OA18889A - New Hydroxyester derivatives, a process for their preparation and pharmaceutical compositions containing them. - Google Patents
New Hydroxyester derivatives, a process for their preparation and pharmaceutical compositions containing them. Download PDFInfo
- Publication number
- OA18889A OA18889A OA1201700511 OA18889A OA 18889 A OA18889 A OA 18889A OA 1201700511 OA1201700511 OA 1201700511 OA 18889 A OA18889 A OA 18889A
- Authority
- OA
- OAPI
- Prior art keywords
- group
- branched
- linear
- alkyl
- phenyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 35
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 25
- 238000002360 preparation method Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 134
- 201000011510 cancer Diseases 0.000 claims abstract description 30
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 96
- 239000000203 mixture Substances 0.000 claims description 90
- 125000000217 alkyl group Chemical group 0.000 claims description 88
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 81
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 81
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 66
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 61
- 229910052757 nitrogen Chemical group 0.000 claims description 49
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 49
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 48
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 39
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 37
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 36
- 125000001424 substituent group Chemical group 0.000 claims description 34
- -1 propan-2-yloxy Chemical group 0.000 claims description 30
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- 125000005843 halogen group Chemical group 0.000 claims description 21
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- 239000002253 acid Substances 0.000 claims description 18
- 238000007792 addition Methods 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 16
- 125000005842 heteroatoms Chemical group 0.000 claims description 16
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- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 14
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
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- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 230000001808 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 6
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 230000003211 malignant Effects 0.000 claims description 5
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- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
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- 208000000587 Small Cell Lung Carcinoma Diseases 0.000 claims description 4
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- 108009000491 Small cell lung cancer Proteins 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 3
- 239000000546 pharmaceutic aid Substances 0.000 claims description 3
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 229940100197 ANTIMETABOLITES Drugs 0.000 claims description 2
- 231100000614 Poison Toxicity 0.000 claims description 2
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- 239000002256 antimetabolite Substances 0.000 claims description 2
- 125000004350 aryl cycloalkyl group Chemical group 0.000 claims description 2
- 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 claims description 2
- 230000001684 chronic Effects 0.000 claims description 2
- 125000006448 cycloalkyl cycloalkyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000005349 heteroarylcycloalkyl group Chemical group 0.000 claims description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 230000000394 mitotic Effects 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 2
- 239000002574 poison Substances 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims 16
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 230000002829 reduced Effects 0.000 description 44
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 34
- 235000019439 ethyl acetate Nutrition 0.000 description 32
- 239000012043 crude product Substances 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 239000003480 eluent Substances 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
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- 238000004809 thin layer chromatography Methods 0.000 description 1
- 102000002933 thioredoxin family Human genes 0.000 description 1
- 108060008226 thioredoxin family Proteins 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 230000003442 weekly Effects 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
Abstract
Compounds of formula (I)
Description
NEW HYDROXYESTER DERIVATIVES, A PROCESS FOR THEIR PREPARATION
AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
The présent invention relates to new hydroxyester dérivatives, to a process for their préparation and to pharmaceutical compositions containing them.
The compounds of the présent invention are new and hâve very valuable pharmacological characteristics in the field of apoptosis and cancerology.
Apoptosis, or programmed cell death, is a physiological process that is crucial for embryonic development and maintenance of tissue hoineostasis.
Apoptotic-type cell death involves morphological changes such as condensation of the nucléus, DNA fragmentation and also biochemical phenomena such as the activation of caspases which cause damage to key structural components of the cell, so inducing its disassembly and death. Régulation of the process of apoptosis is complex and involves the activation or repression of several intracellular signalling pathways (Cory S. et al.. Nature Review Cancer 2002, 2, 647-656).
Deregulation of apoptosis is invotved in certain pathologies. Increased apoptosis is associated with neurodegenerative diseases such as Parkinson’s disease, Alzheimer''s disease and ischaemia. Conversely, déficits in the implémentation of apoptosis play a signîfïcant rôle în the development of cancers and their chemoresîstance, in auto-immune diseases. inflammatory diseases and viral infections. Accordingly, absence of apoptosis is one of the phenotypic signatures of cancer (Hanahan D. et al., Cell 2000, 100. 57-70).
The anti-apoptotic proteins of the Bcl-2 family are associated with numerous pathologies. The involvement of proteins ofthe Bcl-2 family is described in numerous types of cancer, such as colon cancer, breast cancer, small-cell long cancer, non-small-cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphoid ieukaemia, lymphoma, myeloma, acute myeloid leukemia, pancreatic cancer, etc. Overexpression of the antiapoptotic proteins of the Bcl-2 family is involved in tumorigenesis. in résistance to chemotherapy and in the clinical prognosis of patients affected by cancer. Notably,
ORIGINAL
-2Mcl-l, an anti-apoptotic Bcl-2 family member, is overexpressed in various types of cancer (Beroukhim R. ei al.. Nature 2010, 899-905). There is, therefore, a therapeutic need for compounds that inhibit the anti-apoptotic activity of the proteins of the Bcl-2 family.
In addition to being new, the compounds of the présent invention hâve pro-apoptotic 5 properties makîng it possible to use them in pathologies involving a defect in apoptosis, such as, for example, in the treatment of cancer and of immune and auto-immune diseases.
The présent invention relates more especially to compounds of formula (I):
wherein:
♦ A represents the group
I0 in which l is linked to the oxygen atom and 2 is linked to the phenyl ring.
♦ Rj represents a linear or branched (Ci-C&)alkyl group, a linear or branched (Ci-Côjalkenyl group, a linear or branched (Cj-Cejalkynyl group, a linear or branched (Ci-Cô)alkoxy group, a -S-(C|-C6)alkyl group, a linear or branched (Ci-Côjpolyhaloalkyl, a hydroxy group, a hydroxy(C|-Cf,)alkyl group, a cyano group, -NR| iR] i -Cy6, or a halogen atom.
♦ R2, R3, R4 and Rs independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-C(,)alkyl group, a linear or branched
ORIGINAL
-3(C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group. a linear or branched (Cj-Cftjpolyhaloalkyl, a hydroxy group, a hydroxy(Ci-C&)alkyI group, a linear or branched (C|-C&)alkoxy group, a -S-(C|-C6)alkyl group, a cyano group, a nitro group, -alkyi(CQ-C6)-NR9R9, -O-alkyl(Ci-C6)-NR9R9’, -0-alkyl(Ci-Cô)-Rio, -C(O)-OR9, -O-C(O)-R9, -C(O)-NR9R9’, -NR9-C(O)-R9’, -NR9-C(0)-0R<, -alkyl(C,-C6)-NR9-C(O)-R9’, -SO2-NR9R9’, -SO2-alkyl(Ci-C6), or the substituents of one of the pairs (R2, R3), (R3, Rj), (R4, R5), when grafted onto two adjacent carbon atoms, form together with the carbon atoms carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that resulting ring may be substituted by a group selected from a linear or branched (Ci-C6)alkyl group. -NRnRn’. -alkyl(Co-C6)-Cyi. or an oxo, ♦ R6 and R7 independently of one another represent a hydrogen atom, a halogen atom. a linear or branched (C i-C6)alkyl group. a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group. a linear or branched (Ci-Cejpolyhaloalkyl, a hydroxy group, a linear or branched (Cj-C6)alkoxy group, a -S-(C|-C6)alkyl group, a cyano group, a nitro group, -alkyl(Co-C6)-NR9R9’, -O-alkyl(Ci-C6)-NR9R9’, -O-Cyi, -alkyl(Co-C6)-Cyi, -alkenylfCj-Côj-Cyi, -alkynyl(C2-C6)-Cyi, -O-alkyl(C|-C6)-R|0, -C(O)-OR9, -O-C(O)-R9, -C(O)-NR9R9 7, -NR9-C(O)-R9’, -NR9-C(O)-OR9\
-alky!(C|-C6)-NR9-C(O)-R9\ -SO2-NR9R9’, -SO2-alkyl(C,-C6).
or the substituents of the pair (Rc„ R7), when grafted onto two adjacent carbon atoms, form together with the carbon atoms carrying them an aromatic or nonaromatic ring composed of from 5 to 7 ring members, which may contain from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that resulting ring may be substituted by a group selected from a linear or branched (Ci-Cft)alkyl group, -NRnRn', -alkyl(Co-Cfi)-Cyi, or an oxo, ♦ Rs represents a linear or branched (Ci-C^jalky! group, a linear or branched (C2-C(,)alkenyl group, a linear or branched (C2-C6)alkynyl group, -Cy3, -alkyl(C|-C6)-Cy3, -alkenyl(C2-C6)-Cy3, -alkynyl(C2-C6)-Cy3, -Cy3-Cy4, -alkynyl(C2-C6)-O-Cy3, “Cy3-alkyl(Co-C6)-0-alkyl(C0-C6)-Cy4, a halogen atom, a cyano group, -C(O)-Ri2, or -C(O)-NR|2R|2\
ORIGINAL ♦ R9 and R9‘ independently of one another represent a hydrogen atom, a linear or branched (Ci-C6)alkyl group, -alkyl(Cû-C6)-Cyi, or the substituents of the pair (R9, R9’) form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen. it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, or a linear or branched (Ci-Côjalkyl group and it being understood that one or more of the carbon atoms of the possible substituents, may be deuterated.
♦ Rio represents -Cyi, -Cyralkyl(Co-C6)-Cy2, -Cyi-alkyl(Co-C6)-0-alkyl(Co-C6)-Cy2,
-Cyi-alkyl(Co-C6)-NR9-alkyl(Co-C6)-Cy2, -Cyl-Cy2-O-alkyl(C0-C6)-Cy5,
-C(O)-NR9Rq’, -NR9R91, -ORç, -NR9-C(O)-R9', -O-alkyl(C|-C6)-ORç, -SO2-R9, -C(O)-OR9, or -NH-C(O)-NH-R9, ♦ R| 1, Ru’, R12 and R12' independently of one another represent a hydrogen atom or an optionally substituted linear or branched (Cj-C6)alkyl group, ♦ Ru represents a hydrogen atom, a hydroxy group. or a hydroxy(C|-C6)alkyl group.
♦ Ra represents a hydrogen atom or a linear or branched (C|-C6)alkyl group, ♦ Rh represents a -O-C(O)-O-Rc group, a -O-C(O)-NRcRc' group, or a -O-P(O)(ORC)2 group, ♦ Rc and Rc’ independently of one another represent a hydrogen atom, a linear or branched (Cj-C8)alkyl group. a cycloalkyl group, a (Ci-C6)alkoxy(C|-C6)aIkyl group, a (C]-C6)alkoxycarbonyl(C]-C6)alkyl group, or the substituents of the pair (Rc, Rc’) form together with the nitrogen atom carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a linear or branched (C|-C6)alkyl group, ♦ Cyi, Cy2, Cyj, Cy^, Cy3 and Cy& independently of one another, represent a cycloalkyl group, a heterocycloalkyl group. an aryl group or a heteroaryl group, ♦ n is an integer equal to 0 or 1, it being understood that:
ORIGINAL
- 5 - aryl means a phenyl, naphthyl, biphenyl, indanyl or indenyl group, heteroaryl means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen, cycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, and containing from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen. which may include fused, bridged or spiro ring Systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, to be substituted by from l to 4 groups selected from optionally substituted linear or branched (Ci-Côjalkyl, optionally substituted linear or branched (C2-C6)alkenyl group, optionally substituted linear or branched (C2-C6)alkynyl group, optionally substituted linear or branched (C|-C6)alkoxy. optionally substituted (Ci-C6)alkyl-S-, hydroxy, oxo (or A-oxide where appropriate), nitro, cyano, -C(O)-OR\ -O-C(O)-R, -C(O)-NR'R”, -NR'R, -(C=NR')-OR”, linear or branched (Ci-C6)polyhaloalkyl, trifluoromethoxy, or halogen, it being understood that R' and R” independently of one another represent a hydrogen atom or an optionally substituted linear or branched (Ci-C6)alkyl group, and it being understood that one or more of the carbon atoms of the preceding possible substituents, may be deuterated, their enantiomers, diastereoisomers and atropisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid etc. 'ζ'
ORIGINAL
-6Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
Advantageously, at least one of the groups selected from R2, R-3, R-ι and R5 does not represent a hydrogen atom.
More especially, compounds of formula (I) to which préférence is given are compounds wherein n is an integer equal to l.
In another embodiment of the invention, an advantageous possibility consists of compounds of formula (La):
(La)
I0 wherein R(, R2, R3, R4. R5, R(). R?, Ra, Rb, R13 and A are as defined for formula (I).
In the preferred compounds of the invention. Rj represents a linear or branched (Ci-Cô)alkyl group or a halogen atom. More preferably, R| represents a methyl group, an ethyl group, a bromine atom or a chlorine atom.
Atropisomers are stereoisomers arising because of hindered rotation about a single bond, 15 where energy différences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers. For compounds according to the invention, atropisomers are as fbllows:
ORIGINAL
Preferred atropisomer is (5S„).
Preferably, R13 represents a hydrogen atom.
Advantageously, R2 represents a halogen atom, a hydroxy group, a linear or branched 5 (C|-C6)alkoxy group. More preferably. R2 represents a methoxy group, a hydroxy group, a fluorine atom, a bromine atom or a chlorine atom. Even more preferably, R2 represents a chlorine atom.
Rj advantageously represents a hydrogen atom, a hydroxy group, a linear or branched (C|-C6)alkoxy group or -O-alkyKCi-CôI-NRçRt»’. Advantageously, R3 represents I0 -O-alkylÇCj-CôJ-NRqRq .
In some preferred embodiment ofthe invention.
represents
wherein R|, R9 and R9’ are as defined for formula (I).
ORIGINAL
8In the preferred compounds of the invention,
represents
wherein R9 and R9' are as defined for formula (l).
R4 and R5 preferably represent a hydrogen atom.
In an advantageous embodiment. the substituents of the pair (Rj. R5) are identical and the substituents of the pair (R2, R4) are identical. In the preferred compounds of lhe invention, the substituents of the pair (R|, R5) are identical and represent a (C|-C6)alkyl group, preferably a methyl group, whereas the substituents of the pair (R2, R4) are identical and represent a halogen atom, preferably a chlorine atom, or a hydrogen atom.
IO In another embodiment of the invention, R(, represents an optionally substituted linear or branched (Cj-Cftlalkoxy group or a -0-alkyl(C|-C6)-Rio group. Advantageously, R6 represents a 2,2,2-trifluoroethoxy group, a methoxy group, a 2-methoxyethoxy group or a -O-alkyKCj-Côl-Rio group.
R7 preferably represents a hydrogen atom.
I5 In the preferred compounds of the invention.
represents
ORIGINAL
-9wherein R|0 is as defined for formula (I).
In another embodiment of the invention, an advantageous possibility consists of compounds of formula ( I-b):
wherein Rh Rf„ R9. R9', Ra, Rb, Ri3 and A are as defined for formula (I).
In the preferred compounds of the invention. R8 represents a linear or branched (C|-C6)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, an aryl group or a heteroaryl group. Advantageously, Rs represents a linear or branched (C2-C6)alkynyl group, an aryl group or a heteroaryl group. More preferably, Rs represents a prop-l-yn-l-yl group, a but-l-yn-l-yl group, a phenyl group or a furan-2-yl group. In a more preferred embodiment, Rs represents a 4-(benzyloxy)phenyl group. a 4-(pyridin-4-ylmethoxy)pbenyl group, a 4-phenylbut-l-yn-l-yl group, a 4-fluorophenyl group or a 5-fluorofuran-2-yl group. Even more preferentially, Rs represents a 4-fluorophenyl group.
In the preferred compounds of the invention. R9 and R9' independently of one another represent a linear or branched (C]-C6)alkyl group. or the substituents of the pair (R9. R9') form together with the nitrogen atom carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom or a linear or branched (Ci-C6)alkyl group. More preferably, R9 and R9’ represent a methyl group, or the substituents ofthe pair (R9, R9’) form together a 4-methyl-piperazinyI group
ORIGINAL
- ΙΟor a 4-ethyl-piperazinyl group. In a more preferred embodiment, the substituents of the pair (Rg, Rg’) form together a 4-methyl-piperazinyl group. In another preferred embodiment, Rg and Rg’ represent a methyl group.
Advantageously, Rio represents -Cyi, -Cyi-alkyl(Co-Cô)-0-alkyl(Co-C6)-Cy2 or -Cyi-alkyl(Co-C6)-Cy2- More particularly. Rio represents -Cyi, -Cyi-O-CH2-Cy2, or -Cyi-Cy2.
Cyi preferably represents a heteroaryl group, particularly, a pyrimidinyl group, a pyrazolyl group, a triazolyl group, a pyrazinyl group or a pyridinyl group. More preferably, Cyi represents a pyrimidin-4-yl group. a pyrazol-5-yl group, a iriazol-5-yl group, a pyrazin-2-yl group or a pyridin-4-yl group. In the preferred compounds of the invention. Cyi represents a pyrimidin-4-yl group.
In another embodiment of the invention, Cyi represents a heteroaryl group which is substituted by an optionally substituted linear or branched (CrCé)alkyl group, an optionally substituted linear or branched (Ci-Cô)alkoxy group. a -NR R group, or a linear or branched (Cj-C6)polyhaloalkyl group, it being understood that R’ and R” independently of one another represent a hydrogen atom or an optionally substituted linear or branched (CrC6)alkyI group.
Cy2 preferably represents a phenyl group, a pyridinyl group, a pyrazolyl group, a morpholinyl group, a furanyl group or a cyclopropyl group. More preferably, Cy2 represents a phenyl group, a pyridin-2-yl group, a pyridin-3-yl group. a pyridin-4-yl group, a pyrazol-l-yl group, a morpholin-4-yl group, a furan-2-yl group or a cyclopropyl group. In the preferred compounds of the invention, Cyi represents a phenyl group.
Other compounds of the invention to which preference is given are those wherein Rio represents -Cyi-Cy2 in which Cyi represents a pyrimidinyl group and Cy2 represents a phenyl group, a pyridinyl group, a pyrazolyl group, a morpholinyl group, a furanyl group. or a cyclopropyl group. Even more prefèrentially.
ORIGINAL
R.ιο represents
in which Rr and R|> independently of one another represent a hydrogen atom, an optionally substituted linear or branched (Ci-Cèjalkyl group, an optionally substituted linear or branched (C|-C6)alkoxy group, a hydroxy group, a linear or branched (C|-Ct,)polyhaloalkyl group, or a halogen atom. Prefered R|4 and Ri 5 groups are as follows: hydrogen; methyl; ethyl; methoxy; ethoxy; isopropoxy; methoxyethoxy; fluoro; hydroxy; trifluoromethyl. Advantageously, Ri, represents a hydrogen atom and R|4 is located at ortho position of the phenyl group.
More especially, compounds of formula (I) to which preference is given are compounds wherein Ra represents a hydrogen atom or a methyl group.
Advantageously, Rb represents a -O-C(O)-O-(C|-Cs)alkyl group; a -0-C(0)-0-cycloalkyl group; a -O-C(O)-NRcR/ group, in which and Rt’ independently of one another represent a hydrogen atom, a linear or branched (Ci-Cg)alkyl group. a (C|-C6)alkoxy(Ci-C6)alkyl group, a (C]-C6)alkoxycarbonyl(C]-C6)alkyl group. or the substituents ofthe pair (Ru, R/) form together with the nitrogen atom carrying them a non-aromatic ring composed of from 5 to 7 ring menibers, which may contain in addition to the nitrogen atom from l to 3 heteroatoms selected from oxygen and nitrogen; or a -O-P(O)(OH)2 group.
Preferably, Rn represents a methyl group and Rb represents a group selected from -O-C(O)-O-CH3; -O-C(O)-O-CH2CH3; -O-C(O)-O-CH(CH3)2; -O-C(O)-O-C(CH3)3; -O-C(O)-O-cyclopentyl; -O-C(O)-O-C8H|7; -O-C(O)-N(CH3)2; -O-C(O)-N(CH2CH3)2; -O-C(O)-A-morpholine; -O-C(O)-NH-(CH2)2-OCH3; -O-C(O)-N[(CH2)2-OCH3]2;
ORIGINAL
- 12or -O-C(O)-N(CH3)(CH2-C(O)-OCH3). More preferably, Ra represents a niethyl group and Rb represents a group selected from -O-C(O)-O-CH2CH3 or -O-C(O)-N(CH3)2.
Among the preferred compounds of the invention there may be mentioned:
- I -[(methoxycarbonyl)oxy]ethyl (2R)-2- {[( 5Sa)-5~ {3-chloro-2-methyl-4-[2-(4- methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4yl]oxy)-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate;
- l-[(ethoxycarbonyl)oxy]ethyl (2A)-2-{[(5SJ-5-{3-chloro-2-methyl-4-[2-(4-methyl piperazm-l-yl)eihoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl] oxy} -3-(2-{[2-(2-niethoxyphenyl)pyrimidin-4-yl]methoxy)phenyl)propanoate;
’O - l-{[(propan-2-yloxy)carbonyl]oxy}ethyI (2Æ)-2-{[(51S'û)-5-{3-chloro-2-methyI-4[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i7] pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl) propanoate:
- I -[(/e/7-butoxycarbonyl)oxy]ethyl (27?)-2-{ [(55’a)-5-{3-chloro-2-methyl-4-[2-(4- rnethylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-t/]pyrimidin-4yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy} phenyl )propanoate;
l-{[(cyclopentyloxy)carbonyl]oxy}ethyl (2Æ)-2-{[(5SJ-5-{3-chloro-2-methyl-4-[2(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluoropheny[)thieno[2,3-i/]pyrimidin-
4-yl]oxy} -3-(2- {[2-(2-methoxyphenyl )pyrimidin-4-y l]methoxy} phenyl )propanoate;
- l-{[(octyloxy)carbonyl]oxy}ethyl (2Æ)-2-[[(5Sj-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4yI]oxy}-3-(2-{[2-(2-methoxyphenyl)pyriinidin-4-y]]methoxy}phenyl)propanoate;
- I -[(dimethylcarbamoyl)oxy]ethyl (2A)-2-{ [(55„)-5-{3-chIoro-2-methyI-4-[2-(4methylpiperazin-l-y])ethoxy]phenyl}-6-(4-fluoiOphenyl)thieno[2,3-if]pyrimidin-4- yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl Jmethoxy} phenyl )propanoate;
- I -[(diethy Icarbamoyl )oxy]ethyl (2R)-2-{[(5^)-5- {3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-nuorophenyl)thieno[2,3-i/]pyrimidin-4yl]°xy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate;
l-{[(2/?)-2-{[(51S’0)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl }-6-(4-fluorophenyl)thieno[2,3-<:/]pyriniidin-4-yl]oxy}-3-(2- {[2-(2ORIGINAL
- I3methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoyl]oxy}ethyl morpholine-
4-carboxylate;
- l-{[(2-methoxyethyI)carbamoyl]oxy}ethyl (2Æ)-2-{[(5Sa)-5-{3-chloro-2-methyl-4[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl} -6-(4-fluorophenyl)thieno[2.3-<7] pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl) propanoate;
l-{[bis(2-methoxyethyl)carbamoyl]oxy}ethyl (27?)-2-{ [(5Sa)-5-{3-chloro-2methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno [2.3-i/]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy} lû phenyl)propanoate;
l - {[(2-methoxy-2-oxoethyl )(methyl)carbamoyl]oxy} ethyl (27?)-2- {[(55^)-5- {3 - chloro-2-methy l-4-[2-(4-methy Ipiperazin-1 -y l )ethoxy]phenyl} -6-(4-fluoro phenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy} phenyl )propanoate;
I5 - (phosphonooxy)methyl (2/?)-2-{[(5So)-5-{3-chloro-2-methyl-4-[2-(4-methyl piperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl] oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate;
- I -[(ethoxycarbonyl)oxy]ethyl (2/?)-2-{[5- {2,6-dimethyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-rf]pyrimidin-4-yl]oxy}-3-(2-{[2- (2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate;
- I -[{ethoxycarbonyl Joxyjethyl (2Æ)-2- {[5- {3,5-dichloro-2,6-dimethyl-4-[2-(4- methylpiperazin-1 -yl )ethoxy]phenyl} -6-( 4-il uoropheny l)thicno[ 2.3-J|pyrimidin-4yl ]oxy} -3-(2- {[ 2-(2-methoxypheny l)pyrimidin-4-yl]methoxy} phenyl )propanoate;
- l-[(dimethylcarbamoyl)oxy]ethyl (2/?)-2-{[5-{2,6-dimethyl-4-[2-(4-methyl piperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thÎeno[2.3-i7]pyrîmidin-4-yl] oxy}-3-(2-{ [2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy} phenyl )propanoate; l-[(dimethylcarbamoyl)oxy]ethyl (27?)-2-{[5-{3,5-dichloiO-2,6-dimethyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i7]pyriinidin-4y[]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]rnethoxy}phenyl)propanoate.
The invention relates also to a process for the préparation of compounds of formula (l).
ORIGINAL
- 14which process is characterised in that there is used as starting material the compound of formula (II):
C'T^Br (II) wherein A is as defined for formula (I) in which 1 is linked to the chlorine atom and 2 is linked to the bromine atom, which compound of formula (II) is subjected to coupling with a compound of formula (III):
Alk
(III) wherein R(„ R7, R13 and n are as defined for formula (I), and Alk represents an optionally substituted linear or branched (C|-C6)alkyl group.
to yield the compound of formula (IV):
(IV) wherein Rft. R7, R]3, A and n are as defined for formula (I) and Alk is as defined before.
compound of formula (IV) which is further subjected to coupling with compound of formula (V):
ORIGINAL
(V) wherein R|. R2, Rj, R4 and R5 are as defined for formula (I), and Rbi and Rb2 represent a hydrogen atom, a linear or branched (CrCô) alkyl group, or Rbi and Rb2 form with the oxygen carrying them an optionally methylated ring.
to yield the compound of formula (VI):
Alk
(VI) wherein R|, Ri, R3, R4, R5, R(1, R7, Rjj. A and n are as defined for formula (I) and Alk is as defined before.
I0 the Alk-O-C(O)- ester function of which compound of formula (VI) is hydrolysed to yield the carboxylic acid (VII);
(VII)
ORIGINAL
- 16wherein Rb R2, R3, R4, R5, R6, R7, RI3, A and n are as defined for formula (I), which is subjected to coupling with a compound of formula (VIII):
Rb^/Ci | (vni) wherein R;1 and Rb are as defined for formula (I), to yield the compound of formula (I), which may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considered appropriate during the course of the I0 process described above, some groups (hydroxy, amino..,) of the starting reagents or of the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.
The compounds of formulae (II), (III), (V) and (VIII) are either commercially available or can be obtained by the person skilled in the art using conventional Chemical reactions 15 described in the literature.
The invention relates also to compound of formula (VlA), a particular case of compound of formula (VI):
(VIA) wherein:
ORIGINAL
- I7- ♦ R2’, R3, R.)’ and R5' independently of one another represent a halogen atom, a linear or branched (Cj-C6)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (Ci-Cû)polyhaloalkyl, a hydroxy group, a hydroxy(Ci-C6)alkyl group, a linear or branched (Cj-CèJalkoxy group, a -S-(C|-C6)alkyl group, a cyano group, a nitro group,
-alkyl(C0-C6)-NR9R9', -O-alkyl(C,-C6)-NR9R9·, -O-alkyl(C]-C6)-Ri0, -C(O)-OR9, -O-C(O)-R9, -C(O)-NR9R9’, -NR9-C(O)-R9’, -NR9-C(O)-OR9’,
-aIkyl(C|-C6)-NR9-C(O)-R9’, -SO2-NR9R9\ -SO2-alkyl(Cl-C6), ♦ T represents a (C|-C&)alkyl group, a (Ci-C6)carbonyloxy(C|-C6)alkyl group or a
IO di(C|-C6)alkylaminocarbonyl(Ci-C6)alkyl group, ♦ R|. R6, R7. R13, A and n are as defined for formula (I), its enantiomers, diastereoisomers and atropisomers, and addition salis thereof with a pharmaceuticaily acceptable acid or base, as synthesis intermediate but also as compound for use as pro-apoptotic agents.
The invention relates to compound of formula (VIlA), a particular case of compound of
wherein:
♦ R2’. R3’, R|’ and R,' independently of one another represent a halogen atom. a 20 linear or branched (Cj-Côjalkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (C i-Côjpolyhaloalkyl, a hydroxy group, a hydroxy(Ci-C6)alkyl group, a linear or branched (Cj-Cèlalkoxy group, a “S-(C|-Cf>)alkyl group, a cyano group, a nitro group, -alkyl(Co-C6)-NR9R9’, -O-alkyl(CrC6)-NR9R9’, -O-alkyl(CrC6)-RI0. -C(O)-OR9,
ORIGINAL
- 18 -O-C(O)-R9, -C(O)-NR9R9\ -NR9-C(O)-R9’, -NR9-C(O)-OR9’,
-alkyl(CrC6)-NR9-C(O)-R9’, -SO2-NR9R9’, -SO2-alkyl(C,-C6), ♦ R[, Rd, R7, R13, A and n are as defined for formula (I), its enantiomers, diastereoisomers and atropisomers, and addition salts thereof with a 5 pharmaceutically acceptable acid or base, as synthesis intermediate but also as compound for use as pro-apoptotic agents.
Advantageously, for compounds of Formula (VIA) and (VlIA), the substituents of the pair (Ri. Rs’) are identical and the substituents of the pair (R2‘, R4') are identical.
Preferred compound of formula (VIIA) is (2Æ)-2-{[5-{3,5-dichloro-2,6-dimethyl-4-[2-(4I0 methylpiperazin-l-yl)elhoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yI] oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid.
The invention relates also to compound of formula (Vfo), a particular case of compound of formula (VI):
I5 wherein:
♦ R5’ represents a halogen atom, a linear or branched (C|-Cf,)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-Cô)alkynyl group, a linear or branched (Ci-C6)polyhaloalkyl, a hydroxy group, a hydroxy(Ct-C6)alkyl group, a linear or branched (C|-C6)alkoxy group, a -S-(Ci-C6)alkyI group, a cyano group, 20 a nitro group, -alkyl(Co-C6)-NR9R9?, -O-alkyl(C|-C6)-NR9R9\ -O-alkyl(C[-C(,)-Ri0,
-C(O)-OR9, -O-C(O)-R9, -C(O)-NR9R9’, -NR9-C(O)-R9’, -NR9-C(O)-OR9’, -alkyl(CrC6)-NR9-C(O)-R9·. -SO2-NR9R9’, -SO2-alkyl(Cl-C6).
ORIGINAL
- I9- ♦ T represents a (Ci-Cô)alkyl group, a (CrC6)carbonyloxy(C|-C6)alkyl group or a di(C|-C6)alkylaminocarbonyl(CrC6)alkyl group, ♦ R|, R-3, R,,. R7, R]3, A and n are as defined for formula (I), and wherein the substituents of the pair (R,, R5’) are identical, its enantiomers, diastereoisomers and atropisomers, and addition salts thereof with a pharmaceuticaily acceptable acid or base, as synthesis intermediate but also as compound for use as pro-apoptotic agents.
The invention relates to compound of formula (VllB), a particular case of compound of formula (Vil):
wherein:
♦ Rf represents a halogen atom, a linear or branched (C]-C6)alkyl group, a linear or branched (C2-C6)alkenyl group. a linear or branched (C2-C6)alkynyl group, a linear or branched (C|-Cf,)polyhaloalkyl, a hydroxy group, a hydroxy(C|-Cf,)alkyl group, a linear or branched (Cj-CôJalkoxy group, a -S-(C|-C(,)alkyl group, a cyano group. a nitro group, -alkyl(C0-C6)-NR9R9', -O-alkyI(Ci-C6)-NR9R9\ -O-alkyl(C|-C6)-Rl0, -C(O)-OR9, -O-C(O)-R9, -C(O)-NR9R9’. -NR9-C(O)-R9’, -NR9-C(O)-OR9'. -alkyl(Ci-C6)-NR9-C(O)-R9’, -SO2-NR9R9\ -SO2-alkyl(Ci-C6), ♦ Rj, R3, R(„ R7, R13, A and n are as defined for formula (I), and wherein the substituents of the pair (R|, R5’) are identical, its enantiomers, diastereoisomers and atropisomers, and addition salts thereof with a pharmaceuticaily acceptable acid or base,
ORIGINAL
-20as synthesis intermediate but also as compound for use as pro-apoptotic agents.
Preferred compounds of formula (VIIb) is (27?)-2-{[5-{2,6-dimethyl-4-[2-(4-methyl piperazin-1 -yl)ethoxy]phenyl} -6-(4-fluorophenyl)thieno[2,3-t/]pyrimidin-4-yl]oxy}-3-(2{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid.
Pharmacological study of the compounds of the invention has shown thaï they hâve proapoptotic properties. The ability to reactivate the apoptotic process in cancerous cells is of major therapeutic interest in the treatment of cancers and of immune and auto-immune diseases.
More especially, the compounds according to the invention will be useful in the treatment of chemo- or radio-resistanl cancers.
Among the cancer treatments envisaged there may be mentioned, without implying any limitation, treatment of cancers of the bladder, brain. breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
The présent invention relates also to pharmaceutical compositions comprising at least one compounds of formulae (I), (VIA), (VlB), (VIlA) or (VIlB) in combination with one or more pharmaceutically acceptable excipients.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parentéral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets or dragées, sublingual tablets, sachets, paquets, capsules, glossettes. lozenges. suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.
ORIGINAL
-2l The dosage varies according to the sex, âge and weight of the patient, the administration route, the nature of the therapeutic indication, or of any associated treatments, and ranges from 0.01 mg to l g per 24 hours in one or more administrations.
Furthermore, the present invention reiates also to the combination of a compound of formulae (I), (VIA), (VIB), (VIIA) or (VIIB) with an anticancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, protéasome inhibitors, kinase inhibitors and antibodies, and also to pharmaceutical compositions comprising that type of combination and their use in the manufacture of médicaments for use in the treatment of cancer.
Advantageously. the present invention relates to the combination of a compound of formulae (I), (VIA), (VIB), (VIlA) or (VIIB) with an EGFR inhibitor, and also to pharmaceutical compositions comprising that type of combination.
In another embodiment, the present invention relates to the combination of a compound of formulae (I), (VIA), (VlB), (VllA) or (VIlB) with a mTOR/PI3K inhibitor, and also to pharmaceutical compositions comprising that type of combination.
In a preferred embodiment, the present invention relates to the combination of a compound of formulae (I), (VIA), (VIB), (VIIA) or (VIIB) with a MEK inhibitor, and also to pharmaceutical compositions comprising that type of combination.
Preferably, the present invention relates to the combination of a compound of formulae (I), (VlA), (VIB), (VIlA) or (VlIB) with a HER2 inhibitor. and also to pharmaceutical compositions comprising that type of combination.
Advantageously, the present invention relates to the combination of a compound of formulae (I), (VIA), (VIB), (VIIA) or (VIIB) with a RAF inhibitor, and also to pharmaceutical compositions comprising that type of combination.
In another embodiment, the present invention relates to the combination of a compound of formulae (l), (VlA), (VIB), (VlIA) or (VIIB) with a EGFR/HER2 inhibitor, and also to pharmaceutical compositions comprising that type of combination.
In a preferred embodiment, the present invention relates to the combination of a compound of formulae (I), (VIA), (VIB). (VIlA) or (VIIB) with a taxane, and also to pharmaceutical compositions comprising that type of combination.
ORIGINAL
- 22 In another embodiment, the present invention relates to the combination of a compound of formulae (i), (VIA), (VIb), (V1Ia) or (VHb) with a protéasome inhibitor, an immunomodulator or an alkylating agent, and also to pharmaceutical compositions comprising that type of combination.
The combination of a compound of formulae (I), (VlA), (VIb), (VIIA) or (VIIb) with an anticancer agent may be administered simultaneously or sequentially. The administration route is preferably the oral route, and the corresponding pharmaceutical compositions may allow the instantaneous or delayed release of the active ingrédients. The compounds of the combination may moreover be administered in the form of two separate pharmaceutical 10 compositions, each containing one of the active ingrédients, or in the form of a single pharmaceutical composition, in which the active ingrédients are in admixture.
The compounds of the invention may also be used in combination with radiotherapy in the treatment of cancer.
Finally, the compounds of the invention may be linked to monoclonal antibodies or J5 fragments thereof or linked to scaffold proteins that can be related or not to monoclonal antibodies.
Antibody fragments must be understood as fragments of Fv, scFv, Fab, F(ab')2. F(ab'), scFv-Fc type or diabodies, which generally hâve the same specificity of binding as the antibody from which they are descended. According to the present invention, antibody 20 fragments ol' the invention can be obtained starting from antibodies by methods such as digestion by enzymes, such as pepsin or papain, and/or by cleavage of the disulfide bridges by Chemical réduction. In another manner, the antibody fragments comprised in the present invention can be obtained by techniques of genetic recombination likewise well known to the person skilled in the art or else by peptide synthesis by means of, for example, 25 automatic peptide synthesizers such as those supplied by the company Applied Biosystems, etc.
Scaffold proteins that can be related or not to monoclonal antibodies are understood to mean a protein that contains or not an immunoglobulin fold and that yields a binding capacity similar to a monoclonal antibody. The man skilled in the art knows how to select
ORIGINAL
-23the protein scaffold. More particularly, it is known that. to be selected, such a scaffold should display several features as follow (Skerra A., J. Mol. Recogn. 2000, 13, 167-187): phylogenetically good conservation, robust architecture with a well-known threedimensional molecular organization (such as, for example, crystallography or NMR), small size, no or only a low degree of post-translational modifications, easy to produce, express and purify. Such a protein scaffold can be, but without limitation, a structure selected from the group consisting in fibronectin and preferentially the tenth fibronectin type III domain (FNfnlO), lipocalin, anticalin (Skerra A., J. Biotechnol. 2001,74(4), 257-75), the protein Z dérivative from the domain B of staphylococcal protein A. thioredoxin A or any protein with a repeated domain such as an ankyrin repeat (Kohl et al., PNAS 2003, 100(4). 1700-1705), armadillo repeat, leucine-rich repeat or tetratricopeptide repeat. There could also be mentioned a scaffold dérivative from toxins (such as, for example, scorpion, insect, plant or mollusc toxins) or protein inhibitors of neuronal nitric oxide synthase (PIN).
The following Préparations and Examples illustrate the invention but do not limit it in any way.
General Procedures
Ail reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying.
Flash chromatography was performed on ISCO CombiFlash Rf 200i with pre-packed silica-gel cartridges (RediSe/?® Λ r Gold High Performance).
Thin layer chromatography was conducted with 5x10 cm plates coated with Merck Type 60 F254 silica-gel.
ORIGINAL
-24Microwave heating was performed in an Anton Pair MonoWave or CEM Discover® instrument.
Préparative HPLC purifications were performed on an Armen Spot Liquid Chromatography System with a Gemini-NX* 10 pM Cl8, 250 mm x 50 mm i.d. column running at a llow rate of 118 mL min’1 with UV diode array détection (210 - 400 nm) using 25 mM aqueous NH4HCO3 solution and MeCN as eluents unless specilied otherwise.
Analytical LC-MS: The compounds of the present invention were characterized by high performance liquid chromatography-mass spectroscopy (HPLC-MS) on Agilent HP 1200 with Agilent 6140 quadrupole LC/MS, operating in positive or négative ion electrospray ionisation mode. Molecular weight scan range is 100 to 1350. Parallel UV détection was donc at 210 nm and 254 nm. Samples were supplied as a 1 mM solution in ACN, or in THF/H2O (1:1) with 5 pL loop injection. LCMS analyses were performed on two instruments, one of which was operated with basic. and the other with acidic eluents.
Basic LCMS: Gemini-NX, 3 pm, Cl8, 50 mm * 3.00 mm i.d. column at 23 °C, at a flow rate of 1 mL min'1 using 5 mM ammonium bicarbonate (Solvent A) and acetonitrile (Solvent B) with a gradient starting from 100 % Solvent A and finîshing at 100 % Solvent B over various/certain duration of time.
Acidic LCMS: ZORBAX Eclipse XDB-C18. 1.8 pm, 50 mm x 4.6 mm i.d. column at 40 °C, at a flow rate of 1 mL.niin'1 using 0.02 % v/v aqueous formic acid (Solvent A) and 0.02% v/v formic acid in acetonitrile (Solvent B) with a gradient starting from 100% Solvent A and finîshing at 100 % Solvent B over various/certain duration of time.
'H-NMR measurements were performed on Bruker Avance III 500 MHz spectrometer and Bruker Avance III 400 MHz spectrometer, using DMSO-dft or CDCI3 as solvent. '14 NMR data is in the form of delta values, given in part per million (ppm), using the residual peak of the solvent (2.50 ppm for DMSO-dc and 7.26 ppm for CDCI3) as internai standard. Splitting patterns are designated as: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br s (broad singlet), dd (doublet of doublets), td (triplet of doublets), dt (doublet of triplets), ddd (doublet of doublet of doublets).
ORIGINAL
-25Combination gas chromatography and low resolution mass spectrometry were performed on Agitent 6850 gas chromatograph and Agilent 5975C mass spectrometer using 15 m χ 0.25 mm column with 0.25 pm HP-5MS coating and hélium as carrier gas. Ion source: ΕΓ, 70 eV, 230°C, quadrupole: !50°C, interface: 300°C.
HRMS were determined on a Shimadzu IT-TOF, ion source température 200°C, ESI +/-, ionization voltage: (+-)4.5 kV. Mass resolution min. 10000.
Elementary analyses were performed on a Thermo Flash EA 1112 Elemental Analyzer.
| List of abbreviations | ||
| Abbreviation | Name | |
| 10 | Ac | acetyl |
| AlBN | 2-[( l -cyano-1 -methyl-ethyl)azo]-2-methyl-propanenitrile | |
| AtaPhos | b is(di-/cjr/-buty l ( 4-di methy lam i nopheny l )phosphi ne ) dichloropalladium(II) | |
| DCM | dichloromethane | |
| I5 | DIPA | diisopropylamine |
| DMF | dimethylformamide | |
| DMSO | dimethyl sulfoxide | |
| eq. | équivalent | |
| Et | ethyl | |
| 20 | HMDS | hexamethy Id i si I azane |
| 'Pr | isopropyl | |
| Me | methy] | |
| MeCN, ACN | acetonitrile | |
| NBS | A-bro m os ucc i n i m i de | |
| 25 | NCS | A-chlorosuccinimide |
| Bu | ?7-butyl |
ORIGINAL
| Ph | phenyl |
| r.t. | room température |
| 'Bu | /er/-butyl |
| /BuXPhos | 2-di(/er/-butylphosphino)-2’,4',6’-triisopropylbiphenyl |
| TFA | trifiuoroacetic acid |
| THF | tetrahydrofurane |
General procedure I:
Step l eq. of the appropriate alcohol and l .2 eq. pyridine were dissolved in DCM ( l .2 mL/mmol). 1.05 eq. I-chloroethyl chloroformate was slowiy added at -78 °C under nitrogen and the reaction mixture was stirred al -78 °C for 3 hours. The cold mixture was fîitered and the nitrate was concentrated under reduced pressure. The crude product was used without further purification.
Step B l eq. Préparation 12, Préparation 13 or Préparation 14 was dissolved in DMF (20 ml/mmol) under nitrogen. 6.7 eq. CS2CO3 and 8 eq. of the 1-chloroethyl carbonate reagent was added. The reaction mixture was stirred at room température until no further conversion was observed. The mixture was diluted with brine and it was extracted with DCM, dried with Na^SOj, fîitered and concentrated under reduced pressure. The crude product was purified via préparative reverse phase chromatography using 5 mM aqueous NH4HCO3 solution and acetonitrile as eluents to obtain the appropriate carbonate dérivative as a mixture of stereoisomers.
General procedure II:
Step A
1.05 eq. amine reagent and 1.15 eq. pyridine were dissolved in 1.3 mL/mmol DCM, then 1 eq. 1-chloroethyl chloroformate was added at -78 °C under nitrogen. The reaction
ORIGINAL
-27mixture was stirred at -78 °C untîl no further conversion was observed. The cold mixture was filtered; the filtrate was concentrated under reduced pressure (30 mbar) using a 30 °C bath. The crude product was used within 3 hours wilhout further purification.
Step B l eq. Préparation 12, Préparation 13 or Préparation 14 was dissolved in 20 ml/mmol DMF under nitrogen. 10 eq. CS2CO3, then 8 eq carbamate reagent (0.8M solution of crude product from Step A in DMF) was added. The reaction mixture was stirred at r.t. until no further conversion was achieved. The mixture was diluted with brine and it was extracted several times with ethylacetate. Combined organic layer was dried over MgSC>4, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and acetonitrile as eluents to obtain the carbamate dérivative.
Préparation 1: 5-Bromo-4-chIoro-6-iodo-thieno[2,3-rf]pyrimidine
Step A : 6-Iodo-3\A-thieno[2.3-d]pyritnidin-4-one
A 2 L round bottomed flask equipped with mechanical stirrer, thermometer and reflux condenser was charged with the solution of 433 mL acetic acid, 13 mL sulfuric acid and 87 mL water. 69.3 g 3//-thieno[2,3-i/]pyrimidin-4-one (0.46 mol). 51.9 g periodic acid (0.23 mol) and 104 g iodine (0.41 mol) were added lo the stirred solution heated to 60 °C for 1 hour, The resulting suspension was cooled to r.t., filtered off, washed with a mixture of acetic acid and water (5:1) and then with diethyl ether. The resulting beige crystalline solid was air dried. 'H NMR (500 MHz, DMSO-d6): 12.57 (br s, 1H). 8.09 (s, 1 H), 7.65 (s, 1H)
Step B: 4-Chloro-6-iodo-thieno[2.3-d]pyrimidine
A 1 L round bottomed flask equipped with mechanical stirrer, thermometer, reflux condenser and a CaCh-tube was charged with 113 mL phosphorous oxychloride and 35 mL ΛζΑ-dimethylaniline (0.29 mol). 75.54 g 6-iodo-3/7-thieno|2,3-if|pyrimidin-4-one (0.27 mol) was added to the mixture in portions during 5 minutes. The reaction mixture was stirred at 105 °C for 1 hour. The resulting suspension was cooled to 10 °C, filtered and
ORIGINAL
-28washed with hexane. The crude product was added to ice water and stirred for Î0 minutes, fîltered off, washed with cold water, diethyl ether and air dried. Beige crystalline solid was obtained. 'H NMR (400 MHz. DMSO-d6): 8.89 (s, IH), 7.98 (s, IH)
Step C: Préparation 1
A 2 L round bottomed flask equipped with mechanical stirrer, thermometer and a bubbler was charged with 600 mL acetonitrile. 84.9 g 4-chloro-6-iodo-thieno[2,3-iZ]pyrimidine (0.29 mol), 50.9 g NBS (0.29 mol) and 8.5 mL tetrafluoroboric acid diethyl ether complex were added. The reaction mixture was stirred at r.t. for 16 hours. Further 22.9 g (0.12 mol) NBS was added to the mixture in three portions. After cooling the suspension to 0 °C and stirring for further I hour the precipitate was fîltered off, wrashed with acetonitrile and air dried. Préparation 1 was obtained as beige crystalline solid. ‘H NMR (500 MFIz. DMSO-d6): 8.88 (s, IH)
Préparation 2; 5-Bromo-4-chloro-6-(4-fluorophenyl)thieno[2,3-r/]pyrimidinc
75.08 g Préparation 1 (200 mmol), 53.63 g 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2dioxaborolane (240 mmol). 130 g césium carbonate (400 mmol), 2.245 g Pd(OAc)2 (10 mmol) and 8.50 g ‘BuX-Phos (20 mmol) were placed in a 2 L flask. 600 mL THF and 200 mL water were added, and then stirred overnight at 70 °C under argon atmosphère. THF was evaporated, and then the product was collected by filtration. Crude product was sonicated in 250 mL acetonitrile and fîltered again. Then Préparation 2 was crystalized from EtOH / THF (2:1). ’H NMR (400 MHz. DMSO-d6): 9.02 (s, IH), 7.80-7.77 (m, 2H). 7.47-7.43 (m, 2H)
Préparation 3: Ethyl (2Æ)-2-acetoxy-3-(2-liydroxyplienyl)propanoate
Step A: [2-(Bromomethyl)phenyl]ace(ate
60.07 g 2-methylphenyl acetate (400 mmol) and 106.8 g NBS (600 mmol) were placed in a 1 L flask. 500 mL cyclohexane was added. and then with intensive stirring 3.284 g AiBN (20 mmol) was added over 30 minutes. The mixture was stirred at 80 °C until no further conversion was observed, then cooled to r.t. The precipitate was fîltered off and washed
ORIGINAL
-29with cyclohexane. The mother liquor was concentrated under reduced pressure, and the crude product was used in Step B without further purification.
Step B: Préparation 3
23.10 g anhydrous LiCI (545 mmol) and 65.36 g anhydrous ZnClz (479.6 mmol) were placed in a 2 L flask. then dried at 160 °C under O.l mml-lg for I hour. After cooling to r.t.under argon atmosphère, 26.49 g magnésium tumings (l 090 mmol) and l L dry precooled (0 °C) THF were added. The resulting mixture was immersed into an ice-bath, and then stirred for 30 minutes.
100 g [2-(bromomethyl)phenyl]acetate -crude product from Step A- (~ 436 mmol) was dissolved in 120 mL dry THF and was added to the precooled inorganics over 15 minutes. After addition of the reagent the resulting mixture was stirred for 45 minutes while keeping the température between 0-5 °C. To the mixture 64.82 mL ethyl 2-oxoacetate (654 mmol, 50 % in toluene) was added over 5 minutes and the resulting mixture was stirred for another 15 minutes.
From the mixture the remaining inorganics were removed by filtration, and then 500 mL MeOH was added to the filtrate. This mixture was stirred until the intramolecular acetyl group migration from the phenolic oxygen to the alkyl oxygen was completed. To the mixture 30 mL acetic acid was added then the volatiles were evaporated under reduced pressure. To the residue 350 mL water was added and it was extracted with EtOAc. The combined organic layers were washed with saturated NaHCOs and with brine, and then dried over MgSO-i, filtered and evaporated under reduced pressure. To the residue 100 mL hexane was added and it was stirred for 30 minutes at 0 °C. The formed white cryslals were collected by filtration and washed with hexane yieiding enantiomers which were separated via chiral chromatography.
Colttmn: OD; Eiuents: heptane / EtOH; the (Sj-enantiomer eluting earlier was collected with 99.8 % ee and the (Æ)-enantiomer eluting later was collected as Préparation 3 w'ith 99.9 % ee.
‘H NMR (500 MHz, DMSO-d6) δ 9.53 (s, IH), 7.06 (t, IH), 7.04 (d, IH), 6.79 (d, IH),
6.71 (t. IH), 5.l0(dd, l H), 4.05 (q, 2H), 3.06 (dd, IH). 2.94 (dd, IH), 2.00 (s, 3H), l.09 (t, 3H)
ORIGINAL
-30Préparation 4: Ethyl (2Æ)-2-hydroxy-3-(2-tetrahydropyran-2-yloxyphenyl) propanoate
Step A: Ethyl (2R.)-2-acetoxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate
103,3 g Préparation 3 (409 mmol) was dissolved in 280 mL 3,4-dihydro-2H-pyran.
300 mg pizra-toluenesuifonic acid monohydrate was added and the mixture was stirred until no further conversion was observed. Then it was diiuted with l L ethyl acetate, washed with 200 mL saturated NaHCOa solution, then with 200 mL water. Combined organic layers were dried over Na2SO4, filtered and concentrated. Then it was purified via flash chromatography using heptane / EtOAc.
Step B: Préparation 4
137.57 g ethyl (27?)-2-acetoxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate (409 mmol) was dissolved in 600 mL éthanol, then 20 mL sodium ethoxide solution (IM in éthanol) was added and it was stirred until no further conversion was observed. The mixture was concentrated to half of its volume, then 300 mL water and 300 mL brine was I5 added, and it was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated. The enantiopurity of the starting material was conserved. 'H NMR (500 MHz, DMSO-dù, l:l mixture of diastereomers) Ô 7.16 (t, IH). 7.l3(d. IH). 7.04 (d, lH), 6.87 (t, lH), 5.51-5.47 (m. IH), 4.27 (m, lH), 4.04-4.02 (q. 2H). 3.73-3.56 (m, 2H), 3.06-3.04-2.74-2.71 (dd. 2H), I.95-1.64 (m. 2H), 1.79 (m. 2H), l.6520 1.50 (m, 2H), 1.12-1.10 (L 3H)
Préparation 5: Ethyl (2Æ)-2-[5-bromo-6-(4-fluoroplienyl)thicno|2,3-^|pyriniidin-4yl|oxy-3-(2-tetra-liydropyran-2-yIoxyphenyI)propanoate
48.45 g Préparation 2 (I4l mmol). 45.63 g Préparation 4 (155 mmol) and 137.8 g Cs2CO2 (423 mmol) were placed in a 2 L fiask. 1.4 L /er/-butanol was added and the 25 mixture was stirred at 70 °C under N2 until no further conversion was observed.
Approximately i L solvent was evaporated under reduced pressure, then it was diiuted with water, the pH was set to 8 with 2M HCl, and then it was extracted with DCM. The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced
ORIGINAL
- 31 pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Préparation 5 as a mixture of diastereoisomers.
‘H NMR (500 MHz, DMSO-d6): 8.67-8.66 (s, IH), 7.75 (m, 2H), 7.43 (dm. JH), 7.41 (m, 2H), 7.19 (m, IH), 7.08-7.06 (dm, IH), 6.89 (m, IH), 5.87-5.70 (dd, IH), 5.60-5.55 (m. IH), 4.23-4.08 (m, 2H), 3.80-3.48 (m, 2H), 3.52-3.49 (dd, IH), 3.19-3.17 (dd, IH), 2.09l.49(m, 6H), 1.15-1.I0 (t, 3H)
HRMS calculated for C28H26BrFN2O5S: 600.0730, found: 601.0809/601.0798 (M+H)
Préparation 6: 2-Chloro-3-methyl-4-(4,4,5,5-tetraniethyl-13,2-dioxaborolan-2-yl) phénol
Step A : (4-Bfomo-2-chloro-phenoxy)-trimethyl-silane
20.8 g 4-bromo-2-chloro-phenol (100 mmol) was dissolved in 150 mL dry THF then
24.2 g HMDS (150 mmol) was added. The reaction mixture was stirred at 85 °C under argon atmosphère for 1.5 hours then concentrated under reduced pressure resulting in the product used without further purification. ‘H NMR (200 MHz. CDClj): 7.49 (d, IH), 7.23 (dd, 1 H), 6.75 (d, 1 H), 0.26 (s, 9H)
Step B: 4-Bronio-2-chloro-3-niethyl-phenol mL nBuLi solution in hexanes (2.5 M, 120 mmol) was added dropwise to a solution of
12.1 g dry D1PA (120 mmol) in 250 mL dry THF at -78 °C under argon atmosphère. The mixture was stirred for 30 minutes at the same température then 28.0 g (4-bromo-2-chlorophenoxy)-trimethyl-sîlane (100 mmol) was added dropwise. After 2.5 hours 21.3 g Met (150 mmol) was added dropwise then the cooling bath was removed and the mixture was stirred overnighl. The reaction was quenched with 100 mL NH4OH solution and 200 mL NH4CI solution and extracted with EtOAc, dried over NaiSO4, filtered and concentrated under reduced pressure. The resulting dark mass was refluxed with pure hexane several times (150-150 mL aliquots) and decanted leaving a black tar behind. Combined organic phases were concentrated under reduced pressure affording 19.0 g crude product used without further purification. ’H NMR (200 MHz, CDCI3): 7.32 (d. IH), 6.76 (d, IH), 5.62 (s, lH),2.49(s, 3H)
ORIGINAL
-32Step C: (4-Bromo-2-chloro-3-methyl-phenoxy)-lriniethyl-silane
20.8 g HMDS (129 mmol) was added to the solution of 19.0 g 4-bromo-2-chloro-3-methylphenol (86.0 mmol) in 150 mL dry THF. The mixture was stirred at 85 °C under argon balloon for l .5 hours and then concentrated under reduced pressure. The obtained product was used without further purification. 'H NMR (200 MHz, CDCI3): 7.30 (d, IH), 6.63 (d, l H), 2.50 (s. 3H), 0.28 (s, 9H)
Step D: Préparation 6
A solution of 25.2 g (4-bromo-2-chloro-3-methyl-phenoxy)-trimethyl-silane (86.0 mmol) in 250 mL dry THF was cooled to -78 °C under argon and then 38 mL nBuLi in hexanes (2.5M, 94.6 mmol) was added dropwise. After 5 minutes 19.2 g 2-isopropoxy-4.4,5.5tetramethyl-l,3,2-dioxaborolane (103 mmol) was added dropwise. The cooling bath was removed and the mixture was slowly allowed to warm up to r.t. Then the mixture was added to 200 mL NH4CI solution and extracted with EtOAc. Combined organic layers were concentrated under reduced pressure and passed through a pad of silica gel using hexane and EtOAc as eluents. The crude product was recrystallized from a mixture of EtOAc and hexane to obtain Préparation 6. 'H NMR (500 MHz, DMSO-d6): 10.40 (s, IH), 7.42 (d, IH), 6.80 (d, IH), 2.49 (s, 3H), 1.27 (s, 12H)
Préparation 7: Ethyl (27f)-2-[(5^fl)-5-(3-chloro-4-hydroxy-2-methyl-phenyl)-6-(4fluorophenyl)thienof2,3-i/]pyrimidin-4-yl]oxy-3-(2-tetrahydropyran-2-yloxyphenyl) propanoate
186.6 g Préparation 5 (3I0.3 mmol) and 99.99 g Préparation 6 (372.3 mmol) were dissolved in l .2 L THF, then 202.2 g Cs2COj (620.6 mmol) dissolved in 300 mL water was added. Then l L0 g AtaPhos (15.51 mmol) was added, and the mixture was stirred under nitrogen at reflux température until no further conversion was observed. Most of the volatiles were evaporated under reduced pressure, then it was diluted with DCM and brine. After shaking the pH of the aqueous phase was set to 8 with 2M HCl. After phase séparation the aqueous phase was extracted with DCM. The organic layers were combined and dried over Na2SO4, filtered and concentrated under reduced pressure. The diastereoisomers were separated via flash chromatography using heptane and ethyl acetate as eluents. The diastereoisomer pair eluting later was collected as Préparation 7.
ORIGINAL
-33 lH NMR (500 MHz, DMSO-cL, l:l mixture of diastereomers): 10.27 (br s, IH), 8.60 (s, IH), 7.30 (m, 2H), 7.22 (m, 2H), 7.16-7.14 (d, IH), 7.12 (m ,1H), 7.00 (d, IH), 6.96 (d, IH), 6.74-6.73 (t. IH), 6.34-6.36 (d, IH), 5.55-5.52 (m, IH), 5.54-5.41 (dd, IH), 4.06 (q, 2H), 3.68-3.54 (m, 2H), 3.10-3.07 (dd, IH), 2.44 (dd, 1 H), 1.98-1.90 (brs, IH), 1.85-1.83 (s, 3H), 1.79 (br s, 2H), 1.64 (br s, IH), 1.59 (br s, IH), 1.54 (br s, IH), 1.09-1.08 (t, 3H) HRMS: (M+H) = 663.1728 and 663.1717
Préparation 8: Ethyl (21U-2-[(5Se)-5-[3-chloro-2-methyl-4-|2-(4-inethylpiperazin-lyl)ethoxy]phenyl|-6-(4-fluorophcnyl)thieno[2,3-rf| pyrimidin-4-yl|oxy-3-(2-tetrahydro pyran-2-yloxyphenyl)propanoate
132.3 g Préparation 7 (199.5 mmol), 43.17 g 2-(4-methylpiperazin-l-yl)ethanol (299.3 mmol) and 94.20 g PPI13 (359.1 mmol) were dissolved in 1 L dry toluene, then 78.09 g di-/er/-butyl azodicarboxylate (339.2 mmol) was added. The mixture was stirred at 50 °C under N2 until no further conversion was observed. 980 mL toluene was evaporated, then 500 mL EtjO was added, and the mixture was stirred and sonicated. The precipitated white crystals were fîitered. washed with EtiO to give 65.9 g pure triphenylphosphineoxide. The filtrate was concentrated under reduced pressure and purified via flash chromatography using EtOAc and MeOH as eluents to obtain Préparation 8. MS: (M+H) = 789.2
Préparation 9: Ethyl (2RJ)-2-|(5S„)-[3-chloro-2-niethyl-4-[2-(4-methylpiperazin-l-yl) ethoxy]phenyl|-6-(4-fluorophenyl)thicno[2,3-rf|pyrimidin-4-yl]oxy-3-(2-hydroxy phenyl)propanoate
199.5 mmol Préparation 8 was dissolved in 1 L EtOH, then l L 1.25M HCl in EtOH was added and the mixture was stirred at r.t. until no further conversion was observed. Most oi the EtOH was evaporated, then Et^O was added and the precipitated HCl sali (white solid) was fîitered, washed with EtjO. The HCl sait was carefully treated with saturated NaHCOs solution, extracted with DCM, the combined organic phases were dried over Na2SÛ4, fîitered and concentrated under reduced pressure to give Préparation 9.
'H NMR (400 MHz. DMSO-d6): 9.53 (br s. IH), 8.60 (s, IH). 7.30 (m, 2H), 7.28 (d, IH),
7.21 (m, 2H), 7.16 (d, IH), 6.97 (t. IH), 6.72 (d. IH). 6.53 (t. JH), 6.20 (d, IH), 5.46 (dd.
ORIGINAL
-34lH), 4.22 (m, 2H), 4.04 (m, 2H), 2.92 (dd, IH), 2.75 (m, 2H), 2.53 (br s. 4H). 2.44 (dd, l H), 2.36 (br s, 4H), 2.17 (s, 3H), l .88 (s, 3H), l .06 (t, 3H)
HRMS calculated for C37H38ClFN4O5S: 704.2235, found: 705.2288 (M+H)
Préparation 10: (£)-4-(Dimethylamino)-l,l-dimethoxy-but-3-en-2-one
502.1 g l,l-dimethoxypropan-2-one (4.25 mol) and 506.4 g l,l-diinethoxy-A,A-dimethylmethanamine (4.25 mol) were mixed in a 2 L flask and stirred at 105 °C for 3 hours. The formed MeOH was removed continuously via distillation. When MeOH formation stopped (at 65 °C head température) the reaction mixture was vacuum distilled (decreasing the pressure slowly to 30 mbar) to remove side products and unreacted starting materials. The crude product was distilled at 0.1 mbar. Fractions were collected between 107-118 °C head température (bath température 160-165 °C) to give a yellow oil. lH NMR (500 MHz, DMSO-dô): 7.59 (d, 1H), 5.17(d. 1H), 4.42 (s, 1 H), 3.25 (s, 6H), 3.09 (s, 3H), 2.78 (s, 3H)
Préparation 11 : [2-(2-Methoxyphenyl)pyrinùdin-4-ylJinethanol
Step A: 4-(dimethoxyniethyl)-2-(2-methoxyphenyl)pyrimidine
To the mixture of 2-methoxybenzamidine hydrochloride (1.2 eq.) and Préparation 10 (1 eq.) in dry methanol (0.5 mL/mmol) sodium methoxide (1.2 eq.) was added portionwise and the mixture was stirred at 75 °C for 2 hours. The reaction mixture was cooled and concentrated under reduced pressure. To the residue water was added and it was extracted with DCM. The combined organic layers were dried over MgSÛ4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents. 'H NMR (400 MHz, DMSO-df,):
8.93 (d, 1H). 7.55-7.44 (m, 3H), 7.16 (d, 1H), 7.06 (m, 1H). 5.31 (s, 1 H), 3.76 (s, 3H), 3.37 (s, 6H)
Step B: Préparation 11
261 mg 4-(dimethoxymethyl)-2-(2-methoxyphenyl)pyrimidine (1.0 mmol) was dissolved in 2 mL HCl in dioxane (4M solution), then 2 mL water was added and this mixture was stirred at 50 °C for 16 hours. The réaction mixture was cooled to 0 °C, then 320 mg NaOH (8.0 mmol) was added portionwise. The pH was adjusted to 8 using 10 % K.3CO3 solution.
ORIGINAL
- 35 then 76 mg sodium borohydride (2.0 mmol) was added and the mixture was stirred for 30 minutes at 0 °C. The reaction mixture was diluted with 5 mL water and extracted with EtOAc. The combined organic phases were dried over Na^SO,} and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane 5 and EtOAc as eluents to give Préparation 11. ’H NMR (400 MHz. DMSO-dô): 8.84 (d, 1H), 7.50-7.42 (m. 3H), 7.14 (d, 1H), 7.03 (m, 1H), 5.66 (t. 1H), 4.58 (d, 2H), 3.75 (s, 3H)
Préparation 12: (2Æ)-2-{|(51S'„)-5-{3-chloro-2-niethyl-4-[2-(4-methylpiperazin-l-yl) ethoxy|phenyl}-6-(4-fluorophenyl)thieno|2,3-7]pyrimidin-4-yl|oxy}-3-(2-{|2-(2methoxyphenyl)pyrimidin-4-yl]niethoxy}plienyl)propanoic acid
Step A eq. Préparation 9, 2 eq. of Préparation 11 and 2 eq. triphenyl phosphine were dissolved in absolute toluene (0.2M for the phénol), then 2 eq. di-/er/-butyl azodicarboxylate was added. The mixture was stirred at 50 °C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure 15 and the crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents.
Step B
The obtained intermediate was dissolved in dioxane-water 1:1 (10 mL/mmol) and 10 eq. LiOH χ HiO was added. The mixture was stirred at r.t. until no further conversion was 20 observed. Then it was diluted with brine, neutralized with 2M HCl. extracted with DCM.
The combined organic phases were dried over NaiSO^, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. HRMS calculated for C47H44C1FN6O6S: 874.2716; found 438.1415 (M+2H)
Préparation 13: (27f)-2-{[5-{3,5-dichloro-2,6-dimethyl-4-|2-(4-methylpiperazin-l-yl) ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/| pyrimidin-4-yl|oxy}-3-(2-{|2-(2methoxyphenyl)pyrimidin-4-yl|methoxy}phenyl)propanoic acid
ORIGINAL
- 36 Slep A : 4-bromo-2,6-dichloro-3,5-dimethyl-phenol
30.16 g 4-bromo-3,5-dimethyl-phenol (150 mmol) was dissolved in a mixture of 75 mL l,2-dichloroethane and 75 mL acetonitrile, then 40.06 g NCS (300 mmol) was added portionwise and the mixture was stirred at r.t. until no further conversion was observed. Reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCM, washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure and used in the next step without further purification. 'H NMR (400 MHz, DMSO-dft): 10.10 (s, 1H), 2.46 (s, 6H)
Slep B: l-bromo-3,5-dichloro-4-meihoxy-2,6-dimethyl-benzene
To a solution of 26.0 g 4-bromo-2,6-dichloro-3,5-dimethyl-phenol (96.3 mmol) and
26.60 g K2CO3 (192.6 mmol) in 300 mL MeCN 6.6 mL Mel ( 105.9 mmol) was added and the mixture was stirred at r.t. until no further conversion was observed. The solids were filtered off and the filtrate was concentrated under reduced pressure. The crude product was dissolved in DCM, washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure and used in the next step without further purification. 'H NMR (400 MHz, DMSO-d6): 3.78 (s, 3H), 2.49 (s, 6H)
Step C: 2-(3,5-dichloro-4-methoxy-2.6-dimethyl-phenyl)-4,4,5,5-teiramelhyl-1,3,2dioxaborolane
10.0 g l-bromo-3,5-dichloro-4-methoxy-2.6-dimethyl-benzene (35.2 mmol) was dissolved in 360 mL dry THF under nitrogen and was cooled to -78 °C with dry ice-acetone.
23.2 mL nBuLi ( 1.6 M in hexanes) (37.0 mmol) was added and the mixture was stirred for 15 minutes, then 8.6 mL 2-isopropoxy-4,4,5.5-tetramethyl-l,3.2-dioxaborolane (42.24 mmol) was added and the mixture was allowed to warm up to r.t. It was quenched with brine, extracted with DCM, dried over Na2SO4. filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain 2-(3,5-dichloro-4-methoxy-2,6-dimethyl-pheny 1)-4,4,5,5tetramethyl-1,3,2-dioxaborolane. !H NMR (400 MHz, DMSO-db): 3.81 (s, 3H), 2.33 (s, 6H), 1.34 (s, I2H)
Step D: ethyl 4-(3,5-dichloro-4-methoxy-2.6-dimethyl-phenyl)thiophene-3-carhoxylate
ORIGINAL
3.92 g ethyl 4-bromothiophene-3-carboxylate (16.68 mmol) and 9.9 g 2-(3,5-dichloro-4methoxy-2,6-dimethyl-phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (30.0 mmol) were dissolved in 140 mL dioxane, then 10,87 g Cs2COj (33.36 mmol) dissolved in 40 mL water was added. Then 590 mg AtaPhos (0.83 mmol) was added, and the mixture was stirred 5 under nitrogen at reflux température until no further conversion was observed. Then it was diluted with DCM and brine. After phase séparation the aqueous phase was extracted with DCM. The organic layers were combined and dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain ethyl 4-(3,5-dichloro-4-methoxy-2,6-dimethyl10 phenyl )thiophene-3-carboxylate.
’H NMR (400 MHz, DMSO-d(,): 8.53 (d, 1H), 7.47 (d, 1H), 4.02 (q, 2H), 3.83 (s, 311). 1.95 (s, 6H), 1.00 (t,3H)
HRMS (Μ+ΝΗ4Γ = 376.0538
Step E: ethyl 4-(3,5~dichloro-4-methoxy-2,6-dimethyl-phenyl)-2,5-diiodo-thiophene-315 carboxylate
2.65 g 4-(3,5-dichloro-4-methoxy-2,6-dimethyI-phenyl)thiophene-3-carboxylate (7.38 mmol) was dissolved in 75 mL acetonitrile, then 2.2 mL fluoroboric acid diethyl ether complex (16.23 mmol) and 3.65 g N-iodosuccinimide (16.23 mmol) was added and the mixture was stirred at r.t. until no further conversion was observed. Reaction mixture 20 was concentrated under reduced pressure, and the crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain ethyl 4-(3,5-dichloro-4methoxy-2,6-dirnelhyl-phenyl)-2.5-diiodo-thiophene-3-carboxylate. fH NMR (400 MHz. DMSO-d6): 3.98 (q, 2H), 3.84 (s, 3H), 1.92 (s, 6H), 0.84 (t, 3H)
Step F: ethyl 4-(3.5~dichloro-4-methoxy-2,6-dimethyl-phenyl)-5-iodo-thiophene-325 carboxylate
5.29 g 4-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-2,5-diiodo-thiophene-3- carboxylate (8.66 mmol) was dissolved in 90 mL dry THF, then cooled to -78 °C under argon atmosphère. 6.7 mL isopropyl magnésium chloride, lithium chloride complex ( 1.3 M in THF) (8,66 mmol) was added and the mixture was stirred at -78 °C for 30 minutes. Then 30 saturated aqueous NH4CI was added and the mixture was extracted with ethyl acetate. The
ORIGINAL
-38organic layer was dried over Na?SC>4 and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain ethyl 4-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-5-iodo-thiophene-3carboxylate. *H NMR (400 MHz, DMSO-dô): 8.71 (s, l H), 4.01 (q, 2H), 3.86 (s, 3H), 1.89 (s, 6H), 0.99 (t. 3H)
Step G: ethyl 4-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-5-(4-fluorophenyl) thiophene-3-carboxylate
4.20 g ethyl 4-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-5-iodo-thiophene-3carboxylate (8.66 mmol) and 1.82 g 4-fluorophenylboronic acid (13.0 mmol) were dissolved in 80 mL dioxane. then 5.64 g CS2CO3 ( 17.32 mmol) dissolved in 20 mL water was added. Then 500 mg Pd(PPIi3)4 (0.43 mmol) was added, and the mixture was stirred under nitrogen at 80 °C until no further conversion was observed. Then it was diluted with DCM and brine. After phase séparation the aqueous phase was extracted with DCM. The organic layers were combined and dried over Na2SO4. filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain ethyl 4-(3,5-dichloro-4-methoxy-2,6-dîmethyl-phenyl)-5(4-fluorophenyl)thiophene-3-carboxylate.
'H NMR (400 MHz. DMSO-d6): 8.58 (s, IH), 7.22-7.10 (m, 4H), 4.03 (q, 2H), 3.82 (s, 3H), 1.92 (s.6H), l .00 (t, 3H)
HRMS (Mi H)' =453.0498
Step H: ethyl 4-(3,5-dichloro-4-melhoxy-2.6-dimethyl-phenyl)-5-(4-fluorophenyl)-2-nitrothiophene-3-carboxylate l .97 g ethyl 4-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-5-(4-lluorophenyl) thiophene-3-carboxyIate (4.34 mmol) was dissolved in 40 mL dry acetonitrile, then 576 mg nitronium tetra fl uoroborate (4.34 mmol) was added and the mixture was stirred at r.t. until no further conversion was observed. Then it was diluted with DCM and brine. After phase séparation the aqueous phase was extracted with DCM. The organic layers were combined and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain ethyl 4-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-5-(4-fluorophenyl)-2-nitroORIG1NAL
- 39thiophene-3-carboxylate. ’H NMR (400 MHz. DMSO-d6): 7.37-7.33 (m. 2H), 7.32-7.26 (m, 2H), 4.14 (q, 2H), 3.82 (s, 3H), 2.06 (s, 6H), 0.88 (t. 3H)
Step 1: ethyl 2-anüno-4-(3,5-dichloro-4-niethoxy-2,6-dimethyl-phenyl)-5-(4-fliiorophenyl) thiophene-3-carboxylate
1.85 g ethyl 4-(3.5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-5-(4-iluorophenyl)-2-nitrothiophene-3-carboxylate (3.71 mmol) was dissolved in a mixture of 90 mL acetic acid and 18 mL water, then 2.43 g zinc dust (37.1 mmol) was added portionwise and the mixture was stirred at r.t. until no further conversion was observed. Reaction mixture was concentrated under reduced pressure, and the crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain ethyl 2-amino-4-(3,5dichioro-4-methoxy-2,6-dimethyl-phenyl)-5-(4-fluorophenyl)thiophene-3-carboxylate.
‘H NMR (400 MHz, DMSO-d6): 7.73 (s, 2H), 7.12-7.06 (m, 2H), 7.02-6.97 (m, 2H), 3.86-
3.80 (m, 2H). 3.80 (s, 3H), 2.01 (s, 6H), 0.72 (t, 3H)
HRMS (M- H)1 - 456.0598
Step J: 5-(3.5-dichloro-4-methoxy-2.6-dimethyl-phenyl)-6-(4-fluorophenyl)-3W-thieno [2,3-d]pyrimidin-4-one
1.10g ethyl 2-amino-4-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-5-(4-fluorophenyl) thiophene-3-carboxylate (2.35 mmol) was dissolved in 20 mL formamide and it was stirred at 150 °C until no further conversion was observed. Then it was poured onto water and the precipitated product was collected by filtration to give 5-(3,5-dichloro-4-methoxy-2,6dimethyl-phenyl)-6-(4-fluorophenyl)-3/7-thieno[2,3-cf]pyrimidin-4-one.
'H NMR (400 MHz. DMSO-d6): 12.53 (brs, 1H), 8.18 (s, 1H), 7.23-7.16 (m. 4H), 3.84 (s, 3H), 1.96 (s, 6H)
HRMS (M+H)+ = 449.0289
Step K: 4-chloro-5-(3,5-dichloro-4-methoxy-2.6-diinethyl-phenyl)-6-(4-fluorophenyl)thieno [2,3-dJpyrimidine
700 mg 5-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-6-(4-fluorophenyl)-3//-lhieno [2,3-i/]pyrimidin-4-one (1.56 mmol) was dissolved in 6 mL phosphorous oxychloride and it was stirred at 90 °C until no further conversion was observed. Reaction mixture was
ORIGINAL
-40concentrated under reduced pressure, then to the crude product icy water was added and it was sonicated for 10 minutes. The precipitated product was collected by filtration to give
4-chloro-5-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-6-(4-fluorophenyl)thieno[2,3-</] pyrimidine.
‘H NMR (400 MHz, DMSO-d6): 9.02 (s, I H), 7.38-7.26 (m, 4H), 3.86 (s, 3H), 1.99 (s, 6H) HRMS (M+Hf = 466.9954
Step L: 2,6-dichloi o-4-[4-chloro -6-(4-fl uorophenyl)thieno[2,3 -dJpyri midin-5 -yl/-3,5dimethyl-phenol and 4-[4-bromo-6-(4-fluorophenyl)thieno[2,3-à]pyrimidin~5-yl]-2,6dichloro-3.5-dimethyl-phenol
To a stirred solution of 700 mg 4-chloro-5-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-
6-(4-fluorophenyl)thieno[2,3-i/]pyrimidine (1.50 mmol) in 15 mL DCM 3.0 mL boron tribromide (l M in DCM) (3.0 mmol) was added at 0 °C and the mixture was allowed to warm up to r.t. and it was stirred until no further conversion was observed. The mixture was quenched with saturated aqueous NH4Cl and extracted with DCM. The combined organic phases were dried over NajSCE and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and EtOAc as eluents to obtain 2,6-dichloro-4-[4-chloro-6-(4-fluorophenyl)thieno[2,3-<7]pyrimidin-5-yl]-3,5dimethyl-phenol and 4-[4-bromo-6-(4-fluorophenyl)thieno[2,3-i7]pyriinidin-5-yl]-2,6dichloro-3.5-dimethyl-phenoI as a 37:63 mixture of products.
1H NMR (400 MHz. DMSO-dh): 10.14 (br s. 1 H), 9.01 (s, 1H), 7.40-7.23 (m, 4H), 1.95 (s, 6H) and 10.14 (br s. 1H). 8.93 (s, 1H). 7.40-7.23 (m, 4H), 1.93 (s. 6H)
HRMS (M+H)+ = 452.9800 and 496.9287
Step M: 4-chIoro-5-[3.5-dic'hloi‘o-2.6-dimefhyl-4-[2-(4-methylpiperazin-l -yl)ethoxy] phenyl]-6-(4-fluorophenyl)thieno[2,3-àJpyrimidine and 4-bromo-5-[3,5-dichloro-2.6dimethyl-4-[2~(4-methylpiperazin-}-yl)ethoxy]phenyl]-6-(4-fhiorophenyl)thieno[2,3-à] pyrimidine
300 mg mixture of 2,6-dichloro-4-[4-chloro-6-(4-fluorophenyl)thienof2,3-iïr|pyrimidin-5yl]-3,5-dimethyl-phenol and 4-[4-bromo-6-(4-fluorophenyl)thieno[2,3-iirlpyrimidin-5-yl]-
2,6-dichloro-3,5-dimethyl-phenol (0.62 mmol), 286 mg 2-(4-methylpiperazin-l-yl)ethanol (1.98 mmol) and 520 mg triphenyl phosphine (1.98 mmol) were dissolved in 10 mL dry
ORIGINAL
-4l toluene, then 460 mg di/e/7-butyl azodicarboxylate ( l .98 mmol) was added. The mixture w'as stirred at 50 °C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and methanol as eluents to obtain 4-chloro-5-[3,5-dichloro5 2,6-dimethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-i7] pyrimidine and 4-bromo-5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-1 -y] ) ethoxy]phenyI]-6-(4-fluorophenyl)thîeno[2.3-<'/]pyrimidine as a 35:65 mixture of products. ’H NMR (400 MHz, DMSO-d6): 9.02 (S, lH), 7.40-7.22 (ni, 4H), 4.ll (t, 2H), 2.78 (t.
2H), 2.63-2.20 (m, 8H), 2.17 (br s, 3H), 1.98 (s, 6H) and 8.94 (S, IH), 7.40-7.22 (m, 4H),
4.ll (t. 2H), 2.78 (t,2H), 2.63-2.20 (m,8H),2.l 5 (brs, 3H), l.98(s, 6H)
HRMS (M+Hf = 579.0968 and 623.0455
Step N: (E)~4-(Diutethylamino)-l, l-dimethoxy-but-3-en-2-one
502.1 g l,l-dimethoxypropan-2-one (4.25 mol) and 506.4 g l,l-dimethoxy-A,jV-dimethylmelhanamine (4.25 mol) were mixed in a 2 L flask and stirred at 105 °C for 3 hours. The 15 fornied MeOH was removed continuously via distillation. When MeOH formation stopped (at 65 °C head température), the reaction mixture was vacuum distilled (decreasing the pressure slowly to 30 mbar) to remove side products and unreacted starting materîals. The crude product was distilled at O.l mbar. Fractions were collected between 107-118 °C head température (bath température 16O-165°C) to give a yellow oil. *H NMR (500 MHz, 20 DMSO-d6): 7.59 (d. IFI), 5.17 (d, lH), 4.42 (s. IH), 3.25 (s. 6H). 3.09 (s. 3H). 2.78 (s, 3H)
Step O: 4-(diinethoxymethyl)-2-(2-methoxyphenyl)pyrimidine
To the mixture of 2-methoxybenzamidine acetic acid sait (1.2 eq.) and (£7)-4(dimethylamino)-l,l-dimethoxy-but-3-en-2-one (l.O eq.) in dry methanol (0.5 mL/mmol) sodium methoxide (1.2 eq.) was added portionwise and the mixture was stirred at 75 °C for 25 2 hours. The reaction mixture was cooled and concentrated under reduced pressure. To the residue water was added and it was extracted with DCM. The combined organic layers were dried over MgSOj, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give
4-(dimethoxymethyl)-2-(2-methoxyphenyl)pyrimidine. ’H NMR (400 MHz, DMSO-df,):
ORIGINAL
8.93 (d, IH), 7.55-7.44 (m, 3H). 7.16 (d, IH), 7.06 (m, IH), 5.31 (s. IH), 3.76 (s, 3H). 3.37 (s, 6H)
Step P: [2-(2-methoxyphenyljpyrinüdin-4-y!]methanol
261 mg 4-(dimethoxymethyl)-2-(2-methoxyphenyi)pyrimidine (i.00 mmol) was dissolved in 2 mL HCl in dioxane (4 M solution), then 2 mL water was added and this mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled to 0 °C, then 320 mg NaOH (8.0 mmol) was added portionwise. The pH was adjusted to 8 using 10 % K.2CO3 solution, then 76 mg sodium borohydrîde (2.0 mmol) was added and the mixture was stirred for 30 minutes at 0 °C. The reaction mixture was diluted with 5 mL water and extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to give the title product. ’H NMR (400 MHz, DMSO-d6): 8.84 (d, IH), 7.50-7.42 (m, 3H), 7.I4 (d, IH), 7.03 (m, IH), 5.66 (t, l H), 4.58 (d, 2H), 3.75 (s, 3H)
Step Q: (2R.)-2-Hydroxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]inethoxy]phenyl] propanoic acid
37.84 g (150 mmol) Préparation 3, 48.65 g (225 mmol) [2-(2-methoxyphenyl)pyrimidin-
4-yl]methanol and 59.01 g (225 mmol) triphenyl phosphine were dissolved in 160 mL absolute toluene, then 102.47 mL (225 mmol) diethylazodicarboxylate was added. The mixture was stirred at 50 °C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure. Then 400 mL Et2O was added, the mixture was sonicated and filtered (to remove PPI13). Et2O was removed in vacuo. Residue was dissolved in 130 mL THF, then 30 g NaOH in 130 mL H2O was added. The mixture was stirred at r.t. until no further conversion was observed. Then it was acidified with 2 M HCl, THF was removed in vacuo. 300 mL DCM was added. and the precipitate was filtered, washed with cold H2O and DCM dried in vacuo to obtain(2/?)-2-hydroxy-3-[2-[[2(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoic acid. ’H-NMR (400 MHz. DMSO-dft): 8.88 (d, IH), 7.80 (d, IH), 7.55 (dd. IH), 7.49-7-44 (m, IH), 7.26 (dd. IH), 7.17-7.11 (m. 2H), 7.06 (t, IH), 6.98 (d, IH), 6.88 (t. IH), 5.22 (s, 2H), 3.81 (dd, IH), 3.77 (s, 3H), 3.73 (dd, l H), 2.44 (dd, l H)
ORIGINAL
-43 Step R: Ethyl (2R)-2-hydroxy-3-[2-[[2-(2~methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl] propanoate
51,7 g (136 mmol) (2Æ)-2-hydroxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy] phenyl]propaneic acid was dissolved in 520 mL EtOH, then 20 mL concentrated H2SO4 5 was added. The mixture was stirred at 60 °C until no further conversion was observed.
Then it was diluted with water, neutralized with concentrated NaHCOj solution and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure and purified via flash chromatography using EtOAc and MeOH as eluents to obtain ethyl (2/?)-2-hydroxy-3-[2-[[2-(2-methoxyphenyl) !0 pyrimidin-4-yl]niethoxy]phenyl]propanoate. HRMS calculated for C23H24N7O5: 408.1685, found:409.1757 (M+H)
Step S: Préparation 13
200 mg mixture of 4-chloro-5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-l-yl) ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-4/]pyrimidine and 4-bromo-5-[3,5-dichloro15 2,6-dimethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-i/] pyrimidine (0.33 mmol). 211 mg ethyl (27?)-2-hydroxy-3-|2-||2-(2-mcthoxyphenyl) pyrimidin-4-yl]methoxy]phenyl]propanoate (0.52 mmol) and 202 mg CS2CO3 (0.62 mmol) was dissolved in 5 mL /er/-butanol and the mixture was stirred at 70 °C until no further conversion was observed. It was diluted with ethyl acetate and then it was washed with 20 brine. The organic layer was dried over Na2SO4. filtered and concentrated under reduced pressure and purified via flash chromatography using EtOAc and methanol as eluents to obtain ethyl (27?)-2-[ 5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy] phenyi]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy]phenyl]propanoate.
The obtained intermediate was dissolved in 5 mL dioxane-water 1:1 (10 mL/mmol) and 145 mg LiOH * H2O (3.45 mmol) was added. The mixture was stirred at r.t. until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HCl, extracted with DCM, dried over Na2SÛ4, filtered and concentrated under reduced pressure and purified via préparative reversed phase chromatography using 5 mM aqueous 30 NH4HCO3 solution and MeCN as eluents to obtain Préparation 13.
ORIGINAL
-44*H NMR (400 MHz, DMSO-d6): 8.89 (d. IH), 8.60 (s. IH), 7.81 (d. IH), 7.53 (dd, IH),
7.45 (td. IH), 7.29-7.21 (m, 4H), 7.17-7.13 (m, IH), 7.14 (d, IH), 7.04 (td, IH), 7.01 (d, IH), 6.76 (t, IH), 6.20 (d, IH), 5.45 (dd. IH), 5.26 (d. IH), 5.20 (d, IH), 4.06-4.01 (m, 2H), 3.76 (s, 3H), 3.46 (dd, IH), 2.79-2.74 (m, 2H), 2.67-2.38 (m, 8H), 2.33 (s, 3H), 2.26 (s, 3H), 2.22 (dd, IH), 1.73 (s, 3H)
HRMS (M+2H)2+ = 462.1310
Préparation 14: (2/f)-2-{[5-{2,6-diniethyl-4-|2-(4-methylpiperazin-l-yl)ethoxy| phenyl}-6-(4-fluorophenyl)thieno[2,3-rf| pyrimidin-4-yl|oxy}-3-(2-{[2-(2-methoxy phenyl)pyrimidin-4-yl|methoxy}phenyl)propanoic acid
Using the procedure as described in Préparation 13 and starting directiy from Step B with
4-bromo-3.5-dimethyl-phenol instead of 4-bromo-2,6-dichloro-3,5-dimethyl-phenol, Préparation 14 is obtained.
Example 1: l-[(methoxycarbonyl)oxy]ethyl (2/f)-2-{|(55’a)-5-{3-chloro-2-methyl-4-[2(4-methylpiperazÎn-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4yl]oxy}-3-(2-{|2-(2-methoxyplienyl)pyrimidin-4-yl]methoxy}phenyl)propanoate
Using General procedure I with Préparation 12 and methanol as the appropriate alcohol, Example 1 was obtained. HRMS calculated for CjiHsoCIFNôOgS: 976.3033; found 489.1604 and 489.1572 (M+2H)
Example 2: l-|(etlioxycarbonyl)oxy]ethyl (2/f)-2-{|(55n)-5-{3-chloro-2-methyl-4-|2-(4methylpiperazÎn-l-yl)etIioxy]phenyl}-6-(4-fIuorophenyl)thieno[2,3-i/| pyrimidin-4-yl| oxy}-3-(2-{|2-(2-methoxyphenyl)pyrimidin-4-yl|methoxy}phenyI)propanoate
Using General procedure 1 with Préparation 12 and éthanol as the appropriate alcohol, Example 2 was obtained. HRMS calculated for C52H52CIFN6O9S: 990.3189; found 496.1649 and 496.1685 (M+2H)
ORIGINAL
-45Example 3: l-{|(propan-2-yloxy)carbonyl]oxy}ethyI [ (5ΛΥ)-5-{3-cli loro-2methyl-4-|2-(4-methylpiperazin-l-yl)ethoxy|phenyl}-6-(4-fluorophenyl)thieno[2,3-i/] pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl) propanoate
Using General procedure I with Préparation 12 and 2-propanol as the appropriate alcohol, Example 3 was obtained. HRMS calculated for C53H54CIFN6O9S: 1004.3345; found 503.1766 (M+2H)
Example 4: l-|(/£ri-butoxycarbonyl)oxy|ethyl (27f)-2-{|(55, fl)-5-{3-chIoro-2-methyl-4|2-(4-methylpiperazin-l-yl)etlioxy|phcnyl}-6-(4-fluorophenyl)thieno[2,3-i,/]pyrimidin4-yl|oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl|methoxy}pIienyl)propanoate
Using General procedure I with Préparation 12 and 2-methyl-2-propanol as the appropriate alcohol, Example 4 was obtained. HRMS calculated for C54H56CIFN6O9S: 1018.3502; found 510.1837 (M+2H)
Example 5: l-{[(cyclopentyloxy)carbonjl]oxy}ethyl (2Æ)-2-{[(515fl)-5-{3-chloro-2methyI-4-[2-(4-methylpiperazin-l-yl)ethoxy|phenyl}-6-(4-fIuorophenyl)thieno[2,3-i/| pyrimidin-4-yl]oxy}-3-(2-{|2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}plienyi) propanoate
Using General procedure I with Préparation 12 and cyclopentanol as the appropriate alcohol, Example 5 was obtained. HRMS calculated for CjjHjftClFNbOQS: 1030.3502; found 516.1817 (M+2H)
ORIGINAL
-46Example 6: l-{[(octyloxy)carbonyl]oxy}ethyl (2Æ)-2-{[(55’ü)-5-{3-chloro-2-methyl-4-[2(4-methylpiperazin-l-yl)ethoxy|phenyl}-6-(4-fluorophenyl)thieno[2,3-r/]pyrimidin-4yl]oxy}-3-(2-{|2-(2-methoxyphenyl)pyrimidin-4-yl|methoxy}phenyl)propanoate
Using General procedure I with Préparation 12 and 1-octanoi as the appropriate alcohol.
Example 6 was obtained. HRMS calculated for CssHfriClFNsOyS: 1030.3502; found 538.2133 and 538.2149 (M+2H)
Example 7: l-[(dimethylcarbamoyl)oxy|ethyl (2/f)-2-{|(55,„)-5-{3-chloro-2-methyl-4[2-(4-methyipiperazin-l-yl)ethoxy|phenyl}-6-(4-fiuorophenyl)thieno|2,3-i/|pyrimidin4-yl|oxy}-3-(2-{|2-(2-methoxyphenyl)pyrimidin-4-yl]n)ethoxy}phenyl)propanoate
Using General procedure II with Préparation 12 and dimethylamine hydrochloride as amine reagent applying 2.15 eq. of pyridine in Step A, Example 7 was obtained. HRMS calculated for C52H53CIFN7O8S: 989.3349; found 495.6740 and 495.6738 (M+2H)
Example 8: l-[(diethylcarbamoyl)oxy|ethyl (2/?)-2-{[(5.S’ii)-5-{3-chloro-2-niethyl-4-|2(4-methyIpiperazin-l-yl)ethoxy|phenyl}-6-(4-fluorophenyl)thieno|2,3-i/|pyrimidin-415 yl|oxy}-3-(2-{|2-(2-methoxyphenyl)pyrimidin-4-yl[methoxy}phenyl)propanoate
Using General procedure II with Préparation 12 and dielhylamine as amine reagent. Example 8 was obtained. HRMS calculated for Cs4H57ClFN70gS: 1017.3662; found 509.6902 (M+2H)
Example 9: l-{[(2Æ)-2-{[(55„)-5-{3-chloro-2-metbyl-4-[2-(4-metliylpiperazin-l-yl) ethoxy]phenyl}-6-(4-f]uorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{|2-(2niethoxyphenyl)pyrimidin-4-yl]methoxy}phenyI)propanoyl|oxy}ethyl morpholine-4carboxylate
Using General procedure II with Préparation 12 and morpholine as amine reagent. Example 9 was obtained. HRMS calculated for C54H55CIFN7O9S: 1031.3455; found 25 516.6826 and 516.6821 (M+2H)
ORIGINAL
-47Example 10: l-{|(2-methoxyethyl)carbamoyl]oxy}ethyl (2/?)-2-{|(55,7)-5-{3-chloro-2methyl-4-[2-(4-methylpipcrazin-l-yl)ethoxy|phenyl}-6-(4-fluorophenyl)thieno|2,3-//] pyrimidin-4-yl|oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]metlioxy}phenyl) propanoate
Using General procedure II with Préparation 12 and 2-methoxyethanamine as amine reagent, Exaniple 10 was obtained. HRMS calculated for C53H55CIFN7O9S: 1019.3455; found 510.6809 and 510.6813 (M+2H )
Exaniple 11: l-{|bis(2-metlioxyethyl)carbamoyl|oxy}ethyl (2Æ)-2-{[(55e)_5-{3-chloro2-methy]-4-[2-(4-methylpiperazin-l-yl)ethoxy|phenyl}-6-(4-fluorophenyl)thicno[2,3-</| pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyriniidin-4-yl|methoxy}phenyl) propanoate
Using General procedure II with Préparation 12 and 2-methoxy-N-(2methoxyethyl)ethanamine as amine reagent. Example 11 was obtained. HRMS calculated for C56H6|CIFN7OioS: 1077.3873; found 539.7029 and 539.7017 (M+2H)
Example 12: l-{[(2-methoxy-2-oxoethyl)(methyl)carbamoyl|oxy}ethyl (2/f)-2-{|(55(i) 5-{3-cliloro-2-methyl-4-[2-(4-methylpiperazm-l-yl)ethoxy|phenyl}-6-(4-fluoroplienyl) thieno|2,3-r/]pyrimidin-4-yl|oxy}-3-(2-{[2-(2-methoxyphenyI)pyrimidin-4-yl]mcthoxy} phenyl)propanoate
Using General procedure II with Préparation 12 and methyl 2-(methylamino)acetate hydrochloride as amine reagent applying 2.15 eq. of pyridine in Step A, Exaniple 12 was obtained. HRMS calculated for C54H55CIFN7O10S: 1047.3403; found 524.6782 and 524.6781 (M+2H)
ORIGINAL
-48 Exaniple 13: (pliosphonooxy)methyl (2Æ)-2-{|(5Su)-5-{3-chIoro-2-methyl-4-[2-(4methyipiperazin-l-yl)ethoxy]phenyl}-6-(4-fliiorophenyl)thieno|2,3-i/]pyriniidÎn-4yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate
700 mg Préparation 12 (0.8 mmol), 233 mg di-/e/7-butyl chloromethyl phosphate (0.9 mmol), 240 mg sodium iodide (1.6 mmol) and 521 mg Cs2COj (1.6 mmol) were dissolved in 8 mL DMF and the reaction mixture was stirred at room température under nitrogen atmosphère until no further conversion was observed. The mixture was diiuted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO,4 and concentrated under reduced pressure. The crude product was purified via flash chromatography on silica gel using DCM and MeOH eluents to obtain the di-/m-butyl ester intermediate.
160 mg di-/er/-butyl ester (0.15 mmol) was dissolved in 8 mL DCM and cooled with ice water bath. 4 mL TFA was added slowly to the mixture. After the addition of TFA the mixture was stirred for further 15 minutes and then it was concentrated under reduced pressure to obtain the crude product in sait form. Préparative HPLC using formic acid solution and ACN followed by lyophilisation resulted in Example 13 as a white solid. HRMS calculated for C^yClFNôOioPS: 984.2485; found 493.1338 (M+2H)
Example 14: l-[(ethoxycarbonyl)oxy]ethyl (2/f)-2-{|5-{2,6-diniethyl-4-[2-(4-methyl piperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno|2,3-f/|pyrimidin-4-yl]oxy}-3(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]niethoxy}phenyI)propanoate
Using General procedure I with Préparation 14 and éthanol as the appropriate alcohol. Example 14 was obtained.
ORIGINAL
-49Example 15: l-[(ethoxycarbonyl)oxy|ethyl (27t)-2-{|5-{3,5-dichloro-2,6-dimethyl-4-[2(4-methylpiperazin-l-yl)ethoxy|phenyl}-6-(4-fluorophenyl)thieno[2,3-i/|pyrimidin-4yljoxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoatc
Using General procedure I with Préparation 13 and éthanol as the appropriate alcohol.
Example 15 was obtained. HRMS calculated for C53H53CI2FN6O9S: 1038.2955; fourni 520.1543 and 520.1549 (M+2H)2+
Example 16: l-[(dimethylcarbamoyl)oxy]ethyl (27?)-2-{[5-{2,6-dimethyl-4-|2-(4' methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno|2,3-rf|pyrimidin-4yl]oxy}-3-(2-{[2-(2-mcthoxyphenyI)pyrimidin-4-yl|methoxy}phcnyl)propanoate
Using General procedure II with Préparation 14 and dimethylamine hydrochloride as amine reagent applying 2.15 eq. of pyridine in Step A, Example 16 was obtained.
Example 17: l-[(dimethylcarbamoyl)oxy]cthyl (27f)-2-{[5-{3,5-dichloro-2,6-dimethyl4-[2-(4-methylpipcrazin-l-yl)ethoxy]phenyl}-6-(4-fiuorophenyl)thieno|2,3-r/| pyrimidin-4-yl]oxy}-3-(2-{[2-(2-metlioxyplienyl)pyrimidin-4-yl]methoxy}phenyI) propanoate
Using General procedure il with Préparation 13 and dimethylamine hydrochloride as amine reagent applying 2.15 eq. of pyridine in Step A, Example 17 was obtained. HRMS calculated for C53H54CI2FN7O8S: 1037.3115; found 519.6616 and 519.6632 (M+2H)2+
ORIGINAL
-50PHARMACOLOGICAL STUDY
EXAMPLE A: Inhibition of Mcl-1 bv the fluorescence polarisation technique
The relative binding potency of each compound was determined via Fluorescence Polarisation (FP). The method utilised a Fluorescein labelled ligand (Fluorescein-PAla5 Ahx-A-REIGAQLRRMADDLNAQY-OH; mw 2,765) which binds to the Mcl-1 protein (such that Mcl-1 corresponds to the UniProtKB*' primary accession number: Q07820) leading to an increased anisotropy measured in milli-polarisation (mP) units using a reader. The addition of a compound which binds competitively to the same site as the ligand will resuit in a greater proportion of unbound ligand in the System indicated by a decrease in 10 mP units.
An 11 point serial dilution of each compound was prepared in DMSO and 2 μΙ transferred into fiat bottomed, low binding, 384-well plate (final DMSO concentration 5 %). 38 μΙ of buffer (lOmM 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid [HEPES], 150 mM NaCl, 0.05 % Tween 20, pH 7.4), containing the Fluorescein labelled ligand (final 15 concentration 1 nM) and Mcl-1 protein (final concentration 5 nM) was then added.
Assay plates were incubated -2 hours at room température before FP was measured on a Biomek Synergy2 reader (Ex. 528 nm, Em. 640 nm, Cut off 510 nm) and mP units calculated. The binding of increasing doses of test compound was expressed as a percentage réduction in mP compared to a window established between l5 % DMSO only’ 20 and ‘ 100 % inhibition’ Controls. 11 -point dose response curves were plotted with XL-Fit software using a 4-Parameter Logistic Model (Sigmoidal Dose-Response Model) and the inhibitory concentrations that gave a 50 % réduction in mP (IC50) were determined. Results are presented in Table 1 below.
The results show that the compounds of the invention inhibit interaction between the Mcl-1 25 protein and the fluorescent peptide described hereinbefore.
ORIGINAL
-SI EXAMPLE B: In vitro cytotoxicity
The cytotoxicity studies were carried out on the H929 multiple myeloma tumour line.
The cells are distributed onto microplates and exposed to the test compounds for 48 hours.
The cell viability is then quantified by a colorimétrie assay, the Microculture Tétrazolium
Assay (Cancer Res., 1987, 47, 939-942).
The results are expressed in 1C5O (the concentration of compound that inhibits cell viability by 50 %) and are presented in Table l below.
The results show that the compounds of the invention are cytotoxic.
Table 1: IC50 of Mcl-1 inhibition (fluorescence polarisation test) and of cytotoxicity for H929 cells
| ICm(hM) Mcl-I l-P | 1C»(mM)MTT H929 | IC<u (μΜ) Mcl-l FP | IC» (μΜ)ΜΤΤ 11929 | ||
| Examplc 1 | 0.037 | ND | Example 11 | 0.551 | ND |
| Example 2 | 0.361 | ND | Example 12 | 0.318 | ND |
| Example 3 | 0.292 | ND | Examplc 13 | 0.0032 | ND |
| Example 4 | 0.959 | ND | Examplc 14 | ND | ND |
| Examplc 5 | 0.37 | ND | Examplc 15 | 0.453 | 0.068 |
| Example 6 | 0.51 | ND | Example 16 | ND | ND |
| Example 7 | 0.438 | ND | Examplc 17 | 1.536 | 0.702 |
| Examplc 8 | 1.41 | ND | |||
| Example 9 | 0.52 | ND | Préparation 13 | 0.00181 | 0.025 |
| Examplc 10 | 0.147 | ND | Préparation 14 | ND | ND |
ND: not determined
ORIGINAL
-52EXAMPLE C: Quantification of the cleaved form of PARP in vivo
The ability of the compounds of the invention to induce apoptosis, by measuring cleaved PARP levels, is evaluated in a xenograft model of AMO-l multiple myeloma cells.
I.IO7 AMO-l cells are grafted sub-cutaneously into immunosuppressed mice (SCID strain). 12 to 14 days aller the graft, the animais are treated by intraveinous or oral routes with the various compounds. After treatment, the tumour masses are recovered and lysed, and the cleaved form of PARP is quantified in the tumour lysâtes.
The quantification is carried out using the Meso Scale Discovery (MSD) ELIS A platform test, which specifically assays the cleaved form of PARP. It is expressed in the form of an activation factor corresponding to the ratio between the quantity of cleaved PARP in the treated mice divided by the quantity of cleaved PARP in the control mice.
The results show that the compounds ofthe invention are capable of inducing apoptosis in AMO-l tumour cells in vivo.
EXAMPLE D: Anti-tumour activity in vivo
The anti-tumour activity of the compounds of the invention is evaluated in a xenograft model of AMO-l multiple myeloma cells.
IxlO7 AMO-l cells are grafted sub-cutaneously into immunosuppressed mice (SCID strain).
to 8 days after the graft, when the tumour mass has reached about 150 mm3, the mice are treated with the various compounds in a daily schedule (5-day treatment). The tumour mass is measured twice weekly from the start of treatment.
The results obtained using ΔΤ/C ratio (i.e. qualification parameter of the activity of a product, which is defined as the ratio tumour volume of the treated group / tumour volume of the untreated control group) show that the compounds of the invention induce significant tumour régression during the treatment period.
ORIGINAL
- 53 EXAMPLE E: Pharmaceutical composition: Tablets
1000 tablets containing a dose of 5 mg of a compound selected from Examples l to 17 and
Préparations 13 and 14.......................................................................................·...........................5g
Wheat starch.................................................................. 20g
Maize starch......................................................................................................................20g
Lactose........................... 20g
Magnésium stéarate.............................................·..............................................................
Silica' g
Hydroxypropylcellulose................................................................ 2g
ORIGINAL
Claims (44)
1. Compounds of formula (I):
wherein;
♦ A represents the group
in which 1 is linked to the oxygen atom and 2 is linked to the phenyl ring.
♦ R| represents a linear or branched (C j-C(,)alky 1 group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group. a linear or branched (C|-C6)alkoxy group, a -S-(Ci-C6)alkyl group, a linear or branched (C|-C6)polyhaloalkyl, a hydroxy group, a hydroxy(C|-C6)alkyl group. a cyano group. -NRiiRii’, -Cy6, or a halogen atom, ♦ R2, R3, R4 and R5 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-Cô)alkyl group, a linear or branched (C2-Cô)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (Cj-CôJpolyhaloalkyi, a hydroxy group, a hydiOxy(Ci-Cô)alkyl group, a linear or branched (Cj-C6)alkoxy group, a -S-(CrC&)alkyl group, a cyano group, a nitro group, -alkyl(Co-C6)-NR9Rif, -O-alkyl(C|-C6)-NR9R9\ -O-alkylfCi-CtJ-Rio. -C(O)-OR9, -O-C(O)-R9, -C(O)-NR9R9’, -NR9-C(O)-R9’, -NR9-C(O)-OR9\
ORIGINAL
- 55 -alkyl(Cl-C6)-NR9-C(O)-R9’,-SO2-NR9R9’,-SO2-alkyl(Cl-C6), or the substituents of one of lhe pairs (R2, R3), (R3, R4), (Rj, R5), when grafted onto two adjacent carbon atoms, form together with the carbon atoms carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may 5 contain from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen. it being understood that resuiting ring may be substituted by a group selected from a linear or branched (Ci-Côjalkyl group, -NRj i R| i -aIkyl(Co-C6)-Cyi, or an oxo, ♦ R(, and R7 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-Cô)alkyl group, a linear or branched !0 (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (Cj-Céjpolyhaloalkyl, a hydroxy group, a linear or branched (Ci-Cô)alkoxy group, a -S-(C|-C6)alkyl group, a cyano group, a nitro group, -alky!(Co-C6)-NR9R9', -O-alkyl(Ci-C6)-NR9R9\ -O-Cyt, -alkyl(C0~C6)-Cyi, -alkenyl(C2-C6)-Cyi, -alkynyl(C2-C6)-Cyi, -O-alkyl(C1-C6)-R10. -C(O)-OR9,
15 -O-C(O)-R9, -C(O)-NR9R9‘, -NR9-C(O)-R9’, -NR9-C(O)-OR9’·
-alkyl(C|-C6)-NR9-C(O)-R9', -SO2-NR9R9', -SO2-alkyl(CrC6), or the substituents of the pair (R(„ R7), when grafted onto two adjacent carbon atoms. form together with the carbon atoms carrying them an aromatic or nonaromatic ring composed of from 5 to 7 ring members, which may contain from 1 to 20 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that resuiting ring may be substituted by a group selected from a linear or branched (C]-C6)alkyl group, -NRnRif, -alkyl(Co-C6)-Cyi, or an oxo, ♦ Rs represents a linear or branched (Cj-C&)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-Cft)alkynyl group. -Cy3,
25 -alkyl(C|-C6)-Cy3, -alkenyl(C2-C6)-Cy3. -alkynyKCi-Côl-Cyi. -Cy3-Cy4,
-alkynyl(C2-C6)-O-Cy3, -Cy3-alkyl(C0-C(,)-0-alkyl(Co-Cf,)-Cy4, a halogen atom, a cyano group, -C(O)-Rj2, or -C(O)-NRi2R|2', ♦ R9 and R9‘ independently of one another represent a hydrogen atom, a linear or branched (Ci-Cùjalkyl group, -alkyl(Co-C&)-Cyi,
30 or the substituents of the pair (R9, R9) form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3
ORIGINAL
- 56 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, or a linear or branched (Ci-Cjalkyl group and it being understood that one or more of the carbon atoms of the possible substituents, may be deuterated, ♦ Rio represents -Cy,. -Cyi-alkyl(Co-C(,)-Cy2, -Cyi-alkyl(Co~C6)-0-aIkyl(Co-C6)-Cy2.
-CyralkyliCo-CôJ-NRç-alkyliCo-CôJ-Cy,, -Cyi-Cy2-O-alkyl(C0-C6)-Cy5.
-C(O)-NR9R9‘, -NR9R9‘, -OR9, -NR9-C(O)-R9’, -O-alkyl(C]-C6)-OR9, -SO2-R9, -C(O)-OR9, or -NH-C(O)-NH-R7, ♦ R| |, Rh’, R[2 and R)2’ independently of one another represent a hydrogen atom or an optionally substituted linear or branched (Ci-Cû)alkyl group, ♦ R]3 represents a hydrogen atom. a hydroxy group, or a hydroxy(Ci-C6)alkyi group, ♦ Ra represents a hydrogen atom or a linear or branched (C|-C(,)alkyl group.
♦ Rt, represents a -O-C(O)-O-Rc group, a -O-C(O)-NRcRc’ group. or a -O-P(O)(ORC)2 group.
♦ Rc and Rc‘ independently of one another represent a hydrogen atom. a linear or branched (Ci-Cg)alkyl group, a cycloalkyl group, a (Ci-C6)alkoxy(C|-C6)alkyl group. or a (C]-C6)alkoxycarbonyl(Ci-C6)alkyl group, or the substituents of the pair (Rv, R/) form together with the nitrogen atom carrying them a non-aromatic ring composed of from 5 to 7 ring members. which may contain in addition to the nitrogen atom from l to 3 heteroatoms selected from oxygen and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a linear or branched (Ct-Cô)alkyl group, ♦ Cyi, Cy2, Cy3. Cy4, Cy5 and Cy6 independently of one another. represent a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group.
♦ n is an integer equal to 0 or 1, it being understood that:
- aryl means a phenyl. naphthyl, biphenyl, indanyl or indenyl group, heteroaryl means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, cycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group
ORIGINAL
-57containing from 3 to 10 ring members, “heterocycloalkyl means any mono- or bî-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, and containing from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring Systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, to be substituted by from l to 4 groups selected from optionally substituted linear or branched (C|-C6)alkyi, optionally substituted linear or branched (C2-C6)alkenyl group, optionally substituted linear or branched (C2-Cû)alkynyl group, optionally substituted linear or branched (Ci-Cô)alkoxy, optionally substituted (Cj-Cfijalkyl-S-, hydroxy, oxo (or A^oxide where appropriate), nitro, cyano, -C(O)-OR', -O-C(O)-R', -C(O)-NR’R”, -NR’R, -(C=NR’)-OR”, linear or branched (Ci-Côjpolyhaloalkyl, trifluoromethoxy, or halogen, it being understood that R’ and R” independently of one another represent a hydrogen atom or an optionally substituted linear or branched (Ci-Côjalkyl group, and it being understood that one or more of the carbon atoms of the preceding possible substituents, may be deuterated, their enantiomers, diastereoisomers and atropisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
2. Compound of formula (!) according to claim l. wherein at least one of the groups selected from R2, R2, Ri and R5 does not represent a hydrogen atom.
3. Compound of formula (I) according to claim l, wherein n is an integer equal to l.
4. Compound of formula (l) according to claim l, wherein Ri represents a linear or branched (Ci-C6)alkyl group or a halogen atom.
5. Compound of formula (I) according to claim l, wherein Rb represents a hydrogen atom.
ORIGINAL
6. Compound of formula (I) according to claim l, wherein R, and R5 represent a hydrogen atom.
7. Compound of formula (I) according to claim l, wherein
5 wherein R,. R9 and RC are as defined in claim l.
8. Compound of formula (I) according to claim l, wherein
wherein R<> and RC are as defined in claim l.
9. Compound of formula (I) according to claim 1, wherein the substituents of the pair
10 (Ri, R.s) are identical and the substituents ofthe pair (Ri, R-i) are identical.
10. Compound of formula (1) according to claim 1. wherein R6 represents an optionally substituted linear or branched (C]-C6)alkoxy group or a -0-alkyl(CrC6)-Rio group.
ORIGINAL
11. Compound of formula (1) according to claim 1, wherein R7 represents a hydrogen atom.
12. Compound of formula (T) according to claim 1, wherein represents wherein Rio is as defined in claim 1.
13. Compound of formula (I) according to claim I, wherein R« represents a linear or branched (Ci-C&)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2“C6)alkynyl group. an aryl group or a heteroaryl group.
14. Compound of formula (I) according to claim 1, wherein Rç and R</ independently of one another represent a linear or branched (Ci-Cû)alkyl group, or the substituents of the pair (Ry. R9’) form together with the nitrogen atom carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contaîn in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen. sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (Ci-Cô)alkyl group.
15. Compound of formula (1) according to claim 1. wherein R|0 represents -Cyj. -Cyi-alkyl(CQ-C(,)-O-alkyl(C(rC6)-Cy2 or -Cyi-alkyl(Co-C6)-Cy2.
16. Compound of formula (l) according to claim 1, wherein Cyi represents a heteroaryl group.
17. Compound of formula (I) according to claim 1, wherein Cy2 represents a phenyl group, a pyridinyl group, a pyrazolyl group, a morpholinyl group, a furanyl group or a cyclopropyl group.
ORIGINAL
18. Compound of formula (I) according to claim 1. wherein R)0 represents -Cyi-Cy2 in which Cyj represents a pyrimidinyl group and Cy2 represents a phenyl group, a pyridinyl group, a pyrazolyl group, a morpholinyl group, a furanyï group, or a cyclopropyl group.
19. Compound of formula (I) according to claim I, wherein Ra represents a hydrogen atom or a methyl group.
20. Compound of formula (I) according to claim 1, wherein Rb represents a -0-C(O)-0-(C|-Cg)alkyl group; a -O-C(O)-O-cycloalkyl group; a -O-QOj-NRcR/ group. in which Re and Rc' independently of one another represent a hydrogen atom, a linear or branched (Ci-Cg)alkyl group, a (C|-Cû)alkoxy(C|-C6)alkyl group, a (Ci-C6)alkoxycarbonyl(C|-C6)alkyl group, or the substituents of the pair (Rc, Rc’) form together with the nitrogen atom carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen and nitrogen; or a -O-P(O)(OH)2 group.
21. Compounds according to claim 1, which are:
l-[(methoxycarbonyl)oxy]ethyl (2Æ)-2-{[(5Sa)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4yl joxy} -3-( 2-{[2-(2-methoxypheny 1 )pyrimidin-4-yl]methoxy} phenyl )propanoate;
l-[(ethoxycarbonyl)oxy]ethyl (2Â)-2-{[(5Sa)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-<7]pyrimidin-4yl]oxy} -3-(2- {[2-(2-methoxyphenyi)pyrimidin-4-yl]methoxy} phenyl )propanoate;
- l-{[(propan-2-yloxy)carbonyl]oxy}ethyl (2Æ)-2-{[(5Sa)-5-{3-chloro-2-methyl-4[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2.3-ff| pyrimidin-4-yl]oxy} -3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy} phenyl) propanoate;
- 1 -[(/È77-butoxycarbonyl)oxy]ethyl (27î)-2-{[(5Sa)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4yl]oxy )-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy) phenyl )propanoate;
ORIGINAL
-6l -
- l-([(cyclopentyloxy)carbonyl]oxy}ethyl (2/?)-2-([(55ÎI)-5-{3-chloro-2-methyl-4[2-(4-methylpiperazin-l-yl)ethoxy]phenyl )-6-(4-fluorophenyl)thieno[2,3-i/] pyrimidin-4-yl]oxy}-3-(2-([2-(2-methoxyphenyl)pyriniidin-4-yl]methoxy} phenyl) propanoate;
- I - {[(octyloxy)carbony l]oxy} et h y l (2R)-2-([(5Sa)-5- {3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4y l]oxy} -3-(2- {[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy) phenyl )propanoate;
- l-[(diinethylcarbamoyl)oxy]ethyl (2Æ)-2-{[(5\,)-5-{3-chloro-2-methyl-4-[2-(4methylpiperazin-l-yl)ethoxy]phenyl)-6-(4-fluorophenyl)thieno[2,3-i/]pyriniidin-4yljoxy}-3-(2- {[2-(2-methoxyphenyl)pyriniidin-4-yl]niethoxy}phenyl)propanoate;
l-[(diethylcarbanioyl)oxy]ethyl (2/?)-2-{[(5Siï)-5-{3-chloro-2-methyl-4-[2-(4methyIpiperazin-l-yl)ethoxy]phenyl}-6-(4-iluorophenyl)thieno[2,3-i/]pyrimidin-4yl]oxy}-3-(2-{[2-(2-niethoxyphenyl)pyrimidin-4-yl]methoxy} phenyl )propanoate;
l - ( [ (2 R )-2- {[(55fl)-5- {3 -chloro-2-methyl-4-[2-(4-methy Ipiperazin-1 -yl )ethoxy] phenyl} -6-(4-fluorophenyl )thieno[2,3-r/] pyrimidin-4-yl]oxy} -3-(2- {[2-(2niethoxyphenyl)pyriniidin-4-yl]methoxy)phenyl)propanoyl]oxy}ethyl morpholine4-carboxylate;
- l-{[(2-niethoxyethyl)carbamoyl]oxy}ethyl (2Æ)-2-{[(55(,)-5-{3-chloro-2-inethyl4-[2-(4-methy Ipiperazin-l-yl)ethoxy]phenyl}-6-(4-flLiorophenyl)thieno[2,3-i7] pyriniidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyr)pyrimidin-4-y]]methoxy}phenyl) propanoate;
l-{[bis(2-methoxyethyl)carbamoyl]oxy}ethyl (2^)-2-(((55^)-5-(3-011101-0-2methy l-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl }-6-(4-fluorophenyl)thieno [2.3-i/]pyriniidin-4-yl]oxy}-3-(2-{[2-(2-inethoxyphenyl)pyrimidin-4-yl]niethoxy} phenyl )propanoate;
- 1 -( [(2-methoxy-2-oxoethyl)(methyl)carbamoyl]oxy)ethyl (2/?)-2-{ [(55(,)-5-(3chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluoro phenyl )thieno[2,3-i/]pyrimidin-4-yl]oxy} -3-(2-{[2-(2-niethoxyphenyl)pyrimidin-4yljmethoxy} phenyl [propanoate;
(phosphonooxy)methyl (2/?)-2-{[(55a)-5-(3-chloro-2-methyl-4-[2-(4-rnethyl piperazin-l-yl)ethoxy]phenyl)-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl] oxy} -3-(2- {[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate;
ORIGINAL
- I -[(ethoxycarbonyl)oxy]ethyl (2R)-2-{[5-{2.6-dimethyl-4-[2-(4-methylpiperazinl-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-<:/Jpyrimidin-4-yl]oxy}-3-(2-{[2(2-methoxyphenyl)pyrimidin-4-yI]methoxy)phenyl)propanoate;
- l-[(ethoxycarbonyl)oxy]ethyl (27?)-2-{[5-{3,5-dichloro-2,6-dimethyl-4-[2-(4methylpiperazin-1 -yl)ethoxy]phenyl} -6-(4-fluorophenyl)thieno[2.3-i/]pyrimidin-4yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate;
- l-[(dimethylcarbamoyl)oxy]ethyl (2/?)-2- {[5-{2,6-dimethyl-4-[2-(4-methyl piperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-i/]pyriniîdin-4-yl] oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate;
- l-[(dimethylcarbamoyl)oxy]ethyl (27?)-2-{[5-{3,5-dichloro-2,6-dimethyl-4-[2-(4methyIpiperazin-l-y])ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-</]pyrimidin-4yljoxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate.
22. Process for the préparation of a compound of formula (!) according to claim l, characterised in that there is used as starting material the compound of formula (11):
Cl-''Su <>
wherein A is as defined for formula (l) in which l is linked to the chlorine atom and 2 is linked to the bromine atom.
which compound of formula (II) is subjected to coupling with a compound of formula (III):
Alk
(IH) wherein R6, R7, R13 and n are as defined for formula (I). and Alk represenls an optionally substituted linearor branched (Ci-Cft)alkyl group.
to yield the compound of formula (IV):
ORIGINAL
(IV) wherein R6, R7, Rts, A and n are as defined for formula (I), and Alk is as defined before, compound of formula (IV) which is further subjected to coupling with compound of formula (V);
(V) wherein R|. R2, R3, R4 and Rj are as defined for formula (I), and Rbi and RB2 represent a hydrogen atom, a linear or branched (C|-Cô) alkyl group, or RBt and RB2 form with the oxygen carrying them an optionally methylated ring.
IO to yield the compound of formula (VI):
Alk
(VI) wherein Rj, R?, R3, R-ι, Rs, R(>, R7, R13, A and n are as defined for formula (I) and Alk
ORIGINAL
-64is as defined before.
the Alk-O-C(O)- ester fonction of which compound of formula (VI) is hydrolysed to yield the carboxylic acid of formula (VII):
(VII)
5 wherein Rb R2, R3, R4, R5. R(„ R7, R13. A and n are as defined for formula (I), which is subjected to coupling with a compound of formula (VIII):
Rb\XCI
I (VIII)
R-a wherein RiS and Ri, are as defined for formula (I), to yield the compound of formula (I), which may be purified according to a IO conventional séparation technique, which is converted. if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considered appropriate during the course ofthe process described above, some groups (hydroxy. amino...) ofthe starting reagents or
15 of the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.
23. Compound of formula (VlA), a particular case of compound of formula (VI) according to claim 22:
ORIGINAL
wherein:
♦ R2'. R3’, Rî' and Rj' independently of one another represent a halogen atom. a linear or branched (C]-C6)alkyl group, a linear or branched (C2-C6)alkenyl group, a
5 linear or branched (C2-Cft)alkynyl group, a linear or branched (C|-C6)polyhaloalkyl, a hydroxy group, a hydroxy(CrC6)alkyl group, a linear or branched (C|-C6)alkoxy group, a -S-(Ci-C6)alkyl group, a cyano group, a nitro group, -alkyl(C0-C6)-NR9R9', -O-alkyl(Ci-C6)-NR9R9’, -O-alkyl(CrC6)-R!0, -C(O)-OR9, -O-C(O)-R9, -C(O)-NR9R9\ -NR9-C(O)-R9', -NR9-C(O)-OR9', io -alkyl(C|-C6)-NR9-C(O)-R9’, -SO2-NR9R9\ -SO2-alkyl(Cl-C6), ♦ T represents a (Ci-C6)alkyl group, a (Ci-C6)carbonyloxy(Ci-C6)alkyl group or a di(C|-C6)alkylaminocarbonyl(Ct-C6)alkyl group, ♦ R|, Rf„ R7, Ri3, A and n are as defined for formula (I), its enantiomers, diastereoisomers and atropisomers, and addition salts thereoi with a 15 pharmaceutically acceptable acid or base, as synthesis intermediate but also as compound for use as pro-apoptotic agents.
24. Compound of formula (VIA) according to claim 23, wherein the substituents of the pair (Rb R5') are identical and the substituents of the pair (R2‘. Rf ) are identical.
25. Compound of formula (VIIA), a particular case of compound of formula (Vil)
20 according to claim 22:
ORIGINAL
wherein:
♦ Ri’, R3', Rj and R5’ independently of one another represent a halogen atom, a linear or branched (C]-C6)alkyl group, a linear or branched (Ci-Côjalkenyl group. a linear or branched (C2-C6)alkynyl group, a linear or branched (Ci-CôJpolyhaloalkyl, a hydroxy group, a hydroxy(C|-Cô)alkyl group, a linear or branched (C|-C6)alkoxy group. a -S-(C|-Cô)alkyl group. a cyano group, a nitro group. -alkyl(C0-C6)-NR9R9\ -O-alkyhCj-Côj-NRçRy, -O-alkyi(Ct-C6)-RI0. -C(O)-OR9. -O-C(O)-R9, -C(O)-NR9R9·, -NR9-C(O)-R9', -NR9-C(O)-OR9·,
-alkyl(C|-C6)-NR9-C{O)-R9’, -SO2-NR9R9', -SO2-alkyl(C|-C6), ♦ R|. Rô. R7, Ri3, A and n are as defined for formula (l), its enantiomers, diastereoisomers and atropisomers, and addition salts thereof with a pharmaceutically acceptable acid or base, as synthesis intermediate but also as compound for use as pro-apoptotic agents.
26. Compound of formula (VIIA) according to claim 25 wherein the substituents of the pair (R|, R5) are identical and the substituents of the pair (R2\ Rj’) are identical.
27. Compound of formula <VIIA) according to claim 26, which is (2/?)-2-{ [5-{3.5dichloro-2,6-diinethyl-4-[2-(4-methylpiperazin-l -yl)ethoxy]phenyl}-6-(4-fluoro phenyl)thieno[2,3-t/]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyr)pyrimidin-4yl]methoxy} phenyl)propanoic acid.
28. Compound of formula (Vin), a particular case of compound of formula (VI) according to claim 22:
ORIGINAL
-67ΙΟ
(W) wherein:
♦ R5' represents a halogen atom, a linear or branched (Ci-Côjalkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)aikynyl group, a linear or branched (Ci-C6)polyhaloalkyl, a hydroxy group, a hydroxy(Ci-Cf,)alkyl group, a linear or branched (Ci-C6)alkoxy group, a -S-(Ci-C6)alkyl group, a cyano group, a nitro group, -alkyl(Co-C6)-NRgR9\ -O-alkyI(Ci-C6)-NR<)R9', -0-alkyl(C|-Cb)-Rio. -C(O)-OR9, -O-C(O)-R9. -C(O)-NR9R9\ -NR9-C(O)-R9·, -NR9-C(O)-OR9\ -alkyI(C|-C6)-NR9-C(O)-R9', -SO2-NR9R9'. -SO2-alkyl(CrC6), ♦ T represents a (Ci-C6)alkyl group, a (C|-C6)carbonyloxy(C|-C6)alkyl group or a di(C|-C6)alkylaminocarbonyl(C)-C6)alkyl group, ♦ R|, R.3, Rû, R7, R13, A and n are as defined for formula (I).
and wherein the substituents of the pair (Ri, R5’) are identical, its enantiomers, diastereoisomers and atropisomers. and addition salts thereof with a pharmaceutically acceptable acid or base, as synthesis intermediate but also as compound for use as pro-apoptotic agents.
29. Compound of formula (VIlB), a particular case of compound of formula (VII) according to claim 22:
ORIGINAL
(VIIb) wherein:
♦ R5’ represents a halogen atom, a linear or branched (C|-C6)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (Ci-CéJpolyhaloalkyl, a hydroxy group. a hydroxy(Ci-C6)alkyI group, a linear or branched (Ci-Cfi)alkoxy group. a -S-(C|-C6)alkyl group. a cyano group. a nitro group, -alkyl(Co-Cf,)-NR9R9‘, -O-alkyl(C|-Cé)-NR9R9', -0-alkyl(C[-C6)-Rio· -C(O)-OR9, -O-C(O)-R9, -C(O)-NR9R9\ -NR9-C(O)-R9\ -NR9-C(O)-OR9\ -alkyi(CrC6)-NR9-C(O)-R9’. -SO2-NR9R9 ?, -SO2-alkyl(CrC6), ♦ R|, R3, Rf„ R7, Rb, A and n are as defined for formula (I), and wherein the substituents of the pair (Rt, R,') are identical, its enantiomers. diastereoisomers and atropisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
as synthesis intermediate but also as compound for use as pro-apoptotic agents.
30. Compound of formula (VIIb) according to claim 29, which is (2/?)-2-{[5-{2.6dimethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno [2.3-i7]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl |methoxy} phenyl)propanoic acid.
31. Pharmaceutical composition comprising a compound of formulae (I), (VIA), (VIB), (VIIA) or (VIIB), according to any one of daims 1 to 21 or daims 23 to 30, or an addition sait thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients.
ORIGINAL
32. Pharmaceutical composition according to claim 31 for use as pro-apoptotic agents.
33. Pharmaceutical composition according to claim 32 for use in the treatment of cancers and of auto-immune and immune System diseases.
34. Pharmaceutical composition according to claim 33 for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias. acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, nonsmall-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
35. Use of a pharmaceutical composition according to claim 31 in the manufacture of médicaments for use as pro-apoptotic agents.
36. Use of a pharmaceutical composition according to claim 31 in the manufacture oi médicaments for use in the treatment of cancers and of auto-immune and immune System diseases.
37. Use of a pharmaceutical composition according to claim 31 in the manufacture of médicaments for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias. acute myeloid leukaemias, lymphomas. melanomas, malignant haemopathies, myelomas. ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
38. Compound of fonnulae (I), (VI.a), (VIh), (VIIa) or (VII^), according to any one of daims l to 21 or daims 23 to 30. or an addition sait thereof with a pharmaceutically acceptable acid or base, for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias. lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
ORIGINAL
39. Use of a compound of formulae (I), (VIA), (VIB), (VIIA) or (VIIB), according to any one of daims l to 21 or daims 23 to 30, or an addition sait thereof with a pharmaceutically acceptable acid or base, in the manufacture of médicaments for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid
5 leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas. malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-ceil lung cancer.
40. Combination of a compound of formulae (I). (VlA), (VIB), (VIIA) or (VIIB), according
I0 to any one of daims l to 21 or daims 23 to 30, with an anti-cancer agent selected from genotoxîc agents, mitotic poisons, anti-metabolites, protéasome inhibitors, kinase inhibitors and antibodies.
41. Pharmaceutical composition comprising a combination according to daim 40 in combination with one or more pharmaceutically acceptable excipients.
15
42. Combination according to daim 40 for use in the treatment of cancers.
43. Use of a combination according to daim 40 in the manufacture of médicaments for use in the treatment of cancers.
44. Compound of formulae (I), (V1A). (V1B), (V1IA) or (V1IB). according to any one ot daims 1 to 21 or daims 23 to 30, for use in the treatment of cancers requiring
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1555752 | 2015-06-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA18889A true OA18889A (en) | 2019-09-30 |
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