[go: up one dir, main page]

WO1991013868A1 - Derives d'acide phenylthioalkylcarboxylique, leur procede de production et medicaments contenant ces composes - Google Patents

Derives d'acide phenylthioalkylcarboxylique, leur procede de production et medicaments contenant ces composes Download PDF

Info

Publication number
WO1991013868A1
WO1991013868A1 PCT/EP1991/000383 EP9100383W WO9113868A1 WO 1991013868 A1 WO1991013868 A1 WO 1991013868A1 EP 9100383 W EP9100383 W EP 9100383W WO 9113868 A1 WO9113868 A1 WO 9113868A1
Authority
WO
WIPO (PCT)
Prior art keywords
compounds
group
formula
hydrogen
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1991/000383
Other languages
German (de)
English (en)
Inventor
Hansjörg BECKH
Ernst-Christian Witte
Karlheinz Stegmeier
Liesel Dörge
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Diagnostics GmbH
Original Assignee
Boehringer Mannheim GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Mannheim GmbH filed Critical Boehringer Mannheim GmbH
Publication of WO1991013868A1 publication Critical patent/WO1991013868A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/46—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
    • C07C323/49—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms to sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom

Definitions

  • Phenylthioalkylcarboxylic acid derivatives processes for their preparation and medicaments containing these compounds
  • the present invention relates to new sulfonamides of the general formula I.
  • R 1 represents aryl, aralkyl or an aralkenyl group, the aryl radical of which can optionally be substituted one or more times by halogen, cyano, alkyl, trifluoromethyl, alkoxy, alkylthio, trifluoromethoxy, hydroxy or carboxy, n is an integer from 1 to 3, m is an integer from 0 to 2,
  • p is an integer from 1 to 6
  • R 2 can be hydrogen, an alkyl, aralkyl or acyl group
  • R 3 represents hydrogen, halogen, trifluoromethyl, alkyl, aralkyl or alkoxy,
  • R 4 denotes hydroxy, alkoxy or a group
  • R 5 and R 6 are the same or different and are hydrogen
  • R 4 is a tetrazolyl radical
  • R 7 denotes hydrogen or a lower alkyl group with 1-3 C atoms, which may be terminated by carboxyl, aminocarbonyl, alkoxycarbonyl, by alkylthio, hydroxyl,
  • R 8 can be hydrogen, or R 7 together with R 8 forms an alkylene chain with 3 or 4 carbon atoms.
  • salts, esters or amides form, they are - if physiologically harmless - the subject of the invention. If the compounds I contain asymmetric carbons, so are their pure optical isomers (enantiomers) or their
  • the new compounds of general formula I show an excellent antagonistic action against thromboxane A 2 and against prostaglandin endoperoxides. They inhibit activation platelets and other blood cells and prevent the constriction of the smooth muscles of the bronchi and blood vessels as well as the contraction of magnesium lines and similar cells with contractile properties.
  • cardiovascular diseases such as acute heart and brain infarction, cerebral and coronary ischemia, migraines, peripheral arterial occlusive disease and venous and arterial diseases
  • Thrombosis Furthermore, their early application can have a beneficial effect on the occurrence of organ damage in shock patients. They are also suitable for preventing the drop in platelets and leukocytes during interventions with an extracorporeal circuit and during hemodialysis. Their addition to platelet concentrates stabilizes the platelets and thus increases the shelf life of the canned food.
  • thromboxane is a mediator of the inflammatory response in bronchial asthma
  • the use of these thromboxane receptor blockers can, in particular, weaken or even eliminate the hyperreactivity characteristic of chronic asthma.
  • the new thromboxane receptor blockers have a protective effect against gastritis and ulcer tendency and can therefore be used to prevent recurrence.
  • the course could be improved by using a thromboxane antagonist. It is therefore to be expected that at least certain forms of acute pancreatitis in humans can be improved in their prognosis by using these thromboxane antagonists.
  • they are able to inhibit the incorporation of acetate into cholesterol and are therefore also suitable for the treatment of fat metabolism diseases, which are associated with increased cholesterol synthesis.
  • their pronounced anti-atherogenic effect with elevated serum cholesterol values which is shown by a reduction in plaque formation, particularly in the coronary arteries and in the aorta.
  • kidney diseases e.g. Increased excretion of thromboxane B2 in the urine was observed in glomerulonephritis, acute renal failure, graft rejection and kidney damage due to nephrotoxic substances.
  • an intervention with the new thromboxane antagonists is promising in terms of maintaining kidney function.
  • Blocking the thromboxane and PGF2alpha receptors can therefore, in particular, interrupt premature labor and a more favorable course can be achieved with gestational gestation or eclampsia.
  • the prostaglandin-related symptoms of dysmenorrhea and premenstrual syndrome can be treated.
  • alkyl means a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms. Lower alkyl having 1 to 6 carbon atoms is preferred. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl or isooctyl.
  • alkoxy stands for a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms which is bonded via an oxygen atom. Lower alkoxy having 1 to about 6 carbon atoms is preferred. An alkoxy radical having 1 to 4 carbon atoms is particularly preferred. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy.
  • alkylthio is understood to mean a straight-chain or branched hydrocarbon radical having 1 to 12 carbon atoms which is bonded via a sulfur atom. Is preferred
  • Lower alkylthio with 1 to 6 carbon atoms is particularly preferred. Examples include methylthio, ethylthio, propylthio, iso-propylthio, butylthio, isobutylthio, pentylthio, isopentylthio,
  • aryl is intended to mean an aromatic radical having 6 to 14 carbon atoms. Preferred aryl radicals are
  • Phenyl, naphthyl, biphenyl or fluorenyl can be substituted one or more times in all possible positions, the substituents being halogen, C 1 -C 6 alkyl, C 1 -C 6
  • phenyl radical is preferred, which is halogen, preferably chlorine and bromine, cyan, methyl, trifluoromethyl, 4-chlorophenyl or acetyl
  • Aralkenyl means an aryl residue with 6 - 14 carbon atoms which is bonded via 2-6 unsaturated carbon atoms.
  • Aralkenyl radicals having 2 to 4 carbon atoms in the alkenyl part are preferred.
  • the styryl radical and the 4-chlorostyryl radical may be mentioned as examples.
  • aralkyl stands for an aryl radical with 6 to 14 carbon atoms bonded via an alkylene chain.
  • Aralkyl radicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred.
  • the following aralkyl radicals may be mentioned as examples: benzyl, naphthylmethyl, phenethyl or phenylpropyl.
  • the acyl radicals R 2 are derived from aliphatic carboxylic acids with 2-16 C atoms, from araliphatic and from aromatic carboxylic acids.
  • Preferred acyl groups are acetyl, isobutyroyl, cinnamoyl, benzoyl, 4-chlorobenzoyl and 4-aminobenzoyl as well as n-octanoyl or n-hexadecanoyl.
  • Halogen is fluorine, chlorine, bromine or iodine, preferably
  • Halogen is particularly preferably fluorine or chlorine.
  • n is preferably the number 2.
  • R 8 is preferably a hydrogen atom, or R 8 together with R 7 forms an alkylene chain with 3 or 4 carbon atoms, ie there is a 5- or 6-ring which contains a nitrogen atom. Compounds with 5 rings, such as proline, are preferred here.
  • R 7 preferably represents a hydrogen atom, or R 7 is one
  • the preferred substituents are:
  • Substituents optionally contained phenyl nuclei may also contain 1-2 halogen atoms (preferably chlorine).
  • the particularly preferred substituents are: carboxyl, aminocarbonyl, diethylaminocarbonyl, 4-benzyl- or 4- (4-chlorobenzyl) piperazin-1-yl-carbonyl, methoxy- or ethoxy-carbonyl,
  • R 4 represents the residue of an amino acid, this should preferably be understood to mean the amino acids - and ⁇ -alanine, glycine, phenylalanine, serine, proline or histidine.
  • Alcohols such as glycerol in question, but also include alcohols which also contain other functional groups, such as Ethanolamine.
  • the amine component for example ammonia, a lower dialkylamine such as diethylamine or a hydroxyalkylamine such as ethanolamine or is diethanolamine.
  • Other claimed amine components are alkyl, aralkyl and aryl piperazines.
  • the claim also includes the pure optical isomers (enantiomers) of the compounds of the general formula I and their mixtures (racemates).
  • Preferred compounds of the formula I are those in which
  • R 1 is phenyl, 4-chlorophenyl, 4-methylphenyl or 4-trifluoromethyl
  • R 2 is hydrogen, methyl, acetyl or benzyl
  • R 3 is hydrogen, methyl, methoxy or halogen
  • R 1 , R 2 , R 3 and n have the meaning given above, with halocarboxylic acids of the formula III
  • a general sulfonic acid is condensed Formula V,
  • shark e.g. represents chlorine or bromine, sulfohalogenated to a compound of formula IX.
  • the compounds IX are now with reducing agents, for example with tin / hydrochloric acid, in the compounds of
  • the compounds of the formula I in which the thioalkyl radical is in the meta position to the sulfonaminoalkyl group can be prepared by b) an amine of the formula XII
  • R 1 , R 2 , R 3 , n, m and p have the meaning given above, or a reactive derivative thereof, including esters such as methyl, cyanomethyl, ethyl and p-nitrophenyl esters, anhydrides, amides such as Imidazolides and acid halides such as acid chlorides or acid bromides are understood, with 5-amino-1,2,3,4-tetrazole (X), optionally in the form of the hydrate
  • R 7 and R 8 have the meaning given above.
  • X is a group COOR 9 , where R 9 is a hydrogen atom or an equivalent of a metal ion, or a lower alkyl, aralkyl or. Represents silyl group.
  • X can also represent an acid amide group or a residue which, after condensation has occurred, in an acid amide group or is converted into the -COOR 9 group, whereupon, if necessary, a certain substituent R 9 is converted into another substituent R 9 in a manner known per se and the compounds obtained are converted into pharmacologically acceptable salts.
  • c) It is also possible to use the sulfonic acids
  • condensation of the mercaptans II or XVI with haloalkyl carboxylic acids or with their esters or their amides is advantageously carried out with the addition of an acid-binding agent, e.g. an alkali metal carbonate, an alkali metal oxide, an alkali metal bicarbonate or an organic amine (e.g. pyridine, triethylamine) in an inert solvent.
  • an acid-binding agent e.g. an alkali metal carbonate, an alkali metal oxide, an alkali metal bicarbonate or an organic amine (e.g. pyridine, triethylamine) in an inert solvent.
  • an acid-binding agent e.g. an alkali metal carbonate, an alkali metal oxide, an alkali metal bicarbonate or an organic amine (e.g. pyridine, triethylamine) in an inert solvent.
  • examples include acetone, chloroform, low
  • Alcohols methylene chloride, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide or a mixture thereof.
  • thiophenyl ether formation can also be used, e.g. phase transfer catalysis.
  • the oxidation of the sulfenyl compounds IV and XVIII to the sulfinyl and sulfonyl compounds takes place either with an inorganic oxidizing agent such as H 2 O 2 , NaJO 4 , KMnO 4 , NaCIO or Oxon R (potassium hydrogen peroxomonosulfate), or with an organic peracid such as m-chloroperbenzoic acid.
  • an inorganic oxidizing agent such as H 2 O 2 , NaJO 4 , KMnO 4 , NaCIO or Oxon R (potassium hydrogen peroxomonosulfate)
  • an organic peracid such as m-chloroperbenzoic acid.
  • Solvents come water, lower aliphatic carboxylic acids such as Acetic acid, or chlorinated hydrocarbons in
  • reaction of the sulfonic acid of the formula V with a compound of the formula VI or XII is advantageously carried out in a solvent such as dichloromethane, ether, tetrahydrofuran, dioxane or benzene or in a solvent mixture thereof.
  • the process is carried out in the presence of an acid-binding agent such as sodium carbonate, triethylamine or pyridine, the latter two also being able to serve as solvents at the same time.
  • an acid activating or dehydrating agent such as thionyl chloride or phosphorus pentachloride is advantageous.
  • preference will be given to working with a reactive derivative of a sulfonic acid of the formula V, for example with its anhydride or halide.
  • the reaction temperatures are between 0 and 100 ° C, for example at temperatures between room temperature and 50 ° C.
  • sulfohalogenation of sulfonamides VII with halogen sulfonic acids VIII, preferably with chlorosulfonic acid is carried out using methods known from the literature (e.g. Oranikum, VEB Deutscher Verlag dermaschineen, Berlin 1984).
  • the halosulfonic acid is used in excess, and one can work with or without a solvent. Common solvents are
  • reaction temperatures range between -20oC and 150oC, preferably between -10oC and + 120oC. If solvents are used, the reaction temperatures are between -20 ° C and the boiling point of the solvent used.
  • the reduction of the sulfohalides IX to the mercaptans II takes place according to the methods described in the literature (e.g. Houben-Weyl, Methods of Organic Chemistry, Volume “Sulfur Compounds”).
  • the metal powders of zinc, tin, iron or calcium are suitable, but tin (II) chloride, zinc or aluminum amalgam can also be used.
  • the reduction is carried out in the presence of acids; In addition to hydrochloric acid, sulfuric acid and glacial acetic acid mixed with hydrogen chloride gas or with concentrated hydrochloric acid are used.
  • the reduction can also be carried out electrolytically or with metal hydrides, for example with lithium aluminum hydride, aprotic solvents such as ether, THF or dioxane serving as the reaction medium.
  • metal hydrides for example with lithium aluminum hydride, aprotic solvents such as ether, THF or dioxane serving as the reaction medium.
  • TMS trimethylsiyl
  • N group is then protected by reaction with acid chlorides, e.g. B. acetyl chloride, benzoyl chloride or p-nitrobenzoyl chloride.
  • acid chlorides e.g. B. acetyl chloride, benzoyl chloride or p-nitrobenzoyl chloride.
  • Other protecting groups are also possible, such as the t-butyl carbamate (BOC) and benzyl carbamate (CBZ) group.
  • BOC t-butyl carbamate
  • CBZ benzyl carbamate
  • the O-protecting group is then split off again.
  • the reaction of the carbamic acid chloride XIV with the phenolate produced from a phenol and a base is generally carried out in an aqueous medium, the acid chloride, dissolved in inert but water-miscible solvents, such as. B. THF, glyme or diglyme, is added dropwise to the aqueous solution of the phenolate.
  • inert but water-miscible solvents such as. B. THF, glyme or diglyme
  • reaction temperatures are generally between 0 ° and 25 ° C, preferably between 0 ° and 5 ° C.
  • the pyrolysis is carried out in high-boiling solvents, for example diphenylmethane, diphenyl ether or biphenyl, but can also be carried out without a solvent.
  • the reaction is advantageously carried out under an inert gas, for. B. nitrogen or argon.
  • the reaction temperatures are between 250 ° and 300 ° C., preferably between 265 ° and 275 ° C.
  • the reaction time is 30-60 minutes, but usually about 45 minutes.
  • the hydrolysis of the S-aryl-dialkylthiocarbamides XVI to the thiols XVII is carried out using the customary bases, for example KOH, NaOH, Ca (OH) 2 , KO t Bu, K 2 CO 3 or Na 2 CO 3 . It can join the pyrolysis in a one-pot reaction. After the reaction apparatus has cooled, it has proven expedient to add a water-miscible solvent, for example ethylene glycol. The hydrolysis is generally carried out at a reaction temperature which corresponds to the boiling point of the solvent mixture.
  • polyphosphoric acid which then simultaneously serves as a solvent, or isobutyl chloroformate in the presence of an aprotic polar solvent, such as. B. Dimethylformamide.
  • Suitable solvents are methylene chloride, carbon tetrachloride, diethyl ether, toluene, xylene or chlorobenzene.
  • the product precipitates out of the solution and is obtained by filtration. If necessary, the reaction mixture can be concentrated to a point where the product begins to precipitate out of solution.
  • Acidic cation exchangers, sulfonium salts, sulfuric acid halides, 2-halopyridinium salts, phosphonium salts and N, N'-dicyclohexylcarbodiimide are suitable as further condensing agents in this reaction.
  • esters are used instead of the carboxylic acids, then one works in the presence or absence of special solvents at temperatures in the range from 20 ° C. to the boiling point of the mixture.
  • the reaction of approximately equimolar amounts of the amine and the ester in polyphosphoric acid at 50 ° C. to 200 ° C. is preferred, but it is also best in an inert solvent such as methylene chloride, benzene, toluene, chlorobenzene in the presence of a little more than one equivalent a base such as sodium ethanolate or butyllithium or sodium hydride in dimethyl sulfoxide.
  • the reaction with the amine (X) can already be carried out at temperatures between room temperature and 60 ° C. It is preferred to work in an inert solvent such as Dichloromethane, diethyl ether, benzene, toluene.
  • an inert solvent such as Dichloromethane, diethyl ether, benzene, toluene.
  • the amine and the anhydride are combined in approximately equimolar amounts, an exothermic reaction generally starting. After the reaction has subsided, it is gently warmed for a while to complete the reaction.
  • an organic solvent such as tetrahydrofuran, toluene , Benzene or diethyl ether
  • Amines XI have proven to be expedient to use the carboxylic acids in the form of reactive derivatives. Suitable acid halides, anhydrides, imidazolides, the mixed anhydrides of the carboxylic acid and a chloroformate, active esters such as nitrophenyl ester or hydroxyphthalimide or hydroxysuccinimide ester are suitable.
  • active esters such as nitrophenyl ester or hydroxyphthalimide or hydroxysuccinimide ester are suitable.
  • the condensation between free carboxylic acid I and amine component XI in the presence of water-releasing agents such as dicyclohexylcarbodiimide is also favorable.
  • the acid function of the amine component can be in the salt form, but it is often more favorable to start from the esterified aminocarboxylic acid XI, the use of the trialkylsilyl esters having proven to be particularly advantageous.
  • the amino group is optionally silylated at the same time, so that trialkylsilyl esters of N-trialkylsilylamino result.
  • These can be condensed with the activated carboxylic acids X in the same way as non-silylated amino acid esters on nitrogen.
  • the amino group of the amino acids or their esters can optionally also be reacted in the salt form.
  • Possible solvents are: water-alcohol mixtures (e.g.
  • Acid halide a mixed anhydride or an active ester, in an inert solvent in the presence of bases.
  • inert solvents examples include methylene chloride, benzene, dimethylformamide and the like. in question.
  • -COOR 9 group can be converted, for example the nitrile, carbaldehyde, hydroxymethyl, aminomethyl and formyl groups are suitable.
  • a polar solvent for example Water, aqueous methanol, aqueous ethanol or aqueous dioxane
  • the esterification of the carboxylic acids is expediently carried out in the presence of an acidic catalyst, such as, for example, hydrogen chloride, sulfuric acid, p-toluenesulfonic acid or a strong acidic ion exchange resin.
  • transesterifications require the addition of a small amount of a basic substance, for example an alkali metal or alkaline earth metal hydroxide or an alkali metal alcoholate.
  • all alcohols are suitable for the esterification of the carboxy group or for a transesterification.
  • the lower monohydric alcohols such as methanol, ethanol or propane, and polyhydric alcohols, for example glycerol or alcohols with other functional groups, such as ethanolamine or glycerol ether, are preferred.
  • the amides according to the invention are preferably prepared by methods known per se from the carboxylic acids or their reactive derivatives (such as, for example, carboxylic acid halides, esters, azides, anhydrides or mixed anhydrides) by reaction with amines .
  • Examples of amino components are ammonia, alkylamines,
  • Dialkylamines but also amino alcohols such as Ethanolamine and 2-aminopropanol in question.
  • Other valuable amine components are alkyl, aralkyl and aryl piperazines.
  • the compounds of general formula I according to the invention can also contain asymmetric carbon atoms.
  • the invention therefore also relates to diastereomers, racemates and the optically active forms of the compounds of the general formula I according to the invention. If diastereomers are obtained in the synthesis of the compounds according to the invention, they can be separated into the corresponding racemates by column chromatography.
  • optically active compounds can be prepared from their racemic mixtures by methods known per se.
  • Basic or acidic racemic mixtures can e.g. are split into their optically active forms via their diastereomeric salts.
  • racemate resolution e.g. Tartaric acid, malic acid, camphoric acid, camphor sulfonic acid, dibenzoyl tartaric acid, cinchonine, phenethylamine, brucine or quinine can be used.
  • Neutral racemic mixtures can be separated chromatographically into the optically active forms on chiral phases.
  • salts with physiologically compatible organic or inorganic bases such as, for example Sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, methylglucamine, morpholine, triethylamine or ethanolamine can the compounds of formula I with the
  • the compounds of general formula I are known in a manner known per se with suitable pharmaceutical carriers, aroma, flavor and
  • the substances of the general formula I can be administered orally and parenterally in liquid or solid form.
  • Water is preferably used as the injection medium, which contains the stabilizers, solubilizers and / or buffers customary for injection solutions.
  • Such additives are e.g. B. tartrate or borate buffer, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation or polyethylene derivatives of sorbitan hydrides.
  • Solid carriers are e.g. B. starch, lactose, mannitol, methyl cellulose, talc, highly disperse silica, higher molecular weight fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats or solid high molecular weight polymers (such as polyethylene glycols).
  • Preparations suitable for oral administration can optionally contain flavorings and sweeteners.
  • the dosage administered depends on the age, health and weight of the recipient, the extent of the disease, the type of further treatments which may be carried out at the same time, the frequency of the treatments and the type of effect desired.
  • the daily dose of the active compound is usually 0.1 to 50 mg / kg body weight. Typically 0.5 to 40 and preferably 1.0 to 20 mg / kg are effective in one or more applications per day to achieve the desired results.
  • the resulting pale yellow oil can be recrystallized from ethyl acetate / n-heptane.
  • the yield of the title compound is 6.6 g (47%), colorless crystals, mp. 120-123 ° C.
  • the mixture is stirred for a further 5 hours at room temperature, then hydrolyzed with 2N hydrochloric acid, the acid phase is separated off and the organic phase is washed three times each with water, saturated sodium bicarbonate solution and again with water and the ethyl acetate phase with sodium sulfate and evaporated in vacuo on. 137 g (67%) of colorless crystals, mp. 114-115 ° C., are obtained.
  • Example 14 The oily residue of Example 14 (30.3 g, 92.3 mmol) is taken up in 200 ml of ethylene glycol, 5.5 g of NaOH in 60 ml of water and boiled under reflux for 24 hours. After the reaction mixture has cooled to room temperature, 50 ml are added
  • the saponification of 12.0 g (35 mmol) of the ester from Example 16 is carried out with 26 ml of 2N NaOH in 40 ml of methanol. After stirring for 10 minutes at 50 ° C., the solvent is distilled off, acidified with 6N HCl and extracted three times with 40 ml of ethyl acetate each time. To remove by-products, the organic phase is shaken twice with 40 ml of NaHCO 3 solution, the aqueous solution is acidified with 2N HCl and extracted with ethyl acetate. After drying over sodium sulfate, the organic phase is evaporated to dryness. 7.95 g (72%) of a colorless oil are obtained.
  • Platelet aggregation is investigated in platelet-rich plasma from healthy blood donors using the method of BORN and CROSS (J. Physiol. 168, 178 (1963). To inhibit coagulation, 3.2% citrate in a volume ratio of 1: 9 is added to the blood.
  • U 46619 A stable analogue of the prostaglandin endoperoxide PGH 2 , U 46619 (Upjohn & Co, Kalamazoo, USA) is used to induce platelet aggregation.
  • U 46619 has been characterized as a selective thromboxane mimetic (COLEMAN et al., Brit. J. Pharmacol. 68, 127P., 1980).
  • the aggregation test is carried out in a 4-channel aggregometer
  • mice Male NMRI mice of approximately 25 g body weight are used.
  • the test substance was 1% Suspended methyl cellulose solution and administered to the test animals by gavage.
  • the provocation test consists in that a lethal dose for control animals (800-1000 ⁇ / kg) of the thromboxane mimetic (U 46619 from Upjohn) is quickly injected into the tail vein. The duration of the specific antogonistic effect is tested by comparing the animals with 25 mg / kg of the different test substances
  • the survival rate indicates what percentage of the animals used survived the injection of the thromboxane mimetic.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Des composés ont la formule (I), dans laquelle R1 représente un groupe aryle, aralkyle ou aralkényle dont le reste aryle peut être substitué une ou plusieurs fois par halogène, cyanogène, alkyle, trifluorométhyle, alcoxyle, alkylthio, trifluorométhoxyle, hydroxyle ou carboxyle, n est un nombre entier entre 1 et 3, m est un nombre entier entre 0 et 2, p est un nombre entier entre 1 et 6, R2 peut être hydrogène, un groupe alkyle, aralkyle ou acyle, R3 représente hydrogène, halogéne, trifluorométhyle, alkyle, aralkyle ou alcoxyle, R4 représente hydroxyle, alcoxyle ou un groupe amine éventuellement substitué. L'invention concerne également un procédé de production de ces composés et des médicaments à effet antagoniste du tromboxane qui contiennent ces composés.
PCT/EP1991/000383 1990-03-03 1991-03-01 Derives d'acide phenylthioalkylcarboxylique, leur procede de production et medicaments contenant ces composes Ceased WO1991013868A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19904006640 DE4006640A1 (de) 1990-03-03 1990-03-03 Phenylthioalkylcarbonsaeure-derivate, verfahren zu ihrer herstellung sowie diese verbindungen enthaltende arzneimittel
DEP4006640.1 1990-03-03

Publications (1)

Publication Number Publication Date
WO1991013868A1 true WO1991013868A1 (fr) 1991-09-19

Family

ID=6401316

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1991/000383 Ceased WO1991013868A1 (fr) 1990-03-03 1991-03-01 Derives d'acide phenylthioalkylcarboxylique, leur procede de production et medicaments contenant ces composes

Country Status (3)

Country Link
AU (1) AU7443291A (fr)
DE (1) DE4006640A1 (fr)
WO (1) WO1991013868A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4258058A (en) * 1978-03-04 1981-03-24 Boehringer Mannheim Gmbh Phenoxyalkylcarboxylic acid compounds and thrombocyte-aggregation inhibition
EP0353448A1 (fr) * 1988-06-25 1990-02-07 Roche Diagnostics GmbH Sulfonamides, procédé pour leur préparation et médicament les contenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4258058A (en) * 1978-03-04 1981-03-24 Boehringer Mannheim Gmbh Phenoxyalkylcarboxylic acid compounds and thrombocyte-aggregation inhibition
EP0353448A1 (fr) * 1988-06-25 1990-02-07 Roche Diagnostics GmbH Sulfonamides, procédé pour leur préparation et médicament les contenant

Also Published As

Publication number Publication date
AU7443291A (en) 1991-10-10
DE4006640A1 (de) 1991-09-05

Similar Documents

Publication Publication Date Title
EP0253257B1 (fr) Acides amino-5,6,7,8-tétrahydronaphtyl-oxyacétiques substitués, procédé pour leur fabrication et leur utilisation comme médicaments
EP0004011B1 (fr) Dérivés d'acides phénoxyalcoylcarboxyliques, procédé pour leur préparation et médicaments les contenant
DE68914687T2 (de) Hydroxamsäure enthaltende collagenase-inhibitoren.
EP2857015A1 (fr) Modulateurs du récepteur de la prostacycline (PG12) utiles pour le traitement de troubles associés à celui-ci
EP0201735B1 (fr) N-indolyléthylsulfonamides, procédé de préparation et utilisation
DE69809782T2 (de) Npy antagonisten
DE69132167T2 (de) Kondensierte benzoxa-ringverbindung, deren herstellung sowie diese enthaltendes arzneimittel
EP0600949A1 (fr) Nouveaux derives 3,5-di-tert.butyl-4-hydroxyphenyles, leur procede de fabrication et medicaments les renfermant.
EP0239907B1 (fr) Dérivés d'acides phénoxyalcanecarboxyliques, procédé pour leur préparation et médicaments contenant ces composés
JPH0253762A (ja) 新規スルホンアミドおよびこれを含有する、物質代謝機能病および血行障害治療薬
DE69408580T2 (de) 2-amino-1,2,3,4-tetrahydronaphthalenderivate mit cardiovaskulärer wirkung
DE3830060A1 (de) 2-phenylbenzimidazole - verfahren zu ihrer herstellung sowie diese verbindungen enthaltende arzneimittel
DE3305569A1 (de) Biscarboxamide zur bekaempfung von erkrankungen sowie verfahren zu ihrer herstellung
DE3306146A1 (de) Pyridin-derivate und ihre verwendung als arzneimittel
DE2903615A1 (de) Guajakacylester von mercaptopropionsaeurederivaten, verfahren zu ihrer herstellung und ihre therapeutische verwendung
DE69226703T2 (de) Imidazo (4,5-c)pyridinderivate als paf antagonisten
DE69232812T2 (de) Neue cyclische aminophenylessigsäurederivate, ihre herstellung und immunomodulatoren , welche diese als aktiven bestandteil enthalten
EP0356989B1 (fr) Sulphonamides comportant un reste de tétrazolyle, procédé de préparation et médicaments
EP0564499B1 (fr) Nouvelles amines, leur procede de production et medicaments contenant ces composes
WO1991013868A1 (fr) Derives d'acide phenylthioalkylcarboxylique, leur procede de production et medicaments contenant ces composes
EP0371342B1 (fr) 2-Halogéno N-indolyléthyl sulfonamides, procédé pour leur préparation et leur utilisation en thérapeutique
DE3804346A1 (de) Tert.-butylphenyl-pyridyl-amide - verfahren zu ihrer herstellung sowie diese verbindungen enthaltende arzneimittel
DE69713128T2 (de) 4-(1-piperazinyl)benzosäurederivate, verfahren zu ihrer herstellung und ihre therapeutischen verwendungen
EP0152799B1 (fr) Composés ayant une activité périphérique antagoniste du calcium anti-couvulsive et eumétabolique, procédé pour leur préparation et compositions pharmaceutiques les contenant
SU541428A3 (ru) Способ получени простых гликолевых эфиров

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA FI HU JP KR NO SU US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU NL SE

NENP Non-entry into the national phase

Ref country code: CA