Therapeutic agent for diabetes

 

(57) Abstract:

The invention relates to a new therapeutic drug for diabetes and includes the compound of the formula I: R1-C(O)-C(R2')(R2)-X-C(O)-R3where X represents a group of formula-C(R4)(R5)-, -N(R6)-, -O-; where R4is a hydrogen atom, a C1-C5alkyl, carboxy, phenyl, C2-C5acyl, C2-C5alkoxycarbonyl, R5is a hydrogen atom, a C1-C5alkyl; R6is hydrogen; R1is phenyl, optionally substituted C1-C5by alkyl, hydroxy, hydroxyalkyl, C2-C6alkenyl, acyl, carboxy, teinila, C3-C7cycloalkyl; biphenyl, optionally substituted C1-C5the alkyl or hydroxy; naphthyl; terphenyl; C3-C7cycloalkyl, optionally substituted C1-C5the alkyl or phenyl; optionally substituted C1-C5alkyl; pyridyl; sensational; substituted; indanyl; fluorenyl or group ; R2is hydrogen, C1-C5alkyl, optionally substituted by carboxy; R2'is hydrogen; R3- C1-C5alkyl, optionally substituted by phenyl or C1-C4alkoxy, C1-C4alkoxy; hydroxy; phenyl; C3<, brisout group -(CH2)2-; R2and R5taken together, form a simple bond or-CH2-, - (CH2)3-, -(CH2)4-; R2, R2', R4and R5taken together form =CH-CH=CH-CH=; R2' and R3taken together form a-CH(R8)-OH, -CH(R8)-CH(R9)-, -CH(R8)NH; R8and R9is hydrogen, and its pharmaceutically acceptable salts. Also describes compounds of formula II, where R1"is hydrogen, R1" - C3-C7cycloalkyl, monosubstituted C1-C4the alkyl, phenyl; when R3means C1-C4alkoxy, R4means C2-C5acyl, C2-C5alkoxycarbonyl, R1" - C3-C7cycloalkyl, monosubstituted C1-C4the alkyl, phenyl, or its pharmaceutically acceptable salts; the compounds of formula III, where R3"'is hydroxy, R4"'is hydrogen, C1-C4alkyl, carboxy; R3"' denotes hydrogen or C1-C4alkyl, R101means C1-C4alkyl, substituted hydroxy; when R3" - C1-C4alkyl, R4"'is hydrogen, C2-C5acyl; R5"'is hydrogen, C1-C4alkyl, R101- C1-C4alkyl, substituted geolat. The compounds of formula IV, where a and b are different and are CH2, NH, Oh, and when R2"'is hydrogen, R101' - C1-C4alkyl, substituted hydroxy or phenyl; or when R2"' - C1-C4alkyl, R101'is hydrogen, C1-C4alkyl, substituted hydroxy or phenyl; its pharmaceutically acceptable salt, hydrate or MES. Connections do not have side effects and reduce the level of blood glucose during hyperglycemia. 6 C. and 26 C.p. f-crystals, 4 Il., 31 table.

The present invention relates to a new therapeutic drug for diabetes. More specifically, the present invention relates to a new therapeutic drug for diabetes, which contains a compound having a carbonyl structure, its prodrug, pharmaceutically acceptable salt, hydrate or MES, and this drug has no serious side effects, such as hypoglycemia, and has excellent pharmacological activity against improvement only hyperglycemia.

Art

Diabetes is a chronic disease caused by a deficiency of insulin and characterized by abnormal metabolism of glucose, lipids and amino acids. If ega two types - insulin-dependent species and non-insulin-dependent species, of which about 90% of patients with diabetes, refer to the latest.

Insulin-dependent diabetes mellitus can cause the development of ketonemia and acidosis due to the termination of the insulin secretory function, and, if left untreated, inevitably there comes a diabetic coma. Be expected therapeutic effect in the treatment by diet or by taking oral hypoglycemic agents, as this disease can be treated only with insulin.

On the contrary, in the case of non-insulin-dependent diabetes mellitus, although the action of insulin is not enough insulin is not necessarily required for treatment, as in this case, the propensity for the development of ketonemia and acidosis much less.

Some cases of hyperglycemia detected in patients with non-insulin-dependent diabetes mellitus is considered as anomalous stimulated glucose insulin secretion and increased insulin resistance nesenevich cells. Abnormal insulin secretion believe associated with abnormal function of determining the concentration of glucose in the cells of the pancreas, and the appropriate secretion of insulin depending on the op the ina includes not only the failure of secretion of insulin, but also the disappearance of secretion in the early phase and delayed secretion, resulting in hyperglycemia. Resistance to insulin means less insulin action and the seizure of glucose into cells by insulin. In this sense the abnormality of insulin, the anomalous character of the insulin receptor in nesenevich cells and the abnormality transmission system signal in the cells, apparently, are the reasons. However, what exactly causes resistance to insulin, remains subject to further research (Chiryogaku, 29(4), pp 378-381 (1995)).

Currently, there are insulin preparations, sulfonylurea derivatives, derivatives of biguanide, a therapeutic agent for diabetes, which increase resistance to insulin inhibitors-glucosidase, etc., for the treatment of hyperglycemia. Insulin is used for treatment of insulin-dependent diabetes, and for some reduction in the levels of glucose in the blood. But they can be administered only by injection, and this is associated with the ability to cause hypoglycemia. Derivatives, sulfonylureas stimulate cells of the pancreas and stimulate endogenous insulin secretion, and the duration and amount of secreted insulin depends on the availability side effect is hypoglycemia, caused by the prolonged action of the drug. In addition, there is a symptom of digestive system as anorexia. The use of sulfonylureas should be avoided in patients with severe ketosis or disorder of the liver or kidneys. Drugs biguanide deprived drawback associated with stimulating effect on cells of the pancreas, and do not cause hypoglycemia in a single implementation for both healthy people and diabetic patients. Believe that the mechanism of their action is based on increased utilization of glucose due to anaerobic glycolysis, inhibition of gluconeogenesis, suppression of absorption of glucose in the intestines, etc. as a side effect, there is a tendency to relatively serious dairy acetosa. Pharmaceuticals to increase resistance to insulin include derivatives of thiazolidine. Derivatives of thiazolidine not stimulate insulin secretion, but increase the activity of insulin activates the insulin receptor kinase, stimulates the seizure of glucose by peripheral tissues and suppress excessive production of sugar in the liver. As the side effects they cause disturbances in the organs pixelart the human hemoglobin, and increase LDH (Atarashii Tonyobyo Chiryogaku, pp. 90-99 (1984), Pharmaceutical Journal Corp.).

On the other hand, there are other therapeutic drugs for diabetics, which inhibit-glucosidase. Inhibitors-glucosidase slow down the digestion and absorption of glucose in the digestive tract and suppress the increase of glucose in the blood after a meal. However, at the same time, they cause side effects such as a feeling of heaviness, rumbling in the stomach, diarrhea etc. (Joslin's Diabetes Mellitus 13thEdition 521-522). In addition, in Japanese laid patent publication N 54321/1988 described an oral hypoglycemic agent, which causes severe and rapid secretion of insulin, which refers to the type of fast-acting drugs are short-acting. Because it does not cause insulin secretion in accordance with the level of glucose in the blood, and its effect depends on the dose and time of drug administration, the level of glucose in the blood cannot be easily suppressed using such drugs, and skipping a dose of such drugs can lead to hypoglycemia. In addition, in Japanese laid patent publication N 128266/1992 indicated that the inhibitor alsoreported also has a stimulating effect on insulin secretion zawiyas in the blood cannot be suppressed sufficiently well. Therefore, there is a need for a pharmaceutical product, which not just would reduce the level of glucose in the blood, but also could support this level of blood glucose in the normal range.

Some compounds used as active ingredients in pharmaceutical treatment for diabetes is known. However, no publications, which would be described that these compounds are effective excellent therapeutic drug for diabetes, except for data, suggesting such effects. Below are the structural formulas of these known compounds, titles of publications [registration number (R. N.) NN patent publication or publication title] and described them in the main application, which are summarized in tables 1-8.

DESCRIPTION OF THE INVENTION

The present invention aims at the creation of a pharmaceutical agent that has the property to reduce the glucose content in the blood under conditions of hyperglycemia, and which does not cause such side effects like hypoglycemia, etc., the Applicants of the present invention have conducted intensive studies and found such pharmaceutical agent only on hyperglycemia and can be used as a drug for the treatment of diabetes and as a preventive drug for chronic complications of diabetes, that was the subject of invention.

Thus, the present invention relates to therapeutic tools for the treatment of diabetes containing compounds presented in the following paragraphs (1) to(11), their pharmaceutically acceptable salt, hydrate or solvate, to new compounds represented in paragraphs (12)-(28), their prodrugs and their pharmaceutically acceptable salts, hydrate and solvate, including their active metabolites. The invention relates also to pharmaceutical means and compositions according to (29)-(32) and therapeutic tools for the treatment of diabetes in paragraph (33).

(1) a Therapeutic agent for diabetes, which contains a compound of the formula [I]:

< / BR>
where X represents a group of the formula

< / BR>
where R4and R5the same or different, and each represents a hydrogen atom, optionally substituted alkyl containing from 1 to 5 carbon atoms, optionally substituted of alkenyl containing from 2 to 6 carbon atoms, optionally substituted aryl, optionally substituted acyl containing 2 to 5 carbon atoms, carboxy or optionally substituted alkoxycarbonyl containing from 2 to 5 carbon atoms, and R6is ATO from 1 to 5 carbon atoms, optionally substituted of alkenyl containing from 2 to 6 carbon atoms, optionally substituted aryl, optionally substituted heterocyclic group containing at least one nitrogen atom, oxygen atom or sulfur atom, optionally substituted cycloalkyl containing from 3 to 7 carbon atoms, cycloalkenyl containing from 5 to 7 carbon atoms, having at least one double bond in the ring, optionally substituted substituted, optionally substituted of indenyl, optionally substituted fluorenyl, or a group of the formula

< / BR>
R2represents a hydrogen atom, optionally substituted alkyl containing from 1 to 5 carbon atoms, optionally substituted of alkenyl containing from 2 to 6 carbon atoms, optionally substituted aryl, optionally substituted acyl containing 2 to 5 carbon atoms, carboxy or optionally substituted alkoxycarbonyl containing from 2 to 5 carbon atoms;

R'2represents a hydrogen atom;

R3represents optionally substituted alkyl, containing from 1 to 5 carbon atoms, optionally substituted alkoxy containing from 1 to 4 carbon atoms, hydroxy, optionally substituted aryl, optionally substituted ciku formula

-CH2- or -(CH2)2-;

R2and R5optionally taken together form a bond or a group of the formula

-CH2-, -(CH2)2-, -(CH2)3- or -(CH2)4-;

R2, R'2, R4and R5not necessarily, taken together, form a group of the formula

=CH-CH=CH-CH=;

R3and R5not necessarily, taken together, form a group of the formula

< / BR>
< / BR>
and

R'2and R3not necessarily, taken together, form a group of the formula

< / BR>
< / BR>
< / BR>
where R8and R9the same or different, and each represents a hydrogen atom, optionally substituted alkyl containing from 1 to 5 carbon atoms, optionally substituted alkoxy containing from 1 to 4 carbon atoms, optionally substituted alkoxycarbonyl containing from 2 to 5 carbon atoms or optionally substituted alkoxy containing from 2 to 5 carbon atoms;

its prodrug, pharmaceutically acceptable salt, hydrate or MES.

(2) a Therapeutic agent for diabetes under paragraph (1) , where in the formula [I],

X represents a group of the formula

< / BR>
where R4represents a hydrogen atom, alkyl containing from 1 to 5 atoms operatorov carbon carboxy or alkoxycarbonyl containing from 2 to 5 carbon atoms, R5represents a hydrogen atom or alkyl containing from 1 to 5 carbon atoms, and R6represents a hydrogen atom or acyl containing 2 to 5 carbon atoms;

R1represents alkyl containing from 1 to 5 carbon atoms, which is optionally substituted by cycloalkyl containing from 3 to 7 carbon atoms, or aryl, alkenyl containing from 2 to 6 carbon atoms, which may be optionally substituted by cycloalkyl containing from 3 to 7 carbon atoms, or aryl, aryl selected from the group comprising phenyl, biphenyl, naphthyl and terphenyl (these aryl groups are optionally substituted by one or more substituents selected from the group comprising alkyl containing from 1 to 5 carbon atoms, by alkyl, containing from 1 to 5 carbon atoms, which is substituted by hydroxy, alkyl containing from 1 to 5 carbon atoms, which is substituted by an alkoxy containing from 1 to 4 carbon atoms, alkenyl containing from 2 to 6 carbon atoms, acyl containing from 1 to 5 carbon atoms, carboxy, alkoxycarbonyl containing from 2 to 5 carbon atoms, hydroxy, cycloalkyl containing from 3 to 7 carbon atoms, alkoxy containing from 1 to 4 carbon atoms, hamiltonianus amino, containing from 2 to 5 carbon atoms, C2-C5-tildesley amino, heterocyclic group and halogen atom), a heterocyclic group selected from the group comprising furyl, thienyl, pyridyl, sensational and benzofuran (this heterocyclic group optionally substituted by alkyl containing 1 to 5 carbon atoms, alkyl containing from 1 to 5 carbon atoms, which is substituted by hydroxy, alkyl containing from 1 to 5 carbon atoms, which is substituted by an alkoxy containing from 1 to 4 carbon atoms, alkenyl containing from 2 to 6 carbon atoms, acyl containing from 1 to 5 carbon atoms, carboxy, alkoxycarbonyl containing from 2 to 5 carbon atoms, hydroxy, cycloalkyl containing from 3 to 7 carbon atoms, alkoxy containing from 1 to 4 carbon atoms, amino, alkyl substituted amino containing 1 to 5 carbon atoms, C1-C5-alkyldiphenyl amino, allsamsung amino containing from 2 to 5 carbon atoms, C2-C5-acidization amino and halogen atom), cycloalkyl containing from 3 to 7 carbon atoms, which is optionally substituted by alkyl containing 1 to 5 carbon atoms, or aryl, cycloalkenyl containing from 5 to 7 carbon atoms, and containing at the 5 carbon atoms, or aryl, fluorenyl, or a group of the formula

< / BR>
R2represents a hydrogen atom or alkyl containing from 1 to 5 carbon atoms, which is optionally substituted by aryl or carboxy;

R'2represents a hydrogen atom;

R3represents alkyl containing from 1 to 5 carbon atoms, which is optionally substituted alkoxy containing from 1 to 4 carbon atoms or by aryl, alkoxy containing from 1 to 4 carbon atoms, hydroxy, aryl selected from the group comprising phenyl, biphenyl, naphthyl, terphenyl, cycloalkyl containing from 3 to 7 carbon atoms, which is optionally substituted by alkyl containing 1 to 5 carbon atoms, or amino;

R2and R7taken together form a group of the formula

-CH2- or -(CH2)2-;

R2and R5taken together form a bond or a group of the formula

-CH2-, -(CH2)2-, -(CH2)3- or -(CH2)4-;

R2, R'2, R4and R5taken together form a group of the formula

=CH-CH=CH-CH=;

R3and R5taken together form a group of the formula

< / BR>
and

R'2and R3taken together form a group of the formula

< / BR>
< / BR>
< / BR>
where R8and R9adinterax from 1 to 4 carbon atoms, alkoxycarbonyl containing from 2 to 5 carbon atoms, acyloxy containing from 2 to 5 carbon atoms.

(3) a Therapeutic agent for diabetes under paragraph (1), where in the formula [I],

X represents a group of the formula

< / BR>
where R4represents a hydrogen atom, alkyl containing from 1 to 5 carbon atoms, phenyl, acyl containing 2 to 5 carbon atoms, carboxy or alkoxycarbonyl containing from 2 to 5 carbon atoms, R5represents a hydrogen atom or alkyl containing from 1 to 5 carbon atoms, and R6represents a hydrogen atom or acyl containing 2 to 5 carbon atoms;

R1represents alkyl containing from 1 to 5 carbon atoms, which is optionally substituted by cycloalkyl containing from 3 to 7 carbon atoms or aryl, aryl selected from the group comprising phenyl, biphenyl, naphthyl and terphenyl (these aryl groups are optionally substituted by one or more substituents selected from the group comprising alkyl containing from 1 to 5 carbon atoms, alkyl containing from 1 to 5 carbon atoms, which is substituted by hydroxy, alkyl containing from 1 to 5 carbon atoms, which is substituted by alkoxy, containing from 1 to 4 carbon atoms, alkenyl containing from 2 to 6 atoms heterocyclics group and hydroxy), heterocyclic group selected from the group comprising furyl, thienyl, sensational and pyridyl (these heterocyclic group optionally substituted by alkyl containing 1 to 5 carbon atoms, alkyl containing from 1 to 5 carbon atoms, which is substituted by hydroxy, alkenyl containing from 2 to 6 carbon atoms, acyl containing from 1 to 5 carbon atoms, carboxy, cycloalkyl containing from 3 to 7 carbon atoms and hydroxy), cycloalkyl containing from 3 to 7 carbon atoms, which is optionally substituted by alkyl, containing from 1 to 5 carbon atoms or aryl, substituted, indanyl, fluorenyl or a group of the formula

< / BR>
R2represents a hydrogen atom or alkyl containing from 1 to 5 carbon atoms;

R'2represents a hydrogen atom;

R3represents alkyl containing from 1 to 5 carbon atoms, which is optionally substituted alkoxy containing from 1 to 4 carbon atoms or by aryl, alkoxy containing from 1 to 4 carbon atoms, hydroxy, aryl selected from the group comprising phenyl, biphenyl, naphthyl, terphenyl, cycloalkyl containing from 3 to 7 carbon atoms, which is optionally substituted by alkyl containing 1 to 5 carbon atoms;

R2and R7taken together, the together, form a bond or a group of the formula

-CH2-, -(CH2)2-, -(CH2)3- or -(CH2)4-;

R2, R'2R4and R5not necessarily, taken together, form a group of the formula

=CH-CH=CH-CH=;

R3and R5not necessarily, taken together, form a group of the formula

< / BR>
and

R'2and R3not necessarily, taken together, form a group of the formula

< / BR>
< / BR>
< / BR>
where R8and R9the same or different, and each represents a hydrogen atom, alkyl containing from 1 to 5 carbon atoms, alkoxy containing from 1 to 4 carbon atoms, alkoxycarbonyl containing from 2 to 5 carbon atoms or acyloxy containing from 2 to 5 carbon atoms.

(4) a Therapeutic agent for diabetes under paragraph (1), where in the formula [I],

X represents a group of the formula

< / BR>
where R4represents a hydrogen atom, alkyl containing from 1 to 5 carbon atoms, acyl containing 2 to 5 carbon atoms, carboxy or alkoxycarbonyl containing from 2 to 5 carbon atoms, R5represents a hydrogen atom or alkyl containing from 1 to 5 carbon atoms, and R6represents a hydrogen atom;

R1represents alkyl containing from 1 to is, aryl selected from the group comprising phenyl, biphenyl, naphthyl and terphenyl (these aryl groups are optionally substituted by one or more substituents selected from the group comprising alkyl containing from 1 to 5 carbon atoms, alkyl containing from 1 to 5 carbon atoms, which is substituted by hydroxy, alkyl containing from 1 to 5 carbon atoms, which is substituted by an alkoxy containing from 1 to 4 carbon atoms, alkenyl containing from 2 to 6 carbon atoms, acyl containing from 1 to 5 carbon atoms, carboxy, cycloalkyl, containing from 3 to 7 carbon atoms, heterocyclic group and hydroxy), heterocyclic group selected from Furie, teinila, benzothiazyl and pyridyl, cycloalkyl containing from 3 to 7 carbon atoms, which is optionally substituted by alkyl containing 1 to 5 carbon atoms, or aryl, substituted, indanyl, fluorenyl or a group of the formula

< / BR>
R2represents a hydrogen atom or alkyl containing from 1 to 5 carbon atoms;

R'2represents a hydrogen atom;

R3represents alkyl containing from 1 to 5 carbon atoms, which is optionally substituted alkoxy containing from 1 to 4 carbon atoms, or aryl, alkoxy containing from 1 to 4 carbon atoms, hydroxy Il the CTE, form a group of the formula

-CH2-;

R2and R5not necessarily taken together form a bond or a group of the formula

-CH2-, -(CH2)2-, -(CH2)3- or -(CH2)4-;

R2, R'2, R4and R5not necessarily, taken together, form a group of the formula

=CH-CH=CH-CH=; and

R'2and R3not necessarily, taken together, form a group of the formula

< / BR>
< / BR>
< / BR>
where R8and R9each represents a hydrogen atom.

(5) therapeutic agent for the treatment of diabetes under paragraph (1), where in the formula [I],

X represents a group of the formula

< / BR>
where R4represents a hydrogen atom, alkyl containing from 1 to 5 carbon atoms, acyl containing 2 to 5 carbon atoms, carboxy or alkoxycarbonyl containing from 2 to 5 carbon atoms, R5represents a hydrogen atom or alkyl containing from 1 to 5 carbon atoms, and R6represents a hydrogen atom;

R1represents alkyl containing from 1 to 5 carbon atoms, optionally substituted by cycloalkyl containing from 3 to 7 carbon atoms or aryl, the aryl is selected from the group comprising phenyl, biphenyl, naphthyl and terphenyl (these aryl groups optionally semen hydroxy, the alkyl containing from 1 to 5 carbon atoms, substituted alkoxy containing from 1 to 4 carbon atoms, alkenyl containing from 2 to 6 carbon atoms, acyl containing from 1 to 5 carbon atoms, carboxy, cycloalkyl containing from 3 to 7 carbon atoms, heterocyclic group, or hydroxy), heterocyclic group selected from the group comprising furyl, thienyl, sensational and pyridyl, cycloalkyl containing from 3 to 7 carbon atoms, which is optionally substituted by alkyl containing 1 to 5 carbon atoms, or aryl, substituted, indanyl or fluorenyl;

R2represents a hydrogen atom or alkyl containing from 1 to 5 carbon atoms;

R'2represents a hydrogen atom;

R3represents alkyl containing from 1 to 5 carbon atoms, alkoxy containing from 1 to 4 carbon atoms, hydroxy or aryl selected from the group comprising phenyl, biphenyl, naphthyl and terphenyl;

R2and R5not necessarily taken together form a bond or a group of the formula

-(CH2)3- or -(CH2)4-; and

R'2and R3not necessarily, taken together, form a group of the formula

< / BR>
< / BR>
where R8and R9each represents a hydrogen atom.

(6)crystals

< / BR>
where R4represents a hydrogen atom, alkyl containing from 1 to 5 carbon atoms, acyl containing 2 to 5 carbon atoms, carboxy or alkoxycarbonyl containing from 2 to 5 carbon atoms, R5represents a hydrogen atom or alkyl containing from 1 to 5 carbon atoms, and R6represents a hydrogen atom;

R1represents alkyl containing from 1 to 5 carbon atoms, optionally substituted by cycloalkyl containing from 3 to 7 carbon atoms, or aryl, aryl selected from phenyl, biphenyl, naphthyl and terphenyl (these aryl groups optionally substituted by alkyl containing 1 to 5 carbon atoms, alkyl containing from 1 to 5 carbon atoms, a substituted hydroxy, alkyl containing from 1 to 5 carbon atoms, substituted alkoxy containing from 1 to 4 carbon atoms, alkenyl containing from 2 to 6 carbon atoms, acyl, containing from 1 to 5 carbon atoms, carboxy, cycloalkyl containing from 3 to 7 carbon atoms, heterocyclic group or hydroxy), cycloalkyl containing from 3 to 7 carbon atoms, which is optionally substituted by alkyl containing 1 to 5 carbon atoms, or aryl, substituted, indanyl or fluorenyl;

R2represents a hydrogen atom;

R2and R5not necessarily taken together represent a bond; and

R'2and R3not necessarily, taken together, form a group of the formula

< / BR>
< / BR>
where R8and R9each represents a hydrogen atom.

(7) a Therapeutic agent for diabetes under paragraph (1), where in the formula [I],

X represents a group of the formula

< / BR>
where R4represents a hydrogen atom, alkyl containing from 1 to 5 carbon atoms, acyl containing 2 to 5 carbon atoms, carboxy or alkoxycarbonyl containing from 2 to 5 carbon atoms, R5represents a hydrogen atom or alkyl containing from 1 to 5 carbon atoms, and R6represents a hydrogen atom;

R1represents alkyl containing from 1 to 5 carbon atoms, optionally substituted by cycloalkyl containing from 3 to 7 carbon atoms, or aryl, aryl selected from phenyl, biphenyl, naphthyl and terphenyl (these aryl groups optionally substituted by alkyl containing 1 to 5 carbon atoms, alkyl containing from 1 to 5 carbon atoms, which is substituted by hydroxy, alkyl containing from 1 to 5 carbon atoms, which is substituted by an alkoxy containing from 1 d is carboxy, cycloalkyl containing from 3 to 7 carbon atoms, heterocyclic group or hydroxy), or cycloalkyl containing from 3 to 7 carbon atoms, which is optionally substituted by alkyl containing 1 to 5 carbon atoms, or aryl;

R2represents a hydrogen atom;

R'2represents a hydrogen atom;

R3represents alkyl containing from 1 to 5 carbon atoms, alkoxy containing from 1 to 4 carbon atoms or hydroxy;

R'2and R3taken together form a group of the formula

< / BR>
< / BR>
where R8and R9each represents a hydrogen atom.

(8) a Therapeutic agent for diabetes under paragraph (1), where in the formula [I],

X represents a group of the formula

< / BR>
where R4represents a hydrogen atom, alkyl containing from 1 to 5 carbon atoms, acyl containing 2 to 5 carbon atoms, carboxy or alkoxycarbonyl containing from 2 to 5 carbon atoms, R5represents a hydrogen atom or alkyl containing from 1 to 5 carbon atoms, and R6represents a hydrogen atom;

R1is aryl selected from the group comprising phenyl, biphenyl, naphthyl and terphenyl (these aryl groups optionally substituted by alkyl, sodergran from 1 to 5 carbon atoms, which is substituted by an alkoxy containing from 1 to 4 carbon atoms, alkenyl containing from 2 to 6 carbon atoms, acyl containing from 1 to 5 carbon atoms, carboxy, cycloalkyl containing from 3 to 7 carbon atoms, heterocyclic group or hydroxy), or cycloalkyl containing from 3 to 7 carbon atoms, which is optionally substituted by alkyl containing 1 to 5 carbon atoms, or aryl;

R2represents a hydrogen atom;

R'2represents a hydrogen atom; and

R3represents alkyl containing from 1 to 5 carbon atoms, alkoxy containing from 1 to 4 carbon atoms or hydroxy.

(9) a Therapeutic agent for diabetes under paragraph (1), where in the formula [I],

X represents a group of the formula

< / BR>
where R4represents a hydrogen atom, alkyl containing from 1 to 5 carbon atoms, acyl containing 2 to 5 carbon atoms, carboxy or alkoxycarbonyl containing from 2 to 5 carbon atoms, and R5represents a hydrogen atom or alkyl containing from 1 to 5 carbon atoms;

R1is aryl selected from phenyl, biphenyl, naphthyl and terphenyl (these aryl groups optionally substituted by alkyl containing 1 to 5 carbon atoms, Alka, which is substituted by an alkoxy containing from 1 to 4 carbon atoms, alkenyl containing from 2 to 6 carbon atoms, acyl containing from 1 to 5 carbon atoms, carboxy, cycloalkyl containing from 3 to 7 carbon atoms, heterocyclic group or hydroxy), or cycloalkyl containing from 3 to 7 carbon atoms, which is optionally substituted by alkyl containing 1 to 5 carbon atoms, or aryl;

R2represents a hydrogen atom;

R'2represents a hydrogen atom; and

R3represents alkyl containing from 1 to 5 carbon atoms, alkoxy containing from 1 to 4 carbon atoms, or hydroxy.

(10) therapeutic agent for the treatment of diabetes under paragraph (1), where in the formula [I],

X represents a group of the formula

< / BR>
where R4and R5each represents a hydrogen atom;

R1is aryl selected from the group comprising phenyl, biphenyl, naphthyl and terphenyl (these aryl groups optionally substituted by alkyl containing 1 to 5 carbon atoms, alkyl containing from 1 to 5 carbon atoms, which is substituted by hydroxy, alkyl containing from 1 to 5 carbon atoms, which is substituted by an alkoxy containing from 1 to 4 carbon atoms, alkenyl containing from 2 to the s carbon heterocyclic group, or hydroxy), or cycloalkyl containing from 3 to 7 carbon atoms, which is optionally substituted by alkyl containing 1 to 5 carbon atoms, or aryl;

R2represents a hydrogen atom;

R'2represents a hydrogen atom; and

R3represents alkyl containing from 1 to 5 carbon atoms, alkoxy containing from 1 to 4 carbon atoms, or hydroxy.

(11) therapeutic agent for the treatment of diabetes under paragraph (1), where in the formula [I],

X represents a group of the formula

< / BR>
where R4and R5each represents a hydrogen atom;

R1is aryl selected from the group comprising phenyl, biphenyl, naphthyl and terphenyl (these aryl groups optionally substituted by alkyl containing 1 to 5 carbon atoms, alkyl containing from 1 to 5 carbon atoms, which is substituted by hydroxy, alkyl containing from 1 to 5 carbon atoms, which is substituted by an alkoxy containing from 1 to 4 carbon atoms, alkenyl containing from 2 to 6 carbon atoms, acyl containing from 1 to 5 carbon atoms, carboxy, cycloalkyl containing from 3 to 7 carbon atoms, heterocyclic group, or hydroxy), or cycloalkyl containing from 3 to 7 atoms of plastics technology: turning & dstanley a hydrogen atom;

R'2represents a hydrogen atom; and

R3represents hydroxy.

(12) the Compound of the formula

< / BR>
where, if R3represents hydroxy,

R4represents a hydrogen atom, acyl containing 2 to 5 carbon atoms, carboxy or alkoxycarbonyl containing from 2 to 5 carbon atoms, and

R1is cycloalkyl containing from 3 to 7 carbon atoms, which monogamist Deputy selected from the group comprising alkyl containing from 1 to 4 carbon atoms, hydroxy, alkoxy containing from 1 to 4 carbon atoms, aryl, acyl containing 2 to 5 carbon atoms, amino, carboxy and alkoxycarbonyl containing from 2 to 5 carbon atoms; and

when R3represents alkyl containing from 1 to 4 carbon atoms, or alkoxy containing from 1 to 4 carbon atoms,

R4is acyl containing 2 to 5 carbon atoms, carboxy or alkoxycarbonyl containing from 2 to 5 carbon atoms, and

R1is cycloalkyl containing from 3 to 7 carbon atoms, which monogamist Deputy selected from the group comprising alkyl containing from 1 to 4 carbon atoms, hydroxy, alkoxy containing from 1 to 4 carbon atoms, aryl, AC;

its prodrug, pharmaceutically acceptable salt, hydrate or MES.

(13) the Compound according to item (12), where R'3is hydroxy; a prodrug, pharmaceutically acceptable salt, hydrate or MES.

(14) the Compound according to item (12) or (13), where R4represents a hydrogen atom; a prodrug, pharmaceutically acceptable salt, hydrate or MES.

(15) the Compound according to any one of items (12)-(14), where R1is cycloalkyl containing from 3 to 7 carbon atoms, which monogamist an alkyl containing from 1 to 4 carbon atoms; a prodrug, pharmaceutically acceptable salt, hydrate or MES.

(16) the Compound according to any one of items (12)-(15), where R1is cycloalkyl containing from 3 to 7 carbon atoms, which monogamist the stands; its prodrug, pharmaceutically acceptable salt, hydrate and MES.

(17) the Compound according to any one of items (12)-(16), which is chosen from the group including

1) 4-(1-methylcyclohexyl)-4-oxobutanoic acid,

2) TRANS-4-(4-methylcyclohexyl)-4-oxobutanoic acid,

3) TRANS-4-(4-ethylcyclohexyl)-4-oxobutanoic acid,

4) TRANS-4-(4-isopropylcyclohexane)-4-oxobutanoic acid,

5) mulatu,

7) CIS-4-(4-methylcyclohexyl)-4-oxobutanoic acid,

8) 4-(3-methylcyclohexyl)-4-oxobutanoic acid,

9) dimethyl-2-[2-(1-methylcyclohexyl)-2-oxoethyl]propanedioic and

10) of methyl 2-acetyl-4-(1-methylcyclohexyl)-4-oxobutanoate;

its prodrug, pharmaceutically acceptable salt, hydrate or solvate.

(18) the Compound according to any one of items (12) to(17), which is chosen from the group including

1) 4-(1-methylcyclohexyl)-4-oxobutanoic acid,

2) TRANS-4-(4-methylcyclohexyl)-4-oxobutanoic acid,

3) TRANS-4-(4-ethylcyclohexyl)-4-oxobutanoic acid,

4) TRANS-4-(4-isopropylcyclohexane)-4-oxobutanoic acid,

5) TRANS-4-(4-tert-butylcyclohexyl)-4-oxobutanoic acid,

6) TRANS-4-(4-phenylcyclohexyl)-4-oxobutanoic acid,

7) CIS-4-(4-methylcyclohexyl)-4-oxobutanoic acid and

8) 4-(3-methylcyclohexyl)-4-oxobutanoic acid;

its prodrug, pharmaceutically acceptable salt, hydrate or MES.

(19) the Compound of the formula

< / BR>
where R"'3represents hydroxy,

R"'4represents a hydrogen atom, alkyl containing from 1 to 4 carbon atoms, acyl containing 2 to 5 carbon atoms, carboxy or alkoxycarbonyl, Dom carbon acyl containing 2 to 5 carbon atoms, carboxy or alkoxycarbonyl containing from 2 to 5 carbon atoms, and

R101represents alkyl containing from 1 to 4 carbon atoms, which is substituted by hydroxy;

when R"'3represents alkyl containing from 1 to 4 carbon atoms,

R"'4represents a hydrogen atom, alkyl containing from 1 to 4 carbon atoms, acyl containing 2 to 5 carbon atoms, carboxy or alkoxycarbonyl containing from 2 to 5 carbon atoms;

R"'5represents a hydrogen atom, alkyl containing from 1 to 4 carbon atoms, acyl containing 2 to 5 carbon atoms, carboxy or alkoxycarbonyl containing from 2 to 5 carbon atoms, and

R101represents alkyl containing from 1 to 4 carbon atoms, which is substituted by hydroxy, or aryl, substituted Deputy selected from the group comprising carboxy, alkoxycarbonyl containing from 2 to 5 carbon atoms, hydroxy, alkyl containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms, aryl, acyl containing 2 to 5 carbon atoms, and amino; and

when R"'3is alkoxy containing from 1 to 4 carbon atoms,

R"'4represents a hydrogen atom, alkyl, sterzi from 2 to 5 carbon atoms,

R"'5represents a hydrogen atom, alkyl containing from 1 to 4 carbon atoms, acyl containing 2 to 5 carbon atoms, carboxy or alkoxycarbonyl containing from 2 to 5 carbon atoms, and

R101represents alkyl containing from 1 to 4 carbon atoms, which is substituted by hydroxy, or aryl, substituted Deputy selected from the group comprising carboxy, alkoxycarbonyl containing from 2 to 5 carbon atoms, hydroxy, aryl, acyl containing 2 to 5 carbon atoms, and amino;

it, prodrug, pharmaceutically acceptable salt, hydrate or MES.

(20) the Compound according to item (19), where R"'3represents hydroxy; its prodrug, pharmaceutically acceptable salt, hydrate or MES.

(21) the Compound according to item (19) or (20), where R"'4or R"'5represents a hydrogen atom; its prodrug, pharmaceutically acceptable salt, hydrate or MES.

(22) the Compound according to any one of items (19) to(21), where R"'4and R"'5each represents a hydrogen atom; its prodrug, pharmaceutically acceptable salt, hydrate or MES.

(23) the Compound according to any one of items (19) to(22), where R101represents alkyl containing from 1 to 4 carbon atoms, to which the Compound according to any one of items (19) to(23), which is selected from the group including

1) 4-[4-(hydroxymethyl)phenyl]-4-oxobutanoic acid,

2) 1-(4-hydroxymethylene)-1,4-pentandiol,

3) 1-[4-(1-hydroxyethyl)phenyl]-1,4-pentandiol and

4) 1-[4-(2-hydroxyethyl)phenyl]-1,4-pentandiol;

its prodrug, pharmaceutically acceptable salt, hydrate or MES.

(25) the Compound of the formula

< / BR>
where A and B are the same or different, and each represents C, NH or O; and

when R"'2represents a hydrogen atom,

R'101represents alkyl containing from 1 to 4 carbon atoms, which is substituted by hydroxy or optionally substituted aryl; and

when R"'2represents alkyl containing from 1 to 4 carbon atoms,

R'101represents a hydrogen atom, alkyl containing from 1 to 4 carbon atoms, which is substituted by hydroxy or optionally substituted aryl;

its prodrug, pharmaceutically acceptable salt, hydrate or MES.

(26) the Compound according to item (25), where R"'2represents alkyl containing from 1 to 4 carbon atoms; its prodrug, pharmaceutically acceptable salt, hydrate or MES.

(27) the Compound according to item (25) or (26), where R"'2is methyl; its prodrug, headlights which e is selected from the group including:

1) ()-3-benzoyl-3-methyl-1-Cyclopentanone,

2) ()-dihydro-4-(4'-vinylbenzyl)-2(3H)-furanone,

3) ()-dihydro-4-methyl-4-(4'-vinylbenzyl)-2(3H)-furanone,

4) ()-dihydro-4-(4'-hydroxymethylbenzene)-2(3H)-furanone,

5) ()-dihydro-5-(4'-vinylbenzyl)-2(3H)-furanone,

6) ()-dihydro-5-(4'-hydroxymethylbenzene)-2(3H)-furanone,

7) ()-dihydro-5-(4'-hydroxymethylbenzene)-5-methyl-2(3H)-furanone,

8) (-)-dihydro-5-methyl-5-(4'-vinylbenzyl)-2(3H)-furanone,

9) (+)-dihydro-5-methyl-5-(4'-vinylbenzyl)-2(3H)-furanone,

10) (S)-(-)-5-(4'-vinylbenzyl)-2-pyrrolidinone and

11) ()-4-(4'-hydroxymethylbenzene)-2-pyrrolidinone;

its prodrug, pharmaceutically acceptable salt, hydrate or MES.

(29) a Pharmaceutical agent containing the compound according to any one of the preceding paragraphs(12)-(16), (19)-(23) and (25)-(27), its prodrug, pharmaceutically acceptable salt, hydrate or MES.

(30) a Pharmaceutical composition comprising a compound according to any one of the above items(12)-(16), (19)-(23) and (25)-(27), its prodrug, pharmaceutically acceptable salt, hydrate or MES.

(31) a Pharmaceutical agent containing the compound according to any one of the above items(17), (18), (24) and (28), its prodrug, Pharma is out on any of the items (17), (18), (24) and (28), its prodrug, pharmaceutically acceptable salt, hydrate or MES.

(33) for the treatment of diabetes containing the compound according to any one of the above items(17), (18), (24) and (28), its prodrug, pharmaceutically acceptable salt, hydrate or MES.

Brief description of drawings

Fig. 1 is a graph showing the change in blood sugar (y-axis) depending on time (x-axis) by oral administration of the compounds of the present invention (example 93) and carboxymethyl cellulose (control) after administration of glucose.

Fig. 2 is a graph showing the change of sugar (y-axis) against time (x-axis) by oral administration of the compounds of the present invention (example 65) in different quantities or carboxymethyl cellulose (control) after administration of glucose.

Fig. 3 is a graph showing the change in blood sugar (y-axis) against time (x-axis) with a dose of tolbutamide or carboxymethyl cellulose (control) after administration of glucose.

Fig. 4 is a graph showing the change of sugar after a long abstinence from food (y-axis) against time (x-axis) by oral administration of the compounds present is 2">

Detailed description of the invention

In the present invention, the alkyl containing from 1 to 5 carbon atoms in the optionally substituted alkyl containing from 1 to 5 carbon atoms, is linear or branched alkyl containing from 1 to 5 carbon atoms, examples of which can serve as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 3-pentyl, tert-pentyl, etc., the Preferred alkyl containing from 1 to 5 carbon atoms, R1is, for example, isopropyl, tert-butyl, 3-pentyl, and the preferred alkyl containing from 1 to 5 carbon atoms, R2, R3, R4, R5, R8and R9is, for example, methyl and ethyl. Examples of the substituent may be aryl, such as phenyl, naphthyl, biphenyl, terphenyl, etc.,; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.; hydroxy; alkoxy, such as methoxy, ethoxy, propoxy, butoxy etc.; acyl such as formyl, acetyl, propionyl, butyryl, valeryl etc.; carboxy; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl etc.; alkenyl, such as ethynyl, propenyl, butenyl, pentenyl etc.; heterotic oxazolyl, morpholino, piperazinil, piperidinyl, pyranyl, pyridyl, tiopronin, benzothiazyl, benzofuran etc.; amino; alkylamino, such as methylamino, ethylamino, propylamino, butylamino etc.; dialkylamino, such as dimethylamino, diethylamino, dipropylamino, dibutylamino etc.; acylamino, such as formylamino, acetylamino, propionamido, bucillamine, Valeriano etc.; halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, etc;, etc., These substituents can be substituted by other substituents, in addition to these previously. Preferred substituents of alkyl containing from 1 to 5 carbon atoms in R1include aryl, cycloalkyl, hydroxy, alkoxy, amino, and halogen atom; and especially preferred aryl and cycloalkyl. Preferred substituents of alkyl containing from 1 to 5 carbon atoms, R2, R4, R5, R8and R9include acyl, hydroxy, alkoxy and carboxy, and particular preference is given to carboxy. Preferred substituents of alkyl containing from 1 to 5 carbon atoms, R3include aryl, cycloalkyl and alkoxy.

Alkyl containing from 1 to 5 carbon atoms, in the present invention represents a linear or branched alkyl, Butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 3-pentyl, tert-pentyl etc.

Alkyl containing from 1 to 4 carbon atoms, is a linear or branched alkyl containing from 1 to 4 carbon atoms, examples of which can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc., Alkyl containing from 1 to 4 carbon atoms, R1preferably represents methyl and ethyl and particularly preferably methyl. The preferred alkyl containing from 1 to 4 carbon atoms, R3is the methyl and ethyl, especially methyl. The alkyl containing from 1 to 4 carbon atoms in R'4preferably is methyl and ethyl, especially preferred methyl. The alkyl containing from 1 to 4 carbon atoms in R'5preferably is methyl and ethyl, especially preferred methyl. The alkyl containing from 1 to 4 carbon atoms in R101preferably is methyl and ethyl, especially preferred methyl. The alkyl containing from 1 to 4 carbon atoms in R'3preferably is methyl and ethyl, especially preferred methyl. The alkyl containing from 1 to 4 carbon atoms in R'101preferably is methyl and ethyl, especially predatel, especially preferred methyl.

Alkenyl containing from 2 to 6 carbon atoms, optionally substituted by alkenyl containing from 2 to 6 carbon atoms, is linear or branched alkenyl containing from 2 to 6 carbon atoms, examples of which can be ethynyl, propenyl, butenyl, pentenyl, hexenyl, etc. Alkenyl containing from 2 to 6 carbon atoms, R1, R2, R4or R5preferably are ethynyl or propenyl. Deputy represented by aryl, such as phenyl, naphthyl, biphenyl, terphenyl, etc.,; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. ; hydroxy; alkoxy, such as methoxy, ethoxy, propoxy, butoxy etc.; acyl such as formyl, acetyl, propionyl, butyryl, valeryl etc.; carboxy; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl etc.; a heterocyclic group such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, morpholino, piperazinil, piperidinyl, pyranyl, pyridyl, tiopronin, benzothiazyl, benzofuran etc.; amino; alkylamino, such as methylamino, ethylamino, propylamino, butylamino IAK, formylamino, acetylamino, propionamido, bucillamine, Valeriano etc. ; a halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, etc; etc. These substituents themselves can be substituted by other substituents, in addition to the above. Deputy alkenyl containing from 2 to 6 carbon atoms, R1preferably is aryl, cycloalkyl and alkoxy, especially preferred aryl and cycloalkyl. Deputy alkenyl containing from 2 to 6 carbon atoms, R2, R4and R5preferably is aryl, cycloalkyl and alkoxy, especially preferred aryl and cycloalkyl.

Alkenyl containing from 2 to 6 carbon atoms, in the present invention is a linear or branched alkenyl containing from 2 to 6 carbon atoms, examples of which can be ethynyl, propenyl, butenyl, pentenyl, hexenyl etc.

Aryl in the optionally substituted aryl represented specifically by phenyl, biphenyl, naphthyl, terphenyl, etc., the Preferred aryl in R1, R2, R3, R4and R5is phenyl, biphenyl and naphthyl, particularly preferred phenyl and biphenyl. Deputy represented by alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,proximity, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyphenyl etc.; alkenyl, such as ethynyl, propenyl, butenyl, pentenyl, hexenyl etc.; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.; hydroxy; alkoxy, such as methoxy, ethoxy, propoxy, butoxy etc.; acyl such as formyl, acetyl, propionyl, butyryl, valeryl etc. ; carboxy; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl and etc.; the heterocyclic group, such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, morpholino, piperazinil, piperidinyl, pyranyl, pyridyl, tiopronin, benzothiazyl, benzofuran etc.; amino; alkylamino, such as methylamino, ethylamino, propylamino, butylamino etc.; dialkylamino, such as dimethylamino, diethylamino, dipropylamino, dibutylamino etc.; acylamino, such as formylamino, acetylamino, propionamido, bucillamine, Valeriano etc.; a halogen atom such as fluorine atom, chlorine atom, the bromine atom, iodine atom, etc; etc. These substituents themselves can be substituted by other substituents, in addition to those listed earlier. Deputy aryl in R1preferably asobenno preferred alkyl, hydroxyalkyl and hydroxy, and the most preferred hydroxymethyl. Deputy of the aryl in R2, R3, R4, R5and R6preferably are alkyl and hydroxyalkyl.

Aryl in the present invention are represented by phenyl, biphenyl, naphthyl, terphenyl, etc., and aryl in R1preferably represents phenyl and biphenyl, particularly preferred phenyl. The aryl in R101preferably, a is phenyl and biphenyl, particularly preferred phenyl. The aryl in R'101preferably are phenyl and biphenyl, particularly preferred phenyl.

Heterocyclic group of the optionally substituted heterocyclic group is an aromatic heterocyclic ring or saturated heterocyclic ring containing, besides carbon atoms, 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, as atoms constituting the ring. Specific examples include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, morpholino, piperazinil, piperidinyl, pyranyl, pyridine, tiopronin, benzothiazyl, benzofuran, etc., Heterocyclic group in R1is, preferably, the l and benzofuran. As substituents, examples of the alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 3-pentyl, tert-pentyl etc.; hydroxyalkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyphenyl etc.; alkenyl, such as ethynyl, propenyl, butenyl, pentenyl, hexenyl etc.; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.; hydroxy; alkoxy, such as methoxy, ethoxy, propoxy, butoxy etc.; acyl such as formyl, acetyl, propionyl, butyryl, valeryl etc.; carboxy; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl etc.; amino; alkylamino, such as methylamino, ethylamino, propylamino, butylamino etc.; dialkylamino, such as dimethylamino, diethylamino, dipropylamino, dibutylamino etc.; acylamino, such as formylamino, acetylamino, propionamido, bucillamine, Valeriano etc.; halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, etc;, etc., These substituents can be in turn substituted by other substituents, in addition to the above.

Preferred substituents Goethe is laksi, acyl, amino, acylamino and halogen atom, particularly preferred alkyl, hydroxyalkyl and hydroxy.

Cycloalkyl containing from 3 to 7 carbon atoms, optionally substituted cycloalkyl containing from 3 to 7 carbon atoms, in particular, is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl and cycloalkyl containing from 3 to 7 carbon atoms, R1and R3preferably is cyclopentyl and cyclohexyl. Examples of substituents are alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 3-pentyl, tert-pentyl etc.; hydroxyalkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyphenyl etc.; alkenyl, such as ethynyl, propenyl, butenyl, pentenyl, hexenyl etc.; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.; hydroxy; alkoxy, such as methoxy, ethoxy, propoxy, butoxy etc.; acyl such as formyl, acetyl, propionyl, butyryl, valeryl and so forth; aryl such as phenyl, naphthyl, biphenyl, terphenyl, etc.,; a heterocyclic group such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxyl, etc.,; carboxy; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl etc.; amino; alkylamino, such as methylamino, ethylamino, propylamino, butylamino etc.; dialkylamino, such as dimethylamino, diethylamino, dipropylamino, dibutylamino etc.; acylamino, such as formylamino, acetylamino, propionamido, bucillamine, Valeriano etc.; halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, etc;, etc., These substituents can be substituted by other substituents, in addition to the above. Deputy cycloalkyl containing from 3 to 7 carbon atoms in R1preferably is alkyl, hydroxyalkyl and aryl, particularly preferred alkyl and aryl, and the most preferred alkyl. Deputy cycloalkyl containing from 3 to 7 carbon atoms in R3preferably is alkyl, and aryl, particularly preferred alkyl.

An example of cycloalkyl containing from 3 to 7 carbon atoms, the present invention is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Cycloalkyl containing from 3 to 7 carbon atoms, R1, R3and R1are, preferably, cyclopentyl or tsiklogeksane substituted cycloalkenyl, containing from 5 to 7 carbon atoms, specifically, is cyclopentyl, cyclohexenyl, cycloheptyl, and examples of substituents are alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 3-pentyl, tert-pentyl etc.; hydroxyalkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyphenyl etc.; alkenyl, such as ethynyl, propenyl, butenyl, pentenyl, hexenyl etc.; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.; hydroxy; alkoxy, such as methoxy, ethoxy, propoxy, butoxy etc.; acyl such as formyl, acetyl, propionyl, butyryl, valeryl and so forth; aryl such as phenyl, naphthyl, biphenyl, terphenyl, etc.,; a heterocyclic group such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, morpholino, piperazinil, piperidinyl, pyranyl, pyridyl, tiopronin, sensational, benzofuran etc.; carboxy; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl etc.; amino; alkylamino, such as methylamino, ethylamino, propylamino, butylamino etc.; dialkylamino, such as dimethylamino, diethylamino, Valeriano etc.; halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, etc;, etc., These substituents can be substituted by other substituents, in addition to the above. Deputy cycloalkenyl containing from 5 to 7 carbon atoms, R1preferably is alkyl, hydroxyalkyl, aryl and halogen atom, particularly preferred alkyl and aryl.

Alkoxy containing from 1 to 4 carbon atoms, optionally substituted alkoxy containing from 1 to 4 carbon atoms, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, and preferred alkoxy containing from 1 to 4 carbon atoms, R3, R8and R9is methoxy or ethoxy, especially preferred methoxy. Examples of the substituents are cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.; hydroxy; alkoxy, such as methoxy, ethoxy, propoxy, butoxy etc.; acyl such as formyl, acetyl, propionyl, butyryl, valeryl and so forth; aryl such as phenyl, naphthyl, biphenyl, terphenyl, etc.,; a heterocyclic group such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, sokaki; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl etc.; amino; alkylamino, such as methylamino, ethylamino, propylamino, butylamino etc.; dialkylamino, such as dimethylamino, diethylamino, dipropylamino, dibutylamino etc.; acylamino, such as formylamino, acetylamino, propionamido, bucillamine, Valeriano etc.; halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, etc;, etc., These substituents can be substituted by other substituents, in addition to the above.

Vice alkoxy containing from 1 to 4 carbon atoms, R3is, preferably, cycloalkyl or aryl, and Vice alkoxy containing from 1 to 4 carbon atoms, R8and R9is, preferably, hydroxy, alkoxy or amino.

As alkoxy containing from 1 to 4 carbon atoms, the present invention can be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc., Alkoxy containing from 1 to 4 carbon atoms, R1is preferably methoxy or ethoxy, especially preferred methoxy. Alkoxy containing from 1 to 4 carbon atoms and, containing from 1 to 4 carbon atoms, R101preferably represents methoxy, ethoxy, especially preferred methoxy.

Examples of alkoxycarbonyl containing from 2 to 5 carbon atoms, optionally substituted alkoxycarbonyl containing from 2 to 5 carbon atoms, are methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl and tert-butoxycarbonyl and alkoxycarbonyl containing from 2 to 5 carbon atoms, R2, R4, R5, R8and R9is preferably methoxycarbonyl or etoxycarbonyl, most preferably methoxycarbonyl. Example of the substituent is cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. ; hydroxy; alkoxy, such as methoxy, ethoxy, propoxy, butoxy etc.; acyl such as formyl, acetyl, propionyl, butyryl, valeryl and so forth; aryl such as phenyl, naphthyl, biphenyl, terphenyl, etc.,; a heterocyclic group such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, morpholino, piperazinil, piperidinyl, pyranyl, pyridyl, tiopronin, benzothiazyl, Bentiu rbony etc.; amino; alkylamino, such as methylamino, ethylamino, propylamino, butylamino etc.; dialkylamino, such as dimethylamino, diethylamino, dipropylamino, dibutylamino etc.; acylamino, such as formylamino, acetylamino, propionamido, bucillamine, Valeriano etc.; halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, etc;, etc., These substituents can be substituted by other substituents in addition to those mentioned above. Deputy amoxicilline containing from 2 to 5 carbon atoms, R2, R4, R5, R8and R9preferably is hydroxy, alkoxy, halogen atom, acyl, aryl or amino.

Alkoxycarbonyl containing from 2 to 5 carbon atoms, the present invention is represented, for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, etc. and alkoxycarbonyl containing from 2 to 5 carbon atoms, R4preferably, represents methoxycarbonyl and etoxycarbonyl, particularly preferred methoxycarbonyl. Alkoxycarbonyl containing from 2 to 5 carbon atoms in R ' 1preferably, not only is from 2 to 5 carbon atoms, the R"'4preferably, represents methoxycarbonyl and etoxycarbonyl, particularly preferred methoxycarbonyl. Alkoxycarbonyl containing from 2 to 5 carbon atoms, R"'5preferably, represents methoxycarbonyl and etoxycarbonyl, particularly preferred methoxycarbonyl. Alkoxycarbonyl containing from 2 to 5 carbon atoms, R101preferably, represents methoxycarbonyl and etoxycarbonyl, particularly preferred methoxycarbonyl.

Acyloxy containing from 2 to 5 carbon atoms, optionally substituted, acyloxy containing from 2 to 5 carbon atoms, represented, for example, acetoxy, propionyloxy, butyryloxy and acyloxy containing from 2 to 5 carbon atoms, R8and R9preferably, represents the atomic charges and propionyloxy. Examples of the substituents are cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.; hydroxy; alkoxy, such as methoxy, ethoxy, propoxy, butoxy etc.; acyl such as formyl, acetyl, propionyl, butyryl, valeryl and so forth; aryl such as phenyl, naphthyl, biphenyl, terphenyl, etc.,; a heterocyclic group such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, sociosanitary etc.; carboxy; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl etc.; amino; alkylamino, such as methylamino, ethylamino, propylamino, butylamino etc.; dialkylamino, such as dimethylamino, diethylamino, dipropylamino, dibutylamino etc.; acylamino, such as formylamino, acetylamino, propionamido, bucillamine, Valeriano etc.; halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, etc.,, etc., These substituents may be further substituted by other substituents than those listed above. The Deputy acyloxy containing from 2 to 5 carbon atoms, R8and R9preferably represents hydroxy, aryl or amino.

Examples of the optional substituents of the substituted adamantyl include alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 3-pentyl, tert-pentyl etc.; hydroxyalkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyphenyl etc.; alkenyl, such as ethynyl, propenyl, butenyl, pentenyl, hexenyl etc.; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.; alcool etc.; aryl, such as phenyl, naphthyl, biphenyl, terphenyl, etc.,; a heterocyclic group such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, morpholino, piperazinil, piperidinyl, pyranyl, pyridyl, tiopronin, benzothiazyl, benzofuran etc.; carboxy; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl etc.; amino; alkylamino, such as methylamino, ethylamino, propylamino, butylamino etc.; dialkylamino, such as dimethylamino, diethylamino, dipropylamino, dibutylamino etc.; acylamino, such as formylamino, acetylamino, propionamido, bucillamine, Valeriano etc.; halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, etc; etc. These substituents themselves can be substituted by substituents other than those listed above. Deputy adamantyl at R1is, preferably, alkyl, hydroxyalkyl and halogen atom, most preferably alkyl.

Examples of the substituents optionally substituted indanyl include alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 3-pentyl, tert-pentyl etc.; hydroxyalkyl as ethynyl, propenyl, butenyl, pentenyl, hexenyl etc.; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and etc.; alkoxy, such as methoxy, ethoxy, propoxy, butoxy etc.; acyl such as formyl, acetyl, propionyl, butyryl, valeryl and so forth; aryl such as phenyl, naphthyl, biphenyl, terphenyl, etc.,; a heterocyclic group such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, morpholino, piperazinil, piperidinyl, pyranyl, pyridyl, tiopronin, benzothiazyl, benzofuran etc.; carboxy; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl etc.; amino; alkylamino, such as methylamino, ethylamino, propylamino, butylamino etc.; dialkylamino, such as dimethylamino, diethylamino, dipropylamino, dibutylamino etc.; acylamino, such as formylamino, acetylamino, propionamido, bucillamine, Valeriano etc.; halogen atom such as fluorine atom, chlorine atom, bromine atom, the iodine atom, etc; etc. These substituents themselves can be substituted further by Deputy, other than those specified above. Deputy indanyl at R1preferably is alkyl, hydroxyalkyl or halogen atom, especially PR is the aka as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 3-pentyl, tert-pentyl etc.; hydroxyalkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyphenyl etc.; alkenyl, such as ethynyl, propenyl, butenyl, pentenyl, hexenyl etc.; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.; hydroxy; alkoxy, such as methoxy, ethoxy, propoxy, butoxy etc.; acyl such as formyl, acetyl, propionyl, butyryl, valeryl and so forth; aryl such as phenyl, naphthyl, biphenyl, terphenyl, etc.,; a heterocyclic group such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, morpholino, piperazinil, piperidinyl, pyranyl, pyridyl, tiopronin, benzothiazyl, benzofuran etc.; carboxy; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl etc.; amino; alkylamino, such as methylamino, ethylamino, propylamino, butylamino etc.; dialkylamino, such as dimethylamino, diethylamino, dipropylamino, dibutylamino etc.; acylamino, such as formylamino, acetylamino, propionamido, bucillamine, Valeriano etc.; halogen atom, tako the us Deputy other than those listed above. Deputy fluorenyl at R1preferably is alkyl, hydroxyalkyl or halogen atom, particularly preferred alkyl.

Acyl containing 2 to 5 carbon atoms, optionally substituted acyl containing 2 to 5 carbon atoms, represented for example, acetyl, propionyl, Boutillon, Valerian etc., and acyl containing 2 to 5 carbon atoms, R2, R4and R5that is, preferably, acetyl or propionyl, and especially preferred acetyl. Examples of the substituents include cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl etc.; hydroxy; alkoxy, such as methoxy, ethoxy, propoxy, butoxy etc.; acyl such as formyl, acetyl, propionyl, butyryl, valeryl and so forth ; aryl such as phenyl, naphthyl, biphenyl, terphenyl, etc.,; a heterocyclic group such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, morpholino, piperazinil, piperidinyl, pyranyl, pyridyl, tiopronin, benzothiazyl, benzofuran etc.; carboxy; alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl etc.; amino; alkylamino, this is dipropylamino, dibutylamino etc.; acylamino, such as formylamino, acetylamino, propionamido, bucillamine, Valeriano etc. ; halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, etc; etc. These substituents themselves can be substituted further by Deputy, other than those listed above. Deputy acyl containing 2 to 5 carbon atoms, R2, R4and R5preferably is hydroxy, alkoxy or halogen atom, particularly preferred alkoxy.

Acyl containing 2 to 5 carbon atoms, the present invention presents such as acetyl, propionyl, Boutillon, Valerian etc., and acyl containing 2 to 5 carbon atoms, R6preferably an acetyl or propionyl, especially preferred acetyl. The acyl containing 2 to 5 carbon atoms, R4preferred is acetyl and propionyl, especially preferred acetyl. The acyl containing 2 to 5 carbon atoms in R ' 1preferably is acetyl or propionyl, especially preferred acetyl. The acyl containing 2 to 5 carbon atoms, R"'4preferred is acetyl or propionyl, especially preferred acetyl. The acyl containing from 2 on the Il. The acyl containing 2 to 5 carbon atoms, R101preferred is acetyl or propionyl, especially preferred acetyl.

Acyl containing from 1 to 5 carbon atoms, the present invention is represented, for example, formyl, acetyl, propionyl, Boutillon, Valerian etc. Deputy of aryl, preferably is formyl or acetyl.

Aminosidine group is a group that is usually used in organic synthesis, such as benzyl, 3,4-dimethoxybenzyl, 1-phenylethyl, biphenylyl, bis(4-methoxyphenyl)methyl, 2-nitrobenzyl, triphenylmethyl, pencil, acetyl, TRIFLUOROACETYL, benzyloxycarbonyl, tert-butoxycarbonyl etc.

A prodrug is a derivative obtained by chemical modification of the drug molecule itself has no physiological activity. After the introduction, it is rebuilt in a molecule of the original drug in the body and has a pharmaceutical effect.

The active metabolite is a substance that enhances or induces action by metabolised medicine enzyme.

Pharmaceutically acceptable salts include, but are not limited to) such different with the salt and magnesium salt of calcium; aluminium salt, ammonium salt, etc., the Compound of the present invention may contain an asymmetric carbon atom, and in this case, there are optically pure enantiomers, their racemates and mixtures in various optional combinations and relations. The present invention encompasses therapeutic drugs for diabetes, including any of these isomers. In the case of the racemate, in addition, the optical separation

allows to obtain, if necessary, any of optically active compounds. In the asymmetric synthesis can be obtained directly one optically active compound. In addition, the compound of the present invention may be in the form of a hydrate or of MES, as required.

Pharmaceutically preparation containing the compound of the present invention, can be prepared in the form of a mixture of this compound with pharmaceutically acceptable carriers, excipients, diluents, agents that increase the volume, leavening agents, stabilizers, preservatives, buffers, emulsifiers, flavorings, tinted agents, sweeteners, thickeners, flavouring agents, solubilization and other deliveries, known specialist, the polyethylene glycol, glyceryltrinitrate, gelatin, carbohydrates such as lactose and starch, magnesium stearate, talc, lanolin, petrolatum, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, gum, dextrin, hypromellose, polyvinylpyrrolidone, macrogol, resin Carnauba, polyoxyethylene, polyoxypropylene, glycol, cocoa butter, lauriola acid, lecithin, glycerin, parahydroxybenzoate sodium, sodium benzoate, salicylic acid, potassium sorbate, etc. for the preparation of tablets, pills, powders, granules, suppositories, injectable solutions, liquids, capsules, tablets, etc. that can be administered orally or parenterally. Although the dose varies depending on the stage of the disease, the connection that you want to type, method of administration, age, sex and weight of the patient, etc., usually adults impose 0,001-1,000 mg, particularly, 0.1 to 100 mg of the compounds of the present invention in the day.

The present invention is described in more detail with reference to the method of obtaining dicarbonyl compounds, which method of obtaining compounds of the present invention is not limited to.

Below is a synthesis methods, for example where the present invention is explained more in the manual receive 1, where R1, R2, R3, R4and R5used in a General sense of the characters as they are used in the compounds of the present invention. The same symbols will typically show the same values for all formulas, although there may be cases when the value represented by each symbol is different depending on the respective reactions for the corresponding characters.

A common way of obtaining 1 will be further disclosed in more detail in accordance with each stage.

Stage 1

Connection 1 is subjected to interaction with alcohol, such as methanol, ethanol, propanol, butanol, ethylene glycol, triethyleneglycol, etc. in a solvent such as benzene, toluene, xylene, methylene chloride, chloroform, 1,2-dichloroethane, etc., or mixtures of these solvents or without solvent, in the presence of inorganic acids, such as chlorobutadiene acid, sulfuric acid, Hydrobromic acid, or organic acids such as p-toluensulfonate acid, benzolsulfonat acid, methanesulfonate acid, triftormetilfullerenov acid, etc., when heated, preferably, when heated at the boiling point under reflux with getting soedineniya esters (for example, ethyl ether, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, etc. or mixtures of these solvents. Then to the mixture was added the aldehyde, such as acetaldehyde, Propionaldehyde, benzaldehyde, etc., and the resulting mixture is allowed to interact with the temperature of the corresponding heating or cooling. This reaction often leads to better results when using magnesium lower alkylhalogenide, such as methyliodide, ethyliodide, 1,2-dibromoethane, 1,2-diodato, etc. , or iodine. The resulting product is subjected to interaction with an inorganic acid, such as chloromethane acid, sulfuric acid, Hydrobromic acid, etc. or organic acid, such as triperoxonane acid, formic acid, acetic acid, triftormetilfullerenov acid, p-toluensulfonate acid, methanesulfonate acid, benzolsulfonat acid, etc., in water or in a mixture of solvents, such as tetrahydrofuran, 1,4-dioxane, ethanol or chloroform or methylene chloride and water at a temperature corresponding to the heating or cooling, preferably at a temperature from room temperature up to high, to obtain compound 3.

In an alternative method, the stage 2 with the measures 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, N,N-dimethylformamide, acetonitrile, etc., or mixtures of these solvents in the presence of fosfinpalladievogo catalyst, such as tetrakis(tri-phenylphosphine)palladium(0), TRANS-benzyl(chloro)bis(triphenylphosphine)palladium(II), etc. at a temperature corresponding to from low to high, preferably, from room temperature up to high; the resulting product is subjected to interaction with substituted boron such as DIBORANE, a complex of borane-dimethyl sulphide, complex, borane-tetrahydrofuran, 9-borabicyclo[3,3,1]nonan, 2,3-dimethyl-2-butylborane, bis(1,2-dimethylpropyl)borane, bananowy complex, etc. in a solvent such as various esters (e.g. ethyl ether, diglyme, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, etc. or mixtures of such solvents and in aqueous solutions of bases such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, etc. to the reaction mixture was added aqueous hydrogen peroxide and the resulting product is subjected to interaction with the acid such as an inorganic acid, for example, chloromethane acid, sulfuric acid, Hydrobromic acid, etc. or organic collaterial, consisting of tetrahydrofuran, 1,4-dioxane, ethanol, chloroform or methylene chloride and water, at a temperature from low to high, preferably from room temperature to high, to obtain compound 3. When using stage 2, R1in connection 3 represents phenyl, substituted with hydroxymethyl.

Stage 3

Compound 4 is subjected to interaction with the lower alkylhalogenide, such as methylchloroform, methylbromide, ethylchloride, ethylbromide, propylchloride, propylbromide, isopropylcarbamate, isopropylammonium etc., or galogenangidridy, such as Teilhard, pivaloyloxy, etc. in a solvent such as various esters (e.g. ethyl ether, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, methylene chloride, chloroform, etc. or mixtures of these solvents in the presence of organic bases such as triethylamine, pyridine, N-methylmorpholine, etc. and the reaction mixture was added a solution of lithium borohydride, sodium borohydride, potassium borohydride, etc., in water, methanol, ethanol, isopropanol, etc., at a temperature from low to high, preferably from low to room. Received prochlorite, and the reaction mixture is added an organic base, such as triethylamine, N-methylmorpholin, etc. in the presence of a complex of sulfuric anhydride-pyridine or oxalicacid, etc. at a temperature from low to high, preferably, from low to room temperature to obtain compound 3.

Stage 4

Compound 5 is subjected to interaction with lithium borohydride, sodium borohydride, potassium borohydride, etc. in a solvent such as water, various alcohols (e.g. methanol, ethanol, isopropanol, etc.,), etc., or mixtures of these solvents at temperatures from low to high, preferably at a temperature from low to room. Then the obtained product is subjected to interaction with an inorganic acid, such as chloromethane acid, sulfuric acid, Hydrobromic acid, etc. or organic acid, such as p-toluensulfonate acid, benzolsulfonat acid, triperoxonane acid, formic acid, acetic acid, etc. in water or in a mixed solvent consisting of tetrahydrofuran, 1,4-dioxane, methanol, ethanol, chloroform, methylene chloride, etc., and water, to obtain compound 3. When using stage 4, R1

Stage 6

Compound 7 is subjected to interaction with the lower alcohol, such as methanol, ethanol, propanol, etc. in a solvent such as benzene, toluene, etc. or mixtures of these solvents, or without solvent, in the presence of inorganic acids, such as chloromethane acid, sulfuric acid, Hydrobromic acid, etc. or organic acids such as p-toluensulfonate acid, benzolsulfonat acid, methanesulfonate acid, triftormetilfullerenov acid, etc. at a temperature from low to high, preferably at the boiling point under reflux; and the resulting product is subjected to interaction in the presence of alkali metal halide, such as litigare, nutrigold, kalihari, etc. in one dimethylsulfoxide or water N,N-dimethylformamide at a temperature of from Pont subjected to interaction with dialkylammonium, such as diisobutylaluminium etc., laetrilelamygdalin, such as laetrilelamygdalin, etc. or laetrilelamygdalin and such as letitre-tert-butoxyaniline, in a solvent such as various esters (e.g. ethyl ether, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, etc. or mixtures of these solvents at temperatures from low to high, preferably by cooling, to obtain compound 3. When using stage 6, R1the connection 3 is inmanila.

Stage 7

The connection 3 is subjected to interaction with methyl vinyl ketone are, ethylvinylacetate, propylenimine, phenylpiracetam, biphenylmethanol, etc. in a solvent such as various alcohols (e.g. methanol, ethanol, etc.,), N, N-dimethylformamide, 1,4-dioxane, etc. or mixtures of these solvents in the presence of salts Quaternary thiazole, such as 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolidone, 3-ethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolidine, 5-(2-hydroxyethyl)-3,4-dimethylthiazolidine, etc. and organic bases such as triethylamine, N-methylmorpholine, pyridine, etc. or cyanide such as sodium cyanide, cyanide Kali the compounds [I]-1.

Stage 8

When R12is methoxymethyl or tert-butyldimethylsilyl: compound 8 is subjected to interaction with hydroxyamine agent such as chloromethylation ether, tert-butyldimethylsilyloxy, etc. in a solvent such as various esters (e.g. ethyl ether, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, N,N-dimethylformamide, dimethylsulfoxide, acetone, acetonitrile, etc., or mixtures of these solvents in the presence of a base such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, triethylamine, N-methylmorpholine, pyridine, imidazole, tert-butyl chloride, 2-methoxyethoxymethyl, potassium carbonate, etc., at a temperature from low to high, preferably from room temperature to high to obtain compound (9). When R12represents tert-butyl: compound 8 is subjected to interaction with Isobutanol in a solvent such as various esters (e.g. ethyl ether, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, etc. or mixtures of these solvents in the presence of inorganic acids, such as chloromethane acid, sulfuric acid, Hydrobromic acid, etc., the I acid, triftormetilfullerenov acid and so on, to obtain the compound (9).

Stage 9

Magnesium is subjected to interaction with 2-(bromacil)-2-methyl-1,3-dioxolane, and often this reaction leads to better results when using magnesium iodine or 1,2-dibromethane, in a solvent such as various esters (e.g. ethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, etc. or mixtures of these solvents, and then the connection 9 is added to the reaction mixture at a temperature from low to high, preferably, when cooled to obtain compound 10.

Stage 10

Compound 10 was added to dimethyl sulfoxide or a mixed solvent of dimethyl sulfoxide and methylene chloride, in the presence of a complex of sulfuric anhydride-pyridine or oxalicacid, etc., and then subjected to interaction with an organic base, such as triethylamine, N-methylmorpholine, etc. at a temperature from low to high, preferably from room temperature to high to obtain compound (11).

Stage 11

The connection 11 is subjected to interaction with an inorganic acid, such as chloromethane acids is islote, benzolsulfonat acid, formic acid, acetic acid, triperoxonane acid, methanesulfonate acid, triftormetilfullerenov acid, etc. in a solvent such as water or various esters (for example, 1,4-dioxane, tetrahydrofuran, etc.,), methylene chloride, chloroform, various alcohols (e.g. methanol, ethanol, propanol, isopropanol, etc.,), etc., or mixtures of these solvents with water at a temperature from low to high, preferably from room temperature to elevated getting connection [1]-1.

When using the stage 11, R1in compound [1]-1 represents phenyl, substituted hydroxy.

Stage 12

Compound 12 was dissolved in a solvent such as various esters (e.g. ethyl ether, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, methylene chloride, chloroform, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, etc. or in a mixed solvent. The connection 12 is subjected to interaction with the copper halide such as copper chloride, copper bromide, copper iodide, etc., copper acetate, silver oxide, etc. in the presence of a base, such as sitedisability, nutregisterdevice etc. when tempera obtaining compounds [I]-1, where R1and R3represent the same group.

Stage 13

Compound 4 is subjected to interaction with the lower alkyllithium, such as motility, utility, etc. in a solvent such as various esters (e.g. ethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, methylene chloride, chloroform, etc. or mixtures of these solvents, at a temperature from low to high, preferably fromoC to room temperature to obtain compound 13, where2is lower alkyl.

Stage 14

The connection 13 is subjected to interaction with halogen, such as chlorine or bromine, or perbromide 4-(dimethylamino)pyridinylamino in a solvent such as various esters (e.g. ethyl ether, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, methylene chloride, carbon tetrachloride, acetic acid, chloroform, various alcohols (e.g. methanol, ethanol, etc.,), etc., or mixtures of these solvents at temperatures from low to high, preferably fromoC to room temperature to obtain compound 14, where2is lower alkyl. This reaction is often dadia 15

Compound 4 is subjected to interaction with oxalylamino, oxalylamino, thionyl chloride, etc. in a solvent such as benzene, toluene, n-hexane, cyclohexane, methylene chloride, chloroform, etc. or mixtures of these solvents or without solvent at a temperature from low to high, preferably from 0oC to high, with a connection 15. This reaction often gives the best results when added dimethylformamide and the like.

Stage 16

The connection 15 is subjected to interaction with the lower diazoalkane, such as diazomethane, diazoethane, etc. in a solvent such as various esters (e.g. ethyl ether, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, chloroform, dichloromethane, etc., or mixtures of these solvents at temperatures from low to high, preferably from 0oC to room temperature. The resulting product is subjected to interaction with water chloroethanol acid, aqueous Hydrobromic acid or hydrogen bromide in acetic acid solution to obtain compound 14, where R2represents a lower alkyl group.

Stage 17

The connection 14 is subjected to interaction with the.p.), benzene, toluene, n-hexane, cyclohexane, N,N-dimethylformamide, dimethylsulfoxide, etc., or mixtures of these solvents in the presence of a base, such as lithium hydride, potassium hydride, sodium hydride, sodium methoxide, ethoxide sodium, sitedisability, sodium carbonate, potassium carbonate, etc., at a temperature from decreasing to increasing, preferably from 0oC to room temperature, to obtain the compound [I]-2.

Stage 18

When R14represents lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, etc.

Connection [I]-2 subjected to removal of protective groups in water or in a mixed solvent consisting of water and various alcohols (e.g. methanol, ethanol, propanol, isopropanol, etc., or various ethers (for example, 1,4-dioxane, tetrahydrofuran, etc.,) and water, in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, etc., at a temperature from low to high, preferably fromoC to room temperature, to obtain the compound [I]-1.

When R14represents tert-butyl:

Connections [I]-2 subjected to removal of protective groups in RAS is Stroiteley, or without solvent, in the presence or absence of an acid catalyst such as formic acid, acetic acid, triperoxonane acid, p-toluensulfonate acid, etc. at a temperature from low to high, preferably from room temperature to high, to obtain the compound [I] is[1]. The alternate connection [I] -2 subjected to removal of the protective group in a solvent such as dimethylsulfoxide, N,N-dimethylformamide, etc., in the presence of lithium chloride, sodium chloride, potassium chloride, etc., and water, at a temperature from low to high, preferably at the boiling point under reflux, to obtain the compound [I]-1.

When R14is benzyl:

Connections [I]-2 subjected to removal of the protective group in a solvent such as various alcohols (e.g. methanol, ethanol, propanol, etc), various esters (for example, 1,4-dioxane, tetrahydrofuran, etc.,), ethyl acetate, etc. or mixtures of these solvents, in the presence of a palladium catalyst such as palladium on charcoal, palladium black, etc., in an atmosphere of hydrogen at a temperature from low to high, preferably from room temperature to high with receipt is SSI alkyl, R3represents lower alkyl, phenyl, benzyl or 2-phenylethyl and 5represents a hydrogen atom.

Stage 19

In the same way as in stage 17, it is possible to obtain the compound [I]-1 from compound 16 and compound 14. When using stage 19, it is possible to obtain the compound [I] -1, where2represents lower alkyl, R3represents lower alkyl, phenyl, benzyl or 2-phenylethyl, and R5represents the lowest alkylsulphonyl or benzylcarbamoyl.

Stage 20

When R1represents a halogen-substituted aryl, the compound [I]-1 is subjected to interaction with vinyltrimethylsilane or isopropylcarbodiimide in a solvent such as various esters (for example, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, N,N-dimethylformamide, acetonitrile, etc., or mixtures of these solvents in the presence of fosfinpalladievogo catalyst, such as tetrakis(triphenylphosphine)palladium (0), TRANS-benzyl(chloro)bis(triphenylphosphine)palladium (II), etc. at a temperature from low to high, preferably, from room temperature to high, to obtain the compounds [1]-3, where R1modified. Alternatively, in a solvent such as various esters (e.g. ethyl ether, tetr which can be obtained from magnesium and halogen-substituted lower alkylaryl, such as (o-, m-, p-)chlorine substituted toluene, o-, m-, p-)Posledny toluene, o-, m-, p-)chlorine substituted ethylbenzene, o-, m-, p-)Posledny ethylbenzene, o-, m-, p-)chloride replaced propylbenzoyl, (o-, m-, p-)Posledny propylbenzoyl etc., or biphenylmethane, such as 4-chlorophenyl, 4-bromobiphenyl, 3-chlorobiphenyl, 3-bromobiphenyl, 2-chlorophenyl, 2-bromobiphenyl, etc., the Compound [I]-1 is subjected to interaction with the above Grignard reagent in the presence of a zinc halide such as zinc chloride, zinc bromide, etc., and fosfinpalladievogo catalyst, such as tetrakis(triphenylphosphine)palladium (0), TRANS-benzyl(chloro)bis(triphenylphosphine)palladium (II), etc., to obtain the compound [I] -3, where R1modified. Modified R1thus obtained at the stage of 20 connections [I] -3 represents aryl, which is substituted by lower alkenyl or aryl.

Stage 21

When R1is aryl, substituted hydroxy (lower alkyl), such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxyisobutyryl, hydroxy-sec-butyl, hydroxy-tert-butyl, etc.:

Connection [I]-1 is added to the solvent, such as dimethyl sulfoxide or a mixed of rest is or oxalicacid etc., and subjected to interaction with an organic base, such as triethylamine, N-methylmorpholine, etc. at a temperature from low to high, preferably, from low to room temperature, to obtain the compound [I]-4, where R1substituted acyl such as formyl, acetyl, propionyl, butyryl, valeryl etc. Alternative, thus obtained compound [I] -4, which is substituted by acyl such as formyl, acetyl, propionyl, butyryl, valeryl, etc. are subjected to interaction with hydrogen peroxide and oxidizing agent such as sodium chloride, potassium chloride, etc. in water or aqueous acetonitrile in the presence of dinitrigenoxide at a temperature from low to high, preferably from low to room temperature, to obtain the compound [I]- 4, where R1modified. Modified R1thus obtained compound [I]- 4 at the stage 21 is aryl, which is substituted by acyl, carboxy, carboxy (lower alkyl), such as carboxymethyl, carboxyethyl, carboxypropyl etc.

Stage 22

Connection [I] -1 is converted into compound 18 in a solvent such as benzene, toluene, n-hexane, cyclohexane, methylene chloride, chloroform, N,N-dimethylformamide, what these solvents or without solvent in the presence of an inorganic acid, such as chloromethane acid, sulfuric acid, phosphoric acid, polyphosphoric acid, Hydrobromic acid, etc. or organic acids such as p-toluensulfonate acid, benzolsulfonat acid, triperoxonane acid, methanesulfonate acid, triftormetilfullerenov acid, oxalic acid, etc. at a temperature from low to high, preferably at from room temperature to high.

Stage 23

The connection 18 is subjected to interaction with an organic peroxide such as m-chlormadinone acid, peracetic acid, etc. in a solvent such as benzene, toluene, n-hexane, cyclohexane, methylene chloride, tetrachlorophenol, chloroform, etc. or mixtures of these solvents, at a temperature from low to high, preferably at a temperature of from 0oC to room temperature, to obtain the compound [I]-5.

Stage 24

The connection 18 is subjected to interaction with halogen, such as chlorine, bromine, iodine, etc., in aqueous solvent, such as various alcohols (e.g. methanol, ethanol, etc.,), acetone, acetonitrile, etc., or mixtures of these solvents at temperatures from low to high, preferably, is a common way to obtain 2, where R1, R2, R3, R4and R5used in the ordinary sense of the characters, which are adopted in the present invention. The same characters typically have the same values in all the formulas, although there may be cases when a range of values of each of the characters will be different depending on the respective reactions.

Next, a General method of obtaining 2 are described in more detail for each stage (see below).

Stage 25

Compound 19 is subjected to interaction with acid anhydride such as succinic anhydride, maleic anhydride, citraconic anhydride acid, pyruvic acid anhydride, etc. in a solvent such as carbon disulfide, methylene chloride, chloroform, carbon tetrachloride, tetrachlorethane, nitrobenzene, etc., or mixtures of these solvents, or without solvent, in the presence of a Lewis acid such as aluminised, zinc chloride, boron TRIFLUORIDE, etc., at a temperature from low to high, with the receipt of some of the compounds [I]-9, where R3represents hydroxy.

Stage 26

The connection 20 is subjected to interaction with a derivative of succinic acid anhydride such as succinic anhydride, maleic anhydride, citraconic inkarbaeva acid, etc., in a solvent such as various esters (e.g. ethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, etc. or mixtures of these solvents at temperatures from low to high with obtaining compounds [l]-9.

Stage 27

The connection 14 is subjected to interaction with the connection 21 in a solvent such as various esters (e.g. ethyl ether, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, N,N-dimethylformamide, dimethylsulfoxide, water, etc. or mixtures of these solvents in the presence of a base, such as lithium hydride, potassium hydride, sodium hydride, sodium methoxide, ethoxide sodium, diisopropylamide lithium, sodium carbonate, potassium carbonate, etc., at a temperature from low to high, preferably from 0oC to room temperature, to obtain the compound [I]-7.

Stage 28

Connection [I]-7 subjected to removal of protective groups in water or in an alcohol solvent such as water and alcohol, such as methanol, ethanol, propanol, isopropanol, etc. or in a mixed solvent consisting of water and ethers, such as 1,4 - dioxane, tetrahydrofuran, etc., in the presence of a base, such as the from low to high, preferably, from 0oC to room temperature, to obtain the compound [I]-8.

Stage 29

Connection [I]-9 can be obtained by heating the compound [I]-8.

Stage 30

If R3in the compound [I] -9 represents hydroxy, the compound [I]-9 converted into the compound [I]-10 in a solvent such as benzene, toluene, xylene, etc. or mixtures of these solvents, or without solvent in the presence of a lower alcohol, such as methanol, ethanol, propanol, etc., and inorganic acids, such as chloromethane acid, sulfuric acid, Hydrobromic acid, etc. or organic acids such as p-toluensulfonate acid, benzolsulfonat acid, methanesulfonate acid, triftormetilfullerenov acid, etc. at a temperature from low to high, preferably at the boiling point under reflux. In the compound [I]-10 R5represents a hydrogen atom and R3represents lower alkyl, such as methoxy, ethoxy, butoxy etc.

Stage 31

When R1in the compound [I]-10 represents a halogen-substituted aryl, the compound [I] -10 subjected to interaction with complex heterocyclization boric acid, such as pyridinethione boric acid, benzoguanamine boric acid, etc. in a solvent such as various esters (e.g. ethyl ether, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, N,N-dimethylformamide, dimethylsulfoxide, water, etc. or mixtures of these solvents in the presence of a base, such as lithium carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, etc. at a temperature from low to high, preferably, at a temperature of from room temperature up to the boiling temperature under reflux, to obtain the compound [I]-11, where R1is heterocyclizations aryl.

Stage 32

If R3in the compound [I]-11 represents lower alkoxy, such as methoxy, ethoxy, butoxy etc., the compound [I]-11 subjected to the same reaction as in stage 28, to obtain the compound [I]-9, where R3represents hydroxy.

Stage 33

When R1in the compound [I]-10 represents phenyl, substituted stands, the compound [I] -10 subjected to interaction with the N-halogenated succinimides, such as N-chlorosuccinimide, N-bromosuccinimide, N-jodatime, etc., by irradiation with light or by adding a radical initiator, Tania under reflux, and then the resulting product is converted into the compound [I]-12 in the presence of carbonate, such as calcium carbonate, magnesium carbonate, barium carbonate, etc., when heated in water or in a mixed solvent consisting of water and an ether, such as tetrahydrofuran, 1,4-dioxane, etc., In the compound [I]-12, R1represents phenyl, substituted with hydroxymethyl.

Stage 34

When R3in the compound [I]-12 represents lower alkoxy, such as methoxy, ethoxy, butoxy etc., the compound [I]-12 subjected to the same reaction as in stage 28, to obtain the compound [I]-9, where R3represents hydroxy.

Stage 35

The connection 22 hydrolyzing in a solvent such as water or a mixed solvent consisting of various alcohols, such as methanol, ethanol, propanol, etc., or various ethers such as 1,4-dioxane, tetrahydrofuran, etc., and water, in the presence of a metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, etc., at a temperature from low to high, preferably from room temperature to high, to obtain the compound [I]-9. When using stage 35, R3connections [I]-9 is hydroc is oricale, such as various esters (e.g. ethyl ether, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, etc. or mixtures of these solvents, the Grignard reagent can be obtained from magnesium and halogen-substituted lower alkylaryl, such as (o-, m-, p-)chlorine substituted toluene, o-, m-, p-)Posledny toluene, o-, m-, p-)chlorine substituted ethylbenzene, o-, m-, p-)Posledny ethylbenzene, o-, m-, p-)chloride replaced propylbenzoyl, (o-, m-, p- )Posledny propylbenzoyl etc., poslednego (lower alkoxy)methoxybenzene, such as Posledny methoxyethoxymethyl, Posledny ethoxyethanol, Posledny propoxyethanol, Posledny tert - butylacetate, Posledny tert-butyldimethylsilyloxy, etc., the Connection 22 is subjected to interaction with the above Grignard reagent in the presence of a zinc halide such as zinc chloride, zinc bromide, etc., and fosfinpalladievogo catalyst, such as tetrakis(triphenylphosphine)palladium (0)TRANS-benzyl(chloro)bis(triphenylphosphine)palladium (II), to obtain compound 23. When using stage 36, R1in connection 23 is a lower alkyl, such as methyl, ethyl, propyl, etc., or aryl(biphenyl), substituted Nissi is Yes, or in a mixed solvent, consisting of various alcohols, such as methanol, ethanol, propanol, etc., or various ethers such as 1,4-dioxane, tetrahydrofuran, etc., and water, in the presence of a metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, etc., at a temperature from low to high, preferably from room temperature to high, to obtain the compound [I]-9. When R1contains phenolic hydroxyl group having a protective group, then the above product is subjected to removal of the protective group in the presence of inorganic acids, such as chloromethane acid, sulfuric acid, Hydrobromic acid, etc. or organic acids such as triperoxonane acid, formic acid, acetic acid, triftormetilfullerenov acid, p-toluensulfonate acid, methanesulfonate acid, benzolsulfonat acid, etc., in water or in a mixed solvent consisting of tetrahydrofuran, 1,4-dioxane, ethanol, chloroform or methylene chloride with water at a temperature from low to high, preferably, from room temperature to high, to obtain the compound [I]-9. When using stage 37, Re 24 in the solvent, such as benzene, toluene, xylene, methylene chloride, chloroform, 1,2-dichloroethane, etc., or mixtures of these solvents, or without solvent, in the presence of alcohol, such as methanol, ethanol, propanol, ethylene glycol, etc., and inorganic acids, such as chloromethane acid, sulfuric acid, Hydrobromic acid, etc. or organic acids such as p-toluensulfonate acid, benzolsulfonat acid, methanesulfonate acid, triftormetilfullerenov acid, etc. at a temperature from low to high, preferably at the boiling point under reflux.

Stage 39

Connection 24 hydrolyzing in a solvent such as water and various alcohols, such as methanol, ethanol, etc. or mixtures of these solvents, in the presence of a metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, etc., and the reaction is carried out at a temperature from low to high, preferably from room temperature to high, and then the resulting product is converted into the compound [I]-9 in the presence of inorganic acids, such as chloromethane acid, sulfuric acid, Hydrobromic acid, etc., ilisat, methansulfonate acid, triftormetilfullerenov acid, etc. at a temperature from low to high, preferably from 0oC to room temperature. If you use stage 39, R3connections [I]-9 represents hydroxy.

Stage 40

The connection 25 is subjected to interaction with acrylnitrile in a solvent such as N, N-dimethylformamide, 1,4-dioxane, various alcohols (e.g. methanol, ethanol, etc.,), etc., or mixtures of these solvents, in the presence of salts Quaternary thiazole, such as 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolidone, 3-ethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolidine, 5-(2-hydroxyethyl)3,4-dimethylthiazolidine, etc. and organic bases such as triethylamine, N-methylmorpholine, etc. or cyanide such as sodium cyanide, potassium cyanide, etc., and at temperatures from low to high, preferably from room temperature to high, to obtain compound 22. When using stage 40, each of R2, R4and R5in connection 22 represents a hydrogen atom.

Stage 41

Connection 7 in turn dicarboxylic acid in a solvent such as various esters, such as ethyl ether, 1,4-dioxane, then it is carbonated is Ogorodnaya acid, sulfuric acid, Hydrobromic acid, etc. or organic acids such as p-toluensulfonate acid, benzolsulfonat acid, methanesulfonate acid, triftormetilfullerenov acid, etc. at a temperature from low to high, preferably at the boiling point under reflux, and then the above-mentioned dicarboxylic acid decarboxylase heating, receiving the connection 4, where R1represents indanyl.

Stage 42

Compound 4 is subjected to interaction with thionyl chloride, oxalicacid, oxalylamino, etc. in a solvent such as benzene, toluene, n-hexane, cyclohexane, methylene chloride, chloroform, etc. or mixtures of these solvents, or without solvent, at a temperature from low to high, preferably from room temperature to high (this reaction is partially leads to preferable results if added dimethylformamide and so on), and then, the thus obtained product is subjected to interaction with the connection 25 in a solvent such as various esters (for example, ethyl ether, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, N, N-dimethylformamide, etc. or mixtures of these rastvoritelei(chloro)bis(triphenylphosphine)palladium(II), etc., at a temperature from low to high, preferably from room temperature to high, to obtain compound 27, where R1represents indanyl.

Stage 43

The connection 27 is subjected to interaction with acetic acid and cyanide, such as lithium cyanide, sodium cyanide, potassium cyanide, etc. in a solvent such as N, N - dimethylformamide, dimethylsulfoxide, water, various alcohols (e.g. methanol, ethanol, etc.,), etc., or mixtures of these solvents at temperatures from low to high, preferably from room temperature to high, to obtain compound 22, where R1represents indanyl.

In the interaction of compound 22 in accordance with the stage 35, it is possible to obtain the compound [I]-9, where R1represents indanyl.

When using stage 43, R3in the compound [I] -9 represents hydroxy.

Stage 44

The connection 15 is subjected to interaction with monobenzylether or mono-tert-butylmalonate in a solvent such as various esters (e.g. ethyl ether, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, N,N-dimethylformamide, etc. or mixtures of these solvents in the presence of base is lithium utility, etc. at a temperature from low to high, preferably at low, and then the obtained product is subjected to interaction with halogenated lower alkyl acetate such as methylchloride, ethylchloride, propylchloride, methylbromide, ethylbromoacetate, propylbromide, etc. in a solvent such as various esters (e.g. ethyl ether, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, M,N-dimethylformamide, etc. or mixtures of these solvents in the presence of a base, such as lithium hydride, sodium hydride, potassium hydride, sodium methoxide, ethoxide sodium, diisopropylamide lithium utility, etc. at a temperature from low to high, preferably at low. When the obtained product contains benzyl group, the compound is subjected to interaction with hydrogen in a solvent such as ethyl acetate, methanol, ethanol, 1,4-dioxane, tetrahydrofuran, etc. or mixtures of these solvents in the presence of a palladium catalyst such as palladium on charcoal, palladium black, etc., in an atmosphere of hydrogen at a temperature from low to high, preferably from room temperature to high, to obtain coedine in the solvent, such as benzene, toluene, etc. or mixtures of these solvents, in the presence or absence of organic acids, such as acetic acid, formic acid, p - toluensulfonate acid, etc. at a temperature from low to high, preferably at a temperature from room temperature up to high.

Stage 45

Connection [I]-13 hydrolyzing in a solvent such as water or a mixed solvent consisting of 1,4-dioxane, or various alcohols, such as methanol, ethanol, etc., and water, in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, etc., at a temperature from low to high, preferably at room temperature, to obtain the compound [I] -14.

Stage 46

The connection 28 is subjected to interaction with acylhalides or carboxylic acid anhydride in a solvent such as ethers (ethyl ether, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, methylene chloride, chloroform, carbon tetrachloride, N, N-dimethylformamide, dimethylsulfoxide, etc., or mixtures of these solvents, or without solvent, in the presence of organic bases, such IBEC's direct increased, to obtain compounds [1]-15.

Stage 47

When R16is substituted silyl, such as trimethylsilyl, tert-butyldimethylsilyl etc.

The connection 25 is subjected to interaction with substituted salinarium containing substituted silyl, such as trimethylsilyl, tert-butyldimethylsilyl, etc. in a solvent such as various esters (e.g. ethyl ether, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, methylene chloride, chloroform, etc., at a temperature of from cooling with ice up high, preferably from cooling with ice to room temperature to obtain compound 29. The reaction often leads to preferable results if you add organic base, such as triethylamine, N-methylmorpholine, pyridine, 2,6-rotein, etc.

When R16represents the lowest alkoxyalkyl, such as methoxymethyl, ethoxymethyl etc.

The connection 25 is subjected to interaction with cyanide such as sodium cyanide, potassium cyanide, the cyanide of silver, etc. in the presence chloromethylmethylether ether, bromatologia ether, chloromethylation ether, etc. in a solvent such as various alcohols (e.g. methanol, ethanol, etc from cooling with ice up high, preferably from cooling with ice to advanced, to obtain compound 29.

Stage 48

The connection 29 is subjected to interaction with the connection 30 in the presence of a base, such as diisopropylamide lithium hexamethyldisilazide sodium, sodium methoxide, potassium methoxide, tert-piperonyl sodium tert-piperonyl potassium, triethylamine, etc. at low temperature, preferably from -80oC before cooling with ice, to obtain compound 31.

Stage 49

The connection 31 is converted into the compound [I]-16 in a solvent such as various esters (e.g. ethyl ether, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, methylene chloride, chloroform, N,N-dimethylformamide, dimethylsulfoxide, water, various alcohols (e.g. methanol, ethanol, etc.,), or mixtures of these solvents at temperatures from cooling with ice to increased, preferably, from cooling with ice to room temperature. When R16replaced by silicom, such as trimethylsilyl, tert-butylmethylether etc., the addition of fluorine compounds, such as tetrabutylammonium, ammonium fluoride, hydrogen fluoride-pyridine, silver fluoride, etc. often leads to preferable results, and when R1 is adding inorganic acid, such as chloromethane acid, sulfuric acid, nitric acid, etc. to the solvent - water, various alcohols (for example methanol, ethanol, etc.,), etc., often leads to preferable results.

Stage 50

The connection 33 can be obtained, for carrying out the connection 29 and 32 the same reaction as in stage 48.

Stage 51

The connection 34 can be obtained by performing for connection 33 the same reaction as in stage 49.

Stage 52

The connection 34 is converted into the compound [I]-17 in inorganic acid, such as chloromethane acid, sulfuric acid, nitric acid, Hydrobromic acid, etc. or an organic acid such as formic acid, acetic acid, triperoxonane acid, propionic acid, etc. at a temperature of from 0oC to the boiling temperature under reflux. In another embodiment, the connection 34 is converted into the compound [I]-17 in a solvent such as various ethers (e.g. ethyl ether, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, methylene chloride, chloroform, N,N-dimethylformamide, dimethylsulfoxide, water, various alcohols (e.g. methanol, ethanol, etc.,), etc., or mixtures of these rastvoritelj">

Stage 53

The connection 35 is exposed to with N,O-dimethylhydroxylamine in a solvent such as various esters (e.g. ethyl ether, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, methylene chloride, chloroform, N,N-dimethylformamide, dimethylsulfoxide, etc., or mixtures of these solvents, in the presence of dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or their salts at a temperature of from cooling with ice to increased, preferably, from cooling with ice to room temperature, to obtain a connection 36. Adding 1-hydroxybenzotriazole, N, N-dimethylaminopyridine, etc. often leads to preferable results.

Stage 54

The connection 36 is subjected to interaction with hydrogen in a solvent such as various esters (for example, 1,4-dioxane, tetrahydrofuran, etc.,), water, various alcohols (e.g. methanol, ethanol, etc.,), etc., or mixtures of these solvents in the presence of a palladium catalyst such as palladium on charcoal, palladium black, etc., in an atmosphere of hydrogen at room temperature to obtain compound 37.

Stage 55

The connection 37 is subjected to interaction with the connection 38 to dissolve exan etc., or mixtures of these solvents at temperatures from low to high, preferably from -80oC to a temperature under cooling with ice to obtain a compound [1]- 18.

Stage 56

The connection 39 is subjected to interaction with the connection 40 in a solvent such as various esters (e.g. ethyl ether, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, N,N-dimethylformamide, dimethylsulfoxide, etc., or mixtures of these solvents in the presence of a base, such as lithium hydride, sodium hydride, sodium methoxide, ethoxide sodium, sitedisability, sodium carbonate, potassium carbonate, etc., at a temperature from low to high, to obtain a compound [I]-19.

Stage 57

Protection of the compounds [I] -19 removed in water or in a mixed solvent consisting of water and alcohols (e.g. methanol, ethanol, etc.,), or cyclic ethers (for example, 1,4-dioxane, tetrahydrofuran, etc.,) in the presence of alkali, such as lithium hydroxide, sodium hydroxide, sodium hydride, etc. at a temperature from low to high, to obtain the compound [I]-20.

Stage 58

Connection [I] -21 can be obtained by heating the compound [I]-20 to decarboxylation.

Stage 60

The connection 42 is subjected to interaction with oxalylamino, oxalylamino, thionyl chloride, etc. in a solvent such as benzene, toluene, n-hexane, cyclohexane, methylene chloride, chloroform, etc. or mixtures of these solvents, or without solvent, at a temperature from low to high, preferably from 0oC to high, to obtain compound 43. This reaction often leads to preferable results if added dimethylformamide, etc.

Stage 61

The connection 43 is subjected to interaction with the connection 44 in a solvent such as ethers (e.g. ethyl ether, 1,4-dioxane, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, N,N-dimethylformamide, dimethylsulfoxide, etc., or mixtures of these solvents, in the presence of a base, such as lithium hydride, sodium hydride, sodium methoxide, ethoxide sodium, sitedisability, carbonate n/P> Stage 62

The connection 45 is subjected to removal of protective groups and decarboxylate into a solvent such as benzene, toluene, n - hexane, cyclohexane, methylene chloride, chloroform, etc. or mixtures of these solvents, or without solvent, in the presence of an acid catalyst such as formic acid, triperoxonane acid, p-toluensulfonate acid, etc. at a temperature from low to high, preferably from room temperature to high, to obtain the compound [I]-22.

Stage 63

Connection [I]-22 hydrolyzing in water, or mixture of solvents such as water and alcohols (e.g. methanol, ethanol, etc.,) or cyclic ethers (for example, 1,4-dioxane, tetrahydrofuran, etc.,) in the presence of alkali, such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydride, etc. at a temperature from low to high, to obtain the compound [I] -21.

Stage 64

The connection 43 is subjected to interaction with the connection 46 in a solvent such as ethers (e.g. ethyl ether, 1,4-dioxane, tetrahydrofuran, etc), benzene, toluene, n-hexane, cyclohexane, etc. or mixtures of these solvents, in the presence of a base, such as n-utility, sitedisability the Association 47 is subjected to interaction with the connection 48 in the presence of sodium alkoxide, such as sodium methoxide, ethoxide sodium, etc., (an alkyl group, R52, alcohol, or alkoxy, preferably, the same) in a solvent such as alcohols (e.g. methanol, ethanol, etc.,), benzene, toluene, n-hexane, cyclohexane, etc. or mixtures of these solvents, at a temperature from low to high, preferably at the boiling point under reflux, to obtain the compound [I]-23.

Stage 66

Connection [I]-23 hydrolyzing in water or mixture of solvents such as water and alcohols (e.g. methanol, ethanol, etc.,) or cyclic ethers (for example, 1,4-dioxane, tetrahydrofuran, etc.,) in the presence of alkali, such as lithium hydroxide, potassium hydroxide, sodium hydroxide, etc. at a temperature from low to high, and then decarboxylate into a solvent such as benzene, toluene, xylene, etc. or mixtures of these solvents, or without solvent, in the presence of an acid catalyst, such as formic acid, triperoxonane acid, p-toluensulfonate acid, etc. or without a catalyst, at a temperature from low to high, preferably from room temperature to high, to obtain the compound [I]-21.

Stage 67

Connect arid, chloroform, carbon tetrachloride, tetrachlorethane, nitrobenzene, etc., or mixtures of these solvents or without solvent in the presence of a Lewis acid such as aluminised, zinc chloride, boron TRIFLUORIDE, etc., at a temperature from low to high, to obtain the compound [I]-24.

Stage 68

Connection [1] -24 atrificial in a solvent consisting of alcohols (e.g. methanol, ethanol, propanol, etc.,) in the presence of inorganic acids, such as chloromethane acid, sulfuric acid, etc. or an acid catalyst such as p-toluensulfonate acid, benzolsulfonat acid, methanesulfonate acid, etc. at a temperature from low to high, preferably from room temperature to the boiling temperature under reflux, to obtain the compound [I]-25.

Stage 69

Connection [I]-25 subjected to interaction with ethylene glycol in the presence of p-toluensulfonate pyridinium and an ester of trichomonacidal acid, such as triethylorthoformate and triethylorthoformate, at a temperature from room temperature up high, preferably at elevated, thereby removing the formed alcohol, to obtain a connection 50.

Statenhal, ethanol, propanol, etc.,), ethyl acetate, acetic acid, etc. or mixtures of these solvents, in the presence of a platinum catalyst such as platinum on charcoal, platinum on alumina, platinum black, platinum oxide, etc., or rhodium catalyst, such as rhodium on charcoal, rhodium on alumina, etc., under hydrogen pressure of 1-5 atmospheres. at a temperature of from room temperature to high, and then converted into the compound [I] -22 in acetic acid at temperatures from room temperature up high, preferably at elevated.

Stage 71

Connection [I]-22 converted into the compound [I]-21 in water or in a mixture of solvents, such as water and alcohols (e.g. methanol, ethanol, propanol, etc.,) or cyclic ethers (for example, 1,4-dioxane, tetrahydrofuran, etc.,) in the presence of alkali, such as lithium hydroxide, potassium hydroxide, sodium hydroxide, etc. at a temperature from low to high.

Stage 72

The connection 42 is converted into compound 51 in a solvent consisting of alcohols (e.g. methanol, ethanol, propanol, etc.,) in the presence of inorganic acids, such as chloromethane acid, sulfuric acid, etc. or an acid catalyst such as p-toluensulfonate Ki the th, preferably from room temperature up to the boiling temperature under reflux.

Stage 73

The connection 51 is subjected to interaction with succinic anhydride in a solvent such as ethers (e.g. ethyl ether, 1,4-dioxane, tetrahydrofuran, etc.) benzene, toluene, n - hexane, cyclohexane, etc. or mixtures of these solvents, in the presence of a base, such as n-utility, diisopropylamide lithium, sodium hydroxide, etc. at a temperature from low to high, to obtain the compound [I]-26.

Stage 74

Connection [I]-26 converted into the compound [I]-21 in water or in a mixed solvent consisting of water and alcohols (e.g. methanol, ethanol, propanol, etc.,) in the presence of alkali, such as lithium hydroxide, potassium hydroxide, sodium hydroxide, etc. at a temperature from low to high.

Stage 75

The connection 52 is subjected to interaction with thionyl chloride, phosphorus trichloride, with phosphorus pentachloride, gaseous hydrogen chloride, phosphorus oxychloride, etc. in a solvent such as hexane, cyclohexane, methylene chloride, chloroform, tetrachloro carbon, etc. or without a solvent, at a temperature from low to high, preferably at the rot in the solvent, such as ethers (e.g. ethyl ether, tetrahydrofuran, etc.,) in a stream of nitrogen at a temperature of from room temperature up to high, to obtain compound 20'. Additions of iodine in the beginning of the reaction may increase the output.

Stage 77

The connection 20' is subjected to interaction with succinic anhydride in a solvent such as ethers (e.g. ethyl ether, tetrahydrofuran, etc.,) at a temperature from low to high, preferably at reduced, to obtain the compound [I]-21. Adding acetylacetonate Fe (III) as a catalyst can increase the output.

Stage 78

The connection 43 is subjected to interaction with the connection 53 in a solvent such as various esters (e.g. ethyl ether, tetrahydrofuran, etc.,), benzene, toluene, n-hexane, cyclohexane, etc. or mixtures of these solvents, in the presence of copper iodide, fosfinpalladievogo catalyst, such as bis(triphenylphosphine) palladium (II) chloride, etc., or organic bases such as triethylamine, N-methylmorpholine, etc. at a temperature from low to high, preferably at room temperature, to obtain a connection 54.

Stage 79

The connection 54 is subjected to interaction with baladie the initial ether, etc., or without solvent, to obtain compound 55.

Stage 80

The connection 55 is subjected to interaction with hydrogen in a solvent such as various alcohols (e.g. methanol, ethanol, propanol, etc.,), using a palladium catalyst such as palladium on charcoal, palladium black, palladium hydroxide, etc., under hydrogen pressure of 1-5 atmospheres., at room temperature, to obtain the compound [I]-27 and 60.

Stage 81

Connection [I]-27 converted into the compound [I]-29 in an organic solvent such as formic acid and triperoxonane acid, at a temperature from low to high, preferably at room temperature.

Stage 82

Connection [I]-27 converted into the compound [I]-30 in the presence of a base such as lithium hydroxide, potassium hydroxide, sodium hydroxide, etc. in a solvent such as various alcohols (e.g. methanol, ethanol, propanol, tert-butanol, etc.,) at a temperature from low to high.

Stage 83

Connection [I] -31 can be obtained by subjecting compound [I]-30 the same reaction as in stage 81.

Stage 84

The connection 60 is converted into the compound [I]-32 in dimethyl sulfoxide or in a mixture rastvoritelyami etc., and organic bases such as triethylamine, N-methylmorpholine, at a temperature from low to high, preferably at room temperature.

Stage 85

Connection [I] -33 can be obtained by subjecting compound [I]-32 the same reaction as in stage 81.

Stage 86

The connection 43 is subjected to interaction with diazomethane in a solvent such as ethers (e.g. ethyl ether, tetrahydrofuran, etc.,), chloroform, methylene chloride, etc. at a temperature from low to room, and then the obtained product is subjected to interaction with tert-butyl acrylate in a solvent such as ethyl ether, tetrahydrofuran, hexane, cyclohexane, benzene, toluene, chloroform, methylene chloride, etc. or without a solvent under heating to obtain a compound [I]-34.

Stage 87

Connection [I] -34 converted into the compound [I]-35 acid in a solvent such as formic acid, triperoxonane acid solution of hydrogen bromide-acetic acid solution of hydrogen chloride-dioxane, etc. at a temperature from low to high.

Stage 88

Connection [I] -34 subjected to interaction with a base such as lithium hydroxide, potassium hydroxide, hydrokit (for example, methanol, ethanol, propanol, tert-butanol, etc.,) at a temperature from low to high, and then the obtained product is subjected to interaction with chloroethanol acid in water or in a mixed solvent consisting of water and one of methanol, ethanol, tetrahydrofuran, 1,4-dioxane, etc. at a temperature from room temperature up to high, to obtain the compound [I]-36.

Stage 89

The connection 56 can be obtained by subjecting compound 51 and glutaric anhydride same reaction as in stage 73.

Stage 90

Connection 57 can be obtained by subjecting compound 56

the same reaction as in stage 74.

Stage 91

Compound 57 is subjected to interaction with bromine in a solvent such as ethyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, benzene, toluene, n-hexane, cyclohexane, methylene chloride, chloroform and acetic acid, at a temperature from low to high, preferably from 0oC to room temperature to obtain a connection 58.

Stage 92

The connection 58 is converted into the compound [1]-37 in a solvent such as tetrahydrofuran, dimethylformamide, acetonitrile, etc., in the presence of inorganic bases such as hydrocar Immortalis etc., at a temperature of from room temperature up to high.

In the above reactions, when R1represents cyclohexyl, substituted lower alkyl, the compound [1]-21 is thermodynamically stable isomer of CIS-TRANS isomers. The other isomer, which is not thermodynamically stable, can be obtained by subjecting the interaction of a mixture of CIS-TRANS isomers with Isobutanol in a solvent such as ethyl ether, chloroform, methylene chloride, etc. in the presence of an acid catalyst such as sulfuric acid, at a temperature from low to room, to obtain tert-butyl ether, separating CIS-TRANS isomers by HPLC, and detreville tert-butyl ether target isomer in formic acid or in triperoxonane acid.

Example 1 1-phenyl-1,4-pentandiol

a) methyl 2-acetyl-4-oxo-4-phenylbutanoate

To a suspension of sodium hydride (60% oil dispersion, of 1.05 g) in tetrahydrofuran (10 ml) was added dropwise a solution of methylacetoacetate (2,70 ml) in tetrahydrofuran (10 ml) at 0oC, and the mixture is stirred for 1 hour. Then added dropwise a solution of 2-bromoacetophenone (4,99 g) in tetrahydrofuran (8 ml) and the mixture is stirred at room temperature during which the Extract is dried over magnesium sulfate, concentrate and purify by chromatography on a column of silica gel with obtaining specified in the connection header (4,89 g).

b) 1-phenyl-1,4-pentadien

To a solution of methyl 2-acetyl-4-oxo-4-phenylbutanoate (2.35 g) obtained by the method of example 1a) in tetrahydrofuran (20 ml) was added 2 N. aqueous solution of sodium hydroxide (10.5 ml) at room temperature and the mixture is stirred for 12 hours. Then to the reaction mixture was added 10% aqueous citric acid solution. The mixture is stirred, extracted with ethyl acetate. The extract is dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the title compound (0.96 g).

Example 2 1-(4-biphenylyl)-1,4-pentandiol

According to the method of example 1 are as specified in the header connection on the basis of 2-bromo-4'-phenylacetophenone.

Example 3 1-(2-naphthyl)-1,4-pentandiol

According to the method of example 1 are as specified in the header connection on the basis of 2-bromo-2'-acetonaphthone.

Example 4 1-(1-naphthyl)-1,4-pentandiol

a) 2 bromo-1'-acetonaphthone

To a solution of 1'-acetonaphthone (15.2 ml) in acetic acid (200 ml) was added concentrated chloroethanol acid (0.2 ml). Then when the room is 1 hour. The reaction mixture was concentrated and the resulting residue is dissolved in ethyl acetate, washed sequentially with distilled water, saturated aqueous sodium bicarbonate, distilled water and saturated saline solution, dried over magnesium sulfate and concentrated to obtain specified in the connection header (25,86 g).

b) 1-(1-naphthyl)-1,4-pentandiol

According to the method of example 1 are as specified in the header of the connection of 2-bromo-1'-acetonaphthone obtained by the method of example 4a).

Example 5 1-cyclohexyl-1,4-pentandiol

a) 1-cyclohexyl-1-alanon

To a solution of cyclohexanecarbonyl acid (12.9 g) in diethyl ether (700 ml) was added dropwise 1.09 M solution (190 ml) metallice in diethyl ether at 0oC. the Mixture is stirred at room temperature for 4 hours. The reaction mixture was poured into a mixture of 1 N. chloroethanol acid (250 ml) and ice (50 g) and the mixture is stirred. The mixture is extracted with diethyl ether and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate and concentrated to obtain specified in the connection header (for 9.47 ml).

b) 2-bromo-1-cyclohexyl-1-trimera 5A), in methanol (6.0 ml) at 0oC. the Mixture is stirred for 30 minutes At room temperature add distilled water and mix. The mixture is extracted with diethyl ether and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and distilled water, dried over magnesium sulfate and concentrated to obtain specified in the connection header (2,40 g).

C) 1-cyclohexyl-1,4-pentandiol

According to the method of example 1 are as specified in the header connection on the basis of 2-bromo-1-cyclohexyl-1-ethanone obtained by the method of example 5b).

Example 6 1-(1-methyl-1-cyclohexyl)-1,4-pentandiol

According to the method of example 5 is specified in the header connection receive on the basis of 1-methyl-1-cyclohexanecarbonyl acid.

Example 7 1-cyclopentyl-1,4-pentandiol

According to the method of example 5 is specified in the header connection receive on the basis of cyclopentanecarbonyl acid.

Example 8 1-cycloheptyl-1,4-pentandiol

According to the method of example 5 is specified in the header connection receive on the basis of cycloheptanone acid.

Example 9 1-cyclohexyl-2,5-hexandione

a) cyclohexylacetate

To a solution of cyclohexyloxy acid (8.0 g) is d (0.1 ml). The mixture is heated to room temperature and stirred for 1 hour. The reaction mixture was concentrated to obtain specified in the connection header (8,43 g).

b) 1-bromo-3-cyclohexyl-2-propanone

To a solution of cyclohexylethylamine (8,43 g) obtained by the method of example 9a) in diethyl ether (100 ml) was added a solution (0.7 M, 350 ml) diazomethane in diethyl ether and the mixture is stirred at room temperature for 12 hours. The reaction mixture was concentrated and gradually added dropwise a solution of (16,99 ml) 25% of bromovalerate in acetic acid to obtain a precipitate at 0oC. the Reaction mixture was concentrated and the residue is dissolved in diethyl ether and washed with saturated saline solution. The organic layer is dried over sodium sulfate and concentrated to obtain specified in the connection header (10,19 g).

C) 1-cyclohexyl-2,5-hexandione

According to the method of example 1 are as specified in the header connection on the basis of 1-bromo-3-cyclohexyl-2-propanone obtained by the method of example 9b).

Example 10 1-(2-were)-1,4-pentandiol

a) 2-bromo-2'-methylacetophenone

To a solution of 2'-methylacetophenone (5.0 g) in acetic acid (93 ml) was added perbromide 4-(dimethylamino)-billaut distilled water and the mixture extracted with dichloromethane. The organic layer is washed successively with a saturated aqueous solution of sodium bicarbonate and saturated saline solution, dried over sodium sulfate and concentrated to obtain specified in the connection header (7,94 g).

b) tert-butyl 2-acetyl-4-(2-were)-4-oxobutanoate

By way of example 1a) receive specified in the header connection on the basis of 2-bromo-2'-methylacetophenone obtained by the method of example 10a), and tert-butylacetoacetate.

C) 1-(2-were)-1,4-pentandiol

Tert-butyl 2-acetyl-4-(2-were)-4-oxobutanoate (3,45 g) obtained by the method of example 10b) is heated at 185oC for 2.5 hours the Mixture is purified by chromatography on a column of silica gel with obtaining specified in the connection header (0,912 g).

Example 11 1-(3-were)-1,4-pentandiol

a) tert-butyl 2-acetyl-4-(3-were)-4-oxobutanoate

By way of example 10a) and b) specified in the header connection receive on the basis of 3'-methylacetophenone.

b) 1-(3-were)-1, 4-pentandiol

To a solution of tert-butyl 2-acetyl-4-(3-were)-4-oxobutanoate (4.0 g) obtained by the method of example 11a) in dimethylsulfoxide (20 ml) was added distilled water (0,27 ml) and litigare (0.64 g) and steelshot and extracted with chloroform. The organic layer was washed with saturated saline solution, dried over sodium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the title compound (0.50 g).

Example 12 1-(4-tert-butylphenyl)-1,4-pentandiol

a) 2-bromo-4'-tert-butylacetophenone

By way of example 4a) specified in the header connection receive on the basis of 4'-tert-butylacetophenone.

b) tert-butyl 2-acetyl-4-(4-tert-butylphenyl)-4-oxobutanoate

By way of example 10b) specified in the header connection receive on the basis of 2-bromo-4'-tert-butylacetophenone obtained by the method of example 12a).

C) 1-(4-tert-butylphenyl)-1,4-pentandiol

Tert-butyl 2-acetyl-4-(4-tert-butylphenyl)-4-oxobutanoate (50,1 mg) obtained in example 12b), dissolved in formic acid (1.0 ml) and the mixture stirred for 4 h at room temperature and then at 150oC for 10 minutes the Mixture is concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (26.6 mg).

Example 13 1-(4-cyclohexylphenol)-1,4-pentandiol

a) tert-butyl 2-acetyl-4-(4-cyclohexylphenol)-4-oxobutanoate

By way of example 10a) and b) specified in BR>
By way of example 11b) specified in the header connection receive, from tert-butyl 2-acetyl-4-(4-cyclohexylphenol)-4 - oxobutanoate obtained by the method of example 13a).

Example 14 2-methyl-4,7-attention.

a) 1-bromo-4-methyl-2-pentanon

By way of example 9b) specified in the header connection receive on the basis of isovalerylglycine.

b) 2-methyl-4,7-attention

By way of example 10b) and (C) specified in the header connection receive on the basis of 1-bromo-4-methyl-2-pentanone obtained by the method of example 14a).

Example 15 TRANS-1-(4-methylcyclohexyl)-1,4-pentandiol

a) TRANS-2-bromo-1-(4-methylcyclohexyl)-1-alanon

By way of example 9a) and b) specified in the header connection receive on the basis of 4-methyl-1-cyclohexanecarbonyl acid.

CDCl3, 300 MHz

of 0.90 (3H, d, J = 6.0 Hz), 0,97 (2H, DQC, J = 3.0 Hz, 12.0 Hz), 1,41 (2H, DQC, J = 3.0 Hz, 12.0 Hz), 1,26 was 1.43 (1H, m) to 1.79 (2H, DD, J = 3.0 Hz, 12.0 Hz), 1,90 (2H, DD, J = 3.0 Hz, 12.0 Hz), 2,64 (1H, TT, J = 3.0 Hz, 12.0 Hz), of 3.97 (1H, C).

b) TRANS-1-(4-methylcyclohexyl)-1,4-pentandiol

To a solution of benzoylacetate (3,16 g) in tetrahydrofuran (60 ml) was added sodium borohydride (60% oil dispersion, 0,69 g) at 0oC and the mixture is stirred for 30 minutes Then probabl is hydrofuran (20 ml). The mixture is stirred at room temperature for 2 hours To the reaction mixture was added saturated aqueous solution of ammonium chloride and the mixture is stirred and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, concentrated and purified by chromatography on a column of silica gel to obtain benzyl TRANS-2-acetyl-4-(4 - methylcyclohexyl)-4-oxobutanoate (3,96 g). The resulting benzyl TRANS-2-acetyl-4-(4-methylcyclohexyl)-4-oxobutanoate (3,96 g) dissolved in ethanol (59 ml) and add 10% palladium on coal (0,791 g) the Mixture is stirred at room temperature for 1 hour in a hydrogen atmosphere. 10% Palladium on coal is filtered, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the header of the compound (2.00 g).

Example 16 1-(1-substituted)-1,4-pentandiol

a) 1-(1-substituted)-2-bromo-1-alanon

By way of example 5a) and b) receive specified in the header connection on the basis of 1-adamantanecarbonyl acid.

b) 1-(1-substituted)-1,4-pentandiol

By way of example 15b) specified in the header connection receive on the basis of 1-(1 - substituted)-2-bromo-1-ethanone obtained by the method of example 16a).

<>4-Phenylbenzene acid (4.0 g) was added to isoamyl alcohol (400 ml) and the mixture is heated to 130oC, after which the portions added sodium (28,0 g). The mixture is heated to 150oC and stirred for 15 hours, the Reaction mixture was poured into a saturated aqueous solution of ammonium chloride under ice cooling. The mixture is extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate and concentrated to obtain specified in the title compound (4.12 g).

CD3OD 300 MHz

1,47 is 1.70 (4H, m), 1,92 is 1.96 (2H, m), 2,09-2,12 (2H, m), 2,28 (1H, TT, J = 3,6 Hz, 11.7 Hz), to 2.55 (1H, TT, J = 3.0 Hz, 11.7 Hz), 7,14-7,31 (5H, m).

b) TRANS-1-(4-phenylcyclohexyl)-1,4-pentandiol

According to the method of example 15 is specified in the header connection receive on the basis of TRANS-4-phenylcyclohexanecarboxylic acid obtained by the method of example 17a).

Example 18 1-(2-pyridyl)-1,4-pentandiol

To a solution of picolylamine (1.5 g) in ethanol (30 ml) was added methyl vinyl ketone are (1,17 ml), 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolidine (378 mg) and triethylamine (0,782 ml) at room temperature and the mixture is stirred for 12 hours, the Reaction mixture was poured into 5% aqueous solution of potassium hydrosulfate and the aqueous layer was washed of chloroform is washed with saturated salt solution, dried over sodium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the title compound (329 mg).

Example 19 1-(3-pyridyl)-1,4-pentandiol

By way of example 18 get mentioned in the title compound, based on nicotinanilide.

Example 20 1-(4-hydroxymethylene)-1,4-rentention

a) 4-hydroxymethylbenzene

To a solution of sodium borohydride (7,26 g) in methanol (400 g) was added dropwise a solution of mononitrates terephthalaldehyde (26,1 ml) in methanol (20 ml) and the mixture is stirred at room temperature for 2 hours, the Reaction mixture was concentrated and the obtained residue was added brine, and then extracted with diethyl ether. The organic layer was washed with saturated saline and dried over magnesium sulfate. The residue obtained by concentrating the organic layer was dissolved in chloroform (80 ml). At 0oC was added 50% aqueous solution triperoxonane acid (40 ml) and the mixture is stirred for 30 minutes. The reaction mixture is neutralized with sodium bicarbonate and chloroform is evaporated. The residue is dissolved in ethyl acetate, washed with distilled water, dried over magnesium sulfate,4-pentandiol

To a solution of 4-hydroxymethylbenzene (1,94 g) obtained by the method of example 20a) in ethanol (20 ml) of methyl vinyl ketone are added (2.5 ml), triethylamine (0,85 ml) and 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazole chloride (0,410 g) and the mixture refluxed for 8 hours To the reaction mixture was added distilled water and the mixture extracted with diethyl ether. The organic layer is dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (1,32 g).

Example 21 1-[4-(1-hydroxyethyl)phenyl]-1,4-pentandiol

a) ethylenically 4-bromobenzaldehyde

To a solution of 4-bromobenzaldehyde (25,27 g) in benzene (150 ml) was added ethylene glycol (11 ml) and the monohydrate p-toluensulfonate acid (0,264 g) and the mixture refluxed trapped in a Dean-stark within 24 hours, the Reaction mixture was neutralized with potassium carbonate and the organic layer was washed with distilled water and saturated saline solution, dried over magnesium sulfate and concentrated to obtain specified in the connection header (30,49 g).

b) 4-(1-hydroxyethyl)benzaldehyde

To a mixture of magnesium (2,434 g chip) and tetrahydrofuran (10 ml) was added to Etrahedron (70 ml) and added 1,2-dibromoethane (0.2 ml) by heating. After start of the reaction the remaining solution was added dropwise with such a rate as to maintain a low boil under reflux. The mixture is then boiled for 30 min and cooled to room temperature. Added dropwise a solution of acetaldehyde (5,3 ml) in tetrahydrofuran (40 ml) and the mixture stirred for 1 h After completion of the reaction was added a saturated solution of ammonium chloride and the mixture is stirred, extracted with ethyl acetate, dried over potassium carbonate, concentrated and purified by chromatography on a column of silica gel with getting ethylacetate 4-(1-hydroxyethyl)benzaldehyde (7,58 g). To a solution of ethylacetate 4-(1-hydroxyethyl)benzaldehyde (2,92 g) in tetrahydrofuran (10 ml) was added 2 ml of 1 N. chloroethanol acid at room temperature and the mixture is stirred for 2 hours. The reaction mixture is diluted with distilled water and extracted with ethyl acetate. The organic layer was washed with distilled water, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate and concentrated to obtain specified in the title compound (2.14 g).

C) 1-[4-(1-hydroxyethyl)phenyl]-1,4-pentandiol

By way of example 20b)of example 21b).

Example 22 1-[4-(2-hydroxyethyl)phenyl]-1,4-pentandiol

a) ethylenically 4-Universalnaya

To a solution of ethylenically 4-bromobenzaldehyde (5,455 g) obtained by the method of example 21a) in toluene (10 ml) was added in argon atmosphere vinyltrimethylsilane (8,35 g) and tetrakis(triphenylphosphine) palladium (0) (0,555 g) and the mixture refluxed for 2 hours To the reaction mixture was added saturated aqueous solution of sodium fluoride (20 ml) and the mixture is stirred for 12 hours at room temperature, after which the mixture is filtered through a layer of Celite. The filtrate is extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (3,188 g).

b) 4-(2-hydroxyethyl) benzaldehyde

To a solution of ethylacetate 4-Universalnaya (1,417 g) obtained by the method of example 22A) in tetrahydrofuran (10 ml) was added dropwise in an argon atmosphere at 0oC complex, borane-tetrahydrofuran (1.0 M, 10 ml) and the mixture stirred for 1 h To the reaction mixture was added 4 M aqueous sodium hydroxide solution (6.0 ml), and then to the reaction mixture was added 30% aqueous perorm. The organic layer was washed with saturated saline, dried over magnesium sulfate and concentrated. The resulting residue is dissolved in tetrahydrofuran (20 ml) and added 1 N. chloroethanol acid (5 ml). The mixture is stirred for 12 h, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (0,261 g).

C) 1-[4-(2-hydroxyethyl) phenyl]-1,4-pentandiol

By way of example 20b) specified in the header connection receive on the basis of 4-(2-hydroxyethyl)benzaldehyde, obtained by the method of example 22b).

Example 23 1-benzo[b]thiophene-2-yl)-1,4-pentandiol

a) (benzo[b]thiophene-2-yl) methanol

To a solution of benzo[b] thiophene-2 - carboxylic acid (8,925 g) in tetrahydrofuran (50 ml) is added triethylamine (7.7 ml) at 0oC. and Then added dropwise a solution of isopropylcarbamate (6,816 g) in tetrahydrofuran (40 ml), and the mixture was stirred at 0oC for 1 h, the Reaction mixture was filtered through a layer of Celite, and the filtrate was poured into a solution of sodium borohydride (3,801 g) in 50 ml of water at 0oC. the Mixture is stirred at room temperature for 1.5 hours To the reaction mixture add chloroethanol acid at 0oC to acidification, and with whom drocarbons sodium and saturated saline solution, dried over magnesium sulfate and concentrated to obtain specified in the connection header (7,89 g).

b) benzo[b]thiophene-2-carbaldehyde

To a solution of benzo[b]thiophene-2-yl)methanol (4.94 g) was obtained according to the method of example 23a) in dimethyl sulfoxide (35 ml) is added triethylamine (29 ml) and added dropwise the solution of a complex of sulfuric anhydride-pyridine (14,78 g) in dimethyl sulfoxide (40 ml). The mixture is stirred for 1 h To the reaction mixture was added ice water and the mixture extracted with ethyl acetate. The organic layer is washed successively with distilled water, 1 N. chloroethanol acid water sodium hypochlorite solution, saturated aqueous ammonium chloride, and saturated saline, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (to 4.41 g).

C) 1-(benzo[b]thiophene-2-yl)-1,4-pentandiol

By way of example 20b) that is specified in the header connection receive on the basis of benzo[b]thiophene-2-carbaldehyde obtained by the method of example 23b).

Example 24 1-(indan-2-yl)-1,4-pentandiol

a) 2,2-dimethyl-(Spiro[1,3]dioxane-5,2'-indan)-4,6-dione

To a solution of acid Meldrum (5,78 g) in di is dibromo-O-xylene (10,56 g) in dimethyl sulfoxide (50 ml). The mixture is stirred for 20 hours To the reaction mixture was added distilled water, and the mixture is extracted with ethyl acetate and concentrated to obtain specified in the connection header (6,56 g).

b) atiendan-2-carboxylate

To a solution of 2,2-dimethyl-(Spiro[1,3] dioxane-5,2'-indan)-4,6-dione (6,56 g) obtained by the method of example 24a) in ethanol (50 ml) was added monohydrate p-toluensulfonate acid (0,232 g) and the mixture refluxed for 24 hours, the Reaction mixture was concentrated, and the residue is dissolved in dimethyl sulfoxide (140 ml). Add distilled water (0,89 ml) and lithium chloride (1,05 g) and the mixture stirred for 1 h at 150oC. To the reaction mixture was added distilled water and after mixing, the mixture is extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (2,183 g).

C) 2-intangibility

To a solution of atiendan-2-carboxylate (1.98 g) obtained by the method of example 24b) in toluene (10 ml) was added dropwise in an argon atmosphere at -72oC solution (1.01 M; 12.5 ml) Diisobutylene and the mixture is stirred and extracted with ethyl acetate. The organic layer was washed with distilled water, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (0,951 g).

d) 1-(indan-2-yl)-1,4-pentandiol

By way of example 20b) get mentioned in the title compound, based on 2-indocarbocyanine obtained by the method of example 24c).

Example 25 1-(4-vinylphenol)-1,4-pentandiol

a) 1-(4-bromophenyl)-1,4-pentandiol

By way of example 20b) receive specified in the header connection on the basis of 4-bromobenzaldehyde.

b) 1-(4-vinylphenol)-1,4-pentandiol

Solution (20 ml) of 1-(4-bromophenyl)-1,4-pentanedione (3,83 g) obtained by the method of example 25a), vinyltrimethylsilane (8,80 ml) and tetrakis(triphenylphosphine)palladium (0) (0,346 g) in toluene (20 ml) is refluxed for 1 h in argon atmosphere. To the reaction mixture was added an aqueous solution of sodium fluoride (10 ml), and the mixture is stirred at room temperature for 3 h, and filtered through a layer of Celite. To the filtrate was added ethyl acetate and the mixture washed with distilled water and saturated saline solution, dried over magnesium sulfate, concentrated and purified by chromatography on to what phenyl)-1,4-pentandiol

a) isopropylacrylamide

To a mixture of magnesium (6,33 g, shavings) and tetrahydrofuran (20 ml) was added dropwise 10 ml of a solution of 2-bromopropene (20 ml) in tetrahydrofuran (230 ml) in an argon atmosphere by heating. After start of the reaction, the remaining solution are added dropwise with such a rate as to maintain the boil under reflux. The mixture is refluxed for 1 h, and cooled to room temperature to obtain a solution (0,82 M) specified in the connection header in tetrahydrofuran.

b) isopropylcarbodiimide

To a solution of (0,82 M, 170 ml) isopropylacrylamide obtained by the method of example 26a) in tetrahydrofuran, are added dropwise in an argon atmosphere a solution of chloride of anti - (27,0 ml) in tetrahydrofuran (100 ml) and the mixture is refluxed for 12 hours, the Tetrahydrofuran is evaporated from the reaction mixture, and the residue is distilled (because 1,4 Thor, 104-108oC) obtaining specified in the connection header (32,56 g).

C) 1-(4-isopropylphenyl)-1,4-pentadien

By way of example 25b) receive specified in the header connection on the basis of 1-(4 - bromophenyl)-1,4-pentanedione obtained by the method of example 25a) and isopropylcarbodiimide, the floor is Omid

By way of example 26a) specified in the header connection receive on the basis of 4-bromobiphenyl.

b) 1-(p-terphenyl-4-yl)-1,4-pentandiol

To a suspension of zinc bromide (1,09 g) in tetrahydrofuran (10 ml) was added dropwise in an argon atmosphere at 0oC solution (0.73 M, 6,50 ml) 4-biphenylamine obtained by the method of example 27a) in tetrahydrofuran. Then add bis(triphenylphosphine)palladium (II) chloride (56,0 mg), and the mixture is stirred at room temperature for 16 hours To the reaction mixture are added 1 N. aqueous citric acid solution, and the mixture is stirred and extracted with chloroform. The organic layer was washed with distilled water, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (434 g).

Example 28 1-(4-formylphenyl)-1,4-pentandiol

To a solution of 1-(4-hydroxymethylene)-1,4-pentanedione (1,05 g) obtained by the method of example 20b), in dimethyl sulfoxide (12 ml) was added dropwise in an atmosphere of argon triethylamine (4,50 ml) and the solution of complex sulphur amitritpylien (2,39 g) in dimethyl sulfoxide (12 ml), and dare acid (50 ml), and the mixture is stirred, extracted with ethyl acetate and washed with distilled water and saturated saline solution. After drying over magnesium sulfate, the residue is concentrated and purified by chromatography on a column of silica gel with obtaining specified in the title compound (0.85 grams).

Example 29 4-(1,4-dioxaphetyl)benzoic acid

To a solution of 1-(4-formylphenyl)-1,4-pentanedione (0,824 g) obtained by the method of example 28, in acetonitrile (8 ml) was added a solution of dinitrigenoxide (94,8 mg) in water (1 ml) at 0oC, and then add 30% hydrogen peroxide (0,43 ml). Added dropwise a solution of sodium chlorite (to 0.645 g) in water (6 ml), and the mixture is stirred for 3 hours To the reaction mixture was added 10% sodium thiosulfate (2 ml), and 1 N. hydrochloric acid (6 ml) was added for acidification of the reaction mixture. Add distilled water, and the mixture is stirred, and then extracted with ethyl acetate. The organic layer was washed with distilled water and saturated saline solution, dried over magnesium sulfate and concentrated to obtain specified in the connection header (0,815 g).

Example 30 1-(4-hydroxyphenyl)-1,4-pentandiol

a) 4-(methoxyethoxy)benzaldehyde

Potassium carbonate (13,81 g) priba the methyl ether (5,70 ml). The mixture is stirred at room temperature for 10 hours, the Reaction mixture was filtered through a layer of Celite, and the filtrate is concentrated to obtain specified in the connection header (9,19 g).

b) 1-[4-(methoxyethoxy)phenyl]-4,4-Ethylenedioxy-1 - pentanol

To a mixture of magnesium (1,686 g, shavings) in tetrahydrofuran (4 ml) was added 1,2-dibromoethane (30 ml) in an argon atmosphere. A solution of 2-(bromacil)-2-methyl-1,3-dioxolane (4,503 g) in tetrahydrofuran (15 ml) added dropwise with such a rate as to maintain the temperature of the reaction mixture at 25oC. After completion of the addition dropwise, the mixture is stirred at room temperature for 1 hour. To a solution of 4-(methoxyethoxy)benzaldehyde (kzt1.664 g) obtained by the method of example 30a) in tetrahydrofuran (10 ml) was added dropwise previously obtained mixture (10.5 ml) at 0oC in argon atmosphere. The mixture is stirred for 4 hours. To the reaction mixture was added saturated aqueous solution of ammonium chloride, and the mixture is stirred, extracted with ethyl acetate, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (2,068 g).

C) 1-[4-(methoxyethoxy)phenyl]-4,4-atrend is the procedure of example 30b), in dimethyl sulfoxide (10 ml) was added triethylamine (6.6 ml), and then the solution of a complex of sulfuric anhydride-pyridine (3,495 g) in dimethyl sulfoxide (10 ml). The mixture is stirred for 1 h, then poured into ice water and extracted with ethyl acetate. The organic layer is washed successively with an aqueous solution of sodium hypochlorite, 1 N. aqueous citric acid solution and saturated saline solution. The mixture is dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (1,493 g).

d) 1-(4-hydroxyphenyl)-1,4-pentandiol

1-[4-(methoxyethoxy)phenyl] -4,4-Ethylenedioxy-1 - pentanone (1,446 g) obtained by the method of example 30c) is dissolved in tetrahydrofuran (4.0 ml). To the mixture was added isopropanol (4.0 ml) and concentrated chloroethanol acid (2.0 ml). The mixture is stirred at room temperature for 12 hours To the reaction mixture was added distilled water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride and saturated brine. The mixture is dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with getting at enzoyl-4-(4-biphenylyl)-4-oxobutanoate

By way of example 1a) receive specified in the header connection on the basis of 2-bromo-4'-phenylacetophenone and ethylbenzylamine.

b) 1-(4-biphenylyl)-4-phenyl-1,4-butandiol

By way of example 1b) is specified in the header connection receive, based on ethyl-2-benzoyl-4-(4-biphenylyl)-4-oxobutanoate obtained by the method of example 31a).

Example 32 1-(4-biphenylyl)-4-cyclohexyl-1,4-butandiol

a) 3-dimethylamino-4'-phenylpropionitrile

To a solution of 4-acetylbiphenyl (10 g) in isoamyl alcohol (40 ml) was added paraformaldehyde (2.76 g), dimethylaminohydrolase (5,61 g) and concentrated chloroethanol acid (0.1 ml) and the mixture refluxed for 2 hours, the Reaction mixture is filtered while hot, and the obtained filtrate was added acetone (100 ml). The precipitate is collected by filtration to obtain specified in the connection header (6,51 g).

b) 3-(4-biphenylyl)-3-oxopropanenitrile

3-dimethylamino-4'-phenylpropionitrile (6,51 g) obtained by the method of example 32a), dissolved in a saturated aqueous solution of potassium carbonate, and the mixture is extracted with diethyl ether, dried over sodium sulfate and concentrated, and the residue is dissolved in ethanol (30 m is atoi temperature, and loose the precipitate is collected by filtration to obtain specified in the connection header (8,01 g).

C) 4-biphenylene

3-(4-biphenylyl)-3-oxopropanenitrile (8,01 g) obtained by the method of example 32b), dissolved in 16% aqueous solution of sodium bicarbonate (500 ml) and the solution extracted with diethyl ether. The organic layer was washed with 0.1 N. chloroethanol acid and then with saturated saline solution, dried over sodium sulfate, and concentrate to obtain specified in the connection header (1,62 g).

d) 1-(4-biphenylyl)-4-cyclohexyl-1,4-butandiol

By way of example 20b) specified in the header connection receive on the basis of 4-biphenylene obtained by the method of example 32c), and cyclohexanecarboxaldehyde.

Example 33 5-(4-biphenylyl)-1-phenyl-2,5-pentanedione

By way of example 20b) specified in the header connection receive on the basis of phenylacetaldehyde and 4-biphenylene obtained by the method of example 32c).

Example 34 1-(4-biphenylyl)-1,4-heptanediol

By way of example 20b) that is specified in the header connection receive on the basis of 1-butanol and 4-biphenylene obtained by the method of example 32c).

Example 35 1-methoxy-5-Fe is agolove connection get based on 2-bromoacetophenone and methyl-4 - methoxyacetanilide.

b) 1-methoxy-5-phenyl-2,5-pentanedione

By way of example 1b) is specified in the header connection receive on the basis of methyl-2-(methoxyacetyl)-4-oxo-4-phenylbutanoate obtained by the method of example 35a).

Example 36 1,4-DICYCLOHEXYL-1,4-pentandiol

To a solution of sitedisability (1.35 g) in tetrahydrofuran (26,4 ml) was added dropwise a solution of cyclohexanemethylamine (1.51 g) in tetrahydrofuran (5 ml) in an argon atmosphere at -78oC, and the mixture is stirred for 15 minutes Then added dropwise 0.66 M solution of copper chloride (II) in tetrahydrofuran (19 ml), and the mixture is stirred for 40 minutes To the reaction mixture was added 10% aqueous citric acid solution, and the mixture is extracted with diethyl ether. The organic layer is washed sequentially with 10% aqueous citric acid solution and saturated saline solution, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (0,72 g).

Example 37 1,4-bis(1-methylcyclohexyl)-1,4-pentandiol

a) methyl-1-methylcyclohexylamine

By way of example 5a) get mentioned in the title compound, shooby example 36 specified in the header of the connection get based on methyl-1-methylcyclohexylamine obtained by the method of example 37a).

Example 38 (Z)-1-(4-biphenylyl)-2-penten-1,4-dione

a) 2-(4-biphenylyl)-5-methylfuran

To a solution of 1-(4-biphenylyl)-1,4 - pentanedione (7,53 g) obtained by the method of example 2, in benzene (100 ml), add monohydrate p-toluensulfonate acid (0,383 g) and the mixture is subjected to azeotropic dehydration trapped in a Dean-stark for 2 hours, the Reaction mixture was concentrated, and the residue is dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and distilled water, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (3,19 g).

b) (Z)-1-(4-biphenylyl)-2-penten-1,4-dione

m-Chloroperbenzoic acid (0.01 g) was added to a solution of 2-(4 - biphenylyl)-5-methylfuran (1,00 g) obtained by the method of example 38a), in dichloromethane (10 ml) at 0oC, and the mixture is stirred for 1 h To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution and 10% aqueous sodium thiosulfate solution to establish a pH 8 and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution, drying the EP 39 (Z)-1-cyclohexyl-2-penten-1,4-dione

By way of example 38 specified in the header connection receive on the basis of 1-cyclohexyl-1,4-pentanedione obtained by the method of example 5.

Example 40 (Z)-1-(1-methyl-1-cyclohexyl)-2-penten-1,4-dione

By way of example 38 receive specified in the header connection on the basis of 1-(1-methyl-1-cyclohexyl)-1,4-pentanedione obtained by the method of example 6.

Example 41 (E)-1-(4-biphenylyl)-2-penten-1,4-dione

2-(4-biphenylyl)-5-methylfuran (1.0 g) obtained by the method of example 38a), is dissolved in aqueous acetone (acetone: distilled water = 85:15, 100 ml) at -25oC add vodoochistnoy solution of bromine (0.65 M, and 6.6 ml), then stirred at room temperature for 1 h To the reaction mixture was added sodium bicarbonate (4.0 g) and the mixture concentrated. The residue is dissolved in distilled water, add 10% aqueous sodium thiosulfate solution, and after stirring, the mixture is extracted with ethyl acetate. The organic layer is washed sequentially with saturated aqueous

a solution of sodium bicarbonate, distilled water and saturated saline solution, dried over magnesium sulfate and concentrated to obtain specified in the title compound (1.12 g).

Example 42 3-acetyl-bromo-4'-phenylacetophenone and 2,4-pentanedione.

Example 43 3-acetyl-1-(4-biphenylyl)-3-methyl-1,4-pentanedione

By way of example 1a) is specified in the header connection receive on the basis of 2-bromo-4'-phenylacetophenone and 3-methyl-2,4 - pentanedione.

Example 44 3-acetyl-1-(1-methyl-1-cyclohexyl)-1,4-pentanedione

a) 2-bromo-1-(1-methyl-1-cyclohexyl)-1-alanon

By way of example 5b) specified in the header connection receive, based on methyl-1-methylcyclohexylamine obtained by the method of example 37a).

b) 3-acetyl-1-(1-methyl-1-cyclohexyl)-1,4-pentandiol

By way of example 1a) is specified in the header connection receive on the basis of 2-bromo-1-(1-methyl-1-cyclohexyl)-1-ethanone obtained by the method of example 44a) and 2,4 - pentanedione.

Example 45 1-acetyl-1-(4-biphenylyl)-2-penten-1,4-dione

a) 3-acetyl-5-(4-biphenylyl)-2-methylfuran

By way of example 38a) specified in the header connection receive on the basis of 3-acetyl-1- (4-biphenylyl)-1,4-pentanedione obtained by the method of example 42.

b) 1-acetyl-1-(4-biphenylyl)-2-penten-1,4-dione

By way of example 41 is specified in the header connection receive on the basis of 3-acetyl-5-(4-biphenylyl)-2-methylfuran obtained by the method of example 45a).

Example 46 4-oxo-4-phenylbutanoate acid

To the solution is in tetrahydrofuran, and the mixture is refluxed for 3 hours To the reaction mixture are added 1 N. aqueous citric acid solution, and the mixture is stirred and extracted with ethyl acetate. The obtained organic layer is extracted with 1 N. aqueous solution of sodium hydroxide, and 1 N. aqueous solution of citric acid was added until until the aqueous layer was acidified. It is extracted with ethyl acetate and washed with brine. The organic layer is dried over magnesium sulfate and concentrated to obtain specified in the connection header (3,20 g).

Example 47 4-(4-biphenylyl)-4-oxobutanoic acid

To a solution of biphenyl (5.20 g) and succinic anhydride (3.0 g) 1,1,2,2-tetrachloroethane (50 ml) was added aluminum chloride (for 9.47 g) at 0oC, and then stirred at room temperature for 6 hours. The reaction mixture was poured into ice water and acidified with concentrated chloroethanol acid. The mixture is extracted with ethyl acetate. To the organic layer added 1 N. aqueous sodium hydroxide solution for extraction of the water layer. The resulting aqueous layer is acidified with concentrated chloroethanol acid and again extracted with ethyl acetate, washed with saturated saline, dried over sulfamoyl)4-oxobutanoic acid

By way of example 47 is specified in the header connection receive on the basis of fluorenyl.

Example 49 4-[4-(hydroxymethyl)phenyl]-4-oxobutanoic acid

a) 4-(4-were)-4-oxobutanoic acid

To a solution of toluene (5,52 g) and succinic anhydride (4.0 g) in 1,1,2,2-tetrachloroethane (40 ml) was added aluminium chloride (12,78 g) at 0oC, and then stirred at room temperature for 2 hours In the reaction mixture is poured onto ice water, and acidified with concentrated chloroethanol acid. The mixture is extracted with ethyl acetate. To the organic layer added 1 N. aqueous sodium hydroxide solution for extraction in the aqueous layer. The resulting aqueous layer is acidified with concentrated chloroethanol acid, extracted with ethyl acetate, washed with saturated saline solution, dried over sodium sulfate and concentrated to obtain specified in the header of the compound (7.50 g).

b) methyl-4-(4-were)-4-oxobutanoate

To a solution of 4-(4-were)-4-oxobutanoic acid (7,05 g) obtained by the method of example 49a), in methanol (140 ml) was added monohydrate p-toluensulfonate acid (0,698 g) and the mixture is refluxed for 3 hours; it is concentrated and dissolved in these the solution, dried over sodium sulfate and concentrated to obtain specified in the connection header (to 6.43 g).

C) Methyl-4-[4-(hydroxymethyl)]phenyl-4-oxobutanoate

To a solution of methyl-4-(4-were)-4-oxobutanoate (to 6.43 g) obtained by the method of example 49b), tetrachlorophenol (193 ml) was added N-bromosuccinimide (5.30 g). The mixture is refluxed for 30 min under irradiation of 100 watt lamp. Undissolved matter is filtered off and the filtrate concentrated. The resulting residue is dissolved in 1,4-dioxane (75 ml). Add distilled water (75 ml) and calcium carbonate (13,4 g) and the mixture is refluxed for 12 hours the Mixture was poured into 1 N. chloroethanol acid, and the mixture is extracted with chloroform. The organic layer is washed successively with a saturated aqueous solution of sodium bicarbonate and saturated saline solution, dried over sodium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the title compound (3.55 g).

d) 4-[4-(hydroxymethyl) phenyl]-4-oxobutanoic acid

To a solution of methyl-4-[4-(hydroxymethyl) phenyl]-4-oxobutanoate (3.55 g) obtained by the method of example 49c) in tetrahydrofuran (35,5 ml) app is the first temperature. The reaction mixture is neutralized 1 N. chloroethanol acid, and concentrated to remove tetrahydrofuran. The mixture is acidified with 1 N. chloroethanol acid and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate and concentrated to obtain specified in the connection header (2,89 g).

Example 50 (E)-4-oxo-4-phenyl-2-butenova acid

To a solution of maleic anhydride (3,43 g) in benzene (20 ml) was added aluminium chloride (10.5 g) at room temperature, and the mixture is refluxed for 1 h To the reaction mixture was added distilled water at 0oC, and add concentrated chloroethanol acid. The benzene is evaporated, and the residue filtered. The filtrate is extracted with ethyl acetate. The organic layer was washed with distilled water. The organic layer is extracted with 1 N. aqueous sodium hydroxide solution, and the aqueous layer was acidified with concentrated chloroethanol acid, extracted with ethyl acetate, dried over magnesium sulfate, and concentrate to obtain specified in the title compound (5.32 g).

Example 51 4-(4'-methylbiphenyl-4-yl)-4-oxobutanoic acid

a) 4-(4-bromophenyl)-4-oxobutanoic 4-bromobenzaldehyde (25,57 g) in dimethylformamide (100 ml), and then added dropwise a solution of Acrylonitrile (8,90 ml) in dimethylformamide (100 ml), then stirred at 40oC for 2 hours To the reaction mixture was added ice water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate and concentrated to obtain specified in the connection header (19,29 g).

b) 4-(4'-methylbiphenyl-4-yl)-4-oxobutanoic

To a mixture of magnesium (2,68 g, shavings) and tetrahydrofuran (10 ml) was added dropwise under heating in an argon atmosphere of 10 ml solution of 4-bromthymol (17.1 g) in tetrahydrofuran (75,2 ml). After start of the reaction are added dropwise to the rest of the solution with such a rate as to maintain the boil under reflux. After completion of adding dropwise, the mixture is refluxed for 3 hours and Then to a mixture of zinc bromide (1,694 g) and tetrahydrofuran (20 ml) was added dropwise to the above mixture (7.5 ml) in an argon atmosphere at 0oC, and the mixture is stirred at room temperature for one hour. At 0oC was added 4-(4-bromophenyl)-4-oxobutanoate (1.19 g) obtained by the method of example 51a), and tetrakis(triphenylphosphine)palladium (0) (0,119 g), and the mixture is stirred. Specialising aqueous solution of ammonium chloride, and the mixture is extracted with ethyl acetate, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (0,740 g).

C) 4-(4'-were-4-yl)-oxobutanoic acid

To a solution of 4-(4'-methylbiphenyl-4-yl)-4-oxobutanamide (0,537 g) obtained by the method of example 51b), in ethanol (2.0 ml) was added 2 N. aqueous sodium hydroxide solution (3.0 ml) and the mixture is refluxed for 12 hours it added To 1 n chloroethanol acid, and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate and concentrated to obtain specified in the connection header (0,502 g).

Example 52 4-(3'-methylbiphenyl-4-yl)-4-oxobutanoic acid

By way of example 51b) and (C) specified in the header connection receive, based on 3-bromthymol and 4-(4-bromophenyl)4 - oxobutanamide obtained by the method of example 51a).

Example 53 4-(2'-methylbiphenyl-4-yl)-4-oxobutanoic acid

By way of example 51b) and (C) receive specified in the header connection on the basis of 2-bromthymol and 4-(4-bromophenyl)-4-oxobutanamide obtained by the method of example 51a).

Example 54 4-(2 Nola (17,27 g) in acetone (20 ml) was added at 0oC potassium carbonate (27.8 g) and added dropwise chloromethylation ether (12.0 ml). The mixture is stirred at room temperature for 1 h, and filtered through a layer of Celite. The filtrate is concentrated to obtain specified in the connection header (20,42 g).

b) 4-[2'-(methoxyethoxy)biphenyl-4-yl]-4-oxobutanoic

To a mixture of magnesium (1,337 g, shavings) and tetrahydrofuran (5 ml) was added dropwise under heating in an argon atmosphere, 5 ml of a solution of 1-bromo-2-(methoxyethoxy)benzene (10,86 g) obtained by the method of example 54a), in tetrahydrofuran (37 ml). After start of the reaction the remaining solution are added dropwise with such a rate as to maintain gentle boiling under reflux. After completion of adding dropwise, the mixture is refluxed for 3 hours and Then to a mixture of zinc bromide (2,266 g) and tetrahydrofuran (10 ml) was added dropwise a mixture of 9.0 ml) in an argon atmosphere, at 0oC, and the mixture is stirred at room temperature for one hour. At 0oC was added 4-(4-bromophenyl)-4-oxobutanoate (1.19 g) obtained by the method of example 51a), and tetrakis(triphenylphosphine)palladium (0) (0,119 g) and the resulting mixture is stirred. It is refluxed for 3 hours To reaccept with ethyl acetate, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (0,761 g).

C) 4-(2'-hydroxybiphenyl-4-yl)-4-oxobutanoic acid

To a solution of 4-[2'-(methoxyethoxy)biphenyl-4-yl]-4-oxobutanamide (0,761 g) obtained by the method of example 54b), in ethanol (3 ml) was added 2 N. aqueous sodium hydroxide solution (4.0 ml) and the mixture refluxed for 4 hours To the reaction mixture was added distilled water, and washed with a mixture of ethyl acetate. The aqueous layer was acidified with 1 N. chloroethanol acid, extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate and concentrated. The residue is dissolved in tetrahydrofuran (4 ml), to this was added concentrated chloroethanol acid (1 ml), and the mixture is stirred at room temperature for 12 hours, the Tetrahydrofuran is evaporated and the residue extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate and concentrated to obtain specified in the connection header (0,405 g).

Example 55 4-(3'-hydroxybiphenyl-4-yl)-4-oxobutanoic acid

By way of example 54 specified in reception who islot

By way of example 54 specified in the header connection receive on the basis of 4-bromophenol.

Example 57 4-oxo-4-[4-(3-thienyl)phenyl]butane acid

a) 4-(4-bromophenyl)-4-oxobutanoic acid

By way of example 51c) specified in the header connection receive on the basis of 4-(4-bromophenyl)-4 - oxobutanamide obtained by the method of example 51a).

b) methyl-4-(4-bromophenyl)-4-oxobutanoate

By way of example 49b) specified in the header connection receive on the basis of 4-(4-bromophenyl)-4 - oxobutanoic acid obtained by the method of example 57a).

C) methyl-4-oxo-4-[4-(3-thienyl) phenyl] butanoate

To a solution of methyl-4-(4-bromophenyl)-4-oxobutanoate (0,542 g) obtained by the method of example 57b), in benzene (4 ml) was added in an argon atmosphere a solution of thiophene-3-boronic acid (0,445 g) in ethanol (0.5 ml) and 2 M aqueous sodium carbonate solution (2 ml) and the mixture refluxed for 1 h To the reaction mixture was added diethyl ether, and the mixture was washed with saturated saline solution. The organic layer is dried over sodium sulfate and concentrated. The resulting crude product was then purified by chromatography on a column of silica gel with obtaining specified in the connection header (0,586 g).

Example 58 4-cyclohexyl-4-oxobutanoic acid

a) dimethyl-2-(2-cyclohexyl-2-oxoethyl)propanedioic

To a solution of diethylmalonate (2.17 g) in tetrahydrofuran (60 ml) was added sodium hydride (60% oil dispersion, 0,69 g) at 0oC. After stirring for 30 min was added dropwise a solution of 2-bromo-1-cyclohexyl-1-ethanone (3.75 g) obtained by the method of example 5b) in tetrahydrofuran (20 ml). After completion of adding dropwise, the mixture is stirred at room temperature for 1 h To the reaction mixture was added saturated aqueous solution of ammonium chloride and, after stirring, the mixture is extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (3,70 g).

b) 2-(2-cyclohexyl-2-oxoethyl)proportionaly acid

To a solution of dimethyl-2-(2-cyclohexyl-2-oxoethyl)propanoate (2,97 g) obtained by the method of example 58a), in tetrahydrofuran (30 ml) was added 1 N. aqueous sodium hydroxide solution (24.3 ml) at 0othe bath water. The mixture was washed with diethyl ether, and the aqueous layer was acidified with 5% aqueous solution of potassium hydrosulfate, extracted with ethyl acetate. The obtained extract is dried over sodium sulfate and concentrated to obtain specified in the connection header (1,94 g).

C) 4-cyclohexyl-4-oxobutanoic acid

2-(2-cyclohexyl-2-oxoethyl) proporzionale acid (1,94 g) obtained by the method of example 58b), is heated and decarboxylase obtaining specified in the title compound (1.50 g).

Example 59 methyl-4-cyclohexyl-4-oxobutanoate

To a solution of 4-cyclohexyl-4-oxobutanoic acid (1.22 g) obtained by the method of example 58, in methylene chloride (20 ml) was added methanol (12 ml) at room temperature. Then add solution (10%, 14 ml) and (trimethylsilyl)diazomethane in hexane, and the mixture is stirred for 1 h, the Reaction mixture was concentrated and purified by chromatography on a column of silica gel with obtaining specified in the title compound (1.19 g).

Example 60 dimethyl-2-[2-(1-methylcyclohexyl)-2-oxoethyl]propanedioic

By way of example 58a) specified in the header connection receive on the basis of 2-bromo-1-(1-methyl-1-cyclohexyl)-1 - ethanone obtained by the method of example 44a).

PrimeOutput, on the basis of 2-bromo-1-(1-methyl-1-cyclohexyl)-1-ethanone obtained by the method of example 44a).

Example 62 methyl-4-(1-methylcyclohexyl)-4-oxobutanoate

By way of example 59 is specified in the header connection receive on the basis of 4-(1-methylcyclohexyl)-4-oxobutanoic acid obtained by the method of example 61.

Example 63 methyl-2-acetyl-4-(1-methylcyclohexyl)-4-oxobutanoate

By way of example 1a) is specified in the header connection receive on the basis of 2-bromo-1-(1-methyl-1-cyclohexyl)-1-ethanone obtained by the method of example 44a).

Example 64 4-cyclopentyl-4-oxobutanoic acid

a) 2-bromo-1-cycloheptyl-1 alanon

By way of example 5a) and 5b) specified in the header connection receive on the basis of cyclopentanecarbonyl acid.

b) 4-cycloheptyl-4-oxobutanoic acid

By way of example 58 is specified in the header connection receive on the basis of 2-bromo-1-cyclopentyl-1 ethanone obtained by the method of example 64a).

Example 65 TRANS-4-(4-methylcyclohexyl)-4-oxobutanoic acid

The method of obtaining 1

a) dimethyl-2-[2-(TRANS-4 - methylcyclohexyl)-2-oxoethyl]propanedioic

To a solution of diethylmalonate (2.17 g) in tetrahydrofuran (60 ml) was added sodium hydride (in the form of 6 the NS-2-bromo-1-(4-methylcyclohexyl)-1-ethanone (4,00 g), obtained by the method of example 15a), in tetrahydrofuran (20 ml). After completion of adding dropwise, the mixture is stirred at room temperature for 1 h To the reaction mixture was added saturated aqueous solution of ammonium chloride, and the mixture is stirred and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (3,901 g).

b) 2-[2-(TRANS-4-methylcyclohexyl)-2-oxoethyl] proportionaly acid

To a solution of dimethyl-2-[2-(TRANS-4-methylcyclohexyl)-2 - oxoethyl]propanoate (3,901 g) obtained by the method of example 65 (a method of obtaining 1a)) in methanol (39,0 ml) was added 1 N. aqueous sodium hydroxide solution (30,30 ml) at 0oC, and the mixture is stirred for 2 hours, the Reaction mixture was acidified with 5% aqueous solution of potassium hydrosulfate, extracted with ethyl acetate, washed with saturated saline solution, dried over sodium sulfate and concentrated to obtain specified in the title compound (3.50 g).

(C) TRANS-4-(4-methylcyclohexyl)-4-oxobutanoic acid

2-[2-(TRANS-4-methylcyclohexyl)-2-oxoethyl] proporzionale what alsacia of ethyl acetate and hexane to obtain specified in the title compound (1.42 g).

The method of obtaining 2

a) chloride 4-methylcyclohexanecarboxylic

To a solution of 4-methyl-1-cyclohexanecarboxylic acid (36,05 g) in methylene chloride (500 ml) was added dropwise dimethylformamide (0.1 ml) and oxacillin (24,33 ml) at 0oC. the mixture is Then warmed to room temperature, stirred for 1 h and concentrated to obtain specified in the connection header (36,30 g).

b) ethyl-4-(4-methylcyclohexyl)-4-oxo-3,3-bis(tert-butoxycarbonyl)butanoate

To a suspension of sodium hydride (60% oil dispersion, 17,62 g) in tetrahydrofuran (500 ml) was added dropwise at room temperature a solution of di-tert-butylmalonate (98,88 ml) in tetrahydrofuran (500 ml) and the mixture stirred for 2 hours was Added dropwise a solution of ethylbromoacetate (37,57 ml) in tetrahydrofuran (250 ml) atoC, and the mixture is stirred at room temperature for 4.5 hours To the reaction mixture was added saturated aqueous solution of ammonium chloride, and tetrahydrofuran is evaporated under reduced pressure. The mixture is extracted with ethyl acetate, washed with saturated saline solution, dried over sodium sulfate, concentrated and distilled under reduced pressure to obtain di-tert-butyl-2- (ethoxycarbonylmethyl)propanoate dropwise di-tert-butyl-2-(ethoxycarbonylmethyl)propandiol (68,32 g) in tetrahydrofuran (642 ml) at 0oC, and the mixture is stirred at room temperature for 1 h, and to this was added dropwise a solution of 4-methylcyclohexanecarboxylic (36,30 g) obtained by the method of example 65 (a method of obtaining 2a)) in tetrahydrofuran (180 ml) at 0oC. Then the mixture is stirred at room temperature for 2 hours To the reaction mixture was added saturated aqueous solution of ammonium chloride, and the mixture is extracted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over sodium sulfate and concentrated to obtain specified in the connection header (91,47 g).

(C) ethyl-TRANS-4-(4-methylcyclohexyl)-4-oxobutanoate

Monohydrate p-toluensulfonate acid (4,08 g) was added to a solution of ethyl-4-(4-methylcyclohexyl)-4-oxo-3,3-bis(tert-butoxycarbonyl)butanoate (91,47 g) obtained by the method of example 65, (the method of obtaining 2b)) in toluene (914 ml) and the mixture is refluxed for 12 hours To dilute the reaction mixture is added ethyl acetate, and the mixture is washed successively with a saturated aqueous solution of sodium bicarbonate and saturated saline solution, dried over sodium sulfate and concentrated to obtain from the>To a solution of ethyl TRANS-4-(4-methylcyclohexyl)-4-oxobutanoate (46,64 g) obtained by the method of example 65 (a method of obtaining 2 (C)) in ethanol (500 ml), add 1 N. aqueous solution of lithium hydroxide (of 226.7 ml), and the mixture is stirred at room temperature for 12 hours, the Reaction mixture was neutralized with a saturated aqueous solution of ammonium chloride, and the ethanol is evaporated under reduced pressure. The residue is dissolved in a saturated aqueous solution of sodium bicarbonate. The resulting aqueous solution was washed with diethyl ether. The aqueous layer was acidified with potassium hydrosulfate, extracted with ethyl acetate, washed with saturated saline solution, dried over sodium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (27,0 g) and the mixture (8,16 g) CIS-4-(4-methyl - cyclohexyl)-4-oxobutanoic acid and TRANS-4-(4-methylcyclohexyl)-4-oxobutanoic acid.

The method of obtaining 3

a) acylhydrolase

To a solution of cleatimeout (50 g) in water (30 ml) was added dropwise concentrated chloroethanol acid (25 ml) at a temperature of from 5 to 10oC. Precipitated precipitated potassium chloride is filtered off and the filtrate is extracted with diethyl ether, dried the (4-methylcyclohexylamine)acetate

To a solution of ethylhydroxylamine (3.50 g) obtained by the method of example 65 (a method of obtaining 3A)) in tetrahydrofuran (80 ml), added dropwise a solution (1.68 M, 31.5 ml) n-utility in hexane at a temperature of from -78oC to -30oC. the Mixture is stirred at a temperature of -10oC for 30 minutes Then added dropwise a solution of 4-methylcyclohexanecarboxylic (2.0 g) obtained by the method of example 65, (the method of obtaining 2a)), in tetrahydrofuran (20 ml) at -78oC. After completion of the addition dropwise, the mixture is heated to room temperature and stirred for 1 h To the reaction mixture was added 5% aqueous solution of potassium hydrosulfate, and the mixture is extracted with diethyl ether, washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over sodium sulfate and concentrated to obtain specified in the title compound (2.38 g).

C) diethyl-(4-methylcyclohexylamine)butanedioate

To a solution of ethoxide sodium (0,321 g) in ethanol (40 ml) was added dropwise a solution of ethyl-(4-methylcyclohexylamine) acetate (1.0 g) obtained by the method of example 65 (an example of retrieving 3b) in ethanol (4.0 ml) at room temperature. The mixture is then boiled sym fridge for 30 minutes The reaction mixture was neutralized with a saturated aqueous solution of ammonium chloride, and the ethanol is evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed with saturated saline solution, dried over sodium sulfate and concentrated to obtain specified in the title compound (1.40 g).

d) TRANS-4-(4-methylcyclohexyl)-4-oxobutanoic acid

To a solution of diethyl-(4-methylcyclohexylamine) butanedioate (1.40 g) obtained by the method of example 65 (a method of obtaining 3c)) in ethanol (20 ml) was added 1 M aqueous solution of lithium hydroxide (20 ml) and the mixture was stirred at room temperature for 1 h, the Reaction mixture was neutralized with a saturated aqueous solution of ammonium chloride, and the ethanol is evaporated under reduced pressure. The residue is dissolved in diethyl ether and extracted with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was acidified with potassium hydrosulfate, extracted with ethyl acetate, washed with saturated saline solution, dried over sodium sulfate and concentrated. The residue is dissolved in toluene (30 ml) to which was added monohydrate p-toluensulfonate acid (80 mg) and the mixture refluxed for 4 hours, the Reaction mixture was diluted with utilize crystallization from ethyl acetate and hexane to obtain specified in the connection header (0,612 g).

The method of obtaining 4

a) 4-(4-were)-4-oxobutanoic acid

To a solution of aluminum chloride (100 g) in methylene chloride (450 g) was added toluene (44,0 ml) and succinic anhydride (34,02 g) was added at room temperature. The mixture is then stirred for 12 hours, the Reaction mixture was poured on ice (650 g) and the mixture is acidified with concentrated chloroethanol acid and extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution, dried over sodium sulfate and concentrated to obtain specified in the connection header (62,1 g).

b) methyl-4-(4-were)-4-oxobutanoate

To a solution of 4-(4-were)-4-oxobutanoic acid (91,2 g) obtained by the method of example 65 (a method of obtaining 4a)) in methanol (760 ml) was added concentrated sulfuric acid (1,33 ml) and the mixture refluxed for 2 hours, the Reaction mixture was cooled to room temperature, and the methanol is evaporated under reduced pressure. The resulting residue is dissolved in ethyl acetate, washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated saline solution, dried over sodium sulfate and concentrated to obtain specified in the header of loadinitcontent (20,0 g), obtained by the method of example 65 (a method of obtaining 4b) in ethylene glycol (100 ml) was added pyridine-p-toluensulfonate (2,44 g), and triethylorthoformate (64 ml), and the mixture is heated at 95oC for 30 h, removing the formed methanol. The reaction mixture is cooled to room temperature, and add distilled water. The mixture is extracted with toluene, and the organic layer washed sequentially with 5% aqueous citric acid solution, water, saturated aqueous sodium bicarbonate, water and saturated brine, and concentrated to obtain specified in the connection header (23,5 g).

d) methyl-4-(4-methylcyclohexyl)-4-oxobutanoate

To a solution of methyl-4,4-Ethylenedioxy-4-(4-were)butanoate (1.0 g) obtained by the method of example 65 (method 4 (C)) in ethyl acetate (10.0 ml), was added 5% rhodium on coal (0.2 g), and the mixture is stirred at room temperature for 5 hours in a hydrogen atmosphere at 3 ATM. 5% rhodium-carbon is filtered off and the filtrate concentrated. The resulting residue is dissolved in acetic acid (8.0 ml), and added water (2.0 ml). The mixture is refluxed for 1 h, the Reaction mixture was cooled to room temperature, and acetic acid vyparivaya layer is washed successively with water, saturated aqueous sodium bicarbonate, water and saturated saline solution, dried over sodium sulfate and concentrated to obtain specified in the connection header (0,787 g).

(e) TRANS-4-(4-methylcyclohexyl)-4-oxobutanoic acid

To a solution of methyl-4-(4-methylcyclohexyl)-4-oxobutanoate (21,22 g) obtained by the method of example 65 (a method of obtaining 4d) in methanol (15 ml), add 1 N. aqueous sodium hydroxide solution (150 ml) and the mixture refluxed for 2 hours, the Reaction mixture is cooled with ice and acidified with concentrated chloroethanol acid. The mixture is extracted with ethyl acetate, washed with saturated saline solution, dried over sodium sulfate, concentrated and purified via recrystallization from ethyl acetate and hexane, and then recrystallized from ethanol and water to obtain specified in the title compound (10.7 g).

The method of obtaining 5

a) methyl-4-methylcyclohexanecarboxylic

To a solution of 4-methyl-1-cyclohexanecarboxylic acid (25 g) in methanol (250 ml) was added concentrated sulfuric acid (0,94 ml), and the mixture is stirred at room temperature for 12 hours, the Reaction mixture was concentrated, diluted with utilitatem sodium and concentrate to obtain specified in the connection header (27,0 g).

b) 4-(1-methoxycarbonyl-4-methylcyclohexyl)-4-oxobutanoic acid

To a solution of methyl-4-methylcyclohexanecarboxylic (11.87 per g) obtained by the method of example 65 (a method of obtaining 5a) in tetrahydrofuran (15 ml), added dropwise a solution (1.5 M, 53,1 ml) sitedisability in cyclohexane at -5oC, and the mixture is stirred for 2 hours the Solution is added dropwise to a solution of succinic anhydride (to 7.61 g) in tetrahydrofuran (91 ml) at room temperature, and the mixture is stirred for 1 h To the reaction mixture was added saturated aqueous solution of ammonium chloride, and tetrahydrofuran is evaporated under reduced pressure. The reaction mixture is acidified with concentrated chloroethanol acid, and the mixture is extracted with ethyl acetate, washed with water and saturated saline solution, dried over magnesium sulfate, and concentrate to obtain specified in the connection header (17,55 g).

(C) TRANS-4-(4-methylcyclohexyl)-4-oxobutanoic acid

4-(1-methoxycarbonyl-4-methylcyclohexyl)-4-oxobutanoic acid (17,55 g) obtained by the method of example 65 (method 5b)), dissolved in 2 N. aqueous sodium hydroxide solution (120 ml) and the mixture refluxed for 2 hours, the Reaction mixture podci the content of inorganic fillers layer washed with water and saturated saline solution, dried over sodium sulfate and concentrated. The residue is purified by recrystallization from ethyl acetate and hexane to obtain specified in the title compound (6.50 g).

The method of obtaining 6

a) 1-chloro-4-methylcyclohexanol

Piatigorsky phosphorus (497,07 g) suspended in hexane (2,43 l) and added dropwise 4-methylcyclohexane (248,7 g) in the 5oC in nitrogen atmosphere. The reaction mixture is neutralized 5 N. aqueous sodium hydroxide solution. The organic layer was washed with distilled water, dried over sodium sulfate, concentrated and purified by distillation (because4070-71oC) obtaining specified in the connection header (110,65 g).

b) TRANS-4-(4-methylcyclohexyl)-4-oxobutanoic acid

To a mixture of magnesium (9,27 g) and tetrahydrofuran (5.0 ml) was added under nitrogen atmosphere 1-chloro-4-methylcyclohexane (1,00 g) obtained by the method of example 65 (a method of obtaining 6a), and then add 50 mg of iodine, and the mixture is stirred for 5 minutes was Added tetrahydrofuran (150 ml) and 1-chloro-4-methylcyclohexane (49,00 g) obtained by the method of example 65 (a method of obtaining 6a)), added dropwise over 30 minutes while boiling under reflux. The mixture is refluxed for 1 h, and the cooling gap is traditionale (330 ml) and to this mixture is added dropwise a mixture of (210,86 ml) obtained above in 5oC, and it is stirred for 30 minutes To the reaction mixture are added dropwise chloroethanol acid (50 ml) at 10oC, and precipitated precipitated salt is filtered off and the tetrahydrofuran is evaporated. The resulting residue is dissolved in toluene, washed with water. The toluene is evaporated, and the residue is dissolved in a mixed solution of 5 N. aqueous sodium hydroxide solution (100 ml) and ethanol (50 ml). The mixture is stirred for 3oC for 12 hours the Mixture is neutralized with concentrated chloroethanol acid at 0oC, and precipitated precipitated crystals are collected and purified by recrystallization from ethanol and water to obtain specified in the connection header (36,68 g).

Example 66 1,2,3,4-tetrahydro-1-oxo-2-naphthalenyloxy acid

a) 2-bromo-3,4-dihydro-1(2H)-naphthalene

To a solution of 3,4-dihydro-1(2H)-naphtalene (1,99 ml) in acetic acid (30 ml) was added dropwise bromine (0,85 ml) at room temperature, and the mixture is stirred for 1 h To the reaction mixture was added 5% aqueous sodium hypochlorite solution under ice cooling, and the mixture is stirred. The mixture is then extracted with diethyl ether. The organic layer was washed with a feast upon the center with obtaining specified in the connection header (3,24 g).

b) 1,2,3,4-tetrahydro-1-oxo-2-naphthalenyloxy acid

By way of example 58 is specified in the header connection receive on the basis of 2-bromo-3,4-dihydro-1 (2H)-naphtalene obtained by the method of example 66a).

Example 67 Dimethyl-2-(3-cyclohexyl-2-oxopropyl) propanedioic

By way of example 58a) specified in the header connection receive on the basis of 1-bromo-3-cyclohexyl-2-propanone obtained by the method of example 9b).

Example 68 2-(2-oxo-2-phenylethyl)proportionaly acid

By way of example 58a) and (b) specified in the header connection receive, based on 2-bromoacetophenone.

Example 69 2-[2-(4-biphenylyl)-2-oxoethyl]proportionaly acid

By way of example 58a) and (b) specified in the header connection receive on the basis of 2-bromo-4'-phenylacetophenone.

Example 70 2-[2-(4-biphenylyl)-2-oxoethyl]-2-methylpropionate acid

By way of example 58a) and (b) specified in the header connection receive on the basis of 2-bromo-4'- phenylacetophenone and diethylmalonate.

Example 71 3-methyl-4-oxo-4-phenylbutanoate acid

a) 2-bromopropiophenone

By way of example 5b) specified in the header connection receive on the basis of propiophenone.

b) dimethyl-2-(2-oxo-2-phenyl-1-meth is piovesana, obtained by the method of example 71a).

C) methyl-3-methyl-4-oxo-4-phenylbutanoate

To a solution of dimethyl-2-(2-oxo-2-phenyl-1-methylethyl)-propanoate (2.64 g) obtained by the method of example 71b) in dimethyl sulfoxide (60 ml) was added distilled water (0,36 ml) and lithium chloride (0,424 g) at room temperature, and the mixture was stirred at 170oC for 2.5 hours To the reaction mixture was added distilled water, and the mixture is stirred and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (1,33 g).

d) 3-methyl-4-oxo-4-phenylbutanoate acid

By way of example 49d) specified in the header connection receive, based on methyl-3-methyl-4-oxo-4-phenylbutanoate obtained by the method of example 71c).

Example 72 2-methyl-4-oxo-4-phenylbutanoate acid

a) 2-methyl-2-(2-oxo-2-phenylethyl)proportionaly acid

By way of example 70 is specified in the header connection receive, based on 2-bromoacetophenone

b) 2-methyl-4-oxo-4-phenylbutanoate acid

By way of example 58C trainers) specified in the header joint is S="ptx2">

Example 73 4-oxo-2,4-diphenylbutane acid

a) 4-oxo-2,4-diphenylbutane

To a solution of TRANS-chalcone (20,8 g) in ethanol (350 ml) was added acetic acid (5.7 ml) at 35oC and added dropwise a solution of potassium cyanide (13,0 g) in water (30 ml) and the mixture stirred at 40oC for 4 h and Then the mixture is left to stand at 0oC for 12 h, and precipitated precipitated crystals are collected by filtration to obtain specified in the connection header (21,0 g).

and) 4-oxo-2,4-diphenylbutane acid

By way of example 51c) specified in the header connection receive on the basis of 4-oxo-2,4-diphenylbutadiyne obtained by the method of example 73a).

Example 74 4-(2-naphthyl)-4-oxobutanoic acid

a) 4-(2-naphthyl)-4-oxobutanoic

By way of example 51a) specified in the header connection receive, based on 2-naphthaldehyde.

b) 4-(2-naphthyl)-4-oxobutanoic acid

By way of example 51c) specified in the header connection receive on the basis of 4-(2-naphthyl)-4-oxobutanamide obtained by the method of example 74a).

Example 75 4-(indan-2-yl)-4-oxobutanoic acid

a) indan-2-carboxylic acid

To a solution of 2,2-dimethyl-(Spiro[1,3]dioxane-5,2'-indan)-4,6-dione (MINICOM within 4 hours To the reaction mixture add 1 N. aqueous sodium hydroxide solution, it is washed with ethyl acetate, and the aqueous layer was acidified with concentrated chloroethanol acid. The mixture is extracted with ethyl acetate, dried over magnesium sulfate and concentrated. The residue is heated at 170oC for 1 h with obtaining specified in the connection header (2,53 g).

b) 1-(indan-2-yl)-2-propen-1-he

To a solution of indan-2-carboxylic acid (1,624 g) obtained by the method of example 75a), in dichloromethane (20 ml) was added oxalicacid (2.0 ml) at 0oC. was Added dimethylformamide (0.05 ml) and the mixture is stirred for 2 hours, the Reaction mixture was concentrated and the resulting residue is dissolved in chloroform (10 ml), to which are added vinyltrimethylsilane (3.2 ml) and TRANS-benzyl(chloro)bis(triphenylphosphine)palladium(II) (0,070 g) and the mixture refluxed for 1 h To the reaction mixture was added saturated aqueous solution of sodium fluoride (10 ml), and the mixture is stirred at room temperature for 12 hours the Mixture is filtered through a layer of Celite, and the filtrate is extracted with ethyl acetate and dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the header that is received by way of example 75b), in ethanol (24 ml) was added acetic acid (0,40 ml) and added dropwise a solution of sodium cyanide (0,667 g) in water (2.6 ml) at 40oC, then all is stirred for 30 minutes, the Ethanol is evaporated from the reaction mixture, and add distilled water. After stirring the reaction mixture was extracted with ethyl acetate. The organic layer was washed with distilled water and saturated saline solution, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the title compound (1.04 g).

d) 4,4-Ethylenedioxy-4-(indan-2-yl)Botanical

To a solution of 4-(indan-2-yl)-4-oxobutanamide (1,00 g) obtained by the method of example 75c), in benzene (5.0 ml) was added ethylene glycol (0.6 ml) and the monohydrate p-toluensulfonate acid (0,101 g) and the mixture is boiled trapped in a Dean-stark within 12 hours To the reaction mixture was added benzene, and the mixture is washed with saturated sodium hydrogen carbonate solution and saturated saline solution, dried over magnesium sulfate, concentrate and purify by chromatography on a column of silica gel with obtaining specified in the connection header (1,185 g).

e) 4-(indan-2-yl)-4-oxobutanoic acid

To a solution of 2 N. an aqueous solution of sodium hydroxide (4.5 ml) and the mixture is refluxed for 3 hours, the Reaction mixture was acidified with 1 N. chloroethanol acid and extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate and concentrated. The resulting residue is dissolved in tetrahydrofuran (4 ml), to the solution was added concentrated chloroethanol acid (1 ml), and the mixture is stirred at room temperature for 12 hours, the Tetrahydrofuran is evaporated and the residue extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate and concentrated to obtain specified in the connection header (0,597 g).

Example 76 (2R*, 3S*)-2,3-dimethyl-4-oxo-4-phenylbutanoate acid

a) 2-phenyl-2-(trimethylsilyloxy)echanical

To a solution of benzaldehyde (10,2 ml) in dichloromethane (200 ml) was added trimethylsilylacetamide (13.4 ml), and triethylamine (1,40 ml) was added dropwise at 0oC. the Reaction mixture was concentrated and the resulting residue is distilled under reduced pressure (because1,1Torr, 88-97oC) obtaining specified in the connection header (19,193 g).

b) methyl-2,3-dimethyl-4-cyano-4-phenyl-4-(trimethylsilyloxy)-butanoateC in argon atmosphere. Added dropwise a solution of 2-phenyl-2-(trimethylsilyloxy)eternitie (2,059 g) obtained by the method of example 76a) in tetrahydrofuran (6.0 ml), and the mixture is stirred for 30 minutes Add metaltype, and the mixture is stirred for 30 minutes To the reaction mixture was added distilled water, and the mixture is heated to room temperature. To the mixture are added 1 N. chloroethanol acid, and extracted with ethyl ether. The organic layer was washed with saturated saline, dried over magnesium sulfate and concentrated to obtain specified in the connection header (3,148 g).

C) methyl-(2R*, 3S*)-2,3-dimethyl-4-oxo-4-phenylbutanoate

To a solution of methyl-2,3-dimethyl - 4-cyano-4-phenyl-(trimethylsilyloxy)butanoate (is 3.08 g) obtained by the method of example 76b), in tetrahydrofuran (10 ml) was added a solution (1 M, 10 ml) tetrabutylammonium in tetrahydrofuran, and the mixture is stirred for 30 minutes To the reaction mixture was added distilled water and the mixture extracted with diethyl ether, washed with saturated saline, dried over magnesium sulfate and concentrated. The resulting residue is dissolved in methanol (10 ml) to which was added matokie sodium (0,227 g), and the solution of ammonium chloride, and the mixture extracted with diethyl ether. The organic layer was washed with distilled water and saturated saline solution, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (0,412 g).

d) (2R*, 3S*)-2,3-dimethyl-4-oxo-4-phenylbutanoate acid

To a solution of methyl(2R*, 3S*)-2,3-dimethyl-4-oxo-4 - phenylbutanoate (0,218 g) obtained by the method of example 76c), in methanol (2.0 ml) was added 2 N. aqueous sodium hydroxide solution at 0oC, and the mixture is stirred for 1 h To the reaction mixture was added 1 n aqueous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer was washed with distilled water and saturated saline solution, dried over magnesium sulfate and concentrated to obtain specified in the connection header (0,197 g).

Example 77 (1R*, 2S*)-2-benzoylisothiocyanate acid

To a solution of CIS-cyclohexanedicarboxylic anhydride (1,543 g) in diethyl ether (30 ml) was added dropwise in an argon atmosphere at 0oC solution (1.0 M, 12.0 ml) phenylmagnesium in tetrahydrofuran, and the mixture is stirred for 1.5 hours To the reaction is m, the organic layer was washed with distilled water and saturated saline solution, dried over magnesium sulfate and concentrated to obtain specified in the connection header (2,368 g).

Example 78 (1R*, 2S*)-2-benzoylisothiocyanate acid

a) 1-bromocyclopentane

By way of example 4a) specified in the header connection receive on the basis of cyclopentadecanone.

b) 1-cyclopentylphenol

A solution of 1-bromocyclopentane (12,66 g) obtained by the method of example 78a), in pyridine (20 ml) is refluxed for 12 hours, the Reaction mixture was poured into 1 N. chloroethanol acid under ice cooling, and the mixture is extracted with diethyl ether. The organic layer is washed successively with distilled water, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (4,70 d).

C) (1R*THAT 2R*)-2-benzoylisothiocyanate acid

By way of example 73 is specified in the header connection receive, based on 1 cyclopentadienide is xelat

To a solution of (1R*THAT 2R*)-2-benzoylisothiocyanate acid (0,654 g) obtained by the method of example 78c), in dichloromethane (10 ml) was added concentrated chloroethanol acid (0.1 ml), and then isobutan (3.0 ml) at -20oC, and the mixture is heated to room temperature and stirred for 12 hours To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with diethyl ether, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (0,425 g).

(e) tert-butyl (1R*, 2S*)-2-benzoylacetonitrile

Solution (1.5 M, 1,40 ml) sitedisability in tetrahydrofuran, diluted with tetrahydrofuran (3.0 ml) in an argon atmosphere at - 78oC and added dropwise a solution of tert-butyl (1R*THAT 2R*)-2-benzoylisothiocyanate (0,277 g) obtained by the method of example 78d) in tetrahydrofuran (3.0 ml). The mixture is stirred for 2 hours To the reaction mixture was added saturated aqueous solution of ammonium chloride, and the mixture is heated to room temperature, and added 1 n citric acid solution. The mixture is extracted with diethyl ether, and the Ute by chromatography on a column of silica gel with obtaining specified in the connection header (0,122 g).

f) (1R*, 2S*)-2-benzoylisothiocyanate acid

Tert-butyl (1R*, 2S*)-2-benzoylacetonitrile (94 mg) obtained by the method of example 78e), dissolved in formic acid (2 ml), and the mixture is stirred at room temperature for 1.5 hours. Formic acid is evaporated, and add distilled water. The mixture is stirred and extracted with ethyl acetate. The obtained extract is dried over magnesium sulfate and concentrated to obtain specified in the title compound (74 mg).

Example 79 3-(4-phenylbenzyl)intentionaly acid

a) benzylidenemalonate

To a solution of dibenzylamine (5.0 ml) in benzyl alcohol (10 ml) was added dropwise a solution of potassium hydroxide (1,164 g) in benzyl alcohol (10 ml) at room temperature, and the mixture is stirred for 3 hours To the reaction mixture was added diethyl ether, the aqueous layer washed with diethyl ether, acidified with his concentrated chloroethanol acid, and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate and concentrated to obtain specified in the connection header (3,296 g).

b) benzyl(4-phenylbenzyl) acetate
C. Then added dimethylformamide (0.1 ml, the mixture is stirred at room temperature for 1 h, and then stirred at 50oC for 4 h, the Reaction mixture was concentrated to obtain 4-phenylbenzoate (20,11 g). Then to the solution benzylidenemalonate (1.98 g) obtained by the method of example 79a) in tetrahydrofuran (25 ml) was added dropwise a solution of (1,69 M, 12 ml) n-utility in hexane in an argon atmosphere at -78oC. the Mixture is stirred for 30 min, then added dropwise a solution of 4-phenylbenzothiazole (at 2,178 g) in tetrahydrofuran (25 ml) and the mixture stirred for 30 minutes To the reaction mixture at room temperature is added dropwise 1 N. chloroethanol acid, and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (1,285 g).

C) diethyl-3-benzyloxycarbonyl-3-(4-phenylbenzyl) pentanedioic

To a solution of benzyl(4-phenylbenzyl)acetate (0,229 g) obtained by the method of example 79b), in dimethylformamide (3.0 ml) was added sodium hydride (60% oil dispersion, 30 mg) at room temperatare mixture of sodium hydride (60% oil dispersion, 30 mg). Add ethylbromoacetate (150 μl) and the mixture is stirred for 12 hours To the reaction mixture was added distilled water, and the mixture is stirred and extracted with ethyl acetate. The organic layer was washed with distilled water and saturated saline solution, concentrate, and purify by chromatography on a column of silica gel with obtaining specified in the connection header (to 0.263 g).

d) diethyl-3-(4-phenylbenzyl) pentanedioic

To a solution of diethyl-3-benzyloxycarbonyl-3-(4-phenylbenzyl)pentanoate (to 0.263 g) obtained by the method of example 79 ° C), ethyl acetate (6.0 ml) was added 10% palladium on coal (0,301 g) and the mixture is stirred at room temperature in a hydrogen atmosphere for 2 hours Palladium on coal is filtered through a layer of Celite, and the filtrate is concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (0,093 g).

e) 3-(4-phenylbenzyl)pentane acid

To a solution of diethyl-3-(4-phenylbenzyl)pentanoate (93 mg) obtained by the method of example 79d), in methanol (2.5 ml) was added 1 M aqueous solution of lithium hydroxide (0.75 ml) at room temperature, and the mixture is stirred for 12 hours, the Reaction mixture was diluted with destroy washed with distilled water and saturated saline solution, dried over magnesium sulfate and concentrated to obtain specified in the title compound (70 mg).

Example 80 2-acetaminophenol

To a solution of 2-acetaminophenaffeineihydrocodeine (2.0 g) in pyridine (20 ml) was added dropwise acetylchloride (0,829 ml) and the mixture refluxed for 20 minutes, the Reaction mixture was poured into ice water and the mixture extracted with ethyl acetate. The organic layer is washed successively with 50% aqueous solution of potassium hydrosulfate, saturated aqueous sodium hydrogen carbonate and saturated saline solution, dried over sodium sulfate and purified by chromatography on a column of silica gel with obtaining specified in the connection header (1,180 g).

Example 81 ()-4-bersoldier-2(3H)-furanone

a) ()-2-trimethylsilyltrifluoroacetamide

To a solution of benzaldehyde (10,2 ml) and trimethylsilylmethyl (13.4 ml) in methylene chloride (200 ml) was added drop wise addition of triethylamine (140 ml) and the mixture was stirred at room temperature for 3 hours the Solvent is evaporated, and the residue is distilled (because1,1Torr, 88-97oC) obtaining specified in the title compound (19.2 g).

b) ()-4-bersoldier-2(3H)-furanone

To a solution of litigaiton is a solution of ()-2 - trimethylsilyltrifluoroacetamide (1,02 g), obtained by the method of example 81a) in tetrahydrofuran (5 ml), and the mixture was stirred at -72oC for 30 minutes Then added dropwise 2(5H)-furanone (0,36 ml) and the mixture stirred for 1 h, the Reaction mixture was quenched with saturated aqueous ammonium chloride, and the reaction mixture is heated to room temperature. It is extracted with ethyl acetate, the organic layer was washed with distilled water and saturated saline solution, dried over magnesium sulfate. The solvent is evaporated, and a solution of the residue and acetic acid (0,50 ml) in tetrahydrofuran (5 ml) was added dropwise 1.0 M solution of tetrabutylammonium in tetrahydrofuran (5.5 ml). The mixture is stirred at room temperature for 30 minutes To the reaction mixture was added distilled water, and the mixture is extracted with ethyl acetate. The organic layer was washed with distilled water and saturated saline, and dried over magnesium sulfate. The solution is evaporated and the residue purified by chromatography on a column of silica gel with obtaining specified in the title compound (0.68 g). Eluent hexane: ethyl acetate = 62:38.

Example 82 (a)-dihydro-4-(4'-vinylbenzyl)-2(3H)- furanone

a) ()-2-trimethylsilyloxy-4'-biphenylacetic

P is()-dihydro-4-(4'-vinylbenzyl)-2(3H)-furanone

By way of example 81b) specified in the header connection receive on the basis of ()-2-trimethylsilyloxy-4'- biphenylacetic obtained by the method of example 82a).

Example 83 ()-dihydro-4-methyl-4-(4'-vinylbenzyl)- 2(3H)-furanone

By way of example 81b) specified in the header connection receive on the basis of ()-2-trimethylsilyloxy-4'- biphenylacetic obtained by the method of example 82a), and 4-methyl-2(5H)-furanone.

Example 84 ()-3-benzoyl-1-Cyclopentanone

By way of example 81b) specified in the header connection receive on the basis of ()-2-trimethylsilyltrifluoroacetamide obtained by the method of example 81a) and 2-cyclopenten-1-it.

Example 85 ()-3-benzoyl-3-methyl-1-Cyclopentanone

By way of example 81b) specified in the header connection receive on the basis of ()-2-trimethylsilyltrifluoroacetamide obtained by the method of example 81a) and 3-methyl-2-cyclopenten-1-it.

Example 86 ()-3-methyl-3-(4'-vinylbenzyl)-1-Cyclopentanone

By way of example 81b) specified in the header connection receive on the basis of ()-2-trimethylsilyloxy-4'- biphenylacetic obtained by the method of example 82a), and 3-methyl-2-cyclopenten-1-it.

Example 87 (a)-hydroxy-4-(4'-hydroxymethylbenzene)-2 (3H)-furanone

b)()-4'-tert-butyldimethylsilyloxy-2-trimethylsilyltrifluoroacetamide

To a solution of 4-hydroxymethylbenzene (32,8 g) obtained by the method of example 87a), and imidazole (of 40.9 g) in dimethylformamide (200 ml) is added tert-BUTYLCARBAMATE (43,6 g), and the mixture is stirred at room temperature overnight. The reaction mixture was poured into ice water and the mixture extracted with ether. The organic layer is washed with water and saturated saline and dried over potassium carbonate. The solvent is evaporated, and the residue is treated according to the method of example 81a) to obtain akasol)-2(3H) -furanone

By way of example 81b) specified in the header connection receive on the basis of (a)-4'-tert-butyldimethylsilyloxy-2 - trimethylsilyltrifluoroacetamide obtained by the method of example 87b).

Example 88 ()-3-(4'-hydroxymethylbenzene)-3-methyl-1 - Cyclopentanone

By way of example 81b) specified in the header connection receive on the basis of (a)-4'-tert-butyldimethylsilyloxy-2 - trimethylsilyltrifluoroacetamide obtained by the method of example 87b) and 3-methyl-2-cyclopenten-1-it.

Example 89 ()-5-bersoldier-2(3H)-furanone

a) ethyl ()-4-benzoyl-4-hydroxybutyrate

By way of example 81b) specified in the header connection receive on the basis of ()-2 - trimethylsilyltrifluoroacetamide obtained by the method of example 81a) and ethyl-(semi)alteredstate.

b) (+)-5-bersoldier-2(3H)-furanone

()-4-benzoyl-4-hydroxybutiric acid (176 ml) is boiled in acetic acid (2 ml) for 2 h, and the solvent is evaporated to obtain specified in the connection header.

Example 90 ()-dihydro-5-(4'-vinylbenzyl)-2(3H)-furanone

By way of example 89, specified in the header connection receive on the basis of ()-2-trimethylsilyloxy-4'-biphenylacetic obtained by the method of example 82a) is eventail)butyrate

By way of example 89a) specified in the header connection receive on the basis of (a)-4'-tert-butyldimethylsilyloxy-2 - trimethylsilyltrifluoroacetamide obtained by the method of example 87b).

b) ()-dihydro-5-(4'-hydroxymethylbenzene)-2(3H)-furanone

A solution of ethyl ()-4-hydroxy-4-(4'-hydroxymethylbenzene)- butyrate (0,248 g) obtained by the method of example 91a), and hydrate p-toluensulfonate acid (19 mg) in benzene (5 ml) is refluxed for 3 hours, the Reaction mixture was washed with water and saturated saline, and dried over magnesium sulfate. The solvent is evaporated to obtain specified in the connection header.

Example 92 ()-dihydro-5-(4'- hydroxymethylbenzene)-5-methyl-2(3H)-furanone

By way of example 91 specified in the header connection receive on the basis of (a)-4'-tert-butyldimethylsilyloxy-2 - trimethylsilyltrifluoroacetamide obtained by the method of example 87b), and tillemont.

Example 93 (-)-dihydro-5-methyl-5-(4'-vinylbenzyl) -2(3H)-furanone

a) ()-4-hydroxy-4-(4'-vinylbenzyl) valeric acid

Ethyl ()-4-hydroxy-(4'-vinylbenzyl)valerate, receive by way of example 81b), on the basis of ()-2 - trimethylsilyloxy-4'-biphenylacetic obtained by the mixture is stirred at room temperature overnight. The methanol is evaporated, the mixture was acidified with 10% aqueous citric acid solution. The mixture is extracted with ethyl acetate, and dried over magnesium sulfate. The solvent is evaporated to obtain specified in the connection header.

b) (-)-4-hydroxy-(4'-vinylbenzyl)valeric acid

A mixture of ()-4-hydroxy-4-(4'-vinylbenzyl)valerianic acid (0,597 g) obtained by the method of example 93a) and (S)-(-)-1-phenethylamine (0,260 ml), recrystallized from a mixed solvent of methanol (10 ml) and diisopropyl ether (10 ml). The crystals are dissolved in 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and dried over magnesium sulfate. The solvent is evaporated to obtain specified in the connection header.

C) (-)-dihydro-5-methyl-5-(4'-vinylbenzyl)-2(3H)-furanone

(-)-4-hydroxy-4-(4'-vinylbenzyl) valeric acid (77 mg) obtained by the method of example 93b), refluxed in acetic acid (1 ml) for 1.5 hours the Solvent is evaporated to obtain specified in the connection header.

Example 94 (+)-dihydro-5-methyl-5-(4'-vinylbenzyl)-2(3H)-furanone

By way of example 93b) specified in the header of the connection get out the amine.

Example 95 (R)-(+)-5-benzoyl-2-pyrrolidinone

a) (R)-N-carbobenzoxy-N-methoxy-N-methylpropanamide

To a solution of (R)-(+)-N-carbaminohaemoglobin acid (10.0 g) and N, O-dimethylhydroxylamine (3,71 g) in methylene chloride (50 ml) is added triethylamine (to 4.23 g) and 1-hydroxybenzotriazole (5,65 g) under cooling with ice. Then added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (of 7.65 g). The reaction mixture is heated to room temperature and stirred for 2.5 hours, the Reaction mixture was diluted with methylene chloride (100 ml), washed with saturated aqueous sodium bicarbonate, 10% aqueous citric acid solution and saturated saline solution, dried over sodium sulfate and the solvent is evaporated under reduced pressure to obtain specified in the header of the compound (10.0 g).

b) (R)-N-methoxy-N-methylpropanamide

(R)-N-carbobenzoxy-N-methoxy-N-methylpropanamide 5,44 g) obtained by the method of example 95a), dissolved in methanol (100 ml), and added 5% palladium on coal (0.52 g). The mixture is stirred in hydrogen atmosphere at room temperature for 1 h, the Reaction mixture was filtered through a layer of Celite, and the solvent is evaporated to obtain specified in the header Conn is the third by way of example 95b), dissolved in dry tetrahydrofuran (50 ml) and added dropwise 1.8 M solution finelite in cyclohexane (of 9.30 ml) at -78oC in argon atmosphere, the mixture is stirred for 1 h, gradually warming to -30oC. the Reaction is quenched with an aqueous solution of ammonium chloride and an aqueous solution of citric acid. The mixture is extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The solvent is evaporated and the residue purified by chromatography on a column of silica gel (chloroform: methanol = 97:3) to obtain specified in the connection header.

Example 96 (S)-(-)-5-benzoyl-pyrrolidine

By way of example 95 specified in the header connection receive on the basis of (S)-(-)-N-carbobenzoxy acid.

Example 97 ()-5-benzene-2-pyrrolidinone

By way of example 95 specified in the header connection receive on the basis of ()-N-carbaminohaemoglobin acid.

Example 98 (S)-(-)-5-(4'-vinylbenzyl)-2-pyrrolidinone

To a solution of 4-bromophenyl (2.55 g) in dry tetrahydrofuran (30 ml) was added dropwise at -78oC in argon atmosphere, 1.6 M solution of n-utility in hexane (6,50 ml). The mixture is stirred for 10 min, and the reaction mixture when the UP>C in argon atmosphere. The mixture is heated to -40oC, and stirred for 1 h, and then added dropwise to the ammonium chloride and an aqueous solution of citric acid. The mixture is extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over sodium sulfate. The solvent is evaporated, and the residue is recrystallized from ethanol and ethyl acetate to obtain specified in the connection header (0,465 g).

Example 99 (S)-(-)5-(4'-hydroxymethylbenzene)-2-pyrrolidinone

a) 1-bromo-4-tert-butyldimethylsilyloxy

To a solution of 4-bromobenzylamine alcohol (65,6 g), imidazole (55,0 g) in N, N-dimethylformamide (300 ml) was added tert-butyl - dimethylsilane (58,1 g), and the mixture is stirred at room temperature overnight. The reaction mixture was poured into ice water and the mixture extracted with ether. The organic layer is washed with water and saturated saline and dried over potassium carbonate. The solvent is evaporated, and the residue is distilled (because1,5Torr, 129-133oC) obtaining specified in the connection header (101 g).

b) (S)-N-carbobenzoxy-N-methoxy-N-methylpropanamide

To a solution of (S)-(-)-N-carbaminohaemoglobin acid (100 g), N, O-dimethylhydrazine) under ice cooling, and added 1-(3-dimethylaminopropyl)-3-ethoxycarbonylmethylene (76,5 g). The mixture is heated to room temperature and stirred over night. The reaction mixture was washed with saturated aqueous sodium bicarbonate, 5% aqueous solution of potassium hydrosulfate and saturated saline, and dried over sodium sulfate. The solvent is evaporated to obtain specified in the connection header (108 g).

(C) (3)-N-methoxy-N-methylpropanamide

(S)-N-carbobenzoxy-N-methoxy-N-methylpropanamide (108 g) obtained by the method of example 99b), dissolved in methanol (800 ml), and added 5% palladium on coal (10.0 g). The mixture is stirred in hydrogen atmosphere at room temperature for 6.5 hours, the Reaction mixture was filtered through a layer of Celite, and the solvent is evaporated to obtain specified in the connection header (of 58.9 g).

d) (S)-5-[4'-(tert-butyldimethylsilyloxy)benzoyl]-2 - pyrrolidinone

To a solution of 1-bromo-4-tert-butyldimethylchlorosilane (73,5 g) obtained by the method of example 99a), in dry tetrahydrofuran (610 ml) was added dropwise 1.6 M solution of n-utility in hexane (141 ml) at a temperature of -78oC in argon atmosphere. The mixture is stirred for 1 h and the reaction mixtures is -78oC in argon atmosphere. The mixture is heated to -40oC, and stirred for 1 h, then added an aqueous solution of ammonium chloride. The mixture is extracted with ethyl acetate. The organic layer is washed with 10% aqueous citric acid solution and saturated saline, and dried over sodium sulfate. The solvent is evaporated and the residue purified by chromatography on a column of silica gel (chloroform: methanol = 99:1) to obtain specified in the connection header.

(e) (S)-5-(4'-hydroxymethylbenzene)-2-pyrrolidinone

A mixed solution(3)-5-[4'-(tert-butyldimethylsilyloxy)benzoyl]-2-pyrrolidinone (0,406 g) obtained by the method of example 99d), tetrahydrofuran (1 ml) distilled water (1 ml) and acetic acid (3 ml) was stirred at room temperature overnight. The solvent is evaporated, and the residue was washed with a mixed solvent of hexane/ether (4 ml/1 ml) to obtain specified in the connection header (0,240 g).

Example 100 ()-4-benzoyl-2-pyrrolidinone

a) methyl ()-2-oxo-4-pyrrolidinecarboxylic

Dimethylethyl (25,0 g) is stirred 6,2% solution of ammonia in methanol (85 ml) at room temperature over night. The solvent is evaporated and the residue purified by chromatog the LASS="ptx2">

b) methyl ()-N-carbobenzoxy-2-oxo-4-pyrrolidinecarboxylic

A solution of methyl ()-2-oxo-4-pyrrolidinecarboxylic (21,9 g) obtained by the method of example 100a), in dry tetrahydrofuran (150 ml) was added dropwise to a suspension of sodium hydride (3.6 g) in dry tetrahydrofuran (150 ml) at 0oC. was Added dropwise a solution of benzylchloride (23,8 ml) in dry tetrahydrofuran (170 ml) and the mixture warmed to room temperature. The mixture is stirred for 3.5 hours the Reaction mixture is poured into ice water and the mixture extracted with ethyl acetate. The organic layer was washed with distilled water and saturated saline and dried over sodium sulfate. The solvent is evaporated and the residue purified by chromatography on a column of silica gel (hexane: ethyl acetate 1: 1) to obtain specified in the connection header (11.5g).

C) ()-N-carbobenzoxy-2-oxo-4-pyrrolidinecarbonyl acid

To a solution of methyl ()-N-carbobenzoxy-2-oxo-4-pyrrolidinecarboxylic (10.3 g) obtained by the method of example 100b) in methanol (350 ml) was added 0.1 G. of aqueous solution of potassium carbonate (556 ml), and the mixture is stirred at room temperature for 3 hours the Reaction mixture is washed with ether, acidified with 1 N. chloroethanol acid is sodium. The solvent is evaporated to obtain specified in the connection header (6,48 g).

d) ()-N-methoxy-N-methyl-2-oxo-4-pyrrolidinecarboxamido

By way of example 95a) and (b) specified in the header connection receive on the basis of ()-N-carbobenzoxy-2-oxo-4-pyrrolidinecarbonyl acid obtained by the method of example 100c).

e) ()-4-benzoyl-2-pyrrolidinone

By way of example 95c) specified in the header connection receive on the basis of ()-N-methoxy-N-methyl-2-oxo-4 - pyrrolidinecarboxamido obtained by the method of example 100d).

Example 101 ()-4-(4'-hydroxymethylbenzene) -2-pyrrolidinone

By way of example 99d) and (e) specified in the header connection receive on the basis of ()-N-methoxy-N-methyl-2-oxo-4 - pyrrolidinecarboxamido obtained by the method of example 100d).

Example 102 TRANS-4-(4-ethylcyclohexyl)-4-oxobutanoic acid

a) 4-ethylcyclohexylamine acid

To a solution of 4-ethylbenzoyl acid (10 g) in acetic acid (150 ml) was added platinum oxide (IV) (1.0 g), and the mixture is stirred at room temperature under nitrogen atmosphere (3 ATM.) within 3 hours the Platinum catalyst is filtered through a layer of Celite, and the filtrate is concentrated to obtain specified in the connection header (10,0 what I 2) specified in the header of the connection get on the basis of 4-ethylcyclohexylamine acid obtained by the method of example 102a).

Example 103 TRANS-4-(4-isopropylcyclohexane)-4-oxobutanoic acid

By way of example 102 specified in the header connection receive on the basis of Kumanovo acid.

Example 104 TRANS-4-(4-tert-butylcyclohexyl)-4-oxobutanoic acid

By way of example 65 (a method of obtaining 2) specified in the header connection receive, from 4-tert - butylcyclohexanecarboxylic acid.

Example 105 TRANS-4-(4-phenylcyclohexyl)-4-oxobutanoic acid

By way of example 65 (a method of obtaining 2) specified in the header connection receive on the basis of TRANS-4-phenylcyclohexanecarboxylic acid obtained by the method of example 17a).

Example 106 CIS-4-(4-methylcyclohexyl)-4-oxobutanoic acid

a) tert-butyl CIS-4-(4-methylcyclohexyl)-4-oxobutanoate

To a solution of the mixture (2,027 g) obtained by the method of example 65 (a method of obtaining 2d), from TRANS-4-(4-methylcyclohexyl)-4-oxobutanoic acid and CIS-4-(4-methylcyclohexyl)-4-oxobutanoic acid in methylene chloride (20 ml) was added concentrated sulfuric acid (0.2 ml), and isobutane (5.0 ml) was added at -20oC. the Mixture is heated to room temp is sodium, and the mixture is extracted with ethyl acetate, dried over magnesium sulfate, concentrated and purified by HPLC to obtain specified in the connection header (0,500 g).

b) CIS-4-(4-methylcyclohexyl)-4-oxobutanoic acid

A solution of tert-butyl CIS-4-(4-methylcyclohexyl)-4-oxobutanoate (0,500 g) obtained by the method of example 106a), formic acid (5.0 ml) was stirred at room temperature for 2 h, and formic acid is evaporated under reduced pressure. Add distilled water and the mixture extracted with ethyl acetate, dried over magnesium sulfate and concentrated to obtain specified in the connection header (0,355 g).

Example 107 4-(3-methylcyclohexyl)-4-oxobutanoic acid

By way of example 65 (a method of obtaining 2) specified in the header connection receive, based on 3-methyl-1-cyclohexanecarbonyl acid.

Example 108 CIS-2- (TRANS-4-methylcyclohexylamine)- cyclohexanecarbonyl acid

a) TRANS-4-methylcyclohexanecarboxylic

To a solution of TRANS-4-methyl-1 - cyclohexanecarboxylic acid (7,12 g) in methylene chloride (50 ml) was added dropwise oxalicacid (5.5 ml) and dimethylformamide (0.05 ml) at room temperature, and the mixture is stirred for e connection (7,24 g).

b) Tert-butyl TRANS-4-(4-methylcyclohexyl)-4-oxo-2-butenoate

To a suspension of copper iodide (I) (38 mg) and bis(triphenylphosphine)palladium (II) chloride (38 mg) in benzene (20 ml) was added tert-butylbromide (3,30 ml) and triethylamine (3,10 ml). Then add dropwise a solution of TRANS-4 - methylcyclohexanecarboxylic (3.2 g) obtained by the method of example 108a), in benzene (20 ml) at room temperature, and the mixture is stirred for 1 h, the Reaction mixture is cooled with ice, and add distilled water. The mixture is extracted with hexane, washed with distilled water and saturated saline solution, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (a 3.87 g).

C) tert-butyl 2- (TRANS-4-methylcyclohexylamine)-1,4-cyclohexadiene-1-carboxylate.

To a solution of tert-butyl TRANS-4-(4-methylcyclohexyl)-4 - oxo-2-butenoate (3,86 g) obtained by the method of example 108b) in toluene (20 ml) was added 2, g-di-tert-butyl-4-METHYLPHENOL (0.05 g), and 1,3-butadiene (1.0 g) is bubbled into the reaction mixture. It is stirred at 60oC for 12 h under heating, 1,3-butadiene (1.0 g) again bubbled, and the mixture was stirred at 80oC each with obtaining specified in the connection header (4,34 g).

(d) tert-butyl CIS-2-(TRANS-4-methylcyclohexylamine)cyclohexanecarboxylate

To a solution of tert-butyl 2-(TRANS-4-methylcyclohexylamine)-1,4-cyclohexadiene-1-carboxylate (4,34 g) obtained by the method of example 108c), in ethanol (14 ml) was added 5% palladium on coal (0,434 g), and the mixture is stirred in hydrogen atmosphere (1 ATM.) during the 8 o'clock Palladium on coal sucked layer Celite, and the filtrate is concentrated and purified by chromatography on a column of silica gel to obtain tert-butyl-2-[1-hydroxy-1-(TRANS-4-methylcyclohexyl) methyl]benzoate (1.26 g) and are specified in the connection header (2,42 g).

e) CIS-2-(TRANS-4-methylcyclohexylamine) cyclohexanecarbonyl acid

A solution of tert-butyl CIS-2- (TRANS-4-methylcyclohexylamine)cyclohexanecarboxylate (0,623 g) obtained by the method of example 108d), formic acid (5.0 ml) was stirred at room temperature for 4 h, the Reaction mixture was concentrated and the residue is dissolved in diethyl ether. The mixture is washed with distilled water, dried over magnesium sulfate, concentrated and purified by recrystallization from diethyl ether and hexane to obtain specified in the connection header (0,224 g).

Example 109 TRANS-2- (logicalchannel) -cyclohexanecarboxylate

To a solution of tert-butyl CIS-2-(TRANS-4-methylcyclohexylamine) cyclohexanecarboxylate (0,626 g) obtained in

the method of example 108d) in tert-butanol (10 ml) was added tert-piperonyl potassium (35 mg) at room temperature, and the mixture is stirred for 12 hours To the reaction mixture was added 10% aqueous citric acid solution, and tert-butanol is evaporated under reduced pressure. The residue is extracted with diethyl ether, washed with water, saturated aqueous sodium bicarbonate, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (0,526 g).

b) TRANS-2-(TRANS-4-methylcyclohexylamine)cyclohexanecarbonyl acid

A solution of tert-butyl TRANS-2- (TRANS-4-methylcyclohexylamine)cyclohexanecarboxylate (0,526 g) obtained by the method of example 109a), formic acid (5.0 ml) was stirred at room temperature for 2 hours, the Reaction mixture was concentrated and purified via recrystallization from ethyl acetate and hexane to obtain specified in the connection header (0,181 g).

Example 110 2-(TRANS-4-methylcyclohexylamine) benzoic acid

a) tert-butyl 2-(TRANS-4-benzoate (1.26 g), obtained by the method of example 108d), in dimethyl sulfoxide (5.0 ml) is added triethylamine (2,60 ml), and solution of complex sulphur amitritpylien (1,30 g) in dimethyl sulfoxide (5.0 ml), then stirred for 1 h, the Reaction mixture was poured into water and extracted with ethyl ether. The organic layer is washed successively with 5% aqueous citric acid solution, water, aqueous sodium hypochlorite solution and water, dried over magnesium sulfate, concentrated and purified by chromatography on a column of silica gel with obtaining specified in the connection header (0,735 g).

b) 2-(TRANS-4-methylcyclohexylamine)benzoic acid

A solution of tert-butyl 2-(TRANS-4-methylcyclohexylamine)benzoate (0,753 g) obtained by the method of example 110a), formic acid (5.0 ml) was stirred at room temperature for 2 hours, the Reaction mixture was concentrated and washed with hexane to obtain specified in the connection header (to 0.480 g).

Example 111 TRANS-2-(TRANS-4-methylcyclohexylamine) - cyclopropanecarbonyl acid

a) tert-butyl TRANS-2-(TRANS-4 - methylcyclohexylamine)cyclopropanecarboxylate

To a solution (1 M, 80 ml) diazomethane in diethyl ether are added dropwise dissolve, the mixture was stirred at room temperature for 12 hours, the Reaction mixture was concentrated, and the residue is dissolved in tert-butyl acrylate (30 ml). The solution is stirred at 120oC for 1 h and the reaction mixture is purified by chromatography on a column of silica gel with obtaining specified in the connection header (0,850 g).

b) TRANS-2-(TRANS-4-methylcyclohexylamine)cyclopropanecarbonyl acid

A solution of tert-butyl TRANS-2-(TRANS-4-methylcyclohexylamine) cyclopropanecarboxylate (0,538 g) obtained by the method of example 111a) in formic acid (10 ml) was stirred at room temperature for 1 h, the Reaction mixture was concentrated and purified by recrystallization from diethyl ether and hexane to obtain specified in the connection header (0,360 g).

Example 112 CIS-2-(TRANS-4-methylcyclohexylamine) - cyclopropanecarbonyl acid

To a solution of tert-butyl TRANS-2-(TRANS-4-methylcyclohexylamine)cyclopropanecarboxylate (0,238 g) obtained by the method of example 111a), in methanol (10 ml) was added sodium methoxide (0,103 g) and the mixture refluxed for 4 h, and the methanol is evaporated under reduced pressure. The residue is dissolved in tetrahydrofur shall receive 2 hours The reaction mixture was concentrated, and the residue is dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous layer was washed with diethyl ether, and acidified with chloroethanol acid. The mixture is extracted with diethyl ether, concentrated and purified by recrystallization from methanol and water to obtain specified in the connection header (0,107 g).

Example 113 TRANS-5-(4-methylcyclohexylamine)-dihydro-2 (3H)-furanone

a) 5-(1-methoxycarbonyl-4-methylcyclohexyl)-5 - oxopentanoic acid

Solution (1.5 M, 100 ml) sitedisability in cyclohexane are added dropwise to a solution of methyl-4-methylcyclohexanecarboxylic (22,34 g) obtained by the method of example 65 (a method of obtaining 5a)), in tetrahydrofuran (40 ml) at -5oC, and the mixture was stirred at 0oC for 30 minutes and Then thus obtained mixture is added dropwise to a solution of glutaric anhydride (16,32 g) in tetrahydrofuran (160 ml) and 5oC, and the mixture is stirred at room temperature for 2 hours To the reaction mixture was added 5% aqueous solution of potassium hydrosulfate, and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate and concentrated with I acid 5-(1-methoxycarbonyl-4-methylcyclohexyl)-5-oxopentanoic acid (28,75 g), obtained by the method of example 113a), dissolved in sodium hydroxide solution (14,83 g) in water (230 ml), and refluxed for 2 hours While cooling with ice add concentrated chloroethanol acid for acidification of the reaction mixture, and extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution, dried over sodium sulfate and concentrated. The residue is purified by recrystallization from ethyl acetate and hexane to obtain specified in the connection header (8,88 g).

C) 4-bromo-5-(TRANS-4-methylcyclohexyl)-5 - oxopentanoic acid

To a solution of TRANS-5-(4-methylcyclohexyl)-5-oxopentanoic acid (2.0 g) obtained by the method of example 113b) in acetic acid (30 ml) was added bromine (0,485 ml), and the mixture is stirred at room temperature for 1 h, the Reaction mixture was poured into water, and extracted with chloroform. The organic layer was washed with saturated saline solution, dried over sodium sulfate and concentrated to obtain specified in the title compound (2.70 g).

d) TRANS-5-(4-methylcyclohexylamine)-dihydro-2(3H)-furanone

To a solution of 4 - bromo-5-(TRANS-4-methylcyclohexyl)-5-oxopentanoic acid (2.70 g), obtained by komnatnoi temperature for 2 hours To the mixture was added water, and extracted with ethyl acetate. The extract was washed with saturated saline solution, dried over sodium sulfate and concentrated, the residue is recrystallized from ethyl acetate and hexane to obtain specified in the title compound (1.28 g).

The properties of the compounds presented in the examples presented in the following tables.

An example of a song

The present invention is illustrated by the example of obtaining the composition.

Example of getting songs

The compound of formula (I) - 3.0 mg

Crystalline cellulose - 67,0 mg.

Corn starch - 25.0 mg

Talc - 4.0 mg

Magnesium stearate 1.0 mg

These ingredients are thoroughly mixed, granularit, dried and tabletirujut in for tabletting machine to obtain tablets of 100 mg each tablet.

Experimental example

The present invention is illustrated by the following experimental example

Experimental example 1

Test for glucose tolerance using hungry rats

The male rat strain Wistar (Wistar, Japan Charles River) weighing about 250 g do not give food for 16 h from the previous day, and then explore. Intraperitoneally of whodathunkit determined using a hexokinase. The analyzed compound suspended in 0.5% carboxymethyl cellulose or corn oil and administered orally 30 min before the injection of glucose. As a control using carboxymethyl cellulose. The suppression of the increase of glucose in the blood is expressed as the degree of inhibition (%) in the group administered the investigational compound, in relation to increasing glucose for the control group after 30 min after administration of glucose, takes over 100%. The content of glucose in the blood after 120 min also presents the degree (%) change relative to control.

The results obtained are presented in tables 27-31.

As one of the examples in Fig. 1 presents the changes, time-dependent levels of glucose in the blood by oral administration of the compounds of the present invention (example 93) and control, and Fig. 2 shows time-dependent changes of glucose in the blood by oral administration of the compounds of the present invention and control. In Fig. 2 the dose of a compound of the present invention changes, and determine the content of glucose in the blood. Accordingly, in Fig. 1 the connection of the present invention significantly reduces the content gets the glucose levels after 120 min, if hyperglycemia is not observed. Accordingly, in Fig. 2, moreover, the connection of the present invention demonstrates a significant reduction of glucose levels in the blood when hyperglycemia after 30 min after administration of glucose, regardless of the dose, whereas it does not necessarily decrease the level of glucose in the blood after 120 min, if hyperglycemia is not observed. Connections to other examples are characterized by the same tendency.

Experimental example 2

Glucose tolerance with the introduction of tolbutamide in hungry rats

The male rats of the Wistar strain (Japan Charles River) weighing about 250 g do not give food for 16 h from the previous day, and then explore. Intraperitoneally injected with glucose (1 g/kg) and take blood from the tail vein (0.2 ml) after 30, 60 and 120 min after injection. After receiving whey determine the level of glucose using hexokinase. Tolbutamide suspended in 0.5% carboxymethyl cellulose or corn oil and administered orally 30 min before the injection of glucose. As a control using carboxymethylcellulose.

Time-dependent changes in the level of glucose in the blood after oral administration of tolbutamide and Cove as a therapeutic agent for diabetes for the treatment of hyperglycemia in doses which do not cause hypoglycemia, but if used in doses effective for the treatment of hyperglycemia, then after 120 min it causes hypoglycemia. In other words, when the doses, is effective as a therapeutic agent for diabetes, tolbutamide always reduces the level of glucose in the blood, regardless of whether (a hyperglycemic condition, or level of glucose in the blood is normal, leading to a state of hypoglycemia after 120 minutes

Experimental example 3

Impact on the level of glucose in the blood hungry rats

The male rats of the Wistar strain (Japan Charles River) weighing about 250 g do not give food for 16 h from the previous day and then explore. The test substance suspended in 0.5% carboxymethyl cellulose or corn oil, and the blood from the tail vein (0.2 ml) taken after 30, 60 and 120 min after injection. After receiving the serum glucose level in the blood was determined using a hexokinase. As a control using carboxymethyl cellulose and determine the level of glucose in the blood after injection of tolbutamide and compounds of the present invention.

As one of the examples in Fig. 4 presents changes depending on time is of butamide and control. In accordance with Fig. 4 shows that the tolbutamide reduces the level of glucose in the blood hungry rats, whereas the compound of the present invention does not reduces the level of glucose in hungry rats. Join other examples have the same effect.

Industrial applicability

Compounds of the present invention exhibit an excellent effect in reducing the level of blood glucose during hyperglycemia, but do not cause such serious side effects like hypoglycemia. Therefore, compounds of the present invention can be used as a therapeutic agent for diabetics; they can also be used as a preventative means of chronic complications of diabetes.

This application is based on application N 56883/1996 filed in Japan, the contents of which are incorporated here by reference.

1. Therapeutic agent for diabetes, which contains a compound of the formula I

< / BR>
where X represents a group of the formula

< / BR>
where R4represents a hydrogen atom, a C1-5alkyl, carboxy, phenyl, C2-5acyl or2-5alkoxycarbonyl; R5represents a hydrogen atom or a C1-5alkyl;

R1-5by alkyl, hydroxy, hydroxyalkyl,2-6alkenyl, acyl, carboxy, tanila or3-7cycloalkyl; biphenyl, optionally substituted C1-5the alkyl or hydroxy; naphthyl; terphenyl; C3-7cycloalkyl, optionally substituted C1-5the alkyl or phenyl; optionally substituted C1-5alkyl; pyridyl; sensational; substituted; indanyl; fluorenyl or a group of the formula

< / BR>
R2represents a hydrogen atom or a C1-5alkyl, optionally substituted by carboxy;

R'2represents a hydrogen atom;

R3represents a C1-5alkyl, optionally substituted phenyl or1-4alkoxy; C1-4alkoxy; hydroxy; phenyl; C3-7cycloalkyl, optionally substituted C1-5by alkyl;

R2and R7taken together form a group of the formula

-(CH2)2-;

R2and R5taken together, form a simple bond or a group of the formula

-CH2-, -(CH2)3-, -(CH2)4-;

R2, R'2, R4and R5taken together form a group of the formula

=CH-CH=CH-CH=;

R'2and R3taken together form a group of the formula

< / BR>
where R8and R9p the/P> 2. Therapeutic agent for diabetes under item 1, where in formula I, X represents a group of the formula

< / BR>
where R4represents a hydrogen atom, a C1-5alkyl, carboxy, phenyl, C2-5acyl or2-5alkoxycarbonyl;

R5represents a hydrogen atom or a C1-5alkyl;

R6represents a hydrogen atom;

R1represents phenyl, optionally substituted C1-5by alkyl, hydroxy, hydroxyalkyl,2-6alkenyl, acyl, carboxy, tanila or3-7cycloalkyl; biphenyl, optionally substituted C1-5the alkyl or hydroxy; naphthyl; terphenyl; C3-7cycloalkyl, optionally substituted C1-5the alkyl or phenyl; optionally substituted C1-5alkyl; pyridyl; sensational; substituted; indanyl; fluorenyl or a group of the formula

< / BR>
R2represents a hydrogen atom or a C1-5alkyl, optionally substituted by carboxy;

R'2represents a hydrogen atom;

R3represents a C1-5alkyl, optionally substituted phenyl or1-4alkoxy, C1-4alkoxy; hydroxy; phenyl; C3-7cycloalkyl, optionally substituted C1-5by alkyl;

> taken together, form a simple bond or a group of the formula

-CH2-, -(CH2)3-,-(CH2)4-;

R2, R'2, R4and R5taken together form a group of the formula

=CH-CH=CH-CH=;

R'2and R3taken together form a group of the formula

< / BR>
where R8and R9represent hydrogen.

3. Therapeutic agent for diabetes under item 1, where in formula I, X represents a group of the formula

< / BR>
where R4represents a hydrogen atom, a C1-5alkyl, carboxy, phenyl, C2-5acyl or2-5alkoxycarbonyl;

R5represents a hydrogen atom or a C1-5alkyl;

R6represents a hydrogen atom;

R1represents phenyl, optionally substituted C1-5by alkyl, hydroxy, hydroxyalkyl,2-6alkenyl, acyl, carboxy, tanila or3-7cycloalkyl; biphenyl, optionally substituted C1-5the alkyl or hydroxy; naphthyl; terphenyl; C3-7cycloalkyl, optionally substituted C1-5the alkyl or phenyl; optionally substituted C1-5alkyl; pyridyl; sensational; substituted; indanyl; fluorenyl or a group of the formula

< / BR>
R
R3represents a C1-5alkyl, optionally substituted phenyl or1-4alkoxy; C1-4alkoxy; hydroxy; phenyl; C3-7cycloalkyl, optionally substituted C1-5by alkyl;

R2and R7taken together form a group of the formula

-(CH2)2-;

R2and R5taken together, form a simple bond or a group of the formula

-CH2-, -(CH2)3-, -(CH2)4-;

R2, R'2, R4and R5taken together form a group of the formula

=CH-CH=CH-CH=;

R2and R3taken together form a group of the formula

< / BR>
where R8and R9represent hydrogen.

4. Therapeutic agent for diabetes under item 1, where in formula I, X represents a group of the formula

< / BR>
where R4represents a hydrogen atom, a C1-5alkyl, carboxy, C2-5acyl or2-5alkoxycarbonyl;

R5represents a hydrogen atom or a C1-5alkyl;

R6represents a hydrogen atom;

R1represents phenyl, optionally substituted C1-5by alkyl, hydroxy, hydroxyalkyl,2-6alkenyl, acyl, carboxy, tanila or the3-7cycloalkyl, optionally substituted C1-5the alkyl or phenyl; C1-5alkyl, optionally substituted C3-7cycloalkyl or aryl; pyridyl; sensational; substituted; indanyl; fluorenyl or a group of the formula

< / BR>
R2represents a hydrogen atom or a C1-5alkyl;

R2represents a hydrogen atom;

R3represents a C1-5alkyl, optionally substituted phenyl or1-4alkoxy; C1-4alkoxy; hydroxy; phenyl;

R2and R7taken together, form a group of the formula

-(CH2)2-;

R2and R5taken together, form a simple bond or a group of the formula

-CH2-, -(CH2)3-, -(CH2)4-;

R2, R'2, R4and R5taken together, form a group of the formula

=CH-CH=CH-CH=;

R'2and R3taken together form a group of the formula

< / BR>
where R8and R9represent hydrogen.

5. Therapeutic agent for diabetes under item 1, where in formula I, X represents a group of the formula

< / BR>
where R4represents a hydrogen atom, a C1-5alkyl, carboxy, C2-5acyl or2-5alkoxycarbonyl is hydrogen;

R1represents phenyl, optionally substituted C1-5by alkyl, hydroxy, hydroxyalkyl,2-6alkenyl, acyl, carboxy, tanila or3-7cycloalkyl; biphenyl, optionally substituted C1-5the alkyl or hydroxy; naphthyl; terphenyl; C3-7cycloalkyl, optionally substituted C1-5-alkyl or phenyl; optionally substituted C1-5alkyl; pyridyl; sensational; substituted; indanyl; fluorenyl;

R2represents a hydrogen atom or a C1-5alkyl;

R'2represents a hydrogen atom;

R3represents a C1-5alkyl; C1-4alkoxy; hydroxy; phenyl;

R2and R5taken together, form a simple bond or a group of the formula

-(CH2)3-, -(CH2)4-;

R'2and R3taken together form a group of the formula

< / BR>
where R8and R9represent hydrogen.

6. Therapeutic agent for diabetes under item 1, where in formula I, X represents a group of the formula

< / BR>
where R4represents hydrogen, C1-5alkyl, carboxy, C2-5acyl or2-5alkoxycarbonyl;

R5represents hydrogen or C1 is replaced WITH1-5by alkyl, hydroxy, hydroxyalkyl,2-6alkenyl,2-5the acyl, carboxy, tanila or3-7cycloalkyl; biphenyl, optionally substituted C1-5the alkyl or hydroxy; naphthyl; terphenyl; C3-7cycloalkyl, optionally substituted C1-5the alkyl or phenyl; optionally substituted C1-5alkyl; pyridyl; sensational; substituted; indanyl; fluorenyl;

R2represents a hydrogen atom;

R'2represents hydrogen;

R3represents a C1-5alkyl, C1-4alkoxy or hydroxy;

R2and R5taken together, constitute a simple link;

R'2and R3taken together form a group of the formula

< / BR>
where R8and R9represent hydrogen.

7. Therapeutic agent for diabetes under item 1, where in formula I, X represents a group of the formula

< / BR>
where R4represents hydrogen, C1-5alkyl, carboxy, C2-5acyl or2-5alkoxycarbonyl;

R5represents hydrogen or C1-5alkyl;

R6represents hydrogen;

R1represents phenyl, optionally substituted C1-5by alkyl, hydroxy, hydropattern substituted C1-5the alkyl or hydroxy; naphthyl; terphenyl; C3-7cycloalkyl, optionally substituted C1-5the alkyl or phenyl; optionally substituted C1-5alkyl;

R2represents a hydrogen atom;

R'2represents hydrogen;

R3represents a C1-5alkyl, C1-4alkoxy or hydroxy;

R'2and R3taken together form a group of the formula

< / BR>
where R8and R9represent hydrogen.

8. Therapeutic agent for diabetes under item 1, where in formula I, X represents a group of the formula

< / BR>
where R4represents hydrogen, C1-5alkyl, carboxy, C2-5acyl or2-5alkoxycarbonyl;

R5represents hydrogen or C1-5alkyl;

R6represents hydrogen;

R1represents phenyl, optionally substituted C1-5by alkyl, hydroxy, hydroxyalkyl,2-6alkenyl,2-5the acyl, carboxy, tanila or3-7cycloalkyl; biphenyl, optionally substituted C1-5the alkyl or hydroxy; naphthyl; terphenyl; C3-7cycloalkyl, optionally substituted C1-5the alkyl or phenyl;

R2presti C1-5alkyl, C1-4alkoxy or hydroxy.

9. Therapeutic agent for diabetes under item 1, where in formula I, X represents a group of the formula

< / BR>
where R4and R5each represent a hydrogen atom;

R1represents phenyl, optionally substituted C1-5by alkyl, hydroxy, hydroxyalkyl,2-6alkenyl,2-5the acyl, carboxy, tanila or3-7cycloalkyl; biphenyl, optionally substituted C1-5the alkyl or hydroxy; naphthyl; terphenyl; C3-7cycloalkyl, optionally substituted C1-5the alkyl or phenyl;

R2represents a hydrogen atom;

R'2represents a hydrogen atom;

R3represents a C1-5alkyl, C1-4alkoxy or hydroxy.

10. Therapeutic agent for diabetes under item 1, where in formula I, X represents a group of the formula

< / BR>
where R4and R5each represents a hydrogen atom;

R1represents phenyl, optionally substituted C1-5by alkyl, hydroxy, hydroxyalkyl,2-6alkenyl,2-5the acyl, carboxy, tanila or3-7cycloalkyl; biphenyl, optionally substituted Silom or phenyl;

R2represents a hydrogen atom;

R'2represents a hydrogen atom;

R3represents a C1-5alkyl, C1-4alkoxy or hydroxy.

11. Therapeutic agent for diabetes under item 1, where in formula I, X represents a group of the formula

< / BR>
where R4and R5each represents a hydrogen atom;

R1represents phenyl, optionally substituted C1-5by alkyl, hydroxy, hydroxyalkyl,2-6alkenyl,2-5the acyl, carboxy, tanila or3-7cycloalkyl; biphenyl, optionally substituted C1-5the alkyl or hydroxy; naphthyl; terphenyl; C3-7cycloalkyl, optionally substituted C1-5the alkyl or phenyl;

R2represents a hydrogen atom;

R'2represents a hydrogen atom;

R3represents hydroxy.

12. The connection formulas

< / BR>
when R3represents hydroxy, R4represents a hydrogen atom, R1represents a C3-7cycloalkyl, monosubstituted WITH1-4the alkyl or phenyl;

when R3represents a C1-4alkyl or C1-4alkoxy, R4predstaleny1-4the alkyl or phenyl

or its pharmaceutically acceptable salt, hydrate or MES.

13. Connection on p. 12, where R3represents hydroxy, or its pharmaceutically acceptable salt, hydrate or MES.

14. Connection on p. 13, where R4represents a hydrogen atom, its pharmaceutically acceptable salt, hydrate or MES.

15. The compound according to any one of paragraphs. 12-14, where R1represents a C3-7cycloalkyl, monosubstituted WITH1-4the alkyl, its pharmaceutically acceptable salt, hydrate or MES.

16. The compound according to any one of paragraphs. 12-15, where R1represents a C3-7cycloalkyl, monosubstituted the stands, its pharmaceutically acceptable salt, hydrate or MES.

17. The compound according to any one of paragraphs.12-16 selected from the group including:

1) 4-(1-methylcyclohexyl)-4-oxobutanoic acid,

2) TRANS-4-(4-methylcyclohexyl)-4-oxobutanoic acid,

3) TRANS-4-(4-ethylcyclohexyl)-4-oxobutanoic acid,

4) TRANS-4-(4-isopropylcyclohexane)-4-oxobutanoic acid,

5) TRANS-4-(4-tert-butylcyclohexyl)-4-oxobutanoic acid,

6) TRANS-4-(4-phenylcyclohexyl)-4-oxobutanoic acid,

7) CIS-4-(4-metiltsiklogeksil)-2-oxoethyl]-propanedioic and

10) of methyl 2-acetyl-4-(1-methylcyclohexyl)-4-oxobutanoate;

or its pharmaceutically acceptable salt, hydrate or MES.

18. The compound according to any one of paragraphs.12-17 selected from the group including:

1) 4-(1-methylcyclohexyl)-4-oxobutanoic acid,

2) TRANS-4-(4-methylcyclohexyl)-4-oxobutanoic acid,

3) TRANS-4-(4-ethylcyclohexyl)-4-oxobutanoic acid,

4) TRANS-4-(4-isopropylcyclohexane)-4-oxobutanoic acid,

5) TRANS-4-(4-tert-butylcyclohexyl)-4-oxobutanoic acid,

6) TRANS-4-(4-phenylcyclohexyl)-4-oxobutanoic acid,

7) CIS-4-(4-methylcyclohexyl)-4-oxobutanoic acid and

8) 4-(3-methylcyclohexyl)-4-oxobutanoic acid;

or its pharmaceutically acceptable salt, hydrate or MES.

19. The connection formulas

< / BR>
where, when R'3represents hydroxy, R"'4represents a hydrogen atom, a C1-4alkyl or carboxy, R"'5represents a hydrogen atom or a C1-4alkyl;

R101represents a C1-4alkyl, substituted hydroxy;

when R"'3represents a C1-4alkyl, R"'4represents a hydrogen atom or a C2-5acyl, R'5is a is phenyl, substituted by carboxy, hydroxy or phenyl;

or its pharmaceutically acceptable salt, hydrate or MES.

20. Connection on p. 19, where R"'3represents hydroxy, or its pharmaceutically acceptable salt, hydrate or MES.

21. Connection on p. 19 or 20, or where R'4or R"'5represent a hydrogen atom, or its pharmaceutically acceptable salt, hydrate or MES.

22. The compound according to any one of paragraphs. 19-21, where both R'4or R"'5represent a hydrogen atom, or its pharmaceutically acceptable salt, hydrate or MES.

23. The compound according to any one of paragraphs. 19-22, where R101represents a C1-4alkyl, substituted hydroxy, or its pharmaceutically acceptable salt, hydrate or MES.

24. The compound according to any one of paragraphs.19-23 selected from the group including:

1) 4-[4-(hydroxymethyl)phenyl]-4-oxobutanoic acid,

2) 1-(4-hydroxymethylene)-1,4-pentandiol,

3) 1-[4-(1-hydroxyethyl)phenyl]-1,4-pentandiol and

4) 1-[4-(2-hydroxyethyl)phenyl]-1,4-pentandiol;

or its pharmaceutically acceptable salt, hydrate or MES.

25. The connection formulas

< / BR>
where a and b are the same or different and each predstavlja1-4alkyl, substituted hydroxy, or phenyl; or when R'2represents a C1-4alkyl, R'101represents a hydrogen atom, a C1-4alkyl, substituted hydroxy or phenyl;

its pharmaceutically acceptable salt, hydrate or MES.

26. Connection on p. 25, where R"'2represents a C1-4alkyl, or its pharmaceutically acceptable salt, hydrate or MES.

27. Connection on p. 25 or 26, where R"'2represents methyl, or its pharmaceutically acceptable salt, hydrate or MES.

28. The compound according to any one of paragraphs.25-27 selected from the group including:

1) ()-3-benzoyl-3-methyl-1-Cyclopentanone,

2) ()-dihydro-4-(4'-vinylbenzyl)-2(3H)-furanone,

3) ()-dihydro-4-methyl-4-(4'-vinylbenzyl)-2(3H)-furanone,

4) ()-dihydro-4-(4'-hydroxymethylbenzene)-2(3H)-furanone,

5) ()-dihydro-5-(4'-vinylbenzyl)-2(3H)-furanone,

6) ()-dihydro-5-(4'-hydroxymethylbenzene)-2(3H)-furanone,

7) ()-dihydro-5-(4'-hydroxymethylbenzene)-5-methyl-2(3H)-furanone,

8) (-)-dihydro-5-methyl-5-(4'-vinylbenzyl)-2(3H)-furanone,

9) ()-dihydro-5-methyl-5-(4'-vinylbenzyl)-2(3H)-furanone,

10) (S)-(-)-5-(4'-vinylbenzyl)-2-pyrrolidinone and

11) ()-4-(4'-hydroxymethylbenzene)-2-pyrrolidinone;

or is or its pharmaceutically acceptable salt, hydrate or MES, having the property of reducing the amount of glucose in the blood under conditions of hyperglycemia.

30. Pharmaceutical composition having the property to reduce the glucose content in the blood under conditions of hyperglycemia, containing a compound according to any one of paragraphs. 12-16, 19-23 and 25-27 or its pharmaceutically acceptable salt, hydrate or MES.

31. The compound according to any one of paragraphs.17, 18, 24 and 28, or its pharmaceutically acceptable salt, hydrate or MES, having the property of reducing the amount of glucose in the blood under conditions of hyperglycemia.

32. Pharmaceutical composition having the property to reduce the glucose content in the blood under conditions of hyperglycemia, containing a compound according to any one of paragraphs. 17, 18, 24 and 28, or its pharmaceutically acceptable salt, hydrate or MES.

 

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Iodinated esters // 2088579

The invention relates to 1-alkyl, 1-alkenyl, and 1-alkynylaryl-2-amino-1,3-propandiol formula 1:

< / BR>
where R is

< / BR>
< / BR>
R5represents a group of the formula:

CH3(CH2)mCC-, CH3(CH2)mCH CH-,

CH3(CH2)mCH2-CH2-,< / BR>
,< / BR>
m is from 3 to 15 and n is from 0 to 12

The invention relates to the field of organic chemistry, namely the chemistry of azo compounds which are used as acid-base indicators

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RCH (OR1)CHN(R2R3)P4whereOSO

R5-CH3(CH2)mCC,

CH3(CH2)mCH=CH-, CH3(CH2)mCH2-CH2-,-CH2(CH2)nCC-,

-CH2(CH2)nCH= CH or-CH2(CH2)nCH2-CH2-, where m = 3-15; n = 0-12;

R1is hydrogen orR6where R6is hydrogen, alkyl, alkoxy, or OCH2-;

R2is hydrogen or alkyl;

R3is hydrogen, alkyl orOR7where R7is hydrogen or alkyl, or CH2OR8where R8is hydrogen orR6where R6is defined above,

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where R9and R10independently are hydrogen or alkyl

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The invention relates to the chemistry of adamantane derivatives, and in particular to a new method of obtaining amino adamantane General formula AdR, where R=NH2, NHBu-t,

< / BR>
< / BR>
< / BR>
which are biologically active substances and can find application in pharmacology and adamant-1-ylamine is the basis of the drug midantana"
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diketones" target="_blank">

The invention relates to organic chemistry, in particular to an improved method for producing a fluorine-containing-diketones of General formula I

< / BR>
where Rf CF3.C8F17; HCF2H(CF2)2

The invention relates to the field of organic chemistry, namely the synthesis of aromatic and heteroaromatic bis-1,2-diketones

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