NZ738455B2 - 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
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- NZ738455B2 NZ738455B2 NZ738455A NZ73845516A NZ738455B2 NZ 738455 B2 NZ738455 B2 NZ 738455B2 NZ 738455 A NZ738455 A NZ 738455A NZ 73845516 A NZ73845516 A NZ 73845516A NZ 738455 B2 NZ738455 B2 NZ 738455B2
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- New Zealand
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- 239000008194 pharmaceutical composition Substances 0.000 title claims 7
- 238000000034 method Methods 0.000 title claims 3
- 238000002360 preparation method Methods 0.000 title claims 2
- 150000001875 compounds Chemical class 0.000 claims abstract 58
- 206010028980 Neoplasm Diseases 0.000 claims abstract 10
- 239000003814 drug Substances 0.000 claims abstract 6
- 125000000217 alkyl group Chemical group 0.000 claims 48
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 20
- 229910052757 nitrogen Chemical group 0.000 claims 19
- -1 (C -C )alkyl-S- Chemical group 0.000 claims 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 16
- 125000001424 substituent group Chemical group 0.000 claims 16
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 15
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 15
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 14
- 125000003545 alkoxy group Chemical group 0.000 claims 12
- 125000003342 alkenyl group Chemical group 0.000 claims 11
- 125000000304 alkynyl group Chemical group 0.000 claims 11
- 239000002253 acid Substances 0.000 claims 10
- 125000003118 aryl group Chemical group 0.000 claims 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 10
- 150000003839 salts Chemical class 0.000 claims 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims 9
- 125000005843 halogen group Chemical group 0.000 claims 9
- 229910052760 oxygen Inorganic materials 0.000 claims 9
- 239000001301 oxygen Substances 0.000 claims 9
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims 8
- 125000005842 heteroatom Chemical group 0.000 claims 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 8
- 239000003795 chemical substances by application Substances 0.000 claims 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 7
- 125000006684 polyhaloalkyl group Polymers 0.000 claims 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 6
- 239000005864 Sulphur Chemical group 0.000 claims 6
- 125000004432 carbon atom Chemical group C* 0.000 claims 6
- 125000006574 non-aromatic ring group Chemical group 0.000 claims 6
- 230000000861 pro-apoptotic effect Effects 0.000 claims 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 5
- 125000001072 heteroaryl group Chemical group 0.000 claims 5
- 238000004519 manufacturing process Methods 0.000 claims 5
- 206010041067 Small cell lung cancer Diseases 0.000 claims 4
- 230000015572 biosynthetic process Effects 0.000 claims 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims 4
- 208000000587 small cell lung carcinoma Diseases 0.000 claims 4
- 238000003786 synthesis reaction Methods 0.000 claims 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims 3
- 206010025323 Lymphomas Diseases 0.000 claims 3
- 206010033128 Ovarian cancer Diseases 0.000 claims 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 3
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 3
- 206010060862 Prostate cancer Diseases 0.000 claims 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 3
- 210000004556 brain Anatomy 0.000 claims 3
- 210000000481 breast Anatomy 0.000 claims 3
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims 3
- 208000029742 colonic neoplasm Diseases 0.000 claims 3
- 230000008878 coupling Effects 0.000 claims 3
- 238000010168 coupling process Methods 0.000 claims 3
- 238000005859 coupling reaction Methods 0.000 claims 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 3
- 210000004185 liver Anatomy 0.000 claims 3
- 208000003747 lymphoid leukemia Diseases 0.000 claims 3
- 230000003211 malignant effect Effects 0.000 claims 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 3
- 201000001441 melanoma Diseases 0.000 claims 3
- 201000000050 myeloid neoplasm Diseases 0.000 claims 3
- 201000002528 pancreatic cancer Diseases 0.000 claims 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 3
- 210000003932 urinary bladder Anatomy 0.000 claims 3
- 210000004291 uterus Anatomy 0.000 claims 3
- 208000023275 Autoimmune disease Diseases 0.000 claims 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 2
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims 2
- 230000001363 autoimmune Effects 0.000 claims 2
- 125000002837 carbocyclic group Chemical group 0.000 claims 2
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 2
- 125000002541 furyl group Chemical group 0.000 claims 2
- 208000026278 immune system disease Diseases 0.000 claims 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
- 125000002757 morpholinyl group Chemical group 0.000 claims 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims 2
- 125000004076 pyridyl group Chemical group 0.000 claims 2
- 238000001959 radiotherapy Methods 0.000 claims 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims 2
- 125000006685 (C1-C6) polyhaloalkyl group Chemical group 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- 101100490437 Mus musculus Acvrl1 gene Proteins 0.000 claims 1
- 150000001204 N-oxides Chemical class 0.000 claims 1
- 229940079156 Proteasome inhibitor Drugs 0.000 claims 1
- 230000000340 anti-metabolite Effects 0.000 claims 1
- 229940100197 antimetabolite Drugs 0.000 claims 1
- 239000002256 antimetabolite Substances 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 235000010290 biphenyl Nutrition 0.000 claims 1
- 239000004305 biphenyl Substances 0.000 claims 1
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 231100000024 genotoxic Toxicity 0.000 claims 1
- 230000001738 genotoxic effect Effects 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims 1
- 229940043355 kinase inhibitor Drugs 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 230000000394 mitotic effect Effects 0.000 claims 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims 1
- 125000001624 naphthyl group Chemical group 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims 1
- 239000002574 poison Substances 0.000 claims 1
- 231100000614 poison Toxicity 0.000 claims 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 235000019260 propionic acid Nutrition 0.000 claims 1
- 239000003207 proteasome inhibitor Substances 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
Classifications
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
-
- 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
Abstract
Compounds of formula (1) wherein R1, R2, R3, R4, R5, R6, R7, R13, Ra, Rb, A and n are as defined in the description. Medicaments containing them for use in the treatment of cancers.
Claims (45)
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 -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 10 (C -C )polyhaloalkyl, a hydroxy group, a hydroxy(C -C )alkyl group, a cyano 1 6 1 6 group, -NR R ’, -Cy , or a halogen atom, 11 11 6 ? R , R , R and R independently of one another represent a hydrogen atom, a 2 3 4 5 halogen 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 15 branched (C -C )polyhaloalkyl, a hydroxy group, a hydroxy(C -C )alkyl group, a 1 6 1 6 linear or branched (C -C )alkoxy group, a -S-(C -C )alkyl group, a cyano group, a 1 6 1 6 nitro group, -alkyl(C -C )-NR R ’, -O-alkyl(C -C )-NR R ’, -O-alkyl(C -C )-R , 0 6 9 9 1 6 9 9 1 6 10 -C(O)-OR , -O-C(O)-R , -C(O)-NR R ’, -NR -C(O)-R ’, -NR -C(O)-OR ’, 9 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 or the substituents of one of the pairs (R , R ), (R , R ), (R , R ), when grafted onto 2 3 3 4 4 5 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 1 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 (C -C )alkyl group, -NR R ’, -alkyl(C -C )-Cy , or an oxo, 1 6 11 11 0 6 1 ? R and R independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (C -C )alkyl group, a linear or branched 10 (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 linear or branched (C -C )alkoxy group, a -S-(C -C )alkyl group, a cyano group, a nitro group, 1 6 1 6 -alkyl(C -C )-NR R ’, -O-alkyl(C -C )-NR R ’, -O-Cy , -alkyl(C -C )-Cy , 0 6 9 9 1 6 9 9 1 0 6 1 -alkenyl(C -C )-Cy , -alkynyl(C -C )-Cy , -O-alkyl(C -C )-R , -C(O)-OR , 2 6 1 2 6 1 1 6 10 9 15 -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 or the substituents of the pair (R , R ), 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 1 to 20 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 (C1-C6)alkyl group, -NR11R11’, -alkyl(C0-C6)-Cy1, or an oxo, ? R represents a linear or branched (C -C )alkyl group, a linear or branched 8 1 6 (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, -Cy , 2 6 2 6 3 25 -alkyl(C1-C6)-Cy3, -alkenyl(C2-C6)-Cy3, -alkynyl(C2-C6)-Cy3, -Cy3-Cy4, -alkynyl(C -C )-O-Cy , -Cy -alkyl(C -C )-O-alkyl(C -C )-Cy , a halogen atom, a 2 6 3 3 0 6 0 6 4 cyano group, -C(O)-R , or -C(O)-NR R ’, 12 12 12 ? R and R ’ independently of one another represent a hydrogen atom, a linear or branched (C -C )alkyl group, -alkyl(C -C )-Cy , 1 6 0 6 1 30 or the substituents of the pair (R , R ’) 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 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 (C -C )alkyl group and it being understood that one or more of the carbon atoms of the possible substituents, may be deuterated, 5 ? R represents -Cy , -Cy -alkyl(C -C )-Cy , -Cy -alkyl(C -C )-O-alkyl(C -C )-Cy , 10 1 1 0 6 2 1 0 6 0 6 2 -Cy -alkyl(C -C )-NR -alkyl(C -C )-Cy , -Cy -Cy -O-alkyl(C -C )-Cy , 1 0 6 9 0 6 2 1 2 0 6 5 -C(O)-NR R ’, -NR R ’, -OR , -NR -C(O)-R ’, -O-alkyl(C -C )-OR , -SO -R , 9 9 9 9 9 9 9 1 6 9 2 9 -C(O)-OR , or -NH-C(O)-NH-R , ? R , R ’, R and R ’ independently of one another represent a hydrogen atom or a 11 11 12 12 10 linear or branched (C -C )alkyl group, ? R represents a hydrogen atom, a hydroxy group, or a hydroxy(C -C )alkyl group, 13 1 6 ? R represents a hydrogen atom or a linear or branched (C -C )alkyl group, a 1 6 ? R represents a -O-C(O)-O-R group, a -O-C(O)-NR R ’ group, or a -O-P(O)(OR ) b c c c c 2 group, 15 ? R and R ’ independently of one another represent a hydrogen atom, a linear or branched (C -C )alkyl group, a cycloalkyl group, a (C -C )alkoxy(C -C )alkyl 1 8 1 6 1 6 group, or a (C -C )alkoxycarbonyl(C -C )alkyl group, 1 6 1 6 or the substituents of the pair (R , R ’) form together with the nitrogen atom carrying them a non-aromatic ring composed of from 5 to 7 ring members, which 20 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 -C )alkyl group, ? Cy , Cy , Cy , Cy , Cy and Cy independently of one another, represent a 1 2 3 4 5 6 cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, 25 ? 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 30 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 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or 5 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 (C - 1 6 2 C )alkenyl group, linear or branched (C -C )alkynyl group, linear or branched 6 2 6 10 (C -C )alkoxy, (C -C )alkyl-S-, hydroxy, oxo (or N-oxide where appropriate), nitro, 1 6 1 6 cyano, -C(O)-OR’, -O-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 -C )alkyl group, and it being understood that 15 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 at least one of the groups 20 selected from R , R , R and R does not represent a hydrogen atom. 2 3 4 5
3. Compound of formula (I) according to claim 1, wherein n is an integer equal to 1.
4. Compound of formula (I) according to claim 1, wherein R 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 hydrogen 25 atom.
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 represents , 5 wherein R , R and R ’ are as defined in claim 1. 1 9 9
8. Compound of formula (I) according to claim 1, wherein represents , wherein R and R ’ are as defined in claim 1.
9. Compound of formula (I) according to claim 1, wherein the substituents of the pair 10 (R , R ) are identical and the substituents of the pair (R , R ) are identical. 1 5 2 4
10. Compound of formula (I) according to claim 1, wherein R represents a linear or branched (C -C )alkoxy group or a -O-alkyl(C -C )-R group. 1 6 1 6 10
11. Compound of formula (I) according to claim 1, wherein R represents a hydrogen atom.
12. Compound of formula (I) according to claim 1, wherein represents , wherein R is as defined in claim 1. 5
13. Compound of formula (I) according to claim 1, wherein R represents a linear or branched (C -C )alkyl group, a linear or branched (C -C )alkenyl group, a linear or 1 6 2 6 branched (C -C )alkynyl group, an aryl group or a heteroaryl group.
14. Compound of formula (I) according to claim 1, wherein R and R ’ independently of one another represent a linear or branched (C -C )alkyl group, or the substituents of 10 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 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 (C -C )alkyl group.
15.15. Compound of formula (I) according to claim 1, wherein R represents -Cy , -Cy -alkyl(C -C )-O-alkyl(C -C )-Cy or -Cy -alkyl(C -C )-Cy . 1 0 6 0 6 2 1 0 6 2
16. Compound of formula (I) according to claim 1, wherein Cy represents a heteroaryl group.
17. Compound of formula (I) according to claim 1, wherein Cy represents a phenyl 20 group, a pyridinyl group, a pyrazolyl group, a morpholinyl group, a furanyl group or a cyclopropyl group.
18. Compound of formula (I) according to claim 1, wherein R represents -Cy -Cy in 10 1 2 which Cy represents a pyrimidinyl group and Cy represents a phenyl group, a pyridinyl group, a pyrazolyl group, a morpholinyl group, a furanyl group, or a cyclopropyl group. 5
19. Compound of formula (I) according to claim 1, wherein R represents a hydrogen atom or a methyl group.
20. Compound of formula (I) according to claim 1, wherein R represents a -O-C(O)-O-(C -C )alkyl group; a -O-C(O)-O-cycloalkyl group; a -O-C(O)-NR R ’ 1 8 c c group, in which R and R ’ independently of one another represent a hydrogen atom, a 10 linear or branched (C -C )alkyl group, a (C -C )alkoxy(C -C )alkyl group, a 1 8 1 6 1 6 (C -C )alkoxycarbonyl(C -C )alkyl group, or the substituents of the pair (R , R ’) form 1 6 1 6 c c 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) group. 15
21. Compounds according to claim 1, which are: - 1-[(methoxycarbonyl)oxy]ethyl (2R){[(5S ){3-chloromethyl[2-(4- methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate; - 1-[(ethoxycarbonyl)oxy]ethyl (2R){[(5S ){3-chloromethyl[2-(4- 20 methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate; - 1-{[(propanyloxy)carbonyl]oxy}ethyl (2R){[(5S ){3-chloromethyl [2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d] pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl) 25 propanoate; - 1-[(tert-butoxycarbonyl)oxy]ethyl (2R){[(5S ){3-chloromethyl[2-(4- methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate; - 1-{[(cyclopentyloxy)carbonyl]oxy}ethyl (2R){[(5S ){3-chloromethyl [2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d] pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl) propanoate; 5 - 1-{[(octyloxy)carbonyl]oxy}ethyl (2R){[(5S ){3-chloromethyl[2-(4- methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate; - 1-[(dimethylcarbamoyl)oxy]ethyl (2R){[(5S ){3-chloromethyl[2-(4- methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin 10 yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate; - 1-[(diethylcarbamoyl)oxy]ethyl (2R){[(5S ){3-chloromethyl[2-(4- methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate; - 1-{[(2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 15 phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2- methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoyl]oxy}ethyl morpholine- 4-carboxylate; - 1-{[(2-methoxyethyl)carbamoyl]oxy}ethyl (2R){[(5S ){3-chloromethyl- 4-[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d] 20 pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl) propanoate; - 1-{[bis(2-methoxyethyl)carbamoyl]oxy}ethyl (2R){[(5S ){3-chloro methyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno [2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy} 25 phenyl)propanoate; - 1-{[(2-methoxyoxoethyl)(methyl)carbamoyl]oxy}ethyl (2R){[(5Sa){3- chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluoro phenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidin yl]methoxy}phenyl)propanoate; 30 - (phosphonooxy)methyl (2R){[(5S ){3-chloromethyl[2-(4-methyl piperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl] oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate; - 1-[(ethoxycarbonyl)oxy]ethyl (2R){[5-{2,6-dimethyl[2-(4-methylpiperazin- 1-yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2- (2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate; - 1-[(ethoxycarbonyl)oxy]ethyl (2R){[5-{3,5-dichloro-2,6-dimethyl[2-(4- 5 methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate; - 1-[(dimethylcarbamoyl)oxy]ethyl (2R){[5-{2,6-dimethyl[2-(4-methyl piperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl] oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate; 10 - 1-[(dimethylcarbamoyl)oxy]ethyl (2R){[5-{3,5-dichloro-2,6-dimethyl[2-(4- methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate.
22. Process for the preparation of a compound of formula (I) according to claim 1, wherein the starting material is the compound of formula (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): (III) wherein R , R , R and n are as defined for formula (I), and Alk represents a linear or 6 7 13 branched (C -C )alkyl group, to yield the compound of formula (IV): wherein R , R , R , A and n are as defined for formula (I), and Alk is as defined 6 7 13 before, compound of formula (IV) which is further subjected to coupling with compound of 5 formula (V): wherein R , R , R , R and R are as defined for formula (I), and R and R represent 1 2 3 4 5 B1 B2 a hydrogen atom, a linear or branched (C -C ) alkyl group, or R and R form with 1 6 B1 B2 the oxygen carrying them an optionally methylated ring, 10 to yield the compound of formula (VI): wherein R , R , R , R , R , R , R , R , A and n are as defined for formula (I) and Alk 1 2 3 4 5 6 7 13 is as defined before, the Alk-O-C(O)- ester function of which compound of formula (VI) is hydrolysed to yield the carboxylic acid of formula (VII): (VII) 5 wherein R , R , R , R , R , R , R , R , A and n are as defined for formula (I), 1 2 3 4 5 6 7 13 which is subjected to coupling with a compound of formula (VIII): (VIII) wherein R and R are as defined for formula (I), to yield the compound of formula (I). 10
23. Compound of formula (VI ), a particular case of compound of formula (VI) according to claim 22: (VI ) wherein: ? R ’, R ’, R ’ and R ’ independently of one another represent a halogen atom, a 2 3 4 5 linear or branched (C -C )alkyl group, a linear or branched (C -C )alkenyl group, a 1 6 2 6 linear or branched (C -C )alkynyl group, a linear or branched (C -C )polyhaloalkyl, 2 6 1 6 a hydroxy group, a hydroxy(C -C )alkyl group, a linear or branched (C -C )alkoxy 1 6 1 6 5 group, a -S-(C -C )alkyl group, a cyano group, a nitro group, -alkyl(C -C )-NR R ’, -O-alkyl(C -C )-NR R ’, -O-alkyl(C -C )-R , -C(O)-OR , 0 6 9 9 1 6 9 9 1 6 10 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 ? T represents a (C -C )alkyl group, a (C -C )carbonyloxy(C -C )alkyl group or a 1 6 1 6 1 6 10 di(C -C )alkylaminocarbonyl(C -C )alkyl group, 1 6 1 6 ? R , R , R , R , A and n are as defined for formula (I), 1 6 7 13 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. 15
24. Compound of formula (VI ) according to claim 23, wherein the substituents of the pair (R1, R5’) are identical and the substituents of the pair (R2’, R4’) are identical.
25. Compound of formula (VII ), a particular case of compound of formula (VII) according to claim 22: (VII ) 20 wherein: ? R ’, R ’, R ’ and R ’ independently of one another represent a halogen atom, a 2 3 4 5 linear or branched (C -C )alkyl group, a linear or branched (C -C )alkenyl group, a 1 6 2 6 linear or branched (C -C )alkynyl group, a linear or branched (C -C )polyhaloalkyl, 2 6 1 6 a hydroxy group, a hydroxy(C -C )alkyl group, a linear or branched (C -C )alkoxy 1 6 1 6 group, a -S-(C -C )alkyl group, a cyano group, a nitro group, -alkyl(C -C )-NR R ’, -O-alkyl(C -C )-NR R ’, -O-alkyl(C -C )-R , -C(O)-OR , 0 6 9 9 1 6 9 9 1 6 10 9 -O-C(O)-R , -C(O)-NR R ’, -NR -C(O)-R ’, -NR -C(O)-OR ’, 9 9 9 9 9 9 9 5 -alkyl(C -C )-NR -C(O)-R ’, -SO -NR R ’, -SO -alkyl(C -C ), 1 6 9 9 2 9 9 2 1 6 ? R1, R6, R7, R13, A and n are as defined for formula (I), 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. 10
26. Compound of formula (VII ) according to claim 25 wherein the substituents of the pair (R , R ’) are identical and the substituents of the pair (R ’, R ’) are identical. 1 5 2 4
27. Compound of formula (VII ) according to claim 26, which is (2R){[5-{3,5- dichloro-2,6-dimethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluoro phenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidin 15 yl]methoxy}phenyl)propanoic acid.
28. Compound of formula (VI ), a particular case of compound of formula (VI) according to claim 22: (VI ) wherein: 20 ? R ’ represents a halogen atom, a linear or branched (C -C )alkyl group, a linear or 5 1 6 branched (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a linear 2 6 2 6 or branched (C1-C6)polyhaloalkyl, a hydroxy group, a hydroxy(C1-C6)alkyl group, 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 ’, -O-alkyl(C -C )-R , 0 6 9 9 1 6 9 9 1 6 10 -C(O)-OR , -O-C(O)-R , -C(O)-NR R ’, -NR -C(O)-R ’, -NR -C(O)-OR ’, 9 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 5 ? T represents a (C -C )alkyl group, a (C -C )carbonyloxy(C -C )alkyl group or a 1 6 1 6 1 6 di(C -C )alkylaminocarbonyl(C -C )alkyl group, 1 6 1 6 ? R , R , R , R , R , A and n are as defined for formula (I), 1 3 6 7 13 and wherein the substituents of the pair (R , R ’) are identical, its enantiomers, diastereoisomers and atropisomers, and addition salts thereof with a 10 pharmaceutically acceptable acid or base, as synthesis intermediate but also as compound for use as pro-apoptotic agents.
29. Compound of formula (VIIB), a particular case of compound of formula (VII) according to claim 22: (VII ) 15 wherein: ? R5’ represents a halogen atom, a linear or branched (C1-C6)alkyl group, a linear or branched (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a linear 2 6 2 6 or branched (C -C )polyhaloalkyl, a hydroxy group, a hydroxy(C -C )alkyl group, 1 6 1 6 a linear or branched (C -C )alkoxy group, a -S-(C -C )alkyl group, a cyano group, 1 6 1 6 20 a nitro group, -alkyl(C -C )-NR R ’, -O-alkyl(C -C )-NR R ’, -O-alkyl(C -C )-R , 0 6 9 9 1 6 9 9 1 6 10 -C(O)-OR , -O-C(O)-R , -C(O)-NR R ’, -NR -C(O)-R ’, -NR -C(O)-OR ’, 9 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 , R , R , R , R , A and n are as defined for formula (I), 1 3 6 7 13 and wherein the substituents of the pair (R , 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. 5
30. Compound of formula (VII ) according to claim 29, which is (2R){[5-{2,6- dimethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno [2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy} phenyl)propanoic acid.
31. Pharmaceutical composition comprising a compound of formulae (I), (VI ), (VI ), 10 (VII ) or (VII ), according to any one of claims 1 to 21 or claims 23 to 30, or an addition salt thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients.
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 15 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 uterus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non- 20 small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
35. Use of a compound of formulae (I), (VI ), (VI ), (VII ) or (VII ), according to any A B A B one of claims 1 to 21 or claims 23 to 30, or an addition salt thereof with a pharmaceutically acceptable acid or base in the manufacture of a medicament useful as a pro-apoptotic agent. 25
36. Use of a compound of formulae (I), (VI ), (VI ), (VII ) or (VII ), according to any A B A B one of claims 1 to 21 or claims 23 to 30, or an addition salt thereof with a pharmaceutically acceptable acid or base in the manufacture of a medicament for the treatment of cancers or of auto-immune and immune system diseases.
37. Compound of formulae (I), (VI ), (VI ), (VII ) or (VII ), according to any one of A B A B 5 claims 1 to 21 or claims 23 to 30, 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 leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, 10 prostate cancer, pancreatic cancer and small-cell lung cancer.
38. Use of a compound of formulae (I), (VI ), (VI ), (VII ) or (VII ), according to any A B A B one of claims 1 to 21 or claims 23 to 30, or an addition salt thereof with a pharmaceutically acceptable acid or base, in the manufacture of a medicament for the 15 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. 20
39. Combination of a compound of formulae (I), (VI ), (VI ), (VII ) or (VII ), according A B A B to any one of claims 1 to 21 or claims 23 to 30, with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies.
40. Pharmaceutical composition comprising a combination according to claim 39 in 25 combination with one or more pharmaceutically acceptable excipients.
41. Combination according to claim 39 for use in the treatment of cancers.
42. Use of a combination according to claim 39 in the manufacture of a medicament for the treatment of cancers.
43. Compound of formulae (I), (VIA), (VIB), (VIIA) or (VIIB), according to any one of claims 1 to 21 or claims 23 to 30, for use in the treatment of cancers requiring radiotherapy.
44. Use of a compound of formulae (I), (VI ), (VI ), (VII ) or (VII ), according to any A B A B one of claims 1 to 21 or claims 23 to 30, in the manufacture of a medicament for the treatment of cancers requiring radiotherapy. 10
45. A compound according to any one of claims 1 to 21, 23 to 30, 37, or 43; process according to claim 22; pharmaceutical composition according to any one of claims 31 to 34 or 40; use according to any one of claims 35, 36, 38, 42, or 44; or combination according to claim 39 or claim 41, substantially as herein described with reference to any example thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1555752A FR3037957B1 (en) | 2015-06-23 | 2015-06-23 | NOVEL HYDROXYESTER DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
| PCT/EP2016/064433 WO2016207225A1 (en) | 2015-06-23 | 2016-06-22 | New hydroxyester derivatives, a process for their preparation and pharmaceutical compositions containing them |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ738455A NZ738455A (en) | 2024-03-22 |
| NZ738455B2 true NZ738455B2 (en) | 2024-06-25 |
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