DE1445629C - New piperazine derivatives - Google Patents

Description

The invention relates to piperazine derivatives in general Formula I.

C-N N-R

(I)

results

wherein R is a hydrogen atom, a hydroxyethyl group or a lower alkyl group and R ₁ and R _{2 are} methyl or ethyl radicals, and their salts.

For R standing alkyl radicals are, for. B. methyl, ethyl or propyl radicals.

The new compounds have valuable pharmacological, especially anti-inflammatory and antiallergic properties. So they suppress z. B. in rats, guinea pigs and rabbits inflammatory Processes and allergic reactions. They can be used accordingly as anti-inflammatory drugs and Antiallergic drugs are used. They are also valuable intermediate products for the production of further, especially pharmacologically applicable substances.

Particularly noteworthy for their anti-inflammatory effect are 5- (dimethylsulfamyl) -anthranilic acid- (N'-methyl-piperazide) and its salts.

5- (Dimethylsulfamyl) anthranilic acid (N'-methylpiperazide) hydrochloride (A), 5 - (diethylsulfamyl) anthranilic acid (N '- methylpiperazide) hydrochloride), 5- (dimethylsulfamyl) anthranilic acid [ N '- (ß - hydroxyethyl) - piperazid] - hydrochloride (C),' the 5 - (dimethylsulfamyl) - anthranilic acid - (N '- isopropylpiperazid) methanesulfonate, F. 266 to 268 ° C (D) and the 5 - (Dimethylsulfamyl) - anthranilic acid (N '- butylpiperazid) - methanesulfohate, mp 238 to 240 ° C (E) were tested with the well-known 4-butyl-1,2-diphenyl-3,5- with regard to their anti-inflammatory effect and toxicity. pyrazolidinone (F) compared.

method

Exudative pleurisy was reported in male rats based on Spector (Journ. Path. Bact., 72 [1956], 367) by injecting 0.1 ml of turpentine into the right pleural cavity. The to compounds tested were given 30 minutes prior to turpentine injection s.c. or 60 minutes before the turpentine injection given by gastric tube. There were 5 to 10 animals per dose and substance for use. Fifteen rats injected only with turpentine served as controls. 3 hours after After the turpentine injection, the volume of the pleural exudate was determined. Compared to controls the amount of exudate by the examined preparations was given as in the following table decreased.

Ver
5 bond A. [ B. I. 25th F 30th Anti-inflammatory
dose
mg / kg effect
Inhib
effect
% Toxicity in the rat
LD ₅₀ mg / kg > l'000p. 0. **) 1 ^C {
20 I. 30 s. C. 28 |> 6,000p. 0. 10 D. 50 s. C, 33 1'8OO p. 0. E. 70 s. C. 45 3'00O p. 0. 100 s. C. 56 100 p. 0. 33 30 s. C. 42 100 s. C. 65 300 p. 0. 28 Ϊ 3'300 p. 0. 100 p. 0.
300 p. 0. 18th
29 300 p. 0. 28 • 300 p. 0. 49 ' 1 • 500 p. 0. 100 s. C. 11th 200 s. C. *) 48 100 p. 0. 18th 200 p. 0. 31 300 p! 0. 44

*) Sub-toxic, with side effects. (Convulsions) associated

Dosage.
**) Not a single rat was killed up to 1000 mg / kg.

Conclusion

Compound A is more effective and more tolerable than the comparator preparation F. Compound B has s.c. a much greater effect than compound F. Bei When administered orally, the potency of compound B is slightly more than half that of F, while the toxicity of F is more than twice that of compound B. Compounds C and D are much less toxic, with a slightly weaker potency than the comparative compound F. Compound E is very much less with similar effectiveness more toxic than the comparison compound F.

Compounds A to E are consequently superior to compound F.

The compounds of general formula I and their salts are obtained if one is known per se Way either

. a) a 5- (dialkylsulfamyl) anthranilic acid of the general formula II

C-OH

N-SO

NH - R '

wherein R 'represents a hydrogen atom or an acyl test, or a reactive functional derivative such an acid or an internal anhydride

an acid of the general formula II, in which R 'represents an acyl group, with a piperazine of the general type Formula III

Η —Ν

(III)

in which R has the meaning given, and converts it into compounds obtained which contain an acylamino radical in the 2-position, or converts _{this into the NH 2 group by hydrolysis}

b) a benzoic acid piperazide of the general formula IV

NO

(IV)

20th

wherein X is a halogen atom, reacts with ammonia or

c) in a benzoic acid piperazide of the general formula V

N-SO-

NO

(V)

30th

35

where Y is a nitro or azo group, Y is _{reduced to the NH 2} group or

d) in a benzoic acid piperazide of the general formula VI

Q

C-N N -R

NH-acyl ^(VI)

N —SO,

45

the radical —NH — acyl is converted into the NH ₂ group by hydrolysis and, if appropriate, then the free bases obtained are converted into the free bases with acids and their salts or the salts obtained are converted into the free bases with basic agents.

In procedure a) reactive functional derivatives of the to be mentioned as starting materials Acids of the general formula II are, for example, their halides, such as chlorides or bromides, anhydrides, mixed anhydrides, e.g. B. with carbon monoalkyl esters, such as carbon monoethyl or isobutyl ester, or internal anhydrides, e.g. B. those of N - acyl - 5 - (dialkylsulfamyl) - anthranilic acids, d. H. corresponding 6- (dialkylsulfamyl) -4-H-3, l-benzoxazin-4-ones, e.g. B. internal anhydrides of N-acetyl-5- (dialkylsulfamyl) anthranilic acids or 5- (dialkylsulfamyl) -isatoic anhydrides, or esters, e.g. B. alkyl or aralkyl esters, such as methyl, ethyl or benzyl esters or activated esters such as cyanomethyl esters, amides or azides.

The compounds mentioned are reacted with a piperazine of the general formula III primarily in the presence of a solvent or diluent, in the presence or absence of Reaction accelerators, at room temperature or preferably at elevated temperature, if necessary, in a closed vessel under pressure and / or under an inert gas, e.g. B. nitrogen. Possibly one uses condensing agents, z. B. when using the free acid carbodiimides, such as dicycloalkyl-carbodiimides. If one starts with internal anhydrides of N- (a-hydroxyalkyl) -5- (dimethylsulfamyl) -anthranilic acids off, the hydroxyalkyl group is split off in the reaction. If you go from the inside Anhydrides of N-acyl-5- (dialkylsulfamyl) -anthranilic acids, the reaction conditions can be as follows choose that the acyl radical is split off at the same time.

In procedures a) and d), the hydrolysis is advantageously carried out in the presence of alkaline substances Means.

, In the starting materials of the general formula IV, a halogen atom X is, for example, a chlorine, Bromine or iodine atom.

The reduction according to procedure c) can, for. B. with nascent hydrogen (e.g. with iron and hydrochloric acid or with aluminum amalgam) or with catalytically excited hydrogen, such as hydrogen in The presence of platinum, nickel or palladium catalysts can be carried out. '

Depending on the process conditions and starting materials, the end products are obtained in free form or in the form of their salts also included in the invention. For example, basic, neutral, acidic or mixed salts, optionally also hemi-, mono-, sesqui- or polyhydrates thereof can be obtained. The salts of the end products can in a manner known per se, for. B. with alkalis or Ion exchangers, are converted into the free bases. The latter can be broken down by implementation with organic or inorganic acids, especially those that are used to form therapeutically usable salts are suitable. Win salts. Examples of such acids are: hydrohalic acids, sulfuric acids, phosphoric acids, Nitric acid, perchloric acid; aliphatic, alicyclic, aromatic or heterocyclic carbon or Sulfonic acids such as formic, vinegar; Propion, "amber, glycol, milk, apple, wine, lemon, Ascorbic, maleic, hydroxymaleic or pyruvic acid; Phenylacetic, benzoin, p-amino-benzoin, Anthranil, p-hydroxy-benzoic, salicylic, p-amino-salicylic acid, Methanesulfonic, ethanol sulfonic, hydroxyethane sulfonic, ethylene sulfonic acid; Halobenzenesulfone, Toluenesulfonic, naphthalenesulfonic or sulfanilic acid; Methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds, such as the picrates, can also be used to purify the obtained Bases are used by converting the bases into salts, separating them and in turn liberating the bases from the salts.

The starting materials are known or, if they are new, they can be based on known ones Establish methods.

The new compounds can be used as remedies, e.g. B. in the form of pharmaceutical preparations, use find which they or their salts in mixture

with one for enteral, parenteral or topical Application of suitable pharmaceutical organic or inorganic, solid or liquid carrier material contain. For the formation of the same such substances come into question that with the new compounds do not respond, e.g. B. water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, Gum, polyalkylene glycols, petrolatum, cholesterol, or other known excipients. The pharmaceutical preparations can, for. B. as tablets, coated tablets, ointments, creams or in liquid form Form as solutions, suspensions or emulsions. If necessary, they are sterilized and / or or contain auxiliaries such as preservatives, stabilizers, Wetting or emulsifying agents, salts to change the osmotic pressure or buffers. They can also contain other therapeutically valuable substances. The preparations, which are also in the Veterinary medicine are to be used, are obtained by conventional methods.

The following examples illustrate the invention. The temperatures are given in degrees Celsius.

example 1

A solution of 57.3 g of 5- (dimethylsulfamyl) -2-nitro-benzoic acid- (N'-methyl-piperazid) in 2500 ml of ethanol is shaken in the presence of 20 g of nickel catalyst in a hydrogen atmosphere for so long until the theoretical amount of hydrogen is consumed. The catalyst is then filtered off, the filtrate evaporates to a volume of 150 ml and this is mixed with petroleum ether. This is where it falls 5 - (Dimethylsulfamyl) - anthranilic acid - (N '- methylpiperazid) of the formula

CH,

CH,

NO ₂ S

N-CH,

The catalyst was filtered off and the filtrate was evaporated in vacuo. After recrystallization of the residue 5- (Dimethylsulfamyl) -anthranilic acid- [N '- (/? - hydroxyethyl) -piperazid] is obtained from ethanol-petroleum ether the formula

in the form of white crystals; F. 151 to 152 °. Obtained by reacting the same with alcoholic hydrochloric acid one the monohydrochloride; F. 280 to 282 °.

The starting material can be prepared as follows: A solution of 109 g of 5 - (dimethylsulfamyl) - 2 - nitro - benzoic acid chloride in 300 is added dropwise with stirring to a solution, cooled to 10 °, of 80 g of N-methylpiperazine in 800 ml of absolute dioxane ml of absolute dioxane. The reaction mixture is stirred for a further 5 hours at room temperature, water and saturated sodium carbonate solution are then added and it is extracted with chloroform. The water-washed organic phase is dried with magnesium sulfate and evaporated in vacuo to ^s. The solid residue is recrystallized from ethanol-petroleum ether. 5- (Dimethylsulfamyl) -2-nitro-benzoic acid (N'-methyl-piperazide) is obtained; F. 170 to 172 °.

B e i s ρ i e 1 2

A solution of 10 g of 5- (dimethylsulfamyl) -2-nitro-benzoic acid [N '- (/ 9-hydroxyethyl) piperazide] in 100 ml of ethanol is hydrogenated in the presence of 1 g of nickel catalyst. After consuming the theoretical Amount of hydrogen becomes the solution of CH

CH

N-CH, -CH, -0H

in the form of colorless crystals; F. 98 to 100
Monohydrochloride melts at 245 to 247 °.

The starting material can be prepared as follows: To a solution cooled to 0 ° of 9 g of N- (ß-hydroxyethyl) piperazine in 100 ml of toluene a solution of 10 g of 5- (dimethylsulfamyl) -2-nitro-benzoic acid chloride is added dropwise with thorough stirring in 50 ml of toluene. After stirring for 3 hours at room temperature, filtered the excreted substance is removed, stirred with dilute soda solution and filtered off again. After drying, they are crystallized from ethanol. 5- (Dimethylsulfamyl) -2-nitro-benzoic acid [N '- (/? - hydroxyethyl) piperazide] is obtained; F. 138 to 139 °.

Example 3

14.7 g of 5- (diethylsulfamyl) -2-nitro-benzoic acid (N'-methyl-piperazide) are dissolved in 500 ml of ethanol and hydrogenated in the presence of 1 g of palladium carbon until the hydrogen uptake has ceased. The catalyst is then filtered off, evaporated in vacuo and the residue is crystallized out Ethanol — petroleum ether. The 5- (diethylsulfamyl) thus obtained - anthranilic acid - (N '- methylpiperazid) der

40 formula

.. O

NO ₂ S

C ₂ H ₅

N-CH,

melts at 144 to 145 °. The hydrochloride melts at 265 °.

The 5- (diethylsulfamyl) used as starting material - 2 - nitro - benzoic acid - (N '- methylpiperazid) can be prepared as follows: 74 g 5- (chlorosulfonyl) -2-nitro-benzoic acid are poured into a solution of 280 mJ in portions with stirring Diethylamine registered in 700 ml of water. Mari "stirs another 4 hours, then adds activated charcoal) added, filtered off and acidified with concentrated hydrochloric acid while cooling with ice. The eliminated sub punch is recrystallized after drying from ethyl acetate or benzene and melts at 141 to 142 ° 35 g of the 5- (diethylsulfamyl) -nitro-benzoic acid thus obtained are boiled for 3 hours at 300 m Thionyl chloride, evaporation and recrystallizer from benzene petroleum ether into the 5- (diethylsulfamyl) 2-nitro-benzoyl chloride converted; F. 69 to 70 ° A solution of 15 g of this acid chloride in 30 m absolute dioxane is cooled to 10 ° in a «

Solution of 8 g of N-methyl-piperazine in 100 ml of absolute Dioxane entered with stirring. The mixture is stirred for a further 3 hours at room temperature then with water and soda solution, extracted with chloroform, the chloroform solution was washed with water and, after drying over magnesium sulfate, evaporated in vacuo. The residue will be off Recrystallized ethanol petroleum ether. This gives 5- (diethylsulfamyl) -2-nitro-benzoic acid (N'-methyl-piperazide); F. 95 to 96 °.

Example 4

A solution of 8 g of 5- (dimethylsulfamyl) -2-nitrobenzoic acid- (N'-ethyl-piperazide) hydrogenated with hydrogen in 200 ml of ethanol in the presence of 1 g of palladium-carbon (10%). After the uptake of hydrogen has ended, the catalyst is filtered off and the mixture is evaporated the solution in a vacuum and the residue crystallizes from ethanol-petroleum ether, the 5- (dimethylsulfamyl) - anthranilic acid - (N '- ethyl - piperazid) the formula

NC ₂ H ₅

CH ₃

is obtained in the form of white crystals; F. 150 to 151 °. The hydrochloride melts at 266 to 267 °.

The 5- (dimethylsulfamyl) required as starting material - 2 - nitro - benzoic acid - (N '- ethyl - piperazid), mp 150 to 151 °, can be obtained by reacting 5- (dimethylsulfamyl) -2-nitrobenzoyl chloride with N-ethylpiperazine in absolute dioxane in the presence of. Triethylamine can be obtained.

. . B e i s ρ ie I 5

3.2 g of anhydro- [N-acetyl-5- (dimethylsulfamyl) anthranilic acid] [6 - dimethylsulfamyl) - 2 - methyl-4H-3, l-benzoxazin-4-one] are in the presence of 10 ml of N-methyl-piperazine refluxed for 16 hours. It is evaporated in a vacuum and takes up the residue in 2η hydrochloric acid. After about 30 minutes the hydrochloric acid layer will be with Made ammonia alkaline and extracted with methylene chloride. The residue is made from ethanol-petroleum ether recrystallized. This gives 5- (dimethylsulfamyl) - anthranilic acid - (N '- methyl - piperazid); M.p. 151 to 152 °, which is identical to the product obtained in Example 1.

The Ärihydro- [N-acetyl-5- (dimethylsulfamyl) -anthranilic acid] used as starting material can be prepared as follows: 4.5 g of 5- (dimethylsulfaemyl) anthreneic acid are heated to 100 to 105 ° for 2 hours in the presence of 20 ml of acetic anhydride. It is cooled to room temperature and the precipitated crystals are filtered off, which are at 186 to 188 ° melt, off. The crude product thus obtained can be used directly for the above-mentioned reaction will. .

Example 6

2 g of 5- (Dimethyisulfamyl) -isatoic acid anhydride in the presence of 20 ml of N-methylpiperazine Boiled under reflux for 16 hours. It is then evaporated in vacuo, the residue is taken in 2N hydrochloric acid and extracted with ethyl acetate. The hydrochloric watery layer becomes alkaline with ammonia placed and extracted with methylene chloride. The solid residue is made from ethanol-petroleum ether recrystallized. This gives 5- (dimethylsulfamyl) anthranilic acid (N'-methyl-piperazide); M.p. 151 to 152 °, which is identical to the products described in Examples 1 and 5.

The 5- (dimethylsulfamyl) -isatoic acid anhydride used as the starting material can be prepared as follows: 15 g of 2-amino-5- (dimethylsulfamyl) benzoic acid are refluxed for 40 hours in the presence of 90 ml of ethyl chloroformate cooked. It is cooled and the precipitated crystals, mp 215-216 °, filtered off, which as can be processed immediately above.

B e i s ρ i e 1 7

12 g of sodium hydroxide are dissolved in 200 ml of water, the solution is cooled to an internal temperature of about 20 °, then 50 g of N-acetyl-5- (dimethylsulfamyl) anthranilic acid (N'-methylpiperazide) are added while stirring and the mixture is diluted with 50 ml of water. The mixture is stirred for 24 hours at the same temperature, the starting material slowly going into solution, and after a few hours the end product gradually begins to crystallize. The precipitated first base portion is suction filtered and washed with 25 ml of water. and dried at 70712 mm Hg. The filtrate is stirred for a further 24 hours at the same temperature, a second base portion crystallizing out, which is isolated as above. For cleaning, the two parts are dissolved in 180 ml of toluene at boiling temperature, treated with activated charcoal, filtered hot and cooled to -10 ° for 1 to 2 hours. The pale yellow crystals are filtered off with suction, washed with a little cold toluene and dried as above. This gives 5- (dimethylsulfamyl) -anthranilic acid- (N'-methyl-piperazide) with a melting point of 150 ° to 152 °, which is identical to the product described in Example 2. . ^: ·

The required starting compound was prepared as follows: 200 g of anhydro- [N-acetyl-5- (dihiethylsulfamyl) anthranilic acid are heated to boiling with stirring in 1.5 l of absolute toluene and within 1 hour with a solution of 82 g of anhydrous N-methylpiperazine in 500 ml of absolute toluene slowly offset. After the addition, the solution is heated to boiling for a further 10 hours, the N-acetyl-S-idimethylsulfamylJ-anthrahilic acid-iN'-me: thylpiperazid) of the formula

CH,

CH,

N-- O, S

gradually ae-crystallized. Then the Mixture cooled and held at -10 to 5 ° for one hour. The crystallized product is suction filtered, washed twice with 0.11 absolute toluene and dried at 70 ° / vacuum. The Product melts at 192 to 194 °.

Example 8

Tablets containing 300 mg of 5- (dimethylsulfamyl) -anthranilic acid- (N'-methylpiperazid), can e.g. B. be produced in the following composition:

5- (dimethylsulfamyl) -anthranil-

acid- (N'-methyl-piperazid) 300 mg

Wheat starch 95 mg

Aerosil comp 22 mg

Maranta starch 19 mg

Magnesium stearate 2 mg

Talc 12 mg

450 mg alcohol 70% q.s.

The active ingredient, wheat starch and Aerosil comp, will be mixed well and moistened with so much 70% alcohol that a weakly plastic, well granulated ready-to-use Mass arises. .

The mixture is passed through a sieve with a mesh size of about 2 mm and then at 45 ° dried (residual moisture 1%). The granules obtained in this way are reduced to an average grain size of about 0.5 mm and mixed with maranta starch, magnesium stearate and talc. From this mixture 450 mg tablets are pressed in the usual way.

Claims (4)

Claims: .. 1. Piperazine derivatives of the general formula I, C-N N-R N-SO ₂ R, (I) wherein R is a hydrogen atom, a hydroxyethyl group or a lower alkyl group and R ₁ and R _{2 are} methyl or ethyl groups, and their salts. 2. 5- (Dimethylsulfamyl) anthranilic acid (N'-methylpiperazide) and its salts. 3. Process for the preparation of piperazine derivatives according to Claim 1, characterized in that that in a known manner either a) a 5- (dialkylsulfamyl) anthranilic acid of the general formula C-OH Ν —SO, NH-R 40 45 55 60 wherein R 'denotes a hydrogen atom or an acyl radical, or a reactive functional one Derivative of such an acid or an internal hydride of an acid of the general formula II, in which R 'represents an acyl group, with a Piperazine of the general formula III NO (III) in which R has the meaning given, and at the same time converts it into compounds obtained which contain an acylamino radical in the 2-position, or converts _{this into the NH 2 group by hydrolysis} b) a benzoic acid piperazide of the general formula IV N - SO- wherein X is a halogen atom, reacts with ammonia or c) in a benzoic acid piperazide of the general formula V N — SO NO (V) wherein Y is a nitro or azo group, Y is _{reduced to the NH 2} group or d) in a benzoic acid piperazide of the general formula VI Os C-N NO R ₁ \ NH-acyl ^(VI) the radical —NH — acyl is converted into the NH ₂ group by hydrolysis and, if appropriate, then the free bases obtained are converted into their salts with acids or the salts obtained are converted into the free bases with basic agents. 4. A pharmaceutical preparation consisting of one of the claims 1 and 2 mentioned Piperazide or a non-toxic salt thereof and common diluents and / or carriers.