DK154082B - METHOD OF ANALOGUE FOR THE PREPARATION OF 4-AMINO-6,7-DIMETHOXY-2- (PIPERAZIN-1-YL OR HOMOPIPERAZIN-1-YL) -QUINAZOLINE COMPOUNDS OR PHARMACEUTICAL ACCEPTABLE ACID ADDITIONAL SALTS - Google Patents
METHOD OF ANALOGUE FOR THE PREPARATION OF 4-AMINO-6,7-DIMETHOXY-2- (PIPERAZIN-1-YL OR HOMOPIPERAZIN-1-YL) -QUINAZOLINE COMPOUNDS OR PHARMACEUTICAL ACCEPTABLE ACID ADDITIONAL SALTS Download PDFInfo
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- 0 C*C(CN(CC1)C(NC(c2c3)N)N(C4CCCCCC4)c2cc(OC)c3O)N1C(O)=* Chemical compound C*C(CN(CC1)C(NC(c2c3)N)N(C4CCCCCC4)c2cc(OC)c3O)N1C(O)=* 0.000 description 2
- LDBWMDNMCLBUJP-JGJVNGFWSA-N C[C@H]1[C@](C)(CC=C2)C3=C2OCCC1O3 Chemical compound C[C@H]1[C@](C)(CC=C2)C3=C2OCCC1O3 LDBWMDNMCLBUJP-JGJVNGFWSA-N 0.000 description 1
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- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/12—Antihypertensives
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
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Description
i ·i ·
DK 154082 BDK 154082 B
Denne opfindelse angår en analogi fremgangsmåde til fremstilling af hidtil ukendte 4-amino-6,7-dimethoxy-2-(piperazin-l-yl eller homopiperazin-l-yl)-quinazolinfor-bindelser med den i krav l's indledning angivne formel I 5 eller farmaceutisk acceptable syreadditionssalte deraf.This invention relates to an analogous process for the preparation of novel 4-amino-6,7-dimethoxy-2- (piperazin-1-yl or homopiperazin-1-yl) quinazoline compounds of formula I as set forth in claim 1 or pharmaceutically acceptable acid addition salts thereof.
Disse forbindelser er værdifulde som regulatorer af det cardiovaskulære system og især til behandling af hypertension.These compounds are valuable as regulators of the cardiovascular system and especially for the treatment of hypertension.
Fra US patentskrift nr. 3 311 836 kendes bl.a. 2,4,6,7-10 tetrasubstituerede quinazoliner med formlen CH3 0/ NH2 hvori Y kan have en række forskellige betydninger. De mest relevante af disse forbindelser er dem, hvori Y er furoyl || ogU.S. Patent No. 3,311,836 discloses, inter alia, 2,4,6,7-10 tetrasubstituted quinazolines of formula CH3 / NH2 wherein Y may have a variety of meanings. The most relevant of these compounds are those in which Y is furoyl || and
-C-il J-C-il J
Il r)'x 0 benzo furoyl -C-ll 0 uIl r) 'x 0 benzo furoyl -C-11 0 u
Furoylforbinde Isen med det generiske navn prazosin er et meget anerkendt hypotensivt middel som sælges af ansøgeren i hele verden under handelsnavnene "Hypovase" og "Minipress" ©. Det udviser en antihypertensiv aktivitet på mindst 100% ved 5 mg/kg p.o. i rotten. · 2Furoyl compound The ice cream of the generic name prazosin is a widely recognized hypotensive agent sold by the applicant worldwide under the trade names "Hypovase" and "Minipress" ©. It exhibits an antihypertensive activity of at least 100% at 5 mg / kg p.o. in the rat. · 2
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Benzofuroy1 forbinde Isen er den forbindelse, som er nærmest beslægtet med dem, der fremstilles ved fremgangsmåden ifølge opfindelsen. Den udviser en antihypertensiv aktivitet på 33¾ ved 5 mg/kg i rotter.Benzofuroyl linking ice is the compound most closely related to those produced by the process of the invention. It exhibits an antihypertensive activity of 33¾ at 5 mg / kg in rats.
5 Det har overraskende vist sig, at de tilsvarende benzodi- oxancarbony1- og benzodioxepincarbonyl-forbindelser, som fremstilles ved fremgangsmåden ifølge opfindelsen, udviser en antihypertensiv aktivitet, som er mindst dobbelt så høj som den, der udvises af den kendte benzofuroylfor-10 bindelse, og for de flestes vedkommende af samme stør relsesorden som den, der udvises af den kendte furoyl-forbindelse (prazosin), se de farmakologiske prøvningsresultater sidst i denne beskrivelse. Det har endvidere vist sig, at den mest foretrukne af de ifølge opfindel-15 sen fremstillede forbindelser, nemlig 4-amino-2-[ 4-(1,4- benzodioxan-2-carbonyl)piperazin-l-yl]-6,7-dimethoxyqui-nazolin med det generiske navn doxazosin, har en betydeligt længere elimineringshalveringstid og virkningsvarighed end prazosin.Surprisingly, it has been found that the corresponding benzodioxanecarbonyl and benzodioxepincarbonyl compounds produced by the process of the invention exhibit an antihypertensive activity at least twice that of the known benzofuroyl compound, and for most of the same order of magnitude as that exhibited by the known furoyl compound (prazosin), see the pharmacological test results at the end of this description. It has further been found that the most preferred of the compounds of the invention, namely 4-amino-2- [4- (1,4-benzodioxane-2-carbonyl) piperazin-1-yl] -6, 7-Dimethoxyquinazoline of the generic name doxazosin has a significantly longer elimination half-life and duration of action than prazosin.
20 I denne beskrivelse betegner "halogen", fluor, chlor, brom eller iod. Udtrykket "lavere", anvendt på en alkyl-eller alkoxygruppe, angiver at en sådan ligekædet eller forgrenet gruppe indeholder 1-6 carbonatomer, fortrinsvis 1-4 carbonatomer. Udtrykket "lavere", anvendt på en 25 alkanoylgruppe, betyder, at en sådan ligekædet eller forgrenet gruppe indeholder 2-6 carbonatomer, fortrinsvis 2-4 carbonatomer.In this specification, "halogen" means fluorine, chlorine, bromine or iodine. The term "lower", used on an alkyl or alkoxy group, indicates that such a straight or branched group contains 1-6 carbon atoms, preferably 1-4 carbon atoms. The term "lower", used on an alkanoyl group, means that such a straight or branched group contains 2-6 carbon atoms, preferably 2-4 carbon atoms.
Farmaceutisk acceptable syreadditionssalte af de her omhandlede forbindelser er salte dannet med syrer, der dan -30 rier ikke-toxiske syreadditionssalte indeholdende farma ceutisk acceptable anioner, såsom hydrochlorid-, hydro-bromid-, sulfat- eller hydrogensulfat-, phosphat- eller sure phosphat-, acetat-, maleøt-, fumarat-, succinat-.Pharmaceutically acceptable acid addition salts of the compounds of this invention are salts formed with acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions such as hydrochloride, hydrobromide, sulfate or hydrogen sulfate, phosphate or acid phosphate. , acetate, male nut, fumarate, succinate.
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lactat-, tartrat-, citrat-, gluconat-, saccharat- og p -toluensulfonatsalte.lactate, tartrate, citrate, gluconate, saccharate and p -toluenesulfonate salts.
Den mest foretrukne enkeltforbindelse er 4-amino-2-[4-(l,4-benzodioxan-2-carbonyl)piperazin-l-yl]-6,7-dimethoxy-5 quinazolin.The most preferred single compound is 4-amino-2- [4- (1,4-benzodioxane-2-carbonyl) piperazin-1-yl] -6,7-dimethoxy-quinazoline.
De forbindelser, der indeholder et eller flere asymmetriske centre, uil eksistere som et eller flere par af e n -antiomere, og sådanne par eller individuelle isomere kan separeres ued hjælp af fysiske metoder, f.eks. ued frak-10 tioneret krystallisation af egnede salte. Opfindelsen omfatter fremstillingen af de separerede enantiomere såvel som blandinger deraf, som racemiske blandinger eller som adskilte optisk aktive d- og 1-isomerformer.The compounds containing one or more asymmetric centers exist as one or more pairs of e n -antiomers, and such pairs or individual isomers can be separated by physical methods, e.g. unfractionated crystallization of suitable salts. The invention comprises the preparation of the separated enantiomers as well as mixtures thereof, as racemic mixtures or as separate optically active d and 1 isomer forms.
15 Når X er -CH(CH^)_} er cis-/trans-isomeri mulig, og frem stillingen af begge isomere (og blandinger deraf) er omfattet af opfindelsen.When X is -CH (CH2) _}, cis- / trans-isomerism is possible and the preparation of both isomers (and mixtures thereof) is encompassed by the invention.
De omhandlede forbindelser fremstilles ued fremgangsmåden ifølge opfindelsen, som er ejendommelig ued det i krav l's kendetegnende del anførte.The present compounds are prepared by the method according to the invention, which is peculiar to the characterizing part of claim 1.
20 Reaktion (a) i krav 1 udføres typisk ued at opvarme reak tanterne, f.eks. til en temperatur på 80-150 °C, f.eks. under tilbagesualing, i et inert organisk opløsningsmiddel, f.eks. n-butanol. Mår reaktionen er løbet i det væsentlige til ende, kan produktet isoleres og renses ved 25 konventionelle fremgangsmåder. Ved en typisk fremgangs måde går man f.eks. frem på den måde, at reaktionsblandingen afkøles, og det resulterende rå faste produkt opsamles, uaskes med f.eks. kold n-butanol og tørres. Det rå produkt kan renses ued en typisk fremgangsmåde, ved 30 at man opløser det i uarm vandig dimethy1 formamid, fil trerer og koncentrerer den filtrerede opløsning, f.eks.Reaction (a) of claim 1 is typically carried out without heating the reactants, e.g. to a temperature of 80-150 ° C, e.g. under reflux, in an inert organic solvent, e.g. n-butanol. Once the reaction is substantially complete, the product can be isolated and purified by conventional methods. In a typical approach, for example, one goes. further, in that the reaction mixture is cooled and the resulting crude solid product is collected, washed with e.g. cold n-butanol and dried. The crude product can be purified by a typical process by dissolving in dimly aqueous dimethylformamide, filtering and concentrating the filtered solution, e.g.
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i vakuum. Opløsningen afkøles derpå og der tilsættes ether til udfældning af det rene produkt, der kan fra-filtreres og vaskes med ether.in vacuo. The solution is then cooled and ether added to precipitate the pure product which can be filtered off and washed with ether.
Mellemprodukterne med formlerne II og III er enten kendte 15 forbindelser eller de kan fremstilles ved metoder, som er analoge med kendte metoder. F.eks. kan mellemprodukterne med formlen III fremstilles ved følgende reaktion:The intermediates of formulas II and III are either known compounds or can be prepared by methods analogous to known methods. Eg. the intermediates of formula III can be prepared by the following reaction:
/r1 j—( /yV/ r1 j— (/ yV
^ j Y' KflcAoJlii HN HH + a - c —l Jl vj \ / Il ^ 0 3^ j Y 'KflcAoJlii HN HH + a - c —l Jl vj \ / Il ^ 0 3
\ / o ^ O^ (CE,)—' O R\ / o ^ O ^ (CE,) - 'O R
lc\K v ¾ (IV) (V) (III) 1 2 5 hvori m, R , R , R' og X ti ar den i krav i’s indledning angivne betydning.lc \ K v ¾ (IV) (V) (III) 1 2 5 wherein m, R, R, R 'and X are as defined in the preamble of claim 1.
20 Mellemprodukterne med formlerne IV og i er enten kendt-: forbindelser eller de kan fremstilles 'ed kendte metoder.The intermediates of formulas IV and i are either known compounds or can be prepared by known methods.
Når X betyder - C H ( C H - , er c i s - og t r a n s - i s o nr, e r e af forbindelsen V mulige. En blanding af disse isomere kan benyttes, men såfremt der ønsker slutprodukt, der rr 25 hovedsagelig cis eller trans, kan man i almindelighed fremstille det tilsvarende cis- eller trans-udgangsmateriale ved hjælp af en passende chromatografi sk teknik anvendt på den tilsvarende methyl- eller ethylester efterfulgt af omdannelse til syrechlori det.When X means - CH (CH -, cis - and trans -iso), the compound V is possible. A mixture of these isomers can be used, but if the final product which is mainly cis or trans is desired, one can generally prepare the corresponding cis or trans starting material by a suitable chromatographic technique applied to the corresponding methyl or ethyl ester followed by conversion to acid chloride.
30 Et funktionelt ækvivalent af forbindelsen med formlen VIIA functional equivalent of the compound of formula VII
som acyleringsmidde 1 til anvendelse ved reaktion (b) i krav I kan f.eks. være et syrechlorid eller svrebromid, en "aktiveret" ester eller et blandet anhydriri af forbindelsen med formlen Vil.as acylating agent 1 for use in reaction (b) of claim 1, e.g. be an acid chloride or sulfur bromide, an "activated" ester or a mixed anhydrite of the compound of the formula Will.
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Syrechloriderne eller syrebromiderne kan fremstilles ved konventionelle fremgangsmåder, f.eks. ved at omsætte den fri syre med henholdsvis thionylchlorid og thionylbromid.The acid chlorides or acid bromides can be prepared by conventional methods, e.g. by reacting the free acid with thionyl chloride and thionyl bromide, respectively.
Den foretrukne "aktiverede ester" er succinimidoesteren 5 med formlen y~\ νΛ,Λ' -0 - \ (VIII) Η3 ί~^ 2 3 hvori R , R og X har den i krav l's indledning angivne betydning, der på sin side kan fremstilles ved sædvanlige fremgangsmåder, f.eks. ved at omsætte den frie syre med 10 NJ-hydroxysuccinimid i nærvær af et dehydratiserende mid del, f.eks. dicyclohexylcarbodiimid. En anden foretrukket "aktiveret ester" er phthalimidoesteren.The preferred "activated ester" is the succinimido ester 5 of the formula y ~ \ νΛ, Λ '-0 - \ (VIII) Η3 ί ~ ^ 2 3 wherein R, R and X have the meaning given in the preamble of claim 1, which in turn may be prepared by conventional methods, e.g. by reacting the free acid with 10 NJ hydroxysuccinimide in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide. Another preferred "activated ester" is the phthalimido ester.
Egnede blandede anhydrider har formlen R2 o o —c - 0 - c - Y lIX) R3 2 3 15 hvori R , R og X har den i krav l's indledning angivne betydning, og Y betyder en lavere alkylgruppe eller lavtre alkoxygruppe, fortrinsvis en t-butyl- eller isobutoxv-gruppe. De kan fremstilles ved sædvanlige fremgangsmåder, f.eks. ved at omsætte den frie syre med det pågældende 20 lavere alkanoylchlorid eller lavere alkylchlorformiat, f.eks. pivaloylchlorid eller isobutylchlorformiat, i nærvær af en base såsom triethylamin.Suitable mixed anhydrides are of the formula R 2 O - c - 0 - c - Y 12 R 3 wherein R, R and X are as defined in the preamble of claim 1 and Y is a lower alkyl group or lower alkoxy group, preferably a t-group. butyl or isobutoxy group. They can be prepared by conventional methods, e.g. by reacting the free acid with said lower alkanoyl chloride or lower alkyl chloroformate, e.g. pivaloyl chloride or isobutyl chloroformate, in the presence of a base such as triethylamine.
------ - ----—.- V------ - ----—.- V
POOR QUALITY 6 DK 154082BPOOR QUALITY 6 DK 154082B
Når man benytter den frie syreform af forbindelsen VII bor reaktionen almindeligvis udføres i nærvær af et de-hydratiserende middel, såsom dicyclohexylcarbodiimid.When using the free acid form of compound VII, the reaction should generally be carried out in the presence of a dehydrating agent such as dicyclohexylcarbodiimide.
Forbindelserne med formlen VII omsættes fortrinsvis i ς form af deres syrechlorider eller syrebromider.The compounds of formula VII are preferably reacted in the form of their acid chlorides or acid bromides.
Ved en typisk udførplsesform af reaktion (b), hvorved der benyttes et syrechlond af forbindelsen VII, sættes syre-chloridet i et egnet opløsningsmiddel, f.eks. methylen-cblorid, dråbev.s t:l en omrørt suspension af quinazoli-10 nen VI i et egne-t opløsningsmiddel, f.eks. methylenchlo- rid. Blandingen kan derpå omrøres i fri timer ved stuetemperatur, og det i terende faste stof derpå frafil- treres og renses ved hjælp af sædvanlig tpknik.In a typical embodiment of reaction (b) using an acid chondone of compound VII, the acid chloride is added to a suitable solvent, e.g. methylene chloride, dropwise t: in a stirred suspension of quinazoline VI in an intrinsic solvent, e.g. methylene chloride. The mixture can then be stirred for free hours at room temperature and then filtered and purified in the decomposing solid by conventional techniques.
Nar X er -iH . C ri v j. .1 ci s-/ r r,ms- i aomer i værn mulig som 1¾ omtalt under -nakt ion a .When X is -iH. C ri v j. .1 ci s- / r r, ms- in aomer in protection possible as 1¾ referred to under -naked ion a.
Mellemprodukterne med formlerne V! og Vil kan fremstilles ved sædvanlige fremgånqsmåder.The intermediates of formulas V! and Will can be prepared by conventional methods.
De farmaceutisk acceptable sy readd i t. j or.ssa !. te af de omhandlede forbindelser kan M’Pinst i i 1 es er! sædvanlige 20 fremgangsmåder, f.eks. ved at omsætte den frie base med den pågældende syr·· -t \ : r. p r 1 prqanisr oo løsningsmiddel og opsamle det resul t er enge oundfa id af battet ved filtrering. Om nødvendigt kan prcoukiet cmki>sta 11 i ser es til rensning. Det ••ed reakt ionerne a; og ·. b) opnåede 2produkt vil imidlertid ofte være· i s v r ed d i t i o n s s a 11 -form.The pharmaceutically acceptable sy readd in t. J or.ssa !. of the compounds in question, M'Pinst i i 1 es is! usual methods, e.g. by reacting the free base with that acid ·· -t \: r. p r 1 prqanisr oo solvent and collecting the resultant single ounce of the batt by filtration. If necessary, the prcoukie cmki> sta 11 can be cleaned. It •• ed react ions a; and ·. b) However, the 2-product obtained will often be · in s o r ed d i t i o n s s a 11 form.
Den antihypf rtensi« e i ’ rkr« ir·.! af fo rb rndelserne fremstillet ved fremgangsmåden ifoige opfindelsen påvises ved deres evne til at sænke blodtrykket hos ved bevidsthed væ~ 30 rende spontant hypertons i ve rotte, og ved bevidsthed værende hypertensive hunde, yr de indgives oralt i doser på op til 5 mg/kg.The antihypf rtensi «e in 'rkr« ir ·.! of the compounds produced by the method according to the invention are demonstrated by their ability to lower blood pressure in conscious, spontaneously hypertensive, and hypertensive dogs, orally, at doses of up to 5 mg / kg. .
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Forbindelserne kan indgives alene, men vil i almindelighed blive indgivet i blanding med en farmaceutisk bærer, der er valgt under hensyntagen til den tilsigtede indgiv-ningsvej og farmaceutisk standardpraksis. De kan f.eks.The compounds can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected taking into account the intended route of administration and standard pharmaceutical practice. For example, they can
5 indgives oralt i form af tabletter indeholdende sådanne excipienser som stivelse eller lactose, eller i kapsler enten alene eller i blanding med excipienser, eller i form af elixirer eller suspensioner indeholdende duft/ smags-stoffer eller farvningsmidler. De kan injiceres 10 parenteralt, f.eks. intramuskulært, intravenøst eller subcutant. Til parenteral indgivning anvendes de bedst i form af en steril vandig opløsning, der kan indeholde andre opløste stoffer, f.eks. tilstrækkeligt salt eller glucose til at gøre opløsningen isotonisk.5 is administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing fragrances or flavoring agents or coloring agents. They can be injected parenterally, e.g. intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, e.g. sufficient salt or glucose to make the solution isotonic.
15 De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser kan indgives mennesker med henblik på behandling af hypertension ad enten oral eller parenteral vej, og de kan indgives oralt i doseringsniveauer på fra omkring 1 til omkring 20 mg/dag for en voksen gennemsnits-20 patient (70 kg), indgivet i en enkelt dosis eller opdelt i op til 3 doser. Intravenøse doseringsniveauer må forventes at være fra ca. 1/5 til ca. 1/10 af den daglige orale dosis. For en voksen gennemsnitspatient vil således de individuelle orale doser i tablet- eller kapsel-25 form ligge i området fra omkring 1 til omkring 50 mg af den aktive forbindelse. Variationer vil nødvendigvis forekomme afhængigt af vægten og tilstanden af det individ, der behandles, og den valgte indgivningsvej, som det vil være kendt af fagfolk.The compounds of the present invention can be administered to humans for the treatment of hypertension by either oral or parenteral route, and may be administered orally at dosage levels of from about 1 to about 20 mg / day for an average adult patient (70). kg), administered in a single dose or divided into up to 3 doses. Intravenous dosage levels should be expected to be from ca. 1/5 to approx. 1/10 of the daily oral dose. Thus, for an average adult patient, the individual oral doses in tablet or capsule form will range from about 1 to about 50 mg of the active compound. Variations will necessarily occur depending on the weight and condition of the subject being treated and the route of administration chosen, as will be known to those skilled in the art.
30 Fremgangsmåden ifølge opfindelsen belyses nærmere ved de følgende eksempler.The process of the invention is illustrated in more detail by the following examples.
EKSEMPEL 1 8EXAMPLE 1 8
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4-amino-2-[4-(l,4-benzodioxan-2-carbonyl)piperazin-l-yl]-6,7-dimethoxyquinazolin4-Amino-2- [4- (l, 4-benzodioxan-2-carbonyl) -piperazin-l-yl] -6,7-dimethoxyquinazoline
OyCO ^ nh2 6OyCO ^ nh2 6
CH,<3 X N 1 i JCH, <3 X N 1 i J
3γγγν7'|ΛοΛ^ + HC1 NH2 5 4-amino-2-chlor-6,7-dimethoxyquinazolin (140 g) og N-(l,4-benzodioxan-2-carbonyl)piperazin (150 g) blev omrørt sammen under tilbagesvaling i n-butanol (2 liter) i 3 1/2 time. Blandingen blev derpå afkølet til 80 °C, det faste produkt opsamlet, vasket med kold n-butanol (2 x 250 ml) 10 og tørret. Det rå produkt blev opløst i varm (80 °C) di- methylformamid (530 ml) og vand (130 ml), filtreret, koncentreret i vakuum til ca. 300 ml og derpå afkølet, og der blev tilsat 1,8 liter ether. Det således opnåede faste stof blev isoleret og vasket med ether, hvorved 15 opnåedes 4-amino-2-[4-(1,4-benzodioxan-2-carbony1)pipera- zin-l-yl]-6,7-dimethoxyquinazolinhydrochlorid (215 g), smp. 289-290 °C.4-amino-2-chloro-6,7-dimethoxyquinazoline (140 g) and N- (1,4-benzodioxane-2-carbonyl) piperazine (150 g) were stirred together at reflux in n-butanol (2 liters) for 3 1/2 hours. The mixture was then cooled to 80 ° C, the solid product collected, washed with cold n-butanol (2 x 250 ml) and dried. The crude product was dissolved in warm (80 ° C) dimethylformamide (530 ml) and water (130 ml), filtered, concentrated in vacuo to ca. 300 ml and then cooled and 1.8 liters of ether were added. The solid thus obtained was isolated and washed with ether to give 4-amino-2- [4- (1,4-benzodioxane-2-carbonyl) piperazine-1-yl] -6,7-dimethoxyquinazoline hydrochloride ( 215 g), m.p. 289-290 ° C.
Analyse %:Analysis%:
Fundet C 56,9, H 5,4, N 14,4 20 Beregnet for ^23^25^5^5 *HC1: C 56,6, H 5,4, N 14,4 EKSEMPEL 2 9Found C 56.9, H 5.4, N 14.4. Calcd for ^ 23 ^ 25 ^ 5 ^ 5 * HCl: C 56.6, H 5.4, N 14.4 EXAMPLE 29
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4-amlno-2-[4-(l,4-benzodioxan-2-carbonyl)homopiperazin- 1- yl3-6,7-dimethoxyquinazolin 4-amino-2-chlor-6,7-dimethoxyquinazolin (1,58 g) og N-5 (1,4-benzodioxan-2-carbony1)homopiperazin (2,0 g) blev opvarmet under tilbagesvaling i n-butanol (114 ml) i 60 timer. Blandingen blev derpå afkølet, butanol blev fjernet i vakuum, og den faste remanens blev tritureret med ether, optaget i varm methanol, filtreret og afkølet.4-Amino-2- [4- (1,4-benzodioxane-2-carbonyl) homopiperazin-1-yl] 6,7-dimethoxyquinazoline 4-amino-2-chloro-6,7-dimethoxyquinazoline (1.58 g) and N-5 (1,4-benzodioxane-2-carbonyl) homopiperazine (2.0 g) was heated under reflux in n-butanol (114 ml) for 60 hours. The mixture was then cooled, butanol was removed in vacuo, and the solid residue was triturated with ether, taken up in hot methanol, filtered and cooled.
10 Det faste produkt blev opsamlet, den tilbageværende opløsning blev inddampet i vakuum, og remanensen blev optaget i varm isopropanol, afkølet, filtreret, og derpå atter inddampet i vakuum. Remanensen blev forenet med det oprindelige faste produkt, behandlet med kold methanol 15 og omkrystalliseret af ethanol, hvorved opnåedes 4-amino- 2- [4-(l,4-benzodioxan-2-carbonyl)homopiperazin-l-yl]-6,7-dimethoxyquinazolinhydrochlorid (0,57 g), smp. 250-251 °C.The solid product was collected, the residual solution was evaporated in vacuo, and the residue was taken up in hot isopropanol, cooled, filtered, and then evaporated in vacuo. The residue was combined with the original solid, treated with cold methanol and recrystallized from ethanol to give 4-amino-2- [4- (1,4-benzodioxane-2-carbonyl) homopiperazin-1-yl] -6, 7-dimethoxyquinazoline hydrochloride (0.57 g), m.p. 250-251 ° C.
Analyse %:Analysis%:
Fundet C 57,2, H 5,4, N 13,8 20 Beregnet for C24H27N5°5‘HC1: C 57,4, H 5,6, N 14,0 EKSEMPEL 3 10Found C 57.2, H 5.4, N 13.8 Calculated for C 24 H 27 N 5 ° 5'HCl: C 57.4, H 5.6, N 14.0 EXAMPLE 3
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4-amino-2- [4- (6-methoxy-l, 4-benzodioxan-2-carbonyl)-piperazin-l-yl]-6,7-dimethoxyquinazolin4-Amino-2- [4- (6-methoxy-1,4-benzodioxane-2-carbonyl) -piperazin-1-yl] -6,7-dimethoxyquinazoline
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En opløsning af 6-methoxy-l,4-benzodioxan-2-carbonylchlo-rid (2,17 g) (fremstillet ud fra syren og thionylchlorid) i dichlormethan (25 ml) blev sat dråbevis til en omrørt suspension af 4-amino-2-(piperazin-l-y 1-)-6,7-dimethoxy-10 quinazolin (2,48 g) i methylenchlorid (50 ml) ved stue temperatur. Efter at tilsætningen var tilendebragt, blev blandingen omrørt ved stuetemperatur i 4 timer og derpå filtreret, og det faste stof blev suspenderet i vandig kaliumcarbonatopløsning og ekstraheret med chloroform.A solution of 6-methoxy-1,4-benzodioxane-2-carbonyl chloride (2.17 g) (prepared from the acid and thionyl chloride) in dichloromethane (25 ml) was added dropwise to a stirred suspension of 4-amino acid. 2- (piperazine-ly 1-) - 6,7-dimethoxy-quinazoline (2.48 g) in methylene chloride (50 ml) at room temperature. After the addition was complete, the mixture was stirred at room temperature for 4 hours and then filtered, and the solid was suspended in aqueous potassium carbonate solution and extracted with chloroform.
15 De forenede ekstrakter blev vasket med vand, tørret (Na^SO^) og inddampet i vakuum, hvorved opnåedes en fast remanens (4,15 g), der blev chromatograferet på silica (160 g) og elueret med chloroform og derpå med chloroform-methanol (2,5¾). Til hinanden svarende fraktioner 20 (t.l.c.) blev forenet og inddampet i vakuum, og remanen sen blev optaget i ethylacetat-methanol og behandlet med etherisk hydrogenchlorid. Tilsætning af en yderligere 11The combined extracts were washed with water, dried (Na 2 SO 4) and evaporated in vacuo to give a solid residue (4.15 g) which was chromatographed on silica (160 g) and eluted with chloroform and then with chloroform -methanol (2.5¾). Corresponding fractions 20 (t.l.) were combined and evaporated in vacuo and the residue was taken up in ethyl acetate-methanol and treated with ethereal hydrogen chloride. Addition of an additional 11
DK 154082 BDK 154082 B
mængde ether efterfulgt af afkøling gav et fast stof, der blev isoleret og omkrystalliseret af methanol, hvorved opnåedes 4-amino-2-[4-(6-methoxy-l,4-benzodioxan-2-carbo-nyl)piperazin-l-yl]-6,7-dimethoxyquinazolinhydrochlorid-5 hydrat (0,95 g), smp. 220-222 °C.amount of ether followed by cooling gave a solid which was isolated and recrystallized from methanol to give 4-amino-2- [4- (6-methoxy-1,4-benzodioxane-2-carbonyl) piperazine-1 yl] -6,7-dimethoxyquinazoline hydrochloride hydrate (0.95 g), m.p. 220-222 ° C.
AnalyseAnalysis
Fundet C 53,3, H 5,5, N 13,4Found C 53.3, H 5.5, N 13.4
Beregnet for C24H27N506.HC1: C 53,8, H 5,6, N 13,1 EKSEMPLER 4-19 10 De følgende forbindelser blev fremstillet på lignende måde som beskrevet i eksempel 3, idet man gik ud fra 4-amino-2-(piperazin-l-yl eller 3-methyl-piperazin-l-yl)- 6,7-dimethoxyquinazolin og det pågældende carbonylchlorid.Calculated for C24H27N506.HCl: C 53.8, H 5.6, N 13.1 EXAMPLES 4-19 The following compounds were prepared in a similar manner as described in Example 3, starting from 4-amino-2- (piperazin-1-yl or 3-methyl-piperazin-1-yl) - 6,7-dimethoxyquinazoline and the relevant carbonyl chloride.
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Nedenstående præparationseksempler belyser fremstillingen af visse udgangsmaterialer.The following preparation examples illustrate the preparation of certain starting materials.
PRÆPARATION 1 N-(l,4-benzodioxan-2-carbonyl)piperazin .0.PREPARATION 1 N- (1,4-Benzodioxane-2-carbonyl) piperazine .0.
/—\ X JC ^ —* HN NH + Cl—,Χ 5 °o / \ [ [I I + HCl HN\ ^' o/ - \ X JC ^ - * HN NH + Cl—, Χ 5 ° o / \ [[I I + HCl HN \ ^ 'o
En suspension af piperazin (11,88 g) og natriumacetat (20,30 g) i en blanding af vand (70 ml) og acetone (93 ml) blev omrørt ved 10 til 15 °C, hvorpå der blev tilsat 10 koncentreret saltsyre (ca. 35 ml) indtil opløsningens pH- værdi nåede 1,5. Der blev derpå portionsvis tilsat 1,4-benzodioxan-2-carbonylchlorid (31,0 g) og natriumhydroxid (5 N, ca. 45 ml) alt imedens temperaturen blev holdt ved 10-15 °C, og natriumhydroxidet holdt pH-værdien ved 1,7-15 2,2. Efter at tilsætningen var tilendebragt blev pH-vær- dien reguleret til 2,0 ved tilsætning af natriumhydroxid, og suspensionen blev omrørt i yderligere 30 minutter. Der blev derpå tilsat vand indtil der var opnået en homogen opløsning, acetonen blev fjernet i vakuum, og den van-20 dige remanens blev ekstraheret med chloroform (3 x 200 ml). Den vandige fase blev gjort alkalisk til pH 8-9 med natriumhydroxid (5 N) og reekstraheret med chloroform (3 x 200 ml). Ekstrakterne blev vasket med vand, tørret (MgSO^) og inddampet i vakuum.A suspension of piperazine (11.88 g) and sodium acetate (20.30 g) in a mixture of water (70 ml) and acetone (93 ml) was stirred at 10 to 15 ° C to which 10 concentrated hydrochloric acid ( about 35 ml) until the pH of the solution reached 1.5. Then 1,4-benzodioxane-2-carbonyl chloride (31.0 g) and sodium hydroxide (5 N, about 45 ml) were added portionwise while maintaining the temperature at 10-15 ° C and the sodium hydroxide at pH 1.7-15 2.2. After the addition was complete, the pH was adjusted to 2.0 by the addition of sodium hydroxide and the suspension was stirred for an additional 30 minutes. Water was then added until a homogeneous solution was obtained, the acetone was removed in vacuo, and the aqueous residue was extracted with chloroform (3 x 200 ml). The aqueous phase was made alkaline to pH 8-9 with sodium hydroxide (5 N) and extracted with chloroform (3 x 200 ml). The extracts were washed with water, dried (MgSO4) and evaporated in vacuo.
25 Den olieagtige remanens blev opløst i ethylacetat, behandlet med etherisk hydrogenchlorid og inddampet i va 19The oily residue was dissolved in ethyl acetate, treated with ethereal hydrogen chloride and evaporated in water 19
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kuum, og den faste remanens blev tritureret med ether efterfulgt af omkrystallisation af methanol, hvorved opnåedes N-(l,4-benzodioxan-2-carbonyl)piperazinhydrochlo-rid (4,85 g), smp. 265-267 °C.in vacuo and the solid residue was triturated with ether followed by recrystallization of methanol to give N- (1,4-benzodioxane-2-carbonyl) piperazine hydrochloride (4.85 g), m.p. 265-267 ° C.
5 Analyseft:Assay:
Fundet C 54,6, H 5,5, N 9,7Found C 54.6, H 5.5, N 9.7
Beregnet for . HC1: C 54,8, H 6,0, N 9',’8 PRÆPARATION 2 6-methoxy-l,4-benzodioxan-2-carboxylsyreIntended for. HCl: C 54.8, H 6.0, N 9 ',' 8 PREPARATION 2 6-methoxy-1,4-benzodioxane-2-carboxylic acid
/CH20H ^\Z0\C°2H/ CH2 OH ^ \ Z0 \ C ° 2H
10 χΎΤ ^ίϊ T10 χΎΤ ^ ίϊ T
Fint malet kaliumpermanganat (5,02 g) blev i fire portioner sat til en omrørt suspension af 2-hydroxymethy1-6-methoxy-1,4-benzodioxan (4,52 g) i kaliumhydroxidopløsning (1,47 g, i 42 ml vand) ved 5 °C. Under reaktionen 15 blev temperaturen holdt ved 5-15 °C, hvorpå omrøringen, efter at tilsætningen var tilendebragt, blev fortsat ved stuetemperatur i 4 timer. Reaktionsblandingen blev derefter hensat natten over.Finely ground potassium permanganate (5.02 g) was added in four portions to a stirred suspension of 2-hydroxymethyl-6-methoxy-1,4-benzodioxane (4.52 g) in potassium hydroxide solution (1.47 g, in 42 ml water ) at 5 ° C. During reaction 15, the temperature was maintained at 5-15 ° C, after which the stirring, after completion of the addition, was continued at room temperature for 4 hours. The reaction mixture was then left overnight.
Mangandioxid blev fjernet ved filtrering, det faste stof 20 blev vasket med vand, og de forenede vandige faser blev syrnet (pH 1) med koncentreret saltsyre, afkølet og derpå ekstraheret med chloroform.Manganese dioxide was removed by filtration, the solid 20 was washed with water, and the combined aqueous phases were acidified (pH 1) with concentrated hydrochloric acid, cooled and then extracted with chloroform.
De forenede chloroformekstrakter blev vasket med natriumhydroxidopløsning (5 N, 2 x 40 ml), hvorpå den basiske 25 fase blev vasket yderligere med chloroform, afkølet, syr net (pH 1) med koncentreret saltsyre og reekstraheretThe combined chloroform extracts were washed with sodium hydroxide solution (5 N, 2 x 40 ml), then the basic phase was further washed with chloroform, cooled, acidified (pH 1) with concentrated hydrochloric acid and re-extracted
2D2D
DK 1540828 med chloroform. Denne sidste chloroformopløsning blev vasket med vand, tørret (Na^SO^) og inddampet, hvilket gav en rå remanens bestående af 6-methoxy-l,4-benzodioxan-2-carboxylsyre (2,33 g). En prøve blev omkrystalliseret 5 fra vand, smp. 120-121 °C.DK 1540828 with chloroform. This last chloroform solution was washed with water, dried (Na 2 SO 4) and evaporated to give a crude residue consisting of 6-methoxy-1,4-benzodioxane-2-carboxylic acid (2.33 g). A sample was recrystallized from water, m.p. 120-121 ° C.
Analyse %:Analysis%:
Fundet : C 57,1, H 4,8Found: C 57.1, H 4.8
Beregnet for C^gH^gO^: C 57,1, H 4,8 PRÆPARATION 3 10 8- og 5-(blandinq)-isopropyl-l,4-benzodioxan-2-carboxyl- syre (A) En omrørt opløsning af 3-isopropylcatechol (23 g) i acetone (250 ml) blev opvarmet under tilbagesvaling, hvorpå der blev tilsat kaliumcarbonat (28 g). Den hetero- 15 gene blanding blev tilbagesvalet i yderligere 15 minut ter efterfulgt af dråbevis tilsætning af methyl-2,3-di-brompropionat (10 g). Der blev tilsat tre yderligere charger kaliumcarbonat (28 g) og methyl-2,3-dibrompro-pionat (10 g) på lignende måde, hvorpå blandingen blev 20 omrørt under tilbagesvaling i 12 timer. Derpå blev blan dingen inddampet, remanensen blev fortyndet med vand (700 ml) og ekstraheret med chloroform, og de forenede ekstrakter blev vasket med vand, tørret (MgSO^) og inddampet. Den tilbageværende olie blev destilleret, hvorved 25 opnåedes methyl-8(5)-isopropy1-1,4-benzodioxan-2-carboxy- lat (29,3 g) kp. 115-120 °C/0,5 mm. n.m.r. spektroskop! bekræftede, at produktet var en blanding af 8-(71¾) og 5-(29S$)-isomere.Calculated for C C ^HH gOO: C 57.1, H 4.8 PREPARATION 3 8- and 5- (mixture) -isopropyl-1,4-benzodioxane-2-carboxylic acid (A) A stirred solution of 3-Isopropylcatechol (23 g) in acetone (250 ml) was heated under reflux to which potassium carbonate (28 g) was added. The heterogeneous mixture was refluxed for a further 15 minutes followed by the dropwise addition of methyl 2,3-di-bromopropionate (10 g). Three additional batches of potassium carbonate (28 g) and methyl 2,3-dibromo propionate (10 g) were added in a similar manner, and the mixture was stirred at reflux for 12 hours. Then, the mixture was evaporated, the residue was diluted with water (700 ml) and extracted with chloroform, and the combined extracts were washed with water, dried (MgSO4) and evaporated. The residual oil was distilled to give methyl 8 (5) -isopropyl-1,4-benzodioxane-2-carboxylate (29.3 g) bp. 115-120 ° C / 0.5 mm. n.m.r. spectroscopy confirmed that the product was a mixture of 8- (71¾) and 5- (29S $) isomers.
(B) Ovennævnte produkt (29,0 g) blev i natriumhydroxid-30 opløsning (160 ml, 2,5 N) opvarmet ved 100 °C i 1/2 time, hvorpå den resulterende opløsning blev afkølet og syrnet 21(B) The above product (29.0 g) was heated in sodium hydroxide solution (160 ml, 2.5 N) at 100 ° C for 1/2 hour, then the resulting solution was cooled and acidified.
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med koncentreret saltsyre. Blandingen blev ekstraheret med chloroform (3 x 200 ml), de forenede ekstrakter blev tørret (MgSO^) og inddampet i vakuum, hvorved opnåedes en olie (18 g), der blev fast ved henstand. Ved omkry-5 stallisation af methanol opnåedes en blanding af 8- og 5-isopropyl-l,4-benzodioxan-2-carboxylsyre, smp. 86-88 °C.with concentrated hydrochloric acid. The mixture was extracted with chloroform (3 x 200 ml), the combined extracts dried (MgSO 4) and evaporated in vacuo to give an oil (18 g) which was solid on standing. Recrystallization from methanol yielded a mixture of 8- and 5-isopropyl-1,4-benzodioxane-2-carboxylic acid, m.p. 86-88 ° C.
Analyse %:Analysis%:
Fundet : C 64,7, H 6,3 10 Beregnet for Cj2^14^4: ^ 64,9, H 6,3Found: C 64.7, H 6.3 Calcd for C 21 2 14 4: ^ 64.9, H 6.3
Det fremgik af højtryks-væskechromatografi, at produktet var en blanding af de 8-(86%) og 5-(13%)-isornere. [Spectra Physics 3500 CS Machine; kolonne 305 mm x 6,4 mm ydre diam.High pressure liquid chromatography showed that the product was a mixture of the 8- (86%) and 5- (13%) isomers. [Spectra Physics 3500 CS Machine; column 305 mm x 6.4 mm outer diam.
^u Bondapak C-18; elueringsmiddel acetonitril (1)/0,15M 15 kaliumhydrogenphosphatbuffer pH 3,5 (2); strømningshastighed 14 ml/min ; tryk 4,14 MPa].^ u Bondapak C-18; eluant acetonitrile (1) / 0.15M potassium hydrogen phosphate buffer pH 3.5 (2); flow rate 14 ml / min; pressure 4.14 MPa].
PRÆPARATION 4PREPARATION 4
En blanding af 8- og 5-methy1-1,4-benzodioxan-2-carboxyl-syre 20 Kaliumpermanganat (23,15 g) blev i tre portioner sat til en omrørt suspension af en blanding af 8- og 5-methyl-2-hydroxymethy1-1,4-benzodioxan (20 g) i kaliumhydroxidopløsning (6,5 g i 187 ml H2O) ved 5 °C.A mixture of 8- and 5-methyl-1,4-benzodioxane-2-carboxylic acid Potassium permanganate (23.15 g) was added in three portions to a stirred suspension of a mixture of 8- and 5-methyl-2 -hydroxymethyl1,4-benzodioxane (20 g) in potassium hydroxide solution (6.5 g in 187 ml H 2 O) at 5 ° C.
Reaktionstemperaturen blev holdt under 15 °C, og efter 25 at tilsætningen var afsluttet, blev reaktionsblandingen omrørt ved stuetemperatur i 4 timer. Mangandioxid blev fjernet ved filtrering, filtratet blev afkølet og syrnet med koncentreret saltsyre, og det olieagtige produkt, der udskiltes ved yderligere køling, blev ekstraheret 30 med chloroform. Chloroformekstrakterne- blev vasket medThe reaction temperature was kept below 15 ° C and after completion of the addition, the reaction mixture was stirred at room temperature for 4 hours. Manganese dioxide was removed by filtration, the filtrate was cooled and acidified with concentrated hydrochloric acid, and the oily product, which was separated by further cooling, was extracted with chloroform. The chloroform extracts were washed with
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22 5 N natriumhydroxidopløsning, det basiske lag blev vasket med chloroform og derpå syrnet med koncentreret saltsyre til pH 1. Den sure opløsning blev ekstraheret med chloroform, de forenede ekstrakter blev vasket med natriumchlo-5 ridopløsning, tørret (MgSO^) og inddampet i vakuum, hvorved opnåedes en blanding af 8- og 5-methyl-l,4-benzodi-oxan-2-carboxylsyre (7,3 g) som en sirupagtig remanens med de til denne blanding svarende spektroskopiske egenskaber. En lille prøve blev esterificeret med diazomethan 10 og viste sig ved gaschromatografi af være en blanding af isomere (5:2).22 5 N sodium hydroxide solution, the basic layer was washed with chloroform and then acidified with concentrated hydrochloric acid to pH 1. The acidic solution was extracted with chloroform, the combined extracts were washed with sodium chloride solution, dried (MgSO4) and evaporated in vacuo to give a mixture of 8- and 5-methyl-1,4-benzodi-oxane-2-carboxylic acid (7.3 g) as a syrupy residue with the spectroscopic properties corresponding to this mixture. A small sample was esterified with diazomethane 10 and shown by gas chromatography to be a mixture of isomers (5: 2).
PRÆPARATION 5 6,7-dimethyl-l,4-benzodioxan-2-carboxylsyre CH3\ ^0E CH .0 00oC_H_PREPARATION 5 6,7-Dimethyl-1,4-benzodioxane-2-carboxylic acid CH3 · OE CH0.00oC_H_
Vco^5 YV Y 2*5 ji + XBr —> yL· 1Vco ^ 5 YV Y 2 * 5 ji + XBr -> yL · 1
15 I TT15 I TT
ci3Ay\(/ (A) En omrørt opløsning af 4,5-dimethylcatechol (7,0 g) i tør acetone (45 ml) blev opvarmet under tilbagesvaling, hvorpå der blev tilsat kaliumcarbonat (5 g) fulgt af dråbevis tilsætning af ethyl-2,3-dibrompropionat (3,5 g).ci3Ay \ (/ (A) A stirred solution of 4,5-dimethylcatechol (7.0g) in dry acetone (45ml) was heated at reflux, then potassium carbonate (5g) was added followed by the dropwise addition of ethyl acetate. 2,3-dibromopropionate (3.5 g).
20 Tilsætningsproceduren blev gentaget yderligere 3 gange i løbet af 1 1/4 time, hvorpå reaktionsblandingen blev om-rørt under tilbagesvaling i yderligere 3 3/4 time. Efter afkøling blev blandingen filtreret, og de faste stoffer vasket godt sammen med acetone, hvorefter de forenede 23The addition procedure was repeated an additional 3 times over 1 1/4 hour, then the reaction mixture was stirred at reflux for an additional 3 3/4 hours. After cooling, the mixture was filtered and the solids washed well with acetone, then the combined
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filtrater blev koncentreret i vakuum. Der blev tilsat n (35 ml), og det resulterende faste stof blev opsamlet, vasket med benzin og derpå optaget i ether. Den etheri-ske opløsning blev vasket med vand, tørret (Na^SO^) og 5 inddampet i vakuum, hvorved opnåedes ethy1-6,7-dimethyl- 1,4-benzodioxan-2-carboxylat (10,17 g), smp. 70-71 °C.filtrates were concentrated in vacuo. N (35 ml) was added and the resulting solid collected, washed with gasoline and then taken up in ether. The ethereal solution was washed with water, dried (Na 2 SO 4) and evaporated in vacuo to give ethyl 6,7-dimethyl-1,4-benzodioxane-2-carboxylate (10.17 g), m.p. . 70-71 ° C.
Analyse %:Analysis%:
Fundet :C 65,7, H 6,8Found: C 65.7, H 6.8
Beregnet for ^^H^O^sC 66,1, H 6,8 10 (B) Hydrolyse af ovennævnte ester (5,0 g) med natriumhy droxid (10%, 13 ml) i ethanol (125 ml) som beskrevet for beslægtede forbindelser (J.A.C.S., 7_7, 5374 (1956)) gav rå 6,7-dimethyl-l,4-benzodioxan-2-carboxylsyre (4,04 g).Calcd. For H₂O₂SC 66.1, H 6.8 10 (B) Hydrolysis of the above ester (5.0 g) with sodium hydroxide (10%, 13 ml) in ethanol (125 ml) as described for related compounds (JACS, 7_7, 5374 (1956)) gave crude 6,7-dimethyl-1,4-benzodioxane-2-carboxylic acid (4.04 g).
En prøve blev omkrystalliseret af vand, smp. 150-151 °C.A sample was recrystallized from water, m.p. 150-151 ° C.
15 Analyse %iAnalysis% i
Fundet C 63,9, H ,60Found C 63.9, H, 60
Beregnet for ^ ^>5, H 5,8 PRÆPARATION 6 6,7-dichlor-l,4-benzodioxan-2-carboxylsyre 20 Hydrolyse af ethy1-6,7-dichlor-l,4-benzodioxan-2-carbo- xylat (5,0 g) med natriumhydroxid (10%, 10,9 ml) i ethanol (50 ml) gav 6,7-dichlor-l,4-benzodioxan-2-carboxyl-syre (3,4 g ), smp. 155-158 °C med et hertil svarende n.m.r. spektrum og Rf (t.l.c.) identisk med værdien for 25 en autentisk prøve.Calculated for 5, H 5.8 PREPARATION 6 6,7-Dichloro-1,4-benzodioxane-2-carboxylic acid Hydrolysis of ethyl 6,7-dichloro-1,4-benzodioxane-2-carboxylate (5.0 g) with sodium hydroxide (10%, 10.9 ml) in ethanol (50 ml) gave 6,7-dichloro-1,4-benzodioxane-2-carboxylic acid (3.4 g), m.p. 155-158 ° C with a corresponding n.m.r. spectrum and Rf (t.c.) identical to the value for an authentic sample.
PRÆPARATION 7 8-methoxy-I,4-benzodioxan-2-carboxylsyre 8-methoxy-l,4-benzodioxan-2-carboxamid (2,41 g) i 50%PREPARATION 7 8-Methoxy-1,4-benzodioxane-2-carboxylic acid 8-methoxy-1,4-benzodioxane-2-carboxamide (2.41 g) in 50%
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24 saltsyre (35 ml) blev omrørt ved 100 DC i en time. Den resulterende opløsning blev afkølet, fortyndet med vand (200 ml), ekstraheret med chloroform (3 x 100 ml), hvorpå ekstrakterne blev tørret (MgSO^) og inddampet i va-5 kuum. Den faste remanens (1,8 g) blev omkrystalliseret af vand (smp. 75-78 °C) og derpå af ethylacetat/hexan, hvorved opnåedes 8-methoxy-l,4-benzodioxan-2-carboxy1-syre, smp. 131-132 °C.24 hydrochloric acid (35 ml) was stirred at 100 DC for one hour. The resulting solution was cooled, diluted with water (200 mL), extracted with chloroform (3 x 100 mL), then the extracts were dried (MgSO4) and evaporated in vacuo. The solid residue (1.8 g) was recrystallized from water (mp 75-78 ° C) and then ethyl acetate / hexane to give 8-methoxy-1,4-benzodioxane-2-carboxylic acid, m.p. 131-132 ° C.
Analyse 515: 10 Fundet : C 5,69, H 4,8Analysis 515: 10 Found: C 5.69, H 4.8
Beregnet for C^o^gO^: ^ 57,1, H 4,8 PRÆPARATION 8 5- methoxy-l,4-benxodioxan-2-carboxylsyreCalculated for C C C g gOO: 57 57.1, H 4.8 PREPARATION 8 5- Methoxy-1,4-benxodioxane-2-carboxylic acid
Denne forbindelse blev fremstillet ved den i præparation 15 7 beskrevne metode, idet man gik ud fra 5-methoxy-l,4- benzodioxan-2-carboxamid. Produktet blev krystalliseret af vand, smp. 85-87 °C, derpå af ethylacetat-hexan, hvorved opnåedes 5-methoxy-l,4-benzodioxan-2-carboxylsyre, smp. 139-141 °C.This compound was prepared by the method described in Preparation 15 starting from 5-methoxy-1,4-benzodioxane-2-carboxamide. The product was crystallized by water, m.p. 85-87 ° C, then ethyl acetate-hexane to give 5-methoxy-1,4-benzodioxane-2-carboxylic acid, m.p. 139-141 ° C.
20 Analyse %:Analysis%:
Fundet : C 5,69, H 4,8Found: C 5.69, H 4.8
Beregnet for cioh^o°5: C 57,1, H 4,8 PRÆPARATION 9 6- acetyl-l,4-benzodioxan-2-carboxylsyre 25 Jones' reagens (11,6 ml) blev dråbevis sat til en om- rørt opløsning af 6-acetyl-2-hydroxymethyl-l,4-benzodi-oxan (4,0 g) i acetone (70 ml) ved 10-15 °C. Reaktionsblandingen blev omrørt ved stuetemperatur i 18 timer og 25Calcd for CioioH o ° ° 5: C 57.1, H 4.8 PREPARATION 9 6- Acetyl-1,4-benzodioxane-2-carboxylic acid Jones' reagent (11.6 ml) was added dropwise to a stirred solution of 6-acetyl-2-hydroxymethyl-1,4-benzodioxane (4.0 g) in acetone (70 ml) at 10-15 ° C. The reaction mixture was stirred at room temperature for 18 hours and 25 hours
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derpå fortyndet med isopropanol/vand/chloroform; det organiske lag blev fraskilt og inddampet i vakuum. Remanensen blev genopløst i chloroform, ekstraheret med mættet natriumcarbonatopløsning (2 x 30 ml), hvorefter den ba-5 siske fase blev vasket med chloroform, afkølet og syrnet til pH 1 med koncentreret saltsyre.then diluted with isopropanol / water / chloroform; the organic layer was separated and evaporated in vacuo. The residue was redissolved in chloroform, extracted with saturated sodium carbonate solution (2 x 30 ml), after which the basic phase was washed with chloroform, cooled and acidified to pH 1 with concentrated hydrochloric acid.
Den sure opløsning blév ekstraheret med chloroform, og de kombinerede ekstrakter blev vasket med mættet natrium-chloridopløsning, tørret (Na^SO^) og inddampet i vakuum, 10 hvorved opnåedes 6-acety1-1,4-benzodioxan-2-carboxylsyre (1,56 g), smp. 159-162 °C. En prøve blev omkrystalliseret af ethanol/ethylacetat, smp. 174-175 °C.The acidic solution was extracted with chloroform, and the combined extracts were washed with saturated sodium chloride solution, dried (Na 2 SO 4) and evaporated in vacuo to give 6-acetyl-1,4-benzodioxane-2-carboxylic acid (1). , 56 g), m.p. 159-162 ° C. A sample was recrystallized from ethanol / ethyl acetate, m.p. 174-175 ° C.
Analyse %:Analysis%:
Fundet : C 59,0, H 4,8 15 Beregnet for C;q^10^5’* ^ 59,5, H 4,5 PRÆPARATION 10 7-acetyl-l,4-benzod ilo xan-2-carboxylsyre (A) En opløsning af methyl-2,3-dibrompropionat (13 ml) i acetone (50 ml) blev i løbet af 1/2 time sat dråbevis 20 til en omrørt suspension af 3,4-dihydroxyacetophenon (15,1 g) og vandig kaliumcarbonat (28 g) i acetone (100 ml) opvarmet under tilbagesvaling.Found: C 59.0, H 4.8 Calculated for C; q ^ 10 ^ 5 '* ^ 59.5, H 4.5 PREPARATION 10 7-Acetyl-1,4-benzodiloxane-2-carboxylic acid ( A) A solution of methyl 2,3-dibromopropionate (13 ml) in acetone (50 ml) was added dropwise over 1/2 hour to a stirred suspension of 3,4-dihydroxyacetophenone (15.1 g) and aqueous potassium carbonate (28 g) in acetone (100 ml) heated at reflux.
Blandingen blev omrørt under tilbagesvaling i 4 timer og derpå indddampet i vakuum. Remanensen blev fordelt mel-25 lem chloroform og vand. Chloroformekstrakterne blev va sket med vand, tørret (MgSO^) og inddampet, hvorved opnåedes en blanding (18 g) af 6- 0g 7-acetyl-l,4-benzodi-oxan-2-carboxylsyremethylester i forholdet 2:1 som bestemt ved C13 n.m.r. spektroskopi. En prøve af dette rå 30 produkt blev omkrystalliseret af isopropanol, smp. 68-80 °C.The mixture was stirred at reflux for 4 hours and then evaporated in vacuo. The residue was partitioned between chloroform and water. The chloroform extracts were washed with water, dried (MgSO4) and evaporated to give a mixture (18 g) of 6- and 7-acetyl-1,4-benzodioxane-2-carboxylic acid methyl ester in the ratio of 2: 1 as determined by C13 nmr spectroscopy. A sample of this crude product was recrystallized from isopropanol, m.p. 68-80 ° C.
2626
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Analyse %:Analysis%:
Fundet : C 60,7, H 4,9Found: C 60.7, H 4.9
Beregnet for ci2H12°5: C HCalcd for c12 H12 ° 5: C H
(B) En vandig natriumhydroxidopløsning (1,2 g, i 5 ml 5 vand) blev sat til en omrørt opløsning af produktet fra (A) (7 g) i ethanol (25 ml) ved 15 °C. Reaktionstemperaturen blev holdt under 25 °C i 1/2 time, hvorpå blandingen blev inddampet i vakuum. Remanensen blev triture-ret med vand, syrnet med koncentreret saltsyre og eks-10 traheret med chloroform. De forenede chloroformekstrak- ter blev tørret (MgSO^) og inddampet i vakuum, og remanensen (1,46 g) blev omkrystalliseret af ethylacetat/me-thanol, hvorved opnåedes 7-acetyl-l,4-benzodioxan-2-carboxylsyre, smp. 167-168 °C.(B) An aqueous sodium hydroxide solution (1.2 g, in 5 ml of water) was added to a stirred solution of the product of (A) (7 g) in ethanol (25 ml) at 15 ° C. The reaction temperature was kept below 25 ° C for 1/2 hour, then the mixture was evaporated in vacuo. The residue was triturated with water, acidified with concentrated hydrochloric acid and extracted with chloroform. The combined chloroform extracts were dried (MgSO 4) and evaporated in vacuo and the residue (1.46 g) was recrystallized from ethyl acetate / methanol to give 7-acetyl-1,4-benzodioxane-2-carboxylic acid, m.p. . 167-168 ° C.
15 Analyse %:Analysis%:
Fundet : C 59,0, H 4,5Found: C 59.0, H 4.5
Beregnet for O^H^gO,.: C 59,5, H 4,5 Højtryks-væskechromatografi (HPLC) angav isomerisk renhed på ca. 96% {[Spectra Physics 3500 CS Machine; Kolonne 305 mm x 20 6,4 mm ydre diam. ^u-Bondapak C-18; elueringsmiddel acetoni- tril (1)/0,05M kaliumhydrogenphosphatbuffer pH 4,5 (2); strømningshastighed 0,6 ml/min; tryk 5,38 MPaJ.Calcd. For C ^ HH ^ gO,: C 59.5, H 4.5 High-pressure liquid chromatography (HPLC) indicated isomeric purity of ca. 96% {[Spectra Physics 3500 CS Machine; Column 305 mm x 20 6.4 mm outer diam. ^ u-Bondapak C-18; eluent acetonitrile (1) / 0.05M potassium hydrogen phosphate buffer pH 4.5 (2); flow rate 0.6 ml / min; pressure 5.38 MPaJ.
Den sure vandige fase blev inddampet i vakuum, remanensen blev ekstraheret med methanol, og de forenede eks-25 trakter inddampet i vakuum. Produktet (5,5 g) blev om- krystalliseret af ethylacetat/methanol, hvorved opnåedes 6-acetyl-l,4-benzodioxan-2-carboxylsyre. HPLC viste kun én komponent, der svarede til en autentisk prøve fremstillet ifølge præparation 9.The acidic aqueous phase was evaporated in vacuo, the residue was extracted with methanol and the combined extracts evaporated in vacuo. The product (5.5 g) was recrystallized from ethyl acetate / methanol to give 6-acetyl-1,4-benzodioxane-2-carboxylic acid. HPLC showed only one component that corresponded to an authentic sample prepared according to Preparation 9.
2727
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PRÆPARATION 11 (A) ( + ) l,4-benzodioxan-2-carboxylsyre 1,4-benzodioxan-2-carboxylsyre (21J.6 g) og ( + ) dehydro-abietylamin (34,26 g) blev blandet i varm methanoldena-tureret industrisprit (1000 ml), hvorpå man lod blandingen henstå ved stuetemperatur i 24 timer. Det bundfald der dannedes blev opsamlet (20 g), filtratet blev koncentreret til 600 ml og henstillet i 48 timer, hvorved der dannedes en yderligere mængde fastprodukt (4 g).PREPARATION 11 (A) (+) 1,4-benzodioxane-2-carboxylic acid 1,4-benzodioxane-2-carboxylic acid (21J.6 g) and (+) dehydro-abietylamine (34.26 g) were mixed in hot methanol. -toured industrial liquor (1000 ml), then left to stand at room temperature for 24 hours. The precipitate formed was collected (20 g), the filtrate was concentrated to 600 ml and left for 48 hours to give an additional amount of solid product (4 g).
De forenede produkter (24 g, smp. 204-210 °C) blev om-krystalliseret gentagne gange af en blanding af metha-noldenatureret industrisprit og methanol, indtil der blev opået et konstant smeltepunkt på 229-230 °C (3,0 g).The combined products (24 g, mp 204-210 ° C) were recrystallized repeatedly by a mixture of methanol-denatured industrial spirit and methanol until a constant melting point of 229-230 ° C (3.0 g ).
Derpå blev moderluden fra- den sidste og moderluden fra den næstsidste omkrystallisation forenet, og rumfanget blev reduceret. Det faste produkt (5,6 g) blev opsamlet. Dette salt blev omdannet til den fri carboxylsyre (5,5 g) aD + 60,1° (1% i chloroform) på sædvanlig måde og derpå omkrystalliseret to gange af toluen, hvorved opnåedes (+)1,4-benzodioxan-2-carboxylsyre (0,23 g), smp. 98-99 °C,aD = + 62,1° (1¾ opløsning i chloroform).Then the mother liquor from the last and the mother liquor from the penultimate recrystallization were combined and the volume was reduced. The solid product (5.6 g) was collected. This salt was converted to the free carboxylic acid (5.5 g) aD + 60.1 ° (1% in chloroform) in the usual manner and then recrystallized twice by toluene to give (+) 1,4-benzodioxane-2 carboxylic acid (0.23 g), m.p. 98-99 ° C, aD = + 62.1 ° (1¾ solution in chloroform).
Analyse %:Analysis%:
Fundet : C 60,3, H 4,4 25 Beregnet for CgHgO^: C 60,0, H 4,5 (B) (-) l>4-benzodioxan-2-carboxylsyreFound: C 60.3, H 4.4 Calculated for C 6 H 20 O: C 60.0, H 4.5 (B) (-) 1> 4-Benzodioxane-2-carboxylic acid
De oprindelige moderlud-væsker (600 ml) fra det foregående forsøg blev inddampet i vakuum, og den olieagtige remanens blev optaget i acetone (250 ml) og derpå hensat 30 indtil krystallisationen var fuldendt. Det faste produkt (10,0 g) blev opsamlet, krystalliseret af acetone, hvor- 28The original mother liquors (600 ml) from the previous experiment were evaporated in vacuo and the oily residue was taken up in acetone (250 ml) and then allowed to stand until crystallization was complete. The solid product (10.0 g) was collected, crystallized by acetone, where 28
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efter saltet (6,0 g) blev omdannet til den fri syre på sædvanlig måde under anvendelse af svovlsyre. Det rå produkt blev optaget i chloroform, chromatograferet på silicagel (10 x 50 mm søjlestørrelse), idet der blev 5 elueret med chloroform, inddampet i vakuum og derpå kry stalliseret af toluen, hvorved opnåedes (-) 1,4-benzo-dioxan-2-carboxylsyre (0,90 g), smp. 98-99 °C, 0ί^= -66,1° (1?ό opløsning i chloroform).after the salt (6.0 g) was converted to the free acid in the usual manner using sulfuric acid. The crude product was taken up in chloroform, chromatographed on silica gel (10 x 50 mm column size) eluting with chloroform, evaporated in vacuo and then crystallized by toluene to give (-) 1,4-benzodioxane. 2-carboxylic acid (0.90 g), m.p. 98-99 ° C, 0ί ^ = -66.1 ° (1? Løsning solution in chloroform).
Analyse %: 10 Fundet : C 59,9, H 4,5Analysis%: 10 Found: C, 59.9; H, 4.5
Beregnet for cgHg0^: C 60,0, H 4,5 PRÆPARATION 12 N-(l,4-benzodioxan-2- carbonyl)homopiperazinCalcd for cgHgO4: C 60.0, H 4.5 PREPARATION 12 N- (1,4-benzodioxane-2-carbonyl) homopiperazine
Denne forbindelse blev fremstillet som beskrevet under 15 præparation 1 under anvendelse af homopiperazin i stedet for piperazin. En prøve af hydrochloridsaltet blev om-krystalliseret af methanol, smp, 189 °C.This compound was prepared as described under Preparation 1 using homopiperazine instead of piperazine. A sample of the hydrochloride salt was recrystallized from methanol, m.p., 189 ° C.
Analyse %:Analysis%:
Fundet : C 56,2, H 6,2, N 9,3 20 Beregnet for C^H^N^.HC1: C 56,3, H 6,4, N 9,4 PRÆPARATION 13 6- og 7-(blanding)chlor-1,4-benzodioxan-2-carboxylsyre (A) Der blev sendt chlorgas ind i en omrørt iskold opløsning af methy1-1,4-benzodioxan-2-carboxylat (10 g) i 25 chloroform (100 ml) i nærværelse af aluminiumchlorid (0,06 g). Reaktionen blev stoppet efter 20 minutters forløb, hvorefter opløsningen blev gennemstrømmet med nitrogen, vasket med vand, natriumbicarbonatopløsningFound: C 56.2, H 6.2, N 9.3. Calculated for C C HH ^N₂. HCl: C 56.3, H 6.4, N 9.4 PREPARATION 13 6- and 7- ( mixture) Chloro-1,4-benzodioxane-2-carboxylic acid (A) Chlorine gas was charged into a stirred ice-cold solution of methyl1,4-benzodioxane-2-carboxylate (10 g) in chloroform (100 ml) presence of aluminum chloride (0.06 g). The reaction was stopped after 20 minutes, after which the solution was purged with nitrogen, washed with water, sodium bicarbonate solution
DK 154082BDK 154082B
29 og derpå atter med vand, tørret (Na„S0.) og inddampet i o z ^ i3 vakuum. Der opnåedes en blanding (1:1 ved C n.m.r. spektroskopi) af methylestrene af 6- og 7-chlor-l,4-ben-zodioxan-2-carboxylsyre (12,0 g).29 and then again with water, dried (Na₂SO0) and evaporated in vacuo. A mixture (1: 1 at C nm spectroscopy) of the methyl esters of 6- and 7-chloro-1,4-benzodioxane-2-carboxylic acid (12.0 g) was obtained.
5 (B) En prøve af det ovennævnte produkt (1,4 g) i ethanol (20 ml) blev behandlet med en opløsning af natriumhydroxid (0,25 g) i vand (1 ml) ved stuetemperatur, hvorved der udvikledes en sortfarvning. Efter 48 timer ved stuetemperatur blev blandingen koncentreret i vakuum, fortyn-10 det med vand, ekstraheret med chloroform, og chloroform-(B) A sample of the above product (1.4 g) in ethanol (20 ml) was treated with a solution of sodium hydroxide (0.25 g) in water (1 ml) at room temperature to give a black stain. After 48 hours at room temperature, the mixture was concentrated in vacuo, diluted with water, extracted with chloroform, and
laget blev bortkastet. Den vandige fase blev syrnet med koncentreret saltsyre og ekstraheret med chloroform. De forenede ekstrakter blev tørret (MgSO^) og inddampet i vakuum, hvorved opnåedes en blanding (1,0 g) af 6- og 7-15 chlor-1,4-benzodioxan-2-carboxylsyre, smp. 145-146 °Cthe team was wasted. The aqueous phase was acidified with concentrated hydrochloric acid and extracted with chloroform. The combined extracts were dried (MgSO 4) and evaporated in vacuo to give a mixture (1.0 g) of 6- and 7-15 chloro-1,4-benzodioxane-2-carboxylic acid, m.p. 145-146 ° C
med hertil svarende spektroskopiske egenskaber.with corresponding spectroscopic properties.
PRÆPARATION 14 2-methyl-l,4-benzodioxan-2-carboxylsyrePREPARATION 14 2-methyl-1,4-benzodioxane-2-carboxylic acid
Jones' reagens (33,3 ml) blev sat dråbevis til en omrørt 20 opløsning af 2-hydroxymethyl-2-methy1-1,4-benzodioxan (5 g) i acetone (300 ml) ved 5 °C, hvorefter man lod reaktionsblandingen antage stuetemperatur. Der blev derpå tilsat isopropanol (10 ml) efterfulgt af vand (200 ml). Opløsningen blev ekstraheret med chloroform, og ekstrak-25 terne blev inddampet i vakuum. Den tilbageværende olie blev optaget i chloroform (200 ml) og derpå ekstraheret med fortyndet natriumbicarbonatopløsning, og den vandige fase blev yderligere vasket med chloroform. Den vandige fase blev derpå syrnet med saltsyre og ekstraheret med 30 chloroform, og de forenede ekstrakter blev vasket med vand, tørret (MgSO^) og inddampet i vakuum, hvorved opnåedes 2-methyl-l,4-benzodioxan-2-carboxylsyre (1,7 g).Jones' reagent (33.3 ml) was added dropwise to a stirred solution of 2-hydroxymethyl-2-methyl-1,4-benzodioxane (5 g) in acetone (300 ml) at 5 ° C, then the reaction mixture was allowed assume room temperature. Isopropanol (10 ml) was then added followed by water (200 ml). The solution was extracted with chloroform and the extracts were evaporated in vacuo. The residual oil was taken up in chloroform (200 ml) and then extracted with dilute sodium bicarbonate solution and the aqueous phase was further washed with chloroform. The aqueous phase was then acidified with hydrochloric acid and extracted with chloroform, and the combined extracts were washed with water, dried (MgSO4) and evaporated in vacuo to give 2-methyl-1,4-benzodioxane-2-carboxylic acid (1). , 7 g).
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3030
En prøve blev omkrystalliseret af toluen, smp. 133-134 °C. Analyse ?0:A sample was recrystallized from toluene, m.p. 133-134 ° C. Analysis? 0:
Fundet : C 61,8, H 5,2Found: C 61.8, H 5.2
Beregnet for C^gN^gO^: C 61,9, H 5,2 5 PRÆPARATION 15 cis- og trans ethy1-3-methyl-l,4-benzodioxan-2-carboxylatCalculated for C C CN ^ gO ^: C 61.9, H 5.2 Preparation cis- and trans-ethyl-3-methyl-1,4-benzodioxane-2-carboxylate
Disse forbindelser blev skilt fra hinanden ved præparativ HPLC og blev identificeret ved NMR-spektroskopi ifølge offentliggjorte data (se f.eks. J. Med. Chem., Γ0, 880, 10 1967). Hver af de isomere blev hydrolyseret til den til svarende .syre, der blev omdannet til syrechloridet uden yderligere karakterisering.These compounds were separated by preparative HPLC and identified by NMR spectroscopy according to published data (see, e.g., J. Med. Chem., Γ0, 880, 1967). Each of the isomers was hydrolyzed to the corresponding acid which was converted to the acid chloride without further characterization.
PRÆPARATION 16 4-amino-6,7-dimethoxy-2-(3-methylpiperazin-l-yl)quinazolin 15 4-amino-2-chlor-6,7-dimethoxyquinazolin (8,05 g) og 2-me- thyIpiperazin (10 g) blev opvarmet under tilbagesvaling i butanol i 15 timer. Reaktionsblandingen blev derpå inddampet i vakuum, og den tilbageværende olie blev optaget i chloroform (200 ml), vasket med vand (4 x 50 ml), tør-20 ret (Na2S0^) og inddampet i vakuum. Den tilbageværende olie (13 g) blev omkrystalliseret af isopropanol, hvorved opnåedes 4-amino-6,7-dimethoxy-2-(3-methylpiperazin-l-yl)quinazolinhemihydrat (3,0 g), smp. 185-187 °C.PREPARATION 16 4-Amino-6,7-dimethoxy-2- (3-methylpiperazin-1-yl) quinazoline 4-amino-2-chloro-6,7-dimethoxyquinazoline (8.05 g) and 2-methylpiperazine (10 g) was heated under reflux in butanol for 15 hours. The reaction mixture was then evaporated in vacuo and the residual oil was taken up in chloroform (200 ml), washed with water (4 x 50 ml), dried (Na 2 SO 4) and evaporated in vacuo. The residual oil (13 g) was recrystallized from isopropanol to give 4-amino-6,7-dimethoxy-2- (3-methylpiperazin-1-yl) quinazoline hemihydrate (3.0 g), m.p. 185-187 ° C.
Analyse %·.Analysis% ·.
25 Fundet : C 58,1, H 6,8, N 22,8Found: C 58.1, H 6.8, N 22.8
Beregnet for C15H2iN502 l/220: C 57,7, H 7,1, N 22,4 31Calc'd for C 15 H 21 N 5 O 2/220: C 57.7, H 7.1, N 22.4 31
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Farmakologisk^Bl^illEia·Pharmacological ^ Bl ^ illEia ·
Forbindelserne blev indgivet oralt med 5,0 mg/kg til grupper på 6 hypertensive rotter. Systolisk tryk og hjertehastighed blev registreret under anvendelse af en op-5 blæselig halemanchet og en variabe1-kapacitans-transducer forbundet med et oscilloskop. Rotterne blev anbragt i en varm kasse ved 33 °C i 20-30 minutter før blodtryksmålingerne for at muliggøre nøjagtig detektion af pulsen i halearterien. Blodtryk og hjertehastighed blev registre-10 ret før dosering og derpå 1, 2, 4 og 6 timer efter oral indgivning af'prøveforbindelsen gennem sonde. Alle anvendte dyr havde systoliske kontrolblodtryk (dvs. før dosering) på over 160 mmHg.The compounds were administered orally at 5.0 mg / kg to groups of 6 hypertensive rats. Systolic pressure and heart rate were recorded using an inflatable tail cuff and a variable 1 capacitance transducer connected to an oscilloscope. The rats were placed in a warm box at 33 ° C for 20-30 minutes before the blood pressure measurements to allow accurate detection of the pulse of the tail artery. Blood pressure and heart rate were recorded before dosing and then 1, 2, 4 and 6 hours after oral administration of the test compound through probe. All animals used had systolic control blood pressure (ie, prior to dosing) above 160 mmHg.
Under anvendelse af den angivne prøvningsmetode blev der 15 opnået følgende resultater: /—y r°Y^ I j (ch7u«/ c C„ 3 i NH2 ^Qximaif .Using the test method indicated, the following results were obtained: / - y r ° Y ^ I j (ch7u '/ c C' 3 in NH2 ^ Qximaif.
m udre procentuelt fald i blodtryk (i mmHg) 9n e t som maximalt virkeligt blodtryks fa Id n 0/ 1 ' — ___kontrolblodtryk - 130__ 77 2 _____________^_______ 72 ch3on^v _/r1m ex per cent decrease in blood pressure (in mmHg) 9n e t as maximum real blood pressure fa Id n 0/1 '- ___ control blood pressure - 130__ 77 2 _____________ ^ _______ 72 ch3on ^ v _ / r1
I N N — C — ZI N N - C - Z
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Claims (3)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/952,317 US4188390A (en) | 1977-11-05 | 1978-10-18 | Antihypertensive 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl) piperazin-1-yl or homopiperazin-1-yl]quinazolines |
| BG96072A BG60337B2 (en) | 1977-11-05 | 1992-03-16 | 4-amino-2-(4-)1,4-benzodioxan-2-carbonyl(piperazine-1-il or homopiperazine-1-il)quinazolines with antihypertension effect |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB4612877 | 1977-11-05 | ||
| GB4612877 | 1977-11-05 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK428678A DK428678A (en) | 1979-05-06 |
| DK154082B true DK154082B (en) | 1988-10-10 |
| DK154082C DK154082C (en) | 1989-02-27 |
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ID=10439957
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|---|---|---|---|
| DK428678A DK154082C (en) | 1977-11-05 | 1978-09-27 | METHOD OF ANALOGUE FOR THE PREPARATION OF 4-AMINO-6,7-DIMETHOXY-2- (PIPERAZIN-1-YL OR HOMOPIPERAZIN-1-YL) -QUINAZOLINE COMPOUNDS OR PHARMACEUTICAL ACCEPTABLE ACID ADDITIONAL SALTS |
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| DE (1) | DE2847623C2 (en) |
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Families Citing this family (8)
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| WO1985004658A1 (en) * | 1984-04-04 | 1985-10-24 | Takeda Chemical Industries, Ltd. | 1,5-benzoxathiepine derivatives and their preparation |
| WO1985002617A1 (en) * | 1983-12-14 | 1985-06-20 | Takeda Chemical Industries. Ltd. | 1,5-benzoxathiepin derivatives and process for their preparation |
| WO1986002644A1 (en) * | 1984-11-01 | 1986-05-09 | Takeda Chemical Industries, Ltd. | 1,5-benzoxathiepin derivatives and process for their preparation |
| EP0849264A1 (en) * | 1996-12-20 | 1998-06-24 | HEUMANN PHARMA GmbH | Novel polymorphic form of doxazosin mesylate (form I) |
| EP0849266B8 (en) * | 1996-12-20 | 2007-10-03 | Heumann PCS GmbH | Novel polymorphic form of doxazosin mesylate (form III) |
| EP0849265A1 (en) * | 1996-12-20 | 1998-06-24 | HEUMANN PHARMA GmbH | Novel polymorphic form of doxazosin mesylate (form II) |
| TW448155B (en) * | 1999-03-29 | 2001-08-01 | Dev Center Biotechnology | Method for producing amide compounds and quinazolin derivatives |
| EP1403263B1 (en) * | 2002-09-27 | 2005-06-22 | Council of Scientific and Industrial Research | Process for the preparation of N-(2,3-dihydrobenzo 1,4 dioxin-2-carbonyl) piperazine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3663706A (en) * | 1969-09-29 | 1972-05-16 | Pfizer | Use of 2,4-diaminoquinazolines as hypotensive agents |
| US3669968A (en) * | 1970-05-21 | 1972-06-13 | Pfizer | Trialkoxy quinazolines |
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1978
- 1978-09-27 DK DK428678A patent/DK154082C/en active
- 1978-10-03 IN IN712/DEL/78A patent/IN148828B/en unknown
- 1978-10-24 CA CA314,027A patent/CA1088059A/en not_active Expired
- 1978-10-24 PH PH21726A patent/PH13966A/en unknown
- 1978-10-31 SU SU782679598A patent/SU816403A3/en active
- 1978-10-31 UA UA2679598A patent/UA8324A1/en unknown
- 1978-11-02 JP JP13569578A patent/JPS5498792A/en active Granted
- 1978-11-02 PT PT68735A patent/PT68735A/en unknown
- 1978-11-02 NL NLAANVRAGE7810909,A patent/NL174549C/en not_active IP Right Cessation
- 1978-11-02 AR AR274321A patent/AR219562A1/en active
- 1978-11-02 CS CS787166A patent/CS207671B2/en unknown
- 1978-11-02 FI FI783347A patent/FI64366C/en not_active IP Right Cessation
- 1978-11-02 NZ NZ188813A patent/NZ188813A/en unknown
- 1978-11-02 AT AT0784378A patent/AT365186B/en not_active IP Right Cessation
- 1978-11-02 HU HU78PI648A patent/HU176306B/en unknown
- 1978-11-02 IL IL55857A patent/IL55857A/en unknown
- 1978-11-02 SE SE7811382A patent/SE437518B/en not_active IP Right Cessation
- 1978-11-02 DE DE2847623A patent/DE2847623C2/en not_active Expired
- 1978-11-02 GR GR57562A patent/GR81514B/el unknown
- 1978-11-02 CH CH1132178A patent/CH643255A5/en not_active IP Right Cessation
- 1978-11-02 YU YU2553/78A patent/YU40204B/en unknown
- 1978-11-02 ZA ZA00786184A patent/ZA786184B/en unknown
- 1978-11-03 NO NO783705A patent/NO150158C/en unknown
- 1978-11-03 BE BE191544A patent/BE871771A/en not_active IP Right Cessation
- 1978-11-03 FR FR7831126A patent/FR2407929A1/en active Granted
- 1978-11-03 IE IE2179/78A patent/IE47888B1/en active Protection Beyond IP Right Term
- 1978-11-03 IT IT29434/78A patent/IT1100919B/en active Protection Beyond IP Right Term
- 1978-11-03 PL PL1978210681A patent/PL119586B1/en unknown
- 1978-11-03 DD DD78208868A patent/DD139850A5/en unknown
- 1978-11-03 AU AU41322/78A patent/AU509329B2/en not_active Expired
- 1978-11-03 PL PL1978216980A patent/PL119419B1/en unknown
- 1978-11-03 ES ES474805A patent/ES474805A1/en not_active Expired
- 1978-11-03 LU LU80470A patent/LU80470A1/en unknown
- 1978-11-04 EG EG641/78A patent/EG13594A/en active
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1979
- 1979-04-30 ES ES480121A patent/ES8308559A1/en not_active Expired
- 1979-10-18 AR AR278545A patent/AR223015A1/en active
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1983
- 1983-02-17 YU YU386/83A patent/YU40419B/en unknown
- 1983-11-21 KE KE3350A patent/KE3350A/en unknown
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1984
- 1984-11-29 HK HK942/84A patent/HK94284A/en not_active IP Right Cessation
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1985
- 1985-12-30 MY MY286/85A patent/MY8500286A/en unknown
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1991
- 1991-11-22 CS CS913544A patent/CS354491A3/en unknown
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1993
- 1993-06-11 NL NL930062C patent/NL930062I2/en unknown
- 1993-06-24 LU LU88331C patent/LU88331I2/en unknown
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