Claims for Patent: 5,705,517

Summary for Patent: 5,705,517

Title:	Benzimidazole derivatives and use thereof
Abstract:	Benzimidazole derivatives of the formula (I): ##STR1## wherein the ring A is a benzene ring which may optionally contain substitution in addition to the R' group; R' is hydrogen or an optionally substituted hydrocarbon residue; R2 is a group capable of forming an anion or a group convertible thereinto; X is a direct bond or a spacer having an atomic length of two or less between the phenylene group and the phenyl group; R' is carboxyl, an ester thereof, an amide thereof or a group capable of forming an anion or convertible to an anion; Y is --O--, --S(O)m -- or --N(R4)-- wherein m is an integer of 0, 1 or 2 and R4 is hydrogen or an optionally substituted alkyl group; and n is an integer of 1 or 2; and the pharmaceutically acceptable salts thereof, have potent angiotensin II antagonistic activity and antihypertensive activity, thus being useful as therapeutic agents for treating circulatory system diseases such as hypertensive diseases, heart diseases (e.g. hypercardia, heart failure, cardiac infarction, etc.), strokes, cerebral apoplexy, nephritis, etc.
Inventor(s):	Takehiko Naka, Kohei Nishikawa
Assignee:	Takeda Pharmaceutical Co Ltd
Application Number:	US08/131,667
Patent Claims:	1. A compound of the formula: ##STR46## wherein the ring A is a benzene ring which may be substituted or unsubstituted in addition to the --COOCH(R7)OCOR8 group, with a substituent selected from the group consisting of1) halogen; 2) nitro; 3) cyano; 4) amino; 5) N-C1-4 alkylamino; 6) N,N-di-C1-4 alkylamino; 7) phenylamino; 8) naphthylamino; 9) benzylamino; 10) naphthylmethylamino; 11) morpholino; 12) piperidino; 13) piperazino; 14) N-phenylpiperazino; 15) a group having the formula: --W--R13 whereinW is i) a chemical bond, ii) --O--, iii) --S-- or iv) ##STR47## and R13 is i) hydrogen or ii) C1-4 alkyl optionally substituted witha) hydroxyl, b) amino, c) dimethylamino, d) diethylamino, e) piperidino, f) morpholino, g) halogen or h) C1-4 alkoxy; 16) a group having a formula: --(CH2)p --CO--D whereinp is 0 or 1, and D is i) hydrogen, ii) hydroxyl, iii) amino, iv) N-C1-4 alkylamino; v) N,N-di-C1-4 alkylamino; vi) C1-6 alkoxy optionally substituted witha) hydroxyl, b) amino, c) dimethylamino, d) diethylamino, e) piperidino, f) morpholino, g) halogen, h) C1-6 alkoxy, i) C1-6 alkylthio, j) dioxolenyl or k) 5-methyl-2-oxo-1,3-dioxolen-4-yl, on the alkyl moiety, or vii) a group having the formula: --OCH(R9)OCOR10 whereinR9 is a) hydrogen, b) straight or branched C1-6 alkyl, c) cyclopentyl, d) cyclohexyl, or e) cycloheptyl, and R10 is a) straight or branched C1-6 alkyl, b) straight or branched C2-8 alkenyl, c) cyclopentyl, d) cyclohexyl e) cycloheptyl, f) C1-3 alkyl which is substituted with phenyl, p-chlorophenyl or C3-7 cycloalkyl, g) C2-8 alkenyl which is substituted with phenyl or C5-7 cycloalkyl, h) phenyl, i) p-tolyl, j) naphthyl, k) straight or branched C1-6 alkoxy, l) straight or branched C2-8 alkenyloxy, m) cyclopentyloxy, n) cyclohexyloxy, o) cycloheptyloxy, p) C1-3 alkoxy which is substituted with phenyl or C5-7 cycloalkyl, q) C2-3 alkenyloxy which is substituted with phenyl or C5-7 cycloalkyl, r) phenoxy, s) p-nitrophenoxy or t) naphthoxy; 17) tetrazolyl optionally protected withi) C1-4 alkyl optionally substituted with C1-4 alkoxy or phenyl, ii) C2-5 alkanoyl or iii) benzoyl; 18) trifluoromethanesulfonic amido; 19) phosphono (PO(OH)2); and 20) sulfo (SO3 H); whereby one or two of these substituents may be substituted at various positions of the benzene ring, and whereby when two substituents are present at the 4 and 5 or 5 and 6 positions on the ring A, they may be taken together to form a benzene ring whereby such rings may be substituted with the same groups as for the ring A; R1 is1) hydrogen; 2) C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl or C3-6 cycloalkyl group, which groups may be substituted with i) hydroxyl, ii) amino, iii) methylamino, iv) halogen or v) C1-4 alkoxy; 3) phenyl optionally substituted with i) halogen, ii) nitro, iii) C1-4 alkoxy or C1-4 alkyl; or 4) phenyl-C1-4 alkyl optionally substituted with i) halogen, ii) nitro, iii) C1-4 alkoxy or iv) C1-4 alkyl on the benzene ring; R2 is1) carboxyl; 2) tetrazolyl; 3) trifluoromethanesulfonic amido; 4) phosphono (PO(OH)2); 5) sulfo (SO3 H); 6) cyano; or 7) C1-4 alkoxycarbonyl; each of which may be protected with i) C1-4 alkyl optionally substituted with C1-4 alkoxy or phenyl, ii) C2-5 alkanoyl or iii) benzoyl; R7 isa) hydrogen, b) straight or branched C1-6 alkyl, c) cyclopentyl, d) cyclohexyl or e) cycloheptyl, and R8 isa) straight or branched C1-6 alkyl, b) straight or branched C2-8 alkenyl, c) cyclopentyl, d) cyclohexyl, e) cycloheptyl, f) C1-3 alkyl which is substituted with phenyl, p-chlorophenyl or C5-7 cycloalkyl, g) C2-3 alkenyl which is substituted with phenyl, or C5-7 cycloalkyl, h) phenyl, i) p-tolyl, j) naphthyl, k) straight or branched C1-6 alkoxy, l) straight or branched C2-8 alkenyloxy, m) cyclopentyloxy, n) cyclohexyloxy, o) cycloheptyloxy, p) C1-3 alkoxy which is substituted with phenyl or C5-7 cycloalkyl, q) C2-3 alkenyloxy which is substituted with phenyl or C5-7 cycloalkyl, r) phenoxy, s) p-nitrophenoxy or t) naphthoxy; X is a chemical bond or a divalent chain in which the number of atoms constituting the straight chain is 1 or 2; Y is1) --O--; 2) --S(O)m -- wherein m is 0, 1 or 2; or 3) --N(R4)-- wherein R4 is hydrogen or a C1-4 alkyl group optionally substituted with hydroxyl or C1-4 alkoxy; whereby R1 and R4 may be taken together with the N atom to form a piperidino or morpholino ring; n is an integer of 1 or 2;or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein R1 is a C1-5 alkyl or C2-5 alkenyl group optionally substituted with halogen, hydroxyl, an amino group or a C1-4 alkoxy group. 3. A compound or a salt thereof according to claim 1, wherein R1 is phenyl which may be substituted with halogen, nitro, C1-4 alkoxy, or C1-4 alkyl. 4. A compound according to claim 1, wherein R1 is phenyl-C1-4 alkyl which may be substituted with halogen, nitro, C1-4 alkoxy, or C1-4 alkyl. 5. A compound or a salt thereof according to claim 1, wherein R2 is a tetrazolyl group optionally protected with C1-4 alkyl optionally substituted with C1-4 alkoxy or phenyl, C2-5 alkanoyl or benzoyl, a carboxyl group optionally protected with C1-4 alkyl optionally substituted with C1-4 alkoxy or phenyl, or trifluoromethanesulfonic amide. 6. A compound or a salt thereof according to claim 1, wherein R2 is a tetrazolyl group. 7. A compound or a salt thereof according to claim 1, wherein the ring A is a benzene ring which is unsubstituted except for the --COOCH(R7)OCOR8 group. 8. A compound or a salt thereof according to claim 1, wherein X is a chemical bond, C1-4 alkylene wherein the number of carbon atoms in the straight chain of said C1-4, alkylene is 1 or 2, --CO--, --O--, --S--, --NH--, --CONH--, --OCH2 --, --SCH2 -- or --CH═CH--. 9. A compound or a salt thereof according to claim 1, wherein X is a chemical band between the phenylene group and the phenyl group. 10. A compound or a salt thereof according to claim 1, wherein Y is --O-- or --S--. 11. A compound or a salt thereof according to claim 1, wherein --Y--R1 is --N(R4)--R1, and R1 and R4 are taken together with the N atom attached thereto to form a piperidino or morpholino ring. 12. A compound of a salt thereof according to claim 1, wherein R1 is a C1-5 alkyl optionally substituted with hydroxy, amino, halogen or a C1-4 alkoxy group;R2 is a tetrazolyl group optionally protected with a C1-4 alkyl optionally substituted with C1-4 alkoxy or phenyl, C2-5 alkanoyl or benzoyl, or carboxyl optionally substituted with C1-4 alkyl optionally substituted with C1-4 alkoxy or phenyl; and n is 1. 13. A compound or a salt thereof according to claim 12, wherein R1 is C1-4 alkyl. 14. A compound or a salt thereof according to claim 12, wherein R2 is tetrazolyl. 15. A compound or a salt thereof according to claim 12, wherein R2 is carboxyl. 16. A compound or a salt thereof according to claim 12, wherein Y is --O--. 17. A compound or a salt thereof according to claim 1, which is acetoxymethyl 2-ethoxy-1- 2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. 18. A compound according to claim 1, which is propionyloxymethyl 2-ethoxy-1- 2'-(1H-tetrazol-5-yl-biphenyl-4-yl!methyl!benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. 19. A compound according to claim 1, which is butyryloxymethyl 2-ethoxy-1- 2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. 20. A compound according to claim 1, which is isobutyryloxymethyl 2-ethoxy-1- 2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. 21. A compound according to claim 1, which is 1-(ethoxycarbonyloxy)ethyl 2-ethoxy-1- 2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. 22. A compound according to claim 1, which is 1-(isopropoxycarbonyloxy)ethyl 2-ethoxy-1- 2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. 23. A compound according to claim 1, which is cyclohexylcarbonyloxymethyl 2-ethoxy-1- 2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. 24. A compound according to claim 1, which is benzoyloxymethyl 2-ethoxy-1- 2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. 25. A compound according to claim 1, which is (E)-cinnamoyloxymethyl 2-ethoxy-1- 2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. 26. A compound according to claim 1, which is cyclopentylcarbonyloxymethyl 2-ethoxy-1- 2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyl!benzimidazole-7-carboxylate or a pharmaceutically accepted salt thereof. 27. A pharmaceutical composition for antagonizing angiotensin II which comprises a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier, excipient or diluent. 28. A method for antagonizing angiotensin II in a mammal which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 1. A compound of the formula: ##STR46## wherein the ring A is a benzene ring which may be substituted or unsubstituted in addition to the --COOCH(R.sup.7)OCOR.sup.8 group, with a substituent selected from the group consisting of 1) halogen; 2) nitro; 3) cyano; 4) amino; 5) N-C.sub.1-4 alkylamino; 6) N,N-di-C.sub.1-4 alkylamino; 7) phenylamino; 8) naphthylamino; 9) benzylamino; 10) naphthylmethylamino; 11) morpholino; 12) piperidino; 13) piperazino; 14) N-phenylpiperazino; 15) a group having the formula: --W--R.sup.13 wherein W is i) a chemical bond, ii) --O--, iii) --S-- or iv) ##STR47## and R.sup.13 is i) hydrogen or ii) C.sub.1-4 alkyl optionally substituted with a) hydroxyl, b) amino, c) dimethylamino, d) diethylamino, e) piperidino, f) morpholino, g) halogen or h) C.sub.1-4 alkoxy; 16) a group having a formula: --(CH.sub.2).sub.p --CO--D wherein p is 0 or 1, and D is i) hydrogen, ii) hydroxyl, iii) amino, iv) N-C.sub.1-4 alkylamino; v) N,N-di-C.sub.1-4 alkylamino; vi) C.sub.1-6 alkoxy optionally substituted with a) hydroxyl, b) amino, c) dimethylamino, d) diethylamino, e) piperidino, f) morpholino, g) halogen, h) C.sub.1-6 alkoxy, i) C.sub.1-6 alkylthio, j) dioxolenyl or k) 5-methyl-2-oxo-1,3-dioxolen-4-yl, on the alkyl moiety, or vii) a group having the formula: --OCH(R.sup.9)OCOR.sup.10 wherein R.sup.9 is a) hydrogen, b) straight or branched C.sub.1-6 alkyl, c) cyclopentyl, d) cyclohexyl, or e) cycloheptyl, and R.sup.10 is a) straight or branched C.sub.1-6 alkyl, b) straight or branched C.sub.2-8 alkenyl, c) cyclopentyl, d) cyclohexyl e) cycloheptyl, f) C.sub.1-3 alkyl which is substituted with phenyl, p-chlorophenyl or C.sub.3-7 cycloalkyl, g) C.sub.2-8 alkenyl which is substituted with phenyl or C.sub.5-7 cycloalkyl, h) phenyl, i) p-tolyl, j) naphthyl, k) straight or branched C.sub.1-6 alkoxy, l) straight or branched C.sub.2-8 alkenyloxy, m) cyclopentyloxy, n) cyclohexyloxy, o) cycloheptyloxy, p) C.sub.1-3 alkoxy which is substituted with phenyl or C.sub.5-7 cycloalkyl, q) C.sub.2-3 alkenyloxy which is substituted with phenyl or C.sub.5-7 cycloalkyl, r) phenoxy, s) p-nitrophenoxy or t) naphthoxy; 17) tetrazolyl optionally protected with i) C.sub.1-4 alkyl optionally substituted with C.sub.1-4 alkoxy or phenyl, ii) C.sub.2-5 alkanoyl or iii) benzoyl; 18) trifluoromethanesulfonic amido; 19) phosphono (PO(OH).sub.2); and 20) sulfo (SO.sub.3 H); whereby one or two of these substituents may be substituted at various positions of the benzene ring, and whereby when two substituents are present at the 4 and 5 or 5 and 6 positions on the ring A, they may be taken together to form a benzene ring whereby such rings may be substituted with the same groups as for the ring A; R.sup.1 is 1) hydrogen; 2) C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl or C.sub.3-6 cycloalkyl group, which groups may be substituted with i) hydroxyl, ii) amino, iii) methylamino, iv) halogen or v) C.sub.1-4 alkoxy; 3) phenyl optionally substituted with i) halogen, ii) nitro, iii) C.sub.1-4 alkoxy or C.sub.1-4 alkyl; or 4) phenyl-C.sub.1-4 alkyl optionally substituted with i) halogen, ii) nitro, iii) C.sub.1-4 alkoxy or iv) C.sub.1-4 alkyl on the benzene ring; R.sup.2 is 1) carboxyl; 2) tetrazolyl; 3) trifluoromethanesulfonic amido; 4) phosphono (PO(OH).sub.2); 5) sulfo (SO.sub.3 H); 6) cyano; or 7) C.sub.1-4 alkoxycarbonyl; each of which may be protected with i) C.sub.1-4 alkyl optionally substituted with C.sub.1-4 alkoxy or phenyl, ii) C.sub.2-5 alkanoyl or iii) benzoyl; R.sup.7 is a) hydrogen, b) straight or branched C.sub.1-6 alkyl, c) cyclopentyl, d) cyclohexyl or e) cycloheptyl, and R.sup.8 is a) straight or branched C.sub.1-6 alkyl, b) straight or branched C.sub.2-8 alkenyl, c) cyclopentyl, d) cyclohexyl, e) cycloheptyl, f) C.sub.1-3 alkyl which is substituted with phenyl, p-chlorophenyl or C.sub.5-7 cycloalkyl, g) C.sub.2-3 alkenyl which is substituted with phenyl, or C.sub.5-7 cycloalkyl, h) phenyl, i) p-tolyl, j) naphthyl, k) straight or branched C.sub.1-6 alkoxy, l) straight or branched C.sub.2-8 alkenyloxy, m) cyclopentyloxy, n) cyclohexyloxy, o) cycloheptyloxy, p) C.sub.1-3 alkoxy which is substituted with phenyl or C.sub.5-7 cycloalkyl, q) C.sub.2-3 alkenyloxy which is substituted with phenyl or C.sub.5-7 cycloalkyl, r) phenoxy, s) p-nitrophenoxy or t) naphthoxy; X is a chemical bond or a divalent chain in which the number of atoms constituting the straight chain is 1 or 2; Y is 1) --O--; 2) --S(O).sub.m -- wherein m is 0, 1 or 2; or 3) --N(R.sup.4)-- wherein R.sup.4 is hydrogen or a C.sub.1-4 alkyl group optionally substituted with hydroxyl or C.sub.1-4 alkoxy; whereby R.sup.1 and R.sup.4 may be taken together with the N atom to form a piperidino or morpholino ring; n is an integer of 1 or 2; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein R.sup.1 is a C.sub.1-5 alkyl or C.sub.2-5 alkenyl group optionally substituted with halogen, hydroxyl, an amino group or a C.sub.1-4 alkoxy group. 3. A compound or a salt thereof according to claim 1, wherein R.sup.1 is phenyl which may be substituted with halogen, nitro, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl. 4. A compound according to claim 1, wherein R.sup.1 is phenyl-C.sub.1-4 alkyl which may be substituted with halogen, nitro, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl. 5. A compound or a salt thereof according to claim 1, wherein R.sup.2 is a tetrazolyl group optionally protected with C.sub.1-4 alkyl optionally substituted with C.sub.1-4 alkoxy or phenyl, C.sub.2-5 alkanoyl or benzoyl, a carboxyl group optionally protected with C.sub.1-4 alkyl optionally substituted with C.sub.1-4 alkoxy or phenyl, or trifluoromethanesulfonic amide. 6. A compound or a salt thereof according to claim 1, wherein R.sup.2 is a tetrazolyl group. 7. A compound or a salt thereof according to claim 1, wherein the ring A is a benzene ring which is unsubstituted except for the --COOCH(R.sup.7)OCOR.sup.8 group. 8. A compound or a salt thereof according to claim 1, wherein X is a chemical bond, C.sub.1-4 alkylene wherein the number of carbon atoms in the straight chain of said C.sub.1-4, alkylene is 1 or 2, --CO--, --O--, --S--, --NH--, --CONH--, --OCH.sub.2 --, --SCH.sub.2 -- or --CH.dbd.CH--. 9. A compound or a salt thereof according to claim 1, wherein X is a chemical band between the phenylene group and the phenyl group. 10. A compound or a salt thereof according to claim 1, wherein Y is --O-- or --S--. 11. A compound or a salt thereof according to claim 1, wherein --Y--R.sup.1 is --N(R.sup.4)--R.sup.1, and R.sup.1 and R.sup.4 are taken together with the N atom attached thereto to form a piperidino or morpholino ring. 12. A compound of a salt thereof according to claim 1, wherein R.sup.1 is a C.sub.1-5 alkyl optionally substituted with hydroxy, amino, halogen or a C.sub.1-4 alkoxy group; R.sup.2 is a tetrazolyl group optionally protected with a C.sub.1-4 alkyl optionally substituted with C.sub.1-4 alkoxy or phenyl, C.sub.2-5 alkanoyl or benzoyl, or carboxyl optionally substituted with C.sub.1-4 alkyl optionally substituted with C.sub.1-4 alkoxy or phenyl; and n is 1. 13. A compound or a salt thereof according to claim 12, wherein R.sup.1 is C.sub.1-4 alkyl. 14. A compound or a salt thereof according to claim 12, wherein R.sup.2 is tetrazolyl. 15. A compound or a salt thereof according to claim 12, wherein R.sup.2 is carboxyl. 16. A compound or a salt thereof according to claim 12, wherein Y is --O--. 17. A compound or a salt thereof according to claim 1, which is acetoxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-car boxylate or a pharmaceutically acceptable salt thereof. 18. A compound according to claim 1, which is propionyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl-biphenyl-4-yl]methyl]benzimidazole-7-car boxylate or a pharmaceutically acceptable salt thereof. 19. A compound according to claim 1, which is butyryloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-car boxylate or a pharmaceutically acceptable salt thereof. 20. A compound according to claim 1, which is isobutyryloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-car boxylate or a pharmaceutically acceptable salt thereof. 21. A compound according to claim 1, which is 1-(ethoxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-car boxylate or a pharmaceutically acceptable salt thereof. 22. A compound according to claim 1, which is 1-(isopropoxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl- 4-yl]methyl]benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof. 23. A compound according to claim 1, which is cyclohexylcarbonyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-car boxylate or a pharmaceutically acceptable salt thereof. 24. A compound according to claim 1, which is benzoyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-car boxylate or a pharmaceutically acceptable salt thereof. 25. A compound according to claim 1, which is (E)-cinnamoyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-car boxylate or a pharmaceutically acceptable salt thereof. 26. A compound according to claim 1, which is cyclopentylcarbonyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-car boxylate or a pharmaceutically accepted salt thereof. 27. A pharmaceutical composition for antagonizing angiotensin II which comprises a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier, excipient or diluent. 28. A method for antagonizing angiotensin II in a mammal which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.