CA2096847A1 - Pharmaceutical preparations containing sulfonamides novel sulfonamides and processes for their production - Google Patents
Pharmaceutical preparations containing sulfonamides novel sulfonamides and processes for their productionInfo
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- CA2096847A1 CA2096847A1 CA002096847A CA2096847A CA2096847A1 CA 2096847 A1 CA2096847 A1 CA 2096847A1 CA 002096847 A CA002096847 A CA 002096847A CA 2096847 A CA2096847 A CA 2096847A CA 2096847 A1 CA2096847 A1 CA 2096847A1
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- tert
- butyl
- hydroxy
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- sulfo
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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
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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
- C07C311/30—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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Abstract
A b s t r a c t Pharmaceutical agents acting antiatherosclerotically containing a compound having the general formula I
I
in which R1 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 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) alkylamino or nitro, provided that A can also denote valency if Y does not represent an aryl residue, as well as their pharmacologically safe salts, new sulfonamides and processes for their production.
I
in which R1 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 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) alkylamino or nitro, provided that A can also denote valency if Y does not represent an aryl residue, as well as their pharmacologically safe salts, new sulfonamides and processes for their production.
Description
Pharmaceutical preparations containing sulfonamides, novel sulfonamides and processes for their production The present invention concerns pharmaceutical agents which contain sulfonamides having the general formula I
~~ ~ _so2_y in which R1 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 C1-C4 alkyl residue, and - 2 ~ 7 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) alkylamino or by nitro , provided that A can also denote valency if Y does not represent an aryl residue, as well as their pharmacologically safe salts.
Rl and R2 preferably denote hydrogen, methyl or the tert.-butyl group.
The bridge A is pre~erably -CH2-; -CH2 CH2-, or the -CH2-CH(CH3)-- -CH2-ctCH3)2 X preferably represents an H atom or a methyl group.
An aralkyl group preferably denotes benzyl or phenethyl.
An aryl group preferably represented by 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 fluorine, chlorine, methyl, amino, acetylamino, dimethylamino or nitro.
-Benzene sulfonamides with an analogous structure whichdecrease atherogenic lipids are described in the European application EP-A-384 279.
In EP-A 4011, EP-A 255 728 and EP-A 325 245 hydroxyphenyl compounds having the general formula I are described as intermediate products for the production of pharmacologically active phenoxyalkyl carboxylic acids without there being a statement about their own pharmacological action.
Compounds of formula I with A=valency are described in other documents such as for example in US-A 3,737,316, FR-A 2,309,524 and FR-A 2,193,216 without a statement about a pharmacological action.
The compounds of the present invention have a strong antioxidant activity. The lipo~hilicity of this antioxidant group causes an acc:umulation of the compounds in the atherogenic low-density lipoprotein (LDL) and an e~fective 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 prereguisite for the pathologically increased uptake of atherogenic LDL into the atheroma ~ells is their oxidative modi~ication.
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 ef~ect in various animal species and in humans. It is a sterically hindered alkyl phenol which ~ g~'~J1 accumulatas 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 t~. 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 time in 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 plasma lipids by blocking the intestinal absorption of cholesterol which results in a reduction of the intrahepatic pool of free cholesterol and correspondingly 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) react~on. AC,AT catalyses the esterificatior1 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 thoracic duct.
The substances are readily absorbed and inhibit the ~CAT-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 ester.
~ 5 ~ ~ Jt 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-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 Rl, 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 Houblsn-Weyl, Vol. 9, p. 613).
R.~
X 1Ol e.g. pyridine ~o~ A-NH Cl-l-Y >
~ O - HCl R~
II III
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.
- 6 ~ 7 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 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.
The present invention also concerns new sulfonamides having the formula I' W- ~--A--N--SCIz - Y ( I l ) in which Rl and R2 denote in each case a tert. butyl group, A denotes a straight-chained alkylene chain with 1 to 5 C atoms or the group -CH2-CH(CH3)-X denotes a hydrogen atom or a Cl-C~ 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, trifluoromethyl, Cl-C4 alkyl, amino, C1-C4 acylamino, di(Cl-C~) alkylamino or by nitro, : as well as their pharmacologically sa~e salts.
The following compounds of formula I' are particularly preferred:
4-chlorobenzene-sulfo-(3~5-di-tert.butyl-4-hydroxy)-phenethylamide (example ld) 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) ~, Benzylsulfo-(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-[benzylsulfo-(3,5-di-tert.butyl-4-hydroxy)]-phenethylamide (example 5.13) 8 ~9~ 7 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)]-phenylpropylamide (example 5.25) 4-fluorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)-benzylamide (example 5.27) 2-[4-fluorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)]-phenethylamide (example 5.28) 2-[benzylsulfo-(3,5-di-tert.butyl-4-hydroxy)]-phenylpropylamide (example 5.32) 2-[(4-chlorobenzene)-sulfo-(3,5-di-tert.butyl-4-hydroxy)]-phenylpropylamide (example 5.37) 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 9 ~r~t~ r~
usual way with suitable pharmaceutical carrier substances, axomatics, 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 orally and parenterally in liquid or solid form. 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), high-molecular polymers (such as liquid polyethylene oxide) ~or the regulation of viscosity or polyethylene derivatives of sorbitol anhydrides.
Solid carrier materials 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 ~egetable fats or solid high-molecular polymers (such as polyethylene glycols).
Suitable preparations for 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 treatments and the typa of desired effect. The daily dosage of the active compound is usually 0.1 to 10 mg/kg body weight.
- 10 ~ 8ll7 Preferred compounds within the scope of the present invention, apart from 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 Example a) ~-hydroxy-3,5-di-tert.butyl-benzylchloride 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 Na2SO4, 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.butylbenzylcyanide 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 80-85C 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 (Na2SO4), evaporated and crystallized by addition of ligroin.
Yield: 61.1 g (61 % of theory) Melting point: 109-110C
analogous to Fuson and Rabjohn, org. Synth. Vol.
25, 66.
c) 3l5-di-tert.butyl-4-hydroxv-phenethylamine In a shaker autoclave 10 g Raney nickel and 100 ml liquid ammonia are added to 30 g (0.12 mol) 3,5-di-tert.butyl-4-hydroxy-benzylcyanide in 400 ml methanol while deep cooling and subsequently hydrogenated for 16 h in a hydrogen atmosphere at 80C and 140 bar. After releasing 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 MgSO4. After aga~n evaporating green, wax-like crystals remain.
Yield: quantitative (crude product).
-- 12 ~ $ ~ ~7 d) 4-chl~orobenzene-sulfo=~3,5~di-tert.buty1~4-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 o~
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 HCl, the organic phase is separated, washed and dried with Na2SO47 After removing the solvent in a vacuum the residue is purified by filtration over silica gel using 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: 122-23C.
Example 2 4-chlorobenzene-sul~o-(3L5-di-tert.butyl-4-hydroxy~benzylamide Ib 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 HCl, the organic phase - 13 - ~ ~ 9 ~
is separated, dried with Na2SO4 and the solvent is removed in a vacuum. The crude product thus obtained is recrystallized from toluene.
1.3 g colourless crystals, melting point: 119-21C.
~xample 3 N-methyl-4-chlorobenzene-slllfo-L3 5-di-tert.butyl-4-hydroxy)-benzylamide Ic (X = CH3) ==
1~5 g (4 mmol) 4-chlorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)benzylamide Ib is added to a suspension of ==
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 again for 3 h at room temperature. Subsequently it is poured onto l N HCl, 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:
140-43C.
Example 4 a) 3-(3,5-di-tert.butyl-4-hydroxyLehenylpropylamine In a shaker autoclave 10 g Raney nickel and 100 ml liquid ammonia are 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), ~9~7 HOECHST company) in 500 ml methanol while deep cooling and subsequently hydrogenated for 16 h in a hydrogen atmosphere at 80C and 140 bar. After releasing the autoclave, the cataly~er 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 and dried over MgSO4. After evaporating again a semi-solid mass remains which slowly completely solidifies.
70.2 g greenish crystals (crude product).
b) 4-chlorobenzenesulfo-3-(3~5-di-tert butyl-4-hydroxy~phenylpropylamide Id ==
2.04 ml (15 mmol) triethylamine is firstly 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: 152C.
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):
- 15 ~ 8~
Table .. _ _ ..... __ ..
- Example Y A m.p. [C]
. _ ..
~~ ~ _so2_y in which R1 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 C1-C4 alkyl residue, and - 2 ~ 7 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) alkylamino or by nitro , provided that A can also denote valency if Y does not represent an aryl residue, as well as their pharmacologically safe salts.
Rl and R2 preferably denote hydrogen, methyl or the tert.-butyl group.
The bridge A is pre~erably -CH2-; -CH2 CH2-, or the -CH2-CH(CH3)-- -CH2-ctCH3)2 X preferably represents an H atom or a methyl group.
An aralkyl group preferably denotes benzyl or phenethyl.
An aryl group preferably represented by 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 fluorine, chlorine, methyl, amino, acetylamino, dimethylamino or nitro.
-Benzene sulfonamides with an analogous structure whichdecrease atherogenic lipids are described in the European application EP-A-384 279.
In EP-A 4011, EP-A 255 728 and EP-A 325 245 hydroxyphenyl compounds having the general formula I are described as intermediate products for the production of pharmacologically active phenoxyalkyl carboxylic acids without there being a statement about their own pharmacological action.
Compounds of formula I with A=valency are described in other documents such as for example in US-A 3,737,316, FR-A 2,309,524 and FR-A 2,193,216 without a statement about a pharmacological action.
The compounds of the present invention have a strong antioxidant activity. The lipo~hilicity of this antioxidant group causes an acc:umulation of the compounds in the atherogenic low-density lipoprotein (LDL) and an e~fective 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 prereguisite for the pathologically increased uptake of atherogenic LDL into the atheroma ~ells is their oxidative modi~ication.
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 ef~ect in various animal species and in humans. It is a sterically hindered alkyl phenol which ~ g~'~J1 accumulatas 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 t~. 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 time in 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 plasma lipids by blocking the intestinal absorption of cholesterol which results in a reduction of the intrahepatic pool of free cholesterol and correspondingly 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) react~on. AC,AT catalyses the esterificatior1 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 thoracic duct.
The substances are readily absorbed and inhibit the ~CAT-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 ester.
~ 5 ~ ~ Jt 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-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 Rl, 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 Houblsn-Weyl, Vol. 9, p. 613).
R.~
X 1Ol e.g. pyridine ~o~ A-NH Cl-l-Y >
~ O - HCl R~
II III
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.
- 6 ~ 7 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 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.
The present invention also concerns new sulfonamides having the formula I' W- ~--A--N--SCIz - Y ( I l ) in which Rl and R2 denote in each case a tert. butyl group, A denotes a straight-chained alkylene chain with 1 to 5 C atoms or the group -CH2-CH(CH3)-X denotes a hydrogen atom or a Cl-C~ 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, trifluoromethyl, Cl-C4 alkyl, amino, C1-C4 acylamino, di(Cl-C~) alkylamino or by nitro, : as well as their pharmacologically sa~e salts.
The following compounds of formula I' are particularly preferred:
4-chlorobenzene-sulfo-(3~5-di-tert.butyl-4-hydroxy)-phenethylamide (example ld) 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) ~, Benzylsulfo-(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-[benzylsulfo-(3,5-di-tert.butyl-4-hydroxy)]-phenethylamide (example 5.13) 8 ~9~ 7 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)]-phenylpropylamide (example 5.25) 4-fluorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)-benzylamide (example 5.27) 2-[4-fluorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)]-phenethylamide (example 5.28) 2-[benzylsulfo-(3,5-di-tert.butyl-4-hydroxy)]-phenylpropylamide (example 5.32) 2-[(4-chlorobenzene)-sulfo-(3,5-di-tert.butyl-4-hydroxy)]-phenylpropylamide (example 5.37) 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 9 ~r~t~ r~
usual way with suitable pharmaceutical carrier substances, axomatics, 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 orally and parenterally in liquid or solid form. 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), high-molecular polymers (such as liquid polyethylene oxide) ~or the regulation of viscosity or polyethylene derivatives of sorbitol anhydrides.
Solid carrier materials 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 ~egetable fats or solid high-molecular polymers (such as polyethylene glycols).
Suitable preparations for 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 treatments and the typa of desired effect. The daily dosage of the active compound is usually 0.1 to 10 mg/kg body weight.
- 10 ~ 8ll7 Preferred compounds within the scope of the present invention, apart from 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 Example a) ~-hydroxy-3,5-di-tert.butyl-benzylchloride 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 Na2SO4, 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.butylbenzylcyanide 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 80-85C 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 (Na2SO4), evaporated and crystallized by addition of ligroin.
Yield: 61.1 g (61 % of theory) Melting point: 109-110C
analogous to Fuson and Rabjohn, org. Synth. Vol.
25, 66.
c) 3l5-di-tert.butyl-4-hydroxv-phenethylamine In a shaker autoclave 10 g Raney nickel and 100 ml liquid ammonia are added to 30 g (0.12 mol) 3,5-di-tert.butyl-4-hydroxy-benzylcyanide in 400 ml methanol while deep cooling and subsequently hydrogenated for 16 h in a hydrogen atmosphere at 80C and 140 bar. After releasing 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 MgSO4. After aga~n evaporating green, wax-like crystals remain.
Yield: quantitative (crude product).
-- 12 ~ $ ~ ~7 d) 4-chl~orobenzene-sulfo=~3,5~di-tert.buty1~4-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 o~
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 HCl, the organic phase is separated, washed and dried with Na2SO47 After removing the solvent in a vacuum the residue is purified by filtration over silica gel using 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: 122-23C.
Example 2 4-chlorobenzene-sul~o-(3L5-di-tert.butyl-4-hydroxy~benzylamide Ib 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 HCl, the organic phase - 13 - ~ ~ 9 ~
is separated, dried with Na2SO4 and the solvent is removed in a vacuum. The crude product thus obtained is recrystallized from toluene.
1.3 g colourless crystals, melting point: 119-21C.
~xample 3 N-methyl-4-chlorobenzene-slllfo-L3 5-di-tert.butyl-4-hydroxy)-benzylamide Ic (X = CH3) ==
1~5 g (4 mmol) 4-chlorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)benzylamide Ib is added to a suspension of ==
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 again for 3 h at room temperature. Subsequently it is poured onto l N HCl, 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:
140-43C.
Example 4 a) 3-(3,5-di-tert.butyl-4-hydroxyLehenylpropylamine In a shaker autoclave 10 g Raney nickel and 100 ml liquid ammonia are 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), ~9~7 HOECHST company) in 500 ml methanol while deep cooling and subsequently hydrogenated for 16 h in a hydrogen atmosphere at 80C and 140 bar. After releasing the autoclave, the cataly~er 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 and dried over MgSO4. After evaporating again a semi-solid mass remains which slowly completely solidifies.
70.2 g greenish crystals (crude product).
b) 4-chlorobenzenesulfo-3-(3~5-di-tert butyl-4-hydroxy~phenylpropylamide Id ==
2.04 ml (15 mmol) triethylamine is firstly 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: 152C.
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):
- 15 ~ 8~
Table .. _ _ ..... __ ..
- Example Y A m.p. [C]
. _ ..
5.1 ~3C ~C~2)3- valency 115-18 5.2 (C~3)2cX- valency 160-61 5.3 ~ -C~2- va.lency 123-24 5,4 H3C-(C~I2)3- -CH2- 74-75 5.5 ~C~3)2cH- -CX2- 114-15 ~ 16 -Table I continued . .. _ _ _ _ -.. _ Exampl e Y A m . p . [ C ]
.. ___ _", . _ ... __ 5. 6 ~--C~I2~ -~I2- 118-19 5 . 7 02N-~ -CH2~ 144-45 5 . 8 H2N- e~ ~CH2 - o i 1 5 . 9 H3COC-N~ -CH2- 174-76 5 .10 ~ -CH2- 145-4 6 5 .11 H3C- (CH2 ) 3~ -CH2-C~2- 109-10 5 . 12 ( C}I3 ) 2 CE- -CH2 -C~2-- 81- 8 2 5 .13 ~CH2 -CK2-CH2- 163-64 5.14 02N_ ~3 CH2-CX2- 147-48 5 .15 H2N- ~ -CX2-CR2-- oil 5 . 16 H3COC-N-e3 -C~2 -CH2 17 2 -7 8 5 .17 ~ -CH2-CH2 - 159 -6 0 5 .18 ~ -CH2 -CH2 - 9 4 ~9 5 5.~9 ~I3C-(CX2) 3~ -(C}~2) 3~ oil 5 . 2 o ( CH3 ) 2 CH- - ( CH2 ) 3 ~ oi 1 5 . 21 ~--CH2 ~ - ( C}I2 ) 3 oi 1 5 . 2 2 02N ~9 - ( CH2 ~ 3 - oi l Table I continued ~ .
Example Y A m.p. [c]
. ~
5.23 H2N- ~ -(CH2)3- 122 5.24 H3COC-N- ~ -(CH2)3- 164 5.25 ~ -(CH2)3 144 5.26 H3C- ~ -(CH2)3- 129-30 5.27 ~ F -CH2- 131-32 5.28 /~ ,-F -CH2-CH2- 118-20 5.29 ~rCH3 ,l 121-22 5.30 n-Butyl- -CH2-CH- 126 5.31 i-P~opyl- " 113-21 5.32 Benzyl- " 147-48 5.33 ~ ~ N02 " 139-40 5.34 ~ NH2 " 149-51 5.35 ~ N-COCH3 92-93 5.36 / ~ " 128-29 5.37 ~ Cl " 139-40 _ n-Butyl CH2-(CH3)2C- 90-91 . ._ _ s~
~ . ~
Example Y A m.p. [C]
.. _ . ~
5.39 Benzyl- " 143-44 5.40 ~N02 180~81 5.41 ~ ~NH2 " 147-48 5.42 ~N-C-CH3 " 195 - 98 5.43 ~~ " 177-79 5.44 ~Cl " 168-70 - 19 - ~n~
Example 6 Pharmacological investi~ations The compounds of formula I cr I' are antioxidant sul~onamide analogues and inhibitors of cholesterol ester formation in the arterial wall for the treatment of arteriosclerosis.
a) The cytogenesis of atheromatosis Hypercholesterolaemia and syndromes o~
hypercholesterolaemia/hypertriglycerideaemia are risk factors for premature arteriosclerosis. The oxidative modification of lipoproteins in the arterial wall plays an important role in the pathogenesis of the arteriosclerotic lesion itself.
It leads to the release of mediators which act chemotactically and to the migration of macrophagocytic cells from the blood into the arterial wall. In the vessel wall there is a particularly intensive unregulated uptake of oxidatively changed low-density lipoprotein ~LDL) by macrophages. The concomitant increase in cholesterol in~lux and the load on cellular metabolism leads to an increase in intracellular cholesterol, an increase in the reacylation of cholesterol and storage of cholesterol esters which in turn lead to the formation of large cytoplasmic cholesterol ester depots and to the degeneration of these macrophages ("foam cells"). The foam cells are the cellular substrate of the atheroma and create the macroscopically visible strips of fat from which the fibrous plaque lesions develop as the disease progressas.
- 20 ~ 9~7 b) The basis for an antiatherosclerotic therapy_in disturbances of fat metabolism ~n antiatherosclerotic therapy oriented towards causal relationships is ideally based on three pillars- 1. a decrease in the pathologically increased level of lipid in plasma by diet and/or drugs, 2. an effective antioxidant protection in particular for the strongly atherogenic LDL in order to reduce the oxidative LDL catabolism in the atheroma and 3. an inhibition of the formation of cholesterol esters in the foam cells of the early fat strip lesions.
Some agents which lower serum cholesterol act by contracting the hepatic pool of free cholesterol and increasing the catabolism of the atherogenic LDL cholesterol: ion excha;ngers interfere for example with the enterhepatic cholesterol circulation, cause a depleltion of bile acids in the hepatocytes and stimulate the u~take of choles~erol from the plasma compartment by an increased hepatic uptake of cholesterol via LDL and the hepatic apo B,E receptors (LDL receptors). The blockers of cholesterol synthesis, e.g. Lovastatin, act in a similar manner. They decrease hepatic cholesterol and also cause an increased uptake of LDL
cholesterol from the plasma by means of an increase in LDL receptors.
Blockers of cholesterol absorption also cause a lowering of the hepatic cholesterol pool by reducing the exogenous dietary load of cholesterol.
Examples of this are the so-called acyl CoA:
cholesterol acyl transferase (ACAT) inhibitors - 21 ~ 7 which suppress the cholesterol efflux via chylomicrons in the enterocytes by inhibiting the estarification of free cholesterol. In the liver these inhibitors of cholesterol ester formation in addition increase free cholesterol and endogenous hepatic cholesterol biosynthesis is indirectly inhibited by end-product inhibition. In the foam cells of the atheroma the blocking of cholesterol ester formation causes increased free cholesterol to be incorporated into the "reverse cholesterol transport pathway" of the high-density lipoproteins (HDL) and as a consequence this produces an additional direct antiatherogenic effect.
Antioxidants are substances which - when viewed in general - cause a substantial retardation oP the oxidative processes in a product which is to be protected. A potent antiatherosclerotically effective antioxidant is Probucol which, apart from its antioxidant action, has a hypolipidaemic action in various 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 substantially increased oxidative modification of :LDL in atherosclerotic lesi~ns of the arterial wall and as an antioxidant strongly inhibits atheroma formation by retarding the catabolism of LDL cholesterol in the foam cells.
- 22 - ~9~ ~r~
c) Amino substitu ~L~henols with an antiatherogenic actlon The compounds of formula I and I' fulfil all three aforementioned requirements for an effective pharmaceutial agent against premature atheromatosis and progressive arteriosclerosis since they act hypolipidaemically (Table 1) and exhibit a direct antiatherosclerotic activity in the atheroma by inhibition of cholesterol ester formation (Table 2) as well as by their antioxidative activities in LDL
(Table 2~ and in opposition to cellular lipoxygenases (Table 2).
d) Dose-dependent effect of the compound ~rom example 5.28 on the serum cholesterol level in rats with dietary induced hypercholesterolaemia.
Method:
SD rats weighing 220-250 ~ received a standard diet for 4 days which was enriched with 2 %
cholesterol/0.2 % cholic acid. The animals were ; intubated daily between 8 and 9 o'clock and received the stated single doses via a stomach tube in 2 ml vegetable oil. S-cholesterol was determined on day 5 (test kit ~rom Boehringer Mannheim Co.).
- ~3 Table 1:
Dose S-Cholesterol % Controls Statistics (mg/kg/d) (mg %) 0248 +/- 36 100 5187 +/- 23 75 p < 0.05 15120 ~/- 15 48 p < 0.05 50114 +/- 14 46 p < 0.02 10084 +/- 8 33 p < 0.01 . _ .
Mean +/- SEM, n=6 animals/group, statistics: U-test e) In vitro effect of the compounds o~ formula I
and I' Inhibition of cholesterol ester formation in macrophages (according to Huber et al. (1990) Free Rad. Res~ Comms. 8, 167-173):
Human plasma LDL was isolated by sequential ultracentrifugatioll at preselected densities from the plasma of healthy male non-smokers and incubated for 5 hours at 37C in F-10 medium + 1 ~M
Cu(II) to deplete its lipophilic antioxidants. The formation of cholesterol esters in P 388 D.1 macrophages under the influence of conditioned human plasma LDL was measured after incubating the cells (2 x 196/ml) for 18 hours in F-10 medium + 1 ~M Cu(II) + 50 ~g/ml LDL + 5 % FCS and after extracting the neutral fats by thin layar chromatography.
Reference substance: 10 ~M Probucol, 25-42 % (n=7) _ inhibition of cholesterol formation.
2~968~7 Stabilization of plasma LDL (according to Huber et al. (1990) Free Rad. Res. Comms. 8, 167-173):
LDL (125 ~g protein/ml) was oxidized at ~2C in 20 mM Tris-Cl pH 8, 150 mM NaCl, 10 ~M CuCl2 with and without the test compound (dissolved in ethanol, final ethanol concentration 0.5 %). In each case 3 molecules of test substan~e were used per L~L particle. The oxidation was monitored continuously by photometry at A 234 by measuring the diene formation. The so-called "lag phase" is defined as that time interval which is given by the intersection of the tangent to the curve during the propagation reaction of the lipid peroxidation with the time axis.
Reference substance: Probucol, 3 molecules/LDL
particle prolong the lag phase of LDL by 10 ~.
Inhibition o~ soya bean liPoxy~enase (15-li~oxygenase) w~ LDL as substrate (according to Cathcart et al. (1991) J. Lipid Res. 32, 63-70):
LDL (100 ~g protein/ml) was incubated at 37C in 20 mM Tris-Cl pH 8.3, 150 mM NaCl with and without the test substance (dissolved in ethanol, final ethanol concentration 0.5 %) with 5000 U/2 ml soya bean lipoxygenase (Sigma, Munich): The oxidation was monitored continuously by measuring the dienes at A 234. The stated IC50 value is that concentration of the test compound which leads to a halving of the diene formation in the test mixture which is linear over time.
.
- 25 - ~ 7 Reference substance: Probucol, IC50 value=20 ~M.
Table ?:
_ ._ ___ Compound Inhibition of Stabilization Inhibition of example) cholesterol ester of plasma LDL: 15-lipoxy-formation inincrease in genase-mediated macrophages"lag phase" LDL oxidation (P388D.1) % IC50 (~M) IC50 (~M) 10 ~M %
_ . ~
2 2.50 -78~7 44 0.2 3 -54.9 40 2 4b -49.2 0.2 5.10 7 -60.3 99 5 5.17 -78.0 50 3 5.19 -43.8 0.09 5.2~ 1.20 -92.6 25 <0.1 5.31 -33.9 18 0.2 - . . :
' ' -
.. ___ _", . _ ... __ 5. 6 ~--C~I2~ -~I2- 118-19 5 . 7 02N-~ -CH2~ 144-45 5 . 8 H2N- e~ ~CH2 - o i 1 5 . 9 H3COC-N~ -CH2- 174-76 5 .10 ~ -CH2- 145-4 6 5 .11 H3C- (CH2 ) 3~ -CH2-C~2- 109-10 5 . 12 ( C}I3 ) 2 CE- -CH2 -C~2-- 81- 8 2 5 .13 ~CH2 -CK2-CH2- 163-64 5.14 02N_ ~3 CH2-CX2- 147-48 5 .15 H2N- ~ -CX2-CR2-- oil 5 . 16 H3COC-N-e3 -C~2 -CH2 17 2 -7 8 5 .17 ~ -CH2-CH2 - 159 -6 0 5 .18 ~ -CH2 -CH2 - 9 4 ~9 5 5.~9 ~I3C-(CX2) 3~ -(C}~2) 3~ oil 5 . 2 o ( CH3 ) 2 CH- - ( CH2 ) 3 ~ oi 1 5 . 21 ~--CH2 ~ - ( C}I2 ) 3 oi 1 5 . 2 2 02N ~9 - ( CH2 ~ 3 - oi l Table I continued ~ .
Example Y A m.p. [c]
. ~
5.23 H2N- ~ -(CH2)3- 122 5.24 H3COC-N- ~ -(CH2)3- 164 5.25 ~ -(CH2)3 144 5.26 H3C- ~ -(CH2)3- 129-30 5.27 ~ F -CH2- 131-32 5.28 /~ ,-F -CH2-CH2- 118-20 5.29 ~rCH3 ,l 121-22 5.30 n-Butyl- -CH2-CH- 126 5.31 i-P~opyl- " 113-21 5.32 Benzyl- " 147-48 5.33 ~ ~ N02 " 139-40 5.34 ~ NH2 " 149-51 5.35 ~ N-COCH3 92-93 5.36 / ~ " 128-29 5.37 ~ Cl " 139-40 _ n-Butyl CH2-(CH3)2C- 90-91 . ._ _ s~
~ . ~
Example Y A m.p. [C]
.. _ . ~
5.39 Benzyl- " 143-44 5.40 ~N02 180~81 5.41 ~ ~NH2 " 147-48 5.42 ~N-C-CH3 " 195 - 98 5.43 ~~ " 177-79 5.44 ~Cl " 168-70 - 19 - ~n~
Example 6 Pharmacological investi~ations The compounds of formula I cr I' are antioxidant sul~onamide analogues and inhibitors of cholesterol ester formation in the arterial wall for the treatment of arteriosclerosis.
a) The cytogenesis of atheromatosis Hypercholesterolaemia and syndromes o~
hypercholesterolaemia/hypertriglycerideaemia are risk factors for premature arteriosclerosis. The oxidative modification of lipoproteins in the arterial wall plays an important role in the pathogenesis of the arteriosclerotic lesion itself.
It leads to the release of mediators which act chemotactically and to the migration of macrophagocytic cells from the blood into the arterial wall. In the vessel wall there is a particularly intensive unregulated uptake of oxidatively changed low-density lipoprotein ~LDL) by macrophages. The concomitant increase in cholesterol in~lux and the load on cellular metabolism leads to an increase in intracellular cholesterol, an increase in the reacylation of cholesterol and storage of cholesterol esters which in turn lead to the formation of large cytoplasmic cholesterol ester depots and to the degeneration of these macrophages ("foam cells"). The foam cells are the cellular substrate of the atheroma and create the macroscopically visible strips of fat from which the fibrous plaque lesions develop as the disease progressas.
- 20 ~ 9~7 b) The basis for an antiatherosclerotic therapy_in disturbances of fat metabolism ~n antiatherosclerotic therapy oriented towards causal relationships is ideally based on three pillars- 1. a decrease in the pathologically increased level of lipid in plasma by diet and/or drugs, 2. an effective antioxidant protection in particular for the strongly atherogenic LDL in order to reduce the oxidative LDL catabolism in the atheroma and 3. an inhibition of the formation of cholesterol esters in the foam cells of the early fat strip lesions.
Some agents which lower serum cholesterol act by contracting the hepatic pool of free cholesterol and increasing the catabolism of the atherogenic LDL cholesterol: ion excha;ngers interfere for example with the enterhepatic cholesterol circulation, cause a depleltion of bile acids in the hepatocytes and stimulate the u~take of choles~erol from the plasma compartment by an increased hepatic uptake of cholesterol via LDL and the hepatic apo B,E receptors (LDL receptors). The blockers of cholesterol synthesis, e.g. Lovastatin, act in a similar manner. They decrease hepatic cholesterol and also cause an increased uptake of LDL
cholesterol from the plasma by means of an increase in LDL receptors.
Blockers of cholesterol absorption also cause a lowering of the hepatic cholesterol pool by reducing the exogenous dietary load of cholesterol.
Examples of this are the so-called acyl CoA:
cholesterol acyl transferase (ACAT) inhibitors - 21 ~ 7 which suppress the cholesterol efflux via chylomicrons in the enterocytes by inhibiting the estarification of free cholesterol. In the liver these inhibitors of cholesterol ester formation in addition increase free cholesterol and endogenous hepatic cholesterol biosynthesis is indirectly inhibited by end-product inhibition. In the foam cells of the atheroma the blocking of cholesterol ester formation causes increased free cholesterol to be incorporated into the "reverse cholesterol transport pathway" of the high-density lipoproteins (HDL) and as a consequence this produces an additional direct antiatherogenic effect.
Antioxidants are substances which - when viewed in general - cause a substantial retardation oP the oxidative processes in a product which is to be protected. A potent antiatherosclerotically effective antioxidant is Probucol which, apart from its antioxidant action, has a hypolipidaemic action in various 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 substantially increased oxidative modification of :LDL in atherosclerotic lesi~ns of the arterial wall and as an antioxidant strongly inhibits atheroma formation by retarding the catabolism of LDL cholesterol in the foam cells.
- 22 - ~9~ ~r~
c) Amino substitu ~L~henols with an antiatherogenic actlon The compounds of formula I and I' fulfil all three aforementioned requirements for an effective pharmaceutial agent against premature atheromatosis and progressive arteriosclerosis since they act hypolipidaemically (Table 1) and exhibit a direct antiatherosclerotic activity in the atheroma by inhibition of cholesterol ester formation (Table 2) as well as by their antioxidative activities in LDL
(Table 2~ and in opposition to cellular lipoxygenases (Table 2).
d) Dose-dependent effect of the compound ~rom example 5.28 on the serum cholesterol level in rats with dietary induced hypercholesterolaemia.
Method:
SD rats weighing 220-250 ~ received a standard diet for 4 days which was enriched with 2 %
cholesterol/0.2 % cholic acid. The animals were ; intubated daily between 8 and 9 o'clock and received the stated single doses via a stomach tube in 2 ml vegetable oil. S-cholesterol was determined on day 5 (test kit ~rom Boehringer Mannheim Co.).
- ~3 Table 1:
Dose S-Cholesterol % Controls Statistics (mg/kg/d) (mg %) 0248 +/- 36 100 5187 +/- 23 75 p < 0.05 15120 ~/- 15 48 p < 0.05 50114 +/- 14 46 p < 0.02 10084 +/- 8 33 p < 0.01 . _ .
Mean +/- SEM, n=6 animals/group, statistics: U-test e) In vitro effect of the compounds o~ formula I
and I' Inhibition of cholesterol ester formation in macrophages (according to Huber et al. (1990) Free Rad. Res~ Comms. 8, 167-173):
Human plasma LDL was isolated by sequential ultracentrifugatioll at preselected densities from the plasma of healthy male non-smokers and incubated for 5 hours at 37C in F-10 medium + 1 ~M
Cu(II) to deplete its lipophilic antioxidants. The formation of cholesterol esters in P 388 D.1 macrophages under the influence of conditioned human plasma LDL was measured after incubating the cells (2 x 196/ml) for 18 hours in F-10 medium + 1 ~M Cu(II) + 50 ~g/ml LDL + 5 % FCS and after extracting the neutral fats by thin layar chromatography.
Reference substance: 10 ~M Probucol, 25-42 % (n=7) _ inhibition of cholesterol formation.
2~968~7 Stabilization of plasma LDL (according to Huber et al. (1990) Free Rad. Res. Comms. 8, 167-173):
LDL (125 ~g protein/ml) was oxidized at ~2C in 20 mM Tris-Cl pH 8, 150 mM NaCl, 10 ~M CuCl2 with and without the test compound (dissolved in ethanol, final ethanol concentration 0.5 %). In each case 3 molecules of test substan~e were used per L~L particle. The oxidation was monitored continuously by photometry at A 234 by measuring the diene formation. The so-called "lag phase" is defined as that time interval which is given by the intersection of the tangent to the curve during the propagation reaction of the lipid peroxidation with the time axis.
Reference substance: Probucol, 3 molecules/LDL
particle prolong the lag phase of LDL by 10 ~.
Inhibition o~ soya bean liPoxy~enase (15-li~oxygenase) w~ LDL as substrate (according to Cathcart et al. (1991) J. Lipid Res. 32, 63-70):
LDL (100 ~g protein/ml) was incubated at 37C in 20 mM Tris-Cl pH 8.3, 150 mM NaCl with and without the test substance (dissolved in ethanol, final ethanol concentration 0.5 %) with 5000 U/2 ml soya bean lipoxygenase (Sigma, Munich): The oxidation was monitored continuously by measuring the dienes at A 234. The stated IC50 value is that concentration of the test compound which leads to a halving of the diene formation in the test mixture which is linear over time.
.
- 25 - ~ 7 Reference substance: Probucol, IC50 value=20 ~M.
Table ?:
_ ._ ___ Compound Inhibition of Stabilization Inhibition of example) cholesterol ester of plasma LDL: 15-lipoxy-formation inincrease in genase-mediated macrophages"lag phase" LDL oxidation (P388D.1) % IC50 (~M) IC50 (~M) 10 ~M %
_ . ~
2 2.50 -78~7 44 0.2 3 -54.9 40 2 4b -49.2 0.2 5.10 7 -60.3 99 5 5.17 -78.0 50 3 5.19 -43.8 0.09 5.2~ 1.20 -92.6 25 <0.1 5.31 -33.9 18 0.2 - . . :
' ' -
Claims (5)
1. Pharmaceutical agent containing at least one sulfonamide having the general formula I
I
in which R1 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 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) alkylamino or nitro, provided that A can also denote valency if Y does not represent an aryl residue, as well as their pharmacologically safe salts in addition to the usual carrier and auxiliary substances.
I
in which R1 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 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) alkylamino or nitro, provided that A can also denote valency if Y does not represent an aryl residue, as well as their pharmacologically safe salts in addition to the usual carrier and auxiliary substances.
2. New sulfonamides having the formula I' I' in which R1 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 alkyl 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) alkylamino or nitro.
3. Compounds as claimed in claim 2 selected from the group 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 Benzylsulfo-(3,5-di-tert.butyl-4-hydroxy)-benzylamide 2,4,6-tris-isopropyl-benzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)-benzylamide 2-[benzylsulfo-(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)]-phenethylpropylamide 4-fluorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)-benzylamide 2-[4-fluorobenzene-sulfo-(3,5-di-tert.butyl-4-hydroxy)-phenethylamide 2-[benzylsulfo-(3,5-di-tert.butyl-4-hydroxy)]-phenylpropylamide 2-[(4-chlorobenzene)-sulfo-(3,5-di-tert.butyl-4-hydroxy)]-phenylpropylamide
4. Process for the production of compounds of formula I' in which R1 and R2 each denote a tert. butyl group, A denotes a straight-chained alkylene chain with 1 to 5 C atoms or the group X denotes a hydrogen atom or a C1-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, trifluoromethyl, C1-C4 alkyl, amino, C1-C4 acylamino, di(C1-C4) alkylamino or nitro, as well as their pharmacologically safe salts, wherein, either a) an amine having the formula II
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
III
in which Y has the stated meaning, or b) in case A represents an alkylene chain, a sulfonamide having the formula IV
IV
in which X and Y have the stated meanings, is reacted in a known manner with an aralkyl halide having the formula V
V
in which R1 and R2 have the stated meanings, A represents an alkyl chain and Hal represents a halogen atom, and in case X denotes hydrogen, the compounds obtained are subsequently converted in the usual way into other compounds in which X=alkyl and, if desired, the compounds obtained are also converted into pharmacologically safe salts.
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
III
in which Y has the stated meaning, or b) in case A represents an alkylene chain, a sulfonamide having the formula IV
IV
in which X and Y have the stated meanings, is reacted in a known manner with an aralkyl halide having the formula V
V
in which R1 and R2 have the stated meanings, A represents an alkyl chain and Hal represents a halogen atom, and in case X denotes hydrogen, the compounds obtained are subsequently converted in the usual way into other compounds in which X=alkyl and, if desired, the compounds obtained are also converted into pharmacologically safe salts.
5. Use of compounds as claimed in claim 11 2 or 3 as antiatherosclerotic agents.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4037174.3 | 1990-11-22 | ||
| DE4037174A DE4037174A1 (en) | 1990-11-22 | 1990-11-22 | NEW SULPHONAMIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2096847A1 true CA2096847A1 (en) | 1992-05-23 |
Family
ID=6418735
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002096847A Abandoned CA2096847A1 (en) | 1990-11-22 | 1991-11-19 | Pharmaceutical preparations containing sulfonamides novel sulfonamides and processes for their production |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0558569B1 (en) |
| JP (1) | JPH06502632A (en) |
| AT (1) | ATE117674T1 (en) |
| AU (1) | AU659421B2 (en) |
| CA (1) | CA2096847A1 (en) |
| DE (2) | DE4037174A1 (en) |
| FI (1) | FI932323A0 (en) |
| HU (1) | HUT68277A (en) |
| IE (1) | IE914044A1 (en) |
| IL (1) | IL100120A0 (en) |
| MX (1) | MX9102127A (en) |
| NZ (1) | NZ240630A (en) |
| PT (1) | PT99572A (en) |
| TW (1) | TW264466B (en) |
| WO (1) | WO1992009571A1 (en) |
| ZA (1) | ZA919206B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5491170A (en) * | 1994-12-19 | 1996-02-13 | Warner-Lambert Company | β-carboxy sulfonamide ACAT inhibitors |
| JP6410790B2 (en) * | 2013-03-14 | 2018-10-24 | ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー | Mitochondrial aldehyde dehydrogenase-2 modulator and method of use thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3737316A (en) * | 1971-08-31 | 1973-06-05 | Eastman Kodak Co | Two-equivalent sulfonamido couplers |
| US3801321A (en) * | 1972-07-18 | 1974-04-02 | Eastman Kodak Co | Photothermographic element,composition and process |
| US4013621A (en) * | 1975-04-29 | 1977-03-22 | Ciba-Geigy Corporation | Substituted sulfonamide derivatives of hindered phenols and stabilized compositions |
| DE2809377A1 (en) * | 1978-03-04 | 1979-09-13 | Boehringer Mannheim Gmbh | PHENOXYALKYL CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| IL83230A (en) * | 1986-08-06 | 1992-06-21 | Tanabe Seiyaku Co | Phenoxyacetic acid derivatives,their preparation and pharmaceutical compositions containing them |
| EP0325245B1 (en) * | 1988-01-19 | 1993-10-20 | Tanabe Seiyaku Co., Ltd. | Phenoxyacetic acid derivatives, preparation thereof, pharmaceutical compositions comprising them and use |
-
1990
- 1990-11-22 DE DE4037174A patent/DE4037174A1/en not_active Withdrawn
-
1991
- 1991-11-07 TW TW080108804A patent/TW264466B/zh active
- 1991-11-18 NZ NZ240630A patent/NZ240630A/en unknown
- 1991-11-19 EP EP91920295A patent/EP0558569B1/en not_active Expired - Lifetime
- 1991-11-19 MX MX9102127A patent/MX9102127A/en unknown
- 1991-11-19 CA CA002096847A patent/CA2096847A1/en not_active Abandoned
- 1991-11-19 JP JP4500024A patent/JPH06502632A/en active Pending
- 1991-11-19 WO PCT/EP1991/002186 patent/WO1992009571A1/en active IP Right Grant
- 1991-11-19 HU HU9301498A patent/HUT68277A/en unknown
- 1991-11-19 DE DE59104443T patent/DE59104443D1/en not_active Expired - Fee Related
- 1991-11-19 AT AT91920295T patent/ATE117674T1/en not_active IP Right Cessation
- 1991-11-19 AU AU89057/91A patent/AU659421B2/en not_active Ceased
- 1991-11-21 PT PT99572A patent/PT99572A/en not_active Application Discontinuation
- 1991-11-21 IL IL100120A patent/IL100120A0/en unknown
- 1991-11-21 ZA ZA919206A patent/ZA919206B/en unknown
- 1991-11-21 IE IE404491A patent/IE914044A1/en unknown
-
1993
- 1993-05-21 FI FI932323A patent/FI932323A0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1992009571A1 (en) | 1992-06-11 |
| HUT68277A (en) | 1995-06-28 |
| AU659421B2 (en) | 1995-05-18 |
| MX9102127A (en) | 1992-07-08 |
| EP0558569B1 (en) | 1995-01-25 |
| EP0558569A1 (en) | 1993-09-08 |
| FI932323A (en) | 1993-05-21 |
| ATE117674T1 (en) | 1995-02-15 |
| TW264466B (en) | 1995-12-01 |
| JPH06502632A (en) | 1994-03-24 |
| FI932323A0 (en) | 1993-05-21 |
| PT99572A (en) | 1992-10-30 |
| AU8905791A (en) | 1992-06-25 |
| HU9301498D0 (en) | 1993-09-28 |
| IL100120A0 (en) | 1992-08-18 |
| NZ240630A (en) | 1994-12-22 |
| DE59104443D1 (en) | 1995-03-09 |
| ZA919206B (en) | 1992-08-26 |
| DE4037174A1 (en) | 1992-05-27 |
| IE914044A1 (en) | 1992-06-03 |
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