JPH09169735A - Quinoline derivative, its production and use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a new quinoline derivative useful as a preventing or a therapeutic agent for sex hormone-dependent cancer, prostatic hypertrophy, etc., due to excellent antagonistic actions on a gonadotropic hormone-releasing hormone possessed thereby, goodness in peroral absorbability and excellence in stability. SOLUTION: This compound of formula I [R<1> is formula II (R<5> is an aralkyl; R<6> is an alkyl; X is an alkylene) or an alkyl which may be halogenated; R<2> is an acylaminoaryl; R<3> is a halogenoaralkyl; R<4> is carboxyl which may be esterified or amidated] or its salt, e.g. ethyl 6-(N-benzyl-N- methylaminomethyl)-1,4-dihydro-1-(2,6-difluorobenzyl)-7-(4-propionylam inophenyl)-4- oxoquinoline-3carboxylate. The compound is obtained by reacting a compound of formula III (Y is a halogen) with an arylboric acid derivative of the formula R<2> -B(OH)2 in the presence of a base such as sodium carbonate in a solvent such as ethyl ether.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a quinoline derivative having excellent gonadotropin-releasing hormone antagonistic activity, a process for producing the same, and use thereof.

[0002]

2. Description of the Related Art Anterior pituitary hormones are secreted by peripheral hormones secreted from target organs of each hormone and secretagogues or secretory inhibitory hormones (hereinafter referred to as "secretory 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). Up to now, hypothalamic hormones such as thyroid stimulating hormone releasing hormone (TRH) or gonadotropin releasing hormone ｛GnRH (Gonadotropin releasing hormone): luteinizing hormone releasing hormone [LH-RH (Luleinizing)
hormone releasing hormone)]}, etc. have been confirmed (edited by Masaaki Iriki, Keisuke Toyama, Physiology 2, Bunkodo, 610-618, 1986). It is presumed that these hypothalamic hormones exert their hormonal actions through receptors that are thought to be present in the anterior pituitary gland (the same), and in humans as well, including these specific receptor genes Analysis is underway (Hiroo Imura, et al., Receptor Basics and Clinicals, Asakura Shoten, 297-304, 1993). 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.

Examples of such compounds having GnRH antagonistic activity include linear peptides which are derivatives of GnRH (US Pat. No. 5,140,009, US Pat. No. 5,171,835).
No.), a cyclic hexapeptide derivative (JP-A-61-191698) and a bicyclic peptide derivative [Journal of Medicinal Chemist
ry), 36, 3265-3273, 1993].

[0004]

However, since all of these compounds are peptidic, many problems remain such as the dosage form, stability of the drug, duration of action, stability against metabolism and the like. There is. It has excellent therapeutic effects on hormone-dependent cancers such as prostate cancer endometriosis and precocious puberty, and also has a transient pituitary-gonad stimulating action.
There is a strong demand for an oral GnRH antagonist that does not cause (acute action), particularly a non-peptide antagonist.

[0005]

Means for Solving the Problems The inventors of the present invention produced various quinoline derivatives and investigated the action thereof, and found that some of the quinoline derivatives have an excellent GnRH antagonistic action. . The present inventors have further studied based on this finding and completed the present invention.

The present invention provides (1) general formula (I)

Embedded image [Wherein R ¹ is a formula

Embedded image (In the formula, R ⁵ is an aralkyl group, R ⁶ is an alkyl group, X
Represents an alkylene group) or an optionally halogenated alkyl group, R ² is an acylaminoaryl group, R ³ is a halogenoaralkyl group, and R ⁴ is esterified or amidated. Or a salt thereof, (2) R ¹ is a compound represented by the formula:

Embedded image (Wherein R ⁵ 'represents a C _7-13 aralkyl group, R ⁶ ' represents a C _1-6 alkyl group, and X'represents a C _1-6 alkylene group) or a halogenated group. A C _1-6 alkyl group, R ² is a C _1-6 acyl-amino-C _6-14 aryl group, R ³ is a halogeno C _7-13 aralkyl group, and R ⁴ is C _1-6.
The compound according to the above item (1), each of which represents a carboxyl group which may be esterified with an alkyl group, (3) R
^The compound according to the above item (2), wherein ¹ is N-C _7-13 aralkyl-N-C _1-6 alkylaminomethyl, (4) R ¹ is N.
-Benzyl-N-methylaminomethyl, R ² represents propionylaminophenyl, and R ³ represents difluorobenzyl, the compound according to the above item (1), (5) 6-
(N-benzyl-N-methylaminomethyl) -1,4-
Dihydro-1- (2,6-difluorobenzyl) -7-
(4-propionylaminophenyl) -4-oxoquinoline-3-carboxylic acid ethyl ester,

(6) General formula

Embedded image [Wherein Y is halogen and R ¹ is a formula

Embedded image (In the formula, R ⁵ is an aralkyl group, R ⁶ is an alkyl group, X
Represents an alkylene group) or an alkyl group which may be halogenated, R ³ represents a halogenoaralkyl group, and R ⁴ represents a carboxyl group which may be esterified or amidated. Or a salt thereof is reacted with an arylboronic acid derivative represented by the formula R ² —B (OH) ₂ (wherein R ² represents an acylaminoaryl group), or a compound represented by the general formula

Embedded image [Wherein Z is a leaving group, A is an alkylene group, and other symbols have the same meanings as described above]

Embedded image (Wherein R ⁵ and R ⁶ have the same meanings as defined above), and the compound represented by the above (1) or a salt thereof, (7) above ( (1) A pharmaceutical composition comprising the compound or a salt thereof, (8) the pharmaceutical composition according to the above (7), which is a gonadotropin-releasing hormone antagonist, and (9) the prevention and treatment of sex hormone-dependent diseases. The pharmaceutical composition according to the above (8), which is an agent.

4-oxoquinoline which is the skeleton of the compound in the present text is represented by the following formula.

[0009]

Embedded image

The aralkyl group represented by R ⁵ in the above-mentioned group R ¹ is preferably a C _7-19 aralkyl group, and examples thereof include benzyl, phenethyl, biphenylmethyl, benzhydryl and the like. Among them,
Benzyl is preferred. As the alkyl group represented by the above groups R ¹ and R ⁶ , a C _1-6 alkyl group is preferable, and examples thereof include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, s-butyl, t. -Butyl, n-pentyl, isopentyl, neopentyl, hexyl and the like. Among them, a C _1-3 alkyl group is preferable. The alkylene group represented by X and A in the above-mentioned group R ¹ is preferably C _1-6 alkylene, and examples thereof include methylene, ethylene, propylene, butylene pentylene, and hexylene. Among them, a C _1-3 alkylene group is preferable. Examples of the alkyl group in the optionally halogenated alkyl group in the group R ¹ include the same ones as described above. Examples of the halogen include fluorine, chlorine, bromine, and iodine. Preferred examples of the optionally halogenated alkyl group include bromomethyl. R ² above
As the acylaminoaryl group represented by, for example,
A C _1-6 acyl-amino-C _6-14 aryl group is preferable,
Examples of C _1-6 acyl include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and the like, and examples of C _6-14 aryl include phenyl, naphthyl, anthryl and the like.

The halogenoaralkyl group represented by R ³ is preferably a halogeno C _7-19 aralkyl group.
Examples of the halogen in the halogenoaralkyl group include fluorine, chlorine, bromine, and iodine. Examples of the aralkyl group in the halogenoaralkyl group include, for example,
Examples include benzyl, phenethyl, benzhydryl, and the like. Among them, benzyl is preferred. The esterified carboxyl group ester represented by R ⁴ is preferably a C _1-6 alkyl ester, examples of which include methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl. Ester, s-butyl ester, t-butyl ester, n-pentyl ester, isopentyl ester, neopentyl ester, n-hexyl ester and the like can be mentioned. Of these, ethyl ester is most preferable. Examples of the amidated carboxyl group represented by R ⁴ include carbamoyl, methylcarbamoyl, 2-pyridylcarbamoyl, benzylcarbamoyl and isopropylcarbamoyl. The above compound [I]
Most preferred are N-benzyl-N-methylaminomethyl as the group R ¹ , R ² is propionylaminophenyl or isobutyrylaminophenyl, R ³ is difluorobenzyl, and R ⁴ is
Examples include ethoxycarbonyl.

Further, the present invention has a GnRH antagonistic action and has the general formula (X)

Embedded image [In the formula, R ^a , R ^b , R ^c , R ^d , R ^f and R ^g are the same or different and each represents hydrogen or a group through a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom. R ^e represents a group through a carbon atom or an optionally substituted homologous or heterocyclic group. However, R ^a , R ^b , R ^c , R ^d , R ^f and R
^g is not all hydrogen at the same time. ] The compound (X) having a structure represented by

Examples of the group having a carbon atom in the quinoline derivative represented by the above formula (X), which may be substituted, include (1) a hydrocarbon group, (2) an acyl group, and (3) a carbamoyl group. , (4) a heterocyclic group having a bond at the carbon atom, and the like, and further, (5) an optionally esterified or amidated carboxyl group, and (6) a cyano group. The carboxyl group which may be esterified is represented by the formula —COO—R ¹¹ (in the formula, R ¹¹
Represents a hydrogen atom, a hydrocarbon group or a heterocyclic group. ) And the hydrocarbon group and the heterocyclic group may be substituted. The carboxyl group which may be amidated is represented by the formula —CO—NR.
¹² R ¹³ (In the formula, R ¹² represents a hydrogen atom, a hydrocarbon group, a heterocyclic group or a group through a sulfur atom. R ¹³ represents a hydrogen atom or a hydrocarbon group. R ¹² and R ¹³ are A 5- to 7-membered cyclic amino group may be formed with an adjacent nitrogen atom, and R ¹² and R ¹³ may be a nitrogen-containing heterocyclic group formed with an adjacent nitrogen atom.). The hydrocarbon group, the heterocyclic group, the cyclic amino group and the nitrogen-containing heterocyclic group may each be substituted.

Examples of the group via the nitrogen atom in the quinoline derivative represented by the above formula (X) include (1) nitro group and (2) formula --NR ¹⁴ R ¹⁵ [wherein R ¹⁴ is hydrogen or a hydrocarbon group]. , A hydrocarbon-oxy group, an acyl group, a hydroxyl group, a heterocyclic group, -SOp-R ¹⁶ (in the formula, p represents an integer of 1 to 2, R ¹⁶ represents a hydrocarbon group), R
¹⁵ represents hydrogen or a hydrocarbon group, and the group represented by the formula —NR ¹⁴ R ¹⁵ may form a cyclic amino group] and the like. The group, acyl group, hydroxyl group, heterocyclic group and cyclic amino group may each have a substituent. Examples of the group via the oxygen atom in the quinoline derivative represented by the above formula (X) are —O—R ¹⁷ (wherein R ¹⁷ represents a hydrogen atom, a hydrocarbon group, an acyl group or a heterocyclic group). The groups represented are mentioned, and these hydrocarbon group, acyl group and heterocyclic group may each have a substituent. Examples of the group via the sulfur atom in the quinoline derivative represented by the above formula (X) include —S (O)
The group represented by t-R ¹⁸ (in the formula, R ¹⁸ represents a hydrogen atom, a hydrocarbon group, or a heterocyclic group, and t represents an integer of 0 to 2). Each of the groups may have a substituent.

As the hydrocarbon group in the above-mentioned optionally substituted hydrocarbon group and the hydrocarbon group in optionally-substituted hydrocarbon-oxy group, a C _1-20 hydrocarbon group is preferable. Examples of the C _1-20 hydrocarbon group include (1) C _1-15 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, Examples thereof include pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, etc. Among them, C _1-10 is preferable, and C _1-6 alkyl group is particularly preferable.), (2 ) C _3-10 cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like can be mentioned, and among them, C _3-6 cycloalkyl group is preferable), (3). C _2-10 alkenyl group (for example, vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, butadienyl, 2-methylallyl , Hexatrienyl, 3-octenyl and the like,
Of these, a C _2-6 alkenyl group is preferable. ), (4) C _2-10
Alkynyl groups (eg, ethynyl, 2-propynyl,
Examples thereof include isopropynyl, butynyl, t-butynyl and 3-hexynyl, and among them, C _2-6 alkynyl is preferable. ), (5) C _3-10 cycloalkenyl (for example,
Examples thereof include cyclopropenyl, cyclopentenyl, cyclohexenyl and the like, and among them, a C _3-6 cycloalkenyl group is preferable. ), (6) C _6-14 aryl group (for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl, etc. are mentioned, and among them, phenyl and naphthyl are preferable), (7) C _7-20 aralkyl. (As an example, benzyl, phenethyl, benzhydryl,
Trityl and the like can be mentioned, of which benzyl and phenethyl are preferable. ).

Examples of the substituent of the above hydrocarbon group and hydrocarbon-oxy group include (1) halogen, (2) nitro,
(3) nitroso, (4) cyano, (5) substituent {eg, (i) C _1-6 alkyl (wherein C _1-6 alkyl is a hydroxyl group, C _1-6 alkoxy, C _1-3 alkoxy-C _1-3 alkoxy, C _1-3 alkylthio, hydroxy-C _1-3 alkoxy, C _1-6 alkyl-carbonyl, carboxy, carbamoyl, C _1-6 alkyl-carbamoyl, nitrogen-containing 5 to 7-membered heterocyclic group or halogen May be present as a substituent), (ii) C
_1-4 acyl, (iii) C _7-20 aralkyl (the C _7-20 aralkyl group may have halogen, C _1-3 alkoxy or C _1-4 alkyl as a substituent), (iv ) C _6-14 aryl (the C _6-14 aryl may have halogen as a substituent), (v) C _2-6 alkenyl, (vi) C _3-7 cycloalkyl, (vii) C _1-3 alkoxy-carbonyl, (v
iii) mono- or di-C _1-6 alkylamino, (ix) C _2-6
Alkenylamino, (x) C _1-3 alkoxy-carbonyl,
(xi) C _1-6 alkylcarbonyl, (xii) C _3-6 cycloalkyloxycarbonyl or (xiii) hydroxyl optionally having}, (6) Formula —S
(O) f-R ²¹ (wherein f is an integer of 0 to 2 and R ²¹ is a hydrogen atom or a substituent (eg, halogen, nitro, cyano, hydroxy, oxo, thioxo, carboxy, cyano-C).
_6-14 aryl, halogeno C _6-14 aryl, etc.) may be included, and examples of the hydrocarbon group include
Preferred are C _1-20 hydrocarbon groups, especially C _1-6 alkyl, C _6-14 aryl, C _7-20 aralkyl. )}, (7) optionally substituted amino group [eg, formula —NR ²² R ²³ {wherein
R ²² and R ²³ are the same or different and each is a hydrogen atom, C
_1-6 alkyl, showing a C _1-6 acyl or 5-8 membered heterocyclic group. } Or an amino group represented by the above formula], (8) formula —CO—R ²⁴ (wherein R ²⁴ is (i) hydrogen atom, (ii) hydroxy, or (iii) C _1-10 alkyl, (i
v) C _1-6 alkoxy (this alkoxy may be substituted with C _6-14 aryl which may have a substituent such as halogen or nitro), (v) C _3-6 cycloalkyl ,
(vi) C _6-14 aryl, (vii) C _6-14 aryl-oxy,
(viii) C _7-20 aralkyl, (ix) formula —NR ²² R ²³ (in the formula,
R ²² and R ²³ have the same meaning as above. ) Represents an optionally substituted amino group or (x) a 5- to 8-membered heterocyclic group. } Of these, a C _1-10 acyl group is preferable, and (9) a 5- to 8-membered heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom { The heterocyclic group includes (i) a halogen atom, (ii) C
_It may be substituted with _1-4 alkyl, (iii) C _1-3 alkoxy, (iv) C _1-4 alkylthio, and (v) phenoxy which may be substituted with halogen. ｝, (10) Sulfo, (11) C
_6-14 aryl (the C _6-14 aryl group is (a) hydroxyl, (b) amino, (c) mono- or di-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino, 1 to 4 selected from dimethylamino, diethylamino, etc.), (d) C _1-6 alkoxy, and (e) halogen, etc.
May be substituted with a number of substituents. ), (12) C _3-7 cycloalkyl, (13) C _1-6 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, propylenedioxy, 2,2-dimethylenedioxy, etc.), (14) Oxo, (1
5) Thioxo, (16) C _2-4 alkynyl, (17) C _3-10 cycloalkyl group, (18) C _2-10 alkenyl group, among them C _2-6
Alkenyl groups are preferred. ), (19) C _7-20 Aralkyl,
Examples include (20) amidino and (21) azide.

The substituent on the above-mentioned hydrocarbon group having a substituent may further have a substituent. Examples of the substituent which may further have include (1) hydroxyl, (2) amino, (3) mono- or di-C _1-4 alkylamino (eg, methylamino, ethylamino, propylamino , Dimethylamino, diethylamino, etc.), (4) C _1-4 alkoxy, (5) halogen, (6) nitro, etc., and 1 to 4 groups, and more preferably 1 to 2 groups. . The hydrocarbon group is cycloalkyl, when a cycloalkenyl, aryl or aralkyl group may have one to three C _1-6 alkyl as a substituent, the C _1-6 alkyl is further It may be substituted with 1 to 3 hydroxy, oxo, C _1-3 alkoxy, C _1-3 alkylthio, halogen, carbamoyl and the like. The substituted C _1-6 alkyl includes formyl (methyl is substituted by oxo), carboxyl (methyl is substituted by oxo and hydroxy), C _1-6 alkoxycarbonyl (methyl is oxo and alkoxy). Those substituted with) (eg, C _1-6 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl), hydroxy C
_1-6 alkyl (eg, hydroxymethyl, hydroxyethyl, hydroxybutyl, hydroxypropyl, etc.), C
_1-3 alkoxy-C _1-6 alkyl (eg, methoxymethyl,
Ethoxymethyl, ethoxybutyl, propoxymethyl,
Propoxyhexyl etc.) and the like. The number of the substituents in the above is 1 to 6, preferably 1 to 5, more preferably 1 to 3, and most preferably 1 to 2. The number of substituents that the substituent may further have is preferably 1 to 3, and particularly preferably 1 to 2.

Examples of the acyl group in the above-mentioned optionally substituted acyl group include an acyl group derived from a C _1-24 aliphatic carboxylic acid. Examples of the acyl group include formyl, C _1-6 alkyl-carbonyl (eg, acetyl, ethylcarbonyl, propylcarbonyl, tert-propylcarbonyl, etc.), C _1-6 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), C _6-14 aryl-carbonyl (eg, benzoyl etc.), C _6-14 aryloxy-carbonyl (eg, phenoxycarbonyl etc.), C _7-15
Aralkyl-carbonyl (eg, benzylcarbonyl etc.), C _7-19 aralkyloxy-carbonyl (eg, benzyloxycarbonyl etc.) and the like can be mentioned. Examples of the group which may be substituted on the acyl group include the same groups as those which may be substituted on the hydrocarbon group described above. Examples of the group which may be substituted with the C _1-10 acyl group include the same groups as those which may be substituted with the hydrocarbon group described above. Examples of the above-mentioned optionally substituted carbamoyl group include the above-mentioned optionally substituted C.
Examples thereof include a carbamoyl group which may be substituted with a _1-20 hydrocarbon group. Examples of the C _1-20 hydrocarbon group are the same as those mentioned above. Of these, a mono- or di-C _1-15 alkylcarbamoyl group is preferable, and examples thereof include methylcarbamoyl, ethylcarbamoyl,
Hexylcarbamoyl, dimethylcarbamoyl, methylethylcarbamoyl and the like can be mentioned. Examples of the group which may be substituted on the carbamoyl group include the same groups as those described above which may be substituted on the hydrocarbon group.

In the present invention, as the above-mentioned heterocyclic group, a 5- to 8-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atoms, and condensed therewith And a bicyclic or tricyclic fused heterocyclic group. Specific examples of the heterocyclic group include:
For example, (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, triazolidinyl, 1H- or 2
5-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like in addition to carbon atom such as H-tetrazolyl; (2) pyridyl, pyrimidinyl, thiomorpholinyl, morpholinyl, triazinyl, pyrrolidinyl, Piperidinyl, pyranyl, thiopyranyl, 1,4
In addition to carbon atoms such as -oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, oxotriazinyl, pyridazinyl, and pyrazinyl, 1 to 5 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. A 6-membered heterocyclic group containing 4 or the like can be mentioned. (2)
Examples of the bicyclic or tricyclic fused heterocyclic group include benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-
b] Pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indoridinyl, indolyl, quinolidinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, clomanyl, quinazolinyl In addition to carbon atoms such as oxazinyl, phenazinyl, phenothiazinyl, and phenoxazinyl, there can be mentioned bicyclic or tricyclic fused heterocyclic groups containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like. To be

Examples of the group which may be substituted on the heterocyclic group include (1) C _1-6 alkyl, (2) C _2-6 alkenyl,
(3) C _2-6 alkynyl, (4) C _3-6 cycloalkyl, (5) C
_5-7 cycloalkenyl, (6) C _7-11 aralkyl, (7) C
_6-14 aryl, (8) C _1-6 alkoxy, (9) C _6-14 aryloxy (eg, phenoxy, etc.), (10) C _1-6 alkanoyl (eg, formyl, acetyl, propionyl, n-butyryl) , Iso-butyryl etc.), (11) C _6-14 aryl-carbonyl (eg benzoyl etc.), (12) C _1-6 alkanoyloxy (eg formyloxy, acetyloxy, propionyloxy, n-butyryloxy, iso) -Butyryloxy, etc.), (13) C _6-14 aryl-carbonyloxy (eg, benzoyloxy etc.), (14) carboxyl, (15) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, n- propoxycarbonyl, iso- propoxycarbonyl, n- butoxycarbonyl, isobutoxycarbonyl, tert- butoxycarbonyl, etc.), (16) carbamoyl group, (17) N-mono--C _1-4 alkylcarbamoyl (e.g. N- methylcarbamoyl, N- ethylcarbamoyl, N- propylcarbamoyl, N- isopropylcarbamoyl, N- butylcarbamoyl, etc.), (18) N, N- di -C
_1-4 alkylcarbamoyl (eg, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-dibutylcarbamoyl, etc.), (19) cyclic aminocarbonyl (eg, 1- Aziridinyl carbonyl, 1-azetidinyl carbonyl, 1-pyrrolidinyl carbonyl, 1-
Piperidinylcarbonyl, N-methylpiperazinylcarbonyl, morpholinocarbonyl, etc.), (20) halogen, (21)
Mono-, di- or tri-halogeno-C _1-4 alkyl (eg, chloromethyl, dichloromethyl, trifluoromethyl, trifluoroethyl etc.), (22) oxo group, (23) amidino, (24) imino group , (25) amino, (26) mono- or di C _1-4 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutyl Amino etc.), (27)
In addition to carbon atom and one nitrogen atom, oxygen atom, sulfur atom,
3- to 6-membered cyclic amino group optionally containing 1 to 3 hetero atoms selected from nitrogen atom (eg, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, vilazolyl, imidazolidinyl, piperidino, morpholino, Dihydropyridyl, pyridyl, N-methylpiperazinyl, N-ethylpiperazinyl, etc.), (28) C _1-6 alkanoylamino (eg, formamide, acetamide, trifluoroacetamide, propionylamide, butyrylamide, isobutyryl) Amide, etc.),
(29) Benzamide, (30) Carbamoylamino, (31) N-
C _1-4 alkylcarbamoylamino (eg, N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylamino, N-isopropylcarbamoylamino, N-butylcarbamoylamino, etc.), (32) N, N
-Di-C _1-4 alkylcarbamoylamino (eg, N, N-dimethylcarbamoylamino, N, N-diethylcarbamoylamino, N, N-dipropylcarbamoylamino, N, N-dibutylcarbamoylamino, etc.), (33 ) C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), (34) -B (OH) ₂ , (35) hydroxyl, (36) epoxy (—O—), (37) nitro , (38) cyano, (39) mercapto, (40) sulfo, (41) sulfino, (42) phosphono, (43)
Dihydroxyboryl, (44) sulfamoyl, (45) C
_1-6 alkylsulfamoyl (eg, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.), (46) DiC _1-6 alkylsulfamoyl (eg, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, etc.), (47) C _1-6 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, etc.), (48) phenylthio, (49) C _1-6 alkylsulfinyl (eg , methylsulfinyl, ethylsulfinyl, propyl sulfinyl, butylsulfinyl etc.), (50) phenylsulfinyl, (51) C _1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, Ropirusuruhoniru, butylsulfonyl, etc.), (52)
Phenyl sulfonyl etc. are mentioned. The number of substitutions is 1 to 6, preferably 1 to 3 and more preferably 1 to 2.

The heterocyclic group in the heterocyclic group having a bond at an optionally substituted carbon atom includes 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like in addition to carbon atom. Examples thereof include a 5- to 8-membered heterocyclic group, and a bicyclic or tricyclic condensed heterocyclic group condensed therewith, which includes a heterocyclic group having a bond at a carbon atom constituting a ring. Specific examples of the heterocyclic group in the heterocyclic group having a bond at the optionally substituted carbon atom include (1) 2- or 3-thienyl, 2- or 3-furyl, 2- or 3- Pyrrolyl, 2-, 4- or 5-
Oxazolyl, 2-, 4- or 5-thiazolyl, 3
-, 4- or 5-pyrazolyl, 2- or 3-pyrrolidinyl, 2-, 4- or 5-imidazolyl, 2-imidazolinyl, 2-imidazolidinyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 2-, 5- or 6- (1,3,4-oxadiazolyl), 3- or 5- (1,2,4-thiadiazolyl) ) 2
-Or 5- (1,3,4-thiadiazolyl), 4-or 5- (1,2,3-thiadiazolyl), 3-or 4- (1,
2,5-thiadiazolyl), 2- or 5- (1,2,3-
Triazolyl), 3- or 5- (1,2,4-triazolyl), 5- (1H- or 2H-tetrazolyl) and the like, as well as a hetero atom selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like. A 5-membered heterocyclic group containing 4 to 4; (2) 2
-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-thiomorpholinyl, 2- or 3-morpholinyl, 3- or 6-triazinyl,
2-, 3- or 4-piperidinyl, 2- or 3-pyranyl, 2- or 3-thiopyranyl, 2- or 3-
(1,4-oxazinyl), 2- or 3- (1,4-thiazinyl), 1- or 4- (1,3-thiazinyl), 2- or 3-piperazinyl, 3- or 6-triazinyl,
6-membered heterocycle containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atoms such as 3- or 4-pyridazinyl, 2- or 3-pyrazinyl, 3- or 4-pyridazinyl Group; (3) benzofuryl,
Benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-b]
Pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,
In addition to carbon atoms such as quinoxalinyl, indoridinyl, indolyl, quinolidinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl. Examples thereof include a group having a bond at the carbon atom of a bicyclic or tricyclic condensed heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like. Examples of the group which may be substituted on the heterocyclic group having a bond at a carbon atom include the same groups as the above groups which may be substituted on the heterocyclic group.

Examples of the cyclic amino group or the nitrogen-containing heterocyclic group include a 5- to 7-membered nitrogen-containing cyclic group which may further have one atom selected from an oxygen atom, a sulfur atom and a nitrogen atom. To be Examples thereof include, for example, pyrrolidinyl, pyrrolinyl, pyrrolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, imidazolidinyl, imidazolinyl, imidazolyl, 1,2,3-triazinyl, 1,
2,3-triazolidinyl, 1,2,3-triazolyl,
1,2,3,4-tetrazolyl, piperidinyl, piperazinyl, azepinyl, hexamethyleneamino, oxazolidino, morpholino, thiazolidino or thiomorpholino. Among them, those having 5 to 6 members are preferable,
For example, pyrrolidinyl, pyrazolinyl, pyrazolyl, piperidinyl, piperazinyl, morpholino and thiomorpholino are preferable. The nitrogen-containing cyclic amino group or the nitrogen-containing heterocyclic group may have a substituent, and examples of the substituent include (1) C _1-6 alkyl, (2) C _6-14 aryl,
(3) C _7-10 aralkyl, (4) benzhydryl, (5) C _1-6 alkyl-carbonyl, (6) C _6-14 aryl-carbonyl, (7) C _1-6 alkoxy-carbonyl and the like can be mentioned. . Preferred substituents include C _1-6 alkyl, with C _1-3 alkyl being more preferred.

Examples of the homocyclic group which may be substituted in the quinoline derivative represented by the above (X) include a C _6-10 aryl group (eg, phenyl, naphthyl, etc.), C _{3 -7} cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), C _3-7 cycloalkenyl (eg, cyclopronyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, etc.) Also, a 3- to 7-membered carbocyclic group and the like are used. Examples of the substituent that the homocyclic ring may have include (1) C _1-15 alkyl _optionally substituted with halogen (among others, C _1-6 alkyl _optionally substituted with halogen). Preferred)), (2) C _3-10 cycloalkyl, (3)
C _2-10 alkenyl, (4) C _2-10 alkynyl, (5) C _3-10 cycloalkyl, (6) C _6-10 aryl, (7) C _7-20 aralkyl, (8) nitro, (9 ) Hydroxyl, (10) Mercapto, (1
1) oxo, (12) thioxo, (13) cyano, (14) carbamoyl, (15) carboxyl, (16) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), (17) sulfo, (18) halogen, (19) C _1-6 alkoxy, (20) C _6-10 aryloxy (eg, phenoxy, etc.),
(21) C _1-6 acyloxy (eg, acetoxy, propionyloxy), (22) C _1-6 alkylthio (eg, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio, etc.), ( 23) C _6-10
Arylthio (eg, phenylthio, etc.), (24) C _1-6 alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, etc.), (25) C _6-10 arylsulfinyl (eg, phenylsulfinyl, etc.), (26) C _{1 -6} alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.), (27) C _6-10 arylsulfonyl (eg, phenylsulfonyl, etc.), (28) amino, (29) C _1-6 acylamino (eg, acetylamino) , Propionylamino, etc.), (30)
Mono- or di-C _1-4 alkylamino (eg, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, dimethylamino, diethylamino, etc.), (31) C _3-8 cycloalkylamino (Eg,
Cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.), (32) C _6-10
Arylamino (eg, anilino, etc.), (33) C _1-6 alkanoyl (eg, formyl, acetyl, hexanoyl, etc.),
(34) C _1-6 alkanoyloxy (eg, acetyloxy,
Propionyloxy, etc.), (35) C _6-10 aryl-carbonyl (eg, benzoyl, etc.), oxygen other than the (36) carbon atom,
A 5- to 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from sulfur, nitrogen and the like (eg, 2- or 3-thienyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4-
Or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2
-, 4- or 5-imidazolyl, 1,2,3- or 1,2,4-triazolyl, 1H or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidyl, 3- or 4-pyridanidyl, quinolyl, isoquinolyl, indolyl, etc.) and the like.
The number of substitutions is 1 to 6, preferably 1 to 3, and more preferably 1 to 2.

In the above compound (X), R ^{a to} R ^f are
A group via a hydrogen atom, a carbon atom or a nitrogen atom is preferable. As the above group and the group having a carbon atom in R ^{g, a} C _1-20 hydrocarbon group which may have a substituent is preferable. As the C _1-20 hydrocarbon group in the C _1-20 hydrocarbon group which may have a substituent, a C _1-10 alkyl group, a C _1-6 alkyl group or a C _6-14 aryl group is preferable. The substituent in the group having a carbon atom which may have a substituent, (1) halogen, (2) nitro, (3) cyano, (4) optionally substituted amino group,
(5) optionally substituted hydroxyl group, (6) optionally substituted caboxyl group, (7) optionally substituted carbamoyl group, (8) optionally substituted alkenyl group, (9 ) Acyl group, (10) nitro group or (11) formula --S (O) t
A group represented by —R ²⁰ (in the formula, t represents an integer of 0 to 2 and R ²⁰ represents a hydrogen atom or an optionally substituted hydrocarbon group) is preferable. In the group via the carbon atom,
Substituted aminoalkyl groups such as N, N-disubstituted aminoalkyl groups, preferably N-aralkyl-N-alkylaminoalkyl groups, especially N—C _7-11 aralkyl-N.
-C _1-6 alkylamino -C _1-6 alkyl group as preferred.

As the homocyclic group which may be substituted, a C _6-14 aryl group is preferable. The substituent in the homocyclic group which may have a substituent includes (1) halogen, (2) nitro, (3) optionally substituted hydroxyl group or (4) formula —S (O ) t-R ²⁰ (wherein, t
Is an integer of 0 to 2, and R ²⁰ is a hydrogen atom or an optionally substituted hydrocarbon group). Examples of the substituent of the optionally substituted aryl group include (1) alkoxy, (2) alkylcarbonyl,
(3) alkylaminocarbonyl, (4) optionally substituted alkenyl (preferable examples of the substituent include alkylcarbonyl, alkylaminocarbonyl), or (5) optionally substituted amino (substituted) Preferable examples of the group also include alkyl, alkanoyl, alkyl substituted with hydroxy, and hydroxy), and alkanoylamino or alkoxy is particularly preferable. Further, as an optionally substituted aryl group, (i) nitro, (i
i) C _1-6 alkoxy, (iii) C _1-6 a C _1-6 aryl include optionally substituted by selected radicals from also an amino group are alkanoyl substituted. The heterocyclic group in the optionally substituted heterocyclic group is preferably a 5- to 8-membered heterocyclic group, more preferably a 5- to 8-membered heterocyclic group having at least one nitrogen atom, and at least one nitrogen atom. A 5- to 6-membered heterocyclic group having an atom can be mentioned. Examples of preferred heterocyclic groups include, for example, oxazolyl,
Examples include isoxazolyl, thiazolyl, imidazolyl, triazolyl, oxoimidazolyl and thiazinyl. Substituents in the optionally substituted heterocyclic group include (1) halogen, (2) nitro, (3) optionally substituted hydroxyl group, and (4) formula —S (O) t—R ²⁰ (Where t
Is an integer of 0 to 2, R ²⁰ represents a hydrogen atom or an optionally substituted hydrocarbon group), (5) an optionally substituted amino group, or (6) C _1-10 Hydrocarbon groups are preferred. n preferably represents 1.

Halogen in the above definition of the group includes fluorine, chlorine, bromine and iodine. Examples of C _1-6 alkyl in the definition of the above group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl,
Examples include isopentyl, neopentyl, hexyl and the like. C _1-4 alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl. C _1-3 alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl. Examples of C _2-10 alkenyl in the definition of the above groups include, for example, vinyl, allyl, isopropenyl, butenyl, butadienyl, hexatrienyl, 3-octenyl and the like. Examples of C _2-6 alkenyl include, for example, vinyl, allyl, isopropenyl, butenyl, hexatrienyl. Examples of C _2-4 alkenyl include vinyl, allyl, isopropenyl and butenyl. Examples of C _2-10 alkynyl in the definition of the above groups include, for example, ethynyl, 1-propynyl, 2-propynyl, propargyl, 3-hexynyl and the like. Examples of C _2-6 alkynyl and C _2-4 alkynyl in the above definition of the group include, for example, ethynyl, 1-propynyl, 2-propynyl and the like.

Examples of C _3-10 cycloalkyl in the above definition of the group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like. C
Examples of _3-8 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Examples include cycloheptyl and cyclooctyl. C _3-7
Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of C _3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of C _3-7 cycloalkenyl in the above group definition include cyclopropenyl, cyclobutenyl, cyclopentenyl,
Examples of C _5-7 cycloalkenyl such as cyclohexenyl include cyclopentenyl, cyclohexenyl and the like.

Examples of C _6-14 aryl in the definition of the above groups include phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl and anthracenyl. Examples of C _6-10 aryl include phenyl, naphthyl. Of these, phenyl is preferred. Examples of C _7-20 aralkyl in the definition of the above groups include, for example, benzyl, phenethyl, benzhydryl, trityl. Examples of C _7-20 aralkyl and C _7-13 include, for example, benzyl, phenethyl, benzhydryl. Examples of C _7-11 aralkyl and C _7-10 aralkyl include, for example, benzyl, α-methylbenzyl and phenethyl. Examples of C _1-6 alkoxy in the definition of the above groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,
Examples include isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like. Examples of C _1-4 alkoxy include, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy. Examples of C _1-3 alkoxy include, for example, methoxy, ethoxy, propoxy,
Isopropoxy is mentioned. Examples of C _1-6 acyl in the definition of the above group include, for example, formula —CO—R ²⁵ (wherein R ²⁵ is a hydrogen atom, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl. , T
- butyl, C _1-6 alkanoyl represented by showing a pentyl). Examples of C _1-4 acyl in the definition of the above group include, for example, the formula —CO—R ²⁵ ′ (wherein R ²⁵ ′ is
Represents a hydrogen atom, methyl, ethyl, propyl or isopropyl).

The above 5- to 7-membered nitrogen-containing heterocyclic group is
For example, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl,
Flazanyl, tetrahydrofuryl, pyridyl, pyrimidinyl, pyridazinyl, oxadiazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, imidazolyl, 1,
2,3-triazinyl, 1,2,3-triazolidinyl, 1,
2,3-triazolyl, 1,2,3,4-tetrazolyl, piperidinyl, piperazinyl, hexamethylene aminyl, oxazolidinyl, thiazolidinyl and the like can be mentioned. Of these, a 5- or 6-membered heterocyclic group is preferable. Among the 5- or 6-membered heterocyclic groups, pyrrolidinyl, pyrazolinyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl are particularly preferable.

The compound (I) or a salt thereof of the present invention is produced by reacting the compound (II) or a salt thereof with an arylboric acid derivative represented by the formula R ² -B (OH) ₂ . In this reaction, 1 mol to 3 mol of the arylboric acid derivative is used with respect to 1 mol of the compound (II) or a salt thereof. The reaction is performed in a suitable solvent that does not adversely influence the reaction. Suitable solvents 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 ethanol. Etc. are used. This reaction is 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. In order to accelerate the reaction, a catalytic amount of a palladium derivative (eg, tetrakistriphenylphosphine palladium or the like) may be added. This reaction is preferably performed under a stream of an inert gas (eg, argon gas, nitrogen gas, or the like). The reaction temperature is room temperature to about 150 ° C., and the reaction is usually carried out by heating under reflux. The reaction time is about 1 to 12 hours.

The compound (I) or a salt thereof of the present invention can be produced by reacting the compound (III) or a salt thereof with an amine represented by the formula HNR ⁵ R ⁶ . In this reaction, the amines are used in an approximately equimolar amount with respect to the compound (III) or a salt thereof. This 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, nitriles such as acetonitrile, ketones such as acetone, esters such as ethyl acetate, etc. are used. This reaction is performed in the presence of a base. Examples of the base include {tertiary organic amines (eg, triethylamine, trimethylamine, diisopropylethylamine, N-methylmorpholine, etc.). The reaction temperature is usually about 10-10.
0 ° C. The reaction time is about 1 to 10 hours. The reaction is preferably carried out with stirring.

The compounds (I), (X) and salts thereof of the present invention can be produced by a method known per se. As an example thereof, the following manufacturing method can be mentioned. In the following, the R ^I is a hydrogen atom or R ^a, R ^II
Is R ¹ or R ^b , R ^III is R ² or R ^c , and R ^IV is R ³
Alternatively, R ^e , R ^V represents a hydrogen atom or R ^f , and R ^VI represents R ⁴ or R ^g . X'and Y represent halogen. Examples of the halogen include the same as those described above. Z represents a leaving group. As the leaving group represented by Z,
Examples thereof include groups that can be easily subjected to a substitution reaction with a nucleophile [eg, a hydrocarbon residue having a negatively charged hetero atom (eg, oxygen atom, sulfur atom, nitrogen atom, etc.)]. Specifically, for example, a halogen atom (iodine, bromine, chlorine, etc.), alkanoyloxy (eg, acetoxy), alkylsulfonyloxy (eg, methanesulfonyloxy, etc.), alkyl-arylsulfonyloxy (eg, p-toluenesulfonyl). Oxy etc.) and the like.

[Production Method 1] To the 3-halogenated aniline derivative (i), an equal amount to a small excess of ethoxymethylenemalonic acid diethyl ester is added, and the mixture is stirred at 100 ° C to 150 ° C for 1 to 4 hours to obtain the addition derivative (ii). ). The derivative (ii)
Is added little by little to an appropriate solvent (eg, polyphosphoric acid, polyphosphoric acid ester (PPE), Dowtherm, etc.) and stirred at room temperature or while heating to produce a quinoline derivative (iii). The derivative (iii) is dissolved in a suitable solvent that does not adversely influence the reaction (eg, dimethylformamide, dichloromethane, tetrahydrofuran, ethyl ether, dioxane, acetone, etc.), and 1 equivalent to a small excess of a base (eg, carbonate Potassium, triethylamine, sodium hydride, etc.) and 1 equivalent to an excess amount of an alkyl halide derivative (eg, methyl iodide, propyl iodide, benzyl iodide, etc.) are added, and the mixture is stirred at about 0 to 80 ° C. The target compound (Ia) is produced by reacting the obtained derivative (iv) or a salt thereof with an equimolar to small excess (3 mol) of an arylboric acid derivative represented by the formula R ^III -B (OH) _2. To be done. The reaction is performed in a suitable solvent that does not adversely influence the reaction. Suitable solvents 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 ethanol. Etc. are used. This reaction is 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. In order to accelerate the reaction, a catalytic amount of a palladium derivative (eg, tetrakistriphenylphosphine palladium or the like) may be added. This reaction is preferably performed under a stream of an inert gas (eg, argon gas, nitrogen gas, or the like). The reaction temperature is from about room temperature to 150 ° C., and the reaction is usually performed under reflux. The reaction time is about 1 to 12 hours. In this way, the target compound (Ia) can be produced. The above manufacturing process 1 is shown in [Equation 1]. In [Formula 1], Et represents ethyl, Y represents halogen (specific examples are the same as above), and other groups have the same meanings as described above.

[0034]

[Equation 1]

[Production Method 2] Conversion of 6-position group: A solvent which does not adversely affect the reaction of the compound (v) in the reaction formula of [Equation 2] (eg, halogenated hydrocarbon such as carbon tetrachloride, chloroform). In the presence of α, α′-azobisisobutyronitrile (AIBN) and N-bromosuccinimide (NBS) at 30 to 100 ° C.
Stir for 6 hours to obtain compound (vi). A compound (I) or a salt thereof of the present invention is produced by reacting a compound (vi) or a salt thereof with an approximately equimolar amount of an amine (R ¹ ′ -H). The reaction is performed 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, nitriles such as acetonitrile, ketones such as acetone, esters such as ethyl acetate, etc. are used. This reaction is performed in the presence of a base. Examples of the base include {tertiary organic amines (eg, triethylamine, trimethylamine, diisopropylethylamine, N-methylmorpholine, etc.). 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. Thus, the compound (Ib)
Can be manufactured. The above manufacturing process 2 is performed by [Equation 2].
Shown in In [Formula 2], R ¹ 'represents a substituted amino,
Z represents a leaving group, and other groups have the same meanings as described above.

[0036]

(Equation 2)

[Production Method 3] Anthranilic acid derivative (vii)
In a solvent that does not adversely affect the reaction (eg, ethers such as tetrahydrofuran and 1,4-dioxane, etc.)
Add an equivalent or excess of triphosgene and add about 30-110
The mixture was stirred at ℃ C to give isatoic anhydride derivative (vii). Then, the halogenated derivative is converted into a solvent that does not adversely affect the reaction (eg, ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene,
In an amide such as N, N-dimethylformamide and N, N-dimethylacetamide, an alkyl sulfoxide such as dimethyl sulfoxide, and the like, a base (eg, an alkali metal carbonate such as potassium carbonate, sodium hydride, potassium hydride and the like) Alkali metal hydride, alkali metal alkoxides such as potassium butoxide, etc.) in the presence of about 40 to 13
Stir at 0 ° C. to obtain the substituted derivative (xi). The derivative (xi)
In the presence of a base (eg, an alkali metal carbonate such as potassium carbonate, an alkali metal hydride such as sodium hydride and potassium hydride, and an alkali metal alkoxide such as potassium-butoxide) in a solvent that does not adversely affect the reaction ( For example, ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene,
N, N-dimethylformamide, amides such as N, N-dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide, etc.) at 40 to 110 ° C. in an equivalent amount or a small excess (eg, about 1.1 to 1.5). Compound (Ic) can be produced by reacting with an equivalent amount of β-keto acid ester derivative. The above manufacturing process 3 is shown in [Equation 3]. In [Formula 3], Xa represents a leaving group (especially halogen). R ^g ′ represents an alkyl group. Other groups are as defined above.

[0038]

(Equation 3)

[Manufacturing Method 4] Other Method: The substituent in the group of the compound of the present invention can be converted into another substituent by a commonly used method known per se. An example of the method is shown below. (i). A nitro group as a substituent can be converted into an amino group. For example, a raw material compound is dissolved in an appropriate solvent (eg, ethanol, methanol), and (a) palladium-carbon is added and reacted at room temperature for 1 to 12 hours under a hydrogen stream, or (b) iron is added to the above solution. Add flour and hydrochloric acid,
Incubate at room temperature for 1 to 12 hours. (ii). An amino group as a substituent can be converted into an acylated amino group. For example, the raw material compound is dissolved in a suitable solvent (eg, tetrahydrofuran, dimethylsulfoxide), potassium carbonate, and pyridine and triethylamine as a base are added, and further an acid anhydride or an acid halide is added. The mixture is stirred and reacted at room temperature for 1 to 10 hours. (iii). The compound having an amino group can be an alkenylamino compound. For example, the starting compound is dissolved in an appropriate solvent (eg, acetic acid, dimethylformamide, dichloromethane, tethydrofuran, dioxane, acetonitrile), a diazotizing agent (eg, sodium nitrate, isoamyl nitrate) is added, and a palladium catalyst {eg, bis (Dibenzylideneacetone) palladium} and 1 equivalent to a small excess of the alkenyl derivative are added, and the mixture is heated from room temperature to 80 ° C.
And react for 1 to 12 hours. (iv). A carbon atom can be introduced into the amino group. For example, the starting compound is dissolved in a suitable solvent (eg, acetic acid, dimethylformamide, dichloromethane, tetrahydrofuran, dioxane), an acrylic acid derivative or an oxirane derivative (eg, epoxide compound) is added, and the mixture is mixed with 0 to 80
The reaction is allowed to proceed for 6-24 hours under stirring at ℃. (V). A sulfur atom can be introduced into the amino group. For example, the starting compound is dissolved in an appropriate solvent (eg, pyridine, dimethylformamide, dichloromethane, tetrahydrofuran, ethyl ether, dioxane), a halide of a sulfur compound is added, and the mixture is reacted at 0 to 80 ° C. with stirring for 6 to 24 hours.

(Vi). A formyl group as a substituent can be converted into a methyl group. For example, the raw material compound is dissolved in a suitable solvent (eg, tetrahydrofuran), an organic borane derivative (eg, dimethyl sulfide borane) is added, and the mixture is reacted at room temperature to under reflux for several hours (eg, 1 to 3 hours). (Vii). An acetonyl compound can be produced from a methoxy compound. For example, the starting compound is dissolved in a suitable solvent (eg, dichloromethane), 1 equivalent to an excess amount of a Lewis acid {eg, aluminum chloride and a thiol compound or a sulfide compound (eg, dimethyl sulfide)} is added,
The mixture is reacted under ice-cooling to room temperature for 1 to 10 hours, then, the obtained hydroxy form is dissolved in a suitable solvent (eg, dimethylformamide), a base (eg, sodium hydroxide, potassium carbonate) and an alkyl halide are added, 1-12 at room temperature
Let react for hours. (viii). A methoxy group can be converted to an isopropoxy group. For example, a starting compound is dissolved in a suitable solvent (eg, dichloromethane), and 1 equivalent to an excess of a Lewis acid (eg, aluminum chloride) and a thiol compound or a sulfide compound (eg, dimethyl sulfide) are added.
The reaction is performed under ice cooling to room temperature for 1 to 10 hours. (ix). An aminocarbonyl group can be introduced. For example, a raw material compound having a halogen is added to a suitable solvent (eg,
Dimethoxyethane), and an arylboric acid derivative, a base (eg, sodium carbonate) and a palladium compound {eg, tetrakis (triphenylphosphine) palladium (0)} as a catalyst were added, and the mixture was reacted under reflux for 1 to 6 hours. (x). The alkylthio compound can be an alkylsulfinyl compound or an alkylsulfonyl compound. For example, the starting compound is reacted with an oxidizing agent (eg, metachloroperbenzoic acid) in a suitable solvent (eg, dichloromethane). Excessive heating or excessive use of an oxidizing agent results in an alkylsulfonyl compound.

(Xi) The hydroxyl group in the molecule can be substituted with various groups. The reaction is carried out in a suitable solvent, for example
Add halide {eg, alkyl halide (eg, propyl iodide, isobutyl iodide, ethyl bromide acetate), aralkyl halide (eg, benzyl chloride)} in dimethylformamide (DMF), acetonitrile, acetone and the like. The reaction is carried out by stirring the mixture at 0-40 ° C. for 2-18 hours. For example, when using ethyl acetate, the obtained acetic ester is reacted with a suitable solvent and a base (eg, 1N NaOH in ethyl alcohol) at room temperature for 2 to 12 hours. The acetic acid compound is dissolved in a suitable solvent {eg, tetrahydrofuran (THF)}, isobutyl chloroformate is added in the presence of a suitable base (eg, triethylamine), and the reaction is conducted at 0 ° C.
For 1 to 4 hours. Suitable amine compound for reaction solution (eg, methylamine, propylamine, piperidine, etc.)
Is added and the reaction is performed at 0 ° C. to room temperature for 1 to 12 hours. In addition,
The compound having a hydroxyl group in the molecule, which is the above-mentioned raw material compound, can be prepared, for example, by subjecting a compound having an alkoxy group in the molecule to acid hydrolysis.
The acid hydrolysis is carried out by adding 1N hydrochloric acid in a commonly used method, for example, a suitable solvent {eg, alcohols (eg, methanol, ethanol)}, and reacting at 0 ° C. to room temperature for 1 to 10 hours. The compound (xi) which is an alkanoyl-phenyl group can be produced by introducing an alkanoyl-phenyl group into a compound having a halogenated group. To introduce the alkanoyl-phenyl group, first, the halogenated compound is treated with N-bromosuccinimide and a catalytic amount of 2,2′-azobis (in a suitable solvent (eg, carbon tetrachloride, chloroform). Isobutyronitrile) is added and reacted. The reaction is 100-12
It is carried out at 0 ° C. for 1 to 4 hours. The introduction of the alkanoyl-phenyl group is carried out by using a suitable solvent (eg, dimethoxyethane (DM
E)). Alkanoyl-phenylborate, palladium compound {eg, Pd (PPh ₃ ) ₄ ,
Ph = phenyl} and sodium carbonate (2M, Na ₂ C
O ₃₎ is added. The reaction is at room temperature to 1 under an inert gas flow.
It is performed at about 20 ° C. for about 1 to 12 hours. In addition, the production of alkanoyl-phenyl borate is carried out by using alkanoyl-phenyl bromide and a boric acid compound {eg, (i-PrO) ₃ B,
Pr = propyl} with a suitable base (eg, BuLi, Bu =
Butyl).

(Xii) In the compound of the present invention, alkyl-
A compound which is a phenyl group can be obtained by replacing the alkanoyl-phenylborate in the above method (xi) with an alkyl-
It can be carried out by the same reaction using phenyl borate. Further, the introduction of other groups in the compound of the present invention can be carried out using a method known per se. (xiii) The compound having an alkoxycarbonyl group in the compound of the present invention can be produced by introducing a cyano group into a raw material compound and then esterifying the obtained compound. In the reaction for introducing a cyano group, the starting compound is used in an appropriate solvent {eg, dimethyl sulfoxide (DMS
O)} and add sodium cyanide to the solution,
It is carried out by reacting at 60 ° C. for 2 to 12 hours.
The subsequent esterification reaction is carried out using a starting compound and an alcohol solution (eg, ethyl alcohol) in a suitable solvent (eg, ethyl alcohol). Those saturated with hydrochloric acid. }When,
It is carried out by reacting at 80 to 120 ° C. for 12 to 48 hours. (xiv) To introduce a sulfonamide group into the compound of the present invention, halogenate the alkyl group in the starting compound,
Subsequently, the reaction can be carried out by subjecting to a nucleophilic substitution reaction with sulfonamides. The halogenation is carried out in a suitable solvent (eg, carbon tetrachloride) with N-bromosuccinimide or a catalytic amount of 2,2′-azobis (isobutyronitrile).
Is added and the reaction is carried out at 100 to 120 ° C. for 1 to 4 hours. The nucleophilic substitution reaction is carried out, for example, by washing sodium hydride and a sulfonamide derivative (eg, methanesulfonamide, ethanesulfonamide) with n-hexane in a suitable solvent {eg, N, N-dimethylformamide (DMF)}. , Benzenesulfonamide)
The reaction is performed at 0 to 40 ° C for 1 to 24 hours.

The salt of the compound (I) of the present invention thus obtained is preferably a physiologically acceptable acid addition salt. Such salts include, for example, inorganic acids (eg,
With hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.),
Or organic acids (eg formic acid, acetic acid, trifluoroacetic acid,
Fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) and salts thereof are used. Further, the compound (I) of the present invention is -COOH.
In the case of having an acidic group such as, an inorganic base (eg, an alkali metal salt such as sodium, potassium, calcium, magnesium or an alkaline earth metal, ammonia, etc.)
Alternatively, it may form a salt with an organic base (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, etc.). The thus-obtained compound (I) of the present invention or a salt thereof can be isolated and purified by an ordinary 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 It can be converted into an educt or other salt by a similar method. When the compound (I) of the present invention or a salt thereof is an optically active substance, it can be separated into a d-form and an l-form by a usual optical resolution means. When the compound (X) forms a salt, the salt can be produced in the same manner as above.

The compound (I) of the present invention or a salt thereof (hereinafter sometimes referred to as "the compound of the present invention") has an excellent GnRH antagonistic action and has low toxicity. Moreover, it has excellent oral absorbability and stability. Therefore, the compound of the present invention can be administered to mammals (for example, human, monkey, bovine,
(Horses, dogs, cats, rabbits, rats, mice, etc.), by suppressing the secretion of gonadotropin by GnRH receptor antagonism and controlling the sex hormone level in the blood, the sex It can be safely used in the treatment of diseases and of diseases caused by excess of these hormones. That is, the compound of the present invention is a sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), prostatic hypertrophy, uterine fibroids, endometriosis, precocious puberty, amenorrhea, It is useful for treating premenstrual syndrome, multilocular ovary syndrome, acne, etc. In addition, the compound of the present invention regulates reproduction in males and females (eg,
It is also useful as a pregnancy regulator, menstrual cycle regulator, etc.). The compound of the present invention is further used as a male or female contraceptive,
It can also be used as a female ovulation inducer. The compound of the present invention can be used for treating infertility by utilizing the rebound effect after withdrawal. 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 alone, but it is also effective to use it in combination with a steroidal or non-steroidal anti-androgen or anti-estrogen. In addition, 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 a hyperagonist such as leuprorelin acetate. Further, the compound of the present invention may be used in combination with a chemotherapeutic agent for cancer. Preferred specific examples of the combination include, for example, ifosfamide, UTF, and prostate cancer.
Adriamycin, Peplomycin
A chemotherapeutic agent such as mycin) and cisplatin can be used in combination with the compound of the present invention. In addition, for breast cancer, cyclophosphamide (Cyclophospamide),
5-FU, UFT, Methotrexate, Adriamycin, Mitomycin C (Mitomy
A chemotherapeutic agent such as cin C) or mitoxantrone can be used in combination with the compound of the present invention.

Preventing the compound of the present invention from the above diseases
When used as a therapeutic agent or in the field of livestock or fisheries, either oral administration or parenteral administration is possible according to a method known per se, and it is usually mixed with a pharmaceutically acceptable carrier, and usually tablets or capsules. , Solid preparations such as granules and powders, or parenterally as injections, suppositories, sublingual tablets, etc., intravenously, subcutaneously, intramuscularly and the like. Further, it may be administered sublingually, subcutaneously, intramuscularly, etc. as a sustained release preparation such as sublingual tablets and microcapsules. The daily dose varies depending on the degree of symptoms; age, sex, weight, sensitivity difference of administration subject; administration timing, interval, nature of pharmaceutical preparation, preparation, type; type of active ingredient, etc.
Although not particularly limited, it is usually about 0.1 to 30 mg, preferably about 0.1 to 3 mg, and more preferably 0.1 to 1 mg per 1 kg body weight of a mammal, which is usually 1 to 4 times a day. Administer in divided doses. The dosage when used in the field of livestock or fisheries is also based on the above, but about 0.01 to 5 mg, preferably about 0.03 to 3 mg per 1 kg body weight of the subject organism is usually divided into 1 to 3 times a day. Administer.

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 preservatives, antioxidants, coloring agents and sweeteners can also be used. Preferable examples of the above-mentioned excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, 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-
Examples thereof include mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch 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-
Examples thereof include mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Suitable examples of the suspending agent include, for example, stearyl triethanolamine, sodium lauryl sulfate,
Surfactants such as lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc .; such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose Examples include hydrophilic polymers. Preferable examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol and the like. Suitable examples of the buffering agent include, for example, phosphate,
Buffers such as acetate, carbonate, citrate and the like can be mentioned. Preferred examples of the soothing agent include benzyl alcohol and the like. Preferable examples of the above preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the above antioxidant include sulfite, ascorbic acid and the like.

The compound of the present invention, a suspending agent, a solubilizing agent,
Stabilizing agents, isotonic agents, preservatives, and the like are added to obtain intravenous, subcutaneous, or intramuscular injections by a method known per se. At that time, if necessary, a freeze-dried product can be prepared by a method known per se. When the compound of the present invention or a salt thereof is administered to, for example, a human, the compound itself or an appropriate pharmacologically acceptable carrier, excipient, or diluent is mixed, and the compound is orally or parenterally administered as a pharmaceutical composition. It can be administered safely. Examples of the pharmaceutical composition include oral agents (eg, powders, granules, capsules, tablets), injections, drip infusions, external preparations (eg, nasal preparations, transdermal preparations, etc.), suppositories (eg, Rectal suppositories, vaginal suppositories) and the like. These preparations can be produced by a method known per se, which is generally used in the preparation process. The compound of the present invention or a salt thereof is a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HOC 60 (manufactured by Nikko Chemicals) polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.), a preservative (eg, methyl paraben). , Propylparaben, benzyl alcohol, etc.), isotonic agents (eg, sodium chloride, mannitol, sorbitol, glucose, etc.) with aqueous injections, olive oil, sesame oil, cottonseed oil, corn oil, and other vegetable oils, propylene glycol, etc. It can be dissolved, suspended or emulsified and formed into an oily injection to prepare an injection.

In order to prepare a preparation for oral administration, the compound of the present invention can be prepared by, for example, an excipient (eg, lactose, sucrose, starch, etc.), a disintegrating agent (eg, starch, calcium carbonate, etc.), a binder according to a method known per se. (Eg starch, gum arabic,
Carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) are added and compression-molded, and if necessary, taste masking, enteric coating or For long-lasting purposes, the preparation can be made into an oral administration preparation by coating with a method known per se. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Bruronic.
F 68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, copolymerization of methacrylic acid / acrylic acid) and coloring matter (eg, bengara, titanium dioxide, etc.)
Are used. In the case of an enteric-coated preparation, it is preferable to provide an intermediate phase between the enteric phase and the drug-containing phase by a method known per se for the purpose of separating both phases.

As an external preparation, the compound of the present invention or a salt thereof can be prepared as a solid, semisolid or liquid external preparation according to a method known per se. For example, as the above solid, the compound of the present invention or a salt thereof as it is, or an excipient (eg, glycol, mannitol,
Starch, microcrystalline cellulose, etc.), a thickener (eg, natural gums, cellulose derivative, acrylic acid polymer, etc.) are added and mixed to give a powdery composition. The liquid is almost the same as the injection, and is an oily or aqueous suspension. In the case of semi-solid, an aqueous or oily gel or ointment is preferred. In addition, all of these are pH adjusters (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoates, chlorobutanol, benzalkonium chloride, etc.), etc. May be added. For example, in the case of a suppository, the compound of the present invention or a salt thereof 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, witepsol (manufactured by Dynamite Nobel,
Germany) etc.), intermediate fatty acids [eg Miglyols (Dynamite Nobel, Germany) etc.] or vegetable oils (eg sesame oil, soybean oil, cottonseed oil etc.) and the like. Examples of the aqueous base include polyethylene glycols and propylene glycol, and examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers and acrylic acid polymers.

The above compound (X) or a salt thereof also has the same action as the compound (I) of the present invention or a salt thereof, and has the same dose and usage as those of the compound (I) or a salt thereof and has the same purpose. Can be used.

[0051]

EXAMPLES The present invention will be described in more detail with reference to the following Reference Examples and Examples, but the present invention is not limited thereto. ¹ H-NMR spectrum was measured using JEOL (JEO) using tetramethylsilane as an internal standard.
L) Lambda (LAMBDA) 300 (300 MHz) type spectrum meter or Bruker AM500 (50
0MHz) type spectrometer and measure all δ values in pp
Indicated by m. The symbols used in this specification have the following meanings. s: singlet, d: doublet,
t: Triplet, dt: Double triplet, m: Multiplet, br: Wide range.

Reference Example 1 Preparation of (3-bromo-4-methylphenyl) aminomethylenemalonic acid diethyl ester: 3-Bromo-4-methylaniline (20.0 g, 107.5 mmol) was added to ethoxymethylenemalonic acid diethyl ester ( 23.24g, 10
7.5 mmol) was added and the mixture was stirred at 120 ° C. for 2 hours. After cooling, the reaction solution was concentrated to dryness and recrystallized from ether-hexane to give colorless crystals (29.0 g, 76%). mp 6
6-67 ° C.

Reference Example 2 4-hydroxy-6-methyl-7-bromoquinoline-3
-Production of carboxylic acid ethyl ester: The compound (5.0 g, 14.04 mmol) obtained in Reference Example 1 was added in small portions to Dowtherm (50 ml) under heating with stirring at 250 ° C. After stirring at the same temperature for 50 minutes, the reaction solution was cooled, ether was added, and the precipitated solid was collected by filtration and washed with ether again. The obtained powder was recrystallized from ethanol to give colorless crystals (2.89 g, 66%). mp> 250 ° C.

Reference Example 3 1,4-dihydro-1- (2,6-difluorobenzyl)
-6-methyl-7-bromo-4-oxoquinoline-3-
Production of carboxylic acid ethyl ester: A solution of the compound (2.89 g, 9.32 mmol) obtained in Reference Example 2 in dimethylformamide (120 ml) was added with potassium carbonate (1.54 g, 1).
1.18 mmol) and potassium iodide (0.773 g,
4.66 mmol) was added and 2,6-difluorobenzyl chloride (1.82 g, 11.18 mmol) was added dropwise with stirring. The reaction solution was stirred at 50 ° C. for 2 hours, and the residue obtained by concentrating the reaction solution was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane, the extracts were combined, washed with brine, dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a colorless solid, which was recrystallized from chloroform-ether to give colorless crystals (3.0 g, 73%). mp 199-200 ° C.

Example 1 1,4-dihydro-1- (2,6-difluorobenzyl)
Production of -6-methyl-7- (4-propionylaminophenyl) -4-oxoquinoline-3-carboxylic acid ethyl ester: Compound obtained in Reference Example 3 (1.0 g, 2.
To a solution of 29 mmol) in dimethoxyethane (50 ml) was added a 2M aqueous sodium carbonate solution (5.73 ml, 1) under a stream of argon.
1.45 mmol), 4-propionylaminophenyl boric acid (0.487 g, 2.52 mmol) and tetrakistriphenylphosphine palladium (0) (0.266 g, 0.26 g).
23 mmol) was added and the mixture was heated under reflux for 5 hours. After cooling, the reaction solution was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane, the extracts were combined, washed with brine and dried.
After (MgSO ₄ ), the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain a colorless solid, which was recrystallized from chloroform-ether to give colorless crystals (0.72 g, 62%). mp 263-264 ° C.

Example 2 Preparation of 6-bromomethyl-1,4-dihydro-1- (2,6-difluorobenzyl) -7- (4-propionylaminophenyl) -4-oxoquinoline-3-carboxylic acid ethyl ester : The compound obtained in Example 1 (0.70
g, 1.39 mmol), N-bromosuccinimide (0.2
6 g, 1.46 mmol) and α, α′-azobisisobutyronitrile (0.046 g, 0.18 mmol) in 1,2-
The dichloroethane (150 ml) mixture was heated to reflux for 5 hours. After cooling, the insoluble matter was removed by filtration, and the filtrate was diluted with chloroform. The organic layer was washed with brine dried (MgSO _4), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a colorless solid (0.5
8 g, 72%) and recrystallized from chloroform-ether to give colorless crystals (0.443 g, 55%). mp 251-253 ° C.

Example 3 6- (N-benzyl-N-methylaminomethyl) -1,
4-dihydro-1- (2,6-difluorobenzyl)-
Preparation of 7- (4-propionylaminophenyl) -4-oxoquinoline-3-carboxylic acid ethyl ester hydrochloride: Compound obtained in Example 2 (0.42 g, 0.72 mm)
ol) in dimethylformamide (80 ml) under ice-cooling, ethyldiisopropylamine (0.112 g, 0.8)
6 mmol) and N-benzyl-N-methylamine (0.10
5 g, 0.86 mmol) was added. After stirring at room temperature for 2 hours and a half, the reaction solution was concentrated and the resulting residue was partitioned between chloroform and saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with chloroform, the organic layers were combined and dried (MgSO ₄ ), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a colorless oil (0.46 g, 10
0%). To a solution of this oil (0.20 g) in dichloromethane (20 ml) was added 1N ethereal hydrochloric acid (0.04 ml) under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure and the obtained residue was recrystallized from ethyl acetate-ethanol to give the hydrochloride salt (0.138 g, 66%).
Was obtained as white crystals. mp 165-168 ° C [hydrochloride].

The structures of the compounds described in Examples 1 to 3 above are shown in Table 1 below.

[0059]

[Table 1]

Example 4 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.

Example 5 The compound (5 g) produced in Example 3 was dissolved in distilled water for injection to give a total volume of 100 ml. This solution is aseptically filtered using a 0.22 μm membrane filter (Sumitomo Electric Industries, Ltd. or Sartorius) and 2 m in a washed and sterilized vial.
Dispense by l and freeze-dried by standard method to obtain 100mg
/ Produce lyophilized injections of vials.

Example 6 (1) 5 g of the compound prepared in Example 3 (2) Lactose / crystalline cellulose (granules) 330 g (3) D-mannitol 29 g (4) Low-substituted hydroxypropyl cellulose 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)-(11) to form coated fine granules, which are mixed with (12) to prepare 500 g of 1% of the compound fine granules produced in Example 3. This is divided into 500 mg each.

Test Example 1 (1) Preparation of ¹²⁵ I-leuprorelin: 10 μl of 3 × 10 ⁻⁴ M leuprorelin aqueous solution, and 0.01 mg / ml
Take lactoperoxidase (10 μl) into a tube and add N
10 μl (37 MBq) of a ¹²⁵ I solution was added, and after stirring,
10 μl of 0.001% H ₂ O ₂ was added and reacted at room temperature for 20 minutes. The reaction was stopped by adding 700 μl of a 0.05% TFA solution and purified by reverse phase HPLC. HPL
The condition of C is shown below. ¹²⁵ I-leuprorelin was eluted with a retention time of 26-27 minutes. Column: TSKgel ODS-80 ^™ (TM is a registered trademark) CTR (4.6 mm × 10 cm) Eluent: Solvent A (0.05% TFA) Solvent B (40% CH ₃ CN-0.05) % TFA) 0 minutes (100% solvent A) -3 minutes (100% solvent A) -7 minutes (50% solvent A + 50% solvent B) -40 minutes (100% solvent B) Elution temperature: room temperature Elution rate: 1 ml / min

(2) C containing human GnRH receptor
Preparation of HO (Chinese Hamster Ovary) Cell Membrane Fraction: Human GnRH Receptor Expressing CHO Cells (10
⁹ mM) with 5 mM EDTA (ethylenediaminetetraacetic acid)
-Buffered physiological saline (PBS-EDTA)
And centrifuged at 100 × g for 5 minutes. A cell homogenate buffer (10 mM NaH
10 ml of CO ₃ , 5 mM EDTA, pH 7.5) was added and homogenized using a Polytron homogenizer. The mixture was centrifuged at 400 × g for 15 minutes, and the supernatant was collected in an ultracentrifuge tube and centrifuged at 100,000 × g for 1 hour to obtain a precipitate of a membrane fraction. This precipitate was suspended in 2 ml of assay buffer and centrifuged at 100,000 × g for 1 hour. The membrane fraction collected as a precipitate was resuspended in 20 ml of assay buffer, aliquoted, stored at -80 ° C, and thawed at each use. (3) Measurement of ¹²⁵ I-leuprorelin binding inhibition rate: Above
The human membrane fraction prepared in section (2) was diluted with assay buffer to 200 μg / ml and added to the tube at 188 μm.
1 was dispensed. 2 μl of 2 mM compound dissolved in 60% DMSO and 10 μl of 38 nM ¹²⁵ I-leuprorelin were added simultaneously. To determine maximal binding, 2 μl of 60% DMSO and 38 nM ¹²⁵ I-
A reaction solution containing 10 μl of leuprorelin was prepared. In addition, in order to measure the amount of non-specific binding, 2 μ of 100 μM leuprorelin dissolved in 60% DMSO was used.
and 10 μl of 38 nM ¹²⁵ I-leuprorelin were also prepared at the same time. The reaction was carried out at 25 ° C for 60 minutes. After the reaction, the reaction solution was subjected to suction filtration using a polyethylene imine-treated Whatman glass filter (GF-F). After filtration, the radioactivity of ¹²⁵ I-leuprorelin remaining on the filter paper was measured using a γ-counter.

The following formula: (TB-SB) / (TB-NSB) × 100 (wherein SB: radioactivity when a test compound is added, T
B: maximum binding radioactivity, NSB: non-specific binding radioactivity. ) Is calculated to determine the binding inhibition rate (%) of the test compound, and then the concentration of the test compound is changed to determine the inhibition rate. The concentration of the test compound that inhibits 50% binding (IC ₅₀
Value) was calculated from the Hill plot. Using the compound obtained in Example 3 as a test compound, the IC ₅₀ value obtained by the measurement described above is shown in the following [Table 2].

[0066]

[Table 2]

[0067]

INDUSTRIAL APPLICABILITY The compound of the present invention has an excellent gonadotropin-releasing hormone antagonism. In addition, it has good oral absorbability and excellent stability. Therefore, it can be used, for example, as an agent for preventing or treating hormone-dependent diseases.
Specifically, for example, as a drug, sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), benign prostatic hyperplasia, uterine fibroids, endometriosis, precocious puberty, amenorrhea syndrome It is also effective as a preventive or therapeutic agent for multilocular ovary syndrome, acne, etc., or as a pregnancy regulator (eg, contraceptive, etc.), infertility therapeutic agent, menstrual regulator, and in the field of animal husbandry It is also effective as a fish spawning promoter in the field of fisheries, controlling the growth of meat, improving meat quality for meat, controlling the growth of animals.

Claims (9)

[Claims] 1. A compound of the general formula [Wherein R ¹ is the formula: (In the formula, R ⁵ is an aralkyl group, R ⁶ is an alkyl group, X
Represents an alkylene group) or an optionally halogenated alkyl group, R ² is an acylaminoaryl group, R ³ is a halogenoaralkyl group, and R ⁴ is esterified or amidated. Or a salt thereof. 2. R ¹ is of the formula: (Wherein R ⁵ 'represents a C _7-13 aralkyl group, R ⁶ ' represents a C _1-6 alkyl group, and X'represents a C _1-6 alkylene group) or a halogenated group. A C _1-6 alkyl group, R ² is a C _1-6 acyl-amino-C _6-14 aryl group, R ³ is a halogeno C _7-13 aralkyl group, and R ⁴ is C _1-6.
The compound according to claim 1, each of which represents a carboxyl group which may be esterified with an alkyl group. 3. The compound according to claim 2, wherein R ¹ is N—C _7-13 aralkyl-N—C _1-6 alkylaminomethyl. 4. The compound according to claim 1, wherein R ¹ is N-benzyl-N-methylaminomethyl, R ² is propionylaminophenyl, and R ³ is difluorobenzyl. 5. 5- (N-benzyl-N-methylaminomethyl) -1,4-dihydro-1- (2,6-difluorobenzyl) -7- (4-propionylaminophenyl)-
4-Oxoquinoline-3-carboxylic acid ethyl ester. 6. A general formula: [Wherein Y is halogen and R ¹ is of the formula: (In the formula, R ⁵ is an aralkyl group, R ⁶ is an alkyl group, X
Represents an alkylene group) or an alkyl group which may be halogenated, R ³ represents a halogenoaralkyl group, and R ⁴ represents a carboxyl group which may be esterified or amidated. Or a salt thereof is reacted with an arylboric acid derivative represented by the formula R ² —B (OH) ₂ (wherein R ² represents an acylaminoaryl group), or a compound represented by the general formula: Chemical 6] [Wherein Z is a leaving group, A is an alkylene group, and other symbols have the same meanings as described above] and a compound or salt thereof of the formula: The compound represented by the formula (wherein R ⁵ and R ⁶ have the same meaning as defined above) is reacted.
A method for producing the described compound or a salt thereof. 7. A pharmaceutical composition containing the compound according to claim 1 or a salt thereof. 8. The pharmaceutical composition according to claim 7, which is a gonadotropin-releasing hormone antagonist. 9. The pharmaceutical composition according to claim 8, which is a prophylactic / therapeutic agent for sex hormone-dependent diseases.