Melanocortin receptor agonists

FIELD: chemistry.

SUBSTANCE: small peptides of formula X1-X2-X3-X4-X5-X6-X7-R1, containing 7-12 amino acid residues are proposed.

EFFECT: said peptides are MC4 receptor agonists and are therefore useful in treating obesity and related diseases.

31 cl, 2 tbl, 82 ex

 

The scope of the invention

The invention relates to new peptides for use in therapy, in particular for the treatment of obesity and related diseases.

Prior art

Obesity is a well-known risk factor for the development of many common diseases, such as atherosclerosis, hypertension, type 2 diabetes (non-insulin dependent diabetes mellitus (NIDDM)), dyslipidemia, coronary heart disease, and osteoarthritis and various malignant tumors. It also causes significant problems associated with limited mobility and reduced quality of life. The prevalence of obesity, and therefore also of these diseases is increasing in all industrialized world. To date, only a few farmacoterapia, namely sibutramine (acting via serotonergic and noradrenergic mechanisms, Abbott) and orlistat (reducing the absorption of fat from the intestines, Roche Pharm). However, due to the significant impact of obesity as a risk factor in serious and even deadly and prevalent diseases there is still a need in the pharmaceutical compounds useful in the treatment of obesity.

The term "obesity" means the excess of adipose tissue. In this context, obesity is best seen as any degree OFL the exact obesity, which creates a risk to health. The difference between normal individuals and individuals with obesity may be only approximate, but the risk to health created by obesity, probably continuously increases with obesity. However, in the context of the present invention individuals with a body mass index (BMI = body weight in kilograms divided by the square of height in meters) above 25 is considered as obese.

Even a mild degree of obesity increases the risk of premature death, diabetes, hypertension, atherosclerosis, gallbladder disease and some types of cancer. In the Western industrialized world, the prevalence of obesity has increased significantly over the last few decades. Due to the high prevalence of obesity and its health effects, and its treatment must be a priority for the health.

When the energy absorption exceeds energy expenditure, the excess calories are stored in fat tissue, and, if the net positive balance is long, the result is obesity, i.e. in the mass balance of the body there are two components, and the anomaly on either side (absorption or flow) can lead to obesity.

Proopiomelanocortin (POMC) is a precursor peptides β-endorphin and melanocortin, VK is UCA hormone melanocyte-stimulating (α-MSH) and adrenocorticotropin (ACTH). POMC is expressed in several peripheral and Central tissues, including melanocytes, adrenal glands and neurons of the hypothalamus. Processing of precursor POMC occurs differently in different tissues, which results in expression of different melanocortin peptides depending on the site of expression. In the anterior lobe of the adrenal gland is produced mainly ACTH, whereas in the middle lobe and in the neurons of the hypothalamus basic peptides are α-MSH, β-MSH, desacetyl-α-MSH and β-endorphin. Demonstrated that some of the melanocortin peptides, including ACTH and α-MSH, have activity suppress appetite when intracerebroventricularly (icv) injection to rats (Vergoni et al., European Journal of Pharmacology 179. 347-355 (1990)). The effect of suppression of appetite is also obtained with artificial cyclic analogue of α-MSH, MT-II, disclosed in U.S. patent 5731408.

Identified a family of five subtypes of melanocortin receptors (receptors melanocortin 1-5, also called MC, MC2, MC, MS and MS). MC, MC2 and MS mainly expressed in peripheral tissues, whereas MS and MS mainly expressed in the Central tissues, however, MS is also expressed in some peripheral tissues. Receptors MS, which, in addition, povleceni energy homeostasis, also allegedly involved in some inflammatory diseases. Agonist MS can have a positive impact on these diseases, for example, gouty arthritic MS mainly expressed in peripheral tissues and presumably involved in exocrine secretion and inflammation. It is shown that the receptor MS involved in the regulation of body weight and feeding behavior, because the knockout mice on MS developing obesity (Huzar et al., Cell 88, 131-141 (1997)). In further studies or Central ectopic expression of agouti (antagonist MS, MS and MS), or overexpression of endogenous formed antagonist MS and MS (peptide corresponding to the agouti gene, AGRP) in the brain demonstrated that overexpression of these two antagonists leads to the development of obesity (Kleibig et al., PNAS 92, 4728-4732 (1995)). In addition, icv injection of C-terminal fragment of AGRP increases the power and antagonisitic inhibitory effect of α-MSH in relation to the absorption of food.

People have described several familial cases of obesity is mainly due to mutations shift the reading frame in the receptor MS (e.g., Yeo et al., Nature Genetics 20, 111-112 (1998), Vaisse et al., Nature Genetics 20, 113-114).

We can conclude that the agonist MS can serve as anorectics medicine to be useful in the treatment of obesity or diseases, tie is the R with obesity, as well as in the treatment of other diseases, disorders or conditions that are improved as a result of activation of the receptor MS.

Antagonists MS can be useful for the treatment of cachexia, anorexia, and for the treatment of depletion debilitated elderly patients. In addition, antagonists MS can be used for the treatment of chronic pain, neuropathy and neurogenic inflammation.

In a wide number of patent applications, examples of which are WO 03/009850, WO 03/007949 and WO 02/081443, revealed small molecules as modulators of melanocortin receptors.

The use of peptides as modulators of melanocortin receptors are also disclosed in several patents. In EP 292291 revealed a number of derivatives of 7 amino acids of α-MSH characterized with high efficiency, for example, by D-Phe at position 7 in the sequence of α-MSH and due to the presence of a disulfide bridge.

In the US 5731408 disclosed cyclic peptides with a length of seven amino acids with D-2-Nal in position 4, which are antagonists MS.

In the US 4457864 disclosed Tribeca-peptide analogues of α-MSH, which show increased efficiency and prolonged action. Preferred compounds have the Nle, D-Phe at position 4 and 7, respectively.

In WO 98/27113 disclosed peptides with specific affinity binding to receptors on melanocortin containing the structure X-Y-Hi-B-Arg-Z, where X and Y represent an amino acid residue, Z is an aromatic amino acid residue and a represents a D-(2-thienyl)alanine or D-(3-pyridyl)alanine.

Similar MT-II with the structure of Ac-Nle-c[Asp-Hyp-D-Phe-Arg-Trp-Lys]-NH2disclosed in Proc. 2ndInter, and 17thAmerican Peptide Symp., June 9-14, 2001, San Diego, 992, 893; similar MT-II with the structure of Ac-Nle-c[Asp-Ala-D-Phe-Arg-Trp-Lys]-NH2disclosed in Peptides, 20 (3), 1999, 401-409; and similar MT-II with the structure of Ac-Nle-c[Asp-Gln-D-Phe-Arg-Trp-Lys]-NH2disclosed in Bioorg. Med. Chem. Lett, 13 (7), 2003, 1307-1311; two similar MT-II Ac-Nle-c[Asp-Glu-D-Phe-Arg-Trp-Lys]-NH2and Ac-Nle-c[Asp-Lys-D-Phe-Arg-Trp-Lys]-NH2disclosed in Biochem. Res. Commun., 272 (1), 2000, 23-28; and similar MT-II Ac-Nle-c[Asp-Pro-D-Phe-Arg-Trp-Lys]-NH2mentioned in J. Peptide Res., 62, 2003, 199-206.

There remains a need for the development modifiers receptor melanocortin, which are highly efficient and which have suitable solubility and hence bioavailability in combination with appropriate selectivity.

The invention

The authors of the present invention unexpectedly found that specific analogues of MT-II have a high modulating effect in relation to one or more than one receptor melanocortin, for example, receptor MC, MC2, MC, MS and/or MS. Accordingly, the invention relates to peptides of formula I

where X1 represents Nle or X-le, where X represents an amino acid or di-, tri-, Tetra - or Pentapeptide, comprising polar or hydrophilic amino acid residues selected from the D and L forms of Asp, Glu, His, Arg, gameid, Tyr, Asn, Ser, Thr, Lys, Orn, Dap, Dab, and Gln, and where X may in addition contain one or two amino acid residue selected from Gly, β-Ala, or D and L forms Pro, Hyp and Ala;

and where the N-terminal amino group of X1 can be allerban acyl group, R-C(O)-, where R represents an alkyl or alkenyl containing up to 6 carbon atoms, with the specified alkyl may be substituted by one or more than one Deputy, selected from hydroxyl and amino;

X2 represents Glu, Asp, Cys, Cys, Lys, Orn, Dab, Dap;

X3 represents Cit, Dab, Dap, cyclohexylglycine, cyclohexylamine, Val, Ile, tert-butylglycol, Leu, Tyr, Glu, Ala, Nle, Met, Met(O), Met(O2), Gln, Gln(alkyl), Gln(aryl), Asn, Asn(alkyl), Asn(aryl), Ser, Thr, Cys, Pro, Hyp, Tic, 2-PyAla, 3-PyAla, 4-PyAla, (2-thienyl)alanine, 3-(thienyl)alanine, (4-thiazolyl)Ala, (2-furyl)alanine, (3-furyl)alanine, Phe, where the phenyl group specified Phe possibly substituted with halogen, hydroxyl, alkoxy, nitro, benzoyl, stands, trifluoromethyl, amino or cyano;

X4 represents D-Phe, where the phenyl group in the D-Phe may be substituted by one or more than one Deputy, selected from halogen, hydroxy, alkoxy, nitro, methyl, trifloromethyl or cyano;

X5 represents Arg;

X6 performance is to place a Trp, 2-Nal, (3-benzo[b]thienyl)alanine or (S)-2,3,4,9-tetrahydro-1H-β-carbolin-3-carboxylic acid;

X7 represents Glu, Asp, Cys, Cys, Lys, Orn, Dab, Dap;

where between x2 and X7 have a connection with formation of cyclic peptide of formula I, or by a disulfide bridge (x2 and X7 both independently represents Cys or Cys), or by an amide bond formed from the carboxyl group in the side chain x2 or X7 and an amino group in the side chain x2 or X7;

R1represents-N(R")2, or-OR", where each R" independently represents hydrogen or C1-6alkyl which may be substituted by one or more than one amino or hydroxyl group;

provided that when X3 represents Hyp, Ala, Pro, Glu, Lys or Gln, and X1 represents Ac-Nle, then x2 is not Asp;

as well as any pharmaceutically acceptable salt, MES or prodrug.

In another embodiment the invention relates to the use of this peptide in therapy.

In another embodiment the invention relates to therapeutic methods, which impose these peptides entities in need.

In another embodiment the invention relates to the use of these peptides for the manufacture of drugs.

Definition

The term "alkyl", as used here, without a prefix, refers to pravarasena or razvetvlennye monovalent hydrocarbon radical, having, for example, from one to ten carbon atoms, for example, C1-8-alkyl. Typical C1-8-alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylpentyl, neopentyl, n-pentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl and the like. The term "C1-8-alkyl", as used here, also includes secondary3-8-alkyl and tertiary4-8-alkyl. In a more General sense, the term "alkyl" is intended to refer to both primary and secondary and tertiary alkyl.

The term "alkenyl"as it is used here, without a prefix, refers to pravarasena or branched monovalent hydrocarbon radical containing at least one double bond in the carbon-carbon bonds and having, for example, from two to ten carbon atoms, for example With2-8alkenyl. Typical C2-8-alkeline groups include, for example, vinyl, allyl, 1-propenyl, 1,3-butadiene-1-yl and Gex-5-enyl.

The term "halogen" is intended to refer to fluorine, chlorine, bromine and iodine.

The term "alkoxy" is intended to indicate a radical of the formula-O-R', where R' is an alkyl, as described above.

In the context of the present invention, the term "aryl" is intended to denote carbol the " aromatic ring radical or radical, represents a condensed aromatic ring system, where at least one of the rings is aromatic. Typical aryl groups include phenyl, diphenylol, naphthyl and the like.

Reduction of amino acids used in the context of the present invention have the following values

AUH3With-C(O)-
AlaAlanine
AsnAsparagine
Asn(alkyl)
R'=alkyl
Asn(aryl)
R'=aryl
AspAspartic acid
ArgArginine
β-Ala
Cha
Cyclohexylamin
Cgl
Cyclohexylglycine
CitCysCysteine
Dab(S)-2,4-diaminobutane acid
Dap(S)-2,3-diaminopropionic acid
D-Phe
GlnGlutamine
Gln(alkyl)
R'=alkyl
Gln(aryl)
R'=aryl
GluGlutamic acid
HisHistidine
gameid
Homo-arginine
Cys
Homo-cysteine
Hyp4-hydroxyproline
IleIsoleucine
LeuLeucine
LysLysine
MetMethionine
Met(O)
Met(O2)
1-Nal
2-Nal
Nle
Norleucine
OrnOrnithine
PhePhenylalanine
ProProline
2-PyAla
3-PyAla
4-PyAla
SerSerine
tBuGly
Tert-butylglycol
ThrThreonine
(4-thiazolyl)Ala
Tic
TyrTyrosine
TrpTryptophan
ValValine

In the context of the present invention, the term "agonist" is intended to refer to a substance that activates the receptor.

In the context of the present invention, the term "antagonist" is intended to denote a substance which neutralizes the effect of the agonist or counteracts the effect of the agonist by binding to its corresponding receptor.

In the context of the present invention, the term "pharmaceutically acceptable salt" is intended to indicate salts, which are not harmful for the patient. Such salts include pharmaceutically acceptable salts accession acid, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium. Salt accession acid include salts of inorganic acids and organic acids. Representative examples of suitable inorganic acids include hydrochloric, Hydrobromic, iodine, hydrogen, phosphorus, sulfur, nitric acid, and the like. Representative ol the action of suitable organic acids include formic, acetic, trichloroacetic, triperoxonane, propionic, benzoic, cinnamony, citric, fumaric, glycolic, lactic, maleic, malic, malonic, almond, oxalic acid, picric acid, pyruvic acid, salicylic, succinic, methansulfonate, econsultancy, tartaric, ascorbic, pambou, biotranslation, etanislao, gluconic, citraconate, aspartic, stearic, palmitic, EDTA, glycolic acid, para-aminobenzoic, glutamic, benzosulfimide, para-toluensulfonate acid and the like. Additional examples of pharmaceutically acceptable salts of joining inorganic or organic acid include pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated in this description by reference.

Examples of metal salts include salts of lithium, sodium, potassium, magnesium and the like.

Examples of salts of ammonium and alkylated ammonium include ammonium salts, methylamine, dimethylamine, trimethylammonium, ethylamine, hydroxyethylamine, diethylamine, butylamine, Tetramethylammonium and the like.

"Therapeutically effective amount" of a compound, as used here, means a quantity sufficient to treat, alleviate or partial stoppage of the clinical manifestations of this disease and its Oslo the changes. A quantity sufficient for this purpose, is defined as "therapeutically effective amount". The effective amount for each goal will depend on the severity of the disease or damage, and the weight and General condition of the subject. It should be clear that the determination of the appropriate dosage can be achieved using routine experimentation by constructing a matrix of values and testing different points in the matrix, which is within the competence of the ordinary practitioner or veterinarian.

The term "therapy" and "treatment"as used here means helping the patient and care in order to combat the condition, such as a disease or disorder. This term should include a full range of therapies for this condition that affects the patient, such as the introduction of active compounds to relieve symptoms or complications, to slow the progression of the disease, disorder, or condition, to alleviate or ameliorate symptoms and complications and/or for the treatment or elimination of a disease, disorder or condition, and to prevent the state where the warning should be understood as helping the patient and care in order to combat the disease, condition, or disorder and includes the introduction is their active compounds to prevent the onset of symptoms or complications. The patient to be treated, preferably is a mammal, particularly human, but can also include animals such as dogs, cats, cows, sheep and pigs.

The term "MES", as used here, means the complex of a certain stoichiometry formed by the dissolved substance (in this case, the connection according to the present invention and a solvent. Solvents can be, for example, water, ethanol or acetic acid.

Information confirming the possibility of carrying out the invention

In one embodiment X1 is a Nle or R-C(O)-Nle, where R is an alkyl or alkenyl containing up to 6 carbon atoms.

In one embodiment R represents alkyl containing up to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl and hexyl. Special mention should be made of methyl. The specified alkyl may be substituted by one or more than one Deputy, selected from hydroxyl and amino.

In one embodiment R1represents-N(R')2where each R" represents hydrogen, or where one R represents a C1-3alkyl, such as methyl, ethyl or propyl, which may be substituted amino, such as 2-amino-ethyl.

In one embodiment X represents Z1-Z2-Z3-Z4-Z5, Z2-Z3-Z4-Z5, Z3-Z4-Z5, Z4-Z5 or Z5, where

Z1 is an amino acid and is particularly Gly;

Z2 is an amino acid and, in particular, Ser or Ala;

Z3 represents Ser, Ala, Lys, Gln, Asn or D-Ser;

Z4 represents Tyr, Lys, His, Arg, gameid, Gln or Asn; and

Z5 represents Ser, Dab, Ala, Hyp, Gly, Pro or Thr;

and where N is the end of X allerban group R-C(O)-, where R represents alkyl containing up to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl and hexyl, in particular methyl. The specified alkyl may be substituted by one or more than one Deputy, selected from hydroxyl and amino. Special mention should be made of 2-hydroxy-3-methylbutanoyl and 2,4-diaminobutane.

In one embodiment X represents

Ala-Lys-Tyr-Ser- (SEQ ID NO: 1),

Ala-Lys-Ala-,

Asn-Arg-Gly-,

Asn-Arg-Hyp-,

Asn-Asn-Pro-,

Asn-Asn-Thr-,

Asn-His-Gly-,

Asn-His-Pro-,

Asn-gameid-Hyp-,

Asn-gameid-Thr-,

Asn-Tyr-Ser-,

Dab,

D-Ser-Arg-Pro-,

D-Ser-Arg-Thr-,

D-Ser-Asn-Hyp-,

D-Ser-Asn-Ser-,

D-Ser-His-Ser-,

D-Ser-His-Thr-,

D-Ser-gameid-Gly-,

D-Ser-gameid-Pro-,

D-Ser-Tyr-Gly-,

D-Ser-Tyr-Hyp-,

Gln-Arg-Hyp-,

Gln-Arg-Ser-,

Gln-Asn-Pro-,

Gln-Asn-Thr-,

Gln-His-Hyp-,

Gln-His-Thr-,

Gln-gameid-Gly-,

Gln-gameid-Ser-,

Gln-Tyr-Gly-,

Gln-Tyr-Pro-,

Gly-Ser-Gln-His-Ser- (SEQ ID NO: 2),

Gly-Ser-Gln-gameid-Ser- (SEQ ID NO: 3),

Ser-Arg-Gly-,

Ser-Arg-Pro-,

Ser-Arg-Ser-,

Ser-Arg-Thr-,

Ser-Asn-Gly-,

Ser-Asn-Ser-

Ser-Gln-His-Ser- (SEQ ID NO: 4),

Ser-Gln-Ser-,

Ser-His-Gly-,

Ser-His-Hyp-,

Ser-His-Pro-,

Ser-His-Ser-,

Ser-gameid-Pro-,

Ser-gameid-Ser-,

Ser-gameid-Thr-,

Ser-,

Ser-Tyr-Hyp-,

Ser-Tyr-Ser - or

Ser-Tyr-Thr-, each of which allerban on the N-end group R-C(O)-, where R represents alkyl containing up to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl and hexyl, in particular methyl. The specified alkyl may be substituted by one or more than one Deputy, selected from hydroxyl and amino. Special mention should be made of 2-hydroxy-3-methylbutanoyl and 2,4-diaminobutane.

In one embodiment X1 represents Ac-Nle.

In one embodiment X1 represents Ac-Gly-Ser-Gln-His-Ser-Nle (SEQ ID NO: 5).

In one embodiment X1 represents Ac-Ser-His-Ser-Nle (SEQ ID NO: 88).

In one embodiment X3 is a Met(O2), Tic, 3-PyAla, Ser, Cit, Leu, Phe(4-amino), Phe(3,4-dichloro), Phe(3,4-debtor), Dab, Cgl, Val, Cha, Phe, Dap, Ile, Thr, tBuGly, (4-thiazolyl)Ala or Hyp.

In one embodiment X3 represents C(O)2, Tic, 3-PyAla, Ser, Cit, Leu, Phe(4-amino), Phe(3,4-debtor), Dab, Phe, Dap, Thr, (4-thiazolyl)Ala, Hyp, Ans or Gln.

In one embodiment X3 is a Tic, Met(O)2, Ser, Hyp, Cit, Dap, (4-thiazolyl)Ala or 3-PyAla.

In one embodiment X3 is a Met(O)2.

In one embodiment X3 is a Hyp or 3-PyAla.

In one embodiment X4 represents D-Phe, D-Phe(4-chloro), D-Phe(4-iodine), D-Phe(3-trifluoromethyl), D-Phe(2-methyl) or D-Phe(2-chloro).

In one embodiment X4 represents D-Phe or D-Phe(4-chloro), and, in particular D-Phe.

In one embodiment the 6 represents Trp.

In one embodiment x2 represents Glu, and X7 represents Lys, and in another embodiment x2 is an Asp and X7 represents Lys.

In one embodiment x2-X3-X4-X5-X6-X7 represents c[X2-X3-D-Phe-Arg-Trp-Lys], where x2 represents Glu or Asp, and X3 represents a Met(O2), Tic, 3-PyAla, Ser, Cit, Leu, Phe(4-amino), Phe(3,4-dichloro), Phe(3,4-debtor), Dab, Cgl, Val, Cha, Phe, Dap, Ile, Thr, tBuGly, (4-thiazolyl)Ala or Norv particular, x2 can be a Glu. In particular, X3 can be a Tic, Met(O)2, Ser, Hyp, Cit, Dap, (4-thiazolyl)Ala or 3-PyAla, and specifically mention should be made of Hyp.

In one embodiment x2-X3-X4-X5-X6-X7 represents c[Glu-Hyp-D-Phe-Arg-Trp-Lys].

In one embodiment X3 is a Tic, Met(O)2, Ser, Hyp, Cit, Dap, (4-thiazolyl)Ala or 3-PyAla, and X1 represents AC-Gly-Ser-Gln-His-Ser-Nle- (SEQ ID NO: 5) or Ac-Nle.

In one embodiment X3 is a Tic, Met(O2), Ser, Hyp, Cit, Dap, (4-thiazolyl)Ala or 3-PyAla, X1 represents AC-Gly-Ser-Gln-His-Ser-Nle- (SEQ ID NO: 5) or Ac-Nle, and X4 represents D-Phe, and X6 represents Trp, and x2 represents Asp.

In one embodiment X3 is a Tic, Met(O)2, Ser, Hyp, Cit, Dap, (4-thiazolyl)Ala or 3-PyAla, X1 represents Ac-Gly-Ser-Gln-His-Ser-Nle- (SEQ ID NO: 5) or Ac-Nle, and X4 represents D-Phe, and X6 represents Trp, and x2 represents Glu.

In one embodiment, the peptides of the present invention is selected from

Ac-Nle-c[Glu-3-PyAla-D-Phe-Arg-Trp-ys]-NH 2(SEQ ID NO: 6)

Ac-Nle-c[Glu-Leu-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 7)

Ac-Nle-c[Glu-Phe(3,4-dichloro)-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 8)

Ac-Nle-c[Glu-MetO2-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 9)

Ac-Nle-c[Glu-Dab-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 10)

Ac-Nle-c[Glu-Cgl-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 11)

Ac-Nle-c[Glu-Val-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 12)

Ac-Nle-c[Glu-Tic-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 13)

Ac-Nle-c[Glu-Cha-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 14)

Ac-Nle-c[Glu-lle-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 15)

Ac-Nle-c[Glu-tBuGly-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 16)

Ac-Nle-c[Glu-Phe(3,4-debtor)-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 17)

Ac-Nle-c[Glu-Phe-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 18)

Ac-Ser-Tyr-Ser-Nle-c[Glu-3-PyAla-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 19)

H-Ala-Lys-Tyr-Ser-Nle-c[Glu-3-PyAla-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 20)

2-Hydroxy-3-methylbutanoyl-Ser-Nle-c[Glu-3-PyAla-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 21)

H-Dab-Nle-c[Glu-3-PyAla-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 22)

H-Ala-Lys-Ala-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 23)

AC-Nle-C[Glu-Hyp-Phe(4-iodine)-Arg-Trp-Lys]-NH2(SEQ ID NO: 24)

Gex-5-enoyl-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 25)

Ac-Gly-Ser-Gln-His-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 26)

Ac-Gly-Ser-Gln-gameid-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 27)

Ac-Gly-Ser-Gln-His-Ser-Nle-c[Glu-Met(O)2-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO:28)

Ac-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 29)

Ac-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-(2-amino-ethyl)amide (SEQ ID NO: 30)

Ac-Nle-c[Asp-Phe(4-amino)-D-Phe(4-chloro)-Arg-Trp-Lys]-NH2(SEQ ID NO: 31)

Ac-Asn-Tyr-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 32)

Ac-D-Ser-His-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Ly]-NH 2(SEQ ID NO: 33)

Ac-Gln-Arg-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 34)

Ac-Ser-gameid-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 35)

Ac-Gln-gameid-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 36)

Ac-Ser-Asn-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 37)

Ac-D-Ser-Asn-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 38)

Ac-Ser-Tyr-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 39)

Ac-D-Ser-Tyr-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 40)

Ac-Ser-His-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 41)

Ac-Gln-His-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 42)

Ac-Gln-Arg-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 43)

Ac-Asn-Arg-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 44)

Ac-Asn-gameid-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 45)

Ac-D-Ser-Asn-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 46)

Ac-Gln-Tyr-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 47)

Ac-Ser-His-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 48)

Ac-Asn-His-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 49)

Ac-Ser-Arg-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 50)

Ac-D-Ser-Arg-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 51)

Ac-Ser-gameid-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 52)

Ac-D-Ser-gameid-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 53)

Ac-Gln-Asn-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 54)

Ac-Asn-Asn-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 55)

Ac-Ser-Tyr-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 56)

Ac-D-Ser-His-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 57)

Ac-Gln-His-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 58)

Ac-Ser-Arg-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 59)

AcD-Ser-Arg-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2(SEQ ID NO: 60)

Ac-Ser-gameid-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 61)

Ac-Asn-gameid-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 62)

Ac-Gln-Asn-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 63)

Ac-Asn-Asn-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 64)

Ac-D-Ser-Tyr-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 65)

Ac-Gln-Tyr-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 66)

Ac-Ser-His-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 67)

Ac-Asn-His-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 68)

Ac-Ser-Arg-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 69)

Ac-Asn-Arg-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 70)

Ac-D-Ser-gameid-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 71)

Ac-Gln-gameid-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 72)

Ac-Ser-Asn-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 73)

Ac-Ser-Tyr-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 74)

Ac-Ser-His-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 75)

Ac-Ser-Arg-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 76)

Ac-Ser-His-Ser-Nle-c[Asp-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 77)

Ac-Ser-His-Ser-Nle-c[Glu-Ser-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 78)

Ac-Ser-His-Ser-Nle-c[Glu-Hyp-D-Phe(3-trifluoromethyl)-Arg-Trp-Lys]-NH2(SEQ ID NO: 79)

Ac-Ser-His-Ser-Nle-c[Glu-Hyp-D-Phe(2-methyl)-Arg-Trp-Lys]-NH2(SEQ ID NO: 80)

Ac-Ser-His-Ser-Nle-c[Glu-Hyp-D-Phe(2-chloro)-Arg-Trp-Lys]-NH2(SEQ ID NO: 81)

Ac-Nle-c[Asp-Thr-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 82)

Ac-Nle-c[Asp-Dap-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 83)

Ac-Nle-c[Asp-(4-thiazolyl)Ala-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 84)

Ac-Nle-c[Asp-Phe(4-amino)-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 85)

Ac-Nle-c[Asp-Cit-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 8)

Ac-Ser-His-Ser-Nle-c[Asp-(4-thiazolyl)Ala-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 87).

Other embodiments of the invention are clear from the following claims.

In one embodiment of the present invention the compound is an agonist of the receptor melanocortin.

In one embodiment of the present invention the compound is an agonist MS.

In one embodiment of the present invention the compound is a selective agonist MS. In this context, selectivity should be understood in connection with the activity of compounds against MS, MS and/or MS. If the connection is much more effective agonist MS than it is an effective agonist MS, MS and/or MS, it is considered a selective agonist MS. The effectiveness of compounds in relation to MS and MS determined in the analysis of the binding of the receptor, as described in analysis IV (MS) and the analysis of V (S). If the connection is more than 10 times, such as more than 50 times, such as more than 100 times more effective against MS than in relation to MS, it is considered a selective agonist MS towards MS. The effectiveness of compounds in relation to MS, MS and MS determined in functional assays, as described in analysis II (MS and MS) and analysis III (MS). If the connection is more than 10 times, such as more than 50 times, such as more than 100 rappolee effective against MS, than with respect to MS, it is considered a selective agonist MS towards MS. If the connection is more than 10 times, such as more than 50 times, such as more than 100 times more effective against MS than in relation to MS, it is considered a selective agonist MS towards MS. In a particular embodiment of the compound of the present invention is a selective agonist MS towards MS, in relation to MS, in relation to MS, in relation to MS and MS, in relation to MS and MS, in relation to MS and MS or in relation to MS, MS and MS.

In one embodiment the compound of the present invention is a selective agonist MS and antagonist MS. In this context, the connection is considered selective agonist MS and antagonist MS if it is a selective agonist MS towards MS and MS, as discussed above, and antagonisitic MS based on the dimensions described in the analysis II. Connection with the value of the IC50less than 100 nm, such as less than 10 nm, such as less than 5 nm, such as less than 1 nm, is considered the antagonist MS.

In one embodiment the compound of the present invention is a selective agonist MS, and selective agonist MS. In this context, the connection is considered selective agonist MS and MS if it is significantly more effective is active agonist MS and MS, than it is an effective agonist MS and MS. The selectivity of the compounds in relation to MS and MS determined by comparing the effectiveness defined for MS, as described in analysis IV, with efficiency for MS defined, as described in analysis II. If the connection is more than 10 times, such as more than 50 times, such as more than 100 times more effective against MS than in relation to MS, it is considered a selective agonist MS towards MS. The selectivity of the compounds in relation to MS and MS determined by comparing the efficiency, defined as described in the analysis II. If the connection is more than 10 times, such as more than 50 times, such as more than 100 times more effective against MS than in relation to MS, it is considered a selective agonist MS towards MS. Selectivity MS connection towards MS and MS determine, as discussed above.

Compounds of the present invention modulate the receptor melanocortin, and, therefore, are considered particularly suitable for treatment of diseases or conditions that can be treated by modulating the activity of receptor melanocortin. In particular, the compounds of the present invention are particularly suitable for the treatment of diseases or conditions through activation of prescriptions is ora MS.

In one embodiment of the present invention, a method for slowing the progression from impaired glucose tolerance (IGT) to type 2 diabetes, where the patient is in need of this, introducing an effective amount of the compounds of the present invention.

In one embodiment of the present invention, a method for slowing the progression from type 2 diabetes to insulin-dependent diabetes in which the patient is in need of this, introducing an effective amount of the compounds of the present invention.

In one embodiment of the invention relates to a method of treating obesity or preventing overweight, wherein the patient in need this, introducing an effective amount of the compounds of the present invention.

In one embodiment of the present invention a method is proposed for the regulation of appetite, wherein the patient in need this, introducing an effective amount of the compounds of the present invention.

In one embodiment of the present invention relates to a method of inducing satiety, wherein the patient in need this, introducing an effective amount of the compounds of the present invention.

In one embodiment of the invention relates to a method for warning redial body weight after successful weight loss body.

In one embodiment of Britanie relates to a method of preventing weight gain, wherein the patient in need this, introducing an effective amount of the compounds of the present invention.

In one embodiment of the invention relates to a method of increasing power consumption.

In one embodiment of the present invention, a method of treatment of a disease or condition associated with overweight or obesity, wherein the patient in need this, introducing an effective amount of the compounds of the present invention.

In one embodiment of the invention relates to a method for the treatment of bulimia nervosa, in which the patient is in need of this, introducing an effective amount of the compounds of the present invention.

In one embodiment of the invention relates to a method of treating a disease or state selected from atherosclerosis, hypertension, diabetes, type 2 diabetes, impaired glucose tolerance (IGT), dyslipidemia, coronary heart disease, gallbladder disease, gallbladder stones, osteoarthritis, cancer, sexual dysfunction and risk of premature death, in which the patient is in need of this, introducing an effective amount of the compounds of the present invention.

In particular, the compounds of the present invention may be suitable for the treatment of these diseases in patients with obesity or overweight. Accordingly, in the present from which reenie also proposed a method for the treatment of patients with obesity diseases or conditions, selected from type 2 diabetes, impaired glucose tolerance (IGT), dyslipidemia, coronary heart disease, gallbladder disease, gallbladder stones, osteoarthritis, cancer, sexual dysfunction and risk of premature death in patients with obesity where the patient is in need of this, introducing an effective amount of the compounds of the present invention.

In addition, agonists of the receptor MS can have a positive effect on insulin sensitivity, drug dependence by means of modulation feedback system, hemorrhagic shock. In addition, agonist MS and MS has antipyretic effects, and they both allegedly involved in the regeneration of peripheral nerves, and it is known that the receptor MS reduces the stress response.

When all therapeutic methods disclosed here, the connection of the present invention it is possible to enter one. However, it can also enter in combination with one or more additional therapeutically active compound, either sequentially or simultaneously.

In one aspect the invention relates to pharmaceutical compositions containing the compound of the present invention, possibly in combination with one or more additional therapeutically active compound, pax is with one or more pharmaceutically acceptable carrier or excipient in unit dosage form, containing from about 0.05 mg to about 1000 mg, such as from about 0.1 mg to about 500 mg, such as from about 0.5 mg to about 200 mg of the compounds of the present invention.

The present invention also relates to the use of compounds of the present invention for the manufacture of a medicinal product for the treatment of diseases or conditions selected from overweight or obesity, bulimia, atherosclerosis, hypertension, type 2 diabetes, impaired glucose tolerance (IGT), dyslipidemia, coronary heart disease, gallbladder disease, gallbladder stones, osteoarthritis, cancer, sexual dysfunction and risk of premature death.

The present invention also relates to the use of compounds of the present invention, one or in combination with an additional therapeutically active compound, for the manufacture of medicines, is effective in slowing the progression from IGT to type 2 diabetes, slowing the progression from type 2 diabetes to insulin-dependent diabetes, regulation of appetite, inducing satiety, preventing weight gain after successfully losing weight or increase energy expenditure.

As described above, the compounds of the present invention can be entered or used in combination with one or more than one additional the additional therapeutically active compound. Suitable additional compounds may be selected from antidiabetic agents, lipid-lowering agents, agents, anti-obesity, anti-hypertensive agents and agents for the treatment of complications caused by diabetes or associated with diabetes.

Suitable antidiabetic agents include insulin, derivatives of like peptide-1 (GLP-1), such as disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated in this description by reference, as well as orally active hypoglycemic agents.

Suitable orally active hypoglycemic agents preferably include imidazolines, sulfonylureas, biguanides, meglitinide, oxadiazolidine preparations, thiazolidinediones, insulin sensitizers, inhibitors of α-glucosidase, agents acting on the ATP-dependent potassium channel of the β-cells of the pancreas, for example, the discoverers (activators) of potassium channels, such as disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S), which are incorporated in this description by reference, openers potassium channels, such as ornithin, blockers of potassium channels, such as nateglinide or BTS-67582, the glucagon antagonists, such as disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), all of which are included in this description by reference, agonists of GLP-1, such as disclosed in WO 00/42026 (Novo Nordisk A/S and Agourn Pharmaceuticals, Inc.), included in this description by reference, inhibitors dipeptidylpeptidase-IV (DPP-IV)inhibitors patientinitiated (Ptpase), activators of glucokinase, such as described in WO 02/08209 (Hoffmann La Roche), inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, modulators of the seizure of glucose inhibitors glikogensintetazy-3 (GSK-3), compounds modifying the lipid metabolism such as lipid-lowering agents and antilipidemic agents, compounds that reduce the absorption of food, and agonists of the receptor-activated proliferation peroxisome (PPAR agonists and agonists of the receptor retinoid X (RXR agonists, such as ALRT-268, LG-1268 or LG-1069.

Other examples of suitable additional therapeutically active compounds include insulin or insulin analogues, sulfonylurea, for example, tolbutamide, hlorpropamid, tolazamide, glibenclamide, glipizide, glimepiride, glicazide, gliburid, biguanide, for example, Metformin, meglitinides, for example, Repaglinide or sinapinic/nateglinide.

Other examples of suitable additional therapeutically active compounds include thiazolidinedione sensitizers to insulin, such as troglitazone, ciglitazone, pioglitazone, rosiglitazone, isopetasin, darglitazone, englitazone, CS-011/CI-1037 or T or compounds disclosed in WO 97/41097 (DRF-2344), WO97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which are incorporated in this description by reference.

Other examples of suitable additional therapeutically active compounds include insulin sensitizers, such as GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-N, LY510929. Including infrastructure-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313 (NN622/DRF-2725), WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 (Dr. Reddy's Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A/S), which are incorporated in this description by reference.

Other examples of suitable additional therapeutically active compounds include inhibitors of α-glucosidase, such as voglibose, emiglitate, miglitol or acarbose.

Other examples of suitable additional therapeutically active compounds include inhibitors of glycogen phosphorylase, for example, compounds described in WO 97/09040 (Novo Nordisk A/S).

Other examples of suitable additional therapeutically active compounds include glucokinase activator.

Other examples of suitable additional therapeutically active compounds include the agent acting on the ATP-dependent potassium channel of the β-cells of the pancreas, for example, tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or Repaglinide.

Other examples of suitable additional tera is efticiency active compounds include nateglinide.

Other examples of suitable additional therapeutically active compounds include hypolipidemic agent or antilipidemic agent, such as cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.

Other examples of said additional therapeutically active compounds include compounds against obesity or agents that regulate appetite. Such compounds can be selected from the group consisting of agonists CART (transcript regulated by cocaine and amphetamine), antagonists of NPY (neuropeptide Y), agonists MS (melanocortin 3), agonists MS (melanocortin 4), antagonists of orexin, agonists of TNF (tumor necrosis factor)agonists, CRF (factor that stimulates corticotropin), antagonists of CRF BP (binding protein factor that stimulates corticotropin), agonists of urocortin, β3-adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH agonists (melanocytestimulating hormone)antagonists to sit (melaniemelanie hormone)agonists, CCK (cholecystokinin), inhibitors of reuptake of serotonin (fluoxetine, seroxat or citalopram), reuptake inhibitors of serotonin and norepinephrine agonists NT (serotonin)agonists of bombezin, antagonists Galanina, growth hormone, the actors of growth, such as prolactin or placental lactogenic, compounds which release growth hormone, TRH agonists (hormone that stimulates tireotropina), modulators of the UCP 2 or 3 (nswazwi protein 2 or 3), chemical nesvezhih agents, leptin agonists, DA agonists (dopamine) (bromocriptine, dobracina), inhibitors of lipase/amylase, modulators of PPAR, RXR modulators, agonists TR β adrenergic CNS stimulating agents, inhibitors AGRP (protein corresponding to the gene agouti), H3 antagonists of histamine, such as disclosed in WO 00/42023, WO 00/63208 and WO 00/64884 included in this description by reference, exendin-4 agonists of GLP-1 and ciliary neurotrophic factor. Additional agents against obesity are bupropion (an antidepressant), topiramate (anticonvulsant agent), ecopipam (antagonist of dopamine D1/D5), naltrexone (an opioid antagonist) and peptide YY3-36(Batterham et al., Nature 418, 650-654 (2002)).

In one embodiment, the agent against obesity is a leptin.

In one embodiment, the agent against obesity is a peptide YY3-36.

In one embodiment, the agent against obesity is an inhibitor of the reuptake of serotonin and norepinephrine, such as sibutramine.

In one embodiment, the agent against obesity is a lipase inhibitor such as orlistat.

In one embodiment of the Gent against obesity is an adrenergic CNS stimulating agent, for example, dexamfetamine, amphetamine, phentermine, mazindol, phendimetrazine, diethylpropion, fenfluramine or dexfenfluramin.

Other examples of suitable additional therapeutically active compounds include anti-hypertensive agents.

Examples of antihypertensive agents are β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE inhibitors (angiotensin-converting enzyme), such as benazepril, captopril, enalapril, fosinopril, lisinopril, inapril and ramipril, calcium channel blockers, such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and α-blockers such as doxazosin, urapidil, prazosin and terazosin.

In one embodiment of the uses and methods of the present invention, the compound of the present invention can be entered or used in combination with more than one of the aforementioned compounds, e.g. in combination with Metformin and sulfonylurea, such as gliburid; a sulfonylurea and acarbose; nateglinide and Metformin; acarbose and Metformin; a sulfonylurea, Metformin and troglitazone; insulin and a sulfonylurea; insulin and Metformin; insulin, Metformin and a sulfonylurea; insulin and troglitazone; insulin and lovastatin, etc.

The pharmaceutical composition

Compounds according to the present invention can be entered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. Preparations of pharmaceutical compositions according to the present invention can be prepared with pharmaceutically acceptable carriers or diluents, as well as with any of the known adjuvants and excipients in accordance with conventional methods, such as described in Remington: The Science and Practice of Pharmacy, 20thEdition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 2000.

Drugs pharmaceutical compositions can be specially prepared for administration by any suitable route, such as oral, rectal, nasal, pulmonary, local (including transbukkalno and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, preferably by oral route. It should be clear that the preferred path will depend on the General condition and age of the subject to be treated, from the nature of the condition to be treated, and the selected active ingredient.

It is established that many analogues MT-11 exhibit a short half-life, and that the effect of the compounds, therefore, disappears quite quickly the donkey injection. This problem can be overcome by use of dosage regimes with shorter intervals between dosages or dosage regimes without intervals, i.e. continuous dosing or dosage regimes, characterized by periods of continuous dosing, interrupted by periods without dosage.

In the art there are known various pumps and devices that are useful for the introduction of a drug on a continuous circuit or intermittent-continuous scheme. In its simplest form, the reservoir containing the drug is presented in the applicable form, include in such a way that the force of gravity, through the valve, which regulates the current, allows the drug to penetrate through the outer layer of the skin of the subject through a needle or similar device that enables subcutaneous, intradermal or intravenous injection. It is also preferable to use a pump for drug administration, and not the force of gravity. Pump can be an external pump, or they can be together with a reservoir implanted in the subject. The pump described herein may be subject, and the current of the pump can be adjusted individually to optimize the effect, taking into account the existing medicine and the subject to be treated.

Compositions according to the present izaberete the Oia is particularly useful when included in system drug delivery with adjustable, slow, prolonged, delayed and slow release. In particular, these compositions are useful for inclusion in the system of parenteral controlled release and sustained release (where both systems lead to a drastic decrease in the number of introductions), well known to specialists in this field of technology. Even more preferred is a subcutaneous injection systems controlled release and delayed release. Without limiting the scope of the invention, examples of useful systems and compositions of the regulated release are hydrogels, oily gels, liquid crystals, polymeric micelles, microspheres and nanoparticles.

Pharmaceutical compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, lozenges, pills, pills, pellets, powders and granules. Where it is suitable, they can be prepared with coatings, such as intersolubility coating, or can be prepared such drugs, to provide a modified release of the active ingredient, such as a limited or prolonged release, according to methods well known in the art.

Liquid dosage forms for oral administration include solutions, emulsions, aqueous or oil suspensions, sire is dust and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injection solutions, dispersions, suspensions or emulsions, and sterile powders, which prepare sterile injectable solutions or dispersions prior to use. Injection preparations in the form of a depot is also considered as included in the scope of the present invention.

Other suitable forms of introduction include suppositories, sprays, ointments, creams, gels, inhalers, skin patches, implants, etc.

A typical oral dose is in the range from about 0.001 to about 100 mg/kg of body weight per day, preferably from about 0.01 to about 50 mg/kg of body weight per day and more preferably from about 0.05 to about 10 mg/kg of body weight per day with the introduction of one or more than one dose, for example, from 1 to 3 doses. As indicated above, continuous scheme is the introduction or intermittent-continuous scheme of injection may be preferred. The exact dose will depend on the frequency and mode of administration, sex, age, weight and General condition of the subject to be treated, the nature and severity of the condition to be treated, and any concomitant diseases to be treated and other factors evident to the experts in this field of technology.

Drugs can be submitted for convenience is in unit dosage form means, well-known specialists in this field of technology. Typical unit dosage form for oral administration one or more than one time per day, for example, from 1 to 3 times per day, can contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferably from about 0.5 mg to about 200 mg

For parenteral routes such as intravenous, intrathecal, intramuscular, and for such introduction typical dosages are of the order of about half of the dose used for oral administration.

Compounds according to the present invention, generally used in the form of free substance or in the form of its pharmaceutically acceptable salts.

Examples are the salt of the accession acid compounds having the function of a free base and the salt of the attaching base compounds having the function of a free acid. The term "pharmaceutically acceptable salts" refers to non-toxic salts of the compounds according to the present invention, which are usually obtained by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. When the connection according to the present invention, such as compound of formula (I), contains the function of the national group of the free base, such salts receive a conventional manner by treating a solution or suspension of this compound with a chemical equivalent of a pharmaceutically acceptable acid. When the connection according to the present invention, such as compound of formula (I)contains a functional group of the free acid, a salt such receive a conventional manner by treating a solution or suspension of this compound with a chemical equivalent of a pharmaceutically acceptable base. Physiologically acceptable salts of the compounds with the hydroxy-group include the anion of the compounds in combination with a suitable cation such as a sodium cation or ammonium. Other salts which are not pharmaceutically acceptable may be useful for producing compounds according to the present invention, and they form an additional aspect of the present invention.

For parenteral administration may apply the solutions of the compounds according to the present invention in a sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil. If you want such aqueous solutions should contain a buffer agent, and the liquid diluent first make isotonic field add sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, inside isicelo, subcutaneous and intraperitoneal administration. Used sterile water environment can be easily obtained by methods known to experts in this field of technology.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.

Examples of solid carriers are lactose, terra alba (white clay), sucrose, cyclodextrin, talc, gelatin, agar, pectin, Arabic gum, magnesium stearate, stearic acid and lower alkalemia cellulose ethers.

Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, amines, fatty acids, polyoxyethylene and water. The carrier or diluent may include any substance limited release, known in the art, such as glycerylmonostearate or glycerylmonostearate, alone or mixed with wax. The pharmaceutical compositions formed by combining the compounds for use according to the present invention and pharmaceutically acceptable carriers are then readily administered in several dosage forms, suitable for the described routes of administration. Medications may be presented in unit dosage form by methods known in the pharmaceutical field.

Drugs under this and the finding, suitable for oral administration may be presented as discrete units such as capsules or tablets, each of which contains a certain amount of the active ingredient, and which may include a suitable excipient. In addition, orally applicable drugs can be in the form of powder or granules, a solution or suspension in aqueous or non-aqueous liquid or liquid emulsion, oil in water or water in oil.

Compositions intended for oral use can be prepared by any known method, and such compositions may contain one or more than one agent selected from the group consisting of sweeteners, taste-aromatic agents, dyes and preservatives in order to provide pharmaceutically elegant and acceptable to the taste of drugs. Tablets may contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may constitute, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate;

granulating and loosening agents such as corn starch or alginic acid; binding agents, for example starch, gelatin or the Arabian gum; and lubricating agents, for example the extent the rat magnesium, stearic acid or talc. Tablets may be uncoated or they may be coated by known techniques to delay opening and absorption in the gastrointestinal tract and, therefore, can provide a delayed action for a long period. For example, you can use the substance, providing a delayed action, such as glycerylmonostearate or glycerylmonostearate. Tablets can also be coated with the help of the techniques described in U.S. patent No. 4356108, 4166452 and 4,265,874 included in this description by reference, to obtain the osmotic therapeutic tablets for controlled release.

Preparations for oral administration may be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid petroleum jelly or olive oil.

Aqueous suspensions may contain the active compound in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspendresume agents, such as sodium carboxymethyl cellulose, methylcellulose, hydrox is prophylatically, sodium alginate, polyvinylpyrrolidone, resin tragakant and Arabian gum; dispersing and wetting agents may be a natural phosphated, such as lecithin, or condensation products of accelerated with fatty acids, for example polyoxyethylene, or condensation products of accelerated with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of accelerated with partial esters formed from fatty acids and exit, such as polyoxyethylenesorbitan, or condensation products of accelerated with partial esters formed from fatty acids, and anhydrides of exit, such as polyethylenterephthalat. Aqueous suspensions may also contain one or more than one dye, one or more than one aromatic agent and one or more than one sweetener, such as sucrose or saccharin.

Preparations in the form of oil suspensions can be prepared by suspension of the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid petrolatum. Oily suspensions may contain a thickening agent, for example beeswax, hard vaseline or cetyl alcohol. Sweeteners, such as those listed above, the aromatic agents can be added to obtain an acceptable taste oral drug. These compositions may be preserved by adding an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for the manufacture of aqueous slurry by adding water, contain the active compound in a mixture with dispersing or wetting agent, suspenders agent and one or more than one preservative.

Examples of suitable dispersing or wetting agents and suspendida agents mentioned above. Additional excipients, for example sweetening, aromatic agents and colorants may also be present.

Pharmaceutical compositions containing a compound according to the present invention may also be in the form of emulsions of oil in water. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or mineral oil, such as liquid petrolatum, or a mixture thereof. Suitable emulsifying agents may be a natural resin, such as the Arabian gum or resin tragakant, natural phosphatides, for example soy lecithin, and esters or partial esters formed from fatty acids, and anhydrides of exit, such as servicemanual, and condensation products of these partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Emulsion t is the train to contain sweeteners and aromatic agents.

Preparations in the form of syrups and elixirs can be prepared with a sweetener, such as glycerin, propylene glycol, sorbitol or sucrose. These preparations may also contain an emollient, a preservative, as well as aromatic agents and dyes. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oily suspension. Medication in the form of this suspension can be prepared by known methods using suitable dispersing or moisturizing agents and suspendresume agents described above. This sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example in the form of a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils convenient to use as solvent or suspendida environment. For this purpose you can use any soft fixed oils using synthetic mono - and diglycerides. In addition, fatty acids such as oleic acid find use in the manufacture of injection solutions.

The composition can also be in the form of soup is ositories for rectal administration of the compounds according to the present invention. These compositions can be prepared by mixing the drug with a suitable not irritating excipient, which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such substances include, for example, cocoa butter and polyethylene glycols.

For local applications consider creams, ointments, jellies, solutions or suspensions, etc. containing compounds of the present invention. For these purposes, preparations for local application will include a gargle for mouth and throat.

Compounds according to the present invention can also be entered in the form of liposomal delivery systems, such as small single-layer vesicles, large single-layer and multi-layered vesicles vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

In addition, some compounds according to the present invention may form a solvate with water or common organic solvents. Such a solvate is also included in the scope of the present invention.

Thus, in the next incarnation of the proposed pharmaceutical composition comprising a compound according to the present invention or its pharmaceutically acceptable salt, MES or Proletarskoy one or more than one pharmaceutically acceptable carrier, excipient or diluent.

If a solid carrier is used for oral administration, the preparation can be tableted, placed in a hard gelatin capsule in powder form or granules, or it may be in the form of tablets or cakes. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g When using liquid media, the drug may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as liquid water or non-aqueous suspension or solution.

Examples

All connections according to the present invention can be synthesized by specialists in the art using standard stages of synthesis and removal of protection. Description of the necessary equipment and methods of synthesis can be found in "The Fine Art Of Solid Phase Synthesis", 2002/3 Catalog, Novabiochem.

Typical examples of which include stage cyclization below:

Ac-Nle-c[Glu-Met(O2)-D-Phe-Arq-Trp-Lys]-NH2

1A. The resin with the protected peptidyl H-Nle-Glu(OPip)-Met(O2)-D-Phe-Arg(Pmc)-Trp(Boc)-Lys(Mtt)-(Rink resin) was synthesized according to the Fmoc strategy on a peptide synthesizer Applied Biosystems 431 a in 0.25 mmol scale using the protocols of the manufacturer "FastMoc UV, using indirect HBTU (2-(1H-benzotriazol-1-yl-)-1,1,3,3-Tetra is tilorone hexaphosphate) combination in NMP (N-organic and UV monitoring of the removal of the protective Fmoc group. The starting resin used for the synthesis consisted of 0.50 g of (4-((2',4'-acid)-(Fmoc-amino)methyl)-proximodistally resin (Rink resin) (Novabiochem) with loading of 0.51 mmol/g under the protected derivatives of amino acids represented Fmoc-Nle-OH, Fmoc-D-Phe-OH, Fmoc-Arg(Pmc)-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Glu(OPip)-OH, Fmoc-Met(O2)-OH.

1B. Then the resin with the peptide resulting from stage (1A), was etilirovany pre-activated solution of acetic acid (1.0 mmol), HODhbt (3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine) (1.0 mmol), DIC (diisopropylcarbodiimide) (1.0 mmol) and DIEA (N,N-diisopropylethylamine) (0.25 mmol) in NMP (5 ml). After 2 hours at room temperature the resin was filtered and washed with NMP and DHM (dichloromethane).

1B. The resin obtained from stage (1B), was treated with 5 x 10 ml 2% TFU (triperoxonane acid), 2% TPP (triethylsilane) in DHM for 60 minutes with occasional stirring. The resin washed with NMP, NMP with 5% DIEA and NMP. The peptide was subjected to cyclization using HODhbt (1.0 mmol), Rubor (benzotriazol-1 yloxy)triprolidine hexaflurophosphate, 1 N-benzotriazol-1-electroparadise hexaphosphate) (1.0 mmol) and DIEA (2.0 mmol) in NMP (5 ml) with periodic stirring for 4 h, the Resin washed with NMP and DHM.

1, the Peptide was tsalala from the resin obtained in stage (1B), by stirring for 60 minutes at anatoy temperature with 10 ml of 2.5% water and 2.5% TPP in TFU. The mixture was filtered, and the filtrate was concentrated to approximately 1 ml by a stream of nitrogen. The crude peptide was besieged from the obtained oil with 50 ml diethyl ether and washed 3 times with 50 ml diethyl ether.

The crude cyclic peptide was purified preparative RP-HPLC. Analytical data, see example 4 below.

In all the examples below, the Rt values represent the values of the retention time and mass values represent values that are defined by the MS detector, obtained by using one of the following devices LC/MS (liquid chromatography/mass spectrometry).

System LC/MS 1: Agilent 1100 Series, electrospray; column: Waters XTerra® C185 μm to 3.0·50 mm; water/acetonitrile containing 0.05% TFU; gradient: 5%→100% acetonitrile from 0 to 6.75 min, elution of up to t=9,0 min; flow 1.5 ml/min

System LC/MS 2: Sciex API-100 Quadrupole MS, electrospray; column: Waters XTerra® C185 μm to 3.0·50 mm; water/acetonitrile containing 0.05% TFU; gradient: 5%→90% acetonitrile from 0 to 7.5 min, elution of up to t=10,0 min; flow 1.5 ml/min

System LC/MS 3: Sciex API 150 Ex Quadrupole MS, electrospray; column: Waters XTerra® C185 μm to 3.0·50 mm; water/acetonitrile containing 0.05% TFU; gradient: 5%→15% acetonitrile from 1.0 to 2.0 min, 15%→45% acetonitrile from 2.0 to 28.0 min, 45%→90% acetonitrile from 28.0 to 30.0 min, elution of up to t=30,0 min; flow 1.5 ml/min

System LC/MS 4: as described for the system is s 3, but with a different gradient: 5%→20% acetonitrile and 1.0 to 3.0 min, 20%→50% acetonitrile from 3.0-16.0 min, 50%→90% acetonitrile from of 16.0 to 18.0 min, elution of up to t=18,0 minutes

Example 1

Ac-Nle-c[Glu-3-PyAla-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 2): Rt=6,40 min; (m+1)=1050

Example 2

Ac-Nle-c[Glu-Leu-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=a 3.06 min; (m+1)=1015

Example 3

Ac-Nle-c[Glu-Phe(3,4-dichloro)-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=3,41 min; (m+1)=1117

Example 4

Ac-Nle-c[Glu-Met(O2)-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=2,50 min; (m+1)=1065

Example 5

Ac-Nle-c[Glu-Dab-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=2,13 min; ((m+2)/2)=501

Example 6

Ac-Nle-c[Glu-Cgl-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=3,21 min; (m+1)=1040

Example 7

Ac-Nle-c[Glu-Val-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=2,69 min; (m+1)=1000

Example 8

Ac-Nle-c[Glu-Tic-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=2,88 min; (m+1)=1061

Example 9

Ac-Nle-c[Glu-Cha-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=3,17 min; (m+1)=1054

Example 10

Ac-Nle-c[Glu-Ile-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=2,97 min; (m+1)=1015

Por what measures 11

Ac-Nle-c[Glu-tBuGly-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=2,96 min; (m+1)=1015

Example 12

Ac-Nle-c[Glu-Phe(3,4-debtor)-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=is 3.08 min; (m+1)=1084

Example 13

Ac-Nle-c[Glu-Phe-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=2,97 min; (m+1)=1050

Example 14

Ac-Ser-Tyr-Ser-Nle-c[Glu-3-PyAla-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 2): Rt=2,4 min; (m+1)=1387

Example 15

H-Ala-Lys-Tyr-Ser-Nle-c[Glu-3-PyAla-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 2): Rt=2,1 min; (m+1)=1457

Example 16

2-Hydroxy-3-methylbutanoyl-Ser-Nle-c[Glu-3-PyAla-D-Phe-Arg-Trp-Lys]-NH2

The first diastereoisomer

LC/MS (system 2): Rt=2,5 min; (m+1)=1108

The second diastereoisomer

LC/MS (system 2): Rt=2,6 min; (m+1)=1108

Example 17

H-Dab-Nle-c[Glu-3-PyAla-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=1,84 min; ((m+2)/2)=554

Example 18

H-Ala-Lys-Ala-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=1,9 min; (m+1)=1243

Example 19

Ac-Nle-c[Glu-Hyp-D-Phe(4-iodine)-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=2,73 min; (m+1)=1140

Example 20

Gex-5-enoyl-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=2,92 min; ((m+2)/2)=534

When is EP 21

Ac-Gly-Ser-Gln-His-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 2): Rt=2,21 min; ((m+2)/2)=756

Example 22

Ac-Gly-Ser-Gln-gameid-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 1): Rt=2,15 min; ((m+2)/2)=772

Example 23

Ac-Gly-Ser-Gln-His-Ser-Nle-c[Glu-Met(O)2-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 2): Rt=2,54 min; (m+1)=1561

Example 24

Ac-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 4): Rt=5,66 min; (m+1)=1015

Example 25

AC-Nle-C[Clu-Hyp-D-Phe-Arg-Trp-Lys]-(2-amino-ethyl)amide

LC/MS (system 4): Rt=4,71 min; ((m+2)/2)=530

Example 26

Ac-Nle-c[Asp-Phe(4-amino)-D-Phe(4-chloro)-Arg-Trp-Lys]-NH2

LC/MS (system 4): Rt=3.3V min; ((m+2)/2)=543

Example 27

Ac-Asn-Tyr-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=8,46 min; ((m+2)/2)=690

Example 28

Ac-D-Ser-His-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=the ceiling of 5.60 min; ((m+2)/2)=664

Example 29

Ac-Gln-Arg-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,51 min; ((m+2)/2)=694

Example 30

Ac-Ser-gameid-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,75 min; ((m+2)/2)=680

Example 31

Ac-Gln-gameid-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,62 min; ((m+2)/2)=700

Example 32

Ac-Ser-Asn-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=6,87 min; (m+1)=651

Example 33

Ac-D-Ser-Asn-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=6,88 min; (m+1)=652

Example 34

Ac-Ser-Tyr-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=8,11 min; ((m+2)/2)=690

Example 35

Ac-D-Ser-Tyr-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=8,24 min; ((m+2)/2)=690

Example 36

Ac-Ser-His-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,13 min; ((m+2)/2)=676

Example 37

Ac-Gln-His-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,16 min; ((m+2)/2)=697

Example 38

Ac-Gln-Arg-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,2 min; ((m+2)/2)=706

Example 39

Ac-Asn-Arg-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,13 min; ((m+2)/2)=699

Example 40

Ac-Asn-gameid-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,47 min; ((m+2)/2)=707

Example 41

Ac-D-Ser-Asn-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=6.8 min; ((m+2)/2)=665

Example 42

Ac-Gln-Tyr-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=9,06 min; ((m+2)/2)=702

Example 43

Ac-Ser-His-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,7 min; ((m+2)/2)=669

Example 44

Ac-Asn-His-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,59 min; ((m+2)/2)=682

Example 45

Ac-Ser-Arg-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=of 5.92 min; ((m+2)/2)=678

Example 46

Ac-D-Ser-Arg-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,93 min; ((m+2)/2)=678

Example 47

Ac-Ser-gameid-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

p> LC/MS (system 3): Rt=6,06 min; ((m+2)/2)=685

Example 48

Ac-D-Ser-gameid-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=6,13 min; ((m+2)/2)=685

Example 49

Ac-Gln-Asn-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=a 7.85 min; ((m+2)/2)=677

Example 50

Ac-Asn-Asn-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=8,03 min; ((m+2)/2)=671

Example 51

Ac-Ser-Tyr-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=9,04 min; ((m+2)/2)=683

Example 52

Ac-D-Ser-His-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=6,04 min; ((m+2)/2)=671

Example 53

Ac-Gln-His-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,61 min; ((m+2)/2)=691

Example 54

Ac-Ser-Arg-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=6,02 min; ((m+2)/2)=680

Example 55

Ac-D-Ser-Arg-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,77 min; ((m+2)/2)=680

Example 56

Ac-Ser-gameid-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,99 min; ((m+2)/2)=687

Example 57

Ac-Asn-gameid-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,91 min; ((m+2)/2)=701

Example 58

Ac-Gln-Asn-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=7,11 min; ((m+2)/2)=680

Example 59

Ac-Asn-Asn-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=6,95 min; ((m+2)/2)=672

Example 60

Ac-D-Ser-Tyr-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=8,78 min; ((m+2)/2)=661

Example 61

Ac-Gln-Tyr-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=8,48 min; ((m+2)/2)=68

Example 62

Ac-Ser-His-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,73 min; ((m+2)/2)=648

Example 63

Ac-Asn-His-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,56 min; ((m+2)/2)=662

Example 64

Ac-Ser-Arg-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,71 min; ((m+2)/2)=658

Example 65

Ac-Asn-Arg-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,77 min; ((m+2)/2)=672

Example 66

Ac-D-Ser-gameid-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,93 min; ((m+2)/2)=665

Example 67

Ac-Gln-gameid-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,72 min; ((m+2)/2)=685

Example 68

Ac-Ser-Asn-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=6,84 min; ((m+2)/2)=637

Example 69

Ac-Ser-Tyr-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=8,68 min; ((m+2)/2)=676

Example 70

Ac-Ser-His-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,73 min; ((m+2)/2)=664

Example 71

Ac-Ser-Arg-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,94 min; ((m+2)/2)=673

Example 72

Ac-Ser-His-Ser-Nle-c[Asp-Hyp-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,65 min; ((m+2)/2)=656

Example 73

Ac-Ser-His-Ser-Nle-c[Glu-Ser-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,4 min; ((m+2)/2)=650

Example 74

Ac-Ser-His-Ser-Nle-c[Glu-Hyp-D-Phe(3-trifluoromethyl)-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=7,41 min; ((m+2)/2)=697

Example 75

Ac-Ser-His-Ser-Nle-c[Glu-Hyp-D-Phe(2-methyl)-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=5,88 min; ((m+2)/2)=670

Example 76

AcSer-His-Ser-Nle-c[Glu-Hyp-D-Phe(2-chloro)-Arg-Trp-Lys]-NH 2

LC/MS (system 3): Rt=6,22 min; ((m+2)/2)=680

Example 77

Ac-Nle-c[Asp-Thr-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=9,87 min; (m+1)=989

Example 78

Ac-Nle-c[Asp-Dap-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=9,58 min; (m+1)=974

Example 79

AC-Nle-C[Asp-(4-thiazolyl)Ala-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=11.87 per min; ((m+2)/2)=521

Example 80

Ac-Nle-c[Asp-Phe(4-amino)-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=8,98 min; ((m+2)/2)=525

Example 81

Ac-Nle-c[Asp-Cit-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=9,78 min; ((m+2)/2)=523

Example 82

Ac-Ser-His-Ser-Nle-c[Asp-(4-thiazolyl)Ala-D-Phe-Arg-Trp-Lys]-NH2

LC/MS (system 3): Rt=8,28 min; ((m+2)/2)=677

PHARMACOLOGICAL METHODS

Analysis of (I) an Experimental Protocol to test the effectiveness in terms of appetite with analogues MS using the model of free access rats for food

For experiments using rats TAC:SPRD @mol or rats of Wistar M&Breeding and Research Centre A/S, Denmark. At the beginning of the experiment, rats have a body weight of 200-250 gcras bring at least 10-14 days prior to the beginning of the experiment, weighing 180-200 g Per dose of a compound experience in a group of 8 rats. In each series of tests include a group of 8 rats receiving placebo.

When animals are brought in, they are placed individually with alternating light regime (lights off at 7:30 and 19:30), which means that the light is turned off during the day and included Nochnoe time. Since the rats in the normal start to eat when the lights are off and eat the main part of your daily diet at night, these conditions mean that the authors of the invention have changed the time of feeding start at 7:30 when the lights are turned off. During the period of habituation 10-14 days to rats given free access to food and water. During this period the animals pick up at least 3 times. The experiment conducted in the home cages for rats. Just before the introduction of drugs in rats randomly combine in different treatment groups (n=8) body weight. Injected a drug in accordance with the body weight about 7:00-1-3 mg/kg solution, or administered intraperitoneally or orally, or subcutaneously. The time of administration of medication record for each group. After drug administration the rats returned to their home cages, where they now have access to food and water. Food consumption recorded every hour for 7 hours and then after 24 hours and sometimes within 48 hours At the end of the performance of the experiment animals subjected to euthanasia.

Individual data are inserted in a Microsoft Excel spreadsheet. Outliers excluded after using the criterion of statistical estimation Grabba for outliers, and the result is presented graphically by using the program GraphPad Prism.

Analysis (II) Functional analysis of receptor of melanoc the rtina 3 and 5 (MS and MS) at camp with the use of the kit for detection of camp AlphaScreen TM

Analyses of camp receptors for MS and MS performed on cells stably expressing the receptor MS and MS respectively. These receptors clone from cDNA by PCR and inserted into the expression vector pcDNA3. Stable clones are selected using 1 mg/ml G418.

Cells at about 80-90% of confluently washed 3 times the FSB, is separated from the tablets versinon and diluted in phosphate buffer (FSB). Centrifuged 2 min at 1300 rpm and remove the supernatant. Cells are washed twice stimulating buffer and resuspending in stimulating buffer with a final concentration of 1 or 2·106cells/ml 25 ál of cell suspension added to microtiter plates, containing 25 μl of test compound or compounds comparison (all diluted in stimulating the buffer). Tablets incubated for 30 minutes at room temperature (RT) on a shaker for tablets at low speed swing. The reaction is stopped by adding 25 μl of acceptor pellets with anti-camp and 2 min later, 50 μl of donor pellet in the hole with biotinylated camp in lysis buffer. Then the tablets sealed plastic, shake for 30 minutes and left to stand overnight, and then consider the reading device for microplate AlphaTM.

Values EU50calculate using the analysis of nonlinear regression curves dose-response (m is nimum 6 points) using Windows GraphPad Prism, GraphPad software, USA. All results are expressed in nm.

For measuring antagonistic activity in functional analysis MS at camp receptors MS stimulate 3 nm α-MSH and inhibit increasing the number of potential antagonist. The value of the IC50antagonist is determined at a concentration that inhibits the stimulation MS 50%.

Analysis (III) receptor melanocortin 4 (MS) on camp

Cells KSS expressing the receptor MS, stimulate potential agonists MS and measure the degree of stimulation of camp, using analysis of camp Flash Plate® (NENTMLife Science Products catalog No. SMP004).

Expressing the receptor MC cells KSS were obtained by transfection of cDNA that encodes a receptor MS, BHK570/KZ10-20-48, and selection of stable clones expressing the receptor MS. cDNA of the receptor MS bought in Euroscreen in addition to the Cho cell line expressing the receptor MS. Cells are grown in DMEM, 10% FTS (fetal calf serum), 1 mg/ml G418 and 250 nm MTX and 1% penicillin/streptomycin.

Cells at about 80-90% of confluently washed 3 times the FSB, is separated from the tablets versinon and bred in the FSB. Centrifuged 2 min at 1300 rpm and remove the supernatant. Cells are washed twice stimulating buffer and resuspending in stimulating buffer to a final concentration of 75·10 6cells/ml (Use 7 ml/96-well plate). 50 μl of cell suspension added to Flashplate containing 50 μl of test compound or compounds comparison (all diluted in H2O). The mixture is shaken for 5 minutes and allow to stand for 25 minutes at room temperature. The reaction is stopped with 100 μl of the mixture for detection (Detection Mix per well (Detection Mix=11 ml of buffer to detect +100 μl of tracer (~2 µci) camp [125I]). Then the tablets sealed plastic, shake for 30 minutes and allowed to stand overnight (or 2 hours), and consider the counter Topcounter 2 min/hole. In General, the analysis procedure described in the Protocol to the Flashplate kit (analysis of camp Flash Plate® (NENTMLife Science Products catalog No. SMP004)). However, the standards of camp diluted in 0.1% of CSA (human serum albumin) and 0.005% tween-20, not in stimulating the buffer.

Values EU50calculate using the analysis of nonlinear regression curves dose-response (minimum 6 points)using the Windows program GraphPad Prism, GraphPad software, USA. All results are expressed in nm.

Analysis (IV) analysis of the binding of the receptor melanocortin 1 (MS)

Analysis of the binding of the receptor MS spend on cell membranes NECK, stably expressing the receptor MS. This analysis is carried out in a total volume of 250 μl; 25 ál125NDP-α-MSH (22 PM final concentration), 25 µl of the test connection is in control and 200 μl of the cell membrane (35 μg/ml). Test compounds dissolved in DMSO. The radioactive ligand, the membrane and the test compounds diluted in buffer: 25 mm HEPES pH 7.4, 0.1 mm CaCl2, 1 mm MgSO4, 1 mm EDTA, 0.1% CSA and 0.005% tween-20. Samples incubated at 30°C for 90 min in a microtiter tablets Greiner and share using filters, GF/B, which are pre-soaked for 60 min in 0.5% PEI and washed 2-3 times with NaCl (0.9 per cent) before separation of the bound and unbound radioactive ligand by filtration. After filtration, the filters are washed with cooled in ice with 0.9% NaCl 10 times. The filters are dried at 50°C for 30 min, sealed, add to each well 30 μl of Microscint 0 (Packard, catalog No. 6013616) and consider the tablets in the counter Topcounter 1 min/well.

Data analyzed by nonlinear regression analysis of the binding curves using the Windows program GraphPad Prism, GraphPad software, USA.

Analysis (V) analysis of the binding of the receptor melanocortin 4 (MS)

Binding125NDP-α-MSH in vitro with recombinant cells KSS. expressing the human receptor MS (filtration analysis).

This analysis is carried out in 5 ml vials Minisorb (Sarstedt No. 55.526) or in 96-well tablet with Millipore filters MADVN 6550 and using cells KSS expressing the human receptor MS (obtained from Professer Wikberg, Uppsala, Sweden). Cells KSS kept at -80°C until analysis, and analyses of p is avodat directly on the breeding of this cell suspension without additional preparation. The suspension was diluted to obtain the maximum specific binding 10%, approximately 50-100-fold dilution. The analysis is performed in a total volume of 200 μl; 50 MCP cell suspension, 50 μl of125NDP-α-MSH (≈ 79 PM in final concentration), 50 μl of the test peptide and 50 μl of binding buffer pH 7 are mixed and incubated for 2 h at 25°C. Binding buffer: 25 mm HEPES pH 7.0, 1 mm CaCl2, 1 mm MgSO4, 1 mm EGTA, of 0.02% bacitracin and 0.2% BSA (bovine serum albumin)). Peptides dissolved in H2O and diluted in binding buffer. Radioactive ligand and membrane diluted in binding buffer. The incubation is stopped by dilution with 5 ml chilled in ice with 0.9% NaCl followed by rapid filtration through filters Whatman GF/C, pre-treated for 1 hour with 0.5% polyethylenimine. The filters are washed 3·5 ml) cooled in ice NaCl. The radioactivity retained on the filters, consider using an automatic gamma counter Cobra II.

Data analyzed by analysis of nonlinear regression curves of binding using a Windows program GraphPad Prism, GraphPad software, USA.

Analysis (VI) Assessment of energy expenditure

Use rats TAC:SPRD or from Wistar M&Breeding and Research Centre A/S, Denmark. At least, after one week of acclimatization, rats are placed individually in metabolic chambers (Oxymax system, Columbus Instruments, Columbus, Ohio; the system is s calibrated daily). During the measurement, the animals had free access to water, but food chamber is not supplied. The light cycle is 12:12 light include at 6.00. After the animals spend in the cameras about 2 hours (that is, when reached base consumption), enter the connection or media (oral, administered intraperitoneally or subcutaneously), and continue monitoring to set the duration of the connection. Data for each animal (oxygen, producing carbon dioxide gas and the flow rate) collect every 10-18 min total for 22 hours: 2 hour adaptation (baseline) and 20 hours of measurement. Correction for changes in the content of O2and CO2in the incoming air are doing during each 10-18 minute cycle.

Data calculated on metabolic weight ((kg body mass)0'75for the consumption of oxygen and production of carbon dioxide, and on the animal for warmth. Oxygen consumption (VO2) is considered as the main interest parameter power consumption.

All references, including publications, patent applications, and patents, cited here, are included in this description by reference in their entirety and to the same extent as if the reference was made individually and specifically indicated as included by reference and set forth here in full (up to the maximum is largely, permitted by law).

All headings and subheadings used here for convenience only and should not be construed as limiting the invention in any way.

The use of any and all examples, or vocabulary, pointing to examples (e.g., "such as")provided here are intended solely for better disclosure of the invention and not limitations on the scope of the invention unless otherwise claimed. The vocabulary used in the description should not be construed as indicating any claimed element as essential to the invention.

Citation and inclusion of patent documents by reference is for convenience only and do not reflect any view on the validity, patentability and/or practical significance of these patent documents.

In this invention includes all modifications and equivalents of the objects listed in the attached claims, as permitted by applicable law.

1. The peptide of the formula I

where XI represents Nle or X-Nle, where X is a
Ala-Lys-Tyr-Ser- (SEQ ID NO: 1),
Ala-Lys-Ala-,
Asn-Arg-Gly-,
Asn-Arg-Hyp-,
Asn-Asn-Pro-,
Asn-Asn-Thr-,
Asn-His-Gly-,
Asn-His-Pro-,
Asn-homoArg-Hyp-,
Asn-homoArg-Thr-,
Asn-Tyr-Ser-,
Dab,
D-Ser-Arg-Pro-,
D-Ser-Arg-Thr-,
D-Ser-Asn-Hyp-,
D-Ser-Asn-Ser-,
D-Ser-His-Ser-,
D-Ser-His-Thr-,
D-Ser-homoArg-Gly-,
D-Ser-homoArg-Pro-,
D-Ser-Tyr-Gly-,
D-Ser-Tyr-Hyp-,
Gln-Arg-Hyp-,
Gln-Arg-Ser-,
Gln-Asn-Pro-,
Gln-Asn-Thr-,
Gln-His-Hyp-,
Gln-His-Thr-,
Gln-homoArg-Gly-,
Gln-homoArg-Ser-,
Gln-Tyr-Gly-,
Gln-Tyr-Pro-,
Gly-Ser-Gln-His-Ser- (SEQ ID NO: 2),
Gly-Ser-Gln-homoArg-Ser- (SEQ ID NO: 3),
Ser-Arg-Gly-,
Ser-Arg-Pro-,
Ser-Arg-Ser-,
Ser-Arg-Thr-,
Ser-Asn-Gly-,
Ser-Asn-Ser-,
Ser-Gln-His-Ser- (SEQ ID NO: 4),
Ser-Gln-Ser-,
Ser-His-Gly-,
Ser-His-Hyp-,
Ser-His-Pro-,
Ser-His-Ser-,
Ser-homoArg-Pro-,
Ser-homoArg-Ser-,
Ser-homoArg-Thr-,
Ser-,
Ser-Tyr-Hyp-,
Ser-Tyr-Ser - or
Ser-Tyr-Thr-,
and where the N-terminal amino group of X1 can be allerban acyl group, R-C(O)-, where R represents an alkyl or alkenyl containing up to 6 carbon atoms, with the specified alkyl may be substituted by one or more than one Deputy, selected from hydroxyl and amino;
X2 represents Glu, Asp;
X3 represents Cit, Dab, Dap, cyclohexylglycine, cyclohexylamine, Val, Ile, tert-butylglycol, Leu, Tyr, Glu, Ala, Nle, Met, Met(O), Met(O2), Gln, Gln(alkyl), Gln(aryl), Asn, Asn(alkyl), Asn(aryl), Ser, Thr, Cys, Pro, Hyp, Tic, 2-PyAla, 3-PyAla, 4-PyAla, (2-thienyl)alanine, 3-(thienyl)alanine, (4-thiazolyl)Ala, (2-furyl)alanine, (3-furyl)alanine, Phe, where the phenyl group specified Phe possibly substituted with halogen or amino;
X4 represents D-Phe, where the phenyl group in the D-Phe may be substituted by one or more than one Deputy, selected from halogen, methyl, trifloromethyl or cyano;
X5 represents Arg;
X6 represents Trp;
the 7 represents Lys;
where between x2 and X7 have a connection with formation of cyclic peptide of formula I, due to the amide bond formed from the carboxyl group in the side chain x2 and the amino group in the side chain X7;
R1 represents-N(R')2or-OR", where each R" independently represents hydrogen or C1-6alkyl which may be substituted by one or more than one amino or hydroxyl group;
provided that when X3 represents Hyp, Ala, Pro, Glu, Lys or Gin and X1 represents AC-Nle, then x2 is not Asp;
and its pharmaceutically acceptable salt.

2. The peptide according to claim 1, where R1represents-N(R')2where each R" represents hydrogen or where one R represents a C1-3alkyl, possibly substituted by one or more than one Deputy, selected from hydroxyl and amino.

3. The peptide according to claim 1, where X1 represents Nle or R-C(O)-Nle.

4. The peptide according to claim 1, where R represents alkyl containing up to 6 carbon atoms, possibly substituted by one or more than one Deputy, selected from hydroxyl and amino.

5. The peptide according to claim 4, where R represents methyl, ethyl, propyl, butyl, pentyl and hexyl, possibly substituted by one or more than one Deputy, selected from hydroxyl and amino.

6. The peptide according to claim 4, where R represents a 2-hydroxy-3-methylbutanoyl or 2,4-diaminobutane.

7. P is ptid according to claim 1, where X1 represents Ac-Nle.

8. The peptide according to claim 1, where X1 represents AC-Gly-Ser-Gln-His-Ser-Nle (SEQ ID NO: 5) or Ac-Ser-His-Ser-Nle (SEQ ID NO: 6).

9. The peptide according to claim 1, where X3 is a Met(O2), Tic, 3-PyAla, Ser, Cit, Leu, Phe(4-amino), Phe(3,4-dichloro), Phe(3,4-debtor), Dab, Cgl, Val, Cha, Phe, Dap, Ile, Thr, tBuGly, (4-thiazolyl)Ala, Hyp, Ans or Gin.

10. The peptide according to claim 1, where X3 is a Met(O2), Tic, 3-PyAla, Ser, Cit, Leu, Phe(4-amino), Phe(3,4-debtor), Dab, Phe, Dap, Thr, (4-thiazolyl)Ala or Hyp.

11. The peptide according to claim 1, where X3 represents Tic, Met(O)2, Ser, Hyp, Cit, Dap, (4-thiazolyl)Ala or 3-PyAla.

12. The peptide according to claim 1, where X3 is a Met(O2), Hyp or 3-PyAla.

13. The peptide according to claim 1, where X4 represents D-Phe, D-Phe(4-chloro), D-Phe(4-iodine), D-Phe(3-trifluoromethyl), D-Phe(2-methyl) or D-Phe(2-chloro).

14. The peptide according to claim 1, where X4 represents D-Phe or D-Phe(4-chloro).

15. The peptide according to claim 1, where X4 represents D-Phe.

16. The peptide according to claim 1, where x2 represents Glu, and X7 represents Lys.

17. The peptide according to claim 1, where x2 represents Asp and X7 represents Lys.

18. The peptide according to claim 1, where x2-X3-X4-X5-X6-X7 is a[x2-X3-D-Phe-Arg-Trp-Lys], where x2 represents Glu or Asp;
X3 is a Met(O2), Tic, 3-PyAla, Ser, Cit, Leu, Phe(4-amino), Phe(3,4-dichloro), Phe(3,4-debtor), Dab, Cgl, Val, Cha, Phe, Dap, Ile, Thr, tBuGly, (4-thiazolyl)Ala or Hyp.

19. The peptide according p, where x2 represents Glu, and X3 represents Tic, Met(O)2, Ser, Hyp, Cit, Dap, (4-thiazolyl)Ala or 3-PyAla.

20. PEP the ID according to claim 19, where X3 represents Hyp.

21. The peptide according p, where x2-X3-X4-X5-X6-X7 represents c[Glu-Hyp-D-Phe-Arg-Trp-Lys].

22. The peptide according to claim 1, where X3 represents Tic, Met(O)2, Ser, Hyp, Cit, Dap, (4-thiazolyl)Ala or 3-PyAla, a X1 represents Ac-Gly-Ser-Gln-His-Ser-Nle-(SEQ ID NO: 5) or Ac-Nle.

23. The peptide according to claim 1, where X3 represents Tic, C(O)2, Ser, Hyp, Cit, Dap, (4-thiazolyl)Ala or 3-PyAla;
X1 represents Ac-Gly-Ser-Gln-His-Ser-Nle- (SEQ ID NO: 5) or Ac-Nle;
X4 represents D-Phe;
and x2 represents Asp.

24. The peptide according to claim 1, where X3 represents Tic, Met(O)2, Ser, Hyp, Cit, Dap, (4-thiazolyl)Ala or 3-PyAla;
X1 represents Ac-Gly-Ser-Gln-His-Ser-Nle- (SEQ ID NO: 5) or Ac-Nle;
X4 represents D-Phe;
and x2 represents Glu.

25. The peptide according to claim 1, selected from
Ac-Nle-c[Glu-3-PyAla-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 6)
Ac-Nle-c[Glu-Leu-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 7)
Ac-Nle-c[Glu-Phe(3,4-chlor)-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 8)
Ac-Nle-c[Glu-Met(O2)-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 9)
Ac-Nle-c[Glu-Dab-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 10)
Ac-Nle-c[Glu-Cgl-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 11)
Ac-Nle-c[Glu-Val-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 12)
Ac-Nle-c[Glu-Tic-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 13)
Ac-Nle-c[Glu-Cha-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 14)
Ac-Nle-c[Glu-Ile-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 15)
Ac-Nle-c[Glu-tBuGly-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 16)
AC-Nle-c[Glu-Phe(3,4-debtor)-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 17)
Ac-Nle-c[Glu-Phe-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 18)
Ac-Ser-Tyr-Ser-Nle-c[Glu-3-PyAla-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 19)
H-Ala-Lys-Tyr-Ser-le-c[Glu-3-PyAla-D-Phe-Arg-Trp-Lys]-NH 2(SEQ ID NO: 20)
2-Hydroxy-3-methylbutanoyl-Ser-Nle-c[Glu-3-PyAla-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 21)
H-Dab-Nle-c[Glu-3-PyAla-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 22)
H-Ala-Lys-Ala-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 23)
Ac-Nle-c[Glu-Hyp-D-Phe(4-iodine)-Arg-Trp-Lys]-NH2(SEQ ID NO: 24)
Gex-5-enoyl-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 25)
Ac-Gly-Ser-Gln-His-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 26)
Ac-Gly-Ser-Gln-gameid-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 27)
Ac-Gly-Ser-Gln-His-Ser-Nle-c[Glu-Met(O2)-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 28)
Ac-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 29)
Ac-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-(2-amino-ethyl)amide (SEQ ID NO: 30)
Ac-Nle-c[Asp-Phe(4-amino)-D-Phe(4-chloro)-Arg-Trp-Lys]-NH2(SEQ ID NO: 31)
Ac-Asn-Tyr-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 32)
Ac-D-Ser-His-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 33)
Ac-Gln-Arg-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 34)
Ac-Ser-gameid-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 35)
Ac-Gln-gameid-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 36)
Ac-Ser-Asn-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 37)
Ac-D-Ser-Asn-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 38)
Ac-Ser-Tyr-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 39)
Ac-D-Ser-Tyr-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 40)
Ac-Ser-His-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 41)
Ac-Gln-His-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 42)
Ac-Gln-Arg-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 43)
Ac-Asn-Arg-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 44)
Ac-Asn-gameid-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 45)
Ac-D-Ser-Asn-Hyp-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 46)
Ac-Gln-TyrPro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH 2(SEQ ID NO: 47)
Ac-Ser-His-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 48)
Ac-Asn-His-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 49)
Ac-Ser-Arg-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 50)
Ac-D-Ser-Arg-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 51)
Ac-Ser-gameid-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 52)
Ac-D-Ser-gameid-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 53)
Ac-Gln-Asn-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 54)
Ac-Asn-Asn-Pro-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 55)
Ac-Ser-Tyr-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 56)
Ac-D-Ser-His-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 57)
Ac-Gln-His-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 58)
Ac-Ser-Arg-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 59)
Ac-D-Ser-Arg-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 60)
Ac-Ser-gameid-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 61)
Ac-Asn-gameid-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 62)
Ac-Gln-Asn-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 63)
Ac-Asn-Asn-Thr-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 64)
Ac-D-Ser-Tyr-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 65)
Ac-Gln-Tyr-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 66)
Ac-Ser-His-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 67)
Ac-Asn-His-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 68)
Ac-Ser-Arg-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 69)
Ac-Asn-Arg-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 70)
Ac-D-Ser-gameid-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 71)
Ac-Gln-gameid-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 72)
Ac-Ser-Asn-Gly-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 73)
Ac-Ser-Tyr-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID N: 74)
Ac-Ser-His-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 75)
Ac-Ser-Arg-Ser-Nle-c[Glu-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 76)
Ac-Ser-His-Ser-Nle-c[Asp-Hyp-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 77)
Ac-Ser-His-Ser-Nle-c[Glu-Ser-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 78)
AC-Ser-His-Ser-Nle-C[Glu-Nur-D-Phe(3-trifluoromethyl)-Arg-Trp-Lys]-NH2(SEQ NO: 79)
Ac-Ser-His-Ser-Nl-c[Glu-Hyp-D-Phe(2-methyl)-Arg-Trp-Lys]-NH2(SEQ ID NO: 80)
Ac-Ser-His-Ser-Nle-c[Glu-Hyp-D-Phe(2-chloro)-Arg-Trp-Lys]-NH2(SEQ ID NO: 81)
Ac-Nle-c[Asp-Thr-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 82)
Ac-Nle-c[Asp-Dap-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 83)
Ac-Nle-c[Asp-(4-thiazolyl)Ala-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 84)
Ac-Nle-c[Asp-Phe(4-amino)-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 85)
Ac-Nle-c[Asp-Cit-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 86)
and Ac-Ser-His-Ser-Nle-c[Asp-(4-thiazolyl)Ala-D-Phe-Arg-Trp-Lys]-NH2(SEQ ID NO: 87).

26. The compound according to claim 1, having modulating activity in relation to melanocortin receptors.

27. The method of treatment of a disease or condition where treatment is selected from the group comprising treating obesity or preventing overweight, regulation of appetite, saturation induction, prevention of weight gain after successful weight loss body, wherein the patient in need this, introducing an effective amount of a compound according to any one of claims 1 to 26.

28. Pharmaceutical composition having modulating activity against melanocortin receptors containing the compound according to any one of claims 1 to 26 in an amount of 0.1-2000 mg and pharmaceutically acceptable the carrier or diluent.

29. The composition according to p containing compound according to any one of claims 1 to 26 in an amount of 0.1-2000 mg and a pharmaceutically acceptable carrier or diluent in a single dosage form.

30. The use of compounds according to any one of claims 1 to 26 for the manufacture of a medicinal product for treating obesity or preventing overweight, the regulation of appetite, inducing satiety, prevent further weight gain after successful weight loss body.

31. The application of article 30, where the specified drug is intended for patients with obesity.



 

Same patents:

FIELD: medicine.

SUBSTANCE: present invention concerns a compound representing a selective agonist of a melanocortin-4 receptor of formula: Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO:50) and its pharmaceutically acceptable salts, pharmaceutical compositions and methods for application thereof in preparation of drugs.

EFFECT: higher effectiveness of compound application.

20 cl, 8 dwg, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to low-molecular derivatives of peptides which are used for preparing a pharmaceutical agent which inhibits laminin/nidogen reaction.

EFFECT: increased effectiveness of compounds.

2 cl, 12 dwg, 2 tbl, 30 ex

FIELD: medicine.

SUBSTANCE: invention concerns preparation of peptide biologically active substances with activity of vascular endothelium growth factor (VEGF) with respect to angiogenesis stimulation, and can be used in medicine. In silico design is used for making oligopeptide of general formula I: A-X1-X2-X3-X4-X5-B (I) where A is Ac; X1 represents K or R; X2 represents either Q, or E, or N or D; X3 represents R or K; X4 represents either T, or F, or S, or L, or is absent, X5 represents To, or R, or is absent, and B represents OMe.

EFFECT: preparation of oligopeptides with VEGF activity, and extension of range of effective therapeutic agents that accelerates neogenesis.

4 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to biotechnology, specifically to obtaining biologically active substances of peptide nature, with stem cell factor CSF activity towards thymocyte differentiation, and can be used in medicine. An oligopeptide with formula I is obtained through in silico design: A-X1-X2-X3-X4-X5-B (I), where A is Ac; X1 is K or R; X2 is A or G; X3 is S or T; X4 is A, or G, or is absent, X5 is N, or Q, or is absent and B is Ome.

EFFECT: invention allows for obtaining an oligopeptide with stem cell factor CSF activity towards differentiation of immature precursors of T-lymphocytes, and widening the range of effective therapeutic agents for treating myelodysplastic syndrome.

5 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the conjugates of formula (V)

or (VI) : wherein X is -CO-NH- or -O-; their use as radiopharmaceuticals, processes for their preparation, and synthetic intermediates used in such processes.

EFFECT: use as radiopharmaceuticals.

25 cl, 15 ex

Peptide vectors // 2361876

FIELD: chemistry.

SUBSTANCE: invention relates to cytotoxic compounds with directional effect, which are peptide derivatives of camtothecin, doxyrubicin and palitaxel, their pharmaceutical compositions and use in making medicinal agents for treating pathological conditions, related to aberrant or undesirable proliferation, migration and/or physiological activity of cells.

EFFECT: agents are highly effective.

43 cl, 79 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the method for preparation of the cyclic somostatin analogues of formula I and to the intermediates used in the claimed method. The method is implemented by the cyclisation of somostatin having formula II where R1 is -C2-C6 alkylene -NR3R4, R3 and R4 independently of each other are H or acyl, R2 is , where R5 is phenyl, R11 and R12 independently of each other are amino protective groups. If R1 contains the amino end-group the latter is also protected with amino protective group, if necessary the amino protective group(s) is (are) eliminated and thus obtained compound of formula I is reduced in free or salt form.

EFFECT: improvement of method for preparation of somostatin peptides.

6 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula (Ia) and their application in radiological pharmaceutical compositions for linking to receptors associated with angiogenesis.

EFFECT: possible application in diagnostics or therapy, eg for malignant or cardiac diseases, endometriosis, inflammatory diseases, rheumatoid arthritis and sarcoma Kaposi.

FIELD: chemistry.

SUBSTANCE: invention concerns novel compounds in the form of peptide agonists of vasopressin receptor V1a, of the general formula (I) , and treatment method for shock of hypovolemic or vasodilation origin, esophagus vein dilation with hemorrhage, hepatorenal syndrome, cardiopulmonary resuscitation, anesthesia-induced hypotension, orthostatic hypotension, blood circulation malfunction induced by paracentesis, blood loss during operation or in connection with burn treatment, or nosebleeding. Additionally invention concerns pharmaceutical compositions including claimed compounds as active component in therapeutically effective quantity, and application of claimed compounds in medicine manufacturing.

EFFECT: obtaining compounds with agonistic effect on vasopressin receptor V1a.

12 cl, 2 tbl

FIELD: chemistry, biochemistry.

SUBSTANCE: claimed invention relates to biologically active compounds and includes novel peptides containing to 15 amino acid residues, including sequence Thr-Ser-Asp-Xaa-Xaa, where Xaa represents optionally substituted biphenylalanine, and possessing activity of GLP-1 receptor.

EFFECT: obtaining peptides demonstrating higher resistance to proteolytic decomposition, which makes them candidates for therapy by oral or parenteral introduction.

6 cl, 7 dwg, 4 tbl, 14 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention represents ligands MC-4 and/or MC-3 of the formula (I): , wherein X means hydrogen atom, -OR1, -NR1R1' and -CHR1R1' wherein R1 and R1' are taken among the group: hydrogen atom, (C1-C6)-alkyl and acyl; (1) each R2 is taken independently among the group: hydrogen atom, (C1-C6)-alkyl; or (2) (a) R2 bound with carbon atom that is bound with X and Z1 and substitute R5 can be optionally bound to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; or (b) R2 bound with carbon atom that is bound with ring Ar can be bound with R7 to form ring condensed with ring Ar; each among Z1, Z2 and Z3 is taken independently from the following groups: -N(R3e)C(R3)(R3a)-, -C(R3)(R3a)N(R3e)-, -C(O)N(R3d)-, -N(R3d)C(O)-, -C(R3)(R3a)C(R3b)(R3c)-, -SO2N(R3d)- and -N(R3d)SO2- wherein each among R3, R3a, R3b and R3c, R3d, R3e when presents is taken independently among hydrogen atom and (C1-C6)-alkyl; p is a whole number from 0 to 5 wherein when p above 0 then R4 and R4' are taken among hydrogen atom, (C1-C6)-alkyl and aryl; R5 represents 5 substitutes in phenyl ring J wherein each R5 is taken among hydrogen atom, hydroxy-, halogen atom, thiol, -OR12, -N(R12)(R12'), (C1-C6)-alkyl, nitro-, aryl wherein R12 and R12' are taken among hydrogen atom and (C1-C6)-alkyl; or two substitutes R5 can be bound optionally to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; q = 0, 1, 2, 3, 4 or 5 wherein when q above 0 then R6 and R6' are taken among hydrogen atom and (C1-C6)-alkyl; Ar is taken among the group consisting of phenyl, thiophene, furan, oxazole, thiazole, pyrrole and pyridine; R7 are substitutes at ring Ar wherein each R7 is taken among hydrogen, halogen atom, -NR13R13', (C1-C6)-alkyl and nitro- wherein R13 and R13' are taken among hydrogen atom and (C1-C6)-alkyl; r is a whole number from 0 to 7 wherein when r is above 0 then R8 and R8' are taken among hydrogen atom and (C1-C6)-alkyl; B is taken among -N(R14)C(=NR15)NR16R17, -NR20R21, heteroaryl ring and heterocycloalkyl ring wherein R14-R17, R20 and R21 are taken independently among hydrogen atom and (C1-C6)-alkyl; s = 0, 1, 2, 3, 4 or 5 wherein when s is above 0 then R and R9' are taken among hydrogen atom and (C1-C6)-alkyl; R10 is taken among the group consisting of optionally substituted bicyclic aryl ring and optionally substituted bicyclic heteroaryl ring; D is taken among hydrogen atom, amino- and -C(O)R11 wherein R11 is taken among the following group: hydroxy-, alkoxy-, amino-, alkylamino-, -N(R19)CH2C(O)NH2 wherein R19 represents (C1-C6)-alkyl, -NHCH2CH2OH and -N(CH3)CH2CH2OH, or its isomers, salts, hydrates or biohydrolysable ester, amide or imide.

EFFECT: valuable medicinal properties of compounds.

18 cl, 107 ex

The invention relates to new cyclic peptides of General formula 1

< / BR>
where is a bridging group; E=H, halogen, -NO2, -NR8R8'or or13, R8and R8'each independently represents hydrogen or methyl; R13represents hydrogen or methyl; X - substituents on the phenyl ring, selected from hydrogen, halogen, -NR2or8; Z is one or more substituents on the phenyl ring, independently selected from hydrogen, halogen, -OR9or two groups Z may be taken together with the formation of a condensed aryl ring; R9is hydrogen or methyl; D

< / BR>
< / BR>
substituted or unsubstituted, imidazolyl; R2, R3, R4and R5each represents hydrogen, methyl, or any two radicals of R2, R3, R4and R5can be connected to form heterocyclic or heteroaryl ring; R = 1 to 3; and to a pharmaceutical composition having a selectivity for receptors MC-3 and/or MC-4 compared with other receptors melanocarcinoma

Pyrazoles // 2381217

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where one of R1 and R2 is hydrogen or alkyl, and the other is (CH2)PY, where p=0 or 1, Y is a saturated mono-, bi- or tricyclic 5-10-member cycloalkyl ring optionally substituted with alkyl, or R1 and R2 together with N form a 7-10-member saturated bicyclic ring Z, optionally substituted with halogen, or a 5-7-member monocyclic ring Z, optionally substituted with alkyl, phenyl, phenylalkyl or pyridinyl; R3 is [2,2']bithiophenyl, 1-methylindole, 2,3-dihydrobenzo[1,4]dioxin, benzo[1,3]dioxole, benzothiophene, dibenzofuran, furan, naphthalene, quinoline, thianthrene, thiophene or pyrrole, or biphenyl substituted with halogen, or phenyl optionally substituted with one or more amino, cyano, formyls, halogens, hydroxyl, hydroxymethyls, acyls, acylamino, alkoxy, nitro, trifluoromethoxy, trifluoromethyls, phenoxy or benzyloxy, or R3 is a group, where Ar is phenyl substituted with halogen; and R4 is alkyl; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition with inhibitory activity towards the 11β-hydroxysteroid dehydrogenase1 (11(β-HSD1) enzyme.

EFFECT: pyrazole composition is disclosed.

22 cl, 1 tbl, 116 ex

FIELD: medicine.

SUBSTANCE: combined preparation containing thioctic acid in amount 100 to 1000 mg and dalargin in amount 0.1 to 4 mg is applied. The method of treating vascular complications of diabetes and diabetic polyneuropathy implies application of intravenous infusion of thioctic acid and dalargin in a pharmaceutically acceptable solvent within 2 courses of 10 days with a two-week interval. The preferential version of the composition is that one containing thioctic acid (300-600 mg), dalargin 3 mg and physiologic saline (250 ml). Application of the invention allows for prompt reduction or complete elimination of morbidity of vascular complications of diabetes and diabetic polyneuropathy.

EFFECT: development of the effective drug combination, improved life quality of the patients, reduced frequency of invalidisation, extended range of drug products for treating complications of pancreatic diabetes.

5 cl, 1 ex, 1 tbl

FIELD: food industry.

SUBSTANCE: food product is characterised by a low content of glucose - up to 5% or an utter absence of it, balanced content of fat of less than 10%. The product includes a mixture of phytosterol ethers and/or phytostanol ethers (PS-E) with 1,3-diglycerides (DAG), not necessarily disperse or dissolved in food oil or fat. Moreover, content of PS-E exceeds that of DAG.

EFFECT: invention enables to produce a product controlling glucose exchange and insulin secretion suitable for prevention and treatment of conditions caused by diabetes to patients suffering from diabetes or in people predisposed to it.

18 cl, 12 dwg, 4 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to solid unit dosage form for pancreatic diabetes. The solid unit dosage form for pancreatic diabetes contains as an active substance a combination of taurine, butadion, metformin, Riboxinum, arginine and gliclazide, as well as targeted additives in the certain ratio.

EFFECT: drug is effective for pancreatic diabetes.

4 cl, 2 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to inhibitors of enzymes cleaving protein after proline, such as depeptidyl peptidase IV inhibitors, as well as to their pharmaceutical compositions, and methods of application of such inhibitors. Particularly, inhibitors under this invention are improved in comparison with those currently in use in the present art by selecting special classes of side chains in P1 and/or P2 positions of inhibitor which contains carboxylic acid grouping.

EFFECT: compounds of specified formulas I, II and III can have the improved therapeutic index, partially owing to reduced toxicity and improved specificity in relation to target protease.

15 cl, 2 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: there is described pharmaceutical preparation or beverage/foodstuff which can inhibit production of adipocytokine, in particular adipocytokine which can induce insulin resistance. The pharmaceutical preparation or beverage/foodstuff contains as an active component a compound chosen from the group consisting of 4-methylcholest-7-ene-3-ole, 4-methylergost-7-ene-3-ole and 4-methylstigmast-7-ene-3-ole or a herbal extract of Liliaceae family, an organic solvent or hot water, containing at least 0.001 wt % of the compound.

EFFECT: prevention or simplification of the disease cases associated with insulin resistance.

7 cl, 4 ex, 3 tbl

Gsk-3 inhibitors // 2379300

FIELD: medicine.

SUBSTANCE: invention concerns GSK-3 inhibitors of general formula (I), method for making thereof and based pharmaceutical compositions which can be used in medicine: formula I, where R1 means an organic group containing at least 8 atoms, chosen of C or O, including aromatic ring of phenyl, naphthyl or methylene dioxypjenyl, which is not bound directly with N through -C(O)- or oxygen; Ra, Rb, Rz, R3, R4, R5 and R6 represent hydrogen.

EFFECT: production of new biologically active compounds for treatment of GSK-3 mediated diseases.

28 cl, 13 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: present invention presents a preparation to reduce insulin resistance. The preparation contains 3-O-v-D-glucopyranosyl-4-methylergost-7-ene-3-ole, or an extract made with using an organic solvent, or an extract made with using hot water, or a drained liquid of a plant of Liliaceae family, or fraction thereof which contains this compound as an active component.

EFFECT: production of the preparation which is suitable for inhibition of adipocytokine production, particularly adipocytokine which cause insulin resistance, and for prevention of pathological conditions caused by insulin resistance, or simplification of clinical course of said pathological conditions.

9 cl, 3 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry and concerns pharmaceutical composition for prevention and treatment of diseases and disease states connected with metabolic pathways of cycloxygenase-2 (CG-2) and 5-lipooxygenase (5-LO), which contains mixture of extract obtained from Scutellariae and enriched with flavonoids with free B-ring, which include baicalein, and extract obtained from Acacia and enriched with flavans, which include catechine and epicatechine. Claimed invention also relates to method of body weight loss and control over glucose level in blood. Methods by claimed invention include introduction to person, who needs it, of efficient amount of composition by claimed invention together with pharmaceutically acceptable carrier. Claimed invention mainly relates to prevention and treatment of diseases and states connected with metabolic pathways of cycloxygenase-2 (CG-2) and 5-lipooxygenase (5-LO), including, but not confining to it, stopping discomfort and pain in joints, induced by such states as osteoarthritis, rheumatoid arthritis and other injuries caused by overload.

EFFECT: composition possesses high efficiency.

35 cl, 22 ex, 15 tbl

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