FR2548666A1 - New nortropane and granatane derivatives, process for their preparation and their application in therapeutics - Google Patents

Abstract

beta -Nortropanes and beta -granatanes of formula: in which X = CH2, CH2-CH2 or O-CH2; n = 1 or 2; R = H, halogen, CH3 or CH3O; R1 = H, CH3, CH3O, CN or one or two halogen atoms. These compounds are useful as medicaments for the treatment of disorders of the mind (mental disorders).

Description

 The present invention relates to novel derivatives of nor-tropane and granatane, their method of preparation and their therapeutic application.

dans laquelle - X représente un groupe méthylène (-CH2-) ou éthylène (-CH2-CH2-) ou un groupe
oxyméthylène (-0-CH2-) dont l'atome d'oxygène est relié au noyau phényle, - n prend la valeur 1 ou 2, - R représente un atome d'hydrogène ou d'halogène ou un groupe méthyle ou
méthyloxy, et R1 représente l'atome d'hydrogène, un ou deux atomesd'halogène, un groupe
méthyle ou méthyloxy ou le groupe cyano, l'ensemble

étant fixé en position équatoriale ( ss ) sur le cycle nor-tropanique ou
granatane.The novel derivatives according to the invention comprise, first of all, the compounds of general formula

in which - X represents a methylene (-CH2-) or ethylene (-CH2-CH2-) group or a group
oxymethylene (-O-CH 2 -) whose oxygen atom is connected to the phenyl ring, n is 1 or 2, - R is a hydrogen or halogen atom or a methyl group or
methyloxy, and R1 represents the hydrogen atom, one or two halogen atoms, a group
methyl or methyloxy or the cyano group, the whole

being fixed in equatorial position (ss) on the nor-tropanic cycle or
granatane.

 The derivatives according to the invention also comprise the mineral or organic acid addition salts of the compounds of formula (I). They finally comprise the N-oxides of said compounds of formula (I) as well as the optically active isomers of these compounds, salts and N-oxides.

dans laquelle n et R1 ont les mêmes significations que dans la formule (I) et le groupe NH2 est fixé en position équatoriale (/3, j sur le cycle nor-tropani- que ou granatane, respectivement avec les phtalides de formule

dans laquelle R a les memes significations que dans la formule (I), cette condensation étant de préférence effectuée à chaud, en autoclave et en milieu hydroalcoolique, notamment en milieu constitué par un mélange CR3OH-eau ;;
B/ les composés (I) pour lesquels X représente le groupe éthylène (-CH2-CH2-) sont obtenus
- soit par une synthèse en deux étapes qui consiste à traiter les
isocoumarines de formule

The present invention also extends to the processes for preparing the derivatives defined below. So
A / compounds (I) for which X represents the methylene group (-CH2-) are obtained by condensation of compounds of formula

in which n and R 1 have the same meanings as in formula (I) and the NH 2 group is attached to the equatorial position (/ 3, j on the nor-tropanic or granatane ring, respectively with the phthalides of formula

in which R has the same meanings as in formula (I), this condensation being preferably carried out hot, in an autoclave and in an aqueous-alcoholic medium, in particular in a medium consisting of a CR3OH-water mixture;
B / the compounds (I) for which X represents the ethylene group (-CH2-CH2-) are obtained
- either by a two-step synthesis which consists in treating the
isocoumarins of formula

dans laquelle R, R1 et n ont les mêmes significations que dans la formule (I) et l'ensemble :

est fixé enposition équatoriale ( ss ) sur le cycle nor-tropane ou
granatane, par le chlorure de mésyle puis à cycliser le composé
obtenu par l'hydrure de sodium, selon le protocole décrit dans
J.0.C. 44, 1533, mais à partir des réactifs correspondants ; et
C/ les composés (I) pour lesquels X représente le groupe (-0-CH2-) sont obtenus par condensation des composés de formule

dans laquelle R, R1 et n ont les mêmes significations que dans la formule (I), et l'ensemble

est fixé en position équatoriale () ) sur le cycle nor-tropane ou granatane, avec le dibromométhane, en présence d'une base faible telle que le carbonate de potassium, puis en ajoutant une base forte comme la potasse de préférence pulvérisée, en milieu aprotique (de préférence le DMF).in which R has the same meanings as in the formula
(I) by phosphorus pentachloride, then to treat the pro
intermediates obtained respectively by the compounds of
formula (II) according to the protocol described in Il Farmaco., Ed Sciez
1977, page 159, but from the corresponding reagents, or by a three-step synthesis which consists in condensing
isocoumarins of formula (IV) with the compounds (II), according to
the protocol described in Synthesis 1976, 719, but from the
corresponding reagents, then to treat amidoalcohols inter
mediates obtained from formula:

in which R, R1 and n have the same meanings as in formula (I) and the set:

is fixed in equatorial (ss) position on the nor-tropane cycle or
granatane, mesyl chloride and then to cyclize the compound
obtained by sodium hydride, according to the protocol described in
J.0.C. 44, 1533, but from the corresponding reagents; and
C / compounds (I) for which X represents the group (-O-CH 2 -) are obtained by condensation of compounds of formula

in which R, R1 and n have the same meanings as in formula (I), and the whole

is fixed in the equatorial position ()) on the nor-tropane or granatane ring, with dibromomethane, in the presence of a weak base such as potassium carbonate, then adding a strong base such as potassium hydroxide preferably sprayed, in the medium aprotic (preferably DMF).

dans laquelle R, R1 et n ont les mêmes significations que dans la formule (I) et l'ensemble

est fixé en position équatoriale ( /3 ) sur le cycle nor-tropane ou granatane.The compounds (VI) are obtained by acid hydrolysis (preferably with a mixture of 1N hydrochloric acid and methanol), compounds of formula

in which R, R1 and n have the same meanings as in formula (I) and the whole

is fixed in equatorial position (/ 3) on the nor-tropane or granatane cycle.

dans laquelle R a les mêmes significations que dans la formule (I) et les composés (II). The compounds (VII) are in turn obtained by the so-called "BOISSONNAS" reaction between the acids of formula

in which R has the same meanings as in formula (I) and compounds (II).

 The acid addition salts of the compounds of formula (I) can be prepared by simple reaction of these compounds with an organic or inorganic acid according to the usual methods, the compounds (I) and / or the acid being preferably in solution in appropriate solvents.

 As for the N-oxides of the compounds (I), they are prepared by oxidation, according to the usual methods of the compounds (I) either with a peracid (M.C.P.B.A. preferably), or with the aid of hydrogen peroxide.

 The following preparations are given by way of non-limiting examples to illustrate the invention.

Example 1: benzyl-8 / - (5-chloro-isoindolin-1-yl-2) -3 hydrochloride
aza-8 bicyclo [3,2,1] octane (I)
Code number: 2
An autoclave is heated at 1700 ° C. for 24 hours with a mixture of 50 g of 3- (3-aminobenzyl-8-asa-bicyclo [3,2,1] -octane (II) and 39 g of 5-chlorophthalide (III). ) in 100 ml of methanol and 40 ml of water. Then the solvents are evaporated, the residue is taken up in methylene chloride, washed with 2N hydrochloric acid, decanted and the product which crystallizes in methylene chloride is filtered off, washed on the filter with the aid of ethyl ether and recrystallized from ethanol. Thus 15 g of the expected product are obtained. Melting Point:) 2600 ° C Yield: 16% Formula: C 22 H 24 Cl 2 N 2 O. Molecular weight: 403.34. Elemental analysis

<tb><SEP> C <SEP> H <SEP> N
<tb> Calculated <SEP> (%) <SEP> 65.51 <SEP> 6.00 <SEP> 6.95
<tb> Found <SEP> (%) <SEP> 65.29 <SEP> 5.90 <SEP> 6.99
<Tb>
By the same method, but from the corresponding reagents, the hydrochloride of 8-benzyl-1- (1-isoindolin-1-yl) -3-aza-bicyclo [3,2,1] octane, hydrate [(I ), code number 1].

Melting point:> 2600 C
Gross formula: C22H25ClN20
Molecular weight: 378.35
Elemental analysis

<tb><SEP> C <SEP> H <SEP> N
<tb> Calculated <SEP> (%) <SEP> 69.84 <SEP> 6.94 <SEP> 7.40
<tb> Found <SEP>(#)<SEP><SEP> 69.61 <SEP> 6.91 <SEP> 7.35
<Tb>
Example 2: ss-N- (8-tetrazol-8-aza-bicyclo [3,2,1] octanyl) -3-ortho-acetyloxy
benzamide (VII)
To a solution cooled to 0 ° C. of orthoacetyloxybenzoic acid (VIII) in 200 ml of methylene chloride is added 14 ml of triethylamine and then 9.6 ml of ethyl chloroformate. After 30 minutes, 21.6 g of ss- (3-amino-8-benzyl-8-azabicyclo-L3,2,1] octane (II) are added, the temperature is allowed to return to about 200 ° C., the mixture is left for 1 hour. temperature, then washed with saturated sodium bicarbonate solution, then with water, dried over sodium sulfate (or magnesium), filtered and the filtrate evaporated The residue is crystallized from isopropyl ether This gives 28 g of the expected product.

Melting point: 1325 ° C
. Yield: 75%
Gross formula: C23H26N2O3
Molecular weight: 378.45
Example 3: ss-N- (8-benzyl-8-aza-bicyclo [3,2,1] octanyl) -3 ortho-hydroxy
benzamide (VI)
A mixture of 25 g of the above compound (VII) in 150 ml of 1N hydrochloric acid and 150 ml of methanol is refluxed for 1 hour.

Then the solvents are evaporated, the residue is taken up in ethyl acetate, basified with saturated sodium bicarbonate solution, the organic phase decanted, washed with water and dried over sodium sulphate ( or magnesium), filter and evaporate the filtrate. The residue is crystallized in a mixture of isopropyl ether and ethyl acetate. 16.6 g of the expected product are thus obtained.

. Melting point: 1300 C
. Yield: 74%
. Gross formula: C21H24N202
. Molecular weight: 336.42
Example 4: ss - [(N-benzoxazin-1,3-one-4) yl] -3-benzyl-8-aza-8-bicyclo [3,2,1]
octane (I)
Code number: 3
A mixture of 1 g of the preceding compound (VI), 0.250 g of dibromomethane and 0.9 g of potassium carbonate in 30 ml of DMF is heated at 600 ° C. for 3 hours, then 0.05 g of potassium hydroxide is added. sprayed and 0.3 g of dibromomethane and refluxed the mixture for 12 hours. Then the solvent is evaporated under vacuum, the residue is dissolved in a 1N hydrochloric acid solution, washed with ethyl acetate, basified with concentrated sodium hydroxide and extracted with methylene chloride. the extract on sodium sulphate (or magnesium), filter and evaporate the solvent. The residue is chromatographed on a silica column (medium pressure liquid chromatography).

Elution with a mixture of methylene chloride (90%) and methanol (10%) gives 0.18 g of the expected product.

. Melting point: 1010 C
. Yield: 18%
. Gross formula: C22H24N2O2
Molecular weight: 348.43
NMR spectrum (CDCl3), 2 ppm =
7.95, m (aromatic H on the benzoxazine-1,3 nucleus)
- 6.8 to 7.4, m (8 H aromatics)
- 5.15, s (-CO-N-CH2-0- benzoxazin-1,3 cycle)
- 4.6 m (1 tropic H: H in 3 ZX)
- 3.5, s (CH2-)
- 3.25, m (2 tropanic H in 1 and 5)
- 1.6 to 2.2, m (tropic 8 H at 2, 4, 6 and 7).

 The derivatives according to the invention have been tested on the laboratory animal and have shown in particular an activity on the central nervous system, in particular a neuroleptic action.

 This activity has been demonstrated in mice, in particular by the apomorphine uptake antagonism test, carried out according to the protocol described by G. GOURET et al. in J. Pharmacol. (Paris) 1973, 4, 341.

 The acute toxicity of the derivatives according to the invention was also studied (in mice by i.p.).

To illustrate the invention, the table below shows some results obtained in the aforementioned test and toxicological study.

<Tb>

Compound <SEP> tested <SEP> Toxicity <SEP> (mouse) <SEP> Antagonism <SEP> to <SEP> rectifications
<tb> Number <SEP> of <SEP> code <SEP> LD50 <SEP> (mg / kg / ip) <SEP> to <SEP> apomorphine <SEP> (mouse)
<tb><SEP> DE50 <SEP> (mg / kg / ip)
<tb><SEP> 1 <SEP> 45 <SEP> 0.8
<tb><SEP> 2 <SEP> iii <SEP> 0.14
<Tb>
The difference between the toxic doses and the active doses allows the therapeutic use of the compounds (I), their pharmaceutically acceptable acid addition salts and the corresponding N-oxides.

 The present invention therefore extends to the application as medicaments, in particular for the treatment of disorders of the psyche, these compounds, salts and N-oxides. It finally extends to pharmaceutical compositions containing, as active principle, at least one of these drugs in combination with a pharmaceutically acceptable vehicle. Thus, the medicaments according to the invention may for example be administered orally in the form of a dragee, capsule or tablet containing up to 300 mg of active principle (3 to 8 administrations per day) or in the form of a solution containing 0, 1 to 1% of active principle (10 to 60 drops, one to three times a day), or parenterally in the form of an injectable ampoule containing up to 100 mg of active principle (3 to 8 ampoules per day).

Claims (10)

1. Nor-tropanes and granatans corresponding to the general formula

 in which - X represents a methylene (-CH2-) or ethylene (-CH2-CH2-) group or a group  oxymethylene (-O-CH 2 -) whose oxygen atom is connected to the phenyl ring, n is 1 or 2, - R is a hydrogen or halogen atom or a methyl group or  methyloxy, and -R1 represents the hydrogen atom, a two halogen atom, a group  methyl or methyloxy or the cyano group, the whole

 being fixed in equatorial position (/ 3) on the nor-tropanic or granatane ring, as well as their addition salts of organic or inorganic acids, their N-oxides and their optically active isomers.  2. Compounds according to claim 1, wherein X is methylene and the group (n, R, R1) is (1, H, H) or (1,5-Cl, H).  3. Compounds according to claim 1, wherein X represents the oxymethylene group and the group (n, R, R1) has the value (1, H, H).  4. A medicament in particular with activity on the central nervous system, characterized in that it consists of any of the nor-tropanes, granatans, pharmaceutically acceptable salts, optically active N-oxides and isomers according to claim 1, 2 or 3.  5. Pharmaceutical composition, characterized in that it comprises, as an active ingredient, at least one of the medicaments according to claim 4, in association with a pharmaceutically acceptable vehicle.  6. Process for the preparation of the nor-tropanes and granatans of formula (I) defined in claim 1, for which X represents the methylene group, characterized in that it consists in condensing the compounds of formula

 in which n and R 1 have the same meanings as in formula (I) and the NH 2 group is attached to the equatorial position on the nor-tropane or granatane ring, with phthalides of formula

 in which R has the same meanings as in formula (I).  7. Method according to claim 6, characterized in that the condensation is carried out hot, autoclave and hydroalcoholic medium.  8. Process for the preparation of the nor-tropanes and granatans of formula (I) defined in claim 1, for which X represents the oxymethylene group, characterized in that it consists in treating the compounds of formula

 in which R, R1 and n have the same meanings as in formula (I) and the whole

  is fixed in the equatorial position on the nor-tropane or granatane ring, by dibromomethane, first in the presence of a weak base such as potassium carbonate, then a strong base such as potassium hydroxide solution in a solvent aprotic.  9. Process according to claim 8, characterized in that the compounds (VI) are obtained by acid hydrolysis of the compounds of formula

 in which R, R1 and n have the same meanings as in formula (VI) and the whole

 is fixed in equatorial position on the nor-tropane or granatane cycle.  10. As intermediates necessary for the synthesis of the compounds (I), the compounds of formula (VII) defined in claim 9.