CH637370A5 - Racemic forms and optically active forms of 2-(4-biphenylyl)-N-(diethylaminoalkyl)-propionamide, salts thereof and relative preparation processes - Google Patents

Description

15 The present invention relates to new compounds with improved spasmolytic action.

Among the products usually used in therapy as spasmolytics, it is frequently known that the action of some of them is limited to the gastro-intestinal tract,

20 Those products which, following oral administration, also exert their action on other organs or systems other than the gastro-intestinal tract, nevertheless have side effects of the atropinosimile type.

It has now been discovered that the new racemic compounds 25 and optically active, referable to the following general formula I:

CH3

where n = 2 or 3 and Et stands for C2H5

and their salts are particularly suitable for oral use and differ from the products already known for their inhibiting action of transmission from the nerve impulse to the muscle fiber (parasympatholytic activity), for the inhibitory effect of smooth muscle contraction (myolytic activity direct) and for the reduced side effects of the central and peripheral nervous system 40.

It has been found that the new compounds corresponding to the general formula I and their salts are particularly suitable for oral use, and differ from the products already known for their direct parasympatholytic and myolytic activity and for their reduced side effects on the system. central and peripheral nervous.

It has been found that the new compounds corresponding to the general formula I and their salts are particularly suitable for oral use, and differ from the products already known for their direct parasympatholytic and myolytic activity and for their reduced system side effects. central and peripheral nervous.

Compounds referable to structure I are: 1. 2- (4-biphenyls) -N- (2-diethylaminoethyl) propionamide; 55 2. 2- (4-biphenyl) -N- (3-diethylaminopropyl) propionamide;

3. d 2- (4-biphenylyl) -N- (2-diethylaminoethyl) propionamide;

4.] 2- (4-biphenyl-N- (2-diethylaminoethyl) propionamide;

5. d 2- (4-biphenyl-N- (3-diethylaminopropyl) propionamide;

6. 1 2- (4-biphenyl-N- (3-diethylaminopropyl) propionamide.

60 Pharmaceutically acceptable salts of the above compounds are as non-limiting examples the chloride, bromide, iodide, phosphate, as well as methyl bromide, methyl iodide, ethyl bromide, ethyl iodide.

Compounds of formula I can be prepared according to known methods, and in particular by reacting a functional derivative or of 2- (4-biphenyl!) Propionic acid with N, N-diethylethylendiamine or N, N-diethyl-1, 3-propylene diamine in the presence of a suitable solvent. As a functional derivative

3

637370

of the racemic form or of one of the optically active forms of 2- (4-biphenyl) propionic acid, chloride or the corresponding anhydride can be used, as well as an ester of the acid itself, and in particular a lower alkyl ester. Using the acid chloride as a reactive, it is preferable to conduct the condensation reaction with N, N-diethylethylenediamine or with N, N-diethyl-1, 3-propylenediamine in the presence of a base.

Compounds 3, 4, 5, 6 can also be obtained using the methods described in the literature as suitable for the resolution in optical antipodes of racemic forms of basic substances containing an asymmetrical carbon atom starting from 2- (4- biphenylyl) -N- (diethylamino alkyl) propionamide.

The salts of the compounds of formula I are also prepared according to known methods. The alkyl halogen derivatives are prepared by alkylation of the bases referable to formula I, with alkylating agents such as alkyl chloride, alkyl bromide or alkyl iodide in a suitable organic solvent, such as dioxane, acetone, ethyl ether.

Example 1

Preparation of 2- (4-biphenyl) -N- (2-diethylamino ethyl) propionamide (Compound 1).

At 11.6 g of N, N-diethylaminoethylenediamine in 60 ml of benzene, 24.4 g of 2- (4-biphenylyl) -propionic acid dissolved in 60 ml of benzene are slowly dripped under stirring. After keeping 1 hour in reflux, it is concentrated, extracted with ethyl ether and water, precipitated with soda from the aqueous solution; crystallizes from examination: m.p. 67-68 ° C. IR (Nujol), v max (cm-1): 3340 (NH), 1640 (CO) N-NMR (CC14), 8 (ppm): 1 (t, 2 X CH3) 1.6 (d, CH3) 2.3-2.6 (m, 3 X CH2) 3.3 (q, CH2) 3.6 (q, CH) 7.2-7.5 (m, C6H4 and C6H5).

Example 2

Preparation of 2- (4-biphenyl) -N- (3-diethylamino propyl) propionamide (Compound 2).

At 13 g of N, N-distilamino-1, 3-propiendiamine in 60 ml of benzene, 24.4 g of 2- (4-bisphenyl) propionic acid chloride dissolved in 60 ml of benzene are slowly dripped under stirring. After holding for 2 hours in reflux, it is concentrated, extracted with ethyl ether and water, precipitated with soda from the aqueous solution; crystallizes from hexane; p. f. 44-45 ° C. IR (Nujol), v max (cm-1): 3280 (NH), 1640 (CO) H-NMR (CDC13), 8 (ppm): 1.1 (t, 2 X CH3) 1.6-1, 9 (m, CH3 to CH2) 2.4-2.7 (m, 3 X CH2) 3.5 (q, CH2) 3.8 (q, CH) 7.5-7.9 (m, C6H4 and C6H5).

Example 3

Preparation of d 2- (4-biphenyl) -N- (2-diethylaminoethyl) propionamide. (Compound 3).

At 11.6 g of N, N-diethylethylenediamine in 60 ml of benzene, 24.4 g of 2- (4-biphenylyl) -propionic acid chloride dissolved in 60 ml of benzene are slowly dripped under stirring. After keeping 1 hour in reflux, concentrate, extract with ethyl ether and water, precipitate with soda of the aqueous solution: crystallize from hexane: p. f. 88-89 °, [a] D20 = + 7 ° (c = 2% in ethyl alcohol). I. R. (Nujol), max. (cm-1): 3340 (NH), 1640 (CO) N-NMR (CC14), (ppm): 1 (t, 2 X CH3) 1.6 (d, CH3) 2.3-2.6 ( m, 3 X CH2) (q, CH2) 3.6 (q, CH) 7.2-7.5 (m, C6H4 and C6H5).

Example 4

Preparation of d 2- (4-biphenyl) -N- (3-diethylamino propyl) propionamide. (Compound 5).

At 13 g of N, N-diethyl-1, 3-propylenediamine in 60 ml of benzene, slowly drain under stirring 24.4 g

of 2- (4-biphenyl) propionic acid chloride dissolved in 60 ml of benzene. After holding 2 hours to reflux, concentrate, extract with ethyl ether and water, precipitate with soda from the aqueous solution: crystallize from hexane: p. f. 51-53 ° C, [a] D20 = + 17 ° (c = 2% in ethyl alcohol). IR (Nujol), v max (cm-1): 3280 (NH), 1640 (CO) H-NMR (CDC13), S (ppm): 1.1 (t, 2 X CH3) 1.6-1, 9 (m, CH3 and CH2) 2.4-2.7 (m, 3 X CH2) 3.5 (q, CH2) 3.8 (q, CH) 7.5-7.9 (m, C6H4 and C6H5).

Example 5

Preparation of 2- (4-biphenylI) -N- (2-diethylmethylammoni - ethyl) propionamide bromide.

In 8 g of 2- (4-biphenyl) -N- (2-diethylamino-ethyl) propionamide dissolved in 20 ml of acetone, 2.5 g of methyl bromide are gorgolated. The precipitate is filtered and crystallized from isopropyl alcohol: p. f. 161-163 ° C. IR (Nujol) v max (cm-1): 3150 (NH), 1650 (CO) H-NMR (CDCI3), 8 (ppm): 1.3 (t, 2 X CH3) 1.6 (d, CH3 ) 3.2 (s, CHj) 3.4-4.0 (m, 4 X CH2 and CH) 7.4-7.7 (m, C6H4 and C6H5).

Example 6

Preparation of 2- (4-biphenylI) -N- (3-diethylmethylammonium - propyl) propionamide bromide.

In 8.5 g of 2- (4-biphenyl) -N- (3-diethylamino-propyl) propionamide dissolved in 20 ml of acetone, 2.5 g of methyl bromide are bubbled. The precipitate is filtered and crystallized from acetone / ethyl ether: p. f. 116-118 ° C. IR (Nujol), v max (cm-1): 3150 (NH), 1645 (CO) H-NMR (CDC13), 8 (ppm): 1.25 (t, 2 X CH3), 1.55 (d , CH3), 1.8-2.3 (m, CH2) 3 (s, CH3) 3.1-3.7 (m, 4 X CH2) 3.7-4.2 (q, CH) (q , CH) 7.4-7.7 (m, C6H4 and C6H5).

Example 7

Preparation of 2- (4-biphenyl) -N- (2-diethylmethylammonium-ethyl) propionamide iodide.

8.0 g of 2- (4-bifeniiil-N- (2-diethylaminopropiI) propionamide dissolved in 25 ml of ethyl alcohol are added with 4 g of methyl iodide, dried under vacuum and crystallized from acetone: mp 132 -134 ° CIR (Nujol), v max (cnr1): 3200 (NH), 1655 (CO) H-NMR (CDC13), 8 (ppm): 1.3 (t, 2 X CH3) 1.6 (d , CH3) 3.1 (s, CH3) 3.3-4.0 (m, 4 X CH2 and CH) 7.4-7.65 (m, C6H5 and C6H4).

Biological activity

Myolytic activity was tested with the test that measures the transit of coal in the mouse intensity, stimulated by BaCl2 according to the method described by P.A.J. Janssen & A. Jageneau, J. Pharm. Pharmacol. 9, 381, 1957.

The parasympatholytic activity was tested in anesthetized guinea pig by evaluating the inhibitory effect of the products on the action of carbachol at the bronchial level according to the method described by ME Rosenthale & A. Pervinis, Arch. Int. Pharmacodyn 1, 172, 1968 and at the level cardiac and blood pressure, (see JP Long & CY Chiou, J. Pharm. Sciences, 59, 133, 1970).

5

10

15

20

25

30

35

40

45

50

55

60

65

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4

The results are shown in table 1 below:

TABLE 2

TABLE 1

Composed

Inhibition of barium chloride stimulation of intestinal peristalsis (carbon test). Power ratio 0

Anesthetized guinea pig. Inhibition of the following effect induced by carbachol ° (Power ratio)

Bronco- Hypen- Bradi-cardiac constriction

° The compounds were administered intraduodenally at a dose of 25 mg / kg. Carbachol (5 [ig / kg) was injected intravenously before and 40 minutes after administration of the products.

1 = 2- (4-biphenylyl) -N- (2-diethylaminoethyl) acetamide

2 = 2- (4-biphenyl) -N- (2-thiethylaminoethyl) propionamide

3 = 2- (4-biphenyl) -N- (3-diethylaminopropyl) propionamide

4 = d 2- (4-biphenyl-N- (2-diethylaminoethyl) propionamide

5 = d 2 (4-biphenyl) 4- (3-diethylaminopropyl) propionamide

Central anticholinergic activity

5 Enhancement of the effects of Apomorphine according to Sheel-Kriiger (a)

1

0.9

0.2

5

0.2

2

1.5

1

10

1.4

3

1.9

0.9

10

1.2

4

> 2.5

1.3

10

1.5

5

1.5

1.0

6

0.8

Diciclo-

mine

HCl

1

1

1

1

Central and peripheral effects

Inhibition of the effects of oxothremorin (b)

compounds

Activity index

Compound Activities Index I.

15

Dicyclomine HCl

1

Dicyclomine HCl

1

2 (c)

0.5

2 (c)

0.2

Atropine sulphate

1.3

Butylbromide of

scopolamine

1.2

(to)

Average of the effects of 3 doses (30-60-90 mg / kg / os) of the com-20 places administered to female mice (17-25 g) 1 hour before Apomorphine (10 mg / -kg / c.c.). The chewing intensity for the products and the control (H2O) is evaluated for a period of 40 minutes.

25

(B)

Average of the effects of 3 doses (28.6-57.2-114.4 mg / kg / os) of the compounds administered to male mice (18-25 g) 1 hour before oxothremorin (0.5 mg / mg / sc). We evaluate the effect on tearing, salivation, diarrhea and tremor with respect to control (H2O) 15 min-30 min. 1 hour and 2 hours

From these results it can be seen how the presence of a propionamide structure is relevant for the improvement of the activity. In fact the already known 2- (4-biphenyl) -N- (2-diethylamino-ethyl) acctamide [G. Cavallini, P. Ravenna, Farm. Sci. Tecn. 3, 648 (1948)] exhibits significantly lower parasympatholytic and direct myolytic activity than that shown by the racemic and dextrogyric form of 2- (4-bi-phenylyl) -N- (2-diethylaminoethyl) propionamide. The latter in addition, compared to dicyclomine, has an inhibitory effect of the contraction of the smooth muscle (direct myolytic activity) of at least 1.5 times more marked and an action inhibiting the transmission of the nerve impulse to the muscle fiber (parasympatholytic activity) one to ten times more pronounced.

The atropinosimile side effects have been studied with the oxothremorin test according to the method described by Leslie G. Hayman G. Iresen JD & Smith S., Arch. Int. Pharmacodyn 197, 108, 1972, evaluating the central effects (tremors) and peripheral (salivation, lacrimation, diarrhea) and with the apomorphine test according to the method described by J. Scheel-Krüger, Acta Pharmacol. Toxicol. 28, 1, 1970, evaluating the central anticholinergic activity. The data are reported in table 2.

dall'Ossotremorina. (c) 2- (4-biphenyl) -N- (2-diethylaminoethyl) propionamide.

30 From this table 2 it can be observed that in comparison with 2- (4-biphenyl) -N- (2-diethylaminoethyl) propionamide, dicyclomine and scopolamine butylbromide have respectively central and peripheral effects five or six times higher. Due to the central anticholinergic activity, dicyclo-35mine and atropine sulphate have effects about two times greater than 2- (4-biphenyl) -N- (2-dietsIaminoetil) propionamide.

None of the products mentioned shows anti-inflammatory properties on the carrageenan edema test according to the 40 method described by Winter C. A., Risley A. C. & Nuss G. W., Proc. Soc. Exp. Biol. Med. Ili, 544, 1962.

The present invention further provides pharmaceutical compositions comprising at least one compound of formula I in association with a carrier or pharmaceutical excipient. 45 The pharmaceutical compositions can be presented in suitable forms, for example for oral, parenteral or suppositorial administration generally containing from 5 to 40 mg of active substance. Examples of suitable forms of administration include tablets, tablets, sugared almonds, cap-50 gannets, lozenges, dispersible powdes, syrups, elixirs and suppositories. Preferably the compositions are presented in a single dosage form.

v

Claims (16)

637370 A compound according to claim 1, characterized in that it consists of 2- (4-biphenyl) -N- (2-diethyl-aminoethyl) propionamide (n = 2). 2 CLAIMS 1. The racemic and optically active compounds referable to the general formula CH3 where n = 2 or 3, and Et stands for C2H5 and salts of them. A compound according to claim 1, characterized in that it consists of 2- (4-biphenyl-N- (3-diethyl-aminopropyl) propionamide (n = 3). A compound according to claim 1, characterized in that it consists of d 2- (4-biphenyl) -N- (2 - diethylaminoethyl) propionamide (n = 2). 5, since chloride or the corresponding anhydride is used as a functional derivative of 2- (4-bife-nylyl) propionic acid, as well as an ester of the acid itself. A compound according to claim 1, characterized in that it consists of 1 2- (4-biphenyl) -N- (2 - diethylaminoethyl) propionamide (n = 2). A compound according to claim 1, characterized in that it consists of d 2- (4-biphenyl) -N- (3 - diethylaminopropyl propionamide (n = 3). 7. A compound according to claim 1, characterized in that it consists of 12- (4-biphenyl) -N- (3 - diethylaminopropyl) propionamide (n = 3). A compound according to claim 1, characterized in that it consists of a salt of 2- (4-bi-phenylyl) -N- (2-diethylaminoethyl) propionamide included in the group comprising chloride, bromide, iodide, phosphate , sulphate, as well as methyl bromide, methyl iodide, ethyl bromide, ethyl iodide. A compound according to claim 1, characterized in that it consists of a salt of 2- (4-bife-nylyl) -N- (3-diethylaminopropyl propionamide included in the group comprising chloride, bromide, iodide, phosphate, sulphate, as well as methyl bromide, methyl iodide, ethyl bromide, ethyl iodide. 10. A compound according to claim 1, characterized in that it consists of a salt of d 2- (4-biphenyl) -N- (2-diethylaminoethyl) propionamide included in the group comprising chloride, bromide, iodide, phosphate, sulphate, as well as ethyl bromide, methyl iodide, ethyl bromide, ethyl iodide. A compound according to claim 1, characterized in that it consists of a salt of 1 2- (4-bi-phenylyl) -N- (2-diethylaminoethyl) propionamide included in the group comprising chloride, bromide, iodide, phosphate , sulphate, as well as methyl bromide, methyl iodide, ethyl bromide, ethyl iodide. A compound according to claim 1, characterized in that it consists of a salt of 1 2- (4-bi-phenylyl) -N- (3-diethylaminopropyl) propionamide included in the group comprising chloride, bromide, iodide, phosphate , sulphate, as well as methyl bromide, methyl iodide, ethyl bromide, ethyl iodide. A compound according to claim 1, characterized in that it consists of a salt of 1 2- (4-bi-phenylyl) -N- (3-diethylaminopropyl) propionamide included in the group comprising chloride, bromide, iodide, phosphate , sulphate, as well as methyl bromide, methyl iodide, ethyl bromide, ethyl iodide. 14. Method of preparing a compound of claim 1, characterized in that it involves the step of reacting a functional derivative in racemic forms that or optically active of 2- (4-biphenyl) propionic acid with N, N-diethyl-ethylenediamine or N, N-diethyl-1, 3-propylene diamine, in the presence of a suitable solvent. 15. The method of claim 14, characterized 16. A composition for pharmaceutical use which comprises an inert, non-toxic and carrier substance and an active principle essentially comprising at least one compound according to claim 1, in unit doses of 5 to 40 mg.