CH627647A5 - 1,2,3,3a,4,5-Hexahydrocanthine derivatives and therapeutic compositions - Google Patents

Description

627647

2

CLAIMS 1. Therapeutically active compounds of formula

The present invention relates to derivatives of hexahydro-1,2,3,3a, 4,5-canthine as well as therapeutic compositions based on said derivatives, having in particular a vasodilator activity. The derivatives of rhexahydro-1,2,3,3a, 4,5-canthine, which form the (I) 5 first object of the invention, correspond to the formula:

(I)

in which

X] and X2, taken together, represent an oxygen atom, and, taken separately, represent in which

2o X! and X2, taken together, represent an oxygen atom, and, taken d j r separately, represent

/ / 3 .H .R3

\

H

\

OH

/ \

OR

H OH

/ \

R3 being a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl (C1-C6 alkyl) or aryl,

Rj represents a C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl radical, and

R2 represents a hydrogen atom or a group of formula -CH2OH,

Ri is not an alkyl radical when Xj and X2 - taken together - represent an oxygen atom and R2 = H or when R3 is an alkyl radical and R2 = H,

and their salts with pharmacologically acceptable acids.

2. Compounds according to claim 1, characterized in that Xi and X2 each represent a hydrogen atom, Ri represents a methyl radical and R2 a hydrogen atom.

3. Compounds according to claim 1, characterized in that Rj represents a C2-C6 alkenyl or C2-C6 alkynyl radical.

4. Compounds according to claim 3, characterized in that Xj and X2 together represent an oxygen atom.

5. Compound according to claim 4, characterized in that R2 represents a hydrogen atom.

6. Compound according to claim 5, characterized in that Rj is a propargyl radical.

7. Therapeutic composition, characterized in that it contains, as active principle, a compound according to claim 1.

r3 being a q-cß alkyl, c2-c6 alkenyl, c2-c6 alkynyl, aryl (C1-C6 alkyl) or aryl,

R [represents a Q-Q alkyl, C2-C6 alkenyl or C2-C6 alkynyl radical, and r2 represents a hydrogen atom or a group of formula

-ch2oh.

Also part of the invention are their salts with pharmacologically acceptable acids and the compositions which contain them, in particular in admixture with a pharmaceutically acceptable excipient. The salts can in particular be those formed with hydrochloric, sulfuric, phosphoric, methane sulphonic, maleic, succinic, pamoic, acetic, fumaric, lactic, aspartic and citric acids.

The compounds of formula i have vasodilating properties, which are manifested in particular in the brain and can be used therapeutically to achieve an improvement in the oxygenation of brain cells and a psychostimulation. The compounds of formula I are new, except the compound of 45 formula i in which Xj + X2 = o, ri = CH3 and r2 = H, which has been described by W. Zeiger "The Synthesis of Canthiphytine", thesis of the University of Pennsylvania 1972). This thesis does not however describe any application of the product.

The compounds of formula I can be prepared according to the following scheme 50:

have)

Rjx

627647

R3MgX

Thus, the compounds of formula I are prepared from rhexahydro-1,2,3,3a, 4,5-canthinone-6 (II, R2 = H), described by G. Hanh and A. Hansel, "Chem. Ber. " (1938) 71, 2163, or else of the derivative substituted in position 2 (R2 = CH2OH).

Thus, to prepare compounds of formula I in which X1} X2 = O (III), a compound of formula II is reacted with a halide of formula RjX according to the usual methods, in particular in an alcohol or a polar solvent such as dimethylform-amide, in the presence of an acid acceptor such as a carbonate or an alkali or alkaline earth hydroxide or an organic base.

The compounds of formula III can be transformed into compounds of formula I in which

XlX2

/ \

OH

R,

(compounds of formula V) by reaction with an organomagnesium R3MgX under the usual conditions for Grignard reactions, in particular in anhydrous ether under cooling. The compounds of formula I in which

X „X2 =

/ \

H

H

can be obtained by reduction of the compounds of formula III (compounds of formula VI) with lithium aluminohydride.

The following examples illustrate the preparation of the compounds of formula I.

Example 1:

Preparation of the compound of formula III in which R1 = -CH2CH = CH2 R2 = H, hydrochloride.

11.3 g (0.05 mol) of hexahydro l, 2,3,3a, 4,5-canthinone-6 (II, R2 = H) and 6.7 g (0.055 mol) of allyl bromide are dissolved in

100 ml of ethanol and brought to reflux with 4.7 g (0.055 mol) of sodium bicarbonate, for 6 h. After cooling, the insoluble product is drained, washed with water and dissolved hot in a mixture of 120 ml of ethanol, 10 ml of 2.5N HCl and 50 ml of water. After filtration of a slight insoluble material, the filtrate is cooled, and the crystals formed are drained, washed with ethanol and dried.

5.2 g of product are obtained: F> 260 ° C 35 Yield: 34% (base F = 144 ° C)

Analysis for C17H18N20, HCl:

Calculated: C 67.43 H 6.32 N 9.25 Cl 5.28%

Found: C 67.10 H 6.35 N 9.35 Cl 5.35%

40

50

55

Example 2:

Preparation of the compound of formula V in which Rj = CH3, R2 = H, R3 = —CH2CH = CH2.

A solution of allylmagnesium iodide is prepared from 7.5 g (0.3 gram atom) of magnesium and 0.3 mol of allyl iodide in 100 ml of ether. To this solution, cooled to -2 ° C. and under a stream of nitrogen, 23 g (0.096 mol) of 3-methyl-1,2,3,3a, 4,5 canthinone-6 dissolved in 150 ml of tetrahydrofuran are added. , keeping the temperature between —2 and + 3 ° C. After stirring for 3 h at 0 ° C and 12 h at ordinary temperature, the reaction mixture is cooled to 0 ° C and hydrolyzed with 120 ml of a saturated aqueous solution of ammonium chloride. The product is extracted with tetrahydrofuran, then after evaporation of the solvent, recrystallized from ethyl acetate.

F = 210 ° C

Yield: 40%

Analysis for C18H22N20:

Calculated: C 76.53 H 7.85 N 9.92 O 5.66%

Found: C76.4 H 7.75 N 9.85 O 5.80%

The methyl 3-hexahydro-1, 3,3,3a, 4,5 canthinone-6 used above is prepared as the compound described in Example 1.

F = 260 ° C

Analysis for C15H16N20, HCl:

Calculated: C 65.09 H 6.19 N 10.12 Cl 12.81%

Found: C 64.90 H 6.20 N 10.05 Cl 12.70%

627647

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Example 3:

Preparation of the compound of formula VI in which Rj = CH3

r2 = h.

13.8 g (0.05 mol) of 3-methylhexahydro-1,2,3,3a, 4,5-canthinone-6 hydrochloride (III, R, = CH3 and R2 = H) are suspended in 200 ml of ether and added to 5.7 g (0.15 mol) of lithium aluminum hydride suspended in 200 ml of anhydrous ether. With stirring, the mixture is brought to reflux for 2 h, cooled and hydrolyzed by addition of 11 ml of saturated aqueous sodium chloride solution. After filtration and evaporation of the solvent, the residue is recrystallized from ethyl acetate.

7.7 g of product are obtained: F = 116 = C.

Yield: 68%

Analysis for Ci5H18N2:

Calculated: C 79.60 H 8.01 N 12.37%

Found: C 79.50 H 7.95 N 12.40%

Example 4:

Compound of formula III in which RI = - CH2CH = CH - CH3, R2 = H hydrochloride.

It is prepared as the product of Example 1. F = 254 C (dec.)

Analysis for C, 8H20N2O, HCl:

Calculated: C 68.23 H 6.68 Cl 11.19 N 8.84 O 5.05% Found: C 68.19 H 6.63 Cl 11.10 N 8.79 O 5.07%

Example 5:

Compound of formula III in which Rj = - CH2 — C = CH, R2 = H, hydrochloride, crystallized with 0.5 H20.

It is prepared like the product of Example 1, replacing the allyl bromide by propargyl bromide.

F = 245 = C (dec.).

Analysis for C17H16N20, HCl 0.5 H20:

Calculated: C 65.90 H 5.85 Cl 11.45 N 9.04%

Found: C 65.82 H 5.68 Cl 11.40 N 8.98%

Example 6:

Compound of formula III in which Rt = - CH2C = CH, R2 = CH2OH.

It is prepared like the product of Example 5.

Mp 176 ° C.

Analysis for C, 8H18N202:

Calculated: C 73.45 H 6.16 N 9.52 0 10.87%

s Found: C 73.30 H 6.17 N 9.50 0 10.92%

Results of toxicological and pharmacological studies will be given below which demonstrate the advantageous properties of the compounds of formula I, which make them valuable in therapy.

10

1) Acute toxicity: the compounds of formula I are relatively little toxic, both parenterally and orally. In most cases, the toxic manifestations observed at high doses indicate significant brain stimulation. The values of

15 LD 50 obtained are given in the table below.

At doses which do not cause any toxic manifestation, the behavior of the animals is little modified. In particular, animals maintain satisfactory motor coordination.

2) At the level of the cardiovascular system, the compounds of

20 formula I have a very specific action profile. A certain number of them have the property of strongly and durably increasing peripheral blood flow rates without appreciably modifying systematic blood pressure. At the same time, the compounds of Examples 2 and 6 have the property of significantly increasing the cerebral flow in dogs. Results are given in the table below.

3) The compounds of formula I show, in almost all of them, an important protective activity with respect to the lethal effects of hypoxia in mice. Results are given in the table ciao after-

By their psychostimulating properties, their remarkable cardiovascular effects and their antihypoxia activity, the compounds of formula I are of definite therapeutic interest in the treatment of peripheral and cerebral vascular insufficiencies. The compounds of formula I can be administered to patients in the form of bases or of salts obtained with non-toxic acids, in the form of tablets or capsules, containing 5 to 100 mg of active principle, with the usual excipients - or in the form of salts in drops of oral solution containing 5 to 20% of active ingredient. 40 The average dosage is 10 mg to 200 mg / day.

The compounds of formula I, in the form of salts, can also be presented in the form of injectable solutions containing 5 to 50 mg of active principle in a usual injectable solvent.

Board

Examples

\ r °

LD 50 (mg / kg)

Protection against hypobaric hypoxia *

Cardiovascular actions (i.v. route)

i.p.

per os i.p.

% prot.

p.o.

% prot.

Doses

Pressure

Debit

Debit

Dose (mg / kg)

Dose (mg / kg)

(mg / kg)

cardiac femoral arterial i

»200

»200

40

21

100

17

2

33-100

»200

<20

11

I to 5

slightly s

/ • (45-95%)

0

> 40

30

3

33-100

100-200

<20

16

0.1 to 1

slightly / *

(jq 300%)

> 40

20

4

> 200

> 200

20

7

1 to 5

0

/ "

5

> 200

> 200

<10

12

> 20

42

2.5

0

slightly slightly

* The percentage of protection represents the increase in survival time as a percentage at fictitious altitude (atmospheric depression of —600 mmHg compared to normal atmospheric pressure).