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WO1998003174A1 - Procede de traitement de tumeurs ayant des besoins eleves en lipoproteine de basse densite (ldl) a l'aide d'inhibiteurs de la proteine microsomale de transfert des triglycerides (mtp) - Google Patents

Procede de traitement de tumeurs ayant des besoins eleves en lipoproteine de basse densite (ldl) a l'aide d'inhibiteurs de la proteine microsomale de transfert des triglycerides (mtp) Download PDF

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Publication number
WO1998003174A1
WO1998003174A1 PCT/US1997/012158 US9712158W WO9803174A1 WO 1998003174 A1 WO1998003174 A1 WO 1998003174A1 US 9712158 W US9712158 W US 9712158W WO 9803174 A1 WO9803174 A1 WO 9803174A1
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Prior art keywords
alkyl
aryl
heteroaryl
ldl
independently
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PCT/US1997/012158
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English (en)
Inventor
Raymond A. Firestone
Original Assignee
Bristol-Myers Squibb Company
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Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to AU36008/97A priority Critical patent/AU712303C/en
Priority to JP50701298A priority patent/JP2002513379A/ja
Priority to EP97932594A priority patent/EP0954313A4/fr
Publication of WO1998003174A1 publication Critical patent/WO1998003174A1/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
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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

Definitions

  • the present invention relates to a method for treating cancers having high LDL requirements employing a delipidating agent, which preferably is an MTP inhibitor, alone or in combination with a cytotoxic agent .
  • LDL low-density lipoprotein
  • Cholesterol a major constituent of mammalian cell membranes, is obtained by cells either by making it themselves or by picking it up from LDL or both. Cancer cells, like all dividing ones, need large amounts of cholesterol because they are making new membrane. There is ample evidence that many types of cancer cells indeed have unusually great LDL requirements . The evidence is 2-fold: measurements of LDL uptake by tumor cells and depletion of LDL in the blood of cancer patients resulting from high uptake by the tumor ( vide infra) . Thus, if LDL could be made to carry antitumor drugs, it would serve as a targeting vehicle. This concept was proposed in 1981-2 ( 1 , 2) and has been reviewed several times since then (3-7) . "
  • LDL Uptake At page 105 under the topic "LDL Uptake", Firestone, supra, lists numerous tumor types that have especially high LDL requirements including acute myeloid leukemia (AML) , human monocytic (FAB-M5) and myelomonocytic (FAB-M4) leukemias, chronic myeloid leukemia in blast crisis, solid tumors such as epidermoid cervical cancer EC-50, endometrial adenocarcinoma AC-258, gastric carcinoma and parotid adenoma, G2 heptoma, squamous lung cancer, choriocarcinoma, brain tumors such as medulloblastoma, oligodendroglioma, glioma V-251MG, and malignant menigioma, as well as tumor cells that are exceptionally metastatic
  • Plasma high density lipoprotein is increased in man when low density lipoprotein (LDL) is lowered by LDL-pheresis. Proc . Nat . Acad . Sci . U. S.A . 83 , 111 .
  • MTP microso al triglyceride transfer protein
  • TG triglyceride
  • CE cholesteryl ester
  • PC phosphatidylcholine
  • 58 kDa and 88 kDa are hereinafter referred to as 58 kDa and 88 kDa, respectively, or the 58 kDa and the 88 kDa component of MTP, respectively, or the low molecular weight subunit and the high molecular weight subunit of MTP, respectively.
  • Characterization of the 58,000 molecular weight component of bovine MTP indicates that it is the previously characterized multifunctional protein, protein disulfide isomerase (PDI). Wetterau et al . , J. Biol . Chem. 265, 9800-7 (1990) .
  • PDI protein disulfide isomerase
  • PDI normally plays a role in the folding and assembly of newly synthesized disulfide bonded proteins within the lumen of the endoplasmic reticulum. Bulleid & Freedman, Nature 335 , 649-51 (1988) . It catalyzes the proper pairing of cysteine residues into disulfide bonds, thus catalyzing the proper folding of disulfide bonded proteins.
  • PDI has been reported to be identical to the beta subunit of human prolyl 4- hydroxylase. Koivu et al . , J. Biol. Chem. 262 , 6447-9 (1987) . The role of PDI in the bovine transfer protein is not clear.
  • MTP activity in rats has been investigated.
  • Lipid transfer activity was found in liver and intestine. Little or no transfer activity was found in plasma, brain, heart, or kidney.
  • MTP was a soluble protein located within the lumen of the microsomal fraction. Approximately equal concentrations were found in the smooth and rough microsomes .
  • Abetalipoproteinemia is an autosomal recessive disease characterized by a virtual absence of plasma lipoproteins which contain apolipoprotein B (apoB) . Kane & Havel in The Metabolic Basis of Inherited Disease. Sixth edition, 1139-64 (1989) .
  • Plasma TG levels may be as low as a few mg/dL, and they fail to rise after fat ingestion. Plasma cholesterol levels are often only 20-45 mg/dL. These abnormalities are the result of a genetic defect in the assembly and/or secretion of very low density lipoproteins (VLDL) in the liver and chylomicrons in the intestine. The molecular basis for this defect has not been previously determined. In subjects examined, triglyceride, phospholipid, and cholesterol synthesis appear normal. At autopsy, subjects are free of atherosclerosis. Schaefer et al . , Clin. Chem. 34, B9-12 (1988) . A link between the apoB gene and abetalipoproteinemia has been excluded in several families.
  • Subjects with abetalipoproteinemia are afflicted with numerous maladies. Kane & Havel, supra .
  • Subjects have fat ma1absorption and TG accumulation in their enterocytes and hepatocytes . Due to the absence of TG-rich plasma lipoproteins, there is a defect in the transport of fat-soluble vitamins such as vitamin E.
  • Treatment of abetalipoproteinemic subjects includes dietary restriction of fat intake and dietary supplementation with vitamins A, E and K.
  • MTP catalyzes the transport of lipid molecules between phospholipid membranes. Presumably, it plays a similar role in vivo, and thus plays some role in lipid metabolism.
  • the subcellular (lumen of the microsomal fraction) and tissue distribution (liver and intestine) of MTP have led to speculation that it plays a role in the assembly of plasma lipoproteins, as these are the sites of plasma lipoprotein assembly.
  • MTP may catalyze the transport of TG from its site of synthesis in the endoplasmic reticulum (ER) membrane to nascent lipoprotein particles within the lumen of the ER.
  • HDL high density lipoprotein
  • a method for treating tumors having high LDL requirements which method includes the step of administering to a mammalian species in need of treatment a therapeutically effective amount of a delipidating agent to substantially reduce LDL blood levels.
  • the delipidating agent may be optionally administered in combination with a cytotoxic agent .
  • a method for treating tumors having high LDL requirements, especially hematologic tumors, which method includes the steps of administering to a mammalian species in need of treatment a therapeutically effective amount of a delipidating agent to substantially remove LDL (that is, native LDL), and administering a cytotoxic agent carried in reconstituted LDL (rLDL- drug conjugate) .
  • the delipidating compound to be employed in the methods of the invention may be an LDL lowering compound which lowers LDL down to less than 20% of normal (that is less than 20% of 150 mg/dl that is 30 mg/dl) , preferably down to less than 10% of normal (that is less than 15 mg/dl) and most preferably to substantially zero LDL.
  • LDL lowering compound which lowers LDL down to less than 20% of normal (that is less than 20% of 150 mg/dl that is 30 mg/dl) , preferably down to less than 10% of normal (that is less than 15 mg/dl) and most preferably to substantially zero LDL.
  • delipidating agents which may be employed herein include MTP inhibitors, statins, fibrates and resins or combinations thereof, with MTP inhibitors being preferred.
  • the reconstituted LDL (employed as a carrier for the cytotoxic agent in the above method) may be prepared according to the procedures described in the review article Firestone, R.A. ,
  • the cytotoxic agent may be incorporated in the reconstituted LDL to form an LDL-drug conjugate following the procedure described in the Firestone review article, supra, especially as described in cited reference (104) Lundberg, supra.
  • MTP inhibitors to be employed in the methods of the invention include MTP inhibitors disclosed in Canadian Patent Application No. 2,091,102 described hereinbefore (corresponding to U.S. Application Serial No. 117,362), U.S. Application Serial No. 472,067, filed June 6, 1995 (file DC21e) , U.S. Application Serial No. 548,811 (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*) .
  • 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, cyclo- alkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl, hydroxy or o
  • 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, O, S, H
  • R 11 is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms; arylene or mixed arylene-alkylene;
  • R 12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cyclo- alkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl, with the provisos that
  • R 12 is H, aryloxy, alkoxy or
  • Z is bond, O, 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, aryl hio, 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, alkyl- sulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy; or R 1 is a group of the structure (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; or R 1 is a group of the structure
  • 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 independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl , heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycyclo- alkenylalkyl, 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, cycloal
  • 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 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 (R 13 ) (R 14 ) , (where R 13 and R 14 are independently alkyl, aryl, alkoxy, aryloxy, heteroaryl, heteroarylalkyl, heteroaryl
  • the R 1 group may have from one to four substituents, which can be any of the R 3 groups or R 1 groups, and any of the preferred R 1 substituents set out below.
  • R 1 may be substituted with the following preferred substituents: alkylcarbonylamino, cyclo- alkylcarbonylamino, arylcarbonylamino, heteroaryl- carbonylamino, alkoxycarbonylami.no , 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 ,
  • J is : CHR 23 , — ;
  • 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 preferred substituents may either be directly attached to R 1 , or attached via an alkylene chain at an open position.
  • R 2 is the same or different from R 1 and is independently any of the groups set out for R 1 , H, polyhaloalkyl (such as CF 3 CH 2 , CF 3 CF 2 CH 2 or CF 3 ) or cycloheteroalkyl, and may be substituted with one to four of any of the groups defined for R 3 , or any of the substituents preferred 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 optionally substituted with alkyl or aryl, an oxo group; and may be substituted with one to five alkyl or halo groups (preferably F) .
  • 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 3 , haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, amino, thiol, alkylthio, alkyl- sulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl , aminocarbonyl , alkylcarbonyloxy, alkylcarbonylamino, cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar, Ar-alkyl, ArO, Ar-amino, Ar-thio, Ar-sulfinyl,
  • R 3a and R 3b are the same or different and are independently any of the R 3 groups except hydroxy, nitro, amino or thio;
  • heteroaryl ring which may contain 1, 2, 3 or 4 heteroatoms in the ring which are independently N, S or 0; and including N- oxides .
  • X in the fluorenyl type ring is a bond, or is one of the following groups:
  • R 6 is H, lower alkyl, aryl, -C(0)-R 1:1 or -C(0)-0-R 1:L ;
  • 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 -O-R 11 ;
  • R 11 is alky or aryl
  • R 12 is H, alkyl or aryl.
  • R 1 L 1 must contain at least 3 carbons.
  • R 1 is cycloheteroalkyl
  • R 1 is exclusive of 1-piper- idinyl, 1-pyrrolidinyl, 1-azetidinyl or l-(2-oxo- pyrrolidinyl) .
  • 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 I
  • W is H , H or O
  • X is: 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, ary
  • 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, SII , — ,
  • 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 cycloalkyl- alkyl; with the provisos that (1) when R 12 is H, aryloxy, alkoxy or arylalkoxy, then Z 2 is -NH-C— , — N C— -C—
  • 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, cycloheter
  • 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 ;
  • X is. 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, H
  • 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 cycloalkyl- alkyl; with the provisos that (1) when R 12 is H, aryloxy, alkoxy or arylalkoxy, then Z 2 is
  • R 12 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 is independently hydrogen, alkyl,
  • 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, cyclohe
  • 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. provisional application No. 60/017,224, filed May 9, 1996 (file HX79a*) .
  • X 1 and X 2 are H; R 5 is aryl such as phenyl substituted with
  • R 5 is heteroaryl such as or substituted with
  • 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 are aryl, preferably phenyl, heteroaryl, preferably imidazoyl or pyridyl (preferably substituted with one of the preferred R 1 substituents: arylcarbonylamino, heteroarylcarbonyla ino , cycloalkylcarbonylamino , alkoxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino) , PO(OAlkyl) 2 .
  • heteroarylthio benzthi-azole-2-thio, imidazole-2-thio, alkyl, or alkenyl, cycloalkyl such as cyclohexyl, or 1 , 3-dioxan-2-yl .
  • Preferred 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 of the invention include those where B, 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.
  • delipidating agents examples include statins such as pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin and fluvastatin, with pravastatin and atorvastatin being preferred, fibrates such as clofibrate, fenofibrate, bezafibrate, gemfibrozil, ciprofibrate, and clinofibrate, as well as nicotinic acid, probucol and resins such as cholestyramine, colestipol, and DEAE-Sephadex, and/or combinations of two or more thereof, and/or combinations thereof with an MTP inhibitor.
  • statins such as pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin and fluvastatin, with pravastatin and atorvastatin being preferred
  • fibrates such as clofibrate, fenofibrate, bezafibrate, gem
  • the delipidating agent for example MTP inhibitor employed in accordance with the present invention can be administered to various mammalian species, such as dogs, cats, humans, etc .. in need of treatment. These agents can be administered systemically, such as orally or parenterally.
  • the delipidating agent, for example MTP inhibitor can be incorporated in a conventional systemic dosage form, such as a tablet, capsule, elixir or injectable formulation.
  • the above dosage forms will also include the necessary physiologically acceptable carrier material, excipient, lubricant, buffer, antibacterial, bulking agent (such as mannitol) , anti-oxidants (ascorbic acid or 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 the age, weight, and condition of the patient, as well as the route of administration, dosage form and regimen, and the desired result.
  • the dosage forms described above may be administered containing amounts of MTP inhibitor of from about 5 to about 500 mg per day preferably from about 10 to about 400 mg per day, in single or divided doses of one to four times daily.
  • the other delipidating agents will be employed in amounts set out in the latest edition of the Physician's Desk Reference (PDR) .
  • Cytotoxic agents which may be employed in conjunction with the delipidating agent, for example with MTP inhibitors, in accordance with the present invention are preferably lipophilic or rendered lipophilic by addition of LDL anchors such as oleoyl groups either as oleic acid derivatives or oleyl alcohol derivatives, linoleyl derivatives, retinyl derivatives or cholesteryl derivatives (as disclosed at page 107 of the Firestone review article, supra) so that the cytotoxic agent may be more easily constituted with LDL.
  • LDL anchors such as oleoyl groups either as oleic acid derivatives or oleyl alcohol derivatives, linoleyl derivatives, retinyl derivatives or cholesteryl derivatives (as disclosed at page 107 of the Firestone review article, supra) so that the cytotoxic agent may be more easily constituted with LDL.
  • Cytotoxic agents approved by the FDA such as those listed in the Physicians Desk Reference 50 th Ed.
  • doxorubicin may be employed including doxorubicin, doxorubicin valerate, idarubicin HC1 , mitomycin, paclitaxel, taxotere, teniposide, etoposide, carboplatin, busulfan, megestrol acetate, mitotane, altretamine, lomustine, carmustine, estramustine phosphate sodium, procarbazine hydrochloride, cytarabine, and the like.
  • Preferred cytotoxic agents include 9- methoxyellipticine, N-methylellipticinium, compounds 25, 1 and 2 disclosed in Firestone review article, supra, at page 107, that is
  • n l, R-CH 2 OCON(CH2CH 2 Cl)2
  • cytotoxic agents to be employed herein will depend upon the particularly neoplastic disease to be treated as follows.
  • brain tumors including medulloblastoma, oligoden- droglioma, and malignant meningioma (8) squamous and small cell lung tumors
  • the dosages and formulations for the MTP inhibitor delipidating agent will be as disclosed in the various patents and applications discussed above .
  • the dosages and formulations for the delipidating agent and cytotoxic agent to be employed, where applicable, will be as set out in the latest edition of the Physicians ' Desk Reference.
  • Dosages for the LDL-drug conjugate are as follows: from about 10 to about 1000 mg/day, preferably from about 50 to about 250 mg/day, when the patient is at least 90% delipidated, in single or divided doses (2 to 4 times/day) .
  • the reconstituted LDL portion will comprise about 50% of the conjugate.
  • the LDL-drug conjugate may be formulated for intravenous administration employing conventional pharmaceutical practices.

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Abstract

Procédé de traitement de tumeurs hématologiques et de tumeurs solides, dont certains types de leucémies et de tumeurs métastasiques, ayant des besoins élevés en lipoprotéine de basse densité, à l'aide d'un agent dilapidant tel que l'inhibiteur de la protéine microsomale de transfert des triglycérides (MTP) pour réduire considérablement le taux sanguin de LDL. De plus, la présente invention concerne un procédé permettant de traiter des tumeurs des types susmentionnés ayant des besoins élevés en LDL, en particulier les tumeurs hématologiques telles que certaines leucémies, à l'aide d'un composé dilapidant destiné à éliminer pratiquement la LDL endogène, ledit procédé consistant ensuite à administrer un agent cytotoxique porté par de la LDL reconstituée.
PCT/US1997/012158 1996-07-24 1997-07-14 Procede de traitement de tumeurs ayant des besoins eleves en lipoproteine de basse densite (ldl) a l'aide d'inhibiteurs de la proteine microsomale de transfert des triglycerides (mtp) WO1998003174A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU36008/97A AU712303C (en) 1996-07-24 1997-07-14 Method for treating tumors having high LDL requirements employing MTP inhibitors
JP50701298A JP2002513379A (ja) 1996-07-24 1997-07-14 Ｍｔｐ抑制因子を用いる、高ｌｄｌの必要を持つ腫瘍の治療法
EP97932594A EP0954313A4 (fr) 1996-07-24 1997-07-14 Procede de traitement de tumeurs ayant des besoins eleves en lipoproteine de basse densite (ldl) a l'aide d'inhibiteurs de la proteine microsomale de transfert des triglycerides (mtp)

Applications Claiming Priority (2)

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US2286396P 1996-07-24 1996-07-24
US60/022,863 1996-07-24

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6288234B1 (en) 1998-06-08 2001-09-11 Advanced Medicine, Inc. Multibinding inhibitors of microsomal triglyceride transferase protein
WO2005094864A3 (fr) * 2004-03-30 2006-02-09 Max Planck Gesellschaft Traitement de tumeurs qui secretent du wnt et du hedgehog avec des inhibiteurs de biogenese de particule de lipoproteine
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
WO2021167389A1 (fr) * 2020-02-21 2021-08-26 한국과학기술원 Composition pharmaceutique permettant de prévenir ou de traiter le cancer contenant un inhibiteur de signalisation mtor comme principe actif

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5595872A (en) * 1992-03-06 1997-01-21 Bristol-Myers Squibb Company Nucleic acids encoding microsomal trigyceride transfer protein

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU218419B (hu) * 1992-03-06 2000-08-28 E.R. Squibb And Sons, Inc. Mikroszomális triglicerid transzfer protein (MTP) nagy molekulatömegű alegységének rekombináns úton történő előállítására és a protein és inhibitorainak kimutatására szolgáló eljárások

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5595872A (en) * 1992-03-06 1997-01-21 Bristol-Myers Squibb Company Nucleic acids encoding microsomal trigyceride transfer protein

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6288234B1 (en) 1998-06-08 2001-09-11 Advanced Medicine, Inc. Multibinding inhibitors of microsomal triglyceride transferase protein
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
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
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
WO2005094864A3 (fr) * 2004-03-30 2006-02-09 Max Planck Gesellschaft Traitement de tumeurs qui secretent du wnt et du hedgehog avec des inhibiteurs de biogenese de particule de lipoproteine
WO2021167389A1 (fr) * 2020-02-21 2021-08-26 한국과학기술원 Composition pharmaceutique permettant de prévenir ou de traiter le cancer contenant un inhibiteur de signalisation mtor comme principe actif
CN115135322A (zh) * 2020-02-21 2022-09-30 韩国高等科学技术学院 包含哺乳动物雷帕霉素靶蛋白信号传导抑制剂作为有效成分的用于预防或治疗癌症的药物组合物

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AU3600897A (en) 1998-02-10
AU712303B2 (en) 1999-11-04

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