Ortho-substituted derivatives of benzoic acid, method and intermediate compounds for their preparing, pharmaceutical composition based on thereof and using

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzoic acid of the formula (I): , wherein represents 0, 1 or 2; R1 represents halogen atom, (C1-C4)-alkyl group that is possibly substituted with one or more fluorine atoms, (C1-C4)-alkoxyl group that is possibly substituted with one or more fluorine atoms and when n represents 2 then substitutes at R1 can be similar or different; R2 represents direct (C2-C7)-alkyl group; R3 represents hydrogen atom (H) or -OCH3; W represents oxygen (O) or sulfur (S) atom, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition used in treatment of hyperlipidemia, dyslipidemia, diabetes mellitus and obesity and comprising derivative of benzoic acid of the formula (I) in mixture with pharmaceutically acceptable adjuvants, excipients and/or carriers. Also, invention relates to using derivative of benzoic acid of the formula (I) for preparing a medicinal agent used in treatment of resistance to insulin. Also, invention relates to a method for synthesis of derivative of benzoic acid of the formula (I) and used for synthesis of intermediate compound of the formula (II) given in the invention description. Invention provides preparing derivatives of benzoic acid representing selective modulators of PPARα.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 14 ex

 

The scope of the invention

This invention relates to certain new derivatives of benzoic acid, methods of producing such compounds, their use in the treatment of clinical conditions associated with insulin resistance, to methods for their therapeutic use and to pharmaceutical compositions that contain them.

Prior art

The syndrome of insulin resistance (SRI), which includes diabetes mellitus type 2, refers to the cluster of manifestations, including insulin resistance associated with hyperinsulinemia, possible diabetes mellitus type 2, hypertension, Central (visceral) obesity, dyslipidemia observed as abnormal levels of lipoproteins, in typical cases characterized by elevated ANP (VLDL), small dense LDL particles and reduced concentrations of HDL (high density lipoprotein) and reduced fibrinolysis.

Recent epidemiological studies have documented that individuals with insulin resistance affected greatly increased risk of cardiovascular morbidity and mortality, especially suffering from myocardial infarction and stroke. Condition related to atherosclerosis, diabetes type 2 causes up to 80% of all deaths.

In the Kli is practical medicine is an awareness of the need to increase the sensitivity to insulin in patients suffering from SRI, and thus, correction of dyslipidemia, which is considered contributing to the accelerated progression of atherosclerosis. At present, however, it is not a disease with universal clear definition.

S-Enantiomer of the compounds of the formula below

2 ethoxy-3-[4-(2-{4-methysulfonylmethane}-ethoxy)-phenyl]-propanolol acid, disclosed in PCT publication no WO 99/62872. About the connection report that it is a modulator of receptor-activated proliferation peroxisome (PPAR, the review of PPAR see T. M. Willson et al, J Med Chem 2000, Vol 43, 527) and has a combined agonistic activity towards PPARα/PPARγ (Structure, 2001, Vol 9, 699, P.Cronet et al). This compound is effective in the treatment of conditions associated with insulin resistance.

Suddenly found a series of compounds which are selective modulators of PPARα.

Description of the invention

The present invention provides a compound of formula I,

where n represents 0, 1 or 2;

R1represents halogeno,1-4alkyl group which may be substituted by one or more than one fluorine atom, With1-4CNS group which may be substituted by one or more than one fluorine atom, and moreover, when the n is 2, deputies representing R1may be the same or different;

R2represents an unbranched2-7alkyl group;

R3represents H or och3; and

W represents O or S,

and its pharmaceutically acceptable salts and prodrugs.

This is followed by the determination of the values of R1, R2, R3and W in the compound of Formula I. it Should be understood that such values can be used with any of the definitions, claims or embodiments defined here above or below.

In the first aspect, R1represents halogeno,1-4alkyl group or a C1-4CNS group, and n represents 0, 1 or 2. In particular, R1represents a fluorine, chlorine or trifluoromethyl, when n represents 1. In particular, R1represents fluorine, when n represents 2.

In the second aspect of R2represents ethyl or hexyl.

In the third aspect of R3represents N.

In the fourth aspect of R3represents OMe.

In the fifth aspect W represents O.

In the sixth aspect, W is a S.

The term non-branched C2-7a denotes alkyl having a straight chain saturated aliphatic hydrocarbon having 2 to 7 carbon atoms. Examples of seokatalog of alkyl include ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and n-heptyl.

Professionals need to understand that the term "interrupted"as it is used above. means that the oxygen atom is within the alkyl chain and is not a terminal atom. The terms "proletarienne form" or "prodrug" as used in this description are equivalent and include derivatives of carboxylic acid group, which in a mammal, in particular humans, transformed into a carboxylic acid group or its salt or conjugate. It should be understood that, in the absence of theoretical restrictions, believe that much of the activity associated with proletarienne forms, arises from the activity of the compounds of formula I, in which turn proletarienne form. Proletarienne forms are available routine methods well within the abilities of the specialist. In this area there are various proletarienne form carboxy. Examples of such derivatives representing proletarienne forms, see:

a) Design of Prodrugs, edited by N. Bundgaard, (Elsevier, 1985) and Methods in Enzymology. 42: 309-396, edited by K. Widder, et al. (Academic Press, 1985);

b) A Textbook of Prodrug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p.113-191 (1991);

c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992);

d) H.Bundgaard, et al.. Journal of Pharmaceutical Sciences, 77:285 (1988); and

e) N.Kakeya, et al., Chem Pharm Bull, 32:62 (1984).

The above documents are incorporated here by reference.

Cleaved in vivo esters represent only one type proletarienne the shape of the original molecule.

The compounds of formula I have activity as pharmaceuticals, in particular, the compounds of formula I are selective agonists of PPARαthat is, their EC50for PPARα at least four times lower, and preferably at least 10, or 50 times lower than their respective EC50for PPARγand EC50measured and calculated as described in the analysis later in this document. The compounds of formula I are potent and selective.

The present invention provides a compound which is selected from the following:

2-[2-(4-{2-[ethyl(2-terbisil)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid;

2-[2-(4-{2-1(2,4-diferensial)(heptyl)amino]-2-oksidoksi}-3-methoxyphenyl)-ethoxy]-benzoic acid;

2-[2-(4-{2-1(4-chlorbenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethylthio]-benzoic acid;

2-[2-(4-{2-[(4-chlorbenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid;

2-[2-(4-{2-[ethyl(4-trifloromethyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid;

2-[2-(4-{2-[ethyl(4-trifloromethyl)-amino]-2-oksidoksi}-phenyl)-ethylthio]-benzoic acid;

2-{2-[4-(2-{butyl[2-fluoro-4-(trifluoromethyl)-benzyl]-amino}-2-oksidoksi)-phenyl]-the toxi}-benzoic acid;

2-[2-(4-{2-[(2,4-diferensial)(propyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid;

2-[2-(4-{2-[benzyl(ethyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid;

2-{[2-(4-{2-[benzyl(ethyl)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio}-benzoic acid;

2-[2-(4-{2-[(4-tert-butylbenzyl)(ethyl)-amino)-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid;

2-[2-(4-{2-[ethyl(4-terbisil)-amino]-2-oksidoksi)-phenyl)-ethoxy]-benzoic acid;

2-{[2-(4-{2-[ethyl(2-terbisil)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio)-benzoic acid; or

2-{[2-(4-{2-[(2-Chlorobenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio}-benzoic acid

and their pharmaceutically acceptable salts.

In particular, this compound selected from the following:

2-[2-(4-{2-[ethyl(2-terbisil)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid;

2-[2-(4-{2-[(4-chlorbenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethylthio]-benzoic acid;

2-[2-(4-{2-[(2,4-diferensial)(propyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid;

2-[2-(4-{2-[benzyl(ethyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid; or

2-[2-(4-{2-[ethyl-(4-terbisil)-amino]-2-oksidoksi)-phenyl)-ethoxy]-benzoic acid.

It should also be understood that certain compounds of the present invention may exist in solvated, and resolutiony forms. It should be understood that the present invention ovative the t all such solvated forms. Certain compounds of the present invention may exist as tautomers. It should be understood that the present invention covers all such tautomers.

Throughout this description and in the accompanying claims given chemical formula or name shall encompass all stereoisomers and optical isomers and racemates, and mixtures of the individual enantiomers in different proportions, when there are such isomers and enantiomers and their pharmaceutically acceptable salts. The isomers can be divided using conventional techniques, such as chromatography or fractional crystallization. The enantiomers can be isolated by separation of the racemates, for example by fractional crystallization, re-dissolution or HPLC. The diastereomers can be isolated by separation of mixtures of isomers, for example, by fractional crystallization, HPLC or flash chromatography. Or stereoisomers can be obtained by chiral synthesis from chiral starting materials under conditions that should not cause racemization or epimerization, or a chiral derivatization reagent. All stereoisomers are included in the scope of this invention.

Ways to get

Compounds according to this invention can be obtained as outlined below. However, this invention is not limited to these methods, these compounds can also paragraph shall be provided as described for structurally related compounds in the prior art. Interaction can be carried out in accordance with standard procedures or as described in the experimental section.

The compounds of formula 1 can be obtained by the coupling of compounds of formula II,

in which R1, R2, R3, W and n are such as defined above, and PG represents a protective group for a carboxylic hydroxy group as described in the standard text "Protective Groups in Organic Synthesis, 2ndEdition (1991) Green and Wuts, agent unprotect. The protective group may also be a resin, such as resin Wang (Wang), or the resin constituting the chloride 2-chlorotrityl. The protective group can be removed according to methods that are well known in the art. One such protective group is one where PG is a group of C1-6alkoxy or a group of Allakaket, for example benzyl, so COPG is an ester. Such esters can result in interaction with gidrolizuut agent, for example lithium hydroxide in the presence of a solvent, for example a mixture of tetrahydrofuran and water, or potassium hydroxide in C1-3alcohol, for example methanol, at a temperature in the range 0-200°With or microwave radiation with obtaining the compounds of formula I.

The compounds of formula II can be obtained by the coupling of compounds of formula III

or its salts, for example salt, a hydrochloride, in which R1, R2and n are such as defined above, with a compound of formula IV

or its acid chloride, in which R3W and PG such as defined above, in an inert solvent, for example dichloromethane, possibly in the presence of a combining agent, for example 4-dimethylaminopyridine or hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide at a temperature in the range from -25°to 150°C.

The compounds of formula II can also be obtained by the coupling of compounds of formula V,

in which PG is as defined above, with a compound of formula VI,

in which R1, R2, R3, W and n are such as defined above, and L represents a leaving group, for example, methylsulfonylamino or halogen, for example bromine, possibly in the presence of a solvent, for example acetonitrile, and possibly in the presence of a base, for example potassium carbonate, at a temperature in the range from 0 to 150°C.

The compounds of formula III, IV, V and VI can be obtained by methods described in the Examples or by analogous methods known to experts.

The compounds of formula II, III, IV and V are useful intermediate compounds in the connection f is rmula I. Some compounds among them are new. The new compounds of formula II, or formula III, or formula IV, or formula V stated here as an additional aspect of the present invention.

Compounds according to this invention can be isolated from their reaction mixtures using conventional techniques.

Professionals need to understand that to obtain the compounds according to this invention, an alternative and, in some cases, more convenient manner, the individual stages of the ways mentioned here above, can be performed in a different order, and/or individual interaction can be performed at different stages all the way (i.e., chemical transformations can be carried out at other intermediate compounds than those associated it with a specific interaction).

In any of the previous methods of obtaining, if necessary, hydroxy, amino or other interacting groups can be protected with a protective group, Rpas described in the standard text "Protective groups in Organic Synthesis", 2ndEdition (1991) by Greene and Wuts.

The protective group may also be a resin, such as resin Wang (Wang), or the resin constituting the chloride 2-chlorotrityl. Protection of functional groups and the removal of protection may take place before or after any of the stages of interaction described here above. Protect the local group can be removed in accordance with the methods which are well known to specialists.

The expression "inert solvent" refers to a solvent which does not react with the starting materials, reagents, intermediate compounds or products in a manner that undesirable effect on the yield of the desired product.

Pharmaceutical

Compounds according to this invention in the rule should be administered orally, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, cheek, rectal, vaginal, cutaneous and/or nasal route and/or by inhalation in the form of a pharmaceutical preparation containing the active ingredient either as a free acid or as a pharmaceutically acceptable salt in a pharmaceutically acceptable dosage form. Depending on the violation and the patient to be treated, and the route of administration, the compositions can be introduced in varying doses.

Suitable daily doses of the compounds according to this invention in therapeutic treatment of humans are about of 0.0001-100 mg/kg body weight, preferably 0.001 to 10 mg/kg of body weight.

Preferred are oral drugs, in particular tablets or capsules, which can be by methods known in the art, to provide doses of the active compound in the range from 0.5 mg to 500 mg, for example 1 mg, 3 mg, 5 mg, 10 the g 25 mg, 50 mg, 100 mg and 250 mg

Thus, in accordance with an additional aspect of this invention, a pharmaceutical preparation comprising any of the compounds of this invention or its pharmaceutically acceptable salt in a mixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.

An example of a pharmaceutical composition and manufacture of a pharmaceutical preparation in the form of tablets.

EXAMPLE. Manufacturing tablets

Ingredientsmg tablet
1. Active connection10,0
2. Microcrystalline cellulose57,0
3. Phosphate calcium15,0
4. Sodium starch glycolate5,0
5. Silicon dioxide, colloidal0,25
6. Magnesium stearate0,75

The active ingredient mixed with 1 ingredients 2, 3, 4 and 5 for about 10 minutes. Then add the magnesium stearate and the mixture is stirred for approximately 2 minutes and pressed into tablet form, which you can then cover film cover.

Pharmacological properties

These compounds of formula (I) useful for the prevention and and/or treatment of clinical conditions, associated with congenital or induced decreased sensitivity to insulin (insulin resistance and associated metabolic disorders (also known as metabolic syndrome). These clinical condition include the following without limitation by them: General obesity, abdominal obesity, hypertension, hyperinsulinemia, hyperglycemia, type 2 diabetes and dyslipidemia, which is characterized by the way there is a resistance to insulin. This dyslipidemia, also known as the atherogenic urine profile, characterized by moderately elevated levels of nonesterified fatty acids, elevated levels of triglyceride-rich particles, representing a lipoprotein very low density lipoproteins (VLDL), and apolipoproteinb Ares, low levels of high density lipoprotein (HDL)associated with low levels of particles, representing the APO AI, and with high levels of Haro, in the presence of small, dense particles, representing the low-density lipoprotein (LDL) phenotype Century

It is expected that the compounds according to this invention are useful in the treatment of patients with combined or mixed hyperlipidemia or varying degrees of hypertriglyceridemia and postepidemic dyslipidemia in the presence or absence of other manifested the th metabolic syndrome.

It is expected that the treatment of these compounds due to their antidyslipidemic and anti-inflammatory properties will reduce cardiovascular morbidity and mortality associated with atherosclerosis. State, representing cardiovascular disease include macroangiopathies various internal organs, causing myocardial infarction, congestive heart failure, disease of the cerebral vessels and the lack of peripheral arteries of the lower extremities. Because of their actions, consisting in sensitization to insulin, it is expected that the compounds of formula I prevent and slow the development of diabetes type 2, metabolic syndrome and diabetes in pregnancy. It is therefore expected that will slow the development of long-term complications associated with chronic hyperglycemia, such as microangiopathy, causing kidney disease, retinal damage and peripheral vascular disease of the lower extremities in diabetes mellitus. Moreover, these compounds may be useful in the treatment of various conditions outside the cardiovascular system, regardless of their Association with insulin resistance, such as polycystic ovarian syndrome, obesity, cancer and state, representing inflammatory diseases, including neurodegenerative violated the I, such as mild mental disorders, Alzheimer's disease, Parkinson's disease and multiple sclerosis.

It is expected that the compounds according to this invention are useful in controlling glucose levels in patients with type 2 diabetes.

The present invention provides a method of treating or preventing dyslipidemia, syndrome of insulin resistance and/or metabolic disorders (defined above), wherein the compound of formula I is administered to a mammal (especially a human), which needs it.

The present invention provides a method of treatment or prevention of diabetes type 2 in which the compound of formula I is administered to a mammal (particularly a human)that need it.

In an additional aspect, the present invention provides the use of compounds of formula I as medicaments.

In an additional aspect, the present invention provides the use of compounds of formula I in the manufacture of medicaments for the treatment of insulin resistance and/or metabolic disorders.

Combinational therapy

Compounds according to this invention can be combined with another therapeutic agent that is useful in the treatment of disorders associated with the development and progression of atherosclerosis, such as hypertension, hyperlipidemia, d is lipidemia, diabetes and obesity. Compounds according to this invention can be combined with another therapeutic agent, which reduces the ratio of LDL:HDL, or agent that causes a decrease in levels of LDL-cholesterol in the blood. In patients with diabetes compounds according to this invention can also be combined with therapeutic agents used to treat complications related to microangiopathy.

Compounds according to this invention can be used along with other methods of treatment of metabolic syndrome or type 2 diabetes and its associated complications, which includes medicines, representing a biguanide, such as Metformin, phenformin and buformin, insulin (synthetic insulin analogues, Amylin) and oral antihyperglycemics funds (divided into regulators of glucose in the meal and alpha-glucosidase inhibitors). An example of an inhibitor of alpha-glucosidase is acarbose or voglibose or miglitol. An example of a regulator of glucose in the meal is Repaglinide or nateglinide.

In another aspect of this invention the compound of formula I or its pharmaceutically acceptable salt, MES, MES such a salt or Palekastro form can be entered in Association with other PPAR-modulating agent. PPAR-modulating agents include with the BOJ following without limiting them: agonist of PPARα and/or PPARγ and/or PPARδor its pharmaceutically acceptable salt, solvate, solvate of such a salt or proletarienne form. Suitable agonists of PPARα and/or PPARγ, their pharmaceutically acceptable salt, solvate, solvate of such a salt or proletarienne forms well known in this field. They include compounds disclosed in WO 01/12187, WO 01/12612, WO 99/62870, WO 99/62872, WO 99/62871, WO 98/57941, WO 01/40170, J Med Chem, 1996, 39, 665, Expert Opinion on Therapeutic Patents, 10 (5), 623-634 (in particular, the compounds disclosed in the patent applications listed on str) and in J Med Chem, 2000, 43, 527, which are all incorporated here by reference. In particular agonist of PPARα and/or PPARγ refers to BMS 298585, clofibrate, fenofibrate, bezafibrat, gemfibrozil and ciprofibrate; GW 9578, pioglitazone, rosiglitazone, rivoglitazone, balaglitazone, KRP-297, JTT-501, SB 213068, GW-1929, GW 7845. GW-0207, L-796449, L-165041 and GW 2433. In particular agonist of PPARα and/or PPARγ refers to (S)-2-ethoxy-3-[4-(2-{4-methanesulfonate-phenyl)-ethoxy)-phenyl]-propanolol acid and its pharmaceutically acceptable salts.

In addition, the combination of this invention can be used in combination with a sulfonylurea such as glimepiride, glibenclamide (gliburid), gekleidet, glipizide, glikvidona, chlorpropamide, tolbutamide, acetohexamide, glycopyrronium, karbutamidom, glibornuride, glisoxepide, globaliation, what libutan, glyhexamide, glymidine, pipename, fenbutatin, calcination and tolazamide. Preferably a is a sulfonylurea glimepiride or glibenclamide (gliburid). More preferably a is a sulfonylurea glimepiride. Therefore, this invention includes the introduction of compounds according to this invention in combination with one, two or more than two of the existing therapeutic agents described in this paragraph. Doses of other existing therapeutic agents for the treatment of type 2 diabetes and its associated complications should be those known in the field and approved for use by regulatory authorities such as the FDA, and they can be found in the Orange Book, published by the FDA. Or you can use a smaller dose in the benefit from this combination. The present invention also includes the compound of the present invention in combination with an agent lowering cholesterol. Agents lowering cholesterol, specified in this application include, without limitations they reductase inhibitors HMG-COA reductase, 3-hydroxy-3-methylglutaryl-coenzyme A).

Appropriately inhibitor of reductase HMG-COA is a statin, which are selected from the group consisting of atorvastatin, bervastatin, tseriwastatina, dalvastatin, fluvastatin, itavastatin, l is vastatin, mevastatin, mycostatin, mevastatin, pravastatin and simvastatin or its pharmaceutically acceptable salts, in particular sodium or calcium, or MES or MES such salts. Specific statin is atorvastatin or its pharmaceutically acceptable salt, MES, MES such a salt or proletarienne form. More specific statin is the calcium salt of atorvastatin. Especially preferred statin is, however, a compound with the chemical name (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)-amino]-pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-eneva acid [also known as (E)-7-[4-(4-forfinal)-6-isopropyl-2-[N-methyl-N-(methylsulphonyl)-amino]-pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-eneva acid] or its pharmaceutically acceptable salt or MES or MES such salts. The compound (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl-(methylsulphonyl)-amino]-pyrimidine-5-yl]-(3R,5S) - for 3,5-dihydroxide-6-eneva acid and its calcium and sodium salts are disclosed in the Application for a European patent Publication number EP-A-0521471, and in Bioorganic and Medicinal Chemistry, (1997), 5(2), 437-444. This last statin now known as rosuvastatin (generic name).

In this application, the term "agent lowering cholesterol also includes chemical modification reductase inhibitors HMG-COA, such as the complex is e esters, proletarienne forms and metabolites, both active and inactive.

The present invention also includes the compound of the present invention in combination with an agent binding bile acids, such as colestipol or cholestyramine or cholestagel.

The present invention also includes the compound of the present invention in combination with an inhibitor of the transport of bile acids in the small intestine (IBAT-inhibitor).

Been disclosed suitable compounds having activity IBAT inhibitor, see for example the compounds disclosed in WO 93/16055, WO 94/18183, WO 94/18184, WO 94/24087, WO 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, W098/07749, WO 98/38182, WO 98/40375, WO 98/56757, WO 99/32478, WO 99/35135, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/20392, WO 00/20393, WO 00/20410, WO 00/20437, WO 01/34570, WO 00/35889, WO 00/47568, WO 00/61568, WO 01/68637, WO 01/68096, WO 02/08211, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, DB 19825804, JP 10072371, US 5070103, BP 251315, EP 417725, EP 489423, EP 549967, EP 573848, EP 624593, EP 624594, EP 624595, EP 869121, EP 864582 and EP 1070703, and the contents of these patent applications, in particular compounds disclosed in claim 1 of the formula, and named examples incorporated here by reference.

Specific classes IBAT inhibitors suitable for use in the present invention, are benzodiapine, and compounds described in the claims, in particular claim 1, in WO 00/01687, WO 96/08484 and WO 97/33882 incorporated here by reference. The other approach is the following classes IBAT inhibitors represent a 1,2-benzothiazepine, 1,4-benzothiazepine and 1.5-benzothiazepine. Additional suitable class IBAT inhibitors represents a 1,2,5-benzothiadiazepine.

One specific suitable connection with the activity of the IBAT inhibitor is (3R,5R)-3-butyl-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl-β-D-glucopyranoside acid (EP 864 582). Other suitable IBAT inhibitors include one of the following:

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)-carbarnoyl]-methyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-(N'-(carboxymethyl)-carbarnoyl]-4-hydroxybenzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(2-sulfoethyl)-carbarnoyl]-methyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(2-sulfoethyl)-carbarnoyl]-methyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(2-sulfoethyl)-carbarnoyl]-4-hydroxybenzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-(α-[N'-(2-sulfoethyl)-carbarnoyl]-4-hydroxybenzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3-butyl-3-the Teal-5-phenyl-7-methylthio-8-(N-{(R)-α -[N'-(2-carboxyethyl)-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(2-carboxyethyl)-carbarnoyl]-4-hydroxybenzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(5-carboxypentyl)-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-(α-N'-(2-carboxyethyl)-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{α-N'-(2-sulfoethyl)-carbarnoyl]-2-terbisil}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(R)-(2-hydroxy-1-carboxyethyl)-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(R)-(2-hydroxy-1-carboxyethyl)-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-{N-[(R)-α-(N'-{(R)-1-[N'-(R)-(2-hydroxy-1-carboxyethyl)-carbarnoyl]-2-hydroxyethyl}-carbarnoyl)-benzyl]-carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{α-[N'-(2-sulfoethyl)-carbarnoyl]-2-terbisil}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-is ioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N - {(R)-α -[N'-(R)-(2-hydroxy-1-carboxyethyl)-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N - {(R)-α-[N'-(R)-(2-hydroxy-1-carboxyethyl)-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-{N-[(R)-α-(N'-{(R)-1-[N"-(R)-(2-hydroxy-1-carboxyethyl)-carbarnoyl]-2-hydroxyethyl}-carbarnoyl)-benzyl]-carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N'-(carboxymethyl)-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N'-((ethoxy)(methyl)phosphoryl-methyl)-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-4,5-benzothiazepin;

1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N'-{2-[(hydroxy)(methyl)phosphoryl]-ethyl}-carbarnoyl)-benzyl]-carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(2-methylthio-1-carboxyethyl)-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-{N-[(R)-α-(N'-{2-[(methyl)(ethyl)phosphoryl]-ethyl)-carbarnoyl)-4-hydroxybenzyl]-carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-{N-[(R)-α-(N'-{2-[(methyl)(hydroxy)-phosphoryl]-ethyl}-carb is oil)-4-hydroxybenzyl]-carbamoylmethyl}-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[(R)-N'-(2-methylsulfinyl-1-carboxyethyl)-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methoxy-8-[N-{(R)-α-[N'-(2-sulfoethyl)-carbarnoyl]-4-hydroxybenzyl}-carbamoylphenoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthio-ethyl)-carbarnoyl]-4-hydroxybenzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)-carbarnoyl]-4-hydroxybenzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiazepin;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)-carbarnoyl]-4-hydroxybenzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutil-5-Hairdryer Il-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxybutyl)-carbarnoyl]-4-hydroxybenzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)α -[N-((S)-1-carboxy-2-(R)-hydroxypropyl)-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulfoethyl)-carbarnoyl]-4-hydroxybenzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)-carbarnoyl]-4-hydroxybenzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-{(R)-1-carboxy-2-methylthioethyl)-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-{(S)-1-[N - ((S)-2-hydroxy-1-carboxyethyl)-carbarnoyl]-propyl}-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

1,1-dioxo-3,3-dibutil-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)-carbarnoyl]-benzyl}-carbamoylphenoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;

or its pharmaceutically acceptable salt, MES, MES such a salt or Palekastro form.

In accordance with another aspect of the present invention proposed combinational treatment, which is administered an effective amount of the compounds of formula I or its pharmaceutically acceptable salt, MES, MES such a salt or proletarienne form, possibly in conjunction with farmacevtichesky acceptable diluent or carrier, with the simultaneous, sequential or separate introduction of one or more than one of the following agents selected from the following:

inhibitor SETR (protein transfer of cholesterol esters), for example those disclosed in WO 00/38725, page 7, line 22 to page 10, line 17, which is incorporated here by reference to them;

antagonist cholesterol intake, such as azetidinone, such as SCH 58235 and those described in US 5767115, which is incorporated here by reference to them;

inhibitor of MTP (microsomal protein transfer), such as those that are described in Science, 282, 751-54,1998, which is incorporated here by reference to them;

a derivative of nicotinic acid, which includes products for slow release and combination, for example nicotinic acid (Niacin), acipimox and niceritrol;

the Union, representing phytosterols, such as stanely;

probucol;

the connection against obesity, such as orlistat (EP 129748) and sibutramine (GB2184122 and US 4929629);

ω3-fatty acid, such as Omacor™;

antihypertensive compound for example an inhibitor angiotenzinkonvertiruyuschego enzyme (ACE), antagonist of angiotensin II receptor, adrenergic blocker, α-adrenergic blocker, β-adrenergic blocker, such as metoprolol, mixed α/β-adrenergic blocker, adrenergichesky the stimulator, blocker channels for calcium blocker at-1, salureticheskoe means of diuretic or vasodilator agent;

antagonist or inverse agonist SB, for example, which is described in WO 01/70700 and EP 65635;

aspirin;

the antagonist, a melanin-concentrating hormone (sit);

the PDK inhibitor; or

modulators of nuclear receptors for example LXR, FXR, RXR, and RORα;

or its pharmaceutically acceptable salt, MES, MES such a salt or proletarienne form, possibly together with a pharmaceutically acceptable diluent or carrier, to a warm-blooded animal, such as man, in need of such therapeutic treatment.

Specific ACE inhibitors or pharmaceutically acceptable salt, solvate, solvate of such a salt or proletarienne forms, including active metabolites, which can be used in combination with the compound of the formula I include the following compounds without their limitations: alacepril, elatioris, calcium salt of altiopia, uncovered, benazepril, benazepril hydrochloride, benazeprilat, benzoyltartaric, captopril, captopril-cysteine, captopril-glutathione, ceronapril, ceronapril, ceronapril, cilazapril, zilazaprilata, delapril, delapril-dikelola, enalapril, enalaprilat, enapril, epilatory, proximity, fosinopril, fosinopril, sodium salt Posen is prila, fosinopril, sodium salt of fosinopril, fosinoprilat, fosinoprilat acid, glycopeel, hamartin-4, atapryl, imidapril, indrapuri, indrapala, dibenzepin, lisinopril, licien And, licien In, missapril, moexipril, moeksiprilat, multiperil, mortein And, Murzin In, Murzin With, pentopril, perindopril, perindoprilat, pivaloyl, pivotal, quinapril, quinapril hydrochloride, quinaprilat, ramipril, ramiprilat, spirapril, inhibitor spirapril hydrochloride, spirapril, spirapril, spirapril hydrochloride, temocapril, temocapril hydrochloride, ceprotin, trandolapril, trandolaprilat, ulibarri, saucepan, sailpilot, zofenopril and zofenoprilat. Preferred ACE inhibitors for use in the present invention are ramipril, ramiprilat, lisinopril, enalapril and enalaprilat preferred ACE inhibitors for use in the present invention are ramipril and ramiprilat.

Preferred antagonists of angiotensin II, their pharmaceutically acceptable salt, solvate, solvate of such a salt or proletarienne forms for use in combination with the compound of the formula I include, but without limiting them, links: candesartan, candesartan, cilexetil, losartan, valsartan, irbesartan, tasosartan, telmisartan and eprosartan. Particularly preferred antagonists angioten the ina II or their pharmaceutically acceptable derivatives for use in the present invention are candesartan and candesartan cilexetil.

Therefore in an additional feature of the invention, a method for treatment of type 2 diabetes and its associated complications in a warm-blooded animal, such as man, in need of such treatment, in which the above animal is administered an effective amount of the compounds of formula I or its pharmaceutically acceptable salt, MES, MES such a salt or proletarienne form of simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this section of the combinations, or its pharmaceutically acceptable salt, MES, MES such a salt or proletarienne form.

Therefore, in an additional aspect of this invention a method of treatment hyperlipidemics conditions in a warm-blooded animal, such as man, in need of such treatment, in which the above animal is administered an effective amount of the compounds of formula I or its pharmaceutically acceptable salt, MES, MES such a salt or proletarienne form of simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this section of the combinations, or its pharmaceutically acceptable salt, MES, MES such a salt or proletarienne form.

According to updat the enforcement aspect of this invention proposed pharmaceutical composition, which contains a compound of formula I or its pharmaceutically acceptable salt, MES, MES such a salt or Palekastro form and one of the other compounds described in this section of the combinations, or its pharmaceutically acceptable salt, MES, MES such a salt or Palekastro form in Association with a pharmaceutically acceptable diluent or carrier.

In accordance with an additional aspect of the present invention proposed a set containing the compound of formula I or its pharmaceutically acceptable salt, MES, MES such a salt or Palekastro form and one of the other compounds described in this section of the combinations, or its pharmaceutically acceptable salt, MES, MES such a salt or Palekastro form.

In accordance with an additional aspect of the present invention proposed a set containing:

a) a compound of formula I or its pharmaceutically acceptable salt, MES, MES such a salt or Palekastro form in the first unit standard dosage form;

b) one of the other compounds described in this section of the combinations, or its pharmaceutically acceptable salt, MES, MES such a salt or Palekastro form a second single standard dosage form; and

c) container means for receiving said Pervoye second dosage forms.

In accordance with an additional aspect of the present invention proposed a set containing:

a) compound of formula I or its pharmaceutically acceptable salt, MES, MES such a salt or Palekastro the form together with a pharmaceutically acceptable diluent or carrier in a first unit standard dosage form;

b) one of the other compounds described in this section of the combinations, or its pharmaceutically acceptable salt, MES, MES such a salt or Palekastro form a second single standard dosage form; and

c) container means for receiving the above-mentioned first and second dosage forms.

In accordance with another feature of the invention it is proposed to use the compounds of formula I or its pharmaceutically acceptable salt, MES, MES such a salt or proletarienne form and one of the other compounds described in this section of the combinations, or its pharmaceutically acceptable salt, MES, MES such a salt or proletarienne form in the manufacture of medicaments for use in the treatment of metabolic syndrome or type 2 diabetes and associated complications in a warm-blooded animal such as man.

In accordance with another feature of the invention it is proposed to use the compounds of formula 1 or its formats whitesky acceptable salt, the MES, the MES of such salt or proletarienne form and one of the other compounds described in this section of the combinations, or its pharmaceutically acceptable salt, MES, MES such a salt or proletarienne form in the manufacture of medicaments for use in the treatment of hyperlipidemics conditions in a warm-blooded animal such as man.

In accordance with an additional aspect of the present invention proposed combinational treatment, which is administered an effective amount of the compounds of formula 1 or its pharmaceutically acceptable salt, MES, MES such a salt or proletarienne form, possibly together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate introduction of an effective amount of one of the other compounds described in this section of the combinations, or its pharmaceutically acceptable salt, MES, MES such a salt or proletarienne form, possibly together with a pharmaceutically acceptable diluent or carrier, to a warm-blooded animal, such as man, in need of such therapeutic treatment.

Working examples

Performed measurements1H-NMR and13C-NMR spectrometer Varian Mercury 300 or Varian UNITY plus 400, 500 or 600 working for1H at frequencies of 300, 400, 500 and 600 MHz, matched with the public, for13With at frequencies of 75, 100, 125 and 150 MHz, respectively. Did measurements on the Delta scale (5).

Unless otherwise specified, the chemical shifts are given in ppm with the solvent as internal standard.

Reduction
SRIthe syndrome of insulin resistance
Thosethin-layer chromatography
HOBT1-hydroxybenzotriazole hydrate
DEBUGdiisobutylaluminum hydride
DMSOthe sulfoxide
EtOActhe ethyl acetate
DMFN,N-dimethylformamide
THFtetrahydrofuran
HPLChigh performance liquid chromatography
MeCNacetonitrile
TFUtriperoxonane acid
Pd/Cpalladium on carbon
GATAhexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea
DHMDichloromethane
TBTUtetrafluoroborate-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea
DIPEA N,N-diisopropylethylamine
DMAP4-dimethylaminopyridine
TrisaminTris(hydroxymethyl)aminomethan

ISOLUTE® FLASH Si represents a column of silica suitable for chromatography.

Mixing the polymeric substrate is a borohydride on Amberlite IRA-400 from Aldrich.

LC-MSliquid chromatography/mass specrometry
kgroom temperature
ttriplet
sthe singlet
ddoublet
qQuartet
quintquintet
mmultiplet
brwide
Bs dma broad singlet doublet of multiplets
btbroad triplet
ddthe doublet of doublets

Example 1

a) tert-Butyl[4-(2-hydroxyethyl)-phenoxy]-acetate

A mixture of 4-(2-hydroxyethyl)-phenol (3.8 ml, 25,834 mmol)dissolved in acetonitrile (25 ml), potassium carbonate (7,085 g, 51,267 mmol) and tert-butylbromide (5,000 g, 25,834 mmol) was heated at reflux distilled 16 hours. The solvent is evaporated is under reduced pressure. The residue was dissolved in EtOAc and washed with brine and water, dried with magnesium sulfate and evaporated under reduced pressure to give the desired product (6,00 g, yield of 92.8%).

1H-NMR (400 MHz, CDCl3): 1.52 (s, N), 2.98 (t, 2H), 3.46 (t, 2H), 4.92 (s, 2H), 6.89-6.97 (m, 4H).

b) tert-Butyl(4-{2-[(methylsulphonyl)oxy]ethyl}phenoxy)-acetate

Tert-butyl[4-(2-hydroxyethyl)phenoxy]-acetate (6,000 g, 23,781 mmol) and triethylamine (9,9 ml, 71,341 mmol) was dissolved in DHM. This mixture was cooled to -10°and to this mixture was added drops methanesulfonanilide (2.8 ml, 35,671 mmol). This reaction mixture was allowed to reach room temperature and stirred 16 hours. This mixture was diluted with dikhlormetil. The organic layer was washed with water, brine and 0.3 M potassium hydrosulfate, dried with magnesium sulfate and evaporated under reduced pressure. Received 7.5 g of light-yellow crystals (yield 95.5 percent).

1H-NMR (400 MHz, CDCl3): 1.52 (s, N), 2.98 (t, 2H), 3.10 (s, 3H), 3.46 (t, 2H), 4.92 (s, 2H), 6.89-6.97 (m, 4H).

c) Methyl 2-{2-[4-(2-tert-butoxy-2-oksidoksi)-phenyl]-ethoxy}-benzoate

Dissolved methyl salicylate (2.7 ml, 21,187 mmol) in acetonitrile was added potassium carbonate (5,856 g, 42,373 mmol). This mixture was cooled to -10°then added thereto tert-butyl(4-{2-[(methylsulphonyl)-oxy]-ethyl}-phenoxy)-acetate. This mixture is boiled at reflux distilled 16 hours and then the solvent is evaporated under reduced pressure. The remainder R which was storyli in EtOAc, washed with water and brine, then the organic layer was dried with magnesium sulfate and the solvent was removed by evaporation. The crude material was purified flash chromatography (silica gel 60; 0,004-0,063 mm) using a mixture of EtOAc:toluene 50:50 as eluent. Fractions that contained the desired product were pooled pooled, the solvent was evaporated. This gave 5.0 g of pure product (yield 61,1%).

1H-NMR (400 MHz, CDCl3); 1.48 (s, N), 3.08 (s, 3H), 3.87 (t, 2H), 4.18 (t, 2H), 4.49 (s, 2H), 6.84 (d, 2H), 6.90-6.98 (m, 2H), 7.20-7.26 (m, 2H), 7.38-7.43 (m.1H), 7.7 (dd,1H).

d) (4-{2-[2-(methoxycarbonyl)-phenoxy]-ethyl}-phenoxy)-acetic acid

Dissolved methyl-2-{2-[4-(2-tert-butoxy-2-oksidoksi)-phenyl]-ethoxy}-benzoate (0.400 g, 1,0351 mmol) in DHM and added triperoxonane acid (0.8 ml, 8,281 mmol). This mixture was stirred at room temperature for 3 hours. The solvent is evaporated to obtain 325 mg of white powder.

1H-NMR (600 MHz, CDCl3); 3.08 (t, 2H), 3.86 (s. 3H), 4.18 (t, 2H), 4.64 (s, 2H), 6.84-6.96 (m, 4H), 7.23 (d, 2H), 7.37-7.42 (m, 1H), 7.75 (dd, 1H).

e) Methyl-2-[2-(4-[2-[ethyl(2-terbisil)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoate

(4-{2-[2-(Methoxycarbonyl)-phenoxy]-ethyl}-phenoxy)-acetic acid (0,200 mg, 0,605 mmol) was dissolved in dimethylformamide and cooled in an ice bath. Was added N-(2-terbisil)-ethanamine (is 0.102 g, 0,666 mmol), TBTU (0,214 g, 0,666 mmol) and DIPEA (0,22 ml, 1,271 mmol). This reaction mixture was stirred 16 hours at on the th temperature. Added EtOAc and the organic phase is washed with two portions of 20 ml of Na2POPs (saturated). Dried the organic layer with magnesium sulfate and the solvent was removed by evaporation. The crude product was purified preparative HPLC (started with a mixture of acetonitrile/buffer 60/40 and then increased the concentration of acetonitrile to 100% acetonitrile over 25 minutes, the buffer was a mixture of acetonitrile/water 10/90 with ammonium acetate (0.1 M); column KR-100-7-C8, 50*500; the flow rate 80 ml/min). After freeze-drying was received 145 mg of the desired product (yield 71,1%).

1H-NMR (400 MHz, CD3CO) (rotamer); 1.08, 1.17 (t, t, 3H), 2.96 (s, 3H), 3.07 (m, 2H), 3.31, 3.36 (m. 2H), 4.21 (m, 2H), 4.85 (s, 2H), 4.56-4.82 (m, 2H), 6.18 (d, 1H), 6.88-7.06 (m, 3H), 7.18-7.35 (m, 6H), 7.42 (m, 1H), 7.70 (d, 1H).

f) 2-[2-(4-{2-[ethyl(2-terbisil)-amino-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid

Dissolved methyl-2-[2-(4-{2-[ethyl-(2-terbisil)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoate (0,200 g, 0,115 mmol) in 3 ml of tetrahydrofuran in Viale synthesizer Smith and then added to the vial 1.5 ml of water and lithium hydroxide (0,032 g, 1,335 mmol). The vial was closed with a cap and placed in a microwave (Smith synthesizer). Then the reaction mixture is heated to 150°C for 6 minutes. In accordance with LC-MS, the reaction was completed. The solvent is evaporated. The residue was dissolved in diethyl ether (30 ml) and washed with sodium bicarbonate (saturated) (2°20 ml). The school is full-time the aqueous layer was acidified to pH 1 dvuhpolyarniy HCl. The aqueous layer was extracted with three portions of 20 ml DHM, which were combined, dried and evaporated to obtain 160 mg of pure desired product.

1H-NMR (400 MHz, CD3CO) (rotamer); 1.07, 1.15 (t, t, 3H), 3.10 (m, 2H), 3.30, 3.36 (m, m, 2H), 4.21 (m, 2H), 4.55-4.67 (m, 2H), 4.90 (s, 2H), 6.20 (d, 1H), 6.87-7.06 (m, 3H), 7.18-7.35 (m, 6H), 7.40 (m, 1H), 7.70 (d, 1H).

Example 2

a)2-Bromo-N-(2,4-disturbances)-N-heptylene

N-(2,4-diferensial)-N-heptylamine (at 2,004 g 8,304 mmol) was dissolved in DHM (30 ml). Then cooled it in an ice bath. Was added triethylamine (1,092 g 10,796 mmol) and then added drops bromocatechol (1,438 g 9,135 mmol). This mixture was stirred 2 hours (ice bath). Then it was washed with water (with additional 1%hydrochloric acid, pH˜3), water and brine and dried (magnesium sulfate) and was evaporated. The crude product oil was dissolved in DHM, then applied on a column (ISOLUTE®SI 5 g/25 ml) and was suirable additional DHM. Received the product in the form of oil: 2,412 g, yield 80%.

1H-NMR (rotamer. 500 MHz, CDCl3): δ 0.88-0.93 (m, 3H), 1.27-1.34 (m, 8H), 1.52-1.68 (m, 2H), 3.28-3.35 (m. 2H), 3.90-4.15 (m, 2H), 4.61, 4.63 (s, s, 2H), 6.81-6.94 (m, 2H), 7.15-7.20, 7.34-7.39 (m, 1H).

b) N-(2,4-diferensial)-N-heptyl-2-[4-(2-hydroxyethyl)-2-methoxyphenoxy]-ndimethylacetamide

Mixed 2-bromo-N-(2,4-diferensial)-N-heptylaniline (135 mg, 0,373 mmol), homovanillic alcohol (63 mg, 0,373 mmol) and anhydrous potassium carbonate (77 mg, 0,559 mmol) in acetonitrile (10 ml). This mixture is agrawala with delegacia 4 hours and then evaporated to dryness. The remainder (with additional DHM, 1 MLH) was applied on a column (ISOLUTE® SI, 1 g/6 ml). It was suirable dikhlormetil and then the mixture Meon/DHM (0,5:99,5, then 1:99). Fractions of product were combined and evaporated. Received the product in the form of oil: 132 mg, yield 79%.

1H-NMR (rotamer, 400 MHz, CDCl3): δ 0.82-0.87 (m, 3H), 1.17-1.28 (m, 8H), 1.43-1.68 (m, 2H), 2.75-2.80 (m, 2H), 3.24-3.32 (m, 2H), 3.73-3.84 (m, 5H), 4.58, 4.66 (s, s, 2H), 4.74, 4.76 (s, s, 2H), 6.67-6.86 (m, 5H), 7.08-7.14, 7.23-7.29 (m, 1H).

c) 2-(4-{2-[(2,4-Diferensial)(heptyl)-amino-2-oksidoksi)-3-methoxyphenyl)-etil-methanesulfonate

N-(2,4-diferensial)-N-heptyl-2-[4-(2-hydroxyethyl)-2-methoxyphenoxy]-ndimethylacetamide (A) (132 mg, 0,294 mmol) was dissolved in DHM (10 ml). Cooled it in an ice bath. Was added triethylamine (0.05 ml, 0,352 mmol) and then drops added methanesulfonamide (37 mg, 0,323 mmol). The cooling bath was removed after 30 minutes. The mixture was stirred at room temperature overnight. LC-MS showed that about 50% But did not browseinterval. Cooled the mixture in an ice bath was added 0.05 ml of triethylamine and then 0,025 ml of methanesulfonanilide. After addition the cooling bath was removed and the mixture was stirred for another 5 hours. Then it was washed with water (x2) and brine, dried (magnesium sulfate) and was evaporated. Leave the product in the form of oil (138 mg) and used it in the next stage without additional purification.

d) Methyl 2-[2-(4-{2-[(2,4-diferensial)(heptyl)amino]-2-is kaitoke]-3-methoxyphenyl)-ethoxy-benzoate

2-(4-{2-[(2,4-Diferensial)(heptyl)amino]-2-oksidoksi}-3-methoxyphenyl)-ethyl]-methanesulfonate (138 mg, 0,262 mmol) was dissolved in acetonitrile (10 ml). Was added methyl ether 2-hydroxybenzoic acid (40 mg, 0,262 mmol) and then anhydrous potassium carbonate (54 mg, 0,392 mmol). This mixture was heated with delegacia overnight and then was evaporated to dryness. Was added water (10 ml) and ethyl acetate (10 ml) and was divided in two phases. The organic phase is washed with water and brine, dried (magnesium sulfate) and was evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DHM, Meon/GHM (1:99) as eluant gave 78 mg of the desired product, yield 45% (two stages).

1H-NMR (rotamer, 500 MHz, CDCl2): δ 0.87-0.91 (m, 3H), 1.22-1.32 (m, 8H), 1.48-1.63 (m, 2H), 3.09-3.14 (m, 2H), 3.28-3.35 (m, 2H), 3.80, 3.89 (s, s, 3H), 3.89 (s, 3H), 4.21-4.25 (m, 2H), 4.62, 4.71 (s, s, 2H), 4.79, 4.81 (s, s, 2H), 6.77-7.01 (m, 7H), 7.28-7.33 (m, 1H), 7.13-7.18, 7.28-7.33 (m, m, 1H), 7.45 (t, 1H), 7.81 (d, 1H).

e) 2-[2-(4-(2-[(2,4-Diferensial)(heptyl)amino]-2-oksidoksi}-3-methoxyphenyl)-ethoxy-benzoic acid

Methyl-2-[2-(4-{2-[(2,4-diferensial)(heptyl)amino]-2-oksidoksi}-3-methoxyphenyl)-ethoxy]-benzoate (74 mg, to 0.127 mmol)dissolved in THF (2 ml), was mixed with lithium hydroxide (6,1 mg, 0,254 mmol)dissolved in water (1 ml). This mixture was irradiated in a microwave oven (Smith synthesizer) at 150°C for 8 minutes. LC-MS showed that the interaction was incomplete. It continued in the oven on the additional 10 minutes. LC-MS showed almost no change. Was added 3 mg of lithium hydroxide and then kept in an oven at 150°C for 8 minutes. LC-MS showed that all was as before. Was added 3 mg of lithium hydroxide and 1 ml of water. The resulting mixture was in an oven at 150°10 minutes, and LC-MS showed that the interaction was complete. The reaction mixture was evaporated to remove tetrahydrofuran. The residue was acidified using 1%hydrochloric acid, pH˜5, and were extracted with ethyl acetate (10 ml). The extracts were dried (magnesium sulfate) and was evaporated. Chromatography of the residue on a column (ISOLUTE® Sl, 1 g/6 ml) using DHM and then Meon/GHM (1:99) as eluant gave 60 mg of the desired product, yield 83%.

1H-NMR (rotamer, 400 MHz, CDCl3): δ 0.82-0.87 (m, 3H), 1.18-1.28 (m, 8H), 1.43-1.61 (m, 2H), 3.10-3.15 (m, 2H), 3.24-3.31 (m, 2H), 3.77, 3.85 (s, s, 3H), 4.39-4.44 (m, 2H), 4.59, 4.66 (s. s, 2H), 4.77, 4.78 (s, s, 2H), 6.72-6.91 (m, 5H), 7.01 (d, 1H), 7.09 (t, 1H), 7.10-7.17, 7.26-7.32 (m, m, 1H), 7.51 (t, 1H), 8.13 (d, 1H).

13C-NMR (rotamer, 75 MHz, CDCl3): 14.07 5, 22.55, 26.79, 27.02, 28.57, 28.93, 31.70 s, 35.18, 41.30, 41.34, 44.02, at 45.89, 46.99, 55.71, 55.82, 68.19, 68.94, 70.66, 103.38(t), 103.88(t), 111.35(d), 111.39(d), 112.32, 112.41, 112.46, 114.76. 117.64, 119.60(dd), 120.07(dd), 120.53, 122.06, 129.50(dd), 130.54, 130.59, 131.55(dd), 133.60, 134.78, 146.26, 146.39, 149.67, 157.10, 161.60(dd), 160.68(dd), 161.97(dd), 162.24(dd), 165.12, 167.75, 167.93.

Example 3

a) N-(4-chlorbenzyl)-ndimethylacetamide

Dissolved acetic acid (of 1.321 g, 22,000 mmol) in dimethylformamide (10 ml), was added 1-(4-chlorophenyl)-methanamine (2,804 g 19,800 mmol) and cooled the mixture to 0° C. was Added tetrafluoroborate N-[(1H-1,2,3-benzotriazol-1 yloxy)(dimethylamino)methylene]-N-methylmethanamine (7,770 g 24,200 mmol) and N-ethyl-N,N-Diisopropylamine (5,971 g 46,200 mmol). This solution was stirred for two hours at room temperature. Added EtOAc (20 ml) and the organic phase is washed with sodium carbonate (3 × 20 ml water) and hydrochloric acid (0.5 M, 2×10 ml). The organic layer was dried (magnesium sulfate) and the solvent was removed by evaporation. The residue was purified preparative HPLC (initial mobile phase was an isocratic mixture of acetonitrile/buffer 60/40, then the concentration of acetonitrile was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 with ammonium acetate (0.1 M); column KR-100-7-C8, 50 mm × 250 mm; flow rate 40 ml/min). The product-containing fractions were pooled pooled, the acetonitrile was removed by evaporation. Added EtOAc (10 ml) and the organic phase is washed with two portions of brine and dried (magnesium sulfate) and the solvent was removed by evaporation, which gave 2,337 g of N-(4-chlorbenzyl)-ndimethylacetamide (output 57,8%).

1H-NMR (500 MHz, CDCl3): δ 1.96 (s, 3H), 4.31 (d, 2H), 6.46 (bs, 1H), 7.16 (d, 2H), 7.25 (d, 2H).

b) N-(4-chlorbenzyl)-N-ethylamine

N-(4-chlorbenzyl)-ndimethylacetamide (2,337 g 12,726 mmol) was dissolved in THF (100 ml) and cooled to zero degrees under argon atmosphere. Added complex (methylthio)methane with borane (1:1) (2,417 g 31,815 mmol) and heated this is mesh at reflux distilled over night at RT. Caution was added HCI (15 ml, 10%) and stirred over night. The solvent was removed by evaporation. Added diethyl ether (20 ml) and product was extracted into the aqueous phase with potassium carbonate (3×15 ml). The aqueous phase was acidified with hydrochloric acid (10 ml, 10%) and the product was extracted into the organic phase with ethyl acetate (3×15 ml). The organic phase was dried (magnesium sulfate) and the solvent was removed by evaporation to obtain 0,938 g of N-(4-chlorbenzyl)-N-ethylamine (output 43,4%).

1H-NMR (500 MHz, CDCl3): δ 1.11 (t, 3H), 2.65 (q, 2H), 3.74 (s, 2H), 7.23-7.28 (m, 4H).

c) Methyl-2-({2-[4-(2-tert-butoxy-2-oksidoksi)-phenyl]-ethyl}-thio)benzoate

Was dissolved tert-butyl(4-{2-[(methylsulphonyl)-oxy]-ethyl}-phenoxy)-acetate (5,454 g, 17,347 mmol) in acetonitrile (100 ml)was added 2-mercaptobenzoic (3,502 g 20,816 mmol) and potassium carbonate (4,795 g 34,694 mmol). The solution was stirred for 10 hours at 60°C. was Added EtOAc (40 ml) and the organic phase is washed with two portions of brine (2×40 ml water). The organic layer was dried (magnesium sulfate) and the solvent was removed by evaporation to obtain 6,931 g of methyl 2-({2-[4-(2-tert-butoxy-2-oksidoksi)-phenyl]-ethyl}-thio)-benzoate. This material was used in the next stage without additional purification.

d) [4-(2-{[2-(Methoxycarbonyl)-phenyl]-thio}-ethyl)-phenoxy]-acetic acid

Methyl-2-({2-[4-(2-tert-butoxy-2-oksidoksi)-phenyl]-ethyl}-thio)benzoate (4,630 g 11,502 mmol collected in DHM (50 ml) and treated triperoxonane acid (44,40 g, 389,405 mmol) at RT for 4 hours. The mixture was evaporated and azeotropically with toluene. The crude product was purified preparative HPLC (initial mobile phase was an isocratic mixture of acetonitrile/buffer 60/40, then the concentration of acetonitrile was increased to 100%; the buffer was a mixture of acetonitrile/water 10/90 with ammonium acetate (0.1 M); column KR-100-7-C8, 50 mm × 250 mm, flow rate 40 ml/min). The fractions containing the product were pooled pooled, the acetonitrile was removed by evaporation.

Added EtOAc (10 ml) and the organic phase is washed with two portions of brine and dried (magnesium sulfate). The solvent was removed by evaporation to obtain 3,825 g of [4-(2-{[2-(methoxycarbonyl)-phenyl]-thio}-ethyl)-phenoxy]-acetic acid (output in two stages and 63.9% in total).

1H-NMR (500 MHz, CDCl3): δ 2.93-2.98 (m, 2H), 3.12-3.17 (m, 2H), 3.92 (s, 3H), 4.67 (s, 2H), 6.88 (d, 2H), 7.13-7.21 (m, 3H), 7.33 (d, 1H), 7.41-7.46 (m, 1H), 7.96 (dd, 1H).

e) Methyl-2-{[2-4-(2-K4-chlorbenzyl)(ethyl)-amino-2-oksidoksi}-phenyl)-ethyl]-thio}benzoate

Dissolve [4-(2-{[2-(methoxycarbonyl)-phenyl]-thio}-ethyl)-phenoxy]-acetic acid (0,200 g, 0,577 mmol) in dimethylformamide (10 ml), was added N-(4-chlorbenzyl)-N-ethylamine (to 0.108 g, 0,635 mmol) and cooled the mixture to 0°C. was Added tetrafluoroborate N-[(1H-1,2,3-benzotriazol-1 yloxy)(dimethylamino)methylene]-N-methylmethanamine (0,204 g, 0,635 mmol) and N-ethyl-N,N-Diisopropylamine (of) 0.157 g, 1,212 mmol). This solution was stirred over night at room temperature. Was added water (100 ml) and the aqueous phase is extracted with diethyl ether (3×20 ml). The organic phase is washed with sodium carbonate (3×20 ml water) and hydrochloric acid (0.5 M, 2×10 ml). The organic layer was dried (magnesium sulfate) and the solvent was removed by evaporation. The residue was purified flash chromatography (started with isocratic mixture of heptane/EtOAc 30/70 and then increased the concentration of EtOAc to 100%; silica gel 60; 0,004-0,063 mm). The fractions containing the product were pooled pooled, the solvent was removed by evaporation with the receipt of 0.085 g of methyl 2-{[2-(4-{2-[(4-chlorbenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio}-benzoate (yield of 29.6%).

1H-NMR (rotamer, 300 MHz, COCl3): δ 1.09-1.21 (m, 3H), 2.91-2.99 (m, 2H), 3.11-3.18 (m, 2H), 3.32-3.43 (m, 2H), 3.92 (s, 3H), 4.57-4.75 (m, 4H), 6.78, 6.92 (d, d, 2H), 7.12-7.46 (m, 9H), 7.96 (d, 1H).

f) 2-{[2-(4-{2-[(4-chlorbenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl]-ethyl]-thio}-benzoic acid

Dissolved methyl-2-{[2-(4-{2-[(4-chlorbenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio}benzoate (of 0.085 g, 0,170 mmol) in a mixture of acetonitrile/water (1/1, 4 ml) was added lithium hydroxide (0.008 g, 0,341 mmol). The interaction was carried out in a single-node microwave oven (5 min, 150 degrees). The solvent was removed by evaporation and then added hydrochloric acid (2 ml, 1 M). The aqueous phase was extracted with two portions of ethyl acetate (20 ml). The combined organic phases were dried (magnesium sulfate) and the solvent prowess and the process of evaporation, that gave 0,073 g 2-{[2-(4-{2-[(4-chlorbenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl]-ethyl]-thio}-benzoic acid (yield 88,4%) in the form of oil, which hardened upon cooling and standing.

1H-NMR (rotamer, 400 MHz, CDCl3): δ 1.09-1.20 (m, 3H), 2.91-2.98 (m, 2H), 3.11-3.17(m, 2H), 3.33-3.42 (m, 2H), 4.58-4.77 (m, 4H), 6.79, 6.92 (d, d, 2H), 7.11-7.49 (m, 9H), 8.10 (d, 1H).

13C-NMR (rotamer, 100 MHz, CDCl3): δ 12.23, 13.77, 33.70, 33.82, 41.09, 41.30, 47.42, 49.64, 67.37, 67.91, 114.69 last, 114.81, 123.97-135.58 (complex multiplet), 142.22, 156.45, 156.57, 168.20, 170.63.

In the same way received the following two examples.

Example 4

2-[2-(4-{2-[(4-Chlorbenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid.

1H NMR (rotamer, 500 MHz, CDCl3) d 1.09 1 and 18 (t, H), 3.12-3.17 (m, 2H), 3.32-3.41 (m, 2H), 4.40-4.44 (m, 2H), 4.56 and 4.57 (s, 2H), 4.66 and 4.74 (s, 2H), 6.81 and 6.94 (d, 2H), 7.01 (t, 1H), 7.10-7.20 (m, 5H), 7.24 (d, 2H), 7.30 (d, 1H), 7.53 (t, 1H), 8.15 (d, H).

Example 5

2-[2-(4-{2-[Ethyl(4-trifloromethyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid.

1H NMR (rotamer, 500 MHz, CDCl3) d 1.11 and 1.20 (t, 3H), 3.13 and 3.16 (t, 2H), 3.36-3.43 (m, 2H), 4.41 and 4.43 (t, 2H) 4.65 and 4.67 (s, 2H), 4.68 and 4 77 (s, 2H), 6.78 and 6.95 (d, 2H), 7.01 (t, 1H), 7.10-7.21 (m, 3H), 7.30-7.33 (m, 2H), 7.53 (d, 2H), 7.57 (t, 1H), 8.15 (d,1H).

Example 6

a) was Dissolved acetic acid (of 1.321 g, 22,000 mmol) in DMF (10 ml), was added 1-[4-(trifluoromethyl)-phenyl]-methanamine (3,468 g 19,800 mmol) and cooled the mixture to 0°C. was Added tetrafluoroborate N-[(1H-1,2,3-benzotriazol-1 yloxy)(dimethylamino)methylene]-N-meth is methanamine (7,770 g, 24,200 mmol) and N-ethyl-N-Diisopropylamine (5,971 g 46,200 mmol). This solution was stirred for two hours at room temperature. Added EtOAc (20 ml) and the organic phase is washed with sodium carbonate (3 × 20 ml water) and hydrochloric acid (0.5 M, 2×10 ml). The organic layer was dried (magnesium sulfate) and the solvent was removed by evaporation. The crude product was purified preparative HPLC (started with isocratic mixture of acetonitrile/buffer 60/40 and then increased the concentration of acetonitrile to 100%; the buffer was a mixture of acetonitrile/water 10/90 with ammonium acetate (0.1 M); column KR-100-7-C8, 50 mm × 250 mm; flow rate 40 ml/min). The fractions containing the product were pooled pooled, the acetonitrile was removed by evaporation. Added EtOAc (10 ml) and the organic phase is washed with two portions of brine and dried (magnesium sulfate) and the solvent was removed by evaporation, which gave 3,085 g of N-[4-(trifluoromethyl)-benzyl]-ndimethylacetamide (output 64,6%).

1H-NMR (500 MHz, CDCl3): δ 2.0 (s, 3H), 4.42 (d, 2H), 6.58 (bs, 1H), 7.35 (d, 2H), 7.55 (d.2H).

b) N-[4-(trifluoromethyl)-benzyl]-ndimethylacetamide (3,085 g 14,204 mmol) was dissolved in tetrahydrofuran (100 ml) and cooled to zero degrees under argon atmosphere. Added complex (methylthio)methane with borane (1:1) (2,698 g, 35,511 mmol) and holding the mixture at reflux distilled over night at RT. Caution was added HCI (15 ml, 10%) and stirred over night. The solvent was removed upriv the tion. Added diethyl ether (20 ml) and product was extracted into the aqueous phase with potassium carbonate (3×15 ml), the aqueous phase was acidified with hydrochloric acid (10 ml, 10%) and the product was extracted into the organic phase with ethyl acetate (3×15 ml). The organic phase was dried (magnesium sulfate) and the solvent was removed by evaporation to obtain 0,809 g of N-[4-(trifluoromethyl)-benzyl]-ethanamine (yield 28%).

1H-NMR (500 MHz, CDCl3): δ of 1.05 (t, 3H)and 1.3 (s, 1H), 2,62 (q, 2H), of 3.78 (s, 2H), 7,38 (d, 2H), and 7.3 (d, 2H)

c) was Dissolved tert-butyl(4-{2-[(methylsulphonyl)-oxy]-ethyl)-phenoxy)-acetate (5,454 g, 17,347 mmol) in acetonitrile (100 ml)was added methyl-2-mercaptobenzoic (3,502 g 20,816 mmol) and potassium carbonate (4,795 g 34,694 mmol). This solution was stirred for 10 hours at 60°C. was Added EtOAc (40 ml) and the organic phase is washed with two portions of brine (2×40 ml of water).

The organic layer was dried (magnesium sulfate) and the solvent was removed by evaporation to obtain 6,931 g of crude methyl 2-({2-[4-(2-tert-butoxy-2-oksidoksi)-phenyl]-ethyl}-thio)-benzoate. The crude product was used in the next stage without additional purification.

d) Took methyl 2-({2-[4-(2-tert-butoxy-2-oksidoksi)-phenyl]-ethyl}-thio)benzoate (4,630 g 11,502 mmol) in DHM (50 ml) and treated triperoxonane acid (44,40 g, 389,405 mmol) at RT for 4 hours. This mixture is evaporated and azeotropically with toluene. The crude product was purified is preparative HPLC (started with isocratic mixture of acetonitrile/buffer 60/40 and then increased the concentration of acetonitrile to 100%; the buffer was a mixture of acetonitrile/water 10/90 with ammonium acetate (0.1 M); column KR-100-7-C8, 50 mm × 250 mm; flow rate 40 ml/min). The fractions containing the product were pooled pooled, the acetonitrile was removed by evaporation. Added EtOAc (10 ml) and the organic phase is washed with two portions of brine and dried (magnesium sulfate). The solvent was removed by evaporation to obtain 3,825 g of [4-(2-{[2-(methoxycarbonyl)-phenyl]-thio}-ethyl)-phenoxy]-acetic acid (output in two stages and 63.9% in total).

1H-NMR (500 MHz, CDCl3): δ 2.82 (t, 2H), 3.15 (t, 2H), 3.82 (s, 3H), 4.35 (s, 2H), 6.78 (d, 2H), 7.18 (d, 2H), 7.23 percent (t, 1H), 7.51 (d, 1H), 7.55 (t, 1H), 7.85 (d, 1H).

e) was Dissolved [4-(2-{[2-(methoxycarbonyl)-phenyl]-thio}-ethyl)-phenoxy]-acetic acid (0,200 g, 0,577 mmol) in DMF (10 ml), was added N-[4-(trifluoromethyl)-benzyl]-ethanamine (0,129 g, 0,635 mmol) and cooled the mixture to 0°C. was Added tetrafluoroborate N-[(1H-1,2,3-benzotriazol-1 yloxy)(dimethylamino)-methylene]-N-methylmethanamine (0,204 g, 0,635 mmol) and N-ethyl-N,N-Diisopropylamine (of) 0.157 g, 1,212 mmol). This solution was stirred over night at room temperature. Was added water (100 ml) and the aqueous phase is extracted with diethyl ether (3×20 ml). The organic phase is washed with sodium carbonate (3×20 ml water) and hydrochloric acid (0.5 M, 2×10 ml). The organic layer was dried (magnesium sulfate) and the solvent was removed by evaporation. The crude product was purified flash chromatography (n is chinali with isocratic mixture of heptane/t0 30/70 and then increased the concentration of EtOAc to 100% (silica gel 60; 0,004-0,063 mm). The fractions containing the product were pooled pooled and the solvent was removed by evaporation with the receipt of 0.085 g of methyl 2-({2-[4-(2-{ethyl-[4-(trifluoromethyl)-benzyl]-amino}-2-oksidoksi)-phenyl]-ethyl}-thio)-benzoate (yield of 27.7%).

1H-NMR (rotamer, 500 MHz, CDCl3): δ 1.1-1.23 (bm, 3H), 2.95 (q, 2H), 3.15 (q, 2H), 3.42 (m, 2H), 3.9 (s, 3H), 4.7-4.82 (bm, 4H), 6.75-6.95 (m, 2H), 7.1-7.5 (m, 9H), 7.97 (d,1H).

f) was Dissolved methyl-2-({2-[4-(2-{ethyl-[4-(trifluoromethyl)-benzyl]-amino}-2-oksidoksi)-phenyl]-ethyl}-thio)benzoate (of 0.085 g, 0,160 mmol) in a mixture of acetonitrile/water (1/1, 4 ml), then was added lithium hydroxide (0.008 g, 0,320 mmol). The interaction was carried out in a single-node microwave oven (5 min, 150 degrees). Spent processing removal of solvent by evaporation and addition of HCl (2 ml, 1 M). The aqueous phase was extracted with two portions of EtOAc (20 ml), the organic phase was dried (magnesium sulfate) and the solvent was removed by evaporation, which gave 0,07773 g (2-({2-[4-(2-{ethyl[4-(trifluoromethyl)-benzyl]-amino}-2-oksidoksi)-phenyl]-ethyl}-thio)-benzoic acid (yield 93,0%).

1H-NMR (rotamer, 400 MHz, CDCl3): δ 1.02-1.25 (bm, 3H), 2.95 (q, 2H), 3.15 (q, 2H), 3.38 (m, 2H), 4.60-4.82 (bin, 4H), 6.75-6.95 (m, 2H), 7.1-7.5 (m, 9H), 7.97 (d, 1H).

Example 7

Dissolved methyl-2-{2-[4-(2-{butyl-[2-fluoro-4-(trifluoromethyl)-benzyl]-amino}-2-oksidoksi)-phenyl]-ethoxy}-benzoate (0,230 g, 0,410 mmol) in a mixture of tetrahydrofuran/water (1/1, 4 ml). Was added lithium hydroxide (0.015 g, 0,617 mmol). The interaction of the OS is Westley in a single-node microwave oven (14 min 150 degrees). Spent processing removal of solvent by evaporation and addition of HCl (2 ml, 1 M). The aqueous phase was extracted with two portions of EtOAc (20 ml). The organic phase was dried (magnesium sulfate) and the solvent was removed by evaporation to obtain 0,212 g (2-{2-[4-(2-{butyl-[2-fluoro-4-(trifluoromethyl)-benzyl]-amino}-2-oksidoksi)-phenyl]-ethoxy}-benzoic acid (yield of 94.5%).

1H-NMR (rotamer, 500 MHz, CDCl3): δ 0.82-1.0 (bm, 3H). 1.2-1.4 (bm, 2H), 1.65-1.7 (bm, 2H), 3.13 (m, 2H), 3.32 (m, 2H), 4.4 (m, 2H), 4.63-4.8 (M, 4H), 6.7-7.6 (bm, 10H),8.1(d.1H).

Example 8

a) was Dissolved (4-{2-[2-(methoxycarbonyl)-phenoxy]-ethyl}-phenoxy)-acetic acid (0,150 g, 0,454 mmol) in dimethylformamide (10 ml), was added N-(2,4-diferensial)-N-Propylamine (0,084 g, 0,454 mmol) and cooled the mixture to 0°C. was Added tetrafluoroborate N-[(1H-1,2,3-benzotriazol-1 yloxy)(dimethylamino)methylene]-N-methylmethanamine (0,160 g, 0,499 mmol) and N-ethyl-N,N-Diisopropylamine (0,123 g, 0,954 mmol). This solution was stirred for two hours at room temperature. Added EtOAc (20 ml) and the organic phase is washed with sodium carbonate (3×20 ml water) and hydrochloric acid (0.5 M, 2×10 ml). The organic layer was dried (magnesium sulfate) and the solvent was removed by evaporation to obtain 0,220 g of methyl 2-[2-(4-{2-[(2,4-diferensial)(propyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoate (yield of 97.4%).

1H-NMR (rotamer, 500 MHz, CDCl3): δ 0.8-1.0 (bm, 3H), 1.45-1.7 (bm, 2H) 3.1 (m, 2H), .28 (bm, 2H), 3.9 (s, 3H), 4.2 (q, 2H), 4.6-4.75 (M, 4H), 6.7-7.0 (bm, 6H), 7.1-7.3 (bm, 3H), 7.4 (m.1H), 7.78 (d.1H).

b) was Dissolved methyl-2-[2-(4-{2-[(2,4-diferensial)(propyl)-amino]-2-oksidoksi)-phenyl)-ethoxy]-benzoate (0,22 g, 0,442 mmol) in a mixture of tetrahydrofuran/water (1/1, 4 ml). Was added lithium hydroxide (0,021 g, 0,884 mmol). The interaction was carried out in a single-node microwave oven (14 minutes, 150 degrees). Spent processing removal of solvent by evaporation and addition of HCl (2 ml, 1 M). The aqueous phase was extracted with two portions of EtOAc (20 ml), the organic phase was dried (magnesium sulfate) and the solvent was removed by evaporation to obtain 0,180 g 2-[2-(4-{2-[(2,4-diferensial)(propyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid (yield 84.2 per cent).

1H-NMR (rotamer, 500 MHz, COCl3): δ 0.8-1.0 (bm. 3H), 1.45-1.7 (bm, 2H), 3.14 (m, 2H), 3.28 (bm, 2H), 4.4 (q, 2H), 4.62 (s, 2H), 4.75 (s, 2H), 6.7-7.35 (bm, 9H), 7.52 (t,1H), 8.12 (d.1H).

Example 9

a) was Dissolved (4-{2-[2-(methoxycarbonyl)-phenoxy]-ethyl}-phenoxy)-acetic acid (0,150 g, 0,454 mmol) in DMF (10 ml), was added N-benzyl-N-ethylamine (0,061 g, 0,454 mmol) and cooled the mixture to 0°C. was Added tetrafluoroborate N-[(1H-1,2,3-benzotriazol-1 yloxy)-(dimethylamino)-methylene]-N-methylmethanamine (0,160 g, mmol 0,499) and N-ethyl-N,N-Diisopropylamine (0,123 g, 0,954 mmol). This solution was stirred for two hours at room temperature. Added EtOAc (20 ml) and the organic phase is washed with sodium carbonate (3×20 ml water) and salt is th acid (0.5 M, 2×10 ml). The organic layer was dried (magnesium sulfate) and the solvent was removed by evaporation to obtain was 0.138 g of methyl 2-[2-(4-{2-[benzyl(ethyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoate (yield 67,9%).

1H-NMR (rotamer, 500 MHz, CDCl3): δ 1.07-1.22 (bm, 3H), 3.1 (m, 2H). 3.20 (bm, 2H), 3.9 (s, 3H), 4.2 (q, 2H), 4.6-4.8 (M, 4H), 6.8-7.02 (bm, 4H), 6.18-7.5 (bm, 11H),7.78(d,1H).

b) was Dissolved methyl-2-[2-(4-{2-[benzyl(ethyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoate (was 0.138 g, 0,308 mmol) in a mixture of tetrahydrofuran/water (1/1, 4 ml). Was added lithium hydroxide (0.015 g, 0,617 mmol). The interaction was carried out in a single-node microwave oven (14 minutes, 150 degrees). Spent processing removal of solvent by evaporation and addition of HCl (2 ml, 1 M). The aqueous phase was extracted with two portions of EtOAc (20 ml), the organic phase was dried (magnesium sulfate) and the solvent was removed by evaporation to obtain 0,146 g 2-[2-(4-{2-[benzyl(ethyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid.

1H-NMR (rotamer, 500 MHz, CDCl3): δ 1.02-1.22 (bm, 3H), 3.1 (m, 2H), 3.25-3.5 (bm, 2H), 4.2 (q, 2H), 4.55-4.8 (M, 4H), 6.8-7.4 (bm, 11H), 7.5 (m, 1H), 8.1 (d, 1H).

Example 10

a) was Dissolved tert-butyl(4-{2-[(methylsulphonyl)-oxy]-ethyl}-phenoxy)-acetate (5,454 g, 17,347 mmol) in acetonitrile (100 ml)was added methyl 2-mercaptobenzoic (3,502 g 20,816 mmol) and potassium carbonate (4,795 g 34,694 mmol). This solution was stirred for 10 hours at 60°C. was Added EtOAc (40 ml) and washed organic FA is the two portions of brine (2× , 40 ml of water). The organic layer was dried (magnesium sulfate) and the solvent was removed by evaporation to obtain 6,931 g of crude methyl 2-({2-[4-(2-tert-butoxy-2-oksidoksi)-phenyl]-ethyl}-thio)-benzoate. The crude product was used in the next stage without additional purification.

b) Methyl 2-({2-[4-(2-tert-butoxy-2-oksidoksi)-phenyl]-ethyl}-thio)benzoate (4,630 g 11,502 mmol) was taken in DHM (50 ml) and treated triperoxonane acid (44,40 g, 389,405 mmol) at RT for 4 hours. The mixture was evaporated and azeotropically with toluene. The crude product was purified preparative HPLC (started with isocratic mixture of acetonitrile/buffer 60/40 and then increased the concentration of acetonitrile to 100%; the buffer was a mixture of acetonitrile/water 10/90 with ammonium acetate (0.1 M); column KR-100-7-C8, 50 mm × 250 mm; flow rate 40 ml/min). The fractions containing the product were pooled pooled, the acetonitrile was removed by evaporation. Added EtOAc (10 ml) and the organic phase is washed with two portions of brine and dried (magnesium sulfate). The solvent was removed by evaporation to obtain 3,825 g of [4-(2-{[2-(methoxycarbonyl)-phenyl]-thio}-ethyl)-phenoxy]-acetic acid (output in two stages and 63.9% in total).

1H-NMR (500 MHz, CDCl3): δ 2.82 (t, 2H), 3.15 (t, 2H), 3.82 (s, 3H), 4.35 (s, 2H), 6.78 (d, 2H), 7.18 (d, 2H), 7.23 (t, 1H), 7.51 (d, 1H), 7.55 (t, 1H), 7.85 (d. 1H).

c) was Dissolved [4-(2-{[2-(methoxycarbonyl)-phenyl]-thio}-ethyl)-phenoxy]-acetic acid is the (0,200 g, 0,577 mmol) in dimethylformamide (10 ml), was added N-benzyl-N-ethylamine (0,086 g, 0,635 mmol) and cooled the mixture to 0°C. was Added tetrafluoroborate N-[(1H-1,2,3-benzotriazol-1 yloxy)(dimethylamino)methylene]-N-methylmethanamine (0,204 g, 0,635 mmol) and N-ethyl-N,N-Diisopropylamine (of) 0.157 g, 1,212 mmol). This solution was stirred over night at room temperature. Was added water (100 ml) and the aqueous phase is extracted with diethyl ether (3×20 ml). The organic phase is washed with sodium carbonate (3×20 ml water) and hydrochloric acid (0.5 M, 2x, 10 ml). The organic layer was dried (magnesium sulfate) and the solvent was removed by evaporation. The crude product was purified flash chromatography (started with isocratic mixture of heptane/EtOAc 30/70 and then increased the concentration of EtOAc to 100%; (silica gel 60; 0,004-0,063 mm). The fractions containing the product were pooled pooled, the solvent was removed by evaporation to obtain 0,137 g of methyl 2-{[2-(4-{2-[benzyl(ethyl)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio}-benzoate (yield of 51.2%).

d) was Dissolved methyl-2-{[2-(4-{2-[benzyl(ethyl)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio}benzoate (0,137 g, 0,296 mmol) in a mixture of acetonitrile/water (1/1, 4 ml), was added lithium hydroxide (0,014 g, 0,591 mmol). The interaction was carried out in a single-node microwave oven (5 minutes, 150 degrees). Spent processing removal of solvent by evaporation and addition of hydrochloric acid (2 ml, 1 M). Water f the u was extracted with two portions of EtOAc (20 ml), the organic phase was dried (magnesium sulfate) and the solvent was removed by evaporation, which gave 0,111 g 2-{[2-(4-{2-[benzyl(ethyl)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio}-benzoic acid (yield 83.5 per cent).

1H-NMR (rotamer, 400 MHz, CDCl3): δ 1.02-1.30 (bm, 3H), 2.95 (q, 2H), 3.15 (q, 2H), 3.40 (m, 2H), 4.58 (s, 2H), 4.63-4.92 (bm, 4H), 6.85-7.0 (bm, 2H), 7.0-7.53 (m, 10H), 7.97 (d, 1H).

Example 11

a) was Dissolved N-(4-tert-butylbenzyl)-N-ethylamine (0,143 g, 0,746 mmol) in dry acetonitrile under N2and was added N-ethyl-N,N-Diisopropylamine (0,371 g 2,867 mmol). Stirred the mixture for 30 minutes and was added methyl-2-{2-[4-(2-chloro-2-oksidoksi)-phenyl]-ethoxy}-benzoate (0,200 g, 0,573 mmol). This solution was stirred over night at room temperature. The crude product was purified flash chromatography (started with isocratic mixture of heptane/EtOAc 50/50 and then the concentration of the EtOAc was increased to 100%; silica gel 60, 0,004-0,063 mm). The fractions containing the product were combined into a pool, EtOAc was removed by evaporation to obtain 0,229 g of methyl 2-[2-(4-{2-[(4-tert-butylbenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoate (yield 79.3 percent).

1H-NMR (rotamer, 500 MHz, CDCl3): δ 1.07-1.23 (bm, 3H), 2.23 (m, 9H), 3.08 (m, 2H), 3,30-3.5 (bm, 2H), 3.87 (s, 3H), 4.18 (m, 2H), 4.58 (d, 2H), 4.63-4.8 (m, 2H) 6.77-7.43 (m, 11H). 7.78 (d, 1H).

b) was Dissolved methyl-2-[2-(4-{2-[(4-tert-butylbenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoate (0,2290 g, 0,455 mmol) in a mixture of THF (freshly)/water (2/1, 3 ml), to which alali lithium hydroxide (0,218 g, 0,909 mmol). The interaction was carried out in a single-node microwave oven (5 minutes, 150 degrees). THF was removed by evaporation, adding water (10 ml) and washed with an alkaline aqueous phase with diethyl ether (2×10 ml). Was added HCl (2 ml, 1 M, pH 1). The aqueous phase was extracted with two portions DHM (20 ml), the organic phase was dried (magnesium sulfate) and the solvent was removed by evaporation to obtain 0,163 g 2-[2-(4-{2-[(4-tert-butylbenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid (yield 73.2 per cent).

1H-NMR (rotamer, 500 MHz, CDCl3): 5 1.07-1.21 (bm, 3H), 2.28 (m, 9H), 3.12 (m, 2H), 3.28-3.5 (bm, 2H), 4.4 (m, 2H), 4.58 (d. 2H), 4.63-4.78 (m, 2H) 6.80-7.55 (m, 11H),8.1 (d.1H).

Example 12

a) was Dissolved acetic acid (of 1.321 g, 22,000 mmol) in DMF (10 ml), was added 1-(4-forfinal)-methanamine (2,478 g 19,800 mmol) and cooled the mixture to 0°C. was Added tetrafluoroborate N-[(1H-1,2,3-benzotriazol-1 yloxy)(dimethylamino)methylene]-N-methylmethanamine (7,770 g 24,200 mmol) and N-ethyl-N,N-Diisopropylamine (5,971 g 46,200 mmol). This solution was stirred for two hours at room temperature. Added EtOAc (20 ml) and the organic phase is washed with sodium carbonate (3×20 ml water) and hydrochloric acid (0.5 M, 2×10 ml). The organic layer was dried (magnesium sulfate) and the solvent was removed by evaporation. The crude product was purified preparative HPLC (started with isocratic mixture of acetonitrile/buffer 60/40 and then the concentration of acetone is trila increased to 100%; the buffer was a mixture of acetonitrile/water 10/90 with ammonium acetate (0.1 M); column KR-100-7-C8, 50 mm × 250 mm; flow rate 40 ml/min). The fractions containing the product were pooled pooled, the acetonitrile was removed by evaporation. Added EtOAc (10 ml) and the organic phase is washed with two portions of brine and dried (magnesium sulfate) and the solvent was removed by evaporation, which gave 1,344 g of N-(4-terbisil)-ndimethylacetamide (output 36,5%).

1H-NMR (500 MHz, CDCl3): δ 1.98 (s, 3H), 4.35 (d, 2H), 6.25 (bs, 1H), 6.95-7.25 (bm, 4H)

b) was Dissolved N-(4-terbisil)-ndimethylacetamide (1,344 g 8,039 mmol) in tetrahydrofuran (100 ml) and cooled to zero degrees under argon atmosphere. Added complex (methylthio)methane with borane (1:1) (1,527 g 20,098 mmol) and holding the mixture at reflux distilled over night at RT. Caution was added hydrochloric acid (15 ml, 10%) and stirred over night. The solvent was removed by evaporation. Added diethyl ether (20 ml) and product was extracted into the aqueous phase with potassium carbonate (3×15 ml). The aqueous phase was acidified with hydrochloric acid (10 ml, 10%) and the product was extracted into the organic phase with ethyl acetate (3×15 ml). The organic phase was dried (magnesium sulfate) and the solvent was removed by evaporation to obtain 0,309 g of N-(4-terbisil)-ethanamine (output 25,1%).

1H-NMR (400 MHz, CDCl3): δ 1.05 (t, 3H), 1.1 (s, 1H), 2.58 (q, 2H), 3.64 (s, 2H), 6.9 (t, 2H), 7.2 (t, 2H).

c) was Dissolved N-(4-terbisil)-ethanamine 0,114 g, 0,745 mmol) in dry acetonitrile under N2and was added N-ethyl-N,N-Diisopropylamine (0,371 g 2,867 mmol). Stirred the mixture for 30 minutes and was added methyl-2-{2-[4-(2-chloro-2-oksidoksi)-phenyl]-ethoxy]-benzoate (0,200 g, 0,573 mmol). This solution was stirred over night at room temperature. The crude product was purified flash chromatography (started with isocratic mixture of heptane/EtOAc 50/50 and then increased the concentration of EtOAc to 100%; silica gel 60, 0,004-0,063 mm). The fractions containing the product were combined into a pool, EtOAc was removed by evaporation to obtain 0,223 g of methyl 2-[2-(4-{2-[ethyl-(4-terbisil)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoate (yield 83.5 per cent).

1H-NMR (rotamer, 500 MHz, CDCl3): δ 1.07-1.23 (bm, 3H), 3.08 (m, 2H), 3.30-3.45 (bm, 2H), 3.87 (s, 3H), 4.18 (m, 2H), 4.58 (s, 2H), 4.63-4.8 (m, 2H), 6.77-7.45 (m, 11H), 7.78 (d, 1H).

d) was Dissolved methyl-2-[2-(4-{2-[ethyl(4-terbisil)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoate (0,223 g, 0,479 mmol) in a mixture of tetrahydrofuran (freshly)/water (2/1, 3 ml), was added lithium hydroxide (0,229 g, 0,958 mmol). The interaction was carried out in a single-node microwave oven (5 minutes, 150 degrees). Remove the tetrahydrofuran by evaporation, adding water (10 ml) and washed with an alkaline aqueous phase with diethyl ether (2 × 10 ml). Was added HCl (2 ml, 1 M, pH 1). The aqueous phase was extracted with two portions DHM (20 ml), the organic phase was dried (magnesium sulfate) and the solvent in which aleli by evaporation to obtain 0,196 g 2-[2-(4-{2-[ethyl-(4-terbisil)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid (yield of 90.6%).

1H-NMR (rotamer, 500 MHz, CDCl3): δ 1.03-1.21 (bm, 3H), 3.1 (m, 2H), 3.23-3.4 (bm, 2H), 4.38 (m, 2H), 4.55 (s, 2H), 4.63-4.78 (m, 2H), 6.75-7.22 (m, 10H), 7.47 (t, 1H), 8.07 (d, 1H).

Example 13

a) was Dissolved tert-butyl(4-{2-[(methylsulphonyl)-oxy]-ethyl)-phenoxy)-acetate (5,454 g, 17,347 mmol) in acetonitrile (100 ml)was added methyl 2-mercaptobenzoic (3,502 g 20,816 mmol) and potassium bicarbonate (4,795 g 34,694 mmol). This solution was stirred for 10 hours at 60°C. was Added EtOAc (40 ml) and the organic phase is washed with two portions of brine (2 æ 40 ml water). The organic layer was dried (magnesium sulfate) and the solvent was removed by evaporation to obtain 6,931 g of crude methyl 2-({2-[4-(2-tert-butoxy-2-oksidoksi)-phenyl]-ethyl}-thio)-benzoate. The crude product was used in the next stage without additional purification.

b) Methyl-2-({2-[4-(2-tert-butoxy-2-oksidoksi)-phenyl]-ethyl}-thio)benzoate (4,630 g 11,502 mmol) was taken in DHM (50 ml) and treated triperoxonane acid (44,40 g, 389,405 mmol) at RT for 4 hours. This mixture is evaporated and azeotropically with toluene. The crude product was purified preparative HPLC (started with isocratic mixture of acetonitrile/buffer 60/40 and then the concentration of acetonitrile was increased to 100%; the buffer was a mixture of acetonitrile/water 10/90 with ammonium acetate (0.1 M); column KR-100-7-C8, 50 mm × 250 mm; flow rate 40 ml/min). The fractions containing the product were pooled pooled, the acetonitrile UD is ranged by evaporation. Added EtOAc (10 ml) and the organic phase is washed with two portions of brine and dried (magnesium sulfate). The solvent was removed by evaporation to obtain 3,825 g of [4-(2-{[2-(methoxycarbonyl)-phenyl]-thio}-ethyl)-phenoxy]-acetic acid (output in two stages and 63.9% in total).

1H-NMR (500 MHz, CDCl3): δ 2.82 (t, 2H), 3.15 (t, 2H), 3.82 (s, 3H), 4.35 (s, 2H), 6.78 (d, 2H), 7.18 (d, 2H), 7.23 (t, 1H), 7.51 (d. 1H), 7.55 (t, 1H), 7.85 (d, 1H).

c) was Dissolved [4-(2-{[2-(methoxycarbonyl)-phenyl]-thio}-ethyl)-phenoxy]-acetic acid (0,250 g, 0,722 mmol) in DHM (10 ml), was added N-(2-terbisil)-ethanamine (0,105 g, China 0,686 mmol). Added tetrafluoroborate N-[(1H-1,2,3-benzotriazol-1 yloxy)(dimethylamino)methylene]-N-methylmethanamine (0,255 g, 0,794 mmol) and N-tert-N,N-Diisopropylamine (0.187 g, 1,443 mmol). This solution was stirred 2 hours at room temperature. The crude product was purified flash chromatography (started with isocratic DHM 100% and then the concentration of the Meon increased from 0.5% to 20%; silica gel 60, 0,004-0,063 mm). The fractions containing the product were combined into a pool, EtOAc was removed by evaporation. The substance had to be cleaned again, and it was purified preparative HPLC (started with isocratic mixture of acetonitrile/buffer 60/40 and then the concentration of acetonitrile was increased to 100%; the buffer was a mixture of acetonitrile/water 10/90 with ammonium acetate (0.1 M); column KR-100-7-C8, 50 mm × 250 mm; flow rate 40 ml/min). The fractions containing the product are combined the Yali in the pool the acetonitrile was removed by evaporation. Ammonium acetate was removed by sublimation drying of the product during the night to obtain 0.1 g of methyl 2-{[2-(4-{2-[ethyl-(2-terbisil)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio}-benzoate (yield of 29.1%).

1H-NMR (rotamer, 500 MHz, CDCl3): δ 1.03-1.23 (bm, 3H), 2.95 (q, 2H), 3.15 (q, 2H), 3.40 (m, 2H), 3.9 (s, 3H), 4.6-4.8 (bm, 4H), 6.75-6.95 (m, 2H), 6.97-7.5 (m, 9H), 7.97 (d,1H).

d) was Dissolved methyl-2-{[2-(4-{2-[ethyl(2-terbisil)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio}-benzoate in a mixture of THF (freshly)/water (2/1, 3 ml), was added lithium hydroxide (0.015 g, 0,629 mmol). The interaction was carried out in a single-node microwave oven (5 minutes, 150 degrees). Remove the tetrahydrofuran by evaporation, adding water (10 ml) and washed with an alkaline aqueous phase with diethyl ether (2x10 ml). Added hydrochloric acid (2 ml, 1 M, pH 1). The aqueous phase was extracted with two portions DHM (20 ml), the organic phase was dried (magnesium sulfate) and the solvent was removed by evaporation to obtain 0,095 g 2-{[2-(4-{2-[ethyl(2-terbisil)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio}-benzoic acid (yield 96.9 percent)

1H-NMR (rotamer, 400 MHz, CDCl3): δ 1.02-1.25 (bm, 3H), 2.95 (q. 2H), 3.15 (q, 2H), 3.42 (m, 2H), 4.60-4.80 (bm, 4H), 6.75-6.95 (m, 2H), 6.95-7.5 (m, 9H), 8.1 (d, 1H).

Example 14

a) was Dissolved tert-butyl(4-{2-[(methylsulphonyl)-oxy]-ethyl}-phenoxy)-acetate (5,454 g, 17,347 mmol) in acetonitrile (100 ml)was added methyl-2-mercaptobenzoic (3,502 g 20,816 mmol) and carbon is potassium (4,795 g, 34,694 mmol). This solution was stirred for 10 hours at 60°C. was Added EtOAc (40 ml) and the organic phase is washed with two portions of brine (2 × 40 ml water). The organic layer was dried (magnesium sulfate) and the solvent was removed by evaporation to obtain 6,931 g of crude methyl 2-({2-[4-(2-tert-butoxy-2-oksidoksi)-phenyl]-ethyl}-thio)-benzoate. The crude product was used in the next stage without additional purification.

b) Methyl-2-({2-[4-(tert-butoxy-2-oksidoksi)-phenyl]-ethyl}-thio)benzoate (4,630 g 11,502 mmol) was taken in DHM (50 ml) and treated triperoxonane acid (44,40 g, 389,405 mmol) at RT for 4 hours. This mixture is evaporated and azeotropically with toluene. The crude product was purified preparative HPLC (started with isocratic mixture of acetonitrile/buffer 60/40 and then the concentration of acetonitrile was increased to 100%; the buffer was a mixture of acetonitrile/water 10/90 with ammonium acetate (0.1 M); column KR-100-7-C8, 50 mm × 250 mm; flow rate 40 ml/min). The fractions containing the product were pooled pooled, the acetonitrile was removed by evaporation. Added EtOAc (10 ml) and the organic phase is washed with two portions of brine and dried (magnesium sulfate). The solvent was removed by evaporation to obtain 3,825 g of [4-(2-{[2-(methoxycarbonyl)-phenyl]-thio}-ethyl)-phenoxy]-acetic acid (output in two stages and 63.9% in total).

1H-NMR (500 MHz, CDCl3): δ 2.82 (t, 2H), 3.15 (t, 2H), 3.82 (s, 3H), 4.35 (s. 2H), 6.78 (d, 2H), 7.18 (d, 2H), 7.23 (t, 1H), 7.51 (d, 1H), 7.55 (t, 1H), 7.85 (d, 1H).

c) was Dissolved [4-(2-{[2-(methoxycarbonyl)-phenyl]-thio}-ethyl)-phenoxy]-acetic acid (0,250 g, 0,722 mmol) in DHM (10 ml) was added N-(2-Chlorobenzyl)-N-ethylamine (0,116 g, China 0,686 mmol). Added tetrafluoroborate N-[(1H-1,2,3-benzotriazol-1 yloxy)(dimethylamino)methylene]-N-methylmethanamine (0,255 g, 0,794 mmol) and N-ethyl-N,N-Diisopropylamine (0.187 g, 1,443 mmol). This solution was stirred 2 hours at room temperature. The crude product was purified flash chromatography (started with isocratic DHM 100% and then increased the concentration of the Meon from 0.5% to 20%; silica gel 60, 0,004-0,063 mm). The fractions containing the product were combined into a pool, EtOAc was removed by evaporation. The substance had to be cleaned again, and it was purified preparative HPLC (started with isocratic mixture of acetonitrile/buffer 60/40 and then the concentration of acetonitrile was increased to 100%; the buffer was a mixture of acetonitrile/water 10/90 with ammonium acetate (0.1 M); column KR-100-7-C8, 50 mm × 250 mm; flow rate 40 ml/min). The fractions containing the product were pooled pooled, the acetonitrile was removed by evaporation. Ammonium acetate was removed by sublimation drying of the product during the night with obtaining 0,111 g of methyl 2-{[2-(4-{2-[(2-Chlorobenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio}-benzoate (yield of 30.9%).

1H-NMR (rotamer, 500 MHz. CDCl3): δ 1.10-1.25 (bm, 3H), 2.95 (m, 2H), 3.15 (m, 2H), 3.40 (m, 2H), 3.9 (s, 3 is), 4.6-4.8 (bm, 4H), 6.75-6.95 (m, 2H), 7.02-7.5 (m, 9H), 7.95 (d, 1H).

d) was Dissolved methyl-2-{[2-(4-{2-[(2-Chlorobenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio}-benzoate in a mixture of tetrahydrofuran (freshly)/water (2/1, 3 ml), was added lithium hydroxide (0.015 g, 0,629 mmol). The interaction was carried out in a single-node microwave oven (5 minutes, 150 degrees). Remove the tetrahydrofuran by evaporation, adding water (10 ml) and washed with an alkaline aqueous phase with diethyl ether (2×10 ml). Added hydrochloric acid (2 ml, 1 M, pH 1). The aqueous phase was extracted with two portions DHM (20 ml). The organic phase was dried (magnesium sulfate) and the solvent was removed by evaporation to obtain 0,103 g 2-{[2-(4-{2-[(2-Chlorobenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio}-benzoic acid (yield 95.5 per cent)

1H-NMR (rotamer, 400 MHz, CDCl3): δ 1.07-1.25 (bm, 3H), 2.95 (m, 2H), 3.15 (m, 2H), 3.42 (m, 2H), 4.62-4.85 (bm, 4H), 6.75-6.95 (m, 2H), 7.02-7.5 (m, 9H), 8.1 (d, 1H).

Biological activity

Drugs

Dissolved compounds in DMSO to obtain 16 mm stock solutions. Before the analyses were additionally diluted stock solutions of dimethylsulfoxide and cultural environment.

GENERAL CHEMICALS AND REAGENTS

Reagent for determination of luciferase was purchased from Packard, USA. Restriction enzymes were from Boehringer, a Vent polymerase from New England Biolabs.

CELL LINES AND CULTURE CONDITIONS CELLS

U2-OS cells osteogenic sarcoma person is Uchali in ATSS, USA. Multiplied and again froze the cells parties with reseeding number six. Granulosa cells in the environment of the Needle when the modification on Dulbecco (DMEM) with 25 mm glucose, 2 mm glutamine, or 4 mm L-alanyl-L-glutamine, 10%fetal calf serum under 5% CO2. Used phosphate buffered saline (PBS) without the addition of calcium or magnesium. All reagents for cell culture were from Gibco (USA), 96-well plates to cell cultures were purchased from Wallach.

PLASMID CONSTRUCTS FOR HETEROLOGOUS EXPRESSION

Used standard techniques of recombinant DNA as described by Ausubel (7). Luciferase reporter vector pGL5UAS (clone consists of five copies of the DNA binding of GAL4 sequence, 5'-CGACGGAGTACTGTCCTCCGAGCT-3') was cloned into Sacl/Xhol sites of pGL3-promoter (Rgeted). Sacl/Xhol fragment carrying the UAS-sites designed using annealing of overlapping oligonucleotides.

Used expression vectors based on pSG5 (Stratagene). All vectors contain EcoRI/Nhel fragment that encodes a DNA-binding domain of GAL4 (positions encoding amino acids 1-145 in the database under access number R), and then to merge in reading frame with fragment coding for the sequence of localization in the nucleus of the T-antigen of the virus polyoma. The localization sequence in the core was designed using the AI annealed overlapping oligonucleotides, that creates sticky NheI/kpni restriction sites-ends (5'-CTAGCGCTCCTAGAAGAAACGCAAGGTTGGTAC-3'). The ligand-binding domain of PPARα human and mouse PPARγ human and mouse amplified in PCR Cloned as/BamIII fragments and cloned in frame to the DNA-binding domain of GAL4 and the localization sequence in the kernel. The sequence of all plasmid constructs were confirmed by sequencing. For transient transfection used the following expression vectors:

vectorencoded PPAR subtypereference sequence1
pSGGALhPPaPPARα manS74349, nt 625-1530
pSGGALmPPaPPARα mouseX57638, nt 668-1573
pSGGALhPPgPPARγ manU63415, nt 613-1518
pSGGALmPPgPPARγ mouseU09138, nt 652-1577

1refers to the positions of nucleotide records in the database used for the expression of the ligand-binding domain

SHORT TRANSLITEROWANY

Was thawed frozen stocks of cells from reseeding number six and before transferowania multiplied before reseeding number eight. Was trypsinization confluent cells were washed them and laid siege to centrifugirovania at 70 g for 2 minutes. Sediment cells again suspended in cold PBS to a cell concentration of about h6cells/ml After adding DNA incubated cell suspension on ice for approximately 5 minutes prior to electroporation At 230 V, 960 microfarad in Biorad's Gen Pulser™ parties to 0.5 ml In the amount of each party to 0.5 ml of cells was added 50 μg DNA, which includes a 2.5 μg expression vector, 25 μg of reporter vector and 22.5 μg of nonspecific DNA (pBluescript, Stratagene).

After electroporation was diluted cells to a concentration of 320000 cells/ml in DMEM without phenol red and sown approximately 25,000 cells per well in 96-well plates. Order before adding the test compound to give the cells to recover, incubated planted tablets at 37°C for 3-4 hours. In the analyses of PPARα Wednesday cells was supplemented with depleted resin with activated carbon fetal calf serum (FCS) in order to avoid background activation of fatty acid components of the FCS. Depleted resin with activated carbon FCS was prepared as follows: to a 500 ml V / V heat inactivated FCS was added 10 g of activated carbon and 25 g of anion exchange resin Bio-Rad for analysis of grain size 200-400 mesh, and held this solution on a magnetic stirrer at room temperature over night. The next day, FCS was centrifuged and the procedure is badania repeated for 4-6 hours. After the second treatment FCS centrifuged and sterilized by filtration for removal of activated carbon and resin.

Assay PROCEDURE

Diluted in DMSO stock solutions of the compounds to the appropriate concentration ranges in the major tablets. Of the main tablets, diluted compounds in the culture medium in order to obtain solutions of the test compounds for the target doses.

After adjusting the number of environment of the cells in each well up to 75 μl) was added 50 μl of a solution of test compounds. Short transfetsirovannyh cells were exposed to compounds for about 24 hours prior to determination of luciferase. To determine luciferase was added manually to each well 100 μl of the reagent for the analysis and leave the tablet for approximately 20 minutes to allow for cell lysis. After lysis was measured by the luciferase activity in the counter 1420 Multiwell Victor from Wallach.

Reference connection

The TZD pioglitazone was used as reference substance for the activation of both human and mouse PPARγ. 5,8,11,14-Eicosatetraenoic acid (ETYA) was used as reference substance for human PPARα.

Calculation and analysis

To calculate the quantities EC50built curve concentration-effect. Used values produced from the middle two is whether the three independent measurements (after subtracting the average background) and expressed as a percentage of the maximum activation obtained with the reference compound. Values were plotted against the logarithm of concentration of the tested compounds. Estimated value of the EU50linear intercalation between the points, which correspond to the data, calculation of the concentration required to achieve 50% of maximum activation obtained with the reference compound.

The compounds of formula I have EC50less than 50 µmol/l for PPARα and the preferred compounds are EU50less than 5 mmol/L. for Example, the EU50some of the Examples of PPARα person are:

Example 3: 0,499 µmol/l and

Example 5; 0,048 µmol/L.

The data obtained in in vivo tests in mice ob/ob show that agonists of PPARα effectively lowers the levels of glucose, insulin, triglycerides, and prevent weight gain. Therefore, we can conclude that agonists of PPARα can be used for the treatment of hyperglycemia, hyperinsulinemia, dyslipidemia, diabetes, obesity and insulin resistance.

1. The compound of the formula I

where n represents 0, 1 or 2;

R1represents halogeno,1-4alkyl group which may be substituted by one or more than one fluorine atom, With1-4CNS group, which may samewe the one or more than one fluorine atom, moreover, when n is 2, the substituents R1may be the same or different;

R2represents an unbranched2-7alkyl group;

R3represents H or och3; and

W represents O or S;

and its pharmaceutically acceptable salts.

2. The compound according to claim 1, where W represents O.

3. The compound according to claim 1, where W represents S.

4. A compound selected from the following:

2-[2-(4-{2-[ethyl(2-terbisil)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid;

2-[2-(4-{2-[(2,4-diferensial)(heptyl)amino]-2-oksidoksi}-3-methoxyphenyl)-ethoxy]-benzoic acid;

2-[2-(4-{2-[(4-chlorbenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethylthio]-benzoic acid;

2-[2-(4-{2-[(4-chlorbenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid;

2-[2-(4-{2-[ethyl(4-trifloromethyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid;

2-[2-(4-{2-[ethyl(4-trifloromethyl)-amino]-2-oksidoksi}-phenyl)-ethylthio]-benzoic acid;

2-{2-[4-(2-{butyl[2-fluoro-4-(trifluoromethyl)-benzyl]-amino}-2-oksidoksi)-phenyl]-ethoxy}-benzoic acid;

2-[2-(4-{2-[(2,4-diferensial)(propyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid;

2-[2-(4-{2-[benzyl(ethyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid;

2-{[2-(4-{2-[benzyl(ethyl)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio}-benzoic acid;

2-[2-(4-{2-[(4-tert-butylbenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid;

2-[2-(4-{2-[ethyl-(4-terbisil)-amino]-2-oksidoksi}-phenyl)-ethoxy]-benzoic acid;

2-{[2-(4-{2-[ethyl-(2-terbisil)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio}-benzoic acid; or

2-{[2-(4-{2-[(2-Chlorobenzyl)(ethyl)-amino]-2-oksidoksi}-phenyl)-ethyl]-thio}-benzoic acid

and its pharmaceutically acceptable salts.

5. Pharmaceutical composition for treating hyperlipidemia, dyslipidemia, diabetes and obesity, containing a compound according to any one of claims 1 to 4 in a mixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.

6. The use of compounds according to any one of claims 1 to 4 in the manufacture of drugs for the treatment of insulin resistance.

7. The method of obtaining the compounds of formula I, in which is conducted the interaction of the compounds of formula II,

in which R1, R2, R3, W and n are such as defined above, and PG represents a protective group for carboxyl group, hydroxy, agent unprotect.

8. The compound of formula II

in which R1, R2, R3, W, n such as opredelno above, and PG represents the Wallpaper protective group for a carboxylic hydroxy group.



 

Same patents:

The invention relates to a method of deriving dibenzothiazepine interest as intermediate compounds for pharmaceutical preparations

The invention relates to new compounds of the formula (I)

< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)

The invention relates to the production of derivatives of 3-amino-2-mercaptobenzoic acid of the formula I, in which X represents fluorine, n = 0 or 1, Z represents CO-a or CS-A1A represents hydrogen, halogen, OR1or SR2, A1denotes hydrogen or or1, R1and R2denote hydrogen, substituted or unsubstituted, saturated or unsaturated hydrocarbon radical with an open chain, containing not more than 8 carbon atoms; the interaction of the compounds of formula II in which T represents hydrogen, C1-C6alkyl, C3-C6alkenyl,3-C6quinil,3-C6cycloalkyl or substituted or unsubstituted phenyl, benzyl or phenethyl; with aqueous strong base

The invention relates to sulfur-containing derivative of an aryl having antibacterial and antiviral activity, in particular Aristotelianism the following formula (I), their pharmaceutically acceptable salts and solvate, a pharmaceutical composition having antibacterial and antiviral activity, and method of treating bacterial or viral infections

Glp-1 analogs // 2288232

FIELD: peptides, medicine, pharmacy.

SUBSTANCE: invention relates to novel peptide analogs of glucagons-like peptide-1 and its pharmaceutically acceptable salts that are used in treatment of mammals.

EFFECT: valuable medicinal properties of analogs.

10 cl, 1 tbl, 411 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-cyano-4-fluoropyrrolidine of the formula (I): or its pharmaceutically acceptable salt wherein A represents group of the general formula (II): wherein B represents carbonyl or sulfonyl group; R1 represents (C1-C6)-alkyl that can be optionally substituted with group chosen from the group comprising -OH or atoms of fluorine, chlorine, bromine or iodine, phenyl optionally substituted with -CN or morpholinyl group, or if B represents carbonyl then R1 can mean hydrogen atom; R2 represents (C1-C6)-alkyl optionally substituted with hydroxyl group or hydrogen atom. Compounds of the formula (I) are inhibitors of enzyme dipeptidyl peptidase IV that allows its using in pharmaceutical composition that is designated for treatment of insulin-dependent diabetes mellitus (diabetes of type 1), non-insulin-dependent diabetes mellitus (diabetes of type 2), diseases associated with resistance to insulin or obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel analogs of fatty acids of the general formula (I): R1-[Xi-CH2]n-COOR2 wherein R1 represents (C6-C24)-alkene with one or more double bond, and/or (C6-C24)-alkyne; R2 represents hydrogen atom or (C1-C4)-alkyl; n represents a whole number from 1 to 12; I represents an uneven number and shows position relatively to COOR2; Xi is chosen independently of one another from the group comprising oxygen (O), sulfur (S) and selenium (se) atom and -CH2 under condition that at least one among Xi is not -CH2 and under condition that if R1 represents alkyne then a carbon-carbon triple bond is located between (ω-1)-carbon atom and (ω-2)-carbon atom, or between (ω-2)-carbon atom and (ω-3)-carbon atom, or between (ω-3)-carbon atom and (ω-4)-carbon atom, and to their salts and complexes. The claimed compounds can be used in treatment and/or prophylaxis of X syndrome, obesity, hypertension, hepatic fatty dystrophy, diabetes mellitus, hyperglycemia, hyperinsulinemia and stenosis. Also, invention relates to methods for preparing novel analogs of fatty acids. Also, invention relates to a nutrient composition comprising indicated analogs of fatty acids and to a method for reducing the total body mass or amount of lipid tissue in humans or animals. Invention provides the development of novel fatty acid analogs-base compositions or methods for suppression of stenosis, restenosis or associated disorders as result of proliferation and mobilization of vessel smooth muscle cells after, for example, traumatic damages of vessels during surgery operation in vessels.

EFFECT: improved preparing method, valuable medicinal properties of analogs.

12 cl, 2 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: the present insulin solution for peroral intake should be applied for treating patients with diabetes mellitus. The suggested insulin solution consists of water and insulin, additionally, it contains sodium chloride at the following ratio of components, weight%: insulin 0.005-0.02, sodium chloride 0.5-1.0, water - up to 100.0. The innovation provides decreased glucose level in blood of animals in case of peroral intake of the solution up to 40% at insulin dosages being about 10 U/kg animal body weight.

EFFECT: higher efficiency.

12 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: chemistry of heterocyclic organic compounds, medicine.

SUBSTANCE: invention relates to a novel heterocyclic derivative of the formula (I'): , wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents-CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom; R5 represents (C2-C8)-alkenyl; R3 represents hydrogen atom or (C1-C4)-alkyl; X represents oxygen atom or sulfur atom; R20 represents phenyl substituted with unsubstituted (C1-C6)-alkyl, (C1-C6)-alkyl substituted with fluorine atom, (C1-C4)-alkoxy-group, phenyl-(C1-C4)-alkoxy-group, hydroxyl group, halogen atom, nitro-group, unsubstituted amino-group or amino-group substituted with (C1-C4)-alkyl; n means a whole number from 1 to 4, or to its pharmaceutically acceptable salt. Also, invention relates to heterocyclic derivative of the formula (I): , wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents -CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom; R represents (C4-C8)-alkyl or (C2-C8)-alkenyl or -CO-C≡C-R6 wherein R6 represents (C1-C8)-alkyl; R3 represents hydrogen atom or (C1-C4)-alkyl; X represents oxygen atom or sulfur atom; n means a whole number from 1 to 4, or its pharmaceutically acceptable salt. Compounds of the formulas (I') and (I) are effective as a hypoglycemic agent, hypolipidemic agent, agent improving resistance to insulin, therapeutic agent in treatment of diabetes mellitus, therapeutic agent in treatment of diabetes mellitus complications, agents enhancing tolerance to glucose, anti-arteriosclerotic agent, agents against obesity or agent for X syndrome.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 2 tbl, 56 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel condensed cyclopropylpyrrolidines of the formula: wherein x means 0 or 1 and y means 0 or 1 under condition that x means 1 when y means 0, and x means 0 when y means 1; and wherein n means 0 or 1; X means hydrogen atom (H) of group -CN; R1, R2, R3 and R4 are similar or different and chosen independently from H, (C1-C10)-alkyl, (C2-C12)-alkenyl, saturated (C3-C10)-cycloalkyl, saturated (C3-C10)-cycloalkyl-(C1-C10)-alkyl, saturated (C3-C10)-bicycloalkyl, saturated (C3-C10)-tricycloalkyl, hydroxyl-(C1-C10)-alkyl-saturated (C3-C10)-cycloalkyl, (C1-C10)-alkylthio-(C1-C10)-alkyl, (C6-C10)-aryl-(C1-C10)-alkylthio-(C1-C10)-alkyl, (C6-C10)-aryl-(C1-C10)-alkyl, 5- or 6-membered heteroaryl comprising one nitrogen atom (N) or one oxygen atom (O), 5- or 6-membered heteroaryl comprising one atom N condensed with (C6-C10)-aryl ring, 5- or 6-membered heteroaryl comprising one atom N or one atom O, (C1-C10)-alkyl, cycloheteroalkyl that represents (C5-C8)-saturated ring comprising one heteroatom, such as N or O; if necessary, all compounds comprise 1, 2, 3, 4 or 5 groups of substitutes at corresponding carbon atom chosen from halogen atom, (C1-C10)-alkyl, (C2-C12)-alkenyl, hydroxy-group, hydroxy-(C1-C10)-alkyl or cyano-group; R1 and R4 can form in common, if necessary, the group -(CR5R6)m- wherein m means 2-6, and R5 and R6 are similar or different and chosen independently from hydroxy-group, H or (C1-C10)-alkyl including all their stereoisomers; and their pharmaceutically acceptable salt, or prodrug esters and all their stereoisomers. These compound inhibit activity of dipeptidyl peptidase IV that allows their using in pharmaceutical compositions used in treatment of diabetes mellitus of type-2.

EFFECT: valuable medicinal properties of compounds.

20 cl, 6 tbl, 113 ex

FIELD: medicine, pharmaceuticals, in particular compositions for treatment of insulin-independent II type diabetus mellitus.

SUBSTANCE: claimed composition represents single solid dosed pharmaceutical for oral administration and contains effective dose of metformin and glibenclamide, wherein said glibenclamide contains powdery particles with specific surface of 1.7-2.2 m2/g. Also disclosed are method for treatment of insulin-independent diabetes or hyperglycemia; method for providing and enhancing of glibenclamide bioavailability in human body (variants).

EFFECT: composition with increased glibenclamide bioavailability.

68 cl, 3 ex, 7 tbl, 3 dwg

FIELD: organic chemistry.

SUBSTANCE: invention relates to new polymorphous crystalline forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)-amino]-ethoxy]-benzyl]-thiazolidine-2,4-dione maleate of formula and stereomers thereof.

EFFECT: polymorphous crystalline forms of high stability.

12 cl, 1 tbl, 13 dwg, 5 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to the development of a novel vegetable-base agent that can be used in treatment of inflammatory diseases of small pelvis organs and diseases of rectum. Agent used in prophylaxis and treatment of diseases of small pelvis organs and diseases of rectum comprises long turmeric (Curcuma longa L.) rhizome dried extract standardized by curcumin, anesthetic agent and pharmaceutically acceptable excipients. Agent is made as a suppository and comprises benzocaine as an anesthetic agent and vitepsol and cacao butter as a suppository base. Method for preparing agent used in prophylaxis and treatment of diseases of small pelvis organs and diseases of rectum involves mixing long turmeric dried extract standardized by curcumin with anesthetic agent and a pharmaceutically acceptable excipient. Method for prophylaxis and treatment of diseases of small pelvis organs and diseases of rectum involves using the proposed agent.

EFFECT: improved preparing agent, valuable medicinal properties of agent.

9 cl, 3 ex

FIELD: medicine.

SUBSTANCE: method involves talking to patient and parents for setting diagnosis. Detoxication, prohibitory and rehabilitative therapy is carried out in hospital. Basic therapy is administered with Clophellinum, Hemineurine, Tizercine, Galoperidol, Loperamide before beginning detoxication. Ultra-rapid opioid detoxication is carried out and vitamin and cardioprotector therapy is applied for 1-2 days after it is finished. Comatose atropine therapy and electric convulsion therapy are alternated every other day at the prohibitory therapy stage. Total number of procedures is equal to 5-6. Ozone therapy is applied every day at the same stage in 80 mg/l mode at a rate of 0.1 l/min. Premedication is carried out before electric convulsion therapy with 0.5 ml of 0.1% atropine sulfate solution, 2 ml of 2% Ditiline solution, 10-15 ml of 20% sodium oxybarbiturate solution. Transcrtanial electric stimulation is carried out at rehabilitation stage. Electric convulsion therapy is carried out once per two-week period during the whole period. Ozone therapy is carried out on the background of anti-depressant introduction twice per 10-14 days.

EFFECT: wide range of functional applications.

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