NO151289B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE IMIDAZO AND PYRIMIDO PYRIDOINDOLS - Google Patents
ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE IMIDAZO AND PYRIMIDO PYRIDOINDOLS Download PDFInfo
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- NO151289B NO151289B NO794270A NO794270A NO151289B NO 151289 B NO151289 B NO 151289B NO 794270 A NO794270 A NO 794270A NO 794270 A NO794270 A NO 794270A NO 151289 B NO151289 B NO 151289B
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- Prior art keywords
- alkyl
- compound
- radical
- pyrimido
- formula
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- 238000002360 preparation method Methods 0.000 title claims description 6
- 238000000034 method Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 4
- REDWVXCYDSLNMN-UHFFFAOYSA-N C1=NC=NC2=CC3=C(NC=C4)C4=CC=C3N=C21 Chemical class C1=NC=NC2=CC3=C(NC=C4)C4=CC=C3N=C21 REDWVXCYDSLNMN-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- 150000001412 amines Chemical class 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract description 9
- 239000007864 aqueous solution Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- -1 alkoxy radical Chemical group 0.000 abstract 8
- 125000005843 halogen group Chemical group 0.000 abstract 4
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical group [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 abstract 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 abstract 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 2
- 150000003254 radicals Chemical class 0.000 abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical compound C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- PYOUAIQXJALPKW-UHFFFAOYSA-N 2-(5-methyl-1H-indol-3-yl)ethanamine Chemical compound CC1=CC=C2NC=C(CCN)C2=C1 PYOUAIQXJALPKW-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000008098 formaldehyde solution Substances 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- IYGYMKDQCDOMRE-QRWMCTBCSA-N Bicculine Chemical compound O([C@H]1C2C3=CC=4OCOC=4C=C3CCN2C)C(=O)C2=C1C=CC1=C2OCO1 IYGYMKDQCDOMRE-QRWMCTBCSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- AACMFFIUYXGCOC-UHFFFAOYSA-N bicuculline Natural products CN1CCc2cc3OCOc3cc2C1C4OCc5c6OCOc6ccc45 AACMFFIUYXGCOC-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- IYGYMKDQCDOMRE-UHFFFAOYSA-N d-Bicucullin Natural products CN1CCC2=CC=3OCOC=3C=C2C1C1OC(=O)C2=C1C=CC1=C2OCO1 IYGYMKDQCDOMRE-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Foreliggende oppfinnelse vedrører en analogifremgangsmåte for fremstilling av terapeutisk aktive imidazo- og pyrimido-pyridoindoler i form av racemater eller enantiomerer med den generelle formel (I) The present invention relates to an analogue method for the production of therapeutically active imidazo- and pyrimido-pyridoindoles in the form of racemates or enantiomers with the general formula (I)
hvori in which
n er 1 eller 0, n is 1 or 0,
R^ er hydrogen eller halogen, alkyl, alkoksy eller R 1 is hydrogen or halogen, alkyl, alkoxy or
gruppen CF^, the group CF^,
R2er alkyl, cyklopropyl, p-alkoksyfenyl eller benzyl, R^er hydrogen eller alkyl, R2 is alkyl, cyclopropyl, p-alkoxyphenyl or benzyl, R^ is hydrogen or alkyl,
R. er hydrogen eller alkyl, R. is hydrogen or alkyl,
idet alkyl- og alkoksy-gruppene inneholder 1 til 4 kar-bonatomer, wherein the alkyl and alkoxy groups contain 1 to 4 carbon atoms,
med unntagelse av den forbindelse hvori n=l, R1=R3= R4=Hog R2=CH3, with the exception of the compound in which n=1, R1=R3= R4=H and R2=CH3,
og farmasøytisk tålbare syreaddisjonssalter derav, og oppfinnelsen erkarakterisert vedat en forbindelse med formel (II) and pharmaceutically acceptable acid addition salts thereof, and the invention is characterized in that a compound of formula (II)
hvori R^ , R^ og R^ har den ovennevnte betydning omsettes med et amin ^ 2^ 2' nvor"i R2 ^ar ^en oven~nevnte betydning, hvoretter det oppnådde mellomprodukt med formel (III) in which R^ , R^ and R^ have the above-mentioned meaning is reacted with an amine ^ 2^ 2' where"in R2 ^is ^ an above-mentioned meaning, after which the intermediate obtained with formula (III)
hvori R^, R^, R^og R^har den ovennevnte betyd- wherein R^, R^, R^ and R^ have the above meaning-
ning, ringsluttes ved hjelp av 30% vandig foraldehydløs-ning, ning, ring-sealed using a 30% aqueous formaldehyde solution,
og for fremstilling av en forbindelse (I) hvori R^er alkyl, alkyleres en oppnådd tilsvarende forbindelse hvori R. er H. and for the preparation of a compound (I) in which R is alkyl, a corresponding compound obtained in which R is H is alkylated.
4 4
Disse trekk fremgår av patentkr avet. These features appear in the patent no.
Utgangsforbindelsene (II) hvori R^ = alkyl kan fremstilles ved å gå ut fra tryptamin som eventuelt er substituert etter følgende reaksjonsskjerna The starting compounds (II) in which R^ = alkyl can be prepared by starting from tryptamine which is optionally substituted according to the following reaction nucleus
Denne reaksjon er beskrevet i litteraturen av J.A. This reaction is described in the literature by J.A.
MACLAREN, Aust. J. Chem. (1977), 30, 2045-51. MACLAREN, Aust. J. Chem. (1977), 30, 2045-51.
Utgangsforbindelsene (II) hvori R^= H og n = 1 kan fremstilles ved å gå ut fra hydrokloridet av eventuelt substituert tryptamin etter det senere angitte reaksjons-skjema". The starting compounds (II) in which R^ = H and n = 1 can be prepared by starting from the hydrochloride of optionally substituted tryptamine according to the later indicated reaction scheme".
Forbindelsen (n) hvori er lik H og n er 1 er beskrevet avL.H. GROVES og G.A. SWAN,J.C.S., (1952), side 650. The compound (n) in which is equal to H and n is 1 is described by L.H. GROVES and G.A. SWAN, J.C.S., (1952), page 650.
Utgangsforbindelsene (il) hvori R 1 har en annen betydning enn H er nye. The starting compounds (11) in which R 1 has a different meaning than H are new.
Oppfinnelsen skal i det folgende beskrives nærmere ved hjelp av eksempelvise og foretrukne utforelsesformer. In the following, the invention will be described in more detail using exemplary and preferred embodiments.
Eksempel på fremstilling av en forbindelse ( II) Example of preparation of a compound (II)
^. 1 = CH3- 9, n = 1, R3 = H_7 ^. 1 = CH3-9, n = 1, R3 = H_7
1. I 250 ml etanol bringes i suspensjon 52,62 g (0,25 mol) av hydrokloridet av 5-metyl-tryptamin og blandingen bringes til koking under tilbakelop. i 250 ml etanol bringes i suspensjon 57,75 g 3-etoksykarbonyl-l,2-dioksy-l-etoksy-propan og man tilsetter dråpevis i lopet av 10 min. 25 ml konsentrert saltsyre. Denne suspensjon tilsettes til 1. 52.62 g (0.25 mol) of the hydrochloride of 5-methyl-tryptamine are brought into suspension in 250 ml of ethanol and the mixture is brought to boiling under reflux. 57.75 g of 3-ethoxycarbonyl-1,2-dioxy-1-ethoxy-propane are brought into suspension in 250 ml of ethanol and added dropwise over the course of 10 min. 25 ml of concentrated hydrochloric acid. This suspension is added to
suspensjonen av 5-metyl-tryptamin som holdes ved tilbakelops-temperaturen.Blandingen avkjoles over natten. Losnings-midlet fjernes ved avdamping og resten oppleses i 400 ml vann og gjores alkalisk med ammoniakk. Etter ekstraksjon med etylacetat oppnås en olje som kromatograferes på en silikakolonne. Etter eluering med en blanding 8/2 av kloroform/etanol oppnås en olje som storkner ved behandling med petroleter. Etter omkrystallisering fra heksan smelter den oppnådde forbindelse ved 102 - 103°c. 2. 45 g av den ovennevnte forbindelse oppvarmes under tilbakelop i 450 ml av en 10% vandigNaOH-losning i 20 timer. Det tilsettes dråpevis konsentrert saltsyre (100 ml), i lopet av 30 min., til den avkjolte reaksjbnsblanding. Det oppnådde faststoff frafiltreres og torkes over P2°5<»>3. under tilbakelop oppvarmes 99,6 g av det ovenfor oppnådde faste råprodukt i en blanding av 250 ml etanol og 200 ml konsentrert svovelsyre, i 9 timer.Blandingen settes bort over natten. Etanol fjernes ved avdamping og rest-faststoffet gjores alkalisk med ammoniakk. Den basiske lbsning ekstraheres tre ganger med hver gang 300 ml etylacetat. Det inndampes og man oppnår en olje som ved behandling med petroleter gir et hvitt faststoff som filtreres og torkes. the suspension of 5-methyl-tryptamine which is maintained at the reflux temperature. The mixture is cooled overnight. The solvent is removed by evaporation and the residue is dissolved in 400 ml of water and made alkaline with ammonia. After extraction with ethyl acetate, an oil is obtained which is chromatographed on a silica column. After elution with an 8/2 mixture of chloroform/ethanol, an oil is obtained which solidifies on treatment with petroleum ether. After recrystallization from hexane, the obtained compound melts at 102 - 103°c. 2. 45 g of the above compound is heated under reflux in 450 ml of a 10% aqueous NaOH solution for 20 hours. Concentrated hydrochloric acid (100 ml) is added dropwise over the course of 30 min. to the cooled reaction mixture. The solid obtained is filtered off and dried over P2°5<»>3. under reflux, 99.6 g of the solid crude product obtained above are heated in a mixture of 250 ml of ethanol and 200 ml of concentrated sulfuric acid, for 9 hours. The mixture is set aside overnight. Ethanol is removed by evaporation and the residual solid is made alkaline with ammonia. The basic solution is extracted three times with 300 ml of ethyl acetate each time. It is evaporated and an oil is obtained which, when treated with petroleum ether, gives a white solid which is filtered and dried.
Etter omkryst allisering fra heksan smelter den oppnådde forbindelse (n) ved 103°C. After cross-alization from hexane, the obtained compound (n) melts at 103°C.
De folgende eksempler illustrerer oppfinnelsen. Mikro-analyser og spektra IR ogrmn bekrefter strukturen av forbindelsene. The following examples illustrate the invention. Micro-analyses and spectra IR and grmn confirm the structure of the compounds.
EKSEMPEL 1 2, 11 b-dimetyl-2,3,6,5,11,llb-heksahydro-lH-imidazo/1', 5 1:1, 27pyrido/3, 4-b_7indol-l-on. EXAMPLE 1 2,11b-dimethyl-2,3,6,5,11,11b-hexahydro-1H-imidazo[1',5 1:1,27pyrido[3,4-b_7indol-1-one.
/n=0, R1=&,R2=CH3,R3=CH3,<R>4<=>^7 /n=0, R1=&,R2=CH3,R3=CH3,<R>4<=>^7
1. l-metylaminokarbonyl-l-metyl-2,3,4,9-tetrahydro-lH-pyrido/3, 4-l27indol. 1. 1-Methylaminocarbonyl-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-127indole.
4,8 g (0,02 mol) l-metyl-2, 3, 4, 9-tetrahydro-lH-pyrido/3, 4-b_7-indol-l-metylkarboksylat (utgangsforbindelse (II)) bringes i opplosning i 100 ml etanol mettet med metylamin. 4.8 g (0.02 mol) of 1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b_7-indole-1-methylcarboxylate (starting compound (II)) is dissolved in 100 ml ethanol saturated with methylamine.
Blandingen får stå ved vanlig temperatur i 48 timer.Losningsmidlet fjernes og resten opptas i 20 ml etanol. Det filtreres og vaskes med etanol. The mixture is allowed to stand at normal temperature for 48 hours. The solvent is removed and the residue is taken up in 20 ml of ethanol. It is filtered and washed with ethanol.
Smp. = 230 - 231°C. Temp. = 230 - 231°C.
2. 2,llb-dimetyl-2,3,5,6,11,llb-heksahydro-lH-imidazo-£11 , 5 1:1, 27pyrido/3, 4-b_7indol-l-on 2. 2,11b-dimethyl-2,3,5,6,11,11b-hexahydro-1H-imidazo-£11,5 1:1,27pyrido/3,4-b_7indol-1-one
12g (0,05 mol) av den ovenfor oppnådde forbindelse anbringes i 200 ml etanol. Det tilsettes 3 gKOHi pastill-form og deretter 2 5 ml av en 30% vandig losning av formaldehyd. 12 g (0.05 mol) of the compound obtained above is placed in 200 ml of ethanol. 3 gKOHi in pastille form is added and then 25 ml of a 30% aqueous solution of formaldehyde.
Blandingen omrores ved 70°C i 12 timer. The mixture is stirred at 70°C for 12 hours.
Bunnfallet frafiltreres og vaskes med etanol. Etter omkrystallisering fra propanol smelter forbindelsen ved 252 - 253°C. The precipitate is filtered off and washed with ethanol. After recrystallization from propanol, the compound melts at 252 - 253°C.
I v/ I LU / I v/ I LU /
EKSEMPEL 2 9-klor-3-metyl-3,4,6,7,12,12b-heksahydro-pyrimido- EXAMPLE 2 9-Chloro-3-methyl-3,4,6,7,12,12b-hexahydro-pyrimido-
/l',6':1, 2j7pyr ido/3, 4-b7indol-2 (1H)-on /1',6':1,2j7pyrido/3,4-b7indol-2 (1H)-one
/" n=l, R1=Cl-9,R2=CH3, R3=H, R4<=>n7 /" n=l, R1=Cl-9, R2=CH3, R3=H, R4<=>n7
1. N-metyl-6-klor-2,3,4,9-tetrahydro-lH-pyrido/3,4-b7indol-1-acetamid. 1. N-methyl-6-chloro-2,3,4,9-tetrahydro-1H-pyrido/3,4-b7indole-1-acetamide.
8 g av 6-klor-2,3,4,9-tetrahydr-lH-pyrido/3,4-b7indol-l- 8 g of 6-chloro-2,3,4,9-tetrahydr-1H-pyrido/3,4-b7indole-1-
etylacetat (utgangsforbindelse (II)) opploses i en blanding av 150 ml etanol og 150 ml 33% metylaminlosning i etanol. Reaksjonsblandingen oppvarmes ved 200°C i 7 timer i en ethyl acetate (starting compound (II)) is dissolved in a mixture of 150 ml of ethanol and 150 ml of 33% methylamine solution in ethanol. The reaction mixture is heated at 200°C for 7 hours in a
autoklav.Blandingen avkjoles over natten og opplosningen inndampes. autoclave. The mixture is cooled overnight and the solution is evaporated.
Faststoffet som omkrystalliseres fra etanol smelter ved The solid that is recrystallized from ethanol melts at
228 - 230°c. 228 - 230°c.
2. 9-klor-3-metyl-3,4,6,7,12,12b-heksahydro-pyrimido- 2. 9-chloro-3-methyl-3,4,6,7,12,12b-hexahydro-pyrimido-
/l',6': l,27pyrido/3,4-b7'indol-2(lH)-on /1',6':1,27pyrido/3,4-b7'indol-2(1H)-one
1,7 g av den ovenfor oppnådde forbindelse opploses i en blanding av 20 ml etanol og 2 ml 30% vandig formaldehyd- 1.7 g of the compound obtained above is dissolved in a mixture of 20 ml of ethanol and 2 ml of 30% aqueous formaldehyde-
losning ved vanlig temperatur.Blandingen omrores i 30 min.Losningsmidlet fjernes og det hvite faststoff opptas i kold solution at normal temperature. The mixture is stirred for 30 min. The solvent is removed and the white solid is absorbed in the cold
etanol og man filtrerer. Produktet omkrystalliseres fra etanol. ethanol and filter. The product is recrystallized from ethanol.
Smp. = 257°C. Temp. = 257°C.
EKSEMPEL 3 3,12b-dimetyl-3,4,6,7,12,12b-heksahydro-pyrimido EXAMPLE 3 3,12b-dimethyl-3,4,6,7,12,12b-hexahydro-pyrimido
-/l',6':1, 2_/pyrido/3, 4-b7indol-2 (lH)-on -/1',6':1, 2_/pyrido/3, 4-b7indol-2 (1H)-one
/"N=l,R^=H, R2=CH3, R3=CH3, R4=H J7 /"N=1,R^=H, R2=CH3, R3=CH3, R4=H J7
1. N-metyl-l-metyl-2,3,4,9-tetrahydro-pyrido/3,4-b7indol-l- 1. N-methyl-1-methyl-2,3,4,9-tetrahydro-pyrido/3,4-b7indole-1-
acetamid. acetamide.
36,9 g l-metyl-2,3,4,9-tetrahydr-lH-pyrido-/3,4-b/indol-l-etylkarboksylat innfores i en autoklav sammen med 300 ml av en 33% lbsning av CH3NH2 i etanol. Det oppvarmes til 100°c i 8 timer.Losningsmidlet avdrives og resten krystalliseres fra etanol. 36.9 g of 1-methyl-2,3,4,9-tetrahydr-1H-pyrido-[3,4-b]indole-1-ethylcarboxylate are introduced into an autoclave together with 300 ml of a 33% solution of CH3NH2 in ethanol. It is heated to 100°c for 8 hours. The solvent is distilled off and the residue is crystallized from ethanol.
Smp. = 182 - 183°C. Temp. = 182 - 183°C.
2. 3,12b-dimetyl-3,4,6,7,12,12b-heksahydro-pyrimido- 2. 3,12b-dimethyl-3,4,6,7,12,12b-hexahydro-pyrimido-
/l',6': l,27pyrido/3,4-b7indol-2-(lH)-on /1',6':1,27pyrido/3,4-b7indol-2-(1H)-one
I en kolbe innfores 20 g av den ovenfor oppnådde forbindelse og 150 ml etanol. Det tilsettes en vandig 33% formaldehyd-lbsning og det omrores ved vanlig temperatur i 3 timer.Losningsmidlet avdrives og resten torkes ved azeotropisk avdrivning med toluen. Resten opploses i 500 ml kloroform og det torkes over Na-jSO^. Etter inndamping av losningen oppnås en olje.Tort tetrahydrofuran tilsettes hvoretter det foretas avdamping. Det oppnås et hvitt faststoff som omkrystalliseres fra etylacetat. 20 g of the compound obtained above and 150 ml of ethanol are introduced into a flask. An aqueous 33% formaldehyde solution is added and it is stirred at ordinary temperature for 3 hours. The solvent is removed and the residue is dried by azeotropic removal with toluene. The residue is dissolved in 500 ml of chloroform and dried over Na 2 SO 4 . After evaporation of the solution, an oil is obtained. Dry tetrahydrofuran is added, after which evaporation is carried out. A white solid is obtained which is recrystallized from ethyl acetate.
Smp. = 204°c. Temp. = 204°c.
EKSEMPEL 4 3,12,12b-trimetyl-3,4,6,7,12,12b-heksahydro-pyrimido/i ', 6 ':1, 2_/pyrido/3, 4-b7indol-2(lH)-on EXAMPLE 4 3,12,12b-trimethyl-3,4,6,7,12,12b-hexahydro-pyrimido[1',6':1,2_[pyrido[3,4-b7indol-2(1H)-one
/h=l, R^H, R2=CH3,R3=CH3, R4=CH3_7 /h=1, R^H, R2=CH3, R3=CH3, R4=CH3_7
I en kolbe innfores 3 g av forbindelsen oppnådd i eksempel 2 og 30 ml dimetylformamid. Det tilsettes 0,53 g natrium-hydrid og det omrores ved vanlig temperatur i 2 timer. Det tilsettes 0,9 ml metyljodid og omrores i 1 min. ved vanlig temperatur.Losningsmidlet avdrives og resten kromatograferes overSi02. Det elueres med en blanding 8/2 CHCl3/EtOH. Det oppnås et hvitt faststoff som omkrystalliseres fraCH3OC<H>2CH2<O>CH3. 3 g of the compound obtained in example 2 and 30 ml of dimethylformamide are introduced into a flask. 0.53 g of sodium hydride is added and it is stirred at normal temperature for 2 hours. 0.9 ml of methyl iodide is added and stirred for 1 min. at normal temperature. The solvent is driven off and the residue is chromatographed over SiO2. It is eluted with a mixture 8/2 CHCl3/EtOH. A white solid is obtained which is recrystallized from CH3OC<H>2CH2<O>CH3.
Smp. = 159 - 160°C. Temp. = 159 - 160°C.
Flere forbindelser som fremstilles i henhold til oppfinnelsen er angitt i den etterfølgende tabell I. De oppnådde forbindelser ble underkastet farmakologiske forsok og viste seg aktive som anti-konvulsive midler. Several compounds produced according to the invention are listed in the following table I. The obtained compounds were subjected to pharmacological tests and proved active as anticonvulsants.
Akutt giftighet ble bestemt i mus ved intraperitoneal tilforsel.LDvarierer fra 200 til 2000 mg/kg. Acute toxicity was determined in mice by intraperitoneal administration. LD varies from 200 to 2000 mg/kg.
Den antikonvultive virkning ble bestemt ved antagonisme-testen i forhold til konvulsjoner indusert ved hjelp av bikukullin i mus (Perez de la Mora, M. ogTapia R. (1973),Biochem. pharmacol. 22, 2635-2639.). The anticonvulsant effect was determined by the antagonism test in relation to convulsions induced by means of bicuculline in mice (Perez de la Mora, M. and Tapia R. (1973), Biochem. pharmacol. 22, 2635-2639.).
AD^q av forbindelsene varierer mellom 30 og 50 mg/kg tilfort i.p. The AD^q of the compounds varies between 30 and 50 mg/kg administered i.p.
De foregående resultater viser at forbindelsene kan anvendes ved behandling av epilepsier. The previous results show that the compounds can be used in the treatment of epilepsies.
Forbindelsene kan tilfores i vanlige preparatformer ved oral, parenteral eller endorektal tilforsel, f.eks. i form av tabletter, drageer, kapsler, injiserbare eller inntagbare losninger sammen med vanlige tilsetningsmidler. The compounds can be administered in usual preparation forms by oral, parenteral or endorectal administration, e.g. in the form of tablets, dragees, capsules, injectable or ingestible solutions together with usual additives.
Daglig dosering kan utgjore 200 til 1500 mg. Daily dosage can amount to 200 to 1500 mg.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7902839A FR2447921A1 (en) | 1979-02-05 | 1979-02-05 | IMIDAZO AND PYRIMIDO-PYRIDO-INDOLES AND THEIR APPLICATION IN THERAPEUTICS |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO794270L NO794270L (en) | 1980-08-06 |
| NO151289B true NO151289B (en) | 1984-12-03 |
| NO151289C NO151289C (en) | 1985-03-13 |
Family
ID=9221588
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO794270A NO151289C (en) | 1979-02-05 | 1979-12-27 | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE IMIDAZO AND PYRIMIDO PYRIDOINDOLS |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0015786B1 (en) |
| JP (1) | JPS55104282A (en) |
| AT (1) | ATE878T1 (en) |
| AU (1) | AU528425B2 (en) |
| CA (1) | CA1129412A (en) |
| DE (1) | DE3060292D1 (en) |
| DK (1) | DK17080A (en) |
| ES (1) | ES487712A1 (en) |
| FR (1) | FR2447921A1 (en) |
| GR (1) | GR74450B (en) |
| IE (1) | IE49629B1 (en) |
| IL (1) | IL59127A (en) |
| NO (1) | NO151289C (en) |
| PT (1) | PT70697A (en) |
| ZA (1) | ZA80241B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2485538B1 (en) * | 1980-06-24 | 1985-01-11 | Chinoin Gyogyszer Es Vegyeszet | NEW PROCESS FOR THE PREPARATION OF INDOLO (2 ', 3'; 3,4) -PYRIDO (1,2-B) QUINAZOLINE-5-ONES |
| JPH0425576Y2 (en) * | 1987-02-02 | 1992-06-18 | ||
| DE3827727A1 (en) * | 1988-08-16 | 1990-02-22 | Boehringer Ingelheim Kg | ANALYZED TETRAHYDROPYRIDINE IGNESE DERIVATIVES, METHOD FOR THE PRODUCTION AND USE OF SUCH CONNECTIONS FOR CARDIRO PROTECTION |
-
1979
- 1979-02-05 FR FR7902839A patent/FR2447921A1/en active Granted
- 1979-12-27 NO NO794270A patent/NO151289C/en unknown
-
1980
- 1980-01-14 JP JP300280A patent/JPS55104282A/en active Granted
- 1980-01-15 AT AT80400049T patent/ATE878T1/en active
- 1980-01-15 DK DK17080A patent/DK17080A/en not_active Application Discontinuation
- 1980-01-15 PT PT70697A patent/PT70697A/en unknown
- 1980-01-15 ZA ZA00800241A patent/ZA80241B/en unknown
- 1980-01-15 CA CA343,699A patent/CA1129412A/en not_active Expired
- 1980-01-15 IE IE77/80A patent/IE49629B1/en unknown
- 1980-01-15 AU AU54629/80A patent/AU528425B2/en not_active Ceased
- 1980-01-15 DE DE8080400049T patent/DE3060292D1/en not_active Expired
- 1980-01-15 GR GR60961A patent/GR74450B/el unknown
- 1980-01-15 EP EP80400049A patent/EP0015786B1/en not_active Expired
- 1980-01-15 ES ES487712A patent/ES487712A1/en not_active Expired
- 1980-01-15 IL IL59127A patent/IL59127A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FR2447921A1 (en) | 1980-08-29 |
| ATE878T1 (en) | 1982-05-15 |
| EP0015786B1 (en) | 1982-04-21 |
| JPS616073B2 (en) | 1986-02-24 |
| EP0015786A1 (en) | 1980-09-17 |
| NO151289C (en) | 1985-03-13 |
| PT70697A (en) | 1980-02-01 |
| DE3060292D1 (en) | 1982-06-03 |
| NO794270L (en) | 1980-08-06 |
| ZA80241B (en) | 1980-12-31 |
| IE800077L (en) | 1980-08-05 |
| IL59127A (en) | 1983-12-30 |
| IE49629B1 (en) | 1985-11-13 |
| FR2447921B1 (en) | 1982-01-29 |
| DK17080A (en) | 1980-08-06 |
| CA1129412A (en) | 1982-08-10 |
| AU5462980A (en) | 1980-08-14 |
| IL59127A0 (en) | 1980-05-30 |
| GR74450B (en) | 1984-06-28 |
| ES487712A1 (en) | 1980-06-16 |
| JPS55104282A (en) | 1980-08-09 |
| AU528425B2 (en) | 1983-04-28 |
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