Derivatives of rhodanine, the method of production thereof, pharmaceutical composition, use as hypoglycemic agents for the treatment of alzheimer's disease

 

(57) Abstract:

The invention relates to the field of chemistry and medicine. Available derivatives of rhodanine General formula

< / BR>
where Ar is (i) phenyl, (ii) phenyl substituted by one to three substituents that are independently selected from C1-C8alkoxy, or-N(R7)SO2R7and other radicals, are presented in the description of the patent. These derivatives are included in pharmaceutical compositions, proposed for the treatment of hyperglycemia, Alzheimer's disease. These songs are more active and have minimal Toxicological effects. 7 c.p. f-crystals, 12 tab.

The invention relates to certain derivatives of rhodanine, their pharmaceutical compositions and method of production thereof, and to methods of using such compounds to treat Alzheimer's disease and hyperglycemia.

Diabetes mellitus is a common disease characterized by disorders in the metabolism of insulin, carbohydrates, fats and proteins, and the structure and function of blood vessels. Major acute symptom of diabetes is hyperglycemia, which is often accompanied by glucosuria, i.e. the presence in the urine of large quantities of glucose, is lnyh manifestations of diabetes. Such symptoms include the destruction of the walls of blood vessels. Although many organs are under the influence of changes in these vessels, eyes and kidneys are the most sensitive to these changes. As such, long-term manifestations of diabetes mellitus, even in the treatment of insulin are the main cause of blindness.

There are two types of diabetes. Diabetes type I is a "disease of the young, susceptible to ketosis, and develops in early life with much more serious symptoms and has an almost "guaranteed" prospects of subsequent vascular lesions. The control for this type of diabetes is difficult and requires exogenous application of insulin, Diabetes mellitus type II is a disease of adults, resistant to ketosis, and develops in the later stages of life; this condition is weaker disease and has a slower development.

One of the most outstanding achievements in the history of medical science was received in 1922, when Banting and best proven therapeutic effects of insulin on patient diabetic. However, even at present a clear picture of the basic biochemical defect of the disease is absent, and diabetes is still on trade one of the forms of diabetes.

Introduction tematicheskie effective hypoglycemic agents was an important breakthrough in the treatment of hyperglycemia by lowering the concentration of glucose in the blood. Tematicheskie hypoglycemic agents in General use in the treatment of adult diabetics.

A variety of derivatives biguanide and sulfonylurea used in the clinical setting as hypoglycemic agents. However, the biguanides are the cause of milk acidosis, and sulfonylurea, though, and has good hypoglycemic activity, requires great care during use, as it often is the cause of severe hypoglycemia and is most effective within the period of ten years.

In Chemical & Pharmaceutical Bulletin, so 30 p. 3563 /1982/, Chemical & Pharmaceutical Bulletin, so 30 p. 3580 /1982/ and Chemical & Pharmaceutical Bulletin, T. 32, page 2267 /1984/ has links to a variety of preparations of thiazolidinediones, which have activity at lower concentrations of glucose and lipids in the blood. Also known antidiabetic activity of ciglitazone, see Diabetes, T. 32, page 804 /1983/. However, these compounds are difficult to use because of insufficient activity and/or involve serious problems due the ZGA person, continues to reach more and more people all over the world. This disease leads to progressive mental exhaustion, which manifests itself in the form of memory loss, confusion, disorientation and concomitant loss of enjoyment of life associated with the above factors. Currently, there is no scientifically proven method of treatment of Alzheimer's disease. Because of this, and also because of the debilitating effects of the disease, continues to be felt an acute need for an effective means of treatment.

The present invention relates to a series of hypoglycemic agents, which can reduce the concentration of glucose in the blood mlekopitayushchikh. Because of this, one of the purposes of the present invention is to provide compounds with extremely high hypoglycemic activity. Hypoglycemic agents, which are the subject of the present invention seems to have minimal Toxicological effects. It seems, therefore, that the compounds that are the subject of the present invention, can be very useful in the treatment of diabetes.

In addition, the present invention relates also to a series of compounds, Obedinenie, able to inhibit cathepsin /and, in particular, cathepsin D /, can be used for the treatment of Alzheimer's disease. Therefore, another objective of the present invention is to provide compounds that can be used for the treatment of Alzheimer's disease.

Other objectives, features and advantages of the present invention will be clear from the following patent description and appended claims.

In accordance with this invention proposes a method of reducing the concentration of blood glucose in mammals, containing the use of therapeutically effective amounts of compounds of formula (I):

< / BR>
in which Ar is (i) a phenyl, (ii) a phenyl, substituted with one to three substituents that are independently selected from C1-C8of alkyl, C1-C8alkoxy, C1-C8alkylthio, trifloromethyl, C1-C4alkylphenyl, phenyl, NO2, F, Cl, hydroxy, phenoxy, C1-C4allyloxyphenyl, thiophenyl, C1-C4alkylthiophene, -COOR7, -N(R7)SO2R7or - N(R7)2where each R7is independently hydrogen or C1-C6the alkyl, /iii/ 1 - or 2-naphthyl, /iv / 2 - or 3-b is a 3-benzodioxole, /x/ substituted 1,3-benzodioxolyl, /xi/ hyalinella, /xii/ 2 - or 3-indolium or /xiii/ N-substituted 2 - or 3-indolium;

R1is C1-C6the alkyl, C1-C4alkylphenyl, hydrogen, phenyl or phenyl substituted by one or two substituents that are independently selected from Cl, Br, F, I, C1-C4of alkyl, C1-C4alkoxy, hydroxy, trifloromethyl, -NH2, -NH/C1-C4the alkyl/, -N/C1-C4the alkyl /2or C1-C4alkylthio;

R2and R3each is hydrogen or taken together form a bond;

R4and R5each is hydrogen or taken together they are =S, or if one of R4and R5is hydrogen, the other is - SCH3;

R6is hydrogen, C1-C6the alkyl, C3-C8cycloalkyl, C2-C6alkenyl, -SO2CH3or/CH2/p-Y, where p is 0, 1, 2 or 3, and Y is cyano, -OR8, tetrazolyl, -NR10, R11, -SH, C1-C4alkylthio, or:

< / BR>
in which R8is hydrogen, C1-C4the alkyl or alkyl, R9is hydrogen, C1-C4the alkyl, C1-C4alkoxy, hydroxy, or N/SUB> alkenyl, C2-C6the quinil, phenyl, C1-C4alkylphenyl, -/CH2/qOH, -/CH2/qN/C1-C4the alkyl/2or/CH2/qS/C1-C4the alkyl/, where q is an integer from 1 to 6, inclusive, or R10and R11taken together with the nitrogen atom to which they are attached, form morpholinyl, piperidinyl, piperidinium or N-methylpiperazine ring; and

m is 0, 1 or 2;

with the caveat that

Ar cannot be phenyl, substituted only one chloro-substituent in the 4-position of the phenyl ring;

Ar cannot be phenyl, substituted by COOH-component in the 2-position of the phenyl ring;

when Ar is phenyl, substituted two ethoxy-components in 3 - and 4-positions of the phenyl rings, R1must be hydrogen;

Ar cannot be phenyl, substituted only two oxy substituents; and

when R4and R5each is hydrogen, R6may not be C1-C6the alkyl,

or is it acceptable from a pharmaceutical point of view of salt, to the mammal, which is needed to reduce the concentration of glucose in the blood.

In accordance with the present invention offers a t the tion, containing the use of therapeutically effective amounts of compounds of formula Ia/:

< / BR>
in which Ar is (i) a phenyl, (ii) a phenyl, substituted with one to three substituents, independently selected from C1-C8of alkyl, C1-C8alkoxy, C1-C8alkylthio, trifloromethyl, C1-C4alkylphenyl, phenyl, NO2, F, Cl, hydroxy, phenoxy, C1-C4allyloxyphenyl, thiophenyl, C1-C4alkylthiophene, -COOR7, -N(R7)SO2R7or-N(R7)2where each R7is independently hydrogen or C1-C6the alkyl, or /iii/ 1 - or 2-naphthyl;

R1is C1-C6the alkyl, C1-C4alkylphenyl, hydrogen, phenyl or phenyl substituted by one or two substituents that are independently selected from Cl, Br, F, I, C1-C4of alkyl, C1-C4alkoxy, hydroxy, trifloromethyl, -NH2, -NH/C1-C4the alkyl/, -N/C1-C4the alkyl/2or C1-C4alkylthio;

R2and R3each is individually hydrogen or taken together form a bond;

R4and R5each is individually hydrogen or taken together they form a = S, or when one of R4and what Kilom, C3-C8cycloalkyl, C2-C6alkenyl, -SO2CH3or/CH2/p-Y, where p is 0, 1, 2 or 3, and Y is cyano, -OR8, tetrazolyl, -NR10R11, -SH, C1-C4alkylthio, or

< / BR>
in which R8is hydrogen, C1-C4the alkyl or alkyl, R9is hydrogen, C1-C4the alkyl, C1-C4alkoxy, hydroxy or NH2, a R10and R11each independently is hydrogen, C1-C6the alkyl, C2-C6alkenyl, C2-C6the quinil, phenyl, C1-C4alkylphenyl, -/CH2/qOH, -/CH2/qN/C1-C4the alkyl/2or/CH2/qS/C1-C4the alkyl/, where q is an integer from 1 to 6, inclusive, or R10and R11taken together with the nitrogen atom to which they are attached, form morpholinyl, piperidinyl, piperidinium or N-methylpiperazine ring; and

m is 0, 1 or 2;

or is it acceptable from a pharmaceutical point of view of salt to a mammal requiring such treatment.

Some of the compounds that can be used according to the method of the present invention, are new. P is where Ar is /i/ phenyl, (ii) a phenyl, substituted with one to three substituents that are independently selected from C1-C8of alkyl, C1-C8alkoxy, C1-C8alkylthio, trifloromethyl, C2-C4alkylphenyl, NO2, F, Cl, phenoxy, C1-C4allyloxyphenyl, thiophenyl, C1-C4alkylthiophene, -COOR7, -N(R7)SO2R7or-N(R7)2where each R7independently is hydrogen or C1-C6the alkyl, /iii/ 1 - or 2-naphthyl, /iv/ 2 - or 3-benzofuranyl, /v/ 2 - or 3-benzothiophene, /vi/ 2 - or 3-tanila, /vii/ 2-, 3 - or 4-pyridium, /viii/ 2 - or 3-TuranAlem, /ix/ 1,3-benzodioxolyl, /x/ substituted 1,3-benzodioxolyl, /xi/ hyalinella, /xii/ 2 - or 3-indolium or /xiii/ N-substituted 2 - or 3-indolium;

R1is C1-C6the alkyl, C1-C4alkylphenyl, hydrogen, phenyl or phenyl substituted by one or two substituents that are independently selected from Cl, Br, F, I, C1-C4of alkyl, C1-C4alkoxy, hydroxy, trifloromethyl, -NH2, -NH/C1-C4the alkyl/, -N/C1-C4the alkyl/2or C1-C4alkylthio;

R2and R3each is hydrogen or taken together form a bond;

R4and R5to the m, the other is-SCH3;

R6is hydrogen, C1-C6the alkyl, C3-C8cycloalkyl, C2-C6alkenyl, -SO2CH3or/CH2/p-Y, where p is 0, 1, 2 or 3, and Y is cyano, OR8, tetrazolyl, -NR10R11, -SH, C1-C4alkylthio or:

< / BR>
in which R8is hydrogen, C1-C4the alkyl, or alkyl; R9is hydrogen, C1-C4the alkyl or NH2; and R10and R11each independently is hydrogen, C1-C6the alkyl, C2-C6alkenyl, -CH2/qOH, -/CH2/qN /-C1-C4the alkyl/2, -/CH2/qS/C1-C4the alkyl/, C2-C6the quinil, phenyl or C1-C4alkylphenyl, where q is an integer from 1 to 6, inclusive, or R10and R11taken together with the nitrogen atom to which they are attached, form morpholinyl, piperidinyl, piperazinyl or N-methylpiperazine ring; and

m is 0, 1 or 2;

with the caveat that

when Ar is (i) a phenyl, (ii) a phenyl, substituted with one to three substituents selected from C1-C8of alkyl, C1-C8alkoxy, /2or-CCOR7where each R7independently is hydrogen or C1-C6the alkyl, /iii/ 1 - or 2-naphthyl, /iv/ 2 - or 3-benzofuranyl, /v/ 2 - or 3-benzothiophene, /vi/ 2 - or 3-tanila, /vii/ 2 - or 3-indolium, /viii/ 2 - or 3-TuranAlem, /ix/ hyalinella or /x/ 2-, 3 - or 4-pyridium; R1is hydrogen or C1-C6by alkyl; R2and R3taken together form a bond; m is 0; and R4and R5taken together form a = S, R6must be different from hydrogen or C1-C6of alkyl;

when Ar is phenyl; R1is hydrogen, stands or ethyl; R2and R3taken together form a bond; m is 0; R4and R5taken together, form = S; R6must be different from phenyl or C1-C4alkylphenyl;

Ar cannot be phenyl, substituted only one chloro-substituent in the 4-position of the phenyl ring;

when Ar is phenyl, substituted two ethoxy-components in 3 - and 4-positions of the phenyl rings, R1must be hydrogen;

Ar cannot be phenyl, substituted by COOH-component in the 2-position of the phenyl ring; and

when R4and R5each is hydrogen, R6may not be C1-C6Ala is soedinenii, described by formula II above, some other compounds that can be used according to the method of the present invention, are also new. These compounds, despite the fact that are a structure similar to compounds known in the art (see, for example, European patent application NN 343 643, 391 644 and 39 817, as well as U.S. patent No. 4 552 891), actually was not offered in any of the patents or patent applications. Therefore, in accordance with the present invention also offers the following new compounds and their acceptable from a pharmaceutical point of view of the salt.

5-[/2-nitrophenyl/methylene]-2-thioxo-4-thiazolidinone;

5-[/4-forfinal/methylene]-2-thioxo-4-thiazolidinone;

5-[/2-thienyl/methylene]-2-thioxo-4-thiazolidinone;

5-[/2-furanyl/methylene]-2-thioxo-4-thiazolidinone;

5-[/3,4,5-trimethoxyphenyl/METROTILE]-2-thioxo-4-thiazolidinone;

4-[/2 thioxo-4-thiazolidinone/methylene] benzoic acid;

5-[/3-hydroxy-4-nitrophenyl/methylene]-2-thioxo-4-thiazolidinone;

5-[/3 oksifenil/METROTILE]-2-thioxo-4-thiazolidinone;

5-[/3-methoxy-4-phenoxyphenyl/methylene]-2-thioxo-4-thiazolidinone;

5-[/3-hydroxy-4-ethoxyphenyl/methylene]-2-thioxo-4-thiazolidinone;

5-[/4-phenoxyphenyl/methylene]-2-thioxo-4-thiazoline-2-thioxo-4-thiazolidinone;

5-[/3,4-dibromobiphenyl/methylene]-2-thioxo-4-thiazolidinone;

5-[[3-/metalucifer/phenyl]methylene]-2-thioxo-4-thiazolidinone;

5-[[3,5-bis/1,1-dimethylethyl/-4 oksifenil] methylene] -4-oxo-2-thioxo-3-thiazolidine acetic acid;

5-[/3,5-dichloro-4 oksifenil/methylene]-2-thioxo-4-thiazolidinone;

5-[/3-ethoxy-4-butoxyphenyl/methylene]-2-thioxo-4-thiazolidinone;

5-[/3-ethoxy-4-methoxyphenyl/methylene]-2-thioxo-4-thiazolidinone;

5-[[3,5-bis/1-methylpropyl/-4 oksifenil] methylene] -4-oxo-2-thioxo-3-thiazolidine acetic acid;

5-[/4-butoxyphenyl/methylene]-2-thioxo-4-thiazolidinone;

5-[/3-methoxy-4-phenoxyphenyl/methylene]-2-thioxo-3-methyl-4-thiazolidinone;

5-[/3-methoxy-4-acetoxyphenyl/methylene]-2-thioxo-4-thiazolidinone;

5-[/3,5-dimethoxy-4-phenoxyphenyl/methylene]-2-thioxo-4-thiazolidinone;

5-[[3-/1,1-dimethylethyl/-4-hydroxy-5-/methylthiophenyl/phenyl] -methylene] -2-thioxo-4-thiazolidinone;

5-[[3-ethoxy-4-hydroxy-5-/methylthiophenyl/phenyl] methylene] -2-thioxo - 4-thiazolidinone;

5-[[3-ethoxy-4-hydroxy-5-/methylthiophenyl/phenyl] methylene] -2-thioxo-3-methyl-4-thiazolidinone;

5-[[3-ethoxy-4-hydroxy-5-/methylthiophenyl/phenyl] methylene]-4-oxo-2-thioxo-3-thiazolidine acetic acid.

Some of the above compounds, in particular 5-[/4-phenoxyphenyl/methylene]-2-thioxo-4-thioxo-4-thiazolidinone; 5-[/4-butoxyphenyl/methylene] -2-thioxo-4-thiazolidinone; 5-[/3-methoxy-4-phenoxyphenyl/methylene] -2-thioxo-4-thiazolidinone; 5-[/3,5-bis/1,1 - dimethylethyl/-4 oksifenil] -methylene] -4-oxo-2-thioxo-3-thiazolidine acetic acid; and 5-[[3,5-bis/1-methylpropyl/-4 oksifenil]methylene]-4-oxo-2-thioxo-3-thiazolidine acetic acid /especially the last three compounds/, as it turned out, have a surprising ability to reduce the concentration of blood glucose in a mammal when compared to structurally similar compounds known in this technical field. Due to such an amazing activity, these compounds are particularly preferred compounds in accordance with the present invention.

In addition, 5-[[3-/1,1-dimethylethyl/-4-hydroxy-5-/methylthiophenyl]- phenyl]methylene] -2-thioxo-4-thiazolidinone is has the unexpected ability to inhibit the concentration of cathepsin D in comparison with structurally similar compounds known in this technical field. Due to such an amazing activity of these compounds, in addition, especially preferred in accordance with the present invention.

Finally, in accordance with the present invention are also pharmaceutical compositions, the soda is AI with one or more, acceptable from a pharmaceutical perspective, carriers, diluents or fillers.

In this patent application the term "C1-C8alkyl" means a linear or branched alkyl chain containing from one to eight carbon atoms. Representatives of C1-C8alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary.-butyl, isobutyl, tration.-butyl, n-pentyl, etc., the Term "C1-C8alkyl" includes within its definition the terms "C1-C4alkyl" and "C1-C6alkyl".

"C1-C4alkylphenyl" represents a linear or branched alkyl group containing from one to four carbon atoms attached to the phenyl ring. Representatives of C1-C4alkylphenyl groups include were, ethylphenyl, n-propylphenyl, isopropylphenyl, n-butylphenyl, ISO-butylphenyl and tration.-butylphenyl.

The term "C1-C4alkylthiophenes" represents an alkyl group with a linear or branched chain containing one to four carbon atoms attached to teofilovic component. Examples of C1-C4alkyldiphenyl groups are methylthiophenyl, ethylthiophene alkyl group of linear or branched chain, containing from one to four carbon atoms attached to phenoxy-component. Examples of C1-C4allyloxyphenyl groups include methoxyphenyl, ethoxyphenyl, proproxyphene etc.

"C1-C8alkoxy" represents a linear or branched alkyl chain containing from one to eight carbon atoms, which is attached to the remainder of the molecule via an oxygen atom. Examples of C1-C8alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary. -butoxy, tration.- butoxy, pentox, hexose, heptose, etc., the Term "C1-C8alkoxy" includes within itself the definition of C1-C4alkoxy".

"C1-C8alkylthio" represents a linear or branched alkyl chain containing from one to eight carbon atoms, and the chain attached to the remainder of the molecule via the sulfur atom. Examples of C1-C8alkylthio groups include methylthio, ethylthio, propylthio, butylthio, tration.-butylthio, octylthio, etc., the Term "C1-C8alkylthio" includes within itself the term "C1-C4alkylthio".

The term "C2-C6alkenyl" refers to radicals with Si. Therefore, this term includes ethylene, propylene, 1-butene, 2-butene, 2-methyl-1-propene, 1-penten, 2-methyl-2-butene, etc.

The term "C2-C6quinil" refers to linear and branched radicals containing from two to six carbon atoms, inclusive, having a triple bond. Therefore, this term includes acetylene, propyne, 1-butyn, 2-hexyne, 1-penten, 3-ethyl-1-butyn etc.

The term "C3-C8cycloalkyl" refers to saturated alicyclic rings of three to eight carbon atoms, inclusive, such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl etc.

The term "1,3-benzodioxane" and "substituted 1,3-benzodioxolyl" refers to structures having formula

< / BR>
in which R is independently hydrogen or C1-C8the alkyl.

The term "chinoline" refers to the system quinoline ring, which is attached to the remainder of the molecule 4, 5, 6, 7, or 8-positions of this ring system.

N-substituted 2 - or 3-indolyl" refers to 2 - or 3-indolinovoy ring system, substituted at the nitrogen atom of this ring system C1-C6the alkyl, C1-C4alkylphenyl or C3-C8cycloalkyl.

Examples of acceptable from a pharmaceutical point of view of mineral acids that can be used to obtain acceptable from a pharmaceutical point of view salts include hydrochloric acid, phosphoric acid, sulfuric acid, Hydrobromic acid, idiscovered acid, phosphorous acid, etc., Examples of acceptable from a pharmaceutical point of view of organic acids that can be used to obtain acceptable from a pharmaceutical point of view salts include aliphatic mono and dicarboxylic acids, oxalic acid, carbonic acid, citric acid, succinic acid, phenyl-substituted alanovoy acid, aliphatic and mineralnych or organic acids, thus, include hydrochloride, bromohydrin, nitrate, sulfate, persulfate, bisulfate, sulfite, bisulfite, phosphate, acid phosphate, dokily phosphate, metaphosphate, pyrophosphate, iodigital, forgert, acetate, propionate, formate, oxalate, citrate, lactate, para-toluensulfonate, methanesulfonate, maleate, etc.

Many of the compounds of formulas I, Ia, or II, which contain carboxy, carbonyl, hydroxy or a group of solitarii, can be turned into acceptable from a pharmaceutical point of view of salt as a result of interaction with acceptable from a pharmaceutical point of view of a base of an alkali metal or organic base. Examples of acceptable from a pharmaceutical point of view of organic bases that can be used to obtain acceptable from a pharmaceutical point of view salts include ammonia, amines such as triethanolamine, triethylamine, ethylamine, etc., Examples of acceptable from a pharmaceutical point of view of the bases of alkali metals include compounds of General formula MOR13where M represents an alkali metal atom such as sodium, potassium or lithium, a R13represents hydrogen or C1-C4alkyl.

It should be noted that the particular anion or cation, the image is the salt, as a whole, is acceptable from a pharmaceutical point of view, and up until anionic or cationic component does not give undesirable properties.

Preferred series of compounds which are used according to the method of the present invention to reduce the concentration of glucose in the blood, include compounds in which Ar, R1, R2, R3, m, R4and R5such as defined for formula I, and R6is hydrogen, C1-C6the alkyl, C3-C8cycloalkyl, C2-C6alkenyl, -SO2CH3or/CH2/p-Y, where p is 0, 1, 2 or 3, and Y is cyano, -OR8, tetrazolium, NR10R11, -SH, -S/C1-C4the alkyl/ or

< / BR>
in which R8is hydrogen, C1-C4the alkyl or alkyl, R9is hydrogen, C1-C4the alkyl or NH2; and R10and R11each independently is hydrogen, C1-C6the alkyl, C2-C6alkenyl, C2-C6the quinil, phenyl, C1-C4alkylphenyl, -/CH2/qOH, -/CH2/qN/C1-C4the alkyl/2or/CH2/qS/C1-C4the alkyl/, where q is 1 to 6, inclusive, and piperazinone ring.

From this preferred series are those compounds in which m is 0, preferred.

From this preferred series are those compounds in which R4and R5taken together form a = S, are even more preferred.

Of these more preferred compounds are those compounds in which R1is hydrogen are especially preferred.

Of these particularly preferred compounds are those compounds in which R6is hydrogen, C1-C6the alkyl, C2-C6alkenyl or/CH2/p-1, where p is 0, 1, 2, or 3, and Y is-OR8, -NR10R11or C1-C4alkylthio, where R8is hydrogen, C1-C4the alkyl or alkyl, R9is hydrogen, C1-C4the alkyl or NH2; and R10and R11each independently is hydrogen, C1-C6the alkyl, C2-C6alkenyl, C2-C6the quinil, phenyl or C1-C4ALKYLPHENOLS are extremely preferred.

Of these highly preferred compounds are those compounds in which R6is hydrogen, C1-C6the alkyl or C2-CLnyh connections those connections, in which Ar is (i) a phenyl, (ii) a phenyl, substituted with one to three substituents that are independently selected from C1-C8of alkyl, C1-C8alkoxy, C1-C8alkylthio, trifloromethyl, C1-C4alkylphenyl, phenyl, NO2, F, Cl, hydroxy, phenoxy, C1-C4allyloxyphenyl, thiophenyl, C1-C4alkylthiophene, -COOR7, -N/R7/SO2R7or-N/R7/2where each R7is independently hydrogen or C1-C6the alkyl, /iii/ 2-, 3 - or 4-pyridium, or /iv/ 2 - or 3-TuranAlem are greatly preferred.

This significantly preferred family of those compounds in which Ar is phenyl, substituted by one to three substituents selected from C1-C8of alkyl, C1-C8alkoxy, C1-C4alkylphenyl, phenyl, NO2, F, Cl, hydroxy, phenoxy, C1-C4alkylthiophene, -COOR7or N/R7/SO2R7where each R7is independently hydrogen or C1-C6the alkyl, are more preferred.

This more substantial preferred family of those compounds in which Ar is phenyl, substituted by one or t is a/ C1-C8alkoxy (particularly, C1-C6alkoxy/ or hydroxy, are even more preferred.

The most preferred compounds that can be used to carry out the proposed method of reducing the concentration of glucose in the blood include 5-[/3,4 - dioxyphenyl/methylene] -2-thioxo-4-thiazolidinone; 5-[/3-methoxy-4 - butoxyphenyl/methylene] -2-thioxo-4-thiazolidinone; 5-[/3-methoxy-4 - pentoxil-phenyl/methylene] -2-thioxo-4-thiazolidinone; sodium salt of 5-[/3-methoxy-4-phenoxyphenyl/methylene] -2-thioxo-4-thiazolidinone; 5-[/3-methoxy-4-phenoxyphenyl/methyl] -2-thioxo-4-thiazolidinone; 5-[/3,5-bis/1,1-dimethylethyl/-4 oksifenil/methylene] -2-thioxo-4-thiazolidinone; 5-[/3,5-dimethyl-4 oksifenil/-methylene] -2-thioxo-4-thiazolidinone and 5 [/3,5-dimethoxy-4 oksifenil/methylene]-2-thioxo-4-thiazolidinone.

A preferred family of compounds, which are used in accordance with the proposed method for the treatment of Alzheimer's disease, include those compounds in which Ar, R1, R2, R3, m, R4and R5have already been defined in the formula Ia, a R6is hydrogen, C1-C6the alkyl or/CH2/p-Y, in which p is 0, 1, 2 or 3, and Y is-NR10R11in which R10is inveniam.

This preferred family of those compounds in which m is 0 are preferred.

This more preferred family of those compounds in which R4and R5taken together, are = S, are even more preferred.

This is even more preferred family of those compounds in which R2and R3taken together form a bond, are particularly preferred.

This is especially preferred family of those compounds in which Ar is phenyl, substituted by one to three substituents that are independently selected from C1-C8of alkyl, C1-C8alkoxy, C1-C8alkylthio, trifloromethyl, C1-C4alkylphenyl, phenyl, NO2, F, Cl, hydroxy, phenoxy, C1-C4allyloxyphenyl, thiophenyl, C1-C4alkylthiophene, -COOR7, -N/R7/SO2R7or-N/R7/2where each R7independently is hydrogen or C1-C4the alkyl, are highly preferred.

This highly preferred family of those compounds in which R1is hydrogen, are even more highly preferred.

1-C8alkoxy, C1-C8the alkyl (especially C1-C4the alkyl/, hydroxy, Cl, F, C1-C4alkylthiophene, -N/R7/SO2R7and-N/R7/2where each R7independently is hydrogen or C1-C6the alkyl, are greatly preferred.

The most preferred compounds that can be used for the proposed method of treatment of Alzheimer's disease include 5-[/4-phenoxyphenyl/-methylene]-2-thioxo-4-thiazolidinone; 5- [/3-phenoxyphenyl/methylene]-2-thioxo-4-thiazolidinone; 5-[[/1,1'- biphenyl - /-4-yl] methylene]-2-thioxo-4-thiazolidinone; 5-[/3-methoxy-4-hexoxyethanol/methylene] -2-thioxo-4-thiazolidinone; 5-[/3-methoxy-4-epoxyphenol/methylene] -2-thioxo-4-thiazolidinone; 5-[/3-methoxy-4 - acetoxyphenyl/methylene] -2-thioxo-4-thiazolidinone; 5-[[3,5-bis/1,1-dimethylethyl] -4 oksifenil] methylene]-2-thioxo-4 - thiazolidinone; 5-[/3,5-dichloro-4 oksifenil/methylene] -2-thioxo-4-thiazolidinone; 5-[[3-/1,1-dimethylethyl/-4-hydroxy-5- /methylthiophenyl/phenyl] methylene] -2-thioxo-4-thiazolidinone; and 5-[[4- /dimethylamine/phenyl]-methylene]-2-thioxo-4-thiazolidinone.

A preferred family of compounds, which complement and R6already defined in formula II and m is 0. This preferred family of those compounds in which R4and R5taken together, are = S, are preferable. This more preferred family of those compounds in which R2and R3taken together form a bond, are particularly preferred.

This is especially preferred family of those compounds in which R6is hydrogen, C1-C6the alkyl, C2-C6alkenyl or/CH2/p-Y, where p is 0, 1, 2 or 3, and Y is-OR8, -NR10R11or C1-C4alkylthio, where R8is hydrogen, C1-C4the alkyl or alkyl, R9is hydrogen, C1-C4the alkyl or NR2; and R10and R11each independently selected from hydrogen, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil, phenyl, or C1-C4alkylphenyl are extremely preferred.

Of these highly preferred compounds are those compounds in which R6is hydrogen, C1-C6the alkyl or C2-C6alkenyl are more highly preferred. From the scrap, are even more highly preferred.

Of these even more highly preferred compounds are those compounds in which Ar is (i) a phenyl, (ii) a phenyl, substituted with one to three substituents that are independently selected from C1-C8of alkyl, C1-C8alkoxy, C1-C8alkylthio, trifloromethyl, C2-C4alkylphenyl, NO2, F, Cl, phenoxy, C1-C4the alkoxyphenyl, thiophenyl, C1-C4alkylthiophene, -COOR7, -N/R7/SO2R7or-N/R7/2where each R7is independently hydrogen or C1-C6the alkyl, /iii/ 1,3-benzodioxolyl, /iv/ substituted 1,3-benzodioxolyl or /v/ hyalinella are significantly preferred compounds.

This significantly preferred family of those compounds in which Ar is /i/ phenyl substituted by one to three substituents selected from phenoxy or-N/R7/SO2R7where each R7is hydrogen or C1-C6the alkyl or /ii/ 1,3-benzodioxolyl, are more preferred.

Some preferred compounds of the present invention include 5-/diphenylmethylene/-2-thioxo-4-is ledenon; 5-[/3-methoxy-4 - epoxyphenol/methylene]-3-amino-2-thioxo-4-thiazolidinone; 5-[/3 - methoxy-4-epoxyphenol/methylene]-3-dimethylamino-2-thioxo-4 - thiazolidinone; and 5-[/3-methanesulfonamide/methylene]-2-thioxo-4-thiazolidinone.

Alternative preferred family of compounds of the present invention includes those compounds in which Ar, R1, R2, R3, R4, R5and m have already been defined in the formula II, and R6is C3-C8cycloalkyl, C2-C6alkenyl, -SO2CH3or/CH2/p-Y, in which p is 0, 1, 2 or 3, and Y is cyano, -OR8, tetrazolyl, -NR10R11, -SH, C1-C4alkylthio or

< / BR>
in which R8is hydrogen, C1-C4the alkyl or alkyl; R9is hydrogen, C1-C4the alkyl or NH2; and R10and R11each independently is hydrogen, C1-C6the alkyl, C2-C6alkenyl, C2-C6the quinil, phenyl, C1-C4alkylphenyl, -/CH2/qOH, -/CH2/qN/ C1-C4the alkyl/2or /CH2/qS/C1-C4the alkyl/, where q is 1 to 6, inclusive, or R10and R11taken together with the atom rasinovo ring.

This preferred family of those compounds in which m is 0 are preferred.

This more preferred family of those compounds in which R4and R5taken together, are = S, are even more preferred.

This is even more preferred family of those compounds in which R2and R3taken together form a bond, are particularly preferred.

This is especially preferred family of those compounds in which R6is C2-C6alkenyl or/CH2/p-Y, where p is 0, 1, 2 or 3, and Y is-OR8, -NR10R11or C1-C4alkylthio, where R8is hydrogen, C1-C4the alkyl or alkyl, R9is hydrogen, C1-C4the alkyl or NH2; a R10and R11each independently is hydrogen, C1-C6the alkyl, C2-C6alkenyl, C2-C6the quinil, phenyl or C1-C4alkylphenyl, are particularly preferred.

This is especially preferred family of those compounds in which R1is hydrogen or phenyl, are more settled, in which Ar is (i) a phenyl, (ii) a phenyl, substituted with one to three substituents that are independently selected from C1-C8of alkyl, C1-C8alkoxy, C1-C8alkylthio, trifloromethyl, C2-C4alkylphenyl, NO2, F, Cl, phenoxy, C1-C4the alkoxyphenyl, thiophenyl, C1-C4alkylthiophene, -COOR7, -N/R7/SO2R7or-N/R7/2in which each R7independently is hydrogen or C1-C6the alkyl, /iii/ 2-, 3 - or 4-pyridium or /iv/ 2 - or 3-TuranAlem are even more particularly preferred.

This is even more particularly preferred family of those compounds in which Ar is phenyl, substituted by one to three substituents that are independently selected from C1-C8of alkyl, C1-C8alkoxy, C1-C8alkylthio, trifloromethyl, C2-C4alkylphenyl, NO2, F, Cl, phenoxy, C1-C4the alkoxyphenyl, thiophenyl, C1-C4alkylthiophene, -COOR7, -N/R7/SO2R7or-N/R7/2where each R7independently is hydrogen or C1-C6the alkyl, are greatly preferred.

This things is estealam, are independently selected from C1-C8the alkyl or C1-C8alkoxy are preferred.

In accordance with the present invention are also compositions containing the compound of the present invention in combination with acceptable from a pharmaceutical point of view by carrier, diluent or excipient. Preferred compositions in accordance with the present invention are those compositions which contain the preferred compound or family of compounds that are the subject of the present invention, as described above.

Compounds that are the subject of the present invention and the compounds used according to the method of the present invention can be generally obtained by using techniques that are well known to every expert in the field of organic chemistry. For example, such compounds can be obtained by condensation of rhodanine or an appropriately substituted derivative of rhodanine with an appropriately substituted aromatic aldehyde or derivative of an aldehyde, such as one or dvuhkamernyi amine of the formula for This reaction is illustrated by the use of the Ar and R6were already defined in formulas I, Ia and II.

Compounds of the present invention and the compounds which are used according to the method of the present invention, in which R2and R3are hydrogen or taken together they form a bond, and R4and R5each is hydrogen, can be obtained by subjecting the compound in which R4and R5taken together form a = S, catalytic hydrogenation. The relative share of the resulting connection /R2, R3, R4and R5all are hydrogen, or R2and R3taken together form a bond, and R4and R5are hydrogen/ depend on temperature, pressure and duration of the hydrogenation solvent used and the particular catalyst. Alternatively, the above transformation can be carried out by heating the compounds in which R4and R5taken together form a = S, and R2and R3taken together form a double bond in a mixture of hydrochloric acid and alcohol, such as ethanol in the presence of zinc. Recovery thione without breaking benzyl double bond can be carried out by heating thione with vosstanavlivat doctitle variant in the presence of a free radical initiator, such as azobisisobutyronitrile. However, that such recovery worked, it is necessary to use a substrate of N-substituted of rhodanine.

The transformation of compounds in which R2and R3taken together form a bond, and R4and R5taken together, are = S, in compounds in which R2and R3are both hydrogen at the same time, as R4and R5remain unchanged, can be carried out in the processing of unsaturated compounds by dihydropyrido, such as in primary forms diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridine in the presence of silica gel. This reaction is best carried out in the presence of chemically inactive solvent, such as benzene or toluene, in the preferred embodiment, in an inert atmosphere. This reaction can be performed at temperatures from about 25oC to the temperature of reflux distilled mixture. At the preferred temperature of approximately 80oC the reaction is essentially completed after about 12 to 18 hours.

Compounds of formulas I, Ia, or II, in which R1is C1-C6the alkyl, phenyl, substituted phenyl of the type described above, or C1-C4alkylphenol can be obtained when help is matichenkov compounds and acyl halide of the formula R1-C/O/-X, in which R1has already been defined in the formula I or II, and X is chlorine, fluorine, bromine or iodine. The resulting aromatic ketone then condense with Rodnina or an appropriately substituted derivative of rhodanine.

Compounds of the present invention and the compounds used according to the method of the present invention/ varying R6-deputies. These R6the substituents can be obtained as follows.

Compounds of formulas I, Ia and II, in which R6is hydrogen, C1-C6the alkyl, C3-C8cycloalkyl or/CH2/p-Y in which p has already been defined in formulas I, Ia and II, and Y is cyano, or NR10R11in which R10and R11each independently is hydrogen or C1-C6the alkyl, can be obtained using the procedure described in the above reaction scheme. Alternatively, rodann can be used for condensation with aldehyde or derivative of the aldehyde, forming these types of compounds in which R6is hydrogen, followed by alkylation or acylation with the corresponding containing R6, the halide. Alkiline methylformamide and in the presence of a strong base, such as sodium hydride.

Alternatively, compounds of formulas I, Ia and II, in which R6is/CH2/p-Y, where Y is cyano, can be obtained by treatment nationalaverage analog galazalinum aliphatic nitrile. This cyanoderivatives tetrazolyl get by treatment with azide tri-N-butyl tin, for example, dimethyl simple ether of ethylene glycol.

Compounds of formulas I, Ia and II, in which R6is/CH2/p-Y /p=0 / and Y is NR10R11in which R10and R11have already been defined in formulas I, Ia and II, can be obtained by using the appropriately substituted hydrazine. In this sequence of reactions of benzaldehyde interacts with an appropriately substituted hydrazine in an alcohol solvent, giving III. Then appropriately substituted alkyl halide interacts with III in the presence of triethylamine and acetonitrile to give IV, which then interacts with hydrazine, providing R10, R11hydrazine V. Compound V can be alternatively obtained by restoring nitroso-R10R11Amin, using Zinkova with carbon disulfide, Chloroacetic acid and triethylamine, to obtain the intermediate compound VI. Condensation of compound VI appropriately substituted aromatic aldehyde or derivative of the aldehyde gives the target product, which seems to be following reaction scheme following claims.

In addition, Tihonova the proportion of the compound obtained above, can be recovered in the processing of regenerating agent such as a hydride tri-n-butyanova in an inert solvent, such as toluene, in the preferred embodiment, in the presence of a free radical initiator, such as azobisisobutyronitrile. The formation of compounds in which one of R10and R11is hydrogen, can be carried out before or after recovery thione, as required, by means of heating disubstituted compounds in a mixture of ethanol/water in the presence of a catalyst, such as rhodium catalyst.

Compounds of formulas I, Ia and II, in which R6is/CH2/p-Y, and Y is a OR8or NR10R11/in which R8is hydrogen, acetyl or tolilsulfonil, a R10and R11each independently is vodorodometanolnoj after the claims,

where Ts= Tamilselvan, oxyalkyl rodann obtained by condensation of carbon disulphide, Chloroacetic acid and the corresponding oxyalkylene using standard techniques. After condensation with an appropriately substituted aromatic aldehyde /or derived aldehyde/ as described above, the obtained product is condensed 2-thioxo-4-thiazolidinone VIII, who previously turned into acetylene derived. Dioxo-compound VIII can be converted into a methylene compound of formula I or II as described above. Acutiloba group of intermediate compounds IX can be removed by treatment with an aqueous solution of ammonia in a solvent such as acetonitrile to obtain compound X. Then oxycoedone X in turn derived tolilsulfonil by treatment with para-toluensulfonyl chloride in pyridine, in a preferred embodiment, at a temperature of about 0oC. a "universal" tolilsulfonil intermediate compound XI can then be converted into compounds of formulas I or II after processing the corresponding HNR10R11Amin. This last transformation is best carried out by the interaction of XI is veritel, as acetonitrile.

Those compounds in which m is 1 or 2, can be easily obtained from sulfide /m = 0/ as a result of processing oxidizing agent such as meta-chloroperbenzoic acid in an appropriate solvent for a time sufficient for "translation" in the target oxidized state.

Depending on the definitions of R1, R2and R3compounds of formulas I, Ia and II can exist in various isomeric forms. Compounds, compositions and methods that are the subject of the present invention is not tied to any particular isomer but includes all possible isomers and racemates.

Every expert in this field of technology, it should be clear that the aromatic portion of the compounds that are the subject of the present invention or the compounds used according to the method of the present invention/, can be achieved by using compounds that were either manufactured by the industry, or can be easily obtained by using known methods of manufacture industry raw materials. Similarly, rodann or N-substituted Rodnikovy material or produced by the industry, or may be obtained using well-known career illustrate the formation of compounds, which is the subject of the present invention, as well as compounds which can be obtained according to the method of the present invention. These examples serve only the purposes of illustration and should not be considered as limitations of the present invention.

Example 1

5-[/3-Methanesulfonamide/methylene]-2-thioxo-4-thiazolidinone

Thirty-seven grams /185,9 mmole/ 3-methanesulfonamido-benzaldehyde, 25,0 g /187,9 mmole/ Rodnina, 48,0 g /585,3 mmole/ anhydrous sodium acetate and 950 ml of acetic acid was stirred while heating to a temperature of reflux distilled for 20 hours. Then the reaction was stirred at room temperature for about 60 hours. The resulting slurry was poured into a 3,000 ml of 1:1 mixture of ethanol/water. Solid particles to precipitate, which was recovered by filtration, washed with water, and then dried under vacuum to obtain 54 g of compound header example, the melting point 260 - 265oC.

Analysis for C11H10N2O3S3:

Calculated: C, 42,02, H, 3,20, N, 8,91;

Found: C, 42,15, H, 3,57, N, 8,71.

Example 2

5-[/1,3-Benzodioxol-5-yl/methylene]-2-thioxo-4-thiazolidinone

Twenty grams /133,2 mmole/ piperonal Zaimov for about 3 hours. Then the mixture was poured into water and stirred over night. The precipitate, which was removed by filtration, and then dried over night, give 27.8 g connection header example. The temperature of the melting point: 194 - 195oC.

Analysis for C11H7N1O3S2:

Calculated: C, 49, 80mm, H, 2,66, N, 5,28, S, 24,17.

Found: C, 50,04, H, 2,38, N, 5,27, S, 23,98.

Example 3

5-[/4-Chinoline/methylene]-2-thioxo-4-thiazolidinone

Rodanim (2.2 g, of 16.5 mmole), 1.3 ml of concentrated hydroxide ammonium and 1 g of ammonium chloride in 20 ml of ethanol was heated in a steam bath for 15 minutes. Added 4-quinoline carboxaldehyde /2.6 g, of 16.5 mmole / and the resulting mixture was heated in a steam bath for one hour. Upon cooling to 5oC fell sediment. This precipitate was removed by filtration, and then washed with water to obtain 4 g of the compound from the header of example, the melting point 325 - 328oC.

Analysis for C13H8N2OS2:

Calculated: C, 57,33, H, 2,96, N, 10,29.

Found: C, 57,11, H, 3,11, N, Of 10.21.

Example 4

5-/Diphenylmethylene/-2-thioxo-4-thiazolidinone

One hundred ninety grams /1,05 mol/diphenyl ketimine, 140 grams /1,05 mol/ ro who were given the crystals. The solvent was decanted, added fresh toluene to the residue, and the resulting suspension was filtered. The extracted crystals were subjected to recrystallization from methanol, to obtain 172,0 g connection header example, the melting point 192 - 194oC.

Analysis for C16H11NOS2:

Calculated: C, 64,62, H, Of 3.73, O, 5,38, N, 4,71, S, 21,56.

Found: C, 64,13, H, 3,84, O, To 5.57, N, 4,59, S, 22,38.

Example 5

5-[/4-Phenoxyphenyl/methylene]-2-thioxo-4-thiazolidinone

A mixture of 9.9 g /50.0 mmol/ 4-phenoxybenzaldehyde, 6.8 g /51,1 mmole/ Rodnina, 15.5 g of sodium acetate and 60 ml of acetic acid was heated on the steam bath for two hours. The reaction solution is then poured into water, after which the crude product is precipitated. The precipitate was filtered and then washed successively with water, then diethyl simple ether to obtain 8.6 g of the compound from the header of example, the melting point 195 - 200oC.

Analysis for C16H11NO2S2:

Calculated: C, 61,32, H, 3,54, N, 4,47.

Found: C, 61,07, H, 3,63, N, 4,47.

The following compounds were synthesized using procedures which are essentially equivalent to those described in examples 1 to 5 above and p is of 202 - 203,5oC.

Example 7

5-[/2 Oksifenil/methylene] -2-thioxo-4-thiazolidinone, melting point 220 - 222oC.

Example 8

5-[/4 Oksifenil/methylene] -2-thioxo-4-thiazolidinone, the melting point 287 - 290oC.

Example 9

5-[/2-Nitrophenyl/methylene] -2-thioxo-4-thiazolidinone, the melting point 197,5 - 199oC.

Example 10

5-[/3-Nitrophenyl/methylene] -2-thioxo-4-thiazolidinone, the melting point 277 - 280oC.

Example 11

5-[/3 Oksifenil/methylene] -2-thioxo-4-thiazolidinone, melting point 242 - 244oC.

Example 12

5-[/2,4-Acid/methylene] -2-thioxo-4-thiazolidinone, melting point 253 - 255oC.

Example 13

5-[/4-Forfinal/methylene] -2-thioxo-4-thiazolidinone, melting point 225 - 227oC.

Example 14

5-[/2-Thienyl/methylene] -2-thioxo-4-thiazolidinone, melting point 231 - 233oC.

Example 15

5-[/2-Furanyl/methylene] -2-thioxo-4-thiazolidinone, melting point 217 - 219oC.

Example 16

5-[/4-Pyridyl/methylene] -2-thioxo-4-thiazolidinone, the melting point 297 - 298oC.

Example 17

P> Example 18

5-[/4-Methoxyphenyl/methylene] -2-thioxo-4-thiazolidinone, melting point 252 - 254oC.

Example 19

5-[/3,4,5-Trimethoxyphenyl/METROTILE] -2-thioxo-4-thiazolidinone, melting point 210 to 213oC.

Example 20

5-[/3-Methoxy-4 oksifenil/methylene] -2-thioxo-4-thiazolidinone, melting point 229 - 231oC.

Example 21

5-[/4-Methoxyphenyl/phenylmethylene] -2-thioxo-4-thiazolidinone, melting point 169 - 171oC.

Example 22

5-[/3-Pyridyl/methylene] -2-thioxo-4-thiazolidinone, the melting point 286oC.

Example 23

5-[/3-Chlorophenyl/methylene] -2-thioxo-4-thiazolidinone, melting point 233 - 235oC.

Example 24

5-[/2,3-Acid/methylene]-2-thioxo-4-thiazolidinone.

Example 25

5-[/3-Methoxyphenyl/methylene]-2-thioxo-4-thiazolidinone.

Example 26

5-[/2-Methoxyphenyl/methylene]-2-thioxo-4-thiazolidinone.

Example 27

5-[/3-Methyl-4-methoxyphenyl/methylene]-2-thioxo-4-thiazolidinone.

Example 28

5-[[3,5-bis/1,1-dimethylethyl/-4 oksifenil] -methylene] -2-thioxo-4-thiazolidinone, melting point 260oC.

Example 29

5-[[/1,1'-beef is oxo-4-thiazolidinone, the melting point 146 -148oC.

Example 31

5-[/3-Methoxy-4-epoxyphenol/methylene]-2-thioxo-4-thiazolidinone, melting point 130 - 132oC.

Example 32

5-[/3-Ethoxy-4 oksifenil/methylene] -2-thioxo-4-thiazolidinone, melting point 217 - 217,5oC.

Example 33

5-[/3-Were/methylene] -2-thioxo-4-thiazolidinone, melting point 197 - 202oC.

Example 34

5-[/4-Were/methylene] -2-thioxo-4-thiazolidinone, melting point 229 - 234oC.

Example 35

5-[/2-Naphthalenyl/methylene] -2-thioxo-4-thiazolidinone, melting point 224 - 225oC.

Example 36

5-[/3,4-Dichlorophenyl/methylene]-2-thioxo-4-thiazolidinone.

Example 37

4-[/2 Tikoo-4-thiazolidinone/methylene] benzoic acid, melting point 320oC.

Example 38

5-[/3,4-Dioxyphenyl/methylene]-2-thioxo-4-thiazolidinone.

Example 39

5-[/1H-indol-3-yl/methylene]-2-thioxo-4-thiazolidinone.

Example 40

5-[/3-Hydroxy-4-methoxyphenyl/methylene] -2-thioxo-4-thiazolidinone, melting point 218 - 220oC.

Example 41

5-[/3-Methoxy-4-butoxyphenyl/methylene] -2-thioxo-4-thiazolidinone, tempero, the melting point 245 - 250oC.

Example 43

5-[/3-Hydroxy-4-nitrophenyl/methylene] -2-thioxo-4-thiazolidinone, melting point 224oC.

Example 44

5-[/3 Oksifenil/METROTILE]-2-thioxo-4-thiazolidinone.

Example 45

5-[/3-Methoxy-4-phenoxyphenyl/methylene]-2-thioxo-4-thiazolidinone, melting point 170 - 171oC.

Example 46

5-[/3-Hydroxy-4-ethoxyphenyl/methylene] -2-thioxo-4-thiazolidinone, melting point > 225oC.

Example 47

5-[/4-Phenoxyphenyl/methylene] -2-thioxo-4-thiazolidinone, the melting point 158,5 - 160oC.

Example 48

5-[/3-Methoxy-4-ethoxyphenyl/methylene]-2-thioxo-4-thiazolidinone, melting point 207 - 207,5oC.

Example 49

5-[/3-Ethoxy-4-propoxyphenyl/methylene] -2-thioxo-4-thiazolidinone, melting point 156 - 157oC.

Example 50

5-[/3-Propoxy-4-ethoxyphenyl/methylene] -2-thioxo-4-thiazolidinone, the melting point 186,5 - 188oC.

Example 51

5-[/3,4-Dibromobiphenyl/methylene] -2-thioxo-4-thiazolidinone, the melting point 167,5 - 168,5oC.

Example 52

5-[/3-Methoxy-4-butoxyphenyl/methylene] -2-thioxo-4-thiazolidin/-4 oksifenil] methylene] -4 - oxo-2-thioxo-3-thiazolidine acetic acid, the melting point 265oC.

Example 54

5-[/3-Methoxy-4-butoxyphenyl/methyl]-2-thioxo-4-thiazolidinone, melting point 152 - 153,5oC.

Example 55

5-[/3,5-Dichloro-4 oksifenil/methylene]-2-thioxo-4-thiazolidinone, melting point > 260oC.

Example 56

5-[/3-Ethoxy-4-butoxyphenyl/methylene]-2-thioxo-4-thiazolidinone.

Example 57

Sodium salt of 5-[/3-methoxy-4-phenoxyphenyl/methylene]-2 - thioxo-4-thiazolidinone, melting point 254oC.

Example 58

5-[/3-Ethoxy-4-methoxyphenyl/methylene]-2-thioxo-4-thiazolidinone, melting point > 225oC.

Example 59

5-[[3,5-bis/1-methylpropyl/-4 oksifenil] methylene]-4-oxo-2 - thioxo-3-thiazolidine acetic acid, melting point 191 - 193oC.

Example 60

5-[/3,4-Acid/methylene]-2-thioxo-4-thiazolidinone.

Example 61

5-[/4-Butoxyphenyl/methylene] -2-thioxo-4-thiazolidinone, melting point 180oC.

Example 62

5-[/3,5-Dimethyl-4 oksifenil/methylene]-2-thioxo-4-thiazolidinone, melting point 260oC.

Example 63

5-[/3,5-Dimethoxy-4 oksifenil/methylene]-2-thioxo-4-thiazolidinone, A-4-thiazolidinone, the melting point 163 - 164oC.

Example 65

5-[/3-Methoxy-4-phenoxyphenyl/methylene/2-thioxo-3-methyl-4 - thiazolidinone, melting point 117 - 118oC.

Example 66

5-[/3-Methoxy-4-phenoxyphenyl/methylene]-4-thiazolidinone, melting point 174 - 175oC.

Example 67

5-[/3-Methoxy-4-phenoxyphenyl/methyl] -4-thiazolidinone, the melting point of 108 - 109oC.

Example 68

5-[/3-Methoxy-4-hexoxyethanol/methylene]-2-thioxo-4-thiazolidinone.

Example 69

5-[/3-Methoxy-4-acetoxyphenyl/methylene]-2-thioxo-4-thiazolidinone, melting point 125 - 127oC.

Example 70

5-[/3,5-Dimethoxy-4-phenoxyphenyl/methylene] -2-thioxo-4 - thiazolidinone, melting point 166 - 167oC.

Example 71

5-[[3-/1,1-Dimethylethyl/4-hydroxy-5-/methylthiophenyl/phenyl] -methylene] - 2-thioxo-4-thiazolidinone, melting point 181 - 184oC.

Example 72

5-[[3-Ethoxy-4-hydroxy-5-/methylthiophenyl/phenyl] methylene] -2-thioxo - 4-thiazolidinone, melting point 190 - 192oC.

Example 73

5-[[3-Ethoxy-4-hydroxy-5-/methylthiophenyl/phenyl] methylene]-2-thioxo - 3-methyl-4-thiazolidinone, melting point 137< is acetic acid, the melting point 202 - 206oC.

Example 75

5-[/1-Naphthyl/methylene] -2-thioxo-4-thiazolidinone, melting point 224 - 225oC.

Example 76

5-[/2-Naphthyl/METROTILE]-2-thioxo-4-thiazolidinone.

Example 77

5-[/3-Phenoxyphenyl/methylene]-2-thioxo-4-thiazolidinone.

Example 78

5-[/3-Phenoxyphenyl/METROTILE]-2-thioxo-4-thiazolidinone.

Example 79

5-[[3-/Metalucifer/phenyl] methylene] -2-thioxo-4-thiazolidinone, melting point 177 - 180oC.

Example 80

5-[/3-Methoxy-4-epoxyphenol/methylene]-2-thioxo-3-amino - 4-thiazolidinone, melting point 118 - 121oC (decomposition).

Example 81

5-[/3-Methoxy-4-epoxyphenol/methylene] -2-thioxo-3-dimethylamino-4-thiazolidinone

Two hundred and fifty milligrams /1 mmol/ 3-methoxy-4-epoxy benzaldehyde, 233 mg /1.2 mmole/ 2-/ N-dimethylamino-dithiocarboxylic/ acetic acid /compound of formula VI, above/ 330 mg /4 mmole/ anhydrous sodium acetate and 5 ml of acetic acid was stirred while heating to a temperature of reflux distilled for 15 hours. Then the reaction was rapidly cooled by dumping the reaction solution in 10 ml of a mixture of ice/water. The resulting solids retrieve example. The crude compound was subjected to purification via recrystallization from hexane/methylene chloride to obtain 180 mg of pure compound of the title of the example, the melting point of 105 - 108oC.

Example 82

5-[[4-/Dimethylamine/phenyl]methylene]-2-thioxo-4-thiazolidinone.

Example 83

5-[/4-Epoxyphenol/methylene] -2-thioxo-3-dimethylamino-4 - thiazolidinone, melting point 80oC.

In accordance with this invention proposes a method of reducing the concentration of blood glucose in mammals, containing the use of therapeutically effective amounts of compounds of formula I. the Term "therapeutically effective amount", as used here, denotes the number of connections, which is necessary in order to ensure that the hypoglycemic effect after application, in the preferred embodiment, to the person suffering the "older" forms of diabetes.

The hypoglycemic activity of the compounds that are the subject of the present invention, was determined through testing the effectiveness of these compounds in vivo in male viable yellow mice with obesity on diabetes. The test procedure is described in detail n the solution, contains 2% Emulphor /polyoxyethylene surface-active agent of vegetable oil, the company GAF Corp./, in order to obtain the required dose levels. Each test composition was applied to six viable yellow mice suffering from "obesity" by diabetes, intraperitoneal way in the beginning of the experiment. The concentration of blood glucose was determined immediately before the first dose and after 2 and 4 hours using glucose oxidase. Calculated a mean value of 6 values obtained before the first dose and after 2 - and 4-hour intervals. The average values after 2 and 4 hours, calculated as percentages of the average for the first dose, are shown in table 1. In table 1 (see end of description) in column 1 are numbers of examples of the test compound, column 2 shows the concentration of doses of the test compounds, and in columns 3 and 4 shows the results of measurements of the concentrations of glucose in blood of the test animals after 2 and 4 hours after application of the test compounds, respectively, in the form of glucose concentration in blood of the test animal in the percentage concentration before the test.

The hypoglycemic activity of compounds from whom the Wali standard food. The procedure used in this test system, described below.

In this test system used rats /male/ type Sprague Dauley /firm Charles River Labaratories/ weight 175 - 200 g of the Test composition was obtained by suspension of the test compound in 5% solution of acacia /concentration of drug was regulated so that tematicheskoe introduction of 0.25 ml /100 g of body gave the target dose in recalculation on weight of a body. The target dose of each test composition was applied to four rats using tematicheskoe gastric probe at the beginning of the experiment. The concentration of blood glucose was determined immediately before the first dose and after 3 and 5 hours using enzymatic procedures using glucose oxidase and peroxidase glucose associated with a chromogenic oxygen acceptor. Calculated a mean value of 4 values obtained before the first dose and after 3 and 5 hours. The average values after 3 and 5 hours, calculated in percent from the average for the first dose, are collected in table 2. In table 2 (see end of description) column 1 shows the number of sample for the test compound, column 2 shows the dose tested is connected to the wall 3 and 5 hours after administration of the test compounds, respectively, in the form of interest on the concentration of glucose in blood of the test animal before administration of the drug.

The hypoglycemic activity of the compounds that are the subject of the present invention was confirmed in the third system, in vivo tests; namely, in the test system on the basis of diabetic Zucker rats /diabetic obese Zucker rats/. Rats used in this testing were age 6 to 8 months, a lot of from 550 to 625 grams, as well as the concentration of glucose in the blood before the introduction of the drug in the region from 250 to 350 mg/DL. Used the same procedure that was used in the test system on the basis of rats with standard feeding, which was described above. The results of these tests are shown in table 3 (see the end of the description). The format of table 3 is the same as was used in table 2.

Finally, the duration of the hypoglycemic activity of the compounds that are the subject of the present invention, was tested in another system in vivo tests. This system tests the duration of action is included in the test compounds in feed test animals at various concentrations /food control animals did not include the test compound/. Such a diet then used to feed the test or control animal is raised /volume blood samples of 200 400 µl/ 0 /before feeding the above diet/, 7, 14 and, if necessary, on 21 and 28 days after the beginning of application of the above diets. Then received samples of plasma from each blood sample collected previously, and the enzyme was determined glucose concentration in these plasma samples.

The results for the test system prolonged hypoglycemic effect is shown in table 4 (see the end of the description), in column 1 type of rodent used in the test system, in column 2 the number of sample for test compounds or indicated that the numbers correspond to control the animal, column 3 shows the concentration in percent of the test compound in the diet of the test or control of the animal. In columns 4 - 8 shows the concentration of glucose in plasma at 0, 7, 14 and, when necessary, on 21 and 26 days, respectively, for the test animals. The decrease in glucose concentration was not associated with decreased feed intake.

In accordance with the present invention a method of treating Alzheimer's disease in mammals, containing the use of therapeutically effective amounts of compounds of formula Ia. The term "therapeutically apterae need to reduce, full suppression or prevention of physiological effects or complications of Alzheimer's disease, in the preferred embodiment, a person suffering from or prone to Alzheimer's disease.

Disease Alzheimer's disease is a degenerative brain disorder in humans. Clinically it manifests as progressive dementia. Its histopathology is characterized by degeneration of neurons, gliosis and abnormal deposition of proteins in the brain. Reminiscent of protein deposits /called "amyloids"/ occur in the form neurofibrillary "tangles, amyloid cores plates and amyloid congophilic angiopathy. [About review, see Alzheimer's Disease, /Ed. B. Reisberg, ed. The Free Press, 1983/].

At that time, as there is no common opinion on the chemical nature neurofibrillary tangles, as the main component of amyloid cores plates, and amyloid congophilic angiopathy, as shown, is a protein 4500 daltons, which was originally called - protein or amyloid A4. Throughout this patent description this protein is referred to as - amyloid peptide or protein.

- amyloid peptide proteolytic get pic is in, pre-amyloid, are encoded well-expressed gene, see, for example, K. Beyreuther, and B. Muller - Hill, Annual Reviews in Biochemistry I. 58, pages 287 - 307 /1989 /. - amyloid peptide is in its longest form of the 42 or 43 amino acid residues, J. Kang, and others, Nature /London/, so 325, pp. 733-736 /1987/. These peptides, however, have variable aminooctane, C. Hilbich, and others, Journal of Moleculav Biology I. 218, pp. 149 - 163 (1991).

As "senile" vinyl constantly surrounded by dystrophic narinari previously, it was suggested that-amyloid peptide is involved in the process of destruction of neural cells that occurs in Alzheimer's disease, B. YanKner and staff were the first who proved that synthetic-amyloid peptide can be neurotoxic in vitro and in vivo, B. A. YanKner, etc., Science, I. 245, page 417 /1989 /; see also N. W. Kowall and others , Proc. J. the National Acad. Sci. USA., so 88 p. 7247 /1991/. Other groups of researchers, however, could not reliably confirm the direct toxicity-amyloid peptide, see, e.g., Neurobiology of Aging so 13, page 535 /K. KosiK and P. Coleman amended 1992 /. Some groups receiving-amyloid peptide from the same source, was obtained conflicting results, D. Price, and others, Neurobiology of Aging so 13, pages 623 - 625 /1991 / /and links, leads the TCI RDAs, which can lead to the formation of-amyloid protein and subsequent to the formation of "old" records. It seems plausible that such an alternative method of processing takes place in the lysosomes. It was found that compounds that inhibit lysosomal enzymes, inhibit the formation of these fragments, see, for example, Science, T. 155, page 689 /1992/.

Lysosome is a diaphragm tank of hydrolytic enzymes that are responsible for intracellular digestion" of macromolecules. It is known that complementary mechanism contain approximately forty hydrolytic enzymes, including protease, glycosidase, lipases, phospholipases, phosphatases and sulfatase. All these enzymes are acid hydrolases that have optimal activity at a pH of about 5. It is therefore necessary to determine which enzyme or enzymes are responsible for such alternative processing of APP and the subsequent formation of-amyloid protein.

Abnormally high concentrations of proteases cathepsins D and B were noted in the brain of patients with early Alzheimer's disease, Yu Nakamura and others, Neuroscience Letters so 130, pages 195 - 198 /1991/. In addition, increased activity of cathepsin D was about the /1986/. Cathepsin D is a lysosomal-endoproteases, which is found in all mammalian cells, see, for example, "Proteinases in Mammalian Cells and Tissues" /Ed. A. J. Barret/, 1977, pages 209 - 248. As a lysosomal enzyme known only bartlova protease.

Cathepsins are a family of enzymes hydrolases, which are usually contained in the lysosomes. These enzymes are endopeptidases with acidic optimum pH. Cathepsin is A carboxypeptidase serum, cathepsin C [EC 3.4.14.1] is peptidases of dipeptidyl, cathepsin D /EC 3.4.23.5/ is ispartially protease, and cathepsin B2[EC 3.4.16.1] is carboxypeptidase serum. Cathepsin B [EC 3.4.22.1] /also known as cathepsin B1/ and cathepsin L [EC 3.4.22.15] are thiol proteases with activity inside the lysosomes.

It was found that the inhibition of cathepsin D using the inhibitor ispartially protease, reduces the formation of-amyloid protein and the "result" of old records. Thus, compounds that inhibit cathepsins /and, in particular, cathepsin D/ or reduce the formation of-amyloid protein, as you might expect, will be useful in the treatment of Alzheimer's disease. Target activin D

For measuring the activity of renin used fluorometric analysis extracted from the procedures Mirakami and other, Anal. Biochem, T. 110, pages 232-239 /1981/. Cathepsin D human liver /firm Athens Research and Technology, Athens, G. A./ diluted in analytical buffer, 200 mm NaOAc, pH 4.5, 150 mm NaCl to 500 ng/ml, and then 100 μl of this solution cathepsin D was added to each well of the plate with 96 holes except the control wells, which added only 100 ál analytical buffer. Solutions of the compounds were obtained by dissolving a sufficient quantity of each compound to be tested in DMSO to obtain a 10 mg/ml concentration of test compound in DMSO, and then 5 μl of a solution of compounds were added to each of the holes that have been previously prepared. Clean and enzyme control wells received (each) 5 μl of the medium, DMSO.

After incubation for ten minutes at a temperature of 25oC to ensure the interaction of the enzyme/compound, was added 5 μl of a 500 μm solution derived is known fluorometric substrate tetradecapeptide porcine renin /Bachem Biosciences, Inc. Catalog 1993 ID N 1 - 1340; firm Bachem Biosciences, Philadelphia, PA/ DMSO per well to initiate the reaction. After incubation/ml microsomal amino peptidases of leucine/ EC 3.4.11.2, the company Sigma, St. Louis, MO/ 1 M Tris-HCl, pH 8.0.

Then the tablets were analyzed fluorometer /firm Millipore type Cyto Fluor 2350, Bedford MA/ s wavelength excitation 360 nm and emission wavelength of 460 them in order to check the basic fluorescence caused by the test compounds. After two hours incubation at 37 ° oC, to allow aminopeptidase to release the fluorophore, 7-amido-4 - methylcoumarin (AMC) from the products of cleavage of cathepsin D, tablets were again analyzed fluorometer. In order to establish potential false positive additives, i.e. inhibitors of microsomal amino peptidases of leucine, analyzed the residual activity of amino peptidases directly in each well by adding 20 μl/well of 2.5 mm Leu - pNA /firm Bacbem Biosciences, Philadelphia, PA/ 10% DMSO. The amino peptidases activity was measured through the increase of absorption in the range of 405 to them on a reading means for microplate in the UV rangemax/company Molecular Devices, Menlo Park, CA/.

The activity of cathepsin D was linear under these conditions, and the results from control experiments are shown in table 5 below. All these results are presented in the form of the mean value and the motion for inhibition of cathepsin D

Example N - % inhibition of cathepsin D

1 - 36

4 - 50

5 - 74

6 - 29

8 - 64

18 - 38

42 - 88

45 - 62

50 - 40

55 - 90

75 - 43

76 - 32

77 - 87

81 - 21

82 - 79

82 - 68

83 - 47

IC50activity for the inhibition of cathepsin D

The above analysis was repeated with the exception that the solutions of the compounds were obtained in different concentrations, different from 10 μg/ml with the fact that you can get the IC50-values /concentrations of the test compounds, which have a 50% inhibition of cathepsin D/ for the test compounds. The results obtained from this analytical system, are shown in table 6, which is placed below.

Table 6

Example N - IC50(mg/ml)

5 - 2.6

28 - 3.1

31 - 1.6

35 - 8.9

42 - 1.6

47 - 5.2

56 - > 4.15

68 - 3.4

68 - 1.4

69 - 2.4

71 - 1.2

71 - 4.8

77 - 4.5

78 - 25.0

79 - 3.7

80 - 47.0

Inhibition of the production of - amyloid protein

Two lines of cells /cell line 293 human kidney and the cell line CHO Chinese hamster ovary/ stable were subjected to transfection with the gene for APP751 containing the double mutation of Lys-651-Met-652 in Asn-651-Leu-652 /numbering APP-751/ called Sri transfected cells were identified through 293 751 SWE and CHO 751 SWE and put it on the tablets of the type Corning with 96 wells at a concentration of 2.5 to 104or 1 of 104cells per well, respectively, in minimum essential medium Dulbecco /DMEM/ 10% serum embryo calf. After incubation over night at 37 ° oC in the incubator, balanced 10% carbon dioxide /CO2/, the medium was removed and replaced with 200 µl per well of a modified environment /environment containing solutions of compounds; solutions of the compounds were diluted with medium so that the concentration of DMSO in the solution environment /solution compounds did not exceed 0.5%/ during a two-hour pre-treatment, during which cells were incubated as described above. These solutions of the compounds were obtained by dissolving sufficient quantities of specific compounds to be tested in DMSO to obtain a 10 mg/ml concentration. After this period of pre-processing the modified medium was removed and replaced with fresh modified medium, and cells were incubated for another two hours.

After treatment, the plates were centrifuged in a centrifuge Bekman GPR with a speed of 1,200 rpm for five minutes at room temperature in order to obtain the pill from the cell fragments modified environment. From each well, 100 μl of Modific. 359, page 325 -327 /1992/] and kept at a temperature of 4oC during the night before completion of the analysis ELIZA few days.

Cytotoxic effects of the compounds were measured using a modification of the procedure proposed by Hansen and others, J. Immun. Meth, I. 119, pages 203 - 210 /1989/. Cells remaining on the plate in the cultural fabric, was added 25 μl of a solution of bromide 3-/4,5-dimethylthiazol-2-yl/- 2,5 - diphenyltetrazolium /MTT/ 5 mg /ml to a final concentration of 1 mg/ml Cells were incubated at 37oC for one hour and cellular activity was blocked by addition of an equal volume of MTT-buffer for lysis /20% weight/volume of sodium dodecyl sulfate in 50% DMF, pH 4,5/. Complete extraction was achieved with shaking overnight at room temperature. The difference in OD*562nmand OD*650nmmeasured by the reading means for microplate type Molecular Devices UVmaxas an indicator of cell viability.

The results of ELISA analysis-amyloid protein was compared with a standard curve and expressed as ng/ml of peptide-amyloid protein. In order to normalize the results when determining the cytotoxicity of these results for - amyloid proto testing, containing no drug.

*OD - optical density (Tr)

Table 7

Inhibition -/ amyloid protein

Example N - % inhibiting-amyloid protein

5 - 47

5 - 58

31 - 58

42 - 52

70 - 38

71 - 65

77 - 25

81 - 100

As you can see from the data presented in tables 5, 6 and 7, the compounds of formula Ia can be used for preventive and/or therapeutic treatment of diseases associated with the deposition of-amyloid protein such as Alzheimer's disease, down's syndrome and the rapid aging of the brain. In therapeutic applications, the compounds were applied to the host, which is already suffering from such disease. These compounds can be applied in a quantity sufficient to inhibit further deposition plates-amyloid protein.

For prophylactic applications, the compounds of formula Ia applied to the host susceptible to Alzheimer's disease or a disease associated with amyloid protein, but not yet suffering from this disease. This owner can be identified through genetic screening and clinical analysis, as described in the medical literature, stenok-amyloid protein in the symptoms of early stage in a preferred embodiment, prevent early stages of the disease associated with amyloid protein.

Compounds that are the subject of the present invention and the compounds used according to the method of the present invention is effective in a wide range of doses. For example, the daily dose can be changed in the field from about 0.5 to about 500 mg/kg of body weight. In the treatment of adults region from about 1.0 to about 100 mg/kg, in single or multiple doses, is preferred. However, it is obvious that the number of connections, which really should be applied will be determined by the doctor depending on the attendant circumstances, which include the disease to be treated, the choice of compound that is administered to the patient, age, weight and response of each patient, the severity of symptoms of the patient and the choice of method of application. So the above area doses may not be considered as limiting the present invention. Despite the fact that the proposed connection in the preferred embodiment, is used tematicheskim way, you can also apply them in a variety of other ways, such the and that it is possible to use compounds which are the subject of the present invention, or the compounds used according to the present method directly, these compounds in the preferred embodiment, is used in the form of pharmaceutical compositions containing acceptable from a pharmaceutical point of view, the carrier, diluent or excipient and a compound of the present invention. Such compositions will contain from about 0.01 percent to about 90 percent of the compounds that are the subject of the present invention.

Upon receipt of the compositions that are the subject of the present invention, the active ingredient in the General case, is mixed with at least one carrier, or diluted by at least one carrier, or turn it inside carrier, which may be in the form of capsules, pills, paper or other container. When the carrier serves as a diluent, it may be solid, semi-solid or liquid material which acts as a carrier, excipient or medium for the active ingredient. Thus, the compositions can be in the form of tablets, granules, beads, powders, pellets, pills, starch capsules, elixirs, emulsions, solutions, seropositivity media diluents and excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginate, liquid paraffin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, tragakant, gelatin, syrup, methylcellulose, methyl - and propyl-oxybenzoates, vegetable oils, such as olive oil, organic esters for injection, such as etiloleat, talc, magnesium stearate, water, and mineral oil. The composition may also include wettable powders, lubricating agents, emulsifying and suspendresume agents, preservative agents, flavoring agents, flavoring agents, stabilizing agents or fragrance agents. The composition which is the subject of the present invention, can be manufactured in such a way as to provide quick, sustained or delayed release of the active ingredient after application to the patient using procedures that are well known in this technical field.

When staticheskom the use of compounds of the present invention or the compounds used according to the present method, in the ideal case can be admixed with carriers and diluents, and then a mixture of four is given in the form of a unit dose, containing from about 1 to about 500 mg, in a preferred embodiment, from about 5 to about 300 mg, of the active ingredient. The term "form of a unit dosage" refers to physically discrete unit doses that are suitable for use as a standard doses to humans and other mammals, each unit dose contains a predetermined quantity of active material calculated in such a way as to provide a target therapeutic effect, together with acceptable from a pharmaceutical point of view by carrier, diluent or excipient.

In order to more fully illustrate the implementation of the present invention, the following examples of various compositions. These examples are purely for purposes of illustration, and should not be construed as limiting the present invention. In these compositions as the active compounds can be used any compound which is the subject of the present invention.

Example 84

Composition 1

Hard gelatin capsules suitable for use for the treatment of Alzheimer's disease or reduced glucose concentration was obtained using the following the s capsule /460 mg/.

Example 85

Composition 2

Capsules, each containing 20 mg of the drug, was prepared as follows (table 9).

The active ingredient, cellulose, starch and magnesium stearate were mixed, passed through a sieve No. 45 mesh U.S. /0,41 mm - diameter holes - AC/, and the obtained mixture was filled in hard gelatin capsule.

Example 86

Composition 3

Capsules, each containing 100 mg of active ingredient, was prepared as follows (table 10).

These ingredients were thoroughly mixed and placed in an empty gelatin capsule.

Example 87

Composition 4

Tablets, each containing 10 mg of active ingredient, was prepared as follows (table 11).

The active ingredient, starch and cellulose was passed through sieve No. 45 mesh U.S. /0,41 mm - diameter holes trans./ and thoroughly mixed. The solution of polyvinylpyrrolidone were mixed with the resultant powders which are then passed through sieve No. 14 mesh U.S. /1.4 mm - diameter holes - translation /. Thus obtained pellets were dried at a temperature of 50 - 60oC and passed through a sieve No. 18 mesh U.S. /1.1 mm - diameter holes - translation/. Carboxymethyl starch sodium, S./, then added to the granules which, after mixing extruded on the unit for the production of tablets, to obtain tablets weighing 100 mg.

Example 88

Composition 5

The tablet can be obtained by using the ingredients shown in table 12.

These components were mixed, and the mixture is then extruded to obtain tablets each having a weight of 665 mg

Example 89

Composition 6

Suspensions, each containing 5 mg of drug per dose in 40 ml, was prepared as follows: 5 ml suspension

The compound of example N 59 5 mg

The sodium carboxymethyl cellulose 50 mg

The syrup 1.25 ml

A solution of benzoic acid 0.10 ml

Flavouring substance on request

A coloring agent, if necessary

Water up to a volume of 5 ml

Medical agent was passed through sieve No. 45 mesh U.S. /0,41 mm - diameter holes trans. / and mixed with the sodium carboxymethyl cellulose and syrup to obtain a homogeneous paste. Under stirring was added diluted with some water mixture solution of benzoic acid, flavoring agents and coloring agent. Then added enough water, cobsea components, received as follows: - the Concentration by weight /%/

The compound of example N 53 - 0,25

Ethanol - 29,75

Spray agent 22 /Chlorodifluoromethane/ - 70,00 - 100,00

The active compound was mixed with ethanol and the mixture added to a portion of the spray agent 22, cooled to a temperature of -30oC and the resulting mixture was filled in a means for filling. Then the required amount of this mixture was placed in a stainless steel container and then diluted with the remaining amount of the spray agent. Then the container was supplied with the valve.

1. Derived Rodnina General formula

< / BR>
in which Ar is (i) phenyl, (ii) phenyl substituted by one to three substituents that are independently selected from C1- C8alkoxy, or-N(R7)SO2R7where each R7independently is hydrogen or C1- C6the alkyl, (iii) 1,3-benzodioxole;

R1is hydrogen or phenyl,

R2and R3each independently is hydrogen or taken together form a bond;

R4and R5each is hydrogen or together they form a = S;

R6is hydrogen or -(CH2)p-Y, where p is 0 and Y is-NRBR> m is 0,

provided that when Ar is phenyl or phenyl substituted WITH1- C8alkoxy, R1is hydrogen, R2and R3taken together form a bond, m is 0 and R4and R5taken together form a = S, R6must be other than hydrogen; when Ar is phenyl, substituted by two ethoxypropane in 3 - and 4-position of the phenyl ring, R1must be hydrogen, and its pharmaceutically acceptable salts.

2. Derived Rodnina, which is 5-[(3-methoxy-4-phenoxyphenyl)methylene] -2-thioxo-4-thiazolidinone or its pharmaceutically acceptable salt.

3. Derived Rodnina, which is 5-[[3-(1,1-dimethylethyl)-4-hydroxy-5-/methylthiophenyl/phenyl] methylene] -2-thioxo-4-thiazolidinone or its pharmaceutically acceptable salt.

4. Pharmaceutical composition having hypoglycemic activity, including an active agent and one or more pharmaceutically acceptable carriers, diluents or fillers, characterized in that it contains as an active agent derived Rodnina according to any one of paragraphs. 1 to 3 in an effective amount.

5. The method of obtaining derivatives of rhodanine on either the I 0 or NH;

Ar and R1defined in any of paragraphs.1 to 3,

with the compound of the formula

< / BR>
in which R4, R5, m, and R6defined in any of paragraphs.1 to 3,

obtaining the compounds of formula

< / BR>
6. The pharmaceutical composition intended to reduce the concentration of glucose in the blood, including an active agent and one or more pharmaceutically acceptable carriers, diluents or fillers, characterized in that it contains as an active agent derived Rodnina General formula

< / BR>
in which Ar is (i) phenyl, (ii) phenyl substituted by one to three substituents that are independently selected from C1- C8of alkyl, C1- C8alkoxy, C1- C8alkylthio, trifloromethyl,1- C4alkylphenyl, phenyl, NO2, F, Cl, hydroxy, phenoxy,1- C4allyloxyphenyl, thiophenyl,1- C4alkylthiophene, -N(R7)SO2R7- COOR7or-N(R7)2where each R7independently is hydrogen or C1- C6-alkyl, (iii) 1 - or 2 - naphthyl, (iv) 2 -, or 3-benzofuranyl, (v) 2 -, or 3-benzothiophene, (vi) 2 -, or 3-tanila, (vii) 2-, 3 - or 4 - pyridium, (viii) 2 -, or 3-TuranAlem, (ix) 1,3-benzodioxolyl, (x) C>R1is1- C6the alkyl, C1- C4alkylphenyl, hydrogen, phenyl or phenyl substituted by one or two substituents that are independently selected from Cl, Br, F, J, C1- C4of alkyl, C1- C4alkoxy, hydroxy, trifloromethyl, -NH2, -NH(C1- C4the alkyl), -N(C1- C4the alkyl)2or1- C4alkylthio;

R2and R3each is hydrogen or taken together form a bond;

R4and R5each is hydrogen or taken together form a = S, or if one of R4and R5is hydrogen, the other is-SCH3;

R6is hydrogen, C1- C6the alkyl, C3- C8cycloalkyl,2- C6alkenyl, -SO2CH3or -(CH2)p-Y, where R is 0,1,2 or 3, and Y is cyano, -OR8, tetrazolyl, -NR10R11, -SH, C1- C4alkylthio, or

< / BR>
in which R8is hydrogen, C1- C4the alkyl or

< / BR>
R9is hydrogen, C1- C4the alkyl, C1- C4alkoxy, hydroxy or NH2;

R10and R11each independently is hydrogen, C1- what kilfenora, -(CH2)qHE, -(CH2)qN(C1- C4by alkyl)2or -(CH2)qS (C1- C4by alkyl), where q is an integer from 1 to 6, inclusive,

or R10and R11taken together with the nitrogen atom to which they are attached, form morpholinyl, piperidinyl, piperazinilnom or N-methylpiperazine ring,

m is 0,1 or 2,

provided that Ar cannot be phenyl, substituted only by one horsenettle in the 4-position of the phenyl ring, Ar cannot be phenyl, substituted by COOH-group in 2-position of the phenyl ring, when Ar is phenyl, substituted by two ethoxypropane in 3 - and 4-positions of the phenyl rings, R1must be a hydrogen, Ar cannot be phenyl, substituted only two hydroxysultaine, and when R4and R5each is hydrogen, R6can't be WITH1- C6the alkyl,

or its pharmaceutically acceptable salt in an effective amount.

7. The pharmaceutical composition intended for the treatment of Alzheimer's disease, comprising an active agent and one or more pharmaceutically acceptable carriers, diluents or fillers, characterized in that the(ii) phenyl, substituted with one to three substituents that are independently selected from C1- C8of alkyl, C1- C8alkoxy, C1- C8alkylthio, trifloromethyl,1- C4alkylphenyl, phenyl, NO2, F, Cl, hydroxy, phenoxy,1- C4allyloxyphenyl, thiophenyl,1- C4alkylthiophene, - -COOR7, -N(R7)2or-N(R7)SO2R7where each R7is independently hydrogen or C1- C6the alkyl or (iii) 1 - or 2-naphthyl;

R1is1- C6the alkyl, C1- C4alkylphenyl, hydrogen, phenyl, or phenyl substituted by one or two substituents that are independently selected from Cl, Br, F, J, C1- C4of alkyl, C1- C4alkoxy, hydroxy, trifloromethyl, -NH2, -NH (C1- C4the alkyl), -N(C1- C4the alkyl)2or1- C4alkylthio;

R2and R3each is hydrogen or taken together form a bond;

R4and R5each is hydrogen or taken together form a =S, or if one of R4and R5is hydrogen, the other is-SCH3;

R6is hydrogen, C1- C6the alkyl, When R is equal to 0,1,2 or 3, and Y is cyano, -OR8,

tetrazolium, -NR10R11, -SH, C1- C4alkylthio, or

< / BR>
in which R8is hydrogen, C1- C4the alkyl or

R9is hydrogen, C1- C4the alkyl, C1- C4alkoxy, hydroxy or NH2and R10and R11each independently is hydrogen, C1- C6the alkyl, C2- C6alkenyl,2- C6the quinil, phenyl, C1- C4alkylphenyl, -(CH2)qOH, -(CH2)qN(C1- C4by alkyl)2or -(CH2)qS(C1- C4by alkyl), where q is an integer from 1 to 6, inclusive, or R10and R11taken together with the nitrogen atom to which they are attached, form morpholinyl, piperidinyl, piperazinilnom or N-methylpiperazine ring;

m is 0,1 or 2,

or its pharmaceutically acceptable salt in an effective amount.

 

Same patents:

The invention relates to new preparations of thiazolidinediones of the formula I, where A denotes a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic aromatic 5-or 6-membered ring containing an S atom or N; B is-CH=CH-; W represents O; X represents O; Y represents N; R represents pyridyl, thienyl or phenyl, in case you need one - or disubstituted C1-C3-alkyl, CF3, Cl or bromine; R1represents C1-C6-alkyl;n represents 2, and their tautomers, enantiomers, diastereomers or physiologically acceptable salts and medicinal product on the basis of their

The invention relates to the derivatives of saccharin General formula 1, where L denotes 0 or N; when L is 0, R1- 2,6-dichloro-3-[2-(4-morpholinyl)ethoxy] benzoyl, when L is N, then L together with R1represents a 4,5-di(tert-butylsulfonyl)-1,2,3-triazole-1-yl, R2primary or secondary alkyl of 2-4 carbon atoms, R3- lower alkoxy at any of the 5-, 6 - or 7-positions, or their pharmaceutically acceptable additive salts of acids or bases, which inhibit the activity of proteolytic enzymes

The invention relates to new benzothiophen-2-carboxamide-S,S-dioxides having valuable properties, in particular to derive benzothiophen-2-carboxamide - S,S-dioxide of the General formula I

< / BR>
where

R1unbranched or branched alkyl with 1 to 20 carbon atoms, unbranched or branched halogenated, cianelli, oxyalkyl, alkoxyalkyl or alkoxycarbonyl with 1 to 8 carbon atoms in each alkyl part, unbranched or branched alkenyl with 2 to 12 carbon atoms, unbranched or branched quinil with 2 to 12 carbon atoms or unsubstituted or once to six times substituted by alkyl cyclohexyl or cyclohexylmethyl, unsubstituted or once to fivefold substituted in the phenyl part of the same or different substituents phenyl, phenylalkyl or phenylalkyl with 1 to 12 carbon atoms in each unbranched or branched alkyl or alkenylphenol part, moreover, as substituents of the phenyl can be called a halogen atom, hydroxyl, cyano, formylamino, unbranched or branched alkyl, alkoxygroup with 1 to 4 carbon atoms, unbranched or branched girsvetlana or branched, dialkylamino, alkylsulphonyl, alkylcarboxylic, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, formylamino, alifornian;

R2a hydrogen atom or an unbranched or branched alkyl with 1 to 18 carbon atoms, unsubstituted or singly or multiply substituted by identical or different substituents from the group comprising hydroxyl group, a halogen atom, a cyano;

R1and R2together with the nitrogen atom to which they relate, signify unsubstituted or singly or multiply substituted, saturated five - to semicolony a heterocycle, which may contain in addition to the nitrogen atom, an oxygen atom and a Deputy may be alkoxycarbonyl with 1 to 4 carbon atoms;

R3, R4, R5and R6independently from each other mean a hydrogen atom, halogen atom, alkoxygroup with 1 to 6 carbon atoms

The invention relates to optically active derivative of carboxamides with a strong analgezirutuyu activity and low toxicity, or their pharmacologically suitable salts

The invention relates to the chemistry of heterocyclic compounds exhibiting inhibitory activity against elastase

The invention relates to a new above-mentioned compounds, method of their production and the means of containing this compound, useful for combating fungi and insect pests

The invention relates to oxime derivative of formula I, where R1- H, C1-6-alkyl, R2- C2-6-alkylene, X - C6-10-aryl unsubstituted or substituted by 1 Deputy selected from the group comprising C1-6-alkyl, HE, alloctype, C1-4-alkoxygroup, halogen atoms, phenyl, phenylthiourea, phenylsulfonyl group, phenylcarbonylamino, pyridylsulfonyl group, imidazolidine and peredelnye group or heteroaromatic group: pyridyl, chinosol and imidazolyl ; Y = O, S, orZ represents a group of the formula (For), (Zв ), (Zс ) or ( Zd )

The invention relates to new preparations of thiazolidinediones of the formula I, where A denotes a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic aromatic 5-or 6-membered ring containing an S atom or N; B is-CH=CH-; W represents O; X represents O; Y represents N; R represents pyridyl, thienyl or phenyl, in case you need one - or disubstituted C1-C3-alkyl, CF3, Cl or bromine; R1represents C1-C6-alkyl;n represents 2, and their tautomers, enantiomers, diastereomers or physiologically acceptable salts and medicinal product on the basis of their

The invention relates to a number of derivatives of thiazolidine, which are characterized by the presence of quinone group 2 in their molecules

The invention relates to a number of derivatives of thiazolidine, characterized by the presence along with other hydroxynonenal group or naphthohydroquinone groups in their molecules

The invention relates to two intermediate compounds that are useful for a number of compounds characterized 2-[2-/replaced phenyloxy-, thio - or-methyl/-1-methyl-ethyl]-aminoethanol structure and possess valuable anti-diabetic properties, which means struggle with weight

The invention relates to a series of new derivatives of thiazolidinone and oxazolidinone containing nitroacetanilide group, and to methods of producing these compounds may find use of these compounds as vasodilators, for example, for the treatment and prevention of cardiovascular diseases
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