WO2014041349A1 - Pyrimidines ou pyridazines tétrahydropyran-4-yléthylamino- ou tétrahydropyranyl-4-éthyloxy utiles comme inhibiteurs de l'isoprényl-cystéine-carboxy-méthyl-transférase - Google Patents

Pyrimidines ou pyridazines tétrahydropyran-4-yléthylamino- ou tétrahydropyranyl-4-éthyloxy utiles comme inhibiteurs de l'isoprényl-cystéine-carboxy-méthyl-transférase Download PDF

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WO2014041349A1
WO2014041349A1 PCT/GB2013/052378 GB2013052378W WO2014041349A1 WO 2014041349 A1 WO2014041349 A1 WO 2014041349A1 GB 2013052378 W GB2013052378 W GB 2013052378W WO 2014041349 A1 WO2014041349 A1 WO 2014041349A1
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compound according
meoh
nmr
arch
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PCT/GB2013/052378
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Graeme Irvine Stevenson
Agatha GARAVELAS
Kelly Leanne COSGROVE
Kristie Anne REYNOLDS
Nicole Cecilia FRANKEN
Louise Renee WHITTELL
Hasanthi Punyama WIJESEKERA
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Cancer Therapeutics Crc Pty Ltd
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Publication of WO2014041349A1 publication Critical patent/WO2014041349A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to compounds which inhibit
  • a C-terminal CaaX motif where C is cysteine, the a's are aliphatic amino acids, and X can be any of a number of amino acids, targets a variety of eukaryotic proteins to a series of post-translational modifications important for their localization and function (Zhang and Casey, 1996; Kloog and Cox, 2004).
  • This processing is initiated by the covalent attachment of a 15-carbon farnesyl or a 20-carbon geranylgeranyl lipid to the cysteine of the CaaX motif, a reaction catalyzed by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase type I (GGTase-l) (Casey and Seabra, 1996).
  • FTase protein farnesyltransferase
  • GTTase-l protein geranylgeranyltransferase type I
  • Reel a specific endoprotease termed Reel (Boyartchuk et al, 1997; Otto et al, 1999) and the now C-terminal prenylcysteine moiety is methylated by the enzyme isoprenylcysteine carboxyl methyltransferase (ICMT) (Clarke et al, 1988; Hrycyna et al, 1991 ; Dai et al, 1998).
  • ICMT isoprenylcysteine carboxyl methyltransferase
  • ICMT In a number of pathological conditions such as inflammation, acute lung injury and acute respiratory distress syndrome, lung endothelial cells are aberrantly activated leading to increased vascular permeability, culminating in lung edema.
  • Rho GTPases Studies implicating Rho GTPases in this process have led to the evaluation of targeting ICMT. This approach decreased RhoA carboxyl methylation and activation, which correlated with decreased monolayer permeability of pulmonary artery endothelial cells (Lu et al, 2004; Lu et al, 2007). These data suggest that targeting ICMT could be a useful therapeutic strategy against diseases characterized by increased vascular permeability.
  • ICMT may also play a role in inflammatory conditions (WO 98/56924), and therefore inhibitors of ICMT may be useful as anti-inflammatory agents.
  • WO 2006/102126 discloses a class of compounds as ICMT inhibitors.
  • inhibitors of ICMT include:
  • the present inventors have discovered a particular class of compounds which are effective as ICMT inhibitors. These compounds have a lower molecular weight than known compounds and may also have a lower logP value. These compounds may also be competitive binders.
  • a first aspect of the invention provides the use of a compound of formula I :
  • R is selected from:
  • R 2 is selected from:
  • X is selected from NH and O;
  • R 4 is selected from phenyl, a 5-membered heteroaryl or a 6-membered heteroaryl, all of which are optionally substituted by one or more substituents selected from the group consisting of: methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, fluoro, -OC 2 H 4 OMe, and pyrazolyl.
  • a second aspect of the present invention provides a pharmaceutical composition comprising a compound of the first aspect and a pharmaceutically acceptable carrier or diluent. The second aspect of the invention also provides a compound of the first aspect for use in a method of therapy.
  • a third aspect of the present invention provides a compound of the first aspect in the manufacture of a medicament for treating a disease ameliorated by the inhibition of ICMT.
  • the third aspect of the invention also provides a compound of the first aspect for use in the method of treatment of a disease ameliorated by the inhibition of ICMT.
  • Another aspect of the invention provides a method of inhibiting ICMT in vitro or in vivo, comprising contacting a cell with an effective amount of an active compound as described herein.
  • a further aspect of the invention provides an active compound as described herein for use in a method of treatment of the human or animal body, preferably in the form of a pharmaceutical composition.
  • R is selected from:
  • R When R is phenyl, it may be unsubstituted, or bear a single fluoro group. This fluoro group may be in any available position, and thus R can be phenyl, 2-fluorophenyl, 3- fluorophenyl or 4-fluorophenyl:
  • R When R is thienyl, it may be in either possible orientation and thus R can be thiophen-2-yl or thiophen-3-yl:
  • R is furanyl, it may be in either possible orientation and thus R can be furan- 2-yl or furan-3-yl:
  • R When R is Ci_ 4 alkyl, it may methyl (C , ethyl (C 2 ), propyl (C 3 ) or butyl (C 4 ). It may be a linear Ci_ 4 alkyl group, i.e., methyl (Ci), ethyl (C 2 ), n-propyl (C 3 ) or n-butyl (C 4 ), a branched Ci_ 4 alkyl group, i.e. include iso-propyl (C 3 ), iso-butyl (C 4 ), sec-butyl (C 4 ) or tert-butyl (C 4 ), or a cyclic C 3 . 4 alkyl group, i.e. cyclopropyl (C 3 ) or cyclobutyl (C 4 ).
  • R may also be H.
  • R 4 is selected from phenyl, a 5-membered heteroaryl or a 6-membered heteroaryl, all of which are optionally substituted by one or more substituents selected from the group consisting of: methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, fluoro, -OC 2 H 4 OMe and pyrazolyl.
  • 5-membered heteroaryl groups are monovalent groups derived from a compound having an aromatic ring with 5 ring atoms, one of which is not carbon.
  • the non- carbon heteroatoms are usually selected from nitrogen, oxygen and sulphur, so possible groups include, but are not limited to: pyrrolyl (Ni), furanyl (Oi), thiophenyl (Si), oxazolyl (N1O1), isoxazolyl (N1O1), oxadiazolyl (Ni0 2 ), oxatriazolyl (N1O 3 ), thiazolyl (N1S1), isothiazolyl (N1S1), imidazolyl (N 2 ), pyrazolyl (N 2 ), triazolyl (N 3 ) and tetrazolyl (N 4 ).
  • 6-membered heteroaryl groups are monovalent groups derived from a compound having an aromatic ring with 6 ring atoms, one of which is not carbon.
  • the non- carbon heteroatoms are usually selected from nitrogen, oxygen and sulphur, so possible groups include, but are not limited to: pyridyl (N ⁇ , isoxazinyl ( ⁇ ), pyridazinyl (N 2 ), pyrimidinyl (N 2 ), pyrazinyl (N 2 ) and triazinyl (N 3 ).
  • a reference to carboxylic acid also includes the anionic (carboxylate) form (-COO " ), a salt or solvate thereof, as well as conventional protected forms.
  • a reference to an amino group includes the protonated form (-N + HR R 2 ), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group.
  • a reference to a hydroxyl group also includes the anionic form (-0 " ), a salt or solvate thereof, as well as conventional protected forms of a hydroxyl group.
  • isomers are structural (or constitutional) isomers (i.e. isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH.
  • a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
  • Ci- 7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert- butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • H may be in any isotopic form, including H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 2 C, 3 C and 4 C; O may be in any isotopic form, including 6 0 and 8 0; and the like.
  • a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below. It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt.
  • Suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4+ ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2+ , NHR 3+ , NR 4+ ).
  • suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine,
  • benzylamine phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • amino acids such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 ) 4+ .
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: acetic, propionic, succinic, glycolic, stearic, palmitic, lactic, malic, pamoic, tartaric, citric, gluconic, ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, aspartic, benzoic, cinnamic, pyruvic, salicyclic, sulfanilic, 2- acetyoxybenzoic, fumaric, phenylsulfonic, toluenesulfonic, methanesulfonic, ethanesulfonic, ethane disulfonic, oxalic, pantothenic, isethionic, valeric, lactobionic, and gluconic.
  • suitable polymeric anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g. active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
  • chemically protected form pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, that is, are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
  • a protected or protecting group also known as a masked or masking group or a blocked or blocking group.
  • a reactive functional group By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts, Wiley, 1999).
  • a hydroxy group may be protected as an ether (-OR) or an ester
  • an amine group may be protected, for example, as an amide or a urethane, for example, as: a methyl amide (-NHCO-CH 3 ); a benzyloxy amide (- NHCO-OCH 2 C 6 H 5 , -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2- biphenyl-2-propoxy amide (-NHCO-OC(CH 3 )2C 6 H 4 C 6 H5, -NH-Bpoc), as a 9- fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH- Troc), as an allyloxy amide (-NH-Alloc
  • prodrug refers to a compound which, when metabolised (e.g. in vivo), yields the desired active compound.
  • the prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties.
  • metabolically labile esters include those wherein R is C1-7 alkyl (e.g. -Me, -Et); C ⁇ . ⁇ aminoalkyl (e.g. aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4- morpholino)ethyl); and acyloxy-Ci_ 7 alkyl (e.g. acyloxymethyl; acyloxyethyl; e.g.
  • pivaloyloxymethyl acetoxymethyl; 1-acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl- carbonxyloxyethyl; 1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1- isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1-cyclohexyl- carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy- carbonyloxyethyl; (4-tetrahydropyranyloxy) carbonyloxymethyl; 1-(4- tetrahydropyranyloxy)carbonyloxyethyl;
  • R is phenyl.
  • the phenyl group may be unsubstituted or substituted by a single fluoro group. It may be preferred that the phenyl group is unsubstituted (1a) or has a 3-fluoro group (1c).
  • R is thienyl
  • R is furanyl
  • R is d -4 alkyl. It may be preferred it is C 3 . 4 alkyl, and it may be further preferred that it is C 3 alkyl, and in particular, iso-propyl.
  • R is H.
  • R 2 is (2b).
  • R 2 is (2c).
  • R 2 is (2d).
  • R is (3a).
  • R 3 is (3b).
  • X is NH. In some embodiments, X is O.
  • R 4 is phenyl, optionally substituted by one or more substituents selected from the group consisting of: methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, fluoro, -OC 2 H 4 OMe and pyrazolyl.
  • the phenyl group is unsubstituted.
  • the phenyl group is substituted by at least group selected from methoxy, trifluoromethoxy, fluoro and -OC 2 H 4 OMe.
  • R 4 is a 5-membered heteroaryl optionally substituted by one or more substituents selected from the group consisting of: methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, fluoro, -OC 2 H 4 OMe and pyrazolyl.
  • the 5-membered heteroaryl group may contain 1 or 2 nitrogen ring atoms, and may preferably be pyrazolyl.
  • R 4 is a 5-membered heteroaryl, it may be unsubstituted. If it is substituted, the substituent may, in some embodiments, be methyl.
  • R 4 is a 6-membered heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, fluoro, -OC 2 H 4 OMe and pyrazolyl.
  • the 6-membered heteroaryl group may contain 1 or 2 nitrogen ring atoms, and may preferably be selected from pyridyl (e.g. 3-pryidyl) and pyrimidyl (e.g. 5-pyrimidyl).
  • R 4 When R 4 is a 6-membered heteroaryl, it may be unsubstituted. If it is substituted, the substituent may, in some embodiments, be cyano.
  • 5-membered heteroaryl groups are monovalent groups derived from a compound having an aromatic ring with 5 ring atoms, one of which is not carbon.
  • the non- carbon heteroatoms are usually selected from nitrogen, oxygen and sulphur, so possible groups include, but are not limited to: pyrrolyl (Ni), furanyl (Oi), thiophenyl (Si), oxazolyl (N 1 O 1 ), isoxazolyl (N 1 O 1 ), oxadiazolyl (Ni0 2 ), oxatriazolyl (Ni0 3 ), thiazolyl (N 1 S 1 ), isothiazolyl (N 1 S 1 ), imidazolyl (N 2 ), pyrazolyl (N 2 ), triazolyl (N 3 ) and tetrazolyl (N 4 ).
  • 6-membered heteroaryl groups are monovalent groups derived from a compound having an aromatic ring with 6 ring atoms, one of which is not carbon.
  • the non- carbon heteroatoms are usually selected from nitrogen, oxygen and sulphur, so possible groups include, but are not limited to: pyridyl (N ⁇ , isoxazinyl ( ⁇ ), pyridazinyl (N 2 ), pyrimidinyl (N 2 ), pyrazinyl (N 2 ) and triazinyl (N 3 ).
  • R is phenyl, optionally substituted by one fluoro group
  • R 2 is selected from:
  • R 4 is selected from:
  • Y is suitable leaving group such as CI, Br, I or OS0 2 CF 3 .
  • the present invention provides active compounds, specifically, active A/-substituted- 6-aryl-pyrazin-2-amines and A/-substituted 5-fluoro-4-aryl-pyrimidin-2-amines.
  • active pertains to compounds which are capable of inhibiting ICMT activity, and specifically includes both compounds with intrinsic activity (drugs) as well as prodrugs of such compounds, which prodrugs may themselves exhibit little or no intrinsic activity.
  • the present invention further provides a method of inhibiting ICMT in a cell, comprising contacting said cell with an effective amount of an active compound, preferably in the form of a pharmaceutically acceptable composition. Such a method may be practised in vitro or in vivo.
  • the present invention further provides active compounds which inhibit ICMT activity as well as methods of methods of inhibiting ICMT activity comprising contacting a cell with an effective amount of an active compound, whether in vitro or in vivo.
  • Active compounds may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
  • the present invention provides active compounds which are anticancer agents.
  • One of ordinary skill in the art is readily able to determine whether or not a candidate compound treats a cancerous condition for any particular cell type, either alone or in combination.
  • cancers include, but are not limited to, lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carcinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, thyroid cancer, brain cancer, seminoma, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma and leukaemias.
  • Cancers of particular interest are those linked to mutant Ras overactivity, such as pancreatic carcinoma, thyroid carcinoma, colon carcinoma, lung carcinoma, ovarian carcinoma, thyroid carcinoma, seminoma, lung cancer, myelodysplasia syndrome (MDS)/acute myeloid leukemia (AML) and malignant melanoma.
  • MDS myelodysplasia syndrome
  • AML acute myeloid leukemia
  • any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.
  • the anti cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumour agents:-
  • antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5 fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5*-reductase such as finasteride;
  • antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • antiandrogens for example
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti vascular endothelial cell growth factor antibody bevacizumab (AvastinT) and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4- ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2- methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171 ;
  • Example 240 within WO 00/47212 vatalanib (PTK787; WO 98/35985) and SU1 1248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin avb3 function and angiostatin)];
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene directed enzyme pro drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi drug resistance gene therapy; and
  • immunotherapy approaches including for example ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches to decrease T cell anergy, approaches using transfected immune cells such as cytokine transfected dendritic cells, approaches using cytokine transfected tumour cell lines and approaches using anti idiotypic antibodies
  • the active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of
  • the subject may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon), an ape (e.g. gorilla, chimpanzee, orang-utan, gibbon), or a human.
  • a rodent e.g. a guinea pig, a hamster, a rat, a mouse
  • murine e.g. a mouse
  • canine e.g. a dog
  • feline e.g. a cat
  • the active compound While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation) comprising at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.
  • a pharmaceutical composition e.g. formulation
  • pharmaceutically acceptable carriers as used herein pertains to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a subject e.g. human
  • Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington: the science and practice of pharmacy, 21st edition,
  • Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, losenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.
  • a tablet may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free- flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g.
  • binders e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose
  • fillers or diluents e.g. lactose, microcrystalline cellulose, calcium hydrogen
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example,
  • Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • Formulations suitable for topical administration may be formulated as an ointment, cream, suspension, lotion, powder, solution, past, gel, spray, aerosol, or oil.
  • a formulation may comprise a patch or a dressing such as a bandage or adhesive plaster impregnated with active compounds and optionally one or more excipients or diluents.
  • Formulations suitable for topical administration in the mouth include losenges comprising the active compound in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active compound in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active compound in a suitable liquid carrier.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.
  • Formulations suitable for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid for administration as, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser include aqueous or oily solutions of the active compound.
  • Formulations suitable for administration by inhalation include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • Formulations suitable for topical administration via the skin include ointments, creams, and emulsions.
  • the active compound When formulated in an ointment, the active compound may optionally be employed with either a paraffinic or a water-miscible ointment base.
  • the active compounds may be formulated in a cream with an oil-in- water cream base.
  • the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • the oily phase may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier otherwise known as an emulgent
  • the oily phase may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax
  • the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required.
  • mono-isoadipate such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the
  • Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound, such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other micro particulate systems which are designed to target the compound to blood components or one or more organs.
  • appropriate dosages of the active compounds, and compositions comprising the active compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments of the present invention.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient.
  • the amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration in vivo can be effected in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment.
  • Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.
  • NMR spectra were obtained at 298K, at the frequency stated using either a Varian Inova 500 or NMR System 600 MHz instrument and run as a dilute solution on CDCI 3 unless otherwise stated. All spectra were referenced using deuterium locking. All coupling constants are reported in hertz (Hz) with multiplicities labelled s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet) and m (multiplet). NMR spectra where provided, were obtained for the title substance in each Synthesis or Example (or a suitable derivative thereof, such as the free base) unless otherwise stated.
  • Mass spectra were recorded using an Agilent 1200 LC system coupled to an Agilent 6120 Triple quadropole mass spectrometer operating in ES(+) and ES(-) ionisation mode. Analysis was carried out using the same system and using an Agilent Eclipse Ci 8 column (4.5 x 150 mm) with a 5 ⁇ particle size. Mobile phase unless otherwise stated was a gradient of 5% water to 95% acetonitrile increasing over 10 minutes to 95% water 5% acetonitrile using 0.1 % TFA as a modifier and a flow rate of 0.8 mL/min. Microwave reactions were carried out in a Biotage Initiator.
  • Cuprous iodide (Aldrich, CAS: 7681-65-4, CAT: 20,554-0) (56.4 mg, 0.296 mmol) was added to a solution of the unsaturated cyano ester, ethyl 2-cyano-2-(oxan-4- ylidene)acetate (C10)(412.7 mg, 2.114 mmol) in dry Et 2 0 (10 ml) and the mixture was stirred for 5 min.
  • a solution of PhMgBr (Aldrich CAT: 17, 156-5) (3M in diethylether, 1.43 ml_, 0.778 mmol) was added dropwise at 0°C, the solution was allowed to warm to room temperature then left to stir for 3 days.
  • the oil was purified by chromatography (silica, 40 g, 10/90, ethyl acetate/hexane, 13 x 100 mm tubes). Fractions 9-15 were collected (pungent, red oil, 78 mg) and visible by UV and CAM stain. Fractions 16-22 were collected (oil that became red on addition of CDCI 3 , 92.2 mg) and visible by UV and CAM stain.
  • Fractions 23-32 were collected (a colourless oil that solidified on standing, 316.4 mg) and faintly visible by UV and visible by CAM stain.
  • Fractions 33-45 were collected (colourless oil, 80 mg) and faintly visible by UV and visible by CAM stain.
  • Fractions 23-32 and 33-45 were combined and repurified (silica, 25 g, 10/90, ethyl
  • Ethyl 2-cyano-2-(4-phenyloxan-4-yl)acetate (C11)(40.0mg, 1.46 mmol) and potassium hydroxide (41 1 mg, 7.33 mmol) were combined in ethylene glycol (10 mL) and heated to 190°C for 2 h.
  • the reaction mixture was poured into 20 mL water and extracted with ethyl ether (3 x 50 mL).
  • the combined organic phases were dried (Na 2 S0 4 ), filtered, and concentrated to give a colourless viscous oil that crystallized on standing.
  • the sample was dried overnight under high vacuum, (0.2462 g, 84%).
  • Tetrahydrothiopyran-4-one (C14)(520 mg, 4.5 mmol), ethyl cyanoacetate (C5)(1.4 ml, 1.48 g, 13.1 mmol), ammonium acetate (50 mg, 0.65 mmol) and toluene (50 mL) were heated to 150°C using a dean-stark trap.
  • the reaction mixture was then heated at 150°C for a further 24h. The mixture was then concentrated to give a yellow oil.
  • Phenyl magnesium bromide solution (3M in diethyl ether, 1.56 mL, 0.85 g, 4.7 mmol) was added dropwise to a solution of ethyl 2-cyano-2-(tetrahydrothiopyran-4- ylidene)acetate (C15)(330 mg, 1.6 mmol) in diethyl ether (20 mL) at room
  • Phenyl magnesium bromide solution (4.1 mL, 2.2 g, 12.3 mmol, 3M in diethyl ether) was added dropwise to a solution of the compound C10 (810 mg, 4.15 mmol) in diethyl ether (40 mL) at room temperature. The reaction mixture was then heated to reflux for 1 h. The reaction mixture was then cooled to room temperature and quenched with a saturated solution of ammonium chloride (5 mL). The reaction mixture was then further diluted with a saturated solution of ammonium chloride (20 mL) and extracted with ethyl acetate (3 x 50), dried (Na 2 S0 4 ), filtered and
  • reaction mixture was then further diluted with a saturated solution of ammonium chloride (10 mL) and extracted with ethyl acetate (3 x 50), dried (Na 2 S0 4 ), filtered and concentrated to give a yellow oil (crude yield, 527 mg, 88%). This mixture was immediately used in a
  • aqueous layer was then made alkaline (pH 13) by addition of 1 M NaOH solution (aqueous, approx. 50 mL). This was then further extracted with EtOAc (3 x 50 mL). The EtOAc extractions from the alkaline aqueous solution were combined, dried (Na 2 S0 4 ), filtered and concentrated to give a light-yellow oil (140 mg, 49%).
  • the reaction was mildly heated to 40°C for 15 mins, after which time the reaction solution was yellow. The reaction mixture was then allowed to stir for a further 45 mins at room- temperature. A solution of the unsaturated nitrile (Z)-ethyl 2-cyano-2-(2,2-dimethyl- tetrahydropyran-4-ylidene)acetate (C25)(0.55 g, 2.8 mmol) in THF (20 mL) was then added dropwise to the reaction mixture. After all of the nitrile solution had been added, the reaction mixture was refluxed for 1 h. The reaction mixture was then cooled to room temperature. Saturated ammonium chloride solution (aq, 10 mL) was then added carefully to the reaction mixture.
  • reaction mixture was further diluted with a saturated solution of ammonium chloride (10 mL) and extracted with EtOAc (3 x 50 mL). The organic extracts were combined, dried (Na 2 S0 4 ), filtered and concentrated to give an orange oil. This was used in the decarboxylation reaction without further purification.
  • the reaction mixture was then concentrated to give a black residue. This was then suspended in a 1 M HCI solution (aqueous, 50 mL), and extracted with EtOAC (3 x 20 mL). The aqueous layer was then made alkaline (pH13) by addition of 1 M NaOH solution (aqueous, approx. 50 mL). This was then further extracted with EtOAc (3 x 50 mL). The EtOAc extractions from the alkaline aqueous solution were combined, dried (Na 2 S0 4 ), filtered and concentrated to give a yellow oil (113 mg, 34%).
  • the second cartridge was washed with MeOH and this fraction was loaded onto a third silica SCX cartridge.
  • the third cartridge was washed with MeOH. All three of the cartridges were then eluted with 2M NH 3 in MeOH. The ammonium solutions were combined and concentrated to give an orange gum (62 mg, 84%).
  • the cartridge was washed with methanol and the desired product was eluted upon addition of 2M NH 3 in MeOH. Further purification by silica column chromatography (4 g, DCM:MeOH 0-2%; stains - UV, Dragendorff) fractions 13-17 resulted in isolation of the product as an oil. Upon analysis by 1 H NMR the recovered material contained an impurity. Reverse phase (C18 silica) was used to remove the impurity (H 2 0:MeOH - 50:50 - 0: 100%) fractions 14-26 were collected to give the desired product (25.1 mg, 0.065 mmol, 76%).
  • reaction mixture was then concentrated to give a black residue, resuspended in MeOH and loaded onto a SCX cartridge.
  • the cartridge was washed with MeOH and then the desired product eluted with 2M NH 3 in MeOH (4 mL) and concentrated to give a white solid.
  • the product was partially purified via silica column chromatography (2% MeOH in DCM). Fractions resulted in isolation of the impure product. Further purification via column chromatography (silica, DCM) fractions 7-20 were collected to give impure product (25.9 mg).
  • Reverse phase (C18 silica) was used to remove impurity (H20:MeCN - 50:50 - 0: 100%; 50 mL flushes) fractions 9-25 were collected to give the desired product (22.5 mg, 0.049 mmol, 56%).
  • reaction mixture was then concentrated to give a black residue, resuspended in MeOH and loaded onto a SCX cartridge.
  • the cartridge was washed with MeOH and then the desired product eluted with 2M NH 3 in MeOH (4 mL) and concentrated to give a yellow oil.
  • the product was purified via silica column chromatography (DCM:MeOH 0-2%).
  • Example 17 6-(2,5-difluorophenyl)-A/-(2-(4-phenyltetrahydro-2H-pyran-4- yl ethyl)pyrazin-2-amine
  • reaction mixture was then concentrated to give a black residue, resuspended in MeOH and loaded onto a SCX cartridge.
  • the cartridge was washed with MeOH and then the desired product eluted with 2M NH 3 in MeOH (4 ml_) and concentrated to give a yellow oil.
  • the product was partially purified via silica column chromatography (gradient elution: 20% EtOAc in hexane - 40% EtOAc in hexane) to yield a yellow oil.
  • the recovered material was triturated with MeOH to give the off-white solid (5.2 mg, 13% yield) which was 95% pure by NMR and LCMS.
  • reaction mixture was then concentrated to give a black residue, resuspended in MeOH and loaded onto a SCX cartridge.
  • the cartridge was washed with MeOH and then the desired product eluted with 2M NH 3 in MeOH (4 ml_) and concentrated to give a yellow oil.
  • the product was partially purified via silica column chromatography (40% EtOAc in hexane) to give the white solid.
  • the recovered material contained residual grease and was washed with hexane to give the off-white solid (24.5 mg, 73% yield) which was 95% by NMR.
  • Example 20 6-(3-(difluoromethoxy)phenyl)-A/-(2-(2,2-dimethyl-4- phenyltetrahydro-2H-pyran-4-yl)ethyl)pyrazin-2-amine
  • reaction mixture was then concentrated to give a black residue, resuspended in MeOH and loaded onto a SCX cartridge.
  • the cartridge was washed with MeOH and then the desired product eluted with 2M NH 3 in MeOH (4 ml_) and concentrated to give a dark yellow oil.
  • the product was partially purified via silica column chromatography (gradient elution: 100% DCM - 1% MeOH in DCM) to give the off-white solid.
  • the recovered material was triturated with MeOH to give a white solid (18.4 mg, 49%) which was 95% pure by NMR and LCMS.
  • Example 21 V-(2-(2,2-dimethyl-4-phenyltetrahydro-2H-pyran-4-yl)ethyl)-6-(2- fluoro-5-methoxyphenyl)pyrazin-2-amine
  • reaction mixture was then concentrated to give a black residue, resuspended in MeOH and loaded onto a SCX cartridge.
  • the cartridge was washed with MeOH and then the desired product eluted with 2M NH 3 in MeOH (4 ml_) and concentrated to give a yellow oil.
  • the product was purified via silica column chromatography (40% EtOAc in hexane) to yield a white solid (25.7 mg, 63%) which was 95% pure by NMR and LCMS.
  • reaction mixture was then concentrated to give a black residue, resuspended in MeOH and loaded onto a SCX cartridge.
  • the cartridge was washed with MeOH and then the desired product eluted with 2M NH 3 in MeOH (4 ml_) and concentrated to give a yellow oil.
  • the product was partially purified via silica column chromatography (gradient elution: 2% MeOH in DCM - 4% MeOH in DCM) to give the yellow oil, which contained minor impurities by NMR.
  • the recovered material was further purified via silica column chromatography (80% EtOAc in hexane) to give another yellow oil
  • sample A (1 mg) as a white solid
  • sample B 32 mg
  • the sample was passed through a SCX cartridge eluting upon addition of 2M NH 3 in MeOH (4 mL), the solvent was removed at reduced pressure and triturated with hexane to yield a pale yellow solid (29 mg (75%).
  • Example 27 6-(2,5-difluorophenyl)-A/-(2-(2,2,6,6-tetramethyl-4-phenyl- tetrah dro-2H-pyran-4-yl)ethyl)pyrazin-2-amine
  • the reaction mixture was then concentrated to give a black residue. This was then resuspended in MeOH and loaded onto a silica SCX cartridge.
  • the cartridge was washed with MeOH and the desired product was eluted upon addition of 2M NH 3 in MeOH.
  • the MeOH wash fraction mostly contained the starting pyrazine.
  • the recovered material was further purified by silica column chromatography (gradient elution: 100% DCM - 1 % MeOH in DCM) to give a yellow oil. This was further purified by reverse phase C-18 bonded silica cartridge (isocratic: 70% CH 3 CN in water), to yield a white solid (15 mg). This was then dissolved in MeOH and loaded onto a silica SCX cartridge.
  • the cartridge was washed with MeOH and the desired product and impurity eluted upon addition of 2M NH 3 in MeOH. Attempted purification by silica column chromatography (gradient elution: 100% DCM - 1 % MeOH in DCM) failed to remove the impurity. Purification by mass directed semi- preparative HPLC resulted in separation of the impurity from the product. Fractions containing the desired product were concentrated and loaded onto a silica SCX cartridge. The cartridge was washed with MeOH and the desired product was eluted upon addition of 2M NH 3 in MeOH to reveal a white solid (6.75 mg, 9%). 5.73 mg submitted to CDCO and 1.02 mg submitted to the assay.
  • Example 31 V-(2-(4-isopropyl-2,2-dimethyl-tetrahydro-2H-pyran-4-yl)ethyl)-6-(3- methox phenyl)pyrazin-2-amine
  • the reaction mixture was then concentrated to give a black residue. This was then resuspended in MeOH and loaded onto a silica SCX cartridge. The cartridge was washed with MeOH (10 mL), this fraction was then concentrated and then redissolved in MeOH (1 mL) and loaded onto a new silica SCX cartridge. The second cartridge was washed with MeOH (10 mL), the desired product was then eluted from both cartridges by addition of 2M NH 3 in MeOH (4 mL). The combined ammonia solutions were concentrated to give a yellow oil.
  • ICMT methyltransferase
  • SAM S-Adenosylmethionine
  • NaCI Sodium Chloride
  • HEPES 4-(2- hydroxyethyl)-1-piperazineethanesulfonic acid
  • DMSO dimethyl sulfoxide
  • DTT dithiotreitol
  • ICMT membrane protein (10 ⁇ g/ ⁇ L) stored at -80°C were thawed at 37°C and placed on ice.
  • the ICMT membrane protein was diluted in assay buffer (140 mM HEPES, 200 mM NaCI, and 6 mM DTT, pH 7.5) to a 0.06 ⁇ g/ ⁇ L working
  • the compound IC 50 values were determined in Abase using XLFit (IDBS) integrated into Microsoft ExcelTM. Enzyme inhibition data obtained from the SPA assay were analyzed via either a 4 parameter logistic model or sigmoidal dose-response model to return a concentration producing 50% inhibition. Results

Abstract

L'invention concerne un composé de formule (I): dans laquelle: R1 est sélectionné parmi : (i) phényle, éventuellement substitué par un groupe fluoro; (ii) thiényle; (iii) furanyle; (iv) alkyle C1-4; et (v) H; R2 est sélectionné parmi 2a, 2b, 2c, 2d. R3 est sélectionné parmi 3a, 3b; X est sélectionné parmi NH et O; R4 est sélectionné parmi phényle, un hétéroaryle à 5 éléments ou un hétéroaryle à 6 éléments, tous étant éventuellement substitués par un ou plusieurs substituants sélectionnés dans le groupe comprenant: méthyle, méthoxy, trifluorométhyle, trifluorométhoxy, cyano, fluoro, -OC2H4OMe, et pyrazolyle.
PCT/GB2013/052378 2012-09-12 2013-09-12 Pyrimidines ou pyridazines tétrahydropyran-4-yléthylamino- ou tétrahydropyranyl-4-éthyloxy utiles comme inhibiteurs de l'isoprényl-cystéine-carboxy-méthyl-transférase WO2014041349A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2019054944A1 (fr) 2017-09-12 2019-03-21 Agency For Science, Technology And Research Composés utiles en tant qu'inhibiteurs d'isoprénylcystéine carboxyl méthyltranférase

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019054944A1 (fr) 2017-09-12 2019-03-21 Agency For Science, Technology And Research Composés utiles en tant qu'inhibiteurs d'isoprénylcystéine carboxyl méthyltranférase
CN111344284A (zh) * 2017-09-12 2020-06-26 新加坡科技研究局 用作异戊二烯半胱氨酸羧甲基转移酶抑制剂的化合物
EP3681878A4 (fr) * 2017-09-12 2021-02-24 Agency for Science, Technology and Research Composés utiles en tant qu'inhibiteurs d'isoprénylcystéine carboxyl méthyltranférase
US11834430B2 (en) 2017-09-12 2023-12-05 Agency For Science, Technology And Research Compounds useful as inhibitors of isoprenylcysteine carboxyl methyltransferase
CN111344284B (zh) * 2017-09-12 2024-03-12 新加坡科技研究局 用作异戊二烯半胱氨酸羧甲基转移酶抑制剂的化合物

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