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WO1996031505A1 - Composes tricycliques utiles pour l'inhibition de la fonction de la proteine-g et le traitement des maladies proliferatives - Google Patents

Composes tricycliques utiles pour l'inhibition de la fonction de la proteine-g et le traitement des maladies proliferatives Download PDF

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Publication number
WO1996031505A1
WO1996031505A1 PCT/US1996/004170 US9604170W WO9631505A1 WO 1996031505 A1 WO1996031505 A1 WO 1996031505A1 US 9604170 W US9604170 W US 9604170W WO 9631505 A1 WO9631505 A1 WO 9631505A1
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Prior art keywords
compound
alkyl
substituted
formula
group
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PCT/US1996/004170
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English (en)
Inventor
John J. Baldwin
Ge Li
John C. Reader
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Pharmacopeia, Inc.
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Application filed by Pharmacopeia, Inc. filed Critical Pharmacopeia, Inc.
Priority to AU54327/96A priority Critical patent/AU5432796A/en
Publication of WO1996031505A1 publication Critical patent/WO1996031505A1/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
    • C07D401/14—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

  • Y is hydrogen, substituted carboxylate or substituted sulfonyl.
  • potentiating agents include 1 1-(4-piperidylidene)-5H- benzo[5,6]cyclohepta[1 ,2-b]pyridines such as Loratadine.
  • Ras oncoprotein To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation 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 compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention. SUMMARY OF THE INVENTION Inhibition of farnesyl protein transferase by tricyclic compounds of this invention has not been reported previously.
  • 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 geranylgeranyl 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 geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl 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.
  • the compounds useful in the claimed methods are novel compounds represented by Formula (1.0)
  • a and B are independently selected from H, halo or C- ⁇ -C- 6 alkyl; Z is N or CH;
  • W is CH, CH2, O or S, wherein the dotted line to W represents a double bond which is present when W is CH;
  • R 1 is selected from the group consisting of:
  • R 1 is a group D, wherein D is -C(0)-(CH 2 ) s -R 5 . -C(0)0-(CH 2 ) m -R 5 or -C(0)NH-(CH2)m-R 5 .
  • R 5 is aryl, (such as phenyl, B-substituted phenyl wherein B is as defined below), heterparyl, (such as pyridyl or pyridyl N-oxide), heterocycloalkyl, or a group of the formula
  • R 11 represents H, C-i-C ⁇ alkyl, haloalkyi or -C(O)- R 9 wherein R 9 is C C 6 alkyl, C C ⁇ alkoxy or -NH(R 10A ) wherein R 1 °A j S H or alkyl, or the group -C(0)-R 9 represents an acyl radical of a naturally occurring amino acid; or
  • R 1 is a group of the formula:
  • each R a and each R b is independently selected from H, aryl, alkyl, alkoxy, aralkyi, amino, alkylamino, heterocyloalkyl, -COOR 60 ,
  • R 92 can represent H, alkyl, aryl, aryloxy, arylthio, aralkoxy, aralkyi, heteroaryl or heterocycloalkyi;
  • R 60 represents H, alkyl, aryl or aralkyi
  • R is H or C ⁇ -C6 alkyl
  • R2 is selected from: -C(0)OR 6 , -C(0)NR 6 R 7 , C ⁇ -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C ⁇ alkynyl, substituted (C ⁇ -C ⁇ )alkyl, substituted (C 2 -C8)alkenyl, substituted (C 2 -C ⁇ )alkynyl, wherein said substituted groups have one or more substituents selected from:
  • B is selected from C1-C4 alkyl, phenyl, -(CH 2 ) n OR 6 -(CH 2 ) n NR 6 R 7 and halo;
  • R 1 is D, R 2 is not H; where R 1 is D and R 2 is C-
  • R 6 , R 7 and R 12 are independently selected from H, C1-C4 alkyl, (C3-C6)cycloalkyl, aryl, arylalkyl (i.e., aralkyi), heteroaryl, heteroarylalkyl, heterocycloalkyi, substituted (C ⁇ -C4)alkyl, substituted (C3-C6)cycloalkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalky or substituted heterocycloalkyi, wherein said substituted groups have one or more substituents (e.g., 1-3) selected from: C1-C4 alkoxy, aralkyi, heteroarylalkyl, -N0 2 , (C3-C- ⁇ o)alkoxyalkoxy (e.g., -0-(C-
  • R 8 , R 10 and R 15 are independently H, C1-C4 alkyl or arylalkyl;
  • R 14 is C1-C4 alkyl, aryl or arylalkyl;
  • m 0, 1, 2 or 3;
  • n 0, 1 , 2, 3 or 4;
  • s 1, 2 or 3;
  • t 0, 1 or 2; or pharmaceutically acceptable salts thereof.
  • This invention also provides a method for inhibiting tumor growth by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment.
  • 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 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
  • myeloid leukemias for
  • 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 fornv- with said inhibition being accomplished by the administration of an effective amount of the tricyclic compounds 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 tricyclic compounds described herein.
  • the compounds of this invention inhibit farnesyl protein transferase and the famesylation of the oncogene protein Ras.
  • This invention further provides a method of inhibiting ras farnesyl protein transferase, in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above.
  • 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.
  • the tricyclic compounds useful in the methods of this invention inhibit the abnormal growth of cells. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protei ⁇ 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. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cells.
  • 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
  • Tr represents trityl, (i.e., triphenylmethyl);
  • Me represents methyl;
  • alkyl represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms; said alkyl group optionally being substitued with one, two or three groups independently selected from hydroxy, alkoxy, halo (e.g., -CF 3 ), amino, alkylamino, dialkylamino, N-acylalkylamino, N-alkyl-N-acylamino, or -S(0)t- alkyl (wherein t is 0, 1 or 2), and wherein the alkyl portion of said optional groups are as defined above;
  • alkenyl represents straight and branched carbon chains having at least one carbon to carbon double bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms and most preferably from 3 to 6 carbon atoms;
  • alkynyl represents straight and branched carbon chains having at least one carbon to carbon triple bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms;
  • aralkyi represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl moiety have been replaced by one or more aryl groups, as defined below (e.g., benzyl and diphenylmethyl);
  • aryl (including the aryl portion of aryloxy and aralkyi) represents a monocyclic, bicyclic or tricyclic carbocyclic group containing from 6 to 15 carbon atoms and comprising at least one aromatic ring, such as phenyl, naphthyl, phenanthryl, tetrahydronaphthyl or indanyl, with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted with one or more, preferably 1
  • aralkoxy represents an aralkyi group, as defined above, in which the alkyl moiety is covalently bonded to an adjacent structural element through an oxygen atom, for example, benzyloxy;
  • aryloxy represents an aryl group, as defined above, covalently bonded to an adjacent structural element through an oxygen atom, for example, phenoxy;
  • arylthio represents an aryl group, as defined above, covalently bonded to an adjacent structural element through a sulfur atom, for example, phenylthio;
  • cycloalkyl represents a saturated or unsaturated nonaromatic carbocyclic ring of from 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms; "halo" represents fluoro, chloro, bromo and iodo;
  • heterocycloalkyi represents a saturated or unsaturated nonaromatic carbocyclic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, and from 1 to 3 heteroatoms selected from O, S, -SO2- or NR 10 (suitable heterocycloalkyi groups include tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, piperazinyl, dioxanyl, morpholino, diaza-2,2,2- bicyclooctane etc.), wherein any of the available substitutable carbon and nitrogen atoms in the ring are optionally substituted with one, two, three or more groups independently selected from C-i-C ⁇ alkyl, aryl, aralkyi, haloalkyi, amino, alkylamino, dialkylamino, -S(0)t-aryl (where
  • cyclic group being optionally substituted with 1 , 2, 3 or more groups independently selected from halo, alkyl, aryl, aralkyi, heteroaryl, hydroxy, alkoxy, phenoxy, -N0 2> -CF 3 , amino, alkylamino, dialkylamino, and -COOR 60 wherein R 60 is as defined above (e.g., benzyl).
  • tertiary amine base means DMAP, pyridine or a trialkylamine, such as Et 3 N or H ⁇ nigs base;
  • hydroxide base means NH 4 OH or an alkali metal or alkaline earth metal hydroxide, such as LiOH, NaOH, KOH, Mg(OH) 2 or Ca(OH) 2 ;
  • borane reducing agent means a stable complex of borane and a suitable reagent, such as BH 3 » THF, BH 3 » S(CH 3 ) 2 or TBAB; and
  • hydride reducing agent means a metal hydride reagent, such as NaBH , Red-AI, DIBAL-H, L-Selectride, Vitride, LiBH 4 , LiAIH 4 , LiAI(0tBu)3H, NaCNBH 3 , DMAB, zinc borohydride, calcium borohydride, a combination of UBH4 and ZnBr 2 , or a combination of NaBH.4 and LiCI.
  • metal hydride reagent such as NaBH , Red-AI, DIBAL-H, L-Selectride, Vitride, LiBH 4 , LiAIH 4 , LiAI(0tBu)3H, NaCNBH 3 , DMAB, zinc borohydride, calcium borohydride, a combination of UBH4 and ZnBr 2 , or a combination of NaBH.4 and LiCI.
  • acyl radical of a naturally occurring amino acid means a group of the formula -C(0)-R 29 , wherein R 29 is a group of the formula
  • R 30 and R 31 are the residual portions of said amino acid.
  • R 30 and R 31 can be independently selected from H, alkyl or M-substituted alkyl, wherein M is HO-, HS-, CH 3 S-, -NH 2 , phenyl, p-hydroxyphenyl, imidazolyl or indolyl, such that HO-C(0)-R 29 is an amino acid selected from alanine, glycine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, serine, threonine, histidine, cysteine or tyrosine.
  • Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring atoms.
  • Certain compounds of the invention may exist in different isomeric forms (e.g., enantiomers, diastereoisomers and geometric isomers).
  • C11 carbon of the tricyclic ring system i.e., the point of attachment to the piperazine ring
  • the carbon atom of the piperazinyl group to which R 2 is attached can each independently have the S or R absolute configuration.
  • substituent groups e.g. R 1 , R 2
  • R 1 , R 2 can also comprise chiral centers.
  • the invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures.
  • Enol forms are also included, as are the E or Z geometric isomers of compounds which have double bonded substituents, (e.g. where R 2 is an alkenyl group) .
  • 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 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.
  • Certain compounds of the formula (1.0) comprise sulfhydryl groups, (i.e., -CH 2 SH), which sulfhydryl groups are capable of reacting to form disulfide bonds resulting in dimeric compounds.
  • sulfhydryl groups i.e., -CH 2 SH
  • An example of such dimers are disulfides of the formula (la).
  • Said sulfhydryl groups can also form disulfides with another thiol, such as glutathione.
  • Disulfides including but not limited to disulfides of formula (la) are within the scope of the invention and are encompassed by the structure of formula (1.0).
  • the amine (2.0) is reacted with a carboxylic acid of the formula R 5 -CH 2 -C(0)-OH in the presence of a coupling agent such as DEC.CDI or DCC.
  • a coupling agent such as DEC.CDI or DCC.
  • the reaction is typically carried out in a suitable organic solvent such as DMF, THF or CH 2 CI 2 at a temperature of -10° to 100°C, preferably at 0° to 50°C, and most preferably at about room temperature.
  • the coupling agent is DCC or DEC
  • the reaction is preferably conducted in the presence of HOBT.
  • the amine (2.0) can be reacted with a compound of the formula R 1 -L, wherein R 1 is as defined above and L is a leaving group, such as CI, Br, I , -0-C(0)-R 40 wherein R 40 is C C ⁇ alkyl or phenyl, or a sulfonyl group of the formula -OS0 2 -R 2 °, [wherein R 20 is selected from C- ⁇ -C- 6 alkyl, phenyl, CF 3 , tolyl and p-bromophenyl], to form a compound of the formula (1.0).
  • the reaction is carried out in the presence of a base, preferably a tertiary amine base, such as Et 3 N, DMAP, pyridine or H ⁇ nigs base.
  • R 1 and the nitrogen atom to which it is attached together comprise an amine, e.g. where R 1 is a group of the formula
  • the amine (2.0) is reacted with an aldehyde of the formula R 21 -CHO, wherein R 21 is selected such that R 1 corresponds to R 21 -CH 2 -, e.g. an aldehyde of the formula
  • the imine (3.0) is reduced under suitable reaction conditions to form a compound of the formula (1.0).
  • a hydride reducing agent such as NaCNBH 3 .
  • R 1 comprises a chemically reactive group, such as amine thiol group
  • such groups must generally be protected with a suitable protecting group, which can later be removed to complete the synthesis of a compound of formula (1.0).
  • amines can preferably be protected with the BOC protecting group
  • thiols can be protected with the trityl (i.e., triphenyimethyl) protecting group.
  • Deprotection, i.e., the removal of these protecting groups is then generally the final step in the synthesis of such compounds of formula (1.0).
  • an amine (2.0) is reacted with phosgene to form a chloroformate intermediate of the formula (4.0), as shown in Reaction Scheme 3.
  • the chloroformate (4.0) is generally not isolated and is reacted with an amine of the formula R 5 -NH 2 , wherein R 5 is as defined above, to form a compound of the formula (1.0), wherein R 1 is -C(0)-NH-R 5 .
  • compounds of formula (1.0) wherein R 2 is -C(0)NR 6 R 7 can be prepared by reacting a compound of the formula (1.0) wherein R 2 is -C0 2 H with an amine R 6 R 7 NH in the presence of a coupling agent, such as DCC or DEC.
  • a coupling agent such as DCC or DEC.
  • compounds of formula (1.0) wherein R 2 is alkyl substituted by a group of the formula -C(0)OR 6 or -C(0)NR 6 R 7 can be prepared from a compound wherein R 2 is alkyl substituted by -C0 2 H via substantially the same procedures as described above.
  • the transformation is typically carried out immediately prior to deprotection of the amine and thiol groups of such R 1 groups.
  • Amines of the formula (2.0) can be prepared in optically active using appropriate chiral starting materials or alternatively can be prepared using racemic starting compounds to give a mixture of stereoisomeric compounds which can then be separated by resolution or chiral HPLC to give the desired isomer.
  • the amines (2.0) can exist as a mixture of enantiomeric amines, e.g. (2.10) and (2.11), or (2.12) and (2.13), which can be separated by classical resolution techniques using a suitable resolving agent, such as a chiral acid.
  • Chiral acid resolving agents are well known in the art and include such compounds as D- or L- malic acid, D- or L-tartaric acid, di-p-toluoyl-D-tartaric acid, di-p-toluoyl-L- tartaric acid, di-benzoyl-D-tartaric acid and di-benzoyl-L-tartaric acid.
  • the enantiomeric amines (2.11) and (2.10), or (2.12) and (2.13) could be separated using a chiral HPLC column via standard methods.
  • Amines of the formula (2.0) can be prepared from a piperazine derivative of the formula (5.0), wherein R 2 is as defined above, and a compound of the formula (6.0), wherein L is a leaving group as defined above and A, B, W and Z are as defined above, via the process shown in Reaction Scheme 4.
  • the piperazine (5.0) is reacted with compound (6.0) in the presence of a base, such as a tertiary amine base, to form a compound of the formula (7.0).
  • a base such as a tertiary amine base
  • Compound (7.0) is then hydrolyzed using a suitable acid, such as HCI or TFA, in a solvent such as dioxane or CH 2 CI 2 , to form the amine (2.0).
  • the ketone (14.0) is reduced using a hydride reducing agent, preferably UAIH 4 , NaBH 4 , UBH 4 or NaCNBH 3 , in a suitable solvent, such as THF, Et 2 0, or a C 1 -C 4 alcohol, at a temperature of -80° to 80°C, preferably at -40° to 60°C, with the temperature and solvent used being selected in accordance with the particular reducing agent employed, to form the alcohol (22.0).
  • a hydride reducing agent preferably UAIH 4 , NaBH 4 , UBH 4 or NaCNBH 3
  • a suitable solvent such as THF, Et 2 0, or a C 1 -C 4 alcohol
  • boron hydrides such as NaBH 4 and NaCNBH 3
  • alcohol solvents at a temperature of 0° to 50°C
  • more reactive aluminum hydrides such as L1AIH 4
  • solvents such as THF or Et 2 0 at a temperature of -40° to 60°C.
  • the alcohol (22.0) is converted to a compound of formula (6.0).
  • a halogenating agent such as PCI 3 , PCI 5 , POCI 3 , SOCI 2 , SOBr 2 , 1 2 , PBr 3 , PBrs, or a combination of Ph3P and either I 2 or Br 2 .
  • Ketones of the formula (14.0) are known or can be prepared by the procedures described in J. Med. Chem.. 4238 (1992), U.S. Patent 5,089,496, and in PCT International Publications WO92/20681 and WO93/02081.
  • a strong acid such as CF 3 SO 3 H
  • intramolecular Friedel-Crafts acylation of an acid chloride of formula (16.0) may also provide the desired ketone of formula (14.0).
  • the reaction may be carried out under usual Friedel-Crafts conditions in an inert solvent and in the presence of a Lewis acid such as aluminum chloride.
  • Ketones of the formula (14.1), i.e., a compound of the formula (14.0) wherein W is CH, can be prepared by heating a compound of the formula (14.3), i.e., a compound of formula (14.0) wherein W is CH 2 , with Se0 2 in acetic acid.
  • Acid chlorides of formula (16.0) can be obtained by hydrolysis of a compound of formula (11.0) to the corresponding carboxylic acid typically by heating with an aqueous acid (e.g., aqueous HCI), followed by conversion of the acid to the acid chloride of (16.0) under standard conditions well known to those skilled in the art (e.g., by treating with SOCI 2 or oxalyl chloride).
  • aqueous acid e.g., aqueous HCI
  • t-butylamide (18.0) is reacted with an alkyllithium reagent, such as n-butyllithium, at -100° to 0°C, preferably at -60° to -20°C, then treated with NaBr and a benzyl halide of formula (19.0), wherein X 1 is CI, Br or I, and B is as defined above, to form a compound of the formula (11.1).
  • an alkyllithium reagent such as n-butyllithium
  • Step A of Reaction Scheme 7 a compound of the formula (8.1 ), wherein R 22 is C C 6 alkyl, preferably ethyl, and Z, W, B and R 2 are as defined above, is reacted with a tetraalkylammonium nitrate, such as tetrabutylammonium nitrate, and TFAA in a suitable solvent, such as CH 2 CI 2 , at -30° to 20°C, preferably at about 0°C, to form a compound of the formula (20.0), wherein R 22 , B, W, Z and R 2 are as defined above.
  • a suitable solvent such as CH 2 CI 2
  • Step B compound (20.0) is heated with a suitable reducing agent, such as a combination of Fe and CaCI 2 , in a polar solvent, such as a C1-C4 alcohol, preferably EtOH, at a temperature of 40° to 100°, preferably at 50° to 80°C, to form a compound of formula (21.0), wherein R 22 , B, W, Z and R 2 are as defined above.
  • a suitable reducing agent such as a combination of Fe and CaCI 2
  • a polar solvent such as a C1-C4 alcohol, preferably EtOH
  • Step C compound (21.0) is converted to the halide (8.2), wherein X 2 is Br or I, and R 22 , B, W, Z and R 2 are as defined above.
  • compound (21.0) is treated with Br 2 and HBr at a temperature of -30° to 15°C, preferably at -10° to 10°C, to form the bromide, (i.e., a compound (8.2) wherein X 2 is Br).
  • compound (21.0) is treated with I 2 in a suitable solvent, such as benzene, at a temperature of 30° to 100°C, preferably at 50° to 70°C, to form the iodide, (i.e., a compound (8.2) wherein X 2 is I).
  • Step D the amine (8.2) is hydrolyzed via substantially the same process as described above for compounds (8.0) and (7.0), to give an amine of the formula (2.5).
  • the starting BOC-protected amino acids (32.0) are available commercially or can be made by procedures well known in the art.
  • the amino acids (32.0) can be coupled to N-benzylglycine ethyl ester using a coupling agent such as DCC or DEC in a suitable solvent (e.g., DMF, CHCI3 or CH 2 CI 2 ) to produce a compound of Formula (33.0).
  • a coupling agent such as DCC or DEC
  • a suitable solvent e.g., DMF, CHCI3 or CH 2 CI 2
  • the BOC protecting group of compound (33.0) is hydrolyzed via standard methods, such as treatment with an acid, preferably TFA or HCI, in a suitable solvent such as CHCI3 or dioxane at 0° to 50°C, preferably at about 25°C and the deprotected dipeptide is cyclized by treatment with base to produce the compound of formula (34.0).
  • Compound (34.0) is reduced using a hydride reducing agent, preferably UAIH4 in refluxing Et 2 0 or THF to give a piperazine of formula (35.0).
  • a hydride reducing agent preferably UAIH4 in refluxing Et 2 0 or THF.
  • the piperazine (35.0) is protected with a BOC group by procedures well known in the art to give the compound of Formula (36.0).
  • N-benzyl group of compound (36.0) is removed by catalytic hydrogenation (e.g., using Pd/C and hydrogen gas under pressure of 1 to 100 psi, preferably at about 60 psi, to give the compound of Formula (5.0).
  • Compounds of Formula 5.0, wherein R 2 represents alkyl, alkenyl or alkynyl substituted with substituent groups 1), 3), 5) or 4) (wherein t 0), as defined above, wherein R 6 or R 7 are substituted with -C(0)R 14 or -S(0) 2 R 14 are made according to the process shown in Reaction Scheme 13.
  • Compound (40.0) is then protected with a BOC group and then debenzylated according to the procedures described for steps 5 and 6 of Reaction Scheme 12 to produce a compound of Formula (5.10), i.e., a compound of formula (5.0) wherein R 2 is a hydroxy substituted alkyl, alkenyl or alkynyl group.
  • a compound of the formula (5.10) where R 28 is -CH 2 OH can be oxidized to produce the corresponding carboxyl group, i.e., where R 2 is -COOH. This carboxyl group can then be esterified to produce compounds wherein R 2 is -C(0)OR 6 , or converted to an amide to produce compounds wherein R 2 is -C(0)NR 6 R 7 by procedures well known in the art.
  • the hydroxy group of R 28 of a compound of formula (5.10) can be converted to a leaving group, such as chloro, mesyloxy or tosyloxy, by techniques well known in the art.
  • the leaving group can then be displaced by various nucleophiles, to produce other compounds of formula (5.0)
  • the hydroxy group on R 28 of compound (5.10) can also be: acyiated, e.g. with a suitable chloroformate compound, to produce a compound (5.0) wherein R 2 is substituted by 8) or 9), respectively; or alkylated to produce a compound (5.0) wherein R 2 with is substituted by 3).
  • R 28 is alkyl having more than one carbon atom, or alkenyl or alkynyl
  • the hydroxy group can be oxidized, as discussed above, to produce the corresponding carboxyl group (i.e., substituent 13) wherein R 6 is H.
  • This carboxyl group can be esterified to produce compounds wherein substituent 13) is -C(0)OR 6 wherein R 6 is other than H, or converted to amides to produce R 2 with a 12) substituent, by procedures well known in the art.
  • substituent 13) is -C(0)OR 6 wherein R 6 is other than H, or converted to amides to produce R 2 with a 12) substituent, by procedures well known in the art.
  • the leaving group is displaced by an amine (e.g., HNR 6 R 7 ) to produce a substituent 5) as described above, for those substituents wherein at least one of R 6 or R 7 is H, the resulting amine substituent 5) can subsequently be converted to R 2 substituted by 6), 7) or 11) by reacting, with an acyl halide, a carbamyl halide or a sulfonyl halide, respectively, by procedures well known in the art.
  • 2-piperazine carboxylic acid is treated with BOC-ON in the presence of a hydroxide base, preferably NaOH or KOH, in a suitable solvent, such as a mixture of dioxane and water, then with FMOC-CI under substantially the same conditions to form the differentially protected compound (23.0).
  • a hydroxide base preferably NaOH or KOH
  • a suitable solvent such as a mixture of dioxane and water
  • Compound (23.0) is reacted with an amine of the formula R 6 R 7 NH, wherein R 6 and R 7 are as defined above, in the presence of HATU in CH 2 CI 2 .
  • Compound (24.0) is selectively deprotected by treating with piperidine in a suitable solvent, such as DMF, to form a compound of the formula (5.1).
  • compounds of formula (5.0) wherein R 2 is -C(0)OR 6 can be prepared from compound (23.0) by esterification with an appropriate alcohol R 6 OH using standard methods, followed by deprotection as described for compound (24.0).
  • N.N'-dibenzylethylene- diamine is reacted with methyl 4-bromocrotonate and a tertiary amine base, such as Et3N, in a suitable solvent, such as toluene, to form the N.N'-dibenzylpiperazine derivative (25.0).
  • Compound (25.0) is hydrogenated over a catalyst, such as Pd/C, to form piperazine derivative (26.0).
  • a catalyst such as Pd/C
  • the 4-amino group of compound (26.0) is then protected as the BOC derivative using BOC-ON to form compound (27.0).
  • Compound (27.0) is hydrolyzed using a hydroxide base, such as NaOH or KOH, and the free amino group is protected with a suitable amine protecting group, such as an FMOC group to form compound (28.0).
  • a hydroxide base such as NaOH or KOH
  • a suitable amine protecting group such as an FMOC group
  • Compound (28.0) is reacted with an amine of the formula R 6 R 7 NH using a coupling agent, such as DEC, in a suitable solvent, such as CH 2 CI 2 of DMF, then deprotected using TBAF in DMF to form a compound of the formula (5.2), wherein E is -NR 6 R 7 .
  • compound (28.0) is esterified by reacting with SOCI 2 or oxalyl chloride in the presence of a tertiary amine base to form an acid chloride which is reacted with an alcohol of the formula R 6 OH, then deprotected by treating with TBAF in DMF to form a compound of the formula (5.2) wherein E is -OR 6 .
  • a compound of the formula (6.0) is reacted with a compound of formula (42.0), wherein R 1 and R 2 are as defined above for compound (1.0), in a suitable solvent, such as CH3CN or THF, in the presence of a base, such as a tertiary amine base, pentamethylpiperidine or DBU, with pentamethylpiperidine being preferred, to form a compound of formula (1.1).
  • a suitable solvent such as CH3CN or THF
  • a base such as a tertiary amine base, pentamethylpiperidine or DBU, with pentamethylpiperidine being preferred
  • a compound of formula (46.0) is treated with a suitable borane reducing agent, such as BH3 » THF, in a suitable solvent, such as THF, at a temperature of -40° to 50°C, preferably at 0° to 30°C, to give the alcohol (47.0).
  • a suitable borane reducing agent such as BH3 » THF
  • the alcohol (47.0) is then protected as a silyl ether, preferably as the TBS ether, by treating with a halotrialkylsilane, preferably chloro-t-butyldimethylsilane, in a suitable solvent, such as CH 2 CI 2 or DMF, at 0° to 50°C, preferably at about 25°C, in the presence of a base, such as a tertiaryamine base, preferably Et ⁇ N or pyridine, and a catalyst, such as DMAP or imidazole, to give a compound of formula (48.0).
  • a halotrialkylsilane preferably chloro-t-butyldimethylsilane
  • a suitable solvent such as CH 2 CI 2 or DMF
  • a base such as a tertiaryamine base, preferably Et ⁇ N or pyridine
  • a catalyst such as DMAP or imidazole
  • the FMOC protecting group of compound (48.0) can be removed by standard procedures, e.g. by treating with a secondary amine, such as piperidine, in a suitable solvent, such as THF or DMF, at 0° to 50°C, preferably at about 25°C, to give an amine of formula (49.0).
  • a secondary amine such as piperidine
  • a suitable solvent such as THF or DMF
  • T e amine (49.0) is reacted with a compound of the formula (6.0) in the presence of a hindered base, such as 1 ,2,2,6,6-pentamethylpiperidine of DBU, in a suitable solvent, such as THF or CH3CN, preferably CH3CN, at 0° to 8Q°C, preferably at 25° to 80°C and most preferably at 40° to 60°C, to give a compound of formula (50.0).
  • a hindered base such as 1 ,2,2,6,6-pentamethylpiperidine of DBU
  • a suitable solvent such as THF or CH3CN, preferably CH3CN, at 0° to 8Q°C, preferably at 25° to 80°C and most preferably at 40° to 60°C, to give a compound of formula (50.0).
  • the BOC protecting group of compound (50.0) is removed using standard methods, e.g. by treating with an acid, such as TFA or HCI, in a suitable solvent, such as CH 2 CI 2 or dioxane, at 0° to 50°C, preferably at about 25°C, to produce a compound of formula (2.20), [i.e., an amine of formula (2.0), wherein R 2 is -OR 6 substituted. alkyl, wherein R 6 is H, and wherein said -OR 6 group is protected as its TBS ether).
  • an acid such as TFA or HCI
  • a suitable solvent such as CH 2 CI 2 or dioxane
  • Compound (2.20) is converted to a compound of formula (51.0) via the procedures described above for conversion of an amine (2.0) to a compound of formula (1.0).
  • compound (2.20) can be acyiated with a suitable carboxylic acid in the presence of a coupling agent, such as DCC or DEC, and a base, such as DMAP, in a suitable solvent, such as CH 2 CI 2 or DMF, at 0° to 80°C, preferably at about 25°C, to form a compound (51.0), wherein R 1 is -C(0)-CH 2 -R 5 or one of the other acyl groups defined above for R 1 .
  • a coupling agent such as DCC or DEC
  • a base such as DMAP
  • compound (2.20) can be treated with the corresponding acid chloride in the presence of a tertiaryamine base, such as Et3N, to form a compound of formula (51.0), wherein R 1 is -C(0)-CH 2 -R 5 or one of the other acyl groups defined above for R 1 .
  • a tertiaryamine base such as Et3N
  • Compound (51.0) is deprotected using a source of fluoride ion, preferably TBAF, in a suitable solvent, such as THF, at a temperature of 0° to 50°C, preferably at about 25°C, to form a compound of the formula (1.0).
  • a source of fluoride ion preferably TBAF
  • THF a suitable solvent
  • compound (51.0) can be treated with aqueous HF in a suitable solvent, such as CH3CN, to produce the compound of formula (1.0).
  • Compound (53.0) is treated with a strong base such as NaH, in a suitable solvent, such as THF or DMF, preferably THF, at a temperature of -100° to 50°C, preferably at -40° to 10°C, then reacted with an alkyl chloroacetate of the formula CICH 2 C(0)OR 50 , wherein R 50 is C1-C4 alkyl, preferably methyl, to form a compound of the formula (54.0).
  • a strong base such as NaH
  • a suitable solvent such as THF or DMF, preferably THF
  • Compound (54.0) is hydrolyzed under basic conditions, e.g. by treating with a hydroxide base, such as LiOH, in a suitable solvent, such as a combination of THF, or a C1-C4 alcohol (such as MeOH), and water, at a temperature of 0° to 50°C, preferably at about 25°C, to give a compound of formula (55.0).
  • a hydroxide base such as LiOH
  • a suitable solvent such as a combination of THF, or a C1-C4 alcohol (such as MeOH)
  • Compound (55.0) is reacted with an amine of the formula R 15 R 10 NH, wherein R 10 and R 15 are as defined above, in the presence of a coupling agent, such as DCC or DEC, preferably DEC, and a catalyst, such as HOBT or DMAP, in a suitable solvent, such as CH 2 CI 2 or DMF, at a temperature of 0° to 70°C, preferably at about 25°C, to give a compound of formula (56.0).
  • a coupling agent such as DCC or DEC, preferably DEC
  • a catalyst such as HOBT or DMAP
  • the N-benzyl protecting group of compound (56.0) is removed by hydrogenolysis using a catalyst, such as Pd/C, preferably 10% Pd/C, in a suitable solvent, such as a C1-C4 alcohol, preferably MeOH or EtOH, at a pressure of 30 psi to 100 psi, preferably at about 50 psi, at a temperature of 0° to 80°C, preferably at 20° to 30°C, to give a compound of the formula (57.0).
  • a catalyst such as Pd/C, preferably 10% Pd/C
  • a suitable solvent such as a C1-C4 alcohol, preferably MeOH or EtOH
  • the hydrogenolysis can more preferably be carried out as described above with a catalytic amount of HOAc present in the mixture during the reaction.
  • the BOC group of compound (58.0) is hydrolyzed as described above for hydrolysis of compound (50.0) to give a compound of the formula (2.21), [i.e., an amine of formula (2.0), wherein R 2 is -OR 6 substituted alkyl, wherein R 6 is -CH 2 NR 10 R 15 ].
  • Compound (2.21 ) is then converted to a compound of the formula (1.31 ) using substantially the same methods as described above for conversion of compound (2.20) to compound (51.0).
  • a suitable solvent such as THF or DMF, preferably THF
  • the BOC group of compound (61.0) is hydrolyzed as described above for hydrolysis of compound (50.0) to give a compound of the formula (2.22), [i.e., an amine of formula (2.0), wherein R 2 is alkyl substituted by -OR 6 , wherein R 6 is alkyl substituted by -OH, where said -OH group is protected, (i.e., by group R 51 )].
  • Compound (2.22) is then converted to a compound of the formula (62.0) using substantially the same methods as described above for conversion of compound (2.20) to compound (51.0).
  • R 5 protecting group of compound (62.0) is then removed using standard conditions appropriate for removal of the protecting group selected.
  • R 51 is an acyl group, (e.g. CH3C(0)-) compound (62.0) is hydrolyzed using a moderate base, such as K2CO3 or Na 2 C ⁇ 3, in a protic solvent, such as a C1-C4 alcohol or water, or a mixture of two such solvents, at a temperature of 0° to 100°C, preferably at about 25°C, to give a compound of formula (1.32).
  • a moderate base such as K2CO3 or Na 2 C ⁇ 3
  • a protic solvent such as a C1-C4 alcohol or water, or a mixture of two such solvents
  • Step E Combine the product of Step E, CH 2 CI 2 and TFA, and stir at 25°C for 0.5 hours. Concentrate in vacuo to a residue. Acylate the residue by the same method as Step E of Example 8. Concentrate in vacuo to a residue and chromatograph to give the product compound.
  • ASSAYS ASSAYS
  • the inhibition of farnesyl protein transferase was assayed by measuring the transfer of [ 3 H]farnesyl from [ 3 H]farnesylpyrophosphate to biotinylated Ras-peptide (biotin-KKSKTKCVIM) using the conditions described below for each 96-well plate to be tested.
  • An assay buffer is prepared consisting of 40 mM Hepes, pH 7.5; 5 mM dithiothreitol; 20 mM magnesium chloride and 0.01 (v/v)% Igepal non- ionic detergent.
  • a SPA (scintillation proximity assay) bead suspension is prepared consisting of 50 mg of Streptavidin SPA beads (Amersham Life-Science) suspended in 2.5 mL of PBS (phosphate buffered saline).
  • PBS phosphate buffered saline
  • a stop solution is prepared consisting of 480 ⁇ L of the SPA bead suspension mixed with 6720 ⁇ L of a solution consisting of 250 mM EDTA (pH 8.0) and 0.5% Bovine Serium Albumin (Fraction V, 96-99% albumin).
  • An assay mixture is prepared consisting of 480 ⁇ L of assay buffer and 3052.8 ⁇ L of water. This mixture is vortexed to homogeneity and 48 ⁇ L of the Ras peptide is added. The mixture is vortexed and 15.36 ⁇ L of FPP and 3.84 ⁇ L of [ 3 H]FPP are added and the mixture vortexed again. 37.5 ⁇ L of this assay mixture and 2.5 ⁇ L of a DMSO solution (at test concentration) of the compound being tested are then added to each well of a Costar polypropylene U-bottom microtiter plate. The plate is sonicated for 15 minutes at 37°C and then shaken for 15 minutes on a plate shaker.
  • FPT IC5 0 inhibition of farnesyl protein transferase, in vitro enzyme assay
  • GGPT IC5 0 inhibitor of geranylgeranyl protein transferase, in vitro enzyme assay
  • COS Cell IC50 Cell-Based Assay
  • Cell Mat Assay and in vivo tumor activity could be determined by the methods disclosed in WO 95/10516.
  • the compounds of Examples 8 and 8-A had an FPT IC 50 within the range of 0.01 -10 ⁇ M.
  • 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.
  • 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.

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  • Organic Chemistry (AREA)
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Abstract

Composés nouveaux de formule (1.0). Est également décrit un procédé d'inhibition de la fonction Ras, et donc d'inhibition de la croissance anormale des cellules. Le procédé consiste à administrer un composé de la formule indiquée à un système biologique. Le procédé inhibe en particulier la croissance anormale des cellules chez les mammifères tels que l'homme.
PCT/US1996/004170 1995-04-07 1996-04-03 Composes tricycliques utiles pour l'inhibition de la fonction de la proteine-g et le traitement des maladies proliferatives WO1996031505A1 (fr)

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Cited By (14)

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WO1998057960A1 (fr) * 1997-06-17 1998-12-23 Schering Corporation Composes a base de cycloheptane benzpyrido servant d'inhibiteurs de farnesyl proteine transferase
WO1998057964A1 (fr) * 1997-06-17 1998-12-23 Schering Corporation Composes tricycliques utilises comme inhibiteurs de la fonction de la proteine et pour le traitement de maladies proliferantes
WO1998057949A1 (fr) * 1997-06-17 1998-12-23 Schering Corporation Nouveaux sulfonamides tricycliques inhibiteurs de la farnesyle transferase
US5925639A (en) * 1997-06-17 1999-07-20 Schering Corporation Keto amide derivatives useful as farnesyl protein transferase inhibitors
WO1999047497A3 (fr) * 1998-03-13 1999-10-28 Merck Frosst Canada Inc Acides carboxyliques et acylsulfonamides, compositions contenant ces composes et methodes de traitement
US6225322B1 (en) 1997-06-17 2001-05-01 Schering Corporation Compounds useful for inhibition of farnesyl protein transferase
US6242493B1 (en) 1998-03-13 2001-06-05 Merck Frosst Canada & Co. Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment
US6271197B1 (en) 1996-04-11 2001-08-07 Gpc-Biotech Inc. Assays and reagents for identifying anti-fungal agents, and uses related thereto
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
US6372747B1 (en) 1998-12-18 2002-04-16 Schering Corporation Farnesyl protein transferase inhibitors
US6426352B1 (en) 1997-06-17 2002-07-30 Schering Corporation Sulfonamide inhibitors of farnesyl-protein transferase
US6455281B1 (en) 1996-04-11 2002-09-24 Gpc Biotech Inc. Nucleic acids for identifying anti-fungal agents, and uses related thereto
US6696280B2 (en) 1996-04-11 2004-02-24 Gpc Biotech, Inc. Candida geranylgeranyl-protein transferase polypetide, compositions and methods related thereto
WO2005017160A2 (fr) 2003-08-13 2005-02-24 Children's Hospital Medical Center Mobilisation de cellules hematopoietques

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WO1992011034A1 (fr) * 1990-12-18 1992-07-09 The Wellcome Foundation Limited Agents de potentialisation des effects des agents antitumoraux et de lutte contre la resistance a la polychimiotherapie
WO1995000497A1 (fr) * 1993-06-18 1995-01-05 Merck & Co., Inc. Inhibiteurs de farnesyle-proteine transferase
WO1995010516A1 (fr) * 1993-10-15 1995-04-20 Schering Corporation Composes tricycliques a base d'amides et d'uree utiles pour inhiber la fonction de la proteine g et au traitement de maladies proliferatives
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
WO1995010514A1 (fr) * 1993-10-15 1995-04-20 Schering Corporation Composes sulfonamides tricycliques servant a inhiber la fonction de la proteine g et au traitement de maladies proliferatives

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
WO1992011034A1 (fr) * 1990-12-18 1992-07-09 The Wellcome Foundation Limited Agents de potentialisation des effects des agents antitumoraux et de lutte contre la resistance a la polychimiotherapie
WO1995000497A1 (fr) * 1993-06-18 1995-01-05 Merck & Co., Inc. Inhibiteurs de farnesyle-proteine transferase
WO1995010516A1 (fr) * 1993-10-15 1995-04-20 Schering Corporation Composes tricycliques a base d'amides et d'uree utiles pour inhiber la fonction de la proteine g et au traitement de maladies proliferatives
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
WO1995010514A1 (fr) * 1993-10-15 1995-04-20 Schering Corporation Composes sulfonamides tricycliques servant a inhiber la fonction de la proteine g et au traitement de maladies proliferatives

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6455281B1 (en) 1996-04-11 2002-09-24 Gpc Biotech Inc. Nucleic acids for identifying anti-fungal agents, and uses related thereto
US6271197B1 (en) 1996-04-11 2001-08-07 Gpc-Biotech Inc. Assays and reagents for identifying anti-fungal agents, and uses related thereto
US6727082B1 (en) 1996-04-11 2004-04-27 Gpc Biotech Inc. Assays and reagents for identifying anti-fungal agents, and uses related thereto
US6696280B2 (en) 1996-04-11 2004-02-24 Gpc Biotech, Inc. Candida geranylgeranyl-protein transferase polypetide, compositions and methods related thereto
US6277564B1 (en) 1996-04-11 2001-08-21 Gpc Biotech Inc. Assays and reagents for identifying anti-fungal agents, and uses related thereto
US6225322B1 (en) 1997-06-17 2001-05-01 Schering Corporation Compounds useful for inhibition of farnesyl protein transferase
WO1998057964A1 (fr) * 1997-06-17 1998-12-23 Schering Corporation Composes tricycliques utilises comme inhibiteurs de la fonction de la proteine et pour le traitement de maladies proliferantes
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
US6426352B1 (en) 1997-06-17 2002-07-30 Schering Corporation Sulfonamide inhibitors of farnesyl-protein transferase
WO1998057960A1 (fr) * 1997-06-17 1998-12-23 Schering Corporation Composes a base de cycloheptane benzpyrido servant d'inhibiteurs de farnesyl proteine transferase
US5925639A (en) * 1997-06-17 1999-07-20 Schering Corporation Keto amide derivatives useful as farnesyl protein transferase inhibitors
WO1998057949A1 (fr) * 1997-06-17 1998-12-23 Schering Corporation Nouveaux sulfonamides tricycliques inhibiteurs de la farnesyle transferase
US6242493B1 (en) 1998-03-13 2001-06-05 Merck Frosst Canada & Co. Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment
WO1999047497A3 (fr) * 1998-03-13 1999-10-28 Merck Frosst Canada Inc Acides carboxyliques et acylsulfonamides, compositions contenant ces composes et methodes de traitement
US6372747B1 (en) 1998-12-18 2002-04-16 Schering Corporation Farnesyl protein transferase inhibitors
US6740661B2 (en) 1998-12-18 2004-05-25 Schering Corporation Farnesyl protein transferase inhibitors
WO2005017160A2 (fr) 2003-08-13 2005-02-24 Children's Hospital Medical Center Mobilisation de cellules hematopoietques

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