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Details for Patent: 5,602,163

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Details for Patent: 5,602,163

Title: Imidazole, triazole and tetrazole derivatives
Abstract:A class of substituted imidazole, triazole and tetrazole derivatives are selective agonists of 5-HT.sub.1 -like receptors and are therefore useful in the treatment of clinical conditions, in particular migraine and associated disorders, for which a selective agonist of these receptors is indicated.
Inventor(s): Baker; Raymond (Hertfordshire, GB2), Matassa; Victor G. (Hertfordshire, GB2), Street; Leslie J. (Essex, GB2)
Assignee: Merck, Sharp & Dohme Ltd. (Hoddesdon Hertfordshire, GB2)
Filing Date:May 25, 1995
Application Number:08/452,185
Claims:1. A compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof: ##STR36## wherein the broken circle represents two non-adjacent double bonds in any position in the five-membered ring;

two, three or four of V, W, X, Y and Z represent nitrogen and the remainder represent carbon provided that, when two of V, W, X, Y and Z represent nitrogen and the remainder represent carbon, then the said nitrogen atoms are in non-adjacent positions within the five-membered ring;

A.sup.1 is selected from the group consisting of hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl , --OR.sup.x, --SR.sup.x, --NR.sup.x R.sup.y, --NR.sup.x COR.sup.y, --NR.sup.x CO.sub.2 R.sup.y, --NR.sup.x SO.sub.2 R.sup.y, and --NR.sup.z CTNR.sup.x R.sup.y ; wherein R.sup.x and R.sup.y independently represent hydrogen, hydrocarbon or a heterocyclic group as defined above, or R.sup.x and R.sup.y together represent a C.sub.2-6 alkylene group; with the proviso that in the radicals --OR.sup.x and --SR.sup.x, R.sup.x is C.sub.1-6 alkyl;

A.sup.2 represents a non-bonded electron pair when four of V, W, X, Y and Z represent nitrogen and the other represents carbon; or, when two or three of V, W, X, Y and Z represent nitrogen and the remainder represent carbon, A.sup.2 is selected from the group consisting of hydrogen, hydrocarbon a heterocyclic group as defined above, halogen cyano, trifluoromethyl, --OR.sup.x, --SR.sup.x, --NR.sup.x Ry, --NR.sup.x CORY, --NR.sup.x CO.sub.2 R.sup.Y, --NR.sup.x SO.sub.2 R.sup.y, and --NR.sup.z CTNR.sup.x R.sup.y ; wherein R.sup.x and R.sup.y are as defined above; and wherein the hydrocarbon and heterocyclic group, can be substituted by one or more groups selected from C.sub.1-6 alkyl, adarnantyl, phenyl, halogen, C.sub.1-6 haloalkyl, C.sub.1-6 aminoalkyl, trifluoromethyl, C.sub.1-6 alkoxy, phenyloxy, oxo, C.sub.1-3 alkylenedioxy, nitro, cyano, carboxy, C.sub.2-6 alkoxycaxbonyl, C.sub.2-6 alkoxy-carbonyl(C.sub.1-6)alkyl, C.sub.2-6 alkylcarbonyloxy, phenylcarbonyloxy, C.sub.2-6 alkylcarbonyl, phenylcarbonyl, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulphinyl, C.sub.1-6 alkylsulphonyl, phenylsulphonyl, --NR.sup.v R.sup.w, --NR.sup.v COR.sup.w, --NR.sup.v SO.sub.2 R.sup.w, --NR.sup.v SO.sub.2 R.sup.w, --CH.sub.2 NR.sup.v SO.sub.2 R.sup.w, --NHCONR.sup.v R.sup.w, --CONR.sup.v R.sup.w, --SO.sub.2 NR.sup.v R.sup.w, and --CH.sub.2 SO.sub.2 NR.sup.v R.sup.w in which R.sup.v and R.sup.w independently represent hydrogen, C.sub.1-6 alkyl, phenyl or phenyl(C.sub.1 alkyl, or R.sup.v and R.sup.w together represent a C.sub.2-6 alkylene group;

E represents a bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms;

F represents a group of formula ##STR37## U represents C--R.sup.2 ; B represents oxygen, or sulphur;

R.sup.1 represents --CH.sub.2 --CHR.sup.4 --NR.sup.6 R.sup.7 or a group of formula ##STR38## in which the broken line represents an optional chemical bond; R.sup.2, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 independently represent hydrogen or C.sub.1-6 alkyl;

R.sup.x and R.sup.y independently represent hydrogen, hydrocarbon or a heterocyclic group, or R.sup.x and R.sup.y together represent a C.sub.2-6 alkylene group;

R.sup.z represents hydrogen, hydrocarbon or a heterocyclic group;

T represents oxygen, sulphur or a group of formula .dbd.N--G; and

G represents hydrocarbon, a heterocyclic group or an electron-withdrawing group selected from cyano, nitro, --COR.sup.x, CO.sub.2 R.sup.x and SO.sub.2 R.sup.x ; and wherein in each instance "hydrocarbon" represents C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl(C.sub.1-6)alkyl, phenyl or phenyl(C.sub.1-6)alkyl; in each instance "heterocyclic group" represents C.sub.3-7 heterocycloalkyl or C.sub.3-7 heterocycloalkyl(C.sub.1-6)alkyl wherein heterocycloalkyl is selected from azetidinyl, pyrrolidyl, piperidyl, piperazinyl, and morpholinyl; and in each instance "heteroaryl" is selected from pyridyl, quinolyl, isoquinolyl, pyridizinyl, pyrazinyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl imidazolyl, oxadiazolyl and thiadiazolyl.

2. A compound according to claim 1 represented by formula IIA, and pharmaceutically acceptable salts and prodrugs thereof: ##STR39## wherein X.sup.1 represents nitrogen or A.sup.12 --C;

n is zero, 1, 2 or 3;

B.sup.1 represents oxygen, or sulphur;

A.sup.11 and A.sup.12 are independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, aryl, aryl (C.sub.1-6) alkyl, C.sub.3-7 heterocycloalkyl, wherein C.sub.3-7 heterocycloalkyl is selected from the group consisting of azetidinyl, pyrrolidyl, piperidyl, piperazinyl or morpholinly; heteroaryl and heteroaryl(C.sub.1-6)alkyl, wherein heteroaryl is selected from the group consisting of pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl or thiadiazolyl;

any of which groups may be optionally substituted; and hydrogen, halogen, cyano, trifluoromethyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio and--NR.sup.x R.sup.y ;

R.sup.12, R.sup.14, R.sup.16 and R.sup.17 independently represent hydrogen or C.sub.1-6 alkyl; and

R.sup.x and R.sup.y independently represent hydrogen, hydrocarbon or a heterocyclic group, or R.sup.x and R.sup.y together represent a C.sub.2-6 alkylene group.

3. A compound according to claim 1 represented by formula IIB, and pharmaceutically acceptable salts and prodrugs thereof: ##STR40## wherein Y.sup.1 represents nitrogen or A.sup.22 --C;

n is zero, 1, 2 or 3;

B.sup.2 represents oxygen, or sulphur;

A.sup.21 and A.sup.22 are independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, aryl, aryl (C.sub.1-6) alkyl, C.sub.3-7 heterocycloalkyl, wherein C.sub.3-7 heterocycloalkyl is selected from the group consisting of azetidinyl, pyrrolidyl, piperidyl, piperazinyl or morpholinly; heteroaryl and heteroaryl(C.sub.1-6)alkyl, wherein heteroaryl is selected from the group consisting of pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl or thiadiazolyl;

any of which groups may be optionally substituted; and hydrogen, halogen, cyano, trifluoromethyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio and --NR.sup.x R.sup.y ;

R.sup.22, R.sup.24, R.sup.26 and R.sup.27 independently represent hydrogen or C.sub.1-6 alkyl; and

R.sup.x and R.sup.y independently represent hydrogen, hydrocarbon or a heterocyclic group, or R.sup.x and R.sup.y together represent a C.sub.2-6 alkylene group.

4. A compound according to claim 1 represented by formula IIC, and pharmaceutically acceptable salts and prodrugs thereof: ##STR41## wherein Y.sup.2 represents nitrogen or A.sup.32 --C;

Z.sup.1 represents nitrogen or CH;

n is zero, 1, 2 or 3;

B.sup.3 represents oxygen, or sulphur;

A.sup.31 and A.sup.32 are independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, aryl, aryl(C.sub.1-6)alkyl, C.sub.3-7 heterocycloalkyl, wherein C.sub.3-7 heterocycloalkyl is selected from the group consisting of azetidinyl , pyrrolidyl, piperidyl, piperazinyl or morpholinly; heteroaryl and heteroaryl(C.sub.1-6)alkyl, wherein heteroaryl is selected from the group consisting of pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl or thiadiazolyl;

any of which groups may be optionally substituted; and hydrogen, halogen, cyano, trifluoromethyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio and --NR.sup.x R.sup.y ;

R.sup.31 represents --CH.sub.2.CHR.sup.34.NR.sup.36 R.sup.37 or a group of formula ##STR42## R.sup.32, R.sup.34, R.sup.35, R.sup.36 and R.sup.37 independently represent hydrogen or C.sub.1-6 alkyl; and

R.sup.x and R.sup.y independently represent hydrogen, hydrocarbon or a heterocyclic group, or R.sup.x and R.sup.y together represent a C.sub.2-6 alkylene group.

5. A compound according to claim 1 represented by formula IID, and pharmaceutically acceptable salts and prodrugs thereof: ##STR43## wherein W.sup.1 represents nitrogen or C-A42;

n is zero, 1, 2 or 3;

B.sup.4 represents oxygen, or sulphur;

A.sup.41 and A.sup.42 are independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, aryl, aryl(C.sub.1-6)alkyl, C.sub.3-7 heterocycloalkyl, wherein C.sub.3-7 heterocycloalkyl is selected frown the group consisting of azetidinyl, pyrrolidyl, piperidyl, piperazinyl or morpholinly; heteroaryl and heteroaryl(C.sub.1-6)alkyl, wherein said heteroaryl is selected from the group consisting of pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl or thiadiazolyl;

any of which groups may be optionally substituted; and hydrogen, halogen, cyano, trifluoromethyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio and --NR.sup.x R.sup.y ;

R.sup.41 represents --CH.sub.2.CHR.sup.44.NR.sup.46 R.sup.47 or a group of formula ##STR44## R.sup.42, R.sup.44, R.sup.45, R.sup.46 and R.sup.47 independently represent hydrogen or C .sub.1-6 alkyl; and

R.sup.x and R.sup.y independently represent hydrogen, hydrocarbon or a heterocyclic group, or R.sub.x and R.sup.y together represent a C.sub.2-6 alkylene group.

6. A compound according to claim 1 selected from:

3-(2-aminoethyl)-5-(1-methyltetrazol-5-yl)benzo [b]thiophene;

3-(2-aminoethyl)-5-(2-methyltetrazol-5-yl)benzo [b]thiophene;

3-5-(2-methyltetrazol-5-yl)benzo [b]thiophene;

and salts and prodrugs thereof.

7. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in association with a pharmaceutically acceptable carrier or excipient.

8. A method for the treatment and/or prevention of migraine and associated conditions which method comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 1.
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