Substituted imidazopyridine derivatives as melanocortin-4 receptor antagonists

FIELD: chemistry.

SUBSTANCE: present invention relates to substituted imidazopyridine derivatives of general formula (I) or enantiomers, diastereomers and tautomers and pharmaceutically acceptable salts thereof, in which A denotes -NH-, -CH2-, -CH2-CH2- or a bond; X denotes phenyl, phenyl condensed with a saturated heterocyclic 5- or 6-member ring, where the heterocyclic ring can contain one or two heteroatoms selected from O and N, and where the heterocyclic ring can further be substituted with an oxo group, a 6-member saturated heterocyclyl containing O as a heteroatom, a 5-6-member heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, and where each phenyl and heteroaryl is possibly substituted with 1 to 2 R14 and/or 1 substitute R4b and/or 1 substitute R5; R1 and R2 are independently selected from the following groups: C1-6-alkyl and C1-6-alkylene-C3-7-cycloalkyl, and where each alkyl is possibly substituted with a OH group, or R1 and R2 together with the nitrogen atom with which they are bonded form a 5-6-member ring which is possibly substituted with one substitute selected from C1-6-alkyl and O-C1-6-alkyl; R4b denotes C(O)NH2, C(O)OH, C(O)NH-C1-6-alkyl, C(O)N-(C1.6-alkyl)2, SO2-C1-6-alkyl, oxo group, and where the ring is at least partially saturated, NH2, NH-C1-6-alkyl, N-(C1-6-alkyl)2; R5 denotes a 6-member heteroaryl containing N as a heteroatom; R3 denotes -(CR8R9)n-T; R8 and R9 are independently selected from the following groups: H and C1-6-alkyl; n equals 1, 2, 3, 4, 5 or 6; T denotes or NR12R13; R10 denotes H, NH2, OH, C1-6-alkyl, possibly substituted with one OH, a halogen atom, NH(C1-6-alkyl) or N(C1-6-alkyl)2; q equals 1 or 2; Y denotes CH2, NR11 or O; R11 denotes H, or C1-6-alkyl; R12 and R13 are independently selected from the following groups: H, C1-6-alkyl, C1-6-alkynyl, (CH2)0-2-C3-7-cycloalkyl, and C1-6-alkylene-O- C1-6-alkyl, where C1-6-alkyl is possibly substituted with one halogen; R14 denotes a halogen atom, CN, C1-6-alkyl, possibly substituted with 1-3 substitutes selected from halogen atom, OH, O- C1-6-alkyl, O-C(O)C1-6-alkyl, O- C1-6-alkyl, possibly substituted with one substitute selected from OH, O- C1-6-alkyl, and O-C(O) C1-6-alkyl, or OH. The invention also relates to a pharmaceutical composition based on the compound of formula (I).

EFFECT: novel imidazopyridine derivatives are obtained, which can be used as melanocortin-4 receptor modulators.

17 cl, 8 tbl, 22 ex

 

The technical FIELD

The invention relates to substituted derivatives of imidazopyridine used as modulators of receptor melanocortin-4. Depending on the structure and spatial structure, the receptor modulators melanocortin-4 are either agonists or antagonists. Connections, proposed according to the present invention are selective antagonists of the receptor melanocortin-4 (MC-4R). These antagonists suitable for treatment of such disorders and diseases such as cancer cachexia (wasting), muscle atrophy, anorexia, amyotrophic lateral sclerosis (Lou Gehrig's disease) (BASS), anxiety and depression.

The LEVEL of TECHNOLOGY

Melanocortin (MK) are formed from Pro-opiomelanocortin (POMC) by proteolytic cleavage. The composition of these peptides adrenocorticotropic hormone (ACTH), α-melanocyte-stimulating hormone (InterMedia) (α-MSH), β-MSH and γ-MSH, are from 12 to 39 amino acids. Apparently, the most important endogenous agonist for activation of the MC-4R in the Central nervous system is tridecapeptide α-MSH. It is known that α-MSH, which belongs to melanocortins, performs in the brain function of a neurotransmitter or neuromodulator. Peptides MK, in particular, α-MSH, have a wide range of effects on biological functions, including food p is doing, pigmentation and exocrine function. Biological effects of α-MSH mediated by a subfamily of 7-transmembrane receptors coupled with G-proteins, called receptors melanocortin (MK-RC). The activation of any of these MK-RC leads to stimulation of the production of camp (cyclic adenosine monophosphate).

Currently for MK famous five different receptor subtypes (MK-1 to MK-5P), which were found expressed in various tissues.

First in melanocytes was discovered receptors MC-1R. It has been shown that naturally occurring in animals inactive variants of MC-1R lead to changes in pigmentation and the manifestation of a lighter color by controlling the conversion of pheomelanin to eumelanin with the participation of tyrosinase. These and other studies show that MK-1 is an important regulator of melanin, causing the color of the hair of animals and human skin. MC-2R is expressed by the adrenal glands and is a receptor for ACTH. MK-2P is not a receptor of α-MSH, but represents the adrenocorticotropic hormone receptor I (ACTH I).

MK-3P is expressed in brain tissues (mainly localized in the hypothalamus and peripheral tissues such as the intestine and placenta; studies using gene knockout showed that the action of M IS-3P may cause changes in feeding behavior, changes in body mass and thermogenesis.

MC-4R mainly expressed in brain tissues. Extensive evidence supports the role of the MC-4R in energy homeostasis. Experiments on animals using gene knockout and pharmacological effects on MC-4R has shown that agonistic effect on MC-4R causes weight reduction and antagonistic effects on the receptor MC-4R leads to increased body mass (A.Kask, et al., "Selective antagonist for the melanocortin-4 receptor (HS014) increases food intake in free-feeding rats," Biochem. Biophys. Res. Commun., 245:90-93 (1998)).

MK-5P is expressed ubiquitously in many peripheral tissues, including adipose tissue and placenta; in addition, the low level of expression of this receptor has also been detected in brain tissues. However, most of this receptor is expressed in exocrine glands. Gene knockout in respect of the specified receptor in mice leads to changes in the regulation of the functions of the exocrine glands, leading to changes in vodootlivnye and thermoregulation. In addition, MK-5P-knockout mice (with "off" the corresponding gene) there is reduced production of lipids sebaceous glands (Chen et al., Cell, 91:789-798 (1997)).

The study modulators of MC-3R and MC-4R and their use in the treatment of disorders associated with changes in body mass, for example, obesity and anorexia, is of great interest. However, b is lo shows that in addition to regulation of pigmentation, eating behavior and exocrine functions, MK peptides may have other important physiological effects. In particular, it has been previously shown that α-MSH have strong anti-inflammatory effect in both acute and chronic inflammatory processes, including inflammatory bowel disease, renal ischemia/reperfusion injury and hepatitis caused by endotoxins. The introduction of α-MSH in the treatment of such disorders leads to a significant reduction of tissue damage caused by inflammation, a significant reduction in leukocyte infiltration and a sharp decrease elevated levels of cytokines and other mediators of inflammation to levels close to normal. Recent studies have shown that mediators of anti-inflammatory action of α-MSH are MC-1R. It is likely that the mechanism under which agonistic effect on MC-1R leads to an inflammatory process that involves the inhibition of the activator of the proinflammatory transcription, NF-KB. Activator of NF-KB is a major component of Pro-inflammatory cascade, and its activation is the process of initiation of many inflammatory diseases. In addition, an anti-inflammatory effect of α-MSH may be partially mediated agony the political impact on receptors MC-3R and/or MK-5P.

Up to the present time was not yet identified specific MK-RC, which controls the development of obesity, although the data were obtained, showing that the alarm MC-4R plays an important role in mediating feeding behavior (S.Q.Giraudo et al., Feeding effects of hypothalamic injection of melanocortin-4 receptor ligands," Brain Research, 80:302 to 306 (1998)). Other evidence of the involvement of MK-RC in the development of obesity include the following data: 1) the mouse agouti (Avy), which ectopiceski expressed antagonists of MC-1R, MC-3R and MC-4R, obese, indicating that blocking the action of these three MK-RC may lead to the development of bulimia and metabolic disorders; 2) the phenotype of MC-4R knockout mice (D.Huszar et al., Cell 88:131-141 (1997)) is identical to the phenotype of the agouti mice, and these mice also suffer from obesity; 3) intracerebroventricularly (DOI) introduction cyclic heptapeptide melanotaenia II (MT-II) (non-selective agonist of MC-1R, -3R, -4R, and-5P) rodents reduces the consumption of food in some studies of the diets of animals (NPY, ob/ob, agouti, starving rodents), while DAI-entered SHU-9119 (antagonist MK-3P and 4P; agonist of MC-1R and -5P) leads to the opposite effect and can cause the development of bulimia; 4) reported that chronic intraperitoneal injection of suffering from obesity rats of Zucker derived α-NDP-MSH (HP-228) the act is viruet MC-1R, -3P, -4P-5P and leads to normal food consumption and weight gain within 12 weeks (I.Corcos et al., "HP-228 is a potent agonist of melanocortin receptor-4 and significantly attenuates obesity and diabetes in Zucker fatty rats," Society for Neiroscience Abstracts, 23:673 (1997)).

Apparently, MC-4R also affect other physiological functions, controlling grooming, erections and blood pressure. Erectile dysfunction means a medical condition that defines the inability to have an erection of the penis sufficient for successful sexual intercourse. For a description of the specified common condition often use the term "impotence". It was found that synthetic agonists of receptors melanocortin contribute to the emergence of erections in men with psychogenic erectile dysfunction (.Wessells et al., "Synthetic Melanotropic Peptide Initiates Erections in Men With Psychogenic Erectile Dysfunction: Double-Blind, Placebo Controlled Crossover Study," J.Urol., 160:389-393, 1998). Activation of receptors melanocortin in the tissues of the brain, apparently, causes the normal stimulation of sexual arousal. Data on the participation of MK-RC in the development of sexual dysfunction in males and/or female considered in the application WO 00/74679.

Diabetes is a disease in which the body's ability of the mammal to the regulation of glucose concentration in the blood is broken due to the fact that in the body of a mammal decreases sposobnosti the conversion of glucose into glycogen, which is deposited in muscle tissue and in the liver cells. Diabetes type I specified a reduced capacity for such accumulation of glucose caused by decreased production of insulin. Type II diabetes or "sugar ainsliezubaida diabetes" (SNSD) is a form of diabetes caused a significant decrease in sensitivity to stimulatory or regulatory functions of insulin in glucose metabolism and lipids the major insulin-dependent tissues, muscle tissue, liver cells and adipose tissue. Such resistance to the effects of insulin leads to decreased insulin activation of glucose consumption, its oxidation and accumulation in muscle tissue, to inadequate insulin suppression of lipolysis in adipose tissue and inadequate production and secretion of glucose in the liver. When a decrease in the sensitivity of these cells to insulin, the body tries to compensate for this process, producing abnormally high concentrations of insulin, which leads to the development of hyperinsulinemia. Hyperinsulinemia is accompanied by hypertension and increased body weight. Since insulin promotes the entry of glucose, amino acids and triglycerides in the blood, insulin-dependent cells, the insensitivity to insulin may lead to increased concentrations of triglycerides and lipoprotein low p is h (LDL), which are the risk factors in the development of cardiovascular diseases. A number of symptoms that include hyperinsulinemia in combination with hypertension, increased body weight, elevated concentrations of triglycerides and elevated levels of LDL, known as syndrome X. Agonists MC-4R may be suitable for treatment SNSD and syndrome X.

Among the subtypes of receptors MK, also of interest receptors MK4, because they are associated with stress responses and the regulation of emotional behavior that is shown by the following data obtained. Stress triggers a complex cascade of reactions, which include endocrine, biochemical, and behavioral processes. Many of these responses are initiated by the release of corticoliberin (corticotropin releasing factor) (was made the KRF) (Owen M.J., Nemeroff C.B. (1991) discrimination and pharmacology of corticotrophin releasing factor. Pharmacol Rev. 43:425-473). Besides the activation was made the KRF system of the brain, there is some evidence that melanocortin (MK), which are produced from Pro-opiomelanocortin in the enzymatic reactions are important mediators of behavioral and biochemical responses to stress and, therefore, participate in the development caused by stress disorders, such as anxiety and depression (Anxiolytic-Like and Antidepressant-Like Activities of MKL 0129 (1-[(S)-2-(4-Fluorophenyl)-2-(4-isoproplpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine), a Novel and Potent Nonpeptide Antagonist of the Melanocortin-4 Receptor; Shigeyuki Chaki et al, J.Pharm. Exp. Ther. (2003) 304(2), 818-26).

Chronic diseases such as malignant tumors and infection, often accompanied by depletion that occurs with simultaneous reduction of appetite and loss of lean body mass. The rapid decline in lean body mass often is triggered by the inflammatory process and is usually associated with elevated levels of cytokines (eg, TNF-α) in the blood plasma, which causes increased production of α-MSH in the brain. Activation of receptors MK4 in hypothalamus under the influence of α-MSH reduces appetite and increases energy consumption. Experiments conducted on mice with tumors, showed that depletion can be prevented or cured by genetic knockout against receptor MK4 or blocking receptor MK4. The increase of body weight in mice exposed to the indicated effects, attributed to increasing lean body mass, which consists mainly of skeletal muscle (Marks D.L. et al. Role of the central melanocortin system in cachexia. Cancer Res. (2001) 61:1432-1438).

Clinical observations show that can be found in the relationship between the development of amyotrophic lateral sclerosis (als), and loss of body weight (for example, A.C. Ludolph, Neuromuscul Disord. (2006) 16 (8):530-8). Accordingly, inhibitors MK-4P can be used in the treatment of patients suffering from the BASS./p>

The receptor modulators melanocortin-4 described in the published literature. For example, were synthesized substituted derivatives of phenylpiperidine, who investigated the expression of agonistic and antagonistic activity against receptor MC-4R.

Due to shortcomings in the treatment of various diseases and disorders described above, the present invention is to provide new compounds with high potential for penetration through the blood-brain barrier and which can be used as receptor antagonists melanocortin-4 for the treatment of cancer cachexia, muscle wasting, anorexia, amyotrophic lateral sclerosis (als), anxiety, depression and other diseases, the development of which involved the MC-4R.

It has been unexpectedly discovered that the new imidazopyridine corresponding to the Formula (I)below, answer the problem posed in the present invention.

BRIEF description of the INVENTION

The present invention relates to substituted derivatives of imidazopyridine corresponding to the structural formula (I)

in which R1, R2, R3And X are defined below.

Derivatives imidazopyridine corresponding to structural formula (I), represent the th effective receptor modulators melanocortin, and, in particular, they are effective as selective receptor antagonists melanocortin-4 (MC-4R). Thus, they can be used for treating disorders that involve inactivation of MC-4R. These antagonists suitable for treatment of such disorders and diseases such as cancer cachexia, muscle atrophy, anorexia, amyotrophic lateral sclerosis, anxiety and depression.

Thus, the present invention relates to compounds corresponding to the formula (I)intended for the treatment and/or prevention of cancer cachexia, muscle wasting, anorexia, amyotrophic lateral sclerosis (als), anxiety and depression.

Another aspect of the invention concerns the use of compounds corresponding to formula (I), for the preparation of medicaments intended for the treatment and/or prevention of cancer cachexia, muscle wasting, anorexia, amyotrophic lateral sclerosis (als), anxiety and depression.

The present invention also relates to pharmaceutical compositions comprising the compounds, proposed according to the present invention, and a pharmaceutically acceptable carrier.

DETAILED description of the INVENTION

The present invention relates to substituted derivatives of imidazopyridine suitable for use as modulators of receptors melancor the ina, in particular, selective antagonists of MC-4R.

Substituted N-benzyl-N-methyl-2-phenyl-5-diethylamino-3-methylamino-imidazo[1,2-a]pyridine described in the application WO-A-02/066478, which are considered antagonists of GnRH (gonadotropin releasing hormone). The present invention relates to new imidazopyridine that can be used as antagonists of MC-4R.

Connections, proposed according to the present invention represented by structural formula (I)

and include enantiomers, diastereomers, tautomers, solvate and a pharmaceutically acceptable salt of these compounds,

in which

And represents-NH-, -CH2-, -CH2-CH2or communication;

X represents

N

phenyl,

phenyl fused with a saturated heterocyclic 5 - or 6-membered ring, while the heterocyclic ring may contain one or two heteroatoms selected from O and N, and the heterocyclic ring is optionally substituted by exography,

saturated or unsaturated 4-to 8-membered heterocyclyl containing one or two heteroatoms selected from N, O and S,

-5-6-membered heteroaryl containing one or two heteroatoms selected from N, O and S, or

-C(O)-R6,

and each phenyl, heterocyclyl and heteroaryl possibly substituted by one, DV is two or three of the substituents R 14and/or one substituent R4band/or one substituent R5;

R1and R2independently from each other selected from the following groups:

N

C1-6-alkyl,

With1-6-alkylen-O-C1-6-alkyl,

With1-3-alkylen-heterocyclyl,

With1-6-alkylen-C3-7-cycloalkyl, and

each alkyl, alkylene, heterocyclyl and cycloalkyl possibly substituted by a group HE or

R1and R2together with the nitrogen atom to which they are attached, form a 5-6-membered ring which can optionally contain in the ring one oxygen atom and possibly substituted by one or more substituents selected from HE, C1-6-alkyl, O-C1-6-alkyl, C0-3-alkylen-C3-5-cycloalkyl,1-6-alkylen-O-C1-6-alkyl or (CH2)0-3is phenyl;

R4arepresents a halogen atom,

CN,

C1-6-alkyl, possibly substituted by one or more halogen atoms,

O-C1-6-alkyl, possibly substituted by one or more halogen atoms, or

OH;

R4brepresents C(O)NH2,

(O)HE,

C(O)NH-C1-6-alkyl,

C(O)N-(C1-6-alkyl)2,

SO2-C1-6-alkyl,

C(O)NH-SO2-C1-6 -alkyl,

oxoprop, and when this cycle at least partially saturated,

NH2,

NH-C1-6-alkyl,

N-(C1-6-alkyl)2,

NH-SO2-CH3or

NH-SO2-CF3;

R5represents a

5-6-membered saturated or unsaturated heterocyclyl containing one to three heteroatoms selected from N, O and S, or

5-6-membered heteroaryl containing one to three heteroatoms selected from N, O and S, and

this heterocyclyl and heteroaryl possibly substituted by one or two substituents R14;

R6represents a

N

With1-6-alkyl, possibly substituted by one or more halogen atoms,

phenyl, or

4-8-membered saturated or unsaturated heterocyclyl containing one to three heteroatoms selected from N, O and S, and

each phenyl or heterocyclyl possibly substituted by one, two or three substituents R14and/or one substituent R5;

R3represents -(CR8R9)n-T;

R8and R9independently from each other selected from the following groups:

N

HE

the halogen atom,

C1-6-alkyl and

O-C1-6-alkyl;

n is 1, 2, 3, 4, 5 or 6;

T is a

or NR12R13;

R10

H,

NH2,

HE

C1-6the alkyl may have one or more substituents selected from a halogen atom, HE, and O-C1-6-alkyl,

O-C1-6-alkyl, in which alkyl possibly substituted by one or more substituents selected from a halogen atom, HE, and O-C1-6-alkyl,

halogen atom,

NH(C1-6-alkyl),

N(C1-6-alkyl)2,

phenyl or heteroaryl, and

while the phenyl and heteroaryl possibly substituted by one, two or three substituents R4a;

q is 1 or 2;

Y represents CH2, NR11or;

R11represents a

H,

C1-6-alkyl, or

(CH2)0-6-C3-7-cycloalkyl;

R12and R13independently from each other selected from the following groups:

H,

C1-6-alkyl,

With2-6-alkenyl,

With2-6-quinil,

(CH2)0-2-C3-7-cycloalkyl, and

With1-6-alkylen-O-C1-6-alkyl,

while C1-6-alkyl, C1-6-alkylen and C3-7-pilooski possibly substituted by one, two or three substituents R14;

R14represents a

halogen atom,

CN,

C1-6-alkyl, possibly substituted by one or more substituents which, selected from a halogen atom, HE, O-C1-6-alkyl, O-C3-7-picoalgae, O-C(O)1-6-alkyl, O-C(O)3-7-cycloalkyl,

O-C1-6-alkyl, possibly substituted by one or more substituents selected from a halogen atom, HE, O-C1-6-alkyl, O-C3-7-picoalgae, O-C(O)1-6-alkyl, O-C(O)3-7-cycloalkyl, or

HE.

In one of the preferred embodiments And represents-NH - or a bond. More preferably, a represents a bond.

Further, preferably, when R1and R2independently from each other represent a3-6-alkyl, or R1and R2together with the nitrogen atom to which they are attached, form a 5-6-membered ring which can optionally contain in the cycle of one atom of oxygen and possibly substituted by one or more substituents selected from HE, C1-6-alkyl, C0-3-alkylen-C3-5-picoalgae, O-C1-6-alkyl, C1-6-alkylen-O-C1-6-alkyl or (CH2)0-3is phenyl. More preferably, if R1and R2independently from each other represent a3-6-alkyl.

In one of the preferred embodiments T is an NR12R1312and R13preferably independently from each other selected from the group including H, C1-3-alkyl or (CH2)0-2-C3-6-cycloalkyl, and alkyl and cycloalkyl possibly substituted by one, two or three substituents R14.

In an alternative preferred embodiment, T is chosen from the following groups:

Preferably, Y is CH2or NR11. Preferably, R11represents a hydrogen atom.

Further, preferably, R10selected from the group comprising H, NH2C1-6-alkyl, NH(C1-6-alkyl) or N(C1-6alkyl)2. More preferably, R10represents N, NH2or C1-6-alkyl.

As for X, the specified group preferably represents H; phenyl, which is condensed with a saturated heterocyclic 6-membered ring, and the heterocyclic ring may contain one or two heteroatoms selected from O and N, and the heterocyclic ring is optionally substituted by exography, or X represents a 4-8 membered saturated or unsaturated heterocyclyl containing one or two heteroatoms selected from N, O and S, and each phenyl, heterocycle is possibly substituted by one, two or three substituents R14and/or one substituent R4band/or one substituent R5.

In a similar preferred embodiment, X represents phenyl or a 4-to 8-membered heteroaryl containing one or two heteroatoms selected from N, O and S, and each phenyl and heteroaryl possibly substituted by one, two or three substituents R14and/or one substituent R4band/or R5. More preferably, X represents phenyl or pyridyl, most preferably X represents phenyl.

The present invention also includes compounds corresponding to formula (I), in which some or all of these groups represent the preferred or more preferred fragments.

Used in the present description, the terms have the meanings shown below:

Alkyl represents a linear or branched alkyl, including one, two, three, four, five or six carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl.

Alkenyl represents a linear or branched alkyl, including two, three, four, five or six carbon atoms and from one to three double bonds, preferably one or two double bonds, most preferably ar is the double bond. Preferred examples2-6-alkenyl groups include ethynyl, prop-1-enyl, prop-2-enyl, isoprop-1-enyl, n-but-1-enyl, n-but-2-enyl, n-but-3-enyl, isobut-1-enyl, isobut-2-enyl, n-Penta-1-enyl, n-Penta-2-enyl, n-Penta-3-enyl, n-Penta-4-enyl, n-Penta-1,3-enyl, isopen-1-enyl, isopen-2-enyl, neopet-1-enyl, n-Gex-1-enyl, n-Gex-2-enyl, n-Gex-3-enyl, n-Gex-4-enyl, n-Gex-5-enyl, n-Gex-1,3-enyl, n-Gex-2,4-enyl, n-Gex-3,5-enyl and n-Gex-1,3,5-enyl. More preferred examples2-6-alkenyl groups include ethynyl and prop-1-enyl.

Quinil represents a linear or branched alkyl, including two, three, four, five or six carbon atoms and from one to three triple links, preferably one or two triple bond, most preferably one triple bond. Preferred examples2-6-etkinlik groups include ethinyl, prop-1-inyl, prop-2-inyl, n-but-1-inyl, n-but-2-inyl, n-but-3-inyl, n-Penta-1-inyl, n-Penta-2-inyl, n-Penta-3-inyl, n-Penta-4-inyl, n-Penta-1,3-inil, isopen-1-inyl, neopet-1-inyl, n-Gex-1-inyl, n-Gex-2-inyl, n-Gex-3-inyl, n-Gex-4-inyl, n-Gex-5-inyl, n-Gex-1,3-inyl, n-Gex-2,4-inyl, n-Gex-3,5-inil and n-Gex-1,3,5-inil. More preferred examples2-6-etkinlik groups include ethinyl and prop-1-inyl.

Cycloalkyl represents a cyclic alkyl, preferably containing three, even the re, five, six or up to seven carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, more preferably comprising three, four, five or six carbon atoms.

Heteroaryl represents an aromatic group containing one, two, three, four or five carbon atoms and at least one heteroatom selected from O, N and/or S, and preferably represents a group selected from tanila, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazoline, isoxazole, furanyl and imidazolyl, more preferably, teinila, furanyl, imidazolyl, pyridyl and pyrimidinyl.

Heterocyclyl represents a saturated or unsaturated ring containing at least one heteroatom selected from O, N and/or S, and one, two, three, four, five, six or seven carbon atoms. Preferably, heterocyclyl is a 4-8-membered ring, and preferably represents a group selected from tetrahydrofuranyl, azetidine, pyrrolidine, piperidine, pyranyl, morpholinyl, thiomorpholine, more preferably, piperidinyl and pyrrolidinyl.

Halogen is a halogen atom selected from F, Cl, Br and I, preferably F, Cl and Br.

Compounds corresponding to structural formula (I), pre what are effective modulators of receptors of melanocortin and in particular, this applies as selective modulators of MC-4R. They are suitable for the treatment and/or prevention of disorders sensitive to the process of inactivation of MC-4R, for example, cancer cachexia, muscle wasting, anorexia, amyotrophic lateral sclerosis, anxiety, depression and other diseases, developing, with the participation of MC-4R.

OPTICAL ISOMERS, the DIASTEREOMERS and GEOMETRIC ISOMERS - TAUTOMERS

Compounds corresponding to structural formula (I)contain one or more asymmetric centers and can exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention includes all of these isomeric forms of the compounds of structural formula (I).

Compounds corresponding to structural formula (I), can be divided into separate diastereoisomer, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture of these solvents, or via chiral chromatography using an optically active stationary phase. The absolute stereochemical configuration of the compounds can be determined using x-ray crystallographic studies of crystalline products or crystalline p is omegatech compounds, if necessary, obtained using reagent containing an asymmetric center is known absolute configuration.

Alternatively, any stereoisomer of a compound corresponding to General formula (I)may be obtained by stereospecific synthesis using optically pure starting materials or reagents with known absolute configuration.

SALT

The term "pharmaceutically acceptable salt" refers to salts derived from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum salts, ammonium, calcium, copper, iron (II), iron (III), lithium, magnesium, manganese (II), manganese (IV), potassium, sodium, zinc and other cations. Particularly preferred salts are the ammonium, calcium, lithium, magnesium, potassium and sodium. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenziletilendiaminom, diethylamine, 2-Diethylaminoethanol, 2-dimethylaminoethanol, atenolol is on, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, geranamine, Isopropylamine, lysine, methylglucamine, research, piperazine, piperidine, poliamidowych resins, procaine, purines, theobromine, triethylamine, trimethylamine, Tripropylamine, tromethamine and the like substances.

If the connection is proposed according to the present invention, refers to the basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzosulfimide, benzoic, camphorsulfonic, lemon, econsultancy, formic, fumaric, gluconic, glutamic, Hydrobromic, hydrochloric, isetionate, lactic, maleic, malic, almond, methansulfonate acid, malonic acid, mucus, nitrogen, pambou, Pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p-toluensulfonate, triperoxonane acid and similar acids. Especially preferred citric, fumaric, Hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acid.

It should be understood that in accordance with the present description, the compounds corresponding to formula (I)include pharmaceutically acceptable salts of the compounds.

APPLICABILITY

Compounds corresponding to formula (I), PR is astavliaut a receptor antagonists melanocortin and as such, suitable for the treatment, control or prevention of diseases, disorders or conditions that are sensitive to inactivation of one or more receptors melanocortin, non-limiting examples of which include the MC-1R, MC-2R, MC-3R, MC-4R or MK-5P. Non-limiting examples of such diseases, disorders or conditions include cancer cachexia, muscle atrophy, anorexia, amyotrophic lateral sclerosis, anxiety and depression.

Compounds corresponding to formula (I)can also be used to treat, control or prevent diseases, disorders or conditions that are sensitive to inactivation of one or more receptors melanocortin, non-limiting examples of which include the MC-1R, MC-2R, MC-3R, MC-4R or MK-5P. Non-limiting examples of such diseases, disorders or conditions include hypertension, hyperlipidemia, osteoarthritis, cancer, gallbladder disease, sleep apnea syndrome (sudden stopping of breathing during sleep), compulsion, neuroses, insomnia/sleep disorder, substance abuse, pain, fever, inflammation, immunomodulation, rheumatoid arthritis, pigmentation of the skin, skin rashes and other disorders of the skin, neuroprotective effects and cognitive impairment and disturbed the I memory including Alzheimer's disease.

INTRODUCTION AND DOSE RANGE

To ensure a mammal, in particular human, an effective dose of a compound, proposed according to the present invention may be used in any suitable route of administration. For example, the method may include oral, parentline, topical, parenteral, ocular, pulmonary, nasal introduction and similar methods. Dosage forms include tablets, coated tablets, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and similar forms. Preferably compounds corresponding to the formula (I), administered orally or tapicerki.

Used effective dose of the active ingredient may depend on the type of concrete used for the connection, the method of administration, the condition being treated and the severity of the condition being treated. This dose can be easily calculated by a person skilled in the technical field.

In General, satisfactory results in the treatment of cancer cachexia, muscle atrophy or anorexia were obtained by introduction of compounds proposed according to the present invention, the daily dosage comprising from about 0.001 milligram to 100 milligrams per kilogram of body weight, preferably in the form of a single dose or divided to the s, input from two to six times per day, or in the form of dosage forms with delayed release. In the treatment of adults with body mass, component 70 kg, the total daily dose, in General, may range from 0.07 to 3500 milligrams milligrams. This regimen may be adjusted in order to achieve the best therapeutic response.

STRUCTURES

Preferably, the compounds corresponding to formula (I)is administered in the dosage form prior to entering into the body. Accordingly, the present invention also includes a pharmaceutical composition comprising a compound corresponding to the formula (I), and suitable pharmaceutical carrier.

We offer pharmaceutical compositions are prepared in accordance with known methods using well known and readily available ingredients. In the preparation of the compositions used according to the present invention, the active ingredient (the compound having the formula (I)) is usually mixed with a carrier, or diluted by a carrier, or enter into media that can be a capsule, sachet sachet, paper or other container. If the carrier is a diluent, it may be a solid, semi-solid or liquid material, which has the function of auxiliary substances, for which omnitele or medium for the active ingredient. Thus, the compositions can be prepared in the form of tablets, pills, powders, lozenges, sachets, those capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid and in liquid form), soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum Arabic, calcium phosphate, alginates, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl - and propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In addition, the composition may include sliding substances, wetting agents, emulsifying and suspendiruemye substances, preservatives, sweeteners or flavorings. The compositions used according to the present invention, can be selected in such a way as to ensure fast, slow or gradual release of the active ingredient after administration of the composition to the patient.

PREPARATION of COMPOUNDS PROPOSED ACCORDING to the PRESENT INVENTION

If the compounds corresponding to formula (I), exist in the form of diastereoisomeric mixtures, they can is to be divided into diastereomeric pairs of enantiomers by fractional crystallization from a suitable solvent, for example, methanol, ethyl acetate or mixtures of these solvents. Thus obtained pair of enantiomers can be separated into individual stereoisomers by conventional methods using optically active acid as an agent for optical breakdown. Alternatively, any enantiomer of a compound corresponding to the formula (I)may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

Compounds corresponding to formula (I), proposed according to the present invention, can be obtained in accordance with the procedures presented in the following Schemes and Examples, using appropriate materials and methods, specific examples of which are also discussed below. In addition, as described in this application procedures and General information, known in the art, can be easily prepared and other compounds covered by this invention. However, one should not assume that the compounds presented in the examples represent the only possible connections, in accordance with the present invention. The following Examples are given to illustrate the synthesis of compounds proposed is in accordance with the present invention. Specialists in the art should be familiar with the different modifications of terms and methods that are allowed in the proposed processes and allows you to make these connections. The described compounds in General emit in the form of their pharmaceutically acceptable salts, for example salts described above. The free amine base, corresponding to selected salts can be obtained by neutralization with a suitable base, such as aqueous solution of sodium bicarbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, and extraction of released free amine base with an organic solvent followed by evaporation. Thus obtained the free amine base can then be converted into other pharmaceutically acceptable salt by dissolving in an organic solvent and then adding the appropriate acid and subsequent evaporation, precipitation or crystallization. All temperatures are given in degrees Celsius.

In the diagrams, the processes and the examples below, various symbols of the reactants and the abbreviations have the following meanings:

Asónacetic acid
AU2About acetic anhydride
Vostert-butoxycarbonyl
BP.boiling point
CDI1,1'-carbonyldiimidazole
EDC1,2-dichloroethane
DHMdichloromethane
DIEAethyldiethanolamine
DMFN,N-dimethylformamide
DMSOthe sulfoxide
EDC1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Et2Odiethyl ether
EtOActhe ethyl acetate
HATUO-(7-asobancaria-1-yl)-N,N,N,N'-tetramethylurea hexaphosphate
HOAt1-hydroxy-7-asobancaria
HOBt1-hydroxybenzotriazole
hhour (time)
MeCNacetonitrile
MeLimotility
Meonmethanol
Msmethylsulphonyl
NMMN-methylmorpholin
MWmolecular weight
PGprotective group
K.T.room temperature
The teathe triethylamine
TFAAanhydride triperoxonane acid
THFtetrahydrofuran
TMSItrimethylsilylmethyl
tR(min)the retention time HPLC
Tstosyl
Zbenzyloxycarbonyl

The reaction scheme 1:

Synthesis of amides of 2-sulfonylamino-pyridine-5-carboxylic acid

As shown is the reaction Scheme 1, possibly substituted amine and 2-aminopyridine-5-carboxylic acid introduced into the reaction of the amide linking in the presence of reagent combinations, such as EDC in an organic solvent, for example DMF or DHM if the temperature is suitable. The obtained amide can then be introduced into the reaction sulphonylchloride in a solvent, for example pyridine, or any other appropriate solvent, with an organic base, such as triethylamine with the formation of corresponding sulfonylamino-amides.

The reaction scheme 2:

Synthesis of methyl ester of 2-sulfonylamine-5-carboxylic acid

Alternatively, the methyl ester of 2-aminopyridine-5-carboxylic acid can be introduced into the reaction conditions described above, with the formation of corresponding sulfonylamino-ethers, as shown in reaction Scheme 2.

The reaction scheme 3:

Synthesis of imidazo[1,2-a]pyridines

As shown in reaction Scheme 3, possibly substituted ω-alkoxycarbonyl-α-brometane can be obtained from the corresponding ketones by the reaction of, for example, copper bromide (II) in a solvent, for example, a mixture of ethyl acetate and chloroform at the corresponding temperature for a certain period of time. The obtained α-brometane can be introduced into the reaction with sulfonylamino-inorganic salts in plants is oritel for example, MeCN in the presence of an appropriate base, e.g., DIEA, with the formation of N-alkyl, sulfonylamino-amides. These intermediate compounds can then be subjected to cyclization with formation of the corresponding imidazo[1,2-a]pyridines in the processing of TFAA in a suitable solvent, for example, DHM or 1,2-dichloroethane at the corresponding temperature for a certain period of time. The ether functional group possibly substituted, imidazo[1,2-a]pyridines can be hydrolyzed under alkaline conditions using a reagent such as a monohydrate of lithium hydroxide in a suitable solvent, e.g. a mixture of water, THF and Meon.

The resulting acid can be activated under the action of a suitable reagent, for example, isobutylacetate or CDI in the presence of a suitable base, for example, N-methylmorpholine, in an appropriate solvent, for example THF, and then restored with the formation of the corresponding alcohol under the action of a reducing agent, e.g. sodium borohydride in an appropriate solvent, e.g. a mixture of THF and water. Alcohol functional group can be converted into a leaving group under the action of a suitable reagent, for example, methylsulfonylamino or taillored in an appropriate solvent, e.g. a mixture of DHM and THF, in the presence of a suitable base is, such as tea. The product of this reaction can be treated with the amine T-H in an appropriate solvent, for example, MeCN, with the formation of the target molecule.

The reaction scheme 4:

Synthesis of imidazo[1,2-a]pyridines

As shown in reaction Scheme 4, the methyl ether functional group, possibly substituted, imidazo[1,2-a]pyridines can be restored with the formation of the corresponding alcohol groups under the action of a suitable reagent, for example sodium borohydride, in an appropriate solvent, e.g. methanol. The alcohol may be further introduced into the reaction with obtaining a target molecule, as shown in reaction Scheme 3.

The reaction scheme 5:

Synthesis of imidazo[1,2-a]pyridines

As shown in reaction Scheme 5, possibly substituted α-brakeline with acetylene functional group in the ω-position may be obtained from the corresponding ketones and converted into the corresponding possibly substituted, imidazo[1,2-a]pyridine, as described above. These acetals can be split with the formation of the corresponding aldehydes by using the appropriate reagent, e.g., 6N. Model HC1 in water. Possibly substituted aldehydes can be subjected to reductive aminating under the action of a suitable amine T-H in the presence restore the I, for example, triacetoxyborohydride sodium in an appropriate solvent, for example, EDC.

The reaction scheme 6:

Synthesis of imidazo[1,2-a]pyridines

As shown in reaction Scheme 6, possibly substituted N-protected ω-amino-α-brometane can be introduced into reaction with sulfonylamino-inorganic salts in a suitable solvent, for example, MeCN in the presence of an appropriate base, such as DIEA, with the formation of N-alkyl, sulfonylamino-amides. These intermediate compounds can then be subjected to cyclization with formation of the corresponding imidazo[1,2-a]pyridines in the processing of TFAA in a suitable solvent, for example, DHM or 1,2-dichloroethane, at a corresponding temperature for a certain period of time. Removing the protection of the amino groups of the side chain can be carried out using an appropriate reagent, for example, TMSI, in a suitable solvent, for example, in the case of the Z-protective group, MeCN. Phthalimide can be split under the action of hydrazine hydrate is added in an appropriate solvent, such as ethyl acetate. Possibly substituted, imidazo[1,2-a]pyridine having a primary amino group in the side chain, can be directly subjected to biological analysis or further converted into derivatives thereof. For example, the reaction with 1,5-dibromethane in the corresponding dissolve the e, for example, 1,2-dichloroethane, in the presence of a suitable base, for example, DIEA, leads to obtaining the appropriate derivatives of piperidine.

The reaction scheme 7:

Synthesis of imidazo[1,2-a]pyridines

As shown in reaction Scheme 7, possibly substituted lactones can be subjected to acylation alkylamino esters of alkyl-OC(O)a-h in the presence of a suitable base, e.g. sodium hydride, in an appropriate solvent, e.g. toluene, at elevated temperature. These acylated lactones can be transformed into ω-chloretone heating lactones in concentrated hydrochloric acid. The reaction may substituted ω-chloroethanol, for example, copper bromide (II) in a suitable solvent, for example, a mixture of ethyl acetate and chloroform, at a corresponding temperature for a certain period of time results in the corresponding ω-chloro-α-bromoketones. These ω-chloro-α-brometane can be introduced into the reaction with sulfonylamino-inorganic salts in a suitable solvent, for example, MeCN in the presence of an appropriate base, such as DIEA, with the formation of N-alkyl, sulfonylamino-amides. These intermediate compounds can then be subjected to cyclization with formation of the corresponding imidazo[1,2-a]pyridines in the processing of TFAA in a suitable dissolve the e, for example, DHM or 1,2-dichloroethane, at a corresponding temperature for a certain period of time. Protective group T may be introduced by the reaction of substituted chloralkali imidazo[1,2-a]pyridines with a suitable protecting group T-H in an appropriate solvent, for example, MeCN. If the group T-N used in the form of hydrochloride, then, in addition, to free amine T-N use a suitable base, such as DIEA.

The reaction scheme 8:

Synthesis of imidazo[1,2-a]pyridines

As shown in reaction Scheme 8, possibly substituted ω-chloro-α-brometane can also be introduced into reaction with a suitable sulfonylamino in a suitable solvent, for example, MeCN in the presence of an appropriate base, such as DIEA, with the formation of N-alkyl sulfonylamino. These intermediate compounds can then be subjected to cyclization with formation of the corresponding imidazo[1,2-a]pyridines in the processing of TFAA in a suitable solvent, for example, DHM or 1,2-dichloroethane, at a corresponding temperature for a certain period of time. Protective group T may be introduced by the reaction of imidazo[1,2-a]pyridines, substituted chloralkali, with a protective group is T-H in an appropriate solvent, for example, MeCN. If the group T-N used in the form of hydrochloride, then, in addition, d is I free amine T-N use a suitable base, for example, DIEA. The ether functional group possibly substituted, imidazo[1,2-a]pyridines can be hydrolyzed under alkaline conditions using a reagent such as a monohydrate of lithium hydroxide in a suitable solvent, e.g. a mixture of water, THF and Meon. The product of the saponification can be allocated in the form of a lithium salt or in the form of the corresponding acid. Alternatively, the ether functional group can be cleaved in acidic conditions, for example, using a suitable reagent, for example, aqueous hydrochloric acid. The product of the ether cleavage can be entered into the next reaction in the form of acid or lithium salts. Amide can be formed in accordance with the standard procedures of peptide combinations. The acid may be introduced into reaction with a suitable amine HNR1R2in the presence of EDC/HOBt, EDC/HOAt, HATU, bases, for example, diisopropylethylamine, and solvent, for example dichloromethane. For a combination may be used a suitable solvent, for example, DHM, DMF, THF or a mixture of these solvents. Suitable bases include triethylamine (tea), diisopropylethylamine (DIEA), N-methylmorpholine (NMM), kallidin or 2,6-lutidine. When using the EDC/HOBt, it may not be necessary to use the base.

The reaction scheme 9:

Hydrolysis of chloropyridine

As shown in reaction Scheme 9, possibly substituted, imidazo[1,2-a]pyridine, including chloropyridin or bromopyridin as residue And X can be transformed into the corresponding pyridone under the action of a suitable reagent, for example, aqueous hydrochloric acid at a suitable temperature. At the same time produce the hydrolysis of the ether functional group. Acid can be introduced into reaction with amines HNR1R2as explained above.

The reaction scheme 10:

Synthesis of α-bromoketones

As shown in reaction Scheme 10, possibly substituted brometane can be obtained in accordance with the three-step reaction sequence, based on the carboxylic acid. These carboxylic acids can be converted into the corresponding amides Weinrebe (Weinreb) under the action of the hydrochloride of N,O-dimethylhydroxylamine and appropriate acatalog reagent, such as EDC in the presence of a suitable base such as NMM, in an appropriate solvent, for example, DHM. Amides Weinrebe can be converted into the corresponding methylketone under the action of a suitable reagent, for example, metallice, in an inert solvent, for example THF, at a suitable temperature. Bromination can be performed using a mixture of bromine and bromovalerate in acetic acid.

Scheme reacts the th 11:

Synthesis of imidazo[1,2-a]pyridines

As shown in reaction Scheme 11, possibly substituted aminopyridine-amides, which can be obtained as shown in reaction Scheme 1 can be converted into amides of imidazo[1,2-a]pyridine-6-carboxylic acid by reaction with α-bracketname in a suitable solvent, for example, MeCN. This reaction can be carried out either in the flask in a boiling solvent or in any other convenient temperature, either in a microwave reactor. The reaction products can be purified in accordance with standard procedures or can be precipitated directly from solution upon cooling and, thus, can be used in subsequent reactions without further purification.

The reaction scheme 12:

The reaction manniche

As shown in reaction Scheme 12, the products obtained in accordance with reaction Scheme 11, i.e. amides possibly substituted, imidazo[1,2-a]pyridine acids, can be used in the reaction of manniche to obtain amides of 3-aminomethyl-imidazo[1,2-a]pyridine-6-carboxylic acid by the reaction of amides of imidazo[1,2-a]pyridine-6-carboxylic acid with the appropriate amines and aqueous solution of formaldehyde in a suitable solvent, e.g. acetic acid. Removing protection from diamines containing one protective group natte, can be made in the processing of these compounds with a suitable acid, for example Hcl in dioxane or TFU in DHM. These compounds can then be cleaned using standard cleaning procedures, for example, washing chromatography or preparative HPLC.

The reaction scheme 13:

The α,β-unsaturated aldehydes by Michael

As shown in reaction Scheme 13, amides possibly substituted, imidazo[1,2-a]pyridine-6-carboxylic acid can be introduced into the reaction accession by Michael with α,β-unsaturated aldehyde in a suitable solvent, for example, a mixture of acetic acid and acetic anhydride at elevated temperature. The reaction can also be carried out in a microwave reactor. Products mentioned reactions can be treated with base, such as sodium bicarbonate in a suitable solvent, e.g. a mixture of water and methanol, with the formation of the corresponding aldehyde, which can be subjected to reductive aminating under the action of a suitable amine T-N in the presence of a reducing agent, for example, triacetoxyborohydride sodium, in an appropriate solvent, for example, EDC. In the alternative case, as starting materials can be used esters possibly substituted, imidazo[1,2-a]pyridine-6-carboxylic acid. In this is case, the ether functional group can be converted into amide after the introduction of the side chain-CH2CHR8CH2T in accordance with the methods described in reaction Scheme 8.

The reaction scheme 14:

The α,β-unsaturated ketones by Michael

As shown in reaction Scheme 14, the connection according to Michael amides possibly substituted, imidazo[1,2-a]pyridine-6-carboxylic acid can also be carried out using α,β-unsaturated ketones under the reaction conditions described in reaction Scheme 13. In this case, the product connection on Michael can be directly subjected to reductive aminating.

The reaction scheme 15:

Alkylation of the side chain

The products obtained in accordance with reaction Scheme 3, possibly substituted, imidazo[1,2-a]pyridine having a carboxylate group in the side chain, can be activated under the action of a suitable reagent, for example, CDI in an appropriate solvent, for example, DHM, and then introduced into the reaction of the hydrochloride of N,O-dimethylhydroxylamine in the presence of a suitable base, for example, DIEA. The reaction of the obtained product with a suitable reagent, for example, methyllithium, in a suitable solvent, for example THF or diethyl ether, yields a match is their ketones, which can be subjected to reductive aminating under the action of a suitable amine T-N in the presence of a reducing agent, for example, triacetoxyborohydride sodium in an appropriate solvent, for example, EDC.

The reaction scheme 16:

Reaction chloropyridine with amines

Possibly substituted, imidazo[1,2-a]pyridine with a 2-chloropyridinyl Deputy, may be introduced into reaction with amines, as shown in reaction Scheme 16. These chloropyridine can be introduced into the reaction with pure amines HR4bat elevated temperatures with formation of the corresponding 2-aminopyridine. The reaction can also be carried out in a microwave reactor. Benzyl protective group can be removed in the processing of N-benzilidene 2-aminopyridines a suitable reagent, for example, triftormetilfullerenov acid, in an inert solvent, for example, DHM, at the corresponding temperature.

The reaction scheme 17:

Reaction chloropyridine with alcohols

As shown in reaction Scheme 17, possibly substituted, imidazo[1,2-a]pyridine with a 2-chloropyridinyl Deputy, may be introduced into reaction with a suitable alcoholate with the formation of the corresponding alkoxyimino. The alcoholate may be prepared from the corresponding alcohol HR14 and a suitable base, e.g. sodium hydride, in an appropriate solvent, for example DMF. The reaction of the alcoholate with chloropyridine can be conducted at elevated temperatures.

The reaction scheme 18:

Alkylation of Spiridonov

Possibly substituted, imidazo[1,2-a]pyridine, including Spiridonova fragment, can be subjected to N-alkylation, as shown in reaction Scheme 18. The nitrogen atom of the pyridone may be subjected to alkylation under the action of a suitable allylbromide Br-R14in the presence of a base, such as cesium carbonate or potassium carbonate, in a suitable solvent, e.g. acetone, at a corresponding temperature. Alcohol substituents on the remainder R14can be protected, for example, by conversion into ester groups. After alkylation, the free alcohol can be obtained by hydrolysis of the ester under the action of a suitable reagent, for example, a monohydrate of lithium hydroxide, in an appropriate solvent, e.g. a mixture of water and THF.

Analytical liquid chromatography with mass spectrometry (LC-MS)

Connections, proposed according to the present invention having the formula (I), were analyzed using an analytical LC-MS. The terms below.

Condition analysis:

The LC device 10 Advp Pump (Shimadzu) with SPD-M 10 Avp (Shimadzu) V/Vis detector diode matrix with QP 2010 MS detector (Shimadzu) using ESI+ with UV detection at 214,254 and 275 nm.

Column: Waters XTerra MS C18, 3.5 µm, 2.1 a·100 mm, linear gradient of acetonitrile in water (0,15% HCOOH), exception: methods D and E (curvilinear gradient).

The flow rate of 0.4 ml/min

The mobile phase A: water (0,15% HCOOH)

Mobile phase b: acetonitrile (0,15% HCOOH)

Ways:

A: linear gradient from 5% to 95% acetonitrile in water (0.1% HCOOH)

0,00 min 5%

5,00 min 95%

5,10 min 99%

6,40 min 99%

6,50 min 5%

8,00 min Stop pump

In: linear gradient from 10% to 90% acetonitrile in water (0.1% HCOOH)

0,00 min 10%

5,00 min 90%

5,10 min 99%

6,40 min 99%

6,50 min 5%

8,00 min Stop pump

From: linear gradient from 5% to 95% acetonitrile in water (0.1% HCOOH)

0,00 min 5%

10,00 min 95%

10,10 min 99%

11,40 min 99%

11,50 min 5%

13,00 min Stop pump

D: initial concentration of 1% acetonitrile

9,00 Century Conc. 30

10,00 C. Curve 3

12,00 Century Conc. 99

15,00 Century Conc. 99

15,20 Century Conc. 1

18,00 Stop pump

E: the initial concentration of 10% acetonitrile

10,00 Century Conc. 60

11,00 C. Curve 2

12,00 Century Conc. 99

15,00 Century Conc. 99

15,20 Century Conc. 10

18,00 Stop pump

F: the initial concentration of 15% acetonitrile

12,00 Century Conc. 99

15,00 Century Conc. 99

15,20 Century Conc. 15

18,00 Stop 0

Below are described examples of the invention, which can be prepared in accordance with schemes is eacci 1-18.

Below are some illustrative non-limiting examples of embodiment of the invention.

Synthesis Example 9:

Intermediate compound 9a):

A suspension of CuBr2(1071 mg) in tO (10 ml) was heated to boiling and the solution was added methyl ester 5-(3-methoxy-phenyl)-5-oxo-pentanol acid (913 mg) in l3. The reaction mixture is boiled under reflux during the night. Then once added additional amount of CuBr2(300 mg)and the mixture is left to boil for another 4 h, the Reaction mixture was filtered through celite to remove copper salts, and the solvent was evaporated in vacuum to dryness. The residue was purified flash chromatography (tO/cyclohexane)to give the named compound.

Intermediate compound 9b):

To a solution of 6-amino-nicotinic acid (3 g) in DMF/DHM (80/20) was added vitaminen (4.1 g), EDC (5 g), HOBt (3.52 g) and DIEA (4.54 ml). The reaction mixture was stirred at 50°C during the night. The solution was evaporated in vacuum to dryness. The residue was re-dissolved in a small amount of DMF was added in buffer (pH 7). The precipitate was collected, washed with water and dried, obtaining a named connection.

Intermediate compound 9c):

To a solution of intermediate compound 9b) (1 g) in pyridine (25 ml) was added at once p-toluensulfonate (756 mg). The reaction mixture was heated at 85°C for 16 hours the Solution was evaporated in vacuum to dryness and to the residue was added N2O. the Obtained suspension was stirred for 30 min, then was filtered and washed with toluene. The remaining solid was collected and dried, obtaining the named compound as a yellow solid.

Intermediate compound 9d):

To the warm solution of intermediate compound 9c) (1781 mg) and DIEA (1,198 ml) in MeCN (50 ml) was added intermediate compound 9a) (1084 mg). The reaction mixture was heated at 100°C for 4 h the Solution was evaporated in vacuum to dryness, and the residue was purified flash chromatography (EtOAc/cyclohexane)to give the named compound.

Intermediate compound 9F):

p> Intermediate compound 9d) (1,372 g) was dissolved in DHM (50 ml)and the reaction mixture was purged with argon. To this solution was added TFAA (2 ml)and the reaction mixture was left to mix for 16 hours the Solution was evaporated in vacuum to dryness, and the residue was purified flash chromatography (DHM/Meon), getting a named connection in the form of a colorless foam.

Intermediate compound 9f):

Intermediate compound 9F) (568 mg) was dissolved in THF (40 ml) was added methanol (4 ml). The solution was heated to boiling and then added sodium borohydride (87 mg). Then sodium borohydride was added in several portions, and the boiling continued. The reaction was stopped by addition of acetone, and the solvent was removed in vacuum. The residue was purified flash chromatography (DHM/Meon 98:2)to give the named compound.

Intermediate compound 9g):

A solution of intermediate compound 9f) in dry DHM (10 ml) was purged with argon and cooled to 0°C. To this solution was added tea (170 μl) and methylsulfonylamino (95 μl)and the reaction mixture was left to warm up. Stirring was continued for 3 hours, the Reaction mixture was washed with H2O and a saturated solution of NaHCO3. The organic layer was dried over Na2SO4and evaporated in vacuum to dryness, obtaining a named connection, which is used in the next operation without further purification.

Example 9:

To a solution of pyrrolidine (168 mg) in dry MeCN (5 ml) was added a solution of intermediate compound 9g) (86 mg) in dry MeCN. The reaction mixture was heated to 75°C for 14 h, the Solution was evaporated in vacuum to dryness, and the residue was purified preparative HPLC, getting a named connection in the form of a colorless solid.

Example 17 synthesis:

Intermediate compound 17A):

The synthesis was carried out as described for intermediate 9F).

Intermediate compound 17b):

To a solution of intermediate 17A) (370 mg) in THF (15 ml) was added a 2M solution of lithium hydroxide in water (0.74 ml) at 0°C. Then the ice bath was removed and the reaction mixture was allowed to mix at room temperature for 2 days. The mixture was diluted with ethyl acetate and brine and the pH was brought to pH 6 with a solution of 3%citric acid. After separating layers, the organic layer was washed with saline and dried over sodium sulfate. The solvent was removed under reduced pressure, obtaining the titled compound, which was used in the next operation without further purification.

Intermediate compound 17c):

Intermediate compound 17b) (315 mg) was dissolved in THF (20 ml) and added CT is anildigital (162 mg). The mixture was stirred at room temperature for 1 h and then was cooled to 0°C. was Added a solution of sodium borohydride (38 mg) and water, and stirring continued for a further 10 minutes the Reaction was suppressed by the addition of acetone, and the solvent was removed in vacuum. The residue was dissolved in ethyl acetate and water. After separating layers, the organic layer washed with 5% citric acid solution. a saturated solution of sodium bicarbonate and saline. After the day is over sodium sulfate, the solvent was removed in vacuo, and the residue was purified flash chromatography (DHM/Meon), getting a named connection.

Intermediate compound 17d):

Intermediate compound 17c) (100 mg) was dissolved in dichlormethane (10 ml) and at 0°C was added methylsulfonylamino (0,026 ml) and triethylamine (0,046 ml). The ice bath was removed and the mixture was stirred at room temperature, and why they added an extra number of methylsulfonylamino (0,007 ml) and triethylamine (0,012 ml), and stirring continued for another hour. The mixture was diluted with dichloromethane and washed with water/saturated sodium bicarbonate solution and water. The organic layer was dried over sodium sulfate, and the solvent was removed by vacuum, obtaining a named connection, which is used in the next operation without further purification.

Example 17:

/p>

To a solution of pyrrolidine (78 mg) in dry CN (1.5 ml) was added a solution of intermediate compound 17d) (55 mg) in dry acetonitrile. The reaction mixture was heated to 50°C during the night. The mixture was evaporated in vacuum to dryness, and the residue was purified flash chromatography (DHM/Meon), getting a named connection. The free base was converted to the corresponding HCl salt.

Example 21 synthesis:

Intermediate compound 21A):

To a solution of intermediate compound 9F) (300 mg) in THF (12 ml) was added at 0°C. a 2M solution of lithium hydroxide in water (0.61 ml). Then the ice bath was removed and the reaction mixture was allowed to mix at room temperature over night. The mixture was diluted with ethyl acetate and brine and the pH was brought to pH 6 with a solution of 3% citric acid. After separating layers, the organic layer was washed with saline and dried over sodium sulfate. The solvent was removed under reduced pressure, obtaining a named connection that is used and the next operation without further purification.

Intermediate compound 21b):

Intermediate compound 21A) (275 mg) was dissolved in dichloromethane and added carbonyldiimidazole (102 mg). The mixture was stirred at room temperature for 30 min, and then added the hydrochloride of N,O-dimethylhydroxylamine (62 what g) and diisopropylethylamine (0,110 ml). Stirring was continued over night. The mixture was diluted with dichloromethane, and the organic phase is washed with 5% citric acid solution, sodium bicarbonate solution and brine and then dried over sodium sulfate and solvent was removed in vacuum. Purification with flash chromatography (DHM/Meon) allowed to obtain the titled compound.

The intermediate connection s):

To a solution of intermediate compound 21b) (100 mg) in dry tetrahydrofuran solution was added metallyte (1.5 m in diethyl ether, 0,12 ml) at -78°C. the Mixture was stirred for 30 min and then hydrolyzed with a saturated solution of ammonium chloride. After dilution with diethyl ether, the layers were separated, and the aqueous layer was twice extracted with diethyl ether. The combined organic layers were washed with saline, dried over sodium sulfate, and the solvent was removed in vacuum. Purification with flash chromatography allowed us to obtain a named connection.

Example 21:

The intermediate connection s) (65 mg) and pyrrolidine (0,013 ml) was dissolved in dichloroethane (2 ml) and then was added glacial acetic acid (0,008 ml) and triacetoxyborohydride sodium (42 mg). The mixture was stirred at room temperature for 3 days. The solvent was removed under reduced pressure, and the residue was purified flash chrome is cografya (DHM/Meon), getting a named connection. The free base was converted to the Hcl salt.

Example 25 synthesis:

Example 25:

To a solution of Example 17 (407 mg) in tert-butyl alcohol (8 ml) was added finely crushed potassium hydroxide (240 mg), and the mixture was heated to 70°C for 4 hours. Then the mixture was divided between brine and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate. The solvent was removed under reduced pressure, obtaining the titled compound, which was purified preparative HPLC.

Example 27 synthesis:

Intermediate compound 27A):

The copper bromide (547 mg) suspended in ethyl acetate (13 ml) and heated to boiling. Then added 4'-cyano-3-(1,3-dioxane-2-yl)propiophenone (500 mg) in chloroform (13 ml). The reaction mixture is boiled under reflux for 2 hours was Added 340 mg of copper bromide in two portions and then boiled for 2 hours. The mixture was stirred over night at room temperature and then filtered through celite. The solvent was evaporated under reduced pressure, and the product was purified by chromatography.

Intermediate compound 27b):

A mixture of intermediate tosilata 9c) (700 mg) and diisopropylethylamine (0.52 ml) in acetonitrile (20 ml) nag is evali to 50°C. Then was added the intermediate compound 27A) (480 mg) in acetonitrile, and the reaction mixture was stirred at 50°C for 30 min, and at room temperature over night. The solvent was removed under reduced pressure. The mixture was purified flash chromatography, getting a named connection.

Intermediate compound 27C):

Intermediate compound 27b) (620 mg) was dissolved in dry dichloromethane (16 ml). The mixture was cooled to 0°C in an ice bath. Then added triperoxonane anhydride (1,62 ml). The mixture was stirred at 0°C for 30 minutes and then at room temperature for 2 hours. The solvent was removed under reduced pressure. The intermediate product 27) was used in the next operation without purification.

Intermediate compound 27d):

Intermediate compound 27C) (460 mg) was dissolved in tetrahydrofuran (16 ml)and the solution was cooled to 0°C. was Added 6 M Hcl (0.46 ml), and then the reaction mixture was stirred at 60°C over night. Added 3 more equivalent 6N. HCl, and the mixture continued to stir at 60°C. the Mixture was neutralized with sodium carbonate and the product was extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The solvent was removed under reduced pressure, and the mixture was purified flash chromatography, getting a named connection.

the example 27:

Intermediate compound 27d) (19 mg) was dissolved in dichloroethane (0.3 ml), was added 1-methylpiperazine (5 μl)and the reaction mixture was stirred for 30 minutes After adding triacetoxyborohydride sodium (12 mg), the mixture was stirred at room temperature overnight. Was added water, and the aqueous phase was twice extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, and the solvent was removed under reduced pressure. The named compound was purified preparative HPLC.

Example 47 synthesis:

Intermediate compound 47A):

In argon atmosphere, to a stirred suspension of copper bromide (II) (9.523 g) in ethyl acetate (100 ml) was added 2-(5-chlorovaleryl)oxazol (4.000 g) in chloroform (100 ml). The resulting mixture was stirred at the boiling point during the night. The reaction mixture was filtered through celite, and the filtrate evaporated to dryness. The crude product was purified column chromatography.

Intermediate compound 47b):

At 50°C to a stirred solution of intermediate compound 47A) (2665 mg) in acetonitrile (75 ml) was added DIEA (3658 mm). The resulting solution was stirred for 15 minutes and then was added intermediate compound 9c) (4532 mg) in acetonitrile (75 ml). The resulting solution was stirred PR is 50°C for 3 hours Volatiles were removed and the product was purified column chromatography.

The intermediate connection 47s):

At 0°C, stirred solution of intermediate compound 47b) (4.65 g) in dry DHM (45 ml) was added TFAA (5 ml). The reaction mixture was then left to warm to K.T. and was stirred for 3 hours, the Reaction mixture was neutralized with saturated solution of NaHCO3and then the phases were separated. The organic layer was extracted twice with a saturated solution Panso3. The combined aqueous layers was extracted again DHM. The combined organic layers were washed with saline, dried over PA2CO3, was filtered, and volatiles were removed. The crude product was purified column chromatography.

Example 47:

The intermediate connection 47s) (1068 mg) was dissolved in acetonitrile (100 ml). Added pyrrolidine (2003 μl)and the reaction mixture was stirred at 70°C for 8 hours Volatiles were removed and the crude product was purified preparative LC-MS. The purified compound was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with saline, dried over sodium sulfate, and the solvent was removed. The resulting oil restore and in ethyl acetate (10 ml) was added 1 M Hcl in diethyl ether (2 ml). Volatiles were removed and the product was received in the form of a whitish powder.

Example of synthesis 50:

Example 50:

The substance of Example 25 (422 mg) was dissolved in concentrated hydrochloric acid and boiled under reflux for 2 hours. The solvent was removed under reduced pressure, obtaining the titled compound, which was purified preparative HPLC.

Example 54 synthesis:

The intermediate connection 54A):

A mixture of methyl ester of 2-(3-methoxy-phenyl)-imidazo[1,2-a]pyridine-6-carboxylic acid (1000 mg), methacrolein (990 mg), acetic anhydride (5.5 ml) and glacial acetic acid (14.5 ml) was heated in a microwave reactor at 180°C for 75 minutes. Then volatiles were removed under reduced pressure. Added methanol and 1N. an aqueous solution of sodium bicarbonate, and the mixture was stirred for 2 h the Solvent was removed, and the residue was dissolved in ethyl acetate and water. The organic layer was separated and dried over sodium sulfate. The solvent was removed under reduced pressure, obtaining the titled compound, which was used in the next operation without further purification.

The intermediate connection 54b):

The intermediate connection 54A) (450 mg) was dissolved in dichlormethane (27 ml)was added pyrrolidine (0,11 ml)and the mixture AC is stirred for 30 min at room temperature. Then add triacetoxyborohydride sodium (360 mg)and the reaction mixture was stirred over night. Was added water, and the aqueous phase was twice extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, and the solvent was removed under reduced pressure. The product was purified flash chromatography.

The intermediate connection s):

The intermediate connection 54b) (78 mg) was dissolved in tetrahydrofuran (3.5 ml) and cooled to 0°C. Then was added lithium hydroxide (0,19 ml, 2n. in water), and the mixture was left to warm to room temperature and was stirred for 2 days. Added ethyl acetate and brine. A white precipitate was dissolved by adding dropwise citric acid (5%). The organic layer was separated and dried over sodium sulfate. The solvent was removed under reduced pressure, obtaining the intermediate connection s).

Example 54:

The intermediate connection s) (38 mg) was dissolved in DMF (5 ml). Then add hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (HATU, 44 mg), diisopropylethylamine (20 ml) and vitaminen (24 μl)and the mixture was stirred over night at room temperature. The solvents were evaporated. The product was then dissolved in ethyl acetate. The organic layer was washed with saline, then with saturated what astora sodium bicarbonate and again with saline. The organic layer was dried over sodium sulfate, was filtered, and the solvent was evaporated. The product was purified preparative HPLC, obtaining the compound of Example 54.

Example 58 synthesis:

Intermediate compound 58A):

At 0°C, to S-methylpyridin-carboxylic acid (1000 mg) in DHM (25 ml) was added EDC (1608 mg). The reaction mixture was stirred at 0°C for 30 min and then was added the hydrochloride of N,O-dimethylhydroxylamine (818 mg)and then NMM (922 mm). The reaction mixture was left to warm to K.T. and was stirred overnight. The reaction mixture was diluted DHM (25 ml)and then was extracted with a saturated solution of NaHCO3(2×25 ml). The aqueous layer was again extracted DHM (25 ml). The combined organic layers were washed with saline, dried over Na2SO4, was filtered, and the solvents were removed. The crude product was purified column chromatography.

Intermediate compound 58b):

At -78°C in an argon atmosphere, to a stirred solution of intermediate compound 58A) (1270 mg) in dry THF (10 ml) was carefully added motility (1.6 M in Et2O, 13.2 ml). The reaction mixture was stirred at -78°C for 90 minutes, and then hydrolyzed with saturated solution of NH4Cl (10 ml). The reaction mixture was diluted with diethyl ether (50 ml). The aqueous layer was again extrage is ovali diethyl ether (2×10 ml). The combined organic layers were washed with saline, dried over Na2SO4, was filtered, and the solvent was carefully removed. The product was purified by distillation in vacuum in a Kugelrohr apparatus (10 mbar, 130°C).

The intermediate connection s):

When K.T., to stir a solution of intermediate compound 58b) (541 mg) in Asón (10 ml) was added 33% Nug in Asón (2 ml), and then bromine (53 μl). After 30 minutes, was added an additional amount of bromine (50 μl)and the reaction mixture was stirred for 90 minutes. The reaction mixture was concentrated in vacuo and then poured into a saturated aqueous solution Panso3. The mixture was extracted three times with ethyl acetate. The combined organic layers were dried over PA2SO4, was filtered, and the solvent was carefully removed. The crude product was purified column chromatography.

Intermediate compound 58d):

The intermediate connection C) (350 mg) and intermediate compound 9b) (522 mg) was dissolved in MeCN (10 ml) and then heated to 180°C for 30 min under microwave radiation. Volatiles were removed and the crude product was purified column chromatography.

The intermediate connection e):

To a solution of intermediate compound 58d) (381 mg) in glacial acetic acid ( ml) was added acrolein (233 μl), then acetic anhydride (2 ml), and the mixture was heated at 180°C. in a microwave reactor for 30 minutes, the Reaction mixture was poured into a mixture of saturated aqueous sodium bicarbonate (100 ml) and saturated aqueous sodium carbonate (50 ml) to obtain an alkaline pH, and then was extracted with ethyl acetate (2×50 ml). The organic layer was washed with saline, dried over Na2SO4, was filtered, and the solvent was removed. To the crude product in methanol (50 ml) was added 1M solution of sodium bicarbonate in water (10 ml). The reaction mixture was stirred at K.T. during the night. The reaction mixture was concentrated in vacuo and then was divided between saturated aqueous Panso3and DHM. The aqueous layer was extracted twice DHM. The combined organic layers were washed with saline, dried over Na2SO4was filtered, and the solvent was removed.

Example 58:

The intermediate connection e) (83 mg) and 2M dimethylamine in THF (463 μl) was dissolved in 1,2-dichloroethane (5 ml). Was stirred 1 h at K.T. and added triacetoxyborohydride sodium (782 mg). The mixture was stirred at room temperature overnight. The reaction mixture was extracted with 1 M NaHCO3(2×2 ml). The aqueous layer was again extracted with EDC (2 ml). The combined organic layers were washed with saline, dried over Na2SO4 was filtered and evaporated to dryness in a vacuum. The crude product was purified preparative LC-MS.

Example 59 synthesis:

Intermediate compound 59A):

In argon atmosphere, to a stirred suspension of copper bromide (II) (19.36 g) in ethyl acetate (200 ml) was added 6-chloro-3-(5-chlorovaleryl)-pyridine (10.06 g) in chloroform (200 ml). The resulting mixture was stirred at boiling for 20 hours, the Reaction mixture was filtered on celite and concentrated in vacuum.

The residue from the filtration was washed with acetonitrile, and the filtrate was concentrated in vacuum. The residue was dissolved in ethyl acetate (500 ml) and washed with saturated sodium bicarbonate solution (500 ml). The aqueous layer was twice extracted with ethyl acetate. The organic layers were combined with the first selected portion, washed with saturated sodium bicarbonate solution, water and brine, dried over MgSO4, was filtered, and the solvent was removed under reduced pressure.

Intermediate compound 59b):

To a solution of methyl ester of 6-aminonicotinic acid (20,09 g) in dry pyridine (400 ml) in an argon atmosphere was added taillored (28.94 g). The reaction mixture was stirred at 85°C for 16 hours the Solvent was removed under reduced pressure, the residue was dissolved in water and was stirred for 2 h Formed Beja the initial precipitate. It was filtered, washed twice with water and dried over Sicapent.

The intermediate connection 59S):

A mixture of intermediate compound 59b) (9.74 g) and intermediate compounds 59A) (10.24 g) in acetonitrile (300 ml) was treated with ethyldiethanolamine (6654 μl) and stirred at 50°C during the night. The solvent was removed under reduced pressure. The product was purified flash chromatography.

Intermediate compound 59d):

The intermediate connection 59S) (15,07 g) was dissolved in dry DHM (180 ml) and cooled to 0°C. was Added anhydride triperoxonane acid (20 ml)and the reaction mixture was allowed to mix at room temperature over night. The reaction mixture was diluted DHM (200 ml) and carefully extracted with a saturated solution of sodium bicarbonate. The aqueous layer was extracted twice DHM. The combined organic layers were washed with saline, dried over sodium sulfate and the solvent was removed under reduced pressure.

The intermediate connection e):

Intermediate compound 59d) (5.0 g), acetonitrile (120 ml) and pyrrolidine (10.9 ml) was stirred at 70°C during the night. The solvent was removed under reduced pressure. The product was treated by the addition of acetone, filtered and dried in a vacuum oven over night./p>

The intermediate connection 59f):

The intermediate connection e) (4.6 g) was dissolved in 3M Hcl in water (150 ml)and the reaction mixture was stirred at 120°C for 36 hours the Solvent was removed under reduced pressure, the residue is twice was co-evaporated with toluene, and the product was dried in high vacuum for 2 days. The product is directly used in the next operation without further purification.

Example 59:

The intermediate connection 59f) (1000 mg) was dissolved in DMF (10 ml) and then was added EDC (525 mg), HOAt (373 mg) and DIEA (1431 µl). The reaction mixture was stirred for 1 h was Added vitaminen (562 μl)and the reaction mixture was stirred over night. Volatiles were removed, and the residue was dissolved in ethyl acetate (200 ml). The organic layer was washed with saturated solution of NaHCO3(2×100 ml), and then the combined aqueous layers was extracted again with ethyl acetate (100 ml). The combined organic layers were washed with saline, dried over Na2SO4, was filtered, and the solvent was removed under reduced pressure. The crude product was purified preparative LC-MS.

Example 64 synthesis:

Example 64:

The substance of Example 50 (200 mg), hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (HATU, 185 mg) and Diisopropylamine the min (1,95 ml) in dimethylformamide (4 ml) was stirred for 15 minutes at room temperature, then was added 2n. a solution of methylamine in tetrahydrofuran (0.28 ml), and stirring was continued over night. Added ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine and dried over sodium sulfate. The solvent was removed under reduced pressure, obtaining the titled compound, which was purified preparative HPLC.

Example 79 synthesis:

Intermediate compound 79A):

At 50°C to a stirred suspension of intermediate compounds 59A) (679 mg) in acetonitrile (15 ml) was added DIEA (806 μl). The resulting solution was stirred for 10 minutes and then was added intermediate compound 9c) (993 mg) in acetonitrile (15 ml). The resulting solution was stirred at 50°C for 2 h the Solvent was removed and the resulting oil was purified column chromatography.

Intermediate compound 79b):

At 0°C, stirred solution of intermediate compound 79A) (1.35 g) in dry DHM (18 ml) was added TFAA (2 ml). The reaction mixture was then left to warm to K.T. and was stirred overnight. Volatiles were removed and the resulting oil was purified column chromatography.

The intermediate connection s):

Intermediate compound 79b) (100 mg), acetonitrile (5 ml) and pyrrolidin 167 μl) was stirred at 70°C during the night. The solvent was removed under reduced pressure. The product was purified column chromatography.

Example 79:

To a suspension of sodium hydride (31 mg) in DMF (5 ml) in an argon atmosphere was added ethylene glycol (22 μl). The reaction mixture was stirred at room temperature for 30 min, and then added intermediate compound 79) (70 mg) in DMF (5 ml). The mixture was stirred at 140°C during the night. The mixture was cooled and hydrolyzed with water. The solvent was evaporated, and the residue was dissolved in ethyl acetate. The organic layer was extracted with water and brine, and the solvent was removed under reduced pressure. The crude product was purified using preparative LC-MS.

Example 90 synthesis:

The intermediate connection 90A):

Bis-(3-methyl-butyl)-amide 2-(2-chloropyridin-3-yl)-3-(3-pyrrolidin-1-yl-propyl)-imidazo[1,2-a]pyridine-6-carboxylic acid (100 mg) and benzylamine (0.5 ml) was heated in a microwave reactor at 150°C for 2 h the Mixture was purified flash chromatography, getting a named connection.

Example 90:

To the intermediate connection 90A) (78 mg) in dry dichloromethane (1.5 ml) at 0°C was added dropwise triftormetilfullerenov acid (300 mg). Then the mixture was heated to 40°C for 3 hours. The mixture was again cooled to 0°C and DOB is Lyali 300 mg triftormetilfullerenov acid, and then was heated to boiling for 2 hours the Solvent was evaporated under reduced pressure. The named compound was obtained after purification preparative HPLC.

Examples of synthesis 91 and 92:

Examples 91 and 92:

The substance of Example 59) (100 mg) was dissolved in acetone (5 ml) and then was added potassium carbonate (41 mg) and 3-bromo-1-propanol (20 µl). The reaction mixture was stirred at 60°C overnight, was filtered, and the solvent was removed under reduced pressure. The products were divided by preparative LC-MS.

Example 98 synthesis

The intermediate connection 98A):

Before using δ-valerolactone was distilled under reduced pressure (BP. 106°C/22 mbar). To a stirred suspension of sodium hydride (60% in oil, 2.66 g) in dry toluene (100 ml) boiling was added dropwise a mixture of methyl tetrahydro-2H-Piran-4-carboxylate (8.87 ml) and δ-valerolactone (6.34 g) in dry toluene (50 ml). After the addition, the reaction mixture was stirred at the boiling point during the night. After cooling to room temperature, the reaction mixture was poured into ice water (300 ml). The solid in the flask was extracted with water (150 ml) and toluene (50 ml). After phase separation, the aqueous layer was acidified Asón (5 ml) and was extracted with ethyl acetate (3×150 ml). The combined organic CL and washed with saline, dried over Na2SO4, was filtered, and volatiles were removed. The crude product was purified column chromatography.

The intermediate connection 98b):

The intermediate connection 98A) (1.86 g) was stirred in concentrated hydrochloric acid (10 ml) at 80°C for 1 h, the Reaction mixture was poured into a saturated solution of Na2CO3(300 ml) and was extracted with DHM (3×100 ml). The combined organic layers were washed with saline, dried over Na2SO4. was filtered, and volatiles were removed.

The intermediate connection 98S):

In argon atmosphere, to a stirred suspension of copper bromide (II) (1965 mg) in ethyl acetate (25 ml) was added intermediate connection 98b) (934 mg) in chloroform (25 ml). The resulting mixture was stirred while boiling during the night. The reaction mixture was filtered through celite, and the layer of celite thoroughly washed with ethyl acetate. The organic layer was extracted twice with saturated solution of NaHCO3. The aqueous layer was again extracted with ethyl acetate. The combined organic layers were washed with saline, dried over Na2SO4, was filtered, and volatiles were removed.

The intermediate connection 98d):

At 50°C to a stirred suspension 9c) (1994 mg) in acetonitrile (50 m is) was added DIEA (1610 mm). The resulting solution was stirred at 50°C for 15 minutes, and then added the intermediate connection 98S) (1.25 g) in acetonitrile (50 ml). The resulting reaction mixture was stirred at 50°C during the night. Volatiles were removed and the crude product was purified column chromatography.

The intermediate connection e):

In argon atmosphere, to a solution of intermediate compound 98d) (525 mg) in EDC (9 ml) was added TFAA (1 ml)and the reaction mixture was stirred at K.T. within 4 days. Added additional number of TFAA (1 ml) and EDC (9 ml)and the reaction mixture was heated to the boil overnight. Volatiles were removed, and the residue was dissolved in ethyl acetate (50 ml). The organic layer was extracted twice with saturated solution of Na2CO3(25 ml). The combined aqueous layers was extracted again with ethyl acetate (25 ml). The combined organic layers were washed with saline, dried over Na2SO4, was filtered, and volatiles were removed. The crude product was purified column chromatography.

Example 98:

To a stirred solution of intermediate compounds e) (85 mg) in MeCN (10 ml) was added pyrrolidine (172 μl)and the reaction mixture was stirred in a sealed tube at 50°C for 2 days. Volatiles were removed and the crude PR the product was purified preparative LC-MS.

Example 109 synthesis:

The intermediate connection a):

To a solution of cyclopropylacetic acid (2002 mg) in DHM (100 ml) at 0°C. was added EDC (3834 mg) and HOBt (3063 mg). The reaction mixture was stirred at 0°C for 30 minutes was Added cyclopropylamine (1703 mg) and DIEA (10.45 ml)and the reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with 1.0 N. Hcl (100 ml), a saturated solution of NaHCO3(100 ml), water (100 ml) and brine (100 ml). The organic layer was dried over Na2SO4and evaporated in vacuum to dryness.

Intermediate compound 109b):

A solution of intermediate compound a) (2448 mg) in anhydrous THF (40 ml) was added dropwise at room temperature in an argon atmosphere to a suspension of sociallyengaged (1389 mg) in anhydrous THF (60 ml). The reaction mixture was heated to boiling point and stirred for another 2 days. The reaction mixture is hydrolyzed by adding 10% aqueous KOH (100 ml) at 0°C. After stirring for 20 min at room temperature, the reaction mixture was filtered, and the solid is washed with diethyl ether (100 ml). The two-phase filtrate was transferred into a separating funnel, and the organic layer was washed with water and brine. The combined aqueous layers washed twice diatrofi the ether (2×100 ml). The combined organic layers were washed with saline, dried over magnesium sulfate, and the solvent was removed under reduced pressure.

The intermediate connection s):

Intermediate compound 59d) (2.0 g), acetonitrile (30 ml) and 2-methyl-pyrrolidin (1,27 ml) was stirred at 70°C during the night. Added DIEA (500 μl)and the mixture was stirred at 70°C for 20 hours the Solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate and washed twice with saturated sodium bicarbonate solution, water and brine. The organic layer was dried over sodium sulfate, was filtered, and the solvent was removed under reduced pressure. The crude product was purified column chromatography.

Intermediate compound 109d):

The intermediate connection C) (1.7 g) was dissolved in 3M Hcl in water (100 ml)and the reaction mixture was stirred at 120°C for 24 h the Solvent was removed under reduced pressure, the residue is twice was co-evaporated with toluene, and the product was dried in high vacuum for 3 h, and then in an oven at 40°C under reduced pressure for 3 days. The product was used as such in the next operation without further purification.

Example 109:

Intermediate compound 109d) (600 mg) was dissolved in DM is A (5 ml) and then was added EDC (299 mg), At (212 mg) and DIEA (815 μl). The reaction mixture was stirred for 1 h was Added intermediate compound 109b) (239 mg)and the reaction mixture was stirred over night. Volatiles were removed, and then the residue was dissolved in ethyl acetate (100 ml). The organic layer was washed with a saturated solution Panso3(2×50 ml), then the combined aqueous layers was extracted again with ethyl acetate (50 ml). The combined organic layers were washed with saline, dried over Na2SO4, was filtered, and the solvent was removed under reduced pressure. The crude product was purified preparative LC-MS.

Example 110 synthesis:

Example 110:

The substance of Example 109 (230 mg) was dissolved in acetone (7 ml) and then was added cesium carbonate (222 mg) and 2-Bromeliaceae (55 μl). The reaction mixture was stirred at 60°C overnight, was filtered, and the solvent was removed under reduced pressure. N - and O-alkylated products were divided by preparative LC-MS.

Examples of synthesis 111 and 112:

Examples 111 and 112:

A mixture of substances of Example 110 and O-alkilirovanny by-product (crude product before cleaning) (116 mg) was dissolved in THF (10 ml) and cooled to 0°C. was Added monohydrate of lithium hydroxide (30 mg) in water (2 ml)and the reaction mixtures is ü stirred at 0°C for 30 min and at room temperature for 2.5 hours The reaction mixture was concentrated and then separated between ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saline, dried over sodium sulfate, and the solvent was removed under reduced pressure. The products were divided by preparative LC-MS.

Example 114 synthesis:

The intermediate connection a):

To a solution of 6-amino-N,N-bis-(3-methyl-butyl)-nicotinamide (100 mg) in MeCN (2 ml) was added 2-bromo-3'-methoxyacetophenone in MeCN (2 ml) and the mixture was heated at 170°C. in a microwave reactor for 40 min the Solvent was evaporated, and the crude mixture was purified flash chromatography (EtOAc/cyclohexane). getting a named connection.

Example 114:

A solution of 4-dimethylaminopyridine (14.1 mg) in SPLA and formaldehyde (37% aqueous solution, 8.2 ml) was added to the intermediate connection a) (30 mg) in the SPLA, and the mixture was heated at 60°C for 16 hours After evaporation of the solvent, the crude reaction mixture was purified preparative HPLC, getting a named connection.

Example 119 synthesis:

The intermediate connection a):

To a solution of 6-amino-N,N-bis-(3-methylbutyl)-nicotinamide (1000 mg) in MeCN (10 ml) was added 2-bromo-4'-chloroacetophenone in MeCN (10 ml), and the mixture was heated at 160°C in a microwave re store within 15 minutes When cooling, the formed precipitate, which was separated and dried, obtaining a named connection.

Example 119:

A solution of tert-butyl methyl ether [1,4]diazepan-1-carboxylic acid (22.3 mg) in the SPLA and formaldehyde (37% aqueous solution of 13.5 ml) was added to the intermediate connection a) (30 mg) in the SPLA, and the mixture was heated at 60°C for 16 hours After evaporation of the solvent, the crude reaction mixture was purified flash chromatography (DHM/Meon). The resulting BOC-protected intermediate compound is then treated with a mixture of 4M Hcl/dioxane for 1 h, getting a named connection.

The synthesis example 143:

Intermediate compound 143a):

2-Cyclopropyl-ethylamine hydrochloride (700 mg) suspended in dichloromethane (14 ml). The solution was cooled to 0°C, and then added isovalerianic (0.84 ml) and triethylamine (1.60 ml). The reaction mixture was left to warm to room temperature, and the mixture was stirred for 4 h the Solvent was evaporated, and the residue was separated between ethyl acetate (50 ml) and a saturated solution of NaHCO3(40 ml). The aqueous layer was twice extracted with ethyl acetate (50 ml)and the combined organic phases are washed with brine (40 ml). The organic layer was dried over Na2SO4, was filtered, and the solvent was removed under reduced pressure. Untreated the i.i.d. product was purified preparative LC-MS.

Intermediate compound 143b):

Intermediate compound 143a) (838 mg) was treated with a complex of balancetransfer (1M solution in THF, 14.9 ml)and the reaction mixture was stirred at boiling for 6 hours Then the reaction mixture was cooled to 0°C and carefully added methanol (7 ml). The reaction mixture is boiled under reflux for 5 h and cooled to 0°C. was Added di-tert-BUTYLCARBAMATE dissolved in DHM (7 ml)and the reaction mixture was stirred at room temperature overnight. Volatiles were removed, and the residue was dissolved in ethyl acetate (100 ml). The organic layer was washed with water (60 ml) and brine (60 ml). The organic layer was dried over Na2SO4, was filtered, and the solvent was removed under reduced pressure. The crude product was used without purification.

The intermediate connection s):

Intermediate compound 143b) (1.26 g) was dissolved in DHM (30 ml) was added 4M Hcl in dioxane (1,48 ml). The reaction mixture was stirred at room temperature for 14 hours, the Solvent was evaporated, the obtained white solid was treated with ether, and the product was separated by filtration, washed with ether and dried in high vacuum. The obtained solid was used without further purification.

Intermediate with the unity 143d):

In argon atmosphere, to a stirred suspension of copper bromide (II) (3.62 g) in ethyl acetate (60 ml) was added 5-chloro-1-(4-cyanophenyl)-1-oxapentane (3.00 g) in chloroform (60 ml). The resulting mixture was stirred while boiling during the night. Added additional amount of copper bromide (II) (0.60 g)and the reaction mixture is boiled under reflux for 3 hours, the Reaction mixture was filtered through celite, washed with ethyl acetate and concentrated in vacuum. The product was purified flash chromatography.

The intermediate connection e):

The intermediate connection 143d) (3.00 g) was dissolved in acetonitrile (80 ml). Added ethyldiethanolamine (3.2 ml)and the reaction mixture was heated at 85°C. was Added intermediate compound 59b) (2.80 g)dissolved in acetonitrile (20 ml)and the reaction mixture is boiled under reflux for 1 h the Solvent was removed under reduced pressure. The product was purified flash chromatography.

The intermediate connection 143f):

The intermediate connection e) (4.67 g) was dissolved in dry DHM (90 ml) and cooled to 0°C. was Added anhydride triperoxonane acid (12 ml)and the reaction mixture was allowed to mix at room temperature for 6 hours the Solvent was removed under reduced pressure. The remainder R which was storyli in ethyl acetate (200 ml) and poured into a saturated solution of sodium bicarbonate, the obtained white precipitate was filtered, washed with water and dried in high vacuum.

The intermediate connection 143g):

The intermediate connection 143f) (1.50 g), acetonitrile (40 ml) and pyrrolidine (3.5 ml) was stirred at 70°C for 6 hours half of the solvent was removed under reduced pressure and the remaining solution was cooled in an ice bath for 2 hours resulting solid substance was filtered and washed with chilled acetonitrile. The product was dried in high vacuum.

The intermediate connection 143h):

The intermediate connection 143g) (313 mg) was dissolved in THF (10 ml) was added 2M LiOH in water (0.92 ml). The reaction mixture was stirred at room temperature overnight. Added additional amount of THF (1.5 ml) and 2M LiOH in water (0.1 ml)and the reaction mixture was stirred at room temperature for 3 hours resulting solid substance was filtered off, washed with chilled THF and dried in high vacuum. The product was used as such in the next operation without further purification.

Example 143:

The intermediate connection 143h) (40 mg) was dissolved in DMF (3 ml) and then was added HATU (49 mg), DIEA (22 μl) and the intermediate connection C) (23 mg). The reaction mixture was stirred for 1 h, the Reaction was incomplete so I added an additional quantity of the intermediate C) (10 mg) and DIEA (22 μl), and the reaction mixture was stirred for 2 hours Volatiles were removed, and the residue was dissolved in ethyl acetate (50 ml). The organic layer was washed brine (40 ml), a saturated solution of NaHCO3(40 ml) and again with brine (40 ml). The organic layer was dried over Na2SO4. was filtered, and the solvent was removed under reduced pressure. The crude product was purified preparative LC-MS.

BIOLOGICAL STUDIES

A. Analysis linking

To identify competitive inhibitors that bind NDP-alpha-MSH, labeled with a fluorescent label, with membrane preparations of cell line NEC expressing human receptors melanocortin used membrane analysis of binding.

Test compounds or unlabeled NDP-alpha-MSH was prepared using various concentrations, on 384-well microtiter plates. NDP-alpha-MSH, labeled with a fluorescent label, was prepared in the same concentration, after which was added to the membrane preparations. The plates were incubated for 5 h at room temperature.

The degree of fluorescence polarization was determined using fluorescence polarization microplate reader.

C. Functional analysis

Agonistic activity of the human receptor melanocortin was determined by analysis using homogenis is aligned membranes. The competition between unlabeled camp and a fixed quantity of labeled fluorescent-labeled camp for a limited number of binding sites for cyclic amp-specific antibody was determined using fluorescence polarization.

Test compounds or unlabeled NDP-alpha-MSH was prepared using various concentrations, on 384-well microtiter plates. Added membrane preparations of cells NC expressing human receptors melanocortin. After a short period of pre-incubation, was added the appropriate amount of ATP, GTP and antibodies camp, and the plate is again incubated, and then they dosaged conjugate camp labeled with a fluorescent label. The plates were incubated for 2 h at 4°C and then read on a fluorescence polarization microplate reader. The amount of camp produced in response to exposure to the test compounds was compared with the output currents obtained during stimulation under the effect of NDP-alpha-MSH.

Analyzed some compounds, proposed according to the present invention, it was found that they bind the receptor melanocortin-4. In General it was found that the values of the IC50these compounds are less than 2 microns (micromoles). In addition, some compounds proposed in this image is in the shadow, were analyzed in functional analysis, and found that they do not activate the receptor melanocortin-4.

The table lists the values of the IC50obtained in the analysis of binding CMP-4P (human receptor MC-4R), and the values of the IC50obtained in functional analysis. The values of the IC50EU50have been grouped into three classes:

and<0.1 ám; b>of 0.1 μm and <1,0 µm;>1,0 µm

0
Table 8
Biological data obtained for embodiments of the present invention
ExampleAnalysis of the binding of CMP-4P IC50/mcmFunctional analysis of CMP-4P EU50/mcmFunctional analysis, % activation
SHU-9119and-7
NDP-α-MSHandand100
1b-0
2and-
3b-0
4b-0
5b-0

6and-0
7b-0
8and-0
9and-0
10-0
11and-0
12and-0
13- 0
14and-0
15b-0
16and-0
17and-0
18b-0
19and-0
20band-18
21and-0
22b-0
23b-0
24-0
25and-0
26b-0
27-0
28b-0
29and-0
30and-0
31and-0
32b-0

tr> -
33anda-22
34anda-18
35and-0
36-0
37and-0
38-0
39and-0
40b-0
41and-0
42and-0
43and-0
44and-0
45and-0
46b-0
47 and-0
48and-0
49and-0
50b--1
51and-0
52b-0
53b-3
54b-0
55b-0
56a-0
57a-0
580
59a-0

60b-0
61b-0
62b-0
63b-0
64a-0
65a-0
66b-0
67a-0
68b-0
69a -0
70b-0
71b-0
72b-2
73b--3
74b-1
75a-1
76b-4
77a-4
78a-2
79a-11
80bb-35
81a--9
82aa-17
83a--1
84a--8
85a--2
86a--11

-29
87-0
88b--2
89aa-25
90b-41
91bb
92ba-31
93b-0
94--13
95a-0
96a-0
97a-1
98b--8
99a-4
100a--22
101a--25
102a--15
103a--20
104a--15
105b--24
106b-0
107b--17
108b--19
109a--23
110b--23
111b--25
112a--9
113b-0

114b-0
115b0
116b-0
117b-0
118b-0
119b-0
120-0
121-0
122b-0
123-0
124b-0
125b-0
126-0
127b-0
128-0
129-0
130-0
131a-0
132b-0
133b-0
134b-0
135-0
136 b-0
137b-0
138b-0
139b-0
140b-0

141b-0
142a-0
143a-0
144b-0
145a-0
146b-0
147 -0
148b--12
149b-0
150b-0

C. models of food intake in vivo

1. Model of spontaneous power

Examined the food intake of rats after intraperitoneal and oral administration of the test compounds (see, for example, Chen, A.S. et al. Transgenic Res. 2000 Apr; 9(2):145-54).

2. Model anorexia caused by LPS, and exhaustion caused by the presence of a tumor

Researched preventing or reducing the anorexia induced by injection of lipopolysaccharide (LPS), or exhaustion caused by tumor growth, after intraperitoneal and oral administration to rats of the test compounds (see, for example, Marks, D.L.; Ling, N and Cone, R.D.Cancer Res. 2001 Feb. 15; 61(4):1432-8).

D. determine the absorption, distribution, metabolism and excretion (ADME) in vitro

1. Microsomia stability

Experimental methods

Prepared consolidated human liver microsome assay (containing microsome assay of men and women) and combined liver microsomes to us (male rats Sprague Dawley). Before using microsome assay were stored at -80°C.

Microsome assay (final concentration 0.5 mg/ml), 0.1 M phosphate buffer. pH 7.4, and the test compound (final concentration of substrate is 3 μm; final concentration of DMSO=0,25%) were subjected to pre-incubation at 37°C, and then to initiate the reaction was added NADPH (reduced nicotinamide adenine dinucleotide phosphate) (final concentration 1 mm). The final incubation volume was 25 µl. Also had a control incubation of each test compound, in which instead of NADPH was added to 0.1 M phosphate buffer with pH 7.4 (minus NADPH). For each species tested two control connections. For each test compound incubation was performed once.

Each connection were incubated for 0, 5, 15, 30 and 45 minutes Control (minus NADPH) were incubated only for 45 minutes the Reaction was stopped at the appropriate times by adding 50 μl of methanol containing internal standard. Inkubirovanie the plates were centrifuged at 2500 rpm for 20 min at 4°C to precipitate the protein.

Quantitative analysis

After precipitation of protein, liquid precipitation over United in the cassette containing up to 4 connections, and analyzed using conventional conditions LC-MS/MS.

Data analysis

A linear gradient was determined from the Rafik dependence relationship of the peak area from the time (area under the peak for the compound / area under the peak for the internal standard). Then, using the following equations to calculate the half-life and its own clearance:

Rate constant of elimination (k)=(-gradient)

The elimination half-life (t1/2)(min)=0,693/k

Own clearance (CLint) (μl/min/mg protein)=(V×0,693)/t1/2

where V=the Incubation volume ál/mg of microsomal protein.

The analysis produced the incubation of the two control compounds, and if the values obtained for these compounds did not fit within these limits, the results were discarded and the experiment was repeated.

2. The stability of hepatocytes

Experimental methods

To determine the stability of human hepatocytes used suspensions of hepatocytes (merged cells derived from organisms sin of man)that is stored with biotemperature. All hepatocytes stored in biotemperature were provided by In Vitro Technologies, Xenotech or TCS.

Incubation was carried out at concentrations of test or control compounds comprising 3 μm, cell density, accounts for 0.5×106living cells/ml Final concentration of DMSO in the incubation amounted to 0.25%. To detect non-enzymatic decomposition also had a control incubation in the absence of cells.

From the incubation mixture were taken at 2 of the sample (50 µl) of each species in a moments time the Yeni 0, 5, 10, 20, 40 and 60 min (control sample was collected only at 60 min) and added to methanol containing internal standard (100 μl)to stop the reaction.

As control compounds used tolbutamide, 7-hydroxycoumarin and testosterone.

Samples were centrifuged (2500 rpm at 4°C for 20 min) and the liquid above the precipitate obtained at each time point were pooled to conduct cluster analysis in the usual way LC-MS/MS.

Data analysis

A linear gradient was determined from the plot of the relationship of the peak area from the time (area under the peak for the compound/area under the peak for the internal standard). Then, using the following equations to calculate the half-life and its own clearance:

Rate constant of elimination (k)=(-gradient)

The elimination half-life (t1/2) (min)=0,693/k

Own clearance (CLint) (μl/min/million cells)=(V×0,693)/t1/2

where V=the Incubation volume ál/number of cells.

3. The permeability of SASO-2 (in both directions)

Experimental methods

Used for the analysis of cells SASO-2, obtained from ATS when the number of passages equal to 27. Cells (passages 40-60) were sown PA tablets Millipore Multiscreen, SASO-2 at a density of 1×105cells/cm2. Cells were cultured for 20 days in DMEM (modified what about the way Dulbecco Wednesday Needle), replacing the medium every two or three days. Analysis of permeability was carried out on 20 day.

In the analysis of the permeability of the medium used balanced salt solution Hanks (Hanks Balanced Salt Solution (HBSS)), buffer pH 7.4 with addition of 25 mm HEPES (N-2-hydroxyethylpiperazine-N-2-econsultancy acid) and 10 mm glucose at 37°C. the Incubation was made in an atmosphere of 5% CO2and a relative humidity of 95%.

20 days to prepare monolayers, twice washing basolateral (b) and apical (A) surface environment HBSS at 37°C. Cells are then incubated with HBSS in basolateral and apical compartments for 40 min to stabilize physiological parameters.

Then HBSS was removed from the apical compartment and replaced the dosing solutions of the test compounds. The solutions were prepared by diluting the 10 mm test compound in DMSO containing HBSS, getting the final concentration of test compounds, equal to 10 μm (final concentration of DMSO was 1%). The dosing solution also included a fluorescent marker experiment Lucifer yellow. Analytical standards were prepared from the dosing solutions. The permeability of each of the tested compounds was determined by 2 times. As a control on each tablet also used compounds with known permeability.

Insert apical about the division then typed in "appropriate" tablets, containing fresh HBSS. To identify the transition from basolateral to apical (B-A) permeability, started the experiment, replacing the buffer in boxes and then putting them in the appropriate tablets containing the dosing solutions. After 120 minutes corresponding to the tablets were removed, and apical and basolateral samples were diluted to conduct LC-MS/MS analysis. The initial concentration (C0and experimental outputs were calculated based on concentrations in the apical and basolateral branches.

The integrity of the monolayers during the experiment were tested for permeability of Lucifer yellow using fluorescence analysis. If the monolayers are not damaged, the permeability of Lucifer yellow is low. Subjects and control compounds were evaluated quantitatively using LC-MS/MS cluster analysis using the 5-point calibration at the proper dilution of samples. Used ordinary analysis.

If the value of Parrfor Lucifer yellow exceeded the QC limit in one of the individual wells containing the test compound, then take the value n=1. If the values of Rarrfor Lucifer yellow exceeded the QC limit in both holes containing the same test the connection, re-connection test. Sustained high values Prony is emoti Lucifer yellow connection-specific in both holes indicate the presence of toxicity. In this case, further experiments are not conducted.

Data analysis

The permeability coefficient for each connection (Parr) is calculated from the following equation:

Parr=(dQ/dt)/C0×A,

where dQ/dt represents the rate of penetration of the drug through the cell, With0represents the concentration in the donor compartment at time zero, and a is the area of the monolayer of cells. The value of0obtained from the analysis of the donor and receiver compartments after the end of the incubation. I believe that all the tested compounds detected after 120 minutes of incubation, originally present in the donor compartment at time 0 minutes. The measure of skewness is determined as follows:

AI=(Rarr(B-A))/(Rapp(A-B)).

The measure of skewness greater than one indicates the presence of a stream of cells SASO-2, which indicates that the connection may have poor absorption in vivo.

The values of effective permeability (Parr(A-b)) of the test compounds was compared with the corresponding values obtained for the control connection, atenolol and propranolol, the absorbance of which in humans is 50 and 90%, respectively (Zhao, Y.H., et al., (2001). Evaluation of Human Intestinal Absorption Data and Subsequent Derivation of a Quantitative Structure-Activity Relationship(QSAR) with the Abraham Descriptors. Journal of Pharmaceutical Sciences. 90 (6), 749-784). Talinolol (a known substrate of P-gp (Deferme, S., Mols, R., Van Driessche, W., Augustijns, P. (2002). Apricot Extract Inhibits the P-gp-Mediated Efflux of Talinolol. Journal of Pharmaceutical Sciences. 91(12), 2539-48)) was also included as a control connection, which allowed to detect the possible presence of functional P-gp in the monolayer of cells SASO-2.

4. Inhibition of cytochrome P450 (IC50determining at 5 isoforms)

Experimental methods

Inhibition of CYP1A

Six concentrations of test compounds(0,05, 0,25, 0,5, 2,5, 5,25 μm in DMSO; final concentration of DMSO=0,35%) were incubated with human liver microsomes (0.25 mg/ml) and NADPH (1 mm) in the presence of the marker substrate ethoxyresorufin (0.5 µm) for 5 min at 37°C. as a positive control during the test compounds used selective inhibitor of CYP1A, alpha naphthoflavone.

Inhibition of CYP2C9

Six concentrations of test compounds(0,05, 0,25, 0,5, 2,5, 5,25 μm in DMSO; final DMSO concentration=0.25 per cent) were incubated with human liver microsomes (1 mg/ml) and NADPH (1 mm) in the presence of the marker substrate tolbutamide (120 μm) for 60 min at 37°C. as a positive control during the test compounds used selective inhibitor of CYP2C9. sulfaphenazole.

Inhibition of CYP2C19

Six concentrations of test compounds(0,05, 0,25, 0,5, 2,5, 5,25 μm in DM is About; the final DMSO concentration=0.25 per cent) were incubated with human liver microsomes (0.5 mg/ml) and NADPH (1 mm) in the presence of the marker substrate mephenytoin (25 μm) for 60 min at 37°C. as a positive control during the test compounds used selective inhibitor CYP2S19. tranilcipromin.

Inhibition of CYP2D6

Six concentrations of test compounds(0,05, 0,25, 0,5, 2,5, 5,25 μm in DMSO; final DMSO concentration=0.25 per cent) were incubated with human liver microsomes (0.5 mg/ml) and NADPH (1 mm) in the presence of the marker substrate dextromethorphan (5 μm) for 30 min at 37°C. as a positive control during the test compounds used selective CYP2D6 inhibitor, quinidine.

Inhibition of CYP3A4

Six concentrations of test compounds(0,05, 0,25, 0,5, 2,5, 5,25 μm in DMSO; final DMSO concentration of 0.26%) were incubated with human liver microsomes (0.25 mg/ml) and NADPH (1 mm) in the presence of the marker substrate midazolam (2.5 μm) for 5 min at 37°C. as a positive control during the test compounds used selective CYP3A4 inhibitor, ketoconazole.

When incubations CYP1A, the reaction was stopped by adding methanol, and the formation of the metabolite, resorufin, was monitored using fluorescence (wavelength excitation=535 nm, the wavelength of emission = 595 nm). When incubations CYP2C9, CYP219, CYP2D6 and CYP3A4, the reaction was stopped by adding methanol containing internal standard. The samples are then centrifuged, and the liquid above the precipitate were combined to conduct simultaneous analysis of 4-hydroxytryptamine, 4-hydroxymephenytoin, dextrorphan and 1 hydroxymidazolam plus internal standard using LC-MS/MS. Used normal conditions LC-MS/MS. To the final sample prior to analysis was added formic acid in deionized water (final concentration=0.1%of). For calculating the value of the IC50(concentration of the test compound which causes 50% inhibition) was used reducing the rate of formation of metabolites compared with control samples containing media.

5. Binding protein plasma (10%)

Experimental methods

Solutions of test compounds (5 μm, final concentration of DMSO of 0.5%) were prepared in buffer (pH 7.4) and 10% plasma (about./about. in the buffer). The experiment was performed using equilibrium dialysis between the two compartments separated by a semi-permeable membrane. On one side of the membrane was added to the buffer solution, and on the other side - the solution of the plasma. Standards were prepared in plasma and buffer, and incubated them at 37°C. Appropriate solutions for each compound were analyzed cassettes using LC-MS/MS.

The number is the result of the analysis

After equilibration, on both sides of the membrane were sampled. The solution of each batch of compounds were combined into two groups (containing and not containing plasma) and analyzed on tapes using LC-MS/MS using two sets of calibration standards for not containing plasma (7 points) and containing plasma solutions (6 points). Used normal conditions LC-MS/MS. The samples were evaluated using standard curves obtained in the equivalent matrix. Each compound was tested twice. In each experiment involved testing the connection.

Data analysis

fu=(1-(PC-PF))/(PC)

fu=unbound fraction is

PC=concentration of sample in the protein-containing side

PF=concentration of sample in the side that does not contain protein

Values fu, obtained when 10% of plasma were transferred into the values fu, obtained in 100% plasma, in accordance with the following equation:

fu100%=fu10%/(10-(9·fu10%)).

Examples of pharmaceutical compositions

One of the specific embodiments of the composition for oral administration comprising the compound, proposed according to the present invention, is prepared from 33 mg of the compound of Example 9, which is mixed with sufficient finely milled with lactose in such proportions that the composition contains in a hard gelatin capsule of size 0 total to the number of connections, of 580 to 590.

Another specific embodiment of the composition for oral administration comprising the compound, proposed according to the present invention, is prepared from 37 mg of the compound of Example 17, which is mixed with sufficient finely milled with lactose in such proportions that the composition contains in a hard gelatin capsule of size 0 total number of connections of 580 to 590.

Although the present invention has been described and illustrated by means of some preferred embodiments, specialists in the art it is known that in these examples can be made various changes, modifications and substitutions, which are also included in the scope protected by the present invention. For example, depending on the specific pharmacological response, can be used effective dosages other than the doses shown in the present description, which can also be selected depending on the specific active compounds, as well as the type of composition and the applied method of administration, and such expected variations or differences in the results are also included in the objectives of the present invention and the scope protected by the present invention. Thus, the scope protected by the present invention, ogranichennikh Formula of the present invention, which should be given the widest possible interpretation.

1. The compound corresponding to formula (I)

and enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts of the compounds,
in which
And represents-NH-, -CH2-, -CH2-CH2or communication;
X is a
phenyl,
phenyl fused with a saturated heterocyclic 5 - or 6-membered ring, while the heterocyclic ring may contain one or two heteroatoms selected from O and N, and the heterocyclic ring is optionally substituted by exography, 6-membered saturated heterocyclyl, containing O as the heteroatom, 5-6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S,
and each phenyl and heteroaryl possibly substituted by from 1 to 2 R14and/or 1 substituent R4band/or 1 substituent R5;
R1and R2independently from each other selected from the following groups:
C1-6-alkyl and
With1-6-alkylen-C3-7-cycloalkyl, and
each alkyl possibly substituted by a group HE or
R1and R2together with the nitrogen atom to which they are attached, form a 5-6-membered ring which may be substituted by one Deputy, selected from C1-6-alkyl and O-C1-6-alkyl;
R4bbefore the hat is
C(O)NH2,
(O)HE,
C(O)NH-C1-6-alkyl,
C(O)N-(C1-6-alkyl)2,
SO2-C1-6-alkyl,
oxoprop, and when this cycle at least partially saturated,
NH2,
NH-C1-6-alkyl,
N-(C1-6-alkyl)2;
R5represents a 6-membered heteroaryl containing N as heteroatom;
R3represents -(CR8R9)n-T;
R8and R9independently from each other selected from the following groups: N and C1-6-alkyl;
n is 1, 2, 3, 4, 5 or 6;
T is a

or NR12R13;
R10represents a
N
NH2,
HE
C1-6-alkyl, possibly substituted by one IT,
halogen atom,
NH(C1-6-alkyl) or
N(C1-6-alkyl)2;
q is 1 or 2;
Y represents CH2, NR11or;
R11represents a
N, or C1-6-alkyl;
R12and R13independently from each other selected from the following groups:
N
C1-6-alkyl,
C1-6-quinil,
(CH2)0-2-C3-7-cycloalkyl, and
With1-6-alkylen-O-C1-6-alkyl,
while C1-6-alkyl possibly substituted with one halogen;
R14represents a
halogen atom,
CN,
With1-6-alkyl, possibly substituted by one to three substituents selected from atom ha is ogena, HE, O-C1-6-alkyl, O-C(O)1-6-alkyl,
O-C1-6-alkyl, possibly substituted by one Deputy, selected from HE, O-C1-6-alkyl, and O-C(O)1-6-alkyl, or
HE.

2. The compound according to claim 1, in which a represents a-NH-, -CH2-, -CH2-CH2or communication;
X is a
phenyl,
phenyl fused with a saturated heterocyclic 6-membered ring, and the heterocyclic ring may contain 1 or 2 heteroatoms selected from O and N, and the heterocyclic ring is optionally substituted by exography,
6-membered saturated heterocyclyl, containing O as the heteroatom,
5-6-membered heteroaryl containing one or two heteroatoms selected from N, O and S,
each phenyl and heteroaryl possibly substituted by from 1 to 2 R14and/or 1 substituent R4band/or 1 substituent R5;
R1and R2independently from each other selected from the following groups:
C1-6-alkyl, or
With1-6-alkylen-C3-7-cycloalkyl, or
R1and R2together with the nitrogen atom to which they are attached, form a 5-6-membered ring which may be substituted by one Deputy, selected from C1-6-alkyl,
O-C1-6-alkyl;
R14choose from:
the halogen atom,
CN,
With1-6-alkyl, possibly substituted from one to three automaticlogin,
O-C1-6-alkyl, possibly substituted
HE;
R4brepresents a
C(O)NH2,
C(O)NH-C1-6-alkyl,
C(O)N-(C1-6-alkyl)2,
SO2-C1-6-alkyl,
NH2.
NH-C1-6-alkyl, or N-(C1-6-alkyl)2;
R5represents a 6-membered heteroaryl containing N as heteroatom;
R3represents -(CR8R9)n-T;
R8and R9independently from each other selected from the following groups: N and C1-6-alkyl;
n is 1, 2, 3, 4, 5 or 6;
T is a

or NR12R13;
R10represents a
N
NH2,
HE
C1-6-alkyl,
halogen atom,
NH(C1-6-alkyl) or
N(C1-6-alkyl)2;
Y represents CH2, NR11or;
R11represents a
N or
C1-6-alkyl;
R12and R13independently from each other selected from the following groups:
H,
C1-6-alkyl,
(CH2)0-2-C3-7-cycloalkyl, and
With1-6-alkylen-O-C1-6-alkyl,
while C1-6-alkyl possibly substituted with one halogen.

3. The compound according to claim 1 or 2, in which a represents a-NH - or a bond.

4. The compound according to claim 1 or 2, in which R1and R2represent3-6-alkyl, or
R1and R2together with atomo is nitrogen, to which they are attached, form a 5-6-membered ring which may be substituted by one Deputy, selected from C1-6-alkyl and O-C1-6-alkyl.

5. The compound according to claim 1 or 2, in which T represents NR12R13.

6. The compound according to claim 5, in which R12and R13independently from each other selected from H, C1-3-alkyl and (CH2)0-2-C3-6-cycloalkyl, and alkyl possibly substituted with one halogen.

7. The compound according to claim 1 or 2, in which T is chosen from

8. The connection according to claim 7, in which Y is CH2or NR11and R10represents N, NH2With1-6-alkyl, NH(C1-6-alkyl) or N(C1-6-alkyl)2.

9. The compound according to any one of claims 1, 2, 6 and 8, in which
X is a phenyl fused with a saturated 6-membered heterocyclic ring, this heterocyclic ring may contain 1 or 2 heteroatoms selected from O and N, and the heterocyclic ring may optionally be substituted by exography, or
6-membered heteroaryl, containing O as the heteroatom, where each phenyl or heteroaryl possibly substituted by 1 to 2 substituents R14and/or 1 substituent R5.

10. The compound according to any one of claims 1, 2, 6 and 8, in which X represents a
phenyl, or
5-6-clenn the th heteroaryl, containing one or two heteroatoms selected from N, O and S, and
each phenyl and heteroaryl possibly substituted by from 1 to 2 R14and/or 1 R4band/or 1 R5.

11. The connection of claim 10, in which X represents phenyl.

12. The connection of claim 10, in which X represents pyridyl.

13. The compound according to any one of claims 1, 2, 6, 8, 11 and 12, used as a medicine for treatment and prevention of disorders, diseases and conditions, the development of which involved the receptor melanocortin-4.

14. The compound according to any one of claims 1, 2, 6, 8, 11 and 12, used as a receptor antagonist melanocortin-4.

15. The compound according to any one of claims 1, 2, 6, 8, 11 and 12, used for the treatment or prevention of disorders, diseases or conditions of a mammal sensitive to inactivation of the receptor melanocortin-4.

16. The connection 15 for the treatment or prevention of cancer cachexia, muscle wasting, anorexia, amyotrophic lateral sclerosis (als), anxiety and/or depression.

17. Pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier for the treatment and prevention of disorders, diseases and conditions mammal sensitive to inactivation of the receptor melanocortin-4.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new compounds of formula , wherein A represents residues of formulae

, , , X represents O; X1-X4 represents N, CH, CR1 or C-, X9-X12 represents N, CH, CR4 or C-, X13-X16 represents N, CH, CR or C-, wherein C represents an attachment point of the group A to a residue of the structure of formula (I); R' represents H or alkyl; R represents alkoxy, or Het; R1 represents F, CI, Br, I, OH, CN, carboxy, CONR6R7, NR2COR8, NR2COOR8, alkoxy, fluorinated alkoxy, Ar, Het or OHet; or R1 represents one of the following formulas: wherein n is equal to 2 and m is equal to 3; R2 represents H, alkyl, fluorinated alkyl, cycloalkyl, Het or Het-NH-CO-; R4 represents F, Cl, Br, I, OH, alkoxy, cycloalkoxy, Het or OHet; or R4 represents one of the following formulae: , wherein n is equal to 2 and t is equal to 3; each R6 and R7 independently represents alkyl, or cycloalkyl, or R6 and R7 together represent alkylene group containing 5-6 carbon atoms which forms a cycle with N atoms; R8 represent alkyl, or cycloalkylalkyl; R9 represents alkyl; Ar represents aryl group; Het represents heterocyclic group which is completely saturated, particularly saturated or completely unsaturated containing 5 to 10 ring atoms in which at least 1 ring atom represents N, O or S atom which is unsubstituted or substituted once or several times by the substituted specified in cl. 1; and their pharmaceutically acceptable salts or solvates or N-oxides, or solvates of their pharmaceutically acceptable salts, or solvates of N-oxides of their pharmaceutically acceptable salts wherein said compound can be presented in the form of a polymorph, wherein if said compound shows chirality, it can be presented in the form of a mixture of enanthiomers or a mixture of diastereoisomers, or can be presented in the form of single enanthiomer or single diastereoisomer; and wherein at least one of the groups R, R1 or R4 represents Het or OHet, wherein the group Het is specified in each case in substituted or unsubstituted azabicyclooctyl, oxaazabicycloheptyl, diazabicycloheptyl, diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl, hezahydropyrrolopyrazinyl and octahydropyrrolopyridinyl. Also the invention refers to other compounds of formula (I), to specific compounds, to a pharmaceutical composition based on the compound of formula (I), to a method of selective activation/stimulation of α-7 nicotinic receptors, to application of the compound of formula (I) for making the drug.

EFFECT: there are produced new compounds showing effective biological properties.

53 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present application describes substituted bicyclic beta-lactams of formula I: which are class A and class C β-lactamase inhibitors wherein X, R1 and R2 are specified in the application, as well as a method for producing them. The compounds of formula I and their pharmaceutically acceptable salts are applicable for preparing a pharmaceutical composition and for producing a drug. The declared compounds are applicable for treating bacterial infections, optionally in a combination with a β-lactam antibiotic. Particularly, the compounds may be used with such β-lactam antibiotics, as e.g. imipenem, piperacillin or ceftazidime to control microorganisms resistant to β -lactam antibiotics due to the presence of β-lactamases.

EFFECT: preparing the composition for treating bacterial infections.

28 cl, 117 ex, 3 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae

and ,

which can be used to inhibit lipid kinase, including PI3K, and treat lipid kinase-mediated disorders. Values of radicals are given in claim 1.

EFFECT: improved properties of the compound.

11 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae and including their stereoisomers, as well as pharmaceutically acceptable salt, where X denotes O or S; R1 is selected from H, F, CI, Br, I, CN, -CR14R15-NR16R17, -CR14R15-NHR10, -(CR14R15)NR10R11, -(CR14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -(CR14R15)mOR10, -(CR14R15)nS(O)2R10, -C(OR10)R11R14, -C(R14)=CR18R19, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NHR12, -NR12C(=Y)R10, -S(O)2R10, -S(O)2NR10R11, C2-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C4 carbocyclyl, piperidinyl, thiopyranyl, phenyl or C5-C6 heteroaryl; R2 is selected from H, C2-C12 alkyl and thiazolyl; R3 denotes a condensed bicyclic heteroaryl selected from indazole, indole, benzoimidazole, pyrrolopyridine, imidazopyridine and quinoline; R10, R11 and R12 independently denote H, C2-C12 alkyl, C3 carbocyclyl, heterocyclyl selected from pyrrolidine, morpholine and piperazine, phenyl or heteroaryl selected from pyrazole, pyridine, benzothiophene; or R10 and R11 together with a nitrogen atom with which they are bonded possibly form a saturated C3-C6 heterocyclic ring, possibly containing one additional ring atom selected from N or O, where said heterocyclic ring is possibly substituted with one or more groups independently selected from oxo, (CH2)mOR10, NR10R11, SO2R10, C(=O)R10, NR12S(O)R11, C(=Y)NR10R11, C1-C12 alkyl and heterocyclyl selected from pyrrolidine; R14 and R15 are independently selected from H or C1-C12 alkyl; R16 and R17 independently denote H or phenyl; R18 and R19 together with a carbon atom with which they are bonded form a C3-C20 heterocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, phenyl, heteroaryl, piperidinyl and condensed bicyclic heteroaryl possibly substituted with one or more groups independently selected from F, CI, Br, I, CF3, -C(=Y)R10, -C(=Y)OR10, oxo, R10, -C(=Y)NR10R11, -(CR14R15)nNR10R11, -NR10R11, -NR12C(=Y)R10, -NR12C(=Y)NR10R11, -NR12SO2R10, OR10, SR10, -S(O)2R10, -S(O)2NR10R11, possibly substituted with carbocyclyl, selected from cyclopropyl, possibly substituted heterocyclyl selected from piperazine, possibly substituted with alkyl and alkylsulphonyl, pyrrolidine, morpholine, piperdine, possibly substituted CH3, phenyl and possibly substituted heteroaryl selected from imidazole and triazole; Y denotes O; m equals 0, 1 or 2; n equals 1 and t equals 2. The invention also relates to a pharmaceutical composition which modulates lipid kinase activity, based on said compounds.

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used to treat lipid kinase-mediated diseases, for example, cancer.

48 cl, 2 tbl, 372 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula where R1 is selected from H, F, CI, Br, CF3, C1-C6 alkoxy and OH; R2 is selected from H and C1-C6 alkyl; n equals 1-5; m equals 0 or 1; and Y is selected from CH2, NR3, (NR3R4)+X-, O and S; R3 and R4 are independently selected from H and C1-C4 alkyl; and X- is selected from pharmaceutically acceptable anions. The invention also relates to a method of producing said compound and to an antiviral pharmaceutical composition based on said compound of formula (I).

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used in medicine to treat a viral diseases such as herpes.

19 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: described is a compound of general formula: [1], where R1 denotes an optionally substituted C2-C12 alkyl, aryl or heterocyclic group which can be a mono- or bicyclic 5-11-member radical, where the heteroatoms can be nitrogen, oxygen or sulphur; X1 denotes C2-C4 an alkylene group; X2 denotes a bond; X3 denotes a group of general formula NR3 or CR4R5NR3 (where R3 denotes a hydrogen atom, optionally substituted lower alkyl group or imino-protective group) and R4 and R5 are identical or different, and each denotes a hydrogen atom or a lower alkyl group or bond; X4 denotes a lower alkylene or lower alkenylene or lower alkynylene group, which can be substituted with one or more oxo groups or a bond; X5 denotes a sulphur atom or bond; Y1 denotes an optionally substituted divalent 4-, 5- or 6-member alicyclic hydrocarbon residue or an optionally subsituted divalent 5- or 6-member alicyclic amine residue, where the heteroatoms can be nitrogen or oxygen; Z1, Z2, Z3, Z4, Z5 and Z6 are identical or different, and each denotes a nitrogen atom or a group of general formula CR7 (where R7 denotes a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted amino group, or an amino group substituted with one or more C1-6 alkyl groups, a lower alkyl group, a cycloalkyl, a lower alkoxy group or a monocyclic 5-member heterocyclic group which can be substituted with one or more halogen atoms, where the heteroatoms can be nitrogen, acid or sulphur or a group of general formula Q1CO2R10 (where R10 denotes a carboxyl-protective group and Q1 denotes a lower alkenylene group), provided that at least one of Z3, Z4, Z5 and Z6 denotes a nitrogen atom, or salt thereof. The invention also describes an antimicrobial agent based on said compound.

EFFECT: novel compounds which can be used as antimicrobial agents are obtained and described.

25 cl, 176 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of vinflunine ditartrate, production method thereof and use thereof in therapy, especially for cancer pathology treatment.

EFFECT: high stability and wide variety of galenic forms.

8 cl, 3 ex, 5 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a compound presented by formula (1), to its salt or hydrate where in formula R1 represents a methylene group, R2 represents a phenyl group which can contain a substitute(s), or a heterocyclic group which can contain a substitute(s), the cycle A represents a 6- or 7-members cycle (where cycle-making atoms of the cycle A different from a sulfur atom in position 6 are carbon atoms), and R3 represents a hydrogen atom, or 1-3 equal or different substitutes used to substitute the cycle A where the possible substitutes are specified in clause 1 of the patent claim. Also, the invention refers to a pharmaceutical composition exhibiting an anticancer activity, on the basis of the compound presented by formula (1).

EFFECT: there are produced new compounds and pharmaceutical composition on their basis which can find application in medicine for cancer treatment.

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds (la) of formula applied as tyrosine kinase c-Met inhibitors. , where: LA is selected from ,

or ; RA is selected from:

or each RA2 and RA6 represents hydrogen; RA3 represents RAr; or RA3, RA4 and carbon atoms whereto attached form 6-members aryl, optionally substituted, in the amount up to 4 by independent groups RAr, or a 5-6-members heterocyclyl or heteroaryl ring containing at least one O, N or S atom; R represents -OH; RA5 represents hydrogen or RAr; LB represents a covalent bond or -N(R*)-; RB represents halogen, NH2 or C1-8aliphatic group, optionally substituted by R; a 6-10-members aryl ring; a 3-7-members carbocyclyl ring, a 5-10-members heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms, where each said aryl or heteroaryl ring is optionally substituted, in the amount up to five by independent groups RAr; R represents halogen, -R°, -SR°, Ph, optionally substituted R° or -C(O)OR°; each RAr is independently selected from halogen, -R°, -OR°, -SR°, Ph, optionally substituted in the amount up to five by independent groups -R°, -CN, -N(R°)2 or -C(O)OR°; or two adjacent groups RAr taken together, represent 1,2-methylenedixy or 1,2-ethylenedixy; each R* represents hydrogen; and each R° represents independently hydrogen, an optionally substituted C1-6aliphatic radical or an unsubstituted 5-6-members heteroaryl or heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms.

EFFECT: invention refers to pharmaceutically acceptable compositions containing the compounds under the invention, and methods of application of the compositions in treatment of various proliferative disorders.

10 cl, 4 tbl, 548 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I in which A denotes X denotes O; R denotes H; R1 denotes OH, CN, a nitro group, NH2, NR2CSR8, NR2CONR2R9, NR2C SNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted with Ar or He, cycloalkenyl containing 5-8 carbon atoms, alkoxy group containing 1-4 carbon atoms, cycloalkoxy group containing 3-7 carbon atoms, cycloalkylalkoxy group containing 4-7 carbon atoms, fluorinated alkoxy group containing 1-4 carbon atoms, fluorinated hydroxyalkyl containing 1-4 carbon atoms, hydroxyalkoxy group containing 2-4 carbon atoms, an ordinary hydroxyalkoxy group containing 2-4 carbon atoms, monoalkylamino group containing 1-4 carbon atoms, dialkylamine group, where each alkyl group independently contains 1-4 carbon atoms, alkoxycarbonyl containing 2-6 carbon atoms, Het or OAr; R2 denotes H, alkyl containing 1-4 carbon atom, cycloalkyl containing 3-7 carbon atoms, and cycloalkyl alkyl containing 4-7 carbon atoms; R6 and R7 independently denote H, alkyl containing 1-4 carbon atoms, cycloalkyl containing 3-7 carbon atoms, or cycloalkylalkyl containing 4-7 carbon atoms, or R6 and R7 together denote an alkylene group containing 4-6 carbon atoms, which forms a ring with an N atom; R8 denotes alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 3-6 carbon atoms, alkynyl containing 3-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group is unsubstituted or substituted with Ar, cycloalkyl containing 3-7 carbon atoms, or Het; R9 denotes Ar or Het; R10 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar, or NR6R7; Ar denotes an aryl group containing 6-10 carbon atoms, which is unsubstituted or substituted once or several times with an alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, halogen, cyano group or combinations thereof; and Het denotes dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl or naphthyridinyl, which is unsubstituted or substituted once or several times with halogen, aryl containing 6-10 carbon atoms, which is optionally substituted with alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, oxo group, -CXR11 or combinations thereof, or R11 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar or Het; or pharmaceutically acceptable salts thereof, where formula IA is attached to the rest of the bonding molecule in the 3, 4 or 7 positions. The invention also relates to a pharmaceutical composition and to use of compounds in any of claims 1-37.

EFFECT: obtaining novel biologically active compounds, having nicotinic acetylcholine receptor subtype α7 ligand activity.

59 cl, 316 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to compounds that may be applied for HIV infection treatment or prevention or for AIDS or AIDS-associated complex treatment. According to the invention, the compounds represent compounds with formula I, where A stands for A1 , A2 , A3 or A4 and R1, R2, R3, R4a, R4b, R5, R6, Ar, X1, X2, X4, X4 and X5 having values specified in the patent claim. Additionally, this invention relates to a pharmaceutical composition containing the said compounds.

EFFECT: production of compounds possessing inhibition activity with regard to HIV reverse transcriptase.

22 cl, 3 tbl, 29 ex

Polymorphic form // 2448966

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is novel polymorphic form B N-[3-tret-butyl-1-(3-chlor-4-hydroxyphenyl)-1H-pyrazol-5-yl]-N'-{2-[(3-{2-[(2-hydroxyethyl)sulfanyl]phenyl}-[1,2,4]triazolo[4,3-a]pyridin-6-yl)sulfanyl]benzyl]}carbamide, method of its obtaining.

EFFECT: possibility to apply composition in treatment of various states, especially in treatment of inflammatory conditions, such as chronic obstructive lung disease.

4 cl, 12 ex, 9 tbl, 11 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 1-azabicycloalkyl derivatives of formula (I): wherein A represents O or N(R1); Y represents a group of formulas: or R represents substituted or unsubstituted phenyl or indolylradical, to their use as pharmaceutical agents, to pharmaceutical compositions containing them, to methods of treating and preventing mental and neurodegenerative diseases.

EFFECT: preparing pharmaceutical agents for treating and preventing mental and neurodegenerative diseases.

17 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrido[2,3-d]pyrimidines of formula (V) and use of compounds of formula (I), containing a compound of formula (V), to prepare a medicinal agent used for inhibiting HCV replication in mammals infected with HCV, as well as a pharmaceutical composition based on said compounds. In formula (I)

R1 denotes hydrogen, amino, mono- or disubstituted amino, where amino group substitute(s) can be selected from C1-6alkyl, C1-4alkyloxyC1-4alkyl, diC1-4alkylaminoC1-4alkyl/piperidin-1-ylC1-4alkyl, phenylC1-4alkyl, where the phenyl group can further be substituted with C1-4alkoxy; L denotes -NR8-; R2 denotes Het2, where said Het2 denotes an aromatic monocyclic 6-member heterocycle which contains one nitrogen atom and is optionally substituted with one or more substitutes selected from C1-4alkyl; polyhalogenC1-4alkyl, halogen, -COOR7, -CONR4aR4b, -OR7, -SR5, and where C1-4alkyl can further be substituted with -COOR7; R3 denotes phenyl which is optionally substituted with one or two halogen atoms; each of R4a and R4b independently denotes hydrogen, C1-4alkyl, hydroxyC1-4alkyl; each R5 independently denotes C1-4alkyl; each R7 independently denotes hydrogen or C1-4alkyl; and each R8 independently denotes hydrogen or C1-10alkoxycarbonyl. The values of radicals in formula (V) are given in the claim.

EFFECT: improved method.

18 cl, 4 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted methyl-amines of general formula 1, having serotonin 5-HT6 receptor antagonist properties. In formula 1 , W is naphthalene, indolysin or quinoline; R1 is hydrogen, fluorine, chlorine, methyl; R2 is hydrogen, fluorine, methyl, phenyl, thiophen-2-yl, furan-2-yl, pyridyl, piperazin-1-yl or 4-methylpiperazin-1-yl; R3 is methyl; or W is benzene, R3 assumes the value given above; R1 is 3-Cl, R2 is 3-piperazin-1-yl or 3-(4-methylpiperazin-1-yl); or R1 is hydrogen, R2 is phenyl or pyridyl; or R1 is hydrogen, fluorine, chlorine, methyl; R2 is 4-piperazin-1-yl or 4-(4-methylpiperazin-1-yl); or W is oxazole, R3 is optionally substituted methyl; R1 is chlorine or fluorine, R2 is methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is piperazin-1-yl, 4-methylpiperazin-1-yl, or R1 is chlorine, fluorine or methyl; R2 is furan-2-yl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is furan-2-yl, R3 is (tetrahydrofuran-2-yl)methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is thiophen-2-yl, R3 is 2-methoxyethyl, or R1 is chlorine or fluorine, R2 is thiophen-2-yl, R3 is methyl.

EFFECT: compounds can be used to treat central nervous system (CNS) diseases, such as psychiatric disorders, schizophrenia, anxiety disorders, as well as for improving mental capacity, for treating obesity or for studying the molecular mechanism of inhibiting serotonin 5-HT6 receptors.

15 cl, 27 dwg, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the field of chemistry of heterocyclic compounds, and in particular to the compound of formula where X denotes a phenyl group; R1, R3 and R4 denote hydrogen atoms; R2 denotes a non-saturated monocyclic heterocyclic group containing 5 or 6 atoms including from 1 to 2 heteroatoms chosen from N and O; the mentioned heterocyclic group can be replaced by the group -NRcRd; Rc and Rd denotes hydrogen; in the form of a hexone base or acid additive salt. The invention also refers to a drug and pharmaceutical composition based on the formula (I) compound, to application of the formula (I) compound for preparation of the drug. Besides, the invention describes the compound of phenyl[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]piridin-2-yl]methanone and its application in synthesis of the formula (I) compounds.

EFFECT: new compounds of imidazo[1,2-a]piridines that are applicable in treatment or prevention of diseases in which NOT receptors are active.

15 cl, 2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the field of organic chemistry, notably to derivatives of dihydroimidazole with the general formula (I) and to its pharmaceutically acceptable salts where X1 and X2 denote halogen; R1 and R2 are chosen from the group including -H, -CH3, -CH2CH3 on the condition that both R1 and R2 do not denote hydrogen; R3 denotes -H or -C(=O)-R7; and if R6 denotes hydrogen, then R4 denotes -OCH3, -OCH2CH3 or -OCH(CH3)2; R5 denotes -H, - halogen, -CF3, -OCH3, -C(CH3)2, - cyclopropyl, - cyano group, -C(CH3)3, -C(CH3)2OR (where R denotes -H), -C(CH3)2CH-OR (where R denotes -CH3), -C(CH3)2CN, -C(CH3)2COR (where R denotes -CH3), -SR (where R denotes -CH2CH3) or -SO2R (where R denotes -CH3, -CH2CH3, 1-pyrrolidine, -NH-tert-butyl); and if R6 does not denote hydrogen, then R4 denotes -OCH2CH3; R5 denotes hydrogen, -Cl, -OCH3, tert butyl; R6 denotes -Cl, cyclopropyl, -SO2R (where R denotes -CH3, 1-pyrrolidine, -NH-tert-butyl or -N(CH3)2); and R7 is chosen from the group including i) -CH3, -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, cyclobutyl, -CH2CH2Ph, 2-furanyl, phenyl or phenyl substituted with chlorine, -OCH3 or cyano group, ii) 1-piperidinyl, iii) -NRc2 (where Rc denotes -CH2CH2OH, -CH2CH2OCH3 or -CH2CH(OH)CH2OH, iv) substituted piperazidine with the formula where R is chosen from the group including a) hydrogen, c) -CH(CH3)2, k) -CH2CH2Rd (where Rd denotes -OH, -OCH3, -CF3, -SO2CH3, -NH2, -NHCOCH3, -NHSO2CH3, 4-morfolinil, 2-izotiazolidinil-1, 1-dioxide), l) -CH2CH2CH2Re (where Re denotes -OCH3, -SO2CH3, -SO2CH2CH3, -CN), m) -CH2-CO-Rh (where Rh denotes -NH2, 1-pyrrolidinyl, 4-morfolinil), n) -SO2Ri (where Ri denotes -CH3, -CH2CH3), o) -CORj (where Rj denotes -CH3, 2-tetrahydrofuranyl, -NH2, -N(CH3)2), p) 4-tetrahydro-2H-thiopiranyl-1,1-dioxide, q) 4-piperidinyl-1-acetyl, r) 4-piperidinyl-1-dimethylcarboxamide, and s) 3-tetrahydrothiophenyl-1,1-dioxide; v) substituted oxopiperazine with the formula where R denotes -H; and vi) substituted piperidine with the formula where R denotes -CONH2, -OH, -CH2OH, -CH2CH2OH, 1-pyrrolidinyl, 1-piperidinyl, 1-(4-methylpiperazinyl) or 4-morfolinil. Moreover, the invention refers to the pharmaceutical composition based on the compound with the formula (I), to application of the formula (I) compound for production of a drug, to the production process of the formula (I) compound.

EFFECT: new derivatives of dihydroimidazole that may be used as anticancer drugs.

40 cl, 204 ex

Antiviral compouds // 2441869

FIELD: pharmacology.

SUBSTANCE: invention refers to the new compounds or its pharmaceutically acceptable salts where the compound has formula I possessing the activity towards hepatitis C virus (HCV). In the compound of formula I, Each W1 and W2 means nitrogen, W3 is chosen out of group consisting of nitrogen and -CH-, and W4 is -CH-; A is phenyl and is not mandatory substituted, X is chosen out of group consisting out of bond, -O- and -S-, Z is chosen out of group consisting of -CH2- and -NH-; R22 is chosen out of group consisting of hydrogen, benzimidazole, indole and thiophene, where R22 is not mandatory substituted, Y is chosen out of group consisting of C(O)N(R15)- and -N(R15)C(O)-, where R15 in each case is chosen out of group consisting of hydrogen and C1-C6alkyl; R50 is -L1-A1 where L1 is chosen out of group consisting of bond and C1-C6alkylene, and A1 is chosen out of group consisting of phenyl, pyridyl, benzothiazolyl, thiadiazole, isothiazole and thiophene, where A1 is not mandatory replaced, each R10 and R35 means hydrogen; R17 is C1-C6alkyl; and each C3-C18carbocyclil and M3-M18heterocyclil in -LE-Q-LE-(C3-C18carbocyclil) and -LE-Q-LE-( M3-M18heterocyclil) is not mandatory independently substituted in each case.

EFFECT: enhanced cure of hepatitis C.

13 cl, 12 dwg, 459 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

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