RU2430088C2 - Tetrahydrocarbazole derivatives and pharmaceutical composition based on said derivatives - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: disclosed compounds act specifically through antagonistic inhibition of the LHRH receptor. The invention also relates to medicinal agents containing at least one novel compound as an active component. The medicinal agents are suitable particularly for use as measured peroral drug formulations for mammals, particularly humans.

EFFECT: novel tetrahydrocarbazole derivatives have improved properties and can be used as GPCR receptor inhibitors.

23 cl, 11 dwg, 9 tbl, 15 ex

Description

FIELD OF THE INVENTION

The present invention relates to new tetrahydrocarbazole derivatives having improved biological effect, improved oral bioavailability and improved metabolic stability, as ligands for G-protein coupled receptors (GPCR), especially as ligands for luteinizing hormone releasing hormone releasing factor receptor (LHRH-) receptor), their preparation and their use in pharmaceutical compositions for the treatment of pathological conditions mediated by G protein-coupled receptors in mammals, etc. zhde all humans.

State of the art

The content of all publications or comparable sources cited in this application to clarify the rationale of the present invention is included in this application with the aim of more fully disclosing the subject of this invention.

G-protein coupled receptors are a family of receptors associated with cell membranes that play an important role in numerous biochemical and pathobiochemical processes in mammals and, in particular, in humans. All GPCRs consist of seven hydrophobic transmembrane alpha helices that are joined together by three intracellular and three extracellular loops and have an extracellular amino-terminal fragment and an intracellular carboxy-terminal fragment. One or more heterotrimeric G proteins are involved in cellular signal transduction. They mediate and control various physiological stimuli, such as photosensitivity, taste and smell, as well as fundamental processes, such as metabolism, reproduction and development. There are GPCRs for exogenous and endogenous ligands. Peptide hormones, biogenic amines, amino acids, nucleotides, lipids, Ca ²⁺ and photons, among others, have been identified as ligands, in addition, one ligand can activate various receptors.

According to a recent study, 367 sequences were detected in the human genome for G-protein coupled receptors (GPCR) with endogenous ligands, D.K. Vassilatis et al., PNAS 100 (8), 4903-4908 (2003). 284 of them belong to class A, 50 to class B, 17 to class C and 11 to class F / S. Examples belonging to class A are bombesin, dopamine and LHRH receptors, to class B are VIP and calcitonin receptors. Natural ligands for numerous GPCRs are still unknown.

Due to their function, GPCRs are suitable targets for drugs intended for the treatment and prevention of a large number of pathological conditions. It is estimated that about 50% of the currently known targets for active components are GPCR [Y. Fang et al., DDT 8 (16), 755-761 (2003)]. So, GPCRs play an important role in pathological processes, such as, for example, pain (opioid receptor), asthma (β ₂ -adrenergic receptor), migraine (serotonin 5-HT1B / 1D receptor), cancer (1-LHRH receptor), cardiovascular disorders (angiotensin receptor), metabolic disorders (GHS receptor) or depression (serotonin 5-HT1a receptor), KLPierce et al., Nat. Rev. Mol. Cell Biol. 3, 639-650 (2002).

General information about GPCR is available at http://www.gpcr.org.

The present invention describes new ligands with improved properties for GPCR in General, while the compounds of this invention act in particular as antagonists of the LHRH receptor.

The natural ligand for this receptor, the peptide hormone LHRH, is synthesized in hypothalamic cells and is pulsedly released from the hypothalamic neurons into the capillary plexus of ementia mediana. In the anterior pituitary gland, LHRH binds to the LHRH receptor of gonadotropic cells and stimulates certain trimeric G-proteins that initiate a branched signal transduction cascade. The initial event is the activation of phospholipase C, A ₂ and / or D. This leads to increased production of secondary messengers diacylglycerol and IP ₃ , followed by the mobilization of Ca ²⁺ from the intercellular pools and the activation of various dependent protein kinases. Finally, stimulation of the production and release of gonadotropins FSH and LH occurs at certain time intervals. These two hormones are transported through the bloodstream to the target organs, respectively the testes or ovaries. There they stimulate the production and release of the corresponding sex hormones. There is a complex feedback mechanism through which the concentration of sex hormones formed, in turn, regulates the production of LH and FSH.

In the male body, LH binds to the membrane receptors of Leydig cells and stimulates the biosynthesis of testosterone. FSH acts through specific receptors on Sertoli cells and is involved in sperm production. In the female body, LH binds to the LH receptors of theca cells and activates the formation of androgen-synthesizing enzymes. FSH stimulates the proliferation of granulosa cells of certain follicular stages through their FSH receptors. Formed androgens are converted in neighboring granulosa cells into estrogens estrone and estradiol.

Many disorders, the hallmarks of which are benign or malignant proliferation of tissues, depend on stimulation by sex hormones such as testosterone or estradiol. Typical disorders of this type are prostate cancer and benign prostatic hyperplasia (BPH) in men and endometriosis, uterine fibrosis or uterine fibroids, precocious puberty, hirsutism and polycystic ovary syndrome, as well as breast cancer, uterine cancer, endometrial cancer, cervical cancer and ovarian cancer in women.

Since their discovery in 1971, Serially et al. Science 173, 1036-1038 (1971), more than 3,000 synthetic analogues of natural LHRH were synthesized and tested. Peptide agonists, such as triptorelin and levprolide, have been successfully used for many years in the treatment of gynecological disorders and cancer. However, a common disadvantage of agonists is that they stimulate LHRH receptors in the initial stage of use and, thus, lead to side effects due to the initial increase in the level of sex homons. Only after downregulation of the LHRH receptor as a result of this re-stimulation can supergonists show their effect. This leads to a complete decrease in the level of sex hormones and, thus, to pharmacological castration with all the signs and symptoms. This disadvantage is associated with the impossibility of targeted regulation of the level of sex hormones through dosage. Thus, for diseases that do not require a total decrease in the level of sex hormones to the level of castration, such as, for example, benign tissue neoplasms, agonist therapy is not optimal for the patient.

This led to the development of petid antagonists of LHRH receptors, among which, for example, cetrorelix (Cetrotide ™) was successfully used for controlled stimulation of the ovaries in the context of the treatment of female infertility. These antagonists inhibit LHRH receptors immediately and depending on the dosage, and thus lead to an immediate decrease in plasma testosterone or estradiol and progesterone levels. However, peptide antagonists are somewhat less active than agonists, and therefore should be used at higher dosages.

A review of the clinical applications and potential of LHRH agonists and antagonists was made by R.P. Millar et al. at British Med. Bull. 56, 761-772 (2000), R. E. Felberbaum et al., Mol. Cell. Endocrinology 166, 9-14 (2000) and F. Haviv et al. in Itegration of Pharmaceutical Discovery and Development Case Studies, Chapter 7, ed. Borchardt et al., Plenum Press, New York (1998). In addition to the treatment of malignant and benign neoplasms, other possible applications are controlled ovarian stimulation in the context of in vitro conception, conception control (contraception), protection against unwanted side effects from radio and chemotherapy, treatment of HIV infections (AIDS), as well as neurological or neurodegenerative disorders such as Alzheimer's disease. Specific LHRH receptors were found not only in the pituitary cells, but also in the cells of various tumors, such as the chest and ovaries. These receptors can mediate the direct antiproliferative effect of LHRH receptor antagonists on tumors.

Peptide agonists and antagonists of LHRH receptors are mostly decapeptides whose bioavailability is insufficient for oral administration. They are usually given as injectable or topical solutions, subcutaneously or intramuscularly. Such use is associated with inconvenience to the patient, and may cause disagreement. In addition, the synthesis of decapeptides is complex and expensive.

Therefore, it is advisable to look for non-peptide antagonists for LHRH receptors, which, in addition to high activity, have improved metabolic stability and can be used orally.

Compared to peptide agonists and antagonists of the LHRH receptor, so far not a single non-polypeptide compound has been approved and is not in clinical use for any of the possible indications. The current state of development in the field of agonists and antagonists of the LHRH receptor is described in reviews of Y.-F. Zhu et al., Expert Opin. Therap. Patents 14 (2), 187-199 (2004), Y.-F. Zhu et al., Ann. Rep. Med. Chem. (39), 99-110 (2004), F.C. Tucci et al., Curr. Opin. Drug Discovery & Development 7 (6), 832-847 (2004), R.E. Armer, Curr. Med. Chem. 11, 3017-3028 (2004) and M.V. Chengalvala et al., Curr. Med. Chem. Anti-Cancer Agents, 3, 399-410 (2003).

The first of these publications contains a comprehensive list of published patent specifications describing the synthesis and use of low molecular weight LHRH receptor antagonists.

Among the first examples of non-peptide antagonists of the LHRH receptor is the 4-oxothieno [2,3-b] pyridine structure, which has been described by N. Cho et al. in J. Med. Chem. 41, 4190-4195 (1998). Although these compounds, such as, for example, T-98745, have a high affinity for the receptor, their solubility in water is very small and their bioavailability is low. Based on this active structure, numerous further studies have been carried out, examples of publications in international applications WO 95/28405, WO 96/24597, WO 97/14697 and WO 97/41126 can be mentioned. The synthesis of thieno [2,3-d] pyrimidin-2,4-dione as oral antagonists is described by S. Sasaki et al., In J. Med. Chem. 46, 113-124 (2003).

The new 1-arylmethyl-5-aryl-6-methyluracils are described by Z. Guo et al., In J. Med. Chem. 47, 1259-1271 (2004). The preparation of N - [(hetero) arylmethyl] benzenesulfonamides as potential non-peptide antagonists of the LHRH receptor is described in WO 03/078398. Patent Application WO 02/11732 describes tricyclic pyrrolidines as antagonists of the LHRH receptor. Substituted pyridin-4-ones as antagonists of the LHRH receptor are described in WO 03/13528, and substituted 1,3,5-triazino-2,4,6-trions in WO 03/11839.

The synthesis and biological activity of erythromycin A derivatives having LHRH receptor antagonist activity are described by J. T. Randolph et al. in J. Med. Chem. 47 (5), 1085-1097 (2004). Separate derivatives show oral activity at the LH level in castrated rat models.

Quinoline derivatives as non-peptide antagonists of the LHRH receptor are disclosed, for example, in WO 97/14682. Substituted 2-arylindoles are described, inter alia, in WO 97/21435, WO 97/21703, WO 98/55116, WO 98/55470, WO 98/55479, WO 99/21553, WO 00/04013 as antagonists of the LHRH receptor. Useful biological or biophysical data for these compounds are not disclosed.

Patent EP 0679642 B1 describes conjugated heterocyclic compounds as antagonists of the LHRH receptor. The basic tetrahydrocarbazole structure, however, is not the subject of the discovery described there.

1,2,3,4-Tetrahydrocarbazole carboxylic acids are described in patent EP 0239306 B1 as a prostaglandin antagonist. The antagonistic effect on the LHRH receptor is not described and is not obvious. US Pat. No. 3,970,757 describes tetrahydrocarbazole derivatives as gastric antisecretory agents. However, the antagonistic effect on the LHRH receptor in these structures is not described and is not obvious. EP 603432 B1 and US Pat. No. 5,708,187 describe tetrahydrocarbazole derivatives as 5-HT1 agonists, inter alia, for the treatment of migraine. However, the antagonistic effect on the LHRH receptor is not described and is not obvious. WO 2005/033099 A2 describes tetrahydrocarbazole derivatives as dipeptidyl peptidase IV inhibitors. However, the antagonistic effect on the LHRH receptor is not described and is not obvious. There is no reference to the antagonistic effect of the LHRH receptor, and the structures described are different from the compounds of the present invention. DJ Davies et al. described in article J. Med. Chem. 41, 451-467 (1998) tetrahydrocarbazole derivatives having melatonin agonistic or antagonistic effect. However, the antagonistic effect on the LHRH receptor is not described and is not obvious. Derivatives of tetrahydrocarbazole are described by SJ Shuttleworth et al. in the Bioorg article. Med. Chem. Lett. 14, 3037-3042 (2004) as partial agonists of the neuromedin B receptor. However, the antagonistic effect of the LHRH receptor is not described and is not obvious. R. Millet et al. describes, in Letters in Peptide Science 6, 221-233 (1999), tetrahydrocarbazole derivatives as NK ₁ / NK ₂ ligands. The structures described there are different from the compounds of the present invention. Moreover, the antagonistic effect on the LHRH receptor is not described and is not obvious. A description of the solid-phase synthesis of 3-amino-3'-carboxytetrahydrocarbazoles is available in Koppitz et al., THL 46 (6), 911 -914 (2005). The antagonistic effect on the LHRH receptor is not described and is not obvious.

Derivatives of tetrahydrocarbazole as peptidomimetics of LHRH receptor antagonists having good affinity for the receptor are described, for example, in patent WO 03/051837 (DE 10164564 A1). The physicochemical and metabolic properties of these compounds, however, do not make them optimally suitable for the oral dosage form.

Many publications provide an overview of the developmental status of neurokinin antagonists. G. Giardina et al. in the article IDrugs 6 (8), 758-772 (2003) provides an overview of the current patent literature. V. Leroy et al., Expert Opinion on Investigational Drugs 9 (4), 735-746 (2000), and C. Swain et al., Annual Reports in Medicinal Chemistry 34, 51-60 (1999) describe the developmental status with respect to antagonists neurokinin receptors, while, for example, RMNavari et al. Cancer Investigation article 22 (4) 569-576 (2004) describes the results of clinical trials in which NK ₁ receptor antagonists have been used to control chemotherapy-induced vomiting. RGHill et al. describes in Pain, 523-530 (2003) antagonists of the neurokinin receptor as potential analgesics, while A. von Sprecher et al. in IDrugs 1 (1), 73-91 (1998) describes neurokinin receptor antagonists as potentially active components in the treatment of inflammation and rheumatoid arthritis. R. Millet et al. describes, in Letters in Peptide Science 6, 221-233 (1999), tetrahydrocarbazole derivatives as MK ₁ / NK ligands. ₂ . The structures described there are different from the compounds described in the present invention.

Disclosure of invention

The present invention is the development of new compounds with improved oral bioavailability and improved metabolic stability, which can be used to treat pathological conditions mediated by GPCR in mammals and, in particular, in humans. The new compounds are preferably intended to exhibit biological activity by inhibiting the LHRH receptor. The new compounds are intended to achieve the desired effect in dosages that are acceptable for use and the effect of which depends on the dosage when administered orally. This requires that the new compounds be applicable as pharmacologically active components in drugs for mammals or humans. The purpose of the invention is achieved with the help of new improved tetrahydrocarbazole derivatives of the general formula (I) below.

The implementation of the invention

A first aspect of the present invention relates to novel tetrahydrocarbazole derivatives of the general formula (I):

wherein:

X ₁ means S or O,

X ₂ and X ₃ independently of one another mean O or geminally attached H ₂ ,

R1 and R2 are independently selected from the group consisting of a hydrogen atom, aryl, alkyl and arylalkyl radicals, which may be substituted in the alkyl or aryl group with up to 3 substituents independently selected from the group consisting of halogen atoms , —CN and —O-alkyl groups, where R1 and R2 are both primarily hydrogen atoms,

R3 is an alkyl, arylalkyl, or heteroarylalkyl radical, which are optionally substituted with up to 3 substituents independently selected from the group consisting of halogen atoms, —CN, —CO — O — R12, —CO — NR12R12 ′, - OH, -O-R13, -OCO-R13, -O-SO ₂ -OR12, -O-SO ₂ -R12, -SO ₂ -OR12, -SO-R12, -OPO (OR12) (OR12 '), - O-PO (NR12R12 ') 2, -O-CO-O-R13, -O-СО-NR12R12', -O-CS-NR12R12 ', -S-R12, -NR12R12', -NH-CO-R13, -NH-SO ₂ -R12, -NH-CO-OR13, -NH-CO-NHR12, -NH-C (NH) -NH ₂ ,

R4, R5, R6 and R7 are independently selected from the group consisting of a hydrogen atom, halogen atoms, —CN, —CONH ₂ , —COOH, —CF ₃ , —O-alkyl, —OCF ₃ , —NO ₂ groups and alkyl, arylalkyl and heteroarylalkyl radicals;

R9 is a hydrogen atom, an alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl radical, preferably a hydrogen atom;

R10 is a hydrogen atom or a radical —R11, —CO — R11, —CO — OR11, —CO — NHR11, —C (NH) —NHR11, —SO ₂ —R11, or —SO ₂ —NHR11;

R11 is an alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl radical which may be substituted with one or more substituents independently selected from the group consisting of halogen atoms, —CN, alkyl, —CF ₃ , —OCF ₃ groups , -OH, -O-alkyl and -O- (CH ₂ CH ₂ -O) _n -CH ₃ ;

R8 is —C ₁ -C ₆ alkylaryl or —C ₁ -C ₆ alkyl heteroaryl, wherein the aryl or heteroaryl group is substituted with up to three substituents, for example, one, two, or three, but preferably one, independently selected from the group consisting of from the groups —O— (CH ₂ CH ₂ —O) _n —CH ₃ , —O — CO — R12, —O — CO— (CH ₂ CH ₂ —O) _n —CH ₃ , —O — SO ₂ —OR12 , -O-SO ₂ -R12, -O-PO (OR12) (OR12 '), -O-PO (NR12R12') 2, -O-CO-OR13, -O-CO-NR12R12 'and -O-CS -NR12R12 ', or,

if at least

(i) X ₁ means S, or

(ii) R10 is not a hydrogen atom, and R11 is an arylalkyl or heteroarylalkyl radical which are substituted in the aryl or heteroaryl group with one or more substituents, preferably one, two or three substituents, independently selected from the group consisting of halogen atoms, groups -CN, -alkyl, -CF ₃ , -OCF ₃ , -OH, -O-alkyl and -O- (CH ₂ CH ₂ -O) _n -CH ₃ ,

R8 also takes the values indicated for R3;

R12 and R12 'independently of one another represent a hydrogen atom or an alkyl, arylalkyl, aryl, heteroarylalkyl or heteroaryl radical, preferably hydrogen,

R13 is selected from alkyl, arylalkyl, heteroarylalkyl or heteroaryl radicals, or the group - (CH ₂ CH ₂ —O) _n —CH ₃ , and

n is any integer from 1 to 10, preferably from 1 to 6.

The terms indicated for the interpretation of compounds corresponding to the general formula (I) always, unless otherwise indicated in the description or the claims, have the following meanings:

the term “substituted” means that the corresponding radical or group has one or more substituents. If the radical has several substituents, and a selection of different substituents is defined, the substituents are selected independently from each other and are not necessarily identical. The term “unsubstituted” means that the corresponding group has no substituents. The term “optionally substituted” means that the corresponding group is either unsubstituted or substituted with one or more substituents. The term “substituted with substituents in an amount of up to 3” means that the corresponding radical or group is substituted with either one, two, or three substituents.

The term “halogen atom” or “halogen substituent” (Hal-) refers to one and, where applicable, several atoms of fluorine (F, fluorine), bromine (Br, bromine), chlorine (Cl, chloro), or iodine (I, iodine-). The designations “dihalogen”, “trihalogen” and “perhalogen” refer to two, three or four substituents, respectively, where each substituent can be independently selected from the group consisting of fluorine, chlorine, bromine and iodine. “Halogen” preferably means a fluorine or chlorine atom.

The term “alkyl” includes, in the context of the present invention, acyclic saturated or partially unsaturated hydrocarbons having C ₁ -C ₁₂ carbon atoms, which may be linear or branched. The term “alkyl” preferably means alkyl chains of from 1 to 8, particularly preferably from 1 to 6 carbon atoms. Examples of suitable alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, 2- or 3-methylpentyl, n-hexyl, n-heptyl , n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, propenyl, butenyl, pentenyl, hexenyl and octadienyl. The term “alkyl” also means saturated or partially unsaturated cycloalkyl radicals, preferably from the group of cyclo (C ₃ -C ₈ ) alkyl. Examples of suitable cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl, cyclopentenyl, cyclooctadienyl and others. In addition, the term “alkyl” includes cycloalkylalkyl groups, with preference for cyclo (C ₃ -C ₈ ) alkyl (C ₁ -C ₄ ) alkyl radicals. Examples thereof are cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl, cyclohexenylethyl. Thus, the term C ₁ -C ₄ alkyl covers at least the following groups: methyl, ethyl, n-propyl, isopropyl, propenyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl, cyclopropylmethyl, and butenyl. Most preferred as C ₁ -C ₄ alkyls are isopropyl, sec-butyl, and cyclopropylmethyl.

Such an alkyl radical may be unsubstituted, as well as mono- or polysubstituted, where the substituents may be identical or different and be linked at each or more than one desired and possible position of the alkyl. In the case of mono- or polyhalogen-substituted alkyl radicals, substitution with fluorine and / or chlorine atoms is preferred. Examples of such radicals are fluoromethyl, trifluoromethyl and pentafluoroethyl.

"Aryl" corresponds to aromatic hydrocarbon systems having from 3 to 14, preferably from 5 to 14, carbon atoms, which can also be condensed into further saturated, (partially) unsaturated or aromatic ring systems. Examples of “aryls” are, among others, phenyls, naphthyls and anthracenyls, but also indanyls, indenyls, or 1,2,3,4-tetrahydronaphthyls; phenyl is particularly preferred for the purposes of this invention. Such an aryl radical may be unsubstituted or optionally mono- or polysubstituted, where the substituents may be the same or different and be linked at each or more than one desired and possible position of the aryl.

“Heteroaryl” corresponds to 5-, 6- or 7-membered cyclic aromatic radicals, which have at least 1, and where 2, 3, 4 or 5 heteroatoms are also possible, preferably nitrogen, oxygen and / or sulfur, wherein heteroatoms are the same or different. The number of nitrogen atoms is preferably between 0 and 3, and the oxygen and sulfur atoms are between 0 and 1. The term “heteroaryl” also includes systems in which the heterocycle is part of a bi- or polycyclic system, and the connection of the heteroaromatic residue with a substance of general formula (I) is possible through any desired and possible member of the heteroaromatic residue cycle. Examples of “heteroaryl” include pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, and isoquinolinyl. Such heteroaromatic radicals may remain unsubstituted or mono- or polysubstituted, where the substituents may be the same or different and be linked at each or more than one desired and possible heteroaryl position.

"Arylalkyl" or "heteroarylalkyl" corresponds to radicals in which an aryl or heteroaryl radical is connected via a C ₁ -C ₈ -alkyl group to a substance of the general formula (I), where the alkyl, aryl and heteroaryl groups are as defined above. Preferred “arylalkyl” groups are phenyl-C ₁ -C ₄ -alkyl radicals, preferably benzyl or phenylethyl radicals.

A “cyclic system” corresponds to a mono- or polycyclic system having from 3 to 14, preferably from 5 or 5 to 14 atoms in a cycle, which can be exclusively carbon atoms. However, the cyclic system may also include 1, 2, 3, 4 or 5 heteroatoms, in particular nitrogen, oxygen and / or sulfur. The cyclic system can be saturated, mono- or polyunsaturated, or fully or partially aromatic, and in the case of a cyclic system consisting of at least two cycles, these cycles can be condensed, or spiro, or otherwise connected.

As indicated above in connection with general formula (I), the substances of this invention can, because they have at least one center of asymmetry, exist in the form of their racemates, in the form of pure enantiomers and / or diastereomers, or in the form of mixtures of these enantiomers and / or diastereomers. Such mixtures can have any ratio of stereoisomers.

Preferred compounds of the general formula (I) are those having the R configuration at the carbon atom substituted with —NH — CX ₃ - and —CX ₂ —NH—, that is, corresponding to the general formula (Ia):

Particularly preferred compounds of the general formula (I) are those having the R configuration at the carbon atom substituted with the substituents —NH — CX ₃ - and the —CX ₂ —NH—, (S) configuration at the carbon atom substituted with the —CX ₃ substituents -NH-, -R8 and -NR9R10, as well as the (S) -configuration of a carbon atom substituted by the substituents -NH-CX ₂ -, -R3 and -CX ₁ -NR1R2, i.e., have the natural S-configuration of the corresponding amino acids of these stereo centers . These compounds have the general formula (I-b):

Where possible, the compounds of the present invention may be in the form of tautomers.

For example, the compounds of the present invention corresponding to the general formula (I), which have one or more chiral centers and which exist as racemates or as mixtures of diastereomers, can be separated by known methods into their pure optical isomers, i.e. enantiomers or diastereomers . The separation of the compounds of the present invention or their building blocks (amino acids) can be carried out by column separation on chiral or non-chiral phases, or by recrystallization from an optionally optically active solvent, or using an optically active acid or base, or by modifying with an optically active reagent such such as an optically active alcohol, and subsequent removal of the radical.

The compounds of the present invention corresponding to the general formulas (I, Ia and Ib) can, if they have sufficiently basic groups, such as, for example, a secondary or tertiary amine, be converted by inorganic or organic acids into salts. Pharmaceutically acceptable salts with sotoluenesulfonic acid, carbonic acid, formic acid, acetic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid, racemic acid, malic acid, embonic acid, lactic acid, citric acid, taurocholic acid, glutamic acid or aspartic acid. The formed salts are, among others, hydrochlorides, hydrobromides, sulfates, phosphates, methanesulfonates, tosylates, carbonates, bicarbonates, formats, acetates, sulfoacetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates, mandelates, fumarates lactates, citrates and glutamates. The stoichiometry of the formed salts of the compounds of the present invention may, moreover, be a compound or non-composite multiple unit.

The compounds of the present invention corresponding to the general formulas (I, Ia and Ib) can, if they contain a sufficiently acidic group, such as, for example, a carboxylic, sulfonic, phosphoric acid or phenolic group, be converted inorganic or organ-sodium hydroxide, potassium hydroxide , calcium hydroxide, and organic bases - ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylenediamine and lysine. The stoichiometry of the formed salts of the compounds of the present invention may, moreover, be a compound or non-composite multiple unit.

It is also possible for the compounds of the present invention corresponding to the general formulas (I, Ia and Ib) to exist in the form of their solvates and especially hydrates, which are obtained, for example, by crystallization from a solvent or from an aqueous solution. It is also possible for one, two, three or any number of solvent or water molecules to combine with the compounds of the present invention to form solvates or hydrates.

It is known that chemical substances form solids that exist in various ordered states, which are referred to as polymorphic forms or modifications. Various modifications of a polymorphic substance can vary greatly in their physical properties. The compounds of the present invention corresponding to the general formulas (I, Ia and Ib) can exist in various polymorphic forms, and in addition certain modifications can be metastable. All such polymorphic forms of the compounds corresponding to the general formulas (I, Ia and Ib) should be regarded as belonging to this invention.

It is also possible for the compounds of the present invention corresponding to the general formulas (I, Ia and Ib) to exist in the form of any prodrugs, such as, for example, esters, carbonates or phosphates, in which case the true biologically active form is released only through metabolism.

It is known that chemicals in the body are converted into metabolites, which can also, where possible, exhibit the desired biological effect - in some circumstances even in a more pronounced form.

Known for thioamides (X ₁ = S), e.g. (Casarett &Doull's"Toxicology, the Basic Science of Poisons", Chapter 6: Biotransformation of Xenobiotics, CD Klaassen Ed., McGraw-Hill 2001; DMClayton, Biochem. Soc. Trans., 1978, 6 (1), 94-96) that they can also be metabolized to thioamide-3-oxides. These substances can also be obtained by synthesis from the corresponding thioamides by oxidation with hydrogen peroxide (H ₂ O ₂ ) (JRCashman et al., J. Org. Chem., 1982, 47 (24), 4645-4650). So, compound 68 is oxidized, for example, in (R) -S-chloro-6-fluoro-3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2.3, 4,9-tetrahydro-1H-carbazole-3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) amide-S-oxide, and compound 76 is oxidized to (R) -3 - {(S) -2 - [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid ((S) -2-methyl-1- thiocarbamoylbutyl) amide S-oxide.

The corresponding metabolites of the compounds of the general formulas (I, Ia and Ib), especially those with X ₁ = S ⁺ -O ^- , should be regarded as belonging to this invention.

You can further note in this regard that the term “receptor ligand” or “ligand” in the context of the present invention is intended to mean each compound that binds in any way to a receptor (the receptor in this invention is a GPCR receptor, preferably an LHRH receptor) and induces or activation, or inhibition and / or other conceivable effect on this receptor. The term “ligand” thus encompasses agonists, antagonists, partial agonists / antagonists, and other ligands that cause a receptor effect similar to that of agonists, antagonists, or partial agonists / antagonists. The compounds of the present invention corresponding to the general formulas (I, Ia and IB) are preferably antagonists of the LHRH receptor (GnRH receptor).

Preferred compounds according to the general formulas (I, Ia and IB) for the purposes of this invention are those where X is a sulfur atom or S ⁺ -O ^- , preferably a sulfur atom, and R8 is an alkyl, arylalkyl or heteroarylalkyl radical, where these radicals are optional substituted by up to 3 substituents selected from the group consisting of halogen atoms, —CN, —CO — O — R12, —CO — NR12R12 ′, —OH, —O — R13, —O — CO — R13, —O -SO ₂ -OR12, -O-SO ₂ -R12, -SO ₂ -OR12, -SO-R12, -O-PO (OR12) (OR12 '), -O-PO (NR12R12') 2, -O- CO-O-R13, -O-CO-NR12R12 ', -O-CS-NR12R12', -S-R12, -NR12R12 ', -NH-CO-R13, -NH-SO ₂ -R12, -NH-CO -O-R13, -NH-CO-NHR12, -NH-C (NH) -NH2, where R 12, R12 'and R13 have the meanings indicated above.

Preferred for the purposes of this invention are also compounds corresponding to the general formulas (I, Ia and Ib), where

R10 is the radical —R11, —CO — R11, —CO — OR11, —CO — NHR11, —C (NH) —NHR11, —SO ₂ —R11, or —SO ₂ NHR11,

R11 represents an arylalkyl or heteroarylalkyl radical which is substituted in the aryl or heteroaryl group by one or more substituents independently selected from the group consisting of halogen atoms, —CN, -alkyl, —CF ₃ , —OCF ₃ , —OH, —O groups -alkyl and -O- (CH ₂ CH ₂ -O) _n , -CH ₃ , and

R8 represents an alkyl, arylalkyl or heteroarylalkyl radical which is optionally substituted with up to 3 substituents independently selected from the group consisting of halogen atoms, —CN, —CO — O — R12, —CO — NR12R12 ′, —OH, -O-R13, -O-CO-R13, -O-SO ₂ -OR12, -SO ₂ -OR12, -O-SO ₂ -R12, -SO-R12, -O-PO (OR12) (OR12 ') , -O-PO (NR12R12 ') 2, -O-CO-O-R13, -O-CO-NR12R12', -O-CS-NR12R12 ', -S-R12, -NR12R12', -NH-CO- R13, —NH — SO ₂ —R12, —NH — CO — O — R13, —NH — CO — NHR12, —NH — C (NH) —NH ₂ , where R12, R12 ′ and R13 are as defined above.

Also preferred compounds corresponding to the general formulas (I, Ia and IB) for the purposes of this invention are those where R8 is either a —C ₁ -C ₆ alkylaryl or a —C ₁ -C ₆ alkyl heteroaryl radical, where aryl or heteroaryl the group is substituted with substituents in an amount of one to three, preferably one, independently selected from the group consisting of —O— (CH ₂ CH ₂ —O) _n —CH ₃ , —O — CO— (CH ₂ CH ₂ —O— ) _n -CH ₃ , -O-SO ₂ -OR12, -O-SO ₂ -R12, -O-PO (OR12) (OR12 '), -O-PO (NR12R12') ₂ , -O-CO-OR13 , -O-CO-NR12R12 'and -O-CS-NR12R12', where R12, R12 'and R13 have the meanings indicated above.

In a preferred embodiment of the present invention, at least one, preferably two, of the radicals R4, R5, R6, and R7, preferably R5 and R7, are not hydrogen atoms. The radicals R5 and R7 are selected independently from one another, primarily from the group consisting of a hydrogen atom, halogen atoms, —CN, —CF ₃ , —O-alkyl and —OCF ₃ groups, and are preferably a hydrogen, halogen atom or a —CF group ₃ . Particularly preferred are those compounds in which R4 and R6 are each a hydrogen atom, R5 is either a hydrogen atom or a halogen atom, and R7, independently of R5, is either a halogen atom or a —CF ₃ group.

Also preferred compounds corresponding to the general formulas (I, Ia and Ib) for the purposes of this invention are those where X ₂ and X _{3 are} each O.

In a preferred embodiment of the invention, R3 is a C ₁ -C ₆ alkyl radical, preferably a C ₁ -C ₄ alkyl radical.

Preferred compounds for the purposes of this invention are those where R1, R2, R9, and also R12 and R12 ', if any, each represents a hydrogen atom.

Also preferred compounds corresponding to the general formulas (I, Ia and Ib) are those in which R13 is a phenyl-C ₁ -C ₄ -alkyl radical or the group - (CH ₂ CH ₂ -O) _n -CH ₃ .

In preferred compounds of the general formula (I, Ia and IB), R10 is —CO — R11, —CO — OR11 or R11, where R11 is as defined above.

Also preferred compounds corresponding to the general formulas (I, Ia and Ib) are those in which R11 represents a phenyl-C ₁ -C ₄ -alkyl radical, preferably a benzyl or phenylethyl radical, which is optionally substituted in the phenyl group with substituents in an amount from one to three, preferably one or two, independently selected from the group consisting of halogen atoms, —C ₁ -C ₄ alkyl, —CF ₃ , —OCF ₃ , —OH, —O — C ₁ -C ₄ alkyl and —O— (CH ₂ CH ₂ —O) _n —CH ₃ -.

Particularly interesting compounds corresponding to the general formulas (I, Ia and IB), within the framework of the present invention, are those where

X ₁ represents O, S or S ⁺ -O ^- ,

X ₂ and X ₃ both represent O,

R1 and R2 both represent a hydrogen atom,

R3 is a C ₁ -C ₆ alkyl radical, preferably a C ₁ -C ₄ alkyl radical,

R4 and R6 both represent a hydrogen atom,

R5 represents either a hydrogen atom or a halogen atom,

R7 represents either a halogen atom or —CF ₃ ,

R9 represents a hydrogen atom,

R10 represents the radical —CO — R11, or —CO — OR11, or the radical R11,

R11 represents a phenyl-C ₁ -C ₄ -alkyl radical, preferably a benzyl or phenylethyl radical, which is substituted in the phenyl group by substituents in an amount of one to three, preferably one or two, independently selected from the group consisting of halogen atoms, -C ₁ -C ₄ -alkyl, -CF ₃ , -OCF ₃ , -OH, -O-C ₁ -C ₄ -alkyl and -O- (CH ₂ CH ₂ -O) _n -CH ₃ -, and

R8 represents a phenyl-C ₁ -C ₄ -alkyl radical, preferably a benzyl or phenylethyl radical, which is substituted on the phenyl group by a substituent selected from the group consisting of -O- (CH ₂ CH ₂ -O) _n -CH ₃ groups, —O — CO— (CH ₂ CH ₂ —O—) _n —CH ₃ , and —O — PO (OR12) (OR12 ′), —O — CO — OR13, or,

if, however, at least

(i) X ₁ represents S, or

(ii) R11 represents a phenyl-C ₁ -C ₄ -alkyl radical, preferably a benzyl or phenylethyl radical, which is substituted in the phenyl group by at least one of the above substituents, that is, independently selected from the group consisting of halogen atoms, - C ₁ -C ₄ -alkyl, -CF ₃ , -OCF ₃ , -OH, -O-C ₁ -C ₄ -alkyl and -O- (CH ₂ CH ₂ -O) _n -CH ₃ ,

R8 is also a C ₁ -C ₆ -alkyl, preferably a C ₁ -C ₄ -alkyl radical, or a phenyl-C ₁ -C ₄ -alkyl radical, preferably a benzyl or phenylethyl radical, the radicals being optionally substituted with a substituent selected from a group consisting of the groups —OH, —O — P13 and —NR12R12 ′;

R12, R12 'independently from each other represent a hydrogen atom or a C ₁ -C ₄ -alkyl, benzyl or phenylethyl radical, preferably a hydrogen atom;

R13 is selected from C ₁ -C ₄ -alkyl, phenyl-C ₁ -C ₄ -alkyl and a phenyl radical, or from the group - (CH ₂ CH ₂ -O) _n -CH ₃ , and is preferably a benzyl or phenylethyl radical, where n is an integer from 1 to 6, preferably from 1 to 4.

Also preferred compounds corresponding to the general formulas (I, Ia and Ib) are those in which the radical X ₁ represents a sulfur atom.

In particular, the following compounds of general formula (I), or (Ia) or (Ib) should be regarded as particularly preferred:

compounds in which X ₁ represents S or S ⁺ -O ^- , preferably S, R3 and R8 each represent a C ₁ -C ₄ alkyl radical, R4 and R6 each represent a hydrogen atom, R5 and R7 each represent an atom halogen, or R5 represents a hydrogen atom and R7 represents a —CF ₃ group, R10 represents a —COR11 radical, R11 represents a benzyl or phenylethyl radical which is substituted on the phenyl group by one or two substituents independently selected from the group consisting of halogen atoms , groups —OSF ₃ and —OSH ₃ .

Compounds in which X ₁ is O, R3 is a C ₁ -C ₄ alkyl radical, R4 and R6 are each a hydrogen atom, R5 and R7 are each a halogen atom, or R5 is a hydrogen atom and R7 is a group —CF ₃ , R10 represents the radical —CO — R11 or —CO — OR11 or the radical R11, R11 represents a benzyl or phenylethyl radical which is substituted on the phenyl group by one or two halogen atoms, and R8 represents C ₁ -C ₄ - an alkyl, benzyl or phenylethyl radical, where the phenyl radical is yell substituted by -OH.

Compounds in which X ₁ is S or S ⁺ -O ^- , preferably S, R3 is a C ₁ -C ₄ alkyl radical, R4 and R6 are each a hydrogen atom, R5 and R7 are each a halogen atom, R10 represents the radical —CO — R11, R11 represents a benzyl or phenylethyl radical, which is optionally substituted in the phenyl group by one or two halogen atoms, and R8 represents a C ₁ -C ₄ alkyl, benzyl or phenylethyl radical, where the phenyl radical can be substituted with an —OH group.

Compounds in which X ₁ is O or S or S ⁺ -O ^- , preferably O or S, R3 is a C ₁ -C ₄ alkyl radical, R4 and R6 are each a hydrogen atom, R5 and R7 are each a halogen atom, or R5 represents a hydrogen atom and R7 represents a —CF ₃ group, R10 represents a —CO-R11 or —CO-OR11 radical, R11 represents a benzyl or phenylethyl radical which is optionally substituted in the phenyl group by one or two atoms halogen, and R8 represents a benzyl or phenylethyl radical, which ory substituted in the phenyl group of radical -O-PO (OH) _2.

The most preferred compounds corresponding to the general formula (I) are the following:

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylpropylcarbamoyl-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl carbamoyl] -2-methylpropyl} -carbamic acid 4-chlorobenzyl ether (1),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylpropylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- sludge carbamoyl] -2-methylbutyl} -carbamic acid 4-chlorobenzyl ether (2),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 4-chlorobenzyl ether (3),

(R) -6,8-dichloro-3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H-carbazole- 3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (4),

(R) -6,8-dichloro-3 - {(S) -2- [2- (3-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H-carbazole- 3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) -amide (5),

{(S) -1 - [(R) -3 - ((S) -carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl] -2-methylbutyl} -carbamic acid 2-chlorobenzyl ether (6),

{(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} carbamic acid benzyl ester (7),

Benzyl 4 - {(S) -3-benzyloxycarbonylamino-3 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro -1H-carbazol-3-ylcarbamoyl] propyl} phenyl carbonate (8),

[(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2- (4-phosphonooxyphenyl) ethyl] carbamic acid benzyl ester (9),

[(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -3- (4-hydroxyphenyl) propyl] carbamic acid benzyl ether (10),

[(S) -1 - [(R) -3 - ((S) -carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl] -3- (4-phosphonooxyphenyl) propyl] carbamic acid benzyl ester (11),

[(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -3- (4-phosphonooxyphenyl) propyl] carbamic acid benzyl ester (12),

(R) -6,8-dichloro-3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H-carbazole- 3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) -amide (13),

(R) -6,8-dichloro-3 - [(S) -2- [2- (2-fluorophenyl) acetylamino] -4- (4-hydroxyphenyl) butyrylamino] -2,3,4,9-tetrahydro -1H-carbazole-3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) amide (14),

Phosphoric acid mono- (4 - {(S) -3 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro -1H-carbazol-3-ylcarbamoyl] -3- [2- (2-fluorophenyl) acetylamino] propyl} phenyl ether (15),

(R) -6,8-dichloro-3 - {(S) -2- [3- (4-fluorophenyl) propionylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H-carbazole-3 -carboxylic acid ((S) -1-carbamoyl-2-methylpropyl) -amide (16),

(S) -5 - [(R) -3 - ((S) -1-carbamoyl-2-methylpropylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl ] -5- [3- (4-fluorophenyl) propionylamino] pentylammonium trifluoroacetate (17),

(S) -6,8-dichloro-3 - {(S) -2- [3- (2-hydroxyphenyl) propionylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H-carbazole- 3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (18),

and

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2- [4- (2- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} ethoxy) phenyl] ethyl} carbamic acid benzyl ester (19),

(R) -6,8-dichloro-3 - ((S) -2- {3- [2- (2- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} ethoxy) phenyl] propionylamino } -3-methylpentanoylamino) -2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) -amide (20),

(R) -6,8-dichloro-3 - ((S) -2- {2- [2- (2- {2- [2- (2-methoxy-ethoxy) ethoxy] ethoxy} ethoxy) -phenyl] -acetylamino} -3-methylpentanoylamino) -2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) -amide (21),

(R) -6,8-dichloro-3 - [(S) -2- [3- (2-fluorophenyl) propionylamino] -4- (4-hydroxyphenyl) butyrylamino] -2,3,4,9-tetrahydro -1H-carbazole-3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (22),

(R) -6,8-dichloro-3 - {(S) -2- [3- (2-fluorophenyl) propionylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H-carbazole-3 -carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) -amide (23),

{(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -3- [4- (2- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} ethoxy) phenyl] propyl} carbamic acid benzyl ester (24),

{(S) -1 - [(R) -8-chloro-6-fluoro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro-1H-carbazole- 3-ylcarbamoyl] -2-methylbutyl} -carbamic acid benzyl ester (25),

3-methylbenzyl {(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole -3-ylcarbamoyl] -2-methylbutyl} -carbamic acid 3-methylbenzyl ether (26),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 2,6-difluorobenzyl ether (27),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 3,5-difluorobenzyl ether (28),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 3,5-dichlorobenzyl ether (29),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 3-fluorobenzyl ether (30),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 2-fluorobenzyl ether (31),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 3-chlorobenzyl ether (32),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -8-chloro-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole- 3-ylcarbamoyl] -2-methylbutyl} -carbamic acid 3,5-difluorobenzyl ether (33),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -8-chloro-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole- 3-ylcarbamoyl] -2-methylbutyl} -carbamic acid 3-fluorobenzyl ester (34),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -8-chloro-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole- 3-ylcarbamoyl] -2-methylbutyl} -carbamic acid 2-fluorobenzyl ether (35),

[(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -3- (4-hydroxyphenyl) propyl] carbamic acid-3-fluorobenzyl ether (37),

[(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -3- (4-hydroxyphenyl) propyl] carbamic acid 2-fluorobenzyl ether (38),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 2- (2-fluorophenyl) ethyl ether (40),

{(S) -1 - [(R) -8-chloro-6-fluoro-3 - ((8) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro-1H-carbazole- 3-ylcarbamoyl] -2-methylbutyl} -carbamic acid 2-fluorobenzyl ether (41),

{(S) -1 - [(R) -8-chloro-6-fluoro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro-1H-carbazole- 3-ylcarbamoyl] -2-methylbutyl} -carbamic acid 3-fluorobenzyl ether (42),

[(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -3- (4-hydroxyphenyl) propyl] carbamic acid 2-fluorobenzyl ether (43),

[(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -3- (4-hydroxyphenyl) propyl] carbamic acid 3-fluorobenzyl ether (45),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 3-methoxybenzyl ether (47),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 4-fluorobenzyl ether (48),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 2-methylbenzyl ether (49),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 2,3-dimethoxybenzyl ether (50),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 2-methoxybenzyl ether (51),

(R) -6,8-dichloro-3 - {(S) -2- [2- (2-fluorophenyl) ethylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H-carbazole-3 -carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (52),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 2-trifluoromethylbenzyl ether (53),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 3-trifluoromethylbenzyl ether (54),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 3-trifluoromethoxybenzyl ether (55),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 2-trifluoromethoxybenzyl ether (56),

{(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 4-fluorobenzyl ether (57),

(R) -6,8-dichloro-3 - {(S) -2- [2- (4-fluorophenyl) ethylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H-carbazole-3 -carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (58),

(R) -6,8-dichloro-3 - {(S) -2- [2- (2,6-difluorophenyl) acetylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) -amide (59),

{(S) -1 - [(R) -8-chloro-6-fluoro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro-1H-carbazole- 3-ylcarbamoyl] -2-methylbutyl} -carbamic acid 4-fluorobenzyl ether (60),

(R) -6,8-dichloro-3 - {(S) -2- [2- (3-fluorophenyl) ethylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H-carbazole- 3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (61),

(R) -8-chloro-3 - {(S) -2- [2- (2,6-difluorophenyl) acetylamino] -3-methylpentanoylamino} -6-fluoro-2,3,4,9-tetrahydro 1H-carbazole-3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) amide (62),

(R) -8-chloro-6-fluoro-3 - {(S) -2- [2- (4-fluorophenyl) ethylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H-carbazole -3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) -amide (63),

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -8-chloro-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole- 3-ylcarbamoyl] -2-methylbutyl} -carbamic acid 4-fluorobenzyl ether (64),

(R) -8-chloro-6-fluoro-3 - {(S) -2- [2- (4-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) amide (65),

(R) -8-chloro-3 - {(S) -2- [2- (2,4-difluorophenyl) acetylamino] -3-methylpentanoylamino} -6-fluoro-2,3,4,9-tetrahydro- 1H-carbazole-3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) amide (66),

(R) -8-chloro-6-fluoro-3 - {(S) -2- [2- (4-fluorophenyl) ethylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H-carbazole -3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) -amide (67),

(R) -8-chloro-6-fluoro-3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) amide (68),

(R) -8-chloro-6-fluoro-3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (69),

(R) -3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3- carboxylic acid ((S) -2-cyclopropyl-1-thiocarbamoylethyl) -amide (70),

(R) -3 - {(S) -2- [2- (2,6-difluorophenyl) acetylamino] -3-methylpentanoylamino} -8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole- 3-carboxylic acid ((S) -2-cyclopropyl-1-thiocarbamoylethyl) -amide (71),

(R) -8-chloro-6-fluoro-3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H- carbazole-3-carboxylic acid ((S) -2-cyclopropyl-1-thiocarbamoylethyl) -amide (72),

(R) -3 - {(S) -2- [2- (2,6-difluorophenyl) acetylamino] -3-methylpentanoylamino} -8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole- 3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) amide (73),

(R) -3 - {(S) -2- [2- (2,6-difluorophenyl) acetylamino] -3-methylpentanoylamino} -8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole- 3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (74),

(R) -3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3- carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (75),

(R) -3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3- carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) amide (76),

(R) -8-chloro-3 - {(S) -2- [2- (2,6-difluorophenyl) acetylamino] -3-methylpentanoylamino} -6-fluoro-2,3,4,9-tetrahydro 1H-carbazole-3-carboxylic acid ((S) -2-cyclopropyl-1-thiocarbamoylethyl) amide (77).

The above compounds 4, 7, 11, 12, 13, 14, 15, 30, 31, 34, 37, 45, 48, 52, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67 68, 69, 70, 71, 72, 73, 74, 75 and 76 are furthermore preferred.

The novel tetrahydrocarbazole derivatives of the present invention, corresponding to the general formulas (I, Ia and IB), as indicated above, are GPCR ligands. Thus, the aforementioned compounds of the present invention are suitable for the treatment and prophylaxis of pathological conditions mediated by GPCR and pathological conditions that can be affected by modulating this receptor and thus be treated. The compounds of the present invention can be used, in particular, for inhibition, that is, as antagonists of the LHRH receptor or receptors of the neurokinin family, especially the NK ₁ and / or NK ₂ receptor, and are thus suitable, for example, for the treatment of benign and malignant neoplasms, for the treatment and prevention of nausea and vomiting, for example, as a result of emetogenic chemotherapy, for the treatment of pain, inflammation and rheumatic and gouty pathological conditions, for controlling male reproductive function, for rmonalnoy therapy, hormone replacement therapy and for the treatment and / or control.

In the control of male reproductive function, the compounds of the present invention suppress spermatogenesis. Co-administration with androgens, for example testosterone and testosterone derivatives, such as, for example, testosterone esters, is preferred. Derivatives of testosterone in this case can be introduced by injection, for example, intramuscular injection.

The compounds of the present invention corresponding to the general formulas (I, Ia and Ib) can also be used in female hormone therapy, for example, for the treatment of benign hormone-dependent disorders such as endometriosis, uterine fibrosis, uterine fibroids (uterine leiomyoma), sheath hyperplasia uterus, dysmenorrhea and dysfunctional uterine bleeding (menorrhagia, metrorrhagia), in certain cases in combination with other hormones, for example, estrogens and / or progestins. Particularly preferred are combinations of the LHRH receptor antagonists of the present invention and tissue-selective partial estrogen agonists such as raloxefine.

The compounds of the present invention can also be used in hormone replacement therapy, for example, for the treatment of hot flashes.

The compounds of the present invention corresponding to the general formulas (I, Ia and Ib) can, moreover, be used to control female reproductive function, for example, by switching off the endogenous hormonal cycle of controlled ovulation induction ("COS" - controlled ovarian stimulation), and for sterility treatments as part of the capabilities of in vitro fertilization techniques such as in vitro conception (“IVF”).

On the other hand, the new compounds of the present invention, corresponding to the general formulas (I, Ia and Ib), are also applicable for female contraception. Thus, an LHRH receptor antagonist can be administered on days 1 through 15 of the female cycle along with estrogen, preferably with very low doses of estrogen. On admission days 1 through 16 of the cycle, a progestogen is added to the combination of estrogen and an LHRH receptor antagonist. The LHRH receptor antagonist of the present invention can be administered continuously throughout the cycle. In this way, it is possible to achieve a decrease in the dose of the hormone and as a result of a decrease in the side effects of nonphysiological hormone levels. Additionally, it is possible to achieve beneficial effects in women suffering from polycystic ovary syndrome and androgen-dependent disorders such as acne, seborrhea and hirsutism. Improved cycle control is also expected compared to previous administration methods.

Further indications are benign prostatic hyperplasia (BPH), gonadal protection during chemotherapy, developmental disorders in early childhood, such as early puberty, treatment of HIV infection or AIDS, neurological or neurodegenerative disorders, ARC (AIDS-related complex), Kaposi’s sarcoma tumors arising in the brain and / or nervous system and / or meningitis (cf. WO 99/01764), dementia and Alzheimer's disease.

Finally, the compounds of the present invention corresponding to the general formulas (I, Ia and Ib), as defined above, can also be used to treat malignant hormone-dependent neoplasms such as premenopausal breast cancer, prostate cancer, ovarian cancer, uterine cancer, cervical cancer and endometrial cancer, as they suppress endogenous sex steroid hormones, and are also suitable for the treatment and prevention of nausea and vomiting, for example as a result of emetogenic chemotherapy, or for the treatment of pain, inflammation and rheumatic and arthritis x pathological conditions.

The new compounds of the present invention, corresponding to the general formulas (I, Ia and Ib), as defined above, are used as GPCR ligands, in particular LHRH receptor antagonists or neurokinin family receptor antagonists, for treating the aforementioned pathological conditions for administration to mammals, primarily for humans, but also for veterinary medical purposes, for example, 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, especially topically, rectally, intravaginally, nasally, or by injection or implantation. Oral administration is preferred.

The new compounds of the present invention, corresponding to the general formulas (I, Ia and IB), are processed into a form suitable for administration and, if possible, mixed with pharmaceutically acceptable carriers or diluents. Suitable excipients and carriers are described, for example, in Ullman's Encyclopedia of Technical Chemistry. Vol. 4, (1953), 1-39; in articles of the Journal of Pharmaceutical Sciences, vol. 52 (1963), 918 et seq .; H. v. Czetsch-Lindenwald, "Hilfsstoffe fur Pharmazie and angrenzende Gebiete"; Pharm. Ind. 2, 1961, 72 et seq .; Dr. H.P. Fiedler, "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende Gebiete", Cantor K G, Aulendorf in Wurttemberg, 1971.

Oral administration may occur, for example, in solid form, such as tablets, capsules, gel capsules, coated tablets, granules or powder, as well as in the form of a drinking solution. For oral administration, the new compounds of the present invention corresponding to the general formulas (I, Ia and Ib) can be mixed with known and standard, physiologically tolerable excipients and carriers, such as, for example, Arabian gum, talc, starch, sugars, such as e.g. mannitol, methyl cellulose, lactose, gelatin, surfactants, magnesium stearate, cyclodextrins, aqueous and non-aqueous vehicles, diluents, dispersants, emulsifiers, lubricants, preservatives and flavorings (e.g., ether m ALS). The compounds of the present invention can also be dispersed in microparticle compositions, for example, from nanoparticles.

Non-oral administration can be carried out, for example, by intravenous, subcutaneous or intramuscular injection of sterile aqueous or oily solutions, suspensions and emulsions, using implants or ointments, creams or suppositories. If necessary, it is also possible to use a sustained release form. The implants may contain inert materials, for example biodegradable polymers or synthetic silicon-containing compounds, such as, for example, silicone rubber.

Intravaginal administration is possible, for example, with the help of pessaries. Intrauterine administration is possible, for example, using diaphragms or other suitable intrauterine devices. Additionally, transdermal administration is possible, especially with formulations suitable for this purpose and / or suitable devices, such as, for example, patches.

As already mentioned above, the new compounds of the present invention, corresponding to the general formulas (I, Ia and IB), can also be mixed with other pharmaceutical ingredients. In the course of combinatorial therapy, the individual active ingredients can be administered simultaneously or separately, in particular in the same way (for example, orally) or in different ways (for example, orally and by injection). Such components may be present and administered in equal or different amounts in a unit dose. If necessary, you can also use a special dosage regimen. In this case, you can mix several new compounds of the present invention, corresponding to the General formulas (I, Ia and IB), one with the other.

Dosage can vary over a wide range depending on the nature of the indication, the severity of the disease, the mode of administration, age, gender, body weight and sensitivity of the treatment subject. One of skill in the art can determine the “pharmacologically effective amount” of a combined pharmaceutical composition.

A preferred unit dose is, for example, from 0.001 mg to 100 mg of the active ingredient, that is, at least one compound of the present invention corresponding to the general formulas (I, Ia and IB), and, if necessary, an additional active ingredient per kilogram of weight the patient.

A further aspect of the present invention accordingly includes pharmaceutical compositions as described above, comprising one or more new compounds of the present invention, corresponding to the general formulas (I, Ia and Ib), as defined above, and, if necessary, pharmaceutically acceptable carriers and / or excipients . Preferred and particularly preferred pharmaceutical compositions are those which include at least one of the new compounds of the present invention corresponding to the general formulas (I, Ia and IB) mentioned above as preferred or especially preferred, in particular at least one of the compounds 1 to 77 specifically mentioned above, with particular preference for compounds 4, 7, 11, 12, 13, 14, 15, 30, 31, 34, 37, 45, 48, 52, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 and 76 in this regard. In the pharmaceutical compositions of the present invention, the presence, in addition to at least one of the new compounds of the present invention, corresponding to the general formulas (I, Ia and Ib), as defined above, of other active pharmaceutical ingredients, as already detailed above, is also possible.

In the pharmaceutical compositions of the present invention, at least one of the new compounds of the invention (I), as defined above, is present in a pharmacologically effective amount, preferably in a unit dose, for example in the aforementioned unit dose, especially and preferably in an administration form that makes possible oral administration.

The present invention further includes, in a further aspect, compounds corresponding to the general formulas (I, Ia and Ib) for use as pharmaceuticals. As already explained above, the compounds corresponding to the general formulas (I, Ia and Ib) act as GPCR ligands, in particular as antagonists of the LHRH receptor, and are thus particularly suitable for use as pharmaceuticals. The compounds of the present invention corresponding to the general formulas (I, Ia and Ib) for use as pharmaceuticals are preferably intended for administration to treat or alleviate the previously mentioned medical indications or for contraception.

Preferred tetrahydrocarbazole derivatives of the present invention corresponding to the general formulas (I, Ia and Ib), as defined above, for use as medicaments are, in turn, compounds that have been mentioned above as preferred and especially preferred compounds, especially the specially mentioned preferred compounds of 1 to 77 of the present invention and, if not already included, the compounds of the present invention mentioned in the examples.

Regarding pharmaceutical compositions comprising the compounds of the present invention corresponding to the general formulas (I, Ia and IB), and regarding the use of the compounds of the present invention corresponding to the general formulas (I, Ia and IB) as pharmaceuticals, reference can be made to the foregoing in connection with the use of the new compounds of the present invention themselves, corresponding to the general formulas (I, Ia and Ib), with respect to possible uses and methods of administration.

In another aspect, the invention also includes the possibility of using at least one tetrahydrocarbazole derivative of the present invention, corresponding to the general formulas (I, Ia and IB), as defined above, for the manufacture of pharmaceuticals for the treatment of diseases mediated by GPCR, where the GPCR receptor is preferably is an LHRH receptor, and the compounds of the present invention preferably act as antagonists of the LHRH receptor.

Accordingly, in a further aspect, the present invention includes the use of at least one compound of this invention of general formula (I, Ia and Ib), as defined above, or an appropriate pharmaceutical composition, for the manufacture of a pharmaceutical agent that acts as an antagonist of the LHRH receptor, preferably for the treatment of benign and malignant neoplasms, for the control of male reproductive function, for hormone replacement therapy, for hormone replacement therapy, for controlled therapy emulation of the ovaries in the context of conception in vitro, for the treatment and / or control of female sexual function failure and infertility and for female contraception. Hormone therapy in this regard includes, inter alia, the treatment of endometriosis, uterine leiomyomas, uterine fibrosis and benign prostatic hyperplasia (BPH). Regarding further indications and explanations of the indications concerning the current aspect of the present invention, reference can be made to the statements made above regarding the first aspect of the present invention, i.e., the compounds of this invention of general formula (I, Ia and IB) themselves and the explanations given therein.

The compounds of this invention are suitable not only for the treatment or therapy of these pathological conditions, but are equally applicable to the prevention or prevention, as well as the alleviation (for example, by suppressing symptoms) of these pathological conditions or diseases.

In another aspect, the present invention includes the use of compounds (I) of the present invention for the manufacture of a pharmaceutical agent for the treatment of benign and non-benign neoplasms and for hormonal treatment. Preferred and particularly preferred compounds of this invention for such use are those compounds which themselves have already been previously mentioned as preferred and especially preferred compounds of this invention of general formulas (I, Ia and IB) as defined above. The most preferred compounds are also compounds 1 to 77, which were specifically mentioned above.

Similarly, the present invention includes a process for the manufacture of pharmaceuticals for the treatment of pathological conditions mediated by GPCR, wherein the process is characterized by the use of at least one compound of the general formulas (I, Ia and Ib) or the corresponding pharmaceutical composition to the invention. The above explanations regarding the preferred and particularly preferred compounds of the present invention, and regarding these pathological conditions that can be treated, prevented or alleviated by pharmaceutical compositions made using the compounds of the present invention, should also be cited for this aspect of the present invention.

In addition, the present invention includes a method for controlling reproductive function in men or contraception in women, comprising administering at least one compound of the present invention of general formulas (I, Ia and IB) effective for controlling reproductive function in men or contraception in women, if necessary in combination with another active component, a subject, preferably a mammal, especially preferably a human. The above explanations regarding further aspects of the present invention with respect to preferred and particularly preferred compounds of the present invention, as well as explanations regarding dosage, route of administration and so on, are also valid for this paragraph.

Another aspect of the present invention relates to a method for treating pathological conditions mediated by GPCR. The method comprises administering at least one compound (I) of the present invention, as defined above, in a pharmaceutically effective amount to a mammal, especially a human, if such treatment is necessary. As already mentioned above with respect to the novel compounds (I) of the present invention and the pharmaceutical compositions of the present invention, a pharmaceutically effective amount can be determined by one skilled in the art depending on the specific requirements in this particular case. A preferred dosage form is an oral dosage form. As mentioned above, one or more of the compounds (I) of the present invention may also be administered in combination with at least one other active component. Clarifications regarding the above aspects of the present invention with respect to preferred and particularly preferred compounds and specific pathological conditions that can be treated, prevented or ameliorated are also valid for the treatment method discussed in this paragraph. Particularly preferred compounds in this aspect are also compounds 1 to 77.

In addition, the present invention also relates to a method for inhibiting GPCR, in particular an LHRH receptor or a neurokinin family receptor, in a patient, the method comprising administering a pharmaceutically effective amount of at least one compound of general formula (I, Ia and IB), as defined above , if necessary, in combination with another active ingredient, as defined above, to a patient (a mammal and, above all, a human) in need of such treatment. Preferred and particularly preferred compounds of the present invention of general formulas (I, Ia and Ib) are again compounds identical to the preferred and particularly preferred compounds mentioned above with respect to other aspects of the present invention, especially compounds 1 to 77. The above explanations regarding pathological conditions which can be treated by administering the compounds of this invention, preferably by their antagonistic effect on the LHRH receptor, are also valid for I have the treatment method discussed in this paragraph.

The compounds of the present invention of general formulas (I, Ia and IB), as defined above, can be synthesized, for example, in the following way:

First of all, the compounds of the present invention can be synthesized by obtaining the central fragment of tetrahydrocarbazole shown in the figure,

where this optionally protected fragment of tetrahydrocarbazole already contains substituents from R ₄ to R ₇ where necessary in the form of precursors or in a protected form.

The central fragment of tetrahydrocarbazole is obtained, for example, using the Fisher method for the synthesis of indoles. To this end, a cyclohesanone derivative with suitable substituents and optionally protective groups is condensed with a phenylhydrazine derivative, which is required in each case and likewise contains suitable substituents and protective groups (for example, as described in Britten & Lockwood, J. Chem. Soc. Perkin Trans. I 1974, 1824 or Maki et al., Chem. Pharm. Bull. 1973, 21, 240). The cyclohexane structure is substituted at the 4,4 ′ positions by the —COOH and —NH ₂ radicals or, if necessary, by their (protected) precursors. The phenylhydrazine structure is optionally substituted with radicals from R ⁴ to R ⁷ . Commercially inaccessible phenylhydrazines can be obtained by methods known to those skilled in the art of chemistry. The isomers of the position formed when possible during the condensation of the cyclohexanone derivative with the phenylhydrazine derivative can be separated by chromatographic methods, such as, for example, HPLC.

The radicals R ₁₀ R ₉ NCHR ₈ CX ₃ NH - and R ₁ R ₂ NCX ₁ CHR ₃ NHCX ₂ - in principle, can be introduced and modified by various, depending on their nature, methods known to those skilled in the art of chemistry, such as shown, for example, in patent WO 03/051837 examples and general explanations.

Another process for preparing the compounds of this invention of general formulas (I, Ia and Ib) is as follows:

First, the basic tripeptide structure is obtained by combining three suitable amino acids, the first amino acid AA ¹ containing the R3 radical as the side chain, the third amino acid AA ³ containing the R8 radical or the precursor of the R8 radical as the side chain, while the “central” amino acid AA ² is 3-amino-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (Thc for short). The basic structure of Thc may be suitably substituted, depending on the type of substitution in the desired resulting compound of the present invention, with radicals R4 to R7, optionally in the form of their precursors or in a protected form. Peptide synthesis can be carried out by methods known to a person skilled in the art of chemistry, for example, in solid or liquid phase. Modifications of substituents can then be carried out, such as “deprotection” of certain radicals.

The following diagram illustrates the combination of amino acids, for example, in the solid phase:

where R * is —CO-O-benzyl (i.e. Z) or any protecting group, for example Fmoc, where R8 * is either —C ₁ -C ₆ alkylaryl or —C ₁ -C ₆ alkylheteroaryl, where an aryl or heteroaryl group is substituted with substituents in an amount of up to 3, preferably one OH group, or R8 * may also — in accordance with the definitions given for R8 — be R3.

This process is illustrated in detail below for the example of solid-phase and liquid-phase syntheses and for specific examples 1 to 77.

General Methods for the Synthesis of Compounds of the Invention of General Formulas (I, Ia and Ib)

The compounds of the present invention of general formulas (I, Ia and IB) are synthesized either by conventional synthesis in solution, or also in whole or in part on a solid phase.

Method 1A Solid Phase Synthesis of LHRH Peptidomimetics

Specific syntheses of the compounds described in detail in the examples were carried out on the solid phase using a semiautomatic synthesizer SP 650 (Labortec). The standard program is shown in table 1 below:

Table 1 Program for synthesizer SP 650 (Labortec company) one Flushing DMF 2 2 2 Delete 20% piperidine + 1% 5 3 DBU 3 Flushing DMF 2 2 four Flushing 2-propanol 2 one 5 Flushing DMF 2 2 6 Flushing 2-propanol 2 one 7 Flushing DMF 2 2 8 Stop 9 Adding Fmoc-AA + HOBt + DIC 10 Removed

eleven Joining 120-130 one 12 Flushing DMF 2 one 13 Flushing 2-propanol 2 one fourteen Flushing DMF 2 one fifteen Flushing 2-propanol 2 one 16 Flushing DMF 2 one 17 Flushing 2-propanol 2 one eighteen the end Step Function Solvent / reagent Time min Reps one Flushing DMF 2 2 2 Delete 20% piperidine + 1% DBU 5 3 3 Flushing DMF 2 2 four Flushing 2-propanol 2 one 5 Flushing DMF 2 2 6 Flushing 2-propanol 2 one 7 Flushing DMF 2 2 8 Stop Step Function Solvent / reagent Time min Reps 9 Adding Fmoc-AA + HOBt + DIC 10 Removed eleven Joining 120-300 one 12 Flushing DMF 2 13 Flushing 2-propanol 2 one fourteen Flushing DMF 2 one fifteen Flushing 2-propanol 2 one 16 Flushing DMF 2 one 17 Flushing 2-propanol 2 one eighteen the end

In this case, the removal of the Fmoc protective group is carried out with 20% piperidine and 1% DBU in DMF for 5 min. The procedure is performed a total of three times for 5 minutes each time.

DMF and 2-propanol are used as washing solutions.

The addition of the first Fmoc amino acid is carried out with HOBt and DIC in DCM and DMF (volume ratio = 1: 1).

The addition of subsequent Fmoc amino acids is carried out with HATU and HOAt (0.5 M solution in DMF) in the presence of DIPEA.

Method 1 Aa Attachment of the First Amino Acid AA ¹ (Synthesis of Fmoc-AA ¹ Polymer)

1 mmol of the Fmoc polymer [Fmoc-2,4-dimethoxy-4 '- (carbomethoxyloxy) benzhydrylamine bound to an aminomethyl-substituted polystyrene polymer (200-400 mesh; 0.55 mmol / g)] is pretreated according to the synthesizer program, remove the Fmoc protecting group, add 1 mmol of Fmoc amino acids AA ¹ (Fmoc-NH-CHRS-COOH), 2 mmol of HOBt in DCM and DMF (volume ratio = 1: 1) and 3 mmol of DIC, shake at room temperature for 3 hours and then washed in accordance with the program.

Method 1 Ab Joining the second amino acid AA ² (Synthesis of Fmoc-AA ² -AA ¹ polymer)

1 mmol of Fmoc-AA ¹ polymer is pretreated according to the program, 2 mmol of Fmoc amino acids AA ² (Fmoc-Thc-OH), 2 mmol of HATU, 2 mmol of HOAt (0.5 M solution in DMF) and 5 mmol of DIPEA are added and shake at room temperature for 4-6 hours. Check the pH during the reaction and adjust to pH 8-9 by adding DIPEA. When the connection is completed, flushing is carried out in accordance with the program.

Method 1 Ac. Addition of the third amino acid AA ³ (Synthesis of Z-AA ³ -AA ² -AA ¹ polymer)

1 mmol of Fmoc-AA ² -AA ¹ -polymer is pretreated according to the program, 2 mmol of Z-amino acid Z-AA ³ (benzyl-O-CO-NH-CHRS * -COOH), 2 mmol of HATU, 2 mmol of HOAt are added (0.5 M solution in DMF) and 5 mmol DIPEA and shake at room temperature for 4-6 hours. Check the pH during the reaction and adjust to pH 8-9 by adding DIPEA. When the connection is completed, flushing is carried out in accordance with the program.

Method 1 Ad Joining the third amino acid AA ³ (Synthesis of Fmoc-AA ³ -AA ² -AA ¹ -polymer)

1 mmol of Fmoc-AA ² -AA ¹ polymer is pretreated according to the program, 2 mmol of Fmoc amino acids Z-AA ³ (Fmoc-NH-CHR8 * -COOH), 2 mmol of HATU, 2 mmol of HOAt (0.5 M solution, are added in DMF) and 5 mmol DIPEA and shake at room temperature for 4-6 hours. Check the pH during the reaction and adjust to pH 8-9 by adding DIPEA. When the connection is completed, flushing is carried out in accordance with the program.

Method 1 Ae Modification of Fmoc-AA ³ -AA ² -AA ¹ -polymer: Introduction of the terminal residue Z (reaction with Z-Cl)

1 mmol of Fmoc-AA ³ -AA ² -AA ¹ polymer is pretreated according to the program, 2 mmol of Z-chloride, 4 mmol of DIPEA and a catalytic amount of DMAP are shaken for 3 hours, and then washing is carried out in accordance with the program.

Method 1 At Introduction of the terminal residue R10, where R10 is —CO-R11 — reaction with R11-COOH

1 mmol of Fmoc-AA ³ -AA ² -AA ¹ polymer is pretreated according to the program, 3 mmol of carboxylic acid R11-COOH, 3 mmol of HOBt and 4 mmol of DIC are shaken for 3 hours, and then rinses are carried out in accordance with the program .

Method 1 Ag Introduction of the terminal residue R10, where R10 is —CO-OR11, and, if necessary, the modification of R8 * in R8 is a reaction with R-OSu

1 mmol of Fmoc-AA ³ -AA ² -AA ¹ polymer is pretreated according to the program, 3 mmol of R-OSu, 5 mmol of DIPEA and a catalytic amount of DMAP are shaken for 3 hours, and then rinses are carried out in accordance with the program. If R8 * has a free OH group, it is possible that this OH group is converted to —O — CO — O — R13, in which case R11 and R13 are the same radicals.

Method 1Ah Introduction of the terminal residue R10, where R10 is —R11 — reaction with R10-iodide (R10-I)

1 mmol of Fmoc-AA ³ -AA ² -AA ¹ polymer is pretreated in accordance with the program, 1 mmol of R10-I, 3 mmol of sodium bicarbonate are shaken for 3 hours, and then washing is carried out in accordance with the program.

Method 1 Ba. Introduction of a phosphoric acid residue on the OH group hTyr, for example, in the side chain R8 *

Wash 1 mmol of the R10-AA ³ -AA ² -AA ¹ polymer twice with DCM, slurry in DCM, add 2 mmol of bis (dimethylamide) phosphoric acid chloride, 2 mmol of DMAP and 3 mmol of DBU or DIPEA and shake at room temperature 4- 6 hours, and then wash in accordance with the program.

Method 1 Bb Introduction of Fmoc-Tyr- (PO (OBzl) -OH) -OH

1 mmol of Fmoc-AA ² -AA ¹ polymer is pretreated according to the program, 2 mmol of Fmoc-Tyr (PO (OBzl) -OH) -OH, 2 mmol of HATU, 2 mmol of HOAt (0.5 M solution in DMF) are added and 5 mmol DIPEA and shake at room temperature for 3 hours. Check the pH during the reaction and adjust to pH 8-9 by adding DIPEA. When the connection is completed, flushing is carried out in accordance with the program.

Method 2 Solid Phase Thioamide Synthesis

The synthesis is based, for example, on the articles of N. Takuta et al. J. Org. Chem. 1989, 54.4812 and Majer et al. Biochem & Biophys. Res. Commun. 1988, 150, 1017.

The first connection is carried out by method 1Aa.

The conversion of carboxamide to thioamide is carried out using Lawsson’s reagent as follows: 1 mmol of Fmoc-AA polymer and 2-4 mmol of Lawson’s reagent are mixed in 20 ml of dry toluene at a bath temperature of 90-100 degrees Celsius for 7 hours, the polymer is filtered off under vacuum and washed on the filter 5 times alternately with DXM and hot Meon.

Subsequent addition of the second and third amino acids is carried out by methods 1Ab-g and 1B.

Method 3A Removal of Carboxamide from a Polymer

Before removal, the peptide polymer is dried in vacuum at a temperature not exceeding 40 ° C. Usually use 10-15 ml of elimination solution per gram of peptide.

For this purpose, 1 mmol of the peptide polymer is stirred in a mixture of 0.5 ml of water and 15 ml of TFA at a bath temperature not exceeding 40 ° C for 2 hours. The polymer is filtered off under vacuum and washed with a small amount of TFA, and the resulting solution in TFA is concentrated on the diaphragm pump.

The oily crude product is purified by preparative HPLC-cm. Method 4

Method 3B Removal of Thioamide from a Polymer

Before removal, the peptide polymer is dried in vacuum at a temperature not exceeding 40 ° C. Usually use 10-15 ml of elimination solution per gram of peptide.

When thioamide is removed, EDT must be added as a trap.

1 mmol of the peptide polymer is stirred in a mixture of 0.5 ml of water, 0.5 ml of EDT and 15 ml of TFA at a bath temperature of 40-50 ° C for 2-3 hours. The polymer is filtered off in vacuo and washed with a small amount of TFA, and the resulting solution in TFA concentrate on a membrane pump. The crude product is purified by preparative HPLC - see Method 4.

Method 3C Removal of carboxamide from the polymer and simultaneous hydrolysis of the bis (dimethylamide) -phosphoric acid residue

Similar to method 3A.

For complete hydrolysis, after 2 hours of reaction, an additional 1 ml of water is added and stirring is continued at 40 ° C for 60 minutes. The polymer is filtered off in vacuo and washed with a small amount of TFA, and the resulting solution in TFA is concentrated on a membrane pump. The crude product is purified by preparative HPLC - see Method 4.

Method 3D Removal of thioamide from the polymer and simultaneous hydrolysis of the bis (dimethylamide) -phosphoric acid residue

Similar to method 3B.

For complete hydrolysis after 2–3 h of the reaction, an additional 1 ml of water is added and stirring is continued at 40 ° C for 60 minutes The polymer is filtered off in vacuo and washed with a small amount of TFA, and the resulting solution in TFA is concentrated on a membrane pump. The crude product is purified by preparative HPLC - see Method 4.

Method 4 Purification of Raw Products by Semi-Preparative HPLC

Shimadzu analytical and semi-preparative HPLC system; Column 250-50, LiChrospher ™ 100, RP18 (12 μm) from Merck;

flow rate 60 ml / min

Eluents: A = 970 ml of water +30 ml of ACN + 1 ml of TFA

B = 300 ml of water +700 ml ACN + 1 ml TFA

UV detector 220 nm.

All products are isolated by gradient elution.

The crude products are dissolved in eluent B (DMF is added for poorly soluble products) and purified in portions on a column (for example, 500 mg of the crude product is dissolved in 15 ml of B and separated in one go). The separation conditions in this case depend on the sequence of the peptide, the nature and amount of impurities, and are pre-established experimentally on an analytical column.

A typical gradient is: 60% B-100% B for 30 minutes.

If the raw products are mixtures of diastereomers, they are separated by this method.

The isolated fractions are checked by analytical HPLC. ACN and TFA are removed on a rotary evaporator and the remaining aqueous concentrate is freeze dried.

Method 5 Liquid-phase synthesis of benzyl ester {(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro 1H-carbazol-3-ylcarbamoyl] -2-methylbutyl} -carbamic acid (7)

Method 5A Synthesis of tert-butyl ((S) -1-carbamoyl-2-methylbutyl) carbamate (Boc-IIe-NH ₂ )

10 mmol of (S) -H-IIe-NH ₂ hydrochloride was mixed with 20 mmol of an aqueous solution of sodium carbonate. A solution of 11 mmol of Boc ₂ O in dioxane was slowly added dropwise to the aqueous solution at room temperature, and the reaction mixture was stirred at room temperature for another 60 minutes. The precipitated crude product was suction filtered, suspended in water and adjusted to acidic by adding dropwise 20% hydrochloric acid. The crude product was again filtered under vacuum, washed with water and dried over P ₄ O ₁₁ in vacuo at 50 ° C.

Yield 85%, mp. 167 ° C. (lit. 166 ° C.)

Method 5B Synthesis of tert-butyl ((S) -2-methyl-1-thiocarbamoylbutyl) carbamate (Boc-IIe-thioamide)

The synthesis was based, for example, on the articles of N. Takuta et al. J. Org. Chem. 1989, 54, 4812 and Majeretal. Biochem & Biophys. Res. Commun. 1988, 150, 1017.

10 mmol of (S) -Boc-IIe-NH2 was suspended in 50 ml of THF, 6 mmol of Lawson's reagent was added and the mixture was stirred at room temperature for 20 hours. The suspension became a clear solution. Finally, the reaction solution was concentrated on a membrane pump.

The crude product was purified by column chromatography (DCM + ethyl acetate = 9: 1)

Yield 88.9%, mp. 131 ° C. (lit. 132 ° C.)

Method 5C Synthesis of (S) -2-amino-3-methylpentanamide (H-IIe thioamide)

10 mmol of (S) -Boc-IIe thioamide was stirred in 40 ml of DCM and 10 ml of TFA at room temperature for 4 hours. The reaction solution was finally concentrated in a vacuum of a membrane pump, and the residue was mixed with 50 ml of water, adjusted to pH 8 with concentrated ammonia solution, and finally extracted 5 times with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate was concentrated in a vacuum of a membrane pump.

Yield 87.5% (yellow solid)

Method 5D Synthesis of (R / S) -3 - ((S) -2-benzyloxycarbonylamino-3-methylpentanoylamino) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid ( Z- (S) -IIe- (R / S) - (6.8-Cl) -Thc-OH)

10 mmol of (R / S) -H- (6.8-Cl) -Thc, 12 mmol of (S) -Z-IIe-OSu, 30 mmol of DIPEA and DMAP at the tip of a spatula were placed in 50 ml of DMF and stirred at bath temperature 80 ° C. for 4 hours. Then the reaction mixture was evaporated in vacuo of a membrane pump, the residue was mixed with water, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was then washed with a saturated solution of sodium chloride, dried over sodium sulfate and filtered, and the filtrate was evaporated in vacuo of a furniture pump.

Yield 11.9 g of a mixture of diastereomers (1: 1 mixture)

Method 5E Synthesis of benzyl ester {(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro-1H -carbazol-3-ylcarbamoyl] -2-methylbutyl} -carbamic acid (7) ((S) -Z-II- (R) - (6,8-Cl) -Thc- (S) -IIe thioamide)

3 mmol Z-IIe- (R / S) - (6,8-Cl) -Thc-OH, 3 mmol H- (S) -IIe thioamide, 3 mmol HATU and 15 mmol DIPEA were heated in 5 ml of DMF in a microwave at a temperature not exceeding 100 ° C and a maximum power of 150 watts for 3 minutes The reaction solution was diluted with eluent B and separated in two steps on a preparative HPLC column (see Method 4).

The yield of diastereomer 1 = 19% at HPLC purity of 98.5% (compound 7)

The yield of diastereomer 2 = 17.7% at HPLC purity of 95%

Method 6 Exemplary synthesis of C-terminally substituted amides in a solution of - (S) -2 - {[(R / S) -3 - ((S) -2-benzyloxycarbonylamino-3-methylpentanoylamino) -6,8-dichloro-2, 3,4,9-tetrahydro-1H-carbazole-3-carbonyl] amino} -3-methylpentanoic acid ((S) -Z-IIe- (R / S) - (6,8-Cl) -Thc- (S ) -IIe-OH) + R1-NH-R2

1 mmol of (S) -Z-IIe- (R / S) - (6,8-Cl) -Thc- (S) -IIe-OH (*) was suspended in 5 ml of DMF, 1.1 mmol of R1-NH was added -R2, 1.2 mmol of RuBOP and 3 mmol of NMM, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in vacuo of a membrane pump and purified by preparative HPLC (see Method 4). The product thus obtained is (S) -Z-IIe- (R / S) - (6.8-Cl) -Thc- (S) -IIe-NR1R2.

(*) Synthesis of (S) -Z-IIe- (R / S) - (6,8-Cl) -Thc- (S) -IIe-OH can be carried out on a solid support with a 2-chlorotrityl chloride polymer (1.37 mmol (Mr. Alexis Biochemicals 120-002-0000). The first addition is carried out in DXM in the presence of DIPEA, and the second and third additions are carried out by analogy with the methods 1Ab + 1Av-1Azh. Removal is carried out as in method 3A, and cleaning is carried out as in method 4.

Method 7 Reaction of Lawson's reagent with R10-AA ³ -AA ² -AA ¹ -NH ₂ An alternative method of titration of sequences with a C-terminal amide function when AA ² is a Thc building block

1 mmol of R10-AA ³ -AA ² -AA ¹ -NH _{2 was} dissolved in 40 ml of dry toluene, 1 mmol of Lawson's reagent was added at room temperature, the suspension was stirred at a bath temperature of 80 ° C for 3-4 hours, and the reaction mixture was evaporated in a membrane vacuum pump. The residue was fractionated by preparative HPLC by analogy with method 4.

Method 8 Preparation of Mitsunobu Alkyl Aryl Ethers

Alkylaryl ethers are prepared from the corresponding OH compounds by the addition of PPh ₃ and DEAD (Mitsunobu et al., J. Am. Chem. Soc. 1972, 94, 679).

The following summarizes the general methods for the preparation of inventions corresponding to the present invention, indicating the corresponding steps and methods:

a) First, Fmoc-protected AA ^{1 is} attached to the polymer according to method 1Aa

b) if necessary, conversion to thioamide in the second stage is carried out by method 2

c) The product obtained after stage a or b, after deprotection, reacts with protected amino acid 2, appropriately substituted with a Thc derivative, according to method 1Ab:

g) Then the product obtained in stage c, after removal of the protective group, reacts with a third protected AA:

where R * = Z = —CO — O-benzyl (in Method 1Ac) or R * = Fmoc (in Method 1Ad), and R8 * is —C ₁ -C ₆ -alkylaryl or —C ₁ -C ₆ -alkylheteroaryl, where the aryl or heteroaryl group is substituted with substituents in an amount of up to 3, preferably with one OH group, or R8 * may also, according to the definitions given for R8, have the meanings of R3.

d) If R * = Fmoc, the protective group is first removed from the product obtained in step g, and then the free terminal amino group reacts so that the radical R10 is introduced:

Depending on the nature of the radical R10, various processes are used:

(i) method 1Af for R10 = —CO — R11; reaction with R11-COOH

(ii) method 1Ag for R10 = —CO — OR11; reaction with R11-OSu; in this case, it is also possible, if R8 * has a free OH group, to convert this OH group to —O — CO — O — R13, in which case R11 and R13 are the same radicals

(iii) method 1 Ah for R10 = -R11; reaction with RtO iodide (R10-I)

e) If necessary, in an additional step e, R8 * can be converted to R8, for example, by

(i) introducing a phosphorus radical into R8 by converting an OH group, as in the step of method 1Ba; or

(ii) introducing a -CO-O-benzyl radical (Z) into R8 by converting an OH group, as in the step of method 1Ae;

g) Then the tripeptide is removed from the polymer by one of the methods 3A, 3B, 3C or 3D, and purified by method 4.

h) If further modifications of R8 or R11 are also needed, they can also be carried out now, for example, the introduction of alkyl esters from the corresponding OH compounds, as in the stage of method 8.

The compounds of the present invention referred to in Examples 1 to 15 and 16 to 77 were prepared as shown in detail below by methods 1-8 as defined above. The analytical characterization of the compounds of the present invention was carried out by ¹ H-NMR spectroscopy and / or mass spectrometry.

The reagents and solvents used were purchased from conventional suppliers (Acros, Avocado, Aldrich, Bachem, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, etc.) or synthesized by methods known to those skilled in the art of chemistry.

For the examples of transformations shown below, chiral building blocks were usually used in an enantiomerically pure form. In the case of the tetrahydrocarbazole precursor, the racemic building block was used. The final products were purified by semi-preparative HPLC and characterized as pure diastereomers.

Compounds of the present invention of general formulas (I, Ia and IB), especially compounds 1 to 77, were named using AutoNom 2000 software (ISIS ™ / Draw 2.5; MDL).

The invention will be disclosed in detail using the following examples, but, however, is not limited to only these examples.

List of abbreviations used

DBU 1,8-diazabicyclo [5.4.0] undec-7-ene

HOBt 1-hydroxybenzotriazole

Fmoc 9-fluoromethylmethoxycarbonyl

Boc tert-butoxycarbonyl

Z benzyloxycarbonyl

Z-Cl benzyloxycarbonyl chloride

Boc ₂ O di-tert-butyl dicarbonate

Bzl benzyl

AA amino acid

EDT 1,2-Ethanedithiol

DEAD diethyl azodicarboxylate

DIC N, N'-diisopropylcarbodiimide

DCC N, N'-Dicyclohexylcarbodiimide

HATU N, N, N ', N'-tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate

HOAt 1-hydroxy-7-azabenzotriazole

RuVor (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate

OSu N-hydroxysuccinimidyl

DIPEA Diisopropylethylamine

DMAP N, N'-dimethylaminopyridine

DBU 1,8-diazabicyclo [5.4.0] undec-7-ene

NMM N-methylmorpholine

TFA trifluoroacetic acid

DXM Dichloromethane

DMF N, N'-dimethylformamide

DMA N, N'-Dimethylacetamide

ACN acetonitrile

THF tetrahydrofuran

Me methyl

MeOH methanol

Lawson's reagent 2,4-bis (4-methoxyphenyl) -1,3-dithia-2-, 4-diphosphetane 2,4-disulfide

Thc 3-amino-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid

Ala alanine (silt)

Val valine (silt)

IIe iso-leucine (silt)

Leu leucine (sludge)

Gln Glutamine (Il)

Asn asparagine (sludge)

Tyr Tyrosine (sludge)

hTyr homo-tyrosine (sludge)

Arg arginine (silt)

Lys lysine (sludge)

Mp melting temperature

Ml milliliter

Min minutes

H hours

ELISA enzyme-linked immunosorbent assay

HEPES N- (2-hydroxyethyl) piperazine-N'-2-ethane sulfonic acid

DMEM Dulbecco Modified Culture Medium

RIA radio immunological research

LHRH luteinizing hormone releasing factor

LH luteinizing hormone

NK ₁ neurokinin 1

NK ₂ Neurokinin 2

Examples

I. Synthesis of the compounds of the present invention

Example 1:

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylpropylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylpropyl} -carbamic acid 4-chlorobenzyl ether (1),

0.275 g of compound 1 was obtained starting from 3 mmol of polymer, Fmoc-Val-OH (AA ¹ and AA ³ ), Fmoc- (6.8-dichloro) -Thc-OH (AA ² ) and 4-chlorobenzyl 2,5- dioxopyrrolidin-1-yl carbonate according to the general methods 1Aa, b, d, g, 3A and 4.

Yield: 0.275 g (14.44% of theory)

¹ H-NMR (DMSO-d ₆ , 300K, 500 MHz): δ = 11.33 (s, 1H); 7.40-7.02 (m, 10H); 4.94 (d, 1H); 4.75 (d, 1H); 4.15 (dd, 1H); 3.87 (dd, 1H); 3.02 (d, 1H); 2.87 (d, 1H); 2.82-2.68 (m, 2H); 2.12 (m, 1H); 1.95 (m, 1H); 1.87 (m, 1H); 0.88-0.72 (m, 12H) ppm

MS (ESI): Found: 664.1 (M + H ⁺ ) / calculated: 663 g / mol

Example 2

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylpropylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 4-chlorobenzyl ether (2)

0.190 g of compound 2 was obtained starting from 2.5 mmol of polymer, Fmoc-Val-OH (AA ¹ ), Fmoc-IIe-OH (AA ³ ), Fmoc- (6,8-dichloro) -Thc-O-H (AA ² ) and 4-chlorobenzyl 2,5-dioxopyrrolidin-1-yl carbonate according to the general methods 1Aa, b, d, g, 3A and 4.

Yield: 0.190 g (10.64% of theory)

¹ H-NMR (DMSO-d ₆ ), 300K, 500 MHz): δ = 11.33 (s, 1H); 7.38-7.03 (m, 9H); 4.94 (d, 1H); 4.7 (d, 1H); 4.15 (dd, 1H); 3.87 (dd, 1H); 2.98 (d, 1H); 2.88 (d, 1H); 2.78-2.55 (m, 3H); 2.1 (m, 1H); 1.95 (m, 1H; 1.62 (m, 1H); 1.33 (m, 1H); 1.03 (m, 1H); 0.75 (m, 12H) ppm

MS (ESI): Found: 678.2 (M + H ⁺ ) / Calculated: 677 g / mol

Example 3

{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 4-chlorobenzyl ether (3)

0.155 g of compound 3 was obtained starting from 2.5 mmol of the polymer, Fmoc-IIe-OH (AA ¹ and AA ³ ), Fmoc- (6.8-dichloro) -Thc-OH (AA ² ) and 4-chlorobenzyl 2,5- dioxopyrrolidin-1-yl carbonate according to the general methods 1Aa, b, d, g, 3A and 4.

Yield: 0.155 g (8.85% of theory)

¹ H-NMR (DMSO-d ₆ , 300K, 500 MHz): δ = 11.35 (s, 1 H, indole NH); 7.4-7.03 (3 m, 4H, 3H, 3H); 4.96, 4.7 (2 d, 2H, C ₅ H ₆ -CH ₂ ); 4.18 (dd, 1H); 3.89 (dd, 1H); 2.98, 2.88 (2 d, 2H, CH ₂ ); 2.77, 2.71, 2.62, 2.12 (4m, 4H, CH ₂ -CH ₂ ); 1.82 (m, 1H); 1.64 (m, 1H); 1.45-1.3 (m, 2H); 1.05 (m, 2H); 0.84 (d, 3H, CH ₃ ); 0.82 (d, 3H, CH ₃ ); 0.79 (t, 3H, CH ₃ ); 0.73 (t, 3H, CH ₃ ) ppm.

MS (ESI): Found: 692.2 (M + H ⁺ ) / Calculated: 691 g / mol.

Example 4

(R) -6,8-dichloro-3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H-carbazole- 3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (4)

0.995 g of compound 4 was obtained based on 7.0 mmol of polymer, Fmoc-IIe-OH (AA ¹ and AA ³ ), Fmoc- (6.8-dichloro) -Thc-OH (AA ² ) and 2-fluorophenylacetic acid according to general methods 1Aa, b, d, f, 3A and 4.

Yield: 0.995 g (19.64% of theory)

¹ H-NMR (DMSO-d ₆ , 300K, 600 MHz): δ = 11.35 (s, 1H, indole NH); 8.12 (s, 1H); 7.82 (d, 1H); 7.40 (s, 1H); 7.29-7.23 (m, 2H); 7.20-7.13 (m, 3H); 7.12-7.06 (m, 3H); 4.12 (m, 2H); 3.47, 3.21 (2 d, 2H, CH2); 2.99, 2.94 (2 d, 2H, CH2); 2.79, 2.68 (2 m, 2H, CH2); 2.59 (m, 1H); 2.12 (m, 1H); 1.62 (m, 2H); 1.33 (m, 2H); 1.01 (m, 2H); 0.80-0.71 (4 m, 12H, 4 CH3) ppm

MS (ESI): Found: 660.3 (M + H ⁺ ) / Calculated: 659.251 g / mol

Example 5

(R) -6,8-dichloro-3 - {(S) - -2- [2- (3-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H-carbazole -3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) -amide (5)

0.185 g of compound 5 was obtained starting from 3.0 mmol of polymer, Fmoc-IIe-OH (AA ¹ and AA ³ ), Fmoc- (6.8-dichloro) -Thc-OH (AA ² ) and 3-fluorophenylacetic acid according to general methods 1Aa, b, d, f, 3A and 4.

Yield: 0.185 g (11% of theory)

¹ H-NMR (DMSO-d ₆ , 300K, 500 MHz): δ = 11.2 (s, 1H, indole NH); 8.17 (d, 1H, NH); 8.07 (s, 1H, NH); 7.36 (s, 1H); 7.35-7.22 (m, 2H); 7.12-7.0 (m, 6H); 4.12-4.07 (m, 2H); 3.55, 3.45 (2 d, 2H, C ₆ H ₅ F-CH ₂ ); 3.4, 3.0 (2 d, 2H, CH ₂ , Thc);

2.85 (m, 1H); 2.75-2.68 (m, 1H); 2.35-2.28 (m, 1H); 2.1-2.0 (m, 1H); 1.65 (m, 1H); 1.45 (m, 1H); 1.32 (m, 1H); 1.15-1.0 (m, 2H); 0.82-0.7 (m, 7H); 0.5-0.4 (d, t, 6H, CH ₃ ) ppm.

MS (ESI): found: 660.3 (M + H ⁺ ) / calculated: 659 g / mol

Example 6

{(S) -1 - [(R) -3 - ((S) -carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl] -2-methylbutyl} -carbamic acid 2-chlorobenzyl ether (6)

0.255 g of compound 6 was obtained starting from 3.0 mmol of the polymer, Pmoc-IIe-OH (AA ¹ and AA ³ ), Fmoc- (6.8-dichloro) -Thc-OH (AA ² ) and 2-chlorobenzyl 2,5- dioxopyrrolidin-1-yl carbonate according to the general methods 1Aa, b, d, g, 3A and 4.

Yield: 0.255 g (14.72% of theory)

1 H NMR (DMSO-d ₆ , 300K, 500 MHz): δ = 11.35 (s, 1H, indole NH); 7.75 (s, 1H, NH); 7.4 (d, 1H, NH); 7.35-7.2 (m, 6H); 7.1-7.05 (m, 2H); 5.05, 4.82 (2 d, 2H, C ₅ H ₆ -CH ₂ ); 4.18 (dd, 1H); 3.9 (dd, 1H); 2.98, 2.88 (2 d, 2H, CH ₂ ); 2.8, 2.72, 2.62, 2.12 (4 m, 4H, CH ₂ -CH ₂ ); 1.75 (m, 1H); 1.62 (m, 1H); 1.45-1.25 (m, 2H); 1.05 (m, 2H); 0.68 (m, 12H, CH ₃ ) ppm.

MS (ESI): found: 692.2 (M + H ⁺ ) / calculated: 691 g / mol

Example 7

{(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} carbamic acid benzyl ester (7)

0.126 g of compound 7 was obtained starting from 5.0 mmol of polymer, Fmoc-IIe-OH (AA ¹ ), Z-IIe-OH (AA ³ ) and Fmoc- (6,8-dichloro) -Thc-O-H (AA ² ) and according to the general methods 1Aa, 2, 1Ab, s, 3B and 4.

Yield: 0.126 g (3.38% of theory)

¹ H-NMR (DMSO-d ₆ , 300K, 600 MHz): δ = 11.38 (s, 1H, indole NH); 9.71, 9.32 (2 s, 2H, CS-NH ₂ ); 7.73 (s, 1H); 7.36 (s, 1H); 7.30-7.11 (3 m, 8H); 4.96, 4.69 (2 d, 2H, C ₅ H ₆ -CH ₂ ); 4.46 (dd, 1H); 3.89 (dd, 1H); 2.98, 2.88 (2 d, 2H, CH ₂ ); 2.77, 2.71, 2.62, 2.12 (4 m, 4H, CH ₂ -CH ₂ ); 1.77 (m, 1H); 1.64 (m, 1H); 1.50 (m, 1H); 1.34 (m, 1H); 1.04 (m, 2H); 0.84 (d, 3H, CH ₃ ); 0.82 (d, 3H, CH ₃ ); 0.79 (t, 3H, CH ₃ ); 0.73 (t, 3H, CH ₃ ) ppm

MS (ESI): Found: 674.2 (M + H ⁺ ) / Calculated: 673 g / mol

As explained above, compound 7 was also obtained in the liquid phase according to method 5 (AD).

Example 8

benzyl 4 - {(S) -3-benzyloxycarbonylamino-3 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro -1H-carbazol-3-ylcarbamoyl] propyl} phenyl carbonate (8)

0.125 g of compound 8 was prepared starting from 3.5 mmol of polymer, Fmoc-IIe-OH (AA ¹ ), Fmoc-hTyr-OH (AA ³ ), Fmoc- (6.8-dichloro) -Thc-OH (AA ² ) and benzyl carbonate according to the general methods 1Aa, b, d, e, 3A and 4.

Yield: 0.125 g (3.92% of theory)

1 H NMR (DMSO-d ₆ , 300K, 600 MHz): δ = 11.41 (s, 1H, indole NH); 7.77 (s, 1H, NH); 7.54 (d, 1H); 7.48-7.29 (m, 10H); 7.22-7.05 (3 m, 9H); 5.25 (s, 2H, OCOOCH ₂ -C ₆ H ₅ ); 4.96, 4.68 (2 d, 2H, C ₆ H ₅ -CH ₂ -OCON); 4.18 (dd, 1H); 3.92 (dt, 1H); 3.00, 2.92 (2 d, 2H, CH ₂ ); 2.74 (m, 2H); 2.60 (m, 2H); 2.46 (m, 1H); 2.08 (m, 1H); 1.79-170 (m, 3H); 1.37 (m, 1H); 1.01 (m, 1H); 0.83 (d, 3H, CH-CH ₃ ); 0.73 (t, 3H, CH ₂ -CH ₃ ) ppm.

MS (ESI): Found: 856.1 (M + H ⁺ ) / Calculated: 855 g / mol

Example 9

[(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2- (4-phosphonooxyphenyl) ethyl] carbamic acid benzyl ester (9)

0.112 g of compound 9 was obtained starting from 1.3 mmol of polymer, Fmoc-IIe-OH (AA ¹ ), Z-Tyr-OH (AA ³ ) and Fmoc- (6,8-dichloro) -Thc-O-H (AA ² ) by the general methods 1Aa, b, c, 1Ba, 3C and 4.

Yield: 0.112 g (9.98% of theory)

¹ H-NMR (DMSO-d ₆ , 300K, 600 MHz): δ = 11.39 (s, 1H, indole NH); 7.98 (s, 1H); 7.45 (d, 1H); 7.42 (s, 1H); 7.37 (s, 1H); 7.32-7.28 (m, 3H); 7.17-7.12 (m, 6H); 7.10 (m, 1H); 7.02 (d, 2H); 4.90, 4.73 (2d, 2H, C ₆ H ₅ -CH ₂ ); 4.26 (m, 1H); 4.19 (m, 1H); 2.94 (m, 2H); 2.83 (m, 1H); 2.73 (m, 1H); 2.6 (m, 2H); 2.20 (m, 1H); 2.06 (m, 1H); 1.73 (m, 1H); 1.41 (m, 1H); 1.05 (m, 1H); 0.84 (d, 3H, CH-CH ₃ ); 0.79 (t, 3H, CH ₂ -CH ₃ ) ppm.

MS (ESI): found: 788.2 (M + H ⁺ ) / calculated: 787 g / mol

Example 10

[(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -3- (4-hydroxyphenyl) propyl] carbamic acid benzyl ether (10)

0.45 g of compound 10 was obtained starting from 4.4 mmol of polymer, Fmoc-IIe-OH (AA ¹ ), Fmoc-hTyr-OH (AA ³ ), Fmoc- (6.8-dichloro) -Thc-OH (AA ² ) and benzyl carbonate according to the general methods 1Aa, 2, 1Ab, d, e, 3B and 4.

Yield: 0.45 g (19.47% of theory)

¹ H-NMR (DMSO-d ₆ , 300K, 600 MHz): δ = 11.41 (s, 1H, indole NH); 9.71 (s, 1H, CS-NH-CH); 9.28, 9.12 (2 s, CS-NH ₂ ); 7.67 (s, 1H); 7.41 (d, 2H); 7.37 (s, 1H); 7.32-7.28 (m, 4H); 7.17-7.15 (m, 3H); 6.83 (d, 2H); 6.61 (d, 2H); 4.96, 4.65 (2 d, 2H, C ₆ H ₅ -CH ₂ -); 4.44 (dd, 1 H); 3.89 (dd, 1H); 3.02, 2.88 (2d, 2H, CH ₂ ); 2.76 (m, 2H); 2.62 (m, 1H); 2.46 (m, 1H); 2.35 (m, 1H); 2.09 (m, 1H); 1.79-1.74 (m, 3H); 1.48 (m, 1H); 1.02 (m, 1H); 0.83 (d, 3H, CH-CH ₃ ); 0.74 (t, 3H, CH ₂ -CH ₃ ) ppm.

MS (ESI): Found: 738.1 (M + H ⁺ ) / Calculated: 737 g / mol

Example 11

[(S) -1 - [(R) -3 - ((S) -carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-ylcarbamoyl] -3- (4-phosphonooxyphenyl) propyl] carbamic acid benzyl ester (11)

1.511 g of compound 11 was obtained on the basis of 10.0 mmol of polymer, Fmoc-IIe-OH (AA ¹ ), Z-hTyr-OH (AA ³ ) and Fmoc- (6.8-dichloro) -Thc-OH (AA ² ) General methods 1Aa, b, c, 1Ba, 3C and 4.

Yield: 1.511 g (18.37% of theory)

¹ H-NMR (DMSO-d ₆ , 300K, 600 MHz): δ = 11.39 (s, 1H, indole NH); 7.75 (s, 1H); 7.49 (d, 1H); 7.42 (s, 1H); 7.35-7.30 (m, 4H); 7.21-7.16 (m, 3H); 7.14 (d, 1H); 7.11 (s, 1H); 7.02 (m, 4H); 4.96, 4.69 (2 d, 2H, C ₆ H ₅ -CH ₂ ); 4.18 (dd, 1H); 3.92 (dt, 1H); 3.00, 2.94 (2d, 2H, CH ₂ ); 2.75 (m, 2H); 2.56 (m, 1H); 2.43 (m, 2H); 2.09 (m, 1H); 1.75 (m, 3H); 1.38 (m, 1H); 1.05 (m, 1H); 0.83 (d, 3H, CH-CH ₃ ); 0.75 (t, 3H, CH ₂ -CH ₃ ) ppm

MS (ESI): Found: 802.0 (M + H ⁺ ) / Calculated: 801 g / mol

Example 12

[(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -3- (4-phosphonooxyphenyl) propyl] carbamic acid benzyl ether (12)

0.079 g of compound 12 was prepared starting from 10.0 mmol of polymer, Fmoc-IIe-OH (AA ¹ ), Fmoc-hTyr-OH (AA ³ ), Fmoc- (6.8-dichloro) -Thc-OH (AA ² ) and benzyl carbonate according to the general methods 1Aa, 2, 1Ab, d, e, 1Ba, 3D and 4.

Yield: 0.079 g (0.96% of theory)

¹ H-NMR (DMSO-d ₆ , 300K, 600 MHz): δ = 11.41 (s, 1H, indole NH); 9.70, 9.29 (2 s, 2H, CS-NH ₂ ); 7.73 (s, 1H); 7.44 (d, 1H); 7.37 (s, 1H); 7.33-7.27 (m, 4H); 7.20-7.14 (m, 3H); 7.07-7.03 (m, 4H); 4.96, 4.66 (2d, 2H, C ₆ H ₅ -CH ₂ ); 4.44 (dd, 1H); 3.92 (dt, 1H); 3.01, 2.91 (2d, 2H, CH ₂ ); 2.74 (m, 2H); 2.59 (m, 2H); 2.44 (m, 2H); 2.09 (m, H); 1.79 (m, 2H); 1.48 (m, 1H); 1.03 (m, 1); 0.83 (d, 3H, CH-CH ₃ ); 0.75 (t, 3H, CH ₂ -CH ₃ ) ppm

MS (ESI): Found: 818.1 (M + H ⁺ ) / Calculated: 817 g / mol.

Example 13

(R) -6,8-dichloro-3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2,3,4,9-tetrahydro-1H-carbazole- 3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) amide (13)

0.437 g of compound 13 was prepared on the basis of 4.00 mmol of polymer, Fmoc-IIe-OH (AA ¹ and AA ³ ), Fmoc- (6.8-dichloro) -Thc-OH (AA ² ) and 2-fluorophenylacetic acid according to general methods 1Aa, 2, 1Ab, d, f, 3B and 4.

Yield: 0.437 g (15.61% of theory)

¹ H-NMR (DMSO-d ₆ , 300K, 600 MHz): δ = 11.37 (s, 1H, indole NH); 9.69, 9.21 (2s, 2H, CS-NH ₂ ); 8.06 (d, 1H); 7.82 (s, 1H); 7.37 (s, 1H); 7.29-7: 23 (m, 2H); 7.17 (m, 2H); 7.09 (m, 2H); 4.46 (dd, 1H); 4.15 (dt, 1H); 3.45, 3.18 (2 d, 2H, CH ₂ ); 2.97, 2.89 (2 d, 2H, CH ₂ ); 2.77 (m, 1H); 2.68 (m, 1H); 2.68 (m, 1H); 2.12 (m, 1H); 1.71-1.59 (m, 2H); 1.44 (m, 1H); 1.35 (m, 1H); 1.02 (m, 2H); 0.81 (d, 3H, CH-CH ₃ ); 0.78-0.75 (m, 6H, 2 CH ₃ ); 0.73 (t, 3H, CH ₂ -CH ₃ ) ppm.

MS (ESI): Found: 676.2 (M + H ⁺ ) / Calculated: 675 g / mol

Example 14

(R) -6,8-dichloro-3 - [(S) -2- [2- (2-fluorophenyl) acetylamino] -4- (4-hydroxyphenyl) butyrylamino] -2,3,4,9-tetrahydro -1H-carbazole-3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) amide (14)

0.632 g of compound 14 was obtained starting from 4.5 mmol of polymer, Fmoc-IIe-OH (AA ¹ ), Fmoc-hTyr-OH (AA ³ ), Fmoc- (6.8-dichloro) -Thc-OH (AA ² ) and 2-fluorophenylacetic acid according to the general methods 1Aa, 2, 1Ab, d, f, 3B and 4.

Yield: 0.632 g (17.61% of theory)

¹ H-NMR (DMSO-d ₆ , 300K, 600 MHz): δ = 11.37 (s, 1H, indole NH); 9.67, 9.14 (2 s, 2H, CS-NH ₂ ); 9.13 (br. S, 1H, OH); 8.29 (d, 1H); 7.84 (s, 1H); 7.38 (s, 1H); 7.31 (d, 1H); 7.26 (m, 1H); 7.21-7.08 (2 m, 4H); 6.79 (d, 2H); 6.60 (d, 2H); 4.43 (dd, 1H); 4.13 (d, 1H); 3.45, 3.22 (2 d, 2H, CH ₂ ); 2.99, 2.96 (2d, 2H, CH ₂ ); 2.76-2.72 (m, 2H); 2.58 (m, 1H); 2.42 (m, 1H); 2.33 (m, 1H); 2.09 (m, 1H); 1.75 (m, 2H); 1.65 (m, 1H); 1.42 (m, 1H); 0.99 (m, 1H); 0.79 (d, 3H, CH ₂ -CH ₃ ); 0.73 (t, 3H, CH ₂ -CH ₃ ) ppm.

MS (ESI): Found: 740.2 (M + H ⁺ ) / Calculated: 739 g / mol

Example 15

Phosphoric acid mono- (4 - {(S) -3 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro -1H-carbazol-3-ylcarbamoyl] -3- [2- (2-fluorophenyl) acetylamino] propyl} phenyl ether (15)

0.129 g of compound 15 was prepared starting from 3.3 mmol of polymer, Fmoc-IIe-OH (AA ¹ ), Fmoc-hTyr-OH (AA ³ ), Fmoc- (6.8-dichloro) -Thc-OH (AA ² ) and 2-fluorophenylacetic acid according to the general methods 1Aa, 2, 1Ab, d, f, 1Ba, 3D and 4.

Yield: 0.129 g (4.6% of theory)

¹ H-NMR (DMSO-d ₆ , 300K, 600 MHz): δ = 11.38 (s, 1H, indole NH); 9.7, 9.15 (2s, 2H, CS-NH ₂ ); 8.32 (d, 1H); 7.9 (s, 1H); 7.38 (s, 1H); 7.33-7.0 (m, 11H); 4.42 (dd, 1H); 4.17 (d, 1H); 3.47, 3.22 (2 d, 2H, CH ₂ ); 2.99 2.96 (2 d, 2H, CH ₂ ); 2.77-2.67 (m, 2H); 2.6-2.35 (m, 2H); 2.1 (m, 1H); 1.8 (m, 2H); 1.65 (m, 1H); 1.43 (m, 1H); 0.99 (m, 1H); 0.79 (d, 3H, CH ₂ -CH ₃ ); 0.73 (t, 3H, CH ₂ -CH ₃ ) ppm.

MS (ESI): found: 820.0 (M + H ⁺ ) / calculated: 819 g / mol

Data on other conversion examples are compiled in table 2 below:

II. Demonstration of the antagonistic effect of the compounds of the present invention on the LHRH receptor

II. 1A Analysis of the binding of ligands to the LHRH receptor (mebran preparations)

Analysis

Heterologous competitive experiments were performed using membrane preparations from rat pituitary cells, which naturally lead to strong expression of the LHRH receptor. The ligand used in this case was [ ¹²⁵ I] [D-Trp ⁶ ] -LHRH at a concentration of 0.05 nM. Unlabeled [D-Trp ⁶ ] -LHRH at a concentration of 1 μM or test compound at the desired concentration was used for competition. After an incubation period of 90 min at 4 ° C, the bound ligand was measured by scintillation (Halmos et al., Proc. Natl. Acad. Sci. USA, 1996, 93, 2398).

Rating

The result obtained was the percentage of the proportion of bound ligand in the presence of a competitor relative to the proportion of specifically bound ligand in the control experiment (see Results for some compounds in table 3). EC ₅₀ values were calculated by non-linear regression analysis of competition binding curves.

Table 3 The results of the analysis of the binding of ligands to the LHRH receptor, EC ₅₀ and Ki values for some compounds. Compound EC ₅₀ (M) 7 6.9 × 10 ^-9

Compound EC ₅₀ (M) 48 8.0 × 10 ^-9 66 7.2 × 10 ^-10 67 6.9 × 10 ^-9 68 1.0 × 10 ^-9 75 5.9 × 10 ^-10 76 2.7 × 10 ^-10

Figure 1-7 shows the measured curves of competitive binding of ligands to the LHRH receptor with the participation of [ ¹²⁵ I] [D-Trp ⁶ ] -LHRH and some compounds (7, 48, 66, 67, 68, 75 and 76).

II. 1B Analysis of ligand binding to the LHRH receptor (transfected LTK cells)

Materials:

¹²⁵ I-Triptorelin [ ¹²⁵ I- (D) -Trp ⁶ -GnRH] manufactured by Biotrend (Cologne, Germany). The specific activity in each case was 2.13 Ci / mmol.

All other reagents are commercial preparations of the highest degree of purification.

Cell culture:

LTK cells (mouse fibroblasts: ATCC No. CCL-1.3) transfected with the LHRH receptor were grown on DMEM (Invitrogen Life Technologies, Germany) containing penicillin (100 IU / ml), streptomycin (0.1 mg / ml) and glutamine (0.01 mol / L), as well as 10% fetal calf serum (FCS; Invitrogen Life Technologies, Germany) in plastic plates for tissue cultures (Nunc, Germany, 245 × 245 × 20 mm).

Analysis:

Tablets with a 80% confluent cell culture are washed twice with 50 ml of phosphate-buffered saline (PBS), then removed from the surface with a solution of 0.01 M EDTA. Cells are pelleted by centrifugation in a laboratory centrifuge (Kendro, Germany) at 200 g for 5 minutes. Precipitated cells are resuspended in 3 ml of binding medium (DMEM; 10 mM Hepes; 0.5% BSA; 0.1% NaN ₃ ; 1 g / L bacitracin (fresh 100-fold diluted stock solution is added); 0.1 g / L SBTI (fresh 100 is added -fold diluted stock solution) and the number of cells was determined by trypan blue staining in a Neubauer counting chamber.The cell suspension was diluted with binding medium to a concentration of 5 × 10 ⁵ cells / 0.05 ml.

To build competitive binding curves, binding experiments were performed in two parallel experiments. The analytes used in the form of 10 mm solutions in DMSO. They are diluted with binding medium to a concentration of 4 times the final. 25 μl of a diluted solution of the substance is mixed with 25 μl of a solution containing a label ( ¹²⁵ I-triptorelin or ¹²⁵ I-cetrorelix). The concentration of the label-containing substance was adjusted to approximately 50,000 cpm (as measured by a Cobra II γ-radiation counter, PE Liefe Science, Germany) in a final reaction volume of 100 μl.

650 μl of silicone / liquid paraffin mixture (84%: 16%) is added to 650 μl conical tubes (Roth, Germany). Then, 50 μl of the cell suspension and 50 μl of a mixture of the test compound with the compound containing the label are added with a pipette. The tubes are closed with lids and incubated with stirring by vertical rotation in an incubator at 37 ° C for 60 minutes. After incubation, the samples are centrifuged in a centrifuge (Kendro, Germany) at 900 rpm, and then quickly frozen in liquid nitrogen. The lower part of the tubes with cell pellet is cut off and transferred to prepared vials for determining radioactivity (Roth, Germany). The remainder of the conical tube with the remaining supernatant is similarly transferred to the vial to determine radioactivity. Measurements are made in a gamma counter for 1 min / sample.

The activity of the samples is determined by the value of specific binding compared with untreated cells, determined after subtracting the values of non-specific binding (excess unlabeled ligand, 1 μM), using the software GraphPad Prism or OMMM.

II.2 Inhibition of in vitro LHRH-induced secretion of LH from rat pituitary cells

Materials

The concentration of LH in supernatants of cell cultures was determined using an enzyme-linked immunosorbent assay (EIA) of rat LH (rLH) ELISA (RPN 2562) from Amersham Pharmacia Biotech. All other reagents are commercial preparations of the highest degree of purification.

Cell culture

Immature Wistar male rats (Harlan Winkelmann, Germany) were beheaded, their pituitary glands removed and placed in Hank's buffer solution (HBSS) with 0.3% BSA and 10 mM HEPES (pH 7.4). One experiment required pituitary glands from 20 rats. Cells of the anterior pituitary gland were separated from other tissues by incubation in Hank's buffer solution with 10 mM HEPES (pH 7.4), 0.3% BSA, 1 mg / ml hyaluronidase (type VIII), 1 mg / ml soybean trypsin inhibitor, 10 μg / ml DNAsel and 1 mg / ml papain at 37 ° C for 30 minutes. A sterile Pasteur pipette was used to disperse the cells, and subsequently they were precipitated by centrifugation. Cells were plated at a density of 2.5 × 10 ⁵ cells per well in a collagen-coated 48-well plate (Becton Dickinson) in DMEM (Invitrogen Life Technologies, Germany) with 10% fetal calf serum (FCS; Invitrogen Life Technologies, Germany ), 10 ml / L of essential amino acids and 10 ml / L of Pen / Strep (penicillin / streptomycin).

Analysis

The medium was replaced after incubation at 37 ° C, 5% CO ₂ and 95% humidity for 48 hours. The medium was replaced with medium containing LHRH (10 nM), or medium containing LHRH (10 nM) and the analyte at the indicated concentration (see . table). After additional incubation for 3 hours, the cell supernatant was collected and frozen at -20 ° C. The LH content was determined using ELISA three times, in accordance with the manufacturer's instructions (Amersham Pharmacia Biotech).

Table 5 Inhibition of LHRH-stimulated secretion of LH from rat pituitary cells by certain compounds Compound Concentration LH (ng / ml) ± SD % inhibition four 3.3 × 10 ^-8 M 79.3 ± 5.7 67% four 3.3 × 10 ^-9 M - - 7 3.3 × 10 ^-8 M 194.0 ± 13.2 83% 7 3.3 × 10 ^-9 M 194.0 ± 13.2 43% 10 3.3 × 10 ^-8 M 118.7 ± 11.6 39% 10 3.3 × 10 ^-9 M 198.8 ± 4.2 0%

II.3 Suppression of plasma LH concentration in castrated rats

Materials

The plasma LH concentration in castrated rats was measured using an enzyme-linked immunosorbent assay (E1A) LH of rats (rLH) ELISA (RPN 2562) from Amersham Pharmacia Biotech or radioimmunoassay analysis (RIA) for AN R002 rats (Biocode-Hycel, Liège, Belgium). All other reagents are commercial preparations of the highest degree of purification.

Animals

Male Sprague Dawley rats (Harlan Winkelmann, Germany) weighing 190-220 g 10 days before the experiment were euthanized, castrated, and a silicone catheter was implanted for continuous blood sampling.

Analysis

At the beginning of the test, before the introduction of the substance, blood samples were taken and the level of LH was determined. Subsequently, the substance was orally administered at the desired concentration. The number of animals in each group was 8. At the set time, the following blood samples were taken. Blood was collected in heparinized ice-cooled tubes, and plasma was obtained by centrifugation at 3000 g for 10 minutes. Until the determination of LH concentration by ELISA or radioimmunoassay (RIA), plasma samples were stored at -20 ° C. LH concentration was determined by ELISA or radioimmunoassay (RIA) twice, in accordance with the manufacturer's instructions (Amersham Pharmacia Biotech; Biocode-Hycel).

Rating and statistics

Since there were large differences in individual LH concentrations in rats, due to physiologically pulsating secretion of LH, the values before treatment with the analyte were shown as average of individual LH concentrations and correspond to 100%. All other point data for each individual animal was calculated as the relative concentration relative to the concentration of LH before treatment.

Table 6 The relative concentration of LH in rat plasma after treatment with substance 7 at a dosage of 100 mg / kg in Solutol HS15 / 1,2-propanediol (3: 1) Time (h) Relative LH concentration (%) (mean ± SEM compared to pre-treatment concentration) -four 97.4 ± 15.3 -2 110.8 ± 12.2 0 91.8 ± 19.1 +4 19.6 ± 8.9 +6 10.1 ± 3.2 +24 65.1 ± 13.9 +48 110.6 ± 33.0 +72 268.4 ± 93.0

Table 7 The relative concentration of LH in rat plasma after treatment with substance 68 at a dosage of 19 mg / kg in Solutol HS15 / 1,2-propanediol (3: 1) Time (h) Relative LH concentration (%) (mean ± SEM compared to pre-treatment concentration) -24 105.4 ± 12.7 0 95.0 ± 9.3 +4 17.4 ± 3.3 +6 16.0 ± 1.5 +8 12.9 ± 1.0 +12 16.0 ± 2.6 +24 65.7 ± 10.8 +30 78.1 ± 7.7

III. Demonstration of the antagonistic effect of the compounds of the present invention of the general formulas (I, Ia and IB) to receptors of the neurokinin family (NK ₁ and NK ₂ )

Receptor affinity (IC ₅₀ values) of the compounds of the present invention of general formulas (I, Ia and IB) was measured as described in E. Heuillet et al., J. Neurochem., 60: 868-876 (1993) and D. Aharony et al. Mol. Pharmacol, 44: 356-363 (1993), commissioned by Ser (Analysis 826-1h on page 67 and Analysis 826-2h on page 68 of the 2005 catalog).

Analysis Substance IC ₅₀ (M) Ki (M) nH NK1 (h) 68 1.4 × 10 ^-6 6.4 × 10 ^-6 2.0 NK2 (h) 68 1.6 × 10 ^-6 8.5 × 10 ^-6 3.8 NK1 (h) 76 1.9 × 10 ^-6 8.4 × 10 ^-6 2.3 NK2 (h) 76 1.5 × 10 ^-6 8.1 × 10 ^-6 2.3

In FIG. Figures 8–11 show the competitive binding curves obtained by analyzing the binding of ligands to NK ₁ and NK ₂ receptors using [Sar ⁹ , Met (O ₂ ) ¹¹ ] -SP for NK ₁ and [Nle ¹⁰ ] -NKA (4-10) for NK ₂ , as well as some compounds (68 and 76).

IV. Demonstration of ultimate solubility in water for the compounds of the present invention of the general formulas (I, Ia and IB)

The ultimate solubility in water was determined in accordance with the following description: a maximum of 1% DMSO was added to initiate dissolution and improve the wetting of the samples. Content was monitored using an HPLC-UV method. The results are summarized in table 8 below.

V. Demonstration of metabolic stability of the compounds of the present invention of the general formulas (I, Ia and Ib)

Metabolic resistance against liver microsomes (humans, rats) was determined in accordance with the following description: the compounds were incubated at a test concentration of 1 to 10 μM together with rat liver microsomes or human liver microsomes at 37 ° C for 45 min with the addition of NADPH. Then, the non-metabolized amount of the starting compound with respect to 100% was quantified by HPLC MS / MS. The results are summarized in table 9 below.

Claims (23)

1. Derivatives of tetrahydrocarbazole, characterized in that they are represented by the following structural formula (formula I):

in which X ₁ means S or O,
X ₂ and X ₃ mean O,
R1 and R2 are a hydrogen atom,
R3 is a linear, branched C ₁ -C ₆ alkyl or cyclic C ₃ -C ₆ alkyl,
R4 and R6 represent a hydrogen atom,
R5 and R7 are selected independently from one another from the group consisting of a hydrogen atom, halogen atoms, —CF ₃ ;
R9 is a hydrogen atom;
R10 is a hydrogen atom or a radical —R11, —CO — R11, —CO — OR11;
R11 is phenyl-C ₁ -C ₆ alkyl, which is optionally substituted with one or more substituents independently selected from the group consisting of halogen atoms, -C ₁ -C ₆ -alkyl, -CF ₃ , -OCF ₃ , -OH, - OC ₁ -C ₆ -alkyl and -O- (CH ₂ CH ₂ -O) -CH ₃ ;
R8 is phenyl-C ₁ -C ₆ -alkyl, which is substituted on the phenyl group with a substituent selected from the group consisting of -O- (CH ₂ CH ₂ -O) _n -CH ₃ , -O-CO- (CH ₂ CH ₂ —O) _n —CH ₃ , —O — PO (OR12) (OR12 ′), —O — CO — OR13, or, if at least
(i) X ₁ means S, or
(ii) R10 is not a hydrogen atom, and R11 is phenyl-C ₁ -C ₆ -alkyl-,
which is substituted in the phenyl group by one or more substituents independently selected from the group consisting of halogen atoms, —C ₁ –C ₆ alkyl, —CF ₃ , —OCF ₃ , —OH, —OC ₁ —C ₆ alkyl and - O- (CH ₂ CH ₂ -O) _n -CH ₃ ,
R8 is —C ₁ -C ₆ -alkyl- or phenyl-C ₁ -C ₆ -alkyl— in which phenyl is optionally substituted with —OH;
R12 and R12 'mean a hydrogen atom,
R13 is phenyl-C ₁ -C ₆ -alkyl- and
n is any integer from 1 to 10;
and physiologically tolerated salts and enantiomers. 2. Derivatives according to claim 1, in which the compound of formula (I) has an R configuration on a carbon atom substituted by —NH — CX ₃ and —CX ₂ —NH— radicals. 3. The derivatives of claim 2, wherein the compound of formula (I) has an S configuration on a carbon atom substituted with —CX ₃ —NH—, —R8 and —NR9R10 radicals, and also an S configuration on a carbon atom substituted with —NH— radicals CX ₂ -, -R3 and -CX ₁ -NR1R2. 4. Derivatives according to any one of claims 1 to 3, in which X ₁ means S, and R8 means phenyl-C ₁ -C ₆ -alkyl, which is optionally substituted in the phenyl group by a substituent selected from the group consisting of -O- PO (OR12) (OR12 ') and -O-CO-O-R13. 5. The derivatives of claim 1, wherein R8 is phenyl-C ₁ -C ₆ alkyl, which is optionally substituted on the phenyl group with a substituent selected from the group consisting of —O — PO (OR12) (OR12 ′) and —O -CO-O-R13. 6. Derivatives according to any one of claims 1 to 3, in which R10 represents a radical -R11, -CO-R11 or -CO-OR11, and R8 means phenyl-C ₁ -C ₆ -alkyl, which is optionally substituted in the phenyl group up to 3 substituent independently selected from the group consisting of —O — PO (OR12) (OR12 ′) and —O — CO — O — R13. 7. Derivatives according to any one of claims 1 to 3, in which at least one of the radicals R5 and R7 is not a hydrogen atom. 8. The derivatives according to claim 1, in which the radical R5 is a hydrogen or halogen atom, and the radical R7 is a halogen atom or —CF ₃ . 9. Derivatives according to any one of claims 1 to 3, in which R10 represents a radical -CO-R11 or -CO-OR11 or a radical R11. 10. Derivatives according to any one of claims 1 to 3, in which R11 is a benzyl or phenylethyl radical, which is optionally substituted in the phenyl group by one or two substituents independently selected from the group consisting of halogen atoms, groups -C ₁ -C ₆ - alkyl, - CF ₃ , -OCF ₃ , -OH, -OC ₁ -C ₆ -alkyl and -O- (CH ₂ CH ₂ -O) _n -CH ₃ . 11. Derivatives according to any one of claims 1 to 3, in which
R5 represents a hydrogen atom or a halogen atom,
R7 represents a halogen atom or a —CF ₃ group,
R10 represents a radical —CO — R11 or —CO — OR11 or a radical R11,
R11 represents a benzyl or phenylethyl radical which is optionally substituted in the phenyl group by one or two substituents independently selected from the group consisting of halogen atoms, groups —C ₁ -C ₆ -alkyl, —CF ₃ , —OCF ₃ , —OH, -OC ₁ -C ₆ -alkyl and -O- (CH ₂ CH ₂ -O) _n -CH ₃ -, and
R8 is a benzyl or phenylethyl radical which is substituted on the phenyl group with a substituent selected from the group consisting of —O— (CH ₂ CH ₂ —O) _n —CH ₃ , —O — CO— (CH ₂ CH ₂ —O -) _n —CH ₃ , and —O — PO (OR12) (OR12 ′), —O — CO — OR13, or,
if at least
(i) X ₁ represents S, or
(ii) R11 represents a benzyl or phenylethyl radical which is substituted in the phenyl group by at least one of the substituents independently selected from the group consisting of halogen atoms, groups —C ₁ -C ₆ -alkyl, —CF ₃ , - OCF ₃ , —OH, —OC ₁ —C ₆ alkyl and —O— (CH ₂ CH ₂ —O) _n —CH ₃ ,
R8 also represents a benzyl or phenylethyl radical optionally substituted with an —OH group. 12. The derivatives according to claim 1, in which
X ₁ represents S,
R5 and R7 are both halogen atoms, or R5 is a hydrogen atom, and R7 is a —CF ₃ group,
R10 is a radical -CO-R11,
R11 represents a benzyl or phenylethyl radical substituted in the phenyl group by one or two substituents independently selected from the group consisting of halogen atoms, —OCF ₃ and —OCH ₃ groups. 13. The derivatives according to claim 1, in which X ₁ represents O,
R5 and R7 are both halogen atoms, or R5 is a hydrogen atom, and R7 is a —CF ₃ group,
R10 is a radical -CO-R11 or -CO-OR11 or a radical R11,
R11 represents a benzyl or phenylethyl radical substituted in the phenyl group by one or two halogen atoms, and R8 represents a benzyl or phenylethyl radical optionally substituted by an —OH group. 14. The derivatives according to claim 1, in which
X ₁ is S,
R5 and R7 are both halogen atoms,
R10 is a radical -CO-OR11,
R11 represents a benzyl or phenylethyl radical substituted in the phenyl group by one or two halogen atoms, and
R8 represents a benzyl or phenylethyl radical, wherein the phenyl radical is optionally substituted with an —OH group. 15. The derivatives according to claim 1, selected from the group consisting of the following compounds:
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylpropylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- yl carbamoyl] -2-methylpropyl} -carbamic acid 4-chlorobenzyl ether (1),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylpropylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 4-chlorobenzyl ether (2),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutyl carbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3 -alkarbamoyl] -2-methylbutyl} -carbamic acid 4-chlorobenzyl ether (3),
(R) -6,8-dichloro-3 - {(S) -2- [2- {2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2, 3, 4, 9-tetrahydro-1H-carbazole- 3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (4),
(R) -6,8-dichloro-3 - {(S) -2- [2- (3-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2, 3, 4, 9-tetrahydro-1H-carbazole- 3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) -amide (5),
{(S) -1 - [(R) -3 - ((S) -carbamoyl-2-methyl butyl carbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- yl carbamoyl] -2-methylbutyl} -carbamic acid 2-chlorobenzyl ether (6),
{(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2, 3, 4, 9-tetrahydro-1H-carbazole-3- sludge carbamoyl] -2-methyl butyl} -carbamic acid benzyl ester (7),
benzyl 4 - {(S) -3-benzyloxycarbonylamino-3 - [(R) -3 - ((S) -1-carbamoyl-2-methyl butyl carbamoyl) -6,8-dichloro-2, 3, 4, 9 -tetrahydro-1H-carbazol-3-ylcarbamoyl] propyl} phenyl carbonate (8),
[(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2- (4-phosphonooxyphenyl) ethyl] carbamic acid benzyl ester (9),
[(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2,3,4,9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -3- (4-hydroxyphenyl) propyl] carbamic acid benzyl ether (10),
[(S) -1 - [(R) -3 - ((S) -carbamoyl-2-methyl butyl carbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -3- (4-phosphonooxyphenyl) propyl] carbamic acid benzyl ester (11),
[(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutyl carbamoyl) -2, 3, 4, 9-tetrahydro-1H-carbazole-3 -alkarbamoyl] -3- (4-phosphonooxyphenyl) propyl] -carbamic acid benzyl ester (12),
(R) -6,8-dichloro-3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2, 3, 4, 9-tetrahydro-1 H-carbazole -3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) -amide (13),
(R) -6,8-dichloro-3 - [(S) -2- [2- (2-fluorophenyl) acetylamino] -4- (4-hydroxyphenyl) butyrylamino] -2, 3, 4, 9-tetrahydro -1H-carbazole-3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) amide (14),
phosphoric acid mono- (4 - {(S) -3 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2, 3, 4, 9-tetrahydro -1H-carbazol-3-ylcarbamoyl] -3- [2- (2-fluorophenyl) acetylamino] propyl} phenyl ether (15),
(R) -6,8-dichloro-3 - {(S) -2- [3- {4-fluorophenyl) propionylamino] -3-methylpentanoylamino} -2, 3, 4, 9-tetrahydro-1H-carbazole-3 -carboxylic acid ((S) -1-carbamoyl-2-methylpropyl) -amide (16),
(S) -5 - [(R) -3 - ((S) -1-carbamoyl-2-methylpropylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazol-3-ylcarbamoyl ] -5- [3- (4-fluorophenyl) propionylamino] pentylammonium trifluoroacetate (17),
(S) -6,8-dichloro-3 - {(S) -2- [3- (2-hydroxyphenyl) propionylamino] -3-methylpentanoylamino} -2, 3, 4, 9-tetrahydro-1H-carbazole- 3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (18),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutyl carbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3 -alkarbamoyl] -2- [4- (2- {2- [2- (2-methoxy-ethoxy) ethoxy] ethoxy} ethoxy) phenyl] ethyl} carbamic acid benzyl ester (19),
(R) -6,8-dichloro-3 - ((S) -2- {3- [2- (2- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} ethoxy) phenyl ] -propionylamino} -3-methylpentanoylamino) -2, 3, 4, 9-tetrahydro-1H-carbazole-3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) -amide (20),
(R) -6,8-dichloro-3 - ((S) -2- {2- [2- (2- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} ethoxy) phenyl ] -acetylamino} -3-methylpentanoylamino) -2, 3, 4, 9-tetrahydro-1H-carbazole-3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) -amide (21),
(R) -6,8-dichloro-3 - [(S) -2- [3- (2-fluorophenyl) propionylamino] -4- (4-hydroxyphenyl) butyrylamino] -2, 3, 4, 9-tetrahydro -1H-carbazole-3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (22),
(R) -6,8-dichloro-3 - {(S) -2- [3- (2-fluorophenyl) propionylamino] -3-methylpentanoylamino) -2, 3, 4, 9-tetrahydro-1H-carbazole-3 -carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) -amide (23),
{(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2, 3, 4, 9-tetrahydro-1H-carbazole-3- yl carbamoyl] -3- [4- (2- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} ethoxy) phenyl] propyl} carbamic acid benzyl ester (24),
{(S) -1 - [(R) -8-chloro-6-fluoro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2, 3, 4, 9-tetrahydro-1H-carbazole- 3-ylcarbamoyl] -2-methylbutyl} -carbamic acid benzyl ester (25),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- sludge carbamoyl] -2-methylbutyl} -carbamic acid 3-methylbenzyl ether (26),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- yl carbamoyl] -2-methyl butyl} -carbamic acid 2,6-difluorobenzyl ether (27),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutyl carbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3 -alkarbamoyl] -2-methyl-butyl} -carbamic acid 3,5-difluorobenzyl ether (28),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methyl butyl} -carbamic acid 3,5-dichlorobenzyl ether (29),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methyl butyl} -carbamic acid 3-fluorobenzyl ether (30),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutyl carbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3 -alkarbamoyl] -2-methyl-butyl} -carbamic acid 2-fluorobenzyl ether (31),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutyl carbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3 -alkarbamoyl] -2-methyl-butyl} -carbamic acid 3-chlorobenzyl ether (32),
((S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -8-chloro-6-fluoro-2, 3, 4, 9-tetrahydro-1H-carbazole- 3-ylcarbamoyl] -2-methyl butyl} -carbamic acid 3,5-difluorobenzyl ether (33),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -8-chloro-6-fluoro-2, 3, 4, 9-tetrahydro-1H-carbazole- 3-ylcarbamoyl] -2-methyl butyl} -carbamic acid 3-fluorobenzyl ether (34),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -8-chloro-6-fluoro-2, 3, 4, 9-tetrahydro-1H-carbazole- 3-ylcarbamoyl] -2-methyl butyl} -carbamic acid 2-fluorobenzyl ether (35),
[(S) -1 - [(R) -3 - ((8) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -3- (4-hydroxyphenyl) propyl] carbamic acid 3-fluorobenzyl ether (37),
[(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -3- (4-hydroxy-phenyl) propyl] -carbamic acid 2-fluorobenzyl ether (38),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- yl carbamoyl] -2-methyl butyl} -carbamic acid 2- (2-fluorophenyl) ethyl ether (40),
{(S) -1 - [(R) -8-chloro-6-fluoro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2, 3, 4, 9-tetrahydro-1H-carbazole- 3-ylcarbamoyl] -2-methyl butyl} -carbamic acid 2-fluorobenzyl ether (41),
{(S) -1 - [(R) -8-chloro-6-fluoro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2, 3, 4, 9-tetrahydro-1H-carbazole- 3-ylcarbamoyl] -2-methyl butyl} -carbamic acid 3-fluorobenzyl ether (42),
[(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2, 3, 4, 9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -3- (4-hydroxyphenyl) propyl] carbamic acid 2-fluorobenzyl ether (43),
[(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2, 3, 4, 9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -3- (4-hydroxyphenyl) propyl] carbamic acid 3-fluorobenzyl ether (45),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methyl butyl} -carbamic acid 3-methoxybenzyl ether (47),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methyl butyl} -carbamic acid 4-fluorobenzyl ether (48),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 2-methylbenzyl ether (49),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutyl carbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3 -alkarbamoyl] -2-methylbutyl} -carbamic acid 2,3-dimethoxybenzyl ether (50),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 2-methoxybenzyl ether (51),
(R) -6,8-dichloro-3 - {(S) -2- [2- (2-fluorophenyl) ethylamino] -3-methylpentanoylamino} -2, 3, 4, 9-tetrahydro-1H-carbazole-3 -carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (52),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 2-trifluoromethylbenzyl ether (53),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutyl carbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3 -alkarbamoyl] -2-methylbutyl} -carbamic acid 3-trifluoromethylbenzyl ether (54),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 3-trifluoromethoxybenzyl ether (55),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -6,8-dichloro-2, 3, 4, 9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 2-trifluoromethoxybenzyl ether (56),
{(S) -1 - [(R) -6,8-dichloro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2, 3, 4, 9-tetrahydro-1H-carbazole-3- ilcarbamoyl] -2-methylbutyl} -carbamic acid 4-fluorobenzyl ether (57),
(R) -6,8-dichloro-3 - {(S) -2- [2- (4-fluorophenyl) ethylamino] -3-methylpentanoylamino} -2, 3, 4, 9-tetrahydro-1H-carbazole-3 -carboxylic acid (S) -1-carbamoyl-2-methylbutyl) amide (58),
(R) -6,8-dichloro-3 - {(S) -2- [2- (2,6-difluorophenyl) acetylamino] -3-methylpentanoylamino} -2, 3, 4, 9-tetrahydro-1H- carbazole-3-carboxylic acid (S) -1-carbamoyl-2-methylbutyl) amide (59),
{(S) -1 - [(R) -8-chloro-6-fluoro-3 - ((S) -2-methyl-1-thiocarbamoylbutylcarbamoyl) -2, 3, 4, 9-tetrahydro-1H-carbazole- 3-ylcarbamoyl] -2-methylbutyl} -carbamic acid 4-fluorobenzyl ether (60),
(R) -6,8-dichloro-3 - {(S) -2- [2- (3-fluorophenyl) ethylamino] -3-methylpentanoylamino} -2, 3, 4, 9-tetrahydro-1H-carbazole- 3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (61),
(R) -8-chloro-3 - {(S) -2- [2- (2,6-difluorophenyl) acetylamino] -3-methylpentanoylamino} -6-fluoro-2, 3, 4, 9-tetrahydro 1H-carbazole-3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) amide (62),
(R) -8-chloro-6-fluoro-3 - {(S} -2- [2- (4-fluorophenyl) ethylamino] -3-methylpentanoylamino} -2, 3, 4, 9-tetrahydro-1H-carbazole -3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) -amide (63),
{(S) -1 - [(R) -3 - ((S) -1-carbamoyl-2-methylbutylcarbamoyl) -8-chloro-6-fluoro-2, 3, 4, 9-tetrahydro-1H-carbazole- 3-ylcarbamoyl] -2-methylbutyl} carbamic acid 4-fluorobenzyl ether (64),
(R) -8-chloro-6-fluoro-3 - {(S) -2- [2- (4-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2, 3, 4, 9-tetrahydro-1H- carbazole-3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) amide (65),
(R) -8-chlorop-3 - {(S) -2- [2- (2,4-difluorophenyl) acetylamino] -3-methyl pentanoylamino} -6-fluoro-2, 3, 4, 9-tetrahydro -1H-carbazole-3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) amide (66),
(R) -8-chloro-6-fluoro-3 - {(S) -2- [2- (4-fluorophenyl) ethylamino] -3-methylpentanoylamino} -2, 3, 4, 9-tetrahydro-1H -carbazole-3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) -amide (67),
(R) -8-chloro-6-fluoro-3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2, 3, 4, 9-tetrahydro-1H- carbazole-3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) amide (68),
(R) -8-chloro-6-fluoro-3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -2, 3, 4, 9-tetrahydro-1H- carbazole-3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (69),
(R) -3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -8-trifluoromethyl-2, 3, 4, 9-tetrahydro-1H-carbazole-3- carboxylic acid ((S) -2-cyclopropyl-1-thiocarbamoylethyl) -amide (70),
(R) -3 - {(S) -2- [2- (2,6-difluorophenyl) acetylamino] -3-methylpentanoylamino) -8-trifluoromethyl-2, 3, 4, 9-tetrahydro-1H-carbazole- 3-carboxylic acid ((S) -2-cyclopropyl-1-thiocarbamoylethyl) -amide (71),
(R) -8-chloro-6-fluoro-3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methyl pentanoylamino} -2, 3, 4, 9-tetrahydro-1H -carbazole-3-carboxylic acid ((S) -2-cyclopropyl-1-thiocarbamoylethyl) -amide (72),
(R) -3 - {(S) -2- [2- (2,6-difluorophenyl) acetylamino] -3-methyl pentanoylamino} -8-trifluoromethyl-2, 3, 4, 9-tetrahydro-1H-carbazole -3-carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) -amide (73),
(R) -3 - {(S) -2- [2- (2,6-difluorophenyl) acetylamino] -3-methylpentanoylamino} -8-trifluoromethyl-2, 3, 4, 9-tetrahydro-1H-carbazole- 3-carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (74),
(R) -3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -8-trifluoromethyl-2, 3, 4, 9-tetrahydro-1H-carbazole-3- carboxylic acid ((S) -1-carbamoyl-2-methylbutyl) amide (75),
(R) -3 - {(S) -2- [2- (2-fluorophenyl) acetylamino] -3-methylpentanoylamino} -8-trifluoromethyl-2, 3, 4, 9-tetrahydro-1H-carbazole-3- carboxylic acid ((S) -2-methyl-1-thiocarbamoylbutyl) amide (76),
(R) -S-chloro-3 - {(S) -2- [2- (2,6-difluorophenyl) acetylamino] -3-methyl pentanoylamino} -6-fluoro-2, 3, 4, 9-tetrahydro -1H-carbazole-3-carboxylic acid ((S) -2-cyclopropyl-1-thiocarbamoylethyl) amide (77). 16. Derivatives according to any one of claims 1 to 15, which exhibit the activity of LHRH receptor antagonists. 17. A pharmaceutical composition having antagonistic activity for the LHRH receptor, comprising a pharmacologically effective amount of at least one of the derivatives of claims 1-15, and a pharmaceutically acceptable carrier and / or excipient. 18. The composition according to 17, in which the active ingredient is contained in a standard dose of from 0.001 mg to 100 mg per kg of body weight of the patient. 19. The use of derivatives according to any one of claims 1 to 13 for the preparation of a medicament that acts as an antagonist of the LHRH receptor or an antagonist of receptors of the neurokinin family of the NK ₁ and / or NK ₂ receptor. 20. The use according to claim 19 as a medicine for the treatment of benign or malignant neoplasms, for controlling male reproductive function, in hormone therapy, hormone replacement therapy, for treating and / or controlling female reproductive insufficiency or infertility, for controlled stimulation of the ovaries with in vitro conception, for female contraception and for protection against side effects during chemotherapy. 21. The use according to claim 19, in which the drug is intended for the treatment of pathological conditions mediated by the LHRH receptor, or pathological conditions that can be treated by modulating the LHRH receptor, and are selected from the group consisting of benign prostatic hyperplasia (BPH), endometriosis , uterine fibroids, uterine fibroids, endometrial hyperplasia, dysmenorrhea, dysfunctional uterine bleeding (menorrhagia, metrorrhagia), early puberty, hirsutism, polycystic ovary syndrome, hormone-dependent non plastic diseases, HIV infections or AIDS, neurological or neurodegenerative disorders, AIDS dependent complex (ARC), Kaposi’s sarcoma, brain and / or nervous system tumors and / or meningitis, dementia and Alzheimer's disease. 22. The use of claim 21, wherein the hormone-dependent neoplasms are selected from the group consisting of prostate cancer, breast cancer, uterine cancer, endometrial cancer, cervical cancer, ovarian cancer. 23. The use according to claim 19 as a medicine for the treatment or prevention of nausea and vomiting, for the treatment of pain, inflammation, as well as rheumatic and arthritic pathological conditions.

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