GB2105323A - Aporphine compounds - Google Patents
Aporphine compounds Download PDFInfo
- Publication number
- GB2105323A GB2105323A GB08217644A GB8217644A GB2105323A GB 2105323 A GB2105323 A GB 2105323A GB 08217644 A GB08217644 A GB 08217644A GB 8217644 A GB8217644 A GB 8217644A GB 2105323 A GB2105323 A GB 2105323A
- Authority
- GB
- United Kingdom
- Prior art keywords
- substituted
- alkyl
- compound
- phenyl
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000008441 aporphines Chemical class 0.000 title abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 43
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 37
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 21
- 208000000718 duodenal ulcer Diseases 0.000 claims abstract description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 14
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims abstract description 9
- 230000002265 prevention Effects 0.000 claims abstract description 6
- 208000012902 Nervous system disease Diseases 0.000 claims abstract description 5
- 208000025966 Neurological disease Diseases 0.000 claims abstract description 5
- 208000020016 psychiatric disease Diseases 0.000 claims abstract description 5
- 230000000926 neurological effect Effects 0.000 claims abstract description 4
- 230000000694 effects Effects 0.000 claims description 34
- -1 aporphine compound Chemical class 0.000 claims description 26
- 239000003136 dopamine receptor stimulating agent Substances 0.000 claims description 17
- 241000790917 Dioxys <bee> Species 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 14
- 230000001225 therapeutic effect Effects 0.000 claims description 13
- 229950004392 norcodeine Drugs 0.000 claims description 9
- 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 8
- 238000001727 in vivo Methods 0.000 claims description 8
- HKOIXWVRNLGFOR-KOFBORESSA-N norcodeine Chemical compound O[C@H]([C@@H]1O2)C=C[C@H]3[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4 HKOIXWVRNLGFOR-KOFBORESSA-N 0.000 claims description 8
- HKOIXWVRNLGFOR-UHFFFAOYSA-N norcodeine Natural products O1C2C(O)C=CC3C4CC5=CC=C(OC)C1=C5C23CCN4 HKOIXWVRNLGFOR-UHFFFAOYSA-N 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- BZKUYNBAFQJRDM-UHFFFAOYSA-N aporphine Natural products C12=CC=CC=C2CC2N(C)CCC3=CC=CC1=C32 BZKUYNBAFQJRDM-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- QCMQEZNBBPGFKQ-UHFFFAOYSA-N Thalisopynine Natural products CN1CCC2=C(OC)C(OC)=C(OC)C3=C2C1CC1=C3C=C(OC)C(O)=C1 QCMQEZNBBPGFKQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- FVRABHGHBLRNNR-UHFFFAOYSA-N liriodenine Natural products O=C1C=CC=c2c1cc3nccc4cc5OCOc5c2c34 FVRABHGHBLRNNR-UHFFFAOYSA-N 0.000 claims description 5
- 229960004126 codeine Drugs 0.000 claims description 4
- 238000010520 demethylation reaction Methods 0.000 claims description 4
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 claims description 4
- 230000029936 alkylation Effects 0.000 claims description 3
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- 230000008707 rearrangement Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 230000001335 demethylating effect Effects 0.000 claims 2
- MHPQCGZBAVXCGA-GFCCVEGCSA-N (6ar)-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinoline-10,11-diol Chemical compound N1CCC2=CC=CC3=C2[C@H]1CC1=CC=C(O)C(O)=C13 MHPQCGZBAVXCGA-GFCCVEGCSA-N 0.000 claims 1
- 241000700159 Rattus Species 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 206010042008 Stereotypy Diseases 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 14
- 229960004046 apomorphine Drugs 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000007912 intraperitoneal administration Methods 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 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 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000006399 behavior Effects 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- 230000003542 behavioural effect Effects 0.000 description 8
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 8
- 229960003151 mercaptamine Drugs 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000006742 locomotor activity Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- FHIKZROVIDCMJA-UHFFFAOYSA-N 2-(2,2-diphenylpentanoyloxy)ethyl-diethylazanium;chloride Chemical compound Cl.C=1C=CC=CC=1C(C(=O)OCCN(CC)CC)(CCC)C1=CC=CC=C1 FHIKZROVIDCMJA-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229940052760 dopamine agonists Drugs 0.000 description 5
- 229960003878 haloperidol Drugs 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 102000015554 Dopamine receptor Human genes 0.000 description 4
- 108050004812 Dopamine receptor Proteins 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 208000025865 Ulcer Diseases 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- JEHKKBHWRAXMCH-UHFFFAOYSA-N benzenesulfinic acid Chemical compound O[S@@](=O)C1=CC=CC=C1 JEHKKBHWRAXMCH-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000002183 duodenal effect Effects 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229940087098 Oxidase inhibitor Drugs 0.000 description 3
- 238000000692 Student's t-test Methods 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 210000004211 gastric acid Anatomy 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000033001 locomotion Effects 0.000 description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- BTGAJCKRXPNBFI-UHFFFAOYSA-N propylnorapomorphine Chemical compound C1CN(CCC)C2CC3=CC=C(O)C(O)=C3C3=C2C1=CC=C3 BTGAJCKRXPNBFI-UHFFFAOYSA-N 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 231100000397 ulcer Toxicity 0.000 description 3
- QXUACCGHDXHZPW-UHFFFAOYSA-N 10-methoxy-6-propyl-5,6,6a,7-tetrahydro-4h-dibenzo[de,g]quinoline-11-ol Chemical compound C1CN(CCC)C2CC3=CC=C(OC)C(O)=C3C3=C2C1=CC=C3 QXUACCGHDXHZPW-UHFFFAOYSA-N 0.000 description 2
- YSONYEIWWIFWEV-UHFFFAOYSA-N 13-propyl-4,6-dioxa-13-azapentacyclo[10.7.1.02,10.03,7.016,20]icosa-1(19),2(10),3(7),8,16(20),17-hexaene Chemical compound C1CN(CCC)C2CC3=CC=C4OCOC4=C3C3=C2C1=CC=C3 YSONYEIWWIFWEV-UHFFFAOYSA-N 0.000 description 2
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 2
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 2
- PMNLUUOXGOOLSP-UHFFFAOYSA-N 2-mercaptopropanoic acid Chemical compound CC(S)C(O)=O PMNLUUOXGOOLSP-UHFFFAOYSA-N 0.000 description 2
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 208000009132 Catalepsy Diseases 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010047853 Waxy flexibility Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 229910052925 anhydrite Inorganic materials 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 2
- 229960002802 bromocriptine Drugs 0.000 description 2
- UPDHOTIATMFGCI-UHFFFAOYSA-N butylarsonic acid Chemical compound CCCC[As](O)(O)=O UPDHOTIATMFGCI-UHFFFAOYSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
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- 230000003292 diminished effect Effects 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000002964 excitative effect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
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- SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
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- JKAHWGPTNVUTNB-IXPVHAAZSA-N lergotrile Chemical compound C1=CC([C@H]2C[C@@H](CC#N)CN([C@@H]2C2)C)=C3C2=C(Cl)NC3=C1 JKAHWGPTNVUTNB-IXPVHAAZSA-N 0.000 description 2
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- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
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- 238000001556 precipitation Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
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- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
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- 239000000741 silica gel Substances 0.000 description 2
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- 238000012453 sprague-dawley rat model Methods 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
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Abstract
A method for providing orally effective aporphine compounds, and new compounds which are orally effective in the prevention and treatment of duodenal ulcers and in the treatment of neurological and psychiatric disorders having the following formula: <IMAGE> wherein R1 is lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, subsubstituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkynyl, R2 and R3 are hydrogen, methyl, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkynyl and R4 is hydrogen, hydroxy, -O-R5 and <IMAGE> and R5 is methyl and lower alkyl. Particularly effective are compounds wherein R4 is hydrogen.
Description
SPECIFICATION
Orally effective aporphine compounds
Many aporphine compounds have thereapeutic activity. Thus, apomorphine (APO) and N-npropylnorapormorphine (NPA) have potent and selective actions at central and other dopamine receptor sites. Such aporphine compounds have been used clinically, especially in neurological and psychiatric disorders, but their clinical use has been limited by their poor oral bio-availability and short duration of action.
In accordance with this invention, an aporphine compound which has two adjacent hydroxy groups on an aromatic nucleus and which has a therapeutic effect when administered subcutaneously or intraperitoneally can be converted into an orally effective therapeutic compound by bridging the hydroxy groups to form a dioxy group as for example methylene dioxy. The dioxy group is cleavable in vivo to provide the compound with two adjacent hydroxy groups.
Therapeutic aporphine compounds having the following structure are particularly useful in this invention and are convertible to an orally effective therapeutic composition which is cleaved in vivo to release the compound with the two adjacent hydroxy groups.
Wherein R1 is lower alkyl, substituted lower alkyl, cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkynyl, R4 is hydrogen, hydroxy, -O-R5 or -O-C-R5- 0 wherein R5 is methyl, and lower alkyl and R2 and R3 are hydrogen, methyl and R1.
This invention is also generally applicable to dopamine agonist compounds which have two hydroxy groups on adjacent positions on an aromatic nucleus and which have dopamine agonist activity when administered subcutaneously or interperitoneally. Such compounds include not only aporphine compounds but also non-aporphine compounds, as for example, compounds of the following structures:
wherein R1 and R2 are hydrogen, methyl and lower alkyl
wherein R, and R2 are hydrogen, methyl and lower alkyl
wherein R1 and R2 are hydrogen, methyl and lower alkyl.
Also, in accordance with the present invention aporphine compounds are described which are orally effective in treating neurological and psychiatric disorders. In addition aporphine compounds are described which are effective in the prevention and treatment of duodenal ulcers and can be administered orally, subcutaneously or peritoneally.Preferred examples of these novel compounds and dioxy groups have the following structures:
wherein R, is lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkynyl, and R2 and R3 are hydrogen, methyl, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkynyl and pharmaceutically acceptable acid addition salts thereof.
In particular I have found that (-) 10, 1 1-methylene-dioxy-N-n-propyinoraporphine is especially effective when administered orally in the prevention and treatment of psychiatric and neurological disorders. I have also found that the methylene dioxy group is an especially effective dioxy group. It is believed that the compounds of this invention are converted in vivo to the dihydroxy compound and are orally effective and long acting.
As used herein, the term "lower-alkyl" means saturated monovalent aliphatic radicals, including straight and branched-chan radicals, of from two to six carbon atoms, as illustrated by, but not limited to ethyl, propyl, isopropys, butyl, sec.-butyl, amyl, or hexyl.
As used herein, the term "lower-alkenyl" means monovalent, aliphatic radicals of from three to seven carbon atoms which contain at least one double bond, and are either straight or branched-chain, as illustrated by, but not limited to 1-(2-propenyl), 1-(3-methyl-2-propenyl) 1-(1 ,3-dimethyl-2-propenyl), or 1-(2-hexenyl).
As used herein, the term "lower-alkynyl" means monovalent, alphatic radicals of from three to seven carbon atoms which contain at least one triple bond, and are either straight or branched, as illustrated by, but not limited to 1-(2-propynyl), 1-(1-methyl-2-propynyl), or heptynl).
As used herein, the term "cycloalkyl" means cyclic, saturated aliphatic radicals of from three to eight ring carbon atoms, as illustrated by, but not limited to cyclopropyl, cyclobutyl, 2methylcyclobutyl, cyclohexyl, 4-methylcyclohexyl, or cyclooctyl.
As used herein, the terms "phenyl-lower-alkyl", , "phenyl-lower-alkenyl", and "phenyl-loweraikynyl" mean monovalent radicals consisting of a phenyl nucleus bonded to the rest of the molecule through, respectively, a divalent lower-alkylene radical of from one to four carbon atoms, as illustrated by, but not limited to methylene, 1,1-ethylene, 1,2-ethylene, 1,3 propylene, 1 2-propylene, or 1,4-butylene; or through a divalent lower-alkynylene radical of from two to four carbon atoms, as illustrated by, but not limited to 1,2-ethynylene, 1,3propynylene, 1,3-(1-butynylene), and the like.Moreover the benzene ring of such phenyl-loweralkyl, phenyl-lower-alkenyl, and phenyl-lower-alkynyl radicals can be substituted by one of more substituents selected from the group consisting of lower-alkyl, lower-alkoxy, halo(chloro, bromo, iodo, or fluoro), nitro, lower-alkylmercapto, methylenedioxy, and trifluoromethyl.
Appropriate acid addition salts are those derived from such diverse acids as formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid, 4-methoxybenzoic acid, phthalic acid, anthranilic acid, 1 -napthalenecarboxylic acid, cinnamic acid, cyclohexane-carboxylic acid, mandelic acid, tropic acid, crotonic acid, acetylene dicarboxylic acid, sorbic acid, 2furancarboxylic acid, cholic acid, pyrenecarboxylic acid, 2-pyridinecarboxylic acid, 3-indoleacetic acid quinic acid, sulfamic acid, methanesulfonic acid, benzenesulfinic acid, butylarsonic acid, ptoluene-sulfonic acid, benzenesulfinic acid, butylarsonic acid, diethylphosphinic acid, p-aminophenylarsinic acid, phenylstibnic acid, phenylphosphinous acid, methyl-phosphinic acid, phenylphosphinic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrocyanic acid, phosphotungstic acid, molybdic acid, phosphomolybdic acid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid, barbituric acid, boron trifluoride, and the like.
DOPAMINE AGONIST ACTIVITY
With respect to dopamine agonist activity, the compounds of this invention were tested for stereotyped gnawing behaviour of rats in accordance with the techniques described in
Baldessarini, R.J., (Walton, K.G. and Borgman, R.J. 1976, "Prolonged apomorphine-like behavioural effects of apomorphine esters." Neuropharmacology 15, 471.) In some rats forebrain tissue was assayed after administration of (-) 10, 1 1-Methylene-dioxy-N-n-Propylnorapor- phine (MDO-NPA) for the presence of free N-n-Propyinorapomorphine (NPA) by a sensitive and specific high-performace liquid chromato-graphic method with electrochemical detection (HPLC/ec). (Westerink, B.H.C. and Horn, A.S. 1979. "Do neuroleptics prevent the penetration of dopamine agonists into the brain?" Eur. J.Pharmaco. 58, 39.) The results are shown in
Table 1.
The compounds of this invention are very active in inducing stereotypy behaviour in vivo when administered orally.
MDO-NPA at doses above 2 umoles/kg, i.p. (about 0.68 mg/kg) produced dose-dependent increases in general motor activity, NPA and APO exerted very similar effects on motor activity, with increased counts at doses above 2 pmolwes/kg, but no significant effect at lower doses. In contrast, MDO-NPA induced inhibition of locomotor activity at does below 2 ymoles/kg, with a maximum effect found at 0.3 ymole/kg (about 0.1 mg/kg). In addition, only MDO-NPA induced strong catalepsy at doses similar to those which inhibited general activity again, with a maximum effect found at 0.3 pmole/kg, i.p. (at the same molar does, NPA and APO, respectively, produced only 15% and 7% as much stereotypy as MDO-NPA: N = 12).Thus,
MDO-NPA had a clearly biphasic pattern of activity in which low doses exerted significant motor-inhibiting and cataleptic effects resembling those of a classic neuroleptic, while higher doses exerted excitatory and stereotyped behaviours as expected of a typical DA anonist such as
APO or NPA.
The duraction of stereotyped behavioural effects of MDO-NPA exceeded that of NPA at doses above 1 ymole/kg, i.p., and MDO-NPA showed a consistent increase in duration of action with increased dose. The duration of behavioural action of NPA was about equal to, or slightly greater than that of APO, and both NPA and APO showed much less tendency for duration to increase with dose than did MDO-NPA.
When other derivatives of NPA or APO, with substituents at the methylene carbon or an electron-withdrawing group, such as a nitro function, in the 8-position were evaluated, MDO- APO showed relatively weak and inconsistent excitatory effects at a high dose (10 mg/kg, i.p.) and no significant behavioural effects after oral administration (1 to 5 mg/kg.).
MEASUREMENT OF BIOLOGICAL ACTIVITY
Male Sprague-Dawley (Charles River Labs.) rats (initially 175-200 g) were housed four per cage, with free access to food and water, under controlled lighting (on 7:00 a.m. to 7:00p.m.), constant temperature (21-23"C.) and controlled humidity (40-50%). Aporphines were administered, as described below, freshly dissolved in 1 mM citric acid mixed with 0.9% (w/v) saline (1:4, vols) this solvent was also used as a vehicle ("placebo") control. Haloperidol was given in the same medium; 2-diethyl aminoethyl-2,2 diphenylvalerate HCI (SKF-525A) was given in saline.
Locomotor activity was evaluated by use of a printing electronic activity monitor (EAM,
Soelting Co., Chicago, IL) within a sound-attenuated chamber, typically for 60 min., as
described previously (Stewart, Campbell, Sperk and Baldessarini, 1979, Psychopharmacology
60281-289; Campbell and Baldessarini, 1981a, Psychopharmacology 73:219-222.)
Stereotyped behaviour was evaluated by a trained observer according to a rating scale method
reported previously (Campbell and Baldessarini, 1 981 a). Briefly, the ratings were as follows: 0,
no stereotypy, normal locomotion; 1, discontinuous sniffing, reduced locomotion: 2, continuous
sniffing, only periodic exploration; 3, continuous sniffing, mouth movements, infrequent,
exploratory activity. Ratings were made each 10 min. by observation for 30 sec., typically for
60 min. (maximum score = 18.0/hour).
Catalepsy was assessed as described in detail elsewhere (Campbell and Baldessarini, 1981a; 1 981 b, Life Sciences 29 1 341-46). Briefly, rats were evaluated every 10 min. by timing
(stopwatch) their maintenance of an abnormal posture with forelimbs on a 1 cm-diameter steel
bar parallel to, and 8cm above the bench, so that the rate rested on its hindquarters only; 60
sec. was taken as a maximum and nearly all normal untreated rats remained on the bar for less
than 5 sec. Ratings were made as follows: 0, remaining on the bar 0-10 sec; 1, 10-29 sec; 2,
30-59 sec; 3, 2 60 sec. Thus, in a typical 60 min. session, the maximunm score was 18.0.
In all experiments except those which evaluated the time-course of drug effects, rats were
given as injection of vehicle and then allowed to rest for 15 min. to adapt to non-specific
arousal effects, prior to a second in injection of test agent (or placebo) and immediate
behavioural testing. Behavioural data were evaluated by Student's t- test and are always
expressed as + SEM.
The following tables illustrate data evaluating the compounds of this invention for their
dopamine agonist activity. Table 1 compares route of administration and stereotyped behaviour
among MDO-NPA and other aporphines. Table 2 denotes the effects of microsomal oxidase
inhibitor on the behavioural effects of low and high doses of MDO-NPA. Table 3 evaluates the
effects of haloperidol on stereotyped behaviour induced by MDO-NPA. Table 4 compares
characteristics of NPA and MDO-NPA. Table 5 compares MDO-NPA and analogs with respect
to stereotyped behaviour and locomotor activity.
TABLE 1
Route of administration and stereotyped response to MDO-NPA and other aporphines.
Agent Stereotypy Score Duration of Effect
(min) (lmg/kg) P.O S.C l.P. P.O. S.C I.P MDO-NPA 17.011.2 17.510.4 16.5 + 0.8 112 + 20 106 10 116 12 NPA O 17.5+0.8 17.5+1.0 0 7216 70110
APO 0 17.5 + 0.4 16.5 + 2.4 0 70 5 72 + 12
Data are mean values 1 SEM for N = 6 rats per group given doses of each aporphine (1
mg/kg or approximately 3,limole/kg) by orogastric intubation (P.O.), or subcutaneous (S.C.), or
intraperitoneal (I.P.) injection.Stereotypy was rated for one hour as described in Methods and
duration is defined as complete when scores diminished to L 3 (out of a maximum possible
score of 18).
*TABLE 2
Effects of microsomal oxidase inhibitor (SKF-525A) on behav
ioural effects of low and high doses of MDO-NPA
Dose of MDO-NPA Control SKF-525A
(mg/kg) Activity Stereotypy Activity Stereotypy
0 409 + 36 0 422 + 28 0 0.05 190 20 ND 425 + 40* ND 0.10 130+30 ND 415+29* ND
0.20 260 33 ND 410 + 32* ND
0.30 435129 12.8+0.6 440138 1.7+0.6* 1.0 ND 16.5+0.1 ND 0.8+0.2* 3.0 ND 16.210.9 ND 0.8 0.5* Data are mean values + SEM (N = 4 to 8 rats per condition).Animals were pre-treated with
SKF-525A (40 mg/kg, i.p.) or its vehicle 30 min. before MDO-NPA (in the doses noted, from
O to 3 mg/kg, i.p). Activity was then monitored electronically for an hour after the low doses of
MDO-NPA (data in counts/hour), or rated for stereotypy every 10 min. for an hour after higher doses. N.D. indicates "not determined". (*) Indicates a significant difference by t-test between control and oxidase inhibitor-pretreated rats (p 0.01). In a control experiment, rats were pretreated with SKF-525A (40 mg/kg, i.p.) or its vehicle (N = 6) as described and then given
NPA (3 mg/kg, i.p.); the resulting stereotypy scores were 17.4 + 0.2 vs. 17.0 1 0.3 for controls vs. oxidase-inhibited rats, respectively, indicating no significant effect of the drug on actions of NPA itself.
TABLE 3
Effects of haloperidol on stereotyped behaviour induced by MDO-NPA
Haloperidol MDO-NPA (mg/kg) (mg/kg)
0.3 1.0 0 11.6+0.8 16.6+0.4 0.3 0.3 1 0.2* 0.5 10.2* 1.0 0.3 0.2* 1.210.4* Haloperidol or its vehicle was given 30 min. before MDO-NPA (both dissolved in the same citric acid-saline vehicle). Stereotypy was rated for 60 min. as described in Methods. Data are means SEM (stereotypy scores, when 18 = maximum in 1 hour) for N = 6 rats per group; (*) indicates p < 0.0001 by ttest.
TABLE 4
Characteristics of NPA and MDO-NPA. Data are for stimulation of cAMP in rat striatal homogenates; inhibition of binding of (3H)APO to beef caudate synaptosomal membranes; stereotypy scores (maximum possible = 18.0); and cerebral levels of NPA by HPLC/ec; (*) p 0.01.
Condition x SEM (N)
Adenylate cyclase stimulation (cAMP, pmol/assay) Controi (no addition) 2.38 + 0.14 (8)
NPA (50uM) 5.67 + 0.28 (4)* MDO-NPA (100 uM) 2.9210.32(4) (1000 uM) 2.0610.30 (4)
IC50 vs. (3H)APO binding (nM)
NPA 2.5 + 0.2 (3)
MDO-NPA 850 + 85 (3) Stereotypy Score for 30 min. after MDO-NPA (1 mg/kg) i.p 16.5 1.2(5) p.o. 15.511.6(5) Cerebral NPA (ng/g) at 30 min. after MDO-NPA (1 mg/kg) i.p. 6.0 + 0.8 (3) p.o. 3.3 1 1.8 (3)
TABLE 5
Effects of analogs of MDO-NPA on stereotyped behaviour and locomotor activity
Compound ~ Substituents Stereotypy Locomotation
R1 R2 R3 8-Nitro-MDO-NPA CH3(CH2)2 H H 4.4 + 2.5 74.4 ± 9.8 Methyl-ethyl MDO-NPA CH3(CH2)2 CH3 CH3CH2 31.5 1 1.9' ND
Methyl-pentyl-MDO-NPA CH3(CH2)2 CH3 CH3(CH2)2 11.1 + 5.7 86.1 122.3 Data are mean values 1 SEM (N = 3 to 6 rats per condition) for effects of seven aporphine compounds (R = substituents, keyed to the structure above). Full chemical names for all compounds are provided in Methods.Ratings are expressed as percent of the maximum possible score (100%) = 18.0 of stereotypy (placebo-injected controis yielded scores of 4.4 1 2.5%); and as the percent of control locomotor activity (100% = 430 + 86 counts/hr). Data are provided for a dose of 40 mg/kg (i.p.), although doses of 1 and 5 mg/kg were also tested.
(*) MDO-APO yielded a significant effect (p 0.01 by t-test) to inhibit locomotor activity at 10 mg/kg i.p., but induced weak and inconsistent stereotypy (not significant statistically); the methylethyl-substituted analog of MDO-NPA had weak stereotypic activity, the onset of which was delayed about 30 min. and lasted about 60 min.
(ND = not determined
ANTI-ULCEROGENIC ACTIViTY
Cysteamine- or propionitrile-induced duodenal ulcers in the rat have been shown to be suitable models to study the pathogenesis of acute and chronic duodenal ulcer disease as well as to test antiulcer drugs for therapeutic effect. Previous structure-activity, pharmacologic and biochemical studies in these laboratories have suggested the involvement of catecholamines, especially dopamine in the pathogenesis of experimental duodenal ulcer disease in the rat. A marked change in the incidence and intensity of cysteamine-induced duodenal ulcer was demonstrated by the administration of dopamine agonists or antagonists.Dopamine agonists (e.g. bromocriptine or lergotrile) administered either as a pre- or post-treatment, decreased the intensity of the acute and chronic duodenal ulcers and diminished the output of gastric acid in rats given cysteamine or propionitrile. The chemically induced duodenal ulceration was associated with changes in the sensitivity and number of dopamine receptors in the gastric and duodenal mucosa and muscularis propria. Pharmacologica limitations of available potent dopamine receptor agonists such as apomorphine and N-n-propylaporphine (NPA) are notably, short duration of action and poor oral bioavailability. We have found that (-) 10, 11 methylenedioxy-N-n-propylnoraporphine (MDO-NPA) is a unique, orally effective, and long acting apomorphine derivative that appears to act as a pro-drug of NPA to exert activity at dopamine receptors in the brain.
In rats given cysteamine, MDO-NPA caused significant prevention of experimental duodenal ulcers. The cysteamine-induced acute duodenal ulcers were virtually abolished by MDO-NPA in a dose and time-response manner: a single high dose of either MDO-NPA or NPA was active, while a daily treatment with small quantities virtually abolished the cysteamine-induced duodenal ulcers. The dopamine antagonist (+ )-butaclamol aggravated the experimental duodenal ulcers and reversed the beneficial effect of NPA and MDO-NPA.
The dopamine agonist MDO-NPA seems to exert prominent antiduodenal ulcerogenic effect.
Its action is about 200 times more potent that the histamine H2 receptor antagonist cimetidine.
10-fold more active than other dopamine agonists (e.g., bromocriptine, lergotrile), and its potency is identical to naturally occurring prostaglandins which also inhibit this experimental duodenal ulcer. Thus, MDO-NPA is a pro-drug with oraggly effective and prolonged activity at dopamine receptors (e.g., in duodenum and/or brain). The drug or one of its analogs may also have clinical utility for the prevention and/or treatment of duodenal ulcer disease.
As shown in Tables 6 and 7 MDO-NPA administered orally reduces the incidence and intensity of duodenal ulcers and the gastric acid output.
With respect to duodenal antilucerogenic activity, the compoun (-) 10, 11-methylenedioxy- N-n-propylnoraporphine MDO-NPA was administered once daily for seven days to rats before the administration of cysteamine-hydrochloride which induces duodenal ulcers. Doses at the level of 50 or 100 microgramms per hundred grams of body weight were effective in preventing ulcers. This dosage is far less than any other known antiulcer compound which oedinarily required at leas 012 milligrams per hundred grams of body weight.
TABLE 6
Effect of MDO-NPA or NPA on cysteamine-induced duodenal ulcer in the rat
Group Pre-treatment Dose Duodenal Ulcer
Incidence Intensity
(ug/
100g) (Positive/Total) (Scale: 0-3) 1. Control - 10/12 1.8 2. 0 MDO-NPA 50 4/6 0.8 3. " 100 3/6 0.5 4. NPA 50 2/9 1.1 5. " 100 6/9 0.9
The group consisted of 3-4 Sprague-Dawley femal rats (1 60-1 80g). Each experiment was repeated at least twice and the results of those groups were pooled. The dopamine agonists were injected s.c. once daily for seven days prior to the administration of cysteamine HCI (Aldrich) 28mg/100g p.o. three times with 3 hr. intervals. The animals were killed 48 hr. after the duodenal ulcerogen.The intensity of duodenal ulcer was evaluted on a scale of 0-3, wherein 0 = no ulcer, 1 = superficial mucosal erosion, 2 = transmural necrosis, deep ulcer, 3 = perforated or penetrated duodenal ulcer. In the above table, MDO-NPA is converted in vivo to NPA, e.g. N-n-propylnorapomorphine.
TABLE 7
Effect of MDO-NPA on Cysteamine Induced Gastric Acid Output
Pretreatment (A) Initial
Output (B)1 hr 2 hr 3 hr 4 hr 187120 68117 195148 141132 110125 MDO-NPA (0-1mg/100g. 47 + 13***18 66 29 81 40 17 8* X 1 day)
MDO-NPA (0.1mg/100g. 120 + 36 29 10 66 21* 36 9* 14 6** X 1 day, 1 week)
TOTAL OUTPUT
5 hr 6 hr 7 hr (u Eq) 104 18 91 12 99 10 1043 102 MDO-NPA (0-1mg/100g. 10 3** 20+11** 18+6*** 288 67***
X 1 day)
MDO-NPA (0.1mg/100g. 17 7** 18114" 9 4*** 306162"'
X 1 day, 1 week)
(A) In addition, rats of all groups were given cysteamine HCL, 15 mg. 100 g p.o. x 1, 30 min. after (the last dose of) MDO-NPA.
(B) At the opening of gastric fistula * P < O.09; ""= P < 0.01; *** = P < 0.001
Specific Examples of Invention Example 1. Synthesis of (-) 10, II 11-Methylene-dioxy-N-n-propylnoraporphine-HCI (MDO-NPA)
A solution of (-) N-n-propylnorapormorphine-hydrochloride (NPA) (2.0g) in dimethylsulfoxide (DMSO) (16 ml) and aqueous NaOH (0.89 in 8 ml of water) was treated with methylenebromide (1.2g) under nitrogen. The resulting mixture was stirred for 4 h at 80 C, cooled and poured into ince water. The precipitate thus obtained was filtered, dried and extracted from ethyl acetate. Evaopration of the dried extract gave the crude product which was purified by column chromatography using silica gel and a mixture of ethyl acetate and methylene chloride (1:10 vols) as eluant.The free base thus obtained was converted into the hydrochloride salt with ethereal HCI to yield 0.759 of product (36%), mp 245-250"C (dec): mass spectrum, M+ 307;
22 (a) -49.55 546 (c 0.44 g in MeOH). Elemental analysis revealed: C, 99.7%; H, 103.4%; N, 97.3% of expected values calculated for C20H2,NO2. HCI. This was the compound used in the evaluation of
MDO-NPA.
Example 2. Synthesis of (-) 10, 1 1-methylenedioxy-N-n-propyinorapomorphine (MDO-NPA) from codeine
The steps of synthesis are illustrated by the following scheme showing compounds A,B,C,D,E and F:
The first step, that of N-demethylation of codeine (A) to norcodeine (B) is well known in the art and can be carried out in various ways. The procedure described by G.A. Brine. K.G. Boldt,
C. King Hart and F.I Carroll in Organic Preparations and Procedures Int. 8 (3), 103-106 (1976) can be used conveniently. It uses methyl chloroformate to form the intermediate methyl carbamate of (A) and then hydrazine to cleave the carbamate to norcodeine (B).
Alkylation of norcodeine to produce the compound C can be carried out with n-propyl
Chloride, bromide, iodine, p-toluenesulfonate etc. It can be carried in various appropriate solvents, some of them alcohols, such as methanol, ethanol, propanol, methoxyethanol, etc.
Bases can be added as acid acceptor, such as pyridine, sodium or potassium carbonate or magnesium oxide. For the purpose of illustration, n-propyl iodide is used with ethanol as solvent in presence of anhydrous potassium carbonate. The N-n-propyl derivative (C) is obtained in quantitative yield.
Rearrangement of N-n-propyl-norapocodeine can be effected by treatment with various strong acids, such as the common mineral acids; eg. sulfuric or hydrochloride acids, or with sulfonic acids, such as methanesulfonic acid or p-toluenesulfonic acid. Methanesulfonic acid used both as solvent and reagent affords a convenient mode of operating and can result in very high yields of of the derived apocodeine. The intermediate of this invention, compound D can be obtained in yields of up to 98%.
Demethylation of the compound D can be realized with the use of such reagents as 48% aqueous hydrobromic acid, hydrobromic acid in acetic acid, boron trichloride or tribromide, etc.
Best results are obtained using boron tribromide, both in higher yields (78%) and in quality of the material. Boron tribromide can be used in various solvents, but chloroform, chlorobenzene, or methylene chloride are preferred. The reaction requires only a short period of 15-60 minutes at 0, to 20"C.
The final step, that of formation of a methylene bridge between the two phenolic hydroxides can be accomplished with methylene chloride, bromide or iodide. Aprotic dipolar solvents can be employed, such as dimethylformamide, N-, ethylpyrrolidone or dimethylsulfoxide. In the example below a phase transfer method was employed, with methylene bromide in presence of alkali and with a quaternary ammonium salt as a catalyst. The method was first applied to catechois by A.P. Bashall and J.F. Collins in Tetrahedron Letters, No. 40, pp. 3489-3490 (1975). The reaction proceeds around 100"C and is complete within two hours. An 80% yield of the desired compound F is obtained.As quaternary ammonium salt can be used tetra-n-butyl ammonium bromide, benzyl-trimethylammonium bromide or a commercial mixed methyl trialkylammonium chloride, known under a trade name of Adogen 464.
In the following examples of preparation of Compounds C, D, E and F all temperatures are C (Celsius).
Compound C
A mixture of 19.3 g. (0.0678 mole) of norcodeine, 13.3 g. of n-propyl iodide (0.078 mole), 11.74 g. (0.085 mole) of anhydrous potassium carbomate and 1 50 ml. of 95% ethanol was stirred under reflux for 25 hours. Water (300 ml.) was added, the solution was extracted with four portions (150 ml; then 3 X 100 ml.) of chloroform and the extracts dried over anh.
magnesium sulfate. Evaporation to dryness gave 22.15 g. (100% yield) of N-n-propylnorcodeine as a clear oil, which gave only one spot Rf 0.7 on TCL (silica with 10:1 CHCl3/CH3OH) Compound D
N-n-propyl-norcodeine (22.15 g.; 0.0678 mole) was dissolved on warming in 1 20 ml.
methanesulfonic acid and the mixture was stirred under nitrogen at 90-95"C (internal temperature) for one hour. The solution was cooled and diluted with 320 ml. of water, then neutralized with conc. ammonium hydroxide to pH 11 with stirring and cooling. A solid precipitated which was filtered, washed with water and dried in vacuo at 40"C to constant weight. It sintered at 127"C then melted at ca 185 TLC (silica with 20:1 CH3Cl3/CH3OH) shows a green spot Rf 0.9. There was obtained 20.449. (97.8% theory).
Whenever too rapid addition of ammonia caused the precipitate to oil, the oil was extracted with chloroform and the chlorofrom was shaken with successive portions of a sodium carbonate solution until all low Rf material seen on t.l.c. plate would disappear. The hydrochloride was formed quantitatively by addition of ethereal hydrogen chloride solution to a chloroform solution by the base. It sintered at 203"C and melted at 215-22"C.
Compound E
A solution of 2.09. (0.0058 mole) of N-n-propylnor-apocodeine hydrochloride in 1 5 ml methylene chloride was added dropwise under nitrogen, to 17.4 ml of a 1 M solution of boron tribromide (0.00174 mole; three equivalents), stirred at + 5 , over a period of 10 min. The cooling was removed and stirring continued at 20 for one hr. The solution was decanted from a small amount of precipitated tar, and 3.0 ml methanol was slowly added under stirring. After 1 5 min. excess anhydrous ether was added until precipitation was complete.The mixture was kept at 0 C. for one hr., the precipitate was filtered, and dried in vacuo to constant weight, yielding N-n-propylnorapomorphine nydrobromide (1.70 g.; 78.0% theory) as colourless solid, m p. 270"C after sintering at 260"C. TLC on silica in 7:1 CHCl3/CH3OH showed only one spot at Rf 0.7.
Compound F
To a mixture of 6.9g. (0.04 mole) of dibromomethane, 5 ml water and 0.12 g. of Adogne 464 (0.00026 mole), vigorously stirred and heated under reflux under nitrogen, a solution of 10.0 g. (0.0265 mole) of N-n-propylnora-pomorphine hydrobromide in 12.5 ml. water and 7.4 g. of a 50% solution of sodium hydroxide was added slowly over a period of two hours. After the addition was complete, the reaction mixture was stirred and refluxed for a further hour. After cooling methylene chloride (10 ml) was added, the solution was dried with magnesium sulfate and adsorbed on a silica gel column. Elution with methylene chloride gave the desired product.
Ethereal hydrogen chloride was added to the main fraction of the eluant until the precipitation was complete. On drying in vacuo 8.23 g. (80.0% theory) of methylenedioxy-N-n-propylnorapomorphine hydrochloride was obtained as a colourless solid, m.p. 251-253"C.
Example 3
Synethesis of (-) 8-Nitro- 10, 1 1-methylenedioxy-N-n-propyinoraporphine -HCI (8-Nitro-MDO
NPA)
MDO-NPA (80 mg) was added in small portions to 60% (vols nitric acid (10 ml) with stirring.
After 1 5 min., a clear solution formed and was stirred overnight. The reaction mixture was neutralized with aqueous NaOH (4% w/v) and extracted from ether. The ethereal extract was washed with water, dried over CaSO4, filtered and evaporated to dryness. The free base was converted into its hydrochloride salt by adding ethereal HCI to yield 50 mg. of product (55%), m.p. 225-229 C; M+ 352, 351 (M + - 1); 323 M+ -C2H5); 277(323-NO2). Elemental analysis yielded: C, 100.3%, H,102.8%; N, 100.1% of values expected for C20H20N204.HCI.
Example 4 (-) 10, 1 1-Heptylidene-2-dioxy-N-n-propylnoraporhine-HCI (Methyl-pentyl-MDO-NPA) A mixture of NPA (1.0 g) and heptanone-2, (1.0 g) was treated with P2Os (1.0 g) at 25C and then heated to 11 0C for 2 h. The contents were cooled and left overnight at room temperature.
The solid material was added to Na2CO3 solution (10%, w/v), stirred, and extracted in ether.
The ethereal extract was dried over CaSO4, filtered and evaporated to dryness. The crude material was chromatographed using silica genl and a mixture of ether: hexane (1:2, vols) as eluant to yield 300 mg. of base product (26%). The free base was converted to the hydrochloride salt by adding ethereal HCI to an ethereal solution of the base, m.p. 120-125C.
Elemental analysis yielded: C, 100.1 % H, 103.9%; N,98.5% of values expected for C26H32NO2. HCI.
Example 5 (-) 10, 1 1-Butylidene-2-dioxy-N-n-propyinoraporphine HCI (methyl-ethyl-MDO-NPA)
This compound was similarly prepared from NPA (1.0 g) and methylethyl ketone (0.8 g) to yield 200 mg (17%) of product, m.p. 150-156 C. Elemental analysis yielded: C, 100.4%; H, 101.2%; N, 95.0% of expected values calculated for C20H20N203.HCI.
Claims (21)
1. A compound of the formula
wherein R, is lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkynyl and R2 and R3 are hydrogen, methyl, lower alkyl, substituted lower alkyl, cycloalkyl, substitued cycloalkyl, lower alkenyl, substituted lower alkenyl, phenyl lower alkenyl and phenyl lower alkynyl and pharmaceutically acceptable acid addition salts thereof.
2. (-) 10,1 1 -Methylenedioxy-N-n-propylnoraporphine and pharmaceutically acceptable acid addition salts thereof.
3. A method for providing an orally effective therapeutic form of an aporphine compound which has two hydroxy groups on adjacent positions on an aromatic nucleus and which has a therapeutic effect when administered subcutaneously or intraperitoneally, said method comprising providing said compound with a dioxy group bridging said positions, said dioxy group being characterized as being cleaved in vivo to provide the aporphine compound with the two adjacent hydroxy groups.
4. The method of Claim 3 wherein the aporphine compound has the structure
wherein R, is lower alkyl, substituted lower alkyl, cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted, lower alknyl, phenyl lower alkyl, phenyl lower alkyl, and phenyl lower alkynl and R4 is hydrogen, hydroxy, -O-Rs or -O-C-R5
0 wherein R5 is methyl and lower alkyl.
5. A method for providing an orally effective therapeutic form of a dopamine agonist compound which has two hydroxy groups on adjacent positions on an aromatic nucleus and which has dopamine agonist activity when administered subcutaneously or intraperitoneally, said method comprising providing said compound with a dioxy group bridging said position, said dioxy group being characterized as being cleaved in vivo to provide the dopamine agonist compound with the two adjacent hydroxy groups.
6. The method of Claims 3, 4 or 5 wherein the dioxy group has the following structure:
wherein R2 and R3 are hydrogen, methyl, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cyclo alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkenyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkenyl.
7. The method of Claims 3, 4 or 5 wherein the dioxy group has the following structure:
8. An orally effective therapeutic compound made by the method of Claims 3, 4, 5, 6 or 7 for use in the treatment of neurological and psychiatric disorders, and pharmaceutically acceptable acid addition salts thereof.
9. An orally effective therapeutic compound made by the method of Claims 3, 4, 5, 6 or 7 for use in the prevention and treatment of duodenal ulcers, and the pharmaceutically acceptable acid addition salts thereof.
10. An orally effective dopamine agonist made by the method of Claim 5.
11. A compound having orally effective dopamine agonist activity and characterized as having an aromatic nucleus with a dioxy group bridging two adjacent positions on the nucleus and being further characterized in that said dioxy group is cleaved in vivo to provide two adjacent hydroxy groups.
1 2. The compound of Claims 9 or 10 wherein the dioxy group has the following structure:
wherein R2 and R3 are hydrogen, methyl, lower alkyl substituted lower alkyl, cycloalkyl, substituted cyclo alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkenyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkenyl.
1 3. The compound of Claims 9 or 10 wherein the dioxy group has the following structure:
14. An orally effective therapeutic compound having the following structure:
wherein R, is lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkynyl, R2 and R3 are hydrogen, methyl, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower slkyl, phenyl lower alkenyl and phenyl lower alkynyl, R4 is hydrogen, hydroxy, -O-R5 and O-C-R5
C and R5 is methyl and lower alkyl.
1 5. The compound of Claims 1, 2, 8, 9, 10, 11, 12, 1 3 or 14 in a pharmaceutically suitable carrier.
1 6. a process for preparing a compound having the formula:
wherein R1 is alkyl of 1-6 carbon atoms; comprising N-demethylation of codeine to form norcodeine, alkylation of norcodeine to form the N-alkyl derivative, rearrangement by strong acid to form the 10-methoxy 11 -hydroxy N-alkyl norapomorphine, demethylating to form the 10, 11 dihydroxy N-alkyl norapomorphine, and forming the 10, 111 methylene dioxy bridge by reacting with methylene halide.
1 7. A process for preparing (-) 10,11 methylene-dioxy-N-propylnorapomorphine, comprising N-demethylation of codeine to form norcodeine, alkylation of the norcodeine to provide the
N-n-propyl derivative, rearragement by strong acid to form the 1 0-methoxy 11 -hydroxy N-npropyl norapomorphine, demethylating to form the 10, 1 1-dihydroxy N-alkyl-propylnorapomorphine and forming the 10,11 methylinedioxy bridge by reacting with methylene halide.
18. A compound made by the process of Claims 1 6 or 1 7.
1 9. The compound of Claim 1 5 in a pharmaceutically suitable carrier.
20. A process for preparing orally effective therapeutic compounds substantially as described herein with reference to any of the examples.
21. Orally effective therapeutic compounds substantially as described herein with reference to any of the examples.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US27477281A | 1981-06-18 | 1981-06-18 | |
US34684182A | 1982-02-08 | 1982-02-08 | |
US35891782A | 1982-03-17 | 1982-03-17 | |
US35891882A | 1982-03-17 | 1982-03-17 | |
US06/379,557 US4543256A (en) | 1982-03-17 | 1982-05-18 | (-)-10,1L Methylenedioxy-N-N-propylnoraporphine and methods employing it for inhibiting the effects of epileptic seizures and for prevention and treatment of duodenal ulcers |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2105323A true GB2105323A (en) | 1983-03-23 |
GB2105323B GB2105323B (en) | 1985-12-11 |
Family
ID=27540584
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08217644A Expired GB2105323B (en) | 1981-06-18 | 1982-06-18 | Aporphine compounds |
Country Status (8)
Country | Link |
---|---|
CA (1) | CA1270253A (en) |
DE (1) | DE3222840A1 (en) |
DK (1) | DK272182A (en) |
FR (1) | FR2508043B1 (en) |
GB (1) | GB2105323B (en) |
IE (1) | IE53161B1 (en) |
IT (1) | IT1191200B (en) |
NL (1) | NL8202467A (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990012574A1 (en) * | 1989-04-25 | 1990-11-01 | Northeastern University | Dopamine agonist compounds |
WO2000078765A2 (en) * | 1999-06-21 | 2000-12-28 | Purdue Research Foundation | CHROMENO[4,3,2-de]ISOQUINOLINES AS POTENT DOPAMINE RECEPTOR LIGANDS |
US9359303B2 (en) | 2009-04-21 | 2016-06-07 | Purdue Research Foundation | Octahydrobenzoisoquinoline modulators of dopamine receptors and uses therefor |
WO2020070099A1 (en) | 2018-10-02 | 2020-04-09 | H. Lundbeck A/S | Administration of catecholamine prodrugs in combination with a 5-ht2b antagonist |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3717643A (en) * | 1967-05-04 | 1973-02-20 | Sterling Drug Inc | N-substituted-norapomorphines |
US3810987A (en) * | 1972-06-12 | 1974-05-14 | Merck & Co Inc | Blood pressure lowering method using an aporphine |
-
1982
- 1982-06-17 NL NL8202467A patent/NL8202467A/en not_active Application Discontinuation
- 1982-06-17 CA CA000405440A patent/CA1270253A/en not_active Expired
- 1982-06-17 IE IE1441/82A patent/IE53161B1/en unknown
- 1982-06-17 DK DK272182A patent/DK272182A/en not_active Application Discontinuation
- 1982-06-17 IT IT67776/82A patent/IT1191200B/en active
- 1982-06-18 FR FR8210734A patent/FR2508043B1/en not_active Expired
- 1982-06-18 DE DE19823222840 patent/DE3222840A1/en not_active Withdrawn
- 1982-06-18 GB GB08217644A patent/GB2105323B/en not_active Expired
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990012574A1 (en) * | 1989-04-25 | 1990-11-01 | Northeastern University | Dopamine agonist compounds |
WO2000078765A2 (en) * | 1999-06-21 | 2000-12-28 | Purdue Research Foundation | CHROMENO[4,3,2-de]ISOQUINOLINES AS POTENT DOPAMINE RECEPTOR LIGANDS |
WO2000078765A3 (en) * | 1999-06-21 | 2001-06-28 | Purdue Research Foundation | CHROMENO[4,3,2-de]ISOQUINOLINES AS POTENT DOPAMINE RECEPTOR LIGANDS |
US6413977B1 (en) | 1999-06-21 | 2002-07-02 | Purdue Research Foundation | Chromeno[4,3,2-DE]isoquinolines as potent dopamine receptor ligands |
US6916832B2 (en) | 1999-06-21 | 2005-07-12 | University Of North Carolina At Chapel Hill | Chromeno[4,3,2-de]isoquinolines as potent dopamine receptor ligands |
US9359303B2 (en) | 2009-04-21 | 2016-06-07 | Purdue Research Foundation | Octahydrobenzoisoquinoline modulators of dopamine receptors and uses therefor |
WO2020070099A1 (en) | 2018-10-02 | 2020-04-09 | H. Lundbeck A/S | Administration of catecholamine prodrugs in combination with a 5-ht2b antagonist |
Also Published As
Publication number | Publication date |
---|---|
DK272182A (en) | 1982-12-19 |
FR2508043A1 (en) | 1982-12-24 |
IT1191200B (en) | 1988-02-24 |
CA1270253A (en) | 1990-06-12 |
NL8202467A (en) | 1983-01-17 |
GB2105323B (en) | 1985-12-11 |
DE3222840A1 (en) | 1983-05-05 |
FR2508043B1 (en) | 1987-04-30 |
IT8267776A0 (en) | 1982-06-17 |
IE821441L (en) | 1982-12-18 |
IE53161B1 (en) | 1988-08-03 |
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