Cinnamamidine derivatives

Patented Nov. 20, 1951

2,575,991

UNITED STATES PATENT OFFICE

2,575,991

CINNAMAMIDINE DERIVATIVES

Richard Baltzly, New York, and Emil Lorz, Yonkers, N. Y„ assignors to Burroughs Wellcome & Co. (U. S. A.) Inc., Tuckahoe, N. Y., a corporation of New York

No Drawing. Application March 24,1949, Serial No. 83,293

Claims. (Cl. 260—564)

The present invention relates to a new group of chemical compounds and more particularly to a new type of cinnamamidines which possess outstanding properties as local anesthetics in veterinary medicines. Some of the new compounds are particularly efficient as Surface anesthetics, while others have been found to be valuable as injection anesthetics. At least some of the new compounds are also believed to be suitable for application in human medicine, but at present 10 the clinical tests on these compounds have not been completed.

The new compounds are readily prepared in excellent yield by the methods disclosed in our copending U. S. application Serial No. 700,366, filed October 1, 1946, and now abandoned, of which the present application is a continuation in part.

The physiologically active compounds according to the present invention are members of the group consisting of the unsubstituted N,N-dialkylcinnamamidines of the general formula:

<img file="US2575991A_D0001.tif" />

in which R is an alkyl radical containing from two to six carbon atoms, and their ring substituted derivatives in which up to two carbon atoms in the ring are substituted by a radical selected from the group consisting of methoxy, ethoxy and methylene dioxy.

With regard to such local anesthetic potency the cinnamamidines according to the present invention show considerable variation in the type of action. N,N-di-n-butyl cinnamamidine is fourteen times as active as cocaine, tested on the guinea pig cornea, and thirteen times as active as procaine, tested by the guinea pig wheal method. These are both conventional testing procedures the former being designed to detect ac- 40 tion as a surface anesthetic, the latter to discov- ’ er activity in a substance for injection and anesthesia. The compound in question is about four times as toxic as cocaine, tested on mice. Substitution of methoxyl groups in the 3 and 4 positions makes the derived compound somewhat less toxic than cocaine, increases its activity as a surface anesthetic and largely abolishes its activity in injection anesthesia. /

In addition to this local anesthetic activity several of the substances according to the invention have been found to have a disintegrative action on certain lower forms of life and may be of value in combating internal parasites.

In practical application, the new cinnamamidines are preferably used in the form of their water soluble salts. The acid used to form the salt contributes nothing to the physiological activity of the substances and is not of a critical nature, provided It Is not lself highly toxic. Hydrochloric acid, hydrobromic acid, sulfuric acid.

phosphoric acid or organic acids such as malic acid, succinic acid, lactic acid or the like may be employed and any of these may offer advantages in individual cases, but hitherto no other acid has been found preferable to hydrochloric acid. We therefore consider all non-toxic acids to be equivalent for this purpose and regard salts of this family of amidines with any such acid to be comprehended in the invention.

The following list of compounds, though not exhaustive, is believed to be representative of the physiologically active cinnamamidines according to the present invention:

1. :

2.:

3. :

4. : dine.

5. N,N-di-sec-butyl-4-ethoxy cinnamamidine.

6. N,N-di-n - butyl-3,4-dimethoxy cinnamamidine.

7. N,N-di-n-propyl-3,4 - diethoxy cinnamamidine.

8. N,N-di-n-butyl-2,5 - .dimethoxy cinnamamidine.

9. N,N-di-n-hexyl-2,3 - dimethoxy cinnamamidine.

10. N,N-di-n-hexyl-3,4-methylenedioxy cinnamamidine.

11. N,N-di-isopropyl-4-ethoxy-3-methoxy cinnamamidine.

12. N,N,-di-iso-butyl-2-ethoxy-3-methoxy cinnamamidine.

The compounds according to the present invention are conveniently prepared as described in our co-pending application Serial No. 700,366 .above mentioned, by the reaction of a halomagnesium dialkylamide with the appropriate nitrile. The halomagnesium amide is formed by the addition of a secondary amine to a solution of a Grignard reagent, usually ethyl magnesium bromide. The preparation of the amidine therefore involves the following steps:

(1) CaHsMgBr + RsNH (2)

R'

N,N-di-n-butyl cinnamamidine. N,N-diethyl-4-chlorocinnamamidine. N,N-di-n-butyl-4-methoxy cinnamamidine. N,N-di-sec - butyl-2-methoxy cinnamami-

<img file="US2575991A_D0002.tif" />

CH— CHCN + RaNMgBr (3)

<img file="US2575991A_D0003.tif" />

NMgBr

II H;O

CH—C—NR; ---1 eo

RjNMgBr

<img file="US2575991A_D0004.tif" />

NMgBr •i—NR;

<img file="US2575991A_D0005.tif" />

2,676,981

..... 4.............

butyl-4-methoxy cinnamamidine melted at 214°.

By the same method bromomagnesium-di-secbutyl amide reacted with 2-methoxy-cinnamonitrile and with 4-ethoxy cinnamonitrile to give N,N-di-sec-butyl-2-methoxy-cinnamamidine and N,N-di-sec-butyl-4-ethoxy cinnamamidine.

EXAMPLE 3

N,N-di-n-butyl-3,4-dimethoxy cinnamamidine

A. solution of ethyl magnesium bromide was prepared from 2.5 g. (0.1 at.) of magnesium and 10.8 g. (0.1 mole) of ethyl bromide. To it was added 12.9 g. (0.1 mole) of di-n-butylamine and the solution was refluxed 30 minutes. Ten g. (0.05 mole) of 3,4-dimethoxy cinnamonitrile was admitted and the solution was refluxed three hours. After pouring into iced ammonium chloride solution the product was isolated by the method of Example 1. The N,N-di-n-butyl-3,4dimethoxy cinnamonitrile hydrochloride melted at 185-186° after crystallization from ethanolether mixture.

By the same procedure 3,4-diethoxy cinnamonitrile and bromomagnesium di-n-propyl amide yielded N,N-di-n-propyl-3,4-diethoxy cinnamamidine.

ίο . 3 -

All three steps can be performed in one operation but there are practical advantages with this family of compounds in separating the third step as will be seen.

The general procedure is to prepare a solution of ethyl magnesium bromide at least equivalent to the quantity of nitrile to be used. There is then added a slight excess of the requisite secondary amine, and the solution is refluxed 15-30 minutes to complete step (1) which is rapid but not instantaneous. The nitrile is then added at a rate such as to sustain gentle refluxing and the reaction mixture is refluxed for 1-4 hours. If the solution, which now contains the halomagnesium derivative of the desired amidine, is poured into iced ammonium chloride solution there is a precipitate, insoluble in water and ether, consisting of the bulk of the amidine in the form of a magnesium derivative. The precipitate can be filtered off and the product thereby largely separated from unreacted nitrile or secondary amine. Such behavior is not uncommon in amidine syntheses by our method but appears to be the rule with these cinnamamidines. The magnesium derivatives have not been investigated beyond the establishment of their general nature. When they are shaken with dilute solutions of alkalies magnesium hydroxide precipitates-and .the amidine base, usually an oil, is liberated. The amidine base can then be transformed into its salts by conventional procedures.

Methods, for the preparation of the substituted amidines according to the present invention are illustratively exemplified in the following examples which, however, are not intended to limit the scope of the invention.

-’F EXAMPLE 1

N,N-di-n-butyl cinnamamidine

To a solution of ethylmagnesium bromide prepared from 3.7 g. (0.15 at.) of magnesium and 16.9 g. (0.15 mole) of ethyl bromide was added 20 g. (0.15 mole) of di-n-butyl amine. After the resultant solution had been refluxed 30 minutes there was added gradually 12.9 g. (0.1 mole) of cinnamonitrile. The reaction mixture was refluxed two hours and poured into an excess of iced ammonium chloride solution. The bulk of the product separated as a colorless powder which was filtered off and washed with water and ether. .The solid was then shaken with 5% sodium hydroxide solution, and ether. The solid dissolved, magnesium hydroxide precipitated, and the ether layer was found to contain an oily base. The ethereal layer was dried over potassium carbonate and added to an excess of ethanolic hydrogen chloride solution. The amidine hydrochloride separated as colorless crystals which, after recrystallization from ethanol-ether mixture, melted at 204°. By the same procedure 4-chlorocinnamonitrile was reacted with bromomagnesium diethylamide to give N,N-diethyl-4-chlorocinnamamidine.

EXAMPLE 2

N,N-di-n-butyl-4-methoxy cinnamamidine

A Grignard solution was prepared from 2.1 g. (0.085 at.) of magnesium and 9.3 g. (0.085 mole) of ethyl bromide. To this was added 12 g. (0.09 7o mole) of di-n-butyl amine. After the usual reflux period, 12 g. (0.075 mole) of 4-methoxy cinnamonitrile was added. The solution was refluxed four hours and worked up by the method _;of Example 1. The hydrochloride of N,N-di-n- 75 two to six carbon atoms, and 1

EXAMPLE 4

N,N-di-n-butyl-2,5-dimethoxy cinnamamidine

A Grignard reagent was prepared from 1.5 g. (0.06 mole) of magnesium and 6.5 g. of ethyl bromide. To it were added successively by the procedure of Example 1, 9 g. of di-n-butyl amine and 5 g. (0.026 mole) of 2,5-dimethoxy cinnamonitrile. The product, isolated by the method Of Example 1, was N,N-di-n-butyl-2,5-dimethoxy cinnamamidine whose hydrochloride melts at 192°.

In the same way were prepared N,N-di-nhexyl-2,3-dimeth0xy cinnamamidine and N,N-din-hjexyl-3,4-methylene-dioxy cinnamamidine.