CA2671737A1

CA2671737A1 - Prodrugs and methods of making and using the same

Prodrugs and methods of making and using the same Download PDF

Info

Publication number: CA2671737A1
Authority: CA; Canada
Prior art keywords: compound; hydrogen; prodrug; moiety; prodrug moiety
Prior art date: 2006-12-05
Legal status : Abandoned

Application number

CA002671737A

Other languages

English (en)

French (fr)

Inventor

Naweed Muhammad

Keith R. Bley

Current Assignee

NeurogesX Inc

Original Assignee

Individual

Priority date

2006-12-05

Filing date

2007-12-05

Publication date

2008-06-12

2007-12-05 Application filed by Individual filed Critical Individual

2008-06-12 Publication of CA2671737A1 publication Critical patent/CA2671737A1/en

Status Abandoned legal-status Critical Current

Links

229940002612 prodrug Drugs 0.000 title claims abstract description 519
239000000651 prodrug Substances 0.000 title claims abstract description 519
238000000034 method Methods 0.000 title claims abstract description 104
239000003814 drug Substances 0.000 claims abstract description 210
229940079593 drug Drugs 0.000 claims abstract description 206
208000002193 Pain Diseases 0.000 claims abstract description 50
230000000694 effects Effects 0.000 claims abstract description 45
ZJXZSIYSNXKHEA-UHFFFAOYSA-N ethyl dihydrogen phosphate Chemical compound CCOP(O)(O)=O ZJXZSIYSNXKHEA-UHFFFAOYSA-N 0.000 claims abstract description 45
230000036407 pain Effects 0.000 claims abstract description 44
CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical compound COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 claims abstract description 43
238000002560 therapeutic procedure Methods 0.000 claims abstract description 29
230000003247 decreasing effect Effects 0.000 claims abstract description 24
238000011282 treatment Methods 0.000 claims abstract description 9
239000001257 hydrogen Substances 0.000 claims description 150
229910052739 hydrogen Inorganic materials 0.000 claims description 150
150000001875 compounds Chemical class 0.000 claims description 142
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 92
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 85
229940049706 benzodiazepine Drugs 0.000 claims description 74
-1 C1-C10 alkanoate Chemical group 0.000 claims description 73
BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 67
150000003839 salts Chemical class 0.000 claims description 59
SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 57
OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims description 56
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 55
OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 claims description 54
125000000217 alkyl group Chemical group 0.000 claims description 51
239000012453 solvate Substances 0.000 claims description 50
239000002830 appetite depressant Substances 0.000 claims description 38
150000001450 anions Chemical class 0.000 claims description 37
BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 claims description 35
DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 claims description 35
229960003086 naltrexone Drugs 0.000 claims description 34
229960002085 oxycodone Drugs 0.000 claims description 34
229960005181 morphine Drugs 0.000 claims description 33
XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 claims description 30
229960000240 hydrocodone Drugs 0.000 claims description 30
LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 claims description 29
LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 claims description 29
DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 claims description 28
DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 claims description 28
229960003120 clonazepam Drugs 0.000 claims description 28
229960004362 clorazepate Drugs 0.000 claims description 28
XDDJGVMJFWAHJX-UHFFFAOYSA-M clorazepic acid anion Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(C(=O)[O-])N=C1C1=CC=CC=C1 XDDJGVMJFWAHJX-UHFFFAOYSA-M 0.000 claims description 28
229960003528 flurazepam Drugs 0.000 claims description 28
SAADBVWGJQAEFS-UHFFFAOYSA-N flurazepam Chemical compound N=1CC(=O)N(CCN(CC)CC)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1F SAADBVWGJQAEFS-UHFFFAOYSA-N 0.000 claims description 28
229960004391 lorazepam Drugs 0.000 claims description 28
229960001797 methadone Drugs 0.000 claims description 28
WYCLKVQLVUQKNZ-UHFFFAOYSA-N Halazepam Chemical compound N=1CC(=O)N(CC(F)(F)F)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 WYCLKVQLVUQKNZ-UHFFFAOYSA-N 0.000 claims description 27
UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 claims description 27
IKMPWMZBZSAONZ-UHFFFAOYSA-N Quazepam Chemical compound FC1=CC=CC=C1C1=NCC(=S)N(CC(F)(F)F)C2=CC=C(Cl)C=C12 IKMPWMZBZSAONZ-UHFFFAOYSA-N 0.000 claims description 27
SEQDDYPDSLOBDC-UHFFFAOYSA-N Temazepam Chemical compound N=1C(O)C(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 SEQDDYPDSLOBDC-UHFFFAOYSA-N 0.000 claims description 27
VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 claims description 27
229960004538 alprazolam Drugs 0.000 claims description 27
RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 claims description 27
229960004126 codeine Drugs 0.000 claims description 27
CDCHDCWJMGXXRH-UHFFFAOYSA-N estazolam Chemical compound C=1C(Cl)=CC=C(N2C=NN=C2CN=2)C=1C=2C1=CC=CC=C1 CDCHDCWJMGXXRH-UHFFFAOYSA-N 0.000 claims description 27
229960002336 estazolam Drugs 0.000 claims description 27
229960002428 fentanyl Drugs 0.000 claims description 27
229960002158 halazepam Drugs 0.000 claims description 27
DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 claims description 27
229960003793 midazolam Drugs 0.000 claims description 27
ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 claims description 27
229960004535 oxazepam Drugs 0.000 claims description 27
229910052760 oxygen Inorganic materials 0.000 claims description 27
229960001964 quazepam Drugs 0.000 claims description 27
229960003188 temazepam Drugs 0.000 claims description 27
JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 claims description 27
229960003386 triazolam Drugs 0.000 claims description 27
USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 claims description 26
230000009471 action Effects 0.000 claims description 25
229960001736 buprenorphine Drugs 0.000 claims description 25
229960005118 oxymorphone Drugs 0.000 claims description 25
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 24
239000001301 oxygen Substances 0.000 claims description 24
ODLMAHJVESYWTB-UHFFFAOYSA-N propylbenzene Chemical group CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 claims description 24
NETZHAKZCGBWSS-CEDHKZHLSA-N nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 claims description 23
229960000805 nalbuphine Drugs 0.000 claims description 23
229960004127 naloxone Drugs 0.000 claims description 22
VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 claims description 22
229960005301 pentazocine Drugs 0.000 claims description 22
WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 claims description 21
229960004193 dextropropoxyphene Drugs 0.000 claims description 21
XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 claims description 21
XBMIVRRWGCYBTQ-AVRDEDQJSA-N levacetylmethadol Chemical group C=1C=CC=CC=1C(C[C@H](C)N(C)C)([C@@H](OC(C)=O)CC)C1=CC=CC=C1 XBMIVRRWGCYBTQ-AVRDEDQJSA-N 0.000 claims description 21
229960005297 nalmefene Drugs 0.000 claims description 21
WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 claims description 20
229960001410 hydromorphone Drugs 0.000 claims description 20
GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 claims description 20
229960004739 sufentanil Drugs 0.000 claims description 20
XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 claims description 19
IFKLAQQSCNILHL-QHAWAJNXSA-N butorphanol Chemical compound N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 IFKLAQQSCNILHL-QHAWAJNXSA-N 0.000 claims description 19
229960001113 butorphanol Drugs 0.000 claims description 19
HYPPXZBJBPSRLK-UHFFFAOYSA-N diphenoxylate Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 HYPPXZBJBPSRLK-UHFFFAOYSA-N 0.000 claims description 19
229960004192 diphenoxylate Drugs 0.000 claims description 19
229940087121 levomethadyl Drugs 0.000 claims description 19
RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 claims description 19
229960001571 loperamide Drugs 0.000 claims description 19
229960000482 pethidine Drugs 0.000 claims description 19
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 17
125000003342 alkenyl group Chemical group 0.000 claims description 16
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 16
125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 14
238000011161 development Methods 0.000 claims description 14
125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 13
238000002651 drug therapy Methods 0.000 claims description 12
125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 11
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 10
125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 10
239000008194 pharmaceutical composition Substances 0.000 claims description 10
SNGGSNDSVBJVAR-UHFFFAOYSA-N 1,4-diethyltetrazol-5-one Chemical group CCN1N=NN(CC)C1=O SNGGSNDSVBJVAR-UHFFFAOYSA-N 0.000 claims description 9
BTXIJTYYMLCUHI-UHFFFAOYSA-N 2-propylthiophene Chemical group CCCC1=CC=CS1 BTXIJTYYMLCUHI-UHFFFAOYSA-N 0.000 claims description 9
125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 8
230000002035 prolonged effect Effects 0.000 claims description 8
JGFBQFKZKSSODQ-UHFFFAOYSA-N Isothiocyanatocyclopropane Chemical group S=C=NC1CC1 JGFBQFKZKSSODQ-UHFFFAOYSA-N 0.000 claims description 7
PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Chemical group CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 claims description 7
229910052799 carbon Inorganic materials 0.000 claims description 7
UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Chemical group CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 claims description 7
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical group CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 6
125000002877 alkyl aryl group Chemical group 0.000 claims description 6
239000000460 chlorine Chemical group 0.000 claims description 6
239000003937 drug carrier Substances 0.000 claims description 6
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
125000005243 carbonyl alkyl group Chemical group 0.000 claims description 5
125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
229910052801 chlorine Inorganic materials 0.000 claims description 4
125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 4
XFUIODFFBVATPE-UHFFFAOYSA-N 1-ethyl-4-propyltetrazol-5-one Chemical group CCCN1N=NN(CC)C1=O XFUIODFFBVATPE-UHFFFAOYSA-N 0.000 claims description 3
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical group CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 3
KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
239000011737 fluorine Substances 0.000 claims description 3
229910052731 fluorine Inorganic materials 0.000 claims description 3
230000002265 prevention Effects 0.000 claims description 3
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 3
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
150000002431 hydrogen Chemical group 0.000 claims 60
150000001805 chlorine compounds Chemical group 0.000 claims 9
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 3
150000001649 bromium compounds Chemical group 0.000 claims 3
150000002222 fluorine compounds Chemical group 0.000 claims 3
229910052717 sulfur Inorganic materials 0.000 claims 2
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
229910052794 bromium Inorganic materials 0.000 claims 1
125000001246 bromo group Chemical group Br* 0.000 claims 1
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 claims 1
RGPDIGOSVORSAK-STHHAXOLSA-N naloxone hydrochloride Chemical compound Cl.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C RGPDIGOSVORSAK-STHHAXOLSA-N 0.000 claims 1
150000001412 amines Chemical class 0.000 abstract description 5
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 196
JAQUASYNZVUNQP-USXIJHARSA-N Levorphanol Chemical compound C1C2=CC=C(O)C=C2[C@]23CCN(C)[C@H]1[C@@H]2CCCC3 JAQUASYNZVUNQP-USXIJHARSA-N 0.000 description 81
229960003406 levorphanol Drugs 0.000 description 71
239000000203 mixture Substances 0.000 description 70
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 66
239000000243 solution Substances 0.000 description 66
LNJAJHJFSKUCIR-UHFFFAOYSA-N ditert-butyl chloromethyl phosphate Chemical compound CC(C)(C)OP(=O)(OCCl)OC(C)(C)C LNJAJHJFSKUCIR-UHFFFAOYSA-N 0.000 description 53
239000003921 oil Substances 0.000 description 51
235000019198 oils Nutrition 0.000 description 50
201000009032 substance abuse Diseases 0.000 description 47
238000006243 chemical reaction Methods 0.000 description 46
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
239000000047 product Substances 0.000 description 42
230000015572 biosynthetic process Effects 0.000 description 38
239000007787 solid Substances 0.000 description 38
229910052786 argon Inorganic materials 0.000 description 33
238000009472 formulation Methods 0.000 description 29
XULIXFLCVXWHRF-UHFFFAOYSA-N 1,2,2,6,6-pentamethylpiperidine Chemical compound CN1C(C)(C)CCCC1(C)C XULIXFLCVXWHRF-UHFFFAOYSA-N 0.000 description 28
238000005481 NMR spectroscopy Methods 0.000 description 28
IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 28
238000003786 synthesis reaction Methods 0.000 description 28
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
238000004128 high performance liquid chromatography Methods 0.000 description 26
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 25
229940005483 opioid analgesics Drugs 0.000 description 25
201000010099 disease Diseases 0.000 description 24
208000024891 symptom Diseases 0.000 description 24
239000002269 analeptic agent Substances 0.000 description 23
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 description 22
229960001344 methylphenidate Drugs 0.000 description 22
239000007858 starting material Substances 0.000 description 22
UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 21
125000003545 alkoxy group Chemical group 0.000 description 20
238000006460 hydrolysis reaction Methods 0.000 description 20
238000002360 preparation method Methods 0.000 description 20
239000000126 substance Substances 0.000 description 19
KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 18
229910019142 PO4 Inorganic materials 0.000 description 18
229940025084 amphetamine Drugs 0.000 description 18
MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 18
229960001252 methamphetamine Drugs 0.000 description 18
239000010452 phosphate Substances 0.000 description 18
150000001557 benzodiazepines Chemical class 0.000 description 17
VYKNVAHOUNIVTQ-UHFFFAOYSA-N 1,2,2,3,3-pentamethylpiperidine Chemical compound CN1CCCC(C)(C)C1(C)C VYKNVAHOUNIVTQ-UHFFFAOYSA-N 0.000 description 16
VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 15
108020004774 Alkaline Phosphatase Proteins 0.000 description 14
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
210000003169 central nervous system Anatomy 0.000 description 14
230000002255 enzymatic effect Effects 0.000 description 14
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