CA2531810A1

CA2531810A1 - Compositions and methods for the treatment of parkinson's disease and tardive dyskinesias

Compositions and methods for the treatment of parkinson's disease and tardive dyskinesias Download PDF

Info

Publication number: CA2531810A1
Authority: CA; Canada
Prior art keywords: quinoline; composition; amino; diethylamino; methylbutylamino
Prior art date: 2002-07-09
Legal status : Abandoned

Application number

CA002531810A

Other languages

English (en)

French (fr)

Inventor

Jodi Nelson

Current Assignee

Alpha Research Group LLC

Original Assignee

Individual

Priority date

2002-07-09

Filing date

2003-07-09

Publication date

2004-01-15

2002-07-09 Priority claimed from US10/192,414 external-priority patent/US20020198231A1/en

2003-07-09 Application filed by Individual filed Critical Individual

2004-01-15 Publication of CA2531810A1 publication Critical patent/CA2531810A1/en

Status Abandoned legal-status Critical Current

Links

239000000203 mixture Substances 0.000 title claims abstract description 151
208000018737 Parkinson disease Diseases 0.000 title claims abstract description 144
238000011282 treatment Methods 0.000 title claims abstract description 64
238000000034 method Methods 0.000 title claims abstract description 39
206010043118 Tardive Dyskinesia Diseases 0.000 title claims abstract description 28
208000024891 symptom Diseases 0.000 claims abstract description 92
210000002569 neuron Anatomy 0.000 claims abstract description 41
239000002671 adjuvant Substances 0.000 claims abstract description 39
230000001965 increasing effect Effects 0.000 claims abstract description 30
201000000980 schizophrenia Diseases 0.000 claims abstract description 29
150000003943 catecholamines Chemical class 0.000 claims abstract description 20
230000004098 cellular respiration Effects 0.000 claims abstract description 18
208000011580 syndromic disease Diseases 0.000 claims abstract description 11
239000003937 drug carrier Substances 0.000 claims abstract description 9
230000007850 degeneration Effects 0.000 claims abstract description 8
208000009985 drug-induced dyskinesia Diseases 0.000 claims abstract description 6
VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 129
239000004480 active ingredient Substances 0.000 claims description 74
229960003638 dopamine Drugs 0.000 claims description 63
WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims description 55
229960003677 chloroquine Drugs 0.000 claims description 50
NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 43
239000003795 chemical substances by application Substances 0.000 claims description 39
150000001875 compounds Chemical class 0.000 claims description 39
WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims description 38
230000002093 peripheral effect Effects 0.000 claims description 35
239000003136 dopamine receptor stimulating agent Substances 0.000 claims description 30
239000003112 inhibitor Substances 0.000 claims description 30
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 29
150000003839 salts Chemical class 0.000 claims description 22
-1 4-aminopentyl Chemical group 0.000 claims description 18
230000004060 metabolic process Effects 0.000 claims description 18
229960001340 histamine Drugs 0.000 claims description 17
239000003223 protective agent Substances 0.000 claims description 17
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 16
XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 claims description 16
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229960004171 hydroxychloroquine Drugs 0.000 claims description 15
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230000001225 therapeutic effect Effects 0.000 claims description 15
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230000007774 longterm Effects 0.000 claims description 14
229940044551 receptor antagonist Drugs 0.000 claims description 14
239000002464 receptor antagonist Substances 0.000 claims description 14
AEUAEICGCMSYCQ-UHFFFAOYSA-N 4-n-(7-chloroquinolin-1-ium-4-yl)-1-n,1-n-diethylpentane-1,4-diamine;dihydrogen phosphate Chemical compound OP(O)(O)=O.ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 AEUAEICGCMSYCQ-UHFFFAOYSA-N 0.000 claims description 13
208000016285 Movement disease Diseases 0.000 claims description 13
208000027089 Parkinsonian disease Diseases 0.000 claims description 13
230000002207 retinal effect Effects 0.000 claims description 13
239000012528 membrane Substances 0.000 claims description 12
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
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229960001380 cimetidine Drugs 0.000 claims description 11
CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 claims description 11
LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 claims description 10
238000002360 preparation method Methods 0.000 claims description 10
150000003254 radicals Chemical class 0.000 claims description 10
ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 claims description 8
206010003694 Atrophy Diseases 0.000 claims description 8
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239000003963 antioxidant agent Substances 0.000 claims description 8
235000006708 antioxidants Nutrition 0.000 claims description 8
230000037444 atrophy Effects 0.000 claims description 8
210000001577 neostriatum Anatomy 0.000 claims description 8
210000003523 substantia nigra Anatomy 0.000 claims description 8
BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 7
230000006907 apoptotic process Effects 0.000 claims description 7
229910001424 calcium ion Inorganic materials 0.000 claims description 7
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GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 6
CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 6
208000009668 Neurobehavioral Manifestations Diseases 0.000 claims description 6
MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 6
LSGISLMKNCXXNS-UHFFFAOYSA-N n-(7-chloroquinolin-4-yl)-n',n'-diethylbutane-1,4-diamine Chemical compound ClC1=CC=C2C(NCCCCN(CC)CC)=CC=NC2=C1 LSGISLMKNCXXNS-UHFFFAOYSA-N 0.000 claims description 6
230000036542 oxidative stress Effects 0.000 claims description 6
239000002243 precursor Substances 0.000 claims description 6
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LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 claims description 6
230000000542 thalamic effect Effects 0.000 claims description 6
RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 claims description 5
108010001237 Cytochrome P-450 CYP2D6 Proteins 0.000 claims description 5
PLDUPXSUYLZYBN-UHFFFAOYSA-N Fluphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 PLDUPXSUYLZYBN-UHFFFAOYSA-N 0.000 claims description 5
239000003210 dopamine receptor blocking agent Substances 0.000 claims description 5
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229960003878 haloperidol Drugs 0.000 claims description 5
238000004519 manufacturing process Methods 0.000 claims description 5
VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 claims description 5
229960003248 mifepristone Drugs 0.000 claims description 5
WIQRCHMSJFFONW-UHFFFAOYSA-N norfluoxetine Chemical compound C=1C=CC=CC=1C(CCN)OC1=CC=C(C(F)(F)F)C=C1 WIQRCHMSJFFONW-UHFFFAOYSA-N 0.000 claims description 5
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AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 claims description 4
OTKWDNCXANVGKB-UHFFFAOYSA-N 1-n,1-n-diethyl-4-n-(7-fluoroquinolin-4-yl)pentane-1,4-diamine Chemical compound FC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 OTKWDNCXANVGKB-UHFFFAOYSA-N 0.000 claims description 4
CAUPTGHSTDHRCZ-UHFFFAOYSA-N 1-n,1-n-diethyl-4-n-quinolin-4-ylpentane-1,4-diamine Chemical compound C1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 CAUPTGHSTDHRCZ-UHFFFAOYSA-N 0.000 claims description 4
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102000004328 Cytochrome P-450 CYP3A Human genes 0.000 claims description 4
108010081668 Cytochrome P-450 CYP3A Proteins 0.000 claims description 4
108010052832 Cytochromes Proteins 0.000 claims description 4
102000018832 Cytochromes Human genes 0.000 claims description 4
AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 claims description 4
102000019197 Superoxide Dismutase Human genes 0.000 claims description 4
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GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims description 4
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235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 4
ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 claims description 4
229960001076 chlorpromazine Drugs 0.000 claims description 4
WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 claims description 4
CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 claims description 4
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VRBKIVRKKCLPHA-UHFFFAOYSA-N nefazodone Chemical compound O=C1N(CCOC=2C=CC=CC=2)C(CC)=NN1CCCN(CC1)CCN1C1=CC=CC(Cl)=C1 VRBKIVRKKCLPHA-UHFFFAOYSA-N 0.000 claims description 4
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VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 claims description 4
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XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 claims description 3
JXYWFNAQESKDNC-BTJKTKAUSA-N (z)-4-hydroxy-4-oxobut-2-enoate;2-[(4-methoxyphenyl)methyl-pyridin-2-ylamino]ethyl-dimethylazanium Chemical compound OC(=O)\C=C/C(O)=O.C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 JXYWFNAQESKDNC-BTJKTKAUSA-N 0.000 claims description 3
YQDKVTYBHKVETH-UHFFFAOYSA-N 1-(3,4-dihydro-2h-quinolin-1-yl)butan-1-one Chemical compound C1=CC=C2N(C(=O)CCC)CCCC2=C1 YQDKVTYBHKVETH-UHFFFAOYSA-N 0.000 claims description 3
RRWLNRQGJSQRAF-UHFFFAOYSA-N 1-(3,4-dihydro-2h-quinolin-1-yl)ethanone Chemical compound C1=CC=C2N(C(=O)C)CCCC2=C1 RRWLNRQGJSQRAF-UHFFFAOYSA-N 0.000 claims description 3
JOROEVAWQLGPFQ-UHFFFAOYSA-N 1-benzhydryl-4-methylpiperazine;2-hydroxypropanoic acid Chemical compound CC(O)C(O)=O.C1CN(C)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 JOROEVAWQLGPFQ-UHFFFAOYSA-N 0.000 claims description 3
VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 claims description 3
HLYKPDXXIDMNHY-UHFFFAOYSA-N 2-[(7-chloroquinolin-4-yl)amino]-5-(diethylamino)-2-methylpentanoic acid Chemical compound ClC1=CC=C2C(NC(C)(CCCN(CC)CC)C(O)=O)=CC=NC2=C1 HLYKPDXXIDMNHY-UHFFFAOYSA-N 0.000 claims description 3
QDXQZQGNAKIJSA-UHFFFAOYSA-N 2-[(7-chloroquinolin-4-yl)amino]-5-(diethylamino)pentanoic acid Chemical compound ClC1=CC=C2C(NC(CCCN(CC)CC)C(O)=O)=CC=NC2=C1 QDXQZQGNAKIJSA-UHFFFAOYSA-N 0.000 claims description 3
CRCWPKGKPRVXAP-UHFFFAOYSA-N 2-[4-[(7-chloroquinolin-4-yl)amino]pentyl-ethylamino]ethanol;phosphoric acid Chemical compound OP(O)(O)=O.OP(O)(O)=O.ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 CRCWPKGKPRVXAP-UHFFFAOYSA-N 0.000 claims description 3
USCWUEAEIGDJQJ-UHFFFAOYSA-N 2-[amino(quinolin-4-yl)amino]-3-(2-hydroxyethyl)-2-methylheptanoic acid Chemical compound C1=CC=C2C(N(N)C(C)(C(CCO)CCCC)C(O)=O)=CC=NC2=C1 USCWUEAEIGDJQJ-UHFFFAOYSA-N 0.000 claims description 3
SMMCIHJIFFPSCL-UHFFFAOYSA-N 2-[amino(quinolin-4-yl)amino]-5-ethyl-7-hydroxyheptanoic acid Chemical compound C1=CC=C2C(N(N)C(CCC(CCO)CC)C(O)=O)=CC=NC2=C1 SMMCIHJIFFPSCL-UHFFFAOYSA-N 0.000 claims description 3
JIPMJMODMIWJKN-UHFFFAOYSA-N 2-[amino-(7-chloroquinolin-4-yl)amino]-5-ethyl-7-hydroxyheptanoic acid Chemical compound ClC1=CC=C2C(N(N)C(CCC(CCO)CC)C(O)=O)=CC=NC2=C1 JIPMJMODMIWJKN-UHFFFAOYSA-N 0.000 claims description 3
FSYPWNIXVHHTTE-UHFFFAOYSA-N 2-[amino-(7-fluoroquinolin-4-yl)amino]-3-(2-hydroxyethyl)-2-methylheptanoic acid Chemical compound FC1=CC=C2C(N(N)C(C)(C(CCO)CCCC)C(O)=O)=CC=NC2=C1 FSYPWNIXVHHTTE-UHFFFAOYSA-N 0.000 claims description 3
TUDGWCRLCIOVOJ-UHFFFAOYSA-N 2-[amino-(7-fluoroquinolin-4-yl)amino]-5-ethyl-7-hydroxyheptanoic acid Chemical compound FC1=CC=C2C(N(N)C(CCC(CCO)CC)C(O)=O)=CC=NC2=C1 TUDGWCRLCIOVOJ-UHFFFAOYSA-N 0.000 claims description 3
FSFQHUDTQQRPRF-UHFFFAOYSA-N 2-[amino-(7-hydroxyquinolin-4-yl)amino]-3-(2-hydroxyethyl)-2-methylheptanoic acid Chemical compound OC1=CC=C2C(N(N)C(C)(C(CCO)CCCC)C(O)=O)=CC=NC2=C1 FSFQHUDTQQRPRF-UHFFFAOYSA-N 0.000 claims description 3
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HRWYHFWCYCQWQJ-UHFFFAOYSA-N 3-[amino-(7-chloroquinolin-4-yl)amino]-3-methyloctan-1-ol Chemical compound ClC1=CC=C2C(N(N)C(C)(CCO)CCCCC)=CC=NC2=C1 HRWYHFWCYCQWQJ-UHFFFAOYSA-N 0.000 claims description 3
HXQVDILZYYOGIA-UHFFFAOYSA-N 3-[amino-(7-fluoroquinolin-4-yl)amino]-3-methyloctan-1-ol Chemical compound FC1=CC=C2C(N(N)C(C)(CCO)CCCCC)=CC=NC2=C1 HXQVDILZYYOGIA-UHFFFAOYSA-N 0.000 claims description 3
QHILAOKBLSXUFN-UHFFFAOYSA-N 4-[4-(diethylamino)butylamino]quinolin-7-ol Chemical compound OC1=CC=C2C(NCCCCN(CC)CC)=CC=NC2=C1 QHILAOKBLSXUFN-UHFFFAOYSA-N 0.000 claims description 3
CJTXKVVXLANOHU-UHFFFAOYSA-N 4-[5-(diethylamino)pentan-2-ylamino]quinolin-7-ol Chemical compound OC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 CJTXKVVXLANOHU-UHFFFAOYSA-N 0.000 claims description 3
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CVHAOXMRXFUHLJ-UHFFFAOYSA-N 5-(diethylamino)-2-(quinolin-4-ylamino)pentanoic acid Chemical compound C1=CC=C2C(NC(CCCN(CC)CC)C(O)=O)=CC=NC2=C1 CVHAOXMRXFUHLJ-UHFFFAOYSA-N 0.000 claims description 3
CVNZPXRTKNQBRX-UHFFFAOYSA-N 5-(diethylamino)-2-[(7-fluoroquinolin-4-yl)amino]-2-methylpentanoic acid Chemical compound FC1=CC=C2C(NC(C)(CCCN(CC)CC)C(O)=O)=CC=NC2=C1 CVNZPXRTKNQBRX-UHFFFAOYSA-N 0.000 claims description 3
LEBWYNHSLPDMMI-UHFFFAOYSA-N 5-(diethylamino)-2-[(7-fluoroquinolin-4-yl)amino]pentanoic acid Chemical compound FC1=CC=C2C(NC(CCCN(CC)CC)C(O)=O)=CC=NC2=C1 LEBWYNHSLPDMMI-UHFFFAOYSA-N 0.000 claims description 3
PRSVYKDLQBBGOB-UHFFFAOYSA-N 5-(diethylamino)-2-[(7-hydroxyquinolin-4-yl)amino]-2-methylpentanoic acid Chemical compound OC1=CC=C2C(NC(C)(CCCN(CC)CC)C(O)=O)=CC=NC2=C1 PRSVYKDLQBBGOB-UHFFFAOYSA-N 0.000 claims description 3
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