ZA200304351B - Prodrugs of excitatory amino acids. - Google Patents
Prodrugs of excitatory amino acids. Download PDFInfo
- Publication number
- ZA200304351B ZA200304351B ZA200304351A ZA200304351A ZA200304351B ZA 200304351 B ZA200304351 B ZA 200304351B ZA 200304351 A ZA200304351 A ZA 200304351A ZA 200304351 A ZA200304351 A ZA 200304351A ZA 200304351 B ZA200304351 B ZA 200304351B
- Authority
- ZA
- South Africa
- Prior art keywords
- compound
- formula
- substance
- composition
- pharmaceutically acceptable
- Prior art date
Links
- 230000002461 excitatory amino acid Effects 0.000 title claims description 9
- 239000003257 excitatory amino acid Substances 0.000 title claims description 9
- 229940002612 prodrug Drugs 0.000 title description 8
- 239000000651 prodrug Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims description 125
- 238000000034 method Methods 0.000 claims description 58
- 239000000203 mixture Substances 0.000 claims description 54
- 150000003839 salts Chemical class 0.000 claims description 37
- 239000002253 acid Substances 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 208000012902 Nervous system disease Diseases 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 21
- 239000000126 substance Substances 0.000 claims description 21
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 208000020016 psychiatric disease Diseases 0.000 claims description 16
- 208000019901 Anxiety disease Diseases 0.000 claims description 14
- 230000036506 anxiety Effects 0.000 claims description 13
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 claims description 12
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 claims description 12
- 208000035475 disorder Diseases 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 206010052804 Drug tolerance Diseases 0.000 claims description 9
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 8
- 208000025966 Neurological disease Diseases 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 7
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 7
- 230000005586 smoking cessation Effects 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 208000002193 Pain Diseases 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 208000014674 injury Diseases 0.000 claims description 6
- 230000005062 synaptic transmission Effects 0.000 claims description 6
- 230000008733 trauma Effects 0.000 claims description 6
- 208000030507 AIDS Diseases 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 5
- 201000006474 Brain Ischemia Diseases 0.000 claims description 5
- 206010048962 Brain oedema Diseases 0.000 claims description 5
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 5
- 208000000094 Chronic Pain Diseases 0.000 claims description 5
- 206010010904 Convulsion Diseases 0.000 claims description 5
- 206010012289 Dementia Diseases 0.000 claims description 5
- 208000023105 Huntington disease Diseases 0.000 claims description 5
- 208000019695 Migraine disease Diseases 0.000 claims description 5
- 208000037212 Neonatal hypoxic and ischemic brain injury Diseases 0.000 claims description 5
- 208000028017 Psychotic disease Diseases 0.000 claims description 5
- 208000017442 Retinal disease Diseases 0.000 claims description 5
- 206010038923 Retinopathy Diseases 0.000 claims description 5
- 208000005392 Spasm Diseases 0.000 claims description 5
- 206010043118 Tardive Dyskinesia Diseases 0.000 claims description 5
- 206010046543 Urinary incontinence Diseases 0.000 claims description 5
- 206010047700 Vomiting Diseases 0.000 claims description 5
- 208000006752 brain edema Diseases 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 230000000747 cardiac effect Effects 0.000 claims description 5
- 230000002490 cerebral effect Effects 0.000 claims description 5
- 206010008118 cerebral infarction Diseases 0.000 claims description 5
- 208000010877 cognitive disease Diseases 0.000 claims description 5
- 230000036461 convulsion Effects 0.000 claims description 5
- 230000006378 damage Effects 0.000 claims description 5
- 230000006735 deficit Effects 0.000 claims description 5
- 238000009472 formulation Methods 0.000 claims description 5
- 230000002218 hypoglycaemic effect Effects 0.000 claims description 5
- 230000003961 neuronal insult Effects 0.000 claims description 5
- 208000033300 perinatal asphyxia Diseases 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 201000000980 schizophrenia Diseases 0.000 claims description 5
- 210000000278 spinal cord Anatomy 0.000 claims description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 4
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 4
- 206010019196 Head injury Diseases 0.000 claims description 4
- 206010027603 Migraine headaches Diseases 0.000 claims description 4
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 4
- 208000000323 Tourette Syndrome Diseases 0.000 claims description 4
- 208000016620 Tourette disease Diseases 0.000 claims description 4
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 4
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 4
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 claims description 4
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 230000000926 neurological effect Effects 0.000 claims description 4
- 208000019116 sleep disease Diseases 0.000 claims description 4
- 208000020925 Bipolar disease Diseases 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000007787 solid Substances 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 241000700159 Rattus Species 0.000 description 19
- 235000019439 ethyl acetate Nutrition 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
- VTAARTQTOOYTES-RGDLXGNYSA-N eglumegad Chemical compound OC(=O)[C@]1(N)CC[C@H]2[C@H](C(O)=O)[C@@H]12 VTAARTQTOOYTES-RGDLXGNYSA-N 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- -1 alkaline earth metal salts Chemical class 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000001727 in vivo Methods 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- 150000005690 diesters Chemical class 0.000 description 8
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 241000282414 Homo sapiens Species 0.000 description 6
- 102100036837 Metabotropic glutamate receptor 2 Human genes 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 101001071429 Homo sapiens Metabotropic glutamate receptor 2 Proteins 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 230000024188 startle response Effects 0.000 description 5
- 229940086542 triethylamine Drugs 0.000 description 5
- VLZBRVJVCCNPRJ-KPHUOKFYSA-N (1S,2S)-2-[(1S)-1-amino-1-carboxy-2-(9H-xanthen-9-yl)ethyl]-1-cyclopropanecarboxylic acid Chemical compound C([C@@H]1[C@](CC2C3=CC=CC=C3OC3=CC=CC=C32)(N)C(O)=O)[C@@H]1C(O)=O VLZBRVJVCCNPRJ-KPHUOKFYSA-N 0.000 description 4
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 125000006630 butoxycarbonylamino group Chemical group 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 230000036470 plasma concentration Effects 0.000 description 4
- 230000036515 potency Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000035939 shock Effects 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical group C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- WTUIUCZGLGZOSG-UHFFFAOYSA-N 1-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical compound OC(=O)C1C2(N)C1CCC2C(O)=O WTUIUCZGLGZOSG-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000018899 Glutamate Receptors Human genes 0.000 description 3
- 108010027915 Glutamate Receptors Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 150000001413 amino acids Chemical group 0.000 description 3
- 230000000949 anxiolytic effect Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 230000003750 conditioning effect Effects 0.000 description 3
- 239000012351 deprotecting agent Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000000434 field desorption mass spectrometry Methods 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 102000006239 metabotropic receptors Human genes 0.000 description 3
- 108020004083 metabotropic receptors Proteins 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000002287 radioligand Substances 0.000 description 3
- 229960003010 sodium sulfate Drugs 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- ZFGOYLVAXSSNIR-UHFFFAOYSA-N 1-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid;hydrochloride Chemical compound Cl.OC(=O)C1C2(N)C1CCC2C(O)=O ZFGOYLVAXSSNIR-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 208000010496 Heart Arrest Diseases 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- 208000027030 Premenstrual dysphoric disease Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000011609 ammonium molybdate Substances 0.000 description 2
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 description 2
- 235000018660 ammonium molybdate Nutrition 0.000 description 2
- 229940010552 ammonium molybdate Drugs 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- 150000001557 benzodiazepines Chemical class 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
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000002843 carboxylic acid group Chemical group 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 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 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 2
- 229960003529 diazepam Drugs 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000010265 fast atom bombardment Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229960002715 nicotine Drugs 0.000 description 2
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 229940127240 opiate Drugs 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 210000004129 prosencephalon Anatomy 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- VTAARTQTOOYTES-UHFFFAOYSA-N 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical compound OC(=O)C1(N)CCC2C(C(O)=O)C12 VTAARTQTOOYTES-UHFFFAOYSA-N 0.000 description 1
- GPIQOFWTZXXOOV-UHFFFAOYSA-N 2-chloro-4,6-dimethoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(OC)=N1 GPIQOFWTZXXOOV-UHFFFAOYSA-N 0.000 description 1
- ANUFAWHRSIJTHW-UHFFFAOYSA-N 2-methylheptanedioic acid Chemical compound OC(=O)C(C)CCCCC(O)=O ANUFAWHRSIJTHW-UHFFFAOYSA-N 0.000 description 1
- KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- 208000008811 Agoraphobia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-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
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-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
- 206010016279 Fear of open spaces Diseases 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 101150016175 Grm2 gene Proteins 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 101001032848 Homo sapiens Metabotropic glutamate receptor 3 Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010033664 Panic attack Diseases 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N 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 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- BHIIGRBMZRSDRI-UHFFFAOYSA-N [chloro(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(Cl)OC1=CC=CC=C1 BHIIGRBMZRSDRI-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 230000002862 amidating effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 230000035045 associative learning Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- RIVBTTWKPMJRMO-UHFFFAOYSA-N bicyclo[3.1.0]hexan-1-amine Chemical compound C1CCC2(N)C1C2 RIVBTTWKPMJRMO-UHFFFAOYSA-N 0.000 description 1
- MWECKFISVWUYDM-UHFFFAOYSA-N bicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical compound C1CC(C(O)=O)C2C(C(=O)O)C21 MWECKFISVWUYDM-UHFFFAOYSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 description 1
- 229960001768 buspirone hydrochloride Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 230000003491 cAMP production Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 229960003340 calcium silicate Drugs 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- VZDYWEUILIUIDF-UHFFFAOYSA-J cerium(4+);disulfate Chemical compound [Ce+4].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O VZDYWEUILIUIDF-UHFFFAOYSA-J 0.000 description 1
- 229910000355 cerium(IV) sulfate Inorganic materials 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000014797 chronic intestinal pseudoobstruction Diseases 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 229940124301 concurrent medication Drugs 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- JNVALPBEPZSLLZ-UHFFFAOYSA-N dimethyl 1-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate Chemical compound COC(=O)C1C2(C(C2CC1)C(=O)OC)N JNVALPBEPZSLLZ-UHFFFAOYSA-N 0.000 description 1
- AASUFOVSZUIILF-UHFFFAOYSA-N diphenylmethanone;sodium Chemical compound [Na].C=1C=CC=CC=1C(=O)C1=CC=CC=C1 AASUFOVSZUIILF-UHFFFAOYSA-N 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940030980 inova Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 201000010901 lateral sclerosis Diseases 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000013289 male long evans rat Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 108010038421 metabotropic glutamate receptor 2 Proteins 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 101150009274 nhr-1 gene Proteins 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 231100000822 oral exposure Toxicity 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 150000003906 phosphoinositides Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000012058 sterile packaged powder Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(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 1
- 150000005671 trienes Chemical class 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Prodrugs of Excitatory Amino Acids
This invention relates to synthetic excitatory amino . acid prodrugs (and their pharmaceutically acceptable salts) and processes for their preparation. The invention further relates to methods of using, and pharmaceutical compositions comprising, the compounds for the treatment of neurological disorders and psychiatric disorders.
Treatment of neurological or psychiatric disorders, such as anxiety disorder, have been linked to selective activation of metabotropic excitatory amino acid receptors such as (+)-2-aminobicyclo[3.1.0]hexane-2,6- dicarboxylic acid, also known as LY¥354740, which is disclosed in U.S. Patent No. 5,750,566 (the ‘566 patent) issued May 12, 1998 is an active MGLUR2 receptor agonist,
CNS Drug Reviews, 5, pgs. 1-12 (1999).
The present invention provides for a prodrug form of
LLY354740, which enhances the in vivo potency of L¥354740, producing higher oral exposure of the parent compound. In addition, when compounds of the present invention are administered, no circulating level of prodrug was detected with high in vitro bioconversion to the parent molecule.
Further, the peptide prodrugs are stable under all ranges of
PH and are nontoxic. Compounds of the present invention represent the best approach for maintaining LY¥354740-1like i safety and efficacy in humans with increased oral : bioavailability. Preclinical studies with, (1S,25,5R,68S5)-2- . [(2’8)-(2’-Amino) -propionyl] amino-bicyclo[3.1.0]hexane-2, 6- dicarboxylic acid hydrochloride, the compound of the present ‘ 30 invention, has shown greatly enhanced oral potency in the treatment of anxiety without the attendant problems of toxicity, instability at desired pH ranges and low in vivo conversion.
Accordingly, the present invention provides a compound of formula I ,
H
RS
H | : COR" i
COCHCH,NHR" wherein
R13, R4 and R17 are hydrogen; or a pharmaceutically acceptable salt thereof.
Compounds of the invention have been found to be useful prodrugs for LY354740 a selective agonist of metabotropic glutamate receptors and are therefore useful in the pharmaceutical treatment of diseases of the central nervous system such as neurological diseases, for example neurodegenerative diseases, and as antipsychotic, anxiolytic, drug-withdrawal, antidepressant, anticonvulsant, analgesic and anti-emetic agents.
It will be appreciated that the compounds of formula (I) contain at least four asymmetric carbon atoms, three being in the cyclopropane ring and one being at the a-carbon of the amino acid group. Accordingly, the compounds of the invention may exist in and be isolated in enantiomerically pure form, in racemic form, or in a diasterecisomeric mixtuile.
The amino acid moiety preferably has the natural amino acid configuration, i.e. the L-configuration relative to D- glycerol aldehyde. , The present invention includes pharmaceutically acceptable salts of the compound of formula I. These salts can exist in conjunction with the acidic or basic portion of the molecule and can exist as acid addition, primary, secondary, tertiary, or quaternary ammonium, alkali metal, or alkaline earth metal salts. Generally, the acid addition salts are prepared by the reaction of an acid with a compound of formula I. The alkali metal and alkaline earth metal salts are generally prepared by the reaction of the hydroxide form of the desired metal salt with a compound of formula I.
Some particular salts provide certain formulation advantages due to their crystalline form. Non-crystalline forms of compounds may be amorphous and hygroscopic.
Crystalline forms of pharmaceutical compounds are sometimes more desirable because they are not amorphous.
A particular pharmaceutically acceptable salt of the peptide of formula I is (1S8,2S5,5R,68)-2-[(2’8)-(2’-Amino) - propionyl]amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride salt.
Another particular pharmaceutically acceptable salt of the peptide of formula I is (15,2S,5R,685)-2-[(2'8)~(2'-
Amino) -propionyl] amino-bicyclo[3.1.0]hexane-2, 6-dicarboxylic . acid methane sulfonate salt. : Acids commonly employed to form such salts include inorganic acids, for example hydrochloric, hydrobromic, ) 30 nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric,
citric, salicyclic, o-acetoxybenzoic, or organic sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic, methane- sulfonic or naphthalene-2-sulphonic acid. '
In addition to pharmaceutically-acceptable salts, other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically- acceptable, acid addition salts, or are useful for identification, characterization or purification.
A variety of physiological functions have been shown to be subject to influence by excessive or inappropriate stimulation of excitatory amino acid transmission. The formula I compounds of the present invention are believed to have the ability to treat a variety of neurological disorders in mammals associated with this condition, including acute neurological disorder such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage. The formula I compounds are believed to have the ability to treat a variety of chronic neurological disorders, such as Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, ocular damage and retinopathy, cognitive disorders, and idiopathic and drug-induced Parkinson's. The present invention also provides methods fox treating these disorders which comprises administering to a patient in need thereof an effective amount of a compound of formula I or a ' pharmaceutically acceptable salt thereof.
The formula I compounds of the present invention treat : a variety of other neurological disorders in patients that are associated with glutamate dysfunction, including
. - > - muscular spasms, convulsions, migraine headaches, urinary incontinence, pain, premenstrual dysphoric disorder (PDD), ' psychosis, (such as schizophrenia), drug tolerance and . withdrawal (such as nicotine, opiates and benzodiazepines),
Ss anxiety and related disorders, emesis, brain edema, chronic pain, and tardive dyskinesia. The formula I compounds are also useful as antidepressant and analgesic agents.
Therefore, the present invention also provides methods for treating these disorders which comprise administering to a patient in need thereof an effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof.
A compound of Formula I may be made by a process which is analogous to one known in the chemical art for the production of structurally analogous heterocyclic compounds or by a novel process described herein. Such processes and intermediates useful for the manufacture of a compound of
Formula I as defined above are provided as further features of the invention and are illustrated by the following procedures in which, unless otherwise specified, the meanings of the generic radicals are as defined above. (A) For a compound of formula I in which R13, R14, and
R17 are hydrogen (a di-acid), deprotecting the amine group of a compound of formula I where R17 is tert-butoxy carbonyl or a nitrogen protecting group, with an acid as described in the General
Procedures for Examples 3 and 4. (B) For a compound of formula I in which R13 and R14 are both hydrogen (a di-acid), deprotecting a compound of . formula I where R13 and R14 are not both hydrogen as described in Scheme 2.
(C) For a compound of formula I in which R13 and r14 are not both hydrogen, amidating a compound of formula II
H
I
Ny ) 1
H | T=coRr 3
NH, 1 with a corresponding amino acid of formula III.
HOOCCHCH;NHR1” III in which p is O or any integer from 1-10 and R17 is tert- butoxy carbonyl or a nitrogen-protecting group as described in the General Procedure for Example 1. (D) For a compound of formula II where R13 and R14 are not hydrogen, where R13 and R14 may be a carboxy-protecting ester group (a di-ester), esterifying a compound of formula
II where R13 and R14 are both hydrogen (a di-acid). (E) For a compound of formula II in which R13 and r14 are not hydrogen (a di-ester), deprotecting a compound of formula IV
H
’
H ~CO,R" ,
H NH
R™
Iv where KT is a nitrogen protecting group, as described in
Preparation 2. .
(F) For a compound of formula II where R13 and R14 are not both hydrogen (a di-ester), esterifying a compound of formula IV, as described in Preparation 2. . (GB) For a compound of formula IV where R13 and R14 are ] both hydrogen (a di-acid), protecting the amine group of a compound of formula II as described in Preparation 1.
The term “nitrogen protecting group,” as used herein, refers to those groups intended to protect or block the nitrogen group against undesirable reactions during synthetic procedures. Choice of the suitable nitrogen protecting group used will depend upon the conditions that will be employed in subsequent reaction steps wherein protection is required, as is well within the knowledge of one of ordinary skill in the art. Commonly used nitrogen protecting groups are disclosed in T.W. Greene and P.G.M.
Wuts, Protective Groups In Organic Synthesis, 2° Ed. (John
Wiley & Sons, New York (1991)).
The term “carboxy-protecting group” as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups of the compound. Particular values include, for example, methyl, ethyl, tert-butyl, benzyl, methoxymethyl, trimethylsilyl, and the like. Further examples of such groups may be found in T.W. Greene and
P.G.M. Wuts, Protecting Groups in Organic Synthesis, 3rd.
Ed. (John Wiley & Sons, N.Y. (1999)). The ester is ’ decomposed by using a conventional procedure which does not affect another portion of the molecule.
Whereafter, for any of the above procedures, when a pharmaceutically acceptable salt of a compound of Formula I is required, it is obtained by reacting the acid of Formula
I with a physiologically acceptable base or by reacting a basic compound of Formula I with a physiologically acceptable acid or by any other conventional procedure. ’
The term "Cj3-Cipo alkyl" represents a straight, branched, or cyclic alkyl chain having from one to ten carbon atoms.
The term "Cg-Cjyo alkenyl" represents straight or branched unsaturated alkyl chains having from two to ten carbon atoms, and having one or more carbon-carbon double bond, such as, dienes and trienes. This group also includes both E and Z isomers.
The term "aryl" represents groups such as phenyl, substituted phenyl, and naphthyl. The term "arylalkyl" represents a C1-C4 alkyl group bearing one or more aryl groups.
The term "affecting" refers to a formula I compound acting as an agonist at an excitatory amino acid receptor. The term "excitatory amino acid receptor" refers to a metabotropic glutamate receptor, a receptor that is coupled to cellular effectors via
GTP-binding proteins. The term "cAMP-linked metabotropic glutamate receptor" refers to a metabotropic receptor that is coupled to inhibition of adenylate cyclase activity.
The term "neurological disorder" refers to both acute and chronic neurodegenerative conditions, including cerebral deficits subsequent to cardiac bypass surgery and grafting, cerebral ischemia (for ) example stroke resulting from cardiac arrest), spinal cord trauma, head trauma, Alzheimer's Disease,
Huntington's Chorea. amvotrophic lateral sclerosis,
AIDS-induced dementia, perinatal hypoxia, hypoglycemic neuronal damage, ocular damage and retinopathy, cognitive disorders, idiopathic and drug-induced ) Parkinson's Disease. This term also includes other . neurological conditions that are caused by glutamate dysfunction, including muscular spasms, migraine headaches, urinary incontinence, drug tolerance, withdrawal, and cessation (i.e. opiates, benzodiazepines, nicotine, cocaine, or ethanol), smoking cessation, emesis, brain edema, chronic pain, sleep disorders, convulsions, Tourette's syndrome, attention deficit disorder, and tardive dyskinesia.
The term "psychiatric disorder" refers to both acute and chronic psychiatric conditions, including schizophrenia, anxiety and related disorders (e.g. panic attack and stress-related cardiovascular disorders), depression, bipolar disorders, psychosis, and obsessive compulsive disorders.
A particular aspect of the present invention includes a method for affecting the cAMP-linked metabotropic glutamate receptors in a patient, which comprises administering to a patient requiring modulated excitatory amino acid neurotransmission a pharmaceutically-effective amount of a compound of . formula I.
Another particular aspect of the present invention includes a method of administering an effective amount . of a compound of formula II, where R13 and R14 are both hydrogen (a di-acid), which comprises administering to ) a patient requiring modulated excitatory amino acid neurotransmission a pharmaceutically effective amount of a compound of formula I.
Another particular aspect of the present invention includes a method for treating a psychiatric disorder in a patient which comprises administering to the patient in need of treatment thereof a pharmaceutically-effective amount of a compound of formula I.
Another particular aspect of the present invention includes a method for treating a neurological disorder in a patient which comprises administering to the patient in need of treatment thereof a pharmaceutically-effective amount of a compound of formula I.
A preferred method for treating a psychiatric disorder in a patient comprises administering to the patient in need thereof a pharmaceutically-effective amount of a compound of formula I wherein said psychiatric disorder is schizophrenia, anxiety and related disorders, depression, dipolar disorders, psychosis, and obsessive compulsive disorders.
A preferred method for treating a neurological disorder in a patient comprises administering to the patient in need thereof a pharmaceutically-effective amount of a compound of formula I wherein said neurological disorder is cerebral deficits subsequent to cardiac bypass and grafting; cerebral ischemia; spinal cord trauma; head trauma; Alzheimer’s Disease;
Huntington’s Chorea; amyotrophic lateral sclerosis; g
AIDS-induced dementia; perinatal hypoxia; hypoglycemic neuronal damage; ocular damage and retinopathy; cognitive disorders; idiopathic and drug-induced . Parkinsons’ Disease; muscular spasms; migraine
-1 1 - headaches; urinary incontinence; drug tolerance, withdrawal, and cessation; smoking cessation; emesis; brain edema; chronic pain; sleep disorders; convulsions; Tourette’s syndrome; attention deficit disorder; and tardive dyskinesia.
A more preferred method for treating a psychiatric disorder in a patient comprises administering to the patient in need thereof a pharmaceutically-effective amount of a compound of formula I wherein said psychiatric disorder is anxiety and related disorders.
A more preferred method for treating a neurological disorder in a patient comprises administering to the patient in need thereof a pharmaceutically-effective amount of a compound of formula I wherein said neurological disorder is drug tolerance, withdrawal, and cessation; or smoking cessation.
An additional aspect of. the present invention is a compound of formula I, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.
Another aspect of the present invention includes the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating neurological or psychiatric disorders.
As used herein the term “effective amount” refers to the amount or dose of the compound, upon single or . multiple dose administration to the patient, which provides the desired effect in the patient under diagnosis or treatment.
An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount or dose of compound administered, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bicavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. For example, a typical daily dose may contain from about 25 mg to about 300 mg of the active ingredient. The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, bucal or intranasal routes. Alternatively, the compound may be administered by continuous infusion.
As used herein the term “patient” refers to a mammal, such as a mouse, guinea pig, rat, dog or human.
It is understood that the preferred patient is a human.
The term “treating” (or “treat”) as used herein includes its generally accepted meaning which ] encompasses prohibiting, preventing, restraining, and slowing, stopping, or reversing progression of a : resultant symptom. As such, the methods of this invention encompass both therapeutic and prophylactic administration.
- 1 3-
If not commercially available, the necessary starting materials for the above procedures may be made by procedures which are selected from standard techniques of organic and } heterocyclic chemistry, techniques which analogous to the syntheses of known, structurally similar compounds, and the procedures described in the Examples, including novel procedures.
A further aspect of the present invention provides for a method of administering an effective amount of a compound of formula II, where R13 and R14 are both hydrogen (a di- acid), which comprises administering to a patient requiring modulated excitatory amino acid neurotransmission a pharmaceutically-effective amount of a compound of formula
I.
Compounds of formula I are converted via enzymatic or hydrolytic process in vivo, to form compounds of formula II, where R13 and R14 are both hydrogen (a di-acid), as shown in
Scheme 1 below.
I
H
ES:
H : COR"
H NH, n ) Scheme 1: In Vivo Conversion ; 20
In particular, a crystalline form of a compound of formula I may be prepared according to the route outlined in
Scheme 2 below in which each of R3 and R14, respectively,
represents a value defined for the groups R13 and R14. The process described in Scheme 2 is a synthesis method for the preparation of a crystalline hydrochloride salt form of a compound of formula I and a methanesulfonate salt form of a compound of formula I.
Il, where R13 and R* are both hydrogen (a di-acid)
II, where R'3 and R'* are not Iv, where R™ and both hydrogen (a mono-ester) <—— Rarenot hydrogen (a di-ester) m ! : |, where R'3 and R' are both hydrogen (a di-acid);
R16 is tert-butoxycarbonyl or a nitrogen-protecting group 1, where R17 is hydrogen , methane sulfonate salt I, hydrochloride salt; crystalline solid
I, zwitterion
Scheme 2: Process for Preparation of Particular Salt
In scheme 2 above, the monohydrate of II, where R13 and
R14 are both hydrogen (a di-acid), is treated with thionyl chloride and methanol affording the corresponding di-ester of II. Alternatively, catalytic hydrochloric acid may be used in place of thionylchloride. The di-ester, formula II,
is amidated with a compound of formula III using dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl) -3- ethylcarbodiimide (EDCI) or isobutyl chloroformate as a . coupling agent to afford a di-ester protected peptidyl ] compound of formula I. This transformation could also be achieved using the acid chloride or by using a variety of other peptide coupling reagents, for example, diphenyl chlorophosphate and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) , bis (2-oxo-3-oxazolidinyl)phosphinic chloride and
Dbenzotriazol-l-yloxytris (dimethylamino)phosphonium hexafluorophosphate. ’
The hydrolysis of the di-ester protected peptidyl compound of formula I with a suitable base such as lithium hydroxide or sodium hydroxide in THF affords the di-acid protected peptidyl compound of formula I, where R13 and R14 are both hydrogen (a di-acid). The di-acid protected peptidyl compound of formula I may be deprotected with a mineral or organic acid in a suitable solvent. Such conditions may produce the corresponding acid salt of the di-acid peptidyl compound of formula I as an amorphous solid or, directly, a crystalline solid. In the case of an amorphous solid, subsequent crystallization may occur from suitable solvents. For example, a di-acid protected peptidyl compound of formula I when treated hydrogen chloride gas in ethyl acetate provides the deprotected hydrochloride salt as an amorphous solid. The amorphous hydrochloride compound may then be crystallized from acetone } and water to afford the crystalline hydrochloride salt compound of formula I. In the case of a crystalline solid ) 30 which is formed directly, filtration of the reaction mixture may afford the crystalline salt. The zwitterionic compound of formula I is afforded by treatment of the crystalline hydrochloride salt of formula I with sodium hydroxide. It will be appreciated by one of ordinary skill in the art that a compound of formula I may be prepared in one procedure where the indicated intermediates are not isolated.
The ability of compounds to modulate metabotropic glutamate receptor function may be demonstrated by examining their ability to influence either cAMP production (mGluR 2, 3, 4, 6, 7 or 8) or phosphoinositide hydrolysis (mGluR 1 or 5) in cells expressing these individual human metabotropic glutamate receptor (mGluR) subtypes. (D. D. Schoepp, et al., Neuropharmacol., 1996, 35, 1661-1672 and 1997, 36, 1- 11).
The ability of formula I compounds to treat anxiety or a related disorder may be demonstrated using the well known fear potentiated startle and elevated plus maze models of anxiety described respectively in Davis, Psychopharmacology, 62:1;1979 and Listex, Psychopharmacol, 92:180-185; 1987
In Vitro Receptor Binding
To study the ability to affect receptor binding of compounds of the present invention in comparison to
LY354740, displacement of a high affinity mGluR2 antagonist radioligand [3H]LY341495 to cell membranes from human mGluR2, human mGluR3, and native rat brain tissues was determined. (See, Ornstein P. L., Arnold M. B., Bleisch T.
J., Wright R. A., Wheeler W. J., and Schoepp D. D., [3H]LY341495, a highly potent, selective and novel radioligand for labeling group II metabotropic receptors.
Bioorg. Med. Chem. Lett. 8: 1919-1922 (1998); and Johnson B.
G., Wright R. A., Arnold M. B., Wheeler W. J., Ornstein P.
L., and Schoepp D. D., [’H]ILY341495 as a novel rapid filtration antagonist radioligand for group II metabotropic receptors: Characterization of binding to membranes of mGlu . receptor subtype expressing cells. Neuropharmacology 38: 1519-1529 (1999)) . As shown in Table 1 below, LY354740 displaced [3H]LY341495 binding to rat forebrain membranes with a potency similar to that observed in human recombinant receptors. In contrast, the compound of formula I did not appreciably displace [3H]LY341495 binding to rat forebrain membranes at up to 10,000 nM.
Table 1. Comparison of receptor binding of compounds of
Displacement of 3H-LY341495 binding
I rer
Receptor LY354740 Formula I
EE a Bal
In Vivo Actions in Rat Fear Potentiated Startle Anxiety
Model
To study the oral potencies of compounds of the present invention in comparison to LY354740 in an mGlu2/3 receptor linked therapeutic animal model, studies in the rat fear- } potentiated startle assay were performed. This model was specifically chosen, as it is highly sensitive to mGlu2/3 . 20 agonists such as LY354740 and compounds of the present invention. (See, Helton D.R., Tizzano J.P., Monn J.A.,
Schoepp D.D., and Kallman M.J., Anxiolytic and side-effect profile of LY354740: A potent, high selective, orally active : i agonist for group II metabotropic glutamate receptors, J.
Pharmacol. Exp. Ther. 284: 651-660 (1998)). To verify that the actions of a compound of formula I in this model were mGlu2/3 receptor mediated, as has been shown previously for , 1Y354740 (See, Tizzano, J.P., Griffey K.I., Ornstein P.L.,
Monn J.A., and Schoepp D.D., Actions of mGlu receptor agonists on fear-conditioning versus fear-expression in rats, Neuropharmacology, 38:A45 (#144) (1999)), the ability of 1L'Y341495 (an mGlu2/3 receptor antagonist) (See, Kingston
A.E., Ornstein P.L., Wright R.A., Johnson B.G., Mayne N.G.,
Burnett J.P., Belagaje R., Wu S., and Schoepp D.D., LY¥341495 is a nanomolar potent and selective antagonist for group II metabotropic glutamate receptors, Neuropharmacology, 37: 1- 12 (1998)) to block compound-mediated suppression of fear- potentiated startle was also determined. As a positive control in each experiment, diazepam (0.6 mg/kg i.p.) was used. All experiments were performed in fed rats.
In the fear potentiated startle model, animals are exposed to a neutral stimulus such as light (conditioned stimulus) with an aversive stimulus such as a shock (unconditioned stimulus). Following conditioning, when the animals are presented with a loud acoustic stimulus, larger startle responses are elicited when the startle stimulus is preceded by light.
Diazepam and buspirone hydrochloride, which are clinically proven anxiolytics, are effective at reducing the fear (increased startle response) associated with the presentation of light in the fear potentiated startle model, and in reducing the fear of open spaces in the elevated plus maze model.
Male Long Evans rats {180-400 g) or male NIH Swiss mice (18-35 g) were obtained from Harlan Sprague-
Dawley, Cumberland, IN, USA and acclimated at least 3 days before testing. Animals were housed at 23+2°C(relative humidity 30% to 70%) and given Purina . Certified Rodent Chow and water ad libitum. The photoperiod was 12 hours of light and 12 hours of dark, with dark onset at approximately 1800 hours.
Test compounds were dissolved in a vehicle of purified water and neutralized with 5 N NaOH to a pH of 7-8 when applicable. Diazepam (Sigma Chemical Company,
St. Louis, MO) was suspended in purified water by the dropwise addition of Tween 80. Control animals received the respective vehicle.
SL-LAB (San Diego Instruments, San Diego, CA) chambers were used for conditioning sessions and for the production and recording of startle responses. A classical conditioning procedure was used to produce potentiation of startle responses. Briefly, on the first 2 days, rats were placed into dark startle chambers in which shock grids were installed.
Following a 5-minute acclimation period, each rat received a 1mA electric shock (500ms) preceded by a 5 second presentation of light (15 watt) which remained on for the duration of the shock. Ten presentations of the light and shock were given in each conditioning session, rats were gavaged with a solution of test compound of water and startle testing sessions were conducted. A block of 10 consecutive presentations of ’ acoustic startle stimuli (110 dB, non-light-paired) were presented at the beginning of the session in order to minimize the influences of the initial rapid phase of habituation to the stimulus. This was followed by 20 alternating trials of the noise alone or noise preceded by the light. Excluding the initial trial block, startle response amplitudes for each trial type (noise-alone vs. light+noise) were averaged for each rat across the entire test session. .
As shown in the first row of Table 2, below, when given orally to fed rats, compounds of the present invention were active in the rat fear-potentiated startle test at 300 times lower doses when compared to LY354740. If this in vivo animal model data directly predicts human anxiety responses, compounds of the present invention would produce anxiolytic effects in humans at 300 fold lower doses than the parent compound. Furthermore, the ability to produce a longer duration at lower doses when compared to parent may allow for once-a day dosing, as opposed to twice a day dosing.
In Vivo Exposure as Measured by Rat Plasma Concentration
To study the in vivo exposure of 1LY¥354740 following oral dosing of compounds of the present invention in comparigon to LY354740, studies measuring the plasma concentrations of LY354740 in rats were performed. ‘Mature Fischer 344 male rats (190-270 gram) were obtained from Harlan Sprague-Dawley, Cumberland, IN, USA and acclimated in the study housing for 3 days. On day 4, test compounds were dissolved in buffered water (lmg/ml = test compound/20mM potassium dihydrogen phosphate, pH=2) and given orally as a single 5mg/kg dose. Blood samples were collected through orbital sinus or cardiac puncture (last time point) at 0.5 and 1 hour or, alternatively, 1 and 3 hours. Plasma samples were stored at -20°C in the presence of phenylmethylsulfonyl fluoride, a protease inhibitor, prior to analysis. Plasma samples and internal standard compounds were pretreated by sclid phase extraction (SAX support, methanol/water/dilute acetic acid). As shown in the second row of Table 2, below, the plasma concentrations (ng/ml) of LY354740 for each test compound were determined by LC/MS/MS and are presented as a sum of the concentrations at the 0.5 and 1 hour or, alternatively, 1 and 3 hour sample time points.
Table 2. Comparison LY354740 and compounds of the present invention in the rat fear-potentiated startle assay
I EO...
Parameter LY354740 formula I —
MED (1 hour 3.0 mg/kg p.o. 0.01 mg/kg p.o. pre- treatement)
Rat Exposure 466 ng/ml 7114 ng/ml (ng/ml of
L,Y354740 : following mg/kg p.o.)
As shown above in Tables 1 and 2, in vitro studies show that the compounds of the present invention had no 5 appreciable affinity per se for mGlu2/3 receptors. This indicates that the in vivo pharmacology of this compound in rats and humans would likely reflect the conversion of the prodrug to the parent molecule, LY354740, which then acts at mGlu2/3 receptors to produce a therapeutic effect. Further, in fact, when given orally to rats, the compounds of the current invention exhibit a 15 fold increase in plasma concentration of LY354740 when compared to LY354740. This demonstrates compounds of the present invention are converted to LY354740 in vivo.
The compounds of the present invention are preferably . formulated prior to administration. Therefore, another aspect of the present invention is a pharmaceutical . formulation comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically-acceptable carrier, diluent, or excipient.
The pharmaceutical formulations may be prepared by procedures well-known by one of ordinary skill in the art.
In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient.
The compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl ) hydroxybenzoates, talc, magnesium stearate, and mineral oil.
The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
Compositions of the invention may be formulated so as to pr
—- 2 4 - provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
The compositions are preferably formulated in a unit . dosage form, each dosage containing from about 5 mg to about 500 mg active ingredient, preferably about 25 mg to about 300 mg active ingredient. As used herein the term "active ingredient" refers to a compound included within the scope of formula I.
The term "unit dosage form" refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.
The following Examples further illustrate the compounds of the present invention and the methods for their synthesis. The Examples are not intended to be limiting to the scope of the invention in any respect, and should not be so construed. All experiments were run under a positive pressure of dry nitrogen or argon. All solvents and reagents were purchased from commercial sources and used as received, unless otherwise indicated. Dry tetrahydrofuran (THF) was obtained by distillation from sodium or sodium benzophenone ketyl prior to use. Proton nuclear magnetic resonance (lH NMR) spectra were obtained on a Bruker Avance
II bay-500 at 500 MHz, a Bruker Avance I bay-200 at 200MHz or a Varian Inova at 500 MHz. Electrospray mass spectroscopy (ESI) was performed on a Agilent MSD/B } intrument using acetonitrile/agueous ammonium acetate as the mobile phase. Free atom bombardment mass spectroscopy (FABMS) was performed on a VG ZAB-2SE instrument. Field desorption mass spectroscopy (FDMS) was performed using ] either a VG 70SE or a Varian MAT 731 instrument. Optical rotations were measured with a Perkin-Elmer 241 polarimeter. . Chromatographic separation on a Waters Prep 500 LC was generally carried out using a linear gradient of the solvents indicated in the text. The reactions were generally monitored for completion using thin layer . chromatography (TLC). Thin layer chromatography was performed using E. Merck Kieselgel 60 Fg54 plates, 5 cm X 10 cm, 0.25 mm thickness. Spots were detected using a combination of UV and chemical detection (plates dipped in a ceric ammonium molybdate solution [75 g of ammonium molybdate and 4 g of cerium (IV) sulfate in 500 mL of 10% aqueous sulfuric acid] and then heated on a hot plate).
Flash chromatography was performed as described by Still, et al. Still, Kahn, and Mitra, J. Org. Chem., 43, 2923 (1978).
Elemental analyses for carbon, hydrogen, and nitrogen were determined on a Control Equipment Corporation 440 Elemental
Analyzer, or were performed by the Universidad Complutense
Analytical Centre (Facultad de Farmacia, Madrid, Spain).
Melting points were determined in open glass capillaries on a Gallenkamp hot air bath melting point apparatus or a Blchi melting point apparatus, and are uncorrected.
The abbreviations, symbols and terms used in the examples have the following meanings.
Ac = acetyl
Anal. = elemental analysis :
Bn or Bzl = benzyl
Bu = butyl
BOC = butoxycarbonyl calcd = calculated
D0 = deuterium oxide
Et
DCC = dicyclohexylcarbodiimide
DIBAL-H = diisobutyl aluminum hydride
DMAP = dimethylaminopyridine
DMF = dimethylformamide . | DMSO = dimethylsulfoxide
EDC = N-ethyl-N’N’-dimethylaminopropyl carbodiimide
Et = ethyl
EtOH = ethanol
FAB = Fast Atom Bombardment (Mass Spectrascopy)
FDMS = field desorption mass spectrum
HOAt = 1l-hydroxy-7-azabenzotriazole
HOBt = l-hydroxybenzotriazole
HPLC = High Performance Liquid Chromatography
HRMS = high resolution mass spectrum i-PrOH = isopropanol
IR = Infrared Spectrum
L = liter
Me = methyl
MeOH = methanol
MPLC = Medium Pressure Liquid Chromatography
Mp = melting point
MTBE = t-butyl methyl ether
NBS = N-bromosuccinimide
NMR = Nuclear Magnetic Resonance
Ph = phenyl p.o0. = oral administration i-Pr = isopropyl
Rochelle’s Salt = potassium sodium tartrate
SM = starting material
TBS = tert-butyldimethyleilyl
TEA = triethylamine
Temp. = temperature
TFA = trifluoroacetic acid
THF = tetrahydrofuran : . TLC = thin layer chromatography t-BOC = tert-butoxycarbonyl
Overview Scheme for Preparations and Examples
H
[6] woo 2 14
Oo H nu,OH ‘H,0 carboxy . . tecting amine protecting agent pro agents such such as BOC,0 pd as SOCL,,
H MeOH
[0] woo 214 oH 1) carboxy protecting H 0] HHN agents such as Mel, K,CO, 0 0 >=0 —————ttt— g 0 2) amine deprotecting agent s} H NH o—
NT such as HCI, EtOAc 2
HCI
Preparation 1 Preparation 2 ? 16 amide coupling agents
Ho NHICOCHR NH),Boc such as EDCI, DMAP,
HOB, Et;N
R
H
H
[0] wo A704 0 X04 z carboxy deprotecting : 0—
O H nn OH agent, such as LiOH (aq) 0° H NH mm eee eee
To DR . NHBoc NHBoc
Example 2 Example 1 amine deprotecting agent, 1) carboxy deprotecting such as HX, solvent agent, such as LiOH (aq) 2) amine deprotecting agent, such as HCI, EtOAc
H o H wo X04 base such as wo, X04 = NaOH = lo] H ny OH —_— 5 nH Nu OH
Da Da
NH, HX NH,
Example 3 (X = CI) Example §
Example 4 (X = 0S0O,Me)
] Preparation 1
Synthesis of (18,2S,5R,68)-2-tert-Butoxycarbonylamino- . bicyclo[3.1.0]hexane-2,6-dicarboxylic acid
H
Oo 0 Hun OH >=0 “
A 1 L flask was charged with (18,28,5R, 65) -2-amino- bicyclo[3.1.0]lhexane-2,6-dicarboxylic acid monohydrate (24.4 g, 0.12 mol, 1 equiv), dioxane (200 mL) and di- tert-butyl dicarbonate (52.4 g, 0.24 mol, 2.0 equiv). The suspension was vigorously stirred while 1N sodium hydroxide (420 mL, 3.5 equiv) was added. The mixture was stirred for 2 days, then 2.0 more equiv of di-tert-butyl dicarbonate were added and the reaction stirred for 3 additional days at room temperature. After 5 total days of reaction, water (400 mL) ~ was added to dissolve the salts. The aqueous layer was : extracted with ethyl acetate (4 x 100 mL) and acidified to
PH 2 with 6 N hydrochloric acid. The acidic aqueous phase was extracted with ethyl ether (6 x 200 mL). The combined ether extracts were washed with water (250 mL) and brine } (250 mL). After drying over sodium sulfate, solvents were evaporated under vacuum to afford a foamy white solid (26.4 gl. 77% Yield; mp 100-101 °C. []p®® = - 41.1 ° (c = 1.0, MeOH).
Ei
'H NMR (Methanol-d;) 8: 4.98 (brs, 1H), 2.44 (dd, 1H, J = 6.2, 2.6 Hz), 2.19-1.92 {(m, 4H), 1.62 (t, 1H, J = 2.8 Hz), } 1.43 (s, 9H), 1.29 (m, 1H). 3c NMR (Methanol-d,) §: 175.6, 175.2, 158.2, 60.1, 34.6, : 31.9, 28.4, 27.2, 25.6, 20.6.
MS (Electrospray): 285.12.
Preparation 2
Synthesis of (18,28,5R,68)-2-Amino-bicyclo[3.1.0]lhexane-2,6- dicarboxylic acid dimethyl ester hydrochloride : H oO : ~~ 0} H NH, ©
Hal (15,25,5R, 68) -2-tert-Butoxycarbonylamino- bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (20 g, 0.07 mol, 1.0 equiv) was dissolved in 210 ml of dry dimethylformamide and potassium carbonate (21.3 g, 0.154 mol, 2.2 equiv) was added at 0 °C under nitrogen. After 15 minutes, methyl iodide (17.6 ml, 0.28 mol, 4.0 equiv) was added. The reaction mixture was warmed up slowly and stirred at room temperature for 3h. Water (200 ml) was added and the aqueous phase was extracted with ethyl ether (4 x 75 ml each). The . combined organic phase was washed with cold water (4 x 50 ml), and the aqueous phase extracted again with ethyl ether (2 x 50 ml). After drying the organic phase over sodium sul fate and evaporating under vacuum, a foamy sclid f{15,28,5R,68}) -2-tert butoxycarbonylaminc-
bicyclo[3.1.0lhexane-2,6-dicarboxylic acid-2,6-dimethyl . ester) was obtained (19.2 g, 87% yield).
This compound was diluted with 150 ml of a saturated . solution of hydrogen chloride gas in ethyl acetate and the mixture vigorously stirred for 1 hour (a white precipitate appeared within 15 minutes). The solid was filtered, rinsed with ethyl ether and thoroughly dried under high vacuum. 73% Yield; mp 193-194 °C. [@lp?® = + 22.2° (c = 1.0, MeOH). 1H NMR (D,0) &6: 3.86 (s, 3H), 3.67 (s, 3H), 2.31-2.04 (m, 6H), 1.57 (m, 1H). 3C NMR (Methanol-d,) 8: 171.9, 170.2, 65.6, 52.8, 51.2, 32.4, 29.9, 28.5, 26.2, 20.17.
Alternative Synthesis of (15,2S8,5R,6S)-2-Amino- bicyclo[3.1.0] hexane-2, 6-dicarboxylic acid dimethyl ester. hydrochloride
H
O
0) H NH, ©
HCI
:
Thionyl chloride (807 mL, 11.1 mol) was added to methanol (9.5 L) over a period of 1 h while maintaining the temperature between 2 - 20 °C. The solution was maintained for 30 min, then (18,2S,5R,68)-2-amino-bicyclo[3.1.0]hexane- . 25 2,6-dicarboxylic acid monohydrate (1.61 kg, 7.92 mol) was added. The resulting solution was heated to 47 °C and maintained between 47 - 50 OC for 17 h. Approximately 7.3 L of methanol was then removed by vacuum distillation (47 - 50 : j
°C, 240 —- 275 mm Hg). The remaining methanol was removed by azeotropic distillation with t-butyl methyl ether (MTBE) at . atmospheric pressure [added MTBE (10 L), removed 8.5 Lj; added MTBE (10 L), removed 8.5 L; added MTBE (8 L), removed : 5.1 L]. During the course of the distillations a white solid began to precipitate from the solution. After completion of the distillations, MTBE (2 L) was added to the resulting slurry, and the slurry was cooled to 22 °C. The solid was filtered, rinsed with MTBE (2 L) and dried under vacuum to afford 1.94 kg (98%) of the title compound as a white solid.
Analysis Calculated for CjgH1gNO4Cl: C, 48.10; H, 6.46; N, 5.61; Cl, 14.20. Found: C, 47.88; H, 6.25; N, 5.57; C1, 14.52.
General Procedure for the coupling reaction of (15,25,5R,68) -2-Amino-bicyclo[3.1.0]lhexane-2,6-dicarboxylic acid dimethyl ester hydrochloride with N-BOC- (L) -aminoacids.
The starting dimethyl ester hydrochloride salt (1.0 equiv), the product of Example Preparation 2, was suspended in dry dichloromethane (0.1 M solution) under nitrogen. The corresponding N-BOC-aminoacid (1.5 equiv), N-ethyl-N’,6N'- dimethylaminopropylcarbodiimide (EDC, 1.5 equiv) and 1- hydroxybenzotriazole (HOBt, 1.5 equiv) were added in one portion, followed by triethyl amine(1.0 equiv) via syringe and, finally, dimethylaminopyridine (DMAP, 0.1 equiv). The reaction mixture was stirred overnight at room temperature, ; then hydrolyzed by addition of 1N hydrochloric acid (20 ml / mmol) and diluted with methylene chloride (10 ml / mmol).
The aqueous layer was extracted with methylene chloride (5 ml / mmol) and the combined organic layers washed twice with 1 N hydrochloric acid (10 ml / mmol), and finally with water and brine (10 ml / mmol each). After drying over sodium . sulfate and evaporation under vacuum the crude residue was purified by silica gel chromatography using the appropriate eluent (typically mixtures hexanes/ethyl acetate).
Alternative procedure for the coupling reaction of (18,28,5R, 68) ~2-Amino-bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid dimethyl ester hydrochloride with N-BOC-aminoacids.
A solution of dicyclohexylcarbodiimide (DCC) (1.1 equiv) in methylene chloride (4.0 M solution) was added to a mixture of Preparation 2 (1.0 equiv), triethylamine (1.0 equiv) and
N-t-butoxycarbonyl-L-alanine (1.1 equiv) in methylene chloride (1.0 M solution) over a period of approximately 1.5 h while stirring. The resulting mixture was stirred for 1 - 12 h then filtered. The filter cake (dicyclohexylurea) was rinsed with methylene chloride, and the filtrate was washed with 0.1 M NaHCO3 followed by 1.0 N hydrochloric acid. The organic phase was dried (NaySO4), filtered and concentrated to afford the title compound as an oil.
Example 1
Synthesis of (15,2S8,5R,6S8)-2-[(2'8)-(2'-tert-
Butoxycarbonylamino) -propionyl] amino-bicyclo[3.1.0]}hexane- . 2,6-dicarboxylic acid dimethyl ester
H
O oH 0 Hun, 9 6) yy a
The starting dimethyl ester hydrochloride salt (1.0 equiv), the product of Preparation 2, was suspended in dry dichloromethane (0.1 M solution) under nitrogen. N-BOC- (L) - alanine (1.5 equiv), N-ethyl-N’,N'- dimethylaminopropylcarbodiimide (EDC, 1.5 equiv) and 1- hydroxybenzotriazole (HOBt, 1.5 equiv) were added in one portion, followed by triethyl amine (1.0 equiv) via syringe and, finally, dimethylaminopyridine (DMAP, 0.1 equiv). The reaction mixture was stirred overnight at room temperature, then hydrolyzed by addition of 1N hydrochloric acid (20 ml / mmol) and diluted with methylene chloride (10 ml / mmol).
The aqueous layer was extracted with methylene chloride (5 ml / mmol) and the combined organic layers washed twice with 1 N hydrochloric acid (10 ml / mmol), and finally with water and brine (10 ml / mmol each). After drying over sodium sulfate and evaporation under vacuum the crude residue was purified by silica gel chromatography using mixtures of hexanes/ethyl acetate.
-35-~ 50% Yield. Foamy white solid. mp 51-52 °C. [@]p®® = - 27.7 (c = 0.52, CHClj). 'H NMR (CDC1l;) &: 7.28 (brs, 1H), 5.04 (brd, 1H, J = 7.6 Hz), . 4.16 (m, 1H), 3.74 (s, 3H), 3.66 (s, 3H), 2.49 (dd, 1H, J = 13.9, 8.3 Hz), 2.42 (dd, 1H, J = 6.3, 2.8 Hz), 2.18-1.89 (m, 3H), 1.70 (t, 1H, J = 2.9 Hz), 1.45 (s, 9H), 1.33 (d, 3H, J = 7.0 Hz), 1.19 (m, 1H).
Bc NMR (CDCl,) 8: 172.8, 172.6, 172.6, 155.7, 80.2, 66.3, 52.6, 51.8, 45.5, 34.4, 32.0, 28.2, 28.1, 26.6, 21.1, 17.6.
Alternative Synthesis of (15,2S5,5R,68)-2-[(2'8)-(2'-tert-
Butoxycarbonylamino) -propionyl] amino-bicyclo[3.1.0] hexane- 2,6-dicarboxylic acid dimethyl ester
A solution of dicyclohexylcarbodiimide (DCC) (1.1 equiv) in methlyene chloride (4.0 M solution) was added to a mixture of Example Preparation 2 (1.0 equiv), triethylamine (1.0 equiv) and N-t-butoxycarbonyl-L-alanine (1.1 equiv) in methlyene chloride (1.0 M solution) over a period of approximately 1.5 h while stirring. The resulting mixture was stirred for 1 - 12h then filtered. The filter cake (dicyclohexylurea) was rinsed with methlyene chloride, and the filtrate was washed with 0.1 M NaHCO3 followed by 1.0 N hydrochloric acid. The organic phase was dried (NaySO4), filtered and concentrated to afford the title compound as an oil. i
-3 6 -
Example 2
Synthesis of (1S8,2S,5R,68)-2-[(2’8)-(2'-tert-
Butoxycarbonylamino) -propionyl] amino-bicyclo[3.1.0]hexane- 2,6-dicarboxylic acid
H
0 vo X14 0 Hun OF
Oo
Ly
NA a
H oO
A solution of 2 M NaOH (5.45 L, 10.9 mol) was added to a solution of (15,25,5R,6S58)-2-[(2'8)-(2'-tert- butoxycarbonylamino) -propionyl]amino-bicyclo [3.1.0] hexane- 2,6-dicarboxylic acid dimethyl ester (4.52 mol, crude) in
THF (2.8 L). The resulting mixture was stirred at.ambient temperature for 3 h then extracted with CHCl, (2 x 3 L).
Ethyl acetate (5 L) and tetrahydrofuran (3 L) were then added to the aqueous phase. While stirring, concentrated
HCl (970 mL) was added to the mixture until the pH = 2. The organic phase was dried (MgSO,) and filtered. The aqueous phase was then extracted with ethyl acetate (5 L). The organic phase was dried (MgSO,), filtered and combined with the previous organic phase. The combined organics were concentrated to a soft solid. Ethyl acetate was then added, and the mixture was concentrated to a soft solid. Ethyl acetate (3.5 L) was again added. The mixture was concentrated until a freely flowing suspension was present.
Heptane ( 1.8 L) was then added, and the slurry was stirred at ambient temperature for 15 h. The solid was filtered, y washed with heptane (3 L) then dried under vacuum to afford ] the title compound.
Yield 1.36 kg (84%) as an approximate 85:15 mixture of . rotamers as a white solid. [alp 25 - 24.8(C1.0, MeOH) 'H NMR (DMSO-d) & 12.20 (s, 2 H), 8.40 (s, 0.85 H), 8.36 (s, 0.15 H), 6.69 (d, J = 8.2 Hz, 0.85 H), 6.33 (br 4d, 0.15 H), 3.99 (quintet, J = 7.2 Hz, 0.85 H), 3.84 (br m, 0.15 H), 2.18-2.13 (m, 2 H), 1.91-1.84 (m, 1 H), 1.82-1.75 (m, 2 H), 1.46 (br s, 0.85 H), 1.43 (br s, 0.15 H), 1.35 (s, 9 H), 1.23-1.15 (m, 1 H), 1.13 (d, J = 6.9 Hz, 3 H).
Cc NMR (CD;OD) & 176.4, 176.0 (2 C), 157.5, 80.5, 67.3 (minor rotamer), 67.2 (major rotamer), 50.9, 35.6, 32.8, 29.3, 28.7, 27.4, 22.1, 18.5.
MS (EI) calcd for C;e¢HzsN3O; (M + NH,") 374.20, found 374.24 m/z.
Alternative Synthesis of (1S5,28,5R,68)-2-[(278)-(2'-tert-
Butoxycarbonylamino) -propionyl] amino-bicyclo[3.1.0] hexane- 2,6-dicarboxylic acid
H
Oo oO H HN on
Lp aa : A solution of (18,28, 5R, 6S) -2-amino- bicyclo[3.1.0] hexane-2,6-dicarboxylic acid monohydrate (85 g, 418 mmol) and MeOH (850 mL) was cooled to 10 °C. Thionyl ;
chloride (199 g, 1.67 mol) was added at a rate such that the temperature did not exceed 20 °C. The solution was then heated to 50 °C and stirred for 6 h. Upon completion of the reaction, the solution was cooled to room temperature and . concentrated to approximately 170 mL total volume under reduced pressure at 20 - 30 °C. Water (850 mL) was added, and the pH of the solution was adjusted to approximately pH 2.0 with 1.0 N NaOH (300 mL). The solution was concentrated under reduced pressure until the temperature reached approximately 40 °C. Methylene chloride (850 mL) was then added, and the pH of the solution was adjusted to pH 8 with 1.0 N NaOH (180 mL). The phases were separated, and the aqueous phase was extracted with CHCl, (425 mL). The combined organic phases containing the corresponding dimethyl ester were concentrated to approximately 425 mL total volume and held for further processing.
In a separate reaction vessel a solution of N-t- butoxycarbonyl-L-alanine (83.2 g, 439 mmol) and 4- methylmorpholine (44.4 g, 439 mmol) in CHCl, (712 mL) was cooled to -5 - -10 °C. Isobutyl chloroformate (59.9 g, 439 mmol) was then added at rate such that the temperature did not exceed -5 °C. Upon completion of the addition, the solution was stirred for 15 min. Simultaneously, CH,Cl, (20 mL) was added to the dimethyl ester solution previously prepared, and this solution was cooled to -5 °C. The . dimethyl ester solution (445 mL) was then added to the isobutyl mixed anhydride mixture. The cooling bath was removed, and the corresponding mixture was stirred for 30 min. A solution of 1.0 N HCl (445 mL) was then added. The phases were separated, and the organic phase was washed with 1.0 N HCl (445 mL). The organic phase was concentrated tec approximately 180 mL total volume. THF (450 mL) was then added, and the resulting solution was concentrated to . approximately 180 mL total volume. To this solution was added 1.0 N NaOH (1.67 L, 1.67 mol). The resulting mixture . was heated to 40 °C, stirred for 1.5 h then cooled to room temperature. Ethyl acetate (2.4 L) was added, and the pH of the aqueous phase was adjusted to pH 2.1 with concentrated
HCl (150 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (800 mL). The combined organic phases were dried with MgsO,, filtered and washed with EtOAc (2 x 320 mL). The resulting solution was then concentrated to approximately 400 mL total volume.
Ethyl acetate (800 mL) was added, and the solution was concentrated to 400 mL). This ethyl acetate addition/concentration was repeated again, then heptane (640 mL) was added. The resulting mixture was stirred for 2 h, filtered and washed with a 2 : 1 mixture of heptane-ethyl acetate (2 x 320 mL) to afford 115.5 g (78% yield) of (18,25,5R,68)-2-[(2"'8) -(2'-tert-butoxycarbonylamino) - propionyl]amino-bicyclo[3.1.0] hexane-2,6-dicarboxylic acid as a white solid.
Example 3
Synthesis of (18,2S8,5R,6S)-2-[(2’S8)-(2’-Amino) - propionyl] amino-bicyclo[3.1.0] hexane-2,6~-dicarboxylic acid hydrochloride
H
(0)
O Hun HM
Da
NH, HCl y
To a solution of ethyl acetate (500 mL) was added HCl (79.0 g, 2.16 mol). The resulting HCl solution was then ) added to a slurry of (18,2S,5R,6S)-2-[(2'8)-(2'-tert- butoxycarbonylamino) -propionyl] amino-bicyclo [3.1.0] hexane- . 2,6-dicarboxylic acid (100 g, 281 mmol) in ethyl acetate (500 mL) at a rate such that the temperature did not exceed 25 °C. The resulting mixture was stirred for 3.5 hours then filtered affording 82.6 g of (1S,25,5R,65)-2-[(2'S)-(2"-
Amino) -propionyl] amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride as an amorphous, white solid. This white solid was then added to acetone (290 mL) and water (57 mL).
The resulting mixture was heated to 48 - 52 °C, and water (6.4 mL) was added until all of the solid dissolved.
Acetone (2.2 L) was added to the resulting solution over a period of approximately 1 h. When the addition of acetone began, the heating mantle was removed. After the addition was complete, the mixture was cooled to 0 - -10 °C and stirred for 4 h. The mixture was then filtered and washed with cold acetone (75 mb) affording (18,28,5R,68)-2-[(2'8) - (2’ -amino) -propionyl]amino-bicyclo [3.1.0] hexane-2,6- dicarboxylic acid hydrochloride that was dried under vacuum at 40 °C to provide 76.6 g (93% yield) of the title compound as a white, crystalline solid. 72% Yield. White crystalline solid. mp >250 °C, dec. [alp® = - 7.80 (c = 1.0, MeOH). 'H NMR (Methanol-dg) 8: 3.96 (gq, 1H, J = 7.0 Hz), 2.47 (44, 1H, J = 6.3, 2.7 Hz), 2.37 (dd, 1H, J = 13.6, 8.2 Hz), 2.18- 1.92 (m, 3H), 1.66 (t, 1H, J = 3.0 Hz), 1.53 (d, 3H, J = 7.0
Hz), 1.46-1.34 (m, 1H). **C NMR (Methanol-d,) &: 175.2, 1/4.7, 170.2, 66.4, 45.0, 36.6, 32.0, 28.5, 26.3, 21.2, 16.6.
80% Yield. White solid.
Example 4 . Synthesis of (15,2S8,5R,68)-2-1(2’S)-(2’-Amino) - propionyl]amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid methanesulfonate
H
0
HO
2 OH 0) HHN
De ’
NH, -HOSO,CH,
A solution of (1S8,2S,5R,6S8)-2-[(2'8)-(2’'-tert- butoxycarbonylamino) -propionyl]amino-bicyclo[3.1.0]hexane- 2,6~-dicarboxylic acid (1.07 g, 3.00 mmol), methanesulfonic acid (584 pL, 9.00 mmol) and dioxane (10 mL) was stirred for 48 h. The mixture was filtered and dried to afford (1S, 2S, 5R, 6S)-2-[(2’8)- (2’-Amino)- propionyl]amino- bicyclo[3.1.0]lhexane-2,6-dicarboxylic acid methane sulfonate as a crude, white, amorphous solid (1.05 g). A sample of this solid (1.0 g) was dissolved in MeOH (10 mL). The solution was concentrated to 3.3 g total weight and seed crystals were added. Ethyl acetate (10 mL) was then added to } the mixture over a period of 15 min. The mixture was stirred for 30 min, filtered and dried under vacuum to . afford 830 mg of the title compound as a white, crystalline solid.
Yield 78%
Fi
1H NMR (CDs0OD) & 3.96 (g, J = 7.1 Hz, 1 H), 2.71 (s, 3 H), 2.45 (dd, J = 6.4, 2.7 Hz, 1 H), 2.38 (dd, J = 13.9, 8.4 Hz, . 1H), 2.20-2.08 (m, 1 H), 2.01-1.93 (m, 2 H), 1.67 (t, JT = 2.9 Hz, 1 H), 1.52 (d, J = 7.0 Hz, 3 H), 1.46-1.35 (m, 1 H) : 13¢ NMR (CD,OD) & 176.3, 175.7, 171.2, 67.4, 50.0, 39.5, 35.7, 33.1, 29.5, 27.4, 22.2, 17.6.
Anal. Calcd for Cq,H,oN,0gS: C, 40.90; H, 5.72; N, 7.95.
Found: C, 40.81; H, 5.69; N, 7.83.
Example 5
Synthesis of (18,28,5R,68)-2-[(2’8)-(2’-Amino) - propionyl] amino-bicyclo([3.1.0]hexane-2, 6-dicarboxylic acid
H
Oo vo 214 0 Hun 9M
LL
NH, (1s, 28, 5R, 6S)-2-[(2'S)- (2'-Amino)- propionyl]lamino- bicyclo[3.1.0]lhexane-2,6-dicarboxylic acid hydrochloride (1.0 g, 3.42 mmol) was dissolved in water (1 mL), and 1.0 N
NaOH (3.42 mL, 3.42 mmol) was added. The solution was maintained in the refrigerator for 24 h. The solution remained clear. Acetone (2 mL) was added, and the solution was stored in the refrigerator for 16 h. A white solid precipitated out of solution, and mixture could not be stirred. Acetone (4 mL) was added, and the mixture was stirred at rt, then filtered and dried to afford 630 mg of the title compound as a white crystalline solid which contained 2-4% NaCl.
" 02/055481 PCT/US01/45866 -43-~
Yield 72% . IH NMR (CD30D) 8 3.93 (gq, J = 7.1 Hz, 1 H), 2.48 (dd, , J = 6.6, 2.9 Hz, 1 H), 2.32 (dd, , J = 13.5, 8.4 Hz, 1 H), 2.20- : 2.08 (m, 1 H), 2.01-1.90 (m, 2 H), 1.61 (t, , J = 2.9 Hz, 1
H), 1.51 (d, , J =7.0Hz, 3 H), 1.48-1.33 (m, 1 H) 3c NMR (CD3OD) 8 176.9 (2 C), 171.1, 68.0, 50.1, 35.9, 33.2, 29.7, 27.3, 22.5, 17.6.
Claims (38)
1. A compound of formula I H - R¥o,¢ | 3 H ICO," H oo COCHCH,NHR" wherein RII R14 and R17 are hydrogen; ora pharmaceutically acceptable salt thereof. : N
2. A pharmaceutically acceptable salt of a compound of formula I as claimed Claim 1 which is an acid-addition salt made with an acid which provides a pharmaceutically acceptable anion or, for a compound which contains an acidic moiety, which is a salt made with a base which provides a pharmaceutically acceptable anion.
3. The pharmaceutically acceptable salt of a compound of formula as claimed : in Claim 2 which is (1S5,25,5R,65)-2-[(2’ S)-(2’-Amino)-propionyl Jamino- bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride salt. :
4. The pharmaceutically acceptable salt of a compound of formula as claimed in Claim 2 whichis (15.25,5R.65)-2-[(2’ S)~(2’ -Amino)-propionylJamino- bicyclo[3.1.0}hexane-2,6-dicarbox ylic acid methane sulfonate salt. :
5. A pharmaceutical formulation comprising in association with a pharmaceutically acceptable carrier, dilutent or excipient, a compound of formula I (ora pharmaceutically acceptable salt thereof) as provided in any one of Claims 1 to 4. CLEAN COPY _
: PCT/US01/45866
6. A process for preparing the compound of formula I, or a : pharmaceutically acceptable salt thereof, as claimed in any one of Claims 1 to 4 comprising: : deprotecting a compound of formula H i~COR" “r NHR™ where R™ is a nitrogen protecting group; and R" and R" are hydrogen. :
7. Use of a compound of any one of Claims 1 to 4 in the manufacture of a preparation for affecting the cAMP-linked metabotropic glutamate receptors in a subject.
8. A method of administering an effecting amount of a compound of formula II, where R" and R'* are both hydrogen (a di-acid), for modulating excitatory amino acid neurotransmission in a subject, by administering to said subject an effective amount of a compound of any one of Claims 1 to 4. AMENDED SHEET
-46- oo PCT/US01/45866
9. Use of a compound of any one of Claims 1 to 4, in the manufacture of a preparation for treating a neurological disorder in a subject. .
10. Use of Claim 9 wherein said neurological disorder is cerebral deficits subsequent to cardiac bypass and grafting; cerebral ischemia; spinal cord trauma; head . trauma; Alzheimer’s Disease; Huntington’s Chorea; amyotrophic lateral sclerosis; AIDS-induced dementia; perinatal hypoxia; hypoglycemic neuronal damage; ocular damage and retinopathy; cognitive disorders; idiopathic and drug-induced Parkinson’s Disease; muscular spasms; migraine headaches; urinary incontinence; drug tolerance, withdrawal, and cessation; smoking cessation; emesis; brain edema; chronic pain; sleep disorders; convulsions; Tourette's syndrome; attention deficit disorder or tardive dyskinesia.
11. Use of Claim 10 wherein said neurological disorder is drug tolerance, : withdrawal, and cessation or smoking cessation.
12. Use of a compound of any one of Claims 1 to 4, in the manufacture of a preparation for treating a psychiatric disorder in a subject.
13. Use of Claim 12 wherein said psychiatric disorder is schizophrenia, - anxiety and related disorders, depression, bipolar disorders, psychosis or obsessive compulsive disorders. : I
14. Use of Claim 13 wherein said psychiatric disorder is anxiety and related disorders. Co
15. A compound of formula IV H R"“0,C <> H | cor" H = fe AMENDED SHEET
$9 -47- PCT/US01/45866 wherein R™ is a nitrogen protecting group; RIL is co,Rr14 and R12 is hydrogen or fluoro; or Ris hydrogen or fluoro and R12 is Co,R14,; and R13 and R14 are carboxy protecting groups.
16. A compound of formula IV as claimed in Claim 15 wherein R™ is tert- butoxycarbonyl, R!! is CO,R; R13 and R!* are both methyl; and R12 js hydrogen.
17. A novel compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of Claims 1 to 4 for use as a pharmaceutical.
18. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating neurological or psychiatric disorders.
19. A novel compound of formula I substantially as hereinbefore described with reference to any of the Examples.
20. A method for affecting the CAMP-linked metabotropic glutamate receptors in a mammal, by administering to said mammal an effective amount of a compound of formula I, substantially as hereinbefore described with reference to any of the Examples, for modulating excitatory amino acid neurotransmission in said mammal.
21. A process for preparing a novel compound of formula I substantially as hereinbefore described with reference to any of the Examples.
22. A compound which is (15,25,5R,65)-2-[(2’S5)-(2’-Amino)- propionyljamino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride salt.
23. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in Claims | to 4, in the manufacture of a preparation for use in a AMENDED SHEET
\@ -48- PCT/US01/45866 method of treatment.
24. A substance or composition for use in a method for affecting the cAMP- linked metabotropic glutamate receptors in a subject, said substance or composition comprising a compound of any one of Claims 1 to 4, and said method comprising administering to said subject an effective amount of said substance or composition to modulate excitatory amino acid neurotransmission.
25. A substance or composition for use in a method for treating a neurological disorder in a subject, said substance or composition comprising a compound of any one of Claims 1 to 4, and said method comprising administering to the subject an effective amount of said substance or composition.
26. A substance or composition for use in a method of treatment of Claim 25, wherein said neurological disorder is cerebral deficits subsequent to cardiac bypass and grafting; cerebral ischemia; spinal cord trauma; head trauma; Alzheimer’s Disease; Huntington’s Chorea; amyotrophic lateral sclerosis; AIDS-induced dementia; perinatal hypoxia; hypoglycemic neuronal damage; ocular damage and retinopathy; cognitive disorders; idiopathic and drug-induced Parkinson’s Disease; muscular spasms; migraine headaches; urinary incontinence; drug tolerance, withdrawal, and cessation; smoking cessation; emesis; brain edema; chronic pain; sleep disorders; convulsions; Tourette’s syndrome; attention deficit disorder or tardive dyskinesia.
27. A substance or composition for use in a method of treatment of Claim 26, wherein said neurological disorder is drug tolerance, withdrawal, and cessation or smoking cessation. :
28. A substance or composition for use in a method for treating a psychiatric disorder in a subject, said substance or composition comprising a compound of any one of Claims 1 to 4, and said method comprising administering to the subject an effective amount of said substance or composition. AMENDED SHEET
. o -49- PCT/US01/45866
29. A substance or composition for use in a method of treatment of Claim 28 wherein said psychiatric disorders is schizophrenia, anxiety and related disorders, depression, bipolar disorders, psychosis or obsessive compulsive disorders.
30. A substance or composition for use in a method of treatment of Claim 29 wherein said psychiatric disorder is anxiety and related disorders.
31. A substance or composition for use in a method of treatment, said substance or composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of Claims | to 4, and said method comprising administering said substance or composition.
32. A salt according to Claim 2, substantially as herein described and illustrated.
33. A formulation according to Claim 5, substantially as herein described and illustrated.
34. Use according to any one of Claims 7, 9 to 14, 18 or 23, substantially as herein described and illustrated.
35. A method according to Claim 8 or Claim 20, substantially as herein described and illustrated.
36. A compound according to Claim 15 or Claim 22, substantially as herein described and illustrated.
37. A substance or composition for use in a method of treatment according to any one of Claims 24 to 31, substantially as herein described and illustrated.
38. A new compound, a new salt, a new formulation, a new use of a compound as claimed in Claim 1, a new non-therapeutic method of treatment, a new AMENDED SHEET
4 -50- PCT/US01/45866 process for preparing a compound, or a substance or composition for a new use in a method of treatment, substantially as herein described.
AMENDED SHEET
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01500007 | 2001-01-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200304351B true ZA200304351B (en) | 2004-09-03 |
Family
ID=34112448
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200304351A ZA200304351B (en) | 2001-01-11 | 2003-06-03 | Prodrugs of excitatory amino acids. |
Country Status (1)
Country | Link |
---|---|
ZA (1) | ZA200304351B (en) |
-
2003
- 2003-06-03 ZA ZA200304351A patent/ZA200304351B/en unknown
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2488167C (en) | Prodrugs of excitatory amino acids | |
EP1368304B1 (en) | Prodrugs of excitatory amino acids | |
AU2002228737A1 (en) | Prodrugs of excitatory amino acids | |
US20040138304A1 (en) | Prodrugs of excitatory amino acids | |
US7456221B2 (en) | Prodrugs of excitatory amino acids | |
ZA200304351B (en) | Prodrugs of excitatory amino acids. | |
EP1310480A1 (en) | Prodrugs of excitatory amino acids | |
US20040248963A1 (en) | Prodrugs of excitatory amino acids | |
WO2004004706A1 (en) | Prodrugs of excitatory amino acids | |
EP1423411A2 (en) | Prodrugs of excitatory amino acids | |
KR101061663B1 (en) | Prodrugs of Excitable Amino Acids | |
AU2008200612B8 (en) | Prodrugs of excitatory amino acids | |
EP1458671A1 (en) | Prodrugs of excitatory amino acids | |
US20040176459A1 (en) | Prodrugs of excitatory amino acids | |
EP1310482A1 (en) | Prodrugs of excitatory amino acids |