CA2320378A1

CA2320378A1 - Cyclic dipeptides and azetidinone compounds and their use in treating cns injury and neurodegenerative disorders

Cyclic dipeptides and azetidinone compounds and their use in treating cns injury and neurodegenerative disorders Download PDF

Info

Publication number: CA2320378A1
Authority: CA; Canada
Prior art keywords: compound; substituted; group; nrr; alkyl
Prior art date: 1998-02-11
Legal status : Abandoned

Application number

CA002320378A

Other languages

English (en)

French (fr)

Inventor

Alan P. Kozikowski

Alan I. Faden

Gian Luca Araldi

Current Assignee

Georgetown University

Original Assignee

Individual

Priority date

1998-02-11

Filing date

1999-02-10

Publication date

1999-08-19

1999-02-10 Application filed by Individual filed Critical Individual

1999-08-19 Publication of CA2320378A1 publication Critical patent/CA2320378A1/en

Status Abandoned legal-status Critical Current

Links

208000014674 injury Diseases 0.000 title claims abstract description 70
208000027418 Wounds and injury Diseases 0.000 title claims description 51
230000006378 damage Effects 0.000 title claims description 50
208000015122 neurodegenerative disease Diseases 0.000 title claims description 9
108010016626 Dipeptides Proteins 0.000 title description 28
125000004122 cyclic group Chemical group 0.000 title description 16
MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 title description 15
150000001875 compounds Chemical class 0.000 claims abstract description 295
-1 4-substituted-2-azetidinone compounds Chemical class 0.000 claims abstract description 70
210000003169 central nervous system Anatomy 0.000 claims abstract description 41
208000012902 Nervous system disease Diseases 0.000 claims abstract description 27
230000008733 trauma Effects 0.000 claims abstract description 19
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
230000015654 memory Effects 0.000 claims abstract description 9
125000002619 bicyclic group Chemical group 0.000 claims abstract description 8
238000000034 method Methods 0.000 claims description 66
125000001072 heteroaryl group Chemical group 0.000 claims description 64
125000003118 aryl group Chemical group 0.000 claims description 57
125000003342 alkenyl group Chemical group 0.000 claims description 51
125000000304 alkynyl group Chemical group 0.000 claims description 49
125000000217 alkyl group Chemical group 0.000 claims description 45
125000003710 aryl alkyl group Chemical group 0.000 claims description 44
125000004446 heteroarylalkyl group Chemical group 0.000 claims description 36
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 34
125000004953 trihalomethyl group Chemical group 0.000 claims description 29
229910052736 halogen Inorganic materials 0.000 claims description 28
150000002367 halogens Chemical class 0.000 claims description 23
125000002883 imidazolyl group Chemical group 0.000 claims description 20
210000004556 brain Anatomy 0.000 claims description 18
YKYWUHHZZRBGMG-JWTNVVGKSA-N 1-methyl-2-[[(1r,5s)-6-[[5-(trifluoromethyl)pyridin-2-yl]methoxymethyl]-3-azabicyclo[3.1.0]hexan-3-yl]methyl]benzimidazole Chemical compound C1([C@@H]2CN(C[C@@H]21)CC=1N(C2=CC=CC=C2N=1)C)COCC1=CC=C(C(F)(F)F)C=N1 YKYWUHHZZRBGMG-JWTNVVGKSA-N 0.000 claims description 17
125000002877 alkyl aryl group Chemical group 0.000 claims description 16
150000003839 salts Chemical class 0.000 claims description 16
229910052799 carbon Inorganic materials 0.000 claims description 15
239000003112 inhibitor Substances 0.000 claims description 15
230000001154 acute effect Effects 0.000 claims description 13
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims description 11
125000005843 halogen group Chemical group 0.000 claims description 10
208000029028 brain injury Diseases 0.000 claims description 9
239000000546 pharmaceutical excipient Substances 0.000 claims description 9
BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical group O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 claims description 9
210000000278 spinal cord Anatomy 0.000 claims description 9
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
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208000000532 Chronic Brain Injury Diseases 0.000 claims description 7
239000003937 drug carrier Substances 0.000 claims description 6
230000002708 enhancing effect Effects 0.000 claims description 6
125000001041 indolyl group Chemical group 0.000 claims description 6
239000003085 diluting agent Substances 0.000 claims description 5
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
WSLYCILIEOFQPK-UHFFFAOYSA-N 3-methyl-2,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione Chemical compound O=C1C(C)NC(=O)C2CCCN21 WSLYCILIEOFQPK-UHFFFAOYSA-N 0.000 claims description 4
208000024827 Alzheimer disease Diseases 0.000 claims description 4
XLUAWXQORJEMBD-UHFFFAOYSA-N Pyrrolo(1,2-a)pyrazine-1,4-dione, hexahydro-3-(1-methylethyl)- Chemical compound O=C1C(C(C)C)NC(=O)C2CCCN21 XLUAWXQORJEMBD-UHFFFAOYSA-N 0.000 claims description 4
125000003107 substituted aryl group Chemical group 0.000 claims description 4
150000001413 amino acids Chemical class 0.000 claims description 3
GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 3
125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 3
125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 3
SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 claims description 3
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235000010384 tocopherol Nutrition 0.000 claims description 3
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229930003799 tocopherol Natural products 0.000 claims description 3
239000011732 tocopherol Substances 0.000 claims description 3
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BEPSGCXDIVACBU-IUCAKERBSA-N Pro-His Chemical compound C([C@@H](C(=O)O)NC(=O)[C@H]1NCCC1)C1=CN=CN1 BEPSGCXDIVACBU-IUCAKERBSA-N 0.000 claims description 2
RVQDZELMXZRSSI-IUCAKERBSA-N Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1 RVQDZELMXZRSSI-IUCAKERBSA-N 0.000 claims description 2
UEKYKRQIAQHOOZ-KBPBESRZSA-N Pro-Trp Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)[O-])C(=O)[C@@H]1CCC[NH2+]1 UEKYKRQIAQHOOZ-KBPBESRZSA-N 0.000 claims description 2
AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 claims description 2
SZJNCZMRZAUNQT-IUCAKERBSA-N cyclo(L-Leu-L-Pro) Chemical compound O=C1[C@H](CC(C)C)NC(=O)[C@@H]2CCCN21 SZJNCZMRZAUNQT-IUCAKERBSA-N 0.000 claims description 2
QZBUWPVZSXDWSB-RYUDHWBXSA-N cyclo(L-Phe-L-Pro) Chemical compound C([C@@H]1NC([C@@H]2CCCN2C1=O)=O)C1=CC=CC=C1 QZBUWPVZSXDWSB-RYUDHWBXSA-N 0.000 claims description 2
108010076347 cyclo(prolyl-leucyl) Proteins 0.000 claims description 2
108010007383 cyclo(prolyl-valyl) Proteins 0.000 claims description 2
108010014087 cyclo(prolylarginyl) Proteins 0.000 claims description 2
LSGOTAXPWMCUCK-RYUDHWBXSA-N maculosin Chemical compound C1=CC(O)=CC=C1C[C@H]1C(=O)N2CCC[C@H]2C(=O)N1 LSGOTAXPWMCUCK-RYUDHWBXSA-N 0.000 claims description 2
GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 2
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 21
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 20
FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 claims 1
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims 1
125000006528 (C2-C6) alkyl group Chemical group 0.000 claims 1
KUZSBKJSGSKPJH-VXGBXAGGSA-N 5-[(9R)-6-[(3R)-3-methylmorpholin-4-yl]-11-oxa-1,3,5-triazatricyclo[7.4.0.02,7]trideca-2,4,6-trien-4-yl]pyrazin-2-amine Chemical compound C[C@@H]1COCCN1c1nc(nc2N3CCOC[C@H]3Cc12)-c1cnc(N)cn1 KUZSBKJSGSKPJH-VXGBXAGGSA-N 0.000 claims 1
LDIOUQIXNSSOGU-UHFFFAOYSA-N 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5h-cyclopenta[d]pyrazolo[1,5-a]pyrimidine Chemical compound CC1=NN2C(NC(CC)CC)=C3CCCC3=NC2=C1C1=CC=C(OC)C=C1Cl LDIOUQIXNSSOGU-UHFFFAOYSA-N 0.000 claims 1
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230000004770 neurodegeneration Effects 0.000 claims 1
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WBGUMUGCONUXFK-DCAQKATOSA-N (2s)-1-[(2s)-3-(1h-imidazol-5-yl)-2-[[(2s)-4-oxoazetidine-2-carbonyl]amino]propanoyl]pyrrolidine-2-carboxamide Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)C1)CC1=CN=CN1 WBGUMUGCONUXFK-DCAQKATOSA-N 0.000 description 28
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230000009509 cortical damage Effects 0.000 description 21
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