DK167440B1 - ALKYL-SUBSTITUTED N-BENZOPYRANYLLACTAMES, PROCEDURES FOR THEIR PREPARATION AND MEDICINES CONTAINING THESE COMPOUNDS - Google Patents
ALKYL-SUBSTITUTED N-BENZOPYRANYLLACTAMES, PROCEDURES FOR THEIR PREPARATION AND MEDICINES CONTAINING THESE COMPOUNDS Download PDFInfo
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- DK167440B1 DK167440B1 DK055188A DK55188A DK167440B1 DK 167440 B1 DK167440 B1 DK 167440B1 DK 055188 A DK055188 A DK 055188A DK 55188 A DK55188 A DK 55188A DK 167440 B1 DK167440 B1 DK 167440B1
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Description
Ul\ lO/WU D IUl \ lO / WU D I
Den foreliggende opfindelse angår hidtil ukendte alkylsubstituerede N-benzopyranyllactamer, en fremgangsmåde til deres fremstilling samt lægemidler indeholdende disse forbindelser med afslappende virkning på ureteren.The present invention relates to novel alkyl-substituted N-benzopyranyl lactams, a process for their preparation, and to drugs containing these compounds having a relaxing effect on the ureter.
5 De her omhandlede N-benzopyranyllactamer er ejendom melige ved, at de har den almene formel O» 10 (1) *24y^-o.JrR3The N-benzopyranyl lactams disclosed herein are properties in that they have the general formula O »10 (1) * 24y ^ -o.JrR3
Ύ' j VV 'j V
hvor R1 er CN, -SOn-C^g-alkyl eller -S02-phenyl, idet n er 1 15 eller 2, R2 er H eller Ci_2-alkoxy, idet ovennævnte betydninger af R1 og R2 også kan være byttet om, R3 og R4 er ens eller forskellige og er C]_4-alkyl, og 20 X er en kæde (CH2)m, som er substitueret med en C1_2-alkyl-gruppe, og m er 3 eller 4, idet konfigurationen ved C3 og C4 altid er trans.wherein R 1 is CN, -SOn-C 1-6 alkyl or -SO 2 -phenyl, where n is 1 or 2, R 2 is H or C 1 2 alkoxy, the above meanings of R 1 and R 2 may also be substituted, R 3 and R 4 is the same or different and is C 1-4 alkyl, and 20 X is a chain (CH 2) m which is substituted by a C 1-10 alkyl group and m is 3 or 4, the configuration at C 3 and C 4 being always trans.
C-atomerne 3 og 4 i 3,4-dihydro-2H-benzo[b]pyran-25 systemet (herefter også betegnet "chromansystem") med formlen I er asymmetrisk substitueret. Opfindelsen angår kun sådanne forbindelser, som i disse centre udviser trans-konfiguration, dvs. lactamringen som substituent ved C-4 og OH-gruppen ved C-3 er altid orienteret trans i forhold til hinanden.The C atoms 3 and 4 of the 3,4-dihydro-2H-benzo [b] pyran system (hereinafter also referred to as "chromane system") of formula I are asymmetrically substituted. The invention relates only to such compounds which in these centers exhibit trans-configuration, i.e. the lactam ring as a substituent at C-4 and the OH group at C-3 are always oriented trans relative to each other.
30 Ovenstående definition af X betyder, at lactamringen også indeholder et chiralt C-atom. Opfindelsen angår således både forbindelser med R- og S-konfigurerede centre. Det samme gælder, når R1, R2, R3 eller R4 indeholder asymmetri-centre. Forbindelserne kan da foreligge som optiske isomere, 35 som diastereoisomere, som racemater eller som en blanding heraf.The above definition of X means that the lactam ring also contains a chiral C atom. The invention thus relates to both connections with R- and S-configured centers. The same is true when R1, R2, R3 or R4 contain asymmetry centers. The compounds may then be available as optical isomers, as diastereoisomers, as racemates or as a mixture thereof.
22
Foretrukne er sådanne forbindelser med formlen I, hvor R3--R4 har ovennævnte betydninger, og kæden X er substitueret med en C;|-2-alkylgruppe ved det C-atom, som ligger ved siden af N-atomet i lactamringen.Preferred are such compounds of formula I wherein R 3 - R 4 have the above meanings and the chain X is substituted by a C 1-6 alkyl group at the C atom adjacent to the N atom of the lactam ring.
5 Foretrukne er også forbindelser, hvor R1-R4 har oven nævnte betydninger, og C^^-alkylsubstituenten ved det C--atom, som i kæden X ligger ved siden af lactamringens N--atom, er således, at dette C-atoms konfiguration er trans i forhold til C-4-atomet i chromansystemet, og blandt disse 10 foretrækkes især forbindelser med formlen I, hvor R1 er CN eller R2 er H, R3 og R4 er ens eller forskellige og er alkyl med 1-2 car-bonatomer.Also preferred are compounds wherein R 1 -R 4 has the above meanings and the C 1-4 alkyl substituent at the C atom located in the chain X next to the N atom of the lactam ring is such that this C atom configuration is trans with respect to the C-4 atom of the chromane system, and among these, especially preferred are compounds of formula I wherein R 1 is CN or R 2 is H, R 3 and R 4 are the same or different and are alkyl of 1-2 carbons. atoms.
15 I J. Med. Chem. 29, 2194-2201 (1986), er beskrevet de N-benzopyranyllactamer, som ligger nærmest ved forbindelserne ifølge opfindelsen. En stor del af disse forbindelser er også beskrevet i forskellige offentliggørelsesskrifter, blandt hvilke skal nævnes EP-A nr. 107.423, 120.427, 076.075 20 og 120.428.In J. Med. Chem. 29, 2194-2201 (1986) discloses the N-benzopyranyl lactams closest to the compounds of the invention. Much of these compounds are also disclosed in various disclosures, including EP-A Nos. 107,423, 120,427, 076,075 and 120,428.
Om disse forbindelser ved man, at de er i stand til at sænke et sygeligt forhøjet blodtryk, idet de afslapper den glatte karmuskulatur og beskytter den mod pressorpåvirk-ninger eller kan gøre den ufølsom.About these compounds, they are known to be capable of lowering morbidly elevated blood pressure, relaxing the smooth vasculature and protecting it from compressor effects or making it insensitive.
25 Forbindelserne med formlen I ifølge opfindelsen udgør en ny stofklasse, som først og fremmest adskiller sig fra de kendte, ved at de i den lactamring, som er substituent på C-4 i chromansystemet, bærer en c1_2-alkylsubstituent. Denne substituering fører ved sammenligning med den kendte, 30 usubstituerede forbindelse i nogle tilfælde til en formindskelse af den akutte toksicitet.The compounds of formula I according to the invention constitute a new class of substances which differs primarily from the known ones in that they carry in the lactam ring which is substituent on C-4 in the chromane system a C1-2 alkyl substituent. This substitution, when compared to the known, unsubstituted compound, sometimes reduces acute toxicity.
Forbindelserne ifølge opfindelsen med formlen I udviser en kraftig afslappende virkning på ureteren. Derfor er sådanne forbindelser værdifulde terapeutika ved behand-35 lingen af urinlederkolik og ved lithotripsibehandling. IThe compounds of the invention of formula I exhibit a powerful relaxing effect on the ureter. Therefore, such compounds are valuable therapeutics in the treatment of ureteric colic and in lithotripsy therapy. IN
begge tilfælde letter en afslappende virkning på urinlederen 3 UK Ί67440 Bl afgangen af sten.both cases facilitate a relaxing effect on the ureter 3 UK Ί67440 Bl the departure of stones.
Den foreliggende opfindelse angår derfor tillige anvendelsen af en forbindelse med formlen I til fremstilling af et lægemiddel til afslapning af ureteren og et lægemiddel 5 med denne virkning, der er ejendommeligt ved, at det indeholder en aktiv mængde af en forbindelse med formel I.The present invention therefore also relates to the use of a compound of formula I for the manufacture of a medicament for relaxing the ureter and a drug 5 having this effect, which is characterized in that it contains an active amount of a compound of formula I.
Opfindelsen angår endelig en fremgangsmåde til fremstilling af forbindelserne med formlen I, hvilken fremgangsmåde er ejendommelig ved, at 10 (a) en forbindelse med formlenThe invention finally relates to a process for the preparation of the compounds of formula I, which process is characterized in that (a) a compound of the formula
CHCH
r1Br TOT T (II) 15 R4 hvor R1, R2, R3 og R4 har ovennævnte betydninger, omsættes med en lactam med formlen 20 s O^N·^ (IH) 25 hvor X har ovennævnte betydning, eller (b) en forbindelse med formlen R4 hvor Ri, R2, R3 og R4 har ovennævnte betydninger, omsættes med en lactam med formlen III, eller 35 (c) en forbindelse med formlen 4 nh2 2wV3 ™r1Br TOT T (II) R4 wherein R1, R2, R3 and R4 have the above meanings, reacted with a lactam of the formula 20 s O ^ N · ^ (IH) 25 where X has the above meaning, or (b) a compound having the formula R4 wherein R 1, R 2, R 3 and R 4 have the above meanings are reacted with a lactam of formula III, or (c) a compound of formula 4 nh2 2wV3 ™
5 R5 R
Λ hvor R1, R2, R3 og R4 har ovennævnte betydninger, acyleres til en forbindelse med formlen ενΛ* - * ,¾¾ m R4 hvor R^—R4 og X er som defineret ovenfor, og Y er en udtræ-15 dende gruppe, såsom chlor eller brom, og denne cycliseres til en forbindelse med formlen I, eller (d) en forbindelse med formlen G1*2 'χΟχ R4 hvor Rl-R4 og X er som defineret ovenfor, oxideres til en forbindelse med formlen I.Λ where R 1, R 2, R 3 and R 4 have the above meanings are acylated to a compound of formula ενΛ * - *, ¾¾ m R 4 where R 1 - R 4 and X are as defined above and Y is a leaving group such as chlorine or bromine and this is cyclized to a compound of formula I, or (d) a compound of formula G1 * 2 'χΟχ R4 wherein R 1 -R 4 and X are as defined above are oxidized to a compound of formula I.
25 Dersom forbindelserne med formlen I fremstilles ved metoderne (a) eller (b), sker dette ved, at forbindelserne IV eller II i et egnet opløsningsmiddel, fortrinsvis i dipolære, aprote opløsningsmidler, såsom dimethylsulfoxid eller THF, omsættes med lactamerne med formlen III, fortrins-30 vis under indflydelse af baser, såsom natriumhydrid, K-tert.-butylat eller lignende, med henblik på lactam-N-alkyleringer af kendte, egnede baser. Reaktionstemperaturen kan herved varieres indenfor et bredt område, men fortrinsvis arbejdes der mellem O'C og stuetemperatur. Ved anvendelse af racemiske 35 lactamer med formlen III eller optisk ensartede lactamer med formlen III (når X indeholder et usymmetrisk substitueret DK 167440 Bl 5 C-atom) fås i det mindste 2 nye produkter med formlen I.If the compounds of formula I are prepared by methods (a) or (b), this is done by reacting compounds IV or II in a suitable solvent, preferably in dipolar aprotic solvents such as dimethylsulfoxide or THF, with the lactams of formula III, preferably under the influence of bases such as sodium hydride, K-tert-butylate or the like, for lactam N-alkylations of known suitable bases. The reaction temperature can hereby be varied within a wide range, but preferably between 0 ° C and room temperature. By using racemic 35 lactams of formula III or optically uniform lactams of formula III (when X contains an asymmetrically substituted DK 167440 B1 5 atom) at least 2 new products of formula I.
Disse produkter kan ved hjælp af gængse metoder, såsom krystallisation eller chromatografi, adskilles, og i mange tilfælde har en kombination af disse to metoder vist sig 5 fordelagtig. De pågældende produkter kan derpå ved gængse fysiske undersøgelser, såsom røntgenstrukturanalyse eller NMR-spektroskopi, grupperes under de pågældende samlede konfigurationer. Optisk ensartede, dvs. enantiomerrene, forbindelser med formlen I kan fås ved efterfølgende race-10 matspaltning. Hvis der allerede anvendes enantiomerrene lactamer med formlen III, fås de diastereoisomere forbindelser med formlen I ligeledes i enantiomeren form, og en racematspaltning bliver overflødig.These products can be separated by conventional methods, such as crystallization or chromatography, and in many cases a combination of these two methods has proved advantageous. The products in question can then be grouped under the usual overall configurations by conventional physical studies, such as X-ray structure analysis or NMR spectroscopy. Optically uniform, i.e. enantiomerically, compounds of formula I can be obtained by subsequent racemate digestion. If enantiomerically pure lactams of formula III are already used, the diastereoisomeric compounds of formula I are also obtained in enantiomeric form and a racemate cleavage becomes redundant.
Lactamer med formlen III er i mange tilfælde kendt 15 eller kan let fremstilles ifølge metoder, der er kendt fra litteraturen. Også bromhydrinerne med formlen II og epoxider-ne med formlen IV er i mange tilfælde kendt [jfr. de ovenfor anførte offentliggørelsesskrifter eller J. Med. Chem. 29, 2194-2201 (1986)] eller kan fremstilles analogt med de der 20 anførte metoder. Sådanne forbindelser med formlen II og IV, hvor R1 er -S02-phenyl, er hidtil ukendte. De kan f.eks. fremstilles på følgende måde: 2,3-Dihydro-2H-benzo[b]pyran-4-oner med formlenIn many cases, lactams of formula III are known or can be readily prepared by methods known in the literature. The bromohydrin of formula II and the epoxides of formula IV are also known in many cases [cf. the publications cited above or J. Med. Chem. 29, 2194-2201 (1986)] or may be prepared by analogy to the methods cited therein. Such compounds of formula II and IV, wherein R 1 is -SO 2 -phenyl, are novel. For example, they can is prepared as follows: 2,3-Dihydro-2H-benzo [b] pyran-4-one of the formula
25 /•'V'S25 / • 'V'S
30 hvor R2, R3 og R4 har ovennævnte betydninger omsættes med phenylsulfonylchlorid på i og for sig kendt måde (Friedel-Crafts-acylering) til forbindelser med formlen R4 6 uiv iD/q-^υ d i hvor R2, R3 og R4 er som ovenfor defineret.Wherein R 2, R 3 and R 4 have the above meanings are reacted with phenylsulfonyl chloride in a manner known per se (Friedel-Crafts acylation) to compounds of the formula R4 6 ui iD / q- ^ υ di where R2, R3 and R4 are as above defined.
Disse forbindelser med formlen IX omsættes under standardbetingelser ved reduktioner, f.eks. ved hjælp af NaBH4 i methanol, til forbindelserne med formlen 5 OHThese compounds of formula IX are reacted under standard conditions by reductions, e.g. using NaBH 4 in methanol, for the compounds of formula 5 OH
hvori R2, R3 og R4 er som ovenfor defineret, og underkastes 10 derpå en vandfraspaltning, f.eks. ved hjælp af pyridin/phos-phoroxychlorid, hvorved der fås 2H-benzo[b]pyrener med formlen 15 * V (XI) hvori R2, R3 og R4 har ovennævnte betydninger.wherein R 2, R 3 and R 4 are as defined above and then subjected to a water cleavage, e.g. by means of pyridine / phosphorus oxychloride to give 2H-benzo [b] pyrenes of the formula 15 * V (XI) wherein R 2, R 3 and R 4 have the above meanings.
Forbindelserne med formlen XI kan ved hjælp af standardmetoder let omdannes til epoxiderne med formlen IV eller 20 bromhydrinerne med formlen II.The compounds of formula XI can be easily converted by the standard methods to the epoxides of formula IV or the bromohydrin of formula II.
Opfindelsen vil i det følgende blive yderligere forklaret ved hjælp af eksempler.The invention will now be further explained by way of example.
o 7o 7
Eksempel 1 (3R*, 4S*, 51 S*)-6-Cyano-3,4-dihydro-2,2-dimethyl-4-[2'-oxo-5' -methyl-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol og (3R*, 4S*, 5'R*)-6-Cyano-3,4-dihydro-2,2-dimethyl-4-[2’- 5 oxo-51-methyl-l'-pyrrolidinyl)-2H-benzo[b]pyran-3-ol.Example 1 (3R *, 4S *, 51S *) - 6-Cyano-3,4-dihydro-2,2-dimethyl-4- [2'-oxo-5'-methyl-1-pyrrolidinyl) -2H- benzo [b] pyran-3-ol and (3R *, 4S *, 5'R *) - 6-Cyano-3,4-dihydro-2,2-dimethyl-4- [2'-oxo-51- methyl-l'-pyrrolidinyl) -2H-benzo [b] pyran-3-ol.
Til en opløsning af 32 g (0,113 mol) 6-cyano--trans-3-brom-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran--4-ol i 200 ml DMS0 sættes ved 20°C 3,6 g (0,12 mol) 80%'s NaH (suspension i olie). Efter omrøring én time 10 tilsættes yderligere 4,8 g (0,16 mol) 80%'s NaH og 15,9 g (0,16 mol) racemisk 5-methyl-2-pyrrolidon. Efter omrøring i 8 timer ved 20°C hældes reaktionsblandingen i isvand, og bundfaldet omkrystalliseres fra methanol.To a solution of 32 g (0.113 mol) of 6-cyano-trans-3-bromo-3,4-dihydro-2,2-dimethyl-2H-benzo [b] pyran-4-ol in 200 ml of DMSO is added. at 20 ° C 3.6 g (0.12 mol) of 80% NaH (suspension in oil). After stirring for one hour 10 additional 4.8 g (0.16 mol) of 80% NaH and 15.9 g (0.16 mol) of racemic 5-methyl-2-pyrrolidone are added. After stirring for 8 hours at 20 ° C, the reaction mixture is poured into ice water and the precipitate is recrystallized from methanol.
1515
Den omkrystalliserede blanding adskilles o-ver en kiselgelkolonne med C^C^/CH^OH = 95:5. (3R*,- 4S*,5'S*)6-cyano-3,4-dihydro-2,2-dimethyl-4-[2'-oxo--5'-methyl-1'-pyrrolidinyl]-2H-benzo[b]pyran-3-ol isoleres og omkrystalliseres flere gange fra ethanol.The recrystallized mixture is separated over a silica gel column with C ^C ^ / CH₂OH = 95: 5. (3R *, - 4S *, 5'S *) 6-Cyano-3,4-dihydro-2,2-dimethyl-4- [2'-oxo-5'-methyl-1'-pyrrolidinyl] -2H-benzo [b] pyran-3-ol is isolated and recrystallized several times from ethanol.
20 o20 o
Krystaller med smeltepunkt: 239-240 C.Crystals with melting point: 239-240 ° C.
NMR (dg-DMSO) CH3-signaler £ 0,80 (3H, d) 1,17 (3H, s) 1,45 (3H, s)NMR (d 6 -DMSO) CH 3 signals δ 0.80 (3H, d) 1.17 (3H, s) 1.45 (3H, s)
Analyse: Beregnet for ci7H20N2°3: 300,37: 25 C 67,98, H 6,71, N 9,33.Analysis: Calculated for C 17 H 20 N 2 O 3: 300.37: C 67.98, H 6.71, N 9.33.
Fundet: C 67,9, H 6,8, N 9,4.Found: C 67.9, H 6.8, N 9.4.
Den methanoliske moderlud, hvori (3R*,4S*,- 51R*)-6-cyano-3,4-dihydro-2,2-dimethyl-4-[21-oxo-5'- methyl-1'-pyrrolidinyl)-2H-benzo[b]pyran-3-ol er kon-30 centreret, inddampes, og forbindelsen isoleres over en kiselgelkolonne med CH2Cl2/CH3OH = 95:5.The methanolic mother liquor wherein (3R *, 4S *, - 51R *) - 6-cyano-3,4-dihydro-2,2-dimethyl-4- [21-oxo-5'-methyl-1'-pyrrolidinyl) -2H-benzo [b] pyran-3-ol is concentrated, evaporated and the compound is isolated over a silica gel column with CH 2 Cl 2 / CH 3 OH = 95: 5.
Krystaller med smeltepunkt: 190-192°C (fra ethylacetat).Crystals with melting point: 190-192 ° C (from ethyl acetate).
NMR (dc-DMS0) CH,-signaler 5 1,20 (3H, s) 35 bi 1,30 (1,5H, s) 1,43 (4,5H,s) 0NMR (dc-DMSO) CH1 signals δ 1.20 (3H, s) δ 1.30 (1.5H, s) 1.43 (4.5H, s) δ
Lsl\ I Ό/ΗΉ-U D ILsl \ I Ό / ΗΉ-U D I
88
Analyse: Beregnet for C17H20H2°3: 300'37 C 67,98, H 6,71, N 9,33.Analysis: Calculated for C 17 H 20 H 2 3: 300.37 C 67.98, H 6.71, N 9.33.
Fundet: C 68,0, H 6,7, N 9,4.Found: C 68.0, H 6.7, N 9.4.
5 Eksempel 2 (-)-(3S, 4R, 5*R)-6-Cyano-3,4-dihydro-2,2-dimethyl-4-(2*-oxo-5'-methyl-11-pyrrolidinyl)-2H-benzo[b]pyran-3-ol og: (-)-(3R, 4S,5’R)-6-Cyano-3,4-dihydro-2,2-dimethyl-4- (2*- -oxo- 51 - methyl-11- pyrrol idinyl) - 2H- benzo[b]pyran- 3- ol 10 Til en opløsning af 30,2 g (0,15 mol) 6-cyano- -3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo [b] pyran i 150 ml dimethylsulfoxid sættes 6 g (0,2 mol) 80%’sExample 2 (-) - (3S, 4R, 5 * R) -6-Cyano-3,4-dihydro-2,2-dimethyl-4- (2 * -oxo-5'-methyl-11-pyrrolidinyl) -2H-benzo [b] pyran-3-ol and: (-) - (3R, 4S, 5'R) -6-Cyano-3,4-dihydro-2,2-dimethyl-4- (2 * -) -oxo-51-methyl-11-pyrrolidinyl) -2H-benzo [b] pyran-3-ol To a solution of 30.2 g (0.15 mol) of 6-cyano-3,4-dihydro-2 2,2-dimethyl-3,4-epoxy-2H-benzo [b] pyran in 150 ml of dimethyl sulfoxide are added 6 g (0.2 mole) 80%
NaH og 15 g (0,15 mol) (R)-5-methyl-2-pyrrolidon [jfr.NaH and 15 g (0.15 mol) of (R) -5-methyl-2-pyrrolidone [cf.
René Amstutz, Bjorn Ringdahl, Bo Karlén, Margareth Rock 15 og Donald J. Jenden, J. Med. Chem. 28, 1760-1765 (1985)] og der omrøres i 6 timer ved 20°C. Reaktionsblandingen sættes til isvand, bundfaldet vaskes neutralt, tørres og adskilles over en kiselgelkolonne med CH^C^/CE^OH = 19:1 og omkrystalliseres fra ethanol. Der fås først den i o-20 verskriften sidstnævnte forbindelse som krystaller med smeltepunkt 184°C. = -27,8°, c = 1 i ethanol.René Amstutz, Bjorn Ringdahl, Bo Karlén, Margareth Rock 15 and Donald J. Jenden, J. Med. Chem. 28, 1760-1765 (1985)] and stirred for 6 hours at 20 ° C. The reaction mixture is added to ice-water, the precipitate is washed neutral, dried and separated over a silica gel column with CH2 C2 / CE2 OH = 19: 1 and recrystallized from ethanol. The latter compound is first obtained as crystals having a melting point of 184 ° C. = -27.8 °, c = 1 in ethanol.
Som det andet langsommere løbende produkt fås efter yderligere krystallisation fra ethanol den i overskriften førstnævnte forbindelse som krystaller med smel-25 tepunkt 258°C, = -86°, c = 1, ethanol.As the second slower running product, after further crystallization from ethanol, the title compound as crystals having a melting point of 258 ° C, = -86 °, c = 1, ethanol is obtained.
Eksempel 3 6-Cyano-3,4-dihydro-2,2-dimethyl-trans-4- (2' -oxo-31 -methyl-l'-pyrrolidinyl) -2H-benzo[b]pyran-3-ol 30 Diastereomer A og diastereomer B Diastereomer B:Example 3 6-Cyano-3,4-dihydro-2,2-dimethyl-trans-4- (2'-oxo-31-methyl-1'-pyrrolidinyl) -2H-benzo [b] pyran-3-ol Diastereomer A and Diastereomer B Diastereomer B:
Til en opløsning af 16 g (0,056 mol) 6-cyano--trans-3-brom-3,4-dihydro-2,2-dimethyl-2H-benzo [b] pyran--4-ol i 80 ml dimethylsulfoxid tilsættes 1,8 g (0,06 mol) 35 80%'s NaH. Efter omrøring i én time ved 20°C tilsættes yderligere 2,4 g (0,08 mol) 80%'s NaH og 8,6 g (0,084 9To a solution of 16 g (0.056 mol) of 6-cyano-trans-3-bromo-3,4-dihydro-2,2-dimethyl-2H-benzo [b] pyran-4-ol in 80 ml of dimethyl sulfoxide is added. 1.8 g (0.06 mol) of 80% NaH. After stirring for one hour at 20 ° C, an additional 2.4 g (0.08 mol) of 80% NaH and 8.6 g (0.084 g) are added.
OISLAND
mol) racemisk 3-methyl-2-pyrrolidon, hvorefter der om-røres i 16 timer ved 20°C. Efter afkøling og tildryp-ning af 160 ml vand suges bundfaldet fra, vaskes med lidt vand og tørres.mole) racemic 3-methyl-2-pyrrolidone, then stirred for 16 hours at 20 ° C. After cooling and dripping 160 ml of water, the precipitate is sucked off, washed with a little water and dried.
5 Råproduktet omkrystalliceres 2 gange fra eddi kesyreester /methanol og derpå fra dimethylformamid/meth-anol. Diastereomeren kan isoleres ren.The crude product is recrystallized twice from acetic acid ester / methanol and then from dimethylformamide / methanol. The diastereomer can be isolated pure.
Krystaller med smeltepunkt 261-263°C.Crystals, mp 261-263 ° C.
NMR (dg-DMSO) CH3~signaler: c 1,19 (3H, s) 10 1,21 (6H, s) 1,45 (3H, s)NMR (d 6 -DMSO) CH 3 signals: c 1.19 (3H, s) 1.21 (6H, s) 1.45 (3H, s)
Diastereomer A:Diastereomer A:
Moderluden fra ovennævnte forsøg inddampes, og remanensen chromatograferes over en kiselgelkolonne med 15 eddikesyreester/petroleumsether = 9:1. Diastereomeren A skilles fra og omkrystalleres fra ethanol.The mother liquor from the above experiment is evaporated and the residue is chromatographed over a silica gel column with 15 acetic acid ester / petroleum ether = 9: 1. The diastereomer A is separated and recrystallized from ethanol.
Krystaller med smeltepunkt 210-211°C.Crystals of m.p. 210-211 ° C.
NMR (dg-DMSO) CH3-Signaler: £ 1,13 (3H, d) 1,20 (3H, s) 20 1,47 (3H, s)NMR (d 6 -DMSO) CH 3 Signals: δ 1.13 (3H, d) 1.20 (3H, s) δ 1.47 (3H, s)
Eksempel 4 (3R*, 4S*, 5 1 S*) -3,4-Dihydro-2,2-dimethyl-6-methylsulfonyl--4-(2'-oxo-5’-methyl-l-pyrrolidinyl)-2H-benzo[bjpyran-25 -3-olExample 4 (3R *, 4S *, 5 L S *) -3,4-Dihydro-2,2-dimethyl-6-methylsulfonyl-4- (2'-oxo-5'-methyl-1-pyrrolidinyl) - 2H-benzo [bjpyran-25 -3-ol
Til en opløsning af 10,2 g (0,04 mol) 3,4-di-hydro-2,2-dimethyl-3,4-epoxy-6-methylsulfonyl-2H-benzo-[blpyran og 4 g (0,04 mol) racemisk 5-methyl-2-pyrroli-don i 50 ml DMSO sættes ved 20°C 1,5 g (0,05 mol) 80%'s 30 NaH. Der opvarmes i 30 minutter til 45°C og omrøres i 5 timer, hvorefter der hældes i isvand. Der klares med aktivt kul, og produktet udsaltes. Bundfaldet suges fra, og diastereomeren A fraskilles over en kiselgelkolonne med ethanol/eddikesyreester/toluen/petroleumsether = 35 2:2:1:,1 og omkrystalliseres fra eddikesyreester.To a solution of 10.2 g (0.04 mole) of 3,4-dihydro-2,2-dimethyl-3,4-epoxy-6-methylsulfonyl-2H-benzo [b] pyran and 4 g (O, (4 mol) of racemic 5-methyl-2-pyrrolidone in 50 ml of DMSO is added at 20 ° C 1.5 g (0.05 mol) of 80% 30 NaH. Heat for 30 minutes to 45 ° C and stir for 5 hours, then pour into ice water. Activated charcoal is clarified and the product is salted out. The precipitate is aspirated and the diastereomer A is separated over a silica gel column with ethanol / acetic acid ester / toluene / petroleum ether = 35 2: 2: 1: 1 and recrystallized from acetic acid ester.
Krystaller med smeltepunkt 190-193°C.Crystals, mp 190-193 ° C.
DK 167440 B1 10 o NMR (dg-DMSO) CH3-signaler: h' 0,74 (3H, d) 1,18 (3H, s) 1,47 (3H, s) 5 Fremstilling af udgangsmaterialet: p-Methylsulfonylphenyl-1,1-dimethylpropargyl-ether fås af p-methylsulfonylphenol og 3-methyl-3-chlor-butyn på i og for sig kendt måde.NMR (dg-DMSO) CH 3 signals: h '0.74 (3H, d) 1.18 (3H, s) 1.47 (3H, s) 5 Preparation of starting material: p-Methylsulfonylphenylphenyl 1,1-dimethylpropargyl ether is obtained from p-methylsulfonylphenol and 3-methyl-3-chlorobutyne in a manner known per se.
Smeltepunkt 64-65°C (af lidt petroleumsether).Melting point 64-65 ° C (of slightly petroleum ether).
10 2,2-Dimethyl-6-methylsulfonylchromen fås ved at opvarme p-methylsulfonylphenyl-1,1-dimethylpropargyl-etheren i 1,2-dichlorbenzen til 180°C.2,2-Dimethyl-6-methylsulfonylchromene is obtained by heating the p-methylsulfonylphenyl-1,1-dimethylpropargyl ether in 1,2-dichlorobenzene to 180 ° C.
Smeltepunkt 107-108°C (fra diisopropylether).Melting point 107-108 ° C (from diisopropyl ether).
. 3-Brom-3,4-dihydro-2,2-dimethyl-6-methylsul-15 fonyl-2H-benzo[b]pyran-4-ol fås af 2,2-dimethyl-6-meth-ylsulfonylchromen og N-bromsuccinimid i en blanding af dimethylsulfoxid/H20 = 9:1.. 3-Bromo-3,4-dihydro-2,2-dimethyl-6-methylsulphonyl-2H-benzo [b] pyran-4-ol is obtained from 2,2-dimethyl-6-methylsulfonylchromene and N- bromosuccinimide in a dimethyl sulfoxide / H2 O mixture = 9: 1.
Smeltepunkt 140-141°C fra diisopropylether.Melting point 140-141 ° C from diisopropyl ether.
3,4-Dihydro-2,2-dimethyl-3,4-epoxy-6-methyl-sulfonyl-2H-benzo[b]pyran fås ved at omsætte 3-brom-3,4--dihydro-2,2-dimethyl-6-methylsulfonyl-2H-benzo [b]pyran--4-ol med natriumhydrid i DMSO.3,4-Dihydro-2,2-dimethyl-3,4-epoxy-6-methylsulfonyl-2H-benzo [b] pyran is obtained by reacting 3-bromo-3,4-dihydro-2,2-carboxylic acid. dimethyl-6-methylsulfonyl-2H-benzo [b] pyran-4-ol with sodium hydride in DMSO.
Smeltepunkt 165°C (fra eddikesyreester) 25Melting point 165 ° C (from acetic acid ester) 25
Eksempel 5 ( 3R*, 4S*, 5'S*)-2,2-Dimethyl- 7-methoxy- 6- phenyl sulf onyl- 4-(2 ’ - oxo- 5' -methyl-1' -pyrrolidinyl) -2H-benzo[b]pyran- 3-ol og (3R*, 4S*, 5,R*)-2/2-Dimethyl-7-methoxy-6-phenylsulfo-30 nyl-4- (2 ’ -oxo-5' -methyl-1f-pyrrolidinyl)-2H-benzo[b]pyran- 3-olExample 5 (3R *, 4S *, 5'S *) - 2,2-Dimethyl-7-methoxy-6-phenylsulfonyl-4- (2 '- oxo-5'-methyl-1' -pyrrolidinyl) -2H- benzo [b] pyran-3-ol and (3R *, 4S *, 5, R *) - 2/2-Dimethyl-7-methoxy-6-phenylsulphonyl-4- (2'-oxo-5 ') -methyl-1f-pyrrolidinyl) -2H-benzo [b] pyran-3-ol
Til en opløsning af 9,6 g 3-brom-3,4-dihydro--2,2-dimethyl-7-methoxy-6-phenylsulfonyl-2H-benzo [b] py-ran-4-ol i 60 ml dimethylsulfoxid sættes 1,62 g (0,0675 mol) NaH i form af en 80¾1s suspension samt 10,3 g (0,11) o5 mol) (+)-5-methyl-2-pyrrolidinon, og blandingen omrøres DK 167440 Bl o 11 i 4 timer ved 40°C. Derpå sættes blandingen til isvand, og der suges fra. Remanensen vaskes neutral, tørres og underkastes chromatografi på kiselgel med elueringsmid-del toluen/methylenchlorid/methanol = 10:1:1. Som første 5 hovedprodukt elueres den i overskriften sidstnævnte forbindelse med smeltepunkt 214-215°C.To a solution of 9.6 g of 3-bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-2H-benzo [b] pyran-4-ol in 60 ml of dimethylsulfoxide 1.62 g (0.0675 mole) of NaH is added in the form of an 80¾1 suspension and 10.3 g (0.11) of 5 mole) (+) - 5-methyl-2-pyrrolidinone and the mixture is stirred. 11 for 4 hours at 40 ° C. Then add the mixture to ice water and suction. The residue is washed neutral, dried and chromatographed on silica gel with eluent toluene / methylene chloride / methanol = 10: 1: 1. As the first main product, the latter compound is eluted with mp 214-215 ° C.
NMR (dg-DMSO) 8 (ppm) :1,17, 1,27, 1,4 (s,s,s? 9H, 2,2-dimethyl og 5-methyl).NMR (d 6 -DMSO) δ (ppm): 1.17, 1.27, 1.4 (s, s, s? 9H, 2,2-dimethyl and 5-methyl).
Som andet hovedprodukt fås den langsommere lø-10 bende i overskriften førstnævnte forbindelse med smeltepunkt 244-245°C. NMR (dg-DMSO) S (ppm): 0,73 (d, 3H, 5'-CH3).As the second major product, the slower run in the title is obtained from the former compound, mp 244-245 ° C. NMR (d 6 -DMSO) δ (ppm): 0.73 (d, 3H, 5'-CH 3).
Fremstilling af udgangsmateriale: 15 3-Brom-3,4-dihydro-2,2-dimethyl-7-methoxy-6- -phenylsulfonyl-2H-benzo[b]pyran-4-ol fås fra 2,2-dimeth-yl-7-methoxy-6-phenylsulfonyl-2H-chromen og N-bromsuccin-imid i en blanding af dimethylsulfoxid/^O = 9:1. Smeltepunkt 202-203°C.Preparation of starting material: 3-Bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6--phenylsulfonyl-2H-benzo [b] pyran-4-ol is obtained from 2,2-dimethyl-2 -7-methoxy-6-phenylsulfonyl-2H-chromene and N-bromosuccinimide in a mixture of dimethylsulfoxide / O = 9: 1. Melting point 202-203 ° C.
20 2,2-Dimethyl~7-methoxy-6-phenylsulfonyl-2H- -chromen fås fra 2,2-dimethyl-4-hydroxy-7-methoxy-6--phenylsulfonylchroman med pyridin/phosphoroxychlorid i benzen. Smeltepunkt 140-141°C.2,2-Dimethyl ~ 7-methoxy-6-phenylsulfonyl-2H- chromium is obtained from 2,2-dimethyl-4-hydroxy-7-methoxy-6-phenylsulfonylchroman with pyridine / phosphorus oxychloride in benzene. Melting point 140-141 ° C.
2.2- Dimethyl-4-hydroxy-7-methoxy-6-phenylsulfon-25 ylchroman fås fra 2,2-dimethyl-7-methoxy-6-phenylsulfo- nylchroman-4-on med natriumborhydrid i methanol. Smeltepunkt 146-147°C.2.2- Dimethyl-4-hydroxy-7-methoxy-6-phenylsulfonylchroman is obtained from 2,2-dimethyl-7-methoxy-6-phenylsulfonylchroman-4-one with sodium borohydride in methanol. Melting point 146-147 ° C.
2.2- Dimethyl-7~methoxy-6-phenylsulfonylchroman--4-on fås fra phenylsulfonylchlorid, 2,2-dimethyl-7-meth- 30 oxychroman-4-on og aluminiumchlorid i methylenchlorid. Smeltepunkt 223-225°C.2.2- Dimethyl-7-methoxy-6-phenylsulfonylchroman-4-one is obtained from phenylsulfonyl chloride, 2,2-dimethyl-7-methoxychroman-4-one and aluminum chloride in methylene chloride. Melting point 223-225 ° C.
35 1235 12
Eksempel 6 (3R*, 4S*, 5,S*)-3/4-Dihydro-2/2-dimethyl-6-phenylsulfonyl- 4- [2'-oxo-5'-methyl-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol _ oq 3R*, 4S*, 5 *R*3,4-dihydro-2,2-dimethyl-· 6- 5 * _ ; · ... · · phenyl sul f onyf-4- (2' - oxo- 5'-methyl-1-pyrrol idinyl) -2H-benzo[b]pyran- 3- olExample 6 (3R *, 4S *, 5, 5 *) -3 / 4-Dihydro-2/2-dimethyl-6-phenylsulfonyl-4- [2'-oxo-5'-methyl-1-pyrrolidinyl) -2H -benzo [b] pyran-3-ol and 3R *, 4S *, 5 * R * 3,4-dihydro-2,2-dimethyl-6-, 5-yl; Phenylsulfonyl-4- (2 '- oxo-5'-methyl-1-pyrrolidinyl) -2H-benzo [b] pyran-3-ol
Forbindelserne fremstilles analogt med eksempel 5 med racemisk 5-methylpyrrolidin-2-on. Derpå ad-ILo skilles blandingen på en kiselgelkolonne med methylen-chlorid/eddikesyreester/ethanol = 94:3:3.The compounds are prepared analogously to Example 5 with racemic 5-methylpyrrolidin-2-one. Then ad-ILo is separated on a silica gel column with methylene chloride / acetic acid ester / ethanol = 94: 3: 3.
(3R*, 4S*, 5'S*)-3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl- 4- (2 '-oxo-S'-methyl-l-pyrrolidinylJ^H-benzojbJpyran-S-ol 15 Krystaller med smp. 216-217° fra Ethanol' iNMR (d6 -DMSO) 5'-CH3-Signal: 6 0.48 (3H, Pseudoduplett) ' (3R*, 4S*, 5,R*)-3/4-Dihydro-2/2-dimethyl-6-phenylsulfonyl-ί 4- (2,-oxo-5'-methyl-l-pyrrolidinyl)-2H-benzo[b]pyran-3-ol 20 : , Krystaller med smp. 240-241°C fra DMF/Ethanol NMR (dg-DMSO) 5'-CH3-Signal: δ 1,27 (3H, d)(3R *, 4S *, 5'S *) - 3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4- (2'-oxo-S'-methyl-1-pyrrolidinyl) -H-benzoyl] pyran-S ol 15 Crystals, mp 216-217 ° from Ethanol 'iNMR (d6 -DMSO) 5'-CH3 Signal: 6 0.48 (3H, Pseudoduplet)' (3R *, 4S *, 5, R *) - 3/4 -Dihydro-2/2-dimethyl-6-phenylsulfonyl-ile 4- (2, -oxo-5'-methyl-1-pyrrolidinyl) -2H-benzo [b] pyran-3-ol 20:, Crystals with m.p. 240-241 ° C from DMF / Ethanol NMR (dg-DMSO) 5'-CH3 Signal: δ 1.27 (3H, d)
Eksempel 7 25 WC S* 0 yy\ H m n. x o L^I^L-ch, ..-ohExample 7 25 WC S * 0 yy \ H m n. X o L ^ I ^ L-ch, ..- oh
30 V r π T30 V r π T
^__ch5 ch3 35 Til en suspension af 10 g (0,05 mol) af det ovenfor viste epoxid og 8,4 g (0,075 mol) 6-methylpiperidin-2-on i DK 167440 B1 13 100 ml THF sættes 50 ml (0,05 mol) af en bis-(trimethyl-silyl)-lithiumamidopløsning i THF. Oplosningen omrøres i 5 døgn under tilbagesvaling. Reaktionsblandingen hældes ud i is/vand og ekstraheres derefter med methylenchlorid. Methy-5 lenchloridfasen vaskes flere gange med vand, tørres og inddampes. Remanensen chromatograferes over en kiselgelsøjle med ethylacetat/petroleumsether (4:1).To a suspension of 10 g (0.05 mole) of the epoxide shown above and 8.4 g (0.075 mole) of 6-methylpiperidin-2-one in DK 167440 B1 13 100 ml of THF is added 50 ml (0 (05 mol) of a bis (trimethylsilyl) lithium amide solution in THF. The solution is stirred for 5 days under reflux. The reaction mixture is poured into ice / water and then extracted with methylene chloride. The methylene chloride phase is washed several times with water, dried and evaporated. The residue is chromatographed over a silica gel column with ethyl acetate / petroleum ether (4: 1).
Udbytte 6,4 g (41%), smp. 221-222eC.Yield 6.4 g (41%), m.p. 221-222eC.
10 1. (3R, 4S, 5'R)-3,4-Dihydro-2/2-dimethyl-6-methylsulfonyl-4- [2' - oxo- 5' -methyl-1-pyrrol idinyl) - 2-H-benzo[b]pyran- 3- ol 2. (3R*, 4S*, 51 S*) -6-Cyano-3,4-dihydro-2,2- dimethyl- 7- methoxy- 4- [21 - oxo- 5' -methyl-1-pyrrol idinyl) -2H-benzo[b]pyran- 3-ol, 15 6. (3R*, 4S*, 5,S*)-3,4-ii.ihydro-2-methyl-2-.ethyl-6-phenyl- sulf onyl- 4- [2' - oxo- 51 -methyl- 1-pyrrolidinyl) -2H-benzo [b]pyran-3-ol, 12. (3R*, 4S*, 5,R*)-3#4-Dihydro-2,2,-dimethyl-6-phenyl-sulf onyl- 4- [2' - oxo- 4' - methyl-1- pyrrol idinyl ] - 2H- benzo 20 [b]pyran-3-ol, 19. (3R*, 4S*, 6'S*)-6-Cyano-3,4-dihydro-2,2-diethyl-4- [2,-oxo-6’-methyl-l-piperidinyl)-2H-benzo[b]pyran-3-ol.1. (3R, 4S, 5'R) -3,4-Dihydro-2/2-dimethyl-6-methylsulfonyl-4- [2'-oxo-5'-methyl-1-pyrrolidinyl) -2- H-benzo [b] pyran-3-ol 2. (3R *, 4S *, 51S *) -6-Cyano-3,4-dihydro-2,2-dimethyl-7-methoxy-4- [21 - oxo-5'-methyl-1-pyrrolidinyl) -2H-benzo [b] pyran-3-ol, 6. (3R *, 4S *, 5, S *) - 3,4-iihydro-2 -methyl-2-ethyl-6-phenylsulfonyl-4- [2 '- oxo-51-methyl-1-pyrrolidinyl) -2H-benzo [b] pyran-3-ol, 12. (3R *, 4S *, 5, R *) - 3 # 4-Dihydro-2,2, -dimethyl-6-phenylsulfonyl-4- [2 '- oxo-4' - methyl-1-pyrrolidinyl] -2H benzo [b] pyran-3-ol, 19. (3R *, 4S *, 6'S *) - 6-Cyano-3,4-dihydro-2,2-diethyl-4- [2, oxo-6 ' methyl-l-piperidinyl) -2H-benzo [b] pyran-3-ol.
2525
Pharmakologiske dataPharmacological data
Indflydelse på KC1-inducerede, rytmiske kontraktioner på marsvine-uretere in vitro.Influence of KC1-induced rhythmic contractions on guinea pig ureters in vitro.
Metode: Hanmarsvin aflives ved nakkeslag og åreladning 30 fra carotiderne. Begge uretere fjernes straks, idet området nær ved nyrebækkenet undgås på grund af den pacer-aktivitet, der findes der. Derpå befries 2 cm lange stykker i en petriskål, som indeholder Tyrode-opløsning, for bindevæv og ophænges hver især med en forspænding på 4,9 mN (= 0,5 p) i 35 et 25 ml organbad (Fa. Rhema Labortechnik, Hofheim). Organbadet indeholder en Tyrode-opløsning, der holdes på 37eC, 14 som gennembobles med carbogen (95% 02, 5% C02)/ og som har følgende sammensætning (mmol/liter) : NaCl 137, KC1 2,68,Method: Male guinea pigs are sacrificed by neck stroke and yearly charge 30 from the carotids. Both ureters are removed immediately, avoiding the area near the renal pelvis due to the pacer activity found there. Then, 2 cm long pieces in a Petri dish containing Tyrode solution are frozen for connective tissue and each suspended with a bias of 4.9 mN (= 0.5 p) in a 25 ml organ bath (Fa. Rhema Labortechnik, Hofheim ). The organ bath contains a Tyrode solution maintained at 37 ° C, 14 which is bubbled with the carbogen (95% O 2, 5% CO 2) / and having the following composition (mmol / liter): NaCl 137, KCl 2.68,
MgS04 1,05, CaCl2 1,8, NaH2P04 0,41, NaHC03 11,9 og glucose 5,55.MgSO4 1.05, CaCl2 1.8, NaH2 PO4 0.41, NaHCO3 11.9 and glucose 5.55.
5 Kontraktionerne måles isometrisk under anvendelse af5 The contractions are measured isometrically using
Gould/Statham UC2-afgivere. Efter en ækvilibreringstid på mindst 15 minutter sættes der KC1 til organbadet, idet der nås en koncentration på 4 x 10“2 mol/liter. Agonisten forbliver i 2 minutter i badet, hvorved der optræder fasekon-10 traktioner, uden at dette bevirker en nævneværdig stigning af grundspændingen. Derefter skylles der i l minut, hvorpå de rytmiske kontraktioner straks ophører. Efter endnu en gang agonisttilsætning og skylning sættes prøveforbindelsen (benzopyran-derivat) til organbadet (i form af en opløsning 15 i 0,1 ml ethanol; s lutkoncentrat ionerne er i alle tilfælde 10“7 mol/liter), og man afventer en indvirkningstid på ét minut, før der tilsættes KC1. Efter den følgende skylningsoperation følger 2 afsluttende agonisttilsætning/skylningsprocedurer. Ud fra perioderne på hver 2 minutter under ind-20 virkning af KC1 bestemmes følgende parametre; 1. gennemsnitlig kontraktionskraft, 2; kontraktionernes frekvens og 3. produktet af gennemsnitlig kontraktionskraft og frekvens.Gould / Statham UC2 emitters. After an equilibration time of at least 15 minutes, KC1 is added to the organ bath, reaching a concentration of 4 x 10 “2 mol / liter. The agonist stays in the bath for 2 minutes, resulting in phase contractions, without causing a significant increase in the fundamental voltage. Then rinse for 1 minute, which immediately stops the rhythmic contractions. After agonist addition and rinsing again, the test compound (benzopyran derivative) is added to the organ bath (in the form of a solution 15 in 0.1 ml of ethanol; for one minute before adding KC1. Following the following rinse operation, 2 final agonist addition / rinse procedures follow. From the periods of every 2 minutes under the influence of KC1, the following parameters are determined; 1. average contraction power, 2; frequency of contractions and 3. the product of average contracting power and frequency.
Udelukkelseskriterier er gennemsnitlige kontraktionskræfter under 4 mN eller frekvenser under 2/min. ved mere 25 end én af fire perioder, i hvilke kun agonisten KC1 findes i badet. Man bedømmer den procentvise hæmning under prøvestof sammenlignet med middelværdien af de to forforsøg.Exclusion criteria are average contraction forces below 4 mN or frequencies below 2 / min. at more than 25 of one of four periods in which only the agonist KC1 is present in the bath. The percent inhibition under test substance is evaluated compared to the mean of the two tests.
Foruden den aritmetiske gennemsnitsværdi (x) udregnes standardafvigelsen (SEM).In addition to the arithmetic mean value (x), the standard deviation (SEM) is calculated.
30 35 0 DK 167440 B1 1530 35 0 DK 167440 B1 15
Resultater:results:
Gennemsnitlig Gennemsnit- procentvis hæm- lig procent-ning af kon- vis hæmning traktions- af 5 . Forbindelse kraft k frekvéns v k*v n _[%3 <-)-(3R,4S,5'R)- 75 ± 8 89 ± 4 96 ± 2 7 6-Cyano-3,4-di-hydro-2,2-dime-10 thyl-4-(2'-oxo-5'-methyl-1' -pyrrolidinyl)-2H-benzo[b]pyran- 3-ol 15 (fra eksempel nr. 2) ±)-(3R*,4S*,5’R*)- 69 ± 11 86 ± 4 96 ± 1 6 6-Cyano-3,4-dihydro- 2,2-dimethyl-4-(2'- oxo-5'-methyl-1'- · 20 pyrrolidinyl)-2H-benzo[b]pyran-3-ol (fra eksempel nr. 1) ±)-6-Cyano-3,4-di- 8±8 58 ±5 61 ±77 hydro-2,2-dimethyl-25 trans-4-(2-oxo-1-pyrrolidinyl)-3-01 benzo [b] - pyr an-3-ol ( fra J.Med.Chem.Average Average percentage inhibitory percentage of conical inhibition traction of 5. Compound force k frequency wk * vn _ [% 3 <-) - (3R, 4S, 5'R) - 75 ± 8 89 ± 4 96 ± 2 7 6-Cyano-3,4-di-hydro-2.2 -dimethyl-4- (2'-oxo-5'-methyl-1 '-pyrrolidinyl) -2H-benzo [b] pyran-3-ol (from Example # 2) ±) - (3R * , 4S *, 5'R *) - 69 ± 11 86 ± 4 96 ± 1 6 6-Cyano-3,4-dihydro-2,2-dimethyl-4- (2'-oxo-5'-methyl-1 (20 pyrrolidinyl) -2H-benzo [b] pyran-3-ol (from Example # 1) ±) -6-Cyano-3,4-di-8 ± 8 58 ± 5 61 ± 77 hydro-2 , 2-Dimethyl-trans-4- (2-oxo-1-pyrrolidinyl) -3-01 benzo [b] pyran-3-ol (from J.Med.Chem.
1986,29 2194-2201) 30 n = antal uretere Litteratur: 35 P. SCHIANTARELLI og W. MURMANN.1986.29 2194-2201) 30 n = number of ureter Literature: 35 P. SCHIANTARELLI and W. MURMANN.
Antispasmodic Activity of Rociverine on the Smooth *Antispasmodic Activity of Rociverine on the Smooth *
Musculature of the Urinary Tract.Musculature of the Urinary Tract.
Arzneim.-Forsch./Drug Res. 30, 1102-1109 (1980).Arzneim.-Forsch./Drug Res. 30, 1102-1109 (1980).
Claims (8)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19873703229 DE3703229A1 (en) | 1987-02-04 | 1987-02-04 | Alkyl-substituted N-benzopyranyl lactams, processes for their preparation, their use and pharmaceutical preparations based on these compounds |
| DE3703229 | 1987-02-04 | ||
| DE19873724876 DE3724876A1 (en) | 1987-07-28 | 1987-07-28 | Alkyl-substituted N-benzopyranyllactams, processes for their preparation, their use and pharmaceutical preparations based on these compounds |
| DE3724876 | 1987-07-28 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK55188D0 DK55188D0 (en) | 1988-02-03 |
| DK55188A DK55188A (en) | 1988-08-05 |
| DK167440B1 true DK167440B1 (en) | 1993-11-01 |
Family
ID=25852153
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK055188A DK167440B1 (en) | 1987-02-04 | 1988-02-03 | ALKYL-SUBSTITUTED N-BENZOPYRANYLLACTAMES, PROCEDURES FOR THEIR PREPARATION AND MEDICINES CONTAINING THESE COMPOUNDS |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0277611B1 (en) |
| KR (1) | KR880009957A (en) |
| AU (1) | AU604089B2 (en) |
| DE (1) | DE3881714D1 (en) |
| DK (1) | DK167440B1 (en) |
| ES (1) | ES2058148T3 (en) |
| FI (1) | FI92064C (en) |
| HU (1) | HU207729B (en) |
| IE (1) | IE60932B1 (en) |
| IL (1) | IL85289A (en) |
| NO (1) | NO169964C (en) |
| NZ (1) | NZ223384A (en) |
| PH (1) | PH24836A (en) |
| PT (1) | PT86691B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3703227A1 (en) * | 1987-02-04 | 1988-08-18 | Hoechst Ag | SUBSTITUTED 3,4-DIHYDRO-2H-BENZOPYRANES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS |
| GB8800199D0 (en) * | 1988-01-06 | 1988-02-10 | Beecham Group Plc | Pharmaceutical preparation |
| DE3824446A1 (en) * | 1988-07-19 | 1990-01-25 | Hoechst Ag, 6230 Frankfurt | USE OF SUBSTITUTED 3,4-DIHYDRO-2H-BENZOPYRANE AS A MEDICINE AGAINST OBSTRUCTIVE FUNCTIONAL DISORDERS OF THE LUNG AND / OR DISORDERS OF THE LEADING URINE PATHS |
| DE3827532A1 (en) * | 1988-08-13 | 1990-03-01 | Hoechst Ag | 6-AROYL-SUBSTITUTED 3,4-DIHYDRO-2H-BENZOPYRANES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS |
| FR2637896B1 (en) * | 1988-10-17 | 1990-11-30 | Adir | NOVEL AMINO CHROMANOL DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| DE3901720A1 (en) * | 1989-01-21 | 1990-07-26 | Hoechst Ag | SUBSTITUTED BENZO (B) PYRANS, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS |
| US5104890A (en) * | 1989-03-28 | 1992-04-14 | Fujisawa Pharmaceutical Company, Ltd. | Benzopyran derivatives and processes for preparation thereof |
| IE63935B1 (en) * | 1989-06-27 | 1995-06-28 | Chem Pharm Forsch Gmbh | Novel thienopyran derivatives a process for their preparation and their use |
| GB8924373D0 (en) * | 1989-10-30 | 1989-12-20 | Beecham Group Plc | Novel compounds |
| AU651105B2 (en) * | 1990-06-18 | 1994-07-14 | E.R. Squibb & Sons, Inc. | Benzopyran derivatives and heterocyclic analogs thereof as antiischemic agents |
| HUT72741A (en) * | 1992-12-19 | 1996-05-28 | Alkaloida Vegyeszeti Gyar | Method for producing benzopyrane derivatives and pharmaceutical compositions containing them |
| GB9316111D0 (en) * | 1993-08-04 | 1993-09-22 | Pfizer Ltd | Benzopyrans |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE23718T1 (en) * | 1981-09-25 | 1986-12-15 | Beecham Group Plc | BENZOPYRAN COMPOUNDS WITH PHARMACEUTICAL ACTIVITY. |
| EP0107423B1 (en) * | 1982-10-19 | 1986-07-23 | Beecham Group Plc | Novel chromans and chromenes |
| GB8308064D0 (en) * | 1983-03-24 | 1983-05-05 | Beecham Group Plc | Active compounds |
| GB8308062D0 (en) * | 1983-03-24 | 1983-05-05 | Beecham Group Plc | Active compounds |
| GB8419516D0 (en) * | 1984-07-31 | 1984-09-05 | Beecham Group Plc | Treatment |
| DE3726261A1 (en) * | 1986-12-23 | 1988-07-07 | Merck Patent Gmbh | CHROME DERIVATIVES |
| DE3703227A1 (en) * | 1987-02-04 | 1988-08-18 | Hoechst Ag | SUBSTITUTED 3,4-DIHYDRO-2H-BENZOPYRANES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS |
-
1988
- 1988-01-30 DE DE8888101344T patent/DE3881714D1/en not_active Expired - Fee Related
- 1988-01-30 ES ES88101344T patent/ES2058148T3/en not_active Expired - Lifetime
- 1988-01-30 EP EP88101344A patent/EP0277611B1/en not_active Expired - Lifetime
- 1988-02-02 FI FI880468A patent/FI92064C/en not_active IP Right Cessation
- 1988-02-02 HU HU88450A patent/HU207729B/en not_active IP Right Cessation
- 1988-02-02 PH PH36449A patent/PH24836A/en unknown
- 1988-02-02 IL IL8528988A patent/IL85289A/en not_active IP Right Cessation
- 1988-02-02 NZ NZ223384A patent/NZ223384A/en unknown
- 1988-02-03 NO NO880474A patent/NO169964C/en unknown
- 1988-02-03 IE IE29588A patent/IE60932B1/en not_active IP Right Cessation
- 1988-02-03 AU AU11227/88A patent/AU604089B2/en not_active Ceased
- 1988-02-03 PT PT86691A patent/PT86691B/en not_active IP Right Cessation
- 1988-02-03 DK DK055188A patent/DK167440B1/en not_active IP Right Cessation
- 1988-02-03 KR KR1019880000967A patent/KR880009957A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| FI880468A0 (en) | 1988-02-02 |
| PT86691A (en) | 1988-03-01 |
| KR880009957A (en) | 1988-10-06 |
| DK55188D0 (en) | 1988-02-03 |
| FI92064B (en) | 1994-06-15 |
| DE3881714D1 (en) | 1993-07-22 |
| IE60932B1 (en) | 1994-09-07 |
| NZ223384A (en) | 1989-11-28 |
| IE880295L (en) | 1988-08-04 |
| FI880468A (en) | 1988-08-05 |
| NO880474L (en) | 1988-08-05 |
| DK55188A (en) | 1988-08-05 |
| EP0277611A3 (en) | 1990-04-25 |
| ES2058148T3 (en) | 1994-11-01 |
| IL85289A (en) | 1994-04-12 |
| PT86691B (en) | 1992-04-30 |
| AU1122788A (en) | 1988-09-08 |
| NO169964B (en) | 1992-05-18 |
| EP0277611B1 (en) | 1993-06-16 |
| NO880474D0 (en) | 1988-02-03 |
| HU207729B (en) | 1993-05-28 |
| AU604089B2 (en) | 1990-12-06 |
| IL85289A0 (en) | 1988-07-31 |
| EP0277611A2 (en) | 1988-08-10 |
| FI92064C (en) | 1994-09-26 |
| NO169964C (en) | 1992-08-26 |
| PH24836A (en) | 1990-10-30 |
| HUT50165A (en) | 1989-12-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PBP | Patent lapsed |