JP2001520996A - Gonadotropin-releasing hormone antagonist - Google Patents

Abstract

(57) Abstract: Compounds of formula (I) and pharmaceutically acceptable compounds thereof which are useful as GnRH antagonists and, as such, may be useful in the treatment of various sex hormone-related and other conditions in both men and women Acceptable salts 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 treatment. 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, antiprogestin 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
e) and other 5α-reductase-2-inhibitors; WO 93/23420 and WO
4,7β-dimethyl-4-aza-5α-cholestan-3-one, 3-oxo-4-aza-4,7β-dimethyl-16β- (4-chlorophenoxy) -5α-andro as disclosed in U.S. Pat. Stan and 3-oxo-4-aza-4,7β
5α-reductase-1-inhibitors, such as dimethyl-16β- (phenoxy) -5α-androstane; 3-oxo-4-aza-17β- (2,5-trifluoromethylphenyl) disclosed in WO 95/07927 Dual inhibitors of 5α-reductase 1 and 5α-reductase 2, such as -carbamoyl) -5α-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.

[0004] Current GnRH antagonists are GnRH-like decapeptides, which are administered intravenously or subcutaneously because 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.). Another non-peptide G
nRH antagonists have been described in WO 97/21704, WO 97/21707, WO 97/21703 and WO 97/21435.

[0006] 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 is a cardiovascular drug used in the treatment of hypertension, 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.

[0008] Since the compound of the present invention has activity as an antagonist of the hormone GnRH,
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, progesters, antiestrogens and antiprogestogens. The compounds may also be useful as contraceptives in combination with testosterone and other androgens or antiprogestogens 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 compound 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 bone loss prevention 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.

[0009] Further, the compound of the present invention may contain a 5α-amino acid such as finasteride or epristeride.
Reductase-2-inhibitors; WO 93/23420 and WO 95/1125
4,7β-dimethyl-4-aza-5α-cholestan-3-one, 3-
Oxo-4-aza-4,7β-dimethyl-16β- (4-chlorophenoxy)-
5α-androstane and 3-oxo-4-aza-4,7β-dimethyl-16
5α-reductase-1-inhibitors such as β- (phenoxy) -5α-androstan; 3-oxo-4-aza-17β- (2,5-trifluoromethylphenyl-carbamoyl) disclosed in WO 95/07927 Dual inhibitors of 5α-reductase 1 and 5α-reductase 2, such as -5α-androstane; anti-androgens, such as flutamide, catodex and cyproterone acetate; and α-, such as prazosin, terazosin, doxazosin, tamsulosin and alfuzosin.
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 growth hormone deficient children, causing epiphyseal fusion and growth arrest in puberty Before the height increase can be continued.

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention is a compound represented by the following formula or a pharmaceutically acceptable addition salt and / or hydrate of the compound, or, if applicable, It relates to geometric or optical isomers or racemic mixtures of the compounds.

[0012]

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Where R⁰Is hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆Alkyl (substituents are
Aryl, substituted aryl, aralkyl or substituted aralkyl
Kill (substituent is R³, R⁴And R⁵R is defined as above); R¹And R²Is independently hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆Archi
Le, C₃~ C₇Cycloalkyl, substituted C₃~ C₇Cycloalkyl, N, O or
Is a heterocyclic or bicyclic heterocyclic ring having 1 to 4 heteroatoms selected from S
(R³, R⁴And R⁵Or N, O or S
A heterocyclic or bicyclic heterocyclic ring having 1 to 4 heteroatoms (R³ , R⁴And R⁵Which is optionally substituted by₁ ~ C₆Alkyl, C₃~ C₆Alkenyl, substituted C₃~ C₆Alkenyl, C₃~ C ₆ Alkynyl, substituted C₃~ C₆Alkynyl, C₀~ C₅-Alkyl-S (O)_n -C₀~ C₅Alkyl, C₂~ C₆Alkyl (NR¹¹R¹²), C₂~ C₆A
Lequil (OR¹¹) Or C₁~ C₆Alkyl (CONR¹¹R¹²) Is;
Where R¹¹And R¹²Independently or together, aryl, substituted aryl,
Not aralkyl and substituted aralkyl; or R¹And R²Are integrated, and 0, 1 if selected from S, O or N
Or an optionally substituted non-heteroaromatic 3 to 2
Forming an 8-membered ring; 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
, Aryl or substituted aryl; or 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-, NR²¹C (O) R²⁰, NR²¹C (O) NR²⁰R^{2 1} Or SO_nR²⁰R⁷Is hydrogen, C₁~ C₆Alkyl or substituted C₁~ C₆R is alkyl;⁸Is C (O) OR²⁰, C (O) NR²⁰R²¹, NR²⁰R²¹, C (
O) R²⁰, NR²¹C (O) R²⁰, NR²¹C (O) NR²⁰R²¹, NR ²⁰ S (O)₂R²¹, NR²¹S (O)₂NR²⁰R²¹, OC (O) R²⁰ , OC (O) NR²⁰R²¹, OR²⁰, SO_nR²⁰, S (O)_nNR²⁰R ²¹ , A heteroaromatic ring or a substituted heteroaromatic ring, N, O or S
A heterocyclic or bicyclic heterocyclic ring having 1 to 4 heteroatoms (R³, R⁴And
And R⁵May be substituted), C₁~ C₆Alkyl or substituted C₁~ C₆A
Or R.⁷And R⁸Together form one or more heteroatoms selected from N, O and S
Heterocycle having a child (R³, R⁴And R⁵May be substituted) to form
And if m ≠ 0, R⁹And R^9aIs independently hydrogen, C₁~ C₆Alkyl, place
Exchange 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
ＯO; 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 ≠ 0, R⁹And R¹⁰Together form a 3- to 7-membered carbon ring or 1
Forming a heterocyclic ring having the above heteroatoms; or, when m ≠ 0, R⁹And R²Together form 3 to 7 carbon atoms and 1
Forming a heterocycle with the above heteroatoms;¹⁰And R²Together form 3 to 7 carbon atoms and one or more heteroatoms
R to form a heterocyclic ring having¹¹And 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
R²⁰And R²¹Is independently hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆A
Alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaromatic ring
Or a substituted heteroaromatic ring, a 3- to 7-membered carbocyclic ring, a 3- to 7-membered substituted carbocyclic ring, N, O
Or a heterocyclic or bicyclic ring having 1 to 4 heteroatoms selected from S
Heterocycle (R³, R⁴And R⁵Or N, O if
Or a heterocyclic or bicyclic heterocycle having 1 to 4 heteroatoms selected from S
Ring (R³, R⁴And R⁵Which may be substituted by ₁ ~ C₆Is alkyl; or R²⁰And R²¹Is a 3- to 9-membered optionally substituted ring or
X may be N, O, S (O)_n, C (O), (CR¹¹R¹²)_p, R⁸Single bond to
, C₂~ C₆Alkenyl, substituted C₂~ C₆Alkenyl, C₂~ C₆Alkynil
Or substitution C₂~ C₆X is O, S (O)_n, C (O) or C
R¹¹R¹²In the case of R⁸M is from 0 to 3; n is from 0 to 2; p is from 0 to 4;
The substituent is C₁~ C₆Alkyl, C₃~ C₇Cycloalkyl, aryl, substituted ant
Aralkyl, substituted aralkyl, hydroxyl, oxo, cyano, C₁~ C₆Al
Coxy, fluorine, C (O) OR¹¹, Aryl C₁~ C₃Alkoxy, substituted ant
C₁~ C₃Selected from alkoxy; the aryl substituent is R³, R⁴And R ⁵ As defined above.

When R ²⁰ and R ²¹ are combined, preferred substituents include 7-aza-bicyclo [2.2.1] heptane and 2-aza-bicyclo [2.2.2] octane. is there.

[0015] 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), their isomers such as isopentyl and isohexyl.

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

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.

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.

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 tautomeric forms. 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.

Individual optical isomers can be obtained using conventional resolution procedures, such as treatment with an appropriate optically active acid, separation of diastereomers, and subsequent 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 pharmaceutically acceptable salts and solvates thereof, such as hydrates.

The compounds of the present invention that are effective as such are formulated and administered in the form of their pharmaceutically acceptable addition salts, for the purpose of stability, ease of crystallization, enhanced solubility 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 their salts can be used as formulations that alter the 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.

In addition, when an acid (—COOH) group or an alcohol group is present, pharmaceutically acceptable esters can be used, including, for example, methyl esters, ethyl esters, butyl esters, acetates, 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.

[0033]

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[0034]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 azine aqueous solution, the phthalimide group is eliminated and the tryptamine (
5) can be obtained.

[0035]

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[0036]Reaction scheme B  As shown in Scheme B, methylene chloride, chloroform, dimethylformamide
Or at room temperature or near room temperature in an inert organic solvent such as
1-hydroxybenzotriazole (HOBt) and
And tertiary amine bases such as N-methylmorpholine (NMM) and triethylamine
1- (3-dimethylaminopropyl) -3-ethylca in the presence or absence
Rubodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (D
Using a coupling agent such as CC) to convert 2-aryltryptamine to the form of (6)
And the corresponding amide derivative (7) can be obtained.
Alternatively, methylene chloride, chloroform, tetrahydrofuran, diethyl ether
Inert organic solvents such as ter and triethylamine, diisopropylethylamine
In a tertiary amine base such as pyridine or pyridine at a temperature of 0 to 25 ° C for 30 minutes to 4 hours.
On the other hand, 2-aryltryptamine (5) is converted to an active ester or an acid of the form (8).
Treatment with chloride gives (7).

[0037]

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[0038]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;
The amide carbonyl of (7) is converted to borane and lithium hydride for 1 to 8 hours.
Reduced by treating with aluminum or equivalent hydride source.
Amine compound (9) can be obtained.

[0039]

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[0040]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
Hydra 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 0-25 ° C for 1-12 hours.
Treatment with an aldehyde or ketone in the form of 2-aryltryptamine (5
) Can be modified to give the corresponding secondary or tertiary amine derivative (11).
Wear.

[0041]

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[0042]Reaction scheme E  As shown in Reaction Scheme E, methanol, ethanol, n-propanol,
Polar organic solvents such as sopropanol, n-butanol, t-butanol, etc., are preferred
Aliquots in n-butanol 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 anol, n-butanol, t-butanol or mixtures thereof
Medium, at room temperature for 30 minutes to 2 hours
Razine hydrochloride (12) has a leaving group (chlorine, bromine, iodine, O-methanesulfur) at the 4-position.
Phonate, O-trifluoromethanesulfonate, etc.)
Treated with aryl butyl ketone and then heated to a temperature of
After 4 hours, 2-aryltryptamine (5) is produced.

[0043]

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[0044]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 a suitable palladium (0) catalyst such as copper (I) 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.

[0045]

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[0046]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 titanium aluminum.
1) can be obtained.

[0047]

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[0048]Reaction scheme H  As shown in Reaction Scheme H, an N-benzyl derivative of the form (22a) or (2
An N-benzyloxycarbonyl derivative of the form 2b) is
Tetrahydrofuran, ethyl acetate, methanol, ethanol to which 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 treatment with a suitable catalyst such as indium carbon reduces the secondary amine analog (7
) Can be obtained.

[0049]

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[0050]Reaction Scheme I  As shown in Reaction Scheme I, in an inert organic solvent such as ethanol, methanol, etc.
Hydrogen (1 atm) and Raney® D at room temperature for 2-12 hours.
Treatment of nitroindole in form (24) with a suitable catalyst such as
The corresponding aminoindole derivative (25) is obtained.

[0051]

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[0052]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 added.
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 (
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.

[0053]

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[0054]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 1-5 hours.
Treatment with amine gives urea or carbamate analog (28)
.

[0055]

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[0056]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.

[0057]

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[0058]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.

[0059]

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[0060]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.
Or 1-hydroxybenzotria at a temperature near room temperature for 3 to 24 hours.
Zol (HOBt) and N-methylmorpholine (NMM), triethylamine
In the presence or absence of a tertiary amine base such as¹²R¹¹ NH) and benzotriazol-1-yloxy-tris (pyrrolidino) pho
Suphonium hexafluorophosphate (PyBOP), benzotriazole-
1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphine
(BOP), 1- (3-dimethylaminopropyl) -3-ethylcarbodi
Imide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC)
With a suitable coupling agent such as
By treating the amide derivative, the corresponding amide derivative (37) is obtained.

[0061]

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[0062]Reaction scheme O  A preferred method of synthesizing the substituted tryptamines according to the present invention is shown in Scheme O
An important step is the use of Larock's indole synthesis.
You. In this indole synthesis, potassium carbonate combined with triphenylphosphine
Bases such as lithium chloride and palladium catalysts such as palladium acetate.
In the presence of a suitably functionalized ortho-iodoaniline (38) and a configuration such as 39
Reaction with substituted acetylenes. The reaction is carried out at elevated temperatures (eg, 100 ° C)
Reaction in an inert organic solvent such as chloroform. The reaction is carried out for 30 minutes to 24 hours.
U. By standard work-up and isolation, the substituted isomer indole derivative 40 and
And 41 are obtained, and the isomer of the general formula 40 is a preferred isomer. Used in this reaction
The acetylene obtained can be terminal acetylene (39a) or
May have a terminal carbon atom substituted with a substituent Z (39b, 39c). PG
1 is a substituent such as benzyl ether or tert-butyl ether.
Shows a call protecting group. The nature of the Z substituent indicates that the indole isomer (
Determine the distribution of 40 and 41). For example, if the substituent Z on acetylene is a hydrogen atom
If it is a child, isomer 41a is the main product of the reaction. When the substituent Z is
Select to be a substituted silyl group such as luciryl and triethylsilyl (shown).
If chosen, isomer 40b is almost exclusively produced. When Z is a substituted aryl group
In this case, both isomers 40c and 41c are formed and the product mixture is chromatographed.
Separation using the luffy or crystallization method gives the individual isomers.

In the case where silyl-substituted indole 40b is produced by performing indole synthesis using silyl-substituted acetylene 39b, the silyl group is then converted to an aryl group or a substituted aryl group of the general formula 40c by using a reaction described later in Scheme S. Convert to base. The 2-aryl-substituted indole derivative 40c generated directly from the arylacetylenes (39c) according to the method shown in Scheme O or from the silyl-substituted indoles using the method in Scheme S can be further manipulated according to the methods described below. The novel tryptamine derivatives according to the invention are produced.

[0064]

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[0065]Reaction scheme P  Scheme P includes the substituted orols used in the indole synthesis of Lalock shown in Scheme O.
Shown is the manufacture of Toyo Doaniline (38). The ortho-iodoanilines are
Can be prepared by several methods described in the literature on organic synthesis. Some good
The method is to use nitrobenzene or a compound represented by the general formula of formula 42 as a raw material.
A substituted nitrobenzene derivative is used. Invitation of nitrobenzene like 42
Conductors are commercially available or easily prepared using standard methods known in organic chemistry
Can be manufactured. Using a method such as catalytic hydrogenation, a compound of general formula 42
Is reduced to produce an aniline derivative such as 43.
For example, in the presence of a catalyst such as 10% palladium / carbon powder, the atmospheric pressure is reduced to 100 p.
The nitro compound 42 was reacted under a hydrogen atmosphere at a pressure of sig, and the reaction was allowed to proceed from room temperature to 1 hour.
When performed in an inert solvent such as ethanol at a temperature of 00 ° C., it usually takes 15 minutes to 6 minutes.
The substituted aniline derivative 43 is generated within a period of time. Next, aniline 4 represented by the general formula
3 with an iodinating reagent such as iodine, iodine monochloride, N-iodosuccinimide, etc.
By reacting, it is converted to ortho-iodoanilines 38. For example, carbonic acid
In the presence of a base such as calcium, an alcohol (ie, methanol or ethanol)
Phenol) or a suitable inert solvent such as an alcohol-water mixture.
By reacting an aniline derivative such as 43 with iodine monochloride at a temperature of
After a reaction time of 30 minutes to 2 hours, the ortho-iodoaniline derivative 38 is obtained.
It is.

[0066]

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[0067]Reaction scheme Q  The acetylene compound having the general structure 39 depends on the selection of a desired substituent.
It is manufactured using any of these methods. Substituent R⁹, R^9a, R¹⁰And R ^10a Is selected to be hydrogen or a lower alkyl group, the compound of formula 39
Acetylenes such as, 3-butyn-1-ol and 4-pentyn-2-ol
Alcohols or similar acetylenic alcohols reported in the chemical literature
Can be manufactured from The acetylene alcohols of the general formula 44
The conversion to the acetylene derivative is shown in Scheme Q. For clarity, it is shown in Scheme Q.
Hydroxyl protecting group (PG₁) Is exemplified as O-benzyl ether. So
Here, carbon tetrachloride is used in the presence of a catalytic amount of a strong acid such as trifluoromethanesulfonic acid.
44 and O-benzyl-1,1,1-tri at room temperature in a suitable inert organic solvent such as
By reacting chloroacetimidate, the protected acetyl
Alcohol 39a is obtained. Next, an inert organic solvent such as tetrahydrofuran
In a medium, acetylene is deprotonated with a base such as n-butyllithium, and then
Reacting with trialkylsilyl chloride such as triethylchlorosilane
Wherein the compound 39a is an acetylene of the general formula 39 wherein Z is a trialkylsilyl group.
(39b). Deprotonation and silylation reactions
For example, at temperatures as low as −78 ° C. to room temperature, with standard work-up and purification
And the silylacetylene of the formula 39b is obtained.

As described above, acetylenes of general formula 39c (Z is an aryl or substituted aryl group) are also useful in the indole synthesis shown in Scheme O. The aryl acetylenes 39c can be produced using a coupling reaction of copper acetylide derived from the acetylene alcohol of the formula 39a with various aryl halides or aryl triflates (45). With such a coupling reaction,
An arylacetylene compound of general formula 46 shown at the bottom of Scheme Q is prepared.
These reactions are carried out at elevated temperatures (typically 60-120 ° C.) in a basic organic solvent such as triethylamine, and the coupling reaction is carried out using a copper (I) such as cuprous iodide in combination with triphenylphosphine. ) Catalyzed by salts and palladium catalysts such as palladium acetate. Typically, the hydroxyl group of the arylacetylene compound of general formula 46 is then protected with a suitable protecting group, such as the O-benzyl ether group shown in Scheme Q, to form a compound of general formula 39 wherein Z is an aryl or substituted aryl group. Is obtained) aryl acetylene (39c). Further, it is clear that it may be preferable to reverse the order of the steps shown in Scheme Q. For example, after the silylation or arylation of the acetylene alcohol compound (44), the step of protecting the hydroxyl group can be performed.

[0069]

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[0070]Reaction scheme R  The acetylene compound of the general formula 39a is an aldehyde of the general formula 50 shown in the scheme R.
Can be produced by a method using a series of ethynylation reactions. A series of d
Aldehyde (50) used in the tynylation reaction is represented by the general formula 47
The protected hydroxy of formula 48 can be prepared using various methods known in the art of organic synthesis using ter as a starting material.
Alcohols from esters or related to the monohydroxy protected diol of formula 49
And the selection of the preferred raw materials depends on the selected substituent R⁹, R ^9a , R¹⁰And R^10aIs determined by the nature of Schematic R describes the general formula
The strategy using hydroxy ester 47 as a raw material is shown. For example,
Thus, by protecting the hydroxyl group of 47 as O-benzyl ether, the protection of formula 48 is achieved.
A protected hydroxyester is obtained. Next, the ester group of the compound of formula 48 is
Directly in a solvent such as ene using a reagent such as aluminum diisobutyl hydride.
, Or in a two-step procedure. In the latter case, tetrahi
An ester group is formed with a reagent such as lithium aluminum hydride in drofuran.
Reduction gives the alcohol of formula 49, which is then re-oxidized (eg,
, Swern-Moffatt oxidation) to give the desired aldehyde of formula 50.

The ethynylation of the aldehyde of formula 50 is performed in two steps. First, the aldehyde (50) is reacted with carbon tetrabromide and triphenylphosphine in an inert organic solvent such as methylene chloride to produce the dibromoolefin of Formula 51. Second, low temperature (
The dibromoolefin (51) is treated with two equivalents of a strong base such as n-butyllithium in tetrahydrofuran, for example at -78 ° C). The strong base undergoes dehydrohalogenation and metal-halogen exchange to give lithium acetylide, which, upon quenching and work-up, gives the acetylene compound of general formula 39a. Alternatively, the intermediate lithium acetylide formed in the reaction can be treated with a trialkylsilyl chloride such as triethylchlorosilane to provide silylacetylene of general formula 39b.

[0072]

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[0073]Reaction scheme S  2-Aryl substitution of general formula 40c of 2-silyl substituted indole of general formula 40b
Conversion to indole can be performed in two stages as shown in Scheme S. First stage
Is the conversion of a silyl-substituted indole of formula 40b to a 2-haloindole of general formula 52
This is a halo-desilylation reaction for performing the substitution. In Scheme S, using iodine monochloride,
Wherein the product is 2-iodoindole of general formula 52. This
In the example, silver tetrafluoroborate is also used to increase the reactivity of the halogenating reagent.
I have. Other electrophilic halogenations such as N-bromosuccinimide in methylene chloride
A halo-desilylation reaction using a reagent is performed to obtain a 2-bromoindole derivative.
Wherein both 2-bromo and 2-iodoindole of formula 52 are
Useful at a later stage.

The second step is a palladium-catalyzed cross-coupling reaction of 2-haloindole 52 with a suitable aryl or substituted aryl organometallic reagent 53. Scheme S illustrates this method using an aryl or substituted aryl boronic acid as the organometallic reagent. However, other organometallic reagents known to be used in palladium-catalyzed cross-coupling reactions such as arylboronic esters or arylstannanes can also be used. In the illustrated example, a complex of [1,1′-bis (diphenylphosphino) -ferrocene] dichloropalladium (II) with methylene chloride and a catalyst such as tetrakis (triphenylphosphine) -palladium (0) are used. Boronic acid (53) in which 2-iodoindole of the general formula 52 is described by the general formula
And coupling. The reaction is usually carried out at a temperature between room temperature and 100 ° C. (eg 80 ° C.).
). This palladium-catalyzed cross-coupling reaction can be carried out using various combinations of palladium catalysts and solvent compositions known in organic chemistry, and the selection of conditions depends on the type of organometallic reagent (53) used and the two types of This is performed according to the substituent in the raw material. When the organometallic reagent is a boronic acid or boronic ester, a preferred mixed solvent comprises toluene, ethanol and an aqueous solution of a base such as cesium carbonate or sodium carbonate. If instead the organometallic reagent 53 is an arylstannane, no additional base is required and a polar aprotic solvent such as tetrahydrofuran or dimethylformamide is used.

[0075]

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[0076]Reaction scheme T  As shown in Reaction Scheme T, tryptamine 33 is a component of the Mitsunobu reaction of Fukuyama.
It can be modified using modified methods (Fukuyama, T .; Jow, C.-K .; Cheung, M., Tetrahedron Lett ., 1995,36, 6373-74). Inert organic solvents such as methylene chloride
Medium, tryptamine 33 was converted to 2-nitrobenzenesulfonyl chloride,
Robenzenesulfonyl chloride or 2,4-dinitrobenzenesulfonylc
Arylsulfonyl chlorides such as chloride and 2,4,6-collidine;
With sterically hindered amine bases such as 2,6-lutidine to give the corresponding sulfonamido
Can be obtained. Alternatively, in an inert organic solvent such as methylene chloride
, 33 and the arylsulfonyl chloride in excess sodium bicarbonate aqueous solution
, The sulfonamide 54 can be produced. The sulfone
The amide may further comprise benzene, toluene, tetrahydrofuran or a mixture thereof.
Triphenylphosphine and diethylazodicarbo in an inert organic solvent such as
Activation of xylate (DEAD), diisopropyl azodicarboxylate, etc.
Modified by reaction with an alcohol in the form of 55 in the presence of
A rufonamide adduct can be obtained. In inert organic solvents such as methylene chloride
Dinitrobenzene by treatment with a nucleophilic amine such as n-propylamine.
Elimination of the sulfonyl group gives a secondary amine in the form of 56. Mononitrobenze
When a sulfonyl derivative is used, elimination of the sulfonamide is carried out by adding
More nucleophilic such as thiophenol or mercaptoacetic acid in combination with lithium
Perform using a highly reactive reagent.

[0077]

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[0078]Reaction scheme U  Scheme U shows the synthesis of new compounds of formula (I) that are complementary to Scheme T.
It shows how to complete it. In Scheme U, the same Mitsu as shown in Reaction Scheme T
A modified Fukuyama method of the knob reaction is used. However, in this case, the partner compound
The product alcohol is a 2-aryltryptohol of the general formula 57. Ben
In a suitable inert organic solvent such as zen, tetrahydrofuran, 1,4-dioxane
, A 2-aryltryptohol (57) is substituted with a substituted sulfonamide of the general formula 58;
React with triphenylphosphine and diethyl azodicarboxylate.
The reaction is allowed to proceed for 2 to 24 hours, typically overnight or about 12 to 16 hours.
Perform at warm. The product is an N, N-disubstituted sulfonamide, which
Each of them is reacted with a base such as n-propylamine to remove the sulfonamide substituent.
Separation gives the secondary amine related to Formula 57. Sulfonamido of formula 58 used
Can be prepared in an inert organic solvent such as methylene chloride in 2,4,6-collidine, 2,6-
Primary amine and 2-nitrobenzenes in the presence of sterically hindered amine bases such as lutidine
Rufonyl chloride, 4-nitrobenzenesulfonyl chloride or 2,4
-Dinitrobenzenesulfonyl chloride (shown). Synthesis
The final step requires the removal of the protecting group (PG2) on the indole nitrogen atom
, Thereby R⁰Is a hydrogen atom to obtain a compound of the general formula 56. Organic
Those skilled in the art will employ any of the series of synthetic reactions shown in Schemes T or U.
The prioritization of the compounds is performed by selecting the position selected to be present in the compound of formula (I).
It will be clear that this depends on the substituent.

[0079]

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[0080]Reaction scheme V  As shown in Reaction Scheme V, a suitable α, β-unsaturated carbonyl-containing
By treating with a compound, 2-aryltryptamine 33 can be modified.
You. Compound 59 may be substituted in various forms by (R) and has the property of “Z”
Depending on the quality, it can be a ketone, ester or amide. 33 and 59
The reaction is carried out at a temperature of 25 to 70 ° C. for 1 to 24 hours with inactive
The adduct 60 is obtained by proceeding in an organic solvent.

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.

[0082]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.

[0083]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 radioactive ligand was measured with a γ-counter. From the data,
IC of binding of radioligand to GnRH receptor in the presence of compound₅₀To estimate
Was.

[0084]LH release inhibition assay  The active compounds from the GnRH receptor binding assay were further evaluated in vitro.
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%.

[0086] 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 adenocarcinoma. Other sex hormone dependent conditions for which administration of the compounds of the 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. 4,369,795, U.S. Pat. No. 4,411,890, 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. No. 5,438,136,
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).

Typical 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-
Methylpropanamide; 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 may 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 prevention, especially bone loss prevention during treatment with a GnRH antagonist, can also be performed, in combination with estrogen, progesterone and / or androgen in combination with bone loss or transient during treatment with a GnRH antagonist. Prevention or treatment of hypogonadism syndrome such as hot sensation 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.

[0093] The literature discloses various bisphosphonic acids useful in the treatment and prevention of diseases involving bone resorption. Representative examples include U.S. Pat. Nos. 3,251,907, 3,422,137, 3,584,125, 3,940,436, 3,944,599, 3,962,432, and 40545.
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.
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. Organ. 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 (risudronic 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 alendronate (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-
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 .

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

In combination treatments wherein more than one active agent is used and the active agents are in separate formulations, 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 include, 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.

Oral formulations may also include the active ingredient in a hard gelatin capsule wherein 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 peanut oil, liquid paraffin or olive oil. It can also 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 condensation products of fatty acids such as polyoxyethylene stearate with alkylene oxides, or long chain aliphatic alcohols such as heptadecaethyleneoxycetanol and ethylene oxide. Or a condensation product of ethylene oxide with a partial ester derived from hexitol and a fatty acid such as polyoxyethylene sorbitol monooleate, 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 product such as a synthetic mono- or diglyceride can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The compounds of the formula I can 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 shall include mouthwashes 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 dose 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 can be administered in a single daily dose, or the total daily dose can be administered in two, three or four divided doses per day. 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.

Embodiment 1

[0116]

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(S) -1- (7-Azabicyclo [2.2.1] hept-7-yl) -2- [
3- (2-butylamino-1-methylethyl) -2- (3,5-dimethylphenyl
Ru) -1H-indol-5-yl] -2-methylpropan-1-oneStep 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).

[0118]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.

[0119]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 of a 5 mL solution of water).
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 afforded the title compound (2.52 g).

[0120]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.
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).

[0121]Step 1E: To (S)-{2- [5- [2- (7-azabicyclo [2.2.1]] Pt-7-yl) -1,1-dimethyl-2-oxo-ethyl] -2- (3,5- Dimethylphenyl) -1H-indol-3-yl] -propyl} -carbamine Acid tert-butyl ester  (S) -2- [3- (2-tert-butoxycarbonylamino-1-methyl
Ethyl) -2- (3,5-dimethylphenyl) -1H-indol-5-yl]
A stirred solution of -2-methylpropionic acid (2.5 g of dehydrated methylene chloride in 25 mL
Liquid) at 0 ° C with 1-hydroxybenzotriazole (1.0 g) and 1- (3
-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.24 g)
Was added and the reagents were mixed for 1 hour. At that point, 7-aza-bicyclo [2
. 2.1] A solution of heptane hydrochloride (1.44 g) is added and then triethylamine
1.5 mL was added and the reaction was stirred at room temperature. After 21 hours, the mixture was concentrated under reduced pressure.
And flash chromatography on silica gel (hexane: ethyl acetate,
1: 1) Purification was performed to obtain the title compound (2.6 g).

[0122]Step 1F: (S) -2- [3- (2-amino-1-methylethyl) -2- (3 , 5-Dimethylphenyl) -1H-indol-5-yl] -1- (7-azabi Cyclo [2.2.1] hept-7-yl) -2-methylpropan-1-one  (S)-{2- [5- [2- (7-Azabicyclo [2.2.1] hept-7-yl) -1,1-dimethyl-2-oxo-ethyl] -2- (3,5 -Dimethylf
Enyl) -1H-indol-3-yl] -propyl} -carbamic acid tert
-Butyl ester solution (2.6 g of methylene chloride solution in 90 mL) at 0 ° C.
5.2 mL of nisole and then 37 mL of trifluoroacetic acid are added and the mixture is stirred at 0 ° C.
Stirred. After 2 hours, the mixture was concentrated under reduced pressure and the remaining acid was azeotroped with toluene.
Therefore, it was removed. Flash chromatography purification on silica gel (methyl chloride
Ren: methanol: ammonium hydroxide, 90: 7: 1) to give the title compound.
(2.1 g).

[0123]Step 1G: (S) -1- (7-Azabicyclo [2.2.1] hept-7-yl ) -2- [3- (2-Butylamino-1-methylethyl) -2- (3,5-dimethyl) Tylphenyl) -1H-indol-5-yl] -2-methylpropan-1-o In  (S) -2- [3- (2-amino-1-methylethyl) -2- (3,5-dimension
Tylphenyl) -1H-indol-5-yl] -1- (7-azabicyclo [2
. 2.1] Hept-7-yl) -2-methylpropan-1-one solution (69 m
g of dehydrated chloroform (4 mL solution) at 0 ° C.
Then, 0.018 mL of butyraldehyde was added and the mixture was stirred at low temperature.
Thirty minutes later, a sodium borohydride solution (8.3 mg of methanol in 0.5 mL) was dissolved.
Liquid) was added and the reaction was allowed to proceed at 0 ° C. After 15 minutes, add saturated sodium bicarbonate
And the mixture was extracted with ethyl acetate. Organic layer saturated bicarbonate
It was washed with an aqueous solution of lithium and dried over sodium sulfate. Silica gel for concentrate
Chromatography purification (methylene chloride: methanol, 93: 7)
) To give the title compound (787 mg).

[0124]Production of synthetic intermediates  2- (3-bromo-4-hydrazinophenyl) -2-methylpropionic acid ethyl ester
LeStep A: Ethyl (+/-)-2- (4-nitrophenyl) propionate  9.76 g of (+/-)-2- (4-nitrophenyl) propionic acid (50 mm
ol) in anhydrous 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
Washed with 100 mL of aqueous solution of sodium chloride and then 100 mL of saturated aqueous solution of sodium chloride.
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.

[0125]Step B: Ethyl 2-methyl-2- (4-nitrophenyl) propionate  Dehydration of 924 mg (23 mmol) of sodium hydride (60% oil dispersion)
The N, N-dimethylformamide (21 mL) suspension was stirred in an ice bath under nitrogen.
Et al., 4.68 g of ethyl (+/-)-2- (4-nitrophenyl) propionate (
21 mmol) in dehydrated N, N-dimethylformamide (20.5 mL)
It was added slowly over 10 minutes. During the addition, a strong blue-purple color developed. Then raise the mixture
Warmed to room temperature. After about 1 hour, the mixture was cooled again in an ice bath and the internal temperature was reduced to 10
While maintaining at １５15 ° C., 1.44 mL of methyl iodide (3.28 g, 23 mmol
1) Dehydrated N, N-dimethylformamide (5 mL) solution was injected over about 10 minutes
It was dropped with a projectile. The mixture was warmed to room temperature and the color turned brown.
After 1 hour, an additional 187 mL of methyl iodide (426 mg, 3 mmol) was added.
. By the next day, the mixture was a suspension of a slightly grayish solid in a golden liquid
. Stir it vigorously and stop the reaction by slowly adding 10 mL of 5% aqueous potassium bisulfate solution
did. The mixture was partitioned between 400 mL of diethyl ether and 400 mL of water.
The organic layer is washed three times with an additional 400 mL of water and then saturated aqueous sodium chloride 50
Washed with mL. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure.
Was. Flash chromatography on silica gel of the residue (eluent:
19: 1 hexane-ethyl acetate) gave 4.31 g (87%) of an oil.
. It was homogeneous by TLC with 9: 1 hexane-ethyl acetate. 400
MHz¹H NMR (CDCl₃) Was consistent with the specified structure.

[0126]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 absolute ethanol
L mixture was shaken in a pressure vessel with hydrogen (initial hydrogen pressure 47 psig) for 2 hours.
Shaking. The catalyst was removed by celite filtration 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 lower 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).

[0127]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.

[0128]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 added dropwise 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-methylbutane
-1- onStep 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).

[0130]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 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).

[0131]Step CC: (R) -3- (3,5-dimethylbenzoyl) -4-methyldihydrido Lofran-2-one  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).

[0132]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).

The following compounds were prepared according to a method similar to that described in Example 1.

[0134]

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[0135]

[Table 14]

[0136]

[Table 15]

[0137]Example 1.1  2-aza-bicic instead of 7-aza-bicyclo [2.2.1] heptane hydrochloride
B [2.2.1] A method similar to the method described in Example 1 using octane-HCl.
The following compounds were produced according to the method.

[0138]

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[0139]

[Table 16]

[0140]

[Table 17] Example 1.2  2-aza-bicic instead of 7-aza-bicyclo [2.2.1] heptane hydrochloride
B) A method similar to the method described in Example 1 using [2.2.2] octane-HCl
The following compounds were produced according to the method.

[0141]

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[0142]

[Table 18] Example 2

[0143]

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(S) -1- (7-Aza-bicyclo [2.2.1] hept-7-yl) -2-
{2- (3,5-dimethylphenyl) -3-} 2- (4-hydroxypiperidine
-1-yl) -1-methylethyl] -1H-indol-5-yl} -2-methyl
Lupropan-1-oneStep 2A: (S) -2- {2- (3,5-dimethylphenyl) -3- [1-me Tyl-2- (4-oxo-piperidin-1-yl) -ethyl] -1H-indole Ru-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
To the ester solution (Example 1 Step 1B, 0.50 g of ethanol in 2 mL)
, Potassium carbonate 18 mg and then 1-ethyl-1-methyl-piperidinium
A solution of -4-one chloride (513 mg of a 0.80 mL solution of water) was added dropwise.
The mixture was heated to reflux in an oil bath. After 1 hour, cool the mixture to room temperature and add ethyl acetate.
Diluted with water, 10% aqueous sodium bisulfate, water, saturated aqueous sodium bicarbonate
And brine. The organic layer is dried over sodium sulfate and concentrated under reduced pressure.
And flash chromatography on silica gel for residue.
Sun: ethyl acetate, 7: 3) to give the title compound (356 mg).

[0145]Step 2B: (S) -2- {2- (3,5-dimethylphenyl) -3- [1-me Tyl-2- (4-oxo-piperidin-1-yl) -ethyl] -1H-indole Ru-5-yl} -2-methylpropionic acid  (S) -2- {2- (3,5-dimension) substantially according to the method described in Example 1, Step D.
Tylphenyl) -3- [1-methyl-2- (4-oxo-piperidin-1-yl
) -Ethyl] -1H-indol-5-yl} -2-methylpropionate
The title compound was obtained from the ester (356 mg) (156 mg).

[0146]Step 2C: (S) -1- {2- [5- [2- (7-aza-bicyclo [2.2. 1] Hept-7-yl) -1,1-dimethyl-2-oxo-ethyl] -2- (3 , 5-Dimethylphenyl) -1H-indol-3-yl {-propyl} -pipe Lysin-4-one  (S) -2- {2- (3,5-dimethylphenyl) -3- [1-methyl-2-
(4-oxo-piperidin-1-yl) -ethyl] -1H-indole-5-i
A solution of ru-2-methylpropionic acid (2 mg of 148 mg of dehydrated methylene chloride
Solution), 58 mg of 7-aza-bicyclo [2.2.1] heptane hydrochloride was added, and
0.185 mL of triethylamine and 173 mg of PyBOP reagent were added to the mixture, and mixed.
The mixture was stirred at room temperature. After 14 hours, the mixture was concentrated under reduced pressure and the residue was
Dissolve in chill, wash with water and brine, dry organic layer over sodium sulfate
. The concentrate is purified by flash chromatography on silica gel (acetic acid
Chill: hexane, 3: 2) to give the title compound (128 mg).

[0147]Step 2D: (S) -1- (7-aza-bicyclo [2.2.1] hept-7-i ) -2- {2- (3,5-dimethylphenyl) -3-} 2- (4-hydroxy Piperidin-1-yl) -1-methylethyl] -1H-indol-5-yl} -2-methylpropan-1-one  (S) -1- {2- [5- [2- (7-aza-bicyclo [2.2.1] hept]
-7-yl) -1,1-dimethyl-2-oxo-ethyl] -2- (3,5-dimethyl
Hydrogenation at 0 ° C. to a solution of (tylphenyl) -1H-indol-3-yl] -propyl} -piperidin-4-one (15 mg of a 0.10 mL solution of dehydrated methanol).
Add sodium borohydride solution (1 mg solution of methanol in 0.15 mL) and mix
The thing was stirred at low temperature. After 4 hours, the solvent was removed under reduced pressure and the residue was treated with silica.
Flash chromatography purification on gel (methylene chloride: methanol, 9: 9
1) was performed to obtain the title compound (14 mg).

The following compounds were prepared according to a method similar to that described in Example 2.

[0149]

Embedded image

[0150]

[Table 19]

[0151]Example 3  Following a method similar to that described in Example 1, Steps C and E, the following compounds were
Manufactured.

[0152]

Embedded image

[0153]

[Table 20]

Embodiment 4

[0155]

Embedded image (S) -1- (7-Aza-bicyclo [2.2.1] hept-7-yl) -2-
{2- (3,5-dimethylphenyl) -3- {1-methyl-2- (2-morpholy
-4-yl-ethylamino) -ethyl] -1H-indol-5-yl} -2
-Methylpropan-1-oneStep 4A: (S) -N- ｛2- [5- [2- (7-azabicyclo [2.2.1] ] Hept-7-yl) -1,1-dimethyl-2-oxo-ethyl] -2- (3, 5-dimethylphenyl) -1H-indol-3-yl] -propyl} -2,4 -Dinitrobenzenesulfonamide  (S) -2- [3- (2-amino-1-methylethyl) -2- (3,5-dimension
Tylphenyl) -1H-indol-5-yl] -1- (7-azabicyclo [2
. 2.1] Hept-7-yl) -2-methylpropan-1-one solution (1.1
g, 15 mL of dehydrated methylene chloride) at 0 ° C. in 1.3 m of 2,4,6-collidine.
L, and then 1.3 g of 2,4-dinitrobenzenesulfonyl chloride.
The mixture was gradually warmed to room temperature. After 20 hours, the mixture was diluted with ethyl acetate.
And washed with brine, and the organic layer was concentrated under reduced pressure. Flash on silica gel
Chromatography purification (ethyl acetate: hexane, 1: 4, then 2: 3, then
3: 2, then 4: 1) gave the title compound (1.57 g).

[0156]Step 4B: (S) -N- {2- [5- [2- (7-aza-bicyclo [2.2. 1] Hept-7-yl) -1,1-dimethyl-2-oxo-ethyl] -2- (3 , 5-Dimethylphenyl) -1H-indol-3-yl] -propyl} -N- (2-morpholin-4-yl-ethyl) -2,4-dinitrobenzenesulfone Mid  (S) -N- {2- [5- [2- (7-azabicyclo [2.2.1] hept-
7-yl) -1,1-dimethyl-2-oxo-ethyl] -2- (3,5-dimethyl)
Ruphenyl) -1H-indol-3-yl] -propyl} -2,4-dinitro
Benzenesulfonamide solution (52.5 mg of dehydrated benzene 1.6 mL solution)
To this was added 20.3 mg of 2-morpholin-4-yl-ethanol and then
Nylphosphine 40.8 mg and diethyl azodicarboxylate 0.025 mL
It was dropped. After 20 minutes, the mixture was concentrated and the crude reaction product was run on silica gel.
Perform flash chromatography purification (ethyl acetate: hexane, 1: 3)
The title compound was obtained (95.2 mg).

[0157]Step 4C: (S) -1- (7-aza-bicyclo [2.2.1] hept-7-i -)-2- {2- (3,5-dimethylphenyl) -3- {1-methyl-2- (2 -Morpholin-4-yl-ethylamino) -ethyl] -1H-indole-5- Yl @ -2-methylpropan-1-one  (S) -N- {2- [5- [2- (7-aza-bicyclo [2.2.1] hept]
-7-yl) -1,1-dimethyl-2-oxo-ethyl] -2- (3,5-dimethyl
Tylphenyl) -1H-indol-3-yl] -propyl} -N- (2-mol
(Holin-4-yl-ethyl) -2,4-dinitrobenzenesulfonamide solution
(61.3 mg of dehydrated methylene chloride (1.4 mL)) and n-propylamine (0.1 mL).
30 mL was added and the mixture was stirred at room temperature. 60 minutes later, add water to stop the reaction
Stop, extract with ethyl acetate, wash the combined organic layers with saturated aqueous sodium bicarbonate
Was cleaned. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. About residue
, Flash chromatography purification on silica gel (methylene chloride: methanol)
92: 8, then methylene chloride: methanol: ammonium hydroxide 90: 7: 1
) To give the title compound (39 mg).

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

[0159]

Embedded image

[0160]

[Table 21]

[0161]

[Table 22]

Embodiment 4.1

[0163]

Embedded image

(S) -3- {2- [5- [2- (2-aza-bicyclo [2.2.2] oct]
-2-yl) -1,1-dimethyl-2-oxo-ethyl] -2- (3,5-dimethyl
Tylphenyl) -1H-indol-3-yl] -propylamino} -propio
AcidStep 4.1A: (S) -3- {2- [5- [2- (2-aza-bicyclo [2. 2.2] Oct-2-yl) -1,1-dimethyl-2-oxo-ethyl] -2- (3,5-dimethyl-phenyl) -1H-indol-3-yl] -propyla Mino} -propionic acid tert-butyl ester  (S) -2- [3- (2-amino-1-methylethyl) -2- (3,5-dimension
Tylphenyl) -1H-indol-5-yl] -1- (2-aza-bicyclo [
2.2.2] Oct-2-yl) -2-methylpropan-1-one solution (24
8.6 mg of anhydrous ethanol (2.0 mL solution) in tert-butyl acrylate
0.080 mL was added and the mixture was heated to 70 ° C. in an oil bath. After 3 hours, mix
The material was cooled to room temperature and concentrated under reduced pressure. For residue, filter on silica gel.
By rush chromatography purification (methylene chloride: methanol, 94: 6)
Thus, the title compound was obtained (232 mg).

[0165]Step 4.1B: (S) -3- {2- [5- [2- (2-aza-bicyclo [2. 2.2] Oct-2-yl) -1,1-dimethyl-2-oxo-ethyl] -2- (3,5-dimethylphenyl) -1H-indol-3-yl] -propylamido Nodi-propionic acid  (S) -3- {2- [5- [2- (2-aza-bicyclo [2.2.2] oct]
-2-yl) -1,1-dimethyl-2-oxo-ethyl] -2- (3,5-dimethyl
Tyl-phenyl) -1H-indol-3-yl] -propylamino} -propyl
A solution of tert-butyl onionate (248 mg of dehydrated methylene chloride 9.0)
0.50 mL of anisole, and then 3 mL of trifluoroacetic acid.
The mixture was stirred at room temperature. After 7 hours, the mixture was concentrated under reduced pressure. HPL
C purification (RPC-8, methanol: water: trifluoroacetic acid, gradient 65: 35: 0)
. 1 to 75: 25: 0.1) to give the title compound as the trifluoroacetate salt.
(241 mg).

The following compounds were prepared according to the methods described above and in the same manner as in Example 4.

[0167]

Embedded image

[0168]

[Table 23]

[0169]

[Table 24]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 11/00 A61P 11/00 15/00 15/00 15/18 15/18 17/00 17/00 25 / 20 25/20 35/00 35/00 43/00 111 43/00 111 C07D 453/06 C07D 453/06 // C07D 209/14 209/14 (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 (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AU, A , BA, BB, BG, BR, BY, CA, CN, CU, CZ, EE, GD, GE, HR, HU, ID, IL, 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 Gourette, Mark Tay United States, New Jersey 07065, Lowway, East Lincoln Avenue 126 (72) Inventor Walcille, Thomas F United States, New Jersey 07065, Lowway, East Lincoln Avenue 126 (72) Inventor Wittkin, Stephanie L. United States, New Jersey 07065, Lowway, East Linker Avenue 126 (72) Inventor Weibrat, Massie J. United States, New Jersey 07065, Lowway, East Lincoln Avenille 126 F-term (reference) 4C064 AA08 CC01 DD01 FF06 GG09 4C086 AA01 AA03 BC13 BC21 BC42 BC73 CB03 CB14 CB17 GA09 MA01 MA04 NA14 ZA05 ZA86 ZB26 ZC03 4C204 CB04 DB30 EB03 FB09 GB31

Claims (27)

[Claims] 1. A compound of the following formula: or a pharmaceutically acceptable addition salt of said compound.
And / or hydrates or, where applicable, geometric isomers or
Is an optical isomer or a racemic mixture. Embedded image [Where R⁰Is hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆Alkyl (substituents are
Aryl, substituted aryl, aralkyl or substituted aralkyl
Kill (substituent is R³, R⁴And R⁵R is defined as above); R¹And R²Is independently hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆Archi
Le, C₃~ C₇Cycloalkyl, substituted C₃~ C₇Cycloalkyl, N, O or
Is a heterocyclic or bicyclic heterocyclic ring having 1 to 4 heteroatoms selected from S
(R³, R⁴And R⁵Or N, O or S
A heterocyclic or bicyclic heterocyclic ring having 1 to 4 heteroatoms (R³ , R⁴And R⁵Which is optionally substituted by₁ ~ C₆Alkyl, C₃~ C₆Alkenyl, substituted C₃~ C₆Alkenyl, C₃~ C ₆ Alkynyl, substituted C₃~ C₆Alkynyl, C₀~ C₅-Alkyl-S (O)_n -C₀~ C₅Alkyl, C₂~ C₆Alkyl (NR¹¹R¹²), C₂~ C₆A
Lequil (OR¹¹) Or C₁~ C₆Alkyl (CONR¹¹R¹²) Is;
Where R¹¹And R¹²Independently or together, aryl, substituted aryl,
Not aralkyl and substituted aralkyl; or R¹And R²Are integrated, and 0, 1 if selected from S, O or N
Or an optionally substituted non-heteroaromatic 3 to 2
Forming an 8-membered ring; 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
, Aryl or substituted aryl; or 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-, NR²¹C (O) R²⁰, NR²¹C (O) NR²⁰R^{2 1} Or SO_nR²⁰R⁷Is hydrogen, C₁~ C₆Alkyl or substituted C₁~ C₆R is alkyl;⁸Is C (O) OR²⁰, C (O) NR²⁰R²¹, NR²⁰R²¹, C (
O) R²⁰, NR²¹C (O) R²⁰, NR²¹C (O) NR²⁰R²¹, NR ²⁰ S (O)₂R²¹, NR²¹S (O)₂NR²⁰R²¹, OC (O) R²⁰ , OC (O) NR²⁰R²¹, OR²⁰, SO_nR²⁰, S (O)_nNR²⁰R ²¹ , A heteroaromatic ring or a substituted heteroaromatic ring, N, O or S
A heterocyclic or bicyclic heterocyclic ring having 1 to 4 heteroatoms (R³, R⁴And
And R⁵May be substituted), C₁~ C₆Alkyl or substituted C₁~ C₆A
Or R.⁷And R⁸Together form one or more heteroatoms selected from N, O and S
Heterocycle having a child (R³, R⁴And R⁵May be substituted) to form
And if m ≠ 0, R⁹And R^9aIs independently hydrogen, C₁~ C₆Alkyl, place
Exchange 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
ＯO; 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 ≠ 0, R⁹And R¹⁰Together form a 3- to 7-membered carbon ring or 1
Forming a heterocyclic ring having the above heteroatoms; or, when m ≠ 0, R⁹And R²Together form 3 to 7 carbon atoms and 1
Forming a heterocycle with the above heteroatoms;¹⁰And R²Together form 3 to 7 carbon atoms and one or more heteroatoms
R to form a heterocyclic ring having¹¹And 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
R²⁰And R²¹Is independently hydrogen, C₁~ C₆Alkyl, substituted C₁~ C₆A
Alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaromatic ring
Or a substituted heteroaromatic ring, a 3- to 7-membered carbocyclic ring, a 3- to 7-membered substituted carbocyclic ring, N, O
Or a heterocyclic or bicyclic ring having 1 to 4 heteroatoms selected from S
Heterocycle (R³, R⁴And R⁵Or N, O if
Or a heterocyclic or bicyclic heterocycle having 1 to 4 heteroatoms selected from S
Ring (R³, R⁴And R⁵Which may be substituted by ₁ ~ C₆Is alkyl; or R²⁰And R²¹Is a 3- to 9-membered optionally substituted ring or
X may be N, O, S (O)_n, C (O), (CR¹¹R¹²)_p, R⁸Single bond to
, C₂~ C₆Alkenyl, substituted C₂~ C₆Alkenyl, C₂~ C₆Alkynil
Or substitution C₂~ C₆X is O, S (O)_n, C (O) or C
R¹¹R¹²In the case of R⁸M is from 0 to 3; n is from 0 to 2; p is from 0 to 4;
The substituent is C₁~ C₆Alkyl, C₃~ C₇Cycloalkyl, aryl, substituted ant
Aralkyl, substituted aralkyl, hydroxyl, oxo, cyano, C₁~ C₆Al
Coxy, fluorine, C (O) OR¹¹, Aryl C₁~ C₃Alkoxy, substituted ant
C₁~ C₃Selected from alkoxy; the aryl substituent is R³, R⁴And R ⁵ As defined above. ] 2. R ⁷ and R ⁸ are taken together to form 7-aza-bicyclo [2.2
. 1] The compound according to claim 1, which forms heptane or 2-aza-bicyclo [2.2.2] octane. 3. The compound according to claim 1, which has a structure of the following formula. Embedded image (In the formula, R ¹ and R ² are as shown in the following table.) [Table 2] [Table 3] 4. The compound according to claim 1, which has a structure of the following formula. Embedded image (In the formula, -NR ¹ / R ² is as shown in the following table.) 5. The compound according to claim 1, which has a structure of the following formula: Embedded image (In the formula, R ¹ and R ² are as shown in the following table.) 6. The compound according to claim 1, which has a structure of the following formula: Embedded image (In the formula, R ¹ and R ² are as shown in the following table.) [Table 7] [Table 8] 7. The compound according to claim 1, which has a structure of the following formula. Embedded image (In the formula, R ¹ and R ² are as shown in the following table.) 8. The compound according to claim 1, which has a structure of the following formula. Embedded image (In the formula, R is as shown in the following table.) [Table 11] 9. The compound according to claim 1, which has a structure of the following formula. Embedded image (In the formula, R is as shown in the following table.) [Table 13] 10. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 11. A method for 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. 12. The method according to claim 11, wherein the gonadotropin-releasing hormone-derived disorder is a sex hormone-related condition. 13. The method according to claim 11, wherein the disorder derived from gonadotropin-releasing hormone is a sex hormone-dependent cancer, benign prostatic hyperplasia or uterine fibroid. 14. The method according to claim 13, wherein the sex hormone-dependent cancer is selected from the group consisting of prostate cancer, uterine cancer, breast cancer and pituitary gonadotropin adenocarcinoma. 15. The method of claim 12, wherein the sex hormone-related condition is selected from the group consisting of endometriosis, polycystic ovary, uterine fibroids, and precocious puberty. 16. 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. 17. A method of treating systemic lupus erythematosus in a patient in need of treatment, said method comprising administering to said patient an effective amount of a compound of claim 1. 18. A method of treating irritable bowel syndrome in a patient in need of such treatment, comprising administering to said patient an effective amount of a compound of claim 1. 19. A method of treating premenstrual syndrome in a patient in need of such treatment, comprising administering to said patient an effective amount of a compound of claim 1. 20. 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. 21. 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 growth hormone. A method comprising administering the compound of claim 1. 22. A method of treating a sleep disorder in a patient in need of such treatment, comprising administering to said patient an effective amount of a compound of claim 1. 23. The method of claim 22, wherein said sleep disorder is sleep apnea. 24. 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. 25. A pharmaceutical composition produced by combining the compound of claim 1 with a pharmaceutically acceptable carrier. 26. A method for producing a pharmaceutical composition, comprising the step of combining the compound of claim 1 with a pharmaceutically acceptable carrier. 27. A method of treating bone loss during treatment with a GnRH antagonist, comprising co-administering an effective amount of estrogen, progesterone and androgen with an effective amount of a compound of claim 1.