a condensed derivative (iv). The aminopyrimidine derivative can be produced by a known method (for example, described in Journal of Indian Chemical Society, 1925, Vol. 2, p. 61-70). The derivative (iv)
A suitable solvent that does not adversely influence the reaction (eg, dimethylformamide, dichloromethane, tetrahydrofuran,
Ethyl ether, dioxane, acetone, etc.) and dissolved in 1 equivalent to a small excess (about 1 to 3 mol) of a base (eg, potassium carbonate, triethylamine, sodium hydride, etc.) and 1 equivalent to excess amount of compound R -L (R
Is as defined above, and L is a leaving group such as halogen)
And stir at about 0-80 ° C. As the reaction temperature,
It is preferably about 15 to 25 ° C (about 20 ° C). The reaction time of this reaction is about 1 to 24 hours. Further, a metal salt such as potassium iodide or sodium iodide may be added to this reaction. In this way, the target compound (v) can be produced.

The compound (v) is dissolved in a suitable solvent which does not affect the reaction (eg, dichloromethane, chloroform, acetic acid, etc.), about 1 to about 10 equivalents of nitric acid is added, and the mixture is added at about -10 to 150 ° C. Then, by stirring for about 1 to 24 hours, or by dissolving in concentrated sulfuric acid and adding about 1 equivalent to a small excess of nitrate (eg, sodium nitrate, potassium nitrate, etc.), at about 0 to about 50 ° C., about 1 equivalent. Compound (vi) or a salt thereof can be produced by stirring for about 24 hours or by a mixed acid which is a mixture of nitric acid and concentrated sulfuric acid. Further, it can be produced by using acetyl nitrate prepared from acetic anhydride and fuming nitric acid.

Compound (vi) does not affect the reaction
Suitable solvent (eg tetrahydrofuran, dimethoxyethane
Etc.) and about 1 to 20 equivalents of alkali
Aqueous solution (eg, water such as potassium carbonate and sodium carbonate)
Solution) and about 1 equivalent to a slight excess (about 1 to about 3 mol) of R^Four
B (OH)₂(R^FourHas the same meaning as above), 0.05
To 0.5 equivalents of tetrakistriphenylphosphine
Palladium [(Ph₃P) _FourPd] and add about 15-15
By stirring at 0 ° C. for about 1 to 24 hours, the compound (v
ii) or salts thereof can be prepared.

The presence of α, α'-azobisisobutyronitrile (AIBN) in a solvent that does not adversely affect the reaction of compound (vii) (eg, halogenated hydrocarbons such as carbon tetrachloride, chloroform and chlorobenzene). Under N-bromosuccinimide (NBS) at about 30-100 ° C for about 0.5-
After stirring for 6 hours, a compound having a bromomethyl group at the 3-position of the imidazopyrimidine ring is obtained. Further, the compound (viii) of the present invention or a salt thereof is produced by reacting with an approximately equimolar amount of R ² R ³ NH (R ² and R ³ have the same meanings as described above). The reaction is carried out in a suitable solvent that does not adversely influence the reaction. Examples of the suitable solvent include amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, alcohols such as ethanol, ethers such as dimethoxyethane, tetrahydrofuran, dioxane and dimethoxyethane, dichloromethane and the like. Halogenated hydrocarbons, ketones such as acetone, esters such as ethyl acetate, etc. are used. This reaction is carried out in the presence of a non-nucleophilic base. As the base, for example, a tertiary organic amine (eg, triethylamine, trimethylamine, diisopropylethylamine, N-methylmorpholine, etc.) is used. The reaction temperature is usually about 10 to 100 ° C.
The reaction time is about 1 to 10 hours. The reaction is preferably carried out with stirring. In this way, the compound (vii
i) can be manufactured. The compound (viii) can also be produced from the compound (x) described in JP-A No. 11-315079.

[Chemical 21] For example, known methods from 6-position carboxylic acids, aldehydes, nitriles, amides, thioamides, imidates, and thioimidates which are easily derived from compound (x) (Chemical Society of Japan: Experimental Chemistry, Volume 24, Organic Synthesis VI, etc.) The heterocyclic compound such as 2-oxazolinyl, 2-thiazolyl, 2-oxazolyl, 5-oxazolyl, 5-tetrazolyl can be produced by Further, the Curtius rearrangement reaction is applied to the carboxylic acid obtained by hydrolyzing the compound (x) to lead it to an amine compound, which is used as a raw material for 1-pyrrolyl, 2,5
-Dioxo-1-pyrrolidinyl, 1,3-dioxo-2
-Isoindolinyl and the like can be produced. Specifically, the compound (x) is dissolved in an appropriate solvent (hydrous methanol, hydrous ethanol, etc.) with potassium hydroxide, sodium hydroxide, etc. to about 0.
A carboxylic acid compound is obtained by reacting at about 100 ° C for about 1 to 12 hours. This carboxylic acid compound and diphenylphosphoric acid azide are allowed to react in t-butanol at about 50 to 150 ° C. for about 1 to 24 hours in the presence of a base such as triethylamine, and a suitable solvent for the Nt-butyloxycarbonyl compound (dichloromethane, Ethyl acetate, etc.), trifluoroacetic acid or ethyl acetate hydrochloric acid, etc.
The amine compound can be obtained by reacting at about 1 to 6 hours. The amine compound is reacted with 2,5-dimethoxytetrahydrofuran in a solvent such as acetic acid in the presence of a base such as sodium acetate at about 0 to 100 ° C. for about 1 to 12 hours to produce a 1-pyrrolyl compound. it can. Further, the amine compound is added to a solvent such as dichloromethane, acetonitrile, or toluene in the presence or absence of succinic anhydride, succinic acid dichloride, phthalic anhydride, phthalic acid dichloride, and a base such as triethylamine at about 0 to 150%. The reaction can be carried out at a temperature of about 1 to 12 hours for 2,5-dioxo-1-pyrrolidinyl and 1,3-dioxo-2-isoindolinyl compounds.

Compound (viii) is dissolved in a suitable solvent (eg, ethanol, methanol, etc.), (a) palladium-carbon is added, and the mixture is reacted at about 15 to 25 ° C. for about 1 to 24 hours in a hydrogen stream, or Alternatively, (b) a metal such as iron powder or tin powder and an acid such as hydrochloric acid, acetic acid or methanesulfonic acid are added to the above solution, and the mixture is added at about -10 to 100 ° C for about 1 to 12 ° C.
Compound (ix) can be produced by reacting for a time.

Method 1 for producing compound (e) In compound (e), R ¹ has an alkyl group which may have a substituent, an aralkyl group which may have a substituent, and a substituent. When it is an optionally substituted aryl group or an optionally substituted heterocyclic group, the compound (ix) is dissolved in a suitable solvent that does not influence the reaction (eg, tetrahydrofuran, dimethoxyethane, etc.), 1 to about 10 equivalents of an organic or inorganic base (eg, triethylamine, potassium carbonate, sodium carbonate, etc.) and 1 to about 10 equivalents of a carboxylic acid activator (R ¹ COX) (X is a halogen atom (chlorine, bromine). ,
(Iodine, etc.) or a leaving group such as phenol and 4-nitrophenol contained in the active ester, and R ¹ has the same meaning as described above), and added at about 15 to about 150 ° C. to about 1
Compound (e) is obtained by stirring for about 24 hours.
The compound (e) is obtained by combining the compound (ix) and the carboxylic acid compound (R ¹ COOH) in the presence of a base such as triethylamine and the like using a suitable condensing agent (eg, dicyclohexylcarbodiimide, water-soluble carbodiimide, benzotriazole-1-).
Iloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) and the like) can be reacted to produce it.

2) Compound (e) wherein R ¹ is an optionally substituted amino group (-NR ⁶ R ⁷ (R ⁶ and R ⁷ are as defined above)) Compound (Ix) is dissolved in a suitable solvent that does not influence the reaction (eg, tetrahydrofuran, dichloromethane, acetonitrile, pyridine, etc.), and about 1 equivalent to about 10
About 1 to about 10 equivalents of isocyanate in the presence or absence of an equivalent amount of a base such as triethylamine or N, N-diisopropylethylamine, and about 15 to 100 ° C.
Then, the compound (e) is obtained by reacting for about 1 to 24 hours. Alternatively, compound (ix) and carbonyldiimidazole (N,
N'-carbonyldiimidazole; CDI) or phosgene (including dimers and trimers) and the like,
Then, an amine (R ⁶ R ⁷ NH) is reacted to obtain a compound (e). The compound (e) includes the compound (ix) and a chloroformate compound (eg, 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, 4-nitrophenyl chloroformate, etc.) and the like. React, then amine (R
It is also possible to react ⁶ R ⁷ NH).

In the reaction of compound (ix) with carbonyldiimidazole or phosgene, etc., the amount of carbonyldiimidazole, phosgene, etc. used depends on the amount of compound (ix) 1
It is about 1 to 3 mol per mol, respectively. This reaction is
It is usually carried out in a suitable solvent that does not adversely influence the reaction. Examples of the solvent include ethers (eg, ethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, dimethylformamide,
Dimethylacetamide etc.), halogenated hydrocarbons (eg chloroform, dichloromethane etc.) etc. are used. The reaction temperature is generally about 0 to about 150 ° C., preferably room temperature (about 15 to about 25 ° C.). The reaction time is usually about 1 to about 36 hours. This reaction is, if necessary,
It is carried out in the presence of a base. Examples of the "base" include inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and thallium hydroxide, or organic bases such as triethylamine and pyridine. . The amount of the "base" to be used is about 2 mol-20 mol, preferably about 2 mol-12 mol, relative to 1 mol of compound (ix). Then, the reaction conditions with the amine are the compound (ix)
The reaction may be performed under the same conditions as the reaction of carbonyldiimidazole or phosgene. The amount of amine used is approximately 2 to 20 mol, preferably approximately 5 to 12 mol, with respect to 1 mol of the compound (ix). The reaction temperature is usually about 0 to 150.
C., preferably at room temperature (about 15 to 25.degree. C.). The reaction time is usually about 1 to 6 hours. Further, carbonyldiimidazole or phosgene and amine may be simultaneously reacted with the compound (ix).

Method for producing compound represented by formula (c) or salt thereof

[Chemical formula 22] [In the formula, X represents a leaving group, R ′ represents a C _1-6 alkyl group, and other symbols have the same meanings as described above]

The compound represented by the formula (xv) or a salt thereof is
2-aminopyrrole derivative (xi) or a salt thereof and an acrylic acid derivative such as ethoxymethylenecarboxylic acid derivative (x
It is produced by reacting with ii) and then reacting with compound RL (R is as defined above and L is a leaving group such as halogen). Further, for the compound represented by the formula (xv) or a salt thereof, nitration ((xv) → (xvi)) and conversion of the methyl group are carried out in the same manner as in the production method of the compound represented by the formula (e). ((Xvi) → (xvii)), amination ((xvii) → (xvii
Among the compounds represented by the formula (I) of the present invention, the compound (c) can be produced by carrying out i)) and conversion of the amino group ((xviii) → (c)).

In this reaction, compound (xi) or its salt 1
The acrylic acid derivative (xii) is used in an amount of 1 to 3 mol per mol. The reaction is carried out without solvent or in a suitable solvent that does not adversely influence the reaction. Examples of the suitable solvent include, for example,
Ethers such as ethyl ether, dioxane, dimethoxyethane and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, amides such as dimethylformamide and dimethylacetamide, alcohols such as methanol and ethanol are used. This reaction may be performed in the presence of a base. Examples of the base include inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and thallium hydroxide, or organic bases such as triethylamine. The reaction temperature is about 0 to 150 ° C, preferably about 15 to 25 ° C. The reaction time is about 1 to 12 hours. In order to produce the desired fused ring compound, a 2-aminopyrrole derivative (x
i) or a salt thereof and an adduct (xiv) of an acrylic acid-based compound (xii) are isolated once, and the operation of reacting the compound RL in a suitable solvent that does not adversely influence the reaction is added. Good. Examples of the suitable solvent include polyphosphoric acid (PPA), polyphosphoric acid ester (PPE), diphenyl ether and the like. A compound represented by the formula (c) or a salt thereof is produced by performing a method similar to the method for producing the compound represented by the formula (e) or a salt thereof from the compound (xv) thus produced. be able to. That is, compound (xvi) is produced from compound (xv) in the same manner as when producing compound (vi) from compound (v). Compound
(xvii) is produced from compound (xvi) in the same manner as when producing compound (viii) from compound (vii). Compound (xv
iii) is produced from compound (xvii) in the same manner as when producing compound (ix) from compound (viii). Compound (c)
Is produced from compound (xviii) in the same manner as when producing compound (e) from compound (ix).

Compounds (i) to (xvii shown in the above production method
i) may form a salt, and the salt is a compound described below.
Examples thereof include the same as the salt of (I). In addition, compound (i) ~
(xviii) may be a hydrate. Compounds (i)-(xviii)
Can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

In each of the above reactions, when the starting compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. The target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino-protecting group include C _1-6 which may have a substituent.
Alkylcarbonyl (eg acetyl, propionyl etc.), formyl, phenylcarbonyl, C _1-6 alkyloxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl etc.), phenyloxycarbonyl (eg benzoxycarbonyl etc.) , C _7-10 aralkyloxycarbonyl (eg, benzyloxycarbonyl, etc.), trityl, phthaloyl and the like are used. Examples of these substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkylcarbonyl (eg, acetyl,
(Propionyl, butyryl, etc.), nitro group, etc. are used, and the number of substituents is about 1 to 3. As the carboxyl group-protecting group, for example, C _1-6 alkyl _optionally having a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl and the like are used. To be As these substituents, a halogen atom (for example, fluorine, chlorine,
Bromine, iodine, etc.), C _1-6 alkylcarbonyl (eg, acetyl, propionyl, butyryl, etc.), formyl, nitro group, etc. are used, and the number of substituents is 1 to 3
It is about an individual.

Examples of the protective group for the hydroxy group include C _1-6 alkyl which may have a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-alkyl).
Butyl, etc.), phenyl, C _7-10 aralkyl (eg,
Benzyl, etc.), C _1-6 alkylcarbonyl (eg,
Acetyl, propionyl etc.), formyl, phenyloxycarbonyl, C _7-10 aralkyloxycarbonyl (eg benzyloxycarbonyl etc.), pyranyl, furanyl, silyl and the like are used. As these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl, phenyl, C _7-10
Aralkyl, nitro group, etc. are used, and the number of substituents is 1
Or about 4 pieces. In addition, as a method for introducing and removing a protecting group, a known method or a method similar thereto (for example,
The method described in Protective Groups in Organic Chemistry (JFWMcOmie et al., Plenum Press Co.) is used. A method of treating with sodium methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like is used.

The compound of the present invention thus obtained
(I) may form a salt. The salt is preferably a physiologically acceptable acid addition salt. Examples of such salts include inorganic acids (eg, hydrochloric acid, hydrobromic acid, nitric acid,
Salts with 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,
Physiologically acceptable acid addition salts with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. are used. Further, the compound (I) of the present invention is -COOH.
In the case of having an acidic group such as, an inorganic base (eg, alkali metal salt or alkaline earth metal such as sodium, potassium, calcium, magnesium, ammonia, etc.) or an organic base (eg, trimethylamine, triethylamine, pyridine, Picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, etc.) may form a physiologically acceptable salt. In addition, the compound (I) or a salt thereof may be a hydrate or a non-hydrate. Examples of the hydrate include monohydrate, 1.5 hydrate and dihydrate.

The compound (I) of the present invention or a salt thereof thus obtained can be isolated and purified by a conventional separation means such as recrystallization, distillation and chromatography. Thus, when the compound of the present invention 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 According to the method according to
It can be converted into an educt or other salt. Compound (I) or a salt thereof may have an asymmetric carbon,
When obtained as a mixture (racemic body) of optically active substances, each optically active substance can be separated by a usual optical resolution means.

The compound (I) or a salt thereof (hereinafter sometimes abbreviated as "the compound of the present invention") is excellent in GnRH.
Has antagonism and low toxicity. Moreover, it is excellent in oral absorbability and duration of action, and also excellent in stability and pharmacokinetics. Furthermore, the manufacturing method is also simple. Therefore, the compound of the present invention suppresses gonadotropin secretion in mammals (for example, humans, monkeys, cows, horses, dogs, cats, rabbits, rats, mice, etc.) by GnRH receptor antagonism, By controlling the sex hormone concentration of the hormone, it can be safely used for the prevention and treatment of male and female hormone dependent diseases and diseases caused by excess of these hormones. For example, the compound of the present invention can be used for sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), bone hormone metastasis of sex hormone-dependent cancer, benign prostatic hyperplasia, uterine fibroids, endometriosis, Uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multilocular ovary syndrome, polycystic ovary syndrome, acne, baldness, Alzheimer's disease (Alzheimer's disease, Alzheimer-type senile dementia) And / or prevention of sex hormone-dependent diseases such as
Useful for treatment. In addition, the compound of the present invention is also useful for the regulation of reproduction in males and females (eg, pregnancy regulator, menstrual cycle regulator, etc.). The compounds of the present invention can further be used as a male and female contraceptive and as a female ovulation inducer. The compound of the present invention can be used for the treatment of infertility by utilizing the restoration of hormone secretion after withdrawal thereof. In addition, LH- is independent of sex hormone.
It can also be used as a prophylactic / therapeutic agent for RH-sensitive benign or malignant tumors. In addition, the sustained-release composition of the present invention is a preventive / therapeutic agent for irritable bowel syndrome, and a preventive agent for postoperative recurrence of sex hormone-dependent cancer (prostate cancer postoperative recurrence preventive agent, premenopausal and postmenopausal breast cancer or ovarian cancer). It can also be used as a postoperative recurrence preventive agent, particularly preferably as a postoperative recurrence preventive agent for breast cancer or ovarian cancer before menopause. Further, the compound 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 compound of the present invention is also useful as a spawning promoter for fish.

The compound of the present invention can be used for suppressing the transient increase in blood testosterone concentration (flare phenomenon) which is observed upon administration of GnRH hyperagonist such as leuprorelin acetate. The compounds of the present invention are leuprorelin acetate and gonadorelin.
adrelin), Buserelin, Triptorelin, Goserelin, Nafarelin, Histrelin, Deslorelin, Meterelin,
It can be used in combination with a GnRH hyperagonist (preferably leuprorelin acetate) such as Lecirelin. In addition, the compound of the present invention is a steroidal or nonsteroidal antiandrogen or antiestrogen, chemotherapeutic agent, peptide GnRH antagonist, α-reductase inhibitor, α-receptor inhibitor, aromatase inhibitor, 17β -It is also effective to use in combination with at least one of hydroxysteroid dehydrogenase inhibitor, adrenal androgen production inhibitor, phosphorylase inhibitor, hormone therapy agent, drug that inhibits the action of cell growth factor or its receptor. is there. Examples of the “chemotherapeutic agent” include Ifosfamide, UTF, adriamycin (Ad
riamycin), Peplomycin, Cisplatin, Cyclophosphamide
phamide), 5-FU, UFT, metrexate (Metho
trexate), mitomycin C (Mitomycin C), and mitoxantrone. The "peptidic GnRH antagonist" includes parenterally administered peptide Gn such as cetrorelix, ganirelix, abarelix and the like.
RH antagonists can be mentioned. Examples of the “adrenal androgen production inhibitor” include lyase (C _17,20 -lyase)
Examples include inhibitors. Examples of the "phosphorase inhibitor" include tyrosine phosphorylase. Examples of the “hormone therapeutic agent” include an anti-estrogen agent, a luteinizing hormone agent (eg, MPA, etc.), an androgen agent, an estrogen agent, an anti-androgen agent and the like.

The "growth factors" may be any substances as long as they are substances that promote the growth of cells. Usually, they are peptides having a molecular weight of 20,000 or less and are bound to a receptor. Factors that exert an action at a low concentration can be mentioned specifically, (1) EGF (epidermal g
rowth factor) or substances having substantially the same activity (eg, EGF, hallegulin (HER2 ligand))
(2) Insulin or a substance having substantially the same activity as insulin (eg, insulin, IGF (insu
lin-like growth factor) -1, IGF-2, etc.),
(3) FGF (fibroblast growth factor) or a substance having substantially the same activity (eg, aFGF, bF)
GF, KGF (Keratinocyte Growth Factor), HGF
(Hepatocyte Growth Factor), FGF-10, etc.),
(4) Other cell growth factors (eg, CSF (colony stim
ulating factor), EPO (erythropoietin), IL-
2 (interleukin-2), NGF (nerve growth factor),
PDGF (platelet-derived growth factor), TGF
β (transforming growth factor β) and the like. The "receptor for cell growth factor" may be any one as long as it is a receptor capable of binding to the above cell growth factor, and specifically, EGF receptor, hallegulin receptor (HER2). , Insulin receptor-1,
Examples include insulin receptor-2, IGF receptor, FGF receptor-1 or FGF receptor-2. Examples of the drug that inhibits the action of the cell growth factor include Herceptin (HER2 receptor antibody). Examples of the drug that inhibits the action of the above cell growth factor or its receptor include herbimycin and PD153035.
(Science 265 (5175) p1093, (1994)).

HER2 inhibitors can also be mentioned as agents that inhibit the action of cell growth factors or their receptors.
As the HER2 inhibitor, an antibody, a low molecular weight compound (synthetic compound, natural product), antisense, a HER2 ligand, a heregulin or a structure thereof can be used as long as it is a substance that inhibits the activity (eg, phosphorylation activity) of HER2. It may be partly modified or modified. Further, it may be a substance that inhibits HER2 activity by inhibiting HER2 receptor (eg, HER2 receptor antibody). HE
Examples of the low molecular weight compound having an R2 inhibitory action include, for example,
The compounds described in WO98 / 03505, specifically 1
Examples include-[3- [4- [2-((E) -2-phenylethenyl) -4-oxazolylmethoxy] phenyl] propyl] -1,2,4-triazole. For benign prostatic hyperplasia, GnRH hyperagonist, antiandrogen, antiestrogen, peptide GnRH antagonist, α-reductase inhibitor, α-receptor inhibitor, aromatase inhibitor, 17β-hydroxysteroid dehydrogenation Combination use of the compound of the present invention with a drug such as an enzyme inhibitor, an adrenal androgen production inhibitor, a phosphorylase inhibitor and the like can be mentioned.

For prostate cancer, GnRH hyperagonist,
Anti-androgens, anti-estrogens, chemotherapeutic agents [eg, ifosfamide, UTF, adriamycin, peplomycin (Peplomyc)
in), cisplatin, etc.], peptide GnRH antagonist, aromatase inhibitor, 17β-hydroxysteroid dehydrogenase inhibitor, adrenal androgen production inhibitor, phosphorylase inhibitor, hormone therapy agent [eg, estrogen] And a compound such as an agent (eg, DSB, EMP, etc.), an anti-androgen agent (eg, CMA, etc.)], an agent that inhibits the action of cell growth factor or its receptor, and the compound of the present invention. For breast cancer, GnRH hyperagonist, anti-estrogen, chemotherapeutic agent [eg, cyclophosphamide, 5
-FU, UFT, Methotrexate, Adriamycin, Mitomycin C (Mi
tomycin C), mitoxantrone, etc.], peptidic GnRH antagonist, aromatase inhibitor, adrenal androgen production inhibitor, phosphorylase inhibitor, hormone therapy agent [eg, anti-estrogen agent (eg, Tamo)
xifen, etc.), luteinizing hormone agents (eg, MPA, etc.), androgens agents, estrogen agents, etc.], agents such as agents that inhibit the action of cell growth factors or their receptors, and the compounds of the present invention are used in combination.

When the compound of the present invention is used as a prophylactic and / or therapeutic agent for the above-mentioned diseases or in the fields of animal husbandry and fisheries, either oral administration or parenteral administration is possible according to a method known per se. It is usually mixed with a pharmaceutically acceptable carrier and usually orally administered as a solid preparation such as tablets, capsules, granules and powders, or injected intravenously, subcutaneously, intramuscularly, by injection, suppository or sublingually. It is parenterally administered as tablets. Further, it may be administered sublingually, subcutaneously, intramuscularly and the like as a sustained release preparation such as sublingual tablet and microcapsule. The daily dose depends on the degree of symptoms;
Age, sex, body weight, sensitivity difference of the administration subject; timing of administration,
Intervals, properties of pharmaceutical preparations, preparations, types; types of active ingredients, etc., and are not particularly limited, but include the aforementioned sex hormone-dependent cancers (eg, prostate cancer, uterine cancer, breast cancer,
Pituitary tumor, etc.), benign prostatic hyperplasia, uterine fibroids, endometriosis, precocious puberty, etc., usually about 0.01 to 100 mg, preferably about 0.02, per kg body weight of a mammal. ~ 20 mg, more preferably 0.1-1
0 mg, most preferably 0.5 to 10 mg, is usually administered in 1 to 4 divided doses per day. The dosage when used in the field of livestock or fisheries is similar to the above, but the target organism 1k
About 0.01 to 30 mg / g body weight, preferably about 0.
1 to 10 mg is usually administered in 1 to 3 times per day.
The content of the compound (I) in the pharmaceutical composition of the present invention is about 0.01 to 100% by weight of the total composition.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances conventionally used as a formulation material are used. Excipients, lubricants, binders, disintegrants in solid formulations; solvents in liquid formulations , Solubilizer, suspending agent,
It is used as an isotonicity agent, a buffering agent, a soothing agent and the like. If necessary, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can also be used. Preferable examples of the above-mentioned excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the above-mentioned binder include crystalline cellulose, sucrose, D-
Mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like can be mentioned. Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine,
Examples thereof include sodium carbonate and sodium citrate. Preferable examples of the suspending agent include, for example, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, and other surfactants; for example, polyvinyl alcohol. ,
Examples thereof include hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose. Preferable examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol and the like.
Preferable examples of the above buffer include buffers such as phosphate, acetate, carbonate, citrate and the like. Preferable examples of soothing agents include benzyl alcohol and the like. Suitable examples of the above preservatives include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol,
Examples include dehydroacetic acid and sorbic acid. Preferable examples of the above antioxidant include sulfite, ascorbic acid and the like.

The compound of the present invention is added with a suspending agent, a solubilizing agent,
By adding a stabilizer, an isotonizing agent, a preservative and the like, a intravenous, subcutaneous or intramuscular injection can be prepared 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 compound of the present invention is administered to, for example, a human, it is safely administered orally or parenterally as a pharmaceutical composition by mixing itself or with an appropriate pharmacologically acceptable carrier, excipient or diluent. can do. Examples of the pharmaceutical composition include oral agents (eg, powders, granules, capsules, tablets), parenteral agents [eg, injections, drip infusions, external preparations (eg, nasal preparations, transdermal preparations, etc.) , Suppositories (eg, rectal suppositories, vaginal suppositories, etc.)]. These preparations can be produced by a method known per se which is generally used in the preparation process.

The compound of the present invention is a dispersant (eg, Tween (Tw
een) 80 (Atlas Powder, USA), HCO6
0 (manufactured by Nikko Chemicals) polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.), preservatives (eg, methylparaben, propylparaben, benzyl alcohol, etc.), tonicity agents (eg, sodium chloride, mannitol, sorbitol, glucose, etc.), etc. Aqueous injections, or dissolved, suspended or emulsified in olive oil, sesame oil, cottonseed oil, vegetable oils such as corn oil, propylene glycol, etc. can be molded into oily injections to give injections. In order to make an oral preparation, the compound of the present invention can be prepared according to a method known per se, for example, an excipient (eg, lactose, sucrose, starch, etc.), a disintegrating agent (eg, starch, calcium carbonate, etc.), a binder (eg, starch). , Gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.), etc. are added, followed by compression molding, and if necessary, taste masking. For the purpose of enteric or sustained release, an oral administration preparation can be prepared by coating by a method known per se. Examples of the coating agent include hydroxypropyl methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 8
0, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, methacrylic acid / acrylic acid copolymer) and dyes (eg, red iron oxide,
Titanium dioxide etc.) is used. In the case of an enteric-coated preparation, an intermediate phase can be provided 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 compound of the present invention can be prepared as a solid, semi-solid or liquid external preparation according to a method known per se. For example, as the above solid, the compound 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 above liquid form is an oily or aqueous suspension, which is similar to the case of the injection. In the case of semi-solid form, an aqueous or oily gel or ointment form is preferable. In addition, these are all pH adjusting agents (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 compound 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. Further, as the aqueous base, for example, polyethylene glycols, propylene glycol, as the aqueous gel base, for example, natural gums, cellulose derivatives,
Examples thereof include vinyl polymers and acrylic acid polymers.

[0055]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below with reference to Reference Examples, Examples, Formulation Examples and Test Examples, but the present invention is not limited thereto. ¹
The H-NMR spectrum was measured using Varian GEMINI 200 (200M) using tetramethylsilane as an internal standard.
Hz) type spectrum meter, JEOL L
All δ values are shown in ppm, measured by an AMBDA 300 (300 MHz) type spectrometer or a Brooker AM 500 (500 MHz) type spectrometer.
"%" Indicates percent by weight unless otherwise specified. However, the yield shows mol / mol%. Other symbols in the present specification have the following meanings. s: singlet d: doublet t: triplet q: quartet dt: double triplet m: multiplet br: wide TFA: trifluoroacetic acid THF: tetrahydrofuran Me: methyl group Et: ethyl group PyBOP: benzotriazol-1-yloxytripyrrolyl Dinophosphonium hexafluorophosphate room temperature indicates a range of about 15 to 25 ° C, but is not particularly limited.

[0056]

EXAMPLES Reference Example 1 Preparation of 2-Amino-5-bromo-4-hydroxypyrimidine 2-amino-4-hydroxypyrimidine (25.0 g, 225 mm
ol) in acetic acid (220 ml) and bromine (12.2 ml) in acetic acid (2
0 ml) solution is added at room temperature. After stirring at room temperature for 2 hours, the precipitated crystals were collected by filtration, washed with ether and dried to give white powder crystals (59.9 g, 98%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.97 (2H, br), 8.08 (1H, s),
9.0-10.5 (2H, br). Reference Example 2 6-Bromo-5,8-dihydro-3-methyl-5-oxo-8- (1-oxo-1-phenyl-2-propyl)-
2-Phenylimidazo [1,2-a] pyrimidine [6-Bromo-5,8-dihydro-3-methyl-5-oxo-8- (1-oxo-1-ph
enyl-2-propyl) -2-phenylimidazo [1,2-a] pyrimidine]
The pyrimidine compound obtained in Reference Example 1 (15.0 g, 55.37 mm
ol) and potassium carbonate (22.96 g, 166.10 mmol) are suspended in dimethylformamide (200 ml), and 2-bromopropiophenone (16.85 ml, 110.73 mmol) is added under ice cooling. At room temperature 1
After stirring for 7 hours, the mixture was partitioned between water (1000 ml) and chloroform (1000 ml), the aqueous layer was extracted with chloroform, the organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel to obtain a pale yellow solid (9.9 g), which was recrystallized from ethyl acetate and hexane to give a pale yellow crystal (6.
9g, 37%). mp 144-145 ℃ ¹ H-NMR (CDCl ₃ ) δ: 1.76 (3H, d), 2.88 (3H, s), 6.
81 (1H, q), 7.34 (1H, t), 7.42 (2H, t), 7.54 (2H,
t), 7.6-7.7 (3H, m), 8.15 (2H, d).

Reference Example 3 6-Bromo-5-hydroxy-3-methyl-2-phenylimidazo [1,2-a] pyrimidine [6-Bromo-5-hydroxy-3-methyl-2-phenylimidazo [1,2] -
Production of a] pyrimidine] Zinc powder (7.79 g) was added to an acetic acid solution (150 mL) of the compound (5.11 g, 11.71 mmol) obtained in Reference Example 2, and the mixture was heated with stirring at 60 ° C for 20 minutes. The reaction mixture was filtered through Celite to remove zinc, and the resulting substance was filtered off with chloroform (5
It is dissolved in 00 mL), washed twice with water (500 mL), dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by recrystallization (chloroform-hexane), white crystals
I get (2.85g, 80%). ¹ H-NMR (CDCl ₃ ) δ: 2.92 (3H, s), 7.5-7.6 (5H, m),
7.84 (1H, s). FAB-MS m / e 304.1 (MH ⁺ ). Reference Example 4 6-Bromo-8- (2,6-difluorobenzyl) -5,
8-dihydro-3-methyl-5-oxo-2-phenylimidazo [1,2-a] pyrimidine [6-Bromo-8- (2,6-difluorobenzyl) -5,8-dihydro-3-met
Production of hyl-5-oxo-2-phenylimidazo [1,2-a] pyrimidine] DMF (2 mg) of the compound (500 mg, 1.64 mmol) obtained in Reference Example 3
5 ml) potassium carbonate (340 mg, 2.47 mmol), 2,6-difluorobenzyl chloride (320 mg, 1.97 mmol) and potassium iodide (136 mg, 0.82 mmol) are added to the solution, and the mixture is stirred at room temperature for 16 hours. The crystalline substance obtained by concentrating the reaction mixture under reduced pressure was washed with chloroform (300 ml) and water (300 ml).
Distribute to. The aqueous layer was extracted with chloroform (100 ml), the combined organic layers were dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give a brown-white crystalline crude product (700 mg). Purification by flash column chromatography gives white crystals (514 mg, 73%). ¹ H-NMR (CDCl ₃ ) δ: 2.89 (3H, s), 5.47 (2H, s), 7.0
0 (2H, t), 7.3-7.5 (4H, m), 7.6-7.7 (3H, m).

Reference Example 5 6-Bromo-8- (2,6-difluorobenzyl) -5,
8-dihydro-3-methyl-2- (4-nitrophenyl)
-5-oxoimidazo [1,2-a] pyrimidine [6-Bromo-8- (2,6-difluorobenzyl) -5,8-dihydro-3-met
hyl-2- (4-nitrophenyl) -5-oxoimidazo [1,2-a] pyrimidin
Production of e] Compound (500 mg, 1.16 mmol) obtained in Reference Example 4 concentrated sulfuric acid
(4 ml) in a solution of sodium nitrate (104 mg, 1.22 mmol) 1M
The sulfuric acid solution is added dropwise under ice cooling, and the mixture is stirred for 30 minutes under ice cooling.
The reaction mixture is poured into ice water (150 ml) and extracted with chloroform. The combined organic layers were washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give a brown-yellow crystalline crude product.
(590 mg) is obtained. Purified by flash column chromatography, yellow crystals (370mg, 67%)
Is obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.95 (3H, s), 5.46 (2H, s), 7.0
0 (2H, t), 7.3-7.5 (1H, m), 7.76 (1H, s), 7.90 (2
H, d), 8.30 (2H, d). FAB-MS m / e 475.0 (MH ⁺ ). Reference Example 6 8- (2,6-Difluorobenzyl) -5,8-dihydro-6- (4-methoxyphenyl) -3-methyl-2-
(4-Nitrophenyl) -5-oxoimidazo [1,2-
a] Pyrimidine [8- (2,6-Difluorobenzyl) -5,8-dihydro-6- (4-methoxyp
henyl) -3-methyl-2- (4-nitrophenyl) -5-oxoimidazo [1,2
Production of -a] pyrimidine] The compound (500 mg, 1.05 mmol) obtained in Reference Example 5 was added to a 1,2-dimethoxyethane (60 ml) solution degassed under an argon stream, and 4-methoxyphenylboric acid (176 mg, 1.16m
mol), 2N sodium carbonate aqueous solution (5 ml), tetrakistriphenylphosphine palladium (122 mg, 0.11 mmol)
Is added and the mixture is heated under reflux for 21 hours. The reaction mixture is partitioned between chloroform (200 ml) and water (100 ml), and the aqueous layer is further extracted with chloroform (100 ml). The organic layer is dried and concentrated under reduced pressure, and the residue obtained is purified by flash column chromatography to give an orange solid (380 mg, 72%). The orange solid is recrystallized from chloroform-ether to give yellow crystals (358 mg, 68%). mp 240-241 ℃ ¹ H-NMR (CDCl ₃ ) δ: 2.99 (3H, s), 3.84 (3H, s), 5.4
8 (2H, s), 6.94-7.03 (4H, m), 7.3-7.4 (1H, m), 7.4
5 (2H, d), 7.56 (1H, s), 7.92 (2H, d), 8.31 (2H,
d).

Reference Example 7 3- (N-benzyl-N-methylaminomethyl) -8-
(2,6-difluorobenzyl) -5,8-dihydro-6
-(4-Methoxyphenyl) -2- (4-nitrophenyl) -5-oxoimidazo [1,2-a] pyrimidine [3- (N-Benzyl-N-methylaminomethyl) -8- (2,6-difluoro
benzyl) -5,8-dihydro-6- (4-methoxyphenyl) -2- (4-nitor
Production of ophenyl) -5-oxoimidazo [1,2-a] pyrimidine] The compound (150 mg, 0.30 mmol) obtained in Reference Example 6, N-bromosuccinimide (56 mg, 0.31 mmol) and 2,2'-azobis (iso Butyronitrile) (5 mg, 0.03 mmol) suspended in chlorobenzene (15 ml) was heated under reflux for 1 hour,
It becomes a clear brown solution. After returning the reaction mixture to room temperature,
N-Ethyldiisopropylamine (75 mg, 0.60 mmol) and N-methylbenzylamine (43 mg, 0.36 mmol) are added, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is partitioned between saturated aqueous sodium hydrogen carbonate solution (100ml) and chloroform (100ml). The aqueous layer was extracted with chloroform (50 ml), the combined organic layers were washed with saturated brine (100 ml), dried over magnesium sulfate, evaporated to remove the solvent under reduced pressure, and purified by flash column chromatography. Recrystallized from ethyl-n-hexane to give yellow crystals (112mg, 60%)
To get mp 152-153 ℃ ¹ H-NMR (CDCl ₃ ) δ: 2.27 (3H, s), 3.69 (2H, s), 3.8
5 (3H, s), 4.40 (2H, s), 5.50 (2H, s), 6.9-7.1 (4
H, m), 7.1-7.3 (5H, m), 7.3-7.4 (1H, m), 7.48 (2H,
d), 7.59 (1H, s), 8.2-8.4 (4H, m). Reference Example 8 2- (4-aminophenyl) -3- (N-benzyl-N)
-Methylaminomethyl) -8- (2,6-difluorobenzyl) -5,8-dihydro-6- (4-methoxyphenyl) -5-oxoimidazo [1,2-a] pyrimidine [2- (4- Aminophenyl) -3- (N-benzyl-N-methylaminomethy
l) -8- (2,6-difluorobenzyl) -5,8-dihydro-6- (4-methoxy
Production of phenyl) -5-oxoimidazo [1,2-a] pyrimidine] The compound (100 mg, 0.16 mmol) obtained in Reference Example 7, iron powder
A suspension of (45 mg, 0.80 mmol) in ethanol (2 ml) was ice-cooled, methanesulfonic acid (155 mg, 1.61 mmol) was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate solution (100 ml), chloroform (50 ml) is further added, and the mixture is filtered through Celite. The aqueous layer was extracted with chloroform (50 ml) and the combined organic layers were saturated brine.
After washing with (100ml) and drying over magnesium sulfate,
The solvent is distilled off under reduced pressure. The resulting residue is purified by flash column chromatography to give a pale yellow amorphous solid.
(60 mg, 63%) is obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.17 (3H, s), 3.64 (2H, s), 3.8
3 (3H, s), 4.35 (2H, s), 5.48 (2H, s), 6.75 (2H,
d), 6.9-7.0 (5H, m), 7.1-7.4 (5H, m), 7.4-7.5 (3H,
m), 7.90 (2H, d).

Reference Example 9 6-Amino-3- (N-benzyl-N-methylaminomethyl) -8- (2,6-difluorobenzyl) -5,8-dihydro-2- (4-nitrophenyl)- 5-oxoimidazo [1,2-a] pyrimidine [6-Amino-3- (N-benzyl-N-methylaminomethyl) -8- (2,6-
difluorobenzyl) -5,8-dihydro-2- (4-nitrophenyl) -5-ox
Preparation of oimidazo [1,2-a] pyrimidine] 8- (2,6-difluorobenzyl) -5,8-dihydro-3- (N-methyl-N-benzylaminomethyl) -2
-(4-Nitrophenyl) -5-oxoimidazo [1,
2-a] pyrimidine-6-carboxylic acid ethyl ester (JP-A-11-315079) (4.0 g, 6.81 mmol)
Is dissolved in 1% water-containing ethanol (100 ml), potassium hydroxide (0.46 g, 8.17 mmol) is added thereto, and the mixture is stirred at 80 ° C. for 1 hour. The reaction mixture is ice-cooled, neutralized with 1N hydrochloric acid, and concentrated under reduced pressure. Recrystallization of the residue from acetone-water gives yellow crystals (2.98 g). The crystals (1.0 g) were dissolved in t-butanol (20 ml) and then triethylamine (0.76 m
l) and diphenylphosphoric acid azide (0.45 ml) are added, and the mixture is heated under reflux for 2 hours. The resulting reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between chloroform and water, the chloroform layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography to give a yellow amorphous substance (0.87 g). A solution of this yellow amorphous substance (0.7 g) in dichloromethane (20 ml) was ice-cooled, TFA (5 ml) was added, and the mixture was stirred at room temperature for 3 hours. The solvent of the reaction mixture is evaporated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate, and the residue obtained by distilling off chloroform under reduced pressure was purified by flash column chromatography to give a yellow amorphous substance (0.
52g, 53%). FAB-MS m / e 531.1 (MH ⁺ ). Anal. Calcd for C ₂₈ H ₂₄ N ₆ 0 ₃ F ₂・ 0.5H ₂ O: C, 62.33;
H, 4.67; N, 15.58.Found: C, 62.17; H, 4.81; N, 1
5.57. Reference example 10 2- (4-aminophenyl) -3- (N-benzyl-N)
-Methylaminomethyl) -8- (2,6-difluorobenzyl) -5,8-dihydro-5-oxo-6- (1-
Pyrolyl) imidazo [1,2-a] pyrimidine [2- (4-Aminophenyl) -3- (N-benzyl-N-methylaminomethy
l) -8- (2,6-difluorobenzyl) -5,8-dihydro-5-oxo-6- (1-p
Preparation of yrrolyl) imidazo [1,2-a] pyrimidine] The compound obtained in Reference Example 9 (0.47 g, 0.89 mmol) of acetic acid (10
ml) solution, 2,5-dimethoxytetrahydrofuran (129 mg,
0.98 mmol) and sodium acetate (80 mg, 0.98 mmol) are added, and the mixture is stirred at 60 ° C for 4 hr. The resulting reaction mixture was added to saturated aqueous sodium hydroxide solution (200 ml), and chloroform was added.
Extract with (100 ml). The extract is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by flash column chromatography to give a yellow amorphous material (0.18g). This yellow amorphous material
(0.15 g) is dissolved in a mixed solvent of ethanol (5 ml) and dichloromethane (2 ml), iron powder (95 mg) and concentrated hydrochloric acid (0.5 ml) are added under ice cooling, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is neutralized with 1N aqueous sodium hydroxide solution, and the insoluble matter is removed by filtration. The residue obtained by concentrating the filtrate under reduced pressure is partitioned with saturated aqueous sodium hydrogen carbonate solution and chloroform, and the chloroform layer is dried over magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by flash column chromatography,
A pale yellow amorphous material (50 mg, 13%) is obtained. FAB-MS m / e 551.1 (MH ⁺ ).

Example 1 3- (N-benzyl-N-methylaminomethyl) -8-
(2,6-difluorobenzyl) -5,8-dihydro-2
-{4- (3-furylcarbonylamino) phenyl}-
6- (4-methoxyphenyl) -5-oxoimidazo [1,2-a] pyrimidine [3- (N-Benzyl-N-methylaminomethyl) -8- (2,6-difluoro
benzyl) -5,8-dihydro-2- {4- (3-furylcarbonylamino) phe
nyl} -6- (4-methoxyphenyl) -5-oxoimidazo [1,2-a] -pyrim
Preparation of the compound obtained in Reference Example 8 (100 mg, 0.17 mmol), 3-furancarboxylic acid (42 mg, 0.37 mmol) and N-ethyldiisopropylamine (98 mg, 0.76 mmol) in dichloromethane
(5 ml) PyBOP (194 mg, 0.37 mmol) was added to the solution under ice cooling, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was mixed with chloroform (50 ml) and saturated aqueous sodium hydrogen carbonate solution (50
ml). The aqueous layer was extracted with chloroform (30 ml), the combined organic layers were washed with saturated brine, dried over magnesium sulfate, evaporated under reduced pressure, and purified by flash column chromatography to give a pale yellow amorphous substance.
(70 mg, 60%) is obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 3.65 (2H, s), 3.8
3 (3H, s), 4.37 (2H, s), 5.49 (2H, s), 6.76 (1H,
s), 6.9-7.0 (4H, s), 7.1-7.3 (4H, m), 7.3-7.4 (1H,
m), 7.4-7.5 (4H, m), 7.5-7.6 (3H, m), 8.0-8.1 (3H,
m). This pale yellow amorphous material (70 mg) in dichloromethane (5 m
l) To the solution under ice-cooling, 1M ethereal hydrochloric acid (0.2 ml) was added, the solvent was evaporated under reduced pressure, and the residue was recrystallized from chloroform-ethyl acetate-ether to give the hydrochloride (64 mg). mp 203-204 ℃ FAB-MS m / e 686.2 (MH ⁺ ). Anal. Calcd for C ₄₀ H ₃₃ N ₅ 0 ₄ F ₂・ 1.0HCl ・ 0.5H ₂ O: C,
65.71; H, 4.82; N, 9.58. Found: C, 65.51; H, 4.8
9; N, 9.56.

Example 2 3- (N-benzyl-N-methylaminomethyl) -8-
(2,6-difluorobenzyl) -5,8-dihydro-2
-{4- (ethylaminocarbonylamino) phenyl}
-6- (4-Methoxyphenyl) 5-oxoimidazo [1,2-a] pyrimidine [3- (N-Benzyl-N-methylaminomethyl) -8- (2,6-difluoro
benzyl) -5,8-dihydro-2- {4- (ethylaminocarbonylamino)
phenyl} -6- (4-methoxyphenyl) -5-oxoimidazo [1,2-a] pyr
Production of imidine] A solution of the compound (70 mg, 0.12 mmol) obtained in Reference Example 8 and ethyl isocyanate (42 mg, 0.59 mmol) in pyridine (5 ml) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure,
Recrystallized from ethyl acetate-n-hexane to give pale yellow crystals (49
mg, 62%). ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t), 2.21 (3H, s), 3.3
3 (2H, q), 3.67 (2H, s), 3.84 (3H, s), 4.37 (2H,
s), 4.74 (1H, br), 5.49 (2H, s), 6.30 (1H, br), 6.
9-7.0 (4H, s), 7.1-7.5 (11H, m), 8.06 (2H, d) .mp 171-173 ℃ FAB-MS m / e 663.2 (MH ⁺ ). Anal. Calcd for C ₃₈ H ₃₆ N _{60 3} F ₂・ 0.5H ₂ O: C, 67.95;
H, 5.55; N, 12.51. Found: C, 67.57; H, 5.51; N, 1
2.40.

Example 3 3- (N-benzyl-N-methylaminomethyl) -8-
(2,6-difluorobenzyl) -5,8-dihydro-2
-{4- (Methoxyaminocarbonylamino) phenyl} -6- (4-methoxyphenyl) 5-oxoimidazo [1,2-a] pyrimidine [3- (N-Benzyl-N-methylaminomethyl) -8- (2 , 6-difluoro
benzyl) -5,8-dihydro-2- {4- (methoxyaminocarbonylamin
o) phenyl} -6- (4-methoxyphenyl) -5-oxoimidazo [1,2-a] p
Production of yrimidine] A solution of the compound (100 mg, 0.17 mmol) obtained in Reference Example 8 in methylene chloride (5 ml) was charged with carbonyldiimidazole (55 m
g, 0.34 mmol) and triethylamine (0.047 ml, 0.34 mmo
l) is added under ice cooling, and the mixture is further stirred at room temperature for 19 hours. O-Methylhydroxylamine hydrochloride was added to the reaction solution under ice cooling.
(141mg, 1.69mmol) and triethylamine (0.24ml, 1.69mm
ol) is added and the mixture is stirred at room temperature for 2 hours. The reaction mixture was mixed with saturated aqueous sodium hydrogen carbonate solution (50 ml) and chloroform (50 m
l) and extract the aqueous layer with chloroform (50 ml),
The combined organic layers are dried over magnesium sulfate, and the solvent is evaporated under reduced pressure to give a yellow crude product. Purification by flash column chromatography gives a brown-white amorphous substance (100 mg, 89%). ¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 3.65 (2H, s), 3.8
3 (6H, d), 4.37 (2H, s), 5.49 (2H, s), 6.95-7.01
(4H, s), 7.14-7.26 (4H, m), 7.33-7.38 (1H, m), 7.4
9 (3H, t), 7.60 (3H, t), 8.10 (2H, d). This brown-white non-crystalline substance is converted into hydrochloride by the same method as in Example 1. mp 200-204 ℃ FAB-MS m / e 665.2 (MH ⁺ ). Anal. Calcd for C ₃₇ H ₃₄ N _{60 4} F ₂・ 1.0HCl ・ 0.5H ₂ O: C,
62.58; H, 5.11; N, 11.83. Found: C, 62.72; H, 5.0
6; N, 11.71.

Example 4 3- (N-benzyl-N-methylaminomethyl) -8-
(2,6-difluorobenzyl) -5,8-dihydro-2
-{4- (ethylaminocarbonylamino) phenyl}
-5-oxo-6- (1-pyrrolyl) imidazo [1,2-
a] Pyrimidine [3- (N-Benzyl-N-methylaminomethyl) -8- (2,6-difluoro
benzyl) -5,8-dihydro-2- {4- (ethylaminocarbonylamino)
phenyl} -5-oxo-6- (1-pyrrolyl) imidazo [1,2-a] pyrimidi
ne] Production of Reference Example 10 Compound (40 mg, 0.07 mmol) THF (3 m
l) Triethylamine (10 μl) and ethyl isocyanate (55 μl) were added to the solution, and the mixture was stirred at room temperature for 16 hours. The reaction mixture is concentrated under reduced pressure and partitioned with water and chloroform. The chloroform layer was dried over magnesium sulfate, and the residue obtained by evaporating the solvent under reduced pressure was purified by flash column chromatography to give a brown white amorphous substance (32 mg, 75%).
Is obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.07 (3H, t), 2.21 (3H, s), 3.6
0 (2H, s), 3.08-3.12 (2H, m), 4.30 (2H, s), 5.42
(2H, s), 6.29-6.32 (2H, m), 6.75 (2H, d), 6.85-6.8
9 (2H, m), 6.92-7.03 (2H, m), 7.14-7.27 (5H, m),
7.34-7.45 (1H, m), 7.58 (1H, s), 7.90 (2H, d), 8.24
(1H, d), 8.52 (1H, s). This brown-white amorphous substance is converted to the hydrochloride by the same method as in Example 1. mp 181-185 ℃ FAB-MS m / e 622.3 (MH ⁺ ). Anal. Calcd for C ₃₅ H ₃₃ N ₇ 0 ₂ F ₂・ 2.0HCl ・ 2.0EtOAc:
C, 60.16; H, 5.32; N, 13.27. Found: C, 60.34; H,
5.13; N, 13.15.

Test Example 1 (1) Preparation of ¹²⁵ I-leuprorelin: 10 μl of 3 × 10 ⁻⁴ M leuprorelin aqueous solution, and 0.01 mg / m
l Lactoperoxidase 10 μl in a tube,
10 μl (37 MBq) of Na ¹²⁵ I solution was added, and after stirring, 10 μl of 0.001% H ₂ O ₂ was added to obtain about 15-
The reaction was carried out at 25 ° C for 20 minutes. Stop the reaction by adding 700 μl of 0.05% TFA (trifluoroacetic acid) solution,
Purified by reverse phase HPLC. The conditions of HPLC are shown below. ¹²⁵ I-leuprorelin has a retention time of 26-27
Eluted in minutes. Column: TSKgel ODS-80 ^™ (TM indicates a registered trademark. The same applies hereinafter) CTR (4.6 mm × 10 c
m) 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
Min (50% solvent A + 50% solvent B) -40 min (100%
Solvent B) Elution temperature: about 15 to 25 ° C Elution rate: 1 ml / min (2) Preparation of CHO (Chinese Hamster Ovary) cell membrane fraction containing human GnRH receptor: European Patent Application Publication EP-06
Human GnRH receptor-expressing CHO cells (10 ⁹ cells) prepared by the method described in 78577A were treated with 5 mM EDTA.
The suspension was suspended in phosphate buffered saline (PBS-EDTA) containing (ethylenediaminetetraacetic acid) and centrifuged at 100 xg for 5 minutes. Add homogenate buffer for cells (10 mM NaHCO ₃ , 5 mM EDT to the cell pellet).
10 ml of A, pH 7.5) was added and homogenized using a Polytron homogenizer. Centrifuge at 400 xg for 15 minutes and transfer the supernatant to an ultracentrifuge tube at 100,000 xg for 1 minute.
After centrifugation for a time, a precipitate of the membrane fraction was obtained. 2m of this precipitate
l assay buffer (25 mM Tris-HC
1, 1 mM EDTA, 0.1% BSA (bovine serum albumin), 0.25 mM PMSF (phenylmethanesulfonyl fluoride), 1 μg / ml pepstatin, 20 μg / ml leupeptin, 100 μg / ml phosphoramidon, 0.03% horse mackerel Sodium chloride, p
H7.5) and suspended at 100,000 xg 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.

(3) Measurement of ¹²⁵ I-leuprorelin binding inhibition rate: The human membrane fraction prepared in the above (2) was diluted with assay buffer to 200 μg / ml, and 188 μl was dispensed into each tube. did. 2 μl of a 2 mM compound dissolved in 60% DMSO (dimethyl sulfoxide),
10 μl of 38 nM ¹²⁵ I-leuprorelin was added simultaneously. 60% D to determine maximum binding
A reaction solution was prepared by adding 2 μl of MSO and 10 μl of 38 nM ¹²⁵ I-leuprorelin. To measure the amount of non-specific binding, 2 μl of 100 μM leuprorelin dissolved in 60% DMSO and 38 nM of
A reaction solution to which 10 μl of ¹²⁵ I-leuprorelin was added was also prepared at the same time. The reaction was carried out at 25 ° C for 60 minutes. After the reaction, the reaction solution was suction-filtered using a Whatman glass filter (GF-F) treated with polyethyleneimine. After filtration, ¹²⁵ I- remained on the filter paper using a γ-counter
The radioactivity of leuprorelin was measured. The following formula: PMB = (TB-SB) / (TB-NSB) × 100 (wherein TB: maximum binding radioactivity, SB: radioactivity when a test compound is added, NSB: non-specific binding radioactivity The binding inhibition rate (%) of the test compound (P)
MB) look, then determine the inhibitory rate by changing the concentration of the test compound, the concentration giving a density (i.e. PMB = 50% of the test compound to inhibit binding of 50%, IC ₅₀ value) than the Hill plot It was calculated. The following table shows IC ₅₀ values obtained by measuring the compounds obtained in the above Examples as test compounds by the above-mentioned measuring method.

[Table 1]

Formulation Example 1 Compound (100 mg) prepared in Example 3, lactose 1
Using 65 mg, corn starch 25 mg, polyvinyl alcohol 4 mg and magnesium stearate 1 mg,
A tablet is produced by a conventional method.

Formulation Example 2 The compound (5 g) produced in Example 3 was dissolved in distilled water for injection to make a total volume of 100 ml. This solution was aseptically filtered using a 0.22 μm membrane filter (Sumitomo Electric Industries, Ltd. or Sartorius), dispensed in 2 ml aliquots into washed and sterilized vials, and freeze-dried by a conventional method.
Prepare mg / vial of lyophilized injection.

Formulation Example 3 Compound (100 mg) produced in Example 3, lactose 1
Using 65 mg, corn starch 25 mg, polyvinyl alcohol 4 mg and magnesium stearate 1 mg,
A tablet is produced by a conventional method.

Formulation Example 4 The compound (5 g) prepared in Example 3 was dissolved in distilled water for injection to give a total volume of 100 ml. This solution was aseptically filtered using a 0.22 μm membrane filter (Sumitomo Electric Industries, Ltd. or Sartorius), dispensed in 2 ml aliquots into washed and sterilized vials, and freeze-dried by a conventional method.
Prepare mg / vial of lyophilized injection.

Formulation Example 5 Compound (100 mg) produced in Example 3, lactose 1
Using 65 mg, corn starch 25 mg, polyvinyl alcohol 4 mg and magnesium stearate 1 mg,
A tablet is produced by a conventional method.

Formulation Example 6 (1) Compound prepared in Example 3 5 g (2) Lactose / Crystalline Cellulose (granules) 330 g (3) D-mannitol 29 g (4) Low-substituted hydroxypropylcellulose 20 g (5) Talc 25 g (6) Hydroxypropyl cellulose 50g (7) Aspartame 3g (8) Dipotassium glycyrrhizinate 3g (9) Hydroxypropylmethylcellulose 2910 30g (10) Titanium oxide 3.5g (11) Yellow ferric oxide 0.5g (12) Light Silicic anhydride 1 g (1), (3), (4), (5), (6), (7) and (8) are suspended or dissolved in purified water and coated on the core particles of (2). Make fine particles. The fine granules are coated with (9) to (11) to prepare coated fine granules, which are mixed with (12) to prepare 500 g of 1% fine granules of the compound obtained in Example 3. This is divided into 500 mg each.

[0073]

The compounds of the present invention have excellent gonadotropin-releasing hormone antagonism. Furthermore, it has good oral absorbability and is excellent in stability and pharmacokinetics. It is also low in toxicity and excellent in safety. Therefore, it can be used, for example, as a prophylactic or therapeutic agent for hormone-dependent diseases. Specifically, for example, as a drug, sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer,
Pituitary tumor), benign prostatic hyperplasia, uterine fibroids, endometriosis, precocious puberty, amenorrhea syndrome, multilocular ovary syndrome,
It is effective as a prophylactic or therapeutic agent for acne, a pregnancy regulator (eg, contraceptive, etc.), an infertility therapeutic agent, a menstrual regulator, and in the field of animal husbandry, regulation of animal estrus, meat quality for meat. It is also effective as a fish spawning promoter in the field of fisheries control, animal growth control and fisheries.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 15/08 A61P 15/08 15/16 15/16 15/18 15/18 17/10 17/10 17 / 14 17/14 25/28 25/28 35/00 35/00 43/00 123 43/00 123 F term (reference) 4C050 AA01 BB05 CC08 EE03 GG03 HH02 HH04 4C086 AA01 AA02 AA03 CB05 MA01 MA04 NA14 NA15 ZA16 ZA81 ZA86 ZA89 ZB26 ZC03

Claims (17)

[Claims] 1. A formula [Chemical 1] [In the formula, either A or D is a nitrogen atom and the other is
Carbon atom or both are nitrogen atoms, B is nitrogen atom or
Carbon atom, R is a halogenobenzyl group, R¹Is hydrogen
Child, an alkyl group which may have a substituent, a substituent
Optionally having an aralkyl group, optionally having a substituent
An aryl group, a heterocyclic group which may have a substituent, or
Is an amino group which may have a substituent, R²Is a substituent
Optionally having an alkyl group or a substituent
The aralkyl group which may be ³Is a hydrogen atom or a substituent
An alkyl group which may have R^FourIs an expression [Chemical 2] (In the formula, R^FiveIs halogen, alkyl group, acyl group,
Carboxyl that may be tellurized or amidated
Group, hydroxy group, alkoxy group, thiol group, alk
Ruthio group, amino group, monoalkylamino group, dialky
Luamino group, monoacylamino group or diacylamino group
Ring E is R^FiveMay have a substituent in addition to
Represents a benzene ring) or a substituent represented by
A heterocyclic group which may be present] or
Its salt. 2. R ¹ is (1) hydrogen atom, (2) (i) hydroxy, (ii) C _1-7 acyloxy, (iii) benzoyloxy, (iv) C _1-6 alkoxycarbonyl, benzyloxycarbonyl. , C _1-4 acyl, C _1-4 alkyl and C _1-3
An amino optionally having 1 or 2 substituents selected from alkylsulfonyl, (v) C _1-10 alkoxy and
(vi) C _1-3 alkoxy -C _{1 -3} 1 without a substituent selected from alkoxy to 5 optionally having C _1-6 alkyl group, (3) (i) hydroxy, (ii) C _{1 -7} acyloxy, (i
ii) having 1 or 2 substituents selected from benzoyloxy, (iv) C _1-6 alkoxycarbonyl, benzyloxycarbonyl, C _1-4 acyl, C _1-4 alkyl and C _1-3 alkylsulfonyl. May amino, (v) C
_1-10 alkoxy and (vi) C _1-3 alkoxy -C _{1 -3} 1 without a substituent selected from alkoxy to 5 optionally having C _7-12 aralkyl group, (4) (i) hydroxy, (ii)
C _1-7 acyloxy, (iii) benzoyloxy, (iv) C
_1-6 alkoxycarbonyl, benzyloxycarbonyl, C _1-4 acyl, C _1-4 alkyl and amino optionally having 1 or 2 substituents selected from C _1-3 alkylsulfonyl, (v) C _1-10 alkoxy and (vi) C
_1-3 alkoxy -C _{1 -3} 1 without a substituent selected from alkoxy to 5 optionally having C _6-12 aryl group, (5)
(i) hydroxy, (ii) C _1-7 acyloxy, (iii) benzoyloxy, (iv) C _1-6 alkoxycarbonyl, benzyloxycarbonyl, C _1-4 acyl, C _1-4 alkyl and C _1-3 Substituent selected from alkylsulfonyl is 1
Or two may have amino, which may have five to 1 substituent selected from (v) C _1-10 alkoxy and (vi) C _1-3 alkoxy -C _{1 -3} alkoxy 5- to 7-membered heterocyclic group or (6) -NR ⁶ R ⁷ (R ⁶ is a hydrogen atom, a hydroxy group, a C _1-6 alkyl group or a C _1-6 alkoxy group, and R ⁷ is a hydrogen atom or C _{1 -6} alkyl group), R ² is (1) (i) hydroxy, (ii) C _1-7 acyloxy, (iii) benzoyloxy, (iv) C _1-6 alkoxycarbonyl, benzyloxycarbonyl, C _{1 -4acyl} , amino optionally having 1 or 2 substituents selected from C _1-4 alkyl and C _1-3 alkylsulfonyl, (v) C _1-10 alkoxy, (vi) C _1-3 Alkoxy-C
_1-3 alkoxy and (vii) a C _1-6 alkyl group optionally having 1 to 5 substituents selected from a 5- to 6-membered aromatic heterocyclic group, (2) (i) hydroxy, ( ii) C _1-7
Acyloxy, (iii) benzoyloxy, (iv) C _1-6 alkoxycarbonyl, benzyloxycarbonyl, C
_1-4 acyl, C _1-4 alkyl and C _1-3 alkylsulfonyl, amino optionally having 1 or 2 substituents, (v) C _1-10 alkoxy and (vi) C _{1- 3} alkoxy -C _{1 -3} 1 without a substituent selected from alkoxy to 5 optionally having C _7-12 aralkyl group, R ³ (1)
Hydrogen atom or (2) (i) hydroxy, (ii) C _1-7 acyloxy, (iii) benzoyloxy, (iv) C _1-6 alkoxycarbonyl, benzyloxycarbonyl, C _1-4 acyl, C _1-4 alkyl and C _1-3 alkyl substituents selected from alkylsulfonyl which may have one or two amino, from (v) C _1-10 alkoxy and (vi) C _1-3 alkoxy -C _{1 -3} alkoxy A C _1-6 alkyl group _optionally having 1 to 5 substituents selected, R ⁴ is represented by the formula (i): (In the formula, R ⁵ is halogen, C _1-6 alkyl group, C _1-6 acyl group, carboxyl group, C _1-6 alkoxycarbonyl group, carbamoyl group, N-mono C _1-6 alkylcarbamoyl group, N, N-diC _1-6 alkylcarbamoyl group, hydroxy group, C _1-6 alkoxy group, thiol group, C _1-6 alkylthio group, amino group, mono C _1-6 alkylamino group, di C _1-6 alkylamino group group, a mono C _1-6 acylamino group or a di C _1-6 acylamino group, ring E may further halogen, hydroxy, may have a substituent group selected from C _1-6 alkyl or C _{1 -6} alkoxy A group represented by benzene ring), (ii) halogen, C _1-6 alkyl,
C _1-6 acyl, carboxyl, C _1-6 alkoxycarbonyl, carbamoyl, N-mono C _1-6 alkylcarbamoyl, N, N-diC _1-6 alkylcarbamoyl, hydroxy, C _1-6 alkoxy, thiol, C _1-6 alkylthio,
5- or 6-membered aromatic optionally having a substituent selected from amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, mono-C _1-6 acylamino and di-C _1-6 acylamino A heterocyclic group or (iii) C _1-6 alkyl, C _1-6 acyl, carboxyl, C _1-6 alkoxycarbonyl, carbamoyl, N-mono C _1-6 alkylcarbamoyl,
N, N-diC _1-6 alkylcarbamoyl, hydroxy,
C _1-6 alkoxy, thiol, C _1-6 alkylthio, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, substituent selected from mono C _1-6 acylamino and di C _1-6 acylamino The compound according to claim 1, which is a 5- to 6-membered non-aromatic heterocyclic group optionally having. 3. The compound according to claim 1, wherein A is a nitrogen atom. 4. The compound according to claim 1, wherein B is a nitrogen atom. 5. The compound according to claim 1, wherein D is a nitrogen atom. 6. The formula: [In the formula, R represents a halogenobenzyl group, R ¹ represents a hydrogen atom,
An alkyl group which may have a substituent, an aralkyl group which may have a substituent, an aryl group which may have a substituent, a heterocyclic group which may have a substituent or a substituent R ² is an optionally substituted amino group, R ² is an optionally substituted alkyl group or an optionally substituted aralkyl group, and R ³ is a hydrogen atom or a substituent. An optionally substituted alkyl group is represented by R ⁴ (In the formula, R ⁵ is halogen, an alkyl group, an acyl group, an optionally esterified or amidated carboxyl group, a hydroxy group, an alkoxy group, a thiol group, an alkylthio group, an amino group, a monoalkylamino group, a dialkylamino group. A group, a monoacylamino group or a diacylamino group, and ring E represents a benzene ring which may further have a substituent in addition to R ⁵ ) or a heterocyclic group which may have a substituent. Or a salt thereof. 7. R ¹ is (1) a 5- to 7-membered heterocyclic group or
(2) —NR ⁶ R ⁷ (R ⁶ is a hydrogen atom, a hydroxy group, C _1-6
An alkyl group or a C _1-6 alkoxy group, R ⁷ represents a hydrogen atom or a C _1-6 alkyl group), R ² represents a C _7-12 aralkyl group, R ³ represents a C _1-6 alkyl group, and R ⁴ represents Formula The compound according to claim 6, which is a group represented by the formula (wherein R ^5a represents a C _1-6 alkoxy group) or a 5-membered aromatic heterocyclic group. 8. The compound according to claim 7, wherein the 5-membered aromatic heterocyclic group is a nitrogen-containing heterocyclic group. 9. The compound according to claim 7, wherein the 5-membered aromatic heterocyclic group is pyrrolyl. 10. 3- (N-benzyl-N-methylaminomethyl) -8- (2,6-difluorobenzyl) -5,
8-dihydro-2- {4- (3-furylcarbonylamino) phenyl} -6- (4-methoxyphenyl) -5-
Oxoimidazo [1,2-a] pyrimidine, 3- (N-benzyl-N-methylaminomethyl) -8- (2,6-difluorobenzyl) -5,8-dihydro-2- {4-
(Ethylaminocarbonylamino) phenyl} -6-
(4-Methoxyphenyl) -5-oxoimidazo [1,
2-a] pyrimidine, 3- (N-benzyl-N-methylaminomethyl) -8- (2,6-difluorobenzyl)
-5,8-Dihydro-2- {4- (methoxyaminocarbonylamino) phenyl} -6- (4-methoxyphenyl) -5-oxoimidazo [1,2-a] pyrimidine, 3
-(N-benzyl-N-methylaminomethyl) -8-
(2,6-Difluorobenzyl) -5,8-dihydro-
2- {4- (ethylaminocarbonylamino) phenyl} -5-oxo-6- (1-pyrrolyl) imidazo
The compound according to claim 1, which is [1,2-a] pyrimidine or a salt thereof. 11. A prodrug of the compound according to claim 1 or a salt thereof. 12. A pharmaceutical composition comprising the compound according to claim 1, a salt thereof or a prodrug thereof. 13. The pharmaceutical composition according to claim 12, which is a gonadotropin-releasing hormone antagonist. 14. The pharmaceutical composition according to claim 12, which is a prophylactic / therapeutic agent for sex hormone-dependent diseases. 15. Sex hormone-dependent cancer, bone metastasis of sex hormone-dependent cancer, benign prostatic hyperplasia, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, menstruation. Dysfunction, multilocular ovary syndrome, polycystic ovary syndrome, acne, baldness, Alzheimer's disease, infertility, irritable bowel syndrome or hormone-independent and GnRH-sensitive benign or malignant tumor preventive / therapeutic agent, Reproductive regulator,
The pharmaceutical composition according to claim 12, which is a contraceptive agent, an ovulation inducer, or a sex hormone-dependent cancer postoperative recurrence preventive agent. 16. A method for antagonizing gonadotropin-releasing hormone, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to a mammal. 17. Use of the compound according to claim 1 or a salt thereof for producing a gonadotropin-releasing hormone antagonist.