FR2544317A2 - Benzoazacycloalkyl-spiro-imidazolidines and the pharmaceutical compositions containing them - Google Patents

Abstract

Optical isomers of 6-chloro-1,2,3,4-tetrahydroisoquinoline-4-spiro-4'-(imidazolidine-2',5 '-dione). Medicaments.

Description

 This certificate of addition relates to benzoazacycloalkyl-spiro-imidazolidines and the pharmaceutical compositions which contain them.

dans laquelle
R1 représente un atome d'hydrogene ou d ' halogine, un radical hydroxy ou méthoxy,
R2 représente un atome d'hydrogène, un radical allyle inférieur1 phXnyl-alkyle inférieur, alcanoyle inférieur ou p -tolubnesulfonyle, et
n est 1 ou 2, ainsi que leurs sels obtenus avec des bases minérales ou organiques pharmaceutiquement acceptables, ou leurs sels d'addition (excepté pour R2 = acyle) obtenus avec des acides minéraux pharmaceutiquement acceptables.The benzoazacycloalkyl-spiro-imidazolidines according to the main patent correspond to the general formula

in which
R1 represents a hydrogen or halogen atom, a hydroxy or methoxy radical,
R2 represents a hydrogen atom, a lower allyl radical, phXnyl-lower alkyl, lower alkanoyl or p -tolubnesulfonyl, and
n is 1 or 2, as well as their salts obtained with pharmaceutically acceptable mineral or organic bases, or their addition salts (except for R2 = acyl) obtained with pharmaceutically acceptable mineral acids.

 The patent gives, among the examples of compounds of formula 1, 6-chloro-tétrahydro-1,2,3,4 isoquinoline-4spiro-4'-imidazolidine-dione-2 ', 5', in racemic form.

ou un de leurs sels d'addition obtenus avec des acides pharmaceutiquement acceptables.The present invention relates to the optical isomers of chloro-6-tetrahydro-1,2,3,4 isoquinoline-4-spiro-4 '-imidazolidine-dione-2', 5 ', of structural formula

or one of their addition salts obtained with pharmaceutically acceptable acids.

 The optical isomers are prepared by salification of the racemic compound with an optically active acid and separation of the salts by crystallization.

EXAMPLE:
a) Camphosulfonate of the isomer (d).

 100 g (0.036 M) of chloro-6 tetrahydro-1,2,3,4 isoquinoline -4-spiro-4'-imidazolidine-dione-2 ', 5' racemic obtained according to Example 2 of French patent 82.07203, 78 g (0.036 M) of (l) -10-camphosulfonic acid, 1300 cm3 of water and 400 cm3 of ethanol. The solution thus obtained, concentrated to dryness, gives 162 g of expected salt. A first recrystallization of 3200 cm3 of methonol precipitates, after a night in the refrigerator at 30C, 70.7 g of product. A second recrystallization of 2950 cm3 of methanol, 24 hours in the freezer at -180C leads to 54.6 g of (1) -10-(d) -chloro-6-tetrahydro-1,2,3,4-camphosulfonate-1,2,3,4 isoquinoline-4-spiro-4 '- imidazolidine-dione-2', 5 '.

F = 2570 (decomposition)
210 210
La = + 24.6 [α] = + 44 (0.5% in CH3OH)
589,436
b) Isomer (d)
13.8 g (0.0285 M) of the camphosulfonate obtained above are suspended in 145 cm3 of a 2% aqueous solution of triethylamine. It is brought to a bain-marie until a solution of neutral pH is obtained. The mixture is left overnight in the refrigerator at 3 ° C. to precipitate 6.8 g of (d) -chloro-6-tetrahydro-1,2,3,4 isoquinoline-4-spiro-4 'imidazolidine-dione-2', 5 '.

F = 2520 (decomposition and sublimation)
220 220 = = + 44.4 lez = + 86.4 (0.4% in CH3OH)
589,436
c) Isomer hydrochloride (d)
6.4 g (0.0255 M) of the free base obtained above are suspended in 15.4 cm3 of 1.65 N hydrochloric acid. After 20 min of contact and then 3 hours in the refrigerator (3 ° C.) 6.7 g of hydrochloride are obtained.

F = 2450
220 22 = = + 78.3 las = + 177.7 (0.5% in CW3OH)
589,436
d) Isomer (1)
We operate exactly as for the separation of the isomer (d) above, but starting from (d) -10 camphosulfonic acid to obtain ie (d) -10-camphosulfonate from (l} -chloro-6, tétrahydro-1,2,3,4 isoquinoline-4-spiro-4 1 - imidazolidine-2 ', 5'.

The constants. physical are as dismal as those of the isomer (d), the rotary powers being obviously reversed. The optical purity of the isomers was checked and found to be greater than 98 t.

Pharmacological study of the compounds according to the invention 1. The compounds according to the invention were tested for their inhibitory action on the aldose reductase extracted from rat lenses according to the technique described by S. Hayman and J.H. Kinoshita, J. Biol. Chem. 240 (1965) 877, modified by S.D. Warna and J.H. Kinoshita, Biochemical Pharmacology 5 (1976) 2505-2613.

 The products according to the invention dissolved in pH 6.2 buffer are incubated at 250 in a stoppered container containing the aldose reductase extracted from the lens of CD River rats. After 10 min of contact, the substrate is added, and the activity of the enzyme is assessed by the disappearance of the medium from the co-factor Ac. Nicotinamideadenine diphosphorique reduced (NADPH) according to the editorial staff.

D - glucose + NADPH

Sorbitol + NADPH
+
The enzymatic activity is calculated by determining the quantity of NADPH that has disappeared. The results are expressed as a percentage of the enzyme activity of the preparation in the absence of any inhibitor. Under these conditions, the minimum dose which inhibits aldosereductase and the minimum which can inhibit enzymatic activity by 50% can be determined. The compounds according to the invention were tested at concentrations ranging between 10 8 M and 10 5 M.

50% inhibition of the enzyme preparation (IC50) is obtained with the concentration of 5 x 10-8 M of the dextrorotatory isomer and with 10 4 M of the levorotatory isomer.

2. The toxicity of the compounds according to the invention is very low and the LD50 determined on the Swiss mouse is greater than 1 g / kg intraperitoneally. Orally, the dose of 3 g / kg did not lead to any eagle toxicity phenomenon.

3. The in vivo activity of these compounds was studied in rats made diabetic by intravenous injection of streptozotocin at 65 mg / kg. The products tested are administered in suspension in a gummy solution (20%) orally morning and evening. The animals are trained to consume their food between 8 and 16 hours.

 After 7 days of treatment, the animals are sacrificed by decapitation. The blood is collected for assaying the glycaemia according to the glucose oxidase method. The lenses are removed immediately after the more, quickly weighed and immersed in liquid nitrogen. These frozen lenses are ground in an aqueous solution of sedoheptulose used as internal standard for the assay by gas chromatography. Proteins are precipitated. After centrifugation, the supernatant is collected and lyophilized. The dry extract is silylated with TMGS / HDXS and taken up in heptane for chromatography using a "Hewlett Packard 5710" chromatograph, under the following conditions: FID detection, 2.5 m column, 3 min, 9% EGS chromium G AWDMCS 80-100 mesh (0.15 - 0.18 mm) temperature l700C, carrier gas: nitrogen (30 ml / min).

 The results show that the (d) isomer, at a daily dose of 2 x 1 mg / kg po, decreases the content of sorbitol in the lens of the diabetic rat by 88 E (glycemia 4.0 + 0.4 g / l).

 (D) -chloro-6 tetrahydro-1,2,3,4 isoquinoleine4-spiro-4 'imidazolidine-dione-2', 5 'therefore has interesting pharmacological properties. It manifests in particular inhibitory properties of the aldose reductase enzyme, the main enzyme which controls the regulation of the metabolism of aldoses and in particular of aldohexoses like glucose and galactose by transforming them into corresponding polyol (sorbitol or galactitol for example) in the human body.

 An excess of the functioning of such an enzyme in the presence of an excess of substrate can cause an abnormally high production of galactitol or sorbitol in galactosemic subjects. Abnormal polyol concentrations cause these substances to accumulate in the lens, in the peripheral nerves and in the kidneys of diabetic subjects. Indeed, the intervention of the aldosereductase present in the tissues is not very sensitive in a subject whose blood sugar is normal. Its roll becomes much more important in diabetic subjects whose blood sugar is much higher.

 This explains a modification of the capillary functions of disorders of nerve conduction and the appearance of a diabetic cataract with loss of transparency of the lens. The invention aims to reduce or completely avoid these serious complications.

On the other hand, the compounds of the invention decrease the secretion of prolactin by the rat pituitary gland in glass from 10 6 M and in vivo at the dose of 2 to 20 mg / kg. The secretion caused by sympathetic stress is inhibited, a property which may prove particularly advantageous in the treatment of diabetics;
Consequently, the main therapeutic application of the compounds of the invention is the treatment of diabetes, in particular to oppose the increase in capillary permeability at the origin of retinopathy and trophic disorders, prevention or treatment. diabetic neuropathy in its peripheral or visceral manifestations and the prevention and treatment of cataracts and diabetic nephropathy.

 Preferably, the compounds of the invention are administered orally or parenterally. The pharmaceutical forms which are more particularly suitable for such administrations are injectable solutions or suspensions packaged in ampoules or autoinjectable syringes, naked or coated tablets, dragees, capsules, - pills, syrups or drinkable emulsions, - ointments , drops, eye drops, eye gels or saccules (for eyes).

 The unit dosage is variable depending on the route of administration, the age of the patient and the severity of the therapeutic indication. It can range between 15 and 150 mg per unit dose. The daily dosage can range from 30 to 300 mg in adults.

EXAMPLE OF CAPSULE: (d) -chloro-6-tetrahydro-1,2,3,4 isoquinoline hydrochloride -4-spiro-4'-imidazolidine-dione-2 ', 5' .......... 30 mg
lactose ......................................... 40 mg talc ..... ....................................... 10 mg
for one capsule.

Claims (3)

1. The optical isomers of chloro-6 tetrahydro1,2,3,4 isoquinoleine-4-spiro-4'-imidazolidine-dione-2 ', 5' or one of their addition salts with pharmaceutically acceptable acids, according to claim 3 of the main patent. 2. (d) -chloro-6 tétrahydro-1,2,3,4 isoquinoleine- 4-spiro-4 '-imidazolidine-dione-2', 5 'or its hydrochloride. 3. Pharmaceutical composition containing as active ingredient the compound according to claim 2 as well as a pharmaceutically compatible excipient or vehicle.