DE1445654C - omega phenyl omega pyridyl (2) alkyl amine derivatives and process for their preparation - Google Patents

Description

It is known from German patent specification 1,067,436 that compounds of the general formula I.

in which R ₁ denotes a hydrogen or chlorine atom or a hydroxyl group, AIk ₁ and AIk _{2 are} identical or different and optionally denote branched alkylene radicals with 2 to 4 carbon atoms, the sum of the carbon atoms must be at least 6, and their acid addition salts.

2. Process for the preparation of compounds according to claim 1, characterized in that one in a manner known per se

a) 2-Benzylpyridine in the presence of an alkaline condensing agent with a compound of the general formula IV

(IV)

in the shark means either a chlorine or bromine atom, expediently in the case of increased Reacts temperature and in the presence of an inert solvent or

b) a compound of the general formula V.

(V)

with a connection of general

Alc

30th

z. B. the connection

40

45

to manufacture. Compounds of this type are said to be antihistamines and antispasmodics can be used.

Furthermore, US Pat. No. 3,042,680 discloses compounds of the general formula II

60

CH-I-- ^

Alc
NH

R ₃ -C-CH

R ₄

in the alk an alkylene group with 2 to 4 carbon atoms, with at least 1 or 2 atoms forming the bridge

654

between the CH and NH groups, the radicals R ₁ , R ₂ , R ₃ and R _{4 represent} hydrogen atoms or lower alkyl groups and the radicals R ₅ and R _{6 represent} hydrogen atoms, halogen atoms, lower alkyl, lower alkoxy or hydroxy groups described. A coronary-expanding effect and a stimulating effect on the central nervous system are indicated for these compounds.

The invention relates to cu-phenyl-α-pyridyl- (2) -alkylamines of the general formula III

(III)

in which R ₁ denotes a hydrogen or chlorine atom or a hydroxyl group, AIk ₁ and AIk _{2 are} identical or different and optionally denote branched alkylene radicals with 2 to 4 carbon atoms, the sum of the carbon atoms must be at least 6, and their acid addition salts.

The compounds according to the invention are valuable pharmaceuticals and in particular have one good coronary-expanding effect. As the table below shows, those are according to the invention Compounds the known compounds from German patent specification 1,067,436 and the USA patent specification 3 042 680 superior in cardiac effect. In particular, they cause a greater increase of the coronary flow in connection with an increase in cardiac strength. Besides, the The duration of action of the compounds according to the invention is considerably longer. The toxicity of the invention Connections is also lower, which, in connection with the better effect, results in a considerable better therapeutic index results.

substance

Effect on the guinea pig heart

Coronary flow contraction amplitude

Duration of action
Min.

acute toxicity

the mouse

LD ₅₀ ip

mg / kg

Example 2 or 6

Example 3 '

Example 4 Example 5 Example 7 Example 8

Example 4 of German patent specification 1,067,436

Example 1 of U.S. Patent 3,042,680

Example 2 of U.S. Patent 3,042,680 ...;

+ 151 + 152 + 150 + 143 + 135 + 106

99

+ 76

+ 17
+ 22
+ 15
+ 7
+ 16
+ 33

+ 6

.- 6

- 15

4th
3

56.8

56.2

75.2

88

64

55.1

47.6
50.9
52.5

methodology

The cardiac effects of the compounds were carried out based on the Langendorff method (Pflügers Archiv, 61, 219 [1895]) in the form that is internationally valid today. The coronary flow and the contraction amplitude after injection of 10 γ each of the compounds to be examined were measured and the duration of action was recorded.

The results were calculated as a percentage of the initial values.

The acute toxicity was determined by the Miller and Tainter method (Proc. Soc. Exper. Biol. And Med. 57, 261 [1944]). The observation time was 24 hours. ;

The compounds according to the invention can be prepared by in per se known way

a) 2-Benzylpyridine in the presence of an alkaline condensing agent with a compound of general formula IV

Shark

AIk ₁
NH

(IV)

It is refluxed for 4 hours. After the reaction has ended, the mixture is added in the cold with water and separates the benzene layer. The aqueous phase is extracted again with benzene. The combined benzene solutions are concentrated and the residue is fractionated. Kp. 0.8 mm Hg, 215 to 217 ° C.

The free base gives a crystalline salt with 1 mol of maleic acid. The melting point is after recrystallization from isopropanol at 127 to 128 ° C.

Example 2

N- [1- (p-Chloro-phenyl) -2-methyl-propyl- (2)] -3-phenyl-3- [pyridyl- (2)] - n-propylamine

30th

with a compound of the general formula VI NH ₂

reductively condensed.

The free bases obtained in this way can optionally be converted into their acid additions in a manner known per se salts are transferred.

example 1

• N- [1-phenyl-propyl- (2)] -4-phenyl-4- [pyridyl- (2)] - n-butylamine

55 CH ₂

CH ₂ CH ₂ - ^ Q>

CH ₂ NHCH

CH ₃

33.8 g 2-benzyl pyridine are dissolved in 50 ml of benzene, sodium at 80 ⁰ C with 15.6 g of 50% offset NaNH ₂ -Benzolsuspension and heated for 2 hours under reflux. Then 63 g of N- (3-bromo-propyl) -l-phenyl-2-aminopropane in 100 ml of benzene are added dropwise.

in which Hai means either a chlorine or bromine atom, expediently at an elevated temperature and reacts in the presence of an inert solvent or

b) a compound of the general formula V.

(V)

35

40 H.
C.

CH ₂
CH ₂ NHCCH ₃
CH,

33.8 g of 2-benzylpyridine are first, as described in Example 1, mixed with 15.6 g of 50% NaNH ₂ -SuS-pension and then with 73 g of l- (p-chlorophenyl) -2-methyl-2- (co-bromoethylamino) propane implemented. The reaction mixture is worked up as described.

The resulting free base boils at 0.3 mm. Hg between 210 and 223 ° C. A crystalline salt is obtained with 1 mol of maleic acid. Recrystallized from isopropanol, the maleate melts at 137 to 138 ^° C.

B e i s ρ ie I 3

N- [4-phenyl-butyl- (2)] -3-phenyl-3- [pyridyl- (2)] - n-propylamine

- CH ₂

CH? CH ₂

I ₂ yii ₂ V ^ L ₂ - Λχ Λ

CH ₂ NHCH
CH ₃

This base - on the route described in Example 1 from 2-benzylpyridine and N- (2-bromoethyl) -2-amino-4-phenyl-butane manufactured - boils between 210 and 212 ° C at 0.4 mm Hg. With VzMoI Fumaric acid gives a crystalline salt which recrystallizes from isopropanol at 157 to 158 ° C melts.

Example 4

N- [4-phenyl-butyl- (2)] -4-phenyl-4- [pyridyl- (2)] - n-butylamine

w ^CH A /

CH ₂ -CH ₂ -CH ₂ -NH-CH-CH ₂ -Ch ₂ - ^
CH,

The base is prepared by the method described in Example 1 from 33.6 g of 2-benzylpyridine, 7.8 g of NaNH ₂ and 35.1 g of N- [3-bromo-propyl- (l)] - 4-phenyl-2- aminobutane produced. It boils at 0.1 torr between 207 and 212 ° C.

A crystalline salt is obtained with 1 mol of maleic acid. The maleate, recrystallized from isopropanol, melts at 129 to 130 ^° C.

Example 5

N- [1- (p-Chloro-phenyl) -2-methyl-propyl- (2)] -4-phenyl-4- [pyridyl- (2)] - n-butylamine

CH ₃

CH ₂ -CH ₂ -CH ₂ -NH-C-CH ₂

CH ₃

CH,

CH ₂ -CH ₂ -NH-C-CH ₂ ^,
CH ₃

40 g (0.19 mol) of j3-phenyl- | 8-pyridyl- (2) -propionaldehyde are with 35 g (0.19 mol) of 1-p-chloro-phenyl-2-methyl-2-aminopropane in 500 ml abs. Ethanol heated to boiling for 1 hour. After cooling, the resulting Schiff base is mixed with 5 g of sodium

borohydride, dissolved in 50 ml of ethanol, reduced. It is worked up under alkaline conditions and the base is distilled. It boils at 0.05 Torr 175-190 ⁰ C. with 1 mole of maleic acid, a crystalline salt is obtained which, recrystallized from isopropanol, melts at 137 ° to 138 ° C.

Example 7

N- [1- (p-Chloro-phenyl) -propyl- (2)] -4-phenyl-4- [pyridyl- (2)] -n-butylamine

17 g of 2-benzylpyridine are mixed with 7.8 g of 50% NaNH ₂ suspension in toluene and then with 34.4 g of N- [3-bromo-propyl- (l)] - [l- (p-chlorophenyl) -2-methyl-2-aminopropane reacted in toluene at boiling temperature. The reaction mixture is worked up as described. The free base boils at 0.2 Torr 216-220 ⁰ C. with 1 mole of maleic acid is obtained a crystalline salt which - recrystallized from isopropanol - by 129-130 ⁰ C to melt.

Example 6

N- [1- (p-Chloro-phenyl) -2-methyl-propyl- (2)] - .. 3-phenyl-3- [pyridyl- (2)] - n-propylamine

22.6 g of γ- phenyl- γ- pyridyl- (2) -butyraldehyde and 17.0 g of l- (p-chlorophenyl) -2-aminopropane are reacted as described in Example 6 and with 2 g of NaBH ₄ reduced. The base boils at 0.05 torr between 170 and 200 ^° C. With 1 mol of maleic acid, a crystalline salt is obtained which is recrystallized from ethyl acetate. M.p. 142 ° C.

Example 8

N- [1- (4-Hydroxyphenyl) propyl- (2)] -4-phenyl-4- [pyridyl- (2)] n -butylamine

CH

CH,

-CH,

37.5 g of γ- phenyl- γ- pyridyl- (2) -butyraldehyde and 40 g of l- (p-benzyloxyphenyl) -2-aminopropane are heated in 200 ml of ethanol for 1 hour on a water bath. The Schiff base is then reduced with 6.5 g of sodium borohydride. The base is precipitated with water and, without being purified, debenzylated with hydrogen in the presence of 8 g of palladium-carbon (10%) in 300 ml of 90% ethanol. The catalyst is then filtered off, the solvent is distilled off and the residue is dissolved in ether. This solution is neutralized with citric acid. 37 g of citrate are obtained, which is originally crystallized from isopropanol. Mp. 75 ° C.

209 528/588

Claims (1)

Formula VI claims: 1. ω - Phenyl - ω - pyridyl - (2) - alkylamines of the general formula (Vl! The free bases obtained in this way can optionally be converted into their acid addition salts in a manner known per se be transferred.