RU2342362C2 - Substituted arylalkane acid derivatives as pan agonists rapp with high antihyperglycemic and antihyperlipidemic activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: described is obtaining and pharmaceutical application of substituted derivatives of arylalkane acid of formula I

, where ring A, ring B, R¹, R², R³, R⁴, R⁵, X, Alk¹, Alk², Ar¹ and Ar² are such as determined in said description. Said compounds, as selective agonists activating (RAPPs) receptors, activated by peroximal proliferator, in particular, RXRs/RAPPs-alfa, RXRs/RAPPs-gamma and RXRs/RAPPs-delta heterodimers, are applied in treatment and/or prevention of type 2 diabetes and connected with it metabolic syndrome, such as hypertension, obesity, insulin-resistence, hyperlipidemia, hyperglycemia, hyperolesterinemia, artheriaslerosis, coronary artery disease, and other cardio-vascular disorders, and possess improved profile of side effects, connected with common RAPPs-gamma agonists.

EFFECT: obtaining compunds, which possess improved profile of side effects, connected with common RAPPs-gamma agonists.

22 cl, 38 ex, 2 tbl, 10 dwg

Description

Priority for this application is claimed by provisional application US No. 60/429221, filed November 26, 2002; and U.S. Application No. 60/469368, filed May 9, 2003.

FIELD OF THE INVENTION

The present invention relates to the preparation and pharmaceutical use of new substituted arylalkanoic acid derivatives. In particular, this invention relates to new compounds of formula (I), methods for their preparation, their pharmaceutical compositions and their use in the treatment and / or prevention of the occurrence of conditions associated with nuclear receptors, in particular, with PXR and RAPP heterodimers.

These compounds are useful in the treatment and / or prevention of the development of type 2 diabetes and related metabolic syndromes such as hypertension, obesity, insulin resistance, hyperlipidemia, hyperglycemia, hypercholesterolemia, atherosclerosis, coronary artery disease, and other cardiovascular disorders, and have an improved side effect profile, usually associated with conventional RAPP gamma agonists.

BACKGROUND OF THE INVENTION

Metabolic syndrome, including type 2 diabetes and related complications, such as obesity, cardiovascular symptoms and dyslipidemia, are the main high social and economic importance. Despite the fact that antidiabetic drugs increase insulin resistance, they provide little protection against severe cardiovascular risk associated with type 2 diabetes.

Therefore, in general, it is interesting to develop new treatment regimens with the effects of reducing insulin resistance and the ratio of cholesterol / triglycerides.

Diabetes mellitus is a polygenic disorder affecting a significant number of people in the world. This disease is divided into two types. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), little or no insulin is produced in patients, a hormone that regulates glucose uptake.

In type 2 diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), often in patients the level of insulin in the blood plasma is the same as in people without diabetes; however, patients develop resistance to glucose uptake and fat metabolism in the main insulin-sensitive tissues, that is, in the muscles, liver and adipose tissues, and the plasma insulin level is insufficient to overcome pronounced insulin resistance.

Type 2 diabetes accounts for more than 90% of all forms of diabetes. This metabolic disorder is characterized by hyperglycemia, leading to secondary complications, such as neuropathy, nephropathy, retinopathy, hyperglyceridemia, obesity, and other cardiovascular diseases, mainly described as metabolic syndrome.

In type 2 diabetes, the treatment that is mainly prescribed is a combination of diet, exercise, and oral hyperglycemic agents, mainly sulfonylureas and biguanides. However, sulfonylurea therapy has many problems associated with primary and secondary loss of effectiveness, the occurrence of hypoglycemia and obesity. Biguanide therapy can induce lactic acidosis, nausea, and diarrhea. Therefore, a drug capable of stably controlling plasma glucose levels without causing significant side effects would be an important complement to diabetes therapy. It has recently been shown that a class of compounds called "thiazolidinediones" reduces hyperglycemia by stimulating the action of insulin without additional secretion of insulin and without causing unwanted hypoglycemia even at elevated doses. It is assumed that their effect is the result of the initiation and modulation of adipocyte differentiation by the agonistic activity of RAPPgamma.

This class of compounds, capable of activating RAPPgamma, has demonstrated clinical efficacy in the treatment of type 2 diabetes (AVANDIA from GSK and ACTOS from Lilly / Tekada). However, a direct relationship between activation of RAPP-gamma and a change in glucose metabolism, the most significant decrease in muscle insulin resistance, has not been established. This association is effected via free fatty acids in such a way that activation of the RAPP-gamma induces lipoprotein lipase, a protein of transport of free fatty acids and acyl-CoA synthetase in adipose tissue, but not in muscle cells. This effect, in turn, sharply reduces the concentration of free fatty acids in plasma, leading to the final switch from fatty acid oxidation to glucose oxidation in tissues at a high metabolic level, for example in skeletal muscle and other tissues, as a result of substrate competition and compensation of metabolic processes .

This leads to reduced insulin resistance in these tissues. In addition, activation of the RAPP gamma regulates the activity of a set of genes that control glucose metabolism and energy homeostasis, which leads to a decrease in blood glucose (T. M. Wilson et al. "The PPARs: from orphan receptors to drug discovery" J. Med. Chem 2000 43: 527-50; A. Chawla et al. "Nuclear receptors and lipid physiology: Opening the X-files", Science 2001 294: 1866-70).

Despite the benefits achieved by the class of thiazolidinediones as antidiabetic agents, their clinical use is limited by serious unacceptable side effects, including cardiac hypertrophy, blood thinning, and liver toxicity. In the United States and Japan, there have been several cases of liver damage and death from drug liver damage. In addition, RAAP gamma-selective ligands induce adipocyte differentiation and accumulation of white fat, leading to obesity, an important factor directly related to the onset or consequence of type 2 diabetes. Such undesirable effects finally neutralize the insulin-sensitizing benefits of the ligands of the RAAPgamma. Therefore, there is a definite need for a safe and effective agent for the treatment of patients with type 2 diabetes, capable of exhibiting double activity both in insulin sensitization and in reducing the deposition of white fat by regulating the content of free fatty acids and triglycerides.

RAPPgamma is a member of the superfamily of ligand-activated hormonal nuclear receptors and is expressed mainly in adipose tissues. A class of ligands called fibrates, which is known to have triglyceride- and cholesterol-lowering activity and activates another member of this family, RAPPalfa, which is expressed mainly in tissues such as the liver. RAPPalfa stimulates peroxisomal proliferation, which increases the oxidation of fatty acids, leading to a decrease in blood fatty acids (Keller and Wahli: Trends Endocrin Metab 1993, 4: 291-296). More recently, it has been found that RAPP delta regulates lipid metabolism, in which RAPP delta serves as a widespread regulator of fat burning. In vitro activation of RAPP delta in adipocytes and skeletal muscle cells provides oxidation and absorption of fatty acids. The targeted activation of RAPP delta in animal adipose tissue, where RAPPalfa is expressed in much smaller amounts, specifically induces the expression of genes necessary for fatty acid oxidation and energy distribution, which, in turn, leads to an improvement in lipid profiles and a reduction in obesity.

It is important that these animals (Lepr (db / db) are completely resistant to both types of obesity, induced by a high fat diet and a genetic predisposition.

Acute administration of Lepr (db / db) RAPdelta agonists to mice prevents fat accumulation. In parallel, RAPdelta deficient mice that consume high-fat foods exhibit reduced energy breakdown and are prone to obesity (Wang YX et al. Cell 2003 Apr 18; 113 (2): 159-70). Transcriptional repression of atherogenic inflammation due to ligand-activated RAPP delta was also described, which, in addition, shows the significance of RAPP delta in resistance to the development of cardiovascular diseases (Lee, CH et al., Science 302: 453-457, 2003).

RAPPalfa, gamma, and delta form heterodimers with a retinoid X receptor (PXR). RCP / RAPP heterodimers thus play an important role in the control and regulation of cellular processes, such as fat (lipid) and glucose homeostasis and adipocyte differentiation. It was found that several new chemical compounds have either RAPP gamma activity or double RAPP alpha and gamma activity used in the treatment and / or prevention of metabolic syndromes in animals and humans (WO 00/08002, WO 01 / 57001A1, US patent No. 6054453 , EP 088317B1, WO 97/25042, WO 02/26729 A2 and US patent No. 6353018B1). The new pan-agonists that activate RAPPalfa, gamma, and delta should therefore be a very important complement in the comprehensive management of Syndrome X, such as diabetes, hypertension, obesity, insulin resistance, hyperlipidemia, hyperglycemia, hypercholesterolemia, atherosclerosis, coronary artery disease and other cardiovascular disorders.

SUMMARY OF THE INVENTION

One aspect of the present invention provides compounds of formula I:

wherein ring A and ring B fused to a ring containing X and N independently represent a 5-6 membered ring, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen, and optionally may be substituted one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, alkoxy, aryl, aryloxy, arylo heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino; ring A and ring B may be saturated or contain one or more double bonds or may be aromatic;

X is a valence bond, CH ₂ CH ₂ , CH = CH, O, S, or NR ⁶ , where R ⁶ is H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl or heteroaryl;

R ¹ represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryl acyloxy, amino, alkylamino, arylamino or aralkylamino;

R ² represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl or heteroaryl;

R ³ represents H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl or heteroaryl;

R ⁴ and R ⁵ independently are H, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aryloxy, aryloxy, aryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamino;

R ⁴ and R ⁵ may form a 5 or 6 membered ring optionally substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl , alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino or aralkylamino;

Alk ¹ is C _1-6 alkylene;

Alk ² is C _1-6 alkylene;

Ar ¹ represents an arylene, heteroarylene, or a divalent heterocyclic group optionally substituted with one or more halogen, C _1-6 alkyl, amino, hydroxy, C _1-6 alkoxy or aryl;

Ar ² represents an aryl group optionally substituted with one or more halogen, C _1-6 alkyl, amino, hydroxy, C _1-6 alkoxy or aryl; a heteroaryl or heterocyclyl group optionally substituted with one or more halogen, C _1-6 alkyl, amino, hydroxy, C _1-6 alkoxy or aryl.

Another aspect of the present invention relates to a pharmaceutical composition comprising an active ingredient, at least one of the compounds of general formula (I), and / or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent for the treatment and / or prevention of type 2 diabetes and its associated metabolic syndrome, such as hypertension, obesity, insulin resistance, hyperlipidemia, hyperglycemia, hypercholesterolemia, atherosclerosis, coronary artery disease and other cardiovascular diseases wow violations.

It was unexpectedly discovered that the compounds of formula I are able to reduce hyperglycemia and hypertriglyceridemia associated with type 2 diabetes. It was also unexpectedly discovered that the compounds of formula I can be used as pan agonists for PXR / RAPPalfa, PXP / RAPPgamma and PXP / RAPPdelta heterodimers, as well as agents for lowering glucose and triglycerides for the treatment and / or prevention of diabetes 2 type and metabolic syndrome associated with it. The contents of the patents and publications cited here and the contents of the documents cited in these patents and publications are incorporated into this description by reference in the permitted volume.

Brief Description of the Drawings

Figure 1 graphically illustrates the comparative activation of PXR / RAPPalfa heterodimers by the compounds of this invention (Example 30).

Figure 2 shows the comparative activation of PXP / RAPP gamma heterodimers with the compounds of this invention (Example 31).

Figure 3 shows the comparative activation of PXR / RAPP delta heterodimers with the compounds of this invention (Example 32).

Figure 4 shows the comparative activation of PXR / RAPPalfa heterodimers with the compounds of this invention (Example 33).

Figure 5 shows the comparative activation of PXP / RAPP gamma heterodimers with the compounds of this invention (Example 33).

6 shows the comparative activation of PXR / RAPP delta heterodimers with the compounds of this invention (Example 33).

7 graphically illustrates the in vivo decrease in blood glucose caused by the compound of the present invention (Example 34).

Fig. 8 graphically illustrates the increased insulin sensitivity caused by the in vivo compound of the present invention (Example 35).

Fig. 9 graphically illustrates the increased glucose tolerance induced by the in vivo compound of the present invention (Example 36).

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise specified, all technical and scientific terms used herein have the meanings usually implied by the person skilled in the art to which this description relates.

All publications and patents referenced by this description are incorporated herein by reference.

In a preferred embodiment, the compounds of this

the invention represented by formula I are compounds where

ring A is a 6-membered aromatic ring;

ring B is a 6 membered aromatic ring;

X is a valence bond, CH ₂ CH ₂ , CH = CH, O or S;

R ¹ represents H or alkyl;

R ² represents H or alkyl;

R ³ represents H or alkyl;

R ⁴ and R ⁵ are independently H or alkyl;

Alk ¹ is C _2-3 alkylene;

Alk ² is C _1-6 alkylene;

Ar ¹ represents an arylene group;

Ar ² represents a substituted aryl group.

In another preferred embodiment, the compounds of this

the invention are compounds of formula I, where

ring A is a 6-membered aromatic ring;

ring B is a 6 membered aromatic ring;

X is a valence bond, CH ₂ CH ₂ , CH = CH, O or S;

R ¹ represents H or alkyl;

R ² represents H or alkyl;

R ³ represents H or alkyl;

R ⁴ and R ⁵ form a 6-membered aromatic ring;

Alk ¹ is C _2-3 alkylene;

Alk ² is C _1-6 alkylene;

Ar ¹ is a 6 membered aromatic ring;

Ar ² is a substituted aryl group.

In another preferred embodiment, the compounds of this invention are compounds of formula I, where

ring A is a benzene ring;

ring B is a benzene ring;

X is a valence bond, CH ₂ CH ₂ , CH = CH, O or S;

R ¹ represents H;

R ² represents H;

R ³ represents H;

R ⁴ represents methyl; R ⁵ is H;

Alk ¹ represents CH ₂ CH ₂ ;

Alk ² represents CH ₂ ;

Ar ¹ represents a benzene ring;

Ar ² is a benzene ring optionally substituted with one or more fluorine atoms.

In another preferred embodiment, the compounds of this invention are compounds of formula I, where

ring A is a benzene ring;

ring B is a benzene ring;

X is a valence bond, CH ₂ CH ₂ , CH = CH, O or S;

R ¹ represents H;

R ² represents H;

R ³ represents H;

R ⁴ and R ⁵ represent a benzene ring;

Alk ¹ represents CH ₂ CH ₂ ;

Alk ² represents CH ₂ ;

Ar ¹ represents a benzene ring;

Ar ² is a benzene ring optionally substituted with one or more fluorine atoms.

In a further preferred embodiment, the compounds of this invention are compounds of formula I, wherein

ring A is a benzene ring;

ring B is a benzene ring;

X is a valence bond, CH ₂ CH ₂ , CH = CH, O or S;

R ¹ represents H;

R ² represents H;

R ³ represents H;

R ⁴ represents methyl; R ⁵ represents H;

Alk ¹ represents CH ₂ CH ₂ ;

Alk ² represents CH ₂ ;

Ar ¹ represents a benzene ring;

Ar ² is a pyridine ring optionally substituted with one or more halogen atoms.

In another preferred embodiment, the compounds of this invention are compounds of formula I, where

ring A is a benzene ring;

ring B is a benzene ring;

X is a valence bond, CH ₂ CH ₂ , CH = CH, O or S;

R ¹ represents H;

R ² represents H;

R ³ represents H;

R ⁴ and R ⁵ form a benzene ring;

Alk ¹ represents CH ₂ CH ₂ ;

Alk ² represents CH ₂ ;

Ar ¹ is a benzene ring

Ar ² is a pyridine ring optionally substituted with one or more fluorine atoms.

The following terms used here have the indicated meaning: it is understood that the term "alkyl" as used herein includes alkyl groups of a linear or branched configuration. Typical alkyl groups include, but are not limited to methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

As used herein, the term “aralkyl” refers to a straight or branched saturated carbon chain containing from 1 to 6 carbon atoms substituted with aromatic carbohydride, for example benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl and the like.

The term “heteroaralkyl” as used herein refers to a straight or branched saturated carbon chain containing from 1 to 6 carbon atoms substituted with the heteroaryl defined herein, for example, (2-furyl) methyl, (3-furyl) methyl, (2-pyridyl) methyl and the like.

As used herein, the term “aminoalkyl” refers to an alkyl as defined herein to which an amino group is attached, for example aminoethyl, 1-aminopropyl, 2-aminopropyl and the like.

As used herein, the term “alkoxyalkyl” refers to an alkyl defined herein to which an alkoxy group as defined herein is attached, for example, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like.

As used herein, the term “aryloxyalkyl” refers to an alkyl as defined herein to which an aryloxy group as defined herein is attached, for example, phenoxymethyl, phenoxydecyl, 1-naphthyloxyethyl and the like.

As used herein, the term “aralkoxyalkyl” refers to an alkyl defined herein to which an aralkoxy group as defined herein is attached, for example, benzyloxymethyl, 3-phenylpropoxyethyl and the like.

As used herein, the term “hydroxyalkyl” refers to an alkyl defined herein to which a hydroxy group as defined herein is attached, for example hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl and the like.

The term “thioalkyl” as used herein refers to an alkyl as defined herein to which a group of the formula —SR ′ is attached, where R ′ is H, alkyl or aryl, for example thiomethyl, methylthiomethyl, phenylthioethyl and the like.

As used herein, the term "heterocyclyl" means a monovalent saturated or unsaturated single ring group containing one or more heteroatoms, for example pyrrolidine, pyrroline, pyrazoline, imidazolidine, imidazoline, piperidine, morpholine and the like.

As used herein, the term “halogen” means fluoro, chloro, bromo or iodo.

The term “alkoxy” as used herein is intended to include linear, branched or cyclic alkyl groups bonded by ether oxygen having a valence bond to oxygen of the ether group, for example methoxy, ethoxy, propoxy, butoxy, pentoxy, isopropoxy, secbutoxy, cyclopropyloxy cyclohexyloxy and the like.

As used herein, the term “aryl” is intended to include aromatic rings optionally substituted with halogen, amino, hydroxy, alkyl or alkoxy, for example phenyl, naphthyl and the like.

As used herein, the term “aryloxy” refers to phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.

As used herein, the term “aralkoxy” refers to an alkyl defined herein substituted by aromatic carbohydride, for example benzyloxy, phenethoxy, 1-naphthylmethoxy and the like.

The term “heteroaryl” as used herein refers to a monovalent substituent containing a 5-6 membered monocyclic aromatic system or a 9-10 membered bicyclic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, for example furan, thiophene, pyrrole, imidazole, triazole, pyridine, pyrazine, pyrimidine, oxazole, quinoline, indole, benzimidazole and the like.

The term “heteroaryloxy” as used herein refers to a heteroaryl, bonded to an oxygen atom, having a free valence bond from an oxygen atom, for example pyrrole, imidazole, triazole, pyridine, pyrazine, pyrimidine, oxazole, quinoline, indole, benzimidazole bound to oxygen .

As used herein, the term “heteroaralkoxy” refers to heteroaralkyl, as defined herein, bonded to an oxygen atom having a free valence bond from an oxygen atom, for example (2-furyl) methyl, (3-furyl) methyl, (2-pyridyl) methyl, bonded to an oxygen atom.

As used herein, the term “acyl” refers to a monovalent substituent containing an alkyl group attached to a carbonyl group, for example, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl and the like.

As used herein, the term “acyloxy” refers to an acyl, as defined herein, which is bonded to an oxygen atom having its free valence bond from an oxygen atom, for example acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, valeryloxy and the like.

As used herein, the term “alkylamino” refers to a straight or branched or cyclic monovalent substituent containing an alkyl group bonded to an amino group having a free valence bond from a nitrogen atom, for example methylamine, ethylamino, propylamino, butylamino, cyclopropylamino, cyclopentylamino, cyclohexylamino and.

As used herein, the term “arylamino” refers to an aryl, as defined herein, bonded to an amino group having a free valence bond from a nitrogen atom, for example phenylamino, naphthylamino and the like.

As used herein, the term “aralkylamino” refers to an aralkyl group as defined herein linked to an amino group having a free valence bond from a nitrogen atom, for example benzylamino, phenethylamino, 3-phenylpropylamino, 1-naphthylmethylamino and the like.

The compounds of formula (1) can be obtained synthetically, shown in scheme 1:

Compound 1 reacting with β-diketone 2 gives analogs of the amides of vinyl series 3 with a yield of 95-98%. O-alkylation of compounds 3 in the usual way by treatment with KOH and the corresponding dibromoalkane in ethanol gives ether 4 with a yield of 15-20%. N-alkylation of compounds 4 by treatment with NaOH and compound 5 in the presence of tetrabutylammonium bromide gives substituted arylalkanoic acid derivatives 6 with a yield of 20-25%.

The synthetic route shown in Scheme 1 is also suitable for preparing compounds of formula (1), wherein Ar ² is a benzene ring.

The pharmaceutical composition may be in commonly used forms, for example tablets, capsules, powders, syrups, solutions, suspensions, aerosols, and the like, may contain flavorings, sweeteners, etc. in suitable liquid or solid carriers or diluents, or in a suitable sterile medium to form injection solutions and suspensions. In a preferred embodiment, the pharmaceutical composition contains up to about 65% of the compounds of formula I by weight, preferably from about 0.5 to about 40%, more preferably from about 1 to about 20%, and most preferably from about 1 to 10% while the remaining composition is a pharmaceutically acceptable carriers, diluents or solvents or saline solutions.

As used herein, the term "pharmaceutically acceptable carrier" or "diluent" includes, but is not limited to those described in the Handbook of Pharmaceutical Excipients, published in October 1986 by the American Pharmaceutical Association, the contents of which, as far as possible, are incorporated herein by reference .

The compounds of formula (I), as defined above, are clinically administered to mammals, including humans and animals, orally, intranasally, transdermally, intrapulmonally (inhalation) or parenterally. The oral route of administration is preferred, it is more convenient and avoids possible pain and irritation during administration. In a preferred embodiment, the dosage ranges from about 0.01 to about 200 mg / kg body weight per day, administered once or in divided doses, preferably from about 0.01 to about 100 mg / kg, and more preferably from about 0.1 to about 50 mg / kg. However, the optimal dosage for the individual subject is determined by the specialist responsible for the treatment, basically a lower dose is first administered and then the dose is increased to determine the most suitable. Not intending to associate with a specific theory of efficacy, it is likely that administering compounds of Formula I to a patient can cure diabetes and its associated complications by lowering the patient's glucose and triglycerides. Such dual activities, for example, help the patient level hyperglycemia and hypertriglyceridemia associated with type 2 diabetes. It is also believed that treatment of patients with type 2 diabetes and related complications can be more effective and desirable if a reduction in glucose and triglycerides can be achieved with treatment.

The following examples are given to specifically illustrate the present invention. However, it should be understood that the invention is not limited to the specific details presented in the examples. All parts and percentages in the examples, as well as in the remaining description, are given by weight, unless otherwise indicated.

In addition, any number of values cited in this description, or sections hereinafter describing or disclosing various aspects of the present invention, such as those that represent a particular set of properties, units of measure, conditions, physical conditions or percentages, are intended to be complete and the exact coverage, by reference or in any other way, of any number falling within a given interval, including any combination of numbers or values within the specified interval.

The term "about" when used to determine or in relation to a value implies that the values and ranges described herein are flexible, and the use of the present invention by a person skilled in the art using the values of temperature, concentration, amount, content, number of carbon atoms and properties that are outside the given interval or other than a single value will lead to the achievement of the desired result.

Example 1

Preparation of 2- (1-methyl-3-oxo-3-phenyl-propenylamino) -3- (4-hydroxyphenyl) propionic acid methyl ester.

To a solution of L-tyrosine methyl ester (4.00 g, 20.51 mmol) in methanol (150 ml) was added 1-benzoylacetone (3.66 g, 22.56 mmol), then the mixture was heated in a flask at reflux temperature (s reflux) for 24 hours

The solvent was evaporated in vacuo. Ethanol (50 ml) was added to the residue, then ethanol was distilled off at atmospheric pressure. The crude product was purified by silica gel chromatography using hexane / EtOAc (4: 1) as eluent to give the title compound (6.80 g, 98%).

Example 2

Preparation of 2- (1-methyl-3-oxo-3-phenyl-propenylamino) -3- [4 - (- 2-bromoethoxy) phenyl] propionic acid methyl ester.

To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml), methyl 2- (1-methyl-3-oxo-3-phenyl-propenylamino) -3- (4-hydroxyphenyl) - propionic acid (1.00 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). The mixture was then heated under reflux for 8 hours. After cooling, the reaction mixture was filtered to remove solid particles, and then the filtrate was evaporated in vacuo. The crude product was purified by silica gel chromatography using hexane / EtOAc (4: 1) as eluent to give the title compound (0.22 g, 17%).

Example 3

Preparation of 2- (1-methyl-3-oxo-3-phenyl-propenylamino) -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (compound CS023)

To a solution of 2- (1-methyl-3-oxo-3-phenyl-propenylamino) -3- [4- (2-bromoethoxy) phenyl] propionic acid methyl ester (0.22 g, 0.49 mmol) and carbazole (0.082 g, 0.49 mmol) in benzene (10 ml) was added tetrabutylammonium bromide (0.08 g) and an aqueous solution of 50% NaOH (0.084 g, 1.08 mmol), then the mixture was heated under reflux for 10 h. After cooling, benzene (30 ml) was added and the mixture was washed with water (3 × 30 ml). Then, the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography using CHCl ₃ / MeOH (4: 1) as eluent to give the title compound (0.05 g, 20%).

HRMS calculated for C ₃₃ H ₃₀ N ₂ O ₄ : 518.6123. Found: 518.6125. MA calculated for C ₃₃ H ₃₀ N ₂ O ₄ : C 76.43%; H 5.83%; N, 5.40%.

Found,%: C 76.21; H 5.85; N, 5.39.

Example 4

Preparation of 2- [1-methyl-3-oxo-3- (4-fluorophenyl) propenylamino] -3- (4-hydroxyphenyl) propionic acid methyl ester.

To a solution of L-tyrosine methyl ester (4.00 g, 20.51 mmol) in methanol (150 ml) was added 1- (4-fluorobenzoyl) acetone (4.06 g, 22.56 mmol), then the mixture was heated in a flask under reflux for 24 hours. The solvent was evaporated in vacuo. Ethanol (50 ml) was added to the residue, then ethanol was distilled off at atmospheric pressure. The crude product was purified by silica gel chromatography using hexane / EtOAc (4: 1) as eluent to give the title compound (7.03 g, 96%).

Example 5

Preparation of 2- [1-methyl-3-oxo-3- (4-fluorophenyl) propenylamino] -3- [4- (2-bromoethoxy) phenyl] propionic acid methyl ester.

To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) was added 2- [1-methyl-3-oxo-3- (4-fluorophenyl) propenylamino] -3- (4 -hydroxyphenyl) propionic acid (1.05 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). The mixture was then heated under reflux for 8 hours. After cooling, the reaction mixture was filtered to remove solid particles, and then the filtrate was evaporated in vacuo. The crude product was purified by silica gel chromatography using hexane / EtOAc (4: 1) as eluent to give the title compound (0.37 g, 27%).

Example 6

Preparation of 2- [1-methyl-3-oxo-3- (4-fluorophenyl) propenylamino] -3- [4- (2-carbazolylethoxy) phenyl] propionic acid

To a solution of 2- [1-methyl-3-oxo-3- (4-fluorophenyl) propenylamino] -3- [4- (2-bromoethoxy) phenyl] propionic acid methyl ester (0.23 g, 0, 49 mmol) and carbazole (0.082 g, 0.49 mmol) in benzene (10 ml) add tetrabutylammonium bromide (0.08 g) and an aqueous solution of 50% NaOH (0.084 g, 1.08 mmol), then the mixture is heated in a flask with reflux for 10 hours. After cooling, benzene (30 ml) was added and the mixture was washed with water (3 × 30 ml). Then, the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography using CHCl ₃ / MeOH (4: 1) as eluent to give the title compound (0.06 g, 23%).

HRMS calculated for C ₃₃ H ₂₉ FN ₂ O ₄ : 536.6027. Found: 536.6025. MA calculated for C ₃₃ H ₂₉ FN ₂ O ₄ : C 73.86%; H 5.45%; N, 5.22%.

Found,%: C 73.63; H 5.46; N, 5.20.

Example 7

Preparation of 2- [1-methyl-3-oxo-3- (3-pyridyl) propenylamino] -3- [4-hydroxyphenyl] propionic acid methyl ester.

To a solution of L-tyrosine methyl ester (4.00 g, 20.51 mmol) in methanol (150 ml) was added 1-nicotinoylacetone (3.68 g, 22.56 mmol), then the mixture was heated under reflux for 24 hours. The solvent was evaporated in vacuo. Ethanol (50 ml) was added to the residue, then ethanol was distilled off at atmospheric pressure. The crude product was purified by silica gel chromatography using hexane / EtOAc (4: 1) as eluent to give the title compound (5.51 g, 79%).

Example 8

Preparation of 2- [1-methyl-3-oxo-3- (3-pyridyl) propenylamino] -3- [4- (2-bromoethoxy) phenyl] propionic acid methyl ester.

To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml), methyl 2- [1-methyl-3-oxo-3- (3-pyridyl) propenylamino] -3- (4 -hydroxyphenyl) propionic acid (1.00 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol).

The mixture was then heated under reflux for 8 hours. After cooling, the reaction mixture was filtered to remove solid particles, and then the filtrate was evaporated in vacuo. The crude product was purified by silica gel chromatography using hexane / EtOAc (4: 1) as eluent to give the title compound (0.20 g, 15%).

Example 9

Preparation of 2- [1-methyl-3-oxo-3- (3-pyridyl) propenylamino] -3- [4- (2-carbazolylethoxy) phenyl] propionic acid

To a solution of 2- [1-methyl-3-oxo-3- (3-pyridyl) propenylamino] -3- [4- (2-bromoethoxy) phenyl] propionic acid methyl ester (0.22 g, 0, 49 mmol) and carbazole (0.082 g, 0.49 mmol) in benzene (10 ml) add tetrabutylammonium bromide (0.08 g) and an aqueous solution of 50% NaOH (0.084 g, 1.08 mmol), then the mixture is heated in a flask with reflux for 10 hours. After cooling, benzene (30 ml) was added and the mixture was washed with water (3 × 30 ml). Then, the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography using CHCl ₃ / MeOH (4: 1) as eluent to give the title compound (0.04 g, 16%).

HRMS calculated for C ₃₂ H ₂₉ N ₃ O ₄ : 519.6001. Found: 519.6003. MA calculated for C ₃₂ H ₂₉ N ₃ O ₄ : C 73.97%; H 5.63%; N, 8.09%.

Found,%: C 73.84; H 5.65; N, 8.11.

Example 10

Preparation of 2 - ((2-benzoylphenyl) amino) -3- (4-hydroxyphenyl) propionic acid methyl ester.

To a mixture of 2-benzoylcyclohexanone (90.9 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) was added 5% palladium on carbon (20 g), then the mixture is heated in a flask under reflux for 2 hours, the resulting water is removed using a nozzle (apparatus) Dean-Stark. The mixture was cooled to 80 ° C and Pd / C was filtered and washed with anisole (3 × 60 ml). The mixture was cooled to 40 ° C, hexane (1000 ml) was added and the mixture was kept at -20 ° C for 48 hours. The solids were filtered and washed with hexane (5 × 200 ml) to give crude 2 - ((2-benzoylphenyl methyl ester) ) -amino) -3- (4-hydroxyphenyl) propionic acid. The crude product is mixed with 250 ml of methanol and then heated in a flask under reflux for 30 minutes. After cooling to 0 ° C., the product was filtered, washed with methanol (2 × 50 ml) and dried in vacuo to give the title compound (60.2 g, 40.1%).

Example 11

Preparation of 2 - ((2-benzoylphenyl) amino) -3- [4- (2-bromoethoxy) phenyl] propionic acid methyl ester.

To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) was added methyl 2 - ((2-benzoylphenyl) amino) -3- (4-hydroxyphenyl) propionic acid (1.11 g 2.95 mmol) and 1,2-dibromethane (5.54 g, 29.50 mmol). The mixture was then heated under reflux for 8 hours. After cooling, the reaction mixture was filtered to remove solid particles, and then the filtrate was evaporated in vacuo. The crude product was purified by silica gel chromatography using hexane / EtOAc (4: 1) as eluent to give the title compound (0.30 g, 21%).

Example 12

Preparation of 2 - ((2-benzoylphenyl) amino) -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (compound CS0381)

To a solution of 2 - ((2-benzoylphenyl) amino) -3- [4- (2-bromoethoxy) phenyl] propionic acid methyl ester (0.24 g, 0.49 mmol) and carbazole (0.082 g, 0, 49 mmol) in benzene (10 ml), tetrabutylammonium bromide (0.08 g) and an aqueous solution of 50% NaOH (0.084 g, 1.08 mmol) are added, then the mixture is heated under reflux for 10 hours. After cooling, benzene is added (30 ml) and the mixture was washed with water (3 × 30 ml). Then, the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography using CHCl ₃ / MeOH (4: 1) as eluent to give the title compound (0.06 g, 22%).

HRMS calculated for C ₃₆ H ₃₀ N ₂ O ₄ : 554.6453. Found: 554.6451. MA calculated for C ₃₆ H ₃₀ N ₂ O ₄ : C, 77.96%; H 5.45%; N, 5.05%.

Found,%: C 77.83; H 5.46; N, 5.07.

Example 13

Preparation of 2 - [(2-fluorobenzoyl) phenyl) amino] -3- (4-hydroxyphenyl) propionic acid methyl ester

To a mixture of 2- (4-fluorobenzoyl) cyclohexanone (99.0 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) was added 5% palladium on carbon (20 g), then the mixture is heated in a flask under reflux for 2 hours, the resulting water is removed using a Dean-Stark apparatus. The mixture was cooled to 80 ° C, and Pd / C was filtered and washed with anisole (3 × 60 ml). The mixture was cooled to 40 ° C., hexane (1000 ml) was added and the mixture was kept at −20 ° C. for 48 hours. The solids were filtered and washed with hexane (5 × 200 ml) to give crude methyl ester 2 - [(2- ( 4-fluorobenzoyl) phenyl) amino] -3- (4-hydroxyphenyl) propionic acid. The crude product is mixed with 250 ml of methanol and then heated in a flask under reflux for 30 minutes. After cooling to 0 ° C., the product was filtered, washed with methanol (2 × 50 ml) and dried in vacuo to give the title compound (75.6 g, 48.1%).

Example 14

Preparation of 2 - [(2- (4-fluorobenzoyl) phenyl) amino] -3- [4- (2-bromoethoxy) phenyl] propionic acid methyl ester

To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) was added 2 - [(2- (4-fluorobenzoyl) phenyl) amino] -3- (4-hydroxyphenyl) propionic acid methyl ester (1.16 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). The mixture was then heated under reflux for 8 hours. After cooling, the reaction mixture was filtered to remove solid particles, and then the filtrate was evaporated in vacuo. The crude product was purified by silica gel chromatography using hexane / EtOAc (4: 1) as eluent to give the title compound (0.56 g, 38%).

Example 15

Preparation of 2 - [(2- (4-fluorobenzoyl) phenyl) amino] -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (compound CS038)

To a solution of 2 - [(2- (4-fluorobenzoyl) phenyl) amino] -3- [4- (2-bromoethoxy) phenyl] propionic acid methyl ester (0.25 g, 0.49 mmol) and carbazole ( 0.082 g, 0.49 mmol) in benzene (10 ml) add tetrabutylammonium bromide (0.08 g) and an aqueous solution of 50% NaOH (0.084 g, 1.08 mmol), then the mixture is heated under reflux for 10 hours After cooling, benzene (30 ml) was added and the mixture was washed with water (3 × 30 ml). Then, the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography using CHCl ₃ / MeOH (4: 1) as eluent to give the title compound (0.10 g, 36%).

HRMS calculated for C ₃₆ H ₂₉ FN ₂ O ₂ : 572.6357. Found: 572.6354. MA calculated for C ₃₆ H ₂₉ FN ₂ O ₄ : C 75.51%; H 5.11%; N 4.89%. Found,%: C 75.83; H 5.10; N, 4.90.

Example 16

Preparation of 2 - ((2-nicotinoylphenyl) amino) -3- (4-hydroxyphenyl) propionic acid methyl ester

To a mixture of 2-nicotinoylcyclohexanone (914.0 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) was added 5% palladium on carbon (20 g), then the mixture is heated in a flask under reflux for 2 hours, the resulting water is removed using a Dean-Stark apparatus. The mixture was cooled to 80 ° C and Pd / C was filtered and washed with anisole (3 × 60 ml). The mixture was cooled to 40 ° C., hexane (1000 ml) was added and the mixture was kept at -20 ° C. for 48 hours. The solids were filtered and washed with hexane (5 × 200 ml) to give crude methyl 2 - ((2-nicotinoylphenyl) ) amino) -3- (4-hydroxyphenyl) propionic acid. The crude product is mixed with 250 ml of methanol and then heated in a flask under reflux for 30 minutes. After cooling to 0 ° C., the product was filtered, washed with methanol (2 × 50 ml) and dried in vacuo to give the title compound (58.6 g, 39.0%).

Example 17

Preparation of 2 - ((2-Nicotinoylphenyl) amino) -3- [4- (2-bromoethoxy) phenyl) propionic acid methyl ester

To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) was added 2 - ((2-nicotinoylphenyl) amino] -3- (4-hydroxyphenyl) propionic acid methyl ester (1.10 g 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). The mixture is then heated under reflux for 8 hours. After cooling, the reaction mixture is filtered to remove solid particles and then the filtrate evaporated in vacuo The crude product is purified by silica gel chromatography using hexane / EtOAc (4: 1) as eluent to give the title compound ke (0.40 g, 28.2%).

Example 18

Preparation of 2 - ((2-nicotinoylphenyl) amino) -3- [4- (2-carbazolylethoxy) phenyl] propionic acid

To a solution of 2 - ((2-nicotinoylphenyl) amino) -3- [4- (2-bromoethoxy) phenyl] propionic acid methyl ester (0.24 g, 0.49 mmol) and carbazole (0.082 g, 0, 49 mmol) in benzene (10 ml), tetrabutylammonium bromide (0.08 g) and an aqueous solution of 50% NaOH (0.084 g, 1.08 mmol) are added, then the mixture is heated under reflux for 10 hours. After cooling, benzene is added (30 ml) and the mixture was washed with water (3 × 30 ml). Then, the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography using CHCl ₃ / MeOH (4: 1) as eluent to give the title compound (0.05 g, 18%).

HRMS calculated for C ₃₅ H ₂₉ N ₃ O ₄ : 555.6331. Found: 555.6329. MA calculated for C ₃₅ H ₂₉ N ₃ O ₄ : C 75.66%; H 5.26%; N 7.56%.

Found,%: C 75.42; H 5.27; N, 7.53.

Example 19

The method of obtaining 2 - ((2-benzoylphenyl) amino) -3- [4- (2-carbazolylethoxy) phenyl] propionic acid on an industrial scale.

To a solution of potassium carbonate (2 kg) in acetonitrile (5000 ml) was added methyl 2 - ((2-benzoylphenyl) amino] -3- (4-hydroxyphenyl) propionic acid (555 g, 1.48 mol) and 1, 2-dibromoethane (1000 ml). The mixture was then stirred at room temperature for 24 hours. After that, the reaction mixture was filtered and the filtrate was evaporated in vacuo. The crude product was purified by silica gel chromatography using hexane / EtOAc (4: 1) as eluent. to give 2 - ((2-benzoylphenyl) amino) -3- [4- (2-bromoethoxy) phenyl] propionic acid methyl ester (442 g, 62%).

To a solution of methyl 2 - ((2-benzoylphenyl) amino) -3- [4- (2-bromoethoxy) phenyl] propionic acid (240 g, 0.49 mol) and carbazole (82 g, 0.49 mol) ) in benzene (3000 ml) tetrabutylammonium bromide (80 g) and an aqueous solution of 40% NaOH (105 g, 1.05 mol) are added, then the mixture is heated under reflux for 10 hours. After cooling, the upper organic layer is evaporated in vacuo . The crude product was purified by silica gel chromatography using CHCl ₃ / MeOH (8: 1) as eluent to give the title compound (78 g, 28.7%).

Example 20

Method for producing 2 - [(2- (4-fluorobenzoyl) phenyl) amino) -3- [4- (2-carbazolylethoxy) phenyl] propionic acid on an industrial scale

To a solution of potassium carbonate (2 kg) in acetonitrile (5000 ml) was added 2 - [(2- (4-fluorobenzoyl) phenyl) amino] -3- (4-hydroxyphenyl) propionic acid methyl ester (581 g, 1.48 mol) and 1,2-dibromoethane (1000 ml). The mixture was then stirred at room temperature for 24 hours. After that, the reaction mixture was filtered and the filtrate was evaporated in vacuo. The crude product is purified by silica gel chromatography using hexane / EtOAc (4: 1) as eluent to give 2 - [(2- (4-fluorobenzoyl) phenyl) amino] -3- [4- (2-bromoethoxy) methyl ester phenyl] propionic acid (429 g, 58%).

To a solution of 2 - [(2- (4-fluorobenzoyl) phenyl) amino] -3- [4- (2-bromoethoxy) phenyl] propionic acid methyl ester (250 g, 0.50 mol) and carbazole (83, 5 g, 0.50 mmol) in benzene (3000 ml) are added tetrabutylammonium bromide (80 g) and an aqueous solution of 40% NaOH (108 g, 1.08 mol), then the mixture is heated under reflux for 10 hours. After cooling, the upper organic layer was evaporated in vacuo. The crude product was purified by silica gel chromatography using CHCl ₃ / MeOH (8: 1) as eluent to give the title compound (91.52 g, 32%).

Example 21

Preparation of 2 - [(2- (4-tert-butylbenzoyl) phenyl) amino] -3- (4-hydroxyphenyl) propionic acid methyl ester

To a mixture of 2- (4-tert-butylbenzoyl) cyclohexanone (116.1 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) was added 5% palladium on charcoal (20 g), then the mixture is heated in a flask under reflux for 2 hours, the resulting water is removed using a Dean-Stark apparatus. The mixture was cooled to 80 ° C, and Pd / C was filtered and washed with anisole (3 × 60 ml). The mixture was cooled to 40 ° C., hexane (1000 ml) was added and the mixture was kept at −20 ° C. for 48 hours. The solids were filtered and washed with hexane (5 × 200 ml) to give crude methyl ester 2 - [(2- ( 4-tert-butylbenzoyl) phenyl) amino] -3- (4-hydroxyphenyl) propionic acid. The crude product is mixed with 250 ml of methanol and then heated in a flask under reflux for 30 minutes. After cooling to 0 ° C., the product was filtered, washed with methanol (2 × 50 ml) and dried in vacuo to give the title compound (70.7 g, 41.0%).

Example 22

Preparation of 2- [(2- (4-tert-butylbenzoyl) phenyl) amino] -3- [4- (2-bromoethoxy) phenyl] propionic acid methyl ester

To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml), methyl 2 - [(2- (4-tert-butylbenzoyl) phenyl) amino] -3- (4-hydroxyphenyl) - propionic acid (1.27 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). The mixture was then heated under reflux for 8 hours. After cooling, the reaction mixture was filtered to remove solid particles, and then the filtrate was evaporated in vacuo. The crude product was purified by silica gel chromatography using hexane / EtOAc (4: 1) as eluent to give the title compound (0.67 g, 42%).

Example 23

Preparation of 2 - [(2- (4-tert-butylbenzoyl) phenyl) amino] -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (Laboratory code CS0130090)

To a solution of 2 - [(2- (4-tert-butylbenzoyl) phenyl) amino] -3- [4- (2-bromoethoxy) phenyl] propionic acid methyl ester (0.26 g, 0.49 mmol) and carbazole (0.082 g, 0.49 mmol) in benzene (10 ml) was added tetrabutylammonium bromide (0.08 g) and an aqueous solution of 50% NaOH (0.084 g, 1.08 mmol), then the mixture was heated under reflux for 10 h. After cooling, benzene (30 ml) was added and the mixture was washed with water (3 × 30 ml). Then, the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography using CHCl ₃ / MeOH (4: 1) as eluent to give the title compound (0.14 g, 47%).

HRMS calculated for C ₄₀ H ₃₈ N ₂ O ₄ : 610.7496. Found: 610.7493. MA calculated for C ₄₀ H ₃₈ N ₂ O ₄ : C 78.66%; H 6.27%; N, 4.59%.

Found: C, 78.85; H 6.24; N 4.61.

Example 24

Preparation of 2 - [(2- (4-methylbenzoyl) phenyl) amino] -3- (4-hydroxyphenyl) propionic acid methyl ester

To a mixture of 2- (4-methylbenzoyl) cyclohexanone (97.2 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) was added 5% palladium on carbon (20 g), then the mixture is heated in a flask under reflux for 2 hours, the resulting water is removed using a Dean-Stark apparatus. The mixture was cooled to 80 ° C and Pd / C was filtered and washed with anisole (3 × 60 ml). The mixture was cooled to 40 ° C., hexane (1000 ml) was added and the mixture was kept at −20 ° C. for 48 hours. The solids were filtered and washed with hexane (5 × 200 ml) to give crude methyl ester 2 - [(2- ( 4-methylbenzoyl) phenyl) amino] -3- (4-hydroxyphenyl) propionic acid. The crude product is mixed with 250 ml of methanol and then heated in a flask under reflux for 30 minutes. After cooling to 0 ° C., the product was filtered, washed with methanol (2 × 50 ml) and dried in vacuo to give the title compound (59.1 g, 38%).

Example 25

Preparation of 2 - [(2- (4-methylbenzoyl) phenyl) amino] -3- [4- (2-bromoethoxy) phenyl] propionic acid methyl ester

To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) was added 2 - [(2- (4-methylbenzoyl) phenyl) amino] -3- (4-hydroxyphenyl) propionic acid methyl ester (1.15 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). The mixture was then heated under reflux for 8 hours. After cooling, the reaction mixture was filtered to remove solid particles, and then the filtrate was evaporated in vacuo. The crude product was purified by silica gel chromatography using hexane / EtOAc (4: 1) as eluent to give the title compound (0.78 g, 53%).

Example 26

Preparation of 2 - [(2- (4-methylbenzoyl) phenyl) amino] -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (Laboratory code CS0130080)

To a solution of 2 - [(2- (4-methylbenzoyl) phenyl) amino] -3- [4- (2-bromoethoxy) phenyl] propionic acid methyl ester (0.24 g, 0.49 mmol) and carbazole ( 0.082 g, 0.49 mmol) in benzene (10 ml) add tetrabutylammonium bromide (0.08 g) and an aqueous solution of 50% NaOH (0.084 g, 1.08 mmol), then the mixture is heated under reflux for 10 hours After cooling, benzene (30 ml) was added and the mixture was washed with water (3 × 30 ml). Then, the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography using CHCl ₃ / MeOH (4: 1) as eluent to give the title compound (0.15 g, 54%).

HRMS calculated for C ₃₇ H ₃₂ N ₂ O ₄ : 568.6692. Found: 568.6693. MA calculated for C ₃₇ H ₃₂ N ₂ O ₄ : C, 78.15%; H 5.67%; N, 4.93%.

Found,%: C 78.36; H 5.64; N, 4.91.

Example 27

Preparation of 2 - [(2- (2-methylbenzoyl) phenyl) amino] -3- (4-hydroxyphenyl) propionic acid methyl ester

To a mixture of 2- (2-methylbenzoyl) cyclohexanone (97.2 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) was added 5% palladium on carbon (20 g), then the mixture is heated in a flask under reflux for 2 hours, the resulting water is removed using a Dean-Stark apparatus. The mixture was cooled to 80 ° C and Pd / C was filtered and washed with anisole (3 × 60 ml). The mixture was cooled to 40 ° C., hexane (1000 ml) was added and the mixture was kept at −20 ° C. for 48 hours. The solids were filtered and washed with hexane (5 × 200 ml) to give crude methyl ester 2 - [(2- ( 2-methylbenzoyl) phenyl) amino] -3- (4-hydroxyphenyl) propionic acid. The crude product is mixed with 250 ml of methanol and then heated in a flask under reflux for 30 minutes. After cooling to 0 ° C., the product was filtered, washed with methanol (2 × 50 ml) and dried in vacuo to give the title compound (52.9 g, 34%).

Example 28

Preparation of 2 - [(2- (2-methylbenzoyl) phenyl) amino] -3- [4- (2-bromoethoxy) phenyl) propionic acid methyl ester

To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) was added 2 - [(2- (2-methylbenzoyl) phenyl) amino] -3- (4-hydroxyphenyl) propionic acid methyl ester (1.15 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). The mixture was then heated under reflux for 8 hours. After cooling, the reaction mixture was filtered to remove solid particles, and then the filtrate was evaporated in vacuo. The crude product was purified by silica gel chromatography using hexane / EtOAc (4: 1) as eluent to give the title compound (0.83 g, 57%).

Example 29

Preparation of 2 - [(2- (2-methylbenzoyl) phenyl) amino] -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (Laboratory code CS01300110)

To a solution of methyl ester of 2 - [(2- (2-methylbenzoyl) phenyl) amino] -3- [4- (2-bromoethoxy) phenyl] propionic acid (0.24 g, 0.49 mmol) and carbazole ( 0.082 g, 0.49 mmol) in benzene (10 ml) add tetrabutylammonium bromide (0.08 g) and an aqueous solution of 50% NaOH (0.084 g, 1.08 mmol), then the mixture is heated under reflux for 10 hours After cooling, benzene (30 ml) was added and the mixture was washed with water (3 × 30 ml). Then, the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography using CHCl ₃ / MeOH (4: 1) as eluent to give the title compound (0.11 g, 39%).

HRMS calculated for C ₃₇ H ₃₂ N ₂ O ₄ : 568.6692. Found: 568.6689. MA calculated for C ₃₇ H ₃₂ N ₂ O ₄ : C, 78.15%; H 5.67%; N, 4.93%.

Found,%: C 77.96; H 5.68; N, 4.90.

Example 30

Compounds of 2- (1-methyl-3-oxo-3-phenyl-propenylamino) -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (compound CS-023), 2 - ((2-benzoylphenyl) amino) -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (CS-0381), and 2 - [(2- (4-fluorobenzoyl) phenyl) amino] -3- [4- (2- carbazolylethoxy) phenyl] propionic acid (CS-038) act as in vitro RXP / RAPP alpha heterodimer agonists. See figure 1.

The activation of PXR / RAPPalpha heterodimer by said compounds was measured using a luciferase reporter test. Briefly, the entire RAPPalf sequence is cloned by PCR using oligonucleotide primers (5'-acgtgcttcctgcttcataga-3 '(SEQ ID NO: 1) and 5'-cctgagattagccacctccc-3' (SEQ ID NO: 2)) from HepG2 cells. The amplified cDNA is cloned into an expression vector and sequenced. The reporter is constructed by inserting an annealed oligonucleotide containing three copies of the RAPP response element (5'-gatcctctcctttgacctattgaactattacctacatttga-3 '(SEQ ID NO: 3)) above the luciferase gene sequence in the pHD (X3) Luc vector. CV-1 cells are transfected in 96-well RXP and RAPPalfa plates with expression vectors along with the reporter construct. Cells were cultured in a medium containing delipidated serum for 24 hours after transfection, then test compounds and a positive control WY (WY14643) dissolved in DMSO were added. The final concentration of DMSO in the culture medium (200 μl) is 0.5%. Cells are treated with various compounds at various concentrations as described above for 24 hours, followed by analysis of the luciferase reporter in a plate analyzer (Fluoroscan, Thermo Life Sciences).

Example 31

Compounds of 2- (1-methyl-3-oxo-3-phenyl-propenylamino) -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (compound CS-023), 2 - ((2-benzoylphenyl) amino) -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (CS-0381), and 2 - [(2- (4-fluorobenzoyl) phenyl) amino] -3- [4- (2- carbazolylethoxy) phenyl] propionic acid (CS-038) act as in vitro PCP / RAPP agonists of the gamma heterodimer. See figure 2.

The activation of PXR / RAPP gamma heterodimer is measured using the luciferase reporter test. Briefly, the entire sequence of RAPP gamma is cloned by PCR using oligonucleotide primers (5′-ggggtacctgcttcagcagcgtgttcga-3 ′ (SEQ ID NO: 4) and 5′-gctctagatgttggcagtggctcaggac-3 ′ (SEQ ID NO: The amplified cDNA is cloned into an expression vector and sequenced. The reporter is constructed by inserting an annealed oligonucleotide containing one copy of the RAPP response element (5'-cgcgttcctttccgaacgtgacctttgtcctggtccccttttgct-3 '(SEQ ID NO: 6)) above the luciferase gene sequence. CV-1 cells are transfected into 96-well RXP and RAPP gamma expression vectors together with a reporter construct. Cells were cultured in a medium containing delipidated serum for 24 hours after transfection, then test compounds and a positive control Rose (Rosiglitazone) dissolved in DMSO were added. The final concentration of DMSO in the culture medium (200 μl) is 0.5%. Cells are treated with various compounds at various concentrations as described above for 24 hours, followed by analysis of the luciferase reporter in a plate analyzer (Fluoroscan, Thermo Life Sciences).

Example 32

Compounds of 2- (1-methyl-3-oxo-3-phenyl-propenylamino) -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (compound CS-023), 2 - ((2-benzoylphenyl) amino) -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (CS-0381), and 2 - [(2- (4-fluorobenzoyl) phenyl) amino] -3- [4- (2- carbazolylethoxy) phenyl] propionic acid (CS-038) act as in vitro PCP / RAPP agonists of the delta heterodimer. See FIG. 3.

Activation of PXR / RAPP delta heterodimer is measured using a luciferase reporter test. Briefly, the entire sequence of the RAPP delta is cloned by PCR using oligonucleotide primers (5'-ggggtacctgcttcagcagcgtgttcga-3 '(SEQ ID NO: 4) and 5'-gctctagatgttggcagtggctcaggac-3' (SEQ ID NO: The amplified cDNA is cloned into an expression vector and sequenced. The reporter is constructed by inserting an annealed oligonucleotide containing one copy of the RAPP response element (5'-cgcgttcctttccgaacgtgacctttgtcctggtccccttttgct-3 '(SEQ ID NO: 6)) above the luciferase gene sequence. CV-1 cells are transfected in 96-well RXP and RAPP delta plates with expression vectors along with the reporter construct. Cells were cultured in a medium containing delipidated serum for 24 hours after transfection, then test compounds and a positive control of 2-Bros (2-bromohexadecanoic acid) dissolved in DMSO were added. The final concentration of DMSO in the culture medium (200 μl) is 0.5%. Cells are treated with various compounds at various concentrations as described above for 24 hours, followed by analysis of the luciferase reporter in a plate analyzer (Fluoroscan, Thermo Life Sciences).

Example 33

Compounds of 2 - [(2- (4-methylbenzoyl) phenyl) amino] -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (Laboratory Code CS0130080), and 2 - [(2- (4-tert -butylbenzoyl) phenyl) amino] -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (Laboratory Code CS0130090) act as in vitro RXP / RAPP heterodimer agonists. See FIG. 4. (RHR / RAPPalfa), Fig. 5 (RHR / RAPPgamma) and Fig. 6 (RHR / RAPPdelta).

Example 34

Compounds of 2- (1-methyl-3-oxo-3-phenyl-propenylamino) -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (compound CS-023, also named in FIG. 7 CS-98 ), and 2 - [(2- (4-fluorobenzoyl) phenyl) amino] -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (CS-038 at 30 mg / kg / body weight and Rosiglitazone at 4 mg / kg / body weight) reduce the glucose level in mouse db / db (number of animals 10). See FIG. 7.

Example 35

Treatment in a rat model of obesity with the compound 2 - [(2- (4-fluorobenzoyl) phenyl) amino] -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (CS-038) increases insulin sensitivity in the post-insulin tolerance test 13-day drug exposure (doses are shown in FIG. In mg / kg / body weight, Rose means rosiglitazone at a dose of 4 mg / kg / body weight, CS-4 means CS-038 at a dose of 4 mg / kg / body weight and CS -30 means CS-038 at a dose of 30 mg / kg / body weight; normal means a hungry rat.The control is an obese rat and all experiments were performed on obese rats; your animals 10). See FIG.

Example 36

Treatment in an experimental rat obesity model with compound 2 - [(2- (4-fluorobenzoyl) phenyl) amino] -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (CS-038) increases glucose tolerance in oral glucose tolerance test after 13 days of drug treatment (doses are shown in the following figure in mg / kg / body weight. Rose means rosiglitazone at a dose of 4 mg / kg / body weight, CS-4 means CS-038 at a dose of 4 mg / kg / body weight and CS-30 means CS-038 at a dose of 30 mg / kg / body weight; normal means a hungry rat. The control is an obese rat and all experiments are conducted were obese rats; animal number 10). See FIG. 9.

Example 37

Treatment in a rat model of obesity with compound 2 - [(2- (4-fluorobenzoyl) phenyl) amino] -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (CS-038) lowers blood triglycerides after 13-day drug treatment (doses are shown in Fig. 9 in mg / kg / body weight. Norm means a starving rat. The control is an obese rat and all experiments were performed on obese rats; the number of animals is 10).

Table 1

Group of animals Dose (mg / kg) Triglycerides (mg / dl) Cholesterol (mg / dl) Norm - 149.6 ± 39.8 * 73.1 ± 7.8 ** The control - 233.9 ± 101.6 109.4 ± 26.7 CS038 four 150.3 ± 52, I * 98.4 ± 29.4 CS038 thirty 143.2 ± 61.8 * 86.6 ± 37.7 Rose four 273.3 + 87.4 112.7 ± 25.5 In comparison with the normal group: * P <0.05, ** P <0.01

Example 38

Treatment in an experimental rat obesity model with compound 2 - [(2- (4-fluorobenzoyl) phenyl) amino] -3- [4- (2-carbazolylethoxy) phenyl] propionic acid (CS-038) does not affect body weight , and the abdominal fat content rises after a 15-day drug treatment (doses are in mg / kg body weight; Control is an obese rat, and all experiments were performed on obese rats; 10 animals).

table 2 Group of animals Dose (mg / kg) Body weight (g) Abdominal Fat (g) 0 days 6 days 9 days 15 days The control - 576.5 ± 138.0 569.4 ± 142.1 568.5 ± 145.3 562.7 ± 136.5 60.4 ± 21.0 CS038 four 591.5 ± 130.0 580.8 ± 130.2 575.2 ± 130.6 569.4 ± 122.9 55.8 ± 16.8 CS038 thirty 580.5 ± 134.9 586.1 ± 143.2 586.5 ± 144.2 578.3 ± 176.8 56.6 ± 21.1 Rose four 594.9 ± 169.3 604.5 ± 181.4 601.6 ± 183.9 596.4 ± 176.8 63.1 ± 31.4

All publications and patents mentioned in the above document are incorporated into this description by reference.

Various modifications and variations of the described compositions and methods of the invention are obvious to a person skilled in this field within the scope and essence of the invention. Although the invention has been described in connection with certain preferred embodiments, it should be understood that the invention, as claimed, should not be unduly limited to such specific embodiments. In fact, it is understood that various modifications of the described compositions and methods for implementing the invention, which are obvious to a person skilled in this field or in related fields, are within the scope of the following claims.

Claims (22)

1. The compound of formula I

or pharmaceutically acceptable salts thereof, wherein ring A and ring B fused to a ring containing X and N each independently represent a 5-6 membered cyclic aromatic ring; X represents a valence bond; R ¹ represents H; R ² represents H; R ³ represents H; R ⁴ and R ⁵ independently represent H, C _1-6 alkyl; or R ⁴ and R ⁵ may form an aromatic 5- or 6-membered ring; Alk ¹ is C _1-6 alkylene; Alk ² is C _1-6 alkylene; Ar ¹ is an aromatic 6 membered ring; Ar ² is an aromatic 6 membered ring optionally substituted with one or more halogen, C _1-6 alkyl; or is a 5-6 membered monocyclic aromatic ring containing one nitrogen heteroatom. 2. The compound according to claim 1, where ring A is a 6-membered aromatic ring; ring B is a 6 membered aromatic ring; X is a valence bond; R ¹ is H; R ² is H; R ³ is H; R ⁴ and R ⁵ are independently H or alkyl; Alk ¹ is C _2-3 alkylene; Alk ² is C _1-2 alkylene; Ar ¹ is an arylene group; Ar ² is a substituted aryl group. 3. The compound according to claim 1, where ring A is a 6-membered aromatic ring; ring B is a 6 membered aromatic ring; X is a valence bond; R ¹ is H; R ² is H; R ³ is H; R ⁴ and R ⁵ form a 6-membered aromatic ring; Alk ¹ is C _2-3 alkylene; Alk ² is C _1-2 alkylene; Ar ¹ is a 6 membered aromatic ring; Ar ² is a substituted aryl group. 4. The compound according to claim 1, where ring A is a benzene ring; ring B is a benzene ring; X is a valence bond; R ¹ is H; R ² is H; R ³ is H; R ⁴ is methyl; R ⁵ is H; Alk ¹ is CH ₂ CH ₂ ; Alk ² is CH ₂ ; Ar ¹ is a benzene ring; Ar ² is a benzene ring optionally substituted with one or more fluorine. 5. The compound according to claim 1, where ring A is a benzene ring; ring B is a benzene ring; X is a valence bond; R ¹ is H; R ² is H; R ³ is H; R ⁴ and R ⁵ form a benzene ring; Alk ¹ is CH ₂ CH ₂ ; Alk ² is CH ₂ ; Ar ¹ is a benzene ring; Ar ² is a benzene ring optionally substituted with one or more fluorine. 6. The compound according to claim 1, where ring A is a benzene ring; ring B is a benzene ring; X is a valence bond; R ¹ is H; R ² is H; R ³ is H; R ⁴ is methyl; R ⁵ is H; Alk ¹ is CH ₂ CH ₂ ; Alk ² is CH ₂ ; Ar ¹ is a benzene ring; Ar ² is a pyridine ring optionally substituted with one or more halogen. 7. The compound according to claim 1, where ring A is a benzene ring; ring B is a benzene ring; X is a valence bond; R ¹ is H; R ² is H; R ³ is H; R ⁴ and R ⁵ form a benzene ring; Alk ¹ is CH ₂ CH ₂ ; Alk ² is CH ₂ ; Ar ¹ is a benzene ring; Ar ² is a pyridine ring optionally substituted with one or more fluorine. 8. The method of obtaining the compounds of formula I

or pharmaceutically acceptable salts thereof, wherein ring A and ring B fused to a ring containing X and N each independently represent a 5-6 membered cyclic aromatic ring; X represents a valence bond; R ¹ represents H; R ² represents H; R ³ represents H; R ⁴ and R ⁵ independently represent H, C _1-6 alkyl; or R ⁴ and R ⁵ may form an aromatic 5- or 6-membered ring; Alk ¹ is C _1-6 alkylene; Alk ² is C _1-2 alkylene; Ar ¹ is an aromatic 6 membered ring; Ar ² is an aromatic 6 membered ring optionally substituted with one or more halogen, C _1-6 alkyl; or is a 5-6 membered monocyclic aromatic ring containing one nitrogen heteroatom comprising the steps of: a) initiating a condensation reaction between compound 1 and β-diketone 2 to obtain analogs of the vinyl amide series 3;

b) performing 0-alkylation of compound 3 to give compound 4;

c) performing N-alkylation of compound 4 to give substituted arylalkanoic acid derivatives 6.

9. The production method according to claim 8, in which: (a) a condensation reaction is carried out in ethanol at reflux temperature; (b) O-alkylation is achieved by treating compound 3 KOH and dibromoalkane in ethanol; (c) N-alkylation is achieved by treating compound 4 with NaOH and compound 5 in the presence of tetrabutylammonium bromide. 10. The compound of claim 1, wherein said compound is a RAPP pan agonist activating PXP / RAPPalfa, PXP / RAPPgamma, and PXP / RAPPdelta heterodimers. 11. The compound of claim 10, wherein said compound is a partial RAPP pan agonist activating PXP / RAPPalfa, PXP / RAPPgamma, and PXP / RAPP delta heterodimers to various degrees. 12. A pharmaceutical composition for activating nuclear receptors, including a Retinoid X Receptor (PXR) and peroxisomal proliferator (RAPP) activated receptors, comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier or thinner. 13. The pharmaceutical composition according to item 12 in a standard (dosage) dosage form containing from about 0.05 to about 200 mg of the compound according to claim 1. 14. The pharmaceutical composition according to item 13, in a standard (dosage) dosage form containing from about 0.1 to about 100 mg of the compound according to claim 1. 15. The pharmaceutical composition according to item 12, suitable for oral, intranasal, transdermal, pulmonary (inhalation) or parenteral administration. 16. A method for activating nuclear receptors, including a Retinoid X Receptor (PXR) and peroxisomal proliferator (RAPP) activated receptors, comprising administering to a subject in need thereof an effective amount of a compound of formula I

or pharmaceutically acceptable salts thereof, wherein ring A and ring B fused to a ring containing X and N each independently represent a 5-6 membered cyclic aromatic ring; X represents a valence bond; R ¹ represents H; R ² represents H; R ³ represents H; R ⁴ and R ⁵ independently represent H, C _1-6 alkyl; or R ⁴ and R ⁵ may form an aromatic 5- or 6-membered ring; Alk ¹ is C _1-6 alkylene; Alk ² is C _1-2 alkylene; Ar ¹ is an aromatic 6 membered ring; Ar ² is an aromatic 6 membered ring optionally substituted with one or more halogen, C _1-6 alkyl; or is a 5-6 membered monocyclic aromatic ring containing a nitrogen heteroatom. 17. A method of treating or preventing a condition caused by decreased activity of at least one of the nuclear receptors, including the Retinoid X Receptor (RXR) and peroxisomal proliferator (RAPP) receptors, comprising administering to a subject in need thereof an effective amount of a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein ring A and ring B fused to a ring containing X and N are each independently a 5-6 membered cyclic aromatic ring; X represents a valence bond; R ¹ represents H; R ² represents H; R ³ represents H; R ⁴ and R ⁵ independently represent H, C _1-6 alkyl; or R ⁴ and R ⁵ may form a 5- or 6-membered ring; Alk ¹ is C _1-6 alkylene; Alk ² is C _1-2 alkylene; Ar ¹ is an aromatic 6 membered ring; Ar is an aromatic 6 membered ring optionally substituted with one or more halogen, C _1-6 alkyl; or is a 5-6 membered monocyclic aromatic ring containing one nitrogen heteroatom. 18. The method of claim 17, treating or preventing a condition selected from the group consisting of type 1 diabetes, type 2 diabetes, dyslipidemia, X syndrome, cardiovascular disease, atherosclerosis, hypercholesterolemia and obesity. 19. The method of claim 18, treating or preventing type 2 diabetes. 20. The method according to p, where the effective amount of the compound is in the range from about 0.05 to about 200 mg / kg body weight per day. 21. The method according to claim 20, where the effective amount of the compound is in the range from about 0.1 to about 100 mg / kg body weight per day. 22. The method according to item 21, where the effective amount of the compound is in the range from about 0.1 to about 50 mg / kg body weight per day.

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