US3210368A - Certain 2-amino-4-aryl-5-n, n-disubstituted amino-lower alkyl-thiazole compounds - Google Patents

Certain 2-amino-4-aryl-5-n, n-disubstituted amino-lower alkyl-thiazole compounds Download PDF

Info

Publication number
US3210368A
US3210368A US400197A US40019764A US3210368A US 3210368 A US3210368 A US 3210368A US 400197 A US400197 A US 400197A US 40019764 A US40019764 A US 40019764A US 3210368 A US3210368 A US 3210368A
Authority
US
United States
Prior art keywords
amino
lower alkyl
phenyl
thiazole
group
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.)
Expired - Lifetime
Application number
US400197A
Inventor
Huebner Charles Ferdinand
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.)
BASF Corp
Novartis Corp
Original Assignee
Ciba Geigy Corp
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 Ciba Geigy Corp filed Critical Ciba Geigy Corp
Priority to US400197A priority Critical patent/US3210368A/en
Application granted granted Critical
Publication of US3210368A publication Critical patent/US3210368A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

  • the present invention concerns 2-amino-thiazoles. More particularly, it relates to 2-amino-4-carbocyclic aryl-5-N,N-di-substituted amino-lower alkyl-thiazoles, in which lower alkyl separates N,N-disubstituted amino from the 5-position of the thiazole ring by at least two carbon atoms, or salts thereof, as Well as quaternary ammonium compounds thereof.
  • the amino group attached to the 2-position of the thia zole nucleus is above all an N-unsubstituted primary amino group. It may also represent a secondary, or N- monosubstituted amino group, such as N-aliphatic substituted amino, for example, N-lower alkyl-amino, e.g. N-methyl-amino, N-ethyl-amino, N-propyl-arnino, N-isopropylamino, N-butyl-amino and the like, N-cycloalkylamino, in which cycloalkyl has from three to eight, preferably from five to seven, ring carbon atoms, e.g.
  • N- cyclopentylmethyl-amino, N (Zcyclohexylethyl)-amino and the like N-carbocyclic aryl-amino, particularly N- monocyclic carbocyclic aryl-amino, such as N-phenylamino, or N-(substituted phenyl)-amino, in which one or more than one of the same or of difierent substituents may be attached to any position available for substitution, for example, N-(lower alkyl-phenyl)-amino, in which lower alkyl is methyl, ethyl, N-propyl, isopropyl, N-butyl and the like, N-(lower alkoxy-phenyl)-amino, in which lower alkoxy is methoxy, and the like, N-(halogenophenyl)-amino, in which halogeno is chloro, and the like, N-(nitro-phenyl)
  • N-benzylamino, N- (2-phenylethyl)-amino and the like, or N-(substituted phenyl)-lower alkyl-amino for example, N-(lower alkylphenyl)-1ower alkyl-amino, N-(lower alkoxy-phenyl)- lower alkyl-amino, N-(halogeno-phenyl)-lower alkylamino, N-(nitro-phenyl)-lower alkyl-amino, N-(aminophenyl) lower alkyl amino, N (N,N di lower alkylamino-phenyl) -lower alkyl amino, N (trifiuoromethylphenyl)-lower alkyl-amino and the like, as well as a tertiary or N,N-disubstituted amino group, such as one of those described below.
  • the carbocyclic aryl group attached to the 4-position of the thiazole nucleus is above all a monocyclic carbocyclic aryl group, such as phenyl or substituted phenyl, which may have one or more than one of the same or different substituents attached to any of the positions available for substitution; substituents are, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, trifluoromethyl, lower alkoxy, e.g. methoxy, ethoxy, npropyloxy, isopropyloxy, n-butyloxy and the like, lower alkenyloxy, e.g.
  • Substituted phenyl groups are more especially (lower alkylphenyl, (trifiuoromethyl)-phenyl, (lower alkoxy)-phenyl, (lower alkenyloxy)-phenyl (lower alkylenedioxy)-phenyl, (halogeno)-phenyl, (lower alkyl-merca.pto)-phenyl, (nitro)-phenyl, (amino)-phenyl, particularly (N,N-di-lower alkyl-amino)-phenyl and the like, or any other suitably substituted phenyl group.
  • the carbocyclic aryl radical attached to the 4-position may also be a bicyclic carbocyclic aryl radical, such as naphthyl, l-naphthyl or 2- naphthyl, or substituted naphthyl; one or more than one of the same or of different substituents may be attached to any of the positions available for substitution, and substituted naphthyl groups are represented, for example, by (lower alkyl)-naphthyl, (trifluoromethyl)-naphthyl, (lower alkoxy)-naphthyl, (lower alkenyloxy)-naphthyl, (lower alkylenedioxy)-naphthyl, (halogeno)-naphthyl, (lower alkyl mercapto)-naphthyl, (amino)-naphthyl, (nitro)- naphthyl, particularly (N
  • N,N-disubstituted amino portion of the N,N- disubstituted amino-lower alkyl group attached to the 5- position is primarily N,N-disubstituted amino, in which the substituents are above all lower alkyl, as well as lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl, monocyclic carbocyclic aryl, particularly phenyl, monocyclic carbocyclic aryl-lower alkyl, particularly phenyl-lower alkyl and the like.
  • N,N-disubstituted amino groups are therefore, N,N-di-lower alkyl-amino, e.g.
  • N-cyclopentyl-N-methyl-amino N- cyclohexyl-N-ethyl-amino and the like
  • N-lower alkyl- N-phenyl-lower alkyl-amino e.g.
  • N-benZyl-N-rnethylamino N-ethyl-N-(1-phenylethyl)-amino, N-rnethyl-N- (phenylethyl)-amino and the like, or any other N,N-disubstituted amino group, such as, for example, N-lower hydroxy-alkyl-N-lower alkyl-amino, in which hydroxyl is separated from the nitrogen by at least two carbon atoms, e.g. N-ethyl-N-(2-hydroxyethyl)-amino and the like, or N,N-di-lower hydroxy-alkyl-amino, e.g. N,N-di-(2-hydroxyethyl)-amino and the like.
  • the N,N-disubstituted amino portion of the N,N-disubstituted amino-lower alkyl group may also be N,N- alkylene-imino, in which alkylene has from three to eight, preferably from four to six, carbon atoms, e.g. l-pyrrolidino, l-piperidino, Z-methyl-l-piperidino, l-N,N-( 1,6- hexylene)-imino, 1-N,N-(l,7-heptylene)-imino and the like, N,N-oxa-alkylene-imino, in which alkylene has preferably four carbon atoms, e.g.
  • N,N-thia-alkylene-imino in which alkylene has preferably four carbon atoms, e.g. 4-thia-mortholino and the like, or N,N-aza-alkylene-irnino, in which alkylene has from four to six carbon atoms, and in which the azanitrogen may be substituted, for example, by lower alkyl, e.g. methyl, ethyl, isopropyl and the like, hydroxy-lower alkyl, in which hydroxyl is separated from the nitrogen by at least two carbon atoms, e.g.
  • lower alkanoyloxy-lower alkyl in which lower alkanoyloxy is separated from the nitrogen by at least two carbon atoms, e.g. 2-acetoxyethyl and the like, phenyllower alkyl, e.g.
  • benzyl diphenylmethyl, 2-phenylethyl and the like, or any other suitable substituent, and which may be represented by piperazino, 4-methyl-1-piperazino, 4-ethyl-piperazino, 4-(2-hydroxyethyl)-l-piperazino, 4-(2- 3 acetyloxyethyl)-l-piperazino, 4-benzyl 1 piperazino, 1- N,N- 3 -aza-3-methyl-1,6-hexylene)-imino, l-N,N- (4-az a- 4-methyl-l,7-heptylene)-imino and the like.
  • the lower alkyl portion of the N,N-disubstituted amino-lower alkyl substituent of the 5-position of the thiazole nucleus separates the N,N-disubstituted amino group from the latter by at least two carbon atoms; it is represented by lower alkylene having from two to seven, perferably from two to three carbon atoms and separating N,N-disubstituted amino from the 5-position by at least two, preferably by from two to three, carbon atoms.
  • 1,2-ethylene, l-methyl- 1,2-ethylene, 2-methyl-1,2-ethylene or 1,3-propylene as well as, 1-methyl-l,3-propylene, 2-methyl-l,3-propylene, 1,4-butylene, 1-methyl-1,4-butylene 1,5-pentylene 1,6- hexylene, l,7-heptylene and the like.
  • the N,N-disubstituted amino-lower alkyl substituent attached to the 5-position may also be represented by a group, in which the N,N-disubstituted amino portion forms part of a saturated ring system, which is connected directly or through a lower alkylene group with the 5- position of the thiazole nucleus, and in which the N,N- disubstituted amino group is separated from the latter by at least two carbon atoms.
  • groups are, for example, 1 methyl-3-pyrrolidinyl, 1-methyl-3-pyrrolidinylrnethyl, 1 ethyl 3- piperidyl, 1-methyl-4-piperidyl, 1-methyl-3 piperidyl-methyl and the like.
  • Salts of the compounds of this invention are acid addition salts, such as pharmaceutically acceptable acid addition salts with inorganic acids, e.g. hydrochloric, hydr-obromic, nitric, sulfuric, phosphoric acids and the like, or with organic carboxylic acids, e.g. acetic, propionic, glycolic, malonic, succinic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric glucuronic, benzoic, mandelic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, pamoic, nicotinic, isonicotinic acid and the like, or organic sulfonic acids, e.g.
  • inorganic acids e.g. hydrochloric, hydr-obromic, nitric, sulfuric, phosphoric acids and the like
  • organic carboxylic acids e.g. acetic, propionic, glycolic, malonic, succ
  • salts for the latter are, for example, those with certain inorganic acids, e.g. perchloric acid and the like, with acidic organic nitro compounds, e.g. picric, picrolonic, fiavianic acid and the like, or with metal complex acids, e.g. phosphotungstic, phosphomolybdic, chloroplatinic, Reinecke acid and the like.
  • Mono or poly-salts are formed depending on the number of salt forming groups present in the molecule.
  • Quaternary ammonium derivatives of the componuds of this invention are those with reactive esters from alcohols and strong inorganic and organic acids, particularly the lower alkyl or phenyl-lower alkyl quaternary ammonium halides, sulfates or sulfonates, such as those with lower alkyl halides, e.g.
  • quaternary ammonium compounds methyl or ethyl methane sulfonate, ethane sulfonate or p-toluene sulfonate and the like.
  • quaternary ammonium hydroxides and other quaternary ammonium salts in which the anion is derived from an acid other than hydrohalic, sulfuric or sulfonic acid.
  • the compounds of this invention may be represented by the formula in which Ar is a carbocyclic aryl radical, Am, stands for N-unsubstituted amino, N-monosubstituted amino or N,N-disubstituted amino, Am is N,N-disubstituted amino, the letter n stands for an integer from two to seven, and the group (C,,H separates the N,N-disubstituted amino group Am from the S-piston of the thiazole ring by at least two carbon atoms, or salts thereof, as well as quaternary ammonium compounds thereof.
  • the compounds of the present invention antagonize the pressure effects of norepinephrine, thus causing a lowering of the blood pressure. It has been found that this effect is due to a blockade of the nervous transmission along the post-ganglionic sympathetic nerve system, as the compounds do not act centrally, nor along the preganglionic sympathetic nerve pathway or at the ganglia.
  • An additional advantage of the compounds of this invention is the quick onset of the pharmacological action. They are, therefore, useful as anti-hypertensive agents in the treatment of mild hypertension.
  • Ph stands for phenyl, (lower alkyl)-phenyl, (trifluoromethyl)-phenyl, (lower a1koxy)-phenyl, (N,Ndilower alkyl-amino)-pl1enyl or, more especially, halogeno)-phenyl
  • Am is N,N-di-lower alkyl-amino
  • the letter n stands for one of the integers 2 and 3, especially 2
  • the group (C,,H separates the group Am from the 5-position of the thiazole ring from two to three, particularly by two, carbon atoms, or acid addition salts, such as pharmaceutically acceptable acid addition salts, thereof.
  • compositions for enteral or parenteral use which cornprise essentially a pharmacologically effective amount of one of the above compounds in admixture with a solid or liquid carrier.
  • carrier substances such as water, gelatine, sugars, e.g. lactose, glucose, sucrose, and the like, starches, e.g. wheat starch, corn starch and the like, stearic acid or salts thereof, e.g.
  • the latter are in the solid form, e.g. as capsules, ta blets, dragees, suppositories and the like, or in liquid form, e.g. as solutions, suspensions, emulsions and the like.
  • they may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, buffers, etc. They may also contain, in combination, other useful substances.
  • the compounds of this invention may be prepared according to methods known per se. For example, they are formed by reacting an a-reactive esterified hydroxy-N,N- disu'bstituted amino-lower alkyl carbocyclic aryl ketone, in which the N,N-disubstituted amino group is separated from the carbon atom carrying the reactive esterified hydroxyl group by at least two carbon atoms, particularly a compound of the formula in which Ar, Am the letter I: and the group of the formula (C H have the previously given meaning, and X stands for a reactive esterified hydroxyl group, or a salt thereof, with a thiourea, particularly a compound having one of the tautomeric formulae:
  • the reactive esterified hydroxyl group such as the group X of the compounds of the above formula, is primarily halogeno, e.g. chloro, bromo, iodo and the like; it may also be an organic sulfonyloxy group, eg methane sulfonyloxy, ethane sulfonyloxy, p-toluene sulfonyloxy and the like.
  • the reaction is carried out by mixing the two ingredients, preferably in the presence of a solvent, e.g. methanol, ethanol and the like, or solvent mixture, if necessary, while cooling or at an elevated temperature, in a closed vessel and/or in the atmosphere of an inert gas, e.g. nitrogen.
  • a solvent e.g. methanol, ethanol and the like, or solvent mixture, if necessary, while cooling or at an elevated temperature, in a closed vessel and/or in the atmosphere of an inert gas, e.g. nitrogen.
  • the starting materials used in the above procedure are prepared, for example, by esterifying the hydroxyl group in an a-hydroxy-N,N-disubstituted amino-lower alkyl carbocyclic aryl ketone, for example, with an organic sulfonic acid halide, or, more especially, by introducing a halogeno (representing a hydroxyl group esterified with a hydrohalic acid) into the ot'position of an N,N-disubstituted amino-lower alkyl carbocyclic aryl ketone, in which the N,N-disubstituted amino group is separated from the carbonyl portion by at least three carbon atoms.
  • a halogeno presents a hydroxyl group esterified with a hydrohalic acid
  • the latter procedure may be carried out, for example, by reacting the ketone or a salt thereof with halogen, particularly bromine, as Well as chlorine and the like, in the presence of a suitable solvent, e.g. acetic acid and the like, which may contain a hydrogen halide, e.g. hydrogen bromide, hydrogen chloride and the like, to facilitate halogenation.
  • halogen particularly bromine
  • a suitable solvent e.g. acetic acid and the like
  • a hydrogen halide e.g. hydrogen bromide, hydrogen chloride and the like
  • a modification of the above procedure comprises reacting an N,N-disubstituted amino-lower alkyl carbocyclic aryl ketone, in which N,N-disubstituted amino is separated from the carbonyl group by at least three carbon atoms, particularly a compound of the formula in which Ar, Am the letter n and the group of the formula -(C,,H have the previously given meaning, or a salt thereof with a thiourea, particularly a compound having one of the tautomeric formulae HS Am! I NHz IHTH in which Am has the previously given meaning, in the presence of a suitable ring closing reagent, and, if desired, carrying out the optional steps.
  • Ring-closing reagents useful in the above reaction are reagents containing halogen and having oxidative properties, e.g. iodine, sulfuryl chloride, thionyl chloride, chlorosulfonic acid, sulfur monochloride and the like, as well as reagents without halogen, e.g., sulfur trioxide, sulfuric acid and the like; these reagents may cause the oxidation of the thiourea compound to a formamidine disulfide of the formula S- S f h in which Am has the previously given meaning, and which in the above ring closure may replace the thiourea compound and react with the starting material.
  • the reaction is carried out according to known methods.
  • the starting material (which is also used for the manufacture of the starting material in the previously mentioned process modification) is prepared by treating a reactive esterified hydroxy-lower alkyl carbocyclic aryl ketone, particularly a halogeno-lower alkyl carbocyclic aryl ketone, in which the reactive esterified hydroxyl group, particularly the halogeno atom, is separated from the carbonyl group by at least three carbon atoms, with a secondary amine, particularly an amine of the formula Am -H, in which Am has the previously given meaning.
  • the starting material may be obtained from the previously described a-reactive esterified hydroxy-N,N-disubstituted amino-lower alkyl carbocyclic aryl ketone, particularly an a-halogeno-N,N-disu'bstituted amino-lower alkyl carbocyclic aryl ketone, in which N,N-disubstituted amino is separated from the carbon atom carrying halogeno by at least two carbon atoms, by treatment with an alkali metal thiocyanate, e.g. sodium thiocyanate and the like, or an alkaline earth metal thiocyanate, e.g. barium thiocyanate and the like.
  • an alkali metal thiocyanate e.g. sodium thiocyanate and the like
  • an alkaline earth metal thiocyanate e.g. barium thiocyanate and the like.
  • the compounds of this invention may also be prepared by reacting a 2-amino-4-carbocyclic aryl-S-reactive esterified hydroxy-lower alkyl-thiazole, in which the reactive esterified hydroxyl group is separated from the 5position of the thiazole nucleus by at least two carbon atoms, particularly a compound of the formula in which Am Ar, the letter n and the group --(C,,H have the previously given meaning, and X stands for a reactive esterified hydroxyl group, or a salt of such compound, with an N,N-disubstituted amine, particularly an amine of the formula Am H, in which Am has the previously given meaning, and, if desired, carrying out the optional steps.
  • the above reaction is carried out according to known methods, preferably in the presence of an inert solvent and, if necessary, of a base to neutralize generated acid (which may also be achieved by using an excess of the amine), while cooling or at an elevated temperature, in a closed vessel and/ or in the atmosphere of an inert gas, e.g. nitrogen.
  • the starting material may be prepared according to known methods, for example, the above given procedure for the formation of the thiazole nucleus using the appropriate starting materials, and, if necessary, a hydroxyl group in a resulting compound may be converted into the desired reactive esterified hydroxyl group.
  • the compounds of this invention may also be prepared by reacting a 2-halogeno-4-carbocyclic aryl-5-N,N-disubstituted amino-lower alkyl-thiazole, in which N,N-disubstituted amino is separated from the 5-position of the thiazole nucleus by at least two carbon atoms, particularly a compound of the formula in which Ar, Am the letter 12 and the group -(C H have the previously given meaning, and Hal stands for halogeno, or a salt thereof, with ammonia, a primary amine or a secondary amine, particularly a compound of the formula Am H, in which Am has the previously given meaning, and, if desired, carrying out the optional steps.
  • the above reaction is carried out according to known methods, if necessary, in the presence of a suitable solvent and/or a base to neutralize the generated acid (which may also be accomplished by using an excess of ammonia or the amine,) in a closed vessel, at an elevated temperature, and/or under an atmosphere or inert gas, e.g. nitrogen.
  • a suitable solvent and/or a base to neutralize the generated acid (which may also be accomplished by using an excess of ammonia or the amine,) in a closed vessel, at an elevated temperature, and/or under an atmosphere or inert gas, e.g. nitrogen.
  • the starting material may be prepared, for example, by reacting one of the previously described a-thiocyanato- N,N-disubstituted amino-lower alkyl carbocyclic aryl ketones with a hydrogen halide, e.g. hydrogen chloride and the like.
  • a hydrogen halide e.g. hydrogen chloride and the like.
  • a resulting salt may be converted into the free compound according to known methods, for example by treatment with a basic reagent, such as a metal hydroxide, for example, an alkali metal hydroxide or an alkaline earth metal hydroxide, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and the like, a metal carbonate, such as an alkali metal carbonate, or an alkaline earth metal carbonate, e.g. sodium, potassium or calcium carbonate or hydrogen carbonate and the like, ammonia, a hydroxyl ion exchange preparation and the like.
  • a basic reagent such as a metal hydroxide, for example, an alkali metal hydroxide or an alkaline earth metal hydroxide, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and the like
  • a metal carbonate such as an alkali metal carbonate, or an alkaline earth metal carbonate, e.g. sodium, potassium or calcium carbonate or hydrogen carbonate and the like
  • a resulting salt is converted into another salt according to known methods, for example, by treatment with a suitable anion exchange preparation.
  • an addition salt with an inorganic acid may be converted into another acid addition salt, for example, by treating it with a suitable metal salt, e.g. silver, sodium and the like, salt of an acid in the presence of a solvent or solvent mixture, in Which a resulting inorganic compound is insoluble and is thus removed from the reaction medium.
  • a suitable metal salt e.g. silver, sodium and the like
  • a free compound is converted into a salt thereof according to known methods, for example, 'by reacting the free 'base or a solution thereof with one of the previously mentioned acids or a solution thereof, or with a suitable anion exchange preparation, and isolating the desired salt, which may be in the form of a hydrate or may contain solvent of crystallization.
  • the quaternary ammonium derivatives of the compounds of this invention are obtained according to known methods, for example, by reacting the free compound with the reactive ester of an alcohol and a strong inorganic or organic acid, such as a lower-alkyl halide, a phenyllower alkyl halide, a lower alkyl sulfonate, a di-lower alkyl sulfate and the like, if necessary, in the presence of a solvent or solvent mixture, at an elevated temperature, in a closed vessel, and/or in the atmosphere of an inert gas, e.g. nitrogen.
  • the quaternary ammonium compounds may *be isolated as the hydrates.
  • Quaternary ammonium compounds can be converted into other quaternary ammonium derivatives, such as the quaternary ammonium hydroxides, for example, by reacting a quaternary ammonium halide with silver oxide, or a quaternary ammonium sulfate with barium hydroxide, by treating a quaternary ammonium salt with a hydroxyl ion exchange preparation, by electrodialysis or any other suitable method.
  • a resulting quaternary ammonium hydroxide compound is converted into a quaternary ammonium salt, for example by reaction with an acid, a mono-lower alkyl sulfate, e.g.
  • a quaternary ammonium compound may also be converted directly into another quaternary ammonium salt without the formation of the quaternary ammonium hydroxide; for example, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride or'hydrogen chloride in anhydrous methanol to form the quaternary ammonium chloride, or upon treatment with a suitable anion exchange preparation a quaternary ammonium compound may be converted into another quaternary ammonium salt.
  • the invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out, as well as any new intermediates.
  • Example 1 To a solution of 0.37 g. of thiourea in 7.5 ml. of ethanol is added 2.0 g. of a-bromo-p-chloro-v-(N,N-diethylamino)-butyrophenone hydrobromide, and the reaction mixture is warmed on the steam bath for ten minutes. A crystalline precipitate is formed on cooling and is filtered off to give the 2-amino-4-(4-chlorophenyl)-5-(2-N,N-diethylaminoethyl)-thiazole dihydrobromide of the formula which is purified by recrystallization from a mixture of ethanol and water, M.P.
  • the p-chloro-'y-N,N-diethylamino-butyrophenone is extracted with diethyl ether, the organic solution is dried over sodium sulfate and evaporated, and the residue is distilled, B.P. 122/0.8 mm.
  • the hydrochloride, M.P. 169171 is prepared by treating the free base with hydrogen chloride and purified by recrystallization from a mixture of ethanol and diethyl ether.
  • 2-amino 5 (2-N,N-dimethylaminoethyl)-4-(N,N-dimethylamino-phenyl)-thiazole dihydrobromide, M.P. 196- 200, by reacting thiourea with u-bromo-p,'y-bis-(N,N-dimethylamino)-butyrophenone hydrobromide, M.P.
  • 200- 202 (prepared by reacting 'y-chloro-p-(N,N-dimethylamino)-butyrophenone with N,N-dimethylamine and brominating the pyy-bis-(N,N-dimethylamino -butyrophenone hydrochloride) 2-arnino 4 phenyl-5-[2-(l-pyrrolidino)-ethyl]-thiazole dihydrobromide, M.P. 267-269, by reacting thiourea with a-brom0- l-pyrrolidino)-butyrophenone hydrobromide, M.P.
  • Example 2 To a solution of 0.55 g. of thiourea in 5 ml. of ethanol is added 2.5 g. of a-bromo-y-(N,N-dimethylarnino)-butyrophenone hydrobromide. After refluxing for five minutes, the reaction mixture is cooled and diluted with diethyl ether. The resulting precipitate is filtered off, and dissolved in water; the aqueous solution is treated with procedure described in Example 1; the desired product melts at 274-276 after recrystallization from ethanol.
  • Example 5 An equivalent amount of thiourea in ethanol is treated with 1.0 g.- of 1-bromo-5-(N,N-dimethylamino)-pentyl 4chloro-phenyl ketone hydrobromide according to the procedure described in Example 1; the 2-amino-4-(4- chloro-phenyl)-5-(4-N,N-dimethylaminobutyl) thiazole dihydrobromide of the formula is recrystallized from a mixture of ethanol and ethyl acetate, M.P. 225.
  • the starting material is prepared as described in Example 1; the 4-chloro-phenyl 5-(N,N-dimethy1amino)- 3,210,368 1 1 1 2 ,pentyl ketone hydrochloride, M.P. 178180, is brominat- What is claimed is: ed to yield the l-brorno-S-(N,N-dimethylarnino)-pentyl 1.
  • compound of the formula Example 6 0.65 g. of N-phenylthiourea in 10 ml.
  • the solid material is filtered off and dissolved in a small amount of ethanol; gaseous hydrogen bromide is passed through the solution, and the desired 2 amino 4-(4-chloro-phenyl)-5-(2-N,N-dimethylaminothiazo1e ethyD-thiazole dihydrobromide is filtered oil, MP. 227- 7 2 1 .5- 2 1 1 -4 4- h- 228 oxyphenyl -thiazole.
  • the starting material used in the above procedure is 8. 2 amino 4-(4-bromo-phenyl)-5-(2-N,N-dimethylprepared as follows: A mixture of 3.0 g. of Ot-bIOHlO-Pfiarninoethyl)thiazole. dichlorobutyrophenone (M.P. 71-73", prepared by bro- '9. 2 amino 4-(4-N,N-dimethylamino-phenyl)-5-(2- minating pyy-dichlorobutyrophenone with bromine in the N,N-dimethylaminoethyl)-thiflZ01epresence of 1 ml.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Description

United States Patent CERTAIN 2-AMINO 4 ARYL 5 N,N DISUBSTI- TUTED AMINO LOWER ALKYL THIAZOLE COMPOUNDS Charles Ferdinand Huebner, Chatham, N.J., assignor to Ciba Corporation, New York, N.Y., a corporation of Delaware N0 Drawing. Filed Sept. 29, 1964, Ser. No. 400,197
11 Claims. ((31. 260-3068) This applicaiton is a continuation-in-part application of my copending application 166,928, filed January 17, 1962, and now abandoned.
The present invention concerns 2-amino-thiazoles. More particularly, it relates to 2-amino-4-carbocyclic aryl-5-N,N-di-substituted amino-lower alkyl-thiazoles, in which lower alkyl separates N,N-disubstituted amino from the 5-position of the thiazole ring by at least two carbon atoms, or salts thereof, as Well as quaternary ammonium compounds thereof.
The amino group attached to the 2-position of the thia zole nucleus is above all an N-unsubstituted primary amino group. It may also represent a secondary, or N- monosubstituted amino group, such as N-aliphatic substituted amino, for example, N-lower alkyl-amino, e.g. N-methyl-amino, N-ethyl-amino, N-propyl-arnino, N-isopropylamino, N-butyl-amino and the like, N-cycloalkylamino, in which cycloalkyl has from three to eight, preferably from five to seven, ring carbon atoms, e.g. N- cyclopropylamino, N-cyclopentylamino, N-cyclohexylamino and the like, N-cycloalkyl-lower alkylamino, in which cycloalkyl has the above given meaning, e.g. N- cyclopentylmethyl-amino, N (Zcyclohexylethyl)-amino and the like, N-carbocyclic aryl-amino, particularly N- monocyclic carbocyclic aryl-amino, such as N-phenylamino, or N-(substituted phenyl)-amino, in which one or more than one of the same or of difierent substituents may be attached to any position available for substitution, for example, N-(lower alkyl-phenyl)-amino, in which lower alkyl is methyl, ethyl, N-propyl, isopropyl, N-butyl and the like, N-(lower alkoxy-phenyl)-amino, in which lower alkoxy is methoxy, and the like, N-(halogenophenyl)-amino, in which halogeno is chloro, and the like, N-(nitro-phenyl)-arnino, N-(amino-phenyl)-amino, N- (N,N-di-lower alkyl-amino-phenyl)-amino, in which N,N-di-lower alkyl-amino is N,N-dimethyl-amino, N,N- diethylamino and the like, N-(trifluoromethyl-phenyl)- amino, or any other N-carbocyclic aryl-amino group, N- carbocyclic arylaliphatic substituted amino, such as N- monocyclic carbocyclic aryl-lower alkyl-amino, for example, N-phenyl-lower alkyl-amino, e.g. N-benzylamino, N- (2-phenylethyl)-amino and the like, or N-(substituted phenyl)-lower alkyl-amino, for example, N-(lower alkylphenyl)-1ower alkyl-amino, N-(lower alkoxy-phenyl)- lower alkyl-amino, N-(halogeno-phenyl)-lower alkylamino, N-(nitro-phenyl)-lower alkyl-amino, N-(aminophenyl) lower alkyl amino, N (N,N di lower alkylamino-phenyl) -lower alkyl amino, N (trifiuoromethylphenyl)-lower alkyl-amino and the like, as well as a tertiary or N,N-disubstituted amino group, such as one of those described below.
The carbocyclic aryl group attached to the 4-position of the thiazole nucleus is above all a monocyclic carbocyclic aryl group, such as phenyl or substituted phenyl, which may have one or more than one of the same or different substituents attached to any of the positions available for substitution; substituents are, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, trifluoromethyl, lower alkoxy, e.g. methoxy, ethoxy, npropyloxy, isopropyloxy, n-butyloxy and the like, lower alkenyloxy, e.g. vinyloxy, allyloxy and the like, lower ice alkylenedioxy, e.g. methylenedioxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like, lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, nitro, amino, such as N,N-di-lower alkyl-amino, e.g. N,N- dimethylamino, N,N-diethylamino and the like. Substituted phenyl groups are more especially (lower alkylphenyl, (trifiuoromethyl)-phenyl, (lower alkoxy)-phenyl, (lower alkenyloxy)-phenyl (lower alkylenedioxy)-phenyl, (halogeno)-phenyl, (lower alkyl-merca.pto)-phenyl, (nitro)-phenyl, (amino)-phenyl, particularly (N,N-di-lower alkyl-amino)-phenyl and the like, or any other suitably substituted phenyl group. The carbocyclic aryl radical attached to the 4-position may also be a bicyclic carbocyclic aryl radical, such as naphthyl, l-naphthyl or 2- naphthyl, or substituted naphthyl; one or more than one of the same or of different substituents may be attached to any of the positions available for substitution, and substituted naphthyl groups are represented, for example, by (lower alkyl)-naphthyl, (trifluoromethyl)-naphthyl, (lower alkoxy)-naphthyl, (lower alkenyloxy)-naphthyl, (lower alkylenedioxy)-naphthyl, (halogeno)-naphthyl, (lower alkyl mercapto)-naphthyl, (amino)-naphthyl, (nitro)- naphthyl, particularly (N,N-di-lower alkyl-amino)-naph thyl and the like.
The N,N-disubstituted amino portion of the N,N- disubstituted amino-lower alkyl group attached to the 5- position is primarily N,N-disubstituted amino, in which the substituents are above all lower alkyl, as well as lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl, monocyclic carbocyclic aryl, particularly phenyl, monocyclic carbocyclic aryl-lower alkyl, particularly phenyl-lower alkyl and the like. N,N-disubstituted amino groups are therefore, N,N-di-lower alkyl-amino, e.g. N,Ndimethylamino, N- ethyl-N-methyl-amino, N,N-diethylamino, N,N-di-n-propylamino, N,N-di-isopropyl-amino and the like, as well as N-cycloalkyl-N-lower alkyl-amino, in which cycloalkyl has from three to eight, preferably from five to seven, ring carbon atoms, e.g. N-cyclopentyl-N-methyl-amino, N- cyclohexyl-N-ethyl-amino and the like, N-lower alkyl- N-phenyl-lower alkyl-amino, e.g. N-benZyl-N-rnethylamino, N-ethyl-N-(1-phenylethyl)-amino, N-rnethyl-N- (phenylethyl)-amino and the like, or any other N,N-disubstituted amino group, such as, for example, N-lower hydroxy-alkyl-N-lower alkyl-amino, in which hydroxyl is separated from the nitrogen by at least two carbon atoms, e.g. N-ethyl-N-(2-hydroxyethyl)-amino and the like, or N,N-di-lower hydroxy-alkyl-amino, e.g. N,N-di-(2-hydroxyethyl)-amino and the like.
The N,N-disubstituted amino portion of the N,N-disubstituted amino-lower alkyl group may also be N,N- alkylene-imino, in which alkylene has from three to eight, preferably from four to six, carbon atoms, e.g. l-pyrrolidino, l-piperidino, Z-methyl-l-piperidino, l-N,N-( 1,6- hexylene)-imino, 1-N,N-(l,7-heptylene)-imino and the like, N,N-oxa-alkylene-imino, in which alkylene has preferably four carbon atoms, e.g. 4-morpholino and the like, N,N-thia-alkylene-imino, in which alkylene has preferably four carbon atoms, e.g. 4-thia-mortholino and the like, or N,N-aza-alkylene-irnino, in which alkylene has from four to six carbon atoms, and in which the azanitrogen may be substituted, for example, by lower alkyl, e.g. methyl, ethyl, isopropyl and the like, hydroxy-lower alkyl, in which hydroxyl is separated from the nitrogen by at least two carbon atoms, e.g. Z-hydroxyethyl and the like, lower alkanoyloxy-lower alkyl, in which lower alkanoyloxy is separated from the nitrogen by at least two carbon atoms, e.g. 2-acetoxyethyl and the like, phenyllower alkyl, e.g. benzyl, diphenylmethyl, 2-phenylethyl and the like, or any other suitable substituent, and which may be represented by piperazino, 4-methyl-1-piperazino, 4-ethyl-piperazino, 4-(2-hydroxyethyl)-l-piperazino, 4-(2- 3 acetyloxyethyl)-l-piperazino, 4-benzyl 1 piperazino, 1- N,N- 3 -aza-3-methyl-1,6-hexylene)-imino, l-N,N- (4-az a- 4-methyl-l,7-heptylene)-imino and the like.
As mentioned above, the lower alkyl portion of the N,N-disubstituted amino-lower alkyl substituent of the 5-position of the thiazole nucleus separates the N,N-disubstituted amino group from the latter by at least two carbon atoms; it is represented by lower alkylene having from two to seven, perferably from two to three carbon atoms and separating N,N-disubstituted amino from the 5-position by at least two, preferably by from two to three, carbon atoms. It stands for 1,2-ethylene, l-methyl- 1,2-ethylene, 2-methyl-1,2-ethylene or 1,3-propylene as well as, 1-methyl-l,3-propylene, 2-methyl-l,3-propylene, 1,4-butylene, 1-methyl-1,4-butylene 1,5-pentylene 1,6- hexylene, l,7-heptylene and the like.
The N,N-disubstituted amino-lower alkyl substituent attached to the 5-position may also be represented by a group, in which the N,N-disubstituted amino portion forms part of a saturated ring system, which is connected directly or through a lower alkylene group with the 5- position of the thiazole nucleus, and in which the N,N- disubstituted amino group is separated from the latter by at least two carbon atoms. Such groups are, for example, 1 methyl-3-pyrrolidinyl, 1-methyl-3-pyrrolidinylrnethyl, 1 ethyl 3- piperidyl, 1-methyl-4-piperidyl, 1-methyl-3 piperidyl-methyl and the like.
Salts of the compounds of this invention are acid addition salts, such as pharmaceutically acceptable acid addition salts with inorganic acids, e.g. hydrochloric, hydr-obromic, nitric, sulfuric, phosphoric acids and the like, or with organic carboxylic acids, e.g. acetic, propionic, glycolic, malonic, succinic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric glucuronic, benzoic, mandelic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, pamoic, nicotinic, isonicotinic acid and the like, or organic sulfonic acids, e.g. methane sulfonic, ethane sulfonic, 2-hydroxy-ethane sulfonic, ethane 1,2- disulfonic, p-toluene sulfonic, naphthalene 2-sulfonic acid and the like. Other acid addition salts are used as intermediates, for example, in the preparation of other acid salts or in the purification of the free compounds, as well as for characterization and identification purposes. Salts for the latter are, for example, those with certain inorganic acids, e.g. perchloric acid and the like, with acidic organic nitro compounds, e.g. picric, picrolonic, fiavianic acid and the like, or with metal complex acids, e.g. phosphotungstic, phosphomolybdic, chloroplatinic, Reinecke acid and the like. Mono or poly-salts are formed depending on the number of salt forming groups present in the molecule.
Quaternary ammonium derivatives of the componuds of this invention are those with reactive esters from alcohols and strong inorganic and organic acids, particularly the lower alkyl or phenyl-lower alkyl quaternary ammonium halides, sulfates or sulfonates, such as those with lower alkyl halides, e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl chloride, bromide or iodide and the like, phenyl-lower alkyl halides, e.g., benzyl, l-phenylethyl or 2-phenylethyl chloride or bromide and the like, di-lower alkyl sulfates, e.g. dimethyl sulfate, diethyl sulfate and the like, or lower alkyl sulfonates, e.g. methyl or ethyl methane sulfonate, ethane sulfonate or p-toluene sulfonate and the like. Also included as the quaternary ammonium compounds are the quaternary ammonium hydroxides and other quaternary ammonium salts, in which the anion is derived from an acid other than hydrohalic, sulfuric or sulfonic acid.
The compounds of this invention may be represented by the formula in which Ar is a carbocyclic aryl radical, Am, stands for N-unsubstituted amino, N-monosubstituted amino or N,N-disubstituted amino, Am is N,N-disubstituted amino, the letter n stands for an integer from two to seven, and the group (C,,H separates the N,N-disubstituted amino group Am from the S-piston of the thiazole ring by at least two carbon atoms, or salts thereof, as well as quaternary ammonium compounds thereof.
The compounds of the present invention antagonize the pressure effects of norepinephrine, thus causing a lowering of the blood pressure. It has been found that this effect is due to a blockade of the nervous transmission along the post-ganglionic sympathetic nerve system, as the compounds do not act centrally, nor along the preganglionic sympathetic nerve pathway or at the ganglia. An additional advantage of the compounds of this invention is the quick onset of the pharmacological action. They are, therefore, useful as anti-hypertensive agents in the treatment of mild hypertension.
Particularly useful are the compounds of the formula Ph-C N in which Ph stands for phenyl, (lower alkyl)-phenyl, (trifluoromethyl)-phenyl, (lower a1koxy)-phenyl, (N,Ndilower alkyl-amino)-pl1enyl or, more especially, halogeno)-phenyl, Am is N,N-di-lower alkyl-amino, the letter n stands for one of the integers 2 and 3, especially 2, and the group (C,,H separates the group Am from the 5-position of the thiazole ring from two to three, particularly by two, carbon atoms, or acid addition salts, such as pharmaceutically acceptable acid addition salts, thereof.
The compounds of this invention are useful in the form of compositions for enteral or parenteral use, which cornprise essentially a pharmacologically effective amount of one of the above compounds in admixture with a solid or liquid carrier. For making up the preparations there are employed known carrier substances, such as water, gelatine, sugars, e.g. lactose, glucose, sucrose, and the like, starches, e.g. wheat starch, corn starch and the like, stearic acid or salts thereof, e.g. magnesium stearate, calcium stearate and the like, stearyl alcohol, talc, vegetable oils, ethanol, benzyl alcohols, gums, propylene glycol, polyalkylene glycols or any other known carrier material used for the manufacture of such preparations. The latter are in the solid form, e.g. as capsules, ta blets, dragees, suppositories and the like, or in liquid form, e.g. as solutions, suspensions, emulsions and the like. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, buffers, etc. They may also contain, in combination, other useful substances.
The compounds of this invention may be prepared according to methods known per se. For example, they are formed by reacting an a-reactive esterified hydroxy-N,N- disu'bstituted amino-lower alkyl carbocyclic aryl ketone, in which the N,N-disubstituted amino group is separated from the carbon atom carrying the reactive esterified hydroxyl group by at least two carbon atoms, particularly a compound of the formula in which Ar, Am the letter I: and the group of the formula (C H have the previously given meaning, and X stands for a reactive esterified hydroxyl group, or a salt thereof, with a thiourea, particularly a compound having one of the tautomeric formulae:
S\ Ann NIB I IH in which Am has the previously given meaning, and, if
HS\ /Ami I C desired, converting a resulting salt into the free compound or into another salt, and/or, if desired, converting a resulting compound into a salt thereof, and/ or, if desired, converting a resulting compound into a quaternary ammonium compound thereof, and/ or, if desired, converting a quaternary ammonium compound into another quaternary ammonium compound thereof.
In the above starting materials, the reactive esterified hydroxyl group, such as the group X of the compounds of the above formula, is primarily halogeno, e.g. chloro, bromo, iodo and the like; it may also be an organic sulfonyloxy group, eg methane sulfonyloxy, ethane sulfonyloxy, p-toluene sulfonyloxy and the like.
The reaction is carried out by mixing the two ingredients, preferably in the presence of a solvent, e.g. methanol, ethanol and the like, or solvent mixture, if necessary, while cooling or at an elevated temperature, in a closed vessel and/or in the atmosphere of an inert gas, e.g. nitrogen.
The starting materials used in the above procedure are prepared, for example, by esterifying the hydroxyl group in an a-hydroxy-N,N-disubstituted amino-lower alkyl carbocyclic aryl ketone, for example, with an organic sulfonic acid halide, or, more especially, by introducing a halogeno (representing a hydroxyl group esterified with a hydrohalic acid) into the ot'position of an N,N-disubstituted amino-lower alkyl carbocyclic aryl ketone, in which the N,N-disubstituted amino group is separated from the carbonyl portion by at least three carbon atoms. The latter procedure may be carried out, for example, by reacting the ketone or a salt thereof with halogen, particularly bromine, as Well as chlorine and the like, in the presence of a suitable solvent, e.g. acetic acid and the like, which may contain a hydrogen halide, e.g. hydrogen bromide, hydrogen chloride and the like, to facilitate halogenation.
A modification of the above procedure comprises reacting an N,N-disubstituted amino-lower alkyl carbocyclic aryl ketone, in which N,N-disubstituted amino is separated from the carbonyl group by at least three carbon atoms, particularly a compound of the formula in which Ar, Am the letter n and the group of the formula -(C,,H have the previously given meaning, or a salt thereof with a thiourea, particularly a compound having one of the tautomeric formulae HS Am! I NHz IHTH in which Am has the previously given meaning, in the presence of a suitable ring closing reagent, and, if desired, carrying out the optional steps.
' Ring-closing reagents useful in the above reaction are reagents containing halogen and having oxidative properties, e.g. iodine, sulfuryl chloride, thionyl chloride, chlorosulfonic acid, sulfur monochloride and the like, as well as reagents without halogen, e.g., sulfur trioxide, sulfuric acid and the like; these reagents may cause the oxidation of the thiourea compound to a formamidine disulfide of the formula S- S f h in which Am has the previously given meaning, and which in the above ring closure may replace the thiourea compound and react with the starting material. The reaction is carried out according to known methods.
The starting material (which is also used for the manufacture of the starting material in the previously mentioned process modification) is prepared by treating a reactive esterified hydroxy-lower alkyl carbocyclic aryl ketone, particularly a halogeno-lower alkyl carbocyclic aryl ketone, in which the reactive esterified hydroxyl group, particularly the halogeno atom, is separated from the carbonyl group by at least three carbon atoms, with a secondary amine, particularly an amine of the formula Am -H, in which Am has the previously given meaning.
The compounds of this invention may also be prepared by reacting an a-thiocyanato=N,N-disubstituted aminolower alkyl carbocyclic aryl ketone, in which the N,N- disubstituted amino group is separated from the carbon atom carrying the thiocyanato group by at least two carbon atoms, particularly a compound of the formula ll Ar- 0 N in which Ar, Am the letter n and the group of the formula (C H have the previously given meaning, or a salt thereof with ammonia, a primary amine or a secondary amine, particularly a compound of the formula Am -H, in which Am has the previously given meaning, and, if desired, carrying out the optional steps.
The reaction is carried out according to known methods; the starting material may be obtained from the previously described a-reactive esterified hydroxy-N,N-disubstituted amino-lower alkyl carbocyclic aryl ketone, particularly an a-halogeno-N,N-disu'bstituted amino-lower alkyl carbocyclic aryl ketone, in which N,N-disubstituted amino is separated from the carbon atom carrying halogeno by at least two carbon atoms, by treatment with an alkali metal thiocyanate, e.g. sodium thiocyanate and the like, or an alkaline earth metal thiocyanate, e.g. barium thiocyanate and the like.
The compounds of this invention may also be prepared by reacting a 2-amino-4-carbocyclic aryl-S-reactive esterified hydroxy-lower alkyl-thiazole, in which the reactive esterified hydroxyl group is separated from the 5position of the thiazole nucleus by at least two carbon atoms, particularly a compound of the formula in which Am Ar, the letter n and the group --(C,,H have the previously given meaning, and X stands for a reactive esterified hydroxyl group, or a salt of such compound, with an N,N-disubstituted amine, particularly an amine of the formula Am H, in which Am has the previously given meaning, and, if desired, carrying out the optional steps.
The above reaction is carried out according to known methods, preferably in the presence of an inert solvent and, if necessary, of a base to neutralize generated acid (which may also be achieved by using an excess of the amine), while cooling or at an elevated temperature, in a closed vessel and/ or in the atmosphere of an inert gas, e.g. nitrogen.
The starting material may be prepared according to known methods, for example, the above given procedure for the formation of the thiazole nucleus using the appropriate starting materials, and, if necessary, a hydroxyl group in a resulting compound may be converted into the desired reactive esterified hydroxyl group.
The compounds of this invention may also be prepared by reacting a 2-halogeno-4-carbocyclic aryl-5-N,N-disubstituted amino-lower alkyl-thiazole, in which N,N-disubstituted amino is separated from the 5-position of the thiazole nucleus by at least two carbon atoms, particularly a compound of the formula in which Ar, Am the letter 12 and the group -(C H have the previously given meaning, and Hal stands for halogeno, or a salt thereof, with ammonia, a primary amine or a secondary amine, particularly a compound of the formula Am H, in which Am has the previously given meaning, and, if desired, carrying out the optional steps.
The above reaction is carried out according to known methods, if necessary, in the presence of a suitable solvent and/or a base to neutralize the generated acid (which may also be accomplished by using an excess of ammonia or the amine,) in a closed vessel, at an elevated temperature, and/or under an atmosphere or inert gas, e.g. nitrogen.
The starting material may be prepared, for example, by reacting one of the previously described a-thiocyanato- N,N-disubstituted amino-lower alkyl carbocyclic aryl ketones with a hydrogen halide, e.g. hydrogen chloride and the like.
A resulting salt may be converted into the free compound according to known methods, for example by treatment with a basic reagent, such as a metal hydroxide, for example, an alkali metal hydroxide or an alkaline earth metal hydroxide, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and the like, a metal carbonate, such as an alkali metal carbonate, or an alkaline earth metal carbonate, e.g. sodium, potassium or calcium carbonate or hydrogen carbonate and the like, ammonia, a hydroxyl ion exchange preparation and the like.
A resulting salt is converted into another salt according to known methods, for example, by treatment with a suitable anion exchange preparation. Furthermore, an addition salt with an inorganic acid may be converted into another acid addition salt, for example, by treating it with a suitable metal salt, e.g. silver, sodium and the like, salt of an acid in the presence of a solvent or solvent mixture, in Which a resulting inorganic compound is insoluble and is thus removed from the reaction medium.
A free compound is converted into a salt thereof according to known methods, for example, 'by reacting the free 'base or a solution thereof with one of the previously mentioned acids or a solution thereof, or with a suitable anion exchange preparation, and isolating the desired salt, which may be in the form of a hydrate or may contain solvent of crystallization.
. The quaternary ammonium derivatives of the compounds of this invention are obtained according to known methods, for example, by reacting the free compound with the reactive ester of an alcohol and a strong inorganic or organic acid, such as a lower-alkyl halide, a phenyllower alkyl halide, a lower alkyl sulfonate, a di-lower alkyl sulfate and the like, if necessary, in the presence of a solvent or solvent mixture, at an elevated temperature, in a closed vessel, and/or in the atmosphere of an inert gas, e.g. nitrogen. The quaternary ammonium compounds may *be isolated as the hydrates.
Quaternary ammonium compounds can be converted into other quaternary ammonium derivatives, such as the quaternary ammonium hydroxides, for example, by reacting a quaternary ammonium halide with silver oxide, or a quaternary ammonium sulfate with barium hydroxide, by treating a quaternary ammonium salt with a hydroxyl ion exchange preparation, by electrodialysis or any other suitable method. A resulting quaternary ammonium hydroxide compound is converted into a quaternary ammonium salt, for example by reaction with an acid, a mono-lower alkyl sulfate, e.g. methyl sulfate, ethyl sulfate and the like, a suitable anion exchange preparation and the like. A quaternary ammonium compound may also be converted directly into another qua ternary ammonium salt without the formation of the quaternary ammonium hydroxide; for example, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride or'hydrogen chloride in anhydrous methanol to form the quaternary ammonium chloride, or upon treatment with a suitable anion exchange preparation a quaternary ammonium compound may be converted into another quaternary ammonium salt.
The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out, as well as any new intermediates.
In the process of this invention such starting materials are preferably used which lead to final products mentioned as preferred embodiments of the invention.
The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade.
Example 1 To a solution of 0.37 g. of thiourea in 7.5 ml. of ethanol is added 2.0 g. of a-bromo-p-chloro-v-(N,N-diethylamino)-butyrophenone hydrobromide, and the reaction mixture is warmed on the steam bath for ten minutes. A crystalline precipitate is formed on cooling and is filtered off to give the 2-amino-4-(4-chlorophenyl)-5-(2-N,N-diethylaminoethyl)-thiazole dihydrobromide of the formula which is purified by recrystallization from a mixture of ethanol and water, M.P. 227228 The starting material may be prepared as follows: A mixture of g. of p,y-dichloro-butyrophenone and 41.5 g. of N,N-dimethylamine in 320 ml. of ethanol is heated in an autoclave for 10 hours. After cooling, the ethanol is evaporated, the residue is dissolved in water, and the solution is made basic with aqueous ammonia. The organic material is extracted with diethyl ether, the organic solution is shaken with 15 percent aqueous hydrochloric acid, and the acidic extract is made basic with aqueous ammonia. The p-chloro-'y-N,N-diethylamino-butyrophenone is extracted with diethyl ether, the organic solution is dried over sodium sulfate and evaporated, and the residue is distilled, B.P. 122/0.8 mm. The hydrochloride, M.P. 169171, is prepared by treating the free base with hydrogen chloride and purified by recrystallization from a mixture of ethanol and diethyl ether.
To a solution of 5.0 g. of p-chloro- -N,N-dimethylamino-butyrophenone hydrochloride in 15 ml. of glacial acetic acid is added 19 ml. of a 1 molar solution of bromine in glacial acetic acid as follows: about 2 ml. of the halogenating reagent is added and the solution is warmed to about 50 for a few minutes until the bromine decolorizes. The solution is then cooled to room temperature, and the remainder of the reagent is then added dropwise while stirring over a period of about thirty minutes at such a rate that an excess of bromine is never present in the reaction mixture for more than a few seconds. After completion of the reaction, diethyl ether is added to turbidity, the reaction flask is allowed to stand overnight while cooling and the crystalline material is filtered off. The a-bromo-p-chloro-' -N,N-dimethylamino-butyrophenone hydrobromide is recrystallized from ethanol and melts at The following compounds are prepared according to the above or any of the previously described procedures by selecting the appropriate starting materials:
Z-amino 4 (4-chloro-phenyl)-5-[2-(1-pyrro1idino)- ethyl]-thiazole dihydrobromide, M.P. 262-264", by reacting an ethanol solution of thiourea with a-bromo-p-chloro- 'y-( l-pyrrolidino -butyro'phenone hydrobromide, M.P. 134-135 (prepared by reacting p,'y-dichloro-butyrophenone with pyrrolidine and brominating the p-chloro-y-( lpyrrolidino)-butyrophenone hydrochloride, M.P. 168- 170", the free base of which melts at 5 860 i 2 amino 5 (2-N,N-dimethylaminoethyl)-4-(4-me- "thoxy-phenyD-thiazole dihydrobromide, M.P. 255-258, by reacting an ethanol solution of thiourea With wbromo- -(N,N-dimethylamino)-p-rnethoxy butyrophenone hydrobromide M.P. 153-165 (prepared by reacting 'y-ChlO- r-p-methoxy-butyrophenone with N,N-dimethylamine and brominating the 'y-(N,N-dimethylamino)-p-methoxybutyrophenone hydrochloride, M.P. 150, the free base of which boils at 150-156/0.75 mm.);
2 amino 4 (4-bromo-phenyl)-5-(2-N,N-dimethylaminoethyl)-thiazole dihydrobromide, M.P. 248-250, by reacting thiourea with p,a-dibromo-'y-(N,N-dimethylamino)-butyrophenone hydrobromide, M.P. 96-98 (prepared by reacting p-bromo-y-chloro-butyrophenone with N,N-dimethylarnine and brominating the p-bromo-v- (N,N dimethylamino) butyrophenone hydrochloride, M.P. 193-195, the free base of which boils at 119-120/ 0.19 mm);
2-amino 5 (2-N,N-dimethylaminoethyl)-4-(N,N-dimethylamino-phenyl)-thiazole dihydrobromide, M.P. 196- 200, by reacting thiourea with u-bromo-p,'y-bis-(N,N-dimethylamino)-butyrophenone hydrobromide, M.P. 200- 202 (prepared by reacting 'y-chloro-p-(N,N-dimethylamino)-butyrophenone with N,N-dimethylamine and brominating the pyy-bis-(N,N-dimethylamino -butyrophenone hydrochloride) 2-arnino 4 phenyl-5-[2-(l-pyrrolidino)-ethyl]-thiazole dihydrobromide, M.P. 267-269, by reacting thiourea with a-brom0- l-pyrrolidino)-butyrophenone hydrobromide, M.P. 96-98 (prepared by reacting 'y-chloro-butyrophenone with pyrrolidine and brominating the 'y-(l-pyrrolidino)-butyrophenone hydrochloride, M.P. 162-163), as well as the following compounds by selecting the appropriate starting materials and reagents;
10 an aqueous sodium hydroxide solution, and the crystalline 2-amino-5-(2-N,N-dimethylaminoethyl) 4 phenylthiazole of the formula Example 4 The 2 amino-4-(4-chloro-phenyl)-5(3-N,N-dimethyl aminopropyl)-thiazole dihydrobromide of the formula is prepared by reacting 0.45 g. of a-bromo-p-chloro-fi- (N,N dimethylamino) valerophenone hydrobromide (M.P. 138, prepared by heating p,6-dichloro-valerophenone with N,N-dimethylamine in ethanol in a sealed tube and brominating the p-chloro-6-(N,N-dimethylamino)-valerophenone hydrochloride, M.P. Ill-124) with an equivalent amount of thiourea according to the a-Halogeno-N,N-disubstituted amino-lower alkyl carbocyclic Thiourea 2-amin0-4carbocyc1ic aryl-5-N,N-disubstituted amino-lower aryl ketone alkylthiazole a-Bromo-p-ehloro-y N,N-diethylaminobutyrophcnone Thiourea a-Bromo-y-N,N-diethylamino-p-isopropyl-butryophenone a-Bromo-y-N,N-diethylamino-p-trifluoromethyl-butyrophenone.
a,pdibromo-'y-(l-piperidino)-butyrophenone a-Bromo-v-N,N-dimethylamino-p-tertiary butyl-butyrophenone.
a-Bromo-y-N,N-dimethylamino-p-fiuoro-butyropheuone a-Bromo-m,p-dichloro-w-N,N-dl-n'propylamino-butyrophenone..
a-Bromoop-dimethyl-y-[1-N,N-(1,6-11exylcne)-imin0]-thiaz0lc..
a-Bromo-p-chloro-v-(4-morph0lino)-thiazole w-Bromo-o-ethoxy-y-(4-methyl-l-piperazinol)-butyrophenone a-Bromo-ypdi-(N,N-diethylamino)-butyrophenone a-Bromo-y-N,N-di-ethylarnino-p-methylmercapto-butyrophenone.
2-an'iino-4- (4-chloropl1eny1)-5-(Z-N,N-diethylaminoethyl) -thialamina-5-(2-N,N-diethylaminoethyl)A-(ttrifiuoromethylphenyD-thiazole.
2-amino-5-(2 N,N-di-metliylamino ethyl) -4-(4-tertiary butylphenyD-thiazole.
lazo e.
2-amino-4-(3,4-dichloropl1eny1)-5-(2-N,N-di-n-propyl-aminoethyl)-thiazole.
2-amino-4- (2.,4-dimethy1phenyD-5-l 2-[1-N,N- (1,6-hexylene)- iminol-ethyl}-thiaz0le.
2-amino-4-(4-ch10ropheny1)-5-[2-(4.-morpholino)-ethyl] thiazole.
2-amino-4-(2-cthoxy-pheuyD-5-[2-(4-methyl-l-piperazino)- ethyl]-thiazole.
2-amin0-5- (2-N,N-diethylaminoethyl) -4- (4-N.N-diethylamin0- phenyD-thiazole.
2-amino-5-( N,N-diethylaminoethyl)-4-( i-methyl-mercaptopheny1)-thiazo1e.
N Ora-The above compounds are also obtained in the form of acid addition salts thereof.
Example 2 Example 3 To a solution of 0.55 g. of thiourea in 5 ml. of ethanol is added 2.5 g. of a-bromo-y-(N,N-dimethylarnino)-butyrophenone hydrobromide. After refluxing for five minutes, the reaction mixture is cooled and diluted with diethyl ether. The resulting precipitate is filtered off, and dissolved in water; the aqueous solution is treated with procedure described in Example 1; the desired product melts at 274-276 after recrystallization from ethanol.
Example 5 An equivalent amount of thiourea in ethanol is treated with 1.0 g.- of 1-bromo-5-(N,N-dimethylamino)-pentyl 4chloro-phenyl ketone hydrobromide according to the procedure described in Example 1; the 2-amino-4-(4- chloro-phenyl)-5-(4-N,N-dimethylaminobutyl) thiazole dihydrobromide of the formula is recrystallized from a mixture of ethanol and ethyl acetate, M.P. 225.
The starting material is prepared as described in Example 1; the 4-chloro-phenyl 5-(N,N-dimethy1amino)- 3,210,368 1 1 1 2 ,pentyl ketone hydrochloride, M.P. 178180, is brominat- What is claimed is: ed to yield the l-brorno-S-(N,N-dimethylarnino)-pentyl 1. A member selected from the group consisting of a 4-chloro-phenyl ketone hydrobromide, M.P. 135-138". compound of the formula Example 6 0.65 g. of N-phenylthiourea in 10 ml. of ethanol is reacted according to the procedure described in Example 1 to yield the 4 (4 methoxy-phenyl) (2-N,N-dimethylaminoethyl) 2 N-phenylamino-thiazole dihydrobromide of the formula in which Ar is a member selected from the group consisting of phenyl, (lower alkyl)-pheny1, (trifluoromethyl)- phenyl, (lower alkoxy)-phenyl, (N,N-di-lower alkylamino)phenyl, (halogeno)-phenyl and (lower alkyl-mercapt0)-pheny1, Am is a member selected from the group consisting of amino, N-lower alkyl-amino, N,N-di-lower a lkyl-amino, N-cycloalkyl-amino, in which cycloalkyl has from three to eight carbon atoms, N-phenyl-amino, and H;C-O@ .2 HBr N-phenyl-lower alkyl-amino, Am is a member selected from the group consisting of N,N-di-1ower alkyl-amino,
which melts at 121-125 after recrystallization from a y in which l y has from three o mixture f ethanol and diethylethen eight carbon atoms, 4-morphol1n0 and 4-lower alkyl-l- Other compounds, which may b prepared according piperazino, the letter It stands for an integer from two to to the above procedure by selecting the appropriate start- Seven, and the p n 2n) Separates thfi group ing materials are, f exampk, Am from the 5-pos1tion of the thiazole ring by at least C tl l 2-(N substituted amino)-4-carbocyclic ary1-5-N,N-
N-substituted thiourea disubstituted amino-lower aklyl-thiazole a-Halogeno-N,N-disubstituted amino-lower alkyl carbocyelic aryl ketone B o.p. 1 1 .N N diethy1amino.butyr phenone N-meth lthiourea -phe y v methylaminotlnazolc. aBromo-y-N,N-dirnethylamino-o-methyl-butyrophenone. N,N-dimethyl h 1 y y Y (Z-methyLphenyI)-th1azole. p Dibr m .N,N..dimethylamino.va1et0phen0ne N-ethylthiourea q o-p y y y 1mnci-2l;met1hylethybzthiazolei t 1 1) [2 N-c clohex lthiourea 2- -cyco exy aminot- 4-met ymercap op leny 5 a 1133131112); methylmercapto 'y (1 pipendino) butyro 3 y (Lpipcrdino) ethyn thiazole B h1 o 5.N,N.dimqthylaminmvalerophenone N-bsnz lthiourea q -p y y annnopropyD-thrazole. a-Bromo-yN,N-diethylamino-p-nitrobutyrophenone N-(4-ch1oropheny1)-tl1i0urea 2-N-(4-chloro-phenyl)-am1no-5-(2-N,N-d1ethy1am1no ethyl) -4- (4-nitropheny1)-thiaz0le.
No'rn.The above compounds may also be obtained in the form of acid addition salts thereof.
- two carbon atoms, and a pharmaceutically acceptable acid 40 addition salt thereof.
2. 2 amino 4-(4-chloro-phenyl)-5-(2-N,N-dimethylaminoethyl -thiazole.
3. Pharmaceutically acceptable acid addition salts of 2 amino 4-(4-chloro-phenyl)-5-(2-N,N-dimethylaminoethyl)-thiazo1e.
4. 2 amino 4-(4-chloro-pl1enyl)-5-(2-N,N-dimethylaminoethyl) -thiazole dihydrochloride.
5. 2 amino 4-(4-chloro-phenyl)-5-(2-N,N-dimethylaminoethyD-thiazole dihydrobromide.
6. 2 amino 5-(2-N,N-dimethy1aminoethyl)-4-phenyl- Example 7 A mixture of 10.0 g. of 2-amino-5-(2-chloroethyl)-4-(4- chloro-phenyl)-thiazole hydrobromide and 50 ml. of a 10 percent solution of N,N-dimethylamine in ethanol is heated at 80 in a rocking brom tube for twenty-four hours. The solution is then evaporated to dryness, the residue is stirred with ml. of aqueous ammonia, and the mixture is chilled. The solid material is filtered off and dissolved in a small amount of ethanol; gaseous hydrogen bromide is passed through the solution, and the desired 2 amino 4-(4-chloro-phenyl)-5-(2-N,N-dimethylaminothiazo1e ethyD-thiazole dihydrobromide is filtered oil, MP. 227- 7 2 1 .5- 2 1 1 -4 4- h- 228 oxyphenyl -thiazole.
The starting material used in the above procedure is 8. 2 amino 4-(4-bromo-phenyl)-5-(2-N,N-dimethylprepared as follows: A mixture of 3.0 g. of Ot-bIOHlO-Pfiarninoethyl)thiazole. dichlorobutyrophenone (M.P. 71-73", prepared by bro- '9. 2 amino 4-(4-N,N-dimethylamino-phenyl)-5-(2- minating pyy-dichlorobutyrophenone with bromine in the N,N-dimethylaminoethyl)-thiflZ01epresence of 1 ml. of 48 percent hydrogen bromide in ace- 2 'P Y y tic acid) and 1.0 g. of thiourea in 10 ml. of ethanol is reammobutynthiazolefluXed for ten minutes. The crystalline 2-arnino-5-(2-chlo- 5 (2 m l Y- roethyl)-4-(4-ch1orophenyl)-thiazole hydrochloride is filtered oil and recrystallized from a mixture of ethanol and NO references Citedn-propanol and twice from water. NICHOLAS S. RIZZO, Primary Examiner.
UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No a 3, 210,368 October 5, 1965 Charles Ferdinand Huebner It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.
Column 12, line 52, for "-4,(4meth" read 4-(4- methlines 54 and 58, for ")thiazole", each occurrence, read )-thiazole -D A Signed and sealed this 9th day of August 1966.
(SEAL) Attest:
EDWARD J. BRENNER Commissioner of Patents ERNEST W. SWIDER Attesting Officer

Claims (1)

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA
US400197A 1964-09-29 1964-09-29 Certain 2-amino-4-aryl-5-n, n-disubstituted amino-lower alkyl-thiazole compounds Expired - Lifetime US3210368A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US400197A US3210368A (en) 1964-09-29 1964-09-29 Certain 2-amino-4-aryl-5-n, n-disubstituted amino-lower alkyl-thiazole compounds

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US400197A US3210368A (en) 1964-09-29 1964-09-29 Certain 2-amino-4-aryl-5-n, n-disubstituted amino-lower alkyl-thiazole compounds

Publications (1)

Publication Number Publication Date
US3210368A true US3210368A (en) 1965-10-05

Family

ID=23582609

Family Applications (1)

Application Number Title Priority Date Filing Date
US400197A Expired - Lifetime US3210368A (en) 1964-09-29 1964-09-29 Certain 2-amino-4-aryl-5-n, n-disubstituted amino-lower alkyl-thiazole compounds

Country Status (1)

Country Link
US (1) US3210368A (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3542801A (en) * 1968-01-22 1970-11-24 Sandoz Ag 2-aminothiazoles
US3888851A (en) * 1971-05-04 1975-06-10 Boehringer Sohn Ingelheim 2,4-diamino-substituted thieno(3,2-d)pyrimidines and salts thereof
US3951978A (en) * 1972-04-22 1976-04-20 Istituto Luso Farmaco D'italia S.R.L. 1,3-Disubstituted 3-aroylpropanes and process for the preparation thereof
EP0409048A3 (en) * 1989-07-18 1991-05-15 Basf Aktiengesellschaft Aminoalkyl substituted 2-aminothiazoles and medicines containing them
EP0518731A1 (en) * 1991-06-05 1992-12-16 Sanofi Heterocyclic derivatives of substituted 2-acylamino 5-thiazole, their preparation and pharmaceutical compositions containing them
EP0641788A4 (en) * 1991-05-30 1994-03-07 Taisho Pharmaceutical Co Ltd AMINOALKYLTHIAZOLE DERIVATIVES.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3542801A (en) * 1968-01-22 1970-11-24 Sandoz Ag 2-aminothiazoles
US3888851A (en) * 1971-05-04 1975-06-10 Boehringer Sohn Ingelheim 2,4-diamino-substituted thieno(3,2-d)pyrimidines and salts thereof
US3951978A (en) * 1972-04-22 1976-04-20 Istituto Luso Farmaco D'italia S.R.L. 1,3-Disubstituted 3-aroylpropanes and process for the preparation thereof
EP0409048A3 (en) * 1989-07-18 1991-05-15 Basf Aktiengesellschaft Aminoalkyl substituted 2-aminothiazoles and medicines containing them
EP0641788A4 (en) * 1991-05-30 1994-03-07 Taisho Pharmaceutical Co Ltd AMINOALKYLTHIAZOLE DERIVATIVES.
US5502202A (en) * 1991-05-30 1996-03-26 Taisho Pharmaceutical Co., Ltd. Aminoalkylthiazole derivative
EP0518731A1 (en) * 1991-06-05 1992-12-16 Sanofi Heterocyclic derivatives of substituted 2-acylamino 5-thiazole, their preparation and pharmaceutical compositions containing them

Similar Documents

Publication Publication Date Title
US3729469A (en) 4-(3-amino-2-hydroxypropoxy)-1,2,5-thiadiazole compounds
US2928829A (en) Alkyleneimino-lower alkyl-guanidines
US3669968A (en) Trialkoxy quinazolines
KR100895752B1 (en) [4-heteroarylpiperazin-1-yl]-2,5-substituted-phenylmethanone derivatives as glycine transporter 1glyt-1 inhibitors for the treatment of neurological and neuropsychiatric disorders
AU2008312624B2 (en) Preparation of dihydrothieno [3, 2-D] pyrimidines and intermediates used therein
US3340260A (en) 4-amino-pyrimidines
EP1963315B1 (en) Enzyme inhibitors
US3098066A (en) Diaza-heterocyclic guanidine compounds
SE456581B (en) INTERMEDIATES FOR THE PREPARATION OF 3,4-DISUBSTITUTED 1,2,5-THIADIAZOL-1-OXIDES AND -1,1-DIOXIDES WHICH ARE H 71 RECEPTOR ANTAGONISTS
DE60027144T2 (en) Hydroxamic acid derivatives
NO170081B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE TIAZOLD DERIVATIVES WITH ACTIVITY ON COLLINERY SYSTEM
US3210368A (en) Certain 2-amino-4-aryl-5-n, n-disubstituted amino-lower alkyl-thiazole compounds
US3767653A (en) Thiazines
DE69105572T2 (en) 4-phenylphthalazine derivatives.
US3169965A (en) New x-mercapto-pyrazolo
US3093632A (en) Dibenzpolymethylenimino-alkylene-guanidines
US3417085A (en) 3,1-benzothiazines and 3,1-benzoxazines
US3346452A (en) 5, 6-lower alkylene-pyrimidines
MX2007007245A (en) Meta-substituted thiazolidinones, the production thereof and their use as medicaments.
JPS606945B2 (en) Method for producing thiazolidine derivatives
US3288792A (en) Method of preparing 2, 4-diamino-6-alkylpyrido (2, 3-d) pyrimidines
US2510773A (en) Process for preparing a tertiary amino-alkyl thiol-ester hydrochloride
US3133930A (en) Ester and amide derivatives of thieno-[3, 2-b] indole 3-carboxylic acids
US3318882A (en) 2-amino-5-diloweralkyl sulfamoyl-n, n-disubstituted benzamides
US2969358A (en) 2-chloro-10-phenothiazinecarbonylpiperazines