FR2525603A1 - BENZOAZACYCLOALKYL-SPIRO-IMIDAZOLININES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Abstract

THEY MEET THE GENERAL FORMULA: (CF DRAWING IN BOPI) IN WHICH: R REPRESENTS A HYDROGEN OR HALOGEN ATOM, A HYDROXY OR METHOXY RADICAL, R REPRESENTS A HYDROGEN ATOM, A LOWER ALKYL RADICAL, PHENYL-ALKYL LOWER, LOWER ALKANOYL OR P-TOLUENESULFONYL, AND N IS 1 OR 2, AS RACEMIC OR OPTICAL ISOMERS, AS WELL AS THEIR SALTS. USE AS A MEDICINAL PRODUCT.

Description

The present invention relates to benzoazacyc-

  oalkyl-spiro-imidazolidines, a process for preparing them and

  the pharmaceutical compositions which contain them.

  The benzoazacycloalkyl-spiro-imidazolidines

  tooth with the general formula: t -ô NH R 1 I

N R 2

  in which: R 1 represents a hydrogen or halogen atom, a hydroxyl or methoxy radical, R 2 represents a hydrogen atom, an inferior alkyl radical Ur, phenyl-lower alkyl, lower alkanoyl or p-toluenesulfonyl, and n is 1 or 2,

  as well as their salts obtained with mineral bases or

  pharmaceutically acceptable salts, or their

  (except for R 2 = acyl) obtained with

  pharmaceutically acceptable salts.

  The compounds (I) having an asymmetric carbon (spiro bond), they can be in racemic form or 2 -

  optical isomers which form part of the invention.

  The compounds of the invention can be prepared

  res by condensation of a ketonic derivative of formula: o R 1 II

C N R'2

  (CH 2) n in which R'2 has the same meaning as R 2 except for hydro-

  gene, and R 1 and N have the same meaning as in the

the I, -

  with an alkali metal cyanide in the presence of ammonia or an ammonium salt, to provide a spiro-hydantoin of the formula: ## STR1 ## wherein n, R 1 and R '2 have the same meaning as the formula II, which, if appropriate, is benzylated to a compound of formula I in which R 2 is H, and the latter may be subject to

  acylation by means of a halogenide of alkanolque acid

  or p-toluenesulfonyl to obtain the corresponding compound

N-R '2

CH 2 n -3-

  substituent of formula I in which R 2 is a radical

  lower canoyle or p-toluenesulfonyl.

  The condensation reaction of the ketone derivative (II) with the alkaline cyanide is carried out under the usual conditions of the Strecker reaction, in the presence of ammonia or an ammonium salt, in a polar solvent, such as

  alcohol, boiling and, if necessary, under pressure.

  The debenzylation of spiro-hydantoin (I ') can be carried out by hydrogen in the presence of a catalyst such as

than Pd / C in a polar solvent.

  The acylation is carried out in the presence of an accept-

  acid, which can serve as a solvent, for example pyridine

  dine. Intermediate ketones of formula II in

  N = 1 (isoquinolones) are described in the literature.

  The Chemistry of Heterocyclic Compounds, Vol 38 1,

  p 215-16, Interscience, Wiley Editor), or can be pre-

  prepared from benzole esters according to the reaction

next nel:

D C C 2 H 5 / COOC 2 H 5

1 1 | 3 Ri

R> R 1

CHX O CH 2-N-CH 2 COOC 2 H 5

v 2 2 2000 C 2 H 5

COOC 2 H 5 R'2

2 5 RI 2

R 1 -

N PR 2 (II; N = 1)

  III 4 - In these various formulas Rt and R'2 have the same

  that in formula II and X represents a halo

   Preferably, the benzoic ester (V) is condensed.

  with N-substituted ethyl glycinate in the presence of an accept-

  acid, such as triethylamine under reflux, and then the diester (IV) is cyclized to ketone (III) using an alcoholate

  alkali such as sodium ethoxide in refluxing ethanol.

  Ketone (III) is decarboxylated by a strong acid in medium

  aqueous and provides the ketone derivative (II N = 1).

  The intermediate compounds of formula II in which N is 2 (benzazepinones) can be prepared more easily from corresponding alcohols of formula:

R VII

R 1 / EST N

  in which R 1 has the same meaning as in the formula

  I and whose synthesis is described by M LENNON et al.

  (J Chem Soc 1975, 622) These compounds are acylated, or alkylated

  or aralkylated on the nitrogen then the hydroxyl is oxidized to

  provide the corresponding compound (II, N = 2).

  The following examples illustrate the preparation

compounds of the invention.

EXAMPLE 1

  6-chlorobenzyl-2-tetrahydro-1,2,3,4 isoquinoline-4-spir

  -ro-4'-imidazolidine-dione-2 ', 5'.

-5-

  a) N- (4-chloro-2-ethoxycarbonylbenzyl) N-benzyl glycine

te of ethyl.

  55.5 g (0.2 M) of 5-chloro-2-bromomethylbenzoate are dissolved in 270 ml of refluxed ethyl ether and 34.78 g (0.18 M) of N are added. benzyl glycinate and

  18.62 g (0.184 M) of triethylamine in

  After cooling, 150 ml of water and 80 ml of 2.5 N NaOH are added. The organic phase is decanted and subjected to an acid / base treatment. obtained 43.8 g of product in the form of oil (Rt 61%) -1 IR: C = O 1730 cm 1 NMR: 8 H (ar) 7.5 ppm 4 H (q) 4.3 ppm 2 H ( s) 4.2 ppm 2 H (s) 3.8 ppm 2 H (s) 3.3 ppm 6 H (t) 1.3 ppm b) 6-chloro-3-ethoxycarbonyl-2-benzyl-1,2,3-tetrahydro , 4 isoquinolone-4.

  26.9 g (0.069 M) of crude ester obtained according to a) below are dissolved in

  above, in 350 ml of benzene and this solution is poured over 90 minutes into a solution of 2.1 g of sodium ethoxide in 50 ml of ethanol.

  reflux, then cool and treat with chlorinated

  diluted to neutrality The benzene phase is decanted

  rinse with water, dry and evaporate the solvent.

  22.9 g of crystalline product F = 71-76 ° C (Mini Kofler).

  It is recrystallized from 40 ml of ethanol and gives 19 g of

  yield (Rt 80%) F = 75-77 C (M K) 6 - I.R: C = O (ester) 1640 cm 1 C = COH 1610 cm-1 NMR: confirmation of the enol form: 1 H exchangeable

at 11.6 ppm.

  c) 6-chloro-2-benzyl-1,2,3,4-tetrahydro-4-isoquinolone.

  26.1 g (0.076 M) of the compound obtained according to b) in ml of ethanol and 400 ml of 10 N HCl (aq) are added and the mixture is refluxed for 12 hours after the elimination of most of

  ethanol, the hydrochloride of the desired compound precipitates.

  It is filtered, washed and dried. 19 g of crude product are obtained.

  The base is obtained by partitioning between dichloromethane and 5N sodium hydroxide. 16.1 g

F = 82-3 (M K)

  Recrystallization from 35 ml of isopropyl ether gives 14.2 g (Rt 69%) F = 83-5 (MK) IR: C = O 1690 cm-1 NMR: 8 H (ar) 7-8 ppm 2 H (s) 3.4 ppm 4 H (s) 3.8 ppm

  d) 6-chloro-2-benzyl-1,2,3,4-tetrahydro-4-isoquinoline

  spiro-4'-imidazolidine-dione-2 ', 5'.

  13.8 g (0.051 M) of isoquinone are introduced into an autoclave.

  lone obtained in c), 4.97 g (0.0765 M) of potassium cyanide

  sium and 24.48 g (0.255 M) of ammonium carbonate in 170 ml.

  of ethanol and heated to 115 for 22 h.

  and evaporation of the solvent, the residue is taken up in 50 ml.

  of water The solution is acidified to pH 1

  duit, wash with water, then with methanol.

We obtain 13.2 g (Rt 76%)

F 260 C

  -1: C = O 1720 cm 1: 8 H (a) 7-7.5 2 H (s) 2.9 ppm at 1770 cm 1 ppm 4 H (m) 3.5-3.8 ppm

EXAMPLE 2

  6-chloro-1,2,3,4-tetrahydro-isoquinoline-4-spiro-4 '-

imidazolidine-dione-2 ', 5'.

  3.1 g (0.009 M) of the spiro-hydantoin obtained according to Example 1 are hydrolyzed in 60 ml of acetic acid at 60 ° C. under ordinary pressure and in the presence of 500 mg of Pd on charcoal.

at 10%.

  After absorption of the theoretical volume of hydrogen, one filters

  and evaporates the solvent. The residue is recrystallized in a

water-ethanol mixture.

  1.4 g of product are obtained (Rt 63%)

Mp = 234-8 ° C (M K)

EXAMPLE 3

  6-chloro-2-acetyl-1,2,4,4-tetrahydro-4-isoquinoline

ro-4'-imidazolidine-dione-2 ', 5'.

  2.51 g (0.01 M) of the compound obtained according to Example 2 is acetylated with acetyl chloride in the presence of pyridine at ambient temperature. The crude acetylated product is isolated and crystallized.

in methanol.

I.R. NMR 8- 1.4 g are obtained

T R <DM ') NE 3500-2500 n

ilinone) C O 1640 cm 1 (acetyl)

Mp: 2452-40 ° C (M-K)

1 C = C 1700 C and 1765 year (iridazo

XEMPLDE 4

  4-acetyl-3-tetrahydro-3,1,5-benzo-1H-azepine-5-spiro-4'-ridazoa) hydroxy-acetyl 3-tetra-2-bromo-4,5,5-benzoimidazepine

  7 g (0.043 M) of 1-hydroxy benzo [1] perhydroaze were acetylated.

  pine, prepared according to LENNON et al (J CIEM SOC 1975, 622) p) ar Clacetile chloride at room temperature is isolated

  the derivative is -ti and recrystallized in acetonitrile

  the. We obtain 5, 5 g (63%) I R OH 3200 O cmr 1 (

F = 113-16 (M K)

  O 1620 cm -1 b) 3-acetyl-5-tetrahydro-2,3,4,5 ld J 1 -z-Lon

  4, 5 g (0.002) of the 5-tetrahydroepinol obtained in a) are, oxy-

  diluted with 15.4 g of Cro 2 pyridine complex in 200 ml of acetone.

  After the usual treatments, isolate 3 g of product after

Vacuum distillation.

E

0, O lim.

= 80 '

  I.R CO (amnide, 1650 cm CO (oondon) 1690 cm-1 9 -

  c) acetyl 3-tetrahydro-2,3,4,5 benzo [1 H] azepine

  -spiro-4 'imidazolidine-dione-2', 5 '. By operating as in Example 1 d) but starting from 3.5 g (0.017 M) of perhyroazepinone obtained according to b), above (instead of isoquinolone), 1.67 g (0.026 M) of KCN and 8.16 g

  (0.085 M) of (NH 4) 2 C 03, 2.4 g of the desired product are obtained.

  after crystallization in methanol.

F = 268-276 (M K)

-1 -1 -

  I.R: CO (hydantoin) 1770 cm 1 and 1720 cm 1 CO (acetyl) 1660 cm 1

EXAMPLE 5

  Optical isomers of 6-chloro-1,2,4,4-tetrahydro-isoquine

  nolein-4-spiro-4'-imidazolidine-dione-2 ', 5'.

  a) camphosulphonate of the isomer (d).

  100 g (0.036 M) of racemic compound obtained according to Example 2, 78 g (0.036 M) of (l) 10-camphosulphonic acid, 1300 cm 3 of water and 400 cm are refluxed until complete dissolution. The solution thus obtained, concentrated to dryness, gives 162 g of salt expected from a first recrystallization of

  3200 cm 3 of methanol precipitates, after a night in refrigeration.

  3 r C, 70.7 g of product. A second recrystallization of 2950 cm 3 of methanol, 24 hours in the freezer at -18 C gives 54.6 g of (1) 10-camphorsulphonate of (d) -chloro-6

  Tetrahydro-1,2,3,4-isoquinoline-4-spiro-4'-imidazolidine

dione-2 ', 5'.

F = 257 (decomposition)

21 21

= + 24.6 + 4 (0.5% in CH 3 OH)

589,436

  b) Isomer (d) 13.8 g (0.0285 M) of the camphosulphonate obtained above are suspended in 145 cm 3 of a 2% aqueous solution of triethylamine. 'obtaining

  of a solution of neutral pH It is left overnight in refrigeration

  at 3 ° C to precipitate 6.8 g of (d) -chloro-6 tetrahydro 1 zi -E il

-E O 1

Z 6

1 8

1 L

1 9

1 9

Z v

1 ú

1 z

1 1

  N u: 9 sodin D) (UDT 42-mdd-xd: (D) i:% udd1> -lD to 9lD 9-TD 9-TZ) LOD: a

L-0 RD:

L-O, AD:

  L-OD: 1 Ixa UOIGS: 09-G Z Xe u O las 099 Xe u Dias L-GZZ -Mlàz) IaD

9 L-9 SE

  aldmaxe helpumm 09 E z aidswo 8-KZ Xe uolas 9-ESZ Xe uoias EZ x: -Zog -Xe u Dles O I-90 z Zog Xe u O the 6-W Xe uoias 9-M z E znva 1 av 01 - - 09 szsz ti - Pharmacological study of the compounds according to the invention 1 The compounds according to the invention were tested for their

  inhibitory action on aldose reductase extracted from

  rat wools according to the technique described by S Fayman and F. 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 p H 6.2 buffer are placed in incubation at 25 in a clogged container containing the aldose reductase extracted from crystalline CD River rats. After 10 minutes of contact, the substrate is added. 7 and

  the activity of the enzyme is appreciated by the disappearance of

  co-factor Ac Nicotinamide-Diphosporic Adenine

pick (NADPH) according to the reaction.

  D glucose + NADPH Sorbitol + NADPH + e + Enzymatic activity is calculated by determining the amount of NADPE that has disappeared. The results are expressed as a percentage of the enzymatic activity of the preparation in the absence of any inhibitor. Under these conditions, can

  determine the minimum dose that inhibits 100% aldose-reduc-

  and the minimum which inhibits enzymatic activity by 50%.

  The compounds according to the invention have been tested at concentrations

  ranging between 108 M and 10-5 M In general, the 50% inhibition of the enzyme preparation is achieved with the concentration of 108 M and total inhibition is obtained at the concentration of 10-7 M 12 - 2 The toxicity of the compounds according to the invention is very low and the LC 50 determined on the Swiss mouse is greater than

ig / kg intraperitoneally.

  The in vivo activity of these conmeasts was studied in the rat made diabetic by intravenous injection of streptozotcine at 65 mg / kg. The tested products are administered in suspension in a gummy solution (20%) by the oral route, 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 Blood is collected for the determination of gly-

  The crystallins are taken immediately after death, rapidly weighed and immersed in liquid nitrogen. These crystalline lenses are frozen.

  are ground with an aqueous sedoheptulose solution

  as internal standard for chromatographic determination

  in the gas phase Proteins are precipitated after

  trifugation, the supernatant is collected and lyophilized.

  dry line is silylated by TMCS / HDMS and taken up in heptane for chromatography using a Packard 5710 "Iewlett chromatograph, under the following conditions: FID detection, column 2.5 m, 3 mm, 9% EGS chrome G

  AWDMCS 80-100 mesh (C, 150.18 r), temperature 170 C, gas

nitrogen: (30 ml / min).

  The results show that the compounds of the invention, at the daily dose of 2 x 25 mg / kg po, decrease by 70 to% the content of sorbitol in the rat lens made diabetic (blood glucose 4.0 +4, 4 g / l) The compounds according to the invention therefore have properties

_ 13 _

  interesting pharmacological They manifest in particular

  inhibiting properties of the enzyme aldose-reductase, the

  main zyme which controls the regulation of the metabolism of aldoses and in particular aldohexoses such as glucose and galactose by transforming them into the corresponding polyol (sorbite).

  tol or galactitol, for example) in the human body.

  Excessive operation of a small enzyme in the presence of an excess of substrate can lead to abnormal production

  elevated levels of galactitol or sorbitol in galactose

  Abnormal concentrations of polyols lead to the accumulation of these substances in the lens,

  peripheral nerves and in the kidneys of diabetic subjects.

  Indeed, the intervention of aldose-reductase present in the tissues are not very sensitive in a subject whose glycemia is normal its role becomes much more important at

  diabetic subjects whose blood glucose is much higher than

  Vee. It explains a modification of capillary functions, disorders of the nerve conduction and the appearance of a

  Diabetic cataract with loss of crystal transparency

  linen. The invention aims to reduce or completely avoid these

  serious complications and therefore the therapeutic application

  main ingredient of the compounds of the invention is the treatment

  particularly to oppose the increase in

  capillary permeability at the origin of retinopathy.

  thie and trophic disorders, the prevention or treatment of

  Diabetic neuropathy in its peripheral or visceral manifestations and the prevention and treatment of

  Diabetic cataract and nephropathy.

14 -

  In a preferred manner, the compounds of the invention are

  administered orally or parenterally.

  particularly suitable for such administrators.

  are the injectable solutions or suspensions

  packaged in ampoules or in auto-injectable syringes, naked or coated tablets, dragees, capsules, pills,

  syrups or oral emulsions, ointments, drops, colly-

  ophthalmic gels or saccules (for eyes).

  The unit dose is variable depending on the route of administration.

  the age of the patient and the severity of the therapeutic indication.

  It may range from 25 to 250 mg per single dose

  The daily dosage may range from 50 to

500 mg in adults.

EXAMPLE OF GELULE:

  6-chloro-2-acetyl-1,2,3,4-tetrahydro-isoquinoline 4-spiro

  4'-imidazolidine-dione-2 ', 5' 50 mg lactose 40 mg talcum 10 mg

for one capsule.

-

Claims (6)

  1 Derivatives of benzoazacycloalkyl-spiro-imidazclidine corresponding to the general formula: o * NH IN O I R 1 1-1 N R 2 CH 2) 2   in which R 1 represents a hydrogen or halogen atom, a hydroxyl or methoxy radical, R 2 represents a hydrogen atom, a lower alkyl radical, phenyl-lower alkyl, lower alkanoyl or p-toluenesulfonyl, and is 1 or 2 in racemic form or optical isomers, and their salts obtained with pharmaceutically acceptable inorganic or organic bases, or their addition salts (except for R 2 = acyl) obtained with acids   pharmaceutically acceptable minerals.   2 6-Chlorobenzyl-2-Tetrahydro-1,2,3,4-isoquinoline-4 16 -   spiro-4'-imidazolidine-2'-dione, 5 'or a salt thereof.   6-chloro-1,2,4,4-tetrahydro-isoquinoline-4-spiro   4'-imidazolidinedione-2 ', 5' or a salt thereof.   4-Chloro-6-acetyl-2-tetrahydrocarbyl-2,3,4-isoquinoline-4-spiro-imidazolidin-2'-dione, 5 'or a salt thereof. 3-acetylbenzoate perhydroazepine-1-spiro-4'-imidazole   zolidine-dione-2 ', 5' or a salt thereof.   Process for the preparation of the compounds according to Claim 1, characterized in that the condensation of a ketonic derivative of formula II R 1 is carried out.   in which R'2 has the same meaning as R 2 except hydro-   gene, and R and N have the same meaning as in formula I, with an alkali metal cyanide in the presence of ammonia or an ammonium salt, to provide a spiro-hydantoin of formula: CR 1. I ' In which n, R and R '2 have the same meaning as formula II, which, if appropriate, is debenzylated to a compound of formula I in which R 2 is H, and the latter may be acylated by means of a lower alkanoic acid halide or Ptoluenesulfonyl to give the corresponding compound   of formula I in which R 2 is a lower alkanoyl radical or p-toluenesulfonyl.   7 Pharmaceutical Compositions Containing as Principle   at least one compound according to any of the claims   cations 1 to 5 in admixture or addition with an excipient   inert non-toxic pharmaceutically acceptable.