DE2259491A1 - NEW ALPHA-AMINOPROPIONYLPHENTHIAZINE DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION - Google Patents

Description

Dr. F. Zumsteln sen. - Dr. E. Assmann 2259491 Dr. R. Koenlgsberger - Dlpl.-Phys. R. Holzbauer - Dr. F. Zumsteln Jun,

PATENT LAWYERS

TELEPHONE: COLLECTIVE NO. 225341

TELEX 529979

TELEGRAMS: ZUMPAT CHECK ACCOUNT: MUNICH 91139

BANK ACCOUNT: BANK H. HOUSES

8 MUNICH 2.

BRÄUHAUSSTRASSE 4 / III

97 / N

Cas Hd-1499 / D

• ROUSSEL-UCLAP, Paris / France

New a-aminopropionylphenthiazine derivatives and methods of making them

The invention relates to new α-aminopropionylphenthiazine derivatives of the general formula I.

wherein X is chlorine, methoxy or trifluoromethyl, and their acid addition salts.

The acid addition salts can be, for example, the salts formed with hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, alkanesulfonic acid and arylsulfonic acid.

309830/1167

The compounds of general formula I and their addition salts with pharmaceutically acceptable acids are very valuable remedies for human medicine, in particular due to their considerable spasmolytic, anti-ulcer and analgesic properties.

They can therefore be used in particular to treat spasms of the digestive tract, duodenal and gastric ulcers, used to treat chronic gallbladder inflammation and various pain conditions.

The usual dose may, depending on the product used, the patient treated and the disease in question, e.g. between 10 mg and 500 mg per day for oral Administration to humans.

The invention also relates to pharmaceutical compositions, the active ingredient one or more compounds of general formula I and / or their addition salts with pharmaceutically acceptable acids.

The compositions can be solid or liquid and in the pharmaceutical forms used in human medicine, such as, for example, in the form of simple or sugar-coated tablets, gel beads, granules, suppositories, injectable preparations, ointments, creams and gels. They are produced according to the usual methods.

The active ingredient (s) can usually be used in these binders used in pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, fatty substances of animal or vegetable origin, paraffin derivatives, Glycols, various plasticizers, dispersants or emulsifiers and preservatives can be incorporated.

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The invention also relates to a process for the preparation of the compounds of the general formula I and their addition salts with acids, which is characterized in that a phenthiazine of the general in a solvent Formula II

II

wherein X has the meaning given above, reacts with α-chloropropionyl chloride, the compound thus obtained of the general formula III

III

wherein X has the meaning given above, in the presence of a solvent with diethylamine to boiling (under reflux) heated in order to obtain the compound of the general formula I and, if necessary, allowed to act on it with acid, to make the appropriate salt. .

The method according to the invention can advantageously be carried out as follows be performed.

The mixture is heated in an anhydrous solvent, such as anhydrous toluene,. The phenthiazine of the formula II with α-chloropropionyl chloride 2 to 5 hours under reflux and heated in an anhydrous solvent such as anhydrous toluene, the product of the general formula III obtained with diethylamine for 1 to 4 hours under reflux.

3098 30/1167 ...

The acid addition salts of the compounds of the general formula I can advantageously be prepared by one on the compounds of general formula I the corresponding mineral acids or organic acids in the presence a solvent allowed to act.

The following new intermediate compounds can be prepared by the process of the invention:

2-chloro-10- (a-chloropropionyl) -phenthiazine, 2-methoxy-10- (a-chloropropionyl) -phenthiazine and 2-trifluoromethyl 1-10- (a-chloropropionyl) -phenthiazine.

The following examples illustrate the invention without, however, restricting it.

example 1

2-chloro-10- (g-diethylaroinpropionyl) -phenthiazine hydrochloride

A. 2-chloro-10- (a-chloropropionyl) -phenthiazine

50 g of 2-chlorophenthiazine are added to 200 ml with stirring anhydrous toluene, and then 30 g of α-chloropropionyl chloride are added dropwise. Then you heat slightly, to start the reaction and then reflux for 4 hours with constant stirring. At the end the reaction are toluene and excess α-chloropropionyl chloride removed under reduced pressure. The residue obtained is taken in absolute isopropanol in the presence of activated charcoal and heated to boiling for 10 minutes. It is filtered and then what is obtained is left The filtrate stand in the cold for 12 hours. The precipitate formed is filtered off with suction and crystallized from absolute Isopropanol. 52 g of 2-chloro-10- (a-chloropropionyl ) -phenthiasin from F = 102 to 104 ° C.

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225949T

O -,

Analysis; C ₁₅ H ₁₁ Cl ₂ NOS Molecular Weight: 324.22.

Calculated: C 55.5 7 H 3.42 %
Found: 55.75 3.54%

B. 2-chloro-10- (g-diethylaininopropionyl) -phenthiazine hydrochloride

26 g of 2-chloro-10- (a-chloropropionyl) -phenthiazine are added to 80 ml of anhydrous toluene and 12.5 g of diethylamine, this mixture is refluxed for about 2 hours and After cooling, the mixture is filtered in order to separate off the diethylamine hydrochloride formed. It is extracted the collected filtrate first with 100 ml of an aqueous 5% hydrochloric acid solution and then again with 50 ml of an aqueous 5% hydrochloric acid solution. The collected acidic extracts are heated to 50 ° C. for 20 minutes in the presence of activated charcoal. Man removes the latter by filtration and makes the filtrate alkaline with a 40% sodium hydroxide solution. It a viscous mass forms. The solution is decanted, the residue is taken up in toluene and the dried Toluene solution over dry disodium sulfate. It is filtered and a stream of dry hydrogen chloride is passed through the filtrate, until the formation of the precipitate ceases'. After a few hours of storage in the cold, the formed Sucked off precipitate, washed with ether and recrystallized from an ethanol / ether mixture. 7 g of 2-chloro-10- (a-diethyla'minopropionyl) -phenthiazine hydrochloride are obtained in the form of white crystals from F = 223 to 225 ° C.

12 ± ^C 19 ^H 22 ^C1 2 ^rJ 2 ^OS Molecular weight: 397.36

"Calculated: C 5 7.43 H 5.58%
Found: 5 7.17 5, 84 %

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Example 2

2-methoxy-10- (α-diethylaminopropionyl) -phenthiazine

A. 2-Methoxy-10- (g-chloro propionyl ) -phenthiazine

While stirring, 22.9 g of 2-methoxyphenthiazine are introduced into 120 ml of anhydrous toluene and then 14.6 g of α-chloropropionyl chloride are added dropwise. One heats slightly to initiate the reaction and then refluxed with stirring for 4 hours. After completion of the implementation are toluene and excess α-chloropropionyl chloride removed under reduced pressure. The residue obtained is in the presence of activated carbon in absolute Isopropanol added and heated to boiling for 20 minutes. It is filtered and then the filtrate is left stand. The precipitate formed is filtered off with suction and recrystallized from isopropanol. 32 g of 2-methoxy-10- (a-chloropropionyl) -phenthiazine are obtained in the form of a pale green colored crystalline powder.

AnaTy_sej_ C ₁₆ H ₁₄ O ₂ NClS Molecular weight: 319.79 Calculated: C 60.17 H 4.66%
Found: 60.09 4.41%

B. 2-methoxy-10- (g-diethylaminopropionyl) -phenthiazine

12.8 g of 2-r-ethoxy-10- (a-chloropropionyl) -phenthiazine are added to 60 ml of anhydrous toluene and 6.2 g of diethylamine, the mixture heated under reflux for 2 hours and filtered after cooling, the mixture in order to separate off the diethylamine hydrochloride formed, then the filtrate is extracted with it 100 ml of an aqueous 5% hydrochloric acid solution. The acidic filtrate is then heated to 50 to 60 ° C. in the presence of activated charcoal for 20 minutes. One removes the Activated carbon by filtration and makes the resulting filtrate alkaline with a 40% sodium hydroxide solution. It educates a viscous mass. After standing in the cold for 1 hour, it is extracted twice with 100 ml of ether. The extracts are concentrated and the residue

309830/1167

is made with boiling ethanol in the presence of activated charcoal recorded. It is filtered, concentrated and the product obtained is recrystallized from ethanol. You get 3 g of 2-methoxy-10- (a-diethylaminopropionyl) -phenthiazine in the form of a white powder of F = 94 C.

Analysis: C ₂₀ H ₂₄ NpO ₂ S Molecular weight: 356.47 Calculated: C 6 7.38 H 6.78%
Found: 6 7.90 7.00%

Example 3 -

2-trifluoromethyl-10- (a-diethylaminopropionyl) -phenthiazine hydrochloride

A. 2-Trifluoromethyl-10- (g-chloropropionyl) ~ phenthiazine

40.08 g of 2-trifluoromethylphenthiazine are added with stirring to 120 ml of anhydrous toluene and then 21.9 g of α-chloropropionyl chloride are added dropwise. One heats slightly to get the implementation going, and then get under touching Heated to reflux for hours. At the end of the reaction, toluene and excess α-chloropropionyl chloride are added removed under reduced pressure. The residue obtained is in absolute isopropanol in the presence of Activated charcoal was added and heated to boiling for 20 minutes. It is filtered and the collected filtrate is concentrated. 35 g of 2-trifluoromethyl-10- (u-chloropropionyl) -phenthiazine are obtained in the form of a greenish oil sauce

Analysis: C ₁₆ H ₁₁ ClF ₃ NOS Molecular Weight: 357.77

Calculated: C 54.08 H 3.80%
Found: 53.71 3.09 %

B. 2-Trifluoromethyl-10- (g-diethylaminopropionyl) -pnenthiazine hydrochloride

22 g of 2-trifluoromethyl-10- (u-chloropropionyl) -phenthiazine are added to 9 _{S 5 g of diethylamine and 80 ml of anhydrous toluene,}

3 0 9 8 3 0/1167.; ·.,

22i> 9491

heated the mixture to reflux for 3 hours and, after cooling, filtered the mixture to remove the formed Separate diethylamine hydrochloride. The collected filtrate is extracted with 100 ml of an aqueous 5% hydrogen chloride acid solution. The acidic extract is used for 20 minutes heated to 50 to 60 ° C. in the presence of activated charcoal. The solution is filtered and the filtrate is left during Stand for hours. The crystalline precipitate formed is filtered off with suction and recrystallized four times from ethanol. 2.5 g of 2-trifluoromethyl-10- (u-diethylaminopropio - nyl) -phenthiazine hydrochloride in the form of a white powder from F = 200 to 2O2 ° C.

Analysis; C ₂₀ H ₂₂ ClF ₃ N ₂ OS Molecular weight: 430.91 Calculated: C 55.74 H 5.14% Found: 54.81 5.37 %

Manufacture of pharmaceutical compositions

1. Tablets are made containing:

2-chloro-10- (a-diethylaminopropionyl) -phenthiazine hydrochloride 25 mg

Binders (lactose, starch, talc, ma

magnesium stearate) quantum satis for one tablet

2. Tablets are made containing:

2-Trifluoromethyl-10- (a-diethylaminopropionyl) -phenthiazine hydrochloride 25 mg

Binders (lactose, starch, talc, magnesia thi arat) quantum satis for one tablet

3 »Men makes tablets containing:

2 —i-ie tr κ ->; y-- 1.0— ί u — ciii rhy 1 aniinopr cρ i ony I) -

pht-Ruhio ,: in 25 rug

bindsiiiit tvJ (lactose, starch, Te Ik urn, i-magnesium stearate) quantum satis for a tablet

J 0 9 -rf! I Ij / lib ¹ /

Claims (7)

Claims / l / O α-aminopropionylphenthiazine derivatives of the general Formula I. .CQ-CH-H ^ ° 2 ^H 5 (I) wherein X is chlorine, methoxy or trifluoromethyl, as well as their acid addition salts. 2.) 2-chloro-10- (a-diethylaminopropionyl) -phenthiazine hydrochloride. 3.) 2-Trifluoromethyl-10- (a-diethylaminopropionyl) -phenthiazine hydrochloride. 4.) 2-Methoxy-10- (ü: diethylaminopropionyl) -phenthiazine. 5.) Process for the preparation of the compounds according to claim 1, characterized in that one is in the presence of a solvent is a phenthiazine of the general formula wherein X has the meaning given in claim 1, reacts with α-chloropropionyl chloride, the thus obtained Compound of the general formula 309830/1 167 CO-CH-Gl CH _x wherein X has the meaning given above, heated to boiling in a solvent with diethylamine to obtain the desired compound of general formula I according to claim 1, and optionally to the Compound allows an acid to act to form the corresponding salt. 6.) Pharmaceutical compositions containing at least a compound according to the general formula I according to claim 1 or at least one of its addition salts with pharmaceutically acceptable acids as active ingredients. 7.) Compounds of the general formula CO-CH-Cl CH, wherein X is chlorine, methoxy or trifluoromethyl. 309830/1167