WO1997038978A1 - Anticonvulsant (10,11-dihydro) 10-oxy-5h-dibenz[b,f]azepine-5-carboxamides - Google Patents

Abstract

Compounds of formula (I) wherein R is a straight or branched C1-C6 alkyl; C3-C7 cycloalkyl; aryl or arylalkyl optionally substituted with C1-C3 alkoxy groups, halogen atoms, cyano, nitro, C1-C3 alkyl or C1-C3 haloalkoxy groups; are useful in the analgesic, antidepressive and anticonvulsant therapies. New are compounds of formula (I), with the proviso that, when the 10- and 11- positions are linked by a double bond, R is different from methyl, and, when the 10- and 11- positions are linked by a simple bond, R is different from methyl and ethyl.

Description

ANTICONVULSANT ( 10 , 11-DIHYDRO) 10-OXY-5H-DIBENZ[B , F]AZEPINE-5-CARBOXAMIDES

The present invention relates to compounds of formula ( I )

(I) wherein R is straight or branched ^c2~^c6 ^alkY¹' ^c3^-c7 cycloalkyl, aryl, arylalkyl, with the proviso that, when the 10- and 11- positions are linked by a double bond, R is different from methyl, and, when the 10- and 11- positions are linked by a simple bond, R is different from methyl and ethyl. The compounds of formula (I) in which R is methyl or R is ethyl and the 10- and 11- positions are linked by a single bond, and the compound of formula (I) in which R is methyl and the 10- and 11- positions are linked by a double bond were described as intermediates in DD 218 889 and respectively in DE 2.011.087 without any mention to pharmacological properties.

The invention further relates to the use of the compounds of formula (I), as well as of the compounds (I) in which R is methyl or ethyl, aε therapeutical agents.

In compounds of formula (I), when the 10- and 11- positionε are linked by a double bond, a C2^-c6 alkyl group is preferably ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-hexyl; a C₃-C₆ cycloalkyl group is preferably cyclopropyl, cyclopentyl or cyclohexyl; an aryl group is preferably phenyl, optionally substituted with ^cι~^c^ ^alko*Y groups, halogen atoms, cyano, nitro, C^-C^ alkyl, C^-Cg haloalkoxy groups; an aralkyl group is preferably benzyl, optionally substituted as indicated for the phenyl group.

Preferred compounds of formula (I), whan the 10- and 11- positions are linked by a single bond, are par¬ ticularly those in which R is n-propyl, isopropyl, n-bu¬ tyl, isobutyl, t-butyl, n-hexyl, cyclohexyl or benzyl.

The pharmacological activity of some 5H-dibenz- [b,f]-azepine derivatives on the central nervous system has been knovm for a long time, in particular that of 5H-dibenz-[b,f]-azepine-5-carboxamide or CARBAMAZEPINE (IT) and of 10-oxo-10,ll-dihydro-5Hdibenz-[b,f]-azepine- 5-carboxamide or OXCARBAZEPINE (III).

(II) (III) CARBAMAZBPINE OXCARBAZEPINE

They have been usually employed in therapy as analgesics, antidepressants and anticonvulsants, carbamazepine already for about thirty years, oxcarbazepine, although known for the same time, only more recently.

See for instance U.S. 2,948,718 and DE 2,011,087.

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

(III) (III bis)

It should be noted that formula (III) bis corresponds to general formula (I) when R = H.

The compounds of formula (I ) , compared with carbamazepine and oxcarbazepine (II) and (III) have a markedly higher lipophilia, evidenced by the much greater solubility in slightly polar aprotic solvents such as toluene, dichloromethane, ethyl acetate, with a resulting higher bioavailability and more favourable dose/effect ratio.

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

Compounds (I) having the double bond between the

10- and 11- positions (10- alkoxycarbamazepine) are prepared according to the process already described in the Italian Patent application MI 95 A 000056, with suitable, appropriate changes.

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

SCHEME A

CR_jCOOR

R; see formula (I)

(VI) X: Cl, Br

The dihalo acetyliminostilbene (V), prepared according to what disclosed in Belgian Patent 597,796 and USA Re 27,622 is treated with an alkoxide R0~ excess (R having the same meanings as in formula (I)), in a ROH alcohol, optionally diluted con inert solvents such aε benzene, toluene, xylene, monoglyme, diglyme or analogues .

Alkoxy iminostilbene is recovered by concentration of the reaction mixture and dilution with water. After drying, this is reacted with isocyanic acid, prepared in situ from metal cyanates and acids, for example alkali or alkaline-earth cyanates and mineral acids such as sulfuric, hydrochloric or hydrobromic acids dry or in an acetic acid solution, or in acetic, formic, monochloroacetic, monobromoacetic, dichloroacetic, trichloroacetic, 2-chloropropionic acids, in solvents such as benzene, toluene, chlorobenzene, chloroform, di¬ chloromethane, 1,2-dichloroethane, 1,1,1-tricloroethane, trichloroethylene at temperatures from 20^βC to 60^βC, optionally in the presence of water traces (Scheme B).

The resulting alkoxy carbamazepine (I) is recovered after washing the reaction mixture with water, concentrating the solvent and crystallizing from solvents such as benzene, toluene, cyclohexane, ethyl or isopropyl ether alone or in a mixture.

SCHEME B

(VI) (I) R: see formula (I)

The compounds (I) having a single bond between the 10- and 11- positions are prepared starting from oxcarbazepine (III), by reduction of the keto group at the 10- position with sodium borohydride in solvents such as methanol, ethanol tetrahydrofuran, dimethyl¬ formamide or diglyme (possibly aqueous), without recovering the intermediate, and subsequent alkylation in the same reaction medium by means of R - X compounds wherein R has the above mentioned meanings and X is Cl, Br, I, OTs, OMs.

The crude 10-alkoxy-dihydrocarbamazepine is recovered by dilution with water, after neutralization of the sodium borohydride excess and concentration of the reaction solvent. The product is crystallized from solvents such as alcohols (even aqueous), benzene, toluene, xylene, cyclohexane, petroleum ethers with various boiling points, ethers or mixtures thereof. The reaction scheme is the following :

SCHEME C

(Ill) (VII)

(I)

The compounds described above are useful in the analgesic, antidepressive and anticonvulsant therapies.

Bioavailability, tolerability and effectiveness are very good, better than those of other products used in therapy for the same purposes, such as carbamazepine and oxcarbazepine.

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

The administration can be carried out by the oral, rectal, intramuscular or transdermal routes, in formulations such as hard-gelatin capsules with a solid content, soft-gelatin capsules with a liquid content, optionally coated or gastric-coated tablets, sugar- coated pills, suppositories, vials for injectable solutions, plasters for a protracted transdermal absorption, mixing the active ingredient with suitable excipients according to known procedures of pharmaceutical technique.

The following preparation examples further illustrate the invention. Example 1: 10-ETHOXYCARBAMAZEPINE

N-acetyliminostilbene (23.52 g, 0.1 moles) is dissolved in 100 ml of chloroform. The mixture iε cooled at O'C to - 5"C. Bromine (15.98 g, 5.14 ml, 0.1 moles) is dropped without exceeding + 5"C, stirring between - 5^*C and + 5^*C overnight. Chloroform is distilled off under vacuum to dryness, the solid residue is taken up with absolute ethyl alcohol (200 ml); a solution of sodium ethoxide (100 g) in absolute ethanol (300 ml) is added carefully, heating slowly until reflux. A strong reaction takes place which iε controlled by cooling on a cold water bath. When the exothermy has stopped, 200 ml of ethanol are distilled at atmospheric pressure, subsequently refluxing for 24 hours. A further 150 ml of ethanol are distilled, refluxing for a further 24 hours. The mixture is then cooled, taken up with water (200 ml), cooled at r.t. and filtered, washing thoroughly with water, then dried under vacuum at about

60^βC.

Yield: 21.35 g (90% on theoretical) of

10-ETHOXY-IMINOSTILBENE. 10-Ethoxy-iminostilbene is taken up with toluene

(150 m); potassium cyanate (8.1 g, 0.1 moles) and trichloroacetic acid (16.34 g, 0.1 moles) are added. The mixture is heated at about 50^*C stirring vigorously until 10-ethoxy-iminostilbene is lower than 2>t of the starting charge (24 to 48 h).

Water (50 ml) is dropped therein, stirring thoroughly, and the phases are separated, discarding the aqueous one. The organic phase is concentrated to a volume of 50 ml ani cooled at O'C overnight, then it is filtered, washing with some cold toluene.

Crude 10-ETHOXY-CARBAMAZEPINE is obtained (22.7 g).

Recrystallizing from toluene/isopropyl ether, 17.6 g of pure product are obtained, (70% on theoretical), with m.p. 158^βC - 160^βC. Example ?. : 10-n-BUTOXYCARBAMAZEPTNE

The procedure of example 1 is followed, replacing sodium ethoxide with an equimolecular amount of sodium butoxide, prepared from n-butanol (500 ml) and 60% sodium hydride (60 g), added in portions to butanol diluted with toluene (200 ml), then refluxing until effervescence ceases.

The yield in 10-butoxy-iminostilbene iε somewhat lower (80% on theoretical) and that in 10-butoxycar- bamazepine is analogous. The other reagents are used in equal molar ratios, m.p. 165^*C - 167"C.

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

Table A: 10-ALKOXY-CARBAMAZEPINE (I)

m.p. Yield % (on N- acetyliminoεtilbene)

C₂H₅ 158°C - 160^βC 63 n - C₃H₇ 162°C - 164^*C 55 i - C₃H₇ 157^βC - 159"C 44 n - C₄H_g 165^βC - 167°C 56 i - C₄H₉ 148"C - 150°C 58 tert. - C₄H₉ 145^βC - 147"C 25 ⁿ ~ ^C6^H13 172^*C - 174"C 52

ementary analysis

Example 3: 10-n-BUTOXY-DIHYDRO-CARBAZEPINE

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

Keeping temperature between 15^*C and 25^βC, sodium borohydride (1.1 g, 0.029 moles - 0.116 equivalents) is added in portions, stirring at r.t. until an analytic control evidences the disappearance of the starting oxcarbazepine. n-Butyl-bromide (27.4 g, 21.52 ml, 0.2 moles) is added, refluxing for 4 h. The solvent is distilled off to dryness under vacuum, taking up the residue with water (250 ml), pH iε adjusted at ~ 7, and the mixture is stirred strongly and filtered, washing thoroughly the solid with water, then recrystallizing from ethanol/water.

Yield : g. 18.6 (60% on theoretical).

Example 4: 10-ISOPROPOXY-DIHYDRO-CARBAMAZEPINE The procedure of example 1 is followed, but carrying out the reaction in diglyme (250 ml), and using an equimolar amount of isopropyl tosylate instead of n- butylbromide, at 50° - 60°C.

The yields are slightly lower ( ^r 50% on theoretical) .

With a procedure analogous to that of example 3, the derivatives with R = n-propyl, isobutyl, n-hexyl, benzyl are prepared.

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

With a procedure analogous to that of example 4, the derivatives with R = isopropyl, tert-butyl, cyclohexyl are prepared. The derivatives are reported in Table B.

Table B : 10-ALKOXY-DIHYDROCARBAMAZEPINE

R Preparation m.p . Yield % (on meithod Oxcarbazepine)

n-C₃H₇ Es. 3 135°C - 137°C 63 i- C₃H₇ Es. 4 130°C - 132^βC 51 n - C₄H₉ Es. 3 138^βC - 140^βC 65 i - C₄H_g Es. 3 125°C - 127°C 61 tert. - C₄H_g Es. 4 128^*C - 130^*C 15 n - C₆H₁₃ Es. 3 145^βC - 147^βC 53 cycle - CgH₁₂ Es. 4 161^βC - 163^βC 41 ø- CH₂ Es. 3 171°C - 173^*C 55

Identification: IR and H¹ NMR spectra; elementary analysis

Claims

Compounds of formula ( I )

(I) wherein R is straight or branched ^C2~^C6 alkyl/

C₃-C₇ cycloalkyl, aryl, arylalkyl, with the proviso that, when the 10- and 11- positions are linked by a double bond, R is different from methyl, and, when the

10- and 11- positions are linked by a simple bond, R is different from methyl and ethyl.

2. Compounds according to claim 1, wherein the 10- and

11- positions are linked by a double bond.

3. Compounds according to claim 1, wherein the 10- and 11- positions are linked by a single bond.

4. Compounds according to any one of the above claimε, wherein R is selected from n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-hexyl, cyclohexyl or benzyl.

5. Compounds of formula (I)

(I) wherein R is a straight or branched C^-Cg alkyl, C₃~C₇ cycloalkyl, aryl or arylalkyl as therapeutical agents.

6. Pharmaceutical compositionε containing aε the active ingredient the compounds of claims 1 or 5, in admixture with a suitable carrier or excipient.