CS247196B2 - Method of new substituted isochromates and oxopines production - Google Patents

Abstract

Die Erfindung betrifft Isochromane und Oxepine der allgemeinen Formel (I) worin

• R¹ ein Wasserstoffatom oder eine gerade oder verzweigte Alkylgruppe mit bis zu 4 C-Atomen,
• R² ein Wasserstoffatom oder eine gerade oder verzweigte Alkylgruppe mit bis zu 4 C-Atomen oder zusammen mit R¹ eine Alkylengruppe mit 3 bis 5 C-Atomen,
• R³ ein Wasserstoffatom oder eine gerade oder verzweigte Alkylgruppe mit bis zu 4 C-Atomen,
• R⁴ ein Wasserstoffatom oder eine gerade oder verzweigte Alkylgruppe mit bis zu 4 C-Atomen,
• R⁵ ein Wasserstoffatom oder eine gerade oder verzweigte Alkylgruppe mit 1 bis 6 C-Atomen oder eine Pyridinylgruppe,
• R⁶ ein Wasserstoffatom, ein Fluor-, Chlor- oder Bromatom, eine gerade oder verzweigte Alkylgruppe mit 1 bis 6 C-Atomen, eine Hydroxi- oder Alkoxigruppe mit 1 bis 4 C-Atomen oder eine Trifluormethylgruppe,
• R⁷ ein Wasserstoffatom, ein Fluor-, Chlor- oder Bromatom, eine gerade oder verzweigte Alkylgruppe mit 1 bis 6 C-Atomen, eine Hydroxi- oder Alkoxigruppe mit 1 bis 4 C-Atomen oder zusammen mit R⁶ eine Methylendioxigruppe,
• R⁸ ein Wasserstoffatom, eine Hydroxi- oder Alkoxigruppe mit 1 bis 4 C-Atomen, m die Zahlen 1 oder 2 und
• n die Zahlen 1, 2 oder 3 bedeuten, und deren Säureadditionssalze.

Die Verbindungen wirken caiciumantagonistisch und antihypertonisch.

Description

The present invention relates to a process for the preparation of the novel substituted isochromans and oxepines of the formula I

) and their acid addition salts, which have valuable therapeutic properties.

Ve of the above general formula I ^r1 represents a hydrogen atom or a straight or branched alkyl group containing up to 4 carbon atoms, R ² represents hydrogen or a straight or branched alkyl group containing about ⁴ atom ^{d u} ^ ík ^ ^p ole or ^N N ^E R? forms ^a pre-alkylene having ^{the P} inu at ³ to 5 carbon atoms, ^r3 represents a hydrogen atom or a straight or branched alkyl group containing up to 4 carbon atoms, ^r4 represents a hydrogen atom or a straight or branched alkyl group containing up to 4 carbon atoms, ^r5 represents a hydrogen atom, a straight or branched (C 1 -C 6) alkyl group or a pyridinyl group, R ⁶ represents a hydrogen, fluorine, chlorine or bromine atom, a straight or branched alkyl group having 1 to 6 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms or a trifluoromethyl group, ^r7 represents a hydrogen, fluorine, chlorine or bromine atom, a straight or branched alkyl group having 1 to 6 carbon atoms, a hydroxyl group or an alkoxy group having 1 to 6 carbon atoms; 4 carbon atoms, or together with R ° form methylenedioxy, ^r8 represents a hydrogen, fluorine, chlorine or bromine atom, a hydroxyl group or a (C1-C4) alkoxy group, m is a number of 1 or 2; and n is a number of 1, 2, or 3.

Preferred are the isochromans and oxepins of formula (Ia)

in which ^r1,

3, _v ,

R and R may be the same or different and are each a hydrogen atom or a methyl group,

R ⁵ represents an isopropyl group or a pyridinyl group, ^R6 is hydrogen, fluorine or chlorine atom, trifluoromethyl group, or their methoxy.alpha. represents hydrogen, fluorine or chlorine, tert SKU ^{pi nu,} NETIO tvof with common ^e d ^{methylthiophenyl} LEND is hydrogen or methoxy, is 1 or 2 and is 1 or 2, acid addition salts.

Most preferred are compounds corresponding to the general formula

in which

R ⁶ represents a hydrogen atom, a chlorine atom or a methoxy group, a group or a methoxy (Ib) ^{r 7} represents a fluorine atom, a chlorine atom or a methoxy group and ^{r 8} represents a hydrogen atom or a methoxy group, as well as their acid addition salts.

As mentioned above, the present invention provides a process for the preparation of the above novel novel isochroman or oxepin derivatives of formula II ch ₃ o _x

CH ₃ O

(II) in which

3

R, R, R, m and n are as defined above and is a chlorine, bromine or iodine atom, an alkylsulfonyloxy or arylsulfonyloxy group, reacted with the phenylamino-propylacetonitrile of formula III (III)

wherein ^{r 4, r 5, r 6, r 7} and R 8 are as defined above, and the resulting product is optionally converted to its acid addition salt.

The reaction is preferably carried out in an aprotic solvent, for example toluene or an aprotic polar solvent, for example dimethylformamide, with the addition of an acid binding agent, for example an inorganic base such as sodium carbonate, sodium hydroxide, or an organic base such as triethylamine. The reaction temperature may range from room temperature to ^T m ^s Nost ^{and 160} ° C. With the above Oda ^h the reaction is carried ^at te ^ i ^pl OTE limit ^{at 60} and ¹ 20 ° C.

The isochromans and oxepins of formulas I, Ia and Ib contain an asymmetric carbon atom and can be cleaved into antipodes in a known manner. Antipodes are also obtained when starting from optically active starting materials.

The isochromans and oxepines of formula I can be converted into acid addition salts in a conventional manner. Suitable acids for the preparation of salts are, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, valeric acid, oxaic acid, malonic acid, acid succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, ethanephosphonic acid .

The compounds of formula (I) exhibit valuable therapeutic effects on isolated organs and animal tests, in particular calcium antagonistic properties, which are manifested by lowering blood pressure, bradycardia, negative inotropy and coronary and peripheral vascular dilation.

Thus, the novel compounds of the invention can be used, for example, for the treatment or prophylaxis of coronary heart disease and high blood pressure in medicine.

The compounds of the formula I according to the invention can be used either alone or in combination with other active compounds. Suitable dosage forms are, for example, tablets, capsules, suppositories, solutions, syrups, emulsions or dispersible powders.

Corresponding tablets may be prepared by mixing the active ingredient (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or milk sugar, tablet disintegrating agents such as corn starch, alginic acid, binders such as starch or gelatin, glidants such as magnesium stearate or talc; and / or a depot effecting agent such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate, or polyvinyl acetate.

The novel compounds of formula (I) may be administered enterally or parenterally. For oral administration, doses of from 5 to 20 mg, preferably from 10 to 20 mg, have been found to be suitable

The compounds of formula I according to the invention are listed in Table 1 below together with their physical constants.

Table 1

Compounds of formula I according to the invention

Number R 1 R 2 R 3 R 4 R 5 R 6 R 7 what m n R f 1 H H H CH 3 CH (CH3) 2 3-OCH 3 4-OCH 3 H 1 1 0,47 a) 2 H H H ch 3 CH (CH3 ) 2 H 4-F H 1 1 0.48 b) 3 H H H CH 3 ch (ch 3 ) 2 3 CF 3 H H 1 1 0.55 and > 4 H H H CH 3 CH (CH3) 2 3-OCH 3 4-OCH 3 5-OCH 3 1 1 0,48 a) 5 H H H CH 3 CH (CH3) 2 3- CF 3 H H 2 1 0,61 a) 6 H H H CH 3 ch (ch 3 ) 2 2-F 3 4-OCH 3 2 1 0,64 a) 7 H H H CH 3 CH (CH3) 2 2-F 3 4-OCH 3 1 1 9.51 a) 8 CH 3 CH 3 H CH 3 CH (CH3) 2 3-cf 3 H H 1 2 0,43 a) 9 H H H CH 3 CH (CH3) 2 3-CF 3 H H 1 1 0,39 a) 10 H H CH 3 CH 3 CH (CH3) 2 H 4-F H 1 2 0,32 a) 11 CH 3 CH 3 H CH 3 CH (CH3) 2 3-C1 4-C1 H 1 2 0,38 a) 12 H H CH 3 CH 3 CH (CH3) 2 3-C1 4-C1 H 1 2 0,22 a) 13 H H H CH 3 2-C 5 H 4 N 3-OCH 3 4-OCH 3 H 1 1 0,38 a) 14 H H H CH 3 CH (CH3) 2 3-C1 4-C1 H 1 1 0,54 a) 15 Dec H H H CH 3 CH (CH3) 2 3-C1 4-C1 H 2 1 0,55 a) 16 H H H CH 3 2-C 5 H 4 N 3-CF 3 H H 1 1 0,59 C) 17 CH 3 CH 3 H CH 3 CH (CH3) 2 H 4-C (CH 3) '3 H 1 2 0,32 d) 18 H H H CH 3 CH (CH3) 2 H 4-C (CH 3) * 3 H 1 1 0,33 d) 19 Dec CH 3 CH 3 H CH 3 CH (CH3) 2 H 4-F H 1 2 0,52 c) 20 May H H CH 3 CH 3 CH (CH3) 2 3-0CH 3 4-OCH 3 5-OCH 3 1 2 0,27 d) 21 H H CH 3 CH 3 CH (CH3) 2 3.4 · -O-CH 2 O H 1 2 0,27 d) 22nd CH 3 CH 3 H CH 3 2-C 5 H 4 N H 4-F H 1 2 0.13 d > 23 CH 3 CH 3 CH 3 CH 3 CH (CH3) 2 3-C1 4-C1 H 1 2 0,29 d) 24 H H H CH 3 CH (CH3) 2 H 4-F H 1 2 0,43 a)

continuation of Table 1

Number R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ R ⁷ R ⁸ m n R. F 25 H H CH ₃ ^CH 3 CH _{(CH3) 2} H 4-C (CH _3] '3 ^H 1 2 0.51 and) 26 H H H ^CH 3 CH _{(CH3) 2} 3-OCH ₃ 4-OCH ₃ 5-OCH ₃ 1 2 0.42 and) 27 Mar: H H H ^CH 3 CH _{(CH3) 2} 3-OCH ₃ 4-OCH ₃ H 1 2 0.44 and) 28 ^CH 3 H H CH ₃ CH _{(CH3) 2} 3,4- -O-CH ₂ -O- H 1 2 0.41 and) 29 CH ₃ CH ₃ ^CH 3 ^CH 3 CH _{(CH3) 2} 3-OCH ₃ 4-OCH ₃ 5-OCH ₃ 1 2 0.34 and) 30 H H H CH ₃ CH _{(CH3) 2} 3-C1 4-C1 H 1 2 0.30 and) 31 CH ₃ CH ₃ ^CH 3 ^CH 3 CH _{(CH3) 2} H 4-F H 1 2 0.36 and) 32 ^CH 3 ^CH 3 H CH ₃ CH _{(CH3) 2} 3-OCH ₃ 4-OCH ₃ H 1 2 0.39 and) 33 H H H CH ₃ CH _{(CH3) 2} 3-CF ₃ H H 1 2 0.42 and) 34 ^CH 3 CH ₃ H CH ₃ CH _{(CH3) 2} 3-OCH ₃ 4-OCH ₃ 5-OCH ₃ 1. 2 0.43 and) 35 H H CH ₃ ^CH 3 CH _{(CH3) 2} 3-OCH ₃ 4-OCH ₃ H 1 2 0.21 and)

Legend:

eluents for chromatography

(a) dichloromethane - methanol 9: 1

(b) dichloromethane-methanol 95: 5

c) dichloromethane-methanol 8: 2

d) dichloromethane-acetonitrile-ethanol 7: 2: 1

The invention is illustrated by the following non-limiting examples.

Example 1

6,7-Dimethoxy-1- [1- [4- (4-cyano-5-methyl-4-) m-trifluoromethylphenyl) hexyl] -N-methylamino] methyl] isochroman (Table 1, Compound No. 3)

2 g of 1-bromomethyl-6,7-dimethoxyisochroman and 2.1 g of 2-isopropyl-2- [3- (N-methylamino) propyl] -2- (3-trifluoromethylphenyl) acetonitrile are dissolved in 30 ml of absolute dimethylformamide, and addition of 15 ml of triethylamine, the mixture was allowed to react at 110 ° C for 15 hours.

The residue was distilled with 50 ml of 2N hydrochloric acid and then fractionally shaken with diethyl ether at increasing pH values. The ether fractions obtained at pH 6 to 7.5 were combined, dried over sodium sulfate, the solvent was evaporated and the crude product isolated by medium pressure chromatography on a silica gel column (Merck, Lichroprep Si 60, particle size 15-25 µm) according to Helmchen [see G Helmchen et al., Angew. Chem. 91, ⁶⁴ (1979)] at 0.3 to 0.5 MPa.

0.7 g of the desired compound is obtained in the form of a colorless viscous oil.

R = 0.55; eluent: a 9: 1 mixture of dichloromethane and methanol.

Elementary analysis:

C, 66.65; H, 6.99; N, 5.55.

Found: C, 66.55; H, 6.96; N, 5.36.

Example 2

7,8-Dimethoxy-1- [1- (4-cyano-4- (2-fluoro-3,4-dimethoxyphenyl) -5-methylhexyl) -N-methylamino] methyl] -1,3,4 5-tetrahydro-2-benzoxepine (Table 1, Compound No. 6)

2.1 g of 1-bromomethyl-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzoxepine and 2.2 g of 2- (3,4-dimethoxy-2-) are dissolved in 30 ml of absolute dimethylformamide. fluorophenyl) -2'-isopropyl-2- [3- (N-methylamino) propyl] acetonitrile.

To the solution was added 3 g of potassium carbonate, and the mixture was stirred at ¹¹⁰ ° C for 15 hours. ^R ea n ^{s CZK} mixture of ^p RAC Ostu ^{p p p p} o em Sanyo in ^{the examples} and in ^d 1, and the crude ^p ro ^d u ^k t in ^{s YC} ist chromatography.

0.2 g of the desired compound is obtained in the form of a yellowish very viscous oil.

R f = 0.64; eluent: a 9: 1 mixture of dichloromethane and methanol.

Elementary analysis:

H, 7.82; N, 5.30.

Found: C, 67.71; H, 7.65; N, 5.53.

Example 3

^Y 6.7- dimethoxy -4,4'-dimethyl-l- / 2- [N- (4-cyano-4- (3-butylphenyl triflurometh ^{y y} l) -5-meth ^yl lhex ^yl) -N-ethyl methylaminoJ / isochroman (Table 1, Compound No. 8)

In 30 ml of dry dimethylformamide were dissolved 2 g of 2-bromomethyl-6,7-dimethoxy -4,4 ^y - dimethylisochromanu and 2.1 g of 2-isopropyl-2 '- [3- (N-methylamino) ^pyridine 1J- 2- (3-trifluoromethylphenyl) acetonitrile, to the solution was added 3 g of potassium carbonate and the mixture was stirred for 15 hours and te ^{pl lecture} about ^{the 110} ° C. After processing the reaction ^í ^ sires. I ^{to the} IP ^{of the} range of ^l to ^{1 g of p} Roveda chromatography raf ^and CK ^and isolation.

1.15 g of the desired compound is obtained in the form of a colorless, very viscous oil.

R f = 0.43; eluent: a 9: 1 mixture of dichloromethane and methanol.

Elementary analysis:

C, 68.11; H, 7.56; N, 5.12.

Found: C, 68.04; H, 7.67; N, 5.37.

Example 4

6.7-Dimethoxy-1- [2- [N- (4-cyano-4- (4-fluorophenyl) -5-methylhexyl) -N-methylamino] ethyl] -1-

-methylisochroman.

(Table 1, compound no. 10) g of 6, ^{7-dimethoxy-l-methyl-l- 2} - (p-tosyloxy) ethyl] isochroman and 5 g of 2- ^{(4-tluorfeny) -2'-isopropyl-2} - ^[3- (N-methylamino) propyljacetonitrilu rozpusH is in 50 m ^l of toluene and, after the ^p ADDED - ml ^trimethyl eth ^y lam ⁱ Nu ^- u ^{g h} l ^{i C} a potassium carbonate-Lného ^{15 h} of ^di n MIC ^h and ^{at t} EPLO ^{I 115} ° C.

After evaporation of the solvent, the residue is taken up in 100 ml of water and extracted with 100 ml of diethyl ether. The aqueous phase is separated and 50 ml of 2N hydrochloric acid are added to the organic phase. The ether phase is separated and the acidic aqueous phase is fractionally shaken out with diethyl ether at increasing pH values. The organic phases obtained at pH between 6 and 7.5 are combined, dried over sodium sulphate and evaporated.

The product is isolated by medium pressure chromatography on a silica gel column (Merek, Lichroprep Si 60, grain size 15-25 [mu] m) according to Helmchen [see G. Helmchen et al., Angew. Chem. 91, 64 (1979)] at 0 to 0.5 MPa.

Chromatography gave 1.8 g of the desired compound as a viscous colorless oil.

Rf = 0.2; eluent: a 9: 1 mixture of dichloromethane and methanol.

Elemental analysis calculated: 72.17% C, 8.14% H, 5.80% N;

Found: C, 71.71; H, 8.09; N, 5.5%.

Example. 5

6.7-Dimethoxy-4,4-dimethyl-1- [2- [n- (4-cyano-4- (-, 4-dichlorophenyl) -5-ethylhexyl) -N-ethylamino] ethyl / isochroman (Table 1, Compound No. 6) . 11) g of 1- (2-chloroethyl) -6,7-dimethoxy-4,4'-dimethylisochromanu and 2.1 g of 2- (3,4-dichlorophenyl) ^{- 2'-isopropyl-2 - [3 -} ( N-methylamino) -prop ^^ ce ^ n ^ r ^ lu is dissolved at 0 ^- m ^{l di f} ee ^th yl oreamidu ^par idaj ^{í -} gu ^{hlič potassium} and carbonate and mixtures ^of it with ^{6 h} of ^di nm ^even c and ^{crocheted BC t} e rt ^{pl of 100} ° C.

The reaction mixture was evaporated and the residue was subjected to fractional shaking in an analogous manner to Example 4. Ether was evaporated from the desired fractions and the residue was subjected to medium pressure silica gel column chromatography (Merck. Lichroprep Si 60) according to Helmchen, at a pressure of 0 to 0. 5 MPa.

1.1 g of pure title compound are obtained in the form of a slightly yellowish, very viscous oil.

Rj = 0, -8; eluent: a 9: 1 mixture of dichloromethane and methanol.

Elementary analysis:

C, 65.80; H, -6.6; N, 5.12. Found: C, 65.49; H, 7.40; N, 5.22.

Example 6

6.7- ^D iecthoxy-l- (l- ^{[N- (4-cyano-4-} (3, ⁴ - ^d ichlorfenyl) -5-methylhexyl) -N-ecthylaeino] ec ^t hyl / isochroman (Table 1, compound Nos. 14) g of 1-bromoethyl-6,7-diecthoxyisochroanea and 2.1 g of 2 - (-, 4-dichlorophene / 1) -2'-isopropyl-2'-methylaminolpropenacetic acid are dissolved in ^- 0 ml and ^ oli ^ whom you diecthylforeae ^and du ^'p of ^at d ^ck 3 ^g uhiiři-carbonate a potassium-ého mixture was then worked up analogously to ^{15 hours} of ^di- nm ^even c ^{ha at} te ^pl OTE П0 The reaction in Example 4.

0.6 g of the expected product is obtained in the form of a viscous colorless oil.

- 0.54; eluent: a 9: 1 mixture of dichloromethane and methanol.

Elementary analysis:

calculated found

H, 6.78; N, 5.54.

H, 6.77; N, 5.44.

Example^7, 4-Dirnethoxy-1- [1- (N-) -^dic^hlsteed^Finy^l)^-4-^kyan^-5^-met^hy^lhixy^{l) -N-}m^ethylamino] m^ethyl/ -1,3,4,5-tetrah^ydro-2-benzoxipine (Table 1, Compound No. 15)

2.1 g У-broIтоnethyl-7,8-dimethoxy-l, ^{3,4,5-tetrahydro-2-P} in binzoxe and 2.1 g of 2- (3,4-dichlorophenyl) -2'-Crafts acylation of ^{p p} £ 2- yl-3- (N-methylamino) propyljacetonitrilu was dissolved in 30 ml ^of dimethylformamide, and after ^{adding 3 g} n ^s u ethane ^{aluminosilicate} reaction mixture was then treated as ^{d s} raseln it with a mixture ^{of 15 d} in it as described in Example 4.

stirred ^{and Pr} I tepdotě И0 ° C.

0.3 g of the desired compound is obtained in the form of a yellowish, very viscous oil.

Rf = 0.55; eluent: a 9: 1 mixture of dichloromethane and methanol.

Elementary analysis:

calculated found

% C, 64.73;% H, 6.98;% N, 5.39;

% C, 64.79;% H, 6.98;% N, 5.12.

Example

6,7-Dimethoxy-4,4-dimethyl-1- [2- (N- (4-fluorophenyl) -5-methylhexyl) -N-methylamino] ethyl] isochroman (Table 1, Compound No. 19) g 1- (2- chУorethyУ) -6,7-dimethoxy-4,4'-dimithylisochromanu and 1.8 g of 2- (4-fluorophenyl) -2-isopropyl-2- ^yl £ 3- (N-methylamino) ^p ropylj dissolved in acetonitrile 30 ml ^of dimethylformamide and, ^at roztob Daj ^{as 3 g} at ^hL ičitanu drasebého a mixture ^of the 6 ^h of ^di n rnchá ^t e ^{pl at} about ^{the 100} ° C.

After cooling, the reaction mixture is taken up in water and 2N hydrochloric acid and, as the procedure is then increased, is chromatographed. Desired fractions as described in Example 1.

After chromatographic isolation of 0.8 g of pure compound as a colorless OK E. ^{Е я R} f = 0.52; eluent: 8: 2 dichloromethane / methanol.

Example 9

6,7-Djonoxy-1- [2- [N- (4-cyano-5-methyl-4- (3,4,5-trimethoxyphenyl) hexyl) -N-nethylamino] ethyl] isochroman (Table 1, Compound No. 26)

1.8 g of 1- (2-chloroethyl) -6,7-dimethoxyisochroman and 2.1 g of 2-isopropyl-2 '- [3- (N-methylamino) propyl] -2 (- _from 4 _of 5-trimethoxyphenyl) acetonitrile are treated with: -0 ml dissolved in dry dimethylformamide and after adding 10 ml of triethylamine and - g of potassium carbonate, the mixture was ^stirred overnight s te rt ^{pl of 1} 0 ⁰ ° C.

After evaporation of the solvent in vacuo, 150 ml of diethyl ether and 100 ml of water are added to the residue, the mixture is shaken, separated and the organic phase is shaken three times with 80 ml of 2N hydrochloric acid each time. The acidic aqueous phases are combined, neutralized with sodium carbonate and then extracted with 100 ml of diethyl ether.

The organic layer was dried over sodium sulfate and evaporated. The residue was then subjected to silica gel column chromatography (see Example 1).

0.9 g of the desired compound is obtained in the form of a yellowish viscous oil.

Rf = 0.42; eluent: 7: 2: 1 dichloromethane / acetonitrile / ethanol.

Elementary analysis:

H, 8.20; N, 5.18.

Found: C, 68.71; H, 8.29; N, 4.96.

Example 10

6.^7-Dime ^ thoxy-1- / 2-^-N- (4-cyan-4-yl) -4- (3^, 4-Methylenedioxyphenyl-exyl-H-methyl-methyl-methyl] ethyl / -4-methylisochroman (Table 1, Compound No. 28)

1.9 g of 1- (2-chloroethyl) -6,7-dimethoxy-4-methylisochroman and 1.9 g of 2'-isopropyl-2 '- (3,4-methylenedioxyphenyl) -2 - [- (propyl) acetonitrile are dissolved in 10 ml of absolute dimethylformamide and, after addition of 20 ml of triethylamine and - g of potassium carbonate, the mixture ^{for 15 h} from ⁱ n MIC ^h and ^{at t} EPLO ^{i 1} 00 ° C. Rea ^CZK the mixture ^of with the ^p and ^k from ^p RAC ^p Ostu ^p em ^p o ^{p p} in Sanya of manufacture ^kl range of ninth

250 mg of the desired compound is obtained in the form of a viscous colorless oil.

Rf = 0.41; eluent: 9: 1 dichloromethane / chloroform.

Elementary analysis:

C, 70.84; H, 7.93; N, 5.51.

Found: C, 70.83; H, 8.05; N, 5.42.

Example 11

6, ^ D ^ e ^ oxy-1- / 2 '[n- (^4-kyan^-5-Methyl-4-⁽3,^4, 5^-trime^thoxyphenyl)^hexyl) ^^ e ^ y ^ i ^ no] methyl-1,4,4-trimethylisochroman (Table 1, Compound No. 29)

3.4 g of 1- (2 'bromoethyl) -6,7-dimethoxy ^y -l, ^{4,4-trimethyl-y} lisochromanu and 3.1 g of ^2-p ro ^p iso-yl-2' - - [3- ( N-methylamino) -propyl ^^ - ^^ S-trimethyl ^ OX ^ ^^ en cetonitríl.u the rozpusH in 15 ml of dimethyl ^hydroxy lformamidu and after adding 30 ml of triethylamine and 3 g of potassium carbonate, the mixture was stirred for 12 hours at te ^pl OTE 120 [deg.] C. '

The reaction mixture is worked up analogously to Example 1 by fractional shaking.

The desired fractions (pH 6-7.5) were combined, the ether phase was dried and the ether was evaporated. The crude product is purified by chromatography.

After chromatography, 1.9 g of the desired compound is obtained in the form of a slightly yellowish viscous oil.

R f = 0.34; eluent: a 9: 1 mixture of dichloromethane and methanol.

Elementary analysis:

calculated found

% C, 70.07;% H, 8.65;% N, 4.81;

% C, 69.70;% H, 8.90;

Example ⁶ .7 ^- D ^{i h} o ^xy-meth l- ^{/ 2} - [N- (4-cyano-4- H luorfeny].) ^- 5 ^- methyl ^{hylh exy)} -N ^{- meth yl} amino] et ^{hyl / -} · -1,4,4a-trimethylisochroman (table 1, compound no. 31)

3.4 g of 1- ( ² -bromoethyl) -6,7-dimethoxy-1,4,4'-trimethylisochroman, 2.5 g of 2- (4-fluorophenyl) -2'-isopropyl-2- [33 (N (methylamino) propyl] acetonitrile, 20 ml of triethylamine and 3 g of potassium carbonate were reacted in an analogous manner to that described in Example 1, and the reaction mixture was worked up analogously to Example 1.

After chromatographic purification, 1.8 g of pure product is obtained in the form of a colorless, highly viscous oil.

R f = 0.36; eluent: a 9: 1 mixture of dichloromethane and methanol.

Example 13

6.7-Dimethoxy-1- [2- (4-cyano-5-methyl-4- (3-trifluoromethylphenyl) hexyl) -N-methylamino] ethyl] isochroman (Table 1, Compound No. 33)

1.8 g of 1- (2-chloroethyl) -6,7-dimethoxyisochroman, 2.1 g of 2-isopropyl-2- [33 (N-methylamino) propyl] -2- (3-trifluorophenyl) acetonitrile, 10 ml of dimethylformamide 20 ml of triethylamine and 3 g of potassium carbonate were subjected to an analogous reaction to that described in Example 1, and the reaction mixture was worked up analogously to Example 1.

After chromatography, 0.8 g of pure product is obtained in the form of a colorless viscous oil.

Rf = 0.42; eluent: a 9: 1 mixture of dichloromethane and methanol.

Elementary analysis:

C, 67.16; H, 7.19; N, 5.40. Found: C, 66.82; H, 7.22; N, 5.15.

Example 14

6.7-Dimethoxy-1- [2- [N- (4-cyano-4- (3,4-dimethoxyphenyl) -5-methylhexyl) -N-methylamino] ethyl] -1-methylisochroman (Table 1, Compound No. 35) ) 6 ^{g 7} -diinethoxy-l-methyl-l- ² - (p ^- tosyloxy) ethylJisochromanu а ^{2.9 g 2- (3,} 4-diiuethoxyfenyl) - ² "'isopropyl ² - [3- (N- methylamino) propyljacetonitrilu was dissolved in 30 ml of dry toluene and 5 ml of DMF and after the addition of 5 ml triethylamine and 3 g of potassium carbonate ^{chit eh} anu about 15 nm it ^{di s} c ^{ha at t h} e ^p ture 1.00 ° C.

Work-up of the reaction mixture was carried out in a manner analogous to Example 4. After chromatography on silica gel, 3.1 g of the desired compound was obtained as a highly viscous colorless oil.

R _f = 0.21; eluent: a 9: 1 mixture of dichloromethane and methanol.

Elementary analysis:

C, 70.96; H, 8.45; N, 5.34.

Found: C, 70.47; H, 8.49; N, 5.14.

The following are examples of pharmaceutical compositions containing compounds of the invention as active ingredients.

(a) Dragees

Composition of 1 dragee core:

active ingredient according to the invention 2.0 mg milk sugar 28.5 mg cornstarch 17.0 mg gelatine 2.0 mg magnesium stearate 0.5 mg

50.0 mg

Preparation:

The mixture of the active substance, lactose and corn starch, using 10% aqueous solution ^from Elat ⁱ ny ^g wound ^l U is ^p res sieve with size ^also axes of ^three of ^{the 1111 ug} Ranuli ^Whether the ^y su ^{width P} s te ^p Lot ⁴⁰ ° C and sieved again.

The granulate thus obtained is mixed with magnesium stearate and dragee cores are pressed from the mixture. These cores are then coated in a conventional manner using aqueous suspensions of sugar, titanium dioxide, talc and gum arabic. The finished dragee is polished with beeswax. The resulting dragee weight is 100 mg.

(b) Tablets.

Tablet composition:

active ingredient according to the invention 2.0 mg milk sugar 55.0 mg cornstarch 38.0 mg soluble starch 4.0 mg magnesium stearate 1.0 mg

100.0 mg

Preparation:

The active ingredient / magnesium stearate mixture is granulated using an aqueous solution of soluble starch, the granulate is dried and thoroughly mixed with milk sugar and corn starch. Tablets weighing 100 mg each containing 2 mg of active ingredient are then compressed from the mixture.

(c) Suppositories

Composition 1 Suppository:

active ingredient according to the invention 1.0 mg suppository mass 1,699.0 mg

Preparation:

The finely divided active ingredient is mixed into a molten suppository to 40 ° C by means of a dip homogenizer. The resulting mass is then poured into a slightly cooled mold at 35 ° C.

d) Ampoules

Contents of 1 ampoule

active ingredient according to the invention 2.0 mg sodium chloride 18.0 mg Distilled water to 2.0 ml

Preparation:

The active substance and sodium chloride are dissolved in water, the solution is freed from insoluble particles by filtration and, under aseptic conditions, filled with 2 ml ampoules. The ampoules are then sterilized and sealed. Each ampoule contains 2 mg of active substance.

Claims (2)

A process for the preparation of novel substituted isochromans and oxepine of the general formula I (I) in which R ¹ represents hydrogen or straight- or branched- chain alkyl group containing up to 4 carbon atoms, R represents a hydrogen atom or a straight or branched alkyl group containing up to 4 carbon atoms, or together with R forms an alkylene group having 3 to 5 carbon atoms, R ³ represents a hydrogen atom or a straight or branched alkyl group containing up to 4 carbon atoms, R represents a hydrogen atom or a straight or branched alkyl group containing up to 4 carbon atoms, R ⁵ represents a hydrogen atom or a straight or branched (C 1 -C 6) alkyl group or a pyridinyl group, R ⁶ represents a hydrogen, fluorine, chlorine or bromine atom, a straight or branched (C 1 -C 6) alkyl group, a hydroxyl group, a C 1 -C 4 alkyl group or a trifluoromethyl group, R ⁷ represents a hydrogen, fluorine, chlorine or bromine atom, a straight or branched alkyl group having 1 to 6 carbon atoms, a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms, or together with R ⁶ forms a methylenedioxy group, R represents a hydrogen, fluorine, chlorine or bromine atom, a hydroxyl or alkoxy group having 1 to 4 carbon atoms, m is a number of 1 or 2 and n is a number of 1, 2 or 3, and their acid addition salts, characterized by wherein the isochroman or oxepin derivative of formula (II): wherein: 12 3 R, R, R, m and n are as defined above and X represents a chlorine, bromine or iodine atom, an alkylsulfonyloxy or arylsulfonyloxy group, reacted with a phenylamino-propyl acetonitrile of formula III (III) in which: R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above, and the resulting compound is optionally converted to its acid addition salt. 2. The process of claim 1, wherein the reaction is carried out in the presence of an acid binding agent in an aprotic solvent at a temperature in the range of from about 50 ° C to about 160 ° C.