DE1058998B - Process for the preparation of phenthiazine derivatives - Google Patents

Description

GERMAN

The invention relates to processes for the preparation of new derivatives of phenthiazine, their salts and quaternary Ammonium derivatives.

The compounds according to the invention correspond to the general formula

!-NS,

Method of manufacture
of phenthiazine derivatives

B-T

In this formula, T denotes a mono- or dialkylamino radical in which the alkyl radicals have 1 to 5 carbon atoms contain, or the remainder of a cyclic, non-aromatic amine, such as the pyrrolidino, piperidino, morpholino or 4-alkylpiperazino radical; B means a bivalent aliphatic hydrocarbon radical with straight or branched chain and 2 to S carbon atoms, for example the ethylene, propylene, isobutylene, trimethylene, tetramethylene radical, this radical optionally can be substituted by a radical - A - T ', in which A is a single bond or a Means methylene radical and T 'has the meaning of T.

The compounds of the formula I can be according to the following Procedure are obtained:

1. Reaction of an aminoalkyl halogen compound of the general formula X - B - T, in which X is a halogen atom means and B and T have the above meaning, or one of its salts with 3-methylthio-phenthiazine (Numbering according to Beilstein). The reaction can be carried out with or without a solvent and in the presence or absence of a condensing agent. It is beneficial in an aromatic hydrocarbon as a solvent, for example toluene or xylene, and in the presence of a condensing agent, preferably from the group of alkali metals and their derivatives, such as hydrides, amides, hydroxides, Alcoholates, metal alkyls or aryls and in particular metallic sodium, sodium amide, sodium hydroxide or potassium hydroxide in powder form, lithium hydride, sodium tert-butoxide, butyllithium or phenyllithium, to condense, preferably at the boiling point of the solvent. It is beneficial to that Aminoalkyl halogen compound in the form of the free base in solution, for example in benzene, toluene or xylene, to use and the solution to the mixture of the other reaction components in which the 3-methylthio-phenthiazine can already be present at least partially in the form of the alkali salt, to be added. The reaction can likewise with a salt of the aminoalkyl halogen compound but in this case it is necessary to use a much larger amount of the condensing agent . Applicant:

Societe des Usines

Chimiques Rhone-Poulenc,

Paris

Representative: Dr. F. Zumstein "~

and Dipl.-Chem. Dr. rer. nat. A. Assmann,
Patent Attorneys, Munich 2, Bräuhausstr. 4th

Claimed priority:
France from November 25, 1955 and August 16, 1956.

Robert Michel Jacob, Ablon, Seine-et-Oise,

and Gilbert Louis Regnier, Paris (France),

have been named as inventors

to use to neutralize the acidity of the salt used. In the case where T is a monoalkylamino radical means, it is advantageous to carry out the condensation with an acyl derivative of this secondary amine and then hydrolyzing the product thus obtained.

In the case where the divalent aliphatic radical - B - is branched and asymmetrical, such as for example

- C Η «- C H - - C H - C Η« - - _ ·

CH ₃ CH ₃

-CH-CH ₂ -CHo- -CH ₂ -CH ₂ -CH-

CH ₃ CH ₃

A rearrangement can take place in the course of the reaction. This rearrangement is analogous to that which occurs in the Case of the preparation of 10- [2'-dimethylaminopropyl- (1 ')] -phenthiazine by condensation of a dimethylaminohalopropane takes place with phenthiazine (cf. Charpentier, Comptes Rendus hebdomadaires des seances de l'Academie des sciences, Vol. 255 [1947], P. 306). In case of 2-diniethylamino-1-chloropropane or l-dimethylamino-2-chloropropane runs out, one obtains always the same final mixture in which the 10- [2'-dimethyl-

909 030/376

arainopropyl (l ')] phenthiazine in predominant quantities is present.

2. Thermal decomposition of phenthiazine-10-carboxylic acid esters of amino alcohols of the general formula

I - SCH, II

COO — Β — Τ

in which the various symbols have the meanings given above.

In the course of this reaction, the same rearrangement is observed as in the process under 1. in the case branched asymmetrical chains.

The decomposition of the phenthiazine-10-carboxylic acid ester of an amino alcohol is achieved by heating to a temperature above 100 ° C and preferably carried out at temperatures between 150 and 220 ° C. It doesn't offer any It is advantageous to carry out the decomposition at even higher temperatures, since the reaction products then generally are more strongly colored. You can use the substance alone without a diluent or in an inert one Medium, such as vaseline oil, diphenyl, diphenyl ether, a chlorine-containing aromatic solvent or in for Decarboxylation known diluents, such as quinoline or weak bases, heat.

The phenthiazine-10-carboxylic acid esters of amino alcohols can be obtained by known processes, such as, for example, reaction of a phenthiazine-10-carboxylic acid halide (or an ester) with the appropriate amino alcohol; Action of a phenthiazine-10-carboxylic acid haloalkyl ester to an amine; Implementation of the appropriate phenthiazine with a chlorocarbonic acid ester an amino alcohol.

3. Reaction of an amine of the general formula H - T, in which T has the above meaning, with a reactive ester of the general formula

Lithium hydride, sodium tert-butoxide, butyllithium or Phenyllithium. The condensation is preferably carried out at the boiling point of the solvent.

4. Alkylation of primary or secondary amines corresponding to the general formula I according to an known procedures. A reactive ester can be used, or optionally one Dimethyl derivative, formaldehyde and hydrogen.

Certain of these new phenthiazine derivatives have in

ίο the chain B an asymmetric carbon atom and can therefore occur in racemic or optically active form. The optically active derivatives can according to certain of the processes described above can be obtained by starting materials that are themselves are optically active, goes out. You can also choose from the corresponding racemates of the general formula I. can be produced by optical splitting.

The new derivatives all have the characteristic of a remarkable activity on the central nervous system.

This activity enables general use as antimetics, anesthetic agents and enhancers as neuroleptics. In addition, certain of the new compounds, especially those in the 10-position the residues of the phenthiazine

-CH ₂ -CH-N (CH ₃ ) ₂

and

SCH ₃

Β '—Υ

In this formula, Y denotes the radical of a reactive ester, for example a halogen atom, or the Residue of a sulfuric acid or sulfonic acid ester and B 'a divalent aliphatic hydrocarbon residue with a straight or branched chain and 2 to 5 carbon atoms, this radical optionally being replaced by a Radical - A - T 'or - A - Y' can be substituted, where the symbols A and T 'have the meanings given above and Y' has the meaning of Y.

As in the process according to 1. the reaction can be carried out with or without a solvent and in the presence or absence of a condensing agent. It is advantageous to condense in an aromatic hydrocarbon, for example toluene or xylene, as the solvent. You can optionally use a condensing agent, preferably from the group of alkali metals and their derivatives, for. B. the hydrides, amides, hydroxides, alcoholates, metal alkyls or aryls and in particular metallic sodium, sodium amide, sodium hydroxide or potassium hydroxide in powder form, CH ₃

- CH ₂ - CH - CH ₂ --N (CH ₃ ) ₂

CH,

possess a very significant antihistamine effect. After all, those connections are where the chain carries another amino group —A - T “, which is particularly important as antispasmodics and local anesthetics.

The new derivatives are suitable for pharmaceutical use in the form of therapeutically acceptable salts, such as the hydrochlorides, phosphates, nitrates, sulfates, maleates, fumarates, citrates, tartrates, Oxalates, Methanesulfonate, Äthandisulfonate, or in

4-5 form of therapeutically acceptable quaternary ammonium compounds, such as the chlorine, bromine or iodine methylates or ethylates, or chlorine Bromobenzylates or allylates.

As already mentioned above, the phenthiazine derivatives obtainable according to the invention have various aspects very favorable therapeutic properties, being superior to the known analogous compounds are. As can be seen from the following comparative experiments, is for example that obtainable according to the invention 3 - Methylthio -10 - (3 '- dimethylaminopropyl) - phenthiazine to the analogue from the Swiss patent 298 685 known 3-chloro-10- (3'-dimethylaminopropyl) -phenthiazine with regard to the narcosis-potentiating, superior antiemetic and anti-shock effect; said substance obtainable according to the invention namely shows a significantly better anesthetic potentiating effect and in particular a very much better one Anti-shock effect.

_6th Test report

Comparative experiments: The one obtainable according to Example 1

3 - methylthio -10 - (3'-dimethylaminopropyl) - phenthiazine (Product A) was obtained with the compound 3-chloro-10 known from Swiss patent 298 685 - (3'-dimethylaminopropyl) - phenthiazine (product B)

washed with water and extracted with 10 ⁰ / "hydrochloric acid. It is then made alkaline with sodium hydroxide solution (d = 1.33) and extracted with ether. After drying the ethereal solution over anhydrous sodium sulfate and distilling off the solvent under reduced pressure, 11.25 g of the crude base are obtained.

By adding an ethanolic solution of maleic acid, 12.7 g of the acidic acid are obtained after recrystallization Dimaleate of 3-methylthio-10- [3 '- (4 "-methylpiperazino) -2'-methyl-propyl] -phenthiazine from 199 ° C.

The ester used as the starting substance, the dihydrochloride of which melts at about 225 ° C., can be obtained by heating of 3- (4'-methyl-piperazino) -2-methyl-propanol in toluene with 3-methyltnio-phenthiazine-10-carboxylic acid chloride with a temperature of 125 ° C. The latter is in turn caused by the action of phosgene on 3-methylthiophenthiazine obtained in toluene in the presence of pyridine.

Example 5

- ■

12 g of the l ', 3'-bis (dimethylamino) propyl (2) ester of 3-methylthio-phenthiazine-10-carboxylic acid with a melting point of 103 bis 104 ° C in 60 ecm of o-dichlorobenzene for 3 hours Heated to the boil, and the reaction product is treated as described in Example 1. This gives 10.25 g of the crude isomeric bases.

By adding a solution of fumaric acid in ethanol to the solution of these bases in the same Alcohol is obtained after recrystallization from ethanol 6 g of the neutral fumarate of 3-methylthio-10- [2 ', 3'-bis (dimethylamino) propyl] -phenthiazine from 198 ° C.

The ester used as the starting substance can, as described in Example 2, using 1,3-bis (dimethylamino) propanol- (2) can be obtained.

Example 6

4.6 g of 3-MethyltMo-10- (3'-toluenesulfonyloxypropyl) -phenthiazine, dissolved in 42 ecm of anhydrous toluene, are heated with 4.3 g of pure diethylamine in an autoclave at 100 to 110 ° C. for 3 hours. After cooling, the resulting crystalline suspension is diluted with 100 ecm of ether and washed several times with water. It is extracted with 10 ° / ₀ hydrochloric acid. After making alkaline with sodium hydroxide solution (d = 1.33), extracting with ether, drying the ethereal solution over anhydrous sodium sulfate and distilling off the solvent under reduced pressure, 2.5 g of the crude base are obtained.

By adding an ethereal hydrochloric acid solution to a solution of the base in acetone, 2.1 g are obtained 3 - methylthio -10 - (3'-diethylaminopropyl) - phenthiazine hydrochloride from 172 ° C.

The 3-methylthio-10- (3'-toluenesulfonyloxypropyl) -phenthiazine can be prepared by the condensation of toluenesulfochloride with 3-methylthio-10- (3'-oxypropyl) -phenthiazine in pyridine. The latter has a Kp. _{0, 06} about 231 to 233 ° C and is, in turn, by acid hydrolysis of 3-methylthio-lO- (3-tetrahydropyranyloxypropyl) -phenthiazins by condensation of 3-tetrahydropyranyloxy-1-chloropropane with 3- Methylthio-phenthiazine was obtained in boiling xylene in the presence of sodium amide.

Using an analogous procedure, 3-methylthio-10- (3 Prepare '-monomethylaminopropyl) -phenthiazine, the acidic oxalate of which melts at 186 C.

Example 7

2.8 g of 3-methylthio-10- (3'-aminopropyl) -phenthiazine, dissolved in 30 ecm of pure dioxane, are with 9.2 ecm of n-salt. acid neutralized. This solution is mixed with 22.1 cm of an aqueous 30% formaldehyde solution and 0.2 g of platinum oxide and the mixture is then stirred vigorously for 48 hours at normal temperature under a weak hydrogen pressure. After the platinum has been removed by filtration and the solvent is evaporated off under reduced pressure, the residue thus obtained is treated with 50 ecm η-hydrochloric acid. The insoluble constituent is filtered off and the acidic solution is made alkaline with sodium hydroxide solution (d = 1.33). After extraction with ether, drying the ethereal solution over sodium sulfate and distilling off the solvent, 0.2 g of 3-methylthio -10- (3'-dimethylaminopropyl) -phenthiazine, the picrate of which melts at 135 ° C., is obtained.

The 3-methylthio-10- (3'-aminopropyl) -phenthiazine used as the starting substance, whose acidic oxalate melts at 198 ° C is obtained by heating 3-methylthio -10- (3 '-toluenesulfonyloxypropyl) -phenthiazine with excess ammonia in' toluene at 110 ° C.

Claim:

Process for the preparation of phenthiazine derivatives of the general formula

SCH ₃

B-T

in which T is a mono- or dialkylamino radical in which the alkyl radicals contain 1 to 5 carbon atoms, or the radical of a cyclic, non-aromatic amine and B a divalent aliphatic Denotes a hydrocarbon radical with a straight or branched chain and 2 to 5 carbon atoms, it being possible for this radical to be substituted by a radical —A - T 'in which A represents a single bond or a methylene radical, and T 'has the meaning of T; as well as from their salts and quaternary ammonium derivatives, characterized in that a 3-methylthiophenthiazine is used the formula

I — SCH,

.with an aminoalkyl halogen compound of the general Formula X - B - T, in which X is a halogen atom and B and T are those given above Have meanings, or that a phenthiazine-10-carboxylic acid ester of the general formula

SCH ₃

COO -B-T

wherein B and.T have the above meanings, by Heating above 100 ° C, preferably to 150 to 220 ° C,

Claims (1)

compared with regard to the narcosis-potentiating, anti-emetic and anti-shock effects. These comparative tests were carried out in the following way: a) Potentiation of the ether anesthesia The product to be examined is administered to the test animal (mouse) subcutaneously in doses of 5, 10 and 20 mg / kg. 30 minutes later, the mice treated in this way are placed in a bell jar in which a certain Amount of ether has evaporated. After anesthesia has occurred, the mice are taken out of the bell and put in place Duration of anesthesia in minutes in the open air. In the case of the comparison substance (product B), an anesthetic duration of 27 minutes is observed in one dose of 20 mg / kg. This duration of anesthesia is taken as the basis, and the other results that are associated with both the substance obtainable according to the invention as well as with the lower doses were obtained with product B, are expressed as a percentage with respect to product B at 20 mg / kg subcutaneously in the table below. b) Antiemetic effect (Method according to G. Chen and Ch. Ensor - Journal of Pharmacology, Vol. 98 [1950], p. 245) The product to be investigated is administered subcutaneously to the test animal (dog) in various doses 30 minutes before the subcutaneous injection of 0.1 mg / kg apomorphine. The mean number of vomiting occurring during 30 minutes after administration of the apomorphine is recorded. The percentage reduction in vomiting, based on the control animals, is determined for each dose and that dose is calculated which causes a 50% reduction in vomiting (DA _50). The results are given in the table below. c) anti-shock effect (Technique according to Noble and Collip - Quarterly Journal of experimental Physiology and cognate Medical Sciences, Vol. 31 [1942], p. 187) Rats are shocked by placing them in metal drums that rotate on their axis at a speed of 40 revolutions per minute. Before the experiment, the rats receive the product to be examined subcutaneously in various doses. The mortality is determined after 720 revolutions of the drums and the dose of product which _{protects 50% of the animals against this mortality (DA 50} in mg / kg) is determined. The results are given in the table below. Test product A. B.
(Comparative
substance) - Ethereal anesthesia
effect
with 20 mg / kg subcutaneously ....
10 mg / kg subcutaneously
5 mg / kg subcutaneously .... 130
75
63 100
63
32 1.
0 /
/O Antiemetic effect
DA ₅₀ in mg / kg subcutaneous ... 0.5 0.5 2. Anti-shock effect
DA ₅₀ in mg / kg subcutaneous ... under
0.125 0.3 3. increases considerably and is very superior, particularly as an anti-shock agent, to the known comparative compound. The following examples illustrate the invention. the Melting points were determined on the Kofler bench. example 1 4.9 g of 3-methylthio-phenthiazine with a melting point of 136 ° C. are added to 0.88 g in 50 ecm of anhydrous xylene for 1 hour Sodium amide heated to the boil. To the suspension ίο of the sodium salt thus obtained, 2.71 g of 3-dimethylamino-1-chloropropane are added, and the boiling is continued for 6 hours. The solution is then treated with water and then with dilute hydrochloric acid. To ₂ by basifying with sodium hydroxide solution, extra renal with ether and evaporation of the solvent under reduced pressure 4.5 g 10- [3-dimethylamino-propyl (1 ')] -3-methylthiophenthiazin that at Kp. _0, about 206 passes to 218 ° C. The corresponding hydrochloride crystallized from a mixture of acetone and ether melts at 160 ^° C. The corresponding picrate crystallized from acetone melts at 135 ° C. The 3-methylthio-phenothiazine is obtained by cyclizing 3-Methylthiodiphenylamin from Kp. _{0, 12} about 160 to 186 ° C and F. 58 ° C "with sulfur. The 3-Methylthiodiphenylamin is in turn prepared by decarboxylation of the 2-carboxy-3 '-methylthiodiphenylamins, mp 140-141 ⁰ C hergesteUt. Example 2 4.9 g of methylthio-phenthiazine and 0.88 g of sodium amide are treated with 3 g of S-dimethylamino ^ -methyl-1-chloropropane for 20 hours heated to boiling in xylene. The suspension obtained in this way is treated as described in Example 1, and finally 4.6 g of 10- [3'-dimethylamino-2'-methyl-propyl- (1 ')] -3-methylthiophenthiazine from m.p. 88 to 89 ° C. The corresponding picrate crystallized from ethanol melts at 145 ° C. ^{+ o} Example 3 4.9 g of 3-methylthio-phenthiazine with a melting point of 136 ° C. are heated to boiling with 0.88 g of sodium amide in 50 ecm of anhydrous xylene for 1 hour. Then 3.94 g of 3- (4'-methylpiperazino) -l-chloropropane, dissolved in 75 ecm of anhydrous xylene, are added and the mixture is refluxed for 4 hours. The solution is then washed with water and extracted with dilute hydrochloric acid. After making alkaline with sodium hydroxide solution, extraction with ether and evaporation of the solvent under reduced pressure, 4.4 g of 3-methylthio-10- [3 '- (4 "-methylpiperazino) propyl] -phenthiazine, which at bp _{0) 1 are obtained} 250 boils to 256 ° C. The crystallized from a mixture of acetone-ether corresponding dihydrochloride melts at 22O ⁰ C (decomposition). The crystallized from a mixture of acetone-isopropanol corresponding Dipikrat melts at 252 to 253 ° C. By analogous procedure can be obtained: 3-methylthio -10 - [2'-dimethylaminopropyl - (1 ')] - Kp phenthiazine from _{0, 2202-206} ° C;. the hydrochloride melts at 205 to 206 ⁰ C, the picrate at 190 ° C; 3-methylthio-10- (3'-pyrrolidinopropyl) -phenthiazin, bp _{0, 9} about 261 ° C. the hydrochloride melts at 161 ° C. It can be seen from these results that the compound obtainable in accordance with the invention increases the duration of anesthesia Example 4 13.7 g of the 3- (4'-methylpiperazino) -2-methyl-propyl ester of 3-methylthio-phenthiazine-10-carboxylic acid, dissolved in 60 ecm of o-dichlorobenzene, 5 hours for Heated to the boil until the evolution of carbon dioxide has ended. After cooling, add 60 ecm of ether, decomposed or that an amine of the general formula H - T, in which T has the above meaning, with a reactive ester of the general formula Already Β '- Υ brings to implementation, where Y is the radical of a reactive ester, such as a halogen atom, or the remainder of a sulfuric acid or sulfonic acid ester and B 'a divalent aliphatic carbon 10 denotes a hydrogen radical with a straight or branched chain and 2 to 5 carbon atoms and wherein the radical B 'can optionally be substituted by a radical - A - T' or --A - Y ', in which Y' has the meaning of Y and the other symbols have the meanings given, or that the primary or secondary amines corresponding to the formula I by processes known per se alkylated. Considered publications:
German Patent Nos. 825 993, 910 301, 345; German patent application B 28 060 IVb / 12 (published on August 25, 1955); Swiss Patent No. 298 685.