DE3315106A1 - BENZOAZACYCLOALKYL-SPIRO-IMIDAZOLIDINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME - Google Patents

Description

• ·

PATENT LAWYERS TER MEER-MÜLLER-STEINMEISTER

Professional Representatives before the European Patent Office Mandataires agrees pres I'Olfice europeen des brevets

DipL-Chem. Dr. N. ter Meer Dipl.-Ing. H. Steinmeister DipL-lng. FE Müller. . _Ladebeok stra = ^ 51

Triftstrasse A ₁ ^Artur Ladebeck-Strasse 51

D-8OOO MUNICH 22 D-4800 BIELEFELD 1

tM / cb

GA / CG 9918 April 27, 1983

ADIR

22, rue Garnier 92201 Neuilly-sur-Seine, France

Benzoazacycloalkyl-spiro-imidazolidine, method too their manufacture and pharmaceutical products containing them

Preparations

Priority: April 27, 1982, France, no.82.07203

14 * β β

»Β O

description

The invention relates to benzoazacycloalkyl-spiroimidazolidines, a process for their production and pharmaceutical preparations containing them.

The benzoazacycloalkyl-spiro-imidazolidine correspond of the general formula I.

15th

(I)

in the

R, a hydrogen atom, a halogen atom, a hydroxyl group or a methoxy group,

R "represents a hydrogen atom, a lower alkyl group, a phenyl-lower alkyl group, a lower alkanoyl group or a p-toluenesulfonyl group and η 1 or 2
mean,

as well as their salts with inorganic or organic, pharmaceutically acceptable bases or their addition salts (except for the case where R _{? represents} an acyl group) with inorganic, pharmaceutically acceptable acids.

The low molecular weight alkyl groups preferably contain 1 to 4 carbon atoms. The lower alkylphenyl groups or the lower alkanoyl groups or lower acyl

groups R "preferably contain such as alkyl groups with 1 to 4 carbon atoms, the group R ~ especially preferably represents a hydrogen atom.

Since the compounds of the general formula I can have an asymmetric carbon atom (spiro bond) they are in the form of the racemates or the optical isomers, which are also the subject of the invention.

The compounds of the invention can be prepared are made by condensation of a ketone derivative of the general formula II

15th

(II)

in which R 'has the meanings given above for R' with the exception of the hydrogen atom and R- and η have the meanings given above with regard to general formula I,
with an alkali metal cyanide in the presence of ammonia or an ammonium salt to form a spirohydantoin of the general formula I '

30th

¹ V / - ¹

(CH ₂ ) _n

(I ¹ )

in which n, R, and R 'have the meanings given above

• «· ♦» e «i» t ι *

own,

which compound is optionally debenzylated to a compound of the general formula I in which R _{2 represents} a hydrogen atom, which latter compound is formed with a Nxedrigalkansaurhalogenid or with a p-toluenesulphonyl halide to a compound of the general formula I in which R «is a lower alkanoyl group or a . represents p-toluenesulfonyl group, can acylate.

The condensation reaction of the ketone derivative of the general formula II with the alkali metal cyanide takes place under the usual conditions of the Strecker reaction in the presence of ammonia or an ammonium salt in a polar Solvent, such as an alcohol, operating at the boiling point and optionally under pressure.

The debenzylation of the spirohydantoin of the general formula I ¹ can be carried out with hydrogen in the presence of a catalyst such as Pd / C in a polar solvent.

The acylation takes place in the presence of an acid acceptor, which can also serve as a solvent, such as pyridine.

The ketones of the general formula II, in which η has the value 1, used as starting materials (isoquinolones) are described in the literature (The Chemistry of Heterocyclic Compounds, Vol. 38.1, pages 215 to 216, Interscience, ed. Wiley), or starting from benzoic acid esters according to the following reaction scheme getting produced:

COOC ₂ H ₅

CH ₉ -N-CH ₉ COOC ₉ H ₁

(IV) R ¹

COOC ₂ H ₅

(II; η = 1)

(III)

In the above general formulas, R-, and R ' the meanings given in relation to the general formula II, while X is a halogen atom, preferably stands for a bromine atom. The benzoic acid ester of the general formula V is substituted with an N-substituted glycine ethyl ester condensed under reflux in the presence of an acid acceptor such as triethylamine, after which the obtained Diesters of the general formula IV with an alkali metal alcoholate, such as sodium ethoxide, in refluxing ethanol is condensed to the ketone of the general formula III. The ketone of general formula III is made using decarboxylates a strong acid in an aqueous medium and provides the desired ketone derivative of the all-

25 common formula II (n = 1).

The starting materials of the general formula II, in which η has the value 2 (benzazepinones), can be simpler starting from the corresponding alcohols of the general formula VI

R-,

(VI)

in which R, which has the meanings given in relation to the general formula I, are prepared, its Synthesis by M, Lennon et al. (J. Chem. Soc. (1975) 622) has been preserved. These compounds are acylated, alkylated or aralkylated on nitrogen, after which the hydroxyl group is oxidized to form the corresponding compound of the general formula II (n = 2).

The following examples serve to further illustrate the invention.

example 1

6-chloro-2-benzyl-1,2,3,4-tetrahydroisoquinoline-4-spiro-4'-imidazolidine ', 5'-dione

a) N- (4-chloro-2-ethoxycarbonyl-benzyl) -N-benzyl-glycine ethyl ester

55.5 g (0.2 mol) of S-chloro ^ -bromomethyl-benzoic acid ethyl ester are dissolved in 270 ml of refluxed diethyl ether and gives 34.78 g (0.18 mol) of N-benzylglycine ethyl ester and also 18.62 g (0.184 mol) of triethylamine in portions over the course of 12 hours. One holds for a total of 35 hours at reflux. After cooling, 150 ml of water and 80 ml of a 2.5N NaOH solution are added to. The organic phase is decanted and subjected to an acid / base treatment. You get 43.8 g (yield = 61%) of the product in the form of an oil.

IR spectrum: C = O = 1730 cm " ¹

Nuclear Magnetic Resonance Spectrum: 8H (ar.) 7.5 ppm, 4H (q) 4.3 ppm

2H (s) 4.2 ppm 2H (s) 3.8 ppm 2H (s) 3.3 ppm 6H (t) 1.3 ppm

b) 6-chloro-3-ethoxycarbonyl-2-benzyl-1,2,3,4-tetrahydro-4-isoquinolone

26.9 g (0.069 mol) of the crude ester obtained in step a) above are dissolved in 350 ml of benzene and this solution is poured over the course of 90 minutes into a solution of 2.1 g of sodium ethoxide in 50 ml of ethanol. The reaction mixture is refluxed for 1 hour, cooled and treated with dilute hydrochloric acid until neutral. The benzene phase is decanted off, washed with water, dried and the solvent is evaporated off. In this way, 22.9 g of a crystalline product are obtained. F = 71 to 76 ⁰ C (Mini-Kofier).

After recrystallization from 40 ml of ethanol, one obtains 19 g of the product (yield = 80%) with a melting point of 75 to 77 ° C (Mini-Kofier).

IR spectrum: C = O (ester) = 1640 cm " ¹

C = C-OH = 1610 cm " ¹

NMR spectrum: confirmation of enol form: exchangeable IH at 11.6 ppm. 25th

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

26.1 g (0.076 mol) of the compound obtained in step b) are added to 130 ml of ethanol and 400 ml of a 10n aqueous hydrochloric acid, after which during 12 Heated to reflux for hours. After the bulk of the ethanol has been driven off, the desired one falls Hydrochloride of the compound. It is filtered off with suction, washed and dried and 19 g of the crude product are obtained.

By partitioning between dichloromethane and a 5N sodium hydroxide solution the base is obtained in an amount of 16.1 g. F = 82 to 83 ° C (Mini-Kofier).

Recrystallization from 35 ml of diisopropyl ether gives 14.2 g (yield = 69 °) of the compound having a melting point of 83-85 ⁰ C (Mini-Kofler).

IR spectrum: C = O = 1690 cm " ¹
10

Nuclear Magnetic Resonance Spectrum: 8H (ar.) 7 to 8 ppm

4H (s) 3.8 ppm

2H (s) 3.4 ppm

d) 6-chloro-2-benzyl-1,2,3,4-tetrahydroisoquinoline-4-spiro-4'-imidazolidine-2 ', 5'-dione

An autoclave is charged with 13.8 g (0.051 mol) of the isoquinolone obtained in step c), 4.97 g (0.0765 mol) of potassium cyanide and 24.48 g (0.255 mol) of ammonium carbonate in 170 ml of ethanol and heated during 22 hours to a temperature of 115 ° C. After cooling and evaporation of the solvent, the residue is taken up in 50 ml of water, the solution is acidified to a pH of 1, the product is filtered off with suction and washed with water and finally with methanol. The title compound is obtained in an amount of 13.2 g (yield = 76%), F = 260 ^° C.

IR spectrum: C = O = 1720 cm " ¹ to 1770 cm" ¹ 30

Nuclear Magnetic Resonance Spectrum: 8H (ar.) 7 to 7.5 ppm

4H (m) 3.5 to 3.8 ppm

2H (s) 2.9 ppm

• ¥ M · W #

Ψ 9 *

- 12 -

Example 2

6-chloro-1,2,3,4-tetrahydroisoquinoline-4-spiro-4'-imidazolidine-2 ', 5'-dione
5

A hydrogenolysis of 3.1 g (0.009 mol) of the spiro-hydantoin obtained according to Example 1 is effected in 60 ml of acetic acid at 60 ^° C. and under atmospheric pressure in the presence of 500 mg of a catalyst (10% Pd on carbon).

After absorption of the theoretical volume of hydrogen it is filtered and the solvent is evaporated. The residue is crystallized from a water / ethanol mixture and receives 1.4 g (yield = 63%) of the product. P = 234 to 238 ° C (Mini-Kofier).

Example 3

6-chloro-2-acetyl-1,2,3,4-tetrahydroisoquinoline ~ 4-spiro-4'-imidazolidine-2 ', 5'-dione

2.51 g (0.01 mol) of the compound obtained according to Example 2 are acetylated with acetyl chloride in the presence of Pyridine at room temperature. The crude acetylated product is isolated and recrystallized from methanol and receives 1.4 g of the product. F = 252 to 254 ° C (Mini-Kofier)

IR spectrum (dimethyl sulfoxide): NH = 3500 to 2500 cm " ¹ C = O (imidazolinone) = 1700 and 1765 cm"

C = O (acetyl) = 1640 cm " ¹

Example 4
3-acetyl-2, 3,4, 5-tetrahydro-bcir / .o / d / lH-azepine-5-spiro-4 '-

VO · · 4

- 13 -

imidazolidin-2 ', 5'-dione

a) 1-Hydroxy-3-acetyl-2,3,4,5-tetrahydro-benzo / d / 1H-azepine

7 g (0.043 mol) of l-hydroxy-benzo / d / perhydroazepine are acetylated, which one according to the procedure of Lennon et al. (J. Chem. Soc. (1975) 622) with Acetyl chloride at room temperature. The acetyl derivative is isolated and recrystallized it from acetonitrile to give 5.5 g (yield = 63%) of the compound. F = 113 to 116 ° C (Mini-Kofier).

IR spectrum: OH = 3200 cm ", C = O = 1620 cm b) 3-acetyl-2,3,4,5-tetrahydro / d / 1H-azepinone-1

4.5 g (0.002 mol) of the acetylbenzazepinol obtained in step a) are oxidized with 15.4 g of the CrO ^ / 2-pyridine complex in 200 ml of acetone. After the usual treatments, 3 g of the desired product are isolated by distillation in vacuo. Boiling point ~ ₀ -, ^, = 180 ⁰ C.

IR spectrum: C = O (amide) = 1650 cm

C = O (ketone) = 1690 cm 25

c) 3-acetyl-2,3,4,5-tetrahydro-benzo / d / 1H-azepine-1-spiro-4'-imidazolidine-2 ', 5'-dione

Following the procedure of Example 1 d), but starting from 3.5 g (0.017 mol) of the perhydroazepinone obtained in step b) above (instead of the isoquinolone), from 1.67 g (0.026 mol) of potassium cyanide and 8.16 g (0.085 mol) of ammonium carbonate are obtained after recrystallization from methanol, 2.4 g of the desired product. F = 268 to 276 ⁰ C (Mini-Kofier).

«* E« ft «vv ν« ν wm ¥ *

- 14 -

IR spectrum: C = O (hydantoin) = 1770 cm ^"1 and 1720 ^cm-l C = O (acetyl) = 1660 cm" ¹

Example 5
5

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

a) Camphor sulfonate of the (d) isomer 10

100 g (0.036 mol) of the racemic compound obtained in Example 2 and 78 g (0.036 mol) of (I) -camphor-10-sulfonic acid in 1300 ml of water and 400 ml of ethanol are heated to reflux until they have completely dissolved. The solution obtained in this way is concentrated to dryness and gives 162 g of the desired salt. After a first recrystallization from 3200 ml of methanol, 70.7 g of the product ^{precipitate out overnight in a refrigerator at 3 ° C.} A second recrystallization from 2950 ml of methanol yields after 24 hours in the freezer at -18 ⁰ C. 54.6 g of (1) -camphor-10-sulfonate of (d) -6-chloro-1,2,3,4-tetrahydro -isoquinoline-4-spiro-4'-imidazolidine-2 ', 5'-dione. F = 257 ⁰ C (decomposition). M? H ₉ ^{C = +} 24.6 ° / ^ / 435 ° = + 44 ° (0.5% in methanol)

b) (d) isomer

13.8 g (0.0285 mol) of the camphor sulfonate obtained in the above manner are suspended in 145 ml of a 2% strength aqueous triethylamine solution. The mixture is heated in a water bath until a solution with a neutral pH is obtained and then left to stand overnight in the refrigerator at 3 ° C., with 6.8 g of (d) -6-chloro-1,2,3,4-tetrahydroisoquinoline-4-spiro ^ 4'-imidazolidin-2 ', 5'-dione precipitate. F = 252 ° C (decomposed

* 4 «« »Λ * ♦ ft · ····

- 15 -

tongue and sublimation).

0O ⁰ C - - Ο O ° C

/ «/ 539 ^{+ 44} ' ⁴ ° Α / 436 ^{= + 86} ' ⁴ ° ⁽⁰ ' ^{4% in} methanol) c) hydrochloride of the (d) isomer

6.4 g (0.0255 mol) of the free base obtained in the above manner are suspended in 15.4 ml of 1.65N hydrochloric acid solution. After a contact time of 20 minutes and after 3 hours in the refrigerator (3 ^° C.), 6.7 g of the hydrochloride are obtained. F = 245 ° C.

Ä7 ² 5gg = + 78.3 ° ^ / 436 ° ^{= + 177} ' ⁷ ° ⁽⁰ ' ^{5% in} methanol) d) (l) -isomer

The method described above for separating off the (d) -isomer is followed, but the (d) -camphor-10-sulfonic acid is used and receives the (d) -camphor-10-sulfonate des (1) -6-chloro-1,2,3,4-tetrahydroisoquinoline-4-spiro-4'-imidazolidine-2 ', 5'-dione .

The physical constants are the same as that of the (d) -isomer, the rotations of course being reversed.

When examining the optical purity it has been shown that this is more than 98%.

The compounds prepared according to the above examples and other compounds of the general formula I were prepared in an analogous manner and are listed below Table compiled. The formula of each compound was determined by elemental analysis, while the structure was verified via the IR and NMR spectra.

TABEL

Connection no.

R, F ( ⁰ C)

Manufacturing

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

1 1 1 1

CH., 0-7

CH., O-7

CH ₃ O-7 H

CH ₃ O-7 Cl-6 Cl-6 Cl-6

H Cl-6

F-6

F-6

CH.

> -so ₂ -

CH.

CH ₃ CO H

CH ₂ CO-CH ₃ CO-CH ₃ CH ₂ CO-H

1) isomer of compound no.

I I d) isomer of compound no.

1 1

Cl-8 Cl-8

243-246 245-249 208-210 262-263

253-255 (HCl)

234-238

260

(Decomp.)

252-254 268-276 225-227

260 HCl (decomp.)

255-260

275-280 (decomp.)

265 (decomp.)

252 (decomp.)

252 (decomp.) 195-207 (decomp.) 270

(Decomp.) (HCl)

According to Example 1 According to Example 2 According to Example 1 According to Example 1 According to Example 3 Example 2 Example 1 Example 3 Example 4 According to Example 3 According to Example 2 According to Example 1 According to Example 1 According to Example 2 Example 5 Example 5 According to Example 1 According to Example 2

- 17 -

Pharmacological investigation of the compounds according to the invention

1. The compounds of the invention were made with regard to on their inhibiting effect on those from the lenses aldose reductase extracted from rats according to the method described by S. Hayman and J.H. Kinoshita (J. Biol. Chem. 240 (1965) 877) and by S.D. Varna and J.H. Kinoshita (Biochemical Pharmacology 5 (1976) 2505 bis 2613) modified method.

The products according to the invention were in a buffer with a pH value of 6.2 and then incubated at 25 ° C in a closed container that contains the contained aldose reductase extracted from the lenses of CD River rats. After a contact time of 10 minutes the substrate was added and the activity of the enzyme was assessed by the disappearance of the cofactor hydrogenated nicotinamide adenine dinucleotide phosphate (NADPH) according to the following reaction equation:

D- glucose + NADPH + Η® - > sorbitol + NADP®

The enzymatic activity is calculated by determination the vanished crowd of NADPH. The results are as a percentage of the enzymatic activity of the preparation indicated in the absence of any inhibitor. Under these conditions you can get the minimum Determine the dose that inhibits aldose reductase 100% and the minimum dose that inhibits the enzymatic Activity inhibited by 50%. The inventive

_ Q

bindings were made in concentrations between 10 m

_5
and 10 m examined. In general, a concentration of 10 m results in an inhibition of the enzymatic activity of ^r ) 0 '.' ..

2. The toxicity of the compounds according to the invention is very low, wherein the particular mice of the strain Swiss DL, - _n when administered intraperitoneally above 1 g / kg is located.
5

3 · The in vivo activity of the compounds was determined by intravenous injection of 65 mg / kg streptozotocin diabetic-adjusted rats was studied. The examined Compounds were given in the form of a suspension in a gum solution (20%) by the oral route in the morning and administered in the evening. The animals were trained to eat their food between 8 a.m. and 4 p.m.

After 7 days of treatment, the animals are decapitated. Determined in the collected blood glycemia using the glucose oxidase method. The lenses are used immediately after death taken ,. quickly weighed and placed in liquid nitrogen. The frozen lentils are in an aqueous solution of sedoheptulose, which is used as an internal standard for gas chromatographic determination is used, wed. The proteins are precipitated. After centrifugation, the supernatant Separated liquid and freeze-dried. The dry extract is silylated with TMCS / HDMS and added in heptane, after which a gas chromatographic analysis (Hewlett Packard 5710) under the under the following conditions: FID detector, column:

2.5 m, 3 mm, 9% chromium EGS G AWDMCS 80 to 100 mesh (0.15 mm to 0.18), temperature 170 ⁰ C, carrier gas: nitrogen (30 ml / min).

The results show that the compounds of the invention when administered orally and daily

Dose twice (1 to 5) mg / kg the sorbitol content in the lens of diabetic rats (glycemia 4.0+ 0.4 g / l) by 70 to 100%.

The compounds according to the invention thus have interesting pharmacological properties. You unfold in particular, inhibitory effects on the enzyme aldose reductase, the main enzyme found in the human organism it controls the metabolism of aldoses and in particular of aldohexoses such as glucose and galactose converts these into the corresponding polyols (for example sorbitol or galactitol).

An excessive action of such an enzyme in the presence of an excess of the substrate can lead to abnormal high formation of galactitol or sorbitol in galactosemic organisms. Those produced in this way Abnormal polyol concentrations lead to an accumulation of these substances in the lens, in the peripheral one Nerves and kidneys of diabetic organisms. Indeed, the intervention is that present in the tissue Aldose reductase is hardly noticeable in organisms that have normal blood sugar levels. Its effect however, it becomes more important in diabetic organisms, whose blood sugar content is much higher.

In this way one explains a modification of the capillary functions, Nerve conduction disorders. And the appearance of a diabetic cataract with a loss the transparency of the lens of the eye. With the help of the invention Connections can reduce these serious complications or prevent them completely. on the other hand reduce the compounds according to the invention in vitro starting with a dose of 10 m and in vivo starting with a dose of 2 to 20 mg / kg the Prolac-

tin secretion by the rat pituitary gland. The basal secretion of growth hormone is increased under these conditions not modified while inhibiting hypersecretion caused by sympathetic stress, one Property that proves to be of particular interest in the treatment of diabetics.

Accordingly, there is the primary application of the invention Compounds in therapy in the treatment of diabetes and in particular for combating it the increase in capillary permeability at the onset of retinopathy and trophic disorders, for prevention or for the treatment of diabetic neuropathy in its peripheral or visceral manifestations and for the treatment of cataracts and diabetic nephropathy.

The compounds according to the invention are preferred administered by the oral or parenteral route. The pharmaceuticals particularly suitable for this route of administration Preparations are injectable solutions or suspensions that are in ampoules or self-injectable There are syringes, tablets or coated tablets, coated tablets, gelatin capsules, pills, or drinkable syrups Emulsions, ointments, drops, eye drops, eye ointments or gels for eye treatment.

The unit dose varies with the route of administration, the age of the patient and the severity of the therapeutic Indication. It can range between 25 and 250 mg per administration. The daily dose can be in adults between 50 and 500 mg.

'' ■ 33151OG

Example of gelatin capsules

6-chloro-2-acetyl-1,2,3,4-tetrahydroisoquinoline-4-spiro-4'-imidazolidine-2 ', 5'-dione 50 mg lactose 40 mg

Talc 10 mg

for one gelatin capsule.

Claims (7)

Claims 1. Benzoazacycl oalkyl-spiro-i.midazolidine the general Formula I. O = i NH (I) in the R, a hydrogen atom, a halogen atom, a hydroxyl group or a methoxy group, R "is a hydrogen atom, a lower alkyl group, a Phenyl lower alkyl group, a lower alkanoyl group pe or a p-toluenesulfonyl group and η 1 or 2
mean, in racemic form or in the form of the optical isomers, as well as their salts with inorganic or organic, pharmaceutically acceptable bases or their addition salts (except when R "represents an acyl group) with inorganic, pharmaceutically acceptable acids.
30th 2. e-chloro ^ -benzyl-l ^ fS ^ -tetrahydro-isoquinoline-'lspiro-4'-imidazolidine-2 ^f , 5'-dione and its salts. 3. 6-chloro-1,2,3,4-tetrahydroisoquinoline-4-spiro-4'-imidazolidine-2 ', 5'-dione, its (I) and (d) isomers and their salts. 4. 6-Chloro-2-acetyl-1,2,3,4-tetrahydro-isoquinoline-4-spiro-4'-imidazolidine-2 ', 5'-dione and its salts. 5. 3-Acetyl-2,3,4,5-tetrahydro-benzo / d7 ~ 1H-azepine-1-5 spiro-4'-imidazolidin-2 ', 5'-dione and its salts. 6. A method for the preparation of the compounds according to claim 1, characterized in that that a ketone derivative of the general formula II R-, (II) in which R 'has the meanings given in claim 1 for R "with the exception of the hydrogen atom and R, and η have the meanings given in claim 1, with an alkali metal cyanide in the presence of ammonia or an ammonium salt to form a spiro-hydantoin of the general formula I. ¹ (CH ₂ ) _n (I ¹ ) 35 in the n, R, and R ¹ - the meanings given above own, condensed and this compound optionally to a compound of the general formula I in which R ~ represents a hydrogen atom, debenzylated and this latter compound optionally with a halide a low molecular weight alkanoic acid or a p-toluenesulfonyl halide with formation of the corresponding compound of the general formula I in which R "is a lower alkanoyl group or represents a p-toluenesulfonyl group, acylated. 7. Pharmaceutical preparations containing as active ingredient at least one compound according to one of the claims 1 to 5 in admixture or combination with an inert, pharmaceutically acceptable, non-toxic carrier, binder and / or excipient.