IE53161B1 - Orally effective aporphine compounds - Google Patents
Orally effective aporphine compoundsInfo
- Publication number
- IE53161B1 IE53161B1 IE1441/82A IE144182A IE53161B1 IE 53161 B1 IE53161 B1 IE 53161B1 IE 1441/82 A IE1441/82 A IE 1441/82A IE 144182 A IE144182 A IE 144182A IE 53161 B1 IE53161 B1 IE 53161B1
- Authority
- IE
- Ireland
- Prior art keywords
- substituted
- alkyl
- phenyl
- alkenyl
- alkynyl
- Prior art date
Links
- 150000008441 aporphines Chemical class 0.000 title abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 39
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 38
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 35
- 208000000718 duodenal ulcer Diseases 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
- 230000002265 prevention Effects 0.000 claims abstract description 6
- 125000005346 substituted cycloalkyl group Chemical group 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
- -1 aporphine compound Chemical class 0.000 claims description 25
- 239000002253 acid Substances 0.000 claims description 20
- 230000001225 therapeutic effect Effects 0.000 claims description 14
- 241000790917 Dioxys <bee> Species 0.000 claims description 12
- 229950004392 norcodeine Drugs 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 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
- 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
- BZKUYNBAFQJRDM-UHFFFAOYSA-N aporphine Natural products C12=CC=CC=C2CC2N(C)CCC3=CC=CC1=C32 BZKUYNBAFQJRDM-UHFFFAOYSA-N 0.000 claims description 6
- 238000001727 in vivo Methods 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 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 claims description 5
- 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
- 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 3
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 230000001335 demethylating effect Effects 0.000 claims 2
- 230000000694 effects Effects 0.000 description 27
- 241000700159 Rattus Species 0.000 description 21
- 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 14
- 238000007912 intraperitoneal administration Methods 0.000 description 13
- 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 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 229960004046 apomorphine Drugs 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 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
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- 230000006399 behavior Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 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
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 230000006742 locomotor activity Effects 0.000 description 6
- 229960003151 mercaptamine Drugs 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 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
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 229940052760 dopamine agonists Drugs 0.000 description 4
- 230000002183 duodenal effect Effects 0.000 description 4
- 230000033001 locomotion Effects 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
- 239000000047 product Substances 0.000 description 4
- BTGAJCKRXPNBFI-UHFFFAOYSA-N propylnorapomorphine Chemical compound C1CN(CCC)C2CC3=CC=C(O)C(O)=C3C3=C2C1=CC=C3 BTGAJCKRXPNBFI-UHFFFAOYSA-N 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 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 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 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
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 210000004211 gastric acid Anatomy 0.000 description 3
- 229960003878 haloperidol Drugs 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000003786 synthesis reaction Methods 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
- 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
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 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 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- C07D491/02—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 in which the condensed system contains two hetero rings
- C07D491/06—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/18—Ring systems of four or more rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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: 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 and R5 is methyl and lower alkyl. Particularly effective are compounds wherein R4 is hydrogen.
Description
ORALLY EFFECTIVE APORPHINE COMPOUNDS
Background of Invention
Many aporphine compounds have therapeutic activity. Thus, apomorphine (APO) and N-n-propylnorapormorphine (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 cleaved 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 con v ertible to an orally effective therapeutic composition which is cleaved in vivo to release the compound with the two adjacent hydroxy groups
wherein R^ is lower alkyl,substituted lower alkyl, cycloalkyl, lower alkenyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkynyl, is hydrogen, hydroxy, -0-Rg or
-0-R5- wherein Rg is methyl, and lower alkyl.and R2 and R3 are hydrogen, methyl and Ry.
3,1 6 1
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:
Rj 0 — C \
R3 / X 0 DIOXY GROUP wherein is lower alkyl, substituted lower alkyl, cycloaikyl, substituted cycloaikyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkynyl, and Rg and Rg are hydrogen, methyl, lower alkyl, substituted lower alkyl, cycloaikyl, substituted cycloaikyl, 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.
Xn particular I have found that (-) 10, 11-methylenedioxy-N-n-propylnoraporphine is especially effective when admini5 stered 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-chain radicals, of from two to six carbon atoms, as illustrated by, but not limited to ethyl, propyl, isopropyl, 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), l-(3-methyl-2-propenyl)
1-(1,3-dimethyl-2-propenyl), or l-(2-hexenyl).
As used herein, the term lower-alkynyl means monovalent, aliphatic 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 l-(2-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, 2-methylcyclobutyl, cyclohexyl, 4-methylcyclohexyl, or cyclooctyl.
As used herein, the terms phenyl-lower-alkyl, phenyl-lower20 alkenyl, and phenyl-lower-alkynyl11 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-alkenylene radical of from two to four carbon atoms, as illustrated by, but not limited to, 1,2-ethenylene, 1,3-propenylene and 1,3-(1butenylene); or through a divalent lower-alkynylene radical of from two to four carbon atoms, as illustrated by, but not limited to
1,2-ethynylene, 1,3-propynylene, l,3-(l-butynylene), and the like. More30 over the benzene ring of such phenyl-lower-alkyl, phenyl-lower-alkenyl, and phenyl-lower-alkynyl radicals can be substituted by one or more sub6 stituents 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-mercaptopropicnic acid, malic acid, rumaric acid, succinic acid, succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid, 4-roethoxybenzoic acid, phthalic acid, anthranilic acid, 1-naphthalenedarboxylic acid, cinnamic acid, cyclohexane10 carboxylic acid, mandelic acid, tropic acid, crotonic acid, acetylene dicarboxylic acid, sorbic acid, 2-furancarboxylic acid, cholic acid, pyrenecarboxylic acid, 2-pyridinecarboxylic acid. 3-indoleacetic acid, quinic acid, sulfamic acid,· methanesulfonic acid, benzenesulfinic acid, butylarsonic acid, p-toluenesulfonic acid, benzenesulfinic acid, butylarsonic acid, diethylphosphinic acid, p-aminophenylarslnic acid, phenylstibnic acid, phenylphosphinous acid, methylphosphinic acid, phenylphosphinic acid, hydrofluoric acid, hydrochloric acid, nydrobromic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid.
phosphoric acid, hydrocyanic acid, phosphotungstic acid, roolybdic acid, phosphomolybdic acid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid, barbituric acid, boron trifluoride, and the like.
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With respect-to dopamine agonist activity, the compounds of this, invention.were tested for stereotyped gnawing behavior of rats in accordance with the techniques described in Baldessarini, R.J.., (Walton, K.G. and Borgman, R.J. 1976)
Prolonged apomorphine-like·behavioral effects of apomorphine esters,.· NeuropharmacOlogy· 15,· 471.) In some rats forebrain tissue was .assayed after administration of (-) .-10,11-Methylene· dioxy-N-n-Propylnoraporphine (MDO-NPA) for the presence.of free N-n-Propylnorapomorphine (NPA) by a sensitive and· specific high performance liquid chromatographic method with electrochemical detection tHPLC/ec) . (Westerink, -B.H.C. and .Horn, A.S. 1979’. Do neuroleptics, prevent the penetration of dopamine, agonists into the .brain? Eur. J. Pharmacol. 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 Jimoles /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 pmoles/kg, but no significant effect at lower doses. In contrast, MDO-NPA induced inhibition of locomotor activity at doses below 2 pmoles/ kg, with a maximum effect found at 0.3 jimole/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 jmole/kg, i.p. (at the same molar dose, 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 behaviors as expected of a typical DA agonist such as APO or NPA.
The duration of stereotyped behavioral effects of MDONPA exceeded that of NPA at doses above -1 pmole/kg, i.p., and
MDO-NPA showed a consistent increase in duration of action with increased dose. The duration of behavioral 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 behavioral effects after oral administration (1 to 5 mg/kg,).
Measurement of Bimogical 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 o
a.m. to -7:00 p.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. Haloperido'l was given in the same medium; 2-diethyl aminoethyl-2,2 diphenylvale^ate HCl (SKF-525A) was given in saline.
Locomotor activity was evaluated by use of a printing electronic activity mo.nitor (EAM, Stoelting Co.,
Chicago, IL) within a sound-attenuated chamber,. typically for 60 min., as described previously (Stewart, Campbell, Sperk and Baldessarini, 19.79, Psychopharmacology 60 281-289; 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, 1981a). Briefly, the ratings were as follows: 0, no stereotypy, normal locomotion; 1, discontinuous sniffing·, reduced locomotion; J2, continuous sniffing, only periodic exploration; 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; 1981b, Life Sciences 29 1341-46). 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, andiS cm above the bench, so that t-he rat 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^,
-59 sec; sec. Thus, ir a typical 60 min. session, the
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C ' maximum score was 18.0.
In all experiments except those which evaluated the time-course of drug effects’, rats were given an injection of vehicle and then allowed to rest for 15 min. to adapt to non5 specific arousal effects, prior to a second injection of test agent (or placebo) and ’immediate behavioral testing. Behavioral data were, evaluated by Student's.t- test and are always’expressed as mean + 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 behavior among MDO-NPA and other aporphines. Table 2 denotes the effects of· microsomal oxidase inhibitor on the behavioral 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 and locomotor activity.
'11
Table 1·
Route of administration and stereotyped response to MDO-NPA and other aporphines.
Agent Stereotypy Score Duration of Effect ' (min)
(1 mg/kg) P.0. S.C. I.P- P-.O. S.C. I.P. - MDO-NPA 17.0 + 1,2 17.5 + 0.4 16.5 + 0.8 112 + 20 106+ 10 116 + 12 NPA 0 17.5 + 0.8 17.5 + 1.0 0 72 + 6 '70 + 10 APO 0 17.5 + 0.4 16.5 + 2.4 0 70 + 5 72 + 12
Data are mean values + SEM for N = 6 rats per group given doses of each aporphine (1 mg/kg/ or approximately 3'umole/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 3 (out of a maximum possible score of 18).
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Table 2.
Effeces of microsomal oxidase inhibitor (S|(F-52SA) on behavioral effects of low ar.d high doses of MDO-KPA-
Dose of KDO-NPA Control SKK-525A (rag/kg) Activity Stereotypy · Activity Stereotypy 5 0 409 ± 36 0 422 ± 28 0.05 190 ± 20 • ND 425 i 40* 0.10 130 ±.30 ND 415 ± 29* 0.20 260 ± 33 ND 410 ± 32* - 0.30 435 ± 29 12.8 - 0.6 440 ±'38 1.7 0.6* 10 1.0 ND 16.5 - 0.1 ND 0.8 0.2* 3.0 ND 16.2 . 0.9 ND 0.8 0.5*
Daca are mean values ±SEh (N « 4 to 8 rats per condition). Animals vere pretreated with SKF-525A (40 mg/kg, i.p.) or its vehicle 30 min before MDO-NPA (in the doses noted, from C to 3 mg/kg,. i.p.). Activity vas 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 hy t-test between control and oxidase inhibitor-pre created rats (p < 0.01). In a control experiment, rats vere 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 vere 17.4 ±0.2 vs. 17.0 ± o.3 for controls vs. oxidase-inhibited rats, respectively, indicating no significant effect of the drug cr. actions of NPA itself.
.3 i 6 ·*
Table 3
Effects of haloperidol on stereotyped behavior induced by MDO-NPA
Kaloperidal
MDO-NPA (mg/kg)
0.3 -:--trO- 0 11.6 + 0.8 16.6 + 0.4 ·“ 0.3 0.3 + 0.2* 0.5 + 0.2* ““ 1.0 0.3 + 0.2* 1.2 + 0.4*
Haloperidol or its vehicle was given 30.rain before MDO-NPA 10 (both dissolved, ih the same citric acid-saline vehicle).
Stereotypy was rated for 60 min as described in Methods. Data are means SEM (stereotypy scores, when 18 = maximumin 1 hour) for N = 6 rats per group; (*) indicatesp
TABLE 1
Characteristics of NPA and MDO-NPA. Data are for stimulation of cAHP in rat striatal homogenates; inhibition of binding of [ N]AP0 to beef caudate synaptosomal membranes; stereotypy scores (maximum pos5 sible » 18.0); and cerebral levels of NPA by HPLC/ec; (*) p< 0.01.
Condition___X t SEM (K)
Adenylate cyclase stimulation (cAHP, pmol/assay)
Control (no addition) 2.38 1 0.14 (8)_ NPA (50 μΜ) 5.67 ± 0.28 M* MDO-NPA (100’μΜ) 2.92 ± 0.32 (4) Π 000 μΜ) 2.06 ± 0.30 (4) IC^n vs. [3H]AP0 binding (nM) NPA ' . 2.5'. ,i<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. 15.5 * 1.6 (5) Cerebral NPA (r.g/g) at 30 min after MDO-NPA (1 mg/kg) i.p. 6.0 * 0.8 (3) p.o 3.3 ’ 1.8 <3)
Table 5
Effects of analogs of MDO-NPA on stereotyped and locomotor activity „ . Substituents Stereotypy Locomotion
Compound —--=--gR1 R2 3
8-Nitro-MDO-NPA CH3(CH2)2 H
Methyl-ethyl MDO-NPA CH3{Ci.2)2 CH3 Methyl-pentyl-MDO-NPA CH3(CH;)2 CH3
H 4.4 + 2.5· -74.4 + 9.8
CH3CH2 31.5+1.9* *- ND CH3(CH2)4 11.1+ 5.7 · 86.1 + 22.3
Data are mean values + SEM (N = 3to 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 controls yielded scores pf 4.4 + 2.5%); and as the percent of control locomotor activity (100% = 430 + 8 6 counts/hr)·. Data are provided for a dose .of 10 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
(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. Pharmacologic 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, crally effective, and long acting apomorphine derivative tha.t 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 cysteamineinduced acute duodenal ulcers were virtually abolished by MDONPA in a dose and time-response manner: a single high dose of either MDO-NPA or. NEA 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 than 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 orally 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 antiulcerogenic activity, the compound {-) 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 micrograms per hundred grams of body weight were effective in preventing ulcers.
This dosage is far less than any other known antiulcer compound which ordinarily required at least 0.2 milligrams per hundred grams of body weight.
Table 6
Effect of MDO-NPA or NPA on cysteamine-induced duodenal ulcer in the rat. Group Pretreatment Dose Duodenal Ulcer (ug/ lOOg) Incidence (Positive/Total) Intensity (Scale: 0-3) 1. Control - 10/12 1.8 2. MDO-NPA 50 4/6 0.8 3. II 100 3/6 0.5 4. NPA 50 2/9 1.1 5. 11 100 6/9 0.9
The groups consisted of 3-4 Sprague-Dawley female rats (160-180g). Each experiment was repeated at least twice and the resulst of those groups were pooled.. The dopamine agonists were injected s.c. once daily for seven days prior to the administration of cysteamine HCl (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 evaluated on a scale of 0-3,' where 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, eg. N-n-propylnorapomorphine.
EFFECT OF MDO-NPA ON CYSTEAMINE INDUCED GASTRIC ACID OUTPUT
Specific Examples of Invention
Example 1. Synthesis of (-) 10, 11-Methylenedioxy-N-n-propylnoraporphine - HCl (MDO-NPA)
A solution of (-) N-n-propylnorapormorphine - hydro5 chloride (NPA) (2.0 g) in dimethyisulfoxide (DMSO) (16 ml, and aqueous NaOH (0.8 g in 8 ml of water) was treated with methy1enebromide (1.2 g) under nitrogen. The resulting mixture wi».s stirred for 4 h at 80°C, cooled and poured into ice water.
The precipitate thus obtained was filtered, dried and extractt’d
1° from ethyl acetate. Evaporation 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 HCl to yield 0.75 g of product (36%), mp 245-250 °C (dec.): mass spectrum, M+ 307;
(0)545 -49.55 (c 0.44 g in MeOH); Elemental analysis revealed:
C, 99.7%; H, 103,4%; N, ΐ7.3% of expected value’s” calculated for ^20^21^θ2* Νθ! ’ This was the compound used in the evaluation
Of MDO-NPA.
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Example 2
Synthesis of (-) 10, 11-methylenedioxy-N-n-propylnorapomor phine (MDO-NPA) .from codeine The steps of synthesis is illustrated by the following scheme showing compounds A,B,C, D. E and F;
(D) (E) (P)
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-toluene20 sulfonate.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; e.g., 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 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-methylpyrrolidone or dimethylsulfoxide. In the example below a phase transfer met od was employed, with methylene bromide in presence of alkali and with & quaternary ammonium salt as a catalyst. The method was first applied to catechols by A.P. Bashall and J.F. Collins in Tetrahedron Letters,No. 40, pp. 3489-3490 (1975). The reaction proceeds around lOO^cand is complete within two hours. An 80% yield of the desired compound F is obtained. As quaternary . 23 ammonium salt can be used tetra-n-butylammonium bromide, benzy1trimethylammonium 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, 5 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 npropyl iodide (0.078 mole), 11.74 g. (0.085 mole) of anhydrous potassium carbomate and 150 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 Rf0.7 on
TCL (silica with 10:1 CHCiyCH^H) .
Compound D
N-n-propyl-norcodeine (22.15 g.; 0.0678 mole) was dissolved on warming in 120 ml. methanesulfonic acid and the mixture was stirred under nitrogen at 90 - 95° (internal temperature) for one hour. The solution was cooled and diluted with 320 ml. of water, then neutralized with cone, ammonium hydroxide to pH 11 with stirring and cooling. A solid precipitated which was filtered, washed with water and dried in vacuo at 400 to constant weight. It sintered at 127° then melted at ca 18^ TLC (silica with 20:1
CHjClj/CHjOH) shows a green spot Rf 0.9. There was obtained 20.44g. (97.8% theory).
Whenever too rapid addition of ammonia caused the precipitate to oil, the oil was extracted with chloroform and the chloroform 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 of the base.
It sintered at 203° and melted at 215-220 .
Compound Ε
A solution of 2.0 g. (0.0058 mole) of N-n-propylnorapocodeine hydrochloride in 15 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 15 min. excess anhydrous ether was added until pre10 cipitation was complete. The mixture was kept at 0* for one hr., the precipitate was filtered, and dried in vacuo to constant weight, yielding N-n-propylnorapomorphine hydrobromide (1.70 g.; 78.0% theory) as colourless solid, m.p. 270° after sintering at 260° . TLC on silica in 7;1 CHC13/CH3OH showed only one spot at
Rf 0.7.
Compound F
To a mixture of 6.9 g. (0.04 mole) of dibromomethane, 5 ml. water and 0.12 g. of ^dogne 454 (¢.00026 mole), vigorously stirred and heated under reflux under nitrogen, a solution of 10.0 g. (0.0265 mole) of N-n-propylnorapomorphine 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° .
3161
Example 3 (-) 10,ll-Heptylidene-2-dioxy-N-n-propylporaporphineHC1 (Methyl-pentyl-MDO-NPA
A mixture of NPA (1.0 g) and heptanone-2 (1.0 g) was treated with P2°5 & at C and then heated to· 110 C for 2 h. The contents were cooled and left overnight at room temperature. The solid material was added to Na2C0j solution (10%, w/v), stirred, and extracted in ether. The ethereal extract was dried over CaSO^, filtered and evaporated to dryness.
1° The crude material was chromatographed using silica gel 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 HCl to an ethereal solution of the base, m.p. 120-125 C. Elemental analysis yielded: C,
100.1% H, 103.9%; Nt, 98.5% of values expected for CjgH^NOj.HCl.
Example 4 (-) 10, H-Butylidene-2-dioxy-N-n-propylnoraporphine . HCl 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 C20H20N2°3’HC1·
Claims (15)
- An orally effective therapeutic compound of the formula wherein R^ is lower alkyl, substituted lower alkyl, cycloaikyl, 5 substituted cycloaikyl, lower alkenyl, substituted lower alkenyl, lower alkypyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkynyl and R 2 and Rg are hydrogen, methyl, lower alkyl, substituted lower alkyl, cycloaikyl, substituted cycloaikyl, lower alkenyl, substituted lower 10 alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkynyl and pharmaceutically acceptable acid addition salts thereof.
- 2. (-) 10,11-Methylenedioxy-N-n-propylnoraporphine and pharmaceutically acceptable acid addition salts thereof. 15
- 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 20 positions, said dioxy group being characterised 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, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alky, phenyl 5. Lower alkenyl and phenyl lower alkynyl and R4 is hydrogen, hydroxy -O-R5 or -Ο-C-Rg wherein Rg is methyl or lower alkyl.
- 5. The method of claim 3 or claim 4 wherein the dioxy group has the following structure: ./ o10 /\ 0wherein Rg and Rg are hydrogen, methyl, lower alkyl, substituted loweralkyl, cycloalkyl, substituted cyclo alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkynyl. 15 6. The method of claim 3 or claim 4 wherein the dioxy group has the following structure 0ch 2 ^07. An orally effective therapeutic compound made by the method of claims 3, 4, 5 or 6 for use in the treatment of neurological and psychiatric disorders, and pharmaceutically acceptable acid addition salts thereof. §3161
- 6. 8. An orally effective therapeutic compound made by the method of claims 3, 4, 5 or 6 for use in the prevention and treatment of duodenal ulcers, and the pharmaceutically acceptable acid addition salt thereof. 5
- 7. 9. The compound of claim 8 wherein the dioxy group has the following structure 010 wherein R 2 and Rj are hydrogen, methyl, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cyclo alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkynyl.
- 8. 10. The compound of claim 8 wherein the dioxy group has the following structure ^.0ch 2 15
- 9. 11. An orally effective therapeutic compound having the following structure wherein R ] is lower alkyl, substituted lower alkyl, cycloaikyl, substituted cycloaikyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenyl lower alkyl, phenyl lower alkenyl and phenyl lower alkynyl, 5 R 2 and R 3 are hydrogen, methyl, lower alkyl, substituted lower alkyl, cycloaikyl, substituted cycloaikyl, 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-Rg and O-C-Rg and 10 Rg is methyl and lower alkyl.
- 10. 12. The compound of claim 1, 2, 7, 8, 9, 10 or 11, in a pharmaceutically suitable carrier.
- 11. 13. A process for preparing a compound having the formula: wherein R ] 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 Π-hydroxy N-alkyl norapomorphine, demethylating to form the 20 10,11 dihydroxy N-alkyl norapomorphine, and forming the 10,11 methylene dioxy bridge by reacting the methylene halide.
- 12. 14. A process for preparing (-) 10,11 methylenedioxy-Npropylnorapomorphine, comprising N-demethylation of codeine to form norcodeine, alkylation of the norcodeine to provide the N-n-propyl derivative, rearrangement by strong acid to form the 5 10-methoxy Π-hydroxy N-n-propyl norapomorphine, demethylating to form the 10,11-dihydroxy N-alkyl-propylnorapomorphine and forming the 10,11 methylinedioxy bridge by reacting the methylene halide.
- 13. 15. A compound made by the process of claim 13 or 14. 10
- 14. 16. The compound of claim T5 in a pharmaceutically suitable carrier.
- 15. 17. A process for preparing orally effective therapeutic compounds substantially as described herein with reference to any of the examples. 15 18. Orally effective therapeutic compounds substantially as described herewith 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 |
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IE821441L IE821441L (en) | 1982-12-18 |
IE53161B1 true IE53161B1 (en) | 1988-08-03 |
Family
ID=27540584
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE1441/82A IE53161B1 (en) | 1981-06-18 | 1982-06-17 | Orally effective aporphine compounds |
Country Status (8)
Country | Link |
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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) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1990012574A1 (en) * | 1989-04-25 | 1990-11-01 | Northeastern University | Dopamine agonist compounds |
AU4536599A (en) | 1999-06-21 | 2001-01-09 | Geochemistry Research Limited | Metal-rich silica products from geothermal and synthetic aqueous systems nen wie |
EP2421862B1 (en) | 2009-04-21 | 2014-06-11 | 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 |
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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 DK DK272182A patent/DK272182A/en not_active Application Discontinuation
- 1982-06-17 CA CA000405440A patent/CA1270253A/en not_active Expired
- 1982-06-17 IT IT67776/82A patent/IT1191200B/en active
- 1982-06-17 IE IE1441/82A patent/IE53161B1/en unknown
- 1982-06-18 FR FR8210734A patent/FR2508043B1/en not_active Expired
- 1982-06-18 GB GB08217644A patent/GB2105323B/en not_active Expired
- 1982-06-18 DE DE19823222840 patent/DE3222840A1/en not_active Withdrawn
Also Published As
Publication number | Publication date |
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DE3222840A1 (en) | 1983-05-05 |
NL8202467A (en) | 1983-01-17 |
IE821441L (en) | 1982-12-18 |
FR2508043A1 (en) | 1982-12-24 |
IT1191200B (en) | 1988-02-24 |
IT8267776A0 (en) | 1982-06-17 |
CA1270253A (en) | 1990-06-12 |
GB2105323B (en) | 1985-12-11 |
FR2508043B1 (en) | 1987-04-30 |
DK272182A (en) | 1982-12-19 |
GB2105323A (en) | 1983-03-23 |
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