RU2576037C1 - Substituted 4-{[4-(3,3-dioxido-1,3-benzoxathiol-6-yl)aryloxy]methyl}piperidines as gpr119 receptor agonists, pharmaceutical composition, methods for producing and using them - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: compounds have the property of a GPR119 receptor agonist and can be used as an active ingredient for pharmaceutical compositions in the form of tablets, capsules, injections, ointments, rectal suspensions and gels presented in a pharmaceutically acceptable pack, in treating metabolic diseases such as metabolic syndrome, diabetes mellitus, and obesity. In the general formula

R=H, (C₁-C₅)alkyl, halogen-substituted (C₁-C₅)alkyl, acyl specified in a group of C₁-C₅alkylC(=O)- or phenyl(C=O)-, substituted heteroaryl representing an aromatic monocyclic group with two nitrogen atoms, which is substituted by a halogen atom or C₁-C₅alkyl, (C₁-C₃)alkylsulphonyl, phenylsulphonyl; R1, R2, R3, R4 represents hydrogen or one or two substitutes simultaneously specified in a halogen, (C₁-C₃)alkyl, halogen-substituted (C₁-C₃)alkyl, (C₁-C₃)alkylsulphonyl, a cyano group.

EFFECT: improving the properties.

8 cl, 1 dwg, 8 tbl, 15 ex

Description

The invention relates to new physiologically active substances, new GPR119 receptor agonists, active ingredients for pharmaceutical compositions, to pharmaceutical compositions and drugs containing substituted 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) ) aryloxy] methyl} piperidines as agonists of GPR119 receptors, which stimulate the synthesis and secretion of incritins and increase the secretion of insulin; a method for treating metabolic diseases such as diabetes, obesity, metabolic syndrome, as well as concomitant cardiovascular and neurodegenerative diseases.

According to the World Health Organization, in 2008, 347 million people worldwide were ill with diabetes [WHO Newsletter No. 312. September 2012], while the number of patients more than doubled compared to 153 million in 1980 [Danaei G. et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2-7 million participants. Lancet. 2011; 378 (9785): 31-40]. The spread of diabetes is accelerating. In 2010, diabetes was registered in 6.4% of the world population, in 2030 7.7% of patients in the world are projected. [Farag Y, Gaballa M. Diabesity: an overview of a rising epidemic. Nephrol Dial Transplant 2011; 26: 28-35]. Of particular danger is diabetes combined with overweight (obesity or obesity), which is the annual cause of death for more than 280 thousand people in the United States. The new scientific and medical term "Diabesity" (in the Russian version - "Diabetes") has become universally recognized, which means a combination of two interrelated pathologies: diabetes and obesity. At present, diabetes is considered as one of the most serious medical problems of mankind, which has become, in fact, the first non-infectious epidemic [Schmidt MI, Duncan BB. Diabesity: an inflammatory metabolic condition. Clin Chem Lab Med. 2003; 41: 1120-1130], [DangMN, Hashem BE-S. The epidemiology of obesity. Gastroenterol Clin North Am. 2010; 39: 1-7]. Diabetes has become widespread and rapidly spread over the past century. The main causes of this epidemic are sedentary lifestyle and poor diet [Zimmet Ρ., Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001; 414: 782-787], as well as a genetic predisposition [Ling C., Groop L. Epigenetics: a molecular link between environmental factors and type 2 diabetes. Diabetes 2009; 58: 2718-2725]. Diabetes is also an integral component of the metabolic syndrome.

Currently, such simple methods of treating diabetes, such as special diets, do not lead to a solution to the problem - 98% of those who lose weight gain it in excess for 5 years. Various surgical operations in the fight against diabetes (bariatric surgery) have a noticeable effect, but they are associated with a large number of side effects associated with impaired hormonal homeostasis [Tharakan G., Tan Τ., Bloom S. Emerging therapies in the treatment of ′ diabesity ′ : beyond GLP-1. Trend Pharm Sci. 2011; 32: 8-15]. The many efforts of pharmaceutical companies to create highly effective diabetes and diabetes care products have not yet led to noticeable success. Despite the fact that at present more than 130 new drug candidates are undergoing various tests, no more than ten drugs are approved for use. Clinical trials of a large number of candidates have been suspended due to serious side effects. For example, Avandia, the most promising antidiabetic drug (Rosiglitazone, a PPARgamma receptor agonist), has been shown to increase the risk of heart attack and heart failure [Avorn J. Two centuries of assessing drug risks. New Engl J Med. 2012; 193-197]. The main reasons for the constant failure of researchers are a lack of understanding of the complex picture of the disease, in particular, the presence of its many signaling mechanisms. Exposure to only one effector target leads to the "escape" of the pathological process due to the activation of other mechanisms. Therefore, one of the main directions in the development of antidiabetic drugs is currently the search for pharmacological agents that can stop the development of pathology.

Recently, several non-peptide G-protein double receptors (GPCRs) have been isolated. Among them, special attention was paid to the G-protein dual receptor 119 (GPR.119), the expression of which is observed on cells producing incritins, and therefore it is considered as a possible target for the development of drugs for the treatment of type 2 diabetes. Activation of GPR.119 increases intracellular cAMP accumulation, leading to increased insulin secretion by pancreatic β-cells in response to glucose loading and the production of incritins K and L-cells. Preclinical and clinical studies of GPR119 agonists support the view that GPR119 agonists may be acceptable as candidates for the treatment of type 2 diabetes. These studies indicate that an oral bioavailable, active, selective synthetic GPR119 agonist can:

a) Lower blood sugar without severe hypoglycemia

b) Slow down the development of type 2 diabetes

c) Reduce appetite and body weight. [Fyfe (2008) GPR119 agonists as potential new oral agents for the treatment of type 2 diabetes and obesity. Expert Opin Drug Discov. j. 3: 403-413].

In recent years, numerous patents from various pharmaceutical companies for GPR119 agonists have appeared, and several companies have initiated clinical trials for the treatment of type 2 diabetes, see Table 1.

Thus, the search for effective GPR119 receptor agonists seems to be an extremely important, relevant and promising task.

In order to develop new highly effective antidiabetic drugs, the authors of this invention carried out extensive in vitro screening studies of low molecular weight compounds of various classes, hit compounds and leader compounds belonging to several families of heterocyclic compounds were detected, then directed modifications of many positions of the detected structures were performed and tested. the relationship "structure-activity" is established and the most promising series are selected. As a result, a series of new derivatives was synthesized that are original and highly potent GPR119 receptor agonists. The resulting physiologically active heterocyclic compounds include novel 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) aryloxy] methyl} piperidine derivatives, which have not been previously described in the literature. To date, the ability of these compounds to exhibit agonistic properties with respect to GPR119 receptors has also not been known.

The following are definitions of terms that are used in the description of this invention.

“Agonists” means compounds that, by binding to receptors of a particular type, actively contribute to the transmission by these receptors of their specific signal and thereby elicit a biological response from the cell.

“Azaheterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in a ring.

"Alkyl" means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain. “Branched” means that the alkyl chain has one or more “lower alkyl” (C ₁ -C ₅ ) alkyl substituents. Alkyl may have substituents. Preferred alkyl groups are lower (C ₁ -C ₅ ) alkyl or methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, n-pentyl, 2- pentyl, 3-pentyl, neopentyl, n-hexyl, cyclohexyl.

“Aliphatic” radical means a radical obtained by removing a hydrogen atom from a non-aromatic CH bond. An aliphatic radical may additionally contain substituents — aliphatic or aromatic radicals defined in this section. radicals Representatives include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl, aralkiloksialkil, aralkiloksikarbonilalkil, aralkyl, aralkynyl, aralkiloksialkenil, heteroaralkenyl, heteroaralkyl, geteroaralkiloksialkenil, geteroaralkiloksialkil, annelated arylcycloalkyl, annelated heteroarylcycloalkyl, annelated arylcycloalkenyl, annelated heteroarylcycloalkenyl, annelated aryl heterocyclyl, annelated heteroaryl heterocyclyl, annelated aryl hetero cyclenyl, annelated heteroarylheterocyclenyl.

"Alkenyl" means an aliphatic linear or branched hydrocarbon group containing from 2 to 12 carbon atoms and including a carbon-carbon double bond. “Branched” means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. One or more aromatic, cyclic or heterocyclic systems may be attached to an alkenyl group.

"Active component" (drug substance, drug substance, drug-substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, having pharmacological activity and is the active principle of the pharmaceutical composition used for the manufacture and manufacture medicinal product (means).

“Antagonists” means ligands that bind to receptors of a particular type and do not elicit an active cellular response. Antagonists inhibit the binding of agonists to receptors and thereby block the transmission of a specific receptor signal.

“Alkyloxy” or “Alkoxy” means an Alkyl O— group in which alkyl is defined in this section. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

“Amino group” means an R′R′′N-group, substituted or unsubstituted, optionally with the same substituents R ′ and R ′ ′.

“Alkylthio” means an alkyl-S group in which an alkyl group is defined in this section.

“Aminocarbonyl” means C (= O) NR _k ^a R _{k + 1} ^a is a group unsubstituted or optionally substituted with the same carbamoyl substituents R _k ^a and R _{k + 1} ^a , including hydrogen, methyl, cycloalkyl, which forms a pyrrolidine atom with a nitrogen atom cycle.

“Annelated ring” (condensed ring) means a bi- or polycyclic system in which the annelated ring and the ring or ring with which it is annelated have at least two atoms in common. Aromatic, non-aromatic systems and heterocyclic systems can be annelated.

“Aralkyl” means an alkyl group substituted with one or more aryl groups, in which the meanings of aryl and alkyl are defined in this section. Examples of aralkyl groups are optionally substituted benzyl, phenethyl, phenpropyl.

“Aryl” means an aromatic monocyclic or polycyclic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms. Aryl may contain one or more “cyclic system substituents”, which may be the same or different.

“Aromatic cycle” (aromatic system) means a planar cyclic system in which all atoms of the cycle participate in the formation of a single conjugation system, which, according to the Hückel rule, includes (4n + 2) π-electrons (n is a non-negative integer). Examples of aromatic cycles are benzene, naphthalene, anthracene, and the like. In the case of “heteroaromatic cycles”, π-electrons and p-electrons of heteroatoms participate in the conjugation system; their total number is also equal to (4n + 2). Examples of such cycles are pyridine, thiophene, pyrrole, furan, thiazole and the like. An aromatic ring may have one or more “ring system substituents” and may be annelated with a non-aromatic ring, heteroaromatic or heterocyclic ring.

“Acyl group” (Acyl) means H — C (= O) -, optionally substituted C ₁ -C ₅ alkyl-C (= O) -, C ₁ -C ₅ alkenyl-C (= O) -, C ₁ - C ₅ cycloalkyl-C (= O) -, (preferably cyclopropyl-C (= O) -, cyclobutyl-C (= O) -); heterocyclyl-C (= O) -, (preferably 2-methylfuran), aryl-C (= O) - (aroyl), aralkyl-C (= O) -, (preferably 3-phenylpentane-C (= O) -) , heteroaryl-C (= O) - (heteroaroyl), heteroarylalkyl-C (= O) are groups in which C ₁ -C ₅ alkyl-, C ₁ -C ₅ alkenyl-, C ₁ -C ₅ cycloalkyl-, heterocyclyl -, aryl-, aralkyl, heteroaryl-, heteroarylalkyl, methoxy group may have substituents, see "cyclic system substituents", "substituted alkyl", "substituted alkenyl", "heterocyclic system substituents" defined in this section.

“Heteroaryl” (hetaryl) means an aromatic monocyclic or polycyclic system comprising from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms are replaced by heteroatoms or heteroatoms such as nitrogen, sulfur or oxygen. The prefix "aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. The nitrogen atom in the heteroaryl can be oxidized to N-oxide. Heteroaryl may have one or more “ring system substituents”, which may be the same or different. Preferably, pyrrolyl, furanyl, thienyl, pyridinyl, pyrrolidine, imidazolyl, oxazolyl, benzothiadiazole, benzothiazolyl, quinolinyl, imidazolyl, thienopyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinopyridinyl , thienopyrrolyl, furopyrrolyl, etc.

“Heterocyclyl” means an aromatic or non-aromatic saturated or partially saturated monocyclic or polycyclic system comprising from 3 to 10 carbon atoms, preferably from 4 to 6 carbon atoms, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, sulfur phosphorus. The prefix "aza", "oxa" or "thia" before heterocyclyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Heterocyclyl may have one or more substituents, which may be the same or different. The nitrogen and sulfur atoms in the heterocyclyl can be oxidized to N-oxide, S-oxide or S-dioxide. Representative heterocyclyls are piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxan-2-yl, tetrahydrofuryl, tetrahydrothienyl, etc.

“Substituted alkenyl” - substituted alkenyl may also have one or more of the same or different substituents, including halogen, alkenyloxy, aroyl, heteroaroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralkyl alkylsulfonyl, heteroaralkyloxy, etc. Preferred alkenyl groups are ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl and n-hexenyl.

“Substituted alkyl” - substituted alkyl may have one or more, same or different substituents, including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, heteroaryl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonyl, heteroaralkyloxy, R _k ^a R _{k + 1} ^a N-, where R _k ^a and R _{k + 1} ^{a are} independently “amino substituents”, the meanings of which are defined in this section for example, a hydrogen atom, and alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or R _k ^a and R _{k + 1} ^a together with the N atom to which they are bonded, form through R _k ^a and R _{k + 1} ^a 4-7 membered heterocyclyl or heterocyclenyl. The preferred "alkyl substituents" are aryl, heteroaryl, heterocyclyl, hydroxy, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or R _k geteroaralkiloksikarbonil ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (= O) -, annelated arylheterocyclenyl, annelated arylheterocyclyl. Namely: hydroxy group substituted by fluorophenyl oxy group, mono- and diC ₁ -C ₅ alkylamino group (dimethylamino group, methylamino group), C ₁ -C ₅ alkyloxycarbonyl group (ethyloxycarbonyl), phenyl, chlorophenyl, fluorophenyl, C ₁ -C ₅ alkyl (methyl) substituted phenyl, C ₁ -C ₅ cycloalkyl (cyclopentyl) substituted phenyl, C ₁ -C ₅ alkoxy substituted phenyl (methoxyphenyl), thiophenyl, furanyl, pyrrolidine.

"Substituents of the cyclic system" may be representatives of aryl groups, preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be annelated with a non-aromatic ring system or heterocycle. Preferably, the cyclic system substituents are hydrogen, halogens (chlorine, fluorine, bromine), optionally substituted C ₁ -C ₅ alkyl, optionally substituted cycloC ₁ -C ₅ alkyl, C ₁ -C ₅ alkene, hydroxy group, C ₁ -C ₅ alkyloxy group ( methoxy, ethoxy, propoxy, ethylene glycol diester, methanediol diester), cyano group, C ₁ -C ₅ alkyloxycarbonyl (methyl, ethyl), alkylthio group (methylthio), carboxy group, aminocarbonyl (see “aminocarbonyl”), phenyl annelated with 5-7 saturated membered ring containing 1–3 heteroatoms (nitrogen, oxygen, and sulfur atoms ochtitelno).

“Heterocyclyl substituents” may be representatives of aryl groups, preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be annelated with a non-aromatic ring system or heterocycle. Preferred cyclic moieties are hydrogen, halogens (chlorine, fluorine, bromine), optionally substituted C ₁ -C ₅ alkyl, optionally substituted cyclo C ₁ -C ₅ alkyl, C ₁ -C ₅ alkene, hydroxy group, C ₁ -C ₅ alkyloxy group (methoxy, ethoxy, propoxy, glycol diester, diether methanediol), cyano, C ₁ -C ₅ alkyloxycarbonyl (methyl, ethyl), alkylthio (methylthio), carboxy, aminocarbonyl (cm. "aminocarbonyl"), phenyl annelated with 5-7 - membered saturated ring containing 1-3 heteroatoms (nitrogen, oxygen and sulfur atoms before respectfully).

“Substituent” means a chemical radical that is attached to a molecular skeleton (scaffold, fragment), for example, “substituent alkyl”, “substituent of amino group”, “substituent of carbamoyl”, “substituent of cyclic system”, the meanings of which are defined in this section.

“Substituted amidine group” means R′R′′N- (C = NR ″ ″) - a group in which the substituents R ′, R ″ and R ″ ″ can be represented by optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl , aryl, hetaryl and heterocyclyl, the meaning of which is defined in this section. The R′R′′N fragment of the amidine group may be a non-aromatic azaheterocycle, preferably azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, homopiperidine, homopiperazine.

“Substituted aminocarbonyl group” (aminocarbonyl) means R′R′′N-C (= O) is a group in which the substituents R ′ and R ′ ′ may be optionally substituted by alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hetaryl and heterocyclyl, the meaning of which is defined in this section. Preferred substituents of the aminocarbonyl group are optionally substituted C ₁ -C ₅ alkyl, C ₁ -C ₅ alkenyl, C ₁ -C ₅ cycloalkyl, optionally substituted aryl (see the Deputy of the cyclic system), optionally substituted hetaryl (see the Deputy of the cyclic system), optionally substituted heterocyclyl (see heterocyclyl substituent) or an amino group R′R′′N.

“Substituted aminothiocarbonyl group” (aminothiocarbonyl) means R′R′′NC (= S) is a group in which the substituents R ′ and R ′ ′ may be optionally substituted with alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hetaryl and heterocyclyl, the meaning of which is defined in this section. Preferred aminocarbonyl groups are alkylaminothiocarbonyl, cycloalkylaminothiocarbonyl, arylaminothiocarbonyl, hetarylaminothiocarbonyl and benzyl aminothiocarbonyl.

“Substituted oxy group” means a hydroxy group in which hydrogen can be substituted with C ₁ -C ₅ alkyl, C ₁ -C ₅ alkenyl, C ₁ -C ₅ cycloalkyl, aryl, hetaryl and heterocyclyl to form ethers or acyl to form esters or an aminocarbonyl group to form carbamates, or an oxycarbonyl group to form carbonates.

“Substituted oxycarbonyl group” (oxycarbonyl) means R — O — C (= O) - a group in which the substituent R may be optionally substituted by alkyl, alkenyl, cycloalkyl, aryl, hetaryl and heterocyclyl, as defined in this section. Preferred hydroxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl and benzyloxycarbonyl.

“Carbamoyl substituent” means a substituent attached to an aminocarbonyl group, the meaning of which is defined in this section. The carbamoyl substituent is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R _k ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (= O) -alkyl annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclylenyl, annelated arylheterocyclenyl Preferred carbamoyl substituents are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R _k ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (= O) -alkyl annelated arylheterocyclenyl; annelated arylheterocyclyl.

"Carboxyl" means a group -CO ₂ N.

“Combined medicinal product (preparation)” - a combination of several medicinal substances for simultaneous use in the form of tablets, capsules, injections, ointments, rectal suspensions and gels and other formulations designed to restore, correct or change physiological functions in humans and animals, as well as for the treatment and prevention of diseases, diagnosis, anesthesia, contraception, cosmetology and other things. Medicinal substances in one set can be presented in the form of various ready-made forms intended for administration into an animal or human body in various ways, for example, orally and rectally.

"Metabolic diseases" - a group of diseases associated with metabolic disorders. These diseases can be caused by a hereditary predisposition, disruptions in the endocrine and nervous systems, as well as disturbances in the functioning of metabolically active organs. Currently, there are a large number of metabolic disorders, however, this invention mainly addresses diseases associated with the signaling cascade of GPR119 receptors, in particular, such as diabetes, obesity, diabetes, metabolic syndrome, hypercholesterolemia, dyslipidemia, etc.

"Lower alkyl" means a linear or branched alkyl with 1-5 carbon atoms (C ₁ -C ₅ alkyl).

“Neurodegenerative disease” means a specific condition and disease characterized by damage and primary death of populations of nerve cells in certain areas of the central nervous system. Neurodegenerative diseases include, but are not limited to Alzheimer's and Parkinson's; Huntington's disease (chorea); multiple sclerosis; cerebellar degeneration; amyotrophic lateral sclerosis; dementia with Levy bodies; spinal muscular atrophy; peripheral neuropathy; spongiform encephalitis ("mad cow disease", Creutzfeld-Jakob Disease); AIDS-related dementia; multi-infarct dementia; frontotemporal dementia; leukoencephalopathy (a disease of endangered white matter); chronic neurodegenerative diseases; stroke; ischemic, reperfusion, and hypoxic brain damage; epilepsy cerebral ischemia; glaucoma; traumatic brain injury; Down syndrome; encephalomyelitis; meningitis; encephalitis; neuroblastoma; schizophrenia; Depressed In addition, neurodegenerative diseases include pathological conditions and disorders that develop with hypoxia, substance abuse, exposure to neurotoxins, infectious and oncological diseases of the brain, as well as neuronal damage associated with autoimmune and endocrine diseases; and other neurodegenerative processes.

"Receptors" (from the Latin recipere - to receive, to recognize) are biological macromolecules located on the cytoplasmic membrane of a cell or intracellular, capable of specifically interacting with a limited set of physiologically active substances (ligands) and transforming the signal about this interaction into a specific cellular response.

"TGR5 receptors" (also known as GPBAR1, M-BAR, AXOR 109 and GPCR19) are GPCR receptors associated with Gs proteins. They are expressed mainly in the gall bladder, gastrointestinal tract, spleen, lungs, placenta, some parts of the central nervous system, as well as in immune cells (monocytes and dendritic cells).

“Signal cascade” (signal system, signal transmission cascade) means a set of interconnected sequential and parallel molecular processes of regulation of cellular metabolism by external (primary) signals that carry information into the cell, which fundamentally distinguishes them from other chemical compounds entering the cell that serve as its source matter and energy. The molecular mechanisms of transmission (transduction) of external signals into the cell imply not only the transmission of signals as such, but also the whole complex of events associated with it, including amplification, attenuation and suppression (or switching off) of signals.

"Sulfonyl" means R-SO ₂ - a group in which the substituent R can be represented by optionally substituted C ₁ -C ₅ alkyl, C ₁ -C ₅ alkenyl, C ₁ -C ₅ cycloalkyl, optionally substituted aryl (see the Deputy of the cyclic system ), optionally substituted hetaryl (see cyclic system substituent), optionally substituted heterocyclyl (see cyclic system substituent), or R′R′′N amino group, the meanings of which are defined in this section.

“Thioacyl group” (Thioacyl) means optionally substituted alkyl-C (= S) -, alkenyl-C (= S) -, cycloalkyl-C (= S) -, heterocyclyl-C (= S) -, aryl-C ( = S) - aralkyl-C (= S) -, heteroaryl-C (= S) -, heteroarylalkyl-C (= S) - groups.

“Cycloalkyl” means a non-aromatic mono- or polycyclic system containing from 3 to 10 carbon atoms. Cycloalkyl may have one or more “ring system substituents”, which may be the same or different. Representative cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin, norbornyl, adamant-1-yl and the like. Preferred “cyclic system substituents” are alkyl, alkoxy, hydroxy or amino group, the meaning of which is defined in this section.

“Cycloalkenyl” means a non-aromatic mono- or polycyclic system containing from 3 to 10 carbon atoms and containing one or more carbon-carbon double bonds. Representatives of cycloalkenyl groups are cyclopentenyl and cyclohexenyl.

"Pharmaceutical composition" means a composition comprising an active component and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceiving means, delivery vehicles such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial Gent, fungicides, lubricants, and prolonged delivery controllers, the choice and suitable proportions of which depend on the nature and way of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be achieved using a variety of antibacterial and antifungal agents, for example, such as parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and distributors are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms. Pharmaceutical compositions are generally prepared using standard procedures involving the mixing of the active compound with a liquid or finely divided solid carrier. For the manufacture of suppositories, in addition to the active components, cocoa butter, its alloys with paraffin and hydrogenated fats, vegetable and animal hydrogenated fats, solid fat, lanol, alloys of hydrogenated fats with wax, hard paraffin and other bases approved for medical use are also used.

“Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like. (A detailed description of the properties of such salts is given in Berge S. M., et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like. In addition, tetraalkylammonium hydroxides, for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. As amino acids, the main amino acids can be used - lysine, ornithine and arginine.

"Pharmaceutically acceptable excipients" by pharmaceutically acceptable excipients refers to pharmaceutical diluents, excipients and / or carriers.

The purpose of the present invention is to create new selective agonists of GPR119 receptors as potential antidiabetic drugs.

This goal is achieved by 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) aryloxy] methyl} piperidines of the general formula I in the form of free bases, as well as their pharmaceutically acceptable salts.

The subject of the present invention are novel GPR119 receptor agonists, which are derivatives of substituted 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) aryloxy] methyl} piperidines of the general formula I in the form of free bases, and also in the form of their pharmaceutically acceptable salts,

where R = H, (C ₁ -C ₅ ) alkyl, substituted (C ₁ -C ₅ ) alkyl, acyl selected from the group C ₁ -C ₅ alkylC (= O) - or phenyl (C = O) -, substituted heteroaryl, which is an aromatic monocyclic group with two nitrogen atoms, which is substituted by a halogen atom or C ₁ -C ₅ alkyl, (C ₁ -C ₃ ) alkylsulfonyl, phenylsulfonyl; R1, R2, R3, R4 are hydrogen or one or two substituents simultaneously selected from halogen, (C ₁ -C ₃ ) alkyl, halogen-substituted (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkylsulfonyl, cyano .

Preferred are derivatives of 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) aryloxy] methyl} piperidines of the general formula I.1 in the form of free bases, racemic mixtures or individual optical isomers, as well as their pharmaceutically acceptable salts

where R = H, (C ₁ -C ₅ ) alkyl, halogen-substituted (C ₁ -C ₅ ) alkyl, acyl selected from the group C ₁ -C ₅ alkylC (= O) - or phenyl (C = O) - ,, substituted heteroaryl, which is an aromatic monocyclic group with two nitrogen atoms, which is substituted by a halogen atom or C ₁ -C ₅ alkyl, (C ₁ -C ₃ ) alkylsulfonyl, phenylsulfonyl.

More preferred compounds are:

Tert-butyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidine-1-carboxylate (I.1.1);

4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidine hydrochloride (I.1.a);

5-chloro-2- (4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidin-1-yl) pyrimidine (I.1.b );

Tert-butyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2,6-difluorophenoxy] methyl} piperidine-1-carboxylate (I.2.1);

Tert-butyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2- (methylsulfonyl) phenoxy] methyl} piperidine-1-carboxylate (I.3.1);

Tert-butyl 4 - {[2-chloro-4- (3,3-dioxo-1,3-benzoxathiol-6-yl) phenoxy] methyl} piperidine-1-carboxylate (I.4.1);

Tert-butyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-methylphenoxy] methyl} piperidine-1-carboxylate (I.5.1);

Tert-butyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -3-fluorophenoxy] methyl} piperidine-1-carboxylate (I.6.1);

Tert-butyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2- (trifluoromethyl) phenoxy] methyl} piperidine-1-carboxylate (I.7.1);

Tert-butyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -3,5-difluorophenoxy] methyl} piperidine-1-carboxylate (I.8.1);

Tert-butyl 4 - {[2-cyano-4- (3,3-dioxo-1,3-benzoxathiol-6-yl) phenoxy] methyl} piperidine-1-carboxylate (I.9.1);

Tert-butyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-isopropylphenoxy] methyl} piperidine-1-carboxylate (I.10.1);

2- (4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidin-1-yl) -5-fluoropyrimidine (I.1.c) ;

5-bromo-2- (4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidin-1-yl) pyrimidine (I.1.d );

2- (4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidin-1-yl) -5-ethylpyrimidine (I.1.e) ;

Isopropyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidine-1-carboxylate (I.1.f);

4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} -1- (methylsulfonyl) piperidine (I.1.g);

4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} -1- (phenylsulfonyl) piperidine (I.1.h);

1- (2,2-dimethylpropanoyl) -4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidine (I.1.i);

1-benzoyl-4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidine (I.1.j);

4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} -1- (3,3,3-trifluoropropyl) piperidine (I.1.k) ;

(1R) -1-methylpropyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidine-1-carboxylate (I.1.l);

(1S) -1-methylpropyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidine-1-carboxylate (I.1.m);

The subject of this invention is the pharmaceutically acceptable salts of the compounds of general formula I. Some of the compounds of the present invention are neutral molecules and do not form salts, another part contains ionic groups (secondary, tertiary amines or carboxylic acids) and can form salts which were prepared by methods known in the art. this technical field.

The subject of this invention is racemic mixtures and individual optical isomers of compounds of general formula I, since a number of compounds of general formula I have an asymmetric center, and substances can exist in the form of racemic mixtures and isomeric forms.

The subject of this invention is a method for preparing 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) aryloxy] methyl} piperidine derivatives of the general formula I, starting from synton A (Scheme 1). Arylation of synthon A with a suitable arylboronic ester B in the presence of a palladium catalyst (preferably Pd [dppf] C12) in the presence of a base (preferably potassium acetate) leads to a series of substances I.

Scheme 1

where tf is trifluoromethylsulfonyl.

In the case of R = boc or another protecting group, deprotection and subsequent alkylation, arylation, hetarylation, acylation, carbomoylation, sulfonylation of piperidine secondary amide are possible (Scheme 2).

Scheme 2

where R = H, (C ₁ -C ₅ ) alkyl, halogen-substituted (C ₁ -C ₅ ) alkyl, acyl selected from the group C ₁ -C ₅ alkylC (= O) - or phenyl (C = O) -, substituted heteroaryl, which is an aromatic monocyclic group with two nitrogen atoms, which is substituted by a halogen atom or C ₁ -C ₅ alkyl, (C ₁ -C ₃ ) alkylsulfonyl, phenylsulfonyl; R1, R2, R3, R4 are hydrogen or one or two substituents simultaneously selected from halogen, (C ₁ -C ₃ ) alkyl, halogen-substituted (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkylsulfonyl, cyano X-reactive group.

The subject of the present invention is an active component having the property of a GPR119 receptor agonist, which is a derivative of 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) aryloxy] methyl} piperidine of the general formula I.

GPR119 receptor agonists specifically bind to GPR119 receptors and stimulate the production of incretins, which in turn stimulate the production of insulin by pancreatic β-cells in response to glucose loading.

The subject of this invention is a pharmaceutical composition intended for the prevention and treatment of metabolic diseases and related cardiovascular and neurodegenerative diseases, containing in an effective amount an active component having the property of a GPR119 receptor agonist, as well as any of the above pharmaceutical compositions in the form of tablets, capsules and injections placed in pharmaceutically acceptable packaging.

The subject of this invention is a combined drug intended for the prevention and treatment of metabolic diseases and related cardiovascular and neurodegenerative diseases, containing in an effective amount a GPR119 agonist - derivative 4 - {[4- (3,3-dioxo-1,3-benzoxathiol -6-yl) aryloxy] methyl} piperidine of the general formula I and one or more antidiabetic drugs for simultaneous use.

Under metabolic diseases are understood: metabolic syndrome, diabetes mellitus, obesity.

The subject of this invention is a combined pharmaceutical composition intended for the prevention and treatment of metabolic diseases, containing in an effective amount an active component (agonist of the GPR119 receptor is a derivative of 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl ) aryloxy] methyl} piperidine of the general formula I) and one or more antidiabetic drugs, such as dipeptidyl peptidase-IV inhibitors, alpha-glucosidase inhibitors, sulfonylureas, biguanides, receptor activity modulators in activating peroxisome proliferation, a protein tyrosine phosphatase 1B inhibitors, inkretinomimetikidlya simultaneous use in the form of tablets, capsules, injections and other formulations.

The subject of this invention is the aforementioned pharmaceutical compositions in the form of tablets, capsules, ointments, gels, injections and other formulations, placed in a pharmaceutically acceptable package.

The pharmaceutical composition may include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, excipients and / or carriers used in the pharmaceutical field. The pharmaceutical composition along with the active component of the present invention may include other active ingredients, provided that they do not cause undesirable effects, for example, allergic reactions.

If it is necessary to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed for the manufacture of various forms, while they can include traditional pharmaceutical carriers; for example, oral forms (such as tablets, gelatine capsules, pills, solutions or suspensions); injection forms (such as solutions or suspensions for injection or dry powder for injection, which only requires the addition of water for injection before use); local forms (such as ointments or solutions).

The carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to obtain common forms, including: in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, colorless are used agents, flavoring agents of taste; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used.

The new pharmaceutical composition can be obtained by mixing with an inert excipient and / or solvent of the active component, which is at least one of the compounds of general formula I, as well as their free bases, racemic mixtures or individual optical isomers, as well as their pharmaceutically acceptable salts and / or hydrates.

The subject of this invention is a drug.

Medicines may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, topically or rectally). The clinical dosage of the active component (s), pharmaceutical composition or combination drug comprising a pharmaceutically effective amount of the active component in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body, as well as depending on the age, sex and stage of the patient’s disease, while the daily dose in adults is usually 10-300 mg, preferably 50-200 mg . Therefore, during the preparation of the pharmaceutical compositions of the present invention in the form of dosage units, the above effective dosage must be taken into account, with each dosage unit of the preparation containing 5-300 mg, preferably 10-200 mg. In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).

The subject of this invention is a method for the prevention and treatment of metabolic diseases and related cardiovascular and neurodegenerative diseases by administering in an effective amount of a new active component or a new pharmaceutical composition.

The subject of this invention is a method for the prevention and treatment of metabolic diseases and related cardiovascular and neurodegenerative diseases by administering in an effective amount of a combination drug or a combined pharmaceutical composition.

The invention is illustrated by the following drawing:

Fig. 1. The glucose level (mmol / l) in the blood of animals with alloxan diabetes mellitus before and after administration of compound ZB40-0016.

Designations: “control” - a control group of animals with alloxan diabetes mellitus receiving physiological saline; "ZB40-0016" - groups of animals with alloxan diabetes mellitus receiving compound ZB40-0016 in doses of 0.1 or 1 mg / kg; significance of differences: * - p <0.05 - relative to the initial level of glycemia.

The following examples illustrate but do not limit the invention.

The structures of the compounds obtained were confirmed by chemical, chromatographic and spectral analysis.

Example 1. Synthon A synthesis method (Scheme 1 and Scheme 3).

Sinton A was obtained in accordance with scheme 3:

Compound C ₁ .

100 g (0.6 mol) of the starting 6-hydroxy-1,3-benzoxythiol-2-one was dissolved in 1000 ml of abs. acetonitrile, successively, 165 g (1.2 mol, 2 equiv.) of potash calcined and 77.8 ml (0.66 mol, 1.1 equiv) of benzyl bromide were added to the reaction mass. The reaction mass was stirred overnight at 70 ° C. After cooling, inorganic salts were filtered and the filtrate was evaporated to a volume of 150 ml, the precipitate was filtered and washed with 150 ml of cold diethyl ether. After air drying, the yield of 6 - [(phenylmethyl) oxy] -1,3-benzoxythiol-2-one 123.3 g (80%).

Compound C ₂ .

78.2 g (0.3 mol) 6 - [(Phenylmethyl) oxy] -1,3-benzoxythiol-2-one was dissolved in 235 ml of dibromomethane and 16 ml of water, after which 125.5 g of potash (0.9 mol) was successively added. , 3 equiv.) And 2 g of 18-crown-6-ether (0.0075 mol, 0.025 equiv.). The reaction mass was boiled under argon with stirring for 48 h with TLC to control the completion of the reaction. After cooling, the reaction mass was filtered from inorganics, and the bulk of the solvent was evaporated in vacuo. The residue was filled with 400 ml of methylene chloride. The methylene chloride layer was separated, washed with saturated sodium chloride solution (2 × 100 ml), dried over sodium sulfate, filtered, and the filtrate was evaporated in vacuo. The evaporation residue was filled with 200 ml of abs. diethyl ether under cooling with dry ice and stirred for 30 minutes, then the precipitate was quickly filtered and washed on the filter with 100 ml of dry cold diethyl ether. After air drying, the yield of 6 - [(phenylmethyl) oxy] -1,3-benzoxythiol was 62.5 g (85%).

Compound C ₃ .

62.5 g (0.26 mol) of 6 - [(Phenylmethyl) oxy] -1,3-benzoxythiol was dissolved in 625 ml of acetic acid. 125 ml of 30% hydrogen peroxide were added and the reaction mass was stirred overnight at 70 ° C. After cooling, 625 ml of water was added to the reaction mass. The precipitate after stirring for 10 minutes was filtered and washed with 2 × 100 ml of water. After air drying, the yield of 6 - [(phenylmethyl) oxy] -1,3-benzoxythiol 3,3-dioxide was 61.7 g (87%).

Compound C4.

68 g (0.25 mol) 6 - [(Phenylmethyl) oxy] -1,3-benzoxythiol 3,3-dioxide was dissolved in 816 ml THF and Pd / C (10%) was added 6.8 g per min. dist. water. The reaction mass was stirred at room temperature overnight under a pad of hydrogen with TLC control of completion of the reaction. The reaction mixture was filtered through a pad of cellite, and the filtrate was evaporated in vacuo. The precipitate was filtered and washed with 100 ml of diethyl ether. After air drying, the yield of 1,3-benzoxythiol-6-ol 3,3-dioxide was 39.2 g (86%).

Compound (synthon) A.

A solution of 39.2 g (0.21 mol) of 1,3-benzoxythiol-6-ol 3,3-dioxide in 392 ml of abs. pyridine was cooled to 0 ° C and 39 ml (0.23 mol, 1.1 equiv) of trifluoromethanesulfonic anhydride was added dropwise. The reaction mass was stirred for 30 minutes at 0 ° C and night at room. t-re. The reaction mass was evaporated to dryness, the residue was filled in with 400 ml of ethyl acetate. The ethyl acetate layer was washed with 100 ml of a 10% aqueous citric acid solution, 100 ml of a saturated sodium chloride solution, and then with 100 ml of water. The organic layer was dried over sodium sulfate, filtered, and the filtrate was evaporated in vacuo. The precipitate was filtered and washed three times with diethyl ether. Then the technical product was dissolved in methylene chloride and passed through a layer of silica gel (eluent is methylene chloride). After evaporation of methylene chloride, the product was washed with ether, 2 × 50 ml. After air drying, the yield of 3,3-dioxo-1,3-benzoxythiol-6-yl trifluoromethanesulfonate was 54.5 g (85%).

Synthesis of synthons B is performed according to general scheme 4.

Scheme 4

где

Where

R = tert-butyloxycarbonyl or other protecting group;

R1, R2, R3, R4 are hydrogen or one or two substituents simultaneously selected from halogen, (C ₁ -C ₃ ) alkyl, halogen-substituted (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkylsulfonyl, cyano .

Example 2. Synthesis of synton B1.

Compound D1.1 is prepared according to Scheme 5.

Scheme 5

80.0 g (0.27 mol) of tert-butyl 4 - {[(methylsulfonyl) oxy] methyl} piperidine-1-carboxylate, 62.5 g (0.33 mol) of 4-bromo-2-fluorophenol (D 0.1) and 75.38 g (0.55 mol) calcined potash with stirring was heated to 110 ° C in dimethyl sulfoxide (800 ml) for 16 h with TLC monitoring of the progress of the reaction. Upon completion of the reaction, dimethyl sulfoxide was distilled off in vacuo and the residue was poured with water (800 ml). The precipitate was filtered and recrystallized from isopropanol. The yield of tert-butyl 4 - [(4-bromo-2-fluorophenoxy) methyl] piperidine-1-carboxylate was 88.0 g (83.1%).

1H NMR (400 MHz, DMSO-D6) δ 7.50 (dd, J = 10.85, 2.30 Hz, 1 H), 7.30 (m, 1 H), 7.15 (m, 1 H), 3.96 (d, J = 10.74 Hz , 2 H), 3.90 (d, J = 6.36 Hz, 2 H), 2.66-2.79 (m, 2 H), 1.89-1.98 (m, 1 H), 1.72 (d, J = 10.96 Hz, 2 H) , 1.39 (s, 9 H), 1.09-1.23 (m, 2 H).

Sinton B1 is obtained in Scheme 6.

Scheme 6

60.0 g (0.15 mol) tert-butyl 4 - [(4-bromo-2-fluorophenoxy) methyl] piperidine-1-carxylate (D 1.1.), 51.0 g (0.2 mol) 4.4.4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi-1,3,2-dioxoborolan, 5.63 g (0.008 mol) of Pd DPPF and 45.5 g (0.46 mol) of potassium acetate were mixed in acetonitrile (1000 ml ) under argon at 65-70 ° C for 16 hours. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with a saturated solution of sodium chloride. The organic layer was separated, dried over sodium sulfate, filtered, and the filtrate was evaporated in vacuo. The residue after evaporation was purified on a column of silica gel, the eluent was a mixture of hexane-ethyl acetate. Yield of tert-butyl 4 - {[2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) phenoxy] methyl} piperidine-1-carboxylate 50.0 g (74.3 %).

1H NMR (400 MHz, DMSO-D6) δ ppm 7.42 (d, J = 8.11 Hz, 1H), 7.31 (m, 1H), 7.15 (m, 1H), 3.91-4.02 (m, 4 H), 2.66- 2.80 (m, 2H), 1.89-2.02 (m, 1H), 1.73 (d, J = 11.18 Hz, 2 H), 1.39 (s, 9 H), 1.27 (s, 12 H), 1.07-1.22 (m , 2H).

Other syntheses B2-B10 were also obtained according to this synthesis scheme.

Other synthons B obtained by a similar scheme are shown in Table 2.

Example 3. Synthesis of compound 1.1.1. (Scheme 7).

36.1 g (83 mmol) tert-butyl 4 - {[2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) phenoxy] methyl} piperidin-1- carboxylate (Sinton B1), 26.5 g (83 mmol) of 3,3-dioxide-1,3-benzoxythiol-6-yl trifluoromethanesulfonate (Sinton A), 69.0 g (0.5 mmol) of potash and 3.1 g (4 mmol) of PdDPPFCl ₂ were mixed in 0.5 liters of water and 0.5 liters of dioxane (potash was previously dissolved in water, the catalyst was added after degassing under argon). The reaction mixture was stirred under argon for 1 h. The precipitate formed was filtered off and purified by silica gel column chromatography.

The resulting product was purified by stirring with Lewatit mono plus SP-112 resin - 5.0 g in dioxane (200 ml). After filtration and evaporation, the yield of tert-butyl 4 - {[4- (3,3-dioxide-1,3-benzoxothiol-6-yl) -2-fluorophenoxy] methyl} piperidine-1-carboxylate is 28.4 g (71.5%).

1H NMR (400 MHz, DMSO-D6) δ ppm 7.89 (d, J = 8.11 Hz, 1H), 7.71 (dd, J = 12.94, 1.97 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J = 8.11 Hz, 2H), 7.28 (t, J = 8.77 Hz, 1H), 5.43 (s, 2H), 3.94-4.02 (m, 4H), 2.67-2.85 (m, 2H), 1.93 (m, 1H) , 1.74 (d, J = 11.62 Hz, 2H), 1.40 (s, 9H), 1.11-1.24 (m, 2H).

Example 4. Synthesis of compound 1.1.a. (Scheme 8).

24.0 g (50 mmol) of tert-butyl 4 - {[4- (3,3-dioxide-1,3-benzoxothiol-6-yl) -2-fluorophenoxy] methyl} piperidine-1-carboxylate (I.1.1.) was dissolved in dioxane (350 ml), and a saturated solution of hydrogen chloride in dioxane was added to the reaction mixture. The reaction mass was heated to 70 ° C for 24 hours. After cooling, the precipitate was filtered and dried in vacuo. Yield 4 - {[4- (3,3-dioxide-1,3-benzoxothiol-6-yl) -2-fluorophenoxy] methyl} piperidine hydrochloride 19.5 g (93.7%).

1H NMR (400 MHz, DMSO-D6) δ ppm 9.01 (br.s, 1H), 8.69 (br.s, 1H), 7.90 (d, J = 8.11 Hz, 1H), 7.73 (dd, J = 12.83, 2.30 Hz, 1H), 7.62 (s, 1H), 7.59 (d, J = 8.11 Hz, 2H), 7.31 (t, J = 8.88 Hz, 1H), 5.44 (s, 2H), 4.02 (d, J = 6.36 Hz, 2H), 3.29 (d, J = 12.50 Hz, 2H), 2.90 (m, 2H), 2.11 (br.s, 1H), 1.92 (d, J = 12.72 Hz, 2 H), 1.57 (m , 2 H).

Example 5. Synthesis of compound 1.1.b. (Scheme 9).

23.4 g (57 mmol) 4 - {[4- (3,3-dioxide-1,3-benzoxothiol-6-yl) -2-fluorophenoxy] methyl} piperidine hydrochloride (I.1.a), 10.1 g (68 mmol) ) 2,5-dichloropyrimidine and 22.9 g (0.23 mol) of triethylamine were mixed in acetonitrile (500 ml), and the reaction mixture was boiled for 16 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, and the precipitate was filtered and sequentially washed with water, acetonitrile, ether and hexane. After drying in vacuo, the yield of 5-chloro-2- (4 - {[4- (3,3-dioxide-1,3-benzoxothiol-6-yl) -2-fluorophenoxy] methyl} piperidin-1-yl) pyrimidine 26.1 g (94.3%).

1H NMR (400 MHz, DMSO-D6) δ ppm 8.39 (s, 2H), 7.89 (d, J = 8.33 Hz, 1H), 7.71 (dd, J = 12.83, 1.64 Hz, 1H), 7.61 (s, 1H ), 7.58 (dd, J = 8.33, 1.10 Hz, 2H), 7.28 (t, J = 8.77 Hz, 1H), 5.43 (s, 2H), 4.63 (d, J = 12.94 Hz, 2H), 4.01 (d , J = 6.36 Hz, 2H), 2.96 (t, J = 11.84 Hz, 2H), 2.04-2.18 (m, 1H), 1.86 (d, J = 12.28 Hz, 2H), 1.20-1.35 (m, 2H) .

Thus, according to the methods described in examples 3-5 were obtained compounds I.1.1, I.2.1-I.9.1, as well as compounds I.1.a-I.1.m, are presented in Table 3.

The structure of a number of compounds 1.1.1 was also confirmed by ¹ H NMR (DMSO-D ₆ , 400 MHz).

Example 9. General method for the synthesis of salts of compounds of General formula I.

Part of the compounds of the present invention contains ionic groups (secondary and tertiary amines or carboxylic acids) and can form salts, which are obtained by methods known in the art. For this, for example, to a solution of a base in an inert solvent (alcohol, acetone, chloroform, ether, ethyl acetate), a solution of an equivalent amount (sometimes an excess) of an organic or inorganic acid in an inert solvent was added and precipitation of the desired salt was achieved. The inorganic acid may be hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, hydrobromic acid or hydroiodic acid. The organic acid may be methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, lactic acid gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid or vanillic acid, n o not limited to them.

Another option for the synthesis of salts of compounds I is the removal of the protective group in an acidic environment (for example, the removal of tert-butyloxycarbonyl group) with the simultaneous formation of an amine salt. As an example of such a reaction, Example 4 is provided. Synthesis of compound 1.1.a.

Example 10. Determination of the agonistic activity of the compounds with respect to the hGPR119 receptor.

Compounds were tested using the CHO-K1 cell line in which the human GPR119 receptor (hGPR119) was stably expressed. The agonistic activity of the compounds was evaluated by increasing the intracellular concentration of cAMP, since it is known from the literature that activation of the hGPRl 19 receptor by subsequent activation of cellular adenylate cyclase leads to an increase in the intracellular cAMP content. As an experimental platform, the Lance Ultra cAMP (Perkin Elmer) test system was chosen. Known agonists of the hGPRl 19 receptor were used as a positive control and to determine the absolute value of the maximum signal of the experiment. For all compounds, the dependence of the agonistic activity of the substance on the concentration of the substance was analyzed. From the obtained dependency graphs, the EC50 values were determined (the concentration of the substance in micromoles, which causes 50% of the maximum effect).

Cell line: immortalized CHO-K1 line stably expressing hGPRl 19, Cambrex, catalog number A633. The cell culture medium was a mixture of DMEM / F-12, 10% fetal bovine serum, 1% non-essential amino acids, 2 mM L-glutamine, and 400 μg / ml G418 as a selective antibiotic.

Preparing cells for the experiment. Cells were thawed in a water bath at 37 ° C, resuspended in 5 ml of Hanks solution, centrifuged and again resuspended in 6 ml of Hanks solution. Thus, the cells were washed from serum and culture medium. The centrifugation step was repeated and the cells were resuspended in the stimulation buffer of the test system (SB). The final cell concentration was 8.00E + 05 cells / ml, which gave 4000 cells per well. cAMP antibodies were added to the cell suspension in a ratio of 1: 150.

Preparation of tablets with substances. The substances were dissolved in DMSO to a concentration of 3 mM. Next, serial dilution of the substances was prepared in DMSO with step 3.16. Tablets with substances in DMSO were stored at -20 ° C.

Experiment Log

1. On the day of the experiment, the buffer for the experiment (SB) was prepared: 1x HBSS, 5 tM HEPES, 0.1% BSA, pH 7.4. 45 ml of HBSS, 225 μl of 1M HEPES and 600 μl of 7.5% BSA were mixed.

2. A cell suspension including a 4-fold solution of anti-AMP antibodies was added to 384-well experimental plates, 5 μl per well using a Biomek 2000 automated system (Beckman Coulter). Centrifuged at 300 rpm for 1 minute.

3. A 2-fold mixture of [SB + substance] was added to the cell suspension using the Biomek FX 384 robotic system. To prepare a 2-fold mixture of [SB + substance], SB was transferred to a 384 well plate, 99 μl / well. 1 μl of a 200-fold working solution of substances in DMSO was transferred to the same 384-well plate. The resulting mixture was thoroughly mixed. 5 μl of a 2-fold mixture of [SB + substance] was added to the cell suspension at 5 μl per well. The experimental plate was centrifuged at 300 rpm for 1 minute. Then the cell suspension was incubated with substances for 30 min at room temperature on a shaker, 300 rpm.

4. The initial solution of the Eu-cAMP tracer was diluted 1: 100 in the buffer for signal detection, obtaining a 2-fold working solution of the tracer. Next, the solution was added to the experimental plate according to Jumkl using a Biomek 2000 robotic system. The cell suspension was incubated with a solution for signal detection for 60 minutes on a shaker, 300 rpm.

5. The essay signal was measured on a Wallac 1420 Victor ³ multifunction reader (Perkin Elmer) using a wavelength of 665 nm, LANCE protocol High Count_665_OptiPlate.

6. The agonistic activity of the substances was calculated using a script for processing Grand CaLculate_0.1.1 data. As the minimum signal of the experiment, the averaged data of wells 23 of the column of the experimental plate containing unstimulated cells were used. As the maximum signal of the experiment, the averaged data of all wells of the 24th column of the experimental plate containing cells stimulated by the known hGPR119 agonist was used.

Example 11. Determination of EC50 for the most active substances.

Data was analyzed using GraphPad Prizm (GraphPad Software, Inc., San Diego, CA). To build the concentration dependence, the equation was chosen

The EU _{50 was} determined based on the constructed schedule, as the concentration of a substance that causes 50% of the maximum effect. The ranges of agonistic activity in relation to GPR119 of some synthesized compounds are shown in Table 4.

Pharmacological properties of the claimed compounds

Example 12. A study of the pharmacological effect of the compound ZB40-0016 (I.1.b) on glucose metabolism (glucose tolerance test - PGTT).

The test compound was administered orally at doses of 0.1 and 1 mg / kg to intact sexually mature outbred male rats of 200-220 g, 3.5-4 months of age. An oral glucose tolerance test was performed after a 6-hour fasting of animals with intragastric administration of a glucose solution at a dose of 3 g / kg. Measurement of glycemia was carried out before the introduction of glucose and 30, 60 and 120 minutes after its introduction. The glucose content in rat blood was determined by the glucose oxidase method with measuring the optical density of the supernatant in cells with an optical path length of 10 mm at a wavelength of 500 (490-540) nm on a spectrophotometer (PE-5400 V, ECROS) using Glucose PKD kits (Russia). As a control, an equivalent amount of saline was administered.

The results of studies of the effect of compound ZB40-0016 (I.1.b) on glucose metabolism in intact animals under conditions of an oral glucose tolerance test are presented in table 5.

Note: n is the number of animals in the group; (%) is the percentage change in blood glucose relative to the initial level of glycemia; significance of differences: * - ρ <0.05 - relative to the initial level of glycemia; ^ - p <0.05 - relative to the intact group.

As can be seen from the data presented in table 5, with the oral administration of a glucose solution to intact animals (intact), its blood level began to increase 30 minutes after the glucose solution was administered, reaching a maximum after 60 minutes (an increase relative to the baseline was 33%) and decreasing almost to the initial level two hours after glucose administration. Against the background of a preliminary single administration of compound ΖΒ40-0016 (I.1.b) at a dose of 0.1 mg / kg, a slight decrease in the “sugar curve” was observed in comparison with the control group. However, at a dose of 1 mg / kg, this substance already caused a significant decrease in hyperglycemia compared with intact animals during the entire observation period (table 5).

Thus, under the conditions of an oral glucose tolerance test, it was found that compounds ΖΒ40-0016 (I.1.b) at a dose of 1 mg / kg with a single intragastric administration exhibits hypoglycemic properties.

Example 13. The effect of preliminary prophylactic administration of compound ΖΒ40-0016 (I.1.b) on the sensitivity of animals to the diabetogenic effect of alloxan.

Study of the effect of the prophylactic use of compound ZB40-0016 (I.1.b) in doses of 0.1 mg / kg and 1 mg / kg on the survival of animals and their glycemia was performed against the background of administration of alloxan to rats. The inventive compound was administered orally two hours before the injection of alloxan at a dose of 150 mg / kg and then for 21 days after it. Glycemia levels were compared with the corresponding indicators of animals intact (without alloxan injection, but received saline within 21 days) and control groups (alloxan injections at a dose of 150 mg / kg and then saline for 21 days).

The introduction of alloxan at a dose of 150 mg / kg contributed to the development of diabetes mellitus, complicated by toxic damage to a number of vital organs and systems, which led to mortality of 33.3% of control animals already on the 3rd day. The lethality of animals that prophylactically 2 hours before the injection of alloxan and then for the 21st day received the test compound at doses of 0.1 and 1 mg / kg was less than in the control group and amounted to 12.5% and 25%, respectively . It should also be noted that in the course of prophylactic administration of the compound ZB40-0016 (I.1.b), the appearance of the animals of these groups was also significantly better than in the control-diabetes group without pharmacological support.

Preliminary administration of compound ZB40-0016 (I.1.b) in the studied doses contributed to the reduction of hyperglycemia against the background of alloxan diabetes. Thus, in rats, which were administered the test compound at doses of 0.1 and 1 mg / kg two hours before the injection of alloxan and then for 21 days after the injection, the glycemia level was significantly lower compared to control animals treated with physiological physiological conditions. solution (table 6).

An oral glucose tolerance test in animals with alloxan diabetes was performed on the 21st day after the administration of alloxan.

By 21 days in animals treated with the test compound, there was a tendency to improve glucose load tolerance (table 7). So, 30 minutes after the intragastric administration of compound ZB40-0016 at a dose of 0.1 and 1 mg / kg, a decrease in glycemia was recorded by 46% and 49% compared with the control-diabetes. An hour after the introduction of glucose, its level in the blood also continued to decline. In the study of blood samples of the second hour, it was found that the glucose level in the blood of rats receiving ZB40-0016 at a dose of 0.1 and 1 mg / kg was 11 ± 1.5 and 10.9 ± 2.1 mmol / l, respectively which is significantly lower than the values obtained for the control-diabetes group. In addition, there was a decrease in the area under the concentration-glucose-time curve by an average of 37-41% in groups of rats treated with the test compound compared to the control.

Thus, preliminary prophylactic course administration of compound ZB40-0016 at doses of 0.1 and 1 mg / kg against the background of developing alloxan diabetes slows its development, reducing the severity of hyperglycemia in experimental animals.

Example 14. The hypoglycemic activity of compound ZB40-0016 with a single administration to rats with alloxan diabetes.

The hypoglycemic activity of compound ZB40-0016 was studied with its single administration to rats with alloxan diabetes mellitus. For this, the test compound was administered to animals 7 days after alloxan injection. Blood samples were taken to measure glycemia before administration of ZB40-0016 and then every hour for 3 hours.

It was found that a single intragastric administration of the test compound in doses of 0.1 and 1 mg / kg contributed to a decrease in blood glucose levels by an average of 21-22% (Figure 1).

Example 15. The hypoglycemic activity of the compound ZB40-0016 with the course of the introduction of rats with alloxan diabetes.

The influence of the course intragastric administration of the compound ZB40-0016 was studied in the course of the 14-day administration to rats with alloxan diabetes mellitus.

After administration of alloxan to rats, a significant increase in blood glucose was observed in animals: on the seventh day after administration of alloxan, the blood sugar level in rats was on average 6.7-7 times higher (p <0.05) than similar indicators in the group intact control.

Then, for 14 days, the glycemia level in the control-diabetes group remained on average 6.3–6.7 times higher compared with the intact group (p <0.05) (table 8). Such prolonged persistent hyperglycemia led to the death of some animals in the group with experimental diabetes. An external examination of animals of this group revealed a significant increase in the number of erosive lesions on the skin, infection of microtraumas, the coat was gray, dull, its loss was noted.

Under the influence of the analyte, there was a decrease in blood glucose. In the group of animals treated with compound ZB40-0016 at a dose of 1 mg / kg as a treatment, a more pronounced decrease in hyperglycemia was observed than with the administration of the same compound at a dose of 0.1 mg / kg (table 8).

So, after a weekly use of ZB40-0016 at a dose of 1 mg / kg, the glucose level decreased by 20% (p <0.05) compared to the negative control - the control-diabetes group. Over the next 7 days, i.e. up to 14 days, this effect persisted.

The following tendency was observed in the group of animals treated with the test compound at a dose of 0.1 mg / kg: a decrease in hyperglycemia was observed to a greater extent on day 7 (13% (p <0.05)) compared with the group with control diabetes ”, Then on the 14th day of treatment, a statistically insignificant hypoglycemic effect was observed (glucose level was 7% lower compared to the control-diabetes group).

Thus, a 14-day intragastric administration of compound ZB40-0016 at a dose of 1 mg / kg can reduce the severity of diabetes, reducing the severity of hyperglycemia.

Claims (8)

1. The compounds of general formula I, or racemic mixtures thereof, or individual optical isomers, or pharmaceutically acceptable salts,

where R = H, (C ₁ -C ₅ ) alkyl, halogen-substituted (C ₁ -C ₅ ) alkyl, acyl selected from the group C ₁ -C ₅ alkylC (= O) - or phenyl (C = O) -, substituted heteroaryl, which is an aromatic monocyclic group with two nitrogen atoms, which is substituted by a halogen atom or C ₁ -C ₅ alkyl, (C ₁ -C ₃ ) alkylsulfonyl, phenylsulfonyl; R1, R2, R3, R4 are hydrogen or one or two substituents simultaneously selected from halogen, (C ₁ -C ₃ ) alkyl, halogen-substituted (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkylsulfonyl, cyano . 2. Compounds representing:
I.1.1 Tert-butyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidine-1-carboxylate,
I.1.a 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidine hydrochloride,
I.1.b 5-chloro-2- (4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidin-1-yl) pyrimidine,
I.2.1 Tert-butyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2,6-difluorophenoxy] methyl} piperidine-1-carboxylate,
I.3.1 Tert-butyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2- (methylsulfonyl) phenoxy] methyl} piperidine-1-carboxylate,
I.4.1 Tert-butyl 4 - {[2-chloro-4- (3,3-dioxo-1,3-benzoxathiol-6-yl) phenoxy] methyl} piperidine-1-carboxylate,
I.5.1 Tert-butyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-methylphenoxy] methyl} piperidine-1-carboxylate,
I.6.1 Tert-butyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -3-fluorophenoxy] methyl} piperidine-1-carboxylate,
I.7.1 Tert-butyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2- (trifluoromethyl) phenoxy] methyl} piperidine-1-carboxylate,
I.8.1 Tert-butyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -3,5-difluorophenoxy] methyl} piperidine-1-carboxylate,
I.9.1 Tert-butyl 4 - {[2-cyano-4- (3,3-dioxo-1,3-benzoxathiol-6-yl) phenoxy] methyl} piperidine-1-carboxylate,
I.10.1 Tert-butyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-isopropylphenoxy] methyl} piperidine-1-carboxylate,
I.1.c 2- (4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidin-1-yl) -5-fluoropyrimidine,
I.1.d 5-bromo-2- (4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidin-1-yl) pyrimidine,
I.1.e 2- (4 - {[4- (3,3-dioxo-1,3-benzoxatcol-6-yl) -2-fluorophenoxy] methyl} piperidin-1-yl) -5-ethylpyrimidine,
I.1.f Isopropyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidine-1-carboxylate,
I.1.g 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} -1- (methylsulfonyl) piperidine,
I.1.h 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} -1- (phenylsulfonyl) piperidine,
I.1.i 1- (2,2-dimethylpropanoyl) -4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidine,
I.1.j 1-benzoyl-4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidine,
I.1.k 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} -1- (3,3,3-trifluoropropyl) piperidine,
I.1.l (1R) -1-methylpropyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidine-1-carboxylate,
I.1.m (1S) methylpropyl 4 - {[4- (3,3-dioxo-1,3-benzoxathiol-6-yl) -2-fluorophenoxy] methyl} piperidine-1-carboxylate. 3. The method of obtaining compounds of General formula I, which consists in the interaction of synton A with the corresponding synton B in a solvent in the presence of a base and a palladium catalyst 46

where R, R1, R2, R3, R4 have the above meanings;
tf is trifluoromethylsulfonyl. 4. The method of obtaining compounds of General formula Ib, which consists in removing the protective group from substance I, followed by, if necessary, alkylation or hetarylation or acylation or sulfonylation of an unsubstituted secondary amine of piperidine of formula Ia

where R means (C ₁ -C ₅ ) alkyl, halogen-substituted (C ₁ -C ₅ ) alkyl, acyl selected from the group C ₁ -C ₅ alkylC (= O) - or phenyl (C = O) -, substituted heteroaryl, representing an aromatic monocyclic group with two nitrogen atoms, which is substituted by a halogen atom or C ₁ -C ₅ alkyl, (C ₁ -C ₃ ) alkylsulfonyl, phenylsulfonyl; R1, R2, R3, R4 have the above meanings. X-reactive group. 5. The active component having the property of a GPR119 receptor agonist, which is a compound of general formula I according to any one of claims. 12. 6. A pharmaceutical composition for the prevention and treatment of metabolic diseases, containing in an effective amount the active ingredient according to claim 5. 7. The pharmaceutical composition according to claim 6 in the form of tablets, capsules, injections, ointments, rectal suspensions and gels, placed in a pharmaceutically acceptable package. 8. A method for the prevention and treatment of metabolic diseases, such as metabolic syndrome, diabetes mellitus, obesity by the introduction in an effective amount of a new active component according to claim 5 or the pharmaceutical composition according to claim 6, 7.

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