Azacyclic spiro-compounds

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to derivatives of diaza-spiro[4.5]decan-1-one of formula (I) or to their pharmaceutically acceptable salts, where. R1 is a substituted phenyl, which contains one substituent, selected from the group, including C1-4-alkyl, C3-6-cycloalkyl halo-C1-4-alkyl and halo -C1-4-alkoxy, and which can additionally contain one substituent, selected from a halogen; R2 is hydrogen, C1-4-alkyl, phenyl, substituted phenyl, with the substituted phenyl containing one substituent, selected from the group, including C1-4-alkoxy; R3 is -R4, -C(OH)R5R6 or -C(O)NR7R8; R4 is phenyl, phenyl-C1-4-alkyl, substituted phenyl, substituted phenylcarbonyl, with the substituted phenyl, substituted phenylcarbonyl containing from one to two substituents, selected from the group, including a halogen, halo-C1-4-alkyl; one of R5 and R6 is hydrogen, C1-4-alkyl, and the other is aminocarbonyl, phenyl, substituted phenyl or substituted phenyl-C1-4-alkyl, with the substituted phenyl or substituted phenyl-C1-4-alkyl containing from one to two substituents, independently selected from the group, including a halogen; one of R7 and R8 is hydrogen C1-4-alkyl, and the other is C1-4-alkyl, C3-6-cycloalkyl, C1-4-alkoxy-C1-4-alkyl, phenyl-C1-4-alkyl, substituted phenyl or substituted phenyl-C1-4-alkyl, with the substituted phenyl or substituted phenyl-C1-4-alkyl containing one substituent, selected from the group, including a halogen, halo-C1-4-alkyl; or R7 and R8 together with a nitrogen atom, which they are bound to, form pyrrolidinyl; n equals zero or 1/ The invention also relates to a pharmaceutical composition based on the compound of formula (I), application of the formula (I) compound and a method of treatment.

EFFECT: obtained are novel heterocyclic compounds, useful as an inhibitor of hormone-sensitive lipase.

17 cl, 57 ex

 

The present invention relates to new derivatives usacycling Spiro-compounds that can be used as inhibitors gormonchuvstvitelnoy lipase (HSL) for the treatment of diabetes.

In particular, the invention relates to compounds of formula (I)

in which

R1is substituted phenyl, which contains from one to three substituents independently selected from the group comprising alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, hydroxyalkoxy, alkoxyalkyl and haloalkoxy, and which may further contain substituents, independently selected from halogen;

R2is hydrogen, alkyl, cycloalkyl, phenyl, phenylalkyl, substituted phenyl or substituted phenylalkyl, wherein substituted phenyl and substituted phenylalkyl contain from one to three substituents independently selected from the group comprising alkyl, cycloalkyl, halogen, haloalkyl, hydroxy, alkoxy, hydroxyalkoxy, alkoxyalkyl and haloalkoxy;

R3is-R4, -C(OH)R5R6or-C(O)NR7R8;

R4is phenyl, phenylcarbinol, phenylalkyl, substituted phenyl, substituted phenylcarbamoyl or substituted phenylalkyl, the substituted phenyl, substituted phenylcarbinol and substituted phenylalkyl contain from one to three substituents independently selected from the group �comprising alkyl, cycloalkyl, halogen, haloalkyl, hydroxy, alkoxy, hydroxyalkoxy, alkoxyalkyl and haloalkoxy;

one of R5and R6is hydrogen, alkyl or cycloalkyl and another of them is aminocarbonyl, phenyl, phenylalkyl, substituted phenyl or substituted phenylalkyl, wherein substituted phenyl and substituted phenylalkyl contain from one to three substituents independently selected from the group comprising alkyl, cycloalkyl, halogen, haloalkyl, hydroxy, alkoxy, hydroxyalkoxy, alkoxyalkyl and haloalkoxy;

one of R7and R8is hydrogen, alkyl, cycloalkyl, hydroxyalkyl or alkoxyalkyl and the other one is the alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, phenyl, phenylalkyl, substituted phenyl or substituted phenylalkyl, and these substituted phenyl and substituted phenylalkyl contain from one to three substituents independently selected from the group comprising alkyl, cycloalkyl, halogen, haloalkyl, hydroxy, alkoxy, hydroxyalkoxy, alkoxyalkyl and haloalkoxy;

or R7and R8together with the nitrogen atom to which they are attached, form pyrrolidinyl, piperidinyl, azepane, piperidinyl, morpholinyl or thiomorpholine;

n is zero or 1;

or their pharmaceutically acceptable salts.

The main physiological role of white adipose tissue (WAT) is to supply energy when�and need it in other tissues. In mammals, white adipose tissue is the major energy depot accumulating stocks of fuel in the form of triacylglyceride (TAG) during periods of excess energy (M. Wang et al., Sung.Biol., 2006, 13, 1019-1027; F. M. Gregoire et al., Physiol. Rev., 1998, 78, 783-809). Thus, in contrast to the synthesis of TAG, which in large quantities are also made in the liver to produce VLDL (VLDL), lipolysis for the purpose of storing fatty acids as an energy source consumed by other bodies, found only in adipocytes. The release of free fatty acids (FFA) is a regulated and orderly process (Unger R. H, Annu. Rev. Med. 2002, 53, 319-336; Duncan RE. et al, 2007, Annu Rev Nutr, 27, 79-101; K. Jaworski et al, 2007, Am J Physiol Gastrointest Liver Physiol, 293, G1-4), is stimulated by catecholamines and regulated by hormones such as insulin, glucagon and epinephrine.

The most important enzyme of white adipose tissue, which is believed to be responsible for hormonal adjustable triglyceride hydrolysis, is gormonchuvstvitelnoy lipase (HSL). This enzyme is also present in liver, skeletal muscle, pancreas and adrenal glands. In the basal condition of the patient, this enzyme has minimal activity against its substrate. Stimulation of adipocytes by hormones activates protein kinase A, resulting in phosphorylation of HSL and squirrel perilipin, VBOs�lakehouse lipid droplet. The phosphorylation of perilipin leads to the fact that protein escapes from the surface of lipid droplets, and phosphorylated HSL migrates from the cytosol to the lipid droplet, where it catalyzes the hydrolysis of triglycerides (Wang, M. et al., Chem. Biol., 2006, 13, 1019-1027).

Dysregulation of lipolysis in adipocytes, leading to increased levels of circulating nonesterified fatty acids (NEFA), interrelated with obesity and related diseases, including the development of type 2 diabetes mellitus (linger R. H, Annu. Rev. Med. 2002, 53, 319-336). For fat or insulinresistant patients characterized by increased visceral depot of adipose tissue. These depots contain increased amounts of protein HSL (Large, V. et al., 1998, J. Lipid. Res. 39, 1688-1695) and are characterized by increased lipolytic activity, because they are resistant to insulin-mediated suppression of lipolysis. This leads to increased levels of free fatty acids in plasma, which further increases insulin resistance due to the accumulation of triglycerides in tissues different from WAT, for example in the liver, pancreas and muscles. The ectopic deposition of triglycerides causes pathological effects, such as increased production of glucose in the liver, reducing the secretion of insulin by the pancreas, and reduced capture of glucose and fatty acid oxidation in skeletal muscle. Thus, elevated ur�level of FFA in the blood, due to increased activity of HSL, contributes to and exacerbates insulin resistance in obese individuals and those with type 2 diabetes. In addition, there is a relationship between elevated levels of FFA and increased production of adipose tissue proinflammatory cytokine - tumor necrosis factor alpha (TNF-a) (Hotamisigil, G. S.,1995, J. Clin. Invest. 95, 2409-2415). TNF-a further violates insulin signaling through the activation of serine kinases, such as JNK-1, fosforiliruyusciye protein IRS-1, which suppresses insulin signaling (Gao, Z. et. al., Mol Endocrinol, 2004, 18, 2024-2034). Thus, normalization of the increased level of FFA and triglycerides in the blood by inhibiting HSL will reduce the accumulation of triglycerides in tissues different from WAT such as liver, muscle and pancreas, leading to a decrease production of glucose by the liver, increased fatty acid oxidation in muscles and improve the functions of the (3-cells. The production of proinflammatory cytokines will also fall, leading to a further reduction of FFA production and improved insulin signaling. Elevated levels of FFAs, among other things, correlated with an increased risk of cardiovascular disease, including atherosclerosis and myocardial dysfunction (Lopaschuk et. al., Physiol Rev 2005, 85, 1093-129; Oliver, MF, QJM 2006, 99, 701-9). It was also shown that chronic infusion of low doses of lipids healthy patients induce�should markers of endothelial activation independently of its metabolic effects (Cusi, et. al., J. Cardiometab. Syndr. 2009, 3, 141-6). Here it was shown that moderate infusion of lipids increases the levels of markers of endothelial activation, ET-1, ICAM-1, VCAM-1. In addition, the high lipolytic activity and elevated levels of FFAs lead to increased insulin resistance and hypertension in rats with hypertension (Mauriege et. al. J Physiol Biochem. 2009, 65, 33-41).

Because HSL is the main hormone-regulated lipase, it is known that when insulinresistant conditions reduced the ability of insulin to suppress lipolysis, which contributes to increasing the level of FFA, i.e. lipotoxicity. Free fatty acids accumulate in the liver, causing increased production of triglycerides coming inside VLDLs, which are then secreted. There is also the accumulation of lipids in the liver, which leads to the syndrome of fatty liver. Diabetes and obesity have an increased lipolysis, which contributes to the development of this syndrome. Consequently, the decrease in the activity of HSL will reduce the release of FFA into the bloodstream, thus limiting the flow of FFA to the liver and subsequent synthesis of TAG. Therefore, the HSL inhibitors may have a beneficial effect in the treatment of NAFLD (nonalcoholic fatty liver disease) and NASH (nonalcoholic steatohepatitis) Account R. Lewis et al, Dig Dis Sci, 2010, 55: 560-578).

Objects of the present invention are compounds of formula (I) and their aforementioned solii esters, and their use as therapeutically active substances; a method of producing such compounds, intermediates, pharmaceutical compositions, pharmaceutical preparations comprising these compounds, their pharmaceutically acceptable salts or esters; the application of the said compounds, salts or esters for the treatment or prophylaxis of diseases, especially for treatment and prophylaxis of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis, obesity, cardiovascular diseases, myocardial dysfunction, inflammation, non-alcoholic steatosis or nonalcoholic steatohepatitis.

The term "alkyl", alone or in combination, denotes an alkyl group with a linear or branched chain comprising from 1 to 8 carbon atoms, preferably alkyl group with a linear or branched chain comprising from 1 to 6 carbon atoms, and particularly preferably alkyl group with a linear or branched chain comprising from 1 to 4 carbon atoms. Examples are: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentile, isomeric sexily, isomeric Gately and isomeric octile, preferably methyl, ethyl, propyl, isopropyl, butyl and isobutyl. In particular, the preferred alkilani are methyl, ethyl, propyl and butyl.

The term "cycloalkyl",separately or in combination, denotes cycloalkyl ring comprising from 3 to 8 carbon atoms, preferably, cycloalkane ring comprising from 3 to 6 carbon atoms. Examples are cyclopropyl, methyl-cyclopropyl, dimethyl-cyclopropyl, cyclobutyl, methyl cyclobutyl, cyclopentyl, methyl cyclopentyl, cyclohexyl, methyl-cyclohexyl, dimethyl-cyclohexyl, cycloheptyl and cyclooctyl. Preferred cycloalkyl are cyclopropyl and cyclohexyl.

The term "alkoxy", alone or in combination, refers to a group of the formula alkyl-O-in which the term "alkyl" has the above value. Examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, isobutoxy, Deut-butoxy and tert-butoxy, preferably methoxy and ethoxy. In particular, the preferred alkoxygroup is a methoxy group.

The term "hydroxyalkyl", separately or in combination, denotes an alkyl group as defined above in which one or more hydrogen atoms substituted by a hydroxy-group. Examples of hydroxyalkyl are gidroximetil, hydroxyethyl, hydroxypropyl, hydroxymethylpropane and dihydroxypropyl. Preferred hydroxyalkylated are hydroxyethyl and hydroxymethylpropane.

The term "halogen", alone or in combination, signifies fluorine, chlorine, bromine or iodine. Preferred halogen�mi are fluorine and chlorine.

The term "haloalkyl", separately or in combination, denotes an alkyl group as defined above in which one or more hydrogen atoms are replaced by halogen. Examples of haloalkyl are vermeil, deformity, trifluoromethyl, trifluoroethyl, trifloromethyl or pentafluoroethyl. Preferred haloalkyl is trifluoromethyl.

The term "haloalkoxy", separately or in combination, refers to alkoxygroup as defined above in which one or more hydrogen atoms attached to the carbon substituted with halogen. Examples of halogenation are formatosi, deformedarse, triptoreline, triptoreline, cryptometrics, cryptogenetic or pentaborate group. Preferred haloalkoxy is tripterocarpa.

The term "hydroxy", alone or in combination, refers to HE group.

The term "amino", alone or in combination, signifies a primary, secondary or tertiary amino group, attached through a nitrogen atom, with the secondary amino group contains an alkyl or cycloalkyl an alternate, and tertiary amino group contains two identical or different alkyl or cycloalkyl Deputy or two deputies at the nitrogen atom form a ring. Examples are-NH2, meth�lamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidinyl, morpholinyl or piperidinyl, preferably-NH2, dimethylamino and diethylamino and, in particular, -NH2.

The term "protective group" refers to groups which are used to block the reactivity of functional groups, for example amino groups or hydroxy groups.Examples of protective groups are tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) or benzyl (Bn). Preferred protective groups are tert-butyloxycarbonyl (Boc) and benzyl (Bn).

Cleavage of the protective group can be conducted by standard methods known to the person skilled in the art, for example by hydrogenation or in the presence of acids, such as HCl or TFA, preferably HCl, or base, such as triethylamine.

The term "pharmaceutically acceptable salt" refers to those salts that retain the biological activity and properties of the free bases or free acids and which are not undesirable from a biological or a different point of view. Salts can be formed with inorganic acids, for example hydrochloric acid, bromoethanol acid, sulfuric acid, nitric acid, phosphoric acid, etc., preferably hydrochloric acid, and organic acid�Tami, for example acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, grape acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, econsultancy acid, p-toluensulfonate acid, salicylic acid, N-acetylcysteine, etc. in addition, these salts can be obtained by adding an inorganic base or an organic base to the free acid. Salts formed from inorganic bases, include, without limitation, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, etc. Salts formed with organic bases include, without limitation, salts of primary, secondary and tertiary amines, including natural substituted amines, cyclic amines and basic ion exchange resins, for example Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, secondary water ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, palielinamie resin, etc., particularly preferred pharmaceutically acceptable salts of compounds of formula (I) - salts of hydrochloric, methanesulfonic, and citric acids.

Compounds of formula (I) may also be solvated, for example, hitratio�Ana. The solvation can be effected in the manufacturing process or can occur, for example, as a consequence of hygroscopic properties of the initially anhydrous compounds of formula (I) (hydration). The term "pharmaceutically acceptable salt" also includes physiologically acceptable solvates.

"Pharmaceutically acceptable esters" means that the compound of the General formula (I) can be derivateservlet of functional groups with obtaining derivatives, which are able to turn back into the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ether derivatives, for example methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of the General formula (I), similar to the metabolically labile esters, which are capable of forming starting compounds of the General formula (I) in vivo, are included in the scope of this invention. Preferred pharmaceutically acceptable esters of compounds of formula (I) are methyl and ethyl esters.

Compounds of formula (I) can contain several asymmetric centers and can be in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereomers, mixtures of diastereomers, �astromeria of racemates or mixtures diastereomeric of racemates.

Pursuant to rule Kahn-Ingold-Praelonga, the asymmetric carbon atom may have the configuration of "R" or "S".

Preferred is a compound according to formula (I) described above, and its pharmaceutically acceptable salts or esters.

In addition, preferred is a compound according to formula (I) described above, and its pharmaceutically acceptable salts or esters, in particular compound according to formula (I) described above.

Also preferred is a compound of formula (I), in which

R1is substituted phenyl, which contains from one to three substituents independently selected from the group comprising alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, hydroxyalkoxy, alkoxyalkyl and haloalkoxy, and substituted phenyl may additionally contain one or two substituent independently selected from halogen;

R2is hydrogen, alkyl, cycloalkyl, phenyl, phenylalkyl, substituted phenyl or substituted phenylalkyl, wherein substituted phenyl and substituted phenylalkyl contain from one to three substituents independently selected from the group comprising alkyl, cycloalkyl, halogen, haloalkyl, hydroxy, alkoxy, hydroxyalkoxy, alkoxyalkyl and haloalkoxy;

R3is-R4, -C(OH)R5R6or-C(O)NR7R8;

R4is phenyl, phenylalkyl, Sames�nny phenyl or substituted phenylalkyl, wherein substituted phenyl and substituted phenylalkyl contain from one to three substituents independently selected from the group comprising alkyl, cycloalkyl, halogen, haloalkyl, hydroxy, alkoxy, hydroxyalkoxy, alkoxyalkyl and haloalkoxy;

one of R5and R6is hydrogen, alkyl or cycloalkyl and another of them is phenyl, phenylalkyl, substituted phenyl or substituted phenylalkyl, wherein substituted phenyl and substituted phenylalkyl contain from one to three substituents independently selected from the group comprising alkyl, cycloalkyl, halogen, haloalkyl, hydroxy, alkoxy, hydroxyalkoxy, alkoxyalkyl and haloalkoxy;

one of R7and R8is hydrogen, alkyl, cycloalkyl, hydroxyalkyl or alkoxyalkyl and the other one is the alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, phenyl, phenylalkyl, substituted phenyl or substituted phenylalkyl, wherein substituted phenyl and substituted phenylalkyl contain from one to three substituents independently selected from the group comprising alkyl, cycloalkyl, halogen, haloalkyl, hydroxy, alkoxy, hydroxyalkoxy, alkoxyalkyl and haloalkoxy;

or R7and R8together with the nitrogen atom to which they are attached, form pyrrolidinyl, piperidinyl, azepane, piperidinyl, morpholinyl or thiomorpholine;

n is zero or 1;

or Pharma�efticiency acceptable salt.

In addition, also preferably a compound according to formula (I) described above, in which R1is substituted phenyl, which contains from one to three substituents independently selected from the group including cycloalkyl and haloalkoxy, and substituted phenyl may additionally contain one or two substituents independently selected from halogen.

In addition, preferably, the compound according to formula (I) described above, in which R1is substituted phenyl, and substituted phenyl contains from one to three substituents independently selected from cycloalkyl.

In particular, preferably, the compound according to formula (I) described above, in which R1is substituted phenyl, which is as under contains a cyclopropyl.

In addition, preferably, the compound according to formula (I) described above, in which R3is-C(OH)R5R6.

In addition, preferably, the compound according to formula (I) described above in which one of R5and R6is hydrogen or alkyl and the other of them is phenyl, phenylalkyl, substituted phenyl or substituted phenylalkyl, wherein substituted phenyl and substituted phenylalkyl contain from one to three substituents independently selected from the group comprising alkyl, cycloalkyl, halogen, haloalkyl, hydroxy, alkoxy, gidroksila�si alkoxyalkane and haloalkoxy.

In addition, preferably, the compound according to formula (I) described above in which one of R5and R6is hydrogen and the other of them is phenyl, phenylalkyl, substituted phenyl or substituted phenylalkyl, wherein substituted phenyl and substituted phenylalkyl contain from one to three substituents independently selected from the group comprising alkyl, cycloalkyl, halogen, haloalkyl, hydroxy, alkoxy, hydroxyalkoxy, alkoxyalkyl and haloalkoxy.

In particular, preferably, the compound according to formula (I) described above in which one of R5and R6is hydrogen or alkyl and the other is fenelli substituted phenyl, and substituted phenyl contains from one to three substituents independently selected from halogen.

In addition, preferably, the compound according to formula (I) described above in which one of R5and R6is hydrogen and the other is phenyl or substituted phenyl, and substituted phenyl contains from one to three substituents independently selected from halogen.

Also preferably, the compound according to formula (I) described above, in which R3is-C(OH)R5R6and n is zero.

Another preferred variant implementation of the present invention is a compound according to formula (I) described in�more in which R3is-C(O)NR7R8.

Preferably, also a compound according to formula (I) described above in which one of R7and R8is hydrogen or alkyl and the other of them is alkyl, cycloalkyl, alkoxyalkyl, phenylalkyl, substituted phenyl or substituted phenylalkyl, wherein substituted phenyl and substituted phenylalkyl contain from one to three substituents independently selected from the group comprising halogen and haloalkyl.

In addition, preferably, the compound according to formula (I) described above in which one of R7and R8is hydrogen and the other of them is alkyl, substituted phenyl or substituted phenylalkyl, wherein substituted phenyl and substituted phenylalkyl contain from one to three substituents independently selected from the group comprising halogen and haloalkyl.

Also preferably, the compound according to formula (I) described above, in which R7and R8together with the nitrogen atom to which they are attached, form pyrrolidinyl.

Another preferred variant implementation of the present invention is a compound according to formula (I) described above, in which R4is phenyl, phenylalkyl or substituted phenyl, and substituted phenyl contains from one to three substituents independently selected from haloalkyl.

In addition, predpochtitel�but the compound according to formula (I), as described above, in which R4is phenyl, benzyl, phenylethyl, phenylpropyl or substituted phenyl, and substituted phenyl contains as Deputy trifluoromethyl.

In particular, preferably, the compound according to formula (I) described above, in which R4is phenyl.

Also preferably, the compound according to formula (I) described above, in which R2is hydrogen, alkyl or phenyl.

In addition, preferably, the compound according to formula (I) described above, in which R2is hydrogen or alkyl.

In particular, preferably, the compound according to formula (I) described above, in which R2is the hydrogen.

In particular, preferably, also a compound according to formula (I) described above, in which R2is alkyl.

Examples of preferred compounds according to formula (I) described above is selected from the group including:

2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

2-(4-cyclopropyl-phenyl)-8-phenethyl-2,8-Diaz-Spiro[4.5]Dean-1-he;

2-(4-cyclopropyl-phenyl)-8-(4-trifluoromethyl-benzyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

2-(4-cyclopropyl-phenyl)-8-(1-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

2-(4-cyclopropyl-phenyl)-8-[1-(3-trifluoromethyl-phenyl)-ethyl]-2,8-Diaz-Spiro[4.5]Dean-1-he;

2-(2-chloro-4-cyclopropyl-phenyl)-8-(1-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

2-(4-C�chlorophyl-phenyl)-8-(1-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-it;

8-benzyl-2-(4-triptoreline-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide;

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N,N-diethyl-acetamide;

N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-acetamide;

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-trifluoromethyl-benzyl)-acetamide;

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-acetamide;

2-(4-cyclopropyl-phenyl)-8-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

N-benzyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-methyl-acetamide;

N-cyclohexyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-methyl-acetamide;

2-[2-(4-cycle propyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(3-methoxy-propyl)-acetamide;

N-butyl-3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionamide;

3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-trifluoromethyl-benzyl)-propionamide;

3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-propionamide;

N-benzyl-3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-methyl-propionamide;

N-cyclohexyl-3-[2-(4-(4-the cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-methyl-propionamide;

2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-with�IRO[4.5]Dean-1-it;

8-[2-(4-chloro-phenyl)-2-hydroxy-ethyl]-2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-propionamide;

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-butyramide;

N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionamide;

N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-butyramide;

N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-2-phenyl-acetamide;

butylamide 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-hexanoic acid;

N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-3-methyl-butyramide;

2-(4-cyclopropyl-phenyl)-8-((S)-2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

2-(4-cyclopropyl-phenyl)-8-((R)-2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

2-(4-cyclopropyl-phenyl)-8-[(R)-2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-2,8-Diaz-Spiro[4.5]Dean-1-he;

8-[(R)-2-(3-chloro-phenyl)-2-hydroxy-ethyl]-2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

2-(4-cyclopropyl-phenyl)-8-[2-(3,4-dichloro-phenyl)-2-hydroxy-ethyl]-2,8-Diaz-Spiro[4.5]Dean-1-he; and

2-(4-cyclopropyl-phenyl)-8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2,8-Diaz-Spiro[4.5]Dean-1-it.

In addition, preferred examples soedineniya the formula (I), as described above, is selected from the group including:

8-[2-(2-chloro-6-fluoro-phenyl)-2-hydroxy-ethyl]-2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-2-hydroxy-3-(4-methoxy-phenyl)-propionamide;)

butylamide (S)-2-[2-(4-the cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-hexanoic acid;

butylamide(R)-2-[2-(4-the cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-hexanoic acid;

8-[2-(2,4-dichloro-phenyl)-2-oxo-ethyl]-2-(4-ethyl-phenyl)-2,8-Diaz-i Spiro[4.5]Dean-1-he;

8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-[4-(2,2,2-Cryptor-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he;

8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-[6-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridin-3-yl]-2,8-Diaz-Spiro[4.5]Dean-1-he;

8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-[4-(2,2,2-Cryptor-ethyl)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he;

8-[2-(2-chloro-6-fluoro-phenyl)-2-hydroxy-ethyl]-2-[4-(2,2,2-Cryptor-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he;

8-[2-(2-chloro-6-fluoro-phenyl)-2-hydroxy-ethyl]-2-[4-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he;

8-[2-(2-chloro-6-fluoro-phenyl)-2-hydroxy-ethyl]-2-[6-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridin-3-yl]-2,8-Diaz-Spiro[4.5]Dean-1-he;

8-[2-(2-chloro-6-fluoro-phenyl)-2-hydroxy-ethyl]-2-[4-(2,2,2-Cryptor-ethyl)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he;

8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-[4-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-on;

8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-[4-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he;

8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-[6-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridin-3-yl]-2,8-Diaz-Spiro[4.5]Dean-1-he;

8-[2-(2-chloro-6-fluoro-phenyl)-2-hydroxy-ethyl]-2-[4-((8)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he; and

8-[2-(2-chloro-6-fluoro-phenyl)-2-hydroxy-ethyl]-2-[6-((8)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridin-3-yl]-2,8-Diaz-Spiro[4.5]Dean-1-it.

Other preferred examples of compounds according to formula (I) described above is selected from the group including:

2-(4-cyclopropyl-phenyl)-8-(1-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-acetamide;

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-trifluoromethyl-benzyl)-acetamide;

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-acetamide;

3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-trifluoromethyl-benzyl)-propionamide;

3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-propionamide;

2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

8-[2-(4-chloro-phenyl)-2-hydroxy-ethyl]-2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-propionamide;

BU�alamid 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-hexanoic acid;

N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-3-methyl-butyramide;

2-(4-cyclopropyl-phenyl)-8-((R)-2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he; and

2-(4-cyclopropyl-phenyl)-8-[(R)-2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-2,8-Diaz-Spiro[4.5]Dean-1-it.

In addition, preferred examples of compounds according to formula (I) described above is selected from the group including

butylamide (R)-2-[2-(4-the cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-hexanoic acid;

8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-[4-(2,2,2-Cryptor-ethyl)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he;

8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-[4-((8)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-it.

Methods for obtaining compounds of formula (I) are the object of the present invention.

Obtaining compounds of formula (I) according to the present invention can perform sequential or convergent synthesis routes. Synthesis methods of the present invention shown in the following General schemes. Skills required for the reaction and the blasting of the final product, known qualified specialists in this field of technology. In case that during the reaction a mixture of enantiomers or diastereomers, the enantiomers or the diastereomers can be separated by methods that are included in this description or known to the special�sheets, skilled in the art, such as, for example, chiral chromatography or crystallization. The substituents and indices used in the following description of methods are given here for the value.

Compounds of formula (I) in which R3is-R4easily can be obtained by reductive amination as shown in Scheme 1. Compounds of the General formula (II) enter into reaction with compounds of the General formula (III) in the presence of a reducing agent, such as triacetoxyborohydride sodium, sodium borohydride or cyanoborohydride sodium, in a solvent such as, for example, THF, methanol or ethanol, in the presence or absence of acetic acid, with the formation of compounds of formula (I) in which R3is-R4.

Scheme 1

Compounds of formula (I) in which R3is-C(OH)R5R6and n is zero, it is easy to obtain, as shown in figure 2.

Compounds of the General formula (II) enter into reaction with compounds of the General formula (IV) in the presence of base, such as, for example, triethylamine, in a solvent such as, for example, dichloro methane, with the formation of compounds of formula (I) in which R3is-C(OH)R5R6and n is zero.

Scheme 2

Compounds of formula (I) in which R3is-C(O)NR7 R8easy to obtain in several stages, as illustrated in figure 3.

Compounds of the General formula (II) enter into reaction with compounds of the General formula (V) in the presence of base, such as, for example, triethylamine, in a solvent such as, for example, dichloro methane (stage a)), to obtain compounds of the General formula (VI).

Compounds of the General formula (VI) enter into reaction with compounds of the General formula (VII) in the presence of a crosslinking agent such as N,N-carbonyldiimidazole (CDI), 1-hydroxy-1,2,3-benzotriazole (NOVT) or O-benzotriazole-1-yl-N,N,N,N-tetramethyluronium tetrafluoroborate (TBTU), in a solvent such as N. N-dimethylformamide (DMF) or dioxane, in the presence or absence of a base, such as triethylamine, diisopropylethylamine or 4-(dimethylamino)pyridine (step b)), with the formation of compounds of formula (I) in which R3is-C(O)NR7R8.

Compounds of formula (II) can easily be obtained in several stages, as shown in figure 4.

Compounds of the General formula (VIII) can be alkylating the desired position by treatment with a suitable base, such as, for example, diisopropylamide lithium or butyllithium, in a suitable solvent, such as THF, DMF, diethyl ether, followed by the addition of suitable electrophile, such as, for example, 1-bromo-2-Metacity or 1-chloro-2-Metacity, received�of compounds of the General formula (IX) (stage c)).

Compounds of formula (IX) is then injected into the reaction with derivatives of the General formula (X) in the presence of organoaluminum reagent, such as, for example, dimethylaluminum chloride or trimethylaluminium, in a solvent such as toluene or dioxane, with the formation of the spirocyclic compounds of the General formula (XI) (stage d)).

The protective group (PG) of compounds of the General formula (XI) can then be removed under standard conditions, for example, by hydrogenation or interaction with an acid, preferably HCI or TFA, with the formation of compounds of the General formula (II) (stage e)).

Scheme 4

Alkyl - such as methyl or ethyl;

PG - for example, Boc or Bn

Compounds of formula (I) are also easy to obtain in the single-stage process, as illustrated in figure 5.

Scheme 5

X is halogen, for example chlorine or bromine

Compounds of the General formula (II) enter into reaction with compounds of the General formula (XII) in the presence of base, such as, for example, triethylamine, in a solvent such as, for example, dichloro methane, to obtain compounds of the General formula (I).

The preferred method of obtaining the compounds according to formula (I) described above, comprising the following stages:

a) reaction of a compound of formula (II) in the presence of a compound of formula (III).

preferably in the presence of a reducing agent, in particular of triacetoneamine sodium, in a solvent, particularly THF, in the presence or absence of acid, including in the presence of acetic acid, and at temperatures from -20°C to a temperature of delegatie solvent, particularly at room temperature, in which R1, R2and n are defined above, a R3is-R4;

b) reaction of a compound of formula (II) in the presence of a compound of formula (IV)

preferably, the implementation in the presence of base, in particular triethylamine, in a solvent, in particular dichloromethane, and at temperatures from 0°C to a temperature of delegatie solvent, particularly at reflux of the solvent, in which R1, R2, R5and R6defined above, R3is-C(OH)R5R6and n is zero;

or

c) reaction of a compound of formula (VI) in the presence of a compound of formula

preferably in the presence of a crosslinking agent, in particular TBTU, in the presence or absence of a base, in particular in the presence of triethylamine, in a solvent, particularly DMF, and at a temperature from -20°C to temp�tours delegacia solvent, in particular, at room temperature, in which R1, R2, R7, R8and n are defined above, a R3is-C(0)NR7R8.

Preferred intermediate compound selected from the group including

1-tert-butyl 4-ethyl diester of 4-(2-methoxy-ethyl)-piperidine-1,4-dicarboxylic acid;

2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

2-(2-chloro-4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;

ethyl 1-benzyl-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid;

[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-acetic acid;

3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionic acid;

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionic acid;

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-butyric acid;

[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-phenylacetic acid;

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-hexanoic acid; and

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-3-methyl-butyric acid.

Another object of the present invention includes a compound according to formula (I) described above, obtained according to one of the described methods.

Another object of the present invention is a compound according to formula (I) described above, p�rednaznachenie for use as therapeutically active substances.

Similarly, the object of the present invention is a pharmaceutical composition, comprising a compound according to formula (I) described above and a therapeutically inert excipient.

Another object of the present invention is the use of compounds according to formula (I) described above for the treatment and prevention of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity.

Preferably also the use of compounds according to formula (I) described above for the treatment or prophylaxis of cardiovascular diseases, myocardial dysfunction or inflammation.

In particular, preferably the use of compounds according to formula (I) described above for the treatment or prevention of diabetes.

In addition, the preferred use of the compounds according to formula (I) described above for the treatment or prophylaxis of type II diabetes.

Another preferred variant implementation of the present invention is the use of compounds according to formula (I) described above, for the manufacture of a medicinal product for the treatment or prophylaxis of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity.

In addition, preferably the use of compounds according to formula (I) described above, for the manufacture of a medicinal product for the treatment�ia or prophylaxis of cardiovascular diseases, myocardial dysfunction or inflammation.

In particular, preferably the use of compounds according to formula (I) described above, for the manufacture of a medicinal product for the treatment or prevention of diabetes.

In addition, preferably the use of compounds according to formula (I) described above, for the manufacture of a medicinal product for the treatment or prophylaxis of type II diabetes.

The object of the present invention is also the compound according to formula (I) described above for the treatment or prevention of diseases which are caused by disorders associated with, for example, enzyme gormonchuvstvitelnoy lipase.

In addition, preferred is a compound according to formula (I) described above for the treatment or prophylaxis of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity.

In addition, also preferably a compound according to formula (I) described above for the treatment or prophylaxis of cardiovascular diseases, myocardial dysfunction or inflammation.

In particular, preferably, the compound according to formula (I) described above for the treatment or prevention of diabetes.

In addition, preferred is a compound according to formula (I) described above for the treatment or prophylaxis of type II diabetes.

The object of the present izobreteny� is also a method for the treatment or prophylaxis of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity, which comprises administering an effective amount of a compound according to formula (I) described above.

Also preferred is a method for the treatment or prevention of cardiovascular diseases, myocardial dysfunction or inflammation, which comprises administering an effective amount of a compound according to formula (I) described above.

In particular, the preferred method of treatment or prophylaxis of diabetes, which comprises administering an effective amount of a compound according to formula (I) described above.

In addition, the preferred method of treatment or prophylaxis of type II diabetes, which comprises administering an effective amount of a compound according to formula (I) described above.

One of the embodiments of the present invention is also the use of compounds according to formula (I) described above for the treatment or prophylaxis of non-alcoholic fatty liver or nonalcoholic steatohepatitis.

In addition, one of the embodiments of the present invention is the use of compounds according to formula (I) described above, for the manufacture of a medicinal product for the treatment or prophylaxis of non-alcoholic fatty liver or nonalcoholic steatohepatitis.

In cha�particularly, another variant implementation of the present invention is the use of compounds according to formula (I) described above for the treatment or prophylaxis of non-alcoholic fatty liver or nonalcoholic steatohepatitis.

One of the embodiments of the present invention is also a method for the treatment or prophylaxis of non-alcoholic fatty liver or nonalcoholic steatohepatitis, which comprises administering an effective amount of a compound according to formula (I) described above.

Description methods

Getting a full-sized human gormonchuvstvitelnoy lipase - His6:

1) Clone: K-DNA from commercially available by pólya+RNA of human brain and used as template in PCR by the method of overlapping the splice extensions with getting a full-sized human HSL ORF from the 3'-end histidinol label (His6). This full-sized insert was cloned into the vector pFast-BAC and was verified by DNA sequences from several clones. DNA from suitable full-sized clone containing the 3'-terminal His, was used to transform E. coli strain DH10BAC. Received backmenu DNA was used to obtain flow of baculoviruses with known titre for generating protein. The sequence encoded HSL e corresponds�amento number Q05469 in Swissprot database with an additional C-terminal His label 6.

2) protein Purification: Culture: 5.5 l, High Five cells expressing human full-HSL-His6, 48 h, containing 25 µmol E-64. Number of cells: 1.78×1010cells/ml, with 90% viability.

The cells are thawed. Suspended cells on ice in the Main Buffer of the following composition: 10% glycerol, 25 mm Tris-Cl, 300 mm NaCl, 10 mm imidazole, 10 mm 2-mercaptoethanol, pepstatin 2 μg/ml, leupeptin 2 μg /ml, antipain 2 μg/ml, pH 8.0, at 4°C in a final volume of 475 ml, containing 3.75×107cells/ ml Disinfection was carried out 3 times for 30 sec, added Lubrol PX to final concentration of 0.2%, followed by stirring for 15 min at 4°C and centrifugation at 25000×g, 60 min, 4°C. Soluble proteins were mixed with 60 ml of pre-washed and equilibrated Ni-NTA by agarose (Qiagen 30210), after which was stirred by rotation for 45 min, 4°C, centrifuged at 1000 rpm for 5 minutes, and left to precipitate the resin for 5 min. Supernatant was removed, the resin was washed in a vessel for centrifugation five volumes of Basic Buffer containing 0.2% of Lubrol PX. Again centrifuged, and then supernatant was discarded. The resin was poured onto the membrane with a pore diameter of 0.8 μm, a disposable cell to filter (Nalge 450-0080) and washed with five volumes of Basic Buffer containing 0.2% of Lubrol PX. Then it was washed with 30 volumes of the Main Buffer containing 60 mimedata, pH 7.5, at 4°C. Protein was suirable five volumes of buffer of the following composition: 25 mm Tris-Cl, 300 mm NaCl, 200 mm imidazole, 10 mm 2-mercaptoethanol, pH 7.5, at 4°C, for which the resin with the buffer was mixed by rotation for 30 min, 4°C. the Resin was placed in a disposable membrane cell to filter with a pore diameter of 0.2 μm (Millipore SCGP U02 RE) and the eluate was collected. The eluate was concentrated using a filter centrifuge 30k MWCO (Sartorius Vivascience Vivacell 100, VC1022) to 20 ml Then were dialyzed overnight at 4°C, two times against 2 l of buffer of the following composition: 10% glycerol, 25 mm Tris-Cl, 300 mm NaCl, 0.2 mm EDTA, 0.2 mm DTT, pH 7.5, at 4°C. the Protein was filtered through a disposable cell for filtration with a pore diameter of 0.22 µm (Millipore SCGP00525). Protein concentration was calculated by absorbance at 280 nm, using a 280 ratio=0.67 SP-1mg-1. The total output amounted to 235 mg. Protein was stored at -80°C.

Analysis of inhibition of the Enzyme gormonchuvstvitelnoy lipase (HSL) of a person:

The enzyme activity of HSL was measured in the colorimetric analysis using 2,3-dimercapto-1-propanol of tributyrate (Aldrich, St. Louis, MO) as substrate. Typically, 1.5 mm was prepared a solution of 2,3-dimercapto-1-propanol tributyrate (DMPT) in 100 mm MOPS, pH 7.2, containing 0.2 mg/ml BSA, free fatty acids, by treatment with ultrasound at 4°C to obtain a homogeneous suspension. Prepared a series of three times razvedeni� studied substances in DMSO (2 mm of runoff in DMSO). The solutions of compounds were diluted 24 times in a solution containing 1.5 mm DMPT, and put on 18 μl into the hole on a 384-well microplates (Corning Costar). Added to 12 μl into the hole of human HSL (15 μg/ml) and incubated the reaction mixture at 37°C for 20 minutes. Added 6 μl of a 12 mm solution of dithio-bis(2-nitrobenzoic acid) (DTNB) in DMSO containing 1.2% SDS and 0.6% Triton X-100, and incubated the mixture at room temperature for 15 minutes. The formation of product was monitored by reading absorbance at 405 nm on a spectrophotometer with a vertical scanning Envision Reader (PerkinElmer Life and Analytical Sciences, Shelton, CT).

Cellular analysis:

To quantify the inhibitory effects of compounds on lipolysis in intact cells (adipocytes) used the following method.

Pre-adipocyte cells 3T3-L1 seeded on 96-well plates with a density of 20000 cells per well, in 200 μl of nutrient medium (DMEM / 10% calf serum/1x antibiotic-antimycotic) before fusion. 48 h after the onset of the confluence, the medium was removed and underwent differentiation of cells into adipocytes using a medium for differentiation (DMEM/10% FBS/1x antibiotic-antimycotic containing 1 μm IBMX (3-isobutyl-1-methylxanthine) inhibitor phosphodiesterase, 1 μm dexamethasone, 1 μm rosiglitazone, 10 mg/ml insulin). Cells were incubated in this medium for 3 days, after which the medium was replaced by�t-diferenciada medium (DMEM/10% FBS, containing 10 μg/ml insulin), and cells were incubated for another 3 days. Thereafter, the medium was replaced with maintenance medium (DMEM/10% FBS). Cells were fed every three days supportive environment until use. Analysis of lipolysis can be performed at 9-14 days after the initiation of differentiation in 96-well plates.

Analysis of lipolysis was performed as follows. The adipocytes were washed twice using 200 μl of bicarbonate Hepes buffer Krebs-ringer (KRBH) containing 3% BSA. The concentration of the tested compounds in DMSO was 10 mm, initially they were diluted to 5 mm in DMSO. Then prepared a series of fivefold dilutions of these substances in DMSO (5 mm to 320 PM). Each connection is then diluted 200 times in KRBH/3% BSA (total, 0.5% DMSO). The range of concentrations obtained solutions ranged from 25 μm to 1.6 PM. Add 150 ál of the diluted compounds to each well (in triplicate) and preincubate cells for 30 min at 37°C. was Added Forskolin (final concentration 50 μm) to the wells and cells were incubated for 120 minutes at 37°C. Selected 100 µl into a new 96-well plate for analysis on glycerol. The amount of glycerin produced was determined using a kit for the determination of glycerol (Sigma).

ExamplesHSL person IC50(μm) ExamplesHSL person IC50(μm)
10.24300.02
20.07310.02
30.36320.09
40.03330.04
50.17340.1
60.98350.02
70.03360.03
80.04370.03
90.61380.03
100.3839 0.037
110.09400.165
120.03410.047
130.08420.011
140.22430.036
150.08440.026
160.06450.022
170.71460.019
180.46470.035
190.03480.023
200.06490.042
21.09 500.018
220.32510.022
230.07520.02
240.08530.043
250.04540.029
260.05550.038
270.03
280.03
290.04

The compounds described above, the value of IC50is in the range from 0.005 μm to 1000 μm, preferred compounds of the magnitude of IC50is in the range from 0.01 μm to 10 μm. In particular, preferred compounds of the magnitude of IC50is in the range from 0.01 μm to 0.5 μm. These results were obtained using the above analysis of the inhibition of the enzyme SL (μm means micromolar").

Compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicinal substances (for example, in the form of pharmaceutical preparations). Pharmaceuticals can enter inside, for example, orally (e.g., in the form of pills, tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), intranasally (e.g., in the form of nasal sprays) or rectally (e.g. in the form of suppositories). In addition, the introduction can be done parenterally, such as intramuscularly or intravenously (e.g. in the form of solutions for injection).

Compounds of formula (I) and their pharmaceutically acceptable salts can be processional with pharmaceutically inert, inorganic or organic excipients for the manufacture of pills, tablets, coated tablets, dragees and hard gelatin capsules. For tablets, dragees and hard gelatin capsules as such adjuvants can be used, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc.

Suitable adjuvants for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.

Suitable adjuvants for the production of solutions and syrups are, for example, water, polyol�, sucrose, invert sugar, glucose etc.

Suitable adjuvants for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.

Suitable adjuvants for suppositories are e.g. natural or solidified oils, waxes, fats, semi-solid or liquid polyols, etc.

In addition, the pharmaceutical preparations can contain preservatives, soljubilizatory, substances that increase the viscosity, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts to change the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically important substances.

In accordance with the present invention, compounds of formula (I) and their pharmaceutically acceptable salts can be used for the prevention or treatment of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis and obesity. The dosage can be varied over a wide range and, of course, be selected according to the individual requirements in each particular case. In General, for oral administration suitable daily dose is from 0.1 mg da 20 mg per 1 kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (e.g., about 300 mg per person), divided preferably 1-3 individual doses, which consists, e.g.�measures from the similar quantities. It should be borne in mind that the above upper dose limit can be exceeded, if indicated.

The present invention is illustrated further in the Examples which are not limiting in nature.

In cases where given as an example of a substance was obtained as a mixture of enantiomers, the pure enantiomers can distinguish the methods described herein or methods known to those skilled in the art, for example using chiral chromatography or crystallization.

Examples

Example 1

2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

Stage 1:

1-tert-butyl-4-ethyl diester of 4-(2-methoxy-ethyl)-piperidine-1,4-dicarboxylic acid

To a solution of 38 ml (76 mmol) of LDA in THF (2N) was added 9.8 g (38 mmol) of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (commercially available) in 10 ml THF at -5°C and stirred at -5°C for 3 hours was Added dropwise 10.58 g (76 mmol) of 1-bromo-2-ethoxyethane in 10 ml of THF, was stirred for 1 h at -5°C, then stirred at room temperature over night. Added KHSO4water. (1M) and the mixture was extracted with ethyl acetate. The combined organic layers were dried over MgSO4and evaporated to dryness. The residue was purified in codicological chromatography on silica gel, have aliorului gradient of ethyl acetate and heptane. After the evaporation of product containing fractions were receiving 8.19 g (68%) of a substance mentioned in the title, in the form of a yellow oil. MS m/e: 315.2 [M+H]+.

Stage 2:

2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

A mixture of 1.3 g (4.1 mmol) of 1-tert-butyl-4-ethyl diester of 4-(2-methoxy-ethyl)-piperidine-1,4-dicarboxylic acid, 0.604 g (4.5 mmol) 4-cyclopropylalanine and 8.24 ml (8.24 mmol) of dimethylammoniumchloride (1N in hexane) in 100 ml of toluene was stirred at 115°C for 15 h. After cooling to room temperature the mixture was placed on ice, acidified with aqueous HCl to pH 2 and was extracted with ethyl acetate. The aqueous layer was podslushivaet NaOH pellets to pH 8 and extracted with DCM. The combined organic layers were dried over MgSO4and evaporated to dryness. The residue was purified by column chromatography on silica gel (amine) using a gradient formed by ethyl acetate and methanol. After the evaporation of product containing fractions were receiving 0.468 g (42%) of a substance mentioned in the title, in the form of pale yellow crystals. MS m/e: 270.0 [M+H]+.

Stage 3:

2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

A mixture of 20 mg (0.074 mmol) of 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one, 42 μl of acetic acid, 44 mg (0.148 mmol) of triacetoxyborohydride n�try and excess 3-phenyl-Propionaldehyde in 2 ml of THF was stirred at room temperature over night. Was added water, the mixture was extracted with ethyl acetate, and the combined organic layers evaporated to dryness. The residue was dissolved in methanol and purified with preparative reversed-phase HPLC, was suirable gradient of acetonitrile, water and NEt3. Containing the product fractions were evaporated with the formation of 7.1 mg (25%) of a substance mentioned in the title. MS m/e: 389.4 [M+H]+.

Example 2

2-(4-cyclopropyl-phenyl)-8-phenethyl-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 1) indicated in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one and phenyl-acetaldehyde (commercially available) through reductive amination. MS m/e: 375.4 [M+H]+.

Example 3

2-(4-cyclopropyl-phenyl)-8-(4-trifluoromethyl-benzyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 1) indicated in the title substance was obtained from 2-(4-temporaril-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one and 4-trifluoromethyl-benzaldehyde (commercially available) through reductive amination. MS m/e: 429.4 [M+H]+.

Example 4

2-(4-cyclopropyl-phenyl)-8-(1-phenyl-ethyl)-2,8-Diaz-�Piro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-he (example 1) indicated in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one and 1-phenyl-ethanone (commercially available) through reductive amination. MS m/e: 375.3 [M+H]+.

Example 5

2-(4-cyclopropyl-phenyl)-8-[1-(3-trifluoromethyl-phenyl)-ethyl]-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 1) indicated in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one and 1-(3-trifluoromethyl-phenyl)-ethanone (commercially available) through reductive amination. MS m/e: 443.4 [M+H]+.

Example 6

2-(2-chloro-4-cyclopropyl-phenyl)-8-(1-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

Stage 1:

2-(2-chloro-4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

A mixture of 0.275 g (1 mmol) 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-she, 1.57 g (11.3 mmol) of sulfurylchloride and 0.154 g (1.52 mmol) NEt3in 50 ml of CHCI3was stirred at room temperature. After evaporation of volatiles the residue was dissolved in DMF and purified using the drugs�actions by reversed-phase HPLC, was suirable gradient of acetonitrile, water and NEt3. The fractions containing the product were evaporated to obtain 94 mg (30%) of a substance mentioned in the title, in the form of light yellow resin. MS m/e: 305.1 [M+H]+.

Stage 2:

2-(2-chloro-4-cyclopropyl-phenyl)-8-(1-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 1) indicated in the title substance was obtained from 2-(2-chloro-4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one and 1-phenyl-ethanone (commercially available) through reductive amination. MS m/e: 409.4 [M+H]+.

Example 7

2-(4-cyclopropyl-phenyl)-8-(1-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 1) indicated in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one and 1-phenyl-propane-1-one (commercially available) through reductive amination. MS m/e: 389.4 [M+H]+.

Example 8

8-benzyl-2-(4-triptoreline-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

Stage 1:

ethyl 1-benzyl-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid

By analogy with the method described�th for the synthesis of 1-tert-butyl-4-ethyl diester of 4-(2-methoxy-ethyl)-piperidine-1,4-dicarboxylic acid (example 1, stage 1) specified in the title substance was obtained from ethyl 1-benzyl-piperidine-4-carboxylic acid and 1-bromo-2-methoxy-ethane by deprotonation using LDA. MS m/e: 306.2 [M+H]+.

Stage 2:

8-benzyl-2-(4-triptoreline-phenyl)-2,8-sharp-Spiro[4,5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 1, step 2), specified in the title substance was obtained from ethyl 1-benzyl-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid and 4-triptoreline-phenylamine in the presence of chloride dimethylamine. MS m/e: 405.4 [M+H]+.

Example 9

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide

Stage 1:

[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-acetic acid

A mixture of 0.4 g (1.47 mmol) 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one, 0.226 g (1.63 mmol) bromoxynil acid and 0.299 g (2.96 mmol) NEt3in 50 ml DCM was stirred at room temperature for 16 h. the Mixture was concentrated and used without further purification in the subsequent stage. MS m/e: 329.3 [M+H]+.

Stage 2:

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide

A mixture of 42.7 mg (0.13 mmol) [2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-acetic Ki�lots, 54.2 mg (0.195 mmol) of TBTU, 26 mg (0.26 mmol) NEt3and 8.7 mg (0.195 mmol) of ethylamine in 2 ml of DMF was stirred at room temperature for 16 h and evaporated to dryness. The residue was dissolved in DMF and was purified using preparative reversed-phase HPLC, was suirable gradient of acetonitrile, water and NEt3. The fractions containing the product were evaporated to obtain 16.2 mg (35%) of a substance mentioned in the title. MS m/e: 356.3 [M+H]+.

Example 10

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N,N-diethyl-acetamide

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from [2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-acetic acid and diethylamine. MS m/e: 384.4 [M+H]+.

Example 11

N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-acetamide

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from [2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-acetic acid and butylamine. MS m/e: 384.4 [M+H]+.

Example 12

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-trifluoromethyl-benzyl)-acetamide

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from [2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-acetic acid and 4-trifluoromethyl-benzylamine. MS m/e: 486.4 [M+H]+.

Example 13

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from [2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-acetic acid and 4-fluoro-phenylamine. MS m/e: 422.3 [M+H].

Example 14

2-(4-cyclopropyl-phenyl)-8-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from [2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-acetic acid and pyrrolidine. MS m/e: 382.3 [M+H]+.

Example 15

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from [2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-acetic acid�you and benzyl-methyl-amine. MS m/e: 432.4 [M+H]+.

Example 16

N-Cyclohexyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-methyl-acetamide

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from [2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-acetic acid and cyclohexyl-methyl-amine. MS m/e: 424.4 [M+H]+.

Example 17

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(3-methoxy-propyl)-acetamide

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from [2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-acetic acid and 3-methoxy-Propylamine. MS m/e: 400.4 [M+H].

Example 18

N-butyl-3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionamide

Stage 1:

3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionic acid;

By analogy with the method described for the synthesis of [2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-acetic acid (example 9, step 1), specified in the title substance was obtained from 2-(4-cyclopropyl-FeNi�)-2,8-Diaz-Spiro[4.5]Dean-1-one and 3-bromo-propionic acid. MS m/e: 343.3 [M+H]+.

Stage 2:

N-butyl-3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionamide

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from 3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionic acid and butylamine. MS m/e: 398.4 [M+H]+.

Example 19

3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-trifluoromethyl-benzyl)-propionamide

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from 3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionic acid and 4-trifluoromethyl-benzylamine. MS m/e: 500.4 [M+H]+.

Example 20

3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-propionamide

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from 3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionic acid and 4-fluoro-phenylamine. MS m/e: 436.4 [M+H]+.

Example 21

By Ana�Ogii with the way described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from 3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionic acid and benzyl-methyl-amine. MS m/e: 446.4 [M+H]+.

Example 22

N-Cyclohexyl-3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-methyl-propionamide

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from 3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionic acid and cyclohexyl-methyl-amine. MS m/e: 438.4 [M+H]+.

Example 23

2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

A mixture of 34.6 mg (0.128 mmol) of 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one, 23 mg (0.192 mmol) of 2-phenyl-oxirane and 38 mg (0.384 mmol) NEt3in 2 ml of DCM was stirred at 50°C for 2 h and concentrated. The residue was dissolved in methanol and purified with preparative reversed-phase HPLC, was suirable gradient of acetonitrile, water and NEt3. The fractions containing the product were evaporated to obtain 7.1 mg (14%) of a substance mentioned in the title. MS m/e: 391.4 [M+H]+.

Example 24

8-[2-(4-chloro-phenyl)-2-hydroxy-e�yl]-2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-(4-chloro-phenyl)-oxirane. MS m/e: 425.4 [M+H]+.

Example 25

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-propionamide

Stage 1:

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionic acid;

A mixture of 200 mg (0.74 mmol) 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one, 168 mg (1.11 mmol) 2-bromo-propionic acid and 224 mg (2.21 mmol) NEt3in 5 ml of DCE was heated to 80°C for 2 h and concentrated. The residue was dissolved in methanol and purified with preparative reversed-phase HPLC, was suirable gradient of acetonitrile, water and formic acid. The fractions containing the product were evaporated to obtain 49.4 mg (19%) of a substance mentioned in the title. MS m/e: 343.2 [M+H]+.

Stage 2:

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-propionamide

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from 2-[2-(4-cyclopropyl-phenyl)1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionic acid and 4-fluoro-phenylamine. MS m/e: 436.3 [M+H]+.

Example 26

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-butyramide

Stage 1:

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-butyric acid

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionic acid (example 25, step 1), specified in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-bromo-butyric acid. MS m/e: 357.3 [M+H]+.

Stage 2:

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-butyramide

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-butyric acid and 4-fluoro-phenylamine. MS m/e: 450.4 [M+H]+.

Example 27

N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionamide

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionic acid and Boo�of Ilumina. MS m/e: 398.4 [M+H]+.

Example 28

N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-butyramide

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-butyric acid and butylamine. MS m/e: 412.2 [M+H]+.

Example 29

N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4,5]Dec-8-yl]-2-phenyl-acetamide

Stage 1:

[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-phenyl-acetic acid

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionic acid (example 25, step 1), specified in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-she and bromo-phenyl-acetic acid. MS m/e 460.4 [M+H]+.

Stage 2:

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from [2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-phenyl-acetic acid and butylamine. MS m/e 460.4 [M+H]+.

Example 30

butylamide 2-[2-(4-cyclopropyl-phenyl)1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-hexanoic acid

Stage 1:

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-hexanoic acid

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionic acid (example 25, step 1), specified in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-bromo-hexanoic acid. MS m/e: 385.3 [M+H]+.

Stage 2:

butylamide 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-hexanoic acid

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-hexanoic acid and butylamine. MS m/e: 440.4 [M+H]+.

Example 31

N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-3-methyl-butyramide

Stage 1:

2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-3-methyl-butyric acid

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionic acid (example 25, step 1), specified in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Decan-it and 2-bromo-3-methyl-butyric acid. MS m/e:

371.3 [M+H]

Stage 2:

N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-3-methyl-butyramide

By analogy with the method described for the synthesis of 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide (example 9), specified in the title substance was obtained from 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-3-methyl-butyric acid and butylamine. MS m/e:

426.4 [M+H]+.

Example 32

2-(4-cyclopropyl-phenyl)-8-((5)-2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-she (8)-2-phenyl-oxirane. MS m/e: 391.3 [M+H]+.

Example 33

2-(4-cyclopropyl-phenyl)-8-((S)-2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one and (R)-2-phenyl-oxirane. MS m/e: 391.3 [M+H]+.

Example 34

2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-methyl-2-phenyl-oxirane. MS m/e: 405.3 [M+H]+.

Example 35

2-(4-cyclopropyl-phenyl)-8-[(R)-2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one and (R)-2-(4-fluoro-phenyl)-oxirane. MS m/e: 409.3 [M+H]+.

Example 36

8-[(R)-2-(3-chloro-phenyl)-2-hydroxy-ethyl]-2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one and (R)-2-(3-chloro-phenyl)-oxirane. MS m/e: 425.3 [M+H]+.

Example 37

2-(4-cyclopropyl-phenyl)-8-[2-(3,4-dichloro-phenyl)-2-hydroxy-ethyl]-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]DECA�-1-one (example 23), specified in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one and (R)-2-(3,4-dichloro-phenyl)-oxirane. MS m/e 459.3 [M+H]+.

Example 38

2-(4-cyclopropyl-phenyl)-8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-(2,4-dichloro-phenyl)-oxirane. MS m/e 459.3 [M+H]+.

Example 39

8-[2-(2-chloro-6-fluoro-phenyl)-2-hydroxy-ethyl]-2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-(2-chloro-6-fluoro-benzyl)-oxirane. MS m/e: 443.3 [M+H]+.

Example 40

3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-2-hydroxy-3-(4-methoxy-phenyl)-propionamide

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-(4-cyclopropyl-Hairdryer�l)-2,8-Diaz-Spiro[4.5]Dean-1-one amide and 3-(4-methoxy-phenyl)-oxirane-2-carboxylic acid. MS m/e: 464.4 [M+H]+.

Example 41

Butylamide(5)-2-[2-(4-the cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-hexanoic acid

The connection specified in the title, was obtained from butylamide 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-hexanoic acid (example 30) by separation using chiral HPLC. MS m/e: 464.4 [M+H]+.

Example 42

Specified in the title compound was obtained from butylamide 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-hexanoic acid (example 30) by separation using chiral HPLC. MS m/e: 464.4 [M+H]+.

Example 43

8-[2-(2,4-dichloro-phenyl)-2-oxo-ethyl]-2-(4-ethyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

Stage 1:

2-(4-Ethyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 1, step 2), specified in the title substance was obtained from 1-tert-butyl-4-ethyl diester of 4-(2-methoxy-ethyl)-piperidine-1,4-dicarboxylic acid and 4-ethyl-phenylamine. MS m/e: Dali 259.2 [M+H]+.

A mixture of 320 mg (1.24 mmol) 2-(4-ethylphenyl)-2,8-diazaspiro[4.5]Dean-1-she, 431 mg (1.61 mmol) 2-bromo-1-(2,4-dichlorophenyl)ethanone and 376 mg (3.72 mmol) of triethylamine in 50 ml DCM was stirred at 22°C for 6 hours. The crude reaction mixture was concentrated in vacuo. The crude material was purified during flash chromatography, suirable gradient of ethyl acetate and heptane was obtained after the evaporation of product containing fractions 435 mg (79%) of a substance mentioned in the title, in the form of orange crystals. MS m/e 445.2 [M+H]+.

Example 44

8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-[4-(2,2,2-Cryptor-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he

Stage 1:

2-[4-(2,2,2-Cryptor-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 1, step 2), specified in the title substance was obtained from 1-tert-butyl-4-ethyl diester of 4-(2-methoxy-ethyl)-piperidine-1,4-dicarboxylic acid and 4-(2,2,2-Cryptor-ethoxy)-phenylamine. MS m/e: 329.2 [M+H]+.

Stage 2:

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-[4-(2,2,2-Cryptor-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-(2,4-dichloro-phenyl)-oxirane. MS m/e: 517.3 [M+H]+.

Example 45

8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-[6-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridin-3-yl]-2,8-Diaz-Spiro[4.5]Dean-1-he

Stage 1:

2-[6-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridin-3-yl]-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 1, step 2), specified in the title substance was obtained from 1-tert-butyl-4-ethyl diester of 4-(2-methoxy-ethyl)-piperidine-1,4-dicarboxylic acid and 6-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridine-3-ylamine. MS m/e: 344.2 [M+H]+.

Stage 2:

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-[6-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridin-3-yl]-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-(2,4-dichloro-phenyl)-oxirane. MS m/e: 532.3 [M+H]+.

Example 46

8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-[4-(2,2,2-Cryptor-ethyl)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he

Stage 1:

2-[4-(2,2,2-Cryptor-ethyl)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 1, step 2), specified in the title substance was obtained from 1-tert-butyl-4-ethyl diester of 4-(2-methoxy-ethyl)-piperidine-1,4-bicarbonato acid and 4-(2,2,2-Cryptor-ethyl)-phenylamine. MS me: 313.2 [M+H] +.

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-[4-(2,2,2-Cryptor-ethyl)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-(2,4-dichloro-phenyl)-oxirane. MS m/e: 501.3 [M+H]+.

Example 47

8-[2-(2-chloro-6-fluoro-phenyl)-2-hydroxy-ethyl]-2-[4-(2,2,2-Cryptor-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-[4-(2,2,2-Cryptor-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-(2-chloro-6-fluoro-phenyl)-oxirane. MS m/e: 501.3 [M+H]+.

Example 48

8-[2-(2-chloro-6-fluoro-phenyl)-2-hydroxy-ethyl]-2-[4-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he

2-[4-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 1, step 2), specified in the title substance was obtained from 1-tert-butyl-4-ethyl diester of 4-(2-methoxy-ethyl)-piperidine-1,4-dicarboxylic acid and 4-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenylamine. MS m/e: 343.2 [M+H]+.

Stadia:

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-[4-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-(2-chloro-6-fluoro-phenyl)-oxirane. MS m/e: 515.3 [M+H]+.

Example 49

8-[2-(2-chloro-6-fluoro-phenyl)-2-hydroxy-ethyl]-2-[6-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridin-3-yl]-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-[6-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridin-3-yl]-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-(2-chloro-6-fluoro-phenyl)-oxirane. MS m/e: 516.3 [M+H]+.

Example 50

8-[2-(2-chloro-6-fluoro-phenyl)-2-hydroxy-ethyl]-2-[4-(2,2,2-Cryptor-ethyl)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-[4-(2,2,2-Cryptor-ethyl)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-(2-chloro-6-fluoro-phenyl)-oxirane. MS m/e: 485.3 [M+H]+.

Example 51

8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-[4-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-[4-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-(2,4-dichloro-phenyl)-oxirane. MS m/e: 531.3 [M+H]+.

Example 52

8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-[4-((5)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he

Stage 1:

2-[4-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 1, step 2), specified in the title substance was obtained from 1-tert-butyl-4-ethyl diester of 4-(2-methoxy-ethyl)-piperidine-1,4-dicarboxylic acid and 4-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenylamine. MS m/e: 343.2 [M+H]+.

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-[4-((8)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-(2,4-dichloro-phenyl)-oxirane. MS m/e: 531.3 [M+H]+.

Example 53

8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-[6-((8)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridin-3-yl]-2,8-Diaz-Spiro[4.5]Dean-1-he

Stage 1:

2-[6-((5)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridin-3-yl]-2,8-Diaz-Spiro[4.5]Dean-1-he


By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 1, step 2), specified in the title substance was obtained from 1-tert-butyl-4-ethyl diester of 4-(2-methoxy-ethyl)-piperidine-1,4-dicarboxylic acid and 6-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridine-3-ylamine. MS m/e: 344.2 [M+H]+.

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-[6-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridin-3-yl]-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-(2,4-dichloro-phenyl)-oxirane. MS m/e: 532.3 [M+H]+.

Example 54

8-[2-(2-chloro-6-fluoro-phenyl)-2-hydroxy-ethyl]-2-[4-((8)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-[4-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-(2-chloro-6-fluoro-phenyl)-oxirane. MS m/e: 515.3 [M+H]+.

Example 55

8-[2-(2-chloro-6-fluoro-phenyl)-2-hydroxy-�Teal]-2-[6-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridin-3-yl]-2,8-Diaz-Spiro[4.5]Dean-1-he

By analogy with the method described for the synthesis of 2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-one (example 23), specified in the title substance was obtained from 2-[6-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-pyridin-3-yl]-2,8-Diaz-Spiro[4.5]Dean-1-one and 2-(2-chloro-6-fluoro-phenyl)-oxirane. MS m/e: 516.3 [M+H]+.

An example of A

The compound according to formula (I) described above, it is possible to apply known essentially by the method as an active ingredient for the production of tablets of the following composition:

On a tablet

Active ingredient200 mg
Microcrystalline cellulose155 mg
Corn starch25 mg
Talc25 mg
Hydroxypropyl methylcellulose20mg425mg

Example B

The compound according to formula (I) described above, it is possible to apply known essentially by the method as the active �of ingredient for the production of capsules of the following composition:

One capsule

Active ingredient100.0 mg
Corn starch20.0 mg
Lactose95.0 mg
Talc4.5 mg
Magnesium stearate0.5 mg
220.0 mg

1. Compounds of formula (I)

in which
R1is substituted phenyl which contains one substituent selected from the group comprising C1-4-alkyl, C3-6-cycloalkyl, halo-C1-4-alkyl and halo-C1-4-alkoxy, and which may further contain one Deputy, selected from halogen;
R2is hydrogen, C1-4-alkyl, phenyl, substituted phenyl, wherein substituted phenyl has one Deputy, selected from the group comprising C1-4-alkoxy;
R3is-R4, -C(OH)R5R6or-C(O)NR7R8;
R4is phenyl, phenyl-C1-4-alkyl, substituted phenyl, substituted phenylcarbamoyl, wherein substituted phenyl, substituted phenylcarbamoyl contain from one to two substituents selected from the group comprising halogen, halo-C1-4-alkyl;
one of R5 and R6is hydrogen, C1-4-alkyl, and the other one is aminocarbonyl, phenyl, substituted phenyl, or substituted phenyl-C1-4-alkyl, wherein substituted phenyl and substituted phenyl-C1-4-alkyl contains from one to two substituents independently selected from the group comprising halogen;
one of R7and R8is hydrogen, C1-4-alkyl and the other of them is a C1-4-alkyl, C3-6-cycloalkyl, C1-4-alkoxy-C1-4-alkyl, phenyl-C1-4-alkyl, substituted phenyl, or substituted phenyl-C1-4-alkyl, wherein substituted phenyl and substituted phenyl-C1-4-alkyl contain one Deputy, selected from the group comprising halogen, halo-C1-4-alkyl;
or R7and R8together with the nitrogen atom to which they are attached, form pyrrolidinyl;
n is zero or 1;
or their pharmaceutically acceptable salts.

2. The compound according to claim 1, in which R1is substituted phenyl which contains one substituent selected from the group comprising C3-6-cycloalkyl and halo-C1-4-alkoxy, and which may further contain one Deputy, selected from halogen.

3. The compound according to claim 1, in which R1is substituted phenyl which contains one substituent selected from C3-6-cycloalkyl.

4. The compound according to claim 1, in which R3is-C(OH)R5R6.

5. The compound according to claim 1, wherein one of R5and R6is hydrogen and the other of them is phenyl, Samedan�th phenyl or substituted phenyl-C1-4-alkyl, wherein substituted phenyl and substituted phenyl-C1-4-alkyl contains from one to two substituents independently selected from the group including halogen.

6. The compound according to claim 1, wherein one of R5and R6is hydrogen and the other of them is a phenyl or substituted phenyl, and substituted phenyl contains from one to two substituents independently selected from halogen.

7. The compound according to claim 1, in which R3is-C(O)NR7R8.

8. The compound according to claim 1, wherein one of R7and R8is hydrogen and the other of them is a C1-4-alkyl, substituted phenyl, or substituted phenyl-C1-4-alkyl, wherein substituted phenyl and substituted phenyl-C1-4-alkyl contain one Deputy, selected from halogen and halo-C1-4-alkyl.

9. The compound according to claim 1, in which R2is hydrogen, C1-4-alkyl or phenyl.

10. The compound according to claim 1, selected from the group including
2-(4-cyclopropyl-phenyl)-8-(3-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;
2-(4-cyclopropyl-phenyl)-8-phenethyl-2,8-Diaz-Spiro[4.5]Dean-1-he;
2-(4-cyclopropyl-phenyl)-8-(4-trifluoromethyl-benzyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;
2-(4-cyclopropyl-phenyl)-8-(1-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;
2-(4-cyclopropyl-phenyl)-8-[1-(3-trifluoromethyl-phenyl)-ethyl]-2,8-Diaz-Spiro[4.5]Dean-1-he;
2-(2-chloro-4-cyclopropyl-phenyl)-8-(1-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;
2-(4-cyclopropyl-phenyl)-8-(1-phenyl-propyl)-2,8-diazaspiro[4.5]Dean-1-it;
8-benzyl-2-(4-triptoreline-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;
2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-ethyl-acetamide;
2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N,N-diethyl-acetamide;
N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-acetamide;
2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-trifluoromethyl-benzyl)-acetamide;
2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-acetamide;
2-(4-cyclopropyl-phenyl)-8-(2-oxo-2-pyrrolidin-1-yl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;
N-benzyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-methyl-acetamide;
N-cyclohexyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-methyl-acetamide;
2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(3-methoxy-propyl)-acetamide;
N-butyl-3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionamide;
3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-trifluoromethyl-benzyl)-propionamide;
3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-propionamide;
N-benzyl-3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-methyl-propionamide;
N-cyclohexyl-3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-methyl-propionamide;
2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;
8-[2-(4-chlorophenyl)-2-hydroxy-ethyl]-2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-it;
2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-propionamide;
2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-butyramide;
N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-propionamide;
N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-butyramide;
N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-2-phenyl-acetamide;
butylamide 2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-hexanoic acid;
N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-3-methyl-butyramide;
2-(4-cyclopropyl-phenyl)-8-((S)-2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;
2-(4-cyclopropyl-phenyl)-8-((R)-2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;
2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;
2-(4-cyclopropyl-phenyl)-8-[(R)-2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-2,8-Diaz-Spiro[4.5]Dean-1-he;
8-[(R)-2-(3-chloro-phenyl)-2-hydroxy-ethyl]-2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;
2-(4-cyclopropyl-phenyl)-8-[2-(3,4-dichloro-phenyl)-2-hydroxy-ethyl]-2,8-Diaz-Spiro[4.5]Dean-1-he;
and 2-(4-cyclopropyl-phenyl)-8-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2,8-Diaz-Spiro[4.5]Dean-1-it.

11.The compound according to claim 1, selected from the group including
2-(4-cyclopropyl-phenyl)-8-(1-phenyl-propyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;
N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-28-Diaz-Spiro[4.5]Dec-8-yl]-acetamide;
2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-trifluoromethyl-benzyl)-acetamide;
2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-acetamide;
3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-trifluoromethyl-benzyl)-propionamide;
3-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-propionamide;
2-(4-cyclopropyl-phenyl)-8-(2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;
8-[2-(4-chloro-phenyl)-2-hydroxy-ethyl]-2-(4-cyclopropyl-phenyl)-2,8-Diaz-Spiro[4.5]Dean-1-he;
2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-N-(4-fluoro-phenyl)-propionamide;
butylamide 2-[2-(4-temporaril-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-hexanoic acid;
N-butyl-2-[2-(4-cyclopropyl-phenyl)-1-oxo-2,8-Diaz-Spiro[4.5]Dec-8-yl]-3-methyl-butyramide;
2-(4-cyclopropyl-phenyl)-8-((R)-2-hydroxy-2-phenyl-ethyl)-2,8-Diaz-Spiro[4.5]Dean-1-he; and
2-(4-cyclopropyl-phenyl)-8-[(R)-2-(4-fluoro-phenyl)-2-hydroxy-ethyl]-2,8-Diaz-Spiro[4.5]Dean-1-it.

12. The compound according to any one of claims.1-11 intended for use as an inhibitor gormonchuvstvitelnoy lipase.

13. Pharmaceutical composition, inhibiting gormonchuvstvitelnoy lipase, comprising a compound according to any one of claims.1-11 and a therapeutically inert excipient.

14. Use of a compound according to any one of claims.1-11 for the treatment or prophylaxis of diabetes, metabolicheskogo� syndrome, dyslipidemia, atherosclerosis or obesity.

15. Use of a compound according to any one of claims.1-11 for the manufacture of a medicinal product for the treatment or prophylaxis of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity.

16. The compound according to any one of claims.1-11 for the treatment or prophylaxis of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity.

17. A method for the treatment or prophylaxis of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity, comprising administering an effective amount of a compound according to any one of claims.1-11.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) where R1 is phenyl, imidazo[2,1-b][1,3]thiazolyl, pyridinyl, pyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, imidazo[2,1-b][1,3,4]thiadiazolyl, 1H-indazolyl, pyridazinyl, imidazo[1,2-b][1,2,4]triazinyl, 1H-pyrazolo[3,4-b]pyridinyl, imidazo[1,2-b]pyridazinyl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridinyl, oxadiazolyl or imidazo[1,2-a]pyridinyl; each of which is optionally substituted with 1-3 substitutes, independently selected from methyl, methoxy, cyano, cyclopropyl, -C(O)NH2 and -NHC(O)CH3; Ra in each case is hydrogen; each of Z, Z1 and Z2 is independently CH; L is a direct bond; and R2 is hydrogen, phenyl, phenoxy, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, pyridinyl, oxazolyl, oxadiazolyl, pyrazolyl, pyridazinyl, triazinyl or pyrazinyl, each optionally substituted with 1-3 substitutes independently selected from methyl, trifluoromethyl, ethyl, methoxy, cyano or -C(O)NH2; or pharmaceutically acceptable salts thereof, which act as ghrelin antagonists or inverse agonists.

EFFECT: obtaining novel derivatives.

13 cl, 1 dwg, 11 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of general formula , with values of radicals, presented in description, as well as in form of separate stereoisomer or their mixture, free compounds and/or their physiologically compatible salts, which have affinity to ORL 1 - receptor and µ-opioid receptor. Invention also relates to medical preparation, which contains said compounds, and application of said compounds for obtaining medical preparation for treatment of pain, panic attack, stress and syndromes, associated with stress, depressive diseases, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, malfunctions of education and memory (as nootropic agent), abstinent syndromes, abuse and/or addiction to alcohol and/or drugs and/or medications, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, itch, migraine, hearing impairment, disturbance of gastrointestinal tract motility, nutrition irritability, anorexia, bulimia, locomotive malfunctions, diarrhea, cachexia, enuresis, or as muscle-relaxant, anticonvulsive preparation or analgesic medication, or for combined introduction in treatment with opioid analgesic, or anesthetic, for diuresis or anti-natriuresis, anxiolysis, for modulation of motion activity, for modulation of neuromediator release and treatment of associated with it neurodegenerative diseases, for treatment of abstinence syndromes and/or for reduction of possibility of becoming addicted to opioids.

EFFECT: obtaining novel compounds.

10 cl, 36 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to new individual compounds of spiro{indeno[1,2-b]quinoline-10,3'-pyrroles}, namely to ethyl 5-alkyl-7,7-dimethyl-2',9,11-trioxo-5'-phenyl- 1',2', 5,6,7,8,9,11-octahydrospiro{indeno[1,2-6]quinoline-10,3'-pyrrol}-4'-carboxylates of general formula wherein R=CH2Ph, C6H11-c, Ph, C6H4OMe-4, C6H4Me-4; Alk=CH2Ph, All; furthermore, the invention refers to a method for preparing them.

EFFECT: preparing the new compounds which may be used as initial products for synthesis of new heterocyclic systems and in pharmacology as those exhibiting analgesic activity.

4 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to spirocyclic cyclohexane derivatives of formula I where values of R1-10 are given in claim 1.

EFFECT: compounds have affinity for the ORL1 receptor, which enables use thereof in producing a medicinal agent for treating pain, especially sharp, neuropathic or chronic pain.

12 cl, 1 tbl, 52 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to spirocyclic nitriles of formula (1a): wherein the radicals A, B, C, X, Y, R24, R25, R26 and R27 are presented in cl.1 of the patent claim, inhibiting thiol proteases, particularly cathepsins, a method for preparing and using them as a drug for treating the diseases directly or indirectly mediated by cathepsins.

EFFECT: preparing the agent for treating the diseases directly or indirectly mediated by cathepsins.

12 cl, 2 tbl, 105 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (IX) wherein radicals and symbols have values given in the claim, and pharmaceutically acceptable salts or tautomers thereof. Said compounds are inhibitors of poly(ADP-ribose)polymerase (PARP) and can be used to treat cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitisers for cancer treatment. The invention also relates to a pharmaceutical composition containing said compounds, use of said compounds and a method of treating said diseases.

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel spirocyclic cyclohexane derivatives of formula I: , where: R1 and R2 together form a ring and are -CH2CH2CH2-; R3 denotes a saturated, branched or straight, unsubstituted C1-5-alkyl; unsubstituted or monosubstituted with F, Cl, Br, I phenyl; 5-member heteroaryl containing sulphur as a heteroatom; unsubstituted or monosubstituted with F, Cl, Br, I phenyl, attached through a C1-3-alkyl group; R5 denotes H; R6 denotes H, F, Cl; R7, R8, R9 and R10 independently denote H, F, Cl, Br, I; X denotes O, NR17; R17 denotes H, COR12; R12 denotes H, unsaturated, branched or straight, unsubstituted or phenyl-substituted C1-5-alkyl; in form of a racemate; enantiomers, diastereomers, mixtures of enantiomers or diastereomers, or a separate enantiomer or diastereomer; bases and/or salts of physiologically compatible acids or cations.

EFFECT: compounds have binding action on the ORL1 receptor and the µ-opioid receptor, which enables their use to treat various diseases.

12 cl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) where values of substituents are given in description, possessing inhibiting activity with respect to cathepsin K as well as to pharmaceutical compositions for treating diseases, associated with cysteine protease activity and to methods of inhibiting cathepsin K in mammals, requiring such treatment by introduction of efficient amount of compound to mammal.

EFFECT: claimed is application of formula (I) compound or its pharmaceutically acceptable salt in manufacturing medication for application in cathepsin K inhibition in a warm-blooded animal.

10 cl, 45 ex, 5 dwg

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of formula I or their pharmaceutically acceptable salts showing activity with respect to HIV reverse transcriptase, as well as to a based pharmaceutical composition (I). In formula I R1 means phenyl(C1-C3)alkyl, heteroaryl(C1-C3)alkyl, phenyl or heteroaryl optionally substituted by one-three substitutes independently specified in groups (a)-(r), R2 means -CN, -CH=CHCN or halogen; R3 means hydrogen, halogen, amino group, halogen(C1-C6)alkyl, -CN or methyl; R4 means hydrogen, Br or amino group; R5a and R5b independently mean hydrogen, C1-C6alkyl, C1-C6alkoxy group or halogen; R6a and R6b either independently mean hydrogen, or together mean ethylene; X means NH or O. The groups (a)-(r) are such as presented in the patent claim.

EFFECT: preparing pharmaceutically acceptable salts possessing activity with respect to HIV reverse transcriptase.

17 cl, 42 ex, 6 dwg, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to di(arylamino)aryl derivatives presented in the patent claim. The compounds show an inhibitory effect on protein EML4-ALK v1 and protein EGFR kinase activity. Also the invention refers to a pharmaceutical composition containing said compounds, the hybrid protein EML4-ALK and mutant protein EGFR kinase activity inhibitor, the use of said compounds for preparing the pharmaceutical composition, and to a method of preventing or treating non-small-cell lung cancer or EML4-ALK hybrid polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small-cell lung cancer.

EFFECT: use of di(arylamino)aryl as the protein EML4-ALK v1 and protein EGFR kinase activity inhibitors.

12 cl, 95 tbl, 55 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry and represents a formulation specially adapted for insulin transformation into the aerosol state, containing insulin in water from 100 IU/ml to 1,200 IU/ml and 2 to 4 Zn2+ ions per the insulin hexamer, wherein the formulation is preservative-free and wherein the formulation is able to transform into the aerosol state as an aerosol spray when using a holed vibration plate with no foaming of the formulation, when the formulation is kept on a back surface of the holed plate by gravity, and the spray is ejected from the front surface of the holed plate entirely by vibrating the holed plate.

EFFECT: invention provides reducing the foaming of the formulation, the time of transformation into the aerosol state and providing the more effective administration of an insulin dose.

19 cl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the pharmaceutical industry, namely to a medication for the complex therapy of patients with type 2 diabetes mellitus and a method of the complex therapy of patients with type 2 diabetes mellitus. The medication for the complex therapy of patients with type 2 diabetes mellitus contains a cleaned and dried rhizome of Curcuma longa in the form of powder with the specified size of particles. The method of the complex therapy of patients with type 2 diabetes mellitus consists of the daily intake of the cleaned and dried rhizome of Curcuma longa in the form of powder with the specified size of particles twice per day after dinner and supper at the background of the intake of pelleted hypoglycaemic agents without changing the dose and scheme of the drug therapy.

EFFECT: medication produces a direct stimulating impact on β-cells of the pancreas and ensures the development of a hypoglycaemic effect, including early stages of the disease development.

3 cl, 1 dwg, 5 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to therapy and endocrinology, and can be used in treating patients suffering type 2 diabetes mellitus. That is ensured by a continuous exenatide delivery by implanting into a patient into an osmotic delivery device comprising an impermeable container, a semi-permeable membrane, an osmotic mechanism integrated into the container and adjoining the semi-permeable membrane, a piston adjoining the above osmotic mechanism; the above piston forms a movable seal with an inner surface of the container and divides the container into a first chamber comprising the osmotic mechanism, and a second chamber comprising a suspension formulation, and a diffusion adjustor. The suspension formulation contains a particle formulation containing exenatide particles having a diameter of less than 10 to 30 mcm. The delivery formulation contains a solvent specified in a group consisting of benzyl benzoate, lauryl lactate and lauryl alcohol, and polyvinylpyrrolidone polymer. The delivery formulation has a viscosity of approximately 10,000 poise to approximately 20,000 poise at 37°C. The continuous exenatide delivery in the therapeutic concentration is ensured for 5 days or less. The continuous exenatide delivery from the osmotic delivery device in a dose of exenaide of 10 mcg/day, 20 mcg/day, 30 mcg/day, 40 mcg/day, 60 mcg/day, and 80 mcg/day can be effected through at least three months.

EFFECT: method enables the effective treatment of the given pathology by the fast achievement and long maintenance of the exenatide concentration to be completed rapidly with no constant injections or oral administration.

15 cl, 20 tbl, 21 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a citrate of a compound described by formula (II) below, and a pharmaceutical composition containing said citrate.

EFFECT: experimental results of the present inventions prove that said citrate can inhibit activity of phosphodiesterase type 5 and can be used for treating erectile dysfunction, for inhibiting thrombocyte aggregation and treating thrombosis, for reducing pulmonary hypertension and treating cardiovascular diseases, asthma and diabetic gastroparesis.

2 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to a compound of formula (I) or its pharmaceutically acceptable salts of formula (I), wherein X represents O, S; Y represents O, S; R1 independently represents H, alkyl; G1 represents ethyl; each G2 and G3 are independently specified in H, alkyl, trifluoromethyl, halogen, nitro, amido, cyano and tetrazolyl. The invention also refers to a pharmaceutical composition possessing activating action on peroxisome proliferator activated receptors subtype α, subtype δ and subtype γ and containing an effective amount of the compound of formula (I) or its pharmaceutically acceptable salts. The compounds of formula (I) are applicable for treating or producing a drug preparation for treating or preventing the diseases associated with peroxisome proliferator activated receptors subtype α, subtype δ and subtype γ. The compounds of formula (I) are produced by a reaction of the compound of formula (III) and the compound of formula (IV) when heated in acetonitrile under reflux in the presence of potassium carbonate to produce the compound of formula (II), to saponify the compound of formula (II) in alcoholic solution in the presence of alkali and to acidify the reaction mixture to produce the compound of formula (I). X, Y, R1, G1, G2 and G3 have the above values; R3 represents a leaving group specified in OH, Cl, Br, I, OTs, OMs.

EFFECT: compounds of phenylpropionic acid possessing the activating action on peroxisome proliferator activated receptors (PPARα, δ, γ).

15 cl, 2 ex

FIELD: medicine.

SUBSTANCE: agent for treating diabetes mellitus involving dry aqueous extract of Geranium Dieisianium Knuth and dry aqueous extract of Uncaria tomentosa (Willd) D.C. bark enclosed into gelatine capsules. A method of treating diabetes mellitus provides prescribing the above agent in a daily dose of 180-360 mg after a meal. The above agent enables treating diabetes mellitus effectively by reducing dosages of blood glucose lowering drugs.

EFFECT: agent causes the positive effect on carbohydrate metabolism and possesses non-specific immunomodulatory action.

2 cl, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: object of the invention is a method and a pharmaceutical composition in the form of a water-alcohol solution of ethanol 30-60° and water 40-70%, wherein at least one hypoglycaemic active substance is stably and completely dissolved, to be used by administering through the oral mucosa as a therapeutic agent in accurate treatment of postprandial hyperglycemia accompanying type II diabetes mellitus in a human or animal; wherein the water-alcohol solution in the composition has a volume of less than 2 ml, wherein an amount of 250mg or less of the above active substance is stably and completely dissolved, while the hypoglycaemic active substance is specified in lipophilic or amphiphilic active substances, such as gliclazide, glinides, incretins and glyphins. The invention also refers to a method for preparing this dosage form.

EFFECT: preparing the therapeutic agent for treating postprandial hyperglycemia accompanying type II diabetes mellitus.

9 cl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention refers to gene engineering, more specifically to producing the peptide GLP-1, modified by an oligosaccharide chain, and can be used in medicine for treating or preventing diseases associated with GLP-1. In the peptide GLP-1 with SEQ ID NO: 2 or SEQ ID NO: 3 two amino acid peptides are substituted by an amino acid modified by a complex bi-antennal oligosaccharide chain, and wherein each of the centres is specified in a group consisting of positions 18, 22, 26, 30, 34 and 36 in the peptide GLP-1 with SEQ ID NO: 2 or SEQ ID NO: 3. The above modified peptide GLP-1 can involve the deletion, substitution or attachment of 1-5 amino acids, except for the amino acids modified by the oligosaccharide chain.

EFFECT: invention enables producing the peptide GLP-1 modified by the oligosaccharide chain, which shows the stronger activity of blood glucose suppression and twice increased half lifetime as compared to GLP-1 with SEQ ID NO: 3.

24 cl, 5 dwg, 6 tbl, 16 ex

Oxyintomoduline // 2542362

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to peptide analogues of oxyintomoduline (OXM, glucagon-37), which can be modified for providing the stability of cleavage and inactivation with dipeptidyl peptidase IV (DPP-IV) for increasing a half-life time in vivo of the peptide analogue alongside with enabling the peptide analogue acting as a double agonist GLP-1/glucagon receptor (GCGR).

EFFECT: peptide analogues are applicable for treating metabolic disorders, such as diabetes and obesity.

16 cl, 16 dwg, 11 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A represents CRaRb or -CH2-CH2-; R1 represents hydrogen or alkyl; R2 represents hydrogen or alkyl; R3 represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, substituted aryl, 1H-pyrazolyl or substituted 1H-pyrazolyl, wherein substituted aryl represents aryl substituted by 1-3 substitutes independently specified in alkyl, halogen and halogenalkyl, and wherein substituted 1H-pyrazolyl represents 1H-pyrazolyl substituted by 1-3 substitutes independently specified in alkyl and aryl; Ra represents hydrogen or methyl; Rb represents hydrogen or methyl; or Ra and Rb together with a carbon atom, to which they are attached, form cyclopropyl, cyclobutyl or cyclopentyl; provided Ra and Rb both represent hydrogen, or both represent methyl simultaneously, R3 represents (1-methylcyclopropyl)methyl, which possess the inhibitory action on 11b-HSD1.

EFFECT: preparing the compounds, which possess the inhibitory action on 11b-HSD1.

15 cl, 1 tbl, 32 ex

FIELD: veterinary medicine.

SUBSTANCE: product comprises Lycopodium clavatum, Acidum arsenicosum, Phosphorus, Podophyllum peltatum, Thuja occidentalis, Echinacea purpurea, Silybum marianum, Selenocysteine, and the components are taken in the dilutions described below in the following ratio, in parts: Lycopodium clavatum ⌀=D1 0.004, Podophyllum peltatum ⌀ 0.003, Acidum arsenicosum ⌀=D2 0.0001, Phosphorus ⌀=D3 0.001, Thuja occidentalis ⌀ 30, Echinacea purpurea ⌀ 30, Silybum marianum ⌀ 60, Selenocysteine 0.2.

EFFECT: product has an effective stress-protective and growth-stimulating effect, it regulates the metabolism in young farm animals.

3 cl, 10 tbl, 1 ex

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