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33 PATENTNI ZAHTEVKI 1. Postopek za pripravo substituiranih alkandifosfonskih kislin, zlasti heteroarilalkan-difosfonskih kislin s formulo ™3H2 r,-ch2-c-r2 P03H2 v kateri pomeni imidazolilni, 2H-1,2,3-, 1H-1,2,4- ali 4H-l,2,4-triazolilni, tetrazolilni, oksazolilni, izoksazolilni, oksadiazolilni, tiazolilni ali tiadiazolilni ostanek, ki je nesubstituiran ali C-mono- ali disubstituiran z nižjim alkilom, nižjim alkoksi, s fenilom, ki je po svoji strani lahko mono- ali disubstituiran z nižjim alkilom, nižjim alkoksi in/ali halogenom; s hidroksi, dinižjim alkilamino, nižjim alkiltio in/ali halogenom, in N-substituiran ob atomu N, ki se ga da substituirati, z nižjim alkilom ali fenilnižjimalkilom, ki je po svoji strani lahko v fenilnem delu mono- ali disubstituiran z nižjim alkilom, nižjim alkoksi in/ali halogenom, alk pomeni nižji alkilen in R2 pomeni vodik, hidroksi, amino, nižji alkiltio ali halogen, pri čemer imajo nižji ostanki do vključno 7 atomov ogljika, z ukrepi, da je Rj različen od imidazol-4-ila, 2-metiltiazol-4-ila, 2-metiltiazol-5-ila in l,2,5-tiadiazol-4-ila, kadar R2 predstavlja vodik, da je Rt različen od imidazol-2-ila, 5(4)-metilimidazol-4(5)-ila, 2H-1,2,3-triazol-4-ila, lH-l,2,4-triazol-l-ila, lH-l,2,4-triazol-3-ila, 5-etoksi-, 5-etoksi-2-metil-, 2- klor-, 5-metoksi- in 2,5-dimetiloksazol-4-ila, 3-metil- in 3-fenilizoksazol-5-ila, 3- metil-l,2,5-oksadiazol-4-ila, 2-metil-l,3,4-oksadiazol-5-ila, 3-fenil-l,2,4-oksadiazol-5-ila, 2-klor- in 2-metiltiazol-5-ila, 1,2,3- in l,2,5-tiadiazol-4-ila, l,2,3-tiadiazol-5-ila, 4- metil-l,2,3-tiadiazol-5-ila in 3-metil- in 3-fenil-l,2,4-tiadiazol-5-ila, kadar R2 predstavlja hidroksi, in da je Rj različen od imidazol-4-ila, kadar predstavlja R2 amino ali dimetilamino, in njihovih soli, označen s tem, da v spojini s formulo 34 R 1 ch2A process for the preparation of substituted alkandiphosphonic acids, in particular heteroarylalkane-diphosphonic acids of the formula ™ 3H2 r, -ch2-c-r2 P03H2 in which imidazolyl, 2H-1,2,3-, 1H-1,2, 4- or 4H-1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl residue which is unsubstituted or C-mono- or disubstituted by lower alkyl, lower alkoxy, by phenyl which by its nature the sides may be mono- or disubstituted with lower alkyl, lower alkoxy and / or halogen; with hydroxy, lower alkylamino, lower alkylthio and / or halogen, and N-substituted at the substitutable N atom, with lower alkyl or phenyl lower alkyl, which in turn may be mono- or disubstituted in the phenyl moiety by lower alkyl, lower alkoxy and / or halogen, alk represents lower alkylene and R2 represents hydrogen, hydroxy, amino, lower alkylthio or halogen, the lower radicals having up to and including 7 carbon atoms, with the proviso that Rj is different from imidazol-4-yl, 2-methylthiazol-4-yl, 2-methylthiazol-5-yl and 1,2,5-thiadiazol-4-yl, when R2 represents hydrogen, that Rt is different from imidazol-2-yl, 5 (4) -methylimidazole -4 (5) -yl, 2H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl, 5-Ethoxy-, 5-ethoxy-2-methyl-, 2-chloro-, 5-methoxy- and 2,5-dimethyloxazol-4-yl, 3-methyl- and 3-phenylisoxazol-5-yl, 3-methyl -1,2,5-oxadiazol-4-yl, 2-methyl-1,3,4-oxadiazol-5-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, 2-chloro- 2-methylthiazol-5-yl, 1,2,3- and 1,2,5-thiadiazol-4-yl, 1,2, 3-thiadiazol-5-yl, 4-methyl-1,2,3-thiadiazol-5-yl and 3-methyl- and 3-phenyl-1,2,4-thiadiazol-5-yl, when R2 represents hydroxy, and that R 1 is different from imidazol-4-yl when R 2 represents amino or dimethylamino, and their salts, characterized in that in the compound of formula 34 R 1 is ch2(II) , ki je v danem primeru intermediamo zaščitena na atomu N, ki se ga da substituirati, ostanka Rp v kateri pomeni Xj funkcionalno spremenjeno in prosto ali funkcionalno spremenjeno fosfono skupino, prevedemo Xt in v danem primeru v prosto fosfono skupino, in po želji dobljeno spojino prevedemo v drugo spojino s formulo I in/ali dobljeno prosto spojino prevedemo v sol ali dobljeno sol v prosto spojino ali v drugo sol.(II), which is optionally intermediate protected on a substitutable N atom, the residue Rp in which X 1 represents a functionally modified and free or functionally modified phosphonic group, Xt is converted and optionally into a free phosphonic group, and after If desired, the obtained compound is converted into another compound of formula I and / or the obtained free compound is converted into a salt or the obtained salt into a free compound or into another salt.2. Postopek po zahtevku 1, označen s tem, da pripravimo spojine s formulo I, v kateri pomeni Rj nesubstituiran ali z nižjim alkilom, nižjim alkoksi, z nesubstituiranim ali z nižjim alkilom, nižjim alkoksi in/ali halogenom mono- ali disubstituiranim fenilom, hidroksi, dinižjimalkilamino, nižjim alkiltio in/ali halogenom C-mono- ali dis-ubstituiran ostanek in/ali na N-atomu, ki se ga da substituirati, z nižjim alkilom ali nesubstituiranim ali z nižjim alkilom, nižjim alkoksi in/ali halogenom mono- ali disubstituiranim fenilnižjialkilom N-substituiran imidazolilni, 2H-l,2,3-ali 4H-1,2,4-triazolilni, tetrazolilni, oksazolilni, izoksazolilni, oksadiazolilni, tiazolilni ali tiadiazolilni ostanek in R2 pomeni vodik, hidroksi, amino, nižjialkiltio ali halogen, in njihove soli.Process according to Claim 1, characterized in that the compounds of formula I are prepared in which R 1 represents unsubstituted or lower alkyl, lower alkoxy, unsubstituted or lower alkyl, lower alkoxy and / or halogen mono- or disubstituted phenyl, hydroxy, lower alkylamino, lower alkylthio and / or halogen C-mono- or dis-substituted residue and / or on a substitutable N-atom with lower alkyl or unsubstituted or with lower alkyl, lower alkoxy and / or halogen mono - or with disubstituted phenyl lower alkyl N-substituted imidazolyl, 2H-1,2,3- or 4H-1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl residue and R2 represents hydrogen, hydroxy, amino, lower or halogen, and their salts.3. Postopek po zahtevku 1, označen s tem, da pripravimo spojine s formulo I, v kateri pomeni Rt nesubstituiran ali s Cj-Cj-alkilom, C^C^alkoksi, fenilom, hidroksi, di-C^ C4-alkilamino, Cj-C4-alkiltio in/ali halogenom z atomskim številom do vključno 35 C-mono- ali di-substituiran in/ali s C1-C4-alkilom ali fenil-Cj-C^alkilom N-substituiran imidazolilni, 4H-l,2,4-triazol-4-ilni ali tiazolilni ostanek in R2 pomeni hidroksi, vodik ali amino, in njihove soli.Process according to Claim 1, characterized in that the compounds of the formula I in which R 1 represents unsubstituted or by C 1 -C 1 -alkyl, C 1 -C 4 -alkoxy, phenyl, hydroxy, di-C 1 -C 4 -alkylamino, C 1 -C 4 are prepared -C4-alkylthio and / or halogen with an atomic number up to and including 35 C-mono- or di-substituted and / or C1-C4-alkyl or phenyl-C1-C4-alkyl N-substituted imidazolyl, 4H-1,2, 4-triazol-4-yl or thiazolyl residue and R2 represents hydroxy, hydrogen or amino, and their salts.4. Postopek po zahtevku 1, označen s tem, da pripravimo spojine s formulo I, v kateri pomeni R} nesubstituiran ali s fenilom C-substituiran oz. s C1-C4-alkilom, C- ali N-substituiran imidazol-2- ali -4-ilni ostanek, nesubstituiran tiazolilni ostanek ali nesubstituiran ali s C,-C4-alkilom N-substituiran lH-l,2,4-triazolilni ostanek in R2 pomeni hidroksi ali vodik, in njihove soli. 35Process according to Claim 1, characterized in that the compounds of the formula I are prepared, in which R 1 is unsubstituted or p-phenyl-substituted or C1-C4-alkyl, C- or N-substituted imidazol-2- or -4-yl residue, unsubstituted thiazolyl residue or unsubstituted or C1-C4-alkyl N-substituted 1H-1,2,4-triazolyl residue and R2 represents hydroxy or hydrogen, and salts thereof. 355. Postopek po zahtevku 1, označen s tem, da pripravimo spojine s formulo I, v kateri pomeni Rj imidazol-l-ilni, 2-, 4- ali 5-Cj-Cj-alkilimidazol-l-ilni, 3-C,-C4-alkil-lH-1,2,4-triazol-l-ilni, 4H-triazol-4-ilni, 3-Cj-C4-alkil-4H-l,2,4-triazol-4-ilni ali 1H-tetrazol-l-ilni ostanek ter imata alk in R2 v zahtevku 1 navedene pomene, in njihove soli.Process according to Claim 1, characterized in that the compounds of formula I are prepared, in which R 1 represents imidazol-1-yl, 2-, 4- or 5-C 1 -C 1 -alkylimidazol-1-yl, 3-C, -C4-alkyl-1H-1,2,4-triazol-1-yl, 4H-triazol-4-yl, 3-C1-C4-alkyl-4H-1,2,4-triazol-4-yl or 1H -tetrazol-1-yl residue and alk and R2 have the meanings given in claim 1, and their salts.6. Postopek po zahtevku 1, označen s tem, da pripravimo spojine s formulo I, v kateri predstavlja Rt nesubstituiran ali s fenilom oz. s Cj-C^alkilom C-substituiran imidazol-l-ilni, 4H-l,2,4-triazol-4-ilni ali tetrazol-l-ilni ostanek in R2 pomeni hidroksi ali vodik, in njihove soli.Process according to Claim 1, characterized in that compounds of formula I are prepared in which R 1 represents unsubstituted or phenyl or a C 1 -C 4 alkyl C-substituted imidazol-1-yl, 4H-1,2,4-triazol-4-yl or tetrazol-1-yl residue and R 2 represents hydroxy or hydrogen, and their salts.7. Postopek po zahtevku 1, označen s tem, da pripravimo 2-(l-metilimidazol-2-il)-l-hidroksi-etan-l,l-difosfonsko kislino ali njeno sol.Process according to Claim 1, characterized in that 2- (1-methylimidazol-2-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof is prepared.8. Postopek po zahtevku 1, označen s tem, da pripravimo 2-(l-benzilimidazol-2-il)-l-hidroksi-etan-l,l-difosfonsko kislino ali njeno sol.Process according to Claim 1, characterized in that 2- (1-benzylimidazol-2-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof is prepared.9. Postopek po zahtevku 1, označen s tem, da pripravimo 2-(l-metilimidazol-4-il)-l-hidroksi-etan-l,l-difosfonsko kislino ali njeno sol.Process according to Claim 1, characterized in that 2- (1-methylimidazol-4-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof is prepared.10. Postopek po zahtevku 1, označen s tem, da pripravimo l-amino-2-(l-metilimidazol-4-il)-etan-l,l-difosfonsko kislino ali njeno sol.Process according to Claim 1, characterized in that 1-amino-2- (1-methylimidazol-4-yl) -ethane-1,1-diphosphonic acid or a salt thereof is prepared.11. Postopek po zahtevku 1, označen s tem, da pripravimo l-amino-2-(l-benzilimidazol-4-il)etan-l,l-difosfonsko kislino ali njeno sol.Process according to Claim 1, characterized in that 1-amino-2- (1-benzylimidazol-4-yl) ethane-1,1-diphosphonic acid or a salt thereof is prepared.12. Postopek po zahtevku 1, označen s tem, da pripravimo 2-(l-metilimidazol-2-il)-etan-l,l-difosfonsko kislino ali njeno sol.Process according to Claim 1, characterized in that 2- (1-methylimidazol-2-yl) -ethane-1,1-diphosphonic acid or a salt thereof is prepared.13. Postopek po zahtevku 1, označen s tem, da pripravimo 2-(l-benzilimidazol-2-il)-etan-l,l-difosfonsko kislino ali njeno sol.Process according to Claim 1, characterized in that 2- (1-benzylimidazol-2-yl) -ethane-1,1-diphosphonic acid or a salt thereof is prepared.14. Postopek po zahtevku 1, označen s tem, da pripravimo 2-(imidazol-l-il)-l-hidroksi-etan-l,l-difosfonsko kislino ali njeno sol.Process according to Claim 1, characterized in that 2- (imidazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof is prepared.15. Postopek po zahtevku 1, označen s tem, da pripravimo 2-(imidazol-l-il)etan-l,l-difosfonsko kislino ali njeno sol. 36Process according to Claim 1, characterized in that 2- (imidazol-1-yl) ethane-1,1-diphosphonic acid or a salt thereof is prepared. 3616. Postopek po zahtevku 1, označen s tem, da pripravimo 2-(tiazol-2-il)etan-l,l-difosfonsko kislino ali njeno sol.Process according to Claim 1, characterized in that 2- (thiazol-2-yl) ethane-1,1-diphosphonic acid or a salt thereof is prepared.17. Postopek po zahtevku 1, označen s tem, da pripravimo 2-(imidazol-2-il)etan-1,1-difosfonsko kislino ali njeno sol.Process according to Claim 1, characterized in that 2- (imidazol-2-yl) ethane-1,1-diphosphonic acid or a salt thereof is prepared.18. Postopek po zahtevku 1, označen s tem, da pripravimo 2-(4,5-dimetilimidazol- . l-il)-l-hidroksi-etan-l,l-difosfonsko kislino ali njeno sol.Process according to Claim 1, characterized in that 2- (4,5-dimethylimidazol-1,1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof is prepared.Ϊ9. Postopek po zahtevku 1, označen s tem, da pripravimo 2-(2-metilimidazol-l-il)-l-hidroksi-etan-l,l-difosfonsko kislino ali njeno sol.Ϊ9. Process according to Claim 1, characterized in that 2- (2-methylimidazol-1-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof is prepared.20. Postopek po zahtevku 1, označen s tem, da pripravimo 2-(4H-l,2,4-triazol-4-il)-l-hidroksi-etan-l,l-difosfonsko kislino ali njeno sol. Za CIBA-GEIGY AG: ARNA, 0.0.0.Process according to Claim 1, characterized in that 2- (4H-1,2,4-triazol-4-yl) -1-hydroxy-ethane-1,1-diphosphonic acid or a salt thereof is prepared. For CIBA-GEIGY AG: ARNA, 0.0.0.
SI8810711A1988-04-081988-04-08Process for preparing new substituted alkandiphosphonic acids
SI8810711B
(en)