JP2002503661A - Gonadotropin-releasing hormone antagonist - Google Patents

Abstract

(57) Compounds of formula (I) and compounds thereof which are useful as antagonists of GnRH and may themselves be useful in the treatment of various sex hormone related diseases and other conditions in both men and women Are disclosed. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND ART [0002] Gonadotropin-releasing hormone (GnRH), also called luteinizing hormone-releasing hormone (LHRH), is a decapeptide that plays an important role in human reproduction. This hormone is released from the hypothalamus and acts on the pituitary to stimulate the biosynthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH released from the pituitary gland primarily regulates gonadal steroidogenesis in both sexes, whereas FSH regulates spermatogenesis in men and follicular development in women. GnRH agonists and antagonists have been shown to be effective in treating certain conditions that require inhibition of LH / FSH release. In particular, GnRH-based therapies have been used to treat endometriosis, fibroids, polycystic ovaries, precocious puberty and some gonadal steroid-dependent tumorigenesis, most notably prostate, breast and uterine cancer. It has been shown to be effective in therapy. G
nRH agonists and antagonists have also been used in various fertility treatments and are being studied as contraceptive candidates in men and women. They are used in the treatment of pituitary gonadotropin adenocarcinoma, sleep disorders such as sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, and hirsutism; to growth hormone therapy in children with growth hormone deficiency As an adjuvant; and has proven to be useful in a mouse model of lupus. The compounds of the invention may further be used in combination with other agents such as bisphosphonates (bisphosphonic acids) and growth hormone secretagogues such as MK-0677 to treat and prevent disorders of calcium, phosphate and bone metabolism, In particular, bone loss can be prevented during treatment with a GnRH antagonist, and further, treatment with a GnRH antagonist in combination with estrogens, progesterone, antiestrogens, antiprogesterone and / or androgens. Prevention or treatment of hypogonadism syndrome such as bone loss or hot flashes at the time of treatment can be performed.

[0002] The compounds of the present invention may further comprise finasteride or epristerid
5a-reductase-2-inhibitors such as e); WO 93/23420 and WO
4,7b-Dimethyl-4-aza-5a-cholestan-3-one, 3-oxo-4-aza-4,7a-dimethyl-16b- (4-chlorophenoxy) -5a-andro disclosed in U.S. Pat. Stan and 3-oxo-4-aza-4,7b
5a-reductase-1-inhibitors such as dimethyl-16b- (phenoxy) -5a-androstane; 3-oxo-4-aza-17b- (2,5-trifluoromethylphenyl) disclosed in WO 95/07927 Dual inhibitors of 5a-reductase 1 and 5a-reductase 2, such as -carbamoyl) -5a-androstan; anti-androgens such as flutamide, casodex and cyproterone acetate; and prazosin, terazosin, doxazosin,
It can be administered in combination with an alpha-1 blocker such as tamsulosin and alfuzosin.

In addition, the compounds of the present invention, in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues, delay puberty in children with growth hormone deficiency, epiphyseal fusion and growth arrest in puberty Before the height increase can be continued.

Further, the compound of the present invention can be used in combination or co-administration with a compound having a luteinizing hormone releasing activity such as a peptide or a natural hormone or an analog thereof. Such peptide compounds include leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin (de)
slorelin), meterlin and recirelin.

[0005] Furthermore, the compounds of the present invention can be administered to premenopausal women by administering peptide GnRH antagonists such as Antitide and Azaline B to premenopausal women in comparison to mammograms performed without administration. It can be used according to the method described in US Pat. No. 5,824,286, which discloses that the mammographic film has enhanced readability.

[0006] Current GnRH antagonists are GnRH-like decapeptides, which are administered intravenously or subcutaneously since their oral activity is considered to be negligible. The drug usually has amino acid substitutions at positions 1, 2, 3, 6, and 10.

For non-peptide GnRH antagonists, oral administration may be available. Non-peptide GnRH antagonists are described in European Patent Application No. 0219292 and the report of De et al. (De, B et al., J. Med. Chem., 32 , 2036-2038 (1989)), WO 95/2.
8405, WO 95/29900 and EP 0679624 (both Takeda
Chemical Industries, Ltd.).

[0008] Substituted indoles known in the art include those described in the following patents and patent applications. U.S. Pat. No. 5,030,640 discloses .alpha.-heterocyclic ethanolaminoalkylindoles which are potent .beta.-agonists. US Patent 454
No. 4663 discloses indoleamine derivatives described as being useful as male contraceptives. WO 90/05721 describes α-amino-indole-3, which is useful as an antidiabetic, antifertility and antiatherosclerotic agent.
Acetic acids are disclosed. French Patent No. 2,181,559 discloses indole derivatives having sedative activity, neuroleptic activity, analgesic activity, antihypertensive activity, anti-serotonin activity and anti-adrenergic activity. Belgian Patent No. 879381 states that 3 as a cardiovascular drug used in the treatment of hypotension, Raynaud's disease and migraine
-Aminoalkyl-1H-indole-5-thioamide and carboxamide derivatives are disclosed.

DISCLOSURE OF THE INVENTION The present invention is a non-peptide GnRH antagonist, which can be used for treating various sex hormone-related conditions in men and women; a method for producing the compound; The present invention relates to a method for use in animals and a pharmaceutical composition containing the compound for use in mammals.

Since the compound of the present invention has activity as a hormone GnRH antagonist,
It is useful for treating various sex hormone related conditions in both men and women. The condition includes endometriosis, fibroids, polycystic ovaries, hirsutism, precocious puberty,
These include gonad steroid-dependent tumorigenesis such as prostate, breast, and uterine cancer, pituitary gonadotropin adenocarcinoma, sleep apnea, irritable bowel syndrome, premenstrual syndrome, and benign prostatic hyperplasia. The compounds are further useful as adjuvants in the treatment of growth hormone deficiency and short stature and in the treatment of systemic lupus erythematosus. Further, the compounds of the present invention are expected to be useful in in vitro fertilization and as a contraceptive. The compounds may also be useful in the treatment of endometriosis, uterine fibroids and contraception in combination with androgens, estrogens, progesterone, antiestrogens and antiprogesterone. The compounds may also be useful as contraceptives in combination with testosterone or other androgens or antiprogesterone drugs in men. The compounds can further be used to treat uterine fibroids in combination with an angiotensin converting enzyme inhibitor such as enalapril or captopril; an angiotensin II receptor antagonist such as Losartan; or a renin inhibitor. Further, the compounds of the present invention
It can be used in combination with bisphosphonates (bisphosphonic acids) and other drugs to treat and prevent disorders of calcium metabolism, phosphate metabolism and bone metabolism, especially to prevent bone loss during treatment with GnRH antagonists. , Progesterones and / or androgens can be used for the prevention or treatment of hypogonadism syndrome such as bone loss or transient hot sensation during treatment with a GnRH antagonist.

Further, the compounds of the present invention may contain 5a- such as finasteride or epristeride.
Reductase-2-inhibitors; WO 93/23420 and WO 95/1125
4,7b-dimethyl-4-aza-5a-cholestan-3-one, 3-
Oxo-4-aza-4,7b-dimethyl-16b- (4-chlorophenoxy)-
5a-Androstane and 3-oxo-4-aza-4,7b-dimethyl-16
5a-reductase-1-inhibitors such as b- (phenoxy) -5a-androstan; 3-oxo-4-aza-17b- (2,5-trifluoromethylphenyl-carbamoyl) disclosed in WO 95/07927 Dual inhibitors of 5a-reductase 1 and 5a-reductase 2, such as -5a-androstane; anti-androgens, such as flutamide, casodex and cyproterone acetate;
It can be administered in combination with one blocking agent.

In addition, the compounds of the present invention, in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues, delay puberty in children with growth hormone deficiency, epiphyseal fusion and growth arrest in puberty Before the height increase can be continued.

Further, the compound of the present invention can be used in combination or co-administration with a compound having a luteinizing hormone releasing activity such as a peptide or a natural hormone or an analog thereof. Such peptide compounds include leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterulin and resirelin.

Further, the compounds of the present invention include peptides GnR such as untide and azaline B
US Patent No. 5,824,286 discloses that administration of an H antagonist to premenopausal women increases the readability of mammographic films compared to mammograms performed without administration. Can be used according to the method described in (1).

BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to a compound of the formula: or a pharmaceutically acceptable addition salt and / or hydrate of said compound, or, where applicable, It relates to geometric or optical isomers or racemic mixtures.

[0016]

Embedded image Wherein A is C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, substituted C ₃ -C ₇ cycloalkyl, C ₃ -C ₆ alkenyl, substituted C ₃ -C _{6 6 alkenyl,} C 3 -C ₆ alkynyl, substituted _C 3 -C _{6 alkynyl,} C 1 -C ₆ alkoxy or _C 0 -C ₅ alkyl _{-S (O) n -C 0 ~C} 5 _{alkyl, C} 0 ~
C ₅ alkyl _-O-C 0 ~C _{5 alkyl,} and C 0 -C ₅ alkyl ^-NR 18 _-C 0 ~C ₅ alkyl ^{(R 18} and _C 0 -C ₅ alkyl together ring

[0017]

Embedded image May be formed) or a single bond; R ⁰ is hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl (substituents are as defined below), aryl, R ¹ is substituted aryl, aralkyl or substituted aralkyl, wherein the substituents are as defined for R ³ , R ⁴ and R ⁵ ;

[0018]

Embedded image

[0019]

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[0020]

Embedded imageR²Is hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆Alkyl, aralkyl,
Substituted aralkyl, aryl, substituted aryl, alkyl-OR¹¹, C₁~ C₆(
NR¹¹R¹²), C₁~ C₆(CONR¹¹R¹²) Or C (NR¹¹R^{1 2} ) NH; R²And A together form a ring of 5 to 7 atoms; R³, R⁴And R⁵Is independently hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆ Alkyl, C₂~ C₆Alkenyl, substituted C₂~ C₆Alkenyl, CN, nitro,
C₁~ C₃Perfluoroalkyl, C₁~ C₃Perfluoroalkoxy, Ally
, Substituted aryl, aralkyl, substituted aralkyl, R¹¹O (CH₂)_p-, R ¹¹ C (O) O (CH₂)_p-, R¹¹OC (O) (CH₂)_p-,-(CH₂ )_pS (O)_nR¹⁷,-(CH₂)_pC (O) NR¹¹R¹²Or halogen
And R¹⁷Is hydrogen, C₁~ C₆Alkyl, C₁~ C₃Perfluoroalkyl
R, aryl or substituted aryl; R³And R⁴Together form a carbocyclic ring of 3 to 7 carbon atoms or N, O and
R forms a heterocyclic ring having 1 to 3 heteroatoms selected from S; R⁶Is hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆Alkyl, aryl, substitution
Substituted aryl, C₁~ C₃Perfluoroalkyl, CN, NO₂, Halogen, R^{1 1} O (CH₂)_p-, NR¹²C (O) R¹¹, NR¹²C (O) NR¹¹R^{1 2} Or SO_nR¹¹R⁷Is hydrogen, C₁~ C₆Alkyl or substituted C₁~ C₆Alkyl;
However, when X is not hydrogen or halogen, R⁷Does not exist; R⁸Is hydrogen, C (O) OR⁹, C (O) NR¹¹R¹², NR¹¹R¹²,
C (O) R¹¹, NR¹²C (O) R¹¹, NR¹²C (O) NR¹¹R¹²,
NR¹²S (O)₂R¹¹, NR¹²S (O)₂NR¹¹R¹², OC (O) R ¹¹ , OC (O) NR¹¹R¹², OR¹¹, SO_nR¹¹, S (O)_nNR^{1 1} R¹², C₁~ C₆Alkyl or substituted C₁~ C₆X is hydrogen
Or, if not halogen, R⁸Is absent; or R⁷And R⁸And together form a 3- to 7-membered carbocyclic ring; when m is not 0, R⁹And R^9aIs independently hydrogen, C₁~ C₆Archi
, Substitution C₁~ C₆Alkyl, aryl or substituted aryl, aralkyl or
Substituted aralkyl; or if m ≠ 0, R⁹And R^9aTogether form a 3- to 7-membered carbon ring or
= O; m is not 0, R⁹And A together form 3-7 carbon atoms and
Forming a heterocycle with one or more heteroatoms; R¹⁰And R^10aIs independently hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆ Alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl;
Or R¹⁰And R^10aTogether form a 3- to 7-membered carbocycle or = O
If m is not 0, R⁹And R¹⁰Together form a 3- to 7-membered carbon ring or
Forms a heterocycle with one or more heteroatoms; or, when m is not 0, R⁹And R²Together form 3-7 carbon atoms and
And a heterocycle having one or more heteroatoms;¹⁰And R²Together form 3 to 7 carbon atoms and one or more heteroatoms
R to form a heterocyclic ring having¹⁰And A together form 3-7 carbon atoms and one or more heteroatoms
Having a heterocycle; R¹¹And R¹²Is independently hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆A
Alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, 3- to 7-membered charcoal
A prime ring or a 3- to 7-membered substituted carbocycle;¹¹And R¹²Form a 3- to 7-membered optionally substituted ring
R¹³Is hydrogen, OH, NR⁷R⁸, NR¹¹SO₂(C₁~ C₆Alkyl)
, NR¹¹SO₂(Replacement C₁~ C₆Alkyl), NR¹¹SO₂(Aryl),
NR¹¹SO₂(Substituted aryl), NR¹¹SO₂(C₁~ C₃Perfluoroa
Ruquil), SO₂NR¹¹(C₁~ C₆Alkyl), SO₂NR¹¹(Replacement C₁ ~ C₆Alkyl), SO₂NR¹¹(Aryl), SO₂NR¹¹(Replacement Ally
Le), SO₂NR¹¹(C₁~ C₃Perfluoroalkyl), SO₂NR¹¹(
C (O) C₁~ C₆Alkyl), SO₂NR¹¹(C (O) -substituted C₁~ C₆A
Ruquil), SO₂NR¹¹(C (O) -aryl), SO₂NR¹¹(C (O)
-Substituted aryl), S (O)_n(C₁~ C₆Alkyl), S (O)_n(Replacement C₁ ~ C₆Alkyl), S (O)_n(Aryl), S (O)_n(Substituted aryl), C ₁ ~ C₃Perfluoroalkyl, C₁~ C₃Perfluoroalkoxy, C₁~ C ₆ Alkoxy, substituted C₁~ C₆Alkoxy, COOH, halogen, NO₂Or
CN; R¹⁴And R^FifteenIs independently hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆A
Luquil, C₂~ C₆Alkenyl, substituted C₂~ C₆Alkenyl, CN, nitro, C ₁ ~ C₃Perfluoroalkyl, C₁~ C₃Perfluoroalkoxy, aryl
, Substituted aryl, aralkyl, substituted aralkyl, R¹¹O (CH₂)_p-, R^{1 1} C (O) O (CH₂)_p-, R¹¹OC (O) (CH₂)_p-,-(CH₂) _p S (O)_nR¹⁷,-(CH₂)_pC (O) NR¹¹R¹²Or with halogen
Yes; R¹⁷Is hydrogen, C₁~ C₆Alkyl, C₁~ C₃Perfluoroalkyl
R, aryl or substituted aryl; R¹⁶Is hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆Alkyl or N (R ¹¹ R¹²R)¹⁸Is hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆Alkyl, C (O) O
R⁹, C (O) NR¹¹R¹², C (O) R¹¹, S (O)_nR¹¹R¹⁹Is R¹³Or R¹⁴X is hydrogen, halogen, N, O, S (O)_n, C (O), (CR¹¹R¹²) _p , C₂~ C₆Alkenyl, substituted C₂~ C₆Alkenyl, C₂~ C₆Alkynyl
Or substitution C₂~ C₆Alkynyl; when X is hydrogen or halogen, R⁷ And R⁸Is absent; X is O, S (O)_n, C (O) or CR¹¹R^{1 2} In the case of R⁷Or R⁸Z is O, S or NR¹¹M is 0-3; n is 0-2; p is 0-4; the alkyl, alkenyl and alkynyl substituents are₁~ C₆Archi
Le, C₃~ C₇Cycloalkyl, aryl, substituted aryl, aralkyl, substituted
Aralkyl, hydroxyl, oxo, cyano, C₁~ C₆Alkoxy, fluorine, C (O)
OR¹¹, Aryl C₁~ C₃Alkoxy, substituted aryl C₁~ C₃Alkoxy
The aryl substituent is R³, R⁴And R⁵As defined for
is there.

[0021] The following definitions shall be used throughout the specification and claims, unless otherwise indicated or indicated.

When any variable (eg, aryl, heterocycle, R ^1, etc.) occurs more than one time in any constituent or in formula I, its definition for each instance is at every other occurrence It is independent of its definition. Furthermore, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

The term “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, for example, methyl (Me), ethyl (
Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl, and isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (T-B
u), isopentyl, isomers thereof such as isohexyl, and the like.

The term “aryl” includes phenyl and naphthyl, and preferably aryl is phenyl.

The term “halogen” or “halo” is intended to include fluorine, chlorine, bromine and iodine.

The term “heterocycle” is defined as all 3- to 8-membered non-aromatic heterocycles having 1 to 3 heteroatoms selected from N, O and S, for example, oxirane,
Oxetane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, tetrahydropyridine, tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyran, morpholine, hydantoin, valerolactam, pyrrolidinone and the like.

The term “heteroaryl” refers to a 5- or 6-membered monocyclic aromatic hydrocarbon group or an 8- to 10-membered bicyclic aromatic group having one or more heteroatoms O, S or N. Wherein a carbon atom or a nitrogen atom is a bonding site. Heteroaryl groups may be substituted by up to three groups.

Heteroaryl includes aromatic and partially aromatic groups having one or more heteroatoms. Examples thereof include indole, thiophene, purine, imidazopyridine, pyridine, oxazole, thiazole, oxazine, pyrazole,
Examples include tetrazole, imidazole, benzimidazole, pyridine, pyrimidine, pyrazine and triazine.

As used herein, the term “composition” refers to a product comprising a specified amount of a specified component, as well as a product obtained, directly or indirectly, from a combination of a specified amount of the specified component. Shall be included.

Furthermore, it is known to those skilled in the art that many of the above heterocyclic groups can exist in multiple tautomers. All such tautomers are intended to be included in the scope of the present invention.

Also included are optical isomers, ie, mixtures (eg, racemates) or diastereomers of the enantiomers as well as the individual enantiomers or diastereomers of the compounds of the present invention. These individual enantiomers generally have the symbols (+) and (-), (L) and (D), (l) and (d), depending on the optical rotation they perform.
Alternatively, it is displayed by a combination thereof. These isomers can also be represented by (S) and (R), which represent levorotation and dextrorotation, respectively, according to their absolute spatial configuration.

The individual optical isomers can be obtained using conventional resolution procedures, such as treatment with an appropriate optically active acid, separation of diastereomers followed by recovery of the desired isomer. Further, individual optical isomers can be produced by asymmetric synthesis.

Further, a chemical formula or name is intended to include its solvates such as pharmaceutically acceptable salts and hydrates thereof.

The compounds of the present invention that are themselves active can be formulated and administered in the form of their pharmaceutically acceptable addition salts, for the purpose of stability, ease of crystallization, solubility enhancement and other desirable properties. can do.

The compounds of the present invention can be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salts" is intended to include all acceptable salts. Examples of acid salts include hydrochloride, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, maleate, succinate, malonate, methanesulfonate And the like, and the salts can be used as formulations that alter solubility or hydrolysis properties, or can be used in sustained release or prodrug formulations. Depending on the particular functionality of the compound of the invention, pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and the like. And ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine,
Salts formed from bases such as chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane and tetramethylammonium hydroxide. These salts can be prepared by standard procedures, such as the reaction of the free acid with a suitable organic or inorganic base, or the free base with a suitable organic or inorganic acid.

Furthermore, when an acid (—COOH) group or an alcohol group is present, pharmaceutically acceptable esters can be used, such as, for example, methyl ester, ethyl ester, butyl ester, acetate ester, maleic acid Esters, pivaloyloxymethyl esters, and the like, as well as esters known in the art for altering solubility or hydrolysis properties for use as sustained release or prodrug formulations.

The compounds of the present invention may have chiral centers other than the chiral centers shown in Formula I, and thus may be obtained as racemates, racemic mixtures and as individual enantiomers or diastereomers. And all such isomers are included in the present invention, as are their mixtures. Furthermore, some of the crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are included within the scope of the present invention.

The compounds of the present invention are prepared according to the following reaction scheme. Unless otherwise specified, all substituents are as defined above.

[0039]

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[0040]Reaction scheme A  As shown in Reaction Scheme A, an inert organic solvent such as tetrahydrofuran
Tryptamine at a temperature of 0-65 ° C, preferably 65 ° C, for 12-48 hours.
By treating (1) with N-carboxyphthalimide, the corresponding N-phthalic
An imidotryptamine derivative (2) is obtained. N-phthalimidotryptamine induction
The conductor (2) is made of tetrahydrofuran, methylene chloride, chloroform or
For 30 minutes to 4 hours in an inert organic solvent such as a mixture of
Ridinium hydrobromide perbromide, pyrrolidone hydrotribromide, etc.
Is further modified by treating with 2-bromotryptamine (3)
It is thought that it can be obtained. Bromide (3) is converted to toluene, benzene, ethanol
25-100 ° C. in an inert solvent such as ethanol, propanol or a mixture thereof
Arylboronic acid (Gronow) at a temperature of preferably 80 ° C. for 1-6 hours.
itz, S; Hornfeldt, A.-B .; Yang, Y.-H.,Chem.Scr. 1986, 26, 311-314), palladium (0) catalyst, aqueous sodium carbonate, etc.
With a weak base and a chlorine source such as lithium chloride to form a 2-aryltripta
The min derivative (4) can be obtained. Finally, methanol or ethanol
Hydrate (4) in any inert solvent at a temperature of 0-25 ° C for 4-24 hours.
By treating with an aqueous azine solution, the phthalimide group is eliminated, and the tryptamine (
5) can be obtained.

[0041]

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[0042]Reaction scheme B  As shown in Scheme B, methylene chloride, chloroform, dimethylformamide
Or in an inert organic solvent such as a mixture thereof at room temperature or near room temperature,
1-hydroxybenzotriazole (HOBt) and
In the presence or absence of a tertiary amine base such as N-methylmorpholine (NMM)
In the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
(EDC), cups such as 1,3-dicyclohexylcarbodiimide (DCC)
Condensation of 2-aryltryptamine with carboxylic acid of form (6) using a ring agent
Thus, the corresponding amide derivative (7) can be obtained. Alternatively, chloride
Inactive with Tylene, chloroform, tetrahydrofuran, diethyl ether, etc.
Solvents and triethylamine, diisopropylethylamine, pyridine, etc.
2-Alley in a tertiary amine base at a temperature of 0 to 25 ° C for 30 minutes to 4 hours.
Treating ltryptamine (5) with an active ester or acid chloride in the form of (8),
(7) can be obtained.

[0043]

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[0044]Reaction scheme C  As shown in Reaction Scheme C, tetrahydrofuran, diethyl ether, 1,4
Temperature in an inert organic solvent such as dioxane at 25-100 ° C, preferably 65 ° C;
Amide carbonyl of (7) with borane, lithium hydride
Reduced by treating with aluminum or equivalent hydride source.
Amine compound (9) can be obtained.

[0045]

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[0046]Reaction scheme D  As shown in Reaction Scheme D, the presence of weak acids such as trifluoroacetic acid (TFA) and acetic acid
At present, desiccants such as 3 ブ molecular sieves or magnesium sulfate
Hydras such as sodium borohydride or sodium cyanoborohydride
Methanol, ethanol, isopropanol in the presence or absence of
Toluene, tetrahydrofuran, methylene chloride, chloroform or mixtures thereof.
(10) In any inert organic solvent at a temperature of 0 to 25 ° C for 1 to 12 hours
Treatment with an aldehyde or ketone in the form of 2-aryltryptamine (5
) To give the corresponding secondary or tertiary amine derivative (11).
Wear.

[0047]

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[0048]Reaction scheme E  As shown in Reaction Scheme E, methanol, ethanol, n-propanol,
Sopropanol, n-butanol, t-butanol, preferably n-butanol
In a polar organic solvent such as at a temperature of 70-120 ° C. for 8-24 hours.
Hydrhydrazine or arylhydrazine hydrochloride (12)
2-aryltryptamine (5)
Get. Alternatively, methanol, ethanol, n-propanol, isopropanol
Polar solvents such as phenol, n-butanol, t-butanol or mixtures thereof
Medium, at room temperature, for 30 minutes to 2 hours, at a temperature of ~ 120 ° C for 8 to 24 hours.
Or arylhydrazine or arylhydrazine hydrochloride (12)
(Chlorine, bromine, iodine, O-methanesulfonate, O-trifluoromethanesulfon
(14) with aryl butyl ketone of the form (14)
When heated to a temperature of 5-100 ° C. for 4-24 hours, 2-aryltri
Ptamine (5) is produced.

[0049]

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[0050]Reaction scheme F  As shown in Reaction Scheme F, 50 in an inert organic solvent such as triethylamine.
Iodoanilines of the form (15) at a temperature of -88 ° C for 30 minutes to 5 hours
Is an arylacetylene, tetrakis (triphenylphosphine) palladium
And other suitable palladium (0) catalysts, such as copper (I) halides such as cuprous bromide.
In response, diarylacetylene (16) can be obtained. Acetylene (1
6) in an inert organic solvent such as acetonitrile at a temperature of 50-82 ° C.
Minutes, such as palladium (II) chloride or palladium (II) acetate.
Further modification by treatment with any palladium (II) catalyst provides a 2-arylyl
Ndole (17) can be obtained.

[0051]

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[0052]Reaction scheme G  As shown in Scheme G, neat or methylene chloride, chloroform, dichloro
Ethane, in an inert organic solvent such as tetrahydrofuran, at a temperature of 25 to 65 ° C.
The 3-arylindole (17) is converted to oxalyl chloride for 3 to 24 hours.
The acyl chloride adduct (18) can be obtained by treating with an acid chloride. Diethyl ether
Inert organic solvents such as ether, tetrahydrofuran, methylene chloride, chloroform, etc.
Medium and triethylamine, diisopropylethylamine or pyridine etc.
The crude product obtained in an amine base at a temperature of 0 to 25 ° C. for 30 minutes to 4 hours
The product (18) is reacted with an amine of the form (19) to give the amide derivative (20)
Can be The amide (20) is reacted at a high temperature, preferably under reflux, for 1 to 5 hours.
Borane or hydrogen hydride in an inert organic solvent such as tetrahydrofuran.
The compound (2) is further modified by treating with a reducing agent such as
1) can be obtained.

[0053]

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[0054]Reaction scheme H  As shown in Reaction Scheme H, N-benzyl derivatives of the form (22a) or (2
An N-benzyloxycarbonyl derivative of the form 2b) is
Tetrahydrofuran, ethyl acetate, methanol, ethanol to which a weak acid has been added
Or in an inert organic solvent such as a mixture thereof for 10 minutes to 3 hours or
Hydrogen (1 atm) and palladium on carbon or
Reduction by obtaining a secondary amine by treating with a suitable catalyst such as indium carbon
Secondary amine analog (7) can be obtained.

[0055]

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[0056]Reaction Scheme I  As shown in Reaction Scheme I, in an inert organic solvent such as ethanol, methanol, etc.
Hydrogen (1 atm) and Raney® at room temperature for 2-1 / 2 hours
Treatment of nitroindole in form (24) with a suitable catalyst such as nickel
And the corresponding aminoindole derivative (25) is obtained.

[0057]

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[0058]Reaction scheme J  As shown in Reaction Scheme J, acylation under various conditions provides amino- and
Can modify hydroxyindole (25). For example, methyle chloride
Inert organics such as chloroform, chloroform, tetrahydrofuran or mixtures thereof
In a solvent, at a temperature of 0 ° C. to room temperature for 1 hour to 12 hours, acid chlorides and acid anhydrides are also used.
Active ester and triethylamine, diisopropylethylamine,
Treatment of (25) with an amine base such as lysine gives the corresponding amide or
The stele derivative (26) is obtained. Alternatively, many commonly used dehydrating agents
(25) can be coupled with a carboxylic acid by any of
. For example, aminoindole (25) can be obtained by converting methylene chloride, chloroform, dimethyl
Room temperature or room temperature in an inert organic solvent such as ruformamide or a mixture thereof
1-Hydroxybenzotriazole () at ambient temperature for 3 to 24 hours
HOBt) and 3 such as N-methylmorpholine (NMM), triethylamine, etc.
In the presence or absence of a secondary amine base, a suitable carboxylic acid and 1- (3-di
Methylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), 1,3
By treating with dicyclohexylcarbodiimide (DCC) or the like
An amide or ester derivative (26) is obtained.

[0059]

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[0060]Reaction scheme K  As shown in Reaction Scheme K, methylene chloride, chloroform, dimethylforma
0 to 0 in an inert organic solvent such as amide, tetrahydrofuran or a mixture thereof.
Carbamoyl chloride in the form of (27a) at a temperature of 65 ° C. for 1 to 72 hours
(Or alternatively, an isocyanate reagent in the form of (27b)) and pyridyl
, Triethylamine, diisopropylethylamine, N-methylmorpholine
By treating the urea or carbamate derivative of (25) with any amine base,
(28) can be obtained. Compound (25) is methylene chloride, chloroform
In an inert solvent such as at a temperature of -20 ° C to 0 ° C for 20 minutes to 2 hours.
Lysine, triethylamine, diisopropylethylamine, N-methylmorpholine
With or without the addition of amine bases such as phosgene, triphosgene, 1,
1'-carbonyldiimidazole, N, N'-disuccinimidyl carbonate
It can be modified by treating with any bis (electrophilic) agent. After that,
The compound is subjected to the appropriate mono- or di-substitution at -20 ° C to 25 ° C for
Treatment with amine gives urea or carbamate analog (28)
.

[0061]

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[0062]Reaction scheme L  As shown in Scheme L, methylene chloride, chloroform, dichloroethane, etc.
In an inert solvent at a temperature of -20 ° C to 25 ° C for 20 minutes to 2 hours,
, Triethylamine, diisopropylethylamine, N-methylmorpholine
With any amine base, a suitable sulfonyl chloride of the form (29) or (
Modification of amine (25) by treatment with sulfamyl chloride in the form of 30)
And the corresponding N-sulfonamide (31) derivative or N-sulfamide, respectively.
A luamide (32) derivative can be obtained.

[0063]

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[0064]Reaction scheme M  As shown in Reaction Scheme M, methanol, ethanol, isopropanol,
In an inert organic solvent such as tanol, tert-butanol or a mixture thereof
Epoxa such as (34) at a temperature of 65 ° C to 110 ° C for 8 to 20 hours
The 2-aryltryptamine (33) is modified by treatment with
The amino-alcohol derivative (35) can be obtained.

[0065]

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[0066]Reaction scheme N  As shown in Reaction Scheme N, methylene chloride, chloroform, tetrahydrofuran
Room temperature in an inert organic solvent such as dimethylformamide or a mixture thereof.
Alternatively, at a temperature near room temperature for 3 hours to 7 days,
Azole (HOBt) and N-methylmorpholine (NMM), triethylamido
In the presence or absence of a tertiary amine base such as an amine, a suitable amine (R¹²R^{1 1} NH) and benzotriazol-1-yloxy-tris (pyrrolidino)
Phosphonium hexafluorophosphate (PyBOP), benzotriazole
-1-yloxy-tris (dimethylamino) phosphonium hexafluorophos
Fate (BOP), 1- (3-dimethylaminopropyl) -3-ethylcarbo
Diimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC
)) To form an acid-containing indole derivative such as (36).
Treating the amide derivative gives the corresponding amide derivative (37).

[0067]

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[0068]Reaction scheme O  As shown in Reaction Scheme O, 2-diene in an inert organic solvent such as methylene chloride.
Trobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride
Or arylsulfonyl such as 2,4-dinitrobenzenesulfonyl chloride
Steric hindrance such as chlorochloride and 2,4,6-collidine and 2,6-lutidine
By reacting with min base, tryptamine5To the corresponding sulfone
Mid38Can be obtained.38Sulfonamides such as benzene, tol
In an inert organic solvent such as ene, tetrahydrofuran or a mixture thereof,
Phenylphosphine and diethyl azodicarboxylate (DEAD), azodica
In the presence of an activator such as diisopropyl rubonate,39Reaction with alcohol
To give a dialkylsulfonamide adduct.
Wear. Nucleophilicity such as n-propylamine in an inert organic solvent such as methylene chloride
Treatment with an amine to remove the sulfonyl group,23A secondary amine of the type is obtained.

The compounds of the present invention are useful in treating various sex hormone related conditions in men and women. Its utility is manifested in its ability to act as an antagonist of the neuropeptide hormone GnRH, as demonstrated by its activity in the following in vitro assays.

[0070]Human GnRH receptor binding assay  Crude membranes obtained from CHO cells expressing the human GnRH receptor were isolated from a GnRH receptor source.
And [¹²⁵I] Buserelin (peptidyl GnRH analog) is radiolabeled
Used as ligand. Binding activity was determined by the activity of [¹²⁵I] Characteristics of buserelin
IC, the concentration of antagonist required to inhibit 50% of the differential binding₅₀Asked.

[0071]Rat Pituitary GnRH Receptor Binding Assay  Crude cell membranes obtained from rat pituitary tissue were isolated from bovine serum albumin (0.1%), [
I-125] Dt-Bu-Ser6-Pro9-ethylamide-GnRH and
And Tris HCl buffer (50 mM, pH 7.5) containing the test compound at the desired concentration
Incubated in. Incubate the assay mixture at 4 ° C for 90-120 minutes.
After filtration, high-speed filtration and repeated washing were performed using a glass fiber filter. Membrane formation
The radioactivity of the radioligand was measured with a γ-counter. From the data,
IC of binding of radioligand to GnRH receptor in the presence of compound₅₀To estimate
Was.

[0072]LH release inhibition assay  In addition to the active compounds from the GnRH receptor binding assay,
The LH release assay assesses their antagonist activity (GnRH-induced LH release).
Was cut off).

1. Sample preparation The compounds to be assayed were dissolved and diluted in DMSO. The final concentration of DMSO in the incubation medium was 0.5%.

2. Assay Wistar male rats (150-200 g) were obtained (Charles River
Laboratories, Wilmington, MA). Rats were maintained at a constant temperature (25 ° C.) with a 12 hour light and 12 hour dark cycle. Rat feed and drinking water
They were allowed free access. Animals are sacrificed by decapitation and the pituitary gland is aseptically removed.
Placed in Hanks' solution (HBSS) in a 0 mL polypropylene centrifuge tube. The collection tube was centrifuged at 250 xg for 5 minutes and HBSS was removed by suction. The pituitary gland was transferred to a disposable petri dish and minced with a scalpel. The tissue fragments were transferred into 50 mL disposable centrifuge tubes by suspending the tissue sections three times in 10 mL portions of HBSS containing 0.2% collagenase and 0.2% hyaluronidase. 37
The cells were dispersed with gentle stirring in a water bath at 30 ° C for 30 minutes. At the end of the incubation, the cells were aspirated 20-30 times with a pipette and the undigested pituitary fragments were sedimented for 3-5 minutes. The suspended cells were removed by suction and centrifuged at 1200 × g for 5 minutes. Next, the cells were resuspended in the medium. Undigested pituitary fragments were treated with 30 mL of digestive enzyme according to the method described above, and digested with a collagenase / hyaluronidase mixture three times in total. The obtained cell suspensions were combined, counted, and diluted to a concentration of 3 × 10 ⁵ cells / mL.
L was placed in each well of a 24-well tray (Costar, Cambridge, MA). Cells were maintained at 37 ° C. for 3-4 days in a humidified 5% CO ₂ -95% air atmosphere.
The medium was 0.37% NaHCO ₃ , 10% horse serum, 2.5% fetal calf serum, 1%
DMEM containing% non-essential amino acids, 1% glutamine and 0.1% gentamicin
Consisted of On the day of the experiment, 0.37% NaHCO ₃ , 10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids (100 × The cells were washed with DMEM containing 1% glutamine (100 ×), 1% penicillin / streptomycin (10000 units of penicillin and 10000 μg of streptomycin per mL) and 25 mM HEPES (pH 7.4). LH release was initiated by adding 1 mL of fresh medium containing the test compound in the presence of 2 nM GnRH to each well in duplicate. Incubation was performed at 37 ° C. for 3 hours. After incubation, the medium was removed and centrifuged at 2000 × g for 15 minutes to remove cellular material. Take out the supernatant,
Assays for LH content were performed by double antibody RIA using materials obtained from Dr. Parlow (Dr. AFParlow, Harbor-UCLA Medical Center, Torrance, CA).

The compounds of formula I are useful in many areas where GnRH affects. The compound is
It can be useful in sex hormone related conditions, sex hormone dependent cancer, benign prostatic hyperplasia or uterine fibroids. Sex hormone-dependent cancers for which administration of the compounds of the invention may be effective include prostate, uterine, breast and pituitary gonadotropin adenocarcinomas. Other sex hormone dependent conditions for which administration of the compounds of the present invention may be effective include endometriosis, polycystic ovaries, uterine fibroids and precocious puberty. The compound can also be used to treat uterine fibroids in combination with an angiotensin converting enzyme inhibitor such as enalapril or captopril; an angiotensin II receptor antagonist such as losartan; or a renin inhibitor.

The compounds of the present invention may further be used as contraceptives in both men and women for contraception, for artificial insemination, for the treatment of premenstrual syndrome, for the treatment of systemic lupus erythematosus, for the treatment of hirsutism and for irritable bowel. It is considered that it is also useful for treating the syndrome and for treating sleep disorders such as sleep apnea.

Yet another use of the compounds of the present invention is as an adjunct to growth hormone therapy in children with growth hormone deficiency. The compound can be administered with growth hormone or a compound that promotes endogenous production or release of growth hormone. Certain compounds have been developed that stimulate the release of endogenous growth hormone.
Peptides known to stimulate the release of endogenous growth hormone include growth hormone releasing hormone, growth hormone releasing peptide GHRP-6 and GHRP
-1 (described in US Pat. No. 4,411,890, PCT Patent Publication WO 89/07110 and PCT Patent Publication WO 89/07111) and GHRP-2 (described in PCT Patent Publication WO 93/04081), and hexarelin ( hexar
elin; J. Endocrinol. Invest. , 15 (Suppl 4), 45 (1992)). Other compounds that stimulate the release of endogenous growth hormone are described, for example, in U.S. Pat. No. 3,239,345, U.S. Pat.
No. 35, U.S. Pat. No. 5,283,241, U.S. Pat. No. 5,284,841 and U.S. Pat.
No. 10737, US Pat. No. 5,317,017, US Pat. No. 5,374,721, US Pat. No. 5,430,144, US Pat. No. 5,434,261, US Pat.
EPO Patent Publication No. 0144230, EPO Patent Publication No. 0513974, PCT Patent Publication WO 94/07486, PCT Patent Publication WO 94/08583, P
CT Patent Publication WO 94/11012, PCT Patent Publication WO 94/13696
No., PCT Patent Publication WO 94/19367, PCT Patent Publication WO 95/03
No. 289, PCT Patent Publication WO 95/03290, PCT Patent Publication WO 95
No. 09633, PCT Patent Publication WO 95/11029, PCT Patent Publication WO 95/12598, PCT Patent Publication WO 95/13069, PCT Patent Publication WO 95/14666, PCT Patent Publication WO 95/16675, PC
T Patent Publication WO 95/16692, PCT Patent Publication WO 95/17422, PCT Patent Publication WO 95/17423, Science , 260 , 1640-1643 (199
Med . Chem ., 28 , 177-186 (1993), Bioorg . Med. Chem. Ltrs. , 4 (22), 2709-2714 (1994) and Proc. Natl. .Acad.Sci.USA 92 , 7001-70
05 (July 1995).

Representative preferred growth hormone secretagogues for use in the combinations of the present invention include: 1) N- [1 (R)-[(1,2-dihydro-1-methanesulfonylspiro [
3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2-
(1H-indol-3-yl) ethyl] -2-amino-2-methyl-propanamide; 2) N- [1 (R)-[(1,2-dihydro-1-methanecarbonylspiro [
3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2-
(1H-indol-3-yl) ethyl] -2-amino-2-methyl-propanamide; 3) N- [1 (R)-[(1,2-dihydro-1-benzenesulfonylspiro [3H-indole] -3,4'-piperidin] -1'-yl) carbonyl] -2
-(1H-indol-3-yl) ethyl] -2-amino-2-methyl-propanamide; 4) N- [1 (R)-[(3,4-dihydro-spiro [2H-1-benzopyran- 2,4'-piperidin] -1'-yl) carbonyl] -2- (1H-indol-3-yl) ethyl] -2-amino-2-methyl-propanamide; 5) N- [1 (R) -[(2-acetyl-1,2,3,4-tetrahydrospiro [isoquinoline-4,4'-piperidin] -1'-yl) carbonyl] -2-
(Indol-3-yl) ethyl] -2-amino-2-methyl-propanamide; 6) N- [1 (R)-[(1,2-dihydro-1-methanesulfonylspiro [
3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2-
(Phenylmethyloxy) ethyl] -2-amino-2-methyl-propanamide; 7) N- [1 (R)-[(1,2-dihydro-1-methanesulfonylspiro [
3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2-
(Phenylmethyloxy) ethyl] -2-amino-2-methyl-propanamide methanesulfonate; 8) N- [1 (R)-[(1,2-dihydro-1-methanesulfonylspiro [
3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2-
(2 ', 6'-difluorophenylmethyloxy) ethyl] -2-amino-2-
9) N- [1 (R)-[(1,2-dihydro-1-methanesulfonyl-5-fluorospiro [3H-indole-3,4′-piperidin] -1′-yl) carbonyl ] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide; 10) N- [1 (S)-[(1,2-dihydro-1-methanesulfonylspiro [3H-indole- 3,4'-piperidin] -1'-yl) carbonyl] -2
-(Phenylmethylthio) ethyl] -2-amino-2-methylpropanamide; 11) N- [1 (R)-[(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4 ']. -Piperidin] -1′-yl) carbonyl] -3
-Phenylpropyl] -2-amino-2-methylpropanamide; 12) N- [1 (R)-[(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidine]. -1'-yl) carbonyl] -3
-Cyclohexylpropyl] -2-amino-2-methylpropanamide; 13) N- [1 (R)-[(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidine]. -1'-yl) carbonyl] -4
-Phenylbutyl] -2-amino-2-methylpropanamide; 14) N- [1 (R)-[(1,2-dihydro-1-methanesulfonylspiro [3H-indole-3,4'-piperidine]]. -1'-yl) carbonyl] -2
-(5-Fluoro-1H-indol-3-yl) ethyl] -2-amino-2-
Methyl propanamide; 15) N- [1 (R)-[(1,2-dihydro-1-methanesulfonyl-5-
Fluorospiro [3H-indole-3,4'-piperidin] -1'-yl) carbonyl] -2- (5-fluoro-1H-indol-3-yl) ethyl] -2
-Amino-2-methylpropanamide; 16) N- [1 (R)-[(1,2-dihydro-1- (2-ethoxycarbonyl) methylsulfonylspiro [3H-indole-3,4'-piperidine] -1
'-Yl) carbonyl] -2- (1H-indol-3-yl) ethyl] -2-
Amino-2-methylpropanamide; 17) N- [1 (R)-[(1,2-dihydro-1,1-dioxospiro [3
H-benzothiophene-3,4'-piperidin] -1'-yl) carbonyl]-
2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide; and pharmaceutically acceptable salts thereof.

The compounds of the present invention can be used in combination with other agents such as bisphosphonates (bisphosphonic acids) and growth hormone secretagogues (eg, MK-0677) to inhibit disorders of calcium, phosphate and bone metabolism. Treatment and prophylaxis, especially the prevention of bone loss during treatment with GnRH antagonists, can also be used, in combination with estrogen, progesterone and / or androgens, to prevent bone loss or treatment during treatment with GnRH antagonists. Prevention or treatment of hypogonadism syndrome such as hyperthermia can also be performed.

Bisphosphonates (bisphosphonic acids) are known to inhibit bone resorption and are useful in treating osteolithiasis as disclosed in US Pat. No. 4,621,077 to Risini et al.

The literature discloses various bisphosphonic acids useful in the treatment and prevention of diseases involving bone resorption. Representative examples are U.S. Pat. No. 3,251,907, U.S. Pat. No. 3,422,137, U.S. Pat. No. 3,584,125, U.S. Pat. No. 3,940,436, U.S. Pat. No. 3,944,599, U.S. Pat.
No. 98, U.S. Pat. No. 4,267,108, U.S. Pat.
No. 07761, US Pat. No. 4,578,376, US Pat. No. 4,621,077, US Pat. No. 4,624,947, US Pat. No. 4,746,654, US Pat.
U.S. Pat. No. 4922007, U.S. Pat. No. 4,942,157, U.S. Pat.
No. 6, U.S. Pat. No. 5,270,365, EPO Patent Publication No. 0252504 and J. Org. Chem. , 36 , 3843 (1971).

The preparation of bisphosphonic acids and halobisphosphonic acids is known in the art.
Representative examples are found in the above references and disclose that these compounds are useful in treating disorders of calcium or phosphate metabolism, particularly as bone resorption inhibitors.

Preferred bisphosphonates are alendronic acid, etidrononic acid, clodronic acid, pamidronic acid, tiludronic acid, risedronic acid (risdronic acid).
risedronic acid), 6-amino-1-hydroxy-hexylidene-bisphosphonic acid and 1-hydroxy-3 (methylpentyl-amino) -propylidene-bisphosphonic acid; or a pharmaceutically acceptable salt thereof. Selected from the group. A particularly preferred bisphosphonate is alendronic acid (alendronate) or a pharmaceutically acceptable salt thereof. A particularly preferred bisphosphonate is sodium alendronate, including sodium alendronate trihydrate. Alendronate sodium is available from Fosamax
X) has been approved by the regulatory body for marketing in the United States under the trademark X).

Further, the compounds of the present invention may contain 5α-amino acids such as finasteride or epristeride.
Reductase 2 inhibitors; 4,7β-dimethyl-4-aza-5α-cholestan-3-one, 3-oxo-4-aza-4,7β-dimethyl-16β disclosed in WO 93/23420 and WO 95/11254 -(4-chlorophenoxy) -5α
Androstane and 3-oxo-4-aza-4,7β-dimethyl-16β-
5α-reductase 1 inhibitors such as (phenoxy) -5α-androstan; W
5α- such as 3-oxo-4-aza-17β- (2,5-trifluoromethylphenyl-carbamoyl) -5α-androstan disclosed in O 95/07927.
It can be administered in combination with dual inhibitors of reductase 1 and 5α-reductase 2; antiandrogens such as flutamide, catodex and cyproterone acetate; and α-1 blockers such as prazosin, terazosin, doxazosin, tamsulosin and alfuzosin .

Further, the compounds of the present invention can be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogue to delay puberty in children with growth hormone deficiency, to achieve epiphyseal fusion and growth arrest in puberty. Before the height increase can be continued.

Further, the compound of the present invention can be used in combination or simultaneous administration with a compound having a luteinizing hormone releasing activity such as a peptide or a natural hormone or an analog thereof. Such peptide compounds include leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterulin and resirelin.

For combination treatments using more than one active agent and the active agents in separate preparations, the active agents can be administered separately or together. Further, the administration of one component can take place before, simultaneously with, or after the administration of the other agent.

Pharmaceutical compositions containing the active ingredient are, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs The preparation can be in a form suitable for oral use. Oral compositions can be prepared according to methods known in the art for the manufacture of pharmaceutical compositions, wherein such compositions are selected from the group consisting of sweetening, flavoring, coloring and preservative agents. One or more agents may be included to provide a pharmacologically pleasing and savory formulation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia; And lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known methods to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They also include U.S. Patent Nos. 4,256,108 and 4,166,645.
No. 4,265,874 to form a tablet for osmotic treatment for sustained release.

The oral dosage form may also be prepared as a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient may be water or an oil such as, for example, peanut oil, liquid paraffin or olive oil. It can be provided as a soft gelatin capsule mixed with a system medium.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate,
Suspending agents include polyvinylpyrrolidone, tragacanth gum and acacia gum. Dispersing or wetting agents can be natural phosphatides such as lecithin, or the condensation products of fatty acids such as polyoxyethylene stearate with alkylene oxides, or long chain fatty alcohols such as heptadecaethyleneoxycetanol and ethylene oxide. Or a condensation product of ethylene oxide with a partial ester derived from a fatty acid such as polyoxyethylene sorbitol monooleate and hexitol, or derived from a fatty acid and anhydrous hexitol, for example, polyethylene sorbitan monooleate. And the condensation product of the partial ester and ethylene oxide. Aqueous suspensions may contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more fragrances, and one or more sweeteners, such as sucrose, saccharin or aspartame. Can also be contained.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. The sweetening and flavoring agents described above may be added to provide a palatable oral preparation. Such compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. is there. Examples of suitable dispersing or wetting agents and suspending agents include those already mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, can also be present.

The pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. The oily phase can be, for example, a vegetable oil such as olive oil or peanut oil or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers include, for example, natural phosphatides such as soy lecithin, and esters or partial esters derived from fatty acids such as sorbitan monooleate and anhydrous hexitol, and said partial esters such as polyoxyethylene sorbitan monooleate. There can be condensation products with ethylene oxide.
Emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs include, for example, glycerin, propylene glycol,
The preparation can be formulated with a sweetening agent such as sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation is, for example, 1,
It can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. In that regard, any fixed oil commodity such as synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The compounds of formula I may also be administered in the form of suppositories for rectal administration of the drug.
Since such compositions are solid at room temperature but liquid at rectal temperature, admixing the drug with a suitable nonirritating excipient that melts in the rectum and releases the drug can be used. Can be prepared. Such materials are cocoa butter and polyethylene glycols.

For topical administration, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed (for the method of administration, topical administration includes gargles and gargles).

The compounds of the present invention can be administered in a nasal formulation by topical use of a suitable nasal vehicle or by the transdermal route using transdermal patches in a manner known to those skilled in the art. Of course, for administration in the form of a transdermal administration system, the administration will be continuous rather than intermittent throughout the dosage regimen. The compounds of the present invention can also be administered as suppositories using bases such as cocoa butter, glycerogelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

Administration using the compounds of the present invention will depend on the type, animal species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the kidney and liver function of the patient; The choice is made according to various factors such as the particular compound used.
A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, treat, arrest or reverse the progress of the condition.
Optimal accuracy in obtaining drug concentrations in a range that is efficacious without toxicity requires a regimen based on the kinetics of drug availability to the target site. In that case, the distribution, equilibrium and excretion of the drug should be considered. Preferably, the dose of a compound of structural formula I useful in the method of the invention will be from 0.01 to 1000 per adult per day.
mg range. Most preferably, doses will range from 0.1 to 500 mg / day. For oral administration, the compositions are preferably presented in the form of tablets containing 0.01-1000 mg of the active ingredient. Specifically, the amount of the active ingredient is 0.01, 0.05, 0.
1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.
The dosage for the patient to be treated is adjusted for the condition as 0, 100 and 500 mg. Typically, an effective amount of the drug is from about 0.0002 mg / kg per day.
It is provided at a dose level of about 50 mg / kg. More particularly, the range is from about 0.001 mg / kg to 1 mg / kg per day.

Advantageously, the active agents of the present invention may be administered in a single daily dose, or may be administered in two, three or four divided doses a day for a total daily dose. it can.

The amount of active ingredient that can be combined with a carrier material to provide a single dosage form,
It will vary depending on the host treated and the particular mode of administration.

However, specific dosage levels for a particular patient may include age, weight, general health, gender, diet, time of administration, route of administration, excretion rate, concomitant medications and the particular disease being treated. Is determined by various factors such as the severity of

The following examples illustrate the preparation of some of the compounds of the present invention and should not be construed as limiting the invention disclosed herein.

[Example] Example 1

[0105]

Embedded image (S) -2- {2- (3,5-dimethylphenyl) -3- [1-methyl-2-
(3-pyrido [2,3-b] pyrazin-7-yl-propylamino) -ethyl]
-1H-indol-5-yl} -N, N-diethyl-isobutylamide.

[0106]Step 1A: (S) -2- [3- (2-amino-1-methylethyl) -7-bro Mo-2- (3,5-Dimethylphenyl) -1H-indol-5-yl] -2- Ethyl methyl propionate  2- (3-bromo-4-hydrazinophenyl) -2-methylpropionic acid ethyl ester
0.107 g of (R) -4-chloro-1- (3,5-dimethylphenyl) -3
0.066 g of methylbutan-1-one and 2.0 mL of tert-butanol
The mixture was stirred at reflux under nitrogen for 16 hours. The cooled solution is concentrated under reduced pressure and the remaining
The distillate was partitioned between ethyl acetate and 10% aqueous sodium thiosulfate. Organic phase
Was washed with water and brine, dried over sodium sulfate and filtered. Depressurized filtrate
The residue obtained after concentration under reduced pressure is subjected to flash chromatography on silica gel.
(Eluent: chloroform: methanol: ammonium hydroxide, 95: 5: 1)
To give the title compound (53 mg).

[0107]Step 1B: (S) -2- [3- (2-amino-1-methylethyl) -2- (3 , 5-Dimethylphenyl) -1H-indol-5-yl] -2-methylpropyl Ononic acid ethyl ester  (S) -2- [3- (2-amino-1-methylethyl) -7-bromo-2- (
3,5-Dimethylphenyl) -1H-indol-5-yl] -2-methylpro
10% in a solution of ethyl pionate (79 mg of methanol in 1 mL)
8 mg of palladium on carbon catalyst was added. Attach hydrogen balloon to reaction flask and exhaust
The operation of refilling with hydrogen was repeated three times, followed by stirring at room temperature. After 7 hours, add
Pour in nitrogen, filter through diatomaceous earth, concentrate under reduced pressure, flush with silica gel
Purified by chromatography (chloroform: methanol, 92: 8)
The title compound (68 mg) was obtained.

[0108]Step 1C: (S) -2- [3- (2-tert-butoxycarbonylamino- 1-methylethyl) -2- (3,5-dimethylphenyl) -1H-indole- 5-yl] -2-methylpropionic acid ethyl ester  (S) -2- [3- (2-amino-1-methylethyl) -2- (3,5-dimension
Tylphenyl) -1H-indol-5-yl] -2-methylpropionate
A solution of the ester (2.13 g in 30 mL of tetrahydrofuran) at 0 ° C.
A solution of di-tert-butyl dicarbonate (1.9 g of tetrahydrofuran 6
mL solution) and then potassium carbonate (1.2 g solution of water in 5 mL).
The suspension was vigorously stirred at 0 ° C. After 20 minutes, an excess of an aqueous saturated ammonium chloride solution was added.
And the mixture was extracted with ethyl acetate. Organic phase sodium sulfate
And concentrated under reduced pressure. Flash chromatography on silica gel for residue
Matography (hexane: methylene chloride: ethyl acetate, 7.5: 7.5: 1)
Purification gave the title compound (2.52 g).

[0109]Step 1D: (S) -2- [3- (2-tert-butoxycarbonylamino- 1-methylethyl) -2- (3,5-dimethylphenyl) -1H-indole- 5-yl] -2-methylpropionic acid  (S) -2- [3- (2-tert-butoxycarbonylamino-1-methyl
Ethyl) -2- (3,5-dimethylphenyl) -1H-indol-5-yl]
A stirred solution of 2-methylpropionic acid ethyl ester (2.5 g of methanol 8
(0 mL solution) was added 26 mL of 2.0 N potassium hydroxide, and the mixture was heated at 94 ° C. in an oil bath.
Until heated. After 14 hours, the mixture is cooled to 0 ° C., acidified to pH 5 and vinegar
Extracted with ethyl acid. Wash the organic layer with saturated ammonium chloride and add sodium sulfate
And concentrated under reduced pressure to give the crude title compound (2.4 g).

[0110]Step 1E: (S)-{2- [5- (1-diethylcarbamoyl-1-methyle) Tyl) -2- (3,5-dimethylphenyl) -1H-indol-3-yl]- Propyl｝ -carbamic acid tert-butyl ester  (S) -2- [3- (2-tert-butoxycarbonylamino-1-methyl
Ethyl) -2- (3,5-dimethylphenyl) -1H-indol-5-yl]
Stir a solution of -2-methylpropionic acid in methylene chloride and add it to it at 0 ° C.
Droxybenzotriazole and 1- (3-dimethylaminopropyl) -3-
Add ethyl carbodiimide hydrochloride and mix the reagents for 1 hour. at the time
, A solution of diethylamine is added and the reaction is stirred at room temperature. After 24 hours, the mixture
Was concentrated under reduced pressure and purified by flash chromatography on silica gel.
To give the title compound.

[0111]Step 1F: (S) -2- [3- (2-amino-1-methylethyl) -2- (3 , 5-Dimethylphenyl) -1H-indol-5-yl] -N, N-diethyl -Isobutylamide  (S)-{2- [5- (1-diethylcarbamoyl-1-methylethyl) -2
-(3,5-dimethylphenyl) -1H-indol-3-yl] -propyl}
A solution of tert-butyl carbamic acid in methylene chloride at 0 ° C.
To the mixture is added anisole and then trifluoroacetic acid and the mixture is stirred at 0 ° C. 2 hours
Afterwards, the mixture is concentrated under reduced pressure and residual acid is removed azeotropically with toluene
. Flash chromatography purification on silica gel gives the title compound
.

[0112]Step 1G: (S) -2- {2- (3,5-dimethylphenyl) -3- [1-me Tyl-2- (3-pyrido [2,3-b] pyrazin-7-yl-propylamino) -Ethyl] -1H-indol-5-yl} -N, N-diethyl-isobutyla Mid  (S) -2- [3- (2-amino-1-methylethyl) -2- (3,5-dimension
Tylphenyl) -1H-indol-5-yl] -N, N-diethyl-isobutyi
The dehydrated chloroform solution of luamide was brought to 0 ° C., and magnesium sulfate was added thereto.
Next, 3-pyrido [2,3-b] pyrazin-7-yl-propionaldehyde was added.
And stir the mixture at low temperature. One hour later, sodium cyanoborohydride solution
And then a solution of acetic acid in methanol is added, and the reaction is warmed to room temperature.
After 1 hour, the reaction was quenched by adding saturated sodium bicarbonate, and the mixture was washed with ethyl acetate.
Extract with Wash the organic layer with saturated aqueous sodium bicarbonate, add sodium sulfate
Dehydrate with. Flash chromatography purification on silica gel of concentrate
To give the title compound.

[0113]Production of synthetic intermediates  2- (3-bromo-4-hydrazinophenyl) -2-methylpropionic acid ethyl ester
Le.

[0114]Step A: Ethyl (+/-)-2- (4-nitrophenyl) propionate  9.76 g of (+/-)-2- (4-nitrophenyl) propionic acid (50 mm
ol) in pure ethanol (150 mL) was added 3.0 mL of concentrated sulfuric acid. Profit
The resulting solution was stirred under reflux under nitrogen. After 6 hours, the solution is cooled and with high agitation
250 mL of a saturated aqueous sodium bicarbonate solution was gradually added. Next, the mixture is treated with acetic acid.
Partitioned between 750 mL of ethyl and 500 mL of water. Organic layer saturated sodium bicarbonate
And then washed with 100 mL of saturated aqueous sodium chloride solution.
The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an oil.
86 g (97%) were obtained. It is homogeneous by TLC with 9: 1 hexane-ethyl acetate
Met. 400MHz¹H NMR (CDCl₃) Was consistent with the specified structure.

[0115]Step B: ethyl 2-methyl-2- (4-nitrophenyl) propionate  Removal of 924 mg (23 mmol) of sodium hydride (60% oil dispersion)
A suspension of water N, N-dimethylformamide (21 mL) was stirred in an ice bath under nitrogen.
4.68 g of ethyl (+/-)-2- (4-nitrophenyl) propionate
(21 mmol) of a dehydrated N, N-dimethylformamide (20.5 mL) solution
It was added slowly over about 10 minutes. During the addition, a strong blue-purple color developed. Next, the mixture
The temperature was raised to room temperature. After about 1 hour, the mixture was cooled again in an ice bath and the internal temperature was reduced to 1
While maintaining the temperature at 0 to 15 ° C, 1.44 mL of methyl iodide (3.28 g, 23 mm
ol) of dehydrated N, N-dimethylformamide (5 mL) over about 10 minutes
It was dropped with a syringe. The mixture was warmed to room temperature and the color turned brown
. After 1 hour, an additional 187 mL (426 mg, 3 mmol) of methyl iodide was added.
Was. By the next day, the mixture will be a suspension of a slightly grayish solid in a golden liquid.
Was. The mixture was stirred vigorously, and the reaction was stopped by adding 10 mL of a 5% aqueous potassium bisulfate solution.
. The mixture was partitioned between 400 mL of diethyl ether and 400 mL of water. Organic
Wash the layer 3 times with an additional 400 mL of water, then 50 mL of saturated aqueous sodium chloride
And washed. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
Flash chromatography on silica gel of the residue (eluent: 19
: 1 hexane-ethyl acetate) to give 4.31 g (87%) of an oil. So
It was homogeneous by TLC with 9: 1 hexane-ethyl acetate. 400MH
z¹H NMR (CDCl₃) Was consistent with the specified structure.

[0116]Step C: Ethyl 2- (4-aminophenyl) -2-methylpropionate  4.27 g of ethyl 2-methyl-2- (4-nitrophenyl) propionate (1
8 mmol) 200 mg of 10% palladium on carbon and 120 m of pure ethanol
L mixture was shaken with hydrogen (initial hydrogen pressure 47 psig) for 2 hours in a pressure vessel.
Shaking. The catalyst was removed by filtration through celite under nitrogen and the filter cake was added with additional ethanol.
Washed with knol. The filtrate was concentrated under reduced pressure at 50 ° C or less to give 3.74 g of an oil (
100%). It is homogeneous by TLC in 4: 1 hexane-EtOAc
Met. 400MHz¹H NMR (CDCl₃) Was consistent with the specified structure. Mass spectrometry (ESI): m / e = 208 (M + H).

[0117]Step D: 2- (4-amino-3-bromophenyl) -2-methylpropionic acid ethyl  Solution of ethyl 2- (4-aminophenyl) -2-methylpropionate (4.7
4 g of dehydrated methylene chloride (40 mL solution) at 0 ° C. with N-bromosuccinimide 4
. 08 g was added and the mixture was stirred at low temperature. After 1 hour, warm the mixture to room temperature
And concentrated under reduced pressure. Flash chromatography on silica gel for residue
Raffy purification (hexane: ethyl acetate, 9: 1 and then 8: 2) to give the title
5.46 g of the compound was obtained.

[0118]Step E: 2- (3-bromo-4-hydrazinophenyl) -2-methylpropio Ethyl acid  Ethyl 2- (4-amino-3-bromophenyl) -2-methylpropionate 0
. A solution of 091 g of concentrated hydrochloric acid (0.32 mL) was placed in an ice-acetone bath at -10 to -5 ° C.
While stirring, an aqueous solution (0.20 mL of water) of 0.023 g of sodium nitrite was added.
It was dropped over about 15 minutes. Stirring was continued at that temperature for a further 30 minutes. Then, on
Stannous chloride dihydrate stirred under nitrogen in an ice-acetone bath with a syringe
It was added dropwise to a solution of 0.36 g of concentrated hydrochloric acid (0.25 mL) over 10 minutes. Dripping
Performed at a rate such that the internal temperature was maintained at about -5 ° C. During the addition, gum
Released. After completion of the dropwise addition, stirring was continued at -10 to -5C for 1 hour. Next, the mixture is vinegared
Diluted with 60 mL of ethyl acid and washed with sodium carbonate. Organic layer with water and bra
And washed with magnesium sulfate. Concentrate under reduced pressure to give the crude title compound.
I got

(R) -4-Chloro-1- (3,5-dimethylphenyl) -3-methylbutan-1-one.

[0120]Step AA: (R) -4-hydroxy-3-methylbutyronitrile  Solution of (S) -3-bromo-2-methyl-propan-1-ol (5.83 g
Sodium cyanide 9 in 25 mL of dehydrated N, N-dimethylformamide
. 33 g were added and the mixture was heated to 80 ° C. in an oil bath. After 4 hours, cool the mixture
Cooled to room temperature, diluted with water and extracted with ethyl acetate. Combine organic layers with water and
And then washed with brine. Concentration under reduced pressure gave the desired crude product (2.7.
4g).

[0121]Step BB: (R) -4-methyldihydrofuran-2-one  A solution of (R) -4-hydroxy-3-methylbutyronitrile (2.73 g of ed.
Sodium hydroxide solution (1.64 g of water in 13 mL)
Liquor) and the mixture was heated to reflux in an oil bath. After 7 hours, cool the mixture and add 2N salt
It was made acidic by adding an acid. The organic solvent was removed under reduced pressure and the mixture was washed with benzene 9
Extracted with 0 mL. Wash the organic layer with brine and remove the Dean Stark trap
Transferred to attached reaction flask. p-Toluenesulfonic acid (100 mg) was added.
The mixture was heated to reflux in an oil bath. After 3 hours, benzene and the product (138)
C) was collected by vacuum distillation (1.79 g).

[0122]Step CC: (R) -3- (3,5-dimethylbenzoyl) -4-methyldihydride Lofran-2-one  A solution of (R) -4-methyldihydrofuran-2-one (1.68 g of dioxa
5.51 g of 3,5-dimethylbenzoic acid methyl ester
To the mixture was added 1.82 g of sodium hydroxide, and the mixture was heated to reflux in an oil bath. 3 hours later
The mixture was cooled to room temperature and the pH was made neutral by the addition of 0.5N hydrochloric acid.
The mixture was extracted with ethyl acetate, the organic layer was washed with brine and dried over sodium sulfate.
Watered. The concentrate is purified by flash chromatography on silica gel (
Hexane: ethyl acetate, 9: 1) gave the title compound (2.42 g).

[0123]Step DD: (R) -4-chloro-1- (3,5-dimethylphenyl) -3-me Tilbutan-1-one  (R) -3- (3,5-dimethylbenzoyl) -4-methyldihydrofuran-
To a 2-one solution (2.42 g of a dioxane solution in 15 mL) was added 15 mL of concentrated hydrochloric acid.
The mixture was heated to reflux in an oil bath. After 1 hour, cool the reaction to cold saturated sodium bicarbonate
Poured into aqueous solution. Add solid sodium bicarbonate until all acids are neutralized
Was. It was extracted with ethyl acetate and washed with brine. Concentrate under reduced pressure to give the title
The compound was obtained (2.12 g).

3-pyrido [2,3-b] pyrazin-7-yl-propionaldehyde.

[0125]Step AAA: 7- (3,3-diethoxypropyl) -pyrido [2,3-b] pi Razine  A solution of 9-BBN (10.2 mL of a 0.5 M tetrahydrofuran solution) was cooled to 0 ° C.
Then, 0.77 mL of acrolein diethyl acetal was added dropwise thereto, and the mixture was shaken.
The temperature was raised to room temperature. After 15 hours, the mixture was dehydrated in tetrahydrofuran 1
Diluted with 2 mL, then potassium phosphate (1.6 g), palladium (1,1'-bi
(Diphenylphosphino) ferrocenyl) dichloride (160 mg) and
7-Bromo-pyrido [2,3-b] pyrazine (924 mg) was added in that order and the oil was added.
Heated to reflux in the bath. After 5 hours, the mixture was cooled to 0 ° C. and
Dilute and dilute 2N sodium hydroxide (3.5 mL) and 30% hydrogen peroxide (2.5
(mL) was added to handle excess reagent. The mixture was extracted with ethyl acetate,
The concentrate is washed by flash chromatography on silica gel (acetic acid).
Purify by ethyl: hexane, 1: 4 to 1: 1, then 4: 1) to give the title
A compound (1.2 g) was obtained.

[0126]Step BBB: 3-pyrido [2,3-b] pyrazin-7-yl-propional Dehide  Solution of 7- (3,3-diethoxypropyl) -pyrido [2,3-b] pyrazine
(522 mg of chloroform solution in 20 mL) at 0 ° C.
20 mL of oloacetic acid was added and the mixture was slowly warmed to room temperature. 30 minutes later,
Dilute the mixture with methylene chloride and carefully add saturated sodium bicarbonate
The reaction was stopped. Concentrate the organic layer under reduced pressure and flash chromatograph on silica gel.
Raffy (ethyl acetate: hexane, 1: 1 to methylene chloride: methanol, 95
: 5) to give the title compound (0.214 g).

According to a method similar to the above, the following compounds were prepared.

[0128]

Embedded image

[0129]

[Table 2]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4985 A61K 31/4985 31/5025 31/5025 31/519 31/519 A61P 1/04 A61P 1 / 04 5/02 5/02 15/00 15/00 15/18 15/18 35/00 35/00 37/06 37/06 C07D 487/04 140 C07D 487/04 140 498/04 105 498/04 105 513 / 04 343 513/04 343 351 351 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT , SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA ( M, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AU, AZ, BA, BB, BG, BR, BY, CA, CN, CU, CZ, EE, GD, GE , HR, HU, ID, IL, IN, IS, JP, KG, KR, KZ, LC, LK, LR, LT, LV, MD, MG, MK, MN, MX, NO, NZ, PL, RO, RU, SG, SI, SK, SL, TJ, TM, TR, TT, UA, US, UZ, VN, YU (72) Inventor Gret, Mark Tay United States, New Jersey 07065, Lowway, East Lincoln Avenue 126 (72) Inventor Walsh, Thomas F. United States, New Jersey 07065, Lowway, East Lincoln Avenue 126 (72) Inventor Fitzsiah, Mikle H. United States, New Jersey 07065, Lowway, East Lincoln Avenue, 126 F-term (reference) 4C050 AA01 BB05 BB06 CC08 EE03 EE04 EE05 FF02 GG03 GG04 GG05 HH04 4C065 AA03 AA04 BB06 BB12 CC01 4 CC03 CC11 CC16 EE02 EE12 FF07 FF08 FF09 GG01 GG07 GG08 HH07 UU01 4C086 AA01 AA02 AA03 CB05 CB06 CB09 MA01 NA14 ZA05 ZA66 ZA86 ZB11 ZB26 ZC03 ZC04 ZC10 ZC11

Claims (28)

[Claims] 1. A compound of the following formula: or a pharmaceutically acceptable addition salt of said compound.
And / or hydrates, or, if present, geometric isomers of the compound
Or optical isomers or racemic mixtures. Embedded image [Where A is C₁~ C₆Alkyl, substituted C₁~ C₆Alkyl, C₃~ C₇Cycloal
Kill, replace C₃~ C₇Cycloalkyl, C₃~ C₆Alkenyl, substituted C₃~ C₆ Alkenyl, C₃~ C₆Alkynyl, substituted C₃~ C₆Alkynyl, C₁~ C₆A
Lucoxy, C₀~ C₅Alkyl-S (O)_n-C₀~ C₅Alkyl, C₀~ C₅ Alkyl-OC₀~ C₅Alkyl, C₀~ C₅Alkyl-NR¹⁸-C₀~ C ₅ Alkyl (R¹⁸And C₀~ C₅Alkyl and ring togetherOr a single bond; R⁰Is hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆Alkyl (substituents are as follows
, Aryl, substituted aryl, aralkyl or substituted aralkyl
Kill (substituent is R³, R⁴And R⁵R is defined as above); R¹Is Embedded image Embedded image Embedded imageR²Is hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆Alkyl, aralkyl,
Substituted aralkyl, aryl, substituted aryl, alkyl-OR¹¹, C₁~ C₆(
NR¹¹R¹²), C₁~ C₆(CONR¹¹R¹²) Or C (NR¹¹R^{1 2} ) NH; R²And A together form a ring of 5 to 7 atoms; R³, R⁴And R⁵Is independently hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆ Alkyl, C₂~ C₆Alkenyl, substituted C₂~ C₆Alkenyl, CN, nitro,
C₁~ C₃Perfluoroalkyl, C₁~ C₃Perfluoroalkoxy, Ally
, Substituted aryl, aralkyl, substituted aralkyl, R¹¹O (CH₂)_p-, R ¹¹ C (O) O (CH₂)_p-, R¹¹OC (O) (CH₂)_p-,-(CH₂ )_pS (O)_nR¹⁷,-(CH₂)_pC (O) NR¹¹R¹²Or halogen
And R¹⁷Is hydrogen, C₁~ C₆Alkyl, C₁~ C₃Perfluoroalkyl
R, aryl or substituted aryl; R³And R⁴Together form a carbocyclic ring of 3 to 7 carbon atoms or N, O and
R forms a heterocyclic ring having 1 to 3 heteroatoms selected from S; R⁶Is hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆Alkyl, aryl, substitution
Substituted aryl, C₁~ C₃Perfluoroalkyl, CN, NO₂, Halogen, R^{1 1} O (CH₂)_p-, NR¹²C (O) R¹¹, NR¹²C (O) NR¹¹R^{1 2} Or SO_nR¹¹R⁷Is hydrogen, C₁~ C₆Alkyl or substituted C₁~ C₆Alkyl;
However, when X is not hydrogen or halogen, R⁷Does not exist; R⁸Is hydrogen, C (O) OR⁹, C (O) NR¹¹R¹², NR¹¹R¹²,
C (O) R¹¹, NR¹²C (O) R¹¹, NR¹²C (O) NR¹¹R¹²,
NR¹²S (O)₂R¹¹, NR¹²S (O)₂NR¹¹R¹², OC (O) R ¹¹ , OC (O) NR¹¹R¹², OR¹¹, SO_nR¹¹, S (O)_nNR^{1 1} R¹², C₁~ C₆Alkyl or substituted C₁~ C₆X is hydrogen
Or, if not halogen, R⁸Is absent; or R⁷And R⁸And together form a 3- to 7-membered carbocyclic ring; when m is not 0, R⁹And R^9aIs independently hydrogen, C₁~ C₆Archi
, Substitution C₁~ C₆Alkyl, aryl or substituted aryl, aralkyl or
R is a substituted aralkyl; or if m is not 0,⁹And R^9aIs a 3- to 7-membered carbon ring
Or = O; when m is not 0, R⁹And A together form 3-7 carbon atoms and
Forming a heterocycle with one or more heteroatoms; R¹⁰And R^10aIs independently hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆ Alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl;
Or R¹⁰And R^10aTogether form a 3- to 7-membered carbocycle or = O
If m is not 0, R⁹And R¹⁰Together form a 3- to 7-membered carbon ring or
Forms a heterocycle with one or more heteroatoms; or, when m is not 0, R⁹And R²Together form 3-7 carbon atoms and
And a heterocycle having one or more heteroatoms;¹⁰And R²Together form 3 to 7 carbon atoms and one or more heteroatoms
R to form a heterocyclic ring having¹⁰And A together form 3-7 carbon atoms and one or more heteroatoms
Having a heterocycle; R¹¹And R¹²Is independently hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆A
Alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, 3- to 7-membered charcoal
A prime ring or a 3- to 7-membered substituted carbocycle;¹¹And R¹²Form a 3- to 7-membered optionally substituted ring
R¹³Is hydrogen, OH, NR⁷R⁸, NR¹¹SO₂(C₁~ C₆Alkyl)
, NR¹¹SO₂(Replacement C₁~ C₆Alkyl), NR¹¹SO₂(Aryl),
NR¹¹SO₂(Substituted aryl), NR¹¹SO₂(C₁~ C₃Perfluoroa
Ruquil), SO₂NR¹¹(C₁~ C₆Alkyl), SO₂NR¹¹(Replacement C₁ ~ C₆Alkyl), SO₂NR¹¹(Aryl), SO₂NR¹¹(Replacement Ally
Le), SO₂NR¹¹(C₁~ C₃Perfluoroalkyl), SO₂NR¹¹(
C (O) C₁~ C₆Alkyl), SO₂NR¹¹(C (O) -substituted C₁~ C₆A
Ruquil), SO₂NR¹¹(C (O) -aryl), SO₂NR¹¹(C (O)
-Substituted aryl), S (O)_n(C₁~ C₆Alkyl), S (O)_n(Replacement C₁ ~ C₆Alkyl), S (O)_n(Aryl), S (O)_n(Substituted aryl), C ₁ ~ C₃Perfluoroalkyl, C₁~ C₃Perfluoroalkoxy, C₁~ C ₆ Alkoxy, substituted C₁~ C₆Alkoxy, COOH, halogen, NO₂Or
CN; R¹⁴And R^FifteenIs independently hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆A
Luquil, C₂~ C₆Alkenyl, substituted C₂~ C₆Alkenyl, CN, nitro, C ₁ ~ C₃Perfluoroalkyl, C₁~ C₃Perfluoroalkoxy, aryl
, Substituted aryl, aralkyl, substituted aralkyl, R¹¹O (CH₂)_p-, R^{1 1} C (O) O (CH₂)_p-, R¹¹OC (O) (CH₂)_p-,-(CH₂) _p S (O)_nR¹⁷,-(CH₂)_pC (O) NR¹¹R¹²Or with halogen
Yes; R¹⁷Is hydrogen, C₁~ C₆Alkyl, C₁~ C₃Perfluoroalkyl
R, aryl or substituted aryl; R¹⁶Is hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆Alkyl or N (R ¹¹ R¹²R)¹⁸Is hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆Alkyl, C (O) O
R⁹, C (O) NR¹¹R¹², C (O) R¹¹, S (O)_nR¹¹R¹⁹Is R¹³Or R¹⁴X is hydrogen, halogen, N, O, S (O)_n, C (O), (CR¹¹R¹²) _p , C₂~ C₆Alkenyl, substituted C₂~ C₆Alkenyl, C₂~ C₆Alkynyl
Or substitution C₂~ C₆Alkynyl; when X is hydrogen or halogen, R⁷ And R⁸Is absent; X is O, S (O)_n, C (O) or CR¹¹R^{1 2} In the case of R⁷Or R⁸Z is O, S or NR¹¹M is 0-3; n is 0-2; p is 0-4; the alkyl, alkenyl and alkynyl substituents are₁~ C₆Archi
Le, C₃~ C₇Cycloalkyl, aryl, substituted aryl, aralkyl, substituted
Aralkyl, hydroxyl, oxo, cyano, C₁~ C₆Alkoxy, fluorine, C (O)
OR¹¹, Aryl C₁~ C₃Alkoxy, substituted aryl C₁~ C₃Alkoxy
The aryl substituent is R³, R⁴And R⁵As defined for
is there. ] 2. The compound according to claim 1, which has a structure of the following formula. Embedded image [Wherein, A, R ¹ and XR ⁷ R ⁸ are as shown in the following table. [Table 1] 3. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 4. A method of antagonizing gonadotropin-releasing hormone in a patient in need of treatment, said method comprising administering an effective amount to a patient suffering from a gonadotropin-releasing hormone-derived disorder. A method comprising the step of administering a compound. 5. The method according to claim 4, wherein the disorder derived from gonadotropin releasing hormone is a sex hormone-related condition. 6. The method according to claim 4, wherein the gonadotropin-releasing hormone-derived disorder is a sex hormone-dependent cancer, benign prostatic hyperplasia or uterine fibroid. 7. The method according to claim 6, wherein the sex hormone-dependent cancer is selected from the group consisting of prostate cancer, uterine cancer, breast cancer and pituitary gonadotropin adenocarcinoma. 8. The method of claim 5, wherein the sex hormone-related condition is selected from the group consisting of endometriosis, polycystic ovary, uterine fibroids, and precocious puberty. 9. A method of contraception in a patient in need of contraception, comprising the step of administering an effective amount of a compound according to claim 1. 10. A method of treating systemic lupus erythematosus in a patient in need thereof, comprising administering to said patient an effective amount of a compound according to claim 1. 11. A method of treating irritable bowel syndrome in a patient in need of such treatment, comprising administering to said patient an effective amount of the compound of claim 1. 12. A method of treating premenstrual syndrome in a patient in need thereof, comprising administering to said patient an effective amount of a compound according to claim 1. 13. A method of treating hirsutism in a patient in need of such treatment, comprising administering to said patient an effective amount of a compound of claim 1. 14. A method of treating short stature or growth hormone deficiency in a patient in need of such treatment, comprising administering to said patient a compound that stimulates endogenous production or release of an effective amount of growth hormone and an effective amount of a compound. A method comprising administering the compound of claim 1. 15. A method of treating a sleep disorder, such as sleep apnea, in a patient in need of such treatment, comprising administering to said patient an effective amount of a compound of claim 1. 16. The method of claim 15, wherein said sleep disorder is sleep apnea. 17. A method of mammography which comprises the step of administering to a premenopausal woman an effective amount of a compound according to claim 1, wherein said mammography is performed without said method. A method in which the readability of mammography film is enhanced in comparison. 18. A pharmaceutical composition comprising an inert carrier and a compound that stimulates the endogenous production or release of an effective amount of growth hormone in combination with the compound of claim 1. 19. A pharmaceutical composition produced by combining the compound of claim 1 with a pharmaceutically acceptable carrier. 20. A method for producing a pharmaceutical composition comprising the step of combining the compound according to claim 1 with a pharmaceutically acceptable carrier. 21. A drug therapy comprising the step of administering the compound according to claim 1 in combination with a compound having luteinizing hormone-releasing hormone activity. 22. The method according to claim 21, wherein the compound having luteinizing hormone-releasing hormone activity is a peptide compound. 23. The therapy according to claim 22, wherein said peptide compound is a natural hormone or an analog of said hormone. 24. The peptide compound, wherein leuprorelin, gonadorelin,
23. The therapy according to claim 22, which is a compound selected from the group consisting of buserelin, triptrelin, goserelin, nafarelin, histrelin, deslorelin, meterelin and resirelin. 25. A drug combination therapy comprising the step of administering a compound having luteinizing hormone-releasing hormone activity in combination with the compound of claim 1. 26. The method according to claim 25, wherein the compound having luteinizing hormone releasing hormone activity is a peptide compound. 27. The method according to claim 26, wherein the peptide compound is a natural hormone or an analog of the hormone. 28. The peptide compound, wherein leuprorelin, gonadorelin,
27. The therapy according to claim 26, which is a compound selected from the group consisting of buserelin, triptrelin, goserelin, nafarelin, histrelin, deslorelin, meterelin and resirelin.