NO851029L - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE ISOCHROMAN AND OCSEPIN DERIVATIVES - Google Patents

Description

This invention relates to a method for manufacturing

of new substituted isochromanes and oxepines of the general formula (I)

and acid addition salts thereof with valuable therapeutic properties.

In formula (I) means

R"<*>" a hydrogen atom or a linear or branched alkyl group

with up to 4 C atoms,

R 2 a hydrogen atom or a linear or branched alkyl group

with up to 4 C atoms, or together with R an alkylene

group with 3 to 5 C atoms,

R 3 a hydrogen atom or a linear or branched alkyl group

with up to 4 C atoms,

R 4 a hydrogen atom or a linear or branched alkyl group

with up to 4 C atoms,

R^ a hydrogen atom or a linear or branched alkyl group

with 1 to 6 C atoms or a pyridinyl group,

R a hydrogen atom, a fluorine, chlorine or bromine atom, a linear or branched alkyl group with 1 to 6 C atoms, a hydroxy or alkoxy group with 1 to 4 C atoms or a

trifluoromethyl group,

R 7 a hydrogen atom, a fluorine, chlorine or bromine atom, a linear or branched alkyl group with 1 to 6 C atoms, a hydroxy or alkoxy group with 1 to 4 C atoms or

together with R a methylenedioxy group,

R is a hydrogen atom, a fluorine, chlorine or bromine atom, a hydroxy or alkoxy group with 1 to 4 C atoms,

m the numbers 1 or 2, and

n the numbers 1, 2 or 3.

Isochromanes and oxepines of the general formula (Ia) are preferred

12 3

where R , R , and R , which are the same or different, mean a hydrogen atom or a methyl group,

5

R means an isopropyl or pyridinyl group,

R means a hydrogen, fluorine or chlorine atom, a trifluoromethyl or methoxy group,

R 7 means a hydrogen, fluorine or chlorine atom, a tertiary butyl group, a methoxy group or together with R^ a

methylenedioxy group,

R g represents a hydrogen atom or a methoxy group,

m means the numbers 1 or 2, and

n means the numbers 1 or 2, and acid addition salts thereof.

Compounds of the general formula are particularly preferred

(Ib)

where

R means a hydrogen or chlorine atom or a methoxy group, R "7 means a fluorine or chlorine atom or a methoxy group, and R g means a hydrogen atom or a methoxy group,

and acid addition salts thereof.

According to the invention, the new compounds are prepared by an isochroman or oxepine derivative with the general formula (II)

where

12 3

R , R , R , m and n are as indicated above, and X means a chlorine, bromine or iodine atom or an alkylsulfonyloxy or arylsulfonyloxy group, is reacted with a phenyl-aminopropyl-acetonitrile of the general formula (III)

where

R<4>, R^, R<6>, R^ and R^ have the meaning indicated above, and optionally the compound obtained is transferred to an acid addition salt.

The reaction is preferably carried out in an aprotic solvent, for example toluene, or in an aprotic, polar solvent, for example dimethylformamide, with the addition of an acid-binding agent, for example an inorganic base such as sodium carbonate or caustic soda, or an organic base such as triethylamine. The reaction temperature can be selected from room temperature to 16 0°C. The turnover is preferably carried out between 60 and 120°C.

The isochromans and oxpins with the general formulas I, Ia

and Ib contain an asymmetric carbon atom and can be separated into their antipodes in a known manner. The antipodes are also obtained when starting from optically active starting materials.

The new isochromanes and oxepines of the general formula I

can be transferred in the usual way to their acid addition salts.

Acids which are suitable for salt formation 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, valerian acid, oxalic acid, malonic 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, ethane-phosphonic acid.

The compounds of the general formula I have, in isolated organs and in animal experiments, shown valuable therapeutic, particularly calcium-antagonistic properties, which are manifested by a lowering of blood pressure, bradycardia, negative inotropy and dilation of coronary and peripheral vessels.

The new compounds can thus, for example, be used for the treatment or prevention of coronary heart disease and high blood pressure.

The compounds of the general formula I can be used

alone or in combination with other active substances. Suitable forms of use are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. Suitable tablets can, for example, be prepared by mixing the active substance or substances with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or milk sugar; explosives such as corn starch, alginic acid; binders such as starch or gelatin; lubricants such as magnesium stearate or talc and/or agents which cause a depot effect such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate.

The new compounds of the general formula I can be used enterally or parenterally. For oral administration, single doses of 5 to 20 mg, preferably 10 to 15 mg, have proven appropriate.

In the following Table I, the new compounds of the general formula I are compared with their physical characteristic data.

Eluent mixtures:

a) CH2Cl2/CH3OH 9:1; b) CH 2 Cl 2 /CH 3 OH 95:5; c) CH 2 Cl 2 /C<H>3 OH 8:2; d). CH2C<1>2/<C>H3CN/C2H5OH 7:2:1

Manufacturing examples

Example 1

6,7-dimethoxy-1-{1-[N-(4-cyano-5-methyl-4-(m^trifluoromethyl-phenyl)-hexyl)-N-methyl-amino]^methyl}-isochromane

(Table 1, compound no. 31

2 g of 1-bromomethyl-6,7-dimethoxy-isochromane and 2.1 g of 2-isopropyl-21-[3(N-methylaminol-propyl]-2"-(3-trifluoromethylphenyl)-acetonitrile are dissolved in 30 ml of absolute dimethylformamide and reacted for 15 hours at 110°C after the addition of 15 ml of triethylamine. After distilling off the solvent, the residue is stirred with 50 ml of 2N hydrochloric acid and then fractionally extracted with diethyl ether at increasing pH values. The ether fractions with pH 6 to pH 7.5 are collected. After drying with sodium sulfate, the solvent is removed, and the crude product is separated over silica gel (Lichroprep Si 60, grain size 15 to 25 ym; Merck) with a medium pressure chromatography column according to Helmchen (G. Helmchen et al.; Angew. Chem. 91, 64 (1979) ) at 3 to 5 bar.

0.7 g of the compound is obtained as a colorless, viscous oil.

Rf value: 0.55; Eluent: CH2C12/CH3OH = 9:1

Example 2

7,8-dimethoxy-1-{1-[N-(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-fluoro-phenyl)-2< 1->isopropyl-2"-[3-(N-methylamino)-propyl]-acetonitrile is dissolved in 30 ml of absolute dimethylformamide. Then 3 g of potassium carbonate are added, and the whole is stirred for 15 hours at 110°C. Following that in example 1 described preparation, chromatographic separation is carried out.

0.2 g of the compound is obtained as a yellowish, highly viscous oil.

Example 3

6,7-dimethoxy-4,4<1->dimethyl-1-{2-[N-(4-cyano-4-(3-trifluoromethyl-phenyl)-5-methylhexyl)-N-methylamineb]-ethyl} -isochromic

(Table 1, compound no. 8)

2 g of 2-bromomethyl-6,7-dimethoxy-4,4<1->dimethylisochromane and

2.1 g of 2-isopropyl-2'-[3-(N-methylamino)-propyl]-2"-(3-trifluoromethylphenyl)-acetonitrile are dissolved in 30 ml of absolute dimethylformamide. Then 3 g of potassium carbonate are added , where the whole is stirred for 15 hours at 110° C. After the preparation described in example 1, chromatographic separation is carried out.

1.15 g of the compound is obtained as a colorless, highly viscous oil.

Example 4 6,7-dimethoxy-1-{2-[N-(4-cyano-4-(4-fluorophenyl)-5-methylhexyl)-N-methylamino]-ethyl}-1-methyl-isochromane (Table 1 , compound no. 10) 8 g of 6,7-dimethoxy-1-methyl-1-[2-(p-tosyloxy)ethyl-isochromane and 5 g of 2-(4-fluorophenyl)-2'-isopropyl-2"-[ 3-(N-methylamino)-propyl]-acetonitrile is dissolved in 50 ml of toluene and stirred for 15 hours at 115° C after the addition of 3 ml of triethylamine and 3 g of potassium carbonate. After evaporation, the residue is taken up in 100 ml of water and extracted with 100 ml diethyl ether. After separation of the water phase, 50 ml of 2N hydrochloric acid is added to the organic phase. The ether phase is separated, and the hydrochloric acid phase is fractionally extracted with diethyl ether at increasing pH values. Between pH 6 and 7.5, the separated organic phases are collected, dried with sodium sulfate and then evaporated.

Separation is then carried out over silica gel (Lichroprep Sl 60, grain size 15 to 25 µm; Merck) with a medium pressure chromatography column according to Helmchen (G. Helmchen et al.; Angew. Chem. 91, 64 (1979)1 at 3 to 5 bar).

After chromatographic work-up, 3.8 g of the compound was obtained as a tough, colorless oil.

Example 5 6,7-dimethoxy-4,4-dimethyl-1-{2-[N-(4-cyano-4-(3,4-dichlorophenyl)-5-methylhexyl)-N-methylamino]-ethyl}isochromane (Table 1, compound no. 11) 2 g of 1-(2-chloroethyl)-6,7-dimethoxy-4,4'-dimethyl-isochromane are stirred together with 2.1 g of 2-(3,4-dichlorophenyl)- 2'-isopropyl-2"-[3-(N-methylamino)-propyl]-acetonitrile in 30 ml of dimethylformamide with 3 g of potassium carbonate for 6 hours at 100°C. The reaction mixture is then evaporated and fractionally decanted analogously to example 4. After removal of the ether, the desired fractions are separated over silica gel (Lichroprep SI 60, Merck) with a medium-pressure chromatography column according to Helmchen at 3 to 5 bar. 1.1 g of pure substance is obtained as a slightly yellowish, highly viscous oil. Example 6 6.7- Dimethoxy-1-{1-[N-(4-cyano-4-(3,4-dichlorophenyl)-5-methyl-hexyl)-N-methylamino]-methyl}-isochromane (Table 1, compound no. 14) 2 g of 1-bromomethyl-6,7-dimethoxy-isochromane and 2.1 g of 2-(3,4-dichlorophenyl)-2'-isopropyl-2"-[3-(N-methylamino)-propyl]-acetonitrile are dissolved in 30 ml of absolute dimethyl form middle After adding 3 g of potassium carbonate, stir for 15 hours at 110°C. The reaction product is worked up analogously to example 4. One can isolate 0.6 g of the compound as a tough, colorless oil. Rf value: 0.54; Eluent: CH2C12/CH3OH = 9:1

Example 7

7,8-dimethoxy-1-{1-[N-(4-(3,4-dichlorophenyl)-4-cyano-5-methyl-hexyl)-N-methylamino]-methyl}-1,3,4, 5-tetrahydro-2-benzoxepine

(Table 1, compound no. 15)

2.1 g of 1-bromomethyl-7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzoxepine and 2.1 g of 2-(3,4-dichlorophenyl)-2'-isopropyl-2"- [3-(N-methylamino)-propyl]-acetonitrile is dissolved in 30 ml of dimethylformamide. After adding 3 g of potassium carbonate, stir for 15 hours at 110° C. The reaction mixture is worked up as described in example 4.

0.3 g of the compound is obtained as a yellowish, highly viscous oil.

Rf value: 0.55; Eluent: CH2C12/CH3OH = 9:1

Example 8 6,7-dimethoxy-4,4-dimethyl-1-{2-[N-(4-cyano-4-(4-fluorophenyl)-5-methylhexyl)-N-methylamino]-ethyl}-isochroman ( Table 1, compound no. 19) 2 g of 1-(2-chloroethyl)-6,7-dimethoxy-4,4<1->dimethyl-isochromane are dissolved together with 1.8 g of 2-(4-fluorophenyl)-2 '-isopropyl-2"-[3-(N-methylamino)-propyl]-acetonitrile in 30 ml of dimethylformamide. Then 3 g of potassium carbonate are added, and the whole is stirred for 6 hours at 100°C. After cooling, the reaction product is taken up in water and 2N hydrochloric acid. If the pH value rises, fractional extraction is carried out with diethyl ether. The desired fractions up-

is worked on chromatographically as described in example 1.

After the chromatographic separation, 0.8 g of pure compound could be isolated as a colorless oil.

Rf value: 0.52; Eluent: CH 2 Cl 2 /CH 3 OH = 8:2

Example 9

6,7-dimethoxy-1-{2-[N-(4-cyano-5-methyl-4-(3,4,5-trimethoxy-phenyl)hexyl)-N-methylamino]-ethyl}-isochromane (Table 1, connection no. 26)

1.8 g of 1-(2-chloroethyl)-6,7-dimethoxy-isochromane and 2.1 g of 2-isopropyl-2<1->[3-(N-methylamino)-propyl]-2"-(3 ,4,5-trimethoxy-phenyl)-acetonitrile is dissolved in 30 ml of absolute dimethylformamide and stirred overnight at 100° C. after adding 10 ml of triethylamine and 3 g of potassium carbonate. After removing the solvent in vacuo, 150 ml of diethyl ether and 100 ml of water and decanted. The organic phase is decanted 3 times with 80 ml of 2N hydrochloric acid each time. The hydrochloric acid, aqueous phases are collected and then neutralized with soda. Then extracted with 100 ml of diethyl ether. The organic phase is dried over sodium sulfate and then evaporated. The residue is separated chromatographically over a silica gel column (see example 1).

0.9 g of the compound is obtained as a yellowish, viscous oil.

Rf value: 0.42; Eluent: CH2Cl2/CH3CN/C2H5OH =

7:2:1

Example 10

6,7-dimethoxy-1-{2-[N-(4-cyano-5-methyl-4(3,4-methylene-dioxyphenyl-)-hexyl)-N-methylamino]-ethyl}-4-methyl -isochrome (Table 1, compound no. 28)

1.9 g 1-(2-chloroethyl-6,7-dimethoxy-4-methyl-isochromane)

and 1.9 g of 2-isopropyl-2'-(3,4-methylenedioxyphenyl)-2"-[3-(N-methylamino)-propyl]-acetonitrile are dissolved in 10 ml of absolute dimethylformamide and stirred at 100°C for 15 hours after to-

addition of 20 ml of triethylamine and 3 g of potassium carbonate. It is then processed as described in example 9.

You get 250 mg of the compound as a tough, colorless oil.

Rf value: 0.41; Eluent: CH2C12/CH3OH = 9:1

Example 11

6,7-dimethoxy-1-{2-[N-(4-cyano-5-methyl-4-(3,4,5-trimethoxy-phenyl)hexyl)-N-methylamino]-methyl}-1,4 ,4-trimethylisochrome

(Table 1, compound no. 29)

3.4 g of 1-(2-bromomethyl)-6,7-dimethoxy-1,4,4'-trimethyl-isochromane and 3.1 g of 2-isopropyl-2'-[3-(N-methylamino)-propyl ]-2"-(3,4,5-trimethoxyphenyl)-acetonitrile is dissolved in 15 ml of dimethylformamide and stirred at 120°C for 12 hours after the addition of 30 ml of triethylamine and 3 g of potassium carbonate. Then fractionally extracted analogously to example 1. The desired fractions (pH 6 to pH 7.5) are collected.The ether phase is dried and then removed.The crude product is purified chromatographically.

After chromatographic work-up, 1.9 g of the compound is obtained as a pale yellowish, viscous oil.

Rf value: 0.34; Eluent: CH2Cl2/CH3OH = 9:1

Example 12

6,7-dimethoxy-1-{2-[N-(4-cyano-4-(4-fluorophenyl)-5-methylhexyl)-N-methylamino]-ethyl}-1,4,4-trimethyl-isochromane ( Table 1, compound no. 31)

3.4 g 1-(2-bromomethyl)-6,7-dimethoxy-1,4,4'-trimethyl)-isochromane, 2.5 g 2-(4-fluorophenyl)-2'-isopropyl-2"- [3-(N-methylamino)-propyl]-acetonitrile, 20 ml of triethylamine and 3 g of potassium carbonate are reacted and worked up in the same way as in Example 1. After the chromatographic work-up, 1.8 g of pure product could be obtained as a colorless, highly viscous oil.

Rf value: 0.36; Eluent: CH2C12/CH3OH = 9:1

Example 13

6,7-dimethoxy-1-{2-[N-(4-cyano-5-methyl-4-(3-trifluoromethylphenyl)-hexyl)-N-methylamino]-ethyl}-isochromane (Table 1, compound no. 33)

1.8 g 1-(2-chloroethyl)-6,7-dimethoxy-isochromane, 2.1 g 2-isopropyl-2 1 -[3-(N-methylamino)_-propyl]-2"-(3- trifluorophenyl) - acetonitrile, 10 ml of dimethylformamide, 20 ml of triethylamine and 3 g of potassium carbonate are reacted analogously to example 1 and worked up.

After chromatographic separation, 0.8 g of pure product could be isolated as a colorless, viscous oil.

Rf value: 0.42; Eluent: CH2<C1>2</>CH3OH = 9:1

Example 14 6,7-dimethoxy-1-{2-[N-(4-cyano-4-(3,4-dimethoxyphenyl)-5-methyl-hexyl)-N-methylamino]-ethyl}-1-methyl- isochromane (Table 1, compound no. 35) 4 g of 6,7-dimethoxy-1-methyl-1-[2-(p-tosyloxy)-ethyl]-isochromane and 2.9 g of 2-(3,4-dimethoxyphenyl) )-2<1->isopropyl-2"-[3-(N-methylamino)-propyl]-acetonitrile is dissolved in 30 ml of dry toluene and 5 ml of dimethylformamide and stirred at 100°C for 15 hours after the addition of 5 ml of triethylamine and 3 g of potassium carbonate. The work-up takes place analogously to example 4. After the chromatographic separation over silica gel, 3.1 g of the compound is obtained as a highly viscous, colorless oil.

Rf value: 0.21; Eluent: CH2C<1>2OCH3OH = 9:1

Claims (3)

1. Analogous process for the preparation of therapeutically active substituted isochromanes and oxepines of the general formula (I) where R is a hydrogen atom or a linear or branched alkyl group with up to 4 C atoms, R 2 is a hydrogen atom or a linear or branched alkyl group with up to 4 C atoms or together with R" <*> " an alkylene group with 3 to 5 C atoms, R 3 is a hydrogen atom or a linear or branched alkyl group with up to 4 C atoms, R 4 is a hydrogen atom or a linear or branched alkyl group with up to 4 C atoms, R 5 is a hydrogen atom or a linear or branched alkyl group with 1 to 6 C atoms or a pyridinyl group, R^ is a hydrogen atom, a fluorine, chlorine or bromine atom, a linear or branched alkyl group with 1 to 6 C atoms, a hydroxy or alkoxy group with 1 to 4 C atoms or a trifluoromethyl group, R 7 is a hydrogen atom, a fluorine, chlorine or bromine atom, a linear or branched alkyl group with 1 to 6 C atoms, a hydroxy or alkoxy group with 1 to 4 C atoms or together with R a methylenedioxy group, R g is a hydrogen atom, a fluorine, chlorine or bromine atom, a hydroxy or alkoxy group with 1 to 4 C atoms, m are the numbers 1 or 2, and n are the numbers 1, 2 or 3, and their acid addition salts, characterized in that an isochroman or oxepine derivative of the general formula (II) 12 3 where R , R , R , m and n are as indicated above, and X means a chlorine, bromine or iodine atom or an alkylsulfonyloxy or arylsulfonyloxy group, is reacted with a phenyl-aminopropyl-acetonitrile of the general formula (III) 4 5 6 7 8 where R , R , R , R and R have the above meaning, and the compound produced is optionally transferred to an acid addition salt. 2. Process according to claim 1, characterized in that compounds with the general formula (Ia) are prepared 12 3 where R , R and R , which may be the same or different, mean a hydrogen atom or a methyl group, R 5 means an isopropyl or pyridinyl group, R 1 means a hydrogen, fluorine or chlorine atom, a trifluoride methyl or methoxy group, R 7 means a hydrogen, fluorine or chlorine atom, a tertiary butyl group, a methoxy group or together with R a methylenedioxy group, R g represents a hydrogen atom or a methoxy group, m means the numbers 1 or 2, and n means the numbers 1 or 2. 3. Method according to claim 1, characterized in that compounds with the general formula (Ib) are prepared where R<6> means a hydrogen or chlorine atom or a methoxy group, R 7 means a fluorine or chlorine atom or a methoxy group, and R g means a hydrogen atom or methoxy group.