JP5308342B2 - Nitrogen-containing fused ring derivative, pharmaceutical composition containing it, and pharmaceutical use thereof - Google Patents

Abstract

Disclosed is a compound which is useful as a prophylactic or therapeutic agent for a sex hormone-dependent disease or the like. Specifically disclosed are: a nitrogenated fused-ring derivative which is represented by the general formula (I) and which has a GnRH antagonistic activity, or a prodrug or a pharmacologically acceptable salt thereof; a pharmaceutical composition comprising the derivative, the prodrug or the pharmacologically acceptable salt; use of the derivative, the prodrug or the pharmacologically acceptable salt for medical purposes; and others. In the formula (I), the rings A and B independently represent an aryl or a heteroaryl; RA and RB independently represent a halogen, a nitro, an alkyl, -OW1, -COW2, -NW3W4 or the like; E represents an oxygen atom or the like; U represents a single bond or the like; and X represents -SO2-Y, -O-(alkylene)-Y or the like [wherein Y represents Z, an amino or the like; Z represents a heterocycloalkyl, an aryl or the like].

Description

  The present invention relates to a nitrogen-containing fused ring derivative.

  More specifically, the present invention has gonadotropin-releasing hormone antagonistic action, and is prostatic hypertrophy, uterine fibroid, endometriosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, menstruation Nitrogen-containing fused ring derivatives or prodrugs thereof, or pharmacologically acceptable salts thereof, and pharmaceutical compositions containing the same, which can be used for preventive or therapeutic agents for sex hormone dependent diseases such as difficulty It is about.

  Gonadotropin releasing hormone (Gnadotropin Releasing Hormone: GnRH, or luteinizing hormone releasing hormone Luteinizing Hormone Releasing Hormone: LHRH, hereinafter referred to as “GnRH”) is a peptide consisting of 10 amino acids secreted from the hypothalamus (hereinafter referred to as “GnRH”). pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2). GnRH secreted into the pituitary portal vein is a gonadotropin hormone (Luteinizing Hormone: LH, follicular follicle) via a receptor thought to be present in the anterior pituitary gland (GnRH receptor). Promotes production and secretion of stimulating hormone (Follicle Stimulating Hormone: FSH). These gonadotropins act on the gonads (ovary, testis) to promote follicular development, ovulation, luteinization and spermatogenesis, while promoting production and secretion of sex hormones (estrogens, progesterone, androgens) (non-patented) Reference 1). Therefore, this specific and selective antagonist for the GnRH receptor is expected as a prophylactic / therapeutic agent for sex hormone-dependent diseases because it regulates the action of GnRH and regulates the production and secretion of gonadotropins and sex hormones. The

  GnRH receptor superagonist (hereinafter referred to as “GnRH superagonist”) is used as a therapeutic agent for sex hormone-dependent diseases such as prostate cancer, breast cancer and endometriosis as a drug that suppresses GnRH receptor function. It has been. GnRH super-agonist binds to GnRH receptor and causes gonadotropin depletion and GnRH receptor down-regulation after exhibiting transient gonadotropin secretion stimulating action (flare-up phenomenon) at the beginning of administration To suppress its function. Therefore, GnRH superagonists have a problem that their disease state is temporarily worsened based on increased gonadotropin secretion at the initial administration. On the other hand, GnRH receptor antagonists (hereinafter referred to as “GnRH antagonists”) exhibit a suppressive action without gonadotropin secretion because their mechanism of inhibition is binding inhibition to the GnRH receptor. It is expected. In recent years, peptide GnRH antagonists such as abarelix and cetrorelix have been developed as GnRH antagonists, and are used for the treatment of prostate cancer, infertility and the like. However, these peptidic GnRH antagonists are difficult to absorb orally and therefore have to be administered subcutaneously or intramuscularly, and it is expected to avoid local reactivity at the injection site and flexible dosage control. The development of an administrable non-peptide GnRH antagonist is awaited (see Non-Patent Document 2).

As N-aromatic ring-substituted pyrimidinone derivatives, Patent Document 1 discloses various compounds as analgesics, Patent Document 2 as anticancer agents, and Patent Documents 3 and 4 as antiasthma drugs. However, these documents do not describe or suggest that the condensed pyrimidinone derivative of the present invention has a GnRH antagonistic action.
“Standard Physiology”, 5th edition, Medical School, p. 882-891 “Obstetrics and gynecology”, 2004, Vol. 71, No. 3, p. 280-285, p. 301-307 European Patent Application No. 260817 US Pat. No. 6,037,345 European Patent Application No. 994113 JP 2002-308774 A

  An object of the present invention is to provide a compound having a GnRH antagonistic action.

  As a result of intensive studies to solve the above problems, the present inventors have found that the nitrogen-containing fused ring derivative represented by the following general formula (I) exhibits an excellent GnRH antagonistic action, and has completed the present invention. I let you.

That is, the present invention
[1] General formula (I):

〔式中、
環Ａ及び環Ｂは、独立して、アリール又はヘテロアリール；
Ｒ^Ａ及びＲ^Ｂは、独立して、ハロゲン原子、シアノ基、ニトロ基、置換可低級アルキル基、置換可低級アルケニル基、置換可低級アルキニル基、ヒドロキシイミノメチル基、置換可低級アルキルスルホニル基、置換可低級アルキルスルフィニル基、−ＯＷ^１、−ＳＷ^１、−ＣＯＷ^２、−ＮＷ^３Ｗ^４、−ＳＯ_２ＮＷ^３Ｗ^４、置換可アリール基、置換可ヘテロアリール基、置換可シクロアルキル基又は置換可ヘテロシクロアルキル基；
ｍは、０〜３の整数（ｍが２以上である場合、複数のＲ^Ａは同じでも異なっていてもよい。）；
ｎは、０〜２の整数（ｎが２である場合、複数のＲ^Ｂは同じでも異なっていてもよい。）；
Ｅは、酸素原子又は硫黄原子；
Ｕは、単結合又は置換可低級アルキレン基；
Ｘは、Ｙ、−ＣＯ−Ｙ、−ＳＯ_２−Ｙ、−Ｓ−Ｌ−Ｙ、−Ｏ−Ｌ−Ｙ、−ＣＯ−Ｌ−Ｙ、−ＣＯＯ−Ｌ−Ｙ、−ＳＯ−Ｌ−Ｙ、−ＳＯ_２−Ｌ−Ｙ、−Ｓ−Ｚ、−Ｏ−Ｚ、−ＣＯＯ−Ｚ、−Ｎ（Ｑ）−Ｌ−Ｙ、−Ｎ（Ｑ）−ＣＯ−Ｙ、−Ｎ（Ｑ）−ＳＯ_２−Ｙ、−Ｎ（Ｑ）−Ｌ−ＣＯ−Ｙ、−Ｎ（Ｑ）−Ｌ−ＳＯ_２−Ｙ、−Ｎ（Ｑ）−ＣＯ−Ｌ−Ｙ又は−Ｎ（Ｑ）−ＳＯ_２−Ｌ−Ｙで表される基；
（式中、
Ｗ^１は、水素原子、置換可低級アルキル基、置換可アリール基、置換可ヘテロアリール基、置換可シクロアルキル基又は置換可ヘテロシクロアルキル基；
Ｗ^２は、水素原子、水酸基、置換可低級アルキル基、置換可低級アルコキシ基、−ＮＷ^５Ｗ^６、置換可アリール基、置換可ヘテロアリール基、置換可シクロアルキル基又は置換可ヘテロシクロアルキル基；
Ｗ^３及びＷ^４は、独立して、水素原子、置換可低級アルキル基、−ＣＯＷ^７、−ＳＯ_２Ｗ^８、置換可アリール基、置換可ヘテロアリール基、置換可シクロアルキル基又は置換可ヘテロシクロアルキル基であるか、両者が結合して隣接する窒素原子とともに置換可環状アミノ基を形成してもよい；
Ｗ^５及びＷ^６は、独立して、水素原子、置換可低級アルキル基、置換可低級アルコキシ基、置換可アリール基、置換可ヘテロアリール基、置換可シクロアルキル基又は置換可ヘテロシクロアルキル基（但し、同時に置換可低級アルコキシ基ではない）であるか、両者が結合して隣接する窒素原子とともに置換可環状アミノ基を形成してもよい；
Ｗ^７は、水素原子、置換可低級アルキル基、置換可低級アルコキシ基、−ＮＷ^９Ｗ^１０、置換可アリール基、置換可ヘテロアリール基、置換可シクロアルキル基又は置換可ヘテロシクロアルキル基；
Ｗ^８は、置換可低級アルキル基、−ＮＷ^９Ｗ^１０、置換可アリール基、置換可ヘテロアリール基、置換可シクロアルキル基又は置換可ヘテロシクロアルキル基；
Ｗ^９及びＷ^１０は、独立して、水素原子、置換可低級アルキル基、置換可低級アルコキシ基、置換可アリール基、置換可ヘテロアリール基、置換可シクロアルキル基又は置換可ヘテロシクロアルキル基（但し、同時に置換可低級アルコキシ基ではない）であるか、両者が結合して隣接する窒素原子とともに置換可環状アミノ基を形成してもよい；
Ｌは、置換可低級アルキレン基；
Ｙは、Ｚ又は−ＮＷ^１１Ｗ^１２〔Ｗ^１１及びＷ^１２は、独立して、水素原子、置換可低級アルキル基又はＺ（但し、同時に水素原子ではなく、両者が結合して隣接する窒素原子とともに置換可環状アミノ基を形成してもよい）〕で表される基；
Ｚは、縮環していてもよい置換可シクロアルキル基、縮環していてもよい置換可ヘテロシクロアルキル基、縮環していてもよい置換可アリール基又は縮環していてもよい置換可ヘテロアリール基；
Ｑは、Ｗ^３及びＷ^４と独立して、Ｗ^３及びＷ^４と同義（但し、ＱはＲ^Ｂとともに置換可ヘテロアリール基又は置換可ヘテロシクロアルキル基を形成してもよい）；である）
である〕で表される含窒素縮合環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩；

[Where,
Ring A and Ring B are independently aryl or heteroaryl;
R ^A and R ^B independently represent a halogen atom, a cyano group, a nitro group, a substitutable lower alkyl group, a substitutable lower alkenyl group, a substitutable lower alkynyl group, a hydroxyiminomethyl group, a substitutable lower alkylsulfonyl group, optionally substituted lower alkylsulfinyl ^{group, -OW 1, -SW 1, -COW} 2, -NW 3 W 4, -SO 2 NW 3 W 4, an optionally substituted aryl group, optionally substituted heteroaryl group, a substitutable cycloalkyl group, or A substituted heterocycloalkyl group;
m is an integer of 0 to 3 (when m is 2 or more, a plurality of R ^A may be the same or different);
n is an integer of 0 to 2 (when n is 2, a plurality of R ^B may be the same or different);
E represents an oxygen atom or a sulfur atom;
U represents a single bond or a substitutable lower alkylene group;
X _{is, Y, -CO-Y, -SO} 2 -Y, -S-L-Y, -O-L-Y, -CO-L-Y, -COO-L-Y, -SO-L-Y _{, -SO 2 -L-Y, -S} -Z, -O-Z, -COO-Z, -N (Q) -L-Y, -N (Q) -CO-Y, -N (Q) - _{SO 2 -Y, -N (Q)} -L-CO-Y, -N (Q) -L-SO 2 -Y, -N (Q) -CO-L-Y or -N (Q) -SO ₂ A group represented by -LY;
(Where
W ¹ represents a hydrogen atom, a substitutable lower alkyl group, a substitutable aryl group, a substitutable heteroaryl group, a substitutable cycloalkyl group or a substitutable heterocycloalkyl group;
W ² represents a hydrogen atom, a hydroxyl group, a substitutable lower alkyl group, a substitutable lower alkoxy group, —NW ⁵ W ⁶ , a substitutable aryl group, a substitutable heteroaryl group, a substitutable cycloalkyl group or a substitutable heterocycloalkyl group. ;
W ³ and W ⁴ are each independently a hydrogen atom, a substitutable lower alkyl group, —COW ⁷ , —SO ₂ W ⁸ , a substitutable aryl group, a substitutable heteroaryl group, a substitutable cycloalkyl group or a substitutable hetero hetero group. It may be a cycloalkyl group or both may be joined to form a substituted cyclic amino group with the adjacent nitrogen atom;
W ⁵ and W ⁶ independently represent a hydrogen atom, a substitutable lower alkyl group, a substitutable lower alkoxy group, a substitutable aryl group, a substitutable heteroaryl group, a substitutable cycloalkyl group or a substitutable heterocycloalkyl group ( However, they are not simultaneously substitutable lower alkoxy groups) or they may be bonded to form a substituted cyclic amino group together with the adjacent nitrogen atom;
W ⁷ represents a hydrogen atom, a substitutable lower alkyl group, a substitutable lower alkoxy group, —NW ⁹ W ¹⁰ , a substitutable aryl group, a substitutable heteroaryl group, a substitutable cycloalkyl group or a substitutable heterocycloalkyl group;
W ⁸ represents a substitutable lower alkyl group, —NW ⁹ W ¹⁰ , a substitutable aryl group, a substitutable heteroaryl group, a substitutable cycloalkyl group or a substitutable heterocycloalkyl group;
W ⁹ and W ¹⁰ are each independently a hydrogen atom, a substitutable lower alkyl group, a substitutable lower alkoxy group, a substitutable aryl group, a substitutable heteroaryl group, a substitutable cycloalkyl group or a substitutable heterocycloalkyl group ( However, they are not simultaneously substitutable lower alkoxy groups) or they may be bonded to form a substituted cyclic amino group together with the adjacent nitrogen atom;
L is a substitutable lower alkylene group;
Y is Z or —NW ¹¹ W ¹² [W ¹¹ and W ¹² are each independently a hydrogen atom, a substitutable lower alkyl group or Z (however, not a hydrogen atom but a nitrogen atom adjacent to each other by bonding to each other) And a substituted cyclic amino group may be formed together)]
Z is a substituted cycloalkyl group that may be condensed, a substituted heterocycloalkyl group that may be condensed, a substituted aryl group that may be condensed, or a substituent that may be condensed. A heteroaryl group;
Q independently of W ³ and W ⁴ has the same meaning as W ³ and W ⁴ (provided that Q may form a substituted heteroaryl group or a substituted heterocycloalkyl group together with R ^B ); )
Or a prodrug thereof or a pharmaceutically acceptable salt thereof;

[2] The nitrogen-containing fused ring derivative or prodrug thereof or pharmacologically acceptable salt thereof according to [1], wherein E is an oxygen atom;
[3] R ^A is a halogen atom, a nitro group, a substitutable lower alkyl group, —OW ¹ , —COW ² or —NW ³ W ⁴ (W ^{1 to} W ⁴ in the formula have the same meaning as in the above [1]. The nitrogen-containing fused ring derivative or prodrug thereof or pharmacologically acceptable salt thereof according to [1] or [2].
[4] The nitrogen-containing condensation according to any one of [1] to [3], wherein R ^B is a halogen atom and —OW ¹ (wherein W ¹ has the same meaning as in the above [1]). A ring derivative or a prodrug thereof or a pharmacologically acceptable salt thereof.
[5] The ring A is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a pyrrole ring, a furan ring, a thiophene ring, an imidazole ring, a pyrazole ring, a thiazole ring, or an oxazole ring. [4] The nitrogen-containing fused ring derivative or prodrug thereof or pharmacologically acceptable salt thereof according to any one of [4].

[6] Ring A is a formula

の何れかで表される環である、前記〔５〕記載の含窒素縮合環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。

Or a prodrug thereof or a pharmacologically acceptable salt thereof, which is a ring represented by any one of the above.

[7] Ring A is a compound represented by the following formula on the ^{R A} is ring A

で表される位置に結合している何れかの環である、前記〔６〕記載の含窒素縮合環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。
〔８〕 環Ｂがベンゼン環である、前記〔１〕〜〔７〕の何れかに記載の含窒素縮合環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。

The nitrogen-containing fused ring derivative of the above-mentioned [6], a prodrug thereof or a pharmacologically acceptable salt thereof, which is any ring bonded to the position represented by
[8] The nitrogen-containing fused ring derivative or prodrug thereof or pharmacologically acceptable salt thereof according to any one of [1] to [7], wherein Ring B is a benzene ring.

[9] n is 1 or 2, and the formula

の何れかで表される、前記〔８〕記載の含窒素縮合環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。
〔１０〕 Ｕが単結合であり、Ｘが−ＳＯ_２−Ｙ及び−Ｏ−Ｌ−Ｙで表される基（式中、Ｌ及びＹは前記〔１〕と同じ意味である）である、前記〔１〕〜〔９〕記載の含窒素縮合環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。
〔１１〕 ＬがＣ_１−３アルキレン基である、前記〔１〕〜〔１０〕の何れかに記載の含窒素縮合環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。
〔１２〕 Ｚが、縮環していてもよい置換可アリール基である、前記〔１〕〜〔１１〕の何れかに記載の含窒素縮合環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩。
〔１３〕 前記〔１〕〜〔１２〕の何れかに記載の含窒素縮合環誘導体もしくはそのプロドラッグ又はその薬理学的に許容される塩を有効成分として含有する医薬組成物。
〔１４〕 性腺刺激ホルモン放出ホルモン拮抗剤である、前記〔１３〕記載の医薬組成物。

Or a prodrug thereof or a pharmacologically acceptable salt thereof.
[10] U is a single bond, and X is a group represented by —SO ₂ —Y and —O—L—Y (wherein L and Y have the same meaning as in the above [1]). The nitrogen-containing fused ring derivative according to the above [1] to [9], a prodrug thereof or a pharmacologically acceptable salt thereof.
[11] The nitrogen-containing fused ring derivative or prodrug or pharmacologically acceptable salt thereof according to any one of [1] to [10], wherein L is a C _1-3 alkylene group.
[12] The nitrogen-containing fused ring derivative according to any one of the above [1] to [11], a prodrug thereof, or a pharmacologically acceptable salt thereof, wherein Z is a substituted aryl group which may be condensed. Salt.
[13] A pharmaceutical composition comprising, as an active ingredient, the nitrogen-containing fused ring derivative according to any one of [1] to [12], a prodrug thereof, or a pharmacologically acceptable salt thereof.
[14] The pharmaceutical composition according to [13] above, which is a gonadotropin releasing hormone antagonist.

[15] The pharmaceutical composition of the above-mentioned [13], which is a preventive or therapeutic agent for sex hormone-dependent diseases, a reproductive regulator, a contraceptive, an ovulation inducer, or a preventive agent for sex hormone-dependent cancer postoperative recurrence.
[16] Sex hormone dependent diseases are prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, erythema Selected from the group consisting of lupus, hirsutism, dwarfism, sleep disorders, acne, baldness, Alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer and pituitary tumor The pharmaceutical composition according to the above [15], which is a disease.
[17] The pharmaceutical composition according to the above [13], which is for oral administration.
[18] Sex hormone-dependent disease comprising administering an effective amount of the nitrogen-containing fused ring derivative or prodrug thereof or pharmacologically acceptable salt thereof according to any one of [1] to [12] Prevention or treatment method.
[19] Sex hormone-dependent diseases include prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, erythema Selected from the group consisting of lupus, hirsutism, dwarfism, sleep disorders, acne, baldness, Alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer and pituitary tumor The method for prevention or treatment according to [18], wherein the method is a disease.
[20] A method of reproductive regulation and contraception comprising administering an effective amount of the nitrogen-containing fused ring derivative or prodrug thereof or pharmacologically acceptable salt thereof according to any one of [1] to [12] Method, method of inducing ovulation, or method of preventing recurrence after sex hormone-dependent cancer surgery.
[21] The nitrogen-containing fused ring derivative or prodrug thereof or pharmacology thereof according to any one of [1] to [12] for producing a pharmaceutical composition for prevention or treatment of sex hormone-dependent diseases Acceptable salt.
[22] The nitrogen-containing condensed ring according to any one of [1] to [12] above for producing a pharmaceutical composition for reproductive regulation, contraception, ovulation induction or prevention of recurrence after sex hormone-dependent cancer surgery Derivatives or prodrugs thereof or pharmacologically acceptable salts thereof.
[23] GnRH superagonist, chemotherapeutic agent, peptidic GnRH antagonist, 5α-reductase inhibitor, α adrenergic receptor inhibitor, aromatase inhibitor, adrenal androgen production inhibitor, and hormone therapy agent The pharmaceutical composition according to the above [13], further comprising at least one kind of drug further combined.
[24] The pharmaceutical composition of [23] above, wherein the GnRH superagonist is a drug selected from leuprorelin acetate, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterelin and resilerin.

[25] [23] The pharmaceutical composition as described.
[26] The pharmaceutical composition according to [23] above, wherein the peptidic GnRH antagonist is a drug selected from cetrorelix, ganirelix, abarelix, ozalelix, itrelux, degarelix and teverelix.
[27] The pharmaceutical composition of the above-mentioned [23], wherein the 5α-reductase inhibitor is a drug selected from finasteride and dutasteride.
[28] The pharmaceutical composition according to [23] above, wherein the α-adrenergic receptor inhibitor is a drug selected from tamsulosin, silodosin and urapidil.
[29] The pharmaceutical composition according to the above [23], wherein the aromatase inhibitor is a drug selected from fadrozole, letrozole, anastrozole and formestane.
[30] The pharmaceutical composition according to the above [23], wherein the adrenal androgen production inhibitor is liarozole.
[31] The pharmaceutical composition according to [23] above, wherein the hormone therapy agent is a drug selected from an anti-estrogen agent, a luteinizing hormone agent, an androgen agent, an estrogen agent and an anti-androgen agent.
[32] GnRH superagonist, chemotherapeutic agent, peptidic GnRH antagonist, 5α-reductase inhibitor, α adrenergic receptor inhibitor, aromatase inhibitor, adrenal androgen production inhibitor, and hormone therapy agent The method for preventing or treating a sex hormone-dependent disease according to the above [18] or [19], comprising administering at least one drug in combination.
[33] GnRH superagonist, chemotherapeutic agent, peptidic GnRH antagonist, 5α-reductase inhibitor, α adrenergic receptor inhibitor, aromatase inhibitor, adrenal androgen production inhibitor and hormone therapy agent [20] The reproductive regulation method, the contraceptive method, the ovulation induction method or the sex hormone-dependent cancer postoperative recurrence prevention method according to [20], further comprising administering at least one kind of drug in combination.
[34] (A) The nitrogen-containing fused ring derivative or prodrug thereof according to any one of [1] to [12] above for producing a pharmaceutical composition for preventing or treating sex hormone-dependent diseases, Pharmacologically acceptable salts thereof, and (B) GnRH superagonist, chemotherapeutic agent, peptidic GnRH antagonist, 5α-reductase inhibitor, α adrenergic receptor inhibitor, aromatase inhibitor, adrenal androgen production Use of at least one drug selected from the group of inhibitors and hormone therapy agents.
[35] The method according to any one of [1] to [12] above, for producing a pharmaceutical composition for reproductive regulation, contraception, ovulation induction or prevention of recurrence after sex hormone dependent cancer surgery. A nitrogen-fused ring derivative or a prodrug thereof or a pharmacologically acceptable salt thereof, and (B) a GnRH superagonist, a chemotherapeutic agent, a peptidic GnRH antagonist, a 5α-reductase inhibitor, an α adrenergic receptor inhibitor Use of at least one drug selected from the group of an aromatase inhibitor, an adrenal androgen production inhibitor, and a hormone therapy agent;

  Since the nitrogen-containing fused ring derivative (I) of the present invention or a prodrug thereof or a pharmacologically acceptable salt thereof has an excellent GnRH antagonistic action, it regulates the action of the gonadotropin releasing hormone, and the gonadotropin And by controlling the production / secretion of sex hormones, they can be used as preventive or therapeutic agents for sex hormone-dependent diseases.

The meaning of the term in this specification is as follows.
“Aryl” means phenyl or naphthyl.
“Heteroaryl” is a monocyclic heteroaryl having one or more heteroatoms arbitrarily selected from nitrogen, oxygen and sulfur atoms (eg, thiazole, oxazole, isothiazole, isoxazole, pyridine, pyrimidine) , Pyrazine, pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, furazane, etc.), such as 1H-pyridin-2-one and 1H-pyrimidin-2-one Also included are those isomerized when having a hydroxyl group on the carbon atom adjacent to the nitrogen atom.
“Substitutable” means that it may have a substituent.

“Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
“Lower alkyl” is branched from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl and the like. Means good alkyl.
“Lower alkenyl” means an optionally branched alkenyl having 2 to 6 carbon atoms such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 2-methylallyl and the like.
“Lower alkynyl” means alkynyl having 2 to 6 carbon atoms such as ethynyl and 2-propynyl.
“Lower alkylsulfonyl” means sulfonyl substituted with the above lower alkyl.
“Lower alkylsulfinyl” means sulfinyl substituted with the above lower alkyl.
“Lower alkylene” means methylene, ethylene, methylmethylene, trimethylene, dimethylmethylene, ethylmethylene, methylethylene, propylmethylene, isopropylmethylene, dimethylethylene, butylmethylene, ethylmethylmethylene, pentamethylene, diethylmethylene, dimethyltrimethylene , Alkylene having 1 to 6 carbon atoms, such as hexamethylene and diethylethylene.
“C _1-3 alkylene” means the above lower alkylene having 1 to 3 carbon atoms.
“Lower alkoxy” means carbon number such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, etc. 1-6 alkoxy which may be branched is meant.

“Cycloalkyl” means monocyclic cycloalkyl having 3 to 8 carbon atoms (for example, monocyclic cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group, etc.).
“Heterocycloalkyl” is a 3- to 8-membered ring having 1 or 2 or more heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom, and optionally having 1 to 2 oxo groups Heterocycloalkyl (e.g., pyrrolidinyl, piperidinyl, oxopiperidinyl, morpholinyl, piperazinyl, oxopiperazinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dioxothiazepanyl, azocanyl, tetrahydrofuranyl, tetrahydropyranyl, Oxazolidinyl, dioxanyl, dioxolanyl, etc.), and when having a sulfur atom in the ring, the sulfur atom may be oxidized.

  “It may be condensed” means that it may be fused with one ring selected from the above cycloalkyl, the above heterocycloalkyl, the above aryl and the above heteroaryl. As "optionally condensed cycloalkyl", "optionally condensed heterocycloalkyl", "optionally condensed aryl" and "optionally condensed heteroaryl", For example, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, Cinnolinyl, indolizinyl, naphthyridinyl, pteridinyl, indanyl, 1,2,3,4-tetrahydronaphthyl, indolinyl, isoindolinyl, 2,3,4,5-tetrahydrobenzo [b] oxepinyl, 6,7,8,9-tetrahydro 5H- benzocycloheptenyl, chromanyl and the like, bond may have out either ring.

  “Cyclic amino” means a group having at least one nitrogen atom having a bonding site in the ring among the above-mentioned heterocycloalkyl which may be condensed, such as 1-pyrrolidinyl, 1-pyrrolidinyl, Piperidinyl, 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, pyrrolidin-2-one-1-yl, oxazolidin-2-one-3-yl, morpholin-3-one-4-yl, 2,3,4, 5,6,7-hexahydro-1H-azepin-1-yl, 1-indolinyl, 2-isoindolinyl, 3,4-dihydro-1,5-naphthyridin-1 (2H) -yl, 1,2,3,4 -Tetrahydroquinolin-1-yl, 3,4-dihydroquinolin-1 (2H) -yl, 3,4-dihydroisoquinolin-2 (1H) -yl, octahydroquinoline-1 2H) -yl, octahydroisoquinolin-2 (1H) -yl, perhydroquinolin-1-yl, 2,3-dihydro-4H-1,4-benzoxazin-4-yl, 2,3-dihydro-4H -1,4-benzothiazin-4-yl, 3,4-dihydroquinoxalin-1 (2H) -yl, 2,3-dihydro-4H-pyrido [3,2-b] [1,4] oxazine-4- 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl, 1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl, 3,4-dihydro- 1,5-benzoxazepine-5 (2H) -yl, 2,3-dihydro-4,1-benzothiazepin-1 (5H) -yl, 3,4-dihydro-1,5-benzothiazepine -5 (2H) -yl, 2,3-dihydride -4,1-benzoxazepin-1 (5H) -yl, 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl, 2,3,4,5-tetrahydro-1H -1,4-benzodiazepin-1-yl, 5,6,7,8-tetrahydro-4H-thieno [3,2-b] azepin-4-yl, 3,4,5,6-tetrahydro-1-benzoazocine -1 (2H) -yl group and the like.

The “halo lower alkyl” means the lower alkyl substituted with the halogen atom.
“Lower alkylthio” means methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, neopentylthio group, It means an alkylthio having 1 to 6 carbon atoms which may be branched, such as a tert-pentylthio group and a hexylthio group.
“Lower alkoxycarbonyl” means methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutyloxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group , An alkoxycarbonyl group having 2 to 7 carbon atoms such as isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, hexyloxycarbonyl group and the like.
"Lower acyl" means an aliphatic carboxylic acid acyl having 2 to 7 carbon atoms, cycloalkyl carboxylic acid acyl, heterocycloalkyl carboxylic acid acyl, aryl carboxylic acid acyl, heteroaryl carboxylic acid acyl To do.
“(Di) lower alkylcarbamoyl” means carbamoyl mono- or di-substituted with the above lower alkyl, and the two di-substituted lower alkyl groups may be different, and the two lower alkyl groups are both May combine to form a cyclic amino group together with the adjacent nitrogen atom.
“(Di) lower alkylamino” means amino mono- or di-substituted with the above lower alkyl, and the di-substituted two lower alkyl groups may be different, and the two lower alkyl groups are both May combine to form a cyclic amino group together with the adjacent nitrogen atom.

In general formula (I), ring A is preferably a benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, pyrrole ring, furan ring, thiophene ring, imidazole ring, pyrazole ring, thiazole ring or oxazole ring. A benzene ring, a pyridine ring, a pyrimidine ring or a thiophene ring is more preferable. In this case, it is preferable that the nitrogen atom or sulfur atom of ring A is in the position where the (A1) moiety in the following formula (A) is represented by any one of (A2).

When m is 2 or more, the plurality of R ^A may be the same or different. Ring A is a benzene ring or a pyridine ring, when m is 1, ring A R ^A is represented by the following formula

の何れかで表される位置に結合しているものが好ましい。
Ｒ^Ａとしては、ハロゲン原子、ニトロ基、置換可低級アルキル基、−ＯＷ^１、−ＣＯＷ^２又は−ＮＷ^３Ｗ^４（式中のＷ^１〜Ｗ^４は前記〔１〕と同じ意味である）等が好ましい。

What is couple | bonded with the position represented by either of these is preferable.
As R ^A , a halogen atom, a nitro group, a substitutable lower alkyl group, —OW ¹ , —COW ² or —NW ³ W ⁴ (W ^{1 to} W ⁴ in the formula have the same meaning as the above [1]) Etc. are preferred.

  Ring B is preferably a benzene ring, a pyridine ring or a thiophene ring. The bonding position of ring B is the following formula

（式中、左側の結合手は縮合ピリミジン環の窒素原子との結合を、右側の結合手はＵとの結合を示す）の何れかで表されるものが好ましい。環Ｂがベンゼン環であり、ｎが１又は２である場合、下記式

(Wherein, the bond on the left side represents a bond with the nitrogen atom of the condensed pyrimidine ring, and the bond on the right side represents a bond with U). When ring B is a benzene ring and n is 1 or 2,

の何れかで表される化合物が好ましい。

The compound represented by either is preferable.

R ^B is preferably a halogen atom or —OW ¹ (wherein W ¹ has the same meaning as in the above [1]). When n is 2, the plurality of R ^B may be the same or different. Further, ring B is represented by the following formula:

で表される位置にＲ^Ｂ１又はＲ^Ｂ２が結合している何れかのベンゼン環である場合は、Ｒ^Ｂ１としてはフッ素原子又は塩素原子が好ましく、Ｒ^Ｂ２としてはハロゲン原子又は−ＯＷ^１（Ｗ^１は前記〔１〕と同じ意味である）が好ましい。

When R ^B1 or R ^B2 is bonded to the position represented by any of the formulas above, R ^B1 is preferably a fluorine atom or a chlorine atom, and R ^B2 is preferably a halogen atom or —OW ¹ (W ¹ is preferably the same as [1] above.

In general formula (I), U is preferably a single bond, a methylene group or an ethylene group.
When U is a single bond, X is preferably a group represented by —SO ₂ —Y or —O—L—Y (wherein L and Y have the same meaning as in the above [1]).
L is preferably a C _1-3 lower alkylene group.
Z is preferably a substituted aryl group which may be condensed or a substituted heteroaryl group which may be condensed, and more preferably a substituted aryl group which may be condensed. In this case, the substituent that the substituted aryl group may have is preferably a halogen atom or —OW ¹³ (W ¹³ has the same meaning as described later).

Examples of the substituent that the substituted cyclic amino, substituted cycloalkyl or substituted heterocycloalkyl group may have include an oxo group, a halogen atom, a cyano group, a substituted lower alkyl group, and a substituted lower alkenyl group. , optionally substituted lower alkynyl group, optionally substituted lower alkylsulfonyl group, optionally substituted lower alkylsulfinyl ^{group, -OW 13, -SW 13, -COW} 14, -NW 15 W 16, -SO 2 NW 15 W 16, substituent group An aryl group which may be substituted with a group selected from A, a heteroaryl group which may be substituted with a group selected from Substituent Group A, and a group selected from Substituent Group B Or a heterocycloalkyl group optionally substituted with a group selected from substituent group B, and these groups are the same or It may be a plurality of differently substituted.

Examples of the substituent that the substituted aryl or substituted heteroaryl group may have include, for example, a halogen atom, a nitro group, a cyano group, a substituted lower alkyl group, a substituted lower alkenyl group, a substituted lower alkynyl group, optionally substituted lower alkylsulfonyl group, optionally substituted lower alkylsulfinyl ^{group, -OW 13, -SW 13, -COW} 14, -NW 15 W 16, -SO 2 NW 15 W 16, a group selected from substituent group A An optionally substituted aryl group, a heteroaryl group optionally substituted with a group selected from substituent group A, a cycloalkyl group optionally substituted with a group selected from substituent group B, or a substituent A heterocycloalkyl group which may be substituted with a group selected from group B, and the like, and these groups may be the same or different and may be substituted plurally. .

  Substituted cycloalkyl group which may be condensed, substituted heterocycloalkyl group which may be condensed, substituted aryl group which may be condensed and substituted heteroaryl which may be condensed In the group, the above substituents may be substituted with a plurality of the same or different condensed rings.

W ¹³ may be substituted with a hydrogen atom, a substitutable lower alkyl group, an aryl group optionally substituted with a group selected from Substituent Group A, or a group selected from Substituent Group A. A heteroaryl group, a cycloalkyl group optionally substituted with a group selected from substituent group B, or a heterocycloalkyl group optionally substituted with a group selected from substituent group B;
W ¹⁴ represents a hydrogen atom, a hydroxyl group, a substitutable lower alkyl group, a substitutable lower alkoxy group, —NW ¹⁷ W ¹⁸ , an aryl group which may be substituted with a group selected from Substituent Group A, Substituent Group A A heteroaryl group optionally substituted with a group selected from: a cycloalkyl group optionally substituted with a group selected from substituent group B, or a group selected from substituent group B A heterocycloalkyl group which may be
W ¹⁵ and W ¹⁶ are independently a hydrogen atom, a substitutable lower alkyl group, —COW ¹⁹ , —SO ₂ W ²⁰ , an aryl group which may be substituted with a group selected from substituent group A, a substituent Substituted with a heteroaryl group optionally substituted with a group selected from group A, a cycloalkyl group optionally substituted with a group selected from substituent group B, or a group selected from substituent group B A heterocycloalkyl group which may be substituted, or both may be bonded to form a cyclic amino group which may be substituted with a group selected from Substituent Group B together with the adjacent nitrogen atom;
W ¹⁷ and W ¹⁸ are independently a hydrogen atom, a substitutable lower alkyl group, a substitutable lower alkoxy group, an aryl group which may be substituted with a group selected from Substituent Group A, or Substituent Group A. A heteroaryl group optionally substituted with a selected group, a cycloalkyl group optionally substituted with a group selected from substituent group B, or a group selected from substituent group B A cyclic amino group which is a good heterocycloalkyl group (but not simultaneously a substitutable lower alkoxy group), or may be substituted with a group selected from Substituent Group B together with the adjacent nitrogen atom May be formed;
W ¹⁹ is selected from a hydrogen atom, a substitutable lower alkyl group, a substitutable lower alkoxy group, —NW ²¹ W ²² , an aryl group optionally substituted with a group selected from Substituent Group A, and Substituent Group A A heteroaryl group optionally substituted with a group selected from the above, a cycloalkyl group optionally substituted with a group selected from the substituent group B, or a group selected from the substituent group B optionally substituted A heterocycloalkyl group;
W ²⁰ may be substituted with a substitutable lower alkyl group, —NW ²¹ W ²² , an aryl group which may be substituted with a group selected from Substituent Group A, or a group selected from Substituent Group A A good heteroaryl group, a cycloalkyl group optionally substituted with a group selected from substituent group B, or a heterocycloalkyl group optionally substituted with a group selected from substituent group B;
W ²¹ and W ²² are independently a hydrogen atom, a substitutable lower alkyl group, a substitutable lower alkoxy group, an aryl group which may be substituted with a group selected from Substituent Group A, or Substituent Group A. A heteroaryl group optionally substituted with a selected group, a cycloalkyl group optionally substituted with a group selected from substituent group B, or a group selected from substituent group B A cyclic amino group which is a good heterocycloalkyl group (but not simultaneously a substitutable lower alkoxy group), or may be substituted with a group selected from Substituent Group B together with the adjacent nitrogen atom May be formed.

Substituents that the substituted lower alkyl, substituted lower alkylene, substituted lower alkenyl, substituted lower alkynyl, substituted lower alkylsulfonyl, substituted lower alkylsulfinyl or substituted lower alkoxy group may have are halogen A lower alkylsulfonyl group that may be substituted with an atom, a cyano group, a group selected from substituent group C, a lower alkylsulfinyl group that may be substituted with a group selected from substituent group C, -OW ²³ , -SW ²³ , -COW ²⁴ , -NW ²⁵ W ²⁶ , -SO ₂ NW ²⁵ W ²⁶ , an aryl group which may be substituted with a group selected from Substituent Group A, and Substituent Group A A heteroaryl group optionally substituted with a group, a cycloalkyl group optionally substituted with a group selected from substituent group B, or a substituent Optionally substituted with a group selected from Group B also include good heterocycloalkyl group, may be a plurality substituent these groups are the same or different and.

W ²³ is a hydrogen atom, a lower alkyl group which may be substituted with a group selected from substituent group C, an aryl group which may be substituted with a group selected from substituent group A, or a substituent. A heteroaryl group optionally substituted with a group selected from group A, a cycloalkyl group optionally substituted with a group selected from substituent group B, or a group selected from substituent group B An optionally heterocycloalkyl group;
W ²⁴ represents a hydrogen atom, a hydroxyl group, a lower alkyl group that may be substituted with a group selected from substituent group C, a lower alkoxy group that may be substituted with a group selected from substituent group C,- NW ²⁷ W ²⁸ , aryl group optionally substituted with a group selected from substituent group A, heteroaryl group optionally substituted with a group selected from substituent group A, selected from substituent group B A cycloalkyl group optionally substituted with a group selected from the above or a heterocycloalkyl group optionally substituted with a group selected from substituent group B;
W ²⁵ and W ²⁶ are independently selected from a hydrogen atom, a lower alkyl group optionally substituted with a group selected from substituent group C, —COW ²⁹ , —SO ₂ W ³⁰ , and substituent group A. An aryl group optionally substituted with a group selected from the above, a heteroaryl group optionally substituted with a group selected from substituent group A, and a cyclo optionally substituted with a group selected from substituent group B It is a heterocycloalkyl group which may be substituted with an alkyl group or a group selected from substituent group B, or both are bonded and substituted with a group selected from substituent group B together with the adjacent nitrogen atom May form a cyclic amino group which may be
W ²⁷ and W ²⁸ may be independently substituted with a hydrogen atom, a lower alkyl group which may be substituted with a group selected from Substituent Group C, or a group selected from Substituent Group C. Selected from a lower alkoxy group, an aryl group optionally substituted with a group selected from substituent group A, a heteroaryl group optionally substituted with a group selected from substituent group A, and substituent group B A cycloalkyl group optionally substituted with a group or a heterocycloalkyl group optionally substituted with a group selected from Substituent Group B (however, simultaneously substituted with a group selected from Substituent Group C) They may be bonded together to form a cyclic amino group which may be substituted with a group selected from the substituent group B together with the adjacent nitrogen atom;
W ²⁹ is a hydrogen atom, a lower alkyl group which may be substituted with a group selected from Substituent Group C, a lower alkoxy group which may be substituted with a group selected from Substituent Group C, —NW ³¹ W ³² , an aryl group which may be substituted with a group selected from substituent group A, a heteroaryl group which may be substituted with a group selected from substituent group A, or a substituent group B A cycloalkyl group optionally substituted with a group or a heterocycloalkyl group optionally substituted with a group selected from substituent group B;
W ³⁰ is a lower alkyl group which may be substituted with a group selected from Substituent Group C, —NW ³¹ W ³² , an aryl group which may be substituted with a group selected from Substituent Group A, substituted Substituted with a heteroaryl group optionally substituted with a group selected from group A, a cycloalkyl group optionally substituted with a group selected from substituent group B, or a group selected from substituent group B An optionally substituted heterocycloalkyl group;
W ³¹ and W ³² may be independently substituted with a hydrogen atom, a lower alkyl group optionally substituted with a group selected from substituent group C, or a group selected from substituent group C. Selected from a lower alkoxy group, an aryl group optionally substituted with a group selected from substituent group A, a heteroaryl group optionally substituted with a group selected from substituent group A, and substituent group B A cycloalkyl group optionally substituted with a group or a heterocycloalkyl group optionally substituted with a group selected from Substituent Group B (however, simultaneously substituted with a group selected from Substituent Group C) Or a cyclic amino group that may be substituted with a group selected from Substituent Group B together with the adjacent nitrogen atom. is there.

[Substituent group A]
Halogen atom, cyano group, nitro group, hydroxyl group, lower alkyl group, halo lower alkyl group, lower alkoxy group, lower alkenyl group, lower alkynyl group, lower alkylthio group, lower alkylsulfonyl group, lower alkylsulfinyl group, carboxy group, lower Alkoxycarbonyl group, lower acyl group, carbamoyl group, (di) lower alkylcarbamoyl group, amino group, (di) lower alkylamino group, aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group [Substituent Group B ]
Oxo group, halogen atom, cyano group, hydroxyl group, lower alkyl group, halo lower alkyl group, lower alkoxy group, lower alkenyl group, lower alkynyl group, lower alkylthio group, lower alkylsulfonyl group, lower alkylsulfinyl group, carboxy group, lower Alkoxycarbonyl group, lower acyl group, carbamoyl group, (di) lower alkylcarbamoyl group, amino group, (di) lower alkylamino group, aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group [Substituent Group C ]
Halogen atom, cyano group, hydroxyl group, lower alkoxy group, lower alkylthio group, lower alkylsulfonyl group, lower alkylsulfinyl group, carboxy group, lower alkoxycarbonyl group, lower acyl group, carbamoyl group, (di) lower alkylcarbamoyl group, amino Group, (di) lower alkylamino group, aryl group, heteroaryl group, cycloalkyl group, heterocycloalkyl group

  An example of a method for producing the nitrogen-containing fused ring derivative represented by the general formula (I) of the present invention is shown below.

L ¹ in the formula is a halogen atom or trifluoromethanesulfonyloxy, L ² is a chlorine atom, a bromine atom, an iodine atom or trifluoromethanesulfonyloxy, R is a hydrogen atom or a lower alkyl group, R ^{A 1} , R ^B , Ring A, Ring B, m, n, E, U and X have the same meaning as described above.

Process 1
The carboxylic acid compound ( 3 ) is produced by condensing the compound ( 1 ) having a leaving group and the amine compound ( 2 ) by a general coupling method under basic conditions, palladium conditions, or the like. can do.

In the coupling method under basic conditions, the compound ( 1 ) having a leaving group and the amine compound ( 2 ) are converted into, for example, an inert solvent (for example, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidone or a mixed solvent thereof) or a solvent-free base in the presence or absence of an additive such as copper powder (for example, triethylamine, N, N-diisopropylethylamine) , Pyridine, 4-dimethylaminopyridine, sodium hydride, potassium hydride, sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, potassium carbonate, cesium carbonate, cesium fluoride, potassium tert -Butoxide, sodium tert-butoxide, etc.) In general, the reaction may be performed at −78 ° C. to reflux temperature for 30 minutes to 1 day.

In the coupling method under palladium conditions, the compound ( 1 ) having a leaving group and the amine compound ( 2 ) are reacted with, for example, an inert solvent (for example, 1,4-dioxane, 2-propanol, tert-butanol, 1,2-dimethoxyethane, toluene, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidone, water or a mixed solvent thereof, etc. Benzylideneacetone) dipalladium (0), palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0) and the like) and ligands (eg, 4,5-bis (diphenylphosphino) -9,9-dimethyl Xanthene, tri (tert-butyl) phosphine, 2- (dicyclohexylphosphino) -2′-me Rubiphenyl, bis (2-diphenylphosphinophenyl) ether, etc.) in the presence of a base (for example, cesium carbonate, potassium carbonate, cesium fluoride, potassium tert-butoxide, sodium tert-butoxide, etc.) The reaction may be performed at room temperature to reflux temperature for 1 hour to 3 days.

Process 2
Carboxylic acid compound ( 3 ) can also be produced by condensing amine compound ( 4 ) and compound ( 5 ) having a leaving group by a general coupling method. In the condensation reaction, the amine compound ( 4 ) and the compound ( 5 ) having a leaving group are converted into, for example, an inert solvent (for example, 1,4-dioxane, 2-propanol, tert-butanol, 1,2-dimethoxyethane). , Toluene, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidone, water or a mixed solvent thereof, etc.) (for example, tris (dibenzylideneacetone) dipalladium ( 0), palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0) and the like) and ligands (for example, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, tri (tert- Butyl) phosphine, 2- (dicyclohexylphosphino) -2′-methylbiphenyl, bis (2- Phenylphosphinophenyl) ether) in the presence of a base (eg, cesium carbonate, potassium carbonate, cesium fluoride, potassium tert-butoxide, sodium tert-butoxide, etc.), usually at room temperature to reflux temperature. What is necessary is just to make it react for time-3 days.

  In Step 1 and Step 2, when R is a lower alkyl group, subsequent to each step, in an inert solvent (for example, methanol, ethanol, 2-propanol, tetrahydrofuran, water, or a mixed solvent thereof). In the presence of a base (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), the reaction is usually carried out at room temperature to reflux temperature for 1 hour to 3 days to hydrolyze to a carboxy group.

Process 3
The amide compound ( 6 ) can be produced by subjecting the carboxylic acid compound ( 3 ) to a general amidation reaction. In the amidation reaction, for example, the carboxylic acid compound ( 3 ) is added to an additive (for example, 1-hydroxybenzotriazole) in an inert solvent (for example, tetrahydrofuran, N, N-dimethylformamide or a mixed solvent thereof). In the presence or absence of a base (eg, triethylamine, N, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, etc.) or in the absence of a reagent (eg, 1,1′-carbonyldiimidazole) , 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, etc.) and a nitrogen source (for example, ammonia, ammonium chloride, etc.), usually from ice cooling to room temperature for 30 minutes to 1 day. Just do it.

Process 4
By subjecting the amide compound ( 6 ) to a general cyclization reaction, the nitrogen-containing fused heterocyclic derivative (I) of the present invention can be produced. The cyclization reaction is performed by, for example, reacting an amide compound ( 6 ) with a reagent (E is an oxygen atom) in an inert solvent (for example, tetrahydrofuran, N, N-dimethylformamide, methanol, ethanol, methylene chloride, or a mixed solvent thereof). In the case of, for example, phosgene, diphosgene, triphosgene, 1,1′-carbonyldiimidazole and the like; when E is a sulfur atom, for example, carbon disulfide, thiophosgene and the like, and a base (for example, triethylamine, N, N In the presence or absence of diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, etc.), usually at ice-cold to reflux temperature, What is necessary is just to make it react for 30 minutes-1 day.

The amine compound ( 2 ) used as the raw material compound in the above-described production method is, for example, a commercially available product, a nitro compound (7) synthesized according to a method described in the literature or a combination of general synthesis methods, and the like. It can also be obtained by reduction by a simple reduction method or the like. For example, it can be manufactured by the following method.

Rings B, R ^B , n, U and X in the formula have the same meaning as described above.

Process 5
The amine compound ( 2 ) can be produced by reducing the nitro group of the nitro compound ( 7 ) by a general catalytic reduction method or a reducing agent method. In the catalytic reduction method, for example, a nitro compound ( 7 ) is converted into a catalyst (for example, palladium) in an inert solvent (for example, methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, water, a mixed solvent thereof or the like) in a hydrogen atmosphere. In the presence of carbon powder, platinum carbon powder, etc.), the reaction is usually performed at room temperature to reflux temperature for 30 minutes to 1 day. In the reducing agent method, for example, a nitro compound ( 7 ) is converted into a reducing agent (for example, sodium borohydride, hydrosal, etc.) in an inert solvent (for example, methanol, ethanol, tetrahydrofuran, acetonitrile, water or a mixed solvent thereof). Phytosodium etc.) in the presence or absence of additives (eg nickel bromide (II), sodium hydroxide, potassium hydroxide etc.), usually at ice-cold to reflux temperature for 30 minutes to 1 What is necessary is just to react for one day.

  In addition, when the compound used in the above-described production method or the compound to be produced has a functional group that changes depending on the reaction conditions or inhibits the progress of the reaction, this is protected with an appropriate protecting group commonly used by those skilled in the art, Needless to say, it is removed at an appropriate stage.

  The nitrogen-containing fused ring derivative represented by the general formula (I) of the present invention obtained in the production method described above is a fractional recrystallization method which is a conventional separation means, a purification method using chromatography, a solvent extraction method, It can be isolated and purified by a phase extraction method or the like.

  The nitrogen-containing fused ring derivative represented by the general formula (I) of the present invention is a prodrug having its carboxyl group, hydroxyl group and / or amino group converted by reacting with a prodrug-forming reagent by a conventional method. Can do. In addition, the prodrug of the nitrogen-containing fused ring derivative represented by the general formula (I) of the present invention can be used under physiological conditions described in “Development of Pharmaceuticals”, Volume 7, pages 163 to 198 (Hirokawa Shoten). It may be converted to the compound (I) of the present invention.

  The nitrogen-containing fused ring derivative represented by formula (I) or a prodrug thereof can be converted into a pharmacologically acceptable salt thereof by a conventional method. Examples of such salts include inorganic acid salts such as hydrochloric acid and nitric acid; organic acid salts such as acetic acid and methanesulfonic acid; sodium salts and potassium salts; N, N′-dibenzylethylenediamine and 2-aminoethanol. And addition salts with organic bases.

  The nitrogen-containing fused ring derivative represented by the general formula (I) or a prodrug thereof or a pharmacologically acceptable salt thereof includes a solvate with a pharmaceutically acceptable solvent such as water or ethanol. .

  Further, the nitrogen-containing fused ring derivative represented by the general formula (I) or a prodrug thereof may have a tautomer, a geometric isomer and / or an optical isomer. Any isomer can be used, and a mixture thereof can also be used.

  The nitrogen-containing fused ring derivative (I) of the present invention has an excellent GnRH antagonistic action, regulates the action of the gonadotropin releasing hormone, and controls the production and secretion of the gonadotropin and sex hormone. it can. Therefore, the nitrogen-containing fused ring derivative (I) of the present invention or a prodrug thereof or a pharmacologically acceptable salt thereof is, for example, prostatic hypertrophy, uterine fibroid, endometriosis, uterine fibroma, early puberty. Onset, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, lupus erythematosus, hirsutism, dwarfism, sleep disorders, acne, baldness, Alzheimer's disease, infertility, irritable bowel syndrome, Prevention or treatment of sex hormone-dependent diseases such as prostate cancer, uterine cancer, ovarian cancer, breast cancer, pituitary tumors, reproductive regulators, contraceptives, ovulation inducers, or preventive agents for postoperative recurrence of sex hormone-dependent cancer As extremely useful.

  A pharmaceutical composition can be prepared by mixing the nitrogen-containing fused ring derivative (I) of the present invention or a prodrug thereof or a pharmacologically acceptable salt thereof with a conventional pharmaceutical carrier.

  The pharmaceutical carrier may be used in appropriate combination depending on the dosage form described later. For example, excipients such as lactose; lubricants such as magnesium stearate; disintegrants such as carboxymethylcellulose; hydroxypropylmethylcellulose and the like Binding agent; Surfactant such as macrogol; Foaming agent such as sodium bicarbonate; Solubilizing agent such as cyclodextrin; Acidity agent such as citric acid; Stabilizer such as sodium edetate; pH adjustment such as phosphate Agents and the like.

  Examples of the dosage form of the pharmaceutical composition of the present invention include oral administration agents such as powders, granules, fine granules, dry syrups, tablets and capsules; parenteral administration agents such as injections, patches and suppositories. Oral administration agents are preferable.

  The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is in the range of 0.1 to 1000 mg for oral administration and 0.01 to 100 mg for injection per day for adults. It is preferred to produce the formulation so that it is administered.

  The pharmaceutical composition of the present invention may further contain other drugs. Such drugs include, for example, GnRH superagonists (eg, leuprorelin acetate, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterelin, resilerin, etc.), chemotherapeutic agents (eg, ifosfamide, adriamycin, etc.) , Pepromycin, cisplatin, cyclophosphamide, 5-FU, UFT, methotrexate, mitomycin C, mitoxantrone, paclitaxel, dotaxel, etc. ), 5α-reductase inhibitors (for example, finasteride, dutasteride, etc.), α-adrenergic receptor inhibitors (for example, tamsulosin, silodosin, Pyridol, etc.), aromatase inhibitors (eg, fadrozole, letrozole, anastrozole, formestane, etc.), adrenal androgen production inhibitors (eg, riarozole, etc.), hormone therapy agents (eg, antiestrogens (tamoxifen, full Vestrants, etc.), luteinizing hormone agents (such as medroxyprogesterone), androgenic agents, estrogens, antiandrogens (such as oxendron, flutamide, nilutamide, bicalutamide, etc.)).

  The content of the present invention will be described in more detail with reference examples, examples and test examples below, but the present invention is not limited to the content.

Reference example 1
2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) aniline 1,2,3,4-tetrahydroquinoline (3.12 g) and sodium bicarbonate (2.66 g) in tetrahydrofuran ( 60 mL) To the suspension, water (6 mL) and 4-chloro-3-nitrobenzenesulfonyl chloride (5.4 g) in tetrahydrofuran (30 mL) were sequentially added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with water, 1 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1-[(4-chloro-3-nitrophenyl) sulfonyl] -1,2,3,4-tetrahydroquinoline (5.0 g). This was dissolved in tetrahydrofuran (45 mL), methanol (45 mL), nickel (II) bromide (0.15 g) and sodium borohydride (1.61 g) were added under ice-cooling, and the mixture was kept at the same temperature for 30 minutes and then at room temperature. Stir for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 3/1) to obtain the title compound (4.33 g).

Reference example 2
Obtained in the same manner as in Reference Example 1 using the corresponding starting materials.

Reference example 3
3- (3,4-Dihydroquinolin-1 (2H) -ylsulfonyl) -1-bromobenzene 1,2,3,4-tetrahydroquinoline (1.25 g), triethylamine (0.95 g) and 4-dimethylamino To a mixture of pyridine (96 mg) in methylene chloride (30 mL) was added 3-bromobenzenesulfonyl chloride (2 g), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.02 g).

Reference example 4
Methyl 2-amino-5-benzyloxybenzoate benzyl bromide (1.96 g) in a mixture of 5-hydroxy-2-nitrobenzoic acid (1 g) and potassium carbonate (1.89 g) in N, N-dimethylformamide (10 mL) And stirred at room temperature for 3 days. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water (twice) and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Ethanol (10 mL), tetrahydrofuran (10 mL) and 5 mol / L aqueous sodium hydroxide solution (6 mL) were added to the residue, and the mixture was stirred overnight at room temperature. The reaction mixture was acidified with 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (10 mL), potassium carbonate (1.72 g) and methyl iodide (1.41 g) were added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water (twice) and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1-3 / 1) to give methyl 5-benzyloxy-2-nitrobenzoate (1.15 g). The obtained methyl 5-benzyloxy-2-nitrobenzoate (0.5 g) was dissolved in tetrahydrofuran (6 mL), methanol (6 mL), nickel (II) bromide (19 mg) and sodium borohydride (0. 2 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 30 minutes. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.43 g).

Reference Example 5
2,3-difluoro-6-methoxybenzyl bromide To a solution of 2,3-difluoro-6-methoxybenzyl alcohol (1.05 g) and triethylamine (1.09 mL) in ethyl acetate (12 mL) was added methanesulfonyl chloride ( 0.51 mL) was added, and the mixture was stirred at the same temperature for 30 minutes. The insoluble material was removed by filtration, and the insoluble material was washed with ethyl acetate (20 mL). The filtrate and the washing solution were combined, lithium bromide (1.56 g) was added, and the mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.42 g).

Reference Example 6
5-fluoro-2- (2,3-difluoro-6-methoxybenzyloxy) anisole 2,3-difluoro-6-methoxybenzyl bromide (1.42 g), 4-fluoro-2-methoxyphenol (0.94 g) And a mixture of potassium carbonate (1.24 g) in N, N-dimethylformamide (12 mL) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed successively with 1 mol / L aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.68 g).

Reference Example 7
5-fluoro-2- (2,3-difluoro-6-methoxybenzyloxy) -4-nitroanisole 5-fluoro-2- (2,3-difluoro-6-methoxybenzyloxy) anisole (1.68 g) and To a mixture of acetic anhydride (11 mL) was added 60% nitric acid (0.6 mL) under ice cooling, and the mixture was stirred for 45 minutes under ice cooling. Water was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residual solid was suspended in a mixed solvent (n-hexane / ethyl acetate = 9/1), collected by filtration, washed with the same solvent, and dried under reduced pressure to obtain the title compound (1.56 g).

Reference Example 8
2-Fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyaniline 5-fluoro-2- (2,3-difluoro-6-methoxybenzyloxy) -4-nitroanisole (0 .86 g) and 10% palladium carbon powder (0.2 g) in tetrahydrofuran (15 mL) were stirred at room temperature under a hydrogen atmosphere for 6 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.77 g).

Reference Example 9
2-Chloro-5-nitronicotinic acid 2-hydroxynicotinic acid (5 g) was added to concentrated sulfuric acid (14 mL) under ice cooling. Fuming nitric acid (3.57 mL) was added dropwise to the mixture, stirred at room temperature for 15 minutes, and then stirred at 50 ° C. for 5 hours. The reaction mixture was cooled to room temperature, poured into ice and stirred at room temperature for 10 minutes. The precipitated crystals were collected by filtration, washed with cold water, and dried under reduced pressure to obtain 2-hydroxy-5-nitronicotinic acid (5.4 g). A mixture of 2-hydroxy-5-nitronicotinic acid (5.4 g) and phosphorus oxychloride (24.7 g) was heated to reflux for 3 hours. The reaction mixture was ice-cooled, poured into ice water, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residual solid was suspended in a mixed solvent (diethyl ether / n-hexane = 1/3, 200 mL), and the supernatant was removed by a gradient method. The solid was dissolved in ethyl acetate and washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (0.93 g).

Reference Example 10
4-Fluoro-3-nitrobenzenesulfonyl chloride Fuming sulfuric acid (20 mL) was added to 2-fluoronitrobenzene (2.33 g), and the mixture was stirred at 60 ° C. for 30 minutes. The reaction mixture was cooled to room temperature, poured into ice containing potassium chloride (10 g) and stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give 4-fluoro-3-nitrobenzenesulfonic acid (3.15 g). 4-Fluoro-3-nitrobenzenesulfonic acid (3.15 g) and phosphorus pentachloride (2.82 g) were added to phosphorus oxychloride (85 mL) under ice cooling, and the mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ice water was added to the residue and extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane to n-hexane / ethyl acetate = 3/1) to obtain the title compound (2.65 g).

Reference Example 11
Obtained in the same manner as in Reference Example 1 using the corresponding starting materials.

Example 1
1- [2-Chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione 2-chloro To a mixture of nicotinic acid (0.22 g) and 2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) aniline (0.5 g) in N, N-dimethylformamide (2 mL) was added copper. Powder (10 mg) and potassium carbonate (0.21 g) were added, and the mixture was stirred at 150 ° C. for 3 hr. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (8 mL), 1,1′-carbonyldiimidazole (0.5 g) was added, and the mixture was stirred at room temperature for 30 min. A 28% aqueous ammonia solution (4 mL) was added to the reaction mixture, and the mixture was stirred for 2 hours. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1 to 1/2) to give 2- [2-chloro-5- (3,4-dihydroquinoline-1 (2H ) -Ylsulfonyl) phenylamino] nicotinamide (61 mg) was obtained. This was dissolved in N, N-dimethylformamide (2 mL), sodium hydride (55%, 13 mg) was added, and the mixture was stirred at room temperature for 5 min. 1,1′-carbonyldiimidazole (34 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. 1 mol / L hydrochloric acid was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (45 mg).

Example 2 to Example 4
Obtained in the same manner as in Example 1 using the corresponding starting materials.

Example 5
1- [3- (3,4-Dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione 2-aminothiophene-3- Methyl carboxylate (89 mg), 3- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) -1-bromobenzene (0.2 g), tris (dibenzylideneacetone) dipalladium (0) .monochloroform Japanese (29 mg), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (16 mg) and cesium carbonate (0.46 g) in 1,4-dioxane (4 mL) -tert-butanol (2 mL) The mixture was stirred at 90 ° C. overnight under an argon atmosphere. The insoluble material was removed by filtration, and the insoluble material was washed with ethyl acetate. The filtrate and the washing solution were combined, washed with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5/1) to give 2- [3- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenylamino]. Methyl thiophene-3-carboxylate (0.17 g) was obtained. Ethanol (4 mL), tetrahydrofuran (2 mL) and a 5 mol / L aqueous sodium hydroxide solution (0.8 mL) were added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was acidified with 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (8 mL), 1,1′-carbonyldiimidazole (0.13 g) was added, and the mixture was stirred at room temperature for 30 min. A 28% aqueous ammonia solution (4 mL) was added to the reaction mixture, and the mixture was stirred for 2 hours. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1) to give 2- [3- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenylamino]. Thiophene-3-carboxylic acid amide (89 mg) was obtained. This was dissolved in N, N-dimethylformamide (4 mL), sodium hydride (55%, 20 mg) was added, and the mixture was stirred at room temperature for 5 min. 1,1′-carbonyldiimidazole (53 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. 1 mol / L hydrochloric acid was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (88 mg).

Example 6 to Example 7
Obtained in the same manner as in Example 5 using the corresponding starting materials.

Example 8
2-Chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) aniline is used instead of methyl 2-aminothiophene-3-carboxylate and 3- (3,4-dihydroquinoline- It was obtained in the same manner as in Example 5 using methyl 2-chloro-4-iodonicotinate instead of 1 (2H) -ylsulfonyl) -1-bromobenzene.

Example 9
1- [3- (3,4-Dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] pyrimido [4,5-d] pyrimidine-2,4 (1H, 3H) -dione 4-aminopyrimidine-5 Carboxylic acid (79 mg), 3- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) -1-bromobenzene (0.2 g), tris (dibenzylideneacetone) dipalladium (0). Product (29 mg), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (16 mg) and cesium carbonate (0.46 g) in 1,4-dioxane (4 mL) -tert-butanol (2 mL) Was stirred at 90 ° C. overnight under an argon atmosphere. The insoluble material was removed by filtration, and the insoluble material was washed with ethyl acetate. The filtrate and the washing solution were combined, washed with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), 1,1′-carbonyldiimidazole (0.2 g) was added, and the mixture was stirred at room temperature for 30 min. A 28% aqueous ammonia solution (5 mL) was added to the reaction mixture, and the mixture was stirred for 2 hours. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/2 to ethyl acetate) to give 4- [3- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl). Phenylamino] pyrimidine-5-carboxylic acid amide (50 mg) was obtained. This was dissolved in N, N-dimethylformamide (2 mL), sodium hydride (55%, 11 mg) was added, and the mixture was stirred at room temperature for 5 min. 1,1′-carbonyldiimidazole (30 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. 1 mol / L hydrochloric acid was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (40 mg).

Example 10
Obtained in the same manner as in Example 9 using the corresponding starting materials.

Example 11
6-Bromo-1- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)- 1-methyl-2 of dione 5-bromo-2-chloronicotinic acid (0.55 g) and 2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) aniline (0.5 g) -Sodium hydride (55%, 0.14 g) was added to the pyrrolidone (8 mL) mixture and stirred at 100 ° C for 6 hours. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), 1,1′-carbonyldiimidazole (0.73 g) was added, and the mixture was stirred at room temperature for 30 min. A 28% aqueous ammonia solution (10 mL) was added to the reaction mixture, and the mixture was stirred for 2 hours. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2/1 to 1/1) to give 5-bromo-2- [2-chloro-5- (3,4-dihydroquinoline). -1 (2H) -ylsulfonyl) phenylamino] nicotinamide (0.28 g) was obtained. This was dissolved in N, N-dimethylformamide (5 mL), sodium hydride (55%, 48 mg) was added, and the mixture was stirred at room temperature for 5 min. 1,1′-carbonyldiimidazole (0.13 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. 1 mol / L hydrochloric acid was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (0.26 g).

Example 12
Obtained in the same manner as in Example 11 using the corresponding starting materials.

Example 13
1- [2-Chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] pyrimido [4,5-d] pyrimidine-2,4 (1H, 3H) -dione 4-chloro 1-methyl-2-pyrrolidone of ethyl pyrimidine-5-carboxylate (0.4 g) and 2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) aniline (0.69 g) ( To the mixture, sodium hydride (55%, 98 mg) was added and stirred at 100 ° C. for 2 hours. The reaction mixture was poured into 0.5 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/1 to 2/1) to give 4- [2-chloro-5- (3,4-dihydroquinoline-1 (2H ) -Ylsulfonyl) phenylamino] pyrimidine-5-carboxylate (0.42 g). Tetrahydrofuran (2 mL), ethanol (8 mL) and 5 mol / L aqueous sodium hydroxide solution (1.8 mL) were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was acidified with 1 mol / L hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give 4- [2-chloro-5- (3,4-dihydroquinoline-1 ( 2H) -ylsulfonyl) phenylamino] pyrimidine-5-carboxylic acid (0.37 g) was obtained. This was dissolved in tetrahydrofuran (8 mL), 1,1′-carbonyldiimidazole (0.29 g) was added, and the mixture was stirred at room temperature for 30 minutes. A 28% aqueous ammonia solution (4 mL) was added to the reaction mixture, and the mixture was stirred for 2 hours. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residual solid was suspended in ethyl acetate, collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give 4- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl). Phenylamino] pyrimidine-5-carboxylic acid amide (0.11 g) was obtained. This was dissolved in N, N-dimethylformamide (2 mL), sodium hydride (55%, 23 mg) was added, and the mixture was stirred at room temperature for 5 min. 1,1′-carbonyldiimidazole (62 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. 1 mol / L hydrochloric acid was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (50 mg).

Example 14
6-Bromo-1- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -Dione 5-bromo-2-chloronicotinic acid (1.38 g) and 2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyaniline (1.83 g) in tetrahydrofuran (20 mL) ) Lithium hexamethyldisilazide (1.05 mol / L n-hexane solution, 16.6 mL) was added to the mixture at −78 ° C., and the mixture was naturally warmed to room temperature and stirred at room temperature overnight. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to ethyl acetate). The obtained product was suspended in diethyl ether, collected by filtration, washed with diethyl ether and dried under reduced pressure to give 5-bromo-2- [2-fluoro-5- (2,3-difluoro-6- 6). Methoxybenzyloxy) -4-methoxyphenylamino] nicotinic acid (0.44 g) was obtained. This was dissolved in tetrahydrofuran (15 mL), 1,1′-carbonyldiimidazole (0.28 g) was added, and the mixture was stirred at room temperature for 30 minutes. A 28% aqueous ammonia solution (7.5 mL) was added to the reaction mixture, and the mixture was stirred for 2 hours. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residual solid was suspended in diethyl ether, collected by filtration, washed with diethyl ether, and dried under reduced pressure to give 5-bromo-2- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy). ) -4-Methoxyphenylamino] nicotinamide (0.28 g). This was dissolved in N, N-dimethylformamide (5 mL), sodium hydride (55%, 72 mg) was added, and the mixture was stirred at room temperature for 5 min. 1,1′-carbonyldiimidazole (0.18 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. 1 mol / L hydrochloric acid was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (0.3 g).

Example 15
6-hydroxy-1- [3- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] quinazoline-2,4 (1H, 3H) -dione 6-benzyloxy-1- [3- ( To a solution of 3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] quinazoline-2,4 (1H, 3H) -dione (96 mg) in tetrahydrofuran (4 mL) was added 10% palladium carbon powder (30 mg), Stir overnight at room temperature under hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residual solid was suspended in diethyl ether, collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (55 mg).

Example 16
6- (n-Butoxycarbonyl) -1- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione 6-bromo-1- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] pyrido [2,3-d] pyrimidine-2 , 4 (1H, 3H) -dione (0.3 g), palladium (II) acetate (12 mg), 1,3-bis (diphenylphosphino) propane (23 mg), N, N-diisopropylethylamine (0.48 mL) And a mixture of n-butanol (6 mL) in dimethyl sulfoxide (8 mL) was stirred at 105 ° C. overnight under a carbon monoxide atmosphere. The insoluble material was removed by filtration, and the insoluble material was washed with ethyl acetate. The filtrate and the washing solution were combined, washed successively with 0.5 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 2/1 to 1/1) to obtain the title compound (0.18 g).

Example 17
Obtained in the same manner as in Example 16 using the corresponding starting materials.

Example 18
6-carboxy-1- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -Dione 6- (n-butoxycarbonyl) -1- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] pyrido [2,3-d] pyrimidine-2 , 4 (1H, 3H) -dione (0.18 g), tetrahydrofuran (4 mL), methanol (2 mL) and water (2 mL) were added lithium hydroxide monohydrate (0.13 g) at room temperature. For 3 hours. The reaction mixture was acidified with 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residual solid was suspended in methanol, collected by filtration, washed with methanol, and dried under reduced pressure to obtain the title compound (79 mg).

Example 19
Obtained in the same manner as in Example 18 using the corresponding starting materials.

Example 20
6-carbamoyl-1- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H)- Dione 6-carboxy-1- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) 1,1′-carbonyldiimidazole (15 mg) was added to a solution of dione (24 mg) in tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 30 minutes. A 28% aqueous ammonia solution (1 mL) was added to the reaction mixture, and the mixture was stirred for 2 hours. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (23 mg).

Example 21
6-hydroxymethyl-1- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -Dione 6-carboxy-1- [2-chloro-5- (3,4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H Borane / tetrahydrofuran complex (1.2 mol / L tetrahydrofuran solution, 0.26 mL) was added to a tetrahydrofuran (3 mL) solution of) -dione (70 mg) under ice cooling, and the mixture was stirred at room temperature for 1.5 days. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/3) to obtain the title compound (27 mg).

Example 22
Obtained in the same manner as in Example 14 using the corresponding starting materials.

Example 23
Obtained in the same manner as in Example 15 using the corresponding starting materials.

Example 24
6-acetylamino-1- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H ) -Dione 6-amino-1- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] pyrido [2,3-d] pyrimidine-2,4 (1H) , 3H) -dione (30 mg) in pyridine (1 mL) was added acetic anhydride (13 mg) and stirred at room temperature for 5 hours. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain the title compound (30 mg).

Example 25
Obtained in the same manner as in Example 24 using the corresponding starting materials.

Example 26
1- [2-Fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] -6- (3-methoxyureido) pyrido [2,3-d] pyrimidine-2,4 To a solution of (1H, 3H) -dione O-methylhydroxylamine hydrochloride (39 mg) in N, N-dimethylformamide (1 mL) was added triethylamine (0.07 mL) and 1,1′-carbonyldiimidazole (76 mg). And stirred for 10 minutes at room temperature. To the mixture was added 6-amino-1- [2-fluoro-5- (2,3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl] pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -Dione (30 mg) was added and stirred at room temperature for 5 hours. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/2) to give the title compound (33 mg).

Example 27
Obtained in the same manner as in Example 14 using the corresponding starting materials.

Example 28
The compounds of Examples 16 and 18 were prepared in a similar manner to the corresponding starting materials.

The chemical structures and ¹ H-NMR data of Reference Examples 1 to 11 are shown in Tables 1 and 2, and the chemical structures and ¹ H-NMR data of Example Compounds ^{1 to} 28 are shown in Tables 3 to 5, respectively.

The abbreviations in the table are Ref No. Is a reference example number, Ex No. Represents an example number, Strc represents a chemical structural formula, and Solv represents a ¹ H-NMR measurement solvent.

[Test Example 1]
1) Cloning of human GnRH receptor 1 (GnRHR1) and recombination into an expression vector Human GnRHR1 (Accession No. L03380) No. 45 reported by Kakar et al. Using human pituitary-derived cDNA (Becton Dickinson) as a template. To 1115 was amplified by PCR and inserted into the multiple cloning site of pcDNA3.1 (+) (Invitrogen). The nucleotide sequence of the inserted DNA was completely identical to the reported nucleotide sequence.

2) Establishment of HEK293 cell line stably expressing human GnRH receptor 1 A human GnRHR1 expression vector was digested with XhoI to form linear DNA, and then introduced into HEK293 cells by the lipofection method (Lipofectamine 2000: Invitrogen). A neomycin-resistant cell line was obtained with 1 mg / mL G418 (Invitrogen), and the movement of intracellular calcium by GnRH stimulation was measured by the method described later. The strain exhibiting the strongest response was selected and designated as hGnRHR1 # 1, and thereafter cultured in the presence of 0.5 mg / mL G418.

3) Measurement of inhibitory effect of intracellular calcium movement by GnRH The antagonistic action of the compound on human GnRHR1 was evaluated by the degree of inhibition of intracellular calcium movement by GnRH stimulation. A 96-well plate was seeded with ⁵ × 10 ⁵ hGnRHR1 # 1 and cultured for 1 day. The medium was removed, and 200 μL of washing buffer per well (Hanks' Balanced Salt Solutions, 20 mM N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid, 1.3 mM calcium chloride, 0.5 mM magnesium chloride) After washing once with 0.4 mM magnesium sulfate), 100 μL of a dye solution that reacts with calcium ions (FLIPR Calcium Assay Kit, manufactured by Molecular Devices) is added and incubated at 37 ° C. for 1 hour in a 5% CO ₂ incubator. did. Thereafter, the intracellular calcium concentration was measured under the following conditions using FLEXSTATION (registered trademark) (manufactured by Molecular Devices). 50 μL of a test substance diluted with a measuring buffer (washing buffer containing 0.1% fetal bovine serum albumin) was added in a chamber heated to 37 ° C., and 1 μm after that, 50 μL of 10 nM GnRH was added. . The concentration (IC ₅₀ value) that inhibits intracellular calcium movement by GnRH stimulation by 50% was calculated by logit plot (Table 6).

  Since the nitrogen-containing fused ring derivative (I) of the present invention or a prodrug thereof or a pharmacologically acceptable salt thereof has an excellent GnRH antagonistic action, it regulates the action of the gonadotropin releasing hormone, and the gonadotropin And by controlling the production / secretion of sex hormones, they can be used as preventive or therapeutic agents for sex hormone-dependent diseases. Therefore, according to the present invention, prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, lupus erythematosus, Hirsutism, dwarfism, sleep disorders, acne, baldness, Alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer or pituitary tumor preventive or therapeutic agent, reproductive regulator, A contraceptive, an ovulation inducing agent, a sex hormone-dependent cancer postoperative recurrence preventive agent, or the like can be provided.

Claims (2)

Formula :

[Where,
Ring A has the following formula where R ^A is on ring A

A ring bonded to the position represented by
R ^A represents a halogen atom, a nitro group, a C _1-6 alkyl group which may be substituted with a hydroxyl group, —OW ¹ , —COW ² or —NW ³ W ⁴ ;
R ^B is a hydrogen atom, a halogen atom, or —OW ¹ (the plurality of R ^B may be the same or different) ;
m is 1 ;
E is, SansoHara child;
U represents a single binding;
X is a group represented by —SO ₂ —Y or —O—L—Y ;
(Where
W ¹ represents a hydrogen atom or a C _1-6 alkyl group;
W ² represents a hydrogen atom, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, or —NW ⁵ W ⁶ ;
W ³ and W ⁴ are each independently a hydrogen atom, a C _1-6 alkyl group, —COW ⁷ or —SO ₂ W ⁸ ;
W ⁵ and W ⁶ are independently a hydrogen atom or a C _1-6 alkyl group;
W ⁷ represents a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, or —NW ⁹ W ¹⁰ ;
W ⁸ represents a C _1-6 alkyl group;
W ⁹ and W ¹⁰ are each independently a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group;
L represents a C _1-3 alkylene group;
Y is Z or —NW ¹¹ W ¹² [W ¹¹ and W ¹² are independently a hydrogen atom, a C _1-6 alkyl group or Z (provided that they are not hydrogen atoms but are bonded to each other and bonded to each other) A cyclic amino group may be formed together with an atom));
Z is a phenyl group optionally having any group selected from a halogen atom, a hydroxyl group, C _1-6 alkyl or C _1-6 alkoxy ;
Is)
Salts nitrogen-containing fused ring induction body or is a pharmaceutically acceptable represented by any one of. Nitrogen-containing fused-ring induction of claim 1, wherein or a pharmaceutical composition containing a pharmacologically acceptable salt thereof as an active ingredient.