CZ183298A3 - Non-peptidic derivatives antagonizing gonadotropin releasing hormone - Google Patents

Abstract

There are disclosed compounds of formula (I) and pharmaceutically acceptable salts thereof which are useful as antagonists of GnRH and as such may be useful for the treatment of a variety of sex-hormone related and other conditions in both men and women.

Description

Field of technology

The invention relates to non-peptide compounds and pharmaceutically acceptable salts thereof, which are useful as gonadotropin-releasing hormone antagonists, and are useful for the treatment of a number of conditions associated with sex hormones in both males and females, and pharmaceutical compositions containing said compounds useful in mammals.

Current state of the art

Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is a decapeptide that plays a key role in human reproduction. The hormone is released from the hypothalamus and acts in 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 responsible for regulating steroid production in the gonads of both sexes, where FSH regulates sperm production in males and follicular development in females. GnRH antagonists and agonists have been shown to be effective in the treatment of certain conditions that require inhibition of LH/FSH release. GnRH-based treatments have been shown to be particularly effective in the treatment of endometriosis, uterine fibroids, polycystic ovarian disease, precocious puberty, and steroid hormone-dependent gonadal cancers, particularly prostate, mammary, and ovarian cancers. GnRH agonists and antagonists have also been used in various artificial insemination methods and have been investigated as possible contraceptive agents in both males and females. Their possible applicability in the treatment of pituitary gonadotrophic adenomas was also found, period • · · ·

-2 sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, excessive hair growth, as adjuncts in growth hormone treatment in children with growth hormone deficiency and in mouse models of lupus. The compounds of the invention can also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, such as growth hormone secretagogues, for example MK-0677, in the treatment and prevention of disorders of calcium, phosphate and bone metabolism, especially for the prevention of bone loss in GnRH antagonist treatment, and in combination with estrogens, progesterones, antiestrogens, antiprogestins and/or androgens to prevent or treat bone loss or hypogonadal symptoms such as hot flashes with GnRH antagonist treatment.

In addition, the compound of the present invention may be administered with a 5α-reductase 2 inhibitor such as finasteride or epristeride; 5α-reductase inhibitor 1 as 5,73-dimethyl-4-aza-5acholestan-3-one, 3-oxo-4-aza-4,7β-dimethyl-163-(4-chlorophenoxy)-5aandrostane, and 3-oxo -4-aza-4,7β-dimethyl-16β-(phenoxy)-5α-androstane as disclosed in WO 03/23420 and WO 95/11254; dual inhibitors of 5α-reductase 1 and 5α-reductase 2 such as 3-oxo-4-aza-17β-(2,5trifluoromethylphenylcarbamoyl)-5α-androstane as described in WO 95/07927; antiandrogens such as flutamide, casodex, and cyproterone acetate, and alpha-1 blockers such as prazosin, terazosin, doxazosin, tamsulosin, and alfuzosin.

The compound of the present invention can further be used in combination with growth hormone, growth hormone-secreting or growth hormone-releasing hormone, to delay puberty in children with growth hormone deficiency, allowing them to continue growing before the epiphyses close and growth stops at puberty.

Common GnRH antagonists are GnRH-like decapeptides that are usually given intravenously or subcutaneously for

their minute activities when given by mouth. These have amino acids substituted usually in positions 1, 2, 3, 6 and 10.

Non-peptide GnRH antagonists offer the option of convenient oral administration. Non-peptide GnRH antagonists have been described in European Application No. 0,219,292 and in De, B. et al., J. Med. Chem., 32, 2036-2038 (1989), in WO 95/28405, WO 95/29900 and EP 0679642, all Takeda Chemical Industries, Ltd.

Substituted indoles known in the art include compounds described in the following patents and patent applications. US Patent No. 5,030,640 describes α-heterocyclic ethanolaminoalkylindoles which are potent β-agonists. US Patent No. 4,544,663 discloses indoleamine derivatives that are said to be useful as agents for reducing male fertility. WO 90/05721 describes alpha-amino-indole-3-acetic acids useful as agents against diabetes, obesity and sclerosis. French patent 2,181,559 describes indole derivatives with sedative, neuroleptic, analgesic, hypotensive, antiserotonin and adrenolytic effects. Belgian patent 879381 discloses 3-aminoalkyl-1-H-indole 5-thioamide and carboxamide derivatives as cardiovascular agents useful for the treatment of elevated blood pressure, Raynaud's disease and migraine.

The essence of the invention

The present invention relates to compounds that are non-peptide GnRH antagonists that can be used to treat a variety of conditions associated with sex hormones in men and women, methods of making them, and pharmaceutical compositions containing them for use in treating mammals.

Due to their effect of antagonizing the hormone GnRH, the compounds of the present invention are useful for the treatment of a number of diseases associated with sex hormones in both men and women. These states include • · · ·

-4 endometriosis, uterine fibroids, polycystic ovary disease, excessive hair growth, premature puberty, malignant tumors dependent on steroid hormones such as cancer of the prostate, mammary glands and ovaries, gonadotrophic adenomas of the pituitary gland, respiratory arrest during sleep, irritable bowel syndrome, premenstrual syndrome and benign prostatic hypertrophy. They are also useful as an adjunctive agent for the treatment of growth hormone deficiency and short stature and for the treatment of systemic lupus erythematosis. Furthermore, the compounds according to the invention can be used in in vitro fertilization and as contraceptives. The compounds may also be useful in combination with androgens, estrogens, progesterones, antiestrogens and antiprogestogens for the treatment of endometriosis, fibroids and in contraception. They may also be used in combination with testosterone or other androgens or antiprogestogens in men as contraception. These compounds may also be used in combination with an angiotensin-converting enzyme inhibitor such as enalapril or captopril, an angiotensin II receptor antagonist such as losartan, or a renin inhibitor for the treatment of uterine fibroids. In addition, the compounds according to the invention can be used in combination with bisphosphonates (bisphosphonic acids) and other agents for the treatment and prevention of calcium, phosphate and bone metabolism disorders, especially in the prevention of bone loss during treatment with GnRH antagonists and in combination with estrogens, progesterones and/or or androgens to prevent or treat bone loss or hypogonadal symptoms such as hot flashes during GnRH antagonist treatment.

In addition, the compound of the invention may be co-administered with a 5cc-reductase 2 inhibitor such as finasteride or epristeride; a 5α-reductase 1 inhibitor such as 4,73-dimethyl-4-aza-5α-cholestane3-one, 3-oxo-4-aza-4,7β-dimethyl-16β-(4-chlorophenoxy)-5α-androstane, and 3-oxo-4-aza-4,73-dimethyl-163-(phenoxy)-5α-androstane as described in WO 93/23420 and WO 95/11254; dual 5a inhibitors · ·· ··

- 5-reductase 1 and 5α-reductase 2 such as 3-oxo-4-aza-173-(2,5trifluoromethylphenyl-carbamoyl)-5α-androstane as described in WO 95/07927; antiandrogens such as flutamide, casodex, and cyproterone acetate, and alpha-1 blockers such as prazosin, terazosin, doxazosin, tamsulosin, and alfuzosin.

Furthermore, the compound of the present invention can be used in combination with growth hormone, growth hormone-releasing or secreting hormone, to delay puberty in children with growth hormone deficiency, allowing them to continue growing before the epiphyses close and growth stops at puberty.

The present invention relates to compounds of the general 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, Co-Cs alkyl-O-Co-Cs alkyl, C ₀ -C ₅ alkyl-NR 18 -Co-C ₅ alkyl, where R ₁₈ and C 1 -C 5 alkyl may be joined to form a ring, ^r 16 or a single bond.

·♦»· ·· • · · · • · · · • · · · · · • · ·

R o is hydrogen, C 1 -C ₆ alkyl, substituted C 1 -C ₆ alkyl, wherein the substituents are as defined below; aryl, substituted aryl, aralkyl or substituted aralkyl, wherein the substituents are as defined for R ₃ , R ₄ and R ₅ .

Ri is

R ₂ is hydrogen, C 1 -C ₆ alkyl, substituted C 6 -C 6 alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, alkyl-ORn, C ^{1 -} C 6 (NRiiRi ₂ )i Ci-Cs(C0NRiiRi 2 ) or C 1NRuR^NH ;

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

R ₃ , R ₄ and R ₅ are independently a hydrogen atom, C 1 -C ₅ alkyl, substituted C 1 -C ₆ alkyl, C ₂ -C ₆ alkenyl, substituted C ₂ 25 ··· · ····

-7C ₆ alkenyl, CN, nitro, C^Cs perfluoroalkyl, C^Cs perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, RnO(CH ₂ )p-, RnC(0)0(CH ₂ ) _P -, RiiOC (O)(CH ₂ ) _p -, -(CH ₂ ) _p S(O) _n R ₁₇ , -(CH ₂ ) pC(O)NR n R ₁₂ or halogen; where R ₁₇ is hydrogen, C 1 -C ₆ alkyl, C 1 -C 6 perfluoroalkyl, aryl or substituted aryl;

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

R ₆ is a hydrogen atom, Ci-C ₆ alkyl, substituted Ci-C ₆ alkyl, aryl, substituted aryl, C1-C3 perfluoroalkyl, CN, NO ₂ , halogen, RiiO(CH ₂ ) _p -, NR ₁₂ C(0) Rh, NRi ₂ C(O)NRhR ₁₂ or SO _n Ru;

R ₇ is hydrogen, C 1 -C ₆ alkyl or substituted C 1 -C ₆ alkyl, if X is hydrogen or halogen then R ₇ is not present;

R ₈ is a hydrogen atom, C(O)OR ₉ , C(0)NRnR ₁₂ , NR11R12, C(0)Rn, NRuCÍOjRn, NRi ₂ C(O)NRnR ₁₂ , NR ₁₂ S(0) ₂ Rh, NR ₁₂ S(O) ₂ NRnR ₁₂ , 0C(0)Rn, 0C(0)NRnR ₁₂ , ORn,

SO _n Rn, S(0) _n NRnR ₁₂ , ΟνΟ ₆ alkyl or substituted CiC ₆ alkyl, if X is hydrogen or halogen then R ₈ is not present; or

R ₇ and R ₈ together form a carbocyclic ring of 3-7 atoms;

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, where m + 0; or

O

R ₉ and R _9a together form a carbocyclic ring of 3-7 atoms or || where m ψ 0

R ₉ and A together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms where m + 0; or ··*· » »···

- 8 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; or

O

R10 and _R10a together form a carbocyclic ring of 3-7 atoms or ||;

R ₉ and R 10 together form a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing one or more heteroatoms, where m * 0; or

R ₉ and R ₂ together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms, where m * 0; or

R ₁₀ and R ₂ together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;

R ₁₀ and A together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; or

R n and R ₁₂ are independently hydrogen, C 1 -C ₆ alkyl, substituted C 1 -C ₆ alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, carbocyclic ring of 3-7 atoms or substituted carbocyclic ring containing 3-7 atoms;

Rn and Ri ₂ together can form an optionally substituted ring with 3 7 atoms;

R ₁₃ is a hydrogen atom, OH, NRyRe, NR ₁₁ SO ₂ (C ₁ -C ₆ alkyl), NR _n SO ₂ (substituted Ci-C ₆ alkyl), NRnSO ₂ (aryl), NRnSO ₂ (substituted aryl), NRnS0 ₂ (C 1 -C ₃ perfluoroalkyl); SO ₂ NRn(C 1 -C ₆ alkyl), SO ₂ NRn (substituted C 1 -C ₆ alkyl), SO ₂ NRn (aryl), SO ₂ NRn (substituted aryl), SO ₂ NRu (C _{1 -C 3} perfluoroalkyl); SO ₂ NR n (C(O)C 1 -C ₆ alkyl); SO ₂ NR _n (C(O)substituted CH-Ce alkyl); SO ₂ NR n (C(O)-aryl); SO ₂ NRn(C(O)-substituted aryl); 3(0),,((^-06 alkyl); S(O) _n (substituted Ci-C ₆ alkyl), S(O) _n (aryl), S(O) _n (substituted aryl), Ci-C ₃ perfluoroalkyl, Ci-C ₃ •4 4444 • 4

4 ··

-9perfluoroalkoxy, 0ι-0β alkoxy, substituted Ct-Cs alkoxy, COOH, halogen, NO ₂ or CN;

R _u and R ₁₅ are independently hydrogen, C ₁ -C 6 alkyl, substituted C 0 -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, RhO(CH ₂ ) _p -, RuCíOJOCCH^p-, R ₁₁ OC(O)(CH ₂ ) _p -, -(CH _2p S(O) _n Ri7, -(CH ₂ ) _p C(O)NR n R ₁₂ or halogen, where R _{j 7} is hydrogen, C 1 -C ₆ alkyl, C 1 -C 5 perfluoroalkyl, aryl or substituted aryl;

R _{1 6} is a hydrogen atom, C 1 -C ₆ alkyl, substituted C 1 -C 8 alkyl, or N(RhR _{1 2} );

R ₁₈ is a hydrogen atom, C 1-C ₆ alkyl, substituted C-.-C ₆ alkyl, C(O)OR ₉ , C(O)NR„R ₁₂ , C(O)R _n , S(O) _n R _1i;

R 19 is always as defined for R ₁₃ or R ₁₄ ;

X is a hydrogen atom, halogen, N, O, S(O) _n , C(O), (CRnR 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; where X is hydrogen or halogen, R ₇ and R ₃ are absent; where X is O, S(O) _n , C(O), or CRuR ₁₂ only R ₇ or R ₈ is possible;

Z is O, S or NR n ;

m is 0-3;

n is 0-2;

p is 0-4; and the alkyl, alkenyl and alkynyl substituents are selected from the group Ci-C ₆ alkyl, C ₃ -C ₇ cycloalkyl, aryl, substituted aryl, aralkyl substituted aralkyl, hydroxy, oxo, cyano, C^Ce alkoxy, fluorine, C(0) 0Rn, aryl C1-C3 alkoxy, substituted • · · · · · • ·

- 10 aryl C 1 -C ₃ alkoxy, and the aryl substituents are as defined for R ₃ , R ₄ and R ₅ ;

or pharmaceutically acceptable addition salts or hydrates thereof, or where applicable, a geometric or optical isomer or racemic mixture.

Unless otherwise stated or indicated, the following definitions shall apply in the description and claims.

If any variable (eg, aryl, heterocycle, Ri, etc.) occurs more than once in any component of formula I, its iq definition for each occurrence is independent of its definition for each subsequent occurrence. Combinations of substituents and/or variables are permissible only if these combinations result in stable compounds.

The term "alkyl" refers to both branched and straight saturated 15 aliphatic hydrocarbon groups with a specified number of carbon atoms, e.g. methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl , dodecyl and their isomers such as isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane, etc.

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

The term "halogen" or "halo" is intended to refer to fluorine, chlorine, bromine and iodine.

As used herein, the term "composition" is intended to include a product containing specific ingredients in specified amounts, as well as any product that results, directly or indirectly, from a combination of specific ingredients in specified amounts.

It is believed that the linking group A can be attached to any of the available carbon atoms or heteroatoms of the heteroaromatic groups Ri, including both rings per benzene ring

3o fused heterocyclic groups, and similarly R ₁₃ , R ₁₄ and R ₁₅ can • · · · • · ·· • · ·· · · · · · · ·· » ♦· · ·· ··

-11 to be attached to any of the available carbon atoms, heteroaromatic groups Rv

Additionally, it is well known to those skilled in the art that many of the heterocyclic groups disclosed may exist in more than one tautomeric form. All such tautomers are intended to be included within the scope of the invention.

The scope of the invention includes these optical isomeric forms, i.e. mixtures of enantiomers or diastereomers, for example racemates, as well as individual enantiomers or diastereomers of the mentioned compounds.

These individual enantiomers are denoted in the usual way according to the optical rotation caused by them by the symbols (+) and (-), (L) and (D), (I) and (d) or their combinations. These isomers may also be designated according to their absolute spatial configuration by the letters (S) and (R), meaning sinister and rectus.

The individual optical isomers can be prepared using common resolution procedures, for example by treatment with a suitable optically active acid, resolution of the diastereomers and recovery of the desired isomer. Additionally, individual optical isomers can be produced by asymmetric synthesis.

In addition, the given chemical formula or name will include pharmaceutically acceptable addition salts and solvates such as hydrates.

The compounds of the present invention, when effective by themselves, may be administered in compositions in the form of their pharmaceutically acceptable addition salts for reasons of stability, ease of crystallization, increased solubility, and other desirable properties.

The compounds of the invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" is intended to include all acceptable salts. Examples of acids that can be used to form salts are hydrochloric acid, nitric acid, sulfuric acid, · · ·· · ···· · • · · · · ··· ··«· ·· · · · * ·

-12phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, amber, malonic, methanesulfonic, etc., which can be used as a dosage form to modify solubility or hydrolysis characteristics or can be used to obtain delayed release or to obtain precursors. Depending on the particular functional groups present in the compounds of the present invention, pharmaceutically acceptable salts of the compounds of the invention include salts formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonium ion, ethylenediamine, N-methylglutamine, lysine, arginine, ornithine, choline, N,N'dibenzylethylenediamine, chlorprocaine, diethanolamine, procaine, Nbenzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts can be prepared by standard procedures, for example by reacting the free acid with a suitable organic or inorganic base, or alternatively by reacting the free base with a suitable organic or inorganic acid.

In the event that an acid (-COOH) or alcohol group is also present in the compound, pharmaceutically acceptable esters can also be used, for example methyl, ethyl, butyl, acetate, maleate, pivaloyloxymethyl, etc. and esters known in the art for solubility modification or hydrolysis characteristics for use in sustained release formulations or with prodrugs.

The compounds of the present invention may have chiral centers other than those whose stereochemical state is shown in formula I, and therefore may exist in the form of racemates, racemic mixtures and as single enantiomers or diastereomers, all of these isomeric forms being included within the scope of the invention as well as their mixtures. In addition, some crystalline forms of the compounds of the present invention may exist as polymorphs and as such are also included within the scope of the present invention. In addition

-13 some compounds according to the present invention can form solvates with water or common organic solvents. These solvates are also included within the scope of the invention.

The compounds of the invention are prepared according to the following 5 reaction schemes. All substituents are as defined above unless otherwise noted.

• · · · • · • · · · • 9 9 φ • · ·· ··

- 14 Scheme A

pyridine «ΗΒγ·5γ ₂

---->THF/I WANT ₃

B(OH) ₂

R/R,

Na ₂ CO ₃ , Lici Pd(PPh ₃ ) ₄ toluene /EtOH

H ₂ NNH ₂

THF/EtOH

β···

- 15 Reaction scheme A

As shown in Reaction Scheme A, treatment of N-carboxyphthalimide in an inert organic solvent such as tetrahydrofuran at a temperature of 20 to 65 °C, preferably 65 °C, for 12 to 48 hours, on tryptamine (1) affords the corresponding N-phthalimidotryptamine derivative (2) . N-phthalimidotryptamine (2) can be further modified by the action of a brominating agent such as pyridinium bromide perbromide, pyrrolidone tribromide, etc. in an inert organic solvent such as tetrahydrofuran, methylene chloride, chloroform, or mixtures thereof at 0 to 25 °C for 30 min to 4 hours to form 2-bromotryptamine (3). Bromide (3) can be reacted with an arylboronic acid (prepared as described in: Gronowitz, S.; Hornfeldt, A.B.; Yang, A.H., Chem. Ser. 1986, 26, 311-314) catalyzed by palladium, a weak base such as aqueous carbonate sodium etc. and a source of chloride ions such as lithium chloride in an inert solvent such as toluene, benzene, ethanol, propanol or a mixture thereof at a temperature of 25 to 100°C, preferably 80°C, for a period of 1 to 6 hours to provide a 2-aryltryptamine derivative ( 4). Finally, it is possible to remove the phthalimide group by the action of aqueous hydrazine in an inert solution

2o a solvent such as methanol or ethanol at 0 to 25°C for 4 to 24 hours to substance (4) to obtain tryptamine (5).

····

- 16 Scheme B

ΗΟ^(Α) _D

II

triethylamine

CH2CH

Reaction scheme B

As shown in Reaction Scheme B, 2-aryltryptamine can be fused with a carboxylic acid of type (6) using the coupling agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC), etc. with or without the presence of 1-hydroxybenztriazole (HOBt) and a tertiary amine base such as N-methylmorpholine (NMM), triethylamine, etc., in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide or mixtures thereof at room temperature or a similar temperature for 3 to 24 hours to give the corresponding amide derivative (7). Alternatively, 2-aryltryptamine (5) is treated with an active ester or acid chloride of the type (8) in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, diethyl ether, etc. and a tertiary amine base such as triethylamine, diisopropylethylamine , pyridine, etc. at a temperature of 0 to 25 °C for a period of 30 min to 4 hours to provide substance (7).

Scheme C • φφ • · φ « φ φ » φφφ φ · • · · φ · φφφ φφφφ. φφ φ ·· · ·

R ₅ R«t

Reaction scheme C

As shown in reaction scheme C, the amide carbonyl of substance (7) can be reduced by treatment with borane, lithium aluminum hydride or equivalent hydride sources in an inert organic solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane, etc. at a temperature of 25 to 100 °C, preferably 65 °C, for 1 to 8 hours to give the corresponding amine compound (9).

·· · · · ·

Scheme D

At 10 (A)-Ri

->TFA, 0.3 nm sieves NaCNBH ₃ , MeOH

Reaction scheme D

As seen in reaction scheme D, 2-aryltryptamine (5) can be modified by treatment with an aldehyde or ketone type (10) in the presence of a weak acid such as trifluoroacetic acid (TFA), acetic acid, etc. in the presence or absence of a drying agent such as molecular sieves 0.3 nm or magnesium sulfate and hydride sources such as sodium borohydride or cyanoborohydride in an inert organic solvent such as methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dichloromethane, chloroform or mixtures thereof at 0 to 25°C for 1 to 12 hours per providing the corresponding secondary or tertiary amine derivative (11)·

Scheme E

•HCl NHNH ₂

methanol/t-butanoi ··· ·

Reaction scheme E

As shown in reaction scheme E, treatment of an arylcyclopropyl ketone of type (13) in a polar organic solvent such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, t15 butanol, preferably n-butanol, at a temperature of 70 to 120 °C for 8 to 24 hours on arylhydrazine or arylhydrazine chloride (12) affords 2-arytryptamine (5). Alternatively, if the arylhydrazine or arylhydrazine chloride (12) is treated with an arylbutylketone of type (14) containing a leaving group (chloride, bromide, iodide, O-methanesulfonate, 020 trifluoromethanesulfonate, etc.) in the 4-position in a polar solvent such as methanol, ethanol, n -propanol, isopropyl alcohol, n-butanol, t-butanol or mixtures thereof at room temperature for 30 minutes to 2 hours, and then the mixture is heated at 65 to 100°C for 4 to 24 hours, 2-aryltryptamine (5) is obtained .

9009 ·· ···· • 0

99 • · · 9

9 99

9 0 9

9 9

9·

-20 Scheme F

Reaction scheme F

As shown in Reaction Scheme F, iodanilines of type (15) can be reacted with arylacetylenes, a suitable palladium catalyst such as tetrakis(triphenylphosphine)palladium, a copper halide such as copper bromide in an inert organic solvent such as triethylamine at 50 to 88 °C for 30 min to 5 h to form diarylacetylene (16). Acetylene (16) can be further modified by treatment with a palladium catalyst such as palladium chloride or palladium acetate in an inert organic solvent such as acetonitrile at 50 to 82 °C for 30 minutes to 6 hours to provide 2-arylindole (17).

44 ·· ·· 4444 ·· 44 • 4 4 1 • 4 44

4 4 «

4 4 ·* 44

Scheme G

Reaction scheme G

As shown in Reaction Scheme G, treatment of oxalyl chloride alone or in an inert organic solvent such as methylene chloride, chloroform, dichloroethane, tetrahydrofuran, etc. at 25 to 65 °C for 3 to 24 hours on 2-arylindole (17) affords the acyl chloride adduct (18). The crude product (18) can react with an amine of type (19) in an inert organic solvent such as diethyl ether, tetrahydrofuran, methylene chloride, chloroform, etc.

and amine bases such as triethylamine, diisopropylethylamine, or pyridine at 0 to 25°C for 30 minutes to 4 hours to provide the amide derivative (20). Amide (20) can be further modified • 44 · • 4 • · 4 4 4 4

4 4 44 • · 4 444 4 4

4 4 4 4 4 •4 4 44 44

-22 by the action of a reducing agent such as borane or lithium aluminum hydride in an inert organic solvent such as tetrahydrofuran at elevated temperatures, preferably under reflux, for 1 to 5 hours to provide compound (21).

Scheme H

Reaction scheme H

As shown in Reaction Scheme H, N-benzyl derivatives of type (22a) or N-benzyloxycarbonyl derivatives of type (22b) can be reduced to give secondary amine analogs (7) by hydrogen (0.1 MPa) and a suitable catalyst such as palladium on coal, palladium hydroxide on coal, etc. in inert

4444 • 4 • 4 4 4 4 4 4 4 4 • · 4 4 4 4 · 4444 4

444 444

444 4 »4 4 44 44

-23 in an organic solvent such as tetrahydrofuran, ethyl acetate, methanol, ethanol, or mixtures thereof, to which a weak acid such as 30% aqueous acetic acid has been added, for 10 min to 3 h, or until the aryl groups have been removed to form a secondary amine.

Scheme I

Reaction scheme I

2o As shown in reaction scheme I, by the action of hydrogen (0.1

MPa) to nitroindole type (24) in the presence of a suitable catalyst such as Raney® Nickel in an inert organic solvent such as ethanol, methanol, etc. at room temperature for 2 to 12 hours, the corresponding aminoindole derivative (25) is formed.

Scheme J • · · · · ·

Reaction scheme J

As shown in reaction scheme J, amino- or hydroxyindole (25) can be modified by acylation under various conditions. For example, by treating substance (25) with an acid chloride, acid anhydride or active ester and amine base such as triethylamine, diisopropylethylamine, pyridine, etc. in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran or mixtures thereof at 0°C at room temperature for From 1 to 12 hours, the corresponding amide or ester derivatives are formed

2o (26). Alternatively, compound (25) can be reacted with a carboxylic acid using one of the many commonly used dehydrating agents. For example, by the action of a suitable carboxylic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), 1,3-dicyclohexylcarbodiimide (DCC) hydrochloride, etc.

to aminoindole (25) with or without 1-hydroxybenztriazole (HOBt) and a tertiary amine base such as N-methylmorpholine (NMM), triethylamine, etc. in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide or mixtures thereof at a temperature close to

4« 4444

4

4 • 44 • 4 4 • 4 44

4 4 4

4 4 4

444 4 4

4 4

44

-25 at room temperature for 3 to 24 hours, the corresponding amide or ester derivative (26) is formed.

Scheme K

,0

27b —>Reaction scheme K

As shown in Reaction Scheme K, the urea or carbamate derivatives of (25) can be prepared by reaction with a carbamoyl chloride of the type (27a), or alternatively with an isocyanate reagent of the type (27b) and an amine base such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine etc. in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or mixtures thereof at a temperature of 0 to 65°C for 1 to 72 hours to form compound (28). Compound (25) can also be modified by the action of a bis(electrophilic) agent such as phosgene, triphosgene, 1,1'-carbonyldiimidazole, Ν,Ν'-disuccinimidyl carbonate, etc.

with or without the addition of an amine base such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine in an inert solvent such as methylene chloride, chloroform, etc. at a temperature of -20 to 0°C for 20 min to 2 hours. After this time, the reaction mixture is treated with a suitable ···· ·· ♦♦··

- 26 with a mono- or disubstituted amine at -20 to -25 °C for 1 to 5 h to give the urea or carbamate analog (28).

Scheme L r ₇ hn

Rg ?2 ,N-(A)-R,

diisopropylethylamine

CH ₂ CI ₂

diisopropylethylamine

CH ₂ CI ₂

Reaction scheme L

As shown in Reaction Scheme L, amine (25) can be modified by treatment with an appropriate sulfonyl chloride of type (29) or sulfamyl chloride of type (30) together with an amine base such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine in an inert solvent such as methylene chloride, chloroform, dichloroethane, etc. at -20 to -25 °C for 20 min to 2 h to give the corresponding N-sulfonamide (31) or N-sulfamylamide (32).

φφ φφφφ • · ··· · φ · · • · φφφφ φ Φ·Φ φ · • · · · * φφφ • ΦΦΦ φφ φ ·· ··

-27 Scheme Μ

Reaction scheme Μ

As shown in Reaction Scheme M, 2-aryltryptamine (33) can be modified by treating the epoxide as (34) in an inert organic solvent such as methanol, ethanol, isopropyl alcohol, butanol, tert-butanol or mixtures thereof at 65 to 110° C for 8 to 20 h to give the corresponding amino alcohol derivative (35).

Scheme N

R^l1 PySOP

CK ₂ C!/rHF • · • · ···· ·· · · • · · · · • · · · ·· • · · ··· · • · · · ·· · ·· ··

Reaction scheme N

As shown in Reaction Scheme N, amide derivatives of an acid-containing indole derivative such as (36) can be prepared by treatment with an appropriate amine (R12R11NH) and a suitable coupling agent such as benztriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), benztriazol-1-yloxy -tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1-(3dimethylethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,3dicyclohexylcarbodiimide (DCC) etc. with or without 1-hydroxybenzotriazole (HOBt) and a tertiary amine base such as Nmethylmorpholine (NMM) , triethylamine or similar substances in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, dimethylformamide or mixtures thereof at near room temperature for 3 to 24 hours to form the corresponding amide derivative (37).

The compounds of the present invention are useful in the treatment of various conditions associated with sex hormones in males and females. This fact is reflected in their ability to act as antagonists of the neuropeptide hormone GnRH, as shown by the activity in the following in vitro tests.

Rat GnRH receptor binding assay? pituitary gland:

Crude plasma membranes prepared from rat pituitary tissues were incubated in Tris.HCL buffer (50 mM, pH 7.5) containing bovine serum albumin (0.1%), [1-125]Dt-Bu-Ser6-Pro9·· ·· ethylamide-GnRH, and the desired concentration of the tested compound. Test mixtures were incubated for 90 to 120 min at 4°C and then rapidly filtered and repeatedly washed on a glass fiber filter. The radioactivity of the membrane-bound radioligands was determined by a gamma counter. From these data, the IC ₅₀ value of radioligand binding to GnRH receptors in the presence of the test compound was estimated.

LH release inhibition test:

Active compounds from the GnRH receptor binding assay were further evaluated in an in vitro LH release assay to confirm their antagonistic activity (blocking GnRH-induced LH release).

1. Sample preparation.

Test compounds were dissolved and diluted in DMSO. The final concentration of DMSO in the incubation medium was 0.5%.

2. Test.

Male Wistar rats (150–20 g) were obtained from Charles River Laboratories (Wilmington, MA). Rats were kept at a constant temperature (25°C) on a 12-hour light/12-hour dark cycle. Food and water were available ad libitum. Animals were sacrificed by decapitation and the pituitary glands were aseptically removed and placed in Hank's Balances Salt Solution (HBSS) in a 50 ml polypropylene centrifuge cuvette. The cuvette was centrifuged for 5 min at 250 x g and the HBSS was removed by suction. Pituitaries were transferred to a disposable Petri dish and finely dissected using a scalpel. The dissected tissue was then transferred to a 50 ml disposable centrifuge cuvette by suspending the tissue fragments three times consecutively in 10 ml HBSS containing 0.2% coiagenase and 0.2% hyaluronidase. The cell dispersion was transferred to a 37°C water bath with gentle agitation for 30 min. At the end of the incubation, the cells were pipetted 20 to 30 times and the uncleaved pituitary fragments were left • · · · • 4 ··· 4 44 4 ·· ··

- 30 3 to 5 minutes to settle. The suspended cells were removed by aspiration and then centrifuged for 5 min at 12,000 g. The cells were then resuspended in the culture medium. Undigested portions of the pituitary glands were digested with 30 ml aliquots of the digestion enzymes as above a total of three times with a collagenase/hyaluronidase mixture. The resulting cell suspensions were pooled, counted, and diluted to a concentration of 3 x 10 ⁵ cells/ml, and 1.0 ml of this suspension was placed in each well of a 24-well dish (Costar, Cambridge, MA). Cells were maintained in a humidified 5% CO2 - 95% air atmosphere at 37°C for 3-4 days. The culture medium consisted 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, the cells were washed three times 1.5 h before the experiment and twice immediately before the start of the experiment with DMEM medium containing 0.37% NaHCO ₃ , 10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids (100 x), 1% glutamine (100 x) 1% penicillin/streptomycin (10,000 units penicillin and 10,000 pg streptomycin per ml) and 25 mM HEPES pH 7.4). LH release was initiated by adding 1 ml of fresh medium containing test compounds in the presence of 2 nM GnRH to each well in duplicate. Incubation was performed at 37°C for 3 h. After incubation, the medium was removed and centrifuged for 15 min at 2000 x g to remove all cellular material. The supernatant was removed and assayed for the presence of LH by a double-antibody RIA procedure using materials obtained from Drs. AF Parlow (Harbor-UCLA Medical Center, Torrance, CA).

The compounds of formula I are useful in a number of areas affected by GnRH. They may be used in the treatment of sex hormone-related conditions, sex hormone-dependent cancers, benign prostatic hypertrophy, or uterine fibroids. Sex hormone-dependent cancers that can be successfully treated by administration of the compounds of this invention include prostate, uterine, • · · · • · ··· · · · ··· ♦ ·· · ·· ··

-31 mammary glands and gonadotrophic pituitary adenomas. Other sex hormone dependent conditions that may be improved by administration of the compounds of the present invention include endometriosis, polycystic ovary disease, uterine fibroids and precocious puberty. The compounds may also be used in combination with an angiotensin converting enzyme inhibitor such as enalapril or captopril or an angiotensin II receptor antagonist such as losartan or a renin inhibitor for the treatment of uterine fibroids.

The compounds of the invention may also be useful for pregnancy management, as male and female contraceptives, for in vitro fertilization, in the treatment of premenstrual syndrome, in the treatment of lupus erythematosis, in the treatment of excessive hair growth, irritable bowel syndrome and sleep disorders such as interrupted breathing in sleep.

Another use of the compounds according to the invention is as adjuvants in the treatment of growth hormone in children with growth hormone deficiency. The compounds may be administered with a growth hormone or a compound that enhances the endogenous production or release of growth hormone. Certain compounds have been developed that stimulate the release of endogenous growth hormone. Peptides known to stimulate the release of endogenous growth hormone include growth hormone-releasing hormone, growth hormone-releasing peptides GHRP-6 and GHRP-1 (described in US Patent No. 4,411,890, PCT Published Patent Application No. WO 89/07110 and published

PCT patent application no. WO 89/07111) and GHRP-2 (described in published PCT patent application No. WO 93/04081) as well as hexarelin (J. Endocrinol Invest., 15 (Suppl. 4), 45 (1992). Other compounds that stimulate the release of endogenous growth hormone, for example, are described in the following literature: US patent No.

3,239,345; US Patent No. 4,036,979; US Patent No. 4,411,890; US Patent No. 5,206,235; US Patent No. 5,283,241; US Patent No.

• ·

0 ·· • · · · 0 0 · • · · * · ·· •0 99 9 9909 0

9 9 · 9 9 ··· · ··· ····

- 32 5,284,841; US Patent No. 5,310,737; US Patent No. 5,317,017; US Patent No. 5,374,721; US Patent No. 5,430,144; US Patent No. 5,434,261; US Patent No. 5,438,136; published patent application EPO No. 0.144.230; published patent application EPO 0,513,974;

published patent application PCT No. WO 94/07486; published patent application PCT No. WO 94/08583; published patent application PCT No. WO 94/11012; published patent application PCT No. WO 94/13696; published patent application PCT No. WO 94/19367; published patent application PCT No. WO 95/03289; io published patent application PCT No. WO 95/03290; published patent application PCT No. WO 95/09633; published patent application PCT No. WO 95/11029; published patent application PCT No. WO 95/12598; published patent application PCT No. WO 95/13069; published patent application PCT No. WO 95/14666;

published patent application PCT No. WO 95/16675; published patent application PCT No. WO 95/16692; published patent application PCT No. WO 95/17422; published patent application PCT No. WO 95/17423; Science, 260, 1640-1643 (June 11, 1993); Ann. Rep., Med. Chem., 28, 177-186 (1993); Bioorg, Med. Chem. Ltrs,. 4 (22),

2709-2714 (1994); and why. Nati. Acad. Sci, USA 92, 7001-7005 (July 1995).

Examples of preferred growth hormone secretagogues used in the present combination include:

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

2) N-[1 (R)-[(1,2-dihydro-1-methanecarbonylspiro[3H-indol-3,4'piperidin]-T-yl)carbonyl]-2-(1H-indol-3-yl )ethyl]-2-amino-230 methylpropanamide;

• 4 of · · · · · · ·· • · 4 4 4 · * ··· · · • · 4 4 4 444

444« ·· · · * ··

-33 3) N-[1 (R)-[(1,2-dihydro-1-benzenesulfonylspiro[3H-indol-3,4'piperidin]-1'-yl)carbonyl]-2-(1H-indole -3-yl)ethyl]-2-amino-2-methylpropanamide;

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

5) N-[1 (R)-[(2-acetyl-1,2,3,4-tetrahydrospiro-[isoquinoline-4,4'piperidine]-1'-yl)carbonyl]-2-(indole-3 -yl)ethyl]-2-amino-2-methylpropanamide;

6) N-[1 (R)-[(1,2-dihydro-1-methanesulfonylspiro-[3H-indol-3,4piperidin]-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;

• · · · • 4 44 ····

- 34 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'-piperidin]-r-yl)carbonyl]-2-(1H -indol-3-yl)ethyl]-2-amino-2-methylpropanamide;

17) N-[1(R)-[(1,2-dihydro-1,1-dioxospiro[3H-benzothiophen-3,4'piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl] -2-amino-2-methylpropanamide;

and pharmaceutically acceptable salts thereof.

The compounds according to the invention can also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, such as growth hormone secreting agents such as MK0677, for the treatment and prevention of calcium, phosphate and bone metabolism disorders, especially for the prevention of bone loss during antagonist treatment GnRH, and in combination with estrogens, progesterones and/or androgens for the prevention and treatment of bone loss or hypogonadal symptoms such as hot flashes during treatment with a GnRH antagonist.

Bisphosphonates (bisphosphonic acids) are known as bone resorption inhibiting compounds and are useful for the treatment of bone lithiasis as described in US Patent 4,621,077 Rosini, et al.

A number of bisphosphonic acids useful in the treatment and prevention of diseases related to bone resorption are described in the literature. Representative examples can be found in the following documents: US patent no. 3,251,907; US Patent No. 3,422,137; US Patent No. 3,584,125; US Patent No. 3,940,436; US Patent No. 3,944,599; US Patent No. 3,962,432; US Patent No. 4,054,598; US • · ♦ ·

- 35 patent No. 4,267,108; US Patent No. 4,327,039; US Patent No. 4,407,761; US Patent No. 4,578,376; US Patent No. 4,621,077; US Patent No. 4,624,947; US Patent No. 4,746,654; US Patent No. 4,761,406; US Patent No. 4,922,007; US Patent No. 4,942,157; US Patent No. 5,227,506; US Patent No. 5,270,365; published application EPO No. 0.252.504; and J. Org. Chem., 36, 3843 (1971).

The production of bisphosphonic acids and halobisphosphonic acids is well known in the art. Examples can be found in the above references which describe these compounds as useful in the treatment of disorders of calcium or phosphate metabolism, particularly as inhibitors of bone resorption. Preferred bisphosphonates are selected from the group of the following compounds: alendronic acid, ethiouric acid, clodronic acid, pamidronic acid, tiludronic acid, risedronic acid, 6-amino-1-hydroxyhexylidenebisphosphonic acid, and 1-hydroxy-3-(methylpentylamino)-propylidenebisphosphonic acid; and pharmaceutically acceptable salts thereof. A particularly preferred bisphosphonate is alendronic acid (alendronate) or a pharmaceutically acceptable salt thereof. A particularly preferred bisphosphonate is alendronate sodium, including alendronate sodium trihydrate. Alendronate sodium has been approved for marketing in the United States under the trade name FOSAMAX®.

The compounds of the present invention may additionally be administered with a 5α-reductase 2 inhibitor such as finasteride or epristeride; 5α-reductase 1 inhibitor such as 4,7β-dimethyl-4-aza-5acholestan-3-one, 3-oxo-4-aza-4,7β-dimethyl-16β-(4-chlorophenoxy)-5aandrostane, and 3- oxo-4-aza-4,73-dimethyl-16β-(phenoxy)-5α-androstane as described in WO 93/23420 and WO 95/11254; with dual inhibitors of 5α-reductase 1 and 5α-reductase 2 such as 3-oxo-4-aza-173(2,5-trifluoromethylphenylcarbamoyl)-5α androstane, described in WO 95/07927; antiandrogens such as flutamide, casodex and cyproterone acetate • · · · • · · φ φ·

-36 and alpha-1 blockers such as prazosin, terazosin, doxazosin, tamsulosin and alfuzosin.

The compounds of the present invention may further be used in combination with growth hormone, growth hormone-releasing hormone, or growth hormone secretagogues to delay puberty in growth hormone-deficient children, allowing them to continue growing before the epiphyses close and growth stops at puberty.

For combination therapy with more than one active ingredient, where the active ingredients are in separate dosage forms, the active ingredients may be administered separately or together. In addition, administration of one component may be performed before, simultaneously with, or after administration of another component.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example as tablets, lozenges, pills, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Formulations intended for oral use may be prepared by any method known in the art and may contain one or more substances selected from the group of sweetening agents, flavoring agents, coloring agents and preservatives to obtain pharmaceutically elegant and patient acceptable pharmaceutical formulations. The tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients, suitable for the production of tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binders such as starch, gelatin or acacia, and glidants such as for example magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known methods for • · · ·

-37 delaying breakdown and absorption in the gastrointestinal tract and thereby providing a delayed effect over a longer period of time. For example, retarding agents such as glycerol monostearate or glycerol distearate can be used. The compositions may also be coated by methods described in US Patent 4,256,108; 4,166,452; and 4,265,874 for the development of controlled release osmotic therapeutic tablets.

Formulations for oral use may also be in the form of hard gelatin capsules where the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with a water or oil medium , for example groundnut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active substance in a mixture with excipients suitable for the production of aqueous suspensions. These excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, dispersing or wetting agents, which can be naturally occurring phosphatides, for example lecithin, or condensation

2o alkylene oxide products with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl-p-hydroxybenzoate, one or

3o more coloring agents, one or more flavoring agents and one or more sweeteners such as sucrose, saccharin or aspartame.

• · ···· • 44 4

• 4 • 4 • 4 • · • 4 ·

- 38 Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oil suspensions may contain a thickening agent such as beeswax, solid paraffin or cetyl alcohol. Sweeteners such as those listed above and flavoring agents may be added to obtain acceptable oral compositions. These agents can be protected by the addition of an antioxidant such as ascorbic acid.

io Dispersible powders and granules suitable for making an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting and suspending agents are already mentioned above in the form of examples. Other excipients may also be present, such as sweeteners, flavoring agents and coloring agents.

Pharmaceutical compositions according to the invention can also be in the form of oil-in-water emulsions. The oil phase can be vegetable oil, e.g. olive oil or peanut oil, or mineral oil, e.g. liquid

2o paraffin or their mixtures. Suitable emulsifying agents can be naturally occurring phosphatides, for example from soybeans, lecithins and esters or partial esters derived from fatty acids and hexitol anhydrides, e.g. sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, e.g.

polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavorings.

Syrups and elixirs can be formulated using sweeteners, eg glycerol, propylene glycol, sorbitol or sucrose. These compositions may also contain a tranquilizer, a preservative, and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension. This

44 ·· ·· ·· • · · 4 • 4 4 4 · · ·

44 4 444

4··· ·· · ·· **

- 39 suspension can be formulated according to the knowledge of the art using such dispersing or wetting agents and suspending agents as mentioned above. Sterile injectables may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, they are commonly used as solvents or suspending media for sterile fixed oils. Any mixture of fixed oil including synthetic mono- or diglycerides can be used for this purpose as well. In addition, they find use in compositions for injectable fatty acids such as oleic acid.

The compounds of formula I may also be administered in the form of suppositories intended for rectal drug administration. These compositions may be prepared by mixing the drug with a suitable non-irritating carrier which is solid at normal temperatures but liquid at rectal temperature and will therefore melt to release the drug. Usable materials are cocoa butter and polyethylene glycols.

2o For topical application, creams, ointments, gels, solutions or suspensions, etc., containing compounds of formula I are used. (For the purposes of this application, topical application will include mouth rinses and gargles.)

The compounds of the present invention may be administered in intranasal form by topical application of a suitable intranasal carrier or by the transdermal route using such forms of transdermal skin patches as are commonly known in the art. For administration in the form of a transdermal system, administration will of course be continuous rather than intermittent throughout the dosing regimen. The compounds of the present invention may also be provided in the form of suppositories using bases such as cocoa butter, glycerolated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters with polyethylene glycol.

The dosage regimen using the compounds of the present invention is selected according to a number of factors including the type, species, age, weight, sex, and medical condition of the patient; seriousness of the condition being treated; routes of administration, renal and hepatic function of the patient; and the specific compounds used. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe an effective amount of the drug required to prevent, prevent, arrest, or prevent the progression of the condition being treated. Optimal accuracy in achieving drug concentration in the effective range without toxic effects requires a regimen based on the kinetics of drug availability to target sites. This requires consideration of drug distribution, equilibrium, and excretion. Advantageously, doses of the compound of formula I according to the present invention will range from 0.01 to 1000 mg per adult per day. More preferably, doses will range from 0.1 to 500 mg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01 to 1000 mg of the active ingredient, namely 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 mg active

2o components for symptomatic dose adjustment in the treated patient. An effective amount of the drug is usually administered at a dose of from about 0.0002 mg/kg to about 50 mg/kg of body weight per day. In particular, the range is from about 0.001 to 1 mg/kg body weight per day.

Advantageously, the active substance according to the present invention is administered in one daily dose, or the total daily dose can be administered in divided doses two, three or four times a day.

The amount of active ingredient may be combined with carrier materials to form an individual dosage form which will vary depending on the patient being treated and the route of administration used.

3o It is understood, of course, that the specific dosage for each patient will depend on a number of factors including age, body weight, ···· « · · · · · • · general health, sex, diet, time of administration, route of administration, rate of excretion , the combination of drugs and the seriousness of the specific disease being treated.

The following examples illustrate the preparation of some of the compounds of the invention and are not intended to be limiting.

Examples of the embodiment of the invention

Example 1

1-[2-12-(3,4-Dimethoxyphenyl)-1H-indol-3-yl]Hethylaminol-3-(pyridin-415-yloxy)propan-2-ol

To a solution of [2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethylamine (118 mg in 4 mL of dry methanol) was added 20 mg of 4oxoranylmethoxypyridine and the mixture was heated to 80 °C in an oil bath . After 6 hours, the mixture was concentrated under vacuum and purified

2 by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:10:1) to give the title compound (53 mg). m/e = 448 (M+H).

Following a similar procedure as described in Example 1, the following compounds were prepared:

OH

Λα;

-42 • 4444 ·

• 4 ® · • · «·· ·

4444

4 4 4

4 4

4 44

444 4

4 «4

Example # R. R ₃ , R 4 , R ? AND me 1A Pyridine-4-NH-COOCH ₃ 3,4-OMe CH2-O — 1B Pyridm-4-NH ₂ 3,4-OMe CH ₂ .0 463 (M+H)

Example 2.1

Meio (2-f2-(3,5-dimethylphenyl)-1H-indol-3-yl1-ethyl)-(5pyridin-4-yl-pentyl)amine

Step 2.1A

2-Γ2-Π H-indole-3-yl)-ethvinisoindole-1,3-dione

To a stirred suspension of 2-(1H-indol-3-yl)ethylamine (2.0 g in 20 mL of dry tetrahydrofuran) was added N-carbethoxyphthalimide (2.85 g) and the mixture was heated in an oil bath under reflux. After 48 h, the reaction mixture was cooled to room temperature, filtered and the filtrate concentrated in vacuo. The obtained solid was suspended in a mixture of hexane/methylene chloride (2.5:1) and filtered. Purification of the obtained solid fractions by flash chromatography (methylene chloride:methanol, 97:3) gave the title compound (3.1 g).

• · · ·

-43 ·· · ··

Step 2.1B

2-[2-(2-Bromo-1H-indol-3-yl)-ethyn-isoindol-1,3-dione

Pyridinium bromide perbromide was added to a solution of 2-[2-(1H-indol-3-yl)ethyl]-isoindol-1,3-dione (1.0 g in a mixture of 10 ml of dry tetrahydrofuran and 10 ml of dry chloroform) at 0 °C (1.14 g) and the reaction mixture was stirred at 0 °C. After 50 min, the reaction was stopped by the addition of saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic part was washed with a saturated solution of sodium bicarbonate (3x) and 0.3 M sodium hydrogensulfate (3x) and then dried over magnesium sulfate. The concentrate was purified by flash chromatography on silica gel (hexane:ethyl acetate, 3:1) to give the title compound (1.2 g).

and Step 2.1C

2-{2-f2-(3,5-Dimethylphenyl)-1H-indol-3-n-ethyl)-isoindo-1,3-dione

To a solution of 2-[2-(2-bromo-1H-indol-3-yl)-ethyl]-isoindol-1,3-dione (150 mg in a mixture of 5 ml of toluene and 5 ml of ethanol) was added acid 3, 5-dimethylphenylborate (85 mg) and then 1.0 mL of 1 M sodium carbonate. To the stirred solution was added lithium chloride (60 mg) followed by tetrakis(triphenylphosphine)palladium (28 mg) and the mixture was refluxed in an oil bath. After 4 h, the mixture was cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 5:1) afforded the title compound (146 mg).

Step 2.1D

2-[2-(3,5-dimethylphenyl)-1H-indol-3-yn-ethylamine

To a solution of 2-{2-[2-(3,5-dimethylphenyl)-1H-indol-3-ylethyl}3o isoindole-1,3-dione (87 mg in a mixture of 4 ml of tetrahydrofuran and 4 ml • · · · • · · · • ·

-44 ethanol) was added to 0.6 ml of 95% aqueous hydrazine and the reaction mixture was 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 give the title compound (54 mg).

Step 2.1E (242-(3,5-Dimethylphenyl)-1H-indol-3-methyl)-(5-pyridin-4-yl-pentyl)amine io To 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 dry chloroform) was added anhydrous magnesium sulfate (735 mg) and the mixture was stirred for 15 min at 0 °C. Sodium borohydride (92.7 mg) was added simultaneously followed by 3 mL of dry methanol and the mixture was stirred at 0 °C.

After 1 h, the reaction was quenched by pouring into water (25 ml), stirred for 30 min and then extracted with methylene chloride (4 x 25 ml). The combined organic phases were dried over potassium carbonate, concentrated in vacuo and the residue was purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title

2o compound (172 mg), m/e = 412 (M+H).

Production of synthetic intermediates

Step A:

5-(4-pyridyl)-4-pentyn-1-ol

4-Bromopyridine hydrochloride (3.89 g) was dissolved in a solvent mixture containing triethylamine (25 mL) and water (5 mL). Anhydrous lithium chloride (848 mg), powdered copper bromide (30 mg), and 5-pent-4-yn-1-ol (1.68 g) were added to the pyridine salt, and the mixture was stirred under nitrogen bubbling for ; approximately 15 min;

Tetrakis(triphenylphosphine)palladium (231.1 mg) was then added.

• ·

-45 The reaction mixture was heated to reflux under a nitrogen atmosphere and maintained at this temperature for 2.5 h. The heating was then stopped and the reaction mixture was allowed to stand at room temperature. The reaction products were isolated by partitioning between ether and brine. The aqueous layer was further extracted with ether (4 x 50 mL) and the combined fractions were dried over powdered anhydrous sodium sulfate. The extract was filtered and evaporated under reduced pressure to give a dark brown oil. Column chromatography using neat ethyl acetate as eluent gave 2.1 g of a yellow io oil, 5-(4-pyridyl)-4-pentin-1-ol, which solidified slowly and darkened slightly on standing at room temperature from the brown oil.

Step B:

5-(4-pyridyl-pentan-1-ol).

The 5-(4-pyridyl)-pentin-1-ol (1.5 g) obtained in the previous step was dissolved in methanol (35 mL) in a Parr hydrogenation flask and platinum dioxide (Adams catalyst) (0.3 g) was added. . The Parr flask was placed in a Parr hydrogenation apparatus and the solution was hydrogenated at a pressure of 276 kPa for 5.5 hours; after this time the starting material was consumed according to TLC analysis. Spent catalyst was removed by filtration through a bed of celite, which was carefully washed with additional methanol. The combined filtrates were evaporated under reduced pressure on a rotary evaporator and the oily residue was then purified by chromatography on a short silica gel column using neat ethyl acetate as eluent to afford the title compound (1.4 g).

Step C:

·· ··

-46 5-(4-pyrido-pentanal

Oxalyl chloride (2 mL of a 2 M solution in dry methylene chloride) was placed in a cold, oven-dried flask and cooled to -78 °C using a dry ice-acetone bath and added dropwise during

A solution of DMSO (632 mg) in dry methylene chloride (1 ml) was added for 3 min. The solution was then stirred for another 3 minutes. A solution of 5-(4-pyridyl)-4-pentan-1-ol (0.6 g) in dry methylene chloride (5 ml) was added to the reaction vessel over approximately 3 min and the reaction mixture was stirred for 15 min. Anhydrous triethylamine (2.82 mL) was added and the reaction mixture was stirred for an additional 2 h while the ice bath was warmed to room temperature. The reaction was terminated by the addition of a saturated salt solution and the reaction mixture was partitioned with methylene chloride. The aqueous layer was decanted and the methylene chloride extract dried over powdered anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give an oily residue. The product was isolated by silica gel column chromatography using ethyl acetate as eluent (488 mg).

Example 2.2

OMe {2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-ylethyl]-[3-(1H-indol-525yl)propyl]amine

Step 2.2A • · · · • ·

-47 N-{2-f2-(3,4-dimethoxyphenyl)-1H-indole-3-vinthyl)-3-1H-indole-5β-Dpropionamide

To a solution of 3-(1H-indol-5-yl)propionic acid (50 mg in 2.5 ml of Ν,Ν-dimethylformamide) was added 15 hydroxybenztriazole (43 mg) at a temperature of 0 °C, followed by 71 mg of 1-( 3-dimethylaminopropyl)-3-ethylcarbodiimide and the mixture was allowed to warm to room temperature. After 23 min, 155 mg of 2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]-ethylamine was added and the mixture was stirred for another hour at room temperature. The reaction was then quenched by the addition of water and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate, and the concentrated oil was purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to afford the title compound (111 mg).

Step 2.2B (2-(2-(3,4-dimethoxyphenyl)-1H-indole-3-vHethylH3-(1H-indole-5vQpropvllamine

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

The following compounds were prepared by a procedure similar to that described in examples 2.1 and 2.2:

Η ^N W*1

Example JJ. yy Rl R3, R4, R5 A=(CH2)n me 2A 3-phenyltriazine 3,4-OMe 1 428 (M+H) 2B 5-IndoI 3,4-OMe 1 426 (Μ + H) 2C 5-bertzimidazoI 3,4-OMe 1 427 (Μ + H) 2D 4- indole 3,4-OMe 1 426 (M + H) 2E 3-Dvridvi 3.5-Me 5 412 (Μ + H) 2F 4-overhead 3.5-Me 4 398 (M + H) 2G 2-ovridvI 3.5-Me 4 398 (Μ + H) 2H 3-Dvndvl 3.5-Me 4 398 (Μ - H) 21 5-Dvrimidine 3.5-Me 4 399 (M + H) 2J Tx5 3.5-Me 4 453 (M + H) 2K 0 H 3.5-Me 4 455 (M + H) 2L 3.5-Me 4 428 (M+H) 2M at ₀ 3.5-Me 4 415 (M + H)

• · · ·

2N AND 3.5-Me 4 414 (M +H) 20 XL, 3.5-Me 4 413 (M +H) 2P IN? °'· ? X\' ^S -Me H 3.5-Me 4 491 (M -H) 20 4-pvridvl 3.5-Me 2 370 (M ~H) 2R 3-pvridvl 3.5-Me 2 370 (M -H) 2S 2-pvridvi 3.5-Me 2 370 (M -H) 2T 4-ImidazoIvi 3.5-Me 2 359 (M -H) 2U 4-pvridvi 3.5-Me 1 356 (M -H) 2V 2-pvridvI 3.5-Me 1 356 (M -H) 2W 3-wow! 3.5-Me 1 356 (M- -H) 2X 3-pyridv 1 3.5-Me 3 384 (M -H) 2Y 4-pvridvi 3.5-Me 3 384 (M -H) 2Z 3-quinolinyl 3.5-Me 4 448 (M -H) 2AA XXs T ,N ⁿ n 3.5-Me 4 481 (Μ + NH3) 2BB 3.5-Me 4 Ζχ*7»ζ ·'' in Z _r z/ » »,z

4 4 4 • ·

-50 44 4444 ·· • ·· · 4 4 4 · • 4 4 · · · · · • · · · 4 · · · · · 4

4 4 4 4 4 4

44 4 44 44

Example 3 r3-(3-H-benzimidazol-5-vlY-allvH-(2-f2-(3,4-dimethoxyphenyl)-1H-indol-3vllethyl-D-amine)

Step 3A (2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-ylethyl)-[3-(1-methanesulfonyl-1H-benzimidazol-5-yl)-allylamine]

To a solution of 3-(1H-benzimidazol-5-yl)-prop-2-en-1-ol (44 mg) in a mixture of 2 ml of methylene chloride and 0.1 ml of Ν,Ν-dimethylformamide) at 0 °C was gradually added 346 mg of tetrabutylammonium bromide, 0.110 mL of diisopropylethylamine, and 100 mg of methanesulfonic anhydride were added and the mixture was allowed to warm to room temperature. After 1 hour, this mixture was added to a solution of 2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethylamine (300 mg in a mixture of 6 ml of methylene chloride and 1.5 ml of N,N15 dimethylformamide) and stirred continuously for 2.5 h. The mixture was then 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 r 3 -(3 H -Benzimidazol-5-yl)-allyl 1 -(2-1 2 -(3,4-dimethoxyphenyl)-1 H -indol-3ylethyl D-amine

To a solution of (2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethyl}-[3-(1methanesulfonyl-1H-benzimidazol-5-yl)-allyl]amine (24 mg in 1.5 ml of methanol) was added to 0.225 ml of 2 N potassium hydroxide solution and the mixture was allowed to warm to room temperature. After 1.5 h the reaction was quenched by the addition of 0.30 ml of 1 N hydrochloric acid, concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol, 88:12) to give the title compound (12 mg), m/e = 453 (M+H).

• · · · ♦ · · · • ·

- 51 Production of synthetic intermediates

Step A

1H-Benzimidazole-5-carboxylic acid N,N-methoxyvmethylamide

500 mg of 1-hydroxybenztriazole (HOBt) and then 828 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide chloride (EDC) were added to a suspension of 1H-benzimidazole-5-carboxylic acid (500 mg in 7 mL of Ν,Ν-dimethylformamide) at 0 °C. ) and the mixture was also allowed to warm to room temperature. After 42 min, 1.05 g of Ν,Ο-dimethylhydroxylamine hydrochloride and 1.5 mL of triethylamine were added and stirring was continued at room temperature. The reaction was stopped after 1 h by the addition of water and the product was isolated by extraction with ethyl acetate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 90:10) afforded the title compound (458 mg).

Step B

H-benzimidazole-5-carboxaldehyde

2o To a solution of N,N-methoxy,methylamide of 1H-benzimidazole-5-carboxylic acid (458 mg in a mixture of 5 ml of diethyl ether and 10 ml of tetrahydrofuran) at -78 °C was added 3.7 ml of a 1.5 M solution of diisobutylaluminum hydride in toluene and the mixture was stirred at low temperature. After 1 hour, the reaction mixture was transferred with a needle into a 1 M solution of sodium potassium tartrate at a temperature of 0 °C. The resulting slurry was thoroughly stirred at room temperature for 2 hours and then extracted with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated in vacuo to afford the crude title compound (250 mg).

• · · ·

·· ··*· • · · · · • · · · · • · ·· · · ·

- 52 StepC

Methyl ester of 3-(1H-benzimidazol-5-yl)acrylic acid

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

Step D

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

To a solution of 3-(1H-benzimidazol-5-yl)acrylic acid methyl ester (50 mg in 1 ml of dry tetrahydrofuran) was added at -78 °C 1.24 ml of a 1 M solution of lithium tri-sec-butylborohydride in tetrahydrofuran and the mixture was stirred for 4 h at -78 °C and then heated for another 4 h at -40 °C. The reaction was quenched by the addition of aqueous methanol, concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol,

2o 87:13) for providing the title compound (44 mg).

The following compound was prepared by a procedure similar to that described above:

-53 9··· •9 9999

9 9 9

9 9 9

9 99

9999 9

9 9

99

Example # xr ₇ , r ₈ Ri R3, R4, R5 me 3A H è-benzimidazole-N-SOzMe 3,4-OMe —

Example 4.1

12-[2-(3,5-Dimethylphenyl)-5-methanesulfonyl-1H-indol-3-quinone-(4-pyridin-4-yl-butyl)amine

Step 4.1A

2-(2-(3,5-dimethylphenyl)-5-methanesulfonyl-1H-indole-3-vinethylamine

A suspension of 4-(methanesulfonyl)phenylhydrazine (3.0 g, 16.1 mmol) and 3-chloropropyl-3,5-dimethylphenylketone (3.4 g, 16.1 mmol) in t15 butanol (25 mL) was stirred at room temperature temperature for 20 min and quickly heated in a steam bath. Methanol (250 mL) was added and the mixture was heated under reflux overnight. Then the mixture was concentrated to a small volume, the crystals were filtered off and washed with cold methanol. The combined filtrates were evaporated to a residue which was partitioned between ethyl ether and water. The ether layer was then extracted twice with water and the combined aqueous extracts were washed with ethyl ether and basified with 5 N sodium hydroxide. The product was extracted three times with ethyl acetate. The combined organic extracts were washed with water, dried over sodium sulfate and evaporated to a syrup (3.1 g). The raw material was cleaned by flash « »«·* ·< ·*·* ·· ·· ·· · · · · · · · · • · · · · · * ··

-54 by silica gel chromatography (methylene chloride:methanol, 9:1) to give the title compound (1.99 g, 36%), R _f 0.19 (reacts with ninhydrin).

Step 4.1B

N-12-12-(3,5-dimethylphenyl)-5-methanesulfonyl-1H-indole-3-methyl-4-pyridin-4-1-butyramide

A mixture of 2-[2-(3,5-dimethylphenyl)-5-methanesulfonyl-1H-indol-3ylethylamine (1.29 g, 3.77 mmol), 4-(4-pyridyl)butanoic acid (1.37 g, 8.29 mmol), 4-methylmorpholine (1.25 mL, 11.33 mmol), 1-hydroxybenzotriazole (1.53 g, 11.33 mmol), and 2-(3dimethylaminopropyl)-3-ethylcarbodiimide chloride (1, 74 g, 9.08 mmol) in N,N-dimethylformamide (10 ml) was stirred for 14 h at room temperature. The solution was then co-distilled with n-butanol (3x) 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%).

Step 4.1C

2° f2-f2-(3,5-dimethylphenyl)-5-methanesulfonyl-1H-indol-3-vHethvn-(4pyridin-4-yl-butyl)amine

A mixture of borane - THF (1.0 M solution in tetrahydrofuran, 27 mL) was added dropwise to a solution of N-[2-[2-(3,5-dimethylphenyl)-5-methanesulfonyl-1H-indol-3-yl]ethyl ]-4-pyridin-4-yl-butyramide (1.45 g,

2.96 mmol) in dry tetrahydrofuran (20 ml) and the solution was heated under reflux for 2 hours. Methanol was then added to remove excess borane and the remaining solution was evaporated to dryness. The residue was dissolved in tetrahydrofuran (20 mL) and N,Ndimethylethanolamine (8.9 mL, 88.86 mmol) was added. The rest was heated under

3o reflux for 2.5 hours and then concentrated • · · · · ·

-55 dry. The crude material was purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (1.0 g, 71%). m/e = 476 (M+H)

Step 4.1D

4f 2-[2-(3,5-Dimethylphenyl)-5-methanesulfonyl-1H-indol-3-hexyl-(4-pyridin-4-yl-butyl)amine (dihydrochloride)

To a solution of [2-[2-(3,5-dimethylphenyl)-5-methanesulfonyl-1H-indol-3yl]ethyl]-(4-pyridin-4-yl-butyl)amine (300 mg, 0.63 mmol ) in dry io tetrahydrofuran (20 ml) was added dropwise at 0 °C a solution of hydrogen chloride in ethyl ether (1.0 M, 1.4 ml). After 10 min, excess hydrogen chloride and solvents were evaporated to give a solid. The product was further dried under high vacuum at 50 °C to provide the title compound.

Example 4.2

3-[2-(3,5-Dimethylphenyl)-3-[2-(5-pyridin-4-yl-pentylamino)ethyn-1-Hindol-5-νΠ-1,1-dimethylurea

Step 4.2A • · · ·

- 56 242-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]ethylamine, hydrochloride salt

1-(4-chloro-1-oxo-butyl)-3,5-dimethylbenzene (2.5 g) was dissolved in 12 mL of t-butanol and stirred at room temperature, and then 4-nitrophenylhydrazine (1.65 g ). The reaction mixture was stirred for 20 min at room temperature and then water (12 mL) and methanol (108 mL) were added and the mixture was heated under reflux and kept at reflux for 17 h. Then the reaction mixture was cooled to room temperature and the volatile solvents were removed under reduced pressure on a rotary evaporator. The residues were evaporated to dryness using a stream of nitrogen gas overnight. The solid dry residue was triturated with ethyl acetate (approximately 100 mL) and crystallization was initiated by scraping and the sample was placed in the refrigerator for 8 h. The solid obtained was placed in a sintered glass funnel under vacuum and washed with dry ethyl acetate. 1.4 g of solid was obtained.

Step 4.2B

(2-[2-(3,5-Dimethylphenyl)-5-nitro-1H-indole-32o]ylethyl-D-carbamic acid tert-butyl ester

2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3ylethylamine hydrochloride (1 g) was suspended in dry methylene chloride and 0.806 mL of triethylamine was added and the mixture was stirred for 5 min at room temperature. [225(tert-butoxycarbonyloxyimino)phenylacetonitrile] (890 mg) was added to tryptamine in small portions over 5 min and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was partitioned between methylene chloride and 5% citric acid. The methylene chloride layer was separated and washed with brine and dried over anhydrous powdered sodium sulfate.

3o The extract was filtered and evaporated to dryness. The product was isolated by column chromatography using silica gel and ethyl acetate as eluent • ·

-57a mixture of hexanes (36:65 parts by volume). The yield of the title compound was 1 g.

Step 4.2C

(2-5-Amino-2-(3,5-dimethylphenyl)-1H-indole-3-ylethylenecarbamic acid tert-butyl ester

{2-(2-(3,5-Dimethylphenyl)-5-nitro-1Hindol-3-yl]ethyl}carbamic acid tert-butyl ester (0.4 g) was dissolved in methanol (25 mL) and added platinum dioxide (40 mg). The mixture was placed in a Parr io hydrogenation apparatus for 4 h at 310 kPa, during which time the starting material was consumed and converted to product. The catalyst was removed under reduced pressure using a rotary evaporator Evaporates and trace solvents were removed using high vacuum overnight to give the amine (338 mg) as a powder.

Step 4.2D

{2-(2-(3,5-Dimethylphenyl)-5-(3,3-dimethylureido)-1H-indole-3-nHethyl>-carbamic acid tert-butyl ester

2o Finely dispersed {2-[5-amino-2-(3,5-dimethylphenyl)-1Hindol-3-yl]ethyl}carbamic acid tert-butyl ester (265 mg) was suspended in dry tetrahydrofuran (5 mL ) and diisopropylethylamine (0.146 mL) and dimethylcarbamoyl chloride (0.077 mL) were added. The reaction mixture was stirred for 2.5 days at room temperature. The reaction mixture was concentrated on a rotary evaporator and the residue was applied to 4 (20 x 20 cm, 1000 µm) preparative silica gel plates and eluted with a solvent system containing methanol and methylene chloride in a ratio of 1:9 by volume. The product (299 mg) was isolated as a thick gum which solidified on standing.

• · · · • · · · » · · 4 » · · · • · · · • · · • « · ·

-58 Step 4.2E

3-r3-(2-aminoethoxy-2-(3,5-dimethylphenoxy)-1H-indole-5-νΠ-1.1 dimethylurea

{2-(2-(3,5-Dimethylphenyl)-5-(3,35-dimethylureido)-1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester (295 mg) was dissolved in a ternary solvent mixture containing methylene chloride (6 mL), trifluoroacetic acid (2 mL), and anisole (2 mL) for 2.5 h. x 20 cm, 1000 pm) and eluted with a solvent system containing methanol and methylene chloride in a 1:9 volume ratio.The product (222 mg) was isolated as a foamy material.

Step 4.2F

3-[2-(3,5-dimethylphenyl)-3-[2-(5-pyridin-4-yl-pentylamino)-ethyn-1-hindol-5-νΠΙ, 1-dimethylurea

3-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]1,1dimethylurea (25 mg) from the previous step was dissolved

2o in tetrahydrofuran (1 mL) and deuterated chloroform (1 mL) at about 0 °C and 5-(4-pyridyl)pentanal (10.6 mg) was added. The reaction mixture was maintained at this temperature for 15 min and then finely powdered sodium borohydride was added followed by anhydrous methanol. The reaction mixture was stirred for 15 min at approximately 0 °C and then quenched by the addition of 20 drops of 2 N hydrochloric acid and water (1 mL). Volatiles were removed on a rotary evaporator and water using a stream of nitrogen gas. The residues were spotted onto four preparative silica gel plates (20 x 20 cm, 500 µm) and eluted with a solvent system containing methanol and methylene chloride in a 1:9 volume ratio. The product (14.2 mg) was isolated as a thick oil.

• · · · • ·

-59 The following compounds were prepared by a procedure similar to that described in examples 4.1 and 4.2:

Example # X-R7,R8 A = (CH ₂ )n Ri me 4A * 4 4-pvridvl 443 (Μ - H) 4B Bro ** 4-pvridvl 476 (M-H) 4C -NH2 4 4-veridvl 413 (M + H) 4D -NH-COCH3 4 4-pvridvl 455 (M-H) 4E -NH-CO-N(CH 2 CH 3 ) 2 4 4-pvridvl 512 (M^H) 4F -iVH-CO-N(CH 2 CH 3 ) 2 4 3-pvridvl 512ÍM + H) 4G -NH-CO-N(CH 2 CH 3 ) 2 4 6-me±oxy3-pvridvl 542 (Μ - H) 4H -NH-CO-N(CH 3 ) 2 5 3-pvridvi 498 (Μ - H) 41 -NH-CO-N(CH 2 CH 3 ) 2 5 3-pvridvl 526 (Μ - H) 4J -NH-CO-N(CH 2 CH 3 ) 2 5 4-pvridvl 526 (Μ - H) 4K -NH-CO-N(CH 3 ) 2 4 6-methoxy-3-pyridyl 514 (M-H) 4L -SO2-CH2-CO-Me 4 4-pvridvl 518 (M-H) 4M 9 ^H 0.0 Me'^ ^x ^' ^Sv ' 4 4-pyridyl 520 (Μ + H) 4N 0 0 'from 4 4-pyridyl 502 (Μ + H) 40 Ό 0 Λ // 4 4-pyridyl 504 (Μ + H) 4P MeSO ₂ - 4 3-pvridvl 518 (M-H)

• 000 • · · ·

4Q MeSO2- 4 6-methyloxy3-pyridyl 506 (M 4-H) 4R MeSCb- 4 _{in o} 492 (M 4-H) 4S MeSCb- 5 4-pyridyl 490 (M -r H) 4T MeSCb- 5 3-pvridvl 490 (M 4-H) 4 U AV Me^ 4 4-pyridyl 575 (Μ + H)

(*)-Ró = 5-NCb (**) - Ró = Br

Example 5.1

2-(3,5-Dimethylphenyl)-3-[2-]-(pyridin-4-yl)butylamino-1-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-hydrazinebenzoic acid, 10.55 g (50 mmol) of 3-chloropropyl-3,5-dimethylphenyl ketone and 200 ml of absolute • ·· · • · · ·

-61 of ethanol was stirred under nitrogen and refluxed. After 12 hours, the mixture was cooled and filtered. The solid on the filter was washed with additional small volumes of ethanol. 4 mL of concentrated sulfuric acid was added to the filtrate and the mixture was stirred under reflux under nitrogen for 4 days. The cooled mixture was stirred in a water bath and a solution of sodium ethoxide (21% by weight in ethanol) was added dropwise until the mixture became alkaline as measured by pH paper. The mixture was filtered and concentrated in vacuo at 30 °C. The residue was partitioned between diethyl ether and water, and a certain amount of saturated aqueous sodium chloride solution was added to facilitate the separation of the layers. The aqueous phase was washed with another 100 mL of ether. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The obtained gum was purified by flash chromatography on silica gel (elution with methylene chloride:methanol:ammonium hydroxide 97:3:0.3 and then 95:5:0.5) to give the title compound (4.8 g). 400 MHz ¹ H NMR (CDCl ₃ ) was consistent with the desired structure. Mass spectrum (PB-NH3/Cl): m/e=337 (M+H).

Step 5.1B

2-(3,5-Dimethylphenyl)-3-[4-(pyridine-4-yl)-butylamino-1-ethyn-1H-indole-5-carboxylic acid ethyl ester

5.0 g (14.9 mmol) of 3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-525 carboxylic acid ethyl ester, 1.98 g (13.5 mmol) of 4-(pyridin-4-yl)butyraldehyde (prepared exactly as described in Example 2.1; diluted with 0.5 mL of CDCl 3 ), 8.12 g (67.7 mmol) of anhydrous sodium sulfate, and a magnetic stir bar. The flask was purged with nitrogen, cooled to -10 °C, and stirred, gradually adding

11.5 ml of dry CDCl ₃ . The septum was then removed and 670 mg (17.6 mmol) of sodium borohydride was rapidly added. The septum was again « ·

-62 was immediately deployed and the system was flushed with nitrogen again. The mixture was stirred under nitrogen at a temperature of approximately -5°C and 10 ml of dry methanol was gradually added via syringe. After several minutes at this temperature, the reaction mixture was removed from the cooling bath and partitioned between 80 mL of ethyl acetate and 100 mL of water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with a gradient of 4-9% methanol in methylene chloride; repeated again using a gradient of 5-15% methanol in methylene chloride to afford the title compound (3.19 g). 500 MHz ¹ H NMR ( CDCl ₃ ) was consistent with the desired structure.Mass spectrum (PB-NH ₃ /Cl): m/e=470.4 (M+H) was also isolated

1.91 g less pure material.

Step 5.1C

3-F2-Benzyloxycarbonyl-4-(pyridin-4-yl-0-butylamino-1-ethyl-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid ethyl ester

A solution of 3.19 g (6.83 mmol) of 2-(3,5dimethylphenyl)-3[2-[4-(pyridin-4-yl)butylamino]ethyl]-1H-indole-520 carboxylic acid ethyl ester in 25 ml of dry of methylene chloride was stirred under nitrogen and cooled to -78 °C in a dry ice-acetone bath with the addition of 2.38 ml (1.76 g, 13.7 mmol) of Ν,Ν-diisopropylethylamine and then the gradual addition of 3.4 ml (4 .06 g; 23.7 mmol) of benzyl chloroformate using a syringe. After approximately 2.5 h, the solution was removed from the cooling bath and allowed to warm to room temperature. It was then partitioned between ethyl acetate and 5% aqueous potassium bisulfate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (elution with a gradient of 0.5-10% methanol in methylene chloride) gave the product in quantitative yield in the form of a yellow foam. 500 MHz ¹ H NMR was due to the existence of rotamers ·

-63complex, but in accordance with the required structure. Mass spectrum (PB-NH ₃ /Cl): m/e=604.3 (M+H).

Step 5.1 D

3-[2-]Benzyloxycarbonyl-[4-(pyridin-4-yl)-butyl]amino-12-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid chloride

A solution of 4.11 g (6.83 mmol) of 3-[2[benzyloxycarbonyl-[4-(pyridin-4-yl)butyl]amino]ethyl]-2-(3,5dimethylphenyl)-1H-indole-5-acid ethyl ester -carboxylic acid in 161 mL (80.5 mmol) of 0.50 N potassium hydroxide in methanol was stirred at about 60°C with the gradual addition of 19 mL of water. Stirring was continued at reflux overnight. The cooled mixture was concentrated in vacuo to give a yellow solid which was partitioned between 250 mL of 1:1 ethyl acetate-tetrahydrofuran and 250 mL of 0.5 N hydrochloric acid. The organic phase was washed twice with 0.5 N hydrochloric acid, then dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was triturated with diethyl ether and collected on a filter to give (after drying) 3.46 g of a yellow solid, mp 133.5-137.5 °C; the substance is homogeneous according to TLC (95:5:0.5 CH ₂ CI ₂ -MeOH-AcOH). 500 MHz ¹ H NMR (DMSO-de) was consistent with the desired structure. Mass spectrum (ESI): m/e=576.4 (M+H).

Step 5.1E

f2-f5-Diethylcarbamyl-2-(3,5-dimethylphenyl)-1-hindol-3-vinethyl-f4-(pyridin-4-yl)butylcarbamic acid benzyl ester

A mixture of 846 mg (1.38 mmol) of 3-[2[benzyloxycarbonyl-[4-(pyridin-4-yl)butyl]amino]ethyl]-2-(3,5dimethylphenyl)-1H-indole-5-carboxylic acid chloride , 862 mg (1.66 mmol) benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate

·· ··· · ·· ·· • · ·

I · ·· ·· · · · • · ·

9

-64 (PyBOP) and 8.5 mL of dry methylene chloride were mixed with 1.16 mL (839 mg; 8.29 mmol) of triethylamine, and after several minutes 0.715 mL (505 mg, 6.91 mmol) of diethylamine was added. The resulting solution was stirred under nitrogen at room temperature overnight and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient elution of 1 - 5% methanol in methylene chloride) provided the desired product in quantitative and yield; homogeneous on TLC 95:5 CH ₂ Cl 2 -MeOH. 500 MHz ¹ H NMR (CDCl 3 ) was complex due to the presence of rotamers, but consistent with the desired structure. Mass spectrum (ESI):

m/e=631.5 (M+H).

Step 5.1F

2-(3,5-dimethylphenyl)-3-12-14-(pyridin-4yl)butylamino-1-ethyn-1H-indole-5-carboxylic acid diethylamide

A mixture of 871 mg (1.38 mmol) [2-[5-diethylcarbamoyl-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]-[4-pyridin20 4-yl)butyl]carbamic acid benzyl ester , 300 mg of 20% palladium hydroxide on carbon and 40 mL of 2-methoxyethanol were shaken with hydrogen (approx. 310 kPa) in a pressure vessel for 2.3 h. The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient elution 99:1:0.1 to

93:7:0.7 CH ₂ Cl 2 -MeOH-conc. (NH ₄ OH) to give 454 mg (66%) of a yellow foam; homogeneous on TLC 95:5:0.5 CH ₂ CI ₂ -MeOH-conc. NH ₄ OH. 500 MHz ¹ H NMR (CDCl ₃ ) was consistent with the desired structure. Mass spectrum (ESI): m/e=497.5 (M+H).

Step 5.1G • ·

-65 2-(3,5-dimethylphenoxy-3-f2-f4-(pvridin-4-yl)butylamino-1-ethvH-1H-indole-5-carboxylic acid diethylamine dihydrochloride

To a solution of 452 mg (0.914 mmol) of 2-(3,5dimethylphenyl)-3-[2-[4-(pyridin-4-yl)butylamino]ethyl]-1H-indole-55carboxylic acid diethylamide in 45 ml of methanol was added 1.83 mL (3.66 mmol) of 2 N hydrochloric acid. After a few minutes, the solution was evaporated to dryness. The residue was re-concentrated from methanol and then triturated with diethyl ether. The solid was collected on a filter, washed with additional diethyl ether, and dried to give 455 mg (87%) of a yellowish powder, mp 154-157 °C. 500 MHz ¹ H NMR (DMSO-d ₆ ) was consistent with the desired structure.

Example 5.2

Following a procedure similar to that of Example 5, the following compounds were prepared:

• · 9 ·

-66 9 9 99

9 9 9

9 9

99

Example # X-R7£3 R6 ·- Ri me 5A 0 Me^cr^ H 4-pyridyl 470 (M+H) 5B 0 Me' ^x ^'O'^ ^x H 3-pyridyl 470 (Μ + H) 5C 0 Me. JU N Me H 3-pyridyl 469 (Μ + H) 5D 0 Me H 4-pyridyl 469 (Μ + H) 5E 0 Λ Me Me^ H 3-pyridyl 497 (Μ + H) 5F 0 X F ₂ CN ^ H 4-pyridyl 605 (Μ + H)

-67 ·*·· φφ ·· • · · φ · · • · · · ·· ·· ♦ φφφφ · • · φ · · φ φφ φφ

5G ηο^ _ν Λ Me H 3-pyridyl 513 (M + H) 5Η 0 Μβ^ H 4-pyridyl 513 (M + H) 51 0 MeCL Λ MeO^J H 3-pyridyl 557 (Μ + H) 5J HG _x Me U HO^J Me H 3-pyridyl 557 (Μ + H) 5K Qa Me^ H 3-pyridyl 551 (M + H) 5L O-A Me''') H 4-pyridyl 55 i (M + H) 5M etc. Me^J H 4-pyridyl 551 (M + H) 5Ν 0 Me'^^ H 3-pyridyl 553 (Μ + H)

• 4

50 0 X Me^^ H 4-pyridyl 553 (M + H) 5P Me 0 Me^N^ H H 3-pyridyl 483 (Μ + H) 5Q Me 0 Λ Me Me H 4-pyridyl 525 (Μ + H) 5R Me 0 Me ^/ ^N'^ ^X Me^ H 3-pyridiums 511 (M + H) 5S 00 ^Λ H 3-pyridyl 559 (M + H) 5T O/ H 4-pyridiums 559 (Μ + H) 5Ό 0 '^,λ H 3-pyridiums 537 (Μ + H) 5V -CON(Et) ₂ H Me 551 (M + H) 5W -COOM 6-C1 4-pyridyl .49O'(M-rH) 5X -CON(iBu)2 6-C1 4-pvridvl .5871Μ:+Ή>' 5Y -CON(Et)2 H Ό0 ;s°: 0 Me ,68^Μ·+Η> et !tf/yty/S * ^,ft ? W et f~<„.eee—/t:t%/ee i „ / : //''/Λ, Cíz ''ee',/F.

-69 ···· • · * · · • · · · • ·* · ·· ·· • · · · • · 0· ··· · · • · · «· «0

5Z -CON(CH ₂ CH ₂ CN)cyclohexyl H 4-pyridyl ^:: 576íM + H)..... 5AA CU Me H 4-pyridyl _:: 5ό5.(Μ + Β _; 5BB -COOM 4-C1 4-pyridyl 5CC -CON(iBu) ₂ 4-C1 4-pvridvl 5DD -CON(Et) ₂ 6-0 4-pvridvi 531 CM-ΉΪ

Example 6

Diisobutylamide

To a solution of 3-(-aminoethyl)-2-(3,5dimethylphenyl)-1H-indole-5-carboxylic acid diisobutylamide (prepared as described in Example 5.1, 83 mg in 2.5 ml of dry CDCl ₃ ) at 0 °C was added

2o 240 mg of magnesium sulfate and then 30.6 mg of 4-(3-methylisoxazol-5yl)-butyraldehyde and the mixture was stirred at low temperature. After 15 min, a cold solution of sodium borohydride (30.2 mg in 1.5 mL of methanol) was added and the mixture was stirred for another 15 min. The reaction was then quenched by the addition of water, extracted with ethyl acetate, and then methylene chloride and the combined organic phases were dried over sodium sulfate. Purification of the concentrate by preparative TLC on silica gel »··· ·· ····

-70 (methylene chloride:methanol, 9:1) afforded the title compound (28 mg). m/e=557 (M+H).

Production of synthetic intermediates

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

Step A

Tert-butylhex-5-ynyloxydimethylsilane

To a solution of hex-5-yn-1-ol (1.96 g in 40 mL of dry io methylene chloride) at 0 °C was added 3.48 mL of thiethylamine followed by 3.31 g of tert-butyldimethylsilyl chloride and the mixture was stirred with gentle heating to room temperature. After 60 h, the mixture was filtered to remove solids and the filtrate was concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate hexane, 1:9, then 1:3) afforded the title compound (1.62 g).

Step B

5-[4-tert.-butyldimethylsilanyloxy)butyl]H-3-methylisoxazole

2o To a solution of tert-butylhex-5-ynyloxydimethylsilane (1.0 g in 20 mL of dry 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 stirred at room temperature. After 1 h, the contents of the vessel were heated to reflux in an oil bath for another 20 h and then cooled to room temperature and filtered to remove solids. Concentration of the filtrate in vacuo and purification by flash chromatography on silica gel (ethyl acetate-hexane, 1:9, then 1:2) afforded the title compound (388 mg).

Step C • · · · • ·

-71 4-(3-Methylisoxazol-5-vol-butan-1-ol

To a solution of 5-[4-(tert-butyldimethylsilanyloxy)butyl]-3methylisoxazole (350 mg in 5 mL of dry tetrahydrofuran) at 0 °C was added 1.62 mL of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran and the mixture was stirred while warming to room temperature. temperature. After 16 h the mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (ethyl acetate:hexane, 1.3, then 1:1) to give the title compound (147 mg).

and Step D

4-(3-Methylisoxazole-5-y0-butyraldehyde

To a solution of oxaiyl chloride (0.40 mL of a 2M solution in methylene chloride in 2 mL of dry methylene chloride) at -78 °C was added a solution of methyl sulfoxide (126 mg in 1 mL of methylene chloride) and the mixture was stirred at low temperature for 3 min. A solution of 4-(3-methylisoxazol-5-yl)butan-1-ol (100 mg in 1 mL of methylene chloride) was added and the reaction was allowed to proceed for 15 min before 0.67 mL of triethylamine was added and the mixture was allowed to warm to room temperature. After 30 min, salt solution was added and the mixture was extracted

2o methylene chloride. The organic portion was dried over sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (ethyl acetate:hexane, 1:1) afforded the title compound (48 mg).

Following a similar procedure to that described in Example 6, the following compounds were produced:

Example # A = CCH ₂ )n Ri me 6A 4 4-Pyridvi 553 CM + H) 6B 4 3-pyridyl 553 (M + H) 6C 4 6-ammo-3-pvridvl 568 CM + H) FROM 4 6-amino-3-pyridyl 583 (M + H) 6E 4 6-Methoxyv-3-pvridvl 583 (Μ + H) 6F 4 ^{At N} 571 (M + H) 6G 4 Y-Diameter 585 (Μ + H) 6H 4 Y-CC,H ^U -N 587 (Μ + H) 61 4 AVoO _with Et ^U N 615 (M + H) 6J 4 A^CONEtj ^U N 642 (Μ + H) 6K 4 2-cyano-4-pyridyl 578 CM + H) 6L 4 Y^NH in _o 569 (Μ + H) 6M 4 COOEt ^U N 629 (Μ + H) 6N 4 2-(CH ₂ NH-Boc)-4-pyridyl — 60 4 2-(CH ₂ NH ₂ )-4-pyridyl 582 CM + H) 6P 4 6-CSMe)-3-pvridvi 599 CM + H) 6Q 4 5-Carboethoxy-3-pyridyl 625 (Μ + H) 6R 4 6-(NHCOOEt)-3-pyridyl — 6S 4 2,3,5,6-tetrafluoro-4pvidl 625 (Μ + H) 6T 3 3-pyridyl —

··· • · · · · · • · · · · · ♦ · · ·· · · ·

6U 4 6-[NHS(O) ₂ CF ₃ ]-3 pvridvl 6V 4 6-[NHS(O) ₂ CH 3 ]-3 pvridvl 646(M+H) 6W 4 5-cyano-3-pyridyl 6X 4 n-Q II — Me 6Y 4 3,5-dichloro-4-pyridyl SilWie 6Z 4 638 (M+H)

Example 7.1

2-f2-(3,5-dimethylphenyl)-3-F2-f4-(pyridin-4-yl)butylamino-1-ethyl-1-hindol-5-n-N,N-diethylisobutyramide

Step 7.1 A

- 74 2-[3-(2-aminoethv0-2-(3,5-dimethvulfenv0-1H-indole-5-νΠ-Ν,Νdiethylisobutyramide)

A solution of 4.85 g (23 mmol) of 3-chloropropyl 3,5-dimethylphenyl ketone and 6.87 g (27.6 mmol) of N,N-diethyl-2-(4-hydrazinephenyl)isobutyramide in 92 ml of absolute ethanol was stirred under reflux for 43 h. The solution was then cooled and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient elution of 0-5% methanol in methylene chloride followed by 95:5:0.5 methylene chloride-methanol-ammonium hydroxide and 92.5:7.5:0.75 io methylene chloride-methanol-ammonium hydroxide) gave 873 mg (9.4%) of a brick-red solid foam with sufficient purity on TLC 95:5:0.5 CH ₂ CL ₂ -MeOH-conc. NH ₄ OH. 500 MHz ¹ H NMR (CDCl ₃ ) was consistent with the desired structure. Mass spectrum (PB-NH ₃ /CI).

m/e=406 (M+H).

Step 7.1 B

2-f2-(3,5-dimethylphenyl)3-f2-f4-(pvridin-4-v1)butvlaminolethvn-1H-indole5-vH-N,N-diethylisobutyramide

A mixture of 93.3 mg (0.23 mmol) of 2-[3-(2-aminoethyl)-2-(3,520 dimethylphenyl)-1H-indol-5-yl]-N,N-diethylisobutyramide, 37.7 mg ( 0.253 mmol) of 4-(pyridin-4-yl)butyraldehyde, and 138 mg (1.15 mmol) of magnesium sulfate was flushed with nitrogen and cooled in an ice-methanol bath to approximately -10 °C, and 0.50 ml was gradually added by syringe CDCl ₃ . The mixture was stirred under nitrogen at this temperature

1 h. The septum was removed for the time required to add 11.3 mg (0.30 mmol) of sodium borohydride and the solution was again flushed with nitrogen. The mixture was stirred at -10°C to -5°C while gradually adding 0.5 mL of dry methanol and stirring was continued at this temperature. After 35 min, the mixture was divided between 5 ml

3o ethyl acetate and 5 ml water. The ethyl acetate layer was washed with brine, then dried over sodium sulfate, filtered and concentrated • · • · 4 ·

-75 in a vacuum. The residue was purified by two stages of preparative TLC on Analtech tapered silica gel GF plates (first development with a mixture of methylene chloride-methanol-ammonium hydroxide 90:10:1 and again with a mixture of methylene chloride-methanol 90:10). Isolation of product stripes provided

25.7 mg (21%) of a golden shiny residue, homogeneous on TLC in 92.5:7.5:0.75 CH ₂ CI ₂ -MeOH-conc. NH ₄ OH. 500 MHz ¹ H NMR (CDCl ₃ ) was consistent with the predicted structure. Mass spectrum (ESI): m/e=539 (M+H).

io Production of synthetic intermediates

Step A

4-Chloro-N-methoxyv-N-methylbutyramide

To a solution of 4-chlorobutyryl chloride (10.0 g in 200 ml of dry methylene chloride) was added 10.4 g of N,O-dimethylhydroxylamine hydrochloride. The mixture was stirred under nitrogen and kept below 25 °C by cooling in an ice bath as needed, and triethylamine (29.1 mL) was added dropwise over 20 min, resulting in precipitation. After 1.5 h at room temperature, the mixture was concentrated in vacuo. The residue was partitioned between 100 mL diethyl ether and 100 mL saturated aqueous sodium bicarbonate solution. The organic layer was washed with an additional 100 mL of saturated sodium bicarbonate solution and the aqueous fractions were back-extracted with ether. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give 10.5 g (90%) of an oil of satisfactory purity by ¹ H NMR (CDCl ₃ ). Mass spectrum (PB-NH3/Cl): m/e=166 (M+H).

Step B • 9 • ·

-763-chlorophyll 3,5-dimethylphenylketone

A solution of 10.2 mL (13.9 g; 72 mmol) of 5-bromo-m-xylene in 200 mL of anhydrous tetrahydrofuran was stirred under nitrogen at -78 °C and 35.8 mL (84 mmol) of 2 was added dropwise. 5 M n-butyllithium in tetrahydrofuran. After 15 min at -78 °C, a solution of 10.0 g (60 mmol) of 4-chloro-N-methoxy-N-methylbutyramide in 30 ml of anhydrous tetrahydrofuran was added over 25 - 30 min. The obtained solution was kept for 45 min at -78°C and then it was briefly warmed to room temperature. The reaction was quenched by the addition of 40 mL of 2N hydrochloric acid and then the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride. The organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography of the residue yielded 8.91 g (70%) of an oil which had sufficient purity when measured by ¹ H NMR (CDCl ₃ ).

Step AA

Ethyl 2-(4-hydrazinephenyl)acetic acid chloride and 22o(4-hydrazinephenyl)acetic acid chloride

This compound (a mixture of ethyl ester and carboxylic acid) was prepared from 13.4 g (75 mmol) of ethyl 2-(4-aminophenyl)acetate, by diazotization and reduction of the diazonium salt with stannous chloride by the method of LJ Street, et al., J. Med. Chem., 36, 1529 (1993). The material was obtained in two shares. The first portion consisted of 6.40 g of powder, melting point > 200 °C. According to 400 MHz ¹ H NMR (DMSO-d ₆ ) measurements, this material consisted of a mixture of carboxylic acid and ethyl ester in an approximate 4:3 molar ratio. Mass spectrum (PB-NH ₃ /Cl): 195 (arylhydrazonium cation for ethyl ester). The second portion consisted of 4.60 g of powder, melting point >180°C. By measuring 400 MHz ¹ H NMR (DMSO-de this material consisted of a mixture of carboxylic acid ···· • · · · • ·

-77 and ethyl ester in a molar ratio of approximately 7:1. After adjusting the composition of the mixture of these two proportions, the total estimated yield was 69%. Since the esterification of any carboxylic acid present occurs in the next step, both the ester and the acid react to form the same product.

Step AAA

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

To a solution of 9.76 g (50 mmol) of (+/-)-2-(4io nitrophenyl)propionic acid in 150 ml of absolute ethanol was added 3.0 ml of concentrated sulfuric acid. The resulting solution was stirred under nitrogen at reflux. After 6 hours, the solution was cooled and thoroughly stirred with the gradual addition of 250 ml of a saturated aqueous solution of sodium bicarbonate (warning of the occurrence of strong foaming). The mixture was then partitioned between 750 mL of ethyl acetate and 500 mL of water. The organic layer was washed with 100 mL of saturated aqueous sodium bicarbonate solution and then with 100 mL of saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate,

2o filtered and concentrated in vacuo to give 10.86 g (97%) of an oil which was homogeneous on TLC 9:1 hexane-EtOAc. 400 MHz ¹ NMR (CDCl ₃ ) agreed with the predicted structure.

Step BBB

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

A suspension of 924 mg (23 mmol) of sodium hydride (60% in oil) in 21 ml of dry Ν,Ν-dimethylformamide was stirred under nitrogen in an ice bath and a solution of 4.68 g (21 mmol) of the ethyl ester of the acid (+/-) was added -2-(4-nitrophenyl)propionate in 20.5 ml of dry N,N30 dimethylformamide gradually over 10 min. An intense purple color developed during the addition. The mixture was then left • ·

-78 to warm to room temperature. After approximately 1 hour, the mixture was cooled again in an ice bath and a solution of 1.44 ml (3.28 g; 23 mmol) of methyl iodide in 5 ml of dry Ν,Ν-dimethylformamide was added dropwise with a syringe over 10 min while maintaining the internal temperature at 10 5 15 °C. The mixture was allowed to warm to room temperature and the color turned brown. After 1 h, an additional 187 mL (426 mg, 3 mmol) of methyl iodide was added. The next day, the mixture consisted of a suspension of a certain amount of grayish solid in a gold-colored liquid. This mixture was thoroughly stirred and the reaction was terminated by the gradual addition of 10 ml of a 5% aqueous solution of potassium bisulfate. The mixture was partitioned between 400 mL of diethyl ether and 400 mL of water. The organic layer was washed again with 3 x 400 mL water and then with 50 mL saturated aqueous sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography of the residue on silica gel (eluting with hexane-EtOAc 19:1) gave 4.31 g (87%) of an oil which was homogeneous on TLC 9:1 hexane-EtOAc. 400 MHz ¹ H NMR (CDCl ₃ ) agreed with the desired 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 in 1 L of 0.5 M potassium hydroxide in methanol was stirred under nitrogen and heated to approximately 50 °C, when 111 mL of water was gradually added. The resulting solution was stirred at reflux overnight and then concentrated in vacuo. The residue was partitioned between ethyl acetate-tetrahydrofuran and 0.5 N hydrochloric acid. The aqueous layer was also repeatedly extracted with chloroform. The organic fractions were dried over magnesium sulfate and concentrated in vacuo to give 9.4 g (94%) of an amorphous tan solid homogeneous on TLC 95:5:0.5 CH ₂ CI ₂ - 79 ···· ·· · · ► ♦ · « • · · ·· · · <

• · <

·· ··

MeOH-AcOH. 500 MHz ¹ H NMR (CDCb) was consistent with the desired structure.

Step DDD

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

18 ml of cyclohexane and 9 ml of thionyl chloride were added to 8.36 g (40 mmol) of 2-methyl-2-(4-nitrophenyl)propionic acid. The mixture was stirred under nitrogen and heated under reflux. The solid gradually dissolved and gas evolution was observed. After 20 h the solution was cooled and evaporated under a stream of nitrogen and then dried in vacuo. The remaining pale orange solid was dissolved in 50 mL of anhydrous tetrahydrofuran and added dropwise to a solution of 9.10 mL (6.43 g, 88 mmol) of diethylamine in 100 mL of anhydrous tetrahydrofuran and the mixture was stirred in an ice-methanol bath at about -10 to

- 15 °C. After completion of the addition, which was accompanied by precipitation, the mixture was allowed to gradually warm to room temperature. After two days, the mixture was concentrated in vacuo and the residue partitioned between 250 mL ethyl acetate and 200 mL water. The organic phase was further washed with water, then with a saturated aqueous solution of sodium bicarbonate and finally with a saline solution. The ethyl acetate solution was dried over magnesium sulfate, filtered and concentrated in vacuo. The remaining oil was purified by flash chromatography on silica gel (eluting with a mixture of hexane ethyl acetate 6:1 and then 5:1) to obtain 9.45 g (85%) of a pale yellow solid, mp 59.5 - 61 °C homogeneous on TLC 2: 1 hexane-EtOAc.

500 MHz ¹ H NMR (CDCb) was consistent with the desired structure.

Mass spectrum (PB-NH ₃ /Cl): m/e=265 (M+H).

Step EEE

2-(4-Aminophenyl)-N,N-diethylisobutyramide

A mixture of 9.38 g (35.5 mmol) of N,N-diethyl-2-(4nitrophenyl)isobutyramide, 400 mg of 10% palladium on carbon and 120 ml • · · · ·· ···· • ·

- 80 absolute ethanol was shaken with hydrogen (hydrogen pressure at the beginning 324 kPa) in a pressure vessel for 22 hours. The catalyst was removed by filtration through diatomaceous earth under nitrogen and the filter cake was washed with additional ethanol. Concentration of the filtrate in vacuo gave 8.5 g (100%) of an off-white solid, mp 89-90 °C; homogeneous on

TLC 98:2 CH ₂ CL ₂ -MeOH. 500 MHz ¹ H NMR (CDCl ₃ ) was consistent with the desired structure. Mass spectrum (PB-NH ₃ /Cl): m/e=235 (M+H).

io Step FFF

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

35.5 ml of concentrated hydrochloric acid was added to 8.5 g (35.5 mmol) of 2-(4-aminophenyl)-N,N-diethylisobutyramide and the mixture was stirred until a homogeneous solution was obtained. This was then stirred in an ice-acetone bath at a temperature of -10 to -5 °C and a solution of 2.55 g (36.9 mmol) of sodium nitrite in 13.5 ml of water was added dropwise over the course of 25 minutes. Stirring was continued at this temperature for another hour. The mixture was kept cold and added in small portions over 1 hour to a solution of 40.1 g (178 mmol) of chloride dihydrate

2o of tin in 28.5 ml of concentrated hydrochloric acid stirred under nitrogen in an ice-acetone bath (approximately -10 °C). After the addition was complete, stirring was continued in a cooling bath for 1 h. The mixture was then allowed to warm to near room temperature with thorough stirring to form a homogeneous solution. The solution was partitioned between 500 mL ethyl acetate and 50 mL water. The ethyl acetate layer was washed with another 50 mL of water, and then 500 mL of semi-saturated aqueous sodium bicarbonate solution was cautiously added. The mixture was gently stirred to produce considerable gas and precipitation. The thick mixture was filtered before separating the phases. The ethyl acetate phase was washed with 50 mL of brine, then dried over magnesium sulfate, filtered and concentrated in vacuo at room temperature.

-81 temperature. This gave 7.04 g (80%) of a somewhat sticky orange solid that was ill-defined by TLC, NMR, and mass spectroscopy, but suitable for use in the next step.

with Example 7.2

2-[2-(3,5-dimethylphenyl)-3-[2-][4-(pyridin-3-yl)butyl]amino-1-ethyn-1-hindol-5-n-N,N-diethylisobutyramide

Step 7.2A

2-f2-(3,5-dimethylphenyl)-3-f2-f4-(pvridin-3yl)butylamino-1-ethvn-1H-indole-5-vn-2-methylpropionic acid ethyl ester

A dry flask containing 3.00 g (7.93 mmol) of 2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2methylpropionic acid ethyl ester (prepared according to description in example 7.1 step A), 4.76

20 g (39.7 mmol) of anhydrous MgSO ₄ and a magnetic stir bar was fitted with a whistle and needle adapter leading to a Firestone valve. The flask was thoroughly purged with nitrogen and the mixture was cooled in an ice-methanol bath to -10 to -5 °C and stirred thoroughly while gradually adding 1.32 g (8.88 mmol) of 4-(pyridin-325 yl)butyraldehyde in 15 ml of dry CDCI ₃ with a syringe during 10 to 15 min. The resulting mixture was stirred under nitrogen at -10 to -5°C for 40 to 45 min. The septum was then removed for the time necessary to add 390 mg (10.3 mmol) of sodium borohydride. The mixture was stirred under nitrogen at -10 to -5 °C and over several minutes was

• · · · · ·· • · · · · ···· · • · · · · · ·· φ ·· ·· dry methanol (10 ml) was added dropwise with a syringe. After 30 min, the mixture was removed from the cooling bath and partitioned between 90 mL EtOAc and 90 mL H ₂ O. The organic layer was washed with 2 x 30 mL brine and then dried over anhydrous sodium sulfate. The filtered solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (gradient elution 0-10% MeOH in CH ₂ CI ₂ ). Fractions containing the product and a small amount of unreacted starting material were combined and concentrated to give 3.00 g of a pale beige solid foam which was used directly in the next step without further purification or characterization.

Step 7.2B

2-[3]-[2]-Benzyloxycarbonyl-(4-(pyridin-3yl)butylaminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-[H-215]methylpropionic acid ethyl ester

A solution of 3.00 g (theoretical maximum 5.86 mmol) of crude ethyl ester of 2-(2-(3,5-dimethylphenyl)-3-[2-[4-(pyridin-3yl)butylamino]-ethyl]-1H- indol-5-yl]-2-methylpropionate in 30 ml of dry CH ₂ CI ₂ was stirred under nitrogen while cooling in a dry bath

2o ice - acetone. To this solution, 1.106 mL (820 mg, 6.36 mmol) of Ν,Ν-diisopropylethylamine was added via syringe. Then, 956 μΙ (1.14 g, 6.36 mmol) of benzyl chloroformate was added dropwise with a syringe over the course of 5 to 10 min. After 20 min, the solution was removed from the cooling bath and allowed to warm to room temperature. After two hours, the solution was diluted with 50 mL CH ₂ CI ₂ , transferred to a separate flask and shaken with 80 mL H ₂ O. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography of the obtained gum on silica gel (gradient elution 0.2 - 2% MeOH in CH ₂ CI ₂ ) gave 2.81 g (in steps 1 and 2 total 55%) of a pale golden yellow gum which was homogeneous on TLC 95:5 CH ₂ Cl ₂ -MeOH. 500 MHz ¹ H NMR (CDCl ₃ ) was due to the presence of rotamers

........... ··, .*·.

·· · · · ♦···· • · ♦ · ♦ · · ·· • · » · ·· · ···· · ·· · · · · · · ··· · ·· · ·· ··

-83complex but seemed to fit the required structure. Mass spectrum (ESI): m/e=646 (M+H) ⁺ .

Step 7.2C

2-[(3,5-dimethylphenyl)-1H-indole-5-yl]-2-methylpropionic acid

A mixture of 2.78 g (4.30 mmol) of 2-[3-[2[benzyloxycarbonyl-[4-(pyridin-3-yl)butyl]amino]ethyl]-2-(3,5dimethylphenyl)-1H- indol-5-yl]-2-methylpropionate in 43.0 mL (21.5 io mmol) of 0.5 μM KOH in MeOH and 25 mL of THF was stirred under nitrogen and heated to reflux. 18 mL of water was gradually added to the resulting solution, and the solution was refluxed for 39 h. It was then cooled and concentrated to a small volume, with precipitation occurring. The mixture was mixed with 10.75 mL (21.5 mmol) of 2 N HCl and stirred for a further few minutes. The solid was collected on a filter and washed thoroughly with water. After sieve drying under nitrogen, the solid was triturated and washed with diethyl ether and dried in vacuo to give 2.43 g (92%) of a cream colored powder, mp 152 - 154 °C (partial dec) homogeneous on TLC 90:10 CH ₂ Cl ₂ -MeOH. 500 MHz ¹ H NMR (DMSO-de) was consistent with the desired structure. Mass spectrum (ESI): m/e=618 (M+H) ⁺ .

Step 7.2D

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

A solution of 92.7 mg (0.15 mmol) of 2-[3-[2[benzyloxycarbonyl-[4-(pyridin-3-yl)butyl]amino]ethyl]-2-(3,5dimethylphenyl)-1H-indole acid -5-yl]-2-methylpropionate, 83.2 mg (0.16

30 mmol) of PyBOP reagent and 0.151 mL (116 mg; 0.9 mmol) of triethylamine in 0.750 mL of dry CH ₂ Cl ₂ were stirred at room temperature

- 84 ···· ·· ···· ·· ·· • · · · · · • · · · ·· • · · ··· · · • · · · · • · · · · · · in closed flask 2 days. The solution was then partitioned between 10 mL EtOAc and 10 mL 0.5 N HCl. The organic phase was washed with 10 mL of saturated aqueous sodium bicarbonate solution and then with 5 mL of saturated aqueous sodium chloride solution. The EtOAc phase was then dried over magnesium sulfate, filtered and concentrated in vacuo at room temperature. The residue was purified by preparative TLC on six Analtech tapered silica gel plates (20 x 20) developed in 95:5 CH ₂ CI ₂ -MeOH. The product band from each plate was isolated, pooled and extracted with 95:5 CH ₂ Cl ₂ -MeOH. io Concentration of the extracts in vacuo afforded 85.2 mg (78%) of a pale golden yellow gum which was homogeneous on TLC 95:5 CH ₂ CI ₂ -MeOH. 500 MHz ¹ H NMR (CDCl ₃ ) was complex due to the presence of rotamers, but consistent with the desired 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-1-ethyl]-1-hindol-S-yne-N,N-dibutylisobutyramide

A mixture of 76.5 mg (0.105 mmol) [2-[5-(120-dibutylcarbamoyl-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-3yl]ethyl]-[4-( pyridine-3-yl)butyl]carbamate, 40 mg of 10% palladium on carbon, 4 mL of absolute EtOH, and 4 mL of EtOAc were shaken with hydrogen (approx. 324 kPa) in a pressure vessel for 6 h. The catalyst was removed by filtration through celite under nitrogen and the filtrate was concentrated in vacuo at room temperature. The residue was purified by preparative TLC on four Analtech tapered silica gel plates (20 x 20) developed with 92.5:5.5:0.75 CH ₂ CI ₂ -MeOH-concentrated NH ₄ OH. The product bands from each plate were isolated, pooled and extracted with 92.5:7.5:0.75 CH ₂ CI ₂ -MeOH-concentrated NH ₄ OH.

3o Concentration of the extracts in vacuo gave 51.4 mg (82%) of a pale yellow solid gum homogeneous on TLC in 92.5:5.5:0.75 CH ₂ CI ₂ -MeOHφ ·· · φφ φφφφ

-85 concentrated ΝΗ ₄ ΟΗ. 500 MHz ¹ Η NMR (CDCl ₃ ) was consistent with the desired structure. Mass spectrum (ESI): m/e 595.6 (M+H) ⁺ .

Following a procedure similar to that described in Examples 7.1 and 5 7.2, the following compounds were prepared:

···· • 4 4

4 4 • · · · 4 0 4

44 ····

4 0 4

0 44

440 4 4

4 0 ·4

Example # X-R7£8 Ri me 7A Me. 1 Me Me 0 4-pyridyl 539 (M + H) 7A Me. 1 Me Me 0 3-pyridyl 539 (Μ + H) 7B ^Me0 ^Me. Me MeO— 0 3-pyridyl 599 (Μ + H) 7C ^MeQ/ ^Me. Me MeC— Y< 0 4-pyridyl 599 (Μ + H) 7D ^M( r ^Μ θ Me _Me - ^N Y^ 0 4-pyridyl 511 (M+H) 7E ^M( T Me Me Μβ'Υ^ 0 3-pyridyl 511 (M+H) 7F Me ^Me ^|Me _x Me xT Me Me 4-pyridyl 595 (Μ + H) 7G Me ^Me 1 Me. Me X?' Me Me 3-pyridyl 595 (Μ + H)

• · • · · · • ·

7H 1 Me. Me 0 4-pyridiums 595 (Μ + H) 71 X 1 Me Me _Me — ^Ν γ< 0 3-pyridyl 579 (Μ + H) 7J Hmm. Me MeyN^X^ Me 0 3-pyridyl 525 (Μ + H) 7K uMe _x Me 0 3-pvridyI 511 (M+H) 7L Me. 1 Me Me ^Μδ γ ^Ν γΧ Me 0 3-pyridyl 553 (Μ + H) 7M Me. 1 Me Me f^ 3-pyridyl 593 (Μ + H) 7N Me. 1 Me Me σΌ 4-pyridyl 593 (Μ + H) 70 Me Me Η ₂ Νγς 0 3-pyridyl 483 (Μ + H) 7P Me. ΕίΟγΚ ^Μθ 0 4-pyridyl ,/526,(M+H) #/·'??<:'??;??···'·ř?Y: ^: '.A·•••'••ΐ/'γ·· ·

• · • · · ·

-88 Example 8

CH ₃ (2-(2-(3,5-dimethylphenyl)-1H-indole-3-quino-(3-pyridin-3-ylcyclohexylamine)

A solution of 2-(2-(3,4-dimethoxyphenyl)-1H-indol-3yl _] - of ethylamine (45 mg in 1 mL of dry CDCl 3 ) and then 206 mg of magnesium sulfate and the mixture was stirred at low temperature. After 15 min, 26 mg of sodium borohydride and then 1.0 ml of methanol were added and the mixture was stirred for another 30 min the reaction was quenched by addition of 2 N hydrochloric acid and evaporated to dryness Purification of the concentrate by preparative silica gel (methylene chloride:methanol, 9:1) afforded the title compound (8.4 mg).

Production of synthetic intermediates

3-ovridin-3-vl-cyclohexanone

Step A

3-pyridine-3-vl-cyclohex-2-enone

To a solution of 3-ethoxy-2-cyclohexen-1-one (1.4 g in 10 mL of dry tetrahydrofuran) was added 1.58 g of 4-bromopyridine and the mixture was thoroughly stirred at -78 °C. To this mixture was added dropwise tert-butyllithium (11.8 mL of a 1.7 M solution in pentane) and the reaction was allowed to proceed at low temperature. After two hours the reaction was • · • · ·· · 4 4 4 ····

4 4 · · 4 · ·· • 4 44 ·« 4 4444 4 • 4 444 444

4444 44 4 44 44

-89 interrupted by the addition of 2 N hydrochloric acid and heated under reflux for 14 h. The mixture was then cooled and neutralized to pH 7 by careful addition of 1 N sodium hydroxide. The mixture was then extracted with methylene chloride and the organic phase dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane, 1:1, 2:1) afforded the title compound (1.37 g).

Step B io 3-pyridin-3-β-cyclohexanone

To a solution of 3-pyridin-3-yl-cyclohex-2-enone (1.25 g in 50 mL of ethanol) was added 164 mg of platinum oxide catalyst and the mixture was placed under a hydrogen atmosphere at 276 kPa. After 2 h, the catalyst was removed by filtration and the filtrate was concentrated in vacuo.

Purification of the residue by flash chromatography on silica gel (ethyl acetate hexane, 1:1) afforded the title compound (427 mg).

Following a procedure similar to that described in Example 8, the following compounds were prepared:

Example # (AND) R? Rl me 8A -CH2CH2- -(CH ₂ ) ₄ -4(females 1-4OMe) 4-pyridyl 532 (Μ + H)

• ···· ·· ···· ♦· ·· • · · · · · · · · · • · ··· · · ·· • · ·· ·« φ ·· · · * • · «· · ··· • · · · · · · ·· ··

8B -CHgCH?- -(CH ₂ ) ₄ (phenyl-4OH) 4-pyridyl 518 (M+H) 8C -CH<(Me)7CH7CH> -H 4-pyridyl 426 (Μ + H) 8D XX -H 3-pyridyl 424 (Μ + H) 8E O -H 3-pyridyl 410 (M + H) 8F -cx -H 3-pyridiums 440 (Μ + H)

Example 9.1

2-(3,5-Dimethylphenyl)-3-[2-(1-methyl-4-pyridine-3-n-butylamino)ethyne-1H-indole-5-carboxylic acid diisobutylamide

Step 9.1 A

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

To a solution of 3-(2-aminoethyl)-2-(3,5dimethylphenyl)-1H-indole-5-carboxylic acid ethyl ester (prepared as described in Example 5.1, 1.5 g in 30 ml of dry tetrahydrofuran) at 0 °C was added a solution of di-tert-butyl dicarbonate (1.9 g in 3 ml of tetrahydrofuran) and then an aqueous solution of potassium carbonate (1 g in 10 ml of water) • · • ·

- 91 and the resulting suspension was thoroughly stirred at 0 °C. After 12 min, the reaction was terminated by the addition of excess saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic portion was dried over sodium sulfate and concentrated in vacuo.

The resulting solid was washed successively with methylene chloride, hexane and ethyl acetate to give the title compound (1.77 g).

Step 9.1B ¹⁰ 3-(2-tert-butoxycarbonylaminoethyl)-2-(3,5-dimethylphenyl)1H-indole-5-carboxylic acid

To a suspension of 3-(2-tert-butoxycarbonylaminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid ethyl ester (830 mg in 50 mL methanol) was added 8 mL of 1.25 N sodium hydroxide and the mixture was heated to 75°C in an oil bath. After 5.5 h, another 3 mL of 1.25 N sodium hydroxide was added and the reaction was allowed to proceed for another h. At this time, the mixture was cooled to room temperature and the reaction was quenched by the addition of pH 2 buffer. The mixture was extracted with ethyl acetate, washed with sat. chloride

2o of ammonium and the organic part dried over sodium sulfate. Concentration in vacuo gave the crude acid in quantitative yield.

Step 9.1C

(2-N-5-Diisobutylcarbamoyl-2-(3,525-dimethylphenyl)-1H-3-methyl)carbamic acid tert-butyl ester

To a solution of 3-(2-tert.-butoxycarbonylaminoethyl)-2-(3,5dimethylphenyl)-1H-indole-5-carboxylic acid (200 mg in 12 mL of methylene chloride) was added 104 mg of 1-hydroxybenzotriazole and then 118 mg of hydrochloride 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide

3o and the mixture was stirred at room temperature. After 30 min was added • · • ·

- 92 0.35 ml of diisobutylamine and the mixture was stirred for 14 hours at room temperature. The reaction mixture was then concentrated in vacuo and purified by flash chromatography on silica gel (hexane:ethyl acetate, 2:1) to afford the title compound (230 mg).

Step 9.1D

3-(2-AminoethvD-2-(3,5-dimethylphenyl)-1-hindole-5-carboxylic acid diisobutylamide

To a solution of {2-[5-diisobutylcarbamoyl-2io(3,5-dimethylphenyl)-1H-indol-3yl]ethyl}carbamic acid tert-butyl ester (230 mg in 12 mL of methylene chloride) at 0°C was added 0.55 ml of anisole and then 3.4 ml of trifluoroacetic acid and the mixture was stirred at 0 °C. After 1 h the mixture was concentrated in vacuo and the remaining acid was removed by azeotropic distillation with toluene. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:8:1) afforded the title compound (173 mg).

Step 9.1E

Diisobutylamide

To a solution of 2-(2-aminoethyl)-2-(3,5dimethylphenyl)-1H-indole-5-carboxylic acid diisobutylamide (142 mg in dry methanol) was added 19 mg of 5-pyridin-3-yl-pentan-2 -one and the pH was adjusted to 6 by addition of trifluoroacetic acid. To this mixture was added approximately 10 mg of 0.3 nm molecular sieves followed by 27 mg of sodium cyanoborohydride. The pH was adjusted occasionally with trifluoroacetic acid during 36 h to maintain pH 6. The reaction was then terminated by the addition of aqueous potassium carbonate solution and the mixture was extracted with ethyl acetate. The organic part

3o was gradually washed with an aqueous solution of potassium carbonate and

- 93 salt solution, then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:8:1) afforded the title compound (32 mg) [m/e = 567 (M+H)] and unreacted amine (115 mg).

Production of synthetic intermediates

Step A also with 4-pyridine-3-n-butvraldehyd

To a solution of oxalyl chloride (0.74 ml in 5 ml of dry methylene chloride) was added at -78 °C a solution of methyl sulfoxide (0.90 ml in 5 ml of methylene chloride) and the mixture was stirred for 15 min at a low temperature. A solution of 4-pyridin-3-yl-butan-1-ol (prepared as described in Example 2.1, 820 mg in 10 mL of methylene chloride) was added and the reaction was allowed to proceed for a further 45 min before 4 mL of triethylamine was added and the mixture allowed to warm to room temperature. After 35 min, saturated sodium bicarbonate solution was added and the mixture was extracted with methylene chloride. The organic part

2o was washed with saturated sodium bicarbonate solution, 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

To a solution of methylmagnesium bromide (0.75 mL of a 3 M solution (diethyl ether) in 3.5 mL of dry tetrahydrofuran) at 0 °C was added a solution of 4-pyridin-3-yl-butyraldehyde (133 mg in 1 mL of tetrahydrofuran) and the mixture was stirred at low temperature. After 30 min, the reaction was terminated by the addition of saturated ammonium chloride and extracted ·· ··

- 94 with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol, 95:5) afforded the title compound (71 mg).

Step C

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

A solution of methyl sulfoxide (0.075 ml in 0.25 ml of methylene chloride) was added at -78°C to a solution of oxalyl chloride (0.060 ml in 1 ml of dry io methylene chloride) and the mixture was stirred at a low temperature for 18 min. A solution of 5-pyridin-3-yl-pentan-2-ol (71 mg in 1 mL of methylene chloride) was added and the reaction was allowed to proceed for 40 min before 0.35 mL of triethylamine was added and the mixture was allowed to warm to room temperature. After 35 min, water was added and the mixture was extracted with methylene chloride. The organic portion was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (methylene chloride:methanol,

96:4) the title compound (61 mg) was obtained.

Example 9.2

CH • · · · • · •« « · · φ · · · · • φ · · · · · · • φ · · φφ * ·Φ·Φ · • · · φ φ Φ·· • · · · · · · *· *·

- 95 1 424243,5-dimethylphenyl)-1H-indole-3-vHethyl)-1,2,3,4,5,6 ^- hexahydro4,4,1bipyridinev

Step 9.2A ⁵ 142-(3,5-Dimethylphenyl)-1H-indol-3-n-2-(3,4,5,6-tetrahydro-2Hf4,4'1bipyridinyl-1-n)ethane-1,2 -dion

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

Step 9.2B

14242-(3,5-dimethylphenyl)-1H-indole-3-methyl)-1,2,3,4,5,6-hexahydro[4,4'1]bipyridinyl

To a solution of 1-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]-2-(3,4,5,6tetrahydro-2H-[4,4']bipyridinyl-1-yl)ethane -1,2-dione (148 mg in dry tetrahydrofuran) was added dropwise to 2.71 ml of a 1 M solution of lithium aluminum hydride in tetrahydrofuran and the mixture was heated under reflux in an oil bath. After 1.5 h the mixture was cooled and the reaction was stopped by gradually by adding 30 mL of water and 4 mL of ammonium hydroxide and 25 mL of ethyl acetate.The mixture was filtered

3o to remove fixed shares. The organic part was washed with a solution • · · ·

-96 salt, dried over magnesium sulfate and concentrated in vacuo to give the title compound (71 mg), m/e = 410 (M+H).

Example 9.3

io 2-F2-(3,5-dimethylphenyl)-3-n2-dimethyl-f4-(pyridin-4-yl)butylamino1ethyl H-indole-5-yl1-N,N-dibutylisobutyramide

A dry flask containing 67 mg (0.113 mmol) of 2-(2-(3,5dimethylphenyl)-3-[2-[methyl-[4-(pyridin-4-yl)butyl]amino]ethylj-1H-indol-5-yl] -N,N-dibutylisobutyramide (prepared according to Example 7.2), 33.9 mg (1.3 mmol) of paraformaldehyde, and 100 mg of powdered 0.3 nm molecular sieves were whisked and thoroughly purged with nitrogen, then 2.65 mL of MeOH was added and 65.2 μΙ (67.8 mg, 1.13 mmol) of glacial acetic acid, and the mixture was stirred for 35 min at room temperature. of anhydrous THF. After a few minutes, the reaction was filtered and the filtrate was shaken in a separate funnel with CH ₂ Cl ₂ . The combined organic fractions were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo.

The residue was purified by flash chromatography on silica gel (gradient elution 99:1:0.1 to 95:5:0.5 CH ₂ CI ₂ -MeOH-concentrated NH ₄ OH) to give 31.1 mg (45%) of the title compounds as glassy masses homogeneous on TLC 95:5:0.5 CH ₂ CI ₂ -MeOH-conc. NH ₄ OH. 500

4 ··· • ·

4 4 · 4 4 4 44 • 4 44 44 4 4444 4 • 4 ··· 444 • 44 · 44 · ·· ··

-97MHz ¹ H NMR (CDCl ₃ ) was consistent with the desired structure, m/e = 609.5 (M+H).

The following compounds were prepared in a manner similar to that described in Examples 9.1, 9.2 and 9.3.

Example # -N(R ₂ )-(A)- XRTtRs Ri me 9A /-\ ΟΟζθ -NH-CON(Et)2 3-pyridyl 596 (M-H) 9B /-\ - ^C °2 ^H -NH-CON(Et)? 3-pyridiums 568 (M-H) 9C /—< CO ₂ Et -NH-CO(4morpholine) 3-pyridyl 610 (Μ + H) 9D /——γ CO ₂ H -3- -NH-CO(4morpholine) 3-pyridyl 582 (M-H) 9E ^-O- -NH-CON(Et)2 3-pyridiums 524 (M-H)

9F -F/ \/ -H 3-pyridiums 425 (M + H) 9G -H 4-pyridiums 425 (M + H) 9H -H 4-pyrides I 411 (Μ + H) 91 -NHCH2CH2CH2O- -COOEt Pr Et 582 (Μ + H) 9J n?» C(O)N(iBu)2 4-pyrides I 595 (M + H) 9K -NHCH2CH2CH2O- C(O)N(iBu)2 3-pyridyl 555 (M + H) 9L -NHCH(Me)CH2CH2- C(O)N(ÍBu)2 3-pyridiums 553 (M + H) 9M -ΝΉCHfMe)CH2CH ₂ CH2- C(O)N(iBub 4-pyridyl 567 (M + H) 9N (cis) -NHCH ₂ CH=CH- C(O)N(iBu)2 3-pyridiums 537 (Μ + H) 9N (trans) -nhch ₂ ch=ch- C(O)N(iBu)2 3-pyridiums 537 (M + H) 90 -NHCH2CH2CH(Me)- C(O)N(iBu)2 4-pyridyl 553 (M + H) 9P -NHCH2CH2CH(Me)- C(O)N(iBu)2 3-pyridiums 553 (M + H) 9Q -NHCH2CH2-O-CH2- C(O)N(iBu)2 3-pyridyl 555 (M + H) 9R -N(Et)CH2CH2CH2CH2- C(Me)2C(O)N(iBu)2 4-pyridiums f ' //' ' / , ' , , f y Z

• ·

9S -NHCHoCHfCHsKHx ch ₂ - C(O)N(iBu) ₂ 3-pyridiums ' - \ 1·Ο·ΚΙ 9T -nhch ₂ ch ₂ ch ₂ , CHICH3)- C(O)N(iBu) ₂ 4-pyridiums 9U -NHCH ₂ CH ₂ CH(CH 3 )CH ₂ - C(O)N(iBu) ₂ 3-pyridyl ΪΜ+Β 9V -NHCH(CH3) _CH2 - C(O)N(iBu) ₂ 3-pyridiums /539 (Μ.+-Ή) 9W -N(Me)ch ₂ ch ₂ ch ₂ ch ₂ - C(O)N(Et) ₂ 4-pyridyl — 9X -NHC(CH ₃ ) ₂ CH ₂ CH ₂ ch ₂ - C(O)N(íBu) ₂ 3-pyridiums '581 9Y -NHC( _CH3 ) _{2CH2CH2CH1OH )} - C(O)N(iBu) ₂ 3-pyridyl , sn M+H) 9Z -NHC(CH ₃ ) ₂ CH=CHCHfOH)- C(O)N(iBu) ₂ 3-pyridiums 595' 9Z -NHC(CH ₃ ) ₂ CH ₂ CH ₂ ch ₂ - C(Me) ₂ C(O)N(Et) 2 3-pyridiums 9AA -nhch ₂ ch ₂ - C(O)N(iBu) ₂ 3-pyridyl .........525 9BB -nhch ₂ ch ₂ - C(Me) ₂ C(O)N(Et) ₂ 3-pyridyl 511 " 9CC -NHC(CH ₃ )2CH=CHCHÍOH)- C(O)N(iBu)2 4-pyridyl 9DD -NHC(CH3) ₂ CH ₂ CH ₂ CHÍOH)- C(O)N(iBu)2 4-pyridyl Υ'597 ; -IM+HV 9EE -NHC(CH3) ₂ CH ₂ CH ₂ ch ₂ - C(O)N(iBu)2 4-pyridyl WWphW 9FF -NHC(CH ₃ ) ₂ CH=CHCH(OH)- C(Me)2C(O)NCE)2 4-pyridyl Υ58ΙΟ·: ,,. ^/r ''/''.....>:·' ·.·.·.

• ·

- 100 ·· ···· • · · · · · • · · · ·· • · · ·· · · « • · · · · • ·· ·«

9GG -NHC(CH3)2CH2CH ₂ ch ₂ - C(Me) ₂ C(O)N(Et) ₂ 4-pyridyl 567 9HH -NHCH2CH( _CH3 ) _CH2CH2- C(O)N(iBu)2 4-pyridyl 567''' (MIHV 9Π -nhch ₂ CH(CH2CH3)CH2CH ₂ - C(O)N(iBu)2 4-pyridyl 551 / {M+H> 9JJ -NHCH2CH2- C(Me) ₂ C(O)N(Et) 2 4-pyridyl 5ir > {M+H} 9KK -NHCH2CH2- C(O)N(iBu)2 4-pvridyI 525 (M+W

(2-(2-(3,5-dimethylphenyl)-5-methanesulfonyl-1 Η-ίηάοΙ-3-νΠρΓθρνΙ)-(4pyridin-4-yl-butvOamine

Step 10A

2-Methylcyclopropanecarboxylic acid N-methoxy-N-methylamide

To a solution of 2-methylcyclopropanecarboxylic acid (10 g in a mixture of 200 ml of benzene and 2 ml of Ν,Ν-dimethylformamide) at 0 °C was added 10.5 ml of oxalyl chloride and the mixture was stirred for 30 min at 0 °C, and then heated during 30 min at room temperature. 14.6 g of Ν,Ο-dimethylhydroxylamine hydrochloride and 41 ml of triethylamine were then added. The mixture was stirred at room temperature for 1 h and then the reaction was quenched by the addition of saturated sodium bicarbonate. The aqueous part was extracted with ethyl acetate and combined ···· • · · · · 4 · 4 · · * · 4 4 4 44*4

4 44 44 4 4444 ·

444 444

4444 44 4 44 «4

- 101 organic portions were washed with brine, dried over sodium sulfate and concentrated in vacuo. The product was purified by distillation under reduced pressure to give 8.9 g of an oil.

Step 10B (3,5-dimethylphenyl)-(2-methylcyclopropyl)methanone

To a solution of 5-bromo-meta-xylene (5.7 mL in 120 mL of dry tetrahydrofuran) at -78°C was added 30.6 mL of a 1.4 M solution of n-butyllithium in hexane and the mixture was stirred at low temperature. After 15 min, a solution of 2-methylcyclopropanecarboxylic acid N-methoxy-Nmethylamide (5.0 g in 50 ml tetrahydrofuran) was added dropwise over 5 min and the mixture was allowed to slowly warm to room temperature. After 1 hour, the reaction was terminated by the addition of 20 ml of 2 N hydrochloric acid and 40 ml of water. This mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine and dried over sodium sulfate to afford 6.95 g of the crude title compound.

Step 10C

20 2-N 2-(3 _L 5-Dimethylphenyl)-5-methanesulfonyl-1H-indole-3-vinpropylamine

(3,5-Dimethylphenyl)-(2methylcyclopropyl)methanone (2.24 g) was added to a solution of (4-methanesulfonylphenyl)hydrazine (1.88 g in 20 mL of n-butanol) at 95 °C and the mixture was heated in an oil bath at 110 °C. After 16 h, the reaction was cooled to room temperature and poured into 200 ml of diethyl ether, and the resulting brown precipitate was separated by filtration. The solids were dissolved in 300 mL of water and extracted with diethyl ether. The aqueous portion was basified by the addition of 1 N sodium hydroxide and then extracted with diethyl ether. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography • 444

44··

44

4 44 4 4444

4 4 4 4 44 44

4 4 4 4 4 4 444 4 4 • 4 444 444 •444 44 4 ·4 44

- 102 on silica gel (methylene chloride:methanol, 9:1) gave the title compound (313 mg).

Step 10D (2-(2-(3,5-dimethylphenyl)-5-methanesulfonyl-1H-indol-3-yl)-(4-pyridin-4-yl-butylamine)

A mixture of 4-pyridin-4-yl-butyraldehyde (23 mg), 2-[2-(3,5dimethylphenyl)-5-methanesulfonyl-1H-indol-3-yl]propylamine (50 mg) and magnesium sulfate (76 mg ) was diluted with 1.5 ml of CDCl ₃ and stirred at -5 °C. After 15 min, a solution of sodium borohydride (6.8 mg in 1.5 mL of dry methanol) was added and the mixture was stirred at low temperature for another 20 min. The reaction was then quenched by the addition of water, the reaction mixture was extracted with ethyl acetate, and the organic part was successively washed with water and brine, and then dried over sodium sulfate.

Purification of the concentrate by preparative TLC on silica gel (methylene chloride:methanol, 9:1) afforded the title compound (29 g).

Following a procedure similar to that described in Examples 7 and 10, the following compounds were prepared:

Example # H „ R _9a / ^N — XR7, R8 Rl me AND 10A MeO^\ _H -NHC(O)Ph 4 4-pyridyl 575 (M-H)

- 103 ·· ····

10B V* H Χλ m 6 4 4-pyridiums 526 (M + H) 10C H XX Me Me 0 4 4-pyridyl 553 (M + H) 10D H Me _x Me (EDsnXX^ 0 4 3-pyridiums 553 (M + H) 10E H Me. Me 0 4 4-pyridiums llxsff iviv 10F Υθ H X~x Me. Me (E^xX 0 4 4-pyridyl ιββ 10G Y ^e H X~x Me Me (SuíísNXK^ 0 4 4-pyridyl HfflB IBie 10H H XX, K Me Me Me (Εί^χΧ 0 4 3-pyridyl 553 101 Y ^e H x-,··, Me^ Me "γ, 2 3-pyridiums ; 498 (M+H)

Example 11

2-(3,5-dichlorophenyl)-3-[2-(4-pyridin-3-ylbutylamino)ethyl]-1H-indole-5-carboxylic acid diethylamide

Step 11A • · • ·

- 104 2-(3,5-Dichlorophenyl)-3-[2-(4-pyridine-3-ylbutylamino)ethyn-1H-indole-5-carboxylic acid ethyl ester

To a solution of 3-(2-aminoethyl)-2-(3,5-dichloropropyl)-1H-indole-5-carboxylic acid ethyl ester (prepared as described in Example 5.1, 100 mg in 7.0 ml of chloroform) at -5 °C was 172 mg of magnesium sulfate and then 46.3 mg of 4-pyridin-3-ylbutyraldehyde were added and the mixture was stirred at low temperature for 15 min. Then a solution of sodium borohydride (13.7 mg in 1.2 ml of dry methanol) was added, and after another 40 min the reaction was terminated by the addition of water. The mixture was partitioned between ethyl acetate and saturated potassium carbonate, extracted and the organic phase was washed with brine and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methynol, 92:8) afforded the title compound (100 mg).

Step 11B

3-(2-tert-butoxycarbonyl-(4-pyridine-3-butyl)amino-1-ethyl)-2-(3,5-dichlorophenyl)-1H-indole-5-carboxylic acid ethyl ester

To a solution of 2-(3,5-dichlorophenyl)-3-[2-(420 pyridin-3-yl-butylamino)ethyl]-1H-indole-5-carboxylic acid ethyl ester (500 mg in 8 mL of dry tetrahydrofuran) was added 331 mg of di-tert.butyl dicarbonate was added at 0 °C and then an aqueous solution of potassium carbonate (215 g in 4 ml of water and the resulting suspension was thoroughly stirred at 0 °C. After 1 hour the reaction was terminated by the addition of excess aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate.The organic portion was dried over sodium sulfate and concentrated in vacuo.Purification of the residue by flash chromatography on silica gel (methylene chloride:methanol, 96.5:3.5) afforded the title compound (472 mg).

Step 11C

-105 3-f2-tert-butoxycarbonyl-(4-pyridin-3-yl-butyl)aminolethyl·2-(3,5-dichlorophenyl)-1H-indole-5-carboxylic acid

To a suspension of 3-{2-[tert-butoxycarbonyl-(4-pyridin-3-yl-butyl)amino]ethyl}-2-(3,5-dichlorophenyl)-1H-indole-55-carboxylic acid ethyl ester (65 mg in 4 ml of methanol) at 0 °C, 1.4 ml of 1.25 N sodium hydroxide solution was added and the mixture was heated in an oil bath to 75 °C. After 2.5 hours, the mixture was cooled to room temperature and the reaction was terminated by the addition of a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate, washed also with saturated ammonium chloride solution and the organic part was dried over sodium sulfate. Concentration in vacuo afforded the crude title compound (63 mg).

Step 11D

{2-[2-(3 ₁ 5-Dichlorophenyl)-5-diethylcarbamoyl-1H-indole-3-nHethyl)-(4-pyridin-3-yl-butyl)carbamic acid tert-butyl ester

To a solution of 3-{2-[tert-butoxycarbonyl-(4-pyridin-3-ylbutyl)amino]ethyl}-2-(3,5-dichlorophenyl)-1H-indole-5-carboxylic acid (63 mg in 6 mL of methylene chloride) was added to 24.2 mg of 1-hydroxybenzotriazole followed by 26.7 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the mixture was stirred at room temperature. After 30 min, 0.06 ml of diethylamine was added and the mixture was stirred for 16 h at room temperature. The reaction mixture was then 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 • ·

-106 2-(3,5-Dichlorophenyl)-3-f2-(4-pyridine-3-vlbutylamino)ethvH-1H-indole-5-carboxylic acid diethylamide

To a solution of {2-[2-(3,5-dichlorophenyl)-5-diethylcarbamoyl-1H-indol-3-yl]ethyl}-(4-pyridin-3-yl-butyl)carbamic acid tert-butyl ester (63 mg in 3 ml of methylene chloride) at 0 °C, 0.15 ml of anisole and then 0.76 ml of trifluoroacetic acid were added and the mixture was stirred at 0 °C. After 1.5 h, another portion of 0.5 ml of trifluoroacetic acid was added and stirring was continued for another hour, then the mixture was concentrated in vacuo and the remaining acid was removed by azeotropic distillation with toluene. io Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:6.5:1) afforded the title compound (38 mg). m/e=537 (M).

The following compounds were prepared by a procedure similar to that described in Example 11:

Example # XR?d<8 Rl me 11A O 3-pyridyl 582 (Μ + H) 11B -COOEt 3-pvridvi 510 (M) 11C -CON(iBu)2 3-pyridyl 593 (M) 1 ID -CON(nBu) ₂ 3-pvridvl 593 (M) 11E -CON(Et)2 Me too °'N 541 (M)

- 107 Example 12.1

1-(2-(3,5-dimethylphenyl)-3-r2-(4-pyridin-4-1-butylamino)ethyl-1-hindol-5-yl)ethanone io Step 12.1 A

3-N2-tert-Butoxycarbonyl-(4-pyridin-4-yl-butylaminoethyl)-2-(3,5-dimethylphenyl-1H-indole-5-carboxylic acid) ethyl ester

Step A is prepared as described in Example 9.1, starting from 3-(3,5-dimethylphenyl)-3-[2-[4-(pyridin-415yl)butylamino]-ethyl]-1H-indole ethyl ester -5-carboxyl (Example 5.1 step B) and the title compound is formed.

Step 12.1 B

3-(2-tert-butoxycarbonyl-(4-pyridin-4-yl-butyl)aminoethyl) ²⁰ 2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid

It is prepared as described in Example 9.1, step B, starting from 3-{2-[tert-butoxycarbonyl-(4-pyridin-4yl-butyl)-amino]ethyl}-2-(3,5-dimethylphenyl) acid ethyl ester )-1H-indole-5-carboxylic acid and lithium hydroxide is used to form the title compound.

Step 12.1C • · • ·· ·

- 108 {2-[2-(3,5-Dimethylpheniyl-5-(methoxymethylcarbamoyl)-1H-indol-3-yl]-ethyl}(4-pyridin-4-yl-butyl)carbamic acid tert.-butyl ester

To a solution of 3-{2-[tert-butoxycarbonyl-(4-pyridin-4-ylbutyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid (1.44 g in 25 ml of Ν,Ν-dimethylformamide) at 0 °C, 540 mg of 1-hydroxybenztriazole (HOBt) was added, followed by 0.44 ml of 4-methylmorpholine and 365 mg of Ν,Ο-dimethylhydroxylamine hydrochloride. After 15 min, 815 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) was added and the mixture was allowed to warm to room temperature. After three and a half days of reaction, another portion of 540 mg of HOBt, 0.44 ml of 4-methylmorpholine, 365 mg of Ν,Ο-dimethylhydroxylamine hydrochloride and 815 mg of EDC was added. The reaction was stopped after four days by concentration in vacuo and reconcentration from toluene to remove all volatiles. The residue was dissolved in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and brine, then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane-ethyl acetate, 30:70; then 20:80; then 0:100) afforded the title compound (1.4 g).

2o Step 12.1D

3-(2-tert-butoxycarbonyl-(4-pyridin-4-ylbutyl)-amino-1-ethyl)-2-(3,5-dimethylphenyl)-5-(methoxymethylcarbamoyl)indole-1-carboxylic acid tert-butyl ester

It is prepared in the same way as described in example 9.1, step A, starting from tert-butyl ester of {2-(2-(3,5dimethylphenyl)-5-(methoxymethylcarbamoyl)-1H-indol-3-yl]-ethyl} (4-pyridin-4-yl-butyl)carbamate (1.4 g) to afford the title compound (1.55 g).

3o Step 12.1E

- 109 5-Acetyl-3-f2-tert.-butoxvcarbonyl-(4-pyridine4-νΙ^υίνΙ)-3ΠΊίηοΐ6ίΙινΙ}-2-(3,5^ϊηΐ6ΐΙιν1ί6ηνΙ)^οΙ-1-carboxylic acid tert-butyl ester

To a solution of 3-{2-[tert-butoxycarbonyl(4-pyridin-4-yl-butyl)-amino]ethyl}-2-(3,5-dimethylphenyl)-55(methoxymethylcarbamoyl)indole- 1-carboxyl (0.069 g in 3 mL of dry tetrahydrofuran) at -10 °C, 0.20 mL of a 1.5 M solution of methyllithium in ether was added and the mixture was stirred at low temperature. After 45 min, the reaction was terminated by the addition of a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic portion was washed with brine, dried over sodium sulfate, and the concentrate was purified by preparative silica gel TLC (hexane:ethyl acetate, 2:3) to afford the title compound (58 mg).

Step 12.1 F

1-{2-(3,5-dimethylphenyl ^, )-3-[2-(4-pyridin-4-yl-butylamino)ethyn-1-hindol-5-yl)ethanone

It is prepared in the same way as described in example 9.1 step D, starting from tert-butyl ester of 5-acetyl-3-{220 [tert-butoxycarbonyl-(4-pyridin-4-yl-butyl)-amino] ethyl}-2-(3,5-dimethylphenyl)indole-1-carboxylic acid (120 mg) to afford the title compound (82 mg). m/e=440 (M+H).

Example 12.2

• · • · · · • · · · · · · « • · « · · · ♦ · · · · • 9 » · · · · • « · · »· · « · «

-1101-(2-(3,5-dimethylphenyl)-3-f2-(4-pyridin-4-yl-butylamino)ethyl-1Hindol-5-yl)ethanol

To a solution of 1-(2-(3,5-dimethylphenyl)-3-[2-(4-pyridin-4-ylbutylamino)ethyl]-1H-indol-5-yl}ethanone (45 mg in 2 mL of dry tetrahydrofuran) At 0 °C, 0.30 ml of a 1 M solution of lithium aluminum hydride in tetrahydrofuran was added and the mixture was stirred at low temperature. After 45 min, the reaction was terminated by the addition of a saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The organic part was washed with salt solution and dried over sodium sulfate and purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:10:0.25) to give the title compound (40 mg), m/e=442 (M+H).

Example 12.3

O-Methyloxime 1-(2-(3,5-dimethylphenyl)-3-[2-(4-pyridin-4-ylbutylamino)ethyl-1H-indole-5-pyr)ethanone

To a solution of 1-(2-(3,5-dimethylphenyl)-3-[2-(4-pyridin-4-ylbutylamino)ethyl]-1H-indol-5-yl}ethanone (22 mg in 0.50 ml of methanol) was added to 102 mg of sodium acetate trihydrate and 63 mg of methoxylamine hydrochloride and the mixture was stirred at room temperature. After 20 h the mixture was concentrated in vacuo and the residue was suspended in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution was dried over sodium sulfate and the concentrate was purified by preparative TLC • · · · • 4 4 ·

- 111 25

4

4 4 · · ··

4» · 4 ·

4 4 ·· ♦* on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:10:0.25) to afford the title compound (23 mg). m/e=469 (M+H).

Following a procedure similar to Examples 12.1, 12.2 and 12.3, the following compounds were prepared:

Example # XR7.R8 me 12A 0 mA 440 (M+H) . 12B 0 II '502 (M+H) Bye ?'<> en i _f ' AT ' e* >nn /···?' those aunts* „/ .,Λ , „„ffl 12C OH AND 504 (M+H) l/V^· AT 12D 0 HER ;520(M+HX BYE :FtFFF' ' ^rf ! \sZ· 12E 0 Me 468 (M + -H); z z zz^ v ' 12F OH .470:(M-+K>: , zz' * e AND Me Z z z z z V z z*** ' ' s ' ''te +* 12G 0 ^M \ A .482 (M + H); Me^j Me ^z Z' /zz*·» 7,,'/'

- 112 ·♦ · · • 4 4 · • · ·· ··· · *

4 ·

12H Me 0 AA 121 0 Me ^;: 482(K^H); r , 'zs _in ^Λ «Χα ' 12J 0 ,4S2(M^R)· ' Λ, ' ΖΖ _Λ ^Z

Example 13 By procedures similar to those described in Examples 1 to 12, the following compounds are prepared:

• · φ · ·· φφφφ

- 113 • Φ φφ φφ φ φφ φ φφφφ φ · φφφ φφφφ φ φ φφφφ φφφφφφ φφ φφφ φφφ φφφφ φφ φφφφ

Example # X-R7,R8 R, Ro _of ^R 9al X< ^N — RwXoa (A)-R, 13Α Me. Me Me Me 0 /Me Ì H Lx 13B Me ] Me Me 0 H — 13C Me. Me Me Me 0 _x Me -: H X 13D Me 1 Me Me ^Me ^ ^N >X\ 0 Me. Me u XX X. 13E Me 1 Me Me Me^N^X O Me Me h x> 13F Me. I Me Me ^We \^ ^N \X\ 0 Me Me h XX

0 0 • · Φ ·

000 000 000 0 00 « 00 00

-114 -

13G Me 1 Me Me Me^bkjX^ 0 Me Me h X x 13H Me 1 Me Me Me^btX^ 0 H Me Me xc 131 Me l Me Me Me^N^X 0 H Me^Me X 13J Me. | Me Me 0 H <X- ^Z Me Me X 13K Me 1 Me Me Ue^N-,Χ 0 H 'X'- Me Me X 13L Me 1 Me Me 0 H Χγ ^Ν χΧ^ Me 13M Me I Me Me Me^X>\ 0 H Me X» 13N Me 1 Me Me Μβ^ΝγΧ 0 H Me X 130 Me. 1 Me Me ^Me ^r<>\ 0 H Me 0

• · · ·

- 115 ·* ···· ·· 44 * · 4 4 4 4 4 4 · · 4 4 44 • 4 4 4 · 4«« · ♦ • 4 4 4 4 4 •4 4 44 44

13 P Me Me too. Me Me^fkX 0 Xs^X ^r 13Q Me. I Me Me Me^N^X 0 Y ^e Η Π 13R Me. I Me Me Me^N^X 0 h X ^F Lx 13S Me. I Me Me Me^N^X^ 0 Η V 13T Me. I Me Me Μβ^ΝχΧ 0 Y ^e H \ F 13U Me. I Me Me ^Me \X'X ^< \ 0 Y® H \F 13V HF ₂ <X 1 Me. Me hf^vX 0 C; 13W HF ₂ C. 1 Me. Me HF ₂ C^nXX^ 0 γθ s 13X h ₂ fc. 1 Me. Me H ₂ FC^N^X 0 H

• · · ·

·· ··· ·

·· 44 • 9 4 4 *

-116 -

13Y h ₂ fck I Me. Me h ₂ fc^n^X 0 13Z Me too. Me 0 O 13AA P ₃ C\ I Me. Me ^F Í ^C X>CX. 0 H 13BB F ₃ C^ 0 H 13CC f ₃ c^ 0 H —-Q 13DD Me. I Me Me Μθ^.Ν.χ 0 13EE Me. I Me Me Me.^N.X 0 Me 13FF Me. | Me Me 0 H 13GG Me. I Me Me Me^f<X 0 H

- 117 ···· ·· ··<·

99

9 9 9

9 99

999 9 9

9 9

99

- 118 10

Represents:

CALL »

- 119 * ♦· · ·· ···· ·♦ ·· • · · ♦ • · ·· ·· · · · • · ·

99

Claims (1)

PATENT CLAIMS 1. A compound of the formula where 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 _s alkynyl, C 1 -C ₆ alkoxy, or C ₀ -C s alkyl-S(0) _n -Co-C ₅ alkyl, Co-C 8 alkyl-O-Co-C 8 alkyl, Co-C 8 alkyl -NR 18 -C 8 -C 8 alkyl, where R ₁₈ and C ₀ -C ₅ alkyl may be joined to form a ring, , or a single bond. R o is hydrogen, C 1 -C ₆ alkyl, substituted C 1 -C ₆ alkyl, wherein the substituents are as defined below; aryl, substituted aryl, aralkyl or substituted aralkyl, wherein the substituents are as defined for R ₃ , R ₄ and R ₅ . It's coming - 120 44 4444 • 4 < 4 4 4 4 4 4 4 4 4 4 4 44 44<· 4 4 4 44 Λ, 'R R. *13 & .N ^|N \/.\/ ^{N R} ' ¹ N , N *19 <7n *15 Rm ^Λ 19 JsCaJ^' ³ *14 *ιΓ *13 *14 ,A v> NN R,g _n _n rT^N I *13 li/ \-J RÍ?'*14 ^11 _Λ W ^fi ' ³ *15 R14 T/JY' ³ *15 R,4 *15 R· ,^j*13 nY ^Ru Hn R13 Λ n-n Ί1 / Y«13 T.4 R.5 ^N ' ^R N ~1*13 Rl4 -N^N-R iN=N ^4/11 N ^Z NN=< ^Y\r Rií _Ý N Rl4 ^Λ 19 R ₂ is hydrogen, C 1 -C ₆ alkyl, substituted C 1 -C ₆ alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, alkyl-ORn, C 1 -C 6 (NRiiRi ₂ )i Ci -C 6 (CONRiiRi ₂ ) or C (NR„R ₁₂ )NH; R ₂ and A together form a ring of 5 to 7 atoms; R ₃ , R ₄ and R ₅ are independently a hydrogen atom, 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, Ci-C ₃ perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, RnO(CH ₂ ) _p -, RnC(0)0(CH ₂ ) _P -, R ₁₁ OC(O)(CH ₂ ) _p -, - (CH ₂ ) _p S(O) _n R 17 , -(CH ₂ ) _P C(O)NR ₁₁ R ₁₂ or halogen; where R ₁₇ is hydrogen, C 1 -C ₆ alkyl, C 1 -C ₃ perfluoroalkyl, aryl or substituted aryl; R ₃ and R ₄ together form a carbocyclic ring of 3 to 7 carbon atoms or a heterocyclic ring containing 1-3 heteroatoms selected from N, O and S atoms; ·« ···· .:. : ·..· : -121 R ₆ is a hydrogen atom, C^Ce alkyl, substituted Ci-C ₆ alkyl, aryl, substituted aryl, C1-C3 perfluoroalkyl, CN, NO ₂ , halogen, RiiO(CH ₂ ) _p -, NR ₁₂ C(O )R ₁₁₍ NR ₁₂ C(O)NRhR ₁₂ or SO _n Rn; R ₇ is hydrogen, C 1 -C ₆ alkyl or substituted C 1 -C ₆ alkyl, if X is hydrogen or halogen then R ₇ is not present; Rg is a hydrogen atom, C(O)OR ₉ , C(O)NRnR ₁₂ , NRnR ₁₂ , C(O)Rn, NR ₁₂ C(O)R ₁₁₍ NRi^OJNRuRu, NR ₁₂ S(O) ₂ Rh, NRi ₂ S(O) ₂ NRhR ₁₂ , OC(O)R„, OC(O)NRhR ₁₂ , ORn, SO _n Rii. S(O) _n NR 1 -|R ₁₂ , C 1 -C ₆ alkyl or substituted C 1 -C ₆ alkyl, if X is hydrogen or halogen then R _s is not present; or R ₇ and Rg together form a carbocyclic ring of 3-7 atoms; Rg and Rg _a are independently hydrogen, C 1 -C ₆ alkyl, substituted C 1 -C 8 alkyl; aryl or substituted aryl, aralkyl or substituted aralkyl, where m * 0; or O R ₉ and R _9a together form a carbocyclic ring of 3-7 atoms or || where m * 0 Rg and A together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms where m + 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; or O R10 and _R10a together form a carbocyclic ring of 3-7 atoms or ||; R ₉ and R 10 together form a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing one or more heteroatoms, where m * 0; or φ · - 122 φφ φ φ φ φ φ · φ φ φ φ · φ φ φ φ φ φ φ φ φ φφ φ ♦<· · φ φ φ φ φ • φ · φ φ R ₉ and R ₂ together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms, where m * 0; or R ₁₀ and R ₂ together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; R ₁₀ and A together form a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; or R n and R ₁₂ are independently a hydrogen atom, C 1 -C ₆ alkyl, substituted C 1 -C ₆ alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, carbocyclic ring of 3-7 atoms or io substituted carbocyclic ring containing 3-7 atoms; Rn and Ri ₂ together can form an optionally substituted ring with 3 7 atoms; R ₁₃ is a hydrogen atom, OH, NR ₇ R ₈ , NRhSO ₂ (Ci-C ₆ alkyl), NRnSO ₂ (substituted C^Ce alkyl), NRnSO ₂ (aryl), NRnSO ₂ (substituted aryl), NRhSO 2 (C 1 -C ₃ perfluoroalkyl); SO ₂ NRh(C ₁ -C ₆ alkyl), SO ₂ NR _n (substituted Ci-C ₆ alkyl), SO ₂ NRn(aryl), SÓ ₂ NRn(substituted aryl), SO ₂ NR ₁₁ (C ₁ C ₃ perfluoroalkyl ); SO ₂ NR ₁₁ (C(O)C ₁ -C ₆ alkyl); SO ₂ NRu(C(O)substituted C 1 -C ₆ alkyl); SO ₂ NR n (C(O)-aryl); 2o SO ₂ NRn(C(O)-substituted aryl); S(O) _n (C ₁ -C ₆ alkyl); S(O) _n (substituted Ci-C _s alkyl), S(O)„(aryl), S(O) _n (substituted aryl), Ci-C ₃ perfluoroalkyl, Ci-C ₃ perfluoroalkyloxy, Ci-C ₆ alkoxy , substituted by C 1 -C ₆ alkoxy, COOH, halogen, NO ₂ or CN; Ru and Ri ₅ are independently hydrogen atom, 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, -C ₃ perfluoroalkyl, C 1 -C ₃ perfluoroalkoxy, aryl substituted aryl, aralkyl, substituted aralkyl, RiiO(CH ₂ ) _p -, RuCíOOíCH^p-, R,iOC(O)(CH ₂ ) _p -, 3o -(CH ₂ pS(O) _n R ₁₇ , -(CH ₂ ) _p C(0)NRuR ₁₂ or halogen; where R ₁₇ • 4 ···· • · ·· »«· » · 4 4 4 44 -123 is hydrogen, C1 _- C6 alkyl, C1-C3 perfluoroalkyl, aryl or substituted aryl; R ₁₆ is a hydrogen atom, C 1 -C ₆ alkyl, substituted C 1 -C ₆ alkyl, or N(RhR ₁₂ ); Ris is a hydrogen atom, C^Cs alkyl, substituted by Ci-C _s alkyl, C(O)OR ₉ , CCOJNRuR^, C(0)R _11t S(O) _n R _1i: Ris is always as defined for R ₁₃ or R ₁₄ ; X is a hydrogen atom, halogen, N, O, S(0) _n , C(0), (CRnRi ₂ ) _p ; C ₂ -C ₆ alkenyl, substituted C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or substituted C ₂ -C ₆ alkynyl; where X is hydrogen or halogen, R ₇ and R 8 are absent; where X is O, S(0) _n , C(0), or CRiiRi ₂ only R ₇ or R ₈ is possible; Z is O, S or NR n ; m is 0-3; n is 0-2; p is 0-4; and the alkyl, alkenyl and alkynyl substituents are selected from the group Ci-C ₆ alkyl, C ₃ -C ₇ cycloalkyl, aryi, substituted aryl, aralkyl substituted aralkyl, hydroxy, oxo, cyano, Ci-Cg alkoxy, fluorine, C(0) 0 R n , aryl C 1 -C ₃ alkoxy, substituted aryl C 1 -C 3 alkoxy, and aryl substituents are as defined for R ₃ , R ₄ and R ₅ ; or pharmaceutically acceptable addition salts or hydrates thereof, or where applicable, geometric or optical isomers or racemic mixtures. • 444 4444 • 4 4 4 4 4 4 4 4 4 • · ··· 4··· 4 4 4 4 4 4 444 4 4 444 444 • 44 · 04 4 44 44 - 124 2. A compound according to claim 1 of the formula where R _{1 r} R ₃ , R ₄ , Rs and A are as shown in the following table: Rl R3, R4, R5 AND Pyridine -NH-COCH3 3.4-OMe CH2-0 Pyridine -NH? 3,4-OMe CH?-0 3. A compound according to claim 1 of the formula where R _1t R ₃ , R _4i R _s and A are as shown in the table below: Rl R3.R4.R5 A=(CH2) _n 3-phenyltriazine 3,4-OMe 1 5-indole • 3,4-OMe AND 5-benzimidazole 3,4-OMe 1 4-indol 3,4-OMe 1 3-Pyridium 3.5-Me 5 4-pyridiums 35-Me 4 2-pyridyl 3.5-Me 4 3-Pyridium 35-Me 4 5-pyrimidine 35-Me 4 • · · · · · • 9 • · · -125- XX 3.5-Me 4 0 ^I! aa N Me H 3.5-Me 4 ^OMe 3.5-Me 4 at ₀ 3.5-Me X, ^X O 3.5-Me 4 \[P ^N 3.5-Me 4 Ta ^q s ^p N Me H 3.5-Me 4 4-pvridvi 3.5-Me 2 3-pvridvi 3.5-Me 2 2-pvridvi 3.5-Me 2 4-Imidazoiv 3.5-Me 2 4-pvridvi 3.5-Me 1 2-pvridvi 3.5-Me 1 3-pvridvi 3.5-Me 1 3-pvridvi 3.5-Me 3 4-pyridyl 3.5-Me 3 3-quinolinyl 3.5-Me 4 A T n ⁿ -n 3.5-Me 4 4-pyridiums 3.5-Me 5 • · · · • · - 126 ·· · · • · 5-indol I 3,4-OMe 3 3.0-Me 4 N 4. The compound according to claim 1 of the formula where R _1f R ₃ , R _4i Rs and XR ₇ , R ₈ are as shown in the table below: X-R7,R8 Rl R3JU,R5 H 5-benzimidazole-NSO ₂ Me 3,4-OMe H 5-benzimidazole 3,4-OMe 5. The compound according to claim 1 of the formula where A, R _1t R ₆ and XR ₇ , R ₈ is as shown in the table below: X-R7£8 A = ÍCH2)n Rl • · · · • · · · -127 - * 4 4-pvridvi Bro ** 4-pvridyl -ΝΉ2 4 4-pvridvi -NH-COCH3 4 4-pvridvi -NH-CO-N(CH 2 CH 3 ) 2 4 4-pvridvI -NH-CO-N(CH 2 CH 3 ) 2 3-pvridvi -NH-CO-N(CH 2 CH 3 ) 2 4 6-Me±oxy3-pyridvi -NH-CO-N(CH 3 ) 2 5 3-pvridvi -NH-CO-N(CH 2 CH 3 ) 2 5 3-pvridvi -NH-CO-N(CH 2 CH 3 ) 2 5 4-pvridvi -NH-CO-N(CH 3 ) 2 6-Methoxy3-Pvridvi -SO2-CH2-CO-Me 4 4-pvridvi ? ^H o. p 4 4-pyridiums 0 0 b 4 4-pyridyl 0 0 h 4 4-pyridiums MeSO ₂ - 4 3-pvridvi MeSO ₂ - 4 6-methoxy-3-pyridyl MeSCb- 4 _{in o} MeSO ₂ - 5 4-pvridyl MeSO ₂ - 5 3-pvridvi _ XV Me^ 4 4-pyridyl MeSO ₂ - 4 4-pvridvl - 128 - -NH-CO-N(CH 3 ) 2 5 4-pvridvl (*) - Ró = 5-NO2 (**) - R6 = Br 6. A compound according to claim 1 of the formula where R 1 , R ₇ and R ₈ are as shown in the table below: X-R7,R8 iSWii Ri 0 H 4-pyridyl 0 H 3-pyridyl 0 ^M %A Me H 3-pyridiums 0 Me H 4-pyridyl 0 Me^N^ Me^ H 3-pyridyl 0 X F ₃ CN ^ f ₃ ct H 4-pyridyl • · • · • · • · • · · · - 129 - 0 ΗΟχ X Me^ H 3-pyridyl H°—A Me^ H 4-pyridyl 0 MeO. X MeOx^J H 3-pyridyl HQ Μθο IN H. C. J Me H 3-pyridyl Qa Me^ H 3-pyridiums cu Me^ H 4-pyridyl Ο.Λ Me^J H 4-pyridyl 0 /XX Me^^N ^x H 3-pyridiums 0 X Me N Me^^^ H 4-pyridyl - 130 10 Me 0 Me^N^ ^x H H 3-pyridyl Me 0 Me N Λ Me Me H 4-pyridyl Me 0 Μβ'Ί H 3-pyridyl AND H 3-pyridyl oA H 4-pyridyl 0 x/ H 3-pyridyl -CON(Et) ₂ H Me '''Ca-o'' -COOM 6-Cl 4-pvridvl -CON(iBu)2 6-Cl 4-Dvridvi -CON(Et)2 H ΰ Me -CON(CH2CH2CN)cyclohexyl H 4-pyridyl Ga Me H 4-pyridyl - 131 15 -COOM 4-C1 4-pvridvl -CON(iBu)2 4-C1 4-pvridyl -CON(Et) ₂ 6-C1 4-pvridvl 7. A compound according to claim 1 of the formula wherein Ri and A are as shown in the table below: A = (CH?)n Rl 4 4-pyridyl 4 3-pvridvl 4 6-ajnmo-3-pvridvi 4 6-amino-3-pyridyl 4 6-Methoxyv-3-pyridyl 4 Χ^· ^{Ε! at} N 4 ^{At N} 4 ^{At N} 4 (O-COzEt ^U N 4 rV-C0NEt ₂ 4 2-cyano-4-pyridyl 4 _{in o} ···· - 132 10 4 COOEi 4 2-(CH ₂ NH-Boc)-4-pyridyl 4 2-(CH ₂ NH 2 )-α-pyridyl 4 6-(SMe)-3-pyridyl 4 5-Carboethoxy-3-pyridyl 4 6-(NHCOOEt)-3-pyridinium 4 2,3,5,6-Tetr afluoT-4pyridyl 3 3-pvridvl 4 6-[NHS(O) 2 CF ₃ ]-3-pyridyl 4 6-[NHS(O) ₂ CH 3 ]-3 pvridvl 4 5-cyano-3-pyridyl d nQ II λ>— Me X ^ři v- 4 3,5-dichloro-4-pyrides 1 4 8. A compound according to claim 1 of the formula R ₉ AND H ··· · • · »· - 133 10 where R _1t XR ₇ , R ₈ are as shown in the table below: X-R7JR8 Ri Me. Me Me Me 0 4-pyridiums Me. Me Me Me 0 3-pyridyl ^MeO ^Me _x Me MeO— 0 3-pyridyl ^Me0 A Me _x Me O 4-pyridyl ^M ? ^M ® Me Μθ ^Ν γΑ 0 4-pyridyl Me Μ.'Υ< 0 3-pyridyl Me ^MeX |Me. Me rT^ MA, ⁰ Me Me 4-pyridiums Me ^ΜβΧ ^Μθ. Me fr' Me Μβθ 3-pyridyl - 134 • · · φ φ φφφ Me too 0 4-pyridyl | Me. Me O 3-pyridyl X i Me Me Me-^γΑ 0 3-pyridyl Hmm. Me ΜβγΝγ^ς Me 0 3-pyridyl wMe. Me 0 3-pyridyl Me. I Me Me ^Μθ γ ^Ν γΧ Me 0 3-pyridyl Me. Me too. Me 3-pyridyl Me. | Me. Me σ- 4-pyridyl Me Me Η ₂ Νγ< 0 3-pyridyl Me. and EtOy\ ^Μθ 0 4-pyridyl 9. A compound according to claim 1 of the formula 4··· 44 0 4 where Ri, R ₂ and A are as shown in the table below: (AND) R ₂ Ri -CH2CH2- -(CH ₂ ) ₄ -4(phenyl-4OMe) 4-pvridyl -CH2CH2- -(CH ₂ ) ₄ (phenyl-4OH) 4-pyridyl -CH2CíMe)^CH2CH?- -H 4-pvridvl XT -H 3-pyridyl Xr -H 3-pyridiums -H 3-pyridyl 10. Compound according to claim 1 of formula r ₈ i Ro i " where A, Ri, R ₂ and XR ₇ , Rg are as shown in the table below: • ·· · • · -136 - -N(R?)-(A)- XR7JR8 Ri /—\, ^C0 2 ^Et -\X -NH-CON(Et)2 3-pyridyl J-\ , ^C0 2 ^H -x -NH-CON(Et)2 3-pyridyl /-\ , ^CO 2 ^Et -NH-CO(4morpholine) 3-pyridyl /-\ . ^C °2 ^H - ^N v_/- -NH-CO(4morpholin.) 3-pyridyl -X -NH-CON(Et)2 3-pyridyl —N hX \f -H 3-pyridyl —N \F -H 4-pyridyl /—\ —-N N— \F -H 4-pyridyl -NHCH ₂ CH ₂ CH ₂ O- -COOEr Pr Et x C(O)N(iBu) ₂ 4-pyridyl -NHCH2CH2CH2O- C(O)N(iBu) ₂ 3-pyridyl -NHCH(Me)CH ₂ CH ₂ - C(O)NíiBu) ₂ 3-pyridyl -ΝΉCH(Me)CH ₂ CH ₂ CH ₂ - C(O)N(iBu) ₂ 4-pyridyl (cis) -NHCH ₂ CH=CH- C(O)N(iBu) ₂ 3-pyridyl • ·· » • · · » · · • 9 - 137 - (trans) -nhch ₂ ch=ch- C(O)N(iBu) ₂ 3-pyridiums -NHCH ₂ CH ₂ CH(Me)- C(O)N(iBu) ₂ 4-pyridyl -NHCH ₂ CH ₂ CH(Me)- C(O)N(iBu) ₂ 3-pyridinium -NHCH ₂ CH ₂ -O-CH ₂ - C(O)N(iBu) ₂ 3-pyridiums -N(Et)CH ₂ CH ₂ CH ₂ CH ₂ - C(Me) ₂ C(O)N(iBu) ₂ 4-pyridyl -NHCH ₂ CH(CH ₃ )CH ₂ . ch ₂ - C(O)N(iBu) ₂ 3-pyridiums -nhch ₂ ch ₂ ch ₂ . CH(CH3)- C(O)N(iBu) ₂ 4-pyridiums -NHCH ₂ CH ₂ CH(CH ₃ )CH ₂ - C(O)N(iBu) ₂ 3-pyridiums -NHCH(CH ₃ )CH ₂ - C(O)N(iBu) ₂ 3-pyridiums -N(Me)CH ₂ CH ₂ CH ₂ CH ₂ - C(O)N(Et) ₂ 4-pyridyl -NHC(CH ₃ ) ₂ CH ₂ CH ₂ ch ₂ - C(O)N(iBu) ₂ 3-pyridiums -NHC(CH ₃ ) ₂ CH ₂ CH ₂ CH(OH)- C(O)N(iBu) ₂ 3-pyridiums -NHC(CH ₃ ) ₂ CH=CHCHÍOH)- C(O)N(iBu) ₂ 3-pyridiums -NHC(CH ₃ ) ₂ CH ₂ CH ₂ ch ₂ - C(Me) ₂ C(O)N(Et) ₂ 3-pyridiums -nhch ₂ ch ₂ - C(O)N(iBu) ₂ 3-pyridyl -nhch ₂ ch ₂ - C(Me) ₂ C(O)N(Et) ₂ 3-pyridiums -NHC(CH ₃ ) ₂ CH=CHCH(OH)- C(O)N(iBu) ₂ 4-pyridyl -NHC(CH ₃ ) ₂ CH ₂ CH ₂ CH(OH)- C(O)N(fflu) ₂ 4-pyridyl • ee · 99 • 9 9 9 9 0 0 0 9 90 9 9 00· 9 · • 0 9 9 9 9 9« 9 99 ·· ·« ···· -138 - -NHC(CH ₃ )2CH2CH2ch ₂ - C(O)N(iBu)2 4-pyridyl -NHC(CH3hCH=CHCH(OH)- C(Me) ₂ C(O)N(Et) 2 4-pyridyl -NHC(CH3)2CH ₂ CH2ch ₂ - C(Me) ₂ C(O)N(Et) 2 4-pyridyl -NHCH2CH(CH ₃ )CH2ch ₂ - C(O)N(iBu)2 4-pyridyl -NHCH2CH( _CH2CH3 )CH2CH2- C(O)N(iBu)2 4-pyridyl -NHCH2CH2- C(Me) ₂ C(O)N(Et) ₃ 4-pyridyl -NHCH2CH2- C(O)N(iBu)2 4-pyridyl 11. A compound according to claim 1 of the formula where R _1t XR ₇ , R ₈ , Rg, Rsa, R 10 and Rioa are as shown in the table below: H □ ΛεΑ“ Río ^RlOa XR?4<8 KCH^r: .«X/ j 7 · ?' Ri MeO^X _H -NHC(O)Ph 4 4-pyridyl • · · · • · · · · · · • · · · · · · • · · · · ·· · · · • · · · · · w · · · · · · - 139 - Y® H Me. Me ^E X 0 4 4-pyridiums Y® H Yes Me Me O 4 4-pyridyl Y® H We have 0 4 3-pyridyl Y® H Me Me 0 4 4-pyridyl Y® H A....z Me Me 0 4 4-pyridyl Y® K XNs Me Me 0 4 4-pyridyl H Χ'χζ'χ Me Me Me (E^m^X 0 4 3-pyridyl Y® H Aúc Me. Me "OF 0 2 3-pyridyl 12. A compound according to claim 1 of the formula where Ri and XR ₇ , R ₈ are as shown in the table below: XR7JR.8 Ri • · » · · · · · φ φφ φ φφφφ φ φφ φφ φ φφφφ φ φ φ φ · φ φ φ - 140 - T 0 3-pyridiums -COOEt 3-pvridvl -CON(iBu)2 3-pyridyl -CON(hBu)2 3-pvridvi -CON(Et)2 and»N -CON(E1)2 3-pvridvi 13. A compound according to claim 1 of the formula where XRy.Ra is as shown in the table below: · -141 - 14. A compound according to claim 1 of the formula where A, R _b R ₂ , XR ₇ , R ₈ , R ₉ , R _9a , R ₁₀ and R _10a are as shown in the table below: • · - 142- X-R7,R8 r ₂ ^R o A9a 1 A _X ^N —w ^R io ^R toa - ^R 1 Me _x Me Me Me Me : H X\P-X\X Me^N^X 0 AND Me Me, Me Me Me = H /Αχ-Νχ/^Χ' 0 γΧ at Me. _x Me Me Me Me i H χΆ^-Νχ^Χ^Χ' Y^N 0 Me I Me Me Me^NxAX^ 0 Me Me h Xp/\A Yn Me Me, Me w 1 Me Me xAx- Me^Nx>p 0 G Me. Me _x Me w 1 Me. Me 0 XX, Ί X x^N Me Me, Me w 1 Me _x Me M ^e ^IA>p 0 xA •^N AND Me H I Me Me Me^N^X 0 Me Me Ό Me H 1 Me Me Me^N<Y Me Me O 0 -143- • · - 144 10 Me Me too. Me 0 C H \.F "X Me. Me Me Me 0 *ť® H \,F hf ₂ c^ I Me. Me hf ₂ Cv^nXX 0 -O HF ₂ (X I Me. Me 0 H Q h ₂ fcc l Me. Me 0 H HaFX I Me. Me H ₂ F<k^NXX 0 H —-Q f=3<X I Me. Me ^F 3 ^C aXCX 0 H f=3<X Me too. Me A. and X 0 C H f ₃ c^ 0 H Lx F ₃ C^ ^F 3 ^C ^N^^ 0 C H 0 Me I Me Me Μβ^ΝΧχ 0 H Xx>-X\,X X>N ···· ·· ···· ·· ·· • · · · · · · ··· · ·· · ·· ·· -145 - · · - 146 - 15. A compound according to claim 1, which is 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-3yl]ethyl]-(4-pyridin-4-yl-butyl)amine; c) 3-[2-(3,5-dimethylphenyl)-3-[2-(5-pyridin-4-ylpentylamino)ethyl]-1H-indol-5-yl]-1,1-dimethylurea. 16. A pharmaceutical composition, characterized in that it contains an effective amount of the compound according to claim 1 together with a pharmaceutically acceptable carrier. • · • · · · · · · · · ···· • · · · · · · · • « ·· · · · ·· · · · ·· · · · · · · • · · · · · · · · ·· - 147 17. A method of antagonizing gonadotropin-releasing hormone in a patient in need, comprising administering an effective amount of compound 1 to said patient suffering from a gonadotropin-releasing hormone-derived disorder. 18. The method of claim 17, wherein the gonadotropin-releasing hormone-derived disorder is a sex hormone-related condition. 19. The method of claim 17, wherein the gonadotropin-releasing hormone-derived disorder is sex hormone-dependent cancer, benign prostatic hypertrophy, or uterine fibroids. 20. The method of claim 19, wherein the sex hormone-dependent cancer is from the group of prostate, uterine, mammary, and pituitary gonadotrophic adenomas. 21. The method according to claim 18, wherein the sex hormone dependent condition is from the group of endometriosis, polycystic ovary disease, uterine fibroids and precocious puberty. 22. A method of preventing pregnancy in a patient in case of need, comprising administering an effective amount of a compound as defined in claim 1. 23. A method of treating lupus erythematosis in a patient in need, comprising administering to said patient an effective amount of a compound according to claim 1. • · · · • · · · ·· · · · · · · · · • · ·· · ···· • · · · · · · · · · · · · · · 4 4 4 4 4 4 4 ·· 4 ·· 4 · - 148 24. A method of treating irritable bowel syndrome in a patient in need, comprising administering to said patient an effective amount of a compound according to claim 1. 25. A method of treating premenstrual syndrome in a patient in need, comprising administering to said patient an effective amount of the compound of claim 1. io 26. A method of treating excessive hair growth in a patient in need, comprising administering to said patient an effective amount of the compound of claim 1. 27. A method of treating short stature or growth hormone deficiency in a patient in need, comprising administering to said patient 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. 28. A method of treating sleep disorders such as sleep apnea in a patient in need, comprising administering to said patient an effective amount of the compound of claim 1. 29. A pharmaceutical preparation, characterized in that it contains an inert carrier and an effective amount of a compound stimulating the endogenous production or release of growth hormone in combination with the compound according to claim 1. • · · · - 149 • 4 » 4 4 I 4 • 4 4 4 4 4 30. A pharmaceutical composition made by combining a compound according to claim 1 and a pharmaceutically acceptable carrier. 31. A method of producing a pharmaceutical composition, characterized in that it includes the combination of a compound according to claim 1 and a pharmaceutically acceptable carrier. Represents: