NZ240630A - Sulphonamides and pharmaceutical compositions thereof - Google Patents

Sulphonamides and pharmaceutical compositions thereof

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Publication number
NZ240630A
NZ240630A NZ240630A NZ24063091A NZ240630A NZ 240630 A NZ240630 A NZ 240630A NZ 240630 A NZ240630 A NZ 240630A NZ 24063091 A NZ24063091 A NZ 24063091A NZ 240630 A NZ240630 A NZ 240630A
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NZ
New Zealand
Prior art keywords
tert
butyl
hydroxy
sulfo
denotes
Prior art date
Application number
NZ240630A
Inventor
Reinhard Heck
Hans Alois Dresel
Original Assignee
Boehringer Mannheim Gmbh
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Application filed by Boehringer Mannheim Gmbh filed Critical Boehringer Mannheim Gmbh
Publication of NZ240630A publication Critical patent/NZ240630A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/04—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/40—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Vascular Medicine (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pyridine Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Anti-atherosclerotically effective medicaments containing a compound of formula (I) in which: R1? and R2?, which may be the same or different, are a hydrogen atom or a straight-chained or branched alkyl radical with 1 to 4 C atoms; A is a straight-chained or branched alkylene chain with 1 to 5 C atoms; X is a hydrogen atom or a C1?-C4?-alkyl radical, and Y is a straight-chained or branched alkyl radical with 1 to 5 C atoms, an aralkyl or aryl radical, whereby the aryl radical may be substituted singly to triply in all possible positions on the ring by halogen, trifluoromethyl, C1?-C4?-alkyl, amino, C1?-C4?-acylamino, di(C1?-C4?)-alkylamino or nitro; with the proviso that A may also signify valency if no Y signifies an aryl radical, and their pharmacologically acceptable salts, novel sulphonamides and process for producing them.

Description

New Zealand Paient Spedficaiion for Paient Number £40630 2 4 0 6 3 0T Patents Form 5 Priority Datc{s): .... ?&.
Lunijjieie Specification Filed: .'/?!j Ca<s«!: Publication Date: P.O. Journal, No: .
N.Z. No.
NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION PHARMACEUTICAL COMPOSITIONS CONTAINING SULFONAMIDES. NOVEL SULFONAMIDES AND PROCESS FOR THEIR PRODUCTION We, BOEHRINGER MANNHEIM GMBH, a Company of the Federal Republic of Germany of, 6800 Mannheim 31, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (Followed by 1A) N.Z. PATENT GFFJCE 18 NOV 1991 FtECEIV"P 240 6 30 - IA - Pharmaceutical compositions containing sulfonamides, novel sulfonamides and process for their production The present invention concerns pharmaceutical compositions containing sulfonamides having the general formula I in which Rl and R2, which can be the same or different, denote a hydrogen atom or a straight-chained or branched alkyl residue with 1 to 4 C atoms, A denotes a straight-chained or branched alkylene chain with 1 to 5 C atoms, X denotes a hydrogen atom or a Cl-C4-alkyl residue, and (I) R 240 630 Y denotes a straight-chained or branched alkyl residue with 1 to 5 C atoms, an aralkyl or aryl residue whereby the aryl residue can be substituted once to three times in all possible positions on the ring by halogen, trifluoromethyl, C1-C4 alkyl, amino, C1-C4 acylamino, di(C^-C^) alkylamino or by nitro , provided that A can also denote valency if Y does not represent an aryl residue, as well as their pharmacologically acceptable salts.
R1 and R2 preferably denote hydrogen, methyl or the tert.-butyl group.
The bridge A is preferably -CH2-; -CH2-CH2-, or the <fH3 f*3 -CH2-CH-, -CH2-C-, or the -(CH2).j group. ch3 X preferably represents a H atom or a methyl group.
An aralkyl group preferably denotes benzyl or phenethyl.
An aryl group preferably represents phenyl.
An isopropyl, n-butyl, benzyl or phenyl residue is particularly preferred for Y, whereby this can in turn be substituted in all positions once to three times by 2406 fluorine, chlorine, methyl, amino, acetylamino, dimethylamino or nitro.
Benzene sulfonamides with an analogous structure which decrease atherogenic lipids are described in the European application EP-A-384 279.
Hydroxy-phenyl compounds of formula I are described in EP-A-4011, EP—A—255,728 and EP-A-325,245 as intermediates for the production of pharmaceutical active phenoxy-alkyl-carboxylic acids without mentioning a pharmacological effect for the intermediates.
Other documents, i. e. US-A-3,737,316, FR-A-2,309,524 and FR-A-2,193,216 disclose compounds of formula I with A=valency bond without mentioning a pharmacological effect.
The compounds of the present invention have a strong antioxidant activity. The lipophilicity of this antioxidant group causes an accumulation of the compounds in the atherogenic low-density lipoprotein (LDL) and an effective protection of the sensitive components of the LDL against reactive oxygen species. This results in a substantial reduction of the LDL influx into the macrophagic foam cells since a prerequisite for the pathologically increased uptake of atherogenic LDL into the atheroma cells is their oxidative modification. -3a- 240630 Antioxidants are substances which - in general - cause a considerable delay in the oxidative processes in a product to be protected. Probucol® is an antioxidant and potent antiatherosclerotic agent which has a hypolipaemic effect in different animal species and in humans. It is a sterically hindered alkyl phenol which accumulates in LDL. It has been shown in animal experiments that Probucol blocks the oxidative modification of LDL in the arterial wall and directly prevents atheroma formation because of the antioxidant activity (D. Steinberg et al., Amer. J. Cardiol. 57, 16 M (1986)).
The disadvantages of Probucol® are the low absorption of the substance as well as the extremely long retention - 4 240 6 30 time in the body tissue; the excretion of Probucol mainly takes place via the faeces (see M.N. Cayen, Pharmacol. Ther. 29, 157 (1985)).
In addition compounds of the formula I lower the plasmalipids by blocking the intestinal absorption of cholesterol which results in a reduction of the intrahepatic pool of free cholesterol and decreases the secretion of the dietary-dependent lipoproteins from the liver into the plasma. The inhibition of cholesterol absorption is due to the inhibition of the acyl-coenzyme A-cholesterol transferase (ACAT) reaction. ACAT catalyses the esterification of cholesterol in the enterocytes which is necessary in order to package cholesterol in the chylomicrons and to introduce them into the blood circulation via the intestinal lymph and the thoracic duct.
The substances are readily absorbed and inhibit the ACAT-dependent esterification of free cholesterol not only in the enterocytes but also in the cells of the atheroma itself. They thereby prevent their degeneration into xanthoma cells caused by overloading with cholesterol esters.
The compounds of formula I are used as pharmaceutical preparations in particular as antiatherosclerotic agents because of their stabilizing effect on lipoproteins.
Furthermore they act antibiotically - in particular anti-bacterially anti-inflammatorily, cytoprotectively as well as anti-asthmatically. However, they can also be used as inhibitors of reperfusion- 24 0 6 30 dependent lipid peroxidation and as stabilizers of the "lung surfactant factor".
The production of compounds of formula I is characterized in that an amine having the formula II, in which R1, R2, A and X have the meanings stated above is reacted with sulfonic acid chlorides having the formula III in which Y also has the meaning stated above. This is usually carried out at room temperature in a chemically inert solvent such as CH2C12, toluene or such like, preferably in the presence of an acid-binding reagent such as e.g pyridine, triethylamine (e.g. analogously to F. Muth in Houben-Weyl, Vol. 9, p. 613). ho-k N) -a-Na ± C1-S-Y II in e.g. pyridine 0 • - HC1 Alternatively sulfamides which are also substituted at the sulphone group can be alkylated with suitably substituted aralkyl halides to produce compounds having the formula I.
If the compounds obtained in this way having the formula I do not represent the final product, the residue X (e.g. CH3) can be additionally introduced at the sulphonamide nitrogen, if desired using alkyl halides (e.g. methyl iodide).
The required starting materials II and III are in general known from the literature, or can be produced in 240 630 an analogous way by the usual methods (for detailed information see the examples).
If individual reaction products are not produced in sufficient purity, the crude products can be purified by crystallization or column chromatography.
Subject of the invention are also new sulfonamides of formula I1 wherein R]_ and R2 each denotes a tert.butyl group A denotes a straight-chained alkylene chain of 1 to 5 X denotes a hydrogen atom or a Ci-C4-alkyl residue, and Y denotes an aralkyl or aryl residue whereby the aryl residue can be substituted once to three times in all possible positions on the ring by halogen, trifluor-methyl, Ci~C4-alkyl, amino, Ci-C4-acylamino, di(Ci-C4)-alkylamino or by nitro, carbon atoms or the group CH3 I —CH2—CH— as well as their pharmacologically acceptable salts. - 6 a - 240 6 30 Preferred compounds of formula I' are: 4-chlorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)-phenethylamide (example Id) 4-chlorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)-benzylamide (example 2) N-methyl-4-chlorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)-benzylamide (example 3) Benzyl-sulfo-(3,5-di-tert.butyl-4-hydroxy)benzylamide (example 5.6) 2,4,6-tris-isopropyl-benzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)benzylamide (example 5.10) 2-[benzy1-sulfo-(3,5-di-tert.butyl-4-hydroxy)]-phenethyl-amide (example 5.13) 2-[2,4,6-tris-isopropyl-benzene-sulfo-(3,5-di-tert.butyl -4-hydroxy)]phenethylamide (example 5.17) 2-[3-trifluoromethyl-benzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)]phenethylamide (example 5.18) 3-[2,4,6-tris-isopropyl-benzene-sulfo-(3,5-di-tert.butyl- 4-hydroxy)]phenylamide (example 5.25) 4-fluorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)-benzylamide (example 5.27) 2- [4-fluoi§Denzene-sulfo- (3,5-di-tert .butyl-4-hydroxy) ] -phenethylamide (example 5.28) 2-[benzyl-sulfo-(3,5-di-tert.butyl-4-hydroxy)]-phenyl-propylamide (example 5.32) 2-[(4-chlorobenzene)-sulfo-(3,5-di-tert.butyl-4-hydroxy)]-phenylpropylamide (example 5.37) -6b- 14 0 6 3 (F The compounds of formula I can be reacted with the corresponding bases in order to prepare salts with physiologically tolerated organic or inorganic bases such as for example sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, methylglucamine, morpholine, triethylamine or ethanolamine. Mixtures of the acidic compounds with a suitable alkali carbonate or hydrogen carbonate also come into consideration.
For the production of pharmaceutical preparations the compounds having the general formula I are mixed in the usual way with suitable pharmaceutical carrier substances, aromatics, flavourings and dyes and are for example formed as tablets or coated tablets or are suspended or dissolved in water or oil such as e.g. olive oil with the addition of corresponding auxiliary agents.
The substances having the general formula I can be administered in liquid or solid form orally and parenterally. Water, which contains stabilizing agents, solubilisers and/or buffers which are usually used in injection solutions, is preferably used as the injection medium. Such additives are e.g. tartrate buffer or borate buffer, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediamine tetraacetic acid), 240630 highly molecular polymers (such as liquid polyethylene oxide) for the regulation of viscosity or polyethylene derivatives of sorbitol anhydrides.
Solid carrier agents are e.g. starch, lactose, mannitol, methyl cellulose, talcum, highly-dispersed silicic acid, higher molecular fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats or solid high-molecular polymers (such as polyethylene glycols). Suitable preparations for the oral application can contain, if desired, flavourings and artificial sweeteners.
The administered dosage depends on the age, health and weight of the recipient, the extent of the disease, the type of further treatments which may be being carried out at the same time, the frequency of the treatments and the type of desired effect. The daily dosage of the active compound is usually 0.1 to 10 mg/kg body weight.
Preferred compounds within the scope of the present invention in addition to those of formula I mentioned in the examples are the following: N-methyl-4-chlorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)phenethylamide N-methyl-4-fluorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)phenethylamide N-methyl-4-chlorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)phenylpropylamide 240 6 30' Example 1 a) 4-hvdroxv-3.5-di-tert.butvl-benzvlchloride 52.8 g (0.256 mol) 2,6-di-tert.-butylphenol is dissolved in 200 ml n-heptane, 250 ml 37 per cent formalin solution and 500 ml concentrated hydrochloric acid are added, it is flushed with nitrogen and stirred for 8 h at the reflux temperature. After cooling the organic phase is separated off, the aqueous phase is extracted with n-heptane and the combined heptane phases are washed with water. After drying with Na2S04, it is evaporated in a vacuum and the residue is processed further as the crude product.
Yield: almost quantitative (crude product) Lit.: Neureither, J.Org.Chem. 28., 3486 (1963) b) 4-hydroxy—3.5-di-tert.butvlbenzvlcvanide A solution of 104.5 g (0.41 mol) 4-hydroxy-3,5-di-tert. butylbenzylchloride and 155 ml ethanol is added dropwise within 1 hour to a 80-85°C hot mixture of 38.4 g (0.71 mol) sodium cyanide, 50 ml water and 72 ml ethanol. Subsequently it is kept for a further 3 h at the reflux temperature, cooled down and inorganic material is removed by aspiration. The liquid phase is evaporated, water is added to the evaporation residue and it is extracted with ether. The ether phase is dried (Na2S04), evaporated and crystallized by addition of ligroin. 140 030' Yield: 61.1 g (61 % of theory) Melting point: 109-110°C analogous to Fuson and Rabjohn, Org. Synth. Vol. 25. 66. c) 3.5-di-tert.butvl-4-hvdroxv-phenethvlamine In a shaker autoclave 10 g raney-Nickel and 100 ml liquid ammonia is added to 30 g (0.12 mol) 3,5-di-tert .butyl-4-hydroxy-benzyIcyanide in 400 ml methanol while deep cooling and subsequently hydrogenated in a hydrogen atmosphere at 80°C and 140 bar for 16 h. After expanding the autoclave the catalyzer is filtered off and the crude product is freed of solvent in a vacuum. The residue is again dispersed in ether/water, the ether phase is separated and dried over MgS04. After again evaporating green, wax-like crystals remain.
Yield: quantitative (crude product). d) 4-chlorobenzene-sulfo-(3.5-di-tert.butvl-4-hydroxy)-phenethylamide IA A solution of 2.1 g (10 mmol) 4-chlorobenzene-sulfochloride dissolved in 10 ml dichloromethane is added dropwise at room temperature to a solution of 2.49 g (10 mmol) of the amine obtained in section c) in 30 ml dichloromethane and 0.81 ml (10 mmol) pyridine. After stirring for 12 h at room temperature it is poured onto 1 N HC1, the organic phase is separated, washed and dried with Na2S04. After removing the solvent in a vacuum the residue is purified by filtration over silica gel using 240630 hexane/ethyl acetate (3:1) as the mobile solvent. After evaporation the product thus obtained is recrystallized from cyclohexane. 1.4 g colourless crystals, melting point: 122-23°C. Example 2 4-chlorobenzene-sulfo-(3.5-di-tert.butvl-4-hvdroxv)benzylamide lb 1.55 g (8 mmol) 4-chlorobenzene-sulfochloride dissolved in 10 ml dichloromethane is added dropwise at room temperature to a mixture of 1.9 g (8 mmol) 3,5-di-tert . butyl-4 -hydroxy-benzylamine (prepared analogously to : Houben-Weyl, Methoden der Organischen Chemie Vol. 11/1, p. 502, from 3,5-di-tert.butyl-4-hydroxy-benzaldoxime) and 0.63 ml (8 mmol) pyridine in 20 ml dichloromethane. After stirring for 24 h at room temperature it is poured onto 1 N HC1, the organic phase is separated, dried with Na2S04 and the solvent is removed in a vacuum. The crude product thus obtained is recrystallized from toluene. 1.3 g colourless crystals, melting point: 119-21°C. Example 3 N-methvl-4-chlorobenzene-sulfo-(3.5-di-tert.butvl-4-hvdroxv^-benzylamide Ic (X = CH3) 1.5 g (4 mmol) 4-chlorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)benzylamide lb is added to a suspension of L 4 0 6 3 IT 0.1 g (4 mmol) sodium hydride in 10 ml THF. After stirring for 30 min 0.31 ml (5 mmol) methyl iodide is added dropwise and stirred for 3 h at room temperature. Subsequently it is poured onto 1 N HC1, the organic substance is extracted with ether. After drying and evaporating the ether extract an oily crude product is obtained which is purified on a medium pressure column (silica gel; mobile solvent heptane/ethyl acetate 9:1). After removing the solvent the product solidifies to form crystals. 0.35 g yellow crystals, melting point: 140—43 °C.
Example 4 a) 3-(3.5-di-tert.butvl-4-hydroxy)phenvlpropvlamine In a shaker autoclave 10 g raney-Nickel and 100 ml liquid ammonia is added to 77.8 g (0.3 mol) 3-(3,5-di-tert.-butyl-4-hydroxy)phenylpropionitrile (produced according to: DOS 2 240 609 (1972), HOECHST company) in 500 ml methanol while deep cooling and subsequently hydrogenated in a hydrogen atmosphere at 80°C and 140 bar for 16 h. After expanding the autoclave the catalyzer is filtered off and the crude product is freed of solvent in a vacuum. The residue is dispersed again in ether/water, the ether phase is separated off and dried over MgS04. After evaporating again a semisolid mass remains which slowly completely solidifies. 70.2 g greenish crystals (crude product). **0 6 301 12 b) 4-chlorobenzenesulfo-3-(3.5-di-tert.butvl-4-hvdroxv)phenyl-propvlamide Id 2.04 ml (15 mmol) triethylamine is first added to a suspension of 3.95 g (15 mmol) of the amine obtained above in section a) in 50 ml toluene and then 3.2 g (15 mmol) 4-chlorobenzenesulfochloride dissolved in 10 ml toluene is added at room temperature. After stirring- for 12 hours at room temperature 50 ml iced water is added, the organic phase is separated, dried and the solvent is removed in a vacuum. The crude product is purified by filtration over silica gel (hexane/ethyl acetate 1:1 as mobile agent). 1.9 g brownish crystals, melting point: 152°C. Example 5 One can obtain the following compounds in an analogous manner to the compounds mentioned in Examples 1, 2, 3, or 4. (see table) : I £ . £ = k*l. KMhil 4 I I X = H Table I 240 6 Example Y A m.p. [°c] .1 h3c-(CH2)3- valency 115-18 .2 (ch3)2CH- valency 160-61 .3 Q -CH2- valency 123-24 .4 H3C-(CH2')3- -ch2- 74-75 .5 (ch3)2ch- -CH2- 114-15 240630 Table I continued Example Y A 1—1 u 0 1 1 fi • e .6 Q—cs2- -ch2- 118-19 .7 O2N-O -ch2- 144-45 .5.8 h2n-0 -cs2- oil .9 h3coc-n-Q-h ' -cs2- 174-76 .10 -CH2- 145-46 .11 H3C-(CH2)3- -ch2-ch2- 109-10 .12 (ch3)2ch- -gh2-cs2- 81-82 .13 Q-ai 2 -ch2-ch2- 163-64 .14 o2n -{y CZ2-ce2- 147-48 .15 H2N-o —ch2—ch2~~ oil .16 h3coc-n-Q- h —ch2—ch2 172-78 .17 -ch2""<-h2— 159-60 .18 .19 a h3c-(ch2)3- -ch2~ch2~ -(ch2)3- 94-95 oil .20 (ch3)2ch- -(CH2)3- oil .21 q-ch2" -(ch2)3- oil .22 02n- q -<ch2)3- oil 2 4 0 6 30^ Table I continued ___ Example Y A m.p. [°C] .23 h2h-q- -(ch2)3- 122 .24 h3c0c-h-o pt -(CH2)3- 164 .25 "(ch2)3 144 .26 h3c-0- -(ch2)3- 129-30 .27 -ch2- 131-32 .28 0"f -ch2-ch2- 118-20 .29 o-ch3 ii 121-22 .30 n-Butyl- ch3 -ch2-<bl- 126 .31 i-Propyl- 11 113-21 .32 Benzyl- ii 147-48 .33 on02 ii 139-40 .34 0^2 ii 149-51 .35 £j-n-coch3 H ii 92-93 .36 ok ii 128-29 .37 ocl ii 139-40 .38 n-Butyl -CH2-(CH3)2C- 90-91 2 4 0 6 3 0 Example Y A f—• u 0 1 1 • « .39 Benzyl- 11 143-44 .40 OHO2 II 180-81 .41 <2^2 11 147-48 .42 0 ^5"N-C-CH3 H J\ II 195-98 .43 11 177-79 .44 <Q^ci 11 168-70

Claims (8)

WHAT WE CLAIM IS:
1. Pharmaceutical compositions containing at least one sulfonamide having the general formula I in which and R2, which can be the same or different, denote a hydrogen atom or a straight-chained or branched alkyl residue with 1 to 4 C atoms, A denotes a straight-chained or branched alkyiene chain with 1 to 5 C atoms, X denotes a hydrogen atom or a C1~C4 alkyl residue, and Y denotes a straight-chained or branched alkyl residue with 1 to 5 C atoms, an aralkyl or aryl residue whereby the aryl residue can be substituted once to three times in all possible positions on the ring by halogen, trifluoromethyl, C1-C4 alkyl, amino, C1-C4 acylamino, di(C1~C4) alkylam^d tor ■ nitro, // z - 4 FEB 1994 240630 provided that A can also denote valency if Y does not represent an aryl residue, or a pharmacologically acceptable salt thereof in addition to the usual carrier materials and auxiliary agents.
2. Sulfonamides of formula I1 wherein Rl and R2 each denotes a tert.butyl group , A denotes a straight-chained alkylene chain of 1 to 5 carbon atoms or the group CH3 —CH2—CH— X denotes a hydrogen atom or a Ci-C4-alkyl residue, and Y denotes an aralkyl or aryl residue whereby the aryl residue can be substituted once to three times in all possible positions on the ring by halogen, trifluor-methyl, C]_-C4-alkyl, amino, Ci-C4-acylamino, di(C]_-C4)-alkylamino or by nitro, 18 a *4063o Compounds according to claim 2, selected from the group consisting of 4-chlorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)-phenethylamide, 4-chlorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)-benzylamide, N-methyl-4-chlorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)-benzylamide, benzyl-sulfo-(3,5-di-tert.butyl-4-hydroxy)benzylamide^ 2,4,6-tris-isopropyl-benzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)benzylamide, 2-[benzyl-sulfo-(3,5-di-tert.butyl-4-hydroxy)]-phenethylamide, 2-[2,4,6-tris-isopropyl-benzene-sulfo-(3,5-di-tert .butyl-4-hydroxy)]phenethylamide, 2-[3-trifluoromethyl-benzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)]phenethylamide,
3-[2,4,6-tris-isopropyl-benzene-sulfo-(3,5-di-tert .butyl-4-hydroxy) ]phenylamide, 4-fluorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)-benzylamide, 2-[4-fluorobenzene-sulfo-(3,5-di-tert. butyl-4 hydroxy) ] -phenethylamide, f/*- \f-4FEBW9 -18b- 2-[benzyl-sulfo-(3,5-di-tert.butyl-4-hydroxy)]-phenyl-propylamide , and 2-[(4-chlorobenzene)-sulfo-(3,5-di-tert.butyl-4-hydroxy)]-phenylpropylamide.
4. Process for the production of compounds having the formula I * in which and R2' each denotes a tert.butyl group, A denotes a straight-chained alkyiene chain with 1 to 5 C atoms or CH3 -CH2-CH- ' X denotes a hydrogen atom or a C-,-CA alkyl residue, r //v and Y denotes an aralkyl or aryl _ residue whereby the aryl residue can be substituted once to three times in all possible positions on 19 24 06 the ring by halogen, trifluoromethyl, C-j_-C4 alkyl, amino, C1~C4 acylamino, di(C1-C4) alkylamino or nitro, as well as their pharmacologically acceptable salts, wherein, either a) an amine having the formula II in which R1, R2, A and X have the stated meanings, is reacted in the presence of an acid-binding reagent in a known manner with a sulfochloride having the formula III R II 0 II Cl-S-Y III Y has the stated meaning in which ll "■ vi - 20 - ,k M "v or b) a sulfonamide having the formula IV x 1 hn-so2-y iv in which X and Y have the stated meanings, is reacted in a known manner with an aralkyl halide having the formula V *1 SO-{ v -A-Hal v in which R1 , R2 and A have the stated meanings and Hal represents a halogen atom, and when X denotes hydrogen, the compound thus prepared is subsequently converted, in a known manner into another compound of formula I' in which X is alkyl, and if desired the compound of formula I' is converted into a pharmaceutically acceptable salt. 240630 - 21 -
5. Use of compounds as claimed in claim 1, 2 or 3 in the preparation of a composition suitable for the treatment of atherosclerosis.
6. A pharmaceutical composition according to claim 1 substantially as herein described or exemplified.
7. A.compound according to claim 2 substantially as herein described or exemplified.
8. A process according to claim 4 substantially as herein described or exemplified. BOEHRINGER MANNHEIM GMBH By Their Attorneys HENRY HUGHES LTD >4 T or \\ - % v V
NZ240630A 1990-11-22 1991-11-18 Sulphonamides and pharmaceutical compositions thereof NZ240630A (en)

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US4013621A (en) * 1975-04-29 1977-03-22 Ciba-Geigy Corporation Substituted sulfonamide derivatives of hindered phenols and stabilized compositions
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