WO1999018951A1 - Inhibiteurs de la transferase farnesyle proteine - Google Patents

Inhibiteurs de la transferase farnesyle proteine Download PDF

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Publication number
WO1999018951A1
WO1999018951A1 PCT/US1998/019315 US9819315W WO9918951A1 WO 1999018951 A1 WO1999018951 A1 WO 1999018951A1 US 9819315 W US9819315 W US 9819315W WO 9918951 A1 WO9918951 A1 WO 9918951A1
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Prior art keywords
tetrahydro
benzodiazepine
compound
naphthalenylcarbonyl
substituted
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PCT/US1998/019315
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English (en)
Inventor
Charles Z. Ding
John T. Hunt
Katerina Leftheris
Rajeev S. Bhide
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Bristol-Myers Squibb Company
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Priority to CA002304473A priority Critical patent/CA2304473A1/fr
Priority to EP98948279A priority patent/EP1027042A4/fr
Priority to AU94886/98A priority patent/AU735366B2/en
Priority to JP2000515586A priority patent/JP2001519387A/ja
Publication of WO1999018951A1 publication Critical patent/WO1999018951A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to compounds that inhibit farnesyl- protein transferase and ras protein farnesylation, thereby making them useful as anti-cancer agents.
  • the compounds are also useful in the treatment of diseases, other than cancer, associated with signal transduction pathways operating through ras and those associated with proteins other than ras that are also post-translationally modified by the enzyme farnesyl protein transferase.
  • the compounds may also act as inhibitors of other prenyl transferases, and thus be effective in the treatment of diseases associated with other prenyl modifications of proteins.
  • the mammalian ras gene family comprises three genes, H-ras, K-ras and N-ras.
  • the ras proteins are a family of GTP-binding and hydrolyzing proteins that regulate cell growth and differentiation. Overproduction of normal ras proteins or mutations that inhibit their GTPase activity can lead to uncontrolled cell division.
  • the transforming activity of ras is dependent on localization of the protein to plasma membranes. This membrane binding occurs via a series of post-translational modifications of the cytosolic Ras proteins. The first and mandatory step in this sequence of events is the farnesylation of these proteins.
  • the reaction is catalyzed by the enzyme farnesyl protein transferase (FPT), and farnesyl pyrophosphate (FPP) serves as the farnesyl group donor in this reaction.
  • FPT farnesyl protein transferase
  • FPP farnesyl pyrophosphate
  • the ras C-terminus contains a sequence motif termed a "Cys-Aaai-Aaa ⁇ / Xaa” box (CAAX box), wherein Cys is cysteine, Aaa is an aliphatic amino acid, and Xaa is a serine or methionine. Farnesylation occurs on the cysteinyl residue of the CAAX box (cys-186), thereby attaching the prenyl group on the protein via a thio-ether linkage.
  • 7 X is selected from the group consisting of carbon, oxygen, NR or absent.
  • Z is selected from the group consisting of CHR 9 , SO 2 , CO, CO2, O, NR 10 , SO NR 11 , CONR 12 , N - C N - CN O
  • R I 16 R I 17 R 118 R 119 / or Z may be absent
  • Y is selected from the group consisting of CHR 23 , SO 2 , CO, NR 24 ,
  • SO 2 NR 25 , CONR 26 , or Y may be absent;
  • R 38 , R 39 , R 41 , R 42 , R 43 , R 44 , R 45 and R 46 are selected from the group consisting of hydrogen, lower alkyl, substituted alkyl, aryl, or substituted aryl; 0 R 4 , R 5 , R 47 , R 48 , R 49 , R 50 and R 51 are selected from the group consisting of hydrogen, halo, nitro, cyano and U-R 97 ;
  • U is selected from the group consisting of sulfur, oxygen, NR , CO, SO,
  • R , R , and R are selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, cyano, carboxy, carbamyl (e.g. 0 CONH 2 ) or substituted carbamyl further selected from CONH alkyl,
  • R and R are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted 5 alkynyl, aralkyl, cycloalkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo;
  • R, S and T are selected from the group consisting of CR 40 R 41 , NR 42 R 43 ;
  • R 40 is selected from NR 44 R 45 , OR 46 , CN; 0 G is selected from the group consisting of -S-, -SO 2 NH-,
  • A, B, C and D are selected from carbon, oxygen, sulfur or nitrogen, or D may be absent.
  • R 27 may be hydrogen except when U is SO, SO 2 , CO 2 , NR 29 CO 2 or NR 32 SO 2 , or
  • R° may be hydrogen except when Z is SO 2 , CO 2 , or
  • Only one of Y, R, S and T may be nitrogen or
  • Any of Y, R, S, and T may be nitrogen except when G is -S-, -
  • R° may be hydrogen except when G is - NHSO 2 - or
  • G may be imidazole only if X is oxygen or NR or
  • alkyl refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms.
  • lower alkyl refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
  • substituted alkyl refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthiol, alkyl
  • substituent is further substituted it will be with halogen, alkyl, alkoxy, aryl or aralkyl.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
  • aralkyl refers to an aryl group bonded directly through an alkyl group, such as benzyl.
  • substituted aryl refers to an aryl group substituted by, for example, one to four substituents such as alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfony
  • the substituent may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.
  • alkenyl refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four double bonds.
  • substituted alkenyl refers to an alkenyl group substituted by, for example, one to two substituents, such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclo, e.g.
  • alkynyl refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four triple bonds.
  • substituted alkynyl refers to an alkynyl group substituted by, for example, a substituent, such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclo, e.g. imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
  • a substituent such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino,
  • cycloalkyl refers to a optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocylic ring.
  • exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl, cyclododecyl, and adamantyl.
  • substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
  • heterocycle refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen and sulfur, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom.
  • Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl,
  • bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N- oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,l-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo- quinazolinyl), benzisothiazolyl, benz
  • heteroatoms shall include oxygen, sulfur and nitrogen.
  • the "ABCD" fused ring to the diazepine ring may be monocyclic or bicyclic, e.g. napthyl or quinolyl in nature.
  • the compounds of formulas I-II may form salts which are also within the scope of this invention. Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolating or purifying the compounds of this invention.
  • the compounds of formulas I-II may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like.
  • alkali metals such as sodium, potassium and lithium
  • alkaline earth metals such as calcium and magnesium
  • organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like.
  • Such salts may be obtained, for example, by exchanging the carboxylic acid protons, if they contain a carboxylic acid, in compounds I-II with the desired ion in a medium in which the salt precipitates or in an aqueous medium followed by evaporation.
  • Other salts can be formed as known to those skilled in the art.
  • the compounds for formulas I-II may form salt
  • Such salts include those formed with hydrogen chloride, hydroxy methane sulfonic acid, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and various others (e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like).
  • Such salts may be formed by reacting compounds I-II in an equivalent amount of the acid in a medium in which the salt precipitates or in an aqueous medium followed by evaporation.
  • zwitterions inner salts
  • Compounds of the formulas I-II may also have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formulas I-II) is a prodrug within the scope and spirit of the invention.
  • compounds of the formulas I-II may be a carboxylate ester moiety.
  • the carboxylate ester may be conveniently formed by esterifying any of the carboxylic acid functionalities found on the disclosed ring structure(s).
  • prodrugs are well known in the art.
  • prodrug derivatives see: a) Design of Prodrugs. edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzvmologv. Vol.42, p. 309-396, edited by K. Widder, et al. (Acamedic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, "Design and
  • solvates e.g., hydrates
  • Methods of solvation are generally known in the art.
  • the compounds of formulas I-II are inhibitors of S-farnesyl protein transferase. They are thus useful in the treatment of a variety of cancers, including (but not limited to) the following; carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, ovary, prostate, testes, pancreas, esophagus, stomach, gall bladder, cervix, thyroid and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, and Burketts lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promye
  • the compounds of formulas I-II are especially useful in treatment of tumors having a high incidence of ras involvement, such as colon, lung, and pancreatic tumors and in tumors in which a prenyl transferase contributes to tumor maintenance, tumor growth or tumor development.
  • a composition having one (or a combination) of the compounds of this invention development of tumors in a mammalian host is reduced, or tumor burden is reduced, or tumor regression is produced.
  • Compounds of formulas I-II may also inhibit tumor angiogenesis, thereby affecting the growth of tumors. Such anti- angiogenesis properties of the compounds of formulas I-II may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
  • Compounds of formulas I-II may also be useful in the treatment of diseases other than cancer that may be associated with signal transduction pathways operating through ras, e.g., neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, polycystic kidney disease and endotoxic shock.
  • Compounds I-II may be useful as anti-fungal agents.
  • Compounds of formula I-II may induce or inhibit apoptosis, a physiological cell death process critical for normal development and homeostasis. Alterations of apoptotic pathways contribute to the pathogenesis of a variety of human diseases.
  • Compounds of formula I- II, as modulators of apoptosis, will be useful in the treatment of a variety of human diseases with aberrations in apoptosis including cancer (particularly, but not limited to follicular lymphomas, carcinomas with p53 mutations, hormone dependent tumors of the breast, prostrate and ovary, and precancerous lesions such as familial adenomatous polyposis), viral infections (including but not limited to herpes virus, pox virus, Epstein-Barr virus, Sindbis virus and adenovirus), autoimmune diseases (including but not limited to systemic lupus erythematosus, immune mediated glomerulonephritis, rheumatoid arthritis, psoriasis,
  • Compounds of formulas I-II may also be useful in the treatment of diseases associated with farnesyl transferase substrates other than ras (e.g., nuclear lamins, transducin, rhodopsin kinase, cGMP phosphodiesterase, TC21, phosphorylase kinase, Rap2, RhoB, RhoE, PRL1) that are also post-translationally modified by the enzyme farnesyl protein transferase.
  • ras e.g., nuclear lamins, transducin, rhodopsin kinase, cGMP phosphodiesterase, TC21, phosphorylase kinase, Rap2, RhoB, RhoE, PRL1
  • Compounds of formulas I-II may also act as inhibitors of other prenyl transferases (e.g., geranylgeranyl transferase I and II), and thus be effective in the treatment of diseases associated with other prenyl modifications (e.g., geranylgeranylation) of proteins (e.g. the rap, rab, rac and rho gene products and the like).
  • prenyl transferases e.g., geranylgeranyl transferase I and II
  • proteins e.g. the rap, rab, rac and rho gene products and the like.
  • HDV Hepatitis delta virus
  • the compounds of this invention may also be useful in combination with known anti-cancer and cytotoxic agents and treatments, including radiation. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. Compounds of formulas I-II may be used sequentially with known anticancer or cytotoxic agents and treatment, including radiation when a combination formulation is inappropriate.
  • the compounds of this invention may be formulated with a pharmaceutical vehicle or diluent for oral, intravenous, intraperitoneal, subcutaneous, intraabdominal, intramuscular, rectal, vaginal or topical administration.
  • Oral administration may involve the use of slow release formulations, such as biodegradable polymers or prodrugs.
  • the pharmaceutical composition can be formulated in a classical manner using solid or liquid vehicles, diluents and additives appropriate to the desired mode of administration.
  • the compounds can be administered in the form of tablets, capsules, granules, powders and the like.
  • the compounds may be administered in a dosage range of about 0.05 to 200 mg/kg/day, preferably less than 100 mg/kg/day, in a single dose or in 2 to 4 divided doses.
  • R x is selected from H, halo, NO 2 , NH 2 , CN, alkyl, aryl, heteroaryl, substituted alkyl, arylalkyl, alkoxy and substituted amino;
  • R 2 , R 3 and R 4 are selected from alkyl, substituted alkyl, arylalkyl, aryl, heteroaryl;
  • R 2 can also be hydrogen;
  • Z is selected from CO, SO 2 , CO 2 , CONR 5 , SO 2 NR 5 .
  • Step l The isatoic anhydride 2 was formed by reaction of optionally substituted anthranilic acid with a phosgene equivalent, such as, phosgene or triphosgene in a mixed aqueous/organic solvent at from 0°C to 50°C range.
  • a phosgene equivalent such as, phosgene or triphosgene in a mixed aqueous/organic solvent at from 0°C to 50°C range.
  • the isatoic anhydride 2 is reacted with an amino acid ester hydrochloride salt in pyridine at an elevated temperature with reflux as preferred to give benzodiazepinedione 3.
  • the compound 3 wherein Rl is aryl or heteroaryl can be prepared from the compound 3 wherein Rl is bromo by a palladium coupling of an aryl or heteroaryl metaloid derivative such as phenylboronic acid in a mixed aqueous/organic solvent, e.g. THF/DMF/water, in the presence of a base, e.g. sodium carbonate, at from room temperature to 110°C.
  • the compound 3 is reacted with a reducing agent such as lithium aluminum hydride or borane in an inert atmosphere and in an organic solvent, such as, tetrahydrofuran at from room temperature to reflux.
  • a reducing agent such as lithium aluminum hydride or borane
  • organic solvent such as, tetrahydrofuran
  • the product is acylated or sulfonylated under standard conditions at from -78°C to 100°C (e.g., by reaction with an acid halide R3COX wherein X is Cl or Br in an inert organic solvent, e.g. acetonitrile, or in a mixed aqueous/organic solvent e.g. NaOH/dichloroethane; by reaction with a sulfonyl halide R3SO2X wherein X is Cl or Br in an organic solvent such as THF in the presence of a base such as diisopropylethylamine or in a mixed aqueous/organic solvent e.g. NaOH/CH2Cl2).
  • an acid halide R3COX wherein X is Cl or Br in an inert organic solvent, e.g. acetonitrile, or in a mixed aqueous/organic solvent e.g. NaOH/dichloroethane
  • the halide may then be eliminated by a base such as diisopropylethylamine and then nucleophiles such as dimethylamine may be added to the resulting unsaturated sulfonamide by treatment in an organic solvent such as THF or dichloromethane at from room temperature to reflux.
  • a base such as diisopropylethylamine
  • nucleophiles such as dimethylamine
  • aldehydes may be prepared from the appropriate alcohols by oxidation with for example oxalyl chloride/DMSO/triethylamine. They may be prepared from appropriate carboxylic acid derivatives such as esters by reduction with for example diisobutylaluminum hydride in an organic solvent such as methylene chloride at from -78°C to room temperature.
  • Compound 6 may be further manipulated to give the compounds of formula I and II, such as by reaction with a deprotecting agent like TFA/triethylsilane in an organic solvent such as dichloroethane.
  • a deprotecting agent like TFA/triethylsilane in an organic solvent such as dichloroethane.
  • the compound 6 contains a leaving group such as chloride; in the case of a hydroxyl group, such a group may be transformed into a leaving group such as trifluoromethanesulfonate; the compound may be reacted with a nucleaphile such as 2-aminopyridine to give the desired compounds of formula I or II.
  • the compound 5 is acylated with an acylating agent such as an acid chloride in a solvent such as methylene chloride in the presence of an optional base such as diisopropylethylamine.
  • the compound 5 may also be acylated with an isocyanate which in turn can be prepared by an acyl azide like nicotinoyl azide. If R 4 contains a leaving group such as chloride, the compound may be further reacted with a nucleophile such as 2-pyrrolidinone or ammonia to form the compounds of formula I or II .
  • R x is selected from H, halo, NO 2 , NH 2 , CN, alkyl, aryl, heteroaryl, substituted alkyl, arylalkyl, alkoxy and substituted amino;
  • R 2 , R 3 and R are selected from alkyl, arylalkyl, aryl, heteroaryl;
  • R 2 and R 4 can also be hydrogen;
  • R can also be amino;
  • Z is selected from CO, SO 2 , CO 2 , CONR 5 , SO 2 NR 5 .
  • An ester 1 prepared by following Step 5 of Scheme 1 may be saponified to an acid 2 with a base such as LiOH in a solvent such as aq. methanol in THF at about room temperature.
  • a base such as LiOH
  • a solvent such as aq. methanol in THF
  • the acid 2 is converted to hydroxamic acid 3 with hydroxylamine hydrochloride in the presence of a dehydrating agent such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and a base such as triethylamine.
  • a dehydrating agent such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • a base such as triethylamine.
  • the ester 1 may be reduced to an aldehyde 4 by a reducing agent such as diisobutylaluminium hydride in an organic solvent such as methylene chloride.
  • a reducing agent such as diisobutylaluminium hydride in an organic solvent such as methylene chloride.
  • the aldehyde 4 may be reductively aminated with a hydroxylamine derivative such as O-benzyl hydroxylamine and a reducing agent such as sodium cyanoborohydride to give 5.
  • a hydroxylamine derivative such as O-benzyl hydroxylamine
  • a reducing agent such as sodium cyanoborohydride
  • the compound 5 may be acylated with an acylating agent such as formic anhydride to give after deprotection, e. g., by hydrogenation the compound 6.
  • an acylating agent such as formic anhydride
  • Example 16 To a stirred solution of Example 16 (25 mg, 0.05 mmol) in methylene chloride in the presence of sodium bicarbonate was added mCPBA (50 mg) at 0°C. The mixture was stirred for 3 h, and treated with aq. potassium carbonate. The suspension was stirred, filtered, and concentrated. The residue was dissolved in methanol, IN HCl in ether was added, solvent was removed to give title compound as a solid (22 mg). MS (M+H): 502.
  • Example 4 and ethyl glyoxalate by following the procedure for the preparation of Example 6. MS (M+H): 481.

Abstract

Inhibition de la transférase farnésyle qui est une enzyme impliquée dans l'expression de l'oncogène ras, cette inhibition s'effectuant à l'aide des composés ayant les formules (I) et (II), leurs énantiomères, diastéréomères et leurs sels, promédicaments et solvates pharmaceutiquement acceptables qui inhibent la transférase farnésyle protéine, laquelle est une enzyme impliquée dans l'expression de l'oncogène ras.
PCT/US1998/019315 1997-09-29 1998-09-16 Inhibiteurs de la transferase farnesyle proteine WO1999018951A1 (fr)

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CA002304473A CA2304473A1 (fr) 1997-09-29 1998-09-16 Inhibiteurs de la transferase farnesyle proteine
EP98948279A EP1027042A4 (fr) 1997-09-29 1998-09-16 Inhibiteurs de la transferase farnesyle proteine
AU94886/98A AU735366B2 (en) 1997-09-29 1998-09-16 Inhibitors of farnesyl protein transferase
JP2000515586A JP2001519387A (ja) 1997-09-29 1998-09-16 ファルネシルたんぱく転移酵素のインヒビター

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US60/060,823 1997-09-29

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JP (1) JP2001519387A (fr)
AU (1) AU735366B2 (fr)
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FR2796943A1 (fr) * 1999-07-30 2001-02-02 Aventis Pharma Sa Derives de benzoxazinnes, leur procede de preparation et leur utilisation en therapeutique
WO2001081322A1 (fr) * 2000-04-21 2001-11-01 Bristol-Myers Squibb Company Inhibiteurs benzodiazepine non-imidazole de la proteine farnesyl transferase
US6462086B1 (en) * 1999-06-18 2002-10-08 Ramot University Authority For Applied Research And Industrial Development Ltd. Non-malignant disease treatment with Ras antagonists
US6503901B1 (en) 1999-10-08 2003-01-07 Bristol Myers Squibb Pharma Company Amino lactam sulfonamides as inhibitors of Aβ protein production
US6503902B2 (en) 1999-09-13 2003-01-07 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of a β protein production
US6509333B2 (en) 2000-06-01 2003-01-21 Bristol-Myers Squibb Pharma Company Lactams substituted by cyclic succinates as inhibitors of Aβ protein production
US6525044B2 (en) 2000-02-17 2003-02-25 Bristol-Myers Squibb Company Succinoylamino carbocycles and heterocycles as inhibitors of a-β protein production
US6713476B2 (en) 2000-04-03 2004-03-30 Dupont Pharmaceuticals Company Substituted cycloalkyls as inhibitors of a beta protein production
US6759404B2 (en) 2000-04-03 2004-07-06 Richard E. Olson Cyclic malonamides as inhibitors of aβ protein production
EP1443936A2 (fr) * 2001-11-13 2004-08-11 Bristol-Myers Squibb Company Procede de preparation de composes de 3,7-disubstitue-2,3,4,5- tetrahydro-1h-1,4-benzodiazepine
US6900199B2 (en) 2000-04-11 2005-05-31 Bristol-Myers Squibb Pharma Company Substituted lactams as inhibitors of Aβ protein production
US6946485B2 (en) 1999-06-18 2005-09-20 Ramot At Tel Aviv University, Ltd. Treatment of post-angioplasty restenosis and atherosclerosis with Ras antagonists
US6960576B2 (en) 1999-09-13 2005-11-01 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
US7053084B1 (en) 1998-12-24 2006-05-30 Bristol-Myers Squibb Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
EP1744751A2 (fr) * 2004-03-18 2007-01-24 The Brigham And Women's Hospital, Inc. Traitement des synucleinopathies
US9096546B2 (en) 2007-05-10 2015-08-04 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9422281B2 (en) 2013-11-18 2016-08-23 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US9879092B2 (en) 2011-08-10 2018-01-30 Lankenau Institute For Medical Research Anti-RhoB antibodies
US10328053B2 (en) 2016-08-26 2019-06-25 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10336722B2 (en) 2013-11-18 2019-07-02 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof

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WO2006116716A2 (fr) * 2005-04-27 2006-11-02 University Of Florida Materiaux et methodes permettant d'ameliorer la degradation de proteines mutantes associees avec une maladie humaine
EP3967679A1 (fr) * 2016-04-18 2022-03-16 Vivoryon Therapeutics AG Nouveaux inhibiteurs de meprin alpha et bêta

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997030992A1 (fr) * 1996-02-26 1997-08-28 Bristol-Myers Squibb Company Inhibiteurs de la farnesyl-transferase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997030992A1 (fr) * 1996-02-26 1997-08-28 Bristol-Myers Squibb Company Inhibiteurs de la farnesyl-transferase

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US6458783B1 (en) 1997-09-29 2002-10-01 Bristol-Myers Squibb Company Non-imidazole benzodiazepine inhibitors of farnesyl protein transferase
US7304049B2 (en) 1998-12-24 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylaminobenzodiazepines as inhibitors of Aβ protein production
US7456172B2 (en) 1998-12-24 2008-11-25 Bristol-Myers Squibb Pharma Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US7053084B1 (en) 1998-12-24 2006-05-30 Bristol-Myers Squibb Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US7718795B2 (en) 1998-12-24 2010-05-18 Bristol-Myers Squibb Pharma Company Succinoylamino benzodiazepines as inhibitors of aβ protein production
US6462086B1 (en) * 1999-06-18 2002-10-08 Ramot University Authority For Applied Research And Industrial Development Ltd. Non-malignant disease treatment with Ras antagonists
US6946485B2 (en) 1999-06-18 2005-09-20 Ramot At Tel Aviv University, Ltd. Treatment of post-angioplasty restenosis and atherosclerosis with Ras antagonists
FR2796943A1 (fr) * 1999-07-30 2001-02-02 Aventis Pharma Sa Derives de benzoxazinnes, leur procede de preparation et leur utilisation en therapeutique
WO2001009127A1 (fr) * 1999-07-30 2001-02-08 Aventis Pharma S.A. Derives de benzoxazines, leur procede de preparation et leur utilisation en therapeutique
US7112583B2 (en) 1999-09-13 2006-09-26 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
US6503902B2 (en) 1999-09-13 2003-01-07 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of a β protein production
US7423033B2 (en) 1999-09-13 2008-09-09 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of aβ protein production
US7342008B2 (en) 1999-09-13 2008-03-11 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
US6960576B2 (en) 1999-09-13 2005-11-01 Bristol-Myers Squibb Pharma Company Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
US6503901B1 (en) 1999-10-08 2003-01-07 Bristol Myers Squibb Pharma Company Amino lactam sulfonamides as inhibitors of Aβ protein production
US6525044B2 (en) 2000-02-17 2003-02-25 Bristol-Myers Squibb Company Succinoylamino carbocycles and heterocycles as inhibitors of a-β protein production
US6759404B2 (en) 2000-04-03 2004-07-06 Richard E. Olson Cyclic malonamides as inhibitors of aβ protein production
US6713476B2 (en) 2000-04-03 2004-03-30 Dupont Pharmaceuticals Company Substituted cycloalkyls as inhibitors of a beta protein production
US7655647B2 (en) 2000-04-11 2010-02-02 Bristol-Myers Squibb Pharma Company Substituted lactams as inhibitors of Aβ protein production
US7498324B2 (en) 2000-04-11 2009-03-03 Bristol-Myers Squibb Pharma Company Substituted lactams as inhibitors of Aβ protein production
US7276495B2 (en) 2000-04-11 2007-10-02 Bristol-Myers Squibb Pharma Company Substituted lactams as inhibitors of Aβ protein production
US6900199B2 (en) 2000-04-11 2005-05-31 Bristol-Myers Squibb Pharma Company Substituted lactams as inhibitors of Aβ protein production
US7390802B2 (en) 2000-04-11 2008-06-24 Bristol-Myers Squibb Pharma Corporation Substituted lactams as inhibitors of Aβ protein production
WO2001081322A1 (fr) * 2000-04-21 2001-11-01 Bristol-Myers Squibb Company Inhibiteurs benzodiazepine non-imidazole de la proteine farnesyl transferase
US6509333B2 (en) 2000-06-01 2003-01-21 Bristol-Myers Squibb Pharma Company Lactams substituted by cyclic succinates as inhibitors of Aβ protein production
EP1443936A2 (fr) * 2001-11-13 2004-08-11 Bristol-Myers Squibb Company Procede de preparation de composes de 3,7-disubstitue-2,3,4,5- tetrahydro-1h-1,4-benzodiazepine
US7074921B2 (en) 2001-11-13 2006-07-11 Bristol Myers Squibb Company Process for the preparation of 3,7-disubstituted-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine compounds
EP1443936A4 (fr) * 2001-11-13 2006-01-11 Bristol Myers Squibb Co Procede de preparation de composes de 3,7-disubstitue-2,3,4,5- tetrahydro-1h-1,4-benzodiazepine
EP1744751A2 (fr) * 2004-03-18 2007-01-24 The Brigham And Women's Hospital, Inc. Traitement des synucleinopathies
EP1744751A4 (fr) * 2004-03-18 2010-03-10 Brigham & Womens Hospital Traitement des synucleinopathies
US9096546B2 (en) 2007-05-10 2015-08-04 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
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US9879092B2 (en) 2011-08-10 2018-01-30 Lankenau Institute For Medical Research Anti-RhoB antibodies
KR20200042013A (ko) * 2011-08-10 2020-04-22 란케나우 인스티튜트 포 메디칼 리서치 자가면역 및 염증성 질환의 치료를 위한 방법 및 조성물
US10336722B2 (en) 2013-11-18 2019-07-02 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10611750B2 (en) 2013-11-18 2020-04-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as bet bromodomain inhibitors
US10703764B2 (en) 2013-11-18 2020-07-07 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US9422281B2 (en) 2013-11-18 2016-08-23 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11084831B1 (en) 2013-11-18 2021-08-10 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11111229B2 (en) 2013-11-18 2021-09-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10328053B2 (en) 2016-08-26 2019-06-25 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10874640B2 (en) 2016-08-26 2020-12-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
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Also Published As

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JP2001519387A (ja) 2001-10-23
AU735366B2 (en) 2001-07-05
EP1027042A4 (fr) 2004-08-18
EP1027042A1 (fr) 2000-08-16
AU9488698A (en) 1999-05-03
CA2304473A1 (fr) 1999-04-22

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