MXPA01004290A - Somatostatin antagonists and agonists that act at the sst subtype 2 receptor - Google Patents

Abstract

Compounds according formula (I) A-G-Z-W and pharmaceutically acceptable salts, solvates or hydrates thereof;wherein, A is (C6-C10)aryl, (C6-C10)aryl-SO2, (C6-C10)aryl-CH2-, (C6-C10)arylcarbonyl, (C1-C9)heteroaryl, (C1-C9)heteroaryl-SO2-, (C1-C9)heteroaryl-CH2-;or (C1-C9)heteroarylcarbonyl;G is selected from the group consisting of:where B is (C6-C10)aryl or (C1-C9)heteroaryl, and X is CH2, SO2, or carbonyl;where X is CH2, SO2, or carbonyl;and R<1>and R<1'>are each independently selected from H, CN, (C1-C8)alkyl-, and phenyl(CH2)-, wherein said alkyl and phenyl groups are optionally substituted;and where Z and W are as defined in the present Specificiation;and pharmaceutical compositions and methods useful to increase secretion of growth hormone(GH) from the anterior pituitary of mammals, including on a sustained release basis.

Description

PC10720AEVD US 60 / 200,319 filed 28 April 2000 -1- Antagonists and agonists of somatostatin that act on the SST receptor of subtype 2 Field of the invention The present invention provides pharmaceutically active compounds that facilitate the secretion of growth hormone (GH) by the anterior pituitary. Growth hormone (also known as somatotropin) acts indirectly by promoting skeletal growth in the child by stimulating the production by the liver of insulin-like growth factor-1. Growth hormone also stimulates the differentiation of fat cells and chondrocytes (cells that secrete collagen and proteo-glucans to form cartilage). In the adult, growth hormone is involved in the proper maintenance of connective and muscular tissues. Growth hormone deficiency can be congenital or acquired. The deficiency in the child causes a slow growth of the skeleton that, if not corrected, results in a permanent short stature. In older adults, growth hormone deficiency results in frailty. Additional symptoms in the adult GH deficiency may include wrinkled skin and hypoglycemia. For application in veterinary medicine, the regulation of growth hormone is useful to treat frailty in older animals, particularly pets. With respect to livestock, the increasing regulation of growth hormone increases growth and behavior, even in healthy animals with normal GH levels. Improvements are seen in milk production, feed efficiency, weakness, meat quality and fertility. Although direct administration of growth hormone may be effective in certain therapeutic applications, it is difficult in practice. Among other issues, since the half-life of growth hormone in the body is very short, direct administration leads to artificially increased levels of circulating GH concentration, which then decay rapidly. The prolonged release, for example by means of a mechanical pump, has not been established optimally in practice. The concentration in the body of growth hormone in circulation depends on the equilibrium of numerous biochemical pathways, including processes in opposition. Compared to the direct administration approach, shifting the equilibrium of these pathways indirectly provides a safer, more reproducible method of affecting GH secretion on a prolonged basis. Under this approach, since the overall regulatory framework remains intact, secretion rates and circulating GH concentrations conform to a relatively normal pattern, and adverse fluctuations in both secretion rate and GH concentration are avoided. circulation. The present invention provides therapeutic compounds, and their use, for indirectly raising the secretion of growth hormone from the pituitary.

Indicated Developments Growth hormone is released from the anterior pituitary in response to stimulation by the growth hormone-releasing peptide (GHRP) and growth hormone-releasing hormone (GHRH) of hypothalamic origin. However, the release of growth hormone by these or other mechanisms, is inhibited by somatostatin, and therefore the process is tightly regulated. Somatostatin (SRIF) is a cyclic peptide hormone of 14 amino acids (there is also a form of 28 amino acids) that has numerous endocrine functions that, like many hormones, is split from a larger precursor protein. Somatostatin inhibits the growth hormone pituitary secretion, glucagon and insulin pancreatic secretion and gastrin secretion from the intestine. Somatostatin also acts as a neurotransmitter / neurolator (see S.J. Hocart et al., J. Med. Chem., 41, pages 1146-1154, 1998 for a general discussion). The biological effects of somatostatin are, apparently, all of them of an inhibitory nature, and are caused by binding to the surface of a target cell. The receptor is an integral protein of the membrane (which extends over the cell membrane), and is coupled to protein G. The receptors coupled to the G protein represent the main class of cell surface receptors. It is believed that by binding of somatostatin to the receptor, the receptor undergoes a conformational change that facilitates its interaction with a G protein located on the cytoplasmic side of the receptor. This facilitates the binding or release of GTP / GDP into the G protein, and leads to subsequent activation and signaling events within the cell. In particular, somatostatin, which binds to its own receptor coupled to the G protein, is negatively coupled with the activity of adenylyl cyclase, necessary for the production of cyclic AMP. Thus, these subsequent signaling events directly oppose certain mechanisms (for example, those that occur with mediation of calcium ions or cyclic AMP), so that GHRP and GHRH could, on the other hand, trigger the extracellular secretion of the hormone. of growth from storage cytoplasmic granules. For a general review of this, see The Encyclopedia of Molecular Biology, J. Kendrew, compiler, Black ell Science, Ltd. 1994, on page 387. The effects of somatostatin on target cells are mediated by at least 5 classes of receptors (sstl-sst5). Although receptors may have a similar affinity for somatostatin, they are expressed differently in different tissues, and thus positioned, directly or indirectly interact with different intracellular signaling components. This specificity for the tissues of receptor expression is largely the reason for the different effects of somatostatin on different types of target cells. Somatostatin receptors are found, for example, in tissues of the anterior pituitary, other tissues of the brain, the pancreas, the lungs, lymphocytes and mucous cells of the intestinal tract. It is known that the receptor of the type sst2 mediates the inhibition of the secretion of growth hormone in the anterior pituitary. This receptor has also been described in two forms, the sst2A and sst2B proteins, which result from different splicing of the sst2 gene transcript (M.Va-netti, et al., FEBS Letters, 311, pages 290-294, 1992 ). It is also known that the sst2 receptor mediates the inhibition of gastrin and histamine secretion. Additionally, it is known that the sst2 receptor mediates the inhibition of glucagon release from pancreatic alpha cells. Although numerous somatostatin agonists have been described (see, for example, WO 98/44922, WO 98/45285 and WO 98/44921), the development of useful somatostatin antagonists linked to sst2 has lagged behind. . Recent reports of such compounds include the work of W. R. Baumbachh et al., Molecular Pharmacology, 54, pages 864-873, 1998, and S.J. Hocart et al., J. Med. Chem. 41, pages 1146-1154, 1998. However, such compounds are short peptides, a class of molecules often unsuitable for successful use as pharmaceutical compounds, due to their half-life it typically cuts in the body. It would be advantageous to provide antagonists of somatostatin activity, effective in the sst2-type receptor, with superior properties as pharmaceuticals, including bioavailability, stability and similar properties. The present invention provides a series of antagonist compounds that specifically interfere with the binding of somatostatin to sst receptors of subtype 2 of cells existing in the anterior pituitary of mammals, and that possess valuable additional properties.

SUMMARY OF THE INVENTION According to the practice of the present invention, a compound according to formula (I) is provided AGZW (I) or a salt thereof, solvates or hydrates, pharmaceutically acceptable, wherein the group A is aryl of C6-C10 aryl (C5-C10) -SO2-, (C6-C10) -CH2-f arilíCg- Carbonyl, heteroaryl of Cj-Cg, heteroaryl (C1-C8) -S02-, heteroaryl (C1-Cg) -CH-; or heteroaryl (C-Cg) carbonyl; G is: in which formula B is Cg-C ^ aryl or C Cg heteroaryl, and X is CH2, S02 or carbonyl; in which formulas X is CH2, S0 or carbonyl; and Ri1 and Rxi 'are each independently selected from H, CN, alkyl (C? -Cg) -, and phenyl (CH2) -, in which formulas said alkyl and phenyl groups are optionally substituted; or Z is in which formula R is H, C-j-Cg alkyl, or is selected from the groups A above; and E is selected from the groups A above; W is (a) in which formula n is 2 to 5, R3 is selected from H, alkyl (C-j-Cg) -, and phenyl (CH2) -, in which formulas said alkyl and phenyl groups are optionally substituted; R6 is selected from H, C-Cg alkyl), and phenyl (CH2) -, in which formulas said alkyl and phenyl groups are optionally substituted; R4 is selected from H, alkylC ^ Cg) - and phenyl (CH2) -, in which formulas said alkyl and phenyl groups are optionally substituted; or is in which formulas the groups R, R11 and R11 are each independently selected from H, alkyl (C - ^ - Cg) -, and phenyl (CH2) -, and R ° can also be selected from Cg-CjQ aryl in Whose formulas the alkyl, phenyl or other aryl groups are optionally substituted; R ^ is H, alkyl (C-¡-Gg) - and phenyl (CH2) -, in which formulas said alkyl and phenyl groups are optionally substituted, or is in whose formula R 1? and R1? 'are each independently selected from H, alkyl (C ^ Cg) -, and phenyl (CH2) -, in which formulas said alkyl and phenyl groups are optionally substituted; or W is (b) . in whose formula Q is selected from the group consisting of aryl of Cg-C-LQ, heteroaryl of C | -Cg, cycloalkyl of C3-C1Q, and heterocycloalkyl of C3-C0; and 0 q R ', R ° and R' are each independently selected from H, alkyl (C-Cg) -, and phenyl (CH2) -, in which formulas said alkyl and phenyl groups are optionally substituted. In a preferred aspect of the invention, there is provided a compound in which, independently, one or more of the groups A, B, E, and Q existing therein, comprise an aryl group of Cg-C ^ Q selected from phenyl and naphthyl. In a preferred aspect of the invention, there is provided a compound wherein, independently, one or more of the groups A, B, E, and Q therein, comprises a heteroaryl group of Cj-Cg selected from furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2, 3-oxadiazolyl, 1,3,5-thiadiazolyl, 1, 2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1, 2, 3-triazinyl, 1, 3, 5-triazinyl, pyrazolo [ 3, 4-b] pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H- [l] pyrindinyl, benzo [b] thiophenyl, 5,6, 7,8-tetrahidroquino-lin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isotianafte-nile, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, and benzoxazin ilo. In a preferred aspect of the invention, there is provided a compound in which the group Q existing therein is selected from (a) an aryl group of C-C ^ Q, selected from phenyl and naphthyl; (B) a heteroaryl group Cg-Cj, selected from furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3, 5-oxadiazolyl, 1, 2, 4- oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, , 2,3-triazinyl, 1,3,5-triazinyl, pyrazolo [3,4-b] pyridinyl, cinolinyl, pteridinyl, purinyl, 6,7-dihydro-5H- [l] pyrindinyl, benzo [b] thiophenyl, 5,6,7,8-tetrahydroquinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, tianaf-tenyl, isothianaphtenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and benzoxazinyl; (C) a cycloalkyl group of C3-C1Q selected from cyclopropyl, cyclobutyl, cyclopentyl, ciciohexilo, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1, 3-cyclobutadienyl, 1,3-cyclopentadienyl, 1,3-cyclohexadienyl , 1,4-cyclohexanedienyl, 1,3-cycloheptadienyl, 1,4-cycloheptadienyl, 1,3,5-cycloheptatrienyl, bicyclo [3.2. l] octane, bicyclo [2.2.1] hep-tano and its unsaturated form of norborn-2-ene; and (d) a heterocycloalkyl group of C3-C1Q selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxy, chromenyl, isoxazolidinyl, 1, 3-oxazolidin-3-yl, isothiazolidinyl, 1, , l, 2-pyrazolidin-2-yl, 1, 3-pyrazolidin-l-yl, piperidinyl, thiomorpholinyl, 1, 2-tetrahydrothiazin-2-yl, 1, 3-tetrahydro-3-yl tiazin--thiazolidin-3 3-yl, tetrahydrothiadiazinyl, morpholinyl, 3-tetrahydrodiazin-yl l-yl-1,2-tetrahydrodiazin-2, 1, tetrahi-droazepinilo, piperazinyl and chromanyl. In a highly preferred embodiment of the invention, a compound is provided in which the group Z thereof has the stereospecificity In other examples of this embodiment, the group Z defines an L-amino acid selected from the group consisting of L-tryptophanyl-, L-histidinyl-, L-3-methylhistidinyl-, L-phenylalaninyl-, L-diphenylalaninyl-, L -3-fluorophenylalani-nyl-, L-2-fluorophenylalaninyl-, L-4-fluorophenylalaninyl-, and L-tyrosinyl-, and most preferably, L-tryptophanyl-. In another preferred embodiment of the invention, a compound is provided in which the group Z thereof has the stereospecificity and therefore the group Z defines a D-amino acid which is preferably D-tryptophanyl. In another further embodiment of the highly preferred invention, a compound is provided wherein the group W thereof has an absolute stereospecific configuration at the indicated position, corresponding to that of the carbon a of L-amino acids It is further preferred that the group W define a group of L-lysine or one of its C-Cg alkyl esters, or a group of L-arginine or one of its alkyl esters of C - ^ - CQ, more preferably an alkyl ester of Cj-Cg of L-lysine. Additionally, the W group can define a group L-diaminopimel-co, L-canavanine, L-ornithine, L-2,4-diaminobutyric, L-5-hydroxylysine, L-epsilon-N-methyl-lysine, L-histidine , or L-3-methylhistidine. Accordingly, preferred compounds of the invention include: 6-amino-2- [2- [(biphenyl-4-ylmethyl) amino] -3- (lH-indol-3-yl) propionylamino] hexanoic acid methyl ester; 2-methyl ester. { 3- (3-fluorophenyl) -2- [2- (toluene-4-sulfonylamino) acetylamino] propionilamino} -5-guanidinopentanoic acid; 6-amino-2- [2- [(biphenyl-4-carbonyl) amino] -3- (lH-indol-3-yl) propionylamino] hexanoic acid methyl ester; 2-methyl ester. { 2- [(biphenyl-4-carbonyl) amino] -3,3-diphenylpropionylamino} -5-guanidinopentanoic acid; tert-butyl ester of 6-amino-2- [2- [(biphenyl-4-carbonyl) amino] -3- (lH-indol-3-yl) propionylamino] hexanoic acid; tert-butyl ester of 6-amino-2- [2- (2-benzenesulfonylamino-2-methylpropionylamino) -3- (lH-indol-3-yl) propio-nylamino] hexanoic acid ester; and 6-amino-2- [2- [(biphenyl-4-carbonyl) amino] -3- (1H-indol-3-yl) propionylamino] hexanoic acid butyl ester. Additional compounds of the invention include: 2- tertiary butyl ester. { 3- (3-fluorophenyl) -2- [2- (toluene-4-sulfonylamino) acetylamino] ropioni lamino} -5-guanidinopentanoic acid; 2-methyl ester. { 3- (4-fluorophenyl) -2- [2- (toluene-4-sulphonylamino) acetylamino] propionilamino} -5-guanidinopentanoic acid; 2-methyl ester. { 3- (3-fluorophenyl) -2- [2- (toluene-4-sulfonylamino) -2-methylpropionylamino] propionylamine} -5-guanidinopentanoic acid; tert-butyl ester of 6-amino-2- [2- [(biphenyl-4-carbonyl) amino] -3- (lH-indol-3-yl) propionylamino] hexanoic acid; tert-butyl ester of 6-amino-2- [2- [(biphenyl-4-carbonyl) amino] -2-methyl-3- (lH-indol-3-yl) propionylamino] hexanoic acid; N- (3-aminomethylcyclohexylmethyl) -3- (lH-indol-3-yl) -2- (2-benzenesulfonylamino-2-methylpropionylamino) propionamide; Y N- (4-aminomethyl-pyrid-2-ylmethyl) -3- (lH-indol-3-yl) -2- [(bipheni-4-carbonyl) amino] propionamide. In further compounds of the invention, R1 or R is alkyl (C ^ -Cg) - or phenyl (CH2) - and said alkyl or phenyl group is optionally substituted with one or more halo or trifluoroalkyl groups of Cj-Cg. In further compounds of the invention, R is alkylC- Cg) -, optionally substituted with one more halo or trifluoroalkyl groups, most preferably alkyl (C] -C3) -, optionally substituted with one or more halo or trifluoroalkyl groups of C ^ -C. In further compounds of the invention, one or more of R3, R4, R5 and R6 is alkyl (C-Cg) - or phenyl (CH2) -, and said alkyl or phenyl group is optionally substituted with one more halo or trifluoroalkyl groups of C- C In further compounds of the invention, one or more of R7, R8 and R9 is alkyl (C ^ Cg) - or phenyl (CH2) -, and said alkyl or phenyl group is optionally substituted with one or more halo or trifluoroalkyl groups of C - Cg. In additional compounds of the invention, one or more of R10, R11, R11 '. R12 and R12 'is C-Cg alkyl) - or phenyl (CH2) -, and said alkyl or phenyl group is optionally substituted with one or more halo or trifluoroalkyl groups of C ^ -Cg. With respect to the trifluoroalkyl substituent groups of CpC, as mentioned, the preferred group is trifluoromethyl. The compound of formula (I) can have chiral centers and therefore exists in different enantiomeric forms. This invention relates to all optical isomers, tautomers and stereoisomers, of the compounds of formula (I) and mixtures thereof, although as is described in more detail below, certain isomeric structures are preferred.

The present invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of the formula (I). The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned basic compounds of this invention, are those which form non-toxic acid addition salts, ie salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate salts , p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis- (2-hydroxy-3-naphthoate) With respect to the relatively limited number of compounds thus permitted, the invention also relates to the salts of base addition of formula (I) The chemical bases that can be used as reagents for preparing pharmaceutically acceptable base salts of those compounds of the formula ula I that have acidic nature, are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium) ammonium or water-soluble amine addition salts such as N-methylglucamine- (meglumine) and salts of alkanol- (lower) amino and other base salts of pharmaceutically acceptable organic amines. The subject invention also includes isotopically-labeled compounds, which are identical to those cited in Formula (I) except the fact that one or more atoms are replaced by an atom having an atomic mass or a mass number other than the mass atomic or the mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P , 35S, 18F, and 36C1, respectively. Within the scope of this invention, the compounds of the present invention, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs, which contain the aforementioned isotopes and / or other isotopes of other atoms. Certain isotopically-labeled compounds of the invention, for example those in which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug distribution and / or substrate tissue distribution assays. The tritiated isotopes, ie with 3H, and isotopes of carbon-14, ie with 14C, are particularly preferred for their ease of preparation and their suitability for detection. In addition, replacement with heavier isotopes such as deuterium, ie, 2H, may provide certain therapeutic advantages resulting from increased metabolic stability, for example, increased half-life or reduced dosage requirements and, therefore, They may be preferred in some circumstances. The compounds of Formula (I) of this invention and their isotopically-labeled prodrugs can be prepared, in general, by carrying out the operating procedures described in the Schemes and / or in the Examples and Preparations listed below, by substituting a reagent without isotopically labeling by an isotopically-labeled reagent readily available. The present invention also relates to a pharmaceutical composition for increasing the secretion of growth hormone in a mammal, including human, comprising an effective amount of a compound according to formula 1, and a pharmaceutical excipient. The present invention also relates to a pharmaceutical composition for increasing gastrin secretion or secretion of glucagon in a mammal, comprising an effective amount of a compound according to formula 1, and a pharmaceutical excipient.

The present invention also relates to a pharmaceutical composition for the treatment of diseases characterized by decreased levels of growth hormone, glucagon or gastrin in a mammal, including the human being, comprising an amount of a compound of formula (I). ) effective in such treatments and a pharmaceutically acceptable excipient. The present invention also relates to a pharmaceutical composition for the treatment of diseases of a mammal, including the human being, wherein the treatment can be effected by inhibiting the binding of somatostatin to the receptor of the sst2 type, comprising a effective of a compound according to formula 1, and a pharmaceutical excipient. The present invention also relates to a method for treating deficiencies of growth hormone in a mammal, including the human being. The present invention also relates to the elevation of the level of growth hormone in a mammal, including the human being, in which this is beneficial to the mammal, even though the natural levels of growth hormone present in the mammal are within the normal range. In the practice of said method, a pharmaceutical composition of the invention comprising a compound according to formula (I), and a pharmaceutical excipient is administered. Similarly, the methods of the invention provide an increase in gastrin secretion or glucagon secretion in a mammal, including humans, when this is appropriate medication. For example, gastrin is involved in the protection of the gastric mucosa from the damage caused by chemical substances, for example alcohol (S. J. Konturek et al., European Journal of Pharmacology, 278 (3) pages 203-212, 1995). Glucagon is a counter-regulating hormone that is used to treat hypoglycaemia, and which causes inotropic and chronotropic effects without the need for beta-1 adrenergic receptor stimulation. It can also be used to correct the overdoses of blocking agents, verapamil and imipramine, and is used for adjunctive therapeutic treatment in situations of shock, heart failure, and for the treatment of postcontrashock asthma (see CM White, Journal of Clinical Pharmacology, 39 (5), pages 442-447, 1999). In preferred examples of the invention, methods are provided to treat a human being of one or more symptoms of insufficient secretion of growth hormone, or one or more states that may occur thereby and be exacerbated thereby, wherein said condition selected from frailty, hypoglycaemia, wrinkled skin, slow skeletal growth, reduced immune function, reduced organ function, impaired fertility, bone disease, complex related to AIDS, cachexia, heart failure, ischemic heart disease, colon disease , metabolic disorders, renal failure, muscular dystrophy, and Turners syndrome, which comprises administering an effective amount of a pharmaceutical composition, as cited above.

In a further preferred example of the invention, there is provided a method for treating a non-human mammal and improving growth and behavior thereof, which comprises administering an effective amount of a pharmaceutical composition as mentioned above. The growth and behavioral improvement includes, for example, increased feeding efficiency, improved milk yield or fertility, and improved magrez. An example of the highly preferred invention provides a method by which the secretion of growth hormone, gastrin or glucagon can be increased on a prolonged basis, in a mammal, including the human being, in need thereof, which comprises administering a dose of a pharmaceutical composition as mentioned above. According to this example of the invention, the physiologically adverse consequences of artificial fluctuations in the circulatory system (or locally necessary) of concentrations of these hormones can be avoided.

Although the pharmaceutical compositions and methods of the invention are described primarily in terms of use with humans, and non-human mammals, those skilled in the art will appreciate immediately that the invention, in many of its aspects, can be practiced. Useful with regard to birds, such as chickens and turkeys, as well as fish.

Definitions In relation to the practice of the invention, the following definitions generally apply. The term "treating", as used herein, refers to the reversal, alleviation, inhibition of progress, or prevention of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, refers to the act of treating, as "treating" has been defined immediately before. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals possessing linear, branched or cyclic moieties, or combinations thereof. Similarly, the terms "alkenyl" and "alkynyl" define hydrocarbon radicals possessing linear, branched or cyclic moieties, in which at least one double bond or triple bond is present, respectively. Such definitions also apply when the alkyl, alkenyl or alkynyl group is present within another group, such as alkoxy or alkylamino. The term "alkoxy," as used herein, includes O-alkyl groups, wherein "alkyl" is as defined above. The term "halo", as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. An "aryl" group, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon compound of Cg-C ^ Q, monocyclic or bicyclic, by separation of a hydrogen radical of a carbon ring of the aryl compound. An aryl group is optionally substituted with one or more substituents in which, unless otherwise indicated, the selection of each of the optional substituents is independent of the selection of any other optional substituents and, preferably, the number of Optional substituents are between 0 and 3, more preferably between 0 and 2. It can be appreciated that the number of preferred substitutes is determined in part by the ease of synthesis. Representative aryl groups are phenyl and naphthyl. A "heteroaryl" group, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound of C-Cg, monocyclic or bicyclic, by separation of a hydrogen radical of a ring atom of the heteroaryl compound, said ring atom having no charge in said compound. The heteroaryl group is optionally substituted by one or more substituents in which, unless otherwise indicated, the selection of each of the optional substituents is independent of the selection of any other optional substituents, and preferably the number of substituents optional is between 0 and 3, more preferably between 0 and 2. It can be appreciated that the preferred number of substituents is determined in part by the ease of synthesis. Representative heteroaryl groups include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazoyl, 1,2,3. -oxadiazolyl, 1, 3, 5-thiadiazolyl, 1, 2, 3-thiadiazo-lilo, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1, 2, 3 -triazinyl, 1,3,5-triazinyl, pyrazolo [3, 4-b] pyridinyl, cinolinyl, pteridinyl, purinyl, 6,7-dihydro-5H- [l] pyrindinyl, benzo [b] thiophenyl, 5, 6, 7,8-tetrahydroquinolin-3-yl, benzoxazolyl, benzo-thiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazole, tianaphtenyl, isothianaphtenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, and benzoxazinyl; and similar. A "cycloalkyl" group, as used herein, unless otherwise indicated, includes an organic radical derived from a monocyclic C 3 -C 4 cycloalkyl compound, by separation of a hydrogen radical from a carbon ring of the cycloalkyl compound. The cycloalkyl group is optionally substituted with one or more substituents in which > unless otherwise indicated, the selection of each of the optional substituents is independent of the selection of any other optional substituents, and preferably the number of optional substitutes is between 0 and 3, more preferably between 0 and 2. It can be seen that the preferred number of substitutes is determined in part by the ease of synthesis. Representative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,3-cyclobutadienyl, 1,3-cyclopentadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1 , 3-cyclohepta-dienyl, 1,4-cycloheptadienyl, 1, 3,5-cycloheptatrienyl, bicyclo [3.2. l] octane, bicycles [2.2. l] heptane, and its unsaturated form of norborn-2-ene. A "heterocycloalkyl" group, as used herein, unless otherwise indicated, includes an organic radical derived from a monocyclic C 1 -C 1 heterocycloalkyl compound by separation of a hydrogen radical from a ring atom of the heterocycloalkyl compound, said ring atom being without charge in said compound, (fix) A heterocyclic group is optionally substituted with one or more substituents in which, unless otherwise indicated, the selection of each substituent optional is independent of the selection of any other optional substituents and, preferably, the number of optional substituents is between 0 and 3, more preferably between 0 and 2. It can be appreciated that the preferred number of substituents is determined in part by the ease of synthesis . Representative heterocycloalkyl groups include pyrrolidinyl, tetrahydrofranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazoli-dinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazole-din 3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl and chromanyl. In relation to the terms "aryl" group, "heteroaryl" group, "cycloalkyl" group and "heterocycloalkyl" group, as used herein, the term "optionally substituted" means that one or more chemical or pharmaceutically acceptable, can be attached to them. Such a group provides useful properties for the production, storage or use of the compounds of the invention as pharmaceuticals, or at least does not substantially negate their pharmacological activity. Such suitable substituents can be determined by those skilled in the art. Illustrative examples of suitable substitutents include, but are not limited to, hydroxy, halo, amino, trifluoromethyl, carboxy, alkoxy- (Cj-Cg) -, acyloxy Cj-Cg) -, alkylfC ^ -C) amino-, ((alkyl- (C | -Cg)) 2 amino-, acyl (C ^ -C) amino-, cyano, nitro, alkyl- (Cj-Cg) -, alkenyl (C2-Cg) -, alkynyl (C2-Cg) ) -, acyl ^ -Cg) -amino-, cyanoalkyl (C -] - Cg) -, trifluoromethylalkyl (C ^ - Cg) -, nitroalkyl C - Cg) -, alkyl (C - - C3) (difluoromethylene) alkyl - ((^ - 03) -, acylC ^ -CgJaminoalkylC ^ -Cg), alkoxy (C- Cg) acyl- (C-¡-G) amino-, aminoacyl (C - [- Cg) -, aminoacylC ^ -Calkyl - (C C6) -, (C1-C6) alkyl aminoacyl (C1-Cg) -, ((alkyl (-C)) 2-aminoacylC ^ -Cg) -, (C3-Cg) cycloalkyl (C1-) alkyl Cg) -, acyl (C-CgJoxi-alquilíC-Cg) -, alkoxy (C2-Cg) alkyl (C¡-Cg) - piperazi-nilalquil (Cj-Cg) -, acylC ^ C-aminoalkylC - ^ - Cg) -, aryl (Cg-C ^ Q) alkoxy (C-¡-GC) alkyl (Cj-Cg) -, heteroaryl (C2-Cg) alkoxy (Cj-CgJalkyI C ^ Cg) - , alkyl (C ^ CgJtioalkyl (Cj-Cg) -, aryl (Cg-C10) thioalkyl (C1-Cg) -, alkylC- Cg) sulfinylalkyl (C-Cg) -, arylCG-C ^ JsulfinylalkylC ^ Cg) -, alkyl (C ^ Csyglyphonylalkyl-C-Cg) -, arylCG-C- ^ sulphonylalkylC-j-Cg) -, aminoalkyl- (C- Cg) -, aminoalkyl (C- Cg) -, alkylC-LC Jaminoalkyl (C ^ Cg) ) -, alkylC ^ Cg) (difluoromethylene) -, (C1-C3) alkyl (difluoromethylene) alkyl (C1-C3) -, alkoxy (Cj-Cgjacil (C-Cg) -, alkylC- Cg) -aminoacylC ^ Cg) -, ((alkylCj-Cg)) aminoacyl (C? -Cg) -, aryl (Cg-C10) -, heteroaryl (C5-C8) -, aryl (Cg-Cjgíalq ilíC ^ Cg) -, hetero-aryl (C2-C9) alkyl (C1-C6) -, aryl (C6-C10) aryl (Cg-C10) -, aryl (C6-C10) aryl (Cg-C1Q) alkyl (C1-Cg) -, cycloalkyl ^ - C - ^) -, cycloalkyl (C3-C) alkyl (CC) -, heterocycloalkyl hetero-cycloalkyl (C3-C1Q) alkyl (C1-Cg) -, hydroxyalkyl (C2-Cg) -, acyl- (C1-) Cg) oxyalkyl (C2-Cg) -, alkoxy (C ^ C) alkyl (C2-Cg) -, piperazyl-nylalkyl (C-¡-GC) -, acyl (C ^ -Cg) aminoalkyl (C ^ -Cg) -, aryl (Cg-C10) alkoxy (C-Cg) alkyl (C-Cg) -, heteroaryl (C2-Cg) alkoxy (C ^ -C6) ) alkyl (C-Cg) -, alkyl (C ^ C) thioalkyl (Cj-Cg) -, aryl (Cg-C10) -thioalkyl (Cj-Cg) -, alkyl (C? -Cg) sulfinylalkyl (C? - Cg) -, aryl (Cg-C10) sulfinylalkyl (C2-Cg) -, alkylC- CgJsulfonylalkyl-C ^ -Cg) -, arylCG-C ^ Qjsulfonyl-alkylC ^ -Cg) -, aminoalkyl (C ^ -Cg) - , alkylC ^ CgJaminoalkylCj-Cg) -, and ((C ^ -Cg alkyl)) 2-aminoalkyl (C ^ -Cg) -. Other aspects of the invention will be described in accordance with the detailed description of the invention that follows directly.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the practice of the present invention, the secretion of growth hormone from cells (such as those of the anterior pituitary) is facilitated by inhibition of the mechanisms induced by somatostatin (and coupled with the G protein). ) that naturally oppose signals mediated by calcium ions and cyclic AMP, which otherwise trigger the fusion with the cell membrane of granular cytoplasmic structures containing growth hormone, and subsequent release ( secretion) of GH. The present invention provides an effective approach for the treatment of frailty in older people, which may be caused, in whole or in part, by insufficient levels of growth hormone (GH), or the deterioration of serious physiological water effects. down normally associated with the secretion of growth hormone. It is recognized, in general, that GH is important for the maintenance of connective tissue and muscle tissue in adults, and can help, to some extent, the increase in muscle mass. Therefore, growth hormone can be used to help older patients even when growth hormone levels per se are not the cause of, for example, weakness, or muscle and conjunctive tissue wasting. The practice of the invention benefits other patients, such as children, when it can be shown that the secretion of growth hormone is inadequate, but susceptible to improvement. The deficiency in the secretion of GH, or the resulting GH activity, can arise in various ways. For example, the gene sequence encoding GH can be expressed in the nuclei at subnormal levels, the processing of the resulting RNA transcript or nascent polypeptide can be defective, or the fusion of the atomic cytoplasic granules of GH storage with the Cell membrane (with the resulting release of GH) may be defective. Additionally, the patient may possess an allele of the GH gene that encodes a mutant protein of lower biological activity. Alternatively, there may be an underlying GHRH deficiency, or a defect in the GHRH receptor, or defects in the GHRP receptor or deficiency of its endogenous ligand, or in the respective signaling mechanisms. Additionally, there may be an excess of somatostatin. In all such cases, the resulting physiological deficiency can be treated by administration of the pharmaceutical compounds of the invention. In a further aspect of the invention, the behavior and growth rate of non-human mammals, such as cattle, is improved by appropriate administration of the compounds described herein.

Additionally, companion animals, and in particular older pet animals, also benefit from the administration of the present compounds. Although the compounds of the present invention act indirectly by facilitating the release of mature growth hormone from the cytoplasmic storage granules of cells, additional therapeutic substances are known which can directly improve such secretion, and in addition, can indirectly improve hormone production. of growth by way of an improved expression of the DNA encoding GH in the nucleus of the cells. In this regard, both growth hormone releasing peptide (GHRP) and growth hormone releasing hormone (which is also known as growth hormone releasing factor, GHRH / GRF) which act by releasing GH have been cited. from the storage cytoplasmic granules. Since the release of GH from such granules has been implicated as a triggering signal for the production of additional GH protein in the cells, it is expected that GH levels can be appropriately maintained in patients using a "stretch and stretch" approach. loosen up ". So, an example of the preferred additional invention provides coadministration of the somatostatin antagonist compounds of the present invention and GHRP or GHRH or other substances with similar effects. Medical treatment with GHRP (or GHRH) has only been described in the representative publications that follow: M. Thorner et al., Journal of Clinical Endocrinology and Metabolism, 81 (3), pages 1189-1196, 1996; S.G. Celia et al., Peptides, 16 (1), page 81-86, 1995; M.A. Bach et al., Journal of the American Geriatrics Society, 44 (9), SIO, 1996; and J.A. Aloi et al., Journal of Clinical Endocrinology and Metabolism, 79 (4), pages 943-949, 1994. Finally, since growth hormone is very labile, and its half-life in the body is very short, it is difficult to provide a safe dosage program for the direct administration of the growth hormone itself, which avoids large oscillations of the circulating levels of the hormone. Current extended-release technologies for the direct administration of growth hormone can be improved. In this regard, the practice of the present invention is particularly valuable to the clinician, since only by indirectly raising the levels of GH, the profile of release of the hormone remains, at least in part, under the control of the regulatory systems themselves. body feedback, and fluctuations in circulating GH levels are muffled over time. In the practice of the preferred invention, the compounds reveal selectivity for the sst2 receptor compared to other receptor subtypes, for example sstl, sst3, sst4 and sst5. This selectivity minimizes the possibility that other molecular, biological or biochemical pathways are adversely affected while the secretion of growth hormone is being regulated. Most preferably, the affinity of a compound for the sst2 type receptor should be at least about 10 times higher than for the receptors of the other sst subtypes. It should be noted that the compounds of the invention can act by more than one mechanism, including those that are not related to interaction in a sst type receptor, and the utility of the present compounds in the practice of the invention, including the use in the treatment of other disease states not particularly mentioned in this specification, is not limited by any particular theory as described herein or by those theories that are generally recognized by those skilled in the art. Additionally, the compounds of the present invention may beneficially interact with sst-type receptors other than sst2, and may provide therapeutic benefits by acting as somatostatin agonists, rather than as antagonists, in sst2 receptors or other sst receptors. Various types of somatostatin agonists are well known in the art, and the ability of a compound of the present invention to act as an agonist, or antagonist, or both, depending on physiological circumstances, can be predicted from assays that are known in the art. and / or that are described later. For example, the measurement of cyclic AMP, growth hormone release, microphysiometric responses, cell proliferation or protein kinase activity can be measured in cultured pituitary cells, cell lines or other cells such as neuroblastoma cells. expressing somatostatin receptors, and cells transfected with recombinant somatostatin receptors including transfected yeast cells (YC Patel et al., Biochemical and Biophysical Research Communications, 198 (2), pages 605-612, 1944; MG Cattaneo et al., FEBS Letters 397 (2-3), pages 164-168, 1996, JA Koenig et al., Briishish Journal of Pharmacology, 120 (1), pages 45-51, 1997; D. Djordjijevic et al., Endocrinology, 139 (5), pages 2272-2277, 1998; WR Baumbach et al., Molecular Pharmacology, 54 (5), pages 864-73, 1998. In general, somatostatin or its agonists demonstrate inhibitory activity, therefore it is applied first a stimulus ulo (for example, forskolin for cyclic AMP) and the inhibitory effect of somatostatin is observed. Antagonists reverse the inhibitory effects of somatostatin. Somatostatin agonists are recognized as useful therapeutic compounds in the treatment of diabetes, for example, see H.Grfnbaeck et al., Prog. Basi c Clin Pharmacol. (Basel), 10, pages 103-128, 1996. Somatostatin agonists are also recognized (see WO 98/44922) as therapeutic compounds useful in the treatment of, for example, diabetic retinopathy, acromegaly, rheumatoid arthritis. , neuropathic and visceral pain, irritable bowel syndrome, and Crohn's disease, and are useful for inhibiting cell proliferation associated with cancer, and for preventing restenosis following angioplasty. Additionally, it has been determined that compounds that possess affinity for sst2 receptors also possess affinity for receptors such as mcr4 and MCH. The sst2 receptors and the MCH receptors are also homologous in >;fifty%. Therefore, the compounds of the present invention can also be used to treat medical conditions mediated through such receptors. As mentioned above, the compounds of this invention include all conformational isomers (e.g., cis and trans isomers, involving or not double bonds), tautomers, and all optical isomers of compounds of formula I (e.g. , enantiomers and diastereoisomers), as well as the racemic, diastereomeric and other mixtures of all such isomers. With respect to the design of the compounds of the invention, particular features involving conformation isomerism and optical isomerism are to be noted. In the structure of a compound of formula (I) given below, it is preferred that the group Z thereof has the following stereospecificity Thus, the group Z defines an L-amino acid, preferably selected from the group consisting of L-tryptophanyl, L-histidinyl, L-3-methylhistidinyl, L-phenylalaninyl-, L-diphenylalaninyl-, L-3- fluorophenylalaninyl-, L-2-fluorophenylalaninyl-, L-4-fluorophenylalaninyl-, and L-tyrosinyl-, and most preferably, L-tryptophanyl. It is less preferred that group Z have the following stereospecificity wherein the group Z defines an amino acid D; However, in In this case, the use of D-tryptophanyl- is highly preferred. In the structural component of a compound of formula (I) which is shown below, it is preferred that the group W thereof have stereospecificity in the indicated position (corresponding to the carbon atom of an amino acid), so that that L-amino acids are defined, or other structures that have the same absolute stereospecificity.

In preferred examples, the group W defines a group of L-lysine or one of its alkyl esters of C ^ -Cg, or a group of L-arginine or one of its C ^ -Cg alkyl esters, and in one highly preferred example an alkyl ester of C ^ -Cg of L-lysine is defined. Additionally, the group W can define an L-diaminopimelic group, L-canavanine, L-ornithine, L-2, 4-diaminobutyric, L-5-hydroxylysine, L-epsilon-N-methyl-lysine, L-histidine, or L-3-methylhistidine. Additionally, L-lysine is preferably selected to provide the "W" component, when Trp derivatives (both L and R) are employed to provide the Z component. L-arginine is preferably selected to provide the "W" component when Phe (or one of its derivatives such as 2-fluorophenylalaninyl-, 3-fluorophenylalaninyl-, 4-fluorophenylalaninyl- or diphenylalaninyl-) is used to provide the component " Z ". In this case the stereochemistry provided within Phe, or one of its derivatives, should correspond to that of L-amino acids, if possible. Additionally, many of the groups of the compounds present may be optionally substituted. As mentioned above, such substituents provide useful properties for the production, storage or use of the compounds of the invention as pharmaceuticals, or at least do not substantially negate their pharmacological activity. It will be appreciated that the selection of optical substituents is further guided by principles recognized in the art, and / or is capable of validation through the use of the assays described herein.

Pharmaceutical Formulations The compounds of the present invention, which are basic in nature, are capable of forming a wide variety of different salts with various inorganic or organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture, in the form of a pharmaceutically unacceptable salt, and then simply convert the latter into the free base by treatment with an alkaline reagent and then converting this latter free base into a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared, for example, by treating the basic compound with a substantially equivalent amount of the chosen mineral or organic acid, in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. By careful evaporation of the solvent, the desired solid salt is easily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution. Those compounds of the present invention having an acid nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and in particular the sodium and potassium salts. All these salts are prepared by conventional techniques. The chemical bases that are used as reagents to prepare pharmaceutically acceptable base salts, of this invention, are those that form non-toxic base salts with the acid-nature compounds of the present invention. Such non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium, etc. These salts can be prepared easily by treating the corresponding acidic nature compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resultant solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing together solutions in lower alcohols of the acidic compounds and the desired alkali metal alkoxide, and then evaporating the resulting solution to dryness in the same manner as indicated above. In either case, stoichiometric amounts of reagents are preferably employed in order to ensure that the reaction is complete and the maximum desired final product yields. In an example of the preferred invention, the compounds of the present invention can be formulated with additional pharmaceutically active substances that directly or indirectly facilitate the production and storage in additional growth hormone cells or precursor polypeptides thereof, or the release of GH . Such additional substances include growth hormone releasing peptide (GHRP), growth hormone releasing hormone (GHRH), pituitary adenylate cyclase activating polypeptide (PACAP), dopamine agonists (eg, bromocriptine), beta-agonists. adrenergics (eg, isoproterenol) and 1-adrenergic agonists (eg, methoxamine). For fundamental information see the publications of E.O. Soyoola et al., Proceedings of the Society for Experimental Biology and Medicine, 207 (1), pages 26-33, 1994; V. Locatelli et al., Pediatri c Research, 36 (2), pages 169-74, 1994; and B. Velkeniers et al., Journal of Endocrinology, 143 (1), pages 1-11, 1994. Equivalently, additional pharmaceutically active substances can be provided in the form of a separate formulation that is co-administered or that is administered in some other point or time points during the course of treatment. This invention also includes pharmaceutical compositions containing prodrugs of compounds of the formula I. This invention also encompasses methods of treatment or prevention of disorders that can be treated or prevented by lowering somatostatin levels, which comprise administering prodrugs of compounds of the formula I. The compounds of formula I which have free, amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues are conveniently attached via peptide bonds to amino, hydroxy or carboxylic free groups of compounds of formula I. The amino acid residues include the 20 natural amino acids commonly designated by three-letter symbols and also include 4-hydroxyproline, hydroxylysine, demosin, isodemosin, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline , homocysteine, homoserin, ornithine and methionine-sulfone. The prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters are covalently linked to the substituents of formula I above via the carbonyl carbon side chain of the prodrug. An expert of ordinary skill in the art may also appreciate using the compounds of the invention in the treatment of a specific disease, that the compounds of the invention may be combined with various existing therapeutic agents used for such a disease, or other metabolically related or unrelated disease states that may occur simultaneously. As mentioned above, additional pharmaceutically active substances can be provided in the form of a separate formulation that is co-administered or that is administered at some other or other time points during the course of treatment. The compounds of the invention can also be used in combination with existing therapeutic agents such as the aforementioned growth hormone secretagogues, for the treatment of growth hormone deficiencies. For the treatment of growth hormone deficiencies, the compounds of the invention can be combined with agents such as recombinant growth hormone, marketed by Genentech and authorized dealers (Neutropin, Genotropin and Protropin), Bio-Technology General and authorized dealers (Zomacton, Growject, Elvetium and SciTropin), Novo Nordisk (Norditropin), LG Chem (Eutropin), Ares Serono (Saizen and Serostim ), Eli Lilly Co. (Humatrope), Monsanto (the brand Posilac of bovine growth hormone) and Alpharma (brand Reporcin porcine growth hormone). The compounds of the invention can also be used in combination with existing therapeutic agents such as GEREF (sermorelina, GHRH) of Serono Laboratories Inc.

The compounds of the invention can also be used in combination with existing therapeutic agents such as anabolic steroids, for example, androisoxazole androstanolone (DHT, dihydrotestosterone, Stanolone, Anabo-lex, Andractrim), bolandiol, bolasterone, bolazine, boldenone (Equipoise), calusterone, clostebol (clortestosterone, Steranabol, Alfa Trofodermin, Dermanabol, Trofodermin, Trofoseptine), danazol (Cyclomen, Danocrine), dehydrochloro-methyltestosterone (turinabol, Oral-turinabol), drostanolone (dromostanolone, Drolban, Masterid, Masteril, Masteron, Metormon, Premastril), estradiol, etilestrenol, fluoximeste-rone (Halotestin, Oral-Testryl, Android-F), formebolone, furazabol (Miotolon), mestanolone, mesterolone (Proviron, Pluriviron), methandienone (methandrostenolone, Metaboline), ethanediol, methenolone (Primobolan ), methyltestosterone (Methandren, Premarin with methyltestosterone, Android, Oreton, Testred, Methyltestosterone tabs, Geri-Bons, Geri-tabs, Dermona l), mibolerone (Check), nandrolone (Deca-Durabolin, Durabolin, Nandrolin, Anabolin, Androlone, Hybolin, Nandro-lie), norclostebol, noretandrolone (Nilevar), oxabolone, oxandrolone (Anavar), oxymesterone (Oranabol), oxymetholone ( Anapolon 50, Androyd, Anadrol, Anaster, Dynasten, Oxitoso-na, Plenastril, Synasteron, Zenalosyn), Penmesterol, Praste-rone, Quinbolone, Stanozolol (Winstrol, Winstrol-V, Stromba, Strombaject), Stenbolone, Testosterone (Malogen, Dela -testryl, Malogen, Neo-pause, PMS-Testosterone Enanthate, Andriol, Duogex, Neo-Pause, Climacteron, Orchisterone-P, Oreton, Anadiol, Anatest, Testos-100, Heifer-aid, Synovex-H), tibolone, trenbolone (Parabolan, Finaject) or zeranol. The compounds of the invention can also be used in combination with existing therapeutic agents such as Somazon (mecasermin, growth factor, recombinant, insulin-like) of Fujisawa. For the treatment of elderly patients with osteoporosis, agents suitable for use in combination with the compounds of the invention include non-steroidal antiinflammatory agents (hereinafter NSAID's), standard, such as piroxicam, diclofenac, propionic acids, cos such as naproxen, flubiprofen, fenoprofen, ketopro-phene and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazona, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as celecoxib and rofecoxib, analgesics and compounds for intra-articular therapeutic treatments such as corticosteroids and hyaluronic acids such as hyalgan and sinvisc. The compounds of the present invention can also be used in combination with osteoporosis agents such as lasofoxifene, raloxifene, droloxifene or fosomax and immunosuppressive agents such as FK-506 and rapamycin. The compounds of the present invention can also be used in combination with immunostimulating agents for the treatment of reduced immune function. The compounds of the present invention can also be used in combination with fertility agents such as human menopausal gonadotropin, chorionic gonadotropin, follicle stimulating hormone, nafarelin, triptore-lina, cetrorelix and ganirelix, for the treatment of infertility. The compounds of the present invention can also be used in combination with AIDS therapies for the treatment of AIDS-like complexes. The compounds of the present invention can also be used in combination with anti-tumor necrosis factor agents such as infliximab (TNF monoclonal antibody) or etanercept (soluble TNF receptor) for the treatment of cachexia. The compounds of the present invention can also be used in combination with potassium channel blockers, beta-blockers, anticoagulants or vasodilators for the treatment of heart diseases.

The compounds of the present invention can also be used in combination with angiotensin II antagonists (ATII) or erythropoietin for the treatment of renal failure. For administration to cattle, the compounds of the invention can also be used in combination with feed additives such as antibiotics (eg, monensin, lasalocid, salinomycin, semduramycin, narasin, maduramycin, virginiamycin, polymyxin, efrotomycin, avoparcin, lincomycin, bacitracin, bambermiciñas, novobio-ciña, erythromycin, oleandomycin, streptomycin, tylosin, penicillin, tetracycline, oxytetracycline, chlortetracycline, carbadox, olaquindox, neomycin, moenomycin, avilamycin, and flavophospholipol), delivery agents, beta-agonists (eg, Paylean, ractopamine, from Elanco), and also amite-rol, bambuterol, bitolterol, broxaterol, bufenin, carbute-rol, cimaterol, clenbuterol, chlorprenaline, colterol, denopamine, dioxetedrine, dioxifedrine, dobutamine, dopexami-na, doxaminol, ethanol, fenoterol, flerobuterol, formote-rol, hexoprenaline, ibuterol, imoxiterol, isoetarin, isoxsuprine, levisoprenaline, mabuterol, mesuprine, metate-ro l, methoxyphenamine, nardeterol, orciprenaline, picumeterol, pirbuterol, prenalterol, procaterol, protoquilol, quinprena-lina, rimiterol, ritodrine, salbutamol, salmeterol, terbuta-lina, tretoquinol, tolubuterol, xamoterol and zilpaterol. The compositions of the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable excipients. Thus, the active compounds of the invention can be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration, or in a form suitable for administration by inhalation or insufflation. The active compounds of the invention can also be formulated for prolonged release. For oral administration, the pharmaceutical compositions can take the form, for example, of tablets, chewable tablets or capsules, prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (for example, pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose). ); fillers (for example, lactose, micro-crystalline cellulose or calcium phosphate); lubricants (for example magnesium stearate, talc or silica); disintegration agents (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets can be coated by methods well known in the art. Liquid preparations for oral administration may take the form, for example, of solutions, syrups or suspensions, or they may be presented as a dry product to be reconstituted with water or other suitable vehicle before use. Such liquid preparations may be manufactured by conventional means with pharmaceutically acceptable additives such as suspending agents (eg, sorbitol syrup, methylcellulose or edible hydrogenated fats); emulsifying agents (for example, lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservative agents (e.g., methyl or propyl p-hydroxybenzoates, or sorbic acid). For buccal administration, the composition can take the form of conventionally formulated tablets or troches, or mixed with the food or animal feed, or in the form of a premix for mixing with the animal feed. The active compounds of the invention can be formulated for parenteral administration by injection, including the use of conventional catheterization or infusion techniques. Formulations for injection may be presented in unit dosage forms, for example, in ampoules, or in multi-dose containers, with an added preservative agent. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution before use with a suitable vehicle, eg, sterile, depyrogenated water. The active compounds of the invention can also be formulated in the form of rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides. For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently distributed in the form of a solution or suspension from a pump spray container that is tightened or driven by the patient, or in the form of an aerosol presentation from a patient. pressurized container or a nebulizer, with the use of a suitable propellant agent, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of an aerosol placed under pressure, the administration unit can be determined by arranging a valve to distribute a measured quantity. The container placed under pressure or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made of gelatin, for example) for use in an inhaler or insufflator can be formulated containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch. The proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human is 0.1 to 100 mg of the active ingredient per unit dose, which could be administered, for example, 1 to 4 times a day . Aerosol formulations for the treatment of the aforementioned states, in the average adult human, are preferably arranged so that each metered dose or "puff" of aerosol contains 20 μg to 1000 μg of the compound of the invention. The overall daily dose with an aerosol can be within the range of 0.1 mg to 100 mg. The administration can be done several times a day, for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses each time. The injected doses are preferably administered from about once a month to about 1 to 4 times a day, in an individual dosage of 0.01-1 mg / kg (of active ingredient) and can be, for example, intramuscular, intravenous or subcutaneous As is well known, the precise dose, and the method and frequency of administration thereof, are susceptible of determination by those skilled in the art, and depend on numerous factors including the activity of the therapeutic compound, the properties of the formulation of it, the nature and location of the target tissue, and the particular characteristics of the disease state such as those existing in a given patient. Additionally, when the compounds of the present invention are administered to a patient with additional pharmaceutically active substances, one or more pharmaceutical compositions may be used to distribute all of the active agents, which may be administered together or at different times, as determined by the experts in pharmaceutical or medical techniques. The reaction schemes that follow illustrate the preparation of compounds of the present invention. It will be appreciated that the groups represented by letters ("R" groups, and the like) in the Schemes do not always correspond to similarly defined component groups of the compounds of formula (I) themselves, since certain functionalities of the reactants are modified when the products are formed. Therefore, to facilitate the presentation of the schemes, R1 and R, which are alluded to below, correspond to R1 and R1 as used throughout the Descriptive Memory in the definition of the compounds of formula (I), while Ar ^, Ar2, Ar3 and R represent structures that overlap with those that are defined elsewhere, as is easily evident by inspection. For example, Ar ^, Ar2 and A ^ do not correspond to "A" but rather represent any aryl group of C-C ^ g or heteroaryl of C ^ -C, as defined herein. R2 typically represents an alkyl group, whether it is primary, secondary or tertiary, but it can also be aryl or benzyl.

Scheme I LiOH General reaction conditions Generally speaking, the compounds of the present invention are prepared by a series of "condensation" reactions in which certain reactive groups are appropriately protected and the sequence of condensation is regulated. Schemes I and II show that the component materials can be coupled in more than one sequence. With reference to Scheme I, the compounds of formula 1 including a L-arginine residue, can be prepared from compounds of formula 2 by removal of the guanidine protecting nitro group by a reduction reaction using formic acid as a reducing agent , in the presence of palladium on carbon. In a typical operating procedure, the reaction mixture is stirred overnight under nitrogen, filtered, and then the solvent is removed under reduced pressure. The recovered material can then be triturated with diethyl ether and dried overnight in high vacuum obtaining the final product. Even though the preferred protecting group is the nitro group, the Boc group can also be used, in which case the suitable conditions for deprotection are stirring with trifluoroacetic acid or hydrochloric acid. Referring again to Scheme I, the compounds of formula 2 can be prepared by condensation of the compounds of formulas 3 and 4, for example in the presence of 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydroxybenzotriazole hydrochloride and dimethylaminopyridine. The reaction mixture can then be washed successively with portions of 10% aqueous hydrochloric acid solution, followed by washings with saturated 50% sodium bicarbonate solution, and saturated brine. The resulting product 2 can then be dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure. In a preferred example of the invention, compounds 3 and 4 include amino acid residues which confer to the final compounds obtained as products a structure similar to that of a peptide, consistent with its activity as somatostatin analogues. Compound 3 may represent one of several appropriately protected amino acids, comprising, for example, a lysine, arginine, histidine or ornithine residue, in which its carboxyl group is protected, for example, by a suitable alkyl group (R2) . The stereospecificity in the sub-region of the compound obtained as a product that is defined as "W" in this specification is determined by the stereospecificity of the participating amino acid. In the practice of the invention, the stereospecificity corresponding to an L-amino acid is preferred. It is to be appreciated that L-lysine is preferably selected to provide the "W" component, when Trp derivatives (both L and R) are used, to provide the Z component. L-arginine is preferably selected to provide the component "W" when Phe (or its derivatives such as 3-fluorophenylalaninyl- or diphenylalaninyl-) is used to provide the "Z" component. In this case, the stereochemistry provided within Phe, or one of its derivatives, must correspond to that of L-amino acids, if possible. The deprotection that takes place in stage 2? 1 can be carried out with a different agent, for example TFA, or, depending on the amino acid residue contributed by compound 3, a different deprotection strategy can be employed. For example, in case the amino acid residue is lysine or a structure similar to that of lysine, the protection of the alkylamine side chain can be carried out by providing compound 3 as a derivative of BOC, with subsequent copulation, followed by hydrolysis with HCl. The compounds 4 are easily prepared from the compounds 5 by hydrolysis under alkaline conditions, most preferably using LiOH in methanol / water. The compounds 5 are prepared by reaction to form an amide bond between the compounds 6 and 7. It will be appreciated that the compound 5 provides the sub-region Z of the final product 1, and is responsible for its stereospecificity. Even if the group Ar2 existing therein can be any aryl group of C-CjQ or heteroaryl group of Cj-Cg according to the terms and expressions that are defined in the Descriptive Memory, it is preferred, again, that A2 allow the sub-group Z region provides an amino acid residue, for example, a tryptophanyl, histidinyl, phenylalaninyl or tyrosinyl group. In the practice of the invention, the stereospecificity corresponding to an L-amino acid is preferred, although the use of D-tryptophanyl is likewise preferred. Numerous recognized operating procedures can be used to react compounds 6 and 7 as required herein. For example, an alkyl ester of compound 6 can be reacted with a compound of formula 7, in triethylamine / methylene chloride, with stirring overnight with a dehydrating agent such as dicyclohexylcarbodiimide, or more preferably, with hydroxybenzotriazole, 4- dimethylaminopyridine, and 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride in methylene chloride. The solution can then be washed successively with sufficient portions of 10% hydrochloric acid, 50% saturated sodium bicarbonate, and saturated brine. The product can then be dried over anhydrous magnesium sulfate, filtered and the solvent removed, for example. It will be appreciated that the R, Rx and Ar- ^ groups (and the reactants they provide) are selected to allow all of the compounds of the invention obtained as a product. In this regard, the following structures are representative of those which can be used in place of compound 7 in the practice of the invention, whereby the residues [A-G] in the compounds of formula (I) are defined. Ar1-Ar3- C02H Ar, -CH5 Ar¿ -CO, H in which formulas Ar ^ (or Ar) is any aryl group of Cg-C- ^ Q or heteroaryl of C-Cg, and the synthesis of the resulting reactants will be apparent to those skilled in the art. For example, the above structures can be prepared from the corresponding amino acids. As mentioned above, since the general reaction scheme established in this specification involves a series of "condensations", it can be seen that the illustrated reactions can be carried out in a different sequence, or can be replaced by reaction steps. equivalents Scheme II is one such additional possibility, and illustrations of its use are found in the numbered Examples that follow. Schemes I? I (a) and (I? I (b) provide approaches to the "W" group in the general structure A-G-Z-W, where W is the alternative (b) wherein Q is selected from the group consisting of aryl of c6-c10 'neteroaryl of C-C, cycloalkyl of C ^ - ^ Q and heterocycloalkyl of C3-C10 and R', R ° and R 'are selected, each independently, between H, alkyl (C ^ -Cg) - and phenyl (CH2) -, wherein said alkyl and phenyl groups are optionally substituted. Schemes III (a) and III (b) describe representative syntheses of the component W in which each of R, R ° and R 'is H, and Q is, for example, either cyclohexane or pyridine. Numerous equivalent schemes are available to the practitioner of the art. Referring first to Scheme I, the product 14 of Scheme III (a) and similar compounds can replace the compounds of formula 3, whereby compounds analogous to compounds 2 are prepared from compounds of Formula 4. Compounds analogous to those of formula 1 are then prepared from compounds of analogs to those of formula 2 by removal of the BOC protection group, under acidic conditions. With reference to Scheme III (a), compounds of formula 14 can be prepared from compounds of formula 35 by reduction with hydrogen, under appropriate conditions. Compounds of formula 15 can be prepared from compounds of formula 16 by means of a reaction using NaN to displace the mesylate ester of compounds 16. Compounds 16 can be prepared from compounds 17 with mesyl chloride (methanesulfonyl) in basic conditions, for example, in triethylamine / dichloromethane, at O = C, with good performance. Compounds 17 can be prepared from compounds 18 by reduction in the carboxyl group thereof, using BH3. The compounds 18 possessing the stereospecificity indicated in Scheme III (a), are prepared from the racemic compounds by chiral resolution with stereospecific α-methylbenzylamine, followed by selective purification, such as by crystallization. The compounds 20 can be prepared from the corresponding aromatic compounds 21 by reduction with hydrogen, for example under appropriate conditions. In turn, the compounds 21 are prepared from the corresponding compounds 22 (unprotected) by reaction with BOC anhydride under standard conditions. Finally, compounds 22 can be prepared from available starting materials 23, by reduction of the cyano group with hydrogen over a Raney nickel preparation. In Scheme III (b) advantage is obtained from starting materials that are available, to generate compounds of the formula 14 'in 2 steps, firstly from compounds of formula 24 using BOC anhydride. Compounds 24 are generated from compounds of formula 25 by reduction of both cyano groups, again with hydrogen and Raney nickel.

Scheme II Scheme III (a) H2, Pt02, AcOH MsCI 14 16 15 Scheme III (b) 24 14 ' Examples The following are representative compounds of the invention EXAMPLE 1 6-Amino-2- [2- [(biphenyl-4-ylmethyl) amino] -3- (1 H -indol-3-yl) propionylamino] hexanoic acid methyl ester having the specified stereospecificity Step 1 Wang resin (Arogel Wang, Argonaut Technologies, 170 mg, 0.39 mmol / g, 0.066 mmol) in 3 ml of CH2C12 was allowed to swell for 15 minutes, and washed 3X (3 times) with 3 ml of CH2C12. A solution of Fmoc-Lys (Boc) -OH (128 mg, 0.25 mmol), DIC (38 μL, 0.26 mmol), TEA (70 μL, 0.5 mmol) and DMAP (3 mg, 0.026 mmol) in 2.5 ml of CH2C12, and the mixture was stirred by rotation for 1.5 h. Then the resin was washed, consecutively, 3X with 3 ml of CH2C1, 2X with 3 ml of DMF, 2X with 3 ml of EtOH, and finally, 3X with 3 ml of CH2C12. Then 3 ml of a 20% solution of piperidine in CHC12 was added and the composition was stirred by rotation for 1 hour. The resin was then washed, sequentially, 3X with 3 ml of CH2C12, 2X with 3 ml of DMF, 2X with 3 ml of EtOH, and 3X with 3 ml of CH2C1. Then a solution of Fmoc-d-Trp-OH (110 mg, 0.26 mmol), DIC (38 μL, 0.26 mmol), TEA (70 μL, 0.5 mmol) and DMAP (3 mg, 0.026 mmol) in 2.5 ml of CH2C12, and the mixture was stirred by rotation for 1.5 h. The resin was then washed, sequentially, 3X with 3 ml of CH2C1, 2X with 3 ml of DMF, 2X with 3 ml of EtOH, and then with 3 ml of CH2C12. Then 3 ml of a 20% solution of piperidine in CHC12 was added and the mixture was stirred by rotation for 1 hour. The resin was subsequently washed 3X sequentially with 3 ml of CH2C12, 2X with 3 ml of DMF, 2X with 3 ml of EtOH and then 3X with 3 ml of toluene.

Step 2. Preparation of the title compound. To the resin was added 2.5 ml of 10% THF in toluene, followed by biphenylcarboxaldehyde (50 mg). The composition was stirred by rotation for 1 hour, after which 0.5 ml of NaCHBH4 IN (in THF) was added and the rotation continued for 2 hours. The resin was then washed, consecutively, 3X with 3 ml of CH2C12, 2X with 3 ml of DMF, 2X with 3 ml of EtOH and 3X with 3 ml of CH2C12. The composition was then subjected to drying with insufflation, under N, and then passed into an approximately 15 ml vial. 3 ml of a solution of MeOH, DMF, TEA (9: 1: 1) was added, and the composition was mixed on an orbital shaker at 502C for 2.5 days. The resin was then filtered and washed 2X with 3 mL of CH2C12, followed by 3X with 3 mL of EtOH. The resulting solid was evaporated and passed through a pad of Si02 with EtOAc to obtain 10 mg of product. The product was then dissolved in 2 ml of concentrated solution of 20% HCl in EtOH and stirred again at room temperature for 30 minutes. The resulting HCl swas evaporated and triturated with ether to obtain 9 mg of product. MS / +: 613.2; XH NMR: 7.10 (m, 2H), 4.21 (m, 1H), 3.62 (s, 3H), 1.83 (m, 2H). It is to be appreciated that if the L-lysine moiety of the main chain of the exemplary compound is replaced by a moiety provided by 2,4-diaminobutyric acid, the compound was substantially less active in the assays. However, the replacement by L-ornithini- dio resulted in active compounds.

Example 2 2- Methyl ester. { 3- (3-fluorophenyl) -2- [2- (toluene-4-sulfonylamino) acetylamino] propionylamino} -5-guanidinopentanoic, which has the indicated stereospecificity.

Step 1. Preparation of 3-F-Phe-Arg (N02) -OMe To a solution of 2.00 g of BOC-3-F-Phe-OH (7.06 mmol), 2.09 g of Arg (N02) ) -OMe HCl (7.77 mmol), 1.05 g of hydroxybenzotriazole and 2.58 g of 4-dimethylaminopyridine in 50 ml of methylene chloride, 1.5 g of l, 3-dimethylaminopropyl-3 hydrochloride were added. -ethylcarbodiimide. After stirring for 15 hours, an additional 100 ml of methylene chloride was added to the reaction mixture, and it was washed three times with 100 ml portions of 10% aqueous hydrochloric acid solution, twice with 100 ml of saturated sodium hydroxide solution. 50% sodium bicarbonate and once with 100 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure to obtain 2.96 g of product. This product was dissolved in 100 ml of 10% trifluoroacetic acid in methylene chloride, stirred for 2 hours, and the solvent was removed rapidly under reduced pressure. The material was triturated with diethyl ether and dried under high vacuum to obtain the product.

Step 2. Preparation of the title compound To a solution of 104 mg of tosylglycine (0.456 mmol), 273 mg of 3-F-Phe-Arg (N0) -OMe.HCl (0.684 mmol), 93 mg of hydroxybenzotriazole (0.689 mmol) ) and 167 mg of 4-dimethylaminopyridine (1.37 mmol) in 20 ml of methylene chloride were added, 137 mg of 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (0.684 mmol). After stirring for 15 hours an additional 100 ml of methylene chloride was added to the reaction mixture, and it was washed three times with 20 ml portions of 10% aqueous hydrochloric acid solution, twice with 20 ml of saturated aqueous solution. 50% sodium bicarbonate and once with 20 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure. This material was dissolved in 60 ml of methanol and 300 mg of 10% palladium on carbon was added under nitrogen, followed by 2.5 ml of formic acid. The mixture was stirred overnight under nitrogen, filtered, the solvent was removed under reduced pressure, the material was triturated with diethyl ether and dried overnight in high vacuum to obtain the product. This material can also be synthesized by copulating an appropriately protected arginine fragment with a suitably protected tryptophan fragment, deprotecting the amino group of tryptophan, condensing this material with tosylglycine and deprotecting the arginine side chain. * H NMR (CD3OD): d 4.65 (m, 1H), 4.42 (m, 1H), 3.72 (s, 3H), 2.45 (s, 3H). MS: M + l = 565. It is to be appreciated that if the glycinyl moiety existing in the main chain of the exemplary compound is replaced by alaninyl (whether it is D- or L-), the compound was substantially less active in the trials. However, replacement by a-methylalaninyl dioxide resulted in active compounds. The glycinyl residue is also usefully replaced by β-alanine and α-aminobutyric acid.

Example 3 Methyl ester of 6-amino-2- [2- [(biphenyl-4-carbonyl) amino] -3- (1H-indol-3-yl) propionylamino] hexanoic acid, which has the indicated stereospecificity R NMR (CD3OD): d 4.32 (m, 1H), 3.39 (d, 1H), 3.63 (s, 3H), 2.87 (m, 2H). MS: M + 1 = 527 Example 4 Acid methyl ester 2-. { 2- [(biphenyl-4-carbonyl) amy-no] -3,3-diphenylpropionylamino} -5-guanidinopentanoic, which has the indicated stereospecificity.

XH NMR (CD3OD): d 5.45 (d, 1H), 4.55 (d, 1H), 4.25 (m, 2H), 3.49 (s, 3H). MS: M + 1 = 592.

Example 5 6-amino-2- [2- [(biphenyl-4-carbonyl) amino] -3- (1H-indol-3-y1) propionylamino] hexanoic acid tert-butyl ester, which has the indicated stereospecificity.

Step 1. Preparation of L-Trp-OMe 4-biphenylcarbonylamide 3.45 g (13.54 mmol) of hydrochloride were dissolved in L-Trp-Ome and 4.11 g (40.6 mmol) of triethylamine in 500 ml of methylene chloride. Then 2.934 g (13.54 mmol) of 4-biphenylcarbonyl chloride was added in portions, and the reaction mixture was allowed to stir overnight. The solution was then washed twice with 100 ml portions of 10% hydrochloric acid, twice with 100 ml portions of 50% saturated sodium bicarbonate solution and once with 100 ml of saturated brine, dried over sodium sulfate. Anhydrous magnesium was filtered and the solvent was removed under reduced pressure to obtain 4.83 g (90%) of product.

Step 2. Preparation of L-Trp-OH 4-biphenylcarbonylamide L-Trp-Ome 4-biphenylcarbonylamide (4.83 g, 12.12 mmol) was dissolved in 120 ml of methanol and then 2.543 g (60.6 mmol) of lithium hydroxide.monohydrate in 40 ml of water was added. The reaction mixture was heated to 70 = C to dissolve the entire contents, and after maintaining the stirring at that temperature for 30 minutes, the reaction mixture was cooled to room temperature. The methanol was removed by rotary evaporation, and the aqueous suspension was acidified to pH 2.0 with 10% aqueous hydrochloric acid solution. Lego the solid was filtered and dried overnight under vacuum obtaining 3.79 g (81%) of product.

Step 3. Preparation of the title compound to the trifluoroacetate salt state To a solution of 100 mg of L-Trp-OH 4-biphenylcarbonyl-amide (0.26 mmol), 132 mg of Lys (Z) -OtBu.HCl ( , 39 mmol), 53 mg of hydroxybenzotriazole (0.39 mmol) and 191 mg of 4-dimethylaminopyridine (1.56 mmol) in 40 ml of methylene chloride, 150 mg (0.78 mmol) of hydrochloride were added. of 1,3-dimethyl-aminopropyl-3-ethylcarbodiimide. After stirring for 15 hours an additional 100 ml of methylene chloride was added to the reaction mixture, and it was washed three times with 30 ml portions of 10% aqueous hydrochloric acid solution, twice with 20 ml of saturated aqueous 50% sodium bicarbonate and once with 20 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The product was then dissolved in 10 ml of methylene chloride, 1 ml of trifluoroacetic acid was added and the reaction mixture was stirred for 3.5 hours. The solvent was removed rapidly under reduced pressure, the product was triturated with diethyl ether and dried under high vacuum overnight, obtaining 67 mg of product. This material can also be synthesized by coupling a suitably protected lysine fragment with a suitably protected tryptophan fragment, deprotecting the amino group of tryptophan, condensing this material with biphenylcarbonyl chloride and deprotecting the lysine side chain. XH NMR (CD3OD): d 4.36 (m, 1H), 3.40 (m, 1H), 2.85 (m, 2H), 1.43 (s, 9H). MS: M + 1 = 569.

Example 6 Butyl ester of 6-amino-2- [2- [(biphenyl-4-carbonyl) amino] -3- (lH-indol-3-yl) propionylamino] hexanoic acid, which possesses the indicated stereospecificity XH NMR (CD30D): d 4.18 (m, 1H), 3.45 (m, 1H), 2.78 (m, 2H), 1.40 (s, 9H). MS: M + 1 = 569.

Example 7a 6-Amino-2- [2- (2-benzenesulfonylamino-2-methylpropionylamino) -3- (lH-indol-3-yl) propio-nylamino] hexanoic acid tert-butyl ester, which possesses the indicated stereospecificity This compound was synthesized by coupling α-methylalanine-benzenesulfonamide (from a-methylalanine and benzenesulfonyl chloride) with (L) Trp-Ome, using 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, deprotection of the methyl ester with LiOH, coupling with Lys (Boc) -OtBu.HCl using 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, and deprotecting with trifluoroacetic acid. NMR (CD3OD): d 4.38 (m, 1H), 4.65 (m, 1H), 3.47 (d, 2H), 1.45 (s, 6H), 1.41 (s, 9H) . MS: M + l = 614.

Example 7b 6-Amino-2- [2- (2-benzenesulfonylamino-2-methylpropionylamino) -3- (1H-indol-3-yl) propionylamino] hexanoic acid tert-butyl ester, which possesses the indicated stereospecificity The details of the synthesis are as in Example 7a, except for the use of (D) Trp-Ome.

Example 8 The ability of the compounds of formula (I), and pharmaceutically acceptable salts, solvates or hydrates thereof (hereinafter referred to as the compounds of the present invention) to act as antagonists or agonists of somatostatin, and, therefore, to demonstrate its efficacy in the treatment of disease states, it is evidenced by the following tests.

Biological tests EXAMPLE 9 Bovine sst2 ("b") Binding Assay Buffers and solution Wash Buffer (per liter): 50 mM HEPES, 50 mL of stock IM solution (Gibco BRL n = 15630-080) 5 mM MgCl, 0.476 g (Sigma M-8266) pH at 7.4 with HCl or KOH It is brought to 1 liter with ddH20.

Filter pre-wetting solution, 0.2% polyethylenimine (per liter): 4 g of 50% aqueous solution of polyethylenimine (P-3143 Sigma) It is brought to 1 liter with ddH20.

Binding buffer (per liter): 50 mM HEPES, 50 ml of stock IM solution (Gibco BRL No. 15630-080) 5 mM MgCl, 0.476 g (Sigma M-8266) pH at 7.4 with HCl or KOH 1 g of bovine serum albumin (A-7888 Sigma) 20 mg of Bacitracin (B-0125 Sigma) 10 uM of Aprotinin (A-4529 Sigma) 10 uM of Leupeptin (L-8511 Sigma) 10 uM of AEBSF (Sigma A-8456) It is brought to 1 liter with ddH20.

Culture medium (per 500 ml) DMEM, supplemented with 10% fetal bovine serum, and penicillin / streptomycin (55 ml of FBS, 5.5 ml of pen / streptide are pipetted into a 500 ml container) Material's list 1. MgCl2 (Sigma M-8266) 2. HEPES ÍM (Gibco BRL, cat # 15630-080) 3. Bacitracin (B-0125 Sigma) 4. Aprotinin (A-4529 Sigma) 5. Leupeptin (L-8511 Sigma) ) 6. Bovine serum albumin (Sigma, n2 from cat. A-7888) 7. Dulbecco's PBS, Gibco BRL (Cat No. 14040-141) 8. Cell dissociation buffer (Gibco BRL, n = cat. 13150-016) 9. 50% polyethyleneimine (Sigma P-3143) 10. Neuro 2A (ATCC, Manassas, VA, CCL n = 131), mouse neuroblastoma cell line 11. CMV-plasmid bsst2 for transient transfection, which carries a region encoding sst2 ("b) bovine 12. Fugene 6 transfection reagent (Boehringer Mannheim, Cat. No. 1 814 443 13. Titration plate agitator (Lab Line Instruments Inc.) 14. 96-well plates Type C, with filter, fiberglass, Millipore (MAFC NOB 10) 15. Vacuum device for plates, Millipore 16. Block of 96 wells of 1 ml of polypropylene matrix (8100-96) 17. Tabletop centrifuge with housing of tubes d e 50 ml 18. Ice 19. Sterile, 50 ml conical tubes 20. Betaplate counter and Wallac radioactive lumenometer (Jet 1450 microbeta) 21. "Supermix" Wallac scintillation fluid optifase (1200-439) 22. Plate sealants Millipore (MATA09600) 23. Ventilated tissue culture plates of 162 cm2 (Costar ne 3151) 24. Amersham 1251, SRIF-14 (Tyr-11) (Amersham nd M161) . DMEM (Gibco BRL, nS cat. 11965-092) 26. FBS, Gemini Bio-products (cat.no. 100-107 n2, n = batch A1801N) 27. Penicillin-streptomycin (Gibco BRL, Cat. No. 15140) - 122) 28. SRIF-14"cold" (Sigma S-1763) 29. AEBSF (Sigma A-8456) 30. Dimethyl sulfoxide quality ACS (JT Baker, ns of cat 9224-01).

Preparation of DNA encoding a plasmid with bsst2 1.- 300 ml of LB / amp medium are inoculated with a single colony of cells carrying the plasmid PCl-bsst2. The cells are allowed to grow 24 hours and then the cells are agglomerated by centrifugation. A Qiagen plasmid purification protocol (Mega protocol) is used. At the end of the protocol, the DNA is washed with 70% ethanol twice more to ensure a clean DNA. The DNA preparation is then allowed to air dry, followed by resuspension in 1 ml of 10 mM Tris-HCl, pH = 7.4, of quality for molecular biology. The concentration of DNA is quantified using a spectrophotometer. Even though the yield can change, the concentration of plasmid PCl-bsst2 should be about 1 ug / ul. A concentration less than about 0.3 ug / ul could interfere with the transfection protocol that follows and, in such a case, it may be necessary to concentrate the plasmid.

Preparation of Neuro 2A cells and transient transfection of plasmid bsst2 1. Neuroblastoma 2A neuroblastoma is cultured in a ventilated 162 cm2 tissue flask in DMEM (Gibco BRL, n = cat. 11965-092), FBS at 10% and 100 units of sodium penicillin G, 100 ug / ml of streptomycin sulfate (penicillin / streptomycin (Gibco-Brl, n = 15140-122) = 5.5 ml per 550 ml of culture buffer), C02 at 5%, 37SC. The cells are washed once with 13 ml of Dulbecco's PBS at 372C. The cells are harvested by adding 3 ml of dissociation buffer (Gibco BRL, cat no, 13150-016) and incubated for 5 minutes in 5% C02 (no trypsin is used). The flasks are tapped on their side to dissociate the cells from the flask, 10 ml of culture medium is added, and pipetted into sterile, 50 ml polypropylene conical tubes. Centrifuge at 1000 rpm for 5 minutes, at room temperature, to agglomerate the cells. The medium is separated and the cells are resuspended in culture medium. It is ground to disperse the cells into single cell dispersion. It is inoculated in flasks of ventilated tissues, of 162 cm2 'new, distribution 1: 5 (the approximate seeding is 6.5 x 10 ° cells per flask of 162 cm2) 35 ml of culture medium per 162 cm2 ventilated tissue flask are added, the cells are allowed to adhere and cultivated during the night (16-18 hours) in C02 at 5% The cells are ready for transfection (confluence of 50%, approximately) For a 162 cm2 flask, 470 ul of DMEM (without FBS), Pen. Stretch to a 15 ml sterile polypropylene conical tube Directly 30 ul of Fugene 6 transfection reagent (Boehringer Mannheim, cat # 1 814 443) is added to the medium and allowed to equilibrate for 5 minutes (added directly to the medium, the pipette is not brought to the wall of the tube.) In a separate 15 ml sterile conical tube, 8 μg of PCl-bsst2 plasmid is added to the bottom of the tube (this should not be more than 20 μl) Pipette all 50 ul of DMEM / Fugene mixture directly onto DNA and equilibrate at room temperature. for 15 minutes. The reagent will form liposomes that carry DNA plasmid molecules. The total mixture is added directly to the medium of each of the 162 cm2 ventilated tissue flasks, containing approximately 50% confluent Neuro 2A cells and incubated 3 hours in 5% C02, 37SC (in this phase FBS) existing in the medium does not interfere more with transfection). The medium is separated and 35 ml of fresh culture medium are added to the cells. 9. After 72 hours after transfection, the cells are harvested as described above in steps 2-4. The medium is separated from the cells and the cells are frozen in the conical polypropylene tube by placing in the freezer at -80 ° C. Sufficient cells accumulate to prepare large batches of membranes (approximately 80 flasks).

Cell membrane preparation of Neuro 2A cells expressing the bSST2 receptor 1. The transfected cells are resuspended by adding 5.5 ml of ice-cold binding buffer (see above formula) per flask of Neuro 2A cells transfected with bSST. It is agitated with vortex formation obtaining a suspension of isolated cells. 2. Using a 55 ml Wheaton Dounce cell tissue homogenizer, all cells are homogenized (15-20 runs) and combined in a large batch. It is dispensed in 3 ml aliquots (enough for a 96-well plate) and frozen at -702C. A titration of the membranes will be carried out to determine the exact amount of membranes to be added per well.

Preparation of (125I) Somatostatin (SRIF) 125I SRIF of Amersham (n2iM161) is available in 50 uCi bottles. Each 50 uCi bottle is diluted with 10 ml of binding buffer and stored in aliquots of 330 ul at -202C. Each aliquot is diluted to 11 ml with binding buffer, directly, before the assay. This is enough for a 96-well plate.

Preparation of 96-well Millipore GF / C filter plate Pipette 100 ul of a 0.20% polyethyleneimine aqueous solution into each of the wells of a 96-well plate and incubate for 2 hours through least. The liquid is separated by vacuum filtration and the plate is allowed to dry overnight. The dried plates are kept at room temperature in a box indefinitely.

Membrane titration of Neuro membranes 2A / bSST2 In order to normalize the membrane bundles as much as possible, a titration of the membranes is carried out. Approximately 15,000 CPM of freshly diluted SRIF-14 (125-1) are pipetted into each well. Various membrane volumes (10, 20, 40 and 80 ul) are added to triplicate wells. The same membrane volumes and 1 uM of "cold" SRIF-14 are added to triplicate wells to determine nonspecific binding. Additionally, each of the membrane volumes is titrated with "cold" SRIF-14, from 0.03 nM-5nm to obtain an IC50 for the "cold" SRIF-14. The volume that provides approximately 6500-7000 CPM of specific binding and provides an IC50 value for the "cold" SRIF of 60pM-500pM, is diluted with binding buffer so that 50 ul = 6500-7000 CPM, is distributed in portions aliquots appropriately (1 tube per 96-well plate) and frozen at -702C. Preparation of test compounds and somatostatin-14 Non-radioactive somatostatin-14 (in the form of 14 amino acid residues) is purchased from Sigma (Sigma, n S-1763). The Freeze-dried SRIF-14, 1 mg, is resuspended in 500 ul of DMSO and then diluted with binding buffer to 122 ml obtaining a concentration of 5 uM of "cold" SRIF-14. Aliquots of 1 ml are kept frozen at -202C. On the day of the experiment, the aliquot is thawed and serially diluted with binding buffer at the following concentrations: Table of dilutions (for SRIF-14) Conc. Vol. Of onc ns conc (nM) desired (nM) dilution sol est. (Ul) vol buffer (ul) 5000 20 25 5 12 0 45 20 10 2 500 50 0 10 5 2 100 10 0 5 2,5 2 100 10 0 2,5 1,25 2 100 10 0 1 1,, 2255 0 0,, 662255 2 100 10 0 0,625 0,125 5 50 20 0 0,125 0,025 5 50 20 '0 10 nM, 5 nM, 2.5 nM, 1.25 nM, 0.625 nM, 0.125 nM and 0.025 nM are used to be added to the various wells in triplicate as described later. Several compounds are resuspended in 100% DMSO to obtain a concentration of 5 mM. They are then diluted with binding buffer as follows: Table of dilutions (for compounds) conc conc. - Vol of onc n2 (nM) desired (nM) dilution sol est. (Ul) vol buffer (ul) OO 80 62 20.35 12 0, 5 51,525 80 40 2 100 10 0 4400 2200 22 100 10 0 20 10 2 100 10 0 10 5 2 100 10 0 5 1 5 50 20 0 1 0.2 5 50 20 0 80 uM, 40 uM, 20 uM, 10 uM, 5 uM, 1 uM and 0.2 uM are used to add to various wells, in triplicate, as described later.

Test with 96 membrane binding wells at bSST7 100 ul of binding buffer are pipetted into each of the wells of a 96-well block. 50 ul of the reserve solution of the compound are then added in triplicate to the appropriate wells.

All compounds are tested in triplicate in the following format: Co-tax 1 Compound 2 Compound 3 Compound 4 A 1,2,3 4,5,6 7,8,9 10,11,12 B 1,2,3 4,5,6 7,8,9 10,11,12 C 1,2,3 4,5,6 7,8,9 10,11,12 D 1,2,3 4,5,6 7,8,9 10,11,12 E 1,2,3 4,5,6 7,8,9 10,11,12 F 1,2,3 4,5,6 7,8,9 10,11,12 G 1,2,3 4,5,6 7,8,9 10,11,12 Plate 2 will have compounds 5,6,7 and 8 and so on.

A "cold" somatostatin titration in the form of compound 1 is always carried out on plate 1, and the "cold" SRIF-14 concentrations are as follows: A 1,2,3 = 1,667 nM conc. final (added 10 nM) B 1,2,3 = 0,833 nM C 1,2,3 = 0,416 nM D 1,2,3 = 0,208 nM E 1,2,3 = 0,104 nM F 1,2,3 = 0.0208 nM G 1,2,3 = 0.0042 nM All other compounds are tested with the following compound concentrations: A n, n, n = 13,333 nm conc. final (added 80 uM ...) B n, n, n = 6,666 nM C n, n, n = 3,333 nm D n, n, n = 1,666 nM E n, n, n = 833.3 nM F n, n, n = 166.6 nM G n, n, n = 33 nM The controls are established in quadruplicate on each plate, in Row H. H 1,2,3,4 always provides total CPM pipetted to the wells . H5,6,7,8 provides the total membrane binding (without SRIF-14 added). H9, 10, 11, 12 provides the non-specific binding (50 ul of "cold" SRIF, 5 uM, are added to each well). Then, 50 ul of bSST membrane solution is added to each well, except for Hl, 2,3,4 in all the plates. 100 ul of 125 I radiolabeled somatostatin are added to all wells as a tracer solution, except for Hl, 2,3,4 in all plates. Then the 96-well blocks are hermetically sealed with plate sealing tape and placed on a titration plate agitator (Lab line instruments inc.), Fixed in position 3, in the incubator, at 372C. The binding reaction is allowed to continue for 1 hour. The plates are removed after the agitator, vortexed, and the closure tape is separated from the plate (and placed in the 125I waste). A volume of 250 ul from each well of the 96-well block is then passed to its complementary well on the 96-well filter plate. Each of the plates is appropriately labeled to identify the ns of the compound tested. Using a Millipore vacuum apparatus, the filter plate is then sucked through the bottom so that all the liquid flows through the filter. Then 250 ul of wash buffer is added to each well and vacuum is applied to the plate until completely emptying each well by vacuum filtration. The bottom of the plate is then dried over savanillas to separate the residual liquid. Then pipette 100 ul of radiolabeled SRIF-14 to the wells: Hl, 2,3,4 on all plates (these are total CPM wells). To these same wells are added 200 ul of "Supermix" scintillation fluid from Wallac. To all the other wells 250 ul of "Supermix" scintillation fluid of Wallac is added. The bottom and top of the plate are hermetically sealed with plate sealing tape and placed in the Wallac cassette (1450-105). Each plate is read using the Wallac program (filtermate SST2).

The primary CPM is downloaded into the Datafast program for evaluation, the binding% is calculated for each of the compound concentrations, thus generating the appropriate IC50 of each compound. Note:% union = (CPM-CPM (non-specific binding)) / total CPM of mem binding. x 100. Each compound and its IC50 are then indicated to a database for SAR analysis.

Example 10 Rat Pituitary Assay of Somatostatin Receptor Antagonists This assay is intended to quantitate the activity of somatostatin antagonists interacting directly on the somatostatin receptor. The assay facilitates the discovery of agents that increase the secretion of growth hormone by modulating the inhibitory effects of somatostatin. As previously mentioned, somatostatin (also abbreviated SRIF) inhibits the secretion of GH in the anterior pituitary by binding to a high affinity receptor bound to the membrane (and coupled to G protein) that negatively couples to adenylyl cyclase, thereby reducing intracellular levels of cAMP that would otherwise facilitate, for example, the secretion / release of GH from the cytoplasmic granules. Vasoactive intestinal peptide (VIP) is one of several endogenous peptides that stimulate GH secretion by binding to a high-affinity membrane-binding receptor associated with a signal transduction pathway dependent on the G protein. VIP activates the adenylate cyclase and produces increased intracellular levels of cAMP. These peptides can be involved in the coordinated regulation of GH secretion under physiological conditions and be mediated through cAMP. The cell line used for screening is a pituitary clonal cell that synthesizes and secretes GH in response to VIP and SRIF, and many other regulatory hormones, as expected for normal pituitary cells. The scan is designed to quantify the ability of assay agents to reverse the inhibition of SRIFs from the high intracellular levels of cAMP produced by VIP. It should be noted that in this operative procedure, the minimum sample size is approximately 1 mg.

Materials and methods (a) Dulbecco's phosphate buffered saline solution (GibcoBRL, ns 14040-141; PBS) containing 0.1% (w / v) BSA (Boehringer Mannheim, n2 100-351), pH 7.4; (b) F-10 nutrient medium (GibcoBRL, No. 11550-043) containing 2.5% fetal bovine serum (heat inactivated, Gemini Bio Products, n2 100-107), horse serum (heat inactivated; GibcoBRL; No. 26050-088), penicillin and streptomycin (100 units / ml, 100 ug / ml, GibcoBRL, n2 15140-122); (c) Cell dissociation solution (Sigma, n2 C5789); and (d) Assay in FlashPlates of adenyl cyclase activation (NEN, n2 SMP004A), with accompanying kit (kit) containing all reagents necessary to estimate cAMP levels in total cell preparations, after stimulation of adenylate cyclase; A. Stimulation buffer B. Detection buffer C. Pattern of cAMP D. FlashPlate E. Radioactive tracer [125I] -cAMP Peptides: Somatostatin 14, assayed by cell culture (Sigma, n2 S1763) A 1 mM solution in water is prepared deionized Aliquots are stored at -202C Vasoactive intestinal peptide (VIP, Sigma n V3628) A stock solution is prepared (stock) 200 uM in PBS / BSA (stored at -202C) A working solution 200 nM in PBS is prepared / BSA. Compound thinner (optimized for assay of receptor antagonists): Prepare 20 nM SRIF and 200 nM VIP in PBS / BSA.

CAMP pattern The cAMP standard is reconstituted with 2 ml of deionized water (5 nmol / ml, 250 pmol / 50 ul, stored at 42C for <3 weeks); solutions of 1000 are then prepared, 500, 250, 100, 50, 25 and 10 pmol / ml by appropriately diluting the stock solution with stimulation buffer.

Detection mixture 2 uCi (at the date of calibration) of the radioactive tracer cAMP- [125I] are added to 11 ml of detection buffer for each flashplate. If the radioactive tracer is used after the calibration date, the added tracer volume is adjusted taking into account the radioactive decay.

Agitator equipment of titration plates; Lab Line Instruments Microplate scintillation counter: Wallac microbeta, model 1450 Procedures (A) Cell preparation Adherent GH4C1 cells are grown to approximately 75% confluence in 175 ml flasks. The cells are washed with PBS and harvested using 2.5 ml of Cell Dissociation Solution (indicated above). The cells are resuspended in stimulation buffer and the cell number is determined by manual counting using a hemocytometer. The cell concentration is adjusted to 1-2 million cells per ml by diluting the cell suspension with Stimulation Buffer (indicated above).

(B) Preparation of test compounds The compounds are dissolved in an appropriate volume of 100% DMSO to prepare a stock concentration of 10 mM (the solution is maintained at 42C). Typically, the compounds are evaluated first at 10, 1 and 0.1 uM. To achieve these concentrations, 2X concentrations are prepared, that is, 20, 2 and 0.2 uM in Diluent of the compounds.

(C) Assay procedure 1. Standard curve of cAMP 50 ul of PBS / BSA are passed to 16 consecutive wells of the flashplate. 50 ul, in duplicate, of the cAMP solutions of 1000, 500, 250, 100, 50, 25 and 0 pmol / ml, and 5 nmol / ml are transferred to these same wells. 2. The following controls are included: 50 ul, in triplicate, of PBS / BSA buffer is passed to produce an accumulation of unstimulated cAMP; 50 ul of 200 nM VIP are transferred to produce a maximally stimulated cAMP accumulation control, and 50 ul of the compound diluent is passed to produce a partial accumulation control of cAMP inhibited with SRIF. 3. 50 ul of each of the test solutions are transferred, in triplicate, to the wells of the flashplate. 4. The assay is initiated by the addition of 50 ul of cell suspension to each well of the flashplate, except for the wells containing the cAMP standards. The flashplate is capped and incubated at 372C for 20 minutes by mixing on a rotating platform (200 rpm).

. The flashplate is removed from the incubator and 100 ul of detection buffer is added to all wells. 6. A plate cover is placed on the flashplate and incubated for 16-24 hours at room temperature. 7. After incubation, counting is performed to determine - "-" I in the microplate scintillation counter.

Example 11 Effect of a somatostatin antagonist on the release of GH in 12 kg pigs Studies conducted indicate that GH concentrations increase in small pigs after 10 minutes after the administration of somatostatin antagonists, and then return to the pre-treatment levels within 40 minutes after administration. The protocol that follows describes the effects of various doses of a somatostatin antagonist on the release of endogenous porcine GH (or pST, porcine somatotropin).

Experimental animals a. Breed / breed: Hybrid pigs b. Initial weight: approximately 12 kg c. Sex: Male, castrated d. Origin: Swinford / Frantz Farm, Hillsdale, IN e. Identification: Identification plate on the ear Regime a. Feeding and hydration method: ad libi tum b. Accommodation: With thermostatic regulated heating c. Diet: Starting swine diet, PS-9 d. Stables: 10 pigs in each stable of 3.35 m2 Test material Operative procedure The castrated pigs were placed in stables for their acclimatization, marked with identification plates on the ears and the weight was recorded on day 1. General health observations are recorded once a day. Two animals in each stable are excluded. The criteria for making the exclusion include adverse observations about the state of health or the maximum or minimum weight. The treatments are randomly assigned to the pigs with the restriction that each treatment must receive an equal number of animals in each barn. The experimental compound is diluted with sterile saline at appropriate concentrations to achieve the target concentrations in the indicated animals, while allowing a reasonable volume of distribution. The injected volume (T2-T4) varies to provide the appropriate dosage of compound under test (for animals T2-T4) or diluent (for animal TI), and is administered immediately after collection of a blood sample in the time -1, with a 20 gauge needle of 2.5 cm length attached to a 1 ml syringe. The volume of diluent for the injection of IT is approximately 1 ml. The injection site is a hind leg (pernil).

Blood samples are collected using evacuated, heparinized, tubes of 7 ml, at times -1, 10, 20, 30 and 40 min in relation to the injection time of the test compound or diluent. The blood plasma is separated by centrifugation and frozen (-202C). The concentrations of pST are determined by competitive radioimmunoassay.

Observations / Measures 1. Records of daily observations 2. Weights on day -2 (minus 2) 3. Registers of the dosage 4. Records of the collection of blood samples with detailed observations regarding health at the time of the collection and results of laboratory tests.

ACTIVITY PROGRAM DAY TIME MIN ACTIVITY (-2) Arrival of the animals, Identification in the ears, weight record. (0) -1 Sample collection (back leg) of blood, administration of compound or diluent, im. 10 Collection of blood samples. 20 Collection of blood samples. 30 Collection of blood samples. 0 40 Collection of blood samples.

Example 12 RIA procedure to determine plasma GH levels The present assay is used to determine levels of GH (eg, porcine GH or canine GH) in plasma samples. Materials Sodium phosphate, monobasic Sodium phosphate, dibasic Distilled water Sodium ethylenediaminetetraacetate (EDTA Na4) Bovine serum albumin (BSA) Sodium chloride (NaCl) Normal simian serum (NMS): ICN n2 55988 1 vial = 2 ml serum Polyethylene glycol (Molecular weight 8,000) (PEG): Sigma n2P2263 Antiserum for canine growth hormone (Simian) (1st Antibody), courtesy of Dr. AF Parlow, Harbor UCLA Med. Center, ne AFP-21452. Goat anti-simian IgG (22 Antibody); ICN n2 55418 pGH for iodination: Dr. A.F. Parlow or Biogenesis (the iodization has been carried out by Ron Forand in BTI). cGH for iodination: Dr. A.F. Parlow (iodization by Ron Forand, BTI). cGH, reference standard: Dr.A.F. Parlow n2 AFP-1983B Preparation of solutions 1) 0.5 M sodium phosphate, pH 7.4: 1 liter of 0.5 M solution of the monobasic is prepared: 68.99 g of monobasic in 1 liter of water is prepared 1 liter of 0.5 M solution of the dibasic: 70.98 g of dibasic in 1 liter of water; the monobasic solution is added to the dibasic solution until the pH is 7.4. It is kept at room temperature. 2) 0.5 M EDTA, pH 7.5 113 g of NaTA EDTA are dissolved in 500 ml of distilled water. Stir to dissolve The pH is adjusted with acetic acid. It is refrigerated. 3) RIA Buffer: 0.5% BSA, 0.1M sodium phosphate, pH 7.4; 0.1M NaCl; EDTA, Na4 25 mM; pH 7.5. In a 1-liter flask 5 g of BSA 200 ml of 0.5 M sodium phosphate, pH 7.4 5.84 g of NaCl 50 ml of 0.5 M EDTA It is added to 1 liter with distilled water. It is kept at room temperature. 4) NMS (0.5%) To a vial of NMS is added 2 ml of RIA buffer. The NMS solution is diluted to a final concentration of 0.5% by adding an additional amount of 398 ml of RIA buffer. It is kept in aliquots of 40 ml at -702C. ) 7% PEG (Molecular weight 8,000) 70 g of PEG are dissolved in 1000 ml of 0.05M sodium phosphate, pH 7.4 (100 ml of sodium phosphate) 0.5M + 900 ml of water). 6) 1st Antibody (1: 100) Stock n2 l: 0.8 ml of distilled water is added to the original vial. It is frozen in aliquots of 50 ul to -702C. (1: 500) Stock n2 2: Dilute a tube of Stock n2 1, 1: 5 (200 ul are added) with RIA buffer. The final dilution of Stock n2 2 1st Antibody is determined in each new batch of 1st Antibody based on the percentage of binding (usually an additional dilution 1: 100 to 1: 200 of Stock n2 2) 7) 22 Antibody The content of 1 vial is brought up to 2 ml with RIA buffer. Dilute 1:10 (total volume 20 ml) with RIA buffer. It is maintained at -702C after reconstitution.

RIA procedure 1 Day 1. Tubes are marked (patterns in triplicate, samples in duplicate) 1-4 for total counts 5-9 for non-specific binding 10-12 for Whites 13-15 Pattern 1 (0.08) ng / tube) 16-18 Pattern 2 (0.16 ng / tube) 19.21 Pattern 3 (0.32 ng / tube) 22-24 Pattern 4 (0.64 ng / tube) 25-27 Pattern 5 (1.25 ng / tube) 28-30 Standard 6 (2.5 ng / tube) 31 and above, samples in duplicate and control plasma (plasma collected from Lampire) Note: The concentrations calculated for the samples are initially indicated as ng / tube. The values are multiplied by 10 for ng / ml concentrations and are indicated in this format (based on a sample volume per 100 ul tube). 2. Preparation of standards A. 1 vial (5 ug) of standard cGH (Parlow) is dissolved in 1 ml of water B. It is kept in aliquots of 200 ul at -702C C. An aliquot of 200 ul is taken and divided into aliquots of 20 ul (-702C). A 20 ml aliquot is used for the standard preparation.

Pattern 6: 10 ul of cGH standard (5 ug / ml) in 990 ul of RIA Standard 5: 500 ul of standard 6+ 500 ul of RIA Standard 4: 500 ul of standard 5 + 500 ul of RIA Standard 3 buffer : 500 ul of standard 4 + 500 ul of RIA Standard Buffer 2: 500 ul of standard 3 + 500 ul of RIA Standard Buffer 1: 500 ul of standard 2 + 500 ul of RIA buffer 3. The NMS, the 1st antibody and the samples are thawed RIA buffer is added in the following amounts: Tubes 5-12: 300 ul Tubes 13-30: 250 ul Tubes 31-? : 200 ul . 50 ul of standard solution is added to the corresponding tubes. 100 ul of sample is added to the corresponding tubes 6. 100 ul of NMS is added to the tubes 5-9 7. The tubes are shaken with vortex formation 8. 100 ul of 1st canine antibody (final dilution of stock ns 2) is added to tubes 10 and above (dilution is carried out with NMS) 9. The tubes are stirred at room temperature for 2 hours. 10. Tracer preparation: A 1:50 dilution of the starting tracer is prepared. The 1:50 dilution is titrated for each new batch of tracer to determine how many ul of 1:50 solution provide ~ 10,000 cpm. This number of ul of 1:50 is then used for each tube. The working solution is prepared by taking the volume of 1:50 selected, per tube, to 100 ul in total (per tube) with RIA buffer. that is, 1:50 - 64 ul of starting plotter + 3136 ul of RIA buffer, working solution is mixed - 3120 ul of solution 1:50 + 48880 of RIA buffer, mixed 11. 100 ul of working solution is added to all tubes, swine tracer is used for swine samples, canine tracer is used for dog samples 12. The tubes are shaken with vortex formation 13. The tubes are shaken vigorously at room temperature for 20 hours Day 2 14. 100 ul of 22 Antibody is added to tubes 5 and above . 1 ml of PEG solution is added to tubes 5 and above 16. The tubes are shaken with vortex formation 17. The tubes are shaken vigorously at 42C for 2 hours 18. Tubes 1-4 are removed and the remaining tubes are centrifuged at 3000 rpm, 42C, for 30 minutes 19. The supernatants are discarded. The tubes are inverted in a tray lined with a paper towel during -10 minutes to drain . The tubes are put back 1-4 21. It is counted for 3 minutes, the curve is made by log-logit. The values are in ng / tube and then multiplied by ten to obtain the concentration in ng / ml.

Claims (38)

1. Claims 1. - A compound according to the formula A-G-Z-W or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein A is C6-C10 aryl, aryl (C6-C10) -SO2, aryl (C6-C10) -CH2-, arylCG-C ^ Jcarbonyl, heteroaryl of C ^ -Cg, hetero-aryl (C1-C8) -S02-, heteroaryl (C1-C8) -CH2-; or heteroaryl (C-Cg) carbonyl; G is: • .B_X_ (a) in which formula B is aryl of Cg-C ^ g or heteroaryl of Cj-Cg, and X is CH2, S02 or carbonyl; in which formula X is CH2, S02 or carbonyl; and R1 and R1 are each independently selected from H, CN, alkyl (Cj-Cg) -, and phenyl (CH2) -, in which formulas said alkyl and phenyl groups are optionally substituted; or Z is wherein formula R2 is H, Cj-Cg alkyl, or is selected from the groups A above; and E is selected from the groups A above; W is (a): in which formula n is 2 to 5, R3 is selected from H, alkylC-Cg) -, and phenyl (CH2) -, in which formulas said alkyl and phenyl groups are optionally substituted; R6 is selected from H, alkylC-Cg) -, and phenyl (CH2) -, in which formulas said alkyl and phenyl groups are optionally substituted; R4 is selected from H, alkylC ^ Cg) - and phenyl (CH2) -, in which formulas said alkyl and phenyl groups are optionally substituted; or is in which formulas the groups R10, R11 and R11 'are each independently selected from H, alkyl (C ^ -Cg) -, and phenyl (CH) -, in which formulas said alkyl and phenyl groups are optionally substituted; R5 is H, alkylfCj-Cg) - and phenyl (CH2) -, in which formulas said alkyl and phenyl groups are optionally substituted, or in whose formula R 1? and R1? 'are each independently selected from H, alkyl (C ^ -C) -, and phenyl (CH2) -, in which formulas said alkyl and phenyl groups are optionally substituted; or W is (b) in which formula Q is selected from the group consisting of aryl of Cg-Cj, heteroaryl of C ^ C), cycloalkyl of C3-C10 and heterocycloalkyl of and R and R are each independently selected from H, alkylC ^ - Cg) -, and phenyl (CH2) -, in which formulas said alkyl and phenyl groups are optionally substituted.
2. 2. The compound according to claim 1, wherein, independently, one or more of the groups A, B, E and Q consist of, or comprise, an aryl group of Cg-C10 'selected from phenyl and naphthyl.
3. 3. The compound according to claim 1, wherein, independently, one or more of the groups A, B, E and Q consist of, or comprise, a heteroaryl group of C ^ -Cg, selected from furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3, 5-oxadiazolyl, 1,2,4-oxadiazoyl, 1,2,3-oxadiazolyl, 1,3,5- thiadiazolyl, 1,2,3-thiadiazoyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,4-triazinyl, 1,2,3-triazinyl, 1,3,5- triazinyl, pyrazolo [3,4-b] pyridinyl, cinolinyl, pteridinyl, purinyl, 6,7-dihydro-5H [l] pyrindinyl, benzo [b] thiophenol, 5,6,7,8-tetrahydroquinolin-3- ilo, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazole, tianaphtenyl, isothianaphtenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazo-linyl, and benzoxazinyl.
4. 4. The compound according to claim 1, wherein the group Q is selected from: (a) an aryl group of Cg-C ^, selected from phenyl and naphthyl; (b) a heteroaryl group of Cj-C, selected from furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl , 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, , 2,3-triazinyl, 1,3,5-triazinyl, pyrazolo [3,4-b] pyridinyl, cinolinyl, pteridinyl, purinyl, 6,7-dihydro-5H- [l] pyrindinyl, benzo [b] thiophenyl, 5,6,7,8-tetrahydroquinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, tianaphtenyl, isothianaphtenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and benzoxazinyl; (C) a cycloalkyl group of C-C1Q selected from cyclopropyl, cyclobutyl, cyclopentyl, ciciohexilo, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,3-cyclobutadienyl, 1,3-cyclopentadienyl, 1,3-cyclohexadienyl , 1,4-cyclohexanedienyl, 1,3-cycloheptadienyl, 1,4-cycloheptadienyl, 1,3,5-cycloheptatrienyl, bicyclo [3.2. l] octane, bicycles [2.2. l] heptane and its unsaturated form of norborn-2-ene; and (d) a heterocycloalkyl group of C3-C10, selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxy, chromenyl, isoxazolidinyl, l, 3-oxazolidin-3-yl, isothiazolidinyl, l, , l, 2-pyrazolidin-2-yl, 1, 3-pyrazolidin-l-yl, piperidinyl, thiomorpholinyl, 1, 2-tetrahydrothiazin-2-yl, 1, 3-tetrahydro-3-yl tiazin--thiazolidin-3 3-yl, tetrahydrothiadiazinyl, morpholinyl, 3-tetrahydrodiazin-yl l-yl-1,2-tetrahydrodiazin-2, 1, tetrahi-droazepinilo, piperazinyl and chromanyl. 5. A compound according to claim 1. selected from the group consisting of: 6-amino-2- [2- [(biphenyl-4-ylmethyl) amino] -3- (lH-indol-3) methyl ester -yl) propionylamino] hexanoic; 2-methyl ester. { 3- (3-fluorophenyl) -2- [2- (toluene-4-sulfonylamino) acetylamino] propionylamino} -5-guanidinopentanoic acid; 6-amino-2- [2- [(biphenyl-4-carbonyl) amino] -3- (1H-indol-3-yl) propionylamino] hexanoic acid methyl ester; 2-methyl ester. { 2- [(biphenyl-4-carbonyl) ami-no] -3,3-diphenylpropionylamino} -5-guanidinopentanoic acid; tert-butyl ester of 6-amino-2- [2- [(biphenyl-4-carboni1) amino] -3- (lH-indol-3-yl) propionylamino] he-anoic acid; tert-butyl ester of 6-amino-2- [2- (2-benzenesulfonylamino-2-methylpropionylamino) -3- (lH-indol-3-yl) propio-nylamino] hexanoic acid ester; and 6. - A compound according to claim 5, selected from the group consisting of: 6-amino-2- [2- [(biphenyl-4- * carbonyl) amino] -3- (lH) tert-butyl ester -indol-3-yl) propionylamino] hexanoic; and 6-amino-2- [2- (2-benzenesulfonylamino-2-methylpropionylamino) -3- (1H-indol-3-yl) propio-nylamino] hexanoic acid tert-butyl ester. 7. - A compound according to claim 1, wherein its group Z has the stereospecificity 8. - A compound according to claim 7, wherein the group Z defines an L-amino acid selected from the group consisting of L-tryptophanyl, L-histidinyl, L-3-methylhisti-dinyl, L-phenylalaninyl-, L-diphenylalaninyl -, L-2-fluorofe-nilalaninyl-, L-3-fluorophenylalaninyl-, L-4-fluorophenylalaninyl-, and L-tyrosinyl-. 9. A compound according to claim 8, wherein said Z group thereof is L-tryptophanyl-. 10. A compound according to claim 1, wherein the group Z thereof has the stereospecificity 11. - A compound according to claim 10, wherein the group Z defines a D-amino acid which is D-tryptophenyl. 12. A compound according to claim 11, wherein said group Z is D-tryptophanyl-. 13. A compound according to claim 1, wherein its group W has an absolute stereospecific configuration in the indicated position corresponding to that of carbon a of L-amino acids. 14. - A compound according to claim 13, wherein the group W is a L-lysine group, or one of its alkyl esters of C ^ -Cg, an L-ornithine group, or one of its C-alkyl esters Cg, an L-arginine group, or one of its alkyl esters of C | -Cg, an L-histidine group, or one of its C ^ -Cg alkyl esters, or an L-3-methylhistidine group, or one of its C ^ -Cg alkyl esters. 15. A compound according to claim 14, wherein said group W is an alkyl ester of C ^ -C of L-lysine. 16. A compound according to claim 1, wherein R1 is alkyl (C? -Cg) -, or phenyl (CH2) -, and said alkyl or phenyl group is optionally substituted with one or more halo or trifluoroalkyl groups of C ^ -C. 17. A compound according to claim 1, wherein Rx is C-Cg alkyl- or phenyl (CH2) -, and said alkyl or phenyl group is optionally substituted with one or more halo or trifluoroalkyl groups of Cj-C. 18. A compound according to claim 1, wherein R2 is (C1-C) alkyl-, optionally substituted with one or more halo or trifluoroalkyl groups of C] -Cg. 19. A compound according to claim 1, wherein R2 is alkyl (C-Cg) -, optionally substituted with one or more halo or trifluoroalkyl groups of Cj-Cg. 20. A compound according to claim 1, wherein one or more of R3, R4, R5 and R6 is alkyl C-Cg) - or phenyl (CH2) -, and said alkyl or phenyl group is optionally substituted with one or more halo or trifluoroalkyl groups of C-Cg. 21. A compound according to claim 1, wherein one or more of R7, R8 and R9 is alkyl (Cj-Cg) - or phenyl (CH2) -, and said alkyl or phenyl group is optionally substituted with one or more halo or trifluoroalkyl groups of C ^ -Cg. 22. A compound according to claim 1, wherein one or more of R10, R11 and R11 'is alkyl (Cj-Cg) - or phenyl (CH2) -, and said alkyl or phenyl group is optionally substituted with one or more halo or trifluoroalkyl groups of Cj-Cg. 23. - A compound according to claim 1, wherein one or more of R12 and R12 'is alkyl (C-Cg) - or phenyl (CH2) -, and said alkyl or phenyl group is optionally substituted 4fc with one or more halo groups or trifluoroalkyl of C ^ Cg.
5. 5. A compound according to claim 1, wherein a trifluoroalkyl substituent of C-Cg, present in one of its groups B, E, R1, R1 ', R2, R3, R4, R5, R6, R7, R8 , R9, R10, R11, R11 ', R12 or R12', is trifluoromethyl. 25.- A pharmaceutical composition to increase the Secretion of growth hormone in a mammal, comprising an effective amount of a compound according to claim 1, and a pharmaceutical excipient. ^^ 26.- A pharmaceutical composition to increase the ^^ gastrin or glucagon secretion in a mammal, which 15 comprises an effective amount of a compound according to claim 1, and a pharmaceutical excipient. 27. A pharmaceutical composition for inhibiting the binding of somatostatin to the sst2 receptor thereof, comprising an effective amount of a compound according to claim 20, and a pharmaceutical excipient. 28. A method for increasing the secretion of growth hormone in a mammal, comprising administering an effective amount of a pharmaceutical composition according to claim 25. 29.- A method for increasing the secretion of gastrin or glucagon in a mammal, which comprises administering an effective amount of a pharmaceutical composition according to claim 25. 30.- A method for decreasing the regulation induced by Somatostatin of growth hormone secretion in a mammal, comprising administering an effective amount of a pharmaceutical composition according to claim 25. 31.- A pharmaceutical composition useful for causing a prolonged release of growth hormone in a The mammal in need thereof, which comprises a compound according to claim 1, and a pharmaceutical excipient. 32. - A method for facilitating the prolonged secretion of growth hormone in a mammal in need thereof, wherein said mammal possesses: (a) a defect in the expression of the nucleotide sequence encoding growth hormone, the processing of the resulting mRNA, or the translation or intracellular processing and packing of GH or its precursor polypeptide; or (b) an allele of the growth hormone gene encoding a growth hormone polypeptide that is insufficiently active; which comprises administering an effective amount of a pharmaceutical composition according to claim 25. 33. A method for treating a human of one or more symptoms of insufficient secretion of growth hormone, wherein said symptom is selected from frailty, hypoglycemia. , wrinkled skin, slow growth of the skeleton, reduced immune function and reduced organic function, which comprises administering an effective amount of a pharmaceutical composition according to claim 25. 34.- A method for treating a non-human mammal to improve its growth and behavior, which comprises administering an effective amount of a pharmaceutical composition according to claim 25. 35.- A pharmaceutical composition according to claim 25, further comprising growth hormone releasing peptide (GHRP) or growth hormone releasing hormone ( GHRH). 36.- A method for increasing the secretion of growth hormone in a mammal, comprising administering an effective amount of a pharmaceutical composition according to claim 35. 37.- A method for increasing the secretion of growth hormone in a mammal , which comprises administering an effective amount of a pharmaceutical composition according to claim 25. and an additional composition comprising growth hormone releasing peptide (GHRP) or growth hormone releasing hormone (GHRH). 38.- A compound according to claim 13, wherein the group W comprises an L-diaminopimelic group, L-Canavani-na, L-2,4-diaminobutyric, L-5-hydroxylysine, or L-epsilon-N- methyl-lysine, or an alkyl ester of Cj-Cg of any of them. Summary Compounds according to formula (I) A-G-Z-W and pharmaceutically acceptable salts, solvates or hydrates thereof, wherein A is aryl of Cg-C10, aryl (Cg-C10) -SO2, aryl (Cg-C1g) -CH2-, aryl (Cg-C10) carbonyl, heteroaryl of Cj-Cg, heteroaryl (Cj ^ -Cg) -S02 -, heteroaryl (Cj-CgJ-C ^ -, or heteroaryl (C ^ Cg) carbonyl; G is selected from the group consisting of: _ .B_x_ _ (a) in which formula B is aryl of Cg-C ^ Q or heteroaryl of C ^ -Cg, and X is CH, S02 or carbonyl; in which formula X is CH2, S02 or carbonyl; and R1 and R1 'are each independently selected from H, CN, alkylC- Cg) -, and phenyl (CH2) -, in which formulas said alkyl and phenyl groups are optionally substituted; Y wherein Z and W are as defined in the present Descriptive Memory; and pharmaceutical compositions and methods useful for increasing the secretion of growth hormone (GH) from the anterior pituitary of mammals, including on the basis of a prolonged release. Representative compounds of the invention include 10 25 30 Esther González García Certification a / c Elzsburu S, A. Doña Estriar González García Miguel Ángel, 21. 28010 Madrid Sworn Interpreter of English Tal .: 917009400 Fax: 913193810 certifies that the foregoing is a faithful translation and is a Jury interpreter of the English language ptoia al ..ßJfó l ..., ... f of a document - rreeddaaccttaaddoo e enn ..? < ?) < , j '^? j rr In Madrid a -1. ^ i. .Z áT