MXPA01011361A - Quinoline derivatives as inhibitors of mek enzymes - Google Patents
Quinoline derivatives as inhibitors of mek enzymesInfo
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- MXPA01011361A MXPA01011361A MXPA/A/2001/011361A MXPA01011361A MXPA01011361A MX PA01011361 A MXPA01011361 A MX PA01011361A MX PA01011361 A MXPA01011361 A MX PA01011361A MX PA01011361 A MXPA01011361 A MX PA01011361A
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Abstract
A compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for inhibition of MEK in a mammal with a MEK mediated disease wherein:n is 0-1;Y is selected from -NH-, -O-, -S-, or -NR7- where R7 is alkyl of 1-6 carbon atoms R6 is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups;or is a pyridinyl, pyrimidinyl, or phenyl ring;wherein the pyridinyl, pyrimidinyl, or phenyl ring may be substituted with one, two or three specified substituents;or R6 is a group -R8-X-R9 where R8 is a divalent cycloalkyl of 3 to 7 carbon atoms, which may be optionally further substituted with one or more alkyl of 1 to 6 carbon atom groups;or is an optionally pyridinyl, pyrimidinyl, or phenyl ring;wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally further substituted with one or more specified substitutents, X is selected from CH2, -NH-, -O-, -S- or -NR5- where R5 is alkyl of 1-6 carbon atoms, and R9 is a group (CH2)mR10 where m is 0, or an integer of from 1-3 and R10 is an optionally substituted aryl or optionally substituted cycloalkyl ring of up to 10 carbon atoms, or R10 is a heterocyclic ring containing 1 or 2 oxygen atoms and optionally one or more substitutents;and R1, R2, R3 and R4 are each independently selected from hydrogen or various specified organic groups. Novel compounds are also described and claimed.
Description
QUINOLINE DERIVATIVES AS MEK ENZYME INHIBITORS DESCRIPTION OF THE INVENTION The present invention relates to the use of certain quinoline derivatives in the preparation of medicaments, in particular as inhibitors of specific kinase enzymes, especially MEK enzymes, as well as quinoline derivatives new. Additional aspects of the invention include pharmaceutical compositions and methods of treating proliferative disease such as cancer using such compounds. Cancer is a disease in which the cells grow and divide in an uncontrolled way. This uncontrolled growth arises from abnormalities in signal transduction pathways that are used by normal cells to regulate cell growth and division in response to several signaling molecules. Normal cells do not proliferate unless stimulated so for specific signal molecules located on the outside of the cellular derivative of nearby cells or tissues. Growth factors bind to the cell membrane through specific receptors that have intrinsic enzymatic activity. These receptors transmit the growth signal to cell nuclei through a series of signaling proteins. In cancer, a number of defects in the signal trajectories are apparent. For example, cancer cells can produce their own growth factors which bind to their affine receptors, resulting in an autochroneous bond, or the receptors can be mimicked or overexpressed leading to an increase in continuous signal to proliferate. In addition, negative regulators of cell growth can be lost. Oncogenes are cancer-related genes that often encode abnormal versions of signal path components, such as receptor tyrosine kinases, serine-threonine kinases, or signaling molecules to the 3 'end such as ras genes, which code for intimately related small guanine nucleotide binding proteins that hydrolyze the binding of guanosine triphosphate (TP) to guanosine diphosphate (GDP). Ras proteins are active in promoting cell growth and transformation when they bind to GTP and are inactivated when they bind to GDP. The transforming mutants of p21ras are defective in their GTPase activity and therefore remain in the active GTP bound state. The oncogen ras is known to play an integral role in certain cancers, and has been found to contribute to the formation of more than 20% of all human cancer cases. When activated by ligand, the cell surface receptors which bind to the mitogenic response, such as the growth factor rewards, initiate a chain of reactions which lead to the activation of the guanine nucleotide exchange activity in ras When in its active GTP binding state, a number of proteins directly interact with ras in the plasma membrane resulting in signal transmission through several different pathways. The best characterized determinant protein is the product of the raf proto-oncongen. The interaction of raf and ras is a key regulatory step in the control of cell proliferation. The ras-mediated activation of the serine-threonine kinase raf in turn activates the double MEK specificity (MEK1 and MEK2), which is the activator towards the 5 'end intermediate of the activated mitogen protein kinase (MAPKs known as extracellular signal that regulates the protein kinases or ERK1 and ERK2). To date, no substrate of MEK or MAPK have been identified, however recent reports indicate that MEK can also be activated by other signal proteins towards the 5 'end such as MEK kinase or MEKK1 and PKC. Activated MPAK moves and accumulates in the nucleus, where it can phosphorylate and activate transcription factors such as El -1 and Sap, leading to improved expression of genes such as those for c-fos. The ras-dependent MEK-MAPK cascade is one of the path signaling keys responsible for transmitting and amplifying mitogenic signals from the cell surface to the nucleus, resulting in changes in cell expression and gene expression. This ubiquitous trajectory seems essential because of normal cell proliferation and constitutive activation of this trajectory sufficient to induce cell transformation. The transformation mutants of p21ras are constitutively active, resulting in raf, MEK and MAPK activity and cellular transformation. Inhibition of MEK activity using either antisense raf, a dominant negative MEK mutant or the PD098059 selective inhibitor has been shown to block the growth and morphological transformation of ras transformed fibroblasts. The mechanism of activation of raf, MEK and MAPK is through phosphorylation in specific serine, threonine or tyrosine residues. Activated Raf and other kinases phosphorylate MEK1 in S218 and S222 and MEK2 in S222 and S226. This results in the activation of MEK and subsequent phosphorylation and activation of ERK1 in T190 and Y192 and ERK2 in T183 and Y185 by the double MEK specificity. While MEK can be activated by a number of protein kinases, and activates phosphorylated MAPKs and activated a number of substrate proteins including transcription factors and other protein kinases, the MEKs seem specific and unique activators of MAPKs and could act as a point focal for cross-cascade regulation. The isoforms MEK1 and MEK2 show unusual specificity and also contain a proline-rich insert between the catalytic subdomains IX and X that are not present in any of the other known members of the MEK family. These differences between MEK and other protein kinases, together with the known role of MEK in proliferative signaling, suggest that it may be possible to discover and employ selective MEK inhibitors as therapeutic agents for use in proliferative disease. WO 98/43960 describes a range of 3-cyano quinoline compounds and their use in the treatment of cancer. Certain of the compounds are shown as inhibitors of the Epidermal Growth Factor Receptor of Kinase, and to inhibit the growth of the cancer cell. Other quinoline derivatives include fluorine derivatives, which inhibit the effect of growth factors such as VEGF are described in WO98 / 13350. This invention provides compounds that are inhibitors of the kinase activity of MEK and as a result, they can produce therapeutically useful effects in the treatment of proliferative disease and in particular cancer. According to the present invention there is provided a compound of the formula (I) 0) or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the inhibition of MEK in a mammal with an MEK-mediated disease in where: n is 0-1; Y is selected from -NH-, -0-, -S-, or -NR7- wherein R7 is alkyl of 1-6 carbon atoms R6 is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may be substituted with one, two or three groups selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2- 6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenyl, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms, and benzoylamino; or R6 is a group -R8-X-R9 wherein R8 is a divalent cycloalkyl of 3 to 7 carbon atoms, which may be optionally further substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl, or divalent phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally further substituted with one or more groups selected from halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino from 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms and benzoylamino; wherein X is selected from CH2, -NH-, -O-, -S-, or -NR5- wherein R5 is alkyl of 1-6 carbon atoms, and R9 is a group (CH2) mR10 wherein m is 0, or an integer of 1-3 and R10 is an optionally substituted aryl or optionally substituted cycloalkyl ring of up to 10 carbon atoms, or R10 is a heterocyclic ring containing 1 or 2 oxygen atoms and optionally one or more substituents; R1, Rz, R3 and R4 are each independently selected from hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, C? _3 alkyl, -NR1: LR12 (where Ra? And R12, which may be the same or different , each represents hydrogen or C? -3 alkyl), or a group R13-X1- (CH2) X wherein x is 0 to 3, X1 represents -O-, -CH2-, -OCO-, carbonyl, - S-, -SO-, -S02-, -NR14CO-, -CONR15-, -S02NR15-, or -NR18 wherein R, R, 15, R, 16, R 117 'and R, 118B each independently represent hydrogen, C? -3 alkyl or C? -3-C2-3 alkyl-alkoxy) and R13 is selected from one of the following sixteen groups: 1) C1-5 alkyl which may be unsubstituted or may be substituted with one or more selected groups of hydroxy, fluorine and amino;
2) C ?5X2COR19 alkyl (wherein X2 represents -0- or -NR-20 wherein R represents hydrogen, C? -3 alkyl or C? _3-alkoxy of C2_3 alkyl) and R19 represents -NR21R22- or -OR23- (wherein R21, R22 and R23 which may be the same or different each represents hydrogen, C? -3 alkyl or C? -3-C2-3 alkyl alkoxy)); 3) C? -5X3R24 alkyl (wherein X3 represents -O-,
-S-, -SO-, -SO2-, -OCO-, -NR25CO-, -CONR26- -S02NR27-, -NR8SO- or -NR29- (wherein R25, R26, R27, R28 and R29 each represent independently hydrogen, C1-3alkyl or C1-3alkoxy-C2-3alkyl) and R24 represents hydrogen, C1-3alkyl, cyclopentyl, cyclohexyl or a saturated 5- or 6-membered heterocyclic group with one or two heteroatoms, independently selected from 0, S and N, whose C? _3 alkyl group can support one or two substituents selected from oxo, hydroxy, halogen and C? - alkoxy and whose cyclic group can support one or two substituents selected from oxo, hydroxy , halogen, C? _ / hydroxyalkyl alkyl of C? - and C? _4 alkoxy); 4) alkyl of C? _5X4-alkyl of C? _X5R30 (wherein X4 and X5 which may be the same or different are each -0-,
-S-, -SO-, -SO2-, -NR31CO-, -CONR32- SO2NR33-, -NR34S02- or
-NR35- (wherein R31, R32 R33 R34 and R35 each independently represent hydrogen, C? -alkyl or C? -3-C2-3alkoxy) and R30 represents hydrogen or C? _3); 5) C1-5R36 alkyl (wherein R36 is a 5- or 6-membered saturated heterocyclic group with one or two heteroatoms, independently selected from 0, S and N, whose heterocyclic group can support one or two substituents selected from oxo, hydroxy , halogen, C? _4 alkyl, Ci-j hydroxyalkyl, and C? -4 alkoxy); 6) (CH2) qX6R37 (where q is an integer from 0 to 5, X6 represents a direct bond, -O-, -S-, -SO-, -SO; -,
-NR38C0-, -CONR39- -SO2NR40-, -NR1S02- or -NR42- (where R38,
R39, R4s, R41 and R42 each independently represents hydrogen, C1-3alkyl or C3-3alkyl-C2-3alkyl) and R37 is a phenyl group, a pyridone group or an aromatic heterocyclic group of 5 or 6 members with 1 to 3 heteroatoms selected from 0, N and S, whose phenyl, pyridone or aromatic heterocyclic group can carry up to 5 substituents selected from hydroxy, halogen, amino, C? _4 alkyl, C? - alkoxy, hydroxyalkyl C1-4, C? _4 hydroxyalkoxy, C?-Alkylamino aminoalkyl of
C1-4, carboxy, cyano, -CONR 43 -Rr > 44 NR, 4"5C, 0R, 4" 6 (where R "%
R 45 and R 46, which may be the same or different, each represents hydrogen, C alquilo_alkyl or C?-C3-3alkyl-C2-3alkyl));
7) C2-6R36 alkenyl (wherein R35 is as defined above); 8) C2-eR36 alkynyl (wherein R36 is as defined above); 9) X7R47 (wherein X7 is -S02-, -O- or -C0NR48R49- (wherein R48 and R49, which may be the same or different each represents hydrogen, C? _3 alkyl or C? -3 alkoxy) -alkyl of C2_3) and R47 represents C1-5 alkyl which may be unsubstituted or may be substituted with one or more groups selected from hydroxy, fluoro and amino) with the proviso that when X7 is -S02- , X1 is -O-, when X7 is -O-, X1 is carbonyl, when X7 is -CONR48R49-, X1 is -0- or NR18 (wherein R48, R49 and R18 are as defined above); 10) C2-6R37 alkenyl (wherein R37 is as defined above); 11) C2-6 alkynyl 37 (wherein R37 is as defined above); 12) C2-6 alkenyl 8 37 (wherein X8 represents -O-, -S-, -SO-, -S02-, -NR50CO-, -CONR51-, -S02NR52-, -NR53S02- or -NR54- ( wherein R50, R51, R52 and R54 each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxy-C2-3 alkyl) and R37 is as defined above); 13) C2-6 alkynyl 9R37 (wherein X9 represents -O-, -S-, -SO-, -SO2-, -NR55CO-, -CONR56-, -S02NR57-, -NR58S02- or -NR59- (in where R, R, R, R and R, each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxy-C2-3 alkyl) and R37 is as defined above); 14) d3X alkyl-C1-3R alkyl 37 (where X rl O
represents -O-, -S-, -SO-, -S02-, -NR60CO-, -CONR61-, -S02NR6:
, 63 64 NRooS02- O -NR (wherein R, R, 6β1, R 61"2, R, 603J and R, 6M4 each independently represents hydrogen, C1-3alkyl or C3-alkyl-alkyloxy of C2_3) and j7 is as defined above); 15) R36 (wherein R36 is as defined above); and 16) C? -3X10 alkyl-C1-3R36 alkyl (wherein X10 and R36 are as defined) defined above.) In particular, the compounds of the formula (I) or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the inhibition of MEK in a mammal with an MEK mediated disease are compounds wherein : n is 0-1; Y is selected from -NH-, -0-, -S-, or -NR7- wherein R7 is alkyl of 1-6 carbon atoms R6 is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms, or is a pyridinyl, pyrimidinyl, or phenyl ring, wherein the pyridinyl, pyrimidinyl, or phenyl ring may be substituted. optionally being mono-, di-, or tri- substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms , azido, hydroxyalkyl of 1-6 carbon atoms, ethyl halo, alkoxymethyl of 2-7 carbon atoms, alkanoyloxy ethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms carbon, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms , dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms, and benzoylamino; or R6 is a group -R8-X-R9 wherein R8 is a divalent cycloalkyl of 3 to 7 carbon atoms, which may be optionally further substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl or divalent phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally further substituted with one or more groups selected from halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms , azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino from 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms, and benzoylamino; wherein X is selected from -NH-, -O-, -CH2 or -NR5- wherein R5 is alkyl of 1-6 carbon atoms, and R9 is a group (CH2) m10 wherein m is 0, or an integer of 1-3 and R10 is an optionally substituted aryl ring or optionally substituted cycloalkyl of up to 10 carbon atoms, or R10 is a heterocyclic ring containing 1 or 2 oxygen atoms and optionally one or more substituents; R1, R2, R3 and R4 are each independently selected from hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, C1-3 alkyl, -NR1XR12 (wherein R11 and R12, which may be the same or different, each represents hydrogen or C1-3 alkyl), or a group R13-X1- (CH2) X wherein x is 0 to 3, X1 represents -0-, -CH2-, -OCO-, carbonyl, -S-, - SO-, -S02-, -NR1C0-, -S02NR16-, -NR17S02- or
-NR 18 (wherein R 14, R 16, R 17 and R 18 each independently represents hydrogen, C?-3 alkyl or C?-3-alkyl-O 2 -3 -alkoxy) and R 13 is selected from one of the sixteen groups listed previously. Certain compounds of the formula (I) are novel and these form a further aspect of the invention. In particular, the invention provides a compound of the formula (IA) comprising a compound of the formula (I) as defined above, with the proviso that Rd is different from a pyridinyl, pyrimidinyl or phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally mono-di-, or tri- substituted with a substituent selected from the group consisting of halogen, alkyl of 1-3 carbon atoms, alkoxy of 1-3 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, amino. Particular embodiments of the compounds of the formula (IA) are compounds of the formula (I) wherein n is 0-1; Y is selected from -NH-, -O-, -S-, or -NR7- wherein R7 is alkyl of 1-6 carbon atoms R6 is cycloalkyl of 3 to 7 carbon atoms, which may be optionally 'substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl or phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring is substituted with one, two or three groups selected from the group consisting of alkyl of 4-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms , azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, benzoyl, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 atoms of carbon, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms, and benzoylamino; or R ° is a group -R8-X-R9 wherein R8 is a divalent cycloalkyl of 3 to 7 carbon atoms, which may be optionally further substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a divalent pyridinyl, pyrimidinyl, or phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally further substituted with one or more groups selected from halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy , trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms, and benzoylamino; wherein X is selected from CH2, -NH-, -O-, -S-, -CH2 or -NR5- wherein R5 is alkyl of 1-6 carbon atoms,
R9 is a group (CH2) mR10 wherein m is 0, or an integer of 1-3 and R10 is an optionally substituted aryl ring or optionally substituted cycloalkyl of up to 10 carbon atoms, or R10 is a heterocyclic ring containing 1 or 2 oxygen atoms and optionally one or more substituents; R1, R2, RJ R4 are as defined above. Suitable pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulfuric acid. A preferred, pharmaceutically acceptable salt is a hydrochloride salt. The alkyl portion of the alkyl, alkoxy, alkanoyloxy, alkoxymethyl, alkanoyloxymethyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, carboalkoxy, carboalkyl, alkanoylamino aminoalkyl, alkylaminoalkyl, N, N-dicycloalkylaminoalkyl, hydroxyalkyl, and alkoxyalkyl substituents include straight chain as well as carbon chains branched The cycloalkyl portions of the N-cycloalkyl-N-alkylaminoalkyl and N, N-dicycloalkylaminoalkyl substituents include simple carbocycles as well as carbocycles containing alkyl substituents. The alkenyl portion of the alkenyl, alkenyloxymethyl, alkenyloxy, alkenylsulfonamido substituents include straight chain as well as branched carbon chains and one or more sites of unsaturation. The alkynyl portion of the alkynyl, alkyloxyloxymethyl, alkynylsulfonamido, alkynyloxy substituents include straight chain as well as branched carbon chains and one or more sites of unsaturation. The carboxy is defined as a -C02H radical. Carboalkoxy of 2-7 carbon atoms is defined as a -C02R radical ", where R" is an alkyl radical of 1-6 carbon atoms. The carboalkyl is defined as a radical -COR ", wherein R" is an alkyl radical of 1-6 carbon atoms. The alkanoyloxy is defined as a -OCOR radical ", wherein R" is an alkyl radical of 1-6 carbon atoms. The alkanoyloxymethyl is defined as a radical R "C02CH2-, wherein R" is an alkyl radical of 1-6 carbon atoms. The alkoxymethyl is defined as a radical R "0CH2-, wherein R" is an alkyl radical of 1-6 carbon atoms. Alkylsulfinyl is defined as a radical R "S0-, wherein R" is an alkyl radical of 1-6 carbon atoms. Alkylsulfonyl is defined as a radical R "S02-, wherein R" is an alkyl radical of 1-6 carbon atoms. The alkylsulfonamido, alkenylsulfonamido, alkynylsulfonamido are defined as a radical R "S02NH-, wherein R" is an alkyl radical of 1-6 carbon atoms, an alkenyl radical of 2-6 carbon atoms, or an alkynyl radical of 2- 6 carbon atoms, respectively. N-alkylcarbamoyl is defined as a radical R "NHC0-, where R" is an alkyl radical of 1-6 carbon atoms. N, N-dialkylcarbamoyl is defined as a radical R "RtNCO-, where R" is an alkyl radical of 1-6 carbon atoms, R 'is an alkyl radical of 1-6 carbon atoms and R', and R They can be the same or different.When X is substituted, it is preferred that it be mono-, di-, or tri- substituted, with monosubstituted being more preferred.It is preferred that of the substituents, Ri, R2, R3 and 'R4 by at least one is hydrogen and it is more preferred that two or three are hydrogen An azacycloalkyl-N-alkyl substituent refers to a monocyclic heterocycle containing a nitrogen atom in which a straight or branched chain alkyl radical is substituted. Morpholino-N-alkyl substituent is a morpholine ring substituted at the nitrogen atom with a straight or branched chain alkyl radical.A piperidino-N-alkyl substituent is a piperidine ring substituted at one of the nitrogen atoms with a radical straight or branched chain alkyl. N-N-alkyl-piperazino-N-alkyl is a piperazine ring substituted on one of the nitrogen atoms with a straight or branched chain alkyl group and on the other nitrogen atom with a straight or branched chain alkyl radical. When any group contains an alkyl portion, the alkyl portion preferably contains 1-6 carbon atoms, more preferably 1-4 carbon atoms, particularly methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl or tert-butyl. When any group contains an alkenyl or alkynyl portion, the alkenyl or alkynyl portion preferably contains 2-6 carbon atoms, more preferably 2-4 carbon atoms. The term "aryl" used herein includes aromatic carbocyclic compounds, for example, from 6 to 20 atoms such as phenyl or naphthyl. The term "heterocyclic" refers to ring structures conveniently of 5 to 20 atoms in size, up to four of which are heteroatoms such as oxygen, sulfur and nitrogen. The ring structures can be monocyclic, bi- or tricyclic and be aromatic or non-aromatic in character, including the possibility that part of a ring system has aromatic character while other parts do not. The compounds of this invention may contain an asymmetric carbon; in such cases, the compounds of this invention cover the racemate and the individual R and S enantiomers, and in the case where more than one asymmetric carbon exists, the individual diastereomers, their individual racemates and enantiomers. Suitable examples of the groups Y are -NH-. In a preferred embodiment, the group R6 is a group -R8-X-R9 wherein R8, X and R9 are as defined above. Conveniently X is oxygen. Preferably n is 0. Examples of optional substituents for the aryl groups R10 include one or more groups selected from hydroxy; halo; nitro; cyano; carboxy; C6-C6 alkoxy; C? -6 alkyl; C2-e alkenyl; C2-6 alkynyl; C 2-6 alkenyloxy, C 2-6 alkynyloxy / C 3-6 cycloalkyl amino, C 1-6 mono- or di-alkylamino, heterocyclyl optionally substituted with d-6 alkyl or oxo; C (0) Ra, C (0) ORa, S (0) dRa; NRaC (0) R; C (0) NRaS (0) dRb, C (0) NRaRb; NRaC (0) NRbRc; NRaS (0) dRb; or N (S) (0) dR) S (0) dRc wherein d is 0, 1 or 2 and Ra, Rb and Rc are independently selected from hydrogen, C? -6 alkyl, aryl, C3_6 cycloalkyl or heterocyclyl, and wherein any Alkyl, alkenyl or alkynyl group or moiety contained within the substituent of an R10 may themselves be optionally substituted with one or more groups selected from hydroxy; cyano; nitro; halo; carboxy; carboalkoxy of 2-7 carbon atoms, cycloalkyl of C3-6, heterocyclyl optionally substituted with C1-6alkyl or oxo; C (O) Rd, C (O) 0Rd NRdRe, S (O) eRd, NRdC (O) Re; C (O) NRdRe; NRdC (0) ) NReRf; NRdS (0) eRe where e is 0, 1 or 2 and Rd, Re are independently selected from hydrogen or substituted C? -6 alkyl or optionally with one or more groups selected from hydroxy; cyano; nitro; halo; carboxy; carboalkoxy of 2-7 carbon atoms, C3-6 cycloalkyl, heterocyclyl optionally substituted with Ci-β or oxy alkyl; C (0) R9, C (0) 0RgNRgRh, S (0) eRg, NRhC (0) Rg; C (0) NRgRh, NRgC (0) RhRi, NRgS (0) eRh where e is as defined above and Rg, Rh and R1 are independently selected from hydrogen or C? -6 alkyl- Alternatively, two substituents on atoms adjacent ones can be joined to form the second ring of a bicyclic ring system wherein said second ring is optionally substituted with one or more of the groups listed above for R10 and optionally contains one or more heteroatoms. In some embodiments, the substitution level in the R10 group is a chain substituted with complex substituents. Thus, for example, a substituent may comprise a substituted alkyl chain that is optionally interposed with heteroatoms such as groups of sub-formula (i) -Xa-R70- (Xb-R71) q- (Xc) s-R72 ( i) wherein Xa, Xb and Xc are independently selected from any of the groups listed above for X1, R70 and R71 are independently selected from alkylene groups of C6-6, alkenylene of C2-6 or alkynylene of C2-6, any of which it may be optionally substituted with hydroxy; cyano; nitro; halo; carboxy, carboalkoxy of 2-7 carbon atoms or C3-6 cycloalkyl, "R72 is hydrogen or an alkyl group of Ci-e, C2-e alkenyl of O2-6 any of which may be optionally substituted with hydroxy cyano; nitro; halo; carboxy or cycloalkyl of C3-6 / yqys are independently 0 or 1. Particular examples of the substituents for R10 include halo such as fluorine and chlorine, alkylamino of C? _e, cyano, carboxy, carboalkoxy of to 7 carbon atoms, or alkoxy such as methoxy, optionally substituted, in particular by C (0) NRaRb wherein Ra and Rb are as defined above Preferably R10 is an aryl group substituted by an optionally substituted alkoxy group and higher Preferably, R10 is an aryl group substituted by a substituted alkoxy group Preferably n is 0. Particular examples of the R10 groups include phenyl or cycloalkyl of 3-8 and preferably of 6 carbon atoms which are substituted in the ortho position or or meta and preferably with an ortho position. Particularly preferred substituents are alkoxy groups, in particular methoxy. When R10 is phenyl or substituted cycloalkyl, m is preferably 0. Examples of heterocyclic rings R10 include 3-7 members in the ring, above two of which may be oxygen atoms. Such groups include:
wherein each R65 is independently selected from hydrogen or C? _s alkyl and especially methyl. In such compounds, m is conveniently 1, 2 or 3. Further examples of heterocyclic groups R10 include pyridyl, thiazolyl, pyrazinyl, pyrimidinyl, oxadiazole, and in particular is thiazolyl. Additional suitable substituents for R8 include those listed above for pyridyl, pyrimidinyl and phenyl R6 groups. Thus a preferred sub-group of the compounds of the formula (I) are compounds of the formula (II).
R4 (II) wherein R1, R2, R3 and R4 are as defined above and R66 is Ci-β alkyl in particular methyl and R67 is selected from hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of -6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1- 6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 atoms of carbon, and benzoylamino. Conveniently R67 is hydrogen, Examples of preferred groups for R1, R2, R3 and R4 are set forth in WO 98/13350. Preferably x is 0. Conveniently R 13 is selected from one of the following sixteen groups: 1) C 1-5 alkyl which may be substituted or unsubstituted with one or more fluorine atoms, or C 2 -C 5 alkyl which may be substituted or unsubstituted with one or more groups selected from hydroxy and amino; 2) C2-3X2COR19 alkyl (wherein X2 is as defined above and R19 represents -NR2XR22- or -OR23- (wherein R21, R22 and R23 which may be the same or different each represents hydrogen, C-alkyl? -2 or alkoxyethyl of .C1-2)); 3) C2-4X3R24 alkyl (wherein X3 is as defined above and R24 represents hydrogen, alkyl
C? -3, cyclopentyl, cyclohexyl or a saturated heterocyclic group of 5 or 6 members with one or two heteroatoms, independently selected from O, S and N, whose C? _3 alkyl group can support one or two substituents selected from oxo, hydroxy, halogen and C1-3 alkoxy, and whose cyclic group can support one or two substituents selected from oxo, hydroxy, halogen, C? -3 alkyl, hydroxyalkyl of C? -3 and C? -3 alkoxy). 4) C2_3X4 alkyl-C2_3X5R30 alkyl (wherein X4 and X5 are as defined above and R30 represents hydrogen or C3_3 alkyl); 5) C1-5R70 alkyl (wherein R70 is a 5- or 6-membered saturated heterocyclic group with one or two heteroatoms, independently selected from 0, S and N, whose heterocyclic group is attached to C1-5alkyl via a carbon atom and whose heterocyclic group can support one or two substituents selected from oxo, hydroxy, halogen, C? -3 alkyl, C1-3 hydroxyalkyl and C? _3 alkoxy) or C2_5 R71 alkyl (wherein R71 is a 5- or 6-membered saturated heterocyclic group with one or two heteroatoms of which one is N and the other is independently selected from O, S and N, whose heterocyclic group is attached to C2-5 alkyl through a nitrogen atom and whose heterocyclic group can support one or two substituents selected from oxo, hydroxy, halogen, C1-3 alkyl, hydroxyC1-3 alkyl, and C1-3 alkoxy); 6) (CH2) qX6R37 (where X6 is as defined above, q is an integer from 0 to 4, if X6 is a direct link and q is 0, 2 or 3 if X6 is different from a direct link; is a phenyl group, a pyridone group or a 5- or 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from 0, N and S, of which preferably one is N, whose phenyl group, pyridone group or aromatic heterocyclic group can be substituted as defined above, advantageously substituted with up to 2 substituents as defined above, most preferably substituted with a substituent selected from the group of substituents as defined above); 7) C4_5R72 alkenyl (wherein R72 represents R70 or R7X as defined above);
) alkynyl of C4_5R (where R 72 represents R 0 or
R as defined above); 9) X7R47 (wherein X7 is as defined above and R47 represents C? _3 alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro and amino); 10) C3-5R37 alkenyl (wherein R37 is as defined above); 11) C3-5R37 alkynyl (wherein R37 is as defined above); 12) C4-5X8R37 alkynyl (wherein X8 and R37 is as defined above); 13) C4_5X9R30 alkynyl (wherein X9 and R3s are as defined above); 14) C? _3X10 alkyl-C1-3R37 alkyl (wherein X10 and R37 are as defined above); 15) R36 (wherein R36 is as defined above); and 16) C1-3R36 alkyl (wherein X11 and R36 are as defined above). Advantageously R 13 is selected from one of the following eleven groups: 1) C 1-4 alkyl which may be substituted or unsubstituted with one or more fluorine atoms, or C 2-4 alkyl which may be substituted or unsubstituted with one or two groups selected from hydroxy and amino; 2) C2_3X2COR19 alkyl (wherein X2 is as defined above and R19 represents -NR21R22- or -OR23- (wherein R21, R22 and R23 which may be the same or different each represents hydrogen, CL-2 O alkyl) C2_2 alkoxyethyl)); 3) C2-3X3R24 alkyl (wherein X3 is as defined above and R24 is a group selected from C? -, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl alkyl whose group is attached to X3 through a carbon atom and whose C? _3 alkyl group can support one or two substituents selected from oxo, hydroxy, halogen and C? _2 alkoxy and whose cyclopentyl, cyclohexyl, pyrrolidinyl or piperidinyl group can carry a substituent selected from oxo, hydroxy, halogen, alkyl, C? _2, hydroxyalkyl of C? _2 and alkoxy of C? _2); 4) C2_3X4 alkyl-C2-3X5R30 alkyl (wherein X4 and X5 are as defined above) and R30 represents hydrogen or C? -2 alkyl); 5) C alquilo _4R70 alkyl (wherein R70 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-) ilo and 1,3-dithian-2-yl, whose group is attached to C? -4 alquiloalkyl via a carbon atom and whose group can carry one or two substituents selected from oxo, hydroxy, halogen, C-alkyl ? 2, C? -2 hydroxyalkyl and C? 2 alkoxy) or C2-R71 alkyl (wherein R71 is a group selected from morpholino, thiomorpholino, pyrrolidin-1-yl, piperazin-1-yl and piperidino whose group it can carry one or two substituents selected from oxo, hydroxy, halogen, C? _2 alkyl, C? _2 hydroxyalkyl and C? _2 alkoxy); and 6) (CH2) qX6R37 (where X6 is as defined above, q is an integer from 1 to 3 if X6 is a direct link, and q is 2 or 3 if X6 is different from a direct link, and R37 is a phenyl group, a pyridone group or a 5- or 6-membered aromatic heterocyclic group with 1 or 2 heteroatoms selected from O, N and S, of which preferably one is N, whose phenyl group, pyridone group or aromatic heterocyclic group may be substituted as it was previously defined, preferably substituted with a substituent selected from hydroxy, halogen, C? _2 alkyl, C? -2 alkoxy, C? -2 hydroxyalkyl, C? -2 hydroxyalkoxy, carboxy, cyano, -CONR43R44 and - NR45COR46 (wherein R43, R44, R45 and R46, which may be the same or different, each represents hydrogen or C? -2alkyl)); 7) C4-5R71 alkenyl (wherein R71 is as defined above);
8) C4-5R71 alkynyl (wherein R71 is as defined above); C? -3X10 alkyl-C1-3R37 alkyl (wherein X10 and R are as defined above); 10) R36 (wherein R36 is as defined above); and 11) C 1-3 -alkyl-C 1-3 alkyl (wherein X J and R, 36 are as defined above). Preferably R13 is selected from one of the following nine groups: 1) C1-3 alkyl which may be substituted or unsubstituted with one or more fluorine atoms, or C2-3 alkyl which may be substituted or unsubstituted with one or two selected groups of hydroxy and amino; 2) 2- (3, 3-dimethylureido) ethyl, 3- (3, 3-dimethylureido) propyl, 2- (3-methylureido) ethyl, 3- (3-methylureido) propyl, 2-ureidoethyl, 3-ureidopropyl, 2- (N, N-dimethylcarbamoyloxy) ethyl, 3- (N, N-dimethylcarbamoyloxy) -propyl, 2- (N-methylcarbamoyloxy) ethyl, 3- (N-methylcarbamoyloxy) propyl, 2- (carba oyloxy) ethyl, - (carbamoyloxy) propyl; 3) Alkyl of C2-X3R24 (wherein X3 is as defined above and R24 is a group selected from C? -2alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl, the group of which is linked to X3 through an carbon and whose C? -2 alkyl group can support one or two substituents selected from oxo, hydroxy, halogen and C? -2 alkoxy and whose cyclopentyl, cyclohexyl, pyrrolidinyl or piperidipyl group can carry a substituent selected from oxo, hydroxy, halogen, C? _2 alkyl, C? -2 hydroxyalkyl and C? -2 alkoxy); 4) C2-3X4 alkyl-C2-3X5R32 alkyl (wherein X4 and X5 are as defined above) and R30 represents hydrogen or C? -2alkyl); 5) C? -2R 'alkyl (wherein R70 is a group selected from pyrrolidinyl, piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan) -2-yl and 1,3-dithian-2-yl, whose group is linked to C? -2 alquiloalkyl via a carbon atom and whose group can carry a substituent selected from oxo, hydroxy, halogen, alkyl, C? -2, hydroxyalkyl of C? -2 and alkoxy of C? _2) or C2-3R59 alkyl (wherein R59 is a group selected from morpholino, thiomorpholino, piperidino, piperazin-1-yl and pyrrolidin-1-yl) , which group may carry one or two substituents selected from oxo, hydroxy, halogen, C? - alkyl, C hidro-2 hidro hydroxyalkyl and C-2-2 alco alkoxy); 6) (CH2) qX6R37 (where X6 is as defined above, q is an integer from 1 to 3 if X6 is a direct link, and q is 2 or 3 if X6 is different from a direct link, and R37 is a group selected from phenyl, a pyridone, pyridyl, imidazolyl, thiazolyl, thienyl, triazolyl and pyridazinyl group, preferably selected from phenyl, a pyridone, pyridyl, imidazolyl, thiazolyl and triazolyl group whose group may be substituted with a substituent selected from hydroxy, halogen, C? -2 alkyl, C? -2 alkoxy, C? _2 hydroxyalkyl, hydroxyalkoxy
C? -2, carboxy, cyano, -CONR? R44 and -NR 445D, C0R > 446 ° (wherein R, 43, R, 44, R45 and R46 are as defined above); 7) C? _3Xalkyl-Cal3R3J7alkyl (wherein XrlO and R, 37 are as defined above) 8) R, 3J6D (wherein R 36 is as defined above); and 9) C? -3X1 alkyl: C1-3 alkyl L, 3-560 (wherein X 11
and R36 are as defined above). More preferably R13 represents 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, l-methylimidazol-2-yl ethyl, 4-pyridylmethyl, 2- (4-pyridyl) ethyl, 3- (4-pyridyl) propyl, 2- ((N- (1-methylimidazol-4-ylsulfonyl) -N-methyl) amino) ethyl, 2- ((N- (3-morpholinopropylsulfonyl) -N-methyl) amino) ethyl, 2- (( N-methyl-N-4-pyridyl) amino) ethyl, 2- (4-oxido orfolino) ethyl, 3- (4-oxidomorpholino) propyl, 2- (4-oxo-1,4-dihydro-l-pyridyl) ethyl, 3- (4-oxo-l, 4-dihydro-l-pyridyl) propyl, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2- (N, N- dimethylsulfamoyl) ethyl, 2- (N-methylsulfamoyl) ethyl, (1,3-dioxolan-2-yl) methyl, 2- (1,3-dioxolan-2-yl) ethyl, 2- (2-methoxyethylamino) ethyl, 2- (2-hydroxyethylamino) ethyl, 3- (2-methoxyethylamino) propyl, 3- (2-hydroxyethylamino) propyl, 2- (1, 2,4-triazol-1-yl) ethyl, 2- (1, 2) , 4-triazol-4-yl) ethyl, 3- (1,2,4-triazol-1-yl) propyl, 3- (1, 2,4-triazol-4-yl) propyl, 2- (4- pyridyloxy) ethyl, 3- (4-pyridyloxy) ) propyl, 2- (4-pyridylamino) ethyl, 3- (4-pyridylamino) propyl, 2- (2-methylimidazol-1-yl) ethyl, 3- (2-methylimidazol-1-yl) propyl, 2- ( 5-methyl-1,2,4-triazol-1-yl) ethyl, 3- (5-methyl-1,2,4-triazol-1-yl) propyl, morpholino, N-methylpiperazinyl, piperazinyl,
2- (N, N-dimethylamino) ethyl, 3- (N, N-dimethylamino) propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2- (piperazin-1-yl) ethyl, - (piperazin-1-yl) propyl, 2- (pyrrolidin-1-yl) ethyl, 3- (pyrrolidin-1-yl) propyl, 2-methoxyethyl, 3-methoxypropyl, 2- (imidazol-1-yl) ethyl , 2- (1,2,3-triazol-1-yl) ethyl, 2- (1, 2, 3-triazol-2-yl) ethyl, 3- (imidazol-1-yl) propyl, 3- (1 , 2, 3-triazol-1-yl) propyl, 3- (1, 2, 3-triazol-2-yl) propyl, 2-thio orpholinoethyl, 3-thiomorpholinopropyl, 2- (1, 1-dioxothiomorpholino) ethyl, 3- (1,1-dioxothiomorpholino) propyl, 2- (2-methoxyethoxy) ethyl, 2- (4-methylpiperazin-1-yl) ethyl, 3- (4-methylpiperazin-1-yl) propyl, 3- (methylsulfinyl) ) propyl, 3- (methylsulfonyl) propyl, 2- (methylsulfinyl) ethyl, benzyl, 2-sulfamoylethyl or 2- (methylsulfonyl) ethyl ..
Especially R 13 represents methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2- (methylsulfonyl) ethyl, 2- (methylsulfonyl) ethyl, 2- ( N, N-dimethylsulfamoyl) ethyl, 2- (N-methylsulfamoyl) ethyl, 2-sulfamoylethyl, 2- (N, N-dimethylamino) ethyl, 3- (N, N-dimethylamino) propyl, 2-morpholinoethyl, 3-morpholinopropyl , 2-piperidinoethyl, 3-piperidinopropyl, 2- (piperazin-1-yl) ethyl, 3- (piperazin-1-yl) propyl, 2- (pyrrolidin-1-yl) ethyl, 3- (pyrrolidin-1-yl) ) propyl, (1,3-dioxolan-2-yl) methyl, 2- (1,3-dioxolan-2-yl) ethyl, 2- (2-methoxyethylamino) ethyl, 2- (2-hydroxyethylamino) ethyl, - (2-methoxyethylamino) propyl, 3- (2-hydroxyethylamino) propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl, 2- (imidazol-1-yl) ethyl, 2- (1,2,3-triazol-1-yl) ethyl, 2- (1, 2, 3-triazol-2-yl) ethyl, 2- (1,2,4-triazol-1-yl) ) ethyl, 2- (1, 2, 4-triazol-4-yl) ethyl, 4-pyridylmethyl, 2- (4-pyridyl) ethyl, 3- ( 4-pyridyl) propyl, 3- (3-pyridyl) propyl, benzyl, 2- (4-pyridyloxy) ethyl, 2- (4-pyridylamino) ethyl, or 2- (4-oxo-1,4-dihydro) -pyridyl) ethyl. More especially R 13 represents methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2- (methylsulfinyl) ethyl, 2- (methylsulfonyl) ethyl, 2- (N, N-dimethylsulfamoyl) ethyl, 2- (N-methylsulfamoyl) ethyl, 2-sulfamoylethyl, 2- (N, N-dimethylamino) ethyl, 3- (N, N-dimethylamino) propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, 2- (piperazin-1-yl) ethyl, 3- (piperazin-1-yl) ropyl, 2- (pyrrolidin-1-yl) ethyl, 3- (pyrrolidine -1-yl) propyl, (1,3-dioxolan-2-yl) methyl, 2- (1,3-dioxolan-2-yl) ethyl, 2- (2-methoxyethylamino) ethyl, 2- (2-hydroxyethylamino) ) ethyl, 3- (2-methoxyethylamino) propyl, 3- (2-hydroxyethylamino) propyl, 2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl, 2- (imidazol- 1-yl) ethyl, 2- (1,2,3-triazol-1-yl) ethyl, 2- (1, 2, 3-triazol-2-yl) ethyl, 2- (1,2,4-triazole -1-yl) ethyl, 2- (1, 2, 4-triazol-4-yl) ethyl, 4-pyridylmethyl, 2- (4-pyridyl) ethyl, 3- (4-pyridyl) propyl, benzyl, 2- (4-pyridyloxy) ethyl, 2- (4-pyridylamino) ethyl or 2- (4-oxo-l, 4-dihydr? -l-pyridyl) ethyl. In particular R1 and R4 are conveniently hydrogen. Examples of the preferred groups for R 2 include C 1 6 alkoxy. The group R3 is suitably selected from hydrogen or C? -6 alkoxy. Preferably R2 and R3 are Ci-e alkoxy and are preferably methoxy. An additional preferred group for R2 or R3 is 3-morpholinopropyloxy.
Particular examples of the compounds of the formula (I) are listed in Table 1. Table 1
where * indicates the point of union. The compounds of the formula (I) are conveniently prepared by reacting a compound of the formula (III)
R (III)
wherein R1 ', R2', R3 ', R4' represent R1, R2, R3 and R4 respectively as defined in relation to formula (I) or a precursor thereof, and Zt is a leaving group, with a compound of the formula (IV) HY (CH2) nR6 '(IV) wherein Y, X and n are as defined in relation to the formula (I), and R6' is a group R6 as defined in relation to the formula ( I) or a precursor thereof; and thereafter if it is necessary or desired to convert the precursor groups R1 ', R2', R3 ', R4' and R6 'to the groups of the formula R1, R2, R3, R4 and R6 respectively, or to convert a group R1 , R2, R3, R4 and R6 to a different group. Suitable leaving groups for Z 'include halogen such as bromine or chlorine, or a mesylate or tosylate group. In particular Z 'is chlorine.
The reaction is conveniently carried out in an organic solvent such as an alcohol for example propanol or cyclohexanol at elevated temperatures, for example 50 to 150 ° C, for example, at about 105 ° C or 110 ° C. The conversion reactions in which the precursor groups R1 ', R2', R3 ', R4' are converted to the groups of the formula R1, R2, R3 and R4 respectively, or groups R1, R2, R3 and R4 are converted to such a different group that can be carried out using conventional chemistry as described in the literature. The particular precursor groups R1 ', R2', R3 ', R4' are groups of the formula R13'-X1- (CH2) X wherein x and X1 are as defined below, and R13 'is C1-5 alkyl which it is substituted with halo other than fluorine, and in particular chlorine or bromine. The chloro group can easily be converted into many other R13 groups as defined in relation to claim 1. Such compounds are novel and form a further aspect of the invention. They may have activity similar to those of the compounds of the formula (I) in their own right and therefore may be used in place of a compound of the formula (I). Thus the invention further provides a compound of the formula (IB) (IB) wherein Y, n and R6 are as defined in the above and at least one of R1", R2", R3"or R4" is a group R13 '-X1- (CH2) x wherein X1 and x are as in the above and R13' is alkyl substituted by chlorine or bromine; and the rest are groups R1, R2, R3 and R4 respectively. Conversion reactions similarly involve R6 'groups which can be carried out using conventional chemistry. For example, substituent groups in a group R6 can be changed for example, by changing acids to esters or amides, etc. A further method for producing compounds of the formula (I) wherein R6 is a group -R8-X-R9 is to react a compound of the formula (V)
? H
(V) wherein R1 ', R2', R3 ', R4' are as defined in relation to the formula (III) R8, X, Y and n are as defined in relation to the formula (I) with a compound of the formula (VI) R9 -Z "(VI) wherein R9 'is a group R9 as defined in relation to the formula (IV) or a precursor thereof and Z" is a leaving group; and after that if it is necessary or desired to convert the precursor groups R1 ', R2', R3 ', R4' and R9 'to groups of the formula R1, R2, R3, R4 and R9 respectively, or to convert a group R1, R2 , R3, R4 and R9 to a different group. Suitable leaving groups for Z "include halogen such as a bromine or chlorine, or a mesylate or tosylate group The conversion reactions are as described above The reaction is conveniently carried out in an organic solvent such as DMF at elevated temperatures , for example from 40 to 120 ° C, for example at about 80 ° C. Preferably, however, R1, R2, R3, R4 'and R6' are groups R1, R2, R3, R4 and R5 respectively and is not required Subsequent processing The compounds of the formula (IV) are either known compounds (see for example Rev. Chim.
(Bucharest) (1988), 39 (6), 477-82 and DD 110651: 74.01.05) or can be prepared from known compounds using conventional methods. The compounds of the formula (VI) are also known compounds or can be prepared from known compounds by conventional methods. Certain compounds of the formula (III) are described in WO98 / 13350 and others may be prepared from known compounds by analogous methods. For example, they are conveniently prepared by reacting a compound of the formula (V)
wherein R1, R2, R3 and R4 are as defined in relation to formula (I), with a compound of formula (VI) (vi: wherein Z 'is as defined above and R 67
is an additional leaving group such as sulfonyl chloride. A particular example of a compound of the formula (VI) is thionyl chloride.
The reaction is conveniently carried out in an organic solvent such as dimethylformamide, at elevated temperatures, for example 50 to 150 ° C, and conveniently at the reflux temperature of the solvent. The compounds of the formula (V) can be prepared from known compounds by conventional methods such as those described in WO 98/13350. The compounds of the formula (IV) are also either known compounds (see, for example, Rev. Chim. (Bucharest (1988), 39 (6), 477-82, DD110651: 74.01.05) or can be compound preparations known by conventional methods Alternatively the compounds of the formula (III) can be prepared by heating a tetraborofluoroate salt of the formula (VII)
(vp)
wherein R1 ', R2', R3 ', R4' and Z "are as defined in relation to formula (III), suitable temperatures will be of the order of 150 to 200 ° C and preferably to about 170 ° C. of the formula (VII) are conveniently prepared by reacting a compound of the formula (VIII)
(vpi) wherein R, R > 2 ', R, 3', R and defined in relation to formula (III); with fluoroboric acid in the presence of a nitrite salt such as an alkali metal nitrite such as sodium nitrile. The reaction is conveniently carried out in an organic solvent such as tetrahydrofuran. Suitable temperatures are temperatures below -10 ° C to 15 ° C and preferably at about 10 ° C. The compounds of the formula (VIII) in turn can be obtained by hydrolysis and decarboxylation of the compounds of the formula (IX) (DQ where R68 is an alkyl group such as t-butyl, and R1 ', R2', R3 ' , R4 'and z' are as defined in relation to formula (III) .The reaction is conveniently carried out by an organic acid such as TFA in the presence of a scavenger such as triethylsilane.A base such as ammonia can then be used to generate the free base of the formula (VIII): Moderate temperatures, conveniently ambient temperatures are used The compounds of the formula (IX) can be prepared by reacting a compound of the formula (X)
(X) wherein R1 ', R2', R3 ', R4' are as defined in relation to the formula (III) with a compound of the formula (XI) Re & -0H (XI) wherein R68 is as defined in relation to formula (X), in the presence of diphenylphosphoryl azide. The reaction is conveniently carried out in an organic solvent such as DMF or DCM at elevated temperatures, for example 80 to 120 ° C. The compounds of the formula (X) can be obtained by deesterification of the compounds of the formula (XII)
(XII) wherein R1 ', R2', R3 ', R4' and z 'are as defined in relation to the formula (III) and R69 is an alkyl group of C? _6 such as ethyl. The deesterification is effected by alkaline hydrolysis of the compound of the formula (XII) for example using sodium hydroxide as illustrated below.
The compounds of the formula (XII) are known compounds (see for example WO 98343960, USP5318963 and EP-A-304158) or can be obtained from known compounds by analogous methods. The compounds of the invention are useful in inhibiting the activity of the enzyme MEK and can be used in the treatment of proliferative disease. They will conveniently be in the form of a pharmaceutical composition, in combination with a pharmaceutically acceptable carrier. Such compositions form a further aspect of the invention. The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (e.g. as creams, ointments, gels, or aqueous or oily solutions or suspensions), by administration by inhalation (for example as a finely divided powder or a liquid aerosol), by administration by insufflation (for example as a finely divided powder) or by administration parenterally (for example as a sterile aqueous or oily solution by intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository by rectal dosing).
The compositions of the invention can be obtained by conventional procedures, using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavors and / or preservatives. Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl p-hydroxybenzoate, and antioxidants, such as ascorbic acid. The tablet formulations may be uncoated or coated either to modify their disintegration and subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and / or appearance, in any case, using conventional coating agents and well-controlled procedures. known in the art. The compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil. Aqueous suspensions generally contain the active ingredient in fine powder form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example, polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxyketanol, or products of condensation of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethylene oxyketanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, antioxidants (such as ascorbic acid), coloring agents, flavoring agents and / or sweetening agents (such as sucrose, saccharin or aspartame). Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). Thickening agent such as beeswax, hard paraffin or cetyl alcohol Sweetening agents such as those set forth above, and flavoring agents may be added to provide an appetizing oral preparation.These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. The powders and dispersible granules suitable for the preparation of a suspension aqueous n by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents can be, for example, naturally occurring gums such as acacia gum, or tragacanth gum, natural phosphatides such as soy, lecithin, and partial esters or esters derived from fatty acids and hexitol anhydrides (for example monooleate of sorbitan) and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents. The syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain an emollient, preservative, flavoring and / or coloring agent. The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic, parenterally-acceptable diluent or solvent, for example, a solution in 1,3-butanediol. The suppository formulations can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures, but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols. Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, can generally be obtained by formulating an active ingredient with a conventional, topically acceptable vehicle or diluent, using the conventional procedure well known in the art. The compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30 μ or much smaller, the powder itself comprises either the single active ingredient or diluted with one or more physiologically acceptable carriers such as lactose. The powder by insufflation is then conveniently retained in a capsule containing, for example, 1 to 50 mg of the active ingredient for use with a turbo-inhaler device, such as is used by insufflation of the known agent sodium cromoglycate. The compositions for administration by inhalation may be in the form of a conventional pressurized aerosol classified to deliver the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as hydrocarbons or volatile fluorinated hydrocarbons may be used and the aerosol device is conveniently classified to classify a measured amount of the active ingredient. For additional information on the Formulation the reading refers to Chapter 25.2 in Volume 5 of the Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press 1990. The amount of the active ingredient that is combined with one or more excipients to produce a single dose form will necessarily vary depending on the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, 0.5 mg to 2 g of the active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For additional information on the Routes of Administration and Dosage Regimens, the reading refers to Chapter 25.3 in Volume 5 of Comprenhensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press 1990. The size of the dose for therapeutic or prophylactic purposes of a compound of Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the administration route, according to well-known medicine principles. As mentioned above, the compounds of Formula I are useful in treating diseases or medical conditions that are due solely or in part to the effects of MEK enzymes. Using a compound of Formula I for therapeutic or prophylactic purposes will generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per kg of body weight is received, if required in divided doses. . In general lower doses will be administered when a parenteral route is used. Thus, for example, by intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg of body weight will generally be used. Similarly, by administration by inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg of body weight will be used. However, oral administration is preferred. In a further aspect, the invention provides a method for treating proliferative disease by administering a compound of the formula (I), preferably a compound of the formula (IA) as described above, or a pharmaceutical composition as described above. Yet a further aspect of the invention provides the use of a compound of the formula (I) as defined above, in the preparation of a medicament for use in the inhibition of MEK enzymatic activity and in particular for the treatment of proliferative disease such as cancer. The invention will now be particularly described by way of example. Preparation of 4-chloro-6,7-dimethoxy-3-fluoro-quinoline
X & Step 4 d + BF4 - - °? * Step 1 4-Chloro-6,7-dimethoxy-3-quinolinecarboxylic acid ester (ex RSL) (50 g) in ethanol (400 ml) was suspended and 2M sodium hydroxide was added. aqueous (400 ml) with stirring was stirred for 24 hours. The reaction mixture was diluted with water (400 ml), cooled in an ice / water bath and brought to pH4 by careful addition of concentrated hydrochloric acid. The resulting solid was removed by filtration, washed with water and dried in a vacuum oven at 50 ° C. To give 4-chloro-6,7-dimethoxy-3-quinolinecarboxylic acid (52.7 g, 98.7%). Mass Spectrum m / e 268 (M ++ H). NMR spectrum (d-6-DMSO, d values) 4.0 (s, 6H), 7.45 (s, 1H), 7.5 (s, 1H), 8.95 (s, 1H). Step 2 4-Chloro-6,7-dimethoxy-3-quinolinecarboxylic acid (26 g) was suspended in DMF (1000 ml) with stirring under a nitrogen atmosphere, tBuOH (400 ml) was added followed by triethylamine (31 ml) and finally Diphenylphosphoryl azide (25 ml). The reaction was then heated at 100 ° C for 7 hours with stirring. It was cooled and then evaporated in a rotary evaporator. The residue was treated with dichloromethane, some solid was removed by filtration, the filtrate was then taken to a flash column (Merck Art 9385 silica) eluting with dichloromethane with a gradient of 5% methanol.
To give 3-BOCamino-4-chloro-6,7-dimethoxy-quinoline (21.6 g, 65%) and 3-amino-4-chloro-6,7-dimethoxy-quinoline (4.4 g, 19%). 3-BOCamino-4-chloro-6,7-dimethoxyquinoline. Mass Spectrum m / e 339 (M ++ H). NMR spectrum (d-6-DMSO, d values) 1.45 (s, 9H), 3.9 (s, 3H), 3.95 (s, 3H), 7.35 (s, 1H), 7.4 (s, 1H), 8.7 (s) , 1H), 9.1 (s, 1H). Step 3 3-BOC-amino-4-chloro-6,7-dimethoxy-quinoline (18 g) was dissolved in trifluoroacetic acid (200 ml) with stirring, then triethylsilane (80 ml) was added. It was stirred at room temperature for 2 hours. It vanished. The dark red oily residue was treated with ice / water and carefully basified with 880 ammonia. The resulting red gum was scraped and stirred until it solidified slowly. The solid was removed by filtration and washed with water. It was dried to give 3-amino-4-chloro-6,7-dimethoxy-quinoline (7 g). During the night, more solids came out of the filtrate, these were removed by filtration, washed with water and dried to give 3-amino-4-chloro-6,7-dimethoxy-quinoline (3.5 g) (total yield 83%). Mass Spectrum m / e 239 (M ++ H). NMR spectrum (d-6-DMSO, d-values), 3.85 (s, 3H), 3.9 (s, 3H), 5.65 (s, 2H), 7.1 (s 1H), 7.25 (s, 1H), 8.35 (s) , 1 HOUR) . Step 4 3-Amino-4-chloro-6,7-dimethoxy-quinoline (3.3 g) was dissolved in tetrahydrofuran (70 ml) with stirring and then cooled in an ice / water bath to below 10 ° C. 48% aqueous fluoboric acid (7.3 ml) was then added and the mixture was stirred for 5 minutes. A solution of sodium nitrite (1.05 g) in water (2 ml) was added keeping the temperature below 10 ° C. The reaction mixture was then stirred for 30 minutes with cooling. The resulting yellow solid was removed by filtration, washed with freshly prepared tetrahydrofuran. It was dried under vacuum carefully. To give 4-chloro-6,7-dimethoxyquinoline-3-diazonium tetrafluoroborate (4.15 g, 89%). Mass Spectrum m / e without mass ion. NMR spectrum (d-6-DMSO, d values), 3.9 (s, 3H), 3.95 (s, 3H), 7.35 (s, 1H), 7.5 (s, 1H), 9.4 (s, 1H). Step 5: 4-Chloro-6,7-dimethoxy-quinoline-3-diazonium tetrafluoroborate (2.4 g) was carefully heated at 170 ° C. The spontaneous decomposition then took place. The gas evolution stopped quickly. The reaction was cooled and the flash column was eluted with dichloromethane / acetonitrile 95: 5 to give 4-chloro-6,7-dimethoxy-3-fluoroquinoline (0.65 g, 38%). Mass Spectrum m / e 242 (M ++ H). NMR spectrum (d-6-DMSO, d values), 3.9 (s, 3H), 3.95 (s, 3H), 7.3 (s, 1H), 7.45 (s, 1H), 8.8 (s, 1H).
Example 1 Preparation of Compound 1 in Table 1 A solution of acid chloride in ether (1 molar,
0. 34 ml) was added to a mixture of 4-chloro-6,7-dimethoxy-3-fluoro-quinoline (80 mg) and 4- (2-methoxyphenoxy) -aniline
(142 mg) in cyclohexanol (3 ml). The mixture was stirred and heated at 110 ° C for 18 hours. The mixture was cooled to room temperature and then filtered. The crystals were washed with a small volume of diethyl ether and then dried to give 4- (2-methoxyphenoxy) -anilino-3-fluoro-6,7-dimethoxy-quinoline (120 mg, 79%). Mass Spectrum m / e 421 (M ++ H). NMR spectrum (d-6-DMSO, d values), 3.7 (s, 3H), 3.9 (s, 3H),
3. 95 (s, 3H), 6.85 (m, 2H), 6.95 (m, 1H), 7.06 (, 1H), 7.2 (m, 4H), 7.5 (s, 1H), 7.95 (s, 1H), 8.85 ( d, 1H). EXAMPLE 2 By a procedure analogous to that described in
Example 1, but using an alternative aniline, carrying out the reaction for 24 hours instead of 18, the following compounds were prepared as summarized in the following Table 2.
Table 2
Biological Results Assay for inhibitors of the MAP kinase pathway To evaluate MAPK pathway inhibitors, a coupled assay was carried out which measures the phosphorylation of serine / threonine residues present in the substrate in the presence or absence of the inhibitor. The recombinant glutathione S-transferase fusion protein containing human p45MEKl (GST-MEK) was activated by c-raf (Sf9 insect cell lysate of triple baculoviral infection with c-raf / ras / lck) and used for the test. Active GST-MEK was first used to activate a recombinant glutathione S-transferase fusion protein containing p44MAP kinase (GST-MAPK) in the presence of ATP and Mg2t for 60 minutes at room temperature in the presence or absence of potential inhibitors. The activated GST-MAPK was then incubated with myelin basic protein (MBP) as a substrate for 10 minutes at room temperature in the presence of ATP, MG2 + and 33P-ATP. The reaction was stopped by the addition of 20% v / v phosphoric acid. The incorporation of 33P into the myelin basic protein was determined by capturing the substrate on a filter plate, washing and counting using scintillation methods. The dimension of inhibition was determined by comparison with untreated controls. The final assay solution contained 10 mM Tris, pH 7.5, 0.05 mM EGTA, 8.33 uM [? 33P] ATP, 8.33 mM Mg (0Ac) 2, 0.5 mM sodium orthovanadate, 0.05% w / v BSA, 6.5 ng of GST-MEK, 1 μg of GST-MAPK and 16.5 μg of MBP in a reaction volume of 60 μl. The tested compounds of the present invention had IC 50 results typically less than 20 μM. For example, Compound No. ' 5 of Example 2 gave an IC50 of 0.55 μM.
MAP In Vitro Kinase Assay To determine whether the compounds inhibited GST-MEK or GST-MAPK, a direct assay of MAPK activity was employed. GST-MAPK was activated by a constitutively active GST-MEK fusion protein containing two point mutations (S217E, S221E) and was used for the assay in the presence and absence of potential inhibitors. The activated GST-MAPK was incubated with substrate (MBP) for 60 minutes at room temperature in the presence of ATP, Mg2 + and 33P-ATP. The reaction was stopped by the addition of 20% v / v phosphoric acid. The incorporation of 33P into the myelin basic protein was determined by capturing the substrate on a filter plate, washing and counting using scintillation methods. The final assay solution contained 12 mM Tris, pH 7.5, 0.06 mM EGTA, 30 μM [? 33P] ATP, 10 mM Mg (OAc) 2, 0.6 mM sodium orthovanadate, 0.06% w / v BSA, 28 ng of GST-MAPK and 16.5 μg of MPB in a reaction volume of 60 μl. The compounds of the invention showed activity in this screen. Cell proliferation assays The cells were seeded in multi-well plates at 20,000-40,000 cells / ml in a growth medium containing 5% FCS and incubated overnight at 37 ° C. The compounds were prepared in freshly prepared medium at an appropriate concentration and added to the wells containing the cells. These were then incubated for an additional 72 hours. The cells were then removed either from the wells by incubating with trypsin / EDTA and counted using a Coulter counter, or treated with XTT / PMS in PBSA and the optical density reader at 450 nm. The tested compounds of the present invention had IC50 results typically less than 30 μM. For example, Compound No. 4 of Example 2 gave an IC50 of 3.8 μM in HT29 human colon tumor cells.
Claims (16)
- CLAIMS 1. A compound of the formula (I) 0) or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the inhibition of MEK in a mammal with an MEK mediated disease characterized in that: n is 0-1; Y is selected from -NH-, -O-, -S-, or -NR7- wherein R7 is alkyl of 1-6 carbon atoms R6 is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may be substituted with one, two or three groups selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2- 6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenyl, benzoyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms, and benzoylamino; or R6 is a group -R8-X-R9 wherein R8 is a divalent cycloalkyl of 3 to 7 carbon atoms, which may be optionally further substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl, or divalent phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally further substituted with one or more groups selected from halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy , trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms', carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino from 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms and benzoylamino; wherein X is selected from CH2, -NH-, -O-, -S-, or -NR5- wherein R5 is alkyl of 1-6 carbon atoms, and R9 is a group (CH2) mR10 wherein m is 0, or an integer of 1-3 and R10 is an optionally substituted aryl or optionally substituted cycloalkyl ring of up to 10 carbon atoms, or R 10 is a heterocyclic ring containing 1 or 2 oxygen atoms and optionally one or more substituents; R1, R2, R3 and R4 are each independently selected from hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, C? _3 alkyl, -NR11R12 (wherein R11
- R 12 which may be the same different, each represents hydrogen or alkyl of C? _3), or a group R13-X1- (CH2) X where x is 0 to 3, X1 represents -0-, -CH2-, -OCO-, carbonyl, -S-, -SO-, -S02-, -NR1, aCO-, -CONR > 1153-, -S02NR, 16-,
- NR > 1i7'S02- or -NR 18 (wherein R, R> 15, R 16, R117 'and R > 1i8B each independently represent hydrogen, C? -3 alkyl or C? -3-alkyl-alkoxy C2-3) and R13 is selected from one of the following sixteen groups: 1) C1-5 alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro and amino; 2) Ci-5X2COR19 alkyl (wherein X2 represents -0- or -NR '20 (wherein R> 20 represents hydrogen, C1-3alkyl or C3-3alkyl-C2-3alkyl) and R19 represents -NR21R22- or -OR23- (wherein R21, R22 and R23 which may be the same or different each represents hydrogen, C1-3alkyl or C3-3alkyl-C2-3alkyl)); 3) d-5X3R24 alkyl (wherein X3 represents -O-,
- -S-, -SO-, -S02-, -OCO-, -NR25CO-, -CONR26-, -S02NR27-, -NR28S02- or -NR29- (wherein R25, R2d, R27, R28 and R29 each represent independently hydrogen, C3_3alkyl or C1-3alkoxy-C2_3alkyl) and R24 represents hydrogen, C1-3alkyl, cyclopentyl, cyclohexyl or a saturated 5- or 6-membered heterocyclic group with one or two heteroatoms, selected independently of 0, S and N, whose C1-3 alkyl group can support one or two substituents selected from oxo, hydroxy, halogen, and C? -4 alkoxy and whose cyclic group can support one or two substituents selected from oxo, hydroxy, halogen, C? -4 alkyl, C? _4 hydroxyalkyl and C? -4 alkoxy); 4) alkyl of C? _5X5R30 (wherein X4 and X5 which may be the same or different are each -0-, -S-, -SO-, -S02-, -NR31CO-, -CONR32-, S02NR33- , -NR3S02- OR -NR, 3J5O- (wherein R, 31Í, R> 32, R33, R34 and R35 each independently represent hydrogen, C1-3alkyl or C3-3alkyl-C2-3alkyl) ) and R30 represents hydrogen or C? -3 alkyl);
- 5) C ?5R36 alkyl (wherein R36 is a 5- or 6-membered saturated heterocyclic group with one or two heteroatoms, independently selected from 0, S and N, whose heterocyclic group can support one or two substituents selected from oxo, hydroxy , halogen, C? _4 alkyl, hydroxyalkyl of C? _4, and C? -4 alkoxy);
- 6) (CH2) qX6R37 (where q is an integer from 0 to 5, X6 represents a direct bond, -0-, -S-, -SO-, -S02-, -NR38CO-, -CONR39-, - S02NR40-, -NR41S02- or -NR42- (wherein R38, R39, R40, R41 and R42 each independently represents hydrogen, C1-3alkyl or C3-3alkyl-C2-3alkyl) and R37 is a phenyl group, a pyridone group or a 5- or 6-membered aromatic heterocyclic group with 1 to 3 heteroatoms selected from 0, N and S, whose phenyl, pyridone or aromatic heterocyclic group can carry up to 5 substituents selected from hydroxy, halogen, amino , C ?4 alkyl, C? -4 alkoxy, C? _4 hydroxyalkyl, C? -4 hidro hydroxyalkoxy, C? - aminoalkyl, C? _4 alkylamino, carboxy, cyano, -CONR43R44 and -NR45COR46 ( wherein R43, R44, R45 and R46, which may be the same or different, each represents hydrogen, C? -4 alkyl or C? -3-C2_3 alkyl alkoxy));
- 7) C2-eR36 alkenyl (wherein R, 36 is as defined above);
- 8) C2-eR36 alkynyl (wherein R, 36 is as defined above);
- 9) X7R47 (wherein X7 is -S02-, -O- or -CONR48R49- (wherein R48 and R49, which may be the same or different each represents hydrogen, C?-3 alkyl or C? Alkoxy) 3-C2_3 alkyl) and R47 represents C5_5 alkyl which may be unsubstituted or may be substituted with one or more groups selected from hydroxy, fluoro and amino) with the proviso that when X7 is -S02- , X1 is -O-, when X7 is -O-, X1 is carbonyl, when X7 is -CONR48R49-, X1 is 0- or NR18 (wherein R48, R 49 R 18 are as defined above);
- 10) C2_6R37 alkenyl (wherein R 537 is as defined above);
- 11) C2-eR37 alkynyl (wherein R, 37 is as defined above);
- 12) C2_6X8R37 alkenyl (wherein X8 represents -O-, -S-, -SO-, -S02-, -NR50CO-, -CONR51-, -S02NR52-, -NR53S02- or -NR54- (wherein R50, R51, R52, R53 and R54 each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxy-C2-3 alkyl) and R37 is as defined above);
- 13) C2-d alkynyl R (wherein X represents -O-, -S-, -SO-, -S02-, -NR55CO-, -CONR56-, -S02NR57-, -NR58S02- or -NR, 5093- (wherein R, R, R, R ° and R, 59, each independently represents hydrogen, C1-3 alkoxy or C1-3 alkoxy-C2-3 alkyl) and R37 is as defined earlier);
- 14) C1-3X alkyl-C1-3R alkyl 37 (wherein XrlO represents -O-, -S-, -SO-, -S02-, -NR60CO-, -CONR61-, -S02NR62, -NR63S02- or -NR64- (wherein R60, R61, R62, R63 and R64 each represent independently hydrogen, C1-3alkyl or C3-3alkyl-C2-3alkyl) and R37 is as defined above);
- 15) R36 (wherein R36 is as defined above); and
- 16) C? _3X10 alkyl-C1-3R36 alkyl (wherein X10 and R3d are as defined above). 2. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the inhibition of MEK in a mammal with an MEK mediated disease according to claim 1, characterized in that: n is 0-1; Y is selected from -NH-, -O-, -S-, or -NR7- wherein R7 is alkyl of 1-6 carbon atoms R6 is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl or phenyl ring; wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono-, di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, carbon, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms , alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms, and benzoylamino; or R6 is a group -R8-X-R9 wherein R8 is a divalent cycloalkyl of 3 to 7 carbon atoms, which may be optionally further substituted with one or more alkyl groups of 1 to 6 carbon atoms; or is a pyridinyl, pyrimidinyl, or divalent phenyl ring; wherein the pyridinyl, pi'rimidinyl or phenyl ring may be optionally further substituted with one or more groups selected from halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, carbon, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms , hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynylamino of 3-8 carbon atoms and benzoylamino; wherein X is selected from -NH-, -O-, -S-, CH2 or -NR ° - wherein R5 is alkyl of 1-6 carbon atoms, and R9 is a group (CH2) mR10 wherein m is 0, or an integer of 1-3 and R10 is an optionally substituted aryl or optionally substituted cycloalkyl ring of up to 10 carbon atoms, or R10 is a heterocyclic ring containing 1 or 2 oxygen atoms and optionally one or more substituents; R1 R "R3 and R4 are each independently selected from hydrogen, hydroxy, halogen, cyano, nitro, trifluoromethyl, C? - alkyl, -NR1: LR12 (wherein R11 and R, 12, which may be the same or different , each represents hydrogen or C1-3 alkyl) or a group R13-X1- (CH2) X wherein x is 0 to 3, X1 represents -O-, -CH2-, -OCO-carbonyl, -S-, -SO-, -S02-, -NR14CO-, -S02NR? 6-, -NR17S02- or -NR 18 (wherein R14, R16, R17 and R18 each independently represents hydrogen, C1-3 alkyl or C1-3 alkoxy-C2_3 alkyl) and R13 is selected from one of the sixteen groups defined in claim 1 3. The compound of the formula (IA) characterized in that it comprises a compound of the formula (I) according to claim 1, with the proviso that R6 is other than the pyridinyl, pyrimidinyl or phenyl ring; wherein the pyridinyl, pyrimidinyl or phenyl ring may be optionally mono-, di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-3 carbon atoms, alkoxy of 1-3 carbon atoms , hydroxy, trifluoromethyl, cyano, nitro, amino. 4. The compound according to any of the preceding claims, characterized in that R6 is a group -R8-X-R9 wherein R8, R9 and X are as defined in claim 1. 5. The compound according to claim 4, characterized in that R10 is an aryl, carbocyclic or heterocyclic group substituted by one or more groups selected from hydroxy; halo; nitro; cyano; carboxy; C6-C6 alkoxy; C? -6 alkyl; C2-6 alkenyl; C2_6 alkynyl; C2_6 alkenyloxy; C2-6 alkynyloxy; C3-6 cycloalkyl; Not me; mono- or di-alkylamino of C? _s; heterocyclyl optionally substituted with C? _6 alkyl or oxo; C (0) Ra, C (0) 0 Ra, S (0) d Ra; NRaC (0) Rb; C (O) NRaS (O) dRb, C (0) NRaRb; NRaC (0) NRbRc; NRaS (0) dRbo N (S (0) dRb) S (O) dRc wherein d is 0, 1 or 2 and Ra, Rb and Rc are independently selected from hydrogen, C? _6 alkyl, aryl, C3 cycloalkyl -6 or heterocyclyl, and wherein any alkyl, alkenyl or alkynyl group or moiety contained within the substituent, an R10 may be optionally substituted with one or more groups selected from hydroxy; cyano; nitro; halo; carboxy; carboalkoxy of 2-7 carbon atoms, cycloalkyl of C3_s, heterocyclyl optionally substituted by C6_6 alkyl or oxo; C (0) Rd, C (O) ORd NRdRe, S (O) eRd, NRdC (0) Re; C (0) NRdRe; NRdC (0) NReRf; NRdS (0) eRe wherein e is 0, 1 or 2 and Rd, Re and Rf are independently selected from hydrogen or C 1-6 alkyl optionally substituted with one or more groups selected from hydroxy; cyano; nitro; halo; carboxy; carboalkoxy of 2-7 carbon atoms, C 3-7 cycloalkyl, heterocyclyl optionally substituted with C? _6 alkyl or oxy; C (0) Rg, C (0) 0R9NRgRh, S (0) eRgr NRhC (0) R9; C (0) NRgRh, NRgC (0) NRhR ", NRgS (O) eRh wherein e is as defined above and Rg, Rh and R1 are independently selected from hydrogen or C? -6 alkyl," or two substituents on Adjacent atoms can be joined to form the second ring of a bicyclic ring system wherein said second ring is optionally substituted with one or more of the groups listed above for R10 and optionally contains one or more heteroatoms. 6. The compound according to claim 5, characterized in that R10 is phenyl substituted by an optionally substituted alkoxy group. 7. The compound of the formula (IB) (IB) characterized in that Y, n, R6, are as defined in claim 1, and at least one of R1", R2", R3"or R4" is a group R13'-X1- (CH2) x wherein X1 and x are as defined in claim 1 and R13 'is alkyl substituted by chlorine or bromine; and the remainder are groups R1, R2, R3 and R4 respectively, as defined in claim 1. 8. The pharmaceutical composition characterized in that it comprises a compound of the formula (IA) according to claim 3, in combination with a carrier. or pharmaceutically acceptable excipient. 9. The method for preparing a compound of the formula (I) according to claim 1, which method is characterized in that it comprises reacting a compound of the formula (III) R * (IH) wherein R1 ', R2', R3 ', R4' represent R1, R2, R3 and R4 respectively as defined in relation to the formula (I) or a precursor thereof, and Z 'is a leaving group, with a compound of the formula (IV) HY (CH2) nR6' - - * - * - (IV) where Y, X and n are as defined in relation to -with the formula (I), and R6 'is a group R6 as defined in relation to the formula (I) or a precursor thereof; and thereafter if it is necessary or desired to convert the precursor groups R1 ', R2', R3 ', R4' and R6 'to the groups of the formula R1, R2, R3, R4 and R6 respectively, or to convert a group R1 , R2, R3, R4 and R6 to a different group. 10. The compound for use in therapy characterized in that it comprises a compound of the formula (IA) according to claim 3.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GB9910580.1 | 1999-05-08 |
Publications (1)
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MXPA01011361A true MXPA01011361A (en) | 2002-06-05 |
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