HK1185567B - Novel triazole derivatives with improved receptor activity and bioavailability properties as ghrelin antagonists of growth hormone secretagogue receptors - Google Patents

Description

Novel triazole derivatives having improved receptor activity and bioavailability properties as ghrelin antagonists of growth hormone secretagogue receptors

The technical field is as follows:

the present invention relates to novel triazole derivatives having improved receptor activity and bioavailability properties which act as ghrelin analogue ligands for growth hormone secretagogue receptors. These compounds are useful for modulating growth hormone plasma levels in mammals and for treating and/or modulating a variety of physiological and pathophysiological conditions, such as growth retardation, obesity, food intake, energy balance and other metabolic disorders, tumor cell proliferation, wound/burn/bone healing, inflammation, and addictive processes such as food rewards, alcohol-related disorders, and drug abuse.

The prior art is as follows:

ghrelin, a 28 amino acid peptide with a unique octanoyl modification at Ser-3 (Kojima M et al, Nature1999, 402:656-660), was identified as an endogenous ligand for growth hormone secretagogue receptor type 1a (GHS-R1a), a G-protein coupled receptor (HowardAD et al, Science1996, 273: 974-977). Ghrelin is produced primarily in the upper intestine/stomach, but small amounts are also detected in the intestine, pancreas, kidney, immune system, placenta, testis, pituitary, lung, and in the hypothalamus (van der Lely AJ et al, endogrine Rev.2004, 25: 426-.

In humans, ghrelin stimulates Growth Hormone (GH) through a pathway unrelated to the GHRH receptor and coordinated with GHRH on GH secretion (Arvat E et al, J.Clin.Endocrinol.Metab.2001, 86: 1169-. In addition, it also stimulates ACTH, prolactin, cortisol, aldosterone and epinephrine secretion (Arvat E et al, J.Clin.Endocrinol.Metab.2001, 86: 1169-.

Ghrelin is thought to be involved in metabolic regulation and energy expenditure, and therefore the expression and secretion of ghrelin from the stomach into the systemic circulation is expected to be influenced by metabolic hormones. In obese humans, plasma ghrelin levels decreased, indicating that elevated insulin or leptin levels in obese subjects decreased ghrelin secretion (Tschop M et al, Diabetes2001, 50: 707-709).

It is believed that the release of growth hormone in humans and animals treats physiological or pathophysiological conditions characterized by a lack of growth hormone secretion, and treats those conditions ameliorated by the synthetic action of growth hormone.

Initially, the clinical use of GH was limited to the treatment of GH-deficient children, but commercialization of recombinant human growth hormone (rhGH) has led to much research into other potential clinical uses of GH (Strobl JS et al, Pharmacol. Rev.1994, 46: 1-34; Torosian MH, J.Peditar. Endocrinol.1993, 6: 93-97). rhGH has shown promise in treating patients with burns, wounds, fractures, and more recently has shown promise in reversing glucocorticoid catabolism, chemotherapy, and AIDS, as well as improving body composition (Rudman D et al, N.Engl. J.Med.1990, 323: 1-6; Papadaius MA et al, Ann.Intern.Med.1996, 124: 708-.

GH, synthesized and stored in the pituitary, is released under the control of two known hypothalamic hormones: growth Hormone Releasing Hormone (GHRH) and the inhibitory hormone Somatostatin (SRIF). In most cases, GH deficiency is associated with hypothalamic defects rather than pituitary GH deficiency. Thus, as an alternative to rhGH treatment, GH deficient patients may also be treated with any compound that releases endogenous GH from the pituitary. This can be done not only with GHRH, which stimulates GH release, but also with synthetic Growth Hormone Secretagogues (GHs).

Many synthetic peptidyl and non-peptidyl GHSs, such as GHRPs1, 2 and 6, Hixarelin (Hexarelin), MK-0677, EP-01572, have been shown to specifically bind to the orphan receptor "GHS receptor" -several of which were discovered long before ghrelin and ghrelin/GHS receptor (see "Camani F et al, Front neuroendocrinol.1998, 19: 47-72;" Casaneueff et al, Trends Endocrinol.Metab 1999, 10: 30-38; "van der Lely AJ et al, Endocrine Rev.2004, 25: 426-457"). GHS also shows a potential GH release effect and has the same biological activity as mentioned above for ghrelin.

GHS is also disclosed in the following patents or patent applications (non-exhaustive list): US6,071,926, US6,329,342, US6,194,578, US2001/0041673, US6,251,902, US2001/0020012, US2002/0013320, US2002/0002137, WO95/14666, WO96/15148, WO 01/96300.

Although ghrelin/GHS results in GH secretion mediated by activation of ghrelin/GHS receptor type 1a (GHS-R1a), there is evidence to date that at least some other effects of ghrelin and GHS are also mediated by different receptors of the GHS receptor family or even different binding sites on a given GHS receptor.

GHS receptors are concentrated in the hypothalamic-pituitary region, but have also been shown to be distributed in other central and peripheral tissues (Hattori N et al, J.Clin. Endocrinol. Metab.2001, 86: 4284-4291; Gnanapavan S et al, J.Clin. Endocrinol. Metab.2002, 87: 2988-2991; Muccioli G et al, J.Endocrinol.2000, 157: 99-106; Muccioli G et al, Ann.Endocrinol.2000, 61: 27-31; Muccioli G et al, Eur.J.Pharmacol.2002, 440: 235-254; Papotti M et al, J.Clin. Endocrinol.2000, 85: 3803-3807; Soni P et al, J.Endocrinol.Clin.86, 1997-26; Brazil et al, Branch.24: 26-368; BrancoXin.31; Brancoy. J.P.11, J.Pharmacol.2002, 42, M.42-24; Branch.24, 24-368).

Two GHS1 type receptors have been identified, GHS-R1a and GHS-R1b, which are presumably expressed from a single gene and alternatively spliced in humans (van der Lely AJ et al, Endocrine Rev.2004, 25: 426-. In mammalian species, a high degree of sequence identity has been reported for GHS-R1a (Petersen S, MinervaEndocrinol.2002; 27: 243-256: between 91.8% and 95.6%).

Motilin receptors have been found to be members of the GHS receptor family with 52% identity (Smith RG et al, Endocrine2001, 14: 9-14; McKee KK et al, Genomics1997, 46: 426-434). The motilin receptor 1a of the GI tract and GHS-R1a showed high similarity (Smith RG et al, Endocrine2001, 14: 9-14; Feighner SD et al, Science1999, 284: 2184-.

Other GHS receptor family members are shown to be neurotensin receptor, TRH receptor, GPR38(FM1), GPR39(FM2) and FM3(Smith RG et al, Endocr. Rev.1997, 18: 621-42; Smith RG et al, Horm. Res.1999, 51(suppl.3): 1-8; TanCP et al, Genomics1998, 52: 223-229; Howard AD et al, Science1996, 273: 974-977). Other GHS receptor subtypes have been shown to be present in a wide range of central and peripheral tissues (van der Lely AJ et al, endogrine Rev.2004, 25: 426-. For example, cardiac GHS-R (Bodart V et al, Circuit. Res.1999, 85: 796-849) has been reported to have a predicted sequence similar to CD36, a multifunctional receptor known as glycoprotein IV (Bodart V et al, Circuit. Res.2002, 90: 844-849). Cassoni et al (J.Clin. Endocrinol. Metab.2001, 86:1738-1745) report that the GHS-R subtype is present in tumor breast cells, activated by ligands that bind to specific binding sites different from the classical GHS-R1 type. Furthermore, the data collected by these authors support the following assumptions: GHS-R exists even in different binding site subtypes in peripheral tissues, which may be attributed to its endocrine or non-endocrine, and may also be of its normal or neoplastic nature.

The prevalence of GHS binding sites suggests that, irrespective of its strong growth hormone secretagogue properties, ghrelin and synthetic GHS are involved in several important physiological and pathophysiological conditions.

Thus, potential clinical applications include the following

a) Short, medium and long term regulation of energy balance and/or food intake (Tschoep M et al, Nature2000, 407: 908-913; asakawa A et al, Gut2003, 52: 947-; US 2001/0020012; kojima M et al, Curr, Opin, Pharmacol, 2002, 2: 665-; horvath TL et al, Curr.pharm.Des.2003, 9: 1383-; wren AM et al, J.Clin.Endocrinol.Metab.2001, 86: 5992-.

GHS-R1a has been shown to be expressed on subthalamic nuclear neurons. These neurons send efferent nerves to the critical hypothalamic circuits for controlling food intake, such as the generation of the arcuate nucleus of transmitter NPY. Food intake stimulated by ghrelin and/or GHS is thought to be mediated by an increase in NPY in the arcuate nucleus (Willesen MG et al, neuroendocrin.1999, 70: 306-. A single administration (lateral ventricle injection or intraperitoneal injection) of the anti-auxin release peptide IgG in lean rats inhibited acute feeding (Bagnasco M et al, Regul. Pept.2003, 111: 161-167). Long-term administration of anti-auxin-releasing peptide IgG by bi-daily lateral ventricular injection reduced body weight over a 5-day period (Murakami N et al, J.Endocrinol.2002, 174: 283-.

A recent study using the peptides GHS-R1a antagonist, [ D-Lys-3] -GHRP-6, showed a reduction in food intake and weight gain in diet-induced obese mice (Asakawa A et al, Gut, 2003, 52: 947-one 952). Indeed, peptidyl compounds, originally characterized as growth hormone secretagogues, are capable of selectively stimulating food intake in rats without causing growth hormone secretion, suggesting the presence of a GHS-R subtype other than GHS-R1a in the hypothalamus (Torsello A et al, neuroendicin.2000, 72: 327-332; Torsello A et al, Eur.J.Pharmacol.1998, 360: 123-129).

b) Treatment of adipogenesis, adiposity and/or obesity and weight loss (Tschop M et al, Nature2000, 407: 908-913; asakawa A et al, Gut2003, 52: 947-.

Long-term administration of ghrelin and/or GHS in free-feeding mice and rats resulted in increased body weight and decreased fat utilization (Tschop M et al, Nature2000, 407: 908-913). Furthermore, it has been reported that ghrelin and dioctanoyl ghrelin promote lipogenesis in vivo (Thompson NM et al, Endocrinol.2004, 145:234-242) and inhibit isoproterenol-induced lipolysis in rat adipocytes via non-GHS-R1 a type (Muccioli G et al, Eur.J.rmacol.2004, 498: 27-35). On the other hand, there is also a report describing that GHS-R1a expression in rat adipocytes increases with age and during adipogenesis (Choi K et al, Endocrinol.2003, 144, 754-759).

c) Treatment of tumor cell proliferation

As with other members of the hypothalamic-pituitary axis that regulate Growth hormone secretion, evidence suggests that ghrelin and GHS receptors may play important autocrine/paracrine roles in certain cancers (Jeffery PL et al, Cytokine Growth Factor Rev.2003, 14: 113-122). Specific binding sites for ghrelin, peptidyl-and non-peptidyl GHS are present in tumor tissues such as prostate cancer cell line PC3(Jeffery PL et al, J.Endocrinolology 2002, 172: R7-R11), thyroid tissue (Cassoni P et al, J.Endocrinol.2000, 165:139-146), lung cancer cell CALU-1 (Gh. sub.C et al, Endocrinol.2002, 143:484-491) and breast cancer (Cassoni P et al, J.Clin. Endocrinol.Metab.2001, 86: 1738-1745).

In the case of milk, specific binding sites for GHS are found in tumor tissue, whereas normal breast parenchymal tissue does not reveal such receptors. Synthetic GHS has been reported to inhibit the proliferation of lung cancer cells CALU-1 (gheyC et al, endocrinol.2002, 143:484-491) and breast cancer cell lines (Cassoni P et al, J.Clin.endocrinol.Metab.2001, 86: 1738-1745).

Both ghrelin and non-acetylated ghrelin bind to tumor tissue. Since non-acetylated ghrelin is unable to bind to GHS-R1a, the site of binding of GHS to tumor tissue is likely to be different from GHS-R1 a. From these data, one can expect that the binding site in tumor tissue can recognize the ligand of GHS-R1a and other yet uncharacterized chemical structures. The synthetic ligand of GHS-R1a may therefore potentially inhibit the proliferation of tumor cells expressing GHS receptor subtypes.

d) Therapeutic inflammation/anti-inflammatory action

In chronic arthritis with clinical manifestations of hypermetabolism and cachexia, GHRP-2, an agonist of ghrelin, was demonstrated to have anti-inflammatory effects (Granado M et al, am.j. physiol. endocrinol. metab.2005, 288: E486-492). These data show that: the anti-inflammatory effects of GHRP-2 are mediated by activation of ghrelin receptors expressed by immunocompetent cells.

e) Treatment of cachexia

In animal models of cachexia (Roubenoff R et al, Arthritis Rheum.1997, 40(3): 534-. This finding also fits the data of patients with rheumatoid arthritis (Roubenoff R et al, J Clin invest.1994, 93(6): 2379-.

f) Treatment of gastrectomy (ghrelin replacement therapy)

The gastric hormone ghrelin was administered to mice that had undergone gastrectomy or sham surgery (Dornonville de la Cour C et al, Gut2005, 54(7): 907) 913). The results shown show that ghrelin replacement therapy at least partially reversed the decrease in body weight and body fat resulting from gastrectomy.

g) Treating intestinal obstruction after gastric operation

Ghrelin was evaluated for its effect on gastrointestinal motor function in rats. Ghrelin is shown to reverse delayed gastric emptying and is a strong prokinetic agent suitable for the treatment/reversal of post-gastric ileus (Trudel L et al, Am J Physiol Gastrointest Liver Physiol2002, 282(6): G948-G952).

h) Treating diabetes (type I and type II diabetes)

The effect of ghrelin removal in leptin-deficient mice was investigated (Sun et al, Cell Metabolism2006, 3: 379-386). The results show that: removal of ghrelin increases insulin secretion in response to glucose challenge, suggesting that inhibiting ghrelin or resisting its activity may be a possible approach for the treatment of diabetes, including its subtypes I and II (see also WO 03/051389).

i) Treatment of addictive processes such as food rewarding, alcohol disorders and drug abuse

Dopamine projection at the midbrain limbus, originating from neuronal cell populations in the Ventral Tegmental Area (VTA) and terminating in the ventral striatum and prefrontal cortex, is associated with the anticipation, desire or approach phase of motivational behavior (aproach phases), and is important for anticipating food rewards and food seeking behavior (Bassareo and Chiara1999, Neuroscience89, 637 + 641; Richardson and Gratton1998, J Neurosci18, 9130 + 9138). Activation of these dopamine projections is also caused by foods that are rewarded for consumption and by other rewards including natural (e.g., gender) and artificial (e.g., alcohol and drug abuse) (Berridge and Robinson1998, Brain Res Brain ResRev28, 637-641). Cumulative evidence demonstrates that the mesolimbic system is a target for ghrelin. In addition to the hypothalamus, ghrelin receptors have also been identified in the Ventral Tegmental Area (VTA) and dorsolateral tegmental area (LDTg). Recent findings indicate that the effect of ghrelin on food intake is mediated in part by the mesolimbic dopamine system involved in reward seeking behavior (Jerlhag E. et al 2006 Addition Biology11: 45-54; Jerlhag E et al Addit biol.200712: 6-16; Egecioglu E. et al 2010, Addition Biology15, 304-. Furthermore, most recent data confirm the suitability of ghrelin antagonists for the treatment of alcohol disorders (WO2009/020419 and Jerlhag et al 2009.PNAS106,11318-11323) and drug abuse (Jerlhag E. et al 2010, psychopharmacography 211, 415-113422).

Other areas of application include accelerating recovery of patients undergoing major surgery (e.g., US6,194,578); accelerating recovery in burn patients (e.g., US6,194,578); reducing protein catabolic reactions following major surgery (e.g., US6,194,578); reducing cachexia and protein loss due to acute or chronic disease (e.g., US6,194,578); treating a central nervous system disorder in a patient undergoing a medical procedure in combination with an antidepressant (e.g., US2002/0002137a 1); accelerating fracture repair and cartilage growth (e.g., US6,194,578); treating or preventing osteoporosis; stimulating the immune system; accelerating wound healing (e.g., US6,194,578); treating growth retardation associated with Prader-Willi syndrome, Turner syndrome and obesity; treating intrauterine growth retardation, skeletal dysplasia, hypercortisolism, and Cushing's syndrome; treatment of osteochondral dysplasia, Noonan syndrome, schizophrenia, depression, and Alzheimer's disease; treating pulmonary dysfunction and ventilator dependence; treating hyperinsulinemia including islet cell proliferation; the ovulation induction is treated in an auxiliary way; prevention of age-related hypofunction of the thymus; improving muscle strength and motility (e.g., US6,194,578); maintaining skin thickness (e.g., US6,194,578); improving sleep quality (e.g., US6,071,926); prevention of congestive heart failure, alone (e.g. US6,329,342; US6,194,578) and in combination with corticotropin releasing factor antagonists (e.g. US 2001/0041673); metabolic or renal homeostasis (e.g., in the frail elderly) (e.g., US6,194,578); improving glycemic control (e.g., US6,251,902); treatment of systemic lupus erythematosus and inflammatory bowel disease (e.g., US 2002/0013320); treating or preventing frailty associated with aging or obesity (e.g., US6,194,578); and stimulating osteoblasts.

There is no forgetfulness to the animal in potential applications, such as stimulation of food intake in companion animals (Wren AM et al, Diabetes2001, 50: 2540-.

Compounds containing triazole moieties are widely recognized in medicinal chemistry because of their various biological activities. The following patent families all relate to heterocyclic compounds which are described as exhibiting certain biological effects for different pharmaceutical indications. Comprising a triazole moiety, either cryptic or explicit.

Triazole derivatives as ghrelin analog ligands of growth hormone secretagogue receptors with good receptor affinity are disclosed in WO 07/020013.

WO2004/111015 discloses modulators of glucocorticoid receptors. WO2004/052280 describes anti-angiogenic compounds as inhibitors of tyrosine kinase activity of VEGF receptors and their use in cancer. WO2004/096795 also discloses tyrosine kinase inhibitors, preferably C-FMS inhibitors. WO03/011831 and WO03/011210 both describe heteroarylheteroalkylamine derivatives as nitric oxide synthase inhibitors. WO02/00651 relates to factor XA inhibitors for thromboembolic disorders. WO01/94318 and WO01/94317 both describe chemical libraries of substituted azole derivatives and methods of their synthesis for use in high throughput drug discovery screening. However, it fails to provide any biological activity or any pharmaceutical use, nor is it intended to name a particular compound. Both WO00/76971 and WO00/76970 claim serine protease inhibitors useful as antithrombotic agents. WO01/36395 discloses triazole derivatives as farnesyl transferase inhibitors. WO96/33176 and US5,703,092 relate to hydroxamic acid compounds as inhibitors of metalloproteases and TNF. WO93/09095 describes 2-heterocyclic ethylamine derivatives and their use in neurological and neurodegenerative disorders. WO2004/103270 claims compounds useful for the treatment of thrombosis, in particular factor XIa inhibitors. WO98/38177, US6,506,782, US6,849,650 and US2003/0130188 all describe heterocyclic compounds as inhibitors of beta-amyloid peptide release or their synthesis for Alzheimer's disease.

Heterocyclic compounds useful as GHS have also been described in the literature.

For example, WO00/54729 discloses heterocyclic aromatic compounds as GH secretagogues, which are described as stimulating endogenous production and/or release of GH and may also contain a triazole moiety. Furthermore, methods of administering such GHS for increasing the level of endogenous GH or increasing endogenous GH production or release are described. Further, methods are provided for preventing or treating osteoporosis (improving bone density and/or strength), or treating obesity, or increasing muscle mass and/or muscle strength and function, or reversing or preventing frailty in elderly humans administered such GHS.

However, although GH release in vivo is claimed, WO00/54729 fails to actually demonstrate such an effect. Neither in vitro nor in vivo data include data demonstrating any stimulation of or increase in endogenous production and/or release of GH.

Furthermore, WO00/54729 fails to describe and show the effect of those claimed compounds on any biological target, i.e. the claimed compounds are not shown/described as ligands of one or more specific receptors (e.g. receptor family) that bind thereto and modulate their activity.

Furthermore, WO00/54729 fails to describe and demonstrate the inhibitory and/or antagonistic activity of the claimed compounds. Indeed, such compounds have not been shown to reduce endogenous GH levels and/or inhibit or reduce endogenous GH production and/or release. Neither inhibitory effects on any of the receptors mentioned are shown nor made apparent.

US6,525,203, US6,518,292, US6,660,760 are members of the same patent family as WO00/54729, but no longer contain a triazole moiety as the claimed subject matter. In terms of biological activity, the above facts with respect to WO00/54729 apply.

WO2004/021984 describes GH secretagogue heterocyclic aromatic compounds which are described as being suitable for stimulating the endogenous production or release of GH. However, the claimed compounds consist of a di-to tetracyclic aromatic ring and are free of triazoles.

Similar to WO00/54729, GH release is claimed in vivo, but neither in vitro nor in vivo data contain data demonstrating any stimulation of or increase in endogenous production and/or release of GH. In terms of biological activity, the same statements apply as for WO 00/54729.

WO97/23508 claims compounds that are peptide mimetic properties of GHS and are described as acting directly on pituitary cells in vitro to release GH therefrom and show improved properties, such as improved resistance to proteolytic degradation and improved bioavailability. In addition, the claimed compounds may also be administered in vivo to increase GH release. The compounds are peptide derivatives and do not specifically contain a triazole moiety.

However, again and similarly to the above-mentioned WO00/54729 and WO2004/021984, WO97/23508 fails to show any in vitro or in vivo data demonstrating the claimed effect, such as direct action on, release of GH from, and improved properties of pituitary cells. Furthermore, the above facts with respect to WO00/54729 apply in respect of biological targets and inhibitory/antagonistic activity.

US6,127,391, US5,977,178 and US6,555,570 are members of the same patent family as WO 97/23508. The above-mentioned facts for WO97/23508 apply.

The compounds described in the present invention were designed to show improved activity on the ghrelin receptor of at least factor 3 compared to a representative compound, i.e. compound 50 disclosed in WO 07/020013.

Furthermore, the compounds described in the present invention are expected to have improved oral bioavailability. Chemical synthesis involves modification of residues R2, R5 and R7 in order to provide compounds with improved ADME properties.

Compared to the compounds disclosed in WO07/020013, the compounds described herein show improved properties in at least one of the following parameters which are generally considered necessary for reasonable oral bioavailability (Caldwell GW.2000, Curr Opin Drug Discov Devel.3(1), 30-41; Thomas VH. et al 2006, Expert Opin Drug Metab Toxicol2(4), 591-:

CaCo-2 permeability: p_APP(a→b)>1x10⁶cm/s

When b → a/a → b ratio <2 is indicated, there is no evidence of effluence

Metabolic stability: in microsomal in vitro stability studies, rat CL <50 ml/min/kg (alternatively, >30% remains at 60 min).

It is therefore an object of the present invention to provide novel compounds with improved receptor antagonistic activity and ADME properties, which can be used for the treatment of physiological and/or pathophysiological conditions mediated by the GHS receptor in mammals, in particular humans. It is another object of the present invention to provide agonists of the GHS receptor for use in those treatments. It is another object of the present invention to provide inverse agonists for use in the above treatment, wherein said treatment is effected by modulation of the GHS receptor. It is another object of the present invention to provide partial agonists/antagonists of the GHS receptor for those treatments.

Disclosure of Invention

The object of the present invention has been achieved, in one aspect, surprisingly, by providing compounds of the formula (I).

(I)

Wherein:

(A)

r1 and R2 are independently from each other selected from the group consisting of "hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl", optionally substituted in the alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and/or heterocyclylalkyl group with up to 3 substituents independently selected from the group consisting of: "halogen, -F, -Cl, -Br, -I, -N₃、–CN、–NR7R8、-NR11R12、–OH、–NO₂Alkyl, aryl, heteroaryl, arylalkyl, -O-alkyl, -O-aryl, -O-arylalkyl, -C (O) O-alkyl, -C (O) O-cycloalkyl, -C (O) O-cycloalkylalkyl, -C (O) O-aryl, -C (O) O-arylarylArylalkyl, -C (O) O-heteroaryl, -C (O) O-heteroarylalkyl, -C (O) O-heterocyclyl, -C (O) O-heterocyclylalkyl, -C (O) NR9R10, -C (S) NR9R 10; ";

one of the residues R3 and R4 is a hydrogen atom, whereas the other residue is selected from the group consisting of "hydrogen atom, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -alkyl-O-aryl, -alkyl-O-arylalkyl, -alkyl-O-heteroaryl, -alkyl-O-heteroarylalkyl, -alkyl-O-heterocyclyl, alkyl-O-heterocyclylalkyl, -alkyl-CO-aryl, -alkyl-CO-arylalkyl, -alkyl-CO-heteroaryl, -alkyl-CO-heteroarylalkyl, -alkyl-CO-heterocyclyl, -alkyl-CO-heterocyclylalkyl, -alkyl-C (O) O-aryl, -alkyl-C (O) O-arylalkyl, -alkyl-C (O) O-heteroaryl, -alkyl-C (O) O-heteroarylalkyl, -alkyl-C (O) O-heterocyclyl, -alkyl-C (O) O-heterocyclylalkyl, -alkyl-CO-NH₂-alkyl-CO-OH, -alkyl-NH₂-alkyl-NH-C (NH) -NH₂Alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, alkyl-S-alkyl, alkyl-S-H ", optionally substituted in aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and/or heterocyclylalkyl with up to 3 substituents independently selected from the group consisting of: "halogen, -F, -Cl, -Br, -I, -N₃、–CN、–NR7R8、–OH、–NO₂Alkyl, aryl, arylalkyl, -O-alkyl, -O-CF₃-O-aryl, -O-arylalkyl ";

r5 is selected from the group consisting of "-C (S) alkyl, -C (S) -cycloalkyl, -C (S) -cycloalkylalkyl, -C (S) -aryl, -C (S) -arylalkyl, -C (S) -heteroaryl, -C (S) -heteroarylalkyl, -C (S) -heterocyclyl, -C (S) -heterocyclylalkyl, -C (O) O-alkyl, -C (O) O-cycloalkyl, -C (O) O-cycloalkylalkyl, -C (O) O-aryl, -C (O) O-arylalkyl, -C (O) O-heteroaryl, -C (O) O-heteroarylalkyl, -C (O) O-heterocyclyl, -C (O) O-heterocyclylalkylC (O) NR9R10, -C (S) NR9R10 "; optionally substituted in alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and/or heterocyclylalkyl with up to 3 substituents independently selected from the group consisting of: "halogen, -F, -Cl, -Br, -I, -N₃、–CN、-CF₃、–NR7R8、–OH、–NO₂、-NH₂Alkyl, aryl, arylalkyl, -OH, -O-alkyl, -O-aryl, -O-arylalkyl,;

r6 is selected from "hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl";

r7 and R8 are independently from each other selected from the group consisting of "hydrogen atom, alkyl group, cycloalkyl group and cycloalkylalkyl group";

r9 and R10 are independently from each other selected from the group consisting of "hydrogen atom, alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, arylalkyl group and heteroarylalkyl group";

r11 is a "hydrogen atom",

r12 is independently from each other selected from the group consisting of "-C (O) H, -C (O) -alkyl; -C (O) -cycloalkyl, -C (O) -cycloalkylalkyl, -C (O) -aryl, -C (O) -arylalkyl, -C (O) -heteroaryl, -C (O) -heteroarylalkyl, -C (O) -heterocyclyl, -C (O) -heterocyclylalkyl,

or

(B)

R1 is independently selected from "hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl", optionally substituted in the alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and/or heterocyclylalkyl with up to 3 substituents independently selected from the group consisting of: "halogen, -F, -Cl, -Br, -I, -N₃、–CN、–NR7R8、–OH、–NO₂Alkyl, arylAlkyl, -O-aryl, -O-arylalkyl;

r2 is "alkyl" substituted with up to 2 substituents independently selected from the group consisting of: "aryl, heteroaryl, -C (O) O-alkyl, -C (O) O-cycloalkyl, -C (O) O-cycloalkylalkyl, -C (O) O-aryl, -C (O) O-arylalkyl, -C (O) O-heteroaryl, -C (O) O-heteroarylalkyl, -C (O) O-heterocyclyl, -C (O) O-heterocyclylalkyl, -C (O) NR9R10, -NR11R 12", and for aryl, heteroaryl, alkyl must additionally be substituted by-NR 11R 12;

one of the residues R3 and R4 is a hydrogen atom, whereas the other residue is selected from the group consisting of "hydrogen atom, alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -alkyl-O-aryl, -alkyl-O-arylalkyl, -alkyl-O-heteroaryl, -alkyl-O-heteroarylalkyl, -alkyl-O-heterocyclyl, alkyl-O-heterocyclylalkyl, -alkyl-CO-aryl, -alkyl-CO-arylalkyl, -alkyl-CO-heteroaryl, -alkyl-CO-heteroarylalkyl, -alkyl-CO-heterocyclyl, -alkyl-CO-heterocyclylalkyl, -alkyl-C (O) O-aryl, -alkyl-C (O) O-arylalkyl, -alkyl-C (O) O-heteroaryl, -alkyl-C (O) O-heteroarylalkyl, -alkyl-C (O) O-heterocyclyl, -alkyl-C (O) O-heterocyclylalkyl, -alkyl-CO-NH₂-alkyl-CO-OH, -alkyl-NH₂-alkyl-NH-C (NH) -NH₂Alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, alkyl-S-alkyl, alkyl-S-H ", optionally substituted in aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and/or heterocyclylalkyl with up to 3 substituents independently selected from the group consisting of: "halogen, -F, -Cl, -Br, -I, -N₃、–CN、–NR7R8、–OH、–NO₂Alkyl, aryl, arylalkyl, -O-alkyl, -O-aryl, -O-arylalkyl,;

r5 is selected from the group consisting of "hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroAryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -CO-alkyl, -CO-cycloalkyl, -CO-cycloalkylalkyl, -CO-aryl, -CO-arylalkyl, -CO-heteroaryl, -CO-heteroarylalkyl, -CO-heterocyclyl, -CO-heterocyclylalkyl, -CO-C (R9R10) -NH₂、–CO–CH₂–C*(R9R10)–NH₂、–CO–C*(R9R10)–CH₂–NH₂Alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl ", optionally substituted with up to 3 substituents independently selected from the group consisting of: "halogen, -F, -Cl, -Br, -I, -N₃、–CN、–NR7R8、–OH、–NO₂Alkyl, aryl, arylalkyl, -O-alkyl, -O-aryl, -O-arylalkyl,;

r6 is selected from "hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl";

r7 and R8 are independently from each other selected from the group consisting of "hydrogen atom, alkyl group, cycloalkyl group, cycloalkylalkyl group";

r9 and R10 are independently from each other selected from the group consisting of "hydrogen atom, alkyl group, natural amino acid side chain, unnatural amino acid side chain";

r11 is a "hydrogen atom";

r12 is independently from each other selected from the group consisting of "-C (O) H, -C (O) -alkyl; -C (O) -cycloalkyl, -C (O) -cycloalkylalkyl, -C (O) -aryl, -C (O) -arylalkyl, -C (O) -heteroaryl, -C (O) -heteroarylalkyl, -C (O) -heterocyclyl, -C (O) -heterocyclylalkyl;

in (A) and (B)

m is 0, 1 or 2; and is

Meaning a carbon atom of R or S configuration when chiral;

the compounds are useful for the preparation of a medicament for the treatment or prevention of physiological and/or pathophysiological conditions mediated by GHS receptors in mammals.

In another aspect, the object of the present invention has been surprisingly achieved by providing novel triazole compounds selected from the following and their physiologically tolerable salts:

the compound 1 [5- { (R) -2- (1H-indol-3-yl) -1- [ (pyridine-3-carbonyl) -amino ] -ethyl } -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -acetic acid ethyl ester;

the compound 2N- [ (R) -1- [ 5-carbamoylmethyl-4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-b 3-yl ] -2- (1H-indol-3-yl) -ethyl ] -nicotinamide;

the compound 3-pyridine-2-carboxylic acid [ (R) -1- [5- [ (R) -1-acetylamino-2- (1H-indol-3-yl) -ethyl ] -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -amide;

the compound 4 pyridine-2-carboxylic acid [ (R) -1- [5- ((R) -1-acetylamino-2-phenyl-ethyl) -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -amide;

the compound 5 pyridine-2-carboxylic acid [ (R) -1- [5- ((R) -1-formylamino-2-phenyl-ethyl) -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -amide;

the compound 6N- [ (R) -1- [5- ((R) -1-acetylamino-2-phenyl-ethyl) -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -2-hydroxy-acetamide;

the compound 7 (S) -morpholine-2-carboxylic acid [ (R) -1- [5- ((R) -1-acetylamino-2-phenyl-ethyl) -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -amide;

the compound 8N- [ (R) -1- [5- [ (R) -1-acetylamino-2- (1H-indol-3-yl) -ethyl ] -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -2-amino-2-methyl-propionamide;

the compound 92-amino-N- [ (R) -1- [5- [ (R) -1-carboxamido-2- (1H-indol-3-yl) -ethyl ] -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -2-methyl-propionamide;

the compound 10N- [ (R) -1- [5- ((R) -1-acetylamino-2-phenyl-ethyl) -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -2-amino-2-methyl-propionamide;

the compound 11 pyridine-2-carboxylic acid [ (R) -1- [5- [ 1-acetylamino-2- (1H-indol-3-yl) -ethyl ] -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -amide;

compound 122-amino-N- [ (R) -1- [5- ((R) -1-formylamino-2-phenyl-ethyl) -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -2-methyl-propionamide;

the compound 13 pyridine-2-carboxylic acid [ (R) -1- [5- ((S) -1-acetylamino-2-phenyl-ethyl) -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -amide;

the compound 14 pyridine-2-carboxylic acid [ (R) -1- [5- [ 1-formylamino-2- (1H-indol-3-yl) -ethyl ] -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -amide;

the compound 15 { (R) -1- [5- [2- (1H-indol-3-yl) -ethyl ] -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2-naphthalen-2-yl-ethyl } -carbamic acid tert-butyl ester;

the compound 161- { (R) -2- (1H-indol-3-yl) -1- [4- (4-methoxy-benzyl) -5-phenethyl-4H- [1,2,4] triazol-3-yl ] -ethyl } -3-isopropyl-urea;

the compound 17 { (R) -2- (1H-indol-3-yl) -1- [4- (4-methoxy-benzyl) -5-phenethyl-4H- [1,2,4] triazol-3-yl ] -ethyl } -carbamic acid isobutyl ester;

the compound 18 { (R) -2- (1H-indol-3-yl) -1- [4- (4-methoxy-benzyl) -5-phenethyl-4H- [1,2,4] triazol-3-yl ] -ethyl } -carbamic acid tert-butyl ester;

the compound 191-benzyl-3- { (R) -2- (1H-indol-3-yl) -1- [4- (4-methoxy-benzyl) -5-phenethyl-4H- [1,2,4] triazol-3-yl ] -ethyl } -urea;

the compound 201-benzyl-3- { (R) -2- (1H-indol-3-yl) -1- [4- (4-methoxy-benzyl) -5-phenethyl-4H- [1,2,4] triazol-3-yl ] -ethyl } -thiourea;

the compound 21 [ (R) -1- [4- (4-fluoro-benzyl) -5-phenethyl-4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -carbamic acid tert-butyl ester;

the compound 22 { (R) -2- (1H-indol-3-yl) -1- [4- (4-isopropoxy-benzyl) -5-phenethyl-4H- [1,2,4] triazol-3-yl ] -ethyl } -carbamic acid tert-butyl ester;

the compound 23 { (R) -2- (1H-indol-3-yl) -1- [4- (4-methoxy-benzyl) -5-phenethyl-4H- [1,2,4] triazol-3-yl ] -ethyl } -methyl-carbamic acid tert-butyl ester;

compound 24 [ (R) -1- [4- (2, 4-dimethoxy-benzyl) -5-phenethyl-4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -carbamic acid tert-butyl ester;

the compound 25 piperidine-4-thiocarboxylic acid { (R) -2- (1H-indol-3-yl) -1- [4- (4-methoxy-benzyl) -5-phenethyl-4H- [1,2,4] triazol-3-yl ] -ethyl } -amide;

the compound 262-amino-N- { (R) -2- (1H-indol-3-yl) -1- [4- (4-methoxy-benzyl) -5-phenethyl-4H- [1,2,4] triazol-3-yl ] -ethyl } -thioacetamide;

the compound 27 pyridine-2-thiocarboxylic acid { (R) -2- (1H-indol-3-yl) -1- [4- (4-methoxy-benzyl) -5-phenethyl-4H- [1,2,4] triazol-3-yl ] -ethyl } -amide;

the chemical name of the substance was generated using AutoNom2000for ISIS/Draw Add-In.

For the avoidance of doubt, if the chemical name and chemical structure of a compound shown above fails to correspond due to error, the chemical structure may be considered to be clearly defined.

In a preferred embodiment, these compounds are useful for the preparation of a medicament for the treatment or prevention of physiological and/or pathophysiological conditions mediated by GHS receptors in mammals.

In another preferred embodiment, all triazole compounds as shown herein, i.e. generally (via formula (I) above and different R residues) and specifically referred to below as compounds of the invention, are useful for the preparation of a medicament for the treatment or prevention of a physiological and/or pathophysiological condition mediated by the GHS receptor in a mammal, and wherein the treatment can be effected by modulation of the GHS receptor.

Unless otherwise indicated in the specification or in the claims, the terms in which the compounds of formula (I) are indicated above will always have the following meanings for the interpretation of the following:

the term "substituted" means that the corresponding residue or group contains one or more substituents. Wherein the residue has a plurality of substituents, and the selection of the plurality of substituents is specific, the substituents being independently selected from each other and not necessarily identical. The term "unsubstituted" means that the corresponding group contains no substituents. The term "optionally substituted" means that the corresponding group is unsubstituted or substituted with one or more substituents. The term "substituted with up to 3 substituents" means that the corresponding residue or group is substituted with 1 or 2 or 3 substituents.

For the purposes of the present invention, the term "alkyl" includes acyclic saturated hydrocarbons having C1-C12 carbon atoms which may be straight or branched. The term "alkyl" preferably represents an alkyl chain of 1 to 8, particularly preferably 1 to 6 carbon atoms. Examples of suitable alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, 2-or 3-methyl-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl.

The term "cycloalkyl" represents a saturated or partially unsaturated non-aromatic cyclic hydrocarbon group/residue containing 1 to 3 rings, including monocycloalkyl, bicycloalkyl and tricycloalkyl groups, and containing a total of 3 to 20 (preferably 3 to 10) carbon atoms forming the ring, most preferably (C3-C8) -cycloalkyl. Examples of suitable cycloalkyl residues are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctadienyl.

The term "cycloalkylalkyl" means a residue wherein a cycloalkyl group is attached through an alkyl group, wherein alkyl and cycloalkyl have the meaning defined herein, preferably a (C3-C8) -cycloalkyl- (C1-C4) -alkyl residue. Examples thereof are cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl, cyclohexenylethyl.

For the purposes of the present invention, the term "alkenyl" includes acyclic unsaturated or partially unsaturated hydrocarbons having C2-C12 carbon atoms, which may be straight-chain or branched and contain one or more double bonds. The term "alkenyl" preferably represents an alkenyl chain of 2 to 8, particularly preferably 2 to 6, carbon atoms. Examples are ethenyl, propenyl, butenyl, pentenyl, hexenyl, octadienyl and the like.

The term "alkynyl" means an acyclic unsaturated or partially unsaturated hydrocarbon having C2-C12 carbon atoms, which may be straight or branched chain and contain one or more triple bonds. The term "alkynyl" preferably represents an alkynyl chain of 2 to 8, particularly preferably 2 to 6, carbon atoms. Examples are propynyl, butynyl, pentynyl, hexynyl.

The term "aryl" means an aromatic hydrocarbon system having 3 to 14, preferably 5 to 14, carbon atoms, which may also be fused with other saturated, (partially) unsaturated or aromatic ring systems. Examples of "aryl" are especially phenyl, biphenyl, naphthyl and anthryl, and indanyl, indenyl or1, 2,3, 4-tetrahydronaphthyl.

The term "heteroaryl" means an aromatic residue of a 5-, 6-or 7-membered ring, which contains at least 1, and where appropriate also 2,3,4 or 5 heteroatoms, preferably nitrogen, oxygen and/or sulfur, wherein the heteroatoms are identical or different. The number of nitrogen atoms is preferably between 0 and 3 and the number of oxygen and sulphur atoms is between 0 and 1. The term "heteroaryl" also includes systems in which the aromatic ring is part of a di-or polycyclic ring system, for example, in which the aromatic ring is an aryl, cycloalkyl, heteroaryl or heterocyclyl group as defined herein fused through any desired and possible ring members of the heteroaryl residue. Examples of "heteroaryl" include pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, and isoquinolinyl.

The terms "arylalkyl" and "heteroarylalkyl" mean a residue wherein aryl or heteroaryl residues are linked through an alkyl group, wherein alkyl, aryl and heteroaryl have the meanings defined herein. A preferred "arylalkyl" group is phenyl- (C)₁-C₄) -alkyl residues, preferably benzyl or phenylethyl residues. A preferred "heteroarylalkyl" is indolyl- (C)₁-C₄) Alkyl residues, preferably 1H-Indol-3-yl-methyl or 2 (1H-indol-3-yl) -ethyl.

The term "heterocyclyl" means a mono-or polycyclic ring system of 3 to 14, preferably 5 or 6 to 14 ring atoms (possibly only carbon atoms). However, the ring system may also contain 1,2,3,4 or 5 heteroatoms, in particular nitrogen, oxygen and/or sulfur. The ring system may be saturated, mono-or polyunsaturated but not aromatic. In the case of ring systems consisting of at least two rings, these rings may be fused or spiro-or connected by other means. The "heterocyclyl" residue may be attached at any carbon or heteroatom so as to result in a stable structure. Examples include pyrrolidinyl, thiopyrrolidinyl, piperidinyl, piperazinyl, oxapiperazinyl, oxapiperidinyl, and oxadiazolyl.

The term "heterocyclylalkyl" means a residue wherein a heterocyclyl is attached through an alkyl, wherein alkyl and heterocyclyl have the meanings defined above.

The terms "alkylsulfonyl", "arylsulfonyl" and "arylalkylsulfonyl" are intended to mean wherein-SO is passed through₂-a residue of a group linked to an alkyl, aryl or arylalkyl group, wherein the alkyl, aryl and arylalkyl groups have the meaning defined herein. Examples are methanesulfonyl and phenylsulfonyl.

The term "halogen", "halogen atom" or "halogen substituent" (Hal-) means one, where appropriate more, fluorine (F, fluoro), bromine (Br, bromo), chlorine (Cl, chloro) or iodine (I, iodo) atoms. The expressions "dihalogen", "trihalogen" and "perhalogen" mean 2,3 and 4 substituents, respectively, wherein each substituent may be independently selected from fluorine, chlorine, bromine and iodine. "halogen" preferably means a fluorine, chlorine or bromine atom.

For the purposes of the present invention, the term "natural α -amino acid side chains" means all the side chains of the known 20 protein-derived (proteinogenic) α -amino acids as well as the side chains of the following naturally occurring (i.e. in any biological system) α -amino acids: such as selenium hemicystine, pyrrolysine, citrulline, ornithine, homocysteine, N-methylarginine, N-acetyl lysine, gamma-carboxyglutamic acid (salt or ester), 5-hydroxylysine, 3-methylhistidine and/or N, -trimethyllysine. In this connection "side chain" means a residue attached to the α -carbon atom, for example methyl in the Ala side chain or benzyl in the Phe side chain.

For the purposes of the present invention, the term "unnatural alpha amino acid side chain" means all side chains of known alpha-amino acids that are not of protein origin and are not known to occur naturally (i.e., in any biological system). Examples are norleucine, cyclohexylglycine, 2-naphthylalanine, substituted alpha-amino acids (e.g. Tyr or Phe substituted with halogen) and protected alpha-amino acid side chains, wherein protecting groups such as Fmoc, Boc, Z, CBZ, Aloc, trityl, acetyl and/or benzyl can be attached/reacted directly to functional groups (e.g. amino, hydroxyl and/or carboxyl residues). In this regard, "side chain" refers to a "natural alpha amino acid side chain".

The above-described embodiments of residues R1 to R12 having functional groups (e.g., amino, hydroxyl, and/or carboxyl residues), e.g., alkyl-CO-NH₂-alkyl-CO-OH, -alkyl-NH₂-alkyl-NH-C (NH) -NH₂、–CO–C*(R9R10)–NH₂、–CO–CH₂–C*(R9R10)–NH₂、–CO–C*(R9R10)–CH₂–NH₂And/or 2-amino-2-carbonyl-propane (2-amino-isobutyric acid/Aib residue), may be protected with a protecting group as mentioned above. Such protecting groups of embodiments are considered to be within the scope and spirit of the present invention.

All stereoisomers of the compounds of the present invention are contemplated as mixtures or in pure or substantially pure form. The compounds of the present invention may have asymmetric centers at any carbon atom, including any one of the carbon atoms of the R residue. The compounds of the invention may thus be present in their racemic form, in the form of pure enantiomers and/or diastereomers or in the form of mixtures of these enantiomers and/or diastereomers. The mixture can have any desired mixture ratio of stereoisomers. All such different stereochemical forms and mixtures are within the scope of the present invention.

Thus, for example, a compound of the invention having one or more chiral centers and present in the form of a racemate or in the form of a mixture of diastereomers can be resolved into its optically pure isomers, i.e., enantiomers or diastereomers, by methods known per se. The separation of the compounds of the invention can be carried out by column separation in chiral or achiral phase, or by recrystallization from optionally optically active solvents, or using optically active acids or bases, or by derivatization with optically active reagents, for example optically active alcohols, and subsequent removal of the residue.

The compounds of the invention may be in tautomeric form, if possible.

The compounds of the invention may likewise be in the form of any desired prodrug, for example esters, carbonates or phosphates, in which case the actual biologically active form is released merely by metabolism. Any compound that can be converted in vivo to provide a biologically active agent (i.e., a compound of the invention) is a prodrug within the scope and spirit of the invention.

Various forms of prodrugs are well known in the art and are described, for example, in the following references:

(i) the Practice of Medicinal Chemistry (Wermuth CG et al, Chapter 31, Academic Press 1996);

(ii) design of Prodrugs (editor: Bundgaard H, Elsevier 1985); and

(iii) a Textbook of Drug Design and Development (Krogsgaard-Larson P and Bungadard H, eds., Chapter 5: 113. sup. 191, Harwood Academic Publishers 1991).

Said documents are incorporated herein by reference.

It is also known that this chemical substance is converted in the body into a metabolite, which in the appropriate case likewise causes the desired biological effect-in some cases even in a more pronounced form.

Any biologically active compound that is converted in vivo by metabolism of any compound of the invention is a metabolite within the scope and spirit of the invention.

The compounds of the invention, if they have sufficiently basic groups, for example primary, secondary or tertiary amines, can be converted into salts with inorganic and organic acids. The pharmaceutically acceptable salts of the compounds of the present invention are preferably formed with hydrochloric, hydrobromic, iodic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, carbonic, formic, acetic, sulfoacetic, trifluoroacetic, oxalic, malonic, maleic, succinic, tartaric, racemic, malic, pamoic, mandelic, fumaric, lactic, citric, taurocholic, glutaric, stearic, glutamic or aspartic acid. Salts formed are, in particular, the hydrochloride, chloride, hydrobromide, bromide, iodide, sulfate, phosphate, methanesulfonate, toluenesulfonate, carbonate, bicarbonate, formate, acetate, sulfoacetate, trifluoromethanesulfonate, oxalate, malonate, maleate, succinate, tartrate, malate, pamoate, mandelate, fumarate, lactate, citrate, glutarate, stearate, aspartate and glutamate. The stoichiometry of the salt formed from the compounds of the present invention can also be an integer or non-integer multiple of 1.

The compounds of the invention, if they contain sufficiently acidic groups, for example carboxyl, sulfonic acid, phosphoric acid or phenolic groups, can be converted into their physiologically tolerable salts with inorganic and organic bases. Examples of suitable inorganic bases are ammonium, sodium hydroxide, potassium hydroxide, calcium hydroxide, and examples of organic bases are ethanolamine, diethanolamine, triethanolamine, ethylenediamine, t-butylamine, t-octylamine, dehydroabietylamine, cyclohexylamine, dibenzylethylene-diamine, and lysine. The stoichiometry of the salt formed from the compounds of the present invention can also be an integer or non-integer multiple of 1.

The compounds of the invention may likewise be in the form of their solvates, and in particular hydrates, which may be obtained, for example, by crystallization from a solvent or from an aqueous solution. It is also possible that 1,2 or 3 or any number of solvent or water molecules are combined with the compounds of the invention to give solvates and hydrates.

Chemical species are known to form solids that exist in different ordered states, called polymorphs or modifications. Different variants of polymorphs can vary greatly in their physical properties. The compounds of the invention may exist in a variety of polymorphic forms, and certain variants may also be metastable. All such polymorphic forms of the compounds of the present invention are considered to be within the present invention.

Triazole derivatives (compounds of the invention) as shown herein are ghrelin analogue ligands of the GHS receptor. Thus, the above-mentioned compounds of the invention are suitable for the treatment or prevention of physiological and/or pathophysiological conditions mediated by GHS receptors and/or physiological and/or pathophysiological conditions which can be influenced by the modulation of these receptors and which are thus prevented, treated and/or alleviated.

For the purposes of the present invention, the term "treatment" is also intended to include prophylactic treatment or alleviation.

For the purposes of the present invention, the term "ghrelin analog ligand" or "ligand" is intended to refer to each compound that binds in any way to the receptor (which in the present invention is the GHS or ghrelin receptor) and triggers activation, inhibition and/or another possible effect at this receptor. The term "ghrelin analog ligand" or "ligand" thus includes agonists, antagonists, partial agonists/antagonists, inverse agonists, and other ligands that elicit effects at the receptor similar to those of an agonist, antagonist, partial agonist/antagonist, or inverse agonist.

For the purposes of the present invention, the term "GHS or ghrelin receptor antagonist" or "antagonist of GHS or ghrelin receptor" means a compound of the invention that binds to the GHS or ghrelin receptor but does not cause the receptor to activate properly, as assessed by recording the increase in intracellular calcium and the increase in cAMP response element driven reporter gene expression, a characteristic of activating these G Protein Coupled Receptors (GPCRs).

The ability of any of the compounds of the present invention to properly inactivate the GHS-R1A receptor was determined by comparing test compounds (at 10%) in the presence of ghrelin at a saturating concentration (0%) compared to basal levels (100%)^-10M to 10^-4M range) to inhibit GHS-R1a (reducing intracellular calcium and reducing cAMP response element driven reporter gene expression). Such evaluations can be easily carried out by the skilled person due to his expert knowledge. Results are percent values for each test compound.

Any compound of the invention that does not show an activation degree of GHS-R1a of at least 20% (assessed according to the above description) (increase in intracellular calcium and increase in cAMP response element driving reporter gene expression) is considered not to cause appropriate activation and is therefore not considered an agonist of GHS or ghrelin receptor. Preferably, such compounds exhibit antagonism (resistance/reduction) of the increase of intracellular calcium stimulated by ghrelin and/or other GHS, prevent such stimulation or even act as inverse agonists. Inverse agonists are ligands that bind to the same receptor binding site as an agonist or antagonist but cause inhibition of the basal/intrinsic activity of the receptor. Furthermore, such compounds may additionally exhibit inhibitory activity or effect on GH secretion and/or on other physiological or pathophysiological conditions, such as food intake or adipogenesis. Their effects may be unrelated. Thus, while inhibiting other physiological effects, it may have no effect on GH secretion at all. They may even stimulate other physiological effects.

For the purposes of the present invention, the term "GHS receptor agonist" or "agonist of GHS receptor" means a compound of the invention which binds to the GHS receptor and causes the appropriate activation of the receptor, as assessed by recording the increase in intracellular calcium or the increase in cAMP response element driven reporter gene expression, which is characteristic of activated G protein-coupled receptors.

Any compound of the invention that shows an activation degree of GHS-R1a of at least 20% (assessed according to the above description) (increase in intracellular calcium and increase in cAMP response element driving reporter gene expression) is considered to cause appropriate activation and is therefore considered to be a GHS receptor agonist. Such compounds may mimic the effects of ghrelin and/or GHS on GH secretion, such as food intake or lipogenesis. Similar to antagonists, the effect of agonist compounds may not be related to GH secretion. Such compounds may even antagonize (counteract/reduce) ghrelin and/or other GHS-stimulated intracellular calcium increases.

For the purposes of the present invention, the term "GHS receptor" or "GHS-R" or "ghrelin receptor" is intended to include receptors that bind at least one known peptidyl and/or non-peptidyl GHS and/or ghrelin. The term "GHS receptor" or "GHS-R" or "ghrelin receptor" is also intended to include different GHS binding sites in various tissues and/or organs as shown herein that bind at least one known peptidyl and/or non-peptidyl GHS and/or ghrelin and which may not have characterized the GHS-R subtype.

The binding of a given known peptidyl and/or non-peptidyl GHS and/or ghrelin is readily demonstrated by the skilled person on the basis of his expert knowledge by e.g. appropriate binding assays which merely represent routine experiments.

Such GHS receptors may or may not be stimulated/activated by ghrelin (ghrelin reactive) -in the case of acylated and non-acylated ghrelin, respectively. Stimulation/activation of such receptors may, but need not, result in GH production and/or GH secretion and/or increase GH plasma levels.

Preferably, such GHS receptors are selected from the group consisting of "GHS 1 type receptor, GHS-R1a, GHS-R1b, motilin receptor 1a, neurotensin receptor, TRH receptor, GPR38(FM1), GPR39(FM2), FM3, GHS binding site, GHS-R subtype, cardiac GHS-R, breast GHS-R".

More preferably, such GHS receptors are selected from the group consisting of "GHS 1 type receptor, GHS-R1a, GHS-R1 b", and most preferably GHS-R1 a.

As discussed herein, GHS receptors (including GHS binding sites and GHS-R subtypes) are known to be concentrated in the hypothalamic-pituitary region, but also have been shown to be distributed in other central and peripheral tissues. Furthermore, they are also expressed in a variety of tumor tissues under physiological conditions, even in tumor tissues of organs that do not express these receptors.

For the purposes of the present invention, it is intended to include within the scope of the invention all such GHS receptors (including GHS binding sites and GHS-R subtypes) that express organs and/or tissues. The expression of GHS receptors, including the GHS binding site and the GHS-R subtype, in a given organ and/or tissue is readily confirmed by the skilled person on the basis of his expert knowledge, e.g. by appropriate molecular biological tests, such as immunofluorescence or immunoprecipitation tests, which represent only routine tests.

Preferably, such GHS receptors are located in tissues and/or organs selected from the group consisting of: "endocrine tissue, exocrine tissue, peripheral tissue, adipose (adipose)/fat (fat) tissue, brain, hypothalamus, thalamus, hippocampus, striatum, cortex, pituitary, central nervous system, spinal cord, gland, adrenal gland, thyroid, salivary gland, mammary gland, neuron, intestine, small intestine, stomach, heart, liver, pancreas, kidney, bile (bile), gall bladder (gall), bladder, prostate, spleen, muscle, skeletal muscle, aorta, artery, vein, immune cell, leukocyte, lymphocyte, T cell, B cell, granulocyte, monocyte, macrophage, dendritic cell, mast cell, NK cell, neutrophil, eosinophil, basophil, lymph node, bone marrow, tonsil, thymus, placenta, testis, ovary, uterus, lung, adipose cell, tumor/cancer cell, cancer cell, Prostate cancer cells, thyroid cancer cells, lung cancer cells, breast cancer cells ".

As indicated above, the compounds of the present invention are ghrelin analog ligands of the GHS receptor. It can be administered to a variety of mammalian species, including humans, for the treatment or prevention of physiological and/or pathophysiological conditions in such mammals.

For the purposes of the present invention, all mammalian species are included. Preferably, such mammals are selected from "humans, domesticated animals, cattle, livestock, pets, cows, sheep, pigs, goats, horses, ponies, donkeys, mules (hinny), mules (mule), hares, rabbits, cats, dogs, guinea pigs, hamsters, rats, mice". More preferably, such mammal is a human.

The compounds of the present invention which are non-peptide ghrelin analog ligands of the GHS receptor are most unexpectedly characterized as having over a 3-fold improvement in binding affinity to such receptor over the representative example (i.e., compound 50 disclosed in WO 07/020013). For binding to human GHS-R1a, the compounds of the invention may for example preferably show an IC of less than 100nM₅₀The value is obtained. Most preferably, such compounds may exhibit an IC of less than 10nM for binding to human GHS-R1a₅₀The value is obtained.

Due to its unexpectedly strong receptor binding, the compounds of the present invention can be advantageously administered at lower doses than other less potent binding agents (as disclosed in WO 07/020013), while still achieving an equivalent or even superior biological effect to that desired. Furthermore, such a dose reduction advantageously results in less or even no drug side effects. Moreover, the high binding specificity of the compounds of the invention may translate into a reduction of their own undesirable side effects, regardless of the dose administered.

Furthermore, the compounds of the invention, which are non-peptidic in nature, are resistant to degradation by gastrointestinal enzymes. Thus, the compounds offer the advantage of being administered by the oral route. The compounds unexpectedly exhibit improved metabolic stability and/or improved bioavailability. Thus, again, a beneficial dose reduction with less or even no side effects can be achieved.

As shown and defined herein, the compounds of the present invention may be agonists, antagonists or partial agonists/antagonists or inverse agonists of GHS or ghrelin receptors.

As shown and defined herein, the compounds of the present invention may be antagonists or agonists of the GHS receptor.

The GHS receptor antagonists of the invention can be used, for example, to inhibit ghrelin and/or other GHS-stimulated GHS receptors, thereby reducing and/or blocking GH production and/or secretion and/or GH plasma levels. In addition, such GHS receptor antagonists may also be used to inhibit or prevent the physiological or pathophysiological effects of ghrelin that do not involve GH production and/or GH secretion.

Thus, the GHS receptor antagonists of the present invention are useful in the treatment and/or prevention of a variety of physiological and pathophysiological conditions as disclosed herein, in particular for short, medium and/or long term regulation of energy balance, short, medium and/or long term regulation (stimulation and/or inhibition) of food intake, treatment of adipogenesis, adiposity and/or obesity, weight gain and/or reduction and treatment of tumor cell proliferation.

In contrast, the GHS receptor agonists of the present invention may be used, for example, to activate the GHS receptor and stimulate/increase GH production and/or GH secretion, and thus have similar effects or uses of growth hormone itself, ghrelin and/or known GHS.

Thus, the GHS receptor agonists of the present invention are useful for the treatment and/or prevention of a variety of physiological and pathophysiological conditions as disclosed herein, in particular growth retardation, cachexia, inflammation, inflammatory effects, post-gastric ileus, post-operative ileus and/or gastrectomy (ghrelin replacement therapy).

For the purposes of the present invention, all physiological and/or pathophysiological conditions known to be mediated by GHS receptors are intended to be encompassed.

Preferably, these physiological and/or pathophysiological conditions are selected from the group consisting of "acute fatigue syndrome and muscle loss after elective surgery (electrosurgery), adipogenesis, adiposity, age-related decline in thymus function, age-related decline in function (" ARFD ") in the elderly, ageing disorders in companion animals, alcohol-related disorders, alzheimer's disease, anorexia (e.g. associated with cachexia or ageing); anxiety, blood pressure (reduction), weight gain/reduction, bone fracture repair (acceleration), stimulation of bone remodeling, decreased cachexia and protein loss due to chronic diseases such as cancer or AIDS, cardiac dysfunction (e.g., associated with valvular disease, myocardial infarction, cardiac hypertrophy, or congestive heart failure), cardiomyopathy, stimulation of cartilage growth, catabolic disorders associated with pulmonary dysfunction and respiratory dependency, catabolic side effects of glucocorticoids, catabolic states of aging, central nervous system disorders (in combination with antidepressants), chronic dialysis, Chronic Fatigue Syndrome (CFS), improvement in cognitive function (e.g., in dementia, alzheimer's disease), complex bone fractures (e.g., distraction osteogenesis), complications associated with transplantation, congestive heart failure (alone/in combination with corticotropin releasing factor antagonists), Crohn's disease and ulcerative colitis (colits), Cushing's syndrome, dementia, depression, drug abuse, short-, medium-and/or long-term regulation of energy balance, short-, medium-and/or long-term regulation (stimulation and/or inhibition) of food intake, reward of food intake, frailty (fraility) (e.g. in elderly), gastrectomy (ghrelin replacement therapy), postoperative ileus, improved glycemic control, stimulation of growth hormone release in elderly, growth hormone replacement in stressed patients, growth promotion in livestock, growth retardation associated with Prader-Willi syndrome and Turner's syndrome, growth retardation associated with Crohn's disease, growth retardation, hair/finger (nail) growth maintenance, hip fracture, hunger, hypercortisolism, hyperinsulinemia including islet cell hyperplasia, hyperinsulinemia, hipbone fracture, hunger, hypercortisolism, and the like, Hypothermia, immunodeficiency in individuals with reduced T4/T8 cell ratios, improvement in immune response to vaccination, stimulation of the immune system in companion animals, stimulation of the immune system, immunosuppression in immunosuppressed patients, inflammation or inflammatory effects, inflammatory bowel disease, insulin resistance in the heart, insulin resistance in type 2 diabetic patients, insulin resistance including NIDDM, diabetes, type I diabetes, type II diabetes, intrauterine growth retardation, irritable bowel syndrome, lipodystrophy (e.g., HIV-induced), maintenance of metabolic homeostasis, increased milk production in livestock, increased muscle mass/strength, improved muscle motility, improved muscle strength, maintained muscle strength/function in the elderly, muscle atrophy, musculoskeletal injury (e.g., in the elderly), improvement in immune response to vaccination, stimulation of the immune system in companion animals, stimulation of the immune system, immunosuppression in immunosuppressed patients, maintenance of inflammatory responses, insulin resistance in the heart, insulin resistance in type 2 diabetic patients, increased milk, Noonan syndrome, obesity and growth retardation associated with obesity, osteoblast stimulation, osteochondral dysplasia, osteoporosis, ovulation induction (adjuvant therapy), physical short stature including growth hormone deficient children, post-operative ileus, attenuation of protein catabolic response following major surgery/trauma, enhanced protein kinase B activity, psychosocial deprivation, pulmonary dysfunction and ventilator dependence, improvement of pulmonary function, induction of pulsatile growth hormone release, recovery of burn patients and reduction of hospitalization (promotion) of burn patients, renal failure or dysfunction resulting from growth retardation, maintenance of renal homeostasis in the frail elderly, sarcopenia, schizophrenia, maintenance of sensory functions (e.g., auditory, visual, olfactory (oreffective), short bowel syndrome, short stature associated with chronic disease, dysplasia, bone, and the like, Skin thickness maintenance, sleep disorders, improved sleep quality, thrombocytopenia, thymus development stimulation, tooth repair or growth, tumor cell proliferation, ventricular dysfunction or reperfusion events, wasting associated with AIDS, wasting associated with chronic liver disease, wasting associated with Chronic Obstructive Pulmonary Disease (COPD), wasting associated with multiple sclerosis or other neurodegenerative disorders, wasting after fracture, wool growth stimulation in sheep, wound healing (acceleration), delayed wound healing ".

More preferably, these physiological and/or pathophysiological conditions are selected from the group consisting of "alcohol-related disorders; drug abuse; growth retardation, cachexia, short, medium and/or long term regulation of energy balance; short, medium and/or long term regulation (stimulation and/or inhibition) of food intake; intake of reward food; adipogenesis, adiposity, and/or obesity; weight gain and/or loss; diabetes, type I diabetes, type II diabetes, tumor cell proliferation; inflammation, inflammatory effects, post-gastric ileus, post-surgical ileus and/or gastrectomy (ghrelin replacement therapy) ".

Recent findings indicate that the effect of ghrelin on food intake is mediated in part by the mesolimbic dopamine system involved in seeking reward behavior (Jerlhag E. et al, 2006 Addiameter Biology11: 45-54; Jerlhag E, et al, Addit biol.200712: 6-16; Egecioglu E. et al, 2010, Addition Biology15, 304-311). Furthermore, most recent data confirm the applicability of ghrelin antagonists for the treatment of alcohol-related disorders (WO2009/020419 and Jerlhag et al 2009.PNAS106, 11318. beta. 11323) and drug abuse (Jerlhag E. et al 2010, Psychopharmacology211, 415-422).

In another aspect of the invention, the compounds of the invention may be used in combination with at least one additional pharmacologically active substance.

Such additional pharmacologically active substances may be other compounds of the present invention and/or other "suitable therapeutic agents" for the treatment and/or prevention of the above-mentioned physiological and/or pathophysiological conditions. Depending on the purpose of the combined use, the further pharmacologically active substance may be an antagonist of the GHS receptor and/or an agonist of the GHS receptor. The selection and combination of further pharmacologically active substances is readily carried out by the skilled person on the basis of his expert knowledge and depending on the purpose of the combined use and the targeted physiological and/or pathophysiological condition.

In a preferred embodiment, the compounds of the invention are used in the form of medicaments for the treatment and/or prophylaxis of the above-mentioned physiological and/or pathophysiological conditions, wherein such medicaments comprise at least one further pharmacologically active substance.

In another preferred embodiment, the compounds of the invention are used in the form of a medicament for the treatment and/or prophylaxis of the abovementioned physiological and/or pathophysiological conditions, wherein the medicament is applied before and/or during and/or after the treatment with at least one further pharmacologically active substance.

Reference to "suitable therapeutic agents" above includes: "GHS, antidiabetic agent; anti-osteoporosis agents; anti-obesity agents; an anti-inflammatory agent; anxiolytic agents; an antidepressant; an antihypertensive agent; anti-platelet agents; antithrombotic and thrombolytic agents; a cardiac glycoside; cholesterol/lipid lowering agents; mineralocorticoid receptor antagonists; a phosphodiesterase inhibitor; protein tyrosine kinase inhibitors; thyroid mimetic (including thyroid receptor antagonists); an assimilating agent; an HIV or AIDS therapeutic agent; therapeutic agents for the treatment of alzheimer's disease and other cognitive disorders; a therapeutic agent for treating sleep disorders; an antiproliferative agent; an anti-neoplastic agent; antiulcer and gastroesophageal reflux disease agents; progesterone receptor agonists ("PRAs"); an estrogen; testosterone; a selective estrogen receptor modulator; a selective androgen receptor modulator; parathyroid hormone; and/or bisphosphonates ", and preferably" suitable therapeutic agents "are selected from these agents.

Examples of suitable GHS for use in combination with the compounds of the present invention include, for example, those described in U.S. patent nos. 4,411,890; and GHRP-6, GHRP-1 and B-HT920 or growth hormone releasing factor and its analogs or growth hormone and its analogs or growth regulators including IGF-1 and IGF-2 and GHS as described in publications WO89/07110 and WO89/07111 and in WO 01/96300.

Examples of suitable antidiabetic agents for use in combination with the compounds of the present invention include biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulin (including insulin secretagogues or insulin sensitizers), meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), biguanide/glyburide combinations (e.g., kulura), thiazolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR-alpha/gamma dual agonists, SGLT2 inhibitors, fatty acid binding protein (aP2) inhibitors such as those disclosed in U.S. Pat. No. 6,548,529, glucagon-like peptide-1 (GLP-1), and dipeptidyl peptidase IV (DP4) inhibitors.

Examples of suitable anti-osteoporosis agents for use in combination with the compounds of the present invention include alendronate, risedronate, raloxifene, calcitonin, non-steroidal progesterone receptor agonists, RANK ligand agonists, calcium sensitive receptor antagonists, TRAP inhibitors, Selective Estrogen Receptor Modulators (SERMs), estrogens and AP-1 inhibitors.

Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include endocannabinoid receptor antagonists such as the CB1 receptor antagonist of rimonabant (5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide monohydrochloride; CAS registry No. 158681-13-1; SR-141716A; U.S. patent No. 5,624,941), such as the aP2 inhibitors disclosed in U.S. patent No. 6,548,529, PPAR γ antagonists, PPAR agonists, and orlistat.

Examples of suitable anti-inflammatory agents for use in combination with the compounds of the present invention include prednisone, dexamethasone, enrel (Enbrel), cyclooxygenase inhibitors (i.e., COX-1 and/OR COX-2 inhibitors such as NSAIDs, aspirin, indomethacin, ibuprofen, piroxicam, naproxen, celecoxib, pancreatin), CTLA4-Ig agonists/antagonists, CD40 ligand antagonists, integrin antagonists, alpha 4 beta 7 integrin antagonists, cell adhesion inhibitors, interferon gamma antagonists, ICAM-1, Tumor Necrosis Factor (TNF) antagonists (e.g., infliximab, OR 1384), prostaglandin synthesis inhibitors, budesonide, clofazimine, CNI-1493, CD4 antagonists (e.g., priximab), p38 mitogen-activated protein kinase inhibitors, Protein Tyrosine Kinase (PTK) inhibitors, IKK inhibitors and therapeutic agents for the treatment of irritable bowel syndrome (e.g., zelmac and Maxi-K opener as disclosed, for example, in U.S. patent No. 6,184,231).

Examples of suitable anxiolytics for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone, oxazepam and hydroxyoxazine pamoate.

Examples of suitable antidepressants for use in combination with the compounds of the present invention include citalopram, fluoxetine, nefazodone, sertraline and paroxetine.

Examples of suitable antihypertensive agents for use in combination with the compounds of the invention include beta adrenergic blockers, calcium channel blockers (L-and T-forms; e.g., diltiazem, verapamil, nifedipine, amlodipine and mibefradil (mybefradei)), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, methylchlorothiazide, trichlorthiazide, polythiazide, benthiazide, ethacrynafen (tricrynafen), chlorthalidone, furosemide, mozamide (musolimine), bumetanide, triamcinolone (triamtrene), amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril (ceranopril), cilazapril, delapril, topril, quinapril, ramipril (cilazapril), tranapril, and the like), Lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., stastastaxsentan (sitaxsentan), atrasentan (atrsentan), and the compounds disclosed in U.S. patent nos. 5,612,359 and 6,043,265, Dual ET/AII antagonists (e.g., the compounds disclosed in WO 00/01389), Neutral Endopeptidase (NEP) inhibitors, vasopeptidase inhibitors (Dual NEP-ACE inhibitors) (e.g., omatra and gimera), and nitrates.

Examples of suitable antiplatelet agents for use in combination with the compounds of the present invention include GPIIb/lIIa blockers (e.g., abciximab, eptifibatide, tirofiban), P2Y12 antagonists (e.g., clopidogrel, ticlopidine, CS-747), thromboxane receptor antagonists (e.g., ifetroban), aspirin, and PDE-III inhibitors with or without aspirin (e.g., dipyridamole).

Examples of suitable cardiac glycosides for use in combination with the compounds of the invention include digitalis and ouabain.

Examples of suitable cholesterol/lipid lowering agents for use in combination with the compounds of the invention include HMG-CoA reductase inhibitors [ e.g., pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (also known as ivastatin, or Nivastatin ] and ZD-4522 (also known as rosuvastatin, or atorvastatin, or visastatin) ], squalene synthetase inhibitors, clofibrate, bile acid sequestrants, ACAT inhibitors, MTP inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors and cholesteryl ester transfer protein inhibitors (e.g., CP-941524).

Examples of suitable mineralocorticoid receptor antagonists for use in combination with the compounds of the present invention include spironolactone and prilone (eplerenone).

Examples of suitable phosphodiesterase inhibitors for use in combination with the compounds of the invention include PDE III inhibitors such as cilostazol and PDE V inhibitors such as sildenafil.

Examples of suitable thyroid analogs for use in combination with the compounds of the present invention include thyrotropin, polymethine (polythyloid), KB-130015 and dronedarone.

Examples of suitable alkylating agents for use in combination with the compounds of the present invention include testosterone and SARMs.

Examples of suitable therapeutic agents for HIV or AIDS for use in combination with the compounds of the present invention include indinavir sulfate, saquinavir mesylate, amprenavir, ritonavir, lopinavir, ritonavir/lopinavir combinations, lamivudine, zidovudine, lamivudine/zidovudine combinations, zalcitabine, didanosine, stavudine, and megestrol acetate.

Examples of suitable therapeutic agents for use in combination with the compounds of the present invention for the treatment of alzheimer's disease and cognitive disorders include donepezil, tacrine, rivastigmine, 5HT6, gamma secretase inhibitors, beta secretase inhibitors, SK channel blockers, Maxi-K blockers and KCNQs blockers.

Examples of suitable therapeutic agents for the treatment of sleep disorders in combination with the compounds of the present invention include melatonin analogs, melatonin receptor antagonists, ML1B agonists, and GABA/NMDA receptor antagonists.

Examples of suitable antiproliferative agents for use in combination with the compounds of the present invention include cyclosporin A, taxol, FK506, and doxorubicin.

Examples of suitable antineoplastic agents for use in combination with the compounds of the present invention include taxol, doxorubicin, epothilone, cisplatin and carboplatin.

Examples of suitable selective estrogen receptor modulators for use in combination with the compounds of the present invention include tamoxifen and raloxifene.

Examples of suitable selective androgen receptor modulators for use in combination with the compounds of the present invention include the selective androgen receptor modulators disclosed in Edwards, J.P. et al, Bio.Med.chem.Let.,9, 1003-.

Examples of suitable bisphosphonates for combination with a compound of the invention include MK-217 (alendronate).

When used in combination with the compounds of the present invention, the other therapeutic agents described above may be used in amounts such as those indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

In a preferred embodiment, the compounds of the invention are used in the form of medicaments for the treatment and/or prophylaxis of the above-mentioned physiological and/or pathophysiological conditions, wherein such medicaments comprise as further pharmacologically active substance an endocannabinoid receptor antagonist, preferably a CB1 receptor antagonist, most preferably rimonabant (5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide monohydrochloride; CAS registry No. 158681-13-1; SR-141716A; U.S. Pat. No. 5,624,941) and a GHS-R antagonist as a compound of the invention.

In another preferred embodiment, the compounds of the invention are used in the form of a medicament for the treatment and/or prophylaxis of the above-mentioned physiological and/or pathophysiological conditions, wherein the medicament is applied before and/or during and/or after the treatment with at least one further pharmacologically active substance, wherein such further pharmacologically active substance is an endocannabinoid receptor antagonist, preferably a CB1 receptor antagonist, most preferably rimonabant (5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide monohydrochloride; CAS registry No. 158681-13-1; SR-141716A; U.S. Pat. No. 5,624,941), and the compounds of the present invention are GHS-R antagonists.

The compounds of the invention can be administered in a known manner. The route of administration may thus be any route effective to transport the active compound to the appropriate or desired site of action, for example oral or non-oral, in particular topical, transdermal, pulmonary, rectal, intravaginal, nasal or parenteral or by implantation. Oral administration is preferred.

The compounds of the invention are converted into an administrable form and, where appropriate, mixed with a pharmaceutically acceptable carrier or diluent. Suitable excipients and carriers are described, for example, in Ullman's encyclopedia of Technical Chemistry, Vol.4, (1953), 1-39; journal of pharmaceutical Sciences, vol.52(1963),918et seq; Czetsch-Lindenwald, "Hilfsstuff fur Pharmazie and angrenzendenGebiete"; pharm. Ind.2,1961,72et seq.; Dr.H.P.Fiedler,, Lexikon derHilfsstuffe fur Pharmazie, Kosmetik and angrenzende Gebiete ", CantorKG, Aulendorf Turttemberg, 1971.

Oral administration can be carried out in solid form, for example as tablets, capsules, gel capsules, coated tablets, granules or powders, but also in the form of drinkable solutions. The compounds of the invention can be used for oral administration in combination with the following physiologically tolerable excipients and carriers known and commonly used: for example, acacia, talc, starch, sugars such as mannitol, methyl cellulose, lactose, gelatin, surfactants, magnesium stearate, cyclodextrins, aqueous or non-aqueous carriers, diluents, dispersing agents, emulsifying agents, lubricants, preservatives, and flavoring agents (e.g., essential oils). The compounds of the invention may also be dispersed in, for example, microparticles of nanoparticle compositions.

Non-oral administration can be carried out, for example, by intravenous, subcutaneous, intramuscular injection of sterile aqueous or oily solutions, suspensions or emulsions, by implants or by ointments, creams or suppositories. It is also possible, where appropriate, to administer the compounds in sustained-release form. The implant may contain an inert material, such as a biodegradable polymer or a synthetic silicone, such as silicone rubber. Intravaginal administration may be through, for example, a vaginal ring. Intrauterine administration may be by way of example a septum or other suitable intrauterine device. Also provided is transdermal administration, in particular by means of a formulation suitable for this purpose and for a suitable method, for example a patch.

The dosage may vary within wide limits depending on the type and/or severity of the physiological and/or pathophysiological condition, the mode of administration, the age, sex, weight and sensitivity of the subject to be treated. It is within the ability of the skilled person to determine the "pharmacologically effective amount" of the compound of the invention and/or of the additional pharmacologically active substance. Administration can be in a single dose or multiple separate doses.

Suitable unit doses are, for example, from 0.001mg to 100mg of active ingredient, i.e. of at least one compound of the invention, and, where appropriate, of at least one further pharmacologically active substance, per kg of patient body weight.

In another aspect, the present invention relates to a pharmaceutical composition comprising a pharmacologically active amount of at least one triazole compound selected from the group consisting of: compounds 1,2,3,4, 5,6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 and/or 27,

in another aspect, such a pharmaceutical composition may additionally comprise at least one pharmaceutically acceptable carrier and/or excipient, and/or may comprise at least one other pharmacologically active substance.

In a preferred embodiment, such other pharmacologically active substance is an endocannabinoid receptor antagonist, preferably a CB1 receptor antagonist, most preferably rimonabant [5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide monohydrochloride ].

In the case of the pharmaceutical compositions of the present invention, at least one triazole compound as listed above is present in a pharmacologically effective amount, preferably in a unit dose, for example the unit dose mentioned above, and particularly and preferably in an administration form which makes oral administration possible. Furthermore, reference is made to the already cited documents with regard to the possible use and administration of the compounds according to the invention.

GHS-R1a receptor assay

Mouse LTK-cells (ATCC CCL-1.3) were stably transfected with a plasmid containing the CMV minimal promoter (CMVmin) linked to 3 CAMP Response Elements (CRE) followed by a luciferase reporter gene. Based on this mother cell line, single cell clones of stably overexpressed human, rat or mouse GHS-R1A have been established and characterized for suitability of the different test formats.

For receptor competitive binding studies, iodinated ghrelin was used as a tracer under conditions of approximately 80% saturation binding. Tracer shift (displacement) of the different concentrations of the test compound was analysed. For this purpose, the mixture of intact cells plus tracer and the suspension of the different concentrations of the test compound are placed on top of silicon/liquid paraffin, incubated for 60 minutes at 37 ℃ and centrifuged. After freezing in liquid nitrogen, the cell pellet was separated from the supernatant by cutting a tube into the middle silica/liquid paraffin fraction and analyzed by gamma-radiation analysis. The amount of non-specific binding was determined by including a final concentration of 1 μ M of unlabeled ghrelin.

For the CRE/Luc reporter assay, mouse LTK-cells stably expressing human GHS-1RA and a luciferase reporter and CMV minimal promoter were incubated with 1 μ M rolipram in the presence of different concentrations of AEZS-130 for 6 hours under control of the CRE element. Subsequently, cells were lysed and ATP bioluminescence was measured in luminescence mode on FlexStation3(Molecular Devices).

To determine calcium release, each cell line was filled into a Fluo-4NW calcium test kit (molecular Probes/Invitrogen # F10741) at 37 ℃ over 80 minutes. After a 15 minute pre-incubation with different concentrations of assay compounds, ghrelin was added and the signal was monitored by a FlexStation3 microplate reader (Molecular Devices) for 60 seconds.

All data were calculated as% inhibition based on cells treated with saturating concentrations of ghrelin (NeoMPS # sc1357) as negative control (0% inhibition) and untreated cells as positive control (100%). Will IC₅₀Values were determined using the GraphPad Prism analytical program (GraphPad Software).

In the following Table 1, the results obtained for selected compounds of the invention are shown in comparison with those of compound 50 disclosed in WO 07/020013. The values given are the average of up to 9 independent tests performed in a single measurement or in 2 (binding) or 4 (functional test) repetitions of the measurement.

Table 1: tables 1A and 1B, shown on the lower two pages, are the average IC of ghrelin antagonistic activity of selected compounds against ghrelin receptors in human, rat and mouse₅₀The value is obtained.

Displayed in boldIC of ghrelin receptor of₅₀Value ratios of the respective IC's obtained for Compound 50 disclosed in WO07/020013₅₀The value improved by at least 3 times.

TABLE 1A

TABLE 1B

Evaluation of in vitro safety

For the determination of MDR-1 (P-glycoprotein, Pgp) ATPase activity, a commercially available membrane preparation of MDR-1 overexpressing SF9 insect cells (SB-MDR1-Sf 9-ATPase membrane; 2,5 mg/500. mu.L; Solvo/tebu-bio #168SB-MDR1-Sf 9-ATPase) was used. Since transport by MDR-1 is ATP dependent, ATP depletion indicates the transport activity of MDR-1. By using Pgp-Glo^TMA test kit (Promega # V3591) detects ATP depletion as a decrease in luminescence from a secondary reaction with recombinant firefly luciferase.

Predictor^TMhERG fluorescence polarization Assay (Invitrogen, Karlsruhe, GER) determines whether compounds are assayed to block hERG channels [ Piper, D.R. et al, Assay Drug DevTechnol.2008, 6(2):213-23]. The assay uses a protein containing the hERG channel (Predictor)^TMhERG membrane) and a high affinity red fluorescent hERG channel ligand, or "tracer" (Predictor) based on a homogeneous Fluorescence Polarization (FP) format^TMhERG TracerRed). Compounds that bind to hERG channel proteins (competitors) are identified by their ability to translocate the tracer resulting in lower fluorescence polarization. The test was conducted according to the manufacturer's instructions.

Direct and metabolic-dependent inhibition of CYP enzymes was evaluated in human liver microsomes by HPLC-based UV assay methods with specific marker substrates. Incubate 2 times at a final concentration of 0.01. mu.M to 200. mu.M(30 min, 37 ℃ C.). Metabolic-dependent inhibition was assessed by incubation in the presence of NADPH for 30 minutes prior to addition of the marker substrate to allow metabolite production. Plotting percent inhibition versus concentration to calculate or infer IC from sigmoidal curves₅₀The value is obtained.

Table 2: tables 2A and 2B shown on the lower two pages are the EC for the in vitro safety parameters₅₀The result was inhibition of the human transporter MDR-1(Pgp), the hERG cardiac channel, and the CYP3A4 enzyme.

The results, depicted in bold letters, are improved at least 2-fold over the respective results obtained for compound 50 disclosed in WO 07/020013.

TABLE 2A

TABLE 2B

In vitro microsomal stability and Permeability (CaCo-2 cells)

The metabolic stability at 37 ℃ over time in different types of liver microsomes (1 mg/ml microsome protein in the presence of NADPH) was evaluated in 3 replicates at a 10. mu.M assay concentration. The loss of the parent compound was measured by a HPLC-based UV determination method. For the prediction of liver clearance in rats, the first order rate constant k (min) is obtained from the slope of the time vs% residual^-1) To fit the half-life (t)_1/2). In vitro CL was calculated using half-life by using the following rat scaling factors_intAnd predicting liver clearance in rats: 44.8mg microsomal protein/g liver, 40g liver weight per kg body weight, 55.2 ml/min/kg liver blood flow.

For the CaCo-2 permeability test, 80.000CaCo-2 cells (ATCC HTB-37) were seeded in DMEM supplemented with 10% FCS, 1% penicillin/streptomycin, and 1% non-essential amino acids per 24-well transwell plate (Corning3397) and grown for 21 days by changing the medium every 2 days. On day 21, the medium was replaced with HBSS buffer supplemented with 0.25% and 1% BSA (Invitrogen #14065) for donor and recipient chambers, respectively. The compound was added to each donor compartment at a concentration of 3. mu.M or 5. mu.M and incubated at 37 ℃ for 2 hours. The concentration of each compound was determined by LC-MS analysis using API 2000. Data analysis was performed as described in Sun and Pang2008, Drug Metabolism and dispensing 36, 102- & 123.

Table 3: tables 3A and 3B, shown on the lower two pages, are the results of the in vitro stability assessment of the residual% of the compound after 1 hour incubation with human liver microsomes, as well as the intestinal permeability predicted by measuring the flux of the compound through the CaCo-2 cell layer.

The results, depicted in bold letters, are improved at least 2-fold over the respective results obtained for compound 50 disclosed in WO 07/020013.

TABLE 3A

TABLE 3B

Claims (24)

1. A compound selected from:

compound 1: [5- { (R) -2- (1H-indol-3-yl) -1- [ (pyridine-3-carbonyl) -amino ] -ethyl } -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -acetic acid ethyl ester;

compound 3: pyridine-2-carboxylic acid [ (R) -1- [5- [ (R) -1-acetylamino-2- (1H-indol-3-yl) -ethyl ] -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -amide;

compound 4: pyridine-2-carboxylic acid [ (R) -1- [5- ((R) -1-acetylamino-2-phenyl-ethyl) -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -amide;

compound 5: pyridine-2-carboxylic acid [ (R) -1- [5- ((R) -1-formylamino-2-phenyl-ethyl) -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -amide;

compound 6: n- [ (R) -1- [5- ((R) -1-acetylamino-2-phenyl-ethyl) -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -2-hydroxy-acetamide;

compound 7: (S) -morpholine-2-carboxylic acid [ (R) -1- [5- ((R) -1-acetylamino-2-phenyl-ethyl) -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -amide;

compound 8: n- [ (R) -1- [5- [ (R) -1-acetylamino-2- (1H-indol-3-yl) -ethyl ] -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -2-amino-2-methyl-propionamide;

compound 9: 2-amino-N- [ (R) -1- [5- [ (R) -1-carboxamido-2- (1H-indol-3-yl) -ethyl ] -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -2-methyl-propionamide;

compound 10: n- [ (R) -1- [5- ((R) -1-acetylamino-2-phenyl-ethyl) -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2- (1H-indol-3-yl) -ethyl ] -2-amino-2-methyl-propionamide;

compound 15: { (R) -1- [5- [2- (1H-indol-3-yl) -ethyl ] -4- (4-methoxy-benzyl) -4H- [1,2,4] triazol-3-yl ] -2-naphthalen-2-yl-ethyl } -carbamic acid tert-butyl ester;

compound 16: 1- { (R) -2- (1H-indol-3-yl) -1- [4- (4-methoxy-benzyl) -5-phenethyl-4H- [1,2,4] triazol-3-yl ] -ethyl } -3-isopropyl-urea;

compound 17: { (R) -2- (1H-indol-3-yl) -1- [4- (4-methoxy-benzyl) -5-phenethyl-4H- [1,2,4] triazol-3-yl ] -ethyl } -isobutyl carbamate;

compound 18: { (R) -2- (1H-indol-3-yl) -1- [4- (4-methoxy-benzyl) -5-phenethyl-4H- [1,2,4] triazol-3-yl ] -ethyl } -carbamic acid tert-butyl ester;

compound 19: 1-benzyl-3- { (R) -2- (1H-indol-3-yl) -1- [4- (4-methoxy-benzyl) -5-phenethyl-4H- [1,2,4] triazol-3-yl ] -ethyl } -urea;

and physiologically tolerable salts thereof.

2. A pharmaceutical composition comprising a pharmacologically active amount of at least one compound as claimed in claim 1.

3. The pharmaceutical composition according to claim 2, wherein the active ingredient is present in a unit dose of 0.001mg to 100mg per kilogram body weight of the patient.

4. The pharmaceutical composition according to claim 2, wherein the composition further comprises at least one pharmaceutically acceptable carrier and/or excipient.

5. The pharmaceutical composition according to any one of claims 2 to 4, wherein the composition comprises at least one additional pharmacologically active substance.

6. The pharmaceutical composition according to claim 5, wherein the additional pharmacologically active substance is an endocannabinoid receptor antagonist.

7. The pharmaceutical composition according to claim 5, wherein the additional pharmacologically active substance is a CB1 receptor antagonist.

8. The pharmaceutical composition according to claim 5, wherein the additional pharmacologically active substance is rimonabant [5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide monohydrochloride ].

9. Use of a compound according to claim 1 or a pharmaceutical composition according to any one of claims 2 to 8 for the preparation of a medicament for the treatment or prevention of a physiological and/or pathophysiological condition mediated by a GHS receptor selected from the group consisting of GHS-R1a and GHS-R1b in a mammal.

10. The use according to claim 9, wherein the treatment is effected by modulation of the GHS receptor.

11. The use of claim 9, wherein the compound is a GHS receptor antagonist.

12. The use according to claim 11, wherein the GHS receptor antagonist is selected from the group consisting of: compounds 1, 3,4, 5,6, 7, 8, 9,10, 15, 16, 17, 18 and 19.

13. The use according to claim 12, wherein the mammal is selected from the group consisting of humans, livestock, pets.

14. The use of claim 12, wherein the mammal is selected from the group consisting of a pony.

15. The use of claim 12, wherein the mammal is selected from the group consisting of cattle, sheep, pigs, goats, horses, donkeys, mules, hares, rabbits, cats, dogs, guinea pigs, hamsters, rats, mice.

16. The use of claim 12, wherein the mammal is selected from cows, donkeys.

17. The use according to any one of claims 13-16, wherein the physiological and/or pathophysiological condition is selected from the group consisting of acute fatigue syndrome and muscle loss after elective surgery, lipogenesis, adiposity, age-related decline in thymus function, age-related decline in function in the elderly, ageing disorders in companion animals, alcohol-related disorders, alzheimer's disease, anorexia associated with cachexia or ageing; anxiety, reduced blood pressure, weight gain/reduction, accelerated fracture repair, stimulation of bone remodeling, decreased cachexia and protein loss due to a chronic disease selected from cancer or AIDS, cardiac dysfunction associated with valvular disease, myocardial infarction, cardiac hypertrophy, or congestive heart failure, cardiomyopathy, stimulation of cartilage growth, catabolic disorders associated with pulmonary dysfunction and respiratory dependency, catabolic side effects of glucocorticoids, catabolic states of aging, central nervous system disorders in combination with antidepressants, chronic dialysis, chronic fatigue syndrome, improvement of cognitive function in dementia, complex fracture stretch-osteogenesis, complications associated with transplantation, congestive heart failure alone/in combination with corticotropin releasing factor antagonists, cushiki syndrome, dementia, depression, ng's syndrome, diabetes mellitus, drug abuse, short, medium and/or long term regulation of energy balance, short, medium and/or long term stimulation and/or inhibition of food intake, reward for food intake, weakness in the elderly, gastrectomy in combination with ghrelin replacement therapy, improvement of glycemic control, stimulation of growth hormone release in the elderly, growth hormone replacement in stressed patients, growth promotion in livestock, growth retardation, hair/nail/toenail growth maintenance, hip fracture, hunger, hypercortisolism including islet cell proliferation, hypothermia, immunodeficiency in individuals with reduced T4/T8 cell rates, improvement of immune response to vaccination, stimulation of the immune system, immunosuppression in immunosuppressed patients, inflammation or inflammatory effects, prevention of cancer development, cancer progression, cancer, Insulin resistance including NIDDM, diabetes, intrauterine growth retardation, irritable bowel syndrome, HIV-induced lipodystrophy, metabolic homeostasis maintenance, increased milk production in livestock, increased muscle mass/strength, improved muscle motility, improved muscle strength, maintained muscle strength/function in the elderly, muscle atrophy, musculoskeletal injury in the elderly, Noonan syndrome, obesity and obesity-related growth retardation, osteoblast stimulation, osteochondral dysplasia, osteoporosis, ovulation induction adjuvant therapy, physical short stature including growth hormone deficient children, post-operative ileus, attenuation of protein catabolic response following major surgery/trauma, enhancement of protein kinase B activity, psychological social deprivation, pulmonary dysfunction and ventilator dependence, improvement of pulmonary function, improvement of lung function, prevention of obesity, and treatment of obesity, Pulsatile growth hormone release induction, recovery of burn patients and reduction of hospitalization promotion in burn patients, renal failure or insufficiency from growth retardation, maintenance of renal homeostasis in frail elderly, sarcopenia, schizophrenia, maintenance of sensory function, short bowel syndrome, short stature associated with chronic disease, skeletal dysplasia, maintenance of skin thickness, sleep disorders, improvement in sleep quality, thrombocytopenia, thymic development stimulation, tooth repair or growth, tumor cell proliferation, ventricular dysfunction or reperfusion events, wasting associated with AIDS, wasting associated with chronic liver disease, wasting associated with chronic obstructive pulmonary disease, wasting associated with multiple sclerosis or other neurodegenerative disorders, wasting following bone fracture, wool growth stimulation in sheep, accelerated wound healing, and/or delayed wound healing.

18. The use according to any one of claims 13-16, wherein the physiological and/or pathophysiological condition is selected from the group consisting of improved cognitive function in alzheimer's disease, postoperative ileus of the stomach, growth retardation associated with Prader-Willi syndrome and Turner syndrome, growth retardation associated with Crohn's disease, stimulation of the immune system in companion animals, insulin resistance in the heart, insulin resistance in type 2 diabetic patients, type I diabetes, type II diabetes, inflammatory bowel disease.

19. The use according to any one of claims 13-16, wherein the physiological and/or pathophysiological condition is selected from the group consisting of maintenance of auditory, visual, olfactory and gustatory function; alcohol-related disorders; drug abuse; growth retardation, cachexia, short, medium and/or long term regulation of energy balance; short, medium and/or long term stimulation and/or inhibition of food intake; intake of reward food; adipogenesis, adiposity, and/or obesity; weight gain and/or loss; diabetes, tumor cell proliferation; inflammation, inflammatory effects, post-operative ileus, and/or gastrectomy in combination with ghrelin replacement therapy.

20. The use according to any one of claims 13-16, wherein the physiological and/or pathophysiological condition is selected from the group consisting of type I diabetes, type II diabetes, postoperative ileus, Crohn's disease, and ulcerative colitis.

21. The use according to any one of claims 13-16, wherein the medicament comprises at least one additional pharmacologically active substance.

22. Use according to claim 21, wherein the medicament comprises a GHS receptor antagonist and rimonabant [5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide monohydrochloride ] as further pharmacologically active substances.

23. The use according to claim 22, wherein the medicament is for use with at least one additional pharmacologically active substance before and/or during and/or after treatment.

24. Use according to claim 23, wherein the medicament comprises a GHS receptor antagonist and the further pharmacologically active substance is rimonabant [5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide monohydrochloride ].