WO2000067802A1 - Compositions d'acides gras -n-substituted indol-3-glyoxyl-amide et leur utilisation - Google Patents

Compositions d'acides gras -n-substituted indol-3-glyoxyl-amide et leur utilisation Download PDF

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Publication number
WO2000067802A1
WO2000067802A1 PCT/US2000/012752 US0012752W WO0067802A1 WO 2000067802 A1 WO2000067802 A1 WO 2000067802A1 US 0012752 W US0012752 W US 0012752W WO 0067802 A1 WO0067802 A1 WO 0067802A1
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fatty acid
nhcor
compound
conjugate
anti cancer
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PCT/US2000/012752
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English (en)
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Matthews O. Bradley
Charles S. Swindell
Forrest Anthony
Nigel L. Webb
Mark Fisher
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Protarga, Inc.
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Priority to AU48342/00A priority Critical patent/AU4834200A/en
Publication of WO2000067802A1 publication Critical patent/WO2000067802A1/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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid

Definitions

  • the present invention pertains to N-substituted indol-3 -glyoxyl-amides that are conjugates of fatty acids and N-(pyridin-4-yl)-(l-(4-halobenzyl)-indol-3-yl)-glyoxyl-amides).
  • the conjugates are useful in treating cancer.
  • N-(pyridin-4-yl)-(l-(4-chlorobenzyl)-indol-3-yl)-glyoxyl- amide) appears to be a more potent anti-cancer agent in vivo than either taxol or vincristine. Its mechanism of action is believed to involve destabilization of microtubules. N-(pyridin-4-yl)-(l-(4-chlorobenzyl)-indol-3-yl)-glyoxyl-amide) has attracted strong scientific attention, not only because of its unique antiproliferative potency, but also because it is active against nearly all cancers against which it has been tested.
  • N-(pyridin-4-yl)-( 1 -(4-chlorobenzyl)-indol-3-yl)-glyoxyl-amide) ' s strength against cancers of diverse tissue origin also represents a significant drawback.
  • An ideal anti cancer agent has tissue specificity, thereby reducing side-effects on normal (dividing) cells.
  • N-(pyridin-4-yl)-(l-(4-chlorobenzyl)-indol-3-yl)- glyoxyl-amide Another drawback of N-(pyridin-4-yl)-(l-(4-chlorobenzyl)-indol-3-yl)- glyoxyl-amide) is its extreme insolubility. N-(pyridin-4-yl)-(l-(4-chlorobenzyl)-indol-3-yl)- glyoxyl-amide) has only been possible to be administered effectively by oral gavage. Fatty acids previously have been conjugated with drugs to help the drugs as conjugates cross the blood-brain barrier.
  • DHA docosahexaenoic acid
  • DHA is a 22 carbon naturally-occurring, unbranched fatty acid that previously has been shown to be unusually effective in crossing the blood-brain barrier.
  • DHA is conjugated to a drug
  • the entire drug-DHA conjugate is transported across the blood-brain barrier and into the brain.
  • DHA is attached via the acid group to hydrophilic drugs and renders these drugs more hydrophobic (lipophilic). DHA is an important constituent of the brain and recently has been approved as an additive to infant formula. It is present in the milk of lactating women. The mechanism of action by which DHA helps drugs conjugated to it cross the blood-brain barrier is unknown.
  • pipotiazine is a drug that acts within the central nervous system.
  • the purpose of conjugating pipotiazine to the fatty acids was to create an oily solution of the drug as a liquid implant for slow release of the drug when injected intramuscularly. The release of the drug appeared to depend on the particular fatty acid selected, and the drug was tested for its activity in the central nervous system.
  • Lipidic molecules including the fatty acids, also have been conjugated with drugs to render the conjugates more lipophilic than the drug.
  • increased lipophilicity has been suggested as a mechanism for enhancing intestinal uptake of drugs into the lymphatic system, thereby enhancing the entry of the conjugate into the brain and also thereby avoiding first-pass metabolism of the conjugate in the liver.
  • the type of lipidic molecules employed have included phospholipids, non-naturally occurring branched and unbranched fatty acids, and naturally occurring branched and unbranched fatty acids ranging from as few as 8 carbon atoms to more than 30 carbon atoms.
  • enhanced receptor binding activity was observed (for an adenosine receptor agonist), and it was postulated that the pendant lipid molecule interacted with the phospholipid membrane to act as a distal anchor for the receptor ligand in the membrane micro environment of the receptor.
  • This increase in potency was not observed when the same lipid derivatives of adenosine receptor antagonists were used, and generalizations thus were not made possible by those studies.
  • the present invention involves the unexpected finding that conjugates of a fatty acid and a N-substituted indol-3 -glyoxyl-amide, have a different selectivity relative to N- substituted indol-3 -glyoxyl-amide alone.
  • the conjugates render the activity of N- substituted indol-3 -glyoxyl-amide selective for biliary tract cancer, brain cancer (including glioblastomas and medulloblastomas), breast cancer; cervical cancer; choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, hematological neoplasms, including acute lymphocytic and myelogenous leukemia, multiple myeloma, AIDS associated leukemias and adult T-cell leukemia lymphoma, intraepithelial neoplasms, including Bowen's disease and Paget's disease, liver cancer, lung cancer, lymphomas, including Hodgkin's disease and lymphocytic lymphomas, neuroblastomas, oral cancer, including squamous cell carcinoma, ovarian cancer, including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells, pancreatic cancer, prostate
  • the conjugates also unexpectedly, restrict the activity of the N-substituted indol-3 -glyoxyl-amide even within these foregoing categories of cancer relative to that of N-substituted indol-3-glyoxyl-amide.
  • the conjugates further unexpectedly, reduce sharply the activity of a N-substituted indol-3 - glyoxyl-amide relative to that of N-substituted indol-3 -glyoxyl-amide in most cell lines of various tissue types, it is believed, other than bone, bone marrow, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gall bladder, intraepithelium, kidney, liver, lung, ovaries, pancreas, prostate, rectum, skin, squamous cell epithelium, stomach, testicular tissue, and thyroid, thereby reducing potential side effects of the conjugates versus those of N-substituted indol-3-glyoxyl-amide.
  • the therapeutic index of the conjugates is improved, versus that of N-substituted indol-3-glyoxyl-amide for targeted cancers.
  • a preferred N-substituted indol-3 -glyoxyl-amide conjugated to a fatty acid according to the invention is N-(pyridin-4-yl)-(l-(4-halobenzyl)-indol-3-yl)-glyoxyl-amide).
  • N-(pyridin-4-yl)-(l-(4-halobenzyl)-indol-3-yl)-glyoxyl-amide) is N-(pyridin-4- yl)-(l-(4-chlorobenzyl)-indol-3-yl)-glyoxyl-amide).
  • novel compounds and pharmaceutical compositions are provided.
  • Each pharmaceutical composition contains the novel compound, which is a covalent conjugate of a N-substituted indol-3 -glyoxyl-amide and a fatty acid having 8-26 carbons, in an amount effective to treat cancer, and a pharmaceutically acceptable carrier.
  • the fatty acid is an unbranched, naturally occurring fatty acid.
  • the fatty acid has 14-22 carbons.
  • Unbranched common naturally occurring fatty acids include C12:0 (lauric acid), C14.0 (myristic acid), C16:0 (palmitic acid), C16:l
  • C22:6-3 docosahexaenoic acid
  • C24:l-9 nervonic
  • Highly preferred unbranched, naturally occurring fatty acids are those with between 14 and 22 carbon atoms.
  • the fatty acids are ⁇ -3 fatty acids.
  • the most preferred co-3 fatty acid is docosahexaenoic acid.
  • the fatty acids are ⁇ -6 fatty acids.
  • the most preferred ⁇ -6 fatty acid is linoleic acid.
  • the N-substituted indol-3 - glyoxyl-amides are N-(pyridin-4-yl)-(l-(4-halobenzyl)-indol-3-yl)-glyoxyl-amide).
  • the N-(pyridin-4-yl)-(l-(4-halobenzyl)-indol-3-yl)-glyoxyl-amide) is N-(pyridin-4-yl)-(l-(4-chlorobenzyl)-indol-3-yl)-glyoxyl-amide).
  • R is the organic substituent attached to the carboxyl-group in any one of the fatty acids described in the immediately preceding paragraph.
  • the fatty acid preferably, is an ⁇ -3 fatty acid, and most preferably is DHA.
  • the covalent conjugate is selected from the group consisting of:
  • X is H, F, Cl, Br or I;
  • X is H, F, Cl, Br or I
  • Y is -O 2 CR, -NHCOR, -(CH 2 ) n O 2 CR, -(CH 2 ) n NHCOR, -O 2 C(CH 2 ) n O 2 CR, -O 2 C(CH 2 ) n NHCOR, -O(CH 2 ) n O 2 CR, -O(CH 2 ) n NHCOR,
  • X is H, F, Cl, Br or I
  • Y is -O 2 CR, -NHCOR, -(CH 2 ) n O 2 CR, -(CH 2 ) n NHCOR, -O 2 C(CH 2 ) n O 2 CR, -O 2 C(CH 2 ) n NHCOR, -O(CH 2 ) n O 2 CR, -O(CH 2 ) n NHCOR,
  • X is H, F, Cl, Br or I
  • Y is -O 2 CR, -NHCOR, -(CH 2 ) n O 2 CR, -(CH 2 ) n NHCOR, -O 2 C(CH 2 ) obligeO 2 CR,
  • Y is -O 2 CR, -NHCOR, -(CH 2 ) n O 2 CR, -(CH 2 ) deliberatelyNHCOR, -O 2 C(CH 2 ) n O 2 CR, -O 2 C(CH 2 ) n NHCOR, -O(CH 2 ) n O 2 CR, -O(CH 2 ) n NHCOR,
  • X is H, F, Cl, Br or I
  • Y is -O 2 CR, -NHCOR, -(CH 2 ) n O 2 CR, -(CH 2 ) n NHCOR, -O 2 C(CH 2 ) n O 2 CR, -O 2 C(CH 2 ) n NHCOR, -O(CH 2 ) n O 2 CR, -O(CH 2 ) n NHCOR,
  • X is H, F, Cl, Br or I
  • Y is -O 2 CR, -NHCOR, -(CH 2 ) deliberatelyO 2 CR, -(CH 2 ) n NHCOR, -O 2 C(CH 2 ) n O 2 CR, -O 2 C(CH 2 ) n NHCOR, -O(CH 2 ) n O 2 CR, -O(CH 2 ) n NHCOR,
  • X is H, F, Cl, Br or I
  • Y is -O 2 CR, -NHCOR, -(CH 2 ) n O 2 CR, -(CH 2 ) n NHCOR, -O 2 C(CH 2 ) n O 2 CR, -O 2 C(CH 2 ) n NHCOR, -O(CH 2 ) n O 2 CR, -O(CH 2 ) n NHCOR,
  • X is H, F, Cl, Br or I
  • Y is -O 2 CR, -NHCOR, -(CH 2 ) n O 2 CR, -(CH 2 ) n NHCOR, -O 2 C(CH 2 ) n O 2 CR,
  • Y is -O 2 CR, -NHCOR, -(CH 2 ) n O 2 CR, -(CH 2 ) n NHCOR, -O 2 C(CH 2 ) n O 2 CR, -O 2 C(CH 2 ) n NHCOR, -O(CH 2 ) n O 2 CR, -O(CH 2 ) n NHCOR,
  • X is H, F, Cl, Br or I
  • Y is -O 2 CR, -NHCOR, -(CH 2 ) procurO 2 CR, -(CII 2 ) procurNIICOR, -O 2 C(CII 2 ) n O 2 CR, -O 2 C(CH 2 ) n NHCOR, -O(CH 2 ) n O 2 CR, -O(CH 2 ) n NHCOR,
  • the covalent conjugate is conjugate 12:
  • X is F, Cl, Br, I, or Y
  • Y ⁇ -Y ⁇ is selected from the group consisting of -H,-O 2 CR,-NHCOR,-(CH 2 ) n O 2 CR,-(CH 2 ) n NHCOR,-O 2 C(CH 2 ) n O 2 CR,- O 2 C(CH 2 ) n NHCOR,-O(CH 2 ) ⁇ O 2 CR,-O(CH 2 ) n NHCOR,-NHCO(CH 2 ) n O 2 CR,- NHCO(CH 2 ) n NHCOR,-NH(CH 2 ) n O 2 CR,-NH(CH 2 ) n NHCOR,-NH(CH 2 ) n O 2 CR,-NH(CH 2 ) n NHCOR,-COR,-(CH 2 ) n O 2 CR,-
  • (CH 2 ) n NHCOR, -CO(CH 2 ) n O 2 CR, and -CO(CH 2 ) n NHCOR, wherein n l-22, and wherein at least one Y is not Hydrogen (e.g., Yj) and is selected from the group consisting of -O 2 CR,- NHCOR,-(CH 2 ) n O 2 CR, -(CH 2 ) n NHCOR, -O 2 C(CH 2 ) n O 2 CR,-O2C(CH 2 ) n NHCOR,-
  • O(CH 2 ) n O 2 CR, -O(CH 2 ) n NHCOR,-NHCO(CH 2 ) n O 2 CR,-NHCO(CH 2 ) n NHCOR,- NH(CH 2 ) n O 2 CR,-NH(CH 2 ) n NHCOR,-COR,-(CH 2 ) n ⁇ 2 CR,-(CH 2 ) n NHCOR,-CO(CH 2 ) n O 2 CR, and -CO(CH 2 ) n NHCOR, wherein n l-22, the remainining Y groups (e.g.,Y 2 -Y] 4 ) can be substituted, or preferably are unsubstituted and are Hydrogens.
  • Y groups e.g.,Y 2 -Y] 4
  • At least two, at least three, or at least four Y groups are not Hydrogen and are selected from the group consisting of -O 2 CR,-NHCOR,-(CH 2 ) n O 2 CR,- (CH 2 ) n NHCOR, -O 2 C(CH 2 ) n O 2 CR, -O 2 C(CH 2 ) n NHCOR,-O(CH 2 ) ⁇ O 2 CR,-O(CH 2 ) n NHCOR,- NHCO(CH 2 ) n O 2 CR,-NHCO(CH 2 ) n NHCOR,-NH(CH 2 ) n O 2 CR,-NH(CH 2 ) n NHCOR,-COR,- (CH 2 ) n O 2 CR,-(CH 2 ) n NHCOR,-CO(CH 2 ) n O 2 CR, and -CO(CH 2 ) n NHCOR, wherein
  • the covalent conjugate is conjugate 13:
  • X is F, Cl, Br, I, or Y
  • Y ⁇ -Y ⁇ 3 is selected from the group consisting of -H, -O 2 CR, -NHCOR, -(CH 2 ) n O 2 CR, -(CH 2 ) n NHCOR, -O 2 C(CH 2 ) n O 2 CR, - O 2 C(CH 2 ) n NHCOR, -O(CH 2 ) n O 2 CR, -O(CH 2 ) n NHCOR, NHCO(CH 2 ) n O 2 CR, NHCO(CH 2 ) n NHCOR, NH(CH 2 ) n O 2 CR, -NH(CH 2 ) n NHCOR, wherein n-1-22, and wherein at least one Y is not Hydrogen (e.g., Yj) and is selected from the group consisting of -O 2 CR, - NHCOR,
  • any one of conjugates 12 or 13 when the at least one, the at least two, and/or the at least three Y group(s) is (are) not Hydrogen and is (are) selected from any of the foregoing sub-groups, the remaining Y groups may be also substituted, or preferably are unsubstituted and are Hydrogen substituents.
  • One of ordinary skill in the art could identify other substituent molecules that can be utilized to substitute for the Y group(s), and maintain and/or enhance the conjugate's anti-cancer properties.
  • the covalent conjugate is conjugate 14:
  • the covalent conjugates of the invention include only one fatty acid, although sometimes two, three, four, or more are possible.
  • kits are provided.
  • the kit is a package which houses a container which contains a covalent conjugate of the invention and also houses instructions for administering the covalent conjugate to a cancer victim.
  • kits which houses a first container which contains a covalent conjugate of the invention and also houses a second container containing an anti-cancer agent other than the covalent conjugate.
  • the preferred fatty acids, bonds, covalent conjugate and anti-cancer agent other than the covalent conjugate are as described above.
  • a method for treating cancer is provided.
  • the method involves administering to a subject in need of such treatment a covalent conjugate of an N-substituted Indol-3 -glyoxyl-amid and a fatty acid having 8-26 carbons in an amount effective to treat cancer.
  • the preferred N-substituted indol-3 -glyoxyl-amid is N- (pyridin-4-yl)-(l-(4-chlorobenzyl)-indol-3-yl)-glyoxyl-amid).
  • the preferred fatty acids, bonds and covalent conjugates are as described above.
  • the method also can involve co- administering to the subject an anti-cancer agent other than the covalent conjugate. Preferred anti-cancer agents are as described above.
  • a conjugate composition for administration to a subject includes at least one conjugate in a container for administration to a subject.
  • the amount of the conjugate in the container is at least about 10% greater than the maximum tolerated dose (MTD) for the unconjugated at least one anti cancer compound.
  • MTD maximum tolerated dose
  • the amount of the conjugate in the container is at least about 20% greater than the MTD, 30% greater than the MTD, 40% greater than the MTD, 50% greater than the MTD, 75% greater than the MTD, 100% greater than the MTD, 200% greater than the MTD, 300% greater than the MTD, or 400% greater than the MTD for the unconjugated at least one anti cancer compound.
  • the container is a container for intravenous administration.
  • the conjugate is not encapsulated in or in the form of a liposome.
  • methods for treating a subject having an abnormal mammalian cell proliferative disorder include administering a composition including at least one fatty acid conjugate to the subject in an amount which is at least about 10% greater than the maximum tolerated dose (MTD) for the unconjugated at least one anti cancer compound.
  • MTD maximum tolerated dose
  • the amount of the at least one fatty acid-anti cancer compound administered is at least about 20% greater than the MTD, 30% greater than the MTD, 40% greater than the MTD, 50% greater than the MTD, 75% greater than the MTD, 100% greater than the MTD, 200% greater than the MTD, 300% greater than the MTD, or 400% greater than the MTD for the unconjugated at least one anti cancer compound.
  • the conjugate is not encapsulated in or in the form of a liposome.
  • kits for administration of a fatty acid-anti cancer compound conjugate to a subject include a container containing a composition which includes at least one fatty acid-anti cancer compound conjugate of the invention, and instructions for administering the at least one fatty acid-anti cancer compound conjugate to subject in need of such treatment in an amount which is at least about 10% greater than the maximum tolerated dose (MTD) for the unconjugated at least one anti cancer compound.
  • MTD maximum tolerated dose
  • the subject has an abnormal mammalian cell proliferative disorder.
  • the amount of the at least one fatty acid-anti cancer compound conjugate to be administered is at least about 20% greater than the MTD, 30% greater than the MTD, 40% greater than the MTD, 50% greater than the MTD, 75% greater than the MTD, 100% greater than the MTD, 200% greater than the MTD, 300%) greater than the MTD, or 400% greater than the MTD for the unconjugated at least one anti cancer compound.
  • the container is a container for intravenous administration.
  • the conjugate is not encapsulated in or in the form of a liposome.
  • a method for increasing the therapeutic index of anti cancer compounds in a subject includes conjugating a fatty acid to an anti cancer compound as described herein to form a fatty acid-anti cancer compound conjugate of the invention; and administering the fatty acid-anti cancer compound conjugate to the subject.
  • the therapeutic index of the anti cancer compound thus administered is improved relative to non-conjugated formulations of the anti cancer compound.
  • the subject has an abnormal mammalian cell proliferative disorder, and the subject preferably is human.
  • the conjugate is not encapsulated in or in the form of a liposome.
  • a dose of a fatty acid-conjugated anti- cancer compound is administered which exceeds the maximum tolerated dose of the unconjugated anti cancer compound.
  • Figure 1 depicts a kit 11 comprising packaging 15, a first agent of the invention 17 (e.g., a container that contains a fatty acid conjugate of a N-substituted indol-3 -glyoxyl- amide, a second agent of the invention 19 (e.g., a container that contains a nonN-substituted indol-3 -glyoxyl-amide anticancer agent), and instructions 21, for utilizing such agents in therapeutic applications.
  • a first agent of the invention 17 e.g., a container that contains a fatty acid conjugate of a N-substituted indol-3 -glyoxyl- amide
  • a second agent of the invention 19 e.g., a container that contains a nonN-substituted indol-3 -glyoxyl-amide anticancer agent
  • instructions 21 for utilizing such agents in therapeutic applications.
  • N-substituted indol-3 -glyoxyl-amides are synthesized according to PCT
  • N-substituted indol-3 -glyoxyl-amide is N-
  • N-(pyridin-4-yl)-(l-(4-halobenzyl)-indol-3-yl)-glyoxyl- a ide) is N-(pyridin-4-yl)-(l-(4-chlorobenzyl)-indol-3-yl)-glyoxyl-amide).
  • the preferred source of N-(pyridin-4-yl)-(l-(4-chlorobenzyl)-indol-3-yl)-glyoxyl-amide) is ASTA Medica A.G., Dresden, Germany.
  • compositions of matter comprise a conjugate of a fatty acid and a N-substituted indol-3- glyoxyl-amide.
  • the fatty acids are polyunsaturated fatty acids.
  • the fatty acid is preferably a C16-C26 unbranched, naturally occurring fatty acid.
  • the fatty acid can be selected from the group consisting of C8:0 (caprylic acid), C10:0 (capric acid), C12:0 (lauric acid), C14:0 (myristic acid), C16:0 (palmitic acid), C16:l (palmitoleic acid), C16:2, C18:0 (stearic acid), C18:l (oleic acid), C18:l-7 (vaccenic), C18:2- 6 (linoleic acid), C18:3-3 ( ⁇ -linolenic acid), C18:3-5 (eleostearic), C18:3-6 ( ⁇ -linolenic acid), Cl 8:4-3, C20:l (gondoic acid), C20:2-6, C20:3-6 (dihomo-y-linolenic acid), C20:4-3, C20:4- 6 (arachidonic acid), C20:5-3 (eicosapentaenoic acid), C22:l (docosenoic acid), C22:
  • the fatty acid can be linoleic acid, palmitic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, 2-octanoate, 2- hexanoate, CH 3 -hexanoate, CH 3 -butanoate, or oleic acid.
  • the fatty acid is linoleic acid, palmitic acid, arachidonic acid, eicosapentaenoic acid, or docosahexaenoic acid.
  • czs-docosahexaenoic acid (DHA) is a naturally occurring fatty acid. It is an unbranched chain fatty acid with six double bonds, all cis. Its structure is as follows:
  • DHA can be isolated, for example, from fish oil or can be chemically synthesized. These methods, however, can generate trans isomers, which are difficult and expensive to separate and which may present safety problems in humans.
  • the preferred method of production is biological synthesis to produce the all cis isomer.
  • the preferred source of DHA is from Martek Biosciences Corporation of Columbia, Maryland. Martek has a patented system for manufacturing DHA using microalgae which synthesize only a single isomer of DHA, the all cis isomer. Martek's patents include U.S. Pat. Nos. 5,374,657, 5,492,938, 5,407,957 and 5,397,591. DHA also is present in the milk of lactating women, and Martek's licensee has obtained approval in Europe of DHA as a nutritional supplement for infant formula.
  • DHA DHA can be unstable in the presence of oxygen.
  • To stabilize DHA and its conjugates it is important to add anti-oxidants to the material after it is synthesized.
  • One method of stabilization is to make-up the newly synthesized material in the following solution:
  • the conjugate is prepared as a quaternary ammonium salt.
  • the anion preferably is selected from the group consisting of I “ , Cl “ , OH “ , F “ and Br “ . Most preferably the anion is I " . Cancer patients could be evaluated to determine if conjugates 1 -18 are strongly active against the patient's cancer prior to selecting any of the conjugates 1-18 as the anti-cancer agent of choice for that patient.
  • Paclitaxel was first isolated from the bark of Taxus brevifolia (Wani et al., J. Am. Chem. Soc, 93, 2325, 1971). Its isolation and synthesis have been reported extensively in the literature. Applicants obtained paclitaxel from a commercial source, Hauser Laboratories, of Boulder, Colorado.
  • TaxoprexinTM is a covalent conjugate of DHA and paclitaxel. Its chemical structure, synthesis, purification and in vitro action are described in U.S Patne 5,795,909, the entire disclosure of which is incorporated by reference herein. The structure is shown as “conjugate 1" in Example 1 of that patent.
  • the maximum tolerated dose (MTD) for any therapeutic compound is identified as part of its clinical evaluation.
  • phase I trials can include a determination of the maximum tolerated dose, dose limiting toxicities (DLT) and pharmacokinetics of a test compound.
  • Maximum tolerated dose refers to the largest dose of a pharmaceutical agent that an adult patient can take with safety to treat a particular disease or condition.
  • FDA Food and Drug Administration
  • the MTD for any particular therapeutic compound may vary according to its formulation (e.g., injectable formulation, implantable bioerodible polymer formulation, oral formulation), route of delivery (e.g., intravenous, oral, intratumoral), manner of delivery (e.g., infusion, bolus injection), dosing schedule (e.g., hourly, daily, weekly) and the like.
  • the MTD frequently is defined as the highest dose level at which 50% of subjects administered with the drug develop a dose limiting toxicity.
  • the doses for anti-neoplastic pharmaceutical agents found in the Physicians Desk Reference (PDR) are defined as the
  • the MTD for those agents.
  • the MTD is further defined to include only doses for drugs
  • Measurement of maximum tolerated dose may be expressed as weight of drug per weight of subject, weight of drug per body surface area, etc.
  • the MTD of anticancer compounds is frequently expressed as weight per square meters (mg/m 2 ) of body surface area.
  • MTD for paclitaxel infusion in humans is 225 mg/m 2 .
  • the most often used clinical tolerated dose is 175 mg/m .
  • MTD also may be expressed as a dose relative to a time component, such as weight of drug per body surface area per day.
  • MTD For therapeutics which have not yet been subjected to human clinical trails, or subjected to any determination of the MTD in humans (e.g., experimental or highly toxic compounds), one of skill in the art can estimate the MTD by using animal models. Calculation of MTD in animals may be based on a number of physiological parameters, such as death, particular toxicities, drug induced weight loss. Using death as an endpoint, the MTD may be the dose given test animals in which each member of the test group survived. Using toxicity as an endpoint, the MTD may be the dose at which moderate but not severe toxicity is observed. Using weight loss as an endpoint, the MTD may be the dose above which a certain percent change in body weight is induced. Other methods for determining MTDs using animal models and various endpoints are known to one of ordinary skill in the art. Correlation of animal MTDs to human MTDs for a therapeutic compound is an accepted practice in the pharmaceutical arts.
  • a conjugate of DHA and paclitaxel has a maximum tolerated dose in animals (mice, rats and dogs) which is about 4-5 times greater (by weight) than paclitaxel alone or about 3-4 times greater (by molarity) than paclitaxel alone.
  • compositions and formulations for administration to a subject preferably a human subject, containing amounts of a fatty acid- anti cancer compound conjugate which exceeds the maximum tolerated dose for the unconjugated anti cancer compound.
  • the fatty acid-anti cancer compound conjugate preferably is in a container for administration to a subject.
  • the container is a container for intravenous administration, such as an IN bag.
  • the amount of the fatty acid-anti cancer compound in the container is at least about
  • the amount of the fatty acid-anti cancer compound in the container is at least about 20%, 30%, 40%, 50%, 75%,
  • compositions having an abnormal mammalian cell proliferative disorder are provided.
  • Kits containing fatty acid-anticancer compounds in amounts also are provided.
  • the kits contain one or more containers with the conjugated anticancer compound along with instructions for mixing, diluting and/or administering the anticancer compound in amounts greater than the MTD for the unconjugated anticancer compound.
  • the kits also can include other containers with one or more solvents, surfactants, preservatives and/or diluents (e.g. normal saline (0.9% NaCl), or 5% dextrose (D5W)), as well as containers for mixing, diluting, and/or administering the conjugates to a subject in need of such treatment.
  • a kit embodying features of the present invention, generally designated by the numeral 11 is illustrated in Figure 1.
  • Kit 11 is comprised of the following major elements: packaging 15, a first agent of the invention 17 (e.g., a container that contains a fatty acid conjugate of a N- substituted indol-3 -glyoxyl-amide, a second agent of the invention 19 (e.g., a container that contains a nonN-substituted indol-3-glyoxyl-amide anticancer agent), and instructions 21 for utilizing such agents in therapeutic applications.
  • a first agent of the invention 17 e.g., a container that contains a fatty acid conjugate of a N- substituted indol-3 -glyoxyl-amide
  • a second agent of the invention 19 e.g., a container that contains a nonN-substituted indol-3-glyoxyl-amide anticancer agent
  • instructions 21 for utilizing such agents in therapeutic applications.
  • Individuals skilled in the art can readily modify packaging 15 to suit individual needs.
  • the anti cancer compounds in the kit may be provided as liquid solutions, or as dried powders.
  • the powder When the compound provided is a dry powder, the powder may be reconstituted by the addition of a suitable solvent, which also may be provided. Liquid forms of the conjugates may be concentrated (for dilution prior to administration) or ready to administer to a subject.
  • the therapeutic index is the ratio of the median toxic dose to the median effective dose.
  • Conjugation of fatty acids to anticancer compounds to form a fatty acid-anticancer compound conjugate reduces toxicity of the anticancer compounds, and increases effectiveness as compared to the unconjugated anticancer compounds. Therefore the invention also provides methods for increasing the therapeutic index of anticancer compounds in a subject.
  • the methods include conjugating a fatty acid to an anticancer compound to form a fatty acid-anticancer compound conjugate and administering the fatty acid-anticancer compound conjugate to the subject.
  • the therapeutic index of the anticancer compound conjugate is improved relative to unconjugated formulations of the anticancer compound.
  • the anticancer compound is a taxane, particularly paclitaxel or docetaxel.
  • the conjugate may be encapsulated in a liposome, it is preferred that the conjugate is not encapsulated by a liposome.
  • the preferred subjects for the method are humans.
  • the conjugated anti cancer compounds described herein are less toxic and more effective than the corresponding unconjugated anti cancer compounds. Therefore the fatty acid-anti cancer compound conjugates can be administered in amounts which are equally toxic but more effective, or in doses which are equally effective and less toxic than the corresponding unconjugated anti cancer compounds. In general, conjugation of fatty acids to anti cancer compounds permits an increase in the maximum tolerated dose relative to unconjugated anti cancer compounds.
  • the compounds useful in the invention may be delivered in the form of anti-cancer cocktails.
  • An anti-cancer cocktail is a mixture of any one of the compounds useful with this invention with another anti-cancer agent such as an anti-cancer drug, a cytokine, and/or supplementary potentiating agent(s).
  • Another anti-cancer agent such as an anti-cancer drug, a cytokine, and/or supplementary potentiating agent(s).
  • a common administration vehicle e.g., pill, tablet, implant, injectable solution, etc.
  • Anti-cancer agents include, but are not limited to, the following compounds and classes of compounds:
  • Antineoplastic agents such as: Acivicin; Aclarubicin; Acodazole Hydrochloride; Acronine; Adozelesin; Adriamycin; Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin; Cisplatin; Cla
  • Fadrozole Hydrochloride Fazarabine; Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil; 5-FdUMP; Flurocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine;
  • Mitindomide Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper;
  • Mitotane Mitoxantrone Hydrochloride
  • Mycophenolic Acid Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin; Pentamustine; Peplomycin
  • Puromycin Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safingol;
  • Safingol Hydrochloride Semustine; Simtrazene; Sparfosate Sodium; Sparsomycin; Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin;
  • anti-neoplastic compounds include: 20-epi-l,25 dihydroxyvitamin D3 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1 antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid ara-CDP-DL-PTBA; arginine deaminas
  • plasminogen activator inhibitor platinum complex; platinum compounds; platinum-triamine complex; podophyllotoxin; porfimer sodium; porfiromycin; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide
  • Benign prostatic hyperplasia therapy agent Tamsulosin Hydrochloride.
  • Prostate growth inhibitor Pentomone.
  • Radioactive agents Fibrinogen 1 125; Fludeoxyglucose F 18; Fluorodopa F 18;
  • Insulin I 125 Insulin I 131; Iobenguane I 123; Iodipamide Sodium I 131 ; Iodoantipyrine I
  • Tricyclic anti-depressant drugs e.g., imipramine, desipramine, amitryptyline, clomipramine, trimipramine, doxepin, nortriptyline, protriptyline, amoxapine and maprotiline
  • non-tricyclic anti-depressant drugs e.g., sertraline, trazodone and citalopram
  • Ca ++ antagonists e.g., verapamil, nifedipine, nitrendipine and caroverine
  • Calmodulin inhibitors e.g., prenylamine, trifluoroperazine and clomipramine
  • Amphotericin B Triparanol analogues (e.g., tamoxifen); antiarrhythmic drugs (e.g., quinidine); antihypertensive drugs (e.g., reserpine); Thiol depleters (e
  • the compounds of the invention also can be administered with cytokines such as granulocyte colony stimulating factor.
  • Preferred anticancer agents used in anti-cancer coctails include (some with their MTDs shown in parentheses): gemcitabine (1000 mg/m 2 ); methotrexate (15 gm/m 2 i.v.+ leuco. ⁇ 500 mg/m 2 i.v. w/o leuco); 5-FU (500 mg/m 2 /day x 5days); FUDR (100 mg/kg x 5 in mice, 0.6 mg/kg/day in human i.a.); FdUMP;
  • Hydroxyurea 35 mg/kg/d in man
  • Docetaxel 60-100 mg/m
  • discodermolide epothilones
  • vincristine 1.4 mg/m 2
  • vinblastine escalating: 3.3 - 11.1 mg/m 2 , or rarely to 18.5 mg/m 2
  • vinorelbine (30 mg/m 2 /wk); meta-pac; irinotecan (50-150 mg/m 2 , 1 x /wk depending on patient response); SN-38 ( ⁇ 100 times more potent than Irinotecan); 10-OH campto; topotecan
  • a therapeutically effective amount will be determined by the parameters discussed below; but, in any event, is that amount which establishes a level of the drug(s) in the area of the tumor which is effective in inhibiting the tumor growth.
  • the formulations of the invention are applied in pharmaceutically acceptable amounts and in pharmaceutically acceptable compositions.
  • Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic ingredients.
  • the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof and are not excluded from the scope of the invention.
  • Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulfonic, tartaric, citric, methane sulfonic, formic, malonic, succinic, naphthalene-2-sulfonic, and benzene sulfonic.
  • pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.
  • Suitable buffering agents include: acetic acid and a salt (1-2% W/V); citric acid and a salt (1-3% W/V); boric acid and a salt (0.5-2.5% W/V); and phosphoric acid and a salt (0.8- 2% W/V).
  • Suitable preservatives include benzalkonium chloride (0.003-0.03%) W/V); chlorobutanol (0.3-0.9% W/V); parabens (0.01-0.25% W V) and thimerosal (0.004-0.02% W/V).
  • the active compounds of the present invention may be a pharmaceutical composition having a therapeutically effective amount of a conjugate of the invention optionally included in a pharmaceutically-acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler, dilutants or encapsulating substances which are suitable for administration to a human or other animal.
  • carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • the components of the pharmaceutical compositions are capable of being commingled with the molecules of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.
  • compositions suitable for parenteral administration conveniently comprise a sterile preparation of the conjugates of the invention.
  • This preparation may be formulated according to known methods.
  • Formulations for Taxol and other taxanes can be found in Chapter 9 of
  • Taxol Science and Applications, CRC Press, Inc., 2000 Corporate Boulevard, N.W., Boca Raton, FL 33431.
  • Taxol has been formulated as a 6 mg/ml cremophor EL (polyoxyethylated castor oil)/ethanol mixture, which is diluted to final volume with normal saline or 5% dextrose.
  • cremophor EL polyoxyethylated castor oil
  • a 15mg/ml solution of taxotere has been formulated in polysorbate 80 (polyoxyethylene sorbitanmonooleate)/ethanol mixture, diluted with 5% dextrose.
  • the sterile preparation thus may be a sterile solution or suspension in a non-toxic parenterally-acceptable diluent or solvent.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono ordi-glycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Carrier formulations suitable for oral, subcutaneous, intravenous, intramuscular, etc. can be found in Remington's Pharmaceutical Sciences. Mack Publishing Company, Easton, PA.
  • the invention is used in connection with treating subject having, suspected of having, developing or suspected of developing cancer.
  • a subject as used herein means humans, primates, horses, cows, pigs, sheep, goats, dogs, cats and rodents.
  • the conjugates of the invention are administered in effective amounts.
  • An effective amount means that amount necessary to delay the onset of, inhibit the progression of or halt altogether the onset or progression of the particular condition being treated. In general, an effective amount will be that amount necessary to inhibit mammalian cancer cell proliferation in-situ.
  • effective amounts When administered to a subject, effective amounts will depend, of course, on the particular condition being treated; the severity of the condition; individual patient parameters including age, physical condition, size and weight; concurrent treatment; frequency of treatment; and the mode of administration. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgment.
  • Dosage may be adjusted appropriately to achieve desired drug levels, locally or systemically.
  • daily oral doses of active compounds will be from about 0.01 mg/kg per day to 1000 mg/kg per day. It is expected that IN doses in the range of about 1 to 1000 mg/m 2 per day will be effective. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Continuous IN dosing over, for example 24 hours or multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.
  • a variety of administration routes are available. The particular mode selected will depend of course, upon the particular drug selected, the severity of the disease state being treated and the dosage required for therapeutic efficacy.
  • the methods of this invention may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects.
  • modes of administration include oral, rectal, sublingual, topical, nasal, transdermal or parenteral routes.
  • parenteral includes subcutaneous, intravenous, intramuscular, or infusion. Intravenous routes are preferred.
  • compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the conjugates of the invention into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active compound.
  • Other compositions include suspensions in aqueous liquors or non- aqueous liquids such as a syrup, an elixir, or an emulsion.
  • Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the active compounds of the invention, increasing convenience to the subject and the physician.
  • Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer based systems such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactone; nonpolymer systems that are lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-, di and triglycerides; hydrogel release systems; silastic systems; peptide based systems; wax coatings, compressed tablets using conventional binders and excipients, partially fused implants and the like.
  • a pump-based hardware delivery system can be used, some of which are adapted for implantation.
  • a long-term sustained release implant also may be used. "Long-term" release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 30 days, and preferably 60 days.
  • Long-term sustained release implants are well known to those of ordinary skill in the art and include some of the release systems described above. Such implants can be particularly useful in treating solid tumors by placing the implant near or directly within the tumor, thereby affecting localized, high-doses of the compounds of the invention.
  • Type 1 analogs i.e., those containing the -O 2 CR subgroup
  • Type 2 analogs are prepared by reaction of the appropriate amino-group-substituted parent drug with a fatty acid in the presence of dicyclohexylcarbodiimide or other carboxyl-activating agent and 4- dimethylaminopyridine or 4-pyrrolidinopyridine.
  • Type 2 analogs i.e., those containing the -NHCOR subgroup
  • Type 2 analogs are prepared by reaction of the appropriate amino-group-substituted parent drug with a fatty acid in the presence of dicyclohexylcarbodiimide or other carboxyl-activating agent and 4- dimethylaminopyridine or 4-pyrrolidinopyridine.
  • Type 3 analogs i.e., those containing the - (CH 2 ) complicatO 2 CR subgroup
  • Type 3 analogs are prepared by reaction of the appropriate ⁇ -hydroxy alkyl-group substituted parent drug with a fatty acid in the presence of dicyclohexylcarbodiimide or other carboxyl-activating agent and 4-dimethylaminopyridine or 4-pyrrolidinopyridine.
  • Type 4 analogs i.e., those containing the -(CH ) n NHCOR subgroup
  • Type 4 analogs are prepared by reaction of the appropriate ⁇ -amino alkyl-group substituted parent drug with a fatty acid in the presence of dicyclohexylcarbodiimide or other carboxyl-activating agent and 4-dimethylaminopyridine or 4-pyrrolidinopyridine.
  • Type 5 analogs i.e., those containing the -O 2 C(CH 2 ) n O 2 CR subgroup
  • Type 5 analogs are formed by reaction of the appropriate hydroxy-group-substituted parent drug with an ⁇ - benzyloxy-(CH 2 ) n CO 2 H in the presence of dicyclohexylcarbodiimide or other carboxyl- activating agent and 4-dimethylaminopyridine or 4-pyrrolidinopyridine followed by hydrogenolytic removal of the benzyl protecting group and subsequent reaction of the deprotected intermediate with a fatty acid in the presence of dicyclohexylcarbodiimide or other carboxyl-activating agent and 4-dimethylaminopyridine or 4-pyrrolidinopyridine.
  • Type 6 analogs i.e., those containing the -O 2 C(CH 2 ) n NHCOR subgroup
  • Type 6 analogs are formed by reaction of the appropriate hydroxy-group-substituted parent drug with an ⁇ -PhCH 2 OCONH- (CH 2 ) n CO 2 H in the presence of dicyclohexylcarbodiimide or other carboxyl-activating agent and 4-dimethylaminopyridine or 4-pyrrolidinopyridine followed by hydrogenolytic removal of the benzyloxycarbonyl protecting group and subsequent reaction of the deprotected intermediate with a fatty acid in the presence of dicyclohexylcarbodiimide or other carboxyl- activating agent and 4-dimethylaminopyridine or 4-pyrrolidinopyridine.
  • Type 7 analogs i.e., those containing the -O(CH 2 ) n O 2 CR subgroup
  • Type 7 analogs are prepared by reaction of the appropriate hydroxy-group-substituted parent drug with a 1-benzyloxy- ⁇ -iodo-r ⁇ -alkane in the presence of base followed by hydrogenolytic removal of the benzyl protecting group and subsequent reaction of the deprotected intermediate with a fatty acid in the presence of dicyclohexylcarbodiimide or other carboxyl-activating agent and 4-dimethylaminopyridine or 4-pyrrolidinopyridine.
  • Type 8 analogs i.e., those containing the -O(CH 2 ) n NHCOR subgroup
  • Type 8 analogs are prepared by reaction of the appropriate hydroxy-group-substituted parent drug with a 1 -azido- ⁇ -iodo- «-alkane in the presence of base followed by hydrogenation and subsequent reaction of the primary amine intermediate with a fatty acid in the presence of dicyclohexylcarbodiimide or other carboxyl-activating agent and 4-dimethylaminopyridine or 4-pyrrolidinopyridine.
  • Type 9 analogs i.e., those containing the -NHCO(CH 2 ) n O 2 CR subgroup
  • Type 9 analogs are prepared by reaction of the appropriate amino-group-substituted parent drug with an ⁇ -benzyloxy-(CH ) n CO 2 H in the presence of dicyclohexylcarbodiimide or other carboxyl-activating agent and 4-dimethylaminopyridine or 4-pyrrolidinopyridine followed by hydrogenolytic removal of the benzyl protecting group and subsequent reaction of the deprotected intermediate with a fatty acid in the presence of dicyclohexylcarbodiimide or other carboxyl-activating agent and 4-dimethylaminopyridine or 4-pyrrolidinopyridine.
  • Type 10 analogs i.e., those containing the -NHCO(CH 2 ) n NHCOR subgroup
  • Type 10 analogs are prepared by reaction of the appropriate amino-group-substituted parent drug with an ⁇ -PhCH 2 OCONH- (CH 2 ) n CO 2 H in the presence of dicyclohexylcarbodiimide or other carboxyl-activating agent and 4-dimethylaminopyridine or 4-pyrrolidinopyridine followed by hydrogenolytic removal of the benzyloxycarbonyl protecting group and subsequent reaction of the deprotected intermediate with a fatty acid in the presence of dicyclohexylcarbodiimide or other carboxyl- activating agent and 4-dimethylaminopyridine or 4-pyrrolidinopyridine.
  • Type 11 analogs i.e., those containing the -NH(CH 2 ) n O 2 CR subgroup
  • Type 11 analogs are prepared by reaction of the appropriate amino-group-substituted parent drug and a l-benzyloxy- ⁇ -iodo- «-alkane followed by hydrogenolytic removal of the benzyl protecting group and subsequent reaction of the deprotected intermediate with a fatty acid in the presence of dicyclohexylcarbodiimide or other carboxyl-activating agent and 4-dimethylaminopyridine or 4-pyrrolidinopyridine.
  • Type 12 analogs i.e., those containing the -NH(CH 2 ) n NHCOR subgroup
  • Type 12 analogs are prepared by reaction of the appropriate amino-groups-substituted parent drug with a l-azido- ⁇ -iodo- «- alkane followed by hydrogenation and subsequent reaction of the primary amine intermediate with a fatty acid in the presence of dicyclohexylcarbodiimide or other carboxyl-activating agent and 4-dimethylaminopyridine or 4-pyrrolidinopyridine.
  • Type 13 analogs i.e., those containing the -COR subgroup
  • Type 14 analogs i.e., those containing the JCH ) n O 2 CR subgroup
  • Type 14 analogs are prepared by sequential reaction of the parent drug with sodium hydride or another base and a 1-benzyloxy- ⁇ -iodo-w-alkane followed by hydrogenolytic removal of the benzyl protecting group and subsequent reaction of the deprotected intermediate with a fatty acid in the presence of dicyclohexylcarbodiimide or other carboxyl-activating agent and 4- dimethylaminopyridine or 4-pyrrolidinopyridine.
  • Type 15 analogs i.e., those containing the -(CH 2 ) n NHCOR subgroup
  • Type 15 analogs are prepared by sequential reaction of the parent drug with sodium hydride or another base and an 1 -azido- ⁇ -r ⁇ -alkane followed by hydrogenation and subsequent reaction of the primary amine intermediate with a fatty acid in the presence of dicyclohexylcarbodiimide or other carboxyl-activating agent and 4-dimethylaminopyridine or 4-pyrrolidinopyridine.
  • Type 16 analogs i.e., those containing the -CO(CH 2 ) n O 2 CR subgroup
  • Type 16 analogs are prepared by sequential reaction of the parent drug with sodium hydride or another base and an ⁇ -benzyloxy-(CH 2 ) n C ⁇ 2 H-derived acid chloride followed by hydrogenolytic removal of the benzyl protecting group and subsequent reaction of the deprotected intermediate with a fatty acid in the presence of dicyclohexylcarbodiimide or other carboxyl-activating agent and 4-dimethylaminopyridine or 4-pyrrolidinopyridine.
  • Type 16 analogs i.e., those containing the -CO(CH 2 ) n O 2 CR subgroup
  • Type 16 analogs are prepared by sequential reaction of the parent drug with sodium hydride or another base and an ⁇ -benzyloxy-(CH 2 ) n C ⁇ 2 H-derived acid chloride followed by hydrogenolytic removal of the benzyl protecting group and subsequent reaction of the
  • Example 2 The Effects of Taxoprexin and Paclitaxel against M 109 Lung Carcinoma in Mice
  • taxoprexin completely eliminated all measurable tumors in seven out of eight mice (C/T-l/8) at 120 mg/kg/day x 5 days, and in four out of seven mice at 80 mg/kg/day x 5 days. Histological examination of the tissue where the tumors had showed no tumor cells, only scar tissue. These data show that taxoprexin is curative in this model.
  • Taxoprexin has - 100 fold lower clearance rate and volume of distribution (see Table 1).
  • Example 5 Plasma Concentration of Taxoprexin and Paclitaxel in Rats Following I.V. Administrations of Taxoprexin
  • Rats were given a 3 minute intravenous infusion of taxoprexin through the tail vein at 0 time.
  • the drug was dissolved in 10% cremophor EL/10% ethanol/80% saline.
  • the dose was 6.8 mg/kg.
  • the concentrations in serum of both paclitaxel and taxoprexin as a function of time were measured in a reverse phase HPLC assay (see Table 2). Table 2.
  • Taxoprexin ® plasma concentration (ng/ml) following administration of Taxoprexin ® in Rats
  • Example 6 Plasma and Tumor Concentrations of Paclitaxel Derived from an I.V. Dose of 50 mg/kg of Taxoprexin to Mice Bearing M 109 or M 5076 Tumors
  • mice with tumors derived from Ml 09 or M5076 were given a bolus does of taxoprexin through the tail vein at 0 time.
  • the drug was dissolved in 10% cremophor EL/10%) ethanol/80% saline.
  • Mice were sacrificed and tumors immediately excised as a function of time after injecting the drug.
  • Tumor tissue was homogenized and paclitaxel extracted.
  • the concentration of paclitaxel was measured in a reverse phase HPLC assay. Blood was collected at the same time intervals and the amount of paclitaxel determined. The results show that after 24 hours the concentration of paclitaxel derived from taxoprexin is about 3 ⁇ M, 40 times higher than the plasma concentration, 70 nM.
  • mice, rats and dogs Dose comparisons for paclitaxel and taxoprexin were made in mice, rats and dogs.
  • the maximum tolerated dose (MTD) for mice, rats and dogs were about 4-5 times higher for taxoprexin than for paclitaxel on a mg/kg basis, or 3-3.5 times higher on a molar paclitaxel equivalent basis.
  • Dose limiting toxicity for rats and dogs is due to decreases in platelets, neutrophils and lymphocytes. Taxoprexin is less toxic to mice, rats and dogs than is paclitaxel(see Table 3). Table 3.
  • taxoprexin thus appears to have a 100 fold lower clearance rate and volume of distribution than paclitaxel.

Abstract

La présente invention concerne des amides indol-3- glyoxyl substitués à N, qui sont des conjugués d'acides gras et N-(pyridin-4-yl) -(1-(4-halobenzyl) -indol-3-yl) -glyoxyl -amides). Les conjugués sont utiles au traitement du cancer.
PCT/US2000/012752 1999-05-10 2000-05-10 Compositions d'acides gras -n-substituted indol-3-glyoxyl-amide et leur utilisation WO2000067802A1 (fr)

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WO2001045744A3 (fr) * 1999-12-21 2002-05-02 Ramchand Chaniyilparampu Nanap Nouveaux composes d'acides gras non satures
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EP2163552A1 (fr) * 2000-07-28 2010-03-17 AEterna Zentaris GmbH derives d'indol et leur utilisation comme agents antitumeurs
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WO2006030217A3 (fr) * 2004-09-15 2007-03-22 Drug Discovery Lab As Composés
WO2006030217A2 (fr) * 2004-09-15 2006-03-23 Drug Discovery Laboratory As Composés
US8884020B2 (en) 2006-08-07 2014-11-11 Ironwood Pharmaceuticals, Inc. Indole compounds
US9657012B2 (en) 2010-12-22 2017-05-23 Ironwood Pharmaceuticals, Inc. FAAH inhibitors

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