EP0989979A1 - Nouveaux composes d'uree n-substitues inhibiteurs de la farnesyl transferase - Google Patents

Nouveaux composes d'uree n-substitues inhibiteurs de la farnesyl transferase

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Publication number
EP0989979A1
EP0989979A1 EP98932717A EP98932717A EP0989979A1 EP 0989979 A1 EP0989979 A1 EP 0989979A1 EP 98932717 A EP98932717 A EP 98932717A EP 98932717 A EP98932717 A EP 98932717A EP 0989979 A1 EP0989979 A1 EP 0989979A1
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Prior art keywords
hydrogen
compound
alkyl
cells
tumor cells
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EP98932717A
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German (de)
English (en)
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Stacy Remiszewski
Alan K. Mallams
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Merck Sharp and Dohme Corp
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Schering Corp
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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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D401/14—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 three or more hetero rings

Definitions

  • Patent application WO 95/00497 published 5 January 1995 under the Patent Cooperation Treaty describes compounds which inhibit the enzyme, farnesyl-protein transferase (FTase) and the famesylation of the oncogene protein Ras.
  • Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis.
  • Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non- transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer.
  • Ras oncoprotein To acquire transforming potential, the precursor of the Ras oncoprotein must undergo famesylation of the cysteine residue located in a carboxyl- terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, famesyl protein transferase, have therefore been suggested as anticancer agents for tumors in which Ras contributes to transformation. Mutated, oncogenic forms of Ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, Vol. 260, 1834 to 1837, 1993). In view of the current interest in inhibitors of famesyl protein transferase, a welcome contribution to the art would be additional compounds useful for the inhibition of famesyl protein transferase. Such a contribution is provided by this invention.
  • this invention provides a method for inhibiting famesyl protein transferase using tricyclic compounds of this invention which: (i) potently inhibit famesyl protein transferase, but not geranylgeranyl protein transferase I, jn vitro: (ii) block the phenotypic change induced by a form of transforming Ras which is a famesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intraceilular processing of Ras which is a famesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.
  • This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention.
  • Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (.1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.
  • A represents N or N-oxide
  • X represents N, CH or C, such that when X is N or CH, there is a single bond to carbon atom 11 as represented by the solid line; or when X is C, there is a double bond to carbon atom 11 , as represented by the solid and dotted lines;
  • X 1 and X 2 are independently selected from bromo or chloro, and X 3 and X 4 are independently selected from hydrogen, bromo or chloro provided that at least one of X 3 and X 4 is hydrogen;
  • Y 1 and Y 2 are independently selected from hydrogen or alkyl
  • R 10 , R 19 and R 20 independently represent hydrogen, alkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl and heterocycloalkylalkyl, with the proviso that R 19 and R 20 are not both hydrogen; v is zero, 1 , 2 or 3; and w is zero or 1.
  • compound (1.0) there is a single bond at carbon atom 1 1 ;
  • R 19 or R 20 When R 19 or R 20 is alkyl, optional substituents on the alkyl group may include -OR 10 , alkoxy, -OCOR 10 , -CONR 10 R 12 or -COOR 10 , wherein R 10 and R1 2 are independently selected from hydrogen, alkyl or alkoxy.
  • R 19 or R 20 When R 19 or R 20 is aryl, an optional substituent on the aryl group may include alkoxy.
  • R 19 or R 20 is heterocycloalkyl, an optional substituent on the heterocycloalkyl group may include -COOR 10 wherein R 10 is hydrogen or alkyl.
  • Preferred title compounds include those of Examples 3, 4, 6, 7, 11 , 12 and 13, disclosed hereinafter.
  • the present invention is directed toward a pharmaceutical composition for inhibiting the abnormal growth of cells comprising an effective amount of compound (1.0) in combination with a pharmaceutically acceptable carrier.
  • the present invention is directed toward a method for inhibiting the abnormal growth of cells, including transformed cells, comprising administering an effective amount of compound (1.0) to a mammal (e.g., a human) in need of such treatment.
  • Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs, and (4) benign or malignant cells that are activated by mechanisms other than the Ras protein.
  • these compounds may function either through the inhibition of G-protein function, such as ras p21 , by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer, or through inhibition of ras famesyl protein transferase, thus making them useful for their antiproliferative activity against ras transformed cells.
  • the cells to be inhibited can be tumor cells expressing an activated ras oncogene.
  • the types of cells that may be inhibited include pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, prostate tumor cells, breast tumor cells or colon tumors cells.
  • the inhibition of the abnormal growth of cells by the treatment with compound (1.0) may be by inhibiting ras farnesyl protein transferase.
  • the inhibition may be of tumor cells wherein the Ras protein is activated as a result of oncogenic mutation in genes other than the Ras gene.
  • compounds (1.0) may inhibit tumor cells activated by a protein other than the Ras protein.
  • This invention also provides a method for inhibiting tumor growth by administering an effective amount of compound (1.0) to a mammal (e.g., a human) in need of such treatment.
  • a mammal e.g., a human
  • this invention provides a method for inhibiting the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds.
  • tumors which may be inhibited include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, prostate carcinoma and breast carcinoma and epidermal carcinoma.
  • lung cancer e.g., lung adenocarcinoma
  • pancreatic cancers e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma
  • colon cancers e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma
  • this invention also provides a method for inhibiting proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes-i.e., the Ras gene itself is not activated by mutation to an oncogenic form-with said inhibition being accomplished by the administration of an effective amount of the N-substituted urea compounds (1.0) described herein, to a mammal (e.g., a human) in need of such treatment.
  • a mammal e.g., a human
  • the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes may be inhibited by the N-substituted urea compounds (1.0).
  • the present invention is directed toward a method for inhibiting ras farnesyl protein transferase and the famesylation of the oncogene protein Ras by administering an effective amount of compound (1.0) to mammals, especially humans.
  • the administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described above.
  • M+ represents the molecular ion of the molecule in the mass spectrum
  • MH+ represents the molecular ion plus hydrogen of the molecule in the mass spectrum
  • Bu-represents butyl; Et-represents ethyl; Me-represents methyl; Ph-represents phenyl; benzotriazol-1 -yloxy represents
  • CH 3 alkyl-(including the alkyl portions of alkoxy, alkylamino and dialkylamino)-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms; for example methyl, ethyl, propyl, iso-propyl, n-butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; wherein said alkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF3, oxy ( 0), aryloxy, -OR 10 , -OCF3, heterocycloalkyl, heteroaryl, -NR 0 R 12 , -NHS0 2 R 1 °, -S0 2 NH 2 , -S0 2 NHR 1 °, -S0 2 R
  • heteroaryl groups can include, for example, furanyl, imidazoyl, pyrimidinyl, triazolyl, 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl N-oxide wherein pyridyl N-oxide can be represented as:
  • heterocycloalkyl groups can include 2- or 3-tetrahydrofuranyl, 2- or 3- tetrahydrothienyl, 1-, 2-, 3- or 4- piperidinyl, 2- or 3-pyrrolidinyl, 1-, 2- or 3-piperizinyl, 2- or 4-dioxanyl,
  • solvents and reagents are referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N,N- dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1-hydroxybenzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA); triethylamine (Et 3 N); diethyl ether (Et 2 0); ethyl chloroformate (CIC0 Et); and 1 - (3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC).
  • THF tetrahydrofuran
  • EtOH ethanol
  • MeOH methanol
  • acetic acid HOAc or AcOH
  • Certain compounds of the invention may exist in different stereoisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers) .
  • the invention contemplates all such stereoisomers both in pure form and in mixture, including racemic mixtures.
  • the carbon atom at the C-11 position can be in the S or R stereoconfiguration.
  • Certain tricyclic compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
  • Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts.
  • the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids.
  • suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art.
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
  • the free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention. All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purpopses of the invention.
  • A, X, X 1 , X 2 , X 3 , X 4 , Y1, Y2, Z, R5, R6, R 7 and R 8 , R 19 , R 20 , v, w, the solid and dotted lines are as defined hereinbefore.
  • compounds of formula (1.0) can be prepared by reacting the compounds of formula (2.0) with amine (NHR 19 R 20 ) of formula (2.6) with an optional base and/or optional aprotic solvent such as THF, dioxane, acetonitrile, CH2CI2 or DMF.
  • an optional base and/or optional aprotic solvent such as THF, dioxane, acetonitrile, CH2CI2 or DMF.
  • compound (2.0) is reacted with amine (2.6) neat, at temperatures ranging from about 0° to 80°C.
  • compound (2.0) is reacted with about equimolar amounts of amine (2.6) in the presence of a base such as sodium hydride and an aprotic solvent such as CH2CI2 or THF.
  • compound (2.0) is reacted with amine (2.6) neat, using catalytic amounts of base, such as sodium hydride.
  • compound (2.0) is reacted with greater than two equivalents of amine (2.6) in an aprotic solvent at a temperature of about 75°C. Except as noted otherwise, temperatures can range from 0° to 100°C, or reflux of the reaction mixture and amounts of amine (2.6) can range from 1 to about 10 moles per mole of compound (2.0).
  • compounds of formula (1.0) can be prepared by reacting the compounds of formula (3.0) with carbonyl chloride of formula (2.9) with an optional base and/or optional aprotic solvent.
  • compound (3.0) is reacted with carbonyl chloride (2.9) neat, at temperatures ranging from about 0°C to 80°C.
  • compound (3.0) is reacted with about equimolar amounts of carbonyl chloride (2.9) in the presence of a base such as sodium hydride and an aprotic solvent.
  • compound (3.0) is reacted with carbonyl chloride (2.9) neat, using catalytic amounts of base, such as sodium hydride.
  • compound (3.0) is reacted with greater than two equivalents of carbonyl chloride (2.9) in an aprotic solvent at a temperature of about 75°C. Except as noted otherwise, temperatures can range from 0°C to 100°C, or reflux of the reaction mixture and amounts of carbonyl chloride (2.9) can range from 1 to about 10 moles per mole of compound (3.0).
  • compounds of formula (1.0) wherein R 20 is hydrogen can be prepared by reacting the compounds of formula (3.0) with isocyanate R 19 NCO of formula (3.6) with an optional base and/or optional aprotic solvent such as those described hereinbefore.
  • compound (3.0) is reacted with isocyanate (3.6) neat at temperatures ranging from about 0° to 80° C.
  • compound (3.0) is reacted with about equimolar amounts of isocyanate (3.6) in the presence of a base such as triethylamine and an aprotic solvent such as CH 2 C_2 or THF.
  • compound (3.0) is reacted with about equimolar amounts of isocyanate (3.6) in the presence of a base such as sodium hydride and an aprotic solvent such as DMF or THF.
  • compound (3.0) is reacted with greater than two equivalents of isocyanate (3.6) in an aprotic solvent such as DMF at a temperature of about 75°C.
  • compound (3.0) is reacted with excess isocyanate (3.6) using catalytic amounts of a base such as sodium hydride and an aprotic solvent such as DMF or THF. Except as noted otherwise, temperatures can range from 0° to 100°C, or reflux of the reaction mixture and amounts of isocyanate (3.6) can range from 1 to about 10 moles per mole of compound (3.0).
  • Compounds of fomula (1.0) can be isolated from the reaction mixture using conventional procedures, such as, for example, extraction of the reaction mixture from water with organic solvents, evaporation of the organic solvents, followed by chromatography on silica gel or other suitable chromatographic media.
  • compounds (1.0) can be dissolved in a water-miscible solvent, such as methanol, the methanol solution is added to water to precipitate the compound, and the precipitate is isolated by filtration or centrifugation.
  • (+)-lsomers of compounds of formula (5.0, 6.0 and 10.9) wherein X is CH can be prepared with high enantioselectivity by using a process comprising enzyme catalyzed transesterification.
  • a racemic compound of formula (5.0, 6.0 and 10.9) wherein X is C, the double bond is present and X 3 is not H, is reacted with an enzyme such as Toyobo LIP-300 and an acylating agent such as trifluoroethly isobutyrate; the resultant (+)-amide is then hydrolyzed, for example by refluxing with an acid such as H2SO4, to obtain the corresponding optically enriched (+)-isomer wherein X is CH and R 3 is not H.
  • a racemic compound of formula (5.0, 6.0 and 10.9) wherein X is C, the double bond is present and R 3 is not H, is first reduced to the corresponding racemic compound of formula (5.0, 6.0 and 10.9) wherein X is CH and then treated with the enzyme (Toyobo LIP-300) and acylating agent as described above to obtain the (+)-amide, which is hydrolyzed to obtain the optically enriched (+)-isomer.
  • Example 2 Following the procedure described in Example 1 using 90 mg (0.1-5 mmol) of the title compound of Preparative Example 5 and 0.02 mL (0.2 mmol) of ethyl isocyanatoacetate and stirring the mixture 2 h gave a material that was purified by flash chromatography (silica, 2%-4% (NH 3 saturated MeOH)/CH Cl 2 as eluent). The title compound was obtained as a white solid (45 mg, 40%, mp 126.4 - 128.2 °C).
  • Ethyl 4-aminopiperidine carboxylate (1.00 mL, 5.83 mmol) was dissolved in anhydrous THF (5 mL) and the mixture was cooled to 0° C. A 1.93 M solution of phosgene in toluene (4.50 mL 8.69 mmol) was added followed by triethylamine (3.30 mL, 23.7 mmol). The resulting slurry was stirred at 0° C 3 h then at room temperature overnight. The mixture was diluted with ether (20 mL), filtered and the filter cake washed with ether.
  • Example 8 The title compound of Example 8 (330 mg, 0.41 mmol) was dissolved in anhydrous MeOH (2.5 mL) and 6 mL of 10% H2S ⁇ /dioxane (v/v) was added. The mixture was stirred overnight then 0.2 mL cone. H2SO4 was added. After 4 h 1 M NaOH was added, water was added and the mixture extracted with CH2CI2. The combined extracts were washed (brine), dried (MgS04), filtered and evaporated to give the title compound as a white solid (291.1 mg, 96%, mp 122.4-125° C).
  • Example 12 Following the procedure described in Example 7 using 200 mg (0.34 mmol) of the title compound of Preparative Example 5, 0.88 mL of 1.93 M phosgene in toluene (1.7 mmol), two 0.23 mL portions of triethylamine (1.7 mmol each) and 0.04 mL (0.66 mmol) of ethanolamine the title compound was obtained after precipitation from water as a brown solid (138.1 mg, 56%, mp 142.3 -145.9° C).
  • Example 12 Example 12
  • Example 4 The title compound of Example 4 was dissolved in 6 M HCI and the mixture stirred 72 h. The reaction was diluted with H2O and brine and extracted with CH2CI2. The combined organic extracts were dried (MgS ⁇ 4), filtered and evaporated and the residue purified by flash chromatography (C18 reverse phase silica (Aldrich), gradient elution, 1 L 50% MeOH/0.1 % HOAc reservoir A, 1 L 90% MeOH/0.1% HOAc reservoir B) to give the title compound as a white solid (162.2 mg, 31%, mp 123.4 -125.8° C).
  • Example 12 The title compound of Example 12 (60 mg, 0.086 mmol) was dissolved in DMF and NH4CI (7 mg, 0.13 mmol), N-methylmorpholine (0.015 mL, 0.13 mmol), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25 mg, 0.13 mmol) and 1-hydroxybenzotriazole hydrate (17 mg, 0.13 mmol) were added. After 3.5 h an additional 21 mg of NH4CI (0.39 mmol) was added and the mixture stirred overnight. Water was added to give the title compound as a white solid (33.4 mg, 55%, mp 144.8 - 149.8° C). EXAMPLE 14.
  • Patents 5,089,496; 5,151 ,423; 4,454,143; 4,355,036; PCT ⁇ JS94/11390 (WO95/10514); PCT/US94/11391 (WO 95/10515); PCT/US94/11392 (WO95/10516); Stanley R. Sandier and Wolf Karo, Organic Functional Group Preparations, 2nd Edition, Academic Press, Inc., San Diego, California, Vol. 1-3, (1983), and in J. March, Advanced Organic Chemistry, Reactions & Mechanisms, and Structure, 3rd Edition, John Wiley & Sons, New York, 1346 pp. (1985).
  • Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art.
  • R 15 can represent any of the values for R 10 as defined hereinbefore; and T is OH, -OCOR 10 , halo such as chloro or -OR 10 .
  • compounds of formula (10.0) can be prepared by reacting the compounds of formula (11.0) with a nitrating agent and/or optional protic or aprotic solvent such as those described hereinbefore.
  • a nitrating agent such as potassium nitrate
  • acid such as sulfuric acid at temperatures ranging from about -20° to +5° C.
  • compound (11.0) is reacted with about an equimolar amount of nitric acid and acid, such as sulfuric acid at temperatures ranging from about -20° to +5° C.
  • compound (11.0) is treated with a mixture comprised of about two equivalents of trifluoromethanesulfonic acid and about one equivalent nitric acid in a solvent such as trifluoromethanesulfonic acid.
  • compound (11.0) is treated with a mixture comprised of about one equivalent of fuming nitric acid and about ten equivalents of trifluoromethanesulfonic anhydride in a solvent such as nitromethane.
  • compound (11.0) is treated with a nitronium salt, such as nitronium tetrafluoroborate, in a solvent, such as sulfolane.
  • Step B(Scheme IV) compounds of formula (9.0) can be prepared by reacting compounds of the formula (10.0) with a reducing agent.
  • compound (10.0) can be reacted with about ten equivalents of a metal, such as iron, in a solvent, such as ethanol, in the presence of a salt, such as calcium chloride, at temperatures ranging from about 0° to +80° C.
  • compound (10.0) in a second procedure, can be reacted with about ten equivalents of a metal, such as zinc, in a solvent, such as ethanol, in the presence of an acid, such as acetic acid at temperatures ranging from about 0° to +80° C.
  • compound (10.0) in a third procedure, can be reacted with about five equivalents of stannous chloride hydrate in a solvent, such as ethyl acetate.
  • compound (10.0) in a fourth procedure, can be reacted with about ten equivalents of a metal, such as tin, in a solvent, such as ethanol, in the presence of an acid, such as hydrochloric acid.
  • compounds of formula (8.0) can be prepared by reacting compounds of the formula (9.0) with a halogenating agent.
  • a halogenating agent such as bromine
  • a suitable solvent such as acetic acid
  • compound (9.0) can be reacted with an excess of a mineral acid, such as hydrogen bromide, in a suitable solvent, such as dimethyl sulfoxide at temperatures ranging from about 20° C to about 135°C.
  • compound (9.0) can be reacted with a salt, such as pyridinium bromide perbromide, in a solvent, such as THF, at temperatures from about 0° to +40° C.
  • compound (9.0) can be reacted with a halogen, such as chlorine, in the presence of a Lewis acid, such as iron(lll) chloride, in a suitable solvent, such as dichloromethane.
  • compounds of formula (7.0) can be prepared by reacting compounds of the formula (8.0) with an oxidizing agent followed by a reducing agent, or by reacting compounds of the formula (8.0) with an oxidizing agent in the presence of a hydrogen atom source.
  • compound (8.0) can be reacted with a diazotizing agent, such as t-butyl nitrite, in a solvent and hydrogen atom source, such as DMF at temperatures from about 0° to +100° C.
  • a diazotizing agent such as t-butyl nitrite
  • compound (8.0) can be reacted with a diazotizing agent, such as sodium nitrite, and an acid, such as hydrochloric acid, and a reducing agent, such as hypophosphorous acid at temperatures from about -15° to +50° C.
  • compound (8.0) can be reacted with a diazotizing agent, such as sodium nitrite, and an acid, such as aqueous sulfuric acid, followed by treatment with a metal, such as copper.
  • compound (8.0) can be reacted with a diazotizing agent, such as sodium nitrite, and an acid, such as fluoboric acid, followed by treatment with a reducing agent, such as sodium borohydride.
  • compounds of formula (6.0) can be prepared by reacting compounds of the formula (7.0) under hydrolysis conditions.
  • compound (7.0) can be reacted with an acid, such as hydrochloric acid, at temperatures from about 20° to +90° C.
  • compound (7.0) can be reacted with a base, such as aqueous sodium hydroxide, in a suitable solvent, such as ethanol, at temperatures from about 20° to +90° C.
  • compound (7.0) can be reacted with a nucleophile, such as hydrazine hydrate, in a solvent, such as ethanol, with an optional base, such as sodium hydroxide, at temperatures from about 20° to +90° C.
  • compound (7.0) can be reacted with a silyl chloride, such as trimethylsilyl chloride, in a solvent, such as THF or CH2CI2 at temperatures ranging from about 0°C to reflux.
  • compound (7.0) can be reacted with an acid, such as trifluoroacetic acid, in an aprotic solvent, such as CH2CI2.
  • Compound (6.0) can be reacted with an alkyl-metal hydride, such as diisobutyl aluminum hydride, in a solvent, such as toluene, at temperatures from about 0° to +90° C.
  • an alkyl-metal hydride such as diisobutyl aluminum hydride
  • compounds of formula (4.0) can be prepared by reacting compounds of the formula (5.0) with a carboxylic acid under dehydrating conditions.
  • compound (5.0) or (6.0) can be reacted with an carboxylic anhydride in a protic or aprotic solvent such as THF.
  • compounds of formula (3.0) can be prepared by reacting compounds of the formula (4.0) under hydrolysis conditions.
  • compound (4.0) can be reacted with an acid, such as hydrochloric acid, at temperatures from about 20° to +90° C.
  • compound (4.0) can be reacted with a base, such as aqueous sodium hydroxide, in a suitable solvent, such as ethanol, at temperatures from about 20° to +90° C.
  • compound (4.0) can be reacted with a nucleophile, such as hydrazine hydrate, in a solvent, such as ethanol, with an optional base, such as sodium hydroxide, at temperatures from about 20° to +90° C.
  • compound (4.0) can be reacted with a silyl chloride, such as trimethylsilyl chloride, in a solvent, such as THF or CH2CI2.
  • compound (4.0) can be reacted with an acid, such as trifluoroacetic acid, in an aprotic solvent, such as CH2CI2-
  • compounds of formula (2.0) can be prepared by reacting compounds of the formula (3.0) and (3.1) with an excess amount of phosgene or a compound capable of releasing phosgene, in the presence of an optional base, such as Et3N, either neat, or in an optional aprotic solvent.
  • an optional base such as Et3N
  • a sulfurating agent such as Lawesson's Reagent
  • a suitable aprotic solvent such as toluene
  • Alternative sulfurating reagents include bis-(1 ,5-cyclooctanediarylboryl)sulfide in hexane at -78°C; or phosphorous pentasulfide (P2S5, also of the formula P4S10) in toluene at reflux temperatures, or in THF using ultrasound at 40°C; or bis-(9- Borabicyclo[3.3.1]nonane)suifide ((9-BBN)2S) in heptane at reflux temperatures.
  • Step K(Scheme IVa) compounds of formula (6.1) can be prepared by reacting the compound of formula (5.9) with a nitrating agent and/or optional protic or aprotic solvent according to the procedures described in Step A (Scheme IV).
  • Step L compounds of formula (6.2) can be prepared by reacting the compound of formula (6.1) with a reducing agent according to the procedures described in Step B (Scheme IV).
  • Step M compounds of formula (6.31) can be prepared by reacting the compound of formula (6.2) with a halogenating agent according to the procedures described in Step C (Scheme IV).
  • compounds of formula (6.3) can be prepared by reacting the compound of formula (6.31) with an oxidizing agent followed by a reducing agent, or by reacting compounds of the formula (6.31) with an oxidizing agent in the presence of a hydrogen atom source according to the procedures described in Step D (Scheme IV).
  • compounds of formula (6.5) can be prepared by reacting compounds of formula (6.3) with sodium borohydride (NaBH4) in a solvent such as ethanol/toluene under reflux conditions for 10 minutes or at 25°C for two hours or more.
  • NaBH4 sodium borohydride
  • compounds of formula (6.7) can be prepared by reacting compounds of formula (6.5) with SOCI2 in a solvent such as CH2CI2 at a temperature of about 25°C for about 4 hours or more.
  • Step Q Scheme IVa
  • compounds of formula (10.3) can be prepared by reacting compound of formula (10.0) with 1 ,3-dibromo-5,5-dimethyIhydantoin in an acid, such as trifluoromethane sulfonic acid or sulfuric acid for about 24 h or more at 25°C.
  • an acid such as trifluoromethane sulfonic acid or sulfuric acid for about 24 h or more at 25°C.
  • Step BB Scheme V
  • compounds of the formula (10.5) can be prepared by treating the compounds of formula (10.3) with a reducing agent, using the procedures taught in Scheme IV, Step B.
  • compounds of formula (10.7) can be prepared by reacting compounds of formula (10.5) with sodium nitrite (NaN ⁇ 2) in concentrated aqueous HCI at temperatures ranging from about -10°C to 0°C for about 2 h or more, then treating the reaction mixture with phosphorous acid
  • compounds of formula (10.9) can be prepared by reacting compounds of formula (10.7) with concentrated aqueous HCI at about 85°C for about 18 h or more.
  • Compound (10.9) can be reacted using the same procedures described in Scheme IV for treating compound (5.0) and (6.0) and subsequent intermediates therefrom, in order to obtain the desired compounds of formula (1.0).
  • compounds of formula (10.8) can be prepared by reacting compound of formula (10.7) with Nal ⁇ 4 and Ru ⁇ 2 in acetonitrile and water for about 18 to 24 h or more at 25°C.
  • Compound (10.8) can be reacted using the same procedures described in Scheme IVa for treating compound
  • temperatures can range from 0° to 100°C, or reflux of the reaction mixture and amounts of the reagents (e.g. compound 5.5) can range from 1 to about 10 moles per mole of reactant (e.g. compound 5.0 or 6.0).
  • Step C Combine 6.69 g (13.1 mmol) of the product of Step A and 100 mL of 85% EtOH/water, then add 0.66 g (5.9 mmol) of CaC.2 and 6.56 g (117.9 mmol) of Fe and heat the mixture at reflux overnight. Filter the hot reaction mixture through Celite® and rinse the filter cake with hot EtOH. Concentrate the filtrate in vacuo to give 7.72 g of the product. Step C:
  • Step D Combine 7.70 g of the product of Step B and 35 mL of HOAc, then add 45 mL of a solution of Br2 in HOAc and stir the mixture at room temperature overnight. Add 300 mL of 1 N NaOH (aqueous) , then 75 mL of 50% NaOH (aqueous) and extract with EtOAc. Dry the extract over MgS ⁇ 4 and concentrate in vacuo to a residue. Chromatograph the residue (silica gel, 20%-30% EtOAc/hexane) to give 3.47 g of the product (along with another 1.28 g of partially purified product).
  • Step D Step D:
  • Step E Combine 0.557 g (5.4 mmol) of t-butyl nitrite and 3 mL of DMF, and heat the mixture at to 60°-70°C. Slowly add (dropwise) a mixture of 2.00 g (3.6 mmol) of the product of Step C and 4 mL of DMF, then cool the mixture to room temperature. Add another 0.64 mL of t-butylnitrite at 40°C and reheat the mixture to 60°-70°C for 0.5 hrs. Cool to room temperature and pour the mixture into 150 mL of water. Extract with CH2CI2, dry the extract over MgS ⁇ 4 and concentrate in vacuo to a residue. Chromatograph the residue (silica gel, 10%- 20% EtOAc/hexane) to give 0.74 g of the product. Step E:
  • the racemic title compound of Preparative Example 1 is separated by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, using 20% iPrOH/hexane + 0.2% diethylamine), to give the (+)-isomer and the (-)-isomer of the title compound.
  • the enantiomers can also be separated by crystallization with an amino acid such as N-acetylphenylalanine.
  • SCH 72379 Combine 2.56 g (5.44 mmol) of the (+)-isomer of Preparative Example 3 with 1.71 g (7.03 mmol) of N-BOC-4-piperidylacetic acid, 1.01 g (7.47 mmol) 1- hydroxybenzotriazole hydrate and 1.40 mL (12.7 mmol) N-methylmorpholine in 15 mL of anhydrous DMF and add 1.29 g (6.73 mmol) of 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and stir at room temperature for 5 h.
  • the mixture was diluted with 15 mL water and 15 mL saturated NaHC03 solution (aqueous) and extracted with ethyl acetate. The organic extracts were washed with saturated NaHC ⁇ 3 solution, brine and dried (MgS04) to give the product.
  • the racemic title compound from Step F (5.7 g) is chromatographed by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, flow rate 100 mLJmin) using 30% iPrOH/hexane + 0.2% diethylamine, to give 2.88 g of the R-(+)-enantiomer and 2.77 g of the S-(-)-enantiomer of the title compound.
  • the racemic title compound of Step C is separated by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, flow rate 100 mlJmin., 20% iPrOH/hexane + 0.2% diethylamine), to give 9.14 g of the (+)-enantiomer and 9.30 g of the (-)-enantiomer.
  • the racemic title compound of Step A is separated by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, using 5% iPrOH/hexane + 0.2% diethylamine), to give the (+)-enantiomer and the (-)- enantiomer of the title compound.
  • Step A 1 ,1-Dimethylethyl 4-[[[4-(3-bromo-8-chloro-6,11-dihydro-5H- benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -YL)-1 -piperazinyl]carbonyl]methyl]-1 piperidinecarboxylate
  • Step B 1-(3-bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1 ,2- b]pyridin-1 1 -yl)-4-[(4-piperidinyl)acetyl]piperazine
  • FPT IC50 inhibition of farnesyl protein transferase, in vitro enzyme assay
  • FPT IC50 inhibition of farnesyl protein transferase, in vitro enzyme assay
  • the data demonstrate that the compounds of the invention are inhibitors of Ras-CVLS famesylation by partially purified rat brain farnesyl protein transferase (FPT).
  • the data also show that there are compounds of the invention which can be considered as potent (IC50 ⁇ 10 ⁇ M) inhibitors of Ras-CVLS famesylation by partially purified rat brain FPT.
  • COS IC50 values refer to the COS cells activity inhibition of Ras processing, are determined by the methods disclosed in WO/10515 or WO 95/10516.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 70 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection.
  • Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
  • a pharmaceutically acceptable carrier such as an inert compressed gas.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compound is administered orally.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, more preferably from about 1 mg. to 300 mg, according to the particular application.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • a typical recommended dosage regimen is oral administration of from 10 mg to 2000 mg/day preferably 10 to 1000 mg/day, in two to four divided doses to block tumor growth.
  • the compounds are non-toxic when administered within this dosage range.

Abstract

La présente invention concerne de nouveaux composés d'urée halogéno N-substitués et des compositions pharmaceutiquement acceptables de formules (1.0) ainsi que leurs sels ou solvates pharmaceutiquement acceptables, qui sont des inhibiteurs de l'enzyme farnésyl transférase. La présente invention concerne également une méthode d'inhibition de la fonction Ras et donc de la croissance anormale des cellules. Cete méthode, qui consiste à administrer le nouveau composé d'urée halogéno N-substitué à un système biologique permet notamment d'inhiber la croissance anormale des cellules chez des mammifères tel que l'homme.
EP98932717A 1997-06-17 1998-06-15 Nouveaux composes d'uree n-substitues inhibiteurs de la farnesyl transferase Withdrawn EP0989979A1 (fr)

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US87704997A 1997-06-17 1997-06-17
PCT/US1998/011507 WO1998057948A1 (fr) 1997-06-17 1998-06-15 Nouveaux composes d'uree n-substitues inhibiteurs de la farnesyl transferase
US877049 2004-06-25

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WO2016049524A1 (fr) 2014-09-25 2016-03-31 Araxes Pharma Llc Inhibiteurs de protéines mutantes kras g12c
TW201702232A (zh) 2015-04-10 2017-01-16 亞瑞克西斯製藥公司 經取代之喹唑啉化合物及其使用方法
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WO2017172979A1 (fr) 2016-03-30 2017-10-05 Araxes Pharma Llc Composés quinazoline substitués et procédés d'utilisation
US10646488B2 (en) 2016-07-13 2020-05-12 Araxes Pharma Llc Conjugates of cereblon binding compounds and G12C mutant KRAS, HRAS or NRAS protein modulating compounds and methods of use thereof
EP3519402A1 (fr) 2016-09-29 2019-08-07 Araxes Pharma LLC Inhibiteurs de protéines mutantes kras g12c
CN110312711A (zh) 2016-10-07 2019-10-08 亚瑞克西斯制药公司 作为ras抑制剂的杂环化合物及其使用方法
WO2018140514A1 (fr) 2017-01-26 2018-08-02 Araxes Pharma Llc Dérivés de 1-(6-(3-hydroxynaphtalen-1-yl)quinazolin-2-yl)azétidin-1-yl)prop-2-en-1-one et composés similaires utilisés en tant qu'inhibiteurs de kras g12c pour le traitement du cancer
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CN1267291A (zh) 2000-09-20
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CA2293706A1 (fr) 1998-12-23
ZA985205B (en) 1998-12-15
AU8253598A (en) 1999-01-04
NZ501571A (en) 2002-02-01
CO4940458A1 (es) 2000-07-24
AR013094A1 (es) 2000-12-13
CA2293706C (fr) 2008-11-18
JP2002506444A (ja) 2002-02-26
WO1998057948A1 (fr) 1998-12-23
IL133389A0 (en) 2001-04-30
HUP0002954A3 (en) 2002-11-28
HUP0002954A2 (hu) 2001-06-28

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