ES2750640T3 - Ligandos opioides kappa novedosos - Google Patents

Info

Publication number

ES2750640T3

ES2750640T3 ES13829428T ES13829428T ES2750640T3 ES 2750640 T3 ES2750640 T3 ES 2750640T3 ES 13829428 T ES13829428 T ES 13829428T ES 13829428 T ES13829428 T ES 13829428T ES 2750640 T3 ES2750640 T3 ES 2750640T3

Authority

ES

Spain

Prior art keywords

alkyl

cycloalkyl

compound

halo

groups

Prior art date

2012-08-16

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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• 239000003446 ligand Substances 0.000 title description 6
• -1 halo (C1-C6) alkyl Chemical group 0.000 claims abstract description 251
• 150000001875 compounds Chemical class 0.000 claims abstract description 165
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 66
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 54
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 43
• 150000003839 salts Chemical class 0.000 claims abstract description 40
• 125000005843 halogen group Chemical group 0.000 claims abstract description 39
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 39
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 36
• 125000003118 aryl group Chemical group 0.000 claims abstract description 36
• 125000004429 atom Chemical group 0.000 claims abstract description 26
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 21
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 20
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 17
• 125000006763 (C3-C9) cycloalkyl group Chemical group 0.000 claims abstract description 16
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 15
• 229910003827 NRaRb Inorganic materials 0.000 claims abstract description 12
• 125000004122 cyclic group Chemical group 0.000 claims abstract description 12
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims abstract description 11
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 10
• 125000002950 monocyclic group Chemical group 0.000 claims abstract description 5
• 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 claims abstract description 4
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims abstract description 4
• 125000002619 bicyclic group Chemical group 0.000 claims abstract description 4
• 229910052705 radium Inorganic materials 0.000 claims abstract description 4
• 229910052701 rubidium Inorganic materials 0.000 claims abstract description 4
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract 2
• 239000000203 mixture Substances 0.000 claims description 50
• 108020001588 κ-opioid receptors Proteins 0.000 claims description 38
• 102000048260 kappa Opioid Receptors Human genes 0.000 claims description 37
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
• 238000000034 method Methods 0.000 claims description 20
• 239000000460 chlorine Substances 0.000 claims description 14
• 238000011282 treatment Methods 0.000 claims description 14
• 229910052801 chlorine Inorganic materials 0.000 claims description 11
• 208000035475 disorder Diseases 0.000 claims description 11
• 229910052731 fluorine Inorganic materials 0.000 claims description 11
• 208000002193 Pain Diseases 0.000 claims description 8
• 229910052794 bromium Inorganic materials 0.000 claims description 8
• 206010015037 epilepsy Diseases 0.000 claims description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
• 230000036407 pain Effects 0.000 claims description 8
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
• 239000011737 fluorine Substances 0.000 claims description 6
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
• 208000019022 Mood disease Diseases 0.000 claims description 5
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
• 208000018459 dissociative disease Diseases 0.000 claims description 5
• 102000005962 receptors Human genes 0.000 claims description 5
• 108020003175 receptors Proteins 0.000 claims description 5
• DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 claims description 4
• 208000019901 Anxiety disease Diseases 0.000 claims description 4
• 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 4
• 230000036506 anxiety Effects 0.000 claims description 4
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
• 208000007848 Alcoholism Diseases 0.000 claims description 3
• 208000024827 Alzheimer disease Diseases 0.000 claims description 3
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
• 208000004880 Polyuria Diseases 0.000 claims description 3
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
• 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
• 230000007812 deficiency Effects 0.000 claims description 3
• 230000035619 diuresis Effects 0.000 claims description 3
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
• 210000000987 immune system Anatomy 0.000 claims description 3
• 230000004112 neuroprotection Effects 0.000 claims description 3
• 239000008194 pharmaceutical composition Substances 0.000 claims description 3
• 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 claims description 2
• GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
• 201000007930 alcohol dependence Diseases 0.000 claims description 2
• 230000006698 induction Effects 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
• 208000017194 Affective disease Diseases 0.000 claims 1
• 208000004550 Postoperative Pain Diseases 0.000 claims 1
• 230000001149 cognitive effect Effects 0.000 claims 1
• CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims 1
• 201000000980 schizophrenia Diseases 0.000 claims 1
• 208000009935 visceral pain Diseases 0.000 claims 1
• 125000004446 heteroarylalkyl group Chemical group 0.000 abstract description 5
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
• 125000004432 carbon atom Chemical group C* 0.000 description 37
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
• 229910052799 carbon Inorganic materials 0.000 description 27
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 26
• 125000005842 heteroatom Chemical group 0.000 description 26
• 125000001424 substituent group Chemical group 0.000 description 24
• 230000035882 stress Effects 0.000 description 23
• 239000000243 solution Substances 0.000 description 19
• ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 18
• 239000000047 product Substances 0.000 description 18
• 230000002829 reductive effect Effects 0.000 description 17
• 239000003981 vehicle Substances 0.000 description 17
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
• 239000003814 drug Substances 0.000 description 16
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 16
• 150000001412 amines Chemical class 0.000 description 15
• 150000001721 carbon Chemical group 0.000 description 15
• 238000004440 column chromatography Methods 0.000 description 15
• 235000019439 ethyl acetate Nutrition 0.000 description 14
• 230000000155 isotopic effect Effects 0.000 description 14
• 229940079593 drug Drugs 0.000 description 13
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• 201000010099 disease Diseases 0.000 description 12
• 108010065372 Dynorphins Proteins 0.000 description 11
• 102100024622 Proenkephalin-B Human genes 0.000 description 11
• 125000002252 acyl group Chemical group 0.000 description 11
• 125000003545 alkoxy group Chemical group 0.000 description 11
• 238000002360 preparation method Methods 0.000 description 11
• 239000011541 reaction mixture Substances 0.000 description 11
• 239000000126 substance Substances 0.000 description 11
• 238000003786 synthesis reaction Methods 0.000 description 11
• 238000006243 chemical reaction Methods 0.000 description 10
• 125000000392 cycloalkenyl group Chemical group 0.000 description 10
• 230000014509 gene expression Effects 0.000 description 10
• 238000006467 substitution reaction Methods 0.000 description 10
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 9
• 206010012335 Dependence Diseases 0.000 description 9
• 229960003920 cocaine Drugs 0.000 description 9
• 229910052739 hydrogen Inorganic materials 0.000 description 9
• 239000001257 hydrogen Substances 0.000 description 9
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
• 229910052760 oxygen Inorganic materials 0.000 description 9
• JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 8
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
• 239000002253 acid Substances 0.000 description 8
• 239000004480 active ingredient Substances 0.000 description 8
• 125000003710 aryl alkyl group Chemical group 0.000 description 8
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• 125000006239 protecting group Chemical group 0.000 description 8
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• 238000003419 tautomerization reaction Methods 0.000 description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
• 241000124008 Mammalia Species 0.000 description 7
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 7
• 125000003342 alkenyl group Chemical group 0.000 description 7
• 239000005557 antagonist Substances 0.000 description 7
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 7
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• 125000004430 oxygen atom Chemical group O* 0.000 description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
• 229910052717 sulfur Inorganic materials 0.000 description 7
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
• 108090000137 Opioid Receptors Proteins 0.000 description 6
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
• 230000004913 activation Effects 0.000 description 6
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• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 6
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• 239000011701 zinc Substances 0.000 description 1
• 108020001612 μ-opioid receptors Proteins 0.000 description 1