CH624402A5 - Process for the preparation of novel heterocyclic derivatives of 1-alkyl-substituted 4-phenylpiperazine and use of the novel derivatives - Google Patents

Abstract

Novel heterocyclic derivatives of 1-alkyl-substituted 4-phenylpiperazine of the formula X <IMAGE> in which X' is hydrogen, methyl or acyl, are prepared by reacting bromoacetylpyridine hydrobromide with a phenylpiperazine, directly reducing the ketones obtained with NaBH4 to alcohols of the formula X, chlorinating and alkylating the alcohols to prepare the alkoxy derivatives of the formula X. In the formula X, R2 is -H, -Cl, -F, -CH3 or -OCH3. The novel derivatives have a well-defined and efficacious therapeutic action as antihypertensives by vasodilation and alpha-blocking, and as antibradykinin antihistamines.

Description

30 The present invention relates to a process for the preparation of new heterocyclic derivatives of 4-phenyl-piperazine-1-alkyl-substituted. These new derivatives have a pharmacological action.

As is well known, the growing increase in cardiovascular diseases 35 due to the onset of states of functional hypertension and the spread of symptoms attributable to allergic reactions requires the research sectors to continuously study, experiment and prepare products that have improved characteristics of therapeutic activity, with new or significant results.

For this purpose, some heterocyclic derivatives of substituted 4-phenyl-piperazine-1-alkyl having a well-defined and effective therapeutic action as antihypertensives, as vasodilators and alpha-blockers and as antihistamines anti- brachidinici.

An object of this invention is a process for the preparation of new heterocyclic derivatives of the 4-phenyl-piperazine-1-alkyl-substituted formula IV

50

ÇH— CH;

(YOU)

55

OH

O-Gf

R,

(IV)

OX

m cui

X is methyl or ethyl characterized by the fact of

A) chlorinate the alcohol derivatives of formula IV with SOCl2 in CHCl; t

B) add the uncleaned chlorine derivatives to an alcoholic solution of methylate or sodium ethylate and isolate the alkoxy derivatives obtained by diluting the derivatives of formula VI with water and extracting the ether with formula.

Use according to claim 2, characterized in that the l- [2-methoxy-2- (3'-pyridyl) - is prepared

in which

R2 is -H, -Cl, -F, -CH ,, -OCH3.

This process is characterized by the fact of A) reacting bromo-acetyl-pyridine hydrochloride of 60 formula II

(["C ■ CH ^ - ~ Br •

^ I

with phenyl-piperazine of formula III

HBr of)

3

624402

h

-

R,

under a nitrogen atmosphere, in methyl alcohol, in the presence of triethylamine, forming the ketone of the formula I

OR-

OUX

R "

In fact it has been unpredictably found, and this constitutes the primary object of this invention, that the series of derivatives of the substituted 4-phenyl-piperazine-alkyl of formula (III) A has significant efficacy in the treatment of the induced disturbances. by high blood pressure and in the inhibition of the effects caused by histamine and bradykinin. These derivatives have antihypertensive, antihistamine and anti-tibrachidinic action.

Among said derivatives of general formula A, the ones in which the substituents R, R, and R have the combinations meaning and the value indicated in the following table I are particularly preferable.

(THE)

B) directly reduce the ketones obtained in (A) with NaBH4 to alcohols of formula IV in hydroalcoholic solution.

The invention also relates to the use of new alcohols of formula IV

15

20

(IV)

OH

m cui

R2 is -H, -Cl, -F, -CH3, -OCHa;

for the preparation of new heterocyclic derivatives of 4-fe-nyl-piperazine-1-alkyl-substituted of formula VI

25

30

(YOU)

0X

m cui

X is methyl or ethyl.

This use is characterized by the fact of

A) chlorinate the alcohol derivatives of formula IV with SOC1 in CHCI3, and

B) add the uncleaned chlorine derivatives to an alcoholic solution of methylate or sodium ethylate and isolate the alkoxy derivatives obtained by diluting the derivatives of formula VI with water and extracting the ether with formula.

The new heterocyclic derivatives of the substituted 4-phenyl-piperazine-1-alkyl prepared according to the process of the invention or according to the use of the invention of formula IV and VI have the general formula A

B-CH-K5H,

i '

R "

-N N \ /

(TO)

in which

R is

0 *

preferably

Cr-Ò

Ri is -OH, -OCH3 or -OC2H5 R2 is -H, -Cl, -F, -CH3 or -OCH- ,.

TABLE 1

Product no.

R

Re

35

40

45

50 10

55

60

65

11

12

13

-oo., h5

-OH

-OH

-OH

-OH

-OH

-OH

-OH

-OH

-OH

'N

R2

-CL.o

-H

OCH ,. or

-OCH3. m

OCH-i. p

CH.,. or

-ch, 3. p

-Cl.o

-Cl.n

624402

4

TABLE 1 (continued)

Product

14

15

16

17

18

R

Re

-N

-OH

-OH

OCH,

-OC2H,

OCH,

Ra

-CI.p

-F. or

-H

-H

OCH ,. or by dilution with water and extraction with ether.

As regards pyridyl, imidazolyl, and tetrahydroisoquinolyl derivatives, they are obtained by reacting the heterocyclic chloro-alkyls in question with the N-phenyl piperazine 5 or with its derivatives in dimethylformamide (D.M.F.) in the presence of triethylamine.

In particular, as regards pyridylethyl derivatives, these can also be produced according to a process alternative, included in the scope of this invention, by reacting the ketone intermediates obtained, in 1 previously isolated and purified, with hydrazine in diethylene glycol, in presence of sodium.

In particular, as regards the specific products shown in Table I, the operating procedures of the preparation process 15 are in general the following:

(a) Alcoholic derivatives (products 5-15, 21 and 22.

Bromoacetylpyridine II is reacted with phenylpiperazine or its derivatives III under nitrogen in methyl alcohol, in the presence of triethylamine according to the following reaction scheme:

20

li - CO - CH2 - Br +

<XJr-

25

30

(II)

(III)

♦ rc (o2H5),

HeOH

G / = V *

(YOU)

K-CO-CH ^

19

-OC2Hö

OCH ,. or

20

21

22

OCH,

-OH

-OH

-Cl. or

OCH ,. or

-H

and subsequently reducing the VI ketone derivatives with 35 NaBH4 in hydroalcoholic solution VIII

40

h-ch-cit-.it

I 2

Oh

2

V_y

(VIII)

where R and R2 satisfy the following combinations of meanings:

As regards the preparation methods for the derivatives of the substituted 4-phenyl-piperazine-1-alkyl, different operating procedures are provided according to the invention according to whether they are:

(a) alcoholic derivatives

(b) alkoxyl derivatives

(c) pyridyl derivatives.

The basic procedure, in which said different operating schemes are inserted, provides in succession the phases of:

(1) reacting bromo-acetyl-pyridine bromo-hydrate with phenyl piperazine, under a nitrogen atmosphere, in methyl alcohol, in the presence of triethylamine;

(2) directly reducing the ketones obtained in 1 with NaBH4 to alcohols in hydroalcoholic solution (derivatives a),

(3) chlorinate said alcohols with SOCI2 in CHC13 e

(4) adding the chlorine derivatives thus obtained, not purified, 3 to an alcoholic solution of methylated or sodium ethylate, and isolating the alkoxy derivatives b from the reaction mixture

45

50

55

R = beta (C, H, N ~) R2

R = »» R2

R = »» R2

R = »» R?

R = »» Ro

R = gamma (C3H5N-) R.,

R = »» Ro o, m, p, (-OCH,) o, m, p, (-CH3) o, m, p, (-C1) or (-F)

-H -H

c (-och3)

(b) Alkoxyl derivatives (products 4 and 16-20)

The alcoholic derivatives a are chlorinated with SOC1 and the chlorode-rivate obtained not purified is added to an alcoholic solution 60 of sodium alkylate.

According to the reaction scheme:

65 r-ch-ch2-n n. Oh

(VIII)

5

624402

(IX)

wherein R, X and R2 have the combinations of meanings indicated below:

R

= beta (C5H5N-) X = -CH3

R2 =

-H 10

R

= »» X = -C2H3

R2 =

-H

R

= »» X = -CH3

R2 =

or (-OCH,)

R

= »» X = C2H5

r2 =

or (-OCH3) 15

R

»» X = -CH3

r2 =

o (-C1)

R

= »» X = C2H5

R, =

o (-C1)

Pyridyl ethyl derivatives (products 1, 2, 3) can,

in parts- 20

pour, also be prepared by reacting the VI ketone derivatives with hydrazine in the presence of sodium according to the scheme

(you)

(VII)

wherein R, R2 and n have the combinations of meanings indicated below:

R = beta (C5H5N-)

n = 2

R2 = -H, or (-C1), or (-OCH3)

Reference will now be made by way of illustration and without limitation to an example of all the preferred products (products 1-23) indicated in table 1 above, specifying their physical properties, the brute formula, and the percentages of the individual components found and calculated, as well as the general preparation methods, divided into four groups indicated as examples 1, 2, 3 and 4 and concerning the groups of derivatives marked with the letters a, b, and c.

Example 1 l- [2-oxy-2- (3'-pyridyl) ethyl] -4-phenylpiperazine

(n. 5)

Gr. 28.1 (0.1 mol) of bromine-3-acetyl pyridine hydrochloride are solubilized in 500 ml of methyl alcohol. 50 ml of triethylamine and subsequently gr. Are added to this solution under a stream of nitrogen, stirring under cooling. 16.2 (0.1 mol) of N-phenyl piperazine solubilized in 50 ml of methyl alcohol.

During the addition the reaction temperature is maintained at 5 ° -10 ° C, it is then left to rest at room temperature for 4 h. It cools down to 0 ° and at this temperature,

40 always under stirring, a solution of gr. 7.5 of NaBH4 in 100 ml of water.

Once the addition is complete, the reaction mixture is kept under stirring at room temperature for 1 h. It is concentrated up to a small volume, acidified with diluted H2SO4, treated 45 with carbon, filtered and alkalized with lithium hydrate.

The oil separated with CHCIa is extracted, the CHC13 is dried over NaS04 and the solvent is evaporated; it remains a thick oil that crystallizes by rest.

I know P.M. = 283.38 m.p. = 124-26 ° (from ethyl acetate) Yield = 58%

for: C17H2iN30

Calculated: C 72.05 H 7.47 N 14.83 Found. C 72.13 H 7.70 N 14.89 55 In a similar way, the following have been summarized:

1 - [2-oxy-2- (3'-pyridyl) -ethyl] -4- (o-methoxyphenyl) -piperazine (no. 6) P.M. = 313.40 m.p. = 90-91 ° (from ethyl acetate) Yield = 50% for: C18H23N, 302 60 Calculated: C 68.98 H 7.40 N 13.41 Found: C 69.23 H 7.73 N 13.35

1 - [2-oxy-2- (3'-pyridyl) -etii] -4- (m-methoxyphenyl) -piperazine (no. 7)

65 P.M. = 313.40 m.p. = 97-99 ° (from ligroin) Yield = 52% for: C18H23Ni302

Calculated: C 68.98 H 7.40 N 13.41 Found: C 68.86 H 7.62 N 13.56

624402

6

l- [2-oxl-2- (3'-pyridyl) -ethyl] -4- (p-methoxyphenyl) piperazine (no. 8)

P.M. = 313.40 m.p. = 136 ° (daligroin) Yield = 51% for; C; SMI;? ST: X) 2

Calculated: C 68.98 H 7.40 N 13.41 Found: C 69.13 H 7.35 N 13.75

l- [2-oxy-2- (3'-pyridyl) -ethyl] -4- (o, toluil) -piperazine (no. 9) P.M. = 297.40 m.p. = 113-114 ° (daligroin) Yield = 53% for: Ci8H23N.30

Calculated: C 72.70 H 7.80 N 14.13 Found: C 72.94 H 7.99 N 14.38

l- [2-oxy-2- (3'-pyridyl) -ethyl] -4- (m, toluil) -piperazine (no. 10) P.M. = 297.40 m.p. = 81 ° (from ligroin) Yield = 52% for: ClgH23NeO

Calculated: C 72.70 H 7.80 N 14.13 Found: C 72.89 H 8.21 N 14.28

l- [2-oxy-2- (3'-pyridyl) -ethyl] -4- (p, toluil) -piperazine (no. 11) P.M .. = 297.40 m.p. = 142 ° (from ligroin) Yield = 60% for: ClsH23N, sO

Calculated: C 72.70 H 7.80 N 14.13 Found: C 72.53 H 8.07 N 13.76

l-l2-oxy-2- (3'-pyridyl) -ethyl] -4- (or, chlorophenyl) -piperazine (no. 12) P.M. = 317.50 m.p. = 131-133 ° (from ligroin) Yield = 62% for: Ci7H20OCI N3

Calculated: C 64.27 H 6.35 N 13.23 Found: C 64.10 H 6.64 N 12.98

/ - / oxy-2- (3'-pyridyl) ethyl] -4- (m-chlorophenyl) -piperazine (no. 13) P.M. = 317.50 m.p. = 101-103 ° (from ethyl acetate) Yield = 50%

for: C17H20ON3C1

Calculated: C 64.27 H 6.35 N 13.23 Found: C 64.30 H 6.45 N 13.20

l- [oxy-2- (3'-pyridyl) ethyl] -4- (p-chlorophenyl) -piperazine (no. 14) P.M. = 317.50 m.p. = 135-136 ° (from ethyl acetate) Yield = 56%

for: C17H20OC1N3

Calculated: C 64.27 H 6.35 N 13.23 Found: C 64.33 H 6.71 N 12.97

l- [oxy-2- (3'-pyridyl) ethyl] -4- (o-fluorophenyl) -piperazine (no. 15) P.M. = 301.37 m.p. = 85 ° -87 ° (from ligroin) Yield = 57% for: CI7H2nFN30

Calculated: C 67.75 H 6.69 N 13.95 Found: C 67.71 H 6.85 N 14.09

l- [2-oxy-2- (4'-pyridyl) ethyl] -4-phenylpiperazine (no. 22) P.M. = 283.40 m.p. = 108 ° (from ligroin) Yield = 45% for: C17H.MN ,, 0

Calculated: C 72.05 H 7.47 N 14.83 Found: C 71.81 H 7.86 N 14.56

l- [2-oxy-2- (4'-pyridyl) ethyl] -4- (or, methoxyphenyl) -piperazine (no. 21)

P.M. = 313.40 m.p. = 127 ° (from ethyl acetate) Yield = 40% for: C, 8H., 3N.302

Calculated: C 68.98 H 7.41 N 13.42 Found: C 68.73 H 7.80 N 13.38

Example n. 2 l- [2-methoxy-2- (3'piridil) ethyl] -4-phenylpiperazine

(n. 16)

5

Gr. 5.68 of l- [2-oxy-2- (3'piridil) ethyl] -4-phenylpiperazine (0.02 mol) are solubilized in 200 ml of CHC13.

The solution is brought to 0 ° and saturated with gaseous HCl. 4.4 ml 10 of SOCl2 (0.06 mol) dissolved in 20 ml of CHC13 are then added under stirring slowly.

It is kept for h at room temperature and 3 h at reflux.

The mixture is dried, the residue is taken up with the minimum amount of CH3OH and slowly added to this solution and under cooling with sodium methylate in methyl alcohol. (3.5 g of Na in 75 ml of CHaOH).

The mixture is kept under reflux for 3 h, the solvent is distilled off and the residue is taken up in 20 ml of H? O.

The aqueous solution is extracted 2 times with ether. The 20 ethereal solution is dried and the oily residue is distilled under vacuum.

The distillate crystallizes by rest.

P.M. = 297.40 m.p. = 69-70 ° (from hexane) Yield = 42% 25 For: C.MO

Calculated: C 72.70 H 7.80 N 14.13 Found: C 72.45 H 7.90 N 14.40

Similarly, the following were synthesized: 30 l- [2-ethoxy-2- (3'-pyridyl) ethyl-4-phenylpiperazine (no. 17) P.M. = 311.40 p. eboll. = 185 ° (0.1 mm / Hg) Yield = 46%

for. Cj ,, H25N30

Calculated: C 73.29 H 8.09 N 13.50 35 Found: C 73.42 H 8.52 N 13.62

1 - [2-methoxy-2- (3'-pyridyl) ethyl] -4- (or, methoxyphenyl) -piperazine (no. 18)

P.M. = 327.40 p. eboll. = 180-185 ° (0.2 mm / Hg) Yield 40 = 50%

for: Ci8H25Ns02

Calculated: C 69.71 H 7.7 N 12.84 Found: C 69.76 H 8.01 N 12.83

45

l- [2-ethoxy-2- (3'-pyridyljetylJ-4- (or, methoxyphenyl) -piperazine (no. 19)

P.M. = 341.40 p. eboll. = 190 ° (0.2 mm / Hg) Yield = 45%

50 for: C20H27N3O2

Calculated: C 70.34 H 7.97 N 12.30 Found: C 70.10 H 8.28 N 12.61

1 - [2-methoxy-2- (3'-pyridyl) ethyl] -4- (or, chlorojenyl) -piperazine 55 (no. 20)

P.M. = 331.80 p. eboll. = 180 ° (0.2 mm / Hg) Yield = 52%

for: C18H22N3OCl

Calculated: C 65.14 H 6.68 N 12.66 60 Found: C 65.42 H 7.08 N 12.78

l- [2-ethoxy-2- (3'-pyridyl) ethyl] -4- (or, chlorophenyl) -piperazine (no. 4) P.M. = 345.80 p. eboll. = 170-175 ° (0.2 mm / Hg) Yield 65 = 42%

for: CI (1H2 <N, OCI

Calculated: C 65.98 H 6.99 N 12.15 Found: C 65.98 H 7.22 N 12.07

Example n. 3 l- [2- (3'piridil) ethyl] -4- (or, methoxyphenyl) piperazine

(n. 2)

For the preparation of derivatives 1, 2, 3 it is necessary to isolate the ketones relating to formula VI of scheme I.

Their isolation is carried out by conducting the reaction as indicated in example n. 1 to the point where the reaction mixture is kept under stirring for 4 h at room temperature.

At this point it is distilled under vacuum and the residue is taken up in ether.

By evaporation of the solvent, an oil remains which crystallizes by rest.

They isolate themselves like this:

(4-phenyl-piperazinyl) methyl-3'-pyridyl-ketone P.M. = 281.40 m.p. = 103-104 ° (from hexane) Yield = 67% for: C17H19N30

Calculated: C 72.56 H 6.81 N 14.93 Found: C 72.93 H 7.29 N 14.88

[4- (o-chlorophenyl) piperazinyl] methyl-3'-pyridyl-ketone P.M. = 315.50 m.p. = 81-83 ° (from hexane) Yield = 70% for: C17H18N3OCl

Calculated: N 13.32 Found: N 13.48

[4- (o-methoxyphenyl) piperazinyl] methyl-3'-pyridyl-ketone P.M. = 311.40 m.p. = 98 ° (healthy dae) Yield = 72% for: C] gH21N302

Calculated: N 13.50 Found: N 13.72

Gr. 9.4 of [4- (o-methoxyphenyl) piperaziniI] methyl-3'-pyridyl - ketone (0.03 mol) and 75 ml of 98% N2H4 (0.15 mol) are added under stirring to a solution of gr. 4.14 of Na (0.18 mol) in 80 ml of diethylene glycol.

The mixture is heated, always under stirring, at 120 ° -130 ° for 2 h; at this point the temperature is brought to 180-190 ° removing the excess water and hydrazine.

The temperature is maintained at 180 ° -190 ° for 3-4 h and the solvent is distilled off under vacuum.

The residue is taken up with water and the solution extracted with ether.

624402

The ethereal extracts are dried and the residue is dissolved in diluted HCl. The acid solution is extracted with CHC13 and ether.

The organic liquids are removed and the acid solution,

after treatment with coal, it is alkalized with diluted LiOH.

An oil that crystallizes precipitates. It is distilled under vacuum. 178 ° -182 ° at 0.2 mm Hg.

P.M. = 297.70 m.p. = 59 ° -60 ° (from hexane) Yield = 45% for: C! SHK, Nl3lO

Calculated: C 72.70 H 7.8 N 14.13 Found: C 72.45 H 7.9 N 14.37 In a similar way they are prepared, starting from the related ketones:

l- [2- (3'-pyridyl) ethyl] -4-phenylpiperazine (no. 1) P.M. = 267.40 m.p. = 66-67 ° (from hexane) Yield = 50% for: C17H21N3

Calculated: C 76.36 H 7.92 N 15.72 Found: C 76.48 H 8.16 N 15.86

I- [2- (3'-pyridyl) ethyl-4- (or, chlorophenyl) -piperazine (no. 2) P.M. = 301.80 m.p. = 72 ° (from hexane) Yield = 53% for: C17H2 „N3C1

Calculated: C 67.65 H 6.68 N 13.93 Found: C 67.76 H 6.85 N 14.12

Example 4

l- [2-isopropyloxy-2- (3'-pyridyl) Jetil-4- (o-methoxyphenyl) - piperazine

In a similar way of example 2 the derivative of formula VI is prepared, wherein the replacement of the pyridyl nucleus is in position 3, and X is

yCH3 -CH

NCH3

eR2 is o- (OCH3).

P.M. = 355.48 m.p. = 93-96 ° Yield = 30% for: C21H2!) N302

Calculated: "c 70.95 H 8.2 N 11.82 Found: C 70.92 H 8.33 N 11.73

7

5

I0

15

20

25

30

35

40

45

V

Claims (6)

624402 2 CLAIMS 1. Process for the preparation of new heterocyclic derivatives of 4-phenyl-piperazine-1-alkyl-substituted of formula IV (IV) OH m cui R, is -H, -Cl, -F, -CH3, -OCH: ì; characterized by the fact of A) reacting bromo-acetyl-pyridine hydrochloride of formula II Br • HBr of) with phenyl-piperazine of formula III H - oor- -ethyl] -4-phenylpiperazine of formula VI, wherein the replacement of the pyridyl nucleus is in position 3, and X is -CH3, and R2 is hydrogen. Use according to claim 2, characterized 5 zata by the fact that l- [2-ethoxy-2- (3'-pyridiI] -4- is prepared -phenyl-piperazine of formula VI, wherein the replacement of the pyridyl nucleus is in position 3, and X is -C2Hr "and R2 is hydrogen. Use according to claim 2, characterized in that a l- [2-alkoxy-2- (3'-pyridyl) - is prepared io-ethyl] -4- (or, methoxyphenyl) -piperazine of formula VI, wherein the replacement of the pyridyl nucleus is in position 3, and R2 is o (-OOHy. Use according to claim 5, characterized in that the l- [2-methoxy-2- (3'-pyridiI) - is prepared 15-ethyl] -4- (or, methoxyphenyl) -piperazine or l- [2-ethoxy-2- (3'-piri-dil) -ethyl] -4- (or, methoxyphenyl) -piperazine. Use according to claim 2, characterized in that a l- [2-alkoxy-2- (3'-pyridesI) -ethyl] -4- (or, chlorophenyl) -piperazine of formula VI is prepared, wherein the substitution - 20 n and of the pyridyl nucleus is in position 3 and R2 is o (-Cl). Use according to claim 7, characterized in that l- [2-methoxy-2- (3'-pyridyl) -ethyl] - 4- (o, chlorophenyl) -piperazine or l- [2 is prepared ethoxy-2- (3'-pyridyl) ethyl] - 4- (or, chlorophenyl) piperazine. 25 (HI) under a nitrogen atmosphere, in methyl alcohol, in the presence of triethylamine, forming the ketone of the formula I 0 ~ CH, (THE) B) directly reduce the ketones obtained in (A) with NaBHj to alcohols of formula IV in hydroalcoholic solution. 2. Use of new alcohols of formula IV (IV) in which R2 is -H, -Cl, -F, -CU ,, -OCH: i; for the preparation of new heterocyclic derivatives of 4-phenyl-piperazine-1-alkyl-substituted of formula VI