EP1453803A2 - Derives tetrahydrocarbazol servant de ligands de recepteurs couples aux proteines g (gpcr) - Google Patents

Derives tetrahydrocarbazol servant de ligands de recepteurs couples aux proteines g (gpcr)

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Publication number
EP1453803A2
EP1453803A2 EP02796648A EP02796648A EP1453803A2 EP 1453803 A2 EP1453803 A2 EP 1453803A2 EP 02796648 A EP02796648 A EP 02796648A EP 02796648 A EP02796648 A EP 02796648A EP 1453803 A2 EP1453803 A2 EP 1453803A2
Authority
EP
European Patent Office
Prior art keywords
tetrahydro
amino
aminocarbonyl
carbonyl
radical
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Withdrawn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
EP02796648A
Other languages
German (de)
English (en)
Inventor
Marcus Koppitz
Hans Peter Muhn
Ken Shaw
Holger Hess-Stumpp
Klaus Paulini
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.)
Aeterna Zentaris GmbH
Original Assignee
Zentaris AG
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Filing date
Publication date
Priority claimed from DE10164564A external-priority patent/DE10164564B4/de
Application filed by Zentaris AG filed Critical Zentaris AG
Publication of EP1453803A2 publication Critical patent/EP1453803A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • 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
    • A61P15/16—Masculine contraceptives
    • 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
    • A61P15/18—Feminine 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to new tetrahydrocarbazole derivatives which are ligands of G protein-coupled receptors, and in particular to gonadotropin-releasing hormone antagonists, their preparation, their use and pharmaceutical compositions comprising these tetrahydrocarbazole derivatives.
  • the present invention also relates to a method for the treatment of disease states mediated by G protein-coupled receptors in a mammal, in particular a human.
  • GPCR G-protein coupled receptors
  • privileged structures play a special role in the search for new, non-peptide receptor ligands. These “privileged structures” are those molecular structures that provide ligands for a large number of different receptors.
  • the term "privileged structures" was first used by Evans et al. In connection with benzodiazepine-based CCK (cholecyrtokinin) -A antagonists from the natural product asperiicin (BE Evans et al., J. Med Chem.
  • proteases for example, it has long been known that certain structural classes can serve as inhibitors for various enzymes, while mechanism-based inhibitors for various proteases have been described in the past, but more and more examples of compounds have recently been found which, due to their three-dimensional structure, fit well into the active binding region of various enzymes (cf. M. Whittaker, C r. Opi. Chem. Biol. 1998, 2, 386; AS Ripka et al., ibid., 441) Such "privileged structures" have already been described in GPCRs.
  • the present invention generally provides ligands for GPCR's
  • the compounds provided by the present invention are especially as Ligands are suitable for a specific representative of the class of GPCR's, namely the gonadotropin-releasing hormone (GnRH).
  • GnRH gonadotropin-releasing hormone
  • the GnRH can be classified into subfamily A of the GPCR's (cf. U. Gether et al., Endocrine Reviews 2000, 21 (1), 90).
  • GnRH is a hormone that is predominantly, but not exclusively, synthesized in mammalian cells by hypothalamic nerve cells, transported to the pituitary gland via the portal vein and released to the gonadotrophic cells in a regulated manner. By interacting with its seven transmembrane domains, GnRH stimulates the production and release of gonadotropic hormones by means of the second messenger inositol-1, 4,5-trisphosphate and Ca + ions.
  • GnRH gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH) released by GnRH stimulate the production of sex steroids and germ cell maturation in both sexes.
  • LH gonadotropins luteinizing hormone
  • FSH follicle stimulating hormone
  • the GnRH receptor is used as a phanacological target in a number of diseases that depend on a functioning sex homion production, for example prostate cancer, premenopausal breast cancer, endometriosis and uterine fibroids. GnRH superagonists or antagonists can be successfully used in these diseases. Another possible indication is male fertility control in combination with a substitution dose of androgens.
  • GnRH antagonists compared to GnRH superagonists are their immediate effectiveness in blocking gonadotropin secretion.
  • Superagonists initially overstimulate the pituitary gland, which leads to increased gonadotropin and sex steroid releases. This hormonal response only stops after a certain delay due to desensitization and downregulation of the GnRH receptor concentrations. It is therefore possible that GnRH superagonists, both alone and in combination with testosterone, cannot effectively suppress sperm production in men and are therefore not for them suitable for male fertility control.
  • peptide GnRH antagonists especially in combination with a substitution dose of androgen, are able to produce a significant oligozoospe ⁇ nie in humans
  • GnRH peptide antagonists have a number of disadvantages. They are considerably less effective than superagonists and must therefore be administered in considerably higher doses. Their oral bioavailability is also low, so that they have to be administered by injection. Repeated injections in turn lead to a reduction in compliance. In addition, the synthesis of peptide GnRH antagonists is complex and expensive compared to non-peptide compounds.
  • the object on which the present invention is based is to provide new compounds which are suitable for the treatment of disease states mediated by GPCR and in particular have a GnRH-inhibiting (GriRH-antagonistic) action.
  • the new GPCR ligands preferably GnRH antagonists, should be superior to known peptide compounds if possible and should represent an effective alternative or improvement in the ratio of 2 known non-peptide compounds.
  • the new GPCR ligands, in particular GnRH antagonists should above all have a high potency and, if possible, a high oral bioavailability. Furthermore, they should be able to be synthesized easily and at the lowest possible cost.
  • the present invention also provides pharmaceutical compositions containing the new non-peptide GPCR ligands, in particular GnRH antagonists.
  • a further object on which the present invention is based is the provision of new GPCR ligands, preferably GnRH antagonists, for use as a pharmaceutical agent or for use in the production of pharmaceutical agents, comprising the GPCR ligands, preferably GnRH antagonists, /
  • the present invention provides new tetrahydrocarbazole derivatives of the general formula (I).
  • compositions which comprise at least one of the new tetrahydrocarbazole derivatives of the general formula (T).
  • the present invention provides tetrahydrocarbazole derivatives of the general formula (T) for use as a pharmaceutical agent.
  • the present invention relates to the use of a tetrahydrocarbazole derivative of the general formula (I) for the preparation of a pharmaceutical composition for the treatment of disease states mediated by GPCR, in particular for the inhibition of GnRH.
  • the present invention also relates to a method for the treatment of disease states mediated by GPCR, in particular for the inhibition of GnRH in a mammal, preferably a human, an effective amount of a compound of the general formula (I) according to the invention being administered to the mammal, preferably the human, in need of such treatment.
  • the present invention also provides a process for the preparation of tetrahydrocarbazole derivatives of the general formula (I).
  • This method comprises, for example, the steps of condensing an appropriately substituted cyclohexanone derivative anchored to a solid phase with a suitably substituted one Phenylhydrazine derivative, a subsequent derivatization depending on the desired structure of the end compound and finally cleavage from the solid phase and isolation of the product.
  • the radical R 1 is a hydrogen atom, a C 2 - Ce alkenyl or a Cj - C ⁇ alkyl radical and can optionally be substituted by an aryl, hetaryl radical or the group -COOR 11 , the aryl or hetaryl radical having up to three substituents may be substituted, which are independently selected from the group consisting of -NO 2 , -CH 3 , -CFs, -OCH 3, -OCF 3 and halogen atoms and the radical R 11 is a hydrogen atom, a Cj - C 1 2 alkyl , is a -C 2 aralkyl, an aryl, hetaryl radical or the group -COCHs and may optionally be substituted with a substituent selected from the group consisting of -CONH2, -COCH3, -COOCH3, -SO 2 CH3 and aryl radicals; the radicals R 2 , R 3 , R 4 and R J each
  • - C 12 is alkenyl, which is optionally substituted by the radicals R s and R 9 , the radicals R 8 and R 9 each independently of one another a hydrogen atom, a Ci
  • the radical R 7 is a hydrogen atom, a Ci - C 12 alkyl, a Ci - 2 alkenyl, a Ci - C ⁇ z aralkyl, an aryl or hetaryl radical, the group -NR l2 R 13, -NHCOR 14, -NHCONHR 14 , -NHCOOR 14 or NHSO2R 14 and may optionally be substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CONH 2 , -COOH and halogen atoms, the radicals R 12 and R 13 are each independently a hydrogen atom, a C2 - C ⁇ alkenyl or a Ci - C12 aikyl radical and can optionally be substituted with one or more aryl or hetaryl radicals, which in turn can be substituted with up to three substituents which are independent of one another from the group selected from -NO 2 » -CH 3 , -CF3, -
  • C12 is aralkyl, an aryl or hetaryl radical which may optionally be substituted by one or more substituents which are selected from the group consisting of -NO 2 , -CH 3 , -OR 11 , -CF 3 , -OCF 3 , -OH, -N (R ⁇ ) 2 , -OCOR 11 , -COOH, -CONH 2) -NHCONHR 11 , -NHCOOR 11 and halogen atoms;
  • R a , R, R fi , R d , R e and R f each independently represent a hydrogen atom, a halogen atom, the group -COOH, -CONH 2 , -CF 3 , -OCF 3 , -NO 2 , - CN, a Ci - Ce alkyl, C - C 6 alkoxy, an aryl or hetaryl radical;
  • the compound of the general formula (I) does not consist of the from 3- A ino-l, 2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-methoxy-l, 2,3, 4-tetrahydrocarbazole-3-carboxylic acid, 3-am o-6-benzyloxy-l, 2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-acetamido-l, 2,3,4-tetrahydrocarbazole-3-carboxylic acid, methyl -3-acetamido-l, 2,3,4-tetrahydrocarbazole-3-carboxylate, (-) - menthyl-3-acetamido-l, 2,3,4-tetrahydrocarbazole-3-carboxylate or 3-tert-butoxycarbonyl-amino -l, 2,3,4-tetrahydrocarbazole-3-carboxylic acid group
  • An embodiment of the invention are compounds of the general formula (I) as indicated above with all the meanings given above for the radicals contained in (I), the radical R 11 being a heteroalkyl or a: hetarylalkyl radical.
  • alkyl radical means a branched or unbranched, cyclic or non-cyclic, optionally substituted alkyl group having 1 to 6 or 1 to 12 carbon atoms.
  • Alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl , n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl groups and cyclic groups, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl groups, 1-cyclopropyl, 1-cyclobutyl
  • alkenyl a Alkenyixx branched or unbranched, cyclic or noncyclic, substituted or unsubstituted, mono- or poly-unsaturated is meant having 2 to 6 carbon atoms
  • alkenyl groups include vinyl, allyl, Pro ⁇ - 1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-l, 3-dienyl, pent-1-enyl, pent-2-enyl, pent 3-enyl, pent-4-enyl, penta-l, 3-dienyl, penta-l, 4-dienyl, penta-2,3-dienyl, isoprenyl, hex-1-enyl, hex -2-enyl-, hex-3-enyI-, hex-4-enyl-, hex-5-enyl, hexa-l, 3-
  • Alkoxy radical is understood to mean a branched or unbranched, cyclic or non-cyclic, optionally substituted alkoxy group having 2 to 6 carbon atoms.
  • alkoxy groups include methoxy, etboxy, n-propoxy, iso-propoxy -, n-butoxy, iso-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclohexyloxy groups and the like, but are not limited to these.
  • Ci - Cj 2 "aralkyl group” means an alkyl group with 1 to 12 carbon atoms which is substituted by one or more aryl groups.
  • Representative examples of such aralkyl groups for the purposes of the present invention include benzyl, 1-phenylethyl, 1-phenylpropyl -, 1-phenylbutyl-, 1-phenylhexyl-, 1-phenyl-2-methylethyl-, l-phenyl-2-ethylethyl-, l-phenyl-2,2-dimethylethyl- 3 benzhydryl-, triphenylethyl-, 2- or 3-naphthylmethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl groups and the like limited.
  • a "hetaralkyl radical” is an alkyl radical substituted by a heteroaryl radical.
  • Aryl group means an optionally substituted mono- or polycyclic aromatic group. Representative examples of such aryl groups include, but are not limited to, phenyl, naphthyl groups and the like.
  • heteroaryl residue is identical to the term “heteroaryl residue” and stands for an aryl group as defined above, which in its structure comprises one or more heteroatoms, in particular nitrogen, phosphorus, oxygen, sulfur and arsenic atoms.
  • Representative examples of such hetaryl or heteroaryl groups include, but are not limited to, unsubstituted hetaryl groups and substituted hetaryl groups, especially idazolyl, pyridyl, quinolinyl groups and the like.
  • ring structure includes optionally substituted mono- or polycyclic ring structures with different numbers of ring members, but especially five-, six- and seven-membered ring structures.
  • one or more heteroatoms such as in particular nitrogen, phosphorus
  • the ring structures can include saturated, but also partially or completely unsaturated structural elements.
  • ring structures include aza, oxa, thia, phosphacyclopentane, cyclohexane, cycloheptane , Diaza, dioxa, dithia, diphosphacyclopentane, cyclohexane, cycloheptane ring basic structures and the like as well as ring basic structures with mixed heteroator exchange, but are not limited to these.
  • Halogen atoms include in particular fluorine, chlorine, bromine and iodine atoms, particularly preferably chlorine atoms.
  • the term "receptor ligand” or “ligand” for the purposes of the present invention is intended to mean any compound which binds to a receptor in any way (in the present invention, the receptor is a GPCR receptor, preferably a GnRH receptor) and either triggers an activation, inhibition or other conceivable effect on this receptor.
  • the term “ligand” thus encompasses agonists, antagonists, partial agonists / antagonists and other ligands which produce an action on the receptor which is similar to the action of agonists, antagonists or paitial agonists / antagonists.
  • the compounds according to the invention are preferably of the general type Formula (I) antagonists of the GnRH.
  • One embodiment of the present invention are novel tetrahydrocarbazole derivatives according to the invention of the general formula (I) in which the radical R 7 is not a hydrogen atom if the radical R e is also an alkyl radical.
  • a further embodiment of the present invention are compounds of the general formula (I) in which the radical R 7 is in any case not a hydrogen atom.
  • Preferred new tetrahydrocarbazole derivatives of the general formula (I) according to the invention are those compounds in which the radicals R a , R, R c , R d , R * and R are hydrogen atoms.
  • new tetrahydrocarbazole derivatives of the general formula (1) according to the invention are those compounds in which the radical R 1 is a hydrogen atom.
  • Preferred new inventive tetrahydrocarbazole derivatives of the general formula (I) are also those compounds in which the radicals R 2 , R 3 , R 4 and / or R 5 are not hydrogen atoms.
  • Those compounds of the general formula (I) in which the radicals R 2 , R 3 , R 4 and R 5 are, independently of one another, methyl, chloro or methoxy radicals are particularly preferred.
  • Those compounds of the general formula (I) in which at least the radical R 2 is not a hydrogen atom, in particular the compounds are very particularly preferred.
  • Formula (I) are also those compounds in which R 6 is a radical comprising a hydrophobic alkyl, aryl and / or hetaryl structure, which is spaced two to four
  • Phenylalanylamidrest is, in particular the compound phenylmethyl - [(1S, 2S) -1 - [[[(3R) -
  • 3- (3-phenylpropyl) - (- (4-pyridinylmethyl) -IH-carbazole-3-methanol (2S7)) is a carboxyl radical, especially the compound 2,3,4,9-tetrahydro-3- (3-phenylpropyl ) -lH-carbazole-3-carboxylic acid (273), or an ethyl propenate residue, in particular the compound ethyl 3- [2,3,4,9-
  • Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[(2S) -2- (aminocarbonyl) octahydro-lH-indole-1-yJ] carbonyl] -2,3,4,9 -tettahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (190a)), a 4-carboxamidophenylcarboxamide radical, in particular the compound phenylmethyl
  • Formula (I) are also those compounds in which R 7 is a residue comprising a hydrophobic alkyl, aryl and / or etaryl structure. Are particularly preferred
  • Biphenylpropionylamino radical in particular the compound N - [[(3R) -2,3,4,9-
  • 2,3,4,9-tetrahydro-lH-carbazol-3-ca ⁇ boxamid (162a) is an indolylacetylamino radical, in particular the compound (3S) -N - [(1S) -1-
  • R 7 is a phenylmethylcarboxamide radical substituted on the aromatic system, in particular the compounds (3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -
  • 2,3,4,9-tetrahydro-lH-carbazole-3-carboxamide (167a), is a phenylhexylamine radical, in particular the compound (3R) -N - [(1S) -1-
  • the new tetrahydrocarbazole derivatives (T) according to the invention, as defined above, are ligands of GPCR and can in particular be used for inhibition, i.e. can be used as antagonists of the gonadotropin-releasing hormone, for example for male fertility control, for hormone therapy, for the treatment of female sub- or mertility, for female contraception and for combating tumors
  • the compounds of the invention reduce spermatogenesis.
  • Combined administration with androgens e.g. Testosterone or testosterone derivatives, such as testosterone esters.
  • the administration of the testosterone derivatives can, for example, by injection, e.g. by intramuscular depot injection.
  • the compounds (I) according to the invention can optionally be used in combination with other hormones, for example estrogens and / or progestins.
  • hormones for example estrogens and / or progestins.
  • Combinations of the GnRH antagonists according to the invention and tissue-selective partial estrogen agonists such as Raloxifene ® are particularly preferred.
  • the compounds according to the invention can be used in hormone replacement therapy.
  • the compounds (I) according to the invention can be used to increase female fertility, for example by inducing ovulation, and to treat sterility.
  • the new compounds (I) according to the invention are also suitable for contraception in women.
  • the GnRH antagonist according to the invention can be administered on days 1 to 15 of the cycle together with estrogen, preferably with very low estrogen doses.
  • Progestagen of the estrogen-GnRH 'antagonist combination is added on days 16 to 21 of the intake cycle.
  • the GnRH antagonist according to the invention can be used continuously over the entire cycle be administered. In this way, a reduction in hormone doses and thus a reduction in the side effects of unphysiological hormone levels can be achieved.
  • advantageous effects can be achieved in women who suffer from polycystic ovary syndrome and androgen-dependent diseases such as acne, seborrhea and hirsutism.
  • the compounds (I) according to the invention can also be used for the treatment of hormone-dependent tumor diseases, such as premenopausal breast cancer, prostate cancer, ovarian cancer and endometrial cancer, by suppressing the endogenous sex steroid hormones.
  • hormone-dependent tumor diseases such as premenopausal breast cancer, prostate cancer, ovarian cancer and endometrial cancer
  • the new compounds (I) according to the invention are available as GPCR ligands, in particular GnRH antagonists, for the treatment of the disease states listed above for administration to mammals, in particular humans, but also for veterinary purposes, e.g. suitable for domestic and farm animals, but also for wild animals.
  • Administration can be carried out in a known manner, for example orally or non-orally, in particular topically, rectally, intravaginally, nasally or by injection or implantation. Oral administration is preferred.
  • the new compounds (I) according to the invention are brought into a form suitable for administration and, if appropriate, mixed with pharmaceutically acceptable carriers or diluents. Suitable auxiliaries and carriers are described, for example, in Ullman's E cyclopedia of Technical Chemistry, Vol. 4, (1953), 1-39; J rnal of Pharmaceutical Sciences, Vol. 52 (1963), 918 ff; H. v. Czetsch-Lindenwald, “Auxiliaries for pharmacy and neighboring areas 11 ; Pharm. Ind 2, 1961, 72ff; Dr. HP Fiedler,, Garexikon der excipients for pharmacy, Cosmetics and adjacent areas ", Cantor KG, Aulendorf in practise, 1971.
  • Oral administration can take place, for example, in solid form as a tablet, capsule, gel capsule, dragee, granulate or powder, but also in the form of a drinkable solution.
  • the new compounds of the general formula (I) according to the invention can be combined with known and commonly used, physiologically compatible auxiliaries and excipients, such as, for example, Gum arabic, talc, starch, sugar such as Mannitol, methyl cellulose, lactose, gelatin, surfactants, magnesium stearate, cyclodextrins, aqueous or non-aqueous vehicles, diluents, dispersants, emulsifiers, lubricants, preservatives and flavors (e.g. essential oils).
  • the compounds according to the invention can also be used in a microparticulate, e.g. dispersed nanoparticulate composition.
  • the non-oral administration can take place, for example, by intravenous, subcutaneous or intramuscular injection of sterile aqueous or oily solutions, suspensions or emulsions, by means of implants or by ointments, creams or suppositories. If necessary, it can also be administered as a slow-release form.
  • Implants can contain inert materials, e.g. biodegradable polymers or synthetic silicones such as Silicone rubber.
  • Intravaginal administration can e.g. by means of vaginal rings.
  • Intrauterine administration can e.g. using diaphragms etc.
  • transdermal administration in particular by means of a suitable formulation and / or suitable agents such as e.g. Plasters, provided
  • the new compounds (I) according to the invention can also be combined with other active pharmaceutical ingredients.
  • the individual active ingredients can be administered simultaneously or separately, either in the same way (for example orally) or in separate ways (for example, orally and as an injection). They can be present or administered in the same or different amounts in a unit dose. It a certain dosage regimen can also be used, if this seems appropriate. In this way, several of the new compounds (I) according to the invention can also be combined with one another.
  • the dosage can vary within a wide range depending on the type of indication, the severity of the disease, the type of administration, the age, gender, body weight and the sensitivity of the subject to be treated. It corresponds to the skill of a person skilled in the art to determine a “pharmacologically effective amount” of the combined pharmaceutical composition.
  • Preferred doses are from 1 ⁇ g to 100 mg, particularly preferably from 1 ⁇ g to 10 mg and most preferably from 1 ⁇ g to 1 mg per kg Body weight of the subject to be treated and can be administered in a single dose or multiple separate doses
  • compositions as described above comprising at least one of the new compounds (I) according to the invention, as defined above, and optionally pharmaceutically acceptable carriers and / or auxiliaries, are also covered by the present invention.
  • Preferred and particularly preferred pharmaceutical compositions are those which comprise at least one of the abovementioned preferred or particularly preferred new compounds (I) according to the invention, in particular the abovementioned compounds.
  • other pharmaceutical active ingredients can also be present in pharmaceutical compositions according to the present invention, as already detailed above.
  • compositions according to the invention at least one of the new compounds (I) according to the invention, as defined above, is present in one of the preferred, particularly preferred or most preferred unit doses mentioned above, preferably in a form of administration which enables oral administration.
  • present invention provides in a further aspect compounds of the general formula (I) as defined above for use as a pharmaceutical agent.
  • Preferred tetrahydrocarbazole compounds according to the invention of the general formula (I), as defined above, for use as pharmaceutical agents are, in turn, those compounds which have been mentioned above as preferred and particularly preferred compounds, in particular the preferred compounds according to the invention mentioned by name and those mentioned in the examples Links.
  • compositions comprising compounds (I) according to the invention and with regard to the compounds (I) according to the invention for use as pharmaceutical compositions, reference is made to what has already been said regarding the new compounds (I) according to the invention, as defined above, with regard to use and administration options.
  • the present invention also provides the use of at least one tetrahydrocarbazole derivative according to the invention of the general formula (I) as defined above, wherein - as initially defined - the in the publications by Millet et al. and Maki et al. disclosed tetrahydrocarbazoles are excluded from the meaning of the general formula (I), for the preparation of a pharmaceutical composition for the treatment of GPCR-mediated diseases, in particular for the inhibition of the gonadotropin-releasing hormone (GnRH).
  • GnRH gonadotropin-releasing hormone
  • the present invention provides in a further aspect the use of at least one compound according to the invention of the general formula (I) as defined above, but including the compounds from the publications by Millet et al. and Maki et al., namely 3-amino-l ⁇ - tetr- ⁇ ydrocarbazoW-carboxylic acid, 3-ammo-6-methoxy-l, 2,3,4-tetra-hydrocarbazole-3-carboxylic acid, 3-amino- 6-benzyloxy-l 1 2,3,4-tetrahydro-carbazole-3- carboxylic acid, 3-acetamido-I, 2 s 3 ?
  • the radical R 1 is a hydrogen atom, a C 2 - C alkenyl or a Ci - C 6 alkyl radical and can optionally be substituted with an aryl, hetaryl radical or the group -COOR 11 , the aryl or hetaryl radical with up to three substituents can be substituted, which are independently selected from the group consisting of -NO2, -CH 3 , -CF3, -OCHs, -OCF 3 and halogen atoms and the radical R 11 is a hydrogen atom, a Ci - C 12 alkyl, is a Ci - C J2 aralkyl, an aryl, hetaryl or the group -COCH 3 and optionally with one of those from -CONH 2; -COCH3, -C ⁇ OCH 3 , -SO2CH3 and aryl groups consisting of selected substituents may be substituted; the radicals R 2 , R 3 , R 4 and R s each independently
  • the radical R 6 is the group -CONR 8 R 9 , -COOR 8 , -CH 2 NRV, -CH 2 R 8 , -CH 2 OR 8 or a Ci
  • - C 1 2 is alkenyl, which is optionally substituted by the radicals R 5 and R 9 , the radicals R s and R 9 each independently of one another a hydrogen atom, a Ci
  • the radical R 7 is a hydrogen atom, a d - C1 alkyl, a Ci - C ⁇ 2 alkenyl, a Ci - C 12 aralkyl, an aryl or hetaryl radical, the group -NR 12 R 13 , -NHCOR 14 , -NHCONHR 14 , -NHCOOR 14 or -NHSO 2 R 14 and may optionally be substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CONH 2 , -COOH and halogen atoms, the radicals R 12 and R 13 are each independently a hydrogen atom, a C 2 -Cg alkenyl or a Ci - C12 alkyl radical and can optionally be substituted by one or more aryl or hetaryl radicals, which in turn can be substituted by up to three substituents which are independently selected from the group consisting of -NO 2 , -CH 3 , «CF3,
  • - C12 is aralkyl, an aryl or hetaryl radical, optionally with one or can be substituted by a plurality of substituents which are selected from the group consisting of -NO 2 , -CH 3 , -OR 11 , -CF3, -OCF 3 , -OH, -N (R H ) 2 , -OCOR u , -COOH, -CONH 2 , -NHCONHR 11 , -NHCOOR 11 and halogen atoms;
  • R a , R b , R c , R d , R fl and R f independently of one another each represent a hydrogen atom, a halogen atom, the group -COOH, -CONH 2? -CF 3 , -OCF 3 , -NO 2 , -CN, a Ci - C ⁇ alkyl, Ci - Ce alkoxy, an aryl or hetaryl radical.
  • the present invention provides the use of a compound (T) according to the invention as defined above, but also including the compounds excluded by name at the outset, for male fertility control or for female contraception.
  • Preferred and particularly preferred compounds according to the invention for this use are those compounds which have already been mentioned at the beginning as preferred or particularly preferred compounds of the general formula (I) as defined above.
  • the present invention provides a method of male fertility control or female contraception comprising administering male fertility control or female Contraceptive effective amount of a compound of the invention as defined in the immediately preceding paragraph to a subject, preferably a mammal, particularly preferably a human.
  • the present invention relates to a method for treating GPCR-mediated disease states.
  • the method comprises the administration of at least one compound (I) according to the invention, as defined above, to a mammal, in particular a human, in which such treatment is required. Administration is usually in a pharmaceutically effective amount.
  • a pharmaceutically effective amount As already explained above in relation to the new compounds (I) according to the invention and the pharmaceutical compositions according to the invention, it is the specialist knowledge of a person skilled in the art to determine a pharmaceutically effective amount, depending on the special requirements of the individual case.
  • the compounds (I) according to the invention are preferably administered in a unit dose of 1 ⁇ g to 100 mg, particularly preferably from 1 ⁇ g to 10 mg and most preferably from 1 ⁇ g to 1 mg per body weight to be treated.
  • the preferred mode of administration is oral administration. It is also intended to administer one or more of the compounds (I) according to the invention in combination with at least one further active ingredient, as already explained above.
  • the present invention also relates to a method for inhibiting GnRH in a patient, comprising administering to a patient who has a pharmaceutically effective amount of a compound of the general formula (I) as defined above, but including the compounds excluded by name above such treatment is needed.
  • the method is preferably used in male fertility control, hormone therapy, female contraception, treatment of female sub- or infertility and tumor control.
  • the present invention also provides a process for the preparation of the novel tetrahydrocarbazole derivatives of the general formula (I) according to the invention.
  • the process for the preparation of the compounds of the general formula (I) according to the invention can be carried out in various ways, for example in the liquid phase or as partial or complete solid-phase synthesis.
  • a process for the preparation of the compounds of the general formula (I) according to the invention is preferably carried out as follows:
  • the central tetrahydrocarbazole skeleton is accessible through a known Fischer indole synthesis.
  • a suitably substituted and optionally protected cyclohexanone derivative is condensed with the respectively desired, also appropriately substituted and optionally protected phenylhydrazine derivative (e.g. according to Brjtten & Lockwood, JCS Perkinl 1914, 1824 or according to Maki et al., Chem. Ph rm.Bull. 1973, 21, 240).
  • the cyclohexanone skeleton is in the positions 3.3 ', 5.5' and 6.6 'by the radicals R a to R f and in the positions 4.4' by the radicals or, if appropriate, by precursors of the radicals R 6 and R 7 substituted.
  • the phenylhydrazine structure is optionally substituted by the radicals R z to R 5 .
  • Phenylhydrazine derivatives which are not commercially available can be prepared by methods known to the person skilled in the art.
  • positional isomers formed during the condensation of the cyclohexanone derivative and the phenylhydrazine derivative can be separated by chroraatographic methods such as HPLC.
  • the radical R 1 can be obtained by N-alkylation of the nitrogen atom in the 9-position with corresponding R ⁇ halides using base (for example according to Pecca & Albonico, J. Med Chem. 1977, 20, 487 or also according to Mooradian et al., J. Med Chem. 1970, 13, 327).
  • radicals R o and R 7 can, as already indicated above, be introduced in different ways depending on their type, which is explained in more detail below.
  • ⁇ -Aminocarboxylic acid structures in these residues are accessible by treatment of ketones with NH4 (CO) 3 and KCN under known Schotten-Baumann conditions and subsequent alkaline hydrolysis of the hydantoin formed (Britten & Lockwood, J.C ⁇ PerkinI 1974, 1824).
  • Amide residues are preferably generated using methods known per se from peptide chemistry.
  • the acid component with an activating reagent such as DCC or HATU ⁇ Tetrahedron L & tt. 1994, 35, 2279) activated and condensed with the amino component in the presence of a base such as DIPEA and / or DMAP.
  • Ester residues can be obtained under analogous conditions using the desired alcohols.
  • the solvent used here is preferably anhydrous.
  • Secondary or tertiary amine residues are obtained from primary amines either by nucleophilic substitution of alkyl halides or by reductive amination of aldehydes / ketones (e.g. J. Org. Chem. 1996, 61, 3849 or Synth. Comm, 1994, 609).
  • Sulfonamide residues are obtained from the corresponding amines by reaction with sulfonic acid chlorides.
  • Residues of urea are obtained if the amines are reacted with appropriate isocyanates.
  • Urethane residues can be produced by preactivating corresponding alcohols with carbonyldihydroxybenzotriazole ((HOBt) 2 CO) and then reacting them with amines (Warass et al., UPS 1998, 5, 125).
  • Alcohols are accessible from carboxylic acid esters by reduction with LiAl ⁇ .
  • Aldehyde residues are obtained from alcohol precursors by, for example, oxidizing with DMSO / oxalyl chloride under known Swern conditions (Pansavath et al., Synthesis 1998, 436),
  • Substituted amine residues are obtained by reductive amination of amines with aldehydes (J. Org. Chem. 1996, 61, 3849).
  • Ether residues can be obtained by deprotonating the alcohol precursor with a base such as NaH under known Williams conditions and then reacting it with an alkyl halide.
  • Double bonds in the radicals can be introduced by reacting an aldehyde or ketone precursor with corresponding phosphonylidene in accordance with Wittig conditions known per se.
  • a solid phase process for the preparation of compounds of the formula (I) according to the invention preferably comprises the steps (a) to (d) explained in more detail below:
  • Step (a) proceeds essentially analogously to a Fischer indole synthesis z, B. according to Britten & Lockwood, JCS Perkin 1 1914, 1824; Maki et al “Chem. Pharm. Bull. 1973, 21, 240 or Hutchins & Chapman, Tetrahedron Lett. 1996, 37, 4869 and comprises the condensation of a cyclohexanone derivative (IT) containing group G and anchored to a solid phase SP via a linker L suitable for forming the rest * 6.
  • I cyclohexanone derivative
  • the group G is the same as the R 7 radical, and in the event that the R 7 has another of the meanings given for R 7 in formula (I), the group G is a group -NH-Pg, where Pg is a protective group, with a phenylhydrazine derivative (III) substituted by R 2 to R 5
  • R a to R f are defined as indicated above in formula (1). Certain substituents or groups can optionally also be present in protected form, the protective groups being removed again at a suitable point in time during the synthesis by processes which are known per se.
  • the solid phase SP is, in particular, rinkamide resins (Rink, Tetrahedron Lett. 1989, 28, 3787), HMB resins (Sheppard et al., Int. 1 Peptide Protein Res. 1982, 20, 451), Wang resins (Lu et al., J. Org. Chem. 1981, 46, 3433) or chlorotrityl resins (Barlos et al, Int. J. Peptide Protein Res. 1991, 38, 562) if the cyclohexanone derivative (II) is to be anchored to the solid phase SP by means of an (amino) carboxylic acid.
  • the DHP-Li ker Liu & Elman, J. Org.
  • Chem. 1995, 60, 7712 can be used to anchor alcohol precursors of the cyclohexanone derivative (II); aromatic precursors of the cyclohexanone derivative (II) can be “traceless” Triazine resins (Bräse et al ,, Angew. Chem. Int. Ed. 1998, 37, 3413) can be anchored.
  • the protective group Pg which is optionally included in group G and which protects an -amino group -NH 2 is preferably an “Fmoc” (9-fluorenylmethoxycarbonyl) protective group, but can also be another common amino protective group, for example from the series of alkoxycarbonyl protective groups (such as, for example, the “Z” (benzyloxycarbonyl) - or the “Boc” (tert-butoxycarbonyl) group) or another suitable protective group, for example a “trityl” (triphenylmethyl) protective group.
  • Fmoc 9-fluorenylmethoxycarbonyl
  • Another suitable protective group for example a “trityl” (triphenylmethyl) protective group.
  • the linker L is such that after corresponding derivatization (steps (b) and (c)) and workup (step (d)) in the end product, the tetrahydrocarbazole derivative of the general formula (I), the desired R ⁇ with one of the above for R 6 indicated meanings results.
  • R 6 is equal to the group -CONR 8 R 9 .
  • a compound Pg-N (R ⁇ ) -R 9 ' -COOH which forms the linker L is first obtained by means of an activation reagent such as DCC (dicyciohexylcarbodiimide) or HATU (O- (7-azabenzotriazol-l-yl) -N, N-N ', N'-tetramethyluronium hexafluorophosphate) anchored to the solid phase SP via free amino groups of the SP, with Pg and SP the above Have meaning and R 9 ' forms part of the later radical R 9 .
  • an activation reagent such as DCC (dicyciohexylcarbodiimide) or HATU (O- (7-azabenzotriazol-l-yl) -N, N-N ', N'-tetramethyluronium hexafluorophosphate
  • the protective group Pg is then split off, for example in the case of an Fmoc protective group using piperidine DMF. from that results in a connection HR 8 NR 9 -CONH-SP.
  • the latter compound is now with a precursor of the cyclohexanone derivative (II), namely the cyclohexanone carboxylic acid (IT)
  • the linker L has the meaning -CONR 8 -R 9 ' -CONH-SP for the case just described. Any resulting isomers of any kind (enantiomers, diastereomers or positional isomers) can be separated in a known manner by means of HPLC, as at other points in the production process described.
  • step (a) takes place, i.e. the condensation of the cyclohexanone derivative ( ⁇ ) with the substituted phenylhydrazine derivative (HI) and, if appropriate, cleavage of the protective group Pg in group G by means of e.g. Piperidine (in the case of an Fmoc protective group), so that a free ⁇ -amino group is formed again at this point.
  • step ( b) finally derivatization of the now unprotected ⁇ -amino group of the resin-bound cyclohexanone derivative (II) takes place, so that the various alternative radicals R 7 defined above can be formed.
  • the procedure is as follows:
  • R 7 is the group -NHCOR 14
  • the reaction product from step (a) with a carboxylic acid R 14 COOH in the presence of an activation reagent such as DCC or HATU and in the presence of a base such as D ⁇ PEA (diisopropylethylamine) or DMAP (4-dimethylaminopyridine) implemented according to known methods for forming peptide bonds (see, for example, Tetrahedron Leu. 1994, 35, 2279; alternative (i)),
  • R 7 is a sulfonamide group -NHSO 2 R 14
  • a base such as e.g. implemented DMAP or DIPEA (see e.g. Gennari et al., E OC 1998, 2437; alternative (ii)).
  • R 7 is the group -NR 12 R 13 (where R 12 and R 13 are not simultaneously hydrogen atoms)
  • the radical R 12 is a hydrogen atom
  • a reducing agent such as NaH B (OAc) 3.
  • R 7 is the group -NHCONHR 14 (a urea derivative)
  • the reaction product from step (a) is reacted with an isocyanate R 14 NC0 (cf. Brown et al, J ⁇ CS 1997, 119, 288; alternative (iv )).
  • R 7 is a carbamate or urethane group -NHCOOR 14
  • the reaction product from step (a) is reacted with an alcohol H ⁇ R 14 preactivated by carbonyldihydroxybenzotriazole ((HOBt) 2 CO) (cf. Warass et al., LIPS 1998, 5, 125; Alternative (v)).
  • step (b) is omitted since no further derivatization is necessary (alternative (vi)).
  • step (c) also corresponds, i.e. the derivatization on the indole nitrogen atom, various alternatives, which are explained in more detail below:
  • step (b) deprotonation of the reaction product obtained in (b) takes place using a base such as e.g. NaH or NaHMDS and subsequent derivatization using a group R'X, where X is a leaving group, e.g. a halide atom, in particular a chloride atom, is taking place (cf. Collini & Ellingboe, Tetrahedron Leti. 1997, 8, 7963; Pecca & Albonico, J. Med. Chem. 1917, 20, 487 or Mooradian et al., J. Med Chem. 1970, 13, 327).
  • a base such as e.g. NaH or NaHMDS
  • R'X where X is a leaving group, e.g. a halide atom, in particular a chloride atom
  • step (b) For the case (vi) defined in step (b) above, ie if step (b) has been omitted, a deprotonation of the reaction product obtained in (a) by means of a base such as NaH or NaHMDS and a subsequent derivatization takes place analogously to that described above by means of a group K 1 X, where X is a leaving group, for example a halide atom, in particular a chloride atom.
  • a base such as NaH or NaHMDS
  • a subsequent derivatization takes place analogously to that described above by means of a group K 1 X, where X is a leaving group, for example a halide atom, in particular a chloride atom.
  • step (d) essentially comprises the cleavage of the reaction product obtained in (c) from the solid phase SP.
  • the cleavage of the reaction product obtained in (c) takes place with the help an acid, especially with TFA (trifluoroacetic acid) instead.
  • TFA trifluoroacetic acid
  • an aminolytic cleavage from an HMB resin ammonia in methanol, for example, is used as the cleavage reagent.
  • the desired product is then isolated in the usual way.
  • F oc-protected Rink amide resin (166 mg, loading 0.6 mmol / g) are in a vessel with a frit bottom with 1.5 ml DMF for 20 min. pre-swollen. After suction, 1.5 ml of 20% piperidine DMF are added and 5 min. touched. After suction, another 1.5 ml of 20% piperidine DMF are added and the mixture is stirred for 15 min. After suction, washing four times with DMF.
  • DHP resin 0.5 mmol DHP resin (0.5 g, loading density 1 mmol / g) are 15 min. pre-swollen in 2 ml dichloroethane. 2 ml of a solution of 0.75 M alcohol, 0.37 M pyridmium paratoluenesulfonate are added and the mixture is stirred at 80 ° C. for 16 h. After cooling to RT, 5 ml of pyridine are added, briefly shaken and suction filtered. It is washed twice with 5 ml of DMF, DCM and hexane.
  • HATU solution (0.267 M in DMF) and 150 ⁇ l NMM solution (2.4 M in DMF) and 0.01 mmol of DMAP are added to 0.1 mmol of resin-bound amino functions and the mixture is stirred at 40 ° C. for 4 h. After aspiration, the same reagents are added again and the mixture is stirred at 40 ° C. for 4 h. It is then suctioned off and washed four times with DMF.
  • the resin is washed twice with 2 ml DMF and DCE. 1 ml of 0.5 M sulfonic acid chloride in DCE and 400 ⁇ l of 2.5 are added to 0.1 mmol of resin-bound amine
  • the two enantiomers are separated by chiral HPLC.
  • 0.3 mmol (42.6 mg) 4-oxocyclohexane carboxylic acid are dissolved in 1 ml acetic acid and a suspension of 0.3 mmol (43.3 mg) phenylhydrazine hydrochloride and 0.3 mmol (40.0 mg) ZnCl 2 in 1 given ml of acetic acid. After stirring at 70 ° C. for 20 h, the mixture is diluted with 20 ml of water and extracted with ethyl acetate. The ethyl acetate phase is with water washed, dried over Na 2 SO 4 and evaporated to dryness, yield: 65.6 mg (100%) white solid.
  • the synthesis is carried out on a 0.2 mmol scale according to instructions A, I and O.
  • the synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, I and O.
  • the synthesis takes place on a 0.2 mmol scale according to the regulations D, F, G, F, G, I and O.
  • the synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, F, G, F, G and O.
  • the synthesis takes place on a 0.2 mmol scale according to the regulations A, F, G, F, G and O,
  • Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[(IS) -2-amino-2-oxo ⁇ 623 623.7499 1 - (phenylmethyl) ethyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[[(IS) -2-amino-2-oxo-1-SZ 623 623.7499
  • Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[[(IR) -2-amino-2-oxo Z ⁇ 610 609.7231 1 -phenylethyl] amino] carbonyl] -2 , 3,4,9-tetrahydro-1H-carba2 ⁇ l-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
  • the synthesis is carried out on a 0.2 mmol scale according to the regulations B, F, G, F, G, F, G and O.
  • the synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, F, G, F, G, F, G, F,
  • the synthesis takes place on a 0.2 mmol scale according to the regulations A, F, G, F, G, F, H and O.
  • the synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G and O.
  • the synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, F, G, F, G, F, G and O.
  • the synthesis is carried out on a 0.2 mmol scale in accordance with the instructions C, F, G, F, G, F, G and P.
  • the synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, F, G, F and O.
  • the synthesis is carried out on a 0.2 mmol scale according to the regulations D, F, G, F, G, F, H and O.
  • the synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, F, H and O.
  • the synthesis takes place on a 0.2 mmol scale according to the regulations B, F, G and O.
  • the synthesis is carried out on a 0.2 mmol scale according to the regulations B, F, G, F and O.
  • the synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, F, H and O.
  • the synthesis takes place on a 0.2 mmol scale according to the regulations A, F, G, I, F, G and O.
  • the synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, I, F, H and O.
  • the synthesis takes place on a 0.2 mmol scale according to the regulations A, F, G, I, F, G, F and
  • the synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, I, F, G, F, H and O.
  • the synthesis is carried out on a 0.2 mmol scale according to the instructions C, F, G, I, F, G and P.
  • the synthesis takes place on the 0.2 mmol scale in accordance with the regulations A, F, G, I, F, J and O.
  • the synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, I, F, L and O.
  • the synthesis takes place on a 0.2 mmol scale according to the regulations A, F, G, I, F, M and
  • the synthesis is carried out in 0.2 mmol scale according to the rules A, F, G, I, F, K, and O.
  • the synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, I, F, G, N and
  • the synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, I, F, H, N and O.
  • the mixture is allowed to come to RT and stirred for a further 1 hour.
  • Saturated NFL.C1 solution and n-hexane are carefully added to the organic phase and the mixture is stirred for 10 minutes.
  • the organic phase is separated and washed with water. After filtration through a Whatman filter, the mixture is evaporated to dryness.
  • Buserelin is purchased from Welding (Frankfurt / Main, Germany).
  • the compound is labeled with 125 I using the chloramine T method and Na 12 I (4000 Ci / mmol; Amersham-Buchler, Braunschweig, Germany).
  • the marked substance is purified by reverse phase HPLC on a Spherisorb ODS H column (250 x 4 mm, particle size 3 ⁇ m) by means of marriage with 50% acetonitrile / 0.15% trifluoroacetic acid at a flow rate of 0.5 ml / min.
  • the specific activity is 2000 Ci / mmol.
  • Alpha T3-1 cells (Bilezikjian et. Al., Mol Endocrinol 5 (1991), 347-355) are in DMEM medium (Gibco-BRL, Eggenstein-Leopoldshafen, Germany) with penicillin (100 IU / ml), streptomycin (0.1 mg / ml) and glutamine (0.01 mol 1) and 10% fetal calf serum (FCS PAA Laboratories, Coelbe, Germany) on plastic tissue culture plates (Nunc, 245 x 245 x 20 mm).
  • CHO-3-ZelIen (Schmid et al., J. Biol. Chem. 275 (2000), 9193-9200) are cultivated under identical conditions, except that Ha 's F12 medium (Gibco-BRL) is used ,
  • 10 confluent cell culture plates are rinsed twice with 50 ml of phosphate-buffered saline (PBS).
  • PBS phosphate-buffered saline
  • the cells are harvested by scraping with a rubber scraper in 5 ml of PBS and sedimented by centrifugation at 800 rpm for 10 min in a laboratory centrifuge (Heraeus).
  • the cell pellet is resuspended in 5 ml of 0.25 mol / 1 sucrose / 0.01 mol / 1 triethanolamine, pH 7.4.
  • the cells are lysed by freezing in dry ice / ethanol bath and thawing at room temperature for three cycles. The lysate is centrifuged at 900 rpm for 10 min and the sediment is discarded.
  • the supernatant is centrifuged at 18,000 rpm in a Sorvall SS34 rotor for 30 minutes.
  • the pellet (cell membranes) is suspended by pottem in 5 ml assay buffer (0.25 mol / 1 sucrose, 0.01 mol / 1 triethanolamine, pH 7.5, 1 mg / m) ovalbumin) and stored in 200 ⁇ l aliquots at -20 ° C. Protein determination is carried out using the Bradford method (Anal. Biochem, 72: 248-254 (1976).
  • Binding tests for competition curves are carried out as triplicates.
  • a test sample contains 60 ⁇ l cell membrane suspension (10 ⁇ g protein for ⁇ T3-1 cells or 40 ⁇ g protein for CH03 lines), 20 ⁇ l 125 I labeled buserelin (100,000 Ipm per sample for competition curves and between 1,500 and 200,000 Ipm for saturation experiments) and 20 ⁇ l TestpufFer or test connection solution.
  • the test compounds are dissolved in distilled water or 50% ethanol. Serial dilutions (5 x 10 "* mol / 1 to 5 x 10 " 12 mol / 1) are made in test buffer. The non-specific binding is determined in the presence of an excess of unlabeled buserelin IG 6 mol / 1).
  • test samples are incubated for 30 min at room temperature. Bound and free ligand are separated by filtration (Whatman GF / C filter 2.5 cm diameter) using an Amicon 10x collecting device and washed twice with 5 ml 0.02 mol / 1 Tris / HCl, pH 7.4. The filters are moistened with 0.3% polyethyleneimine (Serva; Heidelberg, Germany) for 30 min in order to reduce the non-specific binding. The radioactivity retained by the filters is determined in a 5-channel gamma counter (Wallac-LKB 1470 Wizard) ,
  • Chemicals are obtained from commercial sources in the highest degree of purity available.
  • Transferred LTK " cells are in DMEM medium (Invitrogen Life Technologies, Germany) with penicillin (1001.U./ml), streptomycin (0.1 mg / ml) and giutamine (0.01 mol 1) and 10% fetal calf serum (FCS; Invitrogen Life Technologies, Germany) on plastic tissue culture plates (Nunc, Germany, 245 x 245 x 20 mm).
  • 80% confluent cell culture plates are washed twice with 50 ml of phosphate-buffered saline (PBS) and then removed with 0.01M EDTA solution.
  • the cells are pelleted by centrifugation at 200xg for 5 min in a laboratory centrifuge (Kendro, Germany).
  • the cell pellet is resuspended in 3 ml binding medium (DMEM; lOmM Hepes; 0.5% BSA; 0.1% NaN 3 ; lg / 1 bacitracin (add fresh, stick 100x); O.lg / 1 SBTI (add fresh, stick lOOOx) and determine the cell number by means of trypan blue staining in a Neubauer counting chamber.
  • the cell suspension is adjusted to a concentration of 5x10 5 Z / 0.05 ml with binding medium.
  • Binding tests for competition curves are carried out as duplicates.
  • the test substances are used as 10mm DMSO solutions. They are diluted to 4 times the final concentration with binding medium. 25 ⁇ l of the substance dilution are mixed with 25 ⁇ l tracer solution ( I2 ⁇ I-triptorelin). The concentration of tracer is set to approximately SOOOOcpm (measured in the Cobra H, ⁇ -counter, PE Liefe Science, Germany) in the final reaction volume of 100 ⁇ l. 200 ⁇ l silicone / Pa af ⁇ nöl mixture (84%: 16%) are placed in 650 ⁇ l pointed bottom tubes (Roth, Germany). 50 ⁇ l of the cell suspension are pipetted onto it, followed by 50 ⁇ l of the test substance / tracer mixture.
  • the tubes are closed and incubated for 60 min at 37 ° C. in an incubator overhead. After incubation, the samples are centrifuged in a centrifuge (Kendro, Germany) at 900 rpm and then snap frozen in liquid N. The tip with the cell pellet is cut off and transferred to prepared counting tubes (Roth, Germany). The remaining pointed bottom tube with the remaining supernatant is also transferred to a counting tube. The measurement takes place in the ⁇ -counter for 1min / sample.
  • Stable transfected, GnRH receptor-bearing LTK cells (ATCC No. CCL-1.3), with heterologous expression of cAMP responsive elements and a CMV minimal promoter-driven lucäferase reporter gene are used for the Durcl-conducting functional tests.
  • the cells are in DMEM medium (Invitrogen Life Technologies, Germany) with penicillin (1001.U./ml), streptomycin (0.1 mg ml) and glutamine (0.01 mol / l) and 10% fetal calf serum (FCS ; Invitrogen Life Technologies, Germany) cultivated on plastic tissue culture plates (Nunc, Germany, 245 x 245 x 20 mm).
  • 80% confluent cell culture plates are washed twice with 50 ml of phosphate-buffered saline (PBS) and then removed with trypsin EDTA solution (Invitrogen Life Technologies, Germany). The cells are pelleted by centrifuge at 200xg for 5min in a laboratory centrifuge (Kendro, Germany).
  • PBS phosphate-buffered saline
  • trypsin EDTA solution Invitrogen Life Technologies, Germany.
  • the cells are pelleted by centrifuge at 200xg for 5min in a laboratory centrifuge (Kendro, Germany).
  • the cell pellet is in 3 ml assay medium (Invitrogen Life Technologies, Germany) with penicillin (100 IU / l), streptomycin (0.1 rag ml) and glutamine (0.01 mol / l) and 10% fetal calf serum (FCS; Invitrogen Life Technolgies, Germany) and the cell count was determined by trypan blue staining in a Neubauer counting chamber.
  • the cell suspension is adjusted to a concentration of 1 ⁇ 10 4 Z / 100 ⁇ l with assay medium.
  • the cells are exposed on white 96-well microtiter plates (Costar, Germany) and incubated for 18 hours in the incubator.
  • test substances are diluted as 10 mm DMSO solutions in assay medium to 6 times the final concentration used. 25 ⁇ l of the test substance are added to 100 ⁇ l cells and incubated for 60 min at 37 ° C., 5% CO 2 . This is followed by the addition of triptorelin (D-Trp6-GnRH) / Rolipram solution (6nM / 6 ⁇ M) and a new incubation for 6h at 37 ° C, 5% CO 2 .
  • triptorelin D-Trp6-GnRH
  • Rolipram solution 6nM / 6 ⁇ M
  • lysis / detection buffer (LucLite, PE Life Science) is added and the measurement is carried out in the Lumistar Luminometer (BMG Labtechnologies GmbH, Germany),
  • the samples are evaluated after calculation of the inhibition compared to untreated stimulated cells, after subtracting the non-stimulated control, using GraphPad Prism (GraphPad Software, Inc., USA) or alternatively using OMMM (Accelrys, Germany) software.

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Abstract

La présente invention concerne de nouveaux dérivés tétrahydrocarbazol servant de ligands de récepteurs couplés aux protéines G (GPCR), notamment d'antagonistes de gonadolibérine (GnRH). L'invention concerne également une composition pharmaceutique contenant ces nouveaux dérivés tétrahydrocarbazol ainsi qu'un procédé de fabrication de ceux-ci. L'invention concerne par ailleurs l'administration de dérivés tétrahydrocarbazol pour le traitement de troubles à médiation par GPCR, notamment pour l'inhibition de GnRH, à des mammifères, notamment des humains, nécessitant un tel traitement, ainsi que l'utilisation de dérivés tétrahydrocarbazol pour la fabrication d'un agent pharmaceutique destiné au traitement de troubles à médiation par GPCR, notamment à l'inhibition de GnRH.
EP02796648A 2001-12-14 2002-12-16 Derives tetrahydrocarbazol servant de ligands de recepteurs couples aux proteines g (gpcr) Withdrawn EP1453803A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE10164564A DE10164564B4 (de) 2001-12-14 2001-12-14 Tetrahydrocarbazolderivate als Liganden für G-Protein gekoppelte Rezeptoren (GPCR)
DE10164564 2001-12-14
US34187801P 2001-12-21 2001-12-21
US341878P 2001-12-21
PCT/EP2002/014344 WO2003051837A2 (fr) 2001-12-14 2002-12-16 Derives tetrahydrocarbazol servant de ligands de recepteurs couples aux proteines g (gpcr)

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EP1453803A2 true EP1453803A2 (fr) 2004-09-08

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EP02796648A Withdrawn EP1453803A2 (fr) 2001-12-14 2002-12-16 Derives tetrahydrocarbazol servant de ligands de recepteurs couples aux proteines g (gpcr)

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Country Link
EP (1) EP1453803A2 (fr)
JP (1) JP2005518375A (fr)
CN (1) CN100500654C (fr)
AR (1) AR037863A1 (fr)
AU (1) AU2002361430B2 (fr)
BR (1) BR0214958A (fr)
CA (1) CA2468880A1 (fr)
HR (1) HRP20040609A2 (fr)
HU (1) HUP0500014A3 (fr)
IL (2) IL161626A0 (fr)
MX (1) MXPA04005768A (fr)
NO (1) NO326692B1 (fr)
NZ (1) NZ533430A (fr)
PL (1) PL373400A1 (fr)
RU (1) RU2319692C2 (fr)
TW (1) TWI246423B (fr)
WO (1) WO2003051837A2 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1787817B (zh) * 2003-05-19 2011-09-07 Irm责任有限公司 免疫抑制剂化合物及组合物
EP1654228B1 (fr) * 2003-06-10 2008-10-22 Smithkline Beecham Corporation Derives de tetrahydrocarbazole et leur utilisation pharmaceutique
EP1677794B1 (fr) * 2003-09-12 2014-12-03 Elixir Pharmaceuticals, Inc. Procedes de traitement de troubles
US20060074124A1 (en) * 2003-09-12 2006-04-06 Andrew Napper Methods of treating a disorder
NZ549396A (en) * 2004-03-26 2010-04-30 Hoffmann La Roche Tetrahydrocarbazoles and derivatives
RU2430088C2 (ru) * 2004-07-14 2011-09-27 Центарис Гмбх Производные тетрагидрокарбазола и фармацевтическая композиция на их основе
DE102004033902A1 (de) 2004-07-14 2006-02-16 Zentaris Gmbh Neue Tetrahydrocarbazolderivate mit verbesserter biologischer Wirkung und verbesserter Löslichkeit als Liganden für G-Protein gekoppelte Rezeptoren (GPCR's)
ES2369782T3 (es) * 2004-12-27 2011-12-05 Actelion Pharmaceuticals Ltd. Derivados de 2,3,4,9-tetrahidro-1h-carbazol como antagonistas del receptor crth2.
MX2007015905A (es) * 2005-06-24 2008-03-06 Lilly Co Eli Derivados de tetrahidrocarbazol utiles como moduladores de receptor de androgeno (sarm).
MY147588A (en) * 2006-08-07 2012-12-31 Actelion Pharmaceuticals Ltd (3-amino-1,2,3,4-tetrahydro-9h-carbazol-9-yl)-acetic acid derivatives
EP1967202A1 (fr) * 2007-03-05 2008-09-10 AEterna Zentaris GmbH Utilisation d'antagonistes LHTH pour le traitement des symptômes de tractus urinaires faibles, en particulier la vessie hyperactive et/ou hyperactivité du détrusor
EP1988098A1 (fr) * 2007-04-27 2008-11-05 AEterna Zentaris GmbH Nouveaux dérivés de tétrahydrocarbazole en tant que ligands de récepteurs couplés à la protéine G
EP2095818A1 (fr) * 2008-02-29 2009-09-02 AEterna Zentaris GmbH Utilisation d'antagonistes LHRH dans des doses n'impliquant pas de castration
CA2790139C (fr) 2010-03-22 2018-03-13 Actelion Pharmaceuticals Ltd Derives de 3-(heteroarylamino)-1,2,3,4-tetrahydro-9h-carbazole et leur utilisation comme modulateurs du recepteur de la prostaglandine d2
JP5964945B2 (ja) 2011-04-14 2016-08-03 アクテリオン ファーマシューティカルズ リミテッドＡｃｔｅｌｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ ７−（ヘテロアリ−ル−アミノ）−６，７，８，９−テトラヒドロピリド［１，２−ａ］インド−ル酢酸誘導体及びプロスタグランジンＤ２受容体調節剤としてのそれらの使用
CA2939892C (fr) 2014-03-17 2020-03-31 Idorsia Pharmaceuticals Ltd Derives d'acide aza-indol-acetique et leur utilisation comme modulateurs des recepteurs de la prostaglandine d2
CN106103437A (zh) 2014-03-18 2016-11-09 埃科特莱茵药品有限公司 氮杂吲哚乙酸衍生物及其作为前列腺素d2受体调节剂的用途
CN108026093B (zh) 2015-09-15 2021-11-16 爱杜西亚药品有限公司 结晶形式

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BG25793A3 (bg) * 1973-07-18 1978-12-12 Schering Aktiengesellschaft Метод за получаване на карбазолови деривати
DE3786030T2 (de) * 1986-03-27 1993-12-02 Merck Frosst Canada Inc Tetrahydrocarbazole Ester.
US5607939A (en) * 1994-04-28 1997-03-04 Takeda Chemical Industries, Ltd. Condensed heterocyclic compounds, their production and use
CA2292881A1 (fr) * 1997-06-05 1998-12-10 Merck & Co., Inc. Antagonistes de gonadoliberine

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IL161626A0 (en) 2004-09-27
CA2468880A1 (fr) 2003-06-26
HUP0500014A3 (en) 2010-06-28
WO2003051837A3 (fr) 2004-02-26
RU2319692C2 (ru) 2008-03-20
HRP20040609A2 (en) 2005-06-30
HUP0500014A2 (hu) 2005-04-28
WO2003051837A2 (fr) 2003-06-26
MXPA04005768A (es) 2004-09-10
IL192991A0 (en) 2011-08-01
NO326692B1 (no) 2009-02-02
TWI246423B (en) 2006-01-01
RU2004121776A (ru) 2005-05-10
BR0214958A (pt) 2004-12-28
CN100500654C (zh) 2009-06-17
TW200305405A (en) 2003-11-01
AU2002361430B2 (en) 2007-09-13
JP2005518375A (ja) 2005-06-23
NO20042198L (no) 2004-07-09
NZ533430A (en) 2005-12-23
AU2002361430A1 (en) 2003-06-30
PL373400A1 (en) 2005-08-22
CN1599720A (zh) 2005-03-23
WO2003051837A8 (fr) 2004-05-06
AR037863A1 (es) 2004-12-09

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