Derivatives of indane acetic acid and pharmaceutical composition

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

 

The scope of the invention

The present invention relates to a derivative indoxyl acids and their use in pharmaceutical compositions for the treatment of diseases such as diabetes, obesity, hyperlipidemia, and atherosclerotic disease. The present invention also relates to intermediate products suitable for use in deriving indoxyl acid, and to methods for.

Prior

Diabetes type II is the most common form of diabetes and 90 - 95% of patients suffering from hyperglycemia, found this form of the disease. Diabetes type II, apparently, is the reduced mass β-cells of the pancreas, there is more individual defects of insulin secretion and reduced tissue sensitivity to insulin. The symptoms and consequences of this form of diabetes include fatigue, frequent urination, thirst, blurred eyes, frequent infections and slow healing of wounds caused by diabetes, neurological lesions, retinopathy, micro - and macroscopic lesions of blood vessels and heart disease and kidney failure.

Resistance to the metabolic effects of insulin is one of the main features of type II diabetes. Insulin resistance is characterized by impaired absorption and use of the Oia glucose-sensitive insulin target organs, for example, in adipocytes and skeletal muscle and impaired inhibition of the excretion of glucose by the liver. Functional insulin deficiency, insulin resistance in the periphery and the inability of insulin to suppress excretion of glucose by the liver lead to hyperglycemia on an empty stomach. β-pancreas Cells compensate for insulin resistance by producing insulin at high levels. However, β-cells are unable to support such a significant production of insulin and ultimately induced glucose insulin production is reduced, which leads to disruption of glucose homeostasis and the subsequent development of overt diabetes. Hyperinsulinemia is also associated with insulin resistance, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol and elevated levels of low-density lipoprotein (LDL) in plasma. The combination of insulin resistance and hyperinsulinemia with these metabolic disorders is called "syndrome X" and it is closely associated with an increased risk of hypertension and ischemic heart disease.

Obesity is the excessive accumulation of adipose tissue. The excess of adipose tissue leads to severe pathological conditions, such as type II diabetes, hypertension, coronary artery disease, hyperlipidemia, WA is possible and some malignancies. Adipocytes can also affect glucose homeostasis by producing necrosis factor tumor cells a (TNFa) and other molecules.

It is known that atherosclerotic disease is caused by a number of factors, such as hypertension, low HDL and high LDL levels. Associated with atherosclerosis diseases include cardiovascular disease, coronary heart disease (CHD), cerebrovascular disease and peripheral vascular disease. Coronary heart disease includes death from coronary heart disease, myocardial infarction and coronary revascularization. Cerebrovascular diseases include ischemic or hemorrhagic stroke and transient ischemic attacks.

In line with this, despite the presence of some pharmaceutical drugs that are used for the treatment of these diseases remains a need for new pharmaceutical drugs that are both safe and effective treatments for these diseases, as well as effective methods for their preparation.

The present invention relates to compounds that are suitable for use in the treatment of diabetes and related diseases such as syndrome X, impaired glucose tolerance, impaired glucose in blood glucose and hyperinsulinemia, obesity, atheroscl eroticheskoe disease dyslipidemia and related diseases, such as hypertriglyceridemia, low HDL cholesterol and hypercholesterolemia, cardiovascular disease, and cerebrovascular disease.

Description of the invention

The present invention encompasses the compounds of formula I,

where R is H or C1-C6alkyl;

R1means H, COOR, C3-C8cycloalkyl or C1-C6alkyl, C2-C6alkenyl or C1-C6alkoxyl, each of which may be unsubstituted or may contain as substituents : fluorine, methylenedioxyphenyl, or phenyl which may be unsubstituted or may contain as substituents R6;

R2denotes H, halogen or C1-C6alkyl which may be unsubstituted or may contain as substituents C1-C6alkoxyl, oxoprop, fluorine,

or

R2means phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl, tet-Rasool, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydropyranyl, piperazinil or morpholinyl, each of which may be unsubstituted or may contain as substituents R6;

R3means H, C1-C6lkyl or phenyl, which may be unsubstituted or may contain as substituents R6;

X is O or S;

R4means C1-C6alkyl or C3-C8cycloalkyl, each of which may be unsubstituted or may contain as substituents fluorine, oxoprop or1-C6alkoxy, which may be unsubstituted or may contain as substituents With1-C6alkoxyl or phenyl, optionally containing as substituent R6, each of which can contain as a substituent a phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolyl, tet-rehydration, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinil, morpholinyl, benzofuran, dihydrobenzofuran, benzothiazyl, dihydrobenzofuranyl, indolyl, indolinyl, indazoles, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazole, benzisothiazole, benzodioxolyl, hinely, ethanolic, hintline, enoxaparin dihydrobenzofuranyl, dihydrobenzofuranyl or 1,4-benzodioxane, each of which may be unsubstituted or may contain as substituents R6,

or

C1-C 6alkyl may also contain as a substituent With3-C8cycloalkyl or phenoxy, which may be unsubstituted or may contain as substituents R6or phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinil, morpholinyl, benzofuran, dihydrobenzofuran, benzothiazyl, dihydrobenzofuranyl, indolyl, indolinyl, indazoles, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazole, benzisothiazole, benzodioxolyl, hinely, ethanolic, hintline, enoxaparin, dihydrobenzofuranyl, dihydrobenzofuranyl or 1,4-benzodioxane, each of which may be unsubstituted or may contain as substituents R6,

or

R4means phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinil, morpholine is l, benzofuran, dihydrobis-zofenil, benzothiazyl, dihydrobenzofuranyl, indolyl, indolinyl, indazoles, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazole, benzisothiazole, benzodioxolyl, hinely, ethanolic, hintline, enoxaparin, dihydrobenzofuranyl, dihydrobenzofuranyl or 1,4-benzodioxane, each of which may be unsubstituted or may contain as substituents R6or phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydropyranyl, piperazinil, morpholinyl, benzodioxolyl, dihydrobenzofuranyl, indolyl, pyrimidinyl or phenoxy, each of which may be unsubstituted or may contain as substituents R6;

R5denotes H, halogen or C1-C6alkyl, optionally containing as a substituent oxoprop;

R6means halogen, CF3C1-C6alkyl, optionally containing as a substituent oxoprop or hydroxyl, or C1-C6alkoxyl, optionally containing as a substituent fluorine;

and their pharmaceutically acceptable salts and esters. Defined below, the terms in the entire invention are as follows:

"C1 -C6alkyl" means linear or branched chain alkyl groups containing from one to about six carbon atoms. Such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, 2-pentyl, n-hexyl, 2-hexyl, 3-hexyl, 2,3-dimethylbutyl etc.

"C2-C6alkenyl" means linear or branched chain alkeneamine group containing from two to about six carbon atoms and containing one or more double bonds. Such groups include ethynyl, propenyl, Isopropenyl, 2-isobutene, 4-pentenyl, 5-hexenyl etc.

"C3-C8cycloalkyl" means a saturated monocyclic alkyl groups containing from 3 to about 9 carbon atoms and includes such groups as cyclopropyl, cyclopentyl, cyclohexyl, etc.

"C1-C6alkoxyl" means linear or branched chain CNS group containing from one to about six carbon atoms and includes such groups as methoxy, ethoxyl, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second-butoxyl, tert-butoxyl etc.

"Halogen" means fluorine, chlorine, bromine or iodine.

If you specify that the alkyl, cycloalkyl, Alchemilla or CNS group contains as a substituent fluorine, it may contain the image quality is as substituents one or more fluorine atoms at any available carbon atom up to artificially enhancing the uptake.

If you specified that the alkyl substituent contains as Deputy oxo group, this means the replacement of an oxygen atom with a double bond, which, together with the carbon atom to which it is attached forms a carbonyl group(C=O)-.

If you specify that any portion is substituted, it may contain one or more of these substituents, which may be located at any available position of this fragment. If any fragment has two or more substituents, each Deputy can be defined independently of any other Deputy and accordingly they may be the same or different.

The term "optionally containing substituents" means that this modification of the fragment can be unsubstituted or contain specified Deputy (deputies).

R3can be attached to the heterocyclic portion of the compounds of formula 1 in position 4 or 5 (i.e. to any available carbon atom) and, accordingly, the remainder of the molecule is attached to the remaining available carbon atom.

Examples of compounds of the formula I, which illustrate the present invention but does not limit, are shown in table 1.

Table 1.

Illustrative examples of the soybean is ineni Formula I

No.R1R2R3R4R5X
1NNNCH3NAbout
2NNNn-butylNAbout
3NNNcyclopropylNAbout
4NNNcyclopentylNAbout
5NNNcyclooctylNAbout
6NNNPhNAbout
7NNNPhNS
8NNN2-ClPhNAbout
9NNN2,3-di-FPhNAbout
10NNN2,4-di-CH3PhNAbout
11NNN2-thienylNAbout
12NNNNAbout
13NNN2-furylNAbout
14NNN2-furylNS
15NNN2-(4-CH3)furylNAbout
16NNNNAbout
17NNN4-FPhNAbout
18NNN4-FPhNS

No.R1R2R3R4R5 X
19NNSnz4-FPhHO
20NNEt4-FPhHO
21NNEt4-FPhHS
22NNEt3-pyridylHO
23NNEtHAbout
24NNisopropyl4-FPhHAbout
25NNisopropyl2,4-di-FPhHAbout
26NNn-butyl2,4-di-PPhHAbout
27NNn-hexyl2,4-di-PPhHAbout
28NNPh2,4-di-PPhHAbout
29NN4-F Ph2,4-di-Ph HAbout
30NCH3EtPhHAbout
31NCH3EtPhHS
32NCH3Et3-CH3OPhHAbout
33NNEt3-CH3OPhHAbout
34NNEt3-CH3OPhHS
35NNEt4-CH3OPhHAbout
36NNEt4-CH3OPhHS
37NNEt4-EtOPhHS
38NNEt4-EtOPhHAbout
39NNMeHAbout
40N NMePhCH2HAbout
41NNMe3-Cl-4-F-PhHAbout
42NNMe3-F-4-Me-PhHAbout
43NNMeC-Me-4-F-PhHAbout
44NNMe3-NH2-4-Me-PhHAbout
45NNEt4-Et-PhHAbout
46NNMe4-Et-PhHAbout

S
No.R1R2R3R4R5X
47NNEt4-CN-PhNAbout
48NNEt4-(Et)2N-PhNAbout
49NNMe 4-i-Pr-PhNAbout
50NNMe4-t-Bu-PhNAbout
51NNMe4-Et-PhNAbout
52NNMe4-n-Bu-PhNAbout
53NNEt4-n-Pr-PhNAbout
54NCH3Et4-CH3OPhNAbout
55NCH3Et4-CH3OPhNS
56NCH3Et4-CH3OPhCH3About
57NCH3Et3,4-di-CH3OPhCH3About
58NCH3Et4-PhPhCH3About
59NCH3Et4-PhPhCH3
60NCH3EtCH3About
61NCH3PhcyclopropylNAbout
62NCH3PhcyclohexylNAbout
63NCH3PhcyclohexylNS
64NCH3p-FPhcyclohexylNAbout
65NCli-PrPhNAbout
66NCli-PrPhNS
67NCli-PrPhClAbout
68NCli-Pr4-CH3PhClAbout
69NBrCH3PhBrAbout
70 NBrCH33-FPhBrAbout
71NBrCH33-FPhBrS
72NCH3COCH3n-propylCH3COAbout
73NCH2OCH3Et2-thienylNAbout
74NPhN2,4-di-ClPhNAbout
75NPhN2,4-di-ClPhNS
76NPhCH32,4-di-ClPhNAbout
77NPhEt2,4-di-ClPhNAbout
78NPhPh2,4-di-ClPhNAbout

No.R1R2R3R4R5 X
79NPhPh2,4-di-ClPhNS
80NPh4-CH3O-Ph2,4-di-ClPhNAbout
81N4-F PhCH34-F PhNAbout
82N4-F PhCH32,4-di-ClPhNAbout
83N3-pyridylCH32,4-di-ClPhNAbout
84N3-pyridylCH32,4-di-ClPhNS
85N2-thienylCH3PhNAbout
86N2-thienylCH32,4-di-ClPhNAbout
87N2-thienylCH32,4-di-ClPhNS
88N2-thienylCH33-pyridylNAbout
89N2-thienylCH3checkpointerNAbout
90N2-thienylCH3NAbout
91N2-thienylCH3Ph2-thienylAbout
92CH3NNPhNAbout
93CH3NNPhNS
94CH3NN2-thienylNAbout
95CH3NN2-thienylNS
96CH3NNNAbout
97CH3NNNAbout

Order the th No. R1R2R3R4R5X
98CH3NNHO
99CH3NN2-pyridylHO
100CH3NNHAbout
101CH3NCH3cyclobutylHAbout
102CH3NCH3cyclohexylHAbout
103CH3NCH3cyclohexylHS
104CH3NCH33,4-di-PPhHAbout
105CH3NCH33,4-di-PPhHS
106CH3N. CH32-pyridylHAbout
107CH3NCH3HAbout
108CH3NCH3HAbout
109CH3NEtPhHAbout
110CH3NEtPhHS
111CH3NEt4-CF3PhHAbout
112CH3NEtHAbout
113CH3NEt2-naphthylHAbout
114CH3NEtHAbout
115CH3NEt HAbout
116CH3NEtHS
117CH3NEtHAbout

No.R1R2R3R4R5X
118CH3NEtHO
119CH3Ni-PrPhHO
120CH3Ni-PrPhHS
121CH3Ni-Pr3,4-di-FPhHO
122CH3Ni-Pr3,4-di-ClPhHAbout
123CH3Ni-Pr4-PhPhH About
124CH3Ni-Pr4-PhPhHS
125CH3Ni-Pr4-(4-ClPh)PhHAbout
126CH3Ni-Pr4-(4-ClPh)PhHS
127CH3Ni-PrHAbout
128CH3Ni-PrHAbout
129CH3Ni-PrHAbout
130CH3Ni-PrHAbout
131CH3Ni-Pr3-(5-CH3)pyridylHAbout
132CH3Ni-PrHAbout
133CH3Ni-PrHS

No.R1R2R3R4R5X
134CH3Ni-PrHAbout
135CH3CH3i-Pr3,4-di-ClPhCH3About
136CH3n-propyli-Pr3,4-di-ClPhn-propylAbout
137CH3Cli-Pr4-ClPhNAbout
138CH3Cli-Pr4-ClPhNS
139CH3Cli-Pr3-CH3OPhNAbout
140CH3Cli-Pr3-CH3OPhClAbout
141CH3Cli-Pr3-CH3OPhClS
142CH3Cli-PrClAbout
143CH3Bri-PrPhNAbout
144CH3Bri-Pr3-ClPhNAbout
145CH3Bri-PrPhBrAbout
146CH3Bri-PrPhBrS
147CH3CH3i-PrPhNAbout
148CH3CH3i-PrPhNS
149CH3CH3i-Pr2-ClPhNAbout
150CH3CH3i-Pr NAbout
151CH3CH3COi-Pr3-FPhNAbout
152CH3CH3COi-Pr3-FPhNS
153CH3n-PrCOi-Pr3-FPhNAbout
154CH3n-BuCOi-Pr3-FPhNAbout
155CH3Nn-BuPhNAbout
156CH3Nn-BuNAbout
157CH3Nn-BuNS

No.R1R2R3R4R5X
158CH3Nn-Bu2-ClPhNAbout
159CH3Nn-Bu2,4-di-FPhNAbout
160CH3Nn-Bu3,4-di-CH3OPhNAbout
161CH3Nn-BuNAbout
162CH3Nn-Bu2-furylNAbout
163CH3Nn-BuNAbout
164CH3Nn-BuNAbout
165CH3Nn-BuNS
166CH3Nn-BuNAbout
167CH3Nn-BuNS
168CH3Nn-BuNAbout
169CH3Nn-BuNAbout
170CH3Brn-Bu2,4-di-FPhBrAbout
171CH3Cln-Bu2,4-di-FPhNAbout
172CH3Nn-pentylPhNAbout
173CH3Nn-pentyl2,4-di-FPhNAbout
174CH3Nn-pentyl2,4-di-FPhNS
175CH3Nn-pentyl4-pyridylNabout

No.R1R2R3R4R5X
176CH3Nn-pentylNAbout
177CH3Cln-pentylPhNAbout
178CH3Cln-pentylPhNS
179CH3NPhNAbout
180CH3N2-Cl PhNAbout
181CH3N2-Cl PhNS
182CH3NNPhOCH2NAbout
183CH3NN(4-CH3Ph)och2NAbout
184CH3NNNAbout
185CH3NCH3EtNAbout
186CH3NCH3EtNS
187CH3NCH3CF3CF2NAbout
188CH3NCH3tert-butylNAbout
189CH3NEt3-(5-CH3) pyridylNAbout
190CH3NEt4-pyridylNAbout
191CH3NEt4-pyridylNS
192CH3EtCH3PhOCH2NAbout
193CH3EtCH3PhOCH2NS
194CH3EtCH3hCH 2OCH2NAbout
195CH3n-propylCH3PhOCH2NAbout
196CH3n-propylCH3PhOCH2n-propylAbout
197CH3n-butylCH3PhOCH2NAbout
198CH3n-hexylCH3PhOCH2NAbout
199CH3n-hexylCH3PhOCH2NS
200CH3n-hexylisopro-peel3-ClPhNAbout

No.R1R2R3R4R5X
201CH3n-hexylPh3-ClPhNAbout
202CH 3CH3ONCH3PhOCH2NAbout
203CH3Phn-butyl3,4-di-FPhNAbout
204CH33-FPhCH31-naphthylNAbout
205CH34-pyridylN4-CF3PhNAbout
206CH34-pyridylN4-CF3PhNS
207CH3ClCH33,5-di-F-PhNAbout
208CH3BrCH3CF3CF2NAbout
209CH3Brn-butylCF3CF2NAbout
210CH3Brn-butylCF3CF2BrAbout
211CH3BrCF3CF2BrAbout
212CH32-furylCH3isobutylNAbout
213CH32-furylCH3isobutylNS
214CH32-furylCH32-F-4-CF3PhNAbout
215CH32-furylCH32-naphthylNAbout
216CH32-furyli-PrisobutylNAbout
217CH3EtCOn-propyl3-CH3OPhEtCOAbout
218EtNNcyclopropylNAbout
219EtNN4-F PhNAbout
220EtNN3,5-di-F-PhNAbout
221 EtNN4-Cl PhCH2NAbout
222EtNN2-genoliniNAbout
223EtNCH3PhCH2NAbout
224EtNCH34-F PhCH2NAbout
225EtNCH33,4-di-F-PhOCH2NAbout
226EtNCH3NAbout
227EtNCH3NS

No.R1R2R3R4R5X
228EtHCH3NAbout
229 EtHCH3NAbout
230EtHCH3NS
231EtHCH3NAbout
232EtHCH3NAbout
233EtHCH3NS
234EtHCH32-genoliniNAbout
235EtHCH3NAbout
236EtHCH3NAbout
237EtHCH3NAbout
238EtHCH3NAbout
239EtHCH3NAbout
240EtHCH3NAbout

No.R1R2R3R4R5X
241EtHCH3Habout
242EtHCH3Habout
243EtHCH3(4-CH3Oh)PhCH2CH2Habout
244EtHCH3Habout
245Etl CH3Habout
246EtBrCH3Habout
247EtHEt4-PhPhHabout
248EtHEt4-PhPhHS
249EtHEt4-(4-CH3Ph)PhHabout
250EtCH3CH32-FPhHabout
251EtCH3CH32-FPhCH3about
252EtCH3CH32-FPhCH3about
253EtCH3CH32-FPhCH3S
254Et3-Cl PhEt4-PhPhHabout
255 3-Cl PhEt4-PhPhHS
256EtCH3CON4-FPhHabout
257EtCH3COisopropyl4-FPhHabout
258EtCH3COPh4-FPhHabout
259EtCH3COCH3SikorksyCH3COabout
260EtCH3COCH34-FPhCH3COabout
261EtCH3COPh4-FPhCH3COabout
262EtCH3COPh4-FPhCH3COS
263EtClEt4-(4-CH3Ph)PhHabout
264EtClEt4-(4-CH3Ph)PhClabout

No.R1R2R3R4R5X
265EtClEtClAbout
266EtBrPh2-och3PhBrAbout
267CF3CH2NNn-butylNAbout
268CF3CH2NNPhNAbout
269CF3CH2NN3-pyridylNAbout
270CF3CH2NCH3cyclopentylNAbout
271CF3CH2NCH34-(CF3O)PhNAbout
272CF3CH2NCH34-(CF3O)PhNS
273 CF3CH2NCH34-(CHF2O)PhNAbout
274CF3CH2NCH3NAbout
275CF3CH2Nn-butyl(4-F-Ph)OCH2NAbout
276CF3CH2NPhPhNAbout
277CF3CH2NPhPhNS
278CF3CH2NPh2-(5-CF3)furylNAbout
279CF3CH2NPh2-thienylNAbout
280CF3CH2N4-FPhPhNAbout
281CF3CH2CH3N2-FPhNAbout
282CF3CH2 CH3N2-FPhNS
283CF3CH2CH3N2-FPhCH3About
284CF3CH2CH3Et3-CF3PhnAbout
285CF3CH2CH3n-butyl(4-F-Ph)OCH2NAbout
286CF3CH2CH3n-butyl(4-F-Ph)OCH2NS
287CF3CH2CH3Ph2-thienylNAbout
288n-propylNNCH3NAbout
289n-propylNNCH3NS
290n-propylNNn-propylNAbout
291nNn cyclobutylNAbout

No.R1R2R3R4R5X
cut
292n-propylNNcycloheptylNAbout
293n-propylNN3,4-di-CH3PhNAbout
294n-propylNN2-thienylNAbout
295n-propylNN2-thienylNS
296n-propylNNNAbout
297n-propylNCH3CH3NAbout
298n-propylNCH3CH3 NS
299n-propylNCH33-CF3PhNAbout
300n-propylNCH32-thienylNAbout
301n-propylNCH33-(4-(Osns)thienyl)NAbout
302n-propylNCH32-(5-(CH3)thienyl)NAbout
303n-IlNCH3NAbout
304n-propylNCH3NAbout
305n-propylCH3CH33-BrPhNAbout

No.R1R2R3R4R5X
306n-propylCH 3CH33-BrPhHS
307n-propylCH3CH33-BrPhCH3O
308n-propylCH3CH3HO
309n-propylCH3CH3HAbout
310n-propyln-propylCH33-ClPhHAbout
311n-propyln-propylCH33-ClPhHS
312n-propylCH3Och2CH33-ClPhHAbout
313n-propylCH3COCH33-ClPhHAbout
314n-propylPrCOCH33-ClPhHAbout
315n-propyl PrCOCH33-ClPhPrCOAbout
316n-propylClCH3HAbout
317n-propylClCH3HAbout

No.R1R2R3R4R5X
318n-propylClCH3NAbout
319-propylClNPhClAbout
320n-propylClCH3PhClAbout
321n-propylClCH3PhClS
322n-propylCln-propyl3-CH3OPhClAbout
323 n-propylCln-propyl3-pyridylClAbout
324isopropylNNPhNAbout
325isopropylNN2-genoliniNAbout
326isopropylNNNAbout
327isopropylNCH3CH3NAbout
328isopropylNCH3tert-butylNAbout
329isopropylNCH3n-heptylNAbout
330isopropylNCH3n-heptylNS
331isopropylNCH32,4-di-FPhNAbout
332isopropylNCH32,4-di-FPh NS
333isopropylNCH32-F-4-CF3PhNAbout

Et
No.R1R2R5R4R5X
334isopropylNn-propyl2-F-4-CF3PhHO
335isopropylNn-propyl3,5-di-ClPhHO
336isopropylNPh2,4-di-CF3PhHAbout
337isopropylN4-FPh2-F-4-CF3PhHAbout
338isopropylCH3EtHAbout
339isopropylCH3EtHAbout
340isopropylCH3HAbout
341isopropylCH3EtHS
342isopropylCH3EtHAbout
343isopropylCH3EtHAbout
344isopropylCH3EtHAbout
345isopropylEtCH33-CF3PhHAbout
346isopropylEtCH33-EtPhHAbout

td align="center"> H
No.R1R2R5R4R5X
347isopropyln-propylHPhOCH2O
348isopropyln-propylHPhOCH2n-propylO
349isopropyln-propylHHAbout
350isopropyln-propylHn-propylAbout
351isopropyln-propylHHS
352isopropyln-propylHHAbout
353isopropyln-propyln-butylHAbout
354isopropyln-propylPhHAbout
355isopropyln-butylHHAbout
356 isopropyln-hexylHHAbout
357isopropylPhHCH3HAbout
358isopropylPhHn-propylHAbout
359isopropylPhHn-propylHS
360isopropylPhHHAbout
361isopropylPhHHS

No.R1R2R3R4R5X
362isopropylPhCH3HO
363isopropylPhCH3 HO
364isopropylClEtPhHAbout
365isopropylClEtPhHS
366isopropylClEt2-CH3PhClAbout
367isopropylCln-propyl3-FPhHAbout
368isopropylClisopropyl3-FPhHAbout
369isopropylCl4-FPh3-FPhHAbout
370isopropylBrEt2-CH3PhBrAbout
371isopropylBrEt2-CH3PhBrS
372n-butylHHCyclohexylHAbout
373n-butylHHPhHAbout
374n-butylHH4-FPhHAbout
375n-butylHH3,5-di-ClPhHAbout
376n-butylHH3,5-di-ClPhHS
377n-butylHCH33,4-di-CH3OPhHAbout
378n-butylHCH34-F PhOCH3HAbout

No.R1R2R3R4R5X
379n-butylNCH3NAbout
380n-butylNCH3(4-CH3Oh)PhCH2CH2NAbout
381n-butylNCH3N About
382n-butylNCH3NS
383n-butylNEtNAbout
384n-butylNn-propyltikabaliNAbout
385n-butylNn-propylNAbout
386n-butylNisopropylNAbout
387n-butylNPhn-propylNAbout
388n-butylNPhNAbout
389n-butylNPhPhNAbout
390n-butylNPhPhNS
391 n-butylCH3CH34-CH3PhNAbout
392n-butylCH3CH34-CH3PhCH3About
393n-butylCH3Et4-CH3PhNAbout
394n-butylCH3Ph4-CH3PhNAbout

No.R1R2R3R4R5X
395n-butylCH3Och2CH32,4-di-CH3PhNAbout
396n-butylClCH3NAbout
397n-butylClCH3NAbout
398n-butylClP NAbout
399n-pentylNNCH3NAbout
400n-pentylNNCH3NS
401n-pentylNNEtNAbout
402n-pentylNNcyclopentylNAbout
403n-pentylNNcyclopentylNS
404n-pentylNNcycloheptylNAbout
405n-pentylNNPhNAbout
406n-pentylNNPhNS
407n-pentylNN2-furylNAbout
408n-pentylNN2-(5-CF3 )furylNAbout
409n-pentylNN2-thienylNAbout

No.R1R2R3R4R5X
410n-pentylNn3,4-di-Cl PhHO
411n-pentylNCH3n-butylHO
412n-pentylNCH3n-butylHS
413n-pentylNSnzHO
414n-pentylNCH3PhOCH2HAbout
415n-pentylNCH3PhCH2OCH2HAbout
416n-pentylNEt2-FPhAbout
417n-pentylNEt2-FPhHS
418n-pentylN4-CH3Ph2-FPhHAbout
419n-pentylCH3Et4-CH3PhHAbout
420n-pentylClCH3n-butylHAbout
421n-pentylClCH3PhHAbout
422n-pentylClCH3PhHS
423n-pentylClCH34-PhPhHAbout
424n-pentylClCH3HAbout
425n-pentylClCH3ClAbout

No.R1R2R3R4R5X
426n-pentylPrCOCH34-CH3PhPrCOAbout
427n-pentylPhCH33-BrPhNAbout
428n-pentyl2-thienylCH33-BrPh2-thienylAbout
429n-hexylNN2-FPhNAbout
430n-hexylNCH3cyclopentylNAbout
431n-hexylNCH3cycloheptylNAbout
432n-hexylNCH32-FPhNAbout
433n-hexylNCH32-FPhNS
434n-hexylNEt 2-FPhNAbout
435n-hexylNn-propyl2-FPhNAbout
436n-hexylNisopropyl2-FPhNAbout
437n-hexylNPh2-FPhNAbout
438n-hexylCH3COCH32,4-di-CH3PhNAbout
439n-hexylCH3Och2CH32,4-di-CH3PhNAbout
440n-hexylPhEtPhNAbout
441n-hexylPhEtPhNS
442n-hexylPhEt4-pyridylNAbout

No.R1R2R3R4R5 X
443n-hexylBrEtPhBrO
444n-hexylBrEt2-FPhBrO
445cyclopropylNNcyclopentylHAbout
446cyclopropylNN2,4-di-ClPhHAbout
447cyclopropylNNHAbout
448cyclopropylNCH33-FPhHAbout
449cyclopropylNCH33-FPhHS
450cyclopropylNCH3HAbout
451cyclopropylNEtHAbout
452cyclopropylN n-propyl4-CF3PhHAbout
453cyclopropylNisopropylPhHAbout
454cyclopropylNisopropyl3-pyridylHAbout
455cyclopropylNn-butyl4-CF3PhHAbout
456cyclopropylNn-hexylPhHAbout
457cyclopropylNn-hexyl4-CF3PhHAbout
458cyclopropylNPhPhHAbout

No.R1R2R3R4R5X
459cyclobutylNCH34-CH3PhNAbout
460cyclobutylNEt NAbout
461cyclobutylNEtNAbout
462cyclobutylNEtNAbout
463cyclobutylNEtNAbout
464cyclobutylNEtNAbout
465cyclobutylN4-F PhNAbout
466cyclobutylClCH33-ClPhClAbout
467cyclobutylClCH33-ClPhClS
468cyclopentylNN3-CF3PhNAbout
469cyclopentylNSN 32,4-di-CF3PhNAbout
470cyclopentylNCH32,4-di-CF3PhNS
471cyclopentylNn-butylNAbout
472cyclopentylN3-F Ph4-CH3PhNAbout

cyclopentyl
No.R1R2R3R4R5X
473cyclopentylCH3CH3PhNAbout
474cyclopentylCH3CH33,5-di-ClPhNAbout
475cyclopentylCH3CH3PhNS
476cyclopentylEtCH3PhNAbout
477ClCH3PhClAbout
478cyclopentylClCH3PhClS
479cyclohexylNN3-FPhNAbout
480cyclohexylNN2,4-di-CH3PhNAbout
481cyclohexylNNNAbout
482cyclohexylNCH3n-propylNAbout
483cyclohexylNCH3n-propylNS
484cyclohexylNCH3NAbout
485cyclohexylNCH33-ClPhNAbout
486cyclohexylNCH 3-ClPhNS
487cyclohexylNCH3NAbout
488cyclohexylNEtNAbout

No.R1R2R3R4R5X
489cyclohexylNn-propyl4-CF3PhNAbout
490cyclohexylNn-propyl3-pyridylNAbout
491sikorksyNisopropylPhNAbout
492cyclohexylNisopropyl3-pyridylNAbout
493cyclohexylNn-butyl3-ClPhNAbout
494cyclohexa the Nn-pentyl3-ClPhNAbout
495cyclohexylNn-hexyl4-CF3PhNAbout
496cyclohexylN4-F PhPhNAbout
497cyclohexylCH3CH33-CH3PhNAbout
498cyclohexylCH3CH33-CH3PhNS
499cyclohexylCH3Et3-pyridylCH3About
500cyclohexylEtCH32-F-4-CF3PhEtAbout
501cyclohexyl2-thienyli-Pr3-pyridylNAbout
502cyclohexylClCH32,3-di-CH3PhNAbout
503cyclohexylCl CH32,3-di-CH3PhNS
5042-propenylNNCH3NAbout

No.R1R2R3R4R5X
5052-propenylNNIsopentylNAbout
5062-propenylNNcheckpointerNAbout
5072-propenylNNPhNAbout
5082-propenylNNPhNS
5092-propenylNN2-genoliniNAbout
5102-propenylNNNAbout
5112-propenylNCH3 NAbout
5122-propenylNCH32,4-di-FPhNAbout
5132-propenylNCH32,4-di-FPhNS
5142-propenylNCH32-F-4-CF3PhNAbout
5152-propenylNEt2-naphthylNAbout

No.R1R2R3R4R5X
5162-propenylNEt2-naphthylHS
5172-propenylNEtHO
5182-propenylNEtHO
5192-propenylNn-propyl 2-F-4-CF3PhHAbout
5202-propenylNPh2,4-di-CF3PhHAbout
5212-propenylN4-F Ph2-F-4-CF3PhHAbout
5222-propenylCH3EtHAbout
5232-propenylClCH33-CF3PhClAbout
5242-propenylClCH33-CF3PhClS
5252-propenylBrEt3-CF3PhBrAbout
5262-IsobutanolNN3-pyridylHabout

No.R1R2R3R4R5X
5272-IsobutanolNN HO
5282-IsobutanolNCH34-(CF3O)PhHO
5292-IsobutanolNCH34-(CF3O)PhHAbout
5302-IsobutanolNCH34-(CF3O)PhHS
5312-IsobutanolNn-butyl4-(CH3O)PhHAbout
5322-IsobutanolNn-butyl(4-F-Ph)OCH2HAbout
5332-IsobutanolNn-butyl(4-CH3Oh)PhCH2CH2HAbout
5342-IsobutanolNPh2-thienylHAbout
5352-IsobutanolN4-FPhPhHAbout
5362-IsobutanolCH3COPhqi is logical HAbout
5372-IsobutanolCH3COPh3-F PhHAbout

oraday No.R1R2R3R4R5X
5384-pentenylNCH3PhHO
5394-pentenylNCH3PhHS
5405-hexenylNNPhHO
5415-hexenylNCH32-FPhHO
5425-hexenylNCH32-FPhHS
5435-hexenylNCH3HO
5445-hexenylNisopropyl4-(CF3O)PhH About
5455-hexenylNPh4-(CF3O)PhHAbout
5465-hexenylCH3AboutCH32-CH3PhCH3COAbout
547CH3AboutNNcyclobutylHAbout
548CH3AboutNN2,4-di-FPhHAbout
549CH3AboutNN(4-CH3)PhCH2HAbout
550CH3AboutNN2-genoliniHAbout
551CH3AboutNCH3CH3HAbout
552CH3AboutNCH3CH3HS
553CH3AboutNCH33-CF3PhHAbout

No.R1R2R3R4R5X
554CH3AboutNCH32-furylNAbout
555CH3AboutNCH32-furylNS
556CH3AboutNCH32-thienylNAbout
557CH3AboutNCH33-(4-(och3)thienyl)NAbout
558CH3AboutNCH3NAbout
559CH3AboutNn-propyl4-(CF3O)PhNAbout
560CH3AboutN4-F Ph4-(CF3O)PhNAbout
561CH3AboutBrisobutyl3-CF3PhBrAbout
562CH3AboutNCH3NAbout
563EtO3-F PhEtcyclopentylNAbout
564EtONNCH3NAbout
565EtONNCH3NS
566EtONN3,4-di-CH3PhNAbout
567EtONCH3n-propylNAbout
568EtONCH3cyclobutylNAbout
569EtONCH3cycloheptylNAbout
570EtONCH3cycloheptylNS
571EtONCH3N About
572EtONCH33,4-di-FPhNAbout
573EtONCH3NAbout
574EtONn-butyl2-thienylNAbout
575EtONPh2-thienylNAbout
576EtOCH3CH34-BrPhNAbout
577EtOClCH3n-hexylNAbout
578EtOClCH32-ClPhNAbout
579EtOClCH32-ClPhNS
580EtOCln-butylPhClAbout

No.R1R2 R3R4R5X
581(i-Pr)OHHCH3NAbout
582(i-Pr)OHHCH3NS
583(i-Pr)OHH3,5-di-ClPhNAbout
584(i-Pr)OHCH3NAbout
585(i-Pr)OHCH33-Cl-5-FPhNAbout
586(i-Pr)OHCH33-Cl-5-FPhNS
587(i-Pr)OHCH3NAbout
588(i-Pr)OHisopropyl4-BrPhNAbout
589(i-Pr)OH4-F Ph3,4-di-FPhNAbout
590(i-Pr)OCH Et2-thienylNAbout
591(i-Pr)OCH3COEt2-thienylCH3COAbout
592(i-Pr)OCl3-F Ph2,4-di-FPhClAbout
593n-BuOHHcyclopentylNAbout
594n-BuOHHcyclooctylNAbout
595n-BuOHHcyclooctylNS
596n-BuOHEtcyclooctylNAbout
597n-BuOHEtPhNAbout
598n-BuOHEt2,4-di-FPhNAbout
599n-BuOHEtPhOCH2NAbout
600n-BuOHisopropylcycloalkylN About
601n-BuOHn-hexylcyclooctylNAbout
602n-BuOCH3CH33,5-di-FPhNAbout
603n-BuOPrCOEt3,5-di-CH3PhNAbout
604n-BuOBrPhcyclooctylBrAbout
605(H-pentyl)OHCH33-Br PhNAbout

No.R1R2R3R4R5X
606(n-pentyl)ONCH33-Br PhHS
607(n-pentyl)ONCH32-naphthylHO
608(n-pentyl)ONCH3HO/td>
609(n-hexyl)ONCH3cyclopropylHAbout
610(n-hexyl)ONCH3n-pentylHAbout
611(n-hexyl)ONCH33-Br PhHAbout
612(n-hexyl)ONCH32-naphthylHAbout
613(isohexyl)OCH3Och2EtPhHAbout
614(isohexyl)OCH3Och2EtPhHS
615CO2NNN3,5-di-ClPhHAbout
616CO2NNCH33,5-di-ClPhHAbout
617CO2NNcutPhHAbout
618CO2NNdrunk HAbout
619CO2NNCH3PhHAbout

No.R1R2R3R4R5X
620CO2NHCH3NAbout
621CO2NHCH3NAbout
622CO2NCH3CH33,5-di-ClPhNAbout
623CO2NCH3isopropyl3-BrPhNAbout
624CO2NCH3isopropyl3-BrPhCH3About
625CO2NCH34-F PhcutNAbout
626CO2NEtN4-FPhNAbout
627CO2NEtN4-FPhEtAbout
628CO2NEtCH34-FPhEtAbout
629CO2NEtcutPhNAbout
630CO2NEtcutPhNS
631CO2NPhCH32-furylNAbout
632CO2NPhCH32-furylNS
633CO2N3-Br PhPh2-thienylNAbout
634CO2Nn-PrCON3-ClPhNAbout
635CO2Nn-PrCON3-pyridylNAbout
636CO2Nn-PrCONNAbout
637CO2Nn-PrCOCH33-ClPhNAbout
638CO2Nn-PrCOCH33-ClPhn-PrCOAbout
639CO2Nn-pencilsPh3-ClPhNAbout

Salt of the compounds of formula I can be obtained in situ during the final isolation and purification of the compounds or by introducing purified compounds used in the form of a free base, in a reaction with a suitable organic or inorganic acid and the allocation thus obtained salt. Similarly, when the compound of formula I contains a carboxylic fragment (e.g., R=H), salt of the compounds of formula I can be obtained by a separate introduction into reaction with a suitable organic or inorganic acid and the allocation thus obtained salt.

The term "pharmaceutically acceptable salt" refers to the relatively non-toxic molecular salt with an inorganic or organic acid compounds correspond to the him present invention (see, for example, Berge et al., J. Pharm. Sci. 66:1-19, 1977).

Typical salts of the compounds of formula I include conventional non-toxic salts and the Quaternary ammonium salts which receive, for example, from inorganic or organic acids or bases by methods well known in the art. Such molecular acid salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, bansilalpet, bisulfate, butyrate, citrate, comfort, camphorsulfonate, cinnamate, cyclopentanepropionate, gluconate, dodecyl sulphate, aconsultant, fumarate, glucoheptonate, glycyrrhizinate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate etc.

Basic salts include, for example, alkali metal salts, such as salts of potassium and sodium, alkaline earth metals such as calcium salts and magnesium, and ammonium salts with organic bases, such as dicyclohexylamine and N-methyl-D-glucamine. In addition, nitrogen-containing basic groups in the dual basis can be converted into a Quaternary compounds using such agents as lower Alky the halides, such as methyl-, ethyl-, propyl - and butylchloride, -bromides and iodides; diallylsulfide, such as dimethyl-, diethyl - and dibutylaniline, and dimycolate, halides with long chains, such Cardell-, lauryl-, myristyl and sterilgarda, -bromides and iodides, arylalkylamine, such as benzyl and phenetermine, etc.

Esters of formula I in the present invention are non-toxic, pharmaceutically acceptable esters, for example, alkyl esters, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentalonia esters. You can use the additional esters such as methyl ester or phenyl-C1-C5-alkyl. The compounds of formula I can be atrificial using many different techniques, including the introduction of a suitable anhydride, carboxylic acid or carboxylic acid with the alcohol group of the compounds of formula I. To facilitate acylation with a suitable anhydride, you can enter into reaction with alcohol in the presence of a base such as 1,8-bis[dimethylamino]naphthalene or N,N-dimethylaminopyridine. Suitable carboxylic acid can be introduced into the reaction with alcohol in the presence of a dehydrating reagent such as DICYCLOHEXYL-carbodiimide, 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide or other soluble in the de dehydrating reagents, used for the reaction by removing water, and, optionally, in the presence of an acylation catalyst. The esterification can also be carried out using an appropriate carboxylic acid in the presence of triperoxonane anhydride and, optionally, pyridine, or in the presence of N,N-carbodiimide with pyridine. The reaction of carboxylic acid with alcohol can be carried out with the use of acylation catalyst such as 4-DMAP or pyridine.

Specialist in the art should know how to successfully implement these and other methods of esterification of alcohols.

In addition, during implementation of any of the above methods of obtaining esters to sensitive or reactive groups of the compounds of formula I may be required to attach or remove the protective group. Typically, the protective group can be attached or removed by conventional means, well known in the art (see, for example, .W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis; Wiley: New York, (1999)).

Depending on the position and nature of the various necessary substituents of the compounds of formula I can contain one or more asymmetric centers. The asymmetric carbon atoms can exist in the (R)- or (S)-configuration. Preferred are isomers with so is th absolute configuration, which give the compounds of formula I possessing more desirable biological activity. In some cases, the asymmetry may occur due to slow rotation around the connection, such as the Central link connecting the two aromatic rings of the given connection.

The substituents at the ring may be in CIS - or TRANS-form, and the substituents at the double bond may be in Z - or E-form.

It is assumed that the scope of the present invention includes all isomers, including enantiomers and diastereoisomers), the presence of which is due to the nature of asymmetric centers or braked rotation, as described above, in the form of separated, pure or partially purified isomers or racemic mixtures. Cleaning of these isomers and the separation of these mixtures of isomers can be accomplished by standard techniques known in the art.

The specific method used to obtain the compounds of the present invention depends on the specific connection. All such factors as the choice of a specific fragment X and the specific substituents, possible for different positions in the molecule play a role in the scheme of obtaining specific compounds of the present invention. These factors can be easily installed by a specialist with the soup preparation in this field of technology.

Typically, compounds corresponding to the present invention, can be obtained using standard techniques known in the art, and using similar methods. The compounds of formula I can usually be synthesized according to the Schemes of reactions 1, 2 and 3. The scheme of reactions 1 and 2 show how to obtain intermediate products using combinations shown in the reaction Scheme 3, lead to compounds of formula I.

Path (a) reaction Scheme 1 represents a method of obtaining compounds 4 and 5, in which R" means C1-C6lower alkyl or benzyl, R3means not hydrogen and X means Acting On the first stage shows the protection of the acid group sales derived aspartate 1 using a method well known in the art, such as, for example, salelologa of ester and subsequent N-acylation corresponding derivative of R4-acid, R4COY where Y means useplease group, such as halide. In conclusion, the connections remove the protective group, in a manner well known in the art, such as, for example, in the case salelologa of ester, water treatment with obtaining compound 2. Alternatively, the condensation of a protected form of compound 1 with a free carboxylic acid, such as R4COOH, in the presence of digid tiraumea reagent, such as DCC or EDCl, also gives compound 2. After that, connection 2 in several ways can be converted into compound 3 in which R3is as defined for compounds of formula I. for Example, one such method, when R3=Me, is a well-known reaction Dakine-Vesta, which is usually carried out using acetic anhydride and pyridine. If R3means not hydrogen, compound 2 can be converted into the acid chloride acid using a reagent such as thionyl chloride, and enter into reaction with the Grignard reagent, such as R3Mg-halogen, to obtain compound 3. You can use other ways to obtain a ketone compound 3 from acids and acid derivatives, for example, through the use of amides Weinrebe known to specialists in this field of technology. Then the connection 3 cyclist in the acidic environment in the conditions of dehydration using, for example, phosphorus oxychloride or a mixture of sulfuric acid with acetic anhydride, usually by heating, and receive connection 3, in which X is O and R3attached in position 5.

Experts in the art should understand that the connection 4 and the connector 5 can exist in two regioisomeric forms depending on the point of attachment of groups R3CH2CO2R" and CH2 CH2OH. By using the path () you can obtain a connection 4, in which R3attached in position 4 and carboxymethylate side chain attached at position 5, i.e. in comparison with by (A) the groups were reversed. By using the path (In) selling amino acid, compound 6 can be allievate in an alkaline medium, for example using aqueous sodium hydroxide solution, using a suitable derivative of R4acids (for example, R4COY), where Y means useplease group, such as chloride, to obtain the N-acylated product 7. Connection 7 you can then enter in the reaction mix with a complex ester of acetic acid in the presence of strong dinucleophiles Foundation and receive complex ketoester 8, in which R" means C1-C6alkyl or benzyl. Cyclization of compound 8 using a dehydrating reagent, such as POCl3that gives compound 4, in which X=O and R3attached in position 4. The reaction of compound 8 with sulfur-containing nucleophilic reagent, such as P2S5in solvents such as pyridine or acetonitrile/triethylamine, if necessary with heating, gives compound 4, in which X=S and R3attached in position 4.

Path (C) Scheme of reactions 1 represents the connection 4 of the complex ketoesters 9 or 10, where Y means otscheplaut is uwsa group, such as a halide, and R" means C1-C6alkyl or benzyl. Connection 9 or 10 can be selected as the initial substance in matter, does the group R3in the sought final product hydrogen or she is attached in position 4 or 5. In accordance with this, the connection 9 or 10, you can enter into reaction with Amida or thioamides, where X is O or S, and to obtain compound 4. Complex ketoesters 9 or 10 are commercially available or can be obtained by methods well known in the art, such as bromirovanii sales ketoesters 9 or 10, in which Y represents hydrogen. Amides (R4C(=X)NH2), where X is Oh, can be corrupt inorganic salts of carboxylic acids or can be obtained from the relevant sales acids or anhydrides of the acids, are well known ways. Thioamides (R4C(=X)NH2), where X is S, can be sales thioamides or they can be obtained from the relevant sales amides by known methods such as a method using a reagent of Lawesson. The reaction of complex keeeper 9 amidon or thioamides in the presence of base gives compound 4, i.e. oxazole or thiazole, respectively, where R3means not hydrogen and is located in position 4. The reaction of complex keeeper 10 amidon or thioamides in the presence of base gives the the group of 4, i.e. oxazole or thiazole, respectively, where R3is located in position 5.

All paths (A), (b) and (C) lead to the connection 4, in which R3and R4are as defined for compounds of formula I, in which R" means lower alkyl or benzyl. Then compound 4 can be restored in connection 5 with the use of reductive reagent, such as alumalite lithium, borohydride lithium or other suitable hydrogen donors under conditions well known in the art.

The reaction scheme 1

In the reaction Scheme 2 presents the transformation of the sales hydroxyketone 11 derived with a protective group 12 by reaction with R7-Y in the presence of a base, where R7means C1-C6alkyl, optionally containing as a substituent a phenyl or oxoprop,1-C6trialkylsilyl, arylalkyl or COR8; and R8means C1-C6alkyl or phenyl, optionally containing as a substituent With1-C6alkyl, halogen or nitro-group; and Y means useplease group. "C1-C6trialkylsilyl" means three independently selected linear or branched chain alkyl group containing from 1 to about 6 carbon atoms, each of which is connected with the silicon, and includes such g is PI, as trimethylsilyl, tert-butyldimethylsilyl etc. "Killkillkill" means at least one phenyl or substituted phenyl group associated with silicon, with a corresponding number of independently selected linear or branched chain alkyl groups containing from 1 to about 6 carbon atoms, each of which is connected with the silicon, and includes groups such as tert-butyldiphenylsilyl, methyldiphenylamine, dimethylpentanenitrile etc. "Useplease group" includes a halide, such as I, Br and Cl; carboxylates, such as acetates and triptoreline, and aryl - and alkyl sulphonates, such as methanesulfonate (mesylates) and p-toluensulfonate (tozilaty), etc.

In the connection 12 of the substituents R2(as shown in the formula (I) impose, for example, through reaction with a source of electrophilic halogen or reactions Friedel-in the presence of a Lewis acid and R2-Y, where Y is as described above, to obtain the substituted ketone 13. Alternatively, halogenated compounds thus obtained (for example, bromine or iodine as the substituents), you can enter in the reaction mix with a variety of components during the catalysis with compounds of metals with the use of the complexes and compounds of elements such as palladium and Nickel, a well-known special is Stam in the art, obtaining substituted ketone 13. Examples of such catalysts include tetrakis(triphenylphosphine)-palladium(O) and [1,1'-bis(diphenylphosphino)-ferrocene]-dichloropalladium(And) and similar compounds of Nickel(O) and Nickel(II); and examples of the components for the reaction combinations include boranova acids and esters (a well-known combination Suzuki carried out in solvents, such as toluene, in the presence of a base such as potassium carbonate), and ORGANOMETALLIC compounds such as Grignard reagents, tsinkorganicheskih connection (combination Negishi) and ORGANOTIN derivatives (the combination of the Steele), and conditions for such reactions are well known. In addition, such halogenated compounds can be introduced into the reaction mix with secondary amines such as piperidine, using the same palladium or Nickel catalysts (a combination of Hartwig or Buchwald) with other substituted ketones 13.

Subsequent reaction of compound 13 with a source of halogen or R5-Y (where R5is the same as described for formula (I) under similar conditions gives the disubstituted compound 14. The Wittig reaction or modified Horner-Emmons-Wadsworth, known in the art, can be used to turn 14 in connection 15. For example, the reaction of compound 14 with trialkylphosphine-and what Etat, where R" means lower alkyl and R is as described for formula I, in the presence of a strong base such as sodium hydride, gives compound 15. Similarly, the connection 13 can be converted to compound 15, where R5means N.

Regardless of what mixture of isomers of compound 15 is obtained, any isomer (E or Z) or a mixture of both of them can be turned into connection 17 by catalytic hydrogenation or restore hydride reagent capable of 1,4-accession (paired), which is known to specialists in this field of technology. This path is particularly suitable for connection 17 in which R1means hydrogen.

The connection 17 in which R1means COOR, can be obtained using standard condensation reactions, for example, using well known reactions knoevenagel. In such cases, the ketone 13 or 14 you can enter into reaction with a suitable component reaction mix containing active hydrogen when exposed to acidic reagents, such as titanium tetrachloride, or basic reagents, such as piperidine, in a suitable solvent. Product 15b (compound 15, in which R1means COOR can be recovered in 17b (compound 17 in which R1means COOR), which can optionally be alkilirovanii other group R1in the presence of bases of the tion, to hydrolyze and decarboxylate obtaining 17d (compound 17 in which R1means not COOH and R is H).

Transesterification 17d and the removal of the protective group R7gives 17c. The transesterification can be performed under standard conditions using the well-known Fischer esterification by treatment with acid and alcohol, or by reaction with diazoalkanes reagents or with electrophilic reagents such as, for example, methyliodide or dimethylsulfate. The connection 17 in which R1means alkoxyl, you can get a similar reaction of condensation of ketone 13 or 14 with similarbank complex enol ether of formula R1CH=C(OR') O-alkylsilane, in which R1means alkoxyl, when exposed to acidic reagents, such as titanium tetrachloride, and the restoration of intermediate compound 15, in which R1means alkoxy, in the presence of hydrogen and catalyst, as described above.

The overall reaction of the combination of compound 13 or 14 by the reaction of the reformed gives compound 16 (formula II)in which R1means alkyl or connection 15A, in which R1means N. Ketone condensate with a suitable tsinkorganicheskih compound obtained in situ from Zn and R1CHYCO2R in which Y represents halogen. Alpha-halogen-substituted esters of the formula R1CHYCO2R or are prodain the mi reagents, or get halogenoalkanes sales connections R1CH2CO2R ways, well known to specialists in this field of technology.

Turning 16 and 17 can be performed in standard conditions of hydrogenation, for example using Pd/C and hydrogen; and removing the protective group of compound 17 in which R7means a protective group to obtain compound 17c, in which R7means hydrogen, can be accomplished by standard means. For example, if the group R7means alkyl (e.g. methyl), the connection 17A can be obtained by nucleophilic cleavage by using a reagent, such as tilt alkali metal. Alternatively, the connection 17 in which R7means methyl, can be converted into a compound 17c by reaction with a Lewis acid, such as bromo-borane. If R7means benzyl, the connection 17 can be turned into 17c in the conditions of the hydrogenation is usually carried out using a catalyst, such as palladium. Other conditions for removal of the protective group R7from the connection 17 in which R7means not hydrogen, leading to hydroxycodone 17c, depend on the particular protective group selected from among well-known to specialists in this field of technology.

The scheme of reactions 2

Notes:

A. (R"O)2 P(=O)CHR1COOR, where R1=N, a strong base.

b. R1CH2COOR, where R1=COOR, acidic or basic catalyst.

C. R1CHBrCO2OR, Zn.

The final stage of preparing compounds of formula I is shown in reaction Scheme 3. Alcohol 5 (Scheme of reactions 1) is introduced into the reaction mix with hydroxyindole 17c (from the Scheme of reactions 2) by the reaction of a combination of Mitsunobu, the occurrence of which contribute azodicarboxylate reagent, such as DEAD, and a phosphine, such as triphenylphosphine, and get the compounds of formula I. Alternatively, the hydroxy-group of compounds 5 turn in useplease group, such as halide, tosylate (OTs) or mesilate (OMs), by reaction with a halogenation reagent such as thio-Nellore or CCl4/triphenylphosphine; or by reaction with a compound Y is halogen, in which Y means tosyl (Ts) or mesyl (Ms), in the presence of a base and get a connection 18. Compound 18 can enter into reaction with the compound 17c in the presence of a base to obtain the compounds of formula I.

The compounds of formula I in which R is alkyl, can be converted into compounds of the formula I, in which R is H by treatment with base (e.g., KOH) in a suitable solvent (such as methanol, THF or water or their mixtures) when heated. Alternatively, this transformation can be carried out by reaction with a nucleophile, such as iodide or C is and, in a suitable solvent, such as pyridine. In addition, if R is benzyl, then cleavage with formation of compounds of the formula I, in which R means H can be achieved by hydrogenolysis using methods well known in the art.

The reaction scheme 3

An alternative way of obtaining compounds of the formula I used, when X=S and R4contains one or more substituents R6unsustainable in terms of conducting the reaction according to Scheme 1 or 2, is shown in the reaction Scheme 3A.

The reaction scheme 3A

Scheme 3A 2-aminothiazol 4 can be obtained by using thiourea (similar path, reaction Scheme 1) and turn it into a 2-halogentated 5A, as shown above (Erienmeyer et al., Helv. Chim. Acta 28:362-363,1945). It is then the combination of 5A on Mitsunobu in a manner analogous to the reaction Scheme 3, and for the introduction of a substituent R4product 19 is additionally injected into the cross-reaction mix, catalyzed by palladium. The hydrolysis is carried out as shown in reaction Scheme 3, gives the compounds of formula I in which R=N.

The above reactions is additionally illustrated by the specific Examples described in the present invention.

Salts and esters corresponding to the present image is the shadow, it is easy to obtain using a conventional chemical methods described above in the present invention.

The present invention also relates to new compounds of the formula II (compound 16) and formula III (compounds 17, including compounds 17a-d), shown in reaction Scheme 2. These compounds are applicable for producing compounds of the formula I and additionally described below.

This connection comprises the compounds of formula II and formula III,

where

R, R1, R2, R3, R4, R5, R6and X are as defined above for formula I; and R7means H, C1-C6alkyl, optionally containing as a substituent a phenyl or oxoprop, C1-C6trialkylsilyl, arylalkyl, COR8, COOR8or

;

R8means C1-C6alkyl or phenyl, optionally containing as Deputy C1-C6alkyl, halogen or nitro-group; and their salts.

C1-C6trialkylsilyl means of three independently selected linear or branched chain alkyl group containing from 1 to about 6 carbon atoms, each of which is connected with the silicon, and includes groups such as three-methylsilicone, tert-butyldimethylsilyl etc.

And iliskileri means at least one phenyl or substituted phenyl group, associated with silicon, with a corresponding number of independently selected linear or branched chain alkyl groups containing from 1 to about 6 carbon atoms, each of which is connected with the silicon, and includes groups such as tert-butyldiphenylsilyl, methyldiphenylamine, dimethylpentanenitrile etc.

Salt corresponding to the present invention can be easily obtained using conventional chemical techniques described above in the present invention.

Depending on the position and nature of the various necessary substituents of the compounds of formula II and formula III can contain one or more asymmetric centers. The asymmetric carbon atoms can exist in the (R)- or (S)-configuration. Preferred are isomers with such absolute configuration, which give the compounds of formula II or formula III, which would be suitable for producing compounds of formula I possessing more desirable biological activity. In some cases, the asymmetry may occur due to slow rotation around the connection, for example, the Central link connecting the two aromatic rings of the given connection.

The substituents at the ring may be in CIS - or TRANS-form, and the substituents at the double bond may be in Z - or E-form.

It is assumed, Thu is in the scope of the present invention includes all isomers, including enantiomers and diastereoisomers), the presence of which is due to the nature of asymmetric centers or braked rotation, as described above, in the form of separated, pure or partially purified isomers or racemic mixtures. Cleaning of these isomers and the separation of these mixtures of isomers can be accomplished by standard techniques known in the art, and using the new tools described in this invention.

For example, the compounds of formula II may contain asymmetric center (marked as p-2), and the compounds of formula III can contain two asymmetric center (marked as C-2 and C-1'), which leads to the enantiomers and stereoisomers. Examples of these and other compounds of formula II and formula III, which illustrate the present invention, are shown in table 2.

Table 2

Illustrative examples of compounds II and III

t-BuCO
No.FormulaThe absolute configurationR1R2R5R7
C-2C-1'
1IIR-HN NCH3
2IIIRRHNNCH3
3IIR-ClNN1-Bu(CH3)2Si
4IIIRSClNNt-Bu(CH3)2Si
5IIS-HNNCH3
6IIISSHNNCH3
7IIR-CH3NNCH3
8IIIRRCH3NNCH3
9IIS-CH3NNCH3
10IIISRCH3NNCH
11IIR-CH3NNPhCH2
12IIIRSCH3NNPhCH2
13IIS-CH3NNPhCH2
14IIISSCH3NNPhCH2
15IIR-CH3NNt-Bu(CH3)2Si
16IIIRRCH3NNt-Bu(CH3)2Si
17IIS-CH3NNt-Bu(CH3)2Si
18IIR-CH3NNt-BuCO
19IIIRSCH3NN
20IIS-CH3NNt-BuCO
21IIISSCH3nNt-BuCO
22IIR-CH3CH3NPhCH2
23IIR-CH3CH3CONPhCH2

No.FormulaThe absolute configurationR1R2R5R7
C-2C-1'
24IIS-CH32-thienylNt-Bu(CH3)2Si
25IIISRCH32-thienylNt-Bu(CH3)2Si
26IIS CH3PhNCH3
27IIR-CH3ClNCH3
28IISCH3ClNCH3
29IIISSCH3ClNCH3
30IIR-CH3BrNPh(CH3)2Si
31IIIRRCH3BrNPh(CH3)2Si
32IIS-CH3BrNPh(CH3)2Si
33IIISRCH3BrNPh(CH3)2Si
34IIS-CH3ClClCH3
35 IIR-EtHNCH3
36IIIRREtHNCH3
37IIS-EfHNPhCH2
38IIISSEtHNBSN
39IIR-EtHNt-Bu
40IIS-EtHNt-Bu
41IIS-EtCH3NPh(CH3)2Si
42IIISSEtCH3NPh(CH3)2Si
43IIR-Etn-propylNCH3
44IIS-EtPh NCH3
45IIS-Et3-ClPhNt-Bu(CH3)2Si
46IIISREt3-ClPhNt-Bu(CH3)2Si
47IIS-Et4-pyridylNt-Bu(CH3)2Si
48IIISSEt4-pyridylNt-Bu(CH3)2Si
49IIS-EtCH3NPh(CH3)2Si

No.FormulaThe absolute configurationR1R2R5R7
C-2C-1'
50IIR-Etn-propylClCH3
51II-EtBrBrt-Bu(CH3)2Si
52IIIRREtBrBrt-Bu(CH3)2Si
53IIS-CF3CH2NNCH3
54IIS-CF3CH2CH3CH3(4-CH3Oh)PhCH2
55IIISSCF3CH2CH3CH3(4-CH3Oh)PhCH2
56IIS-n-propylNN(i-Pr)3Si
57IIR-n-propylPrCOPrCOt-Bu
58IIR-n-propylClCl(i-Pr)3Si
59IIIRRn-propylClCl (i-Pr)3Si
60IIS-isopropylCH3NCH3
61IIISRisopropylCH3NCH3
62IIR-isopropyln-hexylN(4-CH3Oh)PhCH2
63IIIRSisopropyln-hexylN(4-CH3Oh)PhCH2
64IIS-n-butylNNPhCH2
65IIS-n-butylCH3Och2Nt-Bu(CH3)2Si
66IIISSn-butylCH3Och2Nt-Bu(CH3)2Si
67IIR-n-butylClNCH3
8 IIR-n-pentylClCl(4-CH3Oh)PhCH2
69IIS-n-pentyl2-thienyl2-thienylCH3
70IIISSn-pentyl2-thienyl2-thienylCH3
71IIR-n-hexylCH3CONt-Bu(CH3)2Si
72IIIRSn-hexylCH3CONt-Bu(CH3)2Si

No.FormulaThe absolute configurationR1R2R5R7
C-2C-1'
73IIR-n-hexylPhHPh(CH3)2Si
74IIIR Rn-hexylPhHPh(CH3)2Si
75IIR-cyclopropylHHt-BuCO
76IIS-cyclopropylCH3H(i-Pr)3Si
77IIS-cyclobutylHHCH3
78IIISScyclobutylHHCH3
79IIS-cyclobutylClCl(4-CH3Oh)PhCH2
80IIR-cyclopenCH3H1-Bu(CH3)2Si
81IIIRScyclopentylCH3H1-Bu(CH3)2Si
82IIS-cyclohexylEtEt 3
83IIR-cyclohexyl2-thienylHCH3CO
84IIR-cyclohexylClHCH3
85IIIRRcyclohexylClHCH3
86IIS-2-propenylHH1-Bu(CH3)2Si
87IIR-2-propenylCH3HCH3CO
88IIS-2-IsobutanolCH3COHCH3
89IIS-5-hexenylCH3COCH3COCH3
90IIS-CH3AboutHHPhCH2
91IIISR CH3AboutHHPhCH2
92IIR-CH3About3-F PhH(4-CH3Oh)PhCH2
93IIS-EtOClClPhCH2
94IIISREtOClClPhCH2

S
No.FormulaThe absolute configurationR1R2R5R7
C-2C-1'
95IIR-(i-Pr)OHHPhCH2
96IIIRR(i-Pr)OHHPhCH2
97IIS-(n-pentyl)OCH3Ht-Bu(CH3)2Si
98IIIS(n-pentyl)OCH3Ht-Bu(CH3)2Si
99IIS-CO2HHH(4-CH3O)PhCH2

Another embodiment of the present invention is an improved method of obtaining compounds with special configuration isomers, when this special configuration desired for the desired end product of formula I. an Improved method makes these intermediate compounds are much more significant excess diastereoisomer than was possible previously.

In particular, previously, in the absence of stereocontrol on stage hydrogenation Scheme of reactions 2, hydrogenation of the compounds of formula II in which R1means alkyl, could lead to mixtures of unequal amounts of the products of formula III, in which one pair of enantiomers contained in larger quantities due to the asymmetric nature of the original substance. The separation of such compounds can be achieved by manual separation of the pairs of enantiomers, followed by separation of each enantiomer via recrystallization or chiral HPLC. Preliminary splitting of the original substance to separate the enantiomers leads to mixtures of adenim one enantiomer, which, probably, can be divided.

However, when you must be connected to one predetermined relative configuration, namely, the SYN-form (defined below), the output is low when R1means alkyl, because the conditions under hydrogenation described in the art, can be conducive to the formation of other diastereoisomers (i.e. anti-form).

The desired isomeric configuration obtained with this improved method, represent the SYN-form, when, for example, in the compounds of formulas Va and Vb (shown in the Schemes of reactions 4 and 5) and R9and methylene carbon atom at the 2' position cyclopentane ring or both are under, or above the plane. Anti-diastereoisomer are such compounds in which, for example, R9is above the plane, and the methylene carbon atom at the 2' position is under the plane. Examples of such systems are given below in figure 1 and 2, which blacked out the V-link is used to denote the location links above the plane, and dashed wedge-shaped relationships are used to denote the location links below the plane.

Figure 1. SYN-diastereoisomer formula V

Figure 2. Anti-diastereoisomer formula V

Improved method corresponding to the present invention, network connection in the SYN-form (formula Va and Vb shown in figure 1 and the Schemes of reactions 4 and 5) with a much more significant excess diastereoisomer than usual was possible.

Intermediate compounds used as starting compounds for this method (compound IV on the Schemes of reactions 4 and 5) related to the compounds of formula II (compound 15) in the reaction Scheme 2 can be obtained the same or similar ways. These intermediate compounds under certain conditions you can enter in the reaction and to obtain the compounds of formula V, which are related to the compounds of formula III (compounds 17 and 17A on the reaction Scheme 2), or directly to obtain the compounds of formula I. However, due to the limitations of better ways to complete this method is suitable only some deputies.

Accordingly, the present invention relates to an improved method of obtaining a substantially enriched SYN-form of the compounds of formula V,

where R9means methoxy, optionally containing fluorine as a substituent, With2-C6alkoxy, C1-C6alkyl or C4-C8cycloalkyl, each of which optionally contains as a substituent fluorine,methylenedioxyphenyl, or phenyl, optionally containing as substituent R13;

R10means hydrogen, fluorine, methyl, optionally containing as a substituent fluorine, oxoprop or2-C6alkyl which may be unsubstituted or may contain as substituents C1-C6alkoxyl, oxoprop, fluorine or phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydropyranyl, piperazinil or morpholinyl, each of which may be unsubstituted or may contain as substituents R13,

or

R10means phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydropyranyl, piperazinil or morpholinyl, each of which may be unsubstituted or may contain as substituents R13;

R11means halogen or C1-C6alkyl, optionally containing as a substituent oxoprop;

R12means hydrogen, methyl, optionally containing as a substituent fluorine or oxoprop,2-C6alkyl, neobythites is but containing as a substituent phenyl, fluorine or oxoprop, C1-C6trialkylsilyl, arylalkyl, COR14, COOR14or

R13means fluorine, CF3C1-C6alkyl, optionally containing as a substituent oxoprop or1-C6alkoxyl, optionally containing as a substituent fluorine;

R14means1-C6alkyl or phenyl, optionally containing as Deputy C1-C6alkyl or fluorine;

R15means hydrogen, C1-C6alkyl or phenyl, containing as substituent R13;

R16means methyl, optionally containing as a substituent fluorine, oxoprop or phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinil, morpholinyl, benzofuran, dihydrobenzofuran, benzothiazyl, dihydrobenzofuranyl, indolyl, indolinyl, indazoles, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazole, benzisothiazole, benzodioxolyl, hinely, ethanolic, hintline, enoxaparin, dihydrobenzofuranyl, dihydro shall isotypical or 1,4-benzodioxane, each of which may be unsubstituted or may contain as substituents R13or4-C8cycloalkyl or2-C6alkyl, each of which may be unsubstituted or may contain as substituents : fluorine, methoxy, C1-C6alkoxyl, optionally containing as a substituent a phenyl or C1-C6alkoxyl, oxoprop or phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinil, morpholinyl, benzofuran, dihydrobenzofuran, benzothiazyl, dihydrobenzofuranyl, indolyl, indolinyl, indazoles, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazole, benzisothiazole, benzodioxolyl, hinely, ethanolic, hintline, enoxaparin, dihydrobenzofuranyl, dihydrobenzofuranyl or 1,4-benzodioxolyl, each of which may be unsubstituted or may contain as substituents R13,

or

With2-C6alkyl, which may also contain as a substituent With4-C8cycloalkyl or phenoxy, which may be unsubstituted or contain the quality of the substituents R 6or phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl, tet-Rasool, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinil, morpholinyl, benzofuran, dihydrobenzofuran, benzothiazyl, dihydrobenzofuranyl, indolyl, indolinyl, indazoles, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazole, benzisothiazole, benzodioxolyl, hinely, ethanolic, hintline, enoxaparin, dihydrobenzofuranyl, dihydrobenzofuranyl or 1,4-benzodioxane, each of which may be unsubstituted or may contain as substituents R13,

or

R16means phenyl, naphthyl, furyl, thienyl, pyrrolyl, tetrahydrofuryl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, piperidinyl, tetrahydropyranyl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinil, morpholinyl, benzofuran, dihydrobenzofuran, benzothiazyl, dihydrobenzofuranyl, indolyl, indolinyl, indazoles, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazole, banditti who was Salil, benzodioxolyl, hinely, ethanolic, hintline, enoxaparin, dihydrobenzofuranyl, dihydrobenzofuranyl or 1,4-benzodioxane, each of which may be unsubstituted or may contain as substituents R13or phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolin, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydropyranyl, piperazinil, morpholinyl, pyrimidinyl or phenoxy, each of which may be unsubstituted or may contain as substituents R13and X is O or S;

including hydrogenation of racemic mixtures or dedicated optical isomers of compounds of formula IV,

where the substituents are as defined above, in the presence of a hydrogen source, a catalyst, optionally in the presence of a base.

Significantly enriched SYN-form means that approximately seventy percent (70%) or more of one or both compounds configuration Va or Vb. This is equivalent to not less than about 40% de (excess diastereoisomer) Shin-diastereoisomer. Excess SYN-diastereoisomer is calculated by the following formula:

in which % de (Shin) means the excess of the SYN-diastereoisomer is,

[Shin] means the concentration of SYN-diastereoisomer,

[anti] means the concentration of anti-diastereoisomer,

and in which the %SYN+%anti=100%.

Thus, for a mixture of 70% SYN-diastereoisomer and 30% anti-diastereoisomer by calculation, it is 40% de Shin-diastereoisomer:

40% de (SYN)=70% SYN-diastereoisomer - 30% anti-diastereoisomer.

The catalyst means one of the catalysts based on transition metal, are well known in the art and used for conducting hydrogenation reactions (R.A. Chaloner, Handbook of Co-ordination Catalysis in Organic Chemistry, Butterworth, 1986), and includes homogeneous hydrogenation catalysts. The homogeneous catalyst is a catalyst which is at least partially soluble in the reaction medium and which affects the recovery of the double bond in the presence of hydrogen. Such catalysts include, for example, ClRh[P(Ph)3]3(Wilkinson catalyst), (1, 5cyclooctadiene)-tricyclohexylphosphine(I)-hexaphosphate(1, 5cyclooctadiene)bis(methyldiphenylphosphine)iridium(I)-hexaphosphate(catalysts Grabtree), etc.

Base means compounds having a pKb value sufficient to education /l situ salt with a carboxylic acid (see, for example, Advanced Organic Chemistry, 3rd Ed., Jerry March, pp 220-222). The base used in this reaction may be an inorganic or organically the base and may be soluble in the reaction medium. Such grounds include, for example, mono-, di - and tri-(C1-C6alkyl)amines, such as Isopropylamine, Diisopropylamine, tri-ethylamine, and the like, additional primary amines, such as, for example, cyclohexanemethylamine and ethanolamine, additional secondary amines, such as morpholine and piperidine, and additional tertiary amines, such as, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-diazabicyclo[4.3.0]non-5-ene, as well as inorganic bases such as hydroxides, carbonates, bicarbonates of alkali metals and alkaline earth metals, and an optically active base, such as quinine, cinchonine and (+)- and (-)-alpha-methylbenzylamine.

Such grounds include, for example, chiral bases listed below that are applicable to separate.

The hydrogen source means any means of hydrogen in the reaction medium and includes the use of gaseous hydrogen. The hydrogenation can be conducted in a wide range of hydrogen pressures, ie, for example, from about atmospheric pressure to about 1000 pounds/inch2preferably from about 20 to about 100 pounds/inch2. Suitable for hydrogenation solvents include (without restrictions) proton solvents, such as ethanol, methanol, water, 2-propanol, tert-butanol, methylethanol and the like, and with whom thou art, or, optionally, mixtures thereof with a blending them aprotic solvents, such as TNR, such to at least partially dissolve the hydrogenation catalyst, a base and a source of the substance.

The splitting of the original derivatives indeloxazine acid of formula IV or derivatives indeloxazine acid of the formula V can be made by methods well known in the art, for example, by using as a separating reagent optically active bases, such as, for example, easily available basis, such as quinine, cinchonine or (+)- or (-)-alpha-methylbenzylamine. The choice of base will depend on the solubility characteristics of the resulting salt, so that it was easily possible to carry out separation by differential recrystallization. Separation of salt each enantiomer can be done by selecting the base with the opposite absolute configuration. For example, in the embodiment represented in the reaction Scheme 4, the desired enantiomer IVc or IVd can be separated, and the unwanted isomer can be regenerated in a starting material of the formula IV by racemization in an alkaline environment.

Solvents suitable for the recrystallization are those solvents in which one diastereoisomer salt soluble mixture better than the other, which allows otdeleniye through recrystallization. Such solvents include, for example, acetonitrile, acetone, tert-butanol, 2-propanol, ethanol, methanol and TPI mixtures thereof.

Aqueous solutions of inorganic acids include, for example, solutions commonly used inorganic acids such as hydrochloric and sulfuric, etc.

The method can be carried out using as starting substances, the racemate of the formula IV (see reaction Scheme 4) or the compound of formula V configuration at the asymmetric carbon atom, which corresponds necessary for the final product (see the reaction Scheme 5). Preferably as a source to use a substance containing mainly one configuration, although any method will lead to the desired configuration of the final product (V), mostly enriched SYN-form.

One way of carrying out the method shown in example Scheme of reactions 4 and involves the following stages:

(1) obtain diastereoisomeric salts IVc and IVd by treating IV with a suitable main separating reagent

(2) separation diastereoisomeric salts IVc and IVd using recrystallization in a suitable solvent for recrystallization,

(3) optional selection of individual antipodes IVa and IVb of the separated salts by treatment with an aqueous solution of an inorganic acid, and

(4) repair or separated diastereoisomers the x salts IVc and Vd, or individual antipodes IVa and IVb by hydrogenation in the presence of a homogeneous hydrogenation catalyst, a suitable solvent and substrate, where M+ denotes a cation selected from the group comprising a cation of alkali metal, alkaline earth metal, ammonium and mono-, di - or Quaternary alkylammonium and arylalkylamine, and R9-R12are as defined above.

The enantiomeric purity of the product Va and Vb will meet enantiomeric purity used isomer IVa or IVb, respectively, but the product will not include a significant number of the other (anti)diastereoisomer.

The reaction scheme 4

The second variant implementation of the method shown in the Scheme of reactions 5 and involves the following stages:

(1) recovery interchromosomal acid of formula IV by hydrogenation in the presence of a homogeneous hydrogenation catalyst, a suitable solvent and base,

(2) obtain diastereoisomeric salts Vc and Vd by processing V suitable primary separating reagent

(3) separation diastereoisomeric salts Vc and Vd using recrystallization in a suitable solvent for recrystallization, and

(4) selection of individual antipodes Va and Vb of the separated salts by treatment with an aqueous solution of inorganic to the slots.

The reaction scheme 5

The separation of racemates of compounds of the formula IV or formula V can be accomplished by methods well known in the art, such as chiral HPLC, chiral recrystallization of salts, chiral esters, etc.

Determination of the absolute chirality IVa, IVb, IVc, IVd, Va and Vb can hold a variety of ways known to specialists in this field of technology. Under certain strictly defined conditions, such information can provide x-ray crystallographic methods. For example, this determination can be done in the presence of a crystallographic unit cell of another component with known chirality, such as chiral separating reagent or auxiliary connection in the form of a salt, complex or group attached through covalent bonds. Another method known in the art, the scattering of a heavy atom, can be used when the analyzed compound contains an atom that has sufficient mass (for example, bromine atom or iodine). You can also use other methods based on optical characteristics, and using the plane-polarized light. In particular, the specialist in the art will understand that, for a given structure or structural class can be used is designed such methods, as circular dichroism.

Specific examples of intermediate products that can be obtained in a way consistent with the present invention are given below as examples, and not to impose restrictions and can be used to obtain the compounds of formula I, having the same absolute configuration.

The compounds of formula III in which R1=N, can also be obtained according to the scheme of obtaining optically active compounds using methods, a summary of which is presented in reaction Scheme 6. The selection of racemic complex ester 17A (formula III in which R1means N) can be achieved by selective enzymatic hydrolysis using lipase PS (Amano) and get 17f. Alternatively, e, which can be obtained by hydrolysis 17A, can be distinguished by recrystallization diastereoisomeric salts formed with optically active amines, for example, (S)-(-)-α-methylbenzylamino, with subsequent regeneration of the carboxylic acid by treatment of the salt with inorganic acid. Subsequent conversion 17f in intermediate products 17g and 17h can be made by methods similar to those described for obtaining 17c in the reaction Scheme 2: transesterification and the removal of the protective group R7.

The scheme of reactions 6

Link the formula I effective in the treatment of diabetes mellitus type II (including associated diabetic dyslipidemia and other diabetic complications), as well as for a number of other applications in the pharmaceutical industry, such as hyperglycemia, hyperinsulinemia, impaired glucose tolerance, the violation level of fasting blood glucose, dyslipidemia, hypertriglyceridemia, syndrome X and insulin resistance. In addition, the compounds corresponding to the present invention is also effective for the regulation of appetite and food intake in such diseases as obesity, and for the treatment of atherosclerotic disease, hyperlipidemia, hypercholesterolemia, low HDL levels, hypertension, cardiovascular disease (including atherosclerosis, coronary heart disease, coronary artery disease and hypertension), cerebrovascular disease and peripheral vascular disease; and for the treatment of lupus, polycystic ovary syndrome, carcinogenesis, and hyperplasia. The compounds of formula I are also applicable for treating physiological disorders related to, for example, differentiation of cells for producing accumulating lipids of cells, regulation of insulin sensitivity and glucose levels in the blood that are involved, for example, in the abnormal function of the beta cells of the pancreas, which secretes insulin tumors and/or autoimmune hypoglycemia due to the presence of autoantibodies to insulin, autoantibodies to the insulin receptor, or autoantibodies that stimulate the beta cells of the pancreas, with the differentiation of macrophages, which leads to the formation of atherosclerotic plaques, inflammatory response, carcinogenesis, hyperplasia, adipocyte gene expression, differentiation of adipocytes, reduced weight β-cells of the pancreas, insulin secretion, tissue sensitivity to insulin, cell growth liposarcoma, polycystic ovarian syndrome, chronic anovulation, hyperandrogenism, produced progesterone, steroidogeneza, redox potential and oxidative stress in cells, synthase nitric oxide (SOA), catalase, triglyceride plasma levels of HDL and LDL cholesterol, etc.

Particularly useful compounds of the formula I, disclosed in this invention are those which are effective to reduce the concentration of blood glucose and levels of triglycerides in the plasma and to increase levels of HDL cholesterol in plasma.

Therefore, it is expected that compounds of the formula I, corresponding to the present invention will be useful as drugs. In accordance with this variant implementation of the present invention includes a method of treating various pathological conditions specified above, the patient (including mammals), which includes the introduction of the indicated patient a composition containing a radically the creation of the compounds of formula I, which is effective in the treatment of the relevant pathological conditions.

As mentioned above, the compound of the formula I can be entered separately or in combination with one or more hypoglycemic agents. Combination therapy includes the introduction of a single pharmaceutical dosage composition which contains a compound of the formula I and one or more hypoglycemic agents, and the introduction of the compounds of formula I and each additional hypoglycemic agent in its own pharmaceutical dosage composition. For example, the compound of formula I and hypoglycemic agent can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent can be administered in separate oral dosage compositions.

If there are separate dosing of the composition, the compound of formula I and one or more additional hypoglycemic agents can be entered almost at the same time (for example, simultaneously or separately at different times (i.e. sequentially).

For example, the compound of the formula I can be introduced in combination with one or more of the following additional hypoglycemic agents: insulin; biguanidine, such as Metformin or Buford is n; the sulfonylureas, such as acetanilid, hlorpropamid, tolazamide, tolbutamide, glyburide, glipizide, glykeria; or any other agent for enhancing insulin secretion, such as, for example, Repaglinide and nateglinide; inhibitors α-glycosidase, such as acarbose, voglibose or miglitol; or agonists (β3-adrenergic receptors, such as CL-316,243).

The compounds of formula I can also be used in the form of a net basis or in compositions, as well as in research and for diagnostics or as analytical reference standards, etc. that are well known in the art. Therefore, the present invention includes compositions which contain an inert carrier and an effective amount of the compounds of formula I or its salt, or a complex ester. The inert medium is any substance that does not interact with the connection, the carrier of which it is, and which for the connection carrier which it is, acts as a retaining means, means of delivery, provide volume labels to trace the connection, etc. Effective amount of compound is an amount which produces a result or exerts an influence on a given procedure.

The present invention also relates to a method of treatment patologicheskoj the condition of the patient, when the disorder is associated with a physiologically detrimental level of insulin, glucose, free fatty acids (FFA), cholesterol or triglycerides in the blood, including the introduction to the patient a therapeutically effective amount of the compounds of formula I. In another embodiment, the present invention relates to a method of treating a pathological condition of the patient, wherein the disease is associated with a physiologically detrimental level of insulin, glucose, free fatty acids (FFA), cholesterol or triglycerides in the blood, including the introduction to the patient a therapeutically effective amount of the compounds of formula I and also the introduction of a therapeutically effective amount of additional hypoglycemic agent, such as, for example, insulin, biguanidine connection etc.

Since it is known that sulfonylureas and other agents to enhance the secretion of insulin is capable of stimulating the production of insulin, but is unable to influence insulin resistance, and the compounds of formula I are able to influence insulin resistance, it is assumed that the combination of these drugs can be used as a means of treating pathological conditions associated with deficiency of insulin secretion, and insulin resistance. Therefore, the present invention also relates to the FPIC of the Bou treatment of diabetes mellitus type II patients, involving the introduction of a therapeutically effective amount of the compounds of formula I and one or more additional hypoglycemic agents such as sulfonylureas, biguanidines antagonists β-adrenergic receptors, inhibitors α-glycosidase and insulin. In addition, the compounds of formula I can be used in combination with inhibitors of HMG Co-A reductase (statins), bile acid binding resins or derivatives of fibrin acid to improve the lipid profile of patients with dyslipidemia and insulin resistance. The compounds of formula I can also be used in combination with agents that regulate hypertension (for example, inhibitors of the angiotensin converting enzyme (ACE), β-blockers, calcium channel blockers) and body weight of patients suffering from insulin resistance or type II diabetes.

To the following specific examples are presented for illustration of the invention described here, but they should not be construed as in any way limit the present invention.

Examples

HPLC-mass spectroscopy with elektrorazpredelenie (HPLC R-MS), make use of the device Hewlett-Packard 1100 HPLC equipped with Quaternary pump, a detector with variable wavelength, column YMC Pro C182,0 mm on; 23 mm and a mass spectrometer with an ion trap and ionization elektrorazpredelenie model Finnigan LCQ. When HPLC is used elution in gradient mode from 90% a to 95% b for 4 min. Buffer solution And contains 98% water, 2% acetonitrile and 0.02% TFA and buffer solution contains 98% acetonitrile, 2% water and 0,018% TFA. Spectra were scanned in the range 140-1200 atomic units of mass with variable flight time of the ions in accordance with the number of ions in the source.

Proton1N) spectra of nuclear magnetic resonance (NMR) remove spectrometer General Electric GN-Omega 300 (300 MHz) using standard Me4Si (δ is 0.00) or residual protonated solvent (CHCl3δ 7,26; Meon δ 3,30; DMSO δ 2,49). Carbon (13(C) NMR spectra shoot spectrometer General Electric GN-Omega 300 (75 MHz) using a standard solvent (CDCl3δ 77,0; d3-MeOD; δ 49,0; d6-DMSO δ 39,5).

Chiral separation is conducted using a commercially available column Chiracel® AD HPLC, elwira in gradient mode with a solution of isopropanol in hexane (from 1% to 15%) with addition of 0.1% triperoxonane acid.

Abbreviations and acronyms

When used in the present invention, the following abbreviations have the following meanings:

Ac2O - acetic anhydride

ADDP - 1,1'-(stickboy)-dipiperidino

VOS - tert-butoxycarbonyl

the n-BuOH - n-butanol

f-BuOH - tert-butanol

f-BuOK t - piperonyl potassium

CDl - carbonyldiimidazole

CD3OD - methanol-d4

Celite® - filter the reagent diatomaceous earth, ®Celite Corp.

CH2Cl2the methylene chloride

HEE-MS (MS (Χ)) - mass spectrometry with chemical ionization

DCC - dicyclohexylcarbodiimide

DCM - dichloromethane

de - excess diastereoisomer

DEAD - diethylazodicarboxylate

DIA - Diisopropylamine

DIBAL-H - diisobutylaluminium

DMAP - 4-(N,N-dimethylamino)-pyridine

DME - dimethoxyethan

DMF - N,N-dimethylformamide

DMSO - dimethyl sulfoxide

EDCl - 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

it is the excess enantiomer

IDSR - evaporative detector scattering

ER-MS - mass spectroscopy with elektrorazpredelenie

EtOAc - acetylated

EtOH - ethanol (100%)

EtSH - ethanthiol

Et2O - diethyl ether

Et3N - triethylamine

GC-MS - gas chromatography - mass spectroscopy

HPLC - high performance liquid chromatography

IPA - Isopropylamine

LAH - alumoweld lithium

LC-MS - liquid chromatography - mass specroscopy

LDA - diisopropylamide lithium

m/z - ratio mass-to-charge

MeCN is acetonitrile

NMM - 4-methylmorpholin

Ph3P - triphenylphosphine

Pd(dppf)Cl2- [1,1 bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)

Pd(PPh3)4- tetrakis(triphenylphosphine)-palladium(0)

Pd(OAc)2the palladium acetate

P(O)Cl3- oxychloride phosphorus

Rf - factor retention (TLC)

WU - retention time (HPLC)

TEA - triethylamine

THF - tetrahydrofuran

TFA - triperoxonane acid

TLC - thin layer chromatography

TMAD - N,N,N',N'-tetramethylethylenediamine

TMSCI - trimethylsilyloxy

Indicate in NMR spectra: s - singlet, d - doublet, t - triplet, q - quadruplet, m - multiplet, br - broad.

Example 1

Obtaining methyl-2-(6-methoxy-1H-inden-3-yl)-butanoate

It dried in a drying Cabinet 5-liter chetyrehkolkoy flask attached thermometer, refrigerator, addition funnel and mechanical stirrer. In an atmosphere of Ar at 60°C (the temperature inside the flask) is stirred suspension of 5-methoxy-1-indanone (80,0 g, 494 mmol), Zn powder (Lancaster, 56,2 g, 865 mmol) in 2 l of anhydrous THF and slowly through an addition funnel was added a solution of methylbromide (134,1 g, 741 mmol) in 400 ml of anhydrous THF. After completion of addition, the reaction mixture was stirred at 60°C (the temperature inside the flask) for 1 h For the reaction course is monitored by conducting analyses of the aliquot, using TLC after treatment 1 N. aqueous solution of HCl. After completion of the reaction, the reaction mixture is cooled in a bath of water with IDOM, and then slowly added 3 l of 1 n HCl solution. The temperature of the flask is kept lower than 20°C. the mixture is Then extracted with 1 l of EtOAc. The organic layer is washed with water to pH 6,0-7,0, then a saturated solution of NaCl and dried over Na2SO4. Product (127 g, >99%), yellow oil obtained after removal of solvent and drying in vacuum.1H NMR (DMSO-d6) δ 7,28 (d, 1H), 7,05 (d, 1H), PC 6.82 (dd, 1H), from 6.22 (s, 1H), and 3.72 (s, 3H), of 3.60 (m, 1H), to 3.58 (s, 3H), of 3.28 (s, 2H), 1,95 (m, 1H), 1,80 (m, 1H), from 0.88 (t, 3H).

Example 2A

Getting 2-(6-methoxy-1H-inden-3-yl)-butane acid

To a solution of ester obtained in Example 1 (14.0 g, of 58.9 mmol)in 140 ml Meon added a solution of KOH (6.4 g, 113,8 mmol) in 5 ml of water. The reaction mixture was stirred at 60°C (temperature in the flask) for 2 hours TLC indicates conversion, equal to 70%. Then, the flask was slowly added a solution of KOH (3.0 g, 53.6 mmol) in 100 ml of water. After 1 h the reaction is finished. After cooling to room temperature, the solvents are removed under reduced pressure. The residue is dissolved in 500 ml of water and then washed with EtOAc. The aqueous layer was cooled in a bath of ice water and then acidified with concentrated HCl to a pH of<a 3.0. The product is extracted with 300 ml of CH2Cl2, washed with water (2×100 ml), then dried over Na2SO4. After filtering off Na2SOsub> 4solution in CH2Cl2stirred with 3.0 g of charcoal for 2 hours, the Charcoal is removed by filtration through a layer of Celite®. The desired product (12.5 g, 95%) was obtained as a light brown solid after removal of solvent and drying in vacuum.1H NMR (DMSO-d6) δ 12,20 (b, 1H), 7,30 (d, 1H), 7,06 (d, 1H), PC 6.82 (dd, 1H), from 6.22 (s, 1H), 3,75 (s, 3H), of 3.45 (t, 1H), 3,30 (s, 2H), 1,90 (m, 1H), 1,78 (m, 1H), from 0.90 (t, 3H).

Example 2b

Getting 2-(6-methoxy-1H-inden-3-yl)-propanoic acid

This substance is produced using the same techniques as described in Examples 1 and 2A, starting from 5-methoxy-1-indanone and methyl-2-bromopropionate. Yield: 68%.1H NMR (CD2Cl2) δ 7,34 (d, J=9, 1H), 7,07 (d, J=2, 1H), 6,85 (dd, J=9, J=2, 1H), 6,32 (m, 1H), 3,82 (m, 4H), to 3.36 (m, 2H), and 1.56 (d, J=7, 3H).

Example 3

Obtain (2S)-2-(6-methoxy-1H-inden-3-yl)-butane acid

To a solution of racemic indene acid obtained in Example 2A (300 g, of 1.29 mol)in 4.5 l CH3CN at room temperature was added quinine (324 g, 1.0 mol). The mixture is stirred for 1 h and get the solution. A small amount of insoluble particles are removed by filtration under vacuum through the filter of the microfibers. Then the filtrate is mechanically stirred in an atmosphere of Ar during the night. After 24 h, a small sample of the solids are taken and analyzed and the result of the get 76,2%. After 2 days stirring ceased. The suspension is filtered. The filter cake is washed with CH3CN (3×200 ml) and then dried in vacuum at 40°C for 3 hours This solid is stirred with 4.5 l CH3CN at 70°till all solid enters solution. The solution is allowed to slowly cool to room temperature. The resulting suspension is stirred at room temperature for 24 hours, the Suspension is filtered. The filter cake is washed with CH3CN (3×250 ml) and then dried in vacuum at 40°within 24 hours This quinine salt is collected in the form of a white solid (254,6 g, yield of 35.4%, 96.8% of it).

The quinine salt (to 544.3 g, 0.98 mol) was dissolved in 4.0 l of CH2Cl2and get a clear solution. It vigorously stirred with 4.0 l of 2 n HCl solution in a 22-liter round bottom flask with bottom valve. After 30 min the mixture is allowed to settle. The bottom layer is separated and the upper aqueous layer is extracted with 1 l of CH2Cl2. The combined layers with CH2Cl2washed with water (3×2.0 l) to a pH of 5.0-6.0 and then dried over Na2SO4. Product (to 230.8 g, 99%, 96.8% of it) will get almost white solid after removal of solvent and drying in vacuum.1H NMR same as in racemic substances described in Example 2A.

Conducted similarly obrabotka.otlichno solution gives (R)-isomer. An alternative implementation for the racemization and retrieve the original racemic substances the mother liquor can be treated with an aqueous solution of the base.

Example 4

Obtain (2S)-2-[(1S)-5-methoxy-2,3-dihydro-1H-inden-1-yl]-butane acid

A solution of the product obtained in Example 3 (105 g, 453 mmol), ClRh(PPh3)3(21,0 g, 5% EQ.) and triethylamine (68,8 g, 679,5 mmol) in EtOH (945 ml) and THF (105 ml), shaken in a 2-liter autoclave at a pressure of H260 pound-force/inch2within 16 hours the Solvent is removed under reduced pressure. The resulting mixture was stirred in 1.5 l of 1 n HCl and 1.5 liters of CH2Cl2. The aqueous layer was extracted with CH2Cl2(2×250 ml). United CH2Cl2layers are washed with 1 l of 1 n HCl solution and stirred with 1 l of 1 n NaOH solution. The organic layer is extracted with 1 N NaOH solution (2×0.5 l). The combined aqueous layers washed with CH2Cl2(2×250 ml) and acidified (to pH 2.0 to 3.0) by slow addition of concentrated HCl solution at a temperature below 15°C. an Acidic mixture is extracted with CH2Cl2(2×1.5 l) and washed with water (2×0.5 l) to a pH of 5.0-6.0. After washing with brine and drying over anhydrous Na2SO4the solvent is evaporated under reduced pressure. The product (101,0g, the output of 95%to 96.8% EE) obtained as a light yellow oil.1H NMR (DMSO-d6) δ 12,20 (s, 1H),? 7.04 baby mortality (d, 1H), 6,78 (d, 1H), 6,66 (dd, 1H), 3,70 (s, 3H), of 3.28 (m, 1H), 2,72 (m, 2H), 2,32 (m, 1H), 2.06 to (m, 1H), 1,80 (m, 1H), 1,50 (m, 1H), 1,36 (m, 1H), of 0.82 (t, 3H).

Example 5A

Receiving SYN-2-[5-methoxy-2,3-dihydro-1H-inden-1-yl]-butane acid

A suspension of racemic indene acid (Example 2, 980 mg, 4.2 mmol), ClRh(PPh3)3(139 mg, 0.15 mmol), NaHCO3(378 mg, 4.5 mmol) in EtOH (20 ml) and H2O (10 ml) is shaken in an autoclave with a volume of 500 ml at a pressure of H260 pound-force/inch2within 30 hours To the reaction mixture was added an additional amount ClRh(PPh3)3(300 mg, 0.33 mmol) and the hydrogenation continued for a further 3 days. After that EtOH is removed under reduced pressure and the residue diluted with 200 ml of water. The black solid is removed by filtration and the filtrate is washed with EtOAc (2×200 ml). The aqueous solution is then acidified with concentrated HCl and extracted with CH2Cl2(2×100 ml). The combined layers containing CH2Cl2, washed with brine and dried over Na2SO4. Removal of solvent in vacuo gives indianabuy acid as a pale yellow oil (600 mg, 60%). The mixture of products leads to a mixture of diastereoisomers (87:13) with a predominance of SYN-isomers, as evidenced by the data analysis with NMR by using the ratio of the integration of NMR peaks, equal δ 7,11 (d, 1H) anti - and δ 7,03 (d, 1H) for the SYN-isomers.

Separation of the optical isomers can be carried out as follows: under stirring with a mechanical stirrer to a solution of SYN-indoxyl acid [(2R,1R) and (2S,1S), 14,69 g, 62,7 mmol] in acetonitrile (290 ml) at room temperature in one portion was added (R)-(+)-α-methylbenzylamine (8,49 ml, 65,9 mmol). The resulting mixture is stirred over night. The formation of small amounts of solids. The reaction mixture is concentrated to dryness and the residue when heated, re-dissolved in acetonitrile (200 ml). To promote deposition carry out stirring with a magnetic stirrer. The mixture is stirred over night. The solids are collected by filtration and washed three times with a small amount of cold acetonitrile. The solids are then dried under vacuum for 1.5 h (8,1 g, 86%). Slightly wet solid is recrystallized in acetonitrile (120 ml) and receive 6,03 g (R)-α-methylbenzylamine salt of (2S)-2-[(1S)-5-methoxy-2,3-dihydro-1H-inden-1-yl]-butane acid (94,4%). The second portion is collected from various filtrates (0,89 g, which is 97.6% EE). The total yield of the separation is 31% (62% in the calculation of the maximum content of (2S,1R)-acid racemate). The substance is identical to the obtained in Example 4.

Optical purity for e is th Example and of Example 4 can be determined by analysis using chiral HPLC; Column: Chiracel AD, 4,6 (inner diameter)×250 mm; mobile phase A:0.1% of TFA (triperoxonane acid) hexano, In:0,1% TFA in IPA (isopropyl alcohol); Methods, isocratic 95% A (5%), 20 min; flow rate, 1.5 ml/min Detector (UV), 284 nm. The retention times for the four possible diastereoisomers equal 5,163 min (2S,1R), 6,255 min (2R,1S), 10,262 min (2R,1R) 14,399 min (2S,1S). The first pointer (2S or 2R) shows the absolute configuration of the carbon atom adjacent to the carboxyl group (position 2); the second index (1S or 1R) shows the absolute configuration of the carbon atom EndInvoke cycle (position 1).

Stereochemical assignment of each peak was carried out by analysis using chiral HPLC of racemic diastereoisomeric mixture of compound 5 with different contents of SYN/anti isomers, which led to four peaks, resolved relative to the baseline. According to the integrated UV-strips peaks 3 and 4, as well as peaks 1 and 2 are a pair of enantiomers. According to x-ray analysis of the absolute configuration of the compound corresponding to peak 4 represents 2S,1S. The compound corresponding to peak 3, the corresponding enantiomer, with certainty attributed configuration 2R,1R. Peak 1 is attributed (2S,1R-diastereoisomer (retention time: 5,363 min, about 0,97% of the area) on the basis of comparison with soderjasimi a small amount of product, obtained by reduction of chiral acid (Example 3) in accordance with the description in Example 4. The remaining peak 2 with certainty can be attributed to the connection configuration 2R,1S.

Example 5b

Receiving SYN-2-[5-methoxy-2,3-dihydro-1H-inden-1-yl]-propanoic acid

The connection is obtained with the yield of 71% and >99% de using the same methodology as that described in Example 4, on the basis of (racemic) of the product of Example 2b:1H NMR (DMSO-d6) δ 12,18 (s, 1H), 7,03 (d, J=8, 1H), 6.75 in (d, J=2, 1H), to 6.67 (dd, J1=8, J2=2, 1H), 3,68 (s, 3H), 3,37 (m, 1H), 2,72 (m, 3H), 2,03 (m, 1H), 1,75 (m, 1H), 0,89 (d, J=7, 3H);13With NMR (CD2Cl2) δ 12,626, 28,228, 31,950, 43,300, 46,445, 55,607, 110,054, 112,510, 124,552, 136,702, 146,411, 159,464, 182,330.

Example 6

Obtaining methyl-(2S)-2-[(1S)-5-methoxy-2,3-dihydro-1H-inden-1-yl]-butanoate

A suspension of the acid obtained in Example 4 (220,0 g of 0.94 mol), NaHCO3(237,0 g, 2.82 mol), CH3l (200 g, of 1.41 mol) in 2.0 l of DMF, stirred in an atmosphere of Ar at room temperature for 18 hours Performed using NMR analysis shows that the reaction was 95%. The addition of CH3l (100 g) and stirring for another 24 h at room temperature leads to the completion of the reaction. The reaction mixture was poured in 4.0 l of water and extracted with EtOAc (2×2 l). The organic layer is successively washed in the Oh (2× 1 l), 1 l of 1 n NaOH solution, water (2×1 l) and 500 ml of brine and dried over Na2SO4. Product (233 g, 99%) was obtained as a light yellow oil after solvent removal and drying in vacuum.1H NMR (DMSO-d6) δ make 6.90 (d, 1H), 6,78 (d, 1H), 6,66 (dd, 1H), 3,70 (s, 3H), of 3.60 (s, 3H), 3,20 (m, 1 H), 2,80 (m, 2H), 2.40 a (m, 1H), 2,08 (m, 1H), 1,80 (m, 1H), 1,58 (m, 1H), 1,40(m, 1H), 0,80 (t, 3H).

Example 7

Obtaining methyl-(2S)-2-[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]-butanoate

To a cold solution (bath of ice water) of the compound obtained in Example 6 (233 g of 0.94 mol) in 2.5 l CH2Cl2slowly add AlCl3(630 g, 4.7 mol) in an atmosphere of Ar. The temperature in the flask is kept lower than 20°and the color of the reaction mixture turns into purple. Using a dropping funnel to the reaction mixture is slowly added EtSH (345 ml, 4.7 mol) and the temperature in the flask is kept lower than 15°C. After 2 h stirring at a temperature below 20°according to analysis by NMR, the reaction is finished. The mixture from the flask with vigorous stirring, slowly poured into 2.5 l of ice water. The organic layer is separated and the aqueous layer was extracted with 1 l of CH2Cl2. The combined layers containing CH2Cl2, washed with water (4×1 l) to pH 6,0-7,0, and then dried over Na2SO4. Product (216 g, 98%) was obtained as white solids after removal the solvent and drying in vacuum. 1H NMR (DMSO-d6) δ 9,10 (s, 1H), 6,78 (d, 1H), return of 6.58 (d, 1H), 6,50 (dd, 1H), 3,60 (s, 3H), 3,20 (q, 1H), 2,70 (m, 2H), 2.40 a (m, 1H), 2,08 (m, 1H), 1,80 (m, 1H), 1,50 (m, 2H), 0,80 (t, 3H).

Example 8

Obtaining methyl-3-[(4-methylbenzoyl)-amino]-4-oxopentanoate

To a suspension of the hydrochloride (3-methyl ester of L-aspartic acid (250 g, of 1.36 mol) cooled (<5° (C) CH2Cl2(4 l) in a steady stream add Et3N (440 g, 4.35 mol), and then slowly add Me3SiCi (324 g, 2,99 mol). The mixture is heated to 25°C and stirred for 1 h, re-cooled (<10° (C) and added dropwise p-taurillon (205 grams of 1.36 mol). Under stirring for 16 h the mixture is allowed to slowly warm to room temperature. Then the reaction mixture was diluted with CH2Cl2(500 ml) and washed with 1 N. HCl (500 ml), brine (500 ml) and dried over Na2SO4. The resulting amine (310 g, 91%), white solid, obtained after the removal of solvent and drying in vacuum. Then it is dissolved in pyridine (1.25 l) and added DMAP (5 g). Slowly added acetic anhydride (840 ml) and then the reaction mixture is heated at 90°C for 2 hours, the Cooled solution was poured into 7 l of ice water and extracted with 6 l of EtOAc. The organic layer is washed with 2 N. HCl (3×1 l) and 1 N. NaOH (1 l), dried over MgSO4and concentrate and which are square-desired compound as a white solid (301 g, 93%).

Example 9

Obtaining methyl-[Chieti-2-(4-were)-1,3-oxazol-4-yl]-acetate

The intermediate product obtained in Example 8 (280 g, 1.06 mol), dissolved in acetic anhydride (650 ml), then slowly added concentrated H2SO4(60 ml). The temperature in the flask rises to 80°C. Then the reaction mixture was kept at 85°C for 1 h, cooled and the acetic anhydride is removed in vacuo. The residue is poured into ice water (2 l) and extracted with EtOAc (4 l). Then the organic layer is stirred with 1 N. NaOH (500 ml) for 1 h, separated, dried over MgSO4and concentrate and get the desired ester as a clear oil (223 g, 87%), which slowly solidifies to a white solid.

Example 10

Obtain 2-[5-methyl-2-(4-were)-1,3-oxazol-4-yl]-ethanol

Ester of oxazole obtained in Example 9 (300 g, 1,22 mol), dissolved in THF (2.7 l) and portions of 5 g was added solid LiBH4(26,6 g, 1,22 mol), keeping the temperature below 45°C. the Reaction is completed within one hour after the addition. The amount of solvent is reduced by half and then the residue is poured into ice water (3 l). The mixture is then acidified slowly adding 1 N. HCl (1 l). A white precipitate is formed and is collected by filtration and drying the clothes in the cupboard above the P 2O5and get the desired ester of oxazole (214 g, 83%).

Example 11

Obtaining methyl-(2S)-2((1S)-5-{2-[5-methyl-2-(4-were)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butanoate

Suspension of hydroxyanthranilate obtained in Example 7 (208 g, 889 mmol), oxazolone alcohol obtained in Example 10 (212 g, 977 mmol), ADDP (335 g of 1.33 mol), Ph3R (348 g of 1.33 mol) in 6.0 liters of anhydrous THF, stirred at room temperature in an atmosphere of Ar. Over the course of the reaction is monitored using1H NMR. After 2 days the further course of the reaction is not observed. After removing the solids by filtration THF is removed under reduced pressure. The remaining mixture is stirred into 3 liters of a mixture of 50/50 EtOAc/hexane for 10 minutes, create additional amounts of solids and is removed by means of filtration. The filtrate is concentrated and treated by the same method using a 25/75 mixture EtOAc/hexane. After removal of the solvent the obtained oily mixture was purified on a column of silica gel (3.0 kg) using CH2Cl2(10,0 l) and 20% SN3CN/CH2Cl2(10,0 l) as solvent. The fractions containing the product are collected and then concentrated. The crude mixture was dissolved in 4.0 l of CH2Cl2unreacted guide-roxicodone removed by promilk is using 1 N. NaOH (3×1 l). The layer containing CH2Cl2, dried over Na2SO4. Product (358 g, 93%) was obtained as a light yellow oil after solvent removal and drying in vacuum.1H NMR (DMSO-d6) δ for 7.78 (d, 2H), 7,30 (d, 2H), 6.90 to (d, 1H), 6.75 in (d, 1H), 6,65 (dd, 1H), 4,15 (t, 2H), 3,60 (s, 3H), 3,25 (q, 1H), 2,90 (t, 2H), 2,75 (m, 2H), 2.40 a (m, 1H), 2,35 (s, 3H), 2,32 (s, 3H), of 2.05 (m, 1H), 1,80 (m, 1H), 1,50 (m, 2H), 0,80 (t, 3H).

Example 12

Obtain (2S)-2-f(1S)-5-{2-[5-methyl-2-(4-were)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid

To a solution of LiOH (90,4 g, 3,76 mol) in 1.3 l of water and 1.3 l Meon added a solution of ester obtained in Example 11 (325 g, 0.75 mol), 3.9 l of THF at room temperature. The solution becomes turbid. This mixture is heated at 60°C (temperature in the flask) for 4 h and analysed using TLC (50% EtOAc/hexane) shows that the reaction proceeded by about 50%. To the reaction mixture was added a solution of LiOH (30.1 g, 1.25 mol) in water (200 ml). After 2 h, analysis by TLC shows that the reaction proceeded for about 85%. To the reaction mixture re-added a solution of LiOH (30.1 g, 1.25 mol) in water (200 ml). After 2 h, analysis by TLC shows that there is very little source of ester. Then the reaction mixture is cooled to room temperature, THF and the Meon removed under reduced pressure. The residue is diluted with water until dissolved TV is rdye substance (use only 60 liters of water). To this aqueous solution is slowly added concentrated HCl solution to pH 2.0 to 3.0. The solid is collected by filtration and dried using a laboratory vacuum line during the night. It is solid for 30 min mixed with 15 l of EtOAc and 2 l of 1 n HCl solution. The layer containing EtOAc, separated, and washed with 1 N HCl solution (2×1 l). Then the organic phase is washed with water (4×2 l) to a pH of 5.0-6.0. In the atmosphere of Ar volume of solution in EtOAc reduced to 2.5 l by distillation at normal pressure, then cooled to room temperature without stirring. Precipitated white solid. After further cooling in a bath of ice water for 2 h, the solid is filtered off and washed with 500 ml of cold EtOAc. After drying in high vacuum at 35°C to constant weight, the final product (266 g, 81%, 98% EE) collected in the form of white crystals.1H NMR (CDCl3) δ of 7.82 (d, 2H), 7,20 (d, 2H), 7,05 (d, 1H), 6.75 in (d, 1H), 6,70 (dd, 1H), 4,20 (t, 2H), 3.42 points (q, 1H), 2.95 and (t, 2H), 2,80 (m, 2H), 2,50 (m, 1H), 2,35 (s, 3H), 2,32 (s, 3H), of 2.20 (m, 1H), 1,90 (m, 1H), 1,65 (m, 1H), 1,45 (m, 1H), from 0.90 (t, 3H). Chiral purity of 99% EE, [α]D=+16,11 (CHCl3), The melting temperature of 149.5-150,5°C.

Example 13

Obtain 2-{5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid

Stage 1. To a solution of 5-methoxy-indanone 10 g) in toluene (150 ml) was added Aids (15 g). The mixture is refluxed for 4 hours until you fall precipitate. The resulting mixture is cooled and poured into ice water (150 ml). The precipitate is filtered and washed with water, then dried in the air and get the desired product (8.5 g, 90%).

Stage 2. Benzylbromide (17 g), 5-hydroxyindole (15 g), K2CO3(20 g) and 200 ml of acetone is stirred in a round bottom flask (500 ml). The mixture is refluxed for 1 h To2CO3filtered off and the filtrate is evaporated. The obtained residue is recrystallized from EtOAc and obtain 18 g of product (75%).

Stage 3. A solution of 5-benzyloxyindole (1,14 g, 4,79 mmol) and diethylmalonate (services, 0.844 g of 5.29 mmol) in THF (20 ml) cooled to 0°in argon atmosphere and added dropwise TiCl4(10 ml, 1 M in CH2Cl2). In the end added pyridine (2 ml). The resulting mixture is stirred over night at room temperature. After filtration the filtrate was added EtOAc (30 ml). The organic layer was washed with brine (20 ml×3), dried over Na2SO4and evaporated. The residue is separated by chromatography on silica gel and receive 800 mg of product (50%).

Stage 4. The product obtained in stage 3 (1.7 g), dissolved in Meon (25 ml) and a suspension of Pd-C (300 mg) was added to the Meon and placed under a pressure of H260 pound-force/inch2in a Parr apparatus for shaking for 6 cosla filtering and concentrating obtain 1.2 g of product (92%).

Stage 5. P(Ph)3(420 mg) and ADDP (420 mg) was dissolved in THF (5 ml) at 0°C and stirred for 10 minutes In a flask was added a solution of oxazole (300 mg) and phenol (430 mg) in THF. The resulting mixture was stirred for 24 h and filtered. The filtrate is evaporated and the resulting residue is separated by chromatography on silica gel and receive the product (320 mg, 45%).

Stage 6. The intermediate product obtained in stage 5 (160 mg), dissolved in THF (5 ml) and to the solution was added Iodate (0.5 ml) and t-BuOK (50 mg) and stirred over night. After filtration the product is separated using TLC, receiving 100 mg (65%).

Stage 7. The intermediate product obtained in stage 6 (30 mg), dissolved in DMSO (1 ml). To the flask was added LiCl (160 mg). The mixture is refluxed for 5 hours From the resulting product mixture is separated using TLC, receiving 13 mg (52%).

Stage 8. The intermediate product obtained in stage 7, is subjected to hydrolysis in aqueous solution of KOH as described in Example 2, and receive the product: LC-MS, WU 3,57 min, M+1 406;1H NMR (CD2Cl2): δ of 0.93 (t, 3H), 1,40-1,70 (m, 2H), 1,80-2,20 (m, 2H), 2,30 (s, 3H), 2.40 a (m, 1H), 2,60 is 2.80 (m, 2H), 2,90 (t, 2H), 3,20-3,40 (m, 1H), 4,10 (t, 2H), 6,60 (dd, 1H), 6,70 (d, 1H), 7,00 (d, 1H), 7,30 (m, 3H), of 7.90 (m, 2H).

Using the methods of Examples 1-13, in some cases, in conjunction with the method of separation using chiral HPLC, as described in the General section, and using the m of suitable starting compounds, the following substances receive and characterize in a similar way:

Example 14

2-(5-{2-[5-Methyl-2-(4-were)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid

LC-MS, WU 3,70 min, M+1 420;1H NMR (CD2Cl2): δ of 0.93 (t, 3H), 1,40-1,70 (m, 2H), 1,80-2,20 (m, 2H), 2,30 (s, 3H),of 2.35 (s, 3H), 2.40 a (m, 1H), 2,60 is 2.80 (m, 2H), 2,90 (t, 2H), 3,20-3,40 (m, 1H), 4,10 (t, 2H), 6,60 (dd, 1H), 6,70 (d, 1H), 7,00 (d, 1H), 7,20 (m, 3H), 7,80 (m, 2H).

Example 15

(2S)-2-{(1S)-5-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid

The enantiomer is isolated using chiral HPLC. LC-MS, WU 3,57 min, M+1 406;1H NMR (CD2Cl2): δ of 0.93 (t, 3H), 1,48 (ddq, 1H), 1,68 (ddq, 1H), 1.93 and (dddd, 1H), 2,18 (dddd, 1H), 2,34 (s, 3H), 2,50 (ddd, 1H), 2,77 (ddd, 1H), 2,87 (ddd, 1H), 2,96 (t, 2H), 3,42 (ddd, 1H), 4,19 (t, 2H), of 6.68 (dd, 1H) 6,77 (d, 1H), was 7.08 (d, 1H), 7,42 (m, 2H), 7,44 (m, 1H), of 7.97 (dd, 2H).13WITH NMR: 510,4, 12,4, 22,4, 26,6, 29,5, 31,8, 46,5, 51,8, 67,2, 110,9, 113,0, 124,7, 126,2, 128,1, 129,1, 130,2, 133,2, 137,1, 145,6, 146,3, 158,7, 159,7, 180,4.

Example 16

(2S)-2-{(1R)-5-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid

The enantiomer is isolated using chiral HPLC. LC-MS, WU 3,57 min, M+1 406;1H NMR(CD2Cl2):δ of 0.93 (t, 3H), 1,61 (ddq, 1H), 1.69 in (ddq, 1H), 1,99 (dddd, 1H),2,19 (dddd, 1H), 2,47 (s, 3H), 2,52 (ddd, 1H), 2,73 (ddd, 1H), 2,89 (ddd, 1H), 3,11 (t, 2H), and 3.31 (ddd, 1H), is 4.21 (t, 2H), 6,66 (dd, 1H) 6,74 (d, 1H), 7,13 (d, 1H), 7,55 (m, 2H), to 7.61 (m, 1H), with 8.05 (dd, 2H).13C NMR: δ 10,5, 12,2, 23,8, 24,8, 30,3, 31,5, 46,4, 50,9, 66,1, 110,8, 112,6, 125,9, 127,4, 123,6, 129,8, 133,3, 129,7, 137,0, 148,4, 146,5, 158,2, 160,5, 181,0.

Example 17

(2R)-2-{(1R)-5-[2-(5-Methyl-2-[4-were]-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid

The enantiomer is isolated using chiral HPLC. LC-MS, WU 3,70 min, M+1 420;1H NMR (CD2Cl2): δ of 0.95 (t, 3H), of 1.40 (m, 1H), 1,70 (m, 1H), 1,90 (m, 1H), measuring 2.20 (m, 1H), 2,30 (s, 3H), of 2.35 (s, 3H), of 2.50 (m, 1H), 2,60 is 2.80 (m, 2H), 2,90 (t, 2H), 3,40 (dd, 1H), 4,20 (t, 2H), 6,60 (dd, 1H), 6,70 (d, 1H), 7,10 (d, 1H), 7,20 (m, 3H), 7,80 (m, 2H).

Example 18

2-(5-{2-[5-Methyl-2-phenyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-propanoic acid

LC-MS, WU 3,41 min, M+1 392;1H NMR (CD2Cl2): δ of 1.10 (d, 3H), 1,90 (m, 2H), measuring 2.20 (m, 1H), 2.40 a (s, 3H), 2.70 height is 3.00 (m, 2H), 2.95 and (t, 2H), 3.45 points (m, 1H), 4,20 (t, 2H), 6,70 (dd, 1H), 6,80 (d, 1H), 7,10 (d, 1H), 7,45 (m, 3H), 8,00 (m, 2H).

Example 19

2-{5-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-malonic acid

LC-MS, WU 3,00 min, M+1 422;1H NMR (CD2Cl2): δ 1,90 (m, 2H), 2.40 a (t, 3H), 2,60-3,00 (m, 3H), 3,40 (t, 2H), 3,70 (m, 1H), 4,20 (t, 2H), 6,60 (dd, 1H), 6,80 (d, 1H), 7,10 (d, 1H), 7,50 (m, 3H), 7,95 (m, 2H).

Example 20

3 Ethoxy-2-{5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-3-oxopropanoic acid

LC-MS, WU 3,39 min, M+1 450;1H NMR (CD2Cl2): δ of 1.20 (t, 3H), 2,00 (m, 1H), 2,30 (m, 1H), 2.40 a (s,3H), 2,90 (m, 2H), 3,10 (t, 2H), 3,80 (m, 1H), 4,20 (t and q, 4H), 6,70 (dd, 1H), 6,80 (d,1H), 7,10 (d, 1H), 7,50 (m, 3H), 8,00 (m, 2H).

Example 21

2-{5-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl]-5-phenylpentane acid

LC-MS, WU 3,98 min, M+1 396;1H NMR (CD2Cl2): δ of 1.40 and 1.80 (m, 4H), 1,90-of 2.20 (m, 2H), 2,35 (s, 3H), 2.40 a-3,00 (m, 5H), 2,90 (t, 2H), 3,35 (m, 1H), 4,10 (t, 2H), 6,60 (dd, 1H), 6,70 (d, 1H), 6.90 to-7,20 (m, 6H), 7,30 (m, 3H), 7,95 (m, 2H).

Example 22

2-(5-{2-[5-Methyl-2-(4-were)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-propanoic acid

LC-MS, WU 3,52 min, M+1 406;1H NMR (CD2Cl2): δ of 1.10 (d, 3H), 1,90 (m, 2H), measuring 2.20 (m, 1H), 2,30 (s, 3H), 2,31 (s, 3H), 2.70 height is 3.00 (m, 2H), 2.95 and (t, 2H), 3,40 (m, 1H), 4,10 (t, 2H), 6,60 (dd, 1H), 6,70 (d, 1H), 7,00 (d, 1H), 7,20 (d, 2H), 7,80 (d, 2H).

Example 23

2-(5-{2-[5-Methyl-2-(4-methyl-phenyl)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-hexanoic acid

LC-MS, WU to 3.92 min, M+1 448;1H NMR (CD2Cl3): δ of 0.93 (t, 3H), 1,10-1,30 (m, 4H), 1,40-1,70 (m, 2H), 1,80-2,20 (m, 2H), 2,30 (s, 3H), 2,31 (s, 3H), 2.40 a (m, 1H), 2,60 is 2.80 (m, 2H), 2,90 (t, 2H), 3,20-3,40 (m, 1H), 4,10 (t, 2H), 6,60 (dd, 1H), 6,70 (d, 1H), 7,00 (d, 1H), 7,20 (d, 2H), 7,80 (d, 2H).

Example 24

4-Methyl-2-(5-{2-[5-methyl-2-(4-were)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-pentane acid

LC-MS, WU 4,00 min, M+1 448;1H NMR (CD2Cl2): δ of 0.93 (m, 6H), 1,20 (m, 1H), 1,40-1,70 (m, 2H), 1,80-2,20 (m, 2H), 2,30 (s, 3H), 2,31 (s, 3 is), is 2.40 (m, 1H), 2,60 is 2.80 (m, 2H), 2,90 (t, 2H), 3,20-3,40 (m, 1H), 4,10 (t, 2H), 6,60 (dd, 1H), 6,70 (d, 1H), 7,00 (d, 1H), 7,40 (d, 2H), 8,40 (d, 2H).

Example 25

4-Methyl-2-(5-{2-[5-methyl-2-(4-methyl-phenyl)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-pontenova acid

LC-MS, WU 3.74 min, M+1 446;1H NMR (CD2Cl2): δ and 1.60 (s, 3H), of 1.70 (m, 2H), 1,80-2,20 (m, 2H), 2,30 (s, 3H), 2,31 (s, 3H), 2.40 a (m, 1H), 2,60 is 2.80 (m, 2H), 2,90 (t, 2H), 3,20-3,40 (m, 1H), 4,10 (t, 2H), ceiling of 5.60 (m, 2H), 6,60 (dd, 1H), 6,70 (d, 1H), 7,00 (d, 1H), 7,20 (d, 2H), 7,80 (d, 2H).

Example 26

Getting 2-{6-chloro-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethylmethanesulfonate and methyl-2-(6-chloro-5-hydroxy-2,3-dihydro-1H-inden-1-yl)-butanoate

Stage 1. To a solution of 2-phenyl-4-methyl-5-hydroxymethylimidazole (500 mg, 2.5 mmol) in 12.5 ml THF is added methanesulfonamide (0,21 ml to 2.75 mmol) and triethylamine (of 0.42 ml, 3 mmol). Solution the reaction mixture was stirred at room temperature in an argon atmosphere for 2 h, then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate, washed with 1% aqueous solution of hydrochloric acid (three times) and brine. Then it is dried over sodium sulfate, filtered and concentrated in vacuo and receive (617 mg, 88%): ER-MS m/g 282 ((M+N)+); HPLC WU 2,67;1H NMR (d6-DMSO) ´ of 2.33 (s, 3H), 2,89 (t, 2H), 3,13 (s, 3H), to 4.41 (t, 2H), 7,47-7,51 (m, 3H), 7,88-to $ 7.91 (m, 2H).

Stage 2. Sulfurylchloride (or 0.035 ml, 0.43 mmol) was added to a solution of methyl-5-hydroxy-2,3-dihydro-1-(2-butanoate) (100 mg, 0.43 mmol) of 2.15 ml of acetic acid. Solution the reaction mixture was stirred at room temperature for 30 min, then concentrated in vacuo. The resulting residue is dissolved in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine. Then it is dried over sodium sulfate, filtered and concentrated in vacuo and obtain 63 mg of the desired intermediate product in the form of a crude yellow oil which is used without further purification: GC-MS 269, ((M+N)+); H.H. WU (min) 8,71;1H NMR (d6-DMSO) δ 0,81 (t, 3H), 1,40-to 1.63 (m, 2H), 1.77 in-a 1.88 (m, 1H), 2.00 in to 2.15 (m, 1H), 2.40 a is 2.80 (m, 3H), 3,15-up 3.22 (m, 1H), 3,50 (s, 3H), 6,76 (s, 1H), 7,13 (s, 1H), 9,84 (s, 1H).

Stage 3. A solution of the product obtained in stage 2 (up to 30.5 mg, 0.12 mmol)in 0.6 ml DMF cooled to 0°in the bath with ice. Then add 60% dispersion of sodium hydride in oil (5.2 mg, 0.13 mmol) and bath with ice removed. After stirring the reaction mixture for 1 h at room temperature add mesilate, obtained in stage 1 (34 mg, 0.12 mmol). The reaction mixture is heated at 50°C for 24 h, then cooled to 0°C. Primav Aut 9.6 mg NaH (60% dispersion in oil) was added and heating continued for another 2 h, then the reaction mixture is cooled to room temperature and stirred for 48 hours At this point, add ethyl acetate and the organic solution washed with water and brine (three times), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue is purified using flash chromatography on silica gel using a mixture of 5:1 hexane:ethyl acetate as eluent and receive the product (19 mg, 35%) as a mixture of diastereoisomers (3:1): ER-MS m/z 454 (M+N)+; HPLC WU (min) 4,21;1H NMR (d6-DMSO) δ to 0.80 (t, 3H), 1,38-to 1.63 (m, 2H), 1,79-1,90 (m, 1H), 2,02 with 2.14 (m, 1H), 2,34 (s, 3H), of 2.51-2.57 m (m, 1H), 2,63-2,84 (m, 2H), 2.91 in (t, 2H), 3,19-of 3.25 (m, 1H), 3,49 (s, 2,3H), to 3.58 (s, 0,7H), 4,22 (t, 2H), 7,00 (s, 1H), 7,21 (s, 1H), 7,43-7,51 (m, 3H), a 7.85-of 7.90 (m, 2H).

Stage 4. At standard conditions, hydrolysis of the ester obtained in stage 3, in turn acid (a mixture of diastereoisomers 3:2): ER-MS m/z 440 (M+N)+; HPLC WU (min) 3,69;1H NMR (d6-DMSO) δ or 0.83 (t, 3H), of 2.34 (s, 3H), of 2.92 (t, 2H), is 4.21 (t, 2H), 7,00-7,02 (d, 1H), 7,12 (s, 0,24H), 7,21 (s, 0,37H), 7,47-of 7.48 (m, 3H), 7,87-of 7.90 (m, 2H).

Example 27

Getting ethyl-2-{5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-pentanoate

Dried in a drying Cabinet round bottom flask with a volume of 15 ml and a rod for mixing cooled in the current Ar (gas) and it is placed ethyl-2-{5-[2-(5-methyl-2-phenyl-1-oxazol-4-yl)-ethoxy]-2,3-dihydro-1 H-inden-1-yl}-acetate (0,070 g, 0,17 mmol), and then add 0.2 ml THF. Then the solution with stirring, cooled to -78°and then added dropwise lithium bis(trimethylsilyl)-amide (1.0 M solution in hexane, 0,86 ml, 0.86 mmol). After complete addition of the base solution was stirred at -78°C for 1 h, then using a syringe to add jumprope (0,142 g, 0.86 mmol). Then the contents are slowly heated to room temperature and incubated for 1 h the Contents of the flask poured into 5 ml of NH4Cl (aqueous solution), and then extracted with ethyl acetate (3×10 ml). The organic layers are combined and dried over Na2SO4and concentrated in vacuo, receiving 3.0 mg (yield 4.0%) of a colorless film. Product features:1H NMR (300 MHz, d6-acetone) δ of 7.96 (dd, 8,1, 1.5 Hz, 2H), of 7.48 (m, 3H), of 6.99 (d, 8,4 Hz, 1H), 6,79 (d, 2.7 Hz, 1H), 6,70 (dd, 8,1, 2.7 Hz, 1H), 4,22 (t, 6.9 Hz, 2H), 4,11 (q, 7.2 Hz, 2H), 3.33 and (q, 6.6 Hz, 1H), 2,94 (t, 6.9 Hz, 2H), 2,78 (m, 3H), of 2.54 (m, 1H), 2,39 (s, 3H), and 2.14 (m, 2H), 1.91 a (m, 1H), 1,63 (qt, 10, 2, 3,9 Hz, 2H), 1,21 (t, 7.2 Hz, 3H), 0,852 (t, 7.5 Hz, 3H); mass spectroscopy gives MN+=USD 448,2 (calculated molecular weight28H33NO4=447,57).

Example 28

Obtain 2-{5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-pentanol acid

Hydrolysis of the product obtained in Example 27, the method described above in Example 2, gives a product with follow what their characteristics. 1H NMR (300 MHz, d6-acetone); δ of 7.96 (dd, 8,1, 1.5 Hz, 2H), of 7.48 (m, 3H), 7,10 (d, 8,4 Hz, 1H), 6,79 (d, 2.7 Hz, 1H), of 6.71 (dd, 8,1, 2.7 Hz, 1H), 4,22 (t, 6.9 Hz, 2H), 3,40 (m, 1H), 2.91 in (t, 6.9 Hz, 2H), 2,74 (m, 1H), 2,58 (m, 1H), 2,39 (s, 3H), and 2.26 (m, 1H), 2,11 (m, 1H), 1,95 (m, 2H), of 1.84 (m, 1H), 1,62 (m, 2H), 0,859 (td, of 6.9, 1.5 Hz, 3H); mass spectroscopy gives MH+=420,1 (calculated molecular weight26H29NO4=419,51).

Example 29

Getting 2-{6-bromo-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid via methyl-2-(6-bromo-5-hydroxy-2,3-dihydro-1H-inden-1-yl)-butanoate

and

Stage 1. A solution of bromine (0,032 ml of 0.60 mmol) in dioxane (3 ml) cooled to 0°C for 15 min, then was added a solution of methyl ester of 2-(5-hydroxyine-1-yl)-butyric acid (141 mg, of 0.60 mmol) in dioxane (3 ml). After 5 min bath with ice is removed and the reaction mixture was stirred at room temperature for 4 hours the Solvent is removed on a rotary evaporator. The residue is purified by chromatography on a column (8% EtOAc in hexane) and get monobromobimane intermediate product (A) (145 mg, 77%) and diplomirovannyi intermediate product (B) (20 mg) as a colorless oil. A:Rf=0,46 (4:1 hexane:EtOAc); GC-MS (+Cl): m/z=313 (M+);1H NMR (DMSO-d6}: δ 0,840 (m, 3H), 1,511 (m, 2H), 1,905 (m, 1H), 2,091 (m, 1H), 2,410-2,793 (m, N), 3,212 (m, 1H), 3,505 and 3,512 (s, 3H), 6,713 and 6,753 (s, 1H), 7,034 and 7,274 (s, 1H), 9,932 and 9,934 (s, HE).

In:Rf=0,30 (4:1 hexane:EtOAc); GC-MS(+Cl): m/z=393 (M+);1H NMR (DMSO-d6): δ 0,817 (m, 3H), 1,459-1,596 (m, 2H), 1,910 (m, 1H), 2,101 (m, 1H), 2,433-2,768 (m, 3H), 3,371 (m, 1H), 3,400 and 3,596 (s, 3H), 7,168 and 7,357 (s, 1H), 9,535 and 9,542 (s, HE).

Stage 2. To solution (A)obtained in stage 1 above (118 mg, 0.38 mmol)in DMF (3.8 ml) at 0°With added NaH (60% in mineral oil, 30 mg). After 1 h, add mesilate, obtained in stage 1, Example 26. The mixture is heated to 50°C for 30 hours the Solution was diluted with water and then extracted three times with ethyl acetate. The combined organic layers washed with water and brine, then dried (Na2SO4) and concentrate. The residue is purified by chromatography on a column (10% ethyl acetate in hexane) and receive the product (63 mg, 34%); Rf=0,46 (2:1 hexane:EtOAc); ER LC-MS: m/z=498 (MN+);1H NMR (DMSO-d6): δ 0,847 (m, 3H), 1,468 (m, 2H), 1,812 (m, 1H), 2,146 (m, 1H), 2,340 (s, 3H), 2,525-at 2,788 (m, 3H), 2,902 (m, 2H), 3,236 (m, 1H), 3,481 and 3,586 (s, 3H), 4,211 (m, 2H), 6,969 (s, 1H), 7,347 and 7,386 (s, 1H), 7,452 (m, 3H), 7,833 (m, 2H).

Stage 3. To a solution of the product obtained in stage 2 (5.6 mg)in methanol was added 3 n KOH (1 ml)and then added THF until a cloudy solution becomes transparent. The mixture is refluxed over night. To establish a pH value of 2, priba the designers concentrated HCl, then extracted three times with ethyl acetate. The organic layers are combined, dried and concentrated and receive a white solid (4 mg). Rf=0,18 (2:1 hexane:EtOAc); ER LC-MS: m/z=484 (MN+);1H NMR (DMSO-d6): δ 0,832 (m, 3H), 1,468 (m, 2H), 1,812 (m, 1H), 2,146 (m, 1H), 2,405 (m, 1H), at 2,788 (m, 2H), 2,904 (m, 2H), 3,015 (m, 1H), 3,136 and 3,138 (s, 3H), 4,209 (m, 2H), 6,987 and 7,344 (s, 1H), 6,972 and 7,251 (s, 1H), 7,487 (m, 3H), 7,882 (m, 2H).

Example 30

Obtain 2-{5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-6-phenyl-2,3-dihydro-1H-inden-1-yl}-butane acid via methyl-2-{5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-6-phenyl-2,3-dihydro-1H-inden-1-yl}-butanoic

Stage 1. A mixture of the product obtained in stage 2, Example 29, and Pd(PPh3)4in THF (1.5 ml) was stirred at room temperature for 30 minutes the solution is then added phenylboronic acid (13.2 mg, to 0.108 mmol) and 2 N. NaOH. The mixture is refluxed for 14 hours the Solution is allowed to cool, diluted with water and extracted three times with ethyl acetate. The combined organic layers washed with brine and dried over sodium sulfate. The crude product is purified by chromatography on a column elwira 5% ethyl acetate in hexane, and get the desired product (8.6 mg). Rf=0,48 (2:1 hexane:EtOAc); ER LC-MS: m/z=496 (MH+);1H NMR (DMSO-d6): δ 0,804 (m, 3H), 1,541 (m, 2H), 1,880 (m, 1H), 1987 (m, 1H), 2,090 (s, 3H), 2,247-2,698 (m, 3H), 2,791 (m, 2H), 3,199 (m, 1H), 3,524 and 3,537 (s, 3H), 4,190 (m, 2H), 6,970 (s, 1H), 7,062 (s, 1H), 7,275 (m, 5H), 7,472 (m, 3H), 7,868 (m, 2H).

Stage 2. Ester hydrolyzing according to the methods described above, and receive the product: Rf=0,16 (2:1 hexane:EtOAc); ER LC-MS: m/z=482 (MN+);1H NMR (DMSO-d6): δ 0,923 (m, 3H), 1,504 (m, 2H), 1,812 (m, 1H), 2,146 (m, 1H), 2,188 (s, 3H), 2,334 (m, 2H), UAH 2.432 (m, 2H), 2,539 (m, 1H), 2,625 (m, 1H), 4,287 (m, 2H), 7,059 (s, 1H), 7,160 (s, 1H), 7,351 (m, 5H), 7,544 (m, 3H), 7,971 (m, 2H).

Example 31

Obtaining methyl-2-{6-(4-chlorophenyl)-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butanoate

A mixture of the product obtained in stage 2, Example 29 (71,4 mg, 0.14 mmol), NaHCO3(14.3 mg, 0,17 mmol), 4-Chlorfenvinphos acid (to 26.8 mg, 0,17 mmol) in dimethyl ether of ethylene glycol (1.5 ml) and water (0.4 ml) Tegaserod within 20 minutes

Then to the solution was added Pd(dppf)Cl2. The mixture is refluxed for 2 days. The mixture is then concentrated and purified by chromatography on a column (10% EtOAc in hexane) and get the desired product (25 mg). Rfor =0.51 (2:1 hexane:EtOAc); ER LC-MS: m/z=530 (MH+);1H NMR (DMSO-d6): δ 0,841 (m, 3H), 1,557 (m, 2H), 1,888 (m, 1H), 1,987 (m, 1H), 2,146 (s, 3H), 2,247-2,698 (m, 3H), 2,791 (m, 2H), 3,214 (m, 1H), 3,487 and 3,5538 (s, 3H), 4,189 (m, 2H), 6,993 (s, 1H), 7,080 (s, 1H), 7,308 (s, 4H), 7,493 (m, 3H), 7,868 (m, 2H).

By using the techniques described in Examples 26-31,using other suitable source of substances are obtained and characterized by the following substances:

Example 32

2-{6-(4-Chlorophenyl)-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}butane acid

ER LC-MS: m/z=516 (MN+);1H NMR (DMSO - d6): δ 0,847 (m, 3H), 1,557 (m, 2H), 1,888 (m, 1H), 1,987 (m, 1H), 2,137 (s, 3H), 2,247-2,687 (m, 3H), 2,819 (m, 2H), 3,234 (m, 1H), 4,187 (m, 2H), 6,994 (s, 1H), 7,089 (s, 1H), 7,298 and 7,308 (m, 4H), 7,484 (m, 3H), 7,869 (m, 2H).

Example 33

Methyl-2-{6-methyl-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butanoic

Rf=0,23 (2:1 hexane:EtOAc); ER LC-MS: m/z=434 (MN+);1H NMR (DMSO-d6): δ 0,804 (m, 3H), 1,522 (m, 2H), 1,830 (m, 1H), 1,987 (m, 1H), 2,037 (s, 3H), 2,335 (s, 3H), 2,410 - 2,550 (m, 3H), 2,901 (m, 2H), 3,146 (m, 1H), 3,507 (s, 3H), 4,163 (m, 2H), 6,777 (s, 1H), 6,939 (s, 1H), 7,483 (m, 3H), 7,875 (m, 2H).

Example 34

2-{6-Methyl-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid

Rf=0,31 (2:1 hexane:EtOAc); ER LC-MS: m/z=420 (MH+);1H NMR (DMSO-d6): δ 0,827 (m, 3H), 1,508 (m, 2H), 1,828 (m, 1H), 1,987 (m, 1H), 2,017 (s, 3H), 2,333 (s, 3H), 2,410-2,550 (m, 3H), 2,894 (m, 2H), 3,146 (m, 1H), 4,116 (m, 2H), 6,773 (s, 1H), 6,942 (s, 1H), 7,467 (m, 3H), 7,880 (m, 2H).

Example 35

Methyl-2-[5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-6-(2-thienyl)-2,3-dihydro-1H-inden-1-yl]-butanoate

Rf=0,60 (2:1 hexane:EtOAc); ER LC-MS: m/z=502 (MN+);1H NMR (DMSO-d6): δ 0,801 (m, 3H), 1,535 (m, 2H), 1,891 (m, 1H), 1,987 (m, 1H), 2,299 (s, 3H, 2,410-2,550 (m, 3H), 2,988 (m, 2H), 3,146 (m, 1H), 3,506 (s, 3H), 4,337 (m, 2H), 7,011-7,041 (m, 2H), 7,405-7,493 (m, 5H), 7,884 (m, 2H).

Example 36

2-[5-[2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-6-(2-thienyl)-2,3-dihydro-1H-inden-1-yl]-butane acid

Rf=0,18 (2:1 hexane:EtOAc); ER LC-MS: m/z=488 (MN+);1H NMR (DMSO-d6): δ 0,801 (m, 3H), 1,535 (m, 2H), 1,891 (m, 1H), 1,987 (m, 1H), 2,299 (s, 3H), 2,410-2,550 (m, 3H), 2,988 (m, 2H), 3,146 (m, 1H), 4,337 (m, 2H), 7,078 (m, 2H), 7,472 (m, 5H), 7,896 (m, 2H).

Example 37

Methyl-2-{4,6-dibromo-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butanoic

Rf=0,35 (4:1 hexane:EtOAc); ER LC-MS: m/z=578 (MH+);1H NMR (DMSO-d6): δ 0,847 (m, 3H), 1,468 (m, 2H), 1,812 (m, 1H), 2,146 (m, 1H), 2,350 (s, 3H), 2,407-at 2,788 (m, 3H), 2,982 (m, 2H), 3,225 (m, 1H), 3,480 and 3,588 (s, 3H), 4,145 (m, 2H), 7,276 (s, 1H), 7,458 (m, 3H), 7,866 (m, 2H).

Example 38

2-[4,6-Dibromo-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl]-butane acid

Rf=0,17 (2:1 hexane:EtOAc); ER LC-MS: m/z=564 (MN+);1H NMR (DMSO-d6): δ 0,847 (m, 3H), 1,468 (m, 2H), 1,812 (m, 1H), 2,146 (m, 1H), 2,361 (s, 3H), 2,414-2,781 (m, 3H), 2,995 (m, 2H), 3,123 (m, 1H), 4,125 (m, 2H), 7,345 (s, 1H), 7,437 (m, 3H), 7,886 (m, 2H).

Example 39

Getting 2-{6-acetyl-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl}-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid via methyl-2-(6-acetyl-5-methoxy-2,3-dihydro-1H-inden-1-yl)-butanoate

Stage 1. To a solution of Aids (103 mg, 0.78 mmol) in methylene chloride (2.5 ml) at 0°With added acetylchloride (0,044 ml, was 0.63 mmol)and then added dropwise a solution of methyl-5-methoxy-2,3-dihydro-1H-inden-1-albuminate (130 mg, 0.52 mmol) in methylene chloride (2.7 ml). The mixture was stirred at 0°C for 15 min Bath with ice is removed and the mixture is stirred at room temperature for 16 hours the Mixture was poured on ice and add 4 drops of concentrated HCl. This mixture is extracted twice with methylene chloride. The combined organic layers washed with water, 0,05 N. NaOH and water. The organic layer is dried, concentrated and purified by chromatography using 10% EtOAc: hexane and get the desired product (103 mg, 68%). Rf=0,28 (4:1 hexane:EtOAc); GC-MS (+Cl): m/z=291 (M+);1H NMR (DMSO-d6): δ 0,840 (m, 3H), 1,536 (m, 2H), 1,876 (m, 1H), 2,108 (m, 1H), 2,505 (s, 3H), 2,521 (m, 1H), 2,760-2,889 (m, 2H), 3,236 (m, 1H), 3,511 and 3,589 (s, 3H), 3,836 (s, 3H), 7,012 and 7,253 (s, 1H), 7,440 (s, 1H).

Stage 2. To a solution of AlCl3(238 mg, 1.77 mmol) in CH2Cl2(1 ml) was added the product obtained in stage 1 (103 mg, 0.35 mmol)in CH2Cl2(2 ml). The mixture is cooled to 0°C for 5 min, then slowly added EtSH (0,13 ml, 1.77 mmol). The mixture is stirred at this temperature for 4.5 hours Then the mixture is poured into ice water, stirred for 10 min and twice extragere the t with CH 2Cl2. The combined organic layers washed with water, dried over sodium sulfate and concentrate and get the product (86 mg, 89%). Rfor =0.51 (4:1 hexane:EtOAc); GC-MS (+Cl): m/z=276 (M+);1H NMR (DMSO-d6): δ 0,841 (m, 3H), 1,574 (m, 2H), 1,888 (m, 1H), 2,094 (m, 1H), 2,585 (s, 3H), 2,639 (m, 1H), 2,729-2,847 (m, 2H), 3,244 (m, 1H), 3,513 and 3,628 (s, 3H), 6,774 and 7,503 (s, 1H), 6,792 and 7,715 (s, 1H), 12,117 and 12,143 (s, 1H).

Stage 3. The combination of ester hydroxypentadecanoic acid, obtained in stage 2, with mesilate, obtained in stage 2 of Example 26. ER LC-MS: m/z=462 (MN+);

Stage 4. Hydrolysis of the product obtained at stage 3, is carried out in a manner analogous to that described above, and receive the product: Rf=0,08 (2:1 hexane:EtOAc); ER LC-MS: m/z=448 (MH+);1H NMR (DMSO-d6): δ 0,848 (m, 3H), 1,468 (m, 2H), 1,812 (m, 1H), 2,146 (m, 1H), 2,305 (s, 3H), 2,368 (s, 3H), 2,405 (m, 1H), at 2,788 (m, 2H), 2,971 (m, 2H), 3,015 (m, 1H), 4,332 (m, 2H), 7,039 and 7,441 (s, 1H), 7,446 (s, 1H), 7,465 (m, 3H), 7,875 (m, 2H).

Using a combination of the procedures described above and using other suitable starting substances are getting lots of the following compounds.

Example 40

Methyl-2-{5-[2-(2,5-diphenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butanoic

Yield: 0.09 g, 46%;1H NMR (CDCl3, 400 MHz) δ 0,83 with 0.93 (t, 3H), 1,55-of 1.78 (m, 2H), 1,87-of 1.97 (m, 1H), 2,10-2,22 (m, 1H), 2,44-2,52 (m, 1H), 2,67-280 (m, 1H), 2,81-of 2.93 (m, 1H), 3,21-3,29 (m, 1H), 3,23-to 3.33 (t, 2H), 3,62 (s, 3H), 4,34-4,43 (t, 2H), 6,66-6,72 (m, 1H), 6,76 (s, 1H), 7,05-7,14 (d, 1H), 7,33-7,39 (t, 1H), 7,43-7,51 (m, 5H), 7,78-to 7.84 (d, 2H), 8,06-to 8.12 (m, 2H).

Example 41

2-{5-[2-(2,5-diphenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid

Yield: 0.07 g, 70%;1H NMR (CDCl3, 400 MHz) δ 0,85-0,98 (m, 3H), of 1.23 to 1.47 (m, 1H), 1,57-of 1.78 (m, 1H), 1,88-2,07 (m, 1H), 2,12-of 2.27 (m, 1H), 2,43-of 2.56 (m, 1H), 2,68-of 2.97 (m, 2H), 3.27 to the 3.35 (t, 2H), 3,42-to 3.50 (m, 1H), 4,34-to 4.41 (t, 2H), 6,66-of 6.73 (d, 1H), 6,77 (s, 1H), 7,02-7,16 (d, 1H), 7,34-7,40 (t, 1H), 7,43-7,52 (m, 5H), 7,78-7,83 (d, 2H), 8,05-to 8.12 (m, 2H).

Example 42

Methyl-2-{5-[2-(5-isopropyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butanoic

Yield: 0.09 g, 45%;1H NMR (CDCl3, 400 MHz) δ 0,78-to 0.96 (t, 3H), 1.26 in-1,32 (d, 6N)and 1.51-of 1.62 (m, 1H), 1,64 is 1.75 (m, 1H), 1,81-of 1.93 (m, 1H), 2,07-of 2.21 (m, 1H), 2.40 a is 2.51 (m, 1H), 2,65 is 2.75 (m, 1H), 2.77-to 2,98 (m, 1H), 2.91 in are 2.98 (t, 2H), 3,09-and 3.16 (m, 1H), 3,21 of 3.28 (m, 1H), 3,62 (s, 3H), 4,10-4,17 (t, 2H), 6,60 of 6.68 (d, 1H), 6,72 (s, 1H), 7,01-7,13 (d, 1H), 7,33 was 7.45 (m, 3H), 7,94-of 8.00 (d, 2H).

Example 43

2-{5-[2-(5-Isopropyl-2-Phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid

Yield: 0.08 g, 97%;1H NMR (CDCl3, 400 MHz) δ 0,91-and 0.98 (t, 3H), 1.30 and of 1.36 (d, 6N), 1,58-to 1.79 (m, 2H), 1,89-2,05 (m, 1H), 2,12-of 2.27 (m, 1H), 2,44-to 2.57 (m, 1H), 2,69 is 2.80 (m, 1H), 2,83-2,96 (m, 1H), 2,97-to 3.02 (t, 2H), 3,10-is 3.21 (m, 1H), 3,24-of 3.32 (m, 1H), 4,14-is 4.21 (t, 2H), 6,63-of 6.71 (d, 1H), 6.75 in (s, 1H),? 7.04 baby mortality-7,16 (d, 1H), of 7.36 was 7.45 (m, 3H), 7,94-of 8.00 (d, 2H).

Example 44

Methyl-2-{5-[2-(5-ethyl-2-phenyl-1,oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-indenyl}-butanoate

Yield: 0.14 g, 60%;1H NMR (CDCl3, 400 MHz) δ 0,85-of 0.91 (t, 3H), 1,25-1,35 (t, 3H), 1,58-to 1.77 (m, 2H), 1.85 to of 1.97 (m, 1H), 2,10-2,22 (m, 1H), 2,44-of 2.64 (m, 2H), 2,68 is 2.80 (q, 2H), 2,82-of 2.93 (m, 1H), 2.95 and-a 3.01 (t, 2H), 3.25 to to 3.34 (m, 1H), 3,62 (s, 3H), 4,16-of 4.25 (t, 2H), 6,66-of 6.71 (d, 1H), 6.75 in (s, 1H), 7,08-7,14 (d, 1H), 7,38-7,46 (m, 3H), 7.95 is shed 8.01 (m, 2H).

Example 45

2-{5-[2-(5-Ethyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid

Yield: 0.05 g, 60%;1H NMR (CDCl3, 400 MHz) δ 0,85-0,98 (m, 3H), of 1.21 and 1.33 (m, 3H), 1,37-and 1.54 (m, 1H), 1.56 to of 1.78 (m, 2H), 1,87-to 2.29 (m, 2H), 2,45-2,60 (m, 1H), 2,69-and 2.79 (q, 2H), 2,85-2,95 (m, 1H), 2,96-a 3.01 (t, 2H), 3.27 to to 3.49 (m, 1H), 4,14-to 4.23 (t, 2H), 6,65-of 6.71 (d, 1H), 6.75 in (s, 1H), 7.03 is-7,17 (d, 1H), 7,38-7,46 (m, 3H), 7.95 is shed 8.01 (d, 2H).

Example 46

Methyl-2-{5-[2-(2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-indenyl}-butanoate

Yield: 0.18 g, 80%;1H NMR (CDCl3, 400 MHz) δ of 0.82 to 0.92 (t, 3H), 1.56 to of 1.66 (m, 1H), 1,67-to 1.77 (m, 1H), 1,88 of 1.99 (m, 1H), 2,12-of 2.23 (m, 1H), 2,43-2,52 (m, 1H), 2,68-of 2.81 (m, 1H), 2,84-of 2.97 (m, 1H), 3,02-3,11 (t, 2H), 3.25 to to 3.33 (m, 1H), 3,63 (s, 3H), 4,21-4,30 (t, 2H), 6,69-6,74 (d, 1H), 6,79 (s, 1H), 7,11-7,16 (d, 1H), 7,41-7,47 (m, 3H), 7,55-7,58 (m, 1H), 7,99-with 8.05 (m, 2H).

Example 47

2-{5-[2-(2-Phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}butane acid

Yield: 0.07 g, 46%;1H NMR (CDCl3, 400 MHz) δ 0,84-a 1.01 (m, 3H), 1,36-is 1.51 (m, 1H), 1,59-of 1.81 (m, 1H), 1,88 is 2.00 (m, 1H), 2,11-to 2.29 (m, 1H), 43-2 2,64 (m, 1H), 2,68-of 2.81 (m, 1H), 2,82-3,00 (m, 2H), 3,02-3,11 (t, 2H), 3,23-3,37 (m, 1H), 4,17-to 4.28 (t, 2H), 6,66-6,74 (d, 1H) 6,78 (s, 1H),? 7.04 baby mortality-7,19 (m, 1H), 7,39-7,47 (m, 2H), 7,55 (s, 1H), 7,98-with 8.05 (m, 2H).

Example 48

Methyl-2-(5-[2-[2-(2,3-dihydro-1-benzofuran-6-yl)-5-methyl-1,3-oxazol-4-yl]-ethoxy]-2,3-dihydro-1H-inden-1-yl)-butanoate

Yield: 0.17 g, 58%;1H NMR (CDCl3, 400 MHz) δ 0,86 to 0.97 (t, 3H), 1.41 to 1,53 (m, 1H), 1,61-to 1.77 (m, 1H), 1,92 is 2.01 (m, 1H), 2,04-of 2.20 (m, 1H), 2.40 a (s, 3H), 2,49-of 2.56 (m, 1H), 2,71 of 2.92 (m, 2H), 3,93 is 3.00 (t, 2H), 3,21-of 3.32 (t, 2H), 3,34-3,49 (m, 1H), 3,75 (s, 3H), 4,18-4,24 (t, 2H), 4,54-4,70 (t, 2H), 6,70-6,76 (d, 1H), 6,79 (s, 1H), PC 6.82-6.89 in (d, 1H), 6,92-7,01 (d, 1H), 7,75-7,80 (d, 1H), 7,87 (s, 1H).

Example 49

2-(5-[2-[2-(2,3-Dihydro-1-benzofuran-6-yl)-5-methyl-1,3-oxazol-4-yl]-ethoxy]-2,3-dihydro-1H-inden-1-yl)butane acid

Yield: 0.10 g, 99%;1H NMR (CDCI3, 400 MHz) δ 0,90 was 1.04 (t, 3H), 1.41 to and 1.54 (m, 1H), 1,60 to 1.76 (m, 1H), 1,83-of 1.97 (m, 1H), 2,12-of 2.23 (m, 1H), 2,35 (s, 3H), 2,48-2,60 (m, 1H), 2,69-2,90 (m, 2H), 2,92-a 3.01 (t, 2H), 3,18 of 3.28 (t, 2H), 3,39-3,50 (m, 1H), 4,08-of 4.12 (t, 2H), 4,46 with 4.64 (t, 2H), 6,76-of 6.71 (d, 1H), 6.73 x (s, 1H), 6,77-6,84 (d, 1H), 7,01-to 7.09 (d, 1H), 7,71 for 7.78 (d, 1H), 7,83 (s, 1H).

Example 50

Getting ethoxy-{5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-acetic acid via ethyl-[5-(benzyloxy)-2,3-dihydro-1H-inden-1-ilidene](ethoxy)-ethanoate

Stage 1. LDA (obtained from 11 mmol DIA and 11 mmol BuLi) was added to methyl 2-ethoxyacetic (10 mmol) in 50 ml THF at -78°C, stirred for 1 h, then added TMSCI (30 mmol). Mixture conc tryout in vacuum and directly used in the next stage without purification.

Stage 2. 5-Benzyloxy-1-indanone in CH2Cl2ml is slowly added to TiCl4in CH2Cl2(10 ml) at -78°C, stirred at -60°C for 10 min and cooled to -78°C. the Product obtained in stage 1, CH2Cl2(5 ml) is slowly added and stirred for 10 minutes the Reaction is stopped with a saturated solution of K2CO3, filtered, extracted with ethyl acetate and dried over sodium sulfate. Chromatography on a column gives the product as colorless oil. LC-MS MN+=353,1, WU=4,00 min; NMR (CDCl3, 400 MHz) δ 7,9 (1H, d), 7,25 (5H, m), 6,78 (2H, m), is 4.93 (2H, s), is 4.15 (2H, q in), 3.75 (2H, q), of 3.05 (2H, m), 2,85 (2H, m), 1,22 (6N, m)

Stage 3. Using as the starting material the product obtained in stage 2, and techniques similar to those described in Example 13, the stage 4-8, receive and characterize the desired final product: LC-MS [MN+]=422,2, WU=3,25 min; NMR (CDCl3, 400 MHz) δ compared to 8.26 (1H, d), 7,55 (2H, m), 7,16 (2H, d)6,70 (3H, m), of 4.16 (2H, q), 3,63 (2H, t) 3,5 (2H, m), 3,30 (1H, m), 3,20 (1H, m), of 2.50 (3H, s), 1,10 (3H, m).

Example 51

Obtain 2-{5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid 2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)-ethanol

Stage 1. To a solution of hydrox is Yes sodium (8,98 g, 224,49 mmol) in water (112,25 ml) was added at room temperature DL-alanine (10 g, 112,25 mmol). The resulting solution was heated at 75°and slowly added benzoyl chloride (15,77 g, 112,25 mmol). The reaction mixture is heated for 30 min, and cooled to 0°in the bath with ice. To bring the pH was added concentrated HCl, then the white solid is filtered on a funnel with a porous glass filter and dried in vacuum over P2O5throughout the night. Cleaning is not required. This procedure gives N-benzoylamino (19.6 g, yield 90,4%) as a white solid.1H NMR (DMSO-d6) δ was 12.61 (br s, 1H), 8,64 (d, 1H), 7,87-a 7.85 (m, 2H), 7,52-the 7.43 (m, 3H), and 4.40 (q, 1H), 1.39 in (d, 3H).

Stage 2. In the first flask N-benzoylamino (2 g, 10,35 mmol) dissolved in THF (20 ml) and added carbonyldiimidazole (CDI) (1.84 g, is 11.39 mmol). The resulting mixture was stirred for 1 h at room temperature and cooled to -78°C. In a second flask ethyl acetate (3,83 g, 43,48 mmol) in THF (40 ml) cooled to -78°and add LDA (24.3 ml, 48,51 mmol, 2 M in THF), pre-cooled to -78°C. the resulting solution was stirred 30 min at -78°and in the first flask via cannula add the resulting lithium enolate. The obtained white suspension was stirred 30 min at -78°and heated to -10°C. the Reaction is stopped with a saturated aqueous solution of the NH 4Cl. The phases are separated and the organic phase is dried over MgSO4and the solvents removed under reduced pressure. The crude product used in the next stage without purification. This gives ethyl-4-(benzoylamine)-3-oxopentanoate (2.6 g, yield 95,5%) as a white solid. ER-MS m/z 263,4 (MN)+; HPLC WU (min) 1,53;1H NMR (acetone-d6) δ 8,13 (br s, 1H), 7,93-to $ 7.91 (m, 2H), 7,58-the 7.43 (m, 3H), 4.72 in (m, 1H), 4,19-to 4.01 (q, 2H), to 3.67 (s, 2H), 1,47 (d, 3H)and 1.15 (t, 3H).

Stage 3. To the crude mixture of ethyl-4-(benzoylamine)-3-oxopentanoate (0.6 g, 2.28 mmol) in DMF (4 ml) at room temperature was added POCl3(1.04 g, at 6.84 mmol). The resulting solution was heated at 90°C for 1 h, then cooled to room temperature and poured on ice for 30 minutes the Aqueous solution is carefully added to saturated aqueous solution of NaHCO3. The phases are separated with EtOAc and the combined organic extracts dried over MgSO4and the solvent is removed under reduced pressure. The crude material is purified on a small Biotage column using a gradient solvent EtOAc/hexane from 0 to 50%. This gives ethyl-(4-methyl-2-phenyl-1,3-oxazol-5-yl)-acetate (0,269 g, yield 48%) as a yellowish oil. ER-MS m/z 246,2 (MN)+; HPLC WU (min) 2,77;1H NMR (COCl3) δ 8,01-7,98 (m, 2H), 7,45-7,41 (m, 3H), 4,20 (q, 2H), 3,71 (s, 2H), of 2.21 (s, 3H), of 1.28 (t, 3H).

<> Stage 4. To ethyl-(4-methyl-2-phenyl-1,3-oxazol-5-yl)-acetate (0,922 g, 3,76 mmol) in THF (6 ml) at room temperature was added LiBH42M/THF (9,41 ml, 4,70 mmol). The reaction mixture was stirred over night at room temperature, then treated with 2 N. HCl to pH 7. The solvent THF is removed under reduced pressure, added EtOAc and separated phases. The combined organic extracts dried over MgSO4and the solvent concentrated in vacuo. The crude material is purified on a Biotage column using a gradient solvent mixture EtOAc/hexane from 10 to 100%. This gives 2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)-ethanol (0,193 g, yield 25%) as a colourless oil. ER-MS m/z 204,2 (MN)+; HPLC WU (min) 2,02;1H NMR (acetone-d6) δ 7,98-to 7.95 (m, 2H), 7,52-7,42 (m, 3H), of 3.95 (br s, 1H), 3,82 (t, 2H) m 2,90 (t, 2H), 2.13 and (s, 3H).

Stage 5. DEAD (from 0.84 ml, 5,28 mmol) in THF (1.5 ml) is slowly added to a solution of the product obtained in stage 3 (of 4.95 mmol), methyl-5-hydroxy-2,3-dihydroindol-1-yl-2-butenoate (0,78 g, 3.3 mmol), PPh3(1.4 g, 5,28 mmol) in THF (13 ml). The mixture is stirred at room temperature overnight. The mixture is filtered, washed with water, brine, dried over sodium sulfate and concentrated. Chromatography on a column gives the product as colorless oil. LC-MS [S26H29NO4N]+=420,4, WU=4,00 min;1H NMR (CDCl3 ): δ to 7.9 (2H, d), was 7.45 (2H, dd), and 7.1 (d), 6,6-6,8 (3H, m), 4.2V (2H, t), 3,62 (3H, s), and 3.3 (1H, m)and 3.15 (2H, t), of 2.6-3.0 (2H, m), 2,5 (1H, m), of 2.21 (3H, s), of 1.95 (1H, m), 1.56 to 1,6 (3H, br, m)to 0.88 (3H, t).

Stage 6. KOH (0.5 ml, 3 N) was added to a solution of the product obtained in stage 4 (42 mg, 0.1 mmol)in THF/MeOH (1 ml), THF:Meon 8:2). The mixture was stirred at 70°C for 6 h, then cooled. The pH value was adjusted to 4 with 1 N. HCl. The mixture is extracted with ethyl acetate (3×2 ml). The combined organic layers dried over sodium sulfate and concentrated in vacuo. Chromatography on a column (2:8 hexane:ethyl acetate) gives the product as a white solid (33 mg, 81%). LC-MS [C25H27NO4H]+=406,3, WU=3,37 min;1H NMR (CDCl3): δ 8,0 (2H, d), was 7.45 (2H, dd), to 7.15 (1H, d), 6,7-6,8 (3H, m), 4.2V (2H, t), and 3.3 (1H, m)and 3.15 (2H, t), of 2.6-3.0 (2H, m), 2,5 (1H, m), of 2.21 (3H, s), of 1.95 (1H, m), 1.56 to 1,6 (3H, br m), 0,88 (3H, t)

By using the techniques described above in Example 51, using other suitable source of substances are obtained and characterized by the following substances:

Example 52

LC-MS [C26H29NO4H]+=420,3, WU=3,52 min;1H NMR (CDCl3): δ 7,87 (2H, d), 7,25 (2H, dd), and 7.1 (1H, d), 6,6-6,8 (3H, m), 4.2V (2H, t), of 3.45 (1H, m), 3,30 (1H, m)and 3.15 (2H, t), of 2.7-3.0 (2H, m, br), 2,5 (1H, m), 2,4 (3H, s) of 1.95 (1H, m), 1.56 to to 1.60 (3H, br, m)to 0.88 (3H, t)

Example 53

2-{5-[2-(4-Methyl-2-propyl-1,3-oxazol-5-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-Boo is anew acid

LC-MS [C22H29NO4H]+=372,3, WU=3,16 min;1H NMR (CDCl3): δ and 7.1 (1H, d), and 6.6 (2H, d)and 4.2 (2H, t), and 3.3 (1H, m), and 3.3 (1H, m), 2,8 (2H, t), 2,7 (1H, m), and 2.6 (2H, t), 2,4 (2H, m), 2,2 (3H, s), 2,0-1,8 (2H, br, m)to 0.88 (3H, t).

By using the techniques described above in Examples 1-53, with the use of other suitable starting compounds similarly obtain the compounds of formula Ia, are shown in table 3.

Table 3

Examples of preparing compounds of formula (Ia)

Example No.RR1R2R3R4R5xLC-MS [M+H]+or NMR
54NEtHMePhOCH2-HO436,2
55NEtHMePhCH2-Ho420
56NHHMePhHabout378,2
57MePh(CH2)3-HMe PhHabout3,45/3,52 (t, 3H), 4,10 (t, 2H), and 7.3 (m, 3H), 7,83 (d, 2H)
58EtEtO2C-HMePhHabout478,2
59EtEtHMePhHabout434,3

Example No.RR1R2R3R4R5XGHS [M+H]+or NMR
60NMeOHMePhHO3,30 (s, 3H), Android 4.04 (d, 1H), 7,98 (m, 2H)
61EtEtOHMePhHO450,3
62NCF3CH2-HMePhHAboutof 2.51 (s, 3H), 4,36 (m, 2H), 8,32 (m, 2H)
63EtCF3CH2-HMePhHAboutof 1.18 (t, 3H), is 4.21 (t, 2H), 7,98 (d,2H)
64MeWM-PrHMePhHAbout432,3
65NWM-PrHMePhHAbout0,02 (m, 1H), 0,12 (m, 1H), 4,18 (m, 2H), 7,94 (m, 2H)
66NHMePhHAbout512,3
67NEtHMePhHS422,3
68NHMePhHAboutto 526.4
69NEtHMePhHS422,3
70MeEtHMePhHS
71MeEtHMePhHAboutof 0.82 (t, 3H), of 3.54 (s, 3H), of 4.16 (t, 2H), of 7.90 (m, 2H)
72N EtHi-PrPhHAbout434,3
73NEtHPhPhHAbout468,3
74NMeHMePhHS422,3
75MeMeHMePhHS
76MeEtMeC(O)MePhHAbout462,4
77MeEt4-MeO-PhMePhHAboutto 526.4
78NEt4-MeO-PhMePhHAbout512,3
79MeEt4-pyridylMePhHAbout497,3

R5 97 About
Example No.RR1R2R3R4XLC-MS [M+H]+or NMR
80NEtHMecyclopentylHO398
81NEtHMecyclohexylHO412
82NEtHMe4-Ph-Ph-HAbout482
83EtEtO2With-HMe4-Me-PhHAbout492,3
84NPhCH2-HMe4-Me-PhHAbout482,4
85Etn-BuHMe4-Me-PhHAbout476,3
86EtMeHMe4-Me-PhHAbout434,3
87EtPhCH2-HMe4-Me-PhHAbout510,4
88 HEtHMe4-MeO-PhHAbout436,1
89HEtHMe4-i-Pr-PhHAboutUSD 448,2
90HEtHMe4-F-PhCH2-HAbout438,3
91HEtHMe4-F-PhHAbout424,3
92HEtHMe4-Et-PhHAbout434,3
93HEtHMe4-Cl-PhOCH2-HAbout470,2
94HEtHMe4-Cl-PhHAbout440
95MeEtHMe4-Cl-PhHS470,3
96MeEtHMe4-Cl-PhHS470,3
HEtHMe4-CF3-PhHS490,3
98MeEtHMe4-CF3-PhHS504,3
99HEtHMe4-CF3-PhHAbout474,3
100HEtHMe4-(n-Bu)-PhHAbout462,3
101HEtHMe4-(f-Bu)-PhHAbout462,3
102HEtHMe3-Me-PhHAbout420,4
103HEtHMe3-MeO-PhHAbout436,3
104HEtHMe3-Me-5-isoxazolylHAbout411,3
105HEtHMe3-F-PhH424,2
106HEtHMeS-F-4-Me-PhHAbout438,2
107HEtHMe4-F-S-Me-PhHAbout438,3
108MeEtHMe3-Cl-PhHS470,3

H
Example No.RR1R2R3R4R5xLC-MS [M+H]+or NMR
109NEtHMe3-Cl-PhHO440,3
110NEtHMe3-Cl-PhHS456,3
111NEtHMeC-CF3-PhHO474,2
112NEtHMe3,5-(CF3)2-PhH O542,1
113NEtHMe3,4-Me2-PhHAbout434,3
114NEtHMe3,4-Cl2-PhHAbout474,2
115NEtHMe2,3-Cl2-PhHAbout474,1
116NEtHMe3,4-(MeO)2-PhHAbout466,3
117NEtHMe3,4-methylendioxy-PhHAbout466,3
118NEtHMe2-thienylHAbout412
119NEtHMe2-naphthylHAbout456,3
120NEtHMe2-Me-PhHAbout420,3
121NEtMe2-furylHAbout396
122NEtHMe2-F-PhHAbout424,1
123NEtHMe2-benzothiazylHAbout462,2
124NEtHMe2,6-F2-PhHAbout442,2
125NEtHMe3,4-F2-PhHAbout442,2
126NEtHMe2,4-Cl2-PhHAbout473
127NEtHMe1-naphthylHAbout456,3
128MeEtHMeHAboutof 0.90 (t, 3H), of 3.45 (bs, 4H), 3,74 (s, 3H)

Example 129

Getting ethyl-(5-methoxy-2,3-dihydro-1H-inden-1-ilidene)-ethanoate

To a solution of 5-methoxyindole (150 g, of 0.91 mol) in anhydrous tetrahydrofuran (4.5 l) was added zinc (30 mesh, 103,64 g of 1.59 mol) and copper chloride(I) (a 4.53 g, 0.045 mol). The suspension is stirred in an atmosphere of Ar and refluxed for 15 min; to boiling under reflux the mixture is slowly added dropwise to about 25% portion of ethylbromoacetate (133 ml, 1.18 mol). After the mixture is allowed to cool and stirred overnight at room temperature, TLC shows the presence of the desired product, indicating the formation of reactive zinc compounds. Added dropwise to the rest of ethylbromoacetate; see the release of heat (the temperature in the flask rises to 35°). After 4 h, TLC indicates complete reaction. After settling of solids on the bottom of the flask, the liquid is drained by the siphon, leaving a small amount, closing solid. In the flask was again placed 5-methoxyindole (157,6 g, just to 1.86 mol), anhydrous tetrahydrofuran (4.5 l) and zinc (80,92 g, just by 2.73 mol). Added dropwise ethylbromoacetate (140 ml, only 2.36 mol). Watch the heat (the temperature in the flask rises to 35°). When mixed, the mixture is cooled to room temperature, TLC indicates complete reaction. Solid substance, allow to settle and the liquid is drained by the siphon. United reactio the basic mixture was concentrated in vacuo to a volume equal ˜2 liters of Liquid is poured into a quantity of 1 N aqueous hydrochloric acid solution (chilled water with ice), sufficient to bring the pH to 1. The product is extracted with ethyl acetate (2×1 l, 1×500 ml). The combined extracts washed with water, brine (1 l each), dried over sodium sulfate, filtered and concentrated in vacuo and get a dark red oil, which gradually solidifies (438,3 g; theoretical output = 432 g).1H NMR (CDCl3): δ and 7.5 (d, 1H), 6,8 (m, 2H), 6,2 (t, 1H)and 4.2 (q, 2H), and 3.8 (s, 3H), 3,3 (m, 2H), 3,0 (t, 2H), 1,3 (t, 3H). MS (HI) m/z 233 [M+H]+.

Example 130

Getting ethyl-(5-methoxy-2,3-dihydro-1H-inden-1-yl]-acetate

The crude product obtained in Example 129, dissolved in absolute ethanol (2.6 liters) and hydronaut when the hydrogen pressure equal to 40 pound-force/inch2over 10% palladium on coal (21,6 g). Filtration through celite and concentration of the filtrate gives 433,3 g brown oil (yield 99% for 2 stages).1H NMR (CDCl3): δ and 7.1 (dd, 1H), 6,8 (d, 1H), 6,7 (dd, 1H)and 4.2 (q, 2H), and 3.8 (s, 3H), 3,5 (m, 1H), 2,9 (m, 2H), and 2.7 (dd, 1H), 2,4 (m, 2H), 1,7 (m, 1H), 1,3 (t, 3H). MS (HI) m/z 235 [M+H]+.

Example 131

Receive (5-methoxy-2,3-dihydro-1H-inden-1-yl)-acetic acid

To a solution of the crude ether complex (416 g, 1.77 mol)obtained in Example 130, in 1 l of EtOH is ribault NaOH solution (142 g, 3.54 mol) in 1.5 l of water. The turbid reaction mixture is refluxed during this procedure, the color becomes dark red and the reaction mixture becomes homogeneous. After 1 h the reaction mixture was cooled to room temperature and EtOH is removed under reduced pressure. The alkaline aqueous layer is washed with Et2O (3×500 ml), then acidified with concentrated HCl to pH ˜4, after which a precipitate of oil. The mixture is extracted with Et2O (4×500 ml). The combined extracts washed with water (2×300 ml), brine, then dried over Na2SO4. Filtration and evaporation of the solvent under reduced pressure followed by drying under vacuum overnight giving the desired compound (305 g, 83%) as a yellow solid.1H NMR (CDCl3) δ 7,34 (d, 1H), of 6.71 (s, 1H), 6,65 (dd, 1H), 3,71 (s, 3H), 3,47 (m, 1H), 2,80 (m, 3H), 2,35 (m, 2H), 1,71 (m, 1H). MS (HI) m/z 207 [M+H]+.

Example 132

Getting [(1S)-5-methoxy-2,3-dihydro-1H-inden-1-yl]-acetic acid

To a solution of acid (341,0 g of 1.65 mol)obtained in Example 131, 8.2 liter of chemically pure acetone with stirring at room temperature is added dropwise (S)-(-)-α-methylbenzylamine (223,8 ml of 1.74 mol). During the addition produces a dense white precipitate. Add another 500 ml of acetone and stirring is continued for the of 1 hour The solid is collected by filtration, washed with 300 ml of acetone and dried under suction. Then the solid is suspended in acetone (8.2 liters) and refluxed until complete dissolution of the solids. The solution is slowly cooled during the night, and during this time a white precipitate is formed. The suspension is cooled to 0°C, then filtered and the solid is washed with 500 ml of acetone. After drying under suction sample analysis using HPLC leads to 95%. The recrystallization procedure is repeated as described above, using 6.7 l of acetone. Analysis by HPLC leads to 99% EE. After drying under suction receive 192 g of salt. Salt is suspended in 2 l of EtOAc and 1 l of 1 N HCl solution and shaken in a separating funnel, while the salt is dissolved. The organic layer is separated, washed with 1 N HCl (500 ml), water (2×300 ml) and brine, then dried over Na2SO4. The solvent is evaporated under reduced pressure, obtaining an oil which soon solidifies. After vacuum drying obtain the desired product (of 120.5 g, 35%) as an almost white solid.1H NMR (CDCl3) δ 7,10 (d, 1H), 6,79 (d, 1H), 6.73 x (dd, 1H), 3,79 (s, 3H), 3,55 (m, 1H), 2,89 (m, 2H), and 2.79 (dd, 1H), 2,46 (dd, 1H), 2,43 (m, 1H), 1,80 (m, 1H). MC (ESI) m/z 207 [M+H]+

Example 133

Getting [(1S)-5-methoxy-2,3-dihydro-1H-inden-1-yl]acetic acid

As an alternative Example 132 the desired compound can also be obtained using an enzymatic process. So, muddy crude mixture of ester (500.0 g, 2,13 mol; purity 87% according to HPLC)obtained in Example 130, in 1 liter of chemically pure acetone, 2.5 l phosphate buffer solution (pH 7.0, 0,05 M) and 2.5 l of deionized water treated with a single dose of lipase PS (Amano) (150 g) and the mixture vigorously stirred at room temperature overnight. Analysis of an aliquot by HPLC (homogeneous aliquot obtained by dissolving an aliquot of the IPA, followed by filtration) leads to a single peak corresponding to unreacted R-ether complex, and another peak corresponding to the desired S-acid. The presence of trace quantities of S-complex ester and R-acid. 2 N. HCl (500 ml, provide pH ˜2) one portion is added to the reaction mixture and stirred for 20 minutes the Mixture is filtered and the solids washed with EtOAc (2×500 ml)and then water (500 ml). The combined filtrates additionally diluted with 1 l of EtOAc and the layers together vigorously stirred. Stirring is stopped and the layers allowed to separate. Found emulsion, but they can be easily dissolved by addition of solid NaCl and stirring. The aqueous layer was removed, then extracted with EtOAc (3× l). The combined organic extracts washed with water (4×500 ml), then brine. The obtained organic layer is extracted with 5% solution of Na2CO3(8×500 ml). Carried out by HPLC analysis of the organic layer indicates that the layer does not contain the S-enantiomer of the acid. The combined extracts containing Na2CO3, washed with EtOAc (2×1 l), then acidified to pH ˜2 by adding 2 N. HCl. Precipitated white solid, which is accompanied by the production of CO2. The mixture is extracted with EtOAc (3×1 l). The combined extracts washed with water (2×1 l) and brine, then dried over Na2SO4. Carried out by HPLC analysis of this solution shows that this substance is characterized by 98%. The solvent is evaporated under reduced pressure, obtaining an oil which soon solidifies. The desired product (172,9 g) after vacuum drying receive in the form of not-quite-white solid. This material is recrystallized from boiling hexanol (8.8 liters). After cooling over night, light yellow needles collected by filtration, washed with hexane (200 ml) and dried under suction. After vacuum drying, the desired product (146,9 g, 38% (based on the crude source ester) obtained as light yellow needles.1H NMR leads to the same results, ka and above.

Example 134

Getting ethyl-[(1S)-5-methoxy-2,3-dihydro-1H-inden-1-yl]-acetate

To a solution of acid (305 g, 1.48 mol)obtained or in Example 132 or 133, 4.8 l of absolute EtOH at room temperature in an atmosphere of argon is added dropwise chlorotrimethylsilane (413 ml, 3.25 mol). During the addition the detected temperature increase of about 5°C. the Reaction mixture was stirred over night. EtOH is evaporated under reduced pressure and receive two-phase liquid mixture. It is diluted with 500 ml of ice water, then extracted with EtOAc (2×750 ml). The combined extracts washed with water (3×300 ml), then with saturated solution of NaHCO3(200 ml). Organic matter once washed with water (300 ml), then brine and dried over Na2SO4. After removal of solvent and drying in vacuum, the desired compound (354 g, 102%) was obtained as light yellow oil.1H NMR (CDCl3) δ 7,07 (d, 1H), 6,78 (d, 1H), of 6.71 (dd, 1H), 4,18 (q, 2H), of 3.78 (s, 3H), 3,52 (m, 1H), 2,89 (m, 2H), 2,72 (dd, 1H), 2,37, 2H), 1,74 (m, 1H), 1.28 (in t, 3H). MC (HEE) m/z 235 [M+H]+.

Example 135

Getting ethyl-[(1S)-5-hydroxy-2,3-dihydro-1H-indenyl]-acetate

To a cold solution (bath of ice water) of the compound (346 g, 1.48 mol)obtained in Example 134, 4.2 l CH2Cl2portions in atmospheres which Ar is added AlCl 3(984,6 g, 7,38 mol)so that the temperature of the reaction mixture remained below 10°C. Light brown suspension is stirred for 10 min, then added dropwise EtSH (546 ml, 7,38 mol) at such a speed that the temperature of the reaction mixture remained below 5°C. After 2.5 h stirring at a temperature below 10°the reaction mixture with vigorous stirring slowly poured into 6 liters of ice water. The organic layer is separated and the aqueous layer was extracted with CH2Cl2(3×1 l). The combined layers containing CH2Cl2, washed with water (2×1 l), dried over Na2SO4. The solvent is removed under reduced pressure, obtaining a brown oil which was filtered through a layer of silica gel (elwira using 0-10% EtOAc/hexane). Fractions are collected and after evaporation of the solvent and drying in vacuum, the desired compound (314 g, 96%) was obtained as a thick yellow oil.1H NMR (CDCl3) 56,92 (d, 1H), 6,62 (d, 1H), 6,55 (dd, 1H), 4,10 (q, 2H), 3.43 points (q, 1H), 2,75 (m, 2H), 2,64 (dd, 1H), 2,31 (dd, 1H), to 2.29 (m, 1H), 1,67 (m, 1H), 1,20 (t, 3H). MC (HEE) m/z 221 [M+H]+.

Example 136

Getting ethyl-2-((1S)-5-{2-[5-methyl-2-(4-were](1,3-oxazol-4-yl)-ethoxy}-indanyl)-acetate

A suspension of ethyl-[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]-acetate obtained in Example 135 (are 507, 5 mg, 2,30 mmol)and 2-[5-methyl-2-(4-were)-1,3-oxazol-4-yl]-ethanol, Paul is obtained in Example 10 (500 mg, 2,30 mmol), TMAD (792,6 mg, 4,60 mmol) and (1,21 g, 4,60 mmol) in 15 ml of anhydrous DCM was stirred at room temperature in Ar atmosphere for 12 hours DCM removed under reduced pressure. Flash chromatography of the residue on silica gel using 1% CH3CN/CH2Cl2gives ethyl-2-((1S)-5-{2-[5-methyl-2-(4-were)(1,3-oxazol-4-yl)]-ethoxy}-indanyl)-acetate (776,3 mg of 1.85 mmol, 80,5%). HPLC/MS (M+N)+m/z 420,5.

Example 137

Getting 2-((1S)-5-{2-[5-methyl-2-(4-were)-(1,3-oxazol-4-yl]-ethoxy}-indanyl)-acetic acid

Ethyl-2-((1S)-5-{2-[5-methyl-2-(4-were)(1,3-oxazol-4-yl)]-ethoxy}-indanyl)-acetate (Example 136, 776,3 mg of 1.85 mmol) in THF (4.0 ml) was added to a mixture aqueous solution of LiOH (2 M, and 3.7 ml, 7.4 mmol), water (2.0 ml) and EtOH (4.0 ml) at room temperature. The mixture becomes cloudy. This mixture is heated at 40°C (oil bath temperature). The reaction is finished after 1.5 hours After cooling to room temperature, to the mixture until pH 4.0 slowly added 1 N HCl solution. The compound extracted with EtOAc (3×20 ml). The combined layers containing EtOAc, dried (Na2SO4) and evaporated. Flash chromatography of the residue gives 2-((1S)-5-{2-[5-methyl-2-(4-were)(1,3-oxazol-4-yl)]-ethoxy}-indanyl)acetic acid (616,8 mg, 1.57 mmol, 85%) as a white solid.1H NMR (CDCl3) δ 7,83 (d, 2H), 7,21 (d, 2H), 7,03 (d, 1H), 6,74 (d, 1H, 6,69 (dd, 1H), 4,19 (t, 2H), 3.45 points (q, 1H), 2,93 (t, 2H), 2,78 (m, 2H), of 2.51 (m, 2H), 2,30 (s, 3H), of 2.25 (s, 3H), of 1.53 (m, 2H).

By using the techniques described above in Examples 129-137, using other suitable starting compounds similarly obtain the compounds of formula 1A, are shown in table 4.

Table 4

Examples of preparing compounds of formula (Ia)

Example No.R3R4LC/MS [M+H]
138Me4-MeO-Ph408,5
139Me3-MeO-Ph408,5
140Me4-Et-Phis 406.5
141Me4-CF3-Ph446,5
142Me2-naphthyl428,5
143Me4-(t-Bu)-Ph434,6
144Me4-(n-Bu)-Ph434,6
145Me422,5
146Me3,4-(Me)2-Phis 406.5
147Me4-Me-Ph392,5
148Me 3-F-Ph396,5
149Me2-benzothiazyl434,5
150Me4-i-Pr-Ph420,6
151Mecyclopentyl370,5
152Mecyclohexyl384,5
153MePhCH2392,5
154Me4-F-3-Me-Ph410,5
155Me3-F-4-Me-Ph410,5
156Me4-F-Ph396,5
157EtPh392,5
158Me3,4-(Cl)2-Ph447,4

Example No.R3R4LC/MS [M+H]
159n-PrPhis 406.5
160Me4-Ph-Ph454,5
161Me3-Cl-Ph412,4
162Me3-Me-Ph392,5
163Me4-CN-Ph403,4
164 Me3-CN-Ph403,4
165Me4-Cl-Ph412,4
166Me3-CF3-PhKZT 446.4
167Et4-Et-Ph420,5
168Et4-Me-Phis 406.5
169Et4-MeO-Ph422,4

Example 170

Obtaining methyl-4-bromo-3-oxopentanoate

In a dry three-neck flask in an atmosphere of Ar was placed a solution of methylpropionamide (20 g, 154 mmol) in CHCl3(100 ml). Using a dropping funnel over 2 h at 0°With added dropwise bromine (7.9 ml, 24.6 g, 154 mmol). Then the reaction mixture is allowed to slowly warm to room temperature and the reaction mixture was stirred over night. Slowly added a saturated solution of Na2CO3(40 ml) and after stirring the reaction mixture for a further 15 min, the layers of the solvents are separated and the aqueous layer was extracted with CH2Cl2(50 ml). The combined organic layers are dried (Na2SO4), filtered and concentrated under reduced pressure. Then the residue purified using flash chromatography on silica gel (10:1 hexane/EtOAc) and get the desired bromide as a pale yellow the oil (25 g, 78%).1H NMR (CDCl3): δ of 1.80 (d, 3H), 3,64-to 3.92 (m, 2H), of 3.78 (s, 3H), br4.61 (q, 1H).

Example 171

Obtaining methyl-(2-amino-5-methyl-1,3-thiazol-4-yl)-acetate

To a solution of the bromide obtained in Example 170 (18 g, 86 mmol)in toluene (100 ml) was added a thiourea (10.5 g, 138 mmol). The reaction mixture is heated to 100°C for 1 h, cooled to room temperature and the solvent is removed under reduced pressure. The residue is dissolved in CH2Cl2(100 ml)was added a saturated solution of NaHCO3(75 ml) and the mixture vigorously stirred for 10 minutes the Organic layer is separated, dried (Na2SO4), filtered and concentrated under reduced pressure. Then the residue is recrystallized from CH2Cl2/hexane and receive the product (10 g, 63%) as a white solid. (C7H10N2O2S): LC-MS, WU 0,76 min, M+H 187,0;1H NMR (CDCl3): δ of 2.23 (s, 3H), 3,70 (s, 2H), of 3.75 (s, 3H), of 4.83-of 4.95 (broad s, 2H).

Example 172

Obtaining methyl-(2-bromo-5-methyl-1,3-thiazol-4-yl)-acetate

To a solution of CuBr2(a 4.03 g of 18.1 mmol) and tert-butylnitrite (2,82 ml of 23.8 mmol) in MeCN (210 ml) at -20°add the compound obtained in Example 170 (2,95 g, 15.9 mmol). The reaction mixture is slowly heated to 15°and at this temperature there is a selection of N2. After PE is emiliania for another 2 h at 15° To the reaction mixture was diluted with Et2O (400 ml) and washed with 10% HCl solution (200 ml). Layers of solvent-separated, the aqueous layer was re-extracted with Et2O (2×300 ml) and the combined organic layers are dried (MgSO4), filtered and concentrated under reduced pressure. Then the residue purified using flash chromatography on silica gel (98:2, hexane/EtOAc) and get the bromide obtained in Example 172 (1.6 g, 40%)as a colorless oil, which during curing hardens. (C7H8BrNO2S): LC-MS, WU 2,56 min, M+H 250,3;1H NMR (CDCl3): δ and 2.26 (s, 3H), of 3.60 (s, 2H), 3,61 (s, 3H).

Example 173

Obtaining 2-(2-bromo-5-methyl-1,3-thiazol-4-yl)-ethanol

To a solution of ester obtained in Example 172 (3.80 g, of 15.2 mmol)in CH2Cl2(100 ml)was added DIBAL-H (33,4 ml, 33.4 mmol of a 1.0 M solution in toluene) at -78°C. After 15 min the solution was heated to 0°C and stirred for further 90 minutes After removal of the excess DIBAL-H are added dropwise 2 N aqueous HCl solution (50 ml). Layers solvents are separated and the aqueous layer was extracted with CH2Cl2(2×200 ml). The combined organic layers are dried (MgSO4), filtered and concentrated under reduced pressure. The residue is purified using flash chromatography on silica gel (5:2 hexane/EtOAc) and receive the product (25 g, 74%) as a yellowish oil, which during curing hardens. (C6H8BrNOS) LC-MS, WU 1,38 min, M+H 221,0;1H NMR (CDCl3): δ 2,31 (s, 3H), 2,82 (t, 2H), 2,90-of 3.00 (broad s, 1H), with 3.89 (t, 2H).

Example 174

Getting ethyl-{(1S)-5-[2-(2-bromo-5-methyl-1,3-thiazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-acetate

Stage 1. To a solution of the compound obtained in Example 173 (975 mg, 4,39 mmol), and ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]-acetate (1.06 g, a 4.83 mmol) in THF (20 ml), add Ph3R (1.88 g, 7,46 mmol) and ADDP (1,96 g, 7,46 mmol). The mixture is vigorously stirred at room temperature for 72 h, the solvent is removed under reduced pressure, and the residue purified using flash chromatography on silica gel (6:1 hexane/EtOAc)to give the product (1.4 g, 76%) as a colourless oil, which during curing hardens. (C19H22BrNO3S) LC-MS, WU to 3.92 min, M+H 424,5;1H NMR (CDCl3): δ of 1.26 (t, 3H), 1,65-of 1.81 (m, 1H), 2,28 at 2.45 (m, 2H), is 2.37 (s, 3H), 2,69 (dd, 1H), 2,75-of 2.93 (m, 2H), of 3.07 (t, 2H), 3,44 of 3.56 (m, 1H), 4,15 (t, 2H), 4,18 (q, 2H), to 6.67 (dd, 1H), 6.73 x (d, 1H), 7,03 (d, 1H).

Obtain ethyl((1S)-5-{2-[2-(4-isopropyl-phenyl)-5-methyl-1,3-thiazol-4-yl-1-ethoxy]-2,3-dihydro-1H-inden-1-yl}-acetate

Stage 2. To a mixture of toluene (15 ml) and 1,4-dioxane (3 ml) was added the compound obtained in stage 1 (300 mg, 0,708 mmol), 4-isopropylbenzylamine acid (464 mg of 2.83 mmol) and PdCl 2(dppf).CH2Cl2(52 mg, 0,071 mmol). Through the mixture for 30 min flow Ar flow, then add 2 N solution of Na2CO3(3,7 ml, was 7.08 mmol) and the reaction mixture is heated at 75°C for 18 h Then the reaction mixture is cooled to room temperature, diluted with EtOAc (200 ml) and washed with saturated solution of NaHCO4(50 ml). The organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure. The residue is purified using flash chromatography on silica gel (8:1 hexane/EtOAc), and receive the product (305 mg, 93%) as a colourless oil. (C28H33NO3S): LC-MS, WU 5,17 min, M+H 464,5;1H NMR (CDCl3): δ of 1.17 to 1.31 (m, 3H), 1.26 in (s, 3H), of 1.27 (s, 3H), 1,65-to 1.82 (m, 1H), 2,30 is 2.43 (m, 2H), 2,46 (s, 3H), of 2.72 (dd, 1H), 2,78-3,00 (m, 3H), 3,17 (t, 2H), 3.46 in is 3.57 (m, 1H), 4,17 (q, 2H), 4,27 (t, 2H), of 6.71 (d, 1H), 6,78 (s, 1H),? 7.04 baby mortality (d, 1H), 7,55 (AB Quartet, 4H).

Example 175

Receive ((1S)-5-{2-[2-(4-isopropyl-phenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-acetic acid

To a solution of the compound obtained in Example 174 (305 mg, 0,657 mmol)in a mixture of THF (8 ml), water (8 ml) and EtOH (4 ml), was added LiOH (63 mg, 2,63 mmol). The reaction mixture was vigorously stirred for 24 h, diluted with water (20 ml), and washed with Et2O (10 ml). Then the aqueous phase is acidified to pH ˜ 1 with 1 N HCl and then extracted with CH2/sub> Cl2(4×50 ml). The combined organic layers are dried (Na2SO4), filtered and concentrated under reduced pressure. Then the residue purified using flash chromatography on silica gel (95:5 CH2Cl2/MeOH) and receive the product(189 mg, 66%) as a white solid. (C26H29NO3S): LC-MS, WU 3,95 min, M+H 436,4;1H NMR (CDCl3): δ 1,25 (s, 3H), of 1.28 (s, 3H), 1.70 to to 1.82 (m, 1H), 2,32 is 2.43 (m, 2H), of 2.45 (s, 3H), 2,74 are 2.98 (m, 4H), 3,18 (t, 2H), 3,47-of 3.54 (m, 1H), 4,28 (t, 2H), 6,72 (dd, 1H), 6,78 (s, 1H), was 7.08 (d, 1H), 7,51 (the AB Quartet, 4H).

Example 176

Obtaining methyl-[5-methyl-2-(4-methyl-phenyl)-1,3-thiazol-4-yl]acetate

To a solution of the bromide obtained in Example 170 (1,15 g, 5,52 mmol)in toluene (20 ml), was added 4-methylcobalamin (1.0 g, 6.6 mmol). The reaction mixture was refluxed for 15 h, cooled to room temperature, diluted with EtOAc (150 ml) and washed with saturated solution of NaHCO3(50 ml)and then with saturated solution of NH4Cl (50 ml). The organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure. Then the residue purified using flash chromatography on silica gel (9:1 hexane/EtOAc) and get the product as a pink oil, which during curing hardens (1,14 g, 62%).1H NMR (CDCl3): δ of 2.38 (s, 3H), of 3.45 (s, 3H), 3,74 (s, 3H), 3,80 (s, 2H), 7,49 (AB Quartet, 4H); Rf (0,4, alue the t 9:1 hexane/EtOAc).

Example 177

Obtain 2-[5-methyl-2-(4-were)-1,3-thiazol-4-yl]-ethanol

To a solution of thiazole obtained in Example 176 (1,14 g, 4,37 mmol)in THF (60 ml) at 0°With portions added LiAIH4(663 mg, 17.5 mmol). After 30 min the reaction mixture was warmed to room temperature and stirred for another 60 minutes and Then the reaction mixture was cooled to 0°and excess LiAIH4remove dropwise successively adding water (5 ml), 1 N NaOH (10 ml) and water (5 ml). The mixture is then diluted with a saturated solution of the salt Rochelle and extracted with EtOAc (4×75 ml). The combined organic phases are dried (Na2SO4), filtered and concentrated under reduced pressure. The residue is purified using flash chromatography on silica gel (3:2 hexane/EtOAc) and get the product as a white solid (830 mg, 82%). (C13H15NOS): LC-MS, WU 2,50 min, M+N of 234.2;1H NMR (CDCl3): S of 2.34 (s, 3H), is 2.37 (s, 3H), and 2.83 (t, 2H), 3,92-4,01 (broad t, 2H), 4.04 the-4,15 (broad s, 1H), 7,45 (AB Quartet, 4H).

The following compounds are synthesized using one of two methods described in the above Examples, 170-177.

Example 178

{(1S)-5-[2-(5-Methyl-2-phenyl-1,3-thiazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}acetic acid

(C23H23NO3S): LC-MS WU of 3.56 min, M+H 394,2;1H the Mr (CDCl 3): δ 1,61-of 1.78 (m, 1H), 2,19-of 2.50 (m, 2H), 2,30 (s, 3H), 2,62-only 2.91 (m, 3H), of 3.12 (t, 2H), 3,17-3,26 (m, 1H), 4,12 (t, 2H), 6,70 (d, 1H), 6,79 (s, 1H), 6,98 (d, 1H), 7,21-7,40 (m, MN), 7,74-7,83 (m, 2H,).

Example 179

((1S)-5-{2-[5-Methyl-2-(4-methyl-phenyl)-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-acetic acid

(C24H25NO3S): LC-MS, WU 3,57 min, M+H 408,5;1H NMR (CDCl3): S 1,61 by 1.68 (m, 1H), to 2.29 (s, 3H), of 2.36 (s, 3H), 2,25-2,37 [hidden] (m, 2H), 2,63-and 2.79 (m, 3H), to 3.09 (t, 2H), 3,35-3,47 (m, 1H), 4,18 (t, 2H), 6,60 (dd, 1H), of 6.68 (s, 1H), 6,97 (d, 1H). 7,42 (AB Quartet, 4H), 7,81-8,30 (br, 1H).

Example 180

((1S)-5-{2-[2-(1,3-Benzodioxol-5-yl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)acetic acid

(C24H23NO5S): LC-MS, WU Android 4.04 min, M+H 438,5;1H NMR (CDCl3): δ 1,71 of-1.83 (m, 1H), 2,36 is 2.51 (m, 2H), of 2.45 (s, 3H), was 2.76-2,96 (m, 3H), 3.15 in (t, 2H), 3,48-to 3.58 (m, 1H), 4,29 (t, 2H), 6,00 (s, 2H), 6,72 (dd, 1H), 6,78 (s, 1H), PC 6.82 (d, 1H), 7,07 (d, 1H), 7,32-7,40 (m, 2H).

Example 181

((1S)-5-[2-[2-(4-Methoxy-phenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy]-2,3-dihydro-1H-inden-1-yl)acetic acid

(C24H25NO4S): LC-MS, WU 4,01 min, M+H 424,5;1H NMR (CDCl3): δ 1,67-to 1.82 (m, 1H), 2,43 (s, 3H), 2,34-2,47 (m, 2H), 2,72-2,95 (m, MN), to 3.09 (t, 2H), 3,42 is 3.57 (m, 1H), 3,84 (s, 3H), of 4.13 (t, 2H), 6,72 (d, 1H), 6,79 (s, 1H), 7,12 (d, 1H), 7,37 (AB Quartet, 4H).

Example 182

[(1S)-5-(2-{5-Methyl-2-[4-(trifluoromethyl)-phenyl]-1,3-thiazol-4-yl}-ethoxy)-2,3-dihydro-1H-inden-1-yl]-acetic acid

(C24H22F3NO3S): LC-MS, WU 4,47 min, M+H 462,4;1H NMR (DMSO-d6): δ 1,63-of 1.81 (m, 1H), 2,28 is 2.43 (m, 2H), 2,50 (s, 3H), 2,69 (dd, 1H), 2,74-2,95 (m, 2H), 3,19 (t, 2H), 3,31-to 3.36 (m, 1H), or 4.31 (t, 2H), of 6.71 (dd, 1H), 6,78 (s, 1H), was 7.08 (d, 1H), 7,87 (AB Quartet, 4H).

Example 183

((1S)-5-{2-[2-(4-Cyanophenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2.3-dihydro-1H-inden-1-yl)acetic acid

(C24H22F3NO3S): LC-MS, WU 3,43 min, M+H 419,6;1H NMR (CDCl3): δ 1,68-of 1.85 (m, 1H), 2,31-2,49 (m, 2H), of 2.51 (s, MN), 2,77 (dd, 1H), 2,83-to 2.94 (m, 2H), 3,18 (t, 2H), 3.43 points of 3.56 (m, 1H), or 4.31 (t, 2H), of 6.71 (dd, 1H), 6,79 (s, 1H), 7,10 (d, 1H), 7,86 (AB Quartet, 4H).

Example 184

((1S)-5-[2-[2-(4-Isopropylphenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy]-2,3-dihydro-1H-inden-1-yl)-acetic acid

(C26H29NO3S): LC-MS, WU 3,95 min, M+H 436,4;1H NMR (CDCl3): δ 1,25 (s, 3H), of 1.28 (s, 3H), 1.70 to to 1.82 (m, 1H), 2,32 is 2.43 (m, 2H), of 2.45 (s, 3H), 2,74 are 2.98 (m, 4H), 3,18 (t, 2H), 3,47-of 3.54 (m, 1H), 4,28 (t, 2H), 6,72 (dd, 1H), 6,78 (s, 1H), was 7.08 (d, 1H), 7,51 (the AB Quartet, 4H).

Example 185

((1S)-5-{2-[2-(3-Chloro-4-forfinal)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)acetic acid

(C23H21ClFNO3S): LC-MS, WU to 3.89 min, M+H KZT 446.4;1H NMR (CDCl3): δ 1,68 is 1.86 (m, 1H), 2,32 is 2.46 (m, 2H), 2,50 (s, 3H), 2,80 (dd, 1H), 2,84-2,96 (m, 2H), 3,18 (t, 2H), 3,47-3,59 (m, 1H), 4,32 (t, 2H), 6,72 (d, 1H), PC 6.82 (s, 1H), 7,12 (d, 1H), 7.23 percent (t, 1H), 7,72-of 7.82 (m, 1H), 7,97-of 8.04 (m, 1H).

Example 186

((S)-5-[2-[2-(3,4-Dichlorophenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy]-2,3-dihydro-1H-inden-1-yl)-acetic acid

(C23H21Cl2NO3S): LC-MS, WU 4,12 min, M+H 462,0;1H NMR (CDCl3): δ 1,74-of 1.88 (m, 1H), 2,36-2,48 (m, 2H), 2,50 (s, 3H), 2,73-of 2.93 (m, 3H), 3,19 (t, 2H), 3,48-3,55 (m, 1H), 4,30 (t, 2H), of 6.71 (d, 1H), 6,79 (s, 1H), to 7.09 (d, 1H), 7,52 (d, 1H), to 7.61 (dd, 1H), 8,02 (d, 1H).

Example 187

((1S)-5-{2-[2-(4-Forfinal)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)acetic acid

(C23H22FNO3S): LC-MS, WU to 3.58 min, M+H 412,4;1H NMR (CDCl3): δ 1.70 to 1.77 in (m, 1H), 2,37 at 2.45 (m, 1H), 2,44 (s, 3H), 2,70-2,90 (m, 4H), and 3.16 (t, 2H), 3,47-to 3.52 (m, 1H), 4,27 (t, 2H), 6,70 (d, 1H), 6,76 (s, 1H), 7,00-7,10 (m, 3H), 7,82-7,87 (m, 2H).

Example 188

((1S)-5-(2-[2-(3,4-Dimetilfenil)-5-methyl-1,3-thiazol-4-yl]-ethoxy)-2,3-dihydro-1H-inden-1-yl)acetic acid

(C25H27NO3S): LC-MS, WU 4,39 min, M+H 422,3;1H NMR (CDCl3): δ 1,70 of-1.83 (m, 1H), to 2.29 (s, 3H), 2,32 (s, 3H), 2,37-2,50 [hidden] (m, 2H), 2,46 (s, 3H), 2,70,-2,90 (m, 3H), of 3.32 (t, 2H), 3.45 points-of 3.60 (m, 1H), 4,30 (t, 2H), 6.73 x (d, 1H), 6,79 (s, 1H), 7,07 (d, 1H), 7,17 (d, 1H), to 7.59 (d,1H), 7,68 (s,1H).

Example 189

((1S)-5-{2-[2-(4-Acetylphenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)acetic acid

(C25H25NO4S): LC-MS, WU 4,01 min, M+H 436,3;1H NMR (CDCl3): δ 1,70-to 1.82 (m, 1H), 2,37-2,49 (m, 2H), 2,50 (s, 3H), 2.63 in (s, 3H), 2,70-2,90 (m, 3H), 3,20 (t, 2H), 3.45 points-of 3.60 (m, 1H), 4,30 (t, 2H), 6,72 (d, 1H), 6,78 (s, 1H), was 7.08 (d, 1H), 7.95 is-8,03 (m, 4H).

Example 190

[(1S)-5-(2-[2-[4-D is methylamino)-phenyl]-5-methyl-1,3-thiazol-4-yl]-ethoxy)-2,3-dihydro-1H-inden-1-yl]-acetic acid

(C25H28N2O3S): LC-MS, WU 2,95 min, M+H 437,2;1H NMR (DMSO-d6): δ 1,53-of 1.65 (m, 1H), 2,12-of 2.24 (m, 2H), a 2.36 (s, 3H), 2,63-2,84 (m, 3H), equal to 2.94 (s, 6H), 3,03 (t, 2H), 3.27 to to 3.38 (m, 1H), 4,18 (t, 2H), of 6.65 (d, 1H), 6.75 in (s, 1H), was 7.08 (d, 1H), 7,17 (AB Quartet, 4H).

Example 191

((1S)-5-{2-[2-(3-Amino-4-were)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)acetic acid

With24H26N2O3S.2F3O2): LC-MS, WU 3,5 min, M+H 423,3;1H NMR (CD3OD): δ 1,67-to 1.82 (m, 1H), 2,25-is 2.37 (m, 2H), of 2.38 (s, 3H), of 2.50 (s, 3H), 2,67-2,90 (m, 3H), 3,20 (t, 2H), 3,41 of 3.56 (m, 1H), 4,32 (t, 2H), of 6.71 (d, 1H), 6,79 (s, 1H), to 7.09 (d, 1H), 7,42 (d, 1H), 7,69 (dd, 1H), to 7.77 (d, 1H).

Example 192

((1S)-5-{2-[2-(2-Forfinal)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-acetic acid

(C23H22FNO3S): LC-MS, WU 4,25 min, M+H 412,2;1H NMR (CDCl3): δ 1,70-to 1.82 (m, 1H), 2,37-2,48 (m, 2H), 2.49 USD (s, 3H), 2,74-to 2.94 (m, 3H), 3,21 (t, 2H), 3,42-of 3.60 (m, 1H), or 4.31 (t, 2H), 6,72 (d, 1H), 6,79 (s, 1H), 7,06-7,35 (m, 4H), 8,21 (t, 1H).

Example 193

((1S)-5-(2-[2-(4-Chlorophenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy)-2,3-dihydro-1H-inden-1-yl)acetic acid

(C23H22ClNO3S): LC-MS, WU of 4.44 min, M+H 428,2;1H NMR (CDCl3): S 1,70-of 1.81 (m, 1H), 2,35 at 2.45 (m, 2H), 2,46 (s, 3H), 2,74-2,89 (m, 3H), 3,17 (t, 2H), 3,42-of 3.60 (m, 1H), 4.28 (t, 2H), of 6.71 (d, 1H), 6,77 (s, 1H), 7,07 (d, 1H), was 7.36 (d, 2H), 7,79 (d, 2H).

Example 194

((S)-5-{2-[2-(4-Ethoxyphenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)acetic acid

(C25H27NO4S): LC-MS, WU 3,55 min, M+H 438,5;1H NMR (CDCl3): δ of 1.40 (t, 3H), 1.70 to to 1.82 (m, 1H), 2,35-2,47 (m, 2H), of 2.45 (s, 3H), 2,74-2,89 (m, 3H), 3,20 (t, 2H), 3,42-3,59 (m, 1H), 4,07 (q, 2H), 4,29 (t, 2H), of 6.71 (d, 1H), 6,76 (s, 1H), 6,91 (d, 1H), 7,06 (d, 2H), 7,82 (d, 2H).

Example 195

((1S)-5-{2-[2-(3,4-acid)-5-metal-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)acetic acid

(C25H27NO5S): LC-MS, WU 3,86 min, M+H 454,2;1H NMR (CDCl3): δ 1,67-to 1.82 (m, 1H), 2,37-2,48 (m, 2H), 2.49 USD (s, 3H), 2.71 to 2,87 (m, 3H), of 3.27 (t, 2H), 3,42 is 3.57 (m, 1H), 3,93 (s, 3H), of 3.96 (s, 3H), 4,29 (t, 2H), 6,35-6,64 (broad s, 1H), to 6.67 (d, 1H), 6.75 in (s, 1H), 6,89 (d, 1H), 7,05 (d, 1H), 7,39 (d, 1H), 7,56 (s, 1H).

Example 196

((1S)-5-{2-[5-Methyl-2-(3-were)-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)acetic acid

(C24H25N3S): LC-MS, WU 3,71 min, M+H 408,2;1H NMR (CDCl3): δ 1,70-to 1.82 (m, 1H), 2,38-2,52 (m, 2H), 2.40 a (s, 3H), 2,47 (s, 3H), 2,75-2,87 (m, 3H), 3,19 (t, 2H), 3.45 points-of 3.60 (m, 1H), 4,29 (t, 2H), 6,72 (d, 1H), 6,78 (s, 1H), 7,07 (d, 1H), 7,19 (d, 1H), 7,30 (t, 1H), to 7.64 (d, 1H), of 7.75 (s, 1H).

Example 197

[(1S)-5-(2-{5-Methyl-2-[3-(trifluoromethyl)-phenyl]-1,3-thiazol-4-yl}-ethoxy)-2,3-dihydro-1H-inden-1-yl]-acetic acid

(C24H22F3NO3S): LC-MS, WU 3,90 min, M+H 462,1;1H NMR (CDCl3): S 1,70-to 1.82 (m, 1H), 2,38-2,48 (m, 2H), 2.49 USD (s, 3H), 2,75-2,87 (m, 3H), 3,19 (t, 2H), 3,44-3,59 (m, 1H), 4,30 (t, 2H), 6,72 (d, 1H), 6,79 (s, 1H), 7,07 (d, 1H), 7,52(t, 1H), to 7.61 (d, 1H), 8,01 (d, 1H), 8,13 (s, 1H).

Example 198

((1S)-5-{2-[2-(3-Forfinal)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)acetic acid

(C23H22FNO3S): LC-MS, WU 3,66 min, M+H 412,1;1H NMR (CDCl3): δ 1,70-to 1.82 (m, 1H), 2,39-2,47 (m, 2H), 2,48 (s, 3H), was 2.76-2,87 (m, 3H), 3,18 (t, 2H), 3.45 points-of 3.60 (m, 1H), 4,30 (t, 2H), 6,72 (d, 1H), 6,78 (s, 1H),? 7.04 baby mortality-to 7.09 (m, 2H), was 7.36-7,42 (m, 1H), 7,58 to 7.62 (m, 2H).

Example 199

((1S)-5-(2-[2-(3, 5dimethylphenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy)-2,3-dihydro-1H-inden-1-yl)acetic acid

(C25H27NO3S): LC-MS, WU 3,88 min, M+H 422,2;1H NMR (CDCl3): δ 1,72-of 1.84 (m, 1H), a 2.36 (s, 6H), 2,37 at 2.45 (m, 2H), 2,46 (s, 3H), 2,75-2,87 (m, 3H), 3,19 (t, 2H), 3.45 points-of 3.60 (m, 1H), 4,28 (t, 2H), 6,72 (d, 1H), 6,79 (s, 1H), 7,01 (s, 1H), 7,07 (d, 1H), of 7.48 (s, 2H).

Example 200

[(1S)-5-(2-{5-Methyl-2-[4-(triptoreline)-phenyl]-1,3-thiazol-4-yl}-ethoxy)-2,3-dihydro-1H-inden-1-yl]-acetic acid

(C24H22F3NO4S): LC-MS, WU 3,95 min, M+H 478,1;1H NMR (CDCl3): δ 1,72-of 1.84 (m, 1H), 2,38 is 2.46 (m, 2H), 2,47 (s, 3H), 2,75-2,87 (m, 3H), 3,18 (t, 2H), 3.45 points-of 3.60 (m, 1H), 4,29 (t, 2H), 6,72 (d, 1H), 6,77 (s, 1H), 7,07 (d, 1H), 7,24 (d, 2H), 7,88 (d, 2H).

Example 201

((1S)-5-(2-[2-(3-Methoxyphenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy)-2,3-dihydro-1H-inden-1-yl)acetic acid

(C24H25NO4S): LC-MS, WU of 3.56 min, M+H 424,2;1H NMR (CDCl3): 61,70-to 1.82 (m, 1H), 2,37-2,52 m, 2H), 2.49 USD (s, 3H), 2,75-2,87 (m, 3H), 3,19 (t, 2H), 3.45 points is 3.57 (m, 1H), a 3.87 (s, 3H), 4,30 (t, 2H), 6,72 (d, 1H), 6,79 (s, 1H), 6,95 (d, 1H), 7,10 (d, 1H), 7,32 (t, 1H), 7,40 was 7.45 (m, 2H).

Example 202

((1S)-5-{2-[2-(1,1'-Biphenyl-4-yl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)acetic acid

(C29H27NO3S): LC-MS, WU 3,96 min, M+H 470,3;1H NMR (CDCl3): δ 1,70-of 1.81 (m, 1H), 2,38-2,48 (m, 2H), 2.49 USD (s, 3H), 2,75-2,87 (m, 3H), 3,20 (t, 2H), 3,43-3,59 (m, 1H), or 4.31 (t, 2H), 6,72 (d, 1H), 6,79 (s, 1H), was 7.08 (d, 1H), was 7.36 (t, 1H), 7,45 (t, 2H), to 7.61-the 7.65 (m, 4H), to 7.93 (d, 2H).

Example 203

Getting ethyl-{(1S)-5-[2-(4-methyl-2-Phenyl-1,3-oxazol-5-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-acetate

ADDP (0,205 g, 0.81 mmol) was added to a mixture of PPh3(0,212 g, 0.81 mmol), ethyl-[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]-acetate (0,107 g, 0.49 mmol) and 2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)-ethanol (stage 4, Example 51, 0,110 g, 0.54 mmol) in THF (5 ml). The reaction mixture was stirred over night at room temperature and additionally added ADDP (0,136 g, 0.54 mmol) and PPh3(0,141 g, 0.54 mmol) CH2Cl2(5 ml). The solution is stirred for 24 h at room temperature and filtered. The filtrate is evaporated and the resulting mixture was purified on a Biotage column using a gradient solvent EtOAc/hexane from 0 to 50%. Get ethyl-{(1S)-5-[2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-acetate (0,145 g, yield 66%) as a yellowish mA is La. ER-MS m/z 406,2 ((MN)+; HPLC WU (min) to 3.89;1H NMR (acetone-d6) δ a 7.85-of 7.82 (m, 2H), was 7.36-7,30 (m, 3H), 6,94 (d, 1H), 6,65 (s, 1H), 6,60-6,55 (m, 1H), 4,10 (t, 2H), 3,98 (q, 2H), 3,31-of 3.27 (m, 1H), 3,03 (t, 2H), 3.27 to of 2.51 (m, 3H), 2,24 with 2.14 (m, 2H), 2,18 (s, 3H), 1,58-of 1.53 (m, 1H), only 1.08 (t, 3H).

Example 204

Obtaining {(1S)-5-[2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-acetic acid

Ethyl{(1S)-5-[2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-acetate (is 0.135 g, 0.33 mmol) dissolved in EtOH (6 ml) and added LiOH (0,024 g, 1.0 mmol). Add water (3 ml) and THF until a cloudy solution becomes transparent. The resulting mixture is stirred over night at room temperature. Add HCl (2 BC)until the pH value becomes equal to 2, then extracted three times with ethyl acetate. The organic layers are combined, dried and concentrated and receive {(1S)-5-[2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}acetic acid (0,039 g, the output of 30.6%) as a colourless oil. ER-MS m/z 378,2 (MN)+; HPLC WU (min) 3,22;1H NMR (acetone-d6S to 8.1 (br s 1H) 8,0-to 7.95 (m, 2H), 7,52-the 7.43 (m, 3H), 7,15 (d, 1H), for 6.81 (s, 1H), 6.73 x (d, 1H), 4,27 (t, 2H) 3,47 is 3.40 (m, 1H), 3,18 (t, 2H), 2,90 of 2.68 (m, 3H), 2,41-to 2.29 (m, 2H), 2,18 (s, 3H), 1.77 in by 1.68 (m, 1H).

By using the techniques described above in Examples 51, 203 and 204, with the use of other suitable source of substances are obtained and characterized by the following connections:

Example 205

Obtaining N-(4-Mei the benzoyl)-alanine

1H NMR (DMSO-d6) δ 12,60 (br s, 1H), to 8.57 (d, 1H), 7,81 (d, 2H), 7,28 (d, 2H), to 4.38 (q, 1H), 2,35 ( s, 3H), of 1.38 (d, 3H).

Example 206

Obtaining N-(3-fluoro-4-methylbenzoyl)-alanine

1H NMR (DMSO-d6) δ 12,54 (br s, 1H), 8,67 (d, 1H), 7,65 to 7.62 (m, 2H), 7,39 (t, 1H), to 4.38 (q, 1H), and 2.27 (s, 3H), of 1.38 (d, 3H).

Example 207

Obtaining N-[4-(trifluoromethyl)-benzoyl]-alanine

1H NMR (DMCO-d6) δ 12,64 (br s, 1H), 8,91 (d, 1H), 8,08 (d, 2H), a 7.85 (d, 2H), 4,42 (q, 1H), 1,40 (d, 3H).

Example 208

Getting ethyl-4-[(4-methylbenzoyl)-amino]-3-oxopentanoate

ER-MS m/z 278,38 ((MN)+); HPLC WU (min) 2,04.1H NMR (acetone-d6) δ 8,08 (br s, 1H), of 7.90 (d, 2H), 7,28 (d, 2H), 4,72-of 4.67 (m, 1H), 4,13 (q, 2H), 3,66 (s, 2H), 2.40 a (s, 3H), of 1.41 (d, 3H), of 1.12 (t, 3H).

Example 209

Getting ethyl-4-[(3-fluoro-4-methylbenzoyl)-amino]-3-oxopentanoate

ER-MS m/z usd296.4 ((MN)+); HPLC WU (min) of 2.26.1H NMR (acetone-d6) δ 7,75-of 7.60 (m, 2H), 7,38 (t, 1H), 4,20 (q, 2H), the 3.65 (s, 2H), of 2.23 (s, 3H), of 1.45 (d, 3H), of 1.20 (t, 3H).

Example 210

Getting ethyl-3-oxo-4-{[4-(trifluoromethyl)-benzoyl]-amino}-pentanoate

ER-MS m/z 332,4 ((MN)+); HPLC WU (min) 2,45.1H NMR (acetone-d6) δ to 8.14 (d, 2H), to 7.84 (d, 2H), 4.80 to 4,74 (m, 2H), 4,20 (q, 2H), 3,70 (s, 2H), to 1.48 (d, 3H), of 1.21 (t, 3H).

Example 211

Getting ethyl-[4-Mei is-2-(4-were)-1,3-oxazol-5-yl]-acetate

ER-MS m/z of 260.2 ((MN)+); HPLC WU (min) 2,96.1H NMR (acetone-d6) δ 7,86 (d, 2H), 7,30 (d, 2H), 4,15 (q, 2H), 3,81 (s, 2H), is 2.37 (s, 3H), and 2.14 (s, 3H), of 1.24 (t, 3H).

Example 212

Getting ethyl-[2-(3-fluoro-4-were)-4-methyl-1,3-oxazol-5-yl]-acetate

ER-MS m/z 278,3 ((MN)+); HPLC WU (min) 2,89.1H NMR (acetone-d6) δ of 7.69 (d, 1H), 7,60 (d, 1H), 7,37 (t, 1H), 4,15 (q, 2H), 3,83 (s, 2H), 2,31 (s, 3H), of 2.15 (s, 3H), of 1.23 (t, 3H).

Example 213

Getting ethyl-{4-methyl-2-[4-(trifluoromethyl)-phenyl]-1,3-oxazol-5-yl}-acetate

ER-MS m/z 314,3 ((MN)+); HPLC WU (min) with 3.27.1H NMR (acetone-d6) δ 8,18 (d, 2H), to 7.84 (d, 2H), 4,17 (q, 2H), 3,88 (s, 2H), measuring 2.20 (s, 3H), of 1.23 (t, 3H).

Example 214

Getting 2-[4-methyl-2-(4-were)-1,3-oxazol-5-yl]-ethanol

ER-MS m/z 218,2 ((MN)+); HPLC WU (min) 2,35.1H NMR (acetone-d6) δ a 7.85 (d, 2H), 7,27 (d, 2H), 3,99 (br s, 1H), 3,83 (t, 2H), 2,90 (t, 2H), is 2.37 (s, 3H), 2,12 (s, 3H).

Example 215

Obtain 2-[2-(3-fluoro-4-were)-4-methyl-1,3-oxazol-5-yl]-ethanol

ER-MS m/z 236,2 ((MN)+); HPLC WU (min) 2,46.1H NMR (CDCl3) δ 7,54 (d, 1 H), the 7.43 (d, 1H), 7,17 (t, 1H), 3,91 (d, 2H), 3,09 (s, 1H), 2,88 (t, 2H), to 2.29 (s, 3H), 2.13 and (s, 3H).

Example 216

Getting 2-{4-methyl-2-[4-(trifluoromethyl)-phenyl]-1,3-oxazol-5-yl}-ethanol

ER-MS m/z 272, ((MN) +); HPLC WU (min) 2,71.1H NMR (CDCl3) δ 8,03 (2, 2N), 7,66 (d, 2H), 3,95 (t, 2H), 2,96 (t, 2H), of 2.21 (s, 3H), of 1.97 (br s, 1H).

Example 217

Getting ethyl-[(1S)-5-(2-{4-methyl-2-[4-(trifluoromethyl)-phenyl]-1,3-oxazol-5-yl}-ethoxy)-2,3-dihydro-1H-inden-1-yl]-acetate

ER-MS m/z 474,5 ((MN)+); HPLC WU (min) 4,10.1H NMR (acetone-d6) δ is 8.16 (d, 2H), 7,83 (d, 2H), to 7.09 (d, 1H), 6,80 (s, 1H), 6,72 (dd, 1H), 4,28 (t, 2H), 4,12 (q, 2H), 3.46 in-to 3.41 (m, 1H), 3,21 (t, 2H), 2,86-to 2.65 (m, 3H), 2,39-of 2.26 (m, 2H), measuring 2.20 (s, 3H), 1,75-1,63 (m, 1H), 1,22 (t, 3H).

Example 218

Obtain ethyl((1S)-5-{2-[4-methyl-2-(4-were)-1,3-oxazol-5-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-acetate

TLC Rf=0,22 hexane/EtOAc 4:1.

Example 219

Obtain ethyl((1S)-5-{2-[2-(3-fluoro-4-were)-4-methyl-1,3-oxazol-5-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-acetate

ER-MS m/z 438,2 ((MN)+); HPLC WU (min) 4,18.1H NMR (acetone-d6) δ to 6.67 (dd, 1H), to 7.59 (dd, 1H), 7,37 (t, 1H), was 7.08 (d, 1H), 6,80 (s, 1H), 6,72 (dd, 1H), 4.26 deaths (t, 2H), 4,12 (q, 2H), 3.46 in-to 3.38 (m, 1H), 3,17 (t, 2H), 2,89-to 2.65 (m, 3H), 2,39-of 2.23 (m, 5H), 2,17 (s, 3H)), a 1.75-to 1.63 (m, 1H), 1,23 (t, 3H).

Example 220

Receive ((1S)-5-{2-[4-methyl-2-(4-were-3-oxazol-5-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-acetic acid

ER-MS m/z 392,2 ((MN)+); HPLC WU (min) 3,36.1H NMR (acetone-d6) δ 7,72 (d, 2H), 7,15 (d, 2H), 6,99 (d, 1H), to 6.67 (s, 1H), 6,59 (dd, 1H), 4,12 (t, 2H), 3.33 and of 3.28 (m, 1H), 3,03 (t, 2H), 2,73-of 2.54 (m, 3H), 2,27-2,2 (m, 5H), 2,02 (s, 3H), 1,64-and 1.54 (m, 1H).

Example 221

Receive ((1S)-5-{2-[2-(3-fluoro-4-were)-methyl-1,3-oxazol-5-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)acetic acid

ER-MS m/z 410,2 ((MN)+); HPLC WU (min) 3,49.1H NMR (acetone-d6) δ to 7.68 (dd, 1H), to 7.59 (dd, 1H), was 7.36 (t, 1H), 7,12 (d, 1H), 6,80 (s, 1H), 6,72 (dd, 1H), 4.26 deaths (t, 2H), 3,47-to 3.41 (m, 1H), 3,18 (t, 2H), 2,86-to 2.67 (m, 3H), 2.40 a-2,28 (m, 5H), 2,17 (s, 3H), 1.18 to 1,65 m, 1H).

Example 222

Getting [(1S)-5-(2-{4-methyl-2-[4-(trifluoromethyl)-phenyl]-1,3-oxazol-5-yl}-ethoxy)-2,3-dihydro-1H-inden-1-yl]acetic acid

ER-MS m/z 446,5 ((MN)+); HPLC WU (min) 3,47.1H NMR (acetone-d6) δ 8,17 (d, 2H), to 7.84 (d, 2H), 7,13 (s, 1H), 6,80 (s, 1H), 6,72 (dd, 1H), 4,28 (t, 2H), 3.46 in-to 3.41 (m, 1H), 3,21 (t, 2H), 2,86-to 2.67 (m, 3H), 2.40 a-2,28 (m, 2H), measuring 2.20 (s, 3H), 1.77 in-1,67 (m, 1H).

Example 223

Obtain (2S)-2{(1S)-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl)-propanoic acid and (2R)-2-{(1H)-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-propanoic acid

and

Stage 1. Obtain (2S)-2-[(1S)-5-methoxy-2,3-dihydro-1H-inden-1-yl]-propanoic acid and (2R)-2-[(1R)-5-methoxy-2,3-dihydro-1H-inden-1-yl]propanoic acid

and

The original acid (Example 2b) is injected into the reaction according to the method similar to that described in Example 4, when davlenie 260 pound-force/inch2and using 4.5 g of original substance, 1.04 g of catalyst and 4.5 ml of triethylamine in 45 ml of ethanol and 5 ml THF. Standard method of extraction gives up 3.22 g of the product. Retention time LC/MS is equal to 2.41 min, NMR (DMCO-d6): of 0.87 (d, 3H, α-methyl), a 1.75 (m, 1H), 2,04 (m, 1H), 3,66 (s, 3H, methoxyl), of 6.65 (m, 1H, aryl), 6,76 (s, 1H, aryl),? 7.04 baby mortality (d, 1H, aryl), 12,18 (bs, 1H, acid.)

Stage 2. Obtaining methyl-(2S)-2-[(1S)-5-methoxy-2,3-dihydro-1H-inden-1-yl]-propanoate and methyl(2R)-2-[(1R)-5-methoxy-2,3-dihydro-1H-inden-1-yl]-propanoate

and

Connection receive by the reaction of 1.5 g of the original acid, with 0.93 ml of iodomethane and 1.75 g of sodium bicarbonate in 10 ml of methanol under standard conditions of esterification as described in Example 6. Processing network of 1.53 g, 96%. (NMR (CD2Cl2): of 1.05 (d, 3H, α-methyl), a 1.88 (m, 1H), 2,19 (m, 1H), 3,44 (m, 1H), 3,68 (s, 3H, methoxyl), of 3.77 (s, 3H, ester).

Stage 3. Receiving: methyl-(2S)-2-[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]-propanoate and methyl(2R)-2-[(1R)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]-propanoate

and

In terms demethylation described in Example 7 (1,53 g of educt, 4.35 g AlCl3and 2.4 ml acentriolar in 20 ml dichloromethane), get to 1.21 g of product (84%). (NMR (CD2Cl2): of 1.05 (d, 3H, α-methyl), a 1.88 (m, 1H), 2,18 (m, 1H), of 3.45 (m, 1H), 3,67 (, 3H, ester), 6,60 (m, 1H, aryl), 6,69 (s, 1H, aryl), 6,93 (d, 1H, aryl).

Stage 4: Obtain methyl(2S)-2-{(1S)-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-propanoate and methyl(2R)-2-[(1R)-[5-methyl-2-phenyl-1,3-oxazol-4-yl-ethoxy]-2,3-dihydro-1H-inden-1-yl]-propanoate

and

Using standard techniques of combinations of Mitsunobu described in Example 11 (0,100 g original phenol, 0,110 g oxazolidinone, 0,143 g of triphenylphosphine and 0.137 g ADDP in 2 ml of dichloromethane), after chromatography in 15% EtOAc/hexane get 0,107 g (58%) of product. NMR (CD2Cl2): 1,62-to 1.87 (m, 4H), 2.40 a (s, 3H, methyl group oxazole), 2,98 (t, 2H, methylene), 3,23 (m, 1H), 3,63 (s, 3H, ester), 6,60 (s, 1H, aryl), only 6.64 (m, 1H, aryl), 7,42 (m, 3H, aryl), 8,00 (m, 2H, aryl).

Stage 5. (2S)-2-{(1S)-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-propanoic acid and (2R)-2-{(1R)-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}propanoic acid

and

For 0,090 g source of ester using the conditions of hydrolysis using LiOH and get 0,082 g (95%) of product. NMR (CD3OD): 0,4-0,75 (m, 4H), of 1.18 (s, 3H), of 1.75 (t, 2H, methylene), 2,00 (m, 1H), 2,99 (t, 2H, methylene), of 5.39 (s, 1H, aryl), of 5.48 (m, 1H, aryl), of 5.83 (d, 1H, aryl), 6,27 (m, 3H, aryl), 6,76 (m, 2H, aryl).

Using the techniques described above, and a suitable source ve is the EU ETS additional (2S,1S) and (2R,1R) connection receive in the same way as mixtures of diastereoisomers (i.e. Shin-{(2S,1S)/(2R,1R)} and or anti-{(2S,1S)/(2S,1R)}) mixtures or as individual enantiomers. These compounds are listed in table 5.

Table 5

Example No.R3R4XIsomerThe HPLC retention time (min)LC-MS [M+H]+
224Me3,4-(Cl)2-PhO2S,1S4,10460,0
225Me3,4-(Cl)2-PhOSYN-racemate4,10460,0
226Me3,4-(Me)2-PhAboutSYN-racemate4,32420,4
227Me3,4-(Me)2-PhAbout2S,1S4,32420,4
228Me3-Me-PhAboutSYN-racemate4,19406,3
229Me4-CF3-PhAboutSYN-racemateto 3.73460,2
20 Me4-CF3-PhAbout2S,1Sto 3.73460,2
231Me4-CF3-PhAbout2R,1Rto 3.73460,2
232Me4-Cl-PhAboutSYN-racemate3,61to 426.2
233Me4-Et-PhAboutSYN-racemate3,70420,3
234Me4-Et-PhAbout2S,1S3,70420,3
235Me4-Et-PhAbout2R,1R3,70420,3
236Me4-Et-PhAboutthe mixture of SYN/anti3,70420,3
237Me4-Et-PhAbout2R,1S3,70420,3
238Me4-Et-PhAbout2S,1R3,70420,3
239Me4-MeO-PhAbout SYN-racemate3,37422,3
240Me4-MeO-PhO2R,1R3,37422,3
241Me4-MeO-PhO2S,1S3,37422,3
242Me4-n-Bu-PhAboutSYN-racemate4,08448,4
243Me4-t-Bu-PhAbout2S,1S4,59448,4
244Et4-t-Bu-PhAboutSYN-racemate4,59448,4
245Me4-MeO-PhAbout2S,1Sto 3.58-
246Me4-CI-PhSSYN-racemate3,84442,2
247Me4-Me-PhSSYN-racemate4,34422,3

Example 248

Getting ethyl-[(1S)-5-(2-{2-[4'-(5-acetyl-2-thienyl)-1.1'-biphenyl-4-yl]-5-methyl-1,3-oxazol-4-yl}-ethoxy)-2,3-dihydro-1H-inden-1-yl]-acetate

To a solution containing ethyl((1S)-5-{2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-acetate (0,100 g, 0.21 mmol) [obtained from 2-[5-methyl-2-(4-bromophenyl)-1,3-oxazol-4-yl]-ethanol and ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]-acetate (Example 135)], 1,1'-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (16,9 mg, 0.02 mmol) and 5-acetyl-2-thienylboronic acid (0,062 g, 0.41 mmol) in degassed toluene and dioxane (4:1, 2 ml), was added 2 M aqueous solution of sodium carbonate (0.5 ml). The mixture is heated at 85°C for 16 hours the Solvent is evaporated in vacuum and the residue is dissolved in methanol and acetonitrile and filtered through extraction of catridge with reversed phase C8. The solvent is evaporated and the residue is dissolved in acetonitrile and purified by HPLC, receiving ethyl-[(1S)-5-(2-{2-[4'-(5-acetyl-2-thienyl)-1,1'-biphenyl-4-yl]-5-methyl-1,3-oxazol-4-yl}-ethoxy)-2,3-dihydro-1H-inden-1-yl]-acetate with a yield of 46% (50 mg, 0.09 mmol) MS (elektrorazpredelenie) 530,4 (M+N)+,1H NMR (CDCl3) δ to 1.24 (t, 3H), 1,71 (m, 1H), 2,37 (m, 5H), to 2.57 (s, 3H), 2,68 (m, 1H), and 2.83 (m, 2H), 3,03 (m, 2H), 3,48 (m, 1H), 4,17 (m, 4H), to 6.67 (m, 2H), 7,02 (d, 1H), 7,39 (d, 1H), to 7.67 (d, 1H), 7,73 (d, 2H), 8,01 (d, 2H).

Other compounds obtained using similar starting compounds and methods described in Example 248, combined with the hydrolysis described in Example 11 below in table 6.

Table 6.

Example No.RR1R2R3R4R5XLC-MS [M+H]+
249HHHMeHO493,3
250NHHMeHO484,2
251HHHMeHAbout502,2

ASSESSMENT CONNECTIONS

To demonstrate the activity of the compounds of the present invention can through research, running in vitro, ex vivo and in vivo are well known in the art. For example, to demonstrate the effectiveness of a pharmaceutical preparation for the treatment of diabetes and related diseases such as syndrome X, impaired glucose tolerance, impaired glucose in blood glucose and hyperinsulinemia or atherosclerotic disease and related diseases, such as Hyper is triglyceridemia and hypercholesterolemia, you can perform the following studies.

The binding of insulin receptors in the cells 3T3-L1 treated with compounds

Cells 3T3-L1 sown on 9300 cells into the hole in the tablets Costar TC with a flat bottom and incubated for 1 week, ending incubation in 2 days after the merger (for example, when cells reached maximum density). Then the cells for 2 days, treated with differentiating medium (medium Needle, modified by way of Dulbecco (DMEM),100 μg/ml penicillin/streptomycin, 2 mmol L-glutamine, 10% fetal bovine serum)containing 0.5 µmol insulin-like growth factor human (IGF-1) and the compounds. After treatment, the medium is replaced with differentiating medium and cells incubated for 4 days. Then analyze the activity of the insulin receptor. After washing the cells with buffer them incubated with 0.1 nmol125|-insulin (+/-) 100 nmol unlabeled insulin and incubation was performed at room temperature for 1 h and Then the cells washed three times with buffer solution, dissolve 1 N. NaOH and shall count using the count of gamma radiation. If you have reached a plateau, determine the value of the EU50and assess the maximal stimulation in percent.

Analysis of the binding of insulin re what atrami
ExampleEC50(nm)%of max stimulation
control74100
4176567
493075
6222476
6514077
6712867
8115979
1031886
10710976
12118862
12735042

Analyses of In Vivo

Methods of measuring the concentration of glucose in the blood

In mice db/db (obtained from Jackson Laboratories, Bar Harbor, ME) take blood (of the eye or tail vein) and they are divided into groups in accordance with an equivalent average concentrations of glucose in the blood. Within 14 days of once per day orally administered (by forced feeding in a pharmaceutically acceptable solvent) investigated the connection. Then the animals re-take blood from the eye or tail vein and using sharimara Glucometer Elite XL (Bayer Corporation, Elkhart, IN) to determine glucose concentration.

The method of measuring the concentrations of triglycerides

Methods of measuring concentrations of HDL-cholesterol

To determine the concentrations of HDL-cholesterol in plasma in mice hApoA1 take blood and they are divided into groups in accordance with an equivalent average concentrations of HDL-cholesterol in the plasma. Within 7 days of once per day to mice orally administered solvent or investigational compound. The concentration of HDL-cholesterol in the plasma is determined using an instrument Synchron Clinical System (CX4) (Beckman Coulter, Fullerton, CA)

Analyses of In vivo
Example No.Insulin binding receptors EU50nmBlood glucose (mouse db/db)Triglycerides (mouse hApoA1)HDL (mouse hApoA1)
1277 14-SIM. peroral. introduction: -20% against the outcomes. level at 3 mg/kg once a day, -45% at 10 mg/kg once a day8-SIM. peroral. introduction: -35% against the source. level at 3 mg/kg once a day, -45% at 10 mg/kg once a day8-SIM. peroral. introduction: +30% against the source. level at 30 mg/kg once a day
517-SIM. peroral. introduction: -160 mg/DL vs. source. level at 3 mg/kg once a day, -220 mg/DL at 10 mg/kg once a day5-SIM. peroral. introduction: -45 mg/DL vs. source. level at 10 mg/kg once a day
1372414-SIM. peroral. introduction: -32% against the source. level at 3 mg/kg once a day8-SIM. peroral. introduction: -31% against the source. level at 10 mg/kg once a day8-SIM. peroral. introduction: +19% against the source. level at 10 mg/kg once a day
13828,58-SIM. peroral. introduction: -19% against the source. level at 10 mg/kg once a day8-SIM. peroral. introduction: +15% against the source. level at 10 mg/kg once a day
1412038-SIM. peroral. introduction: -18% against the source. level at 10 mg/is g once a day 8-SIM. peroral. introduction: +31% against the source. level at 10 mg/kg once a day
145318-SIM. peroral. introduction: -31% against the source. level at 10 mg/kg once a day8-SIM. peroral. introduction: +21% against the source. level at 10 mg/kg once a day

Example No.Insulin binding receptors EU50nmBlood glucose (mouse db/db)Triglycerides (mouse hApoA1)HDL (mouse hApoA1)
150208-SIM. peroral. introduction: -23% against the source. level at 10 mg/kg once a day8-SIM. peroral. introduction: +14% against the source. level at 10 mg/kg once a day
1551018-Daniel. introduction: -25% against the source. level at 10 mg/kg once a day8-SIM. peroral. introduction: +9% against the source. level at 10 mg/kg once a day
1571868-SIM. peroral. introduction: -22% against the source. level at 10 mg/kg once a day8-SIM. peroral. introduction: +9% against the source. level at 10 mg/kg once a day
1605814-SIM. peroral. introduction: -48% against the source. level at 3 mg/kg once a day8-SIM. peroral. introduction: -38% against the source. level at 30 mg/kg once a day8-Daniel. introduction: +29% against the source. level at 30 mg/kg once a day
1673514-SIM. peroral. introduction: -40% against the source. level at 10 mg/kg once a day8-SIM. peroral. introduction: -43% against the source. level at 30 mg/kg once a day8-SIM. peroral. introduction: +29% against the source. level at 30 mg/kg once a day
1694814-SIM. peroral. introduction: -48% against the source. level at 10 mg/kg once a day8-Daniel. introduction: -33% against the source. level at 30 mg/kg once a day8-SIM. peroral. introduction: +21% against the source. level at 30 mg/kg once a day
179628-SIM. peroral. introduction: -32% against the source. level at 30 mg/kg once a day8-SIM. peroral. introduction: +3% against the source. level at 30 mg/kg once a day
1811678-SIM. peroral. introduction: -15% against the source. level at 10 mg/kg once a day 8-SIM. peroral. introduction: +2% against the source. level at 10 mg/kg once a day
1939708-SIM. peroral. introduction: -22% against the source. level at 30 mg/kg once a day8-SIM. peroral. introduction: +7% against the source. level at 30 mg/kg once a day

Example No.Insulin binding receptors EU50nmBlood glucose (mouse db/db)Triglycerides (mouse hApoA1)HDL (mouse hApoA1)
2002078-SIM. peroral. introduction: -19% against the source. level at 30 mg/kg once a day8-SIM. peroral. introduction: +12% against the source. level at 30 mg/kg once a day
2022808-SIM. peroral. introduction: -25% against the source. level at 30 mg/kg once a day8-SIM. peroral. introduction: +6% against the source. level at 30 mg/kg once a day

Methods of measuring concentrations of total cholesterol, HDL-cholesterol, triglycerides and glucose

In another study in vivo in obese monkeys take blood, and then within 4 weeks of once per day orally administered Rast is oritel or investigated the connection and then re-take blood. To determine serum concentrations of total cholesterol, HDL-cholesterol, triglycerides and glucose with the use of device Synchron Clinical System (CX4) (Beckman Coulter, Fullerton, CA). Analysis of lipoprotein subclasses performed using NMR spectroscopy in accordance with the description in the work of Oliver et al. (Proc. Natl. Acad. Sci. USA 98:5306-5311,2001).

The methods of studying the effects on cardiovascular parameters

Also determine cardiovascular parameters such as heart rate and blood pressure). The SHR rats for 2 weeks once daily orally administered solvent or investigational compound. Blood pressure and heart rate were determined using the methods of the cuff to tail in accordance with the description in the work Grinsell et al. (Am. J. Hypertens. 13:370-375, 2000). The monkeys blood pressure and heart rate determined in accordance with the description in the work of Shen et al. (J. Pharmacol. Exp. Therap. 278:1435-1443, 1996).

Compounds corresponding to the present invention was investigated using the above methods of analysis and according to the activity profiles found that they influence the level of blood glucose and triglyceride levels in the serum and therefore they have potential applicability for the treatment of diabetes and related diseases such as syndrome X, impaired glucose tolerance, failure is their level of fasting blood glucose and hyperinsulinemia, or cardio-vascular diseases and related disorders such as hypertriglyceridemia and hypercholesterolemia.

The pharmaceutical composition

Based on the above tests, or other known methods of analysis used to determine the effectiveness of the treatment of the above pathological States in mammals, and by comparison of these results with the results for known drugs used for the treatment of these pathological conditions, you can easily determine the effective dosage of the compounds of the present invention, for treatment in each and every case. The number of the active component, which should be entered in the treatment of one of these pathological conditions can vary significantly depending on such factors as the particular used the connection and single dose, route of administration, duration of treatment, age and gender affected the treatment of the patient and the nature and severity at treatment of a pathological condition.

The full amount is subject to the introduction of the active component generally may vary from about 0.0001 to about 200 mg/kg, and preferably from about 0.01 to about 200 mg/(kg body weight)/day. Single dose can contain from about 0.05 to about 1500 mg of the active component and the can is to be entered one or more times per day. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and using the methods of infusion may be from about 0.01 to about 200 mg/(kg full body weight)/day. Percutaneous concentration may be such that requires daily maintenance dose comprising from 0.01 to 200 mg/kg

Of course, for each patient's specific initial and continuing dosage regime will change in accordance with the nature and severity of the pathological condition, as determined by the attending physician, for whom the diagnosis, time of administration, route of administration, rate of excretion of a drug, combination of drugs, etc. Preferred mode of treatment and number of doses of the compounds corresponding to the present invention, or its pharmaceutically acceptable salt can be determined by experts in the art using conventional tests for treatment.

Compounds corresponding to the present invention, can be used to achieve the desired pharmacological effect by introducing needs it the patient is appropriately prepared pharmaceutical composition. For the objectives of the present invention the patient is a mammal, including man, in need of treatment con the specific pathological condition or disease. Therefore, the present invention includes pharmaceutical compositions that include pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound identified by the methods described in the present invention, or its pharmaceutically acceptable salt or a complex ester. Pharmaceutically acceptable carrier is any carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active component, so that any side effects attributed to the media, did not undermine the beneficial effects of the active component. Pharmaceutically effective amount of a compound represents the amount which produces a result or exerts an influence on a specific pathological condition being treated. Compounds identified by the methods described in this invention can be administered together with a pharmaceutically acceptable carrier using any effective standard discrete dosage forms, including, for example, drugs immediate or delayed allocation, oral, parenteral, local, etc.

For oral administration the compounds can be included in solid or liquid preparations, such as capsules, pills, tablets, lozenges, pellets, melting drugs, powders, solutions, suspensions or emulsions and can be prepared according to methods known in the field of preparation of pharmaceutical compositions. Solid single dosage form can be a capsule, which may be a conventional capsule of hard or soft gelatin containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, calcium phosphate and corn starch.

In another embodiment, compounds corresponding to the present invention can be molded into tablets using a conventional bases for tablets, such as lactose, sucrose and cornstarch in combination with binders, such as gum acacia, corn starch or gelatin; substances that provide raspadaemost designed to facilitate the destruction and dissolution of the tablet after administration such as potato starch, alginic acid, corn starch, and guar gum; lubricants intended to improve the flowability of the pellets and to prevent adhesion of the material of the tablets to the surface of dies and punches for forming tablets, for example talc, stearic acid or stearate of magnesium, calcium or zinc; dyes, colorants and and flavors, designed to improve the aesthetic characteristics of the tablets and make them more acceptable to the patient. Suitable fillers, designed for use in liquid oral dosage forms include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols with addition or without addition of pharmaceutically acceptable surfactant, suspending reagent or emulsifying agent. Various other substances may be contained as a coating or the means to otherwise modify the physical characteristics of the dosage form. For example, tablets, pills or capsules can be coated with shellac, sugar or both of these substances.

Dispersible powders and granules suitable for preparation of aqueous suspensions. They contain the active ingredient mixed with dispersing or wetting agent, suspenders substance and one or more preservatives. Examples of suitable dispersing or wetting agents are substances that have already been specified above. Can also contain additional excipients, for example, sweeteners, flavorings and colorants described above.

Pharmaceutical compositions corresponding to the present invention, can also ahadiths in the form of emulsions of oil-in-water. The oil phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) natural gums, such as gum acacia and tragacanth gum, (2) natural phosphatides, such as soybean lecithin, (3) esters or partial esters derived from liquid acids and anhydrides of exit, such as servicemanual, and (4) condensation products of these partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may contain sweeteners and flavorings.

Oil suspensions can be obtained by suspension of the active substance in vegetable oil, such as, for example, peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, such as, for example, beeswax, hard paraffin or cetyl alcohol. Suspensions can also contain one or more preservatives, for example ethyl or n-propyl-p-hydroxybenzoate; one or more coloring agents; one or more flavoring and one or more sweeteners, such as sucrose or saccharin.

Syrups and elixirs may be formulated with the inclusion of the treatment tip can is astutely, such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such compositions can also contain a tool that eliminates irritation, and preservative, flavoring and coloring substances.

Compounds corresponding to the present invention, it is also possible to enter parenteral, i.e. subcutaneously, intravenously, intramuscularly, or intraperitoneally in the form introduced by injection of doses of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and solutions similar sugars; alcohol, such as ethanol, isopropanol or hexadecylamine alcohol, glycols, such as propylene glycol and polyethylene glycol; ketals of glycerol, such as 2,2-dimethyl-1,1-dioxolane-4-methanol, ethers, such as the polyethylene glycol 400; oil; fatty acid ester or fatty acid glycerides, or acetylated fatty acid glycerides, with addition or without addition of pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agents, such as pectin, carbomer, methylcellulose, hypromellose, or carboxymethylcellulose, or emulsifying agent and other auxiliary Pharma is iticheskie substances.

Examples of oils that can be used in parenteral compositions of the present invention are oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid and isostearoyl acid. Suitable esters of fatty acids are, for example, etiloleat and isopropylmyristate. Suitable Soaps include salts of alkali metals, ammonium and triethanolamine fatty acids and suitable detergents include cationogenic detergents, for example, dimethyldiallylammonium, alkylpyridinium and alcaligenaceae; anionic detergents, for example, alkyl-, aryl - and reincorporate, alkyl-, olefin -, and ether - and monoglycerides and sulfosuccinates; nonionic detergents, for example, fatty aminoxide, alkanolamide fatty acids and copolymers of polyoxyethylenesorbitan; and amphoteric detergents, for example, alkyl-beta-aminopropionic and Quaternary ammonium salt 2-alkylimidazole, as well as the mixture.

Parenteral compositions corresponding to the present invention may contain in solution from about 0.5 d is about 25 wt.% the active component. With success you can also use preservatives and buffer solutions. To minimize or avoid irritation at the site of injection, such compositions may contain a nonionic surfactant having an indicator hydrophilic-lipophilic balance (products HLB), is equal to from about 12 to about 17. The amount of surfactant contained in such compositions is from about 5 to about 15 wt.%. Surfactant can be onecomponent with the above products HLB index, or may be a mixture of two or more components, with the necessary products HLB index.

Illustrative examples of surfactants used in parenteral compositions is the class polietilensorbit esters of fatty acids, for example, servicemanuals and high molecular weight addition products of ethylene oxide to hydrophobic base, obtained by condensation of propylene oxide with propylene glycol.

The pharmaceutical compositions can be in the form of a sterile aqueous suspension for injection. Such suspension may be in accordance with known methods using suitable dispersing or wetting agents and suspendida substances, such as, for example, sodium salt to the of roximately, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum acacia, and dispersing or wetting substances, which may be natural phosphatides, such as lecithin, condensation product of ethylene oxide with a fatty acid, for example, polyoxyethylenated, the condensation product of ethylene oxide with an aliphatic alcohol having long chain, for example, heptadecafluorooctane, the condensation product of ethylene oxide with partial esters derived from fatty acids and anhydride exit, for example, polyoxyethylene sorbitan monooleate.

A sterile preparation for injection may also be a sterile solution or suspension for injection in a non-toxic acceptable for injecting the diluent or solvent. Diluents and solvents that can be used are, for example, water, ringer's solution and isotonic sodium chloride solution. In addition, as solvents or suspendida funds typically use sterile non-volatile oil. For this purpose you can use any mixed fixed oils, including synthetic mono - and diglycerides. In addition, in the manufacture of drugs for injection you can use fatty acids such as oleic acid.

The song, soo is relevant to the present invention, you can also type in the form of suppositories for rectal administration of medicinal preparation. These compositions can be prepared by mixing the drug with a suitable't have irritating influence of the filler, which is solid at ordinary temperatures but liquid at the temperature in the rectum and therefore will melt in the rectum to release the drug product. Such substances are, for example cocoa butter and polyethylene glycol.

For the other compositions used in the methods of the present invention, used for percutaneous delivery device (patches). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention, carried out orderly manner. The operation and use of percutaneous patches for delivery of pharmaceutical preparations are well known in the art (see, for example, U.S. patent No. 5023252, which is included in the present invention for a link). Such patches can be made for continuous, periodic or ongoing if necessary, delivery of pharmaceuticals.

It may be desirable or necessary to introduce the patient a pharmaceutical composition using mechanical is daysago device. Design and application of mechanical feed device for the delivery of pharmaceutical preparations are well known in the art. For example, direct methods in the injection of the drug directly to the brain usually include the introduction of in-feed medication catheter into the ventricular system of the patient to bypass the blood-brain barrier. One such implantable supply system used to supply drugs to specific anatomical regions of the body, is described in U.S. patent No. 5011472, which is included in the present invention for reference.

Compositions corresponding to the present invention, if necessary or desired, can also contain other pharmaceutically acceptable intended for mixing the components, usually referred to as carriers or diluents. Any songs that match the present invention, can be saved by adding antioxidants such as ascorbic acid or by using other suitable preservatives. You can use the usual methods of preparing such compositions in appropriate dosage forms.

Commonly used pharmaceutical components that can be used as suitable for the preparation of compositions intended for the particular path you entered is I, include acidifying substances, for example (without restrictions), acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid; and alkalizing substances, such as (without restrictions), ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine.

Other pharmaceutical components include, for example (without restrictions), adsorbents (e.g., powdered cellulose and activated charcoal); propellants for aerosols (e.g., carbon dioxide, CCl2F2F2ClC-CClF2and CClF2); replacement air substances (e.g., nitrogen and argon); antifungal preservatives (e.g. benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (e.g., benzylaniline, benzenehexachloride, benzyl alcohol, cetylpyridinium, chlorobutanol, phenol, finitely alcohol, PHENYLMERCURIC and thimerosal); antioxidants (such as ascorbic acid, ascorbyl palmitate, bottled hydroxyanisol, bottled hydroxytoluene, hypophosphorous acid, monothioglycerol, propylgallate, sodium ascorbate, sodium bisulfite, formaldehydeinduced sodium, metabisulfite the sodium); binders (for example, block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones and styrene-butadiene copolymers); buffering agents (for example, metaphosphate potassium, one-deputizing potassium phosphate, sodium acetate, anhydrous sodium citrate and citrate dihydrate sodium); substance-carriers (for example, syrup, gum acacia, aromatic syrup, aromatic elixir, cherry syrup, syrup, cocoa, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection); chelating reagents (for example, the disodium salt of ethylenediaminetetraacetic acid and ethylenediaminetetraacetic acid), colorants (for example, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, burnt sugar and red iron oxide(III)); brightening chemicals (e.g. bentonite); emulsifying agents (without restrictions - gum acacia, cetomacrogol, cetyl alcohol, glycerylmonostearate, lecithin, sorbitan-monooleate, polyethylene 50 stearate); kapsulirujushchej substances (for example, gelatin and acetylcellulose); flavorings (such as anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin), water-retaining substance (for example, CH is zerin, propylene glycol and sorbitol); otmuchivanie substances (for example, mineral oil and glycerin); oils (e.g. peanut oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); bases for ointments (e.g., lanolin, hydrophilic ointment, polietilenglikolja ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment and ointment with rose water); substances that increase the permeability (percutaneous supply) (for example, monohydroxy - or polyhydroxystearic, saturated or unsaturated fatty alcohols, esters of saturated or unsaturated fatty acids, saturated or unsaturated dicarboxylic acids, essential oils, vospalitelnye derivatives, cephalin, terpenes, amides, ethers, ketones and urea); plasticizers (e.g., diethylphthalate and glycerol); solvents (such as alcohol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); thickening agents (e.g., cetyl alcohol, tetravinyl wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); bases for suppositories (for example, cocoa butter and polyethylene glycols (mixtures)); surfactants (for example, benzo is CONI-chloride, nonoxynol 10, octoxynol 19, Polysorbate 80, sodium lauryl sulfate and servicemanagement); suspendresume substances (for example, agar, bentonite, carbomer, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hypromellose, kaolin, methylcellulose, tragacanth gum and veegum); sweeteners (e.g. aspartame, dextrose, glycerol, mannitol, propylene glycol, sodium salt of saccharin, sorbitol and sucrose), substances that prevent the sticking of the tablets (such as magnesium stearate and talc); a binder for tablets (for example, gum acacia, alginic acid, sodium carboxymethyl cellulose, presswise sugar, ethylcellulose, gelatin, liquid glucose, methyl cellulose, povidone and pre gelatinizing starch); thinners for tablets and capsules (e.g., disubstituted calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); substances for the formation of coatings on tablets (for example, liquid glucose, hydroxyethyl cellulose, hydroxypropylcellulose, hypromellose, methylcellulose, ethylcellulose, acetylcellulose and shellac); excipients for direct compression of tablets (e.g., disubstituted, the FOSFA is tons of calcium); substances providing raspadaemost tablets (for example, alginic acid, calcium salt of carboxymethylcellulose, microcrystalline cellulose, calcium salt polacrilin, sodium alginate, sodium salt of starch glycolate and starch); substances that give the tablets lubricity (for example, colloidal silicon dioxide, corn starch and talc); lubricants for tablets (for example, calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); substances that give the tablets/capsules opacity (e.g., titanium dioxide);

substances, polishing tablets (for example, Carnauba wax and white wax); zag-ban substances (for example, beeswax, cetyl alcohol and paraffin); tonic substances (e.g., dextrose and sodium chloride); substances that increase the viscosity (for example, alginic acid, bentonite, carbomer, sodium carboxymethyl cellulose, methylcellulose, povidone, sodium alginate and tragacanth gum); and wetting agents (for example, heptadecafluorooctane, lecithins, polietilenglikolmonostearat, polyoxyethylenesorbitan-oleate and polyoxyethylene).

Compounds identified by the methods described in the present invention, can be introduced in the form of one pharmaceutical drug or in combination with one or the great number of other pharmaceutical preparations if this combination does not cause unacceptable side effects. For example, compounds corresponding to the present invention, can be combined with known anti-obesity drug or with known antidiabetic drugs or other drugs shown, etc. and their mixtures and combinations.

Compounds identified by the methods described in the present invention can also be used in the form of a net basis or in compositions, as well as in research and for diagnostics or as analytical reference standards, etc. Therefore, the present invention includes compositions which contain an inert carrier and an effective amount of a compound identified by the methods described in the present invention, or its salt, or a complex ester. The inert medium is any substance that does not interact with the connection, the carrier of which it is, and which for the connection carrier which it is, acts as a retaining means, means of delivery, provide volume labels to trace the connection, etc. Effective amount of compound is an amount which produces a result or exerts an influence on a given procedure.

Formulations suitable for subcutaneous, NR is trevenna, intramuscular, etc. introduction; suitable pharmaceutical carriers and methods of making and injection can be prepared by any of the methods well known in the art (see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20thedition, 2000).

The following examples are provided for illustration of the invention described here, but they should not be construed as in any way limit the present invention.

Composition for capsules

Ingredients for the capsules are made of:

The compound of the present invention 40 mg

Starch 109 mg

Magnesium stearate 1 mg

The components are mixed, passed through a sieve with a suitable size of the cells and placed in capsules of hard gelatin.

Composition for tablet

The tablet is made of:

The compound of the present invention 25 mg

Microcrystalline cellulose 200 mg

Colloidal silicon dioxide 10 mg

Stearic acid 5.0 mg

The components are mixed and pressed into tablets. To improve the taste, improve the appearance and stability or slow down the intake it is possible to apply a suitable coating for aqueous and non-aqueous basis.

Sterile solution for intravenous injection

The solution is necessary connections corresponding to the present invention, the concentration of 5 mg/ml is prepared to use what Itanium sterile water for injection and, if necessary, adjust the pH value. For the introduction of a solution diluted to a concentration equal to 1-2 mg/ml with sterile 5% dextrose and administered as an intravenous infusion over 60 minutes

Suspension for intramuscular injection

Prepare the following suspension for intramuscular injection:

The compound of the present invention 50 mg/ml

Sodium carboxymethyl cellulose, 5 mg/ml

TWEEN 804 mg/ml

Sodium chloride 9 mg/ml

Bentley alcohol 9 mg/ml

This suspension is injected intramuscularly.

Capsules, hard shell

A large number of capsules with usual doses are prepared by filling each standard two capsules of hard gelatin with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Capsules soft gelatin

The mixture of the active component with an edible oil such as soybean oil, cottonseed oil or olive oil is prepared and using a piston pump is injected into molten gelatin to obtain capsules soft gelatin containing 100 mg of the active component. The capsules are washed and dried. To obtain miscible with water a mixture of a drug active ingredient can be dissolved in a mixture of glycol, glycerol and sorbitol.

Tablets/capsules direct allocation

They are particularly the solid oral dosage forms, carrier made using conventional and new methods. These drugs are taken orally without water, and they are designed for direct dissolution and extraction of the medicinal product. The active ingredient is mixed with a liquid containing components, such as sugar, gelatin, pectin and sweeteners. These fluids utverjdayut obtaining solid tablets or oval tablets coated using the methods of freeze drying and solid-phase extraction. Medications can be crushed together with visco-elastic and thermoelastic sugars and polymers or components used for the manufacture of effervescent forms, and to obtain a porous matrix, which are intended for direct selection without the use of water.

Specialist with General training in the art it should be clear that without deviating from the essence and scope of the invention described here in the present invention it is possible to make changes and modifications.

1. The compound of the formula I

where R is H or C1-C6alkyl;

R1means H, COOR, C3-C8cycloalkyl or C1-C6alkyl, C2-C6alkenyl or C1-C6alkoxyl, each of which may be unsubstituted or may contain in image quality is as substituents fluorine or phenyl, which may be unsubstituted or may contain as substituents R6;

R2denotes H, halogen or C1-C6alkyl which may be unsubstituted or may contain as substituents C1-C6alkoxyl, oxoprop, fluorine, or R2means phenyl, furyl, thienyl, pyridyl, each of which may be unsubstituted or may contain as substituents R6;

R3means H, C1-C6alkyl or phenyl which may be unsubstituted or may contain as substituents R6;

X is O or S;

R4means C1-C6alkyl or C3-C8cycloalkyl, each of which may be unsubstituted or may contain as substituents fluorine, oxoprop or C1-C6alkoxy, which may be unsubstituted or may contain as substituents C1-C6alkoxyl or phenyl, optionally containing as substituent R6or

C1-C6alkyl may also contain as a substituent With3-C8cycloalkyl or phenoxy, which may be unsubstituted or may contain as substituents R6or phenyl which may be unsubstituted or may contain as substituents R6or

R4means phenyl, naphthyl, FSD is l, thienyl, oxazolyl, thiazolyl, isoxazolyl, pyridyl, piperidinyl, benzofuran, dihydrobenzofuran, benzothiazyl, dihydrobenzofuranyl, benzodioxolyl, each of which may be unsubstituted or may contain as substituents R6or phenyl, thienyl, indolyl, each of which may be unsubstituted or may contain as substituents R6;

R5denotes H, halogen or C1-C6alkyl, optionally containing as a substituent oxoprop;

R6means halogen, CF3C1-C6alkyl, optionally containing as a substituent oxoprop, or hydroxyl, or C1-C6alkoxyl, optionally containing as a substituent fluorine;

and their pharmaceutically acceptable salts and esters.

2. The compound according to claim 1, in which

R means H or C1-C6alkyl;

R1means H, COOR, C3-C8cycloalkyl or C1-C6alkyl, C2-C6alkenyl or C1-C6alkoxyl, each of which may be unsubstituted or may contain as substituents fluorine or phenyl which may be unsubstituted or may contain as substituents R6;

R2denotes H, halogen or C1-C6alkyl which may be unsubstituted or may contain in the quality of the ve Vice-C 1-C6alkoxyl, oxoprop, fluorine, or R2means phenyl, furyl, thienyl, pyridyl, each of which may be unsubstituted or may contain as substituents R;

R3means H, C1-C6alkyl or phenyl which may be unsubstituted or may contain as substituents R6;

X is O;

R4means C1-C6alkyl or C3-C8cycloalkyl, each of which may be unsubstituted or may contain as substituents fluorine, oxoprop or C1-C6alkoxy, which may be unsubstituted or may contain as substituents C1-C6alkoxyl or phenyl, optionally containing as substituent R6,

or

C1-C6alkyl may also contain as a substituent With3-C8cycloalkyl or phenoxy, which may be unsubstituted or may contain as substituents R6or phenyl which may be unsubstituted or may contain as substituents R6,

or R4means phenyl, naphthyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, pyridyl, piperidinyl benzofuran, dihydrobenzofuran, benzothiazyl, dihydrobenzofuranyl, benzodioxolyl, each of which can be unsubstituted or contain as replace the it R 6or phenyl, thienyl, indolyl, each of which may be unsubstituted or may contain as substituents R6;

R5denotes H, halogen or C1-C6alkyl, optionally containing as a substituent oxoprop;

R6means halogen, CF3C1-C6alkyl, optionally containing as a substituent oxoprop or hydroxyl or C1-C6alkoxyl, optionally containing as a substituent fluorine;

and their pharmaceutically acceptable salts and esters.

3. The compound according to claim 1, in which

R means H or C1-C6alkyl;

R1means H, COOR, C3-C8cycloalkyl or C1-C6alkyl, C1-C6alkenyl or C1-C6alkoxyl, each of which may be unsubstituted or may contain as substituents fluorine, or phenyl which may be unsubstituted or may contain as substituents R6;

R2denotes H, halogen or C1-C6alkyl which may be unsubstituted or may contain as substituents C1-C6alkoxyl, oxoprop, fluorine,

or

R2means phenyl, furyl, thienyl, pyridyl, each of which may be unsubstituted or may contain as substituents R6;

3means H, C1-C6alkyl or phenyl which may be unsubstituted or may contain as substituents R6;

X is S;

R4means C1-C6alkyl or C1-C6cycloalkyl, each of which may be unsubstituted or may contain as substituents fluorine, oxoprop or C1-C6alkoxy, which may be unsubstituted or may contain as substituents C1-C6alkoxyl or phenyl, optionally containing as substituent R6,

or C1-C6alkyl may also contain as Deputy C3-C8cycloalkyl or phenoxy, which may be unsubstituted or may contain as substituents R6or phenyl which may be unsubstituted or may contain as substituents R6,

or R4means phenyl, naphthyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, pyridyl, piperidinyl, benzofuran, dihydrobenzofuran, benzothiazyl, dihydrobenzofuranyl, benzodioxolyl, each of which may be unsubstituted or may contain as substituents R6or phenyl, thienyl, indolyl, each of which may be unsubstituted or may contain as substituents R6;

R5denotes H, halogen or C1-C6alkyl, not battelino containing as a substituent oxoprop;

R6means halogen, CF3C1-C6alkyl, optionally containing as a substituent oxoprop or hydroxyl or C1-C6alkoxyl, optionally containing as a substituent fluorine;

and their pharmaceutically acceptable salts and esters.

4. The compound according to claim 1, in which

R denotes H;

R1means H, COOR, C3-C8cycloalkyl or C1-C6alkyl, C2-C6alkenyl or C1-C6alkoxyl, each of which may be unsubstituted or may contain as substituents fluorine or phenyl which may be unsubstituted or may contain as substituents R6;

R2denotes H, halogen or C1-C6alkyl which may be unsubstituted or may contain as substituents C1-C6alkoxyl, oxoprop, fluorine;

R3means N or C1-C6alkyl or phenyl which may be unsubstituted or may contain as substituents R6;

X is S;

R4means phenyl, naphthyl, furyl, thienyl oxazolyl, thiazolyl, isoxazolyl, pyridyl, piperidinyl, benzofuran, dihydrobenzofuran, benzothiazyl, dihydrobenzofuranyl, benzodioxolyl, each of which may be unsubstituted or may contain as substituents R6 or phenyl, thienyl, indolyl, each of which may be unsubstituted or may contain as substituents R6;

R5denotes H, halogen or C1-C6alkyl, optionally containing as a substituent oxoprop;

R6means halogen, CF3C1-C6alkyl, optionally containing as a substituent oxoprop, or hydroxyl, or C1-C6alkoxyl, optionally containing as a substituent fluorine;

and their pharmaceutically acceptable salts and esters.

5. The compound according to claim 1, in which

R denotes H;

R1means H, COOR, C3-C8cycloalkyl or C1-C6alkyl, C2-C6alkenyl or C1-C6alkoxyl, each of which may be unsubstituted or may contain as substituents fluorine, or phenyl which may be unsubstituted or may contain as substituents R6;

R2denotes H, halogen or C1-C6alkyl which may be unsubstituted or may contain as substituents C1-C6alkoxyl, oxoprop, fluorine;

R3means N, or C1-C6alkyl or phenyl which may be unsubstituted or may contain as substituents R6;

X is O;

R4means enil, naphthyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, pyridyl, piperidinyl, benzofuran, dihydrobenzofuran, benzothiazyl, dihydrobenzofuranyl, benzodioxolyl, each of which may be unsubstituted or may contain as substituents R6or phenyl, thienyl, indolyl, each of which may be unsubstituted or may contain as substituents R6;

R5denotes H, halogen or C1-C6alkyl, optionally containing as a substituent oxoprop;

R6means halogen, CF3C1-C6alkyl, optionally containing as a substituent oxoprop or hydroxyl or C1-C6alkoxyl, optionally containing as a substituent fluorine;

and their pharmaceutically acceptable salts and esters.

6. The compound according to claim 1, in which

R denotes H;

R1means H, COOR, C3-C8cycloalkyl or C1-C6alkyl, C2-C6alkenyl or C1-C6alkoxyl, each of which may be unsubstituted or may contain as substituents fluorine or phenyl which may be unsubstituted or may contain as substituents R6;

R2means phenyl, furyl, thienyl, pyridyl, each of which can be unsubstituted or contain as the Deputy is th R;

R3means H, C1-C6alkyl or phenyl which may be unsubstituted or may contain as substituents R6;

X is O;

R4means C1-C6alkyl or C3-C8cycloalkyl, each of which may be unsubstituted or may contain as substituents fluorine, oxoprop or C1-C6alkoxy, which may be unsubstituted or may contain as substituents C1-C6alkoxyl or phenyl, optionally containing as substituent R6,

or C1-C6alkyl may also contain as Deputy C3-C8cycloalkyl or phenoxy, which may be unsubstituted or may contain as substituents R6or phenyl which may be unsubstituted or may contain as substituents R6,

or R4means phenyl, naphthyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, pyridyl, piperidinyl, benzofuran, dihydrobenzofuran, benzothiazyl, dihydrobenzofuranyl, benzodioxolyl, each of which may be unsubstituted or may contain as substituents R6or phenyl, thienyl, indolyl, each of which may be unsubstituted or may contain as substituents R6;

R5denotes H, halogen or C1-the 6alkyl, optionally containing as a substituent oxoprop;

R6means halogen, CF3C1-C6alkyl, optionally containing as a substituent oxoprop or hydroxyl or C1-C6alkoxyl, optionally containing as a substituent fluorine;

and their pharmaceutically acceptable salts and esters.

7. The compound according to claim 1, in which the C-1' is in S-configuration or R-configuration.

8. The compound according to claim 1, in which the configuration of C-1' and C-2 selected from the group comprising C-1' in R and S-2 - R; s-1' in R and S-2 - S; C-1' - S and s-2 is in S; and (C-1' - S and S-2 - R.

9. The compound according to claim 1, selected from the group including

5-{2-[2-(4-ethylphenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-(2-{5-methyl-2-[4-(trifluoromethyl)-phenyl]-1,3-oxazol-4-yl}-ethoxy)-2,3-dihydro-1-inden-1-luksusowe acid;

5-{2-[5-methyl-2-(2-naphthyl)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(4-tert-butylphenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(4-butylphenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(3,4-dimetilfenil)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(1-benzothieno-2-yl)-5-methyl-1,3-oxazol-4-yl]-this is XI}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(4-isopropylphenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-[2-(2-cyclopentyl-5-methyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(3-fluoro-4-were)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid; and

5-{2-[2-(4-forfinal)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid.

10. The connection according to claim 9, in which the C-1' is in S-configuration or R-configuration.

11. The compound according to claim 1, selected from the group including

2-(5-{2-[2-(4-ethylphenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-propanoic acid;

2-(5-{2-[2-(3,4-dichlorophenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-propanoic acid;

2-(5-(2-{5-methyl-2-[4-(trifluoromethyl)-phenyl]-1,3-oxazol-4-yl}-ethoxy)-2,3-dihydro-1H-inden-1-yl)-propanoic acid;

2-(5-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-propanoic acid; and

2-(5-{2-[2-(3,4-dimetilfenil)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-propanoic acid.

12. Connection by claim 11, in which the configuration of C-1' and C-2 selected from the group comprising C-1' in R and S-2 - R; s-1' in R and S-2 - S; C-1' - S and s-2 is in S; and (C-1' - S and S-2 - R.

13. The compound according to claim 1, selected from the group including

5-[2-(5-methyl-2-phenyl-1,3-oxazo the-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-luksusowe acid;

5-[2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(3-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(1,3-benzodioxol-5-yl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[5-methyl-2-(4-were)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(3-forfinal)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(4-fluoro-3-were)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(3,4-dichlorophenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(1,1'-biphenyl-4-yl)-5-methyl-1,3-oxazol-4-yl]-ethoxy }-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(1,3-benzodioxol-5-yl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-(2-{5-methyl-2-[4-(trifluoromethyl)-phenyl]-1,3-thiazol-4-yl}-ethoxy)-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(4-cyanophenyl-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(4-isopropylphenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(3-chlorophenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(4-cyanophenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(3-cyanophenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(4-chlorophenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-(2-{5-methyl-2-[3-(trifluoromethyl)-phenyl]-1,3-oxazol-4-yl}-ethoxy)-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(3-chloro-4-forfinal)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(3,4-dichlorophenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(4-forfinal)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(3,4-dimetilfenil)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(4-acetylphenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

triptorelin 5-{2-[2-(3-amino-4-were)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luxusni acids;

5-{2-[2-(2-forfinal)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2[2-(4-chlorophenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(4-ethoxyphenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(3,4-acid)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[5-methyl-2-(3-were)-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-(2-{5-methyl-2-[3-(trifluoromethyl)-phenyl]-1,3-thiazol-4-yl}-ethoxy)-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(3-forfinal)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(3, 5dimethylphenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-(2-{5-methyl-2-[4-(triptoreline)-phenyl]-1,3-thiazol-4-yl}-ethoxy)-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(3-methoxyphenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[2-(1,1'-biphenyl-4-yl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[5-ethyl-2-(4-ethylphenyl)-1,3-oxazol-4-yl]-ethoxy }-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[5-ethyl-2-(4-were)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-{2-[5-ethyl-2-(4-methoxyphenyl)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-luksusowe acid;

5-(2-{2-[4'-(hydroxymethyl)-1,1'-biphenyl-4-yl]-5-methyl-1,3-oxazol-4-yl}-ethoxy)-2,3-dihydro-1H-inden-1-luksusowe acid;

5-(2-{2-[4-(5-acetyl-2-thienyl)-phenyl]-5-methyl-1,3-oxazol-4-yl}-ethoxy)-2,3-dihydro-1H-inden-1-luksusowe acid;

5-(2-{2-[3-(1H-indol-5-yl)-phenyl]-5-methyl-1,3-oxazol-4-yl}-ethoxy)-2,3-dihydro-1H-inden-1-luksusowe acid;

(5-{2-[2-(3-fluoro-4-were)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-acetic acid; and

(5-{2-[5-methyl-2-(3-were)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-acetic acid.

14. The connection 13, in which the C-1' is in S-configuration or R-configuration.

15. The compound according to claim 1, selected from the group including

2-{5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid;

3 ethoxy-2-{5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-3-oxo-propanoic acid;

2-(5-{2-[5-methyl-2-(4-were)-1,3-oxazol-4-yl]-ethoxy }-2,3-dihydro-1H-inden-1-yl)-propanoic acid;

2-(5-{2-[5-methyl-2-(4-were)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-sh-inden-1-yl)-butane acid;

4-methyl-2-(5-{2-[5-methyl-2-(4-were)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-pentane acid;

2-{5-[2-(5-ethyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid;

2-(5-{2-[2-(4-chlorophenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[5-methyl-2-(3-were)-1,3-oxazol-4-yl]-this is si}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[2-(4-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[2-(3,4-dichlorophenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[5-methyl-2-(2-naphthyl)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[5-methyl-2-(1-naphthyl)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[2-(4-forfinal)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[2-(3-chlorophenyl)-5-methyl-1,3-thiazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[2-cyclopentyl-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[2-cyclohexyl-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[2-(3-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[2-(4-ethylphenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[2-(1-benzothieno-2-yl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-[5-(2-{5-methyl-2-[3-(trifluoromethyl)-phenyl]-1,3-oxazol-4-yl}-ethoxy)-2,3-dihydro-1H-inden-1-yl]-butane acid;

2-(5-{2-[2-(4-tert-butylphenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane is Yu acid;

2-(5-{2-[2-(3-forfinal)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[2-(4-isopropylphenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[2-(1,3-benzodioxol-5-yl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-{5-[2-(2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid;

2-(5-{2-[2-(3,4-differenl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-[5-(2-{5-methyl-2-[4-(trifluoromethyl)-phenyl]-1,3-oxazol-4-yl}-ethoxy)-2,3-dihydro-1H-inden-1-yl]-butane acid;

2-(5-{2-[5-methyl-2-(phenoxymethyl)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[2-(4-fluoro-3-were)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[2-(3-fluoro-4-were)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[2-(4-butylphenyl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[2-(3,4-dimetilfenil)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-(5-{2-[5-methyl-2-(4-chlorphenoxy)-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid;

2-{6-chloro-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-digitron-nden-1-yl}-butane acid;

2-{5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-6-phenyl-2,3-dihydro-1H-inden-1-yl}-butane acid;

2-{6-(4-chlorophenyl)-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid;

2-{6-(4-methoxyphenyl)-5-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-2,3-dihydro-1H-inden-1-yl}-butane acid; and

2-(5-{2-[2-(2,3-dihydro-1-benzofuran-6-yl)-5-methyl-1,3-oxazol-4-yl]-ethoxy}-2,3-dihydro-1H-inden-1-yl)-butane acid.

16. The connection indicated in paragraph 15, in which the configuration of C-1' and C-2 selected from the group comprising C-1' in R and S-2 - R; s-1' in R and S-2 - S; C-1' - S and s-2 is in S; and (C-1' - S and S-2 - R.

17. The compound of formula II

in which R denotes H or C1-C6alkyl;

R1means H, COOR, C3-C8cycloalkyl or C1-C6alkyl, C2-C6alkenyl or C1-C6alkoxyl, each of which may be unsubstituted or may contain as substituents fluorine or phenyl which may be unsubstituted or may contain as substituents R6;

R2denotes H, halogen or C1-C6alkyl which may be unsubstituted or may contain as substituents C1-C6alkoxyl, oxoprop, fluorine,

or R2means phenyl, thienyl, pyridyl, each of which can businessesand or contain as substituents R 6;

R5denotes H, halogen or C1-C6alkyl, optionally containing as a substituent oxoprop;

R6means halogen, CF3C1-C6alkyl, optionally containing as a substituent oxoprop or hydroxyl or C1-C6alkoxyl, optionally containing as a substituent fluorine;

R7means H, C1-C6alkyl, optionally containing as a substituent a phenyl or oxoprop, C1-C6trialkylsilyl, arylalkyl, COR8;

R8means C1-C6alkyl;

and their salts.

18. The compound of formula III

in which R denotes H or C1-C6alkyl;

R1means H, C3-C8cycloalkyl or

C1-C6alkyl, C2-C6alkenyl or C1-C6alkoxyl, each of which may be unsubstituted or may contain as substituents fluorine;

R2denotes H, halogen or C1-C6alkyl which may be unsubstituted or may contain as substituents C1-C6alkoxyl, oxoprop, fluorine,

or R2means phenyl, thienyl, each of which can be unsubstituted or contain as replace the it R 6;

R5denotes H, halogen or C1-C6alkyl, optionally containing as a substituent oxoprop;

R6means halogen, CF3C1-C6alkyl, optionally containing as a substituent oxoprop or hydroxyl or C1-C6alkoxyl, optionally containing as a substituent fluorine;

R7means H, C1-C6alkyl, optionally containing as a substituent a phenyl or oxoprop, C1-C6trialkylsilyl, Uralkaliy or COR8;

R8means C1-C6alkyl;

and their salts.

19. Pharmaceutical composition that affect the level of blood glucose and triglyceride levels in serum, comprising an effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt or a complex ester in combination with a pharmaceutically acceptable carrier.

20. Pharmaceutical composition that affect the level of blood glucose and triglyceride levels in serum, comprising an effective amount of a compound according to claim 7 or 8, or its pharmaceutically acceptable salt or a complex ester in combination with a pharmaceutically acceptable carrier.

21. Pharmaceutical composition that affect the level of blood glucose and triglyceride levels in serum, including JFK and the objective amount of the compound according to claim 9 or its pharmaceutically acceptable salt or a complex ester in combination with a pharmaceutically acceptable carrier.

22. Pharmaceutical composition that affect the level of blood glucose and triglyceride levels in serum, comprising an effective amount of a compound of claim 10 or its pharmaceutically acceptable salt or a complex ester in combination with a pharmaceutically acceptable carrier.

23. Pharmaceutical composition that affect the level of blood glucose and triglyceride levels in serum, comprising an effective amount of a compound according to claim 11 or its pharmaceutically acceptable salt or a complex ester in combination with a pharmaceutically acceptable carrier.

24. Pharmaceutical composition that affect the level of blood glucose and triglyceride levels in serum, comprising an effective amount of the compound according to item 12 or its pharmaceutically acceptable salt or a complex ester in combination with a pharmaceutically acceptable carrier.

25. Pharmaceutical composition that affect the level of blood glucose and triglyceride levels in serum, comprising an effective amount of the compound according to item 13 or its pharmaceutically acceptable salt or a complex ester in combination with a pharmaceutically acceptable carrier.

26. Pharmaceutical composition that affect the level of blood glucose and triglyceride levels in serum, comprising an effective amount of a compound according to 14 or its pharmaceutically acceptable salt and the complex ester in combination with a pharmaceutically acceptable carrier.

27. Pharmaceutical composition that affect the level of blood glucose and triglyceride levels in serum, comprising an effective amount of the compound according to clause 15 or its pharmaceutically acceptable salt or a complex ester in combination with a pharmaceutically acceptable carrier.

28. Pharmaceutical composition that affect the level of blood glucose and triglyceride levels in serum, comprising an effective amount of the compound according to clause 16 or its pharmaceutically acceptable salt or a complex ester in combination with a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to using compounds of the general formula (I): and their pharmaceutically acceptable acid-additive salts. Compounds are used for preparing medicinal agents used in treatment diseases and state associated with system of adenosine receptors A2A, such as Alzheimer's disease, Parkinson's diseases, Huntington's syndrome, schizophrenia, anxiety state, pain, depression, narcomania to such substances as amphetamine, cocaine, opioides, ethyl alcohol, nicotine, cannabinoids, or in treatment of hypoxia, ischemia, epileptic attack. Also, proposed compounds exert neuroprotective effect and can be used as sedative, antipsychotic or anti-epileptic agents.

EFFECT: valuable medicinal properties of compounds.

18 cl, 1 tbl, 49 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new compounds of general formula I , wherein one from V or X is N and another is CRa or both V and X are CRa (each CRa is independently hydrogen atom); Y is O, S; Z is N(R2)(R3); R1 is hydrogen, C1-C10-alkyl, C3-C7-cycloalkyl, etc.; R4 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, etc.; A is hydrogen, C1-C10-alkyl, halo-C1-C6-alkyl, etc.; B is optionally substituted 5-membered aromatic ring containing at least one nitrogen atom and 0-3 additional heteroatoms; U is -NR5; meanings of the rest substituents are as defined in specification, and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical composition and intermediates of formula I.

EFFECT: new biologically active compounds and pharmaceutical compositions based on the same having inhibition activity in relates to IKK-β enzyme.

26 cl, 13 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 means hydrogen atom or lower alkyl; R2 means lower alkyl, -(CH2)n-O-lower alkyl, -(C3-C6)-cycloalkyl or -(CH2)n-NR'2 wherein R' means hydrogen atom, lower alkyl or -(CH2)n-O-lower alkyl independently of one another for R'2; or R'2 in common with nitrogen atom can form pyrrolidine ring, and wherein n = 1, 2 or 3. Also, invention relates to a pharmaceutical composition possessing antagonistic activity with respect to A2 receptors and containing one or some compounds of the general formula (I) and its pharmaceutically acceptable excipients. Invention provides synthesis of compound of the general formula (I) possessing antagonistic activity with respect to A2 receptors.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

11 cl, 19 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 2-(3',5'-diamino-1',2',4'-triazol-1'-yl)-4-R1-5-R2-1,3-thiazoles of the general formula (I): , wherein R1 represents hydrogen atom (H), direct or branched (C1-C4)-alkyl or COO-(C1-C4)-alkyl or phenyl optionally substituted with one or some substitutes chosen from halogen atom; R2 represents H, direct or branched (C1-C4)-alkyl, COO-(C1-C4)-alkyl. Method for synthesis involves addition to aqueous solution of 4-R1-5-R2-1-hydrazino-1,3-thiazole hydrochloride of the formula (II): , wherein R1 and R2 have above given values of N-cyanoguanidine of the formula (III): in the mole ratio (II) : (III) = (1.10-1.20):100. Prepared mixture is heated at temperature 80-95°C followed by its neutralization, filtering off and recrystallization. Method provides preparing 2-(3',5'-diamino-1',2',4'-triazol-1'-yl)-4-R1-5-R2-1,3-thiazole from inexpensive and available raw and without using complex technological procedures. Synthesized compounds can be used in synthesis of medicinal and biologically active substances.

EFFECT: improved method of synthesis.

10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 3-oxo-1-cyclobutene of the general formula (I): and their salts, solvates, hydrates and N-oxides wherein R1 represents group of the formula: Ar1L2Ar2Alk wherein Ar1 represents aromatic or heteroaromatic group; L2 represents a covalent bond or -O-, -NH- or -CONH-; Ar2 represents arylene or heteroarylene group; Alk represents chain -CH2CH(R) or -CH(CH2R)- wherein R represents -CO2H or -COOAlk7 wherein Alk7 represents (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-heterocycloalkyl group and others; X represents group -N(R2)- wherein R2 represents hydrogen atom or (C1-C6)-alkyl group; V represents oxygen atom; Rx, Ry and Rz represent atom or group -L1(Alk1)n(R3)v wherein L1 represents covalent bond or -O-, -S-, -Se-, -S(O)-, -NH- or -N(CH3)-; Alk1 represents aliphatic group; R3 represents hydrogen, halogen atom, group -OR3a, -SR3a and others wherein R3a represents hydrogen atom, (C1-C6)-alkyl and others; n = 0 or 1; v = 1, 2 or 3 under condition that if n = 0 and L1 represents covalent bond then v = 1; or Rz represents atom or group given above, and Rx and Ry taken together form spiro-bound cycloaliphatic or heterocycloaliphatic group. Compounds of the formula (I) possess inhibitory activity with respect to α4-integrin and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 216 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

18 cl, 138 tbl, 527 ex

Benzothiazoles // 2293736

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 represents 3,6-dihydro-2H-pyran-4-yl, 5,6-dihydro-4H-pyran-3-yl, 5,6-dihydro-4H-pyran-2-yl, tetrahydropyran-2,3- or 4-yl, cyclohex-1-enyl, cyclohexyl, or it represents 1,2,3,6-tetrahydropyridin-4-yl or piperidin-4-yl that are optionally substituted with -C(O)CH3 or -C(O)OCH3 in position 1 at nitrogen atom (N); R2 represents lower alkyl, piperidin-1-yl substituted with hydroxy-group optionally, or it represents phenyl optionally substituted with -(CH2)n-N(R')-C(O)-(CH2)n-NR'2, -(CH2)n-halogen, lower alkyl or -(CH2)n-N(R')-(CH2)n-O-lower alkyl, or it represents morpholinyl or pyridinyl that is substituted optionally with halogen atom, -N(R')-(CH2)n-O-lower alkyl, lower alkyl, lower alkoxy-group, morpholinyl or -(CH)n-pyrrolidinyl; n = 0, 1 or 2; R' represents hydrogen atom or lower alkyl, and to their pharmaceutically acceptable acid-additive salts. Also, invention relates to a medicament possessing affinity to adenosine A2A-receptors and containing one or some compounds of the general formula (I) and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of compounds.

17 cl, 47 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention elates to derivatives of benzothiazole of the general formula (I): wherein R means hydrogen atom, -(CH2)n-phenyl optionally substituted with a substitute chosen from the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl or -N(R')-C(O)-(lower)-alkyl, -(CH2)n-pyridinyl optionally substituted with (lower)-alkyl, -(CH2)n-(C3-C6)-cycloalkyl optionally substituted with hydroxy-group, -(CH2)n-benzo[1,3]dioxolyl, -(CR'2)-thiophenyl, -(CR'2)n-thiazolyl optionally substituted with (lower)-alkyl, -(CH2)n-C(O)-thiophenyl optionally substituted with halogen atom, -(CH2)-furanyl optionally substituted with (lower)-alkyl, -(CHR')n-benzofuran-1-yl, -(CH2)n-benzo[b]thiophenyl, -(CH2)n-N(R')-C(O)-phenyl optionally substituted with halogen atom or (lower)-alkoxy-group. -(CH2)n-C(O)-phenyl optionally substituted with (lower)-alkoxy-group, -(CH2)n-C(O)-2,3-dihydrobenzo[1,4]dioxine-6-yl, -(CH2)n-N(R')-C(O)-pyridinyl, -(CH2)n-tetrahydrofuranyl, -CH-biphenyl, -CH-(phenyl)pyridinyl, -(CH2)n-1-oxo-(CH2)n-CH-(phenyl)tetrahydropyranyl, -(CH2)n-1-oxo-1,2,3,4-tetrahydroquinoline-3-yl or -(CH2)n-S-[1,3,4]thiadiazol-2-yl optionally substituted with amino-group; R' means hydrogen atom or (lower)-alkyl and independently of one another in case R'2; n = 0, 1, 2, 3 or 4. Also, invention relates to a medicament possessing high affinity to adenosine A2A-receptors and high selectivity with respect to A1-receptors and comprising one or more derivatives of benzothiazole of the formula (I) and pharmaceutically acceptable excipients. Invention provides using derivatives of benzothiazole as ligands of adenosine receptors.

EFFECT: valuable medicinal properties of compounds and medicament.

13 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of azethedine of the formula (I): in free form or as a salt wherein Ar means phenyl optionally substituted with one or some substitutes chosen from halogen atom, (C1-C8)-alkyl, cyano-group; R1 means hydrogen atom (H), (C1-C8)-alkyl optionally substituted with hydroxy-, (C1-C8)-alkoxy-, (C1-C8)-alkylcarbonyloxy-group, halogen atom, carboxy-group, (C1-C8)-alkoxycarbonyl; R2 means H, (C1-C8)-alkyl, (C3-C10)-cycloalkyl; R3 means (C1-C8)-alkyl substituted with phenyl, phenoxy-, (C1-C8)-alkylcarbonyloxy-group, naphthyl; or R2 represents (C3-C10)-cyclalkyl optionally comprising benzo-group, condensed benzo-group, 5-6-membered heterocyclic group comprising 1-3 different heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S), or up to 4 N atoms, or it means 5-6-membered heterocyclic group comprising 1 or 2 ring O or N atoms and optionally substituted with substitutes enumerated in the formula; or R3 means phenyl or naphthyl wherein indicated phenyl, phenoxy- or naphthyl group is substituted optionally with one or some substitutes chosen from halogen atom, cyano-, hydroxy-group, (C1-C8)-alkylcarbonyl, -SO2NH2, (C1-C8)-alkyl, optionally substituted (C1-C8)-alkoxy-, (C1-C8)-alkylthio-group, -SO2-(C1-C8)-alkyl, (C1-C8)-alkoxycarbonyl, (C1-C8)-acylamino-group substituted optionally with (C1-C8)-alkyl by nitrogen atom, (C1-C8)-alkylamino-group, aminocarbonyl, (C1-C8)-alkylaminocarbonyl, di-(C1-C8-alkyl)amino-group, di-(C1-C8-alkyl)aminocarbonyl, di-(C1-C8-alkyl)aminocarbonylmethoxy-group; X means -C(=O)-, -O-, -CH2- or -CH(OH); Y means O, S; m means 1, 2, 3 or 4; each n, p and q means 0 or 1, n + p + q = 1, n + q = 1 and p+ q = 1 and when n means 0 then p means 0. Compounds of the formula (I) inhibit binding eotaxine with CCR-3 receptor that allows their using as component of pharmaceutical composition and for preparing a medicinal agent used in inflammatory or allergic state.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 5 tbl, 201 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts. Proposed compounds possess properties of agonists of receptors activated by peroxisome proliferators (PPAR agonists) and can be used in treatment of such diseases as diabetes mellitus, hypertension, atherosclerotic diseases and others. In the general formula (I) R1 means lower alkyl, monocyclic (C3-C6)-cycloalkyl; R2 means hydrogen atom, halogen atom, lower alkyl, lower alkoxy-group wherein at least one of three radicals R3, R4, R5 or R6 is not hydrogen atom; or R3 and R4 are bound together to form a ring with carbon atoms to which they are bound, and R3 and R4 mean in common -CH=CH-S-, -S-CH=CH-, -CH=CH-CH=CH-, and R5 and R6 are given above; R7 means lower alkyl, lower alkenyl; R8 means hydrogen atom or lower alkyl; n = 1, 2 or 3. Also, invention relates to a pharmaceutical composition based on the invention compounds and to using compounds of the invention in preparing medicinal agents used in treatment and/or prophylaxis of diseases mediated by agonists PPARα and/or PPARγ.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 1 tbl, 13 sch, 71 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel imidazoline-2-yl-aminophenylamides of the formula (I): wherein R1 means phenyl optionally substituted with one, two or three substitutes chosen independently from group comprising alkyl, alkenyl, alkoxy-group, optionally substituted aryl, optionally substituted aryloxy-, aralkyloxy-group, halogen atom, halogenalkyl, halogenalkoxy-, hydroxy-group, hydroxyalkyl, alkylsulfonyl, alkoxyalkyloxy-, hydroxyalkyloxy-, cyano-, hydroxy-group, cycloalkyl, cycloalkyloxy-, cycloalkylalkoxy-, amino-, alkylamino-, dialkylamino-group, optionally substituted heterocyclyl, optionally substituted heterocyclyloxy-group, optionally substituted heterocyclylsulfonyl, optionally substituted heterocyclylalkyloxy-group, sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl; R2 means hydrogen atom; A means -C(O)-NRa-(CRbRc)n- or -NRa-C(O)-(CRbRc)n-; n = 1-6; each among Ra, Rb and Rc means independently hydrogen atom or alkyl, or their pharmaceutically acceptable salt or solvates, and to compounds of the formula (II): wherein R1, R2, Rb, Rc and A have above given values; each R3 and R4 means independently hydrogen atom or alkoxycarbonyl; Ra means hydrogen atom, alkyl or cycloalkyl. These compounds are effective modulators of IP receptors and firstly antagonists of IP receptors. Except for, invention involves pharmaceutical compositions containing indicated compounds.

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical composition.

11 cl, 1 tbl, 10 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein (a) each R1 is chosen independently from hydrogen atom and alkoxy-group; (b) R2 represents hydrogen atom; (c) each R3 and R4 is chosen independently of one another from hydrogen atom, alkyl, alkynyl, heteroalkyl group, aryl; or R3 and R4 in common with nitrogen atom bound with them form heteroaryl or heterocycloaryl substitute optionally substituted with one or more hydroxo-group, carboxyl group, keto-, thioketo-, phenyl group, alkyl, heteroalkyl group, heteroaryl, heterocycloalkyl, spirocycloalkyl and their combinations; (d) each R5 and R6 represents hydrogen atom; or optical isomers, diastereomers and enantiomers represented by above given formula, and their pharmaceutically acceptable salts also. Also, invention describes using compound of the formula (I) for preparing a pharmaceutical composition possessing antibacterial activity and antibacterial pharmaceutical composition containing the safety and effective amount of compound of the formula (I) and a pharmaceutically acceptable carrier. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable properties of compounds and pharmaceutical composition.

7 cl, 37 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes derivatives of aminotetraline of the formula (I) wherein R1 means (C1-C6)-alkyl; R2 means halogen atom or -OR'; R3 means hydrogen atom (H) or -OR' wherein R' means (C1-C6)-alkyl or -SO2R'' wherein R'' means phenyl, thienyl, isoxazolyl; R4 means (C1-C6)-alkyl, phenyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, diazepinyl, furanyl, isoxazolyl, imidazolyl and pyrazolyl that can be substituted optionally, and pharmaceutical compositions containing derivatives of aminotetraline. Proposed compounds are selective antagonists of M2/M3 muscarinic receptors and designated for treatment and prophylaxis of diseases associated with smooth muscle disorder.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 1 tbl, 16 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new amide-type carboxamide derivatives of formula [1] , wherein X represents -N= or -CH= group; R1 represents halogen atom, lower alkyl and a like; R1 represents -CO-R21-R22 (meanings of R21 and R22 are as defined in claim 1); Y1 and Y2 are independently halogen atom, lower alkyl, lower alcoxy group, and a like; ring A represents phenyl and a like; or pharmaceutically acceptable salts thereof. Said derivatives are useful as FXa inhibitors. Also disclosed are pharmaceutical composition based on abovementioned compounds and uses thereof.

EFFECT: new amide-type carboxamide derivatives.

7 cl, 105 ex

FIELD: organic synthesis.

SUBSTANCE: invention relates to a method for preparing N-dibenzoylpaclitaxel (formula I ) via esterification of 7-protected baccatin (III) with reactive carboxylic acid derivatives of general formula II (wherein R1 is aryl or heteroaryl) and single-step removal of protecting ester groups under acid conditions. Compound I can be suitable for preparation of paclitaxel and its analogues.

EFFECT: simplified synthetic procedure.

15 cl, 7 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention relates to hydroxamate derivatives described by general formula I: , in which R1 represents H or linear C1-C6-alkyl; R2 hydrogen, С110-alkyl optionally substituted by 1-5 constituents selected from hydroxy, amino, hydroxyalkyl; C4-C9-cycloalkyl; aryl; C4-C9-heterocycloalkyl, C4-C9-heterocycloalkylalkyl containing 2 heteroatoms (nitrogen and/or oxygen); C4-C9-cycloalkylalkyl; arylalkyl; heteroarylalkyl containing 1-4 nitrogen atoms as heteroatoms; -(CH2)nC(O)R6, -(CH2)nOC(O)R6, -N(R12)C(O)-W; HONH-C(O)-CH=C(R1)arylalkyl, and (CH2)nR7; R3 and R4, identical or different, independently denote hydrogen, optionally OH-substituted C1-C6-alkyl; C(O)-O-W, or -N(R12)C(O)W; or R3 and R4 together with carbon atom, to which they are linked, represent C=O; or R2 together with carbon atom, to which it is linked, and R3 together with carbon atom, to which it is linked, can form C4-C9-heterocycloalkyl containing 2 nitrogen atoms as heteroatoms; or mixed aryl or non-aryl polyheterocyclic ring; R5 is selected from hydrogen; C1-C6-alkyl; C4-C9-cycloalkyl; C(O)-W; aryl optionally substituted by 1-2 constituents selected from halogen and hydroxyalkyl; heteroaryl containing nitrogen as heteroatom; arylalkyl; aromatic polycycle; polyheteroaryl containing 1-2 nitrogen atoms as heteroatoms and optionally substituted by 1-2 substituents selected from hydroxyalkyl, halogen, alkyl, and aryl; mixed aryl-nonaryl polyheterocycle containing nitrogen or oxygen atom as heteroatom and optionally substituted by groups -N-OH, =N-OH; n, n1, n2, and n3, identical or different, are independently selected from within a range of 0-6; X and Y, identical or different, are independently selected from hydrogen, halogen, and nitro group; or pharmaceutically acceptable salt thereof. Invention also relates to a pharmaceutical composition showing inhibitory activity toward hydroxamate derivative of general formula I in combination with one or several pharmaceutically acceptable carriers. Hydroxamate derivative of general formula I are also appropriate for treating proliferative disease and regulating p21 promoter.

EFFECT: enabled use of hydroxamate derivatives as deacetylase inhibitors.

42 cl, 6 tbl, 272 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes substituted benzoylpyrazoles of the general formula (I): wherein Q means oxygen atom (O); R1 means alkyl with 1-6 carbon atoms; R2 means hydrogen atom; R3 and R4 mean independently of one another hydrogen atom, halogen atom, alkyl with 1-4 carbon atoms substituted with halogen atom; R5 means hydrogen atom, alkyl with 1-6 carbon atoms; Y means hydrogen atom; Z means alkoxyamino-group with 1-6 carbon atoms, alkylamino-group with 1-6 carbon atoms, substituted alkoxy-group with 1-4 carbon atoms, N-alkylalkoxyamino-group with 1-4 carbon atoms, phenyl substituted with halogen atom, monocyclic heterocyclyl, heterocyclylamino-group, group -N=(heterocyclyl) chosen from the group: furyl, tetrahydrofurylmethylamino-group, isoxazolyl, dihydroisoxazolyl (isoxazolinyl), tetrahydroisoxazolyl (isoxazolidinyl), tetrahydro-(2H)-1,2-oxazine-2-yl, dihydrothiazolyl (thiazolinyl), oxadiazolylamino-, thiadiazolylamino-group, piperidinyl, piperidinylamino-group, 2-oxo-1,3-diazacyclohexyl, morpholinyl, morpholinylamino-group, respectively, and substituted if necessary with alkyl with 1-4 carbon atoms, halogenalkyl with 1-4 carbon atoms, cycloalkyl with 3-6 carbon atoms involving their all possible tautomeric forms and possible salts. Also, invention describes a herbicide agent based in proposed compounds. Proposed compounds possess herbicide activity.

EFFECT: valuable properties of compounds and agent.

4 cl, 5 tbl, 77 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to 2-hetaryl-substituted derivatives of 1,2-tropolones of the general formula (Ia): wherein R1 and R2 mean (C1-C6)-alkyl; R3 means hydrogen atom, (C1-C6)-alkyl, nitro-group; Het means six-membered nitrogen heterocycle condensed with one or two benzyl rings that can be substituted with substitutes chosen from group comprising halogen atom, nitro-group, (C1-C6)-alkyl, oxy-(C1-C6)-alkyl, secondary amino-group chosen from anilino-, substituted anilino-, hydroxyethylamino-group, or tertiary amino-group chosen from morpholino-, piperidino-, piperazino-group, 1H-1-imidazolyl. Also, invention relates to a method for synthesis of 2-hetaryl-substituted derivatives of 1,3-tropolone. Method involves condensation of benzoquinones-1,2 with 2-methylheterocycles at heating in the presence of acetic acid taken in the amount providing its role as both a catalyst and a solvent. Also, invention relates to a pharmaceutical composition with antibacterial effect based on 2-hetaryl-substituted derivatives of 1,3-tropolone.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 5 tbl, 3 ex

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