DES0032079MA - - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Registration date: February 5, 1953. Advertised on November 3, 1955

GERMAN PATENT OFFICE

PATENT APPLICATION UNG

CLASS 12p GROUP 4

S 32079 IVb / 12 ρ

Paul Gailliot, Paris, and Jacques Gaudechon, Thiais, Seine (France)

have been named as inventors

Societe des Usines Chimiques Rhone-Poulenc, Paris

Representative: Dr. F. Zumstein, patent attorney, Munich 2

proceedings

for the production of 10- (dialkylaminoalkyl) -phenoxyphenthiazines

and their salts

The priority of the application in France of March 20, 1952 has been claimed

The invention relates to the production of new phenthiazine derivatives, namely io- (dialkylaminoalkyl) -i-phenoxyphenthiazines and io- (dialkylaminoalkyl) -3-phenoxyphenthiazines of the general formula

as well as their salts.

In the above formula, A denotes a straight divalent aliphatic chain with 2 or 3 carbon atoms, R denotes a methyl or ethyl radical; the phenoxy radical is in the 1- or 3-position (Numbering according to Beilstein).

According to the invention, these new amines are prepared by the action of a tertiary haloalkylamine of the formula X - A - N (R) ₂ , where X denotes a halogen atom, on the corresponding phenoxyphenthiazine. The reaction is preferably carried out in the presence of a condensing agent capable of forming a metal derivative with the phenthiazine

509 578/44

S 32079 IVb / 12p

able. These condensation agents belong to the group of alkali metals or their derivatives (hydroxides, Hydrides, amides, alcoholates, metal alkyls or aryls). In particular, the sodium amide is metallic Sodium, powdered sodium hydroxide or potassium hydroxide, lithium hydride, sodium tert-butoxide, Butyllithiuin and Phenyllithium mentioned.

It is preferable to work in an organic one

ίο Solvent at the boiling point of this solvent. Ks is particularly advantageous, the tertiary haloalkylamine in the form of the free base in Solution, e.g. B. in benzene, toluene or xylene to use and add it to the mixture of the other reaction components admit, in which the phenthiazine is already at least partially in the form of the alkali salt is present. However, the reaction can also be carried out without a condensing agent, with the solution of the ilalogenalkylamine is gradually introduced into the molten phenthiazine.

The reaction can also be effected with a salt of the tertiary Ilalogenalkylamin, but is in this case to take into account that a larger amount of condensing agent is used the acid of the salt of the tertiary haloalkylamine to neutralize.

The phenoxyphenthia / .in used as the starting material can be prepared by heating 3-phenoxydiphenylamine with sulfur. This reaction is conveniently carried out by heating a mixture of the reactants in the presence of a small amount of iodine, preferably to a temperature above 150 ^0, and preferably about 175 to 190 "is performed.

The products obtained according to the invention are in can be used in human and veterinary therapy, e.g. as antihistin drugs, anti-inflammatory drugs, spasmolytics, Anti-blocking agents, enhancers of the effectiveness of anesthetics.

For example, they are more similar to known products as the effectiveness of anesthetics Constitution clearly superior, as can be seen from the following comparison tests:

ICs became io- (3'-Diincthylamino-propyl) -phenoxy-pheiithia / .in with the boiling point Kp _{1> 3} --- 252 ⁰ (F. des maleate 115 11 (T), which probably has the following formula

and which is to be referred to below as RP 5.039, also the io- (3'-dimethylamino-propyl) -phenoxy-phenlhiaziii with your boiling point Kp ₀₁₈ - = 245 ° (F. des oxalate - 153 "), the presumably the following formula owns

OC ₆ H ₅

(CH ₂ ) ₃ N (CH ₃ ) ₂

and which is to be referred to below as RP 5.084, and also the io- (3'-diethylamino-propyl) -phenoxy-phenthiazine (F. of the chlorohydrate = go up to 91 °), which probably has the following formula

-OC ₀ H ₆

(CH ₂ ) ₃ N (C ₂ H ₅ ),

and which is to be referred to in the following as RP 5.083, with the one from German patent specification 824 944 known io- [2'-dimethylamino-2'-methylethyl- (i ')] - 2-methoxy-phenthiazine the formula

OCH,

CH ₂ -CH-N (CH ₃

CH,

which is to be referred to in the following as RP 4.739, with regard to its effect-increasing activity of the Hexobarbitals (= i, 5-dimethyl-5-zli-cyclohexenylbarbituric acid) \ 'compared.

The comparative tests were carried out as follows: The product to be tested is the Test animal (mouse) applied subcutaneously at a dose of 20 mg / kg; 30 minutes later it becomes hexobarbital administered intravenously at a dose of 50 mg / kg. One puts the average duration of the Anesthesia, with a control experiment on mice that received only hexobarbital alone, is carried out. The following values were obtained for the duration of the anesthesia:

10 minutes in the control animals that received no treatment prior to the administration of the hexobarbital learned;

38 minutes for the known product RP 4.739;

80 minutes for the product RP 5.039 obtained according to the invention;

70 minutes for the product RP 5.083 obtained according to the invention;

82 minutes for the product RP 5.084 obtained according to the invention.

From these results, the superiority of the products obtained according to the invention over

578 / 4-1

S 32079 IVb / 12 ρ

known products of similar constitution clearly visible.

The following example is intended to explain the invention in more detail.

example

Used as a starting material i- or 3-phenoxy-phenthiazine is prepared as follows: A mixture of 25 g of 3-phenoxy-diphenylamine, 6.1 g of flowers of sulfur and 0.5 g of iodine ι hour ⁰ 150 175 in the metal . At the end of this period, the evolution of hydrogen sulfide ceased. The crude product obtained is dissolved in a mixture of 130 ecm benzene and 100 ecm cyclohexane. It is filtered and rinsed with a mixture of 20 ecm benzene and 20 ecm cyclohexane. Then 200 ecm of cyclohexane are added to facilitate crystallization. The mixture is filtered and the precipitate formed, washing with 50 cc of cyclohexane and dried at 45 ⁰ in vacuo. Are thus obtained 10 g of i-phenoxy (or 3-phenoxy) -phenthiazin which melts after recrystallization from benzene at 153-154 ^0th By evaporation of the mother liquors and crystallization of the residue from 100 cc of cyclohexane, 14.2 g of 3-phenoxy (or i-phenoxy) -phenthiazin which melts after recrystallization from cyclohexane at 121-122 ^0th

The 3-phenoxydiphenylamine used as the starting compound can be prepared by reacting the sodium salt of 2-chloro-benzoic acid with 3-phenoxy-aniline in isoamyl alcohol in the presence of copper powder; there is obtained the 2-carboxy-3-phenoxy-diphenyl-amine (F. = about 120 ^0), containing about gives the 3-phenoxy-diphenyl-amine by heating at 200 °; Kp _ll2 = 190 to 200 ⁰ . F. = 72 to 73 ⁰ .

To a boiling suspension of 29.1 g of phenoxyphenthiazine (m.p. = 166 to 154 ⁰ ) and 6.5 g of sodium amide (go ° / ₀ ig) in 250 ecm of xylene gradually within 1 hour 90 ecm of a 16% Solution of 3-dimethylamino-i-chloropropane in xylene and boils for a further 2 hours after the addition has ended. After cooling, it is taken up in 500 ecm of water and acidified with 34 ecm of hydrochloric acid (d = 1.17) against methyl orange. The xylene is separated off, the aqueous layer is made ^{alkaline against phenolphthalein by adding 48 ecm sodium hydroxide solution of 36 0} Be in order to set the base free and extracted four times with 150 ecm ether each time. This essential extract is dried over sodium sulphate, the ether is driven off and rectified.

This gives 27 g of io- (3'-dimethylamino-propyl) -phenoxy-phenthiazine, which _{boils at bp 1) 3} = 252 °. The maleate is prepared therefrom by the action of a solution of maleic acid in ethyl acetate on the base dissolved in ethyl acetate. This maleate melts at 115 to 11 °.

If one works in the same way but starting from one of Phenoxyphenthiazin mp = 121-122 °, one obtains the corresponding io- (3'-dimethylamino-propyl) -phenoxy-phenthiazine, _0j8 Kp = 245 ^0; F. of the oxalate = 153 ⁰ .

From Phenoxyphenthiazin mp = 153-154 ⁰ to set in the same way by reaction with 3-diethylamino-i-chloropropane the appropriate io- (3-diethylamino-propyl) -phenoxy-phenthiazine forth; F. of the chlorohydrate = 90 to 91 °.

Claims (1)

PATENT CLAIM: Process for the preparation of io- (dialkylaminoalkyl) -phenoxy-phenthiazines the general formula , S, - OC «H _R N (R) ₂ where A is a straight aliphatic divalent chain with 2 or 3 carbon atoms and R is a methyl or ethyl radical and the phenoxy radical is in the 1- or 3-position, and salts thereof, characterized in that a tertiary haloalkylamine of the formula X - A - ■ N (R) ₂ , where X ι denotes halogen atom and A and R have the meaning given above, on the corresponding phenoxyphenthiazine, optionally in the presence of a condensing agent which is able to form a metal derivative with the phenthiazine, and allows the phenthiazine derivatives obtained to act if necessary converted into their salts in a conventional manner. Referred publications:
German patent specification No. 824 944.