JP2002030087A - Thienopyridine-5-carboxylic ester compound, method for producing the same and use of the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a thienopyridine-5-carboxylic ester compound having gonadotropin-releasing hormone antagonism, and to provide a pharmaceutical composition containing the above compound. SOLUTION: This compound (or a salt thereof) is shown by the formula [wherein, R1 is H or a 1-3C alkyl; R2 is H, OH or a 1-3C alkoxy; and R3 is a (substituted) 3-7C branched alkyl or (substituted) 3-7C cycloalkyl].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to gonadotropin releasing hormone (GnRH).
one)) It relates to a thienopyridine-5-carboxylate compound exhibiting an antagonistic action, its production method and use.

[0002]

2. Description of the Related Art Anterior pituitary hormones are secreted by peripheral hormones secreted from target organs of each hormone and secretagogues or secretory inhibitory hormones (hereinafter referred to as "secretory hormones") secreted from the hypothalamus, which is the upper center of the anterior pituitary gland. In the specification, these hormone groups are collectively referred to as hypothalamic hormones). To date, hypothalamic hormones such as thyroid stimulating hormone releasing hormone (TRH) or gonadotropin releasing hormone ｛GnRH (Gonadotropin releasing hormone): luteinizing hormone releasing hormone [LH-RH (Luteinizing)
hormone releasehormone)], and nine other types have been confirmed. These hypothalamic hormones, through receptors thought to be in the anterior pituitary gland,
It is presumed to exhibit its hormonal action and the like, and analysis of receptor genes specific to these, including in the case of humans, is underway. Therefore, specific and selective antagonists or agonists for these receptors regulate the action of hypothalamic hormones and control anterior pituitary hormone secretion. As a result, prevention or treatment of such anterior pituitary hormone-dependent disease can be expected. As a thienopyridine compound having a GnRH antagonistic action, WO 95/28405 (JP-A-8-28405)
-295693), WO 97/41126 (Japanese Unexamined Patent Publication No.
0-36373), WO 00/00493 and the like.

[0003]

[Problems to be Solved by the Invention] Hormone-dependent cancer,
For example, there is a strong demand for non-peptide antagonists that have excellent therapeutic effects on prostate cancer, endometriosis, precocious puberty, etc., and that do not cause a transient pituitary-gonad stimulating action (acute action). Have been.

[0004]

Means for Solving the Problems As a result of diligent search, the present inventors have found that the para-position of the 2-position phenyl group of the thieno [2,3-b] pyridine compound has the formula -NH-CO-NR ¹ R
² is substituted with a group represented by the following formula (each symbol is as defined below), and the 5-position of the compound further has a formula -COOR
³ A compound having a chemical structural feature in that it is substituted with a group represented by the formula (each symbol is as defined below).

Embedded image Wherein R ¹ is a hydrogen atom or a C _1-3 alkyl group, R ² is a hydrogen atom, a hydroxyl group or a C _1-3 alkoxy group, and R ³ is an optionally substituted C _3-7 branched alkyl group or substituted _{Represents a} C _3-7 cycloalkyl group which may be represented by the following formula (hereinafter sometimes abbreviated as compound (I)):
Is synthesized for the first time, and the compound (I) is represented by the formula —NH—CO—NR
By combining the substituent represented by ¹ R ² and the substituent represented by the formula —COOR ³ , unexpectedly excellent GnRH is obtained.
Antagonistic action, especially having strong antagonist activity, improvement in physical properties such as solubility, and
For the first time, they found that these compounds had extremely low toxicity and were sufficiently satisfactory as drugs having GnRH antagonistic activity, and further studied based on these findings, and completed the present invention.

That is, the present invention provides: (1) the compound (I); (2) the compound according to the above (1), wherein R ¹ is a C _1-3 alkyl group or a salt thereof; (3) R ² is a hydrogen atom (4) the compound or a salt thereof according to the above (1), wherein R ³ is a C _3-7 branched alkyl group;

Embedded image Wherein R ³ is as defined above, or a salt thereof (hereinafter may be abbreviated as compound (II)) with carbonyldiimidazole or phosgene;

Embedded image Wherein each symbol is as defined above, or a salt thereof (hereinafter sometimes abbreviated as compound (III)) to produce compound (I). (6) a pharmaceutical composition containing the compound (I); (7) a pharmaceutical composition according to the above (6), which is a gonadotropin-releasing hormone antagonist; and (8) prevention / treatment of a sex hormone-dependent disease. And a pharmaceutical composition according to the above (7).

The definition of each substituent in the above formula is described below.
Examples of the “C _1-3 alkyl group” represented by R ¹ include methyl,
Ethyl, propyl and isopropyl are mentioned. Of these, methyl and ethyl are preferred. More preferably, it is methyl. The “C _1-3 alkoxy group” represented by R ² includes methoxy, ethoxy, propoxy, and isopropoxy. Of these, methoxy and ethoxy are preferred. More preferably, it is methoxy. “C _3-7 ” in the “ _optionally substituted C _3-7 branched alkyl group” for R ³
_{As the `` 3-7} branched alkyl group '', for example, isopropyl,
Isobutyl, 1-methylpentyl, 2-methylpentyl, 5-methylhexyl, sec-butyl, tert-
Butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, 2,4-dimethyl-3-pentyl and the like. Among them, isopropyl, isobutyl, 2,4-dimethyl-3-pentyl and the like are preferable.
More preferably, it is isopropyl.

[0007] The optionally substituted C represented by R ³
Examples of the “substituent” of the “ _3-7 branched alkyl group” include (i) a hydroxyl group, (ii) a C _1-7 acyloxy group (eg, C _1-6 alkyl-carbonyloxy such as acetoxy, propionyloxy, etc .; benzoyloxy Etc.), (iii) C
_1-10 alkoxy groups (eg, methoxy, ethoxy, propoxy, tert-butoxy, etc.) and the like. The “C _3-7 branched alkyl group” may have, for example, 1 to 3 substituents at the substitutable position. When the number of substituents is 2 or more, each substituent is the same or different. May be. “Optionally substituted C _{3-7 represented} by R ³
As the “C _3-7 cycloalkyl group” of the “cycloalkyl group”, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like can be mentioned. Of these, cyclohexyl is preferred. As the “substituent” of the “optionally substituted C _3-7 cycloalkyl group” for R ³ , the same number as the above “substituent” can be mentioned. When the number of substituents is two or more, each substituent may be the same or different. Preferred specific examples of compound (I) include isopropyl {3- (N-benzyl-N-methylaminomethyl) -4,7-dihydro-7- (2,6-difluorobenzyl) -2- [4- ( 3-methylureido) phenyl] -oxothieno [2,3-b] pyridine-5-carboxylic acid ester} or a salt thereof.

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

Compound (I) can be produced by a method known per se, for example, the method described in WO 95/28405 or a method analogous thereto. As a specific example, compound (II) and carbonyldiimidazole (N, N ′)
-Carbonyldiimidazole; CDI) or phosgene (including dimers and trimers) and the like, followed by reaction with compound (III) to give compound (I). Examples of the salts of compounds (II) and (III) include the same as the salts of compound (I). Compound (I
I) can be produced by the method described in WO 95/28405 or a method analogous thereto. Compound (II
For I), commercially available products can be used. The amount of carbonyldiimidazole, phosgene, etc. to be used is determined by the amount of compound (II)
Each mole is about 1 to 5 moles. The reaction of compound (II) with carbonyldiimidazole or phosgene is usually carried out in a suitable solvent that does not adversely influence the reaction. Examples of the solvent include ethers (eg, ethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, dimethylformamide, dimethylacetamide, etc.) And halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.) and the like. The reaction temperature is usually about 0-5.
0 ° C., preferably about 0-25 ° C. The reaction time is usually about 1 to 12 hours.

This reaction is carried out in the presence of a base, if necessary. As the "base", for example, an inorganic base such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, thallium hydroxide, or an organic base such as triethylamine or pyridine is used. . The amount of the "base" to be used is about 1-5 mol, preferably about 1-3 mol, per 1 mol of compound (II). The subsequent compound (II
The reaction conditions with I) may be the same as those for reacting compound (II) with carbonyldiimidazole or phosgene. The amount of compound (III) used is the same as that of compound (II)
About 1 to 10 moles, preferably about 1 to 5 moles, per mole.
Is a mole. The reaction temperature is generally about 0-50 ° C,
Preferably it is about 0 to 25 ° C. The reaction time is usually about 1
~ 12 hours. Further, carbonyldiimidazole or phosgene and compound (III) are simultaneously reacted with compound (I
And I).

The compound (I) of the present invention can be isolated and purified by a separation means known per se, for example, recrystallization, distillation, chromatography and the like. When compound (I) is obtained in a free form, it can be converted to a target salt by a method known per se or a method analogous thereto, and conversely, when compound (I) is obtained as a salt, a method known per se Alternatively, it can be converted into a free form or another desired salt by a method analogous thereto. Compound (I) may be a hydrate or a non-hydrate. Examples of the hydrate include monohydrate, 1.5 hydrate, and dihydrate. Compound (I) is an isotope (eg,
³ H, ¹⁴ C, ³⁵ S) and the like.

The compound (I) of the present invention or a salt thereof (hereinafter may be abbreviated as “the compound of the present invention”) has excellent GnRH antagonistic activity and low toxicity. In addition, it has excellent action persistence, and is also excellent in stability and pharmacokinetics. Furthermore, manufacture is simple. In mammals (for example, humans, monkeys, cows, horses, dogs, cats, rabbits, mice, and the like), GnRH receptor antagonism suppresses gonadotropin secretion and regulates blood sex hormone levels. , For the treatment of male or female hormone dependent diseases and for the prevention and treatment of diseases caused by excess of these hormones. For example, the compound of the present invention can be used for sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), benign prostatic hyperplasia, uterine fibroids, endometriosis, precocious puberty, amenorrhea, It is useful for prevention and treatment of premenstrual syndrome, multilocular ovary syndrome, acne, Alzheimer's disease (Alzheimer's disease, Alzheimer's senile dementia and a combination thereof), baldness, and the like. The compounds of the present invention are also useful for regulating reproduction in males and females (eg, pregnancy regulators, menstrual cycle regulators, etc.). The compounds of the present invention can further be used as contraceptives for men or women and as ovulation inducers for women. The compound of the present invention can be used for the treatment of infertility by utilizing the rebound effect after drug withdrawal. Further, the compound of the present invention is useful in the field of animal husbandry for regulating estrus in animals, improving meat quality for meat, and promoting animal growth. The compound of the present invention is also useful as a spawning promoter for fish.

The compound of the present invention can be used to suppress a transient increase in blood testosterone concentration (flare phenomenon) observed when a GnRH superagonist such as leuprorelin acetate is administered. The compound of the present invention includes leuprorelin acetate (Leuprorelin), gonadrelin (Gon
adorelin), Buserelin, Triptorelin, Goserelin, Nafarelin, Histrelin, Deslorelin, Meterelilin
n), GnRH super agonist (preferably leuprorelin acetate) such as Lecirelin can be used in combination. In addition, the compound of the present invention may be a steroidal or non-steroidal antiandrogen or antiestrogen, a chemotherapeutic agent, a peptide GnRH antagonist,
α-reductase inhibitor, α-receptor inhibitor, aromatase inhibitor, 17β-hydroxysteroid dehydrogenase inhibitor, adrenal androgen production inhibitor, phosphorylase inhibitor, hormone therapy agent, cell growth factor or its receptor It is also effective to use in combination with at least one kind of drug that inhibits the action of the body. The “chemotherapeutic agent” includes Ifosfamide, UTF, Adriamycin, Peplomycin, Cisplatin, Cyclophosphamide
phosphamide), 5-FU, UFT, metrexate (M
ethotrexate), mitomycin C, mitoxantrone and the like.
The “peptide GnRH antagonist” includes parenterally administered peptide G such as Cetrorelix, Ganirelix, and Abarelix.
nRH antagonists. The "adrenal androgen production inhibitor" includes, for example, lyase (C _17,20- lyas
e) inhibitors. Examples of the "phosphorase inhibitor" include tyrosine phosphorylase. Examples of the "hormone therapy agent" include an anti-estrogen agent, a progestin agent (eg, MPA, etc.), an androgen agent, an estrogen agent, an anti-androgen agent and the like.

The "cell growth factor" may be any substance that promotes cell growth, and is usually a peptide having a molecular weight of 20,000 or less, which binds to a receptor. Factors that exert their effects at lower concentrations are mentioned, specifically, (1) EGF (epidermal g
rowth factor) or a substance having substantially the same activity as that (eg, EGF, hallegulin (HER2 ligand))
(2) insulin or a substance having substantially the same activity as insulin (eg, insulin, IGF (insul)
in-like growth factor) -1, IGF-2, etc.),
(3) FGF (fibroblast growth factor) or a substance having substantially the same activity as that (eg, aFGF, bF
GF, KGF (Keratinocyte Growth Factor), HGF
(Hepatocyte Growth Factor), FGF-10, etc.)
(4) Other cell growth factors (eg, CSF (colony stim
ulating factor), EPO (erythropoietin), IL-
2 (interleukin-2), NGF (nerve growth factor),
PDGF (platelet-derived growth factor), TGF
β (transforming growth factor β). The “cell growth factor receptor” may be any receptor as long as it has the ability to bind to the above-mentioned cell growth factor, and specifically, EGF receptor, hallegulin receptor (HER2) , Insulin receptor-1,
Examples include insulin receptor-2, IGF receptor, FGF receptor-1 or FGF receptor-2. Examples of the drug that inhibits the action of the cell growth factor include Herceptin (HER2 receptor antibody). Examples of the drug that inhibits the action of the cell growth factor or its receptor include, for example, herbimycin, PD153030
(Science 265 (5175) p1093, (1994)).

[0015] HER2 inhibitors are also examples of agents that inhibit the action of cell growth factors or their receptors.
As a HER2 inhibitor, if it is a substance that inhibits HER2 activity (eg, phosphorylation activity), an antibody, a low-molecular compound (synthetic compound, natural product), an antisense, a HER2 ligand, a hallegulin, or a structure thereof may be used. Any of modified or modified parts may be used. Further, it may be a substance that inhibits HER2 activity by inhibiting HER2 receptor (eg, HER2 receptor antibody). HE
Examples of the low-molecular compound having an R2 inhibitory action include:
Compounds described in WO 98/03505, specifically 1
-[3- [4- [2-((E) -2-phenylethenyl) -4-oxazolylmethoxy] phenyl] propyl] -1,2,4-triazole and the like. For benign prostatic hyperplasia, GnRH super agonists, antiandrogens, antiestrogens, peptidic GnRH antagonists, α-reductase inhibitors, α-receptor inhibitors, aromatase inhibitors, 17β-hydroxysteroid dehydrogenation Combinations of a compound of the present invention with agents such as enzyme inhibitors, adrenal androgen production inhibitors, and phosphorylase inhibitors are also included.

For prostate cancer, GnRH super agonists,
Anti-androgens, anti-estrogens, chemotherapeutic agents [eg, Ifosfamide, UTF, Adriamycin, Peplomyc
in), cisplatin, etc.], peptidic GnRH antagonists, aromatase inhibitors, 17β-hydroxysteroid dehydrogenase inhibitors, adrenal androgen production inhibitors, phosphorylase inhibitors, hormone therapy agents [eg, estrogens Agents (eg, DSB, EMP, etc.), antiandrogen agents (eg, CMA, etc.), and agents that inhibit the action of cell growth factors or their receptors, and the compounds of the present invention in combination. For breast cancer, GnRH super agonist, antiestrogen, chemotherapeutic agent [eg, cyclophosphamide,
-FU, UFT, Methotrexate, Adriamycin, Mitomycin C (Mitomycin C)
tomycin C), mitoxantrone, etc.], peptidic GnRH antagonists, aromatase inhibitors, adrenal androgen production inhibitors, phosphorylase inhibitors, hormonal therapeutic agents [eg, anti-estrogenic agents (eg, Tamo
xifen, etc.), progestin (eg, MPA, etc.), androgen, estrogen, etc.), and agents that inhibit the action of cell growth factors or their receptors, and the compounds of the present invention in combination. Further, the compound of the present invention is, for example, central drugs (eg, anxiolytics, sleep-inducing agents,
Schizophrenia treatment, Parkinson's disease treatment, anti-dementia agent (eg, cerebral circulation improver, cerebral metabolic activator, etc.), antihypertensive agent, diabetes agent, antihyperlipidemic agent, nutritional agent (eg , Vitamins, etc.), digestion and absorption enhancers, gastrointestinal drugs and the like. The above-mentioned drugs may be administered to the same subject simultaneously with the compound of the present invention or at an interval.

When the compound of the present invention is used as a prophylactic and / or therapeutic agent for the above-mentioned diseases or in the field of livestock or fisheries, it can be administered orally or parenterally according to a method known per se. Yes, mixed with a pharmaceutically acceptable carrier, usually administered orally as a solid preparation such as tablets, capsules, granules, powders, etc., or injected intravenously, subcutaneously, intramuscularly, etc., suppository or tongue It is administered parenterally as a lower tablet. Further, it may be administered sublingually, subcutaneously or intramuscularly as a sustained release preparation such as sublingual tablets and microcapsules. The daily dose varies depending on the degree of symptoms; age, sex, body weight, sensitivity difference of administration subject; timing of administration, interval, properties of pharmaceutical preparation, preparation, type; type of active ingredient, and is not particularly limited. For example, sex hormone-dependent cancers (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumors, etc.), benign prostatic hyperplasia, uterine fibroids, endometriosis,
When used for the treatment of precocious puberty, the compound (I) is usually administered in an amount of about 0.01 to 30 m / kg of the mammal.
g, preferably about 0.02 to 10 mg, more preferably 0.1 to 10 mg, most preferably 0.1 to 5 mg, usually 1 to 4 times a day. For example, when used for the treatment of Alzheimer's disease, the compound (I) is usually used in an adult at a daily dose of 0.1 to 300 mg, preferably about 1 to 300 mg, more preferably about 10 to 200 mg.
mg, usually 1 to 4 times a day. The dose for use in the animal husbandry or fisheries field is the same as described above, but the compound (I) is added in an amount of about 0.01 per kg body weight of the organism to be administered.
The dose is about 30 to 30 mg, preferably about 0.1 to 10 mg, usually 1 to 3 times a day. The content of compound (I) in the pharmaceutical composition of the present invention is about 0.01 to 100% by weight of the whole composition.

As the above-mentioned pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as preparation materials can be used, such as excipients, lubricants, binders and disintegrants in solid preparations; , Dissolution aids, suspending agents,
It is blended as a tonicity agent, a buffer, a soothing agent and the like. If necessary, formulation additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used. Preferable examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like. Preferable examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferred examples of the binder include crystalline cellulose, sucrose, D-
Mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like can be mentioned. Preferable examples of the above disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch and the like. Preferred examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizer include, for example, polyethylene glycol, propylene glycol, D-
Examples include mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferred examples of the suspending agent include, for example, stearyltriethanolamine, sodium lauryl sulfate,
Surfactants such as laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose Examples include hydrophilic polymers. Preferable examples of the tonicity agent include sodium chloride, glycerin, D-mannitol and the like. Suitable examples of the buffer include, for example, phosphate,
Buffers such as acetate, carbonate, citrate and the like can be mentioned. Preferred examples of the soothing agent include benzyl alcohol and the like. Suitable examples of the preservative include, for example, p-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Suitable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.

The compound of the present invention may be added with a suspending agent, a solubilizing agent,
Stabilizing agents, isotonic agents, preservatives and the like can be added to give intravenous, subcutaneous, or intramuscular injections by a method known per se. At that time, if necessary, a freeze-dried product can be obtained by a method known per se. When the compound of the present invention is administered to a mammal such as a human, for example, the compound itself or a suitable pharmacologically acceptable carrier, excipient, or diluent is mixed, and the compound is orally or parenterally administered as a pharmaceutical composition Can be safely administered. Examples of the pharmaceutical composition include oral preparations (eg, powders, granules, capsules, tablets), injections, drops, external preparations (eg, intranasal preparations, transdermal preparations, etc.), suppositories (eg, Rectal suppositories, vaginal suppositories) and the like. These preparations can be produced by a method known per se, which is generally used in the preparation process.

The compound of the present invention may contain a dispersant (eg, Tween (T
Ween) 80 (Atlas Powder Co., USA), HO
C60 (Nikko Chemicals) polyethylene glycol,
Carboxymethylcellulose, sodium alginate, etc.), preservatives (eg, methyl paraben, propyl paraben, benzyl alcohol, etc.), tonicity agents (eg, sodium chloride, mannitol, sorbitol, glucose, etc.) and the like for aqueous injection or olive oil, It can be dissolved, suspended or emulsified in vegetable oils such as sesame oil, cottonseed oil and corn oil, propylene glycol and the like, molded into an oily injection, and used as an injection.

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

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

[0023]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described more specifically with reference to Reference Examples, Examples, Formulation Examples and Test Examples, but the present invention is not limited thereto. ¹
The H-NMR spectrum was obtained by using Varian GEMINI 200 (200M) using tetramethylsilane as an internal standard.
Hz) type spectrum meter, JEOL L
It is measured with an AMBDA 300 (300 MHz) type spectrometer or a Brooker AM 500 (500 MHz) type spectrometer, and all δ values are shown in ppm.
The symbols used in the present specification have the following meanings. s: singlet d: doublet t: triplet dt: double triplet m: multiplet br: wide At room temperature indicates a range of about 15 to 25 ° C, but is not particularly strictly limited.

[0024]

EXAMPLES Reference Example 1 Ethyl 7- (2,6-difluorobenzyl) -4-hydroxy-2-phenyl-3-methylthieno [2,3-b] pyridine-5-carboxylate

Embedded image 4- produced by the method described in WO 95/28405.
Hydroxy-2-phenyl-3-methylthieno [2,3
-B] pyridine-5-carboxylic acid ethyl ester (3
1.3 g (100 mmol) in DMF (100 m
l) to potassium carbonate (13.8 g, 100 mmol)
Potassium iodide (8.30 g, 50 mmol) was added, and a DMF solution of 2,6-difluorobenzyl chloride (17.9 g, 110 mmol) was added dropwise thereto under ice cooling. After stirring at room temperature overnight, the reaction solution was poured into water and extracted twice with chloroform. After the combined organic layers were dried (MgSO ₄ ), the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from chloroform-ethyl acetate-ether to give the title compound as colorless needles (39.4 g, 90%).
%). mp: 171-173 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.41
(3H, t, J = 6.9 Hz), 2.68 (3H, t, J = 6.9 Hz)
s), 4.40 (2H, q, J = 6.9 Hz), 5.2
6 (2H, s), 7.00 (2H, t, J = 10.8H
z), 7.34-7.48 (6H, m), 8.39 (1
H, s).

Reference Example 2 3-Methyl-4,7-dihydro-7- (2,6-difluorobenzyl) -2-phenyl-4-oxothieno [2,3-b] pyridine-5-carboxylic acid isopropyl ester

Embedded image Compound obtained in Reference Example 1 (65.9 g, 150 mmol)
l) To a dichloromethane solution (200 ml) of isopropyl alcohol (200 ml) was added, and tetraisopropyl orthotitanate (5.68 g, 50 mmol) was added thereto.
l) was added. After stirring at 70 ° C. for 1 hour, the reaction solution was poured into water and extracted twice with chloroform. After the combined organic layers were dried (MgSO ₄ ), the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from chloroform-ethyl acetate-ether to give the title compound as pale yellow needles (61.3 g, 9
0%). mp: 202-204 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.38
(6H, d, J = 6.2 Hz), 2.68 (3H,
s), 5.17-5.31 (1H, m), 5.25 (2
H, s), 6.99 (2H, t, J = 8.0 Hz),
7.33-7.48 (6H, m), 8.34 (1H,
s).

Reference Example 3 3-bromomethyl-4,7-dihydro-7- (2,6-
Difluorobenzyl) -2-phenyl-4-oxothieno [2,3-b] pyridine-5-carboxylic acid isopropyl ester

Embedded image Compound obtained in Reference Example 2 (61.2 g, 135 mmol
1), N-bromosuccinimide (28.8 g, 162
mmol) and α, α'-azobisisobutyronitrile (1.64 g, 10 mmol) in ethyl acetate (600
ml) The mixture was heated at reflux for 2 hours. After cooling, insoluble materials were removed by filtration, and the filtrate was diluted with chloroform. The organic layer was washed with brine, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from chloroform-ethyl acetate to give the title compound as colorless needle crystals (64.9 g, 90%).
%). mp: 168-170 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.38
(6H, d, J = 6.2 Hz), 5.05 (2H,
s), 5.18-5.31 (1H, m), 5.27 (2
H, s), 7.01 (2H, t, J = 8.0 Hz),
7.36-7.54 (4H, m), 7.63 (2H, d
d, J = 8.0 Hz, 1.8 Hz), 8.34 (1H,
s).

Reference Example 4 3-bromomethyl-4,7-dihydro-7- (2,6-
Difluorobenzyl) -2- (4-nitrophenyl)-
4-oxothieno [2,3-b] pyridine-5-carboxylic acid isopropyl ester

Embedded image Compound obtained in Reference Example 3 (63.9 g, 120 mmol)
To a methanesulfonic acid solution (360 ml) of l), sodium nitrate (10.7 g, 126 mmol) was added under ice-cooling. After stirring at 10 ° C. for 2 hours, the reaction solution was poured into ice water and extracted with chloroform. The combined extracts were washed with brine, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ether to give the title compound as a yellow powder (55.4 g, 80%). mp: 145-147 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.38
(6H, d, J = 6.2 Hz), 5.03 (2H,
s), 5.18-5.29 (1H, m), 5.29 (2
H, s), 7.04 (2H, t, J = 8.0 Hz),
7.38-7.53 (1H, m), 7.85 (2H,
d, J = 9.2 Hz), 8.36 (2H, d, J = 9.
2Hz), 8.41 (1H, s).

Reference Example 5 3- (N-methyl-N-benzylaminomethyl) -4,
7-dihydro-7- (2,6-difluorobenzyl)-
2- (4-nitrophenyl) -4-oxothieno [2,
3-b] pyridine-5-carboxylic acid isopropyl ester

Embedded image Compound obtained in Reference Example 4 (55.4 g, 80 mmol
l) in dimethylformamide (400 ml) solution under ice-cooling, diisopropylethylamine (11.4 g, 8).
8 mmol) and N-methylbenzylamine (10.
(2 g, 88 mmol). After stirring at room temperature for 18 hours, the reaction solution was concentrated and the resulting residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ether to give the title compound as yellow powdery crystals. mp: 146-148 ° C. Elemental analysis: C (%) H (%) N (%) calculated as C ₃₃ H ₂₉ N ₃ O ₅ SF ₂ 0.25 H ₂ O Calculated: 63.70; 4.78; 6.75 Actual: 63. 63; 4.85; 6.50 ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.37
(6H, d, J = 6.2 Hz), 2.18 (3H,
s), 3.67 (2H, s), 4.21 (2H, s),
5.18-5.31 (1H, m), 5.28 (2H,
s), 7.03 (2H, t, J = 8.0 Hz), 7.1
2-7.26 (5H, m), 7.36-7.51 (1
H, m), 8.09 (2H, d, J = 8.8 Hz),
8.26 (2H, d, J = 8.8 Hz), 8.33 (1
H, s).

Reference Example 6 3- (N-methyl-N-benzylaminomethyl) -4,
7-dihydro-7- (2,6-difluorobenzyl)-
2- (4-aminophenyl) -4-oxothieno [2,
3-b] pyridine-5-carboxylic acid isopropyl ester

Embedded image Compound obtained in Reference Example 5 (30.9 g, 50 mmol
l) In a mixture of isopropyl alcohol (50 ml),
Water (1 ml) was added, and 1 drop of concentrated hydrochloric acid was added dropwise to make a homogeneous solution. To this was added iron powder (11.2 g, 200 mmol) and concentrated hydrochloric acid (50 ml, 6.00 mmol) dropwise. After the addition, the mixture was stirred for 1 hour under ice cooling. The obtained residue was poured into iced water, neutralized with sodium bicarbonate, added with ethyl acetate, stirred, and filtered through celite. The organic layer was separated, washed with brine, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from chloroform-ether to give the title compound as yellow powdery crystals (28.6 g, 97
%). mp: 106-108 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.36
(6H, d, J = 6.2 Hz), 2.10 (3H,
s), 3.65 (2H, s), 3.84 (2H, s),
4.14 (2H, s), 5.17-5.30 (1H,
m), 5.24 (2H, s), 6.72 (2H, d, J
= 8.4 Hz), 7.00 (2H, t, J = 8.0H)
z), 7.12-7.26 (5H, m), 7.30-
7.48 (1H, m), 7.62 (2H, d, J = 7.
8Hz), 8.28 (1H, s).

Example 1 3- (N-methyl-N-benzylaminomethyl) -4,
7-dihydro-7- (2,6-difluorobenzyl)-
2- [4- (3-methylureido) phenyl] -4-oxothieno [2,3-b] pyridine-5-carboxylic acid isopropyl ester

Embedded image Compound obtained in Reference Example 6 (27.8 g, 48 mmol)
l) and triethylamine (10.1 g, 100 mm
ol) in a dichloromethane (200 ml) solution,
N, N'-carbonyldiimidazole (11.7 g, 7
2 mmol) and stirred under ice cooling. After returning to room temperature and stirring for further 8 hours, the mixture was ice-cooled again, and a 2N-methylamine tetrahydrofuran solution (60 ml, 120 mmol) was added. After stirring for 1 hour while returning to room temperature, the reaction solution was diluted with water (400 ml), and then chloroform (400 ml).
Extracted. The aqueous layer is again chloroform (100 ml)
Extracted. The extracts were combined, washed with brine, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography,
The obtained residue was recrystallized from chloroform-isopropanol to give the title compound as colorless needle crystals (24.9 g, 80%).
%). mp: 204-206 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.33
(6H, d, J = 6.2 Hz), 1.95 (3H,
s), 2.83 (3H, d, J = 4.4 Hz), 3.4
7 (2H, s), 4.04 (2H, s), 5.16-
5.29 (1H, m), 5.25 (2H, s), 6.3
2-6.48 (1H, br), 6.98 (2H, t, J
= 8.0 Hz), 6.97-7.12 (5H, m),
7.32-7.47 (1H, m), 7.49 (2H,
d, J = 8.4 Hz), 7.60 (2H, d, J = 8.
4Hz), 8.36 (1H, s), 8.40 (1H,
s).

Formulation Example 1 Tablets are prepared by a conventional method using the compound prepared in Example 1 (100 mg), lactose (165 mg), corn starch (25 mg), polyvinyl alcohol (4 mg) and magnesium stearate (1 mg). I do.

Test Example 1 (1) Preparation of ¹²⁵ I-leuprorelin 10 μl of 3 × 10 ⁻⁴ M leuprorelin aqueous solution and 10 μl of 0.01 mg / ml lactoperoxidase
Into a tube and add 10 μl of Na ¹²⁵ I solution (37M
Bq), and after stirring, 10 μl of 0.001% H ₂ O ₂ was added and reacted at room temperature for 20 minutes. The reaction was stopped by adding 700 μl of a 0.05% trifluoroacetic acid (TFA) solution, followed by purification by reverse phase HPLC. The HPLC conditions are shown below. ¹²⁵ I-leuprorelin has a retention time of 26.
Eluted at ~ 27 minutes. Column: TSKgel ODS
-80 ^™ (TM indicates a registered trademark; the same applies hereinafter) CTR (4.6 mm × 10 cm) Eluent: Solvent A (0.05% TFA) Solvent B (40% CH ₃ CN-0.05% TFA) 0) (100% solvent A) -3 minutes (100% solvent A) -7
Min (50% solvent A + 50% solvent B) -40 min (100%
Solvent B) Elution temperature: room temperature Elution rate: 1 ml / min

(2) Preparation of anterior pituitary membrane fraction containing rat GnRH receptor Anterior pituitary gland was excised from 40 Wistar rats (8-week-old, male), and ice-cooled homogenate buffer 25m
M Tris [tris (hydroxymethyl) aminomethane] -HCl｝, 0.3 M sucrose, 1 mM E
GTA (glycol ether diamine tetraacetic acid), 0.2
5 mM PMSF (phenylmethylsulfonyl fluoride), 10 U / ml aprotinin, 1 μg / ml pepstatin, 20 μg / ml leupeptin, 100 μ
g / ml phosphoramidone and 0.03% sodium azide; pH 7.5). The pituitary gland was suspended in 2 ml of a homogenate buffer, and homogenized using a polytron homogenizer. 1 at 700xg
After centrifugation for 5 minutes, the supernatant was collected in an ultracentrifuge tube and 100,000 ×
g for 1 hour to obtain a precipitate of the membrane fraction. The precipitate was added to 2 ml of assay buffer (25 mM Tris-
HCl, 1 mM EDTA (ethylenediaminetetraacetic acid), 0.1% BSA (bovine serum albumin), 0.1%
25 mM PMSF, 1 μg / ml pepstatin, 2
0 μg / ml leupeptin, 100 μg / ml phosphoramidone and 0.03% sodium azide; pH 7.5), and suspended.
For 1 hour. The membrane fraction collected as a precipitate was suspended again in 10 ml of assay buffer, dispensed,
It was stored at -80 ° C and thawed each time it was used.

[0034] (3) CHO containing human GnRH receptor (Chinese Hamster Ovary) phosphate buffered saline cell membrane fraction prepared human GnRH receptor-expressing CHO cells (10 ⁹⁾ was added 5 mM EDTA (P
(BS-EDTA) and centrifuged at 100 × g for 5 minutes. Add cell homogenate buffer (10 mM NaHCO ₃ and 5 mM EDTA; p.
H7.5) was added, and the mixture was homogenized using a Polytron homogenizer. The mixture was centrifuged at 400 × g for 15 minutes, and the supernatant was collected in an ultracentrifuge tube and centrifuged at 100,000 × g for 1 hour to obtain a precipitate of a membrane fraction. This precipitate was suspended in 2 ml of the assay buffer, and 100,000 × g for 1 hour.
Centrifuged for hours. The membrane fraction recovered as a precipitate was
Suspend in 0 ml of assay buffer, aliquot and -8
It was stored at 0 ° C. and thawed each time it was used.

(4) Measurement of ¹²⁵ I-leuprorelin binding inhibition rate The rat and human membrane fractions prepared in the above (2) and (3) were diluted with an assay buffer to give 200 μg /
ml and dispensed 188 μl each into a tube. When rat anterior pituitary membrane fraction was used, 60% DMSO
2 μl of various concentrations of the compound (compound obtained in Example 1) dissolved in (dimethyl sulfoxide) and 38 nM
10 l of ¹²⁵ I-leuprorelin were added simultaneously. When the human GnRH receptor-expressing CHO cell membrane fraction was used, 2 μl of various concentrations of the compound (the compound obtained in Example 1) dissolved in 60% DMSO and 38 n
10 μl of M ¹²⁵ I-leuprorelin was added simultaneously. To determine the maximum binding, 60% DMSO
2 μl and 38 nM ¹²⁵ I-leuprorelin 10
A reaction solution to which μl was added was prepared. In order to measure the amount of non-specific binding, 10% dissolved in 60% DMSO was used.
2 μl of 0 μM leuprorelin and 38 nM ¹²⁵
A reaction solution to which 10 μl of I-leuprorelin was added was also prepared at the same time. When the rat anterior pituitary membrane fraction was used,
The reaction was carried out at 4 ° C. for 90 minutes.
When the HO cell membrane fraction was used, the reaction was performed at 25 ° C. for 60 minutes. After the reaction, the reaction solution was subjected to suction filtration using a polyethylene imine-treated Whatman glass filter (GF-F). After filtration, the radioactivity of ¹²⁵ I-leuprorelin remaining on the filter paper was measured using a γ-counter.
(TB-SB) / (TB-NSB) × 100 (SB: radioactivity when a compound is added, TB: maximum binding radioactivity, NSB: non-specific binding radioactivity) and calculate the binding inhibition of each compound. The rate (%) was determined. Further, varying concentrations of the compound sought inhibition rate, the concentration of the test substance which inhibits 50% binding of (IC ₅₀ value) was calculated from Hill plot. The results are shown below. Binding inhibition rate (%) IC ₅₀ value (μM) Compound Rat (1 μM) Human (20 μM) Rat Human Example 1 90 NT 0.04 0.00008 NT: Not measured

Test Example 2 Inhibition of Blood Testosterone in Normal Monkeys The compound obtained in Example 1 was subcutaneously administered to male cynomolgus monkeys, and the blood testosterone concentration was measured. Male cynomolgus monkeys having a body weight of 6.7 kg to 7.4 kg at the time of the experiment were used. To the test animals (n = 3), 30 mg / kg of the compound solubilized with glucuronylglucosyl-β-cyclodextrin was subcutaneously administered. Immediately before administration, after administration 3,
After 6, 12, 24, and 30 hours, blood was collected from the forearm vein to prepare serum, and immediately frozen and stored. The blood testosterone concentration was determined by radioimmunoassay (CIS).
Diagnostics). The results are summarized in FIG. Each measured value was shown as an average value ± standard error. Compound means the compound obtained in Example 1. The control is the value when only the lysate containing no compound was subcutaneously administered to the same animal (n = 3). In the control, the blood testosterone concentration showed a circadian fluctuation, and no sustained decrease was observed. On the other hand, in the compound administration group, a gradual decrease in blood testosterone concentration was observed immediately after administration, and almost reached castration level 30 hours after administration. The circadian variation disappeared with the dosing. From the above results, it was shown that the compound obtained in Example 1 had a remarkable blood testosterone concentration lowering effect when administered subcutaneously. From these results, the compound of the present invention antagonizes LH-RH at the GnRH (LH-RH) receptor present in the pituitary gland, thereby suppressing the secretion of LH / FSH from the pituitary gland and via these It can be seen that testosterone production is suppressed.

[0037]

The compounds of the present invention have excellent gonadotropin-releasing hormone antagonism. Furthermore, it has good oral absorbability and is excellent in stability and pharmacokinetics. Also,
It has good solubility in various organic solvents, and it is easy to prepare, for example, sustained-release injections. It is low in toxicity and excellent in safety. In addition, there is also a feature that there is almost no difference in drug efficacy depending on animal species. Therefore, it can be used, for example, as an agent for preventing or treating hormone-dependent diseases. In particular,
For example, as a medicine, sex hormone-dependent cancer (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), benign prostatic hyperplasia, uterine fibroids, endometriosis, precocious puberty, amenorrhea syndrome, multilocular ovary It is effective as a preventive or therapeutic agent for syndrome, acne, Alzheimer's disease, baldness, etc., or as a pregnancy regulator (eg, contraceptive), infertility treatment, menstrual regulator. Control of estrus,
It is also effective as a spawning promoter for fish in the field of improving meat quality, regulating animal growth, and fisheries.

[Brief description of the drawings]

FIG. 1 shows testosterone concentration in test monkey serum.
In the figure,-○-indicates a control group, and-●-indicates a compound administration group.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor: Ki Imada 5-1-1, Mayoka, Ikeda-shi, Osaka Inside Takeda Pharmaceutical Mayoka-ryo (72) Inventor: Masataka Harada 2--14-5, Higashi, Tsukuba, Ibaraki 5-5 Option 201 F term (reference) 4C071 AA01 BB01 CC01 CC21 DD12 EE12 FF06 GG05 HH08 HH28 JJ01 LL01 4C086 AA01 AA02 AA03 AA04 CB29 MA01 MA04 NA14 ZB26 ZC02

Claims (8)

[Claims] (1) Formula (1)[Wherein, R¹Is a hydrogen atom or C_1-3Alkyl group, R^TwoIs
Hydrogen atom, hydroxyl group or C_1-3Alkoxy group, R^ThreeIs replaced
C that may be_3-7Branched alkyl or substituted
May be C _3-7Represents a cycloalkyl group)
Or a salt thereof. 2. The compound according to claim 1, wherein R ¹ is a C _1-3 alkyl group, or a salt thereof. 3. The compound according to claim 1, wherein R ² is a hydrogen atom, or a salt thereof. 4. The method according to claim 1, wherein R ³ is a C _3-7 branched alkyl group.
Or a salt thereof. 5. A compound of the formula Wherein R ³ is as defined in claim 1 or a salt thereof with carbonyldiimidazole or phosgene; The method for producing a compound or a salt thereof according to claim 1, wherein the compound is reacted with a compound represented by the formula: or a salt thereof. 6. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof. 7. The pharmaceutical composition according to claim 6, which is a gonadotropin releasing hormone antagonist. 8. The pharmaceutical composition according to claim 7, which is a preventive or therapeutic agent for a sex hormone-dependent disease.