WO2011151782A1

WO2011151782A1 - A role for somatostatin to modulate initiation of follicular growth in the human ovary

Info

Publication number: WO2011151782A1
Application number: PCT/IB2011/052380
Authority: WO
Inventors: Alain Gougeon; Jean-Pierre Gotteland; Ernest Loumaye
Original assignee: Preglem Sa
Priority date: 2010-06-02
Filing date: 2011-05-31
Publication date: 2011-12-08

Abstract

The present invention relates to a method of treating and/or preventing gynecological diseases, by modulating a receptor which is specifically and highly expressed in granulosa cells and oocytes of primates.

Description

A role for somatostatin to modulate initiation of follicular growth in the human ovary

ABSTRACT The present invention relates to a method of treating and/or preventing gynecological diseases, by modulating a receptor which is specifically and highly expressed in granulosa cells and oocytes of primates.

BACKGROUND OF THE INVENTION

In mammals, the mechanisms regulating initiation of follicle growth, a critical step for female reproduction, remain poorly understood. Whether follicle growth results from activation of resting follicles, from removal of an inhibition, or both, remains to be

established. Kit ligand (KL) is the first peptide that was demonstrated to trigger initiation of follicular growth (1-3). However, recent studies have increased the number of molecules suggested to activate transition from resting to early growing follicles.

By using a system of neonatal rat ovary cultured during 12-14 d, basic fibroblast growth factor (4), leukemia inhibiting factor (5), insulin (6,), bone morphogenetic protein 4 (7), nerve growth factor, brain-derived neurotrophic factor and neurotrophins (8, 9), keratinocyte growth factor (10) and platelet-derived growth factor (11) have been shown to promote the primordial to primary follicle transition. Conversely, analyses of aging ovaries in anti-Mullerian hormone (AMH) knockout mice (12) and of neonatal mice ovaries cultured in the presence of AMH, where ovaries contained 40% fewer growing follicles compared with control ovaries (13), led to the conclusion that AMH may maintain follicles at the resting stage.

The kit system, which includes the ligand (KL) and a tyrosine kinase receptor (c-kit), is so far the best documented molecular pathway involved in the activation of resting follicles. KL is produced by granulosa cells (GC), and c-kit is present at the theca interna and oocyte cell surface (14-18). In mice bearing spontaneous mutations of Steel, the gene coding for KL (19), follicular growth is more or less impaired according to the degree of gene inactivation (1). Similarly, in mice bearing an inactivating mutation of the gene coding for the receptor c- kit (20) or treated with an antibody against c-kit (2), folliculogenesis

is strongly impaired. In addition, KL stimulates GC proliferation via an oocyte-mediated effect (21). As demonstrated by Packer et al. (22), cAMP up-regulates Steel, and

consequently, molecules that have the ability to inhibit cAMP generation might inhibit KL production and subsequently activation of resting follicles and follicle growth.

Somatostatin (SST), a peptide found in the central nervous system and several peripheral tissues, is an inhibitory regulator of a variety of systems, including cAMP generation in many cell types (23). Its effects are mediated by five SST receptor (SSTR) subtypes (SSTR-1 to SSTR-5) that are heterogeneously distributed in various tissues. SSTR-2 and SSTR-5 are the major subtypes. In the boar testis, SST inhibits KL production by Sertoli cells (24). It can therefore be hypothesized that SST displays the same inhibitory effect on KL produced by GC in the ovary. By inhibiting KL synthesis, SST could subsequently inhibit both initiation and follicle growth. Previous studies in various species have shown that SST (25-29) and SSTR-5 (30) are present in the ovary and that SST (31-34) or its agonist octreotide (35) may alter ovarian function in vitro. Although they sometimes induce ovarian alterations, such as increased follicle atresia (36), reduction of either androgen (37) or IGF- binding protein production (38), ovulation improvement in women suffering from of polycystic ovary syndrome (39-41), in vivo treatments with SST or its agonist octreotide do not demonstrate a direct effect on the ovary because of their effect on insulin and

gonadotropins.

However, Nestorovic et al. (42) have shown that SST administered in vivo to peripubertal mice not only decreased FSH and LH circulating levels but also blocked initiation of follicle growth, a process that occurs without FSH and LH (43), therefore suggesting that SST might directly act on ovarian cells.

However, to Inventor's knowledge, the effect of SST antagonists on ovarian function has not yet been tested.

In a recent study (44), the Inventors looked for the presence of a functional SST system in the mouse ovary and tested the hypothesis that conversely to SST or its agonists, a SSTR-2 antagonist could stimulate initiation as well as subsequent follicle growth. The SSTR-2 and -5, but not SSTR-1, -3 or -4, were identified at the transcriptional and translational (mainly in granulosa cells) levels. Both KL and BIM-23627 triggered a reduction of the percentages of primordial follicles and an increase of the percentages of primary and secondary follicles when compared with control ovaries from the same animal.

However, despite the above disclosure, there is still a need to specifically

i) act on the ovarian reserve and ii) treat and/or prevent gynecological diseases, by modulating a receptor which is specifically and highly expressed in granulosa cells and oocytes of primates.

SUMMARY OF THE INVENTION

The present invention concerns a method of modulating early follicle growth and/or ovarian follicle atresia comprising administering to a patient in need thereof a medicament comprising a somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof.

A further object of the present invention is to provide the use of a somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof, for preparing a medicament intended to modulate early follicle growth and/or ovarian follicle atresia.

Another object concerns a method of treating and/or preventing a gynecological disease or condition in a patient in need thereof comprising administering to said patient a

pharmaceutical composition comprising a somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof.

Still other objects of the invention are to provide the use of a somatostatin receptor 4 ligand analog antagonist or antagonist, a pharmaceutically acceptable salt thereof or an active metabolite thereof, for preparing a medicament in the treatment and/or prevention of a gynecological disease or condition BRIEF DESCRIPTION OF THE FIGURES

Figure 1 : SSTR4 immunostaining (red precipitate) of oocytes in resting (black arrows) and primary (blue arrows) monkey follicles.

The immunostaining is homogeneous in the oocytes and follicles. However in certain oocytes and follicles regions the immunostaining is particularly visible reflecting important

concentration of SSTR4

Figure 2: SSTR4 immunostaining (red precipitate) of the oocyte ooplasm in a resting primordial follicle in the human ovary.

The immunostaining is homogeneous in the follicles. However in certain follicles regions the immunostaining is particularly visible reflecting important concentration of SSTR4

Figure 3: SSTR4 immunostaining (red precipitate) in the oocyte of resting follicles (black arrow) and in the oocyte (O) and granulosa cells (GC) of growing follicles (blue arrow) in the monkey ovary. The immunostaining is homogeneous in the oocytes and follicles. However in certain oocytes and follicles regions the immunostaining is particularly visible reflecting important concentration of SSTR4 Figure 4: SSTR4 immunostaining (red precipitate) in a large antral follicle from a human ovary; granulosa cells (GC) and theca interna (TI) are strongly positive.

The immunostaining is homogeneous in the follicles. However in certain follicles regions the immunostaining is particularly visible reflecting important concentration of SSTR4 DESCRIPTION OF THE INVENTION

The present invention relates to the a method of modul ating early fol licl e growth and/or ovarian follicle atresia comprising administering to a patient in need thereof a medicament comprising a somatostatin receptor 4 (SSTR-4) analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof .

Surprisingly, the inventors of the present invention have shown the presence of SST receptors (SSTRs), and especially of SSTR-4, in primate ovary. This SSTR-4 receptor is expressed at the highest level, when compared to the other SSTRs, in small number of extra- ovarian tissues. These results are relevant for therapeutic applications of somatostatin analogs in modulating the ovarian reserve in primates as well as for treating and/or preventing gynecological diseases in which the SSTR-4 is involved. Somatostatin receptor type 4 (SSTR4) is a protein that in humans is encoded by the SSTR4 gene. Somatostatin acts at many sites to inhibit the release of many hormones and other secretory proteins. The biologic effects of somatostatin are probably mediated by a family of G protein-coupled receptors that are expressed in a tissue-specific manner. SSTR4 is a member of the superfamily of receptors having seven transmembrane segments and is expressed in highest levels in fetal and adult brain and lung.

Usually, the "patient in need thereof is well-recognized in the art, and, is used herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human patient, and even more preferably a human female.

The general term "analog" is commonly used to describe compounds derived from the native structure and selected for their enhanced agonist or antagonist activity. By

"somatostatin analog" is thus meant a compound derived from the native structure of somatostatin and selected for its enhanced agonist or antagonist activity. A somatostatin analog can be either i) synthetic, i.e. obtained by chemical synthesis (e.g peptide synthesis) or ii) recombinant i.e. obtained by recombinant techniques, where the somatostatin analog amino acid sequence is encoded by a cloned gene and expressed and recovered from expression cells.

Generally, the somatostatin receptor 4 ligand analog of the invention is selected among the somatostatin receptor antagonist analogs or the somatostatin receptor agonist analogs.

As used herein, a "somatostatin receptor agonist" is meant a compound that has a high binding affinity (e.g., Ki of less than 100 nM, or preferably less than 10 nM, or more preferably less than 1 nM) for a somatostatin receptor, in particular SSTR-4, and elicits a somatostatin-like effect; for example, in an assay for the inhibition of cAMP intracellular production. Preferably, the somatostatin receptor agonist analog is a selective agonist analog. A selective agonist analog is meant a somatostatin receptor 4 agonist which has a higher binding affinity (i.e., lower Ki) for the SSTR-4 subtype than for any other somatostatin receptor subtype. This binding affinity can readily bee assessed by those skilled in the art.

By "somatostatin antagonist analog" is meant a compound that has a high binding affinity (e.g., Ki of less than 100 nM, or preferably less than 10 nM, or more preferably less than 1 nM) for a somatostatin receptor, in particular SSTR-4, as determined in an antagonist test effect. Preferably also, the somatostatin antagonist analog is a "somatostatin selective antagonist" which is meant a somatostatin receptor 4 antagonist which has a higher binding affinity (i.e., lower Ki) for the SSTR-4 subtype than for any other somatostatin receptor subtype. This binding affinity can readily been assessed by those skilled in the art. An "active metabolite" is a product produced through metabolism in the body of a specified compound or salt thereof and which exhibits the same biological activity as the specified compound. Active metabolites of a somatostatin receptor analog or of a salt of said somatostatin receptor analog may be identified using routine techniques known in the art and their activities determined using tests such as known in the art. Such metabolites may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterifi cation, enzymatic cleavage, monohydroxylation, di-hydroxylation methylation, glucuronidation, O- glucuronidation, sulfation, amide-hydrolysis, de-esterification, activation and the like, of the administered somatostatin receptor analog or of a salt of said somatostatin receptor analog. Accordingly, the invention includes active metabolites of somatostatin receptor analog or of a salt of said somatostatin receptor analog, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such metabolite may also be produced in vitro by oxidation, reduction, hydrolysis, amidation, deamidation,

esterification, deesterification, or enzymatic cleavage of the corresponding somatostatin receptor analog or salt of said somatostatin receptor analog.

A "peptide" as used herein, designates a series of amino acid residues, modified or not, usually connected to the other by peptide bonds between the alpha-amino and carboxy groups of adjacent residues. The term "modulating" (or "'modulate'') refers to altering (negatively or positively) the early follicle growth and/or ovarian follicle atresia by administering a somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof. "Ovarian follicle atresia" refers to a process through which ovarian follicles undergo a degenerative process called atresia during reproductive life. Almost 99% of ovarian follicles undergo this process and only 1 % proceeds into ovulation the few that are selected to become ovulatory follicles are transformed into corpora lutea following ovulation. Somatostatin agonist analog:

Somatostatin agonist analogs or somatostatin receptor agonist analogs that are considered for this invention are selected from the group comprising, but not limited to, native somatostatin, natural somatostatin, recombinant somatostatin, recombinant agonist analogs of somatostatin or synthetic agonist analogs of somatostatin. Natural or native Somatostatin (SST) is a cyclic peptide present in two forms in the organism, one form containing 14 amino acids and one form containing 28 amino acids. The biological activity of these two forms of SST is similar. The SST-14 form is the predominant form in the central nervous system. It inhibits the secretion of the growth hormone by the

somatotrope cells of the anterior pituitary. The SST-28 form is preferably expressed in the stomach and the pancreas. The biological activity of SST is induced by means of a series of membrane receptors coupled with a protein G, 5 sub-types of which have been characterized, namely the sub-types SSTR1, SSTR2, SSTR3, SSTR4 and SSTR5 (45-47).

Agonist analogs of somatostatin have been described in particular in patent applications WO 01/00676, WO 98/08528 or in patents US 6,387,932, US 6,268,342, US 6,057,338, US 6,025,372. U.S. published Patent Application No. 2002/0137676 discloses methods for treatment of endothelial cells using somatostatin receptor-selective ligands which are specific either to SSTR1 or SSTR4.

According to a particular variant of the invention, the somatostatin agonist analogs can be compounds of general formula (I)

in which:

Xi is a radical of formula (a) or (b)

Rl independently representing each time it occurs an optionally substituted phenyl radical in which the optional substituents are independently chosen from a halogen atom and the methyl, ethyl, methoxy and ethoxy radicals,

R2 representing -Z1-CH2-R1, -CH2-CO-0- CH2-R1,

Zl being O or S;

X2 is an -amino acid having an aromatic residue on the side chain C a, or an amino acid unit chosen from Dab, Dpr, Dpm, His, (Bzl)HyPro, thienyl-Ala, cyclohexyl-Ala and t-butyl- Ala;

A is a divalent residue chosen from Pro,

R3 is NR8R9-C2-6alkylene, guanidino-C2-6alkylene or C2-6alkylene-COOH, R3a is H, Cl-4alkyl or has, independently, one of the meanings given for R3, R3b is H or CI -4 alkyl, Ra is OH or NR5R6, Rb is -(CH2)l-3- or -CH(CH3)-, R4 is H or CH3, R4a is benzyl optionally substituted on the aromatic ring, each of R5 and R6 is independently H, Cl-4alkyl, ω-amino- Ci_₄alkylene, co-hydroxy-Ci_₄alkylene or acyl, R7 is a direct bond or Cl-6alkylene, each of R8 and R9 is independently H, Cl-4alkyl, co-hydroxy-C₂_₄alkylene, acyl or CH20H-(CHOH)c- CH2- in which c is 0, 1, 2, 3 or 4, or R8 and R9 form together with the nitrogen atom to which they are attached a heterocyclic group which can include an additional heteroatom, and Rl 1 is benzyl optionally substituted on the aromatic ring, -(CH2)l-3-OH, CH3-CH(OH)- or - (CH2)l-5-NR5R6, and ZZa is a natural or unnatural -amino acid unit; it being understood that XI, X2 and Lys each have the configuration L; or are pharmaceutically acceptable salts or protected forms of compounds of general formula

(I). ZZa can have a configuration D or L. ZZa can be for example Thr, Ser, Ala, Val, lie, Leu, Nle, His, Arg, Lys, Nal, Pal, Tyr, Trp, Phe substituted on the aromatic ring or N^a-benzyl-Gly. When ZZa is Phe, its benzene ring can be substituted for example by NH2, N02, CH3, OCH3 or a halogen atom, preferably in position para. When ZZa is Phe, its benzene ring is preferably not substituted.

When A comprises a Pro amino acid residue, any substituent present on the proline ring, for example R3-NH-CO-0- etc., is preferably in position 4. Such substituted proline residues can be in the cis form, for example

such as in the trans form. Each geometric isomer individually as well as mixtures of these isomers are included in the uses according to the invention. When A is (NR8R9-C2-6alkylene-NH-CO-0)Pro- in which NR8R9 forms a heterocyclic group, said group can be aromatic or saturated and can include a nitrogen atom or a nitrogen atom and a second hetero atom chosen from nitrogen and oxygen. Preferably, the heterocyclic group is for example pyridyl or morpholino. The C2-6alkylene radical in this residue is preferably -CH2-CH2-.

An acyl group such as R5, R6, R8 and R9 in A can for example be an R12CO- group in which R12 is H, Cl-4alkyl, C2-4alkenyl, C3-6cycloalkyl or benzyl, and methyl or ethyl. When R4a or Rl 1 in A is benzyl substituted on the aromatic ring, the benzene ring can be substituted as indicated above for ZZa. According to an other variant of the invention, the somatostatin agonist analogs can be compounds of general formula (II)

in which R is NRioRn-C₂_₆alkylene or guanidine-C₂_₆alkylene, and each of Rio and Rn is independently H or Ci_₄alkyl or are pharmaceutically acceptable salts or protected forms of compounds of general formula (II).

Preferably, R is NRioRn-C₂-6alkylene. The preferred compounds of general formula (II) are those such that R is 2-aminoethyl (and in particular the peptide SOM 230 of the formula cyclo[{4-(NH₂-C₂H4-NH-CO-0-)Pro}-Plig-DTrp-Lys-Tyr(4-Bzl)-Plie] the structure of which is reproduced below).

By "protected form" of a compound of general formula (I) or (II), is meant in the present application a somatostatin analog in which at least one of the amino groups is protected and the deprotection of which (which preferably is itself carried out in physiological medium) leads to a compound of general formula (I) or (II). Suitable protective groups for amino groups are for example those described in the ref. 48. An example of such a protective group for an amino group is the acetyl group.

Among the somatostatin agonist analog s which can be used according to the invention, lanreotide, octreotide, vapreotide, SOM 230 (see structure below), MK-678 (peptide of structure cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe)), BIM-23190 (peptide of structure N- hydroxyethylpiperazinyl-acetyl-D-Phe-cyclo[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH₂), BIM- 23197 (peptide of structure Hepes-D-Phe-cyclo[Cys-Tyr-D-Trp-Lys-Abu-Cys]-Thr-NH₂ in which Abu represents aminobutyric acid), BIM-23268 (peptide of structure cyclo[Cys-Phe- Phe-D-Trp-Lys-Thr-Phe-Cys]-NH₂), PTR-3173 (see structure below), TT-232 (of structure D-Phe-cyclo[Cys-D-Trp-Lys-Cys]-Thr-NH₂), and their pharmaceutically acceptable salts can more particularly be mentioned; the synthetic peptide of formula c[Tic-Tyr-DTrp-Lys-Abu- Phe] and its pharmaceutically acceptable salts can also be mentioned; finally the KE 108 peptide of formula Tyr°-(cyclo-D-Dab-Arg-Phe-Phe-D-Trp-Lys-Thr-Phe) described in particular in the ref. 49, can be mentioned. The use of lanreotide, octreotide or one of their pharmaceutically acceptable salts, and more particularly lanreotide or one of its

pharmaceutically acceptable salts is quite particularly preferred.

In a similar way to the compounds of general formula (I) or (II), the above-mentioned peptides can also be presented in a protected form. The definition of the protected form given above for the compounds of general formulae (I) or (II) is applicable mutatis mutandis. Somatostatin antagonist analog:

Somatostatin antagonist analogs are also considered for this invention and are selected from the group comprising, but not limited to recombinant antagonist analogs of somatostatin or synthetic antagonist analogs of somatostatin.

The somatostatin antagonist analog can be a cyclic or non cyclic polypeptide, a fusion or recombination protein, a non-peptide chemical entity (i.e. a peptidomimetic) or also a "SS- like " peptide such as corticostatin. The antagonist analogs to be used must have a high affinity for the SST receptor 4 and inhibit the functional activity of SST14 or SST28 such as the inhibition of the secretion of growth hormone by somatotrope cells of the pituitary and/or the inhibition of the in vitro proliferation of pituitary adenoma cells. Preferably, the somatostatin antagonist analog has a high affinity for sub-type 4.

A somatostatin antagonist analog which can be used in the present invention can for example be a peptide of general formula

in which:

A¹ is an optionally substituted aromatic -amino acid;

A is an optionally substituted aromatic a-amino acid;

A is Dab, Dap, Lys or Orn; A⁴ is y5-Hydroxyvaline, Ser, Hser, or Thr;

A⁵ is an optionally substituted aromatic D- or L- a-amino acid; and

Y¹ is OH, NH₂ or NHR¹, R¹ being (Ci_₆)alkyl;

each optionally substituted aromatic a-amino acid being optionally substituted with one or more substituents independently chosen from the group comprising a halogen atom and the groups N0₂, OH, CN, (C_1-6)alkyl, (C₂-₆)alkenyl, (C₂-₆)alkynyl, (Ci-₆)alkoxy, Bzl, O-Bzl and NR⁹R¹⁰, R⁹ and R¹⁰ each being independently H, O, or (Ci-₆) alkyl; and each nitrogen atom with a peptide amide bond and the amino group of A¹ being optionally substituted with a methyl group, it being understood that there is at least one such methyl group in a peptide of general formula (III);

or a pharmaceutically acceptable salt of a peptide of general formula (III).

By "aromatic a-amino acid" is meant an amino acid residue of formula

in which Zi is a radical containing an aromatic ring and Z₂ is a hydrogen atom or a radical containing an aromatic ring. Examples of such radicals containing an aromatic ring include, but are not limited to, a benzene or pyridine ring and the following structures with or without one or more X substituents on the aromatic ring (X being, independently each time that it occurs, a halogen atom, N0₂, C¾, OCH₃, CF₃ or OH):

Other examples of an "aromatic a-amino acid" according to the invention are substituted His, such as MeHis, His (τ-Me) or His (π-Me).

Other somatostatin antagonist analogs have been described in particular in the patent applications PCT WO 98/08528, WO 98/08529, WO 98/24807, WO 98/44921, WO

98/44922, WO 98/45285 and WO 99/22735, or also in the patents US 6,387,932, US 6,262,229, US 6,063,796, US 6,057,338, US 6,025,372, US 5,925,618, US 5,846,934 and US 4,508,711.

Among the somatostatin antagonist analogs which can be used according to the invention and their pharmaceutically acceptable salts, there may more particularly be mentioned the following peptides of general formula (III):

- Cpa-cyclo[D-Cys-Pal-D-Trp-N-Me-Lys-Thr-Cys]-D-Trp-NH_2;

- Cpa-cyclo[D-Cys-Tyr-D-Trp- N-Me-Lys-Thr-Cys]-Nal-NH_2;

- Cpa-cyclo[D-Cys-Pal-D-Trp- N-Me-Lys-Thr-Cys]-Nal-NH_2; the peptide known by the code name AC- 178,335 (of structure acetyl-D-His-D-Phe-D-Ile-D- Arg-D-Trp-D-Phe-NH₂); the octapeptide known by the code name ODN-8 (cf. Fig. 1 of the ref. 50);

the peptide known by the code name SB-710411 (of structure Cpa-cyclo[D-Cys-Pal-D-Trp- Lys-Val-Cys]-Cpa-amide);

- the peptide known by the code name BIM-23056 (of the structure represented below); - the compound known by the code name BN-81674 (of the structure represented below);

- the compound known by the code name SRA-880 (of the structure represented below); and their pharmaceutically acceptable salts.

In a similar way to the compounds of general formula (I) or (II), the above-mentioned peptides (including those corresponding to general formula (III)) can also be presented in a protected form. The definition of the protected form given above for the compounds of general formulae (I) or (II) is applicable mutatis mutandis.

Also particularly considered are the following compounds wherein Al is Cpa, A2 is Pal, A3 is Lys, A4 is Thr, and A5 is Nal and wherein Al is Cpa, A2 is 4Pal, A3 is Lys, A4 is Thr, and A5 is 2Nal. The present invention also provides for the use of a somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof, for preparing a medicament intended to modulate early follicle growth and/or ovarian follicle atresia.

By "pharmaceutically acceptable salt" of a somatostatin receptor 4 ligand analog is meant, in particular in the present application, addition salts with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, diphosphate and nitrate or with organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulphonate, p-toluenesulphonate, pamoate and stearate. Also included in the field of the present invention, when they can be used, the salts formed from bases such as sodium or potassium hydroxide. For other examples of pharmaceutically acceptable salts, reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.

Administration;

According to the present invention, the pharmaceutical composition, preparation or medicament containing the somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof, as applicable in this invention, can be administered by parenteral route (subcutaneous, intramuscular, intraperitoneal, intravenous, or in an implant), by oral, vaginal, rectal, nasal, sublingual or transdermal route.

The vaginal route is preferred because it allows effective concentrations of the active ingredient to be delivered to the ovary while minimizing systemic exposure. The

somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof used is formulated with the necessary excipients known to a person skilled in the art, in order to allow an effective and reproducible administration for each

administration route.

One variation of the present invention also foresees a pharmaceutical composition or preparation suitable for delayed and controlled release of the somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof as defined in the present invention. The somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof, for exam ple, may be incorporated in a matrix of biocompatible polymer allowing delayed and controlled release. All biocompatible polymers, well known by those skilled in the art are potential candidate to be used in this invention. Vaginal rings or intra-uterine devices are also contemplated options.

Sustained-release preparations maybe prepared. Suitable examples of sustained-release preparations include semi permeable matrices of solid hydrophobic polymers containing th e somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyemyl-memacrylate), or pory(vinylalcohoi)), polylac tides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and [gamma] ethyl-L-glutamate, non- degradable ethylene- vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT(TM) (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

The formulations to be used for in vivo administration must be sterile. This is readily accomplished for example by filtration through sterile filtration membranes.

Dose: The dose of a product according to the present invention, intended for the treatment of the gynaecological disease or condition mentioned herein, varies according to the method of administration, the age and body weight of the subject to be treated as well as the condition of the subject, and the final decision is made by the attending doctor or vet. Such a quantity determined by the attending doctor is called "therapeutically effective amount" here. Usually, the somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof will be administered, preferably daily, by vaginal route for a period of 1 to 180 days. However, the appropriate period will depend on the somatostatin receptor 4 ligand analog, the pharmaceutically acceptable salt thereof or the active metabolite thereof and the mode of administration. During this treatment period, the administration can be stopped if the disease or condition has been corrected, treated or prevented.

Alternatively, the somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof will be administered, every other day, once a week or once every month, preferably, as a onetime administration.

Usually, the somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof is administered at a daily dose between 0.1 to 1000 mg.

However, the appropriate dosage will depend on the somatostatin receptor 4 ligand analog, the pharmaceutically acceptable salt thereof or the active metabolite thereof and the mode of administration. Possibilities mode of administration include tablets, capsules, lozenges, pills, dental pastes, suppositories, inhalants, solutions, ointments , parenteral depots, vaginal rings and intra-uterine delivery systems. In cases where somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof is included in a solution, the formulation may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, among others.

Useful intranasal formulations of somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof thereof may contain a stabilizers and a surfactants. Among the pharmaceutically acceptable surfactants are polyoxyethylene castor oil derivatives, such as polyoxyethylene-glycerol- triricinoleate, also known as polyoxyl 35 caster oil (CREMOPHOR EL), or poloxyl 40 hydrogenated castor oil (CREMOPHOR RH40) both available from BASF Corp.; mono-fatty acid esters of polyoxyethylene (20) sorbitan, such as polyoxyethylene (20) sorbitan monolaurate (TWEEN 80), polyoxyethylene monostearate (TWEEN 60), polyoxyethylene (20) sorbitan monopalmitate (TWEEN 40), or polyoxyethylene 20 sorbitan monolaurate (TWEEN 20) (all available from ICI Surfactants of Wilmington, Del); polyglyceryl esters, such as polyglyceryl oleate; and polyoxyethylated kernel oil (LABRAFIL, available from Gattefosse Corp.). Preferably, the surfactant will be between about 0.01% and 10% by weight of the pharmaceutical composition. Among the pharmaceutically useful stabilizers are antioxidants such as sodium sulfite, sodium

metabisulfite, sodium thiosulfate, sodium formaldehyde sulfoxylate, sulfur dioxide, ascorbic acid, isoascorbic acid, thioglycerol, thioglycolic acid, cysteine hydrochloride, acetyl cysteine, ascorbyl palmitate, hydroquinone, propyl gallate, nordihydroguaiaretic acid, butylated hydroxytoluene, butylated hydroxyanisole, alpha-tocopherol and lecithin. Preferably, the stabilizer will be between about 0.01% and 5% by weight of the pharmaceutical composition.

Suspensions may also include chelating agents such as ethylene diamine tetraacetic acid, its derivatives and salts thereof, dihydroxyethyl glycine, citric acid and tartaric acid among others. Additionally, proper fluidity of a suspension can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants, such as those previously mentioned. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants such as glycerol; (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (e) solution retarding agents such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate;(h) absorbents such as kaolin and bentonite clay; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, capsules, pills and granules can be prepared with coatings and shells such as enteric coating and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.

Alternatively, or additionally, it will become apparent that the pharmaceutical composition or formulation described herein may be administered alone or in combination with other treatments, therapeutics or agents, either simultaneously or sequentially dependent upon the condition or disease to be treated. For example, the somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof in the method of the invention may be administered in association with, e.g. an oestrogen either simultaneously or sequentially.

Carriers:

Somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof for use in the method as described herein, are usually in the form of a pharmaceutical composition that may contain one or more pharmaceutically acceptable carriers, such as excipients, carriers and/or auxiliaries or stabilizers which facilitate processing of the active compounds into preparation which can be used pharmaceutically.

Acceptable carriers, excipients, or stabilizers are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as

octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl orbenzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as TWEEN®, PLURONICS® or polyethylene glycol (PEG).

Method of treating:

The present invention also provides for a method of treating and/or preventing a gynecological disease or condition in a patient in need thereof comprising administering to said patient a pharmaceutical composition comprising a somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof.

"A gynecological disease or condition" refers to a disease or condition related to the health of the female reproductive system (uterus, vagina, and ovaries). Generally, the somatostatin receptor 4 ligand analog is selected among the somatostatin receptor antagonist analogs or the somatostatin receptor agonist analogs.

In case the somatostatin receptor 4 ligand analog is an antagonist analog then the gynecological disease or condition is selected from the group comprising Incipiens ovarian failure, Premature ovarian failure, infertility, anovulation, infertility characterized by "poor ovarian response" to gonadotropin therapy, delayed puberty, infertility associated with elevated FSH levels, pre-treatment to IVF and ART (Assisted Reproductive Technology), spontaneous premature ovarian failure (early menopause), polycystic ovarian disease (reduction of the number of growing follicles), and bad responders to COS (controlled ovarian stimulation).

In case the somatostatin receptor 4 ligand analog is an agonist analog then the gynecological disease or condition is selected from the group comprising Polycystic ovarian disease, anovulation, infertility associated to Polycystic ovarian disease, Hyperandrogenism, virilism, female hirsutism, oligomenorrhea, amenorrhea, acnea, acanthosis nigricans.

Also contemplated is the use of a somatostatin receptor 4 ligand analog antagonist, a pharmaceutically acceptable salt thereof or an active metabolite thereof, for preparing a medicament in the treatment and/or prevention of a gynecological disease or condition selected from the group comprising Incipiens ovarian failure, Premature ovarian failure, infertility, anovulation, infertility characterized by "poor ovarian response" to gonadotropin therapy, delayed puberty, infertility associated with elevated FSH levels, pre-treatment to IVF and ART (Assisted Reproductive Technology), spontaneous premature ovarian failure (early menopause), polycystic ovarian disease (reduction of the number of growing follicles), and bad responders to COS (controlled ovarian stimulation).

Further contemplated is the use of a somatostatin receptor 4 ligand analog agonist, a pharmaceutically acceptable salt thereof or an active metabolite thereof, for preparing a medicament in the treatment and/or prevention of a gynecological disease or condition selected from the group comprising Polycystic ovarian disease, anovulation, infertility associated to Polycystic ovarian disease, Hyperandrogenism, virilism, female hirsutism, oligomenorrhea, amenorrhea, acnea, acanthosis nigricans. Kit:

The present invention also contemplates a kit for treating and/or preventing a gynecological disease or condition comprising a somatostatin receptor 4 ligand analog agonist, a pharmaceutically acceptable salt thereof or an active metabolite thereof, optionally with reagents and/or instructions for use.

Generally, the Kit comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds the a somatostatin receptor 4 ligand analog agonist, a pharmaceutically acceptable salt thereof or an active metabolite thereof of the invention which is effective for treating and/or preventing a gynecological disease or condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle or an aerosol spray device). The label or package insert indicates that the composition is used for treating the condition of the invention.

Alternatively, or additionally, the Kit may further comprise a second (or third) container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI)5 phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications without departing from the spirit or essential characteristics thereof. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. The present disclosure is therefore to be considered as in all aspects illustrated and not restrictive, the scope of the invention being indicated by the appended Claims, and all changes which come within the meaning and range of equivalency are intended to be embraced therein.

Various references are cited throughout this Specification, each of which is incorporated herein by reference in its entirety. The foregoing description will be more fully understood with reference to the following Examples. Such Examples, are, however, exemplary of methods of practicing the present invention and are not intended to limit the scope of the invention.

EXAMPLES Example 1 - Material and methods:

Pairs of ovaries from 5-day-old mice were incubated in vitro during 15 days in the presence of either KL or BIM-23627. For every mouse, one ovary was cultured in culture medium

(control), the other ovary was cultured in the presence of either KL or BIM-23627. After 5, 10 and 15 days of culture, the ovaries were histologically assessed for the content of primordial, primary and secondary follicles. Expression of SST and SSTR mRNA were assessed by RT- PCR in non cultured mouse ovaries. The presence and localization of SST and SSTR in mouse, as well as in monkey and human ovaries was analyzed by immunohistochemical methods. Example 2 - Results:

In the mouse, SSTR-2 and -5, but not SST, were identified at the transcriptional and translational (mainly in granulosa cells) levels. Both KL and BIM-23627 triggered a reduction of the proportion of primordial follicles and an increase of the proportion of primary and secondary follicles, when compared to control ovaries from the same animal. In the primate ovary, SSTR-2, -4 and -5 were observed in granulosa cells and oocytes, but SSTR-4 was expressed at the highest level.

In the mouse, functional SSTR-2 and -5 are present in oocytes and ovarian follicles. SST antagonist, as KL, promotes primordial follicle growth in the in vitro model. In the primate ovary, the presence of SSTR, and especially of SSTR-4, which is present in a small number of extra-ovarian tissues, suggests that these results are relevant for therapeutic application of SST analog s in modulating the ovarian reserve, early follicle growth and/or ovarian follicle atresia as well as for treating and/or preventing gynecological disease in which the SSTR-4 is involved.

These results also validate the concept that SST analogs especially SST-antagonists are

potential therapeutic agents for promoting ovarian follicle growth in patients with low

responsiveness to gonadotropin therapy.

Figures 1 to 4 show that SSTR4 is significantly expressed at different stage of the follicle

development, notably from primordial follicle stage to the large antral stage.

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Volume 456, Issues 1-3, Pages 45-49

Claims

1. A somatostatin ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof, for use in a method of modulating early follicle growth and/or ovarian follicle atresia.

2. The somatostatin ligand analog of claim 1, wherein said somatostatin receptor 4 ligand analog is an antagonist analog.

3. The somatostatin ligand analog of claim 2, wherein said somatostatin receptor 4 antagonist ligand analog is a selective antagonist analog.

4. The somatostatin ligand analog of claim 1, wherein said somatostatin receptor 4 ligand analog is an agonist analog.

5. The somatostatin ligand analog of claim 4, wherein said somatostatin receptor 4 ligand analog is a selective agonist analog.

6. The somatostatin ligand analog of claim 2 or 3, wherein the somatostatin receptor 4 antagonist ligand analog, or somatostatin receptor 4 selective antagonist ligand analog, is a compound of general formula

A^cyclop-Cys-A^D-Trp-A^-Cysl-A^Y¹

(III)

in which:

A¹ is an optionally substituted aromatic a-amino acid;

A is an optionally substituted aromatic a-amino acid;

A is Dab, Dap, Lys, or Orn;

A⁴ is ?-Hydroxyvaline, Ser, Hser, or Thr; A⁵ is an optionally substituted aromatic D- or L- a-amino acid; and

Y¹ is OH, NH₂ or NHR¹, R¹ is (d_₆)alkyl; each aromatic a-amino acid being optionally substituted with one or more substituents independently selected from a halogen atom, N0₂, OH, CN, (C_1-6) alkyl, (C₂_₆) alkenyl, (C₂_₆) alkynyl, (Ci-₆) alkoxy, Bzl, O-Bzl or NR⁹R¹⁰, wherein R⁹ and R¹⁰ are each independently H, O, or (Ci-₆) alkyl; and each nitrogen atom of a peptide amide bond and the amino group of A¹ are optionally substituted with a methyl group, with the proviso that there is at least one said methyl group in a peptide of general formula (III); the pharmaceutically acceptable salts or protected forms of said peptides , or combinations thereof.

7. The somatostatin ligand analog of claim 6, wherein A¹ is Cpa, A² is Pal, A³ is Lys, A⁴ is Thr, and A⁵ is Nal.

8. The somatostatin ligand analog of claim 6 or 7, wherein the somatostatin receptor 4 antagonist ligand analog, or somatostatin receptor 4 selective antagonist ligand analog, is Cpa-cyclo(DCys-3-Pal-DTrp-NMeLys-Thr-Cys)-2-Nal-NH2.

9. The somatostatin ligand analog of claim 6, wherein A 1 is Cpa, A2 is 4Pal, A 3 is Lys, A⁴ is Thr, and A⁵ is 2Nal.

10. The somatostatin ligand analog of claim 6, wherein the somatostatin receptor 4 antagonist analog, or somatostatin receptor 4 selective antagonist analog, is selected among the group comprising the following peptides of general formula (III):

- Cpa-cyclo[D-Cys-Pal-D-Trp-N-Me-Lys-Thr-Cys]-D-Trp-NH_2;

- Cpa-cyclo[D-Cys-Tyr-D-Trp- N-Me-Lys-Thr-Cys]-Nal-NH_2;

- Cpa-cyclo[D-Cys-Pal-D-Trp- N-Me-Lys-Thr-Cys]-Nal-NH_2;

the peptide known by the code name AC- 178,335 (of structure acetyl-D-His-D-Phe-D-Ile-D- Arg-D-Trp-D-Phe-NH₂); the octapeptide known by the code name ODN-8; the peptide known by the code name SB- 710411 (of structure Cpa-cyclo[D-Cys-Pal-D-Trp-Lys-Val-Cys]-Cpa-amide);

- the peptide known by the code name BIM-23056 (of the structure represented below);

- the compound known by the code name BN-81674 (of the structure represented below); - the compound known by the code name SRA-880 (of the structure represented below); and their pharmaceutically acceptable salts.

or their pharmaceutically acceptable salts or protected forms, or combinations thereof.

11. The somatostatin ligand analog of claim 4 or 5, wherein the somatostatin receptor 4 agonist ligand analog, or somatostatin receptor 4 selective agonist ligand analog, is a compound of general formula (I)

in which: Xi is a radical of formula (a) or (b)

Rl independently representing at each time that it occurs an optionally substituted phenyl radical in which the optional substituents are independently chosen from a halogen atom and the methyl, ethyl, methoxy and ethoxy radicals,

R2 representing -Z1-CH2-R1, -CH2-CO-0- CH2-R1,

Zi being O or S;

X₂ is an -amino acid having an aromatic residue on the side chain C _a, or an amino acid unit chosen from Dab, Dpr, Dpm, His, (Bzl)HyPro, thienyl-Ala, cyclohexyl-Ala and t-butyl-Ala;

A is a divalent residue chosen from Pro,

R₃ is NR₈R -C₂-₆alkylene, guanidino-C₂_₆alkylene or C₂_₆alkylene-COOH, R_3a is H,

Ci_₄alkyl or has, independently, one of the meanings given for R₃, R_3b is H or Ci_₄ alkyl, R_a is OH or NR₅R₆, R_b is -(CH₂)i_₃- or -CH(CH₃)-, R4 is H or CH₃, R_4a is benzyl optionally substituted on the aromatic ring, each of R5 and R^ is independently H, Ci_₄alkyl, ro-amino-Ci_ 4alkylene, co-hydroxy-Ci_₄alkylene or acyl, R₇ is a direct bond or Ci_₆alkylene, each of Rs and R is independently H, Ci_₄alkyl, co-hydroxy-C₂_₄alkylene, acyl or CH₂OH-(CHOH)_c-CH₂- in which c is 0, 1, 2, 3 or 4, or Rg and R form together with the nitrogen atom to which they are attached a heterocyclic group which can include an additional heteroatom, and Rn is benzyl optionally substituted on the aromatic ring, -(CH₂)i_₃-OH, CH₃-CH(OH)- or -(CH₂)i_₅-NR₅R6, and ZZ_a is a natural or unnatural -amino acid unit; it being understood that X_ls X₂ and Lys each have the configuration L; or is a pharmaceutically acceptable salt or protected form of a compound of general formula (I).

12. The somatostatin ligand analog of claim 4 or 5, wherein the somatostatin receptor 4 agonist ligand analog, or somatostatin receptor 4 selective agonist ligand analog, is a compound of general formula (II)

in which R is NRIORI l-C2-6alkylene or guanidine-C2-6alkylene, and each of RIO and Rl 1 is independently H or Cl-4alkyl or is a pharmaceutically acceptable salt or a protected form of a compound of general formula (II) , or combinations thereof.

13. The somatostatin ligand analog of claim 12, wherein the somatostatin receptor 4 agonist ligand analog, or somatostatin receptor 4 selective agonist ligand analog, includes lanreotide, octreotide, vapreotide, SOM 230, MK-678, BIM-23190, BIM-23197, BIM-23268, PTR-3173, TT-232, the peptide of formula c[Tic-Tyr-DTrp-Lys-Abu-Phe], the KE 108 peptide of formula TyrO-(cyclo-D-Dab-Arg-Phe-Phe-D-Trp-Lys— Thr-Phe) or their pharmaceutically acceptable salts or protected forms, or combinations thereof.

14. A somatostatin ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof, for use in treating and/or preventing a gynecological disease or condition in a patient in need thereof.

15. The somatostatin ligand analog of claim 14, wherein said somatostatin receptor 4 ligand analog is an antagonist analog.

16. The somatostatin ligand analog of claim 14 or 15, wherein the gynecological disease or condition is selected from the group comprising Incipiens ovarian failure, Premature ovarian failure, infertility, anovulation, infertility characterized by "poor ovarian response" to gonadotropin therapy, delayed puberty, infertility associated with elevated FSH levels, pre- treatment to IVF and ART (Assisted Reproductive Technology), spontaneous premature ovarian failure (early menopause), polycystic ovarian disease (reduction of the number of growing follicles), and bad responders to COS (controlled ovarian stimulation).

17. The somatostatin ligand analog of claim 14, wherein the somatostatin receptor 4 ligand analog is an agonist analog.

18. The somatostatin ligand analog of claim 17, wherein the gynecological disease or condition is selected from the group comprising Polycystic ovarian disease, anovulation, infertility associated to Polycystic ovarian disease, Hyperandrogenism, virilism, female hirsutism, oligomenorrhea, amenorrhea, acnea, acanthosis nigricans.

19. A method of modulating early follicle growth and/or ovarian follicle atresia comprising administering to a patient in need thereof a medicament comprising a

somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof.

20. The method of claim 19, wherein the somatostatin receptor 4 ligand analog is an antagonist analog.

21. The method of claim 20, wherein the somatostatin receptor 4 antagonist ligand analog is a selective antagonist analog.

22. The method of claim 19, wherein the somatostatin receptor 4 ligand analog is an agonist analog.

23. The method of claim 22, wherein the somatostatin receptor 4 ligand analog is a selective agonist analog.

24. The method of claim 20 or 21, wherein the somatostatin receptor 4 antagonist ligand analog, or somatostatin receptor 4 selective antagonist ligand analog, is a compound of general formula

A^cyclop-Cys-A^D-Trp-A^-Cysl-A^Y¹

(III) in which:

A¹ is an optionally substituted aromatic a-amino acid; A is an optionally substituted aromatic a-amino acid; A is Dab, Dap, Lys, or Orn; A⁴ is ?-Hydroxyvaline, Ser, Hser, or Thr;

A⁵ is an optionally substituted aromatic D- or L- a-amino acid; and Y¹ is OH, NH₂ or NHR¹, R¹ is (d_₆)alkyl; each aromatic a-amino acid being optionally substituted with one or more substituents independently selected from a halogen atom, N0₂, OH, CN, (C_1-6) alkyl, (C₂_₆) alkenyl, (C₂_₆) alkynyl, (Ci-₆) alkoxy, Bzl, O-Bzl or NR⁹R¹⁰, wherein R⁹ and R¹⁰ are each independently H, O, or (Ci-₆) alkyl; and each nitrogen atom of a peptide amide bond and the amino group of A¹ are optionally substituted with a methyl group, with the proviso that there is at least one said methyl group in a peptide of general formula (III); the pharmaceutically acceptable salts or protected forms of said peptides , or combinations thereof.

25. The method of claim 24, wherein A¹ is Cpa, A² is Pal, A³ is Lys, A⁴ is Thr, and A⁵ is Nal.

26. The method of claim 24 or 25, wherein the somatostatin receptor 4 antagonist ligand analog, or somatostatin receptor 4 selective antagonist ligand analog, is Cpa-cyclo(DCys-3-

Pal-DTrp-NMeLys-Thr-Cys)-2-Nal-NH2.

27. The method of claim 24, wherein Al is Cpa, A2 is 4Pal, A3 is Lys, A4 is Thr, and A5 is 2Nal.

28. The method of claim 24, wherein the somatostatin receptor 4 antagonist analog, or somatostatin receptor 4 selective antagonist analog, is selected among the group comprising the following peptides of general formula (III): - Cpa-cyclo[D-Cys-Pal-D-Trp-N-Me-Lys-Thr-Cys]-D-Trp-NH₂;

- Cpa-cyclo[D-Cys-Tyr-D-Trp- N-Me-Lys-Thr-Cys]-Nal-NH_2;

- Cpa-cyclo[D-Cys-Pal-D-Trp- N-Me-Lys-Thr-Cys]-Nal-NH_2;

the peptide known by the code name AC- 178,335 (of structure acetyl-D-His-D-Phe-D-Ile-D- Arg-D-Trp-D-Phe-NH₂);

the octapeptide known by the code name ODN-8; the peptide known by the code name SB- 710411 (of structure Cpa-cyclo[D-Cys-Pal-D-Trp-Lys-Val-Cys]-Cpa-amide);

29. The method of claim 22 or 23, wherein the somatostatin receptor 4 agonist ligand analog, or somatostatin receptor 4 selective agonist ligand analog, is a compound of general formula (I)

in which:

Xi is a radical of formula (a) or (b)

R2 representing -Z1-CH2-R1, -CH2-CO-0- CH2-R1,

Zi being O or S;

X₂ is an -amino acid having an aromatic residue on the side chain C _a, or an amino acid unit chosen from Dab, Dpr, Dpm, His, (Bzl)HyPro, thienyl-Ala, cyclohexyl-Ala and t-butyl-Ala; A is a divalent residue chosen from Pro,

P 3 is NPv8Pv9-C₂_₆alkylene, guanidino-C₂_₆alkylene or C₂_₆alkylene-COOH, R_3a is H,

Ci_₄alkyl or has, independently, one of the meanings given for R₃, R₃b is H or Ci_₄ alkyl, R_a is OH or NR₅R₆, Rb is -(CH₂)i_₃- or -CH(CH₃)-, R4 is H or CH₃, R_4a is benzyl optionally substituted on the aromatic ring, each of R₅ and Re is independently H, Ci_₄alkyl, ω-amino-Ci- 4alkylene, co-hydroxy-Ci_₄alkylene or acyl, R₇ is a direct bond or Ci_₆alkylene, each of Rs and R₉ is independently H, Ci_₄alkyl, co-hydroxy-C₂_₄alkylene, acyl or CH₂OH-(CHOH)_c-CH₂- in which c is 0, 1, 2, 3 or 4, or Rs and R₉ form together with the nitrogen atom to which they are attached a heterocyclic group which can include an additional heteroatom, and Rn is benzyl optionally substituted on the aromatic ring, -(CH₂)i_₃-OH, CH₃-CH(OH)- or -(CH₂)i_5-NRsR₆, and ZZ_a is a natural or unnatural a-amino acid unit; it being understood that X_ls X₂ and Lys each have the configuration L; or is a pharmaceutically acceptable salt or protected form of a compound of general formula (I).

30. The method of claim 22 or 23, wherein the somatostatin receptor 4 agonist ligand analog, or somatostatin receptor 4 selective agonist ligand analog, is a compound of general formula (II)

31. The method of claim 30, wherein the somatostatin receptor 4 agonist ligand analog, or somatostatin receptor 4 selective agonist ligand analog, includes lanreotide, octreotide, vapreotide, SOM 230, MK-678, BIM-23190, BIM-23197, BIM-23268, PTR-3173, TT-232, the peptide of formula c[Tic-Tyr-DTrp-Lys-Abu-Phe], the KE 108 peptide of formula TyrO- (cyclo-D-Dab-Arg-Phe-Phe-D-Trp-Lys— Thr-Phe) or their pharmaceutically acceptable salts or protected forms, or combinations thereof.

32. A method of treating and/or preventing a gynecological disease or condition in a patient in need thereof comprising administering to said patient a pharmaceutical composition comprising a somatostatin receptor 4 ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof.

33. The method of claim 32, wherein the somatostatin receptor 4 ligand analog is an antagonist analog.

34. The method of claim 32 or 33, wherein the gynecological disease or condition is selected from the group comprising Incipiens ovarian failure, Premature ovarian failure, infertility, anovulation, infertility characterized by "poor ovarian response" to gonadotropin therapy, delayed puberty, infertility associated with elevated FSH levels, pre-treatment to IVF and ART (Assisted Reproductive Technology), spontaneous premature ovarian failure (early menopause), polycystic ovarian disease (reduction of the number of growing follicles), and bad responders to COS (controlled ovarian stimulation).

35. The method of claim 32, wherein the somatostatin receptor 4 ligand analog is an agonist analog.

36. The method of claim 35, wherein the gynecological disease or condition is selected from the group comprising Polycystic ovarian disease, anovulation, infertility associated to Polycystic ovarian disease, Hyperandrogenism, virilism, female hirsutism, oligomenorrhea, amenorrhea, acnea, acanthosis nigricans.

37. A kit for treating and/or preventing a gynecological disease or condition comprising a somatostatin receptor 4 ligand analog agonist or somatostatin receptor 4 selective agonist ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof, optionally with reagents and/or instructions for use.

38. A kit for treating and/or preventing a gynecological disease or condition comprising a somatostatin receptor 4 ligand antagonist analog or somatostatin receptor 4 selective antagonist ligand analog, a pharmaceutically acceptable salt thereof or an active metabolite thereof, optionally with reagents and/or instructions for use.