CH558784A - Sulphonanilides - Google Patents

Abstract

(A) Sulphonanilides of general formula (I) and their pharmaceutically acceptable salts. X = H, OH, NH2, (is not >4C) alkyl or alkoxy, benzyloxy, halogen, or -NH.O2S.R2 R1 and R2 = same or different (is not >4C) alkyl, Ph (opt. subst.) Z = or Alk. = (is not >4C) alkylene (is not >2C between Z and N. The Ph substituent may be ( is not >4C) alkyl or alkoxy, benzyloxy, or halogen. = N subst. heterocycle ( is not >7C) group or N subst. ( is not >11C) heteropolycyclic group or R4 = H, ( is not >4C) alkyl, or benzyl R5 = H, (is not >10C) alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, polycycloalkyl polycycloalkenyl, polycycloalkylalkyl, polycycloalkenylalkyl, aryl, aralkyl, aralkenyl, aryloxyalkyl, heterocyclic, heterocycloalkyl, heteropolycyclic, or heteropolycycloalkyl. R5 contains up to 10 carbon atoms apart from any substituents attached thereto, of which there may be one or two selected from hydroxy, carboxy, amino, lower alkoxy, benzyloxy, halogen, lower alkyl, R2SO2NH, or methylenedioxy. X and Z may be o-, m- or p- to -NHSO2R1 and adjacent or not.

Description

  

  
 



   The invention relates to a process for the preparation of sulfonanilides of the formula
EMI1.1
 or salts thereof, which is characterized in that a compound of the formula II
EMI1.2
 with a compound of the formula III
EMI1.3
 is implemented, where in the formulas mean:
A = halogen,
X = hydrogen, hydroxy, nitro, lower alkoxy, benzyloxy, halogen, lower alkyl or R2SO2NH-, R1 and R2 = lower alkyl, phenyl or substituted phenyl, whose substituents are lower alkyl groups, halogen, lower alkoxy or benzyloxy,
Z => C = O or> CHOH,
R3 = hydrogen, methyl or ethyl,
R4 = hydrogen, lower alkyl or benzyl,
R5 = hydrogen, optionally hydroxy-substituted lower alkyl, a ring-substituted or ring-unsubstituted aralkyl or

  Aryloxyalkyl group, where the ring substituents are hydroxy, chlorine, methoxy, methanesulfonamido or methylenedioxy and the ring-substituted or ring-unsubstituted aralkyl or aryloxyalkyl groups have up to 10 carbon atoms; also alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkenyl, a heterocyclic group or

   heterocyclically substituted alkyl groups with up to 10 carbon atoms, not including any ring substituents present, which are carboxy, amines, lower alkoxy groups with at least 2 carbon atoms, benzyloxy, lower alkyl groups, groupings of the formula R2SO2NH- or halogen and where the lower alkyl and Lower alkoxy groups have up to 4 carbon atoms, and
EMI1.4
 also represents a heteromonocyclic group with 6 or 7 carbon atoms or a heteropolycyclic group with up to 11 carbon atoms.



   The compound thus obtained can, if Y is a nitro group, be converted into an amino group by catalytic hydrogenation or chemical reduction, and the product thus obtained can optionally be brought into contact with an acid or base to form an acid addition salt or metal salt.



   Examples of Rs substituents in the compounds obtainable according to the invention are as follows:
EMI1.5
 The term lower alkyl radicals and lower alkoxy radicals are understood to mean radicals with up to 4 carbon atoms. The groupings
EMI1.6
   and X can be in the o-, m- or -position of the sulfonanilidine ring. They can be adjacent or separate from one another.



   Starting materials suitable for the preparation of the compounds of the formula I are shown below under formula III.



   These starting materials are haloalkyl ketones which can be converted into compounds of the formula I by reaction with a corresponding amine (cf. the following equation). It may be advisable to introduce the desired core substituent after the introduction of the radical R4R5N-, for example if X in the end product is an amino group or the grouping R2SO2NH-.
EMI1.7
  



   The compounds of the formula III or of the formula I in which Z is a carbonyl group represent a further class of intermediates which can be converted by catalytic or chemical reduction into the phenalkanolamines of the formula I in which Z is the group> CHOH . The latter reaction is widely applicable, especially in those cases in which the benzene ring of the end product has a group susceptible to catalytic hydrogenations.



   The process according to the invention can be used to a large extent, since there are numerous different products using different amines
EMI2.1
 can be obtained as starting materials. While primary and secondary amines can be used, the latter are preferred. If R4 is to be hydrogen in the end product, the amine can be a compound of the formula
EMI2.2
 use, and in a final stage of the process, replace the benzyl group with hydrogen by means of catalytic hydrogenolysis.



   A large number of haloalkyl ketones of the formula III (Z is carbonyl) can be used in the above process for the above process. These haloalkyl ketones are generally prepared by reacting a haloalkanoyl halide with a suitable sulfonanilide.



  Below are some amines of the formula
EMI2.3
 indicated, which can be condensed with success with such haloalkyl ketones. The resulting aminoalkyl ketones can then be reduced to form the phenalkanolamines of the formula I (Z is CHOH):
2-aminoindane, 2-aminobicyclo [2.2.1] octane, 2-aminomethylbicyclo [2.2.1] octane, 4-azabicyclo [3.2.2] nonane, pentamethyleneimine, indoline, 1-carboxycyclopentylamine, Cyclohexylamine, 3-amino-cyclohex-1-ene, a-aminoisobutyric acid, N- (2-aminoethyl) -pyrrole, N- (2-aminoethyl) -piperazine, 2-phenylcyclopropylamine, N-benzyl4-aminopiperidine, 1-aminoindane, 3- Phenylpropylamine,

   3-aminoazabicyclo [2,2,2] octane, 2-amino-1-phenylpropanol- (1), 1-aminoadamantane, 1-aminobicyclo [2,2,1] -heptane, 2-amino-2-methyl-1 propanol, 2-aminopentane, 2-hydroxy-2-phenethylamine, cyclopentylmethylamine, cyclopent-2-en-1 -ylmethyl amine, 2-aminobicyclo [2.2 1] -heptane, 2-amino-1-propanol, ss - (p-chlorophenyl), a -dimethylethylamine, 2- (p-chlorophenyl) ethylamine, cyclopropylamine, 1,3-dimethylbutylamine, 1,4-dimethylpentylamine, 2,2-diphenylethylamine, 2-amino1,3-dihydroxy- 2 -ethylpropane, 2-amino-3-dimethylbutane, benzhydrylamine, 2-aminoheptane, 2-amino -1-methoxypropane, aminomethylcyclopropane, 2-amino-2-methyl-1,3-propanediol,

   2-ethylhexylamine, hexylamine, 3-methoxypropylamine, a-methylbenzylamine, allylamine, methallylamine, 2 aminomethylbicyclo [2,2, 1] -5-heptane, pyrrolidine, piperidine, hexamethyleneimine, thiomorpholine, morpholine, piperazine, nor-tropane, perhydroisoquinoline, Tetrahydroisoquinoline, perhydroquinoline, tetrahydrochindline, 2-aminopyridine, aniline, naphthylamine and styrylamine.



   Another process is that substituted anilines of the formula IV are reacted with a corresponding sulfonyl halide or sulfonic anhydride:
EMI2.4
 Various products according to the invention can thus be produced with various sulfonyl halides or anhydrides.



   Above, the preparation of various compounds of the formula I is described in which Z in the form of a carbonyl group or a group -CHOH- are connected to one another via a single carbon atom with the radical NR4R5. Two other methods are suitable for the production of compounds in which the link consists of 2 carbon atoms. Starting materials of the formula III suitable for this can be obtained by Friedel-Crafts reaction of an β-haloalkanoyl halide, wiess-bromobutyryl bromide, with a suitable sulfonanilide. These intermediate products are then reacted with an amine, whereupon the keto group is reduced and the corresponding phenpropanolamine is obtained.



   Another method consists in the Mannich reaction between a secondary amine, formaldehyde and a sulfonamidoacetophenone, for example the conversion of dimethylamine, formaldehyde and 3-acetylmethanesulfonanilide.

 

  The resulting product is then reduced to phenpropanolamine. The conditions of the Mannich reaction are usually: Mixing the reactants with or without a solvent in the presence of an acid at room temperature or slightly elevated temperatures of about 30 to 110.degree.



   The carbinol group in formula I represents an asymmetric carbon atom. In those carbinols in which Z contains no further asymmetric carbon atoms, two enantiomorphic forms exist. In the case of carbinols of the formula I in which Z has a further asymmetric carbon atom in addition to the carbinol group, there are two racemic forms, each of which consists of a pair of enantiomorphs.



   The compounds I are amphoteric substances which form salts both with acids and with bases. The salts represent desired end products as well as useful intermediates. For example, acid addition salts with optically active acids such as D-camphor sulfonic acid, L or D-tartaric acid are suitable for separating enantiomorphic forms of compounds obtainable according to the invention.



   Pharmacologically acceptable acid addition salts of the present compounds are the hydrochlorides, hydrobromides, acetates, propionates, phosphates, nitrates, succinates, gluconates, mucates, sulfates, methanesulfonates, ethanesulfonates, p-toluenesulfonates and the like. Pharmaceutically approved metal salts are the sodium, potassium, lithium, magnesium, calcium, barium, zinc and aluminum salts.



   The salts can be prepared in a conventional manner by treating the compounds I with an acid or base. For the preparation of salts with monobasic acids and monobasic bases, equimolar amounts of the reactants are preferred. When forming salts with polyacid bases and polybasic acids, it is advisable to reduce the molar amount of acid or base so that only one chemical equivalent is used.



   The sulfonanilides of the formula I, in which Z = CHOH, are pharmacologically active phenethanolamines, the effect of which is similar to or opposes that of the adrenal cortical hormones or adrenergic neurotransmitters. Some have papaverine-like effects on smooth muscles. They are of lower toxicity and have a novel, selective effect, with side effects associated with previously known phenethanolamines being largely eliminated. They also have greater stability and are more easily absorbed when administered orally.

  It has also been found that the phenalkanolamines substituted by alkyl and arylsulfonamido groups on the core exert beneficial pharmacological effects, through which they act as vasopressors, vasodepressors, analgesics, bronchodilators, α-receptor stimulants, ss receptor stimulants, 0 -receptor blocking agents, ss - receptor blocking agents , papaverine-like drugs for smooth muscle, as well as anti-inflammatory agents to combat and prevent anaphylaxis. The dosage varies widely among the individual limbs, but is generally between 0.1 micrograms to 20 milligrams per kilogram of body weight.



   Compounds with a particularly strong adrenergic receptor-blocking effect are 4- (2-isopropylamino 1-hydroxyethyl) methanesulfonanilide, 4- [2-t-butylamino) 1-hydroxyethyl] methanesulfonanilide and 4- (2-methylamino 1-hydroxypropyl) - methanesulfonanilide and their pharmaceutically acceptable acid addition salts. They are suitable for the treatment of various degenerative diseases or physiological abnormalities in which the autonomic nervous system is functioning poorly, for example in degenerative cardiovascular diseases. Here are those
Dosages at 0.02 to 5.0 milligrams per kilogram.



   Among the compounds obtainable according to the invention there are numerous which effectively inhibit the activity of the smooth muscles. In particular 2-hydroxy-5 - [1-hydroxy-2- (4-methoxyphenethylamino) propyl] methanesulfonanilide,
2-Hydroxy-5- [1-hydroxy-2- (1-phenoxy-2-propyl-amino) propyl] -methanesulphonanilide and 2-hydroxy-5 - (1-hydroxy-2-isopropylaminoethyl) -methanesulphonanilide and their
Acid addition salts show this property. The connections are suitable as peripheral vasodilators and relax the muscles; they can be used when the function of the uterus, the biliary tract and the digestive tract is impaired and also serve as bronchodilators. The dose here is 0.01 to 1.0 milligrams per kilogram. It can be administered orally.



   The compounds can be processed into various dosage forms such as tablets, capsules, elixirs, solutions, suspensions, ointments and the like, the usual diluents, preservatives, lubricants and carriers of the solid and liquid type being used; suitable carriers are e.g. B. corn starch, lactose, calcium phosphate, stearic acid, polyethylene glycol, water, sesame oil, peanut oil, propylene glycol and the like.



   In addition to the sulfonanilides obtainable according to the invention, preparations of this type can also contain further active ingredients, for example tranquilizers, sedatives, analeptics, analgesics, antipyretics, hypnotics, antibiotics such as polymixin, tyrothrycin, grammacidin, tyrocidin and neomycin, antihystamines such as chlorprophenpyridamine-maleate, methdilazine-hydrochloride Agents like cortisone phosphate, surface active agents, antiseptics like Thimerasol, Benzalkonium Chloride or expectorants like Tyloxypal.



   example
Preparation of 2-nitro-4 - (2 -benzylmethylaminoacetyl) methanesulfonanilide
A solution of 7.27 g (0.026 mol) of N-benzylmethylamine in 25 ml of acetonitrile is added dropwise over 10 minutes to a solution of 0.03 mol of 2-nitro4- (2-bromoacetyl) methanesulfonanilide in 100 ml of acetonitrile.



  The outside of the reaction vessel is cooled to maintain a reaction temperature of 10 ° C. After removing the cooling bath, the solution is stirred for 20 minutes.



  After evaporation of the reaction mixture, a yellow oil remains, which is dissolved in 300 ml of ether and then washed with water to separate the N-benzylmethylamine hydrobromide by-product. The ether solution is dried over magnesium sulfate and evaporated to give a viscous oil. The oily residue is dissolved in ether for purification and the solution is filtered through diatomaceous earth to remove colored impurities. The ether solution treated in this way is diluted with 100 ml of acetonitrile.



  By treating the resulting solution with an ethereal solution of methanesulfonic acid, the product 2-nitro 4- (2-benzylmethylaminoacetyl) methanesulfonanilide methanesulfonate is precipitated, which is filtered off, washed with a 1: 1 mixture of acetonitrile-ether and then dried.



   Production of 2-amino-4- (2-methylamino-1-hydroxy-ethyl) methanesulfonanilide
A solution of 0.74 mol of the product obtained in 700 ml of absolute ethanol is in a hydrogen atmosphere at a pressure of 0.28 to 0.71 kg / cm2 above atmospheric pressure for 24 hours with a 10% palladium
Catalyst made with 320 mg palladium chloride and 2 g powdered activated carbon was reduced. To
The calculated amount of hydrogen will absorb the
The catalyst is filtered off, the filtrate is concentrated to approx. 100 ml, mixed with approx. 50 ml of ether and the pale crystalline precipitate which separates out is filtered off. The precipitation is that
Methanesulfonate salt of the desired product, which is treated first with a base and then with hydrochloric acid to form the corresponding dihydrochloride salt.

  After recrystallization from ethanol and a water / ether mixture, the product melts at 198-199 C with decomposition.



  Analysis found:
C 36.63 H 6.00 N 12.28 Cl 20.84%
Table I contains a summary of the production possibilities and the physical properties of the aminoalkanolsulfonanilides obtained by the process according to the invention.



      Table I.
Production method and physical properties of other aminoalkanolsulfonanilides Product Starting material Compound Solvent F (C) Analysis Infrared
Absprption (u)
3.00 3.10 3.30
C: 41.99 6.20 6.40 6.60 2-Hydroxy-5- [1-hydroxy-2- (2-hydroxy-5- (2-bromopropionyl) -2-benzyloxy- H: 6.35 7 , 54 7.80 8.60 ethyl-amino) -propyl] methanesulphonanilide methanesulphonanilide and N-benzylethanol-methanol-iso- N: 8.02 9.08 9.40 10.24 amine hydrochloride propyl ether 182.5-184 S: 9.31 12.14 13.20 2-Benzyloxy-5- [2- (4-chlorophenethyl- 5- (2-bromopropionyl) -2-benzyloxy- C: 56.88 2.98 6.20 6.60 amino ) -1-hydroxypropyl] methanesulfon methanesulfonanilide and 4-chlorophen hydrochloride 208.5-210 H: 5.79 7.55 8.64 8.92 anilide ethylamine (erythro) methanol-ethanol (decomp.) S:

   6.19 9.94 10.20 2-Hydroxy-5- [1-hydroxy-2- (4-methane 5- (2-bromopropionyl) -2-benzyloxy hydrochloride, methanol-iso-226-227 C: 46 , 01 3.00 3.10 6.20 sulfonamidophenethylamino) propyl] methanesulfonanilide and 4-methanesulfonpropyl ether (decomposition). H: 5.92 6.62 7.60 8.70 methanesulfonanilide amidophenethylamine N: 8.43 9.00 10.20
S: 12.09 4 '- (2-Isopropylamino-1-hydroxybutyl) -methanesulfonanilide and n-α-halo-methanesulfonanilide, butyryl chloride, isopropylamine 4- (3-amino-1-hydroxypropyl) -methanesulfonanilide, ss-chloropropionyl- p -Toluenesulfonate 95% Ethanol 229-230 C: 49.31 3.2 7.5 8.7 9.7 methanesulfonanilide chloride (Erythro) H: 5.81 9.9 14.6
S: 15.41 4- (3-hexamethyleneimino-1-hydroxy-4-acetylmethanesulfonanilide, hexa- propyl) -methanesulfonanilide methylenimine 4- (2-methylamino-1-hydroxybutyl) - n-butyrylchloride and methanesulfonanilide hydrochloride ethanol ether 234-235 C:

   46.43 3.1 3.3 6.22 methanesulfonanilide (Erythro) (dec.) H: 6.79 6.38 6.62 6.85
S: 10.65 7.08 7.53 8.3
8.67 9.4 10.25
11.0 11.2 and
13.0 Product Solvent F (C) analysis on-infrared
Absorption (u) 2-Benzyloxy-5- [2- (4-chlorophenethyl-acetonitrile 178-180 C: 57.40 2.95 6.20 6.62 amino) -1-hydroxypropyl] -methanesul- H: 5, 83 7.54 8.64 8.94 fonanilide, hydrochloride (Threo) S: 6.24 9.86 10.30 4 '- (1-Hydroxy-3-methylamino absolute 121.5-123.5 C: 50 , 46 3.3 7.5 8.7 9.7 propyl) methanesulfonanilide, p-toluene-ethanol H: 6.27 9.9 14.6 sulfonate S: 14.90

 

Claims (1)

PATENT CLAIM I Process for the preparation of sulfonanilides of the formula I. EMI5.1 or salts thereof, characterized in that a compound of the formula II EMI5.2 with a compound of the formula III EMI5.3 is implemented, where in the formulas mean: A = halogen, X = hydrogen, hydroxy, nitro, lower alkoxy, benzyloxy, halogen, lower alkyl or R2SO2NH-, R1 and R2 = lower alkyl, phenyl or substituted phenyl, the substituents of which are lower alkyl groups, halogen, lower alkoxy or benzyloxy, Z => C = O or> CHOH, R3 = hydrogen, methyl or ethyl, R4 = hydrogen, lower alkyl or benzyl, R5 = hydrogen, optionally hydroxy-substituted lower alkyl, a ring-substituted or ring-unsubstituted aralkyl or Aryloxyalkyl groups, where the ring substituents are hydroxy, chlorine, methoxy, methanesulfonamido or methylenedioxy and the ring-substituted or ring-unsubstituted aralkyl or aryloxyalkyl groups have up to 10 carbon atoms; also alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkenyl, a heterocyclic group or heterocyclically substituted alkyl group with up to 10 carbon atoms, any ring substituents not included, which carboxy, amino, lower alkoxy groups with at least 2 carbon atoms , Benzyloxy, lower alkyl groups, groupings of the formula R2SO2NH- or halogen, and wherein the lower alkyl and lower alkoxy groups have up to 4 carbon atoms and EMI5.4 represents a heteromonocyclic group with 6 or 7 carbon atoms or a heteropolycyclic group with up to 11 carbon atoms. SUBCLAIMS 1. The method according to claim I for the preparation of 2 -B enzyloxy-5 - [2- (N-2 -hydroxyethyl-N-benzylamino) - propionyl] methanesulfonanilide, characterized in that 5- (2-bromopropionyl) -2 -benzyloxy-methanesulfonanilide and N-benzylethanolamine are reacted with one another in the presence of a solvent which is inert under the reaction conditions. 2. The method according to claim I for the preparation of 2-benzyloxy-5 - [2 - (4-chlorophenethylamino) propionyl] methanesulfonanilide, characterized in that 5 (2-bromopropionyl) -2-benzyloxy-methanesulfonanilide and 4-chlorophenethylamine in Reacts the presence of an inert solvent under the reaction conditions. 3. The method according to claim I for the preparation of 2-benzyloxy-5 - [2- (4-methanesulfonamidophenäthylamino) - propionyl] methanesulfonanilide, characterized in that 5 - (2-bromopropionyl) -2 -benzyloxy-methanesulfonanilide and 4 -Methanesulfonamidophenäthylamin in the presence of an inert solvent under the reaction conditions with each other. 4. The method according to claim I for the preparation of 4 '- (2-isopropylamino-butyryl) methanesulfonanilide. 5. The method according to claim I for the preparation of 4- (2-aminopropionyl) methanesulfonanilide, characterized in that 4- (2-chloropropionyl) methanesulfonanilide and ammonia are reacted with one another in the presence of a solvent which is inert under the reaction conditions. 6. The method according to claim I for the preparation of 4- (2-methylamino-butyryl) methanesulfonanilide. 7. The method according to claim I or the dependent claims 1 to 6, characterized in that a compound of formula I, in which Z is a carbonyl group, is reduced, for. B. catalytically, with formation of the corresponding compound in which Z represents the group> CHOH. PATENT CLAIM II Use of the compounds of formula I obtained by the process according to claim I, in which X is the nitro group, for the preparation of corresponding compounds in which X is the primary amino group, characterized in that the nitro group is reduced to the primary amino group.