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1. WO1996005188 - HYPOLIPIDEMIC 1,4-BENZOTHIAZEPINE-1,1-DIOXIDES

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

CLAIMS

1. The compounds of the formula (I) :



wherein R is a straight chained C\_6 alkyl group; R2 is a straight chained C\. _ alkyl group; R3 is hydrogen or a group OR1 1 in which R1 is hydrogen, optionally substituted C\. alkyl or a C \. alkylcarbonyl group; R4 is pyridyl or optionally substituted phenyl; R5, R6, R7 and R8 are the same or different and each is selected from hydrogen, halogen, cyano, R1 -acetylide, OR15, optionally substituted Cι_6 alkyl, COR15, CH(OH)R15, S(O)nR15, P(O)(OR15)2, OCOR15, OCF3, OCN, SCN, NHCN, CH2OR15, CHO, (CH2)pCN, CONR12R13, (CH2)pCO2R15, (CH2)pNR12R13, CO2R15, NHCOCF3, NHSO2R15, OCH2OR15, OCH=CHR15, O(CH2CH2O)nR15, O(CH2)pSO3R15, O(CH2)pNR12R13 and

O(CH2)pN+R 2R13R14 wherein p is an integer from 1-4, n is an integer from 0-3 and R 2, R 3, R14 and R 5 are independently selected from hydrogen and optionally substituted Cj.^ alkyl; or R > and R7 are linked to form a group


wherein R1 and R 3 are as hereinbefore defined and m is 1 or 2; and R9 and R* are the same or different and each is hydrogen or C 1.5 alkyl; with the proviso that when R3 is hydrogen either R7 is not hydrogen or at least two of R5, R>, R7 and R8 are not hydrogen; and salts, solvates and physiologically functional derivatives thereof.

2. The compounds as claimed in claim 1 which are of the formula (II)



wherein R1 to R1^ are as hereinbefore defined and R7a is selected from halogen, cyano, R15-acetylide, OR15, optionally substituted C\. alkyl, COR15, CH(OH)R15, S(O)nR15, P(O)(OR15)2) OCOR15, OCF3, OCN, SCN, HNCN, CH2OR15, CHO, (CH2)pCN, CONR12R13, (CH2)pCO2R15, (CH2)pNR12R13, CO2R15, NHCOCF3, NHSO R15, OCH2OR15, OCH=CHR15, O(CH2CH2O)nR15, O(CH2)pSO3R15, O(CH2)pNR1 R13 and

O(CH2)pN+R12R13R14 wherein n, p and R12 to R15 are as hereinbefore defined; and salts, solvates or physiologically functional derivatives thereof.

The compounds as claimed in claim 1 which are of the formula (HI) :



wherein R^R^ are as defined in claim 1; and salts, solvates and physiologically functional derivatives thereof.

The compounds as claimed in claim 1 which are of the formula (IV)


wherein R^RΪO are as defined in claim 1; and salts, solvates and physiologically functional derivatives thereof

5. The compounds as claimed in claim 1 which are of the formula (IVa)


wherein R^R^ are as defined in claim 1; and salts, solvates and physiologically functional derivatives thereof.

6. The compounds as claimed in claim 1 wherein:
R and R2 are straight chained Cι_6 alkyl;
R3 is hydrogen or hydroxy;
R4 is unsubstituted phenyl;
R5 is hydrogen;
R9 and R^O are both hydrogen; and either
R7 is selected from halogen, hydroxy, C\. alkoxy, optionally substituted

C!_6 alkyl, -S(O)nR15, -OC(O)R15, and -CH2OR15 wherein R15 is hydrogen or

Cι_6 alkyl; and
R6 and R8 are independently selected from hydrogen and those groups listed in the definition of R7; or
R8 is hydrogen and R > and R7 are linked to form a group -O-(CH2) -O- wherein m is 1 or 2;
and salts, solvates, and physiologically functional derivatives thereof

7. A compound according to any of claims 1 to 6 wherein R^ and R7 are both
methoxy.

8. A compound selected from the group consisting of :

(3R, 5R)-3-Butyi-3-ethyl-2,3 ,4, 5-tetrahydτo-7, 8-dimethoxy-5-phenyl- 1 ,4- benzothiazepine 1,1 -dioxide;

(3R,5R)-3-ButyI-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-l,4- benzothiazepin-4-ol 1, 1 -dioxide;

(+-)-Trans-3 -butyl-3-ethyl-2,3 ,4, 5-tetrahydro-7, 8-dimethoxy-5-phenyl- 1 ,4- benzothiazepiπe 1,1 -dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahyαro-7,8-climethoxy-5-phenyl-l,4,- benzothiazepin-4-ol 1 , 1 -dioxide;

(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4- benzothiazepine 1 , 1 -dioxide;

(3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4- benzothiazepin-4-ol 1 , 1 -dioxide;

(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepine-7,8-diol 1,1 -dioxide;

(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4- benzothiazepin-7-ol 1,1 -dioxide;

(3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l,4-benzothiazepin-8-ol 1,1 -dioxide;

(+-)-Trans-3 -butyl-3 -ethyl-2,3 ,4, 5-tetrahydro-8-methoxy-5-phenyl- 1 ,4-benzothiazepine 1 , 1 -dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-8-ol 1,1 -dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepine-4,8-diol;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4-benzothiazepine-7-carbaIdehyde 1 , 1 -dioxide;

(+-)-Trans-2-((3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4- benzothiazepin-7-yl)methoxy) ethanol S,S-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-l,4- benzothiazepine-7-carbaldehyde 1 , 1 -dioxide;

(+-)-Trans-3 -butyl-3 -ethyl-2,3 ,4, 5-tetrahydro-5-phenyl- 1 ,4-benzothiazepin-8-thiol 1, 1 -dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-8- sulfonic acid 1,1 -dioxide;

(7R,9R)-7-Butyl-7-ethyl-6,7,8,9-tetrahydro-9-phenyl-l,3-dioxolo(4,5-H)(l,4)- benzothiazepine 5,5-dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-l,4-benzothiazepine 1,1 -dioxide;

(3R,5R)-3-butyl-3-ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-7,8-dimethoxy-l,4-benzothiazpin-4-ol 1 , 1 -dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4-benzothiazepine-7-methanol S , S-dioxide;

(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-nitro-5-phenyl-l,4-benzothiazepine 1,1 -dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-7-(methoxymethyl)-5-phenyl- 1 ,4-benzothiazepine 1 , 1 -dioxide;

(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-7,8-diyl diacetate 1,1 -dioxide;

(8R,10R)-8-Butyl-8-ethyl-2,3,7,8,9,10-hexahydro-10-l,4-dioxono(2,3-H)(l,4)-benzothiazepine 6,6-dioxide;

(3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl- 1 ,4-benzothiazepine 1, 1- dioxide;

(+-)-Trans-3 -butyl-8-ethoxy-3 -ethyl-2, 3 , 4, 5 -tetrahydro-5 -phenyl- 1,4- benzothiazepine 1 , 1 -dioxide;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-l,4- benzothiazepine 1,1 -dioxide hydrochloride;

(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-8- carbaldehyde 1,1 -dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl- 1 ,4-benzothiazepine 1,1- dioxide;

3,3-Diethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-8-methoxy-l,4-benzothiazepine 1,1 -dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-l,4-benzothiazepine 1,1- dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl- 1 ,4-benzothiazpin-4,8-diol 1 , 1 -dioxide;

(RS)-3,3-Diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-ρhenyl-l,4-benzothiazepine 1,1 -dioxide;

(+-)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-4-ol 1 , 1 -dioxide;

(-t--)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-l,4-benzothiazepin-4-ol 1 , 1 -dioxide;

(-ι--)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-trimethoxy-5-phenyl-l,4-benzothiazepin-4-ol 1,1 -dioxide;

(3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazpin-4,7,8-triol 1,1 -dioxide;

(+-)-Trans-3 -butyl-3-ethyl-2,3 ,4, 5-tetrahydro-4, 7, 8-trimethoxy-5-phenyl- 1 ,4- benzothiazepine 1 , 1 -dioxide;

(+-)-Trans-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-7,8-dimethoxy-l,4- benzothiazepin-4-yl acetate S,S-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-8-ol 1,1-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-l,4-benzothiazepin-8-ol 1,1- dioxide;

3,3-Dibutyl-2,3,4,5-tetrahydro-5-phenyl-l,4-benzothiazepin-8-ol 1,1-dioxide;

(+-)-Trans-3 -Butyl-3-ethyl-2,3 ,4, 5-tetrahydro- 1 , 1 -dioxo-5-phenyl- 1,4- benzothiazepin-8-yl hydrogen sulfate;

(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-l,l-dioxo-5-phenyl-l,4- benzothiazepin-8-yl dihydrogen phosphate;

3,3-Diethyl-2,3,4,5-tetrahydro-l , 1 -dioxo-5-phenyl- 1 ,4-benzothiazepin-8-yl
hydrogen sulfate;

3 ,3 -Diethyl-2,3 ,4,5-tetrahydro- 1 , 1 -dioxo-5-phenyl- 1 ,4-benzothiazepin-8-yl
dihydrogen phosphate;

(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro- 1 , 1 -dioxo-5-phenyl- 1 ,4- benzothiazepin-8-yl aspartate; and

3,3-Diethyl-2,3,4,5-tetrahydro-l,l-dioxo-5-phenyl-l,4-benzothiazepin-8-yl
aspartate.

9. (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7, 8-dimethoxy-5-phenyl-l,4- benzothiazepine 1,1 -dioxide, or a salt, solvate, or physiologically functional
derivative thereof.

10. A method of treating a clinical condition in a mammal for which a bile acid uptake inhibitor is indicated which comprises, administering to a mammal an effective bile acid uptake inhibition amount of a compound of the formula (I)


wherein R is a straight chained Cj.g alkyl group; R2 is a straight chained Cj.^ . alkyl group; R3 is hydrogen or a group OR1 1 in which R 1 is hydrogen, optionally substituted Cι_6 alkyl or a C]_6 alkylcarbonyl group; R4 is pyridyl or optionally substituted phenyl; R5,
R7 and R8 are the same or different and each is selected from hydrogen, halogen, cyano, R1 -acetylide, OR15, optionally substituted C\. alkyl, COR15, CH(OH)R15, S(O)nR15, P(O)(OR15)2, OCOR15, OCF , OCN, SCN, NHCN, CH2OR15, CHO, (CH2)pCN, CONR12R13, (CH2)pCO2R15, (CH2)pNR12R13, CO2R15, NHCOCF3, NHSO2R15, OCH2OR15, OCH=CHR15, O(CH2CH2O)nR15, ©(CH^pSOsR15, O(CH2)pNR12R13 and

O(CH )pN+R R R14 wherein p is an integer from 1-4, n is an integer from 0-3 and R12, R13, R14 and R15 are independently selected from hydrogen and optionally substituted Ci.g alkyl; or R > and R7 are linked to form a group



wherein R 2 and R 3 are as hereinbefore defined and m is 1 or 2; and R9 and RΪ are the same or different and each is hydrogen or Cj__ alkyl; with the proviso that when R3 is hydrogen either R7 is not hydrogen or at least two of R5, R° R7 and R8 are not hydrogen; and salts, solvates and physiologically functional derivatives thereof.

11. A method of treating a hyperlipidemic condition in a mammal which comprises,
administering to the mammal an effective hyperlipidemic treatment amount of a
compound of formula (I):

wherein R1 is a straight chained C\. alkyl group; R2 is a straight chained C .Q alkyl group; R3 is hydrogen or a group OR1 1 in which R1 1 is hydrogen, optionally substituted nyl group; R4 is pyridyl or optionally substituted
e same or different and each is selected from hydrogen, halogen, cyano, R15-acetylide, OR15, optionally substituted Cι _6 alkyl, COR15, CH(OH)R15, S(O)nR15, P(O)(OR15)2, OCOR15, OCF , OCN, SCN, NHCN, CH2OR15, CHO, (CH2)pCN, CONR12R13, (CH2)pCO2R15, (CH2)pNR1 R13, CO R15, NHCOCF3, NHSO2R15, OCH2OR15, OCH=CHR15, O(CH2CH2O)nR15, O(CH2)pSO3R15, O(CH2)pNR12R13 and

O(CH2)pN+R12R1 R14 wherein p is an integer from 1-4, n is an integer from 0-3 and R12, R13, R 4 and R15 are independently selected from hydrogen and optionally substituted Cμg alkyl; or R > and R7 are linked to form a group

-O
(CR12R13)m
-O
wherein R12 and R13 are as hereinbefore defined and m is 1 or 2; and R9 and R10 are the same or different and each is hydrogen or C 1.5 alkyl; with the proviso that when R3 is hydrogen either R7 is not hydrogen or at least two of R5, R^, R7 and R8 are not hydrogen; and salts, solvates and physiologically functional derivatives thereof.

12. The method of claim 11 wherein the hyperlipidemic condition is atherosclerosis.

13. A method according to claim 11 or 12 which comprises administering a compound of formula (I) wherein R^ and R7 are each -OCH3.

14. A pharmaceutical composition comprising a compound of formula (I) :



wherein R1 is a straight chained Cι_<j alkyl group; R2 is a straight chained Cj.^ alkyl group; R3 is hydrogen or a group OR1 1 in which R1 1 is hydrogen, optionally substituted C\. alkyl or a C\.^ alkylcarbonyl group; R4 is pyridyl or optionally substituted phenyl; R5, R^, R7 and R8 are the same or different and each is selected from hydrogen, halogen, cyano, R15-acetylide, OR15, optionally substituted Cι_6 alkyl, COR15, CH(OH)R15, S(O)nR15, P(O)(OR15)2, OCOR15, OCF3, OCN, SCN, NHCN, CH2OR15, CHO, (CH2)pCN, CONR1 R13, (CH2)pCO R15, (CH2)pNR1 R13, CO2R15, NHCOCF3, NHSO2R15, OCH2OR15, OCH=CHR15, O(CH2CH2O)nR15, O(CH2)pSO R15, O(CH2)pNR12R13 and

O(CH2)pN+R 2R13R14 wherein p is an integer from 1-4, n is an integer from 0-3 and R12, R13, R14 and R15 are independently selected from hydrogen and optionally substituted Ci _g alkyl; or R^ and R7 are linked to form a group



wherein R12 and R13 are as hereinbefore defined and m is 1 or 2; and R9 and R^ are the same or different and each is hydrogen or Cj_6 alkyl; with the proviso that when R3 is hydrogen either R7 is not hydrogen or at least two of R5, R^, R7 and R8 are not hydrogen; or a salt, solvate or physiologically functional derivative thereof, at least one pharmaceutically acceptable carrier, and optionally one or more other physiologically active agents.

15. A pharmaceutical composition according to claim 14 comprising a compound of formula (I) wherein R^ and R7 are each -OCH3.

16. A method for the preparation of a compound of formula (I) :



wherein R is a straight chained Cι_6 alkyl group; R2 is a straight chained
alkyl group; R3 is hydrogen or a group OR11 in which R 1 is hydrogen, optionally substituted Cj_6 alkyl or a Cj.^ alkylcarbonyl group; R4 is pyridyl or optionally substituted phenyl; R5, R° R7 and R8 are the same or different and each is selected from hydrogen, halogen, cyano, R1 -acetylide, OR15, optionally substituted C\. alkyl, COR15, CH(OH)R15, S(O)nR15, P(O)(OR15)2, OCOR15, OCF3, OCN, SCN, NHCN, CH2OR15, CHO, (CH2)pCN, CONR12R13, (CH2)pCO2R15, (CH2)pNR12R13, CO2R15, NHCOCF3, NHSO2R15, OCH2OR15, OCH=CHR15, O(CH2CH2O)nR15, O(CH2)pSO3R15, O(CH2)pNR12R13 and

O(CH2)pN+R12R13R14 wherein p is an integer from 1-4, n is an integer from 0-3 and R 2, R13, R14 and R15 are independently selected from hydrogen and optionally substituted C\. alkyl; or R > and R7 are linked to form a group


wherein R12 and R 3 are as hereinbefore defined and m is 1 or 2; and R9 and R^ are the same or different and each is hydrogen or C\.$ alkyl; with the proviso that when R3 is hydrogen either R7 is not hydrogen or at least two of R5, R^, R7 and R8 are not hydrogen; and salts, solvates and physiologically functional derivatives thereof; which comprises

(a) wherein R3 is hydrogen; by oxidation of a compound of
formula (V):

wherein R1 to R ^ are as hereinbefore defined and 1 is 0 or 1; or

(b) wherein R3 is OH; by oxidation of a compound of formula (I) wherein R3 is hydrogen; and optionally,

(c) separating the mixture of isomers so obtained and/or coverting the compound of formula (I) so formed to a corresponding salt, solvate, or physiologically functional derivative thereof.

17. A compound of formula (I) according to any one of Claims 1 to 9 or a pharmaceutically acceptable salt, solvate, or physiologically acceptable salt, solvate, or physiologically functional derivative thereof for use in medical therapy.

18. A compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for use in the prophylaxis or treatment of clinical conditions for which a bile acid uptake inhibitor is indicated.

19. Use of a compound of formula (I) according to any one of Claims 1 to 9 or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which a bile uptake inhibitor is indicated.