The invention relates to new berbane derivatives, to pharmaceutical compositions containing these compounds and a process for the preparation of same.

The berbane analogues of the biologically active alcaloides of the Rauwolfia plant family exhibit in many cases much better pharmacological activity than the indol analogues. The α^-receptor blocking activity of the berbane analogues (see e.g.

Vizi, E.S., Tόth, I., Somogyi, G.T., Szabό, L. , Harsing, L.G. and Szantay, Cs.: J. of Med. Chem. 30,

1355 (1987)., EP No. 202 950) is particularly interesting.

The aim of our invention is to provide new compounds which are more selective than the known Qi2 adrenoceptor antagonists and so may advantageously be used in the therapy.

It has been found that the racemic and optically active new 13,14-didehydroberbane derivatives of formula (I)

SUB

- wherein

R ¹ and R ² together form a methylene dioxy group, and R ³ stands for a straight or branched alkyl having 1-6 carbon atoms -

obtained in the course of our experiments, meet this requirement.

According to the process of the invention the new 13,14-didehydroberbane derivatives of formula (I) - wherein R ¹ , R ² and R ³ are the same as mentioned above - may be prepared by eliminating water from a racemic or optically active 14-hydroxy derivative of formula (II)

- wherein R ¹ , R ² and R ³ are the same as mentioned above. The elimination of the water may be carried out e.g. by the known Vilsmeier reaction (see L.Szabό, ■ I. Tόth, L. Tδke, Cs.Szantay; Liebigs Ann. Chem. 1977, 642) , wherein thionyl chloride is used as eliminating agent in the presence of dimethyl formamide. The bases obtained are converted into salts by reacting them with physiologically acceptable acids (e.g. hydrochloric acid, sulfuric acid, citric acid, tartaric acid) , as these compounds are more suitable for biological use. The starting compounds of formula (II) are

SUBSTITUTESHEET

disclosed in EP No. 202 950 and may be prepared according to the methods described therein and in the references cited therein.

The new compounds according to the invention exhibit 0*2-adrenoceptor antagonistic activity and so they may be used in the pharmaceutical compositions according to the invention as active ingredient optionally in combination with other known active compounds. The pharmaceutical compositions according to the invention may be prepared by any known method, e.g. by admixing the compounds of formula (I) or salts thereof optionally with known additives (e.g. diluents, solvents, lubricants, fillers, etc.) and converting the mixture obtained into a form suitable for administ¬ ration, e.g. for parenteral, oral or rectal administ¬ ration. As pharmaceutical compositions e.g. tablets, pills, solutions, suspensions, powders, sprays may be prepared. Methyl-7,8-( ethylene-dioxy)-13,14-didehydro- -alloberbane-13-carboxylate (compound la) is one of the preferred compounds of the formula (I) and shows a very effective 0 ^* 2-adrenoceptor antagonistic activity in comparison with yohimbine. Moreover this compound does not possess any α-l adrenoceptor blocking activity.

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Table 1

Comparison of the α-2 and α-i adrenoceptor antagonistic activity of yohimbine and compound Ia

Compound A2 c.-2 pA2 α-2 Selectivity adreno- adreno- pA2 α-l/ A2 α-2 ceptor ^" ceptor ⁺⁺

Yohimbine 6.3+ 0.2 (3)K 5.9 (2) 2.4

Compound Ia 8.3+ 0.2 (6)K 4 (3) 22387

+ rat's vasa deferens stimulated with electricity, xylazine antagonist; ++ rat's vasa deferens, phenylephrine agonist (see Vizi, E.S. et al.: J. Pharmacol. Exp. Ther. , 1986, 238. 701-706, Vizi, E.S. et al.. J. Med. Chem., 1987, in press) .

Mean + S.E.M. : in brackets the number of the experiments is given; : competitive

The invention is illustrated in detail by the following Examples.

Example 1 Methyl-7,8-(methylene-dioxy)-13,14-didehydro- alloberbane-13-carboxylate (compound Ia) , corresponding to compound of formula (I) , wherein

R _lr R ₂ =0CH ₂ 0,

R ₃ =COOCH3

SUBSTITUTESHEET

To the solution of 2 g (5.56 mmoles) of methyl- -7,8-(methylene-dioxy)-14-hydroxy-alloberbane-13- -carboxylate prepared with 20 ml of dimethyl formamide at 0°C 4 ml of thionyl chloride are added dissolved in 20 ml of DMF and allowed to stay at room temperature for 2 days. The mixture is thereafter poured onto 100 ml of ice-water, made alkaline with cone. NH4OH (to pH=9) , the precipitate is filtered, dried and recrystallized from ether or methanol. Yield: 1.8 g (94.8 %) ; m.p. (of the HCl salt) 187-189°C (MeOH) .

Analysis for C20H23 O4 (341.39): Calculated: C 70.36 H 6.79 N 4.10 Found: C 70.31 H 6.78 N 4.05

MS m/Z%: 341 /79/, 340 /100/, 326 /79/, 310 /!/ , 300 /2.5

282 /12/, 254 /0.8/, 252 / !/ , 240 /4/, 226 /!/ ,

216 /17/, 214 /20/, 202 /8/, 189 /83/, 176 /9/,

175 /21/, 174 /22/ NMR /CDCI ₃ /: 7.00 /lH,m,C ₁₄ -H/, 6.74, 6.53 /2H,S,C ₆ -H,

Cg-H/, 5.86 /2H,S,OCH ₂ 0/, 3.77 /3H,S,COOCH ₃ / IR /KBr/: 1720 /COOCH ₃ /, 1650 cm ^-1 /c=c/.

Example 2 Hydrochloride salt of compound Ia

1 g (2.93 mmoles) of base Ia is admixed with 5 ml of methanol and acified with 30% mixture of HCl/MeOH to pH=3, thereafter the precipitated crystalline material is dried and washed with a 1:1 mixture of MeOH/ether. Yield: 1.05 g (95 %) ; m.p. 187-189°C (MeOH).

SUBSTITUTE SHEET