JP2002080397A - Therapeutic pharmaceutical formulation for sex hormone-dependent disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic pharmaceutical formulation for a sex hormone-dependent disease and the like capable of rapidly recovering concentration of a sex hormone (for example, testosterone, LH, FSH, estrogen and the like) after duration of drug efficacy of a compound having an antagonistic action to a luteinizing hormone-releasing hormone, a salt thereof or a formulation (preferably a sustained release preparation) containing these compounds and clearly determining a drug withdrawal period in intermittent therapy. SOLUTION: In order to administer the compound having the antagonistic action to the luteinizing hormone-releasing hormone, the salt thereof or the formulation containing these compounds after administration of a compound having a luteinizing hormone-releasing hormone action or a salt thereof, the compound having the luteinizing hormone-releasing hormone action or the salt thereof is combined with the compound having the antagonistic action to the luteinizing hormone-releasing hormone or the salt thereof in the therapeutic pharmaceutical formulation for a sex hormone-dependent disease and the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a luteinizing hormone-releasing hormone for administering a compound having a luteinizing hormone-releasing hormone action or a salt thereof after administration of a compound having a luteinizing hormone-releasing hormone action or a salt thereof. Pharmaceutical preparation for treating sex hormone-dependent diseases, which is obtained by combining a compound having an action or a salt thereof and a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof, a compound having a luteinizing hormone-releasing hormone action or a salt thereof. Administering a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof after administration, or a compound having a luteinizing hormone-releasing hormone action for producing a pharmaceutical composition for treating a sex hormone-dependent disease or Release its salt or luteinizing hormone Compounds having Mont antagonism or to such use of a salt thereof.

[0002]

BACKGROUND OF THE INVENTION Luteinizing hormone-releasing hormone, known as LHRH (or GnRH), is released from the hypothalamus and binds to pituitary receptors. The released LH (luteinizing hormone) and FSH (follicle-stimulating hormone) act on the gonads to synthesize steroid hormones. Continuous administration of compounds with a strong luteinizing hormone-releasing hormone action results in a decrease in the number of available receptors and suppresses the formation of gonadal steroid hormones. Utilizing this fact, compounds having a luteinizing hormone-releasing hormone action can be used for sex hormone-dependent diseases such as prostate cancer, benign prostatic hyperplasia, endometriosis, uterine fibroids, uterine fibroids, precocious puberty, and breast cancer. Clinically indicated as a therapeutic agent.

[0003]

SUMMARY OF THE INVENTION Compounds having a luteinizing hormone-releasing hormone action as a treatment for preventing or delaying the aforementioned sex hormone-dependent diseases (particularly prostate cancer) from changing to sex hormone-independent. Intermittent therapies have been employed to discontinue drug administration, withdraw, and expose the disease to a restored concentration of sex hormones to keep the disease treatable and hormone dependent (see, eg, Cancer, 71 (1993) 2782- Two
790). Since compounds with luteinizing hormone-releasing hormone action are agonists for the LHRH receptor, testosterone and estrogen levels increase due to the pituitary gland stimulatory action of the compound immediately after the first administration of the preparation,
Transient disease worsening (flare phenomenon) is observed. After that, the number of LHRH receptors decreased and became effective in treating hormone-dependent diseases, but the number of LHRH receptors did not recover rapidly even after the blood concentration reached below the onset level,
Exposure to hormones at the concentrations required for intermittent therapy requires an extra period. For this reason, there is a long-awaited need for a treatment method that can define a clear drug holiday during intermittent therapy or achieve clearer sex hormone recovery after completion while achieving sex hormone suppression during the administration period.

[0004]

Means for Solving the Problems The inventors of the present invention diligently studied to solve the above-mentioned problems, and as a result, completed the present invention. That is, the present invention relates to (1) the administration of a compound having a luteinizing hormone-releasing hormone action or a salt thereof after administration of a compound having a luteinizing hormone-releasing hormone action, or the administration of a compound having a luteinizing hormone-releasing hormone antagonistic action. A pharmaceutical preparation for treating a sex hormone-dependent disease, which is obtained by combining a compound having a luteinizing hormone-releasing hormone action or a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof, (2) a compound having a luteinizing hormone-releasing hormone action or a salt thereof Is the peptide compound or a salt thereof, the preparation according to the above (1),
(3) the preparation according to the above (2), wherein the peptide compound is a natural hormone or an analog thereof; (4) the peptide compound is a compound of the formula 5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu- Arg-Pro-Z
[Wherein, Y is a residue selected from DLeu, DAla, DTrp, DSer (tBu), D2Nal and DHis (ImBzl), and Z is NH-C ₂ H ₅ or
Gly-NH ₂ ), the preparation according to the above (2), wherein the peptide compound or its salt is leuprorelin, gonadrelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, The preparation according to the above (2), which is a compound selected from meterelin and resirelin or a salt thereof, (6) the preparation according to the above (1), wherein the compound having a luteinizing hormone-releasing hormone action or a salt thereof is used as an injection, 7) The preparation according to the above (1), wherein the compound having a luteinizing hormone-releasing hormone action or a salt thereof is used as a sustained-release preparation; The preparation according to the above (1), which is used as
(9) the preparation according to the above (1), wherein the compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof is a peptide compound or a salt thereof; (10) a peptide compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof; Salt is NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Ni
c) -Leu-Lys (Nisp) -Pro-DAlaNH ₂ , N (4H2-furoyl) Gly-D2N
al-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Nis
p) -Pro-DAlaNH ₂ , a preparation according to the above (9), which is a compound or a salt thereof selected from the group consisting of cetrorelix, ganirelix, antarelix, detylelix, azaline, untide, lamorelix and abarelix, and (11) luteinizing hormone-releasing hormone antagonist The preparation according to the above (1), wherein the compound having an action or a salt thereof is used as an injection, and (12) the compound according to the above (1), wherein the compound having a luteinizing hormone releasing hormone antagonistic action or a salt thereof is used as a sustained release preparation. (13) The preparation according to the above (1), wherein the compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof is used as a nasal preparation.
4) The preparation according to the above (1), wherein the compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof is a non-peptide compound or a salt thereof.

(15) The non-peptidic compound or a salt thereof is represented by the formula (I):

Embedded image Wherein R ¹ and R ² each represent a hydrogen atom, a hydroxy group, a C _1-4 alkoxy group, a C _1-4 alkoxy-carbonyl group or a C _1-4 alkyl group which may have a substituent. , R ³ represents a hydrogen atom, a halogen atom, a hydroxy group or a C _1-4 alkoxy group which may have a substituent, or two adjacent R ³ are linked to form a C _1-4 alkylenedioxy. R ⁴ represents a hydrogen atom or a C _1-4 alkyl group, and R ⁶ represents a C 5 optionally substituted group.
_1-4 alkyl group or formula

Embedded image (Wherein R ⁵ represents a hydrogen atom or R ⁴ and R ⁵ may be linked to form a heterocyclic ring), and n represents an integer of 0 to 5 And (16) the non-peptidic compound or a salt thereof is 5- (N-benzyl-N-
Methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4- (3-methoxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-
The preparation according to the above (14), which is 2,4 (1H, 3H) -dione or a salt thereof, (17) a non-peptidic compound or a salt thereof, having the formula (VIII):

Embedded image[Wherein, R⁹Is optionally substituted C_1-7Alkyl group,
Optionally substituted C _3-7Cycloalkyl group, substituted
C that may be_1-6Alkoxyamino group or substituted
An optionally substituted hydroxyamino group is represented by R^TenIs replaced
May be C_1-7Alkyl group or substituted
Or a salt thereof.
The preparation according to the above (14), wherein (18) non-peptidic
When the compound or a salt thereof is 3- (N-benzyl-N-methyl)
Ruaminomethyl) -4,7-dihydro-5-isobutylyl
Ru-7- (2,6-difluorobenzyl) -2- [4-
[(1-hydroxycyclopropyl) carbonylamido
No] phenyl] -4-oxothieno [2,3-b] pyri
The preparation according to the above (14), which is gin or a salt thereof, (1)
9) Compound having luteinizing hormone-releasing hormone action
Or luteal form before, during or immediately after administration of the salt
A compound having an antagonistic effect on adult hormone releasing hormone or
(20) The preparation according to the above (1), wherein the salt is administered.
A compound or a compound that has a forming hormone releasing hormone action
Luteinizing hormone-releasing hormone antagonism after administration of salt
Or a salt thereof,
Manufacturing pharmaceutical preparations for the treatment of sex hormone-dependent diseases
Compounds having luteinizing hormone-releasing hormone action
Release of substance or salt and / or luteinizing hormone
Use of a compound having hormone antagonism or a salt thereof
(21) For the treatment of sex hormone-dependent diseases,
A compound having a somatic hormone releasing hormone action or
Luteinizing hormone-releasing hormone antagonism after administration of its salt
Characterized by administering a compound having a use or a salt thereof.
Have luteinizing hormone-releasing hormone action
Compound or its salt or luteinizing hormone releasing form
Sex compounds containing a compound having an antagonistic action or a salt thereof
Pharmaceutical preparation for treatment of rumon-dependent disease, (22) lutein formation
A compound having hormone-releasing hormone antagonistic activity or its compound
Hormonal therapy maintenance agent, characterized by containing a salt of
(23) has luteinizing hormone-releasing hormone antagonism
Drug holiday characterized by using a compound or a salt thereof
(24) Luteinizing hormone-releasing hormone
The use of a compound having an antagonistic activity or a salt thereof is particularly preferred.
Method of restoring in vivo sex hormone concentration as a feature, (25)
Luteinizing hormone-releasing hormone action on dairy animals
Luteal after administering an effective amount of a compound or salt thereof having
A compound having an antagonistic action on the forming hormone-releasing hormone or
Is an effective amount of a salt thereof.
(26) For a mammal,
A compound having a luteinizing hormone-releasing hormone action or
Releases luteinizing hormone after administering an effective amount of its salt
Effective amount of compound having hormone antagonism or salt thereof
A method of maintaining hormonal therapy, characterized by administering
(27) luteinizing hormone releasing hormone
Administering an effective amount of a compound having a monotropic action or a salt thereof.
After luteinizing hormone-releasing hormone antagonism
Administering an effective amount of the compound or a salt thereof.
(28) Yellow for mammals
A compound having a somatic hormone releasing hormone action or
After administering an effective amount of the salt, the release of luteinizing hormone
An effective amount of a compound having a rumon antagonism or a salt thereof
Recovery of in vivo sex hormone concentration characterized by administration
And (29) providing a luteinizing hormone to a mammal.
A compound having a mon-releasing hormone effect or a salt thereof
Luteinizing hormone-releasing hormone antagonism after administering an effective dose
Administration of an effective amount of a compound having an action or a salt thereof.
Restores sex hormone dependence by
And a method for treating a sex hormone-dependent disease.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, a sex hormone-dependent disease means a sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), prostatic hypertrophy, endometriosis. , Uterine fibroids, precocious puberty, dysmenorrhea, amenorrhea, premenstrual syndrome, multilocular ovary syndrome, and the like. The compound having a luteinizing hormone-releasing hormone action or the compound having a luteinizing hormone-releasing hormone antagonism used in the present invention is not particularly limited as long as it is pharmacologically useful. It may be a peptide compound. Examples of the peptidic compound include a molecular weight of about 300 to about 40,000,
Preferably about 400 to about 30,000, more preferably about 500 to about 20,000 bioactive peptides are suitable. Specifically, Treatment With Gn
RH Analog: Contraversis and Perspective (Treatment with GnRH analogs: Controversies a
ndperspectives) [The Parthenon Publishing Group Ltd. published 1
996], JP-T-3-503165, JP-A-3-3-165
Nos. 101695, 7-97334 and 8-25
Peptides described in No. 9460 and the like. Specific examples of the peptide compound having a luteinizing hormone-releasing hormone action include, for example, a compound of the formula 5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z (where Y is DLeu , DAla, DTrp, DSer (tBu ), a residue selected from D2Nal and DHis (ImBzl), Z is NH-C ₂ H ₅ or
Gly-NH ₂ is used]. In particular, Y is at DLeu, Z is NH-C ₂ H ₅ in which the peptide (i.e., 5-oxo-Pro-His -Trp-Ser-Tyr-DLeu-Leu-A
rg-Pro-NH-C ₂ peptide represented by H _5; leuprorelin) or its acetate salt are preferred. Further, specific examples of the peptidic compound having a luteinizing hormone-releasing hormone action include gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterelin and resirelin. Specifically as a peptide compound having a luteinizing hormone-releasing hormone antagonistic action, for example, wherein X-D2Nal-D4ClPhe-D3Pal- Ser-AB-Leu-C-Pro-DAlaNH 2 [wherein, X is N (4H ₂ -furoyl) Gly or NAc, A is NMeTy
r, Tyr, Aph (Atz), a residue selected from NMeAph (Atz),
B is DLys (Nic), DCit, DLys (AzaglyNic), DLys (AzaglyF
ur), DhArg (Et ₂ ), DAph (Atz) and DhCi, and C represents Lys (Nisp), Arg or hArg (Et ₂ ). In particular, X is NAc, A is NMeTyr, B is DLys (Nic), and C is Lys (Ni
sp) (ie, NAcD2Nal-D4ClPhe-D3Pal-Se
r-NMeTyr-DLys (Nic) -Leu-Lys (Nisp) -Pro-DAlaNH ₂ is preferable. Further, specifically as a peptide compound having a luteinizing hormone-releasing hormone antagonistic action, NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DL
ys (Nic) -Leu-Lys (Nisp) -Pro-DAlaNH ₂ , N (4H2-furoyl) Gl
y-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys
(Nisp) -Pro-DAlaNH ₂ , Cetrorelix, Ganirelix,
Antarex, detilelix, azaline, untide, lamorelix and abarelix.

[0007] These peptides can be produced by the method described in the above-mentioned literature or publication or a method analogous thereto. The compound having luteinizing hormone-releasing hormone action or the compound having luteinizing hormone-releasing hormone antagonism used in the present invention may be itself or a pharmacologically acceptable salt. Such salts include inorganic acids (also called inorganic free acids) when the compound having luteinizing hormone-releasing hormone action or the compound having luteinizing hormone-releasing hormone antagonistic action has a basic group such as an amino group. (Eg, carbonic acid, bicarbonate, hydrochloric acid, sulfuric acid, nitric acid, boric acid, etc.), salts with organic acids (also referred to as organic free acids) (eg, succinic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.) No. When the physiologically active substance has an acidic group such as a carboxyl group,
Inorganic bases (also referred to as inorganic free bases) (eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium) and organic bases (also referred to as organic free bases) (eg, organic such as triethylamine) Amines, basic amino acids such as arginine, etc.). Further, the physiologically active peptide may form a metal complex compound (eg, a copper complex, a zinc complex, etc.). In particular, the aforementioned NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-
DLys (Nic) -Leu-Lys ( Nisp) peptides represented by -Pro-DAlaNH _2, and 5-oxo-Pro-His- Trp-Ser-Tyr-DLeu-Leu-Arg
-Pro-NH-C ₂ H ₅ peptide represented by (leuprorelin) are both preferably used as the acetate salt. Further, as the non-peptidic compound having a luteinizing hormone-releasing hormone antagonistic action, any compound may be used as long as it has a luteinizing hormone-releasing hormone antagonistic action. For example, the compound (I), In addition to the compound (VIII), WO99 / 21553, WO99 / 21557, WO99 / 4
No. 1251, WO99 / 41252, WO99 / 51231, WO99 / 51232,
WO99 / 51233, WO99 / 51234, WO99 / 51595, WO99 / 515
No. 96, WO99 / 44987, WO99 / 50275, WO99 / 50276, WO
00/04013, WO00 / 12521, WO 00/12522, WO 00/2
No. 9380, WO 00/20358 and the like.

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

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

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

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

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

Embedded image As the group represented by, for example,

Embedded image And the like. Of these, the formula

Embedded image The group represented by is preferred. R ⁶ is of the formula

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

[0013] In compound (I), preferred compounds, R ¹ is hydroxy group, a methoxy group or a C _1-3 alkyl group; R ² is a hydrogen atom or a C _1-3 alkyl group; R ⁴ is C
_A compound wherein R ⁶ is a benzyl group; and n is 0, or a salt thereof. Among them, R ¹ is preferably a C _1-3 alkoxy group; R ² and R ⁵ are each a hydrogen atom; R ⁴ is a C _1-3 alkyl group; R ⁶ is a benzyl group;
And a compound in which n is 0 or a salt thereof. Specific examples of compound (I) include 5- (N-benzyl-N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4- (3-methoxyureido)
Phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, 5- (N-benzyl-N-methylaminomethyl) -1- (2,6-difluorobenzyl ) -6- [4- (3-Hydroxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione, 5- (N-benzyl-N-methyl) Aminomethyl) -1- (2,6-difluorobenzyl) -6- [4- (3-methylureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -Dione, 5- (N-benzyl-N-methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4- (3-ethylureido) phenyl] -3-phenylthieno [2,3 -D] pyrimidine-2,4 (1H, 3H) -geo Or salts thereof. Among them, 5- (N-benzyl-N-
Methylaminomethyl) -1- (2,6-difluorobenzyl) -6- [4- (3-methoxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-
2,4 (1H, 3H) -dione or a salt thereof is preferred.

The definition of each substituent in the above formula (VIII) is described below. Examples of the “C _1-7 alkyl group” of the “ _optionally substituted C _1-7 alkyl group” for R ⁹ include, for example, a linear C _1-7 alkyl group (eg, methyl, ethyl, propyl,
Butyl, pentyl, hexyl, heptyl, etc.), branched C
_3-7 alkyl group (eg, isopropyl, isobutyl, sec-
Butyl, tert-butyl, isopentyl, neopentyl and the like). Of these, a branched C _3-7 alkyl group is preferred. Especially, isopropyl is preferable. R
Indicated by ⁹ "optionally substituted C _1-7 alkyl group"
Examples of the “substituent” include (i) a hydroxy group, (i)
i) C _1-7 acyloxy (eg, C _1-6 alkyl-carbonyloxy such as acetoxy, propionyloxy; benzoyloxy, etc.); (iii) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl,
tert-butoxycarbonyl, etc.), benzyloxycarbonyl, C _1-3 acyl (eg, C _1-2 alkyl-carbonyl such as acetyl, propionyl, etc.), C _1-3 alkylsulfonyl (eg, methanesulfonyl, etc.) and C _{1 -3}
Amino (eg, amino, methoxycarbonylamino, ethoxycarbonylamino, tert-butoxycarbonylbenzyloxycarbonylamino, etc.) which may have one or two substituents selected from alkyl (eg, methyl, ethyl, etc.); Acetylamino, methanesulfonylamino, methylamino, dimethylamino, etc.), (i
v) C _3-7 cycloalkyloxy-carbonyl (e.g., such as cyclohexyloxycarbonyloxy) and C _1-3 alkoxy (e.g., methoxy, which may have three, 1 to substituents selected from ethoxy, etc.) C _1-10 (preferably C _1-4) alkoxy (e.g., methoxy, ethoxy, propoxy, tert- butoxy, cyclohexyloxycarbonyloxy-1-ethoxy, methoxymethoxy, ethoxymethoxy, etc.), (v) C _1-6 alkoxy -Carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.) and the like. Of these, a hydroxy group is preferred. The “C _1-7 alkyl group” is
For example, 1 to 5 substituents may be substituted at substitutable positions,
It preferably has 1 to 3 substituents. When the number of substituents is 2 or more, each substituent may be the same or different.

The optionally substituted C represented by R ⁹
_As the “C _3-7 cycloalkyl group” of the “ _3-7 cycloalkyl group”, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like can be mentioned. Of these, cyclopropyl is preferred. “Optionally substituted C _{3-7 represented} by R ⁹
Examples of the “substituent” of the “cycloalkyl group” include 1 to 3 same groups as the “substituent” of the “optionally substituted C _1-7 alkyl group” for R ⁹ . When the number of substituents is two or more, each substituent may be the same or different. Represented by R ⁹ in the "optionally substituted C _1-6 alkoxy group" as "C _1-6 alkoxy group" is, for example, mono- - or di -C _1-6 alkoxy group (eg, Methoxyamino, ethoxyamino,
Dimethoxyamino, diethoxyamino, ethoxymethoxyamino, etc.). Among them, Mono-C _1-3
An alkoxyamino group (eg, methoxyamino, etc.) is preferred. Represented by R ⁹ in the "optionally substituted C _1-6 alkoxy group" as the "substituent", the represented by R ⁹ in the "optionally substituted C _1-7 alkyl group", " And the same number as the “substituent”. When the number of substituents is two or more, each substituent may be the same or different. The "substituent", "C _1-6 alkoxy group" of the C _1-6 alkoxy amino or "nitrogen atom of the amino group"
May be substituted. The "optionally substituted C
Specific examples of " _1-6 alkoxyamino group" include methoxyamino, N-methyl-N-methoxyamino, N-ethyl-N-methoxyamino, ethoxyamino, dimethoxyamino, diethoxyamino, ethoxymethoxyamino and the like. Can be Preferred examples include a C _1-3 alkoxyamino group and an NC _1-3 alkyl-NC _1-3 alkoxyamino group.

R⁹The “optionally substituted
As the “substituent” for the “droxyamino group”, hydroxy
"Hydroxy group" of amino group or "nitrogen atom of amino group"
May be substituted, and a position on the “hydroxy group” may be substituted.
As the substituent, (i) C_1-7Acyloxy group (eg, aceto
C such as xy, propionyloxy, etc._1-6Alkyl-cal
Bonyloxy; benzoyloxy, etc.), (ii) C_1-6
Alkoxy-carbonyl (eg, methoxycarbonyl,
Ethoxycarbonyl, tert-butoxycarbonyl, etc.),
Benzyloxycarbonyl, C_1-3Acyl (eg, acetyl
C, e.g._1-2Alkyl-carbonyl
Etc.), C_1-3Alkylsulfonyl (eg, methanesulfonyl
And C)_1-3Alkyl (eg, methyl, ethyl
Having one or two substituents selected from
Amino group (specific examples: amino, methoxycarbonyl
Amino, ethoxycarbonylamino, tert-butoxyca
Rubonylbenzyloxycarbonylamino, acetyla
Mino, methanesulfonylamino, methylamino, dimethyl
Rumino), (iii) C_3-7Cycloalkyloxyca
Rubonyl (eg, cyclohexyloxycarbonyloxy
Etc.) and C_1-3Alkoxy (eg, methoxy, ethoxy,
Has 1 to 3 substituents selected from
Good C_1-10(Preferably C_1-4) Alkoxy group (eg,
Methoxy, ethoxy, propoxy, tert-butoxy,
Clohexyloxycarbonyloxy-1-ethoxy,
Methoxymethoxy, ethoxymethoxy, etc.)
As a substituent on the “nitrogen atom of the amino group”,
Groups described in (i) to (iii) above and C_1-6Alkyl group
(Eg, methyl, ethyl, propyl, isopropyl,
, Isobutyl, sec-butyl, tert-butyl, pliers
, Isopentyl, neopentyl, hexyl, etc.)
Is mentioned. The number of substituents of the hydroxyamino group is generally
It is usually 1 to 5, preferably 1 to 3. Replace
When the number of groups is 2 or more, each substituent is the same or different
May be. "Optionally substituted hydroxyamino
Preferred examples of "group" include NC _1-6Alkyl-N-
Hydroxyamino group (eg, N-methyl-N-hydroxy
Amino, N-ethyl-N-hydroxyamino, etc.)
Is mentioned. More preferably N-C_1-3Alkyl-
And N-hydroxyamino group.

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

R ⁹ is preferably a substituted branched C _3-7
An alkyl group or a substituted C _3-7 cycloalkyl group,
More preferably, it is a C _1-7 alkyl group substituted with a hydroxy group or a C _3-7 cycloalkyl group substituted with a hydroxy group. Of these, a substituted C _3-7 cycloalkyl group is preferred. Further, a C _1-3 alkyl group optionally substituted with a hydroxy group, a C _3-7 cycloalkyl group optionally substituted with a hydroxy group, mono-C _1-3 alkoxyamino, NC _1-3 Alkyl-N-hydroxyamino groups, hydroxyamino groups and the like are also preferred. R
⁹ is particularly preferably a cyclopropyl group or a methoxyamino group which may be substituted with a hydroxy group. Most preferred is a cyclopropyl group substituted with a hydroxy group. R ¹⁰ is preferably an optionally substituted C _1-7 alkyl group. More preferred are a C _1-3 alkyl group which may be substituted with a hydroxy group. Particularly preferred is isopropyl.
Also, phenyl is preferable. Preferred examples of the compound (VIII) include a compound in which R ⁹ is a C _1-3 alkyl group optionally substituted with a hydroxy group, a C _3-7 cycloalkyl group optionally substituted with a hydroxy group, or mono-C _1-3 alkoxyamino group; a compound in which R ¹⁰ is a C _1-3 alkyl group or a salt thereof. More preferably, R
⁹ is (1) C substituted with 1 or 2 hydroxy groups
C _3-7 substituted with _1-4 alkyl group and (2) hydroxy group
A cycloalkyl group, or (3) a C _1-3 alkoxyamino group; a compound in which R ¹⁰ is an isopropyl group or a phenyl group, or a salt thereof.

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

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

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

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

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

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

[0024]

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

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

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

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

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

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

Compound (I) can be isolated and purified by a separation means known per se, for example, recrystallization, distillation, chromatography and the like. When the compound (I) is obtained in a free form, it can be converted to a target salt by a method known per se or a method analogous thereto. Alternatively, it can be converted into a free form or another desired salt by a method analogous thereto. Compound (I) may be a hydrate or a non-hydrate. Examples of the hydrate include monohydrate, 1.5-hydrate and dihydrate. When the compound (I) is obtained as a mixture of optically active compounds, it can be separated into the desired (R) -form or (S) -form by a known optical resolution means. Compound (I) is an isotope (eg, ³ H, ¹⁴ C, ³⁵ S)
It may be labeled with, for example. Compound (VIII) or a salt thereof can be prepared by a method known per se, for example, WO 95/284.
It can be produced by the method described in JP-A No. 05, WO 00/00493 or a method analogous thereto.

The compound having a luteinizing hormone-releasing hormone action or a salt thereof or the compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof may be coated, if necessary, with a sugar-coated tablet, capsule, elixir, sustained release drug, etc. As a preparation orally, or aseptic solution or suspension with water or other pharmaceutically acceptable liquid, or an injection such as a sustained release preparation, or a solution,
It can be used parenterally in the form of nasal formulations such as suspensions. For example, a compound having a luteinizing hormone-releasing hormone action or a salt thereof, or a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof, which is known as a physiologically acceptable carrier, flavor, excipient, vehicle, preservative, The above-mentioned preparations can be produced by mixing with a stabilizer, a binder and the like in a unit dosage form generally required for the practice of the preparations.

Examples of additives which can be mixed with tablets, capsules and the like include binders such as gelatin, corn starch, tragacanth and acacia, excipients such as crystalline cellulose, corn starch, gelatin, alginic acid and the like. And a lubricating agent such as magnesium stearate, a sweetening agent such as sucrose, lactose or saccharin, a flavoring agent such as peppermint, reddish oil or cherry, and the like. When the preparation unit form is a capsule, a liquid carrier such as oil and fat can be further contained in the above-mentioned type of material. Sterile compositions for injection can be formulated according to normal pharmaceutical practice such as dissolving or suspending the active substance in vehicles such as water for injection, and naturally occurring vegetable oils such as sesame oil, coconut oil and the like. As the aqueous solution for injection, for example, physiological saline, isotonic solution containing glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride, etc.) and the like are used. For example, it may be used in combination with an alcohol (eg, ethanol), a polyalcohol (eg, propylene glycol, polyethylene glycol), a nonionic surfactant (eg, polysorbate 80 (TM), HCO-50).
As the oily liquid, for example, sesame oil, soybean oil and the like are used, and may be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol.

The above-mentioned preparations include, for example, buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (eg, human Serum albumin, polyethylene glycol, etc.), preservatives (eg, benzyl alcohol, phenol, etc.), antioxidants and the like may be added. The prepared injection solution is usually filled in an appropriate vial or ampoule. Among them, a compound having a luteinizing hormone-releasing hormone action or a salt thereof or a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof is preferably used as an injection for nasal administration or sustained-release preparation. A compound having a luteinizing hormone-releasing hormone action or a salt thereof or a sustained-release preparation containing a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof (preferably a sustained-release injection) can be prepared by a method known per se. See, for example,
JP-A-100516, JP-A-62-201816, JP-A-4-321622, JP-A-6-192068, JP-A-9-132524, JP-A-9-221417,
JP-A-11-279054, WO 99/36009
It can be manufactured according to the method described in JP-A No. 9 and the like. Oral, injection and nasal preparations of a compound having a luteinizing hormone-releasing hormone action or a salt thereof or a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof can also be produced by a known method or a method analogous thereto.

In the present invention, after administering a compound having a luteinizing hormone-releasing hormone action or a salt thereof or a preparation containing the same (preferably a sustained-release preparation), the compound having a luteinizing hormone-releasing hormone action or a compound thereof is preferably administered. A compound having a luteinizing hormone-releasing hormone antagonistic activity, a salt thereof, or a preparation containing the compound (preferably, a sustained release preparation) is administered within the effective period of the salt. The administration interval of each compound or a salt thereof or a preparation containing the same is preferably one day or more and can be appropriately selected from within the effective period of the compound having a luteinizing hormone-releasing hormone action. For example, when a sustained-release preparation containing a compound having a luteinizing hormone-releasing hormone action or a salt thereof is used, the duration of action of the compound having a luteinizing hormone-releasing hormone action or a salt thereof is usually 7
Days or more and 12 months or less, preferably 10 days or more and 6 months or less, more preferably 14 days or more and 4 months or less, and can be appropriately selected from within these effective periods. During the required treatment period, the administration prescribed by the duration of the previously administered compound having luteinizing hormone-releasing hormone action or a salt thereof or a preparation containing it (preferably a sustained release preparation) It may be administered continuously at intervals. A compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof or a preparation containing it (preferably a sustained-release preparation) is used as the last dose during the treatment period, but ensures the definition of the drug holiday May be administered continuously. Further, before administration (for example, 1 to 3 weeks), during or immediately after administration (for example, 1 to 6 hours) of a compound having a luteinizing hormone-releasing hormone action or a salt thereof, A compound having a morphogenic hormone-releasing hormone antagonistic action, a salt thereof, or a preparation containing the same may be administered. In the case of the sustained-release preparation, the duration of the drug is measured by measuring the in vivo hormone concentration (eg, testosterone, LH, FSH, estrogen, etc.) or PSA concentration by a method known per se such as EIA or RIA or a method similar thereto. You can judge by doing. The compound having a luteinizing hormone-releasing hormone action or antagonistic action or a salt thereof is administered to mammals (eg, humans, monkeys, dogs, cows, sheep, pigs, mice, rats, etc.) as safe and low-toxic drugs. be able to. The dose of the compound having a luteinizing hormone-releasing hormone action or antagonistic action or a salt thereof varies depending on the target disease, the target animal and the like, but the dose per dose is, for example, preferably adult prostate cancer patients. It can be appropriately selected from the range of about 0.01 mg-100 mg / kg body weight per person. More preferably, it can be appropriately selected from the range of about 0.05 mg-50 mg / kg body weight. The dosage of the sustained-release preparation containing the compound having a luteinizing hormone-releasing hormone action or antagonistic action or a salt thereof depends on the type and content of the main compound, a compound having a luteinizing hormone-releasing hormone action or antagonistic action, or a salt thereof. Depending on the dosage form, duration of release of the main drug, target disease, target animal, etc., for example, in the case of a sustained release formulation with a drug effect period of 1 month, the dose of the sustained release formulation per dose may be Preferably, it can be appropriately selected from the range of about 0.1 mg to 500 mg / kg body weight per prostate cancer patient. More preferably about
It can be appropriately selected from the range of 0.2 mg-300 mg / kg body weight.

As shown in Example 1 below, after administration of a compound having a luteinizing hormone-releasing hormone action or a salt thereof or a preparation containing the same (preferably a sustained-release preparation), the luteinizing hormone-releasing hormone antagonism is observed. When a compound having the compound or a salt thereof or a preparation containing the compound (preferably a sustained-release preparation) is administered, a sex hormone (eg, testosterone, LH, FS
Because of rapid recovery of concentrations (H, estrogens, etc.), the method of use of the present invention allows for a clear drug holiday in intermittent therapy. That is, the present invention uses a preparation (preferably a sustained-release preparation) containing a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof (preferably, a compound having a luteinizing hormone-releasing hormone action or a salt thereof). Characterized by using a combination of a preparation (preferably a sustained-release preparation) and a preparation containing a compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof (preferably a sustained-release preparation). It provides a method for defining the duration of the drug and a method for restoring the levels of endogenous hormones (eg, testosterone, LH, FSH, estrogen, etc.). In the present invention, the drug holiday can be defined by measuring the concentration of an in-vivo hormone (eg, testosterone, LH, FSH, estrogen, etc.) or PSA concentration. The withdrawal period means that the concentration of the in vivo sex hormone is restored to the level when the preparation containing a compound having a luteinizing hormone-releasing hormone action or a salt thereof is not administered (normal), and then administered again. This is the period until you do it. The restoration of the in vivo sex hormone concentration in the present invention can be evaluated by a sex hormone measurement standard usually performed medically. Since the concentration of in vivo sex hormones varies depending on the measurement method, blood sampling time, etc., it is difficult to quantify “recovery” uniquely, but for example, a compound having a luteinizing hormone releasing hormone action or a salt thereof is contained. The "recovery" refers to a concentration of about 50% or more, preferably about 60% or more, more preferably about 70% or more of the concentration when the preparation is not administered (normal). By using a preparation containing a compound having a luteinizing hormone-releasing hormone action or a salt thereof as described above, the in vivo property decreased with the administration of a preparation containing a compound having a luteinizing hormone-releasing hormone action or a salt thereof The hormone concentration can be recovered quickly, and the drug holiday can be defined more clearly and shorter. In addition, by using a compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof or a preparation containing the same (preferably a sustained release preparation), an in vivo hormone (eg, testosterone, LH,
FSH, estrogens, etc.) recover rapidly, so that a clearly defined withdrawal period can keep sex hormone-dependent diseases hormone-dependent. Therefore, the present invention also provides a hormone therapy maintenance agent comprising a compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof. After the sex hormone concentration is restored, a compound having a luteinizing hormone-releasing hormone action or a salt thereof or a preparation containing the compound and / or a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof or a preparation containing the same is administered. can do.

Further, the present invention provides a method for administering a compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof after administration of the compound having a luteinizing hormone-releasing hormone action or a salt thereof as described above. A pharmaceutical preparation for treating a sex hormone-dependent disease, which is obtained by combining a compound having a morphogenetic hormone-releasing hormone action or a salt thereof and a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof, (B) luteinizing hormone-releasing hormone action Administering a compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof after administration of a compound having a luteinizing hormone-releasing hormone or a salt thereof for producing a pharmaceutical preparation for treating a sex hormone-dependent disease, which comprises administering a compound having a luteinizing hormone-releasing hormone antagonism, A compound having a hormonal action or a salt thereof and / or Method of using a compound having a somatic hormone-releasing hormone antagonistic action or a salt thereof, (C) Luteinizing hormone release after administration of a compound having a luteinizing hormone-releasing hormone action or a salt thereof for the treatment of a sex hormone-dependent disease Administering a compound having a hormone antagonizing action or a salt thereof, comprising a compound having a luteinizing hormone-releasing hormone action or a salt thereof, or a compound having a luteinizing hormone releasing hormone antagonizing action or a salt thereof. A pharmaceutical preparation for treating a hormone-dependent disease, (D) a hormonal therapy maintenance agent comprising a compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof, and (E) a luteinizing hormone-releasing hormone antagonistic activity. Drug holiday characterized by using a compound or salt thereof Defining method, (F)
In addition to the method of restoring the in vivo hormone concentration, which comprises using a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof, (G) after administration of a compound having a luteinizing hormone-releasing hormone action or a salt thereof, Combination dosage form for administering a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof, a compound having a luteinizing hormone-releasing hormone action or a salt thereof and a compound having a luteinizing hormone-releasing hormone antagonistic action or a compound thereof A pharmaceutical composition for treating a sex hormone-dependent disease, which comprises a combination with a salt, (H) having a luteinizing hormone-releasing hormone antagonistic activity after administration of a compound having a luteinizing hormone-releasing hormone action or a salt thereof. Administering a compound having the above or a salt thereof. The method of treating sex hormone-dependent diseases, the administration of the compounds or salt thereof having a luteinizing hormone-releasing hormone antagonistic effect after administration of a compound or a salt thereof with a (I) luteinizing hormone releasing hormone activity,
A method for defining a drug holiday during intermittent treatment of a sex hormone-dependent disease, which comprises measuring the hormone concentration of a compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof after the drug effect period, (J) luteal body A sex hormone-dependent disease characterized by recovering sex hormone dependence by administering a compound having a luteinizing hormone-releasing hormone action or a salt thereof after administering a compound having a luteinizing hormone-releasing hormone action or a salt thereof. It also relates to the method of treatment.

The sex hormone (eg, testosterone, LH, FSH, estrogen, etc.) concentration during or after the drug effect period can be measured by a method known per se (EIA, RIA, etc.) or a method analogous thereto. Also,
In the method of use of the present invention, a compound having a luteinizing hormone-releasing hormone antagonistic action or a compound having a luteinizing hormone-releasing hormone antagonistic activity before administration of a compound having a luteinizing hormone-releasing hormone action or a salt thereof or a preparation containing the compound (preferably a sustained-release preparation). By administering a salt or a preparation containing the same (preferably a sustained release preparation), the compound having a luteinizing hormone-releasing hormone action or a salt thereof or a preparation containing the same (preferably a sustained release preparation) is administered. The occurrence of the flare phenomenon can be prevented.

The meanings of the abbreviations used in the present specification are as follows. Abbreviation Name N (4H ₂ -furoyl) Gly: N-tetrahydrofuroylglycine residue NAc: N-acetyl group D2Nal: D-3- (2-naphthyl) alanine residue D4ClPhe: D-3- (4-chloro) Phenylalanine residue D3Pal: D-3- (3-pyridyl) alanine residue NMeTyr: N-methyltyrosine residue Aph (Atz): N- [5 '-(3'-amino-1'H-1', 2 ', 4'-Triazolyl)] phenylalanine residue NMeAph (Atz): N-methyl- [5'-(3'-amino-1'H-1 ', 2', 4'-triazolyl)] phenylalanine residue DLys (Nic): D- (eN-nicotinoyl) lysine residue Dcit: D-citrulline residue DLys (AzaglyNic): D- (azaglycylnicotinoyl) lysine residue DLys (AzaglyFur): D- (azaglycylfura) Nyl) lysine residue DhArg (Et ₂ ): D- (N, N′-diethyl) homoarginine residue DAph (Atz): DN- [5 ′-(3′-amino-1′H-1 ′, 2) ', 4'-Triazolyl)] phenylalanine residue DhCi: D-homocitrulline residue Lys (Nisp): (eN-isopropyl) Shin residue _{hArg (Et 2): (N} , N'- diethyl) homoarginine residue D2Nal: D-3- (2- naphthyl) alanine residue DSer (tBu): O-tert- butyl -D- serine Dhis (ImBzl): N ^im -benzyl-D-histidine and other amino acids, when indicated by an abbreviation, IUPAC-IU
B Commission of Biochemical Nomenclature
(European Journal of Biochemistry, Vol. 138, 9
To page 37 (1984)) or a common abbreviation in the relevant field, and when an amino acid may have an optical isomer, the L-form is indicated unless otherwise specified.

[0038]

EXAMPLES The present invention will be described more specifically with reference to the following Reference Examples and Examples, which do not limit the present invention. Reference Example 1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Ly
480 mg of s (Nisp) -Pro-DAlaNH ₂ acetate (TAP company's LHRH antagonist compound) was added to glycolic acid (GA) -2-hydroxybutyric acid (HBA) copolymer (GA / HBA: 60/40 (mol %), Mw: 16,3
00) and an equal weight mixture of polylactic acid (Mw: 4,200) 3.52 g
Was added to and dissolved in 4.5 ml of dichloromethane. After cooling this solution to 16 ° C, 1,000 m of a 0.1% aqueous polyvinyl alcohol solution previously adjusted to 16 ° C
l, using a turbine-type homomixer, 7,000
An oil / water emulsion was made at rpm. This emulsion is stirred at room temperature for 3 hours to evaporate dichloromethane and solidify the oil phase, and then centrifuged (05PR-22, Hitachi, Ltd.)
And collected at 2,000 rpm. This was dispersed again in distilled water and then centrifuged to wash free drugs and the like. The collected microcapsules were redispersed by adding a small amount of distilled water, 1 g of D-mannitol was added, and the dispersion was freeze-dried to obtain a powder. The encapsulation rate of the LHRH antagonist compound in the microcapsules was 88%.
About 15 mg of this microcapsule is dispersed in a dispersion medium (2.5 mg of carboxymethylcellulose, 0.5 mg of polysorbate 8).
0, 25 mg of mannitol in distilled water) was dispersed in 0.5 ml and administered subcutaneously to the back of 10-week-old male SD rats with a 22G injection needle (dose of 3 mg / k as an LHRH antagonistic compound).
g). After blood was removed from the inferior aorta at regular intervals after administration and sacrificed, the microcapsules remaining at the administration site were collected,
As a result of quantifying the LHRH antagonist compound therein by HPLC, it was confirmed that about 80% of the initial content of the LHRH antagonist compound was continuously released from the microcapsules for 4 weeks. Testosterone concentration in blood collected at each time point was 4
It was suppressed below the weekly detection limit (0.05 ng / ml) and recovered to about 50% of the mean value of non-treated rats (2.5 ng / ml) after 6 weeks, indicating that the LHRH antagonist compound at this dose was gradually reduced. The drug duration of the release was determined to be 4 weeks.

Example 1 Experiments were conducted on the following four groups using 10-week-old male SD rats. Fourth week after the first administration, the second administration was performed, and before the second administration and one day, one week, two weeks, three weeks, four weeks, and six days after the second administration.
The testosterone in the serum obtained by collecting blood after 8 weeks
Measured by Method A. First-dose formulation Second-dose formulation Group I No administration Reference example formulation Group II Leupulin injection 3.75 Reference example formulation Group III No administration Leupulin injection 3.75 Group IV Reference formulation Lupulin injection 3.75 Obtained in Reference Example 1 375 mg / kg of sustained-release microcapsules of LHRH antagonistic compound or Leuplin for injection 3.75 (1-month sustained-release microcapsules of LHRH agonist compound, manufactured by Takeda Pharmaceutical Co., Ltd., S130)
Was administered subcutaneously. The detection limit of the adopted RIA is 0.
Testosterone concentrations below 05 ng / mL were calculated as 0.00 ng / mL. Table 1 shows the average testosterone concentration and standard deviation (SE, n = 5) (unit: ng / mL).

[0040]

[Table 1] Group I and II receiving the sustained release microcapsules of the LHRH antagonist compound for the second time were 6 or 8 weeks compared to Groups III and IV receiving the sustained release microcapsules of the LHRH agonist compound Testosterone after normal 2.5 n
It is close to g / mL and recovers more quickly after the last administration of the LHRH antagonist compound. The timing of drug withdrawal is clear, indicating that it is more suitable for intermittent therapy.

[0041]

EFFECT OF THE INVENTION The use of the preparation of the present invention comprising a compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof or a preparation containing the same (preferably a sustained-release preparation) allows the effect of luteinizing hormone-releasing hormone to be reduced. The compound or its salt or a preparation containing it (preferably compared with the sustained release preparation alone treatment group) quickly recovers the concentration of sex hormones (eg, testosterone, LH, FSH, estrogen) after the effective period In other words, a clear drug holiday in intermittent therapy can be defined.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61P 5/24 A61P 13/08 13/08 15/00 15/00 35/00 35/00 A61K 37/02 F-term ( Reference) 4C076 AA94 BB25 CC17 CC27 CC30 4C084 AA20 BA01 BA09 BA17 BA23 CA59 CA62 DB09 DB71 MA01 MA59 MA66 NA05 NA12 NA14 ZA811 ZB261 ZC031 ZC032 ZC751 4C086 AA01 AA02 CB26 MA01 MA04 MA59 MA66 Z05A12 Z14

Claims (29)

[Claims] A compound having a luteinizing hormone-releasing hormone action or a salt thereof for administering a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof after administration of a compound having a luteinizing hormone-releasing hormone action or a salt thereof. A pharmaceutical preparation for treating a sex hormone-dependent disease, comprising a combination of a salt and a compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof. 2. The preparation according to claim 1, wherein the compound having a luteinizing hormone-releasing hormone action or a salt thereof is a peptide compound or a salt thereof. 3. The preparation according to claim 2, wherein the peptide compound is a natural hormone or an analog thereof. (4) a peptidic compound represented by the formula 5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z (where Y is DLeu, DAla, DTrp, DSer (tBu), Z is NH-C ₂ H ₅ or a residue selected from D2Nal and DHis (ImBzl).
Gly-NH ₂ , respectively). 5. The preparation according to claim 2, wherein the peptide compound or a salt thereof is a compound selected from leuprorelin, gonadrelin, buserelin, triptrelin, goserelin, nafarelin, histrelin, deslorelin, meterelin and resirelin, or a salt thereof. 6. The preparation according to claim 1, wherein the compound having a luteinizing hormone-releasing hormone action or a salt thereof is used as an injection. 7. The preparation according to claim 1, wherein the compound having a luteinizing hormone-releasing hormone action or a salt thereof is used as a sustained-release preparation. 8. The preparation according to claim 1, wherein the compound having a luteinizing hormone-releasing hormone action or a salt thereof is used as a preparation for nasal administration. 9. The preparation according to claim 1, wherein the compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof is a peptide compound or a salt thereof. 10. A peptidic compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof is NAcD2Nal-D4C.
lPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Nisp) -Pro-
DAlaNH ₂ , N (4H2-furoyl) Gly-D2Nal-D4ClPhe-D3Pal-Ser-
10. A compound selected from NMeTyr-DLys (Nic) -Leu-Lys (Nisp) -Pro-DAlaNH ₂ , cetrorelix, ganirelix, antarelix, detylelix, azaline, untide, lamorelix and abarelix, or a salt thereof.
A formulation as described. 11. The preparation according to claim 1, wherein the compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof is used as an injection. 12. The preparation according to claim 1, wherein the compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof is used as a sustained-release preparation. 13. The preparation according to claim 1, wherein the compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof is used as a preparation for nasal administration. 14. The preparation according to claim 1, wherein the compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof is a non-peptide compound or a salt thereof. 15. The non-peptidic compound or a salt thereof is represented by the formula (I): Wherein R ¹ and R ² each represent a hydrogen atom, a hydroxy group, a C _1-4 alkoxy group, a C _1-4 alkoxy-carbonyl group or a C _1-4 alkyl group which may have a substituent. , R ³ represents a hydrogen atom, a halogen atom, a hydroxy group or a C _1-4 alkoxy group which may have a substituent, or two adjacent R ³ are linked to form a C _1-4 alkylenedioxy. R ⁴ represents a hydrogen atom or a C _1-4 alkyl group, and R ⁶ represents a C 5 optionally substituted group.
_1-4 alkyl group or formula (Wherein, R ⁵ represents a hydrogen atom, or R ⁴ and R ⁵ may be linked to form a heterocyclic ring), and n represents an integer of 0 to 5 The preparation according to claim 14, which is a compound represented by the formula: or a salt thereof. (16) the non-peptidic compound or a salt thereof,
-(N-benzyl-N-methylaminomethyl) -1-
(2,6-difluorobenzyl) -6- [4- (3-methoxyureido) phenyl] -3-phenylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione or a salt thereof 15. The formulation according to claim 14, wherein 17. The non-peptidic compound or a salt thereof has the formula
(VIII):[Wherein, R⁹Is optionally substituted C_1-7Alkyl group,
Optionally substituted C _3-7Cycloalkyl group, substituted
C that may be_1-6Alkoxyamino group or substituted
An optionally substituted hydroxyamino group is represented by R^TenIs replaced
May be C_1-7Alkyl group or substituted
Or a salt thereof.
The preparation according to claim 14, which is: (18) the non-peptidic compound or a salt thereof,
-(N-benzyl-N-methylaminomethyl) -4,7
-Dihydro-5-isobutyryl-7- (2,6-difluorobenzyl) -2- [4-[(1-hydroxycyclopropyl) carbonylamino] phenyl] -4-oxothieno [2,3-b] pyridine or a derivative thereof The preparation according to claim 14, which is a salt. 19. The preparation according to claim 1, wherein the compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof is administered before, during or immediately after the administration of the compound having a luteinizing hormone-releasing hormone action or the salt thereof. 20. A medicament for treating a sex hormone-dependent disease, which comprises administering a compound having a luteinizing hormone-releasing hormone action or a salt thereof after administration of a compound having a luteinizing hormone-releasing hormone action or a salt thereof. Use of a compound having a luteinizing hormone-releasing hormone action or a salt thereof and / or a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof for producing a preparation. 21. For the treatment of a sex hormone-dependent disease,
A compound having a luteinizing hormone-releasing hormone action or a salt thereof, comprising administering a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof after administration of the compound having a luteinizing hormone-releasing hormone action or a salt thereof. Alternatively, a pharmaceutical preparation for treating a sex hormone-dependent disease, comprising a compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof. 22. An agent for maintaining hormone therapy, comprising a compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof. 23. A method for defining a drug holiday comprising using a compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof. 24. A method for restoring the in vivo hormone concentration, which comprises using a compound having a luteinizing hormone-releasing hormone antagonistic activity or a salt thereof. (25) administering to a mammal an effective amount of a compound having a luteinizing hormone-releasing hormone action or a salt thereof followed by administration of an effective amount of a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof; A method for treating a sex hormone-dependent disease, characterized by the following. (26) administering to a mammal an effective amount of a compound having a luteinizing hormone-releasing hormone action or a salt thereof followed by administration of an effective amount of a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof; A method for maintaining hormonal therapy, characterized by: (27) administering to a mammal an effective amount of a compound having a luteinizing hormone-releasing hormone action or a salt thereof followed by administration of an effective amount of a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof; A method for defining a drug holiday period characterized by the following. (28) administering to a mammal an effective amount of a compound having a luteinizing hormone-releasing hormone action or a salt thereof followed by administering an effective amount of a compound having a luteinizing hormone-releasing hormone antagonistic action or a salt thereof; A method for restoring a sex hormone concentration in a living body, characterized in that: 29. An effective amount of a compound having a luteinizing hormone-releasing hormone action or a salt thereof after administering an effective amount of a compound having a luteinizing hormone-releasing hormone action or a salt thereof to a mammal. A method for treating a sex hormone-dependent disease, characterized in that sex hormone dependency is restored by the method.