ITMI960709A1 - DERIVATIVES OF 5H-DIBENZ- (B, F) -AZEPIN-5-CARBOXYAMIDE, THEIR PREPARATION AND USE AS MEDICINAL ACTION SUBSTANCES AND FORMULATIONS THAT - Google Patents

Description

Description of the industrial invention entitled: "DERIVATIVES OF 5H-DIBENZ- [b, f] -AZEPIN-5-CARBOSSIAMMIDE, THEIR PREPARATION AND USE AS SUBSTANCES WITH MEDICINAL ACTION AND FORMULATIONS THAT CONTAIN THEM"

The present invention relates to compounds of formula I

wherein R is linear or branched C2-C6 alkyl, C3-C7 cycloalkyl, aryl, arylalkyl, with the proviso that, when positions 10 and 11 are connected by a double bond, R is different from ethyl.

The compounds of formula I in which R is methyl or in which R is ethyl and positions 10 and 11 are connected by a carbon atom, have been described as intermediates in DE 2011087 and in DD 218889 without any mention of their respective pharmacological properties.

The invention also relates to the use of the compounds of formula I, as well as of the compounds I in which R is methyl or ethyl, as therapeutic agents.

In the compounds of formula I, a C2-C 6 group per kilo is preferably ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tbutyl, n-hexyl;

a C3-C5 cycloalkyl or preferably cyclopropyl, cyclopentyl or cyclohexyl group;

an aryl group is preferably phenyl, optionally substituted by C1-C3 alkoxy groups, halogen atoms, cyano, nitro, C1-C3 alkyl, C1-C3 haloalkoxy;

an ar alkyl group is preferably benzyl, optionally substituted as indicated for the phenyl group.

Preferred compounds of formula I are in particular those in which R is n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-hexyl, cyclohexyl or benzyl.

The pharmacological activity on the central nervous system of some derivatives of 5H-dibenz- [b, f] -azepines, in particular of 5H-dibenz- [b, f] -azepin-5-carboxyamide or CARBAMAZEPINE ( II) and 10-oxo-10, 11-dihydro-5H-dibenz- [b, f] -azepin-5-carboxyamide or OXCARBAZEPINE (III).

CARBAMAZEPINE OXCARBAZEPINE

They are commonly used in therapy as analgesics, antidepressants and anticonvulsants, carbamazepine for about thirty years, oxcarbazepine, although known for just as long, only more recently.

In this regard, see eg. U.S. 2,948,718 and DB 2,011,087.

From the structural point of view, oxcarbazepine (III) is a tautomer, in equilibrium between a ketone (III) and an enol (III bis) form.

Note that the formula III bis corresponds to the general formula (I) when R = H.

Compared to carbamazepine and oxcarbazepine (II) and (III), the compounds of formula I show a much higher lipophilicity, highlighted by the much greater solubility in non-polar aprotic solvents such as toluene, dichloromethane, ethyl acetate, with consequent greater bioavailability and more favorable dose / effect relationship.

In fact, some preliminary tests on animals, in vivo, show a remarkable activity at doses lower than those commonly used for (II) and (III).

The products (1) having the double bond between positions 10 and 11 (10-alkoxycarbamazepine) are prepared according to the process already described in the Italian patent application MI 95 A 000056, with the appropriate logical adaptations.

The desired 10-alkoxy-iminostilbene (VI) is first prepared according to the scheme:

SCSBA A

An excess of alcohololate RO (R with the same meanings indicated in formula (I), in ROH alcohol, possibly diluted with inert solvents such as benzene, toluene, xylene, monoglyme, diglyme or analogues.

The alkoxy iminostilbene is isolated by concentration of the reaction mixture and dilution with water.

After drying it is reacted with isocyanic acid, generated extemporaneously from metallic and acid cyanates, for example alkaline or alkaline-earthy cyanates and mineral acids such as sulfuric, hydrochloric or hydrobromic anhydrous or in acetic acid solution and also acetic, formic, monochloroacetic acids, monobromoacetic, dichloroacetic, trichloroacetic, 2-chloropropionic, in solvents such as benzene, toluene, chlorobenzene, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,1-trichloroethane, trichlorethylene at temperatures between 20 ° C and 60 ° C, possibly in the presence of traces of water (Scheme B).

The alkoxy carbamazepine (I) is thus obtained which is isolated after washing the reaction mixture with water, solvent concentration and crystallization from solvents such as benzene, toluene, cyclohexane, ethyl or isopropyl ether alone or in a mixture.

DIAGRAM B

R: see fòrmula (I)

Compounds I having a simple bond between positions 10 and 11 are prepared starting from oxcarbazepine (III), by reduction with sodium borohydride in solvents such as methanol, ethanol tetrahydrofuran, dimethylformamide or diglyme, also aqueous, of the ketone group in position 10, without isolating the intermediate, and subsequent alkylation in the same reaction environment by means of compounds R - X where R has the same meanings already explained and X is Cl, Br, I, OTs, OMs.

Crude 10-alkoxy-dihydrocarbamazepine is isolated by dilution with water, after neutralization of excess sodium borohydride and concentration of the reaction solvent. The product is crystallized from solvents such as alcohols, even aqueous ones, benzene, toluene, xylene, cyclohexane, petroleum ether at various boiling points, ethers or mixtures thereof.

The reaction scheme is the following:

SCHHt C

The compounds described above are useful in analgesic, antidepressant and anticonvulsant therapy.

Bioavailability, tolerability and efficacy appear very good and superior to those of other products used in therapy with the same indications, such as carbamazepine and oxcarbazepine.

Depending on the product, the use, the subjects and the route of administration, the dosages for humans can vary from 1 to 1000 mg for a single administration, with repeated doses from 1 to 3 times a day.

Administration can take place orally, rectally, intramuscularly or through the skin in the form of hard gelatin capsules with solid filling, soft gelatin capsules with liquid filling, tablets also painted or with gastro-resistant coating, sugared almonds, suppositories, ampoules of solution for injection, patches for prolonged percutaneous absorption, by mixing the active principle with suitable excipients according to known pharmaceutical technique methods.

The following preparation examples further illustrate the invention.

Example 1: 10-ETOXYCARBAMAZEPINE

N-acetyliminostilbene 23.52 g (0.1 moles) is dissolved in 100 ml chloroform.

It is cooled between 0 ° C and - 5 ° C.

Without exceeding 5 "C 15.98 g bromine is poured (5.14 ml - 0.1 moles). It is then stirred at - 5 ° C and 5 ° C for one night. All the chloroform is distilled under vacuum to dryness. The solid is taken up again. residue with absolute ethyl alcohol 200 ml, a solution of sodium ethylate 100 g in absolute ethanol 300 ml is carefully added. It is heated slowly until reflux.

There is a lively reaction which is moderated by cooling with a cold water bath. At the end of the exotherm, 200 ml of ethanol are completely distilled; it is then heated under reflux for 24 hours. Another 150 ml of ethanol is distilled and it is refused for another 24 hours.

It is cooled, taken up with 200 ml water, cooled at T.A. and filtered, washing well with water.

It is dried under vacuum at about 60 ° C.

Yield 21.35 g (90% of the theoretical) of 10-ETHOXY-IMINOSTILBENE.

10-ethoxy-iminostilbene is taken up with 150 ml toluene; add 8.1 g potassium cyanate (0.1 moles) and 16.34 g trichloroacetic acid (0.1 moles).

It is heated to about 50 ° C by stirring well and is kept thus until the 10-ethoxy-iminostilbene is less than 2% of the initial charge (from 24 to 48 h).

50 ml of water is poured, stirred well and the phases are separated, discarding the aqueous one.

The organic phase is concentrated up to a volume of 50 ml and cooled to 0 ° overnight. It is filtered, washing with a little cold toluene.

10-ETHOXY-CARBAMAZEPINE is obtained raw 22.7 g.

Recrystallizing from toluene / isopropyl ether, 17.6 g (70% of the theoretical) of pure product are obtained, with m.p. 158 ° C - 160 ° C.

Example 2; 10-n-BUTOXYCARBAMAZEPINE

Proceed as for example 1, replacing the sodium ethylate with sodium butylate, in an equimolecular quantity, prepared from n-butanol 500 ml and 60% sodium hydride 60 g, added in portions to butanol diluted with toluene 200 ml and then refluxing until the effervescence ceases.

The yield in 10-butoxy-iminostilbene is a little lower (80% of the theoretical) and that in 10-butoxycarbamazepine analogous. The other reagents are used in equal molar ratios, m.p. 165 ° C - 167 ° C.

With a procedure similar to example 2, the derivatives indicated in Table A are prepared.

Table A: 10-ALOOXY-CARBAMAZEPINE (I)

Identification: IR and H <1> NMR spectra, elemental analysis Example 3: 10-n -BUTOXY-DIHYDRO-CARBZEPINE

Oxcarbazepine (formula III) 25.23 g (0.1 moles) is partially dissolved in 70% aqueous tetrahydrofuran 500 ml, at room temperature.

Maintaining between 15 ° C and 25 ° C, 1.1 g sodium borohydride (0.029 moles - 0.116 equivalent) is added in portions. He agitates at T.A. until an analytical control reveals the disappearance of the starting oxcarbazepine.

27.4 g (ml 21.52 - 0.2 moles) n-but the -bromide is added, refluxed and reflexed for 4 h.

The solvent is distilled under vacuum to dryness, taken up with water 250 ml, the pH corrected to ≈ 7, stirred well and filtered, washing the solid well with water. It recrystallizes from ethanol / water. Yield: g. 18.6 (60% of theoretical).

Example 4: 10-ISOPROPOSSI-DIHYDRO-CARBAMAZEPINE

One proceeds as in example 3, but operating in diglyme ml 250, and using an equimolar quantity of isopropyl tosylate instead of n butylbromide, at T 50 ° C - 60 ° C.

The yields are somewhat lower (≈ 50% of the theoretical).

With a procedure similar to Example 3 the derivatives are prepared with R = n-propyl, isobutyl, n-hexyl, benzyl.

Bromides or iodides can be used indifferently, or chlorides in the presence of catalytic quantities of sodium iodide.

With the procedure analogous to example 4 the derivatives with R = isopropyl, tert are prepared. butyl, cyclohexyl.

Everything is listed in Table B.

Table B: 10-ALCOXY-DIHYDROCARBAMAZEPINE

Identification: IR H <1> NMR spectra, elemental analysis

Claims (6)

CLAIMS 1. Compounds of formula I wherein R is linear alkyl or branched cycloalkyl aryl, arylalkyl, with the proviso that, when positions 10 and 11 are connected by a double bond, R is different from ethyl. Compounds according to claim 1, wherein positions 10 and 11 are connected by a double bond. Compounds according to claim 1, wherein positions 10 and 11 are connected by a simple bond. 4. Compounds according to one of the preceding claims in which R is selected from n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, nesyl, cyclohexyl or benzyl. 5. Formulas compounds I wherein R is linear or branched alkyl cycloalkyl aryl or arylalkyl as therapeutic agents. 6. Pharmaceutical compositions containing as active principle the compounds of claims 1 or 5, in admixture with a suitable vehicle or excipient.