Human growth hormone secretion stimulants

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, in which X is or ; Y is H; Z is -C(O)-; R1 and R3 each independently denotes H or (C1-C4) alkyl; R2 and R4 each independently denotes , , or ; R5 denotes H or (C1-C6) alkyl; R8 and R9 each independently denote (C1-C6) alkyl; and Q is H.

EFFECT: possibility of use in stimulating the growth hormone in a subject based on the said compounds.

49 cl, 2 tbl, 57 ex

 

The prior art inventions

Pulsating release of growth hormone from the somatotroph pituitary is regulated by two hypothalamic hormones: hormone that stimulates growth hormone and somatostatin. Hormone that stimulates growth hormone stimulates the release of growth hormone, while somatostatin inhibits the secretion of growth hormone (Frohman et al., Endocrinology Review, (1986), 7: 223-253 and Strobi et al., Pharmacol. Review, (1994), 46: 1-34).

The release of growth hormone from the somatotroph pituitary can also be controlled by peptides growth hormone (GHRP). The Hexapeptide GHRP, His-D-Trp-Ala-Trp-D-Phe-Lys-amide (GHRP-6), as was found, releases growth hormone somatotroph dozozawisimam way in some species, including humans (Bowers et al., Endocrinology, (1984), 114: 1537-45). Further chemical studies of GHRP-6 has led to the identification of other potent stimulators of GH secretion, such as GHRP-1, GHRP-2 and hexarelin (Cheng et al., Endocrinology, (1989), 124: 2791-8; Bowers, C.Y., Novel GH-Releasing Peptides, Molecular and Clinical Advances in Pituitary Disorders, Ed: Melmed, S., Endocrine Research and Education, Inc., Los Angeles, CA, USA, (1993), 153-7 and Deghenghi et al., Life Science, (1994), 54: 1321-8). The structure of these three stimulators of growth hormone secretion are as follows:

GHRP-1Ala-His-D-(2')-Nal-Ala-Trp-D-Pe-Lys-NH 2;
GHRP-2D-Ala-D-(2')-Nal-Ala-Trp-D-Nal-Lys-NH2; and
hexarelinHis-D-2-MeTrp-Ala-Trp-D-Phe-Lys-NH2.

GHRP-1, GHRP-2, GHRP-6 and hexarelin are synthetic stimulants secretion of growth hormone (hereinafter in this document collectively as “GHS”). GHS stimulate the secretion of growth hormone by a mechanism different from that of the hormone that stimulates growth hormone (Bowers, C.Y. et al., Endocrinology, (1984), 114: 1537-45; Cheng et al., Endocrinology, (1989), 124: 2791-8; Bowers, C.Y., Novel GH-Releasing Peptides, Molecular and Clinical Advances in Pituitary Disorders, Ed: Melmed, S., Endocrine Research and Education, Inc., Los Angeles, CA, USA, (1993), 153-7 and Deghenghi et al., Life Science, (1994), 54: 1321-8).

Low biological activity upon oral application (usually taken as <1%) of these peptidyl-stimulators of GH secretion stimulated the search for ones compounds that mimic the action of GHRP-6 in the pituitary gland. Some benzolactams and pirondini, as described, stimulate the release of growth hormone in various animal species and in humans (Smith et al., Science, (1993), 260: 1640-3; Patchett et al., Proceedings of the National Academy Science USA, (1995), 92: 7001-5; and Chen et al., Bioorganic Medical Chemistry Letter, (1996), 6: 2163-9). A concrete example of such a small spiropentane is MK-0677 (Patchett et al., Proceedings of the National Academy Science USA, (1995), 92: 7001-5), which has digislide the th structure:

.

The steps above GHS (as peptides and dipeptides) manifests itself through the mediation of specific receptor stimulator of growth hormone secretion (hereinafter in this document collectively as “GHS-receptor”) (Howard et al., Science, (1996), 273: 974-7 and Pong et al., Molelular Endocrinology, (1996), 10: 57-61). GHS-receptor found in the glands of the pituitary gland and hypothalamus in different mammalian species (GHSR1a), differs from the receptor hormone that stimulates growth hormone (hereafter in this document referred to as “GHRH-receptor”). GHS-receptor was also detected in other tissues of the Central nervous system and in peripheral tissues such as the adrenal and thyroid glands, as well as heart, lung, kidney and skeletal muscle tissue (Chen et al., Bioorganic Medical Chemistry Letter, (1996), 6: 2163-9; Howard et al., Science, (1996), 273: 974-7 and Pong et al., Molelular Endocrinology, (1996), 10: 57-61; Guan et al., Molecular Brain Research, (1997), 48: 23-9 and McKee et al., Genomics, (1997), 46: 426-34). A shortened version of GHSR1a has also been reported (Howard et al., Science, (1996), 273: 974-7).

GHS-receptor is a G-proteinopathy receptor. The effects of activation of the GHS-receptor include depolarization and inhibition of calcium channels, increasing intracellular concentrations inositoltrifosfata (IP3) and intracellular calcium concentrations, despite intermittent condition for the latter index (Pong et al., Moleluar Endocrinology, (1996), 10: 57-61; Guan et al., Molecular Brain Research, (1997), 48: 23-9 and McKee et al., Genomics, (1997), 46: 426-34).

Ghrelin is a naturally occurring peptide, which is considered to be the endogenous ligand for the GHS-receptor (Kojima et al., Nature, (1999), 402: 656-60). Known natural patterns of ghrelin for various species of mammals and of memleketim (Kaiya et al., Journal of Biological Chemistry, (2001), 276: 40441-8 and international patent application PCT/JP 00/04907 [WO 01/07475]). The Central part of the molecules presented in ghrelin, which is responsible for the observed activity of GHS-receptor. The Central part includes four N-terminal amino acids, in which the serine in the third position is usually modified by n-octanoic acid. In addition to the acylation of n-octane acid, natural ghrelin may also be allerban n-decanoas acid (Kaiya et al., Journal of Biological Chemistry, (2001), 276: 40441-8).

GHS-molecules, such as ghrelin and its analogues, have a number of different therapeutic (Inui, A., FASEB J., (2004), 18: 439-56; Muller et al., Neurobiology of Aging, (2002), 23: 907-19; Casanueva, F.F. et al., TEM, (1999), 10: 30-8, and Ankerson, M. et al., DDT, (1999) 4: 497-506) and diagnostic applications. Were detected compounds exhibiting the actions of agonists on the GHS-receptor, to help stimulate the secretion of growth hormone. Themselves analogs of ghrelin shown to improve the condition of growth hormone deficiency (U.S. patent No. 6861409, U.S. patent No. 6967237 and Casanueva, F.F. et al., TEM, (1999), 10: 30-8), increasing isichei mass (U.S. patent No. 6861409, U.S. patent No. 6967237) and/or physical force (Ankerson, M. et al., DDT, (1999) 4: 497-506), improvement of bone density (U.S. patent No. 6861409 and 6967237, and Sibilia, V. et al., Growth Horm. IGF Res., (1999), 9: 219-27), treatment of osteoporosis (WO 97/24369, WO 98/58947, Casanueva, F.F. et al., TEM, (1999), 10: 30-8), overcoming male and female sexual dysfunction (U.S. patent No. 6967237, Casanueva, F.F. et al., TEM, (1999), 10: 30-8), the treatment of cardiovascular diseases (WO 97/24369, WO 98/58947, U.S. patent No. 6251902, DeGennaro Colonna, V. et al., Eur. J. Pharmacol., (1997), 334: 201-7 and Casanueva, F.F. et al., TEM, (1999), 10: 30-8), easing the pain of arthritis (Granado, M., AJP Endo., (2005), 288: 486-92) and the treatment of systemic erythematous lupus or inflammatory bowel disease (such as Crohn's disease or ulcerative colitis) (patent publication U.S. 2002/0013320). Agonistic analogs of ghrelin may contribute to weight gain (U.S. patent No. 6967237, Tschop, M. et al., Endocrinology, (2002), 143: 558-68), which, in turn, can be used to maintain the desired body weight (U.S. patent No. 6861409 and 6967237) and/or to restore physical function (U.S. patent No. 6967237 and 6251902 and WO 97/24369).

Ghrelin increases appetite (U.S. patent No. 6967237 and Okada, K. et al., Endocrinology, (1996), 137: 5155-8). For this reason, ghrelin is used to treat patients suffering from certain diseases or disorders, or taken medical regimes, which are usually accompanied by unwanted weight loss. Such diseases and Rosstroy the VA include anorexia (U.S. patent No. 6967237; Tschop, M. et al., Endocrinology, (2002), 143: 558-68), bulimia (U.S. patent No. 6967237), cachexia (U.S. patent No. 6967237 and 6251902), especially caused by cancer cachexia (U.S. patent No. 6967237, Tschop, M. et al., Endocrinology, (2002), 143: 558-68), AIDS (U.S. patent No. 6861409 and 6967237, Tschop, M. et al., Endocrinology, (2002), 143: 558-68), wasting syndrome with weakness and/or old age (U.S. patent No. 6861409 and 6967237, WO 97/24369; Ankerson, M. et al., DDT, (1999) 4: 497-506) and chronic renal failure (Casanueva, F.F. et al., TEM, (1999), 10: 30-8). Medical methods of treatment, usually accompanied by weight loss include chemotherapy, radiation therapy, temporary or permanent withdrawal of mobility (immobilization) and/or dialysis (U.S. patent No. 6967237 and 6251902).

Obesity is the most significant risk factor in diabetes, and the majority of patients with non-insulin-dependent diabetes mellitus (otherwise referred to as “NIDDM”) are fat. Both pathological condition characterized by elevated levels of circulating insulin and low levels of GH. It was shown that treatment with GH adult GH-deficient patients (Jorgensen, J.O.L., et al., Lancet, (1989), 1: 1221), fat women (Richelsen, B., et al., Am. J. Physiol, (1994), 266: E211) and older men (Rudman, D., et al., Horm. Res., (1991), 36 (Suppl 1): 73) leads to increases in showevent body, liver and muscle mass, while for fat reduction is observed. Thus, the introduction of AG is nista ghrelin is an acceptable therapy for obesity, except diabetogenic effects GH (U.S. patent No. 6251902; Ankerson, M. et al., DDT, (1999) 4: 497-506; Casanueva, F.F. et al., TEM, (1999), 10: 30-8). Concomitant diabetes disorders such as retinopathy and/or treatable cardiovascular disorders (U.S. patent No. 6967237 published patent application U.S. 2003/0211967), can be indirectly treated with ghrelin as well.

It is ironic that ghrelin antagonists can be used to promote weight loss fat a patient is, in the case where the above-mentioned obesity is not associated with the manifestation of NIDDM (U.S. patent No. 6967237 published patent application U.S. 2003/0211967), and in the case of some other identified symptoms. The compounds exhibiting the actions of the antagonists GHS-receptor, contribute to the suppression of growth hormone secretion, for example, analogs of ghrelin antagonists prescribed for the treatment of excessive secretion of growth hormone (published patent application U.S. 2002/0187938), to promote weight loss patient non-obese individuals (U.S. patent No. 6967237), to maintain an ideal weight and reduce appetite (U.S. patent No. 6967237). Excessive weight is a contributing factor to many diseases and pathological conditions such as hypertension, dyslipidemia and cardiovascular disease (published patent application U.S. 2003/0211967; U.S. patent No. 6967237), as well as gall stones, osteoarthritis (Pat the t U.S. No. 6967237), some types of cancer (published patent applications U.S. 2003/0211967 and 2004/0157227, U.S. patent No. 6967237) and Prader-Willi syndrome (U.S. patent No. 6950707). The antagonists of ghrelin to promote weight loss, therefore, will be useful to reduce the likelihood of such diseases or pathological conditions and/or may be useful, at least as an integral part of the treatment of such diseases or pathological conditions.

Analogues stimulators of GH secretion is also used to cause gastrointestinal contractility, especially in patients with decreased gastrointestinal contractile ability in the postoperative intestinal obstruction or gastroparesis, collateral attack diabetes or chronic diabetes (U.S. patent No. 6548501).

Given the wide variety of therapeutic effects of stimulants secretion of growth hormone, you should pay attention that there is a need, in accordance with the development level of technology in effective agonists or antagonists GHS-molecules.

The invention

The present invention describes peptidyl analogs active against GHS-receptor. Analogs of the invention can be contacted with the GHS-receptor and, preferably, to cause the transmission of the signal. Thus, in the first speaker is the subject of the present invention describes a connection, corresponding to the formula (I):

where X represents a

,or;

Y represents N or NR12R13;

Z represents-C(O)- or-SO2-;

n is, independently from each other, for each case, 1, 2, 3, 4, 5, 6, 7 or 8;

R1and R3each, independently of one another, in each case represents H or (C1-C4)alkyl;

R2and R4each, independently of one another, for each case, is a

,,or;

R5represents H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, substituted (C1-C6)alkyl, substituted (C2-C6)alkenyl, substituted (C2-C6)quinil, aryl, alkylaryl, alkylaromatic or arylalkylamine;

R8and R9each, independently of one another, for each case, is a (C1-C6)alkyl or substituted (C1-C6)alkyl;

R6, R7, R10, R11, R12and R13each, independently of one another, in each case represents H, (C1-C6)alkyl or replacement of the seal (C 1-C6)alkyl; and

Q represents H or(C1-C4)alkyl;

provided that each of R2and R4is notin the specified connection;

or its pharmaceutically acceptable salt.

A preferred group of compounds of the above formula represents an area where at least one of R2and R4represents a

.

A preferred compound of formula (I) or its pharmaceutically acceptable salt, called compound group 1, is a compound corresponding to the formula (I), where:

R2represents;

R4represents;

Z represents-C(O)-;

X representswhere R6and R7each, independently of one another, represent H, and R8and R9each, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13independently from each other represents H;

R1represents N;

R3PR is dstanley a H or methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

A preferred compound of formula (I) or its pharmaceutically acceptable salt of the titled compound of group 1A, is a compound corresponding to the formula (I), where:

R2represents;

R4represents;

Z represents-SO2-;

X representswhere R6and R7each, independently of one another, represent H, and R8and R9each, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13independently from each other represents H;

R1represents N;

R3represents H or methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

The most preferred compounds of group 1 or group 1A are:

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and

or their pharmaceutically acceptable salt.

A preferred compound of formula (I) or its pharmaceutically acceptable salt, called compound group 2, is a compound corresponding to the formula (I), where:

R2represents;

R4representsor;

Z represents-C(O)-;

X representswhere R6and R7each, independently of one another, represent H, and R8and R9each, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13independently from each other represents H;

R1represents N;

R3represents H or methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

R2represents;

R4representsor;

Z represents-SO2-;

X representswhere R6and R7each, independently of one another, represent H, and R8and R9each, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13independently from each other represents H;

R1represents N;

R3represents H or methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

The most preferred compounds of group 2 or group 2A are:

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or their pharmaceutically acceptable salt.

A preferred compound of formula (I) or its pharmaceutically acceptable salt, called compound group 3, is a compound corresponding to the formula (I), where:

R2represents;

R4representswhere Q represents N;

Z represents-C(O)-;

X representswhere R6and R7each, independently of one another, represent H, and R8and R9each, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13independently from each other represents H;

R1represents N;

R3represents H or methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

A preferred compound of formula (I) or its pharmaceutically acceptable salt, called connection group 3A, is the unity, corresponding to the formula (I), where:

R2represents;

R4representswhere Q represents N;

Z represents-SO2-;

X representswhere R6and R7each, independently of one another, represent H, and R8and R9each, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13independently from each other represents H;

R1represents N;

R3represents H or methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

The most preferred compounds of group 3 or group 3A are:

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and

or their pharmaceutically acceptable salt.

A preferred compound of formula (I) or its pharmaceutically acceptable salt of the titled compound of group 4, is a compound corresponding to the formula (I), where:

R2representsor;

R4represents;

Z represents-C(O)-;

X representswhere R6and R7each, independently of one another, represent H, and R8and R9each, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13independently from each other represents H;

R1represents N;

R3represents H or methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

A preferred compound of formula (I) or its pharmaceutically acceptable salt, called connection group 4A, is a compound corresponding to the ormula (I), where:

R2representsor;

R4represents;

Z represents-SO2-;

X representswhere R6and R7each, independently of one another, represent H, and R8and R9each, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13independently from each other represents H;

R1represents N;

R3represents H or methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

The most preferred compounds of group 4 or group 4A are:

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and

or their pharmaceutically acceptable salt.

A preferred compound of formula (I) or its pharmaceutically acceptable salt, called connection group 5, is a compound corresponding to the formula (I), where:

R2representswhere Q represents N;

R4represents;

Z represents-C(O)-;

X representswhere R6and R7each, independently of one another, represent H, and R8and R9each, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13independently from each other represents H;

R1represents N;

R3represents H or methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

A preferred compound of formula (I) or its pharmaceutically acceptable salt, called connection group 5A, is a compound corresponding to the formula (I), where:

R2represents where Q represents N;

R4represents;

Z represents-SO2-;

X representswhere R6and R7each, independently of one another, represent H, and R8and R9each, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13independently from each other represents H;

R1represents N;

R3represents H or methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

The most preferred compounds of group 5 or group 5A are:

,

,

,

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,

and

or their pharmaceutically acceptable salt.

A preferred compound of formula (I) or its pharmaceutically acceptable salt, called connection group 6, is a compound corresponding to the formula (I), where:

R2predstavljaet a or;

R4representsor;

Z represents-C(O)-;

X representswhere R6and R7each, independently of one another, represent H, and R8and R9each, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13independently from each other represents H;

R1represents N;

R3represents H or methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

A preferred compound of formula (I) or its pharmaceutically acceptable salt, called connection group 6A, is a compound corresponding to the formula (I), where:

R2representsor;

R4representsor;

Z represents-SO2-;

X representswhere R6and R7each, independently of one another, not only is em a N, and R8and R9each, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13independently from each other represents H;

R1represents N;

R3represents H or methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

The most preferred compounds of group 6 or group 6A are:

,

,

and

or their pharmaceutically acceptable salt.

A preferred compound of formula (I) or its pharmaceutically acceptable salt, called connection group 7, is a compound corresponding to the formula (I), where:

R2representsor;

R4representswhere Q represents N;

Z represents-C(O)-;

X representswhere R6and R7each, independently of one another, represent H, and R8and R9each is, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13independently from each other represents H;

R1represents N;

R3represents H or methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

A preferred compound of formula (I) or its pharmaceutically acceptable salt, called connection group 7A, is a compound corresponding to the formula (I), where:

R2representsor;

R4representswhere Q represents N;

Z represents-SO2-;

X representswhere R6and R7each, independently of one another, represent H, and R8and R9each, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13that is ezavisimo from each other, represents N;

R1represents N;

R3represents H or methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

The most preferred compounds of group 7 or group 7A are:

and

or their pharmaceutically acceptable salt.

A preferred compound of formula (I) or its pharmaceutically acceptable salt of the titled compound of a group 8, is a compound corresponding to the formula (I), where:

R2representswhere Q represents N;

R4representsor;

Z represents-C(O)-;

X representswhere R6and R7each, independently of one another, represent H, and R8and R9each, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13independently from each other represents H;

R1represents N;

R3represents N is whether methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

A preferred compound of formula (I) or its pharmaceutically acceptable salt, called connection group 8A, is a compound corresponding to the formula (I), where:

R2representswhere Q represents N;

R4representsor;

Z represents-SO2-;

X representswhere R6and R7each, independently of one another, represent H, and R8and R9each, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13independently from each other represents H;

R1represents N;

R3represents H or methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

The most preferred compounds of group 8 or group 8A are:

and

or their pharmaceutically acceptable salt.

Another Avenue is doctitle compound of formula (I), named group 9, is a compound corresponding to the formula:

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or its pharmaceutically acceptable salt.

The pharmaceutical composition containing the compound directly above group of compounds with a pharmaceutically acceptable carrier, is preferred.

repectfully connection group 9 is the connection group 9A, corresponding to the formula:

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or its pharmaceutically acceptable salt.

The pharmaceutical composition containing the compound directly above group of compounds with a pharmaceutically acceptable carrier, is preferred.

The preferred connection group 9A is a connection group 9B corresponding to the formula:

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or its pharmaceutically acceptable salt.

The pharmaceutical composition containing the compound directly above group of compounds with a pharmaceutically acceptable carrier, is p impactfully.

The preferred connection group 9A is a connection group 9C corresponding to the formula:

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and

or its pharmaceutically acceptable salt.

The pharmaceutical composition containing the compound directly above group of compounds with a pharmaceutically acceptable carrier, is preferred.

The preferred connection group 9A is a connection group 9D corresponding to the formula:

,

and

or its pharmaceutically acceptable salt.

The pharmaceutical composition containing the compound directly above group of compounds with a pharmaceutically acceptable carrier, is preferred.

The preferred connecting groups 9D is a connection group 9E corresponding to the formula:

or its pharmaceutically acceptable salt.

The pharmaceutical composition containing the compound directly above group of compounds with a pharmaceutically acceptable carrier, is preferred.

The preferred compound of group 9 are the two what is the connection group 9F, corresponding to the formula:

and

or its pharmaceutically acceptable salt.

The pharmaceutical composition containing the compound directly above group of compounds with a pharmaceutically acceptable carrier, is preferred.

The preferred compound of group 9 is the connection group 9G corresponding to the formula:

,

and

or its pharmaceutically acceptable salt.

The pharmaceutical composition containing the compound directly above group of compounds with a pharmaceutically acceptable carrier, is preferred.

In the second aspect of the present invention describes a compound of formula (II):

where X represents a

,or;

Y represents N or NR12R13;

Z represents-C(O)- or-SO2-;

n is, independently from each other, for each case, 1, 2, 3, 4, 5, 6, 7 or 8;

R1and R3each, independently of one another, in each case represents H or (C1-C4)alkyl;

R2and R4each, independently of the other the other, for each case, is a

,,or;

R5represents H or (C1-C6)alkylhalides;

R8and R9each, independently of one another, for each case, is a (C1-C6)alkyl or substituted (C1-C6)alkyl;

R6, R7, R10, R11, R12and R13each, independently of one another, in each case represents H, (C1-C6)alkyl or substituted (C1-C6)alkyl; and

Q represents H or(C1-C4)alkyl;

provided that each of R2and R4is notin the specified connection;

or its pharmaceutically acceptable salt.

A preferred compound of formula (II) or its pharmaceutically acceptable salt, called connection groups 10, is a compound corresponding to the formula (II), where:

R2represents;

R4representswhere Q represents N;

Z represents-C(O)-;

X representswhere R6and R7each, independently of one another, represent H, is R 8and R9each, independently from each other represents CH3; or

X representswhere Y represents N; or

X representswhere Y represents NR12R13and each of R12and R13independently from each other represents H;

R1represents N;

R3represents H or methyl and

R5represents H, methyl, ethyl, isopropyl or tert-butyl.

The most preferred compound of group 10, called the group 10A is:

or its pharmaceutically acceptable salt.

The pharmaceutical composition containing the compound directly above group of compounds with a pharmaceutically acceptable carrier, is preferred.

Compounds of the invention are active against GHS-receptor. Compounds can be contacted with the receptor and preferably to stimulate receptor activity, thus, the connection of the invention is useful as a functional analog of ghrelin and as a research tool and/or as a therapeutic agent. Use as a research tool typically includes the use of compounds of the invention and the presence of GHS-receptor or its fragment GHS-receptor can be represented in different environments, such as a mammal creature, a cell or fragment of the cell membrane. Examples of use as a research tool include screening compounds to the GHS-receptor, determining the presence of GHS-receptor in a sample or preparation and verification of the role or effect of ghrelin.

One aspect of the invention shows a method of determining the ability of the compound to contact the GHS-receptor, the method includes a step of measuring the ability of the compound to effective binding to compounds corresponding to formula (I) or formula (II), or corresponding to any one of groups 1, 1A, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, 8A, 9, 9A, 9B, 9C, 9D, 9E, 9F, 9G, 10 and 10A to the specified receptor, a fragment of a specified receptor to the polypeptide comprising the specified fragment or specified receptor, or a derivative of the specified polypeptide.

Another aspect of the invention shows a method of screening ghrelin agonists and/or antagonists of ghrelin. Screening for agonists of the ghrelin may be, for example, through the use of compounds corresponding to formula (I) or formula (II), or corresponding to any one of groups 1, 1A, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, 8A, 9, 9A, 9B, 9C, 9D, 9E, 9F, 9G, 10 and 10A, or their pharmaceutically acceptable salts in the competitive binding experiment with the control compounds. The screen is ng ghrelin antagonists can be carried out, for example, through the use of compounds corresponding to formula (I) or formula (II), or corresponding to any one of groups 1, 1A, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, 8A, 9, 9A, 9B, 9C, 9D, 9E, 9F, 9G, 10 and 10A, or their pharmaceutically acceptable salts to stimulate the activity of GHS-receptor, and then measuring the ability of the control connection to alter the activity of GHS-receptor.

Agonists of the ghrelin can be used to achieve therapeutic effect in the subject. For example, ghrelin triggers the release of growth hormone from a primary culture of pituicytes dozozawisimam way, without stimulating the release of other pituitary hormones. Ghrelin injected intravenously shot rats stimulates pulsating release of growth hormone (Kojima et al., Nature, (1999), 402: 656-60). In one aspect, the invention shows a method of achieving a therapeutic effect in a subject, comprising the introduction of a specified subject an effective amount of a compound corresponding to the formula (I) or formula (II), or corresponding to any one of groups 1, 1A, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, 8A, 9, 9A, 9B, 9C, 9D, 9E, 9F, 9G, 10 and 10A, or their pharmaceutically acceptable salts, which the specified amount effective to produce a therapeutic effect by promoting the treatment or contributing to the prevention of diseases, ailments or pathologizes the condition. What is meant by "assisted treatment", is either a cure for a particular disease or disorder, or reducing the severity of symptoms of a particular disease or disorder. What is meant by "promoting prevention", is either reduce the probability of occurrence of a certain disease or disorder, or reducing the severity of symptoms of a particular disease or disorder.

In another aspect, the invention shows a method of stimulation of growth hormone secretion in a subject in case of need of such stimulation, comprising the stage of introduction to the subject an effective amount of a ghrelin agonist, corresponding to the formula (I) or formula (II), or corresponding to any one of groups 1, 1A, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, 8A, 9, 9A, 9B, 9C, 9D, 9E, 9F, 9G, 10 and 10A, or their pharmaceutically acceptable salts, which specified the effective amount is at least the amount sufficient to cause a noticeable increase in the secretion of growth hormone and, preferably, is an amount sufficient to achieve a therapeutic effect in a patient.

In one embodiment of the invention directly above aspect of this stimulation of growth hormone secretion is determined in the treatment of the AI status of growth hormone deficiency. A non-exclusive list of examples in which this therapeutic effect can be determined, could include: treatment status, growth hormone deficiency, increase muscle mass and/or bone density, overcoming sexual dysfunction, contributing to weight gain, maintaining ideal body weight, physical functioning, restore physical function and/or increasing weakened appetite. Weight gain, maintaining a constant body mass and/or increased appetite especially useful for subjects having the disease or disorder or undergoing medical exposure, accompanied by weight loss. More preferably, the above diseases or disorders accompanied by weight loss, represent, but are not limited to, anorexia, bulimia, cachexia, fatigue, AIDS and/or weakness in old age. Also preferably, specified medical treatment accompanied by weight loss include, but are not limited to, chemotherapy, radiation therapy, loss of mobility (for example, forced bed rest) and/or dialysis.

The ghrelin antagonists can also be used to achieve a therapeutic effect in the patient. In another aspect, the invention shows a method of suppressing the secretion of growth hormone is object in case of need of such suppression, includes stage introduction to the subject an effective amount of a ghrelin antagonist, corresponding to the formula (I) or formula (II), or corresponding to any one of groups 1, 1A, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, 8A, 9, 9A, 9B, 9C, 9D, 9E, 9F, 9G, 10 and 10A, or their pharmaceutically acceptable salts, which specified the effective amount is at least a quantity sufficient to cause a noticeable increase in the secretion of growth hormone, and, preferably, is an amount sufficient to achieve a therapeutic effect in a patient.

In one embodiment of the invention directly above aspect of the specified suppression of growth hormone secretion is indicated for the treatment of a disease or a pathological state characterized by excessive secretion of growth hormone, to facilitate weight loss, to reduce excessive appetite, to maintain the desired weight, for the treatment of obesity, for the correctional treatment of the diabetic condition, including complications due to such, such, retinopathy and/or prevention of cardiovascular disorders.

In the preferred embodiment of the invention directly above aspect specified overweight is a contributing factor in the disease or pathological condition, in the including, but not limited to these examples, obesity, hypertension, diabetes, dyslipidemia, cardiovascular disease, gallstones, osteoarthritis, Prader-Willi syndrome, arthritis and some cancers. More preferably, the specified relief weight loss reduces the likelihood of such diseases or pathological conditions. Also more preferably, the specified relief weight loss includes at least part of the treatment of such diseases or pathological conditions.

And still further, in the preferred embodiment of the invention, the compounds of the invention can also be applied in order to cause gastrointestinal contractility in need of subjects by introducing to a subject suffering from such a pathological condition, an effective amount of one or more compounds of the formula (I) or (II), or corresponding to groups 1, 1A, 2, 2A, 3, 3A, 4, 4A, 5, 5A, 6, 6A, 7, 7A, 8, 8A, 9, 9A, 9B, 9C, 9D, 9E, 9F, 9G, 10 and 10A, or their pharmaceutically acceptable salts, which specified the effective amount is at least the amount sufficient to ensure the gastrointestinal contractility, and, preferably, is an amount sufficient to achieve a therapeutic effect in a patient.

In preference the equipment example embodiment of the invention the immediately preceding method specified lower gastrointestinal contractility is created from the subjects in the post-operative ileus, paresis of the stomach, ulcerative colitis or inflammatory bowel disease such as Crohn's disease.

In another more preferred embodiment of the invention the immediately preceding method specified gastroparesis is a concomitant attack of diabetes or chronic diabetic state.

Other distinctive features and advantages of the present invention more apparent from the descriptions provided in this document includes various examples. The provided examples illustrate the various components and methodology useful in the practical implementation of the present invention. The examples do not limit the invention. Based on this disclosure of the invention, a specialist in the art can identify and use other components and methodology useful for the practical implementation of the present invention.

Detailed description of the invention

The present invention describes peptidyl analogs, active GHS-receptor. Analogs of the invention can be contacted with the GHS-receptor and, preferably, to cause the transmission of a signal.

The nomenclature used to define the peptides is usually used in this technical field, where the amino group of the N-end is indicated on the left and the carboxyl GRU is PA-the end is indicated on the right, i.e. occupy a certain position in the structure-NH-C(R)(R')-CO-, where R and R' each, independently of one another, represents hydrogen or a side chain amino acids (for example, R=CH3and R'=H for Ala), or R and R' can be connected with the formation of the ring system. In the case when the amino acid is isomeric form, it is the L-form of the amino acid that is represented unless expressly stated otherwise. If not defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by any ordinary person skilled in the art to which this invention relates. All publications, patent applications, patents, and other references mentioned in this document are included as references.

Nomenclature and abbreviations

SymbolValue
Aibα-aminoisobutyric acid
D-BalD-3-benzothiadiazin with structure:
DgTrprepresented by the structure:
DgTrp-Hrepresent the priority structure:
DgTrp-CHOrepresented by the structure:
DgTrp-C(O)CH3represented by the structure:
DgTrp-SO2CH3represented by the structure:
D-TrpD-tryptophan

There are other abbreviations used in this document are defined as follows:

Acacetyl
AcOEtthe ethyl acetate
Boctert-butyloxycarbonyl
BSAbovine serum albumin
BTIBbis(triptoreline)iadanza
Bzlbenzil
DCMdichloromethane
DICN,N-diisopropylcarbodiimide
diisopropylethylamine
Dmab4-{N-(1-(4,4-dimethyl-2,6-dioxocyclohex)-3-methylbutyl)amino}benzyl
DMAP4-(dimethylamino)pyridine
DMFdimethylformamide
DNP2,4-dinitrophenyl
EDC1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
EDTAethylenediaminetetraacetic acid
Fmocfluorenylmethoxycarbonyl
HBTU2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyleneglutaric
cHexcyclohexyl
HOATO-(7-asobancaria-1-yl)-1,1,3,3 - tetramethyleneglutaric
HOBt1-hydroxybenzotriazole
HOSuN-hydroxysuccinimide
HPLChighly effective is alcosta chromatography
Meshhydrate morpholinepropanesulfonic acid
Mmt4-methoxytrityl
NMPN-organic
Pbf2,2,4,6,7-pentamethylcyclopentadiene-5-sulfonyl
tButert-butyl
TIStriisopropylsilane
TOStosyl
Trttrail
TNtriperoxonane acid
TFFHtetramethylpiperidinyloxy
Zbenzyloxycarbonyl

"Alkyl" refers to a hydrocarbon group containing one or more carbon atoms, in which in the presence of multiple carbon atoms they are connected by single bonds. Alkyl hydrocarbon group may be a straight chain or may contain one or more branches or cyclic groups.

"Substituted alkyl" refers to Alki is, in which one or more hydrogen atoms of the hydrocarbon group substituted by one or more substituents selected from the group consisting of halogen (e.g. fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, -CF3, -OCH3, -OCF3, -(CH2)0-4-COOH and-C1-2of alkyl, itself optionally can be substituted by one or more independent from each other substituents, selected from the group consisting of halogen (e.g. fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, -CF3, -OCH3, -OCF3, -(CH2)0-4-COOH. In various embodiments of the invention contains from one to four substituents. The presence of -(CH2)0-4-COOH leads to the production of alkyl acid. Not limiting the scope of invention examples of alkyl acids containing or consisting of -(CH2)0-4-COOH, include 2-norbornanamine acid, tert-butyric acid, 3-cyclopentylpropionic acid and the like.

"Heteroalkyl" refers to an alkyl in which one or more carbon atoms in the hydrocarbon group is substituted by one or more of the following groups: amino, amido, or carbonyl. In various embodiments of the invention are heteroatoms.

"Substituted heteroalkyl" refers to heteroalkyl, what oterom one or more hydrogen atoms of the hydrocarbon group substituted by one or more substituents, selected from the group consisting of halogen (e.g. fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, -CF3, -OCH3, -OCF3, -(CH2)0-4-COOH and-C1-2of alkyl, itself optionally can be substituted by one or more independent from each other substituents, selected from the group consisting of halogen (e.g. fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, -CF3, -OCH3, -OCF3, -(CH2)0-4-COOH. In various embodiments of the invention contains from one to four substituents.

"Alkenyl" refers to a hydrocarbon group, composed of two or more carbon atoms where one or more carbon-carbon double bonds. Alchemilla hydrocarbon group may be a straight chain or may contain one or more branches or cyclic groups.

"Replaced alkenyl" refers to alkenyl, in which one or more hydrogen atoms of the hydrocarbon group substituted by one or more substituents selected from the group consisting of halogen (e.g. fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, -CF3, -OCH3, -OCF3, -(CH2)0-4-COOH and-C1-2of alkyl, itself optionally can be substituted one or more h is scrapping independent from each other substituents, selected from the group consisting of halogen (e.g. fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, -CF3, -OCH3, -OCF3, -(CH2)0-4-COOH. In various embodiments of the invention contains from one to four substituents.

"Quinil" refers to a hydrocarbon group, composed of two or more carbon atoms where one or more carbon-carbon triple bonds. Alchemilla hydrocarbon group may be a straight chain or may contain one or more branches or cyclic groups.

"Substituted quinil" refers to the quinil, in which one or more hydrogen atoms of the hydrocarbon group substituted by one or more substituents selected from the group consisting of halogen (e.g. fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, -CF3, -OCH3, -OCF3, -(CH2)0-4-COOH and-C1-2of alkyl, itself optionally can be substituted by one or more independent from each other substituents, selected from the group consisting of halogen (e.g. fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, -CF3, -OCH3, -OCF3, -(CH2)0-4-COOH. In various embodiments of the invention contains from one to four C is mustiala.

"Aryl" refers to optionally substituted aromatic group with at least one ring having a conjugated PI-electron system containing up to two conjugated or linked ring systems. Aryl includes, but is not limited to, carboxylic aryl, heterocyclic aryl and marilou group. Preferably, the aryl is a five - or six-membered ring. Preferred heterocyclic atoms for the aryl are one more atoms of sulfur, oxygen and/or nitrogen. Not limiting the scope of invention examples of aryl include phenyl, 1-naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole, and 9-anthracene and the like. The substituents of the aryl may be selected from the group consisting of halogen (e.g. fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, -CF3, -OCH3, -OCF3, -(CH2)0-4-COOH and-C1-2of alkyl, itself optionally can be substituted by one or more independent from each other substituents, selected from the group consisting of halogen (e.g. fluorine, chlorine, bromine and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, -CF3, -OCH3, -OCF3, -(CH2)0-4-COOH. In various embodiments of the invention contains from one to four substituents. In various embodiments of the invention the aryl function is 0, 1, 2, 3, or 4 substituent.

"Arylalkyl" or "alkylaryl" applies to "alkyl"attached to "aryl".

"Acyl" refers to the X'-R"-C(O)-, where R" is alkyl, substituted alkyl, heteroalkyl, replaced by heteroalkyl, alkenyl, replaced by alkenyl, quinil, replaced by quinil, aryl, alkylaryl or substituted by alkylaryl and X' is H or is absent.

The present invention includes diastereomers, as a racemate, and separated enantiomerically pure form. The claimed analogs can contain D-amino acids, L-amino acids or a combination of both. Preferably, unless otherwise indicated, the presence of amino acids in the analog of ghrelin in the form of L-enantiomer.

EXAMPLES

Examples are provided below to further illustrate various features of the present invention. The examples also illustrate a useful methodology for the practical implementation of the invention. These examples do not limit the invention.

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p> Synthesis

Compounds of the invention can be obtained by applying the methods disclosed in the examples of this document, as well as methods that are well known in the prior art. For example, the polypeptide plot GHRP-analogue may be chemically or biochemically synthesized and modified. Examples of methods of biochemical synthesis, including the introduction of nucleic acid into the cell and expression of nucleic acids provided by Ausubel, Current Protocols in Molecular Biology, John Wiley, 1987-1998, and Sambrook et al., in Molecular Cloning, A Laboratory Manual, 2ndEdition, Gold Spring Harbor Laboratory Press, 1989. Methods of chemical synthesis of polypeptides are well known to the prior art, for example, Vincent in Peptide and Protein Drug Delivery, New York, N.Y., Dekker, 1990. For example, the peptides of this invention can be obtained by standard solid-phase peptide synthesis (see, for example, Stewart J.M. et al., Solid Phase Synthesis (Pierce Chemical Co., 2d ed. 1984)).

Deputy R1in the above formula (I) may be attached to the free amino group of the N-terminal amino acids by standard methods known from the prior art. For example, alkyl groups, for example, (C1-C30)alkyl, can be attached by reductive alkylation. Hydroxyalkyl group, for example (C1-C30)hydroxyalkyl, can also be attached by reductive alkylated what I this free of hydroxy-group-protected tert-butyl ether complex. Acyl group, for example SOY1can be attached by the interaction of the free acid, for example E1COOH, with free amine N-terminal amino acids prepared by mixing the polymer with 3 molar equivalents of both the free acid and diisopropylcarbodiimide in methylene chloride for about one hour. If the free acid contains free hydroxy-group, for example p-hydroxyphenylpropionic acid, then the interaction should be done with extra 3 molar equivalents NOWT.

The peptides of the invention can also be synthesized and were synthesized in parallel on a synth ACT 396 Multiple Biomolecular Synthesizer®(Advanced Chem Tech®, Louisville, KY) (hereinafter referred to as "synthesizer"). The synthesizer was programmed to implement the following reaction cycle:

(1) washing with dimethylformamide (DMF);

(2) removing the Fmoc protective group using 20% piperidine in DMF initially for 5 minutes and the second time for 25 minutes.

(3) rinsing with DMF;

(4) interaction with Fmoc-amino acid within one hour at room temperature in the presence of diisopropylcarbodiimide (DIC) and 1-hydroxybenzotriazole (HOBt), and

(5) repeat step 4).

Intermediate compound a: N-α-Boc-Aib-D-Bal-D-Trp(Boc)-NH2

Specified in the title compound was automatically collected on the synth ACT 396 Synthesizer®(Advanced Chem Tech®, Louisville, KY) by applying fluorenylmethoxycarbonyl (Fmoc) chemistry. Used polymer Sieber (50 µmol - load for each reaction cell, AnaSpec®, San Jose, CA) with the substitution of 0.44 mmol/g of Boc-Aib-OH and Fmoc-D-Trp(Boc)-OH were purchased from Novabiochem®(San Diego, CA). Fmoc-D-Bal-OH was purchased from Chem-Impex International, Inc.®(Wood Dale, IL). The polymer in the two reaction cells were initially treated with 25% solution of piperidine in DMF for half an hour to remove the Fmoc protective group, then washed three times with 1.5 ml of DMF. Fmoc-D-Trp(Boc)-OH (300 μmol, 6 EQ.) was attached to the polymer using DIC (0,4 N. solution in DMF, 300 μmol, 6 EQ.) and HOBt (0,3 N. solution in NMP, 300 μmol, 6 EQ.) as of binders and NMP as solvent. Duplicate binding was performed twice with an interval of one hour. The polymer is then washed with DMF (3×1.5 ml). The above cycle unprotect/wash/attach/leaching was repeated to attach D-Bal and Boc-Aib residues using Foci-D-Bal-OH and Boc-Aib-OH-protected amino acids. The polymer after the build process, washed with DCM and moved into the reaction vessel on a shaker device. The polymer vstrechi the Ali with 1% of TN in DCM (10 ml) for 10 minutes. The solution was filtered into a flask containing 10% pyridine in 4 ml of Mesh. This procedure was repeated twice. The polymer is then washed Mesh and DCM. The filtrates were combined and concentrated under reduced pressure. The resulting solution is then:

1). was diluted with 50 ml DCM;

2). washed with 20 ml saturated aqueous sodium bicarbonate solution, 20 ml of 1 M aqueous solution of potassium hydrosulfate and 20 ml of a saturated aqueous solution of sodium chloride;

3). was dried over anhydrous sodium sulfate;

4). was filtered and

5). was evaporated to dryness under reduced pressure.

Received white powder weighing 57 mg. of Mass spectrometric analysis with electrospray ionization (ESI-MS) showed a molecular mass 692,4 (in accordance with the calculated molecular weight 691,9). The final product was determined by the purity of 99% based on analysis analytical HPLC.

Intermediate compound: N-α-Boc-Aib-D-Bal-DgTrp(Boc)-H

A solution of N-α-Boc-Aib-D-Bal-D-Trp(Boc)-NH2(intermediate compound a, for 48.9 mg, 62 μmol), pyridine (136 mmol, 2.2 EQ.) and bis(triptoreline)yogashala (to 34.4 mg, 1.1 EQ.) in water and acetonitrile (1:1) was stirred at room temperature for 45 minutes. The solvents were removed under reduced pressure. The residue was dissolved in 10 ml of AcOEt and washed three times with 2 ml of a saturated solution of NaHCO3three times with 2 ml of saturated solution of KHSO4 and three times with 2 ml of saturated salt solution. The organic layer was dried over Na2SO4, filtered and evaporated to dryness in vacuum. There was obtained a yield of 47.3 mg of the desired product. ESI-MS analysis showed the molecular weight 664,0 (in accordance with the calculated molecular weight 663,8). The final product was determined by the purity of 99% based on analysis analytical HPLC.

The intermediate connection: N-α-Boc-Aib-D-Bal-DgTrp(Boc)-SNO

A mixture of N-α-Boc-Aib-D-Bal-D-Trp(Boc)-H (intermediate connection, of 47.3 mg, 71,2 µmol), SOON3(10.3 ml) and DIEA (100 μl) was kept under heating at 50°C during the night. The mixture was diluted with 5 ml of toluene and freed from lightweight components. The residue was dissolved in 10 ml ethyl acetate and washed three times with 2 ml of saturated solution of KHSO4and three times with 2 ml of saturated salt solution. The organic layer was dried over Na2SO4was filtered and the solvent was removed in vacuum. There was obtained a yield of 40.5 mg of the desired product. The final product was determined by the purity of 99% based on analysis analytical HPLC. ESI-MS analysis showed the molecular weight 692,3 (in accordance with the calculated molecular weight 691,9).

Example 1: Aib-D-Bal-DgTrp-SNO

N-α-Boc-Aib-D-Bal-DgTrp(Boc)-SNO (intermediate connection, of 35.5 mg, or 51.3 mmol) was treated with 5 ml of a mixture of TN/thioanisole/anisole (about./about./about.: 4/0,5/0,5) at 0°C for the floor of the ora hours. The solution was evaporated in vacuum. The residue is triturated in cold ether and the precipitate was collected by filtration. The crude product was purified HPLC using a column Luna®(40×130 mm) C18-(2) (Phenomenex®Torrance , CA). The column was suirable using a linear gradient from 95% a and 5% In the up to 60% a and 40% for one hour, where a represents 0.1% of TN in the water and represents 0.1% of TN in acetonitrile. The fractions containing the product were combined and were liofilizovane. Was given a sample of the desired connection weight of 8.4 mg For the final product was determined by the purity of 99% based on analysis analytical HPLC. ESI-MS analysis showed the molecular weight 491,4 (in accordance with the calculated molecular weight 491,6).

Example 11: Aib-D-Bal-DgTrp-C(O)CH3

A mixture of N-α-Boc-Aib-D-Bal-DgTrp(Boc)-H (intermediate connection, 50.0 mg, 75,3 mmol), acetic acid (82,8 mmol), EDC (82,8 mmol), HOBt (82,8 mmol) and DIEA (82,8 mmol) in DCM (10 ml) was stirred at room temperature overnight. The mixture was diluted with 15 ml of DCM, washed twice with 5% aqueous solution of NaHCO3twice washed with 5% aqueous citric acid solution and twice washed with a saturated saline solution, dried over MgSO4, filtered and concentrated under reduced pressure, resulting in the N-α-Boc-Aib-D-Bal-DgTrp(Re)-C(O)CH3. The intermediate compound was used without additional is Noah cleanup.

N-α-Boc-Aib-D-Bal-DgTrp(Re)-C(O)CH3(50.0 mmol) was treated with 5 ml of a mixture of TN/thioanisole/anisole (about./about./about.: 4/0,5/0,5) at 0°C for an hour and a half. The solution was evaporated in vacuum. The residue is triturated in cold ether and the precipitate was collected by filtration. The crude product was purified HPLC using a column Luna®(40×130 mm) C18-(2) (Phenomenex®Torrance , CA). The column was suirable using a linear gradient from 95% a and 5% In the up to 60% a and 40% for one hour, where a represents 0.1% of TN in the water and represents 0.1% of TN in acetonitrile. The fractions containing the product were combined and were liofilizovane, receiving the requested connection. The final product was determined by the purity of 99.3% on the basis of analysis analytical HPLC. ESI-MS analysis showed the molecular weight 505,5 (in accordance with the calculated molecular weight 505,64).

Example 57: Aib-D-Bal-DgTrp-SO2CH3

A mixture of N-α-Boc-Aib-D-Bal-DgTrp(Vos)-H (intermediate connection, 50.0 mg, 75,3 µmol), methanesulfonamide (75,3 mmol) and DIEA (82,8 mmol) in 10 ml DCM was stirred at room temperature overnight. The mixture was diluted with 15 ml of DCM, washed twice with 5% aqueous solution of NaHCO3twice washed with 5% aqueous citric acid solution and twice washed with a saturated saline solution, dried over MgSO4, was filtered and was concentrated at bonigen the m pressure, received as a result of N-α-Boc-Aib-D-Bal-DgTrp(Vos)-SO2CH3.The intermediate compound was used without further purification.

N-α-Boc-Aib-D-Bal-DgTrp(Vos)-SO2CH3(50.0 mmol) was treated with 5 ml of a mixture of TN/thioanisole/anisole (about./about./about.: 4/0,5/0,5) at 0°C for an hour and a half. The solution was evaporated in vacuum. The residue is triturated in cold ether and the precipitate was collected by filtration. The crude product was purified HPLC using a column Luna®(40×130 mm) C18-(2) (Phenomenex®Torrance , CA). The column was suirable using a linear gradient from 95% a and 5% In the up to 60% a and 40% for one hour, where a represents 0.1% of TN in the water and represents 0.1% of TN in acetonitrile. The fractions containing the product were combined and were liofilizovane, receiving the requested connection.

Other peptides of the invention can be obtained by the average expert in the art using synthetic methods similar to those that are mainly disclosed above and/or disclosed, in particular, in the above examples, as compounds shown in table 1.

Table 1
ExampleStructureMolecular weight (calculated)The molecular is the first mass
(MS-ES)
Purity (%)
#12505,640505,500097,40%
#1491,6130491,400094,10%
#65485,5850485,600095,00%
#51533,6930533,600099,40%
#11505,6400505,500099,30%
#50519,6670519,300099,30%
#52547,7200547,5000 99,70%
#4508,6640508,200095,00%
#73560,5940559,500099,90%
#6502,6360502,300095,00%
#18517,6510517,300095,00%
#20528,6740528,600095,00%
#7502,6360502,300095,00%
#2502,6360502,200095,00%
491,6130491,600095,00%

Biological tests

Action of the compounds of the invention on the GHS-receptor may, and it was determined using such methods, which are described in the examples provided below. In various embodiments of the invention, the analogue of ghrelin had at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of the functional activity relative to the natural ghrelin, as determined by application of one or more tests of functional activity, as described below, and/or had IC50more about 1000 nm, greater than about 100 nm or more, about 50 nm, as determined by testing binding to the receptor, as described below. About the size of the IC50that "more" comes to activity and thus indicates a smaller amount required to achieve inhibition of the binding.

Measurement tests the ability of the compound to contact the GHS-receptor use GHS-receptor, a fragment of the receptor, including Greenaway the binding site polypeptide comprising a fragment or derivative of the polypeptide. Preferably the use of the test GHS-receptor or its fragment. A polypeptide comprising a fragment of the GHS-receptor that binds ghrelin may also contain one or more polypeptide sections not found in the GHS-receptor. A derivative of this polypeptide includes a fragment of the GHS-receptor that binds ghrelin together with one or more ones of the components.

Amino acid sequence GHS-receptor involved in the binding, can be easily determined using labeled ghrelin or using a structural or functional analogs of ghrelin and various fragments of the receptor. You can apply different approaches for the selection of fragments for testing to narrow down the binding site. Examples of such approaches include testing of sequential fragments with a length of approximately fifteen amino acids starting from the N-Terminus, and testing of longer fragments. If tested longer fragments that bind ghrelin fragment can be divided to further detect the exact location of ghrelin binding site. The fragments used for studies of binding, can be obtained using the techniques of recombinant nucleic acids.

Test binding can be performed using individual compounds or preparations containing different the number of connections. A preparation containing different number of connections that have the ability to bind GHS-receptor, can be divided into smaller groups of compounds that can be tested to identify the compound(s)binding to the GHS-receptor. In the exemplary embodiment of the present invention tested the product contains at least ten compounds used in the test link.

Test binding can be performed using recombinante derived polypeptides GHS-receptor in different environments. Conditions such environments include, for example, cell extracts and purified cell extracts containing polypeptides GHS-receptor, expressed from a recombinant nucleic acid or of a naturally occurring nucleic acid, and also include, for example, using a purified polypeptide GHS-receptor, obtained by recombinant means or based on naturally occurring nucleic acid that is introduced into a different environment.

Screening compounds to the GHS-receptor

Screening compounds to the GHS-receptor, is facilitated by the use recombinante is the downregulation of the receptor. Application recombinante-expressed GHS-receptor provides several advantages such as the ability of the former is to reservati receptor in a particular cell system, to respond to the connection GHS-receptor can be more easily distinguished from the response of other receptors. For example, the GHS receptor can be expressed in cell lines, such as HEK 293, COS 7 and CHO, which is not usually expresses the receptor, by means of the expression vector, with the same cell line without vector expresii can act as a control.

Screening compounds that lower the activity of GHS-receptor is facilitated by applying the test of functional analogue of ghrelin. The use of a functional analog of ghrelin in the screening test provides the activity of GHS-receptor. The effect of test compounds on such activity may be measured to identify, for example, allosteric modulators and antagonists.

The activity of GHS-receptor can be measured using various methods, such as detection of changes in the intracellular conformation of the GHS-receptor, determination of the binding energies of the G-protein and/or detection of intracellular messengers. Preferably, the activity of GHS-receptor is measured using this method, which measures intracellular CA2+. Examples of methods that can be used to measure the CA2+well known in the art and include dyes such as Fura-2® and the use of the Sa2+-bioluminescent sensitive signaling proteins, such as acorin. An example of a cell line using aquolina for measuring the activity of G-protein is HEK293/aeq17 (Button et al., Cell Calcium, (1993), 14: 663-71 and Feighner et al., (1999), 284: 2184-8).

Hybrid receptors containing ghrelin binding site functionally connected with other G-protein, can also be used for measuring the activity of GHS-receptor. Hybrid GHS-receptor contains an N-terminal extracellular domain (transmembrane domain, composed of transmembrane sites, extracellular loop sections and the intracellular loop plots) and intracellular carboxyl end. Methods of obtaining hybrid receptors and measure associated with G-protein responses provided, for example, in international patent publication no WO 97/05252 and in U.S. patent No. 5264565, each of which is thus incorporated by reference in this document.

Stimulation of the activity of GHS-receptor

Structural and/or functional analogs of ghrelin can be used to stimulate the activity of GHS-receptor. Such stimulation can be applied, for example, to study the effect of regulation GHS-receptor, to study the effect of growth hormone secretion, to search or investigate ghrelin antagonists, or to achieve a therapeutic effect to the subject. uchebnyy effect which can be achieved, includes one or more of the following: treatment status, growth hormone deficiency, increase muscle mass and/or bone density, overcoming sexual dysfunction, contributing to weight gain, reaching your ideal weight, restoring and/or maintaining physical function and/or increasing weakened appetite.

Increase weight and/or appetite may be useful to achieve and/or maintain an ideal body weight caused by weight gain or increased growth of appetite, or by controlling the weight of the subject, or when the transfer of the patient's disease and/or pathological conditions, and/or medical treatment, which affects the weight and appetite. In addition, for example, agricultural animals such as pigs, cows and chickens, can be subjected to treatment for weight gain. The entities, which are controlled by weight, include those who have a body weight of about 10% or less, 20% or less, or 30% or less than the lower end of the normal range of body weight or Body Mass Index ("BMI"). BMI measures the ratio of the size/weight of the subject and is determined by rasschityvayet weight in kilograms divided by the square of the height in meters. BMI "normal" range for a man is usually considered equal 19-22. The "normal" range, the weight of the body is well known in the prior art, and takes into account factors such as the age of the subject, growth and/or body type.

Biological tests - Examples

1. Analysis of the receptor binding

A. Obtaining Cho-K1 cells expressing recombinant human GHS-receptor-1A:

cDNA of the human receptor-1A, secreting growth hormone (hGHS-R1a) was cloned by polymerase chain reaction (PCR) using human brain RNA as template (Clontech®, Palo Alto, CA), gene-specific primers adjacent to the primary full-size sequence that encodes a hGHS-R1a, (S:5'-ATGTGGAACGCGACGCCCAGCGAAGAG-3' AS: 5'-TCATGTATTAATACTAGATTCTGTCCA-3') and Advantage 2 PCR Kit®(Clontech®). The PCR product was cloned in the vector R2.1 using Original TA Cloning Kit®(Invitrogen®, Carisbad, CA). Primary full-hGHS-R1a was subcloned into the expression vector mammalian pcDNA 3.1 (Invitrogen®, Carisbad, CA). The plasmids were made by the method of transfection into a cell line of Chinese hamster ovary, Cho-K1 (American Type Culture Collection®, Rockville, MD) calcium phosphate method (Wigler, m. et al., Cell, (1977), 11:223). Isolated cell clones stably expessialy hGHS-R1a, were obtained by selection of transfected cells grown in cycles of cloning in medium RPMI 1640, supplemented with 10% fetal bovine serum and 1 mm sodium pyruvate, containing 0.8 mg/ml G18 (Gibco ®, Grand Island, NY).

C. analysis of the binding of hGHS-R1a

Membranes for radioligand studies linking can be obtained and were obtained by homogenization of the above-mentioned cells Cho-K1 expressing hGHS-R1a, in 20 ml of ice-cold 50 mm Tris-Hcl buffer using a Brinkman transmitter station®(Westbury, NY) (setting 6, 15 sec). The homogenates were twice washed by centrifugation (39000 g/10 min) and the resulting pellet re-suspended in 50 mm Tris-Hcl buffer containing 2.5 mm MgCl2and 0.1% BSA. For analysis, aliquots (0.4 ml) were incubated with 0,05 nm (125I)ghrelin (~2000 curies/mmol) (Perkin Elmer Life Sciences®, Boston, MA) in the presence and in the absence of 0.05 ml aradioactive competing for the tested compounds of the invention. After sixty minutes of incubation at 4°C. bound (125I)ghrelin was separated from the free by rapid filtration through GF/C filters (Brandel®, Gaithersburg, MD), which was pre-soaked in 0.5% polyethylenimine/0,1% S. The filters are then washed three times with 5-ml aliquot of ice-cold 50 mm Tris-Hcl buffer and 0.1% bovine serum albumin, and the associated radioactivity, detained on the filters were counted using a gamma spectrometer (Wallac LKB®, Gaithersburg, MD). Specific binding was defined as total associated (125I)ghrelin minus the one that is linked in the presence of 1000 nm ghrelin (Bacem ®, Torrence, CA).

Table 2
ExampleStructureKi (nm)SEM
#122,56to 1.86
#115,014,20
#6516.78 infor 9.64
#5120,1810,63
#1138,228,31
#5061,5113,74
#5265,08#492,1415,60
#7392,9922,70
#6100,3022,08
#18119,509,50
#20132,675,70
#7226,2543,17
#2235,8888,10
#5279,5090,50

2. Analysis of the GHS-R functional activity

A.In vitroactivation of hGHS-R1a, mediated in nutriclean iCa 2+

Compounds of the invention were tested for their ability to stimulate hGHS-R1a activity mediated intracellular iCa2+using cells expressing hGHS-R1a. The above-mentioned cells Cho-K1 expressing hGHS-R1a, were obtained by incubation in 0.3% EDTA/phosphate buffer saline (25°C) and were washed twice by centrifugation. The washed cells are re-suspended in saline buffer solution Hank (HBSS) to load fluorescent CA2+indicator Fura-2AM. Cell suspension with a concentration of approximately 106cells/ml were incubated with 2 μm Fura-2AM for approximately thirty minutes at about 25°C. Unloaded Fura-2AM was removed by centrifugation twice in HBSS and the resulting suspension was placed in a spectrofluorimeter (Hitachi®F-2000), equipped with a magnetic stirrer and a cuvette holder with adjustable temperature. After the establishment of 37°C. compounds of the invention were added to measure the activation of intracellular CA2+. The wavelengths of excitation and emission were 340 and 510 nm, respectively.

CenturyIn vivoGH release/suppression

Using methods well known in the prior art, the compounds of the present invention were tested for their ability to stimulate or suppress the release of growth hormone (GH)in vivo(Deghnghi, R., et al., Life Sciences, (1994), 54: 1321-8; international patent publication number WO 02/08250). In order to identify the ability of compounds to stimulate GH releasein vivocompounds were subcutaneously injected with ten rats in a predefined dose of, for example, 300 mg/kg of Circulating GH was measured in approximately fifteen minutes after injection and compared with GH levels in rats injected with control solution.

Similarly compounds of the present invention can be tested for their ability to antagonize ghrelin-induced GH secretionin vivo.The connection can be injected subcutaneously ten rats in a predefined dose of, for example 300 mg/kg, together with ghrelin. Circulating GH can be measured, for example, fifteen minutes after injection and compared with GH levels in rats injected only one ghrelin.

Application

The compound or compounds of the invention can be applied to the subject. "Subject" refers to mammals and memleketim animals, including, for example, but not limited to, human, rat, mouse, or farm animals. Reference to entity does not necessarily indicate a disease or disorder, thus, the term "subject" also includes, for example, a mammal or n is a mammal animal, which introduced the dose of the analogue of ghrelin as part of the experiment, a mammal or namecapital the animal, which is treated in order to facilitate disease or impairment, and the mammal or namecapital animal who carried a prophylactic treatment to inhibit or prevent development of the disease or disorder.

"Therapeutic effect" refers to any improvement for the subject suffering from a disease or medical pathological condition. Such improvements may include, but is not limited to, reducing the severity of symptoms in a subject, the observed reduction and/or weakening of the actually existing ailments, such as reduction in tumor size or increasing bone density or actual reversal of the disease or pathological state.

Compounds of the invention can be applied to the subject using the recommendations provided in this document together with methods well known in the prior art. The preferred method of application ensures that the effective number of connections reaches the goal. Recommendations for pharmaceutical applications in the General case given in, for example, Remington''s Pharmaceutical Sciences, 18thEdition, Ed. Gennaro, Mack Publishing (1990) and in Modern Pharaceutics 2 ndEddition, Eds. Banker and Rhodes, Marcel Dekker, Inc., (1990), and both, therefore, are incorporated herein as references.

Compounds of the invention can be obtained in the form of acidic or basic salts. Pharmaceutically acceptable salts (in the form of water - or fat-soluble or dispersion products) include commonly used non-toxic salts or the Quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases. Examples of such salts include acid conjugate salts, such as acetate, adipate, alginate, aspartate, benzoate, bansilalpet, bisulfate, butyrate, citrate, comfort, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, fumarate, glucoheptonate, glycyrrhizinate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, and toilet undecanoate; basic salts such as ammonium salts including alkali metal salts like sodium and potassium salts, such salts of alkaline earth metals as calcium salts and magnesium salts, such salts with organic bases, as salt dicyclohexylamine, N-methyl-D-glucamine, and salt so the mi amino acids, as arginine and lysine.

Compounds of the invention can be applied by injecting and/or by using different application methods, including oral, nasal, transdermal and transmucosally. The active ingredients used orally as a suspension, can be prepared according to methods well known in the prior art the preparation of pharmaceutical preparations and may contain microcrystalline cellulose as inactive volumetric filler, alginic acid or sodium alginate as suspendisse agent, methylcellulose as an amplifier viscosity and sugar as a sweetening/flavoring agents. In the case of tablets with rapid release of the active ingredient, the compositions comprising the compounds under consideration of the invention may further comprise microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other AIDS, binders, fillers, dezintegriruetsja substances, diluents and lubricants.

Nasal aerosol or inhalation of the medicinal product can be prepared, for example, as solutions in saline, using benzyl alcohol or other suitable preservatives, stimulants absorption to enhance bi the availability the fluorocarbons and/or solubilizing or dispersing agents.

Compounds of the invention can also be applied intravenous (bolus or infusion), administered intraperitoneally, subcutaneously, locally with or without absorption, or intramuscular form. If used through injections, injectable solution or suspension can be prepared using suitable non-toxic, parenterally acceptable diluents or solvents, such as ringer's solution or isotonic sodium chloride solution, or suitable dispersing or moisturizing and suspendida agents, such as sterile, light, fixed oils, including synthetic mono - or diglycerides, and fatty acids, including oleic acid.

Convenient regulation of dispensing it is preferable to install, taking into account factors well known in the prior art, including the type of the entity to which is injected doses of drug, age, weight, sex and medical condition of the subject; a method of drug administration; the renal and hepatic function of the subject; the desired effect; and the feature used for the connection.

Optimal precision in achieving concentrations of drugs within the range that brings in the efficiency without Tox is knosti, requires regulations based on the kinetic characteristics of availability for drug target sites. This includes consideration of the distribution, equilibrium, and remove from the body of the drug. Daily dose for the subject is assumed between 0.01 and 1000 mg for a subject in the day.

Compounds of the invention may be provided in the set of medical instruments. This set of medical instruments typically contains the active substance in the dosage forms for application. Dosage forms contain a sufficient amount of an active compound, such that it was possible to get the desired effect when applied to a subject during such regular intervals as from 1 to 6 times a day, during the course of 1 or more days. Preferably, the number of medical instruments contained instructions that specify the use of dosage forms to achieve the desired effect and the number of dosage forms that should be used for a certain period of time.

The invention is described in an illustrative manner, and it should be understood that the terminology which is used, has the intention to represent essentially the words to describe, not to limit. Obviously, many modifications and variations of the present invention are possible in light of VicePresident the x methods. Therefore, it should be understood that, within the scope of the accompanying claims, the invention may be applied otherwise than as specifically described.

The patent and scientific literature referred to in this document represents the knowledge available to one who is skilled in the art. All patents, publications, patents, and other publications, placed in this document is thus included as references in that they are entitled to the fullness.

Other examples of carrying out the invention

It should be understood that, although the invention is described in conjunction with the detailed description, that the above description has the intention to illustrate and not to limit the scope of the invention defined by the scope of the attached claims. Other aspects, achievements and modifications are within the claims.

1. The compound of formula (I)
,
where X is a
or;
Y represents N;
Z represents-C(O)-;
R1and R3each, independently of one another, represents H or (C1-C4)alkyl;
R2and R4each, independently of one another, represents a
, ,or;
R5represents H or (C1-C6)alkyl;
R8and R9each, independently of one another, represents a (C1-C6)alkyl; and
Q represents H;
provided that each of R2and R4is notin the specified connection; or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which at least one of R2and R4represents.

3. The compound according to claim 2, in which
R2represents;
R4represents.

4. The compound according to claim 2, in which
R2represents;
R4representsor.

5. The compound according to claim 2, in which
R2represents;
R4represents.

6. The compound according to claim 2, in which
R2representsor;
R4represents.

7. The compound according to claim 2, in which
R2represents;
R4before the hat is .

8. Connection PP, 4 and 6, in which
X represents;
R6and R7each, independently from each other represents H; and
R8and R9each, independently from each other represents CH3.

9. Connection p, 4, 6, which
X represents;
Y represents N.

10. The compound according to any one of p, 9, which
R1represents H;
R3represents H; and
R5represents H, methyl, ethyl, isopropyl or tert-butyl.

11. The compound according to claim 3, selected from the group consisting of:
,
,
,
,
,
,
,

or its pharmaceutically acceptable salt.

12. The compound according to claim 4, selected from the group consisting of:
,
,
,
,
,
,
,

or its pharmaceutically acceptable salt.

13. The compound according to claim 5, selected from the group status is the present of:
,
,
,
,
,
,
,
,
,
,
,

or its pharmaceutically acceptable salt.

14. The compound of claim 6 selected from the group consisting of:
,
,
,
,
,
,
,

or its pharmaceutically acceptable salt.

15. The connection according to claim 7, selected from the group consisting of:
,
,
,

or its pharmaceutically acceptable salt.

16. The compound according to claim 1, in which
R2representsor;
R4representsor.

17. The compound according to claim 1, in which
R2representsor ;
R4represents.

18. The compound according to claim 1, in which
R2represents;
R4representsor.

19. Connection P16, which
X represents;
R6and R7each, independently from each other represents H; and
R8and R9each, independently from each other represents CH3.

20. Connection P16, which
X represents;
Y represents N.

21. The compound according to any one of p, 20, in which
R1represents H;
R3represents H; and
R5represents H, methyl, ethyl, isopropyl or tert-butyl.

22. Connection P16 selected from the group consisting of:
,
,
and

or its pharmaceutically acceptable salt.

23. The connection 17, selected from the group consisting of:
and

or its pharmaceutically acceptable salt.

24. Connection p selected from the group consisting of:
and

or its pharmaceutically acceptable salt.

25. The compound according to claim 1, in which the indicated compound corresponds to the formula:
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
,
and

or its pharmaceutically acceptable salt.

26. Connection A.25, in which the indicated compound corresponds to the formula:
,
,
,
,
,
,
,
,
,
,
,
,
and

or its pharmaceutically acceptable salt.

27. Connection p, in which the indicated compound corresponds to the formula:
,
,
,
,
,
,
,
and

or its pharmaceutically acceptable salt.

28. Connection item 27, which specified the the group corresponds to the formula:
,
,
,
and

or its pharmaceutically acceptable salt.

29. Connection p, in which the indicated compound corresponds to the formula:

and

or its pharmaceutically acceptable salt.

30. The connection clause 29, in which the indicated compound corresponds to the formula:

or its pharmaceutically acceptable salt.

31. Connection A.25, in which the indicated compound corresponds to the formula:
and

or its pharmaceutically acceptable salt.

32. Connection A.25, in which the indicated compound corresponds to the formula:
,
and

or its pharmaceutically acceptable salt.

33. Pharmaceutical composition for the stimulation of growth hormone in a subject, comprising the compound according to any one of p-32 and a pharmaceutically acceptable carrier.

34. The compound of formula (II)
,
where X is a

Z represents-C(O)-;
R1and R3each n is independently from each other, represents H;
R2and R4each, independently of one another, represents a
or;
R5is a (C1-C6)alkylhalides;
R8and R9each, independently of one another, represents a (C1-C6)alkyl;
R6and R7each, independently from each other represents H; and
Q represents H;
provided that each of R2and R4is notin the specified connection;
or its pharmaceutically acceptable salt.

35. The connection 34, which
R2represents;
R4represents.

36. Connection p, in which
X represents;
R6and R7each, independently from each other represents H; and
R8and R9each, independently from each other represents CH3.

37. Connection p, in which
R1represents H;
R3represents H; and
R5represents-CF3.

38. The connection 34 of the formula:

or its pharmaceutically acceptable salt.

39. Pharmaceutical composition for the stimulation of hormone secretion R. the hundred in the subject, including connection § 38 and a pharmaceutically acceptable carrier.

40. Agonist ghrelin, corresponding to the compound of formula (I) or (II) or its pharmaceutically acceptable salts, for the stimulation of growth hormone secretion in a subject in need of such stimulation, taken in an effective amount, where the specified effective amount is at least sufficient to cause a noticeable increase in the secretion of growth hormone, and preferably is an amount sufficient to achieve a therapeutic effect in a patient.

41. Agonist of ghrelin on p where the specified stimulation of growth hormone secretion is required for treatment of the condition of deficiency of growth hormone to increase muscle mass, increase bone density, for the treatment of sexual dysfunction in men or women, for the promotion of weight gain, for facilitating maintenance of weight loss, to promote the maintenance of physical functioning, and to facilitate restoration of physical function and/or promoting increased appetite.

42. Agonist of ghrelin in paragraph 41, in which the indicated promote weight gain, promote weight maintenance and/or stimulate appetite requires the patient having the disease or disorder or treatment resistance is odusanya loss of body weight.

43. Agonist of ghrelin in § 42, where the disease or disorder involving loss of body weight, includes anorexia, bulimia, cancer cachexia, wasting, AIDS cachexia.

44. Antagonist of ghrelin, corresponding to the formula (I) or (II) or its pharmaceutically acceptable salts, to inhibit the secretion of growth hormone in a subject in need of such suppression, taken in an effective amount, where the specified effective amount is at least sufficient to cause a noticeable decrease in the secretion of growth hormone, and preferably, is an amount sufficient to achieve a therapeutic effect in a patient.

45. Antagonist of ghrelin on item 44, where the specified suppression of secretion of growth hormone is required for treatment of a disease or pathological condition characterized by excessive secretion of growth hormone, to promote the loss of body weight, to facilitate reduction of appetite, promote weight maintenance to treat obesity, for the prophylaxis and treatment of diabetes, for the treatment of diabetic complications, including retinopathy.

46. Antagonist of ghrelin on § 45, where the specified excess weight is a contributing factor to the disease or pathological condition, including hypertension, diabetes, dyslipidemia).

47. Ant is honest ghrelin on p.46, where the specified promoting weight loss lowers the probability of such diseases or pathological conditions or where the specified promoting weight loss includes at least part of the treatment of such diseases or pathological conditions.

48. Agonist ghrelin, corresponding to the formula (I) or (II) or its pharmaceutically acceptable salt, to identify the actions of ghrelin agonist to the subject, where the specified antagonist of ghrelin taken in an effective amount which is at least sufficient to cause a noticeable decrease in the secretion of growth hormone, and preferably is an amount sufficient to achieve a therapeutic effect in a patient.

49. Antagonist of ghrelin, corresponding to the formula (I) or (II) or its pharmaceutically acceptable salt, to identify the actions of the antagonist of ghrelin on the subject, taken in an effective amount, where the specified effective amount is at least sufficient to cause a noticeable decrease in the secretion of growth hormone, and preferably is an amount sufficient to achieve a therapeutic effect in the patient.



 

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Aromatic compound // 2416608

FIELD: chemistry.

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EFFECT: preparation of the pharmaceutical composition which can find application in treating a malignant growth.

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32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula 1, its pharmaceutically acceptable salts and stereoisomers: $ (1), where: R1 means H, amidino, C1-C4-alkyl amidino, C1-C4alkanoylamidino, C1-C10-alkyl, C3-C7-cycloalkyl, C6-C10-aryl, 6-members heterocycle with O atom, 5-members heterocycle with two N atoms, 6-members heteroaryl with one or two N atoms, 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, C1-C6-alkylcarbonyl, C3-C7-cycloalkylcarbonyl, C1-C4-alkoxycarbonyl, C6-C10-aryl-C1-C4-alkoxycarbonyl, -SO2-C1-C4-alkyl, -C(O)-N(R6)(R7) or -C(S)-N(R6)(R7); and, R6, R7 means H, C1-C6-alkyl, C3-C7-cycloalkyl; alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are unsubstituted or substituted; R2 means C6-C10-aryl which is unsubstituted or mono- or disubstituted; R3 means H, CN, C1-C6-alkyl, C3-C7-cycloalkyl, C2-C6-alkenyl, monocyclic 5-members heterocycle with N and O, monocyclic 5-members heteroaryl with two heteroatoms, one of which is N, and the other is O or S, C(O)-R8 or -C(S)-R8; and R8 means OH, C1-C4-alkyl, C1-C4-alkyloxy or N(R9)(R10); R9, R10 mean N, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyloxy, phenyl or 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, 6-members heteroaryl with N; R9, R10 together with N whereto attached can form a single 4-6-members ring which can include in addition O or S; and alkyl, cycloalkyl, heterocycle, phenyl or heteroaryl are unsubstituted or substituted. R4 means C3-C8-cycloalkyl, C6-C10-aryl, 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, 6-members heteroaryl with N, 6-members heterocycle with O, and C6-C10-aryl or heteroaryl are unsubstituted or mono- or polysubstituted. R5 means N, C1-C6-alkyl, -C(O)-R11, C1-C6-alkylsulphonyl, C6-C10-arylsulphonyl, -(CH2)p-C6-C10-aryl, -(CH2)p-heteroaryl or -(CH2)p-C3-C8-cycloalkyl where heteroaryl means 5-members heteroaryl with O or with N or with S which can contain in addition N. p is equal to 1 or 2; R11 means C1-C10-alkyl, C1-C6-alkenyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl, NH2, C1-C4alkylamino, (C1-C4-alkyl)(C1-C4-alkyl)amino, C6-C10-aryl, 5-members heteroaryl with N or with O or with 8 which can contain in addition N, 6-members heterocycle with N and O, 5- or 6-members heterocycle with O, and alkyl is unsubstituted or substituted with one substitute. Aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycle are unsubstituted or mono- or disubstituted.

EFFECT: compounds are melanocortin receptor agonists so presented to be used in a pharmaceutical composition for treatment and prevention of obesity, diabetes, inflammation, erectile dysfunction.

19 cl, 18 tbl

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

Dna-pk inhibitors // 2408596

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I: and salts thereof, where R1 and R2 together with a nitrogen atom with which they are bonded can form a morpholine group; Q denotes -NH-C(=O)- or -O-; Y denotes a saturated aliphatic group C1-5alkylene group; X is selected from SR3 or NR4R5, where R3 denotes triazolyl; R4 and R5 are described in the claim.

EFFECT: compounds are DNA-PK inhibitors.

5 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: tricyclic compounds of formula I: $ substituted with heterocycle are disclosed, or pharmaceutically acceptable salt or solvate of specified compound, isomer or racemic mixture, where stands for optional double link, dotted line stands for link or does not stand for link, which results in double or single link according to requirements of valency and where A, B, G, M, X, J, n, Het, R3, R10, R11, R32 and R33 and other substituents are such as indicated in formula of invention. Invention also relates to pharmaceutical compositions, which contain them, method of thrombin receptor or cannabinoid receptor inhibition, and to method for treatment of disease related to thrombosis, atherosclerosis, restenosis, hypertension, stenocardia, arrhythmia, cardiac failure and cancer by administration of specified compounds.

EFFECT: production of compounds having properties of antagonists of thrombin receptors.

33 cl, 6 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula:

, A and B denote a pair of condensed saturated or unsaturated 5- or 6-member rings, where the said system of condensed rings A/B contains 0-2 nitrogen atoms, and said rings are further substituted with 0-4 substitutes independently selected from halogen, lower alkyl or oxo; and a and b are bonding positions for residues Y and D, respectively, and these positions a and b are in the peri-position relative each other on the said condensed ring system A/B; d and e are condensed positions between ring A and ring B in the said condensed ring system A/B; D is an aryl or heteroaryl cyclic system which denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S; which can be further substituted with 0-4 substitutes independently selected from lower alkyl and amine; Y is selected from -CH2 and -O-; M is selected from aryl, aryl substituted with a halogen or alkoxy; R1 is selected from aryl, aryl substituted with a halogen, heteroaryl, heteroaryl substituted with a halogen, where heteraryl denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S, and CF3; and if Y denotes -CH2- or -O-, then R1 further denotes a lower alkyl. The invention also pertains to use of compounds in claim 1, a pharmaceutical composition, a screening method on selective ligands of prostanoid receptors, as well as compounds of the formula.

EFFECT: obtaining novel biologically active compounds for inhibiting binding of prostanoid E2 with EP3 receptor.

25 cl, 46 ex

Aromatic compound // 2416608

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound of general formula (1), where radicals R1, R2, X1, Y and A are as described in claim 1 of the invention. The invention also describes a method of obtaining compounds of formula (1), as well as a pharmaceutical composition based on said compounds, for treating fibrosis.

EFFECT: novel compounds with excellent collagen formation suppression, cause fewer side-effects and which are safer are obtained.

62 cl, 2717 ex, 432 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) or pharmaceutically acceptable salts thereof, where Q is CH or N; R2 is C1-C4 alkyl or C3-C4-cycloalkyl; Y is R5-O; where R5 is propynyl; X is selected from a group consisting of aryl, heteroaryl, C1-C5-alkyloxy, heterocycloalkyl, arylamino, heteroarylamino, heteroaryl-C1-C4-alkylamino, aryloxy, aryl-C1-C2-alkyloxy or C3-C6-cycloalkyl-C1-C4-alkyloxy, each of which is optionally substituted with 1-3 times; the optional substitute(s) for X is(are) independently selected from a group comprising halogen, cyano, trifluoromethyl, nitro, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkyloxy-C1-C4-alkoxy, -SMe, SO2-C1-C2-alkyl, -NMe2, - C(O)O-C1-C5-alkyl, -SCF3, -SO2-NH2, -SO2-C2-alkyl-OH, -CONH2, -COMe, - CONH-C1-C4-alkyl, -CONMe2, -NHCOMe, -CH2COOEt, -OCH2COOEt, -CH2- cyclopropyl, and each R3 and R4 is H; where aryl denotes phenyl or naphthyl; heteroaryl denotes monocyclic or bicyclic hydrocarbon containing 5-10 ring atoms, one or more of which are heteroatoms selected from O, N or S; heterocyclyl denotes piperidinyl or benzodioxolyl; or a compound or pharmaceutically acceptable salt thereof, selected from a group comprising (4-dimethylaminophenyl)-[4-(4-cyclopropylphenyl)-6-propargyloxyquinazolin-2-yl]methanone, (3-sulphamoylphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, [3-(2-hydroxyethanesulphonyl)phenyl]amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, (3-methylsulphanylphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, (3-methanesulphonylphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4-dihydroquinazoline-2-carboxylic acid, and (5-ethanesulphonyl-2-hydroxyphenyl)amide 4-(4-isopropylphenyl)-6-prop-2-ynyloxy-3,4- dihydroquinazoline -2-carboxylic acid. The invention also relates to a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel benzoquinazoline derivatives, which are useful in treating bone disorders, are obtained.

6 cl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a heterocyclic compound or salt thereof, having formula (1): where R2 is hydrogen or a lower alkyl group; A is a lower alkylene group or a lower alkenylene group and R1 is a cyclo(C3-C8)alkyl group, an aromatic group or a heterocyclic group selected from a group consisting of groups (I)-(IV), defined in the formula of invention. The invention also relates to a pharmaceutical composition, having activity as a partial agonist of dopamine D2 receptors and/or a serotonin 5-HT2A receptor antagonist and/or an adrenalin α1 receptor antagonist and/or a serotonin absorption inhibitor and/or serotonin reuptake inhibitor based on said compounds, a method of preparing a pharmaceutical composition, use of said compounds as a partial agonist of dopamine D2 receptors and/or a serotonin 5-HT2A receptor antagonist and/or an adrenalin α1 receptor antagonist and/or a serotonin absorption inhibitor and/or serotonin reuptake inhibitor, as well as a method of producing formula I compounds.

EFFECT: novel compounds are obtained and described, which have a wide range of curative effect on mental disorders, including central nervous system disorders, without side effects and with high degree of safety.

22 cl, 3110 ex, 314 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described 3,4-substituted piperidines applicable in diagnostics and drug therapy of a warm-blooded animal, preferentially for therapy of a disease which depends on renin activity; application of a compound of such kind for preparing a pharmaceutical composition for therapy of the disease which depends on renin activity; application of the compound of such kind for therapy of the disease which depends on renin activity; the pharmaceutical compositions containing 3,4-substituted piperidine, and/or a therapeutic mode involving administration of 3,4-substituted piperidine, a method for producing 3,4-substituted piperidine. The preferential compound (which also can be presented in the form of salts) are described by formula I' wherein R1, R2, T, R3 and R4 are such as described by the patent claim.

EFFECT: production of the compounds for therapy of the disease which depends on renin activity.

28 cl, 1 tbl, 375 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrolidine derivatives of general formula (1) or its pharmaceutically acceptable salts where R101 and R102 values are described by the patent claim. The compounds inhibit serotonin and/or norepinephrine and/or dopamine reabsorption thereby allowing to be used for treating depression and anxiety disorder. A method for preparing thereof is described.

EFFECT: preparation of new pyrrolidine derivatives.

10 cl, 162 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing (R)-(-)-sertaconazole mononitrate, in which first, a chemical reaction takes place between (R)-(-)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)-ethanol and an intermediate of general formula where L denotes a leaving group, in the presence of an interphase catalyst and a base in a medium consisting of water and a water-immiscible solvent; followed by treatment with nitric acid and recrystallisation of the solid product formed from a suitable solvent which contains a mixture of an alcohol containing 1-4 carbon atoms and acetone; the formed polyacetone of R-(-)-sertaconazole mononitrate is converted to R-(-)-sertaconazole mononitrate by drying at temperature between 80 and 90°C; and the obtained R-(-)-sertaconazole mononitrate (V) is purified. The invention also relates to polyacetonate of R-(-)-sertaconazole mononitrate .

EFFECT: novel interphase process of producing R-(-)-sertaconazole mononitrate (V).

24 cl, 1 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel substituted imidazole compounds of formula I where values of radicals are given in description, as well as to their based on them pharmaceutical compositions.

EFFECT: formula I compounds, as well as their salts, esters and compositions based on them possess ability to inhibit protein of kinesin spindle (KSP) and can be used for treatment of cancer diseases.

40 cl, 15 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I: where Y1 and Y2 are independently selected from N and CR10, where R10 is selected from group, including hydrogen, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, R1 is selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino, C1-C6alkylsulfanyl, dimethylaminoethoxy and pyperasinyl, substituted up to 2 radicals C1-C6alkyl, R2 and R5 are independently selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy and dimethylamino, R3 and R4 are independently selected from group, including hydrogen, halogen, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, or R1 and R5 with phenyl, to which they are bound, form C5-C10heteroaryl, R6 and R7 are independently selected from group, including hydrogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkyl, on condition that R6 and R7 both do not represent hydrogen, R8 is selected from group, including hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkoxy, R9 is selected from -S(O)2R11, -C(O)R11, -NR12aR12b and -R11, where R11 is selected from group, including aryl, cycloalkyl and heterocycloalkyl, R12a and R12b are independently selected from (C1-C6)alkyl and hydroxy(C1-C6)alkyl, and said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in composition of R9 optionally contain as substituents from 1 to 3 radicals, independently selected from group, including (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, C6-C10aryl(C0-C4)alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl and C3-C8heterocycloalkyl, where said arylalkyl substituent in composition of R9 optionally contains as substituents from 1 to 3 radicals, independently selected from group, including halogen, cyano, (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino and methyl-pyperasinyl, as well as to its pharmaceutically acceptable salts, hydrates, solvates and isomers. In addition, invention relates to method of inhibiting hedgehog pathway in cell and to method of inhibiting undesirable cell proliferation, when cell contacts with compound described above.

EFFECT: obtained and described are novel compounds, which can be applied in medicine.

13 cl, 153 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula: or its pharmaceutically acceptable salts, where Y represents COOR2; A represents -(CH2)6-, cys-CH2CH=CH-(CH2)3-, where 1 carbon atom can be substituted with O; or A represents -(CH2)m-Ar-(CH2)0-, where Ar represents phenylene or 5-member heteroarylene, which contains one heteroatom selected from O or S, sum of m and o constitutes from 1 to 4, and where one of groups CH2 can be substituted with O; and B represents phenyl, which can be substituted with C1-12 alkyl, hydroxy C1-12 alkyl; R2 represents H, C1-6 alkyl.

EFFECT: obtaining compounds for ophthalmological composition.

15 cl, 1 tbl, 16 dwg, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to thiophene derivatives of formula (I):

where A denotes -CONH-CH2-, -CO-CH=CH-, -CO-CH2CH2-, -CO-CH2-O-, -CO-CH2-NH-, or ; R1 denotes hydrogen, C1-5-alkyl or C1-5-alkoxy; R2 denotes hydrogen, C1-2-alkyl, C1-5-alkoxy, trifluoromethyl or halogen, R3, R31, R32, R33, R34, R4, R5, R6, R7, k, m, n are described in claim 1. The invention also relates to a pharmaceutical composition for preventing or treating diseases and disorders associated with an activated immune system, based on said compounds and to use thereof as therapeutically active compounds for preventing or treating diseases or disorders such as graft rejection, graft versus host reaction and autoimmune syndromes.

EFFECT: improved properties of the compound.

27 cl, 2 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: described is a compound selected from a group consisting of formula II formula III and formula IV , or its salt or ester, where G1 is selected from a group which includes - (CR1R2)n-, n equals 0 or 1; R1 and R2 are independently selected from a group which includes hydrogen; X1, X2 and X3 are independently selected from a group consisting of hydrogen, optionally substituted lower alkyl, halogen, optionally substituted lower alkoxy, G2 is a heterocycloalkyl linker optionally substituted with X4 and X5, where the heterocycloalkyl linker is selected from a group consisting of piperazinyl, 3,6-dihydro-2N-pyridinyl, [1,4]diazepanyl, 3,9-diazabicyclo[3,3,1]nonyl; X4 and X5 are independently selected from a group consisting of hydrogen and optionally substituted lower alkyl; CO2R; R is selected from a group consisting of optionally substituted lower alkyl and hydrogen; G3 is a bond; G4 is selected from a group consisting of hydrogen, aryl, selected from phenyl which is optionally substituted with a lower alkyl, halogen, lower haloalkyl or lower haloalkoxy; heteroaryl selected from pyridinyl which is optionally substituted with a halogen or lower haloalkyl; and optionally substituted cycloheteroalkyl selected from 1,3-benzodioxolyl. Described also are specific compounds and a pharmaceutical composition.

EFFECT: disclosed compounds are used as modulators of receptors activated by a peroxisomal proliferator.

5 cl, 2 tbl, 117 ex

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