NL8005946A - AGENTS AGAINST FATIGUE AND INCREASED FAT MIRROR. - Google Patents

Description

II.0. 29,570

Anti-obesity drugs and increased fat levels

Within the scope of the invention, it has been found that "certain compounds which inhibit thromboxane synthase exhibit insulin-lowering and obesity-inhibiting activity. Thanks to the activity of lowering the insulin level of these thromboxane synthase-inhibiting compounds They are suitable for the treatment of ailments caused by a high insulin level. In addition to the obesity mentioned above, these are ailments, such as symptoms of the coronary arteries, the peripheral arteries and the cerebral arteries, as well as insulinoma 10 (tumor of pancreatic cells with the insulin secretion).

The invention therefore relates to the use of the thromboxane synthase inhibiting compounds belonging to the group of the following: imidazoles, 3-substituted pyridines, substituted indoles, 4-substituted pyrimidines, 3- ( 5-tetrazolyl) -thioxanthen-9-on-10,10-dioxide, 1,2-diphenyl-4- [2- (phenylsulfinyl) -ethyl] -3,5-pyrazolidinedione, 1-isopropyl-7-methyl-4 -phenyl-2 (1E) -quinazolines and 7-isopropoxy-9-oxoxanthene-2-carboxylic acid in lowering insulin levels and fighting obesity.

The imidazoles useful within the scope of the invention correspond to the formula 1, wherein R is a hydrogen atom or a

a

nitro or C 1-6 alkenyl group and R represents a hydrogen atom or an alkyl, acyl, aryl, substituted aryl, aralkyl or indol-3-yl-O-1 alkyl group.

The pyridines substituted in place 3 within the scope of the invention correspond to the formula 2, in which 2 R represents a hydrogen atom or a C 1-6 alkyl, aralkyl, optionally by a straight or branched alkyl group on the position 2 represents substituted 3 "indolyl, aryl, substituted aryl or 2-hydroxy-1-naphthyl-30 methylene hydrazino group.

The pyrimidines substituted in the context of the invention for the 4-substituted pyrimidines correspond to the formula 3 in which 3 R represents an arylthio or alkoxyoxalylmethyl group.

The indoles usable within the scope of the invention correspond to the formula 4 wherein R4 is a straight or branched C 1-4 alkyl group or carboxyl group, R5 a straight or branched C 1-6 alkyl 1-4 group, R represents a substituted aryl or substituted benzoyl group 8005946 2 7 and R represents a -alkoxy group.

Within the scope of the invention, alkyl groups are understood to mean straight or branched radicals having 1 to 18 carbon atoms and preferably 1 to 11 carbon atoms. Alkoxy groups are understood to mean straight or branched radicals, such as methoxy, ethoxy and iso-propoxy groups. Alkenyl groups are understood to mean straight or branched noble aliphatic radicals containing one double bond. Acyl groups are understood to mean radicals derived from an organic acid with 1 to 18 carbon atoms, in particular an alkane carboxylic acid, such as an acetyl, propionyl and butyryl group. An aryl group is understood to mean a residue derived from an aromatic hydrocarbon, such as a phenyl or naphthyl group. Substituted aryl groups denote aryl groups which are substituted by one or two alkoxy, C 1 -alkyl groups, chlorine, fluorine, bromine, nitro, aoyl and / or hydroxyl groups. In a phenyl group, the hydroxyl substituent is preferably present at the p-position. An aralkyl is understood to mean an alkyl group substituted by an optionally substituted aryl group.

Examples of the compounds that inhibit thromboxane synthase are: 4-imidazolophenol, 3-imidazol methyl indole, 1- (2-isopropylphenyl) imidazole, 2-isopropyl-3-nicotinoylindole, 1- (4-imidazolophenyl) - ethanone, 3-imidazolophenol, 1- (4-isopropoxyphenyl) imidazole, 1- (4-ethoxyphenyl) imidazole, 30 1-butylimidazole, 1-nonylimidazole, 1-triphenylmethylimidazole, 1-benzylimidazole, 1 - [(2-chlorophenyl) ) -diphenylmethyl] -imidazole, 1- (4-methoxyphenyl) -imidazole, 4-phenylpyrimidine, 1-nicotinoyl-2- (2-hydroxy-1-naphthylmethylene) -hydrazine, imidazole, 1- (4-nitrophenyl) imidazole 40 1- (2,4-Dinitrophenyl) -imidazole, 8005946 9 -% 5 1 - [2- (2,4-dichlorophenyl) -2 - [(2,4-dichlorophenyl) -methoxy] -ethyl-imidazole, methyl 4-imidazole acrylate, 2-methyl-1,2-di-3-pynidyl-1-propanone bis-tartrate, 5 [1- (4-chlorobenzoyl) -5-methoxy-2-methyl-3-indolyl] -acetic acid, 4- (ethoxy-oxalylmethyl) -pyrimidine, 3- (5-tetrazolyl) -thioxanthen-9-on-10,10-dioxide, 1,2-diphenyl-4- [2- (phenylsulfinyl) -ethyl] -3,5-pyrazolidinedioa, 1-acet ylimidazole, 10 1-methylimidazole, 1-ethylimidazole, 4-nitro imazazo o1, 1-isopropyl-7-methyl-4-phenyl-2 [1 H] quinazolinone, and 7-isopropoxy-9-oxoxanthene-2 -carboxylic acid.

A number of the thromboxane synthase inhibitory compounds were tested in vitro for their insulin-lowering activity. These compounds were further tested in vivo for the obesity-inhibiting activity thereof.

Preferred compounds within the scope of the invention are imidazoles of the formula 1, wherein E is a hydrogen atom and R is a G 1 -alkyl-, indol-3-ylmethyl- or p-hydroxy- 1-9 represent phenyl group, and pyridines of formula 2 wherein R represents a 3-indolyl group substituted in position 2 by a straight or branched C 1-6 alkyl group. Particularly preferred are the following compounds: 4-imidazolophenol, 3-imidazolomethylindole, 1 - (4-imidazolophenyl) ethanone, 1- (4-isopropoxyphenyl) imidazole, 1- (triphenylmethyl) imidazole, and 2 isopropyl-3-nicotinoylindole.

Within the scope of the invention, the thromboxane synthase inhibiting compounds can be used in the form of pharmaceutically acceptable non-toxic salts, preferably hydrochlorides, nitrates, sulfates and tartrates.

A suitable pharmaceutical dosage amount can be from 0.1 to 200, preferably from 0.1 to 50, and especially from 0.1 to 10 mg / kg per day.

Within the scope of the invention, the thromboxane synthase 40 inhibitory compounds can be administered with the usual organic or inorganic 8005946 4 carriers, such as water, gelatin, rubber, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycol and petroleum jelly. The pharmaceutical preparations prepared in this way can be in the form of dosage units and may contain other therapeutically valuable substances or conventional auxiliary substances, such as preservatives, stabilizers, wetting or emulsifying agents and buffers. These preparations can be in solid form, for example as tablets, capsules and dragees, in semisolid form, for example as ointments, in liquid form, for example as solutions, suspensions or emulsions or in another usual form, such as dry ampoules and suppositories, are being brought. They can be subjected to the usual treatment methods, such as sterilization.

The following examples serve to illustrate the insulin level lowering and obesity inhibiting activity of the thromboxane synthase inhibitors.

Example I

Determination of insulin seorisation in the isolated pancreas of a rat.

In anesthetized female Charles Eiver rats, the pancreas was removed and bandaged with perfusion equipment.

The perfusion solution contained 133 mM HaCl, 4> 4 mM KCl, 2.5 mM MgSO., 2.4 mM Ca gluoonate, 1.5 mM K1oP0., 29.4 mM NaHCO2, 4% dextran, 0.2 % master serum albumin as well as glucose, as detailed below. The perfusion rate was kept constant at 4 ml / minute.

The perfusion was performed in the following manner: 10 minutes with 5 »6 mM glucose 30 minutes with 16.7 mM glucose (internal reference) 30 10 minutes with 5> 6 mM glucose 30 minutes with 16.7 mM glucose and test substance 10 minutes with 16.7 mM glucose 10 minutes with 5-6 mM glucose 5 minutes with 20 mM arginine (pancreatic viability control).

The compounds to be tested were dissolved in 90% ethanol and the solution was diluted to the desired concentration. The perfusion effluent was collected every minute or every 4 minutes, after which in the collected fractions the insulin secretion 40 was determined by "radioimmunoassay". An inhibition index was calculated to determine the 8005946 inhibitory activity of the test compounds. This index is the ratio between the insulin secretion value of the reference perfusion and the value obtained with the test compound. As shown in Table A below, the compounds of the invention which inhibit thromboxane synthase give rise to a significant inhibition of insulin secretion.

TABLE · A

10 Compounds insulin seoretion concentration inhibition index reference 1 imidazole 100 2 15 1000 3 1- (triphenylmethyl) imidazole 10 2 1- (4-imidazolophenyl) -ethanone 100 2 4-imidazolophenone 10 2 3- (imidazolomethyl) - indole 10 1 20 50 13 ^ 100 32 1- (4-isopropoxyphenyl) imidazole 100 4 2- isopropyl-3-nicotinoyl indole 100 5 1-benzylimidazole 1000 3 1 - [(2-chlorophenyl) -diphenyl- 25 methyl] ~ imidazole 10 3 3-imidazolophenol 1000 2 1- (2-isopropylphenyl) imidazole 10 2 1000 25 1-butylimidazo1 1000 5 30 -

Example II

Determination of in vivo activity against obesity

Lean and fat male and female sugar rats were fed ad libitum 1 to 3 weeks before the start of the experiment.

They were then kept on a low-glucose (1% corn oil) diet (G-70: 1% CO) diet. After this 1 to 4 week period, the rats were divided into groups of 4 to 7 animals. Food consumption and body weight were determined daily or twice a week. For each group of animals, the active ingredient was administered in an amount corresponding to food consumption per kg body weight 8005946 6. The weight data indicate the difference between the weight gain of the control animals and the treated animals. Food consumption and insulin levels were reported as the percentage of the reference. As shown in Table B5, the weight gain by administration of the compounds of the invention could be significantly reduced.

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Claims (13)

1. The use of compounds which inhibit the thromboxane synthase and which correspond to the formula 1, in which R is a hydrogen atom or a nitro or C 1-4 alkenyl group and R is a hydrogen atom 5 or a C 1-6 alkyl- , acyl, aryl, substituted aryl, aralkyl, or indol-3-yl-C 1 -C 3 alkyl, or a salt thereof with a pharmaceutically acceptable acid in the treatment of obesity and lowering the insulin level. Use of a compound of the formula 1 according to claim 1, wherein R represents a hydrogen atom and R represents a C, rt-alkyl, -y indol-3-ylmethyl or p-hydroxyphenyl group. The use of 4-imidazolophenol according to claim 1. The use of 3-imidazolomethylindole according to claim 1. Use of 1- (2-isopropylphenyl) imidazole according to claim 1. The use of 1- (4-imidazolophenyl) -ethanone according to claim 1. The use of 3-imidazolophenol according to claim 1. 8. Use of 1- (4-isopropoxyphenyl) imidazole according to claim 1. 9. Use of a compound belonging to the group of the following: 1- (4-ethoxyphenyl) imidazole, 1-nonylimidazole, 1-butylimidazole, 1-benzylimidazole, 1- (4-at-thoxyphenyl) imidazole, 1- (2,4-Dinitrophenyl) imidazole, 1- (4-nitrophenyl) imidazole, imidazole, 1-acetylimidazole, 1-ethylimidazole, 1-methylimidazole or 4-nitroimidazole according to claim 1. 10. The use of compounds which inhibit the troboxan synthase p and which correspond to the formula 2, wherein R represents a hydrogen atom or a C 1-6 alkyl, aralkyl, optionally through a straight or branched C 1-6 alkyl group. the position 2 represents substituted 3-indolyl, aryl, substituted aryl or 2-hydroxy-1-naphthylmethylenehydrazino group, or a salt thereof with a pharmaceutically acceptable acid in the treatment of obesity and lowering the insulin level. The use of a compound of the formula 2 according to claim 2, wherein R represents a 3-indolyl group optionally substituted in the position 2 by a straight or branched C 1-4 alkyl group. Use of 2-phsopropyl-3 "nicotinoylindole according to claim 10. 8 0 0 5 9-4 6 - 7 * = IJ. Use of compounds which inhibit the thromboxane synthase and correspond to the formula 3 wherein R represents an arylthio or alkoxyoxalylmethyl group, or a salt thereof with a pharmaceutically acceptable acid in the treatment of obesity and lowering the insulin level. 14. Use of compounds which inhibit the thromboxane synthase and which correspond to the formula wherein R 1 is a carboxylic or branched C-alkyl group, R a straight or branched 6-alkyl group, R a substituted aryl or substituted Π-4 β-benzoyl group and R 'represent an O 2 -alkoxy group in the treatment of obesity and lowering the insulin level. Use of the thromboxane synthase inhibitory compounds belonging to the group of the following: 3- (5-tetrazolyl) -thioxanthen-9-on-10,10-dioxide, 1,2-diphenyl-4- [2- ( phenylsulfinyl) -ethyl:] -3> 5-pyrazolidinslione, 1-isopropyl-7-methyl-4-phenyl-1-2 [1 H] quinazolinone and 7-isopropoxy-9-oxoxanthene-2-carboxylic acid in the treatment of obesity and lowering the insulin level. 1005946 JL "ς> R1 L · if ^ V00" 2 λ ^ AR3 4. 7 -iï — CH_R4 R - s 2 R6 80 0 5 9 4 6