Source: http://www.google.com/patents/US5883109?dq=7143430
Timestamp: 2014-07-13 05:51:26
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Matched Legal Cases: ['Application No. 60', 'Application No. 2', 'application No. 60', 'application No. 60', 'application No. 60', 'Application No. 2', 'application No. 60', 'application No. 60', 'application No. 60', 'application No. 60', 'application No. 60', 'application No. 60', 'application No. 60', 'application No. 60', 'Application No. 0221025', 'Application No. 0']

Patent US5883109 - Method for lowering serum lipid levels employing an MTP inhibitor in ... - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign in<nobr>Advanced Patent Search</nobr>PatentsA method is provided for lowering serum lipids, cholesterol and/or triglycerides and thereby inhibiting atherosclerosis by administering to a patient an MTP inhibitor, in combination with a cholesterol lowering drug, such as pravastatin....http://www.google.com/patents/US5883109?utm_source=gb-gplus-sharePatent US5883109 - Method for lowering serum lipid levels employing an MTP inhibitor in combination with another cholesterol lowering drugAdvanced Patent SearchPublication numberUS5883109 APublication typeGrantApplication numberUS 08/854,311Publication dateMar 16, 1999Filing dateMay 12, 1997Priority dateJul 24, 1996Fee statusPaidAlso published asCA2260995A1, EP1014791A1, EP1014791A4, WO1998003069A1Publication number08854311, 854311, US 5883109 A, US 5883109A, US-A-5883109, US5883109 A, US5883109AInventorsRichard E. Gregg, Hubert G. Pouleur, R. Wetterau II JohnOriginal AssigneeBristol-Myers Squibb CompanyExport CitationBiBTeX, EndNote, RefManPatent Citations (25), Non-Patent Citations (49), Referenced by (14), Classifications (14), Legal Events (6) External Links: USPTO, USPTO Assignment, EspacenetMethod for lowering serum lipid levels employing an MTP inhibitor in combination with another cholesterol lowering drugUS 5883109 AAbstract A method is provided for lowering serum lipids, cholesterol and/or triglycerides and thereby inhibiting atherosclerosis by administering to a patient an MTP inhibitor, in combination with a cholesterol lowering drug, such as pravastatin.
What is claimed is: 1. A pharmaceutical combination comprising an MTP inhibitor and another cholesterol lowering agent wherein the cholesterol lowering agent is selected from the group of HMG CoA reductase inhibitors or fibric acid derivatives.
2. The combination as defined in claim 1 wherein the MTP inhibitor has the structure ##STR59## where Q is ##STR60## X is: CHR8, ##STR61## R8, R9 and R10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl; ##STR62## wherein m is 2 or 3; R1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl wherein alkyl has at least 2 carbons, diarylalkyl, arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkynyl, diarylalkylaryl, heteroarylalkyl wherein alkyl has at least 2 carbons, cycloalkyl, or cycloalkylalkyl wherein alkyl has at least 2 carbons, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from halo, haloalkyl, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cyclo-alkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl, hydroxy or oxo;or R1 is a fluorenyl-type group of the structure ##STR63## R1 is an indenyl-type group of the structure ##STR64## Z1 and Z2 are the same or different and are independently a bond, O, S, ##STR65## with the proviso that with respect to B, at least one of Z1 and Z2 will be other than a bond; R11 is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms; arylene or mixed arylene-alkylene; R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkyl-alkyl, with the provisos that (1) when R12 is H, aryloxy, alkoxy or arylalkoxy, then Z2 is ##STR66## or a bond and (2) when Z2 is a bond, R12 cannot be heteroaryl or heteroarylalkyl; Z is bond, O, S, N-alkyl, N-aryl, or alkylene or alkenylene from 1 to 5 carbon atoms; R13, R14, R15, and R16 are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cyclo-heteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl or aryloxy; R15a and R16a are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy; or R1 is a group of the structure ##STR67## wherein p is 1 to 8 and R17 and R18 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl at least one of R17 and R18 being other than H; or R1 is a group of the structure ##STR68## wherein R19 is aryl or heteroaryl; R20 is aryl or heteroaryl; R21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or cycloalkylalkoxy; R2, R3, R4 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; R5 is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, arylamino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl; R6 is hydrogen or C1 -C4 alkyl or C1 -C4 alkenyl; all optionally substituted with 1, 2, 3 or 4 groups which may independently be any of the substituents listed in the definition of R5 set out above; R7 is alkyl, aryl or arylalkyl wherein alkyl by itself or as part of arylalkyl is optionally substituted with oxo ##STR69## are the same or different and are independently selected from heteroaryl containing 5- or 6-ring members; and N-oxides ##STR70## thereof; and pharmaceutically acceptable salts thereof; with the provisos that where in the first formula X is CH2, and R2, R3 and R4 are each H, then R1 will be other than 3,3-diphenylpropyl, and in the fifth formula, where one of R2, R3 and R4 is 6-fluoro, and the others are H, R7 will be other than 4-(2-methoxyphenyl). 3. The combination as defined in claim 2 wherein the MTP inhibitor has the formula ##STR71##
4. The combination as defined in claim 2 where in the MTP inhibitor R1 is ##STR72##
5. The combination as defined in claim 1 wherein the MTP inhibitor has the structure ##STR73## or the piperidine N-oxide thereof or a pharmaceutically acceptable salt thereof, wherein Z is a bond, O or S;X1 and X2 are independently selected from H or halo; x is an integer from 2 to 6; R5 is heteroaryl, aryl, heterocycloalkyl or cycloalkyl, each R5 group being optionally substituted with 1, 2, 3 or 4 substituents which may be the same or different. 6. The combination as defined in claim 2 where in the MTP inhibitor R5 is substituted with 1, 2, 3 or 4 of one or more of the followingI, Cl, F, CF3 ##STR74## where x is 1 to 5 ##STR75## alkyl, phenyl, phenyl substituted with halo, alkyl, CF3 O, alkoxy, ##STR76## CF3, or phenyl; ##STR77## where p is 1 to 5, --N(CH3)C6 H5 ; --S--(CH2)p CF3 where p is 1 to 5, ##STR78## --S--alkyl, ##STR79## --O--(CH2)p --CF3, ##STR80## OCH3 ; cyclohexyl, ##STR81## amino, ##STR82## alkanoyl, alkoxycarbonyl, aroyl, heteroarylaminocarbonyl, arylalkyloxycarbonyl, --CH2 --S--C6 H5, ##STR83## 7. The combination as defined in claim 2 where in the MTP inhibitor R5 is phenyl substituted with haloalkylphenyl or heteroaryl.
8. The combination as defined in claim 7 where in the MTP inhibitor R5 is ##STR84##
9. The combination as defined in claim 2 where in the MTP inhibitor is ##STR85##
10. The combination as defined in claim 1 wherein the MTP inhibitor has the structure ##STR86## or pharmaceutically acceptable salts thereof, or N-oxides thereof, wherein q is 0, 1 or 2;A is(1) a bond; (2) --O--; or (3 ) ##STR87## where R5 is H or lower alkyl, or R5 together with R2 forms a carbocyclic or heterocyclic ring system containing 4 to 8 members in the ring; B is a fluorenyl-type group of the structure ##STR88## B is an indenyl-type group of the structure ##STR89## Rx is H, alkyl or aryl; R1 is alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or aryl)3 Si (where each alkyl or aryl group is independent), cycloalkyl, cycloalkenyl, substituted alkylamino, substituted arylalkylamino, aryl, arylalkyl, arylamino, aryloxy, heteroaryl, heteroarylamino, heteroaryloxy, arylsulfonylamino, heteroarylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, --PO(R13) (R14), (where R13 and R14 are independently alkyl, aryl, alkoxy, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy, or cycloheteroalkylalkoxy); aminocarbonyl (where the amino may optionally be substituted with one or two aryl, alkyl or heteroaryl groups); cyano, 1,1-(alkoxyl or aryloxy)2 alkyl (where the two aryl or alkyl substituents can be independently defined, or linked to one another to form a ring connected to L1 (or L2 in the case of R2) at the 2-position); 1,3-dioxane or 1,3-dioxolane connected to L1 (or L2 in the case of R2) at the 4-position; the R1 group which is substituted as indicated above or may optionally be substituted with 1, 2, 3 or 4 substituents, which can be any of the R3 or R1 groups or alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxylcarbonylamino, uriedo (where the uriedo nitrogens may optionally be substituted with alkyl, aryl or heteroaryl), heterocyclylcarbonylamino (where the heterocycle is connected to the carbonyl group via a nitrogen or carbon atom), alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, ##STR90## where J is: CHR23, ##STR91## R23, R24 and R25 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl; R20, R21, R22 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; and these substituents may either be directly attached to R1, or attached via an alkylene at an open position; R2 is independently any of the groups set out for R1, H, polyhaloalkyl, or cycloheteroalkyl, and may be optionally substituted with one to four of any of the groups defined for R3 or substituents defined for R1 ; L1 is a linking group containing from 1 to 10 carbons in a linear chain including alkylene, alkenylene or alkynylene, which may contain, within the linking chain any of the following: one or two alkenes, one or two alkynes, an oxygen, an amino group, an oxo group, acid may be substituted with one to five alkyl or halo groups; L2 may be the same or different from L1 and may independently be any of the L1 groups set out above or a singe bond; R3, R3 ', R4 and R4 ' may be the same or different and are independently selected from H, halogen, CF3, haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, amino, thiol, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar-, Ar-alkyl, ArO, Ar-amino, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, Ar-carbonyl, Ar-carbonyloxy or Ar-carbonylamino, wherein Ar is aryl or heteroaryl and Ar may optionally include 1, 2 or 3 additional rings fused to Ar which rings can be aryl, cycloalkyl, heteroaryl or cycloheteroalkyl; R3a and R3b are the same or different and are independently any of the R3 groups except hydroxy, nitro, amino or thio; ##STR92## are the same or different and independently represent a 5 or 6 membered heteroaryl ring which contains 1, 2, 3 or 4 heteroatoms in the ring which are independently N, S or O; and including N-oxides; X is a bond, or is one of the following groups: ##STR93## wherein Y is O, N--R6 or S; n' is 0, 1 or 2; R6 is H, lower alkyl, aryl, --C(O)--R11 or --C(O)--O--R11 ; R7 and R8 are the same or different and are independently H, alkyl, aryl, halogen, --O--R12, or R7 and R8 together can be oxygen to form a ketone; R9, R10, R9 ' and R10 ' are the same or different and are independently H, lower alkyl, aryl or --O--R11 ; R9 " and R10 " are the same or different and are independently H, lower alkyl, aryl, halogen or --O--R11 ; R11 is alky or aryl; R12 is H, alkyl or aryl;with the following provisos for compound of the structure ##STR94## (a) when R1 is unsubstituted alkyl or unsubstituted arylalkyl, L1 cannot contain amino; (b) when R1 is alkyl, L1 cannot contain amino and oxo in adjacent positions (to form an amido group); (c) when R2 L2 A-- is H2 N--, R1 L1 cannot contain amino; (d) when R1 is cyano, L1 must have more than 2 carbons; (e) R1 L1 must contain at least 3 carbons; with respect to compounds of formulas I, IA and IB, where R1 is cycloheteroalkyl, R1 is exclusive of 1-piperidinyl, 1-pyrrolidinyl, 1-azetidinyl or 1-(2-oxo-pyrrolidinyl); with respect to the sulfur containing compounds and alcohols, R2 L2 cannot have an O or N atom directly attached to S=(O)q or CRx (OH), and for IA, R2 L2 cannot be H. 11. The combination as defined in claim 10 wherein the MTP inhibitor has the structure ##STR95##
12. The combination as defined in claim 10 where in the MTP inhibitor B is a fluorenyl-type group.
13. The combination as defined in claim 10 wherein the MTP inhibitor has the formula ##STR96## wherein B is ##STR97## A is NH; X is a bond, oxygen or sulfur;R3 and R4 are the same or different and are H or F; R1 is aryl, phenyl, heteroaryl, imidazolyl, pyridyl, cyclohexyl, PO(R13) (R14), heteroarylthio, benzthiazole-2-thio, imidazole-2-thio, alkyl, alkenyl or 1,3-dioxan-2-yl, wherein each of the above is optionally substituted; R2 is alkyl, polyfluoroalkyl, alkenyl, aryl, phenyl, heteroaryl, imidazolyl or pyridyl, wherein each of the above is optionally substituted; L1 is a chain containing 1 to 5 atoms in a linear chain; L2 is a bond or lower alkylene. 14. The combination as defined in claim 2 wherein the other cholesterol lowering drug is an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase.
15. The combination as defined in claim 2 wherein said inhibitor of the enzyme HMG CoA reductase is lovastatin, pravastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin.
16. The combination as defined in claim 1 wherein the other cholesterol lowering drug is a fibric acid derivative which is gemfibrozil, fenofibrate, clofibrate, bezafibrate, ciprofibrate or clinofibrate.
17. The combination as defined in claim 1 wherein the MTP inhibitor is present in a weight ratio to said cholesterol lowering drug of within the range of from about 0.001:1 to about 1000:1.
18. The combinaiton as defined in claim 2 wherein the MTP inhibitor is BMS 201,038 and the cholesterol lowering drug is pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin.
19. A method for preventing, inhibiting or treating atherosclerosis, pancreatitis or obesity in a mammalian species, which comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical combination as defined in claim 1.
20. A method of lowering serum lipid levels, cholesterol or triglycerides, or inhibiting or treating hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia and/or hypertriglyceridemia, or preventing, inhibiting or treating atherosclerosis, pancreatitis or obesity, in a mammalian species, which comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical combination as defined in claim 1.
21. The method as defined in claim 20 wherein the LDL blood level is reduced to at least 20% of normal LDL blood level.
22. The method as defined in claim 20 wherein the LDL blood level is reduced to about zero.
This application claims the benefit of U.S. Provisional Application No. 60/022,866, filed Jul. 24, 1996.
FIELD OF THE INVENTION The present invention relates to a method for lowering serum lipids, cholesterol and/or triglycerides in mammalian species by administering an MTP inhibitor in combination with another cholesterol lowering drug, for example, an HMG CoA reductase inhibitor, such as pravastatin, lovastatin or simvastatin.
BACKGROUND OF THE INVENTION The use of microsomal triglyceride transfer protein (MTP) inhibitors for decreasing serum lipids including cholesterol and triglycerides and their use in treating atherosclerosis, obesity and pancreatitis is disclosed in Canadian Patent Application No. 2,091,102 (corresponding to U.S. application Ser. No. 117,362, now U.S. Pat. No. 5,595,872), U.S. application Ser. No. 472,067, filed Jun. 6, 1995, now U.S. Pat. No. 5,739,135 (file DC21e), U.S. application Ser. No. 548,811, now U.S. Pat. No. 5,712,279 (file DC21h), U.S. provisional application No. 60/017,224, (file HX79a*), U.S. provisional application No. 60/017,253, (file HX82*) and U.S. provisional application No. 60/017,254, (file HX84*).
DESCRIPTION OF THE INVENTION In accordance with the present invention, a method for preventing, inhibiting or treating atherosclerosis, pancreatitis or obesity is provided, wherein an MTP inhibitor in combination with another cholesterol lowering drug is administered in therapeutically effective amounts to lower LDL cholesterol and triglycerides.
Furthermore, in accordance with the present invention, a method is provided for lowering serum lipid levels, cholesterol and/or triglycerides, or inhibiting and/or treating hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia and/or hypertriglyceridemia, wherein a combination of an MTP inhibitor and another cholesterol lowering drug is administered in therapeutically effective amounts.
In addition, in accordance with the present invention, a novel combination of cholesterol lowering agents is provided which includes an MTP inhibitor and another cholesterol lowering drug.
Cholesterol lowering drugs or drugs which are inhibitors of cholesterol biosynthesis which may be used in the method of the invention in combination with the MTP inhibitor include HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, bile acid sequestrants, probucol, niacin, niacin derivatives, neomycin, aspirin, and the like.
It is believed that the combination of MTP inhibitor and other cholesterol lowering drug, which works by a mechanism other than inhibiting MTP, is a surprising and unique concept in treating diseases involved with elevated cholesterol and/or triglycerides and atherosclerosis, obesity and/or pancreatitis, in that the combination may provide additional anticholesterolemic effects over that which may be obtained using each of the components of the combination alone. It is expected that reduced levels of each of the MTP inhibitor and other cholesterol lowering drug may be employed to achieve desired results, albeit with reduced side effects.
The term "MTP" refers to a polypeptide or protein complex that (1) if obtained from an organism (e. g., cows, humans, etc.), can be isolated from the microsomal fraction of homogenized tissue; and (2) stimulates the transport of triglycerides, cholesterol esters, or phospholipids from synthetic phospholipid vesicles, membranes or lipoproteins to synthetic vesicles, membranes, or lipoproteins and which is distinct from the cholesterol ester transfer protein Drayna et al., Nature 327, 632-634 (1987)! which may have similar catalytic properties.
The combination of the MTP inhibitor and other cholesterol lowering drug will be employed in a weight ratio to each other of within the range of from about 1000:1 to about 0.001:1 and preferably from about 0.05:1 to about 100:1.
MTP inhibitors to be employed in the methods of the invention include MTP inhibitors disclosed in Canadian Patent Application No. 2,091,102 (corresponding to U.S. application Ser. No. 117,362, now U.S. Pat. No. 5,595,872), U.S. application Ser. No. 472,067, filed Jun. 6, 1995, now U.S. Pat. No. 5,739,135 (file DC21e), U.S. application Ser. No. 548,811, now U.S. Pat. No. 5,712,279 (file DC21h), U.S. provisional application No. 60/017,224, (file HX79a*), U.S. provisional application No. 60/017,253, (file HX82*) and U.S. provisional application No. 60/017,254, (file HX84*).
The MTP inhibitors disclosed in U.S. application Ser. No. 472,067, filed Jun. 6, 1995, now U.S. Pat. No. 5,739,135 (file DC21e) are piperidine compounds of the structure ##STR1## where Q is ##STR2## X is: CHR8, ##STR3## R8, R9 and R10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl; ##STR4##
R1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl wherein alkyl has at least 2 carbons, diarylalkyl, arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkynyl, diarylalkylaryl, heteroarylalkyl wherein alkyl has at least 2 carbons, cycloalkyl, or cycloalkylalkyl wherein alkyl has at least 2 carbons, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from halo, haloalkyl, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cyclo-alkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl, hydroxy or oxo;
or R1 is a fluorenyl-type group of the structure ##STR5##
R1 is an indenyl-type group of the structure ##STR6##
Z1 and Z2 are the same or different and are independently a bond, O, S, ##STR7## with the proviso that with respect to B, at least one of Z1 and Z2 will be other than a bond; R11 is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms; arylene or mixed arylene-alkylene; R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cyclo-alkyl, aryloxy, alkoxy, arylalkoxy or cycloalkyl-alkyl, with the provisos that
(1) when R12 is H, aryloxy, alkoxy or arylalkoxy, then Z2 is ##STR8## or a bond and
or R1 is a group of the structure ##STR9## wherein p is 1 to 8 and R17 and R18 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl at least one of R17 and R18 being other than H;
or R1 is a group of the structure ##STR10## wherein R19 is aryl or heteroaryl;
R7 is alkyl, aryl or arylalkyl wherein alkyl by itself or as part of arylalkyl is optionally substituted with oxo ##STR11## are the same or different and are independently selected from heteroaryl containing 5- or 6-ring members; and
N-oxides ##STR12## thereof; and
The MTP inhibitors disclosed in U.S. application Ser. No. 548,811 filed Jan. 11, 1996, now U.S. Pat. No. 5,712,279 (file DC21h), have the structure ##STR13## including the piperidine N-oxide thereof or a pharmaceutically acceptable salt thereof, wherein Z is a bond, O or S;
The MTP inhibitors disclosed in U.S. provisional application No. 60/017,224, filed May 9, 1996 (file HX79a*) have the structure ##STR14## including pharmaceutically acceptable salts thereof, wherein q is 0, 1 or 2;
(1) a bond;
(2) --O--; or
(3) ##STR15## where R5 is H or lower alkyl or R5 together with R2 forms a carbocyclic or heterocyclic ring system containing 4 to 8 members in the ring.
B is a fluorenyl-type group of the structure: ##STR16## (the above B is also referred to as a fluorenyl-type ring or moiety); or
B is an indenyl-type group of the structure ##STR17## (the above B is also referred to as an indenyl-type ring or moiety);
Rx is H, alkyl or aryl;
R1 is alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or aryl)3 Si (where each alkyl or aryl group is independent), cycloalkyl, cycloalkenyl, substituted alkylamino, substituted arylalkylamino, aryl, arylalkyl, arylamino, aryloxy, heteroaryl, heteroarylamino, heteroaryloxy, arylsulfonylamino, heteroarylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, --PO(R13) (R14), (where R13 and R14 are independently alkyl, aryl, alkoxy, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy, or cycloheteroalkylalkoxy); R1 can also be aminocarbonyl (where the amino may optionally be substituted with one or two aryl, alkyl or heteroaryl groups); cyano, 1,1-(alkoxyl or aryloxy)2 alkyl (where the two aryl or alkyl substituents can be independently defined, or linked to one another to form a ring, such as 1,3-dioxane or 1,3-dioxolane, connected to L1 (or L2 in the case of R2) at the 2-position); 1,3-dioxane or 1,3-dioxolane connected to L1 (or L2 in the case of R2) at the 4-position.
R1 may be substituted with the following preferred substituents: alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxylcarbonylamino, uriedo (where the uriedo nitrogens may be substituted with alkyl, aryl or heteroaryl), heterocyclylcarbonylamino (where the heterocycle is connected to the carbonyl group via a nitrogen or carbon atom), alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, ##STR18## where J is: CHR23, ##STR19## R23, R24 and R25 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
R3a and R3b are the same or different and are independently any of the R3 groups except hydroxy, nitro, amino or thio; ##STR20## are the same or different and independently represent a 5 or 6 membered heteroaryl ring which may contain 1, 2, 3 or 4 heteroatoms in the ring which are independently N, S or O; and including N-oxides.
X (in the fluorenyl type ring) is a bond, or is one of the following groups: ##STR21## wherein
Y is O, N--R6 or S;
The following provisos apply to formula I compounds:
With respect to compounds IA and IB, R2 L2 cannot have an O or N atom directly attached to S=(O)q or CRx (OH), and for IA, R2 L2 cannot be H.
With respect to compounds IA and IB, where R1 is cycloheteroalkyl, R1 is exclusive of 1-piperidinyl, 1-pyrrolidinyl, 1-azetidinyl or 1-(2-oxopyrrolidinyl).
The MTP inhibitors disclosed in U.S. provisional application No. 60/017,253, filed May 10, 1996, (file HX82*) are pyrrolidine compounds and have the structure ##STR22## where Q is ##STR23## W is H,H or O; X is CHR8, ##STR24## R8, R9 and R10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
R1 is a fluorenyl-type group of the structure ##STR25##
R1 is an indenyl-type group of the structure ##STR26##
Z1 and Z2 are the same or different and are independently a bond, O, S, ##STR27## with the proviso that with respect to B, at least one of Z1 and Z2 will be other than a bond;
R11 is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms, arylene (for example ##STR28## or mixed arylene-alkylene (for example ##STR29## where n is 1 to 6;
R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cyclo-alkyl, aryloxy, alkoxy, arylalkoxy or cycloalkyl-alkyl; with the provisos that (1) when R12 is H, aryloxy, alkoxy or arylalkoxy, then Z2 is ##STR30## or a bond;
R13, R14, R15, and R16 are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, aryl-sulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonyl-amino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy;
or R1 is ##STR31## wherein p is 1 to 8 and R17 and R18 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, at least one of R17 and R18 being other than H;
or R1 is ##STR32## wherein R19 is aryl or heteroaryl;
R5 is alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryloxy, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, arylamino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all of the R5 substituents and R6 substituents (set out hereinafter) being optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino (wherein the amino includes 1 or 2 substituents which are alkyl, aryl or heteroaryl, or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, or alkylsulfinyl. Where R5 is phenyl, aryl, heteroaryl or cycloalkyl; this group preferably includes an ortho hydrophobic substituent such as alkyl, haloalkyl (with up to 5 halo groups), alkoxy, haloalkoxy (with up to 5 halo groups), aryl, aryloxy or arylalkyl;
R6 is hydrogen or C1 -C4 alkyl or C1 -C4 alkenyl; ##STR33## are the same or different and are independently selected from heteroaryl containing 5- or 6-ring members; and
including N-oxides of the formulae I and II compounds, that is ##STR34##
The MTP inhibitors disclosed in U.S. provisional application No. 60/017,254, filed May 10, 1996, (file HX84*) are azetidine compounds which have the structure ##STR35## where Q is ##STR36## X is: CHR8, ##STR37## n is 0 or 1; R8, R9 and R10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
R1 is a fluorenyl-type group of the structure ##STR38##
R1 is an indenyl-type group of the structure ##STR39##
Z1 and Z2 are the same or different and are independently a bond, O, S, ##STR40## with the proviso that with respect to B, at least one of Z1 and Z2 will be other than a bond;
R11 is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms, arylene (for example ##STR41## or mixed arylene-alkylene (for example ##STR42## where q is 1 to 6;
R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cyclo-alkyl, aryloxy, alkoxy, arylalkoxy or cycloalkyl-alkyl; with the provisos that (1) when R12 is H, aryloxy, alkoxy or arylalkoxy, then Z2 is ##STR43## or a bond;
or R1 is ##STR44## wherein p is 1 to 8 and R17 and R18 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, at least one of R17 and R18 being other than H;
or R1 is ##STR45## wherein R19 is aryl or heteroaryl;
R6 is hydrogen or C1 -C4 alkyl or C1 -C4 alkenyl; ##STR46## are the same or different and are independently selected from heteroaryl containing 5- or 6-ring members; and
including N-oxides of the formulae I and II compounds, that is ##STR47## including pharmaceutically acceptable salts thereof.
Most preferred MTP inhibitors to be employed in accordance with the present invention include preferred MTP inhibitors as set out in U.S. patent application Ser. No. 548,811, filed Jan. 11, 1996, now U.S. Pat. No. 5,712,279 (file DC21h) and in U.S. provisional application No. 60/017,224, filed May 9, 1996 (file HX79a*).
Thus, preferred compounds in U.S. patent application Ser. No. 548,811, now U.S. Pat. No. 5,712,279 (file DC21h) for use herein are compounds
(1) aryl such as phenyl, ##STR48## (2) heteroaryl such as ##STR49## (3) halo such as Cl R5 is heteroaryl such as ##STR50## substituted with (1) aroyl such as ##STR51## (2) arylthio such as ##STR52## wherein the R5 substituent is preferably in the position adjacent to the carbon linked to ##STR53##
(CH2)x is --(CH2)4 -- or ##STR54##
9- 4- 4- 2-(2,2,2-Trifluoroethoxy)benzoyl!amino!-1-piperidinyl!butyl!-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide ##STR55##
Preferred compounds in U.S. provisional application No. 60/017,224 (file HX79a*) for use herein are MTP inhibitor compounds of formula I that is ##STR56## wherein A is NH,
B is ##STR57##
X is a bond, oxygen or sulfur; R3 and R4 are independently H or F.
The other cholesterol lowering drug to be used in combination with the MTP inhibitor in accordance with the present invention is preferably an HMG CoA reductase inhibitor.
The HMG CoA reductase inhibitors suitable for use herein include, but are not limited to, mevastatin and related compounds as disclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and related compounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Pat. No. 4,346,227, simvastatin and related compounds as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171, with pravastatin, lovastatin or simvastatin being preferred. Other HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, cerivastatin, atorvastatin, pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactone derivatives as disclosed in PCT application WO 86/03488, 6- 2-(substituted-pyrrol-1-yl)alkyl!pyran-2-ones and derivatives thereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a 3-substituted pentanedioic acid derivative) dichloroacetate, imidazole analogs of mevalonolactone as disclosed in PCT application WO 86/07054, 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed in French Patent No. 2,596,393, 2,3-di-substituted pyrrole, furan and thiophene derivatives as disclosed in European Patent Application No. 0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat. No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No. 4,499,289, keto analogs of mevinolin (lovastatin) as disclosed in European Patent Application No. 0,142,146 A2, as well as other known HMG CoA reductase inhibitors.
The squalene synthetase inhibitors suitable for use herein include, but are not limited to, α-phosphonosulfonates disclosed in U.S. application Ser. No. 08/266,888, filed Jul. 5, 1994, now U.S. Pat. No. 5,712,396 (HX59b), those disclosed by Biller et al, J. Med. Chem. 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid (phosphinylmethyl)phosphonates such as those of the formula ##STR58## including the triacids thereof, triesters thereof and tripotassium and trisodium salts thereof as well as other squalene synthetase inhibitors disclosed in U.S. Pat. Nos. 4,871,721 and 4,924,024 and in Biller et al, J. Med. Chem., 1988, Vol. 31, No. 10, pp 1869 to 1871.
In carrying out the method of the present invention, the MTP inhibitor in combination with the cholesterol lowering drug may be administered to mammalian species, such as monkeys, dogs, cats, rats, humans, etc., and, as such, may be incorporated in a conventional systemic dosage form, such as a tablet, capsule, elixir or injectable. The above dosage forms will also include the necessary carrier material, excipient, lubricant, buffer, antibacterial, bulking agent (such as mennitol), anti-oxidants (ascorbic acid of sodium bisulfite) or the like. Oral dosage forms are preferred, although parenteral forms are quite satisfactory as well.
For oral administration, a satisfactory result may be obtained employing the MTP inhibitor in an amount within the range of from about 0.01 mg/kg to about 100 mg/kg and preferably from about 0.1 mg/kg to about 75 mg/kg.
A preferred oral dosage form, such as tablets or capsules, will contain the MTP inhibitor in an amount of from about 5 to about 500 mg, preferably from about 10 to about 400 mg, and more preferably from about 20 to about 250 mg.
For parenteral administration, the MTP inhibitor will be employed in an amount within the range of from about 0.005 mg/kg to about 10 mg/kg and preferably from about 0.005 mg/kg to about 8 mg/kg.
For oral administration, a satisfactory result my be obtained employing the HMG CoA reductase inhibitor in dosages employed, for example, for pravastatin, simvastatin, fluvastatin and lovastatin, as indicated in the Physician's Desk Reference, such as in an amount within the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.
A preferred oral dosage form, such as tablets or capsules, will contain MTP inhibitor in an amount of from about 10 to about 400 mg, and the HMG CoA reductase inhibitor in an amount of from about 0.1 to about 100 mg, preferably from about 5 to about 80 mg, and more preferably from about 10 to about 50 mg.
The MTP inhibitor and other cholesterol lowering agent may be employed together in the same oral dosage form or in separate oral dosage forms taken at the same time.
The formulations as described above will be administered for a prolonged period, that is, for as long as the potential for elevated cholesterol and/or triglycerides and/or atherosclerosis and other diseases set out above remains or the symptoms continue. Sustained release forms of such formulations which may provide such amounts biweekly, weekly, monthly and the like may also be employed. A dosing period of at least one to two weeks are required to achieve minimal benefit.
EXAMPLES 1 AND 2 Formulations suitable for oral administration for reducing serum cholesterol are prepared as described below.
Capsules each containing about 5 mg MTP inhibitor BMS 201,038 (Example 1) and capsules each containing about 50 mg BMS 201,038 (Example 2) are produced form the following ingredients.
______________________________________                Example 1      Example 2                Amount (mg/    Amount (mg/Ingredient           Capsule)       Capsule)______________________________________BMS-201038-methane   5.7            56.9sulfonic acid salt (1)Lactose, Hydrous, NF          ca.   151.1      ca. 99.9Microcrystalline Cellulose,                50.0           50.0NFPregelatinized Starch, NF                25.0           25.0Sodium Starch Glycolate, NF                12.5           12.5Colloidal Silicon Dioxide,                5.0            5.0NFMagnesium Stearate, NF                0.6            0.6Purified Water, USP or                q.s.           q.s.Water for Injection, USP                q.s.           q.s.Gray, Opaque, Size #0                One Capsule    One CapsuleCapsule ShellTotal Fill Weight    about 250.0    about 250.0______________________________________
(1) This amount is expressed in terms of the amount of methane sulfonic acid salt per capsule at 100% potency. This is equivalent to 5 mg and 50 mg (Examples 1 and 2, respectively) of the free base.
EXAMPLE 3 Pravastatin tablets (10, 20 or 40 mg as described in the 1996 PDR) and MTP inhibitor (BMS 201,238) tablets may be administered as a combination in accordance with the teachings of the present invention to lower serum cholesterol. In addition, the pravastatin and MTP inhibitor tablets may be ground up into powders and used together in a single capsule.
EXAMPLE 4 Tablets containing 500 mg clofibrate in combination with 10 mg BMS 201,038 may be employed in separate dosage forms or combined in a single capsule form to lower serum cholesterol in accordance with the present invention.
EXAMPLES 5, 6 and 7 Ciprofibrate, bezafibrate, gemfibrozil in combination with an MTP inhibitor may also be prepared in a manner described hereinbefore in Examples 1 to 3 for use in lowering serum cholesterol.
Patent CitationsCited PatentFiling datePublication dateApplicantTitleUS3674836 *Apr 24, 1969Jul 4, 1972Parke Davis & Co2,2-dimethyl-{11 -aryloxy-alkanoic acids and salts and esters thereofUS3910931 *Nov 15, 1974Oct 7, 1975Wyeth John & Brother Ltd1-(Naphthylalkyl- or indenylalkyl)-piperidinesUS4289781 *Aug 14, 1980Sep 15, 1981Astra Lakemedel AktiebolagAnti-psychotic phthalimidine derivativesUS4346277 *Apr 22, 1981Aug 24, 1982Eaton CorporationPackaged electrical heating elementUS4367232 *Oct 27, 1977Jan 4, 1983Fordonal, S.A.Piperidine derivativesUS4576940 *Aug 10, 1984Mar 18, 1986Yoshitomi Pharmaceutical Industries, Ltd.Anti-allergic 3-indolecarboxamidesUS4581355 *Dec 12, 1984Apr 8, 1986Yoshitomi Pharmaceutical Industries, Ltd.3-indolecarboxamides for control of circulatory diseasesUS4607042 *Feb 25, 1985Aug 19, 1986John Wyeth & Brother Ltd.Method for increasing plasma high density lipoprotein (HDL)US4826975 *Dec 10, 1986May 2, 1989Maggioni-Winthrop S.P.A.Fused cycloaliphatic aminoalcoholsUS5026858 *Apr 5, 1985Jun 25, 1991Walton S.A.Used for treating nausea, vomating, gastrointestinal disorders and centarl nervous systemUS5028616 *Sep 5, 1989Jul 2, 1991G. D. Searle & Co.N-benzylpiperidine amidesUS5032598 *Dec 8, 1989Jul 16, 1991Merck & Co., Inc.Nitrogens containing heterocyclic compounds as class III antiarrhythmic agentsUS5098915 *Sep 5, 1989Mar 24, 1992G. D. Searle & Co.Antiarrhythmia agentsUS5130333 *Oct 19, 1990Jul 14, 1992E. R. Squibb & Sons, Inc.Method for treating type II diabetes employing a cholesterol lowering drugUS5189045 *May 17, 1991Feb 23, 1993Adir Et CompagnieAntiserotonine agentUS5212182 *Oct 3, 1990May 18, 1993American Home Products CorpoorationSubstituted quinolinyl- and naphthalenylbenzamides or benzylamines and related compounds useful as analgesicsUS5215989 *Jul 15, 1991Jun 1, 1993Merck & Co., Inc.Nitrogen-containing heterocyclic compounds as class III antiarrhythmic agentsUS5292883 *May 27, 1993Mar 8, 1994Hoechst-Roussel Pharmaceuticals Incorporated2-(4-piperidinyl)-1H-pyrido[4,3-B]indol-1-ones and related compoundsUS5470845 *Jul 5, 1994Nov 28, 1995Bristol-Myers Squibb CompanyMethods of using α-phosphonosulfonate squalene synthetase inhibitors including the treatment of atherosclerosis and hypercholesterolemiaUS5527801 *Sep 14, 1992Jun 18, 1996Dainippon Pharmaceutical Co., Ltd.Ameliorant for blood lipid metabolismEP0584446A2 *Mar 8, 1993Mar 2, 1994E.R. SQUIBB &amp; SONS, INC.Microsomal triglyceride transfer proteinEP0643057A1 *Sep 2, 1994Mar 15, 1995Bristol-Myers Squibb CompanyInhibitors of microsomal triglyceride transfer proteinWO1993005778A1 *Sep 14, 1992Apr 1, 1993Dainippon Pharmaceutical CoBlood lipid metabolism ameliorantWO1996040640A1 *Jun 7, 1995Dec 19, 1996George ChangBIPHENYL-2-CARBOXYLIC ACID-TETRAHYDRO-ISOQUINOLIN-6-YL AMIDE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS INHIBITORS OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN AND/OR APOLIPOPROTEIN B (Apo B) SECRETIONWO1997026240A1 *Jan 13, 1997Jul 24, 1997Squibb Bristol Myers CoConformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method* Cited by examinerNon-Patent CitationsReference1 *Archibald, J. L., et al., Journal of Medicinal Chemistry, vol. 14, No. 11, pp. 1054 1059 (1971).2Archibald, J. L., et al., Journal of Medicinal Chemistry, vol. 14, No. 11, pp. 1054-1059 (1971).3 *Bulleid & Freedman, Nature 335, 649 651 (1988). Defective co translational formation of disulphide bonds in protein disulphideisomerase deficient microsomes .4Bulleid & Freedman, Nature 335, 649-651 (1988). "Defective co-translational formation of disulphide bonds in protein disulphideisomerase-deficient microsomes".5 *Conn s Current Therapy, W.B. Saunders Company, pp. 504 509, 1992.6Conn's Current Therapy, W.B. Saunders Company, pp. 504-509, 1992.7 *Cortizo, L. et al., J. Med. Chem., 34, pp. 2242 2247, 1991.8Cortizo, L. et al., J. Med. Chem., 34, pp. 2242-2247, 1991.9 *Drayna et al., Nature 327, 632 634 (1987). Cloning and sequencing of human cholesteryl ester transfer protein cDNA .10Drayna et al., Nature 327, 632-634 (1987). "Cloning and sequencing of human cholesteryl ester transfer protein cDNA".11 *Edman et al., Nature 317, 267 270 (1985). Sequence of protein disulphide isomerase and implications of its relationship to thioredoxin.12Edman et al., Nature 317, 267-270 (1985). Sequence of protein disulphide isomerase and implications of its relationship to thioredoxin.13 *Hall, I. H. et al., Pharmaceutical Research, vol. 9, No. 10, pp. 1324 1329, 1992.14Hall, I. H. et al., Pharmaceutical Research, vol. 9, No. 10, pp. 1324-1329, 1992.15 *Hall, I. H., et al., Pharmacological Research Communications, vol. 19, No. 12, pp. 839 858, 1987.16Hall, I. H., et al., Pharmacological Research Communications, vol. 19, No. 12, pp. 839-858, 1987.17 *Kane & Havel in the Metabolic Basis of Inherited Disease, Sixth Edition, 1139 1164 (1989). Disorders of the Biogenesis and Secretion of Lipoproteins Containing The B Apolipoproteins .18Kane & Havel in the Metabolic Basis of Inherited Disease, Sixth Edition, 1139-1164 (1989). "Disorders of the Biogenesis and Secretion of Lipoproteins Containing The B Apolipoproteins".19 *Kao et al., Connective Tissue Research 18, 157 174 (1988). Isolation of cDNA Clones and Genomic DNA Clones of Subunit of Chicken Prolyl 4 Hydroxylase* .20Kao et al., Connective Tissue Research 18, 157-174 (1988). "Isolation of cDNA Clones and Genomic DNA Clones of β-Subunit of Chicken Prolyl 4-Hydroxylase*".21 *Koivu et al., J. Biol. Chem. 262, 6447 6449 (1987). A Single Polypeptide Acts Both as the Subunit of Prolyl 4 Hydroxylase and as a Protein Disulfide Isomerase* .22Koivu et al., J. Biol. Chem. 262, 6447-6449 (1987). "A Single Polypeptide Acts Both as the β Subunit of Prolyl 4-Hydroxylase and as a Protein Disulfide-Isomerase*".23 *Morton, R.E. et al., J. Biol. Chem. 256, 1992 1995 (1981). A Plasma Inhibitor of Triglyceride and Chloesteryl Ester Transfer Activities .24Morton, R.E. et al., J. Biol. Chem. 256, 1992-1995 (1981). "A Plasma Inhibitor of Triglyceride and Chloesteryl Ester Transfer Activities".25 *Murthy et al., Eur. J. Med. Chem. Chim. Ther., vol. 20, No. 6, pp. 547 550, 1985.26Murthy et al., Eur. J. Med. Chem.--Chim. Ther., vol. 20, No. 6, pp. 547-550, 1985.27 *Pihlajaniemi et al., EMBO J. 6, 643 649 (1987). Molecular cloning of the subunit of human prolyl 4 hydroxylase. This subunit and protein disulphide isomerase are products of the same gene .28Pihlajaniemi et al., EMBO J. 6, 643-649 (1987). "Molecular cloning of the β-subunit of human prolyl 4-hydroxylase. This subunit and protein disulphide isomerase are products of the same gene".29 *Presentation Materials, Aspen Bile Acid/Cholesterol Conference, Aug. 15, 1992.30 *Schaefer et al., Clin. Chem. 34, B9 B12 (1988). Genetics and Abnormalities in Metabolism of Lipoproteins .31Schaefer et al., Clin. Chem. 34, B9-B12 (1988). "Genetics and Abnormalities in Metabolism of Lipoproteins".32 *Wetterau, J. and Zilversmit, D.B., Biochimica et Biophysica Acta 875, 610 617 (1986). Localization of intracellular triacylglycerol and cholesteryl ester transfer activity in rat tissues .33Wetterau, J. and Zilversmit, D.B., Biochimica et Biophysica Acta 875, 610-617 (1986). "Localization of intracellular triacylglycerol and cholesteryl ester transfer activity in rat tissues".34 *Wetterau, J. and Zilversmit, D.B., Chem. and Phys. of Lipids 38, 205 22 (1985). Purification and Characterization of Microsomal Triglyceride and Cholesteryl Ester Transfer Protein From Bovine Liver Microsomes .35Wetterau, J. and Zilversmit, D.B., Chem. and Phys. of Lipids 38, 205-22 (1985). "Purification and Characterization of Microsomal Triglyceride and Cholesteryl Ester Transfer Protein From Bovine Liver Microsomes".36 *Wetterau, J. and Zilversmit, D.B., J. Biol. Chem. 259, 10863 10866 (1984), A Triglyceride and Cholestryl Ester Transfer Protein Associated with Liver Microsomes .37Wetterau, J. and Zilversmit, D.B., J. Biol. Chem. 259, 10863-10866 (1984), "A Triglyceride and Cholestryl Ester Transfer Protein Associated with Liver Microsomes".38 *Wetterau, J. et al., Biochem 30, 9728 9735 (1991). Protein Disulfide Isomerase Appears Necessary To Maintain the Catalytically Active Structure of the Microsomal Triglyceride Transfer Protein .39Wetterau, J. et al., Biochem 30, 9728-9735 (1991). "Protein Disulfide Isomerase Appears Necessary To Maintain the Catalytically Active Structure of the Microsomal Triglyceride Transfer Protein".40 *Wetterau, J. et al., Biochem. 30, 4406 4412 (1991): Structural Properties of the Microsomal Triglyceride Transfer Protein Complex .41Wetterau, J. et al., Biochem. 30, 4406-4412 (1991): "Structural Properties of the Microsomal Triglyceride-Transfer Protein Complex".42 *Wetterau, J. et al., J. Biol. Chem. 265, 9800 9807 (1990). Protein Disulfide Isomerase Is a Component of the Microsomal Triglyceride Transfer Protein Complex .43Wetterau, J. et al., J. Biol. Chem. 265, 9800-9807 (1990). "Protein Disulfide Isomerase Is a Component of the Microsomal Triglyceride Transfer Protein Complex".44 *Wetterau, J. R., et al., Science, vol. 258, 999 1001, Nov. 6, 1992, Absence of Microsomal Triglyceride Transfer Protein in Individuals with Abetalipoproteinemia .45Wetterau, J. R., et al., Science, vol. 258, 999-1001, Nov. 6, 1992, "Absence of Microsomal Triglyceride Transfer Protein in Individuals with Abetalipoproteinemia".46Wetterau, J., Grant Application entitled: "Intracellular Triglyceride Transport and Metabolism". (1987).47 *Wetterau, J., Grant Application entitled: Intracellular Triglyceride Transport and Metabolism . (1987).48 *Yamaguchi et al., Biochem. Biophys. Res. Comm. 146, 1485 1492 (1987). Sequence of Membrane Associated Thyroid Hormone Binding Protein From Bovine Liver: Its Identity with Protein Disulphide Isomerase .49Yamaguchi et al., Biochem. Biophys. Res. Comm. 146, 1485-1492 (1987). "Sequence of Membrane-Associated Thyroid Hormone Binding Protein From Bovine Liver: Its Identity with Protein Disulphide Isomerase".* Cited by examinerReferenced byCiting PatentFiling datePublication dateApplicantTitleUS6444225 *Sep 16, 1998Sep 3, 2002Bernard Charles ShermanBioavailability;melting, solidificationUS6756364 *Jul 25, 2001Jun 29, 2004Hoffmann-La Roche Inc.Method of reducing gastrointestinal side effects associated with orlistat treatmentUS6982281Nov 17, 2000Jan 3, 2006Lipocine IncPharmaceutical compositions and dosage forms for administration of hydrophobic drugsUS7001919Dec 14, 2000Feb 21, 2006Teva Gyogyszergyar ReszvenytarsasagCrystallization from solvent systemUS7262218Aug 9, 2005Aug 28, 2007Teva Gyogyszergyar Zartkoruen Mukodo ReszvenytarsasagPolymorphic forms are suitable for use as active substances of pharmaceutical dosage forms for reduction of serum cholesterol levels in the bloodstreamUS7425644Nov 23, 2004Sep 16, 2008TEVA Gy�gyszergy�r Z�rtk�rűen Műk�dő R�szv�nyt�rsas�gMeasuring level of compactin C in samples; selecting a compactin batch that comprises little compactin C; synthesizing pravastin having little pravastin C by hydroxylation of fermentation of compactinUS7932268 *Mar 7, 2005Apr 26, 2011The Trustees Of The University Of PennsylvaniaMethods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effectsUS8071571Apr 20, 2010Dec 6, 2011Hoffman-La Roche Inc.Orlistat compositionsUS8618135Mar 11, 2011Dec 31, 2013The Trustees Of The University Of PennsylvaniaMethods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effectsUS20130102635 *Apr 11, 2012Apr 25, 2013Gerald L. WislerMethods for Treating Disorders Associated with Hyperlipidemia in a MammalEP1099438A2 *Nov 3, 2000May 16, 2001Pfizer Products Inc.Use of APO B secretion/MTP inhibitorsWO2001043723A1 *Dec 14, 2000Jun 21, 2001Judith AronhimeNovel forms of pravastatin sodiumWO2005087234A1 *Mar 7, 2005Sep 22, 2005Univ PennsylvaniaMethods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effectsWO2013106358A1 *Jan 9, 2013Jul 18, 2013Hussain M MahmoodMethod of treating hyperlipidemia and atherosclerosis with mir-30c* Cited by examinerClassifications U.S. Classification514/321, 514/824, 514/325International ClassificationA61K31/445, A61K31/4468, A61K31/454, A61K31/22, A61K31/351, A61P3/06, A61K31/38, A61K45/06Cooperative ClassificationY10S514/824, A61K45/06European ClassificationA61K45/06Legal EventsDateCodeEventDescriptionSep 16, 2010FPAYFee paymentYear of fee payment: 12Aug 28, 2006FPAYFee paymentYear of fee payment: 8Aug 9, 2006ASAssignmentOwner name: THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, PEFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BRISTOL-MYERS SQUIBB COMPANY;REEL/FRAME:018075/0248Effective date: 20060522Aug 7, 2006ASAssignmentOwner name: UNIVERSITY OF PENNSYLVANIA, PENNSYLVANIAFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BRISTOL-MYERS SQUIBB COMPANY;REEL/FRAME:018061/0206Effective date: 20060522Aug 22, 2002FPAYFee paymentYear of fee payment: 4May 12, 1997ASAssignmentOwner name: BRISTOL-MYERS SQUIBB COMPANY, NEW JERSEYFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GREGG, RICHARD E.;POULEUR, HUBERT G.;WETTERAU, JOHN R., II;REEL/FRAME:008555/0161;SIGNING DATES FROM 19970430 TO 19970508RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google