WO2006117570A1 - Dérivés de quinoléine servant d'inhibiteurs d'une enzyme de type kinase - Google Patents
Dérivés de quinoléine servant d'inhibiteurs d'une enzyme de type kinase Download PDFInfo
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- WO2006117570A1 WO2006117570A1 PCT/GB2006/001644 GB2006001644W WO2006117570A1 WO 2006117570 A1 WO2006117570 A1 WO 2006117570A1 GB 2006001644 W GB2006001644 W GB 2006001644W WO 2006117570 A1 WO2006117570 A1 WO 2006117570A1
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- 0 C*(CCC*)c1cc(Cl)c(cc(*)c(*)c2)c2n1 Chemical compound C*(CCC*)c1cc(Cl)c(cc(*)c(*)c2)c2n1 0.000 description 1
- KOJFIAAMJBFQPL-UHFFFAOYSA-N COC(CCCOc1cc2nccc(Oc(cc3)ccc3NC(c3ccccc3)=O)c2cc1OC)=O Chemical compound COC(CCCOc1cc2nccc(Oc(cc3)ccc3NC(c3ccccc3)=O)c2cc1OC)=O KOJFIAAMJBFQPL-UHFFFAOYSA-N 0.000 description 1
- ISMRQHAVJWJKNB-XIFFEERXSA-N COc(c(OCCCCN[C@H](C(O)=O)c1ccccc1)cc1ncc2)cc1c2Oc(cc1)ccc1NC(c1ccccc1)=O Chemical compound COc(c(OCCCCN[C@H](C(O)=O)c1ccccc1)cc1ncc2)cc1c2Oc(cc1)ccc1NC(c1ccccc1)=O ISMRQHAVJWJKNB-XIFFEERXSA-N 0.000 description 1
- GIYPQZJJERZOKW-ZDUSSCGKSA-N N[C@@H](Cc1ccccc1)C(OC1CCCC1)=O Chemical compound N[C@@H](Cc1ccccc1)C(OC1CCCC1)=O GIYPQZJJERZOKW-ZDUSSCGKSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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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
- This invention relates to compounds which inhibit members of the aurora kinase family of enzymes and to their use in the treatment of cell proliferative diseases, including cancer, and inflammation.
- DNA is packaged with histones, to form chromatin.
- chromatin Approximately 150 base pairs of DNA are wrapped twice around an octamer of histones (two each of histones 2A, 2B, 3 and 4) to form a nucleosome, the basic unit of chromatin.
- the ordered structure of chromatin needs to be modified in order to allow transcription of the associated genes. Transcriptional regulation is key to differentiation, proliferation and apoptosis, and is, therefore, tightly controlled. Control of the changes in chromatin structure (and hence of transcription) is mediated by covalent modifications to histones, most notably of the N-terminal tails.
- Covalent modifications for example methylation, acetylation, phosphorylation and ubiquitination
- Covalent modifications for example methylation, acetylation, phosphorylation and ubiquitination
- Covalent modifications of the side chains of amino acids are enzymatically mediated
- a review of the covalent modifications of histones and their role in transcriptional regulation can be found in Berger SL 2001 Oncogene 20, 3007-3013; See Grunstein, M 1997 Nature 389, 349-352; Wolffe AP 1996 Science 272, 371- 372; and Wade PA et al 1997 Trends Biochem Sci 22, 128-132 for reviews of histone acetylation and transcription).
- the aurora kinases are a family of serine/threonine kinases which have been identified as key regulators of the mitotic cell division process (Bischoff and Plowman, 1999 Trends Cell Biol 9, 454-459) which may become deregulated in cancer and other hyperproliferative diseases (Warner et al, 2003, MoI Can Ther 2, 589-595).
- the three members of this family identified so far are referred to as Aurora-A, Aurora-B and Aurora-C.
- Higher eukaryotic cells typically express two or more Aurora kinases. It has been shown that inhibition of Aurora B affects several facets of mitosis including histone H3 phosphorylation, chromosome segregation and cytokinesis.
- Aurora A and C localise to spindle poles with Aurora A being required for bipolar spindle formation in a number of systems (Giet and Prigent, 1999, J.Cell.Sci 11 , 3591-3601)..
- Aurora A and B have been shown to be overexpressed in a number of human cancers and their overexpression in cells in vitro leads to transformation, centrosome abnormalities and aneuploidy (Bischoff et al, 1998, EMBO J. 17, 3052). Cells which overexpress Aurora A have been shown to form tumours in athymic mice.
- the observations contained in these manuscripts suggest that increase in Aurora kinase activity may serve to promote tumour development by providing growth advantage or by inducing genetic instability and that Aurora Kinase inhibition should have therapeutic benefit in cancer, and other proliferative diseases.
- Q is CH, C-CN or N
- the group Ra is variable but often a small alkoxy group such as methoxy
- the group Rb is a solubilising group
- W is a hetero radical such as NH or O
- A is an aromatic or heteroaromatic ring
- L 2 is a linker radical, usually containing nitrogen and carbonyl
- the -W-A-L 2 - (B) r -H can be thought of as the side chain of the quinoline/quinazoline ring system, and it is the quinoline/quinazoline plus side chain which plays the major role in binding to the Aurora kinase enzyme.
- the substituent Rb appears to be oriented away from enzyme when bound, and is therefore a suitable location for modification to improve properties such as solubility.
- prodrugs to enhance the delivery to target organs and tissues, or to overcome poor pharmacokinetic properties of the parent drug, is a well known medicinal chemistry approach.
- This invention is based on the finding that the introduction of an alpha amino acid ester grouping into the Aurora kinase inhibitor molecular template (A) above facilitates penetration of the agent through the cell membrane, and thereby allows intracellular esterase activity to hydrolyse the ester to release the parent acid. Being charged, the acid is not readily transported out of the cell, where it therefore accumulates to increase the intracellular concentration of active Aurora kinase inhibitor. This leads to increases in potency and duration of action.
- the invention therefore makes available a class of compounds whose structures are characterised by having an alpha amino acid ester moiety which is a substrate for intracellular carboxylesterase (also referred to herein as an "esterase motif)_covalently linked to an Aurora kinase inhibitor molecular template, and to the corresponding de-esterified parent acids, such compounds having pharmaceutical utility in the treatment of diseases such as cancers which benefit from intracellular inhibition of Aurora kinase.
- carboxylesterase also referred to herein as an "esterase motif”
- Ri is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular esterase enzymes to a carboxylic acid group;
- R 2 is the side chain of a natural or non-natural alpha amino acid
- L 1 is a divalent radical of formula -(Alk 1 ) m (Q 1 ) n (Alk 2 ) p - wherein m, n and p are independently 0 or 1 ,
- Q 1 is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members, or (ii), in the case where p is 0, a divalent radical of formula -Q 2 -X 2 - wherein X 2 is -O-, -S- or NR A - wherein R A is hydrogen or optionally substituted C 1 -C 3 alkyl, and Q 2 is an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5 - 13 ring members,
- AIk 1 and AIk 2 independently represent optionally substituted divalent C 3 -C 7 cycloalkyl radicals, or optionally substituted straight or branched, C 1 -C 6 alkylene, C 2 -C 6 alkenylene ,or C 2 -C 6 alkynylene radicals which may optionally contain or terminate in an ether (-O-), thioether (-S-) or amino (-NR A -) link wherein R A is hydrogen or optionally substituted C 1 - C 3 alkyl;
- z is O or 1 ;
- R 4 is C 1 -C 4 alkoxy, hydrogen or halo
- L 2 represents a radical of formula -(Alk 3 ) a -Z-(Alk 4 ) b - wherein a and b are independently 0 or 1 ;
- AIk 3 and AIk 4 independently represent optionally substituted divalent C 3 -C 7 cycloalkyl radicals, or optionally substituted straight or branched, C 1 -C 6 alkylene, C 2 -C 6 alkenylene ,or C 2 -C 6 alkynylene radicals which may optionally contain or terminate in an ether (-O-), thioether (-S-) or amino (-NR A -) link wherein R A is hydrogen or optionally substituted C 1 -C 3 alkyl;
- r and s are independently 0 or 1 ;
- rings A, B and C are mono- or bi-cyclic carbocyclic or heterocyclic rings or ring systems having up to 12 ring atoms.
- the invention provides the use of a compound of formula (IA) or (IB) as defined above, or an N-oxide, salt, hydrate or solvate thereof in the preparation of a composition for inhibiting the activity of an aurora kinase enzyme, particularly aurora-A.
- the compounds with which the invention is concerned may be used for the inhibition of aurora kinase activity, particularly aurora-A activity, ex vivo or in vivo.
- the compounds of the invention may be used in the preparation of a composition for the treatment of cell-proliferation disease, for example cancer cell proliferation and in inflammation.
- the invention provides a method for the treatment of the foregoing disease types, which comprises administering to a subject suffering such disease an effective amount of a compound of formula (IA) or (IB) as defined above.
- (C a -C b )alkyl wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms.
- a 1 and b is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
- divalent (C a -C b )alkylene radical wherein a and b are integers refers to a saturated hydrocarbon chain having from a to b carbon atoms and two unsatisfied valences.
- (C a -C b )alkenyl wherein a and b are integers refers to a straight or branched chain alkenyl moiety having from a to b carbon atoms having at least one double bond of either E or Z stereochemistry where applicable.
- the term includes, for example, vinyl, allyl, 1- and 2-butenyl and 2-methyl-2-propenyl.
- divalent (C a -C b )alkenylene radical means a hydrocarbon chain having from a to b carbon atoms, at least one double bond, and two unsatisfied valences.
- C a -C b alkynyl wherein a and b are integers refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1-propynyl, 1- and 2-butynyl, 2- methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5- hexynyl.
- divalent (C a -C b )alkynylene radical wherein a and b are integers refers to a divalent hydrocarbon chain having from 2 to 6 carbon atoms, and at least one triple bond.
- Carbocyclic refers to a mono-, bi- or tricyclic radical having up to 16 ring atoms, all of which are carbon, and includes aryl and cycloalkyl.
- cycloalkyl refers to a monocyclic saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- aryl refers to a mono-, bi- or tri-cyclic carbocyclic aromatic radical, and includes radicals having two monocyclic carbocyclic aromatic rings which are directly linked by a covalent bond.
- Illustrative of such radicals are phenyl, biphenyl and napthyl.
- heteroaryl refers to a mono-, bi- or tri-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O, and includes radicals having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring, which are directly linked by a covalent bond.
- Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl and indazolyl.
- heterocyclyl or “heterocyclic” includes “heteroaryl” as defined above, and in its non-aromatic meaning relates to a mono-, bi- or tri-cyclic non-aromatic radical containing one or more heteroatoms selected from S, N and O, and to groups consisting of a monocyclic non-aromatic radical containing one or more such heteroatoms which is covalently linked to another such radical or to a monocyclic carbocyclic radical.
- radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups.
- substituted as applied to any moiety herein means substituted with up to four compatible substituents, each of which independently may be, for example, (C r C 6 )alkyl, (C r C 6 )alkoxy, hydroxy, hydroxy(CrC 6 )alkyl, mercapto, mercaptoCCVC ⁇ alkyl, (Ci-C 6 )alkylthio, phenyl, halo (including fluoro, bromo and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), oxo, -COOH, -COOR A , -COR A , -SO 2 R A , -CONH 2 , -SO 2 NH 2 , -CONHR A , -SO 2 NHR A , -CONR A R B , -SO 2 NR A R B , -NH 2
- side chain of a natural or non-natural alpha-amino acid refers to the group R 1 in a natural or non-natural amino acid of formula NH 2 -CH(R 1 )-COOH.
- side chains of natural alpha amino acids include those of alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, histidine, 5-hydroxylysine, 4- hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, a-aminoadipic acid, ⁇ -amino-n-butyric acid, 3,4- dihydroxyphenylalanine, homoserine, ⁇ -methylserine, ornithine, pipecolic acid, and thyroxine.
- Natural alpha-amino acids which contain functional substituents, for example amino, carboxyl, hydroxy, mercapto, guanidyl, imidazolyl, or indolyl groups in their characteristic side chains include arginine, lysine, glutamic acid, aspartic acid, tryptophan, histidine, serine, threonine, tyrosine, and cysteine.
- R 2 in the compounds of the invention is one of those side chains, the functional substituent may optionally be protected.
- salts includes base addition, acid addition and quaternary salts.
- Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g.
- salts including pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g.
- esters of the invention are converted by intracellular esterases to the carboxylic acid. Both the esters and carboxylic acids may have aurora kinase inhibitory activity in their own right.
- the compounds of the invention therefore include not only the ester, but also the corresponding carboxylic acid hydrolysis products.
- R 1 is a carboxylic acid group.
- compounds of this class may be administered as the carboxylic acid or a salt thereof, it is preferred that they be generated in the cell by the action of an intracellular esterase on a corresponding compound in which Fl 1 is an ester group.
- the ester group R 1 must be one which in the compound of the invention is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group.
- Intracellular carboxylesterase enzymes capable of hydrolysing the ester group of a compound of the invention to the corresponding acid include the three known human enzyme isotypes hCE-1 , hCE-2 and hCE-3. Although these are considered to be the main enzymes, other enzymes such as biphenylhydrolase (BPH) may also have a role in hydrolysing the ester.
- BPH biphenylhydrolase
- the carboxylesterase hydrolyses the free amino acid ester to the parent acid it will, subject to the N- carbonyl dependence of hCE-2 and hCE-3 discussed below, also hydrolyse the ester motif when covalently conjugated to the inhibitor.
- the broken cell assay described herein provide a straightforward, quick and simple first screen for esters which have the required hydrolysis profile. Ester motifs selected in that way may then be re-assayed in the same carboxylesterase assay when conjugated to the inhibitor via the chosen conjugation chemistry, to confirm that it is still a carboxylesterase substrate in that background.
- R 9 may be, for example, methyl, ethyl, n- or iso-propyl, n-, sec-, or tert-butyl, cyclohexyl, allyl, phenyl, benzyl, 2-, 3- or 4-pyridy I methyl, N-methylpiperidin-4-yl, tetrahydrofuran-3-yl or methoxyethyl.
- R 9 is cyclopentyl.
- Macrophages are known to play a key role in inflammatory disorders through the release of cytokines in particular TNF ⁇ and IL-1 (van Roon ef a/ Arthritis and Rheumatism, 2003, 1229- 1238). In rheumatoid arthritis they are major contributors to the maintenance of joint inflammation and joint destruction. Macrophages are also involved in tumour growth and development (Naldini and Carraro Curr Drug Targets lnflamm Allergy, 2005, 3-8 ). Hence agents that selectively target macrophage cell proliferation could be of value in the treatment of cancer and autoimmune disease. Targeting specific cell types would be expected to lead to reduced side-effects.
- the inventors have discovered a method of targeting aurora kinase inhibitors to macrophages which is based on the observation that the way in which the esterase motif is linked to the aurora kinase inhibitor determines whether it is hydrolysed, and hence whether or not it accumulates in different cell types. Specifically it has been found that macrophages contain the human carboxylesterase hCE-1 whereas other cell types do not.
- ester group Ri be hydrolysable by intracellular carboxylesterase enzymes
- identity of the side chain group R 2 is not critical.
- amino acid side chains examples include:
- C 1 -C 6 alkyl phenyl, 2,- 3-, or 4-hydroxyphenyl, 2,- 3-, or 4-methoxyphenyl, 2,- 3-, or 4-pyridylmethyl, benzyl, phenylethyl, 2-, 3-, or 4-hydroxybenzyl, 2,- 3-, or 4-benzyloxybenzyl, 2,- 3-, or 4- C 1 -C 6 alkoxybenzyl, and benzyloxy(C 1 -C 6 alkyl)- groups;
- AIk is a (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl group optionally interrupted by one or more -O-, or -S- atoms or -N(R 7 )- groups [where R 7 is a hydrogen atom or a (CrC 6 )alkyl group], n is 0 or 1 , and R 6 is an optionally substituted cycloalkyl or cycloalkenyl group; a benzyl group substituted in the phenyl ring by a group of formula -OCH 2 COR 8 where R 8 is hydroxyl, amino, (C 1 -C 6 JaIkOXy, phenyl(CrC 6 )alkoxy, (CrCeJalkylamino, di((C 1 -C 6 )alkyl)amino, phenyl(C.i-C 6 )alkylamino, the
- heterocyclic(C 1 -C 6 )alkyl group either being unsubstituted or mono- or di-substituted in the heterocyclic ring with halo, nitro, carboxy, (C 1 -C 6 JaIkOXy, cyano, (Ci-C 6 )alkanoyl, trifluoromethyl (Ci-C 6 )alkyl, hydroxy, formyl, amino, (Ci-C 6 )alkylamino, dKCrCeJalkylamino, mercapto, (C 1 - C 6 )alkylthio, hydroxy(C 1 -C 6 )alkyl, or (Ci-C 6 )alkylphenylmethyl; and
- each of R a , R b and R c is independently hydrogen, (C
- R 0 is hydrogen and R 3 and R b are independently phenyl or heteroaryl such as pyridyl; or
- R 0 is hydrogen, (CrCeJalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C
- R 3 , R b and R 0 together with the carbon atom to which they are attached form a tricyclic ring (for example adamantyl); or
- R a and R b are each independently (C r C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C r C 6 )alkyl, or a group as defined for R 0 below other than hydrogen, or R 3 and R b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic ring, and R 0 is hydrogen, -OH, -SH, halogen, -CN, -CO 2 H, (C 1 -C 4 )perfluoroalkyl, -CH 2 OH, - CO 2 (C 1 -C 6 )alkyl, -O(C r C 6 )alkyl, -O(C 2 -C 6 )alkenyl, -S(C 1 -C 6 )alkyl, -SO(C r C 6 )alkyI, - SO 2 (
- R 2 groups include hydrogen (the glycine "side chain"), benzyl, phenyl, cyclohexylmethyl, cyclohexyl, pyridin-3-ylmethyI, tert-butoxymethyl, iso-butyl, sec-butyl, tert- butyl, 1-benzylthio-1-methylethyl, 1-methylthio-1-methylethyl, 1-mercapto-1-methylethyl, and phenylethyl.
- Presently preferred R 2 groups include phenyl, benzyl, and iso-butyl.
- esters with a slow rate of carboxylesterase cleavage are preferred, since they are less susceptible to pre-systemic metabolism. Their ability to reach their target tissue intact is therefore increased, and the ester can be converted inside the cells of the target tissue into the acid product.
- ester is either directly applied to the target tissue or directed there by, for example, inhalation, it will often be desirable that the ester has a rapid rate of esterase cleavage, to minimise systemic exposure and consequent unwanted side effects.
- R 2 is CH 2 R Z (R z being the mono-substituent)
- R z being the mono-substituent
- This radical arises from the particular chemistry strategy chosen to link the amino acid ester motif R 1 CH(R 2 )NH- to the quinoline or quinazoline ring system.
- the chemistry strategy for that coupling may vary widely, and thus many combinations of the variables Y, L 1 , X 1 and z are possible.
- the precise combination of variables making up the linking chemistry between the amino acid ester motif and the quinoline or quinazoline ring system will often be irrelevant to the primary binding mode of the compound as a whole. On the other hand, that linkage chemistry will in some cases pick up additional binding interactions with the enzyme.
- z may be 0 or 1 , so that a methylene radical linked to the quinoline or quinazoline ring system is optional;
- examples of AIk 1 and AIk 2 radicals, when present, include
- CH 2 C CCH 2 .
- Additional examples of AIk 1 and AIk 2 include -CH 2 W-,
- AIk 1 and AIk 2 include divalent cyclopropyl, cyclopentyl and cyclohexyl radicals.
- L 1 when n is O, the radical is a hydrocarbon chain (optionally substituted and perhaps having an ether, thioether or amino linkage). Presently it is preferred that there be no optional substituents in L 1 .
- L 1 is a divalent mono- or bicyclic carbocyclic or heterocyclic radical with 5 - 13 ring atoms (optionally substituted).
- L 1 is a divalent radical including a hydrocarbon chain or chains and a mono- or bicyclic carbocyclic or heterocyclic radical with 5 - 13 ring atoms (optionally substituted).
- Q may be, for example, a divalent phenyl, naphthyl, cyclopropyl, cyclopentyl, or cyclohexyl radical, or a mono-, or bi-cyclic heterocyclic radical having 5 to13 ring members, such as piperidinyl, piperazinyl, indolyl, pyridyl, thienyl, or pyrrolyl radical, but 1 ,4-phenylene is presently preferred.
- a divalent phenyl, naphthyl, cyclopropyl, cyclopentyl, or cyclohexyl radical or a mono-, or bi-cyclic heterocyclic radical having 5 to13 ring members, such as piperidinyl, piperazinyl, indolyl, pyridyl, thienyl, or pyrrolyl radical, but 1 ,4-phenylene is presently preferred.
- L 1 , m and p may be 0 with n being 1. In other embodiments, n and p may be 0 with m being 1. In further embodiments, m, n and p may be all 0. In still further embodiments m may be 0, n may be 1 with Q being a monocyclic heterocyclic radical, and p may be 0 or 1.
- AIk 1 and AIk 2 when present, may be selected from -CH 2 -, -CH 2 CH 2 -, and -CH 2 CH 2 CH 2 - and Q may be 1 ,4-phenylene.
- R 4 is hydrogen; halogen, for example fluoro or chloro; or C 1 -C 4 alkoxy for example methoxy, ethoxy or n- or iso-propoxy. Presently it is preferred that it be methoxy.
- Ring A may be, for example a piperidine, piperazine, pyridine, pyrimidine, pyrazoline, triazoline, furan, thophene, pyrrole, thiazole, isothiazole, oxazole, isoxazole, or thiadiazole ring.
- Currently preferred rings A are optionally substituted 1 ,4-phenylene, 1 ,3-phenylene and 5-membered heterocycles such as A-K, the 6-membered heterocycle L, and 9-membered heterocycles such as M-O:
- any of these rings A may contain optional substitutents such as, halo, nitrile, trifluoromethyl, C 1 -C 6 alkoxy such as methoxy and ethoxy, C 1 -C 6 alkyl such as methyl, ethyl and n-and isopropyl, although presently it is preferred that ring A be unsubstituted (except for the radicals -L 2 [B]r and -L 2 [C] r , if present).
- Rings B and C may be present in the compounds (IA) and (IB), or absent, according to whether the integers r and s are 1 or 0.
- ring B may be any of the ring options discussed above in relation to ring A, for example optionally substituted phenyl and can also include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl.isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,3,4-triazolyl, 1 ,2,5-triazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4- oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,3,4-thiadiazole, pyridyl, pyrimidinyl,
- Preferred rings are: 1 ,4-phenylene, 1 ,3-phenylene, pyridyl, pyrimidinyl and pyrazinyl.
- Substituents which may be present in rings B and C include halo, nitrile, trifluoromethyl, C 1 -C 6 alkoxy such as methoxy and ethoxy, C 1 -C 6 alkyl such as methyl, ethyl and n-and isopropyl, although presently it is preferred that rings B and C be unsubstituted.
- linker radical L 2 represents a radical of formula -(Alk 3 ) a -Z-(Alk 4 ) b - wherein AIk 3 and AIk 4 when present represent optionally substituted, straight or branched, C 1 -C 3 alkylene, C 2 -C 3 alkenylene or C 2 -C 3 alkynylene radicals.
- methylene (-CH 2 -) is preferred for AIk 3 , when present, and for AIk 4 , when present.
- both a and b may be 0, so that both AIk 3 and AIk 4 are absent, or a may be 1 b may be 0 so that only AIk 3 is present, or a may be 0 and b may be 1 so that only AIk 4 is present.
- Z preferably represents an amido (-CONR B -) link in either orientation, wherein R B is hydrogen.
- a particular subset of compounds of the invention consists of those of formula (IC) or a salt, N- oxide, hydrate or solvate thereof:
- R 1 , R 2 , Y, L , X and z are as defined and discussed above.
- a particularly preferred subset of compounds of the invention consists of those of formula (ID) or a salt, N-oxide, hydrate or solvate thereof:
- R 1 and R 2 are as defined and discussed, and the radical L 3 is -CH 2 CH 2 CH 2 -, or - CH 2 CH 2 CH 2 CH 2 -.
- the compounds with which the invention is concerned may be prepared by coupling the alpha amino acid ester R 1 R 2 CHNH 2 WUh the main fragment (NIA) or (HIB) of the desired compound:
- J represents a leaving group, such as a tosyl or chloro group, which facilitates the formation of the desired N-Y bond.
- the intermediates (NA) and (HB) may be built up in stages, for example by a condensation reaction between a chloro-quinoline compound (IVA) or (IVB) and the desired side chain precursors (V).
- reaction product may then be modified by removal of the protecting group P and the addition of the linker moiety J-Y-L 1 -.
- the compounds with which the invention is concerned are inhibitors of the Aurora kinase family, namely Aurora kinases A and/or B and/or C, particularly Aurora A and/or Aurora B, and are therefore of use in the treatment of cell proliferative disease, such as cancer, in humans and other mammals.
- the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing treatment. Optimum dose levels and frequency of dosing will be determined by clinical trial.
- the compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties.
- the orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
- Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
- the tablets may be coated according to methods well known in normal pharmaceutical practice.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
- suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats
- emulsifying agents for example lecithin, sorbitan monooleate, or acacia
- non-aqueous vehicles which may include edible oils
- almond oil fractionated coconut oil
- oily esters such as glycerine, propy
- the drug may be made up into a cream, lotion or ointment.
- Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
- the drug may be formulated for aerosol delivery for example, by pressure-driven jet atomizers or ultrasonic atomizers, or preferably by propellant- driven metered aerosols or propellant-free administration of micronized powders, for example, inhalation capsules or other "dry powder" delivery systems.
- Excipients such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, and fillers (e.g. lactose in the case of powder inhalers) may be present in such inhaled formulations.
- the drug may be made up into a solution or suspension in a suitable sterile aqueous or non aqueous vehicle.
- Additives for instance buffers such as sodium metabisulphite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.
- the active ingredient may also be administered parenterally in a sterile medium.
- the drug can either be suspended or dissolved in the vehicle.
- adjuvants such as a local anaesthetic, preservative and buffering agent can be dissolved in the vehicle.
- Mass spectra were obtained over the range m/z 150 to 850 at a sampling rate of 2 scans per second or 1 scan per 1.2 seconds using LC/MSD Quad SW ESI interface. Data were integrated and reported using OpenLynx and OpenLynx Browser software.
- the 4-chloroquinoline derivative (A) can be synthesized by methods described in Org. Synth. CoI. Vol. 3, 272 (1955) and US006143764A (Kirin Beer Kabushiki Kaisha). This key intermediate is then used as detailed in Scheme 1
- N-[4-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-phenyl]-benzamide (0.56g, 1.17mmol) and 10% Pd/C (O.O ⁇ g) in 10% cyclohexene/ethanol (80ml) was heated under reflux for 3 hours.
- the Pd/C catalyst was filtered off through a pad of celite, washing twice with methanol. The filtrate was concentrated under reduced pressure to yield a yellow solid (0.34g, 75% yield), m/z 387 [M+H] + .
- the ethyl acetate layer was washed with brine and dried over magnesium sulphate before evaporation under reduced pressure.
- the crude product was purified by column chromatography eluting with methanol/DCM to provide the title compound (0.015g, 80%).
- the crude residue was diluted with DCM (50ml) and washed with 1 M HCI, 1 M NaHCO 3 and brine before drying over magnesium sulphate and evaporation under reduced pressure.
- the crude product was purified by column chromatography eluting with methanol/DCM to provide the title compound (0.066g, 24%) as a pale yellow solid.
- Examples 8-12 were prepared by using the appropriate 1-chloro-4-bromobutane in Stage 3 of Scheme 2.
- Examples 13-16 were prepared by methods shown previously in Scheme 2, using methyl-4- bromobutyrate at Stage 3. This key intermediate is then used with the corresponding (S)-Phe- cyclopentyl ester and (S)-Leu-cyclopentyl ester as detailed in Scheme 4.
- Y- 33 P-ATP and Aurora-A were incubated in a myelin basic protein (MBP)-coated Flashplate® to generate a scintillation signal.
- MBP myelin basic protein
- the plates were formatted to contain the inhibitor, controls, positive control (staurosporin) and blanks. After incubation at 37 0 C for 1 hour and a subsequent wash procedure, the plates were read on a TopCount-NXTTM.
- the 384-well basic Flashplate® and the v- 33 P-ATP were obtained from PerkinElmer Life Sciences, Boston, MA.
- IC50 values were determined by non-linear regression analysis, after fitting the data point results to the equation for sigmoidal dose response with variable slope (% activity against log concentration of compound), using Graphpad Prism software.
- Range A IC50 ⁇ 2000nM
- Range B IC50 from 200OnM to 10,00OnM
- Range C IC50 >10,000nM.
- the Aurora-B enzyme assay follows the identical protocol as Aurora-A.
- Cancer cell lines (U937, HCT116 and HUT) growing in log phase were harvested and seeded at 1000 cells/well (200ul final volume) into 96-well tissue culture plates. Following 24h of cell growth cells were treated with compounds (final concentration of 2OuM). Plates were then re- incubated for a further 72h before a sulphorhodamine B (SRB) cell viability assay was conducted according to Skehan 1990 J Natl Cane Inst 82, 1107-1112.
- SRB sulphorhodamine B
- % inhibition 100-((S'/S o )x100) where S' is the signal in the presence of inhibitor and S 0 is the signal in the presence of DMSO.
- IC50 values were determined by non-linear regression analysis, after fitting the results of eight data points to the equation for sigmoidal dose response with variable slope (% activity against log concentration of compound), using Graphpad Prism software.
- Range A IC50 ⁇ 1000nM
- Range B IC50 from 100OnM to 500OnM
- Range C IC50 >5000nM.
- the resulting supernatant was used as a source of esterase activity and could be stored at -8O 0 C until required.
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Abstract
Les composés de formule (IA) ou (IB) sont des inhibiteurs de l'activité de la kinase Aurora et sont utiles dans le traitement de maladies de prolifération de cellules et d'autres affections associées à une activité inadéquate de la kinase Aurora, dans lesquelles formules R1 est un groupe acide carboxylique (-COOH) ou un groupe ester qui est hydrolysable par une ou plusieurs enzymes estérases intracellulaires en un groupe acide carboxylique ; R2 est la chaîne latérale d'un acide aminé alpha naturel ou synthétique ; Y est une liaison, -C(=O)-, -S(=O)2-, -C(=O)O-, -C(=O)NR3-, -C(=S)-NR3, -C(=NH)-NR3 ou -S(=O)2NR3- , R3 étant un hydrogène ou un alkyle en C1-C6 facultativement substitué ; L1 et L2 sont des radicaux de liaison tels que définis dans les revendications ; X1 représente une liaison, -NR4C(=O)-, -C(=O)NR4-, -NR4C(=O)-NR5-, -NR4S(=O)2- ou -S(=O)2NR4-, R4 et R5 étant indépendamment un hydrogène ou un alkyle en C1-C6 facultativement substitué ; -C(=O)- ; ou -S(=O)2- ; z est 0 ou1 ; R4 est un alcoxy en C1-C4, un hydrogène ou un halo; r et s sont indépendamment 0 ou 1 ; et les cycles A, B et C sont des cycles carbocycliques ou hétérocycliques monocycliques ou bicycliques ou des systèmes cycliques ayant jusqu'à 12 atomes de cycle.
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GB0509224.2 | 2005-05-05 | ||
GBGB0509224.2A GB0509224D0 (en) | 2005-05-05 | 2005-05-05 | Inhibitors of intracellular enzymatic activity |
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PCT/GB2006/001644 WO2006117570A1 (fr) | 2005-05-05 | 2006-05-04 | Dérivés de quinoléine servant d'inhibiteurs d'une enzyme de type kinase |
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Cited By (24)
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US7432377B2 (en) | 2004-01-16 | 2008-10-07 | Wyeth | Quinoline intermediates of receptor tyrosine kinase inhibitors and the synthesis thereof |
EP1964578A3 (fr) * | 2005-05-05 | 2008-11-05 | Chroma Therapeutics Limited | Conjugués d'un ester d'aminoacide alpha et d'un médicament hydrolysables par la carboxylestérase. |
WO2010097586A1 (fr) | 2009-02-27 | 2010-09-02 | Chroma Therapeutics Ltd. | Inhibiteurs d'enzymes |
US7973164B2 (en) | 2006-03-02 | 2011-07-05 | Astrazeneca Ab | Quinoline derivatives |
US8119655B2 (en) | 2005-10-07 | 2012-02-21 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
US8138347B2 (en) | 2007-05-18 | 2012-03-20 | Glaxosmithkline Llc | Quinoline derivatives as PI3 kinase inhibitors |
US8153643B2 (en) | 2004-10-12 | 2012-04-10 | Astrazeneca Ab | Quinazoline derivatives |
US8278450B2 (en) | 2007-04-18 | 2012-10-02 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
WO2014001247A1 (fr) | 2012-06-26 | 2014-01-03 | Bayer Pharma Aktiengesellschaft | N-[4-(quinolin-4-yloxy)cyclohexyl(méthyl)](hétéro)arylcarboxamides utilisables en tant qu'antagonistes des récepteurs aux androgènes, leur production et leur utilisation en tant que médicaments |
US9353122B2 (en) | 2013-02-15 | 2016-05-31 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
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US9556426B2 (en) | 2009-09-16 | 2017-01-31 | Celgene Avilomics Research, Inc. | Protein kinase conjugates and inhibitors |
US9688688B2 (en) | 2013-02-20 | 2017-06-27 | Kala Pharmaceuticals, Inc. | Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof |
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WO2019170543A1 (fr) | 2018-03-07 | 2019-09-12 | Bayer Aktiengesellschaft | Identification et utilisation d'inhibiteurs d'erk5 |
US10752640B2 (en) | 2014-08-01 | 2020-08-25 | Nuevolution A/S | Compounds active towards bromodomains |
US10766907B2 (en) | 2016-09-08 | 2020-09-08 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
WO2020234103A1 (fr) | 2019-05-21 | 2020-11-26 | Bayer Aktiengesellschaft | Identification et utilisation d'inhibiteurs de kras |
CN112778217A (zh) * | 2019-11-08 | 2021-05-11 | 沈阳化工研究院有限公司 | 一种喹唑啉类化合物及其应用 |
WO2021152113A1 (fr) | 2020-01-31 | 2021-08-05 | Bayer Aktiengesellschaft | Dérivés de 2,3-benzodiazépines substitués |
US11542492B2 (en) | 2009-12-30 | 2023-01-03 | Celgene Car Llc | Ligand-directed covalent modification of protein |
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US7432377B2 (en) | 2004-01-16 | 2008-10-07 | Wyeth | Quinoline intermediates of receptor tyrosine kinase inhibitors and the synthesis thereof |
US8153643B2 (en) | 2004-10-12 | 2012-04-10 | Astrazeneca Ab | Quinazoline derivatives |
EP1964578A3 (fr) * | 2005-05-05 | 2008-11-05 | Chroma Therapeutics Limited | Conjugués d'un ester d'aminoacide alpha et d'un médicament hydrolysables par la carboxylestérase. |
EP1964577A3 (fr) * | 2005-05-05 | 2008-11-05 | Chroma Therapeutics Limited | Conjugués d'un ester d'aminoacide alpha et d'un médicament hydrolysables par la carboxylestérase |
US8119655B2 (en) | 2005-10-07 | 2012-02-21 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
US7973164B2 (en) | 2006-03-02 | 2011-07-05 | Astrazeneca Ab | Quinoline derivatives |
US8278450B2 (en) | 2007-04-18 | 2012-10-02 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
US8138347B2 (en) | 2007-05-18 | 2012-03-20 | Glaxosmithkline Llc | Quinoline derivatives as PI3 kinase inhibitors |
US8404837B2 (en) | 2007-05-18 | 2013-03-26 | Glaxosmithkline Llc | Quinoline derivatives as P13 kinase inhibitors |
US8633187B2 (en) | 2007-05-18 | 2014-01-21 | Glaxosmithkline Llc | Quinoline derivatives as PI3 kinase inhibitors |
US8785433B2 (en) | 2007-05-18 | 2014-07-22 | Glaxosmithkline Llc | Quinoline derivatives as PI3 kinase inhibitors |
WO2010097586A1 (fr) | 2009-02-27 | 2010-09-02 | Chroma Therapeutics Ltd. | Inhibiteurs d'enzymes |
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