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WO1998050028A1 - Combinaisons therapeutiques d'inhibiteur de mtp et de vitamine liposoluble destinees a reduire les taux de lipides seriques - Google Patents

Combinaisons therapeutiques d'inhibiteur de mtp et de vitamine liposoluble destinees a reduire les taux de lipides seriques Download PDF

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Publication number
WO1998050028A1
WO1998050028A1 PCT/US1998/008269 US9808269W WO9850028A1 WO 1998050028 A1 WO1998050028 A1 WO 1998050028A1 US 9808269 W US9808269 W US 9808269W WO 9850028 A1 WO9850028 A1 WO 9850028A1
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Prior art keywords
alkyl
aryl
heteroaryl
arylalkyl
alkenyl
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PCT/US1998/008269
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English (en)
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Richard E. Gregg
John R. Ii Wetterau
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Bristol-Myers Squibb Company
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Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to EP98918680A priority Critical patent/EP1024804A4/fr
Priority to JP54813898A priority patent/JP2001527551A/ja
Priority to AU71559/98A priority patent/AU748608B2/en
Priority to CA002286341A priority patent/CA2286341A1/fr
Publication of WO1998050028A1 publication Critical patent/WO1998050028A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a combination of an MTP inhibitor and a fat soluble vitamin such as Vitamin E, Vitamin A, Vitamin K and/or Vitamin D, and optionally another cholesterol lowering drug, for example, an HMG CoA reductase inhibitor, such as pravastatin, lovastatin or simvastatin, and to a method for lowering serum lipids, cholesterol and/or triglycerides in mammalian species by administering such combination.
  • a fat soluble vitamin such as Vitamin E, Vitamin A, Vitamin K and/or Vitamin D
  • another cholesterol lowering drug for example, an HMG CoA reductase inhibitor, such as pravastatin, lovastatin or simvastatin
  • MTP microsomal triglyceride transfer protein
  • a novel combination which includes an MTP inhibitor and a fat soluble vitamin such as Vitamin E, Vitamin A, Vitamin K and/or Vitamin D, and optionally another cholesterol lowering agent.
  • a method for preventing, inhibiting or treating atherosclerosis, pancreatitis, hyperglycemia, or obesity is provided, wherein an MTP inhibitor in combination with a fat soluble vitamin such as Vitamin E, Vitamin A, Vitamin K and/or Vitamin D, and optionally another cholesterol lowering drug, is administered in therapeutically effective amounts to lower LD cholesterol and triglycerides .
  • a method 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 a fat soluble vitamin such as Vitamin E, Vitamin A, Vitamin K and/or Vitamin D, and optionally another cholesterol lowering drug, is administered in therapeutically effective amounts .
  • MTP inhibitors inhibit the production of triglyceride rich plasma Hpoproteins, very low density
  • Vitamins E, A, K and D are fat soluble vitamins which are, in part, transported throughout the body on these Hpoproteins, or Hpoproteins which are metabolic products of these Hpoproteins . Because MTP inhibitors block lipoprotein production, they may interfere with the normal absorption and transport of fat soluble vitamins . Abnormal absorption of fat soluble vitamins has been observed in abetalipoproteinemic subjects who lack MTP due to a genetic defect in the gene encoding MTP.
  • Fat soluble vitamin supplements in abetalipoproteinemic subjects ameliorate most if not all the complications associated with fat soluble vitamin deficiencies (Kane, J.P., et al, "Disorders of the Biogenesis and Secretion of Lipoproteins Containing the B Apolipoproteins" , Chapter 57, pp. 1853-1885, "The Metabolic and Molecular Bases of Inherited Disease", 7th Ed., Vol. 11 (1995)) .
  • Vitamins E, A, K, and/or D supplements in subjects treated with an MTP inhibitor will ameliorate adverse effects of MTP inhibitors associated with fat soluble vitamin deficiencies.
  • Cholesterol lowering drugs or drugs which are inhibitors of cholesterol biosynthesis which may optionally be used in combination with the MTP inhibitor and the fat soluble vitamin include HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, bile acid sequestrants, probucol, niacin, niacin derivatives, neomycin, aspirin, and the like.
  • the combination of MTP inhibitor and other cholesterol lowering drug which works by a mechanism other than inhibiting MTP, together with a fat soluble vitamin is a surprising and unique concept in treating diseases involved with elevated cholesterol and/or triglycerides and atherosclerosis, hyperglycemia, obesity and/or pancreatitis, in that the combination may provide additional anticholesterolemic effects over that which may be obtained using each of the cholesterol lowering 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.
  • 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.
  • an organism e. g., cows, humans, etc..
  • treating atherosclerosis includes stabilizing atherosclerosis and/or causing the regression of atherosclerosis.
  • stabilizing atherosclerosis refers to slowing down the development of and/or inhibiting the formation of new atherosclerotic lesions.
  • fat soluble vitamin refers to Vitamin E, Vitamin A, Vitamin K or Vitamin D, including combinations of any two or more of the above vitamins.
  • pancreatitis refers to pancreatitis which is secondary to hypertriglyceridemia .
  • preventing, inhibiting or treating hyperglycemia refers to preventing, inhibiting or treating hyperglycemia or diabetes (Type I or II) by
  • “obesity” as employed herein refers to preventing, inhibiting or treating obesity by causing reduced malabsorption of dietary fat through MTP inhibition.
  • the pharmaceutical combination of the invention will preferably include Vitamin E in an amount within the range from about 100 to about 15,000 mg/day, preferably from about 200 to about 5,000 mg/day. Where present, Vitamin A will be employed in an amount within the range from about 1,000 to about 50,000 International Units (IU)/day, preferably from about 10,000 to about 35,000 IU/day.
  • Vitamin E in an amount within the range from about 100 to about 15,000 mg/day, preferably from about 200 to about 5,000 mg/day.
  • Vitamin A will be employed in an amount within the range from about 1,000 to about 50,000 International Units (IU)/day, preferably from about 10,000 to about 35,000 IU/day.
  • Vitamin K will be employed in an amount within the range from about 0.1 to about 25 mg/day, preferably from about 5 to about 15 mg/day.
  • Vitamin D will be employed in an amount within the range from about 50 to about 1,000
  • IU/day preferably from about 100 to about 400 IU/day.
  • Preferred combinations of vitamins include Vitamin E and Vitamin A in amounts of each as set out above.
  • Vitamin K and Vitamin E in amounts of each as set out above .
  • Vitamin D and Vitamin E in amounts of each as set out above .
  • the combination of the MTP inhibitor and other cholesterol lowering drug will be employed in a weight ratio to each other within the range of from about 1000:1 to about 0.001:1 and preferably from about 100:1 to about
  • 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.
  • X is. CHR 8 , ' -
  • R 8 , R 9 and R 10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl , cycloalkyl, or cycloalkylalkyl;
  • Y is -(CH 2 ) m - or — C—
  • R 1 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, cycloalkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl, hydroxy or ox
  • R 1 is an indenyl-type group of the structure
  • Z 1 and Z 2 are the same or different and are independently a bond, 0, S, » . f » ⁇ ' -NH-C- ,-N C- , -C- or -C- ,
  • R 11 is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms; arylene or mixed arylenealkylene;
  • R 12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl , heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl, with the provisos that (1) when R 12 is H, aryloxy, alkoxy or arylalkoxy,
  • Z 2 is O alkyl O o or a bond
  • R 12 when Z 2 is a bond, R 12 cannot be heteroaryl or heteroarylalkyl ;
  • Z is bond, 0, S, N-alkyl, N-aryl, or alkylene or alkenylene from 1 to 5 carbon atoms;
  • R 13 , R 14 , R 15 , and R 16 are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl , alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl or aryloxy;
  • R 15a and R 16a 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 R 1 is a group of the structure
  • R 18 wherein p is 1 to 8 and R 17 and R 18 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl at least one of R 17 and R 18 being other than H; or R 1 is a group of the structure s20
  • R 19 is aryl or heteroaryl
  • R 20 is aryl or heteroaryl
  • R 21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or eyeloalkylalkoxy;
  • R 2 , R 3 , R 4 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl;
  • R 5 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, cyclo
  • R 6 is hydrogen or C 1 -C 4 alkyl or C 1 -C 4 alkenyl; all optionally substituted with 1, 2, 3 or 4 groups which may independently be any of the substituents listed in the definition of R 5 set out above;
  • R 7 is alkyl, aryl or arylalkyl wherein alkyl by itself or as part of arylalkyl is optionally substituted with oxo " ' ;
  • R5 is heteroaryl, aryl, heterocycloalkyl or cycloalkyl, each R ⁇ group being optionally substituted with 1, 2, 3 or 4 substituents which may be the same or different.
  • R 5 where R 5 is H or lower alkyl or R 5 together with R 2 forms a carbocyclic or heterocyclic ring system containing 4 to 8 members in the ring.
  • B is a fluorenyl-type group of the structure
  • B is an indenyl-type group of the structure
  • R x is H, alkyl or aryl
  • R 1 is H, 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, cycloheteroalkyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, -PO (R 13 ) (R 14 ) , (where R 13 and
  • heterocycle (where the heterocycle is connected to the carbonyl group via a nitrogen or carbon atom) , alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,
  • R v» 2 24 ' )25 ,24 p25 R 23 , R 24 and R 25 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
  • R 20 , R 21 , R 22 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 R 1 , or attached via an alkylene at an open position;
  • R 2 is independently any of the groups set out for R 1 , H, polyhaloalkyl , or cycloheteroalkyl, and may be optionally substituted with one to four of any of the groups defined for R 3 or substituents defined for R 1 ;
  • L 1 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, and may be substituted with one to five alkyl or halo groups;
  • L 2 may be the same or different from L 1 and may independently be any of the L 1 groups set out above or a singe bond;
  • R 3 , R 3 ' , R 4 and R 4 ' may be the same or different and are independently selected from H, halogen, CF , haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, amino, thiol, alkylthio, alkyIsulfinyl, 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 ary
  • 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:
  • R 6 is H, lower alkyl, aryl, -C(0)-R n or
  • R 7 and R 8 are the same or different and are independently H, alkyl, aryl, halogen, -O-R 12 , or
  • R 7 and R 8 together can be oxygen to form a ketone
  • R 9 , R 10 , R 9 ' and R 10 ' are the same or different and are independently H, lower alkyl, aryl or -O-R 11 ;
  • R 9 " and R 10 " are the same or different and are independently H, lower alkyl, aryl, halogen or
  • R 11 is alky or aryl
  • R 12 is H, alkyl or aryl; with the following provisos for compound of the
  • W is H, H or 0 ;
  • R 8 , R 9 and R 10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
  • R 1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl (wherein alkyl preferably has at least 2 carbons, more preferably at least 3 carbons) , diarylalkyl, arylalkenyl, diarylalkenyl , arylalkynyl, diarylalkynyl , diarylalkylaryl , heteroarylalkyl (wherein alkyl preferably has at least 2 carbons, more preferably at least 3 carbons) , cycloalkyl, or cycloalkylalkyl (wherein alkyl preferably has at least 2 carbons, more preferably at least 3 carbons) ; all of the aforementioned R 1 groups being optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from halo, haloalkyl, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmer
  • R 1 is a fluorenyl-type group of the structure
  • R 1 is an indenyl-type group of the structure
  • Z 1 and Z 2 are the same or different and are independently a bond, 0, S,
  • R 11 is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms, arylene (for example
  • n 1 to 6;
  • R 12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl , trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl; with the provisos that (1) when R 12 is H, aryloxy, alkoxy or
  • Z is a bond, 0, S, N-alkyl, N-aryl, or alkylene or alkenylene of from 1 to 5 carbon atoms;
  • R 13 , R 14 , R 15 , and R 16 are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy;
  • R 15a and R 16 are independently any of the R 15 or R 16 groups except hydroxy, nitro, amino or thio; or R 1 is
  • R 17 (CH 2 ) P ⁇ R 18 wherein p is 1 to 8 and R 17 and R 18 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, at least one of R 17 and R 18 being other than H;
  • R 21 wherein R 19 is aryl or heteroaryl; R 20 is aryl or heteroaryl; R 21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or eyeloalkylalkoxy;
  • R 2 , R 3 , R 4 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl;
  • R 5 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 R 5 substituents and R 6 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,
  • R 5 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 ;
  • R 6 is hydrogen or C 1 -C 4 alkyl or C 1 -C 4 alkenyl
  • 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
  • O Xis:CHR 8 , — R 8 , R 9 and R 10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
  • R 1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl (wherein alkyl preferably has at least 2 carbons, more preferably at least 3 carbons) , diarylalkyl, arylalkenyl, diarylalkenyl , arylalkynyl, diarylalkynyl , diarylalkylaryl, heteroarylalkyl (wherein alkyl preferably has at least 2 carbons, more preferably at least 3 carbons), cycloalkyl, or cycloalkylalkyl (wherein alkyl preferably has at least 2 carbons, more preferably at least 3 carbons) ; all of the aforementioned R 1 groups being optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from halo, haloalkyl, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto,
  • R 1 is a fluorenyl-type group of the structure
  • R 1 is an indenyl-type group of the structure
  • Z 1 and Z 2 are the same or different and are independently a bond, 0, S,
  • R 11 is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms, arylene (for example
  • R 12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl , trihaloalkylalkyl , heteroaryl , heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl; with the provisos that (1) when R 12 is H, aryloxy, alkoxy
  • Z 2 is 0 alkyl 0 > 0 or a bond; and (2) when Z 2 is a bond, R 12 cannot be heteroaryl or heteroarylalkyl ;
  • Z is a bond, 0, S, N-alkyl, N-aryl, or alkylene or alkenylene of from 1 to 5 carbon atoms;
  • R 13 , R 14 , R 15 , and R 16 are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino , arylalkyl , heteroaryl , heteroarylalkyl , or aryloxy;
  • R 15a and R 16 are independently any of the R 15 or R 16 groups except hydroxy, nitro, amino or thio; or R 1 is
  • R 17 and R 18 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, at least one of R 17 and R 18 being other than H; or R 1 is
  • R 21 wherein R 19 is aryl or heteroaryl; R 20 is aryl or heteroaryl;
  • R 21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or cycloalkylalkoxy;
  • R 2 , R 3 , R 4 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl , hydroxy or haloalkyl ;
  • R 5 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 R 5 substituents and R 6 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, halo
  • R 5 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; R 6 is hydrogen or C 1 -C 4 alkyl or C 1 -C 4 alkenyl;
  • MTP inhibitors to be employed in accordance with the present invention include preferred MTP inhibitors as set out in U.S. patent application Serial No. 548,811, filed January 11, 1996 (file DC21h) and in U.S. Application Serial No. 08/767,923, filed December 17, 1996 (file HX79c*) .
  • X 1 and X 2 are H; R 5 is aryl such as phenyl substituted with
  • aryl such as phenyl cl
  • R 5 is heteroaryl such as or substituted with o ⁇ c-
  • A is NH
  • B is
  • X is a bond, oxygen or sulfur; R 3 and R 4 are independently H or F.
  • Preferred R 1 groups in Application Serial No. 08/767,923 are aryl, preferably phenyl, heteroaryl, preferably imidazoyl, benzimidazolyl, indolyl, or pyridyl (preferably substituted with one of the preferred R 1 substituents : arylcarbonylamino, heteroarylcarbonylamino , cycloalkylcarbonylamino, alkoxycarbonylamino , alkylsulfonylamino, arylsulfonylamino, heteroaryl- sulfonylamino) , PO(OAlkyl) 2 , heteroarylthio, benzthiazole- 2-thio, imidazole-2-thio, alkyl, or alkenyl, cycloalkyl such as cyclohexyl, or 1, 3-dioxan-2-yl .
  • R 2 groups are alkyl, polyfluoroalkyl (such as 1, 1, 1-trifluoroethyl) , alkenyl, aryl or heteroaryl (preferably substituted with one of the preferred R 1 substituents above), or PO(OAlkyl) 2 -
  • R 2 is alkyl, 1, 1, 1-trifluoroethyl, or alkenyl, it is preferred that R 1 is other than alkyl or alkenyl .
  • L 1 contains 1 to 5 atoms in the linear chain and L 2 is a bond or lower alkylene.
  • Preferred embodiments of formula IA and formula IB compounds in Application Serial No. 08/767,923 include those where B, L 1 , L 2 , R 1 and R 2 are as set out with respect to the preferred embodiments of the formula I compounds, q is 0 or 2 and R x is H.
  • A is NH
  • L 2 is a bond
  • R 2 is CF 3 CH 2 , ,
  • L 1 is -CH 2 CH 2 CH 2 - or -CH2CH2CH2CH2-, and R 1 is heteroaryl which is a 5-membered aromatic ring which includes 2 nitrogens, which ring is fused to an aryl ring and is substituted on the aryl moiety.
  • R 1 groups include substituted benzimidazole groups including
  • Most preferred pharmaceutical combinations of the invention include an MTP inhibitor (such as a preferred MTP inhibitor as set out above) in combination with Vitamin E.
  • Other preferred pharmaceutical combinations of the invention include a preferred MTP inhibitor in combination with Vitamin E and Vitamin A.
  • 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.
  • HMG CoA reductase inhibitors suitable for use herein include, but are not limited to, mevastatin and related compounds as disclosed in U.S. Patent No. 3,983,140, lovastatin (mevinolin) and related compounds as disclosed in U.S. Patent No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Patent No. 4,346,227, simvastatin and related compounds as disclosed in U.S. Patent Nos. 4,448,784 and 4,450,171, and atorvastatin, with pravastatin, atorvastatin, lovastatin or simvastatin being preferred.
  • HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, cerivastatin, pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Patent 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. Patent No.
  • phosphinic acid compounds useful in inhibiting HMG CoA reductase suitable for use herein are disclosed in GB 2205837.
  • the squalene synthetase inhibitors suitable for use herein include, but are not limited to, -phosphono- sulfonates disclosed in U.S. application Serial No. 08/266,888, filed July 5, 1994 (HX59b) , those disclosed by Biller et al, J. Med. Chem. 1988, Vol. 31, No.
  • squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chem.; 1977, 2Q_, 243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc. 1976, 98, 1291-1293, phosphinylphosphonates reported by McClard, R.W.
  • pravastatin pravastatin
  • lovastatin lovastatin
  • simvastatin Preferred are pravastatin, lovastatin or simvastatin. All of the above U.S. applications are incorporated herein by reference .
  • cholesterol lowering drugs suitable for use herein include, but are not limited to, antihyperlipoproteinemic agents such as fibric acid derivatives, such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol, and related compounds as disclosed in U.S. Patent No.
  • bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex (Secholex ® , Polidexide ® ) , as well as clofibrate, lipostabil (Rhone-Poulenc) , Eisai E-5050 (an N- substituted ethanolamine derivative) , imanixil (HOE-402) , tetrahydrolipstatin (THL) , istigmastanylphosphorylcholine (SPC, Roche) , aminocyclodextrin (Tanabe Seiyoku) , Ajinomoto AJ-814 (azulene derivative) , melinamide (Sumitomo) , Sandoz 58-035, American Cyanamid C -277,082 and C -283,546 (disubstituted urea derivatives) , nicotinic acid, aciprofidex , cholestyramine, col
  • the MTP inhibitor in combination with the fat soluble vitamin namely, Vitamin E, Vitamin A, Vitamin K and/or Vitamin D, and optionally the other 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, anti-bacterial, 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.
  • the dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.
  • the MTP inhibitor 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; and the fat soluble vitamin as set out hereinbefore.
  • 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; and the fat soluble vitamins will be employed as follows : where present, Vitamin E will be employed in an amount within the range preferably to provide from about 200 to about 5,000 mg/day;
  • Vitamin A will be employed in an about within the range preferably to provide from about 10,000 to about 35,000 IU;
  • Vitamin K will be employed in an amount within the range preferably to provide from about 5 to about 15 mg/day;
  • Vitamin D will be employed in an amount within the range preferably to provide from about 100 to about 400 IU/day.
  • the MTP inhibitor will be employed in an amount within the range from about 0.005 mg/kg to about 10 mg/kg and preferably from about 0.005 mg/kg to about 8 mg/kg, while the fat soluble vitamin will be employed in amounts conventionally used in parental administration of such vitamins .
  • HMG CoA reductase inhibitor for oral administration, a satisfactory result may be obtained employing the HMG CoA reductase inhibitor in dosages employed, for example, for pravastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin and lovastatin, as indicated in the Physician's Desk Reference, or in the patents which disclose these compounds, such as in an amount within the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.
  • the squalene synthetase inhibitor may be employed in dosages in an amount within the range of from about 10 mg to about 2000 mg and preferably from about 25 mg 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 other serum cholesterol lowering drugs when present will be employed in dosages normally employed as indicated in the Physician's Desk Reference, for each of such agents such as in an amount within the range of from about 2 mg to about 7500 mg and preferably from about 2 mg to about 4000 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.
  • compositions described above may be administered in the dosage forms as described above in single or divided doses of one to four times daily. It may be advisable to start a patient on a low dose combination and work up gradually to a high dose combination.
  • Tablets of various sizes can be prepared, e.g., of about 2 to 2000 mg in total weight, containing one or both of the active substances in the ranges described above, with the remainder being a physiologically acceptable carrier of other materials according to accepted pharmaceutical practice. These tablets can, of course, be scored to provide for fractional doses .
  • Gelatin capsules can be similarly formulated.
  • Liquid formulations can also be prepared by dissolving or suspending one or the combination of active substances in a conventional liquid vehicle acceptable for pharmaceutical administration so as to provide the desired dosage in one to four teaspoonsful .
  • Such dosage forms can be administered to the patient on a regimen of one to four doses per day.
  • the active substances may be administered separately in individual dosage units at the same time or carefully coordinated times . Since blood levels are built up and maintained by a regulated schedule of administration, the same result is achieved by the simultaneous presence of the two substances.
  • the respective substances can be individually formulated in separate unit dosage forms in a manner similar to that described above. Fixed combinations of MTP inhibitor and fat soluble vitamin, and optionally other cholesterol lowering drug are more convenient and are preferred, especially in tablet or capsule form for oral administration.
  • the active substances in the amounts described above, are compounded according to accepted pharmaceutical practice with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in the particular type of unit dosage form.
  • Illustrative of the adjuvants which may be incorporated in tablets are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate or cellulose; a disintegrating agent such as corn starch, potato starch, alginic acid or the like; a lubricant such as stearic acid or magnesium stearate; a sweetening agent such as sucrose, aspartame, lactose or saccharin; a flavoring agent such as orange, peppermint, oil of wintergreen or cherry.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate or cellulose
  • a disintegrating agent such as corn starch, potato starch, alginic acid or the like
  • a lubricant such as stearic acid or magnesium stearate
  • a sweetening agent such as sucrose, as
  • tablets or capsules may be coated with shellac, sugar or both.
  • a syrup of elixir may contain the active compound, water, alcohol or the like as the carrier, glycerol as solubilizer, sucrose as sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange.
  • Some of the active substances described above form commonly known, pharmaceutically acceptable salts such as alkali metal and other common basic salts or acid addition salts, etc. References to the base substances are therefore intended to include those common salts known to be substantially equivalent to the parent compound.
  • 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.
  • 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 from the following ingredients.
  • Example 1 Example 2 Amount (mg/ Amount (mg/
  • 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.
  • the MTP inhibitor BMS 201,038, and colloidal silicon dioxide are blended in a suitable blender with lactose hydrous, microcrystalline cellulose, pregelatinized starch and a portion of sodium starch glycolate.
  • the resulting blend is wet granulated with water.
  • the wet granulation is dried in a suitable dryer .
  • the remaining portion of sodium starch glycolate is added to the granulation and mixed therein.
  • Magnesium stearate is added to the granulation and mixed therein.
  • the resulting blend is filled into capsules .
  • Example 3 and 4 MTP inhibitor (BMS 201,238) tablets and Vitamin E, Vitamin A, Vitamin K and/or Vitamin D in tablet or capsule form may be administered as a combination in accordance with the teachings of the present invention to lower serum cholesterol and to treat the various disease states mentioned above.
  • the vitamins and MTP inhibitor may be used together in a single capsule.
  • the pravastatin or any of the statins 2) -6), vitamins and MTP inhibitor tablets may be ground up into powders and used together in a single capsule.
  • Tablets containing 500 mg clofibrate in combination with 10 mg BMS 201,038 and fat soluble vitamin may be employed in separate dosage forms or combined in a single capsule form to lower serum cholesterol and to treat the various disease states mentioned above in accordance with the present invention.
  • Examples 1 . 8, 9 and 10 Ciprofibrate, bezafibrate, or fenofibrate, gemfibrozil in combination with fat soluble vitamins and an MTP inhibitor may also be prepared in a manner described hereinbefore in Examples 1 to 5 to treat the various diseases mentioned above.

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Abstract

La présente invention concerne une combinaison pharmaceutique comprenant un inhibiteur de MTP (protéine de transfert de triglycéride microsomale) et une vitamine liposoluble telle que les vitamines E, A, K et/ou D, et, facultativement, un autre médicament permettant de réduire le cholestérol. Ladite combinaison pharmaceutique est utilisée dans un procédé destiné à réduire les taux sériques de lipides, de cholestérol et/ou de triglycérides et, ce faisant, à prévenir ou traiter l'athérosclérose, la pancréatite, l'hyperglycémie et/ou l'obésité.
PCT/US1998/008269 1997-05-01 1998-04-23 Combinaisons therapeutiques d'inhibiteur de mtp et de vitamine liposoluble destinees a reduire les taux de lipides seriques WO1998050028A1 (fr)

Priority Applications (4)

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EP98918680A EP1024804A4 (fr) 1997-05-01 1998-04-23 Combinaisons therapeutiques d'inhibiteur de mtp et de vitamine liposoluble destinees a reduire les taux de lipides seriques
JP54813898A JP2001527551A (ja) 1997-05-01 1998-04-23 Ｍｔｐインヒビターと脂溶性ビタミンの組合せおよび該組合せを用いる血清脂質レベルの降下法
AU71559/98A AU748608B2 (en) 1997-05-01 1998-04-23 MTP inhibitors and fat soluble vitamin therapeutic combinations to lower serum lipid levels
CA002286341A CA2286341A1 (fr) 1997-05-01 1998-04-23 Combinaisons therapeutiques d'inhibiteur de mtp et de vitamine liposoluble destinees a reduire les taux de lipides seriques

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US4540597P 1997-05-01 1997-05-01
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001000183A3 (fr) * 1999-06-25 2001-05-10 Bayer Ag COMBINAISON D'INHIBITEURS DE MTP (PROTEINE DE TRANSFERT MICROSOMALE) ET INHIBITEURS DE HMG-CoA-REDUCTASE ET LEUR UTILISATION DANS DES MEDICAMENTS
WO2001000184A3 (fr) * 1999-06-25 2001-07-05 Bayer Ag Combinaison d'inhibiteurs de proteine de transfert microsomale (mtp) et d'agents hypolipidemiants et leur utilisation dans des medicaments
WO2001000189A3 (fr) * 1999-06-25 2001-08-02 Bayer Ag Combinaison d'inhibiteurs de mtp et principes actifs agissant sur le metabolisme et leur utilisation dans les medicaments
WO2004032968A1 (fr) * 2002-10-11 2004-04-22 Les Laboratoires Servier Association entre un compose heterocyclique favorisant les metabolismes glucidiques et lipidiques et un agent antioxydant dans le traitement de l'obesite
WO2007047725A3 (fr) * 2005-10-18 2007-07-12 Aegerion Pharmaceuticals Methodes permettant de traiter les troubles associes a l'hyperlipidemie chez un mammifere
CN103690960A (zh) * 2013-12-18 2014-04-02 北京科源创欣科技有限公司 甲磺酸洛美他派药物组合物及制备方法
US9265758B2 (en) 2004-03-05 2016-02-23 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
DE202017007052U1 (de) 2016-10-06 2019-04-18 Bioenergy Healthcare GmbH Lipidsenker

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FR2868313B1 (fr) * 2004-03-31 2008-08-15 Servier Lab Nouvelle association entre un compose heterocyclique et un agent antioxydant et les compositions pharmaceutiques qui les contiennent

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US3674836A (en) * 1968-05-21 1972-07-04 Parke Davis & Co 2,2-dimethyl-{11 -aryloxy-alkanoic acids and salts and esters thereof
US3983140A (en) * 1974-06-07 1976-09-28 Sankyo Company Limited Physiologically active substances
US5739135A (en) * 1993-09-03 1998-04-14 Bristol-Myers Squibb Company Inhibitors of microsomal triglyceride transfer protein and method

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001000183A3 (fr) * 1999-06-25 2001-05-10 Bayer Ag COMBINAISON D'INHIBITEURS DE MTP (PROTEINE DE TRANSFERT MICROSOMALE) ET INHIBITEURS DE HMG-CoA-REDUCTASE ET LEUR UTILISATION DANS DES MEDICAMENTS
WO2001000184A3 (fr) * 1999-06-25 2001-07-05 Bayer Ag Combinaison d'inhibiteurs de proteine de transfert microsomale (mtp) et d'agents hypolipidemiants et leur utilisation dans des medicaments
WO2001000189A3 (fr) * 1999-06-25 2001-08-02 Bayer Ag Combinaison d'inhibiteurs de mtp et principes actifs agissant sur le metabolisme et leur utilisation dans les medicaments
JP2003503342A (ja) * 1999-06-25 2003-01-28 バイエル アクチェンゲゼルシャフト ＭＴＰ阻害剤とＨＭＧ−ＣｏＡ還元酵素阻害剤との組み合わせ並びに薬剤におけるその使用
WO2004032968A1 (fr) * 2002-10-11 2004-04-22 Les Laboratoires Servier Association entre un compose heterocyclique favorisant les metabolismes glucidiques et lipidiques et un agent antioxydant dans le traitement de l'obesite
US9364470B2 (en) 2004-03-05 2016-06-14 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US9265758B2 (en) 2004-03-05 2016-02-23 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US9433617B1 (en) 2004-03-05 2016-09-06 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US9861622B2 (en) 2004-03-05 2018-01-09 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
US10016404B2 (en) 2004-03-05 2018-07-10 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects
US10555938B2 (en) 2004-03-05 2020-02-11 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects
US11554113B2 (en) 2004-03-05 2023-01-17 The Trustees Of The University Of Pennsylvania Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects
WO2007047725A3 (fr) * 2005-10-18 2007-07-12 Aegerion Pharmaceuticals Methodes permettant de traiter les troubles associes a l'hyperlipidemie chez un mammifere
CN103690960A (zh) * 2013-12-18 2014-04-02 北京科源创欣科技有限公司 甲磺酸洛美他派药物组合物及制备方法
DE202017007052U1 (de) 2016-10-06 2019-04-18 Bioenergy Healthcare GmbH Lipidsenker
DE202017007052U9 (de) 2016-10-06 2019-09-26 Bioenergy Healthcare GmbH Lipidsenker

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AU7155998A (en) 1998-11-27
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EP1024804A1 (fr) 2000-08-09
EP1024804A4 (fr) 2001-03-21

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