DE1103322B - Process for the preparation of N-allyl-2-methyl-2-n-propyl-1,3-propanediol carbamate - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN MrkL PATENT OFFICE

kl 12 ο 17/01

INTERNAT. KL. C 07 C

EXPLAINING EDITORIAL 1103 322

C 19453 IVb / 12 ο

REGISTRATION DATE: APRIL 23, 1958

NOTICE
THE REGISTRATION
AND ISSUE OF THE
FROM LE GE S CHRIFT: MARCH 30, 1961

The invention relates to a new organic compound that has a muscle relaxing effect of has high activity. So far, many drugs have been used for the purpose of reversing muscle spasms, caused by various disorders, e.g. B. rheumatic and related disorders, cerebral palsy and various kinds neurological conditions. For many years, salicylates have been used for this Purpose used, but they were not generally effective; because it resolved painful discomfort for only one short time. Later 3-o-toloxy l, 2-propanediol was used extensively under various conditions, where muscle plasma is a factor. The very short duration of action of this compound is its main disadvantage. The newest drug that has found widespread use to dissolve muscle plasma is this 2-methyl-2-n-propyl-1,3-propanediol dicarbamate. Its muscle relaxing effect is similar to that of the former compound, but of greater potency and longer duration.

It has now been found that N-allyl-2-methyl-2-n-propyl-1,3-propanediol carbamate of the formula method of manufacture

of N-allyl ^ -methyl - ^ - n-propyl-

1,3-propanediol carbamate

Applicant:

Carter Products, Inc., New York, N.Y. (V. St. A.)

Representative: Dr. H.-H. Willrath, patent attorney, Wiesbaden, Hildastr. 32

Claimed priority: V. St. v. America April 18, 1958

Frank Milan Berger, Princeton, N. J., and Bernard John Ludwig, North Brunswick, N. J.

(V. St. A.),
have been named as inventors

CH ₃

CH ₂ OCONH-Ch ₂ -CH = CH ₂

nC ₃ H ₇

CH ₉ OCONH ₉

or that the monocarbamate of the general formula

a muscle-relaxing effect of greater potency than any previously used muscle-relaxing agent owns.

According to the invention, the dicarbamate is prepared in such a way that either the monocarbamate is used the general formula

CH,

nC ₃ H ₇

, CH ₂ O-CO-NH-CH ₂ -Ch = CH ₂ ⁴⁰

CH ₂ OH

CH ₃ CH ₂ -OCONH ₂

nC ₃ H ₇ CH ₂ OH

a) first reacts with phosgene and the chlorocarbonate formed in the process then reacts with allylamine lets or

b) reacts with allyl isocyanate.

The new 45 dicarbamate, which is N-monosubstituted by an allyl residue, has unexpectedly intense muscle-relaxing activity. This can be seen from the results of the table, which lists the mean paralyzing doses and mean lethal doses which are obtained in mice after intraperitoneal administration of two b) _{pandiol dicarbamate compounds related} to the carbamic acid ester of a low-boiling 50 p _rO

a) with cyanic acid or

Alcohol or

c) first reacts with phosgene and the chlorocarbonate formed in the process then reacts with ammonia leaves

PD ₅₀ - and

LD ₅₀ doses are in millimoles

became. the

(mm) of active components expressed per kilogram of mouse weight. In the table these are N-allyl-2-methyl-2-n-propyl-1 , 3-propanediol dicarbamate and as a control

109 538/562

Substance the well-known 2-methyl-2-propyl-1,3-propanediol dicarbamate listed:

R CH ₂ O-CN:

R ' C.
/ \ , ^X '
R 'CH ₂ O-CN;
Il ^x v ' X Y X ' Y ' PD ₅₀ LD ₅₀ nC ₃ H ₇ Il
0 CH ₂ = CH - CH ₂ - (allyl) H H H 114 500 R. nC ₃ H ₇ H H H H 235 800 CH ₃ CH ₃

The results compiled in the table show the unexpectedly high muscle relaxing activity the new connection. Apparently, their increased activity depends on the well-known 2-methyl-2-propyl-1,3-propanediol dicarbamate once from the substitution of one and no more than one of the four hydrogen atoms, which are attached to the carbamate nitrogen atom with an aliphatic group and on the other hand from the unsaturated nature of the dicarbamate. So it has actually been found that, in general, the multiple Substitution of aliphatic groups decreases rather than increases muscle relaxation activity. aside from that could the surprisingly improved muscle relaxing activity that the new compound be evidenced by the fact that other representatives of this particular class, i.e. H. 2,2-disubstituted N-monosubstituted propanediol dicarbamates, to which the compound according to the invention belongs, have a far less muscle-relaxing effect than the control substance has, and that this is of course even less than the unique muscle relaxing activity of the new compound.

The compound obtainable according to the invention is a colorless liquid with a high boiling point. It is good in most organic solvents, but poor in water at room temperature soluble. With hot alkali hydroxide solution or strongly acidic solution it becomes with the formation of the corresponding Diol, easily hydrolyzed by ammonia, a primary amine, and carbon dioxide.

The following example illustrates the production process of the compound of the invention.

example

Preparation of N-allyl-2-methyl-2-n-propyl-1,3-propanediol dicarbamate (C ₁₂ H ₂₂ O ₄ N ₂ )

57 parts of allylamine are slowly added to 52 parts of 5-methyl-2-n-propyl-2-m-dioxanone with stirring. When the addition is complete, the reaction mixture is heated on a steam bath for 2 hours. The excess allylamine is then removed by distillation under reduced pressure and the residue is purified by vacuum distillation. 40 parts of N-allyl-2-methyl-2-n-propyl-3-oxypropylcarbamate of the formula C ₁₁ H ₂₁ O ₃ N, which distills at a pressure of 0.05 mm at 102 to 104 ^° C., are obtained. N _BE r = 6.51, N _GEF = 6.80, refractive index wf = 1.4683.

A solution of 18.8 parts of N-allyl-2-methyl-2-n-propyl-3-oxypropyl carbamate, 8.9 parts of ethyl urethane and 200 parts of xylene was distilled to remove any traces of residual water. After cooling, 1 part of aluminum isopropoxide was added. The mixture was distilled until practically the theoretical amount of alcohol had been removed in the form of the azeotropic mixture with xylene. The xylene is removed by distillation under reduced pressure and 100 parts of water are added. The water is distilled off under reduced pressure and the residue is dissolved in 150 parts of isopropanol. Insoluble products are removed by filtration and the isopropanol is driven off by distillation. The remaining oil is purified by molecular distillation using a bath temperature of approximately 110 to 135 ^° C. and a pressure of approximately 0.025 mm. A yield of 14 parts of purified product is obtained. N _B er = 10.85, N _G ef = H, 03, refractive index η * § = 1.4760.
In addition to having a unique muscle relaxant effect of extreme value as a drug for dissolving muscle plasma, the distinctive central depressive properties of the compound obtainable according to the invention also suggest that it is useful as a sedative, sedative, hypnotic, and agent for influencing abnormal behavior.

The new compound obtainable according to the invention is preferably administered orally in the form of pills, tablets or capsules are administered which are formed by known methods. A typical composition consists from the active ingredient mixed in a dry, powdery state with gelatin, starch, Magnesium stearate and algae acid, compressed into a tablet. The active ingredient can also be in a suitable solution. An effective dose of the active ingredient will generally be in the range from 0.05 to 2.0 g.

Claims (1)

Claim: Process for the preparation of N-allyl-2-methyl-2-n-propyl-1,3-propanediol dicarbamate the formula CH ₃ CH ₂ OCONH - CH ₂ --CH = CH, nC ₃ H ₇ CH ₂ OCONH ₂ characterized in that one either 5 6 Monocarbamate of the general formula or that the monocarbamate of the general CH ₃ CH ₂ O-Co-NH-CH ₂ -CH = CH ₂ formula X * / CH ₃ CH ₂ -OCONH ₂ nC ₃ H ₇ CH ₂ OH _κ ° _χ a) with cyanic acid or nC ₃ H ₇ CH ₂ OH b) with the carbamic acid ester of a low-boiling alcohol or io a) initially reacted with phosgene and that at the same time c) first reacts with phosgene and then the chlorocarbonate formed with allylamine Chlorocarbonate formed then reacts with ammonia or reacts b) reacts with allyl isocyanate. © 109 538/562 3. 61