Derivatives of catechol and method of production thereof

 

(57) Abstract:

The compounds of formula I, where R1is so electronegative Deputy, as nitro, halogen or cyano, R2is a group selected among Ia and Ib, where R is hydrogen or alkyl, cycloalkyl, aralkyl or aryl, where X1X2, Y and Z independently is oxygen, sulfur or NR, where R has the values given above, and pharmaceutically acceptable esters and salts of these compounds, which are useful for the prevention or treatment of tissue damage induced by paraxylene lipids. 4 C. and 6 C.p. f-crystals, 1 table.

The invention relates to new derivatives of catechol and their pharmaceutically acceptable salts and esters which are useful as medicines antioxidants. The invention also relates to pharmaceutical compositions containing these compounds, and to the way they are received.

Medical antioxidants are compounds that can be used for prevention or treatment of tissue damage caused by perechislenie lipids. Usually believe that cellular damage by radicals derived from oxygen, especially the fact that the om arthritis, cancer, certain inflammatory diseases, rejection reactions by transplantation, ischemia, and even the aging process.

In EP-A-343643 described pharmaceutical compositions containing the compounds of formula:

< / BR>
where Ar is (i) unsubstituted phenyl, (ii) a phenyl, substituted with one to three lower alkilani, lower alkoxy, hydroxyl, Norodom, trifluoromethyl, NR10N11where R10and R11independently are hydrogen or lower alkyl, NO2, mercapto or lower alkylthio, /iii/ naphthyl, /iv/ benzofuranyl, /v/ benzothiophenes, /vi/ 2 - or 3-tanila, /vii/ 2 - or 3-indlela, /viii/ 2 - or 3-TuranAlem, or /ix/ 2-, 3 - or 4-pyridium, X is sulfur, oxygen, NH or NCH3X1is NH or NCH3, Y and Y1are oxygen or sulfur, and their pharmaceutically acceptable salts, which, as installed, are inhibitors of 5-lipoxygenase and/or cyclooxygenase. In Japanese patent publication N 1052765, which is shown in chemical Abstract /CA 111/17/153788/ described derivatives of thiazolidinone, which are useful as inhibitors of allow-reductase. Gupta with TCS. Eur J Med. Chem. 17 /5/, 448 52, 1982 and Srivastava with TCS. in Pharmazic 36 /4/, 252 3, 1981 describes a 2-thioxo-4,6-pyrimidinedione suede 2-Mixolydian, having antiulcer activity.

Compounds of the present invention can be represented by formula I

< / BR>
where R2is electronegative Deputy, such as nitro, halogen or cyano, and R2is a group selected among:

< / BR>
where R is hydrogen or alkyl, cycloalkyl, aralkyl, or aryl, where X1X2, Y and Z are independently oxygen, sulfur or NR, where R has the previously indicated meaning.

In one embodiment, R2is a group containing a five-membered heterocyclic ring, which has the formula

< / BR>
in which X1and X2both are NR, where R is hydrogen or alkyl, Y is oxygen or sulfur. Preferred ring systems include 2-dioxoimidazolidin-5-ones and 2, 5-imidazolidin-5-ones. Examples of such compounds include 4-/3,4-dioxy-5-nitrophenyl/methylidene-2-dioxoimidazolidin-5-Oh, 4-/3,4-dioxy-5-chlorophenyl/methylidene-2-dioxoimidazolidin-5-Oh, 4-/3,4-dioxy-5-nitrophenyl-methylidene/-2,5-imidazolidinedione and 4//3, 4 deoxy-5-cyanophenyl/Meriden/-2-dioxoimidazolidin-5-he.

In another embodiment, R2is a group

< / BR>
in which X1and Z independently awsomee systems include 2-thioxothiazolidin-4-ones, 3-methyl-2-thioxothiazolidine and 4-thioxothiazolidin-2-ones. Specific examples are 5- //3,4-dioxy-5-nitrophenyl)-methylidene/-2-thioxothiazolidin-4-one, 5-//3, 4 deoxy-5-nitrophenyl/Meriden/-3-methyl-2-thioxothiazolidin-4-one, 5-//3, 4 deoxy-5-nitrophenyl/Meriden/-thiazolidin-2, 4-dione, 5-//3, 4 deoxy-5-chlorophenyl/Meriden/thiazolidin-2, 4-dione, 5-//3, 4 deoxy-5-nitrophenyl/Meriden/-4 - thioxo-2-exfoliation, 5-//3, 4 deoxy-5-nitrophenyl/Meriden/ -4 - oxothiazolidine-2-he 5-//3, 4 deoxy-5-cyanophenyl/Meriden/-2-thioxothiazolidin-4-one.

In another embodiment, R2is a group of the formula

< / BR>
in which X1and Z are independently oxygen or sulfur, and Y and X2are NR, where R is hydrogen. Preferred ring system is a 2-aminothiazoline-4-one. A concrete example is 5-//3, 4 deoxy-5-nitrophenyl/Meriden/ 2 aminothiazoline-4-one.

In another embodiment, R2is a group containing six-membered heterocyclic ring, which has the formula:

< / BR>
where Y is oxygen or sulfur, X1is NR where R is hydrogen or alkyl. Preferably is oxygen. Preferred ring systems include pyrimidine-2, 4, 6-trions. P-5-nitrophenyl)methyl/-(1H, 3H, 5H)-pyrimidine-2, 4, 6-Trion.

The term "alkyl" as used here in relation to itself or part of another group, refers to groups with straight or branched chain, preferably 1 to 8 atoms, more preferably 1 to 4 carbon atoms.

The term "aryl", as used here, refers to monocyclic or bicyclic group containing 6 or 10 carbon atoms in the ring. A concrete example is phenyl.

The term "apil", as used here, refers to alkylcarboxylic, an alkyl group defined above.

The term "aroyl" refers to arylcarbamoyl, aryl group defined above.

The term "cycloalkyl", as used here, refers to saturated cyclic hydrocarbon groups, preferably having 5 to 7 carbon atoms.

The term "halogen", as used here, refers to fluorine, chlorine, bromine or iodine. Especially preferred is chlorine.

If is hydrogen, the compounds of the present invention can also exist in the corresponding tautomeric forms depending on the pH of the solution.

So when R2is five-membered ring when X1is N is then X2is NR where R is hydrogen

< / BR>
Tautomeric forms of the compounds, in which R2is a six-membered ring, respectively, are:

< / BR>
The invention also relates to a method for producing compounds of the formula I. the Invention provides a method for producing compounds of the formula I, in which the aldehyde of formula II

< / BR>
where R1has these values, condense when acidic or alkaline catalysis with the compound of the formula III or IV, having an active methylene group

< / BR>
where X1X2, Y and Z have the previously indicated meanings, to obtain the compound Ia according to the present invention, and then double carbon-carbon bond can be restored to obtain compounds Ib according to the invention.

The invention also relates to pharmaceutically acceptable salts and esters of these compounds. Usually esters, which are easily hydrolyzed under physiological conditions, are those that are attached to a phenolic hydroxyl group in compounds of formula I Or one of the hydroxyl groups, or both can be tarifitsirovana and hydrolysis group or groups forming esters, hatshepsuts, visvobodit the ptx2">

Salts of the compounds, when applicable, may be obtained by known methods. Physiologically acceptable salts are useful as the active medication. However, preferred are sodium, potassium, ammonium, calcium and magnesium salts.

The effective dose of the compound varies significantly depending on the used compounds for the prevention or treatment, the severity of the condition of the patient and route of administration. The effective dose for humans is about 1 to 1000 mg per day.

The compounds used in the present invention, formulated in the form of dose, using principles well known to specialists in this field. Compounds according to the present invention, give the patient as such or in combination with a suitable pharmaceutical material in the form of tablets, pills, capsules, suppositories, emulsions, suspensions or solutions, resulting in the content of active compound in the formulation is from 1 to 100 wt.%

The choice of auxiliary ingredients for a recipe is normal for specialists in this field. Obviously, suitable solvents, glioblastoma ingredients, ingredients, forming a dispersion paint is about.

The results of the test.

The ability to absorb radicals and compounds.

Compound is subjected to controlled perechislenie peroxyradicals formed during thermal decomposition of 2,2-azobis-(1-aminopropane)HCl at 37oC. the Rate of formation of radicals is determined by the gain of chemiluminescence (CHL) lyuminola. Stoichiometric factors calculated from the duration of incubation and the fact that phenolic antioxidant analog of vitamin TROZOXRpicks up two radical (L. Barclay et al. J. Am. Chem. Soc. 106 2479 2481, 1984). The results are shown in the table.

1. 4-/(3,4-Dioxy-5-chlorophenyl)methylidene/-2-dioxoimidazolidin-5-he

2. 5-/(3,4-Dioxy-5-cyanophenyl/Meriden/-2-dioxoimidazolidin-4-one

3. 4-/(3,4-Dioxy-5-nitrophenyl)methylidene/-2, 5-imidazolidin

4. 5-/(3,4-Dioxy-5-nitrophenyl)methylidene/-2-thioxothiazolidin-4 - one

5. 4-/(3,4-Dioxy-5-nitrophenyl)methylidene/-2-dioxoimidazolidin-5-he

6. 5-/(3,4-Dioxy-5-nitrophenyl)methylidene/-2, 4, 6-(1H, 3H, 5H)pyrimidinetrione

7. 4-/(3,4-Dioxy-5-cyanophenyl)methylidene/-2-dioxoimidazolidin-5-he.

The following examples illustrate the formation of compounds according to the invention.

Example 1. 4-/(3,4-Dioxy-5-nitrophenyl)methylidene/-2-the nitrobenzaldehyde and 0.25 ml of piperidine in 50 ml of acetic acid is heated for 7 to 8 hours at 100oC. is Filtered, the crystals washed with 2-propanol. Yield 5.0 g (71,). So pl. 350oC (decomp.).

Example 2. 5-/(3,4-Dioxy-5-nitrophenyl)methylidene/-3-thioxothiazolidin-4-one.

A solution containing 2.1 g (0,0157 mol) of rhodanine, 2.76 g (0,0151 mol) 3, 4 deoxy-5-nitrobenzaldehyde and 0.15 ml of piperidine in 10 ml of acetic acid is heated for 7 to 8 hours at 100oC. After cooling, the crystals are filtered and washed with 2-propanol. Yield 4.0 g (89%), so pl. 350oC (decomp.).

Example 3. 5-/(3,4-Dioxy-5-nitrophenyl)methylidene/-thiazolidin-2, 4-dione a Solution containing 0,59 g (0,005 mol) thiazolidin-2,4-dione, 0,92 g (0,005 mol) of 3,4-dioxy-5-nitrobenzaldehyde and 0.05 ml of piperidine in 5 ml of acetic acid is heated for 7 to 8 hours at 80oC. is Filtered off the crystals and wash with ethanol. Yield 1.0 g (72%), so pl. 295 298oC.

Example 4. 5-/(3,4-Dioxy-5-nitrophenyl)methylidene/-2-aminothiazoline-4-one.

A solution containing of 0.58 g (0,005 mol) 2-aminothiazoline-4-it, 0,92 g (0,005 mol) of 3,4-dioxy-5-nitrobenzaldehyde and 0.05 ml of piperidine in 5 ml of acetic acid is heated for 24 hours at 100oC. the product is Filtered off and washed with ethanol. Yield 1.2 g (86%), so pl. 250oC (decomp.).

Example 5. 5-/(3, 4-Dioxy-5-nitrophenyl)methylidene/-4-Tiksi-5-nitrobenzaldehyde and 0.05 ml of piperidine in 10 ml of acetic acid is heated for 8 hours at 100oC. the Product is filtered and washed with 2-propanolol. The output of 1.14 g (76.5%), so pl. 350oC (decomp.).

Example 6. 5-/(3,4-Dioxy-5-nitrophenyl)methylidene/-3-methyl-2-thioxothiazolidin-4-one.

The solution containing 0.74 g (0,005 mol) 3-methyl-2-thioxothiazolidin-4-it, 0,92 g (0,005 mol) of 3,4-dioxy-5-nitrobenzaldehyde, 0.05 ml of piperidine in 10 ml of acetic acid is heated for 8 hours at 100oC. the Product is filtered and washed with 2-propanol. Yield 0.87 g (56%), so pl. 274 276oC.

Example 7. 5-/(3,4-Dioxy-5-nitrophenyl)methylidene/-2, 4, 6 (1H, 3H, 5H)pyrimidinetrione.

To a solution containing 1.28 g (0.01 mol) of barbituric acid and 1.83 g (0.01 mol 3,4-dioxy-5-nitrobenzaldehyde in 20 ml of 2-propanol, gradually add 5.0 ml of thionyl chloride. The mixture is stirred for 100 hours at room temperature. The product is filtered, washed with 2-propanol and recrystallized from acetic acid. Yield 1.28 g (44%), so pl. 269 - 272oC.

Example 8. 4-/(3,4-Dioxy-5-nitrophenyl) methylidene/-2, 5-imidazolidinedione.

A solution containing 0.65 g as 0,92 g 3, 4 deoxy-5-nitrobenzaldehyde and 0.15 g of ammonium acetate in 15 ml of acetic acid is refluxed over night. The product is filtered and washed with acetic KIS the oxo-2-oxazolidinone.

A solution containing 0.25 g of 4-thioxo-2-oxazolone, 0,38 g 3, 4 deoxy-5-nitrobenzaldehyde and 0.1 ml of piperidine in 5 ml of acetic acid is heated overnight at 100oC. the Product is filtered and washed with acetic acid, the Yield 0.05 g, so pl. 245oC

Example 10. 4-/(3,4-Dioxy-5-cyanophenyl)methylidene/-2-dioxoimidazolidin-5-he.

The solution containing 0,58 g thiohydantoin, of 0.82 g of 3,4-dioxy-5-cyanobenzaldehyde and 0.1 ml of piperidine in 10 ml of acetic acid is heated for 4 hours at 100oC. the Product is filtered and washed with ether. The yield of 0.51 g, so pl. 210 213oC.

Example 11. 5-/(3,4-Dioxy-5-cyanophenyl)methylidene/-2-thioxothiazolidin-4-one.

The solution containing 0,61 g Rodnina, 0,72 g 3, 4 deoxy-5 - cyanobenzaldehyde and 0.1 ml of piperidine in 10 ml of acetic acid is heated for 4 hours at 100oC. the Product is filtered and washed with 2-propanol. Yield 0.35 g so pl. 350oC.

Example 12. 4-/(3,4-Dioxy-5-chlorophenyl)methylidene/-2-dioxoimidazolidin-5-he.

The solution containing 1,16 g thiohydantoin, 1,72 g of 3,4-dioxy-5-chlorobenzaldehyde and 0.2 ml of piperidine in 20 ml of acetic acid is heated for 4 hours at 100oC. the Product is filtered and washed with ether. Yield 1.0 g, so pl. 303 304oC.

Example 13. 5-/(3,4-Dioxy-5-chlorophenyl)methylide is uridine in 20 ml of acetic acid, heated 5 hours at 100oC. Yield of 1.9 g (70%). So pl. 299 301oC.

Example 14. 5-/(3,4-Dioxy-5-nitrophenyl)methyl/-(1H, 3H, 5H)-pyrimidine-2,4,6-Trion.

To a suspension of 5-/(3,4-dioxy-5-nitrophenyl)methylidene/-(1H, 3H, 5H)-pyrimidine-2,4,6-trione (example 7) (1 g) in 30 ml of water is gradually added a solution of 2 g of sodium borohydride in 10 ml of water. The solution is stirred for 15 minutes at room temperature and acidified with 1 N. hydrochloric acid. The product is filtered and washed with water. Yield 0.7 g so pl. 263 6oC.

1. Derivatives of catechol General formula I

< / BR>
where R1the nitro-group, and R2group

< / BR>
where X1X2, Y and Z, independently is oxygen, sulfur or NR, where R is hydrogen or C1-3- alkyl,

or R1cyano and R2as defined above, and X1NH or S; X2NH; Y IS S; Z IS 0,

or R1chlorine; R2as defined above; X1NH or S; X2NH; Y is S or 0; Z 0,

or R1the nitro-group, and R2group

< / BR>
or

< / BR>
where Y is oxygen; X1NH,

or its pharmaceutically acceptable salt or ester.

2. Connection on p. 1, wherein R2a group of the formula Ia

< / BR>
where X1and X2both are NR, where R Eski acceptable salt or ester.

3. Connection on p. 2, characterized in that it is selected from the group consisting of 4-[(3,4-dioxy-5-nitrophenyl)methylidene]-2-dioksiinitaolisi-5-Oh, 4-[(3,4-dioxy-5-chlorophenyl)methylidene]-2-dioxoimidazolidin-5-Oh and 4-[(3,4-dioxy-5-nitrophenyl)methylidene] -2.5-imidazolidinedione, or 4-[(3,4-dioxy-5-cyanophenyl)methylidene] -2-dioxoimidazolidin-5-it, or its pharmaceutically acceptable salt, or ester.

4. Connection on p. 1, wherein R2a group of the formula Ia

< / BR>
in which X1and Z is independently oxygen or sulfur;

X2NR, in which R is hydrogen,

or its pharmaceutically acceptable salt or ester.

5. Connection on p. 4, characterized in that it is selected from the group consisting of 5-[(3,4-dioxy-5-nitrophenyl)methylidene]-2-thioxothiazolidin-4-one, 5-[(3,4-dioxy-5-nitrophenyl)methylidene] -3-methyl-2-thioxothiazolidin-4-one, 5-[(3,4-dioxy-5-nitrophenyl)methylidene] -thiazolidin-2,4-dione, 5-[(3,4-dioxy-5-chlorophenyl)methylidene] -thiazolidin-2,4-dione, 5-[(3,4-dioxy-5-chlorophenyl)methylidene] -thiazolidin-2,4-dione, 5-[(3,4-dioxy-5-nitrophenyl)methylidene] -4-Tiksi-2-oxazolidinone and 5-[(3,4-dioxy-5-nitrophenyl)methylidene]-4-thioxothiazolidin-2-or 5-[(3,4-dioxy-5-cyanophenyl) methylidene] 2-thioxothiazolidin 4-one, or in pharmaceutical preparations is; 2a group of the formula Ia

< / BR>
where X1Z is independently oxygen or sulfur; Y and X2NR, where R is hydrogen,

or its pharmaceutically acceptable salt, or ester.

7. 5-[(3,4-dioxy-5-nitrophenyl)methylidene] -2-aminothiazoline-4-one or its pharmaceutically acceptable salt or ester.

8. Connection on p. 1, wherein R1the nitro-group, and R2group

< / BR>
or

< / BR>
where Y is oxygen; X1NH, or its pharmaceutically acceptable salt, or ester.

9. 5-[(3,4-dioxy-5-nitrophenyl)methylidene] -2,4,6(1H, 3H, 5H)-pyrimidinetrione or 5-[(3,4-dioxy 5-nitrophenyl)methyl] (1H, 3H, 5H)-pyrimidine-2,4,6-Trion, or its pharmaceutically acceptable salt, or ester.

10. The method of obtaining the compounds of formula I

< / BR>
where R1the nitro-group, and R2group

< / BR>
where X1X2, Y and Z are independently oxygen, sulfur or NR, where R is hydrogen or C1-3-alkyl,

or R1cyano and R2as defined above, and X1NH or S and Z O

or R1chlorine and R2as defined above; X1NH or S; X2NH; Y is S or 0; Z 0,

or R1the nitro-group, and R2group

< / BR>
or

< / BR>
where Y CI the above value,

with the compound of the formula III or IV, having an active methylene group

< / BR>
or

< / BR>
where X1X2, Y and Z have the above values,

obtaining compounds of formula I, when R2a group of the formula

< / BR>
the double bond can then be restored.

Priority signs:

27.04.90 R1the nitro-group, and R2group

< / BR>
where X1X2, Y and Z, independently, oxygen, sulfur or NR, where R is hydrogen or C1-3-alkyl,

or R1cyano and R2as defined above; X1- NH or S; X2NH; Y IS S; Z IS 0,

or R1the nitro-group, and R2group

< / BR>
or

< / BR>
where Y is oxygen; X is NH.

24.01.91 R1chlorine; R2as defined above; X1- NH or S; X2NH; Y is S or 0; Z O.

 

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