DE1545869A1 - Process for the preparation of 3-phenyl-3-pyridyl (2 ') -propylamine derivatives - Google Patents

Description

Process for the preparation of 3-phenyl-3-pyridyl (2 ') propylamine derivatives

Zuscitz to patent

= Fw '1794)

(Patent application F 46 262 IVb / 12 q

The main patent relates to a process for the preparation of diphenylpropylamine derivatives of the general formula I.

CII-CH ₀ -CH _n -NII-CH-CH

R,

(I)

11.

in which R ₁ and R ₀ denote hydrogen or an alkoxy group with at most k carbon atoms, R denotes hydrogen or the methyl group, U ₁ and R _r denote alkyl groups with at most 4 carbon atoms and their salts, which is characterized in that one

n) compounds of the general formula II

909849/1529

Fvr 479 ^ a

-N-CH-C

R,

R.

(II)

in which R is hydrogen or the benzyl group and R ₁ to R _{r have} the above meanings, reduced

b) compounds of the general formula III

_Bl > -v

0R <
-N-OH-CH- /

(III Ir

in which R to R- have the above meanings and R> - means an alkyl or den.benzyl radical treated with ether-splitting agents or catalytically hydrogenated,

c) compounds of the general formula IV

Y T3? ^A %

CH ₂ -CH ₂ -N-CH-CH - //

(IV)

in which R, bis.R_-have the above meanings and Ac is an acyl radical, saponified in alkaline or acidic conditions,

d) Compounds of the general formula V

(V)

R.

9O9849 / I5i9

ORIGINAL INSPECTED

- 3 - Fw fr79fr a

in which R to R have the above meanings and X is an oxygen atom or the group ^ means catalytically hydrogenated

e) Compounds of the general formula VI

CH-CH ₀ -CH ₀ -NH (VI) R

in which R to R _{0 have} the above meanings, either with ethylene oxides of the general formula VII

! ³ fv "'

HC - CH- ^ *> (VII)

^ b R ₅

in which R- to R- have the above meanings to sets or with compounds of the general formula VIII

X ^ R

(VIII)

in which R- to R- have the above meanings, condensed and reduced at the same time or afterwards,

f) Diphenylpropionaldehydes of the general formula IX R 'CH-CH _n -CHO (IX) ■

»2 ^

. . _ 909849/1529

xn where R ₁ and R _{0 have} the above meanings,

Fw 479fr a

with compounds of the general formula X

(X)

Il \ -) C

in which X, R and R to R- have the above meanings, condensed and reduced at the same time or subsequently.

g) compounds of the general formula XI

(XI)

in which X and R to R- have the above meanings reduced or with complex metal hydrides

h) Compounds of the general formula I in which R, and / or R is hydroxy groups treated with alkylating agents and in all procedures

subsequently splitting off any N-benzyl group which may be present and the basic compounds obtained, optionally by treatment with inorganic or organic Acids converted into their salts.

In a further embodiment of the method according to the invention it has now been found that compounds which act on the heart and blood pressure are obtained if one follows the procedure of the main application produces compounds in which instead of a phenyl radical in the Dxphenylpropylgruppe a pyridyl (2) radical is included.

The invention thus relates to a method for production

909849/1529

/ 5

Fw 4794 a

of 3-phenyl-3-pyridyl (2 ') propylamine derivatives der general formula I.

1 CH-CH ₀ -CH,

-NH -CII -CII

(D

in which R _{1 is} hydrogen or an alkoxy group with at most k carbon atoms, R_ is hydrogen or the Methy1gruppe, R. and R_ are alkyl groups with at most k carbon atoms and their salts, which is characterized in that one

a) Compounds of the general formula II

(II)

H-CH ₀ -CH ₀ -N-CH-C- /

in which R is hydrogen or the benzyl group and R to R have the above meanings, reduced

b) compounds of the general formula III

CH-CH ₀ -CH ₉

(III)

in R to R ₁ . have the above meanings and R is an alkyl or benzyl radical, treated with ether-splitting agents or catalytically hydrogenated,

c) compounds of the general formula IV

/ 6

903849/1529

Fw 4794 a

H-CH ₀ -CH ₁

R R- OAc -N-CH-CHh

(IV)

in which R to R have the above meanings and Ac means an acyl radical, saponified alkaline or acidic,

d) Compounds of the general formula V

= CH-CH.

Ms f

. -N-CH-C

(V)

R.

\ = lN

in which R to R have the above meanings and X

H denotes an oxygen atom or the group <^ ",

catalytically hydrogenated ^H

e) Compounds of the general formula VI

CH-CH ₂ -CH ₂ -NH R

(VI)

in which R and R have the above meanings, either with ethylene oxides of the general formula VII

? ³

HC - Z V

(VII)

in which R to R have the above meanings, reacts or with compounds of the general formula VIII

909849/1529

/ 7

15458B9

- 7 - Fvf k79 ^l ta

O = CC- / \ (VIII)

in which R- to R_ have the above meanings, condensed and reduced at the same time or subsequently,

f) Phenyl-pyridyl (2) -propionaldehyde of the general Formula IX

(IX)

in which R ₁ has the above meaning, with compounds of the al Igen "inen formula X

HN-C-C · / 'R X

in which X, and R ₁ R. to R_ have the above meanings, condensed and reduced simultaneously or subsequently

g) compounds of the general formula XI

H-CH ₂ -CO-NC-

^R 5

in which X and R to R_ have the above meanings, reduced with complex metal hydrides or

h) Compounds of the general formula I in which R _{1 is} a

909849/1529

Hydroxy group means treated with alkylating agents and in all procedures

then an optionally present N-benzyl group split off and the basic compounds obtained, if appropriate by treatment with inorganic or organic Acids converted into their salts.

The procedures listed under a) -g) are how described in the main patent. The preparation of the starting compounds of the general formulas II, III and IV takes place in the manner described in the main patent, but 1-phenyl-lpyridyl- (2 ') -propyl / sinine is used instead of 1,1-diphenylpropyl-3-amine. This amine can can also be used for the procedure described under e), while for the procedures listed under f) the starting materials used are the compounds of the formula IX corresponding phenyl-pyridyl (2) -propionaldehyde and for the The procedure listed under g) the corresponding phenyl-pyridyl (2) -propionic acid amides are used.

The products of the process are valuable pharmaceuticals and, in addition to having a very good cardiovascular effect, also have a favorable lowering of blood pressure.

For example, the 1-t3 ', 4'-dimethylphenyl) -2- ^ phenyl-pyridyl (2 ") -propylamino7-px * opanol- (1) -hydrochloride in rats that have a Have high kidney pressure, high and persistent blood pressure:

The mean blood pressure in 11 hypertensive rats averaged 192 now Hg. 2 hours after the subcutaneous administration of 40 mg / kg of the product of the process was the blood pressure of 136 mm Hg dropped and 24 hours after the injection it was 168 mm Hg, so had not yet reached the initial value again.

The above-mentioned product also shows a strong sympathicolytic effect. For example, it shows a Tyrode solution on the tracheal chain according to Castillo with only 2.5f to 50 ecm

909849/1529

/ 9

Reduction of the effect of 5 V isopropyl noradrenaline by approx. 50 %.

In the isolated guinea pig heart according to Langendorff, the product of the process decreased with continuous infusion of 0.1 qt per minute caused by 0.1 ^ f isopropyl noradrenaline Increase in heart rate by a third. On the guinea pig heart According to Langendorff, the coronary flow was significantly increased by $ 15 of the process product.

Due to the combination of the 3 mentioned effects, the process products have particular advantages over them previously known compounds. The products of the process are particularly favorable for the treatment of hypertension, because especially in hypertensive patients there is a coronary artery dilatation This is beneficial because the heart of the hypertensive patient has a greatly increased muscle mass that needs to be nourished got to. In addition, the hypertensive person is prone to atherosclerosis Coronary arteries, the consequences of which may be due to an enlargement the small, non-calcifying vessels can be compensated.

/ 10

909849/1529

Fw fr79fr a

- 10

Example :

l- (3 '»4' -Dimethylphenyl) -2- ^ phenyl-pyridyl- (2") propylamine ^ - propanol (1) hydrochloride

'CH.

H-CH ₂ -CH ₂ -NH-CH-CH

7.1 g of ß-phenyl-ß-pyridyl- (2) -propionaldehyde and 6.0 g of 1- (3 ', V-dimethylphenyl) -2-aminopropanol- (1) (melting point 90), (prepared by bromination of 3,4-dimethylpropiopfenone, reaction of the bromine compound obtained with benzylamine and then catalytic hydrogenation), are dissolved together in 30 ecm benzene, the solution warms up slightly. The benzene is distilled off in vacuo, the residue is dissolved in methanol and 1 g of sodium borohydride entered in small portions, with one vigorous reaction occurs. It is left to stand for about 15 minutes, acidified with dilute hydrochloric acid and the methanol is distilled off in vacuo. The residue is diluted with sodium hydroxide and Ether shaken. The ethereal phase is separated off, dried with potassium carbonate and the ether is distilled off. Of the The residue is dissolved with a little methanol and hydrochloric acid is added. * After the solvent has been distilled off, the residue is recrystallized from acetone / ether. 9.5 g of 1- (3 ', V-dimethylphenyl) -2 ^ / phenyl-pyridyl (2 ") -propylamino /' -propanol (I) hydrochloride of melting point 196-197 are obtained.

11

909849/1529

Claims (1)

Claim Process for the preparation of 3-phenyl-3-pyridyl (2 ') propylamine derivatives of the general formula I 11-CH ₂ -CH ₂ -NH-CH-CH (I) in which R _{1 is} hydrogen or an alkoxy group with a maximum of 4 carbons, R _{3 is} hydrogen or the methyl group, R 1 and R_ alkyl groups are a maximum of 4 carbon atoms and their salts according to patent ........... ( Patent application F 46 262 IVb / 12 q = Fw 4794), characterized in that nan a) Compounds of General Forsiel II CH-CH ₂ -Cl ₂ T? 3 J j -N-CH-C -C (II) in which R is hydrogen or the benzyl group, IUuUR ₁ to R- have the above meanings, reduced b) Compounds of the general formula III 1 h ? ^R 6 H-CH ₂ -CH ₂ -N-CH-CH (III) R. in which R to R _{5 have} the above meanings 90-9849 / -15-19 / 12 iind R / - denotes an alkyl or the benzyl radical, treated with ether-splitting agents or catalytically hydrated, c) compounds of the general formula IV ? Tj TW CH ₂ -CH ₂ -N-CH-CH -Jf $ (IV) in which R to R have the above meanings and Ac means an acyl radical, saponified alkaline or acidic, d) Compounds of the general formula V ' ^ΓΛ · RRXR I | 3 H r — χ k
= CH-CH ₂ -N-CH-C - </ ^ (V) in which R to R_ have the above meanings and X denotes an oxygen atom or the group S , catalytically hydrogenated e) Compounds of the general formula VI ^R l 'CH-CH ₀ -CH ₀ -NH (VI) / 2 2 ι in which R and R. have the above meanings, either with xethylene oxides of the general formula VII 909849/15 154böb9 Fw 4794 a (VII) R. in which R- to R. have the above meanings, reacts or with compounds of the general formula VIII O = C-C X (VIII) in which R. to R have the above meanings, condensed and reduced at the same time or afterwards, f) Phenyl ~ pyridyl (2) propionaldehydes of the general formula IX (IX) ₁ CH-CH ₂ -CHO <y in which R. has the above meaning, with compounds of the general formula X HN-C-C- ^ (X) R. in which X, and R, R "to R_ have the above meanings , condensed and reduced simultaneously or subsequently g) compounds of the general formula XI 909849/1529 Fw H-CH ₂ -CO-NC- (I- / ^ (XI) in which X and R to R- have the above meanings, reduced with complex metal hydrides or h) Compounds of the general formula I in which R. is a hydroxyl group, treated with alkylating agents and in all procedures then any N-benzyl group present is split off and the basic compounds obtained, if appropriate by treatment with inorganic or organic ones Acids converted into their salts> 909849/1529