UA77627C2 - Method (variants) and composition (variants) for reducing body weight and modulating body lipid metabolism in mammals - Google Patents

Abstract

Methods, pharmaceutical compositions, and compounds for reducing body weight, modulating body lipid metabolism, and reducing food intake in mammals are provided. The compounds of the invention include tally acid ethanolamide compounds, homologues and analogs of which the prototype is the endogenous fatty acid ethanolamide, oleoylethanolamide.

Description

Description of the invention

This application claims priority to (US patent application MobO/336,289 dated October 31, 2001 and US patent application No. 2 MobOo/279,542 dated March 27, 2001), the contents of each of which are incorporated herein by reference.

This invention was created with the support of government grant MobA 12653, provided by the National Institutes of Health. The United States Government owns the relevant rights to this invention.

The present invention relates to fatty acid ethanolamides, their homologues and analogues and their use as pharmaceutically active substances for reducing body fat mass, food consumption, and also for modulating 70 lipid metabolism.

Obesity is a worldwide health problem that has become particularly large in the United States and other countries. An estimated 97 million US adults are overweight. Among them, 40 million suffer from obesity. Obesity and overweight significantly increase the risk of many diseases. Thus, hypertension, type 2 diabetes, dyslipidemia, coronary heart disease, angina pectoris, gall bladder disease, osteoarthritis, sleep apnea attacks and other respiratory disorders, as well as various types of intrauterine cancer, breast cancer, were associated with increased body weight. gland, prostate cancer and intestinal cancer. People with increased body weight also have an increased mortality rate in all groups of causes that cause it. According to the National Institutes of Health, approximately 280,000 deaths among adults in the United States each year may be partially attributable to obesity.

For people suffering from obesity and overweight, losing body weight is desirable. Losing weight can help prevent many of the ill effects listed above, and especially those associated with diabetes and cardiovascular disease (SMO: sagaiomazciag disease). Weight loss can also lower blood pressure in obese, hypertensive and nonhypertensive individuals, serum triglyceride levels, and increase the beneficial form of cholesterol, which is high-density lipoprotein (HDL). with

Losing weight in the general case also allows to reduce to a certain extent the levels of total serum He) cholesterol and lipoprotein (I ОI: Iom/-depeyu IProrgoieipl) form of cholesterol of low density. Losing weight can also reduce blood glucose levels in obese and overweight people.

But achieving the desired weight loss is quite difficult. There are many different ways to get rid of excess weight, but there are very frequent cases of its recovery. About 40,905 women and 2,495 men are trying to get rid of excess weight permanently. For this, low-calorie and low-fat diets, increased physical activity, behavioral therapy and pharmacotherapy aimed at reducing food consumption, surgical methods and various combinations of these approaches are used. eh

The pharmacopoeia of weight loss is relatively poor. Fatty adults can achieve weight loss with long-term use of such medications as sibutramine, dexfenfluramine, orlistat, 3o-phenylpropanolamine, phentermine, fenfluramine, etc. However, generally speaking, the safety of long-term use of pharmacotherapy for weight loss still remains unstudied. For example, recently due to concern about cases of heart valve defects in patients using fenfluramine and dexfenfluramine, these drugs were withdrawn from the market. Therefore, in view of the insufficiently developed relevant pharmacopoeia and the alarming prevalence of obesity cases, there is an urgent need for new pharmaceutical methods and formulations for long-term weight loss. c Fatty acid ethanolamides (BAEE: Tacyu acii e(ipapoiatides) are unusual components of animal and

of plant lipids, and their concentration in unstimulated cells is generally small

U. Vioi. Spet., 240: 1019-1024 (1965); Zsptia ei ai., Spet. RNUvz. Iiriav, 80:133-142 (1996); Spartap, K. 0,.,

Spent RNuz. I iriaz, 108: 221-229 (2000) Y. However, REAE biosynthesis can rapidly increase in response to a variety of physiological and pathological stimuli, including such as the action of fungal pathogens in tobacco cells and (Spartap et al., Riapi Rnuzioi., 116: 1163-1168 (1998)), activation of neurotransmitter receptors in Neurons -I of rat brain |Oi Mag2o ei ai., Mayte, 372: 686-691 (1994); Szishtida ey aiYi., Mai. Meiygovsi., 2: 358-363 (1999)) and the action of stressogenic metabolic factors in epidermal cells of mice (|Vegauznem ei ai., Viospet. b 3., 346: 369-374 (2000). It is believed that the mechanism that lies in the basis of the stimulus-dependent generation of EAE in ka 20 mammalian tissues, involves two coordinated biochemical reactions of membrane phospholipid cleavage,

M-acylphosphatidylethanolamine (MARE) catalyzed by an unknown phospholipase-O, and synthesis of MARE catalyzed by M-acyltransferase (MAT) activity regulated by calcium ion and cyclic AMP (ri Maggo ei a)i., Mayige, 372: 686-691 (1994); Sadaz ei aiYi., 9. Meitsygossi., 6:3934-3942 (1996); Sadaz ei ai.,, N., 9. Meshygovsi., 17: 1226-1242 (1997). 29 The fact that both plant and animal cells release ERAE in a stimulus-dependent manner suggests that these

HF) compounds can play a significant role in intercellular communication. Additional confirmation of this idea is the discovery that polyunsaturated ERAE, in particular, anandamide (arachidonylethanolamide) is an endogenous ligand for o cannabinoid receptors. - C-protein-bound receptors expressed in neurons and immune cells that recognize the marijuana component, l-tetrahydrocannabinol (LA 9-TNe), see review (Regimee, V. 0., Ehr. Orip. Ipmevi. Ogoidv, 9:1553-1571 (20001).

The impossibility of participation in cannabinoid neurotransmission by other RAEs is evidenced by two such observations.

First, the BAE family consists mostly of saturated and monounsaturated species such as palmitylethanolamide and oleoylethanolamide, which do not significantly interact with cannabinoid receptors (Oemape v5 eg a)"., Zsiepse, 258:1946-1949 (1992); giyip ei a), 9. Rpaptasoi Ehr. TNeg., 292:886-894. (2000)).

Secondly, detailed studies of the pharmacological properties of BAE, as is the case, for example, with palmylethanolamide, show that such properties differ from those of AZ-TNO and are independent of the activation of known subtypes of cannabinoid receptors. 277-281 (1998)). Thus, the biological significance of EAE remains elusive.

Oleoylethanolamide (OEA) is a natural analogue of the endogenous cannabinoid anandamide. Like anandamide, OEBA is produced in cells by a stimulus-like pathway and is rapidly removed by enzymatic hydrolysis, indicating its role in cell signaling. However, unlike anandamide, OEA does not activate cannabinoid receptors, and its biological functions have been largely unknown until now.

There is a need for additional methods and substances for the treatment of obesity, as well as for the maintenance of an achieved state of weight loss. This invention meets this need by offering new methods and pharmaceutical compositions resulting from the authors' discovery of the ability of oleoylethanolamide (OEA) and other ethanolamides of fatty acids (for example, palmylethanolamide, elaidylethanolamide) to reduce appetite, food intake, body weight and body fat mass, and also to change fat metabolism

The present invention provides compounds, compositions and methods for reducing body fat and for the treatment and prevention of obesity and overweight in mammals, as well as diseases associated with these health conditions. In one of its variants, the invention provides methods of reducing body fat mass or weight and treating and preventing obesity and overweight, as well as reducing food intake by administering pharmaceutical compositions containing a fatty acid alkanolamide, its homolog or analogue in an amount sufficient to reduce fat mass or body weight or prevention of obesity and gaining body weight. In other variants of implementation of the invention, fatty acid ethanolamides and their homologues are provided. and analogs, as well as pharmaceutical compositions containing them, and methods of their use.

Variants of the invention are possible, in which the fatty acid component of the alkanolamide or ethanolamide of a fatty acid, its homologue or analogue can be both saturated and unsaturated, and in the case of unsaturation, it can be monounsaturated or polyunsaturated. with

In other embodiments of the invention, the fatty acid component of the alkanolamide of a fatty acid, its homolog or analogue is a fatty acid selected from the group consisting of oleic acid, i) palmitic acid, elaidic acid, palmitoleic acid, linoleic acid, alpha-linoleic acid and gamma -linoleic acid. In other embodiments, the fatty acid components have from 12 to 20 carbon atoms in their composition. rch-

In other variants of implementation of the invention, variation of the hydroxyalkylamide component of the fatty acid amide, its homolog or analogue is provided. In these variants, the introduction of a substituted or unsubstituted c (C4-C3) alkyl group into the hydroxyl group of the alkanolamide or ethanolamide component is provided to form (Te) the corresponding lower alkyl ether. In another embodiment, the hydroxy group of the alkanolamide or ethanolamide component is linked to the carboxylate group of a substituted or unsubstituted C 1 to C 1 alkyl carboxylic acid to form the corresponding fatty acid ethanolamide ester. In such variants, the presence of alkanolamides or ethanolamides of fatty acids in ester bonds with such organic carboxylic acids as acetic acid, propionic acid and butanoic acid is assumed. In one embodiment, the fatty acid alkanolamide is oleoylalkanolamide. In another embodiment, the fatty acid alkanolamide is oleoylethanolamide.

A variant of the implementation of the invention is also provided, where fatty acid ethanolamide, its homologue or analogue This c also contains a substituted or unsubstituted lower (C4-C3) alkyl group covalently bound to the nitrogen atom and fatty acid ethanolamide. "» In its other variants, the invention provides a pharmaceutical composition that includes a pharmaceutically acceptable excipient and a compound or its pharmaceutically acceptable salt described by the formula:

V. and whose; Teh she; lo sh- i v a shi i what i Ya r t mo 20 c. me "I In this formula, H takes values from 0 to 5, and the sum of a and B can be from 0 to 4; 7 is a member selected from -Ф(О)М(Б2)-, -К2)МС(О )-, - OS(O)-, --FOSO-, O, ME: and 8, where B: and K2 are independently selected from the group consisting of unsubstituted or substituted alkyl, hydrogen, substituted or unsubstituted Si-Ce alkyl, substituted or unsubstituted lower (C.4-Cv) acyl, homoalkyl, and aryl; up to four hydrogen atoms of both the fatty acid and ethanolamine components of the compound may also be substituted with a methyl or double bond; in addition, a molecular bond between carbon atoms c and y may be unsaturated or saturated.In other embodiments, the fatty acid ethanolamide of the above formula is a naturally occurring compound.

In other embodiments of the invention, in the proposed methods and compositions, ethanolamide and ethanolamide 60 fatty acids, their homologues and analogs are used to reduce body weight, and the specified compounds, their homologues and analogs cause weight loss when administered to experimental animals (for example, rats, mice, rabbits , hamsters, guinea pigs).

In other variants of implementation of the invention, methods of using arylthiazolidinedione compounds and compounds of the heteroaryl and aryloxyacetic acid type are provided for reducing body fat mass, body weight and appetite. 65 According to its other variants, the invention provides methods of application and administration of the proposed compounds and compositions for reducing body weight, appetite, food intake and for causing hypophagia in mammals (for example, in humans, cats and dogs). The compositions of the present invention can be administered by a variety of routes, including oral.

Fig.1. Fasting increases circulating levels of oleoylethanolamide in rats: (a) time course of the effect of food deprivation on plasma levels of oleoylethanolamide (oleylethanolamide, OEA); (B) the effect of water deprivation (18 hours) on the level of oleoylethanolamide in plasma; (c) the effect of food deprivation (18 hours) on the level of oleoylethanolamide in cerebrospinal fluid (SE: segergosripa! Yashidb); (4) the time course of the effect of food deprivation on the level of anandamide (arachidonylethanolamide, AEA) in plasma; (f) the effect of water deprivation (18 hours) on the level of anandamide in plasma; (Her) effect of food deprivation (18 hours) on anandamide levels in C5RE. The given /o results are expressed through the average value xz average statistical extremum; one asterisk: R«O,05; two stars: P«eO,01; n-10 per group.

Fig. 2. Adipose tissue is the primary source of oleoylethanolamide circulation. Fasting-induced changes in the activity of M-acyltransferase (MAT) and fatty acid amide hydrolase (GAAN: Tayu asii atide PuagoYase) in various rat tissues: (a) adipose tissue; (B) brain; (c) liver; (4) stomach; (e) small intestine. 7/5 Undarkened columns: animals in free feeding conditions; darkened columns: animals in conditions of 18h. starvation Activity is expressed in pmol/mg protein/min. Star: R«O,05, p-3.

Fig. 3. Adipose tissue is the primary source of oleoylethanolamide circulation. Starvation-induced changes in MARE and oleoylethanolamide (OEA) content in adipose and liver tissues: (a) structures of oleoylethanolamide precursors: alk-1-palmitoenyl-2-arachidonyl-zp-glycerophosphoethanolamine-M-oleyl (left, MARE 1) and alk- 1-palmityl-2-arachidonyl-zp-glycerophosphoethanolamine-M-oleyl (right, MARE 2); (B) typical curves of NRI C/M5 (high-performance liquid chromatography/mass spectrometry) for selected characteristic ions MARE 1 (left, t/2-987, deprotonated molecule, IM-NI) and MARE 2 (right, t/2 -1003, M-NO) in freely fed rats (top) and rats exposed to 18 h. starvation (below); (c) increase in MARE content in adipose tissue and decrease in liver tissue caused by food deprivation (18 hours). A quantitative assessment of all types of MARE that could be identified was carried out, including the precursors of oleoylethanolamide MARE 1 and MARE 2 and the precursor REA - MARE 3; (a) increase in the content of oleoylethanolamide in adipose tissue and liver caused by food deprivation (18h). Unshaded columns: freely fed animals; darkened columns: animals in conditions of 18h. starvation Asterisk: Р«0.05, Student's criterion; n--3.

Fig. 4. Oleoylethanolamide/pranamide selectively suppresses food intake: (a) dose-dependent effect of oleoylethanolamide (oleoylethanolamide/OEA/pranamide) (intraperitoneal, shaded squares), elaidethanolamide (unshaded circles), REA (triangles), oleic acid (shaded squares ) and anandamide SC (darkened rings) on food intake in rats subjected to food deprivation for 24 hours. Administration of vehicle alone (7090 UOM5O in physiological solution, Tml/kg, intraperitoneally) had no significant effect on rapid food intake; (B) time course of hypophagic effect of oleoylethanolamide (2Omg/kg, intraperitoneally) (squares) or vehicle (diamonds) on food intake; (c) the effect of vehicle (M), lithium chloride (CI, 0.4 mol, 7.5 ml/kg) or oleoylethanolamide (2Omg/kg) in conditioned taste aversion tests.

Undarkened speakers: water intake; shaded columns: intake of saccharin. Effect of vehicle (M) or oleoylethanolamide (5 or 2Omg/kg) on: (4) water intake (expressed in ml per 4h); (e) body temperature; (Y) latency to jump in the hot plate analgesia test; (9) percentage of time spent in open branches in the cascade plus-maze anxiety test; (j) the number of crossings in the activity test in an open field; (i) the number of effective food responses. Asterisk: Р«О0.05, n-8-12 per group. Fig. 5. Effect of subchronic administration of oleoylethanolamide on food intake and body weight: (a) effect of oleoylethanolamide (OEA) (5 mg/kg, intraperitoneally, once daily) (unshaded columns) and vehicle (590

Tmeep 80/595 propylene glycol in sterile physiological solution; darkened columns) for cumulative food intake; (5) time course of the effect of oleoylethanolamide (triangles) and vehicle (squares) on body weight change; (c) - And the effect of oleoylethanolamide and the carrier on the change in net body weight; (4) effect of oleoylethanolamide (5 mg/kg) and vehicle on -1 cumulative meal. Star: R«O,05; two stars: P«0.01, p-10 per group.

Fig. 6. The role of peripheral sensory fibers in oleoylethanolamide-induced anorexia. Effect of carrier (M), (e) oleoylethanolamide (oleoylethanolamide/pranamide/OEA) (5mg/kg, intraperitoneally), SSK-8 (1Omg/kg) and 50 SR-93129 (mg/kg), a centrally active receptor agonist 5-HT.c, on food intake in control rats (a) and rats treated with capsaicin (c). Water intake in control rats (B) and capsaicin-treated rats (4). Star: P<0.05; n-8-12 per group.

Fig. 7. Oleoylethanolamide/pranamide increases c-o5 gene mRNA expression in discrete brain regions associated with energy homeostasis and feeding behavior: (a) Pseudocolor images of film autoradiograms show that oleoylethanolamide (right section) causes a sharp, selective increase in labeling

Cys mRNA in the paraventricular (RUM) and supraventricular (50) hypothalamic nuclei, as evidenced by IP hybridization

IF) with. A typical section taken from a vehicle-treated rat is shown on the left. The marking density is shown in color: blue, green, yellow, red. (B) Quantification of c-o5z mRNA labeling in forebrain sections

IRMM, 5O, arcuate (Ags), piriform cortex I! layer (rii), ventrolateral thalamus (MI) and cortex 51 60 of the front limbs (Z1RI)| rats receiving vehicle, oleoylethanolamide, and oleic acid; (c) film autoradiogram shows increased expression of 235 c-oz mRNA in the nucleus of the isolated tract (MT: piseiiv oyi (PezoYiagu igas) of a mouse injected with oleoylethanolamide; the inset shows that labeling of c-oz cRNA in M5T (red) identified it localization relative to neighboring efferent nuclei (hypoglossal and dorsal motor nuclei of the vagus nerve) that express choline acetyltransferase (SPAT) 65 mRNA (shown in purple); (4) oleoylethanolamide increases c-o5 mRNA expression in M5T, but not in the hypoglossal nucleus (HN). Two stars: P«0.0001, p-5 per group.

Fig. 8. The influence of OEA, oleic acid (OA), AEBA, REA and methyl-OBA on the oxidation of fatty acids in the soleus muscle.

The present invention relates to the discovery that OEA and other fatty acid apicanolamides cause reductions in food intake, body weight and body fat mass and modulate fatty acid oxidation. Oleoylethanolamide (OEA), a naturally occurring lipid with a hitherto unknown biological function in mammals, has been found to be a compound that, when administered to experimental animals, has shown its powerful ability to reduce fat mass and regulate body weight. (U.S. Patent Application Mob0/279,542 dated Mar. 27, 2001), assigned to the same assignee and incorporated herein by reference in its entirety, discloses OEA and OEA-like 7/0 compounds as being capable of reducing body fat mass and appetite in mammals.

After the invention of the OEA prototype, it turned out that other fatty acid alknolamides and their homologues are also active.

OEBEA can serve as a model for the development of other fatty acid alkanolamide-like compounds that reduce body fat and are suitable for treating obesity, initiating weight loss, reducing /5 appetite and food intake. The compounds of this invention are described below.

The finding that OEA reduces appetite, food intake, and body weight can be used to identify other fatty acid ethanolamides, their homologues, and analogs that are agents for regulating body weight and appetite. Such agents are provided by the present invention.

Terminology

Abbreviations used in this description have their usual meanings generally accepted in the fields of chemistry and biology.

Where groups of substituents are defined by their usual chemical formulas written from left to right, they also include chemically identical substituents that have a structure written from right to left. For example, the group -Сно»О- can also be defined by the formula -ОСН»-. high school

The term "composition", meaning a pharmaceutical composition, includes in its meaning a product containing an active ingredient(s) and an inert ingredient(s) forming a carrier, as well as any i) product that can be obtained directly or indirectly by combining, complexing or aggregating any two or more ingredients, or by dissociating one or more ingredients, or by other types of reactions or interactions of one or more ingredients. Accordingly, pharmaceutical compositions of the present invention include any composition created by mixing a compound of the present invention with a pharmaceutically acceptable carrier. The term "pharmaceutical composition" means a composition suitable for pharmaceutical use by its object of treatment, which can be both a person and an animal. Ge

The pharmaceutical composition generally contains an effective amount of the active agent and a pharmaceutically acceptable carrier. uh-

The compounds of this invention may have one or more asymmetric centers and thus may be created as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. The present invention covers all such isomeric forms of the proposed compounds.

Some of the compounds described herein contain olefinic double bonds and, unless otherwise noted, include both E- and 2-isomers. "

Some of the compounds described here can exist with different points of hydrogen attachment, that is, as tautomers. An example of such a compound can be a ketone and its enol form, known as ketoenol tautomers. Submitted. here, the formulas cover both individual tautomers and their mixtures. a Among the compounds proposed by the invention are also diastereoisomers of pairs of enantiomers.

Diastereomers can be obtained, for example, by fractional crystallization from a suitable solvent at

A sample of methanol or ethyl acetate or their mixture. The pair of enantiomers obtained in this way can be separated into -And individual stereoisomers using conventional means, for example, using an optically active acid as a resolving agent. Alternatively, the enantiomer of the compound of the present invention can be prepared by

He" of stereospecific synthesis from optically pure starting materials or reagents of known configuration.

As used herein, the term "heteroatom" means oxygen (0), nitrogen (M), sulfur (5), and silicon (51). As used herein, the term "alkanol" means saturated or unsaturated, substituted or unsubstituted,

And a branched or unbranched alkyl group having a hydroxyl substituent or a substituent that can be derived from a hydroxyl moiety, for example, an ether or an ester. In the best version, the alkanol is also replaced by a nitrogen-, sulfur- or oxygen-containing substituent included in bond 7 (formula I) between the "fatty in decezel" and the alkanol.

As used herein, the term "fatty acid" means a saturated or unsaturated, substituted or unsubstituted, (F, branched or unbranched alkyl group having a carboxyl substituent. The preferred fatty acids are the C.-C.o. acids). Said fatty acids also include acids, in which the carboxyl substituent is substituted with a -Cno- -component. As used herein, the term "alkyl" by itself or as part of another substituent means, unless otherwise specified, a straight or branched chain or cyclic hydrocarbon radical, or a combination thereof, which may be fully substituted , mono- or polyunsaturated and may include bivalent and multivalent radicals with the specified number of carbon atoms (i.e. С.-С4о means: from one to ten carbon atoms). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, p-propyl, isopropyl, p-butyl, i-butyl, isobutyl, secondary butyl, cyclohexyl, (cyclohexyl)methyl, c ilkopropylmethyl, homologues and isomers, for example, p-pentyl, p-hexyl,

p-heptyl, p-octyl, etc. An unsaturated alkyl group is one that has one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1 - and

Z-propynyl, Z-butynyl and their higher homologues and isomers. The term "alkyl" as used herein, unless otherwise indicated, also includes the alkyl derivatives described in detail below, such as heteroalkyl. Alkyl groups limited only to hydrocarbon groups are called "homoalkyl".

As used herein, the term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane, for example -"CH-CHNoCHNoCH"-, and also includes the groups described below under the heading of "heteroalkenes". Of course, an alkyl (or alkylene) group contains from 1 to 24 carbon atoms and is preferably 10 or less carbon atoms according to the present invention. "Lower alkyl" or "lower alkylene" is a shorter-chain alkyl or alkylene group, generally having eight or fewer carbon atoms.

The terms "alkyl", "alkylamino" and "alkylthio" (or tsalkoxy) are used herein in their usual sense and 7/5 refer to those alkyl groups which are linked to the rest of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.

As used herein, the term "heteroalkyl" by itself or in combination with other terms, unless otherwise indicated, means a stable straight or branched chain or cyclic hydrocarbon radical or combinations thereof consisting of the specified number of carbon atoms and at least one heteroatom, selected from the group consisting of O, M, 5i and 5, and where the nitrogen and sulfur atoms can optionally be oxidized, and the nitrogen heteroatom can optionally be quaternized. Heteroatom(s) O, M, 5 and 5i can be placed in any internal position of the heteroalkyl group or in the position in which the alkyl group is connected to the rest of the molecule. Examples can be mentioned here, without being limited to them: -bn.-СсСн.-О-СНуУ, -Сн.-СнNoОМн-СН», -Сн.-Сн.-М(СН3)-СНу», -Сно-5 -СНо-СНу», -Сно-Сн», -5(0)-СН»У, с 28 "СНо-СНо-5(0)2-СН3, "СНАСН-О-СН», -З(СНаз) with, "-СНо-СНАМ-ОСН with and "СНАСНАМЖ(СНУИ)-СНаз. Up to two heteroatoms can be consecutive, for example, as in -СН 5-МН-ОСНз and -СН.-О-5(СН»)з Similarly, the term i) "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from a heteroalkyl, for example -СНо-СН.-53-СНО-СНо- and -СН.-53-СН.- СНо-МН-СНо-. In heteroalkylene groups, heteroatoms can also occupy any one or both ends of the chain (for example, alkyleneoxy, isoalkylenedioxy, alkyleneamino, alkylenediamino, etc.). In addition, for oalkylene and heteroalkylene linking groups, the orientation of the linking group is not determined by the direction of writing its formula. For example, the formula -С(0)К'- equally expresses both -С(О)21К- and -К"С(О) »-. Ge

The terms "cycloalkyl" and "heterocycloalkyl" by themselves or in combination with other terms, unless otherwise indicated, mean the cyclic versions of "alkyl" and "heteroalkyl", respectively. In addition, in 1-35 Heterocycloalkyl, the heteroatom can occupy a position in which the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl,

Z-cyclohexenyl, cycloheptyl, etc. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2- yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, « 2-piperazinyl, etc. The terms "halo" or "halogen" by themselves or as part of another substituent mean, unless otherwise specified. another, an atom of fluorine, chlorine, bromine or iodine. In addition, terms such as "haloalkyl" include monohaloalkyl and ? polyhaloalkyl. For example, the term "halo(C1-C1)alkyl" includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

The term "aryl" means, unless otherwise indicated, a polyunsaturated, aromatic hydrocarbon substituent, -I which may consist of one or more rings (preferably 1 to 3 rings) which may be fused or covalently bonded to each other. The term "heteroaryl" means aryl groups (or rings) containing from 1 to - 4 heteroatoms selected from M, O and 5, where the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom (or atoms) when of necessity are quaternized. A heteroaryl group can be attached to a residue

Molecules through a heteroatom. Examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, where 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, "M 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, Z-furyl, 2-thienyl, Z-thienyl, 2-pyridyl, Z-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and b-quinolyl Substituents for the above aryl and heteroaryl ring systems are selected from the group of suitable substituents described below.

F) For brevity, the term "aryl" includes both aryl and heteroaryl rings as defined above. Therefore, the term "arylalkyl" includes those radicals in which the aryl group is attached to an alkyl group (for example, benzyl, phenethyl, pyridylmethyl, etc.), including such alkyl groups, because in which a carbon atom (for example, a methylene group) is substituted, for example, an oxygen atom (for example, phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, etc.).

All of the above terms (eg, "alkyl," "heteroalkyl," "aryl," and "heteroaryl") include both substituted and unsubstituted forms of said radical. The best substituents for each type of radical are described below. 65 Substituents for alkyl and heteroalkyl radicals (including groups often called alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to:- OK, 50, MAK, -M-OK, -MA'K", -ZAK, -halogen, -ZIK"K", -OFSH(OK, -FKOK, -SO, -SOMAK", -OS(OMeK", -MA"O(O)K, 0 -MA-S(OM'KLAK", 0 -MA"S(O)»K, -MK-S(MA' KK MA", 0 -MK-S(MA KOMA . in such a radical. KK, KK", Kk" and Kk" each independently means hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, for example, aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy- or thioalkoxy groups or arylalkyl groups.If the compound according to the present invention contains more than one group K, then, for example, each of gr groups K are chosen independently as groups KU" KK" Kk" when more than one of these groups is available. When K' and K" are bonded to the same nitrogen atom, they can be conjugated to that nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, -MK'K" means, but is not limited to only them, 1-pyrrolidinyl and 4-morpholinyl. From the above description of substituents, one of ordinary skill in the art will appreciate that the term "alkyl" encompasses groups containing carbon atoms bonded to groups other than hydrogen, such as haloalkyl (eg, -CE 2 and -SNCE 2 ) and /5 acyl (for example, -С(О)СН3, -С(О)СР3, -Ф(О)СНоОСН», etc.).

Like the substituents for the alkyl radical, the substituents for the aryl and heteroaryl groups can be different and are selected from, for example: halogen, -OK, 50, -MK, -M-OK, -MA'K", -5K, -halogen, -5IK "KK", -OFOJ, -5(OJK, -SOZH, -SOMAyaK", -OS(OMAvK", -MA"E(), 0 -MK-S(OMA"TK", 0 -MA"E (O»K, -MA-S(MA' "KM", -MAK-S(MA'K"Z-MA", -B(O), -5(0)", -5(0)2MA' K", -MKBO»K, -SM Her -MO", -K, -M3, 2о 7 СН(РМ)2, fluoro(Ci-Cd)alkyl and fluoro(C.--C/)alkyl in the amount of zero to the total number of open valences on the aromatic ring; and where KK, KK", AK" Her Kk" are preferably independently selected from hydrogen, (C.i-Cv) alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl) -(C.--C.sub.1)alkyl and (unsubstituted aryl)oxy(C.-C.sub.1)alkyl. In the case when the compound according to the present invention contains more than one group K, then, for example, each of the groups K is independently selected as each of the groups KK, K", K" and Kk", when there are more than one of these groups.

As used here, the term "body fat loss" refers to the loss of a portion of body fat. and)

Body mass index (BMI: Vodu Magzz Ipdeh) is determined by the formula: |weight in pounds / height in inches / height in inches) x703. Limit values of BMI for adults are fixed numbers that are established regardless of age and gender according to the following norms: an adult with excess weight is characterized by BMI values from 25.0 to 29.9; an obese adult is characterized by BMI values of 30.0 or more; an adult with reduced weight is characterized by BMI values less than 18.5. For adults with a normal body weight, BMI indices lie in the range from 18.5 to 25. Limit values of BMI for children under 16 years of age (Ge) are determined according to percentiles: overweight is characterized by BMI values for the age of the 85th percentile, and obesity characterized by BMI values for the age of the 95th percentile. Underweight is characterized by the values of VMI for age "5th percentile. Normal body weight for a child is characterized by i- values of BMI for age above the 5th percentile and below the 85th percentile.

The term "fatty acid oxidation" refers to the conversion of a fatty acid (eg, oleate) to ketone bodies. "

The term "hepatocytes" refers to cells derived from liver tissue. Hepatocytes can be freshly isolated from liver tissue or established cell lines. - c The term "modulate" means to cause a change, including an increase or decrease (eg, a modulator of fatty acid oxidation increases or decreases the rate of fatty acid oxidation). "» The term "muscle cells" refers to cells derived from the dominant cells of a given muscle tissue. Muscle cells can be freshly isolated from muscle tissue or established cell lines.

The term "obese" means that the body weight is 2095 times greater than the ideal body weight, determined by the body mass index. -1 The term "oleoylethanolamide" (OEA) means a natural lipid that has the following structure:

In the formulas given here, "Me" means a methyl group.

The term "weight loss" means the loss of part of the total body weight.

As used herein, the term "pharmaceutically acceptable carrier" includes all standard 59 pharmaceutical carriers, buffers, and excipients, including phosphate-buffered saline, water, and

GF) emulsions (such as oil-in-water or water-in-oil) and various types of wetting agents and/or 7 adjuvants. Suitable pharmaceutical carriers and their compositions are described in KEMIMOTOMYE RNAKMASEISHTISAY 5SIEMSE5 (Mask Rybiizpipud So., Eaviop, 1917 ey. 1995)). The selection of the best pharmaceutical carriers depends on the chosen method of administration of the active agent. Typical input methods are described below.

The term "effective amount" means a dose sufficient to produce the desired result. The desired result can be a subjective or objective improvement of the condition of the recipient of a given dose. A subjective improvement may be a decrease in appetite or food cravings. An objective improvement may be a decrease in body weight, body fat mass, food intake or food consumption, or behavioral signs of reduced food seeking. ve The term "prophylaxis" means preventive treatment prescribed to a patient who does not show signs of the disease or shows only early signs of it, with the aim of reducing the risk of developing a pathology associated with weight gain or body fat mass. The compounds according to the present invention can be prescribed for prevention in order to prevent unwanted weight gain.

The term "therapy" means treatment prescribed to a patient exhibiting signs of a pathology in order to reduce or eliminate these pathological signs.

The term "weight management" refers to the loss of body weight or the reduction of body weight gain over time.

The methods, compounds and compositions of the present invention can generally be used to reduce or regulate fat mass and body weight in mammals. For example, the methods, compositions, and compounds of the present invention are useful in reducing appetite or inducing hypophagia in mammals. These methods, compounds, and 7/0 Compositions are also useful in preventing or alleviating diseases associated with being overweight or obese by promoting the loss of body fat and weight.

The methods, compounds and compositions of the present invention include modulators of lipid metabolism and, in particular, catabolism of fats and fatty acids.

Compounds of the present invention

Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. The scope of this invention also covers racemates, diastereomers, geometric isomers and individual isomers of the proposed compounds.

The compounds of the present invention can be separated into diastereoisomeric pairs of enantiomers, for example, by fractional crystallization from a suitable solvent such as methanol or ethyl acetate or a mixture thereof.

The pair of enantiomers obtained in this way can be separated into individual stereoisomers by conventional means, for example, an optically active acid as a resolving agent.

Alternatively, any enantiomer of such a compound of the present invention may be obtained by stereospecific synthesis from optically pure starting materials of known configuration.

The compounds of the present invention may have unnatural ratios of atomic isotopes of one or more of their atoms. For example, compounds can be radiolabeled with isotopes such as tritium or carbon-14. All isotopic variants of the compounds of this invention, whether or not they are radioactive, are encompassed within the scope of this invention.

The proposed compounds can be isolated in the form of their pharmaceutically acceptable addition salts of acids, such as salts obtained from inorganic and organic acids. Such acids may include hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, oleic, succinic, malonic and other acids. In addition, certain compounds containing an acidic functional group can have the form of their c inorganic salt, in which the counterion can be selected from sodium, potassium, lithium, calcium, magnesium, etc., as well as He from organic bases. The term "pharmaceutically acceptable salts" means salts obtained from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. -

The present invention also covers prodrugs of the proposed compounds, which, after their introduction, undergo chemical transformation as a result of metabolic processes before becoming active pharmacological substances. In general, such prodrugs are derivatives of the compounds of the present invention that are readily converted into functional compounds of the invention. Generally accepted methods of selection and preparation of appropriate derivative prodrugs are described (for example, in "Oevidp oyi Rgodgydv", ey. N. Vypadaaga, "

Eisemov, 1985). The invention also covers active metabolites of the proposed compounds. from p. A. Fatty acid alkanolamides, their homologues and analogs

The compounds according to the present invention include alkanolamides of fatty acids, which reduce body fat mass, and? including fatty acid ethanolamides and their homologues and some fatty acid alkanolamide analogues. Such compounds can be identified and determined by their ability to cause a decrease in appetite, food intake and/or body weight or body fat mass after their administration to experimental animals ip mimo. -I The invention provides various variants of such alkanolamides of fatty acids, their homologues and analogues. Therefore, this invention covers compounds described by the following general formula:

F Жоон юю 50 ей ий и Й 1 чщ и т.

In this formula, H takes values from 0 to 5, and the sum of a and b can be from 0 to 4; 7 is a member selected from -F(O)M(B2)-, -"K2)MS(O)-, - OS(O)-, --FOSO-, O, ME: and 8, where B: and K2 is independently selected from the group consisting of unsubstituted or substituted alkyl, hydrogen, substituted or unsubstituted C.1-C6 alkyl, substituted or unsubstituted lower (C.4-C6) acyl, homoalkyl, and aryl; up to four hydrogen atoms as a fatty acid, and (F. alkanolamine (for example, ethanolamine) component of the compound can also be replaced by methyl or

GI double bond; in addition, the molecular bond between carbon atoms c and y can be unsaturated or saturated. In some embodiments, the fatty acid ethanolamide according to the above formula is a compound of natural origin.

Among the compounds according to this invention are also those described by the formula:

In one of the variants of the implementation of the invention, the compounds according to the formula Ia have n from 0 to 5, and the sum of their and 6 is from 0 to 4; members B' and K2 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C4-C6 alkyl, substituted or unsubstituted lower (C4-C6) acyl, homoalkyl, and substituted or unsubstituted aryl. In this embodiment, up to four hydrogen atoms of the fatty acid component and the alkanolamine (for example, ethanolamine) component of the compounds of the above formula may also be substituted with methyl or a double bond. In addition, the molecular bond between carbon atoms c and a can be unsaturated or saturated. In some embodiments, with acyl groups, these acyl groups can be acetic, propionic, or butyric acids, and can be attached through an ester bond such as B or through an amide bond such as B.

In another embodiment of the present invention, the above compounds include, in particular, those in which the fatty acid component includes oleic acid, elaidic acid, or palmitic acid. Such compounds include oleoylethanolamide, elaidylethanolamide, and palmylethanolamide. t Her, too

In another embodiment of the invention, the compounds of formula Ia have n from 1 to 3, and the sum of their and 6 is from 1 to 3; members B' and B2 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 4 -C 6 alkyl, and substituted or unsubstituted lower (C 4 -C 6 ) acyl. In this embodiment, up to four hydrogen atoms of the fatty acid component and the alkanolamine (for example, ethanolamine) component of the compounds of the above formula may also be substituted with methyl or a double bond. with

In addition, the molecular bond between carbon atoms c and y can be unsaturated or saturated. In another embodiment, the molecular bond between carbon atoms c and y is unsaturated, and none of the other hydrogen atoms is substituted. A variant of implementation is also possible in which members K" and K2 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 41-C3 alkyl and substituted or unsubstituted m 2 lower (C.4-C3) acyl.

Monomethyl-substituted compounds, including ethanolamides of formula Ia, are typical. Among such compounds. SM belong to: (Se)

She ey so Vii - h-me pan still o . ,» She you a "| I Penya ime) sh- 60 s Sh

Methyl-substituted compounds according to the above formulas include, in particular, compounds in which

IN! Its 2 are both H: (KK)-methyloleoylethanolamide, (5)1-methyloleoylethanolamide, (K)2-methyloleoylethanolamide, because (5)2-methyloleoylethanolamide, (K)1-methyl oleoyl ethanolamide and (5)1-methyloleoylethanolamide .

Reverse OEA-like compounds

Among the compounds according to the present invention are also numerous analogues of OEA. They include the reverse BOTH compounds described by the following general formula: both of them V Yari eshche" with 70 In some variants of implementation of the invention, compounds of formula II are offered. Typical compounds of formula I have n from 1 to 5, and the sum of their a and 6 is from 0 to 4. In this embodiment, member b2 is selected from the group consisting of hydrogen, substituted or unsubstituted C 4 -C 4 alkyl, substituted or unsubstituted lower (C4-C6) acyl, homoalkyl and aryl. In addition, up to four hydrogen atoms of both the fatty acid component and the alkanolamine (for example, ethanolamine) component of compounds according to /5 of the above formula can also be replaced by methyl or a double bond.

Typical compounds according to formula II include those in which the alkanolamine component is ethanolamine, compounds in which vk: eHn, and compounds in which a and 5 are each 1, as well as compounds where n is 1.

In one of the variants of implementation of the invention, the compound according to formula II is 7 me

In another embodiment, the compounds of formula II have n from 1 to 5, and the sum of their a and 5 is from 1 s 25 y y y y y to 3. In this variant, the member ВЕ? is selected from the group consisting of hydrogen, substituted or unsubstituted C41-C80) alkyl and substituted or unsubstituted lower (C1-C8) acyl. In addition, up to four hydrogen atoms of both the fatty acid component and the alkanolamine (for example, ethanolamine) component of the compounds according to the above formula can also be replaced by methyl or a double bond. m zo Oleoylalkanol esters

The compounds according to the present invention also include oleoylalkanol esters described by the following general C formula: (Ce) 35 ! well -

In some embodiments, the compounds of formula I have n from 1 to 5, and the sum of their a and 6 is from 0 to 4. Member KE? they are selected from the group consisting of hydrogen, substituted or unsubstituted C.4-Cv alkyl, substituted or unsubstituted lower (Ci-Cv) acyl, homoalkyl and aryl. In addition, up to four hydrogen atoms of both the fatty acid component and the alkanolamine (for example, ethanolamine) component - t0 compounds according to the above formula can also be replaced by methyl or a double bond. c In other embodiments, compounds of the formula ІІ have H from 1 to 3, and the sum of their a and 6 is from :z» 1 to 3. Member KE? they are selected from the group consisting of hydrogen, substituted or unsubstituted C.4-Cv alkyl and substituted or unsubstituted lower (C4-Ce5) acyl. Up to four hydrogen atoms of the fatty acid component and the alkanolamine (for example, ethanolamine) component of the compounds according to the above formula can also -1 be replaced by methyl or a double bond.

Compounds described by formula II include such compounds in which EC 2 is H, compounds in which 5 is - 1, and compounds in which n is 1. Examples of compounds according to formula II include oleoyldiethanol ester:

Me, edshe t vish shi shi. her choice and and A and sha and "I g

Compounds of formula III also include monomethyl-substituted oleoylethanol esters, such as (K or 5)-2-methyloleoylethanol esters, (k or Z)-1-methyloleoylethanol esters and (k or 5B3) 1-methyloleoylethanol esters. respectively: name) 60 b5 крб с ИН. y v o a y y ay y tv vyh mes sce, r NI ЗB ba sche y o zhiv y ot. kerosene

Eat ov U and

Oleoylalkanol ethers

The compounds according to the present invention also include oleoyl alkanol ethers, which are described by the following general formula:

KY rr and Adm. Chon

She BZ shock

What else?

Place;

In some embodiments, compounds of formula IM have n from 1 to 5, and the sum of their a and 5 can be from 0 to 4. Member B2 is selected from the group consisting of hydrogen, substituted or unsubstituted C 4-Ce alkyl, substituted or unsubstituted lower (C.4-Cv) acyl, alkyl and substituted or unsubstituted aryl. Up to four hydrogen atoms of both the fatty acid component and the alkanol (for example, ethanol) component of compounds according to the above formula can also be replaced by methyl or a double bond.

In other embodiments of the invention, the compounds according to the formula IM have n from 1 to 3, and the sum of their a and 5 can be from 1 to 3. their BC member? is selected from the group consisting of hydrogen, substituted or unsubstituted C.4-Cv M zo alkyl and substituted or unsubstituted lower (C.4-Cv) acyl. Up to four hydrogen atoms of both the fatty acid component and the alkanol (for example, ethanol) component of compounds according to the above formula c can also be replaced by methyl or a double bond. Ge

The number of compounds according to the formula IM includes such compounds in which B. 2? is H, compounds in which both b is 1, and compounds in which n is 71. Examples of compounds described by the formula IM include (KK or 5)-1-oleoylethanol ethers and (K or 5)-2' - oleoylethanol ethers: - о сей свт и ве " , ме - - Analogues of alkanolamides of fatty acids with variants of the polar head part -1 The number of compounds according to the present invention also include numerous analogues of OEBA with polar head parts. These compounds include those that have a fatty acid component, described by the general formula b"

In some embodiments, compounds of formula M have the sum of a and B from 0 to 4. In other embodiments

HF) the implementation of the sum of a and 6 is from 1 to 3. In these variants, up to four hydrogen atoms of compounds according to the above formula can also be replaced by methyl or a double bond. In addition, the molecular bond between carbon atoms c and y can be unsaturated or saturated. In a particularly preferred embodiment, the fatty acid component is oleic acid: 60 and 65 The KZ group in the above structures can be selected from the following groups:

HO-(CHO),MH-, where 72 is from 1 to 5, and the alkyl component is an unbranched methylene chain.

Example:

NaMm-(СНо),-МН-, where 72 is from 1 to 5, and the alkyl component is an unbranched methylene chain.

For example: 70 HO-(CHOo)X-MH-, where X is from 1 to 8, and the alkyl component can be branched or cyclic. Example, "

Additional main polar groups of KZ can be, for example, compounds containing furanic, dihydrofuranic, and tetrahydrofuranic functional groups: ad

In the above structures, 2 can be from 1 to 5.

The compounds according to the present invention include, for example, those having the main polar groups of KZ based on pyrrole, pyrrolidine or pyrroline rings: сч 7 С о

From | high school

In the above compounds, 7 can be from 1 to 5.

Other examples of the main polar groups include various imidazoles and oxazoles, for example: (Se)shi and -

In compounds with the above structures, 7 can be from 1 to 5.

Typical main polar groups are also oxazolpyridines: neck Я De ой в с фе: в! zah, se zve i I i t i ai y . i ai ki and s. and and -1 Analogues of fatty acid alkanolamides having apolar tail variants

The compounds of the present invention include numerous alkanolamides and ethanolamides having diverse and flexible apolar tails. These compounds include those having formulas where K is an ethanolamine component, an alkanolamine component, or their stable analog. In the case of ethanolamine, the ethanolamine component is preferably attached through its nitrogen atom, and not through its oxygen atom:

There is nothing but poison 65 There is still g y

In the above structures, t is from 1 to 9 and p is independently from 1 to 5.

A typical compound is:

Another typical compound is an ethanolamine analogue with an apolar tail, having the following structural formula: 70 B ne (I

Typical compounds include alkanolamide analogs of fatty acids. Such analogs may include the compounds disclosed in US Pat. No. 6,200,998 (incorporated herein by reference). The compounds described in this source have the following general formula: o

In the above formula according to |(US Patent Mob,200,998) Ag" is (1) arylene or (2) heteroarylene, where arylene and heteroarylene are optionally substituted with 1-4 groups selected from KU; Ag? is (1) ortho substituted aryl or (2) ortho-substituted heteroaryl, wherein said ortho-substituent is selected from K; aryl and heteroaryl are, in addition, optionally substituted 1-4 groups independently selected from KU; X and M are independently O, 5, m-c ? or CH"; 7 is O or 5; n is from 0 to 3; K is (1) C3 alkyl optionally substituted with 1-4 groups selected from halo and C3 6 cycloalkyl, (2) C3. 4o alkenyl or (3) C3 8 cycloalkyl; KZ is (1) C..45 alkanoyl, (2) C 45 He alkyl, (3) Sov alkenyl, (4) Sov alkynyl, (5) halo, (6) OB , (7) aryl or (8) heteroaryl, where said alkyl, alkenyl, alkynyl and alkanoyl are optionally substituted 1-5 groups selected from K 7, and said aryl and heteroaryl are optionally substituted with 1-5 groups selected from K 9; B? is (1) hydrogen, (2) Si4o alkyl, (3) Co10 and - alkenyl, (4) Co o alk inyl, (5) aryl, (6) heteroaryl, (7) aryl C..45 alkyl, (8) heteroaryl C. 45 alkyl, (9) C. 45 alkanoyl, (10) Czv cycloalkyl, where alkyl, alkenyl, alkynyl is optionally substituted 1-4 substituents independently selected from KU, and cycloalkyl, aryl and heteroaryl are optionally substituted 1-4 substituents independently selected from KU; or B: is (1) halo, (2) aryl, (3) heteroaryl, (4) CM, (5) MO", (6) OB; (7) 5(O)tpv, then - 70 4 or 2, provided that В! is not H when t is 1 or 2; (8) MAV", (9) MASS, (10) Mv'SOovi, (11) MV'sSOM(B to, (12) s MAV /802B! provided that B! is not H, (13) SELF , (14) SOBI, (153 СОМ(ВО», (16) 802М(2Д», (17) OSOM(КО», or :з» (18) C3.8 cycloalkyl, where the specified cycloalkyl, aryl and heteroaryl are non-observed by optionally substituted 1-3 halo or C 1-6 alkyl groups; BZ is (1) a group selected from B, (2) C 1-4o alkyl, (3) C 1-4o alkenyl, (4) C 1-4o alkynyl , (5) aryl C 40 alkyl, or (6) heteroaryl C 1-10 alkyl, where alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted by a -I group independently selected from Ke; K is (1) halogen . aryloxy; B is (1) hydrogen, (2) C1-40 alkyl, (3) C1-40 alkenyl, (4) C1-40 alkynyl, (5) aryl, (6) heteroaryl, (7) aryl C ..45 alkyl, (8) heteroaryl C..45 alkyl, (9) C..45 alkanoyl, (10) Cz 8

Ge) cycloalkyl; wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkanoyl and cycloalkyl are optionally substituted with 50 1-4 groups selected from KU.

Analogues disclosed in US Patent No. 5,859,051 are also better. These analogues have the following general formula: "chi a Y shchi ЖИ shi shi vasye y vv.

GF) In the implementation options corresponding to the formula MI! according to US Patent No. 5,859,051), КВ" is selected from the group consisting of H, C 46 alkyl, C 40 aryl, and C 30 heteroaryl, wherein said alkyl, aryl, and o heteroaryl are optionally substituted 1-3 K2 groups ; ЕК" is selected from the group consisting of: H, C 445 alkyl, Сов alkenyl, Соч5 alkynyl and С34о cycloalkyl, where the specified alkyl, alkenyl, alkynyl and cycloalkyl are 60 optionally substituted 1-3 K 2 groups; KZ is selected from the group consisting of: H, MNE", Shacylu, C-45 alkyl, C3-40 cycloalkyl, C4-45 alkenyl, C4-45 alkoxy, CO" alkyl, OH, C45 alkynyl, C3-40 aryl, C10 heteroaryl, where the indicated alkyl, cycloalkyl, alkenyl, alkynyl, aryl, and heteroaryl are optionally substituted 1-3 CZ groups; (7-MU-) is 7-СВОВ "-, 7-СН -СН- or: b5

BZ is selected from the group consisting of CE 9", 0, MA5 and 5(O)p; 9 and KK" are independently selected from the group consisting of H, C..6 alkyl; B is selected from the group consisting of: 1) a 5- or b-membered heterocycle containing from O to 2 double bonds and 1 heteroatom selected from the group consisting of O, 5 and M, and the heteroatom is substituted in any position of a five- or six-membered heterocycle, and the heterocycle is optionally unsubstituted or substituted by 1-3 KU groups; 2) a 5- or b-membered carbocycle containing from 0 70 to 2 double bonds, where this carbocycle is optionally unsubstituted or substituted by 1-3 K 2 groups in any position of the five- or six-membered carbocycle; and 3) 5- or b-membered heterocycle containing from

O to 2 double bonds and C heteroatoms selected from the group consisting of O, M, and 5, which are substituted at any position of a five- or six-membered heterocycle, the heterocycle being optionally unsubstituted or replaced by 1-3 groups of KU; X! and X? independently selected from the group consisting of: H, OH, C 45 alkyl, C 40 alkenyl, C 40 alkynyl, halo, OKU, OVSE»z, C 6 aryl, C 40 aralkyl, C 40 heteroaryl and C 40 acyl, where indicated alkyl, alkenyl, alkynyl, aryl and heteroaryl are optionally substituted 1-3 KU groups; Ka is a member selected from the group consisting of: halo, acyl, aryl, heteroaryl, CEz, OSE3, -O-, CM, MO", VU,

Ov; 883. are optionally substituted 1-3 halo or C1-6 alkyl groups; XM is selected from the group consisting of: 5(О) р, -СН»-, -Ф0)-, -ФО)МН-, -МК-, -О-, -502МН-, -МНВО»; M! selected from the group consisting of: O and C; 7 selected from the group consisting of: SO KU,

VZCO283, SOMNZOoMe, SOMNOO», SOMN» and 5-(1H-tetrazole); and M are independently 0 or 1, so that Y-M-1; 0 is a saturated or unsaturated straight-chain hydrocarbon containing 2-4 carbon atoms, and p is 0-2 provided that when 2 is CO and B is a 5-membered heterocycle consisting of O, then BZ is not methyl. d)

In addition, analogs suitable for use in the proposed methods and compositions may be compounds disclosed in US Patent Nos. 5,847,008, 6,090,836 and 6,090,8391, incorporated herein by reference in their entirety to the extent not inconsistent with this invention.

In addition, a number of suitable analogs are disclosed |in US Patent Mob,274,608)|. Aryl-(i-heteroaryl-acetic acid and oxyacetic acid analogs are described, (for example, in US Patent Mob, 160,0001; c-substituted 5-aryl-2,4-thiazolidinedione analogs are described | in US Patent Mob, 200,998); others are also known possible analogues such as polyunsaturated fatty acids and eicosanoids, |see, for example, Bogtap, VM, Spep, ./, apa re)

Emapz KM, RMAZ 94: 4312-4317). The compounds described in these publications (incorporated herein by reference in their entirety to the extent not inconsistent with the present invention) may be prepared by the methods described below

Zo to obtain compounds that could be used to reduce body fat mass and weight, modulate fat catabolism and reduce appetite according to this invention.

Synthesis of alkanolamides of fatty acids

Compounds suitable for use in accordance with the present invention can be readily synthesized and purified using methods generally accepted in the art. According to a typical synthesis scheme (Scheme 1), the reaction of a carboxylic acid with an amino alcohol (or its O-protected derivative) is carried out in the presence of a dehydrogenating agent, for example, dicyclohexylcarbodiimide in a suitable solvent. Fatty acid alkanolamide is isolated using an appropriate method, for example, extraction, crystallization, precipitation, chromatography, etc. If the final product is an O-protected adduct, it is usually deprotected using a generally accepted method, and a fatty acid adduct containing a free hydroxyl group is obtained.

CUP and

It is well understood by a person skilled in the art that numerous variants of the above scheme are possible.

Me. For example, an active derivative such as an acyl halide, active ester, etc. can be used. ko 20 Similarly, a glycol (preferably mono-O-protected) can replace an amino alcohol with the formation of an ester bond between these two components of the molecule. "m Reverse esters and reverse amides are also easily synthesized using well-known methods.

For example, the reaction of an oxycarboxylic acid with an amino or hydroxyl derivative of a long-chain alkyl (i.e. C./-Co") in the presence of a dehydrogenating agent can be used for this purpose. In the process of some reactions, it is desirable to protect the hydroxyl part of the oxycarboxylic acid.

GF) Ethers and mercaptans are obtained using methods well known to specialists in this field, for example, by synthesis by the Williamson method (UmPShiatvzgop). To do this, for example, a long-chain alkyl alcohol or a thiol is deprotonated with a base (for example, Mann) and the active alcohol derivative, for example, halo, tosyl, mesyl alcohol, or its protected derivative is reacted with the resulting anion to form an ester or 60 mercaptan.

The above-mentioned methods and their variants are described,

Asia Oegimaime5, Kpoipe S, ey. Ateg. OII Spetiv Bosieiu 1999; Sotrgepepzime Maishiga!| Rhodysiv Spetivigu apa OSheg BbBesopdaagu Meijaroiyevz Ipsitsdipd Ranu Asidz apa TNeig Oegimaimez5, MaKapizpi K, eid., Regdatop

Rgezv, 1999; Ogdapis Zupipevziz SoPesiei Moishtev I-M, doyp UMPeu apa ope; Sotrepaisht oi Ogdapis Zupipeis bo Meijyodz, Moitsevs 1-6, MUPeu Ipiegesiepse 1984; Ogdapis EBypsyopa! Sgoir Rgeragayop, Moishtez I-II, Asadetis

Rgezz Tsa. 1983; Sgeepe T, Rgoiesiipd sSgoishrz ip Ogdapis Zupipeviv, 2a ed., UMieu Ipiegzsiepse 19911.

Methods of application, pharmaceutical compositions and their administration

Methods of application

Compounds, compositions and methods according to the present invention (for example, fatty acid alkanolamides, fatty acid ethanolamides, their analogues and homologues) are used to reduce fat mass and body weight in mammals, including dogs, cats and, especially, humans. Weight loss can be done for aesthetic or therapeutic purposes. The proposed compounds can also be used to reduce appetite or to induce hypophagia. 70 The compounds, compositions and methods of the present invention are used to prevent body weight gain or increase in body fat mass in humans and animals within the range of normal weight. These compounds can also be used in consumers who are otherwise perfectly healthy and do not require pharmacological intervention to treat diseases such as diabetes or hyperlipidemia or cancer. In some embodiments, the user of the proposed compounds may not have disorders related to 7/5 Chakra or lipid or metabolic disorders or risk factors for cardiovascular and cerebrovascular diseases. The consumer may not be diabetic and may have normal blood sugar levels.

The consumer may also have normal levels of lipids (such as cholesterol) or triglycerides in the blood. The consumer may also not have atherosclerosis. The consumer may also be free of diseases such as cancer and other tumors, diseases associated with insulin resistance, syndrome X and pancreatitis.

In other embodiments, the consumer is overweight or obese and needs to reduce body fat or weight. In these variants, the methods, compounds and compositions of the present invention can be prescribed to stimulate weight loss, as well as to prevent weight gain, if the body weight of the user of the given sex, age and height has been set within normal limits. The proposed compounds may be useful for healthy consumers who do not require any pharmacological treatment for diseases associated with diabetes, hyperlipidemia or cancer. The consumer may also not have risk factors for cardiovascular and cerebrovascular diseases. In other embodiments, consumers may not have diseases, i) related to sugar (for example, glucose) or lipid metabolism. The consumer may not be diabetic and have normal blood sugar levels. The consumer may also have normal levels of lipids (eg, cholesterol, NOI, HO, total cholesterol) or triglycerides in the blood. The consumer may not need M for the treatment of atherosclerosis.

The compounds, compositions, and methods of the present invention may also be used to suppress appetite in mammals, including cats, dogs, and humans. In some embodiments, the proposed compounds can be used by otherwise healthy consumers who do not require pharmaceutical intervention for a particular disease. In some embodiments, the consumer may not need preventive or curative therapy for diseases such as cancer, diabetes, or hyperlipidemia. In some embodiments, the consumer may not have diseases associated with abnormal sugar or lipid levels. In some embodiments, the consumer may have no risk factors for cardiovascular or cerebrovascular disease. The consumer may not be diabetic and may have normal blood sugar levels. The consumer may also have normal levels of lipids (such as cholesterol) or triglycerides in the blood. The consumer may not suffer from atherosclerosis. The compounds, compositions, and methods of the present invention can be used to modulate fat metabolism (eg, increase fat catabolism) in mammals, including cats, dogs, and humans. In some;" in embodiments, the proposed compounds may be used to reduce appetite by otherwise healthy consumers. In some embodiments, the consumer may not suffer from diseases related to sugar or lipid metabolism (eg, diabetes, hypercholesterolemia, low levels of NOI and high levels of GO). The consumer may not be diabetic and may have normal blood sugar levels. The consumer may also have normal levels of lipids (such as cholesterol) or triglycerides in the blood. A consumer may not have atherosclerosis. b The use of the compounds and compositions according to the present invention can last for a certain time, which is determined by the required degree and amount of weight loss or the achievement of the normal limits of the BMI index in the consumer. The use of the compounds and compositions of this invention may be reduced if the desired degree or amount of weight loss or normal BMI is achieved.

The compounds and compositions according to the present invention can be used only for the purpose of reducing body fat or appetite.

Pharmaceutical compositions

According to another aspect of the present invention, pharmaceutical compositions containing compounds of

F) this invention and a pharmaceutically acceptable carrier. The pharmaceutical compositions according to the present invention contain as an active ingredient a compound according to the present invention or a pharmaceutically acceptable salt thereof and may also contain a pharmaceutically acceptable carrier and, if necessary, also other pharmaceutical ingredients.

The invention provides compositions suitable for oral, rectal, local, parenteral (including subcutaneous, intramuscular and intravenous), ocular (eye), pulmonary (via nasal or intraoral inhalation) or nasal administration. At the same time, the most suitable way in a specific case may depend to a certain extent on the nature and severity of the condition to be treated, as well as on the nature of the active ingredient. The typical route of administration is oral. The proposed compositions may have a single dosage form and be prepared in any manner well known in the field of pharmacology.

In practice, compounds according to the present invention can be combined as active ingredients in homogeneous mixtures with pharmaceutical carriers according to conventional technologies for the preparation of pharmaceutical formulations. The carrier can take various forms depending on the form of the drug intended for administration, for example, oral or parenteral (including intravenous). In the preparation of compositions for oral dosage forms, conventional pharmaceutical media can be used, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, dyes, etc. in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions. The carrier can also be starch, sugar, 7/0 microcrystalline cellulose, solvent, granulator, lubricant, binder, disintegrant, etc., if the drug has a solid form intended for internal use, for example, the form of powder, solid or m any capsules or tablets. At the same time, solid oral preparations are more acceptable than liquid ones.

The ease of administration makes tablets and capsules the most acceptable forms of internal use of single dosage forms, in which, obviously, solid pharmaceutical carriers are used. If necessary, tablets can be coated using standard aqueous or anhydrous techniques.

Such compositions and preparations can contain at least 0.190 of the active compound. The percentage of active compound in such compositions may, quite understandably, vary from about 295 to 6095 by weight of the unit dose.

The amount of the active compound in such therapeutic compositions corresponds to the condition of providing a therapeutically effective dose. Active compounds can also be administered intranasally, for example, with the help of a spray or drops.

Tablets, pills, capsules, etc. may contain: a binding agent, for example, tragacanth, gum arabic, corn starch or gelatin; an excipient such as dicalcium phosphate; disintegrator, such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; a sweetener such as sucrose, lactose or saccharin. If the dosed drug is in the form of a capsule, according to the TO, it may contain, in addition to the above-mentioned materials, a liquid carrier such as liquid fat.

A variety of other materials may also be used in the preparations, such as coatings or i) modifiers of the physical form of the unit dose. For example, tablets can be coated with shellac, sugar, or both. A syrup or elixir, in addition to the active ingredient, may contain sucrose as a sweetener, methyl and propylparabens as preservatives, as well as a coloring and flavoring agent such as Corygent cherry or orange juice. To prevent destruction during passage through the upper part of the gastrointestinal tract, the composition may have an enteric coating. with

Introduction of Ge

The compounds of the present invention can also be administered parenterally. Solutions or suspensions of the proposed active compounds can be prepared in water in appropriate mixtures with surface-active substances such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and their mixtures with oils. Designed for normal conditions of storage and use, these preparations contain a preservative to prevent the development of microorganisms.

Pharmaceutical forms suitable for injections can be sterile aqueous solutions or dispersions and sterile powders for injection solutions or dispersions prepared for immediate use. In all "cases, such forms should be sterile and liquid enough to ensure the possibility of easy pt)s introduction of them using a syringe. They must be stable in the conditions of manufacture and storage, as well as protected from possible contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

The compounds of the present invention can be effective over a wide dosage range. For example, for -I adults, their doses can be approximately from 10 to 100 Ωg, from 100 to 50 Ωg or from 1 to 100 mg per day. Doses ranging from about 0.05 to 10 Ωg and preferably from about 0.1 to 100 mg per

Day The best doses of the proposed compounds range from about 0.1mg to 7Omg per day. Choosing

Depending on the appropriate regimen for a given patient, doses of approximately 2 to 7 mg per day may often be required, and when the patient's condition is under control, the dose may be reduced to approximately 0.1 to 100 mg per day. For example, in the treatment of adults, doses ranging from approximately 0.05 to 10 Ω, preferably from approximately 0.1 to 100 mg per day, can be used. The exact dose depends on the method of administration, the desired therapy, the form of administration of the drug, and the patient himself. and his body weight, as well as from the experience of the attending physician or veterinarian and the concepts they prefer.

In general, the compounds of the present invention may be dispensed in a unit dosage form, preferably containing from about 0.1 to 10 mg of the active ingredient together with a pharmaceutically acceptable (F) carrier per dose. Typically, dosage forms suitable for oral, nasal, pulmonary, or transdermal administration contain from about 0.001 mg to 10 mg, and preferably from about 0.01 mg to 5 mg, of the compounds mixed with a pharmaceutically acceptable carrier or diluent. For storage and use, it is desirable that these preparations contain a preservative that prevents the growth of microorganisms.

Administration of an appropriate amount of the prescribed compound can be by any well-known route, for example, oral or rectal, parenteral, intraperitoneal, intravenous, subcutaneous, intranasal or intramuscular. In some embodiments, transdermal administration of these compounds is used. The appropriate amount or dose of the prescribed compound can be determined empirically by a method according to generally accepted practice. An appropriate or therapeutic amount is an amount sufficient to cause a loss of body fat or a loss of body weight in the patient over time. The intended compound can be administered at a frequency necessary to achieve a loss of body fat or body weight, for example, every hour, every b, 8, 12 or 18 hours, daily or weekly.

Preparations for oral administration can be (a) liquid solutions, for example, of an effective amount

DOSES of nucleic acid suspended in a solvent, for example, in water, saline or RES 400; (5) capsules, sachets or tablets containing a certain amount of the active ingredient in the form of liquid, solid mass, granules or jelly; (c) suspensions in a suitable liquid; and (4) corresponding emulsions. Tableted forms may contain one or more of the following components: lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide 7/0, talc, magnesium stearate, stearic acid and other excipients. dyes, fillers, binders, solvents, buffering agents, preservatives, flavorings, dyes, disintegrants and pharmaceutically compatible carriers. Tablet forms can contain the active ingredient in a corrigent, for example, sucrose, and also take the form of pastilles containing the active ingredient in an inert base, such as gelatin and glycerin or emulsions of sucrose and gum arabic, gels, etc., containing, in addition to of the active ingredient, generally accepted in pharmacological practice noses.

Solutions and suspensions for injections can be prepared from sterile powders, granules and tablets of the above type. Preparations for parenteral administration, for example, intra-articular, intravenous, intramuscular, intradermal, intraperitoneal and subcutaneous, contain aqueous and non-aqueous, isotonic sterile solutions for injection, which may include antioxidants, buffers, bacteriostatic substances and solutes, which make the drug isotonic with the patient's blood, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents, solubilizers, thickeners, stabilizers and preservatives.

The methods of transdermal administration of medicines are described in (Ketipdiopye RNagtaseciisa! Zsiepsev, 171

Edikop, (Seppago eyi a). Eaz., Mask Rybiizpipd So., 1985)). The preferred means for transdermal delivery of the compounds of this invention are dermal or epidermal patches. Such plasters should have an absorption enhancer such as OM5O to increase the absorption of the proposed compounds. Other methods of i) transdermal drug delivery are described in US Patent Nos. 5,962,012 and 6,261,595), incorporated herein in their entirety by reference.

Patches that regulate the rate of delivery of medicine to the skin can be named among the best. Patches can have a variety of dosing systems, including a reservoir system or a monolithic system.

The reservoir system can, for example, have a four-layer structure, which consists of: an adhesive layer that is in direct contact with the skin; regulating membrane, which regulates the diffusion of He molecules of the medication; a reservoir of drug molecules and a water-resistant base. Such a structure allows to deliver the medicine in a uniform amount during a certain time at a speed lower than the saturation limit of different types of skin. uh-

A monolithic patch design can consist, for example, of only three layers: an adhesive layer; polymer matrix containing this compound; and waterproof base. Such a structure ensures the delivery of a saturating amount of medication to the skin. At the same time, the speed of delivery is regulated by the skin itself. If the amount of medicine in the patch decreases below the saturation level, the rate of delivery decreases. "

The compounds of the present invention may be used in combination with other compounds of the present invention or with other medicaments useful in dietary therapy or treatment, prevention, suppression or improvement of body fat mass. Such medicines can be administered in the usual way for them;" and in conventional amounts simultaneously or sequentially with the compounds of the present invention. If the compound according to the present invention is simultaneously used with another medication or medications, it is preferable to use a pharmaceutical composition in a single dosage form containing this medication and the compound according to the present invention. When used in combination with other active ingredients, the compound of the present invention and other active ingredients can be used in smaller doses than when they are used separately.

Ш- Accordingly, the pharmaceutical compositions according to the present invention may contain, in addition to the compounds described above, another active ingredient or ingredients.

Identification of compounds of the present invention o Compounds of the present invention according to the above can be obtained for their use by methods well known in the field. For example, compounds for reducing body fat can be identified by animal bioassays using methods well known specialists in this field. At the same time, the tested compounds and corresponding control carriers or caloric control drugs can be administered to the subjects of the experiment by any of the known routes (for example, oral or parenteral) with monitoring of the obtained results during the course of therapy. this is people or

F) experimental animals (for example, rats, mice). ka The effect of a given compound on appetite or inducing hypophagia or reducing food intake can be assessed, for example, by monitoring the food intake of test subjects (for example, by measuring the amount of food consumed or not consumed by the subject of the experiment in units of weight or calories). The effect of these compounds on appetite can also be evaluated subjectively, including surveys regarding the appetite or food cravings of people who are the subjects of the experiment. The effect of the tested compounds on lipid metabolism can be evaluated by monitoring blood lipids and fatty acid oxidation. The methodology of such assessments is well known to specialists in this field. Based on the duration of drug administration, such studies can be acute, 65 subacute, chronic or subchronic and/or follow the effect of drug use.

Reduction in body fat mass can be determined, for example, by directly measuring changes in animal fat mass or by measuring changes in animal body weight. The test animal can be selected from the group consisting of mouse, rat, guinea pig and rabbit. The experimental animal can also be the oB/or mouse, the ar/db mouse, the 2isKeg rat, and other animals used in weight-related medical research. Human studies can also be conducted.

Combinatorial chemical libraries

Recently, the use of combinatorial chemical libraries in creating keys to new chemical compounds has attracted the attention of researchers. A combinatorial chemical library is a collection of various chemical compounds created by chemical synthesis or biological synthesis by combining numerous chemical "building blocks" such as reagents. For example, a linear combinatorial chemical library of polypeptides is formed by combining a series of chemical building blocks called amino acids in all possible ways for a given length of compound (ie, the number of amino acids in a polypeptide compound). By such combinatorial mixing of chemical building blocks, millions of chemical compounds can be synthesized. For example, one reviewer observed that systematic combinatorial mixing of 100 interchangeable chemical building blocks /5 theoretically allows the synthesis of 100 million tetrameric compounds or 10 billion pentameric compounds

ISaiIor ei ai., U. Med. Spent 37(9): 1233(1994)|.

The method of preparation and screening of combinatorial chemical libraries is well known to specialists in this field.

Such combinatorial chemical libraries were created, for example, for benzodiazepines |US Patent Mo5,288,5141, different sizes such as hydantoins, benzodiazepines and dipeptides (Norr5 ei a, RMAB BA 90: 6909(1993)|, 2000 analog organic synthesis of libraries of small compounds | SNep eyi aYi., U. Ateg. Speth. Zos. 116: 2661(19941, oligocarbamates |СНО, eyi AYi., Zsiepse 261: 1303(1993)| and/or peptidylphosphonates (Satrbrei! eyi ai., 9. Oga.

Spent 59: 658(1994)| and libraries of small organic molecules, |see, for example, benzodiazepines (White SEM, suppl. 18, rade 33(1993)), thiazolidinones and metathiazanones (US Patent No. 5,549,974), pyrrolidines |US Patents

MoMo5,525,735 and 5,519,134), benzodiazepines (US Patent Mo5,288,514), etc. with

Devices for creating combinatorial libraries are commercially available, see, for example, 357 MR5, 390

MRB, Aduapsey Spet Tespi, I ocizmPe KMU, Zutriopu, Kaipip, MUorigp, MA, 43Z3A Arriiied Viozuvietv, Rovieg Syu, (8)

SA, 9050 Reeve, Miyiroge, Wedioga, MA).

Well-known robotic systems for solution-phase chemical processes were also developed. Among such systems are automated laboratory installations, similar to the automated synthesis apparatus, M. zo developed by the firm of TaKeda Spetis! Ipdyzilevz, I TO. (OzakKka, Udarap), and many robotic systems in which robot hands are used (7utaiye II, 7utagk Sogrogayop, NorkKipiop, Mazgv.; Ogsa, NemieyRaskKaga, Raio s

A, CA), which simulate manual synthesis operations performed by a chemist-operator. But none of the above Ge devices can be used in the present invention. For specialists in the relevant field, the methods and nature of those modifications that are necessary in the above-mentioned devices in order for them to -

Зз5 Could work according to the requirements of this invention. In addition, there are numerous combinatorial libraries that are commercially available, see, for example, Sotbzepeh, Rhipsefop, M.), Avipeh, Mozsomu, Ky, Tgirov, Ips., ZI.

Yi otsiz, MO, Spetbviag, Tsa., Mozsomu, KI, ZO RpagtaseciisaIv, Ehiop, RA, Mapek Viozsiepsevs, Soishtbia, MO, eis.).

High-throughput testing of chemical libraries

The tests of the compounds described here fully meet the conditions of high-throughput screening. Therefore, for "

Tests to detect activation of transcription (ie, activation of mRNA production) with a test compound (or compounds), activation of protein expression by a test compound (or compounds), or binding to a gene product (eg, an expressed protein) by a test compound (or compounds) are proposed. , with either a fatty acid modulating action, as described below.

High-throughput tests for the presence, absence or quantification of specific protein products or binding tests are well known to those skilled in the art. Therefore, in US Patent No. 5,559,410) high-throughput screening methods for proteins are described, and in US Patent Nos. No. 5,576,220 and 5,541,061 high-throughput screening methods for ligand/antibody binding are described.

Ш- In addition, high-throughput screening systems can be purchased commercially (see, for example, 7utagk

Ge» Sogr., Norkipiop, MA; Aegis Thesppis! Ipdivzigiev, Mepiog, ON; VesKtap Ipvigitepiv, Ips. AshPegiop, SA;

Rgesiviop Zuvietv, Ips., Mask, MA, eis.). In these systems, all processes are typically automated, including pipetting of samples and reagents, liquid dispensing, timed incubation, and final reading of the microplate in the detector(s) appropriate for the test data. These configurable systems provide high throughput and quick start, as well as a high degree of flexibility and adaptation to the consumer. Manufacturers of such systems supply detailed protocols of various high-throughputs. For example, the company 7utagk Sogr. supplies technical bulletins describing screening systems for the detection of modulation of gene transcription, ligand binding, etc.

F) Determination of the ability of compounds to influence food intake, body weight, body fat mass, appetite, food-seeking behavior or modulation of fatty acid oxidation

Compounds of the present invention can be administered to animals to determine whether they affect food intake, body weight, body fat mass, appetite, foraging behavior, or modulation of fatty acid oxidation.

For this purpose, obese and normal guinea pigs, rats, mice and rabbits can be used as experimental animals. Suitable rats for this can be, for example, 7isKeg rats, suitable mice can be, for example, normal mice, AI Z/ M, C3.5MUU-N-25/5p), (MOML YukhM2O/N19)E1, M2O/NITU, AGKLY, 65 MOMLU, KK.Sa-AAI VL, MOMLU, KK.Sa-AUL), Vvb.Ne5(VK8)-Srezuyu, Vb.129R2-sskIlEt vbM-I er,

VKV.Sa-ta/ yan er"Chry and C57VI /6.) with obesity caused by diet.

Administration of an appropriate amount of the test compound can be by any known route, for example, oral or rectal, parenteral, for example, intraperitoneal, intravenous, subcutaneous, subdermal, intranasal or intramuscular. The best method of administration is intraperitoneal or oral. A suitable effective amount of a test compound can be determined empirically, well known to those skilled in the art. A suitable effective amount may be an amount sufficient to effect loss of body fat, loss of body weight, and reduction of food intake over a period of time. The test compound can be administered at the frequency required to effect body fat loss or body weight loss, for example, hourly, every 6, 8, 12, and 18 hours, daily, or weekly. 70 Formulations suitable for oral administration include: (a) liquid solutions, such as an effective amount of the test compound suspended in solvents such as water, saline, or PE 400; (B) capsules, sachets or tablets, each of which contains a certain amount of the active ingredient in the form of liquid, solid mass, granules or gelatin; (c) suspensions in a suitable liquid; (4) suitable emulsions. Tableted forms may contain one or more of the following components: lactose, sucrose, /5 Mmannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid and other excipients, dyes , fillers, binders, solvents, buffering agents, wetting agents, preservatives, flavorings, dyes, disintegrants and pharmaceutically compatible carriers. Tablet forms can contain the active ingredient in a corrigent, for example, sucrose, and also have the form of lozenges containing the active ingredient in an inert

BASES, such as gelatin and glycerin or emulsions of sucrose and gum arabic, gels, etc., containing, in addition to the active ingredient, carriers generally accepted in pharmacological practice.

Solutions and suspensions for injections can be prepared from sterile powders, granules, tablets of the type described above. Preparations suitable for parenteral administration can be, for example, aqueous and non-aqueous isotonic sterile solutions for injections, which may contain antioxidants, buffers, bacteriostats, excipients that make the preparation isotonic with the blood of the recipient, and aqueous or non-aqueous sterile solutions , which may contain suspending agents, solubilizers, thickeners, stabilizers and preservatives. and)

The dose administered to the animal is sufficient to cause changes in body weight, body fat mass, and fatty acid oxidation over time. Such a dose can be administered according to the effectiveness of the specific test compound and the condition of the animal, as well as according to the body weight or body surface area of the animal. The size of the dose of M zo is also determined by the existence, nature and severity of harmful side effects accompanying the introduction of this compound; by the value of И О5о of the tested compound and its side effects in different concentrations. In the general case, the dose is 0.1-50mg/kg, better - 1-25mg/kg, and best if 1-20mg/kg of body weight. Ge's method of determining the dose-response relationship is conventional and well known to specialists in this field.

Reduction of body fat mass i-

Reduction in body fat mass is usually determined by direct measurements of changes in body fat mass or body weight loss. Fat mass and body weight of the animal are determined before administration, during administration and after administration of the test compound. Changes in fat mass are measured using well-known methods, for example, the method of measuring fat folds of the skin with a special tool, the method of bioelectrical impedance, the method of hydrostatic weighing, or the method of measuring the double absorption of X-ray radiation. In a preferred embodiment, the animals show at least 295, 595, 890, or 1095 suture loss per body fat mass. Changes in body weight can be measured using such well-known tools as portable scales, digital scales, lever scales, floor scales, table scales. In the best version, animals demonstrate, ;" at least 295, 595, 1095 or 1595 body weight loss. Body weight loss is measured before administration of the test compound and at regular intervals during and after treatment. In the best version, the weight of the white is measured every 5 days, even better - every 4 days, even better - every 3 days, even better - every 2 days and - and best - daily.

Changes in the metabolism of fatty acids w- Changes in the metabolism of fatty acids can be measured, for example, in the process of observing oxidation

He" of fatty acids in cells from the main tissues of fat burning, for example, from the liver (Veupep, ei ai., Oiare(ev 5o 28:828 (1979)), muscles |SNpiazvop Gar. Apai. oi Kai, (1980) ), heart (RipK, ek ai., U. Vioi. Spet. 267: 9917 yu (1992)) and adipocytes (Koarbei! U. Vioi. Spet. 239: 375 (1964)). Cells can be obtained from primary cultures or from cell lines. For primary cultures, cells can be prepared by any known method, such as enzymatic digestion and dissection. Suitable cell lines are well known to those skilled in the art. Suitable hepatocyte lines are, for example, Rao, MNI1S1, H-4-P-E, NATO, H4a-IPI-E-SZ3, Msa-KN7777, Msa-KNV994, M1-51

Evtsag, M1-51, AKI-6, Nera 1-6, Nera-1s1s7, VrkKa, (go VrkKa, MSTeS siope 1469 (MSTS clone 1469), RI S/RKRE/5, Ner 382.1-7 |Ner ZVI, Ner 02 |Nerbo2), 5K-NER-1, MUSN-17. Suitable skeletal muscle cell lines are (F, for example, 16, 18, C8, MOMK-10, VIGO-11, VSZNI, 0-7, 0-8, C2C12, P19, Zo18, 5OKNZO I(KM5 13) , OM. ka Suitable cardiac cell lines are, for example, HO9c2(2-1), P19, ССО-32 0, ССО-325К, bigagai, EVNE.

Suitable adipocyte lines are, for example, MSTS clone 929 | a derivative of strain I; 1-929; I -cells) |), MSTOS in 2971, I-M, I-M (TKU) MTK-; MKU), A9 (ARKT and NRKT negative derivative of strain I), MSTS clone 2472, MSTS clone 2555, 313-111, 926, y027-peo, 927-87, MTKR 97-12 rMro7T (TKMroe7-121, G-MOeS- 5HT2, CC-11, I-alpha-ib,

Y -alpha-2A, I -alpha-2C, 882.

The rate of oxidation of fatty acids can be measured by the oxidation of "C-oleate with conversion to ketone bodies". .). 287:487 (19823) and oxidation of "C-oleate with conversion to CO" 65 (Egoeriz RMAB 98:2005 (2001); Viagdtse ei aiYi., U. Meigospet 71: 1597 (1998)). Lipolysis can be measured by the release of fatty acid or glycerol using suitable labeled precursors or by spectrophotometric analysis (Zegtaadeii-I za! GEVZ I ey 415:150 (2000)). In the "C-oleate oxidation to ketone body assay, freshly isolated cells or cultured cell lines can be incubated with "C-oleic acid for an appropriate time, such as 30, 60, 90, 120, or 180 minutes. By measuring the amount of "C-radioactivity in the incubation medium, it is possible to determine the rate of their oleate oxidation.

Oleate oxidation can be expressed in nanomoles of oleate produced within X minutes per gram of cells.

In the lipolysis and glycerol release assay, freshly isolated cells or cultured cell lines are washed and then incubated for an appropriate time. The amount of glycerol released into the incubation medium allows you to determine the lipolysis index.

Examples

The following examples are purely illustrative and do not limit the present invention in any way. For those skilled in the art, the goal is obvious non-critical parameters that can be changed or modified to achieve virtually the same results.

Example 1. Synthesis of ethanolamides of fatty acids, their homologues and analogues

Methods of making fatty acid ethanolamides from ethanolamines and the corresponding fatty acyl are progressing relatively quickly and are well known to those skilled in the art. For example, fatty acid ethanolamides can be synthesized by reacting a fatty acid or a fatty acid chloride with an aminoalcohol, as described | Abavdii, M.,

Mp, 5. U., Tana, O., Ogiyip, S., Ziemepzop, I. A., Regimee, K. b. 5 McGiuappivs, A. U. Med. Spent 37, 1889-1893 (1994)). Fatty acids can be obtained in a similar way in the manner described by Zegdagemisn apa Saitoi | Zegdagemisn, V. b Satoii, K. K. 9. Iiriy Kev. 7, 277-284 (1966)). Radioactively labeled ethanolamides of fatty acids can be prepared by reacting acyl chlorides (My-Snesk Rger, EIuviap, MM) with | "With ethanolamine (10-30 C/mmol; Ategisap Cadioiarei Spetisaiiv, 51. I otsiv), as described (Oezagpatsa, R., Sadaz, N. " Rioteyi,

O. (1995) in Vioi Spent 270, 6030-6035) Compounds can be purified using flash column chromatography or high performance liquid chromatography (HPLC). The identity of the compounds can be established using NMR analysis and/or gas chromatography with mass spectrometry, as well as d) thin-layer chromatography.

Starting reagents and materials can be obtained from the companies Amapiia Roiag Iiridz, Sautap Spetisaiv (App Agrog,

MI), Mi-Spesk Rger, Kezeagsp Viospetisaiz, or Zidta. In a few words, according to the methods described

Sitsytida, A. ei ai. see Sishytida, A apa Rioteii, O. ip I irii besopi Mezzepdege (IausosK, 5.0. apa Kybip, - 20 VR. Edv. rr.113-133 SKS Rgezv IS, Vosa Kap, Riogida) and YuOemape ei a). (Oemape MU., Napyv, Y. ei ai., p

Zsiepse 258, 1946-1949 (1992)), unlabeled or labeled fatty acylethanolamines can be synthesized by reacting chlorides of the corresponding fatty acids with unlabeled or labeled ethanolamine. The chlorides of fatty acids are dissolved in dichloromethane (1 mg/ml) and reacted with ethanolamine at a temperature of 0-42C for 15 minutes. The reaction mixture is cooled by adding purified water. After intensive stirring, the phases are allowed to separate. The upper, aqueous phase is removed. The organic phase washed twice with water. At the same time, unreacted ethanolamine is removed. This method makes it possible to obtain fatty acylethanolamines in satisfactory quantities. These ethanolamines are concentrated to dryness in a stream of nitrogen and reconstituted in an organic solvent such as dichloromethane at a concentration of 200mmol. The resulting solution of fatty acylethanolamine can be stored at at a temperature of -202C before its use. The chemistry of carboxylic acid groups, primary and secondary amines, and primary alcohol groups of the fatty series is well known to specialists in this field. Ethanolamides of fatty acids with various substituents in the "z ethanolamine part" can be formed in many different ways, but it is best to use substituted ethanolamine and fatty acid as starting materials. Such substituted ethanolamines include alkylaminoethanol ethers and acylaminoethanol esters, as well as secondary alkylethanolamines. Alternatively, individual fatty acid ethanolamides can be synthesized from the corresponding fatty acid ethanolamides 7 by adding suitable substituent groups. -I Example 2. Methods of screening fatty acid ethanolamide (FAE) ip mimo and other compounds according to the present invention

Experimental animals. Male Umiviag rats (200-350g) were used. The methods used should meet the standards of the US National Institutes of Health (NIH), set out in the Guidelines for the Care and Use of Laboratory Animals, as well as the European Community Directive 86/609/EEC on the regulation of animal research.

Reagents. Compounds EAE and |NA) EAE were synthesized in the laboratory of |Sishiida ei ai., "Piriy Zesopa

Mezzepdege" (ie. IausposK, 5.05. 5 Kirip, K.R.) 113-133 (SKS Rgezv IS, Vosa Kap, RIY, 1998); 1,2-dioleyl-5p-glycerophosphoethanolamine-M-oleyl was purchased from the firm Amapii Royag I iriaz (AiIbravieg, AI); 59 ZK141716A was obtained from KVI (MayisK, MA) under the Spetis program!

GF) psychotherapy MIMN (USA) (МО1МНЗО0003); 5144528 was kindly provided by Zapoiyi KespegsNpe; all the rest

HF reagents were obtained from the company Tosgiz (VaYIMm/p, MO) or Zidt (Zaipi I otsiz, MO). HAE compounds were dissolved in dimethylsulfoxide (0OM5O) and administered in the composition of 70956 OM5O in sterile physiological solution (acute treatment) or 595 Tm'eep 80/595 propylene glycol in sterile physiological solution (subchronic treatment) (ml/kg, intraperitoneally). Capsaicin was administered in a mixture of 1095 Tmeep 80/1095 ethanol/8095 saline; 5ZK141716A, 5144528, SSK-8 and SR-93129 in a mixture of 596 Tmeep 80/595 propylene glycol/909o physiological solution (Iml/kg, intraperitoneally).

Enzymatic tests. In all biochemical experiments, rats were sacrificed and tissues collected between 1400 and 1600 h after varying periods of food deprivation. Microsomal fractions were 65 prepared (as described in JuOezagpatsa ei ai., 9. Vioi. Spet., 270:6030-6035 (1995)). MAT tests were performed,

using 1,2-di| as a basis "SI|palmityl-5/7-glycerophosphocholine (108mCi/mmol, Ategzyat, Rivsagamau,

MU) I(Sadavz ei ai., N., U. Meshygovsi, 17:1226-1242 (1997)). EAAN-tests were performed according to the method described by Oyuezagpatsa ei ai., 9. Vioi Speth., 270:6030-6035 (1995) with the exception that as a basis IZNIanandamide (arachidonyl-|(1-ZNIiethanolamide, bOoSi/mmol) was used; AKS, 5th Iotsib5, MO) and radioactivity was measured in the aqueous phase after chloroform extraction.

Chromatographic (NRI C) and mass spectrometric (M5) analyses. Plasma was prepared from blood obtained by cardiac puncture (Sishytida ei ai., ApaiYi. Biospet., 280:87-93 (2000), and C5E was collected from sysviegpa tadpa using a 270 1/2 needle (Rhesiopdiide, USA). Compounds EGAE and MARE were extracted from tissues with a mixture of methanol and 70 chloroform and fractionated using column chromatography

Mezzepdege" (Ey. HausposK, 5.0. 5 Kybrip, K.R.) 113-133 (SKS Rgezz IS, Vosa Kap, RI, 1998)). Quantitative evaluation of the GAE product was done with the help of NRIS/M5-analysis, using the dilution method isotopes

ISishytida ei ai., Apa! Viospet., 280:87-93 (2000)) MARE compounds were identified and quantified by species using NRI S/M5-analysis by the method of the external standard ISaiidpago ei ai., Mayte, 408:96-101 (2000).

Blood chemistry. B-Hydroxybutyrate and plasma glycerol were measured using industrial kits (firms

Zidta, 5. Iociz, MO). Prolactin, corticosterone, and plasma luteinizing hormone were quantified by radioimmunoassay (Mamaggo et al., Meshigogerogi, 8:491-496 (1997).

Feeding experiments. Acute experiments. Food intake was measured in rats from 24 hours. food deprivation (Mamaito ei ai.,9). Meygospet., 67:1982-1991 (1996)), administering medications 15 minutes before food is served. Subchronic experiments. Rats fed ai Irisht received vehicle injections for 3 days. On the fourth day, the animals were divided into two equal groups and received daily one group - injections of the carrier, and the other - OEA (5 mg/kg at 1900 h.) for 7 consecutive days with measurements of body weight, food intake and water intake.

Conditioned taste aversion. Rats were subjected to water deprivation for 24 hours, and then accustomed to drinking from a graduated bottle in ZOhv. trial period for 4 days. On the fifth day, the water was replaced with a 0.196% solution of saccharin, and ZOkhv. later, animals received injections of vehicle, OEBA (2Omg/kg) or lithium chloride (04mol, about 75ml/kg). During the next two days, water consumption was recorded in 3 min. trial periods. Afterwards, the animals were given water or saccharin and their intake was measured.

Effective response to food. Rats were trained to lift a lever press to obtain food under a fixed-ratio feeding schedule of 1 (EC) with the amount of food limited to 20g per rat per day. 5th issue, 20:1109-1114 (1999). As soon as a stable response was achieved, the animals were taught to accept feeding according to the EC5 schedule from 2 min. break and kept under conditions of limited access to food. see

When a stable baseline level was reached, the animals were used in tests for the effect of the vehicle or BOTH (1.5 « or 20 mg/kg), administered 15 min before their access to the lever. The duration of the tests was 2 min.

Other behavioral tests. The restlessness test in the cascade plus-maze was performed as described - Mamaito ei ai!., Meigogerogi, 8:491-496 (1997)), after the administration of vehicle or OEA (20Omg/kg, intraperitoneally). uh-

After 15 min. after injections of vehicle or OEA (20 mg/kg), horizontal activity was measured in an open field

Iveigato ei ai., U, Meshygovsi., 20:3401-3407 (2000)| and pain threshold in tests on a hot plate (55 C)

Iveigato ei ai., Zsiepse, 277:1094-1097 (1997). Rectal temperature was measured using a digital "thermometer". U. Rpagtasoi., 344:7 7-86. (1998).

Hybridization of IP Zyya. Rats were trained to the manipulation and injection procedure for 5 days. On the sixth - sth day, they were injected with the vehicle or the drug OEA (1Omg/kg, intraperitoneally), or oleic acid (1Omg/kg), and "through the bOhv. The animals were killed by decapitation under anesthesia. In the hybridization analyzes of i.p., Z58 probes were used -labeled RNA for s-yuz (Oshygiei ei aiYi., Rgos. Mai. Asad. Zsi. |I.5.A,., 90:3329-3333 (1993))| and choline acetyltransferase (SPAT) (I ashegrogp ei ai!., Vgaiip Kev. Moi! Vgaiip Kev., 17:59-69 (1993)). The average value of the hybridization density was determined from at least three tissue sections per rat. - Statistical significance was assessed by one-way analysis of variance (AMO) followed by a post hoc Tukey-Kramer (Tikeu-Kgateg) test for pairwise comparisons.

Data analysis. The obtained results are expressed in their average value 4 the average statistical extremum in individual experiments. Unless otherwise noted, the significance of differences between groups was assessed using the 20 AMOMA test followed by the Student-Newman-Keuls (Zishaepi-Mezhmtap-Ketsiv) post-hoc test.

Example 3. Effect of fasting on the level of OEA and other EAE in rats "m In one embodiment, the invention provides methods of treatment in which patients in need of weight and/or body fat reduction are tested for OEA levels before fasting and/or For patients with low OEA levels before or in response to fasting, treatment with OEA is particularly indicated.

HF) Rats were subjected to food deprivation with periodic measurement of RAE levels in heart blood using high-performance liquid chromatography (HPLC) together with electrospray mass spectrometry (M5). BOTH plasma remained at baseline levels during the first 12 hours of fasting, increased significantly in the period from 18 to 24 hours, and returned to normal levels after 30 hours (Fig. and). Such an effect was not observed 60 after water deprivation (Fig. 15) and the use of such stressogenic factors as immobilization and the introduction of lipopolysaccharide (GR) (|pmol/ml; 10.3-0.8; bOv. after 15 minutes of immobilization, 8, 4 -1.6; bOv after injection

IRB (Img/kg), 7.0-0.7; n-6-9). None of these treatments had a significant effect on plasma REA (data not shown), whereas after meal removal, anandomide decreased rapidly, remaining below baseline throughout the experiment (Figure 14). Anandomide levels also fell after immobilization (pmol/ml, control bo 3.6--0.4; immobilization 1.1 0.5; n-7-8; P«0.01), injection of ARZ (control 2 .0-0.55 IRB, 0.20.2; n-6; P«0.01) and, although not significantly, after water deprivation (Fig. 1e). These results indicate that the levels of circulating OBA transiently increase during fasting. This response is more selective for OEAs than for anandamide and other EAEs and temporally coincides with increases in blood glycerol and β-hydroxybutyrate (Table 1), suggesting a shift in energy metabolism from carbohydrates to fatty acids as the primary fuel (Sanpii et al. .

E., Siip. Epdosthippo! Meyar., 5:397-415 (1976)|. of glycerol in the plasma of rats that were starved for OO vna | holy

Food deprivation did not significantly affect the levels of OEA in the cerebrospinal fluid (Fig. 1c), indicating that the surge in plasma OEA may not originate from the central nervous system. To test this hypothesis, studies of the effect of fasting on the metabolism of OEA in various tissues of rats were conducted. Biochemical Science The way in which animal cells produce and break down OEA and other RHAEs apparently consists of three key enzymatic steps. Stimulated by calcium ions, the activity of MAT transfers the fatty acid i) group from the zp-1 position of the donor phospholipid to the primary amine of phosphatidylethanolamine, producing MARE2

IZsptiy ei ai,, Spet. RNA University Iiridz, 80: 133-142 (1996); Rioteiiyi ei aiYi., Meiygobio!Yi. Oiv., 5: 462-473 (1998)|).

Cleavage of the distal phosphodiester bond in MARE by an unknown phospholipase-O creates compounds EAE M zo (Zsptii ei a, Set. RPuz. Priav, 80: 133-142 (1996); Rioteii ei ai., Meshgobrioi. Oiv., 5: 462 -473 (1998), which are ultimately broken down into fatty acid and ethanolamine under the action of intracellular fatty acid amide hydrolase (EAAN) ., Maishge, 384: 83-87 Ge (1996)). Food deprivation (18 hours) was accompanied by a significant increase in MAT activity in white adipose tissue (Fig. 2a), but did not show this in the brain, stomach, and kidneys (Fig. 25, and data not shown). In the liver, eat-

In the intestine and skeletal muscles, MAT activity rapidly decreased (Figs. 2c, 4 and data not shown). These enzymatic changes were compared with corresponding changes in the content of MARE in tissues. In the tissues of rats, there are several molecular types of MAPE, including precursors of OEA: alk-1-palmitoenyl-2-arachidonyl-zp-glycerophosphoethanol-amine-M-oleyl (MAPE 1; Fig. 3a), alk-1-palmityl-2- arachidonyl-bl-glycerophosphoethanolamine-M-oleyl (MAPE 2; FigZa) and the REA precursor alk-1-palmityl-2-arachidonyl-zp-glycerophosphoethanolamine-M-palmityl (not shown). In agreement with the measurements of MAT activity, food deprivation leads to an increase in the content of MARE in fat and to a decrease in it in the liver (Fig. 3B, c). ;" Since the biosynthesis of MARE and the formation of EAE are closely related processes (Sadaz ei ai., N., y.). Meygovsi., 17:1226-1242 (1997)), fasting can be expected to increase the levels of OEA and other RAE in adipose tissue and not in other tissues. Consistent with this, fat taken from fasted rats contained -I more OBEA and REA than fat taken from freely fed control animals (Fig. 1a and data not shown), while brain, stomach, and intestine no such difference was observed (data not shown). However, on the contrary

As expected by the authors, the content of OEA and REA in the liver was also higher in rats subjected to food deprivation than in

Ge" of freely fed rats (Fig.za and data not shown). This discrepancy may be caused by the accumulation of BEAE 5r by the liver, which coincides with the postulated role of this organ in the repeated capture and exchange of EAE |Vaspyg ei o a!., u. Vioi Spet., 240:1019-1024 (1965); Bsptia ei ai., 9. Vioi. Spet., 260: 14145-14149 (19853). "M The breakdown into fatty acid and ethanolamine catalyzed by RAAN hydrolase is the key stage in the cleavage

EAE |Vasnyg ei ai., 9. Vioi. Spet., 240: 1019-1024 (1965); Zsytiy ek ai., 9. Vioi. Spet., 260: 14145-14149 (1985); Stamatsy ei aiYi., Maishge, 384: 83-87 (1996); YuOezagpatsa ei ai., 9U. Vioi Spet., 270: 6030-6035 (1995), dv Food deprivation significantly reduces the activity of RAAN in fat membranes, but does not affect the activity

EAAN in the brain, liver, stomach, intestine, kidney, and skeletal muscle (Fig. 2a-e and data not shown). So,

F) food deprivation can increase the levels of OEA and other EAE in white fat by two energetic pathways, which are mechanistically different from other reactions occurring in the process of lipolysis; stimulation of MAT activity can lead to an increase in the biosynthesis of MARE and RAE, while inhibition of EAAN activity can increase the life span of newly synthesized EAE. Although several tissue types may contribute to normal circulating OEA levels, the dynamic chemical changes observed in adipose indicate a critical role for this tissue in the generation of OEA during fasting.

Example 4. Suppression of food intake under the influence of OEA and other EAE

The effect of systemically administered EOBA on food intake in rats can be assessed in 24 hours. experiments with 65 Starvation. In this case, OEA causes a dose- and time-dependent suppression of food intake (Fig. 4a, 5). To determine the selectivity of this response, various OEA analogues were evaluated for their ability to produce hypophagia.

Anandamide and oleic acid have no effect.

Palmylethanolamide was active but significantly less potent than OEA.

Elaidylethanolamide (an unnatural analogue of OEA) was similar in potency to OEA (Fig. 4a).

These results suggest that OEA reduces food intake in a structure-selective manner and that other fatty acid ethanolamide-like compounds may be identified for use in accordance with the present invention.

Example 5. Withdrawal from activators of cannabinoid receptors 70 The molecular requisites for OEA-hypophagia differ from those involved in the interaction of anandamide with its known cannabinoid targets (|KpapoiKag ei ai., iMe si, 65: 607-616 (1999)). Cannabinoid receptor antagonists do not affect OEA-hypophagia in ip mimo, and OEA does not displace cannabinoid binding to brain membranes of ip mygo rats. Thus, despite its structural and biogenetic affinity to anandamide, OEA is independent of the endogenous cannabinoid system in producing anorexia.

Example 6. Prolonged reduction in body weight

In some embodiments, the compounds of the present invention achieve a prolonged reduction in body fat or body weight after long-term administration to mammals. This effect is an advantage, since numerous known medicines suppress food intake after their acute administration, but lose their ability to do so with prolonged treatment IVisopaea, 9., Ttepaz Ripagtasoi. Zsi., 12: 147-157 (1991)).

Subchronic administration of OEA to rats was carried out. Daily injections of OEA (5 mg/kg, intraperitoneally) for 7 days produced a small but significant reduction in cumulative food intake (Fig.ba), which was accompanied by a profound inhibition of weight gain (Fig.5p,c). OEA is not affected by water intake (Fig. 54). The effect of OEA on body weight is only partially explained by its moderate reducing effect on food intake, indicating that other factors, such as stimulation of energy expenditure or inhibition of food energy storage, may also contribute to this effect.

Example 7. EAE can have a peripheral site of action and)

In one embodiment, the invention provides compounds with a peripheral site of action. Such a site has the advantage of reducing the likelihood of side effects on the central nervous system (CNS).

OEA, which is powerful when administered peripherally, becomes ineffective when directly injected into the ventricles of the brain (Table 2). This suggests that the primary sites of action of this compound may be blocked outside the CNS.

This is also indicated by the fact that the sensory fibers in the vagus nerve and other peripheral nerves were chemically damaged as a result of the treatment of adult rats with neurotoxin and capsaicin. .. Ge

RPuzioi, 275: 051056-51062 (1998). Rats treated with capsaicin did not react to peripherally injected cholecystokinin-8 (CSK-8) (Fig.ba, c), drank more water than control animals (Fig. bB, a) and lost the corneal chemosensory reflex (data not shown). These are three indications that the neurotoxin disrupted the sensory afferent nerves (Masi eap, Y. W., Kedy. Reri, 11: 321-333 (1985); Kinneg et al.,

At. in). RNuzioi!., 248: KB5О0О1-К504 (1985); Sypiv ei ai, At. in. Research, 272: K704-K709 (1997)). Treated animals were also unresponsive to OEA (1 ug/kg, intraperitoneally) but responded normally to the compound

SR-93129, targeting 5-HT receptors in the CNS (Fig.ba, c) (ee ei ai., Rzusporpaptasiodu, 136:304-307 « 40. J1998)). These facts support the hypothesis that OEA causes hypophagia by acting on a peripheral site and that sensory fibers are required for this effect. :» brain pranamid for eating

Ov -i no -

F

» ime) : food. p-12 per group.

Appetite suppressant compounds of the present invention may utilize peripheral sensory inputs. 22 Peripheral sensory inputs related to appetite suppression involve several CNS structures to which

F! belong to the nucleus of the isolated tract (MBT: pisieiz oi (She zoiyagu igas) in the brainstem and the arcuate and paraventricular (RUM) nuclei in the hypothalamus (Zspmagi" ei ai., Mayige, 404: 661-671 (2000))І. To identify o brain pathways involved in OEA-induced hypophagia, the mRNA levels of the c-o5 gene with regulated activity were mapped |Siggap eii aY,, Opsodepe, 2: 79-84 (1987) by means of ip-hybridization after 60 systemic administration of OEA, oleic acid and vehicle. Compared with controls, OBA (1 µg/kg, intraperitoneally) caused a highly localized increase in os-o55 mRNA levels in the PMUM, suprafoveolar nucleus (Fig. 7a), and MT (Fig. 7c). This increase was specific to the data areas to the extent that the expression of s-yuz in other areas of the brain was not significantly affected by OEA injections (Fig. 7b, a).

The fact that OEA stimulates the expression of s-yus mRNA in M5T (which processes vagal sensory inputs to the CNS) and RUM bo (the primary site for the harmonization of central catabolic signals) (Zspmagi» ei ai., Maishge, 404: 661-671 (2000 )), consistent with the physiological role of this lipid as a peripheral mediator of anorexia.

It is possible that OEA reduces food intake by inducing a nonspecific state of behavioral suppression. If this is so, then OEA should cause a conditioned taste aversion, which can be easily provoked in rats by numerous harmful substances (Sgeep eyi a!., 5siepse, 173: 749-751 (1971)), including lithium chloride (Fig. 4c). However, the maximum dose of OEA (20 ug/kg, intraperitoneally) had only a minor effect in this experiment (Fig. 4c), indicating that this compound may not be aversive. This behavioral specificity of BOTH is confirmed by several additional observations. OBA does not change water intake, body temperature, pain threshold (Fig. 44) and activity of the hypothalamus-pituitary-adrenal axis (HPA) (Table 3). In addition, OEBA does not produce symptoms similar to restlessness (Fig. 49), although it reduces motor activity and effective response to food, 7/0. He did this at doses much higher than the doses needed to produce hypophagia (Fig. 4p-i). This pharmacological profile distinguishes OEA from other appetite suppressants such as amphetamine and glucagon-like peptide 1 (which often cause aversion, hyperactivity, restlessness, and activation of the NRA axis), as well as from the endogenous cannabinoid anandamide (which stimulates food intake in partially satiated animals , increases the pain threshold, lowers body temperature and activates the NRA axis) |Regimee, K. 0., Ehr. Orip. Ipmevi Ogydv, 9: 7u75.1553-1571 (2000)). in Gan o

Listed in Table C, the levels of plasma hormones - corticosterone (B), prolactin (RCI) and luteinizing hormone (LH) - were measured by radioimmunoassay on plasma samples taken through the bohv. after injections of vehicle and pranamide (prana, mg/kg, intraperitoneally) and expressed in ng/ml. n-6-9 per group.

OBEA causes hypophagia at physiologically acceptable doses. After an hour after the administration of the maximally effective dose (5 mg/kg, intraperitoneally) the levels of circulating OEA (16.1-2.6 pmol/ml) were significantly higher than the baseline (10.1-1.1; P«0.05, criterion St 'judenta; p-5), but below the levels measured in animals exposed to 18 h. food deprivation (Fig. 1a). Therefore, the concentrations reached by OEA in the blood during fasting may be sufficient to induce significant behavioral responses.

Example 8. Identification of compounds that reduce body fat mass p

This example shows how to identify appetite suppressants using OEA as a positive He) control. In particular, the synthesis of OEA, measurement of reduction in body fat mass and oxidation of fatty acids are described.

Synthesis of BOTH in

Oleyl chloride is obtained from My-Spesk Rger (EIUviap, MM) or prepared using standard methods. Oleyl chloride is dissolved in dichloromethane (1Omg/ml) and allowed to react with 5 equivalents of ethanolamine for 15 minutes. at a temperature of 0-492C. The reaction is stopped by adding purified water. After intensive mixing and phase separation, the upper, aqueous phase is removed, and the organic phase is washed twice with water, removing unreacted ethanolamine from it. The OEA obtained as a result is concentrated to dryness in flow M", reconstituted in chloroform at 20 mmol and stored at a temperature of -202C until use. - c Measuring the reduction in body fat mass caused by the test compounds a There are numerous methods for evaluating the ability of a compound to reduce body fat mass. According to one of them, "" suitable amounts of OEA or test compounds are administered to rats by intraperitoneal injections. OEA and test compounds can be prepared in mixtures of 7095 UOM5O in sterile saline, 596 Tueep 80/596 propylene glycol in sterile saline, or 1095 Tm' eep 80/1095 ethanol/8095 saline solution. Bmg/kg OEA can be used as a positive control. The amounts of test compounds administered can be, for example, 1-25mg/kg. Usually, to determine the optimal dose, each test compound can be administered to different groups of rats in doses of 1, 2, 5, 10, 15 and 2Omg/kg. Injections can be (o) made under ZOv. before the main feeding of animals for 7-14 days. kyu 50 Effect of the tested compound on total fat body weight can be determined by directly measuring the fat mass of experimental rats using a suitable skinfold thickness measuring instrument. one of the animal's paws is clamped in the measuring jaws of such an instrument, and in this way measurements are carried out before the introduction of OEA and/or the tested compound and every 48 hours. during and after administration of OEA and/or test compound. Differences in the results of measurements in at least two places where the skin is clamped reflect the change in the total fat mass of the animal. o Measurement of fatty acid oxidation caused by test compounds (namely) Compounds can also be tested for their effects on fatty acid metabolism. The effect of the test compound on fatty acid metabolism can be assessed by measuring fatty acid oxidation in primary liver cell cultures. Hepatocytes can be used to determine the rate of rat oleate oxidation with its conversion to ketone bodies and carbon dioxide. Such cells can be isolated from the liver of an adult rat by enzymatic digestion (as described in Veupep et al. ip Oiarei(ez 28: 828 (1979)). In this case, the cells are usually cultured in suspension and incubated in Krebs-Henseleit bicarbonate medium (Kgerz- Nepseyei), supplemented with bovine serum albumin (B5A) and glucose, (as described in Zy2tap 5 Seeijep, 65 Biospet. 9. 287: 487(1992)). The protein concentration of cultured cells can be determined, and the cells are seeded in 2 ml of medium so that each the reaction mixture contained 4-bmg of protein per milliliter.Cells are incubated for 1 hour.

at 372C with | "With SI-oleic acid (Ategepat) in the presence of 10 μmol of OEA or without it, the reaction is stopped by adding 200 μl of 2 mol perchloric acid, and the acid-soluble products are extracted with a mixture of chloroform, methanol, and water, taken in a ratio of 5:1:1, respectively (06 .).The aqueous phase is removed and washed two or more times.The concentration of white is determined, for example, by the Lowry assay (I ohm/g).

The rate of conversion of oleate to ketone bodies is expressed in nanomoles of oleate oxidized over a certain time per mg of protein and is determined by liquid scintillation counting. The measurements carried out in this way show that OEA increases oleate oxidation by 21-695 (n-4, p«0.01 relative to control incubations according to the Student's test). 70 Example 9. Effect of OEA on the metabolism of fatty acids

Oleoylethanolamide (OEA) reduces body weight not only by suppressing appetite, but possibly also by enhancing fatty acid catabolism. The effect of OEBA on fatty acid oxidation in the main fat-burning tissues (soleus muscles, liver, cultured cardiac myocytes and astrocytes) was investigated.

OEA significantly stimulates fatty acid oxidation in primary cultures of liver, skeletal (soleus) muscle 75 and heart cells, while it does not affect cultures of astroglial cells from the brain. In addition, OEBA induces significant mobilization of triacylglycerol accumulations from primary cells of white adipose tissue. Table 4 describes in detail the methods and effects of OEA in the oxidation of fatty acids in these cells. Experimental studies of the relationship between structure and activity showed that the effect of OEA on the oxidation of fatty acids in skeletal muscles is specific (Fig. 8). Therefore, the effects of OEA are mimicked by the hydrolysis-resistant homologue methyl-OEA, only partially by -palmylethanolamide (PEA), and not by arachidonylethanolamide (AEA) or oleic acid (OA). In summary, these results suggest that lipid oxidation and mobilization are enhanced by OEA and that the effects of OEA are limited to peripheral sites. high school

A rat, an adult rat, a newborn, a newborn rat, an adult rat, a rat

Selection method | Fermentative. Directorate (Spiavzzop, | Fermentative. Fermentative. Digestion Fermentative. p dl Zheln. ELEUKT VER Z a!., 1979) a!., 1992) (Kodbrei, 1964) sia n environment bicarbonate plus VZA NEREB5" plus VZA and OMEM"" plus VZA (Mi insulin, transferrin, NERE5" plus B5A and and glucose (by2tap 8 |glucose (Egoeriv ei (ei a!., 2000) progesterone, putrescine and glucose (Kearbei, -

Seviep, 1992) a!., 2001) selenite (Via7ace? ei a!., 1998) 1965; parameters (I Sioleate on (I Sioleate on CO2 GSioleate on CO2 ketone bodies (Viagatse? ei (release of ketone bodies (Rgoebiv ei a1I., 2001) |((Viagdtse ei a!., 1998) (ai., 1998) glycerol) (bigtap 8. Seeviep, (Zegtaadei-IGe Sai 1992) ей а!., 2000) " е з я "z effect 1Ommol I BOTH (95) significance -I relative to the control : ""OMEM: modified according to Dulbecco's method Igla medium. (22)

Cited references: Veupep AS ei ai., Oiarebez 28: 828-835 (1979); Viagdce Seyi a, ) Meygospet 71: o 1597-1606 (1998); Spiazvop KV "I aroghaiogu Apaiotu oi (She MUpye Ka MUSV, Yuiridie, Isula (1980); ERshpk I. ei "I aI., In Vioi Speth 267: 9917-9924 (1992); ERgoeriv .). ei AI., Rhos MaNTSAsai si OBA 98: 2005-2010 (2001); by2tap

Mei ai., Viospet 4 287: 487-492 (1992); MeSapnu KO ei ai., 9 Seiyi Vioi 85: 890-902 (1980); Codey! M UVIO!

Speth 239: 375-380 (1964); Cody! M App MU Asai Zsi 131: 302-314 (1965); Zegtadeiy-Ye Sa! S ei ai., REE5 I ey 5B 415: 150-156 (2000); Mi MU ei a, U Vioi Speth 275: 40133-40119 (2000).

Example 10. The role of endogenous OEA in the intestine i) The influence of feeding on the biosynthesis of intestinal OEA was investigated. Analysis by high-performance liquid chromatography in combination with mass spectrometry showed that the tissue of the small intestine of a freely fed rat contains significant amounts of OEA (354 -8bpmol/g, n-3). Intestinal OEA levels were significantly reduced after 60 food deprivation, but returned to baseline after refeeding. In contrast, no such changes were observed in the stomach (pmol/g: control 210 420; fasting 238 4-84; fasting with resumption of feeding 239 -60, n-3). Changes in the levels of intestinal OEBA were accompanied by parallel changes in the activity of MAT, which participates in the formation of OEBA, but not in the activity of fatty acid amide hydrolase, which catalyzes the hydrolysis of OEBA. These observations indicate that fasting and feeding regulate 65 OEA biosynthesis in the small intestine in opposite directions. In agreement with the intra-abdominal source

OEA plasma OEA levels in fasted rats were higher in portal vein blood than in vena cava blood

(pmol/ml: portal vein 14.6--1.8; vena cava 10.3-42.8, n-5). The contribution of other intra-abdominal tissues to the formation of OEA cannot currently be excluded. These results indicate multiple interventions in the use of OEBA systems in eating behavior. According to this model, food intake can stimulate the activity of MAT, which enhances the biosynthesis of OEA in the small intestine and possibly other intra-abdominal tissues.

Newly produced OEBAs can activate local sensory fibers, which, in turn, can inhibit feeding by involving brain structures such as MT and RUM.

The results obtained by the authors highlight the hitherto unexpected role of OEA in the peripheral regulation of nutrition and provide a conceptual basis for the development of new medical drugs to reduce weight or 7/0 body fat mass, prevent body weight gain or increase in body fat mass, suppress appetite or reduce food cravings or reducing food intake and for the treatment of eating disorders, overweight and anxiety. These preparations may contain not only analogues and homologues of OEA, but also agents that control OEA levels by influencing the formation of OEA and hydrolyzing systems and enzymes, as described above.

All publications and patent applications cited in this description are incorporated herein by reference to the extent that they do not conflict with the present invention, as if each individual publication or patent application were specifically and individually indicated as being incorporated by reference.

It should be noted that the present invention is described here in detail as an illustration and example for the purpose of its clarification and clear understanding. Therefore, it is quite clear to those skilled in the art that the given description in no way excludes changes and modifications that can be made therein without going beyond the idea and scope defined by the appended Formula of the invention.

Claims (61)

The formula of the invention and 0, . c 25 1. A method of reducing food intake by a mammal in need of it, which includes administering to said mammal in an amount effective to reduce food intake, a compound according to the formula o 30 IU s or a pharmaceutically acceptable salt thereof, where p is from 0 to 5, the sum of a and B can be from 0 to 4; 7 is the ith member selected from the group consisting of -С(О)М(К2)-, -(Б)МС(О0)-, - ОС(О)-, --О)СО-, О ,-МКе-и-5- ии are и- 35 members independently selected from the group consisting of unsubstituted or substituted alkyl, hydrogen, C 4-Cv M alkyl and Co-Cv acyl, and up to four hydrogen atoms of the fatty acid component and alkanol component of the above compound are substituted by methyl or a double bond between adjacent carbon atoms, and the bond between carbon atoms c and 4 can be unsaturated or saturated. 2. The method according to claim 1, which differs in that the specified compound according to the formula is an alkanolamide of a fatty acid, which contains fatty acid and alkanolamine components connected by an amide bond. - about the village 3. The method according to claim 1, which differs in that the alkanolamide of a fatty acid is a compound with the formula "sho a a M C y B that -I or its pharmaceutically acceptable salt, where p is from 0 to 4, the sum of a and 5 is from 1 to 3; B1B2 are members independently selected from the group consisting of hydrogen, C.4-Cv alkyl and C.v.-Cv acyl, and up to four hydrogen atoms of the fatty acid component and the alkanolamine component of the above compound are substituted by 50 methyl or a double bond between adjacent carbon atoms, and the bond between carbon atoms c and 4 can be unsaturated or saturated. 4. The method according to claim 1, which differs in that the specified compound is oleoylethanolamide. 5. The method according to claim 2, which is characterized by the fact that the fatty acid alkanolamide contains a fatty acid component covalently linked to the ethanolamine component by an amide bond. 99 6. The method according to claim 2, which differs in that the fatty acid component is monounsaturated. GF) 7. The method according to claim 2, which differs in that the fatty acid component is oleic acid. 7 8. The method according to claim 2, which differs in that the fatty acid component is selected from the group consisting of elaidic acid, palmitoleic acid, palmitic acid, linoleic acid, alpha-linolenic acid and gamma-linolenic acid. 60 9. The method according to any of claims 1-8, characterized in that the mammal is a human. 10. The method according to claim 9, which differs in that the introduction is carried out orally. 11. The method according to claim 10, which is characterized by the fact that the specified compound has an enteric coating. 12. A method of modulating fatty acid metabolism in a mammal in need thereof, comprising administering to said mammal an amount effective to modulate fatty acid metabolism of a compound of formula IV or a pharmaceutically acceptable salt thereof, wherein p is from O to 5, the sum of a and B can be from 0 to 4: 7 is a member selected from the group consisting of -С(О)М(В2)-, -«"КУМС(0)-, - ОС(О )-, -F)CO-, O, -ME»- and-5-, and 82 2 are /olenes independently selected from the group consisting of unsubstituted or substituted alkyl, hydrogen, C 4-Ce alkyl and Co -Cv acyl, and up to four hydrogen atoms of the fatty acid component and the alkanol component of the above compound are substituted by methyl or a double bond between adjacent carbon atoms, and the bond between carbon atoms c and 4 can be unsaturated or saturated. 13. The method according to claim 12, which is characterized by the fact that the specified compound according to the formula is a fatty acid alkanolamide, which contains fatty acid and alkanolamine components connected by an amide bond. 14. The method according to claim 12, which is characterized by the fact that the alkanolamide of a fatty acid is a compound with the formula КУ ШЙ ОО ШЙ to n КВЙ or its pharmaceutically acceptable salt, where n is from 0 to 4, the sum of a and 5 is from 1 to 3 ; B1B2 are members independently selected from the group consisting of hydrogen, C4-C6 alkyl, and C6-C6 acyl, wherein up to four hydrogen atoms of the fatty acid component and the alkanolamine component of the above compound are substituted by methyl or a double bond between adjacent atoms carbon, and the bond between these carbon atoms can be (3) unsaturated or saturated. 15. The method according to claim 12, which is characterized by the fact that the indicated compound is oleoylethanolamide. 16. The method according to claim 13, which is characterized by the fact that the fatty acid alkanolamide contains a fatty acid meso component covalently linked to the ethanolamine component by an amide bond. 17. The method according to claim 13, which is characterized by the fact that the fatty acid component is monounsaturated. Ge 18. The method according to claim 13, which differs in that the fatty acid component is oleic acid. with 19. The method according to claim 13, which is characterized by the fact that the fatty acid component is selected from the group consisting of elaidic acid, palmitoleic acid, palmitic acid, linoleic acid, alpha-linolenic acid and gamma-linolenic acid. m 20. The method according to any of claims 12-19, characterized in that the mammal is a human. 21. The method according to claim 20, which differs in that the introduction is carried out orally. 22. The method according to claim 21, which is characterized by the fact that the specified compound has an enteric coating. 23. A method of reducing or regulating the body fat mass of a mammal in need of it, which includes "administering to the indicated mammal in an amount effective for reducing or regulating the body fat mass of the mammal, a compound according to the formula Ч пра ДИ нни и НК и"? pIAOMI AVOVE, j, iivZ hi Mel sho ko -I or a pharmaceutically acceptable salt thereof, where p is from 0 to 5, the sum of a and B can be from 0 to 4; 7 is a F member selected from the group consisting of - С(СО)М(К2)-, -«(Бе)МС(О0)-, - OS(О)-, -«О)СО-, О, -Me- and -5-, and 2 and 2 are members independently selected from the group consisting of unsubstituted or substituted alkyl, hydrogen, C 4-C 250 alkyl and Co-C acyl, and up to four hydrogen atoms of the fatty acid component and the alkanol component of the above compound are substituted by methyl or a double bond bond between adjacent carbon atoms, and the bond between carbon atoms c and 4 can be unsaturated or saturated. 24. The method according to claim 23, which differs in that the indicated compound according to the formula is a fatty acid alkanolamide, which contains fatty acid and alkanolamine components connected by an amide bond. 25. The method according to claim 23, which is characterized by the fact that the alkanolamide of a fatty acid is a compound according to the formula ET: Хи MДИ сагат ВВЕ 60 нин и or its pharmaceutically acceptable salt, where p is from 0 to 4, the sum of a and 5 is from 1 to 3; B1B2 are members independently selected from the group consisting of hydrogen, C4-C6 alkyl, and C6-C6 acyl, wherein up to four hydrogen atoms of the fatty acid component and the alkanolamine component of the above compound are substituted by methyl or a double bond between adjacent atoms carbon, and the bond between carbon atoms c and y can be unsaturated or saturated. 26. The method according to claim 23, which is characterized by the fact that the specified compound is oleoylethanolamide. 27. The method according to claim 24, which is characterized by the fact that the fatty acid alkanolamide contains a fatty acid component covalently linked to the ethanolamine component by an amide bond. 28. The method according to claim 24, which is characterized by the fact that the fatty acid component is monounsaturated. 29. The method according to claim 24, which differs in that the fatty acid component is oleic acid. ZO. The method according to claim 24, which is characterized in that the fatty acid component is selected from the group consisting of elaidic acid, palmitoleic acid, palmitic acid, linoleic acid, α-alpha-linolenic acid and gamma-linolenic acid. 31. The method according to any of claims 23-30, characterized in that the mammal is a human. 32. The method according to claim 31, which differs in that the introduction is carried out orally. 33. The method according to claim 32, which is characterized by the fact that the specified compound has an enteric coating. 34. A method of regulating appetite in a mammal in need thereof, comprising administering to said mammal 7/5 of an amount effective to reduce food intake of a compound of the formula or a pharmaceutically acceptable salt thereof, wherein n is 0 to 5, the sum of a and B can be from 0 to 4; 7 is a member selected from the group consisting of -C(OM(B23-, -««B3MS(O)-, -OC(O)-, -F)CO-, O, -ME9- and -85- , and Be and B are members independently selected from the group consisting of unsubstituted or substituted alkyl, hydrogen, C 4 -C 1 alkyl and Co -C 2 acyl, wherein up to four hydrogen atoms of the fatty acid component and the alkanol component of the above compound are substituted methyl or a double bond between adjacent carbon atoms, and the bond between carbon atoms c and 4 can be unsaturated or saturated. 35. The method according to claim 34, which differs in that the specified compound according to the formula is a fatty acid alkanolamide, which contains fatty acid and alkanolamine components connected by an amide bond. what- 36. The method according to claim 34, which differs in that the alkanolamide of a fatty acid is a compound according to the formula pn i NN ih sh re Av CHEMIYU Ia pi MBT U moya shi v - or its pharmaceutically acceptable salt, where p is from 0 to 4, the sum of a and 5 is from 1 to 3; B1B2 are members independently selected from the group consisting of hydrogen, C4-C6 alkyl, and C2-C6 acyl, wherein up to four hydrogen atoms of the fatty acid component and the alkanolamine component of the above compound are substituted by "di methyl or a double bond between adjacent carbon atoms, and the bond between carbon atoms c and 4 can be unsaturated or saturated. with 37. The method according to claim 34, which is characterized by the fact that the indicated compound is oleoylethanolamide. :with" 38. The method according to claim 35, which is characterized by the fact that the fatty acid alkanolamide contains a fatty acid component covalently linked to the ethanolamine component by an amide bond. 39. The method according to claim 35, which is characterized by the fact that the fatty acid component is monounsaturated. - 75 40. The method according to claim 35, which differs in that the fatty acid component is oleic acid. 41. The method according to claim 35, which is characterized by the fact that the fatty acid component is selected from the group that -| consists of elaidic acid, palmitoleic acid, palmitic acid, linoleic acid, b-alpha-linolenic acid and gamma-linolenic acid. 42. The method according to any one of claims 34-41, characterized in that the mammal is a human. to 50 43. The method according to claim 42, which differs in that the introduction is carried out orally. - h 44. The method according to claim 43, which is characterized by the fact that the specified compound has an enteric coating. 45. A pharmaceutical composition for reducing food intake comprising a pharmaceutically acceptable excipient and a compound of formula 60 or a pharmaceutically acceptable salt thereof, wherein n is from 0 to 5, the sum of a and 5 can be from 0 to 4, 7 is a member selected from groups consisting of -С(О)М(Б2)-, "BUM С(О0)-, - ОС(О)-, -Ф)СО-, О, -Me- and -5-, B: and B? are members independently selected from the group consisting of unsubstituted or substituted alkyl, hydrogen, C 4-Cv alkyl, and C 4-Cv acyl, wherein up to four hydrogen atoms of the fatty acid component and the alkanol component of the above compound are substituted by methyl or a double bond between adjacent carbon atoms, and because the bond between carbon atoms c and y can be unsaturated or saturated, and the composition is in the form of a unit dose, and this unit dose contains the specified compound in an amount effective to reduce food intake. 46. The composition according to claim 45, which is characterized by the fact that the specified compound is a fatty acid alkanolamide, which contains fatty acid and alkanolamine components connected by an amide bond. 47. The composition according to claim 45, which is characterized by the fact that the alkanolamide of a fatty acid is a compound according to the formula E with the action of She Vs et or its pharmaceutically acceptable salt, where p is from 0 to 4, the sum of a and 5 is from 1 to Q, Her ET? are members independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and C 1 -C 2 acyl, wherein up to 75 Four hydrogen atoms of the fatty acid component and the alkanolamine component of the above compound are substituted by methyl or a double bond between adjacent carbon atoms, and the bond between carbon atoms c and a can be unsaturated or saturated. 48. The composition according to claim 45, which differs in that the indicated compound is oleylethanolamide. 49. The composition according to claim 46, which differs in that the fatty acid alkanolamide contains a fatty acid component covalently linked to the ethanolamine component by an amide bond. 50. The composition according to any one of claims 45-49, which is characterized by the fact that it is a preparation for oral administration. 51. The composition according to any one of claims 45-49, which is characterized in that said compound has an enteric coating. school 25 52. The composition according to claim 45, which is distinguished by the fact that it additionally contains one or more other drugs useful in diet, treatment, prevention, suppression or improvement of body fat mass. (at) 53. A pharmaceutical composition for reducing or regulating body fat mass, or modulating the metabolism of fatty acids in a mammal, which contains a pharmaceutically acceptable excipient and a compound according to the formula Ше и Ше я ге зо ж я ков ки рч- or its pharmaceutically acceptable salt, where p is from 0 to 5, the sum of a and 5 can be from 0 to 4, 7 is a member 35 selected from the group consisting of -С(О)М(В2)-, "KUM С(О0)-, - ОС( O)-, -F)SO-, O, -Me- and -5-, B: and B? are members - independently selected from the group consisting of unsubstituted or substituted alkyl, hydrogen, C 4-Cv alkyl and Co-Cv acyl, where up to four hydrogen atoms of the fatty acid component and the alkanol component of the above compound are substituted by methyl or a double bond between adjacent carbon atoms, and the bond between carbon atoms c and y may be unsaturated or saturated, and the composition is in the form of a unit dose, and this unit dose contains said compound in an amount effective to reduce or c regulate body fat mass . :with" 54. The composition according to claim 53, which is characterized by the fact that the specified compound is a fatty acid alkanolamide, which contains fatty acid and alkanolamine components connected by an amide bond. 55. The composition according to claim 53, which differs in that the alkanolamide of a fatty acid is a compound according to the formula - and BU in t 7 Vk pyt KK mu -- . or a pharmaceutically acceptable salt thereof, where n is from 0 to 4, the sum of a and 5 is from 1 to 3. are members independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl and C 1 -C 2 acyl, and up to four hydrogen atoms of the fatty acid component and the alkanolamine component of the above compound are substituted by methyl or a double bond between adjacent carbon atoms, and the bond between carbon atoms c and 22 and can be unsaturated or saturated. GF) 56. The composition according to claim 53, which differs in that the specified compound is oleylethanolamide. 57. The composition according to claim 54, which differs in that the fatty acid alkanolamide contains a fatty acid component covalently linked to the ethanolamine component by an amide bond. 58. The composition according to any one of claims 53-57, which is characterized by the fact that it is a preparation for oral 60 administration. 59. The composition according to claim 58, which is characterized by the fact that the specified compound has an enteric coating. 60. A composition containing oleylethanolamide, which is characterized by having a form for oral administration. 61. The composition according to claim 60, which differs in that it has an enteric coating. b5