DK146046B - METHOD FOR PREPARING THIENO (3,2-C) - OR THIENO (2,3-C) PYRIDINES - Google Patents
METHOD FOR PREPARING THIENO (3,2-C) - OR THIENO (2,3-C) PYRIDINES Download PDFInfo
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Description
i 146046in 146046
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af hidtil ukendte thieno[3,2-c]- eller [2,3-c]- pyridiner med en af følgende formler ____R1 gQ , - ςχ* * <i, cov 1 2 5 hvori R og R uafhængigt af hinanden betegner hydrogen, en C^-Cg-alkylgruppe, en C2~C4 alkenylgruppe, en C2-C4-alkynylgruppe, en phenyl- eller phenyl-C^-C^-alkylgruppe, der eventuelt i phenylkernen er substitueret med et til tre halogenatomer eller C^-C^-alkyl-, C^-C^-alkoxy-, hydroxy-, 1Q eller trifluormethylgrupper, en pyridyl-C1-C4-alkyl-eller thienyl-C^-C4~alkylgruppe, eller en gruppe med formlen ^r3 -(ch9) n 2 B v.‘ 3 4 hvori n er 2 eller 3, og R og R uafhængigt af hinanden er en C^_4~alkylgruppe eller sammen med det nitrogenatom, 15 hvortil de er knyttet, danner en 5- eller 6-leddet mættet heteroring, som kan indeholde et yderligere heteroatom valgt blandt oxygen, svovl og nitrogen, hvilket yderligere nitrogen kan være substitueret med en C^_4~alkylgruppe, eller hvor R"*" og R^ sammen med det nitrogenatom, hvortil de er knyttet, dan-20 ner en 5- eller 6-leddet mættet heteroring, som kan indeholde et yderligere heteroatom valgt blandt oxygen, svovl og nitro= gen, hvilket yderligere nitrogenatom kan være substitueret med en C^C^-alkylgruppe, en benzylgruppe eller en phenyl= gruppe, der eventuelt er substitueret med et til tre halogen= 25 atomer eller C^-C^-alkyl-, C^-C4-alkoxy- eller trifluormethyl= grupper, eller farmaceutisk acceptable syreadditionssalte deraf, hvilken fremgangsmåde ifølge opfindelsen er ejendommelig ved det i kravets kendetegnende del angivne.The present invention relates to a particular process for the preparation of novel thieno [3,2-c] or [2,3-c] pyridines having any of the following formulas ____R1 gQ, - ςχ * * <i, cov 1 2 5 wherein R and R are independently hydrogen, a C 1 -C 6 alkyl group, a C 2 -C 4 alkenyl group, a C 2 -C 4 alkynyl group, a phenyl or phenyl-C 1 -C 4 alkyl group optionally in the phenyl nucleus. substituted with one to three halogen atoms or C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, 1Q or trifluoromethyl groups, a pyridyl C 1 -C 4 alkyl or thienyl C 1 -C 4 alkyl group or a group of the formula R3 - (CH9) n 2 B v. 3 4 wherein n is 2 or 3 and R and R are independently a C1-4 alkyl group or together with the nitrogen atom to which they are attached. is attached, forming a 5- or 6-membered saturated heterocycle which may contain an additional heteroatom selected from oxygen, sulfur and nitrogen, which additional nitrogen may be substituted by a C 1-4 alkyl group or wherein R "*" and R ^ along with d a nitrogen atom to which they are attached forms a 5- or 6-membered saturated heterocycle which may contain an additional heteroatom selected from oxygen, sulfur and nitrogen, which additional nitrogen atom may be substituted by a C -alkyl group, a benzyl group or a phenyl group optionally substituted with one to three halogen = 25 atoms or C 1 -C 4 alkyl, C 1 -C 4 alkoxy or trifluoromethyl groups, or pharmaceutically acceptable acid addition salts thereof which method according to the invention is characterized by the characterizing part of the claim.
U6046 2U6046 2
Sammenlignet med fremgangsmåden ifølge den foreliggende opfindelse består en fra USA-patentskrift nr. 3.845.065 kendt fremgangsmåde til fremstilling af thienopyridincarboxamider med den almene formel (Ila) i, at man går frem i overensstem-5 melse med følgende reaktionsskema: O Cl Cl u POC1, 1 RNEL· i uuw-ώ—>gy [ svaling | [Compared to the process of the present invention, a process known for U.S. Patent No. 3,845,065 consists of the preparation of thienopyridine carboxamides of the general formula (IIa) by proceeding in accordance with the following reaction scheme: POC1, 1 RNEL · i uuw-ώ—> gy [swallow | [
COOH COC1 CONHRCOOH COC1 CONHR
(la) (Ila)(la) (Ila)
Thienopyridincarboxylsyren omdannet til syrechloridet (la) tjener som acyleringsmiddel for aminen RNI^.The thienopyridine carboxylic acid converted to the acid chloride (Ia) serves as an acylating agent for the amine RNI
I tilfælde af thienopyridincarboxylsyrer, der har syre-10 funktionen fordelt i forhold til pyridinnitrogenatornet, således som det er tilfældet for de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser med formlerne (I) og (II), forløber omdannelsen til chlorid ikke.In the case of thienopyridine carboxylic acids having the acid function distributed over the pyridine nitrogen network, as is the case for the compounds of formulas (I) and (II) prepared by the process of the invention, the conversion to chloride does not proceed.
Ved fremgangsmåden ifølge den foreliggende opfindelse benyt-15 tes derfor en anderledes og hidtil ukendt fremgangsmåde, ved hvilken man benytter det blandede anhydridmecl en af de i kravet angivne almene formler (III) eller (IV) som mellemprodukt.Therefore, the process of the present invention utilizes a different and novel process using the mixed anhydride molecule one of the general formulas (III) or (IV) of the claim as intermediate.
Reaktionen ved fremgangsmåden ifølge opfindelsen er f.eks. som følger: cicooc2h5 —^ 2o ni i —nr iThe reaction of the process according to the invention is e.g. as follows: cicooc2h5 - ^ 2o ni i - no i
VsA^S00B HEt3 ttii)|'0i‘0C2H5 [™Η2 °VsA ^ S00B HEt3 ttii) | '0i'0C2H5 [™ Η2 °
C'O^'-C-NHRC'O ^ '- C-NHR
3 U60463 U6046
En sammenligning mellem de ovenfor anførte reaktionsskemaer viser, at fremgangsmåden ifølge opfindelsen er en hidtil ukendt fremgangsmåde sammenlignet med den i USA patentskrift nr. 3.845.065 beskrevne. Den gør brug af et mellemprodukt, der 5 adskiller sig fra det ved fremgangsmåden ifølge det amerikanske patentskrift benyttede.A comparison of the above reaction schemes shows that the process of the invention is a novel method compared to that described in US Patent No. 3,845,065. It uses an intermediate product that differs from that used in the process of the US patent.
Udgangsforbindelserne (III) og (IV) kan fremstilles ved kondensation, i nærværelse af triethylamin, af en thienopyridin med formlen (V) eller (VI) ·“" oCr”" (V) (VI) med et alkylchlorformiat med formlen C1COOR, hvori R har den i kravet anførte betydning.The starting compounds (III) and (IV) can be prepared by condensation, in the presence of triethylamine, of a thienopyridine of formula (V) or (VI) · “oCr” (V) (VI) with an alkyl chloroformate of formula C1 COOR wherein R has the meaning set forth in the claim.
Denne reaktion og fremgangsmåden ifølge opfindelsen foretages fortrinsvis i rækkefølge i den samme beholder. De blandede an-15 hydrider (III) og (IV) fremstilles f.eks, først ved temperaturer mellem ~5°C og. +15°C i et indifferent opløsningsmiddel, såsom chloroform eller methylenchlorid, og aminen med formlen HN , hvori R1 og 2 R har de i kravet angivne betydninger, i ren form eller opløst 20 i et opløsningsmiddel, såsom benzen, toluen, chloroform eller methylenchlorid, kan derpå tilsættes ved samme temperatur, hvorefter blandingen henstilles ved stuetemperatur.This reaction and the process according to the invention are preferably carried out in order in the same container. For example, the mixed anhydrides (III) and (IV) are prepared, first at temperatures between ~ 5 ° C and. + 15 ° C in an inert solvent such as chloroform or methylene chloride, and the amine of formula HN, wherein R 1 and 2 R have the meanings specified, in pure form or dissolved in a solvent such as benzene, toluene, chloroform or methylene chloride , can then be added at the same temperature, after which the mixture is left at room temperature.
Thienopyridinerne (V) og (VI) kan fremstilles ved en frem-25 gangsmåde omfattende omsætning af en forbindelse med formlen: ί 4 146046The thienopyridines (V) and (VI) can be prepared by a process comprising reacting a compound of the formula:
OHOH
^ __λ,ΟΟΟΕ gCr euer ζΧί s T tOOH b^ __λ, ΟΟΟΕ gCr euer ζΧί s T tOOH b
OHOH
(VID (VIII) med saltpetersyrling og dehydratisering samt fjernelse af den resulterende forbindelses nitrosogruppe ved omsætning med et alkalimetaliiydroxid og efterfølgende neutralisering.(VID (VIII) with salt parsing and dehydration as well as removal of the resulting compound nitroso group by reaction with an alkali metal hydroxide and subsequent neutralization).
5 udgangsmaterialerne med formlerne (VII) eller (VIII) kan fremstilles ved omsætning af en forbindelse med formlenThe starting materials of formulas (VII) or (VIII) can be prepared by reacting a compound of formula
OH COOHOH COOH
ΠΙ f — rfYΠΙ f - rfY
COOH NH2COOH NH2
OHOH
med en vandig formaldehydopløsning i nærværelse af en stærk syre. ^ 10 Forbindelserne fremstillet ifølge opfindelsen kan til oral administration sammensættes som tabletter, overtrukne tabletter, kapsler, dråber og sirupper. De kan til rektal administration også sammensættes som suppositorier og til parenteral administration sammensættes som injicerbare 15' opløsninger.with an aqueous formaldehyde solution in the presence of a strong acid. The compounds of the invention can be formulated for oral administration as tablets, coated tablets, capsules, drops and syrups. They may also be formulated as suppositories for rectal administration and for parenteral administration formulated as injectable 15 'solutions.
Hver enhedsdosis vil fordelagtigt indeholde fra 0,050 g til 0,500 g aktiv bestanddel. Den daglige dosisbehandling kan variere fra 0,050 g til 1,50 g aktiv bestanddel, afhængigt af patientens alder og af den tilstand, som behandles.Advantageously, each unit dose will contain from 0.050 g to 0.500 g of active ingredient. The daily dose treatment may vary from 0.050 g to 1.50 g of active ingredient, depending on the age of the patient and the condition being treated.
20 som følge af deres sedative og antikonvulsive virkning formindsker derivaterne med formlen (I) eller (II) person= lighedsmæssige og opførselsmæssige forstyrrelser og letter personlige kontakter på grund af forbedret mental ligevægt.As a result of their sedative and anticonvulsant effects, the derivatives of formula (I) or (II) decrease personality = similarity and behavioral disorders and facilitate personal contacts due to improved mental equilibrium.
De kan administreres til børn og voksne i tilfælde af ag= · gressivitet, irritabilitet, ustabilitet, ophidselse og psykomotorisk uro samt også ved alle manifestationer af excitabilitet.They can be administered to children and adults in cases of aggression, irritability, instability, arousal and psychomotor unrest as well as in all manifestations of excitability.
146046 5 På grund af deres antiinflammatoriske virkning, når de ad= 5 ministreres til kortvarige eller langvarige behandlinger, virker de effektivt på den inflammatoriske reaktion til bekæmpelse af ødem, hypersekretion og exudation under for= løbet af inflammationens forskellige trin. De er velegnede i tilfælde af kronisk inflammatorisk rheumatisme, degene= 10 rativ rheumatisme, abartikulære tilstande, akut podagra, inden for postoperativ plastisk kirurgi, indenfor traumato= logi og inden for oto-rhino-laryngologi.Due to their anti-inflammatory effects when administered to short-term or long-term treatments, they effectively act on the inflammatory response to fight edema, hypersecretion and exudation during the course of the various stages of inflammation. They are well suited in cases of chronic inflammatory rheumatism, dough = 10 rheumatism, abarticular conditions, acute podagra, in post-operative plastic surgery, in traumatology and in oto-rhino-laryngology.
De efterfølgende eksempler illustrerer nærmere fremgangsmåden ifølge opfindelsen.The following examples further illustrate the process of the invention.
15 Eksempel 1 6-methylaminocarbonyl-thieno[3,2-c]pyridin 1 2Example 1 6-methylaminocarbonyl-thieno [3,2-c] pyridine 1 2
Formel (I): NR R = NHCH^. Derivat nr. 1.Formula (I): NR R = NHCH Derivative # 1.
Til en opløsning af 6-carboxy-thieno[3,2-c]pyridin (10 g, 0,05 mol) og triethylamin (5,6 g, 0,057 mol) i tør chloro= 20 form (500 ml), der holdes ved 10°C, sættes langsomt ethyl= chlorformiat (6,2 g, 0,057 mol) under kraftig omrøring. Ef= ter afsluttet tilsætning fortsættes omrøringen ved stuetem= peratur i yderligere 40 minutter, hvorefter en opløsning af methylamin (2 g, 0,064 mol) i benzen (50 ml) dråbevis sæt= 25 tes dertil. Reaktionsblandingen henstilles ved stuetempe= ratur i 4 timer, inddampes til tørhed, og resten optages i ether. Etherfasen vaskes med mættet, vandig natriumcarbonat= opløsning, tørres over natriumsulfat og inddampes til tør= hed.To a solution of 6-carboxy-thieno [3,2-c] pyridine (10 g, 0.05 mol) and triethylamine (5.6 g, 0.057 mol) in dry chloro = 20 form (500 ml) is kept At 10 ° C, ethyl = chloroformate (6.2 g, 0.057 mol) is slowly added with vigorous stirring. After the addition is complete, stirring at room temperature is continued for an additional 40 minutes, after which a solution of methylamine (2 g, 0.064 mol) in benzene (50 ml) is added dropwise = 25 th. The reaction mixture is allowed to stand at room temperature for 4 hours, evaporated to dryness and the residue taken up in ether. The ether phase is washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate and evaporated to dryness.
30 Den faste rest rekrystalliseres fra benzen-diisopropylether. Lyserøde krystaller med smeltepunkt 99°C. Udbytte: 79%.The solid residue is recrystallized from benzene diisopropyl ether. Pink crystals, melting point 99 ° C. Yield: 79%.
66
Eksempel 2 146046 6-e-dimethylaminoethylaminocarbonyl-thieno[3,2-c]pyridlnExample 2 6-e-Dimethylaminoethylaminocarbonyl-thieno [3,2-c] pyridine
Formel (I): NR1^ = NH(CH2)2N(CH3)2- Derivat nr. 2.Formula (I): NR1 = NH (CH2) 2N (CH3) 2- Derivative # 2.
Til en opløsning af 6-carboxy-thieno[3,2-c]pyridin (10 g, 5 0,056 mol) og triethylamin (5,6 g, 0,057 mol) i tør chlo= roform (300 ml), der holdes ved 10°C, sættes langsomt ethyl= chlorformiat (6,2 g, 0,057 mol) under kraftig omrøring. Ef= ter afsluttet tilsætning fortsættes omrøringen ved stuetem= peratur i yderligere 40 minutter, hvorefter p-dimethylami= 10 noethylamin (5,4 g, 0,061 mol) dråbevis tilsættes. Reak= tionsblandingen henstilles ved stuetemperatur i 3 1/2 ti= me, hvorefter den inddampes til tørhed, og resten optages i IN saltsyre. Den sure, vandige fase vaskes med ether og gøres derpå alkalisk med 6N natriumhydroxid og ekstrahe= 15 res med methylenchlorid. Methylenchloridekstrakterne tør= res over tørt natriumsulfat og inddampes til tørhed. Den olieagtige rest renses via sit dihydrochlorid. Beige kry= staller med smeltepunkt 170°C (isopropanol—methanol). Ud= bytte: 75%.To a solution of 6-carboxy-thieno [3,2-c] pyridine (10 g, 5 0.056 mol) and triethylamine (5.6 g, 0.057 mol) in dry chloroform (300 ml) maintained at 10 ° C, slowly add ethyl = chloroformate (6.2 g, 0.057 mol) with vigorous stirring. After addition is complete, stirring is continued at room temperature for a further 40 minutes, after which p-dimethylamide = 10 noethylamine (5.4 g, 0.061 mol) is added dropwise. The reaction mixture is left at room temperature for 3 1/2 hours, then evaporated to dryness and the residue is taken up in 1N hydrochloric acid. The acidic aqueous phase is washed with ether and then made alkaline with 6N sodium hydroxide and extracted with methylene chloride. The methylene chloride extracts are dried over dry sodium sulfate and evaporated to dryness. The oily residue is purified via its dihydrochloride. Beige crystals having a melting point of 170 ° C (isopropanol-methanol). Out = exchange: 75%.
20 Eksempel 3 5-(4-p-chlorphenyl-l-piperazinyl)carbonyl-thieno[2,3-c] -pyridinExample 3 5- (4-p-chlorophenyl-1-piperazinyl) carbonyl-thieno [2,3-c] pyridine
Formel (II): NR1R2 = -Cl. Derivat nr. 3.Formula (II): NR1R2 = -Cl. Derivative No. 3.
Til en opløsning af 5-carboxy-thieno[2,3-c]pyridin (12 g, 25 0,067 mol) og triethylamin (6,9 g, 0,068 mol) i tør chlo= roform (250 ml), der holdes ved 10°C, sættes langsomt ethylchlorformiat (7,3 g, 0,068 mol) under kraftig omrø= ring. Omrøringen fortsættes ved stuetemperatur i 50 minut= ter, og p-chlorphenylpiperazin (13,2 g, 0,067 mol) opløst 30 i chloroform (50 ml) tilsættes dråbevis. Reaktionsblandin= 7 146046 gen henstilles ved stuetemperatur i 5 timer, hvorefter den inddampes til tørhed, og resten optages i methylenchlorid. Methylenchloridfasen vaskes med en mættet vandig natriumbi= carbonatopløsning, tørres over tørt natriumsulfat og ind= 5 dampes til tørhed. De resulterende krystaller renses ved hjælp af søjlekromatografi gennem silica (elueringsmiddel: ethylacetat).To a solution of 5-carboxy-thieno [2,3-c] pyridine (12 g, 0.067 mol) and triethylamine (6.9 g, 0.068 mol) in dry chloroform (250 ml) maintained at 10 ° C, slowly add ethyl chloroformate (7.3 g, 0.068 mol) with vigorous stirring. Stirring is continued at room temperature for 50 minutes and p-chlorophenylpiperazine (13.2 g, 0.067 mol) dissolved in chloroform (50 ml) is added dropwise. Reaction mixture = 7 is left at room temperature for 5 hours, then evaporated to dryness and the residue is taken up in methylene chloride. The methylene chloride phase is washed with a saturated aqueous sodium bicarbonate solution, dried over dry sodium sulfate and evaporated to dryness. The resulting crystals are purified by column chromatography through silica (eluent: ethyl acetate).
Hvide krystaller med smeltepunkt 170°C (isopropanol-diiso= propylether). Udbytte 41%.White crystals, melting point 170 ° C (isopropanol-diiso = propyl ether). Yield 41%.
10 Eksempel 4 6-ethylaminocarbonyl-thienoI3,2-cjpyridin Formel (I): NR^R2 = NHC„Hc. Derivat nr. 4.Example 4 6-Ethylaminocarbonyl-thieno-3,2-cipyridine Formula (I): NR 2 R2 = NHC + Hc. Derivative No. 4.
Δ DΔ D
Denne forbindelse fremstilles i overensstemmelse med pro= ceduren ifølge eksempel 1 ud fra 6-carboxy-thieno[3,2-c]py= 15 ridin og ethylamin. Beige krystaller med smeltepunkt 110°C (diisopropylether). Udbytte: 87%.This compound is prepared according to the procedure of Example 1 from 6-carboxythieno [3,2-c] py = 15 ridin and ethylamine. Beige crystals, mp 110 ° C (diisopropyl ether). Yield: 87%.
Eksempel 5 5-isopropylaminocarbonyl-thieno[2,3-c]pyridinExample 5 5-Isopropylaminocarbonyl-thieno [2,3-c] pyridine
Formel (II): NR^R2 = NH CgH^ . Der;*-vat nr· 5.Formula (II): NR 2 R 2 = NH C Der; * - vat no · 5.
20 Denne forbindelse fremstilles i overensstemmelse med pro= ceduren ifølge eksempel 1 ud fra 5-carboxy-thieno[2,3-c]py= ridin og isopropylamin. Lysebrune krystaller med smelte= punkt 102°C (diisopropylether). Udbytte: 80%.This compound is prepared according to the procedure of Example 1 from 5-carboxythieno [2,3-c] pyridine and isopropylamine. Light brown crystals with melt = point 102 ° C (diisopropyl ether). Yield: 80%.
Eksempel 6 25 6-n-butylaminocarbonyl-thieno[3,2-c]pyridin Formel (I) : NR1R2 = NHC^g. Derivat nr. 6.Example 6 6-n-Butylaminocarbonyl-thieno [3,2-c] pyridine Formula (I): NR 1 R 2 = NHC 2 g. Derivative No. 6.
8 1460468 146046
Denne forbindelse fremstilles i overensstemmelse med proce= duren ifølge eksempel 2 ud fra 6-carboxy-thieno[3,2-c]py= ridin og n-butylamin. Hydrochlorid: orange-gule krystaller med smeltepunkt 104°C (acetonitril). Udbytte: 55%.This compound is prepared according to the procedure of Example 2 from 6-carboxythieno [3,2-c] pyridine and n-butylamine. Hydrochloride: orange-yellow crystals, m.p. 104 ° C (acetonitrile). Yield: 55%.
5 Eksempel 7 6-octylaminocarbonyl-thieno[3,2-c]pyridinExample 7 6-Octylaminocarbonyl-thieno [3,2-c] pyridine
Formel (I): NR1R2 = NHCgH17. Derivat nr. 7.Formula (I): NR1R2 = NHCgH17. Derivative No. 7.
Denne forbindelse fremstilles i overensstemmelse med proce= duren ifølge eksempel 1 ud fra 6- carboxy-thieno[3,2-c]pyri= din og octylamin. Hvide krystaller med smeltepunkt 63°C (di= isopropylether). Udbytte: 54%.This compound is prepared according to the procedure of Example 1 from 6- carboxythieno [3,2-c] pyridine and octylamine. White crystals, melting point 63 ° C (di = isopropyl ether). Yield: 54%.
Eksempel 8 6-dimethylaminocarbonyl-thieno[3,2-cjpyridinExample 8 6-Dimethylaminocarbonyl-thieno [3,2-c] pyridine
Formel (I): NR^R2 = N(CHg)2· Derivat nr. 8.Formula (I): NR 2 R2 = N (CH 3) 2 · Derivative # 8.
15 Denne forbindelse fremstilles i overensstemmelse med proce= duren ifølge eksempel 2 ud fra 6-carboxy-thieno[3,2-c]pyri= din og dimethylamin. Hvide krystaller med smeltepunkt 93°C (diisopropylether). Udbytte: 55%,This compound is prepared according to the procedure of Example 2 from 6-carboxythieno [3,2-c] pyridine and dimethylamine. White crystals, m.p. 93 ° C (diisopropyl ether). Yield: 55%,
Eksempel 9 20 6-diethylaminocarbonyl-thieno[3,2-c] pyridinExample 9 6-Diethylaminocarbonyl-thieno [3,2-c] pyridine
Formel (I): NR^R2 = N(C2H,-)2. Derivat nr. 9.Formula (I): NR 2 R 2 = N (C 2 H 2 -) 2. Derivative No. 9.
Denne forbindelse fremstilles i overensstemmelse med proce= duren ifølge eksempel 1 ud fra 6-carboxy-thieno[3,2-c]pyri=This compound is prepared according to the procedure of Example 1 from 6-carboxythieno [3,2-c] pyridine
din og diethylamin. Beige krystaller med smeltepunkt 119°Cyours and diethylamine. Beige crystals, mp 119 ° C
9 146046 (diisopropylether). Udbytte 80%.9 146046 (diisopropyl ether). Yield 80%.
Eksempel 10 6- (l-pyrrolidlnyl) -carbonyl-thieno [3,2-c] pyridinExample 10 6- (1-Pyrrolidinyl) carbonyl-thieno [3,2-c] pyridine
Formel (I) : NR1!*2 = | . Derivat nr. 10.Formula (I): NR1! * 2 = | . Derivative No. 10.
5 Denne forbindelse fremstilles i overensstemmelse med proce= duren ifølge eksempel 1 ud fra 6-carboxy-thieno[3,2-c]pyri= din og pyrrolidin. Off-white krystaller med smeltepunkt 105°C (diisopropylether). Udbytte: 52%.This compound is prepared according to the procedure of Example 1 from 6-carboxythieno [3,2-c] pyridine and pyrrolidine. Off-white crystals, mp 105 ° C (diisopropyl ether). Yield: 52%.
Eksempel 11 10 6-piperidinocarbonyl-thieno[3,2-c]pyridinExample 11 6-Piperidinocarbonyl-thieno [3,2-c] pyridine
Formel (I) : NR^R2 = . Derivat nr. 11.Formula (I): NR2 R2 =. Derivative No. 11.
Denne forbindelse fremstilles i overensstemmelse med pro= ceduren ifølge eksempel 1 ud fra 6-carboxy-thieno[3,2-c]py= ridin og piperidin. Lysebrunt pulver med smeltepunkt 145°C 15 (diisopropylether). Udbytte 96%.This compound is prepared according to the procedure of Example 1 from 6-carboxythieno [3,2-c] pyridine and piperidine. Light brown powder, m.p. 145 ° C (diisopropyl ether). Yield 96%.
Eksempel 12 6-morpholinocarbonyl-thieno[3,2-c]pyridinExample 12 6-morpholinocarbonyl-thieno [3,2-c] pyridine
Formel (I) : NR3!*2 = o . Derivat nr. 12.Formula (I): NR3! * 2 = o. Derivative No. 12.
Denne forbindelse fremstilles i overensstemmelse med proce= 20 duren ifølge eksempel 1 ud fra 6-carboxy-thieno[3,2-c]pyri= din og morpholin. Hvide krystaller med smeltepunkt 136°C (benzen-diisopropylether). Udbytte: 79%.This compound is prepared according to the procedure of Example 1 from 6-carboxythieno [3,2-c] pyridine and morpholine. White crystals, mp 136 ° C (benzene diisopropyl ether). Yield: 79%.
Eksempel 13 10 146046 5- benzylaminocarbonyl-th.ieho [2, 3-c3 pyridinExample 13 10-Benzylaminocarbonyl-thieho [2,3-c3 pyridine
Formel (II): NR^R2 = NHCI^CgHg. Derivat nr. 13.Formula (II): NR2 R2 = NHCl3 CgHg. Derivative No. 13.
Denne forbindelse fremstilles i overensstemmelse med proce= 5 duren ifølge eksempel 1 ud fra 5-carboxy-thieno[2,3-c]pyri= din og benzylamin. Beige krystaller med smeltepunkt 113°C (isopropanol). Udbytte: 75%.This compound is prepared in accordance with the procedure of Example 1 from 5-carboxythieno [2,3-c] pyridine and benzylamine. Beige crystals mp 113 ° C (isopropanol). Yield: 75%.
Eksempel 14 6- o-chlorbenzylaminocarbonyl-th.ieno [3,2-c] pyridin d 10 Formel (I) : NR^R2 = NHCH^—· Derivat nr. 14.Example 14 6- O-Chlorobenzylaminocarbonyl-thieno [3,2-c] pyridine d Formula (I): NR 2 R 2 = NHCH 4 - Derivative No. 14.
Denne forbindelse fremstilles i overensstemmelse med pro= ceduren ifølge eksempel 1 ud fra 6-carboxy-thieno[3,2-c]py= ridin og o-chlorbenzylamin. Beige krystaller med smelte= punkt 169°C (methanol). Udbytte: 58%.This compound is prepared according to the procedure of Example 1 from 6-carboxythieno [3,2-c] pyridine and o-chlorobenzylamine. Beige crystals with melt = point 169 ° C (methanol). Yield: 58%.
15 Eksempel 15 6-phenethylaminocarbonyl-thieno[3,2-c]pyridinExample 15 6-Phenethylaminocarbonyl-thieno [3,2-c] pyridine
Formel (I): NR1R2 = NHCH2CH2C6H5. Derivat nr. 15.Formula (I): NR1R2 = NHCH2CH2C6H5. Derivative No. 15.
Denne forbindelse fremstilles i overensstemmelse med pro= ceduren ifølge eksempel 1 ud fra 6-carboxy-thieno[3,2-c]py= 20 ridin og phenethylamin. Beige krystaller med smeltepunkt 127°C (isopropanol-diisopropylether). Udbytte 66%.This compound is prepared in accordance with the procedure of Example 1 from 6-carboxythieno [3,2-c] py = 20 ridin and phenethylamine. Beige crystals, m.p. 127 ° C (isopropanol-diisopropyl ether). Yield 66%.
U6046U6046
Eksempel 16 11 6-allylaminocarbonyl-thieno [ 3,2:-c] pyridinExample 16 11 6-Allylaminocarbonyl-thieno [3,2: -c] pyridine
Formel (I): NR1R2 = NHCH2-CH=CH2.Derivat nr. 16.Formula (I): NR1R2 = NHCH2-CH = CH2. Derivative # 16.
Denne forbindelse fremstilles i overensstemmelse med proce= 5 duren ifølge eksempel 1 ud fra 6-carboxy-thieno[3,2-c]pyri= din og allylamin. Oxalat: hvide krystaller med smeltepunkt 131°C (ethylacetat). Udbytte: 54%.This compound is prepared according to the procedure of Example 1 from 6-carboxythieno [3,2-c] pyridine and allylamine. Oxalate: white crystals, mp 131 ° C (ethyl acetate). Yield: 54%.
Eksempel 17 6-propargylaminocarbonyl-thieno[3,2-c]pyridin 10 Formel (X): NR1!*2 = NHCH2C=CH. Derivat nr. 17.Example 17 6-Propargylaminocarbonyl-thieno [3,2-c] pyridine Formula (X): NR1 * 2 = NHCH2C = CH. Derivative No. 17.
Denne forbindelse fremstilles i overensstemmelse med proce= duren ifølge eksempel 1 ud fra 6-carboxy-thieno[3,2-c]pyri= din og propargylamin. Lyserøde krystaller med smeltepunkt 134°C . (isopropanol-diisopropylether). Udbytte: 60%.This compound is prepared according to the procedure of Example 1 from 6-carboxythieno [3,2-c] pyridine and propargylamine. Pink crystals melting at 134 ° C. (Isopropanol-diisopropyl ether). Yield: 60%.
15 Eksempel 18 6-3-diethylaminoethylaminocarbonyl-thieno[3,2-c]pyridinExample 18 6-3-Diethylaminoethylaminocarbonyl-thieno [3,2-c] pyridine
Formel (I): NRXR2 = NH (CHj) 2N (C^) 2. Derivat nr. 18.Formula (I): NRXR2 = NH (CH2) 2N (C2) 2. Derivative No. 18.
Denne forbindelse fremstilles i overensstemmelse med pro= ceduren ifølge eksempel 2 ud fra 6-carboxy-thieno[3,2-c] 20 pyridin og β-diethylarninoethylamin. Dihydrochlorid: beige krystaller med smeltepunkt 145°C (isopropanol-methanol).This compound is prepared according to the procedure of Example 2 from 6-carboxythieno [3,2-c] pyridine and β-diethylarino aminoethylamine. Dihydrochloride: beige crystals, mp 145 ° C (isopropanol-methanol).
Udbytte: 81%.Yield: 81%.
Eksempel 19 6-3-morpholinoethylaminocarbonyl-thieno[3,2-c]pyridin 12 146046 1 ? / \Example 19 6-3-morpholinoethylaminocarbonyl-thieno [3,2-c] pyridine 12? / \
Formel (I): NR R = NH(CH0)_N o - Derivat nr. 19.Formula (I): NR R = NH (CHO) _N o - Derivative No. 19.
2 2 \_/2 2 \ _ /
Denne forbindelse fremstilles i overensstemmelse med pro= ceduren ifølge eksempel 2 ud fra 6-carboxy-thieno[3,2-c] pyridin og N-(2-aminoethyl)-morpholin. Hvide krystaller med 5 smeltepunkt 104°C (isopropanol-diisopropylether). Udbytte: 71%.This compound is prepared according to the procedure of Example 2 from 6-carboxythieno [3,2-c] pyridine and N- (2-aminoethyl) -morpholine. White crystals having a melting point of 104 ° C (isopropanol-diisopropyl ether). Yield: 71%.
Eksempel 20 6-Y-dimethylaminopropylaminocarbonyl-thieno[3,2-c]pyridinExample 20 6-Y-Dimethylaminopropylaminocarbonyl-thieno [3,2-c] pyridine
Formel (I): NR1!*2 = NH(CH2)3N(CH3)2. Derivat nr. 20.Formula (I): NR1 * 2 = NH (CH2) 3N (CH3) 2. Derivative No. 20.
10 Denne forbindelse fremstilles i overensstemmelse proceduren ifølge eksempel 2 ud fra 6-carboxy-thieno[3,2-c]pyridin og γ-dimethylaminopropylamin. Dihydrochlorid: beige krystaller med smeltepunkt 146°C (ethanol). Udbytte: 77%.This compound is prepared according to the procedure of Example 2 from 6-carboxythieno [3,2-c] pyridine and γ-dimethylaminopropylamine. Dihydrochloride: beige crystals, mp 146 ° C (ethanol). Yield: 77%.
Eksempel 21 15 5-(4-pyridyl-methyl)aminocarbonyl-thieno]2,3-c]pyridinExample 21 5- (4-Pyridylmethyl) aminocarbonyl-thieno] 2,3-c] pyridine
Formel (II) : NR^R2 = _ Derivat nr. 21.Formula (II): NR ^ R2 = - Derivative No. 21.
Denne forbindelse fremstilles i overensstemmelse med procedu= ren ifølge eksempel 3 ud fra 5-carboxy-thieno[2,3-c]pyridin og 4-aminomethyl-pyridin. Lysebrune krystaller med smelte= 20 punkt 167°C (isopropanol-diisopropylether). Udbytte: 78%.This compound is prepared according to the procedure of Example 3 from 5-carboxythieno [2,3-c] pyridine and 4-aminomethyl-pyridine. Light brown crystals with melt = 20 point 167 ° C (isopropanol-diisopropyl ether). Yield: 78%.
Eksempel 22 6-(4-pyridyl-methyl)aminocarbonyl-thieno[3,2-c]pyridin Formel (I): NR1R2 = NHCH2-^Q^N . Derivat nr. 22.Example 22 6- (4-Pyridylmethyl) aminocarbonyl-thieno [3,2-c] pyridine Formula (I): NR1R2 = NHCH2- ^ Q ^ N. Derivative No. 22.
13 14604613 146046
Denne forbindelse fremstilles i overensstemmelse med proce= duren ifølge eksempel 3 ud fra 6-carboxy-thieno[3i2-c]pyri= din og 4-aminomethyl-pyridin. Orange krystaller med smelte= punkt 146°C (ethylacetat). Udbytte: 98%.This compound is prepared according to the procedure of Example 3 from 6-carboxythieno [3,2-c] pyridine and 4-aminomethylpyridine. Orange crystals with melt = point 146 ° C (ethyl acetate). Yield: 98%.
5 Eksempel 23 5- (3-pyridyl-methyl)aminocarbonyl-thieno[2,3-c]pyridinExample 23 5- (3-Pyridyl-methyl) aminocarbonyl-thieno [2,3-c] pyridine
Formel (III): NR^R2 = NHCH2~^Q^ . Derivat nr. 23.Formula (III): NR ^ R2 = NHCH2 ~ ^ Q ^. Derivative No. 23.
Denne forbindelse fremstilles i overensstemmelse med proce= duren ifølge eksempel 3 ud fra 5-carboxy-thieno[2,3-c]pyri= 1° din og 3-aminomethyl-pyridin. Beige krystaller med smelte= punkt 143°C (isopropanol-diisopropylether). Udbytte: 73%.This compound is prepared according to the procedure of Example 3 from 5-carboxythieno [2,3-c] pyrid = 1 ° din and 3-aminomethyl-pyridine. Beige crystals with melt = point 143 ° C (isopropanol-diisopropyl ether). Yield: 73%.
Eksempel 24 6- (3-pyridyl-methyl) aminocarbonyl-thieno[3,2-c]pyridinExample 24 6- (3-Pyridyl-methyl) aminocarbonyl-thieno [3,2-c] pyridine
Formel (I): NR^R2 = . Derivat nr. 24.Formula (I): NR2 R2 =. Derivative No. 24.
15 Denne forbindelse fremstilles i overensstemmelse med proce= duren ifølge eksempel 3 ud fra 6-carboxy-thieno[3,2-c]pyri= din og 3-aminomethyl-pyridin. Beige krystaller med smelte= punkt 137°C (ethylacetat). Udbytte: 55%.This compound is prepared according to the procedure of Example 3 from 6-carboxythieno [3,2-c] pyridine and 3-aminomethyl-pyridine. Beige crystals with melt = point 137 ° C (ethyl acetate). Yield: 55%.
Eksempel 25 20 6-(3-trifluormethyl-phenyl)aminocarbonyl-thieno[3,2-c]pyri=Example 25 6- (3-Trifluoromethyl-phenyl) aminocarbonyl-thieno [3,2-c] pyridine
din CFyour CF
rKrK
Formel (I): NR^R2 = . Derivat nr. 25.Formula (I): NR2 R2 =. Derivative No. 25.
Denne forbindelse fremstilles i overensstemmelse med proce= duren ifølge eksempel 1 ud fra 6-carboxy-thieno[3,2-c]pyri= 25 din og m-trifluormethylanilin. Hvide krystaller med smelte= 14 146046 punkt 151°C (isopropanol-diisopropylether). Udbytte: 62%. Eksempel 26 6-(4-p-tolyl-l-piperazinyl)carbonyl-thieno[3,2-c]pyridinThis compound is prepared according to the procedure of Example 1 from 6-carboxythieno [3,2-c] pyridine = 25 din and m-trifluoromethylaniline. White crystals with melt = 14 ° C, 151 ° C (isopropanol-diisopropyl ether). Yield: 62%. Example 26 6- (4-p-tolyl-1-piperazinyl) carbonyl-thieno [3,2-c] pyridine
Formel (I): NR1^ = N^~^—CH3 . Derivat nr. 26.Formula (I): NR1 ^ = N ^ ~ -CH3. Derivative No. 26.
5 Denne forbindelse fremstilles i overensstemmelse med proce= duren ifølge eksempel 3 ud fra 6-carboxy-thieno[3,2-c]pyri= din og 1-p-tolyl-piperazin. Beige krystaller med smelte= punkt 150°C (isopropanol-diisopropylether). Udbytte: 82%.This compound is prepared according to the procedure of Example 3 from 6-carboxy-thieno [3,2-c] pyridine and 1-p-tolyl-piperazine. Beige crystals with melt = point 150 ° C (isopropanol-diisopropyl ether). Yield: 82%.
Eksempel 27 10 6-(4-o-chlorphenyl-l-piperazinyl)carbonyl-thieno[3,2-c- pyridin C1Example 27 6- (4-O-Chlorophenyl-1-piperazinyl) carbonyl-thieno [3,2-c-pyridine C1
Formel (I) : NR1R2 = . Derivat nr. 27Formula (I): NR1R2 =. Derivative No. 27
Denne forbindelse fremstilles i overensstemmelse med pro= ceduren ifølge eksempel 3 ud fra 6-carboxy-thieno[3,2-c]py= 15 ridin og 1-o-chlorphenyl-piperazin. Beige krystaller med smeltepunkt 140°C (isopropanol-diisopropylether). Udbytte: 52%.This compound is prepared in accordance with the procedure of Example 3 from 6-carboxy-thieno [3,2-c] py = 15-ridin and 1-o-chlorophenyl-piperazine. Beige crystals, melting point 140 ° C (isopropanol-diisopropyl ether). Yield: 52%.
Eksempel 28 6-(4-m-chlorphenyl-l-piperazinyl)carbonyl-thieno[3,2-c]py= 20 ridinExample 28 6- (4-m-chlorophenyl-1-piperazinyl) carbonyl-thieno [3,2-c] py = 20 ridin
ClCl
Formel (I): NR1R2 = N—(j^) Derivat nr. 28Formula (I): NR1R2 = N— (j ^) Derivative No. 28
Denne forbindelse fremstilles i overensstemmelse med pro= ceduren ifølge eksempel 3 ud fra 6-carboxy-thieno[3,2-c] pyridin og 1-m-chlorphenyl-piperazin. Hvide krystaller med 15 146046 smeltepunkt 157°C (ethylacetat). Udbytte: 52%.This compound is prepared according to the procedure of Example 3 from 6-carboxythieno [3,2-c] pyridine and 1-m-chlorophenyl-piperazine. White crystals having a melting point 157 ° C (ethyl acetate). Yield: 52%.
Eksempel 29 6-(4-p-methoxyphenyl-l-piperazinyl)-thieno[3,2-cj pyrldinExample 29 6- (4-p-methoxyphenyl-1-piperazinyl) -thieno [3,2-c] pyridine
Formel (I): NR1]*2 = N^ )~(q)—OCH3. Derivat nr. 29 5 Denne forbindelse opnås i overensstemmelse med proceduren ifølge eksempel 3 ud fra 6-carboxy-thieno[3,2-c]pyridin og 1-p-methoxyphenyl-piperazin. Hvide krystaller med smel= tepunkt 152°C (ethylacetat-diisopropylether). Udbytte: 72%.Formula (I): NR1] * 2 = N2) ~ (q) -OCH3. Derivative No. 29 This compound is obtained according to the procedure of Example 3 from 6-carboxy-thieno [3,2-c] pyridine and 1-p-methoxyphenyl-piperazine. White crystals with melting point = 152 ° C (ethyl acetate-diisopropyl ether). Yield: 72%.
Eksempel 30 10 5-(4-o-methoxyphenyl-l-piperazinyl)carbonyl-thieno[2 ,3-c] BTCWfl 0€H3Example 30 5- (4-O-Methoxyphenyl-1-piperazinyl) carbonyl-thieno [2,3-c] BTCWfl0 € H3
Formel (II) : NR1R2 = N\ · Derivat nr. 30Formula (II): NR1R2 = N \ · Derivative No. 30
Denne forbindelse fremstilles i overensstemmelse med pro= ceduren ifølge eksempel 3 ud fra 5-carboxy-thieno[2/3-c]py= ridin og 1-o-methoxyphenyl-piperazin. Beige krystaller med smeltepunkt 171°C (isopropanol). Udbytte: 62%.This compound is prepared according to the procedure of Example 3 from 5-carboxythieno [2/3-c] pyridine and 1-o-methoxyphenyl-piperazine. Beige crystals, m.p. 171 ° C (isopropanol). Yield: 62%.
Eksempel 31 6-carbamoyl-thieno[3,2-c]pyridinExample 31 6-carbamoyl-thieno [3,2-c] pyridine
Formel (I): NR1]*2 = NH3. Derivat nr. 31 20 Denne forbindelse fremstilles i overensstemmelse med proce= duren ifølge eksempel 1 ud fra 6-carboxy-thieno[3,2-c]pyri= din og ammoniak. Hvide krystaller med smeltepunkt 172°C (acetonitril). Udbytte: 68%.Formula (I): NR1] * 2 = NH3. Derivative No. 31 This compound is prepared according to the procedure of Example 1 from 6-carboxy-thieno [3,2-c] pyridine and ammonia. White crystals, m.p. 172 ° C (acetonitrile). Yield: 68%.
146046 16146046 16
Eksempel 32 5-carbamoyl-thieno[2,3-c]pyridin 1 2Example 32 5-Carbamoyl-thieno [2,3-c] pyridine 1 2
Formel (II): NR R = NH . Derivat nr. 32.Formula (II): NR R = NH. Derivative No. 32.
44
Denne forbindelse fremstilles i overensstemmelse med pro= 5 ceduren ifølge eksempel 1 ud fra 5-carboxy-thieno[2,3-c]py= ridin og ammoniak. Hvide krystaller med smeltepunkt 200°C (acetonitril). Udbytte: 76%.This compound is prepared according to the procedure of Example 1 from 5-carboxythieno [2,3-c] pyridine and ammonia. White crystals, m.p. 200 ° C (acetonitrile). Yield: 76%.
Eksempel 33 5- phenethylaminocarbonyl-thieno[2,3-c]pyridin 10 Formel (II): NR1R2 = NHCH2CH2CgH5. Derivat nr. 33.Example 33 5- Phenethylaminocarbonyl-thieno [2,3-c] pyridine Formula (II): NR1R2 = NHCH2CH2CgH5. Derivative No. 33.
Denne forbindelse fremstilles i overensstemmelse med pro= ceduren i eksempel 1 ud fra 5-carboxy-thieno[2,3-c]pyri= din og phenethylamin. Beige krystaller med smeltepunkt 130° C (isopropanol-diisopropylether. Udbytte: 79%.This compound is prepared according to the procedure of Example 1 from 5-carboxythieno [2,3-c] pyridine and phenethylamine. Beige crystals, mp 130 ° C (isopropanol-diisopropyl ether. Yield: 79%.
15 Eksempel 34 6- (4-ben2yl-l-piperazinyl)carbonyl-thieno[3,2-c]pyridinExample 34 6- (4-Benzyl-1-piperazinyl) carbonyl-thieno [3,2-c] pyridine
Formel (I): NR^R2 = N^~^N-CH?CfiHq * Derivat nr.34.Formula (I): NR ^ R2 = N ^ ~ ^ N-CH? CfiHq * Derivative No. 34.
Denne forbindelse fremstilles i overensstemmelse med pro= ceduren ifølge eksempel 3 ud fra 6-carboxy-thieno[3,2-c]py= 20 ridin og 1-benzyl-piperazin. Dihydrochlorid: hvide krystal= ler med smeltepunkt 187°C (isopropanol-ethanol). Udbytte: 49%.This compound is prepared in accordance with the procedure of Example 3 from 6-carboxy-thieno [3,2-c] py = 20-ridin and 1-benzyl-piperazine. Dihydrochloride: white crystals m.p. 187 ° C (isopropanol-ethanol). Yield: 49%.
Eksempel 35 17 146040 6-(3,4-dimethoxy-phenethyl)-aminocarbonyl-thieno[3,2-c]py= ridin - och3Example 35 17 6- (3,4-Dimethoxy-phenethyl) -aminocarbonyl-thieno [3,2-c] pyridine - and 3
Formel (I) : νΑ2 = NHCH2CH2- 4- OCH^. Derivat nr. 35.Formula (I): νΑ2 = NHCH2CH2- 4- OCH ^. Derivative No. 35.
Denne forbindelse fremstilles i overensstemmelse med proce= 5 duren ifølge eksempel 1 ud fra 6-carboxy-thieno[3,2-c]py= ridin og (3,4-dimethoxy-phenethyl) amin. Hvide krystaller med smeltepunkt 125°C (isopropanol-diisopropylether). Ud= bytte: 77%.This compound is prepared according to the procedure of Example 1 from 6-carboxythieno [3,2-c] pyridine and (3,4-dimethoxy-phenethyl) amine. White crystals, m.p. 125 ° C (isopropanol-diisopropyl ether). Out = exchange: 77%.
Eksempel 36 1° 5-(3,4-dimethoxy-phenethyl)aminocarbonyl-thieno[2 #3-c3py=Example 36 1 ° 5- (3,4-Dimethoxy-phenethyl) aminocarbonyl-thieno [2 # 3-cy
ridin OOBLridin OOBL
//
Formel (II) : Ar2 = NHCH2CH2 OCH^. Derivat nr. 36.Formula (II): Ar 2 = NHCH 2 CH 2 AND 2. Derivative No. 36.
Denne forbindelse fremstilles i overensstemmelse med pro= ceduren ifølge eksempel 1 ud fra 5-carboxy-thieno[2,3-c] i5 pyridin og (3,4-dimethoxy-phenethyl)amin. Hvide krystaller med smeltepunkt 125°C (isopropanol-diisopropylether). Ud= bytte: 73%.This compound is prepared according to the procedure of Example 1 from 5-carboxy-thieno [2,3-c] pyridine and (3,4-dimethoxy-phenethyl) amine. White crystals, m.p. 125 ° C (isopropanol-diisopropyl ether). Out = exchange: 73%.
Eksempel 37 6-(4-methyl-l-piperazinyl)-carbonyl-thieno[3,2-c]pyridin 20 Formel (I) : NR^ 2=o - CH3< Derivat nr. 37.Example 37 6- (4-methyl-1-piperazinyl) carbonyl-thieno [3,2-c] pyridine Formula (I): NR 2 = o - CH 3 <Derivative No. 37.
Denne forbindelse fremstilles i overensstemmelse med pro= ceduren ifølge eksempel 1 ud fra 6-carboxy-thieno[3,2-c] pyridin og 1-methyl-piperazin. Maleat: brunt pulver med smeltepunkt 168°C (isopropanol). Udbytte: 83%.This compound is prepared according to the procedure of Example 1 from 6-carboxythieno [3,2-c] pyridine and 1-methyl-piperazine. Maleate: brown powder, m.p. 168 ° C (isopropanol). Yield: 83%.
Eksempel 38 18 146046 6-[2-(2-thienyl)-ethylaminocarbonyl]-thieno(3,2-c)pyridin.Example 38 18 6- [2- (2-Thienyl) -ethylaminocarbonyl] -thieno (3,2-c) pyridine.
Formel (I) : NR1!*2 = NHCH^H^JTjjFormula (I): NR1! * 2 = NHCH ^ H ^ JTjj
Denne forbindelse fremstilles ved at gå frem som beskrevet 5 i eksempel 1 ud fra 6-carboxy-thieno(3,2-c)pyridin og 2—(2— thienyl)-ethylamin. Hvide krystaller med smp. 114°C (iso= propanol) i et udbytte på 57%.This compound is prepared by proceeding as described in Example 1 from 6-carboxythieno (3,2-c) pyridine and 2- (2-thienyl) ethylamine. White crystals with m.p. 114 ° C (iso = propanol) in a yield of 57%.
Eksempel 39 5- [2-(2-thienyl)-ethylaminocarbonyl]thieno(2,3-c)pyridin.Example 39 5- [2- (2-Thienyl) -ethylaminocarbonyl] thieno (2,3-c) pyridine.
10 Formel (II) : ^½2 = NHCH2CH2~CPFormula (II): ^ ½2 = NHCH2CH2 ~ CP
Denne forbindelse fremstilles ved fremgangsmåden ifølge eksempel 1 ved at gå ud fra 5-carboxy-thieno(2,3-c)pyridin og 2-(2-thienyl)-ethylamin. Hvide krystaller med smp. 120°C (isopropanol) i et udbytte på 72%.This compound is prepared by the method of Example 1 starting from 5-carboxy-thieno (2,3-c) pyridine and 2- (2-thienyl) -ethylamine. White crystals with m.p. 120 ° C (isopropanol) in 72% yield.
15 Eksempel 40 6- (1-piperazinyl-carbonyl) - thieno (3,2-c) pyridin.Example 40 6- (1-piperazinyl-carbonyl) -thieno (3,2-c) pyridine.
Formel (I) : NR^2 = N NHFormula (I): NR 2 = N NH
WW
Denne forbindelse fremstilles som beskrevet i eksempel 3 ved at gå ud fra 6-carboxy-thieno(3,2-c)pyridin og et over-20 skud af piperazin. Dichlorhydrat som okkerfarvede krystal ler med smp. 200°C (methanol-vand) i et udbytte på 30%.This compound is prepared as described in Example 3 by starting from 6-carboxythieno (3,2-c) pyridine and an excess of piperazine. Dichlorohydrate as ocher-colored crystal clay with m.p. 200 ° C (methanol-water) in a yield of 30%.
Eksempel 41 6- (2-pyr idyl-methyl) aminocarbonyl-thieno-( 3,2-c) pyridin.Example 41 6- (2-Pyridylmethyl) aminocarbonyl-thieno- (3,2-c) pyridine.
Formel (I) : NR1R2 = NH-CH2-^^ 19 148046Formula (I): NR1R2 = NH-CH2 -
Denne forbindelse fremstilles ved fremgangsmåden ifølge eksempel 1 ved at gå ud fra 6-carboxy-thieno(3,2-c)pyridin og 2-aminomethyl-pyridin. Beige krystaller med sxnp. 110°C (di= isopropylether-isopropanol) i et udbytte på 74%.This compound is prepared by the method of Example 1 starting from 6-carboxythieno (3,2-c) pyridine and 2-aminomethyl-pyridine. Beige crystals with sxnp. 110 ° C (di = isopropyl ether isopropanol) in a yield of 74%.
5 Eksempel 42 5-(2-pyridyl-methyl)aminocarbonyl-thieno(2,3-c)pyridin.Example 42 5- (2-Pyridyl-methyl) aminocarbonyl-thieno (2,3-c) pyridine.
N—\N- \
Formel (II): NR^R2 = NH-CH2-/0/Formula (II): NR 2 R 2 = NH-CH 2 - / O /
Denne forbindelse fremstilles ved fremgangsmåden ifølge eksempel 1 ved at gå ud fra 5-carboxy-thieno(2,3-c)pyridin 10 og 2-aminomethyl-pyridin. Hvidlige krystaller med smp. 95°C (diisopropylether-isopropanol) i et udbytte på 53%.This compound is prepared by the method of Example 1 starting from 5-carboxythieno (2,3-c) pyridine 10 and 2-aminomethyl-pyridine. White crystals with m.p. 95 ° C (diisopropyl ether isopropanol) in a yield of 53%.
De nedenfor anførte farmakologiske og toksikologiske data viser egenskaberne af derivaterne fremstillet ifølge opfindelsen roed hensyn til såvel deres tolerans som deres virkninger, ty= 15 pisk deres sedative, antikonvulsive og antiinflammatoriske virkninger.The pharmacological and toxicological data set forth below show the properties of the derivatives of the present invention in consideration of both their tolerance and their effects, typically their sedative, anti-convulsive and anti-inflammatory effects.
I. Toksikologisk undersøgelseI. Toxicological examination
Forbindelserne med formlerne (I) og (II) har en fortrinlig tolerans og en lav toksicitet.The compounds of formulas (I) and (II) have an excellent tolerance and low toxicity.
20 Med hensyn til akut toksicitet er LDj.q/24 timer /kg legems= vægt, bestemt hos mus i overensstemmelse med fremgangsmå= den ifølge Miller og Tainter ad den orale vej, højere end 400 mg for alle derivater.In the case of acute toxicity, LDj.q / 24 hours / kg body weight, determined in mice according to the method of Miller and Tainter according to the oral route, is higher than 400 mg for all derivatives.
Bestemt ved hjælp af samme metode er LD^Q/24 timer/kg le= 25 gemsvægt, bestemt ad den intravenøse vej, eksempelvis 154 mg for derivat nr. 1, 89 mg for derivat nr. 2, 184 mg for derivat nr. 10, 130 mg for derivat nr. 11, 350 mg for de= rivat nr. 12, 65 mg for derivat nr. 18, 90 mg for derivat nr. 22, 96 mg for derivat nr. 24 og 105 mg for derivat nr.Determined by the same method is LD 2/24 h / kg le = 25 g / m, determined by the intravenous route, for example 154 mg for derivative # 1, 89 mg for derivative # 2, 184 mg for derivative # 10 , 130 mg for derivative # 11, 350 mg for derivative # 12, 65 mg for derivative # 18, 90 mg for derivative # 22, 96 mg for derivative # 24, and 105 mg for derivative no.
31.31st
146046 20146046 20
Forsøgene udført vedrørende akut, kronisk, subkronisk og forsinket toksicitet hos forskellige dyrearter viste des= uden intet tegn på nogen lokal eller systemisk reaktion, nogen perturbation eller anomali ved de biokemiske, mi= 5 kroskopiske eller makroskopiske undersøgelser, som blev udført under nævnte forsøg.The tests performed on acute, chronic, subchronic and delayed toxicity in various animal species, however, showed no evidence of any local or systemic response, any perturbation or anomaly in the biochemical, mi = 5 croscopic or macroscopic studies performed during the said experiments.
II. Farmakologisk undersøgelse 1) Sedativ virkning A) Studium af opførslen.II. Pharmacological study 1) Sedative effect A) Study of the behavior.
10 Denne undersøgelse blev udført i overensstemmelse med den metode, der er beskrevet af Samuel Irwin (Ph. D. Animal and Clinical Pharmacology Technics i Drug Evaluation). Derivaterne med formlerne (I) og (II) administreres oralt til mus i en dosis på 100 mg/kg. De behandlede dyr obser= 15 veres i løbet af de 4 timer, som følger efter administra= tion af den aktive forbindelse. Deres opførsel studeres, og endvidere bestemmes de forskellige fysiologiske para= metre (temperatur, hjerteslag og respirationshastighed).10 This study was performed according to the method described by Samuel Irwin (Ph. D. Animal and Clinical Pharmacology Technics in Drug Evaluation). The derivatives of formulas (I) and (II) are orally administered to mice at a dose of 100 mg / kg. The treated animals are observed = 15 during the 4 hours following administration of the active compound. Their behavior is studied, and further the various physiological parameters (temperature, heartbeat and respiratory rate) are determined.
En mærkbar formindskelse af den motoriske aktivitet og 20 muskulære tonus samt en formindskelse af adrætheden og af reaktionerne over for støj og omgivelserne iagttages hos de behandlede dyr.A noticeable decrease in motor activity and muscular tone, as well as a decrease in fatigue and reactions to noise and the environment are observed in the treated animals.
B) Virkning på hypnotika.B) Impact on hypnotics.
Forbindelserne med formlerne (I) og (II) potentierer sær= 25 deles mærkbart virkningen af hypnotika. Ved oral admini= stration til forskellige grupper mus i en dosis på 100 mg/kg, 30 minutter før intraperitoneal indsprøjtning af en infra-hypnotisk dosis af natriumpentobarbital, frembrin= ger de således en udtalt potentiering af barbituratets 30 virkning i forhold til de ubehandlede referencedyr.The compounds of formulas (I) and (II) strongly potentiate = 25 the appreciable effect of hypnotics. Thus, by oral administration to various groups of mice at a dose of 100 mg / kg, 30 minutes before intraperitoneal injection of an infra-hypnotic dose of sodium pentobarbital, they produce a pronounced potentiation of the effect of barbiturate 30 relative to the untreated reference animals. .
Antallet af sovende mus, den gennemsnitlige indsovnings= tid og varigheden af søvnen er således mærkbart forøget 21 146046 i behandlingsgrupperne. Resultaterne opnået med de mere aktive forbindelser er anført i den efterfølgende tabel I.Thus, the number of sleeping mice, the average sleep time, and the duration of sleep were noticeably increased in the treatment groups. The results obtained with the more active compounds are given in the following Table I.
TABEL ITABLE I
5 Behandling Procent Gennemsnit= Gennemsnit= sovende lig indsov= lig sove= dyr ningstid tid5 Treatment Percent Average = Average = sleeping equals sleep = equal sleep = duration of time
O (referencegruppe) O O OO (reference group) O O O
Derivat nr. 1 70 8 m 30 s 1 t 30 m 10 Derivat nr. 5 80 9 m 15 s 1 t 45 mDerivative No. 1 70 8 m 30 s 1 t 30 m 10 Derivative No. 5 80 9 m 15 s 1 t 45 m
Derivat nr. 6 80 8 m 40 s 1 t 48 mDerivative No. 6 80 8 m 40 s 1 t 48 m
Derivat nr. 10 90 8 m 25 s 1 t 35 mDerivative No. 10 90 8 m 25 s 1 t 35 m
Derivat nr. 15 90 8 m 10 s 1 t 50 mDerivative No. 15 90 8 m 10 s 1 t 50 m
Derivat nr. 16 70 7 m 50 s 1 t 42 m 15 Derivat nr. 18 80 9 m 45 s 1 t 38 mDerivative No. 16 70 7 m 50 s 1 t 42 m 15 Derivative No. 18 80 9 m 45 s 1 t 38 m
Derivat nr. 22 70 9 m 20 s 1 t 45 mDerivative No. 22 70 9 m 20 s 1 t 45 m
Derivat nr. 23 80 7 m 55 s 1 t 50 mDerivative No. 23 80 7 m 55 s 1 t 50 m
Derivat nr. 25 90 8 m 10 s 1 t 38 mDerivative No. 25 90 8 m 10 s 1 t 38 m
Derivat nr. 26 90 8 m 50 s 1 t 35 m 20 Derivat nr. 28 80 7 m 45 s 1 t 40 mDerivative No. 26 90 8 m 50 s 1 t 35 m 20 Derivative No. 28 80 7 m 45 s 1 t 40 m
Derivat nr. 29 90 8 m 15 s 1 t 47 m ___ 2) Antikonvulsiv virkning.Derivative No. 29 90 8 m 15 s 1 t 47 m ___ 2) Anti-convulsive action.
Denne virkning blev undersøgt i forhold til elektrochok.This effect was investigated in relation to electroshock.
Hos rotter frembringer anvendelse af en elektrisk stimu= 25 lering, som overskrider den elektrokonvulsive tærskel, eksperimentelle konvulsioner. Tilstedeværelsen og varig= heden af hver konvulsive fase og også intensiteten af det samlede anfald blandt referencedyrene og blandt be= handlingsdyrene sammenlignes.In rats, the use of an electrical stimulation that exceeds the electroconvulsive threshold produces experimental convulsions. The presence and duration of each convulsive phase and also the intensity of the total seizure among the reference animals and the treatment animals are compared.
30 Grupper på 10 dyr anvendes pr. forsøgsmateriale, og til hvert dyr administreres oralt 100 mg/kg af nævnte forsøgs= materiale.30 groups of 10 animals are used per day. test material, and for each animal 100 mg / kg of said test material is orally administered.
En elektrode placeres på hver side af hvert dyrs halerod U6Q46 22 og 30 minutter efter behandlingen bliver dyret, der er anbragt i et glasindelukke, i 50 millisekunder udsat for en sinusformet, strøm af 50 perioder/sekunder med 120 volt.An electrode is placed on each side of each animal's tail root U6Q46 22 and 30 minutes after treatment, the animal, placed in a glass enclosure, is subjected to a sinusoidal, current of 50 periods / second at 120 volts for 50 milliseconds.
Strømpassagen frembringer et konvulsivt anfald, og hver 5 fase deraf (tonisk, klonisk, muskulær afslapning) tids= måles. Intensiteten af anfaldet registreres derpå i over= ensstemmelse med en skala fra O til 4, afhængigt af til= stedeværelsen af hver enkelt af faserne og deres varighed. Derivaterne med formlerne (I) og (II) afprøves i sammen= 10 ligning med phenobarbital, der har en udpræget antikonvul= siv virkning (intensitet af anfaldet = 2), hvorimod der i de ubehandlede referencedyr maksimalt opnås en intensi= tet på 4.The current passage produces a convulsive seizure and every 5 stages thereof (tonic, clonic, muscular relaxation) time = is measured. The intensity of the seizure is then recorded in accordance with a scale of 0 to 4, depending on the presence of each of the phases and their duration. The derivatives of formulas (I) and (II) are tested in equation = 10 with phenobarbital having a pronounced anticonvulsant effect (intensity of seizure = 2), whereas in the untreated reference animals a maximum intensity of 4 is obtained.
Det fastslås således, at alle forbindelserne med formler= 15 ne (I) og (II) frembringer en væsentlig beskyttelse mod elektrochok, eftersom middelværdierne af intensiteten af anfaldene inden for hver gruppe er 2,5 for derivat nr, 1, 3 for derivat nr. 4, 2,5 for derivat nr. 5, 2,5 for deri= vat nr. 9, 3 for derivat nr. 13, 2,5 for derivat nr. 19, 20 2,5 for derivat nr. 25, 2,5 for derivat nr. 30 og 2,5 for derivat nr. 31.Thus, it is determined that all the compounds of formulas = 15 ne (I) and (II) provide substantial protection against electrocution, since the mean values of the intensity of the seizures within each group are 2.5 for derivative no, 1.3 for derivative no. 4, 2.5 for derivative # 5, 2.5 for derivative # 9, 3 for derivative # 13, 2.5 for derivative # 19, 2.5 for derivative # 25, 2 , 5 for derivative 30 and 2.5 for derivative 31.
3) Antiinflammatorisk virkning a) Lokal-carragenininduceret ødem-metode.3) Anti-inflammatory effect a) Local carrageenin-induced edema method.
En 1% carrageninopløsning (0,1 ml) indsprøjtes på tids= 25 punktet 0 i mellemfodens bøjemuskier i rotters højre bag= ben. Til dyrene i behandlingsgruppen administreres des= uden oralt 100 mg/kg af forsøgsmaterialet, henholdsvis 1 time før, samtidig med, og derefter 1 time og 2,5 timer efter indsprøjtning af det phlogogene middel. Den procen= 30 tiske antiinflammatoriske virkning bestemmes som funktion af tiden med hensyn til referencegruppen ved hjælp af be= stemmelser udført med et ROCH-mikrometer på tidspunkterne 23 146046 O, 1 time/ 2 timer, 3 timer og 5 timer efter carragenin= administrationen.A 1% carrageenin solution (0.1 ml) is injected at time = 25 point 0 into the middle leg flexor muscles of the rat's right posterior leg. For the animals in the treatment group, 100 mg / kg of test material is administered orally 1 hour before, simultaneously with, and then 1 hour and 2.5 hours after injection of the phlogogenic agent. The percent = 30 anti-inflammatory effect is determined as a function of time with respect to the reference group by determinations performed with a ROCH micrometer at the times 23, 1 hour / 2 hours, 3 hours and 5 hours after carrageenin administration.
Resultaterne opnået med derivater med formlen (I) eller (II) er anført i den efterfølgende tabel II.The results obtained with derivatives of formula (I) or (II) are given in the following Table II.
5 TABEL IITABLE II
Derivat nr. Procent antiinflammatorisk virkning efter 1 time 2 timer 3 timer 5 timer 1 35-42 46 47 4 41 46 50 58 5 43 49 54 56 10 37 42 46 51 13 34 40 45 51 15 38 45 49 53 18 41 46 50 55 21 40 48 51 54 22 41 47 51 55 25 39 46 49 52 27 41 49 52 54 30 38 45 49 53 32 34 41 45 ' 47 b) ovalbumininduceret systemisk ødem-metodeDerivative No. Percent anti-inflammatory effect after 1 hour 2 hours 3 hours 5 hours 1 35-42 46 47 4 41 46 50 58 5 43 49 54 56 10 37 42 46 51 13 34 40 45 51 15 38 45 49 53 18 41 46 50 55 21 40 48 51 54 22 41 47 51 55 25 39 46 49 52 27 41 49 52 54 30 38 45 49 53 32 34 41 45 '47 b) Ovalbumin-induced systemic edema method
En samtidig intraperitoneal insprøjtning af 1 ml ovalbumin og af 0,5 ml af en 1% Evans blå opløsning foretages i rot= ter. Til dyrene i behandlingsgruppen administreret endvi= 10 dere oralt 100 mg/kg af forsøgsderivatet 1 time før og samtidigt med ovalbuminadministrationen. Intensiteten af det således fremkaldte fænomen vurderes i overensstemmelse 24 146046 med en skala fra 1 til 5 afhængigt af udviklingen af det inflammatoriske syndrom. Middelødemintensiteten og den pro= centiske formindskelse af den ødematøse reaktion i for= hold til kontroldyrene bestemmes således som funktion af 5 tiden.A simultaneous intraperitoneal injection of 1 ml of ovalbumin and 0.5 ml of a 1% Evans blue solution is done in rats. For the animals in the treatment group, 100 mg / kg of the test derivative was also administered orally 1 hour before and simultaneously with the ovalbumin administration. The intensity of the phenomenon thus developed is assessed in accordance with a scale of 1 to 5, depending on the development of the inflammatory syndrome. Thus, the mean death intensity and the percentage decrease in the edematous response to the control animals are determined as a function of time.
Den procentiske antiinflammatoriske aktivitet opnået 2 og 3 timer efter ovalbuminindsprøjtning er anført i den efterfølgende tabel III for nogle derivater med formlen (I) eller (II).The percent anti-inflammatory activity achieved 2 and 3 hours after ovalbumin injection is given in the following Table III for some derivatives of formula (I) or (II).
10 TABEL IIITABLE III
Derivat nr. Procent antiinflammatorisk aktivitet efter 2 timer 3 timer 1 48 56 4 47 56 5 52 60 10 47 55 13 50 56 15 53 60 18 49 58 21 45 52 22 51 58 25 51 59 27 47 56 30 48 56 32 52 60Derivative No. Percentage of anti-inflammatory activity after 2 hours 3 hours 1 48 56 4 47 56 5 52 60 10 47 55 13 50 56 15 53 60 18 49 58 21 45 52 22 51 58 25 51 59 27 47 56 30 48 56 32 52 60
Resultaterne af de nævnte undersøgelser godtgør den lave toksicitet og gode tolerans samt de nyttige sedative, anti= konvulsive og antiinflammatoriske egenskaber hos derivater= ne med formlen (I) eller (II), som gør dem særdeles værdi= ^ fulde inden for human-og veterinærmedicin.The results of the mentioned studies demonstrate the low toxicity and good tolerance as well as the useful sedative, anti = convulsive and anti-inflammatory properties of derivatives of formula (I) or (II) which make them extremely valuable in human and veterinary medicine.
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| FR7804561 | 1978-02-17 | ||
| FR7804561A FR2417512A1 (en) | 1978-02-17 | 1978-02-17 | THIENO (3,2-C) AND THIENO (2,3-C) PYRIDINES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THERAPEUTICS |
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| FR2525595A1 (en) * | 1982-04-27 | 1983-10-28 | Pharmuka Lab | NOVEL ARENE AND HETEROARENECARBOXAMIDE DERIVATIVES AND THEIR USE AS MEDICAMENTS |
| DE3621413A1 (en) * | 1986-06-26 | 1988-01-07 | Boehringer Ingelheim Kg | USE OF CARBOCYCLIC AND HETEROCYCLICALLY FURNISHED DIHYDROPYRIDINE AS A CARDIOPROTECTIVE AGENT AND NEW HETEROCYCLIC AND CARBOCYCLICALLY FURNISHED DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND ITS ADDITIONAL PRODUCTS |
| WO1988002751A1 (en) * | 1986-10-13 | 1988-04-21 | Asahi Kasei Kogyo Kabushiki Kaisha | Pyridine derivatives |
| CN101815718A (en) * | 2007-08-10 | 2010-08-25 | 克里斯捷诺米有限公司 | Pyridine derivate and using method thereof |
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