WO1997036584A1 - Inhibitors of farnesyl-protein transferase - Google Patents
Inhibitors of farnesyl-protein transferase Download PDFInfo
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- WO1997036584A1 WO1997036584A1 PCT/US1997/005237 US9705237W WO9736584A1 WO 1997036584 A1 WO1997036584 A1 WO 1997036584A1 US 9705237 W US9705237 W US 9705237W WO 9736584 A1 WO9736584 A1 WO 9736584A1
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- UGVMLJXBFLWFEM-UHFFFAOYSA-N CN(CC(N(C)CCc1cnc[n]1Cc(cc1)ccc1C#N)=O)Cc1ccccc1 Chemical compound CN(CC(N(C)CCc1cnc[n]1Cc(cc1)ccc1C#N)=O)Cc1ccccc1 UGVMLJXBFLWFEM-UHFFFAOYSA-N 0.000 description 3
- PBDWOGKSXRMUMB-UHFFFAOYSA-N CN(CCC(N(C)CCc1cnc[n]1Cc(cc1)ccc1C#N)=O)CC(c1ccccc1)c1ccccc1 Chemical compound CN(CCC(N(C)CCc1cnc[n]1Cc(cc1)ccc1C#N)=O)CC(c1ccccc1)c1ccccc1 PBDWOGKSXRMUMB-UHFFFAOYSA-N 0.000 description 3
- YXDNDZFMPAGLLP-UHFFFAOYSA-N CN(Cc1ccccc1)C(CCc1ccccc1)CC(N(C)CCc1cnc[n]1Cc(cc1)ccc1C#N)=O Chemical compound CN(Cc1ccccc1)C(CCc1ccccc1)CC(N(C)CCc1cnc[n]1Cc(cc1)ccc1C#N)=O YXDNDZFMPAGLLP-UHFFFAOYSA-N 0.000 description 3
- KKKDZZRICRFGSD-UHFFFAOYSA-N C(c1ccccc1)[n]1cncc1 Chemical compound C(c1ccccc1)[n]1cncc1 KKKDZZRICRFGSD-UHFFFAOYSA-N 0.000 description 1
- 0 CN(CCc1cnc[n]1Cc(cc1)ccc1C#N)C(CN(c1cc(Cl)cc(Cl)c1)I1C*C1)=O Chemical compound CN(CCc1cnc[n]1Cc(cc1)ccc1C#N)C(CN(c1cc(Cl)cc(Cl)c1)I1C*C1)=O 0.000 description 1
- SOLKJKYCUCSCHD-UHFFFAOYSA-N NCCc1cnc[n]1Cc(cc1)ccc1C#N Chemical compound NCCc1cnc[n]1Cc(cc1)ccc1C#N SOLKJKYCUCSCHD-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to compounds which inhibit farne yl protein transferase, a protein which is implicated in the oncogenic pathway mediated by Ras.
- the Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
- Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conforma- tional change.
- the GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M. Willumsen, Ann. Rev. Bio hem. 62:851 - 891 (1993)).
- Mutated ras genes d' -ras, K ⁇ 4a-ras, Ki4b-r ⁇ .v and N-ras are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
- Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras.
- the Ras C-terminus contains a sequence motif termed a "CAAX” or "Cy -Aaa ⁇ -Aaa ⁇ -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature J/0:583-586 (1984)).
- this motif serves as a signal sequence for the enzymes famesyl-protein transferase or geranylgeranyl -protein transferase. which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively.
- Ras proteins are known to undergo post-translational famesylation.
- famesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also famesylated. James, et al., have also suggested that there are famesylated proteins of unknown structure and function in addition to those listed above.
- Inhibition of famesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells.
- direct inhibition of famesyl- protein transferase would be more specific, and thus preferable.
- Inhibitors of famesyl-protein transferase have been described in two general classes. The first are analogs of famesyl diphosphate (FPP), while the second class of inhibitors is related to the protein substrates (e.g., Ras) for the enzyme.
- the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation.
- Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the famesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141 ,851 , University of Texas; N.E. Kohl et al., Science, 260: 1934-1937 (1993); Graham, et al., /. Med. Chem., 37, 725 (1994)).
- FPT-ase inhibitors also inhibit the proliferation of vascular smooth muscle cells and are therefore useful in the prevention and treatment of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-1 12930).
- R l a, R i b R2 anc j Rio are independently selected from the group consisting of: hydrogen, aryl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 0-, R9S(0) m -, R C(0)NR 8 -, CN, N ⁇ 2, (R 8 )2NC(NR 8 )-, R8 O)-, R 8 OC(0)-, N3, -N(R )2.
- R 9 OC(0)NR 8 - and C1 -C6 alkyl, unsubstituted or substituted by 1 -3 groups selected from the group consisting of: halo, aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 0-, R9s(0) m -, R C(0)NR 8 -, CN, (R )2NC(NR 8 )-, R «C(0)-, R 8 OC(0)-, N3, -N(R )2 and R9 ⁇ C(0)NR 8 -;
- R3 and R4 are independently selected from the group consisting of: H, F, CI, Br, -N(R h, CF3, N ⁇ 2, R 8 0-, R s 0) m -, CF3(CH 2 ) n O-, R C(0)NH-, H2NC(NH)-.
- A3 is : -NR5C(0)-;
- a 4 is selected from O, S(0)m, wherein m is 0, 1 or 2, NR 5 , OC(O), C(0)0, NR5S(0)m and S(0) m NR 5 , with m as defined above and R5 selected from the group consisting of: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C3-C 10 cycloalkyl, and C1 -C alkyl unsubstituted or substituted with 1 -3 members selected from the group consisting of: unsubstituted or substituted aryl, unsubstituted or substituted hetero- cyclyl, unsubstituted or substituted C3-C10 cycloalkyl, N(R 8 )2, CF3, N02, (R 8 )0-, (R9)S(0)m-, (R 8 )C(0)NH-, H2N-C(NH)-, (R 8 )C(0)-
- R° and R 7 are independently selected from the group consisting of: hydrogen, aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-6 perfluoroalkyl, F, Cl, Br, R 8 0-, R9S(0) m -, R C(0)NR 8 -, CN, N02, (R 8 )2NC(NR 8 )-, R C(0)-, R OC(0)-, N3, -N(R 8 )2, R 9 OC(0)NR 8 - and Ci -C ⁇ alkyl unsubstituted or substituted by 1 -3 groups selected from: aryl, heterocyclyl.
- each R 8 is independently selected from hydrogen, Cl -C alkyl, aryl and aralkyl;
- each R9 is independently selected from C1 -C6 alkyl and aryl;
- V is selected from the group consisting of: hydrogen, heterocyclyl, aryl, C] -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C2-C20 alkenyl, provided that V is not hydrogen if A ⁇ is S(0)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(0) m ;
- W represents heterocyclyl
- Y represents aryl
- each n and p independently represents 0, 1 , 2, 3 or 4; q is 1 , 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen, and t is 0 or 1.
- the compounds of this invention are useful in the inhibition of famesyl-protein transferase and the famesylation of the oncogene protein Ras, and thus are useful for the treatment of cancer.
- the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
- any variable e.g. aryl, heterocycle, Rl , R 2 etc.
- alkyl and the alkyl portion of alkoxy, aralkyl and similar terms, is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, or 1 -6 carbon atoms if unspecified. Cycloalkyl means 1-2 carbocyclic rings which are saturated and contain from 3-10 atoms.
- Halogen or "halo” as used herein means fluoro, chloro, bromo and iodo.
- aryl and the aryl portion of aralkyl, are intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
- a preferred aralkyl group is benzyl.
- heterocyclyl, heterocycle and heterocyclic mean a 5- to 7-membered monocyclic or 8- to 1 1 - membered bicyclic heterocyclic rings, either saturated or unsaturated, aromatic, partially aromatic or non-aromatic, and which consist of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S.
- it includes any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
- the ring or ring system may be attached at any heteroatom or carbon atom which results in a stable structure, and may contain 1 -3 carbonyl groups.
- heterocycles include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, mo holinyl, naphthyridinyl, oxadiazolyl,
- Heteroaryl is a subset of heterocyclic, and means a monocyclic or bicyclic ring system, with up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S.
- Examples include benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl.
- oxadiazolyl pyridyl, pyrazinyl.
- pyrazolyl pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl and thienyl.
- Lines drawn into ring systems from substituents indicate that the bond may be attached to any of the substitutable ring atoms.
- substituted as used, e.g., with substituted alkyl. substituted aryl, substituted heterocyclyl and substituted cycloalkyl, means alkyl, aryl, heterocyclyl and cycloalkyl groups, respectively, having from 1 -3 substituents which are selected from: halo, aryl, heterocyclyl, C3-10 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, R x O-, R 9 S(0) m -, R «C(0)NR «-, CN, (R «) 2 NC(NR «)-, R «C(0)-, R «OC(0)-, N3, -N(R 8 ) 2 and R ⁇ OC(0)NR «-.
- 1 -2 groups are present on substituted alkyl, substituted aryl, substituted heterocyclyl and substituted cycloalkyl, which are selected from: halo, aryl, R 8 0-, CN, R 8 C(0)- and -N(R 8 )2-
- Rla ,Rlb an( j R2 are independently selected from: hydrogen, -N(R )2, R 8 C(0)NR 8 - or unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl -C6 alkyl is selected from unsubstituted or substituted aryl, -N(R )2, R 8 0- and R 8 C(0)NR 8 -.
- R3 and R 4 are selected from: hydrogen and C1 -C6 alkyl.
- a 3 represents -NR 5 C(0)-. wherein R5 represents hydrogen.
- R6 represents CN, NO2 or R s O-.
- R7 represents hydrogen, unsubstituted or substituted C l -C6 alkyl.
- R 8 represents H or Ci -6 alkyl
- R9 is Ci -6 alkyl
- a l and A 2 are independently selected from: a bond, -C(0)NR 8 -, -NR 8 C(0)-, -O-, -N(R 8 )-, -S(0)2N(R 8 )- and- N(R )S(0)2-.
- V is selected from hydrogen, heterocyclyl and aryl. More preferably V is phenyl.
- W is heterocyclyl selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyrrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
- m is 2.
- n and p are 0, 1, 2 or 3.
- t is 1.
- R ⁇ R 4 , A- , A - Y, R x , R y , m, n, p and r are as originally defined;
- each R la , R l t>, R2 and R 10 is independently selected from hydrogen and C] -C6 alkyl;
- R5 is selected from the group consisting of: hydrogen and
- Cl -C6 alkyl unsubstituted or substituted with 1 -3 members selected from the group consisting of: unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C3-C10 cycloalkyl, -N(R )2, -CF3, -NO2, (R 8 )0-, (R9)S(0) m -, (R )C(0)NH-, H2NC(NH)-, (R 8 )C(0)-, (R 8 )OC(0)-, N3, CN and (R9)OC(0)NR 8 -;
- R6 and R 7 are independently selected from: hydrogen, C1 -C6 alkyl, C2-C alkenyl, C2-C6 alkynyl, Cj -C6 perfluoroalkyl, F, Cl, R 0-, R 8 C(0)NR 8 -, CN, NO2, (R 8 )2N-C(NR 8 )-, R C(0)-,
- V is selected from: hydrogen; aryl; heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl and thienyl; C1 -C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a hetero- atom selected from O, S, and N, and C2-C2O alkenyl, provided that V is not hydrogen if A is S(0)m and V is not hydrogen if Al is a bond and A 2 is S(0) m .
- a second subset of compounds of the present invention is represented by formula lb:
- R la, R ib, R2, R IO, Al , A2, A 4 , Y, R3, R 4 , R5, R6, RX, R9, m, n, p, q and r are as originally defined;
- R7 is selected from: hydrogen and -C alkyl
- V is selected from: hydrogen, heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, aryl, C 1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C2-C20 alkenyl,
- V is not hydrogen if Al is S(0)m and V is not hydrogen if A l is a bond, n is 0 and A 2 is S(0) m ;
- W represents heterocyclyl selected from pyrrolidinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl and isoquinolinyl.
- each Rib and RlO is independently selected from hydrogen and C1-C6 alkyl
- R3, R4, A 4 , RK, R 9 , m, p, q and Y are as originally defined;
- R6 is selected from the group consisting of: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cj-C ⁇ perfluoroalkyl, F, Cl, R 0-, R C(0)NR 8 -, CN, NO2, (R 8 )2N-C(NR 8 )-, R C(0)-,
- R 8 OC(0)-, -N(R )2, or R9 ⁇ C(0)NR 8 - and C[-C ⁇ alkyl substituted by C1-C6 perfluoroalkyl, R 8 0-, R 8 C(0)NR 8 -, (R )2N-C(NR 8 )-, R C(0)-, R OC(0)-, -N(R )2 or R9 ⁇ C(0)NR 8 -.
- the pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids.
- such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
- the pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
- Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in Schemes 1 -12, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
- Substituents R and R CH2, as shown in the Schemes, represent the substituents R 8 , R and others, depending on the compound of the instant invention that is being synthesized.
- the variable p' represents p-1.
- ⁇ Y ⁇ R4 can likewise be coupled to the chain by displacement of a leaving group, e.g., a halo group.
- the sulfur can be oxidized to a sulfoxide or sulfone using a suitable oxidizing agent.
- a 4 represents an amino or ether linkage
- the amino or ether linkage can similarly be formed as in Schemes 3 or 4, respectively.
- Schemes 5-8 illustrate syntheses of suitably substituted amines wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that inco ⁇ orate other hetero ⁇ cyclic moieties for variable W are also suitable.
- the diamine IX can be derived from the aldehyde IV as shown in Scheme 9.
- the aldehyde IV is first reductively aminated and then can be debenzylated to give the amine VI.
- Coupling with a difunctionalized compound such as bromo acetylbromide in a polar solvent such as DMF with an organic base (e.g. triethylamine) followed by addition of an arylthiol VII yields VIII. Deprotection affords the instant compound IX.
- Compound IX can further be selectively protected to obtain X which can subsequently be reductively alkylated with a second aldehyde, such as XI, to obtain XII.
- a second aldehyde such as XI
- Removal of the protecting group (to XIII), and conversion to cyclized products such as the dihydroimidazole XIV can be accomplished by literature procedures.
- the aminoalkanol XVI (derived by reduction of the amino acid XV using standard procedures) is coupled under conditions previously described one obtains an alcohol such as XVII (Scheme 1 1 ).
- the alcohol can be oxidized under standard conditions to e.g. an alde ⁇ hyde XVIII, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XIX.
- the fully deprotected amino alcohol XX (Scheme 12) can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXI, or tertiary amines.
- the Boc protected amino alcohol XVII can also be utilized to synthesize 2-aziridinylmethylamides such as XXII (Scheme 13). Treating XVII with l , l '-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide leads to the formation of aziridine XXII. The aziridine may be reacted with a nucleophile, such as a thiol. in the presence of base to yield the ring-opened product XXIII. Deprotection then affords XXIV.
- the diamine XXIX can be derived from amino acids such as O-alkylated tyrosines XXVI, according to standard procedures, as shown in Scheme 14. Intermediate XXIX is first coupled with a difunctionalized compound such as bromo acetylbromide followed by addition of an arylthiol VII (as described above) to yield XXX.
- R' is an aryl group
- XXX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XXXII.
- the amine protecting group in XXX can be removed, and O-alkylated phenolic amines such as XXXI produced.
- Cancers which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors. Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e., neurofibromin (NF-1), neu, scr, abl , lck, fyn) or by other mechanisms.
- the compounds of the instant invention inhibit famesyl- protein transferase and famesylation of the oncogene protein Ras.
- the instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575- 4580 (1995)).
- Such anti-angiogenic properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
- the compounds of this invention are also useful for inhibiting other diseases where 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 compounds of the invention to a mammal in need of such treatment.
- a component of NF- 1 is a benign proliferative disorder.
- the instant compounds may also be useful in the treatment of viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256:13 1 -1333 (1992).
- the compound.s of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1 :541 -545(1995).
- the instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al.
- the instant compounds may also be useful for the treatment of fungal infections.
- the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, in the form of a pharmaceutical composition, which is comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier.
- the compounds can be administered orally, topically, rectally, vaginally transdermally or parenterally, including the intravenous, intramuscular, intraperitoneal and subcutaneous routes of administration.
- the compound is administered, for example, in the form of tablets or capsules, or as a solution or suspension.
- carriers which are commonly used include lactose and com starch; lubricating agents, such as magnesium stearate, are commonly added.
- diluents also include lactose and dried com starch.
- the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
- sterile solutions of the active ingredient are usually prepared, the pH of the solution is suitably adjusted and the product is buffered.
- the total concentration is controlled to render the preparation substantially isotonic.
- the compounds of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
- the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents.
- the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF- 1 , restinosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
- Such combination products employ a compound of this invention substantially within the dosage range described below and other pharmaceutically active agent(s) typically within the acceptable dosage range.
- Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation i inappropriate.
- the daily dosage will normally be determined by the prescribing physician, who may vary the dosage according to the age, weight, and response of the individual patient, as well as the severity of the patient's condition.
- a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
- the compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of famesyl-protein transferase (FPTase) in a composition.
- FPTase famesyl-protein transferase
- the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention.
- the chemical content of the assay mixtures may be determined by well known immuno- logical, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested. It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain famesyl-protein transferase and quanti- tating the enzyme.
- potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample.
- a series of samples composed of aliquots of a tissue extract containing an unknown amount of famesyl- protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention.
- the concentration of a sufficiently potent inhibitor i.e.. one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
- concentration of a sufficiently potent inhibitor i.e. one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
- Nr-Pivaloyloxymethyl-N ⁇ -phthaloylhistamine (4.55 g, 12.8 mmol; prepared as previously described (J. C. Emmett, F. H. Holloway, and J. L. Turner, J. Chem. Soc, Perkin Trans. 1 , 1341 . (1979)) and ⁇ -bromo-p-tolunitrile (3.77 g, 19.2 mmol) were dissolved in acetonitrile (70 mL). The solution was heated at 55°C for 4 h, cooled to room temperature, and filtered to remove the white solid. The acetonitrile (30 mL) was concentrated to 1/2 its volume under reduced pressure and the solution was heated at 55°C overnight.
- the solution was cooled and filtered to give a white solid.
- the volume of the filtrate was reduced to 10 mL, the solution was heated at 55°C for 1 hr, then cooled to room temperature, diluted with EtOAc (25 mL) and filtered to obtain additional white solid.
- the solids were combined, dried, and used without further purification.
- Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM N-(2- hydroxy ethyl) piperazine- V'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM HJ-farnesyl diphosphate ([3H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 ⁇ g/ml FPTase at 31 °C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol.
- Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB ⁇ - plate counter.
- the assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [3H]-FPP was utilized during the reaction period.
- Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
- Human FPTase was prepared as described by Omer et al.,
- the cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
- the assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51 :712-717, (1991 ). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1 %).
- the cells After 4 hours at 37°C, the cells are labelled in 3 ml methionine-free DMEM supple- meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[35S]methionine ( 1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer ( 1 % NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the lysate cleared by centrifugation at 100,000 x g for 45 min.
- 1 ml lysis buffer 1 % NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF
- the immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1 % Triton X- 100.0.5% deoxycholate/0.1 %/SDS/0.1 M NaCl) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to famesylated and nonfamesylated ras proteins are compared to determine the percent inhibition of famesyl transfer to protein.
- IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1 % Triton X- 100.0.5% deoxycholate/0.1 %/SDS/0.1 M NaCl
- Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x IO 4 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer (0.6%). Both layers contain 0.1 % methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay).
- the cells are fed twice weekly with 0.5 ml of medium A containing 0.1 % methanol or the concentration of the instant compound. Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP97917129A EP0935464A1 (en) | 1996-04-03 | 1997-03-31 | Inhibitors of farnesyl-protein transferase |
JP9535511A JP2000507586A (en) | 1996-04-03 | 1997-03-31 | Farnesyl-protein transferase inhibitor |
AU25557/97A AU706629B2 (en) | 1996-04-03 | 1997-03-31 | Inhibitors of farnesyl-protein transferase |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US1477696P | 1996-04-03 | 1996-04-03 | |
US60/014,776 | 1996-04-03 | ||
GB9613690.8 | 1996-06-28 | ||
GBGB9613690.8A GB9613690D0 (en) | 1996-06-28 | 1996-06-28 | Inhibitors of farnesyl-protein transferase |
Publications (1)
Publication Number | Publication Date |
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WO1997036584A1 true WO1997036584A1 (en) | 1997-10-09 |
Family
ID=26309602
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US1997/005237 WO1997036584A1 (en) | 1996-04-03 | 1997-03-31 | Inhibitors of farnesyl-protein transferase |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0935464A1 (en) |
JP (1) | JP2000507586A (en) |
AU (1) | AU706629B2 (en) |
CA (1) | CA2250937A1 (en) |
WO (1) | WO1997036584A1 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0880320A1 (en) * | 1996-01-30 | 1998-12-02 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
EP1035852A1 (en) * | 1997-12-04 | 2000-09-20 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
EP1035849A1 (en) * | 1997-12-04 | 2000-09-20 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
US6358985B1 (en) | 1998-07-02 | 2002-03-19 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferase |
US6410534B1 (en) | 1998-07-02 | 2002-06-25 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferase |
US7514457B2 (en) | 2005-05-31 | 2009-04-07 | Pfizer Inc. | Substituted aryloxymethyl bicyclicmethyl acetamide compounds |
WO2012079164A1 (en) * | 2010-12-16 | 2012-06-21 | The Governing Council Of The University Of Toronto | Activators of cylindrical proteases |
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US5248689A (en) * | 1989-11-06 | 1993-09-28 | Smithkline Beecham Corporation | Substituted N-(imidazolyl)alkyl alanine derivatives |
US5278148A (en) * | 1989-03-28 | 1994-01-11 | Hoffmann-La Roche Inc. | Amino acid derivatives useful for treating high blood pressure |
WO1994019326A1 (en) * | 1993-02-25 | 1994-09-01 | Smithkline Beecham Plc | Imidazole derivatives as 5-ht3 receptor agonists |
US5478934A (en) * | 1994-11-23 | 1995-12-26 | Yuan; Jun | Certain 1-substituted aminomethyl imidazole and pyrrole derivatives: novel dopamine receptor subtype specific ligands |
US5571792A (en) * | 1994-06-30 | 1996-11-05 | Warner-Lambert Company | Histidine and homohistidine derivatives as inhibitors of protein farnesyltransferase |
-
1997
- 1997-03-31 EP EP97917129A patent/EP0935464A1/en not_active Withdrawn
- 1997-03-31 AU AU25557/97A patent/AU706629B2/en not_active Ceased
- 1997-03-31 CA CA002250937A patent/CA2250937A1/en not_active Abandoned
- 1997-03-31 JP JP9535511A patent/JP2000507586A/en active Pending
- 1997-03-31 WO PCT/US1997/005237 patent/WO1997036584A1/en not_active Application Discontinuation
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5278148A (en) * | 1989-03-28 | 1994-01-11 | Hoffmann-La Roche Inc. | Amino acid derivatives useful for treating high blood pressure |
US5248689A (en) * | 1989-11-06 | 1993-09-28 | Smithkline Beecham Corporation | Substituted N-(imidazolyl)alkyl alanine derivatives |
WO1994019326A1 (en) * | 1993-02-25 | 1994-09-01 | Smithkline Beecham Plc | Imidazole derivatives as 5-ht3 receptor agonists |
US5571792A (en) * | 1994-06-30 | 1996-11-05 | Warner-Lambert Company | Histidine and homohistidine derivatives as inhibitors of protein farnesyltransferase |
US5478934A (en) * | 1994-11-23 | 1995-12-26 | Yuan; Jun | Certain 1-substituted aminomethyl imidazole and pyrrole derivatives: novel dopamine receptor subtype specific ligands |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0880320A1 (en) * | 1996-01-30 | 1998-12-02 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
EP0880320A4 (en) * | 1996-01-30 | 1999-06-16 | Merck & Co Inc | Inhibitors of farnesyl-protein transferase |
EP1035852A1 (en) * | 1997-12-04 | 2000-09-20 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
EP1035849A1 (en) * | 1997-12-04 | 2000-09-20 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
EP1035852A4 (en) * | 1997-12-04 | 2001-09-12 | Merck & Co Inc | Inhibitors of farnesyl-protein transferase |
EP1035849A4 (en) * | 1997-12-04 | 2001-09-12 | Merck & Co Inc | Inhibitors of farnesyl-protein transferase |
US6358985B1 (en) | 1998-07-02 | 2002-03-19 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferase |
US6410534B1 (en) | 1998-07-02 | 2002-06-25 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferase |
US7514457B2 (en) | 2005-05-31 | 2009-04-07 | Pfizer Inc. | Substituted aryloxymethyl bicyclicmethyl acetamide compounds |
WO2012079164A1 (en) * | 2010-12-16 | 2012-06-21 | The Governing Council Of The University Of Toronto | Activators of cylindrical proteases |
Also Published As
Publication number | Publication date |
---|---|
AU2555797A (en) | 1997-10-22 |
EP0935464A1 (en) | 1999-08-18 |
AU706629B2 (en) | 1999-06-17 |
JP2000507586A (en) | 2000-06-20 |
CA2250937A1 (en) | 1997-10-09 |
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