MC598A1 - New chemical compounds and process for their preparation - Google Patents

Description

JRB/ M-MC-44

3 y. ^ 67o 598

3S6*"F£V 13 h 33

O /? / Cj / l _

PATENT OF INVENTION

New; chemical compounds and process for their preparation

Roland-Yves MAUVERNAY

The present invention relates to a new class of chemical compounds, useful in particular as anti-inflammatory and analgesic drugs, as well as a process for their preparation.

These compounds are piperazine derivatives, which can be defined by the following general formula:

"N\- (CH0)

2 n

-0

N

R-,

2 ■

%

10

—/-- 2

in which:

R^ represents a phenyl group that can be substituted by one or more halogen atoms (such as F or Cl) or one or more alkoxy groups (such as methoxy, methylenedioxy or allyloxy), which may be identical or different;

Rg represents a phenyl group substituted at the ortho or para position by a halogen (such as P or Cl), or by an alkoxyethyl group, with the formula:

- CH - CHg -

t

GOLD

in which R is a lower alkyl group such as methyl, ethyl, propyl, butyl or iso-arnyl,

and n is a chosen integer from 1 to

The invention also relates to salts of these compounds with pharmaceutically acceptable acids.

According to the invention, these .ososes are prepared by the reaction of a substituted piperazine, cnoi..-ie, between phenylpiperazine and lialogenophenylpiperazine, of formula:

H.N.

20

t h2

in which Rg has the previous meaning,

and l-(2-alkoxy-2-phenyl)-ethyl-piperazines, with a

1,2,4-oxadiazole, with the formula:

Cl - (CH2)n"l 0

R1

25 in which R-^' and n have the same meanings as before. £

10

15

20

These intermediate products can themselves be prepared by the process described by G. Palazzo, Col. (J. Med. Pharm. Chem. Vol. 4, No. 2, 1911).

It should be noted here that in the case where n = 2 it is preferable to use a variant of the process according to the invention, in which one starts, not from 1,2,4-oxadiazole, but from the corresponding acryloyl-benzanidoxime, of formula:

CH„ = CH - C - 0

d n t

0 N

NHg

Rn which is reacted with the chosen piperazine, in boiling toluene.

A number of examples of how this process can be implemented are given below:

EXAMPLE 1

Oh, preparation of l-(2-phenyl-2-ethoxy)-ethyl- dihydrochloride

)

4-/~5-3-(3,4,5)-trimethoxyphenyl-l,2,4-oxadiazole 7-

m ethylpyrazine

- CH,

0

?H2

CH - OC^H,-d 0

N

NX

CH-jO-

OCH-

OCH-Ï

2.4 µmol (0.1 mol) of 1-(2-phenyl-2-ethoxy)-ethylpiperazine is heated for 2 hours under reflux with 0.55 g of 1-(2-phenyl-2-ethoxy)-ethylpiperazine.

(0.1 mole) of ;;-(>,4.5)^ethoxy-phenyl-5-crilorc--.ethyl-1,2,4-oxadiazole (melting point: 91-92°C) at the same time as 8.5 g of CO HNa and 150 ml of n-butanol. After

10

15

20

Upon cooling, the NaCl formed is filtered and the butanol is expelled under vacuum. The mixture is then redistributed with absolute ethanol, filtered, and acidified with absolute ethanol saturated with HCl. The dihydrochloride crystallizes. After two recrystallizations, the product is obtained in the form of white crystals. Melting point: 176°C.

EXAMPLE 2

Preparation of 1-(4-fluoro) dihydrochloride -> 4-henyl

/~5,3-(3, 5")-dimethoxyphenyl-1,2,4-oxadiazole_7-

methylpiperazine

.Ne— CH,

-N"

F

CH-, 0

CH, 0

18 µmol of 1-(4-fluoro)-phenylpiperazine is heated for 3 hours under reflux with 15 µmol of 3-(3-5)-dimethoxy-4-allyloxy-7-phenyl-5-c-Ioromethyl-1,2,4-oxadiazole (melting point: 72°C), along with 100 mL of toluene and 8.5 g of NaOH. The 1-(4-fluoro)-phenylpiperazine hydrochloride is filtered, and the toluene is expelled. The residue crystallizes upon cooling. It is recrystallized twice in ethanol to obtain the product as a white crystalline powder. Melting point: 87°C.

EXAMPLE 3

Preparation of l-phenyl-4-2-5-3-(fluoro)-phenyl-

1,2,4-oxadiazole-7-ethylpiperazine

— ^

N

N

V

F

a) First step: preparation of 1' aer;, loyl--;.-fluoro-phenyl-benzamidoxime:

In a 3-necked flask equipped with a mechanical stirrer, a thermometer, a CaCl₂ tube, and a mixing bowl

To a bromine solution, 110 g of 4-fluorophenylbenzamide, 360 mL of acetone, and 60 g of anhydrous CQ-Kg are introduced. The mixture is placed in an ice bath, and a solution of 70 g of acrylic acid chloride in 80 mL of acetone is added while stirring, maintaining the temperature between 5 and 10°C. When the addition is complete, the ice bath is removed, and stirring continues for 3-4 hours at room temperature. Under these conditions, some of the product precipitates and is washed with cold water. The remainder is recovered by evaporating the acetone. The two portions are combined and washed with a cold 5% aqueous CO₂ solution, then with water. Crystallization in acetone gives the desired intermediate product (melting point: 99-100°C).

b) Second step: preparation of the final product.

10.4 g (0.05 moles) of acryloyl-4-fluorophenyl-benzamidoxime and 8.1 g of 1-phenylpiperazine are heated under reflux with 80 ml of toluene in a flask fitted with a Dean-Starck decanter and an ascending condenser.

6

Once the reaction is complete, which is assessed by the amount of water collected (this takes 5-6 hours), the toluene is evaporated, leaving a residue that crystallizes. After two recrystallizations of the etha-

s.

No, white needles are obtained (melting point: 101°C).

EXAMPLE 4

Preparation of 1-(4-fluoro)-phenyl-4-;-/~5-(3-phenyl)-1,2,4-oxadiazole 7-P^opylpi perazine

10

15

20

25

- CHU-CriL -CH„

\ c. CL d

"N'

-0

N N

F

We heat for 10 hours.:, uous reflux en ; tant 22.25 Ë (0.1 mole) of 7-phenyl-5-(è'-chloro )-; ro;.>yl-1,2,4-oxadiazole and 18 e; (0.1 mole) of 1-(4-fli-oro)-phenylpiperazine with 8.5 ' of sodium bicarbonate and 151 ml of n-butanol.

The formed NaCl is filtered, then after heating the solvent under vacuum, a thick oil is obtained which crystallizes slowly. After two recrystallizations in methanol, white crystals with a melting point of 67°C are obtained.

In all cases, dichlorohydrates are obtained by adding the necessary amount of ethanol saturated with HCl.

The compounds thus defined and prepared possess a very interesting anti-inflammatory and analgesic activity, which has been evaluated by classical tests.

Q

siaues. namely ï

a - Acute toxicity: Behrens and Karber method (Arch. Exp. Path. Pharm., 177, 379, 1935) -LD50 (mg/kg)

b - Anti-phlogistic activity: method of Wilhelmi and Domenjoz (Arz. Frosch., 1, 151, 1951) - DA 50 (mg/kg)

c - Anti-inflammatory activity: Bush method and

Alexander (Act. Endocrin., ^5, 268, i960) - % d - Analgesic activity: (mg/kg)

1 - Caloric stimulus: Eddy and Leimoaeh methods

(J. Pharm. Exp. Ther., 107, 385, 1953) and Chen (Science, 113, 631, 1951)

2 - Chemical stimulus: Koster's methods (Fed.

Proe., l8y 412, 1959) and Witkin (J. Pharm. Exp. Ther., 133, 400, 1961).

In addition, the ulcerogenic potential of some of these products was evaluated by the dose, in mg/kg, causing gastric ulcerations in a certain percentage of treated animals, as this effect is generally considered to determine the authenticity of an anti-inflammatory action.

The results, expressed comparatively, are summarized in Table I below:

TABLE I

Product Product Product Product Product property 12345

has

> 3000

1500

2005

2005

180

b

125

50

250

200

75

c

V25

*25

Vi 13

VilO

* 22

d 1

125

50

75

150

200

d 2

125

40

75

100

150

e

DA40=250

DA50=150

DA10=150

-

75

The identity of the products in Table I is established as follows, with reference to the preceding general formula

Claims (1)

~/~ 8 10 15 20 25 Product No. 1 2 3 4 R1 phenyl phenyl phenyl R2 -chlorophenyl -fluorophenyl phenyl n F 3 (dichl.) 172 367 3 (dichel.) 148 1 (dichl.) 176 3,4,5-trimed-2-phenyl-2-thoxyphenyl ethoxyethyl 3,4,5-pheny-1-butazone In general, this experimentation shows that, since not all products according to the invention possess the aforementioned pharmacological properties to the same degree, certain rules emerge for evaluating their suitability. Thus, in order of activity, the most suitable compounds are those in which n - 3, those halogenated at position 4, and those in which the halogen is fluorine. Therefore, the most suitable of the compounds listed above is the one whose preparation is described in Example 4, and designated as Product 2 in Table I. The attached drawing is a table grouping the identification and properties of a number of other compounds according to the invention. SUMMARY I - New chemical compounds usable particularly as anti-inflammatory and analgesic drugs, characterized by the formula ï <ch2i„ -N" *;R„;N N R,; in which:;R^ represents a phenyl group that can be substituted;—/~ il; by one or more halogen atoms (such as F or Cl) or one or more alkoxy groups (such as methoxy, methyledioxy, or allyloxy), which may be identical or different.; represents a phenyl group substituted in the ortho or para position by a halogen (such as F or Cl), or by an alkoxyethyl group, of formula:;- CH - CH2 -;I;OR; in which R is a lower alkyl group such as methyl, ethyl, propyl, butyl, or isoamyl.; and n is an integer chosen from 1 to 3.;2 - Process for preparing the compounds according to 1, characterized in that a substituted piperazine, chosen from phenylpiperazine, halophenylpiperazines, of formula :;H;in which R_ has the preceding meaning,;z and the 1- (2-alkoxy-2-phenyl)-ethyl-piperazines, with a 1,2,4-oxadiazole, of formula :;Cl - (CH ) - [j 0;|;N N;V;Ri -;in which R^. and n have the preceding meanings.;.3 - Process according to 1, characterized in that in the case where n = 2, it is preferable to use a;~/~ 10;variant of the process according to the invention, according to which one starts, not from the 1,2,4-oxadiazole, but from the corresponding acryloyl-benzamidoxime, of formula :;CH2 - CH - C - 0;H I;O N NH;2;Ri which is reacted with the chosen piperazine, in boiling toluene. (3 q i n-/91_ s&nsj o ■T'Jfc CUrfty/J ot? citi. Q. rft '-bj otu yp i fteu 'j i