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NZ744408B2 - New ammonium derivatives, a process for their preparation and pharmaceutical compositions containing them - Google Patents
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NZ744408B2 - New ammonium derivatives, a process for their preparation and pharmaceutical compositions containing them - Google Patents

New ammonium derivatives, a process for their preparation and pharmaceutical compositions containing them

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Publication number
NZ744408B2
NZ744408B2 NZ744408A NZ74440816A NZ744408B2 NZ 744408 B2 NZ744408 B2 NZ 744408B2 NZ 744408 A NZ744408 A NZ 744408A NZ 74440816 A NZ74440816 A NZ 74440816A NZ 744408 B2 NZ744408 B2 NZ 744408B2
Authority
NZ
New Zealand
Prior art keywords
group
pyrimidinyl
ethyl
methyl
thieno
Prior art date
Application number
NZ744408A
Other versions
NZ744408A (en
Inventor
Balazs Balint
Maia Chanrion
Didier Demarles
Olivier Geneste
Andras Kotschy
Ana Leticia Maragno
Attila Paczal
Szabolcs Sipos
Zoltan Szlavik
Original Assignee
Les Laboratoires Servier
Vernalis (R&D) Limited
Filing date
Publication date
Priority claimed from FR1650411A external-priority patent/FR3046792B1/en
Application filed by Les Laboratoires Servier, Vernalis (R&D) Limited filed Critical Les Laboratoires Servier
Publication of NZ744408A publication Critical patent/NZ744408A/en
Publication of NZ744408B2 publication Critical patent/NZ744408B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Abstract

The present invention relates to compounds of formula I, a process for their preparation and to pharmaceutical compositions containing them. The compounds are useful as pro-apoptotic agents and for the treatment of cancers, auto-immune and immune system diseases.

Claims (34)

1. Compounds of formula (I): wherein: 5 ? Y represents a -NH- group or an oxygen atom, ? R represents a linear or branched (C -C )alkyl group, a linear or branched 1 1 6 (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a linear or 2 6 2 6 branched (C -C )alkoxy group, a -S-(C -C )alkyl group, a linear or branched 1 6 1 6 (C -C )polyhaloalkyl group, a hydroxy group, a hydroxy(C -C )alkyl group, a 1 6 1 6 10 cyano group, -NR R ’, -Cy or a halogen atom, 9 9 1 ? R , R and R independently of one another represent a hydrogen atom, a halogen 2 3 4 atom, a linear or branched (C -C)alkyl group, a linear or branched (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a linear or 2 6 2 6 branched (C -C )polyhaloalkyl, a hydroxy group, a hydroxy(C -C )alkyl group, 1 6 1 6 15 a linear or branched (C -C )alkoxy group, a -S-(C -C )alkyl group, a cyano group, 1 6 1 6 a nitro group, -alkyl(C -C )-NR R’, -O-alkyl(C -C )-NR R’, -C(O)-OR , 0 6 9 9 1 6 9 9 9 -O-C(O)-R, -C(O)-NR R’, -NR -C(O)-R’, -NR -C(O)-OR ’, 9 9 9 9 9 9 9 -alkyl(C -C )-NR -C(O)-R ’, -SO -NR R ’, -SO -alkyl(C -C ), 1 6 9 9 2 9 9 2 1 6 ? R represents a hydrogen atom, ? , , R represents the group ? R represents a hydrogen atom or a linear or branched (C -C )alkyl group, 7 1 6 - - - ? R8 represents a -O-P(O)(O )(O) group, a -O-P(O)(O )(OR10) group, 5 a -O-P(O)(OR )(OR ’) group, a -O-SO -O group, a -O-SO -OR group, -Cy , 10 10 2 2 10 2 a -O-C(O)-R group, a -O-C(O)-OR group or a -O-C(O)-NR R ’ group; 9 9 9 9 ? R9 and R9’ independently of one another represent a hydrogen atom, a linear or branched (C -C )alkyl group or a linear or branched amino(C -C )alkyl group, 1 6 1 6 ? R and R ’ independently of one another represent a hydrogen atom, a linear or 10 10 10 branched (C -C )alkyl group or an arylalkyl(C -C ) group, 1 6 1 6 ? Cy and Cy independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, it being possible for the ammonium so defined to exist as a zwitterionic form or to have a monovalent anionic counterion, 15 it being understood that: - “aryl” means a phenyl or naphthyl 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, 20 - “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 1 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 1 to 4 groups selected from linear or branched (C -C)alkyl, linear or branched 5 (C -C )alkenyl group, linear or branched (C -C )alkynyl group, linear or branched 2 6 2 6 (C -C )alkoxy, (C -C )alkyl-S-, hydroxy, oxo, N-oxide, nitro, cyano, -C(O)-OR’, -O- 1 6 1 6 C(O)-R’, -C(O)-NR’R’’, -NR’R’’, -(C=NR’)-OR’’, linear or branched (C - C )polyhaloalkyl, trifluoromethoxy or halogen, it being understood that R’ and R’’ independently of one another represent a hydrogen atom or a linear or branched (C - 10 C )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.
2. Compound of formula (I) according to claim 1, wherein Y represents an oxygen atom. 15
3. Compound of formula (I) according to claim 1, wherein at least one of the groups selected from R , R and R does not represent a hydrogen atom. 2 3 4
4. Compound of formula (I) according to claim 1, wherein R1 represents a linear or branched (C -C )alkyl group or a halogen atom.
5. Compound of formula (I) according to claim 1, wherein R represents a halogen atom, 20 a hydroxy group, a linear or branched (C -C )alkoxy group.
6. Compound of formula (I) according to claim 1, wherein R and R represent a hydrogen atom.
7. Compound of formula (I) according to claim 1, wherein the substituents of the pair (R1, R4) are identical and the substituents of the pair (R2, R3) are identical.
8. Compound of formula (I) according to claim 1, wherein R represents the group or , wherein R and R are as defined in claim 1.
9. Compound of formula (I) according to claim 1, wherein R represents the group , wherein R and R are as defined in claim 1. 5
10. Compound of formula (I) according to claim 1, wherein R represents a methyl group or a hydrogen atom.
11. Compound of formula (I) according to claim 1, wherein R represents a -O-P(O)(O )(OR ) group in which R represents a hydrogen atom, a benzyl group 10 10 or a methyl group. 10
12. Compound of formula (I) according to claim 1, wherein R represents a 5-methyloxo-1,3-dioxolyl group; a -O-C(O)-CH group; a -O-C(O)-tBu group; a -O-C(O)-CH -NH group; a -O-C(O)-CH[CH(CH ) ]-NH group; 2 2 3 2 2 a -O-C(O)-O-CH CH group; or a -O-C(O)-N(CH CH ) group. 2 3 2 3 2
13. Compounds according to claim 1, which are: 15 - {4-[2-(4-{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chloromethylphenoxy)ethyl]methylpiperaziniumyl}methyl hydrogen phosphate; - benzyl {4-[2-(4-{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin- 4-yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chloromethylphenoxy)ethyl]methylpiperaziniumyl}methyl phosphate; - {4-[2-(4-{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin 5 yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chloromethylphenoxy)ethyl]methylpiperaziniumyl}methyl methyl phosphate; - {4-[2-(4-{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} 10 chloroethylphenoxy)ethyl]methylpiperaziniumyl}methyl hydrogen phosphate; - {4-[2-(3-bromo{(5Sa)[(1R)carboxy(2-{[2-(2- methoxyphenyl)pyrimidinyl]methoxy}phenyl)ethoxy](4- fluorophenyl)thieno[2,3-d]pyrimidinyl}chlorophenoxy)ethyl] 15 methylpiperaziniumyl}methyl hydrogen phosphate; - benzyl {4-[2-(3-bromo{(5S )[(1R)carboxy(2-{[2-(2- methoxyphenyl)pyrimidinyl]methoxy}phenyl)ethoxy](4- fluorophenyl)thieno[2,3-d]pyrimidinyl}chlorophenoxy)ethyl] methylpiperaziniumyl}methyl phosphate; 20 - {4-[2-(3-bromo{(5S )[(1R)carboxy(2-{[2-(2- methoxyphenyl)pyrimidinyl]methoxy}phenyl)ethoxy](4- fluorophenyl)thieno[2,3-d]pyrimidinyl}chlorophenoxy)ethyl] methylpiperaziniumyl}methyl methyl phosphate; - N-[(5S ){3-chloro[2-(4-{[(hydroxyphosphinato)oxy]methyl} 25 methylpiperaziniumyl)ethoxy]methylphenyl}(4- fluorophenyl)thieno[2,3-d]pyrimidinyl]{[2-(2-methoxyphenyl)pyrimidin yl]methoxy}-D-phenylalanine; - {4-[2-(4-{4-[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl}-2,6- 30 dichloro-3,5-dimethylphenoxy)ethyl]methylpiperaziniumyl}methyl hydrogen phosphate; - {4-[2-(4-{4-[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl}-3,5- dimethylphenoxy)ethyl]methylpiperaziniumyl}methyl hydrogen phosphate; 5 - {[2-(4-{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chloromethylphenoxy)ethyl](dimethyl)ammonio}methyl hydrogen phosphate; - 1-{4-[2-(4-{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} 10 chloromethylphenoxy)ethyl]methylpiperaziniumyl}ethyl hydrogen phosphate; - 1-{4-[2-(3-bromo{(5Sa)[(1R)carboxy(2-{[2-(2- methoxyphenyl)pyrimidinyl]methoxy}phenyl)ethoxy](4- fluorophenyl)thieno[2,3-d]pyrimidinyl}chlorophenoxy)ethyl] 15 methylpiperaziniumyl}ethyl hydrogen phosphate; - {1-[2-(4-{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chloromethylphenoxy)ethyl]methylpiperaziniumyl}methyl hydrogen phosphate; 20 - {1-[2-(3-bromo{(5S )[(1R)carboxy(2-{[2-(2- methoxyphenyl)pyrimidinyl]methoxy}phenyl)ethoxy](4- fluorophenyl)thieno[2,3-d]pyrimidinyl}chlorophenoxy)ethyl] methylpiperaziniumyl}methyl hydrogen phosphate; - {4-[2-(4-{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin 25 yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chloromethylphenoxy)ethyl]methylpiperaziniumyl}methyl sulfate; - 1-[(acetyloxy)methyl][2-(4-{(5S )[(1R)carboxy(2-{[2-(2- methoxyphenyl)pyrimidinyl]methoxy}phenyl)ethoxy](4- fluorophenyl)thieno[2,3-d]pyrimidinyl}chloromethylphenoxy)ethyl] 30 methylpiperazinium; - 4-[2-(4-{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chloromethylphenoxy)ethyl]{[(ethoxycarbonyl)oxy]methyl} methylpiperazinium; - 4-[2-(4-{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} 5 chloromethylphenoxy)ethyl]{[(diethylcarbamoyl)oxy]methyl} methylpiperazinium; - 4-[2-(4-{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chloromethylphenoxy)ethyl][(glycyloxy)methyl]methylpiperazinium; 10 - 4-[2-(4-{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chloromethylphenoxy)ethyl]{1-[(diethylcarbamoyl)oxy]ethyl} methylpiperazinium; - 4-[2-(4-{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin 15 yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chloromethylphenoxy)ethyl]methyl[(5-methyloxo-1,3-dioxol yl)methyl]piperazinium; - 4-[2-(4-{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} 20 chloromethylphenoxy)ethyl]methyl[(L-valyloxy)methyl]piperazinium; - 4-[2-(4-{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chloromethylphenoxy)ethyl]{[(2,2-dimethylpropanoyl)oxy]methyl} methylpiperazinium; 25 - 1-[(acetyloxy)methyl][2-(3-bromo{(5S )[(1R)carboxy(2-{[2-(2- methoxyphenyl)pyrimidinyl]methoxy}phenyl)ethoxy](4- fluorophenyl)thieno[2,3-d]pyrimidinyl}chlorophenoxy)ethyl] methylpiperazinium; - 4-[2-(3-bromo{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin- 30 4-yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chlorophenoxy)ethyl]{[(ethoxycarbonyl)oxy]methyl}methylpiperazinium; - 4-[2-(3-bromo{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin- 4-yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chlorophenoxy)ethyl]{[(diethylcarbamoyl)oxy]methyl}methylpiperazin 5 - 4-[2-(3-bromo{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin- 4-yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chlorophenoxy)ethyl][(glycyloxy)methyl]methylpiperazinium; - 4-[2-(3-bromo{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin- 4-yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} 10 chlorophenoxy)ethyl]{1-[(diethylcarbamoyl)oxy]ethyl}methylpiperazin - 4-[2-(3-bromo{(5Sa)[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin- 4-yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chlorophenoxy)ethyl]methyl[(5-methyloxo-1,3-dioxol 15 yl)methyl]piperazinium; - 4-[2-(3-bromo{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin- 4-yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chlorophenoxy)ethyl]methyl[(L-valyloxy)methyl]piperazinium; - 4-[2-(3-bromo{(5S )[(1R)carboxy(2-{[2-(2-methoxyphenyl)pyrimidin- 20 4-yl]methoxy}phenyl)ethoxy](4-fluorophenyl)thieno[2,3-d]pyrimidinyl} chlorophenoxy)ethyl]{[(2,2-dimethylpropanoyl)oxy]methyl}methylpiperazin- 1-ium.
14. A compound according to claim 1, which is {4-[2-(4-{(5S )[(1R)carboxy(2- {[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)ethoxy](4- 25 fluorophenyl)thieno[2,3-d]pyrimidinyl}chloromethylphenoxy)ethyl] methylpiperaziniumyl}methyl hydrogen phosphate.
15. A compound according to claim 1, which is {4-[2-(3-bromo{(5S )[(1R) carboxy(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)ethoxy](4- fluorophenyl)thieno[2,3-d]pyrimidinyl}chlorophenoxy)ethyl] 30 methylpiperaziniumyl}methyl hydrogen phosphate.
16. A compound according to claim 1, which is {[2-(4-{(5S )[(1R)carboxy(2-{[2- (2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)ethoxy](4- fluorophenyl)thieno[2,3-d]pyrimidinyl}chloro 5 methylphenoxy)ethyl](dimethyl)ammonio}methyl hydrogen phosphate.
17. Process for the preparation of a compound of formula (I) according to claim 1, wherein there is used as starting material the compound of formula (II): wherein R , R , R , R , R and Y are as defined for formula (I), and R ’ represents 1 2 3 4 5 6 10 a -N(CH ) group or a 4-methyl-piperazinyl group, which is subjected to a reaction protecting the carboxylic acid function to yield the compound of formula (III): (III) wherein R , R , R , R , R ’ and Y are as defined hereinbefore, and T represents 1 2 3 4 6 a protecting group for the carboxylic acid function such as, for example, a para-methoxybenzyl group, 5 which is subjected to coupling with a compound of formula (IV): wherein R and R are as defined for formula (I), to yield the compound of formula (V): wherein R , R , R , R , T and Y are as defined hereinbefore, and R is as defined in 1 2 3 4 6 claim 1, which is then subjected to a reaction deprotecting the carboxylic acid function, 5 to yield the compound of formula (I), which may be purified according to a conventional separation 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 separation technique, it being understood that at any moment considered appropriate during the course of the 10 process described above, some groups of the starting reagents or of the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.
18. Pharmaceutical composition comprising a compound of formula (I), according to any one of claims 1 to 16, or an addition salt thereof with a pharmaceutically acceptable 15 acid or base in combination with one or more pharmaceutically acceptable excipients.
19. Pharmaceutical composition according to claim 18 for use as pro-apoptotic agents.
20. Pharmaceutical composition according to claim 19 for use in the treatment of cancers and of auto-immune and immune system diseases.
21. Pharmaceutical composition according to claim 20 for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, cancer of the 5 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.
22. Use of a compound of formula (I), according to any one of claims 1 to 16 in the manufacture of a medicament for the treatment of cancers and of auto-immune and 10 immune system diseases.
23. Compound of formula (I), according to any one of claims 1 to 16, or an addition salt thereof with a pharmaceutically acceptable acid or base, for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid 15 leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
24. Use of a compound of formula (I), according to any one of claims 1 to 16, or an addition salt thereof with a pharmaceutically acceptable acid or base, in the 20 manufacture of a medicament for the treatment of cancers of the bladder, brain, breast and uterus, 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.
25. 25 25. Combination of a compound of formula (I), according to any one of claims 1 to 16, with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti- metabolites, proteasome inhibitors, kinase inhibitors and antibodies.
26. Pharmaceutical composition comprising a combination according to claim 25 in combination with one or more pharmaceutically acceptable excipients.
27. Combination according to claim 25 for use in the treatment of cancers.
28. Use of a combination according to claim 25 in the manufacture of a medicament for 5 the treatment of cancers.
29. Compound of formula (I), according to any one of claims 1 to 16, for use in the treatment of cancers requiring radiotherapy.
30. Use of a compound of formula (I), according to any one of claims 1 to 16, in the 10 manufacture of a medicament for the treatment of cancers requiring radiotherapy.
31. A compound according to any one of claims 1 to 16, substantially as herein described with reference to any example thereof. 15
32. A process according to claim 17, substantially as herein described with reference to any example thereof.
33. A pharmaceutical composition according to any one of claims 18 to 21 or claim 26, or a combination according to claim 25 or claim 27, substantially as herein described 20 with reference to any example thereof.
34. Use according to any one of claims 22, 24, 28, or 30, or a compound for use according to claim 23 or claim 29, substantially as herein described with reference to any example thereof.
NZ744408A 2016-12-19 New ammonium derivatives, a process for their preparation and pharmaceutical compositions containing them NZ744408B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR1650411A FR3046792B1 (en) 2016-01-19 2016-01-19 NOVEL AMMONIUM DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
PCT/EP2016/081688 WO2017125224A1 (en) 2016-01-19 2016-12-19 New ammonium derivatives, a process for their preparation and pharmaceutical compositions containing them

Publications (2)

Publication Number Publication Date
NZ744408A NZ744408A (en) 2025-02-28
NZ744408B2 true NZ744408B2 (en) 2025-06-04

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