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WO1998057950A1 - Nouveaux composes tricycliques de phenyle substitues inhibiteurs de farnesyl proteine transferase - Google Patents

Nouveaux composes tricycliques de phenyle substitues inhibiteurs de farnesyl proteine transferase Download PDF

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Publication number
WO1998057950A1
WO1998057950A1 PCT/US1998/011509 US9811509W WO9857950A1 WO 1998057950 A1 WO1998057950 A1 WO 1998057950A1 US 9811509 W US9811509 W US 9811509W WO 9857950 A1 WO9857950 A1 WO 9857950A1
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Prior art keywords
compound
alkyl
cells
hydrogen
methyl
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PCT/US1998/011509
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Inventor
Adriano Afonso
Joseph M. Kelly
Jay Weinstein
Ronald L. Wolin
Stuart B. Rosenblum
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Merck Sharp and Dohme LLC
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Schering Corp
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Priority to NZ501613A priority Critical patent/NZ501613A/en
Priority to AU82537/98A priority patent/AU8253798A/en
Priority to CA002293549A priority patent/CA2293549C/fr
Priority to JP50450399A priority patent/JP2002504150A/ja
Priority to HU0003215A priority patent/HUP0003215A2/hu
Priority to EP98932719A priority patent/EP0989981A1/fr
Priority to IL13344698A priority patent/IL133446A0/xx
Publication of WO1998057950A1 publication Critical patent/WO1998057950A1/fr
Anticipated expiration legal-status Critical
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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
    • C07D401/12—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
    • 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
    • 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, farnesyl 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).
  • a welcome contribution to the art would be additional compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.
  • this invention provides a method for inhibiting farnesyl protein transferase using tricyclic compounds of this invention which: (i) potently inhibit farnesyl protein transferase, but not geranyigeranyl protein transferase I, in vitro: (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranyigeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranyigeranyl 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.
  • Compounds useful in the claimed methods are represented by Formula 1.0:
  • 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;
  • R 1 is hydrogen, bromo, chloro, trifluoromethyl, acyl, alkyl, cycloalkyl, amino, acylamino or alkoxy;
  • R 2 is hydrogen, halo, trifluoromethyl, alkyl, alkoxy, -OCF3, hydroxy, amino or acylamino;
  • R 3 is hydrogen, bromo, chloro, alkoxy, -OCF3 or hydroxy
  • R 4 is hydrogen, halo, trifluoromethyl, alkyl or alkoxy
  • R 2 or R 3 or R 4 is alkyl or alkoxy
  • R 1 , R 2 , R 3 or R 4 are substituents other than hydrogen;
  • Q is hydrogen when there is a single bond to carbon atom 11 , or Q is hydrogen or hydroxy when there is a single bond to carbon 11 and X is CH, or Q is not a substituent when there is a double bond to carbon 11 ;
  • R 5 , R 6 , R 7 and R 8 independently represent hydrogen, alkyl or -CONHR 50 wherein R 50 can be any of the values represented for R, below ;
  • Y is -C-R or -S0 2 -R, wherein ;
  • R is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl.
  • X is N, CH or C
  • R 1 is H, halo, alkyl, cycloalkyl or alkenyl
  • R 2 is H, halo, alkoxy, or alkyl
  • R 3 is H, halo, alkoxy, hydroxy or alkyl
  • R 4 is H, halo or alkyl
  • R 5 , R 8 , R 7 and R 8 are hydrogen
  • Y is -S0 CH 3 or -COR wherein R is heteroarylalkyl, preferably pyridinyl N-oxide-methyl or heterocycloalkylalkyl, preferably piperidinyl-methyl.
  • R 1 is other than hydrogen, preferably the halo moiety is bromo, the alkyl is methyl or ethyl, the cycloalkyl is cyclopropyl or the alkenyl is vinyl.
  • R 2 is other than hydrogen, preferably the alkoxy moiety is methoxy, the halo moiety is bromo or the alkyl is methyl.
  • R 3 is other than hydrogen, preferably the alkoxy moiety is methoxy, the halo moiety is bromo or the alkyl is methyl.
  • R 4 is other than hydrogen, preferably the halo moiety is chloro or the alkyl is methyl.
  • Preferred title compounds include those of Examples 1-10 and 14-37, preferably those of Examples 1 , 2, 3, 6, 7, 8, 10, 16, 18, 19, 21 , 22, 24, 26, 27, 29, 33, 34, 35, 36 and 37, more preferably those of Examples 3, 21 , 22, 24 and 33, 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 farnesyl protein transferase, thus making them useful for their antiproliferative activity against ras transformed cells.
  • G-protein function such as ras p21
  • ras farnesyl 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
  • -OR 10 -OCF3, heterocycloalkyl, heteroaryl, -NR 10 R 12 , -NHS0 2 R 10 , - S0 2 NH 2 , -S0 2 NHR 10 , -S0 2 R 1 °, -SOR 10 , -SR 10 , -NHS0 2 , -N0 2 , -CONR 10 R 12 , -NR 12 COR 10 , -COR 10 , -OCOR 10 , -OC0 2 R 1 ° or -COOR 10 , wherein R 10 and R ' 2 are as defined hereinabove.
  • 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); lithium di-isopropylamide (LDA) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI or DEC).
  • THF tetrahydrofuran
  • EtOH ethanol
  • MeOH methanol
  • 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-methylgiucamine and the like. Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, 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.
  • 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.
  • the amount of base can range from catalytic to about 1.5 moles per mole of compound (11 , 11.3), (19, 19.3) or (20, 20.3).
  • the compounds of formula (1.0) wherein A is N-0 can be prepared by treating compound (1.0) wherein A is N with metachloroperbenzoic acid (MCPBA) in an aprotic solvent such as methylene chloride at temperatures ranging from about 0° to 25°C, using 1 to 2 equivalents of MCPBA per mole of compound (1.0).
  • MCPBA metachloroperbenzoic acid
  • 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-
  • Compounds of formula (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 centhfugation.
  • Compounds of formula 1.0, 1.0a and 1.0b in Scheme I, wherein X is CH or N may be racemates.
  • (+)-lsomers of compounds of formula (19, 19.3, 20, 20.3) wherein X is CH can be prepared with high enantioselectivity by using a process comprising enzyme catalyzed transesterification.
  • a racemic compound of formula (19, 19.3, 20, 20.3) 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.
  • 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 (19, 19.3, 20, 20.3) 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.
  • the enzyme Toyobo LIP-300
  • Example 1 1-(3-Bromo-6,11-dihydro-8,10-dimethoxy-5H- benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -yl)-4-(4-pyridinylacetyl)piperazine N4-oxide
  • Phosphorous oxychloride (12 ml) is added dropwise to a solution of B (2.3g) in toluene (20ml). The mixture is heated in an oil bath (115°C). After one hour a droplet of DMF is added, the solution is heated for an additional 4 hrs and is then cooled to room temp before evaporation under reduced pressure. The residual oil is dissolved in ethylacetate (50 ml) and ice/water (20ml) and stirred while adding 10% sodium hydroxide until the aqueous phase is basic. The basic solution is extracted with ethylacetate, the organic extracts are combined, washed with brine, dried and evaporated.
  • Product D of Step 3 is dissolved in 2N hydrochloric acid.
  • the solution is heated in an oil bath (120°C) for 1.5hrs, cooled, made basic with 10% sodium hydroxide and extracted with dichloromethane (4 x 50 ml portions).
  • the crude product is obtained by concentration of the combined extract filtered through a silica gel plug; evaporation of the filtrate affords the title ketone E as an amorphous solid (0.81 g, 91%).
  • MS m/e 348, 350 (MH) + is dissolved in 2N hydrochloric acid.
  • Phosphorous oxychloride (2.0ml) is added dropwise to a solution of product F (0.45 g) in dichloromethane (5 ml) under nitrogen.
  • the reaction mixture is stirred at room temperature for one hour and is then evaporated under reduced pressure at 45°C.
  • the dark residual gum is azeotroped with toluene (2 x10 ml) and is then dissolved in acetonitrile (15 ml) containing piperazine (0.5 g).
  • the reaction mixture is stirred at room temperature for 2 hrs and is worked up by evaporating under reduced pressure and diluting with water followed by addition of 10% sodium hydroxide(5 ml).
  • reagent A (5-methyl-t-butyl amide) is first treated with di-isopropylamine and butyl lithium, then reacted with benzylbromide 2 to give compound B.
  • Example 1 Using similar reaction conditions as described in Step 2, Example 1 , the crude product B is reacted with phosphorous oxychloride to afford compound C: m.p. 188-190 °C, MS: m/e 301 (MH).
  • Nitrile compound C (1.65g) is added with stirring to cold (0°C) triflic acid (30 ml). The solution is stored overnight at room temperature, diluted with ice/water (50 ml) and heated in an oil bath (120 °C) for 4 hrs. The reaction mixture is then cooled, neutrallized with 50% sodium hydroxide and the crude product is extracted with dichloromethane (6 x 50 ml) and flash chromatographed on silica gel (300 ml). Elution with 1 :1 ethylacetate-hexane followed by crystallization from ethylacetate-hexane affords compound D (1.54g): MS m/e 302 (MH).
  • a paste obtained by combining compound H (0.58g) with polyphosphoric acid (PPA) (1.5ml) is heated in an oil bath at 100 °C for 30 min.
  • the dark brown liquid is cooled and stirred with ice-water (10 ml), the resulting solution is made basic with 50% sodium hydroxide and then extracted with dichloromethane (5 x 30 ml).
  • the extract is filtered through a plug of silica gel which is then eluted with 10% methanol-dichloromethane.
  • the combined filtrates are evaporated and chromatographed on silica gel (50ml). Elution with 5%methanol-dichloromethane affords compound I as a tan solid.
  • Diisobutylaluminum hydride (DIBAL H) (1 M solution in toluene, 4.8ml) is added dropwise with stirring to a solution of compound J (0.45 g) in dry toluene (10 ml) at 15°C.
  • DIBAL H Diisobutylaluminum hydride
  • the reaction mixture is stirred at room temperature for 2 hrs and is then quenched by addition of water (10 ml) and 10% sodium hydroxide.
  • the mixture is extracted with dichloromethane and the crude product is chromatographed on silica gel (30ml). Elution with 10% methanol-2% ammonium hydroxide-dichloromethane affords compound J: MS m/e 337 (MH).
  • Triflic acid 55 ml is added with stirring to compound D (2.9 g) and the dark syrupy solution is stored overnight at 4°C.
  • the reaction mixture is worked up by pouring on ice, making basic with 50% NaOH, followed by extraction with dichloromethane (3 x 50ml). The extract is evaporated under reduced pressure and the crude product is flash chromatographed on silica gel. Elution with 5% methanol-dichloromethane affords compound E (1.37g); MS m/e 413 (MH).
  • Step 1-6 gives compound A, below.
  • Example 10 The racemic title compound of Example 10 (67 mg) is dissolved into 50/50 i-propanol/hexane containing 0.2% diethylamine and the solution is injected into a preparative high performance liquid chromatography column, chiralpak AD 5 by 50cm column (Daicel Chemical Ind.).
  • Step 1
  • Product B from Step 1 is converted to intermediate C by following the procedures described in Steps 3 and 4, Example 27. Tan powder, MS(CI)381.
  • Product C from Step 2 is converted to the title compound D by following the procedure described in Example 1 , Step 7.
  • Example 27 4-(3-Ethenyl-6,11 -dihydro-10-methoxy-8-methyl-5H- benzo[5,6]cyclohepta[1 ,2-b]pyridin-1 1 -yl)-1 -(4-pyridinylacetyl)piperidine N1 -Oxide
  • Step 1 1 ,1-Dimethylethyl-4-(3-bromo-5,6-dihydro-10-methoxy-8-methyl-11 H- benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -ylidene)-1 -piperidinecarboxylate
  • Step 2. 1 ,1-Dimethylethyl-4-(3-ethenyl-5,6-dihydro-10-methoxy-8-methyl-11 H- benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -ylidene)-1 -piperidinecarboxylate.
  • Step 5 4-(3-Ethenyl-6,11 -dihydro-10-methoxy-8-methyl-5H- benzo[5,6]cyclohepta[1 ,2-b]pyridin-1 1 -yl)-1 -(4-pyridinylacetyl)piperidine N1 -Oxide.
  • Example 28 4-(3-Ethenyl-6,11 -dihydro-10-methoxy-8-methyl-5H- benzo[5,6]cyclohepta[1 ,2-b]pyridin-1 1 -yl)-1 -(methylsulfonyl)piperidine
  • Methanesulfonyl chloride (0.5 ml, 6.46 mmol) is added to a solution of the title compound of Example 27, Step 4 (30 mg, 0.086 mmol) in anhydrous pyridine (2 ml) at 0°C, then 4-dimethylaminopyridine (10 mg, 0.08 mmol) is added, and the solution stirred overnight at 20°C. The solvent is evaporated, water (30 ml) and CH2CI2 (60 ml) are added.
  • Step 2 4-(3-Ethyl-6,11-dihydro-10-methoxy-8-methyl-5H- benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -yl)-1 -(4-pyridinylacetyl)piperidine, N1 -Oxide
  • EDCI 75 mg, 0.39 mmol
  • HOBT 70mg, 0.51 mmol
  • NMM 0.5 ml, 4.5 mmol
  • Step 1
  • Product B from Step 1 is converted to intermediate C by following the procedures described in Steps 3 and 4, Example 27. Tan powder, MS(CI) 362
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 7 and R 8 , the solid and dotted lines are as defined hereinbefore.
  • compound 5 and 5.3 is prepared by alkylating compound 1 and 1.3 with an electrophile compound 3 and 3.3 employing a base such as lithium di-isopropylamide (LDA) in an aprotic solvent such as THF, toluene, benzene, ether and the like, at temperatures ranging from about -78° to 20°C, using about 1 to 1.5 moles of electrophile compound 3 per mole of compound 1 and 1.3.
  • a base such as lithium di-isopropylamide (LDA)
  • an aprotic solvent such as THF, toluene, benzene, ether and the like
  • Step B compound 7 and 7.3 is prepared by treating compound 5 and 5.3 with a dehydrating agent such as phosphorus oxychloride (POCI3) or thionyl chloride in an aprotic solvent, at temperatures ranging from about 80° to 120°C, using about 3 to 10 moles of dehydrating agent per mole of compound 5 and 5.3.
  • a dehydrating agent such as phosphorus oxychloride (POCI3) or thionyl chloride in an aprotic solvent
  • Step C compound 7.5 and 7.53 is prepared by treating compound 7 and 7.3 with a Lewis acid such as triflic acid (CF3SO3H) or aluminum chloride (AICI3).
  • a Lewis acid such as triflic acid (CF3SO3H) or aluminum chloride (AICI3).
  • the reaction can be practised neat (i.e. no additional solvents).
  • a solvent such as dichloroethane can be employed.
  • the reaction can be conducted at temperatures ranging from about 20° to about 175°C, using about 3 to 10 moles of the Lewis acid per mole of compound 7 and 7.3.
  • Step D compound 8 and 8.3 is prepared by treating compound 7.5 and 7.53 with a dilute acid such as aqueous hydrochloric or aqueous sulfuric acid, at temperatures ranging from about 20°C to reflux of the reaction mixture, using about 20 to 100 volumes of the aqueous acid per mole of compound 7.5 and 7.53.
  • a dilute acid such as aqueous hydrochloric or aqueous sulfuric acid
  • Step E compound 13a and 13.3a is prepared by treating compound 8 and 8.3 with a Grignard reagent 12 derived from N-methyl-4-chloropiperidine in an aprotic solvent, at temperatures ranging from about 0° to 50°C, using about 1 to 1.5 moles of Grignard reagent 12 per mole of compound 8 and 8.3.
  • Step F compound 13b and 13.3b is prepared by treating compound
  • Step G compound 13c is prepared by subjecting compound 13b to catalytic hydrogenation at pressures ranging from atmospheric (ambient) to 50 pounds per square inch (psi) using hydrogen (H 2 ) and 10% palladium (Pd)/Carbon (C) as a catalyst.
  • compound 13c can be prepared by treating compound 13b with a hydrogen source such as ammonium formate, using 10% Pd/C as a catalyst at atmospheric pressure, at temperatures ranging from 50° to 70°C, optionally using a protic solvent such as methanol or ethanol.
  • compound 15 and 15.3 is prepared by treating compound 13c and 13.3c with an acid such as polyphosphoric acid (PPA).
  • PPA polyphosphoric acid
  • the reaction can be practised neat. The reaction can be conducted at temperatures ranging from about 60° to 100°C, using about 5 to 10 volumes of polyphosphoric acid per mole of compound 13c and 13.3c.
  • 13.3d can be prepared by treating compound 13c and 13.3b with aqueous hydrochloric acid (Hcl) or aqueous sulfuric acid (H 2 S04) such as 2 N to concentrated hydrochloric acid at temperatures ranging from about 80° to
  • Step I compound 19 and 19.3 is prepared by treating compound 15 and 15.3 with an aqueous acid such as 3 N to concentrated hydrochloric acid (HCI), at temperatures ranging from about 80° to 100°C, using 5 to 10 volumes of the aqueous acid per mole of compound 15 and 15.3.
  • an aqueous acid such as 3 N to concentrated hydrochloric acid (HCI)
  • HCI concentrated hydrochloric acid
  • Step J compound 20 and 20.3 is prepared by treating compound 19 and 19.3 with a reducing agent such as diisobutyl aluminum hydride (DBAHAI) in an aprotic solvent, at temperatures ranging from about 0° to 20°C, using 1 to
  • a reducing agent such as diisobutyl aluminum hydride (DBAHAI) in an aprotic solvent
  • alcohol compound 9 and 9.3 is prepared by reducing compound 8 and 8.3 with a reducing agent such as as sodium borohydride
  • NaBH4 NaBH4 in a protic solvent such as methanol, ethanol and acetic acid, at temperatures ranging from 0° to 20°C, using one to three moles of the reducing agent per mole of compound 8 and 8.3.
  • Step FF compound 10 and 10.3 is prepared by treating alcohol compound 9 and 9.3 with a chlorinating agent such as thionyl chloride or phosphorous oxychloride (POCI3) in an aprotic solvent such as 1 ,2- dichoroethane or methylene chloride, at temperatures ranging from 0° to 25°C, using one to two moles of the chlorinating agent per mole of compound 9 and
  • a chlorinating agent such as thionyl chloride or phosphorous oxychloride (POCI3)
  • POCI3 phosphorous oxychloride
  • Step GG compound 11 and 11.3 is prepared by reacting compound 10 and 10.3 with a piperazine compound 12 and 12.3 in a solvent such as acetonitrile, toluene or methylene chloride at temperatures ranging from 0° to
  • Step K the desired compound of formula 1.0 can prepared from compounds (11 , 11.3), (13d, 13.3d), (19, 19.3) or (20, 20.3) as described in Scheme I described hereinbefore.
  • Scheme IV the desired compound of formula 1.0 can prepared from compounds (11 , 11.3), (13d, 13.3d), (19, 19.3) or (20, 20.3) as described in Scheme I described hereinbefore.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 7 and R 8 , the solid and dotted lines are as defined hereinbefore.
  • Step L compound 25 is prepared by reacting compound 7.3 with a Grignard reagent 12 derived from N-methyl-4-chloropiperidine in an aprotic solvent, at temperatures ranging from about 0° to 50°C, using about 1 to 1.5 moles of Grignard reagent 12 per mole of compound 7.3.
  • Step M compound 26 is prepared by treating compound 25 with a dilute acid such as aqueous hydrochloric or aqueous sulfuric acid, at temperatures ranging from about 20°C to reflux of the reaction mixture, using about 20 to 100 volumes of the aqueous acid per mole of compound 25.
  • a dilute acid such as aqueous hydrochloric or aqueous sulfuric acid
  • Step N compound 27 is prepared by treating compound 25 with a Lewis acid such as triflic acid or aluminum chloride (AICI3).
  • AICI3 triflic acid or aluminum chloride
  • the reaction can be practised neat (i.e. no additional solvents).
  • triflic acid the reaction can be conducted at temperatures ranging from 0° to 70°C, using 5 to 100 moles of triflic acid per mole of compound 25.
  • a solvent such as dichloroethane can be employed.
  • the reaction can be conducted at temperatures ranging from about 20° to about 175°C, using about 3 to 10 moles of the Lewis acid per mole of compound 25.
  • Step O compound 28 is prepared by treating compound 27 with ethylchloroformate in an aprotic solvent, at temperatures ranging from about 60° to 90°C, using 5 to 10 moles of ethylchloroformate per mole of compound 27.
  • Step P compound 29 is prepared by treating compound 28 with an aqueous acid such as 3 N to concentrated hydrochloric acid (HCI), at temperatures ranging from about 80° to 100°C, using 5 to 10 volumes of the aqueous acid per mole of compound 28.
  • HCI concentrated hydrochloric acid
  • Step Q compound 30 is prepared by treating compound 29 with a reducing agent such as diisobutyl aluminum hydride (DIBALH) in an aprotic solvent, at temperatures ranging from about 0° to 20°C, using 1 to 4 moles of reducing agent per moles of compound 29.
  • DIBALH diisobutyl aluminum hydride
  • Step K compound 30 is converted to desired compound (1.0) as described in Scheme I, described hereinbefore.
  • 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 glycehdes 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. In such 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.

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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Abstract

La présente invention concerne des composés tricycliques à substitution phényle de formule (1.0) et des compositions pharmaceutiques, lesquels sont inhibiteurs de l'enzyme farnésyle protéine transférase. La présente invention concerne également un procédé d'inhibition de la fonction Ras et donc d'inhibition de la croissance anormale des cellules. Le procédé consiste à administrer le nouveau composé d'urée à substitution halo-N à un système biologique. Ce procédé inhibe, en particulier, la croissance anormale des cellules chez des mammifères tel que l'homme.
PCT/US1998/011509 1997-06-17 1998-06-15 Nouveaux composes tricycliques de phenyle substitues inhibiteurs de farnesyl proteine transferase Ceased WO1998057950A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
NZ501613A NZ501613A (en) 1997-06-17 1998-06-15 Benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl) piperazine derivatives useful as inhibitors of farnesyl-protein transferase
AU82537/98A AU8253798A (en) 1997-06-17 1998-06-15 Novel phenyl-substituted tricyclic inhibitors of farnesyl-protein transferase
CA002293549A CA2293549C (fr) 1997-06-17 1998-06-15 Composes tricycliques substitues de phenyle servant a inhiber la farnesyl-proteine transferase
JP50450399A JP2002504150A (ja) 1997-06-17 1998-06-15 ファルネシルタンパク質トランスフェラーゼの新規フェニル置換三環式インヒビター
HU0003215A HUP0003215A2 (hu) 1997-06-17 1998-06-15 Farnezil-protein-transzferáz új fenil-szubsztituált triciklusos inhibitorai
EP98932719A EP0989981A1 (fr) 1997-06-17 1998-06-15 Nouveaux composes tricycliques de phenyle substitues inhibiteurs de farnesyl proteine transferase
IL13344698A IL133446A0 (en) 1997-06-17 1998-06-15 Novel phenyl-substituted tricyclic inhibitors of farnesyl-protein transferase

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US87705297A 1997-06-17 1997-06-17
US08/877,052 1997-06-17

Publications (1)

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WO1998057950A1 true WO1998057950A1 (fr) 1998-12-23

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EP (1) EP0989981A1 (fr)
JP (1) JP2002504150A (fr)
KR (1) KR20010013945A (fr)
CN (1) CN1267292A (fr)
AU (1) AU8253798A (fr)
CA (1) CA2293549C (fr)
HU (1) HUP0003215A2 (fr)
IL (1) IL133446A0 (fr)
NZ (1) NZ501613A (fr)
WO (1) WO1998057950A1 (fr)

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JP3258342B2 (ja) 1997-06-17 2002-02-18 シェーリング コーポレイション ファルネシルタンパク質トランスフェラーゼインヒビターとして有用なベンゾ（５，６）シクロヘプタピリジン化合物

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WO1995010515A1 (fr) * 1993-10-15 1995-04-20 Schering Corporation Composes carbamates tricycliques servant a inhiber la fonction de la proteine g et au traitement de maladies proliferatives
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WO1996030362A1 (fr) * 1995-03-24 1996-10-03 Schering Corporation Composes d'amide tricyclique et d'uree pour l'inhibition de la fonction proteine g et pour le traitement des maladies proliferatives
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WO1995010515A1 (fr) * 1993-10-15 1995-04-20 Schering Corporation Composes carbamates tricycliques servant a inhiber la fonction de la proteine g et au traitement de maladies proliferatives
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3258342B2 (ja) 1997-06-17 2002-02-18 シェーリング コーポレイション ファルネシルタンパク質トランスフェラーゼインヒビターとして有用なベンゾ（５，６）シクロヘプタピリジン化合物

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HUP0003215A2 (hu) 2001-06-28
KR20010013945A (ko) 2001-02-26
EP0989981A1 (fr) 2000-04-05
CA2293549A1 (fr) 1998-12-23
IL133446A0 (en) 2001-04-30
AU8253798A (en) 1999-01-04
NZ501613A (en) 2001-11-30
CN1267292A (zh) 2000-09-20
CA2293549C (fr) 2008-08-05
JP2002504150A (ja) 2002-02-05

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