KR19990072124A - Antagonists of gonadotropin releasing hormone - Google Patents

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof, which are useful as antagonists of GnRH and which are themselves useful in the treatment of various sex hormone related and other conditions in both men and women, are described.

Formula I

Description

Antagonists of gonadotropin-releasing hormone

Gonadotropin-releasing hormone (GnRH), also referred to as luteinizing hormone-releasing hormone (LHRH), is a 10-peptide that plays an important role in human reproduction. The hormone is released from the hypothalamus and acts on the pituitary gland to stimulate the biosynthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH released from the pituitary gland is primarily involved in regulating gonad steroid production in both men and women, while FSH regulates spermatogenesis in men and follicle development in women. GnRH agonists and antagonists have proven effective in treating certain conditions that require inhibition of LH / FSH release. In particular, GnRH-based therapies have proven to be effective in the treatment of endometriosis, uterine fibroids, polycystic ovarian disease, spring spondylosis and some gonad steroid-dependent neoplasias, especially prostate, breast and ovarian cancer. In addition, GnRH agonists and antagonists are widely used to assist in fertilization techniques and have been studied as potential pregnancy control agents in both men and women. In addition, they grow in rats of growth hormone deficient children and lupus in the treatment of pituitary gonadotrophic adenoma, sleep disorders (eg sleep suffocation), pizza polar bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, and hirsutism. It has been found to be useful as an adjunct to hormonal therapy. The compounds of the present invention secrete bisphosphonates (bisphosphonic acids) and other agents, such as growth hormones, for the treatment and prevention of disorders of calcium, phosphate and bone metabolism, in particular to prevent bone loss during treatment with GnRH antagonists. Estrogens, progesterones, antiesterones, used in combination with accelerators (e.g. MK-0677), or for the prevention and treatment of bone loss or hypogonadism, such as hot flashes, during treatment with GnRH antagonists It can be used in combination with antiprogestin and / or androgen.

In addition, the compounds of the present invention may be selected from 5α-reductase 2 inhibitors such as finasteride or epristeride; 5α-reductase 1 inhibitors such as 4,7β-dimethyl-4-aza-5α-cholestan-3-one, 3-oxo-4-aza-4,7β-dimethyl-16β- (4-chlorophenoxy C) -5α-androstan and 3-oxo-4-aza-4,7β-dimethyl-16β- (phenoxy) -5α-androstane (WO 93/23420 and WO 95/11254); Double inhibitors of 5α-reductase 1 and 5α-reductase 2, for example 3-oxo-4-aza-17β- (2,5-trifluoromethylphenyl-carbamoyl) -5α-androstane [WO 95/07927; It may be administered in combination with antiandrogens such as flutamide, carsodex and cyproterone acetate, and alpha-1 blockers such as prazosin, terrazosin, doxazosin, tamsulosin and alfuzosin.

In addition, the compounds of the present invention may be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues to delay the adolescence of a growth hormone deficient child, thereby allowing the child to continue to stretch before the physiolysis fuses and growth stops in adolescence. It allows you to.

Current GnRH antagonists are GnRH-like 10-peptides, which are generally administered intravenously or subcutaneously due to negligible oral activity. They typically have amino acid substituents at the 1, 2, 3, 6 and 10 positions.

Non-peptide GnRH antagonists offer the benefit of oral administration. Non-peptide GnRH antagonists are described in European Patent Application No. 0 219 292, De, B. et al., J. Med. Chem., 32, 2036-2038 (1989), WO 95/28405, WO 95/29900 and EP 0679642; All of these are owned by Takeda Chemical Industries, Ltd.].

Substituted indole known in the art includes those described in the following patents and patent applications. U.S. Patent 5,030,640 describes alpha-heterocyclic ethanol aminoalkyl indole, a potent β-agent. US Pat. No. 4,544,663 describes indoleamine derivatives which are claimed to be useful as male contraceptives. WO 90/05721 describes alpha-amino-indole-3-acetic acid which is useful as an anti-diabetic, anti-obesity and anti-atherosclerotic agent. French Patent No. 2,181,559 describes indole derivatives with sedative, neuroleptic, analgesic, hypotensive, antiserotoninic and antiadrenergic activity. Belgian patent no. 879381 describes 3-aminoalkyl-1H-indole-5-thioamide and carboxamide derivatives which are cardiovascular agents used to treat hypertension, Raynaud's disease and migraine headaches.

Summary of the Invention

The present invention relates to a compound which is a non-peptide antagonist of GnRH which can be used to treat various sex-hormone related conditions in men and women, and methods for its preparation and pharmaceutical compositions for mammals comprising the compound.

Because of the activity of the hormone GnRH as an antagonist, the compounds of the present invention are useful for treating various sex-hormone related conditions in both men and women. These conditions include endometriosis, uterine fibroids, polycystic ovarian disease, hirsutism, spermatozoa, gonadotropin-dependent neoplasia such as prostate, breast and ovarian cancer, pituitary gonadotrophic adenoma, sleep choking, pizza polar bowel syndrome, Premenstrual syndrome and benign prostatic hyperplasia. In addition, they are useful as therapeutic aids for growth hormone deficiency and short stature and for the treatment of systemic lupus erythematosus. The compounds of the invention are also useful in in vitro fertilization and as fertility control agents. The compounds may also be used in combination with androgens, estrogens, progesterones, antiestrogens and antiprogestogens in the treatment and contraception of endometriosis and fibrosis. They can also be mixed with testosterone or other androgens or antiprogestogens and used as male pregnancy control agents. In addition, the present compounds can be used in combination with angiotensin-converting enzyme inhibitors such as Enalapril or Captopril, angiotensin II-receptor antagonists such as Losartan, or renin inhibitors in the treatment of uterine fibroids. Moreover, the compounds of the present invention may be used in combination with bisphosphonates (bisphosphonic acids) and other agents to treat and prevent the disorders of calcium, phosphate and bone metabolism, in particular to prevent bone loss during treatment with GnRH antagonists or , In combination with estrogens, progesterone and / or androgens for the prevention or treatment of bone loss or hypogonadism, such as heat scintillation, during treatment with GnRH antagonists.

In addition, the compounds of the present invention may be selected from 5α-reductase 2 inhibitors such as finasteride or epristeride; 5α-reductase 1 inhibitors such as 4,7β-dimethyl-4-aza-5α-cholestan-3-one, 3-oxo-4-aza-4,7β-dimethyl-16β- (4-chlorophenoxy C) -5α-androstan and 3-oxo-4-aza-4,7β-dimethyl-16β- (phenoxy) -5α-androstane (WO 93/23420 and WO 95/11254); Double inhibitors of 5α-reductase 1 and 5α-reductase 2, for example 3-oxo-4-aza-17β- (2,5-trifluoromethylphenyl-carbamoyl) -5α-androstane [WO 95/07927; It may be administered in combination with antiandrogens such as flutamide, carsodex and cyproterone acetate, and alpha-1 blockers such as prazosin, terrazosin, doxazosin, tamsulosin and alfuzosin.

In addition, the compounds of the present invention may be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues to delay the adolescence of a growth hormone deficient child, thereby allowing the child to continue to stretch before the physiolysis fuses and growth stops in adolescence. It allows you to.

The present invention relates to compounds of formula (I) or pharmaceutically acceptable addition salts and / or hydrates thereof, where appropriate geometric or optical isomers or racemic mixtures thereof.

In the above formula,

A is C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, substituted C ₃ -C ₇ cycloalkyl, C ₃ -C ₆ alkenyl, substituted C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, substituted C ₃ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, or C ₀ -C ₅ alkyl-S (O) _n -C ₀ -C ₅ alkyl, C ₀ -C ₅ alkyl-OC ₀ -C ₅ alkyl, C ₀ -C ₅ alkyl-NR ₁₈ -C ₀ -C ₅ alkyl, where R ₁₈ and C ₀ -C ₅ alkyl are linked Or a single bond,

R ₀ is hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl where the substituents are as defined below, aryl, substituted aryl, aralkyl or substituted aralkyl where the substituents are As defined in R ₃ , R ₄ and R ₅ );

R ₁ is ego;

R ₂ is hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, alkyl-OR ₁₁ , C ₁ -C ₆ (NR ₁₁ R ₁₂ ), C ₁ -C ₆ (CONR ₁₁ R ₁₂ ) or C (NR ₁₁ R ₁₂ ) NH,

R ₂ and A together form a 5 to 7 membered ring;

R ₃ , R ₄ and R ₅ are independently hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl, CN, nitro , C ₁ -C ₃ perfluoroalkyl, C ₁ -C ₃ perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, R ₁₁ O (CH ₂ ) _P- , R ₁₁ C (O ) O (CH ₂ ) _P- , R ₁₁ OC (O) (CH ₂ ) _P -,-(CH ₂ ) _P S (O) _n R ₁₇ , wherein R ₁₇ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₃ perfluoroalkyl, aryl or substituted aryl),-(CH ₂ ) _P C (O) NR ₁₁ R ₁₂ or halogen,

R ₃ and R ₄ together form a carbocyclic ring of 3 to 7 carbon atoms or a heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and S,

R ₆ is hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, aryl, substituted aryl, C ₁ -C ₃ perfluoroalkyl, CN, NO ₂ , halogen, R ₁₁ O (CH ₂ ) _P- , NR ₁₂ C (O) R ₁₁ , NR ₁₂ C (O) NR ₁₁ R ₁₂ or SO _n R ₁₁ ,

R ₇ is hydrogen, C ₁ -C ₆ alkyl, or substituted C ₁ -C ₆ alkyl, provided that R ₇ is absent when X is not hydrogen or halogen,

R ₈ is hydrogen, C (O) OR ₉ , C (O) NR ₁₁ R ₁₂ , NR ₁₁ R ₁₂ , C (O) R ₁₁ , NR ₁₂ C (O) R ₁₁ , NR ₁₂ C (O) NR ₁₁ R ₁₂ , NR ₁₂ S (O) ₂ R ₁₁ , NR ₁₂ S (O) ₂ NR ₁₁ R ₁₂ , OC (O) R ₁₁ , OC (O) NR ₁₁ R ₁₂ , OR ₁₁ , SO _n R ₁₁ , S (O) _n NR ₁₁ R ₁₂ , C ₁ -C ₆ alkyl or substituted C ₁ -C ₆ alkyl, provided that when ₈ is not hydrogen or halogen, R ₈ is absent,

R ₇ and R ₈ together form a 3-7 membered carbocyclic ring,

R ₉ and R _9a are independently hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, aryl or substituted aryl, aralkyl or substituted aralkyl when m is not 0;

R ₉ and R _9a together are a 3-7 membered carbocyclic ring when m is not 0, or Form the

R ₉ and A form a heterocyclic ring comprising 3 to 7 carbon atoms and one or more heteroatoms when m is not 0, or

R ₁₀ and R _10a are independently hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl,

R ₁₀ and R _10a together are a 3-7 membered carbocyclic ring or Form the

R ₉ and R ₁₀ together form a carbocyclic ring of 3 to 7 carbon atoms or a heterocyclic ring comprising one or more heteroatoms when m is not 0, or

R ₉ and R ₂ together form a heterocyclic ring comprising 3 to 7 carbon atoms and one or more heteroatoms when m is not 0, or

R ₁₀ and R ₂ together form a heterocyclic ring comprising 3 to 7 carbon atoms and one or more heteroatoms,

R ₁₀ and A together form a heterocyclic ring comprising 3 to 7 carbon atoms and one or more heteroatoms,

R ₁₁ and R ₁₂ are independently hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, a 3-7 membered carbocyclic ring or A substituted carbocyclic ring containing 3 to 7 atoms,

R ₁₁ and R ₁₂ together may form an unsubstituted or substituted 3-7 membered ring,

R ₁₃ is hydrogen, OH, NR ₇ R ₈ , NR ₁₁ SO ₂ (C ₁ -C ₆ alkyl), NR ₁₁ SO ₂ (substituted C ₁ -C ₆ alkyl), NR ₁₁ SO ₂ (aryl), NR ₁₁ SO ₂ (substituted aryl), NR ₁₁ SO ₂ (C ₁ -C ₃ perfluoroalkyl), SO ₂ NR ₁₁ (C ₁ -C ₆ alkyl), SO ₂ NR ₁₁ (substituted C ₁ -C ₆ alkyl ), SO ₂ NR ₁₁ (aryl), SO ₂ NR ₁₁ (substituted aryl), SO ₂ NR ₁₁ (C ₁ -C ₃ perfluoroalkyl), SO ₂ NR ₁₁ (C (O) C ₁ -C ₆ Alkyl), SO ₂ NR ₁₁ (C (O) -substituted C ₁ -C ₆ alkyl), SO ₂ NR ₁₁ (C (O) -aryl), SO ₂ NR ₁₁ (C (O) -substituted aryl) , S (O) _n (C ₁ -C ₆ alkyl), S (O) _n (substituted C ₁ -C ₆ alkyl), S (O) _n (aryl), S (O) _n (substituted aryl) , C ₁ -C ₃ perfluoroalkyl, C ₁ -C ₃ perfluoroalkoxy, C ₁ -C ₆ alkoxy, substituted C ₁ -C ₆ alkoxy, COOH, halogen, NO ₂ or CN,

R ₁₄ and R ₁₅ are independently hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, substituted C _2- C ₆ Al, CN, nitro, C ₁ -C ₃ perfluoroalkyl, C ₁ -C ₃ perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, R ₁₁ O (CH ₂ ) _p- , R ₁₁ C (O) O ( CH ₂ ) _p- , R ₁₁ OC (O) (CH ₂ ) _P -,-(CH ₂ ) _P S (O) _n R ₁₇ , wherein R ₁₇ is hydrogen, C ₁ -C ₆ alkyl, C _1- C ₃ perfluoroalkyl, aryl or substituted aryl),-(CH ₂ ) _P C (O) NR ₁₁ R ₁₂ or halogen;

R ₁₆ is hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl or N (R ₁₁ R ₁₂ ),

R ₁₈ is hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C (O) OR ₉ , C (O) NR ₁₁ R ₁₂ , C (O) R ₁₁ , S (O) _n R ₁₁ ,

R ₁₉ is as defined in R ₁₃ or R ₁₄ ,

X is hydrogen, halogen, N, O, S (O) _n , C (O), (CR ₁₁ R ₁₂ ) _p , C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl, C _2- C ₆ alkynyl, or substituted C ₂ -C ₆ alkynyl, when X is hydrogen or halogen R ₇ and R ₈ are absent, and _{X O, S (O) n} , C (O), or CR ₁₁ For R ₁₂ only R ₇ or R ₈ is possible,

Z is O, S or NR ₁₁ ,

m is 0 to 3,

n is 0 to 2,

p is 0 to 4,

Alkyl, alkenyl and alkynyl substituents include C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, hydroxy, oxo, cyano, C ₁ -C ₆ alkoxy, fluoro, C (O) OR ₁₁ , aryl C ₁ -C ₃ alkoxy, substituted aryl C ₁ -C ₃ alkoxy and the aryl substituents are as defined in R ₃ , R ₄ and R ₅ .

Unless otherwise stated or indicated, the following definitions will apply throughout the specification and claims.

If a particular variant (eg, aryl, heteroaryl, R ₁ , etc.) is present in one or more of a particular constituent or formula I, its definition at each occurrence is separate from the definition at all else present. to be. In addition, combinations of substituents and / or variants may only be tolerated if such combinations result in stable compounds.

The term "alkyl" refers to both saturated and straight chain saturated hydrocarbon groups having a certain number of carbon atoms, for example methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl , Decyl, undecyl, dodecyl; And isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), secondary-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane, and the like. It is understood to include.

The term "aryl" includes phenyl and naphthyl. Preferably, aryl is phenyl.

The term "halogen" or "halo" is understood to include fluorine, chlorine, bromine and iodine.

As used herein, the term "composition" is understood to include products that contain a particular amount of a particular component, as well as all products that are produced directly or indirectly as a result of the combination of a particular amount of a particular component.

Linking group A may be bonded to any of the available carbon or heteroatoms of the heteroaromatic group, including all rings of the benzo-fused heterocyclic group, and likewise, R ₁₃ , R ₁₄ and R ₁₅ are also It may be bonded to any one of the available carbon atoms of heteroaromatic group R ₁ .

It is also well known to those skilled in the art that many of the aforementioned heterocyclic groups may exist in one or more tautomeric forms. All such tautomers are understood to be within the scope of the present invention.

Also included are optical isomeric forms of the invention, ie mixtures of enantiomers or diastereomers (eg racemates) and respective enantiomers or diastereomers. Each of these enantiomers is typically designated upon optical rotation, which is represented by the symbols of (+) and (-), (L) and (D), (l) and (d) or a combination thereof. These isomers may also be designated as (S) and (R), which symbolize left and right, respectively, according to their absolute spatial form.

Each optical isomer can be prepared by treatment with conventional analytical processes such as a suitable optically active acid, separation of the diastereomers and recovery of the desired isomers. In addition, each optical isomer may be prepared by asymmetric synthesis.

In addition, given formulas or chemical names include pharmaceutically acceptable addition salts and solvates such as hydrates.

The compounds of the present invention, which are themselves effective, can be formulated and administered in the form of pharmaceutically acceptable addition salts thereof for stability, convenience of crystallization, increased solubility and other desired properties.

The compounds of the present invention can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to all acceptable salts such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, succinic acid, malonic acid, methane sulfonic acid It is understood to include acid salts, and the like, which may be used as a dosage form for modifying solubility or hydrolyzability or in sustained release or pro-drug formulations. Depending on the specific functional groups of the compounds of the present invention, pharmaceutically acceptable salts of the compounds of the present invention include cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc; And ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, di Those formed from bases such as ethylamine, piperazine, tris (hydroxymethyl) aminomethane, and tetramethylammonium hydroxide. These salts can be prepared as standard processes, for example by reacting the free acid with a suitable organic or inorganic base, or by reacting the free base with a suitable organic or inorganic acid.

In addition, when acids (-COOH) or alcohol groups are present, pharmaceutically acceptable esters such as methyl, ethyl, butyl, acetate, maleate, pivaloyloxymethyl and the like can be used, and these esters have solubility in water. Or it is known in the art that it can be used as a sustained release or pro-drug formulation since it modifies hydrolyzability.

Since the compounds of the present invention have chiral centers in addition to the centers chemically indicated in Formula I, they may exist as racemates, racemate mixtures and respective enantiomers or diastereomers, all such isomeric forms and mixtures thereof It is included within the scope of the present invention. In addition, some of the crystalline forms of the compounds of the present invention may exist as polymorphs, which are likewise included within the scope of the present invention. In addition, some of the compounds of the present invention may form solvates with water or conventional organic solvents. Such solvent compounds are included within the scope of the present invention.

Compounds of the present invention are prepared by the following scheme. All substituents are as defined above unless otherwise noted.

Scheme A

As shown in Scheme A, tryptamine (1) is treated with N-carboxyphthalimide in an inert organic solvent such as tetrahydrofuran at a temperature of 20 to 65 ° C., preferably at 65 ° C. for 12 to 48 hours. The corresponding N-phthalimidotrytamine derivative (2) is obtained. In addition, the N-phthalimidotrytamine derivative (2) is added to a brominating agent such as pyridinium hydrobromide perbromide, pyrrolidone hydro in an inert organic solvent such as tetrahydrofuran, methylene chloride, chloroform, or mixtures thereof. Treatment with tribromide or the like at 0-25 ° C. for 30 minutes to 4 hours gives 2-bromotryptamine (3). The bromide (3) is arylboronic acid using a chloride base such as lithium chloride, a weak base such as a palladium (0) catalyst, an aqueous sodium carbonate or the like in an inert solvent such as toluene, benzene, ethanol, propanol or mixtures thereof. See Gronowitz, S .; Hornfeldt, A.-B .; Yang, Y.-H. Chem. Scr. 1986, 26, 311-314) and 25-100 ° C., preferably Preferably, the reaction is carried out at a temperature of 80 ° C. for 1 to 6 hours to obtain 2-aryltryptamine derivative (4). Finally, tryptamine 5 is obtained by treating compound 4 with an aqueous hydrazine in an inert solvent such as methanol or ethanol at a temperature of 0-25 ° C. for 4 to 24 hours to remove the phthalimido group.

Scheme B

As shown in Scheme B, 2-aryltrytamine is reacted with a 1-hydroxybenzotriazole (HOBt) and a tertiary amine base in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide or mixtures thereof. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) as a coupling agent, with or without N-methylmorpholine (NMM), triethylamine, 1,3-dicyclohex Condensation of the carboxylic acid type (6) with a carboxylic acid form (6) at room temperature or near room temperature for 3 to 24 hours using, for example, silk carbodiimide (DCC), affords the corresponding amide derivative (7). On the other hand, 2-aryltryptamine (5) can be prepared by the active ester or acid chloride type (8) and triethylamine, diisopropyl in an organic inert solvent such as methylene chloride, chloroform, tetrahydrofuran, diethyl ether and the like. Treatment with tertiary amine base such as ethylamine, pyridine or the like at a temperature of 0 to 25 ° C. for 30 minutes to 4 hours yields compound (7).

Scheme C

As shown in Scheme C, amide carbonyl (7) is 25 to borane, lithium aluminum hydride or the corresponding hydride source in an inert organic solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane and the like. Treatment at 1O < 0 > C, preferably 65 [deg.] C, for 1-8 hours to reduce yields the corresponding amine compound (9).

Scheme D

As shown in Scheme D, 2-aryltryptamine (5) may be prepared by drying a desiccant, for example 3 ′ molecular sieve, in an inert organic solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, chloroform, or mixtures thereof. sieve) or an aldehyde in the presence of a weak acid such as trifluoroacetic acid (TFA), acetic acid, etc., with or without magnesium sulfate and hydride sources such as sodium borohydride or sodium cyanoborohydride. Treatment with ketone form 10 at a temperature of 0-25 ° C. for 1-12 hours yields a corresponding secondary or tertiary amine derivative 11.

Scheme E

As shown in Scheme E, arylhydrazine or arylhydrazine hydrochloride 12 is aryl in a polar organic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, preferably n-butanol. Treatment with cyclopropyl ketone type 13 at a temperature of 70 to 120 ° C. for 8 to 24 hours yields 2-aryltryptamine 5. On the other hand, arylhydrazine or arylhydrazine hydrochloride (12) is substituted in a polar organic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, or mixtures thereof (chloride, bromide, Iodide, O-methanesulfonate, O-trifluoromethanesulfonate, etc.) is treated with the arylbutyl ketone type 14 comprising 4-position at room temperature for 30 minutes to 2 hours, followed by 65 to 100 Heating at 4 ° C. for 4 to 24 hours gives 2-aryltryptamine (5).

Scheme F

As shown in Scheme F, iodoaniline form (15) may be prepared in a suitable palladium (0) catalyst such as tetrakis (triphenylphosphine) palladium and an inert organic solvent such as triethylamine and copper (I). In the presence of a halide, when reacted with aryl acetylene at a temperature of 50 to 88 ° C. for 30 minutes to 5 hours, diarylacetylene 16 is obtained. In addition, the acetylene (16) is 30 minutes to 6 hours at a temperature of 50-82 ° C. with a palladium (II) catalyst, for example palladium (II) chloride or palladium (II) acetate, in an inert organic solvent such as acetonitrile. During the treatment, the 2-arylindole 17 is obtained.

Scheme G

As shown in Scheme G, 2-arylindoles (17) can be added at 3 to a temperature of 25-65 ° C. with oxalyl chloride in an inert organic solvent such as methylene chloride, chloroform, dichloroethane, tetrahydrofuran or the like or without such solvent. After 24 hours of treatment, the acylchloride adduct 18 is obtained. This crude product 18 may be prepared in an inert solvent such as diethyl ether, tetrahydrofuran, methylene chloride, chloroform and the like with an amine base (19) and an amine base such as triethylamine, diisopropylethylamine or pyridine or the like. When reacted for 30 minutes to 4 hours at a temperature of 캜, an amide derivative 20 is obtained. Further, the amide 20 is modified by treatment with a reducing agent such as borane or lithium aluminium hydride in an inert organic solvent such as tetrahydrofuran at elevated temperature, preferably at reflux for 1 to 5 hours. (21) is obtained.

Scheme H

As shown in Scheme H, the N-benzyl derivative form 22a or N-benzyloxycarbonyl derivative form 22b is added to an inert organic solvent to which a weak acid such as 30% aqueous acetic acid is added, for example tetrahydrofuran, ethyl In acetate, methanol, ethanol, or mixtures thereof, hydrogen (1 atm) and a suitable catalyst such as palladium on carbon, palladium hydroxide on carbon, etc. for 10 minutes to 3 hours or aryl groups are removed to remove secondary amines. Treatment and reduction until production yields a secondary amine homologue 7.

Scheme I

As shown in Scheme I, the nitroindole type 24 is treated with hydrogen (1 atm) and an appropriate catalyst such as Raney ^R nickel for 2 to 12 hours at room temperature in an inert organic solvent such as ethanol, methanol, or the like. An aminoindole derivative (25) is obtained.

Scheme J

As shown in Scheme J, the amino- or hydroxyindole 25 can be modified by acylation under various conditions. In an inert organic solvent such as, for example, methylene chloride, chloroform, tetrahydrofuran or mixtures thereof, with acid chlorides, acid anhydrides or active esters and amine bases such as triethylamine, diisopropylethylamine, pyridine and the like. Treatment of compound 25 at 0 ° C. to room temperature for 1 to 12 hours yields the corresponding amide or ester derivative 26. On the other hand, compound (25) can be coupled with the carboxylic acid as one of many commonly used dehydrating agents. For example, aminoindole 25 may be prepared in 1-hydroxybenzotriazole (HOBt) and N-methylenemorpholine (NMM), triethyl in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide or mixtures thereof. Suitable carboxylic acids and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) in the presence or absence of tertiary amine bases such as amines and the like Treatment at room temperature or near room temperature for 3 to 24 hours or the like yields the corresponding amide or ester derivative 26.

Scheme K

As shown in Scheme K, the urea or carbamate derivative of compound (25) is in carbamoyl chloride type (27a) in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or mixtures thereof, or Otherwise isocyanate reagent type 27b, treated with an amine base such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine and the like for 1 to 72 hours at a temperature of 0 to 65 ° C. ) Is obtained. Compound (25) may be prepared by adding a bis (electrophilic) reagent with or without adding an amine base such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like in an inert solvent such as methylene chloride, chloroform, etc. For example, it can be modified by treating with phosgene, triphosgene, 1,1'-carbonyldiimidazole, N, N'-diuccisinimidyl carbonate, etc. at a temperature of -20 to 0 ° C. for 20 minutes to 2 hours. . Subsequently, the reaction mixture is treated with 1- or 2-substituted suitable amine at -20 to -25 [deg.] C. for 1-5 hours to obtain urea or carbamate homologue 28.

Scheme L

As shown in Scheme L, amine (25) is pyridine, triethylamine, diiso in the appropriate sulfonyl chloride type (29) or sulfamyl chloride type (30) in an inert solvent such as methylene chloride, chloroform, dichloroethane and the like. Modification by treatment with an amine base such as propylethylamine, N-methylmorpholine, etc. for 20 minutes to 2 hours at a temperature of −20 to 25 ° C. yields the corresponding N-sulfonamide (31) or N-sulfylamide ( 32) Derivatives are obtained respectively.

Scheme M

As shown in Scheme M, 2-aryltrytamine (33) is 65 to 110 ° C. with an epoxide such as compound (34) in an inert organic solvent such as methanol, ethanol, isopropanol, butanol, tert-butanol or mixtures thereof. Treatment with 8-20 hours at a temperature of 4 gives the corresponding amino-alcohol 35 derivatives.

Scheme N

As shown in Scheme N, the amide derivative of an acid-containing indole derivative, such as compound (36), is prepared in 1-hydroxybenzotria in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, dimethylformamide or mixtures thereof. Suitable amines (R ₁₂ R ₁₁ NH) and suitable coupling agents, for example benzotria, with or without sol (HOBt) and tertiary amine bases such as N-methylmorpholine (NMM), triethylamine, etc. Zol-1-yloxy-tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), 1- ( Treatment with 3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) and the like at room temperature or near room temperature for 3 to 24 hours results in a corresponding amide. Judo A 37 is obtained.

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

Rat Pituitary GnRH Receptor Binding Assay

Crude plasma membranes obtained from rat pituitary tissues were treated with Tris HCl buffer containing bovine serum albumin (0.1%), [I-125] Dt-Bu-Ser6-Pro9-ethyl amide-GnRH, and the test compound at the desired concentration. Incubate at (50 mM, PH 7.5). The assay mixture is incubated at 4 ° C. for 90-120 minutes, then rapidly filtered and washed repeatedly through a glass fiber filter. The radioactivity of the membrane bound radioligand is measured with a gamma-counter. From this data, the IC ₅₀ of the radioligand binding to the GnRH receptor in the presence of the test compound is calculated.

LH release inhibition assay

In addition to the in vitro LH release assay, the antagonist activity (GnRH-induced LH release) of the active compound is confirmed from the GnRH receptor binding assay.

1. Sample Manufacturing

The compound to be analyzed is dissolved and diluted in DMSO. The final concentration of DMSO in incubation medium is 0.5%.

2. Analysis

Wistar male rats (150-200 g) are purchased from Charles River Laboratories (Wilmington, Mass.). Rats are maintained at 12 hours week, 12 hours night cycles at constant temperature (25 ° C.). Rat food and water can be supplied without limitation. The animal is decapitated and sacrificed, the pituitary gland is removed aseptically and placed in Han's Balanced Salt Solution (HBSS) in a 50 ml polypropylene centrifuge tube. The collection tube is centrifuged at 250 x g for 5 minutes and the HBSS is aspirated off. Transfer the pituitary gland to a disposable petri plate and chop it with a small knife. The chopped tissue is then suspended in 50 successive centrifuge tubes by suspending the tissue fragments in three consecutive 10 ml fractions of HBSS containing 0.2% collagenase and 0.2% hyaluronidase. The cell dispersion is bathed at 37 ° C. with gentle stirring for 30 minutes. At the end of the incubation, the cells are aspirated 20-30 times with a pipette and the undigested pituitary fragments are left standing for 3-5 minutes. The suspended cells are degassed and removed and centrifuged at 1200 g for 5 minutes. The cells are then resuspended in culture medium. Undigested pituitary fragments are treated with 30 ml fractions of digestive enzymes such as a total of three digests with the collagenase / hyaluronidase mixture described above. The resulting cell suspension is collected, counted and diluted to a concentration of 3 × 10 ⁵ cells / ml and 1.0 ml of this suspension is placed in each well of a 24-well tray (Costar, Cambridge, Mass.). Cells are maintained at 37 ° C. for 3-4 days in a humidified 5% CO ₂ to 95% air atmosphere. The culture medium consists of DMEM containing 0.37% NaHCO ₃ , 10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids, 1% glutamine, and 0.1% gentamicin. On the day of the experiment, 0.37% NaHCO ₃ , 10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids (100 ×), 1% glutamine (100 ×), 1% penicillin / streptomycin (10,000 penicillins and Wash three times 1 1/2 hours before starting the experiment with DMEM containing 10,000 μg streptomycin per ml) and 25 mM HEPES (pH 7.4) and at least twice before starting the experiment. 1 ml of fresh medium containing test compounds in the presence of 2 nM GnRH is added to each well twice to initiate LH release. Incubation is carried out at 37 ° C. for 3 hours. After incubation, the medium is removed and centrifuged at 2,000 x g for 15 minutes to remove specific cellular material. The supernatant is removed and analyzed for LH content in a dual antibody RIA process using materials purchased from Dr. AF Parlow (Harbor-UCLA Medical Center, Torrance, Calif.).

Compounds of formula (I) are useful at many sites affected by GnRH. They are useful for sex-hormone related conditions, sex-hormone dependent cancers, benign prostate hypertrophy or myoma of the uterus. Sex-hormone dependent cancers that may benefit from administration of a compound of the present invention include prostate cancer, uterine cancer, breast cancer and pituitary germline adenoma. Other sex-hormone dependent conditions that may benefit from administration of a compound of the present invention include endometriosis, polycystic ovarian disease, uterine fibroids, and spring spondylosis. The compounds can also be used in combination with angiotensin-converting enzyme inhibitors such as Enalapril or Captopril, angiotensin II-receptor antagonists such as Losartan or renin inhibitors to treat uterine fibroids.

In addition, the compounds of the present invention are useful as contraceptives for controlling pregnancy and in vitro fertilization in both men and women, for the treatment of premenstrual syndrome, for the treatment of lupus erythematosus, for the treatment of hirsutism, for the treatment of pizza polar bowel syndrome. And sleep disorders such as sleep disorders.

Another use of the compounds of the invention is as a growth hormone therapeutic aid in children with growth hormone deficiency. The compound may be administered with a growth hormone or compound that increases endogenous production and 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 hormones include growth hormone releasing hormones, growth hormone releasing peptides GHRP-6 and GHRP-1 (see US Pat. No. 4,411,890, PCT Patent Publication No. WO 89/07110, and PCT). Patent Publication WO 89/07111] and GHRP-2 (PCT Patent Publication WO 93/04081), as well as hexarelin [J. Endocrinol Invest., 15 (Suppl4), 45 (1992)] There is this. Other compounds that stimulate the release of endogenous growth hormones are described, for example, in US Pat. No. 3,239,345, US Pat. No. 4,036,979, US Pat. No. 4,411,890, US Pat. No. 5,206,235, US Pat. 5,283,241, U.S. Patent 5,284,841, U.S. Patent 5,310,737, U.S. Patent 5,317,017, U.S. Patent 5,374,721, U.S. Patent 5,430,144, U.S. Patent 5,434,261, U.S. Patent 5,438,136, EPO Patent Publication 0,144,230 Patent No. 0,513,974, PCT Patent Publication No. WO 94/07486, PCT Patent Publication No. WO 94/08583, PCT Patent Publication No. WO 94/11012, PCT Patent Publication No. WO 94/13696, PCT Patent Publication WO 94/19367, PCT Patent Publication WO 95/03289, PCT Patent Publication WO 95/03290, PCT Patent Publication WO 95/09633, PCT Patent Publication WO 95/11029, PCT Patent Publication WO 95/12598, PCT Patent Publication WO 95/13069, PCT Patent Publication WO 9 5/14666, PCT Patent Publication WO 95/16675, PCT Patent Publication WO 95/16692, PCT Patent Publication WO 95/17422, PCT Patent Publication WO 95/17423; Science, 260, 1640-1643 (June 11, 1993); Ann. Rep. Chem., 28, 177-186 (1993); Bioorg. Med. Chem. Ltrs., 4 (22), 2709-2714 (1994); And Proc. Natl. Acad. Sci. USA 92, 7001-7005 (July 1995).

Representative preferred growth hormone secretagogues used in the present formulations include:

1) N- [1 (R)-[(1,2-dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -2 -(1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide;

2) N- [1 (R)-[(1,2-dihydro-1-methanecarbonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -2 -(1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide;

3) N- [1 (R)-[(1,2-dihydro-1-benzenesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -2 -(1H-indol-3-yl) ethyl] -2-amino-2-methylpropanamide;

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-methylpropanamide;

5) N- [1 (R)-[(2-acetyl-1,2,3,4-tetrahydrospiro [isoquinolin-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-indol-3,4'-piperidin] -1'-yl) carbonyl] -2 -(Phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide;

7) N- [1 (R)-[(1,2-dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -2 -(Phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide methanesulfonate;

8) N- [1 (R)-[(1,2-dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -2 -(2 ', 6'-difluorophenylmethyloxy) ethyl] -2-amino-2-methylpropanamide;

9) N- [1 (R)-[(1,2-dihydro-1-methanesulfonyl-5-fluorospiro [3H-indol-3,4'-piperidin] -1'-yl) Carbonyl] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide;

10) N- [1 (S)-[(1,2-dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -2 -(Phenylmethylthio) ethyl] -2-amino-2-methylpropanamide;

11) N- [1 (R)-[(1,2-dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -3 -Phenylpropyl] -2-amino-2-methylpropanamide;

12) N- [1 (R)-[(1,2-dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -3 -Cyclohexylpropyl] -2-amino-2-methylpropanamide;

13) N- [1 (R)-[(1,2-dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -1'-yl) carbonyl] -4 -Phenylbutyl] -2-amino-2-methylpropanamide;

14) N- [1 (R)-[(1,2-dihydro-1-methanesulfonylspiro [3H-indol-3,4'-piperidin] -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-indol-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-dioxospyro [3H-benzothiophen-3,4'-piperidin] -1'-yl) carbonyl ] -2- (phenylmethyloxy) ethyl] -2-amino-2-methylpropanamide; And

Pharmaceutically acceptable salts thereof.

The compounds of the present invention secrete bisphosphonates (bisphosphonic acids) and other agents, such as growth hormones, for the treatment and prevention of disorders of calcium, phosphate and bone metabolism, in particular to prevent bone loss during treatment with GnRH antagonists. May be used in combination with promoters (e.g. MK-0677) or in combination with estrogens, progesterone and / or androgens for the prevention and treatment of bone loss or hypogonadism, such as heat flashes during treatment with GnRH antagonists have.

Bisphosphonates (bisphosphonic acids) are known to inhibit bone resorption and are useful in the treatment of bone stones (see US Pat. No. 4,621,077, Rosini, et al.).

This document describes various bisphosphonic acids useful for the treatment and prevention of diseases associated with bone resorption. Representative examples can be found in the following documents: US Patent 3,251,907, US Patent 3,422,137, US Patent 3,584,125, US Patent 3,940,436, US Patent 3,944,599, US Patent 3,962,432, US Patent 4,054,598, U.S. Patent 4,267,108, U.S. Patent 4,327,039, U.S. Patent 4,407,761, U.S. Patent 4,578,376, U.S. Patent 4,621,077, U.S. Patent 4,624,947, U.S. Patent 4,746,654, U.S. Patent 4,761,406 US Patent No. 4,922,007, US Patent 4,942,157, US Patent 5,227,506, US Patent 5,270,365, EPO Patent 0,252,504, J. Org. Chem., 36, 3843 (1971).

The preparation of bisphosphonic acids and halobisphosphonic acids is well known in the art. Representative examples can be found in the aforementioned documents, which describe the compounds as useful in the treatment of calcium or phosphate metabolic disorders, in particular as inhibitors of bone resorption.

Preferred bisphosphonates are selected from the group of the following compounds: alendronic acid, etidronic acid, clodronic acid, pamidronic acid, tiludronic acid, risedronic acid, 6-amino-1-hydroxyhexylidene-bisphosphate Phonic acid and 1-hydroxy-3 (methylpentylamino) -propylidene-bis phosphonic acid, or any pharmaceutically acceptable salt thereof.

Particularly preferred bisphosphonates are alendronic acid (alendronate) or pharmaceutically acceptable salts thereof.

Particularly preferred bisphosphonates are alendronate sodium, for example alendronate sodium trihydrate. Alendronate sodium has been approved by the authorities for sale in the United States under the FOSAMAX ^R brand name.

In addition, the compounds of the present invention may be selected from 5α-reductase 2 inhibitors such as finasteride or epristeride; 5α-reductase 1 inhibitors such as 4,7β-dimethyl-4-aza-5α-cholestan-3-one, 3-oxo-4-aza-4,7β-dimethyl-16β- (4-chlorophenoxy C) -5α-androstan and 3-oxo-4-aza-4,7β-dimethyl-16β- (phenoxy) -5α-androstane (WO 93/23420 and WO 95/11254); Double inhibitors of 5α-reductase 1 and 5α-reductase 2, for example 3-oxo-4-aza-17β- (2,5-trifluoromethylphenyl-carbamoyl) -5α-androstane [WO 95/07927; It may be administered in combination with antiandrogens such as flutamide, carsodex and cyproterone acetate, and alpha-1 blockers such as prazosin, terrazosin, doxazosin, tamsulosin and alfuzosin.

In addition, the compound of the present invention may be used in combination with a growth hormone, growth hormone releasing hormone or growth hormone secretagogue to delay the adolescence of a growth hormone deficient child, thereby allowing the child to continue to grow before the physiolysis fuses and growth stops in adolescence. To do it.

For mixed therapy with one or more active agents in which the active agents are separate dosage forms, the active agents can be administered separately or together. In addition, administration of one component may be administered before, simultaneously with, or after administration of the other agent.

Pharmaceutical compositions containing the active ingredient may be in an oral suitable form, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs Can be. Oral compositions can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, which compositions are pharmaceutically odorable and symbolic by including one or more agents selected from the group consisting of sweetening, flavoring, coloring and preservatives. Formulations can be provided. Tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. Examples of these excipients include 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 gum arabic; And lubricants such as magnesium stearate, stearic acid or talc. Tablets may be unencapsulated or encapsulated by known techniques to retard disintegration and absorption in the gastrointestinal tract, thereby providing long-lasting action. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used. They can also be encapsulated by the techniques described in US Pat. Nos. 4,256,108, 4,166,452, and 4,265,874 to form osmotic therapeutic tablets for controlled release.

In addition, oral formulations may contain a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin or the active ingredient in water, or an oily medium such as peanut oil, liquid paraffin, or It may be provided as a soft gelatin capsule mixed with olive oil.

Aqueous suspensions include the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethyl-cellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, tragacanth rubber and gum arabic; Dispersants or wetting agents, which are naturally present phosphatides such as lecithin, or condensation products of fatty acids with alkylene oxides (eg polyoxyethylene stearate), condensation products of long chain aliphatic alcohols with ethylene oxide ( Eg heptadecaethylene-oxycetanol), partial esters derived from fatty acids and hexitol and condensation products of ethylene oxide (eg polyoxyethylene sorbitol monooleate), or fatty acids and hexitol anhydrides Condensation products of partial esters with ethylene oxide, such as polyethylene sorbitan monooleate. Aqueous suspensions also include one or more preservatives, such as ethyl, or n-propyl, p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame can do.

Oily suspensions may be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin. Oily suspensions may contain thickening agents, for example beeswax, hard paraffin or cetyl alcohol. The sweetening agent and the flavoring agent as described above can be added to provide an oral preparation suitable for taste. These compositions can be preserved by adding an antioxidant such as ascorbic acid.

Water may be added to dispersible powders and sequestrants suitable for the preparation of aqueous suspensions to obtain the active ingredients in admixture with dispersants or wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be exemplified by those mentioned above. Additional excipients may also be present, such as sweeteners, flavors and colorings.

In addition, the pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. Oily phases include vegetable oils such as olive oil or peanut oil; Or mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifiers include naturally occurring phosphatides such as soybean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and ethylene oxide with the partial esters. Condensation products, such as polyoxyethylene sorbitan monooleate. In addition, emulsions may include sweetening and flavoring agents.

Syrups and elisirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. In addition, such formulations may include thickeners, preservatives, flavors and coloring agents. The pharmaceutical composition may be in the form of a sterile aqueous or oily suspension for injection. 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. In addition, the sterile preparation for injection can be a sterile solution or suspension for injection in a parenterally acceptable non-toxic diluent or solvent, for example a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally employed as a solvent or suspending medium. For this purpose, certain blended nonvolatile oils can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

In addition, the compounds of formula (I) may be administered in the form of suppositories for rectal administration of the medicament. These compositions can be prepared by mixing the medicament with a suitable non-irritating excipient which melts in the rectum and releases the medicament since it is solid at ordinary temperatures but liquid at the rectal temperature. Such materials include cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions, etc., comprising the compounds of formula (I) may be used. (For purposes of this application, topical applications will include mouthwashes and gargles.)

The compounds of the present invention may be administered in intranasal form through topical use of a suitable intranasal vehicle, or may be administered via the transdermal route using forms of transdermal skin patches well known to those skilled in the art. In order to be administered in the form of a transdermal delivery system, the dose administration should of course be continuous rather than intermittent throughout the administration process. The compounds of the invention can also be administered as suppositories using bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

Optimal methods of administration using the compounds of the invention include the type, race, age, weight, sex and medical condition of the patient; Severity of the condition to be treated; Route of administration; Kidney and liver function of the patient; And various factors including the specific compound to be used. A physician or veterinarian of ordinary skill can readily determine and prescribe an effective amount of a drug required to prevent, treat, inhibit or improve the progression of the disease state. Optimal precision in achieving concentrations of a drug within the range of efficacy without toxicity requires an optimal method based on the availability activity of the drug to the target site. For this purpose, consideration should be given to the distribution, equilibrium, and elimination of the agent. Preferably, the dosage of the compound of formula I, useful in the method of the present invention, is in the range of 0.01 to 1000 mg per day for adults. Most preferably, it is in the range of 0.1 to 500 mg per day. For oral administration, the compositions contain 0.01 to 1000 mg of the active ingredient, in particular the dosages are adjusted according to the symptoms, so that the active ingredient 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 And to a patient to be treated in the form of a tablet containing 500 mg. An effective amount of the medicament is typically supplied at a dosage level of about 0.0002 mg to about 50 mg per kg body weight per day. This range is particularly preferably about 0.001 mg to 1 mg / kg body weight per day.

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

The amount of active ingredient which can be combined with a carrier material to produce a single dosage form can vary greatly depending upon the patient to be treated and the particular mode of administration.

However, the specific dosage level for a particular patient depends on age, weight, general health, sex, meal, time of administration, route of administration, rate of release, drug combination and severity of the particular disease being treated.

The following examples illustrate the preparation of some of the compounds of the invention, but do not limit the invention described herein.

Example 1

1- [2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] ethylamino] -3- (pyridin-4-yloxy) propan-2-ol

To a solution of [2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] ethylamine (118 mg in 4 ml of anhydrous methanol) was added 20 mg of 4-oxyranylmethoxypyridine and the mixture was washed with an oil bath. Heated to 80 ° C. After 6 h, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride: methanol: ammonium hydroxide, 90: 10: 1) to afford the title compound (53 mg). m / e = 448 (M + H)

In a similar manner as described in Example 1, the following compounds are prepared:

Example 2.1

{2- [2- (3,5-Dimethylphenyl) -1H-indol-3-yl] -ethyl}-(5-pyridin-4-yl-pentyl) -amine

Step 2.1A 2- [2- (1H-Indol-3-yl) -ethyl] -isoindole-1,3-dione

To a stirred suspension of 2- (1H-indol-3-yl) ethylamine (2.0 g in 20 ml anhydrous tetrahydrofuran) was added N-carbethoxyphthalimide (2.85 g) and the mixture was heated in an oil bath. To reflux. After 48 hours, the reaction is cooled to room temperature, filtered and the filtrate is concentrated in vacuo. The resulting solid is suspended in a mixture of hexane / methylene chloride (2.5: 1) and filtered. The collected solid is purified by flash chromatography (methylene chloride: methanol, 97: 3) to give the title compound (3.1 g).

Step 2.1B 2- [2- (2-Bromo-1H-indol-3-yl) -ethyl] -isoindole-1,3-dione

Pyridinium bromide at 0 ° C. in a solution of 2- [2- (1H-indol-3-yl) -ethyl] -isoindole-1,3-dione (1.0 g in a mixture of 10 ml anhydrous tetrahydrofuran and 10 m anhydrous chloroform) at 0 ° C. Perbromide (1.14 g) is added and the reaction is stirred at 0 ° C. After 50 minutes, saturated sodium bicarbonate is added to quench the reaction and extract with ethyl acetate. The organic fraction is washed with saturated sodium bicarbonate (3 ×) and 0.3M sodium bisulfate (3 ×) and then dried over magnesium sulfate. Purify the concentrate by flash chromatography on silica gel (hexanes: ethyl acetate, 3: 1) to afford the title compound (1.2 g).

Step 2.1C 2- {2- (2- (3,5-Dimethylphenyl) -1H-indol-3-yl] -ethyl} -isoindole-1,3-dione

3,5-dimethylphenyl boron in a solution of 2- [2- (2-bromo-1H-indol-3-yl] ethyl] -isoindole-1,3-dione (150 mg in a mixture of 5 ml of toluene and 5 ml of ethanol) Acid (85 mg) is added followed by 1.0 ml of 1 M sodium carbonate Lithium chloride (60 mg) is added to the stirred solution followed by addition of tetrakis (triphenylphosphine) palladium (28 mg) and the mixture is then oil bathed. After 4 hours, the mixture is cooled to room temperature and concentrated in vacuo Purification by flash chromatography on silica gel (hexane: ethyl acetate, 5: 1) affords the title compound (146 mg).

Step 2.1D 2- [2- (3,5-Dimethylphenyl) -1H-indol-3-yl) -ethylamine

To a solution of 2- {2- [2-3,5-dimethylphenyl) -1H-indol-3-yl] ethyl] -isoindole-1,3-dione (87 mg in a mixture of 4 ml of tetrahydrofuran and 4 ml of ethanol) 0.6 ml of 95% aqueous hydrazine is added and the reaction is stirred at room temperature. After 18 h, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride: methanol: ammonium hydroxide, 9: 6: 1) to afford the title compound (54 mg).

Step 2.1E {2- [2- (3,5-Dimethylphenyl) -1H-indol-3-yl) -ethyl}-(5-pyridin-4-yl-pentyl) -amine

Anhydrous in a solution of 2- [2- (3,5-dimethylphenyl) -1H-indol-3-yl] ethylamine (162 mg) and 5- (4-pyridyl) -pentanal (100 mg in 2 ml anhydrous chloroform) Magnesium sulfate (735 mg) is added and the mixture is stirred at 0 ° C. for 15 minutes. At this time, sodium borohydride (92.7 mg) was added, followed by 3 ml of anhydrous methanol, and the mixture was stirred at 0 ° C. After 1 hour, the reaction was quenched in water (25 ml), stirred for 30 minutes, and then extracted with methylene chloride (4 x 25 ml). The combined organics are dried over potassium carbonate, concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride: methanol, 95: 5) to afford the title compound (172 mg). m / e = 412 (M + H).

Preparation of Synthetic Intermediates

Step A: 5- (4-pyridyl) -4-pentyn-1-ol

4-bromopyridine hydrochloride salt (3.89 g) is dissolved in a solvent mixture comprising triethylamine (25 ml) and water (5 ml). Anhydrous lithium chloride (848 mg), copper (I) bromide powder (30 mg) and 5-pent-4-yn-1-ol (1.68 g) are added to the pyridine salts, the mixture is stirred and the active nitrogen gas stream described above. After gently passing through the solution for about 15 minutes, tetrakis (triphenylphosphine) -palladium (231.1 mg) is added. The reaction mixture is heated to reflux under a nitrogen atmosphere to maintain reflux for 2.5 hours, after which time the heating is stopped and the reaction is left at room temperature. The reaction product is separated by partitioning between ether and brine. In addition, the aqueous layer is extracted with ether (4 x 50 ml) and the combined extracts are dried over anhydrous sodium sulfate powder. The extract is filtered and evaporated under reduced pressure to give a dark brown oil. The brown oil thus obtained was subjected to column chromatography using only ethyl acetate as eluent to give 5- (4-pyridyl) 4-pentin-1-ol (2.1 g) as a yellow oil, which was left at room temperature, It slowly solidifies and becomes somewhat dark in color.

Step B: 5- (4-pyridyl) -pentan-1-ol

5- (4-pyridyl) -4-pentyn-1-ol (1.5 g) obtained in the previous step was dissolved in methanol (35 ml) in a Parr hydrogenation bottle and platinum (IV) oxide [Adams' Catalyst] (0.3 g) is added. The Parr bottle is placed on a Parr hydrogenation apparatus and the solution is hydrogenated at 40 psi for 5.5 hours. At this time, it is determined that the starting material was consumed by TLC. After the catalyst used is filtered off with a pad of celite, the pad is carefully washed several times with methanol. The combined filtrates are evaporated under reduced pressure in a rotary evaporator, and the oily residue is then column chromatographed on a short silica column using only ethyl acetate as eluent to afford the title compound (1.4 g).

Step C: 5- (4-Pyridyl) -pentanal

Oxalyl chloride (2 ml of 2M solution in anhydrous methylene chloride) was placed in a cold oven-drying flask, cooled to -78 ° C using dry ice and acetone cooling bath, and a solution of DMSO (632 mg) in anhydrous methylene chloride (1 ml) To the oxalyl chloride was added dropwise over 3 minutes, and further stirred for 3 minutes. A solution of [5- (4-pyridyl) -4-pentan-1-ol (0.6 g) in anhydrous methylene chloride (5 ml) is added to the reaction flask over about 3 minutes and the reaction is stirred for 15 minutes. Anhydrous triethylamine (2.82 ml) is added and the reaction mixture is stirred again for 2 hours during which time the cooling bath is raised to room temperature or lower. Saturated brine is added to quench the reaction, which is then partitioned between methylene chloride. The aqueous layer is discarded, the methylene chloride extract is dried over anhydrous sodium sulfate powder, filtered and evaporated under reduced pressure to give an oily residue. The product (488 mg) is isolated by column chromatography on silica gel using ethyl acetate as eluent.

Example 2.2

{2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] ethyl}-[3- (1H-indol-5-yl) propyl] amine

Step 2.2A N- {2- [2- (3,4-Dimethoxyphenyl) -1H-indol-3-yl] ethyl} -3- (1H-indol-5-yl) propionamide

To a solution of 3- (1H-indol-5-yl) propionic acid (50 mg in 2.5 ml of N, N-dimethylformamide) 43 mg of 1-hydroxy-benzotriazole was added at 0 ° C., followed by 1- (3-dimethylamino After adding 71 mg of propyl) -3-ethylcarbodiimide hydrochloride, the mixture is allowed to warm to room temperature. After 23 minutes, 155 mg of 2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] -ethylamine are added and the mixture is stirred for an additional hour at room temperature. Subsequently, water is added to quench the reaction and the mixture is extracted with ethyl acetate. The combined organics are washed with water and brine, dried over sodium sulfate and the concentrated oil is purified by flash chromatography on silica gel (methylene chloride: methanol, 95: 5) to give the title compound (111 mg).

Step 2.2B {2- [2- (3,4-Dimethoxyphenyl) -1H-indol-3-yl] ethyl} -3- (1H-indol-5-yl) propyl] amine

N- {2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] ethyl} -3- (1H-indol-5-yl) propionamide (in 2.0 ml of anhydrous tetrahydrofuran) 60 mg) to the solution is added 26 mg of lithium aluminum hydride at 0 ° C. and the mixture is heated to 77 ° C. in an oil bath. After 5.5 hours, the mixture was cooled to 0 ° C., quenched by addition of 0.025 ml of water, stirred vigorously for 30 minutes, and then the suspension was filtered through a pad of sodium sulfate and the filtrate was concentrated in vacuo. Purification by flash chromatography (methylene chloride: methanol, 92: 8) affords the title compound (32 mg). m / e = 454 (M + H).

In a similar manner as described in Examples 2.1 and 2.2, the following compounds are prepared:

Example 3

[3- (3H-Benzoimidazol-5-yl) -allyl]-{2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] -ethyl} -amine

Step 3A

{2- [2- (3,4-Dimethoxyphenyl) -1H-indol-3-yl] -ethyl}-[3- (1-methanesulfonyl-1H-benzoimidazol-5-yl) -allyl ] Amine

346 mg in a solution of 3- (1H-benzoimidazol-5-yl) -prop-2-en-1-ol (44 mg in a mixture of 2 mL methylene chloride and 0.1 mL N, N-dimethylformamide) at 0 ° C. Tetrabutylammonium bromide, 0.110 mL diisopropylethylamine and 100 mg methanesulfone anhydride are added successively and the mixture is allowed to warm to room temperature. After 1 h, the mixture was poured into a solution of 2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] -ethylamine (6 mL of methylene chloride and 1.5 mL of N, N-dimethylform 300 mg in a mixture of amides) is added and stirring is continued for 2.5 hours. At this time the mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (methylene chloride: methanol, 91: 9) to afford the title compound (24 mg).

Step 3b

[3- (3H-Benzoimidazol-5-yl) -allyl]-{2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] -ethyl} -amine

{2- [2- (3,4-Dimethoxyphenyl) -1H-indol-3-yl] -ethyl}-[3- (1-methanesulfonyl-1H-benzoimidazol-5-yl at 0 ° C. To a solution of) -allyl] amine (24 mg in 1.5 mL methanol) add 0.225 mL of 2N solution of potassium hydroxide and allow the mixture to warm to room temperature. After 1.5 hours, the reaction is quenched by addition of 0.30 mL of 1N hydrochloric acid, concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride: methanol, 88:12) to afford the title compound (12 mg). m / e = 453 (M + H)

Preparation of Synthetic Intermediates

Step A

1H-benzoimidazole-5-carboxylic acid N, N-methoxymethylamide

500 mg of 1-hydroxybenzotriazole (HOBt) followed by 828 mg of 1- (3-dimethylamino) in a suspension of 1H-benzoimidazole-5-carboxylic acid (500 mg in 7 mL N, N-dimethylformamide) at 0 ° C. Propyl) -3-ethylcarbodiimide hydrochloride (EDC) is added and the mixture is allowed to warm to room temperature. After 42 minutes, 1.05 g of N, O-dimethylhydroxylamine hydrochloride and 1.5 mL triethylamine are added and stirring is continued at room temperature. After 1 hour the reaction is quenched by addition of water and the product is separated by extraction with ethyl acetate. The concentrate is purified by flash chromatography on silica gel (methylene chloride: methanol, 90:10) to afford the title compound (458 mg).

Step B

1H-benzoimidazole-5-carboxaldehyde

3.7 mL diisobutyl in toluene in a solution of 1H-benzoimidazole-5-carboxylic acid N, N-methoxy, methyl amide (458 mg in a mixture of 5 mL diethyl ether and 10 mL tetrahydrofuran) at -78 ° C. 1.5M solution of ammonium hydride is added and the mixture is stirred at low temperature. After 1 hour, the reaction mixture is cannulated into 1M solution of sodium potassium tartrate at 0 ° C. The resulting slurry is vigorously stirred at room temperature for 2 hours and then extracted with ethyl acetate. The organics are washed with water, dried over sodium sulphate and concentrated in vacuo to afford the crude title compound (250 mg).

Step C

3- (1H-benzoimidazol-5-yl) -acrylic acid methyl ester

To a solution of 1 H-benzoimidazole-5-carboxaldehyde (250 mg in 12 mL anhydrous tetrahydrofuran) at 0 ° C. was added 1.43 g of methyl (triphenylphosphoranilidene) acetate and the mixture was allowed to warm to room temperature. Be sure to After 24 hours, the mixture is concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride: methanol, 93: 7) to afford the title compound (257 mg).

Step D

3- (1H-benzoimidazol-5-yl) -prop-2-en-1-ol

1.24 mL of lithium tri-tert-butylboro in tetrahydrofuran to a solution of 3- (1H-benzoimidazol-5-yl) -acrylic acid methyl ester at -78 ° C (50 mg in 1 mL anhydrous tetrahydrofuran) 1M solution of hydride is added and the mixture is stirred at -78 ° C for 4 hours and then warmed at -40 ° C for an additional 4 hours. The reaction is quenched by addition of aqueous methanol, concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride: methanol, 87:13) to afford the title compound (44 mg).

A process similar to that described above is carried out to produce the following compounds:

Example 4.1

[2- [2- (3,5-dimethylphenyl) -5-methanesulfonyl-1H-indol-3-yl] ethyl]-(4-pyridin-4-yl-butyl) amine

Step 4.1A

[2- [2- (3,5-dimethylphenyl) -5-methanesulfonyl-1H-indol-3-yl] ethylamine

A suspension of 4- (methanesulfonyl) phenylhydrazine (3.0 g, 16.1 mmol) and 3-chloropropyl 3,5-dimethylphenyl ketone (3.4 g, 16.1 mmol) in t-butanol (25 mL) was stirred at room temperature for 20 minutes. Stir and heat slightly on steam bath. Methanol (250 mL) is added and the mixture is heated at reflux overnight. The mixture is then concentrated in small amounts, the crystals are filtered off and washed with cold methanol. The combined filtrates are evaporated to a residue, which is partitioned between ethyl ether and water. The ethereal layer is extracted with water (2x) and the combined aqueous extracts are washed with ethyl ether and basified with 5N sodium hydroxide. The product is extracted with ethyl acetate (3x). The combined organic extracts are washed with water, dried over sodium sulphate and evaporated with syrup (3.1 g). The crude material is purified by flash chromatography on silica gel (methylene chloride: methanol, 9: 1) to give the title compound (1.99 g, 36%), Rf 0.19 (ninhydrin positive).

Step 4.1B

N- [2- (2- (3,5-Dimethylphenyl) -5-methanesulfonyl-1H-indol-3-yl] ethyl] -4-pyridin-4-yl-butyramide

2- [2- (3,5-dimethylphenyl) -5-methanesulfonyl-1H-indol-3-yl] ethylamine (1.29 g, 3.77 mmol) in N, N-dimethylformamide (10 mL), 4 -(4-pyridyl) butanoic acid (1.37 g, 8.29 mmol), 4-methylmorpholine (1.25 mL, 11.3 mmol), 1-hydroxybenzotriazole (1.53 g, 11.33 mmol) and 1- (3- A mixture of dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.74 g, 9.08 mmol) is stirred at room temperature for 14 hours. At this time, the solution was evaporated with n-butanol (3 ×) to give a residue, which was purified by flash chromatography on silica gel (methylene chloride: methanol, 97: 3) to give the title compound (1.45 g, 79%). To obtain.

Step 4.1C

[2- [2- (3,5-dimethylphenyl) -5-methanesulfonyl-1H-indol-3-yl] ethyl]-(4-pyridin-4-yl-butyl) amine

Borane-THF (1.0 M solution in tetrahydrofuran, 27 mL) was dissolved in N- [2- [2- (3,5-dimethylphenyl) -5-methanesulfonyl-1H-indole- in anhydrous tetrahydrofuran (20 mL). To the solution of 3-yl] ethyl] -4-pyridin-4-yl-butyramide (1.45 g, 2.96 mmol) is added dropwise and the solution is heated under reflux for 2 hours. At this time, methanol is added to quench the excess borane and the resulting solution is evaporated to dryness. The residue is dissolved in tetrahydrofuran (20 mL) and N, N-dimethylethanolamine (8.9 mL, 88.86 mmol) is added. The solution is heated at reflux for 2.5 h and then concentrated to dryness. The crude material is purified by flash chromatography on silica gel (methylene chloride: methanol, 95: 5) to afford the title compound (1.0 g, 71%). m / e = 476 (M + H).

STEP 4.1D

4- [2- [2- (3,5-dimethylphenyl) -5-methanesulfonyl-1H-indol-3-yl] ethyl]-(4-pyridin-4-yl-butyl) amine (dihydrochloride )

Hydrogen chloride in ethyl ether (1.0 M, 1.4 mL) was dissolved in anhydrous tetrahydrofuran (20 mL) at 0 ° C. in [2- [2- (3,5-dimethylphenyl) -5-methanesulfonyl-1H-indole-3- Dropwise to a solution of yl] ethyl]-(4-pyridin-4-yl-butyl) amine (300 mg, 0.63 mmol). After 10 minutes, excess hydrogen chloride and solvents are evaporated to yield a solid material. The product is further dried at 50 ° C. under high pressure to afford the title compound.

Example 4.2

3- [2- (3,5-dimethylphenyl) -3- [2- (5-pyridin-4-yl-pentylamino) -ethyl] -1 H-indol-5-yl] -1,1-dimethylurea

Step 4.2A

2- [2- (3,5-Dimethylphenyl) -5-nitro-1H-indol-3-yl] -ethylamine hydrochloride salt

Dissolve 1- (4-chloro-1-oxo-butyl) -3,5-dimethylbenzene (2.5 g) in 12 mL of t-butanol, and after stirring at room temperature, add 4-nitrophenylhydrazine (1.65 g). do. The reaction mixture was stirred at room temperature for 20 minutes, then water (12 mL) and methanol (108 mL) were added, heated to reflux and maintained at reflux for 17 hours. The reaction mixture is cooled to room temperature and the volatile solvent is removed on a rotary evaporator under reduced pressure. The residue is evaporated to dryness overnight using an active nitrogen gas flow. The solid anhydrous residue is triturated with ethyl acetate (about 100 mL), scratched to initiate crystallization and the sample is left in the refrigerator for 8 hours. The solid material thus obtained is collected under suction into a sintered glass funnel and the solid material is washed with anhydrous ethyl acetate. Obtained 1.4 g yield of solids.

Step 4.2B

{2- [2- (3,5-Dimethylphenyl) -5-nitro-1H-indol-3-yl] -ethyl} -carbamic acid tert-butyl ester

2- [2- (3,5-dimethylphenyl) -5-nitro-1H-indol-3-yl] -ethylamine hydrochloride salt (1 g) is suspended in anhydrous methylene chloride (25 mL) and anhydrous triethylamine (0.806 mL) is added and stirred at room temperature for 5 minutes. [2- (tert-butoxycarbonyloxyimino) phenylacetonitrile] (890 mg) is added to tryptamine in small fractions over 5 minutes and the reaction mixture is stirred at room temperature overnight. The reaction is partitioned between methylene chloride and 5% citric acid. The methylene chloride layer is separated, washed with brine and dried over anhydrous sodium sulfate powder. The extract is filtered and evaporated to dryness. The product is separated by column chromatography using silica gel and eluent as ethyl acetate and hexane (35:65 v / v). Yield of the title compound is 1 g.

Step 4.2C

{2- [5-Amino-2- (3,5-dimethylphenyl) -1H-indol-3-yl] -ethyl} -carbamic acid tert-butyl ester

{2- [2- (3,5-Dimethylphenyl) -5-nitro-1H-indol-3-yl] -ethyl} -carbamic acid tert-butyl ester (0.4 g) was dissolved in methanol (25 mL) Platinum (IV) oxide (40 mg) is added. The mixture is placed on a Parr hydrogenation apparatus and hydrogenated at 45 psi for 4 hours, at which point the starting material is consumed and converted to one product. The catalyst is removed by filtration, the filtrate is evaporated in a rotary evaporator under reduced pressure and the traces of the final solvent are removed overnight using high pressure. Amine (338 mg) is obtained as a powder.

Step 4.2D

{2- [2- (3,5-Dimethylphenyl) -5- (3,3-dimethylureido) -1H-indol-3-yl] -ethyl} -carbamic acid tert-butyl ester

Finely divided {2- [5-amino-2- (3,5-dimethylphenyl) -1H-indol-3-yl] -ethyl} -carbamic acid tert-butyl ester (265 mg) was dried with anhydrous tetrahydrofuran (5 mL). ) And diisopropylethylamine (0.146 mL) and dimethylcarbamoyl chloride (0.077 mL) are added. The reaction mixture is stirred for 2.5 days at room temperature. The reaction mixture is concentrated on a rotary evaporator and the residue is applied to four preliminary silica gel plates (20 × 20 cm 1000 μ) and eluted with a solvent system comprising 1: 9 v / v of methanol and methylene chloride. The product (299 mg) is separated by a viscous gum, which is left for a long time to solidify.

Step 4.2E

3- [3- (2-aminoethyl) -2- (3,5-dimethylphenyl) -1H-indol-5-yl] -1,1-dimethylurea

{2- [2- (3,5-dimethylphenyl) -5- (3,3-dimethylureido) -1H-indol-3-yl] -ethyl} -carbamic acid tert-butyl ester (295 mg) Dissolve for 2.5 hours in a ternary solvent mixture comprising methylene chloride (6 mL), trifluoroacetic acid (2 mL) and anisole (2 mL). The volatile solvent components are removed on a rotary evaporator and the residue is purified in four preliminary silica gel plates (20 × 20 cm 1000 μ) in methanol and eluted with a solvent system comprising a 1: 9 v / v ratio of methanol and methylene chloride. . The product (222 mg) is separated as effervescent material.

Step 4.2F

3- [2- (3,5-dimethylphenyl) -3- [2- (5-pyridin-4-yl-pentylamino) -ethyl] -1 H-indol-5-yl] -1,1-dimethylurea

From the previous step, 3- [3- (2-aminoethyl) -2- (3,5-dimethylphenyl) -1H-indol-5-yl] -1,1-dimethylurea (25 mg) was converted to tetrahydrofuran ( 1 mL) and deuterochloroform (1 mL) at about 0 ° C. and 5- (4-pyridyl) pentanal (10.6 mg) is added. The reaction mixture is held at this temperature for 15 minutes, followed by addition of finely divided sodium borohydride powder and then anhydrous methanol. The reaction mixture is stirred at about 0 ° C. for 15 minutes and then quenched by addition of 20 drops of 2N hydrochloric acid and water (1 mL). Volatile material is removed on a rotary evaporator and water is removed using an active flow of nitrogen gas. The residue is purified on four preparative silica gel plates (20 × 20 cm 500 μ) and eluted with a solvent system comprising a 1: 9 v / v ratio of methanol and methylene chloride. The product (14.2 mg) is isolated as viscous oil.

A process similar to that described in Examples 4.1 and 4.2 is performed to prepare the following compounds:

Example 5.1

2- (3,5-dimethylphenyl) -3- [2- [4- (pyridin-4-yl) butylamino] ethyl] -1H-indole-5-carboxylic acid diethylamide dihydrochloride

Step 5.1A

3- (2-aminoethyl) -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid ethyl ester

A mixture of 7.60 g (50 mmol) of 4-hydrazinobenzoic acid, 10.55 g (50 mmol) of 3-chloropropyl 3,5-dimethylphenyl ketone and 200 mL of anhydrous ethanol is stirred under nitrogen, heated to reflux. After 12 hours, the mixture is cooled and filtered. The solid on the filter is washed with an additional small amount of ethanol. The filtrate is treated with 4 mL of concentrated sulfuric acid and stirred for 4 days under reflux under nitrogen. The cooled mixture is stirred in an ice bath dropwise with a solution of sodium ethoxide (21% w / w in ethanol) until the mixture becomes basic by pH paper. This mixture is filtered and concentrated in vacuo at 30 ° C. The residue is partitioned between diethyl ether and water, and some saturated aqueous sodium chloride solution is added to separate the layers. The aqueous phase is washed with an additional 100 mL of ether. The combined organic extracts are dried over sodium sulfate, filtered and concentrated in vacuo. The residual gum is purified by flash chromatography on silica gel (eluted with methylene chloride: methanol: ammonium hydroxide at 97: 3: 0.3 and then 95: 5: 0.5) to afford the title compound (4.8 g). 400 MHz ¹ H NMR (CDCl ₃ ) is consistent with the defined structure. Mass spectrum (PB-NH ₃ / Cl): m / e = 337 (M + H).

Step 5.1B

2- (3,5-dimethylphenyl) -3- [2- [4- (pyridin-4-yl) butylamino] -ethyl] -1 H-indole-5-carboxylic acid ethyl ester

5.0 g (14.9 mmol) of 3- (2-aminoethyl) -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid ethyl ester, 1.98 g (13.5 mmol) of 4- ( Pyridin-4-yl) butyraldehyde (prepared as described in Example 2.1; diluted with 0.5 mL of CDCl ₃ ), 8.12 g (67.7 mmol) of anhydrous magnesium sulfate and a magnetic stirring bar are added. The flask is purged with nitrogen, cooled to -10 ° C, and stirred while slowly introducing 11.5 mL of anhydrous CDCl ₃ into the syringe. The mixture is stirred for about 20 minutes under nitrogen. The septum is then removed and 670 mg (17.6 mmol) of sodium borohydride are added rapidly. The diaphragm is immediately removed and the system purged again with nitrogen. 10 mL of anhydrous methanol is slowly added by syringe while stirring this mixture at about -5 degreeC under nitrogen. After a few minutes at this temperature, the reaction is removed from the cold bath and partitioned between 80 mL of ethyl acetate and 100 mL of water. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (eluted with a methanol gradient of 4-9% in methylene chloride, repeated using 5-15% methanol in methylene chloride) to afford the title compound (3.19 g). 500 MHz ¹ H NMR (CDCl ₃ ) is consistent with the designated structure. Mass spectrum (PB-NH ₃ / CI): m / e = 470.4 (M + H). 1.91 g of additional less pure material is also separated.

Step 5.1C

3- [2- [benzyloxycarbonyl- [4- (pyridin-4-yl) butyl] amino] ethyl] -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid ethyl ester

3.19 g (6.83 mmol) 2- (3,5-dimethylphenyl) -3- [2- [4- (pyridin-4-yl) butylamino] ethyl] -1H-indole-5- in 25 mL of anhydrous methylene chloride The solution of carboxylic acid ethyl ester was stirred under nitrogen, 2.38 mL (1.76 g, 13.7 mmol) of N, N-diisopropylethylamine was added while cooling in anhydrous ice-acetone bath at -78 ° C, followed by 3.4 mL (4.06 g) , 23.7 mmol) benzyl chloroformate is slowly added in portions by syringe. After about 2.5 hours, the solution is removed from the cooling bath and allowed to warm to room temperature. Then partition between ethyl acetate and 5% aqueous sodium bisulfate solution. The organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (eluted with a gradient of 0.5 to 10% methanol in methylene chloride) by flash chromatography to give the product as a yellow foam in quantitative yield. 500 MHz ¹ H NMR is complex due to the presence of rotamers, but is consistent with the defined structure. Mass spectrum (PB-NH ₃ / Cl): m / e = 604.3 (M + H).

STEP 5.1D

3- [2- [benzyloxycarbonyl- [4- (pyridin-4-yl) butyl] amino] -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid hydrochloride

4.11 g (6.83 mmol) 3- [2- [benzyloxycarbonyl- [4- (pyridin-4-yl) butyl] amino] ethyl] in 161 mL (80.5 mmol) 0.50 N potassium hydroxide in methanol 19 mL of water is slowly added while stirring the solution of (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid ethyl ester at about 60 ° C. Stir overnight at reflux. The cooled mixture is concentrated in vacuo to yield a yellow solid, which is partitioned between 250 mL of 1: 1 ethyl acetate-tetrahydrofuran mixture and 250 mL 0.5 N hydrochloric acid. The organic phase is washed twice with 0.5N hydrochloric acid, dried over magnesium sulfate and filtered and concentrated in vacuo. The solid obtained was triturated with diethyl ether and collected on a filter to give 3.46 g of a homogeneous yellow solid having a melting point of 133.5 to 137.5 ° C. and TLC (95: 5: 0.5 CH ₂ Cl ₂ -MeOH-AcOH). do. 500 MHz ¹ H NMR is consistent with the defined structure. Mass spectrum (ESI): m / e = 576.4 (M + H).

Step 5.1E

[2- [5-Diethylcarbamoyl-2- (3,5-dimethylphenyl) -1H-indol-3-yl] ethyl]-[4- (pyridin-4-yl) butyl] carbamic acid benzyl ester

846 mg (1.38 mmol) 3- [2- [benzyloxycarbonyl- [4- (pyridin-4-yl) butyl] amino] ethyl] -2- (3,5-dimethylphenyl) -1H-indole-5 1.16 mL (839 mg) of a mixture of carboxylic acid hydrochloride, 862 mg (1.66 mmol) of benzotriazol-1-yloxy-tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP) and 8.5 mL of anhydrous methylene chloride; 8.29 mmol) of triethylamine followed by several minutes of 0.715 mL (505 mg, 6.91 mmol) of diethylamine. The resulting solution was stirred overnight at room temperature under nitrogen and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient elution with 1-5% methanol in methylene chloride) to give a homogeneous quantitative yield of the desired product by TLC in 95: 5 CH ₂ Cl ₂ -MeOH. do. 500 MHz ¹ H NMR (CDCl ₃ ) is complex due to rotamers, but is consistent with the defined structure. Mass spectrum (ESI): m / e = 631.5 (M + H).

Step 5.1F

2- (3,5-dimethylphenyl) -3- [2- [4- (pyridin-4-yl) butylamino] -ethyl] -1 H-indole-5-carboxylic acid diethylamide

871 mg (1.38 mmol) of [2- [5-diethylcarbamoyl-2- (3,5-dimethylphenyl) -1H-indol-3-yl] -ethyl- [4- (pyridin-4-yl] butyl ] A mixture of carbamic acid benzyl ester, 300 mg of 20% palladium hydroxide on carbon and 40 mL of 2-methoxyethanol is shaken with hydrogen (about 45 psig) in a pressure vessel for 2.3 hours The catalyst is removed by filtration through diatomaceous earth and The filtrate is concentrated in vacuo The residue is purified by flash chromatography on silica gel (eluted with a gradient from CH ₂ Cl ₂ -MeOH-concentrated NH ₄ OH of 99: 1: 0.1 to 93: 7: 0.7). 454 mg (66%) of a homogeneous yellow foam was obtained by TLC in 95: 5: 0.5 CH ₂ Cl ₂ -MeOH-rich NH ₄ OH 500 MHz ¹ H NMR (CDCl ₃ ) is consistent with the defined structure. Spectrum (ESI): m / e = 497.5 (M + H).

Step 5.1G

2- (3,5-dimethylphenyl) -3- [2- [4-pyridin-4-yl) butylamino] -ethyl] -1 H-indole-5-carboxylic acid diethylamide dihydrochloride

452 mg (0.914 mmol) of 2- (3,5-dimethylphenyl) -3- [2- [4- (pyridin-4-yl) butylamino] ethyl] -1H-indole-5-carboxylic acid di in 45 mL methanol The solution of ethylamide is treated with 1.83 mL (3.66 mmol) of 2N hydrochloric acid. After a few minutes, the solution is evaporated to dryness. The residue is reconcentrated from methanol and then triturated with diethyl ether. The solid is collected on a filter, washed with additional diethyl ether and dried to yield 455 mg (87%) of yellow powder having a melting point of 154 to 157 ° C. 500 MHz ¹ H NMR (DMSO-d ₆ ) is consistent with the defined structure.

Example 5.2

A process similar to that described in Example 5 was followed to prepare the following compounds:

Example 6

2- (3,5-dimethylphenyl) -3 {2- [4- (3-methylisoxazol-5-yl) butylamino] -ethyl} -1H-indole-5-carboxylic acid diisobutylamide

3- (2-aminoethyl) -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid diisobutylamide at 0 ° C. (prepared as described in Example 5.1, 2.5 mL of anhydrous CDCl _To a solution of 83 mg ₃ ) is added 240 mg of magnesium sulfate followed by 30.6 mg of 4- (3-methylisoxazol-5-yl) -butyraldehyde and the mixture is stirred at low temperature. After 15 minutes, a cold solution of sodium borohydride (30.2 mg in 1.5 mL anhydrous methanol) is added and the mixture is stirred for an additional 15 minutes. The reaction is then quenched by addition of water, extracted with ethyl acetate and then methylene chloride and the combined organics are dried over sodium sulfate. Purify the concentrate on silica gel (methylene chloride: methanol, 9: 1) by preparative TLC to afford the title compound (28 mg). m / e = 557 (M + H).

Preparation of Synthetic Intermediates

4- (3-Methylisoxazol-5-yl) -butyraldehyde

Step A

Tert-butylhex-5-ynyloxydimethylsilane

To a solution of hex-5-in-1-ol (1.96 g in 40 mL of anhydrous methylene chloride) at 0 ° C., 3.48 mL of triethylamine and then 3.31 g of tert-butyldimethylsilyl chloride are added and the mixture is stirred While warming slowly to room temperature. After 60 hours, the mixture is filtered to remove solids and the filtrate is concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate: hexane 1: 9, then 1: 3) affords the title compound (1.62 g).

Step B

5- [4- (tert-butyldimethylsilanyloxy) butyl] -3-methylisoxazole

To a solution of tert-butylhex-5-ynyloxydimethylsilane (1.0 g in 20 mL anhydrous toluene) was added 530 mg of nitroethane followed by 1.31 mL of triethylamine and 1.1 g of 4-chlorophenyl isocyanate and the mixture was cooled to room temperature. Stir in After 1 hour, the components are heated to reflux for an additional 20 hours on an oil bath, cooled to room temperature and filtered to remove solids. The filtrate is concentrated in vacuo and purified by flash chromatography on silica gel (ethyl acetate: hexane, 1: 9, then 1: 2) to afford the title compound (388 mg).

Step C

4- (3-methylisoxazol-5-yl) -butan-1-ol

1.62 mL of tetrabutylammonium in tetrahydrofuran in a solution of 5- [4- (tert-butyldimethylsilanyloxy) butyl] -3-methylisoxazole (350 mg in 5 mL of anhydrous tetrahydrofuran) at 0 ° C. Fluoride 1M solution is added and the mixture is allowed to warm to room temperature with stirring. After 16 h, the mixture is concentrated in vacuo and the residue is purified by flash chromatography on silica gel (ethyl acetate: hexane, 1: 3, then 1: 1) to afford the title compound (147 mg).

Step D

4- (3-Methylisoxazol-5-yl) -butyraldehyde

To a solution of oxalyl chloride (0.40 mL of a 2M solution of methylene chloride in 2 mL of anhydrous methylene chloride) at −78 ° C. is added a solution of methyl sulfoxide (126 mg in 1 mL of methylene chloride) and the mixture is stirred at low temperature for 3 minutes. 4- (3-methylisoxazol-5-yl) -butan-1-ol (100 mg in 1 mL methylene chloride) was added and the reaction was allowed to proceed for 15 minutes, followed by 0.67 mL of triethylamine and the mixture was allowed to stand at room temperature. Allow to warm up. After 30 minutes brine is added and the mixture is extracted with methylene chloride. The organic fraction is dried over sodium sulfate and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (ethyl acetate: hexane, 1: 1) to afford the title compound (48 mg).

The following compounds are prepared in a similar process as described in Example 6:

Example 7.1

2- [2- (3,5-dimethylphenyl) -3- [2- [4- (pyridin-4-yl) butylamino] ethyl] -1H-indol-5-yl] -N, N-diethyl Isobutyrylamide

Step 7.1A

2- [3- (2-aminoethyl) -2- (3,5-dimethylphenyl) -1H-indol-5-yl] -N, N-diethylisobutyramide

4.85 g (23 mmol) 3-chloropropyl 3,5-dimethylphenyl ketone and 6.87 g (27.6 mmol) N, N-diethyl-2- (4-hydrazinophenyl) isobutyramide in 92 mL of absolute ethanol The solution of is stirred for 43 hours under reflux under nitrogen. The solution is cooled and concentrated in vacuo. Gradient elution with silica gel (0-5% methanol in methylene chloride followed by 95: 5: 0.5 methylene chloride-methanol-ammonium hydroxide and 92.5: 7.5: 0.75 methylene chloride-methanol-ammonium hydroxide) Purification by flash chromatography on) afforded 873 mg (9.4%) of reddish-brown viscous foam (73%) with purity by TLC in CH ₂ Cl ₂ -MeOH-rich NH ₄ OH of 95: 5: 0.5. Is satisfactory. 500 MHz ¹ H NMR (CDCl ₃ ) is consistent with the defined structure. Mass spectrum (PB-NH ₃ / CI): m / e = 406 (M + H).

Step 7.1B

2- [2- (3,5-dimethylphenyl) -3- [2- [4- (pyridin-4-yl) butylamino] ethyl] -1H-indol-5-yl] -N, N-diethyl Isobutyrylamide

93.3 mg (0.23 mmol) of 2- [3- (2-aminoethyl) -2- (3,5-dimethylphenyl) -1H-indol-5-yl] -N, N-diethylisobutyramide, 37.7 0.50 mL of CDCl while purging with nitrogen and a mixture of mg (0.253 mmol) of 4- (pyridin-4-yl) butyraldehyde and 138 mg (1.15 mmol) of magnesium sulfate and cooling at about −10 ° C. in an ice-methanol bath Slowly add ₃ with a syringe. The mixture is stirred at room temperature under nitrogen for 1 hour. The septum is removed sufficiently to add 11.3 mg (0.30 mmol) of sodium borohydride and the solution is repurged with nitrogen. 0.50 mL of anhydrous methanol is slowly added while stirring this mixture at -10 to -5 ° C, and stirring is continued at this temperature. After 35 minutes, the mixture is partitioned between 5 mL of ethyl acetate and 5 mL of water. The ethyl acetate layer is washed with brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was subjected to preparative TLC on Silica gel GF plates (analyzed with 90: 10: 1 methylene chloride-methanol-ammonium hydroxide and then repeated with 90:10 methylene chloride-methanol) by Analtech computer readout. Purify in two steps. The product band was separated to give 25.7 mg (21%) of a pale gold transparent residue that was visually homogeneous by TLC in 92.5: 7.5: 0.75 CH ₂ Cl ₂ -MeOH-rich NH ₄ OH. 500 MHz ¹ H NMR (CDCl ₃ ) is consistent with the defined structure. Mass spectrum (ESI): m / e = 539 (M + H).

Preparation of Synthetic Intermediates

Step A

4-chloro-N-methoxy-N-methylbutyrylamide

To a solution of 4-chlorobutyryl chloride (10.0 g in 200 mL anhydrous methylene chloride) 10.4 g of N, O-dimethylhydroxylamine hydrochloride is added. The mixture is stirred under nitrogen and precipitated by dropwise addition of triethylamine (29.1 mL) over about 20 minutes while maintaining below 25 ° C. while cooling in an ice bath. After 1.5 h at rt, the mixture is concentrated in vacuo. The residue is partitioned between 100 mL of diethyl ether and 100 mL of saturated aqueous sodium bicarbonate solution. The organic layer is further washed with 100 mL of saturated sodium bicarbonate and the aqueous fractions are back-extracted with ether. The combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo to yield 10.5 g (90%) of oil with satisfactory purity by ¹ H NMR (CDCl ₃ ). Mass spectrum (PB-NH ₃ / CI): m / e = 166 (M + H).

Step B

3-chloropropyl 3,5-dimethylphenyl ketone

A solution of 10.2 mL (13.9 g; 72 mmol) of 5-bromo-m-xylene in 200 mL of anhydrous tetrahydrofuran was stirred at -78 ° C. under nitrogen with 35.8 mL (84 mmol) of 2.5 M n-butyl in tetrahydrofuran. Lithium is added dropwise. After 15 minutes at −78 ° C., a solution of 10.0 g (60 mmol) of 4-chloro-N-methoxy-N-methylbutyramide in 30 mL of anhydrous tetrahydrofuran is added dropwise over 25-30 minutes. The resulting solution is held at −78 ° C. for 45 minutes and then warmed slightly at room temperature. The solution was quenched by addition of 40 mL of 2N hydrochloric acid and then partitioned between ethyl acetate and water. The organic phase is washed with saturated aqueous sodium bicarbonate solution followed by saturated sodium chloride aqueous solution. The organic solution is dried over sodium sulfate, filtered and concentrated in vacuo. The residue was flash chromatographed to yield 8.91 g (70%) of oil, which has a satisfactory purity by ¹ H NMR (CDCl ₃ ).

Step AA

Ethyl 2- (4-hydrazinophenyl) acetate hydrochloride and 2- (4-hydrazinophenyl) acetic acid hydrochloride

Compound (a mixture of ethyl ester and carboxylic acid) was eluted from 13.4 g (75 mmol) of ethyl 2- (4-aminophenyl) acetate. second. LJ Street et al., J. Med. Chem., 36, 1529 (1993)] by diazotization and tin chloride reduction of diazonium salts. This material is obtained as two products. The first product consists of 6.40 g of powder (melting point> 200 ° C.). By 400 MHz ¹ H NMR (DMSO-d ₆ ), this material consists of a mixture of carboxylic acid and ethyl ester in a molar ratio of approximately 4: 3. Mass spectrum (PB-NH ₃ / CI): 195 (arylhydrazonium cation for ethyl ester). The second product consists of 4.60 g of powder (melting point> 180 ° C.). By 400 MHz ¹ H NMR (DMSO-d ₆ ) this material consists of a carboxylic acid and ethyl ester mixture in a molar ratio of approximately 7: 1. After adjusting the mixture composition of the two products, the calculated total yield is 69%. As esterification of the carboxylic acid takes place in the next step, both ester and acid are reacted to give the same product.

Step AAA

(+/-)-2- (4-nitrophenyl) propionic acid ethyl ester

3.0 mL of concentrated sulfuric acid is added to a solution of 9.76 g (50 mmol) of (+/-)-2- (4-nitrophenyl) propionic acid in 150 mL of absolute ethanol. The resulting solution is stirred under reflux under nitrogen. After 6 hours, the solution is cooled and slowly added 250 mL of saturated aqueous sodium bicarbonate solution with vigorous stirring (Note: foaming). The mixture is partitioned between 750 mL of ethyl acetate and 500 mL of water. The organic layer is washed with 100 mL of saturated aqueous sodium bicarbonate solution followed by 100 mL of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo to yield a homogeneous 10.86 g (97%) oil by TLC in 9: 1 hexane-EtOAc. 400 MHz ¹ H NMR (CDCl ₃ ) is consistent with the defined structure.

Step BBB

2-methyl-2- (4-nitrophenyl) propionic acid ethyl ester

4.68 g (21 mmol) in 20.5 mL of anhydrous N, N-dimethylformamide while stirring a suspension of 924 (23 mmol) of sodium hydride (60% in oil) in 21 mL of anhydrous N, N-dimethylformamide under nitrogen in an ice bath. A solution of +/-)-2- (4-nitrophenyl) propionic acid ethyl ester is added slowly over about 10 minutes. Dark purple appears when added. Allow this mixture to warm to room temperature. After about 1 hour, the mixture was cooled again in an ice bath, while a solution of 1.44 mL (3.28 g; 23 mmol) of methyl iodide in 5 mL of anhydrous N, N-dimethylformamide was added dropwise over about 10 minutes by syringe. The temperature is kept at 10-15 ° C. Allow the mixture to warm to room temperature and turn brown. After 1 hour, additional 187 mL (426 mg, 3 mmol) of methyl iodide is added. The next day, the mixture consists of a suspension of a gray solid in a gold liquid. This is vigorously stirred and quenched by the slow addition of 10 mL of 5% aqueous potassium bisulfate solution. The mixture is partitioned between 400 mL diethyl ether and 400 mL water. The organic layer is washed with an additional 3 × 400 mL of water followed by 50 mL of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was flash chromatographed on silica gel eluting with 19: 1 hexane-EtOAc to give a homogeneous 4.31 g (87%) of oil by TLC in 9: 1 hexane-EtOAc. 400 MHz ¹ H NMR (CDCl ₃ ) is consistent with the defined structure.

Step CCC

2-Methyl-2- (4-nitrophenyl) propionic acid

A solution of 11 g (24 mmol) of 2-methyl-2- (4-nitrophenyl) propionic acid ethyl ester in 1 L of 0.5 M potassium hydroxide in methanol is slowly added under stirring with nitrogen and heated to about 50 ° C. The resulting solution is stirred under reflux overnight and then concentrated in vacuo. The residue is partitioned between ethyl acetate-tetrahydrofuran and 0.5N hydrochloric acid. The aqueous layer is also extracted repeatedly with chloroform. The organic fractions are dried over magnesium sulphate and concentrated in vacuo to yield 9.4 g (94%) of a homogeneous amorphous tan solid by TLC in 95: 5: 0.5 CH ₂ Cl ₂ -MeOH-AcOH. 500 MHz ¹ H NMR (CDCl ₃ ) is consistent with the defined structure.

Step DDD

N, N-diethyl-2- (4-nitrophenyl) isobutyramide

To 8.36 g (40 mmol) of 2-methyl-2- (4-nitrophenyl) propionic acid is added 18 mL of cyclohexane and 9 mL of thionyl chloride. The mixture is stirred under nitrogen and heated to reflux. The solid is slowly dissolved and gas evaporation is observed. After 20 hours, the solution is cooled, evaporated under a stream of nitrogen and dried in vacuo. The remaining pale orange solid was dissolved in 50 mL of anhydrous tetrahydrofuran and 9.10 mL (6.43 g, 88 mmol) of diethylamine in 100 mL of anhydrous tetrahydrofuran stirred in a cold-methanol bath at about −10 to −15 ° C. Add dropwise to the solution. When the dropwise addition with precipitation is complete, allow the mixture to slowly warm to room temperature. After 2 days, the mixture is concentrated in vacuo and the residue is partitioned between 250 mL of ethyl acetate and 200 mL of water. The organic phase is further washed with water, then with saturated aqueous sodium bicarbonate solution and finally with brine. The ethyl acetate solution is dried over magnesium sulfate, filtered and concentrated in vacuo. The residual oil was purified by flash chromatography on silica gel (eluted with hexane-ethyl acetate at 6: 1 and then 5: 1) to give a melting point of 59.5-61 ° C. and 9.45 g homogeneous by TLC in 2: 1 hexane-EtAc. (85%) of a pale yellow solid is obtained. 500 MHz ¹ H NMR (CDCl ₃ ) is consistent with the defined structure. Mass spectrum (PB-NH ₃ / CI): m / e = 265 (M + H).

Step EEE

2- (4-aminophenyl) -N, N-diethylisobutyramid

A mixture of 9.38 g (35.5 mmol) of N, N-diethyl-2- (4-nitrophenyl) isobutyramide, 400 mg of 10% palladium on carbon and 120 mL of anhydrous ethanol was mixed in a pressure vessel for 22 hours with hydrogen ( Shaking with an initial hydrogen pressure of 47 psig). The catalyst is removed by filtration through diatomaceous earth under nitrogen and the filter cake is washed with additional ethanol. The filtrate is concentrated in vacuo to yield a homogeneous 8.5 g (100%) of off-white solid by TLC in CH ₂ Cl ₂ -MeOH with a melting point of 89-90 ° C. 500 MHz ¹ H NMR (CDCl ₃ ) is consistent with the defined structure. Mass spectrum (PB-NH ₃ / CI): m / e = 235 (M + H).

Step FFF

N, N-diethyl-2- (4-hydrazinophenyl) isobutyramide

35.5 mL of concentrated hydrochloric acid is added to 8.5 g (35.5 mmol) of 2- (4-aminophenyl) -N, N-diethylisobutyramid and the mixture is stirred until a homogeneous solution is obtained. This is then added dropwise over about 25 minutes in a solution of 2.55 g (36.9 mmol) of sodium nitrite in 15.3 mL of water with stirring at -10 to -5 ° C in an ice-acetone bath. Stirring is continued for additional time at this temperature. The mixture is kept cold and added in portions over 1 hour to a solution of 40.1 g (178 mmol) of tin chloride in 28.5 mL of concentrated hydrochloric acid under nitrogen in an ice-acetone bath (approximately -10 ° C.). After the addition is complete, stirring is continued in the cooling bath for 1 hour. The mixture is stirred vigorously while being allowed to warm to approximately room temperature, yielding a homogeneous solution. The solution is partitioned between 500 mL of ethyl acetate and 50 mL of water. The ethyl acetate layer is further washed with 50 mL of water and then carefully treated with 500 mL of half saturated sodium bicarbonate aqueous solution. This mixture is carefully agitated to result in considerable gas evolution and precipitation. The thick mixture is filtered before phase separation. The ethyl acetate phase is washed with 50 mL of brine, then dried over magnesium sulfate, filtered and concentrated in vacuo at room temperature. This yields 7.04 g (80%) of a slightly viscous orange solid, which is poorly defined by TLC, NMR and mass spectra but used appropriately in the next step.

Example 7.2

2- [2- (3,5-dimethylphenyl) -3- [2- [4- (pyridin-3-yl) butylamino] ethyl] -1H-indol-5-yl] -N, N-dibutyl Isobutyrylamide

Step 7.2A

2- [2- (3,5-dimethylphenyl) -3- [2- [4- (pyridin-3-yl) butylamino] ethyl] -1H-indol-5-yl] -2-methylpropionic acid ethyl ester

3.00 g (7.93 mmol) of 2- [3- (2-aminoethyl) -2- (3,5-dimethylphenyl) -1H-indol-5-yl] -2-methylpropionic acid ethyl ester (Example 7.1 step A needle adapter with a septum and refractory valve in a dry flask containing 4.76 g (39.7 mmol) of anhydrous MgSO ₄ and a magnetic stir bar. The flask was completely purged with N ₂ and the mixture was cooled in an ice-MeOH bath at −10 to −5 ° C. and vigorously stirred with 1.32 g (8.88 mmol) of 4- (pyridine- ₃ in 15 ml of anhydrous CDCl ₃ . The solution of -yl) butyraldehyde is slowly added over 10-15 minutes with a syringe. The resulting mixture is stirred at −10 to −5 ° C. under N ₂ for 40 to 45 minutes. The barrier is then removed enough to add 390 mg (10.3 mmol) of sodium borohydride. 10 ml of anhydrous MeOH is added dropwise through the syringe over a few minutes while stirring the mixture under N ₂ at -10 to -5 ° C. After 30 minutes, the mixture is removed from the cold bath and partitioned between 90 ml EtOAc and 90 ml H ₂ O. The organic layer is washed with 2x30 ml brine and then dried over anhydrous NaSO ₄ . The filtered solution is concentrated in vacuo and the residue is flash chromatography on silica gel (gradient eluting with 0-10% MeOH in CH ₂ Cl ₂ ). The fractions containing the product and a small amount of unreacted starting material are combined and concentrated to yield 3.00 g of a light beige viscous foam which is used directly in the next step without further purification or characterization.

Step 7.2B

2- [3- [2- [benzyloxycarbonyl- [4- (pyridin-3-yl) butyl] amino] ethyl] -2- (3,5-dimethylphenyl) -1 H-indol-5-yl- 2] -methylpropionic acid ethyl ester

3.00 g (30 theoretical maximum 5.86 mmol) in 30 mL of anhydrous CH ₂ Cl ₂ crude 2- [2- (3,5-dimethylphenyl) -3- [2- [4- (pyridin-3-yl) butylamino] A solution of ethyl] -1H-indol-5-yl] -2-methylpropionic acid ethyl ester is stirred with N ₂ while cooling in anhydrous ice-acetone bath. 1.106 ml (820 mg, 6.36 mmol) of N, N-diisopropylethylamine are added to the solution by syringe. 956 μl (1.14 g, 6.36 mmol) of benzyl chloroformate is then added dropwise via syringe over 5-10 minutes. After 20 minutes, the solution is removed from the cooling bath and allowed to warm to room temperature. After 2 hours, the solution is diluted with 50 ml of CH ₂ Cl ₂ and transferred to a separatory funnel and shaken with 80 ml of H ₂ O. The organic phase is dried over MgSO ₄ , filtered and concentrated in vacuo. Flash chromatography residual gum on silica gel (CH ₂ Cl ₂ gradient elution of from 0.2 to 2% in MeOH) to 95: 5 CH ₂ Cl ₂ visibly homogeneous pale golden yellow gum 2.81g (step by TLC of -MeOH 55%) for both 1 and 2. 500 MHz ¹ H NMR (CDCl ₃ ) is complex due to rotamers, but is consistent with the defined structure. Mass spectrum (ESI): m / e = 646 (M + H) ⁺ .

Step 7.2C

2- [3- [2- [benzyloxycarbonyl- [4- (pyridin-3-yl) butyl] amino] ethyl] -2- (3,5-dimethylphenyl) -1H-indol-5-yl] 2-methylpropionic acid

43.0 mol (21.5 mmol) in 0.5 M KOH 2.78 g (4.30 mmol) 2- [3- [2- [benzyloxycarbonyl- [4- (pyridin-3-yl) butyl] amino] ethyl] in MeOH A mixture of -2- (3,5-dimethylphenyl) -1H-indol-5-yl] -2-methylpropionic acid ethyl ester and 25 ml of THF is stirred under N ₂ and heated to reflux. 18 ml of H ₂ O is slowly added to the resulting solution, and the solution is kept at reflux for 39 hours. This is then cooled and concentrated to a small volume causing precipitation. The mixture is treated with 10.75 ml (21.5 mmol) 2N HCl and shaken for several minutes. Collect the solid on the filter and wash thoroughly with H ₂ O. After suction drying under N ₂ , the solid was ground, washed with diethyl ether, and vacuum-dried to give a melting point of 152 to 154 ° C. (partial decomposition) and homogeneous by TLC in CH ₂ Cl ₂ -MeOH at 90:10. 2.43 g (92%) of a creamy powder are obtained. 500 MHz ¹ H NMR (DMSO-d ₆ ) is consistent with the defined structure. Mass spectrum (ESI): m / e = 618 (M + H) ⁺ .

Step 7.2D

[2- [5- (1-Dibutylcarbamoyl-1-methylethyl) -2- (3,5-dimethylphenyl) -1H-indol-3-yl] ethyl]-[4- (pyridine-3- 1) butyl] carbamic acid benzyl ester

92.7 mg (0.15 mmol) of 2- [3- [2- [benzyloxycarbonyl- [4- (pyridin-3-yl) butyl] amino] ethyl] -2- (in 0.750 mL of anhydrous CH ₂ Cl ₂ ) 3,5-dimethylphenyl) -1H-indol-5-yl] -2-methylpropionic acid, a solution of 83.2 mg (0.16 mmol) PyBOP reagent and 0.151 mL (116 mg; 0.9 mmol) triethylamine stopper for 2 days Stir at room temperature in a flask with. The solution is partitioned between 10 ml EtOAc and 10 ml 0.5N HCl. The organic phase is washed with 10 ml of saturated aqueous NaHCO ₃ and then with 5 ml of saturated aqueous NaCl solution. The EtOAc phase is then dried (MgSO ₄ ), filtered and concentrated in vacuo at room temperature. The residue is purified by preparative TLC on 6 analtec tapered silica gel plates (20 × 20 cm) developing in 95: 5 CH ₂ Cl ₂ -MeOH. The product bands are separated from each plate, combined and extracted with 95: 5 CH ₂ Cl ₂ -MeOH. The extract was concentrated in vacuo to give 85.2 mg (78%) of a pale golden gum which was visually homogeneous by TLC in 95: 5 CH ₂ Cl ₂ -MeOH. 500 MHz ¹ H NMR (CDCl ₃ ) is complex due to rotamers, but is consistent with the defined structure. Mass spectrum (ESI): m / e = 729.7 (M + H) ⁺ .

Step 7.2E

2- [2- (3,5-dimethylphenyl) -3- [2- [4- (pyridin-3-yl) -butylamino] ethyl] -1 H-indol-5-yl] -N, N-di Butyl isobutyramide

76.5 mg (0.105 mmol) of [2- [5- (1-dibutylcarbamoyl-1-methylethyl) -2- (3,5-dimethylphenyl) -1H-indol-3-yl] ethyl]-[ A mixture of 4- (pyridin-3-yl) butyl] carbamic acid benzyl ester, 40 mg of 10% palladium on carbon, 4 ml of anhydrous EtOH and 4 ml of EtOAc with H ₂ (approximately 47 psig) in a pressure vessel for 6 hours. Shake. The catalyst is removed by filtration through celite under N ₂ and the filtrate is concentrated in vacuo at room temperature. The residue is purified by preparative TLC on 4 analtec tapered silica gel plates (20 × 20 cm) that develop in 92.5: 7.5: 0.75 CH ₂ Cl ₂ -MeOH-rich NH ₄ OH. Separate product bands from each plate and combine and extract with 92.5: 7.5: 0.75 CH ₂ Cl ₂ -MeOH-rich NH ₄ OH. The extract was concentrated in vacuo to give a homogeneous 51.4 mg (82%) pale yellow viscous gum by TLC in 92.5: 7.5: 0.75 CH ₂ Cl ₂ -MeOH-rich NH ₄ OH. 500 MHz ¹ H NMR (CDCl ₃ ) is consistent with the defined structure. Mass spectrum (ESI): m / e = 595.6 (M + H) ⁺ .

A process similar to that described in Examples 7.1 and 7.2 is performed to prepare the following compounds:

Example 8

{2- [2- (3,5-dimethylphenyl) -1H-indol-3-yl] ethyl}-(3-pyridin-3-yl-cyclohexyl) amine

2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] in a solution of 3-pyridin-3-yl-cyclohexanone (30 mg in 1.5 mL anhydrous CDCl ₃ ) at 0 ° C. A solution of ethylamine (45.3 mg in 1 mL anhydrous CDCl ₃ ) and then 206 mg magnesium sulfate are added and the mixture is stirred at low temperature. After 15 minutes, 26 mg sodium borohydride is added followed by 1.0 mL of methanol and the mixture is stirred for an additional 30 minutes. At this time, 2N hydrochloric acid was added to quench the reaction, and evaporated to dryness. The concentrate is purified by preparative TLC on silica gel (methylene chloride: methanol, 9: 1) to afford the title compound (8.4 mg).

Preparation of Synthetic Intermediates

3-pyridin-3-yl-cyclohexanone

Step A

3-pyridin-3-yl-cyclohex-2-enone

To a solution of 3-ethoxy-2-cyclohexen-1-one (1.4 g in 10 mL anhydrous tetrahydrofuran) is added 1.58 g of 4-bromopyridine and the mixture is stirred vigorously at -78 ° C. . To this was added dropwise tert-butyllithium (11.8 mL of 1.7 M solution in pentane) and the reaction proceeded at low temperature. After 2 hours, the reaction is quenched by the addition of 2N hydrochloric acid and heated to reflux for 14 hours. At this time the mixture is cooled and neutralized to pH7 by careful addition of 1N sodium hydroxide. This mixture is then extracted with methylene chloride and the organic fractions are dried over sodium sulfate. The concentrate is purified by flash chromatography on silica gel (ethyl acetate: hexane, 1: 1; then 2: 1) to afford the title compound (1.37 g).

Step B

3-pyridin-3-yl-cyclohexanone

To a solution of 3-pyridin-3-yl-cyclohex-2-enone (1.25 g in 50 mL ethanol) is added 164 mg of platinum oxide and the mixture is applied to 40 psi of hydrogen. After 2 hours, the catalyst is removed by filtration and the filtrate is concentrated in vacuo. The residue is purified by flash chromatography on silica gel (ethyl acetate: hexane, 1: 1) to afford the title compound (427 mg).

A process similar to that described in Example 8 was followed to produce the following compounds:

Example 9.1

2- (3,5-dimethylphenyl) -3- [2- (1-methyl-4-pyridin-3-yl-butylamino) ethyl] -1 H-indole-5-carboxylic acid diisobutylamide

Step 9.1A

3- (2-tert-butoxycarbonylamino-ethyl) -2- (3,5-dimethylphenyl) -1 H-indole-5-carboxylic acid ethyl ester

A solution of 3- (2-aminoethyl) -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid ethyl ester at 0 ° C. (prepared as described in Example 5.1, 30 mL of anhydrous tetrahydro To 1.5 g in furan) a solution of di-tert-butyl dicarbonate (1.9 g in 3 mL tetrahydrofuran) and then aqueous potassium carbonate solution (1 g in 10 mL water) were added and the resulting suspension was vigorously stirred at 0 ° C. do. After 12 minutes, the reaction is quenched by addition of excess saturated aqueous ammonium chloride and the mixture is extracted with ethyl acetate. The organic fraction is dried over sodium sulfate and concentrated in vacuo. The solid obtained is washed successively with methylene chloride, hexane and ethyl acetate to give the title compound (1.77 g).

Step 9.1B

3- (2-tert-butoxycarbonylaminoethyl) -2- (3,5-dimethylphenyl) -1 H-indole-5-carboxylic acid

1.25 N sodium hydroxide in a suspension of 3- (2-tert-butoxycarbonylaminoethyl) -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid ethyl ester (830 mg in 50 mL methanol) 8 mL of solution is added and the mixture is heated to 75 ° C. on an ice bath. After 5.5 hours, additional 3 mL of 1.25N sodium hydroxide is added and the reaction proceeds for another 2 hours. At this time the mixture is cooled to room temperature and the reaction is quenched by the addition of pH 2 buffer. The mixture is extracted with ethyl acetate and washed with saturated ammonium chloride solution and the organic fractions are dried over sodium sulfate. Concentration in vacuo affords the premature birth in quantitative yield.

Step 9.1C

{2- [5-Diisobutylcarbamoyl-2- (3,5-dimethylphenyl) -1H-indol-3-yl] ethyl} carbamic acid tert-butyl ester

104 mg of 1-hydride in a solution of 3- (2-tert-butoxycarbonylaminoethyl) -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid (200 mg in 12 mL methylene chloride) Roxybenzotriazole and then 118 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are added and the mixture is stirred at room temperature. After 30 minutes, 0.35 mL of diisobutylamine is added and the mixture is stirred for 14 hours at room temperature. The reaction is then concentrated in vacuo and purified by flash chromatography on silica gel (hexanes: ethyl acetate, 2: 1) to afford the title compound (230 mg).

Step 9.1D

3- (2-aminoethyl) -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid diisobutylamide

{2- [5-Diisobutylcarbamoyl-2- (3,5-dimethylphenyl) -1H-indol-3-yl] -ethyl} carbamic acid tert-butyl ester at 12 ° C. in 12 mL methylene chloride To a solution of 230 mg) is added 0.55 mL of anisol and then 3.4 mL of trifluoroacetic acid and the mixture is stirred at 0 ° C. After 1 hour, the mixture is concentrated in vacuo and the remaining acid is azeotropically distilled with toluene. The concentrate is purified by flash chromatography on silica gel (methylene chloride: methanol: ammonium hydroxide, 90: 8: 1) to afford the title compound (173 mg).

Step 9.1E

2- (3,5-dimethylphenyl) -3- [2- (1-methyl-4-pyridin-3-yl-butylamino) ethyl] -1 H-indole-5-carboxylic acid diisobutylamide

19 mg of 5-pyridin-3-yl- in a solution of 3- (2-aminoethyl) -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid diisobutylamide (142 mg in anhydrous methanol) Pentan-2-one is added, and trifluoroacetic acid is added to adjust the pH to 6. To this is added approximately 10 mg of 3 ′ molecular sieve followed by 27 mg of sodium cyanoborohydride. Trifluoroacetic acid is carefully added over 36 hours to maintain the pH at 6. Then aqueous potassium carbonate and brine are added to quench the reaction and the mixture is extracted with ethyl acetate. The organic fraction is washed successively with aqueous potassium carbonate and brine and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride: methanol: ammonium hydroxide, 90: 8: 1) gave the title compound (32 mg) [m / e = 567 (M + H)] and no reaction. Amine (115 mg) is obtained.

Preparation of Synthetic Intermediates

Step A

4-pyridin-3-yl-butyraldehyde

To a solution of oxalyl chloride (0.74 mL in 5 mL anhydrous methylene chloride) at −78 ° C. is added a solution of methyl sulfoxide (0.90 mL in 5 mL methylene chloride) and the mixture is stirred at low temperature for 15 minutes. A solution of 4-pyridin-3-yl-butan-1-ol (essentially prepared as described in Example 2.1, 820 mg in 10 mL of methylene chloride) and the reaction was allowed to proceed for 45 minutes followed by addition of 4 mL of triethylamine Allow this mixture to warm to room temperature. After 35 minutes, saturated sodium bicarbonate is added and the mixture is extracted with methylene chloride. The organic fractions are washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo to afford the crude title compound (813 mg).

Step B

5-pyridin-3-yl-pentan-2-ol

A solution of 4-pyridin-3-yl-butyraldehyde (133 mg in 1 mL tetrahydrofuran) was added to a solution of methylmagnesium bromide (0.75 mL of 3M diethylether in 3.5 mL anhydrous tetrahydrofuran) at 0 ° C. And keep the mixture at low temperature. After 30 minutes, saturated ammonium chloride is added to quench the reaction and extract with ethyl acetate. The organic fraction is washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride: methanol, 95: 5) affords the title compound (71 mg).

Step C

5-pyridin-3-yl-pentan-2-one

To a solution of oxalyl chloride (0.060 mL in 1 mL anhydrous methylene chloride) at −78 ° C. is added a solution of methyl sulfoxide (0.075 mL in 0.25 mL methylene chloride) and the mixture is stirred at low temperature for 18 minutes. The solution and reaction of 5-pyridin-3-yl-pentan-1-ol (71 mg in 1 mL methylene chloride) was allowed to proceed for 45 minutes before 0.35 mL of triethylamine was added and the mixture was allowed to warm to room temperature. After 35 minutes, water is added and the mixture is extracted with methylene chloride. The organic fraction is washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (methylene chloride: methanol, 96: 4) affords the title compound (61 mg).

Step 9.2

1- {2- [2- (3,5-dimethylphenyl) -1H-indol-3-yl] ethyl} -1,2,3,4,5,6-hexahydro- [4,4 '] BP Lidinyl

Step 9.2A

1- [2- (3,5-dimethylphenyl) -1H-indol-3-yl] -2- (3,4,5,6-tetrahydro-2H- [4,4 '] bipyridinyl-1 -Ethane) ethane-1,2-dione

To a solution of 2- (3,5-dimethylphenyl) -1H-indole (200 mg in 2 mL anhydrous methylene chloride) 0.083 mL of oxalyl chloride is added dropwise and the mixture is stirred at room temperature. After 1 hour, 213 mg of 1,2,3,4,5,6-hexahydro- [4,4 '] bipyridinyl dihydrochloride was added, followed by 1.5 mL of methylene chloride and 0.567 mL of triethylamine. Add the mixture and keep stirring at room temperature. After 4 hours the reaction is diluted with ethyl acetate and washed successively with water, saturated aqueous ammonium chloride and brine. The organic fraction is dried over sodium sulfate and the concentrate is purified by flash chromatography on silica gel (methylene chloride: methanol, 96: 4) to afford the title compound (148 mg).

Step 9.2B

1- {2- [2- (3,5-dimethylphenyl) -1H-indol-3-yl] ethyl} -1,2,3,4,5,6-hexahydro- [4,4 '] BP Lidinyl

1- [2-[(3,5-dimethylphenyl) -1H-indol-3-yl] -2- (3,4,5,6-tetrahydro-2H- [4,4 '] bipyridinyl- To a solution of 1-yl) ethane-1,2-dione (148 mg in anhydrous tetrahydrofuran), 2.71 mL of a lithium aluminum hydride 1M solution in tetrahydrofuran is added dropwise and the mixture is heated to reflux in an oil bath. After 1.5 h, the mixture is cooled and quenched by successively adding 30 mL of water, 4 mL of ammonium hydroxide and 25 mL of ethyl acetate. The mixture is filtered to remove solids. The organic fractions are washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (71 mg). m / e = 410 (M + H).

Example 9.3

2- [2- (3,5-dimethylphenyl) -3- [2- [methyl- [4- (pyridin-4-yl) butyl] amino] ethyl] -1 H-indol-5-yl] -N, N-dibutyl isobutyramide

67 mg (0.113 mmol) 2- [2- (3,5-dimethylphenyl) -3- [2- [methyl- [4- (pyridin-4-yl) butyl] amino] ethyl] -1H-indole-5 -Yl] -N, N-dibutylisobutyramide (prepared according to Example 7.2), partition wall mounted in anhydrous flask containing 33.9 mg (1.3 mmol) paraformaldehyde and 100 mg powdered 3 ′ molecular sieve And completely purge with N ₂ . Then, 2.65 mL of MeOH and 65.2 μl (67.8 mg, 1.13 mmol) of glacial acetic acid are added, and the mixture is stirred at room temperature for 35 minutes. Then 28.4 mg (0.452 mmol) of sodium cyanoborohydride are added and after another 20 minutes 2.5 mL of anhydrous THF is added. After a few minutes, TLC indicates the reaction is complete. Thus, the mixture is filtered and the filtrate is shaken with brine in a separating funnel. The aqueous phase is extracted three more times with CH ₂ Cl ₂ . The combined organic fractions are dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel by flash chromatography on a (99: 1: 0.1 to 95: 5: 0.5 CH ₂ Cl ₂ -MeOH- perch NH ₄ gradient elution with OH) 95: 5: 0.5 CH ₂ Cl ₂ -MeOH -31.1 mg (45%) of the title compound homogeneous by TLC in concentrated NH ₄ OH as a glass. 500 MHz ¹ H NMR (CDCl ₃ ) is consistent with the defined structure. Mass spectrum (ESI): m / e = 609.5 (M + H).

A process similar to that described in Examples 9.1, 9.2 and 9.3 is carried out to prepare the following compounds:

Example 10

{2- [2- (3,5-Dimethylphenyl) -5-methanesulfonyl-1H-indol-3-yl] propyl}-(4-pyridin-4-yl-butyl) amine

Step 10A

2-Methylcyclopropanecarboxylic acid N-methoxy-N-methylamide

To a solution of 2-methylcyclopropanecarboxylic acid (10 g in a mixture of 200 mL benzene and 2 mL N, N-dimethylformamide) at 0 ° C., 10.5 mL of oxalyl chloride was added and the mixture was stirred at 0 ° C. for 30 minutes. Warm to room temperature for 30 minutes. At this time, 14.6 g of N, O-dimethylhydroxylamine hydrochloride is added followed by 41 mL of triethylamine. The mixture is stirred at room temperature for 1 hour and then quenched by addition of saturated sodium bicarbonate. The aqueous fraction is extracted with ethyl acetate and the combined organics are washed with brine, dried over sodium sulphate and concentrated in vacuo. The product is purified by distillation under reduced pressure to give 8.9 g of oil.

Step 10b

(3,5-dimethylphenyl)-(2-methylcyclopropyl) methanone

To a solution of 5-bromo-meth-xylene (5.7 mL in 120 mL anhydrous tetrahydrofuran) at −78 ° C. is added 30.6 mL 1.4 n solution of n-butyllithium in hexane and the mixture is stirred at low temperature. After 15 minutes, a solution of 2-methylcyclopropanecarboxylic acid N-methoxy-N-methyl-amide (5.0 g in 50 mL of tetrahydrofuran) is added dropwise over 5 minutes and the mixture is slowly warmed to room temperature. After 1 hour, 20 mL of 2N hydrochloric acid and 40 mL of water are added to quench the reaction. It is extracted with ethyl acetate, washed with saturated sodium bicarbonate and brine and dried over sodium sulfate to give 6.95 g of the title compound (crude).

Step 10C

2- [2- (3,5-dimethylphenyl) -5-methanesulfonyl-1H-indol-3-yl] propylamine

To a solution of (4-methanesulfonylphenyl) hydrazine (1.88 g in 20 mL of n-butanol) at 95 ° C., 2.24 g of (3,5-dimethylphenyl)-(2-methylcyclopropyl) methanone was added and dissolved in an oil bath. Heat to 110 ° C. After 16 hours, the reaction is cooled to room temperature, poured into 200 mL of diethyl ether and the resulting brown precipitate is collected by filtration. The solid is dissolved in 300 mL of water and extracted with diethyl ether. The aqueous fraction is basified by addition of 1N sodium hydroxide and extracted with diethyl ether. The combined organics are dried over sodium sulphate and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride: methanol, 9: 1) affords the title compound (313 mg).

Step 10D

{2- [2- (3,5-Dimethylphenyl) -5-methanesulfonyl-1H-indol-3-yl] propyl}-(4-pyridin-4-yl-butyl) amine

4-pyridin-4-yl-butyraldehyde (23 mg), 2- [2- (3,5-dimethylphenyl) -5-methanesulfonyl-1H-indol-3-yl] propylamine (50 mg) and sulfuric acid The mixture of magnesium (76 mg) is diluted with 1.5 mL of CDCl ₃ and stirred at -5 ° C. After 15 minutes, a solution of sodium borohydride (6.8 mg in 1.5 mL anhydrous methanol) is added and the mixture is stirred for an additional 20 minutes at low temperature. The reaction is quenched by addition of water, extracted with ethyl acetate and the organic fractions washed successively with water and brine and dried over sodium sulfate. The concentrate is purified by preparative TLC on silica gel (methylene chloride: methanol, 9: 1) to afford the title compound (29 mg). MASS

A process similar to that described in Examples 7 and 10 was performed to prepare the following compounds:

Example 11

2- (3,5-Dichlorophenyl) -3- [2- (4-pyridin-3-yl-butylamino) ethyl] -1 H-indole-5-carboxylic acid diethylamide

Step 11A

2- (3,5-Dichlorophenyl) -3- [2- (4-pyridin-3-yl-butylamino) ethyl] -1 H-indole-5-carboxylic acid ethyl ester

3- (2-aminoethyl) -2- (3,5-dichlorophenyl) -1H-indole-5-carboxylic acid ethyl ester at −5 ° C. (prepared as described in Example 5.1, 100 mg in 7.0 mL of chloroform To 172 mg of magnesium sulfate and then 46.3 mg of 4-pyridin-3-yl-butyraldehyde are added and the mixture is stirred at low temperature for 15 minutes. At this time, a solution of sodium borohydride (13.7 mg in 1.2 mL of anhydrous methanol) was added, and after 40 minutes, water was added to quench the reaction. The mixture is partitioned between ethyl acetate and saturated potassium carbonate, extracted and the organic fractions are washed with brine and dried over sodium sulfate. The concentrate is purified by flash chromatography on silica gel (methylene chloride: methanol, 92: 8) to afford the title compound (100 mg).

Step 11B

3- {2- [tert-butoxycarbonyl- (4-pyridin-3-yl-butyl) amino] ethyl} -2- (3,5-dichlorophenyl) -1H-indole-5-carboxylic acid ethyl ester

A solution of 2- (3,5-dichlorophenyl) -3- [2- (4-pyridin-3-yl-butylamino) ethyl] -1H-indole-5-carboxylic acid ethyl ester at 0 ° C. (8 mL of anhydrous tetra 331 mg of di-tert-butyl dicarbonate and then an aqueous potassium carbonate solution (215 g in 4 mL of water) are added to 500 mg in hydrofuran, and the suspension obtained is stirred vigorously at 0 ° C. After 1 h, excess saturated aqueous ammonium chloride is added to quench the reaction and the mixture is extracted with ethyl acetate. The organic fraction is dried over sodium sulphate and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (methylene chloride: methanol, 96.5: 3.5) affords the title compound (472 mg).

Step 11c

3- {2- [tert-Butoxycarbonyl- (4-pyridin-3-yl-butyl) amino] ethyl} -2- (3,5-dichlorophenyl) -1 H-indole-5-carboxylic acid

3- {2- [tert-butoxycarbonyl- (4-pyridin-3-yl-butyl) amino] ethyl} -2- (3,5-dichlorophenyl) -1H-indole-5- at 0 ° C To a suspension of carboxylic ethyl ester (65 mg in 4 mL methanol) is added 1.4 mL of 1.25 N sodium hydroxide solution and the mixture is heated to 75 ° C. on an oil bath. After 2.5 hours the mixture is cooled to room temperature and saturated aqueous ammonium chloride is added to quench the reaction. The mixture is extracted with ethyl acetate, washed with saturated ammonium chloride solution and the organic fractions are dried over sodium sulfate. Concentration in vacuo affords the crude title compound (63 mg).

Step 11D

{2- [2- (3,5-Dichlorophenyl) -5-diethylcarbamoyl-1H-indol-3-yl] ethyl}-(4-pyridin-3-yl-butyl) carbamic acid tert-butyl ester

3- {2- [tert-Butoxycarbonyl- (4-pyridin-3-yl-butyl) amino] ethyl} -2- (3,5-dichlorophenyl) -1 H-indole-5-carboxylic acid (6 mL To 24.2 mg of 1-hydroxybenzotriazole followed by 26.7 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and stirred at room temperature do. After 30 minutes, 0.06 mL of diethylamine is added and the mixture is stirred for 16 hours at room temperature. The reaction is concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride: methanol, 95: 5) to afford the title compound (63 mg).

Step 11E

2- (3,5-Dichlorophenyl) -3- [2- (4-pyridin-3-yl-butylamino) ethyl] -1 H-indole-5-carboxylic acid diethylamide

{2- [2- (3,5-Dichlorophenyl) -5-diethylcarbamoyl-1H-indol-3-yl] ethyl}-(4-pyridin-3-yl-butyl) carbamic acid 3 at 0 ° C To a solution of the tert-butyl ester (63 mg in 3 mL methylene chloride) is added 0.15 mL of anisole and then 0.76 mL of trifluoroacetic acid and the mixture is stirred at 0 ° C. After 1.5 hours, additional 0.5 mL of trifluoroacetic acid is added and stirring is continued for an additional hour, at which time the mixture is concentrated in vacuo and the remaining acid is removed by azeotropic distillation with toluene. The concentrate is purified by flash chromatography on silica gel (methylene chloride: methanol: ammonium hydroxide, 90: 6.5: 1) to afford the title compound (38 mg). m / e = 537 (M)

A process similar to that described in Example 11 was performed to prepare the following compounds:

Example 12.1

1- {2- (3,5-dimethylphenyl) -3- [2- (4-pyridin-4-yl-butylamino-ethyl] -1H-indol-5-yl} ethanone

Step 12.1A

3- {2- [tert-Butoxycarbonyl- (4-pyridin-4-yl-butyl) -amino] -ethyl} -2- (3,5-dimethylphenyl) -1 H-indole-5-carboxylic acid Ethyl ester

2- (3,5-Dimethylphenyl) -3- [2- [4- (pyridin-4-yl) butylamino] -ethyl] -1 H-indole-5-carboxylic acid ethyl ester (Example 5.1, Step B) Starting from essentially essentially as described in Example 9.1 Step A, the title compound is obtained.

Step12.1B

3- {2- [tert-butoxycarbonyl- (4-pyridin-4-yl-butyl) amino] ethyl} -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid

3- {2- (tert-butoxycarbonyl- (4-pyridin-4-yl-butyl) -amino] -ethyl} -2- (3,5-dimethylphenyl) -1H-indole-5-carboxylic acid Starting from ethyl ester and made essentially as described in Example 9.1 Step B using lithium hydroxide to afford the title compound.

Step 12.1C

{2- [2- (3,5-Dimethylphenyl) -5- (methoxymethylcarbamoyl) -1H-indol-3-yl] -ethyl} (4-pyridin-4-yl-butyl) carbamic acid 3 Class-butyl ester

3- {2- [tert-butoxycarbonyl- (4-pyridin-4-yl-butyl) amino] ethyl} -2- (3,5-dimethylphenyl) -1H-indole-5- at 0 ° C To a solution of carboxylic acid (1.44 g in 25 mL N, N-dimethylformamide) 540 mg of 1-hydroxybenzotriazole (HOBt) followed by 0.44 mL of 4-methylmorpholine and 365 mg of N, O-dimethylhydroxyl Amine hydrochloride is added. After 15 minutes, 815 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) is added and the mixture is allowed to warm to room temperature. After 3 days of reaction time, an additional fraction of 540 mg HOBt, 0.44 mL 4-methylmorpholine, 365 mg N, O-dimethylhydroxylamine hydrochloride and 815 mg EDC are added. After 4 days, the reaction is stopped by concentration in vacuo and reconcentrated from toluene to remove all volatile components. The residue is solvated in ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The concentrate is purified by flash chromatography on silica gel (hexanes: ethyl acetate, 30:70; then 20:80; then 0: 100) to afford the title compound (1.4 g).

Step 12.1D

3- {2- [tert-butoxycarbonyl- (4-pyridin-4-yl-butyl) amino] ethyl} -2- (3,5-dimethylphenyl) -5- (methoxymethylcarbamoyl) Indole-1-carboxylic acid tert-butyl ester

{2- [2- (3,5-Dimethylphenyl) -5- (methoxymethylcarbamoyl) -1H-indol-3-yl] -ethyl} (4-pyridin-4-yl-butyl) carbamic acid 3 Starting from the tert-butyl ester (1.4 g) it is prepared essentially as described in Example 9.1 Step A to give the title compound (1.55 g).

Step 12.1E

5-acetyl-3- {2- [tert-butoxycarbonyl- (4-pyridin-4-yl-butyl) amino] ethyl} -2- (3,5-dimethylphenyl) indole-1-carboxylic acid 3 Class-butyl ester

3- {2- [tert-butoxycarbonyl- (4-pyridin-4-yl-butyl) amino] ethyl} -2- (3,5-dimethylphenyl) -5- (methoxy at -10 ° C To a solution of methylcarbamoyl) indole-1-carboxylic acid tert-butyl ester (0.069 g in 3 mL anhydrous tetrahydrofuran) is added 0.20 mL of 1.5 M methyllithium solution in ether and the mixture is stirred at low temperature. After 45 minutes, the reaction is quenched by addition of saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic fractions are washed with brine, dried over sodium sulfate and the concentrate is purified by preparative TLC on silica gel (hexanes: ethyl acetate, 2: 3) to afford the title compound (58 mg).

Step 12.1F

1- {2- (3,5-dimethylphenyl) -3- [2- (4-pyridin-4-yl-butylamino) ethyl] -1H-indol-5-yl} ethanone

5-acetyl-3- {2- [tert-butoxycarbonyl- (4-pyridin-4-yl-butyl) amino] ethyl} -2- (3,5-dimethylphenyl) indole-1-carboxylic acid 3 Starting from the tert-butyl ester (120 mg) it is prepared essentially as described in Example 9.1, Step D to afford the title compound (82 mg). m / e = 440 (M + H).

Example 12.2

1- {2- (3,5-dimethylphenyl) -3- [2- (4-pyridin-4-yl-butylamino) ethyl] -1H-indol-5-yl} ethanol

A solution of 1- {2- (3,5-dimethylphenyl) -3- [2- (4-pyridin-4-yl-butylamino) ethyl] -1H-indol-5-yl} ethanone at 0 ° C. (2 mL 0.30 mL of a 1 M solution of lithium aluminum hydride in tetrahydrofuran is added to 45 mg of anhydrous tetrahydrofuran) and the mixture is stirred at low temperature. After 45 minutes, the reaction is quenched by addition of saturated aqueous ammonium chloride and the mixture is extracted with ethyl acetate. The organic fractions are washed with brine, dried over sodium sulfate and purified by flash chromatography on silica gel (methylene chloride: methanol: ammonium hydroxide, 90: 10: 0.25) to afford the title compound (40 mg). m / e = 442 (M + H).

Example 12.3

1- {2- (3,5-dimethylphenyl) -3- [2- (4-pyridin-4-yl-butylamino) ethyl] -1H-indol-5-yl} ethanone O-methyloxime

A solution of 1- {2- (3,5-dimethylphenyl) -3- [2- (4-pyridin-4-yl-butylamino) ethyl] -1H-indol-5-yl} ethanone (0.50 mL methanol To 22 mg), 102 mg of sodium acetate (trihydrate) and then 63 mg of methoxylamine hydrochloride are added and the mixture is stirred at room temperature. After 20 hours, the mixture is concentrated in vacuo, the residue is suspended in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate and brine. The organic fraction is dried over sodium sulfate and the concentrate is purified by preparative TLC on silica gel (methylene chloride: methanol: ammonium hydroxide, 90: 10: 0.25) to give the title compound (23 mg). m / e = 469 (M + H).

A process similar to that described in Examples 12.1, 12.2, and 12.3 is performed to prepare the following compounds:

Example 13

A process similar to that described in Examples 1-12 is performed to prepare the following compounds:

Claims (31)

Compounds of formula (I) or pharmaceutically acceptable addition salts and / or hydrates thereof, where appropriate geometric or optical isomers or racemic mixtures thereof. Formula I In the above formula, A is C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, substituted C ₃ -C ₇ cycloalkyl, C ₃ -C ₆ alkenyl, substituted C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, substituted C ₃ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, or C ₀ -C ₅ alkyl-S (O) _n -C ₀ -C ₅ alkyl, C ₀ -C ₅ alkyl-OC ₀ -C ₅ alkyl, C ₀ -C ₅ alkyl-NR ₁₈ -C ₀ -C ₅ alkyl, where R ₁₈ and C ₀ -C ₅ alkyl are linked Or a single bond, R ₀ is hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl where the substituents are as defined below, aryl, substituted aryl, aralkyl or substituted aralkyl where the substituents are As defined in R ₃ , R ₄ and R ₅ ); R ₁ is ego; R ₂ is hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, alkyl-OR ₁₁ , C ₁ -C ₆ (NR ₁₁ R ₁₂ ), C ₁ -C ₆ (CONR ₁₁ R ₁₂ ) or C (NR ₁₁ R ₁₂ ) NH, R ₂ and A together form a 5 to 7 membered ring; R ₃ , R ₄ and R ₅ are independently hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl, CN, nitro , C ₁ -C ₃ perfluoroalkyl, C ₁ -C ₃ perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, R ₁₁ O (CH ₂ ) _P- , R ₁₁ C (O ) O (CH ₂ ) _P- , R ₁₁ OC (O) (CH ₂ ) _P -,-(CH ₂ ) _P S (O) _n R ₁₇ , wherein R ₁₇ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₃ perfluoroalkyl, aryl or substituted aryl),-(CH ₂ ) _P C (O) NR ₁₁ R ₁₂ or halogen, R ₃ and R ₄ together form a carbocyclic ring of 3 to 7 carbon atoms or a heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and S, R ₆ is hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, aryl, substituted aryl, C ₁ -C ₃ perfluoroalkyl, CN, NO ₂ , halogen, R ₁₁ O (CH ₂ ) _P- , NR ₁₂ C (O) R ₁₁ , NR ₁₂ C (O) NR ₁₁ R ₁₂ or SO _n R ₁₁ , R ₇ is hydrogen, C ₁ -C ₆ alkyl, or substituted C ₁ -C ₆ alkyl, provided that R ₇ is absent when X is not hydrogen or halogen, R ₈ is hydrogen, C (O) OR ₉ , C (O) NR ₁₁ R ₁₂ , NR ₁₁ R ₁₂ , C (O) R ₁₁ , NR ₁₂ C (O) R ₁₁ , NR ₁₂ C (O) NR ₁₁ R ₁₂ , NR ₁₂ S (O) ₂ R ₁₁ , NR ₁₂ S (O) ₂ NR ₁₁ R ₁₂ , OC (O) R ₁₁ , OC (O) NR ₁₁ R ₁₂ , OR ₁₁ , SO _n R ₁₁ , S (O) _n NR ₁₁ R ₁₂ , C ₁ -C ₆ alkyl or substituted C ₁ -C ₆ alkyl, provided that when ₈ is not hydrogen or halogen, R ₈ is absent, R ₇ and R ₈ together form a 3-7 membered carbocyclic ring, R ₉ and R _9a are independently hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, aryl or substituted aryl, aralkyl or substituted aralkyl when m is not 0; R ₉ and R _9a together are a 3-7 membered carbocyclic ring when m is not 0, or Form the R ₉ and A form a heterocyclic ring comprising 3 to 7 carbon atoms and one or more heteroatoms when m is not 0, or R ₁₀ and R _10a are independently hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl, R ₁₀ and R _10a together are a 3-7 membered carbocyclic ring or Form the R ₉ and R ₁₀ together form a carbocyclic ring of 3 to 7 carbon atoms or a heterocyclic ring comprising one or more heteroatoms when m is not 0, or R ₉ and R ₂ together form a heterocyclic ring comprising 3 to 7 carbon atoms and one or more heteroatoms when m is not 0, or R ₁₀ and R ₂ together form a heterocyclic ring comprising 3 to 7 carbon atoms and one or more heteroatoms, R ₁₀ and A together form a heterocyclic ring comprising 3 to 7 carbon atoms and one or more heteroatoms, R ₁₁ and R ₁₂ are independently hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, a 3-7 membered carbocyclic ring or Substituted carbocyclic ring containing 3 to 7 atoms, or R ₁₁ and R ₁₂ together may form an unsubstituted or substituted 3-7 membered ring, R ₁₃ is hydrogen, OH, NR ₇ R ₈ , NR ₁₁ SO ₂ (C ₁ -C ₆ alkyl), NR ₁₁ SO ₂ (substituted C ₁ -C ₆ alkyl), NR ₁₁ SO ₂ (aryl), NR ₁₁ SO ₂ (substituted aryl), NR ₁₁ SO ₂ (C ₁ -C ₃ perfluoroalkyl), SO ₂ NR ₁₁ (C ₁ -C ₆ alkyl), SO ₂ NR ₁₁ (substituted C ₁ -C ₆ alkyl ), SO ₂ NR ₁₁ (aryl), SO ₂ NR ₁₁ (substituted aryl), SO ₂ NR ₁₁ (C ₁ -C ₃ perfluoroalkyl), SO ₂ NR ₁₁ (C (O) C ₁ -C ₆ Alkyl), SO ₂ NR ₁₁ (C (O) -substituted C ₁ -C ₆ alkyl), SO ₂ NR ₁₁ (C (O) -aryl), SO ₂ NR ₁₁ (C (O) -substituted aryl) , S (O) _n (C ₁ -C ₆ alkyl), S (O) _n (substituted C ₁ -C ₆ alkyl), S (O) _n (aryl), S (O) _n (substituted aryl) , C ₁ -C ₃ perfluoroalkyl, C ₁ -C ₃ perfluoroalkoxy, C ₁ -C ₆ alkoxy, substituted C ₁ -C ₆ alkoxy, COOH, halogen, NO ₂ or CN, R ₁₄ and R ₁₅ are independently hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, substituted C _2- C ₆ Al, CN, nitro, C ₁ -C ₃ perfluoroalkyl, C ₁ -C ₃ perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, R ₁₁ O (CH ₂ ) _p- , R ₁₁ C (O) O ( CH ₂ ) _p- , R ₁₁ OC (O) (CH ₂ ) _P -,-(CH ₂ ) _P S (O) _n R ₁₇ , wherein R ₁₇ is hydrogen, C ₁ -C ₆ alkyl, C _1- C ₃ perfluoroalkyl, aryl or substituted aryl),-(CH ₂ ) _P C (O) NR ₁₁ R ₁₂ or halogen; R ₁₆ is hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl or N (R ₁₁ R ₁₂ ), R ₁₈ is hydrogen, C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, C (O) OR ₉ , C (O) NR ₁₁ R ₁₂ , C (O) R ₁₁ , S (O) _n R ₁₁ , R ₁₉ is as defined in R ₁₃ or R ₁₄ , X is hydrogen, halogen, N, O, S (O) _n , C (O), (CR ₁₁ R ₁₂ ) _p , C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl, C _2- C ₆ alkynyl, or substituted C ₂ -C ₆ alkynyl, when X is hydrogen or halogen R ₇ and R ₈ are absent, and _{X O, S (O) n} , C (O), or CR ₁₁ For R ₁₂ only R ₇ or R ₈ is possible, Z is O, S or NR ₁₁ , m is 0 to 3, n is 0 to 2, p is 0 to 4, Alkyl, alkenyl and alkynyl substituents include C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, hydroxy, oxo, cyano, C ₁ -C ₆ alkoxy, fluoro, C (O) OR ₁₁ , aryl C ₁ -C ₃ alkoxy, substituted aryl C ₁ -C ₃ alkoxy and the aryl substituents are as defined in R ₃ , R ₄ and R ₅ . The compound of claim 1, wherein the formula is: In the above formula, R ₁ , R ₃ , R ₄ , R ₅ and A are the same combinations: R ₁ R ₃ , R ₄ , R ₅ A Pyridine-NH-COCH ₃ 3,4-OMe CH ₂ -O Pyridine-NH ₂ 3,4-OMe CH ₂ -O The compound of claim 1, wherein the formula is: In the above formula, R ₁ , R ₃ , R ₄ , R ₅ and A are the same combinations: The compound of claim 1, wherein the formula is: In the above formula, R ₁ , R ₃ , R ₄ , R ₅ and XR ₇ , R ₈ are the same combinations: XR ₇ , R ₈ R ₁ R ₃ , R ₄ , R ₅ H 5-benzimidazole-N-SO ₂ Me 3,4-OMe H 5-benzimidazole 3,4-OMe The compound of claim 1, wherein the formula is: In the above formula, A, R ₁ , R ₆ , XR ₇ and R ₈ are the same combinations: XR ₇ , R ₈ A = (CH ₂ ) _n R ₁ The compound of claim 1, wherein the formula is: In the above formula, R ₁ , R ₆ , XR ₇ and R ₈ are the same combinations: The compound of claim 1, wherein the formula is: In the above formula, R ₁ and A are the same combinations: The compound of claim 1, wherein the formula is: In the above formula, R ₁ , XR ₇ and R ₈ are the same combinations: The compound of claim 1, wherein the formula is: In the above formula, R ₁ , R ₂ and A are the same combinations: The compound of claim 1, wherein the formula is: In the above formula, A, R ₁ , R ₂ , XR ₇ and R ₈ are the same combinations: The compound of claim 1, wherein the formula is: In the above formula, n, R ₁ , XR ₇ , R ₈ , R ₉ , R _9a , R ₁₀ and R _10a are the same combinations: The compound of claim 1, wherein the formula is: In the above formula, R ₁ , XR ₇ and R ₈ are the same combinations: XR ₇ , R ₈ R ₁ The compound of claim 1, wherein the formula is: In the above formula, XR ₇ , R ₈ are the same combination: The compound of claim 1, wherein the formula is: In the above formula, A, R ₁ , R ₂ , XR ₇ , R ₈ , R ₉ , R _9a , R ₁₀ and R _10a are the same combinations: The method of claim 1, a) 1- [2- [2- (3,4-dimethoxyphenyl) -1H-indol-3-yl] ethylamino] -3- (pyridin-4-yloxy) propan-2-ol; b) [2- [2- (3,5-dimethylphenyl) -5-methanesulfonyl-1H-indol-3-yl] ethyl]-(4-pyridin-4-yl-butyl) amine; And c) 3- [2- (3,5-dimethylphenyl) -3- [2- (5-pyridin-4-yl-pentylamino) -ethyl] -1 H-indol-5-yl] -1,1- Dimethylureain compound. A pharmaceutical composition comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier thereof. A method for antagonizing a gonadotropin-releasing hormone in a subject characterized by administering an effective amount of the compound of claim 1 to a subject suffering from a gonadotropin-releasing hormone. 18. The method of claim 17, wherein the disease caused by gonadotropin-releasing hormone is a sex-hormone related condition. 18. The method of claim 17, wherein the disease caused by gonadotropin-releasing hormone is sex-hormone dependent cancer, benign prostate hypertrophy or uterine myoma. 20. The method of claim 19, wherein the sex hormone dependent cancer is selected from the group consisting of prostate cancer, uterine cancer, breast cancer, and pituitary gland cell adenoma. 19. The method of claim 18, wherein the sex hormone dependent condition is selected from the group consisting of endometriosis, polycystic ovarian disease, uterine fibroids, and spring spitting. An effective amount of the compound of claim 1 is administered, thereby administering the subject. An effective amount of the compound of claim 1 is administered to a subject in need of treatment for lupus erythematosus, wherein the subject is treated with lupus erythematosus. An effective amount of the compound of claim 1 is administered to a subject in need of treatment for pizza polar bowel syndrome, the method of treating pizza polar bowel syndrome in the subject. An effective amount of the compound of claim 1 is administered to a subject in need of treatment of premenstrual syndrome, the method of treating premenstrual syndrome in the subject. An effective amount of the compound of claim 1 is administered to a grandmother's subject, and the method of treating grandmothers in the said subject. An effective amount of a compound that stimulates endogenous production or release of growth hormone and an effective amount of the compound of claim 1 are administered to a subject with short stature or growth hormone deficiency, thereby treating short stature or growth hormone deficiency in the subject. . An effective amount of the compound according to claim 1 is administered to a subject in need of treatment for sleep disorders including sleep suffocation, wherein the subject has a sleep disorder including sleep suffocation. A pharmaceutical composition comprising, together with a compound of claim 1, an effective amount of a compound that stimulates endogenous production or release of growth hormone and an inert carrier. A pharmaceutical composition prepared by mixing the compound of claim 1 and a pharmaceutically acceptable carrier thereof. A method for preparing a pharmaceutical composition, comprising mixing the compound of claim 1 and a pharmaceutically acceptable carrier.