SK279658B6 - Catechol derivatives, method of their preparation, pharmaceutical composition them containing and their use - Google Patents

Abstract

Disclosed is a compound of the general formula (I), wherein R1 is nitro, halogen or cyano group and R2 is a group selected from the groups (Ia) and (Ib), in which R is hydrogen or alkyl, cycloalkyl, aralkyl or aryl group, wherein X1, X2, Y and Z are independently from each other selected from the oxygen, sulphur or NR group, wherein R may have stated meaning, and their physiologically acceptable salts, esters and their use in the prevention or treatment of tissue damage induced by lipid peroxidation.

Description

Field of the invention

SUMMARY OF THE INVENTION

The invention relates to novel catechol derivatives and pharmaceutically acceptable salts and esters thereof which are useful as medicinal antioxidants. The invention also relates to pharmaceutical compositions containing these compounds and to a process for their preparation.

The compounds of the present invention are represented by the general formula (I)

BACKGROUND OF THE INVENTION

Medicinal antioxidants are compounds that can be used in the prevention or treatment of tissue damage induced by lipid peroxidation. It is generally believed that cellular damage by oxygen-derived radicals, particularly those associated with lipid peroxidation, is a significant factor in heart disease, rheumatoid arthritis, cancer, certain inflammatory diseases, transplant rejection reactions and aging processes.

EP-A-343643 discloses pharmaceutical compositions comprising compounds of the formula

where is the

(I) unsubstituted phenyl; (ii) phenyl substituted with one to three lower alkyls, lower alkoxy groups, hydroxyls, halogen, trifluoromethyls, NR40R4j, wherein Rjq and Rjj are independently hydrogen or lower alkyl, NO2 mercapto or lower alkylthio, (iii) naphthyl (iv) benzofuranyl,

(v) benzothiophenyl; (vi) 2- or 3-thienyl; (vii) 2- or 3-indolyl; (viii) 2- or 3-furanyl; or (ix) 2-, 3- or 4-pyridyl;

Y oxygen or sulfur,

Y1 oxygen or sulfur,

X is sulfur, oxygen, NH or NCH 3 and

X1 NH or NCH3, and pharmaceutically acceptable salts thereof, which are 5-lipoxygenase and / or cyclooxygenase inhibitors. Japanese patent application no. No. 1052765, which is cited in Chemical Abstracts (CA 111/17 / 153788y), discloses thiazolidinone derivatives useful as aldose reductase inhibitors. Gupta et al. v Eur. J. Med. Chem. - Chim. Ther., 17 (5), 448-52, 1982 and Srivastava et al., In Pharmazie, 36 (4), 252-3, 1981 disclose 2-thioxo-4,6-pyrimidinedione compounds having anticonvulsant activity. Sohda et al. in Chem. Pharm. Bull., 31 (2), 560-9, 1983 disclose 2,4-thioxolidione derivatives having anticelutam activity.

where is the

R 1 is nitro, halogen or cyano; and

R 2 is selected from formulas

from

wherein X 1, X ₂ , Y and Z are independently oxygen, sulfur or NR, wherein R is hydrogen, straight or branched C 1-6 alkyl, C 5-6 cycloalkyl, phenylC 1-6 alkyl or phenyl, or a pharmaceutically acceptable salt or ester thereof.

A preferred ring system includes 2-thioxoimidazolidin-5-ones and 2,5-imidazolidinediones. Examples of such compounds include 4 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] -2-thioxoimidazolidin-5-ones; 4 - [(3,4-dihydroxy-5-chlorophenyl) methylidene] -2-thioxoimidazolidin-5-one; 4 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] -2,5-imidazolidinedione and 4 - [(3,4-dihydroxy-5-cyanophenyl) methylidene] -2-thioxoimidazolidin-5-one.

In another embodiment, R 2 is a group of formula

Z wherein X 1, Y and Z are independently oxygen or sulfur and X 2 is NR, wherein R is hydrogen or alkyl. Preferred ring systems are 2-thioxothiazolidin-4-ones, 3-methyl-2-thioxothiazolidin-4-ones, thiazolidine-2,4-dione, 4-thioxo-2-oxyzolidinones and 4-thioxothiazolidin-2-ones. Specific examples include 5 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] -2-thioxothiazolidin-4-one, 5 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] -3-methyl- 2-thioxothiazolidin-4-one, 5 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] -thiazolidin-2,4-dione, 5 - [(3,4-dihydroxy-5-chlorophenyl) methylidene] - thiazolidin-2,4-dione, 5 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] -4-thioxo-2-oxazolidmonone, 5 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] - 4-thioxothiazolidin-2-one and 5 - [(3,4-dihydroxy-5-cyanophenyl) methylidene] -2-thioxothiazolidin-4-one.

In another embodiment, R 2 is a group comprising a six membered heterocyclic ring of formula

a process for the preparation of compounds of formula (I) wherein the aldehyde of formula (H)

wherein Y is oxygen or sulfur, X 1 is NR, where R is hydrogen or alkyl. Preferably, Y is oxygen. Preferred ring systems include pyrimidine-2,4,6-trione. Examples of such compounds include 5 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] -2,4,6-pyrimidinetrione and 5 - [(3,4-dihydroxy-5-nitrophenyl) methyl] - (1H, 3H, 5H) pyrimidine-2,4,6-trione.

The term "alkyl", used alone or as part of another group, represents straight or branched groups, preferably having 1 to 8 atoms, most preferably having 1 to 4 carbon atoms

As used herein, the term "halogen" refers to fluoro, chloro, bromo and iodo substituents. Chlorine is very preferred.

When R is hydrogen, the compounds of the present invention may also exist in the appropriate tautomeric forms depending on the pH of the solution.

When R ₂ is a five-membered ring, X 1 is NR, where R is hydrogen, the tautomeric forms of the compounds of formula (Ia) are

and atautomeric forms when X ₂ is NR, where R is hydrogen, are

Tautomeric forms of the compounds wherein R ₂ is a six membered ring are

wherein R 1 is as defined herein, condenses by a base or acid catalyzed reaction with a compound of formula (III) or (IV) having an active methylene group

or

wherein X 1, X ₂ , Y and Z are as defined above to form a compound of formula (Ia) of the present invention wherein the carbon-carbon double bond of formula (Ia) can be reduced to form a compound of formula (Ib) of the invention.

The invention also relates to pharmaceutically acceptable salts and esters of said compounds. In general, esters that hydrolyze in a physiological environment are more easily those that are attached to the phenolic hydroxyl group (s) in the compounds of formula (I) of the invention. Either one or both of the hydroxyl groups can be esterified and hydrolysis of the ester-forming groups cleaves and releases the active compound. Preferred esters are acyl or aroyl derivatives.

Salts of the compounds, if used, can be prepared by known methods. Physiologically acceptable salts are suitable as active drugs. Preferred salts are sodium, potassium, ammonium, calcium and magnesium salts.

The effective dose of the compounds varies according to whether the compounds are administered prophylactically or therapeutically, according to the severity of the condition to be treated and the mode of administration. An effective dose for humans will likely be from about 1 to 1000 mg per day.

The compounds used in this invention are formulated into dosage forms using bases known to those of ordinary skill in the art. The compounds of the invention are administered to the patient alone or in combination with a suitable pharmaceutical material, in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions, wherein the active ingredient content of the formulation is from 1 to 100 wt. %.

The choice of suitable ingredients for the routine preparation of preparations is clear to those skilled in the art. It will be appreciated that suitable solvents, gelling agents, dispersing agents, coloring agents and the like are used in conventional manner.

The present invention also relates to a process for the preparation of compounds of formula (I). The present invention relates to

SK 279658 Β6

The formulations may be administered enterally or parenterally.

Test results

Radical capture capacity of compounds

Test compounds were subjected to controlled peroxidation by peroxyradicals resulting from thermal decomposition of 2,2'-azobis- (2-amidinopropane) x HCl at 37 ° C. The degree of radical formation was followed by luminol enhanced chemiluminescence (CL). Stoichiometric factors were calculated from the course of CL and the fact that the TROLOX (R) analog of the phenolic antioxidant vitamin E captures two radicals (Barclay L. et al., J. Am Chem. Soc. 106: 2479-2481, 1984). The results are shown in Table 1.

Table 1

Binding of peroxy radicals by various test compounds

Animal Model of Inflammation Compound Dose Administration Inhibition —_____ Imkg) _________ (¾) Iscbdmium Induced

□ smell Labky Allopurlnol 1 L .v. 27- allopurinol 1 iv 12 Dexamatazón 0.01 S. c. L7 - 0.1 «.E. 24 - - 1 s <c. 34 · - 0.1 iv 19 pr. 12 10 iv 37 « CVF-induced swelling Paws allopurinol 1 L.V. e Doxanstazón 0.01 i .v, 43- pr. 12 10 L.V. 0 trokut 300 after. 0 ALlapurlnol 300 after. 3 pr. 12 300 after. 15

other induced carrageenan

swelling of paws I suffer » 300 p.o. 12 Al lepurinol 300 p.o. 0 pr. 12 300 p.a. 7 AEA ^B -induced kalitída pr. 12 30 l.col. 22 'Statistically significant inhibition · (P < 0.05)  statistically marked inhibition (P < 0.01) ··· Statistically significant inhibition (P < 0.001)

Compound etechlometric factor

17.1

29.6

34.7 * 4.4

34.2

64.0

74.0

TROLOX2,0 ascorbic acid9 *

4 - [(3,4-dihydroxy-5-chlorophenyl) methylidene] -2-thioxoimidazolidin-5-one,

5 - [(3,4-dihydroxy-5-cyanophenyl) methylidene] -2-tioxotiazolidin-4-one,

4 - [(3,4-dihydroxy-5-nitro-phenyl) -methylene] -2,5-imidazolidinedione,

5 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] -2-tioxotiazolidin-4-one,

4 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] -2-thioxoimidazolidin-5-one,

5 - [(3,4-dihydroxy-5-nitro-phenyl) -methylene] -2,4,6- (1H, 3H, 5H) -pyrimidine trione,

4 - [(3,4-Dihydroxy-5-cyano-phenyl) -methylene] -2-thioxoimidazolidin-5-one.

The following examples illustrate the preparation of the compounds of the invention.

Anti-inflammatory activity of Example 12 (Ex. 12) The compound of Example 12 was tested in rat paw-induced swelling models

- ischemic reperfusion (occlusion) - activating xanthine oxidase,

- CVF (cobra venom factor) - activates complement -> neutrophil infiltration,

- carrageenin - prostaglandins,

- ABAP - induced colitis in rats - ABAP induces lipid peroxidation.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

4 - [(3,4-Dihydroxy-5-nitrophenyl) methylidene] -2-thioxoimidazolidin-5-one

A solution containing 2.9 g (0.025 mol) of 1-thiohydantoin, 4.6 g (0.025 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.25 ml of piperidine in 50 ml of acetic acid is heated for 7-8 h for 100 hours. C. The crystals were filtered off and washed with 2-propanol. 5.0 g (71%) of m.p. > 350 ° C (dec.).

Example?

5 - [(3,4-Dihydroxy-5-nitrophenyl) methylidene] -2-thioxothiazolidinA-one

A solution containing 2.1 g (0.0157 mol) of iodoanine, 2.76 g (0.0151 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.15 ml of piperidine in 10 ml of acetic acid is heated for 7 to 8 hours for 100 hours. After cooling, the crystals were filtered off and washed with 2-propanol, yield 4.0 g (89%), mp> 350 ° C (dec.).

Example 3

5 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] thiazolidine-2,4-dione

A solution containing 0.59 g (0.005 mol) of thiazolidine-2,4-dione, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.05 ml of piperidine in 5 ml of acetic acid is heated for 7 to 7 days. 8 h at 80 ° C. The crystals were filtered off and washed with ethanol. Yield 1.0 g (72%), m.p. Mp 295-298 ° C.

Example 4

5- (3,4-dihydroxy-5-nitrophenyl) methylidene] -2-aminotiazolidin-4-one

A solution containing 0.58 g (0.005 mol) of 2-aminothiazolidin-4-one, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.05 ml of piperidine in 5 ml of acetic acid is heated for 24 h. at 100 ° C. The product was filtered off and washed with ethanol. Yield 1.2 g (86%), m.p. 250 ° C (dec.).

Example 5 5 - [(3,4-Dihydroxy-5-nitrophenyl) methylidene] -4-thioxothiazolidin-2-one

A solution containing 0.67 g (0.005 mol) of 4-thioxothiazolidin-2-one, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.05 ml of piperidine in 10 ml of acetic acid is heated for 8 h. at 100 ° C. The product was filtered off and washed with 2-propanol. Yield 1.14 g (76.5%), m.p. > 350 ° C (dec.).

Example 6 5 - [(3,4-Dihydroxy-5-nitrophenyl) methylidene] -3-methyl-2-thioxothiazolidin-4-one

A solution containing 0.74 g (0.005 mol) of 3-methyl-2-thioxothiazolidin-4-one, 0.92 g (0.005 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.05 ml of piperidine in 10 ml of acetic acid was heated at 100 ° C for 8 h. The product was filtered off and washed with 2-propanol. Yield 0.87 g (56%), m.p. Mp 274-276 ° C.

Example 7

5 - [(3,4-Dihydroxy-5-nitrophenyl) methylidene] -2,4,6 (1H, 3H, 5H) -pyrimidine trione

To a solution containing 1.28 g (0.01 mol) of barbituric acid and 1.83 g (0.01 mol) of 3,4-dihydroxy-5-mtrobenzaldehyde in 20 ml of 2-propanol was gradually added 5.0 ml of thionyl chloride. The mixture was stirred at room temperature for 100 h. The product was filtered off, washed with 2-propanol and recrystallized from acetic acid. Yield 1.28 g (44%), m.p. Mp 269-272 ° C.

Example 8

4 - [(3,4-Dihydroxy-5-nitro-phenyl) -methylidene] -2,5-imidazolidinedione

A solution containing 0.65 g of hydantoin, 0.92 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.15 g of ammonium acetate in 15 ml of acetic acid is refluxed overnight. The product was filtered off and washed with acetic acid and 2-propanol. Yield 0.56 g (42%).

Example 9

5 - [(3,4-Dihydroxy-5-nitrophenyl) methylidene] -4-thioxo-2-oxazolidinone

A solution containing 0.25 g of 4-thioxo-2-oxazolone, 0.38 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.1 ml of piperidine in 5 ml of acetic acid is heated at 100 ° C overnight. The product was filtered off and washed with acetic acid. Yield 0.05 g, m.p. 245 “C.

Example 10

4 - [(3,4-Dihydroxy-5-cyanophenyl) methylidene] -2-thioxoimidazolidin-5-one

A solution containing 0.58 g of thiohydantoin, 0.82 g of 3,4-dihydroxy-5-cyanobenzaldehyde and 0.1 ml of piperidine in 10 ml of acetic acid is heated at 100 ° C for 4 h. The product was filtered off and washed with ether. Yield 0.51 g, m.p. Mp 210-213 ° C.

Example 11

5 - [(3,4-Dihydroxy-5-cyanophenyl) methylidene] -4-thioxothiazolidin-4-one

A solution containing 0.61 g of rodanine, 0.72 g of 3,4-dihydroxy-5-cyanobenzaldehyde and 0.1 ml of piperidine in 10 ml of acetic acid is heated at 100 ° C for 4 hours. The product was filtered off and washed with 2-propanol. Yield 0.35 g. > 350 ° C.

Example 12

4 - [(3,4-Dihydroxy-5-chlorophenyl) methylidene] -2-thioxoimidazolidin-5-one

A solution containing 1.16 g of thiohydantoin, 1.72 g of 3,4-dihydroxy-5-chlorobenzaldehyde and 0.2 ml of piperidine in 20 ml of acetic acid is heated at 100 ° C for 4 h. The product was filtered off and washed with ether. Yield 1.0 g, 1.1. 303 DEG-304 DEG.

Example 13

5 - [(3,4-Dihydroxy-5-chlorophenyl) methylidene] thiazohidine-2,4-dione

A solution containing 1.33 g of thiazolidine-2,4-dione, 1.72 g of 3,4-dihydroxy-5-chlorobenzaldehyde and 2 ml of piperidine in 20 ml of acetic acid was heated at 100 ° C for 5 h. Yield 1.9 g (70%), m.p. 299 to 301 'C.

Example 14

- [(3,4-Dihydroxy-5-nitrophenyl) methyl] - (1H, 3H, 5H) pyrimidine-2,4,6-trione

To a suspension of 5 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] - (1H, 3H, 5H) pyrimidine-2,4,6-trione (Example 7) (1 g) in water (30 mL) was added a solution of sodium borohydride (2 g) in water (10 mL) was added portionwise. The solution was stirred at room temperature for 15 minutes and acidified with 1N hydrochloric acid. The product was filtered off and washed with water. Yield 0.7 g, m.p. Mp 263-266 ° C.

Claims (21)

PATENT CLAIMS A catechol compound of formula (I) wherein is R 1 is nitro, halogen or cyano; and R 2 is selected from the formulas wherein X 1, X ₂ , Y and Z are independently oxygen, sulfur or NR, wherein R is hydrogen, straight or branched C 1-6 alkyl, C 1-6 cycloalkyl, phenylC 1-6 alkyl or phenyl, or a pharmaceutically acceptable salt thereof or an ester. A compound according to claim 1, wherein R 1 is cyano. The compound of claim 1, wherein R 1 is nitro. SK 279658 Β6 The compound of claim 1, wherein R 1 is halogen. A compound according to any one of claims 1 to 4, wherein in formula (I), R _{2 is a} group of formula (Ia) ϊ wherein X 1 and X ₂ are both NR, wherein R is hydrogen or C 1-6 alkyl, Y is oxygen or sulfur, Z is oxygen or sulfur. A compound according to claim 5, selected from the group consisting of 4 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] -2-thioxoimidazolidin-5-one, 4 - [(3,4-dihydroxy-5-chlorophenyl) methylidene] -2-thioxoimidazolidin-5-one, 4 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] -2,5-imidazolinedion. 4 - [(3,4-Dihydroxy-5-cyanophenyl) methylidene] -2-thioxoimidazolidin-5-one or a pharmaceutically acceptable salt or ester thereof. A compound according to any one of claims 1 to 4, wherein in formula (I), R _{2 is a} group of formula (Ia) from wherein X 1, Y and Z are independently oxygen or sulfur and X ₂ is NR, wherein R is hydrogen or C 1-6 alkyl. A compound according to claim 8, selected from the group consisting of 5 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] -2-tioxotiazolidin-4-one, 5 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] -3-methyl-2-tioxotiazolidin-4-one, 5 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] thiazolidine-2,4-dione, 5 - [(3,4-dihydroxy-5-chlorophenyl) methylidene] thiazolidine-2,4-dione, 5 - [(3,4-dihydroxy-5-nitrenylphenyl) methylidyl] -4-thioxo-2-oxazolidinone; and 5 - [(3,4-dihydroxy-5-nitrophenyl) methylidene] -4-tioxotiazolidin-2-one. 5 - [(3,4-Dihydroxy-5-cyano-phenyl) -methylene] -2-thio-thiazolidin-4-one or a pharmaceutically acceptable salt or ester thereof. A compound according to any one of claims 1 to 4, wherein R ₂ is a group 12. 5 - [(3,4-Dihydroxy-5-nitrophenyl) methylene] -2-amino-thiazolidin-4-one or a pharmaceutically acceptable salt or ester thereof. A compound according to any one of claims 1 to 4, wherein R ₂ is a group of formula (Ia) wherein R ₂ is oo wherein Y is oxygen or sulfur, X 1 is NR, wherein R is hydrogen or C 1. -salkyl. The compound of claim 13, wherein Y is oxygen. 5 - [(3,4-Dihydroxy-5-nitrophenyl) methylidene] -2,4,6- (1H, 3H, 5H) -pyramidinium trione or a pharmaceutically acceptable salt or ester thereof. 16. 5 - [(3,4-Dihydroxy-5-nitrophenyl) methyl] - (1H, 3H, 5H) pyrimidine-2,4,6-trione or a pharmaceutically acceptable salt or ester thereof. A compound according to any one of claims 1 to 16 for use in a method of surgical treatment, therapy or diagnosis. A pharmaceutical composition for use in the prevention or treatment of tissue damage caused by lipid peroxidation, comprising a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier or diluent. Use of a compound according to any one of claims 1 to 16 for the manufacture of a medicament for use in preventing or treating tissue damage induced by lipid peroxidation. The use of claim 19, wherein the tissue injury to be treated or prevented is heart disease, rheumatoid arthritis, cancer, inflammatory disease, transplant rejection, ischemia, or angina. A process for preparing a catechol compound of formula (I) wherein is R 1 is nitro, halogen or cyano; and R ₂ is selected from the formulas wherein X 1 and Z are independently oxygen or sulfur, and Y and X ₂ are NR, wherein R is hydrogen. z wherein X 1, X ₂ , Y and Z are independently oxygen, sulfur or NR, wherein R is hydrogen, straight or branched C 1-6 alkyl, C 3-6 cycloalkyl, phenylC 1-8 alkyl or a phenyl group, characterized in that the aldehyde is condensed of formula (II) wherein R 1 is as defined hereinabove, with compounds of formula (III) or (IV) having an active methylene group wherein X 1, X ₂ , Y and Z are as defined, to give compounds of formula (Ia) and a double the carbon-carbon bond in the compound of formula (Ia) is optionally reduced to give a compound of formula (1b) of the invention.