MXPA00010171A - Cubane derivatives as metabotropic glutamate receptor antagonists and process for their preparation - Google Patents
Cubane derivatives as metabotropic glutamate receptor antagonists and process for their preparationInfo
- Publication number
- MXPA00010171A MXPA00010171A MXPA/A/2000/010171A MXPA00010171A MXPA00010171A MX PA00010171 A MXPA00010171 A MX PA00010171A MX PA00010171 A MXPA00010171 A MX PA00010171A MX PA00010171 A MXPA00010171 A MX PA00010171A
- Authority
- MX
- Mexico
- Prior art keywords
- compound
- formula
- group
- amino
- cooh
- Prior art date
Links
- 108010010914 Metabotropic Glutamate Receptors Proteins 0.000 title claims abstract description 36
- 102000016193 Metabotropic Glutamate Receptors Human genes 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims description 24
- 238000000034 method Methods 0.000 title claims description 11
- TXWRERCHRDBNLG-UHFFFAOYSA-N Cubane Chemical class C12C3C4C1C1C4C3C12 TXWRERCHRDBNLG-UHFFFAOYSA-N 0.000 title abstract description 8
- 239000003194 amino acid receptor blocking agent Substances 0.000 title 1
- 239000003825 glutamate receptor antagonist Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 143
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 6
- -1 phosphono, phosphino Chemical group 0.000 claims description 111
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 47
- 239000011780 sodium chloride Substances 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 31
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 20
- 150000002148 esters Chemical class 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 229960004756 ethanol Drugs 0.000 claims description 14
- 125000006239 protecting group Chemical group 0.000 claims description 12
- 230000002378 acidificating Effects 0.000 claims description 11
- 230000003000 nontoxic Effects 0.000 claims description 11
- 231100000252 nontoxic Toxicity 0.000 claims description 11
- 150000001408 amides Chemical class 0.000 claims description 10
- 229940079593 drugs Drugs 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 8
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 8
- CTAPFRYPJLPFDF-UHFFFAOYSA-N Isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 7
- JGMSYYKHPCNKBF-UHFFFAOYSA-N S(=O)(O)OB(O)C1=NN=NN1 Chemical compound S(=O)(O)OB(O)C1=NN=NN1 JGMSYYKHPCNKBF-UHFFFAOYSA-N 0.000 claims description 7
- 230000000051 modifying Effects 0.000 claims description 7
- 206010002855 Anxiety Diseases 0.000 claims description 6
- 206010057666 Anxiety disease Diseases 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 230000036506 anxiety Effects 0.000 claims description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- 206010001897 Alzheimer's disease Diseases 0.000 claims description 5
- 208000002193 Pain Diseases 0.000 claims description 5
- 125000001931 aliphatic group Chemical group 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 230000003301 hydrolyzing Effects 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 230000001537 neural Effects 0.000 claims description 5
- 201000001971 Huntington's disease Diseases 0.000 claims description 4
- 206010061536 Parkinson's disease Diseases 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 230000000926 neurological Effects 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 4
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 claims description 3
- 206010007515 Cardiac arrest Diseases 0.000 claims description 3
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 3
- 206010010904 Convulsion Diseases 0.000 claims description 3
- 206010012289 Dementia Diseases 0.000 claims description 3
- 208000010496 Heart Arrest Diseases 0.000 claims description 3
- 206010033664 Panic attack Diseases 0.000 claims description 3
- 206010061920 Psychotic disease Diseases 0.000 claims description 3
- 206010039911 Seizure Diseases 0.000 claims description 3
- 210000000278 Spinal Cord Anatomy 0.000 claims description 3
- UMGDCJDMYOKAJW-UHFFFAOYSA-N Thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 3
- 201000006474 brain ischemia Diseases 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- 230000002490 cerebral Effects 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 230000002218 hypoglycaemic Effects 0.000 claims description 3
- 208000000094 Chronic Pain Diseases 0.000 claims description 2
- 206010019233 Headache Diseases 0.000 claims description 2
- 206010021143 Hypoxia Diseases 0.000 claims description 2
- 206010022114 Injury Diseases 0.000 claims description 2
- 206010027599 Migraine Diseases 0.000 claims description 2
- 208000008085 Migraine Disorders Diseases 0.000 claims description 2
- 206010028334 Muscle spasms Diseases 0.000 claims description 2
- SNICXCGAKADSCV-JTQLQIEISA-N Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 2
- 229960002715 Nicotine Drugs 0.000 claims description 2
- 206010038923 Retinopathy Diseases 0.000 claims description 2
- 206010038932 Retinopathy Diseases 0.000 claims description 2
- 208000005392 Spasm Diseases 0.000 claims description 2
- 206010043118 Tardive dyskinesia Diseases 0.000 claims description 2
- 208000000323 Tourette Syndrome Diseases 0.000 claims description 2
- 206010044126 Tourette's disease Diseases 0.000 claims description 2
- 206010046543 Urinary incontinence Diseases 0.000 claims description 2
- 206010047700 Vomiting Diseases 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 claims description 2
- 230000000747 cardiac effect Effects 0.000 claims description 2
- 229960003920 cocaine Drugs 0.000 claims description 2
- 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 claims description 2
- ZPUCINDJVBIVPJ-BARDWOONSA-N cocaine Natural products O([C@@H]1C[C@H]2CC[C@H](N2C)[C@@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-BARDWOONSA-N 0.000 claims description 2
- 231100000040 eye damage Toxicity 0.000 claims description 2
- 231100000869 headache Toxicity 0.000 claims description 2
- 230000001146 hypoxic Effects 0.000 claims description 2
- 229930015196 nicotine Natural products 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 230000005586 smoking cessation Effects 0.000 claims description 2
- 238000001356 surgical procedure Methods 0.000 claims description 2
- 206010003736 Attention deficit/hyperactivity disease Diseases 0.000 claims 1
- 206010004938 Bipolar disease Diseases 0.000 claims 1
- 206010048962 Brain oedema Diseases 0.000 claims 1
- 206010057668 Cognitive disease Diseases 0.000 claims 1
- 208000008208 Craniocerebral Trauma Diseases 0.000 claims 1
- 208000010125 Myocardial Infarction Diseases 0.000 claims 1
- 206010037175 Psychiatric disease Diseases 0.000 claims 1
- 201000006287 attention deficit hyperactivity disease Diseases 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 1
- 201000000980 schizophrenia Diseases 0.000 claims 1
- 210000003169 Central Nervous System Anatomy 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 description 48
- 239000000243 solution Substances 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-Glutamic acid Natural products OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 27
- 239000004480 active ingredient Substances 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- 102000005962 receptors Human genes 0.000 description 20
- 108020003175 receptors Proteins 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 230000003042 antagnostic Effects 0.000 description 19
- 239000005557 antagonist Substances 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 15
- 238000006460 hydrolysis reaction Methods 0.000 description 14
- 239000000556 agonist Substances 0.000 description 13
- 210000004027 cells Anatomy 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 210000002569 neurons Anatomy 0.000 description 12
- 239000003826 tablet Substances 0.000 description 12
- 239000003981 vehicle Substances 0.000 description 12
- 238000009472 formulation Methods 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- WJRBRSLFGCUECM-UHFFFAOYSA-N Hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 229920002472 Starch Polymers 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 239000008107 starch Substances 0.000 description 8
- 235000019698 starch Nutrition 0.000 description 8
- 102000015404 Amino Acid Receptors Human genes 0.000 description 7
- 108010025177 Amino Acid Receptors Proteins 0.000 description 7
- 102100006616 GRM2 Human genes 0.000 description 7
- 239000003257 excitatory amino acid Substances 0.000 description 7
- 230000002461 excitatory amino acid Effects 0.000 description 7
- 239000000796 flavoring agent Substances 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 150000002576 ketones Chemical class 0.000 description 7
- 108010038421 metabotropic glutamate receptor 2 Proteins 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 210000004556 Brain Anatomy 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 230000001681 protective Effects 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- YFYNOWXBIBKGHB-FBCQKBJTSA-N (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid Chemical compound OC(=O)[C@]1(N)CC[C@@H](C(O)=O)C1 YFYNOWXBIBKGHB-FBCQKBJTSA-N 0.000 description 5
- 229960002989 Glutamic Acid Drugs 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000003086 colorant Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 230000005284 excitation Effects 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 238000005755 formation reaction Methods 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 229940057995 liquid paraffin Drugs 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 230000036961 partial Effects 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 230000002335 preservative Effects 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 4
- 102000019460 EC 4.6.1.1 Human genes 0.000 description 4
- 108060000200 EC 4.6.1.1 Proteins 0.000 description 4
- 229940049906 Glutamate Drugs 0.000 description 4
- HOKKHZGPKSLGJE-GSVOUGTGSA-N NMDA Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 4
- NNFCIKHAZHQZJG-UHFFFAOYSA-N Potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 230000000240 adjuvant Effects 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N cd3od Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000008079 hexane Substances 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 125000005647 linker group Chemical group 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 230000036407 pain Effects 0.000 description 4
- 239000000546 pharmaceutic aid Substances 0.000 description 4
- 230000002829 reduced Effects 0.000 description 4
- 230000035945 sensitivity Effects 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- OHCQJHSOBUTRHG-KGGHGJDLSA-N (3R,4aR,5S,6S,6aS,10S,10aR,10bS)-3-ethenyl-6,10,10b-trihydroxy-3,4a,7,7,10a-pentamethyl-1-oxododecahydro-1H-benzo[f]chromen-5-yl acetate Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 3
- PRKQVKDSMLBJBJ-UHFFFAOYSA-N Ammonium carbonate Chemical compound N.N.OC(O)=O PRKQVKDSMLBJBJ-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- 229960003563 Calcium Carbonate Drugs 0.000 description 3
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 3
- 229940095074 Cyclic AMP Drugs 0.000 description 3
- 108091006011 G proteins Proteins 0.000 description 3
- 102100006613 GRM4 Human genes 0.000 description 3
- 102000030007 GTP-Binding Proteins Human genes 0.000 description 3
- 108091000058 GTP-Binding Proteins Proteins 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 208000009025 Nervous System Disease Diseases 0.000 description 3
- 206010029305 Neurological disorder Diseases 0.000 description 3
- 235000019483 Peanut oil Nutrition 0.000 description 3
- 230000001154 acute Effects 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000001099 ammonium carbonate Substances 0.000 description 3
- 235000012501 ammonium carbonate Nutrition 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- IVOMOUWHDPKRLL-KQYNXXCUSA-N cAMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 235000010216 calcium carbonate Nutrition 0.000 description 3
- 230000001684 chronic Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000007859 condensation product Substances 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 230000002964 excitative Effects 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 150000002367 halogens Chemical group 0.000 description 3
- 229940091173 hydantoin Drugs 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 108010038422 metabotropic glutamate receptor 4 Proteins 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- IAYPIBMASNFSPL-UHFFFAOYSA-N oxane Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 239000012188 paraffin wax Substances 0.000 description 3
- 239000000312 peanut oil Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 230000000946 synaptic Effects 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 230000001225 therapeutic Effects 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 238000002604 ultrasonography Methods 0.000 description 3
- UCSJYZPVAKXKNQ-HZYVHMACSA-N 1-[(1S,2R,3R,4S,5R,6R)-3-carbamimidamido-6-{[(2R,3R,4R,5S)-3-{[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy}-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy}-2,4,5-trihydroxycyclohexyl]guanidine Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 2
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 206010002660 Anoxia Diseases 0.000 description 2
- 241000976983 Anoxia Species 0.000 description 2
- 210000004369 Blood Anatomy 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- MATPZHBYOVDBLI-JJYYJPOSSA-N DCG-IV Chemical compound OC(=O)[C@@H](N)C1[C@@H](C(O)=O)[C@@H]1C(O)=O MATPZHBYOVDBLI-JJYYJPOSSA-N 0.000 description 2
- 206010015037 Epilepsy Diseases 0.000 description 2
- 102100006614 GRM3 Human genes 0.000 description 2
- 102100006612 GRM5 Human genes 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 102000006541 Ionotropic Glutamate Receptors Human genes 0.000 description 2
- 108010008812 Ionotropic Glutamate Receptors Proteins 0.000 description 2
- 206010061255 Ischaemia Diseases 0.000 description 2
- DDOQBQRIEWHWBT-VKHMYHEASA-N L-AP4 Chemical compound OC(=O)[C@@H](N)CCP(O)(O)=O DDOQBQRIEWHWBT-VKHMYHEASA-N 0.000 description 2
- 229940067606 Lecithin Drugs 0.000 description 2
- JORQDGTZGKHEEO-UHFFFAOYSA-N Lithium cyanide Chemical compound [Li+].N#[C-] JORQDGTZGKHEEO-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N Oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- XCRBXWCUXJNEFX-UHFFFAOYSA-N Peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 206010039966 Senile dementia Diseases 0.000 description 2
- MNWBNISUBARLIT-UHFFFAOYSA-N Sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- LEIMLDGFXIOXMT-UHFFFAOYSA-N Trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- GUBXYMKIJFOYOA-YMGPVYFXSA-N [(2R)-2-formyloxy-3-[hydroxy-[(2R,3S,5R,6R)-2,3,4,5,6-pentahydroxycyclohexyl]oxyphosphoryl]oxypropyl] formate Chemical compound OC1[C@H](O)[C@@H](O)C(OP(O)(=O)OC[C@@H](COC=O)OC=O)[C@H](O)[C@@H]1O GUBXYMKIJFOYOA-YMGPVYFXSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000011149 active material Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 2
- 125000005157 alkyl carboxy group Chemical group 0.000 description 2
- 125000006242 amine protecting group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000003957 anion exchange resin Substances 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 230000000903 blocking Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 230000019771 cognition Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000002860 competitive Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000008387 emulsifying waxe Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000003492 excitotoxic Effects 0.000 description 2
- 231100000318 excitotoxic Toxicity 0.000 description 2
- 239000010685 fatty oil Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 230000013016 learning Effects 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000001404 mediated Effects 0.000 description 2
- 230000003340 mental Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000036963 noncompetitive Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 150000003905 phosphatidylinositols Chemical class 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 230000001242 postsynaptic Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 230000002633 protecting Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 235000003441 saturated fatty acids Nutrition 0.000 description 2
- 150000004671 saturated fatty acids Chemical class 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000001187 sodium carbonate Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 239000011778 trisodium citrate Substances 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- FIWSRSRCWYARAJ-SQOFCNSWSA-N (2R,3R,4R,5S)-hexane-1,2,3,4,5,6-hexol;(Z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O FIWSRSRCWYARAJ-SQOFCNSWSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- WEAYCYAIVOIUMG-UHFFFAOYSA-N 1-methyl-4-(4-methylphenyl)sulfonylbenzene Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C1=CC=C(C)C=C1 WEAYCYAIVOIUMG-UHFFFAOYSA-N 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M 2,3-dimethylbenzenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- ZMKBTZQKANQZSK-UHFFFAOYSA-N 2-(methylamino)-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid Chemical compound CNC(C(O)=O)CC1=C(C)ON=C1O ZMKBTZQKANQZSK-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-SZSCBOSDSA-N 2-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2H-furan-5-one Chemical compound OC[C@H](O)C1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-SZSCBOSDSA-N 0.000 description 1
- HPBPNWPROCLLAA-UHFFFAOYSA-N 2-bromoethanone Chemical group BrC[C]=O HPBPNWPROCLLAA-UHFFFAOYSA-N 0.000 description 1
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 1
- BIPVHDWOTMWEBI-UHFFFAOYSA-N 2H-tetrazol-5-ylboronic acid Chemical compound OB(O)C1=NN=NN1 BIPVHDWOTMWEBI-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3-Isobutyl-1-methyl-2,6(1H,3H)-purinedione Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 1
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- VTMJKPGFERYGJF-UHFFFAOYSA-N 4-Carboxyphenylglycine Chemical compound OC(=O)C(N)C1=CC=C(C(O)=O)C=C1 VTMJKPGFERYGJF-UHFFFAOYSA-N 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 description 1
- SJZRECIVHVDYJC-UHFFFAOYSA-M 4-hydroxybutyrate Chemical compound OCCCC([O-])=O SJZRECIVHVDYJC-UHFFFAOYSA-M 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- IWNPWQRBFNOGHM-UHFFFAOYSA-N 9H-thioxanthen-9-ol Chemical compound C1=CC=C2C(O)C3=CC=CC=C3SC2=C1 IWNPWQRBFNOGHM-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N AI2O3 Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229940005513 ANTIDEPRESSANTS Drugs 0.000 description 1
- 229940005530 ANXIOLYTICS Drugs 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N Aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 1
- BVCZEBOGSOYJJT-UHFFFAOYSA-N Ammonium carbamate Chemical compound [NH4+].NC([O-])=O BVCZEBOGSOYJJT-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 210000001218 Blood-Brain Barrier Anatomy 0.000 description 1
- 208000001183 Brain Injury Diseases 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L Calcium hydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 108091005504 Cation channels Proteins 0.000 description 1
- 210000000170 Cell Membrane Anatomy 0.000 description 1
- 210000001638 Cerebellum Anatomy 0.000 description 1
- 210000004289 Cerebral Ventricles Anatomy 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N Cetyl alcohol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- OHCQJHSOBUTRHG-ZYIXGEAZSA-N Coleonol Natural products O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@H](O)CCC1(C)C OHCQJHSOBUTRHG-ZYIXGEAZSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010013663 Drug dependence Diseases 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- IRXSLJNXXZKURP-UHFFFAOYSA-N Fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 1
- 230000036328 Free drug Effects 0.000 description 1
- 101700043312 GRM3 Proteins 0.000 description 1
- 102100002039 GRM6 Human genes 0.000 description 1
- 101700022058 GRM6 Proteins 0.000 description 1
- 102100002041 GRM7 Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 201000004311 Gilles de la Tourette syndrome Diseases 0.000 description 1
- 240000007842 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 210000001320 Hippocampus Anatomy 0.000 description 1
- 229940021223 Hypertonic solutions Drugs 0.000 description 1
- 206010020993 Hypoglycaemia Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- IRJCBFDCFXCWGO-UHFFFAOYSA-N Ibotenic acid Chemical compound OC(=O)C(N)C1=CC(=O)NO1 IRJCBFDCFXCWGO-UHFFFAOYSA-N 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N Inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 Inositol Drugs 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- GZOVEPYOCJWRFC-UHFFFAOYSA-N L-trans-α-Amino-2-carboxycyclopropaneacetic acid Chemical compound OC(=O)C(N)C1CC1C(O)=O GZOVEPYOCJWRFC-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- GUWSLQUAAYEZAF-UHFFFAOYSA-L Lead(II) acetate Chemical compound O1C(C)=O[Pb]21O=C(C)O2 GUWSLQUAAYEZAF-UHFFFAOYSA-L 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 229960005015 Local anesthetics Drugs 0.000 description 1
- 229940083877 Local anesthetics for treatment of hemorrhoids and anal fissures for topical use Drugs 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N Methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- HHVIBTZHLRERCL-UHFFFAOYSA-N Methylsulfonylmethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 1
- HGINADPHJQTSKN-UHFFFAOYSA-N Monoethyl malonic acid Chemical compound CCOC(=O)CC(O)=O HGINADPHJQTSKN-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 210000004940 Nucleus Anatomy 0.000 description 1
- 229940005483 OPIOID ANALGESICS Drugs 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 210000001672 Ovary Anatomy 0.000 description 1
- 229940049954 Penicillin Drugs 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N Phenylpropanoic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 102000011420 Phospholipase D Human genes 0.000 description 1
- 108090000553 Phospholipase D Proteins 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N Phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene (PE) Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J Pyrophosphate Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 210000000664 Rectum Anatomy 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N Saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 Saccharin Drugs 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 210000002265 Sensory Receptor Cells Anatomy 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- 229940005550 Sodium alginate Drugs 0.000 description 1
- JNYAEWCLZODPBN-CTQIIAAMSA-N Sorbitan Chemical compound OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 description 1
- 229960005322 Streptomycin Drugs 0.000 description 1
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfizole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 1
- 240000000280 Theobroma cacao Species 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- NWGKJDSIEKMTRX-HSACVWGTSA-N [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (E)-octadec-9-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-HSACVWGTSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 230000003213 activating Effects 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000005083 alkoxyalkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005671 alkyl alkenyl alkyl group Chemical group 0.000 description 1
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000005038 alkynylalkyl group Chemical group 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000202 analgesic Effects 0.000 description 1
- 230000001773 anti-convulsant Effects 0.000 description 1
- 230000001430 anti-depressive Effects 0.000 description 1
- 230000003474 anti-emetic Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 230000003078 antioxidant Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 230000000949 anxiolytic Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 238000010936 aqueous wash Methods 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 1
- 229960000626 benzylpenicillin Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- PUPZLCDOIYMWBV-UHFFFAOYSA-N butylene glycol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- QXJJQWWVWRCVQT-UHFFFAOYSA-K calcium;sodium;phosphate Chemical compound [Na+].[Ca+2].[O-]P([O-])([O-])=O QXJJQWWVWRCVQT-UHFFFAOYSA-K 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M caprate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M caproate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000000271 cardiovascular Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000001413 cellular Effects 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 230000002999 depolarising Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 230000005059 dormancy Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N ethylene glycol monomethyl ether Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- UKFXDFUAPNAMPJ-UHFFFAOYSA-N ethylmalonic acid Chemical compound CCC(C(O)=O)C(O)=O UKFXDFUAPNAMPJ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000001605 fetal Effects 0.000 description 1
- 238000000434 field desorption mass spectrometry Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 229930002911 forskolin Natural products 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003823 glutamate receptor agonist Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000002333 glycines Chemical class 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000000819 hypertonic solution Substances 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 230000001057 ionotropic Effects 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-M isobutyrate Chemical compound CC(C)C([O-])=O KQNPFQTWMSNSAP-UHFFFAOYSA-M 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229940046892 lead acetate Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Inorganic materials [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229940064003 local anesthetic throat preparations Drugs 0.000 description 1
- 230000027928 long-term synaptic potentiation Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000002503 metabolic Effects 0.000 description 1
- 108010038445 metabotropic glutamate receptor 3 Proteins 0.000 description 1
- 108010038449 metabotropic glutamate receptor 7 Proteins 0.000 description 1
- 102000006239 metabotropic receptors Human genes 0.000 description 1
- 108020004083 metabotropic receptors Proteins 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M methanoate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- GTAGIQAUVGTSKJ-UHFFFAOYSA-N methyl 4-carbonochloridoylcubane-1-carboxylate Chemical compound C12C3C4(C(=O)OC)C1C1C4C3C12C(Cl)=O GTAGIQAUVGTSKJ-UHFFFAOYSA-N 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- QAJKVPPCVSZGBX-UHFFFAOYSA-N methylsulfonyl(phenyl)methanone Chemical group CS(=O)(=O)C(=O)C1=CC=CC=C1 QAJKVPPCVSZGBX-UHFFFAOYSA-N 0.000 description 1
- 230000003278 mimic Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 230000003020 moisturizing Effects 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 201000009457 movement disease Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 210000003867 nerve cell Anatomy 0.000 description 1
- 230000000626 neurodegenerative Effects 0.000 description 1
- 230000003088 neuroexcitatory Effects 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 230000002887 neurotoxic Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 230000003364 opioid Effects 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000001590 oxidative Effects 0.000 description 1
- YFPJFKYCVYXDJK-UHFFFAOYSA-N oxo(diphenyl)phosphanium Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 230000001575 pathological Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-M phenylacetate Chemical compound [O-]C(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-M 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- 229960004723 phenylbutyrate Drugs 0.000 description 1
- 150000005331 phenylglycines Chemical class 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229940094025 potassium bicarbonate Drugs 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000003518 presynaptic Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrugs Drugs 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-M propane-1-sulfonate Chemical compound CCCS([O-])(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L propanedioate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 230000000541 pulsatile Effects 0.000 description 1
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 1
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N rac-1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000241 respiratory Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 230000001235 sensitizing Effects 0.000 description 1
- 230000001953 sensory Effects 0.000 description 1
- 230000021317 sensory perception Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 230000000707 stereoselective Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000000542 thalamic Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
Abstract
The present invention relates to therapeutically active cubane compounds, a method of preparing the same, and to pharmaceutical compositions comprising the compounds. The novel compounds are useful in treating diseases of the central nervous system related to the metabotropic glutamate receptor system.
Description
CUBAN DERIVATIVES AS ANTAGONISTS OF METABOTROPIC GLUTAMATE RECEPTOR AND PROCESS FOR PREPARATION.
FIELD OF THE INVENTION
This invention relates to therapeutically active Cuban derivatives, to a method for preparing the same, to the pharmaceutical compositions comprising the compounds and to a method for the treatment of diseases of the Central Nervous System (CNS) with them.
BACKGROUND OF THE INVENTION
The acidic L-glutamate amino acid is recognized as the main excitatory neurotransmitter in the CNS. The receptors that respond to L-glutamate are called excitatory amino acid receptors. Thus, excitatory amino acid receptors have a great physiological importance, playing a role in various physiological processes, such as long-term potency (learning and memory), the development of synaptic plasticity, motor control, respiratory regulation and cardiovascular and sensory perception.
Excitatory amino acid receptors are classified into two general types, both of which are activated by L-glutamic acid and its analogues. The receptors activated by L-glutamic acid that are directly coupled to the opening of cation channels in the cell membrane of neurons, are called "ionotropic". This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-Methyl-D-aspartate
(NMDA), α-Amino-3-hydroxy-5-methyl isoxazole-4-proplonic acid (AMPA), and Cainic acid (CA).
The second general type of receptor is the G-protein or second "metabotropic" excitatory amino acid receptor bound to messengers. This second type is coupled to multiple second messenger systems that lead to an expanded phosphoinositide hydrolysis, to an activation of phospholipase D, to increases or decreases in the formation of cAMP, and to changes in the function of ion channels (Schoepp and Conn, Trends in Pharmacological Science, 14:13, 1993). It seems that both types of receptors are not only mediators in normal synaptic transmission along the excitatory pathways, but also participate in the modification of synaptic connections during development and during life.
Up to now, eight different clones of glutamate metabotropics coupled to the G-protein (mGluRs) have been identified (Knopfel et al., 1995, J. Med. Chem., 38, 1417-1426). These receptors function to modulate the synaptic release of L-Glutamate, and the post-synaptic sensitivity of the neuronal cell to excitation by L-Glutamate. Based on pharmacology, sequential homology and the signal transduction path that activate), mGluRs have been subclassified into three groups. The mGluRi and mGluR5 receptors form Group I. They are coupled to the hydrolysis of phosphatidylinositol (Pl) and are selectively activated by (? 5) -3,5-dihydroxyphenylglycine (Brabet et al., Neurpharmacology, 34,895-903, 1995). Group II comprises the mGluR2 and MGLUR3 receptors. These are negatively coupled to adenylate cyclase and are selectively activated by (2S, 1R, 2'R, 3'R) -2- (2,3-dicarboxycyclopropyl) glycine (DCG-IV, Hayashi et al., Nature , 366, 687-690, 1993). Finally, the mGluR4, mGluR6, mGLUR7 and mGluRs receptors belong to Group III. They are also negatively coupled to adenylate cyclase and are selectively activated by (L) -2-amino-4-phosphonobutyric acid (L-AP4; Knopfel et al., 1995, J. Med. Chem.38, 1417-1426. ).
It is believed that the agonists and antagonists of these receptors are useful for the treatment of acute chronic neurodegenerative conditions, and as antipsychotic agents, analgesic anticonvulsants, anxiolytics, antidepressants and antiemetics.
Antagonists and agonists of neural receptors are classified as selective for a specific receptor or receptor subtype, or as non-selective. Antagonists can also be classified as competitive and non-competitive. Although competitive and non-competitive antagonists act on receptors in different ways to produce similar results, selectivity is based on observations that some antagonists have high levels of activity in only one type of receptor, and little or no activity in others. receivers. In the case of specific diseases and conditions of a receptor, the selective agonists and antagonists are of the highest value.
It is known that compounds such as L-glutamic acid, Quiscualic acid and Ibotenic acid act as non-selective agonists on mGluRs, whereas selective ionotropic glutamate receptor agonists, such as NMDA, AMPA and Cainic acid have little effect on these receptors. Recently, a few compounds have been identified without activity in the ionotropic glutamate receptors, but with activity in the metabotropic receptors. These include the trans-ACPD acid (trans (lS, 3R-l-aminociclopentano-l, 3-dlcarboxílico), the partial agonist acid L-AP3 (L-2-amino-3-fosfonopropiónico); Palmer, E. , Monaghan, DT and Cotman, CW, Eur. J. Pharmacol., 166, 585-587, 1989; Desai, M. and Conn, P.
Neurosclence Lett. 109, 157-162, 1990; Schoepp, D. D. et al., J. Neurochemistry. 56, 1789-1796, 1991; Schoepp, D. D.and Johnson, B.G. J. Neurochemistry 53, 1865-1613, 1989), L-AP4 (L-2-amino-4-phosphonobutyric acid), which is an agonist at the mGluR4 receptor (Thomsen C. et al., Eur. J. Pharmacol .227, 361-362, 1992) and some of the isomers of CCG (2- (carboxycyclopropyl) glycines), especially L-CCG-I and L-CCG-II (Hayashi, Y. et al., Br J. Pharmacol. 107, 539-543, 1992).
Very few selective antagonists have been reported in mGluRs. However, it has been reported that some of the derivatives of phenylglycine, S-4-CPG (4-carboxyphenylglycine), 5L4C3HPG (5L4-carboxy-3-hydroxyphenylglycine) and S-MCPG (-methyl ^ -carboxyphenylglycine), antagonize the phosphoinositide-stimulated hydrolysis of trans-ACPD, and therefore possibly act as antagonists in the mGluRl and mGluR2 subtypes (Thomsen, C. and Suzdak, P., Eur. 1 Pharmacol 245-299, 1993).
Research directed at mGluRs is beginning to show that mGluRs may be involved in various normal, as well as pathological, mechanisms in the brain and spinal cord. For example, the activation of these receptors on neurons can: influence the levels of mental acuity, attention and cognition; protect nerve cells from excitotoxic damage resulting from ischemia, hypoglycemia and anoxia; modulate the level of neuronal excitation; influence the mechanisms involved in the control of movement; reduce sensitivity to pain; reduce anxiety levels
The use of the active compounds in mGluRs for the treatment of epilepsy has been corroborated by investigations of the influence of trans-ACPD on the formation of seizures (Sacaan and Schoepp, Neuroscience Lett. 139, 77, 1992), and that Phosphoinosulide hydrolysis mediated through mGluR is increased after excitation experiments in rats (Akiyama et al., Brain Res. 569, 71, 1992). It has been known that Trans-ACPD increases the release of dopamine in the brain of rats, which indicates that compounds acting on mGluRs can be used for the treatment of Parkinson's disease and Huntington's disease (Sacaan et al., J. Neurochemistry 59, 245, 1992).
It has also been shown that Trans-ACPD is a neuroprotective agent in a middle cerebral artery occlusion (MCAO) model in mice (Chiamulera et al., Eur. J. Pharmacol, 215, 353, 1992), and it has been shown that The NMDA-induced neurotoxicity in nerve cell cultures is inhible (Koh et al., Proc. Nati, Acad. Sci. USA 88, 9431, 1991). The active compounds of mGluR are also involved in the treatment of pain. This is proven by the fact that the antagonists in the receptors
metabotropics of glutamate anatomize the synaptic sensory response to the harmful stimuli of the thalamic neurons (Eaton, S.A. et al., Eur. J. Neurosclence, 5, 186, 1993).
The use of active compounds in mGluRs for the treatment of neuronal diseases, such as senile dementia, has also been indicated in the investigations of Zheng and Gallagher (Neuron 9, 163, 1992) and Bashir et al. (Nature 363, 347, 1993), who demonstrated that the activation of mGluRs is necessary for the induction of a long-term potentiation (PLP) in cells (septal nucleus, hippocampus), and by the investigation that the depression of Long term is induced after the activation of the metabotropic glutamate receptors in the granular cells of the cerebellum (Linden et al., Neuron 7, 81, 1991).
Thus, compounds that demonstrate either an activating or inhibitory action in mGluRs have a therapeutic potential for the treatment of neurological disorders. These compounds have application as new drugs to treat both acute and chronic neurological disorders, such as attacks and brain injuries; epilepsy, movement disorders associated with Parkinson's disease and Huntington's chorea; pains; anxiety; dementia of AIDS, and Alzheimer's disease. Since mGluRs can influence mental acuity, attention and cognition levels; protect nerve cells against excitotoxic damage resulting from ischemia, hlpoglicemia and anoxia; modulate the level of neuronal excitation, influence the central mechanisms involved in the control of movement; reduce the sensitivity to pain, and reduce the levels of anxiety, these compounds can also be used to influence these situations, and they also find use in learning and memory deficiencies, such as senile dementia. MGluRs can also be involved in addictive behaviors, alcoholism, drug addiction, sensitization and suspension of drug use (Science, 280: 2045, 1998), so that compounds that act on mGluRs could also be used to treat these sufferings.
The current pharmaceutical options for treating neurological disorders tend to be highly general and not specific in their actions, in the sense that, although they can reduce the clinical symptoms associated with a specific neurological condition, they can also negatively impact normal function. of the central nervous system of patients. Therefore, it is necessary to identify and develop new cellular targets and drugs that are more specific in their actions and, therefore, susbsists the need for chemical compounds that demonstrate specific linkage characteristics towards mGluRs.
SUMMARY OF THE INVENTION
An object of this invention is to provide novel compounds demonstrating activity at the various metabotropic glutamate receptors (mGluRs), in particular, a compound of Formula I and the stereoisomers thereof:
in which:
R1 may be an acidic group selected from the group consisting of carboxyl, phosphono, phosphino, sulphono, sulfino, borono, tetrazole, isoxazole, -CH2-carboxyl, -CH2-phosphono, -CH2-phosphino, -CH2-sulfono, - CH2-sulfino, -CH2-borono, CH2-tetrazole, -CH2-isoxazole and higher homologs thereof;
R 2 may be a basic group selected from the group consisting of amino Io, amino 2o, amino 3o, quaternary ammonium salts, aliphatic amino, aliphatic amino 2, aliphatic amino 3, aliphatic quaternary ammonium salts, aromatic amino or amino-2-aromatic, amino-3-aromatic, aromatic salts of quaternary ammonium, imidazole, guanidino, boronoamino, allyl, urea, thiourea;
R3 can be H, aliphatic, aromatic or heterocyclic;
R 4 can be an acidic group selected from the group consisting of carboxyl, phosphono, phosphino, sulfone, borono, tetrazole, isoxazole;
and the pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION.
The terms and abbreviations used in the following examples have their normal meanings, unless otherwise indicated. For example, "° C" refers to degrees Celsius; "N" refers to normal or normal; "mmol" refers to millimole or mimoles, "g" refers to gram or grams; "mL" means milliliter or milliliters; "M" refers to molar or molarity; "MS" refers to mass spectrometry; "IR" refers to infrared spectroscopy; and "NMR" refers to nuclear magnetic resonance spectroscopy.
As will be understood by those skilled in the art, during the synthesis of the compounds of Formula I, it may be necessary to employ an amino protecting group or a carboxyl protecting group, in order to reversibly preserve an amino reactive susceptible or carboxy functionality during the reaction of other functional groups on the compound.
Examples of such amine-protecting groups include formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups, such as benzyloxycarbonyl; 4-phenylbenzyloxycarbonyl; 2-methylbenzyloxycarbonyl; 4-methoxybenzyloxycarbonyl; 4-phenylbenzyloxycarbonyl; 4-chlorobenzyl-oxycarbonyl; 3-chlorobenzyloxycarbonyl; 2-chlorobenzyloxycarbonyl; 2,4-dichlorobenzyloxycarbonyl; 4-bromobenzyloxycarbonyl; 3-bromobenzyloxycarbonyl; 4-Nitrobenzyloxycarbonyl; 4-cyano-benzyloxycarbonyl; f-butoxycarbonyl; 2- (4-xenyl) isopropoxycarbonyl; 2,1-diphenyl-1-yloxycarbonyl; 1,1-diphenylprop-1-chlorocarbonyl; 2-phenylprop-2-yloxycarbonyl; 2- (-toluyl) -prop-2-yloxycarbonyl; cyclopentanyloxycarbonyl; 1-methylcyclopentanyloxycarbonyl; cyclohexaniloxycarbonyl; 1-methylcyclohexaniloxycarbonyl; 2-methylcyclohexaniloxycarbonyl; 2- (4-tolylsulfone) -ethoxycarbonyl; 2- (methylsulfone) -ethoxycarbonyl; 2- (triphenylphosphino) -ethoxycarbonyl; fluorenylmethoxycarbonyl ("FMOC"); 2- (trimethylsilyl) ethoxycarbonyl; allyloxycarbonyl; 1- (trimethylsilylmethyl) prop-1-enyloxycarbonyl; 5-benzisoxalylmethoxycarbonyl; 4-acetoxybenzyloxycarbonyl; 2,2,2-trichloroethoxycarbonyl; 2-ethynyl-2-propoxycarbonyl; 4-acetoxybenzyloxycarbonyl; 2,2,2-trichloroethoxycarbonyl; 2-ethynyl-2-propoxycarbonyl; cyclopropylmethoxycarbonyl; 4- (decycloxy) benzyloxycarbonyl; isobornyloxycarbonyl; 1-piperidyloxycarbonyl and the like; the benzoylmethylsulfone group, 2-nitrophenylsulfenyl, the diphenylphosphine oxide and the similar aminoprotective groups. The species of the aminoprotective group used does not have critical importance, as long as the derivative amino group is stable to the condition of the subsequent reaction (s) in other positions of the intermediate molecule, and can be selectively removed in the appropriate point without altering the rest of the molecule, including another aminoprotective group (s). Preferred aminoprotective groups are 1-butoxycarbonyl (1-boc), allyloxycarbonyl and benzyloxycarbonyl (Cb Z). Additional examples of these groups appear in Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis), by E. Haslam; McOmie, J.G.W.,
1973 edition, in Chapter 2; and in Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis), by Greene, T.W. and Wuts, P.G., Second Edition; Wiley Interscience: 1991; Chapter 7.
Examples of such carboxyl protecting groups include methyl, > nitrobenzyl, -methylbenzyl, p-methoxy benzyl, 3,4-dimethoxybenzyl; 2,4-dimethoxybenzyl; 2,4,6-tri methoxy benzyl lo; 2,4,6-trimethylbenzyl; pentamethylbenzyl; 3,4-methylenedioxylbenzyl; benzhydryl; 4,4'-dimethoxybenzhydryl; 2,2 ', 4,4'-tetrametoxylbenzhydryl, i-butyl; amyl; trityl; 4-
methoxytrityl; 4,4'-dimethoxytrityl; 4,4'4"-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, β- (di (n-butyl) methylisilyl) ethyl, and s-toluenesulfonoethyl; -nitrobenzyl sulfonoethyl, aillo, cinnamyl, l- (trlmethylsilylmethyl) prop-l-ene-3-yl and similar portions The preferred carboxyl protecting groups are allyl, benzyl and f-butyl Additional examples of these groups are found in the work of E. Haslam cited above, in Chapter 5, and in the work of TW Greene and PGM Wuts cited above, in Chapter 5.
The present invention provides a compound of the formula:
in which:
R1 can be an acidic group selected from the group consisting of carboxyl, phosphono, phosphino, sulphono, sulfino, borono, tetrazole, soxazole, -CH2-carboxyl, -CH2-phosphono, -CH2-phosphino, -CH2-sulfono, - CH2-sulfino, -CH2-borono,-Ch2-tetrazole, -CH2-isoxazole and higher analogs thereof;
R2 can be a basic group selected from a group consisting of amino Io, amino 2o, amino 3o, quaternary ammonium salts, aliphatic amino or I,
• aliphatic amino 2, aliphatic amino 3o, aliphatic quaternary ammonium salts, aromatic aminoo, aromatic amino 2o, aromatic amino 3o, aromatic quaternary ammonium salts, imidazole, guanidino, boronoamino, allyl, urea, thiourea;
R3 can be H, aliphatic, aromatic or heterocyclic;
R 4 can be an acidic group selected from the group consisting of carboxylic, phosphono, phosphino, sulphono, sulfino, borono, tetrazole, isoxazole;
and pharmaceutically acceptable salts thereof.
In particular, compounds in which the compound of Formula I is selected from the group consisting of:
in which:
Rí is COOH; R2 is NH2 R3 can be H or methyl or xanthyl or thioxanthyl or -CH2-xanthyl or -CH2-thioxanthyl, and R4 is COOH.
Although all compounds of Formula I are believed to exhibit activity at the metabotropic glutamate receptors (mGluRs), certain groups of the compounds of Formula I are more preferred for such use.
As noted above, this invention includes pharmaceutically acceptable salts of the compounds defined by Formula I. A compound according to this invention may possess a sufficiently acidic group, a sufficiently basic one, or both functional groups, and therefore may react with any of a variety of organic and inorganic bases, and with organic and inorganic acids, to form a pharmaceutically acceptable salt.
The term "pharmaceutically acceptable salt", as used herein, refers to salts of the compounds of the above formula that are substantially non-toxic to living organisms. The pharmaceutically acceptable salts include salts that are prepared by the reaction of the compounds of the present invention, with a pharmaceutically acceptable mineral or organic acid or organic or inorganic base. Said salts are known as acid addition salts and base addition salts.
Acids commonly employed to form acidic addition salts are inorganic acids, such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid and the like, and organic acids such as > toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts are sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen sulfate, dihydrogen phosphate, metaphosphate, pyrophosphate, bromide,
iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hex no-l, 6-dioate, benzoate, chlorobenzene, methyl benzoate, hydroxybenzoate, methoxy benzoate, phthalate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene -1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids, such as hydrochloric and hydrobromic acid, and those formed with organic acids, such as maleic acid and methanesulfonic acid.
The salts of the amine groups may also include the quaternary ammonium salts in which the amine nitrogen incorporates an appropriate organic group, such as an alkyl alkenyl, alkynyl or aralkyl moiety.
Base addition salts include those derived from inorganic bases, such as ammonium or alkali or hydroxides, carbonates, alkaline earth metal bicarbonates and the like. Said bases, which are useful for the preparation of the salts of this invention, thus include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and the like. . The forms of potassium and sodium salts are particularly preferred.
It should be recognized that the specific counter-ion that is part of any salt of this invention is generally not critical, as long as the salt as a whole is pharmacologically acceptable, and the counter-ion does not provide undesirable qualities to the salt as a whole. This invention also encompasses pharmaceutically acceptable solvates of the compounds of the
Formula I. Many of the compounds of Formula I can be combined with solvents, such as water, methanol, ethanol and acetonitrile, to form pharmaceutically acceptable solvates, such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
The compounds of the present invention have multiple asymmetric (chiral) centers. As a consequence of said chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diestereomers and mixtures of diastereomers. All symmetric forms, individual isomers and combinations thereof, fall within the scope of this invention.
The prefixes "'and" S "are used herein as commonly used in organic chemistry to denote the absolute configuration of a center
chiral, according to the Cahn-Ingold-Prelog system. The stereochemical descriptor R (rectus) refers to that configuration of a chiral center with a clockwise relation of the groups that trace the path from the highest to the second lowest priority, when observed from the opposite to that of the lowest priority group. The S (sinister) stereochemical descriptor refers to that configuration of a chiral center with a counter-clockwise relation of the groups that trace the path from the highest to the second lowest priority, to be observed from the opposite side to that of the highest priority group. The priority of the groups is decided using the sequence rules described by Cahn et. al., Angew Chem., 78, 413-447, 1996 and Prelog, V. and Helmchen, G .; Angew. Chem. Int. Ed. Eng. 21, 567-583, 1982.
In addition to the R S system used to designate the absolute configuration of a chiral center, the old D-L system is also used in this document to denote relative configuration, especially with reference to amino acids and amino acid derivatives. In this system, a Fischer projection of the compound is oriented in such a way that the carbon-1 of the mother chain is in the upper part. The prefix "D" is used to represent the relative configuration of the isomer in which the functional group (determinant) is on the right side of the carbon atom in the chiral center, and "L" represents that of the isomer in which find on the left.
As would be expected, the stereochemistry of the compounds of Formula I is of critical importance for their potency as agonists or antagonists. Relative stereochemistry is established at an early stage during synthesis, which avoids subsequent separation problems later in the process. The additional manipulation of the molecules then employs stereospecific methods in order to maintain the preferred chirality. Preferred methods of this invention are methods employing those preferred compounds.
The metabolically labile non-toxic esters and amides of the compounds of Formula I are the ester and amide derivatives of Formula I which are hydrolyzed in vivo in order to obtain said compounds of Formula I and an alcohol or pharmaceutically acceptable amine. Examples of locally labile meta esters include esters formed with (1-6C) alkanols, in which the alkanol portion may optionally be substituted by an alkoxy group (1-8C), for example, methanol, ethanol , propanol and methoxyethanol.
Examples of the metabolically labile amides include the amides formed with amines, such as methylamine.
According to another aspect, the present invention provides a process for the preparation of a compound of the Formula I, or a metabolically labile pharmaceutically acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof, which comprises:
(a) hydrolyzing a compound of the formula (Ha):
wherein: R'I is an acidic group selected from the group consisting of carboxyl, phosphono, phosphino, sulphono, sulfino, borono, tetrazole, isoxazole, -CH2-carboxyl, -CH2-phosphono, -CH2-phosphino, -CH2 -sulfone, -CH2-sulfino, -CH2-borono, -CH2-tetrazole, -CH2-isoxazole and higher analogs thereof, or a protected form thereof; R3 can be H, aliphatic, aromatic or heterocyclic, and R5 represents a hydrogen atom or an acyl group. Preferred values for R5 are hydrogen and alkanoyl (2-6C) groups, such as acetyl; or
(b) deprotecting and hydrolyzing a compound of the formula (Ilb):
in which: R'l and R3 are as defined above; or
(c) hydrolyzing a compound of the formula:
wherein: R'l and R3 have the meanings defined above, each of R6 and R7, independently, represents a hydrogen atom, an alkanoyl group (2-6C), an alkyl group (1-4C), an alkenyl group (3-4C) or a phenyl (1-4C) alkyl group in which the phenyl is unsubstituted or substituted by halogen, (1-4C) alkyl, (1-4C) alkoxy, or a salt thereof. same; or
(d) deprotecting a compound of the formula:
wherein: R'l and R3 have the meaning indicated above, R8 represents a hydrogen atom or a carboxyl protecting group, or a salt thereof, and R9 represents a hydrogen atom or a nitrogen protecting group;
proceeding subsequently, if necessary or if desired, to:
(i) solving the compound of Formula I;
(ii) converting the compound of Formula I to a metabolically non-toxic labile ester or amide thereof; I
(iii) converting the compound of Formula I or a metabolically labile non-toxic lamellar ester thereof into a pharmaceutically acceptable salt.
The protection of the carboxylic acid and amine groups is described generally in the work of McOmie, Protecting Groups in Organic Chemistry, Plenum Press, NY, 1973, and in the
work of Greene and Wuts, Protecting Groups in Organic Synthesis (Protective Groups in Organic Synthesis), 2nd Ed., John Wiley & Sons, NY, 1991. Examples of carboxyl protecting groups include alkyl groups, such as methyl, ethyl, isobutyl, and t-am \\ o; aralkullo groups, such as benzyl; 4-nitrobenzyl; 4-methoxy benzyl; 3,4-dimethoxybenzyl; 2,4-dimethoxybenzyl; 2,4,6-tri methoxy benzyl; 2,4,6-tri methyl benzyl; benzidril, and trityl; silyl groups, such as trimethylsilyl and f-butyldimethylsilyl; and allylic groups, such as allyl and l- (trimethylsilylmethyl) prop-l-ene-3-yl.
Examples of the amine protecting groups include acyl groups, such as the groups of the formula R9 CO, in which R9 represents (1-6C) alkyl, (3-10C) cycloalkyl, (1-6C) phenyl alkyl, (1-6C) alkoxy, or cycloalkoxy (3-10C), in which a phenyl group may optionally be substituted by one or two substituents selected independently from amino, hydroxy, nitro, halogen, alkyl (1-) 6C), (1-6C) alkoxy, alkoxycarbonyl (1-6C), carbamoyl, alkanolammon (1-6C), alkylsulfonylamino (1-6C), phenylsulfonylamino, toluenesulfonylamino, and fluoroalkyl (1-6C).
The compounds of Formula II are conveniently hydrolyzed in the presence of an acid, such as hydrochloric acid or sulfuric acid, or a base, such as an alkali metal hydroxide, for example, sodium hydroxide. The hydrolysis is conveniently carried out in an aqueous solvent, such as water, and at a temperature within the range of 50 to 200 ° C.
The compounds of Formula III are conveniently hydrolyzed in the presence of a base, for example, an alkali metal hydroxide, such as lithium, sodium or potassium hydroxide, or an alkaline earth metal hydroxide, such as barium hydroxide. Water is included among the suitable media for the reaction. The temperature is conveniently within the range of 50 to 200 ° C.
The compounds of Formula IV can be deprotected by a conventional method. Thus, an alkylcarboxyl protecting group can be extracted by hydrolysis. The hydrolysis can be conveniently carried out by heating the compound of Formula IV, in the presence of either a base, for example, an alkali metal hydroxide, such as lithium, sodium or potassium hydroxide, or an alkaline earth metal hydroxide, such as barium hydroxide, or an acid, such as hydrochloric acid. The hydrolysis is conveniently carried out at a temperature within the range of 10 to 300 ° C. A protective aralkyl carboxyl group can conveniently be extracted by hydrogenolysis. Hydrogenolysis can conveniently be carried out by reacting the compound of Formula IV with hydrogen in the presence of a Group VIII metal catalyst, for example, a palladium catalyst, such as palladium on charcoal. Among the solvents
Alcohols, such as ethanol, are suitable for the reaction. The reaction is conveniently carried out at a temperature within the range of 0 to 100 ° C. An acylamino protecting group is also conveniently extracted by hydrolysis, for example, as described for the removal of an alkylcarboxyl protecting group.
The compounds of the Formula II can be prepared by the reaction of a compound of the formula (V):
with an alkali metal cyanide, such as lithium, sodium or potassium cyanide, and an ammonium halide, such as ammonium chloride, conveniently in the presence of ultrasound. Thus, the ammonium halide is mixed with chromatography grade alumina, in the presence of an appropriate diluent, such as acetonitrile. The mixture is then irradiated with ultrasound, after which the compound of Formula V is added, and the mixture is again irradiated. The alkali metal cyanide is then added, followed by further irradiation with ultrasound.
Individual isomers of the compounds of Formula I can be prepared by reacting a compound of Formula V with the stereoisomers of the chiral agent (5) - and (/?) - phenylglycine and a reactive cyanide, such as trimethylsilyl cyanide.
The compounds of Formula III can be prepared by reacting a compound of Formula V with an alkali metal cyanide, such as lithium, sodium or potassium cyanide, and ammonium carbonate or ammonium carbamate. Suitable solvents include water, dilute ammonium hydroxide, alcohols, such as methanol, aqueous methanol and aqueous ethanol. The reaction is conveniently carried out at a temperature within the range of 10 to 150 ° C. If desired, the compounds of Formula III can then be alkylated, using, for example, an appropriate compound of the formula R6 Cl and / or R7 Cl.
The compounds of the formula V can be prepared by reacting a compound of the formula:
with a chlorinating agent, such as thienyl chloride or phosphorus chloride (V), followed by reaction with organic copper or organic metal or with a Grignard reagent derived from R3X, or by reaction with ethyl malonate in the presence of hydrogen organolithium, in which R3 has the above defined meaning, and X is halogen.
The compounds of the formula V can also be prepared by oxidizing a compound of the formula:
under the conditions of Swern.
The compounds of the formula VI can be prepared from compounds of the formula:
by reduction.
When R'l is C02Me, this compound can be purchased commercially. When R'I is another substituent, the compound of formula VIII can be made using normal procedures.
Many of the intermediates described herein, for example, the compounds of Formulas II, III and IV, are considered as novel, forming an integral part of the invention, as additional aspects.
The compounds of Formula I of the present invention are agonists or antagonists in certain metabotropic excitatory amino acid receptors (mGluRs). Therefore, another aspect of the invention constitutes a method to affect mGluRs in mammals, which comprises the
administration to a mammal that requires the modulated neuroexcitatory transmission of an amino acid, of a pharmacologically effective amount of a compound of Formula I. The term "pharmacologically effective amount" is used to represent an amount of the compound of the invention that is capable of have an effect on the mGluRs. Through its effect, a compound of the invention acts as an agonist or as an antagonist. When a compound of the present invention acts as an agonist, the interaction of the compound with the excitatory amino acid receptor mimics the response of the interaction of this receptor with its natural ligand (ie, glutamic acid.) When a compound of the invention acts as a antagonist, the interaction of the compound with the excitatory amino acid receptor blocks the response of the interaction of this receptor with its natural ligand (ie, L-glutamic acid).
The specific dose of the compound administered according to this invention will, of course, be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the specific condition being treated and similar considerations.
The compounds can be administered by a variety of routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal. Alternatively, the compound can be administered by continuous infusion. A typical daily dose will contain from about 0.001 mg / kg to about 100 mg / kg of the active compound of this invention. Preferably, the daily doses will be from about 0.05 mg / kg to about 50 mg / kg, and more preferably from about 0.1 mg / kg to about 20 mg / kg.
It has been shown that a variety of physiological functions are subject to the influence of excessive or inadequate stimulation of excitatory transmission with amino acids. It is believed that the compounds of Formula I of the present invention (through their actions in mGluRs), have the ability to treat a variety of conditions associated with this condition in mammals, including acute neurological conditions, such as brain deficits. Subsequent to implant surgery and graft of cardiac deviations, cerebral ischemia (for example, attack or cardiac arrest), traumas in the spinal cord, perinatal hypoxia and hypoglycemic neuronal damage. It is considered that the compounds of Formula I have the ability to treat a variety of chronic neurological conditions, such as Alzheimer's disease, Huntington's disease, lateral amyotrophic sclerosis, dementia caused by AIDS, eye damage and retinopathy, cognocitive diseases, and idiopathic and drug-induced Parkinson's disease. The present invention also provides methods for treating these conditions, which comprise
administration of an effective amount of a compound of Formula I to a patient who requires it.
It is considered that the compounds of Formula I of the present invention (through their interactions in mGluRs), have the ability to treat a variety of additional conditions associated with glutamate dysfunction in mammals, including muscle spasms, seizures, migraine, headaches, urinary incontinence, psychosis, tolerance to withdrawal and discontinuation of drugs (eg, opioids, benzodiazepines, nicotine, cocaine or ethanol), smoking cessation, anxiety and associated conditions (eg , panic attacks), emesis, cerebral edama, chronic pains, sleeping problems, Tourette syndrome, deficiency problems of ethnicity, and tardive dyskinesia. Therefore, the present invention also provides methods for treating these conditions, which comprise administering an effective amount of the compound of Formula I to a patient who requires it.
The pharmacological properties of the compounds of the invention can be illustrated by determining their effects in various in vitro evaluation tests. The compounds of the invention were studied in an in vitro evaluation that measured the inhibition of Pl hydrolysis or the formation of cyclic AMP in the cell lines of the ovaries of Chinese guinea pigs, expressing the metabotropic glutamate receptors cloned mGluRα, mGluR2 and mGluR4a-
Beginning
Up to now, eight different clones of mGluRs coupled to the G protein have been identified (Knopfel et al., 1995, J. Med. Chem., 38, 1417-1426). These receptors function to modulate the presynaptic release of L-Glutamate, and the post-synaptic sensitivity of the neuronal cell to the excitation of L-Glutamate. Based on pharmacology, on the homology of the sequences and on the path of transduction of the signals that they activate, the mGluRs have been subclassified into three groups. The mGluRi and mGluR5 receptors form group I. They are coupled to the hydrolysis of phosphatidylinositol (Pl) and are selectively activated by (7,5-3,5-dihydroxyphenylglycine (Brabet et al., Neuropharmacology, 34, 895-903, 1995 Group II comprises the mGluR2 and mGluR3 receptors, which are negatively coupled to adenylate cyclase and are selectively activated by (2S, 1R, 2'R, 3'R) -2- (2,3-dicarboxyliccopropropyl). ) glycine (DCG-IV, Hayashi et al., Nature, 366, 687-690, 1993) Finally, the mGluR4, mGluRß, mGluR7 and mGluRs receptors belong to Group III, which are also negatively coupled to adenylate cyclase and are selectively activated by (5) -2-amino-4-phenylphonylbutyric acid (L-AP4; Knopfel et al., 1995, J. Med. Chem., 38, 1417-1426).
Cultivation of Cells
The ovarian cell lines of Chinese guinea pigs expressing the mGluRα, mGluR2 and mGluR4a receptors have been previously described (Aramori and Nakanishi, Neuron 8, 757-765; 1992; Tanabe et al., Neuron 8, 169- 179, 1992; Tanabe et al., J. Neurosci., 13, 1372-1378). The cells are maintained at 37 ° C in a humidified C02 incubator at 5%, in a Modified Dulbecco's Eagle Medium (MADM) containing a reduced concentration of (S) -glutamine (2 mM), and were supplemented with 1% proline, penicillin (100 U / ml), streptomycin (100 mg / ml) and 10% dialyzed fetal calf serum (all from GIBCO, Paisley). Two days before the evaluation, 1.8 x 106 cells were divided into the pocilities of 24-well plates.
Evaluations of Second Messengers
The hydrolysis of Pl was measured, as described previously (Hayashi et al., Br. J. Pharmacol., 107, 539-5431992, Hayashi et al., J. Neurosci., 14, 3370-3377, 1994). Briefly described, the cells were labeled with [3H] inosito1 (2μCi / ml), 24 hours before the evaluation. For agonist evaluations, the cells were incubated with the binder dissolved in phosphate buffered saline (PBS) -LiCl for 20 minutes, and the agonist activity was determined by measuring the level of the mono-, bis- and trisphosphate phosphates. inositol labeled with 3H, by ion exchange chromatography: For antagonist evaluations, cells were pre-incubated with the linker dissolved in PBS-üCl for the 20 minutes prior to incubation with the linker and 10 μM acid (L) -Glutamic for 20 minutes. The antagonist activity was then determined as the inhibitory effect of the response mediated by (L) -Glutamic acid. The evaluation of cyclic AMP formation was performed as described above (Hayashi et al., Br.
J. Pharmacol. 107, 539-543, 1992; Hayashi et al., J. Neurosci. 14, 3370-3377, 1994). Briefly described, the cells were incubated for 10 minutes in PBS containing the linker and 10 μM of forscolin and lmM of 3-Isobutyl-1-methyxanthine (IBMX, both from Sigma, St. Louis MO, E.U.A.). The agonist activity was then determined as the Inhibitory effect of the formation of cyclic AMP induced by forskolin. For the antagonist evaluation, the cells were pre-incubated with the ligator dissolved in PBS containing IBMX lmM for the 20 minutes prior to the 10 minute incubation in PBS containing the linker, 20 μM (mGluR2) or 50 μM (mGluR4a) , (L) -Glutamic acid, 10 μM of Forscolin and 1 mM of IBMX.
Results
Some of the compounds of the invention were subjected to tests of antagonistic activity against the ovarian cell lines of mGluRs cloned with mGluRia, mGluR2 and mGluR4a, at a concentration of 1 mM. When tested as antagonists of the increased hydrolysis of Pl induced with 10 mM (L) -Glutamic acid, some compounds of the invention effectively blocked this increase in PI hydrolysis by an action on the mGluRα receptor. The data for one of the compounds of the invention are shown in Figure 1 below.
According to another aspect, the present invention provides a method for modulating one or more of functions of metabotropic glutamate in a warm-blooded mammal, which comprises administering an effective amount of a compound of Formula I, or an ester or a metabolically labile non-toxic amide thereof, or a pharmaceutically acceptable salt thereof.
The compounds of the present invention are preferably formulated before their administration. Therefore, another aspect of the present invention is a pharmaceutical formulation comprising a compound of Formula I and a pharmaceutically acceptable vehicle, excipient diluent. The present pharmaceutical formulations are prepared by known methods, using widely known and readily available ingredients. In formulating the compositions of the present invention, the active ingredient will generally be mixed with a vehicle, or diluted in a vehicle, or contained in a vehicle, and may be presented in the form of a capsule, wrapper, paper or other container. When the vehicle serves as a diluent, it may be a solid, semi-solid or liquid material that acts as a vehicle, excipient or medium for the active ingredient.
The compounds of Formula I are generally administered in the form of pharmaceutical compositions. These compounds can be administered by various routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. These compounds are effective in both injectable and oral compositions. Said compositions are prepared in a manner well known to those skilled in the pharmaceutical art, and comprise at least one active compound.
The present invention also provides pharmaceutical compositions containing the compounds described in the claims, in combination with one or more pharmaceutically acceptable inert or physiologically active materials, diluents or adjuvants. The compounds of the invention can be freeze-dried and, if desired, combined with other pharmaceutically acceptable excipients, to prepare formulations
for its administration. These compositions may be presented in any form appropriate to the contemplated route of administration.
The compounds of Formula I can be administered orally, topically, parenterally, by inhalation or aspersion or rectally, in unit dose formulations containing conventional, non-toxic and pharmaceutically acceptable carriers, adjuvants and vehicles. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular injections, intra-sternal injection, or infusion techniques. Additionally, a pharmaceutical formulation comprising a compound of the general Formula I and a pharmaceutically acceptable carrier is provided. One or more of the compounds of the general Formula I may be present, in association with one or more pharmaceutically acceptable vehicles and / or diluents and / or non-toxic adjuvants and, if desired, other active ingredients. The pharmaceutical compositions containing the compounds of the general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups and elixirs.
Compositions intended for oral use can be prepared according to any of the methods concocted by those skilled in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents , coloring agents and preservatives, in order to provide faramacetically elegant and palatable preparations. The tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulation and disintegration agents, for example, corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the intestinal tract, and thereby provide a sustained action for a longer period. For example, an action-retarding material, such as glyceryl monostearate or glycyl distearate, may be used.
Formulations for oral use may also be presented as hard gelatin capsules, capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules in which the
Active ingredient is mixed with water or with an oily medium, for example, peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxylmethylcellulose, methyl cellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, acacia gum; the dispersing or humidifying agents may be a natural phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty oils, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with aliphatic alcohols of long chain, for example decathylene glycol heptane, or ethylene oxide products with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono-oleate, or products of the condensation of ethylene oxide with partial esters derived from fatty acids and anhydrides of hexitol, for example, polyethylene sobritan mono-oleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl or / 7-propyl / hydroxybenzoate, one or more coloring agents, one or more flavoring agents or one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active agents in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those indicated above, and flavoring agents can be added to provide palatable preparations: These compositions can be preserved by the addition of an antioxidant, such as ascobic acid.
Powders and dispersible granules suitable for the preparation of an aqueous suspension by the addition of water, provide the active ingredient in admixture with a dispersing or moisturizing agent, a suspending agent and one or more preservatives. The dispersing and humidifying agents and the appropriate suspending agents are exemplified by those already mentioned above. Additional excipients may also be present, for example, sweetening, flavoring and coloring agents.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil, for example, olive oil or peanut oil, or a mineral oil, for example, liquid paraffin, or mixtures thereof. Suitable emulsifying agents can be natural gums, for example, gum
acacia or tragacanth gum, natural phosphatides, for example, soybeans, lecithin and esters or partial esters derived from fatty acids and hexidol, anhydrides, for example, sorbitan mono-oleate, and condensation products of said partial esters with oxide of ethylene, for example, polyoxyethylene mono-oleate sorbitan. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Said formulations may also contain an emollient, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known to the skilled person, using the appropriate dispersing or humidifying agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a solution or suspension in a non-toxic diluent or solvent of acceptable origin, for example, a solution in 1,3-butanediol. Among the vehicles and solvents that can be used are water, the Rlnger solution and the isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any soft oil including synthetic mono- or diglycerides can be used. In addition, fatty oils such as oleic acid are usable in the preparation of injectables.
The compound (s) of the general Formula I can be administered (s), jointly or separately, in the form of suppositories for the rectal administration of the medicament. These compositions can be prepared by mixing the medicament with a suitable non-irritating excipient that is solid at normal temperatures, but liquid at the rectal temperature and that, therefore, melts in the rectum to release the medicament. Such materials are cocoa cream and polyethylene glycols.
The compound (s) of the general Formula I can be administered, jointly or separately, parenterally in a sterile medium. The medication, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. Adjuvants such as local anesthetics, preservatives and buffering agents can be advantageously dissolved in the vehicle.
The dose to be administered is not subject to defined limits, but will generally be an effective amount. Ordinarily, it will be the equivalent, on a molar basis of the pharmacologically active free form produced from a dosage formulation dependent on the release
metabolic of the active free drug, to achieve its desired pharmacological and physiological effects. The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, and more commonly from about 1.0 to about 30 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units as unit doses for human patients and other mammals, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect, in association with an appropriate pharmaceutical excipient. .
The active compound is effective within a wide range of dosage. For example, the dosages per day are usually within the range of about 0.01 to about 30 mg / kg of body weight. A typical daily dose will contain from about 0.01 mg / kg to about 30 mg / kg of the active compound of this invention. Preferably, the daily doses will be from about 0.05 mg / kg to about 50 mg / kg, and more preferably from about 01. mg / kg to about 25 mg / kg. In the treatment of humans, adults range from about 0.1 to about 15 mg / kg / day, in a single dose or in partial doses, is especially preferred. However, it should be understood that the amount of the compound that is actually administered will be determined by a doctor, in light of the relevant circumstances, including the condition to be treated, the route of administration selected, the compound actually administered, the age, the weight and the response of the individual patient, and the severity of the patient's symptoms, and that therefore it is not intended that the preceding dosage ranges in any way limit the scope of the invention. In some cases, dosage levels lower than the lower limit of the aforementioned range may be more than adequate, while in other cases even higher doses may be applied without causing any collateral damage, as long as such higher doses are first divided into several smaller doses for administration during the day.
The compositions are preferably formulated in unit dosage form, each dosage containing from about 5 mg to about 500 mg, and more preferably from about 25 mg to about 300 mg of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable for unit dosage for humans and other mammals, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical vehicle, diluent or excipient. The
following formulation examples are illustrative only, and are not intended to limit the scope of the invention in any way.
Formulation 1 Hard gelatin capsules are prepared using the following ingredients:
Quantity (mg / capsule)
Active ingredient 250 Dry starch 200 Magnesium stearate 10 Total 460
The above ingredients are mixed and filled into hard gelatin capsules in amounts of 460 mg.
Formulation 2
A tablet is prepared using the following ingredients:
Amount (mg / tablet)
Active ingredient 250 Microcrystalline cellulose 400 Gasified silicon dioxide 10 Stearic acid 5 Total 665
The components are mixed and compressed to form tablets, each of which weighs 66 mg.
Formulation 3
An aerosol solution containing the following components is prepared:
Weight% Active ingredient 0.25 Ethanol 29.75
Propellant 22 (Chlorodifluoromethane) 70.00 Total 100
The active compound is mixed with ethanol and the mixture is added to a part of the Propellant 22, cooled to -30 ° C and transferred to a filling device. The required quantity is then fed to a stainless steel container with the rest of the propellant. The valve units are then installed in the container.
F o r m u l a n i 4
Tablets containing 60 mg of the active ingredient, each, are prepared as follows:
Amount (mg / tablet) Active ingredient 60 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone 4 Sodium carboxymethyl starch 4.5 Magnesium stearate 0.5 Talc 1.0 Total 150
The active ingredient, starch and cellulose are passed through a U.S. No. 45 and mixed carefully. The solution of polyvinylpyrrolidone is mixed with the resulting powders, all of which is then passed through a U.S. No. 14. The granules thus produced are dried at 50 ° C and passed through a U.S. No. 18. Sodium carboxymethyl starch, magnesium stearate and talc are previously passed through a U.S. No. 60, and then they are added to the granules, which, after mixing, are compressed in a tabletting machine, to produce tablets weighing 150 mg each.
F o rm u l a tio n 5
Capsules are prepared containing 80 mg of the medically, each, as follows:
Quantity (mg / capsule) Active ingredient 80 Starch 59 Microcrystalline cellulose 59 Magnesium stearate 2 Total 200
The active ingredient, cellulose, starch and magnesium stearate are mixed, passed through a U.S. No. 45 and filled in hard gelatin capsules, in amounts of 200 mg.
F o rm a l i n e 6
Amount (mg / suppository)
Active ingredient 225 Glycerides of saturated fatty acids 2000 Total 2225
The active ingredient is passed through a U.S. No. 60 and suspended in the glycerides of saturated fatty acids previously melted using the minimum necessary heat. The mixture is then poured into a suppository mold with a nominal capacity of 2 g, then left to cool.
F or r m u l a l i n e 7
Suspensions containing 50 mg of medication per 5 mL of doses, each, are prepared as follows:
Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 mL Benzoic acid solution 0.10 mL Savoring c.v. Colorant c.v. Purified water up to the total 5 mL
The drug is passed through a U.S. No. 45 and it is mixed with the carboxymethyl cellulose of sodium and the syrup, to form a smooth paste. The solution of benzoic acid, flavor and coloring is diluted with part of the water
and it is added with agitation. Sufficient water is then added to produce the required volume.
Formulation 8
An intravenous formulation can be prepared as follows:
Quantity
Active ingredient 100 mg Mannitol 100 mg Sodium hydroxide 5 N 200 mL Purified water up to the total 5 mL
Formulation 9
A topical formulation can be prepared as follows:
Quantity Active ingredient 1-10 g Emulsifying wax 30 g Liquid paraffin 20 g Soft white paraffin up to 100 g
The soft white paraffin is heated until melted. The liquid paraffin and the emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until it is dispersed. The mixture is cooled until it becomes solid.
Formulation 10
Sub-lingual or buccal tablets containing 10 mg of the active ingredient, each, can be prepared as follows:
Amount (mg / tablet)
Active ingredient 10.0 Glycerol 210.5 Water 143.0 Sodium Citrate 4.5
Polyvinyl alcohol 26.5 Polyvinylpyrrolidone 15.5 Total 410.0
Glycerol, water, sodium citrate, polyvinyl alcohol and polyvinylpyrrolidone are mixed together by continuous stirring and maintaining the temperature at about 90 ° C. When the polymers have come into solution, the solution is cooled to about 50 ° -55 ° C and the medication is mixed slowly. The homogenous mixture is poured or in forms made of an inert material to form a diffusion matrix with a thickness of approximately 2-4 mm, which contains the medicament. The matrix is then cut to form individual tablets of the appropriate size.
Another preferred formulation that is used in the methods of the present invention employs the transdermal delivery devices (patches). Such transdermal patches can be used to provide a continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the release of pharmaceutical agents is well known to those skilled in the art (see, for example, US Patent No. 5,023,252, issued June 11, 1991, which is incorporated herein by reference). It is incorporated herein by reference, such patches 5 can be constructed for the continuous, pulsatile, or as required, release of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques or generally involve the placement of a delivery catheter of the drug into the patient's ventricular system to bypass the cerebral blood barrier. Another such implantable delivery or release system is described in the U.S. Patent. No. 5,011,472, issued April 30, 1991, which is incorporated herein by reference. Indirect techniques, which are generally preferred, ordinarily involve the formulation of the compositions to provide for a medicament to be released by converting the hydrophilic medicaments into medicaments or lipid-soluble prodrugs. The dormancy or is generally achieved by blocking the hydroxy, carbonyl, sulfate and primary amino groups present in the drug, in order to make it more soluble in lipids and susceptible to transport through the blood barrier in the brain. Alternatively, the delivery of hydrophilic drugs can be increased by intra-arterial infusion of
hypertonic solutions that can temporarily open the blood brain barrier.
EXAMPLES
The following examples illustrate the invention. The following abbreviations are used in the examples: EtOAc, ethyl acetate; THF, tetrahydrofuran; EtOH, ethanol; CCD, thin layer chromatography, GC, gas chromatography; CLAP, high pressure liquid chromatography; m-CPBA, m-chloroperbenzoic acid; Et20, diethyl ether; DMSO, dimethyl sulfoxide; DBU, 1,8-diazabicyclo- [5.4.0] undec-7-ene; MTBE, methyl f-butyl ether; EMDC, field desorption mass spectrometry, and t.a., room temperature.
Example 1: Synthesis of Cubanilgllcinates series 1.0 IGT
Preparation 1: 4-methoxycarbonyl-cubano-carboxylic acid
A solution of Cuban dimethyl ester (6.0 g, 27.24 mmol) in 182 mL of dry THF is stirred under N2 at room temperature. A solution of methanolic NaOH (26.7 mmol, 10.7 mL 2.5M) is added by dripping from an addition funnel with equal pressure, and the resulting solution is stirred at room temperature for 16 h. The mixture is evaporated under pressure
reduced to t.a., the residue is taken up in 66 mL of water and extracted with 3 x 25 mL of chloroform. The aqueous layer is acidified to a pH of 3 with concentrated HCl and extracted with 3 x 30 mL of chloroform. The combined organic layers are dried over magnesium sulfate, filtered and evaporated at 182-183 ° C, to give (2) as follows: * H NMR (CDCl 3) d 3.72 (s, 3H), 4.27
(m6H) Yield 5.1 g (91%).
Preparation 2: 4-methoxycarbonyl-l- (hydroxymethyl) cuban 0 The monoacid (2) (0.48 g) is dissolved in dry THF (5 mL) and cooled to -70 ° C. A solution of BH3 in THF is slowly added with agitation. The reaction mixture is stirred at -78 ° C for 4 hours and allowed to reach room temperature. Water (3 mL) is added and the mixture is stirred for 30 minutes, potassium carbonate (0.85 g) is added and the solution is extracted with Et20. The organic phase is dried over magnesium sulphate and evaporated to yield alcohol (3) 0.46 g (100%) mp 83-85 ° C. * H NMR (200 MHz, solvent) d: 1.58 (s, ÍH), 3.62 (s, 3H), 3.72 (s, 2H), 3.81 (m, 3H), 4.1 (m, 3H).
o Preparation 3: 4-methoxycarboinyl-l- (formyl) cuban
DMSO (0.7 mL, 9.68 mmmol) is added to oxalyl chloride (0.42 mL, 4.84 mmol) in 12 mL of CH2Cl2 at 78 ° C. Alcohol (3) (0.46 g, 2.42 mmol) in 3 mL of CH2CI2 is added and stirred at -78 ° C for 1.5 hours. Triethylamine (2.0 mL, 14.4 mmol) is added and the mixture is allowed to reach 0 ° C. A saturated ammonium chloride solution is added and the phases are separated, the aqueous layer is extracted with CH2Cl2 and the combined organic layers are dried (MgSO4), then evaporated to give a crude product, which is purified by scintillation chromatography (1: 1 hexanes: diethyl ether) to yield 0.35 g (76%) of pure product (4). * H NMR (200 MHz, solvent) d: 3.7 (s, 3H), 4.2 (m, 3H), 4.32 (m, 3H), 9.72 (s, ÍH).
Preparation 4: 4-methoxycarbonyl-l- [2'-hydroxy-1-phenylethyl] methylnitrilocuban
(7?) - phenylglycinol (257 mg, 1.87 mmol) is added to a solution of aldehyde (4) (0.35 g, 1.84 mmol) in 14 mL of methanol. The solution is cooled to 0 ° C and TMSCN (0.49 mL, 3.68 mmol) is added and the mixture is stirred at 0 ° C overnight. Evaporation of the solvent leaves a residue which is purified by chromatography (diethyl ether: hexanes, 3: 1) to yield 0.48 g (77%) of 0 pure product (5). * H NMR (CDCI3) d: 2.23 (s, ÍH), 2.6 (br, ÍH), 3.5-3.75 (m,
2H), 3.7 (s "3H), 3.9 (m, 3H), 4.11 (dd, ÍH), 4.2 (m, 3H), 7.3 (s, 5H).
Preparation 5: 4-carboxy-l-cubanylglycyl
Lead acetate (0.69 g, 1.57 mmol) is added to a stirred solution of nitrile (5) (0.48 g, 1.42 mmol) in dry methanol / dichloromethane 1: 1 (12 mL). After 10 minutes, add 10 mL of water and the solution is filtered through celite. The organic layer is dried and evaporated to produce the crude mine. The crude imine is refluxed with 6N HCl (30 mL) for 6 hours. The solution is evaporated to dryness and placed in an anion exchange resin, eluting to give the result (6). mp. 241 ° C (dec.) * H NMR (D20) d: 3.96 (s, ÍH), 4.01 (m, 3H), 4.14 (m, 3H).
Example 2
Preparation 1: 4-methoxycarbonyl-cubano-carboxylic acid
A solution of Cuban dimethyl ester (6.0 g, 27.24 mmol) in 182 mL of dry THF is stirred under N2 at rt, a solution of methanolic NaOH (27.6 mmol, 10.7 mL 2.5 M) is added by dripping from an addition funnel equalized, and the resulting solution is stirred at for 16 hours. The mixture is evaporated under reduced pressure at t.a.The residue is taken up in 66 mL of water and extracted with 3 x 25 mL of chloroform. The aqueous layer is acidified to a pH of 3 with concentrated HCl, and extracted with 3 x 30 mL of chloroform. The combined organic layers were dried over magnesium sulfate, filtered and evaporated at 182-183 ° C to yield (2): X NMR (CDCl 3) d 3.72 (s, 3H), 4.27 (m, 6H). Yield 5.1 g (91%). Preparation 2: 4-methoxycarbonylcuban-1-carbonyl chloride
The monomethyl ester (2) (1.37 g, 6.65 mmol) is dissolved in 15 mL of thionyl chloride and is subjected to gentle reflux overnight. The thionyl chloride is evaporated and the resulting residue containing (3) is used immediately without further purification.
Preparation 3: 4-methoxycarbonylcuban-1-methyl ketone
A suspension of copper iodide (1.49, 7.83 mmol) in 30 mL of dry THF is stirred at 0 ° C. Methyl lithium (15.75 mmol, 1.4 M) is added and stirred at 0 ° C for 30 minutes, then cooled at -78 ° C. A solution of 1.6 g, 7.12 mmol of (3) in 10 mL of dry THF is added and the resulting mixture is stirred for 1 hour at -78 ° C. The mixture was quenched with a chloride solution. of saturated ammonium (15 mL) and extracted with 3 x 30 mL of diethyl ether. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give the crude product (4). The product was purified by silica chromatography (hexanes: ethyl acetate, 2: 1) to provide 1.0 g of the product (69% yield) m.p. 244-248 ° C. NMR (DMSO) d 1.18 (s, 3H), 3.9 (m, 3H), 4.0 (m, 3H), 8.1 (s, ÍH), 10.6 (s, ÍH).
^ eyC ^? ^ s ^ ^^ - methoxycarbonylcuban-l-methyl-l-IS ^ 'hydantoin)
A solution of methyl ketone (4) (1.0 g, 4.9 mmol) in 40 mL of ethanol and 5.8 mL of 1 N NaOH is stirred at 70 ° C for 4 hours. The resulting solution is evaporated to dryness under pressure and is redissolved in 1: 1 ethanol: water (20 mL). To this solution are added potassium cyanide (0.35 g, 5.4 mmol) and ammonium carbonate (0.96 g, 9.8 mmol) and the mixture is heated in a sealed tube at 85 ° C for 24 hours. The reaction mixture is cooled, acidified with 6 N NCl and reduced in volume until a precipitation is formed. The precipitate is filtered and the product of the filtration is evaporated to dryness and extracted with ethyl acetate. The solvent was evaporated and the product was combined with the residue of the above-mentioned product to afford the product (5) as a white solid. Yield 0.95 g (75%) m.p. 244-248 ° C. NMR X (DMSO) d 1.18 (s, 3H), 3.9 (m, 3H), 4.0 (m, 3H), 8.1 (s, ÍH), 10.6 (s, ÍH).
Preparation 5: 4-carboxicuban-l-methylglycine
The hydantoin (5) (0.95 g, 3.65 mmol) is dissolved in 30 mL of 2 N NaOH and heated at 170 ° C in a sealed tube for 20 hours. The reaction mixture is cooled and filtered to remove the filtrate and the filter cake is washed with 3 x 10 mL of water. The combined aqueous wash products are evaporated to provide a crude product (6), which is applied to a
1X4 Spectral anion exchange resin, eluted with 0.5 N acetic acid. Isolation by evaporation and crystallization results in colorless crystals. m.p > 250 ° C. (decomposed) NMR * H (D20) d 1.38 (s, 3H), 3.95 (m, 6H),
Example 3
Preparation . 4-methoxycarbonylcuban-l-acetyl-Ii rboxi lato
N-Butyl lithium (34.83 mmol, 23.5 mL of 1.5 M) is added dropwise to a stirred solution of ethyl hydrogen malonate (2.32 g, 17.41 mmol) in 80 mL of dry THF under N2 at -78 ° C. it was tempered at -30 ° C for 5 hours and then re-cooled to -78 ° C. The monomethyl ester of Cuban acid chloride of example (2) above (2.35 g, 10.46 mmol) in 7 mL of THF, is added drip to the stirred solution. The product of the reaction is heated slowly until t.a. and is stirred for an additional hour. The solution is poured into 50 mL of 1 N HCl and extracted with 3 x 10 mL of diethyl ether. The combined organic extracts are further extracted with 20 mL with saturated sodium hydrogen carbonate and brine, dried over magnesium sulfate, filtered and evaporated to give a crude product (2). The product is purified by column chromatography on silica with hexanes: ethyl acetate 2: 1, to give a yield of 2.5 g (86%) of (2). H NMR (CDCl 3) d 1.2 (t, 3 H), 3.4 (s, 2 H), 3.65 (s, 3 H), 4.2 (m, 8 H).
Preparation 2: 4-methoxycarbonylcuban-1- (toxantyl) -acetylethylcarboxylate
Cuban-β-keto ester (2) (1.15 g, 16 mmol) and thioxanthene-9-ol (0.88 g, 4.1 mmol) are dissolved in 18 mL of a mixture of ethanol: acetic acid in
ratio of 1: 1, and stirred at t.a. for 3 days. The resulting crystalline solid was filtered to yield 1.52 g (77%) of the pure product (3), m.p. 147-149 ° C. * H NMR (CDCl 3) 1.00 (t, 3H), 3.24 (s, 3H), 3.75 (m, 3H), 3.9 (q, 2H), 4.0 (m, 3H), 4.6 (d , ÍH) 5.0 (d, ÍH), 7.3 (m, 8H).
Preparation 3: 4-carboxy-cubano-l-methylthioxanthyl ketone
The product of thioxantilcubano (3) (1.69 g, 3.57 mmol) is dissolved in 33 mL of ethanol and 8.7 mL of 1 N NaOH and heated at 70 ° C for 4 hours. The resulting solution is evaporated and redissolved in 25 mL of water, acidified with 6 N HCl and extracted with 3 x 50 mL of diethyl ether. The combined organic layers are dried over magnesium sulfate, filtered and concentrated to give a crude product containing (4). Chromatography on silicon using ethyl acetate yields 1.26 g (88%) of the product (4). * H NMR (CDCl 3) d 2.8 (d, 2H), 3.8 (m, 3H), 4.0 (m, 3H) 4.7 (t, ÍH), 7.3 (m, 8H), 9.5 (br, ÍH).
Preparation 4: 4-carboxlcuban-l-toxanthyl-l- (5,5'-hydantoin)
The Cuban thioxanthyl ketone (4) (1.24 g, 3.22 mmol) is dissolved in 1: 1 ethanol: water (20 mL). Potassium cyanide (0.522 g, 8.0 mmol) and ammonium carbonate (1.39 g, 14.4 mmol) are added and the solution is heated in a sealed tube at 85 ° C for 65 hours. The product of the reaction is cooled and acidified with 2 N HCl and extracted with 3 x 40 mL of ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and evaporated to yield 1.3 g (88%) of the product (5) as a crude. This material was hydrolyzed in the next stage, without purification. H NMR (CD3OD) d 1.7 (m, HH), 2.7 (m, HH), 3.8 (m, 3H), 4.0 (m, 3H), 4.3 (m, HH), 7.4 (m, 8H).
Preparation 5: 4-carboxicuban-l-toxanthyl-l-glycine
The product (5) of hydantoin (300 mg, 0.65 mmol) is taken in 1 N NaOH (10 mL) and is heated at 170 ° C for 20 hours in a sealed tube. The mixture is cooled and the pH is adjusted to between 7 and 8 with 6 N HCl. The formed precipitate is filtered and washed with water. The filtrate and the washing products are combined and evaporated to dryness. The resulting residue is purified by column chromatography and finally by reverse phase chromatography, to result in a product (6) in the form of colorless crystals. 70 mg. l NMR (CD3OD + D2O) d 2.3 (m, 2H), 3.9 (s, 6H), 4.4 (m, ÍH), 7.4 (m, 8H).
Claims (21)
1. A compound of the formula where: R1 may be an acidic group selected from the group consisting of carboxyl, phosphono, phosphino, sulphono, sulfino, borono, tetrazole, isoxazole, -CH2-carboxyl, -CH2-phosphono, -CH2-phosphino, -CH2-sulfono, -CH2 -sulfin, -CH2-borono, -CH2-tetrazole, and -CH2-isoxazole; R2 can be a basic group selected from the group consisting of amino 1, amino 2, amino 3 °, quaternary ammonium salts, aliphatic amino 1, aliphatic amino 3, aliphatic quaternary ammonium salts, aromatic amino 1, amino 2 ° aromatic, amino 3 ° aromatic, salts of quaternary ammonium aromatic, imidazole, guanidino, boronoamino, allyl, urea, thiourea; R3 can be H, aliphatic, aromatic or heterocyclic; R 4 can be an acidic group selected from the group consisting of carboxyl, phosphono, phosphino, sulphono, sulfino, borono, tetrazole, isoxazole; and pharmaceutically acceptable salts thereof.
2. A compound as claimed in claim 1, wherein R 1 is COOH.
3. A compound as claimed in claim 1, wherein R2 is NH2.
4. A compound as claimed in claim 1, wherein R3 may be -H, or -Me, or xanthyl or thioxanthyl, or -CH2-xanthyl, or -CH2-thioxanthyl, and R4 is -COOH.
A process for the preparation of a compound of the Formula I, or a pharmaceutically acceptable and metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof, which comprises: (a) hydrolyzing a compound of the formula: wherein R'I is an acidic group selected from the group consisting of carboxyl, phosphono, phosphino, sulphono, sulfino, borono, tetrazole, isoxazole, -CH2-carboxyl, -CH2phosphono, -CH2-phosphino, -CH2-sulphono, -CH2-sulfino, -CH2-borono, -CH2-tetrazole, -CH2-isoxazole, and higher analogs thereof, R3 can be an H, aliphatic, aromatic or heterocyclic, and R5 represents a hydrogen atom or a group acyl, and in which the preferred values for R5 are hydrogen and the alkanoyl (2-6C) groups, such as acetyl, or (b) deprotect and hydrolyze a compound of the formula wherein R'l and R3 are as defined above; or (c) hydrolyzing a compound of the formula: wherein each of R6 and R7 independently represents a hydrogen atom, an alkanoyl group (2-6C), an alkyl group (1-4C), an alkenyl group (3-4C) in which the phenyl is unsubstituted or substituted by halogen, (1-4C) alkyl or (1-4C) alkoxy, or a salt thereof, R'l and R3 are as defined above; or (d) deprotecting a compound of the formula: wherein: R8 represents a hydrogen atom or a carboxyl protecting group, or a salt thereof, and R9 represents a hydrogen atom or a nitrogen protecting group, R'l and R3 are as defined above; after which, if necessary and / or if desired: (i) a compound of Formula I is resolved; (ii) the compound of Formula I is converted to a non-toxic, metabolically labile ester or amide thereof; I (iii) the compound of Formula I or the non-toxic metabolically labile ester or amide thereof is converted into a pharmaceutically acceptable salt thereof.
A pharmaceutical formulation, which comprises a compound as claimed in claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
The use of a compound according to claim 1, for modulating one or more functions of the metabotropic glutamate receptor in a warm-blooded mammal, said use comprising administering an effective amount of a compound of Formula I, as claimed in claim 1.
A compound of the formula: R wherein R'l, R3 and R5 have the meanings defined in claim 5.
A compound of the formula: wherein: R'l, R3, R6 and R7 have the meanings defined in claim 5. n composed of the formula: wherein R'l, R3, R8 and R9 have the meanings defined in claim 5.
A compound according to claim 1, wherein R 1 is -COOH, R 2 is -NH 2, R 3 is H and R 4 is COOH.
A compound according to claim 1, wherein R 1 is COOH, R 2 is -NH 2, R 3 is CH 3 and R 4 is COOH.
A compound according to claim 1, wherein R 1 is COOH, R 2 is -NH 2, R 3 is -CH 2 -thioxanti and R 4 is COOH.
The use of a compound according to claim 1, for the treatment of a disease or neurological condition selected from the group comprising: cerebral deficits subsequent to surgery and cardiac bypass graft, cerebral ischemia, attack or cardiac arrest, trauma of spinal cord, head trauma, perinatal hypoxia, and hypoglycemic neuronal damage, Alzheimer's disease, Huntington's disease, lateral amyotrophic sclerosis, dementia caused by AIDS, eye damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscle spasms, seizures, migraine, headaches, urinary incontinence, psychosis, tolerance, withdrawal and interruption in the use of drugs (opiates, benzodiazepines, nicotine, cocaine or ethanol), smoking cessation, anxiety and related conditions (for eg, panic attack), emesis, cerebral edema, chronic pain, ailments of his Year, Tourette's syndrome, attention deficit disorder, and tardive dyskinesia, said use comprising administering an effective amount of a compound of Formula I.
The use of the compound according to claim 1, for the treatment of a psychiatric disease or condition selected from the group comprising: schizophrenia, anxiety and related conditions (eg, panic attack), depression, bipolar disorders, psychosis and compulsive abscessive conditions, said use comprising the administration of a compound of Formula I.
The use according to any of claims 7, 14 or 15, wherein said compound is selected from the group of compounds comprising:
The use of the compound: for the treatment of cerebral ischemia, heart attack and arrest, said use comprising administering an efedive amount of said compound.
A compound of formula R
(Ilb) wherein: R'l and R3 have the meanings defined in claim 5.
19. A compound according to claim 18, wherein: R'l is COOMe, R3 is H.
20. A compound according to claim 9, wherein: R'I is i or COOH, R3 is CH3, R6 = R7 is H.
21. A compound according to claim 9, wherein: R'I is COOH, R3 is -CH2-thioxanthyl, R6 = R7 is H.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2,235,119 | 1998-04-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA00010171A true MXPA00010171A (en) | 2002-03-26 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1280760B1 (en) | Novel spiro[2.4]heptane amino carboxy compounds and derivatives thereof | |
US6784202B1 (en) | Cubane derivatives as metabotropic glutamate receptor agonists or antagonists and process for their preparation | |
US6172058B1 (en) | Compounds with pharmaceutical properties | |
US20030199533A1 (en) | Novel amino carboxy alkyl derivatives of barbituric acid | |
WO1996015108A1 (en) | Pyrrolidinyl di-carboxylic acid derivatives as metabotropic glutamate receptor agonists | |
AU6420700A (en) | Novel 1,4-benzodiazepine compounds and derivatives thereof | |
JPH03101685A (en) | Substituted alpha amino acid, method of its preparation and pharmaceutical preparation thereof | |
EP0569333B1 (en) | Novel N-aralkyl and N-heteroaralkylamino alcane phosphinic acids | |
US7034055B1 (en) | 2-aminoindane analogs | |
US6699909B1 (en) | Aminoindanes | |
MXPA00010171A (en) | Cubane derivatives as metabotropic glutamate receptor antagonists and process for their preparation | |
US5990104A (en) | Polycyclic alcaloid-derivatives as NMDA-receptor antagonists | |
US20060025471A1 (en) | Xanthenyl cubane analogs with activity at the metabotropic glutamate receptors | |
CA2407777A1 (en) | Novel spiro¬2.4|heptane amino carboxy compounds and derivatives thereof | |
CA2406396A1 (en) | Novel amino carboxy alkyl derivatives of barbituric acid | |
CA2376470A1 (en) | Novel aminoindanes | |
CA2376476A1 (en) | 2-aminoindane analogs | |
EP0826663B1 (en) | Alkynylamino acid derivatives and their use as pharmaceutical compounds | |
CA2328984A1 (en) | Cubane derivatives as metabotropic glutamate receptor antagonists and process for their preparation |