Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
  • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
  • C07C279/24—Y being a hetero atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
  • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton

Definitions

• the invention relates to a new method for the preparation of amidino-urea derivatives.
• amidino-urea derivatives possess numerous favourable physiological properties [Fort Whitneye der Arzneistoffforschung 28, 1435 (1978)]. Of them 1-(2,6-dimethylphenyl)-2-(N-methylamidino)-urea (lidamidine) is of particular interest.
• the hydrochloride of this compound is an excellent antidiarrhoeal agent with a still unknown mechanism of effect, which exerts much less undesired side effects than the commonly applied antidiarrhoeal substances.
• Several methods have been described in the literature for the preparation of amidino-urea derivatives.
• amidino-urea derivatives can be prepared by subjecting the respective biguanide compounds to acidic hydrolysis.
• the large scale applicability of this method is, however, rather restricted, since numerous undesired side reactions may occur simultaneously during the synthesis [Fortönennee der Arzneistoffforschung 28, 1436 (1978)].
• Amidino-urea derivatives can also be prepared by reacting the respective isocyanates with guanidino derivatives (US patents Nos. 4,060,635, 4,147,804, 4,203,920 and
• isocyanates can be prepared from reactants other than phosgene and can be converted directly into the desired amidino-urea derivatives (Spanish patents Nos. 546,126 and 548,902).
• Amidino-urea derivatives can also be prepared by reacting the appropriately substituted aromatic carbamates with guanidine derivatives (published South African patent application No. 78/1574), the yield is, however, very poor even when applying phenyl esters as starting substances.
• guanidine derivatives published South African patent application No. 78/1574
• phenyl chloroformate required as starting substance to prepare phenyl carbamates, is an expensive chemical, it is obvious that the above method cannot be applied for large scale production.
• the utilization of alkyl carbamates, which require much less expensive starting substances, is not even mentioned as an example in the cited reference.
• the invention relates to a method for the preparation of an amidino-urea derivative of the general formula (I),
• R 1 , R 2 and R 3 each stand for hydrogen, halogen, lower alkyl, lower alkoxy , trifluoromethyl, nitro or optionally substituted amino
• R 4 is hydrogen or lower alkyl
• R 5 is hydrogen or C 1-10 alkyl, by reacting an alkyl carbamate of the general formula (II) ,
• R 1 , R 2 and R 3 are as defined above and R 6 is a C 1-1 alkyl group , with a guanidine derivative of the general formula (III) , wherein R 4 and R 5 are as defined above.
• the reaction is performed in the presence of a bipolar aprotic solvent.
• dimethyl formamide, dimethyl acetamide, dimethyl sulphoxide, hexamethylphosphoric acid triamide, diethyl acetamide or any mixture of these liquids as bipolar aprotic solvent.
• the alkyl carbamate of the general formula (II) is reacted with the guanidine derivative of the general formula (III) generally in a molar ratio near to the equimolar value, preferably in a molar ratio of 1 : (0.8-1.25).
• the reaction is performed preferably under heating the reaction mixture. Since a lower alkanol splits off in the reaction, it is preferred to perform the reaction at a temperature which enables one to remove the thus formed alkanol from the mixture within a short period of time. The removal of the alkanol can also be facilitated by simultaneously lowering the pressure of the reaction.
• the resulting compound of the general formula (I) is separated from the reaction mixture in a manner known per se.
• the reaction mixture is poured into water, and the amidino-urea derivative, separated as a crystalline substance, is removed e.g. by filtration.
• Solvents other than water can also be applied as precipitating agents.
• the end products obtained are generally sufficiently pure, however, if desired, they can be purified by standard methods, e.g. by recrystallization, chromatography or salt formation.
• Any of the mineral and organic acids applicable for pharmaceutical purposes can be used in the salt formation step, of which hydrochloric acid is preferred.
• the lidamidine - dimethyl sulphoxide adduct is a new compound, a stable, crystalline substance melting at 160-162oC . This compound can be prepared in extreme ly pure state, and can be utilized for the preparation of highly pure lidamidine.
• the lidamidine - dimethyl sulphoxide adduct can be utilized, however, even as such for the preparation of pharmaceutical compositions, since the small amount of dimethyl sulphoxide present is physiologically tolerable.
• the invention also relates to a method for the preparation of a lidamidine - dimethyl sulphoxide adduct. According to the invention one proceeds in such a way that lidamidine, prepared optionally directly in the reaction mixture, is reacted with dimethyl sulphoxide optionally in the presence of one or more inert organic solvent(s).
• the reaction can be performed most simply in such a way that lidamidine is suspended in dimethyl sulphoxide under stirring, and the resulting adduct is separated from the reaction mixture preferably by filtration.
• Lidamidine can also be prepared directly in the reaction mixture.
• One can proceed e.g. in such a way that a salt of lidamidine is applied as starting substance, and lidamidine base is liberated from its salt directly in dimethyl sulphoxide or in a mixture of dimethyl sulphoxide with one or more inert solvent(s).
• the lidamidine - dimethyl sulphoxide adduct can be converted directly into pharmaceutical compositions, such as tablets, capsules, suspensions, etc., by routine pharmacotechnological methods utilizing conventional pharmaceutical additives (e.g. carriers, diluents or other auxiliary agents).
• pharmaceutical additives e.g. carriers, diluents or other auxiliary agents.
• lidamidine - dimethyl sulphoxide adduct can be converted into lidamidine by reacting it with water. In this operation lidamidine is obtained in particularly pure state. This method is also embraced by the scope of the invention.
• the lidamidine - dimethyl sulphoxide adduct is decomposed with water generally at 0-100°C, preferably at 20-80°C. It is preferred to apply at least one molar equivalent of water for the reaction. The upper limit of water to be added is not decisive and is determined essentially by economical factors.
• the resulting lidamidine is separated from the mixture by a method known per se.
• a mixture of 7.17 g (0.04 mole) of methyl 2,6-dimethylphenyl-carbamate, 3.21 g (0.044 mole) of methyl-guanidine and 15 cm 3 of dimethyl formamide is warmed to 100°C with stirring.
• Methanol which forms in the reaction is re moved continuously at a pressure of 100 mmHg.
• the mixture is stirred for additional one hour, thereafter it is cooled to room temperature, poured into 160 cm 3 of cold water, and the aqueous mixture is stirred at 10-15°C for 2 hours.
• the separated precipitate is filtered off, auctioned, and then washed with deionized water and finally with a small amount of acetone.
• the resulting crude product is dissolved in 80 cm 3 of methanol, the solution is decolourized with a small amount of activated carbon, filtered, and the filtrate is acidified to pH 2 with methanolic hydrogen chloride solution. The solvent is removed under reduced pressure, and the residue is triturated with acetone. The precipitate is filtered off, suctioned, washed with a small amount of acetone and then with ether, and dried.
• 1-(2,6-Dimethylphenyl)-3-(N-methylamidino)-urea hydrochloride is obtained; m.p.: 194-197°C.
• the IR spectrum of the product is identical with that of the authentic sample.
• Example 3 One proceeds as described in Example 1 with the difference that 15 cm 3 of hexamethylphosphoric acid triamide are utilized as reaction medium, and the mixture is maintained at 100°C for 2 hours. 6.87 g (78.1 %) of 1-(2,6-dimethylphenyl)-3-(N-methylamidino)-urea are obtained.
• the hydrochloride of the product is identical with the compound obtained according to Example 1.
• Example 3 6.69 g (80.6 %) of 1- (2, 6-dimethylphenyl)-3-(N-methylamidino)-urea are obtained.
• Example 1 One proceeds as described in Example 1 with the difference that 15 cm 3 of dimethyl acetamide are applied as reaction medium and the reaction is performed for 2 hours.
• the mixture is processed as described in Example 1. 6.06 g (68.8 %) of 1-(2,6-dimethy1phenyl)-3-(N-methylamidino)-urea are obtained.
• the hydrochloride of the product is identical with the compound prepared according to Example 1.
• Example 6 7.36 g (0.050 mole) of 2,6-dimethylphenyl-isocyanate are added dropwise, at room temperature, to a stirred suspension of 4.04 g (0.055 mole) of N-methylguanidine in 20 cm 3 of dimethyl sulphoxide.
• lidamidine - dimethyl sulphoxide adduct separates slowly during the addition of the reactant.
• the reaction mixture is stirred for additional one hour, thereafter the crystals are filtered off, washed with a small amount of cold methanol and dried. 14.80 g (99 %) of lidamidine - dimethyl sulphoxide adduct are obtained; m.p.: 160-162°C. Analysis: calculated: C: 52.30%, H: 7.37%, N: 18.77 %, S: 10.73 %; found: C: 52.00%, H: 7-53%, N: 18.90 %, S: 11.51 %.
• Example 8 A suspension of 36.55 g (0.5 mole) of N-methylguanidine and 80.5 g (0.45 mole) of methyl 2,6-dimethylphenyl-carbamate in 170 cm 3 of dimethyl sulphoxide is warmed to 100°C with stirring. The crystalline product starts to separate during the warming period. The mixture is stirred at 100°C for one hour, thereafter cooled to room temperature, the crystals are filtered off, washed with dichloromethane and dried. 131.2 g (97.7 %) of lidamidine - dimethyl sulphoxide adduct, melting at 160-162°C, are obtained. The purity grade of the product is identical with that obtained according to Example 6.
• Example 9 A suspension of 36.55 g (0.5 mole) of N-methylguanidine and 80.5 g (0.45 mole) of methyl 2,6-dimethylphenyl-carbamate in 170 cm 3 of dimethyl sulphoxide is warmed to 100°C with stirring. The
• lidamidine - dimethyl sulphoxide adduct 100 g are suspended in 700 cm 3 of deionized water, and the suspension is stirred at 50°C for 0.5 hour. Thereafter the suspension is cooled to room temperature, the separated white crystalline substance is filtered off, washed with deionized water and dried. 71.8 g (97.2 %) of lidamidine are obtained.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 1988
  • 1988-04-08 KR KR1019880701357A patent/KR910008221B1/ko active IP Right Grant
  • 1988-04-08 WO PCT/HU1988/000017 patent/WO1988007990A1/en not_active Application Discontinuation
  • 1988-04-08 AU AU15980/88A patent/AU605584B2/en not_active Expired - Fee Related
  • 1988-04-08 EP EP88903333A patent/EP0325620A1/en not_active Withdrawn
  • 1988-12-08 FI FI885700A patent/FI885700A0/fi not_active IP Right Cessation

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