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Details for Patent: 6,844,443

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Details for Patent: 6,844,443

Title: Benzimidazole derivatives, their production and use
Abstract:A method for producing a compound represented by the formula: ##STR1## wherein the ring A is a benzene ring which may be substituted in addition to the R' group; R.sup.1 is hydrogen or an optionally substituted hydrocarbon residue; X is a direct bond or a spacer having an atomic length or two or less between the phenylene group and the phenyl group; Y is --O--, --S(O)m- or --N(R.sup.4)-- wherein m is an integer of 0, 1 or 2 and R.sup.4 is hydrogen or an optionally substituted alkyl group; R' is carboxyl, an ester thereof, an amide thereof or a group capable of forming an anion or a group convertible thereinto; n is an integer of 1 or 2; or a salt thereof, which comprises deprotecting a compound represented by the formula: ##STR2## wherein R is triphenylmethyl, 2-tetrahydropyranyl, methoxymethyl or ethoxy methyl, the other symbols as defined above; or a salt thereof.
Inventor(s): Naka; Takehiko (Hyogo, JP), Nishikawa; Kohei (Kyoto, JP), Kato; Takeshi (Osaka, JP)
Assignee: Takeda Pharmaceutical Company, Ltd. (Osaka, JP)
Filing Date:Jul 07, 2003
Application Number:10/612,984
Claims:1. A method for producing a compound represented by the formula: ##STR47##

wherein the ring A is a benzene ring which may be substituted in addition to the group of --COOR.sup.6 group; R.sup.1 is hydrogen or an optionally substituted hydrocarbon residue; X is a direct bond or a spacer having an atomic length of two or less between the phenylene group and the phenyl group; Y is --O--, --S(O)m- or --N(R.sup.4)-- wherein in is an integer of 0, 1 or 2 and R.sup.4 is hydrogen or an optionally substituted alkyl group; R.sup.6 is a lower (C.sub.1-6) alkyl optionally substituted with lower (C.sub.2-6) alkanoyloxy, 1-lower (C.sub.1-6) alkoxycarbonyloxy; a is an integer of 1 or 2; or a pharmaceutically acceptable salt thereof, which comprises; (i) reacting a compound represented by the formula: ##STR48##

wherein R is triphenylmethyl, 2-tetrahydropyranyl, methoxymethyl or ethoxy methyl, and the other symbols have the same meanings as defined above, or a pharmaceutically acceptable salt thereof; with an alkylating agent to give a compound represented by the formula: ##STR49##

wherein each symbol has the same meaning as defined above; or a pharmaceutically acceptable salt thereof; and then, (ii) deprotecting the compound (Ip) or a pharmaceutically acceptable salt thereof.

2. A method according to claim 1, wherein R.sup.1 is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl group.

3. A method according to claim 1, wherein R.sup.1 is an alkyl, alkenyl, alkynyl, or cycloalkyl group, which may be substituted with hydroxyl, an optionally substituted amino group, halogen or a lower (C.sub.1-4) alkoxy group.

4. A method according to claim 1, wherein R.sup.1 is a lower (C.sub.1-5)alkyl or lower (C.sub.2-5)alkenyl group optionally substituted with hydroxyl, an amino group, halogen or a lower (C.sub.1-4) alkoxy group.

5. A method according to claim 3, wherein the alkyl is a lower alkyl group having about 1 to about 8 carbon atoms, which may be straight or branched.

6. A method according to claim 5, wherein the lower alkyl group is unsubstituted or substituted with hydroxyl, an optionally substituted amino group, halogen or a lower (C.sub.1-4) alkoxy group.

7. A method according to claim 1, wherein R.sup.1 is a lower alkyl group having 1 to about 8 carbon atoms.

8. A method according to claim 2, wherein the aryl group is phenyl which may be substituted with halogen, nitro, lower (C.sub.1-4) alkoxy, or lower (C.sub.1-4) alkyl.

9. A method according to claim 2, wherein the aralkyl group is phenyl-lower (C.sub.1-4) alkyl which may be substituted with halogen, nitro, lower (C.sub.1-4) alkoxy, or lower (C.sub.1-4) alkyl.

10. A method according to claim 1, wherein the ring A is a benzene ring which may contain, in addition to the --COOR.sup.6 group, a substituent being selected from the group consisting of halogen nitro, cyano, optionally substituted amino, a group having the formula: --W--R.sup.13 wherein W is a chemical bond, --O--, --S--, or ##STR50## and R.sup.13 is hydrogen or an optionally substituted lower alkyl group, a group having the formula; --(CH.sub.2).sub.p --CO--D wherein D is hydrogen, hydroxyl, optionally substituted amino, or optionally substituted alkoxy, and p is 0 or 1, tetrazolyl optionally protected with an optionally substituted lower alkyl group or an acyl group, trifluoromethanesulfonic amide, phosphoric acid, or sulfonic acid.

11. A method according to claim 1, wherein the ring A is a benzene ring which contains no substitution in addition to the --COOR.sup.6 group.

12. A method according to claim 1, wherein X is a chemical bond, lower (C.sub.1-4) alkylene, ##STR51##

13. A method according to claim 1, wherein X is a chemical bond between the phenylene group and the phenyl group.

14. A method according to claim 1, wherein Y is --O--, --SO.sub.m -- wherein m is 0, 1, or 2, or --N(R.sup.4)-- wherein R.sup.4 is hydrogen or an optionally substituted lower (C.sub.1-4) alkyl group.

15. A method according to claim 1, wherein Y--R.sup.1 is --N(R.sup.4)--R.sup.1 wherein R.sup.1 and R.sup.4 are taken together with the N atom attached thereto to form a heterocyclic ring.

16. A method according to claim 1, wherein the alkylating reaction is conducted in the presence of a base.

17. A method according to claim 1, wherein the deprotecting reaction is conducted under acid condition.

18. A method according to claim 1, wherein the alkylating agent is a halide.

19. A method according to claim 1, wherein the alkylating agent used in the reaction of compound (Io) with alkylating agent, is selected from cyclohexyl 1-iodoethyl carbonate, ethyl 1-iodaethyl carbonate, and pivaloyloxyrnethyl iodide.

20. A merthod for producing 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-car boxylate or a pharmaceutically acceptable salt thereof, which comprises reacting 2-ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]benzi midazole-7-carboxylic acid or a pharmaceutically acceptable salt thereof with an alkylating agent, and then subjecting the resulting compound to deprotecting reaction of the tetrazole group.
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