NO314081B1 - Substituerte isokinolin-derivater og deres anvendelse og fremstilling, samtfarmasöytiske preparater inneholdende forbindelsene - Google Patents
Substituerte isokinolin-derivater og deres anvendelse og fremstilling, samtfarmasöytiske preparater inneholdende forbindelsene Download PDFInfo
- Publication number
- NO314081B1 NO314081B1 NO19994510A NO994510A NO314081B1 NO 314081 B1 NO314081 B1 NO 314081B1 NO 19994510 A NO19994510 A NO 19994510A NO 994510 A NO994510 A NO 994510A NO 314081 B1 NO314081 B1 NO 314081B1
- Authority
- NO
- Norway
- Prior art keywords
- tetrahydroisoquinolin
- methyl
- bromo
- nmr
- iso
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 142
- 238000002360 preparation method Methods 0.000 title claims description 35
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 4
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title 1
- -1 C-1-C6-alkoxy Chemical group 0.000 claims description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 33
- 238000004519 manufacturing process Methods 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 208000035475 disorder Diseases 0.000 claims description 14
- 239000012458 free base Substances 0.000 claims description 14
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
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- VOSHURDHUZSVNH-UHFFFAOYSA-N 3-bromo-n-(5-chloro-2-methyl-3,4-dihydro-1h-isoquinolin-7-yl)-4-ethoxybenzamide Chemical compound C1=C(Br)C(OCC)=CC=C1C(=O)NC1=CC(Cl)=C(CCN(C)C2)C2=C1 VOSHURDHUZSVNH-UHFFFAOYSA-N 0.000 claims description 3
- PMTOIIMQZMMEPR-UHFFFAOYSA-N 3-chloro-n-(2-methyl-3,4-dihydro-1h-isoquinolin-7-yl)benzamide Chemical compound C1=C2CN(C)CCC2=CC=C1NC(=O)C1=CC=CC(Cl)=C1 PMTOIIMQZMMEPR-UHFFFAOYSA-N 0.000 claims description 3
- VLJGTIAWOFBIRR-UHFFFAOYSA-N 5-benzoyl-n-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxybenzamide Chemical compound C1=C(C(=O)NC=2C=C3CNCCC3=C(I)C=2)C(OC)=CC=C1C(=O)C1=CC=CC=C1 VLJGTIAWOFBIRR-UHFFFAOYSA-N 0.000 claims description 3
- PMRSETIJSQHJTO-UHFFFAOYSA-N 5-benzoyl-n-(7-iodo-2-methyl-3,4-dihydro-1h-isoquinolin-5-yl)-2-methoxybenzamide Chemical compound C1=C(C(=O)NC=2C=3CCN(C)CC=3C=C(I)C=2)C(OC)=CC=C1C(=O)C1=CC=CC=C1 PMRSETIJSQHJTO-UHFFFAOYSA-N 0.000 claims description 3
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
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- KFNMVJFJHCQFAI-UHFFFAOYSA-N 3-cyano-4-ethoxy-n-(2-methyl-3,4-dihydro-1h-isoquinolin-7-yl)benzamide Chemical compound C1=C(C#N)C(OCC)=CC=C1C(=O)NC1=CC=C(CCN(C)C2)C2=C1 KFNMVJFJHCQFAI-UHFFFAOYSA-N 0.000 claims description 2
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- ALSCJJJLXIVYAR-UHFFFAOYSA-N 4-fluoro-3-methyl-n-(2-methyl-3,4-dihydro-1h-isoquinolin-7-yl)benzamide;hydrochloride Chemical compound Cl.C1=C2CN(C)CCC2=CC=C1NC(=O)C1=CC=C(F)C(C)=C1 ALSCJJJLXIVYAR-UHFFFAOYSA-N 0.000 claims description 2
- VIDPFUAQNRZKEX-UHFFFAOYSA-N 4-hydroxy-n-(2-methyl-3,4-dihydro-1h-isoquinolin-7-yl)-3-(trifluoromethyl)benzamide Chemical compound C1=C2CN(C)CCC2=CC=C1NC(=O)C1=CC=C(O)C(C(F)(F)F)=C1 VIDPFUAQNRZKEX-UHFFFAOYSA-N 0.000 claims description 2
- LRBSCNASLDWCOR-UHFFFAOYSA-N 5-benzoyl-n-(7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxybenzamide Chemical compound C1=C(C(=O)NC=2C=3CCNCC=3C=C(I)C=2)C(OC)=CC=C1C(=O)C1=CC=CC=C1 LRBSCNASLDWCOR-UHFFFAOYSA-N 0.000 claims description 2
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- MNRSUGVCPQRZPE-UHFFFAOYSA-N [4-[(2-methyl-3,4-dihydro-1h-isoquinolin-7-yl)carbamoyl]phenyl] acetate Chemical compound C1=C2CN(C)CCC2=CC=C1NC(=O)C1=CC=C(OC(C)=O)C=C1 MNRSUGVCPQRZPE-UHFFFAOYSA-N 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
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- KYXSVGVQGFPNRQ-UHFFFAOYSA-N 2-methyl-1,2,3,4-tetrahydroisoqioniline Natural products C1=CC=C2CN(C)CCC2=C1 KYXSVGVQGFPNRQ-UHFFFAOYSA-N 0.000 claims 1
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- 235000013772 propylene glycol Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003653 radioligand binding assay Methods 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008221 sterile excipient Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical class OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
Classifications
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- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Description
Foreliggende oppfinnelse angår nye forbindelser, fremgangsmåter for fremstilling av dem og anvendelse av dem til fremstilling av terapeutiske midler, samt farmasøytiske preparater inneholdende dem.
W097/48683 (SmithKline Beecham), upublisert på innleveringsdatoen for denne søknaden, beskriver tetrahydroisokinolinyl-benzamider hvor benzamidgruppen har en 2-alkoksy-substituent, omfattende forbindelsene: N-(7-jod-2-metyl-1,2,3,4-tetrahydroisokinolin-5-yl)-5-benzoyl-2-metoksybenzamid, N-(y<->jod-I^.S^-tetrahydroisokinolin-S-yO-S-benzoyl^-metoksybenzamid, N-(5-jod-1,2,3,4-tetrahydroisokinolin-7-yl)-5-benzoyl-2-metoksybenzamid, N-(5-jod-I^.S^-tetrahydroisokinolin-y-yl^-metoksy^-trifluormetyldiazirinylbenzamid, N-tS-jod-I^.S^-tetrahydroisokinolin-y<->ylJ^-metoksy-S-trifluormetyldiazirinyl-benzamid, N-tT-jod-I^S^-tetrahydroisokinolin-S-yl^-metoksy-S-trifluormetyldiazirinyl-benzamid og N-(8-fluor-2-metyl-1,2,3,4-tetrahydroisokinolin-5-yl)-4-Nbutyl-2-metoksybenzamid.
Det er nå overraskende funnet at karboksamid-forbindelsene med formel (I) nedenfor har antikonvulsiv aktivitet og er derfor antatt å være nyttige ved behandling og/eller forebygging av angst, mani, depresjon, paniske lidelser og/eller aggresjon, lidelser forbundet med subarachnoidal blødning eller nervesjokk, effektene forbundet med avvenning fra misbruk av stoffer så som kokain, nikotin, alkohol og benzodiazepiner, lidelser som kan behandles og/eller forhindres med antikonvulsive midler, så som epilepsi omfattende post-traumatisk epilepsi, Parkinson's sykdom, psykose, migrene, cerebral ischemi, Alzheimers sykdom og andre degenerative sykdommer så som Huntingdon's chorea, schizofreni, obsessive kompulsive lidelser (OCD), nevrologiske defekter forbundet med AIDS, søvnforstyrrelser (omfattende døgnrytmeforstyrrelser, søvnløshet & narkolepsi), tics (f.eks. Giles de la Tourette's syndrom), traumatisk hjerneskade, tinnitus, nevralgi, spesielt trigeminusnevralgi, nevropatisk smerte, dental smerte, kreftsmerte, upassende nevronal aktivitet som resulterer i nevrodystesi ved sykdommer så som diabetes, multippel sklerose (MS) og motorisk nevron-sykdom, ataksi, muskelstivhet (spastisitet), temporomandibulær ledd-dysfunksjon og amyotrofisk lateralsklerose (ALS).
Følgelig tilveiebringer foreliggende oppfinnelse en forbindelse med formel (I) eller et farmasøytisk godtagbart salt derav:
hvor Q er fenyl, tiofenyl, naftyl, tienyt, benzotriazolyl, benztiazolyl,
benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, pyrazolyl, tiazolyl, isoksazolyl, oksokromanyl eller indolyl,
R<1>er hydrogen eller Ci^ alkyl eventuelt substituert med hydroksy, Ci-Ce-alkoksy, eller formyl,
R<2>er hydrogen, hydroksy eller opptil tre substituenter valgt fra halogen, NO2, CN, N3, CF3O-, CF3S-, CF3CO-, C^alkyl, C^perfluoralkyl, C-j.
galkylO-, C^galkylCO-, C3_6cykloalkylO-, C3_6cykloalkyl-C-|^alkylO-,
acetoksy, fenyl, fenoksy, fenylmetoksy, C^galkylS-, C-^alkylSC^-; og X er hydrogen, halogen eller trifluoracetylamino;
men når X er hydrogen utelukkes forbindelsen 7-(3,4,5-trimetoksybenzamido)-2-metyl-1,2,3,4-tetrahydroisokinolin, forbindelser hvor R2 er 2-alkoksy og når X er halogen utelukkes forbindelsene N-(7-jod-2-metyl-1,2,3,4-tetrahydroisokinolin-5-yl)-5-benzoyl-2-metoksybenzamid, N-(7-jod-1,2,3,4-tetrahydroisokinolin-5-yl)-5-benzoyl-2-metoksybenzamid, N-(5-jod-1,2,3,4-tetrahydroisokinolin-7-yl)-5-benzoyl-2-metoksybenzamid, N-(5-jod-1,2,3,4-tetrahydroisokinolin-7-yl)-2-metoksy-4-trifluormetyldiazirinylbenzamid, N-(5-jod-1,2,3,4-tetrahydroisokinolin-7-yl)-2-metoksy-5-trifluormetyldiazirinylbenzamid, N-(7-jod-1,2,3,4-tetrahydroisokinolin-5-yl)-2-metoksy-5-trifluormetyldiazirinyl-benzamid og N-(8-fluor-2-metyl-1,2,3,4-tetrahydroisokinolin-5-yl)-4-r-butyl-2-metoksybenzamid.
Forbindelsene ifølge foreliggende oppfinnelse er typisk, (tetrahydroisokinolin-7-yl)-karboksamider, spesielt (tetrahydroisokinolin-7-yl)benzamider. Når substituenten X ikke er hydrogen kan den være i 5-, 6- eller 8-stilling av tetrahydroisokinolin-gruppen, spesielt stilling 5.
Ringsystemet Q er typisk eventuelt substituert fenyl eller eventuelt substituert heteroaryl, typisk tiofenyl eller 3-isoksazolyl. Når to R<2>grupper danner en karbocyklisk ring, er denne typisk en 5-7-leddet ring og Q kan være et naftalen- eller et indan- eller indanon-ringsystem eller bicyklisk heteroaryl så som 5-dihydrobenzofuranyl.
I formel (I) kan alkylgrupper, omfattende alkylgrupper som er del av andre grupper, så som alkoksy eller acyl, være lineære eller forgrenede. Egnede C3_6cykloalkylgrupper omfatter cyklopropyl, cyklobutyl, cyklopentyl og cykloheksyl. Egnede halogen-substituenter omfatter fluor, klor, jod og brom.
En egnet gruppe av forbindelser ifølge foreliggende oppfinnelse har formel (IA)
og en annen egnet gruppe har formel (IB)
hvori R<1>, R<2>og X er som definert ovenfor.
Eksempler på foretrukne forbindelser med formel (I) er: N-(1l2,3,4-tetrahydroisokinolin-7-yl)-5-klortiofen-2-karboksamid N-(2-metyl-1, 2, 3, 4-tetrahydroisokinolin-7-yl)-5-klortiofen-2-karboksamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)benzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-klorbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-f-butylbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-/so-propoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-fenoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-nitrobenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-ylH-fenylbenzamid N-{2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-metylbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-fluorbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-cyanobenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3p4-diklorbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-jodbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-brombenzamid N-(2-metyl-1,2l3,4-tetrahydroisokinolin-7-yl)-4-rnetylbenzamid N-(2-metyl-1,2,3l4-tetrahydroisokinolin-7-yl)-3-nitrobenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-etoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-n-butylbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-2-acetoksybenzamid N-(2-metyl-112,3,4-tetrahydroisokinolin-7-yl)-3-trifluormetylbenzamid N-(2-metyl-1l2,3,4-tetrahydroisokinolfn-7-yl)-2,4-difluorbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3,4-dimetoksybenzamid N-{2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-2-fluor-4-trifluqrmetylbenzam N-(2-metyl-1,2l3l4-tetrahydroisokinolin-7-yl)-4-klor-3-nitrobenzamid N-^-metyM^.S^-tetrahydroisoki^ N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-2,4-diklor-5-fluorbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-fluor-54rifluormet<y>lbenzarnid N-(2-metyl-1,2I3,4-tetrahydroisokinolin-7-yl)-3-brom-4-rnetoksybenzamid N-(2-metyl-112,3,4-tetrahydroisokinolin-7-yl)-3,4,5-trimetoksybenzamid N-(2-metyl-1,2,3l4-tetrahydroisokinolin-7-yl)-4-trifluormetoksybenzamid N-(2-metyl-1l2,3,4-tetrahydroisokinolin-7-yl)-3-pivaloylbenzamid N-(2-metyl-1p2,3l4-tetrahydroisokinolin-7-yl)-3-brom-4-/so-propoksybenzamid N^-metyl-I^.S^-tetrahydroisokinolin^-ylJ^-acetoksybenzamid N-(2-metyl-1,2,3l4-tetrahydroisokinolin-7-ylH-cyklopentyloksybenzamid N-(2-metyl-1,2I3,4-tetrahydroisokinolin-7-yl)-4icyklopropylmetoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3<yano-4-metoksybenzamid N-(2-metyl-1,2,3l4-tetrahydroisokinolin-7-yl)-2-naftamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-metylbenzamid N-(2-metyl-1p2,3,4-tetrahydroisokinolin-7-yl)-naftalen-1-karboksamid N-(2-metyl-1,2l3,4-tetrahydroisokinolin-7-yl)-3-klor-4-metoksybenzamid N-(2-metyl-1,2,314-tetrahydroisokinolin-7-yl)-4-fetr-butoksybenzamid N-C2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-/i-propoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl) benzotriazol-5-karboksamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)benzotiazol-6-karboksamid N-(2-metyl-112,3,4-tetrahydroisokinolin-7-yl)-2,3-dihydrobenzofuran-5-karboksamid N-(2-metyl-1,2l3l4-tetrahydroisokinolin-7-yl)-2-metylbenzimidazol-5-karboksamid N^-metyl-l^^^-tetrahydroisokinolin^-ylJ-S-klor^-zso-propoksybenzamid N-(2-metyl-1,2I3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-klor-4-etoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metoksy-3-trifluormetylbenzam N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3,5-diklor-4-metoksybenzamid N-(2-metyl)-1l2,3l4-tetrahydroisokinolin-7-yl)-3,5Hdiklor-4-etoksybenzamid N-(2-metyl)-1l2,3,4-tetrahydroisokinolin-7-yl)-3l5-diklor-4-/s(>propoksybenzamid N-(2-metyl-1,2,3l4-tetrahydroisokinolin-7-yl)-3-metylsulfonylbenzarnid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-fef^butylbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-2-brom-5-metoksybenzamid N-(2-metyf-1,2,3,4-tetrahydroisokinolin-7-yl)-4-fluor-3-metoksybenzamid-hydroklorid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yt)-1-metylpyrazol-4-karboksamid N-(2-metyl-1l21314-tetrahydroisokinolin-7-yl)-4-trifluormetylpyrazol-3-karboksamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yt)-2-metyltiazot-4-karboksamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-5-metylisoksazol-3-karboksamid N-(2-metyl-1l2l3,4-tetrahydroisokinolin-7-yl)-5-fetr-butylisoksazol-3-karboksamid N-(2-metyl-1,2l3l4-tetrahydroisokinolin-7-yl)-3-metoksyisoksazol-5-karboksamid-hydroklorid
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yt)indol-2-karboksamid. N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4w'so-propylbenzamid-hydroklorid
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-cyano-4-/so-propylbenzamid-hydroklorid
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-fluor-4-metoksybenzamid N-(2-metyl-1,2,3,4-tetrahydrotsokinolin-7-yl)-3-cyano-4-/7-propoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-cyano-4-etoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-n-propoksybenzamid N-{2-metyl-i,213)4-tetrahydroisokinolin-7-yl)-3-brom-4-etylbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-jod-4-metoksybenzarnid N-(2-metyl-1l2,3,4-tetrahydroisokinolin-7-yl)-4-/so-propoksy-3-trifluorme1yl-benzamid N-(2-metyl-1,2l3,4-tetrahydroisokinolin-7-yl)-4-klor-3-rnetoksybenzamid N-(2-metyl-1,2l3l4-tetrahydroisokinolin-7-yl)-4-n-propoksy-3-trifluormetyl-benzamtd
N-(2-metyl-1l2l3,4-tetrahydroisokinolin-7-yl)-3-klor-4-fefr-butylbenzarriid-hydroklorid
N-(2-metyl-1l2,3,4-tetrahydroisokinolin-7-yl)-4-metoksybenzamid-hydroklorid. N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)^-fluor-3-met<y>lbenzarnid-hydroklorid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-klor-4-/so-propylbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-cyano-4-etylbenzamid-hydroklorid N-(2-metyl-1,2,3,4-tetrahydroisokino!in-7-yl)-4-/so-propyl-3-trifluormetyl-benzamid-hydroklorid
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-etyl-3-trifluormetylbenzamid-hydroklorid
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-cyanc^-/so-propoksybenzamid-hydroklorid
N-tl^.S^-tetrahydroisokinolin^-ylH-metoksy-S-trifluormetylbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metyl-3-metylsuffonyl-benzam N-(2-metyl-1,2p3,4-tetrahydroisokinolin-7-yl)-4-etyl-3-metylsulfonylbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-metylsulfonyl-4-/so-propylbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-metylsulfonyl-4-metoksybenzam N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-trifluoracetylbenzamid-hyd N-(2-metyl-1,2,3,4-tetrahydroisokinoIin-7-yl)-4-metoksy-3-pentafluoretyl-benzamid-hydroklorid N-(2-n-porpyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid N-(2-rj-propyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metoksy-3-trifluormetylbenzamid
N-(2-n-propyl-1,2,3,4-tetrahydroiskinolin-7-yl)-3-klor^-/so-propoksybenzamid
N-(2-metyl-1,2,3,4-tetrahydro hydroklorid
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4w'so-butyl-3-trifluormetyl-benza hydroklorid
N-(2-etyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid N-(2-etyl-1,2,3,4-tetrahydro-isokinolin-7-yl)-4-metoksy-3-trifluormetyl-benzamid N-(2-/so-propyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid N-(2-/so-propyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metoksy-3-trifluorrTietyl-benzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-etoksy-3-metylsulfonyl-benzamid N-(2-metyl-1,2,3l4-tetrahydroisokinolin-7-yl)-4-oksochroman-6-karboksamid-hydroklorid N-(2-formyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metoksy-3-trifluormetylbenzamid N-{2-hydroksyetyH,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid N-(2-hydroksyetyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etylbenzamid N-{2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-fenylmetoksy-3-trifluormetyl-benzamid N-(2-metyl-112,3,4-tetrahydroisokinolin-7-yl)-4-hydroksy-3-trifluormetyl-benzamid N-(2-metoksyetyl-1,2,3l4-tetrahydroisokinolin-7-yl)-3-brom-4-/so-propoksybenzamid
N-(2-metoksyetyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-klor-4-/so-propoksybenzamid
N-(2-metoksyetyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metoksy-3-trifluormetylbenzamid
N-tS-jod-I^.S^-tetrahydroisokinolin^-yO^-azidobenzamid-trifluoracetat N-(2-metyl-5-trifluoracetylamino-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-metoksybenzamid
N-{2-metyl-5-klor-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid N-{2-metyl-5-klor-112,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etylbenzamid
Når de syntetiseres foreligger disse forbindelsene ofte i saltform, så som hydrokloridet eller trifluoracetatet, og slike salter utgjør også del av foreliggende oppfinnelse. Slike salter kan anvendes for fremstilling av farmasøytisk godtagbare salter. Forbindelsene og deres salter kan oppnås som solvater, så som hydrater og disse utgjør også del av foreliggende oppfinnelse.
Forbindelsene ovenfor og farmasøytisk godtagbare salter derav, spesielt hydrokloridét og farmasøytisk godtagbare solvater, spesielt hydrater, utgjør et foretrukket aspekt ved foreliggende oppfinnelse.
Administreringen av slike forbindelser til et pattedyr kan gjøres ved oral, parenteral, sub-lingval, nasal, rektal, topisk eller transdermal administrering.
Mengden som er effektiv for å behandle lidelsene beskrevet ovenfor avhenger av de vanlige faktorer så som typen og alvorlighetsgraden av lidelsene som behandles og vekten til pattedyret. Imidlertid vil en enhetsdose normalt inneholde 1 til 1000 mg, hensiktsmessig 1 til 500 mg, for eksempel en mengde i området fra 2 til 400 mg så som 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 og 400 mg av den aktive forbindelse. Enhetsdoser vil normalt administreres én gang eller mer enn én gang pr. dag, for eksempel 1, 2, 3, 4, 5 eller 6 ganger pr. dag, mer vanlig 1 til 4 ganger pr. dag, slik at den totale daglige dose for en voksen på 70 kg normalt er i området 1 til 1000 mg, for eksempel 1 til 500 mg, dvs. i området omtrent 0,01 til 15 mg/kg/dag, mer vanlig 0,1 til 6 mg/kg/dag, for eksempel 1 til 6 mg/kg/dag.
Det er sterkt foretrukket at forbindelsen med formel (I) blir administrert i form av et enhetsdose-preparat, så som enhetsdose av et oralt, omfattende sub-lingvalt, rektalt, topisk eller parenteralt (spesielt intravenøst) preparat.
Slike preparater blir fremstilt ved blanding og blir hensiktsmessig tilpasset for oral eller parenteral administrering og kan som sådanne være i form av tabletter, kapsler, orale flytende preparater, pulvere, granuler, pastiller, rekonstituerbare pulvere, injiserbare og infuserbare løsninger eller suspensjoner eller suppositorier. Oralt administrerbare preparater er foretrukket, spesielt formede orale preparater, siden de er mer hensiktsmessige for generell anvendelse.
Tabletter og kapsler for oral administrering blir vanligvis presentert i en enhetsdose og inneholder konvensjonelle tilsetningsmidlerså som bindemidler, fyllmidler, fortynningsmidler, tabletteringsmidler, smøremidler, desinteg<p>eringsmidler, farvemidler, smakstilsetninger og fuktemidler. Tabletten kan belegges i henhold til velkjente metoder på området.
Egnede fyllmidler for anvendelse omfatter cellulose, mannitol, laktose og andre lignende midler. Egnede desintegreringsmidler omfatter stivelse, polyvinylpyrrolidon og stivelses-derivater så som natrium-stivelse-glykollat. Egnede smøremidler omfatter for eksempel magnesiumstearat. Egnede farmasøytisk godtagbare fuktemidler omfatter natriumlaurylsulfat.
Disse faste orale preparater kan fremstilles ved konvensjonelle metoder som blanding, fylling, tablettering eller lignende. Gjentatte blande-operasjoner kan anvendes for å fordele det aktive middel godt i de preparater hvor det anvendes store mengder fyllmidler. Slike operasjoner er selvfølgelig konvensjonelle på området.
Orale flytende preparater kan foreligge i form av for eksempel vandige eller oljeaktige suspensjoner, løsninger, emulsjoner, siruper eller eliksirer eller kan presenteres som et tørt produkt for rekonstituering med vann eller annen egnet konstituent før anvendelse. Slike flytende preparater kan inneholde konvensjonelle additiver så som suspenderingsmidler, for eksempel sorbitol, sirup, metylcellulose, gelatin, hydroksyetylcellulose, karboksymetylceilulose, aluminiumstearatgel eller hydrogenerte spiselige fett, emulgeringsmidler, for eksempel lecitin, sorbitan-monooleat eller akasie; ikke-vandige konstituenter (som kan omfatte spiselige oljer), for eksempel mandelolje, fraksjonert kokosnøttolje, oljeaktig estere så som estere av glycerin, propylenglykol eller etylalkohol; konserveringsmidler, for eksempel metyl- eller propyl-p-hydroksybenzoat eller sorbinsyre og om ønsket konvensjonelle smakstilsetninger eller farvemidler. Orale preparater omfatter også konvensjonelle preparater med forsinket frigjøring, så som tabletter eller granuler som har et enterisk belegg.
For parenteral administrering blir flytende enhetsdose-former fremstilt inneholdende forbindelsen og en steril bærer. Forbindelsen, avhengig av konstituenten og konsentrasjonen, kan være enten suspendert eller oppløst. Parenterale løsninger blir normalt fremstilt ved oppløsning av forbindelsen i en konstituent og filter-sterilising før fylling i et egnet medisinglass eller ampulle og forsegling. Fordelaktig blir tilsetningsmidler så som et lokålbedøvelsesmiddel, konserveringsmidler og buffermidler også oppløst i konstituenten. For å forbedre stabiliteten kan preparatet fryses etter fylling i medisinglasset og vannet fjernes under vakuum.
Parenterale suspensjoner blir fremstilt på i det vesentlige samme måte, bortsett fra at forbindelsen blir suspendert i konstituenten istedenfor å bli oppløst og sterilisert ved å bli utsatt for etylenoksyd før suspendering i den sterile konstituent. Fordelaktig blir et overflateaktivt middel eller fuktemiddel inkludert i preparatet for å lette jevn fordeling av forbindelsen ifølge foreliggende oppfinnelse.
Som det er vanlig praksis vil preparatene vanligvis følges av skrevne eller trykkede retningslinjer for anvendelse ved den aktuelle medisinske behandling.
Følgelig tilveiebringer foreliggende oppfinnelse videre et farmasøytisk preparat for anvendelse ved behandling og/eller forebyggelse av angst, mani, depresjon, paniske lidelser og/eller aggresjon, lidelser forbundet med subarachnoidal blødning eller nervesjokk, effektene forbundet med avvenning fra misbruk av stoffer så som kokain, nikotin, alkohol og benzodiazepiner, lidelser som kan behandles og/eller forhindres med antikonvulsive midler, så som epilepsi omfattende post-traumatisk epilepsi, Parkinson's sykdom, psykose, migrene, cerebral ischemi, Alzheimers sykdom og andre degenerative sykdommer så som Huntingdon's chorea, schizofreni, obsessive kompulsive lidelser (OCD), nevrologiske defekter forbundet med AIDS, søvnforstyrrelser (omfattende døgnrytmeforstyrrelser, søvnløshet & narkolepsi), tics (f.eks. Giles de la Tourette's syndrom), traumatisk hjerneskade, tinnitus, nevralgi, spesielt trigeminusnevralgi, nevropatisk smerte, dental smerte, kreftsmerte, upassende nevronal aktivitet som resulterer i nevrodystesi ved sykdommer så som diabetes, multippel sklerose (MS) og motorisk nevron-sykdom, ataksi, muskelstivhet (spastisitet), temporomandibulær ledd-dysfunksjon og amyotrofisk lateralsklerose (ALS) som omfatter en forbindelse med formel (I) eller et farmasøytisk godtagbart salt eller solvat derav og en farmasøytisk godtagbar bærer.
Forbindelsene ifølge foreliggende oppfinnelse kan anvendes for behandling og/eller forebyggelse av angst, mani, depresjon, paniske lidelser og/eller aggresjon, lidelser forbundet med subarachnoidal blødning eller nervesjokk, effektene forbundet med avvenning fra misbruk av stoffer så som kokain, nikotin, alkohol og benzodiazepiner, lidelser som kan behandles og/eller forhindres med antikonvulsive midler, så som epilepsi omfattende post-traumatisk epilepsi, Parkinson's sykdom, psykose, migrene, cerebral ischemi, Alzheimers sykdom og andre degenerative sykdommer så som Huntingdon's chorea, schizofreni, obsessive kompulsive lidelser (OCD), nevrologiske defekter forbundet med AIDS, søvnforstyrrelser (omfattende døgnrytmeforstyrrelser, søvnløshet & narkolepsi), tics (f.eks. Giles de la Tourette's syndrom), traumatisk hjerneskade, tinnitus, nevralgi, spesielt trigeminusnevralgi, nevropatisk smerte, dental smerte, kreftsmerte, upassende nevronal aktivitet som resulterer i nevrodystesi ved sykdommer så som diabetes, multippel sklerose (MS) og motorisk nevron-sykdom, ataksi, muskelstivhet (spastisitet), temporomandibulær ledd-dysfunksjon og amyotrofisk lateralsklerose (ALS) ved administering til pasienten med behov for dette av en effektiv eller profylaktisk mengde av en forbindelse med formel (I) eller et farmasøytisk godtagbart salt eller solvat derav.
Således tilveiebringes i et ytterligere aspekt av oppfinnelsen anvendelse av en forbindelse med formel (I) eller et farmasøytisk godtagbart salt eller solvat derav, for fremstilling av et medikament for behandling og/eller forebyggelse av angst, mani, depresjon, paniske lidelser og/eller aggresjon, lidelser forbundet med subarachnoidal blødning eller nervesjokk, effektene forbundet med avvenning fra misbruk av stoffer så som kokain, nikotin, alkohol og benzodiazepiner, lidelser som kan behandles og/eller forhindres med antikonvulsive midler, så som epilepsi omfattende post-traumatisk epilepsi, Parkinson's sykdom, psykose, migrene, cerebral ischemi, Alzheimers sykdom og andre degenerative sykdommer så som Huntingdon's chorea, schizofreni, obsessive kompulsive lidelser (OCD), nevrologiske defekter forbundet med AIDS, søvnforstyrrelser (omfattende døgnrytmeforstyrrelser, søvnløshet & narkolepsi), tics (f.eks. Giles de la Tourette's syndrom), traumatisk hjerneskade, tinnitus, nevralgi, spesielt trigeminusnevralgi, nevropatisk smerte, dental smerte, kreftsmerte, upassende nevronal aktivitet som resulterer i nevrodystesi ved sykdommer så som diabetes, multippel sklerose (MS) og motorisk nevron-sykdom, ataksi, muskelstivhet (spastisitet), temporomandibulær ledd-dysfunksjon og amyotrofisk lateralsklerose (ALS).
Et annet aspekt ved oppfinnelsen er en fremgangsmåte for fremstilling av forbindelser med formel (I), som omfatter omsetning av en forbindelse med formel (II) hvor R1 A er R<1>som definert for formel (I) eller en gruppe som kan omdannes til R<1>og X er som definert i krav 1, med en forbindelse med formel (III)
hvor Q er som definert i formel (I), Y er Cl eller OH og R<2A->grupper er uavhengig R<2>som definert for formel (I) eller grupper som kan omdannes tilR2.
og om nødvendig omdannelse av en R^ - eller R2jfik -gruppe til en R^ - eller R<2>
-gruppe,
omdannelse av én R^ - eller R<2>-gruppe til en annen R^ - eller R<2>-gruppe, omdannelse av et saltprodukt til den frie basen eller et annet farmasøytisk godtagbart salt eller omdannelse av et fritt base-produkt til et farmasøytisk godtagbart salt.
Omsetningen av en forbindelse med formel (III) som er et syreklorid (Y=CI) vil føre direkte til hydrokloridsaltet. Egnede oppløsningsmidler omfatter etylacetat eller diklormetan, eventuelt i nærvær av en base så som trietylamin.
Når forbindelsen med formel (III) er en aromatisk syre (Y=OH), kan konvensjonelle betingelser for kondensering av slike syrer med aminer anvendes, for eksempel omsetning av komponentene i en blanding av (dimetylaminopropyl)-etyl-karbodiimid/hydroksybenzotriazol i et egnet oppløsningsmiddel så som dimetylformamid.
Omdannelser av en R<1A>- eller R<2A>-gruppe til en R^ - eller R<2>-gruppe skjer typisk når en beskyttelsesgruppe er nødvendig under koblingsreaksjonen ovenfor eller under fremstilling av reaktantene ved metodene beskrevet nedenfor. Interomdanneise av én R<1>- eller R<2>-gruppe til en annen skjer typisk når én forbindelse med formel (I) blir anvendt som den umiddelbare forløper for en annen forbindelse med formel (I) eller når det er lettere å innføre en mer kompleks eller reaktiv substituent ved slutten av en syntese-sekvens.
. Forbindelser med formel (II) hvor X er hydrogen kan fremstilles fra et nitro-tetrahydroisokinolin med formel (IV).
ved omsetning med en forbindelse R^Z hvor Z er en utgående gruppe så som halogen, spesielt jod eller tosylat for å oppnå et mellomprodukt med formel (V)
som kan reduseres, for eksempel ved anvendelse av enten tinn (ll)klorid og HCI eller hydrogen og en palladium/aktivert karbon-katalysator, hvilket gir et amino-tetrahydroisokinolin med formel (II).
Når den ønskede R<1A>-gruppe er metyl, kan forbindelsen med formel (IV) også omsettes med maursyre og formaldehyd for å innføre N-metylgruppen.
Nitro-tetrahydroisokinolinet med formel (IV) kan fremstilles ved hydrolyse av 2-trifluoracetyl-nitro-tetrahydroisokinolin oppnådd ved omsetning av et N-(nitrofenyl)etyl-trifluoracetamid og paraformaldehyd under sure betingelser ved anvendelse av metoden ifølge Stokker, Tet.Lett.,1996, 37, 5453. N-(nitrofenyl)etyl-trifluoracetamider kan fremstilles fra lett tilgjengelige materialer ved omsetning av trifluoreddiksyreanhydrid med lutidin og nitrofenetylamin-hydroklorid, som illustrert i beskrivelsene nedenfor.
Forbindelser med formel (II) kan også fremstilles fra det tilsvarende amino-isokinolin (eller dets nitro-analog) med formel (VI)
hvorR<N>erNH2eller N02
ved omsetning med en forbindelse R^Z hvor Z er en utgående gruppe så som halogen, spesielt jod eller tosylat for å oppnå et mellomprodukt med formel (VII)
som kan reduseres, for eksempel ved anvendelse av natrium-borhydrid eller hydrogenering, for eksempel ved anvendelse av hydrogen og en palladium/aktivert karbon-katalysator, hvilket gir et tetrahydroisokinolin med formel (II). Når forbindelsen med formel (VII) blir erstattet med et nitro-isokinolin, blir nitrogruppen omdannet til en aminogruppe i hydrogeneringstrinnet.
Når den ønskede R1 er hydrogen, blir N i tetrahydroisokinolinet eller isokinolinet fortrinnsvis konvensjonelt beskyttet, før koblingstrinnet som danner karboksamidet med formel (I), for eksempel med tert.-butoksykarbonyl eller trifluoracetyl. Forbindelsen kan avbeskyttes under standard betingelser, for eksempel ved anvendelse av trifluoreddiksyre/metylenklorid.
Amino/nitro-isokinoliner med formel (VI) og de anvendte reagensene er kommersielt tilgjengelige eller kan fremstilles fra kommersielt tilgjengelige materialer ved anvéndelse av konvensjonelle prosedyrer beskrevet i litteraturen.
Når substituenten X er forskjellig fra hydrogen kan den innføres under hvilken som helst av metodene ovenfor, for eksempel ved konvensjonell substitusjon av den aromatiske ring i forbindelsene med formel (IV), (V) eller (VII) eller kan være til stede på kommersielt tilgjengelige utgangsmaterialer som kan anvendes ved de ovenfor beskrevne prosedyrer. Mest hensiktsmessig blir substituenten X innført i en forbindelse med formel (II) hvor X er hydrogen. For eksempel kan X som halogen innføres via en aminogruppe ved anvendelse av Sandmeyer-kjemi som illustrert i beskrivelsene nedenfor.
Forbindelser med formel (III) kan fremstilles ved videre substitusjon av kommersielt tilgjengelige benzosyre- eller tiofenkarboksylsyre-derivater ved anvendelse av konvensjonelle prosedyrer eller ved oksydasjon av tilsvarende substituerte benzylalkoholer. Alternativt kan benzosyrer fremstilles fra tilsvarende substituerte fenoler, for eksempel ved dannelse av acetatet, omdannelse til et acetofenon og deretter til den ønskede syre.
Når de ovenfor beskrevne mellomprodukter er nye forbindelser, utgjør de også del av foreliggende oppfinnelse.
Fremstilling av forbindelser ifølge foreliggende oppfinnelse er videre illustrert av de følgende Mellomprodukter og Eksempler. Nytten av forbindelsene ifølge foreliggende oppfinnelse er vist ved de Farmakologiske Data som følger etter eksemplene.
Mellomprodukt 1
N-2-(4-nitrofenyl)etyl-trifluoracetamid
En oppløsning av trifluoreddiksyreanhydrid (10,6 ml) i diklormetan (100 ml) ble satt dråpevis til en omrørt løsning av 2,6-lutidin (17,44 ml) og 4-nitrofenetylamin-hydroklorid (15,2 g; 75 mmol) ved 0°C. Blandingen ble omrørt ved 25°C natten over under argon og deretter vasket med fortynnet sitronsyre (x2), saltvann og tørket over Na2SC*4. Materialet i den organiske fasen ga tittelforbindelsen som et blekgult, fast stoff (19,04 g).
Mellomprodukt 2
7-nitro-1,2,3,4-tetrahydro-2-trifluoracetylisokinolin
Nitro-forbindelsen B1 (2,26 g; 9,15 mmol) og paraformaldehyd (0,45 g; 14,4 mmol) i eddiksyre (10 ml) og kons. H2SO4(15 ml) ble omrørt ved 25°C i 20 timer i henhold til metoden ifølge G.E. Stokker., Tet. Lett., 1996, 37, 5453. Opparbeidelse ga tittelforbindelsen som et hvitt, fast stoff (2,17 g).
<1>H NMR (CDCI3) 8: 3,10 (2H, m), 3,92 (2H, m), 4,85 + 4,92 (2H, 2xs), 7,38 (1H,
t), 8,10 (2H, m);<m>/z(El): 274 (M<+>)
Mellomprodukt 3
7-nitro-1,2,3,4-tetrahydroisokinolin
Trifluoracetamidet B2 (17,22 g; 63 mmol) ble hydrolysen ved romtemperatur ved anvendelse av en oppløsning av kaliumkarbonat (46,6 g) i 10% vandig metanol (660 ml). Opparbeidelse med diklormetan ga tittelforbindelsen (11 g).
Mellomprodukt 4
2-metyl-7-nitro-1,2,3,4-tetrahydroisokinolin
Aminet B3 (2,08 g; 11,7 mmol) ble behandlet med 88% maursyre (3,45 ml) og 37% vandig formaldehyd (5,88 ml) ved 80<6>C i 2 timer i henhold til metoden ifølge G.M. Carrera og D.S. Garvey, J. Het. Chem., 1992, 29, 847. Alkalisering med 10% natriumhydroksyd fulgt av opparbeidelse med etylacetat ga en oransje gummi (2,3 g). Kromatografi på Kiesegel 60 i 0-3% metanol - etylacetat ga tittelforbindelsen som et oransje, fast stoff (1,7 g).
m/z(CI): 193 (MH<+>).
Mellomprodukt 5
7-amino-2-metyl-1,2,3,4-tetrahydroisokinolin
7-nitro-forbindelsen B4 (0,25 g; 1,3 mmol) i metanol (40 ml) ble hydrogenert over 10% palladium på karbon (100 mg) ved atmosfærisk trykk natten over. Katalysatoren ble fjernet ved filtrering gjennom en pute av Kieselguhr og inndamping / vakuum ga tittelforbindelsen som et hvitt, fast stoff (213 mg).
m/z(CI): 163 (MH<+>)
Mellomprodukt 6
7-amino-2-(f-butyloksykarbonyl)-1,2,3,4-tetrahydroisokinolin
Tittelforbindelsen ble fremstilt fra forbindelsen ifølge Mellomprodukt B3 ved anvendelse av di-f-butyl dikarbonat i 10% vandig hydroksyd i dioksan ved 25°C fulgt av katalytisk hydrogenering i henhold til metoden beskrevet for B5.
Mellomprodukt 7
N-(2-f-butyloksykarbonyH,2,3,4-tetrahydroisokinolin-7-yl)-5-klortiofen-2-karboksamid
5-klortiofen-2-karboksylsyre (214 mg; 1,3 mmol), etyldimetylaminopropyl karbodiimid (250 mg; 1,3 mmol) og 1-hydroksybenzotriazol (176 mg; 1,3 mmol) i tørr DMF (25 ml) ble omrørt ved romtemperatur i 30 min. En oppløsning av N-boc-aminet B6 (300 mg; 1,21 mmol) i diklormetan (5 ml) ble tilsatt og blandingen ble holdt ved romtemperatur natten over. Opparbeidelse ga en rosa gummi som ble kromatografert på Kieselgel 60 i 30% etylacetat-heksan. Kombinasjon av passende fraksjoner ga tittelforbindelsen som et gråhvitt, fast stoff (0,5 g).<1>H NMR (400MHz, CDCI3) 8: 1,51 (9H, s), 2,82 (2H, t), 3,65 (2H, t), 4,56 (2H, s), 6,95 og 7,37 (2H, ABq), 7,12 (1H, d), 7,28 (1H, s), 7,46 (1H, br).
Mellomprodukt 8
7-nitro-2-n-propyl-1,2,3,4-tetrahydroisokinolin
Nitro-forbindelsen B3 (1,55 g, 8,7 mmol) og propionaldehyd (2,52 g, 43,5 mmol) i 1,2-dikloretan (50 ml) ble behandlet med natrium-triacetoksyborhydrid (0,28 g, 13,1 mmol) og iseddik (0,6 ml, 9,0 mmol). Blandingen ble omrørt ved 25°C over weekenden og deretter fortynnet med diklormetan (50 ml). Blandingen ble vasket med mettet NaHC03, tørket (Na2S04) og inndampet / vakuum. Kromatografi på Kieselgel 60 i etylacetat ga tittelforbindelsen.
Mellomprodukt 9
7-amino-2-n-propyl-1,2,3,4-tetrahydroisokinolin
Nitro-forbindelsen B8 (0,73 g, 3,32 mmol) i etanol (100 ml) ble oppvarmet til 50°C og behandlet med en oppløsning av tinn(ll)klorid (2,52 g, 13,27 mmol) i kons. HCI (10 ml) og omrøring ble fortsatt i 3 timer. Blandingen ble gjort basisk med 40% NaOH og produktet ekstrahert inn i diklormetan. Opparbeidelse og kromatograft på Kieselgel 60 i 10% metanol:dtklormetan ga tittelforbindelsen som en viskøs, gul olje (0,26 g; 41%).
<m>/z(APl<+>): 191 (MH<+>;80%).
Mellomprodukt 10
7-amino-2-/so-propyl-1,2,3,4-tetrahydroisokinolin
Tittelforbindelsen ble fremstilt fra B3 og aceton i 10% totalt utbytte ved anvendelse av en metode lignende den beskrevet i Mellomproduktene 8 og 9.
Mellomprodukt 11
7-amino-2-etyl-1,2,3,4-tetrahydroisokinolin
Tittelforbindelsen ble fremstilt i 14% totalt utbytte fra B3 og acetaldehyd ved anvendelse av en metode lignende den beskrevet i Mellomproduktene 5 og 8.
Mellomprodukt 12
2-formyl-7-nitro-1,2,3,4-tetrahydroisokinolin
En blanding av eddiksyreanhydrid (1,4 ml) og maursyre (0,7 ml) ble omrørt ved 50°C i 15 min. Etter avkjøling til 0°C ble en oppløsning av B3 (1,78
g) og 4-dimetylaminopyridin (0,1 g) i diklormetan (30 ml) tilsatt og omrøring ble fortsatt ved 25°C i 2 timer. Reaksjonsblandingen ble vasket med vandig
kaliumkarbonat, vann, saltvann og tørket (MgS04). Inndamping/vakuum ga tittelforbindelsen (2,4 g).
<1>H NMR (250 MHz, CDCI3) 8: 3,0 (2H, m), 3,72(t) og 3,88 (t) (sammen 2H), 4,68 (t) og 4,80 (t) (sammen 2H), 7,28-7,40 (1H, m), 8,04 (2H, m), 8,22 (s) og 8,30 (s) (sammen 1H), ™/z (API<+>): 207 (MH<+>; 80%).
Mellomprodukt 13
7-amino-2-formyl-1,2,3,4-tetrahydroisokinolin
Forbindelsen B12 (2,3 g) ble oppløst i etanol (50 ml) og ristet ved romtemperatur og 3,5 kg/cm<2>hydrogen i nærvær av en 5% Pd/C-katalysator (0,8 g). Filtrering og inndamping ga deretter tittelforbindelsen som et hvitt, fast stoff (1,6 g).
<1>H NMR (250 MHz, d6-DMSO) 6: 2,55(t) og 2,59(t) (sammen 2H), 3,56 (2H, t),
3,39 (s) og 3,41 (s) (sammen 2H), 6,35-6,45 (2H, m), 6,79 (1H, d), 8,15 (s) og 8,18 (s) (sammen 1H), m/z(API+): 177 (MH<+>).
Mellomprodukt 14
2-(2-tert-butyldimetylsilyloksyetyl)-7-nitro-1,2,3,4-tetrahydrodisokinolin
. 7-nitro-tetrahydroisokinolin (5,0 g; 28,0 mmol) ble oppløst i DMF (150 ml). Denne løsningen ble behandlet med (2-brometoksy)-fe/t-butyl-dimetylsilan (12,0 ml; 56,0 mmol) og omrørt ved 80°C natten over. Blandingen ble avkjølt til romtemperatur og oppløsningsmidlet ble fjernet/vakuum. Rensning ved kolonnekromatografi gjennom SiC>2, under eluering med 50% dietyleter/petroleter ga tittelforbindelsen (4,2 g, 44%).
<1>H NMR (250 MHz; CDCI3) 5: 0,00 (6H, s), 0,83 (9H, s), 2,66 (2H, t, J = 6 Hz),
2.79 (2H, t, J = 6 Hz), 2,90 (2H, t, J = 6 Hz), 3,71 (2H, s), 3,77 (2H, t, J = 6 Hz), 7,16 (1H, d, J = 9 Hz), 7,82 (1H, d, J = 2 Hz), 7,89 (1H, dd, J = 9, 2 Hz).
Mellomprodukt 15
7-amino-2-(2-fert-butyldimetylsilyloksyetyl)-1i213,4-tetrahydroisokinolin
2-(2-ferf-butyldimetylsilyloksyetyl) forbindelse B14 (2,88 g; 8,57 mmol) og 10% Pd/C (0,5 g, 60% pasta i vann) i metanol (100 ml) ble hydrogenert på en måte lignende den i Mellomprodukt 5, hvilket ga tittelforbindelsen (2,62 g).
<1>H NMR (250 MHz, CDCI3) 5: 0,00 (6H, s), 0,83 (9H, s), 2,61 (2H, t, J = 6 Hz),
2,71 (4H, s, overlappende signaler), 3,55 (2H, s), 3,77 (2H, t, J = 6 Hz), 6,27 (1H, d, J = 2 Hz), 6,43 (1H, d, J = 8 Hz), 6,80 (1H, d, J = 8 Hz).
Mellomprodukt 16
2-(2-fert-butyldimetylsilyloksyetyl>-1,2,3,4-tetrahydro-isokinolin-7-yl)-3-brom-4-etoksybenzamid
Trietylamin (0,112 ml; 0,81 mmol) og 3-brom-4-etoksybenzoylklorid (193 mg; 0,73 mmol) ble oppløst i diklormetan (100 ml) med omrøring. Til denne blandingen ble satt forbindelsen fra B15 (204 mg; 0,67 mmol). Blandingen ble omrørt natten over og deretter inndampet / vakuum. Det resulterende residuum ble renset ved kromatografi på silika med 10% metanol:diklormetan, hvilket ga tittelforbindelsen (123 mg; 35%).
<1>H NMR«(250 MHz; CDCI3) S: 0,0 (6H, s), 0,82 (9H, s), 1,42 (3H, t, J = 7 Hz),
2.80 (2H, t, J = 5 Hz), 2,91 (2H, t, J 5 Hz), 2,95 (2H, t, J = 4 Hz), 3,81 (2H, s), 3,87 (2H, t, J = 6 Hz), 4,08 (2H, q, J = 7 Hz), 6,84 (1H, d, J = 9 Hz), 7,00 (1H, d, J = 8 Hz), 7,29 (2H, d, J = 8 Hz), 7,33 (1H, s), 7,77 (1H, dd, J = 9, 2 Hz), 8,00 (1H,d,J = 2Hz).
Mellompdodukt 17
7-amino-2-(2-metoksyetyl)-1,2,3,4-tetrahydroisokinolin<1>H NMR (250 MHz; CDCI3) 5: 2,74 (6H, m), 3,38 (3H, s,), 3,60 (4H, m), 3,20 - 3,70 (2H, br), 6,37 (1H, s), 6,50 (1H, dd, J = 8, 2 Hz), 6,88 (1H, d, J = 8 Hz).
Mellomprodukt 18
5-jod-7-nitro-1,2,3,4-tetrahydroisokinolin
Nitro-forbindelsen i Mellomprodukt 3 (750 mg; 3,9 mmol) og N-jodsuccinimid (1,13 g) i trifiinsyre (5 ml) ble omrørt ved 25°C natten over. Blandingen ble hellet forsiktig i mettet NaHC03og deretter ekstrahert inn i eter (2x). De samlede organiske ekstrakter ble vasket med vandig natriumtiosulfat og tørket (MgSOij) og inndamping/vakuum ga et residuum. Kromatografi på Kieselgel 60 i 2% metanol - diklormetan ga tittelforbindelsen (650 mg).
Mellomprodukt 19
7-amino-5-jod-1,2,3,4-tetrahydroisokinolin
En oppløsning av nitro-forbindelsen B18 (650 mg, 2,14 mmol) i etanol (20 ml) ved 50°C ble behandlet med en oppløsning av tinn(ll)klorid (1,42 g) i kons. HCI (3 ml). Den resulterende gule løsningen ble gjort basisk med 10% vandig natriumhydroksyd og produktet ble ekstrahert inn i diklormetan. "Flash"-kromatografi på Kieselgel 60 (5% metanol - diklormetan) ga tittelforbindelsen (428 mg; 73%).
Mellomprodukt 20
7-amino-5-jod-2-(te/t-butoksykarbonyl)-1)2«3,4-tetrahydroisokinolin
Jodaminet B19 (580 mg, 2,12 mmol) i DMF (30 ml) ble behandlet med DMAP (20 mg) og dkerf-butyl-dikarbonat (466 mg, 2,13 mmol) og løsningen ble omrørt ved romtemperatur natten over. Reaksjonsblandingen ble inndampet til tørrhet / vakuum. Kromatografi på Kieselgel 60 (2% metanol - diklormetan) ga tittelforbindelsen (745 mg; 94%).
Mellomprodukt 21
5,7-dinitro-1,2,3,4-tetrahydroisokinolin
5-nitro-1,2,3,4-tetrahydroisokinolin (1,0 g, 5,6 mmol) i kons. svovelsyre (3 ml) ble behandlet med kons. salpetersyre (1 ml) og blandingen ble omrørt ved romtemperatur i 1 time. Blandingen ble avkjølt, gjort basisk med 40% vandig NaOH og opparbeidelse med diklormetan ga tittelforbindelsen (1,14g).
Mellomprodukt 22
5,7-dinitro-2-metyl-1,2,3,4-tetrahydroisokinolin
Aminet B21 (1,8 g) i maursyre (5 ml) og paraformaldehyd (7 ml) ble omsatt på lignende måte som i Mellomprodukt 2, hvilket ga tittelforbindelsen (1,74g, 91%).
<1>H NMR (CDCI3)5: 2,51 (3H, s), 2,75 (2H, t), 3,27 (2H, t), 3,75(2H, s), 8,16 (1H,
d, J = 2Hz), 8,66 (1H, d, J = 2Hz);<m>/z(Cl): 238,1(MH<+>; 100%).
Mellomprodukt 23
5-amino-7-nitro-2-metyl-1,2,3,4-tetrahydroisokinolin
Dinitro-forbindelsen B22 (1,7 g) ble redusert méd tinn(ll)klorid (5,42 g) på en måte lignende den i Mellomprodukt 19, hvilket ga tittelforbindelsen (0,6 g).
Mellomprodukt 24
5-trif1uoracetylamino-7-nitro-2-metyl-1,2,3,4-tetrahydroisokinolin
Aminet B23 (0,5 g) i diklormetan (10 ml) og trietylamin (1,5 ekv.) ble behandlet med trifluoreddiksyreanhydrid (1,1 ekv.) og blandingen ble omrørt ved 25°C i 3 timer. Opparbeidelse med diklormetan fulgt av kromatografi på Kieselgel 60 i 3%-metanol:diklormetan ga tittelforbindelsen (0,7 g, 96%).
<m>/z(Cl): 304 (MH<+>; 80%).
Mellomprodukt 25
7-amino-5-trifluoracetylamino-2-metyl-1,2,3,4-tetrahydroisokinolin
Nitro-forbindelsen B24 (0,7 g, 2,28 mmol) i etanol (20 ml) ble hydrogenert over 10% Pd/C (70 mg). Katalysatoren ble fjernet ved filtrering gjennom Celite, og inndamping /' vakuum ga tittelforbindelsen som et blekt fast stoff (0,6 g, 93%).
Mellomprodukt 26
5-klor-7-nitro-2-metyl-1,2,3,4-tetrahydroisokinolin
5-amino-forbindelsen B23 (1,6 g, 7,7 mmol) i 5M HCI (25 ml) ved 0°C ble behandlet med en oppløsning av natriumnitritt (0,55 g, 8,0 mmol) i vann (3 ml) over 5 min. Den kalde løsningen ble deretter satt gradvis til en oppløsning av kobber(l)klorid (1,0 g, 10 mmol) i 5M HCI (25 ml). Blandingen ble omrørt ved 25°C i 30 min og deretter gjort basisk med 40% NaOH. Opparbeidelse med diklormetan (300 ml) fulgt av "flash" kromatografi på Kieselgel 60 (5% metanokdiklormetan) ga tittelforbindelsen (1,1 g, 62%) som et gult, fast stoff.<1>H NMR (CDCl3)5: 2,32 (3H, s), 2,61 (2H, t), 2,79 (2H, t), 3,57(2H, s), 7,96 (1H,
d, J = 2Hz), 8,08 (1H, d, J = 2Hz).
Mellomprodukt 27
7-amino-5-klor-2-metyl-1,2,3,4-tetrahydroisokinolin
Nitro-forbindelsen B26 (0,80 g, 3,5 mmol) i eta.nol (70 ml) og kons. HCI (7 ml) ble oppvarmet til 50°C og tinn(ll)klorid (2,66 g, 14 mmol) ble tilsatt. Blandingen ble oppvarmet i 15 min og fikk avkjøles. Opparbeidelse lignende den beskrevet i Mellomprodukt 19 ga tittelforbindelsen som en gul olje (0,48 g).<1>H NMR (CDCI3) 5: 2,42 (3H, s), 2,64 (2H, m), 2,77 (2H, m), 3,45(2H, d), 6,27 (1H, d, J = 2Hz), 6,59 (1H, d, J = 2Hz).
Fremstilling 1
3-brombenzyl-TBMS-eter
Til en oppløsning av 3-brombenzylalkohol (5,00 g, 0,027 mole) i diklormetan (30 ml) og Et3N (4,2 ml, 0,03 mol) ble dråpevis satt en 1M løsning av tert-butyldimetylsilylklorid i diklormetan (28,0 ml) dråpevis. Blandingen fikk omrøres ved romtemperatur natten over, og deretter ble vann (30 ml) tilsatt. Det organiske laget ble vasket med saltvann, tørket (Na2S04) og inndampet, hvilket ga en rød olje som ble renset ved "flash" kromatografi på silikagei ved anvendelse av 20% eter i heksan, hvilket ga en farveløs olje (8,0 g).
Fremstilling 2
3-pivaloylbenzylalkohol-TBDMS-eter y
n-butyllitium (2,80 ml, 7,00 mmol, 2,5M i heksart) ble langsomt satt til en oppløsning av Fremstilling 1 TBDMS-eter (1,80 g, 6,0 mmol) i tørr TH F (10 ml) over 5 min ved -78°C. Reaksjonsblandingen ble holdt under argon ved -78°C i 1 time og N.O-dimetyl-hydroksy-pivaloylamid (0,86 g, 6,60 mmol) i THF (2 ml) ble tilsatt dråpevis med omrøring ved -78°C. Den resulterende blanding fikk omrøres ved -78°C i 2,5 timer, ble behandlet med NH4CI-løsning og fikk oppvarmes til romtemperatur. Blandingen ble ekstrahert med eter (2x50 ml), de samlede organiske lag ble tørket (Na2SC*4) og konsentrert / vakuum, hvilket ga tittelforbindelsen som en farveløs olje (1,75 g)
m/z(API+): 307 (MH<+>; 8%).
Fremstilling 3
3-pivaloylbenzylalkohol
Eteren fra Fremstilling 2 (1,47 g, 4,80 mmol) ble oppløst i metanol (25 ml); kons. HCI (20 dråper) ble tilsatt og det hele fikk omrøres ved romtemperatur i 4 timer. Mettet NaHC03-løsning ble tilsatt og blandingen ble ekstrahert med eter (2x50 ml). Det organiske laget ble tørket over natriumsulfat, og inndamping/vakuum ga tittelforbindelsen som en farveløs olje (0,80 g).
m/z(API+): 193 (MH<+>; 17%).
Fremstilling 4
3-pivaloylbenzosyre
3-pivaloylbenzylalkohol (0,80 g, 4,16 mmol) ble oppløst i dioksan (20 ml). En oppløsning av KOH (0,35 g, 6,30 mmol) i vann (5 ml) ble tilsatt fulgt av KMn04(1,45 g, 9,17 mmol). Blandingen ble omrørt ved romtemperatur over weekenden. Løsningen ble filtrert gjennom Celite og ekstrahert med eter. Den vandige fasen ble surgjort med fortynnet HCI og ekstrahert med eter (3x50 ml). Det organiske laget ble tørket over magnesiumsulfat og konsentrert / vakuum, hvilket ga tittelforbindelsen som et hvitt, fast stoff (0,80 g).
^H NMR (250MHz, CDCI3) 8: 1,38 (9H, s), 7,55 (1H, t), 7,92 (1H, d, J = 6,5Hz),
8,20 (1H, d, J = 6,5Hz), 8,44 (1H, s).
Fremstilling 5
3-trifluoracetylbenzosyre
Tittelforbindelsen ble fremstilt fra dietyl-trifluoracetamid og 3-brombenzyl-TBDMS-eter ved anvendelse av en metode lignende den beskrevet i Fremstillingene 1, 2, 3 og 4.
<m>/z(API-): 217 (M-H+; 20%).
Fremstilling 6
Metyl-3-klor-4-/so-propoksybenzoat
Metyl-3-klor-4-hydroksybenzoat (5 g, 26,8 mmol) i DMF (45 ml) ble behandlet med kaliumkarbonat (7,41 g, 53,6 mmol), 2-jodpropan (3,85 ml, 40,2 mmol) og deretter omrørt ved 25°C i 18 timer. Opparbeidelse med etylacetat ga tittelforbindelsen (6,1 g).
Fremstilling 7
3-klor-4-/so-propoksybenzosyre
Metyl-3-klor-4-/so-propoksybenzoat (5,5 g, 24,1 mmol) ble hydrolysert ved anvendelse av 1M NaOH (36 ml) i metanol (80 ml). Ekstraksjon og opparbeidelse med etylacetat ga tittelforbindelsen (4,3 g).
<*>H NMR (DMSO-D6) 8: 1,33 (6H, d), 4,79 (1H, m), 7,24 (1H, d), 7,87 (2H, m).
Fremstilling 8
3-brom-4-etoksybenzosyre
Tittelforbindelsen ble fremstilt fra 4-etoksybenzosyre på en måte lignende den i Fremgangsmåte 1.
<1>H NMR (DMSO-D6) S: 1,45 (3H, t, J = 7 Hz), 4,26 (2H, q, J = 7 Hz), 7,26 (1H,
d, J = 9 Hz),-7,98 (1H, dd, J = 2, 9 Hz), 8,12 (1H, d, J = 2 Hz)
Fremstilling 9
3-brom-4-etylbenzosyre
Tittelforbindelsen ble fremstilt fra 4-etylbenzosyre.
<1>H NMR (DMSO-D6) 6: 1,20 (3H, t, J = 7 Hz), 2,78 (2H, q, J = 7Hz), 7,50 (1H, d,
J = 8 Hz), 7,90 (1H, dd, J = 2, 8 Hz), 8,07 (1H, d, J = 8 Hz
Fremstilling 10
3- cyano-4-/so-propylbenzosyre
Tittelforbindelsen ble fremstilt fra 4-/'so-propylbenzosyre på samme måte som beskrevet i Fremgangsmåte 5.
<1>H NMR (DMSO-Dg) 5: 1,07 (6H, d, J = 7 Hz), 3,13 (1H,m, overlappet), 7,48
(1H, d, J = 7 Hz), 7,96 (1H, dd, J = 2, 8 Hz)), 8,00 <1H, d, J = 2 Hz).
Fremstilling 11
4- metoksy-3-trifluormetylbenzosyre
Tittelforbindelsen ble fremstilt fra 3-brom-4-metoksybenzosyre og kalium-trifluoracetat på en måte lik den i Fremgangsmåtene 3 og 4.
<1>H NMR (DMSO-D6) 8: 3,78 (3H, s), 7,18 (1H, d, J = 9 Hz), 7,90 (1H, d, J = 2 Hz), 8,00 (1H, dd, J = 2, 9 Hz), 12.70 -13,10 (1H, br, utskiftbar)
Fremstilling 12
4-metoksy-3-trifluormetylbenzoylklorid
Tittelforbindelsen ble fremstilt fra 4-metoksy-3-trifluormetylbenzosyre med oksalylklorid og DMF i kloroform ved romtemperatur [D. Levin, Chem. Br., 1977, 20] fulgt av inndamping /' vakuum.
Fremstilling 13
Metyl-3-brom-4-/so-propoksybenzoat
Metyl-3-brom^-hydroksybenzoat (2,5 g, 10,8 mmol) i DMF (35 ml) ble behandlet med kaliumkarbonat (3,0 g, 21,6 mmol), 2-jodpropan (2,76, 21,6 mmol) og deretter omrørt ved 25°C i 48 timer. Opparbeidelse med etylacetat ga tittelforbindelsen (3,0 g).
1H NMR (250MHz, CDCI3) 8: 1,41 (6H, d, J=7Hz), 3,89 (3H, s), 4,66 (1H, m), 6,90 (1H, d, J = 8 Hz), 7,93 (1H, dd, J = 8, 2 Hz), 8,22 (1H, d, J = 2 Hz)
Fremstilling 14
Metyl-3-cyano-4-/so-propoksybenzoat
Metyl-3-brom-4-/so-propoksybenzoat (2,0 g, 7,3 mmol) og kobber(l)cyanid i N-metylpyrrolidon (50 ml) ble oppvarmet under kraftig tilbakeløp i 4 timer. Opparbeidelse med etylacetat ga tittelforbindelsen (1,0 g).
'H NMR (250MHz, CDCI3) 8: 1,56 (6H, d, J=7Hz), 4,05 (3H, s), 4,88 (1H, m), 7,13 (1H, d, J = 8 Hz), 8,31 (1H, dd, J = 8, 2 Hz), 8,38 (1H, d, J = 2 Hz)
Fremstilling 15
Metyl-3,5-diklor-4-etoksybenzoat
Tittelforbindelsen ble fremstilt i 69% utbytte fra metyl-3,5-diklor-4-hydroksybenzosyre og jodetan på en måte lignende den i Fremstilling 6.
<1>H NMR (250MHz, CDCI3) 8: 1,47 (3H, t, J=7 Hz), 3,91 (3H, s), 4,16 (2H, q, J = 7 Hz), 7,96 (2H, s).
Fremstilling 16
3-metansulfonyl-4-/so-propylbenzosyre
3-klorsulfonyl-4-/so-propylbenzosyre (2,62 g, 10 mmol) [fremstilt fra 4-/so-propyl-benzosyre på en måte lignende den beskrevet i Fremgangsmåter 7 og 8] ble langsomt satt til en oppslemning av NaHC03(2,52 g, 30 mmol) og Na2S03
(1,26 g 10 mmol) i vann (9 ml) ved 75°C. Blandingen ble omrørt i 1time og
deretter behandlet med bromeddiksyre (2,08 g, 15 mmol) og NaOH (0,60 g, 15 mmol). Temperaturen ble hevet til 105°C og blandingen ble oppvarmet ved tilbakeløp i 24 timer. Blandingen ble avkjølt, surgjort til pH 1 og det resulterende, utfelte stoff oppsamlet, vasket og tørket, hvilket ga tittelforbindelsen (1,43 g, 59%).
<1>H NMR (250MHz, aceton-Dg) 8: 1,24 (6H, d, J=7 Hz), 3,13 (3H, s), 3,88 (1H,
m), 7,72 (1H, d, J = 7 Hz), 8,15 (1H, dd, J = 7 Hz), 8,52 (1H, d, J = 2 Hz).
Fremstilling 17
4-metyl-3-metansulfonylbenzosyre
Fremstilt i 30% totalt utbytte på en måte lignende den i Fremstilling 16.<1>H NMR (250MHz, aceton-D6) 8: 2,57 (3H, s), 2,99 (3H, s), 7,39 (1H, d, J = 7 Hz), 7,97 (1H, dd, J = 7, 2 Hz), 8,39 (1H, d, J = 2 Hz).
Fremstilling 18
4-etyl-3-metansulfonylbenzosyre
Fremstilt i 44% totalt utbytte på en måte lignende den i Fremstilling 16.
'H NMR (250MHz, aceton-D6) 8:1,22 (3H, t, J = 7 Hz), (3H, s), 3,05 (2H, q, J = 7 Hz), 3,12 (3H, s), 7,57 (1H, d, J = 7 Hz), 8,13 (1H, dd, J = 7, 2 Hz), 8,51 (1H, d, J = 2Hz).
Fremstilling 19
3- metansulfonyl-4-metoksybenzosyre
Fremstilt i 20% totalt utbytte på en måte lignende den i Fremstilling 16.<1>H NMR (250MHz, aceton-D6) 8: 3,00 (3H, s), 3,89 (3H, s), 7,17 (1H, d, J = 7 Hz), 8,06 (1H, dd, J = 7, 2 Hz), 8,31 (1H, d, J = 2 Hz)!
Fremstilling 20
4- etoksy-3-metansulfonylbenzosyre
Fremstilt i 20% totalt utbytte på en måte lignende den i Fremstilling 16.<1>H NMR (250MHz, aceton-D6) 8: 1,44 (3H, t, J = 7 Hz), (3H, s), 3,30 (3H, s),
4,35 (2H, q, J = 7 Hz), 7,40 (1H, d, J = 7 Hz), 8,20 (1H, dd, J = 7, 2 Hz), 8,37 (1H,d, J = 2Hz).
Fremstilling 21
3-klor-4-etoksybenzosyre
M NMR {DMSO-Dq) 8:1,39 (3H, t, J = 7 Hz), 4,20 (2H, q, J = 7 Hz), 7,22 (1H,
d, J = 7 Hz),-7,87 (2H, m).
Fremstilling 22
4-/$o-propyloksy-3-trifluormetylbenzosyre
Metyl-3-brom-4-/so-propyloksybenzoat (828 mg; 3,03 mmol) i DMF (25 ml) ble behandlet med kalium-trifluoracetat (922 mg; 6,06 mmol), kobber (I) jodid (1,15 g; 6,06 mmol) og toluen (50 ml). Den resulterende blanding ble oppvarmet ved tilbakeløp i 1,5 time (Dean og Stark med fjerning av ca 50 ml destillat) fulgt av tilbakeløp i 18 timer og deretter avkjølt. Blandingen ble hellet i Et20 (100 ml) og H20 (100 ml). To-fase-blandingen ble omrørt ved romtemperatur i 0,5 time og deretter filtrert gjennom Celite. De to faser ble separert, den vandige fasen ble videre ekstrahert med Et20 (50 ml) og de organiske ekstrakter samlet, vasket med mettet, vandig Na2S203, H2O, mettet saltvann, tørket (MgS04) og inndampet / vakuum, hvilket ga en brun olje. Denne ble oppløst i MeOH (ca. 20 ml) og behandlet med 2M NaOH (2 ml; 4 mmol) og den resulterende løsning ble oppvarmet ved tilbakeløp i 3 timer. De flyktige stoffene ble fjernet / vakuum og residuet ble fordelt mellom EtOAc og H20. Fasene ble separert, den vandige fasen surgjort til pH1 med 2M HCI i nærvær av EtOAc og fasene separert. Den vandige fasen ble videre ekstrahert med EtOAc, ekstraktene ble samlet, vasket med H20, mettet saltvann, tørket (MgS04) og inndampet til tørrhet / vakuum, hvilket ga tittelforbindelsen som et hvitt, fast stoff (671 mg; 89%).
<1>H NMR (250MHz; (CD3)2CO) 5: 1,02 (6H, d, J = 6 Hz), 4,53 - 4,63 (1H, m), 7,01 (1H, d, J = 9 Hz), 7,85 - 7,88 (2H, m);<m>/z(API): 205,0 [M-Pr<1>].
Fremstilling 23
4-etyl-3-trifluormetylbenzosyre
Fremstilt som beskrevet i Fremstilling 22 fra metyl-4-etyl-3-brombenzoat (1,10 g; 4,52 mmol) og isolert som et hvitt, fast stoff (923 mg; 93%).
<1>H NMR (250MHz; (CD3)2CO) 8: 0,98 (3H, t, J = 7 Hz), 2,60 (2H, q, J = 7 Hz), 7,36 (1H, d, J = 8 Hz), 7,89 og 7,93 (1H, m), 7,96 (1H, br s);
<m>/z(API)r217,1 [M-H].
Fremstilling 24
4-n-propyloksy-3-trifluormetylbenzosyre
Fremstilt som beskrevet i Fremstilling 22 fra metyl-3-brom-4-n-propyloksybenzoat (1,43 g; 5,23 mmol) og isolert som et hvitt, fast stoff (1,18 g; 91%).
'H NMR (250MHz; (CD3)2SO) 5: 1,09 (3H, t, J = 7 Hz), 1,79 -1,93 (2H, m), 4,26 (2H, t, J = 6 Hz), 7,45 (1H, d, J = 9 Hz), 8,19 (1H, d, J = 2 Hz), 8,25 og 8,28 (1H, dd, J=9, 2 Hz);<m>/z(API): 203,1 [M-C02H].
Fremstilling 25
4-?-butyl-3-trifluormetylbenzosyre
Fremstilt som beskrevet i Fremstilling 22 fra metyl-3-brom-4-f-butylbenzoat (2,46 g; 9,1 mmol) og isolert som et hvitt, fast stoff (1,55 g; 69%).<1>H NMR (250MHz; (CD3)2SO) 5: 1,42 (9H, s), 7,86 - 7,90 (1H, m), 8,09 - 8,13 (1H, m), 8,23 (1H, d, J = 2 Hz);<m>/z(API): 245,1 [M-H].
Fremstilling 26
4-oksokroman-6-karboksylsyre
3-(4-karboksyfenoksy)propionsyre (2,5 g) [fremstilt i henhold til metoden ifølge J. Lichtenberger og R. Geyer. Bull. Soc. Chim. Fr., 1963 275] i kons. svovelsyre (20 ml) ble oppvarmet til 100°C i 4 timer og deretter hellet i knust is. Det resulterende, utfelte stoff ble filtrert og tørket/vakuum, hvilket ga tittelforbindelsen (1,6 g).
<1>H NMR (DMSO-D6) 6: 2,99 (2H, t, J = 7 Hz), 4,77 (2H, t, J = 7 Hz), 7,28 (1H, d,
J = 8 Hz), 8,21 (1H,dd, J = 8, 2 Hz), 8,46 (1H, d, J = 2 Hz).
Fremstilling 27
3-brom-4-/so-propoksybenzosyre
Tittelforbindelsen ble fremstilt ved anvendelse av en metode lignende den i Fremstilling 7.
<1>H NMR (DMSO-D6) 8: 1,29 (6H, d, J = 7 Hz), 4,77 (1H, sep, J = 7 Hz), 7,20 (1H, d, J = 8 Hz), 7,87 (1H, dd, J = 8, 2 Hz), 8,02 (1H, d, J = 2 Hz), 12,92 (1H, brs).
Fremstilling 28
4- azidobenzosyre
Til en oppløsning av 4-aminobenzosyre (2,00 g, 14,00 mmol) i trifluoreddiksyre (10 ml) ved 5°C, ble porsjonsvis tilsatt natriumnitritt (3,50 g) og blandingen fikk omrøres i 30 min. Natriumazid (3,79 g,) ble deretter tilsatt porsjonsvis og blandingen ble omrørt i ytterligere 30 min ved 0°C. Blandingen ble fortynnet med vann og et hvitt, fast stoff ble utfelt. Det faste stoffet ble filtrert, vasket med kaldt vann og tørket, hvilket ga tittelforbindelsen (1,66 g, 73%).
Fremgangsmåte 1
5- brom-2,4-dimetoksybenzosyre
Til en oppløsning av 2,4-dimetoksybenzosyre (4,0 g, 0,022 mol) i kloroform (60 ml) ble dråpevis satt brom (1,13 ml, 0,022 mol) i kloroform (20 ml). Etter omrøring natten over ved romtemperatur ble fellingen filtrert fra og tørket, hvilket ga tittelforbindelsen som et hvitt, fast stoff (2,87 g).
Fremgangsmåte 2
5-brom-4-/so-propyl-2-metoksybenzosyre
Til en oppløsning av 2-metoksy-4-/so-propyl-benzosyre (7,0 g, 36,0 mmol) i kloroform (100 ml) ble dråpevis satt brom (1,86 ml) i kloroform (20 ml). Reaksjonsblandingen ble omrørt ved romtemperatur natten over. Inndamping /' vakuum ga en olje (9,27 g).<m>/z(Cl): 275, 273 (MH<+>;70%).
Fremgangsmåte 3
Metyl-5-brom-4-/so-propyl-2-metoksy-benzoat
5-brom-4-/so-propyl-2-metoksybenzosyre (9,268 g 34,0 mmol) ble oppløst i metanol (250 ml) og kons. H2SO4(2 ml) tilsatt. Blandingen ble tilbakeløpskokt i 5 timer og konsentrert / vakuum. Gjenværende materiale ble tatt opp med etylacetat og vann og det organiske laget ble tørket (MgSC>4). Konsentrasjon / vakuum ga en olje, som ble renset ved Biotage
kolonnekromatografi på silikagel ved anvendelse av 10% eter i heksan, hvilket ga en olje (5,5 g).
Fremgangsmåte 4
2,4-dimetoksy-5-trifluormetylbenzosyre
2,4-dimetoksy-5-brombenzosyre-metylester (1,5 g; 5,4 mmol) i DMF (25 ml) og toluen (8 ml) under argon ble behandlet med kaliumtrifluoracetat (1,53 g; 10,1 mmol) og kobber(l)jodid (2,1 g, 10,9 mmol). Blandingen ble oppvarmet til 170°C med fjerning av vann (Dean/Stark) og deretter ved 155°C natten over. Blandingen fikk avkjøles, ble hellet i eter og vann og filtrert gjennom Kieselguhr. Det organiske laget ble tørket (Na2S04) og konsentrert/vakuum, hvilket ga et brunt, fast stoff. Kromatografi på Kieselgel 60 med 1:1 eter/petrol ga et fast stoff (1,03 g) som ble hydrolysert i 1:1 metanolisk: vandig NaOH (50 mi) ved 50°C. Opparbeidelse ga tittelforbindelsen som et hvitt, fast stoff (1 g).
Fremgangsmåte 5a
Metyl-2-metoksy-5-cyano-4-/so-propylbenzoat
Kobber(l)cyanid (550 mg, 6 mmol) ble satt til en oppløsning av metyl-2-metoksy-5-brom-4-/'so-propylbenzoat (861 mg) i N-metyl-2-pyrrolidinon (30 ml). Blandingen ble omrørt under argon og kokt under tilbakeløp i 4 timer. Blandingen ble avkjølt, hellet i overskudd av is/vann og etylacetat og filtrert. Den organiske fasen ble separert, vasket med vann, saltvann og tørket(MgS04). Inndamping ga et rått, brunt fast stoff som ble renset ved kromatografi på silikagel under eluering med etylacetat/n-heksan (1:4). Produktet ble oppnådd som et hvitt, fast stoff (523 mg).
<1>H NMR (250MHz, CDCI3) 5: 1,33 (6H, d, J=7Hz), 3-<3>8 (1H, sep, J=7Hz), 3,89
(3H, s), 3,98 (3H, s), 6,91 (1H, s), 8,08 (1H, s);<m>/z (API<+>): 234 (MH<+>, 30%).
Fremgangsmåte 5b
2-metoksy-5-cyano-4-/so-propylbenzosyre
2N NaOH (1,25 ml) ble satt til en oppløsning av metylesteren F5a (490 mg) i metanol (10 ml). Løsningen ble omrørt natten over ved romtemperatur. Løsningen ble deretter fortynnet med vann, konsentrert /' vakuum og vasket med
etylacetat. Den vandige fasen ble deretter surgjort med 2N HCI og ekstrahert med etylacetat. Ekstrakten ble vasket med saltvann, tørket (MgSCvg) og inndampet til tørrhet, hvilket ga produktet som et hvitt, fast stoff (418 mg).
<1>H NMR (250MHz, CDCI3) 8: 1,35 (6H, d, J=7Hz), 3,43 (1H, sep, J=7Hz), 4,14
(3H,s), 7,00 (1H, s), 8,41 (1H, s);<m>/z (API<+>): 220 (MH<+>, 100%).
Fremgangsmåte 6a
Etyl-2-etoksy-4-/so-propyl-5-cyanobenzoat
Etyl-2-etoksy-4-/so-propyl-5-brombenzoat (1,2 g, 3,8 mmol) ble behandlet med kobber(l)cyanid (682 mg, 7,6 mmol) i N-metyl-2-pyrrolidinon (40 ml) som
beskrevet i Fremgangsmåte 5, hvilket ga tittelforbindelsen som en olje (400 mg).<1>H NMR (250MHz, CDCI3) 8: 1,12 (6H, d, J=7Hz), 1,30 (3H, t, J=7Hz), 1,84 (3H,
t, J=7Hz), 3,17 (1H, sep, J=7Hz), 3,99 (2H, q, J=9Hz), 4,16 (2H, q, J=7Hz), 6,69 (1H, s), 7,86 (1H, s);<m>/z (API<+>): 262 (MH<+>, 100%).
Fremgangsmåte 6b
2-etoksy-4-/so-propyl-5-cyanobenzosyre
Esteren F6a (370 mg, 1,41 mmol) ble oppløst i metanol (5 ml) og over en 24 timers periode ble 1N NaOH (2,1 ml, 2,1 mmol) tilsatt. Løsningen ble konsentrert under vakuum, fortynnet med vann og vasket med etylacetat. Den vandige fasen ble surgjort med 2N HCI og ekstrahert med etylacetat. Ekstrakten ble vasket med saltvann, tørket (Mg SO4) og inndampet, hvilket ga tittelsyren (306 mg).
'H NMR (250MHz CDCI3) 8: 1,39 (3H, d, J=7Hz), 1,66 (3H, t, J=7Hz), 3,47 (1H,
sep, J=7Hz), 4,46 (2H, q, J=7Hz), 7,03 (1H, s), 8,47 (1H, s);<m>/z (API<+>): 234 (MH<+>, 100%).
Fremgangsmåte 7
4-etoksy-2-metoksy-5-metylsulfonylbenzosyre
4-etoksy-2-metoksy-5-klorsulfonyl-benzosyre ble fremstilt i 49% utbytte ved anvendelse av metoden ifølge M.W. Harrold et al., J. Med. Chem., 1989, 32
874, Denne ble anvendt i henhold til metoden ifølge R.W. Brun, J. Org. Chem., 1991, 56, 4974, for tittelforbindelsen i 19% utbytte.
<1>H NMR (DMSO-D6) 6: 1,30 (3H, t), 3,10 (3H, s), 3,83 (3H, s), 4,24 (2H, q), 6,73
(1H, s), 8,07 (1H,s).
Fremgangsmåte 8
4-/so-propyl-2-metoksy-5-metylsulfonylbenzosyre
Denne ble fremstilt på lignende måte til metoden ifølge C. Hansch, B. Schmidhalter, F. Reiter, W. Saltonstall. J. Org. Chem., 1956, 21, 265, hvilket ga mellomproduktet 5-klorsulfonyl-4-isopropyl-2-metoksybenzosyre som ble omdannet til tittelforbindelsen ved anvendelse av metoden ifølge Fremgangsmåte 7.
<1>H NMR (DMSO-D6) 5: 1,30 (6H, d), 3,21 (3H, s), 3,80 (1H, m), 3,94 (3H, s),
7,26 (1H, s), 8,19 (1H,s).
Eksempel 1
N-(1,2,3,4-tetrahydroisokinolin-7-yl)-5-klortiofen-2-karboksamid-monotrifluoracetat
N-boc-aminet B7 {0,48 g; 1,22 mmol) i diklormetan (25 ml) inneholdende trifluoreddiksyre (2 ml) ble holdt ved 25°C i 18 timer. Inndamping / vakuum fulgt av krystallisasjon av residuet fra etylacetat - eter ga tittelforbindelsen som gråhvite krystaller (0,46 g; 92%), sm.p. 153-5X.
<1>H NMR (400MHz, DMSO-d^) 8: 2,96 (2H, t), 3,38 (2H, t), 4,29 (2H, s), 7,23 (1H, d), 7,28 (1H, d, ABq), 7,51 (1H, dd), 7,63 (1H, d), 7,90 (1H, d, ABq), 9,01 (2H, br, s), 10,33 (1H, s); ™/z (Cl): 293 (MH<+>; 100%).
Eksempel 2
N-(2-metyl-tetrahydroisokinolin-7-yl)-5-klortiofen-2-karboksamid
Forbindelsen i eksempel 1 (200 mg; 0,5 mmol), 98% maursyre (0,4 ml) og vandig formaldehyd (0,6 ml) ble behandlet i henhold til metoden ifølge Beskrivelse 4. Kromatografi på Kieselgel 60 i metanol - etylacetat fulgt av krystallisasjon fra etylacetat - eter ga tittelforbindelsen som et gråhvitt pulver, sm.p. 138-40°C.
<1>H NMR (250MHz, CDCI3) 5: 2,46 (3H, s), 2,69 (2H, t), 2,89 (2H, t), 3,54 (2H,
s), 6,93 og 7,37 (2H, ABq), 7,07 (1H, d), 7,25 (1H, dd), 7,34 (1H, d), 7,63 (1H, br, s);
<m>/z(CI): 307 (MH<+>; 100%).
Eksempel 3
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)benzamid
N-metylaminet B5 i diklormetan (25 ml) inneholdende trietylamin (0,5 ml) ble behandlet med benzoylklorid og blandingen ble holdt ved 25°C i 18 timer. Normal opparbeidelse ga produktet som ble kromatografert på Kieselgel 60 ved gradient-eluering i etylacetat:heksan. Kombinasjon av passende fraksjoner ga tittelforbindelsen.
<1>H NMR (250MHz, CDCI3) 8: 2,46 (3H, s), 2,69 (2H, t), 2,91 (2H, t), 3,58 (2H, s), 7,10 (1H, d), 7,30 (1H, dd), 7,40 - 7,60 (4H, overlappende m), 7,75 (1H, br s), 7,87 (2H, m);
De følgende Eksempler ble fremstilt ved anvendelse av metoder lik fremgangsmåtene beskrevet tidligere.
Eksempel 4
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-klorbenzamid
<1>H NMR (250MHz, CDCI3) 8: 2,46 (3H, s), 2,68 (2H, t), 2,90 (2H, t), 3,57 (2H,
s), 7,10 (1H, d), 7,29 (1H, dd, overlappende med CHCI3), 7,39 (1H, s), 7,42 (1H, d), 7,52 (1H, m), 7,73 (1H, m), 7,83 (2H, m).
Eksempel 5
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-f-butylbenzamid
<1>H NMRj(250MHz, CDCI3) 8: 1,34 <9H, s), 2,44 (3H, s), 2,68 (2H, t), 2,89 (2H,
t), 3,55 (2H, s), 7,07 (1H, d), 7,29 (1H, dd overlappende med CHCI3signal), 7,38 - 7,53 (3H, m, overlappende signaler), 7,75 - 7,90 (3H, m, overlappende signaler).
Eksempel 6
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-/so-propoksybenzamid
<1>H NMR (250MHz, CDCI3) 5: 1,38 (6H, d), 2,46 (3H, s), 2,69 (2H, t), 2,90 (2H,
t), 3,58 (2H, s), 4,64 (1H, septet), 6,94 (2H, m), 7,09 (1H, d), 7,23 - 7,34 (1H, m, overlappende CHCI3), 7,42 (1H, s), 7,70 (1H, br s), 7,81 (2H, m); ™/z (Cl): 325
(MH<+>, 100%).
Eksempel 7
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-fenoksybenzamid
<1>H NMR (250MHz, CDCI3) 5: 2,46 (3H, s), 2,69 (2H, t), 2,91 (2H, t), 3,59 (2H, s), 7,00 - 7,50 (10H, overlappende m), 7,72 (1H, br s), 7,83 (2H, m).
Eksempel 8
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-nitrobenzamid
<1>H NMR (CDCI3) 5: 2,45 (3H, s), 2,70 (2H, m), 2,90 (2H, m), 3,60 (2H, s), 7,10
(2H, dd), 7,25 (1H, dd), 7,40 (1H, d), 8,00 (2H, dd), 8,35 (2H, dd), 7,80 (1H, s).
m/z(CI): 312 (MH+, 70%).
Eksempel 9
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-fenylbenzamid
<1>H NMR (CDCI3) 6: 2,45 (3H, s), 2,70 (2H, m), 2,90 (2H, m), 3,60 (2H, s), 6,30
(1H, d), 6,50 (1H, dd), 6,90 (1H, dd), 7,10 (1H, d), 7,40 (2H, m), 7,60 (1H, dd), 7,70 (1H, dd), 7,80 (1H, s), 7,90 (1H, d), 8,05 (1H, s);<m>/z(Cl): 343 (MH<+>; 90%).
Eksempel 10
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-metylbenzamid
<1>H NMR (CDCI3) 8: 2,43 (3H, s), 2,47 (3H, s), 2,70 (2H, t), 2,90 (2H, t), 3,60 (2H, s), 7,05 (1H, dd), 7,30 (1H, m), 7,35 (2H, m), 7,45 (1H, s), 7,65 (3H, m).
m/z(Cl): 281 (MH<+>; 90%).
Eksempel 11
N-{2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-fluorbenzamid 1H NMR (CDCI3) 8: 2,50 (3H, s), 2,75 (2H, t), 2,90 (2H, t), 3,65 (2H, s), 7,10 .
(1H, dd), 7,28 (2H, m), 7,40 (2H, m), 7,60 (2H, m), 7,75 (1H, s); ™/z (Cl): 285
(MH<+>; 100%).
Eksempel 12
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-cyanobenzamid
<1>H NMR (CDCI3) 8: 2,47 (3H, s), 2,70 (2H, t), 2,90 (2H, t), 3,60 (2H, s), 7,12 {1H, dd), 7,30 (1H, m), 7,40 (1H, s), 7,65 (1H, dt), 7,80 (2H, m), 8,10 (1H, d), 8,15 (1H, s).
m/z(Cl): 292 (MH<+>).
Eksempel 13
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3,4-diklorbenzamid
<1>H NMR (CDCI3) 8: 2,50 (3H, s), 2,80 (2H, t), 2,90 (2H, t), 3,70 (2H, s), 7,10 (1H, d), 7,30 (1H, dd), 7,40 (1H, s), 7,55 (1H, d), 7,70 (1H, dd), 8,00 (2H, m).
m/z(Cl): 335 (MH<+>).
Eksempel 14
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-jodbenzamid
<1>H NMR (CDCI3) 8: 2,47 (3H, s), 2,71 (2H, t), 2,89 (2H, t), 3,58 (2H, s), 7,10 (1H, d), 7,30 (1H, m), 7,43 (1H, s), 7,60 og 7,85 (4H, ABq), 7,82 (1H. s).
m/z(CI): 393 (MH+; 100%).
Eksempel 15
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-brombenzamid
<1>H NMR (CDCI3) 8: 2,47 (3H, s), 2,71 (2H, t), 2,89 (2H, t), 3,60 (2H, s), 7,10 (1H, d), 7,30 (1H, m), 7,43 (1H, s), 7,64 og 7,74 (4H, ABq), 7,70 (1H, s).<m>/z(Cl): 347, 345 (MH<+>; 100%).
Eksempel 16
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-ylH-metylbenzamid
<1>H NMR (CDCI3) 8: 2,44 (3H, s), 2,48 (3H, s), 2,75 (2H, t), 2,90 (2H, t), 3,63 (2H, s), 7,10 (1H, d), 7,28 og 7,78 (4H, ABq), 7,30 (1H, m), 7,44 (1H, s), 7,74 (1H,m). m/z(CI): 281,2 (MH<+>; 100%).
Eksempel 17
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-nitrobenzamid
<1>H NMR (CDCI3) 8: 2,48 (3H, s), 2,71 (2H, t), 2,92 (2H, t), 3,61 (2H, s), 7,13
(1H, d), 7,34 <1H, dd), 7,42 <1H, s), 7,71 (1H, t), 8,00 (1H, d), 8,26 (1H. d), 8,40 (1H, d), 8,70 (1H, t);<m>/z(Cl): 312,1 (MH<+>; 100%).
Eksempel 18
N-(2-metyl-1,2,3,4-tetrahydroisokinoHn-7-yl)-4-etoksybenzamid
<1>H NMR (CDCI3) 8: 1,46 (3H, m), 2,47 (3H, s), 2,71 (2H, t), 2,90 (2H, t), 3,61
<2H, s), 4,11 <2H, m), 7,14 (1H, d), 7,30 (1H, m), 7,49 (1H, s), 7,68 (1H, s), 7,82 (2H, d), 8,10 (3H, m);<m>/z(Cl): 311,2 (MH<+>; 100%).
Eksempel 19
N-(2-metyl-1,2,3,4-tetrahydroisokrnolin-7-yl)-4-tr-butylbenzamid<1>HNMR{CDCI3) 8: 0,93 (3H, t), 1,25- 1,48 (2H, m), 1,52- 1,70 (2H, m), 2,51
(3H, s), 2,66 (2H, m), 2,80 (2H, t), 2,95 (2H, t), 3,69 (2H, s), 7,12 (1H, d), 7,20 (1H, d), 7,29 (2H, d), 7,32 (1H, m), 7,47 (1H, s), 7,78 (2H, d), 7,93 (1H, d);<m>/z(Cl): 323,2 (MH<+>; 100%).
Eksempel 20
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-2-acetoksybenazmid
<1>H NMR (CDCI3) 5: 2,33 (3H, s), 2,48 (3H, s), 2,71 (2H, t), 2,91 (2H, t), 3,61
(2H, s), 7,10 (1H, d), 7,16 (1H, d), 7,23 (1H, m), 7,32 - 7,45 (2H, m), 7,52 (1H, t), 7,83 (1H, d), 7,94 (1H, s);<m>/2(Cl): 325,2 (MH<+>; 100%).
Eksempel 21
N-(2-mety 1-1,2,3,4-tetrahydroisokinolin-7-yl)-3-trifluormetylbenzamid
<1>H NMR (CDCI3) 8: 2,48 (3H, s), 2,73 (2H, t), 2,92 (2H, t), 3,62 (2H, s), 7,11(1H, d), 7,32 (1H, d), 7,42 (1H, s), 7,63 <1H, t), 7,75 - 7,91 (2H, m), 8,07 (1H, t), 8,12 (1H,s).
m/z(CI): 335,1 (MH<+>; 100%)
Eksempel 22
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-2,4-difluorbenzamid
<1>H NMR (CDCI3) 8: 2,47 (3H, s), 2,71 (2H, t), 2,92 (2H, t), 3,61 (2H, s), 6,95
(1H, m), 7,00 - 7,18 (2H, m), 7,32 (1H, dd), 7,44 (1H, s), 8,14 - 8,36 (2H, m). m/z(Cl): 303,1 (MH<+>; 100%).
Eksempel 23
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3,4-dimetoksybenzamid<m>/z(CI): 327,2 (MH<+>; 100%).
Eksempel 24
N-(2-metyl<->1,2,3,4-tetrahydroisokinolin-7-yl)-2-fluor-4-trifluormetyl-benzamid
<1>H NMR (CDCI3) 8: 2,47 (3H, s), 2,70 (2H, t), 2,92 (2H, t), 3,61 (2H, s), 7,11 (1H, d), 7,35 (1H, dd), 7,45 (2H, s), 7,50 (1H, s), 7,59 (1H, d), 8,20 - 8,40 (2H, br m). m/z(CI): 353,1 (MH<+>; 100%).
Eksempel 25
N-(2-metyl-1,2,3,4-tetrahydroisokrnolin-7-yl)-4-klor-3-nitrobenzamid 1H NMR (CDCI3) 8: 2,48 (3H, s), 2,72 (2H, t), 2,94 (2H, t), 3,60 (2H, s), 7,10
(1H, d), 7,32 (1H, d), 7,38 (1H, s), 7,67 (1H, d), 7,95 - 8,13 (2H, br m), 8,38 (1H,
d).
<m>/z(Cl): 348 (MH<+>; 33%), 346,1 (MH<+>; 100%). Eksempel 26 N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3,5-di-trifluormetylbenzamid<1>H NMR (CDCI3) 8: 2,52 (3H, s), 2,78 (2H, t), 2,94 (2H, t), 3,66 (2H, s), 7,14 (1H, d), 7,36 (1H, d), 7,42 (1H, s), 7,94 (1H, m), 8,04 (1H, s), 8,32 (2H, s).<m>/z(Cl): 403,1 (MH<+>; 100%). Eksempel 27 N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-2,4-diklor-5-fluorbenzamid<1>H NMR (CDCI3) 8: 2,47 (3H, s), 2,70 (2H, t), 2,91 (2H, t), 3,60 (2H, s), 7,11 (1H, d), 7,25 (1H, d), 7,38 (1H, s), 7,52 (1H, dd), 7,62 (1H, dd), 7,90 (1H, brs).<m>/z(Cl): 353,0 (MH+; 100%).
Eksempel 28
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-fluor-5-trifluormetyl-benzamid
<1>H NMR (CDCI3) 8: 2,49 (3H, s), 2,73 (2H, t), 2,91 (2H, t), 3,62 (2H, s), 7,13 (1H, d), 7,32 (1H, dd), 7,40 (1H, s), 7,50 (1H, d), 7,80 (1H, m), 7,90 (1H, s), 8,02
<1H,s).
m/z(CI): 353,1 (MH<+>; 100%).
Eksempel 29
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-metoksybenzamid ^H NMR (CDCI3) 8: 2,47 (3H, s), 2,71 (2H, t), 2,91 (2H, t), 3,60 (2H, s), 3,97 (3H, s), 6,96 (1H, d), 7,10 (1H, d), 7,29 (1H, m), 7,40 (1H, s), 7,67 (1H, s), 7,84 (1H, dd), 8,02 (1H, s), 8,05 (1H, d);<m>/z(Cl): 377, 375 (MH<+>; 30%).
Eksempel 30
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3,4,5-trimetoksybenzamid
<1>H NMR (CDCI3) 8: 2,42 (3H, s), 2,66 {2H, t), 2,88 {2H, t), 3,55 (2H, s), 3,83 (3H, s), 3,86 (6H, s), 7,00 (1H, s), 7,05 (1H, d), 7,19 (1H, s), 7,26 (1H, d), 7,34 (1H, s), 7,68 (1H, s), 7,94 (1H, s);<m>/2(Cl): 357,2 (MH<+>; 100%).
Eksempel 31
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-trifluormetoksybenzamid<1>H NMR {CDCI3) 8: 2,47 (3H, s), 2,70 (2H, t), 2,91 (2H, t), 3,60 (2H,s), 7,10 (1H, d), 7,25 (1H, m), 7,32 (2H, d), 7,40 (1H, s), 7,74 (1H, s), 7,90 (2H, d); m/z(CI): 351,1 (MH<+>; 100%).
Eksempel 32
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-pivaloylbenzamid-hydroklorid
Syren i Fremstilling 5 (200 mg, 1,0 mmol) og oksalylklorid (140 mg, 1,1 mmol) i diklormetan (10 ml) inneholdende DMF (5 dråper) ble omrørt ved 25°C i 1 time og deretter inndampet til tørrhet/vakuum. Residuet i diklormetan ble behandlet med aminet B5 (162 mg, 1,0 mmol) og holdt ved 25°C natten over. Opparbeidelse lignende den i Eksempel 2 ga tittelforbindelsen (110 mg), sm.p. 197 - 201 °C (fra metanol:eter).
1H NMR (fri base; 250 MHz; CDCI3)8: 1,38 (9H, s), 2,45 (3H, s), 2,68 (2H, t),
2,89 (2H, t), 3,55 (2H, s), 7,08 (1H, d), 7,30 (1H, d), 7,40 (1H, s), 7,49 (1H, t), 7,83 (1H, d), 7,95 (1H, d), 8,08 (1H, s), 8,14 (1H, s);<m>/z(Cl): 351,2 (MH<+>; 100%).
Eksempel 33
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-/so-propoksybenzamid
<1>H NMR (CDCI3) 6: 1,42 (6H, d, J = 6 Hz), 2,47 (3H, s), 2,71 (2H, t, J = 6 Hz), 2,91 (2H, t, J = 6 Hz), 3,60 (2H, s), 4,67 (1H, dt, J = 6 Hz), 6,96 (1H, d, J = 9 Hz), 7,10 (1H, d, J = 8 Hz), 7,30 (1H, m), 7,40 (1H, d, J = 2 Hz), 7,71 (1H, s), 7,80 (1H, dd, J = 2 og 9 Hz), 8,05 (1H, d, J = 2 Hz).
Eksempel 34
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-acetoksybenzamid
<1>H NMR (CDCI3) 5: 2,34 (3H, s), 2,48 (3H, s), 2,73 (2H, t, J = 6 Hz), 2,92 (2H, t,
J = 6 HZ), 3,62 (2H, s), 7,11 (1H, d, J = 8 Hz), 7,21 (2H, m), 7,31 (1H, m), 7,43 (1H, s), 7,75 (1H, s), 7,88 (2H, m);<m>/z(Cl: 325 (MH<+>; 100%)
Eksempel 35
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-cyklopentyloksybenzamid<1>H NMR (CDCI3) 5: 1,56 - 1,68 (2H, bm), 1,74 -1,97 (6H, bm), 2,61 (3H, s),
2,95 (4H, m), 3,79 (2H, s), 4,81 (1H, m), 6,38 (1H, s), 6,54 (1H, dd, J = 2 og 8 Hz), 6,85 (2H, m), 6,93 (2H, d, J = 8 Hz), 7,95 (2H, d, J = 8 Hz); m/2 (Cl): 349
<MH<+>; 20%)
Eksempel 36
N-(2-mety 1-1,2,3,4-tetrahydroisokinolin-7-yl)-4-cyklopropyl-metoksybenzamid
<1>H NMR (CDCI3) 8: 0,36 (2H, m), 0,66 (2H, m), 1,28 (1H, m), 2,44 (3H, s), 2,81
(2H, t, J = 6 Hz), 2,89 (2H, t, J = 6 Hz), 3,51 (2H, s), 3,86 (2H, m), 6,34 (1H, d, J = 2 Hz), 6,50 (1H, dd, J = 2 og 8 Hz), 6,92 (2H, m), 7,06 (1H, d, J = 8 Hz), 7,31 (1H, dd, J = 2 og 8 Hz), 7,82 (1H, m), 8,00 (1H, m);<m>/z(Cl): 337 (MH<+>; 100%).
Eksempel 37
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-cyano-4-metoksybenzamid
NMR (CDCI3) 5: 2,47 (3H, s), 2,70 (2H, t, J = 6 Hz), 2,91 (2H, t, J = 6 Hz),
3.59 (2H, s), 4,02 (3H, s), 7.09 (2H, t, J = 8 Hz), 7,29 (1H, dd, J = 2 og 8 Hz), 7,39 (1H, d, J = 2 Hz), 7,80 (1H, s), 8,10 (2H, m); ™/z (Cl): 322 (MH<+>; 100%) •
Eksempel 38
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-2-naftamid
<1>H NMR (CDCI3) 8: 2,50 (3H, s), 2,75 (2H, t, J = 6 Hz), 2,94 (2H, t, J = 6 Hz), 3.65 (2H, s), 7,13 (1H, d, J = 8 Hz), 7,38 (1H, dd, J = 2 og 8 Hz), 7,50 (1H, d, J
= 2 Hz), 7,56 - 7,22 (3H, bm), 7,88 - 8,07 (4H, bm), 8,38 (1H, s);<m>/z(Cl): 317
(MH<+>; 100%)
Eksempel 39
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-methybenzamid
<1>H NMR (CDCI3) 8: 2,47 (6H, bs). 2,71 (2H, t, J = 6 Hz), 2,91 <2H, t, J = 6 Hz),
3.60 (2H, s), 7,10 (1H, d, J = 8 Hz), 7,23 - 7,39 (2H, bm), 7,42 (1H, s), 7,70 (2H, dd, J - 2 og 8 Hz), 8,02 (1H, d, J = 2 Hz);<m>/z(Cl): 359, 361 (MH<+>; 100%)
Eksempel 40
N-(2-metyl-1,2,3,4-tetrahydroisokinoljn-7-yl)-naftalen-1-karboksamid .
<1>H NMR (CDCI3) 8: 2,50 (3H, s), 2,75 (2H, t, J = 6 Hz), 2,92 (2H, t, J = 6 Hz),
3.66 (2H, s), 7,12 (1H, d, J = 8 Hz), 7,35 (1H, d, J = 8 Hz), 7,45 - 7,70 (5H, m), 7,75 (1H, d, J = 8 Hz), 7,90 (1H, m), 7,96 (1H, d, J = 7 Hz), 8,36 (1H, d, J = 8 Hz).
m/z(API<+>): 317,2 (MH<+>; 100%).
Eksempel 41
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-klor-4-metoksybenzamid<1>H NMR (CDCi3) 8: 2,47 (3H, s), 2,70 (2H, t, J = 6 Hz), 2,91 (2H, t, J = 6 Hz),
3,59 (2H, s), 3,97 (3H, s), 6,99 (1H, d, J = 9 Hz), 7,09 (1H, d, J = 8 Hz), 7,32 (1H, dd, J = 2 og 8 Hz), 7,40 (1H, s), 7,79 (2H, m), 7,90 (1H, d, J = 2 Hz).
Eksempel 42
N-(2-metyl-1,2,3l4-tetrahydroisokinolin-7-yl)-4-te/f-butoksybenzamid
<1>H NMR (CDCI3) 5: 1,41 (9H, s), 2,47 (3H, s), 2,71 (2H, t, J = 6 Hz), 2,91 (2H, .t, J = 6 Hz), 3,61 (2H, s), 7,03 - 7,12 (3H, b m), 7,30 (1H, dd, J = 2 og 8 Hz), 7,43 (1H, d, J = 2 Hz), 7,68 (1H, s), 7,79 (2H, d, J = 9 Hz);<m>/z(Cl): 339 (MH<+>;
100%).
Eksempel 43
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-n-propoksybenzamid
<1>H NMR (CDCI3) S: 1,01 (3H, t, J = 7 Hz), 1,83 (2H, m), 2,87 (3H, s), 3,19 (2H,
m), 3,44 (2H, t, J = 7 Hz), 3,61 (2H, s), 3,87 (2H, m), 4,40 (2H, s), 6,93 (2H, d), 7,09 (1H, d), 7,51 (1H, dd, J = 8, 2 Hz), 7,61 (1H, d,), 7,92 (2H, d), 8,39 (1H, s).
Eksempel 44
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl) benzotriazol-5-karboksamid m/z(Cl): 308 (MH<+>; 65%)
Eksempel 45
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)benzotiazol-6-karboksamid<1>H NMR (CDCI3) 5: 2,48 (3H, s), 2,72 (2H, t, J = 6 Hz), 2,93 (2H, t, J = 6 Hz), 3,62 (2H, s), 7,13 (1H, d, J = 8 Hz), 7,34 (1H, dd, J = 2 og 8 Hz), 7,45 (1H, d, J = 2 Hz), 7,88 (1H, s), 7,97 (1H, dd, J = 2 og 8 Hz), 8,22 (1H, d, J = 8 Hz), 8,56 (1H, d, J = 2 Hz), 9,15 (1H, s);<m>/2(Cl): 322 (MH~: 100%)
Eksempel 46
N-(2-mety 1-1,2,3,4-tetrahydroisokinolin-7-yl)-2,3-dihydrobenzofuran-5-karboksamid
<1>H NMr CCDCI3) 5: 2,48 (3H, s), 2,73 (2H, t, J = 6 Hz), 2,91 (2H, t, J = 6 Hz), 3,27 (2H, t, d = 9 Hz), 3,62 (2H, s), 4,66 (2H, t, J = 9 Hz), 6,83 (1H, d, J = 8 Hz), 7,08 (1H, d, J = 8 Hz), 7,28 (1H, dd, J = 2 og 8 Hz), 7,42 (1H, s), 7,64 (1H, d, J = 8 Hz), 7,76 (2H, m).<m>/2.(CI): 309 (MH<+>; 100%).
Eksempel 47
N-<2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-2-metylbenzimidazol-5-karboksamid
<1>H NMR (d4MeOH) 6: 2,51 (3H, s), 2,61 (3H, s), 2,92 (2H, t, J = 6 Hz), 2,96 (2H,
t, J = 6 Hz), 3,69 (2H, s), 7,14 (1H, d, J = 9 Hz), 7,47 (3H, m), 7,56 (1H, d, J = 8 Hz), 7,80 (1H, dd, J = 2 og 8 Hz), 8,10 (1H, s);<m>/z(Cl): 321 (MH<+>; 100%).
Eksempel 48
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-klor-4-/so-propoksybenzamid
<1>H NMR (CDCI3) 5: 1,42 (6H, d, J = 6 Hz), 2,49 (3H, s), 2,74 (2H, t, J = 6 Hz), 2,92 (2H, t, J = 6 Hz), 3,63 (2H, s), 4,67 (1H, kintet, J = 6 Hz), 6,98 (1H, d, J = 9 Hz), 7,09 (1H, d, J = 8 Hz), 7,28 (1H, dd, J = 2 og 8 Hz), 7,40 (1H, d, J = 2 Hz), 7,67 - 7,81 (2H,. bm), 7,88 (1H, d, J = 2 Hz);<m>/z(Cl): 359 (MH<+>; 100%).
Eksempel 49
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid
<1>H NMR (CDCI3) 8: 1,51 (3H, t, J = 7 Hz), 2,49 (3H, s), 2,74 (2H, t, J = 6 Hz), 2,92 (2H, t, J = 6 Hz), 3,62 (2H, s), 4,17 (2H, q, J = 7 Hz), 6,93 (1H, d, J = 9 Hz), 7,09 (1H, d, J = 8 Hz), 7,28 (1H, dd, J = 2 og 8 Hz), 7,39 (1H, d, J = 2 Hz), 7,71 (1H, s), 7,80 (1H, dd, J = 2 og 9 Hz), 8,05 (1H, d, J = 2 Hz);<m>/2(Cl): 389, 391
(MH<+>; 100%)
Eksempel 50
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-klor-4-etoksybenzamid
<1>H NMR<*>(CDCl3) 8: 1,51 (3H, t, J = 7 Hz), 2,49 (3H, s), 2,74 (2H, t, J = 6 Hz),
2,92 (2H, t, J = 6 Hz), 3,62 (2H, s), 4,18 (2H, q, J = 7 Hz), 6,96 (1H, d, J = 9 Hz), 7,09 (1H, d, J = 8 Hz), 7,31 (1H, dd, J = 2 og 8 Hz), 7,39 (1H, d, J = 2 Hz), 7,76 (2H, m), 7,89 (1H, d, J = 2 Hz); ™/2(CI): 345 (MH<+>; 100%)..
Eksempel 51
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metoksy-3-trifluormetyl-benzamid
<1>H NMR (CDCI3) 5: 2,48 (3H, s), 2,72 (2H, t, J = 6 Hz), 2,92 (2H, t, J = 6 Hz),
3,60 (2H, s), 3,98 (3H, s), 7,09 (2H, m), 7,32 (1H, dd, J = 2 og 8 Hz), 7,41 (1H, d, J = 2 Hz), 7,83 (1H, s), 8,07 (2H, m);<m>/z(Cl): 365 (MH<+>; 100%)
Eksempel 52
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3,5-diklor-4-metoksybenzamid<1>H NMR (CDCI3) 5: 2,46 (3H, s), 2,69 (2H, t, J = 6 Hz), 2,90 (2H, t, J = 6 Hz),
3,57 (2H, s), 3,96 (3H, s), 7,09 (1H, d, J = 8 Hz), 7,30 (1H, dd, J = 2 og 8 Hz), 7,34 (1H, d, J = 2 Hz), 7,81 (2H, s), 7,89 (1H, s);<m>/z(Cl): 365 (MH<+>; 100%)
Eksempel 53
N-(2-metyl)-1,2,3,4-tetrahydroisokinolin-7-yl)-3,5-diklor-4-etoksybenzamid<1>H NMR (CDCI3) 5: 1,49 .(3H, t, J = 7 Hz), 2,46 (3H, s), 2,69 (2H, t, J = 7 Hz),
2.90 (2H, t, J = 6 Hz), 3,56 (2H, s), 4,17 (2H, q, J = 7 Hz), 7,09 (1H, d, J = 8 Hz), 7,29 (1H, dd, J = 2 og 8 Hz), 7,32 (1H, s), 7,80 (2H, s), 7,86 (1H, s);<m>/z(Cl): 379 (MH+; 100%)
Eksempel 54
N-(2-metyl)-1,2,3,4-tetrahydroisokinolin-7-yl)-3,5-diklor-4-/so-propoksybenzamid
<1>H NMR (CDCI3) 5: 1,39 (6H, d, J = 6 Hz), 2,47 (3H, s), 2,70 (2H, t, J = 6 Hz),
2.91 (2H, t, J = 6 Hz), 3,59 (2H, s), 4,72 (1H, kintet, J = 6 Hz), 7,10 (1H, d, J = 8 Hz), 7,30 (1H, dd, J = 2 og 8 Hz), 7,36 (1H, s), 7,76 (d, J = 2 Hz), 7,80 (2H, s).
m/z(CI): 393 (MH<+>, 100%)
Eksempel 55
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-metylsulfonylbenzamid 1H NMR (CDCI3) 8: 2,48 (3H, s), 2,71 (2H, t, J = 6 Hz), 2,92 (2H, t, J = 6 Hz),
3,12 (3H, s), 3,60 (2H, s), 7,12 (1H, d, J = 8 Hz), 7,35 (1H, dd, J = 2 og 8 Hz), 7,42 (1H, s), 7,73 (1H, t, J = 8 Hz), 8,05 (1H, s), 8,11 (1H, d, J = 8 Hz), 8,22 (1H, d, J = 8 Hz), 8,40 (1H, s);<m>/z(Cl): 345 (MH<+>; 100%)
Eksempel 56
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-terf-butylbenzamid
En oppløsning av aminet B5 (162 mg; 1,0 mmol) og 3-brom-4-fert-butylbenzosyre (257 mg; 1,0 mmol) i vannfri N,N-dimetylformamid (7 ml), ble behandlet med 1-hydroksybenzotriazol (135 mg; 1,0 mmol) og 1-(3-dimetylaminopropyl)-3-etylkarbodiimid (192 mg; 1,0 mmol) ved 25°C. Blandingen ble ristet i 48 timer før produktet ble ekstrahert i diklormetan og vasket med 10% vandig NaHC03, vann<p>g til slutt saltvann. Det organiske laget ble tørket over MgSO-4 og inndampet/vakuum, hvilket ga 373 mg av tittelforbindelsen i 93% utbytte.
<1>H NMR (CDCI3)8: 1,54 (9H, s), 2,47 (3H, s), 2,71 (2H, t, J = 6 Hz), 2,91 (2H, t, J = 6 Hz), 3,60 (2H, s), 7,10 (1H, d, J = 8 Hz), 7,31 (1H, dd, J = 2 og 8 Hz), 7,41 (1H, d, J = 2 Hz), 7,54 (1H, d, J = 8 Hz), 7,72 (2H, m), 8,06 (1H, d, J = 2 Hz).
Eksempel 57
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-2-brom-5-metoksybenzamid<1>H NMR (CDCI3) 8: 2,47 (3H, s), 2,70 (2H, t, J = 6 Hz), 2,91 (2H, t, J = 6 Hz), 3,61 (2H, s), 3,83 (3H, s), 6,88 (1H, dd), 7,11 (1H, d, J = 8 Hz), 7,21 (1H, d), 7,31 (1H, dd, J = 8, 2 Hz), 7,44 (1H, d,), 7,50 (1H, d), 7,71 (1H, s); ™/z (API+);
375,0 (MH<+>; 100%)
Eksempel 58
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-fIuor-3-metoksybenzamid-hydroklorid
<1>H NMR (fri base CDCI3) 8: 2,53 (3H, s), 2,76 (2H, t, J = 6 Hz), 2,97 (2H, t, J = 6 Hz), 3,63 (2H, s), 4,01 (3H, s), 7,16 (1H, dd, J = 6, 2Hz), 7,21 (1H, d), 7,32 - 7,50 (3H, m), 7,64 (1H, dd, J = 6, 2Hz), 8,00 (1H, brs);<m>/z(API+): 315,1 (MH<+>;
100%)
Eksempel 59
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-1-metylpyrazol-4-karboksamid<1>H NMR (250 MHz, CDCI3) 8: 2,30 (3H, s), 2,53 (2H, m), 3,40 (2H, s), 3,78 (3H,
s), 6,91 (1H, d, J = 8 Hz), 7,11 (1H, m), 7,21 (1H, d), 7,20 (1H, brs), 7,46 (1H, br), 7,68 (1H, s), 7,76 (1H, s);<m>/z(API+): 271 (MH<+>; 100%)
Eksempel 60
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-trifluormetylpyrazol-3-karboksamid
<1>H NMR (250 MHz, Dq DMSO) 8: 2,41 (3H, s), 2,81 - 2,85 (4H, m), 7,13 (1H, d,
J = 8 Hz), 7,46 (2H, m), 8,64 (1H, s);<m>/z(API+): 325 (MH<+>; 100%)
Eksempel 61
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-2-metyltiazol-4-karboksamid<1>H NMR (250 MHz, CDCI3) 8: 2,47 (3H, s), 2,67 - 2,76 (5H, m), 2,89 (2H, m),
3,60 (2H, s), 7,10 (1H, d, J = 8 Hz), 7,40 (1H, dd, J = 8, 2 Hz), 7,49 (1H, brs), 8,02 (1H, br), 9,12 (1H, br); ™ tz (API+): 288 (MH<+>; 100%)
Eksempel 62
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-5-metylisoksazol-3-karboksamid
<1>H NMR (250 MHz, CDCI3) 8: 2,46 (3H, s), 2,51 (3H, s), 2,68 (2H, m), 2,90 (2H,
m), 3,58 (2H, s), 6,51 (1H, s), 7,10 (1H, d, J = 8 Hz), 7,33 (1H, dd, J = 8, 2 Hz), 7,41 (IH.brs), 8,47 (1H, brs);<m>/z(API+): 272 (MH<+>; 100%)
Eksempel 63
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-5-fert-butylisoksazol-3-karboksamid 1H NMR (250 MHz, CDCI3) 8: 1,38 (9H, s), 2,46 (3H, s), 2,66 - 2,71 (2H, m),
2.89 (2H, m), 3,59 (2H, s), 6,48 (1H, s), 7,10 (1H, d, J = 8 Hz), 7,30 (2H, brd, J = 8 Hz), 7,41 (1H, brs), 8,43 (1H, brs);<m>/z(API+): 314 (MH<+>; 100%)
Eksempel 64
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-metoksyisoksazol-5-karboksamid-hydroklorid
<1>H NMR (250 MHz, DMSO-d6) 8: bla. 2,81 (3H, brs), 3,88 (3H, s), 7,00 (1H, s),
7,16 (2H, d, J = 8 Hz), 7,52 (2H, m); ™/z (API+): 288 (MH<+>; 100%)
Eksempel 65
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)indol-2-karboksamid.
B5 ble omdannet til tittelforbindelsen ved omsetning med indol-2-karboksylsyre, på lignende måte som metoden ifølge Beskrivelse 7.
<1>H NMR (Dg DMSO) 8: 2,84 (3H, s), 3,07 (2H, t, J = 6 Hz), 3,29 (2H,t, J = 6 Hz), 3,97 (2H, s), 5,01 (1H, m), 7,53 (2H, m), 7,70 (2H, m), 8,08 (4H, m), 9,90 (1H, brs).
m/z (API+): 306 (MH+; 100%)
Eksempel 66
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-/so-propylbenzamid-hydroklorid
<1>H NMR (fri base, CDCI3) 8: 1,26 (6H, d, J = 7 Hz), 2,48 (3H, s), 2,75 (2H, m), 2.90 (2H, m), 3,41 (1H, sep, J = 7 Hz), 3,62 (2H, s), 7,09 (1H, d, J = 8 Hz), 7,31 (2H, dd, J = 8, 2 Hz), 7,37 (2H, m), 7,76 (1H, dd, J = 8, 2 Hz), 7,90 (1H, brs),
8,02 (1H, d, J = 2 Hz);<m>/z(API+): 387, 389 (MH<+>; 100%)
Eksempel 67
N-(2-metyl-t,2,3,4-tetrahydroisokinolin-7-yl)-3-cyano-4-/'so-propylbenzamid-hydroklorid
NMR (fri base, CDCI3) 8: 1,25 (6H, d, J = 7 Hz), 2,37 (3H, s), 2,60 (2H, m),
2,80 (2H, m), 3,45 (1H, sep, J = 7 Hz), 3,62 (2H, s), 7,00 (1H, d, J = 8 Hz), 7,25 (2H, m), 7,41 (1H, d), 7,97 (1H, dd, J = 8, 2 Hz), 8,03 (1H, d, J = 2 Hz), 8,10 .
(1H,brs);
<m>/z(API+): 334 (MH<+>; 100%)
Eksempel 68
N-(2-metyl-1,2,3,4-tetjahydroisokinolin-7-yl)-3-fluoM-metoksybenzarriid<1>H NMR (250 MHz CDCI3) 8: 2,48 (3H, s), 2,73 (2H, t, J = 6 Hz), 2,92 (2H, t, J = 6 Hz), 3,61 (2H, s), 3,96 (3H, s), 7,05 (2H, m), 7,30 (1H, dd, J = 6, 2Hz), 7,40
(1H, s), 7,63 (2H, d), 7,80 (1H, d);<m>/z(API+): 315,2 (MH<+>; 100%)
Eksempel 69
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-cyano-4-n-propoksy-benzamid
<1>H NMR (250 MHz CDCI3) 8: 1,10 (3H, t, J = 8 Hz), 1,92 (2H, m), 2,47 (3H, s), 2,70 (2H, t, J = 6 Hz), 2,90 (2H, t, J = 6 Hz), 3,58 (2H; s), 4,10 (2H, , J = 8 Hz), 7,02 (1H, d,), 7,09 (1H, d), 7,33 (1H, dd, J = 6, 2Hz), 7,38 (1H, s), 8,02 (1H, s), 8,08 (2H, m);
m/z(API+): 350,2 (MH<+>; 100%)
Eksempel 70
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-cyano-4-etoksybenzamid<1>H NMR (250 MHz CDCI3) 8: 1,53 (3H, t, J = 8 Hz), 2,49 (3H, s), 2,74 (2H, t, J = 6 Hz), 2,92 (2H, t, J = 6 Hz), 3,62 (2H, s), 4,23 (2H, q, J = 8 Hz), 7,04 (1H, d), 7,10 (1H, d), 7,32 (1H, dd, J = 6, 2Hz), 7,40 (1H, d), 7,92 (1H, s), 8,09 (2H, m);
m/z(API+): 336,2 (MH<+>; 100%)
Eksempel 71
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-n-propoksy-benzamid<1>H NMR (250 MHz CDCI3) 5: 1,10 (3H, t, J = 8 Hz), 1,90 (2H, m), 2,46 (3H, s),
2,69 (2H, t, J = 6 Hz), 2,90 (2H, t, J - 6 Hz), 3,58 (2H, s), 4,05 (2H, t, J = 8 Hz), 6,93 (1H, d), 7,09 (1H, d), 7,30 (1H, dd, J = 6, 2Hz), 7,39 (1H, d), 7,72 (1H, s), 7,80 (1H, dd, J = 6, 2Hz), 8,05 (1H, d);<m>/z(API+): 403,1 (MH<+>; 90%)
Eksempel 72
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etylbenzamid
<1>H NMR (250 MHz CDCI3) 8: 1,26 (3H, t, J = 8 Hz), 2,46 (3H, s), 2,69 (2H, t, J = 6 Hz), 2,82 (2H, q, J = 8 Hz), 2,90 (2H, t, J = 6.Hz), 3,59 (2H, s), 7,10 (1H, d), 7,28 (1H, dd, J = 6, 2 Hz), 7,34 (1H, d), 7,41 (1H, d), 7,74 (2H, dd), 8,03 (1H,s);
m/z(API+): 373,1 (MH<+>; 100%)
Eksempel 73
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-jod-4-metoksybenzamid
<1>H NMR (250 MHz CDCI3) 8: 2,50 (3H, s), 2,79 (2H, t, J = 6 Hz), 2,93 (2H, t, J = 6 Hz), 3,64 (2H, s), 3,94 (3H, s), 6,85 (1H, d), 7,21 (1H, d), 7,08 (1H, d), 7.34 (1H, dd, J = 6, 2Hz), 7,38 (1H, d), 7,89 (1H, dd), 8,12 (1H, s), 8,29 (1H, d);
m/z(API+): 423,0 (MH<+>; 100%)
Eksempel 74
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-/so-propoksy-3-trifluormetyl-benzamid
<1>H NMR (250 MHz CDCI3) 8: 1,39 (6H, d, J = 8 Hz), 2,48 (3H, s), 2,70 (2H, t, J = 6 Hz), 2,87 (2H, t, J = 6 Hz), 3,54 (2H, s), 4,72 (1H, m), 7,06 (2H, t), 7,30 (1H, dd, J = 6, 2Hz), 7,37 (1H, s), 8,03 (3H, m); ™/z (API+): 393,2 (MH<+>; 100%)
Eksempel 75
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-klor-3-metoksybenzamid
<1>H NMR (250 MHz CDCI3) 8: 2,47 (3H, s), 2,70 (2H, t, J = 6 Hz), 2,88 (2H, t, J = 6 Hz), 3,59 (2H, s), 3,98 (3H, s), 7,11 (1H, d), 7,21 (1H, d), 7,30 (2H, m), 7,40 (1H, d), 7,45 (1H, d), 7,75 (1H, s);<m>/z(API+): 331,1 (MH<+>; 100%)
Eksempel 76
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-n-propoksy-3-trifluormetyl-benzamid
<1>H NMR (250 MHz CDCI3) 6: 1,08 (3H, t, J = 8 Hz), 1,86 (2H, m), 2,46 (3H, s),
2,70 (2H, t, J = 6 Hz), 2,90 (2H, t, J = 6 Hz), 3,58 (2H, s), 4,08 (2H, t, J = 8 Hz), 7,07 (2H, m), 7,29 (1H, dd, J = 6, 2Hz), 7,41 (1H, d), 7,97 (1H, s), 8,03 (1H, d), 8,07 (1H,s);
m/z(API+): 393,2 (MH<+>; 100%)
Eksempel 77
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-klor-4-*ert-butylbenzamid-hydroklorid
<1>H NMR (250 MHz, DMSO-d6) 5: bia. 1,68 (9H, s), 7,36 (1H, d, J = 8 Hz), 7,77 (3H, m), 8,00 (1H, dd, J = 8, 2 Hz), 8,11 (1H, d, J = 2 Hz);
<m>/z(API+): 357 (MH<+>; 100%)
Eksempel 78
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metoksybenzamid-hydroklorid.
B5 ble omdannet til tittelforbindelsen i 95% utbytte ved omsetning med 4-metoksybenzoylklorid på en måte lignende den beskrevet i Eksempel 3.
<1>H NMR (D20) 5: 3,13 (3H, s), 3,25 (2H, brs), 3,68 (2H, brs), 3,96 (3H, s), 4,48 (2H, brs), 7,15 (2H, d, J = 9 Hz), 7,35-7,50 (3H, m), 7,90 (2H, d, J = 9 Hz).
Eksempel 79
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-fluor-3-metylbenzamid-hydroklorid
<1>H NMR^fri base CDCI3) 6: 2,34 (3H, s), 2,46 (3H, s) 2,69 (2H, t, J = 6 Hz), 2,90 (2H, t, J = 6 Hz), 3,58 (2H, s), 7,08 (2H, m), 7,30 (1H, dd), 7,40 (1H, d,), 7,60 - 7,80 (2H, m), 7,74 (1H, s);<m>/z(API+): 299,2 (MH<+>; 100%)
Eksempel 80
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-klor-4-/so-propylbenzamid<1>H NMR (fri base 250 MHz CDCI3) 5: 1,40 (6H, d, J = 7 Hz), 2,59 (3H, s), 2,82.
(2H, m), 3,03 (2H, m), 3,58 (1H, sep, J = 7 Hz), 3,71 (2H, s), 7,23 (1H, d, J = 8 Hz), 7,42 (1H, dd, J = 8, 2 Hz), 7,53 (2H, m), 7,82 (2H, m), 7,96 (1H, d, J = 2 Hz);
<m>/z(API+): 343, 345 (MH<+>; 100, 50%)
Eksempel 81
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-cyano-4-etylbenzamid-hydroklorid
<1>H NMR (fri base 250 MHz, CDCI3) 8: 1,31 (3H, t, J = 8 Hz), 2,43 (3H, s), 2,66
(2H, m), 2,90 (4H, m), 3,55 (2H, s), 7,09 (1H, d, J = 8 Hz), 7,28 (2H, dd, J = 8, 2 Hz), 7,36 (1H, brs), 7,44 (1H, d, J = 8 Hz), 7,86 (1H, brs), 8,00 (1H, dd, J = 8, 2 Hz), 8,09 (1H, d, J = 2 Hz);<m>/z(API+): 320 (MH<+>; 100%)
Eksempel 82
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-;'so-propyl-3-trifluormetyl-benzamid-hydroklorid
<1>H NMR (fri base 250 MHz, CDCI3) 8: bla. 1,38 (6H, d, J = 6 Hz), 2,32 (3H, s), 2,57 (2H, m), 2,76 (2H, m), 3,25 (1H, m), 3,45 (2H, s), 6,95 (1H, d, J = 8 Hz), 7,16 (1H, brd, J = 8 Hz), 7,26 (1H, brs), 7,43 (1H, d, J = 8 Hz), 7,72 (1H, brs), 7,84 (1H, d, J = 8 Hz), 7,93 (1H, brs); ™/z (API+): 377 (MH<+>; 100%)
Eksempel 83
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4^tyl-3-trifluormetylbenzamid-hydroklorid
<1>H NMR (fri base 250 MHz, CDO3) 5: bia. 1,25 (3H, t, J = 8 Hz), 2,46 (3H, s),
2,68 (2H, mh 2,90 (2H, m), 3,58 (2H, brs), 7,10 (1H, d, J = 8 Hz), 7,30 (1H, dd, J = 8, .2 Hz), 7,47 (1H, d, J = 8 Hz), 7,40 (1H, brs), 7,78 (1H, brs), 7,97 (1H, dd), 8,08 (1H, brs);<m>/z(API-): 361 (MH~; 100%)
Eksempel 84
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-cyano-4-/so-propoksy-benzamid-hydroklorid
<1>H NMR (250 MHz CDCI3) 8:1,45 (6H, d, J = 8 Hz), 2,47 (3H, s), 2,70 (2H, t, J
= 6 Hz), 2,91 (2H, t, J = 6 Hz), 3,59 (2H, s), 4,75 (1H, m), 7,04 (1H, d), 7,10 (1H, d), 7,29 (1H, dd, J = 6, 2Hz), 7,37 (1H, d), 7,71 (1H, s), 8,05 (2H, m);
<m>/z(API+): 350,2 (MH<+>; 100%)
Eksempel 85
N-(1,2,3,4-tetrahydroisokinolin-7-yl)^-metoksy-3-trifluormetylbenzamid<1>H NMR (250 MHz CDCI3) 8: 2,65 (2H, t, J = 6 Hz), 3,00 (2H, t, J = 6 Hz), 3,85 (3H, s), 3,89 (2H, s), 6,95 <2H, d), 7,17 (1H, dd, J = 6, 2Hz), 7,25 (1H, s), 7,57 (1H, s), 7,93 (2H, m);<m>/z(API+): 351,1 (MH<+>; 100%)
Eksempel 86
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metyl-3-metylsulfonyl-benzamid
<1>H NMR (CDCI3) 8: 2,48 (3H, s), 2,71 (2H, t, J = 7 Hz), 2,80 (3H, s), 2,92 (2H, t,
J = 7 Hz), 3,15 (3H, s), 3,61 (2H, s), 7,13 (2H, d), 7,35 (1H, dd), 7,43 (1H, s), 7,52 (1H, d), 7,93 (1H, s), 8,14 (1H, dd), 8,45 (1H, d);<m>/z(API<+>): 359,2 (MH<+>; 100%)
Eksempel 87
N-(2-metyM,2,3,4-tetrahydroisokinolin-7-yl)-4-etyl-3-metylsulfonyl-benzamid
<1>H NMR (CDCI3) 8: 1,49 (3H, t, J = 8 Hz), 2,59 (3H, s), 2,81 (2H, t, J = 7 Hz),
3,03 (2HJ, J = 7 Hz), 3,27 (5H, m), 3,71 (2H, s), 7,23 (2H, d), 7,46 (1H, dd), 7,54 (1H, d):7,69 (1H, d), 8,04 (1H, s), 8,29 (1H, dd), 8,55 (1H, d);<m>/z(API<+>): 373,2 (MH<+>; 100%)
Eksempel 88
N-{2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-metylsulfonyl-4-/so-propylbenzamid
<1>H NMR (CDCI3) 5:1,27 (6H, d, J = 8 Hz), 2,37 (3H, s), 2,60 (2H, t, J = 7 Hz),
2,81 (2H, t, J = 7 Hz), 3,06 (3H, s), 3,46 (2H, s), 3,85 (1H, m), 7,00 (2H, d), 7,26 (1H, dd), 7,31 (1H, d), 7,57 (1H, d), 8,10 (1H, dd), 8,21 (1H, s), 8,37 (1H, d);
m/z(API<+>): 387,2 (MH<+>; 100%)
Eksempel 89
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-metylsulfonyl-4-metoksybenzamid
<1>H NMR (CDCI3) 8: 2,31 (3H, s), 2,54 (2H, t, J = 7 Hz), 2,75 (2H, t, J = 7 Hz), 3,09 (3H, s), 3,42 (2H, s), 3,87 (3H, s), 6,95 (2H, m), 7,12 (1H, s), 7,21 (1H, d), 8,08 (2H, m), 8,23 (1H, d);<m>/z(API<+>): 375,2 (MH+; 75%)
Eksempel 90
N-(2-metyl'1,2,3,4-tetrahydroisokinolin-7-yl)-3-trifluoracetylbenzamid-hydroklorid
<1>H NMR (fri base CDCI3) 5: 2,47 (3H, s), 2,46 (3H, s) 2,77 (2H, t, J = 6 Hz),
2;94 (2H, t, J = 6 Hz), 3,63 (2H, s), 7,13 (1H, d, J = 6 Hz), 7,45 (1H, d, J = 6 Hz), 7,54 (1H, t, J = 6 Hz), 7,81 (1H, d, J = 6 Hz), 7,97 (1H, d, J = 6 Hz); 8,20 (1H, s);
<m>/z(API+): 363,2 (MH<+>; 60%)
Eksempel 91
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metoksy-3-pentafluoretyl-benzamid-hydroklorid
<1>H NMR (fri base 250 MHz, CDCI3) 8: 2,46 (3H, s), 2,70 (2H, m), 2,90 (2H, m),
3,59 (2H, s), 3,94 (3H, s), 7,10 (2H, m), 7,30 (1H, dd, J = 8, 2 Hz), 7,39 (1H, brs), 7,73 (1TH, brs), 8,01 (1H, d, J = 2 Hz), 8,06 (1H, dd, J = 9, 2 Hz);<m>/z(API+):415(MH+; 100%)
Eksempel 92
N-(2-n-propyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid<1>H NMR (CDCI3) 8: 0,95 (3H, t, J = 7 Hz), 1,51 (3H, t, J = 7 Hz), 1,62 (2H, m),
2.47 (2H, t, J = 8 Hz), 2,72 (2H, t, J = 6 Hz), 2,88 (2H. t, J = 6 Hz), 3,61 (2H, s), 4,17 (2H, q, J = 7 Hz), 6,92 (1H, d, J = 9 Hz), 7,07 (1H, d, J = 8 Hz), 7,26 (1H, dd, J = 8, 2 Hz), 7,39 (1H, d, J = 2 Hz), 7,72 (1H, brs), 7,79 (1H, dd, J = 9, 2 Hz), 8,04 (1H,d, J = 2Hz).
m/z(API<+>): 417, 419 (MH<+>; 95%)
Eksempel 93
N-(2-n-propyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metoksy-3-trifluormetylbenzamid
<1>H NMR {CDCI3) 8: 0,96 (3H, t, J = 7 Hz), 1,61 (2H, m), 2,47 (2H, t, J = 8 Hz), 2,73 (2H, t, J = 6 Hz), 2,88 (2H, t, J = 6 Hz), 3,62 (2H, s), 3,98 (3H, s), 7,08 (2H, m), 7,30 (1H, m), 7,41 (1H, d, J = 2 Hz), 7,76 (1H, brs), 8,05 (2H, m);<m>/z(API<+>): 393 (MH<+>; 100%)
Eksempel 94
N-(2-n-propy 1-1,2,3,4-tetrahydroiskinolin-7-yl)-3-klor-4-/so-propoksybenzamid
<1>H NMR (CDCI3) 8: 0,95 (3H, t, J = 7 Hz), 1,42 (6H, d, J = 6 Hz), 1,62 (2H, m),
2.48 (2H, t, J = 8 Hz), 2,73 (2H, t, J = 6 Hz), 2,88 (2H, t, J = 6 Hz), 3,63 (2H, s), 4,66 (1H, sept., J = 6 Hz), 6,98 (1H, d, J = 9 Hz), 7,08 (1H, d, J = 8 Hz), 7,26 (1H, m), 7,41 (1H, d, J = 2 Hz), 7,65 {1H, brs), 7,73 (1H, dd, J = 9, 2 Hz), 7,87 (1H,d, J = 2Hz).
<m>/z(API<+>): 387 (MH<+>; 90%)
Eksempel 95
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-cyano-4-/so-butylbenzamid-hydroklorid<1>H NMR (250 MHz, DMSO-d6) 6: bl. a. 0,95 (6H, d, J = 7 Hz), 1,99 (1H, sep, J = 7 Hz), 2,77 (2H, brs), 7,26 (1H, d, J = 8 Hz), 7,65 (3H, m), 8,21 (1H, dd, J = 8, 2
Hz), 8,41 (1H, d, J = 8 Hz);<m>/z(API+): 348 (MH<+>; 100%)
Eksempel 96
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-/so-butyl-3-trifluormetyl-benzamid-hydroklorid
<1>H NMR (250 MHz, DMSO-d6) 8: bl. a. 1,01 (6H, d, J = 6,5 Hz), 2,09 (1H, sep, J
= 6,5 Hz), 7,35 (1H, d, J = 8 Hz), 7,75 (3H, m), 8,32 (1H, d, J = 8 Hz);
m/z(API+): 391 (MH<+>; 100%)
Eksempel 97
N-(2-etyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid
<1>H NMR (CDCI3) 8: 1,20 (3H, t, J = 7 Hz), 1,51 (3H, t, J~7 Hz), 2,61 (2H, q, J = 7 Hz), 2,76 (2H, m), 2,90 (2H, m), 3,64 (2H, s), 4,16 (2H, q, J = 7 Hz), 6,91 (1H, d, J = 9 Hz), 7,07 (1H, d, J = 8 Hz), 7,26 (1H, m), 7,40 (1H, d, J = 2 Hz), 7,79 (2H, m), 8,05 (1H, d, J = 2 Hz);<m>/z(API<+>): 403, 405 (MH<+>; 65%)
Eksempel 98
N-(2-etyH,2,3,4-tetrahydro-isokinolin-7-ylH-metoksy-3-trifluormetyl-benzamid
<1>H NMR (CDCI3) 8: 1,21 (3H, t, J = 7 Hz), 2,65 (2H, q, J = 7 Hz), 2,80 (2H, d, J
= 6 Hz), 2,92 (2H, t, J = 6 Hz), 3,67 (2H, s), 3,97 (3H, s), 7,07 (2H, m), 7,30 (1H, m), 7,41 (1H, d, J = 2 Hz), 7,89 (1H, brs), 8,06 (2H, m);<m>/z(API<+>): 379 (MH<+>; 100%)
Eksempel 99
N-(2-/so-propyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid<1>H NMR (CDCI3) 8: 1,13 (6H, d, J = 7 Hz), 1,51 (3H, t, J = 7 Hz), 2,84 (5H, m), 3,71 (2H, s), 4,16 (2H, q, J = 7 Hz), 6,91 (1H, d, J = 9 Hz), 7,06 (1H, d, J = 8 Hz), 7,25 (1H, m), 7,42 (1H, d, J = 2 Hz), 7,78 (2H, m), 8,04 (1H, d, J = 2 Hz).
m/z (API<+>): 419 (MH<+>; 90%)
Eksempel 100
N-(2-/so-propyl-1,2,3)4-tetrahydroisokinolin-7-yl)-4-metoksy-3-trifluormetyl-benzamid
<1>H NMR (CDCI3) 5: 1,13 (6H, d, J~7 Hz), 2,84 (5H, m), 3,72 (2H, s), 3,97 (3H,
s), 7,07 (2H, m), 7,26 (1H, m), 7,43 (1H, d, J = 2 Hz), 7,83 (1H, brs), 8,04 (2H, m)
<m>/z(API<+>): 393 (MH<+>; 100%)
Eksempel 101
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-etoksy-3-metylsulfonyl-benzamid
<1>H NMR {CDCI3) 6: 1,52 (3H, t, J = 8 Hz), 2,46 (3H, s), 2,69 (2H, t, J = 7 Hz), 2,90 (2H, t, J = 7 Hz), 3,26 (3H, s), 3,57 (2H, s), 4,27 (2H, q, J = 7 Hz), 7,09 (2H, dd), 7,36 (1H, dd), 7,42 (1H, s), 7,83 (1H, brs),. 8,12 (1H, s), 8,20 (1H, dd), 8,37 (1H,d);
m/z(API<+>): 389,2 {MH<+>; 100%)
Eksempel 102
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-oksokroman-6-karboksamid-hydroklorid
<1>H NMR (D6DMSO) 5: 2,63 (3H, smal d), 3,02 (2H, t, J = 7Hz), 3,14 (2H, brm), 3,60 (2H, brm), 4,54 (2h, brs), 4,77 (2H, d, J = 7 Hz), 7,25 (1H, m), 7,31 (1H, d, J = 8 Hz), 7,44 (2H, d, J = 6 Hz), 8,20 (1H, dd, J = 8, 2 Hz), 8,59 (1H, d, J = 2 Hz), 10,31 (1H, s), 10,95 (1H, brs); m/z (API<+>): 337,4 (MH<+>; 100%)
Eksempel 103
N-(2-formyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metoksy-3-trifluormetylbenzamid
7-amino-2-formyM ,2,3,4-tetrahydroisokinolin (0,176 g) ble omdannet til tittelforbindelsen ved omsetning med 4-metoksy-3-trifluormetylbenzoylklorid, ved å følge metoden ifølge Eksempel 3. Produktet ble isolert som et hvitt, fast stoff (0,035 g).
<1>H NMR (d6-DMSO) 5: 2,80 (2H, m), 3,65 (2H, bred t), 4,00 (3H, s), 4,59 (2H, d), 7,17 (1H, d, J = 8 Hz), 7,45 (1H, d, J = 8 Hz), 7,60 (2H, m), 8,26 (3H, m), 10,30 (1H, s).
m/z (API+): 379 (MH<+>).
Eksempel 104
N-(2-hydroksyetyH,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid
Forbindelsen B16 (115 mg; 0,22 mmol) ble oppløst i THF med omrøring og tetra-butylammoniumfluorid (1 M i THF; 0,216 mmol) tilsatt. Reaksjonsblandingen ble omrørt natten over og blandingen renset ved kolonnekromatografi gjennom SiO, under eluering med 10% metanol:diklormetan. Utgnidning med petroleter ga tittelforbindelsen (48 mg; 49%).
<1>H NMR (250 MHz, CDCI3) 5: 1,51 (3H, t, J = 7 Hz), 2,77 (2H, t, J = 5 Hz), 2,90
(4H, m, overlappende signal), 3,74 (4H, m, overlappende signal), 4,17 (2H, q, J = 7 Hz), 6,93 (1H, d, J = 10 Hz), 7,10 (1H, d, J = 8 Hz), 7,36 (1H, dd, J = 8, 2 Hz), 7,48 (1H, d, J = 2 Hz), 7,87 (1H, dd, J = 9, 2 Hz), 7,97 (1H, s), 8,08 (1H, d, J = 2 Hz)
Eksempel 105
N-(2-hydroksyetyM,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etylbenzamid
Tittelforbindelsen ble fremstilt i 40% totalt utbytte fra B15 på en måte lignende den i Beskrivelse 16 og Eksempel 106.
<1>H NMR-(250 MHz, CDCI3) 5: 2,77 (10H, m, overlappende signaler), 3,68 (5H,
m, overlappende signaler), 7,08 (1H, d, J = 8 Hz), 7,30 (2H, m, overlappende signaler), 7,48 (1H, d, J = 2 Hz), 7,75 (H, dd, J = 8, 2 Hz), 8,02 (1H, d, J = 2 Hz), 8,17 (1H, s).
Eksempel 106
N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-fenylmetoksy-3-trifluormetyl-benzamid
<1>H NMR (CDCI3) 8: 2,50 (3H, s), 2,75 (2H, t, J = 6 Hz), 2,94 (2H, t, J = 6 Hz), 3,64 (2H, s), 7,10 (2H, d, J = 8 Hz), 7,30 - 7,60 (7H, m, overlappende), 7,70 (1H, brs), 8,04 (1H, dd, J = 8, 2 Hz), 8,10 (1H, d, J = 2 Hz);<m>/z(Cl): 441,2 (MH<+>;
100%)
Eksempel 107
N-{2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-hydroksy-3-trifluormetyl-benzamid
<m>/z(CI): 351,1 (MH<+>; 100%)
Eksempel 108
N-(2-metoksyetyM,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-/so-propoksybenzamid
<1>H NMR (250 MHz, CDCI3) 8: 1,41 (6H, d, J = 6 Hz), 2,75 (4H, t, overlappende,
J = 6 Hz), 2,83 (2H, d, J = 5 Hz), 3,39 (3H, s), 3,61 (4H, t, overlappende, J = 6 Hz), 4,64 (1H,m), 6,91 (1H, d, J = 9 Hz), 7,01 (1H, d, J = 8 Hz), 7,20 <1H, dd, J = 8, 2 Hz), 7,29 (1H, d, J = 2 Hz), 7,80 (1H, dd, J = 9, 2 Hz), 8,07 (1H, d, J = 2 Hz), 8,10 (1H, s);
m/z (API+): 447, 449 (MH+, 90%)
Eksempel 109
N-(2-metoksyetyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-klor-4-/so-propoksybenzamid
<1>H NMR (250 MHz, CDCI3) 8: 1,41 (6H, d, J = 6 Hz), 2,75 (4H, t, overlappende,
J = 6 Hz), 2,83 (2H, d, J = 5 Hz), 3.39 (3H, s), 3,61 (4H, t, overlappende, J = 5 Hz), 4,64 (1H, m), 6,94 (1H, d, J = 9 Hz), 7,01 (1H, d, J = 8 Hz), 7,20 (1H, d, J = 8 Hz), 7,30 (1H, s), 7,75 (1H, dd, J = 9, 2 Hz), 7,90 (1H, d, J = 2 Hz); m/z (API+): 403, 405 (MH+)
Eksempel 110
N-(2-metoksyetyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metoksy-3-trifluormetylbenzamid
<1>H NMR (250 MHz, CDCI3) 5: 2,75 (4H, m), 2,85 (2H, d, J = 5 Hz), 3,39 (3H, s), 3,61 (4H, t, overlappende), 3,96 (3H, s), 7,04 (2H, m), 7,25 (1H. d, J = 10Hz), 7,35 (1H, s), 8,07 (3H, m); m/z (API+): 409 (MH+, 100%)
Eksempel 111
(a) N-(2-f-butyloksykarbonyl-5-jod-1,2,3,4-tetrahydroisokinolin-7-yl)-4-azidobenzamid
Tittelforbindelsen ble fremstilt i 81% utbytte fra syren i Fremstilling 28 og aminet B6. (b) N-(5-jod-1,2,3,4-tetrahydroisokinolin-7-yl)-4-azidobenzamid-trifluoracetat.
Tittelforbindelsen ble fremstilt i 91% utbytte ved anvendelse av en metode lignende den i Eksempel 1.
m/z(Cl): 420 (MH<+>; 100%).
Eksempel 112
N-(2-metyl-5-trifluoracetylamino-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-metoksybenzamid
Tittelforbindelsen (0,66 g) ble fremstilt fra B25 (0,50 g) og 3-brom-4-metoksybenzosyre (0,63 g) ved anvendelse av en fremgangsmåte lignende den i Beskrivelse 7.<m>/z(Cl): 486, 488 (MH<+>; 90%).
Eksempel 113
N-(2-metyl-5-klor-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid
m/z (Cl): 425 (MH<+>; forventet isotop-mønster).
Eksempel 114
N-(2-metyl-5-klor-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etylbenzamid<1>H NMR (CDCl3)5: 1,25 (3H, t, J = 7Hz), 2,48 (3H, s), 2,70-3,00 (6H, m,
overlappende signaler), 3,59 (2H, s), 7,29 (1H, d, J = 2Hz), 7,33 (1H, d, J = 7Hz), 7,51 (1H, d, J = 2Hz), 7,71 (1H, dd, J = 7,2Hz), 7,83 (1H,brs), 8,01 (1H,d,J = 2Hz);<m>/z(Cl): 409 (MH<+>; forventet isotop mønster).
FARMAKOLOGISKE DATA
1. Bindi ngsforsøksmetode
WO 92/22293 (SmithKline Beecham) beskriver forbindelser som har antikonvulsiv aktivitet, omfattende bl.a. forbindelsen frans-(+)-6-acetyl-4S-(4-fluorbenzoylamino)-3,4-dihydro-2,2-dimetyl-2H-1-benzopyran-3R-ol (nedenfor referert til som Forbindelse A). Det er funnet at forbindelsene ifølge WO 92/22293 binder til en ny reseptor som kan oppnås fra rotte-forhjerne-vev, som beskrevet i WO 96/18650 (SmithKline Beecham). Affiniteten av testforbindelser til det nye reseptor-setet blir bedømt som følger.
Metode
Helt forhjerne-vev blir tatt fra rotter. Vevet blir først homogenisert i buffer (vanligvis 50 mM Tris/HCI, pH 7,4). Det homogeniserte vevet blir vasket ved sentrifugering og resuspensjon i samme buffer, og deretter lagret ved -70°C inntil det skal anvendes.
For å utføre radioligand-bindingsforsøket blir aliquoter av vev fremstilt som ovenfor (vanligvis i en konsentrasjon på 1-2 mg protein/ml) blandet med aliquoter av [3H]-Forbindelse A oppløst i buffer. Den endelige konsentrasjon av [3H]-Forb*indelse A i blandingen er vanligvis 20nM. Blandingen blir inkubert ved romtemperatur i 1 time. [3H]-Forbindelse A bundet til vevet blir deretter separert fra ubundet [3H]-Forbindelse A ved filtrering gjennom Whatman GF/B glassfiber-filtere. Filtrene blir deretter vasket raskt med is-kald buffer. Mengden av radioaktivitet bundet til vevet festet på filtrene blir målt ved tilsetning av væske-scintillations-cocktail til filtrene fulgt av telling i en væske-scintillasjonsteller.
For å bestemme mengden av "spesifikk" binding av [3H]-Forbindelse A, blir parallelle forsøk utført som ovenfor hvor [3H]-Forbindelse A og vev blir inkubert sammen i nærvær av umerket Forbindelse A (vanligvis 3 uM). Mengden av binding av gjenværende [3H]-Forbindelse A i nærvær av denne umerkede forbindelsen blir definert som "ikke-spesifikk" binding. Denne mengden blir trukket fra den totale mengde av [3H]-Forbindelse A-binding (dvs. den som er til stede i fravær av umerket forbindelse) for å oppnå en mengde av "spesifikk" binding av [3H]-Forbindelse A til det nye setet.
Affiniteten til bindingen av testforbindelser til det nye setet kan beregnes ved å inkubere sammen [3H]-Forbindelse A og vev i nærvær av en rekke konsentrasjoner av forbindelsen som skal testes. Reduksjon i nivået av spesifikk [3H]-Forbindelse A-binding som et resultat av konkurranse fra økende konsentrasjoner av forbindelsen som skal testes er plottet grafisk og ikke-lineær regresjonsanalyse av den resulterende kurve blir anvendt for å gi et estimat av forbindelsesaffinitet som pKi-verdi.
Resultater
Forbindelser ifølge foreliggende oppfinnelse var aktive i denne testen. Foreksempel ga forbindelsene ifølge Eksempler 1, 4, 5, 6, 7, 10 og 13 pKi-verdier større enn 7.
2. MEST-test
Maksimal elektrosjokk-krampe- (MEST) terskel-test i gnagere er spesielt sensitiv for å detektere potensielle antikonvulsive egenskapet. I denne modellen hever antikonvulsive midler terskelen for elektrisk fremkalt sjokk mens prokonvulsive midler nedsetter sjokk-terskelen.
Metode for musemodell
Mus (naive hanndyr, Charles River, U.K. CD-1 stamme, 25 - 30 g) blir tilfeldig fordelt i grupper på 10 - 20 og dosert oralt eller intraperitonealt med et dose-volum på 10 ml/kg med forskjellige doser av forbindelse (0,3 - 300 mg/kg) eller konstituent. Musene blir deretter underkastet et enkelt elektrosjokk (0,1 sek., 50Hz, sinusbølge-form) administrert via korneale elektroder 30 eller 60 min. etter dosering. Den gjennomsnittlige strømstyrke og standard avvik nødvendig for å fremkalle tonisk krampe hos 50% (CC59) av musene i en spesiell behandlings-gruppe blir bestemt ved 'opp og ned' metoden ifølge Dixon og Mood (1948)2. statistiske sammenligninger mellom konstituent- og medikament-behandlede grupper blir gjort ved anvendelse av metoden ifølge Litchfield og Wilcoxon (1949)3.
Hos kontroll-dyr er CC50vanligvis 14-18 mA. Det første dyret i kontrollgruppen blir således utsatt for en strømstyrke på 16 mA. Hvis tonisk krampe ikke følger blir strømstyrken øket for en påfølgende mus. Hvis tonisk krampe forekommer blir strømstyrken redusert osv. inntil alle dyrene i gruppen var testet.
Undersøkelser blir utført ved anvendelse av en Hugo Sachs Electronik Constant Current Shock Generator med totalt variabelt sjokk-kontroll-nivå fra 0 til 300 mA og trinn på 2 mA blir vanligvis anvendt.
Resultater
Forbindelser ifølge foreliggende oppfinnelse dosert oralt med 10 mg/kg som en suspensjon i metylcellulose og testet én time etter dosering viste en økning i krampe-terskel. For eksempel viser forbindelsene ifølge Eksemplene 4, 5, 6 og 7 økninger på henholdsvis 24%, 36%, 90% og 23%.
Metode for rottemodell
Terskelen for maksimale (tonisk baklem-utstrekning) elektrosjokk-kramper hos hannrotter (Sprague Dawley, 80 -150 g, 6 uker gamle) ble bestemt ved en Hugo Sachs Electronik stimulator som leverte en konstant strøm (0,3 sek. varighet; fra 1-300 mA i trinn på 5-20 mA). Metoden er lignende den beskrevet ovenfor for mus og fullstendige detaljer er som publisert av Upton et al, 4.
Prosentvis økning eller reduksjon av CC50for hver gruppe sammenlignet med kontrollen blir beregnet.
Medikamenter blir suspendert i 1% metylcellulose.
Resultater
I en dose på 2 mg/kg p.o. etter 2 timer viser forbindelsene ifølge Eksempler 48, 49, 51 og 67 økninger på henholdsvis 389%, 325%, 545% og 303%.
Referanser
1. Loscher, W. og Schmidt, D. (1988). Epilepsy Res., 2,145-181
2. Dixon, W.J. og Mood, A.M. (1948). J. Amer. Stat. Assn., 43,109-126
3. Litchfield, J.T. og Wilcoxon, F.(1949). J. Pharmacol. exp. Ther., 96, 99-113 4. N.Upton, T.P.BIackburn, C.A.Campbell, D.Cooper, M.L.Evans, H.J.Herdon, P.D.King, A.M.Ray, T.O.Stean, W.N.Chan, J.M.Evans og M.Thompson. (1997). B. J. Pharmacol., 121, 1679-1686
Claims (6)
1. Forbindelse,karakterisert vedformel (I) eller et farmasøytisk godtagbart salt derav:
hvor Q er fenyl, tiofenyl, naftyl, tienyl, benzotriazolyl, benztiazolyl,
benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, pyrazolyl, tiazolyl, isoksazolyl, oksokromanyl eller indolyl,
R<1>er hydrogen eller Ci.6 alkyl eventuelt substituert med hydroksy, C-i-C6-alkoksy, eller formyl,
R<2>er hydrogen, hydroksy eller opptil tre substituenter valgt fra halogen, NO2, CN, N3, CF3O-, CF3S-, CF3CO-, Ci_ealkyl, C<j_6perfluoralkyl, C-j.
6alkylO-, C^alkylCO-, C3_6cykloalkylO-, C3_6c<y>kloalkyl-Ci^alkylO-, acetoksy, fenyl, fenoksy, fenylmetoksy, C^galkylS-, C-^alkylSO^-; og
X er hydrogen, halogen eller trifluoracetylamino;
men når X er hydrogen utelukkes forbindelsen 7-(3,4,5-trimetoksybenzamido)-2-metyl-1,2,3,4-tetrahydroisokinolin, forbindelser hvor R2 er 2-alkoksy og når X er halogen utelukkes forbindelsene N-(7-jod-2-metyl-1,2,3,4-tetrahydroisokinolin-5-yl)-5-benzoyl-2-metoksybenzamid, N-(7-jod-l,2,3,4-tetrahydroisokinolin-5-yl)-5-benzoyl-2-metoksybenzamid, N-(5-jod-1,2,3,4-tetrahydroisokinolin-7-yl)-5-benzoyl-2-metoksybenzamid, N-(5-jod-1,2,3,4-tetrahydroisokinolin-7-yl)-2-metoksy-4-trifluormetyldiazirinylbenzamid, N-(5-jod-1,2,3,4-tetrahydroisokinolin-7-yl)-2-metoksy-5-trifluormetyldiazirinylbenzamid, N-(7-jod-1,2,3,4-tetrahydroisokinolin-5-yl)-2-metoksy-5-tnfluormetyldiazirinyl-benzamid og N-(8-fluor-2-metyl-1,2,3,4-tetrahydroisokinolin-5-yl)-4-f-butyl-2-metoksybenzamid.
2. Forbindelse ifølge krav 1,karakterisert vedformel (IA) eller (IB):
hvor R<1>, R<2>og X er som definert i krav 1.
3. Forbindelse ifølge krav 1 .karakterisert vedat den er valgt fra gruppen bestående av: N-(1,2,3,4-tetrahydroisokinolin-7-yl)-5-klortiofen-2-karboksamid N-(2-metyM, 2, 3, 4-tetrahydroisokinolin-7-yl)-5-klortiofen-2-karboksamid N-(2-metyl-112,3,4-tetrahydroisokinolin-7-yl)benzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-klorbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-f-butylbenzamid N-(2-metyl-1,2l3,4-tetrahydroisokinolin-7-yl)-4-/'so-propoksybenzamid N-(2-metyi-1,2,3,4-tetrahydroisokinolin-7-yl)-4-fenoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-nitrobenzamid N-(2-metyM,2,3,4-tetrahydroisokinolin-7-yl)-4-fenylbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-metylbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-fluorbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-cyanobenzamid N-(2-metyl-1,2,3l4-tetrahydroisokinolin-7-yl)-3,4-diklorbenzamid N-(2-metyl-1l2,3,4-tetrahydroisokinolin-7-yl)-4-jodbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-brombenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metylbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-nitrobenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-etoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-/7-butylbenzamid N-{2-metyl-1,2(3,4-tetrahydroisokinolin-7-yl)-2-acetoksybenzamid N^-metyl-I^.S^-tetrahydroisokinolin-T-ylJ-S-trifluormetylbenzamid N^-metyl-i^.S^-tetrahydroisokinolin-y-yO^^-difluorbenzamid N-{2-metyl-112,3,4-tetrahydroisokinolin-7-yl)-3,4-dimetoksybenzamid N-(2-metyl-1,2,314-tetrahydroisokinolin-7-yl)-2-fluor^-trifluormetyl-benzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-klor-3-nitrobenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3,5-di-trifluormetylbenzamid N-(2-metyl-1,2l3,4-tetrahydroisokinolin-7-yl)-2,4-diklor-5-fluorbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-fluor-5-trifluormetyl-benzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-metoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-trifluormetoksybenzamid N^-metyl-I^.S^-tetrahydroisokinolin^-ylJ-S-pivaloylbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4w'so-propoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-acetoksybenzamid N^-metyl-I^.S^-tetrahydroisokinolin^-yO^-cyklopentyloksybenzamid N-(2-metyl-1,2,3l4-tetrahydroisokinolin-7-yt)-4rcyklopropylmetoksybenzamid N-(2-metyl-1I2,3,4-tetrahydroisokinolin-7-yl)-3-cyano-4-metoksybenzarnid N^-metyl-I^.S^-tetrahydroisokinolin^-yl^-naftamid N^-metyl-I^.S^-tetrahydroisokinolin^-yO-S-brom^-methybenzamid N^-metyl-I^.S^-tetrahydroisokinolin^-ylJ-naftalen-l-karaoksamid N-(2-metyl-1l2l314-tetrahydroisokinolin-7-yl)-3-klor-4-metoksybenzamid N-(2-metyl-1t2,3,4-tetrahydroisokinolin-7-yl)-4-fe/t-butoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-/7-propoksybenzamid N-(2-metyl-1,2,3,4-tetrahydrpisokinolin-7-yl) benzotriazol-5-karboksamid N-(2-metyl-1l2l3l4-tetrahydroisokinolin-7-yl)benzotiazol-6-karboksamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-2,3-dihydrobenzofuran-5-karboksamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-2-metylbenzimidazol-5-karboksamid N-(2-metyl-1,2,3l4-tetrahydroisokinolin-7-yl)-3-klor-4-/so-propoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-klor-4-etoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metoksy-3-tritluormetyl-benzam N-(2-metyl-1,2,3l4-tetrahydroisokinolin-7-yl)-3,5-diklor-4-metoksybenzamid N-(2-metyl)-1,2l3,4-tetrahydroisokinolin-7-yl)-3,5-diklor-4-etoksybenzamid N-(2-metyl)-1l2,3,4-tetrahydroisokinolin-7-yt)-3,5-diklor-4-/so-propoksybenzamid N-^-metyl-I^.S^-tetrahydroisokinolin-y<->ylJ-S-metylsulfonylbenzamid N-{2-metyl-i,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-fert-butylbenzamid N-(2-met7l-1p2,3,4-tetrahydroisokinolin-7-yl)-2-brom-5-metoksybenzamid N-(2-metyl-1l2,3,4-tetrahydroisokinolin-7-yl)-4-fluor-3-metoksybenzamid-hydroklorid N^-metyl-I^.S^-tetrahydroisokinolin^-yO-l-metylpyarzoM-karboksamid N-(2-metyl-1,213l4-tetrahydroisokinolin-7-yl)-4-trifluormetylpyrazoi-3-karboksamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-2-metyltiazol-4-karboksamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-5-metylisoksazol-3-karboksamid N^-metyl-I^.S^-tetrahydroisokinolin^-yO-S-fert-butylisoksazol-S-karboksamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-metoksyisoksazol-5-kaoroksamid-hydroklorid N^-metyl-I^.S^-tetrahydroisokinolin^-yOindol^-karboksamid. N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-/so-propylbenzamid-hydroklorid N-(2-metyl-1)2,3,4-tetrahydroisokinolin-7-yl)-3-cyano-4-/so-propylbenzamid-hydroklorid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-fluor-4-rnetoksybenzamid N-(2-metyl-1,2l3,4-tetrahydroisokinolin-7-yl)-3-cyano-4-n-propoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-cyano-4-etoksybenzamid N-(2-metyl-1,2,3)4-tetrahydroisokinolin-7-yl)-3-brom-4-n-propoksybenzamid N-{2-metyl-1,2l3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etylbenzarriid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-jod-4-metoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-/so-propoksy-3-tritluormetyl-benzamid N-(2-metyl-1,2t3,4-tetrahydroisokinolin-7-yl)-4-klor-3-metoksybenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-n-propoksy-3-trifluormetyl-benzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-klor-4-re/t-butylbenzamid-hydroklorid _ N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metoksybenzamid-hydroklorid. N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-fluor-3-metylbenzamid-hydroklorid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-klor-4-/so-propylbenzamid N-{2-metyl-1,2,3,4-tetrahydro N-{2-metyl-i,2,3,4-tetrahydroisokinolin-7-yl)-4-/so-propyl-3-tritluormetyl-benzamid-hydroklorid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-etyl-3-tirfluormetylbenzamid-hydroklorid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-cyanc^4-/sc-propoksybenzamid-hydroklorid N-{1p2,3,4-tetrahydroisokinolin-7-yl)-4-metoksy-3-trifluormetylbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metyl-3-metylsulfonyl-benzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-etyl-3-metylsulfonylbenzam N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-metylsulfonyl-4-/so-propylbenzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-metylsulfonyl-4-metoksybenzam N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-trifluoracetylbenzamid-hydroklorid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metoksy-3-pentafluoretyl-benzamid-hydroklorid N-(2-/7-propyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid N-(2-n-propyl-1,2,3,4-tetrahydroisokinolih-7-yl)-4-metoksy-3-trifluormetylbenzamid N-(2-n-propyl-1)2)3,4-tetrahydroiskinolin-7-yl)-3-klor-4-/so-propoksybenzamid N-(2-metyl-1,2l3l4-tetrahydroisokinolin-7-yl)-3-cyano-4-/so-butylbenzamid-hydroklorid N-(2-metyl-1,2I3,4-tetrahydroisokinolin-7-yl)^w'so-butyl-3-trifluormetyl-benzamid-hydroklorid N-(2-etyl-1,2,3p4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid N-(2-etyl-1,2,3,4-tetrahydro-isokinolin-7-yl)-4-metoksy-3-trifluormetyl-benza N-(2-/so-propyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid N-(2-/sc-propyl-1,2,3I4-tetrahydroisokinolin-7-yl)-4-metoksy-3-trifluorrnetyl-benzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-etoksy-3-metylsulfonyl-benzamid N-(2-metyl-1J2,3,4-tetrahydroisokinolin-7-yl)-4-oksochroman-6-kaoroksamid-hydroklorid N-(2-formyl--1,2,3,4-tetrahydroisokinolin-7-yl)-4-metoksy-3-trifluorme N-(2-hydroksyetyl-1>2,314-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid N^-hydroksyetyl-l^^^-tetrahydroisokinolin-Z-ylJ-S-brom^-etylbenzamid N-{2-metyl-1,2,3)4-tetrahydroisokinolin-7-ylH-fenylmetoksy-3-trifluorme benzamid N-(2-metyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-hydroksy-3-trifluormetyl-benzam N-(2-metoksyetyl-112,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-/'so-propoksybenzamid N-(2-metoksyetyl-1,2,3,4-tetrahydroisokinolin-7-yl)-3-klor-4-/so-propoksybenzamid N-(2-metoksyetyl-1,2,3,4-tetrahydroisokinolin-7-yl)-4-metoksy-3-trifluormetylbenzamid N-(5-jod-1,2,3,4-tetrahydroisokinolin-7-ylH-azidobenzamid, trifluoracetat N^-metyl-S-trifluoracetylamino-I^.S^-tetrahydroisokinolin^-yO-S-brom^-metoksybenzamid N-(2-metyl-5-klor-1,2,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etoksybenzamid N-(2-metyl-5-klor-112,3,4-tetrahydroisokinolin-7-yl)-3-brom-4-etylbenzamid
4. Farmasøytisk preparat for anvendelse ved behandling og/eller forebyggelse av angst, mani, depresjon, paniske lidelser og/eller aggresjon, lidelser forbundet med subarachnoidal blødning eller nervesjokk, effektene forbundet med avvenning fra misbruk av stoffer så som kokain, nikotin, alkohol og benzodiazepiner, lidelser som kan behandles og/eller forhindres med antikonvulsive midler, så som epilepsi omfattende post-traumatisk epilepsi, Parkinson's sykdom, psykose, migrene, cerebral ischemi, Alzheimers sykdom og andre degenerative sykdommer så som Huntingdon's chorea, schizofreni, obsessive kompulsive lidelser (OCD), nevrologiske defekter forbundet med AIDS, søvnforstyrrelser (omfattende døgnrytmeforstyrrelser, søvnløshet & narkolepsi), tics (f.eks. Giles de la Tourette's syndrom), traumatisk hjerneskade, tinnitus, nevralgi, spesielt trigeminusnevralgi, nevropatisk smerte, dental smerte, kreftsmerte, upassende nevronal aktivitet som resulterer i nevrodystesi ved sykdommer så som diabetes, multippel sklerose (MS) og motorisk nevron-sykdom, ataksi, muskelstivhet (spastisitet), temporomandibulær ledd-dysfunksjon og amyotrofisk lateralsklerose (ALS),karakterisert vedat det omfatter en forbindelse ifølge hvilket som helst av kravene 1 til 3 eller et farmasøytisk godtagbart salt eller solvat derav og en farmasøytisk godtagbar bærer.
5. Anvendelse av en forbindelse ifølge hvilket som helst av kravene 1 til 3 eller et farmasøytisk godtagbart salt eller solvat derav, for fremstilling av et medikament for behandling og/eller forebyggelse av angst, mani, depresjon, paniske lidelser og/eller aggresjon, lidelser forbundet med subarachnoidal blødning eller nervesjokk, effektene forbundet med avvenning fra misbruk av stoffer så som kokain, nikotin, alkohol og benzodiazepiner, lidelser som kan behandles og/eller forhindres med antikonvulsive midler, så som epilepsi omfattende post-traumatisk epilepsi, Parkinson's sykdom, psykose, migrene, cerebral ischemi, Alzheimers sykdom og andre degenerative sykdommer så som Huntingdon's chorea, schizofreni, obsessive kompulsive lidelser (OCD), nevrologiske defekter forbundet med AIDS, søvnforstyrrelser (omfattende døgnrytmeforstyrrelser, søvnløshet & narkolepsi), tic (f.eks. Giles de la Tourette's syndrom), traumatisk hjerneskade, tinnitus, nevralgi, spesielt trigeminusnevralgi, nevropatisk smerte, dental smerte, kreftsmerte, upassende nevronal aktivitet som resulterer i nevrodystesi ved sykdommer så som diabetes, multippel sklerose (MS) og motorisk nevron-sykdom, ataksi, muskelstivhet (spastisitet), temporomandibulær ledd-dysfunksjon og amyotrofisk lateralsklerose (ALS).
6. Fremgangsmåte for fremstilling av forbindelse ifølge hvilket som helst av kravene 1 til 3,karakterisert vedat den omfatter omsetning av en forbindelse med formel (II)
hvor p<JA>er R 1 som definert for formel (I) eller en gruppe som kan omdannes tilR1
og X er som definert i krav 1
med en forbindelse med formel (III)
hvor Q er som definert i krav 1, Y er Cl eller OH og R<2A->grupper er uavhengig R<2>som definert for formel (I) eller grupper som kan omdannes til R<2>,
og om nødvendig omdannelse av en R<1A>- eller R<2A>-gruppe til en R<1->eller R<2->gruppe,
omdannelse av én R<1->eller R<2->gruppe til en annen R<1->eller R<2->gruppe, omdannelse av et saltprodukt til den frie basen eller et annet farmasøytisk godtagbart salt eller omdannelse av en fri base til et farmasøytisk godtagbart salt.
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US6291476B1 (en) * | 1999-05-12 | 2001-09-18 | Ortho-Mcneil Pharmaceutical, Inc. | Pyrazole carboxamides useful for the treatment of obesity and other disorders |
GB9915589D0 (en) | 1999-07-02 | 1999-09-01 | Smithkline Beecham Plc | Novel compounds |
FR2795724B1 (fr) * | 1999-07-02 | 2002-12-13 | Sanofi Synthelabo | Nouveaux derives du benzene, un procede pour leur preparation et les compositions pharmaceutiques les contenant |
TW200403223A (en) * | 2002-02-15 | 2004-03-01 | Glaxo Group Ltd | Novel compounds |
GB0210762D0 (en) * | 2002-05-10 | 2002-06-19 | Glaxo Group Ltd | Compounds |
AU2003249534A1 (en) * | 2002-08-13 | 2004-02-25 | Warner-Lambert Company Llc | 6,6-fused heteroaryl derivatives as matrix metalloproteinase inhibitors |
GB0226724D0 (en) | 2002-11-15 | 2002-12-24 | Merck Sharp & Dohme | Therapeutic agents |
WO2004110986A1 (ja) | 2003-06-12 | 2004-12-23 | Astellas Pharma Inc. | ベンズアミド誘導体又はその塩 |
GB2413129A (en) * | 2003-10-07 | 2005-10-19 | Renovis Inc | Aromatic amide compounds as ion channel ligands and uses thereof |
US20050197364A1 (en) * | 2003-10-07 | 2005-09-08 | Kelly Michael G. | Amide compounds as ion channel ligands and uses thereof |
CA2553968A1 (en) * | 2004-01-23 | 2005-08-11 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments of inflammatory and neuropathic pain |
JP2008513426A (ja) * | 2004-09-20 | 2008-05-01 | バイオリポックス エービー | 炎症の治療に有用なピラゾール化合物 |
SE0403117D0 (sv) * | 2004-12-21 | 2004-12-21 | Astrazeneca Ab | New compounds 1 |
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WO1997048683A1 (en) * | 1996-06-17 | 1997-12-24 | Smithkline Beecham Plc | Substituted benzamide derivatives and their use as anticonvulsants |
-
1998
- 1998-03-16 CN CNB988048809A patent/CN1183116C/zh not_active Expired - Fee Related
- 1998-03-16 EP EP98909647A patent/EP0968190A1/en not_active Withdrawn
- 1998-03-16 AU AU64128/98A patent/AU737955B2/en not_active Ceased
- 1998-03-16 NZ NZ337424A patent/NZ337424A/en unknown
- 1998-03-16 BR BR9809047-0A patent/BR9809047A/pt not_active Application Discontinuation
- 1998-03-16 IL IL13175698A patent/IL131756A0/xx active IP Right Grant
- 1998-03-16 WO PCT/GB1998/000782 patent/WO1998041508A1/en not_active Application Discontinuation
- 1998-03-16 KR KR1019997008443A patent/KR100568654B1/ko not_active IP Right Cessation
- 1998-03-16 JP JP54024898A patent/JP3690423B2/ja not_active Expired - Fee Related
- 1998-03-16 TR TR1999/02283T patent/TR199902283T2/xx unknown
- 1998-03-16 PL PL335676A patent/PL192116B1/pl unknown
- 1998-03-16 CA CA002284218A patent/CA2284218A1/en not_active Abandoned
- 1998-03-17 AR ARP980101199A patent/AR012092A1/es unknown
- 1998-03-18 CO CO98015157A patent/CO4950553A1/es unknown
- 1998-03-20 TW TW087104135A patent/TW555694B/zh not_active IP Right Cessation
-
1999
- 1999-09-17 NO NO19994510A patent/NO314081B1/no unknown
Also Published As
Publication number | Publication date |
---|---|
CA2284218A1 (en) | 1998-09-24 |
WO1998041508A1 (en) | 1998-09-24 |
AU737955B2 (en) | 2001-09-06 |
TW555694B (en) | 2003-10-01 |
PL192116B1 (pl) | 2006-08-31 |
PL335676A1 (en) | 2000-05-08 |
CN1255124A (zh) | 2000-05-31 |
BR9809047A (pt) | 2000-08-01 |
CO4950553A1 (es) | 2000-09-01 |
AR012092A1 (es) | 2000-09-27 |
NO994510D0 (no) | 1999-09-17 |
JP3690423B2 (ja) | 2005-08-31 |
EP0968190A1 (en) | 2000-01-05 |
AU6412898A (en) | 1998-10-12 |
KR20000076342A (ko) | 2000-12-26 |
NZ337424A (en) | 2001-08-31 |
IL131756A0 (en) | 2001-03-19 |
KR100568654B1 (ko) | 2006-04-07 |
TR199902283T2 (xx) | 1999-12-21 |
CN1183116C (zh) | 2005-01-05 |
JP2001515504A (ja) | 2001-09-18 |
NO994510L (no) | 1999-09-17 |
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