WO2013016531A2 - Composés et méthodes de traitement d'une néoplasie ou d'un cancer - Google Patents

Composés et méthodes de traitement d'une néoplasie ou d'un cancer Download PDF

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WO2013016531A2
WO2013016531A2 PCT/US2012/048334 US2012048334W WO2013016531A2 WO 2013016531 A2 WO2013016531 A2 WO 2013016531A2 US 2012048334 W US2012048334 W US 2012048334W WO 2013016531 A2 WO2013016531 A2 WO 2013016531A2
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compound
alkyl
optionally substituted
group
pharmaceutically acceptable
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PCT/US2012/048334
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WO2013016531A3 (fr
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Richard A. Gibbs
Joel A. BERGMAN
Kalub HAHNE
Christine A. Hrycyna
Liza SHRESTHA
Markus A. Lill
Gregory Wilson
Jaimeen MAJMUDAR
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Purdue Research Foundation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a novel method for the treatment of neoplasia, including cancer and other diseases and conditions in animals, including mammals, especially humans. More particularly, in preferred aspects, the present invention provides a method for the use of a novel class of chemical agents which are inhibitors of isoprenylcysteine methyltransferase, for the treatment of both neoplasia and cancer, and a number of
  • Cancer is a disease of abnormal cell growth often leading to death. Cancer is treated by three principal means; surgical removal of the tumor, therapeutic radiation, and treatment with anti-tumor chemical compounds. Treatment with chemical compounds, termed chemotherapy, is often hindered by the inherent toxicity of the chemicals to the patient and resistance of the tumor to the chemical treatment. Therefore the identification of less toxic anti-tumor agents capable of inhibiting growth of resistant tumors is of great importance.
  • Ras proteins and many other important signal transduction proteins must undergo significant post-translational modification in order to be functional in the eucaryotic cell. These proteins possess a signature carboxyl -terminal CaaX box motif (See Figure 1), with is recognized by one of the two prenyltransferases, FTase (protein-farnesyltransferase) or GGTase I (protein-geranylgeranyltransferase I).
  • FTase protein-farnesyltransferase
  • GGTase I protein-geranylgeranyltransferase I
  • Ras proteins and certain other proteins are farnesylated, but the majority of naturally-occuring CaaX proteins are geranylgeranylated by GGTase I.
  • CaaX motif proteins are subjected to removal of the aaX residues by the protease RCEl, followed by SAM-dependent methylation of the resulting cysteine carboxylate by Icmt.
  • These two membrane-bound enzymes recognize and modify both farnesylated and geranylgeranylated proteins.
  • the overall result of these three post-translational steps is to convert a hydrophillic protein into a more hydrophobic, membrane-associated one.
  • Icmt inhibitors may be intriguing potential anticancer agents.
  • the present application is thus directed to the examination of the substrate specificity of Icmt with a view toward the development of substrate-based inhibitors of the enzyme.
  • active compounds are disclosed as anti-cancer/anti-tumor agents as well as agents to treat disease states or conditions which are modulated through isoprenyl cysteine methyltransferase enzyme, including hyperproliferative cell growth, restenosis following cardiovascular surgery, hyperplasia, including renal hyperplasia, psoriasis, chronic inflammatory diseases including rheumatoid and osteoarthritis, among others.
  • Ras and other - CaaX proteins undergo three sequential reactions: isoprenylation of the cysteine, in particular farnesylation by farnesyltransferase (FTase); proteolysis of the three terminal amino acids (- aaX); and a-carboxyl methylation of the isoprenylated cysteine.
  • FTase inhibitors are being evaluated in clinical trials as cancer chemotherapeutic agents. Unfortunately, these compounds have surprisingly little effect on many Ras-transformed tumors.
  • Icmt isoprenylcysteine methyltransferase
  • Carboxyl methylation is critical for the proper localization of Ras proteins in yeast and mouse cells. Given this finding, we believe that Icmt represents an excellent target for chemotherapeutic intervention. Potent cell permeable inhibitors will be evaluated for their ability to mislocalize Ras, interfere with Ras-mediated signaling, block anchorage-independent growth of pancreatic ductal carcinoma, and block tumor growth in vivo.
  • an object of the present invention is to provide compounds and methods for the treatment of tumors and/or cancer in mammals.
  • an object of the present invention is to provide pharmaceutical compositions useful for the treatment of tumors and/or cancer, hyperproliferative cell growth, restenosis following cardiovascular surgery, hyperplasia, including renal hyperplasia, psoriasis, chronic inflammatory diseases including rheumatoid and osteoarthritis, among others.
  • objects of the present invention provide compounds and methods for the treatment of neoplasia, hyperproliferative cell growth, restenosis following cardiovascular surgery, hyperplasia, including renal hyperplasia, psoriasis, chronic inflammatory diseases including rheumatoid and osteoarthritis, among others.
  • objects of the invention provide methods of inhibiting isoprenylcysteine methyltransferase, an enzyme which is believed to modulate a number of disease states or conditions including neoplasia, hyperproliferative cell growth, restenosis following cardiovascular surgery, hyperplasia, including renal hyperplasia, psoriasis, chronic inflammatory diseases including rheumatoid and osteoarthritis, among others.
  • the present invention relates to a series of novel FTP-triazole compounds as potent inhibitors of Icmt, through a focus on thioether and prenyl mimetics. These mimetics were coupled utilizing a copper-assisted cycloaddition to assemble the potential inhibitors.
  • TAB-Me biphenyl substituted FTP triazole
  • STAB-Me a more potent inhibitor, "STAB-Me”, with a calculated Kj value of 140 nM for Icmt. Both of these compounds block the membrane localization of K-Ras and the methylation of famesylated proteins in cellular model systems. Moreover, they exhibit selective cytostatic effects toward Icmt+/+ MEFs, and block the growth of the pancreatic tumor cell line PaTu (STAB-ME in PaTu - 7.3 ⁇ +/- 0.7; TAB-Me in PaTu - 8.15 ⁇ +/- 3).
  • the present invention is directed to compounds of the chemical formula (I):
  • A is -(CH 2 ) lake-, -C(O)-, -(CH 2 )iC(R A ) 2 -, -C(R A ) 2 (CH 2 )i-, C 1-6 alkyl optionally substituted with 1-3 halogens,
  • B is S, S(O), S(O) 2 , or -C(O)- ;
  • n is an integer from 0-12 (0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12);
  • R s is H, N 3 , CN, N0 2 , halogen, C 1 -C 6 alkyl optionally substituted with one or two hydroxyl groups or up to three halogen groups (often F), OR 1 , SR 1 ,
  • R s and R Sa form a five or 6-membered carbocyclic or heterocyclic group (e.g. a 1,3 dioxolane group, etc.);
  • R N is H or a C 1- C 3 alkyl group
  • Each R 1 is independently H, C 1 -C 6 alkyl which is optionally substituted with one or two hydroxyl groups or up to 3 halogen groups, an optionally substituted C 4 -C 20 hydrocarbyl group, preferably an alkyl or alkene group (which may include multiple unsaturations, preferably a C5-C 10 alkyl group (including butyl, sec-butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, nonyl, isononyl, decyl), an optionally substituted aryl group (e.g., phenyl including benzyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, C 1 -C 4 alkyl phenyl, heteroarylphenyl or heterocyclylphenyl or an optional
  • R 2 is G-D, where G is an optionally substituted C 1 -C 20 alkyl, alkenyl, alkynyl or aryl group and D is absent, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-optionally substituted aryl, (optionally substituted C 1 -C 10 alkyl, alkenyl or alkynyl)-optionally substituted aryl, (optionally substituted C 1 -C 10 alkyl, alkenyl or alkynyl)- (optionally substituted aryl)- (optionally substituted aryl (optionally substituted C 1 -C 10 alkyl or alkenyl)-0-(optionally substituted aryl-optionally substituted aryl);
  • compounds of the invention have the chemical formula (II):
  • x is 1-6, preferably 1-4, more preferably 2 or 3; y is 1-3, preferably 1-2, more preferably 1; and z is 1-3, preferably 1-2, more preferably 2, or a pharmaceutically acceptable salt, stereoisomer, enantiomer, solvate or polymorph thereof.
  • the present invention relates to a compound according to the chemical formula (II):
  • R is H or a C 1 -C 4 alkyl group, preferably H or CH 3 , more preferably CH 3 ;
  • R 1 is an optionally substituted C 4 -C 20 hydrocarbyl group, preferably an alkyl or alkene group (which may include multiple unsaturations, preferably a C 5 -C 10 alkyl group (including butyl, sec-butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, nonyl, isononyl, decyl), an optionally substituted phenyl (including benzyl, ethylphenyl,
  • aryl-aryl including optionally substituted bi-phenyl, C 1- C4 alkyl, alkenyl or alkynyl-optionally substituted aryl- aryl including C 1 -C 4 alkyl, alkenyl or alkynyl- optionally substituted bi-phenyl,
  • R 1 of formula (II) is a group, where z is 1-3, preferably 2.
  • One or more additional compounds according to the present invention are disclosed in further detail herein, and include such exemplary compounds as the following:
  • compositions according to the present invention comprise an effective amount of one or more of the above-depicted compounds or as otherwise described in the attached appendices hereof, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient and further optionally in combination with an additional anticancer agent.
  • the method of the present invention involves the use of compounds to treat neoplasia and other diseases and conditions such as hyperproliferative cell growth, restenosis following cardiovascular surgery, hyperplasia, including renal hyperplasia, psoriasis, chronic inflammatory diseases including rheumatoid and osteoarthritis, among others of animals, especially mammals, including humans, encompassed by a compound as otherwise described above or in the attached appendices hereof.
  • an effective amount of one or more compounds according to the present invention, optionally in combination with at least one additional anticancer agent is administered to a patient in need.
  • the compounds of the present invention are used to treat benign and malignant neoplasia, including various cancers such as, stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, prostate, testis, bladder, renal, brain/ens, head and neck, throat, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms Tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx, oesophagus, larynx, melanoma, kidney, lymphoma, among others.
  • Compounds according to the present invention are particularly useful in the treatment of breast cancer,
  • cardiovascular surgery hyperplasia, including renal hyperplasia, among others using one or more of the disclosed compositions are other inventive aspects of the present invention.
  • inventive aspects of the present invention relate to the use of the present compositions in the treatment of arthritis and chronic inflammatory diseases, including rheumatoid arthritis and osteoarthritis, among others.
  • the present invention also relates to methods for inhibiting the growth of neoplasia, including a malignant tumor or cancer comprising exposing the neoplasia to an inhibitory or therapeutically effective amount or concentration of at least one of the disclosed compounds.
  • This method may be used therapeutically, in the treatment of neoplasia, including cancer or in comparison tests such as assays for determining the activities of related analogs as well as for determining the susceptibility of a patient's cancer to one or more of the compounds according to the present invention.
  • Methods for treating abnormal cell proliferation or growth of non-transformed cells including the treatment of psoriasis, restenosis following cardiovascular surgery, hyperplasia, including renal hyperplasia, among others, chronic inflammatory diseases including rheumatoid and osteoarthritis, among others, comprising administering a therapeutically effective amount of one or more of the disclosed compounds for treating the condition or disease are also contemplated within the scope of the present invention.
  • the present invention also relates to a method for inhibiting isoprenylcysteine methyltransferase comprising exposing said enzyme to an effective amount of any one or more of the compounds which are set forth hereinabove.
  • Others aspects according to the present invention relate to a method of inhibiting isoprenyl cysteine methyltransferase enzyme in a patient in order to treat a disease or condition modulated by said enzyme comprising administering to said patient an effective amount of any one or more of the compounds compound which are set forth hereinabove.
  • Disease states or conditions which are believed to be modulated by this enzyme include for example, neoplasia, hyperproliferative cell growth, restenosis following cardiovascular surgery, hyperplasia, including renal hyperplasia, psoriasis, chronic inflammatory diseases including rheumatoid and osteoarthritis, among others.
  • FIG. 1 Simplified schematic depicting the post-translational modifications of the Ras family of proteins.
  • Farnesylation (FTase), endoproteolysis (Rce-1) of the C-terminal -AAX residues and carboxylmethylation (Icmt) are necessary for biological activation of Ras proteins.
  • FIG. 1 Structures of Icmt substrates (a,b) and inhibitors (c,d).
  • Figure 3 Plausible mechanistic pathway of analog 16 under assay conditions to yield 12.
  • Figure SI Possible intra-molecular hydrogen bonding in compound 29 could result in lack of activity vis-a-vis compound 12.
  • Figure S2 Compound 12 (Farnol) is a mixed competitive Icmt inhibitor with a predominant competitive component (alpha value greater than 1).
  • FIG. 1 Compound 12 alters the subcellular localization of GFP K-Ras in Jurkat T cells.
  • Jurkat T cells were transiently transfected with GFP K-Ras and treated with DMSO as a control, simvastatin (45 ⁇ ) or compound 12 at the indicated concentration for 24 hours.
  • the histogram depicts the differences in GFP K-Ras localization after indicated treatment.
  • FIG. 1A Cell growth inhibition of mouse embryonic fibroblasts by 12n.
  • a MEFs are plated in 96 well plates at a density of 1000 cell/well in DMEM supplemented with 10% FBS. After incubation for 24 hrs, the media is replaced with DMEM supplemented with 5% FBS and 12n (various cone.) or DMSO (0.1%).
  • the cell viability is determined after five days using MTT. Twenty microliters of MTT (5 mg/ml) is added to each well and incubated for 4 hrs at 37°C. Afterwards, the media is removed and 150 ⁇ of DMSO is added to each well. The absorbance is determined at 590 nm using a Molecular Devices VERSAmax microplate reader.
  • the IC 50 of Icmt + + was determined to be 33 ⁇ ⁇ 1 and Icmt ⁇ of > ⁇ . IC 50 determinations were made using Graphpad Prism V4.
  • FIG. 2A This figure represents a generic illustration to library building that led to the identified lead structures.
  • Table 1 A shows the enzymatic inhibition of a number of compounds according to the present invention. Enzymatic inhibitory determinations of each compound were establish by incubating His-hlcmt crude membrane extracts (5 ⁇ g), AFC (10 ⁇ ) and 14 C-SAM (20 ⁇ ) in Tris-HCl (pH 7.5). These reaction mixtures were incubated for 30 min (30 °C) before the reaction was stopped using NaOH and the base labile l4 C-methyl groups transferred were determined using a Packard 1600A Liquid Scintillation Analyzer. Competitive and uncompetitive inhibition constants were determined using the Cheng-Prusoff method (Y.C. Cheng and W.H.
  • compound refers to any specific chemical compound disclosed herein. Within its use or description in context, the term generally refers to a single compound, but in certain instances may also refer to stereoisomers (cis and/or trans, etc.), anomers, epimers and/or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomerically enriched mixtures of disclosed compounds as well as pharmaceutically acceptable salts, solvates and polymorphs thereof.
  • patient is used throughout the specification to describe a subject animal, such as a mammal, preferably a human, to whom treatment, including prophylactic treatment, with the compositions according to the present invention is provided.
  • a subject animal such as a mammal, preferably a human
  • treatment including prophylactic treatment
  • patient refers to that specific animal.
  • an effective amount is used throughout the specification to describe concentrations or amounts of compounds according to the present invention which may be used to produce an effect within context, whether that effect relates to a favorable change in the disease or condition treated, or the change is a remission, a decrease in growth or size of cancer or a tumor, a favorable physiological result, a reduction in the growth or elaboration of a microbe, or the like, depending upon the disease or condition treated.
  • non-existent or “absent” refers to the fact that a substituent is absent and the group to which such substituent is attached forms an additional bond with an adjacent atom or group.
  • alkyl is used throughout the specification to describe a hydrocarbon radical containing between one and twenty carbon units, one and eight, four and twelve, five and ten, five and fifteen or one and four carbon units.
  • Alkyl groups for use in the present invention include linear, branched-chain groups or cyclic groups (cycloalkyl groups).
  • hydrocarbyl refers to a substituent or group having carbon and hydrogen groups and may be saturated or unsaturated. Alkyl groups are subsumed under the term hydrocarbyl in describing the present invention.
  • Aryl refers to a substituted or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene or phenyl) or multiple condensed rings (e.g., naphthyl) and can be bound to a compound according to the present invention at any position on the ring(s).
  • aryl groups include heterocyclic aromatic ring systems "heteroaryl” having one or more nitrogen, oxygen, or sulfur atoms in the ring, such as imidazole, furyl, pyrrole, pyri- dyl, indole and fused ring systems, among numerous others, which may be substituted or unsubstituted.
  • Biphenyl and triphenyl groups also represent aryl groups according to the present invention.
  • Alkoxy refers to an alkyl group bound through an ether linkage; that is, an "alkoxy” group may be represented as ⁇ 0 ⁇ alkyl where alkyl is as defined above.
  • Acyl referes to an alkyl or other hydrocarbyl group bound through a keto linkage.
  • Ester refers to a carboxy ester (where the carbonyl of the ester is attached to the basic pharmacophore) or ester (where the oxygen is attached to the basic pharmacophore).
  • Amide refers to an amide group where the nitrogen is attached to the basic pharmacophore and "carboxamide” refers to an amide group where the carbonyl is attached to the basic pharmacophore.
  • cyclic shall refer to a carbocyclic or heterocyclic group, preferably a 5- or 6-membered ring, but may include 4 and 7-membered rings or fused rings.
  • Bicyclic or “bicyclo” refers to bicyclic
  • heterocycle or “heterocyclic” shall mean an optionally substituted moiety which is cyclic and contains at least one atom other than a carbon atom, such as a nitrogen, sulfur, oxygen or other atom.
  • a heterocyclic ring shall contain up to four atoms other than carbon selected from nitrogen, sulfur and oxygen. These rings may be saturated or have unsaturated bonds. Fused rings are also contemplated by the present invention. Bicyclo groups are also contemplated for use herein.
  • a heterocycle according to the present invention is an optionally substituted imidazole, a piperazine (including piperazinone), piperidine, furan, pyrrole, imidazole, thiazole, oxazole or isoxazole group, among numerous others.
  • a heterocyclic ring may be saturated and/or unsaturated. In instances where a heterocyclic ring is fully unsaturated, there is overlap with the term "heteroaryl".
  • heterocyclic groups which term subsumes exemplary heteroaryl groups within context
  • pyrrole imidazole, diazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, dihydrofuran, tetrahydrofuran, pyran, oxanyl, oxepine, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, iso
  • tetrahydropyrimidine perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroaepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine, tetrahydrooxepine, perhydrooxepine, thiirane, thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,
  • dihydrooxadiazine tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine,
  • perhydroisobenzothiophene dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, tetrahydropyrrolopyridine, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane, dihydrobenzoxazine, dihydro
  • hexahydropyrazolopyridoazepine tetrahydropyrimidoindole, dihydrothiazinoindole, tetrahydrothiazinoindole, dihydrooxazinoindole, tetrahydrooxazinoindole, hexahydroin- dolizinoindole, dihydroindolobenzdiazepine, octahydroindoloquinolizine,
  • substituted shall mean substituted only with hydrogen atoms.
  • substituted shall mean, within the chemical context of the compound defined, a substituent (each of which substituents may itself be substituted) selected from a hydrocarbyl (which may be substituted itself, preferably with an optionally substituted alkyl or halogen (fluoro) group, among others), preferably an alkyl (preferably, about 1-8 carbon units in length, up to about 12 or more carbon units), an optionally substituted aryl (which also may be heteroaryl and may include an alkylenearyl or alkyleneheteroaryl), an optionally substituted heterocycle (especially including an alkyleneheterocycle), CF 3 , halogen (especially fluoro), thiol, hydroxyl, carboxyl (carboxylic acid), oxygen (to form a keto group), C 1 -C 8 alkoxy, CN, nitro, an optionally substituted amine (e.g...
  • substituents may themselves be substituted with substituents as otherwise described herein.
  • Various optionally substituted moieties may be substituted with 5 or more substituents, preferably no more than 3 substituents and preferably from 1 to 3 substituents.
  • the term substituted may include, within context, substituents such as alkylene groups (represented as a -(CH 2 ) n or-(CH 2 ) y group where n is 0, 1, 2, 3, 4, or 5, preferably from 1 to 3 and y is 1, 2, 3, 4 or 5, preferably 1 to 3) which can bridge one moiety to a ring or other group on a pharmacophore or other moiety or substituent.
  • preferred substitutents include (within an appropriate context) one or more halogen groups (F, CI, Br or I) or a C 2 -C 10 alkyl, acyl, ester, amido or carboxamido group, preferably no more than three halogen groups, preferably two halogen groups, which are most preferably F
  • Neoplasia is used to describe the pathological process that results in the formation and growth of a neoplasm, i.e., an abnormal tissue that grows by cellular proliferation more rapidly than normal tissue and continues to grow after the stimuli that initated the new growth cease.
  • Neoplasia exhibits partial or complete lack of structural organization and functional coordination with the normal tissue, and usually form a distinct mass of tissue which may be benign (benign tumor) or malignant (carcinoma).
  • cancer is used as a general term to describe any of various types of malignant neoplasms, most of which invade surrounding tissues, may metastasize to several sites and are likely to recur after attempted removal and to cause death of the patient unless adequately treated.
  • cancer is subsumed under the term neoplasia.
  • Representative cancers include, for example, squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias, including non-acute and acute leukemias, such as acute myelogenous leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia (APL), acute T-cell lymphoblastic leukemia, T-lineage acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia, basophilic leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukopenic leukemia, lymphatic leukemia
  • sarcomas including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hod
  • additional anticancer agent is used to describe a compound which may be combined with one or more compounds according to the present invention in the treatment of cancer and include such compounds/agents as everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101 , pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY- 142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR T inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk
  • cyproterone cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine,
  • hydrocortisone interleukin-11 , dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard,
  • metoclopramide metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof.
  • hypoproliferative cell growth is used to describe conditions of abnormal cell growth of a non-transformed cell often, of the skin, distinguishable from cancer.
  • restenosis is used to describe the recurrence of stenosis after corrective surgery on the heart, including the heart valve, or the narrowing of a structure (usually a coronary artery) following the removal or reduction of a previous narrowing of such structure. It is usually a result of a form of hyperplasia-neointimal hyperplasia.
  • hyperplasia hyperplasia
  • hypertrophy hypertrophy
  • number of hypertrophy is used to describe an increase in the number of cells in a tissue or organ, excluding tumor formation, and refers to all types of hyperplasia, including cystic hyperplasia, cystic hyperplasia of the breast, nodular hyperplasia of the prostate and renal hyperplasia, neointimal hyperplasia, among numerous others.
  • a preferred therapeutic aspect according to the present invention relates to methods for treating neoplasia, including benign and malignant tumors and cancer in animal, especially mammalian, including human patients, comprising administering effective amounts or concentrations of one or more of the compounds according to the present invention to inhibit the growth or spread of or to actually shrink the neoplasia in the animal or human patient being treated.
  • compositions based upon these novel chemical compounds comprise the above-described compounds in an effective amount for the treatment of a condition or disease state such as neoplasia, including cancer, hyperproliferative cell growth, restenosis following cardiovascular surgery, hyperplasia, including renal hyperplasia, psoriasis, chronic inflammatory diseases including rheumatoid and osteoarthritis, among others or a related condition or disease as otherwise described, optionally in combination with a condition or disease state such as neoplasia, including cancer, hyperproliferative cell growth, restenosis following cardiovascular surgery, hyperplasia, including renal hyperplasia, psoriasis, chronic inflammatory diseases including rheumatoid and osteoarthritis, among others or a related condition or disease as otherwise described, optionally in combination with a condition or disease state such as neoplasia, including cancer, hyperproliferative cell growth, restenosis following cardiovascular surgery, hyperplasia, including renal hyperplasia, p
  • Certain of the compounds, in pharmaceutical dosage form may be used as prophylactic agents for preventing a disease or condition from manifesting itself.
  • the pro-drug form of the compounds according to the present invention may be preferred.
  • present compounds or their derivatives, including prodrug forms of these agents can be provided in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts or complexes refers to appropriate salts or scomplexes of the active compounds according to the present invention which retain the desired biological activity of the parent compound and exhibit limited toxicological effects to normal cells.
  • Nonlimiting examples of such salts are (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, and polyglutamic acid, among others; (b) base addition salts formed with metal cations such as zinc, calcium, sodium, potassium, and the like, among numerous others, which are formed at the carboxylic acid position of compounds according to the present invention.
  • inorganic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic
  • Modifications of the active compound can affect the solubility, bioavailability and rate of metabolism of the active species, thus providing control over the delivery of the active species. Further, the modifications can affect the anticancer activity of the compound, in some cases increasing.the activity over the parent compound. This can easily be assessed by preparing the derivative and testing its anticancer activity according to known methods well within the routineer's skill in the art.
  • the compounds of this invention may be incorporated into formulations for all routes of administration including for example, oral, topical and parenteral including intravenous, intramuscular, intraperitoneal, intrabuccal, transdermal and in suppository form, among numerous others.
  • compositions based upon these novel chemical compounds comprise the above-described compounds in an effective amount for treating neoplasia, cancer and other diseases and conditions which have been described herein, including psoriasis, hyperproliferative cell growth, restenosis following cardiovascular surgery, hyperplasia, including renal hyperplasia, chronic inflammatory diseases including rheumatoid and osteoarthritis, among others, optionally in combination with a pharmaceutically acceptable additive, carrier and/or excipient.
  • a therapeutically effective amount of one of more compounds according to the present invention will vary with the infection or condition to be treated, its severity, the treatment regimen to be employed, the pharmacokinetics of the agent used, as well as the patient (animal or human) treated.
  • the compound according to the present invention is formulated preferably in admixture with a
  • compositions in orally-administrable form may be administered via a parenteral, intravenous, intramuscular, transdermal, buccal,
  • Intravenous and intramuscular formulations are preferably administered in sterile saline.
  • one of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity.
  • the modification of the present compounds to render them more soluble in water or other vehicle may be easily accomplished by minor modifications (salt formulation, esterification, etc.) which are well within the ordinary skill in the art.
  • It is also well within the routineer's skill to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect to the patient.
  • the pro-drug form of the compounds may be preferred.
  • One of ordinary skill in the art will recognize how to readily modify the present compounds to pro-drug forms to facilitate delivery of active compounds to a targeted site within the host organism or patient.
  • the routineer also will take advantage of favorable pharmacokinetic parameters of the pro-drug forms, where applicable, in delivering the present compounds to a targeted site within the host organism or patient to maximize the intended effect of the compound.
  • the amount of compound included within therapeutically active formulations according to the present invention is an effective amount for treating the infection or condition.
  • a therapeutically effective amount of the present preferred compound in dosage form usually ranges from slightly less than about 0.025mg./kg. to about 2.5 g./kg., about 0.1-50 mg/kg, about 1-25 mg/kg, about 2.5-5 mg/kg to about 100 mg/kg of the patient or about 10-50 mg/kg, depending upon the compound used, the condition or infection treated and the route of administration, although exceptions to this dosage range may be contemplated by the present invention.
  • Administration of the active compound may range from continuous (intravenous drip) to several oral administrations per day (for example, Q.I.D.) and may include oral, topical, parenteral, intramuscular, intravenous, sub-cutaneous, transdermal (which may include a penetration enhancement agent), buccal and suppository administration, among other routes of administration.
  • a therapeutically effective amount of one or more of the compounds according to the present invention is preferably intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose.
  • a carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral.
  • any of the usual pharmaceutical media may be used.
  • suitable carriers and additives including water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents and the like may be used.
  • suitable carriers and additives including starches, sugar carriers, such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used.
  • the tablets or capsules may be enteric-coated or sustained release by standard techniques.
  • the carrier will usually comprise sterile water or aqueous sodium chloride solution, though other ingredients including those which aid dispersion may be included.
  • sterile water is to be used and maintained as sterile, the compositions and carriers must also be sterilized.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the present compounds may be used to treat animals, and in particular, mammals, including humans, as patients.
  • humans, equines, canines, bovines and other animals, and in particular, mammals, suffering from tumors, and in particular, cancer, or other diseases as disclosed herein can be treated by administering to the patient an effective amount of one or more of the compounds according to the present invention or its derivative or a
  • pharmaceutically acceptable salt thereof optionally in a pharmaceutically acceptable carrier, additive or excipient, either alone, or in combination with other known pharmaceutical agents, depending upon the disease to be treated.
  • This treatment can also be administered in conjunction with other conventional cancer therapies, such as radiation treatment or surgery.
  • the active compound is included in the pharmaceutically acceptable carrier, additive or excipient in an amount sufficient to deliver to a patient a therapeutically effective amount for the desired indication, without causing serious toxic effects in the patient treated.
  • the compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing from less than 1 mg to a gram or more, from about 1 to 3000 mg, about 5 to 500 mg of active ingredient per unit dosage form.
  • An oral dose of about 0.5 to 750 mg, about 1-500 mg, about 5-500mg, about 10-500 mg, about 15 to about 350 mg, about 25-250 mg is usually convenient.
  • the concentration of active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the
  • compositions and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed
  • the active ingredient may be administered at once, or may be divided into a .number of smaller doses to be administered at varying intervals of time.
  • Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a dispersing agent such as alginic acid or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a dispersing agent such as alginic acid or corn starch
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin
  • a flavoring agent
  • the active compound or pharmaceutically acceptable salt thereof may also be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the active compound or pharmaceutically acceptable salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as other anticancer agents, and in certain instances depending upon the desired therapy or target, other antiprolierative agents, antirestenosis agents, antinflammatories, or other related compounds which may be used to treat disease states or conditions according to the present invention.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include.the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as
  • ethylenediaminetetraacetic acid ethylenediaminetetraacetic acid
  • buffers such as acetates, citrates or phosphates
  • agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • preferred carriers include, for example, physiological saline or phosphate buffered saline (PBS).
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • Liposomal suspensions may also be pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared by dissolving appropriate lipid(s) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension. Other methods of preparation well known by those of ordinary skill may also be used in this aspect of the present invention.
  • test panels of cancer cell lines These tests evaluate the in vitro anti-cancer activity of particular compounds in cancer cell lines, and provide predictive data with respect to the use of tested compounds in vivo.
  • Other assays include in vivo evaluations of the compound's effect on human or in an appropriate animal model, for example, using mouse tumor cells implanted into or grafted onto mice or in other appropriate animal models.
  • Representative Compounds include, but are not limited to, those described in this section.
  • A is -(CH 2 ) n -, -(CH 2 ) i C(R A ) 2 -, or -C(R A ) 2 (CH 2 ) i - ;
  • R s is OH, halogen, O-(C 1 -C 6 alkyl), -C(O)OR 1 or (CH) n -OH, where n is 1-6;
  • R 1 is H or C 1 -C 6 alkyl which is optionally substituted with one or two hydroxyl groups or up to 3 halogen groups;
  • G is an optionally substituted C 1 -C 10 alkyl or optionally substituted C 1 -C 10 alkenyl; and D is absent or is a five or six membered heteroaryl which contains 1 , 2 or 3 nitrogens and which is substituted by a C 1 -C 12 alkyl, C 1 -C 12 alkenyl or C 1 -C 12 alkoxy, said C 1 -C 12 alkyl, C 1 -C 12 alkenyl or C 1 -C 12 alkoxy being optionally substituted by (1) an optionally-substituted phenyl (2) an optionally-substituted biphenyl (3) an optionally-substituted triphenyl (4) an optionally-substituted phenyl which itself is optionally substituted by a five or six membered heteroaryl, or (5) a five or six-membered partially or completely saturated heterocyclic group containing a N, S or O atom.
  • A is CH 2 ;
  • R Sa and R Sb are H
  • R s is OH or halogen
  • G is an optionally substituted C 1- C20 alkyl or alkenyl group
  • A is CH 2 ;
  • R Sa is H and R sb is -OH or d-C 6 alkyl;
  • R s is (CH)n-OH, where n is 1 -3 ;
  • G is an optionally substituted C]-C 20 alkyl or alkenyl group
  • A is C 1-6 alkyl optionally substituted with one or two halogens
  • R s is (CH) n -OH, where n is 1-3;
  • G is an optionally substituted C1-C20 alkenyl group
  • A is C 1 -6 alkyl optionally substituted with one or two halogens
  • R Sa and R Sb are H
  • R s is halogen
  • G is an optionally substituted C 1 -C 2 o alkenyl group
  • A is CH 2 ;
  • R Sa and R sb are H
  • R s is OH or halogen
  • G is an optionally substituted C ! -C 20 alkyl or alkenyl group
  • A is C 1 -3 alkyl
  • R s is OH
  • G is an optionally substituted C 1 -C 6 alkenyl group
  • D is triazole which is substituted by a C 1 -C 12 alkyl, C 1 -C 12 alkenyl or C 1- C12 alkoxy, said C 1- C 1 2 alkyl, C 1 -C 12 alkenyl or C 1 -C 12 alkoxy being optionally substituted by (1) an optionally- substituted phenyl (2) an optionally-substituted biphenyl (3) an optionally-substituted triphenyl (4) an optionally-substituted phenyl which itself is optionally substituted by a five or six membered heteroaryl, or (5) a five or six-membered partially or completely saturated heterocyclic group containing a N, S or O atom.
  • A is C1.3 alkyl
  • R is C 1-3 alkoxy
  • G is an optionally substituted C 1 -C 6 alkenyl group
  • D is triazole which is substituted by a C 1 -C 12 alkyl, said C 1 -C 12 alkyl being substituted by (1) an optionally-substituted phenyl (2) an optionally-substituted biphenyl (3) an optionally- substituted triphenyl (4) an optionally-substituted phenyl which itself is optionally substituted by a five or six membered heteroaryl, or (5) a five or six-membered partially or completely saturated heterocyclic group containing a N, S or O atom.
  • A is C 1-3 alkyl
  • R is C 1-3 alkoxy
  • G is an optionally substituted C 1 -C 6 alkenyl group
  • D is triazole which is substituted by a C 1 -C 12 alkyl, said C 1 -C 12 alkyl being substituted by an optionally-substituted biphenyl.
  • a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, in the compound has the formula:
  • R is H or a CH 3 and R 1 is selected from the group consisting of:
  • L is -OH or a C 1 -C 3 alkoxy
  • M is selected from the group consisting of:
  • any phenyl of a M group may be optionally substituted with 1-3 substituents selected from the group consisting of C 1-6 alkyl, alkenyl or alkynyl, C 1-6 alkoxy, or halogen.
  • x is independently an integer from 0 to 3, preferably 1 to 3, R z1 and are
  • R z1 or R z2 can be the same or different and is independently 0, 1, 2 or 3
  • R sa and R sb are the same or different and are the same as above or preferably selected from the group consisting of H, -OH, -(CH 2 ) n -OH, C 1-6 alkyl, alkenyl or alkynyl, C 1-6 alkoxy, and halogen
  • R s is the same as above or preferably -(CH 2 ) n -OH
  • M is selected from the group consisting of:
  • R z1 , R z2 R z3, and R z4 are independently H, C 1-6 alkyl, alkenyl or alkynyl, C 1-6 alkoxy, or halogen, g for any of R z1 , R z2 R z3 , and R z4 can be the same or different and is independently 0, 1, 2 or 3, and M is selected from the group consisting of:
  • R q and R q are independently H or halogen
  • R s is selected from the group consisting of H, -OH, -(NH)OH, halogen, N 3 , C 1-6 alkyl, alkenyl or alkynyl, C 1-6 alkoxy, a 5 or 6-membered saturated, partially unsaturated or aromatic heterocyclic ring containing one or two heteroatoms selected from the group consisting of N and O,
  • R k is 0, 1, 2 or 3; or where x is 1, 2 or 3, y is 0 or l, R l and R q2 are independently H or halogen, R sa and R sb are each H, and R is selected from the group consisting of H, -OH, -(NH)OH, halogen, N 3 , -(CH 2 ) n -OH, where n is 0, 1, 2, or 3
  • k is 0, 1, 2 or 3; or pharmaceutically acceptable salt, stereoisomer, enantiomer, solvate or polymorph thereof.
  • R z1 and R z2 are independently H, C 1- alkyl, alkenyl or alkynyl, C 1-6 alkoxy, or halogen
  • g for R z1 and R z2 can be the same or different and is independently 0, 1, 2 or 3
  • R sa and R sb are the same or different and are selected from the group consisting of H, - OH, C 1-6 alkyl, alkenyl or alkynyl, C 1- alkoxy, and halogen
  • R SA is
  • the compounds according to the present invention are synthesized by methods which are well known in the art.
  • Compounds which contain the aryl, including naphthyl, or biphenyl groups as depicted above, may be readily synthesized by analogy following the well-described methods set forth in the attached manuscript and thesis which are attached as appendices.
  • AMFCs farnesylcysteine derivatives
  • This initial library was screened against Icmt, and six inhibitors possessing bulky aromatic and aliphatic groups attached to the a-nitrogen of the cysteine were identified.
  • a farnesylcysteine analog containing a N-l-adamantylcarbonyl group, 4j was identified as the most potent inhibitor of Icmt with an IC 50 of 12 ⁇ .
  • a method was developed for the solid-phase synthesis of prenylcysteine analogs to facilitate the synthesis of a more comprehensive library of AMFCs.
  • Icmt is a membrane bound protein for which no crystal structure is available to aid in the rational design of inhibitors. Therefore it was necessary to synthesize a library of AMFCs to better understand the structure-activity relationships for this class of inhibitors. To validate this technique, a set of AMFCs based on the initial adamantyl lead were prepared.
  • the 2-chlorotrityl chloride resin has proven to be a versatile and useful tool for the synthesis of a variety of peptides. Sohma, et al., J Pep. Sci, 2005, 1 1, 441 and Kitagawa, et al., Tet. Lett., 1997, 38, 599.
  • the 2-chlorotritylchloride resin has certain advantages over other solid supports. First, due to the SNI mechanism of the loading step, attaching the cysteine to the chlorotrityl resin does not require activation of the cysteine carboxyl group, which decreases the likelihood of racemization. Second, the cleavage conditions are very mild and result in the rapid, quantitative release of the modified cysteine from the bead.
  • the resin is commercially available and relatively inexpensive.
  • amino acid residues can be anchored to the chlorotrityl linker through not only the carboxyl group, but also the a-amino group and certain side chains, which allow for synthesis of peptides in the N to C direction (See, Thieriet, and Albericicio, Org. Lett., 2000, 2, 1815) and selective functionalization of the carboxyl group.
  • prenylcysteine was obtained in good purity (70-90%, by HPLC). Purification by C 18 sep pak cartridge, (Fisher) afforded prenylcysteine analogs suitable in purity for characterization and biochemical evaluation in 45-65% yield based on resin loading.
  • Ras protein superfamily The post-translational processing of members of the Ras protein superfamily is under active investigation because approximately 20% of human cancers result from mutated Ras proteins.
  • These proteins contain a -CaaX motif that is first isoprenylated on the cysteine thiol with a farnesyl group by farnesyltransferase (FTase) or a geranylgeranyl group by geranyl geranyl transferase- 1 (GGTase-1). Following lipidation, two critical modifications occur sequentially at the endoplasmic recticulum (ER) by membrane-associated enzymes.
  • FTase farnesyltransferase
  • GTTase-1 geranylgeranyl transferase- 1
  • the endoprotease Ras converting enzyme- 1 (Rce-1) cleaves the terminal -aaX residues, resulting in a newly exposed prenylcysteine at the C-terminus of the protein.
  • SAM S- adenosyl-methionine
  • Icmt Substrate specificity studies revealed several key elements necessary for recognition by Icmt, including a 15-20-carbon unit isoprene chain and a requirement for a thioether bond bridging the prenyl and cysteine motifs. 6 ' 7 Early work by the Rando group identified the minimal substrate for Icmt as farnesyl thiopropionic acid (FTP, l). 8 Using this information as a starting point, inhibitors of Icmt have been developed from studies of rotationally restricted prenylcysteines, 9 library screening efforts, 10 amide-, 11 ' 12 and prenyl-modified 13
  • prenylcysteines In recent studies, we have established the prenylcysteine analog POP-3MB as a low micromolar inhibitor of human Icmt. 12
  • Reagents and Conditions (a) NaN 3 , DMF, 80 °C; (b) i. TMS-propyne, nBuLi, THF, -78-0 °C ii. TBAF, THF, rt (c) i. nBuLi, THF, 0 °C ii. Ethynyl-MgCl, CuCN -10 °C; (d) sodium ascorbate, cupric sulfate, tBuOH/H 2 0, rt. b Number in parenthesis indicates Icmt specific activity as percent of AFC control in the presence of 10 ⁇ inhibitor.
  • the triazole may be positioned within the prenyl-binding site, in a manner that prevents the proper alignment of the carboxylate.
  • the methyl esters (12a-m) also were not substrates, since a free carboxylate is required for methyl transfer.
  • prenyl mimetic In order to achieve both a higher-affinity interaction and more drug-like properties, a more suitable prenyl mimetic was utilized.
  • Natural prenylcysteine substrates have a high degree of flexibility and the
  • a key indicator of inhibitor specificity is the dependence of its cellular effects on the presence of the enzymatic target.
  • a model system utilizing either Icmt + + or Icmt " " MEF cells was available for use in determining the cellular selectivity for 12n. 4 These cell lines were derived from wild-type and knockout Icmt mice, as described previously. 4 Both cell lines were incubated with increasing amounts of 12n for 24 h and cell viability was measured by a standard MTT assay. Treatment of MEF Icmt 7" cells with 12n had little effect on cell viability (Figure 1) demonstrating an IC50 above the highest concentration tested (>100uM). On the other hand, wild-type MEF + + cell viability decreased upon 12n treatment, with an observed IC50 of 33 ⁇ 0.9 ⁇ .
  • FTP-triazole 12n is a potent inhibitor of Icmt both in a biochemical assay and in a model MEF cell system. Removal of the amide motif of the prenylcysteine analogs, and insertion of the biphenyl prenyl-mimetic has led to a paradigm shift in the design of substrate-based inhibitors of Icmt.
  • FTP-triazole 12n is a potent inhibitor of Icmt both in a biochemical assay and in a model MEF cell system. Removal of the amide motif of the prenylcystein
  • Icmt Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. J. Clin. Invest. 2004, 113, 539- 550.
  • the general synthetic design for the synthesis of the phenoxy phenyl and related analogs begins with treating L-cysteine methylester hydrochloride 2.1 with trans-trans- farnesylchloride 2.2 under basic conditions of 7N ammonia in methanol.
  • the resulting farnesylcysteine methylester 2.3 was coupled with the appropriate carboxylic acid using HOBT and HBTU to yield the methylester derivatives (2.4a-h) of the compound of interest. Saponification using lithium hydroxide yielded the final compounds of choice (2.5a-h).
  • Carboxylic acids needed for the synthesis for compounds 2.5a-d were commercially available.
  • each carboxylic acid was synthesized as shown in Scheme 2.2A-D.
  • the general method involved using an alkoxide anion as the nucleophile to displace a benzylic halide to obtain the respective phenoxy-phenyl analog.
  • the aromatic bromide was then converted into a Grignard reagent using magnesium turnings in THF and quenching the formed Grignard with dry ice.
  • Carboxylic acid 2.8 used to prepare analog 2.5e was synthesized using the Ullmann-type ether coupling.
  • NCS dimethylsulfide, DCM, -50 °C to rt, 2 hours, 73% (c) NaH, OMF, 0 °C to rt, 4 hours,
  • N-methyl analog 2.32 was synthesized using a solid-phase methodology using the advanced intermediate 2.28, which was synthesized as reported previously.
  • Compound 2.28 was loaded on the 2-chlorotrityl-chloride
  • phenoxy phenyl analogs and related compounds include, but are not limited to, those described below.
  • trans-trans -faraesylchloride (1.0 eq., 4.54 mmol, 1.2 mL) was syringed into the flask.
  • the reactants were allowed to stir together for 3 hours at 0 °C.
  • the reaction was monitored by TLC analysis. Upon completion of the reaction, the contents of the round bottom flask were evaporated to dryness under reduced pressure.
  • reaction was monitored by TLC analysis. On completion of the reaction, 10% aqueous citric acid (15 mL) was added to the reaction mixture and the product was extracted using ethylacetate (3 x 20 mL) as the solvent. The combined organic extracts were pooled together, dried over anhydrous sodium sulfate (1 g) and filtered. The organic solvent was removed under vacuum utilizing a rotary evaporator and the residue was loaded on a short (2-3 inches) gravity silica gel plug. The silica gel plug was flushed with 3% methanol in dichloromethane to obtain the crude coupling product.
  • Chromatographic separation was performed under the influence of gravity using
  • 2-Chlorotrityl chloride resin (750 mg, 1.01 mmol/g loading capacity) was placed in a 25 mL fritted peptide vessel under argon. To the vessel was added 15 mL of anhydrous methylene chloride and the resin was allowed to swell by allowing the contents to gently rock on a peptide shaker for 30 minutes. Meanwhile, in a separate vial, 2.28 (1.68 g, 3.78 mmol) was dissolved in 5 mL of anhydrous methylene chloride to which was added 2,4,6- collidine (501 ⁇ , 3.78 mmol). After the resin was swollen, the solvent was removed from the resin, the solution of 2.28 was transferred to the resin.
  • the solvent was drained, and the resin was rinsed as before.
  • the carbamate library (3.8a-g) was afforded through S-alkylation of cysteine with farnesylchloride, followed by reaction of farnesylcysteine 3.7 with various commercially available chloroformates in presence of potassium carbonate and acetone (Scheme 3.2).
  • Hlcmt inhibitor has a submicromolar IC50.
  • Alcohol analog and related compounds can be synthesized as shown in Schemes 4.1 and 4.2 below.
  • Methylthiopropionate 4.1 was S-alkylated with all-traw-farnesyl chloride 4.2 to yield thioether 4.3.
  • Compound 4.3 was either saponified to yield FTP A 4.4, or reduced using diisobutylaluminium hydride to yield the alcohol analog 4.5. Coupling of the carboxylic acid 4.4 with hydroxylamine hydrochloride afforded hydroxamic acid 4.8.
  • the alcohol analog 4.5 was modified via bromination to analog 4.6, and then converted to the phosphonate ethyl ester 4.7.
  • Compound 6.53 was synthesized based on its predicted potency from the predictive QSAR model. This compound matched its prediction, and has provided us with the first sub- 100 nanomolar substrate-based hlcmt inhibitor described till date.
  • Both compounds 6.60 and 6.61 display superior hlcmt inhibition and are equipotent to their ester counterparts.
  • Compound 6.60 has an IC50 of 250 ⁇ 0.02 nM, while the IC50 for compound 6.61 was experimentally determined to be 93 ⁇ 0.003 nM.
  • Compound 6.62 inhibits hlcmt by 97% at 10 ⁇ in vitro.
  • reaction on certain occasions, the reaction proceeded very sluggishly and complete reaction, as evidenced by disappearance of starting material, was only observed after 96 hours), the contents of the reaction mixture were evaporated under reduced pressure.
  • a dry round bottom flask was charged with 2-methylbutane-l -thiol (1.0 eq., 2.14 mmol, 263 ⁇ ) and the atmosphere in the flask was replaced with argon.
  • the flask was placed in an ice bath and 7N ammonia in methanol (3 mL) was syringed into the flask and the contents were allowed to react with each other for not more than one minute.
  • Example 1 The invention is illustrated further in the following non-limiting examples.
  • Example 1 The invention is illustrated further in the following non-limiting examples.
  • Pancreatic cancer has one of the poorest prognoses amongst all cancers. 1 Over 85% of all pancreatic cancers are caused by mutations in the K-Ras oncogene that permanently activate the enzyme. K-Ras, and other members of the Ras protein superfamily, possess a CaaX motif at the C-terminus, where C is a cysteine, "a” is an aliphatic amino acid and "X" can be one of many different amino acids. K-Ras undergoes three sequential post- translational modifications 3 (Figure 1) beginning with famesylation of the cysteine residue sulfur by farnesyltransferase (FTase).
  • FTase farnesyltransferase
  • Icmt is a promising drug target for K-Ras driven cancers.
  • Small molecule inhibitors of human Icmt have been identified both from high throughput screens of synthetic and natural product libraries 13"15 and from substrate-based design approaches. 16, 17
  • Our previous substrate-based inhibitors used N- Acetyl -S- farnesylcysteine (AFC, Figure 2a), the minimal peptidic Icmt substrate, as the scaffold molecule for further modifications. Modifications to the AFC scaffold at both the amide and the prenyl regions yielded several low micromolar inhibitors, the most potent being POP- 3MB-FC, which demonstrated an in vitro IC 50 of 2.5 ⁇ ( Figure 2d).
  • esters 31a-c were derived from the esters 31a-c using DIBAL-H as the reducing agent.
  • Compound 12 was then further evaluated for its cellular activity. As the lack of methylation leads to -Ras mislocalization in cells, we examined the effect of treatment of 12 on Jurkat T cells transiently expressing GFP-K-Ras. These cells were treated with DMSO as a negative control, simvastatin (45 ⁇ ) as a positive control, or 12 (10 ⁇ ) for 24 h. We observed that treatment with 12 resulted in partial mislocalization of GFP-K-Ras in Jurkat T cells at 10 ⁇ . At 45 ⁇ , the simvastatin control treatment results in almost complete GFP K-Ras mislocalization in Jurkat T cells (see Figure S3).
  • a full determination of the structure-activity relationships around a ligand for a biological target is a key step in the development of a therapeutically useful agent based on the ligand.
  • we have not examined the carboxylate due in part to a lack of success in Rando's early attempts to replace this moiety. 21
  • 37 there are particular reasons to develop replacements for the carboxylate moiety.
  • AFC analogs with a lipid mimic on one end and a carboxylate on the other end, resembles a surfactant, and may lead to unfavorable physical properties (such as micelle formation).
  • AFC analogs and methylated derivatives thereof have also exhibited a variety of biological effects believed to result from binding to proteins other than Icmt, and removal of the carboxylate may decrease the risk of these off-target effects.
  • the methyl ester analog 3 and the bromo variant analog 6 were very poor hicmt inhibitors.
  • the modest inhibitory potency of 3 was surprising in view of the potency of ester analogs in one of our previous hicmt inhibitor series.
  • the bromide is not a carboxylic acid isostere, we chose to evaluate this synthetic intermediate in our screen. Icmt is a target with no structural information, and through the use of such chemical probes, we intend to garner as much information as possible about the enzyme binding pocket.
  • the phosphonate ester 7 was synthesized to evaluate the bioisosteric compatibility of the phosphonate ester in our compounds. The poor potency of analog 7 suggests that phosphonate replacements are not a promising approach for hicmt inhibition.
  • the amide derivative 10b inhibited hicmt with similar potency as the FTA analog 11.
  • the equipotency of these analogs adds evidence to the hypothesis that the carboxylate motif may be replaceable for substrate-based hicmt inhibitors.
  • analogs that bore an aldehyde, phosphonate or azide 14, 17 and 18 were poor hicmt inhibitors.
  • the azide 18 was an intermediate for the synthesis of a terminal tetrazole and we chose to evaluate this intermediate as well; unfortunately, synthesis of the tetrazole scaffold did not provide us enough pure material for biochemical evaluation.
  • the alcohol-bearing analog 12 is the most potent inhibitor in the series.
  • the nature of the interactions this analog may have with the hicmt binding pocket is not known, but some conclusions can be drawn from the biochemical activities of the analogs synthesized based on alcohol 12.
  • Esterification of the alcohol to the acetate (analog 15) diminished the activity significantly.
  • Analogs 20h, 22 and 23 are all poor inhibitors of hlcmt. Particularly striking is the observation that analog 23, which bears the hydroxy group, was a poor hlcmt inhibitor. The presence of the gem-dimethyl group appears to lend steric impedance to analog binding.
  • the ketone bearing analog 26a and the 1,3-dioxolane analog 26b were also synthesized to evaluate the effects of these molecular modifications on hlcmt inhibition. Both these analogs were poor hlcmt inhibitors at the test concentration.
  • analogs 31-33 Analogs where the farnesyl group was replaced by the one-carbon longer homofarnesyl chain (analogs 31a and 33a) were two-fold and four-fold less potent compared to their counterparts (analogs 10 and 12) with the farnesyl chain, respectively.
  • Analogs 31a and 33a Analogs where the farnesyl group was replaced by the one-carbon longer homofarnesyl chain (analogs 31a and 33a) were two-fold and four-fold less potent compared to their counterparts (analogs 10 and 12) with the farnesyl chain, respectively.
  • Analogs that bear the shorter geranyl moiety in place of the farnesyl chain are completely devoid of any inhibitory activity (analogs 31b, 32b and 33b).
  • the 20-carbon geranylgeranyl scaffold in analog 33c exhibited intermediate behavior, with 40% of the activity of analog 12.
  • 18 ' 20 This focused prenyl replaced study with the seven analogs 31-33 highlights the importance of the isoprene region of the molecule. All these data are evidences that support our hypothesis that the prenyl chain may be the most important pharmacophoric requirement for hicmt inhibition.
  • Our cellular studies with 12 have shown that this novel alcohol bearing small farnesylated molecule inhibits hicmt in cells and that it also causes GFP-K-Ras mislocalization in cells.
  • a substrate-based sub-micromolar inhibitor of hicmt that does not contain the carboxylate functionality, which is methylesterified in hicmt substrates.
  • This compound also appears to have critical interactions in the hicmt binding pocket, which do not appear to be present in the analogs where the alcohol is masked as an ester or ether.
  • the prenyl region is a crucial molecular motif required for hicmt inhibition.
  • the contents were allowed to react with each other for 3 h at 0 °C. Following the completion of the reaction, the solvent from the flask was removed under reduced pressure using a rotary evaporator. The residue was adsorbed on silica gel (dry loading). The product was isolated using column chromatography by isocratic elution with 5% ethyl acetate in hexanes. The isolated yield regularly ranges from 70-75%.
  • the contents were allowed to react at -78 °C for 2 h and then the temperature of the flask was allowed to slowly increase to 0 °C. The contents were allowed to react for a further 2h.
  • the reaction mixture was added slowly to a cooled solution of 10% citric acid.
  • the contents were transferred to a separatory funnel and the aqueous layer was extracted with methylene chloride (3 x 15 mL). The organic extracts were combined, washed with brine and concentrated under reduced pressure.
  • the residue was subjected to column chromatography using isocratic elution using 30% ethyl acetate in hexanes, which yielded compound 5 in 65% yield as a viscous oil.
  • the reaction was quenched with 10% citric acid (5 mL) and the contents were transferred to a separatory funnel. The mixture was extracted with ethyl acetate and the aqueous phase was further extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were concentrated under reduced pressure to yield an oily mixture, which upon isocratic column chromatic elution with 50% ethyl acetate in hexanes yielded phosphonate 7 in 50% yield.
  • Compound 16 (2-bromoethyl)((2E,6E)-3,7,ll-trimethyIdodeca-2,6,10-trien-l-yl)sulfane was prepared by bromination of compound 12 using the method described for preparation of compound 6. Column chromatographic purification yielded 77% of isolated product as a viscous liquid.
  • Compound 20a isopropyl((2E,6E)-3,7,ll-trimethyldodeca-2,6,10-trien-l-yl)suIfane: 1H
  • Compound 20c 2-(((2E,6E)-3,7,ll-trimethvIdodeca-2,6,10-trien-l-yl)thio)ethanethiol:
  • Compound 26a 1-(((2E,6E)-3,7,1 l-trimethyldodeca-2,6,10-trien-l-yl)thio)propan-2-one
  • Compound 26a was prepared in a similar fashion as compound 28. Isocratic column chromatographic purification was performed using ethyl acetate (10%) and hexanes (90%) to yield 65% of isolated 26a as a colorless oil.
  • Methylthiopropionate (9, 0.95 eq.) was added to the flask and the contents were allowed to cool to 0 °C. This was followed by addition of DIEA (2.0 eq.). The contents were allowed to stir for 5 minutes. The electrophile (30a-c) was then added slowly as a solution in methylene chloride (1 mL/mmol) to the reaction mixture. The contents were allowed to stir for 5 hours (15 hours for compound 31a). The reaction progress was monitored by TLC analysis. Upon completion of the reaction (as monitored by TLC, visualized by vanillin staining), the contents of the reaction flask were evaporated under reduced pressure.
  • Compound 21 was purified using column chromatography (15% ethyl acetate in hexanes) to yield 63 - 81% of isolated product as a viscous oil.
  • membrane fractions from yeast cells were isolated as previously described. 27 Crude membrane protein concentration was determined using Coomassie Plus Protein Assay Reagent (Pierce) according to the manufacturer's instructions, and compared with a bovine serum albumin standard curve. Brief Procedure for biochemical evaluation of analogs using the vapor diffusion assay:
  • membrane protein (5 ⁇ g) was added to a solution of Tris-HCl buffer (100 m , pH 7.4) and AFC (200 ⁇ ). After 5 min incubation on ice, 20 of S-adenosyl-L- [methyl- 14 C]methionine ([ 14 C]SAM) (50-60 mCi/mmol) (60 ⁇ ) is added and the solution is incubated at 30 °C in a water bath for 30 min. After 30 min the reaction is stopped by the addition 50 ⁇ ⁇ of 1 M NaOH/1% SDS. The reaction mixture is vortexed and spotted on to a pleated filter paper.
  • S-adenosyl-L- [methyl- 14 C]methionine [ 14 C]SAM)
  • the filter paper is lodged into the neck of a scintillation vial filled with 10 mL of scintillation fluid and capped.
  • the filter papers were removed after 2.5 h and the radioactivity was measured using a Packard 1600CA Liquid Scintillation Analyzer.
  • the IC50 was calculated using GraphPad Prism 5.0
  • the coverslips were washed again for 10 min with PBS (3 times). After mounting the coverslips onto the slides using FluorSaveTM Reagent (Calbiochem), the slides were dried for 45 min at room temperature. Images of cells were viewed using an Olympus BH- 2 microscope and captured with a Qlmaging Microimager II. The captured images were viewed using Northern Eclipse software. Cells were classified as either full (fully mislocalized GFP-K-Ras construct with diffuse cellular staining), partial (partial proper localization), and normal (normal, primarily plasma membrane localization of GFP-K-Ras) by visual inspection. 32 ' 33 The subcellular localization of GFP K-Ras was quantified using fluorescence microscopy (performed on an Olympus BH-2RFCA) as previously described. 34 ' 35
  • Icmt inhibitor Although two of the isoprene groups were replaced, increased lipidic character from an n-octyl chain is necessary for potency. Note that 2.16 exhibited a much poorer inhibitory potency than 2.19, and has nearly 15% less inhibitory activity at 10 muM. This does reveal that non-prenyl groups, bearing sufficient hydrophobic bulk, can suffice as farnesyl proxies and occupy the prenylcysteine-binding site. This finding advances our understanding of Icmt inhibitors.
  • a 1 ,4-disubstituted 1,2, 3 -triazole was positioned as thioether replacement and cysteine backbone modifier that would join the lipid and carboxylate region of the FTP/FTA analog together. This would also employ the replacement of the thioether
  • TMSprOpyne The anion of TMSprOpyne was used to alkylate the desired position of either geranyl bromide or famesyl chloride. Deprotection with TBAF where necessary afforded the requisite terminal alkynes 4.6-4.7 in good yields.

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Abstract

L'invention concerne une nouvelle méthode de traitement d'une néoplasie, y compris le cancer et d'autres maladies et affections touchant l'homme ou les autres mammifères. L'invention concerne plus particulièrement, dans des aspects préférés, une méthode d'utilisation de nouveaux composés pour le traitement d'une néoplasie, d'une hyperprolifération cellulaire dont le psoriasis, la resténose consécutive à une chirurgie cardiovasculaire, l'hyperplasie, notamment l'hyperplasie rénale, les maladies inflammatoires chroniques, notamment la polyarthrite rhumatoïde et l'arthrose, entre autres.
PCT/US2012/048334 2011-07-26 2012-07-26 Composés et méthodes de traitement d'une néoplasie ou d'un cancer WO2013016531A2 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
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US8735436B2 (en) 2009-05-08 2014-05-27 Pronova Biopharma Norge As Polyunsaturated fatty acids for the treatment of diseases related to cardiovascular, metabolic and inflammatory disease areas
US8741966B2 (en) 2007-11-09 2014-06-03 Pronova Biopharma Norge As Lipid compounds for use in cosmetic products, as food supplement or as a medicament
US8759558B2 (en) 2008-07-15 2014-06-24 Pronova Biopharma Norge As Sulphur containing lipids for use as food supplement or as medicament
US9394228B2 (en) 2010-11-05 2016-07-19 Pronova Biopharma Norge As Methods of treatment using lipid compounds
CN107001209A (zh) * 2014-12-17 2017-08-01 帝斯曼知识产权资产管理有限公司 在金(i)络合物存在的情况下基于炔烃与二甲基呋喃的分子间反应形成色满
US10722481B2 (en) 2015-04-28 2020-07-28 Basf As Substituted fatty acids for treating non-alcoholic steatohepatitis
US11351139B2 (en) 2013-02-28 2022-06-07 Basf As Composition comprising a lipid compound, a triglyceride, and a surfactant, and methods of using the same
US11925614B2 (en) 2017-12-06 2024-03-12 Basf As Fatty acid derivatives for treating non-alcoholic steatohepatitis

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US6180611B1 (en) * 1994-10-05 2001-01-30 Darwin Discovery, Ltd. Peptidyl compounds
WO2002074730A1 (fr) * 2001-03-16 2002-09-26 Merck Patent Gmbh Inhibiteurs de l'integrine $g(a)v$g(b)¿6?
WO2004087064A2 (fr) * 2003-03-26 2004-10-14 Purdue Research Foundation Compositions et methodes utilisees dans le traitement de la neoplasie et du cancer, basees sur des inhibiteurs de l'isoprenylcysteine methyltransferase
WO2009048541A2 (fr) * 2007-10-05 2009-04-16 Purdue Research Foundation Composés et procédés destinés à être utilisés dans le traitement de la néoplasie et du cancer

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WO2002074730A1 (fr) * 2001-03-16 2002-09-26 Merck Patent Gmbh Inhibiteurs de l'integrine $g(a)v$g(b)¿6?
WO2004087064A2 (fr) * 2003-03-26 2004-10-14 Purdue Research Foundation Compositions et methodes utilisees dans le traitement de la neoplasie et du cancer, basees sur des inhibiteurs de l'isoprenylcysteine methyltransferase
WO2009048541A2 (fr) * 2007-10-05 2009-04-16 Purdue Research Foundation Composés et procédés destinés à être utilisés dans le traitement de la néoplasie et du cancer

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8741966B2 (en) 2007-11-09 2014-06-03 Pronova Biopharma Norge As Lipid compounds for use in cosmetic products, as food supplement or as a medicament
US8759558B2 (en) 2008-07-15 2014-06-24 Pronova Biopharma Norge As Sulphur containing lipids for use as food supplement or as medicament
US8735436B2 (en) 2009-05-08 2014-05-27 Pronova Biopharma Norge As Polyunsaturated fatty acids for the treatment of diseases related to cardiovascular, metabolic and inflammatory disease areas
US9394228B2 (en) 2010-11-05 2016-07-19 Pronova Biopharma Norge As Methods of treatment using lipid compounds
US11351139B2 (en) 2013-02-28 2022-06-07 Basf As Composition comprising a lipid compound, a triglyceride, and a surfactant, and methods of using the same
CN107001209A (zh) * 2014-12-17 2017-08-01 帝斯曼知识产权资产管理有限公司 在金(i)络合物存在的情况下基于炔烃与二甲基呋喃的分子间反应形成色满
US10047065B2 (en) * 2014-12-17 2018-08-14 Dsm Ip Assets B.V. Formation of chromanes based on intermolecular reaction of alkynes with dimethylfuran in the presence of gold(I) complexes
CN107001209B (zh) * 2014-12-17 2021-02-19 帝斯曼知识产权资产管理有限公司 在金(i)络合物存在的情况下基于炔烃与二甲基呋喃的分子间反应形成色满
US10722481B2 (en) 2015-04-28 2020-07-28 Basf As Substituted fatty acids for treating non-alcoholic steatohepatitis
US11234948B2 (en) 2015-04-28 2022-02-01 Basf As Substituted fatty acids for treating non-alcoholic steatohepatitis
US11911354B2 (en) 2015-04-28 2024-02-27 Basf Substituted fatty acids for treating non-alcoholic steatohepatitis
US11925614B2 (en) 2017-12-06 2024-03-12 Basf As Fatty acid derivatives for treating non-alcoholic steatohepatitis

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