EP1011667A1 - Antagonistes de l'hormone de liberation de la gonadotrophine - Google Patents

Antagonistes de l'hormone de liberation de la gonadotrophine

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Publication number
EP1011667A1
EP1011667A1 EP98926171A EP98926171A EP1011667A1 EP 1011667 A1 EP1011667 A1 EP 1011667A1 EP 98926171 A EP98926171 A EP 98926171A EP 98926171 A EP98926171 A EP 98926171A EP 1011667 A1 EP1011667 A1 EP 1011667A1
Authority
EP
European Patent Office
Prior art keywords
substituted
alkyl
aryl
compound
aralkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98926171A
Other languages
German (de)
English (en)
Other versions
EP1011667A4 (fr
Inventor
Mark Goulet
Feroze Ujjainwalla
Thomas F. Walsh
Matthew J. Wyvratt, Jr.
Jonathan R. Young
Lin Chu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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Filing date
Publication date
Priority claimed from GBGB9719839.4A external-priority patent/GB9719839D0/en
Priority claimed from GBGB9800451.8A external-priority patent/GB9800451D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1011667A1 publication Critical patent/EP1011667A1/fr
Publication of EP1011667A4 publication Critical patent/EP1011667A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the gonadotropin-releasing hormone also referred to as luteinizing hormone-releasing hormone (LHRH)
  • LHRH luteinizing hormone-releasing hormone
  • the hormone is released from the hypothalamus and acts on the pituitary gland to stimulate the biosynthesis and secretion of luteinizing hormone (LH) and follicle- stimulating hormone (FSH).
  • LH released from the pituitary gland is primarily responsible for the regulation of gonadal steroid production in both sexes, whereas FSH regulates spermatogenesis in males and follicular development in females.
  • GnRH agonists and antagonists have proven effective in the treatment of certain conditions which require inhibition of LH/FSH release.
  • GnRH-based therapies have proven effective in the treatment of endometriosis, uterine fibroids, polycystic ovarian disease, precocious puberty and several gonadal steroid-dependent neoplasia, most notably cancers of the prostate, breast and ovary.
  • GnRH agonists and antagonists have also been utilized in various assisted fertilization techniques and have been investigated as a potential contraceptive in both men and women.
  • GnRH antagonists are GnRH-like decapeptides which are generally administered intravenously or subcutaneously presumably because of negligible oral activity. These have amino acid substitutions usually at positions one, two, three, six and ten.
  • Non-peptide GnRH antagonists offer the possible advantage of oral adminstration.
  • Non-peptide GnRH antagonists have been described in European Application 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 to Takeda Chemical Industries, Ltd.
  • Substituted indoles known in the art include those described in the following patents and patent applications.
  • US Patent No. 5,030,640 discloses alpha-heterocyclic ethanol aminoalkyl indoles which are potent ⁇ -agonists.
  • WO 90/05721 discloses alpha-amino-indole-3-acetic acids useful as anti-diabetic, anti-obesity and anti-atherosclerotic agents.
  • French patent 2,181,559 discloses indole derivatives with sedative, neuroleptic, analgesic, hypotensive, antiserotonin and adrenolytic activity.
  • Belgian patent 879381 discloses 3-aminoalkyl-lH-indole-5-thioamide and carboxamide derivatives as cardiovascular agents used to treat hypertension, Raynaud's disease and migraine.
  • WO 97/21435, WO 97/21703, WO 97/21707 and WO 97/21704 disclose non-peptidyl, indole derivatives as GnRH antagonists.
  • the present invention relates to compounds which are non-peptide antagonists of GnRH which can be used to treat a variety of sex-hormone related conditions in men and women, to methods for their preparation, and to methods and pharmaceutical compositions containing said compounds for use in mammals.
  • the compounds of the present invention are useful to treat a variety of sex-hormone related conditions in both men and women. These conditions include endometriosis, uterine fibroids, polycystic ovarian disease, hirsutism, precocious puberty, gonadal steroid- dependent neoplasias such as cancers of the prostate, breast and ovary, gonadotrophe pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome and benign prostatic hypertophy.
  • the compounds of the invention are also useful as an adjunct to treatment of growth hormone deficiency and short stature, and for the treatment of systemic lupus erythematosis.
  • the compounds of the invention may be useful 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 useful in combination with testosterone or other androgens or antiprogestogens in men as a contraceptive.
  • the compounds may also be used in combination with an angiotensin-converting enzyme inhibitor such as Enalapril or Captopril, an angiotensin Il-receptor antagonist such as Losartan or a renin inhibitor for the treatment of uterine fibroids. Additionally, the compounds of the invention may also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, such as growth hormone secretagogues, e.g.
  • MK-0677 for the treatment and prevention of disturbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones, antiestrogens, antiprogestins and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with the GnRH antagonist.
  • a compound of the present invention may be co-administered with a 5a-reductase 2 inhibitor, such as finasteride or epristeride; a 5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza- 5a-cholestan-3-one, 3-oxo-4-aza-4,7b-dimethyl-16b-(4-chlorophenoxy)-5a- androstane, and 3-oxo-4-aza-4,7b-dimethyl-16b-(phenoxy)-5a-androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5a- reductase 1 and 5a-reductase 2 such as 3-oxo-4-aza-17b-(2,5-trifluoro- methylphenyl-carbamoyl)-5a-androstane as disclosed in WO 95/07927; antiandrogens such as flutamide, casodex and
  • a compound of the present invention may be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues, to delay puberty in growth hormone deficient children, which will allow them to continue to gain height before fusion of the epiphyses and cessation of growth at puberty.
  • a compound of the present invention may be used in combination or co-administered with a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof.
  • a compound having luteinizing hormone releasing activity such as a peptide or natural hormone or analog thereof.
  • peptide compounds include leuprorelin, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterlin and recirelin.
  • the present invention relates to compounds of the general formula
  • R ⁇ is hydrogen, Ci-C ⁇ alkyl, substituted C1-C6 alkyl, wherein the substituents are as defined below; aryl, substituted aryl, aralkyl or substituted aralkyl, wherein the substituents are as defined for R3, R4 and R5;
  • the nitrogen atoms contained in the Rl heteroaromatic rings may exist either as drawn or, when chemically allowed, in their oxidized (N ⁇ O) state;
  • R2 is hydrogen, Cl-C6 alkyl, substituted Cl-C ⁇ alkyl, aralkyl, substituted aralkyl, aryl, substituted aryl,; or R2 and A can optionally be taken together to form a ring of 5-7 atoms;
  • R3, R4 and R5 are independently hydrogen, Cl-C ⁇ alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, RnO(CH2)p, (CH2)pS(O) n Rl7 or halogen; wherein R17 is hydrogen, C1-C6 alkyl, C1-C3 perfluoroalkyl, aryl or substituted aryl; or R3 and R4 taken together form
  • R7 is hydrogen, C1-C6 alkyl, or substituted Cl-C ⁇ alkyl, unless X is hydrogen or halogen, then R7 is absent;
  • R8 is hydrogen, C(O)OR9, C(O)NRnRi2, NR11R12, C(O)Rn,
  • R9 and Rg a are independently hydrogen, Cl-C ⁇ alkyl, substituted Cl-C ⁇ alkyl; aryl or substituted aryl, aralkyl or substituted aralkyl when m ⁇ O; or
  • R9 and Rg a taken together form a carbocyclic ring of 3-7 atoms or when m ⁇ O;
  • RlO and RlOa are independently hydrogen, Ci-C ⁇ alkyl, substituted Ci- C ⁇ alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl; or
  • RlO and RlOa taken together form a carbocyclic ring of 3-7 atoms or ; R9 and Rio when taken together form a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing one or more heteroatoms when m ⁇ O; or
  • Rll and R12 are independently a bond, hydrogen , Ci-C ⁇ alkyl, substituted Cl-C ⁇ alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, a carbocyclic ring of 3-7 atoms, a substituted carbocyclic ring containing 3-7 atoms, a heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4 heteroatoms selected from N, O or S which can be optionally substituted by R3, R4 and R5, Ci-C ⁇ -alkyl substituted by a heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4 heteroatoms selected from N, O or S which can be optionally substituted
  • Rl3 is hydrogen, OH, NR7R8, NRi ⁇ S ⁇ 2(Ci-C ⁇ alkyl),
  • Rl4 and R15 are independently hydrogen, C1-C6 alkyl, substituted Cl-C ⁇ alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, CN, nitro, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, Ri ⁇ O(CH2)p-, Rl ⁇ C(O)O(CH 2 )p-, Ri ⁇ OC(O)(CH 2 )p-, -(CH 2 )pS(O) n Rl7, -(CH2)pC(O) N(Ri ⁇ ) 2 or halogen; wherein R17 is hydrogen, Cl-C ⁇ alkyl, C1-C3 perfluoroalkyl, aryl or substituted aryl; Rl ⁇ is hydrogen , Cl-C ⁇ alkyl, substituted Cl-C ⁇ alkyl, aryl, substituted
  • R22 is C0-C4 alkyl, substituted C1-C4 alkyl
  • X is N, O, S(0) n , C(O), (CRnRi2)p, a single bond to Rs, C2-C6 alkenyl, substituted C2-C6 alkenyl,C2-C ⁇ alkynyl, or substituted C2-C6 alkynyl; when X is O, S(O)n, C(O), or
  • CR11R12 only Rs is possible;
  • Z is O, S or NRli;
  • m is 0, 1, 2 or 3;
  • n is 0, 1 or 2;
  • p is 0, 1, 2, 3 or 4;
  • the alkyl, cycloalkyl, alkenyl and alkynyl substituents are selected from Ci-C ⁇ alkyl, C3-C7 cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, hydroxy, oxo, cyano, Ci-C ⁇ alkoxy, fluoro, C(O)ORn ; aryl C1-C3 alkoxy, substituted aryl C1-C3 alkoxy, and the aryl substituents are as defined for R3,
  • A is R22-[phenyl]-R22- or R22- [substituted phenyl]-R22S
  • R3 are independently hydrogen, Cl-C ⁇ alkyl, substituted Cl-C ⁇ alkyl or halogen;
  • R8 is C(O)NRnRi2
  • Rll and R12 are independently a bond, hydrogen , Cl-C ⁇ alkyl, substituted Cl-C ⁇ alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, a carbocyclic ring of 3-7 atoms, a substituted carbocyclic ring containing 3-7 atoms, a heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4 heteroatoms selected from N, O or S which can be optionally substituted by R3, R4 and R5, Ci-C ⁇ -alkyl substituted by a heterocyclic ring or bicyclic heterocyclic ring with from 1 to 4 heteroatoms selected from N, O or S which can be optionally substituted by R3, R4 and R5; or Rll and R12 when taken together can form an optionally substituted ring of 3-9 atoms; X is (CR ⁇ Ri2) P ; or a pharmaceutically acceptable addition salt and/or hydrate thereof, or where applicable, a geometric or optical
  • Rn and Rl2 are taken together include 7-aza-bicyclo [2.2.1] heptane and 2-aza-bicyclo[2.2.2] octane. Unless otherwise stated or indicated, the following definitions shall apply throughout the specification and claims.
  • variable e.g., aryl, heterocycle, Rl, etc.
  • its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane, etc.
  • aryl includes phenyl and naphthyl.
  • aryl is phenyl.
  • halogen or halo is intended to include fluorine, chlorine, bromine and iodine.
  • heterocycle or “heterocyclic ring” is defined by all non-aromatic, heterocyclic rings of 3-7 atoms containing 1-3 heteroatoms selected from N, O, and S, such as oxirane, oxetane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, tetrahydropyridine, tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyran, morpholine, hydantoin, valerolactam, pyrrolidinone, and the like.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • heterocyclic groups can exist in more than one tautomeric form. It is intended that all such tautomers be included within the ambit of this invention.
  • optical isomeric forms that is mixtures of enantiomers, e.g., racemates, or diastereomers as well as individual enantiomers or diastereomers of the instant compound are included.
  • These individual enantiomers are commonly designated according to the optical rotation they effect by the symbols (+) and (-), (L) and (D), (1) and (d) or combinations thereof.
  • These isomers may also be designated according to their absolute spatial configuration by (S) and (R), which stands for sinister and rectus, respectively.
  • the individual optical isomers may be prepared using conventional resolution procedures, e.g., treatment with an appropriate optically active acid, separating the diastereomers and then recovering the desired isomer.
  • the individual optical isomers may be prepared by asymmetric synthesis.
  • a given chemical formula or name shall encompass pharmaceutically acceptable addition salts thereof and solvates thereof, such as hydrates.
  • the compounds of the present invention while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience of crystallization, increased solubility and other desirable properties.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt is intended to include all acceptable salts.
  • acid salts are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methane sulfonic and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or prodrug formulations.
  • salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethyl- ammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminome
  • esters can be employed, e.g. methyl, ethyl, butyl, acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • the compounds of the present invention may have chiral centers other than those centers whose stereochemistry is depicted in formula I, and therefore may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers, with all such isomeric forms being included in the present invention as well as mixtures thereof.
  • some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
  • reaction Scheme A treatment of tryptamine (1) with ⁇ T-carboxyphthalimide in an inert organic solvent such as tetrahydrofuran at a temperature of 20-65°C, preferably 65°C, for a period of 12-48 hours gives the corresponding ⁇ -phthalimidotryptamine derivative (2).
  • an inert organic solvent such as tetrahydrofuran
  • the ⁇ T-phthalimidotryptamine (2) could be further modified by treatment with a brominating agent such as pyridinium hydrobromide perbromide, pyrrolidone hydrotribromide, or the like in an inert organic solvent such as tetrahydrofuran, methylene chloride, chloroform, or mixtures thereof at 0-25°C for a period of 30 minutes to 4 hours to provide the 2-bromotryptamine (3).
  • Bromide (3) may be reacted with an arylboronic acid (prepared essentially as described in: Gronowitz, S.; Hornfeldt, A.-B.; Yang, Y.-H. Chem. Ser.
  • the 2-aryl tryptamine may be condensed with a carboxylic acid of type (6) using the coupling reagent l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) or the like with or without 1-hydroxybenzotriazole (HOBt) and a tertiary amine base such as N- methylmorpholine (NMM), triethylamine or the like in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, or mixtures thereof at or near room temperature for a period of 3-24 hours to provide the corresponding amide derivative (7).
  • EDC 1-hydroxybenzotriazole
  • NMM N- methylmorpholine
  • NMM N- methylmorpholine
  • 2-aryltryptamine (5) can be treated with an active ester or acid chloride of type (8) in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, diethyl ether, or the like and a tertiary amine base such as triethylamine, diisopropylethylamine, pyridine or the like at a temperature of 0°-25°C for 30 minutes to 4 hours to give (7).
  • an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, diethyl ether, or the like
  • a tertiary amine base such as triethylamine, diisopropylethylamine, pyridine or the like
  • the amide carbonyl of (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 or the like at 25°-100°C, preferably 65 °C, for a period of 1-8 hours to give the corresponding amine compound (9).
  • an inert organic solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane or the like
  • the 2-aryltryptamine (23 or 5) can be modified by treatment with an aldehyde or ketone of type (10a or 10b) in the presence of a weak acid such as trifluoroacetic acid (TFA), acetic acid or the like, with or without a dessicant such as 3A molecular sieves or magnesium sulfate, and a hydride source such as sodium borohydride or sodium cyanoborohydride, in an inert organic solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, chloroform, or mixtures thereof at a temperature of 0°-25°C for a period of 1-12 hours to give the corresponding secondary or tertiary amine derivative (11).
  • a weak acid such as trifluoroacetic acid (TFA), acetic acid or the like
  • a dessicant such as 3A molecular sieves or magnesium sulfate
  • reaction Scheme E treatment of an arylhydrazine or arylhydrazine hydrochloride (12) with an arylcyclopropylketone of type (13) in a polar organic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, preferably n-butanol, at a temperature of 70°-120°C for a period of 8-24 hours gives 2-aryltryptamine (5).
  • a polar organic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, preferably n-butanol
  • an arylhydrazine or arylhydrazine hydrochloride (12) is treated with an arylbutyl ketone of type (14) containing a leaving group (chloride, bromide, iodide, O-methansulfonate, 0-trifluoromethansulfonate, or the like) at the 4-position in a polar solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, or mixtures thereof at room temperature for a period of 30 minutes to 2 hours followed by heating to a temperature of 65°-100°C for 4-24 hours, 2-aryltryptamine (5) is produced.
  • Scheme F 2-aryltryptamine
  • iodoanilines of type (15) may be reacted with aryl acetylenes, an appropriate palladium (0) catalyst such as tetrakis(triphenylphosphine)palladium, a copper (I) halide such as cuprous bromide in an inert organic solvent such as triethylamine at a temperature of 50°-88°C for a period of 30 minutes to 5 hours to provide the diarylacetylene (16).
  • an appropriate palladium (0) catalyst such as tetrakis(triphenylphosphine)palladium
  • a copper (I) halide such as cuprous bromide in an inert organic solvent such as triethylamine at a temperature of 50°-88°C for a period of 30 minutes to 5 hours to provide the diarylacetylene (16).
  • Acetylene (16) may be further modified by treatment with a palladium (II) catalyst such as palladium (II) chloride or palladium (II) acetate in an inert organic solvent such as acetonitrile at a temperature of 50°- 82°C for a period of 30 minutes to 6 hours to give 2-arylindole (17).
  • a palladium (II) catalyst such as palladium (II) chloride or palladium (II) acetate in an inert organic solvent such as acetonitrile at a temperature of 50°- 82°C for a period of 30 minutes to 6 hours to give 2-arylindole (17).
  • the crude product (18) may be reacted with an amine of type (19) in an inert organic solvent such as diethylether, tetrahydrofuran, methylene chloride, chloroform or the like and an amine base such as triethylamine, diisopropylethylamine or pyridine at a temperature of 0°C-25°C for a period of 30 minutes to 4 hours to provide the amide derivative (20).
  • Amide (20) may be further modified by treatment with a reducing agent such as borane or lithium aluminum hydride in an inert organic solvent such as tetrahydrofuran at elevated temperatures, preferably reflux, for a period of 1-5 hours to give compound (21).
  • N-benzyl derivatives of type (22a) or N-benzyloxycarbonyl derivatives of type (22b) may be reduced to provide the secondary amine analogs (7) by treatment with hydrogen (1 atm) and an appropriate catalyst such as palladium on carbon, palladium hydroxide on carbon, or the like in an inert organic solvent such as tetrahydrofuran, ethyl acetate, methanol, ethanol, or mixtures thereof to which has been added a weak acid such as 30% aqueous acetic acid for a period of 10 minutes to 3 hours or until the aryl group has been removed to give the secondary amine.
  • an appropriate catalyst such as palladium on carbon, palladium hydroxide on carbon, or the like
  • an inert organic solvent such as tetrahydrofuran, ethyl acetate, methanol, ethanol, or mixtures thereof to which has been added a weak acid such as 30% aqueous acetic acid for a period of 10 minutes to 3
  • amino- or hydroxyindole (25) may be modified by acylation under a variety of conditions.
  • treatment of (25) with an acid chloride, acid anhydride or active ester and an amine base such as triethylamine, diisopropylethylamine, pyridine, or the like in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, or mixtures thereof at 0°C to room temperature for a period of 1 to 12 hours gives the corresponding amide or ester derivatives (26).
  • (25) may be coupled with a carboxylic acid by one of the many dehydrating agents commonly employed.
  • urea or carbamate derivatives of (25) can be prepared by treatment with a carbamoyl chloride of type (27a), or alternatively with an isocyanate reagent of type (27b), and an amine base such as pyridine, triethylamine, diisopropylethylamine, ⁇ -methylmorpholine or the like in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or mixtures thereof at a temperature of 0°-65°C for a period of 1-72 hours to give (28).
  • an amine base such as pyridine, triethylamine, diisopropylethylamine, ⁇ -methylmorpholine or the like
  • an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or mixtures thereof at a temperature of 0°-65°C for a period of 1-72 hours to give (28
  • Compound (25) can also be modified by treatment with a bis(electrophilic) reagent such as phosgene, triphosgene, l,l'-carbonyldiimidazole, N,N'-disuccinimidyl carbonate, or the like with or without the addition of an amine base such as pyridine, triethylamine, diisopropylethylamine, ⁇ -methylmorpholine in an inert solvent such as methylene chloride, chloroform, or the like at a temperature of -20°-0°C for a period of 20 minutes to 2 hours. After this time, the reaction mixture is treated with an appropriate mono- or disubstituted amine at -20° to 25°C for a period of 1-5 hours to give the urea or carbamate analog (28).
  • a bis(electrophilic) reagent such as phosgene, triphosgene, l,l'-carbonyldiimidazole
  • amine (25) can be modified by treatment with an appropriate sulfonyl chloride of type (29) or sulfamyl chloride of type (30) with an amine base such as pyridine, triethylamine, diisopropylethylamine, .N-methylmorpholine in an inert solvent such as methylene chloride, chloroform, dichloroethane or the like at a temperature of -20°-25°C for a period of 20 minutes to 2 hours to give the corresponding AT-sulfonamide (31) or ⁇ -sulfamylamide (32) derivatives, respectively.
  • an amine base such as pyridine, triethylamine, diisopropylethylamine, .N-methylmorpholine in an inert solvent such as methylene chloride, chloroform, dichloroethane or the like
  • the 2-aryltryptamine (33) can be modified by treatment with an epoxide such as (34) in an inert organic solvent such as methanol, ethanol, isopropanol, butanol, tert- butanol, or mixtures thereof at a temperature of 65°-110°C for a period of 8-20 hours to give the corresponding amino-alcohol derivative (35).
  • an epoxide such as (34) in an inert organic solvent such as methanol, ethanol, isopropanol, butanol, tert- butanol, or mixtures thereof at a temperature of 65°-110°C for a period of 8-20 hours to give the corresponding amino-alcohol derivative (35).
  • amide derivatives of an acid-containing indole derivative such as (36) can be prepared by treatment with an appropriate amine (Rl2Rll NH) and a suitable coupling agent such as benzotriazol-l-yloxy-tris(pyrrolidino) phosphonium hexafluorophosphate (PyBOP), benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate (BOP), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) or the like with or without 1- hydroxybenzotriazole (HOBt) and a tertiary amine base such as N- methylmorpholine (NMM), triethylamine or the like in an inert organic solvent such as methylene chloride, chloroform,
  • the tryptamine 5 can be modified by reaction with an arylsufonyl chloride such as 2-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride or 2,4-dinitrobenzenesulfonyl chloride and a hindered amine base such as 2,4,6-collidine, 2,6-lutidine or the like in an inert organic solvent such as methylene chloride to provide the corresponding sulfonamide 38.
  • an arylsufonyl chloride such as 2-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride or 2,4-dinitrobenzenesulfonyl chloride and a hindered amine base such as 2,4,6-collidine, 2,6-lutidine or the like
  • an inert organic solvent such as methylene chloride
  • Sulfonamides such as 38 can be further modified by reaction with an alcohol of type 39 in the presence of triphenylphosphine and an activating agent such as diethyl azodicarboxylate (DEAD), diisopropyl azodicaboxylate or the like in an inert organic solvent such as benzene, toluene, tetrahydrofuran or mixtures thereof to give the dialkylsulfon- amide adduct.
  • DEAD diethyl azodicarboxylate
  • diisopropyl azodicaboxylate or the like in an inert organic solvent such as benzene, toluene, tetrahydrofuran or mixtures thereof to give the dialkylsulfon- amide adduct.
  • DEAD diethyl azodicarboxylate
  • diisopropyl azodicaboxylate diisopropyl azodicaboxylate or the like
  • an inert organic solvent
  • the compounds of the present invention are useful in the treatment of various sex-hormone related conditions in men and women. This utility is manifested in their ability to act as antagonists of the neuropeptide hormone GnRH as demonstrated by activity in the following in vitro assays.
  • Human GnRH receptor binding assay Crude membranes prepared from CHO cells expressing human
  • GnRH receptors were the sources for GnRH receptor.
  • [125rjB usere ij n (a peptidyl GnRH analog) was used as the radiolabelled ligand.
  • the binding activity was determined as an IC50 which is the antagonist concentration required to inhibit the specific binding of [125l] buserelin to GnRH receptors by 50%.
  • the Wistar male rats (150-200 grams) were obtained from Charles River Laboratories (Wilmington, MA). Rats were maintained at a constant temperature (25°C) on a 12-hr light, 12-hr dark cycle. Rat chow and water were available ad libitum. The animals were sacrificed by decapitation and pituitary glands were aseptically removed and placed in Hank's Balanced Salt Solution (HBSS) in a 50-mL polypropylene centrifuge tube. The collection tube was centrifuged for 5 min at 250 x g, and HBSS was removed by aspiration. Pituitary glands were transferred to a disposable petri plate and minced with a scalpel.
  • HBSS Hank's Balanced Salt Solution
  • the minced tissue was then transferred to a 50-mL disposable centrifuge tube by suspending the tissue fragments in three successive 10-mL aliquots of HBSS containing 0.2% collagenase and 0.2% hyaluronidase.
  • the cell dispersion was carried out in a water bath at 37°C with gentle stirring for 30 min.
  • the cells were aspirated 20 to 30 times with a pipet and the undigested pituitary fragments were allowed to settle for 3 to 5 min.
  • the suspended cells were removed by aspiration, and then subjected to a 1200 x g centrifugation for 5 min. The cells were then resuspended in Culture medium.
  • the undigested pituitary fragments were treated with 30 mL aliquots of the digestion enzymes as above for a total of 3 digestions with the collagenase/hyaluronidase mixture.
  • the resulting cell suspensions were pooled, counted and diluted to a concentration of 3 x 10 ⁇ cells/ml, and 1.0 ml of this suspension was placed in each well of a 24-well tray (Costar, Cambridge, MA). Cells were maintained in a humidified 5% CO2-95% air atmosphere at 37°C for 3 to 4 days.
  • the culture medium consisted of DMEM containing 0.37% NaHCO3, 10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids, 1% glutamine, and 0.1% gentamycin.
  • the compounds of formula I are useful in a number of areas affected by GnRH. They may be useful in sex-hormone related conditions, sex-hormone dependent cancers, benign prostatic hypertrophy or myoma of the uterus. Sex-hormone dependent cancers which may benefit from the administration of the compounds of this invention include prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenomas. Other sex-hormone dependent conditions which may benefit from the administration of the compounds of this invention include endometriosis, polycystic ovarian 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, an angiotensin Il-receptor antagonist such as Losartan or a renin inhibitor for the treatment of uterine fibroids.
  • an angiotensin-converting enzyme inhibitor such as Enalapril or Captopril
  • an angiotensin Il-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 controlling pregnancy, as a contraceptive in both men and women, for in vitro fertilization, in the treatment of premenstrual syndrome, in the treatment of lupus erythematosis, in the treatment of hirsutism, in the treatment of irritable bowel syndrome and for the treatment of sleep disorders such as sleep apnea.
  • a further use of the compounds of this invention is as an adjunct to growth hormone therapy in growth hormone deficient children.
  • the compounds may be administered with growth hormone or a compound which increases the endogenous production or release of growth hormone.
  • Certain compounds have been developed which stimulate the release of endogenous growth hormone.
  • Peptides which are known to stimulate the release of endogenous growth hormone include growth hormone releasing hormone, the growth hormone releasing peptides GHRP-6 and GHRP-1 (described in U.S. Patent No. 4,411,890, PCT Patent Pub. No. WO 89/07110, and PCT Patent Pub. No. WO 89/07111) and GHRP-2 (described in PCT Patent Pub. No. WO 93/04081), as well as hexarelin (J. Endocrinol Invest.. 15(Suppl 4), 45 (1992)).
  • Other compounds which stimulate the release of endogenous growth hormone are disclosed, for example, in the following: U.S.
  • Representative preferred growth hormone secretagoues employed in the present combination include the following:
  • the compounds of the invention may also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, such as growth hormone secretagogues, e.g. MK-0677, for the treatment and the prevention of disturbances of calcium, phosphate and bone metabolism, in particular, for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones and or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with the GnRH antagonist.
  • bisphosphonates bisphosphonic acids
  • other agents such as growth hormone secretagogues, e.g. MK-0677
  • Bisphosphonates are known to inhibit bone resorption and are useful for the treatment of bone lithiasis as disclosed in U.S. Patent 4,621,077 to Rosini, et al.
  • the literature discloses a variety of bisphosphonic acids which are useful in the treatment and prevention of diseases involving bone resorption. Representative examples may be found in the following: U.S. Patent No. 3,251,907; U.S. Patent No. 3,422,137; U.S.
  • bisphosphonic acids and halo- bisphosphonic acids are well known in the art. Representative examples may be found in the above mentioned references which disclose the compounds as being useful for the treatment of disturbances of calcium or phosphate metabolism, in particular, as inhibitors of bone resorption.
  • Preferred bisphosphonates are selected from the group of the following compounds: alendronic acid, etidrononic acid, clodronic acid, pamidronic acid, tiludronic acid, risedronic acid, 6-amino-l-hydroxy-hexylidene-bisphosphonic acid, and l-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid; or any pharmaceutically acceptable salt thereof.
  • a particularly preferred bisphosphonate is alendronic acid (alendronate), or a pharmaceutically acceptable salt thereof.
  • An especially preferred bisphosphonate is alendronate sodium, including alendronate sodium trihydrate. Alendronate sodium has received regulatory approval for marketing in the United States under the trademark FOSAMAX®.
  • a compound of the present invention may be co-administered with a 5a-reductase 2 inhibitor, such as finasteride or epristeride; a 5a-reductase 1 inhibitor such as 4,7b-dimethyl-4-aza- 5a-cholestan-3-one, 3-oxo-4-aza-4,7b-dimethyl-16b-(4-chlorophenoxy)- 5a-androstane, and 3-oxo-4-aza-4,7b-dimethyl-16b-(phenoxy)-5a- androstane as disclosed in WO 93/23420 and WO 95/11254; dual inhibitors of 5a-reductase 1 and 5a-reductase 2 such as 3-oxo-4-aza- 17b-(2,5-trifluoromethylphenyl-carbamoyl)-5a-androstane as disclosed in WO 95/07927; antiandrogens such as flutamide, casodex and
  • a compound of the present invention may be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues, to delay puberty in growth hormone deficient children, which will allow them to continue to gain height before fusion of the epiphyses and cessation of growth at puberty.
  • the active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a 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
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy beans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation 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-butane diol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Compounds of Formula I may also be administered in the form of a suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity ofthe condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
  • a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, arrest or reverse the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • doses of the compound of structural formula I useful in the method of the present invention range from 0.01 to 1000 mg per adult human per day. Most preferably, dosages range from 0.1 to 500 mg/day.
  • the compositions are preferably provided in the form of tablets containing 0.01 to 1000 milligrams of the active ingredient, particularly 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 milligrams ofthe active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 50 mg/kg of body weight per day. The range is more particularly from about 0.001 mg/kg to 1 mg/kg of body weight per day.
  • the active agent of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in dividend doses of two, three or four times daily.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • Step 1A 2-[3-(2-Aminoethyl)-2-(3.5-dimethyl-phenyl)-lH-indol-5-yll-2- methylpropionic acid ethyl ester
  • Step IB 2J3J2-fer£-Butoxycarbonylaminoethyl)-2J3.5- dimethylphenyP-lH-indol- ⁇ -yll -2-methylpropionic acid ethylester
  • Step ID (2-r5-[2-(7-Azabicvclo[2.2. ⁇ hept-7-yl)-l.l-dimethyl-2-oxo- ethvn-2-(3.5-dimethylphenyl)-lH-indol-3- yllethyllcarbamicacid tert-butyl ester
  • 2- [3-(2-fer - butoxycarbonylaminoethyl)-2-(3,5-dimethylphenyl)-lH-indol-5-yl]-2- methylpropionic acid (856 mg in 8.0 mL methylene chloride) at 0° C was added 310 mg of 1-hydroxybenzotriazole ( ⁇ OBt)followed by 400 mg l-(3-dimethylaminopropyl)-3-eth
  • Step A Ethyl (+/-)-2-(4-nitrophenyl)propionate To a solution of 9.76 g (50 mmol) of (+/-)-2-(4- nitrophenyDpropionic acid in 150 mL of absolute ethanol was added 3.0 mL of concentrated sulfuric acid. The resulting solution was stirred at reflux under nitrogen. After 6 hours, the solution was cooled and stirred vigorously as 250 mL of saturated aqueous sodium bicarbonate solution was added gradually (Caution: foaming). The mixture was then partitioned between 750 mL of ethyl acetate and 500 mL of water.
  • Step B Ethyl 2-methyl-2-(4-nitrophenyl)propionate
  • a suspension of 924 (23 mmol) of sodium hydride (60% in oil) in 21 mL of dry ⁇ -dimethylformamide was stirred under nitrogen in an ice bath as a solution of 4.68 g (21 mmol) of ethyl (+/-)-2-(4- nitrophenyDpropionate in 20.5 mL of dry A ⁇ AT-dimethylformamide was added gradually over about 10 minutes. An intense violet color developed during the addition. The mixture was then allowed to warm to room temperature.
  • Step AA 4-Chloro- ⁇ methoxy-A ⁇ methylbutyramide
  • 4-chlorobutyryl chloride 10.0 g in 200 L of dry methylene chloride
  • AT O-dimethylhydroxylamine hydrochloride
  • the mixture was stirred under nitrogen and maintained below 25 °C by cooling in an ice bath as necessary while triethylamine (29.1 mL)was added dropwise over about 20 minutes, resulting in precipitation. After 1.5 hours at room temperature, the mixture was concentrated in vacuo. The residue was partitioned between 100 mL of diethyl ether and 100 mL of saturated aqueous sodium bicarbonate solution.
  • Step BB 3-Chloropropyl 3.5-dimethylphenyl ketone
  • Step AAA 4-Iodobenzoic acid methyl ester
  • a solution of 4-iodobenzoic acid (5.0 g in a mixture of 50 mL methanol and 2.2 mL of cone, sulfuric acid) was heated to reflux on an oil bath. After 15 hours, the mixture was concentrated to half-volume in vacuo then poured into saturated sodium bicarbonate. This mixture was extracted with diethyl ether and the organic portion washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 95:5) gave the title compound (5.12 g).
  • Step BBB Pyridine-3-boronic acid
  • the aqueous layer was acidified to pH 6 by the dropwise addition of IN hydrochloric acid and extracted with methylene chloride. The combined organics were dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with 20 mL acetonitrile: water (1:1) and filtered to give the title compound (1.0 g).
  • Step CCC 4-Pyridin-3-yl-benzoic acid methyl ester
  • Step 2A (S)-2-[3-(2-amino-l-methylethyl)-7-bromo-2-(3.5- dimethylphenyl)-lH-indol-5-vn-2-methylpropionic acid ethyl ester
  • Step 2B (S)-2-f3-(2-amino-l-methylethyl)-2-(3.5-dimethylphenyl)-lH- indol-5-yl]-2-methylpropionic acid ethyl ester
  • (S)-2-[3-(2-amino-l-methylethyl)-7-bromo- 2-(3,5-dimethylphenyl)-lH-indol-5-yl]-2-methylpropionic acid ethyl ester (79 mg in 1 mL methanol) was added 8 mg of 10% palladium on carbon catalyst.
  • reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 7 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth, concentrated in vacuo and purified by flash chromatography on silica gel (chloroform:methanol, 92:8) to provide the title compound (68 mg).
  • Step 2C (S)-2J3-(2-fe ⁇ butoxycarbonylamino-l-methylethyl)-2-(3.5- dimethylphenyl)-lH-indol-5-vn-2-methylpropionic acid ethyl ester
  • Step 2D (S)-2J3-(2-fer ⁇ butoxycarbonylamino-l-methylethyl)-2J3.5- dimethylphenyl)-lH-indol-5-yl1 -2-methylpropionic acid
  • (S)-2-[3-(2-£er;£-butoxycarbonylamino- l-methylethyl)-2-(3,5-dimethylphenyl)-lH-indol-5-yl]-2-methylpropionic acid ethyl ester (2.5 g in 80 mL methanol) was added 26 mL of 2. ON potassium hydroxide and the mixture heated to 94°C on an oil bath.
  • Step 2E (S)-(2-[5-r2-(7-azabicvclor2.2.Hhept-7-yl)-lJ-dimethyl-2-oxo- ethyl1-2J3.5-dimethylphenyl)-lH-indol-3-yl1-propyl)- carbamic acid tert-butyl ester
  • Step 2F (S)-2-r3-(2-amino-l-methylethyl)-2-(3.5-dimethylphenyl)-lH- indol-5-yn-l-(7-azabicyclof2.2. ⁇ hept-7-yl)-2-methylpropan-l- one
  • Step 2G (S)-A -(2-r5-f2-(7-azabicvclor2.2.11hept-7-yl)-lJ-dimethyl2-oxo- ethyll -2- ( 3.5-dimethylphenyl)-lH-indol-3-vn -propyl)-2.4- dinitrobenzenesulfonamide
  • Step AA (R)-4-hydroxy-3-n ⁇ ethylbutyronitrile
  • Step BB (R)-4-methyldihydrofuran-2-one
  • Step DD (R)-4-chloro-l-(3.5-dimethylphenyl)-3-methylbutan-l-one
  • Step AAA 4-(2-benzyloxyethyl)nitrobenzene To a solution of 2-(4-nitrophenyl)ethanol (5.05g in 60 mL
  • Step CCC 4J4J2-benzyloxyethyl)phenvn-4H-n.2.41triazole
  • Step DDD 2-(4-n.2.41triazol-4-yl-phenyl)ethanol To a stirred solution of 4-[4-(2-benzyloxyethyl)phenyl]-4H-
  • Step 3A A* r .A- r -Diisopropyl-4-nitrobenzamide
  • a solution of 3.51 mL (2.53 g, 25 mmol) of diisopropyl- amine and 3.62 mL (2.63 g, 26 mmol) of triethylamine in 50 mL of anhydrous tetrahydrofuran was stirred under nitrogen and maintained at -5 °C as a solution of 4.11 g (22.1 mmol) in 10 mL of anhydrous tetrahydrofuran was added dropwise over 15 minutes. The mixture was allowed to warm gradually to room temperature.
  • Step 3C 4-Hydrazino-A? r .Ar-diisopropylbenzamide
  • Step 3D 3- ( 2-Aminoethyl ) -2-(3.5-dimethylphenyl)-lH-indole-5- carboxylic acid diisopropylamide
  • a solution of 3.51 g (14.9 mmol) 4-hydrazino-A ;r N- diisopropylbenzamide (from Step 3) in 18 mL of 2-methoxyethanol was stirred at 100 °C under nitrogen as 3.77 g (17.8 mmol) of 3-chloropropyl 3,5-dimethylphenyl ketone in 7 mL of 2-methoxyethanol was added dropwise over 20 minutes.
  • Step A 4-Chloro-A ⁇ -methoxy-A ⁇ -methylbutyramide

Abstract

L'invention concerne des composés de formule (I) et leurs sels pharmaceutiquement acceptables, qui sont des antagonistes de l'hormone de libération de la gonadotrophine (GnRH) et qui peuvent donc être utiles dans le traitement d'affections liées aux hormones sexuelles et d'autres affections chez l'homme et la femme.
EP98926171A 1997-06-05 1998-06-01 Antagonistes de l'hormone de liberation de la gonadotrophine Withdrawn EP1011667A4 (fr)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
US4863797P 1997-06-05 1997-06-05
US4863697P 1997-06-05 1997-06-05
US48637P 1997-06-05
US48636P 1997-06-05
GB9719839 1997-09-18
GBGB9719839.4A GB9719839D0 (en) 1997-09-18 1997-09-18 Antogonists of gonadotropin releasing hormone
GBGB9800451.8A GB9800451D0 (en) 1998-01-09 1998-01-09 Antagonists of gonadotropin releasing hormone
GB9800451 1998-01-09
PCT/US1998/011204 WO1998055119A1 (fr) 1997-06-05 1998-06-01 Antagonistes de l'hormone de liberation de la gonadotrophine

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EP1011667A1 true EP1011667A1 (fr) 2000-06-28
EP1011667A4 EP1011667A4 (fr) 2001-03-28

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JP (1) JP2002503252A (fr)
AU (1) AU7806998A (fr)
CA (1) CA2291829A1 (fr)
WO (1) WO1998055119A1 (fr)

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WO1999021557A1 (fr) * 1997-10-28 1999-05-06 Merck & Co., Inc. Antagonistes de la gonadoliberine
AU1124399A (en) * 1997-10-28 1999-05-17 Merck & Co., Inc. Antagonists of gonadotropin releasing hormone
US6346534B1 (en) 1998-09-23 2002-02-12 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US6537998B1 (en) 1999-10-15 2003-03-25 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
DK1255738T3 (da) 2000-01-25 2012-06-25 Neurocrine Biosciences Inc Gonadotropin-frigivende hormonreceptor-antagonister og fremgangsmåder relateret dertil
GB0022670D0 (en) 2000-09-15 2000-11-01 Astrazeneca Ab Molecules
SE0100566D0 (sv) 2001-02-20 2001-02-20 Astrazeneca Ab Compounds
SE0101692D0 (sv) 2001-05-14 2001-05-14 Astrazeneca Ab Compounds
WO2003013528A1 (fr) 2001-08-02 2003-02-20 Neurocrine Biosciences, Inc. Pyridin-4-ones substituees et leur utilisation en tant qu'antagonistes du recepteur de l'hormone de liberation de la gonadotrophine
AU2002324586B2 (en) 2001-08-02 2008-04-24 Neurocrine Biosciences, Inc. 1,3,5-triazine-2,4,6-triones, preparation and use as gonadotropin-releasing hormone receptor antagonists
EP1412363A1 (fr) 2001-08-02 2004-04-28 Neurocrine Biosciences, Inc. Antagonistes du recepteur de l'hormone liberatrice de la gonadotropine
WO2003011293A2 (fr) 2001-08-02 2003-02-13 Neurocrine Biosciences, Inc. Antagonistes du recepteur de l'hormone liberant la gonadotropine et procedes associes
WO2003011841A1 (fr) 2001-08-02 2003-02-13 Neurocrine Biosciences, Inc. 1,2,4-triazin-3,5-diones comme antagonistes du recepteur de l'hormone de liberation des gonadotrophines (gnrh)
TW200407127A (en) 2002-08-21 2004-05-16 Astrazeneca Ab Chemical compounds
DE60318716T2 (de) 2002-08-21 2009-01-08 Astrazeneca Ab Thieno-pyrrole verbindungen als antagonisten der gonadotropin-freisetzenden hormonrezeptoren
TW200413351A (en) 2002-08-21 2004-08-01 Astrazeneca Ab Chemical compounds
GB0219472D0 (en) 2002-08-21 2002-10-02 Astrazeneca Ab Chemical compounds
WO2004018459A1 (fr) 2002-08-21 2004-03-04 Astrazeneca Ab Derives de pyrazole en tant qu'inhibiteurs de gnrh
CA2531507C (fr) 2003-07-07 2013-10-01 Neurocrine Biosciences, Inc. Derives de pyrimidine-2,4-dione, servant d'antagonistes au recepteur de l'hormone de liberation de la gonadotropine
ATE557007T1 (de) 2003-07-07 2012-05-15 Neurocrine Biosciences Inc Arylpyrimidine geeignet zur behandlung von sexualhormonbedingten zuständen wie endometriose, prostatakrebs und dergleichen
DK1646389T3 (da) 2003-07-07 2009-01-05 Neurocrine Biosciences Inc Pyrimidin-2,4-dionderivater som gonadotropinfrigörende hormonreceptorantagonister
WO2012175514A1 (fr) 2011-06-21 2012-12-27 Bayer Intellectual Property Gmbh Dérivés de pyridinone et compositions pharmaceutiques les contenant

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AU709090B2 (en) * 1995-12-14 1999-08-19 Merck & Co., Inc. Antagonists of gonadotropin releasing hormone

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No further relevant documents disclosed *
See also references of WO9855119A1 *

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EP1011667A4 (fr) 2001-03-28
AU7806998A (en) 1998-12-21
WO1998055119A1 (fr) 1998-12-10
JP2002503252A (ja) 2002-01-29
CA2291829A1 (fr) 1998-12-10

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