FR284F - New derivatives of nicotinic acid. - Google Patents

Description

French Republic

MINISTRY OF INDUSTRIAL AND SCIENTIFIC DEVELOPMENT

INDUSTRIAL PROPERTY SERVICE

1HE ADDITION

THE PATENT OF INVENTION

No. 5.535 M

P.y. n ° 139.503 N ° 284 CAM

Classical. boarding school. : A 61 k // C 07 c; C 07 d

New derivatives of nicotinic acid.

Company known as: AMERICAN CYANAMID COMPANY residing in the United States ^^ fé ^? | 4th ^ ek

[Main patent issued March 30, 1966.) îPtflC »Incl. Ei & etldoi

Requested on February 12, 1968, at I5h 13m, in Paris. 1 0; 13/1 Issued by decree of October 6, 1969.

(Official Bulletin of Industrial Property [B.S.M.], No. 46 of November 17, 1969.) {Patent application filed in the United States of America on November 14, 1966, under No. 593,638, in the names of MM. Ruddy Littell, James Miller Smith Jr. and Duff Shederic Allen Jr.)

(Patent resulting from the division of the application for a certificate of addition, P.V. n "127,923,

filed November 13, 1967.)

The present addition relates to novel hydrazinium salts of nicotinic acid derivatives.

In the main patent, we have described: certain derivatives of nicotinic acid which can be represented by the following formula:

in which R may represent identical or different groups chosen from the following: a CF3 group, a halogen atom or a lower alkyl group; R 1 represents hydroxyl, lower alkoxy, di- (lower alkyl) -amino-lower alkyl, amino, lower alkyl-amino or di- (lower alkyl) -amino; n is an integer from 1 to 3.

Studies have been carried out by the Applicant to prepare new compounds and in particular new hydrazinium salts derived from nicotinic acid.

The compounds according to the present addition are coochj

(ix)

0 210 030 7

physiologically active and therefore useful in the pharmaceutical field. The Applicant has found that they are particularly advantageous as anti-inflammatory agents, analgesics without addiction and diuretics.

The nicotinic acid esters according to the main patent react with the asymmetrically disubstituted hydrazines to give the hydrazinium salts derived from nicotinic acid according to the invention of formula:

Xv, N (Î ^ = 3 ~ 'b' "

AI? =

"v ^ cocr nh„ n-r4 * RÎ

in which R is defined above, and R3, R4 and R5 are lower alkyl or aryl groups, R3 and R4 taken together may represent with the nitrogen atom a pyrrolidino, piperidino, morpholino, 4-lower alkyl group piperazino, 4- (beta-hydroxy-lower alkyl) -piperazino, or hydroxy-piperidino.

+ (ch3), nnh2-

-O "

^ coo-h2nn (cii3),

X

fY

[284 CAM / 5.535 M] - 2

Treatment of methyl 4- (alpha, alpha, alpha-trifluoro-m-toluidino) -nicotinate (IX) with asymmetric di-methyl-hydrazine, using excess hydrazine as a solvent, or in the presence of an inert solvent, makes it possible to prepare the hydrazinium salt (X).

The compounds of list A are prepared according to methods described in the main patent.

The following example illustrates the preparation of the compounds according to the invention:

Example. - Preparation of 1,1,1-tri-methylhydrazinium 4- (alpha, alpha, alpha-trifluoro-m-toluidino) -nicotinate.

A solution is heated at reflux overnight.

(See formula, previous page)

Analogously, by the process described above, reaction of the 4-substituted nicotinic esters of list A with the asymmetrically substituted hydrazines of list B gives the desired hydrazi-nium derivatives, indicated in list C as follows :

of 2.2 g of methyl 4- (alpha, alpha, alpha-trifluoro-m-tolui-dino) -nicotinate in 15 ml of asymmetric dimethylhydrazine. After evaporation of the solvent, the residue is crystallized from a dichloromethane-ether mixture to obtain 2.3 g of 1,1,1-trimethylhydrazinium 4- (alpha, alpha, alpha-trifluoro-TO-toluidino) -nicotinate in the form of 'white needles, melting at 118-121 ° C.

Table 1 Diuretic action in rats

Compound

Number of rats

Urine, ml

Chloride, meq *

Sodium, meq *

Potassium, meq *

0-5 h.

0-24 h.

0-5 h.

0-24 h.

0-5 h.

0-24 h.

0-5 h.

0-24 h.

Witnesses

126

3.2

14.2

0.7

2.1

0.5

1.9

0.8

2.8

AT

10

22.2

31.9

3.1

3.6

2.1

2.8

1.0

2.9

B

4

25.8

36.8

3.8

4.7

2.9

3.9

1.8

4.5

AT

B

VS

Methyl 4 - (a, a, a-Trifluoro-m-toluidino) -nicoti-nate.

Methyl 4 - (a, a, a-Trifluoro-m-toluidino) -nicoti-nate.

4 - (a, a, a-Trifluoro-m-toluidino) -nicotinate of butyl.

Methyl 4 - (a, a, a-Trifluoro-m-toiuidino) -nicoti-nate.

Methyl 4 - (p-Chloro-a, a, a-trifluoro-m-toluidino) nicotinate.

Methyl 4 - (et, a, ct-Trifluoro-m-toluidino) -nicoti-nate.

4 - (a, a, a, -Trifluoro-77i-toluidmo) -nicoti-nate of methyl.

4 - (a, a, a-Trifluoro-m-toiuidino) -nicoti-nate of methyl.

non-sym- Diphenylhydrazine.

1 - Methyl-1-phenylhydrazine.

1 - Aminopyrrolidine 1 - Aminopiperidine.

1 - Aminomorpholine.

1 - Amino4-methylpiperazine.

1 - Amino-3-hydroxypiperidine.

1 - Amino-4 - ((3-hydroxyethyl) -piperazine.

4 - (oc, a, a-Trifluoro- / re-toluidino) -nicotinate of 1-Methyl-1,1-diphenylhydra-zinium.

4 - (a, a, a-Trifluoro-m-toluidino) -nicoti-nate of 1, 1-Dimethyl-1-phenylhydra-zinium.

4 - (a, a, a-Trifluoro-771-toluidino) -nicoti-nate of 1-Ammo-1-butyipyn-olidinium.

4 - (a, a, a-Trifluoro-77> tolmdmo) -nicoti-nate of 1-Amino-1-methylpiperidinium.

1-Amino-1-methyl-morpholinium 4 - (p-chloro-a, a, a - Trifluoro - m - tolui-dino) -nicotinate.

4 - (a, a, a-Trifluoro-m-toluidino) -nicoti-nate of 1-Amino-1,4-dimethylpipera-zinium.

1-Amino-3-hydroxy-1-methyl-piperidinium 4 - (a, a, a-Trifluoro-m-to] uidmo) -nicoti-nate.

1 - Amino-4 - ({3-hydroxyethyl) -1-methylpiperazinium 4 - (a, a, a-Trifluoro-m-toluidino) -nicoti-nate.

- 3

The new hydrazinium salts according to the invention have an interesting diuretic action, and we studied, in particular, the diuretic action of 4- (alpha, alpha, alpha-trifluoromethyl-m-toluidino) - nicotinate of 1,1 , 1-trimethyl-hydrazinium (designated compound B in the tables below), compared to that of 4- (alpha, alpha, alpha-trifluoromethyl- m - toluidino) - nicotinic acid (designated compound A in the tables below) below).

The two compounds were administered at a dose of 25 mg in rats, and the volume was determined.

- [284 CAM / 5.535 M]

of urine and its concentration of chloride, sodium and potassium. The results are given in the table below; they are statistically significant (p <0.05).

(See table I, previous page)

The same compounds were administered to dogs at a dose of 5 mg / kg; and the same determinations were made as before. The results are given in the table below, in terms of the average rice standard deviation.

Table 2 Diuretic action in dogs

Compound

Witnesses

Number of dogs

Urine, ml

Chloride, meq *

Sodium, meq *

Potassium, meq *

0-6 hrs.

0-24 h.

0-6 hrs.

0-24 h.

0-6 li.

0-24 h.

0-6 hrs.

0-24 h.

101

223 ± 77

288 ± 88

3.3 ± 2.7

7.0 ± 3.9

3.1 ± 2.7

8.4 ± 4.8

2.9 ± 1.9

7.7

± 3.7

5

289 ± 84

374 ± 125

13.5 ± 8.5

17.2 ± 12.5

14.9 ± 7.8

20.5 ± 11.5

4.6 ± 1.3

9.3 ± 0.6

3

322 ± 115

382 ± 111

19.3 ± 6.1

20.2 ± 6.7

18.4 ± 3.7

21.6 ± 3.4

4.3 ± 1.7

8.2 ± 1.3

* summarized milliequivalent

The present invention relates to, as medicaments useful in particular as anti-inflammatories and diuretics:

1 ° Hydrazinium salts of nicotinic acid derivatives of formula:

^ / "YW

A J

V ^ vcoo 'NH2N-R4 Ri in which R represents identical or different groups chosen from the following: CF3,

halo or lower alkyl, R3, R4 and R5 represent lower alkyl or aryl groups and R3 and R4 taken together with the nitrogen atom represent pyrrolidino, piperidino, morpholino, 4-lower alkyl-piperazino, 4 - (beta - hydroxy - lower alkyl) -piperazino, or hydroxypiperidino; n is an integer of 1 to 3, and in particular 1,1,1-trimethyl-hydrazinium 4- (alpha, alpha, alpha-trifluoro-m-toluidino) -nicotinate;

2 ° Pharmaceutical compositions containing, with a pharmaceutically acceptable vehicle, at least one of the compounds according to 1 as active ingredient.

Company known as: AMERICAN CYANAMID COMPANY By proxy:

Cabinet Beau de Loménie

DOCUMENTARY NOTICE ON THE NEW FEATURE

Documents likely to affect the novelty of the medicinal product: none.

Documents illustrating the state of the art in this area: Belgian patent n ° 678.694.

For the praise of the booklets, “'address to the National Imphimkrie, 27, rue de la Convention, Paris (15th).