DK166777B1 - 2- (SUBSTITUTED BENZOYL) -AMINO-1,2,3,4-TETRAHYDROISOQUINOLINE DERIVATIVES, PROCEDURES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATION CONTAINING THEM. - Google Patents
2- (SUBSTITUTED BENZOYL) -AMINO-1,2,3,4-TETRAHYDROISOQUINOLINE DERIVATIVES, PROCEDURES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATION CONTAINING THEM. Download PDFInfo
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DK 166777 B1DK 166777 B1
Den foreliggende opfindelse angår hidtil ukendte 2-(substitueret benzoyl)-amino-1,2,3,4-tetrahydroisoquino-1 inderivater, som er ejendommelige ved, at de har den almene formel (I) 5 NH—CO—\oV-CI t R3 ^S02NH2 ' 15 hvori R betyder hydrogen eller chlor, 20 R1 og R2 betyder hydrogen, methoxy eller ethoxy, og R3 og R4 betyder hydrogen eller methyl, en fremgangsmåde til deres fremstilling samt et farmaceutisk præparat, som er ejendommeligt ved, at det som aktiv bestanddel indeholder en forbindelse med den almene formel 25 (I), hvor R, R1, R2, R3 og R4 er som ovenfor defineret.The present invention relates to novel 2- (substituted benzoyl) amino-1,2,3,4-tetrahydroisoquino-1 derivatives which are characterized in that they have the general formula (I) 5 NH-CO Wherein R is hydrogen or chloro, R 1 and R 2 are hydrogen, methoxy or ethoxy, and R 3 and R 4 are hydrogen or methyl, a process for their preparation and a pharmaceutical composition which is characterized in that: the active ingredient contains a compound of the general formula (I) wherein R, R1, R2, R3 and R4 are as defined above.
De hidtil ukendte forbindelser udviser diuretisk, hypertensiv og saluretisk aktivitet.The novel compounds exhibit diuretic, hypertensive and saluretic activity.
Der kendes allerede diuretiske midler af chlorbenzen-sulfonamidtypen, der på benzenringen indeholder en fri car-30 boxy1syregruppe (Furosemid, DE-PS nr. 1.122.541 og K. Sturm, W. Siedel, R. Weyer, H. Ruschig: Chem. Ber. 99, side 328 (1966)), en carboxyamidgruppe (Diapamid, DE-OS nr. 1.158.957 og L. T. Blouin, D. H. Kaump, R. L. Fransway, D. Williams: J. New Drugs 3, side 302 (1963)) eller en carboxylsyrehy-35 drazidgruppe (Clopamid, HU-PS nr. 150 352 og 152 300, A. Lindemann, E. Schenker, E. Fluckinger, M. Taeschler: Arz- 2 DK 166777 B1 neim.-Forsch.. 13, side 269 (1963)). Af de i sidstnævnte litteratursted beskrevne forbindelser er kun Clopamid kommercielt tilgængeligt.There are already known diuretic agents of the chlorobenzene-sulfonamide type which contain on the benzene ring a free carboxylic acid group (Furosemide, DE-PS No. 1,122,541 and K. Sturm, W. Siedel, R. Weyer, H. Ruschig: Chem. Ber. 99, page 328 (1966)), a carboxyamide group (Diapamide, DE-OS No. 1,158,957, and LT Blouin, DH Kaump, RL Fransway, D. Williams: J. New Drugs 3, page 302 (1963)) or a carboxylic acid hydrazide group (Clopamide, HU-PS Nos. 150 352 and 152 300, A. Lindemann, E. Schenker, E. Fluckinger, M. Taeschler: Arz-2 DK 166777 B1 Neim.-Forsch .. 13, page 269 (1963)). Of the compounds described in the latter literature, only Clopamide is commercially available.
Den kemiske struktur af forbindelserne ifølge opfin-5 delsen er signifikant forskellig fra de diuretiske forbindelser af kendt struktur som ovenfor nævnt. Forbindelser af betydning som diuretika og indeholdende et ringsystem af isoquinoliner er ikke blevet beskrevet, og det er derfor overraskende, at forbindelserne med den almene formel (I) 10 viser en signifikant diuretisk og salure'tisk aktivitet. I et screeningforsøg udført på rotter (indgift per os 5 mg/kg) sammenlignes forbindelserne ifølge opfindelsen med dihydro-chlorthiazider og furosemid. Forbindelser fremstillet ifølge eksempel 1 og 2 er særligt fordelagtige, fordi deres Na/K-15 -forhold (forholdet mellem udskilt Na og udskilt K) er så gunstigt.The chemical structure of the compounds of the invention is significantly different from the diuretic compounds of known structure as mentioned above. Compounds of importance as diuretics and containing a ring system of isoquinolines have not been described, and it is therefore surprising that the compounds of general formula (I) 10 show significant diuretic and saluretic activity. In a screening experiment performed in rats (administration per os 5 mg / kg), the compounds of the invention are compared with dihydrochlorothiazides and furosemide. Compounds prepared according to Examples 1 and 2 are particularly advantageous because their Na / K-15 ratio (the ratio of separated Na to separated K) is so favorable.
Det er nemlig kendt, at den kaliumudtømmende aktivitet af Clopamid er den samme som Chlorthiazid, hvilket betyder, at det er nødvendigt med et kaliumtilskud ved længerevarende 20 behandling, jfr. Martindale: The Extra Pharmacopoeia, 28. udg., 592 (1982). Ved forsøg på hunde har det vist sig, at Na/K-forholdet for Clopamid er ca. 5 for alle afprøvede doser, jfr. B. Terry og J.B. Hook, J. Pharmacol. Exp. Ther.Namely, it is known that the potassium depleting activity of Clopamide is the same as Chlorothiazide, which means that a potassium supplement is needed for prolonged treatment, cf. Martindale: The Extra Pharmacopoeia, 28th ed., 592 (1982). In dogs, it has been found that the Na / K ratio of Clopamide is approx. 5 for all tested doses, cf. B. Terry and J.B. Hook, J. Pharmacol. Exp. Ther.
160. 369 (1968).160, 369 (1968).
25 For den foretrukne forbindelse med ovenstående formel (I) (forbindelsen ifølge eksempel 1) gælder derimod, at Na/K-forholdet er så højt som 9,09, jfr. nedenstående tabel, hvilket betyder, at denne forbindelse ikke har nogen signifikant kaliumudtømmende aktivitet, og dette er en uventet 30 fordel sammenlignet med kendte diuretika og benzensulfon-amidtypen (Chlorthiazid, Furosemid, Clopamid).In contrast, for the preferred compound of formula (I) (the compound of Example 1), the Na / K ratio is as high as 9.09, cf. The following table indicates that this compound has no significant potassium depleting activity and this is an unexpected benefit compared to known diuretics and the benzenesulfone amide type (Chlorothiazide, Furosemide, Clopamide).
Ud over deres aktivitet er det en fordel ved forbindelserne ifølge opfindelsen, at deres terapeutiske anvendelse er fordelagtigere end anvendelsen af ,,højt-loft,,-forbin-35 delser (forbindelser, som hurtigt når op på et meget højt aktivitetsniveau), da den diuretiske og saluretiske proces 3 DK 166777 B1 ikke er så hurtig og akut. Efter indgiften er varigheden af aktiviteten 24 timer.In addition to their activity, it is an advantage of the compounds of the invention that their therapeutic use is more advantageous than the use of "high-ceiling" compounds (compounds which rapidly reach a very high activity level) as diuretic and saluretic process 3 B1 is not so fast and acute. After administration, the duration of the activity is 24 hours.
Den akutte toksicitet af forbindelserne ifølge opfindelsen er meget lav, og som følge heraf er det terapeutiske 5 indeks også fordelagtigt.The acute toxicity of the compounds of the invention is very low and, as a result, the therapeutic index is also advantageous.
Der anvendes tabletter, overtrukne tabletter eller kapsler indeholdende 1-300 mg aktiv bestanddel, som indeholder de gængse fyld- og bærestoffer, der anvendes til oral indgift i human terapi.Tablets, coated tablets or capsules containing 1-300 mg of active ingredient are used which contain the usual fillers and carriers used for oral administration in human therapy.
10 Den her omhandlede fremgangsmåde til fremstilling af forbindelserne med den almene formel (I), hvori R, R1, R2, R3 og R4 er som ovenfor nævnt, er ejendommelig ved, at et 2-amino-l,2,3,4-tetrahydroisoquinolinderivat med den almene formel (II) 15 R1 r4 ρ2>^γΝ-ΝΗ2 20 R3 „ hvori R1, R2, R3 og R4 er som ovenfor nævnt, omsættes med et carboxylsyrederivat med den almene formel (III) 25 ς R\ Ml 6no2s>->-co-x 30 R III.The process of preparing the compounds of general formula (I), wherein R, R 1, R 2, R 3 and R 4 are as mentioned above, is characterized in that a 2-amino-1,2,3,4 tetrahydroisoquinoline derivative of the general formula (II) wherein R 1, R 2, R 3 and R 4 are as mentioned above are reacted with a carboxylic acid derivative of the general formula (III) 25 ς R \ Ml 6no2s > -> - co-x 30 R III.
hvori R er som ovenfor anført, 35 X betyder chlor, -OH, -OCH2CN, -OCH3, -OC2H5, -OCOCH3 eller -OCOC2H5, og 4 DK 166777 B1 R5 og R6 betyder hydrogen eller sammen betyder =CHN(CH3)2, og beskyttelsesgruppen =CHN(CH3)2, såfremt der er dannet en forbindelse med den almene formel (la) ^S02N=CHN(CH3)2 hvori R, R1, R2, R3 og R4 er som ovenfor anført, fraspaltes i et alkalisk medium.wherein R is as indicated above, X represents chlorine, -OH, -OCH 2 CN, -OCH 3, -OC 2 H 5, -OCOCH 3 or -OCOC 2 H 5, and 4 represents hydrogen or together means = CHN (CH 3) 2, and the protecting group = CHN (CH 3) 2, if a compound of the general formula (Ia) S SO 2 N = CHN (CH 3) 2 wherein R, R 1, R 2, R 3 and R 4 are as above, is decomposed in an alkaline medium .
15 Denne fremgangsmåde er illustreret i nedenstående reaktionsskema A, hvor R, R1, R2, R3, R4, R5, R6 og x har den ovenfor anførte betydning.This process is illustrated in Reaction Scheme A below, wherein R, R1, R2, R3, R4, R5, R6 and x have the meaning given above.
5 DK 166777 B1 REAKTIONSSKEMA "A" R^^Yn“nh2 XOC-^^-SOoN ri- R3 2 \R6 II. III.5 DK 166777 B1 REACTION SCHEME "A" R ^^ In “nh2 XOC - ^^ - SOoN ri- R3 2 \ R6 II. III.
10 ^r2^3Cn-NH-C0^oVcI r5 .10 ^ r2 ^ 3Cn-NH-C0 ^ oVcI r5.
is r3 S02Nxr6is r3 S02Nxr6
Ib -^)3yiRNH-co^Va R3 I. ^S02NH2 25 I denne reaktion anvendes til acylering en fri car boxylsyre eller et reaktivt derivat deraf som defineret for X, dvs. et syrechlorid, en alkyl- eller aktiv ester deraf eller et blandet anhydrid med eddike- eller propion-syre. Som alkylester kan anvendes en methyl- eller ethylester 30 og som aktiv ester en cyanomethylester. Reaktanterne anvendes i en ækvimolær mængde, og der sættes triethylamin eller natriumamid til reaktionsblandingen..In this reaction, for the acylation, a free carboxylic acid or a reactive derivative thereof as defined for X, i.e., X, is used. an acid chloride, an alkyl or active ester thereof, or a mixed anhydride with acetic or propionic acid. As an alkyl ester, a methyl or ethyl ester can be used and as an active ester a cyanomethyl ester. The reactants are used in an equimolar amount and triethylamine or sodium amide is added to the reaction mixture.
I visse tilfælde foretrækker man at beskytte sul-fonamidgruppen. Til dette formål kan anvendes kondensering 35 med formamidacetaler, hvor der dannes aminomethylidensulf-amider ifølge reaktionsskema B.In some cases, it is preferred to protect the sulfonamide group. For this purpose, condensation 35 can be used with formamide acetals forming aminomethylidene sulfamides according to Scheme B.
6 DK 166777 B1 REAKTIONSSKEMA "B" 5 clYiY'R JM- H2N02S"A^C00H ^‘3 no2s^s>Scooh CH-N(CH3)2 !V. . V.6 DK 166777 B1 REACTION SCHEME "B" 5 clYiY'R JM- H2N02S "A ^ C00H ^ '3 no2s ^ s> Scooh CH-N (CH3) 2! V. V
. ci-v^s^R. C v ^ p ^ R
~ NOoS'^^'COCl 15 1 c CH-N(CH3)2~ NOoS '^^' COCl 15 1 c CH-N (CH3) 2
Ea.Ea.
2020
Denne reaktion er især vigtig, hvis der anvendes syrechlorider til acylering ifølge reaktionsskema A. Disse "beskyttede" syrechlorider er langt stabilere forbindelser end tilsvarende forbindelser indeholdende et frit sulfonamid.This reaction is particularly important if acid chlorides are used for acylation according to Scheme A. These "protected" acid chlorides are far more stable compounds than similar compounds containing a free sulfonamide.
25 Reaktionen kan gennemføres i dimethyl formamid ved en temperatur i området fra 40 til 80“C og ved anvendelse af dimethyl-formamiddimethylacetal.The reaction can be carried out in dimethyl formamide at a temperature in the range of 40 to 80 ° C and using dimethyl-formamide dimethyl acetal.
Fremstillingen af forbindelserne med den almene formel (V)The preparation of the compounds of the general formula (V)
c,^rRC, ^ rR
N02S'^sxNxX)HN02S '^ sxNxX) H
35 CH-N(CH3)2 V.CH-N (CH3) 2 V.
7 DK 166777 B1 kan fortrinsvis gennemføres ved fremstilling af dimethyl-formamiddimethylacetal in situ i reaktionsblandingen og ved omgående omsætning af denne sulfonamidgruppe med den "beskyttede" syre med formlen (V), og den dannede forbindelse oms-5 ættes med thionylchlorid, og herved opnås syrechloridet med den almene formel (Illa) 10 NO2S^^C0Cl CH-N(CH3)2Preferably, B1 can be carried out by preparing dimethyl-formamide dimethyl acetal in situ in the reaction mixture and by immediately reacting this sulfonamide group with the "protected" acid of formula (V), and the resulting compound is reacted with thionyl chloride and thereby obtained the acid chloride of the general formula (IIa) NO2S ^^ COCl CH-N (CH3) 2
Ill.a.Ill.a.
15 med et godt udbytte.15 with a good yield.
Acyleringen med syrechlorider eller blandede anhydri-der kan udføres i polære opløsningsmidler, såsom tetrahydro-furan, dioxan, pyridin, dimethylformamid, dimethylacetamid, dimethylurinstof. Under reaktionen kan temperaturen være i 20 området fra -20°C til kogepunktet for opløsningsmidlet. Hvis der anvendes et ikke-basisk opløsningsmiddel, såsom pyridin, kan der som syrebindende middel anvendes organiske baser, såsom triethylamin, dimethylanilin.The acylation with acid chlorides or mixed anhydrides can be carried out in polar solvents such as tetrahydrofuran, dioxane, pyridine, dimethylformamide, dimethylacetamide, dimethylurea. During the reaction, the temperature may range from -20 ° C to the boiling point of the solvent. If a non-basic solvent such as pyridine is used, organic bases such as triethylamine, dimethylaniline can be used as an acid-binding agent.
Syrechloriderne med den almene formel (III) (hvori X 25 betyder chlor) kan anvendes til acylering, og man kan gå frem på den måde, at acyleringen genemføres i en blanding af vand og et vand-blandbart organisk opløsningsmiddel og i nærværelse af et alkali- eller jordalkalimetalcarbonat eller et -hydrogencarbonat som et syrebindende middel.The acid chlorides of the general formula (III) (in which X 25 means chlorine) can be used for acylation, and one can proceed in that the acylation is effected in a mixture of water and a water miscible organic solvent and in the presence of an alkali or alkaline earth metal carbonate or hydrogen bicarbonate as an acid binding agent.
30 Som vand-blandbare organiske opløsningsmidler kan der anvendes protiske eller aprotiske opløsningsmidler. Som et aprotisk opløsningsmiddel kan der anvendes opløsningsmidler af ethertypen, såsom dioxan, tetrahydrofuran, eller opløsningsmidler af ketontypen, såsom acetone, eller syre-35 amid, såsom dimethylformamid, dimethylacetamid. Som protisk opløsningsmiddel foretrækkes lavere aliphatiske alkoholer, s DK 166777 B1 såsom methyl-, ethyl- eller propylalkohol.As water-miscible organic solvents, protic or aprotic solvents may be used. As an aprotic solvent, ether-type solvents such as dioxane, tetrahydrofuran, or ketone-type solvents such as acetone, or acid amide such as dimethylformamide, dimethylacetamide may be used. As the protic solvent, lower aliphatic alcohols, such as methyl, ethyl or propyl alcohol, are preferred.
Som alkalimetalcarbonat kan anvendes natriumcarbonat eller kaliumcarbonat og som jordalkalimetalcarbonat magnesium og calciumcarbonat, og som alkalimetalhydrogencarbonat 5 kan anvendes natrium- og kaliumhydrogencarbonat. Reaktionen kan fortrinsvis udføres ved en temperatur fra 0 til 100°C, især foretrukket ved 10 til 30°C.As alkali metal carbonate can be used sodium carbonate or potassium carbonate and as alkaline earth metal carbonate magnesium and calcium carbonate and as alkali metal hydrogen carbonate 5 can be used sodium and potassium hydrogen carbonate. The reaction can preferably be carried out at a temperature of 0 to 100 ° C, especially preferably at 10 to 30 ° C.
For at fremstille det blandede anhydrid kan en syre med den almene formel (V) omsættes med en methyl- eller 10 ethylester af chlorcarbonsyre. Det blandede anhydrid kan frasepares eller fortrinsvis fremstilles i reaktionsblandingen og omsættes yderligere uden isolering med en aminoforbin-delse med den almene formel (II).To prepare the mixed anhydride, an acid of the general formula (V) can be reacted with a methyl or 10 ethyl ester of chlorocarbon acid. The mixed anhydride can be separated or preferably prepared in the reaction mixture and further reacted without isolation with an amino compound of general formula (II).
Fjernelse af beskyttelsesgruppen kan udføres ved 15 alkalisk hydrolyse. Reaktionen kan gennemføres i et vandigt medium ved anvendelse af stærke, uorganiske baser, fortrinsvis natrium- eller kaliumhydroxid. Den anvendte temperatur er mellem 20 og 80eC, fortrinsvis 50-60°C. Til 1 mol forbindelse, der skal hydrolyseres, anvendes 2-6, fortrinsvis 3-4, 20 mol uorganisk base.Removal of the protecting group can be carried out by alkaline hydrolysis. The reaction can be carried out in an aqueous medium using strong inorganic bases, preferably sodium or potassium hydroxide. The temperature used is between 20 and 80 ° C, preferably 50-60 ° C. For 1 mole of compound to be hydrolyzed, 2-6, preferably 3-4, 20 moles of inorganic base are used.
Hvis der som carboxylsyre anvendes en forbindelse, hvor i den almene formel (III) X betyder hydroxyl og R, R5 og R6 er som angivet ovenfor, som et acyleringsmiddel, gennemføres reaktionen i nærværelse af et kondenseringsmiddel.If, as a carboxylic acid, a compound is used in which in the general formula (III) X is hydroxyl and R, R5 and R6 are as indicated above as an acylating agent, the reaction is carried out in the presence of a condensing agent.
25 Til dette formål kan anvendes dicyclohexylcarbodiimid eller tetrachlorsilan. Reaktionen udføres fortrinsvis i pyridin.For this purpose, dicyclohexylcarbodiimide or tetrachlorosilane may be used. The reaction is preferably carried out in pyridine.
I rotteeksperimenter kan man bestemme den udmærkede saluretiske aktivitet af forbindelserne ifølge opfindelsen, aktiviteten kan observeres 1 til 2 timer efter indgift. Den 30 maksimale aktivitet opnåes inden for 3-5 timer, og den varer i 24 timer, idet den derved sikrer en beskyttende og langvarig diurese. En særlig fordel ved de hidtil ukendte forbindelser er det fordelagtige natrium-kalium forhold og den lave toksicitet. LD50-dosis for mus er ved indgift per 35 os højere end 3,000 mg/kg.In rat experiments, one can determine the excellent saluretic activity of the compounds of the invention, the activity being observed 1 to 2 hours after administration. The maximum activity is achieved within 3-5 hours, and it lasts for 24 hours, thereby ensuring a protective and long-lasting diuresis. A particular advantage of the novel compounds is the advantageous sodium-potassium ratio and the low toxicity. The LD50 dose for mice is higher than 3,000 mg / kg when administered per 35 oz.
Der anvendes 1-300 mg aktiv bestanddel for oral ind- DK 166777 B1 9 gift i humanterapi, og der anvendes tabletter, overtrukne tabletter og kapsler indeholdende de sædvanlige fyldstoffer og bærestoffer.1-300 mg of active ingredient is used for oral administration in human therapy, and tablets, coated tablets and capsules containing the usual fillers and carriers are used.
Detaljer ifølge opfindelsen fremgår af følgende ek-5 sempler.Details of the invention are set forth in the following examples.
EKSEMPEL 1 43,2 g 2-amino-l,2,3,4-tetrahydro-isoquinolin-hydro-chlorid (fremstilles ifølge J. Het. Chem. 20, side 121 10 (1983)) og 24,5 g calciumcarbonat omrøres i 30 minutter i en 2:1 blanding af 400 cm3 dioxan og vand. Der tilsættes i små portioner under omrøring 59,5 g 4-chlor-3-sulfamoylben-zoylchlorid til suspensionen ved stuetemperatur (fremstillingen er beskrevet i J. Med. Chem. 11, side 970 (1968)).EXAMPLE 1 43.2 g of 2-Amino-1,2,3,4-tetrahydroisoquinoline hydrochloride (prepared according to J. Het. Chem. 20, p. 121 10 (1983)) and 24.5 g of calcium carbonate are stirred. for 30 minutes in a 2: 1 mixture of 400 cc dioxane and water. 59.5 g of 4-chloro-3-sulfamoylbenzoyl chloride are added to the suspension at room temperature with stirring (preparation is described in J. Med. Chem. 11, p. 970 (1968)).
15 Reaktionsblandingen omrøres i 2 timer og fortyndes med 300 cm3 vand. De fraskilte krystaller frasuges og vaskes med vand, med 0,5 N saltsyre og derefter igen med vand. Der opnåes 71,9 g (84%) 2- (3'-sulfamoyl-4'-chlor)-benzoyl-amino- 1.2.3.4- tetrahydroisoguinol in i form af hvide krystaller.The reaction mixture is stirred for 2 hours and diluted with 300 cm 3 of water. The separated crystals are aspirated and washed with water, with 0.5 N hydrochloric acid and then again with water. 71.9 g (84%) of 2- (3'-sulfamoyl-4'-chloro) -benzoylamino-1,2,3,4-tetrahydroisoguinol are obtained in the form of white crystals.
20 Efter rekrystallisation fra en ludopløsning smelter produktet ved 225-228eC,After recrystallization from a broth solution, the product melts at 225-228 ° C.
Analyse for formlen Ci6Hi6ClN303S:Analysis for Formula C16 H16 ClN3 O3 S:
Beregnet: C 52,53%, H 4,41%, N 11,49%, Cl 9,69%, S 8,77%Calculated: C 52.53%, H 4.41%, N 11.49%, Cl 9.69%, S 8.77%
Fundet: C 52,26%, H 4,41%, N 11,32%, C 9,86%, S 8,90% 25 EKSEMPEL 2Found: C 52.26%, H 4.41%, N 11.32%, C 9.86%, S 8.90% EXAMPLE 2
Der gås frem i overensstemmelse med eksempel l, og som udgangsmateriale anvendes 28,2 g l-methyl-2-amino-l,2,- 3.4- tetrahydro—isoquinolin, 17,5 g calciumcarbonat, 43,2 g 30 4-chlor-3-sulfamoylbenzoylchlorid og en 2:1 blanding af 350 cm3 dioxan og vand. Man opnår 48,3 g (74,8%) 1-methyl- 2- [ (3'-sulfamoyl-4'-chlor)-benzoyl]-amino-1,2,3,4-tetrahy-dro-isoquinolin. Efter udfældning fra en ludopløsning smelter det opnåede produkt ved 227-229°C.Proceed according to Example 1 and as starting material 28.2 g of 1-methyl-2-amino-1,2,4,4-tetrahydro-isoquinoline, 17.5 g of calcium carbonate, 43.2 g of 4-chloro are used. -3-sulfamoylbenzoyl chloride and a 2: 1 mixture of 350 cc of dioxane and water. 48.3 g (74.8%) of 1-methyl-2- [(3'-sulfamoyl-4'-chloro) -benzoyl] -amino-1,2,3,4-tetrahydro-isoquinoline are obtained. After precipitation from a broth solution, the product obtained melts at 227-229 ° C.
35 Analyse for formlen C^HigCl^C^S:Analysis for Formula C CHigCl ^C ^S:
Beregnet: C 53,75%, H 4,78%, N 11,06%, Cl 9,33%, S 8,44% 10 DK 166777 B1Calculated: C 53.75%, H 4.78%, N 11.06%, Cl 9.33%, S 8.44% DK 166777 B1
Fundet: C 53,86%, H 4,66%, N 11,17%, Cl 9,41%, S 8,48%Found: C 53.86%, H 4.66%, N 11.17%, Cl 9.41%, S 8.48%
Fremstilling af udgangsmaterialer A) 21,5 g 1-methyl-l, 2,3,4-tetrahydro-isoquinolin-hydro- 5 chlorid (fremstilling: Monatshefte, vol. 53-54, side 959 (1929)) opløses i 50 cm3 vand, og til opløsningen sættes dråbevis en opløsning af 8,22 g natriumnitrit i 25 cm3 vand indenfor 1 time ved 75°C. Reaktionsblandingen afkøles ved 75°C efter omrøring i 2 timer og ekstraheres med 6 x 30 10 cm3 chloroform. Chloroformopløsningen vaskes med 50 cm3 vand, tørres og inddampes ved vakuum. Man opnår 19,2 g (93%) l-methyl-2-nitroso-l,2,3,4-tetrahydroisoquinolin som en brun olie, der anvendes til næste trin uden yderligere rensning.Preparation of Starting Materials A) 21.5 g of 1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (Preparation: Monthly Booklet, Vol. 53-54, page 959 (1929)) are dissolved in 50 cm 3 water, and to the solution is added dropwise a solution of 8.22 g of sodium nitrite in 25 cc of water within 1 hour at 75 ° C. The reaction mixture is cooled at 75 ° C after stirring for 2 hours and extracted with 6 x 30 cm 3 of chloroform. The chloroform solution is washed with 50 cm 3 of water, dried and evaporated in vacuo. 19.2 g (93%) of 1-methyl-2-nitroso-1,2,3,4-tetrahydroisoquinoline are obtained as a brown oil which is used for the next step without further purification.
15 B) Nitrosoforbindelsen, der er opnået i det tidligere trin, opløses i 32 cm3 iseddikesyre, og opløsningen sættes dråbevis under afkøling med isvand under omrøring til en suspension af 31,9 g zinkpulver i 30 cm3 vand. Reaktionsblan- 20 dingen afkøles i 1 time med isvand og omrøres uden afkøling i 2 timer. Blandingen opvarmes til 85°C, den filtreres, og det resterende zink vaskes med 3 x 20 cm3 5%'s vandig varm saltsyre. Filtratet gøres alkalisk med en 40%'s natriumhydroxidopløsning og ekstraheres med 4 x 100 cm3 chloroform.B) The nitroso compound obtained in the previous step is dissolved in 32 cc of glacial acetic acid and the solution is added dropwise with cooling with ice water while stirring to a suspension of 31.9 g of zinc powder in 30 cc of water. The reaction mixture is cooled for 1 hour with ice water and stirred without cooling for 2 hours. The mixture is heated to 85 ° C, filtered and the remaining zinc is washed with 3 x 20 cm 3 of 5% aqueous hot hydrochloric acid. The filtrate is made alkaline with a 40% sodium hydroxide solution and extracted with 4 x 100 cm 3 of chloroform.
25 Chloroformopløsningen vaskes med vand, tørres og inddampes i vakuum. Der opnåes 18 g (100%) l-methyl-2-amino-l,2,3,4-tetrahydroisoquinolin som en brun olie, der kan anvendes uden yderligere rensning.The chloroform solution is washed with water, dried and evaporated in vacuo. 18 g (100%) of 1-methyl-2-amino-1,2,3,4-tetrahydroisoquinoline is obtained as a brown oil which can be used without further purification.
30 EKSEMPEL 3EXAMPLE 3
Man anvender fremgangsmåden ifølge eksempel 2, og som udgangsmateriale anvendes 28,1 g l-methyl-2-amino-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin (fremstillingen heraf er beskrevet i J. prakt. Chem. 327, side 445 (1985)), 35 7 g calciumcarbonat, 32,1 g 4-chlor-3-sulfamoylbenzoylchlo- rid og 20 cm3 af en 2:1 blanding af dioxan og vand. Man 11 DK 166777 B1 opnår 50 g (90%) i-methyl-2-[ (3 '-sulfamoyl-41-chlorbenzoyl) -amino]-6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinolin-monohy-drat, smp. 230-233°C.The procedure of Example 2 is used and starting material is used 28.1 g of 1-methyl-2-amino-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (the preparation thereof is described in J. Pract. Chem. 327, page 445 (1985)), 7 g of calcium carbonate, 32.1 g of 4-chloro-3-sulfamoylbenzoyl chloride and 20 cm 3 of a 2: 1 mixture of dioxane and water. 50 g (90%) of 1-methyl-2- [(3'-sulfamoyl-41-chlorobenzoyl) amino] -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline are obtained. -monohy-draat, m.p. 230-233 ° C.
Analyse for formlen Cxgl^Cl^OsSxI^O: 5 Beregnet: C 49,83%, H 5,28%, N 9,18%, Cl 7,74%, S 7,00%Analysis for Formula Cxgl 2 Cl 2 OsSxl 2 O: 5 Calculated: C 49.83%, H 5.28%, N 9.18%, Cl 7.74%, S 7.00%
Fundet: C 49,58%, H 5,00%, N 8,84%, Cl 7,50%, S 6,81% EKSEMPEL 4Found: C 49.58%, H 5.00%, N 8.84%, Cl 7.50%, S 6.81% EXAMPLE 4
Man anvender fremgangsmåden ifølge eksempel 1, men 10 reaktionen gennemføres i en 2:1 blanding af 400 cm3 isopro-pylalkohol og vand. Der opnåes 70,1 g (82%) 2-[(3'-sulfa-moyl-41 -chlorbenzoyl) -amino] -1,2,3,4-tetrahydro-isoquinolin. Efter rekrystall isat ion fra en ludopløsning smelter produktet ved 226-228°C.The procedure of Example 1 is used, but the reaction is carried out in a 2: 1 mixture of 400 cc of isopropyl alcohol and water. 70.1 g (82%) of 2 - [(3'-sulphamoyl-41-chlorobenzoyl) -amino] -1,2,3,4-tetrahydroisoquinoline are obtained. After recrystallization from a broth solution, the product melts at 226-228 ° C.
15 EKSEMPEL 5EXAMPLE 5
Der opløses 22,6 g 2-amino-1,2,3,4-tetrahydro-isoquinolin i 400 cm3 dioxan, og til opløsningen sættes en opløsning af 12,7 g vandfrit natriumcarbonat i 200 cm3 vand.Dissolve 22.6 g of 2-amino-1,2,3,4-tetrahydro-isoquinoline in 400 cc of dioxane and add to the solution a solution of 12.7 g of anhydrous sodium carbonate in 200 cc of water.
20 Blandingen afkøles med koldt vand og omrøres, og der tilsættes dråbevis en opløsning af 68 g 4-chlor-3-[(N-dimethyl-aminomethyliden) -sulfamoylbenzoyl) ]-chlorid i 400 cm3 dioxan, medens temperaturen holdes på 15-20°C. Når tilsætningen er tilendebragt, omrøres blandingen i 2 timer ved 20"C, og 25 den filtreres for at få en klar opløsning. Filtratet fortyndes med 2 liter vand, og de udskilte krystaller frasuges, vaskes med vand og tørres ved 80°c. Det rå produkt (63 g) omrøres i 8 timer ved 50°C med 430 cm3 2N natriumhydroxidopløsning. Opløsningen aktiveres med aktivt kul, filtreres, 30 og filtratets pH-værdi indstilles på 6 ved tilsætning af 2 N saltsyre under afkøling og omrøring.The mixture is cooled with cold water and stirred, and a solution of 68 g of 4-chloro-3 - [(N-dimethyl-aminomethylidene) -sulfamoylbenzoyl)] chloride in 400 cc of dioxane is added dropwise while maintaining the temperature of 15-20 ° C. When the addition is complete, the mixture is stirred for 2 hours at 20 ° C and filtered to obtain a clear solution. The filtrate is diluted with 2 liters of water and the separated crystals are suctioned off, washed with water and dried at 80 ° C. crude product (63 g) is stirred for 8 hours at 50 ° C with 430 cc of 2N sodium hydroxide solution The solution is activated with activated carbon, filtered, and the pH of the filtrate is adjusted to 6 by the addition of 2N hydrochloric acid under cooling and stirring.
Det udfældede produkt frasuges, vaskes med vand og tørres ved 80°C. Man opnår 43,9 g (60%) 2-[(3'-sulfamoyl-4'-chlor) -benzoyl]-amino-l,2,3,4-tetrahydroisoquinolin, smp.The precipitated product is aspirated, washed with water and dried at 80 ° C. 43.9 g (60%) of 2 - [(3'-sulfamoyl-4'-chloro) -benzoyl] -amino-1,2,3,4-tetrahydroisoquinoline are obtained, m.p.
35 225—2270 C.225-22270 C.
12 DK 166777 B112 DK 166777 B1
Fremstilling af udgangsmaterialer: 14,5 g 4-chlor-3-[ (N-dimethylaminomethyliden) -sulfa-moyl]-benzoesyre (se NL-PS nr. 7.604.356) suspenderes i 50 cm3 thionyichlorid, og til suspensionen sættes 2 dråber 5 dimethylformamid, og reaktionsblandingen koges under omrøring i 2 timer. Blandingen filtreres for at få en klar opløsning, og filtratet inddampes under vacuum. Man opnår 12,7 g (82%) 4-chlor-3- [ (N-dimethylaminomethyliden) -sulfamoyl]-benzoyl-chlorid i form af hvide krystaller, der smelter ved 140°C.Preparation of starting materials: 14.5 g of 4-chloro-3- [(N-dimethylaminomethylidene) sulfamoyl] benzoic acid (see NL-PS No. 7,604,356) are suspended in 50 cm 3 of thionyl chloride and 2 drops are added to the suspension. 5 dimethylformamide and the reaction mixture is boiled under stirring for 2 hours. The mixture is filtered to obtain a clear solution and the filtrate is evaporated under vacuum. 12.7 g (82%) of 4-chloro-3- [(N-dimethylaminomethylidene) sulfamoyl] -benzoyl chloride is obtained as white crystals melting at 140 ° C.
10 Efter omkrystallisation fra benzen er smeltepunktet 154-155 °C.After recrystallization from benzene, the melting point is 154-155 ° C.
Analyse for formlen C10H10C12N2°3S:Analysis for Formula C10H10C12N2 ° 3S:
Beregnet: C 38,84%, H 3,26%, N 9,06%, Cl 22,93:, S 10,37% Fundet: C 38,28%, H 3,07%, N 8,94%, Cl 23,14%, S 10,58% 15 EKSEMPEL 6 8,27 g 2-amino-l,2,3,4-tetrahydro-isoquinolin suspenderes i 25 cm3 pyridin, og der tilsættes til suspensionen 17,25 g 4-chlor-3-[(N-dimethylaminomethyliden)-sulfamoyl]-20 benzoylchlorid, og reaktionsblandingen opvarmes til 60-70“C, og der opnås en gul opløsning. Den tykke, gule opløsning får lov til at stå natten over, og næste dag tilsættes 200 cm3 vand. Der udskilles et gult gummi, som sønderdeles efter få minutters omrøring til et beige pulver. Produktet fra-25 suges, vaskes med vand og tørres. 21 g rå produkt hydrolyseres som beskrevet i eksempel 5 med 143 cm3 2 N natriumhydroxidopløsning. Der opnås 15,4 g (75%) 2-[(3'-sulfamoyl-4-chlor-benzoyl)-amino]-1,2,3,4-tetrahydro-isoquinolin, smp. 225-227°C.Calcd: C 38.84%, H 3.26%, N 9.06%, Cl 22.93:, S 10.37% Found: C 38.28%, H 3.07%, N 8.94% EXAMPLE 6 8.27 g of 2-amino-1,2,3,4-tetrahydroisoquinoline are suspended in 25 cm 3 of pyridine and 17.25 g of 4 are added to the suspension. -chloro-3 - [(N-dimethylaminomethylidene) -sulfamoyl] -20 benzoyl chloride and the reaction mixture is heated to 60-70 ° C and a yellow solution is obtained. The thick yellow solution is allowed to stand overnight and the next day 200 cm3 of water is added. A yellow rubber is excreted, which after a few minutes is stirred to a beige powder. The product is removed by suction, washed with water and dried. 21 g of crude product is hydrolyzed as described in Example 5 with 143 cc of 2 N sodium hydroxide solution. 15.4 g (75%) of 2 - [(3'-sulfamoyl-4-chloro-benzoyl) -amino] -1,2,3,4-tetrahydroisoquinoline are obtained, m.p. 225-227 ° C.
- 30 EKSEMPEL 7EXAMPLE 7
Der gås frem som beskrevet i eksempel 4 med undtagelse af, at reaktionen gennemføres i 350 cm3 i en 2:1 blanding af ethanol og vand.Proceed as described in Example 4 except that the reaction is carried out in 350 cc in a 2: 1 mixture of ethanol and water.
35 13 DK 166777 B135 13 DK 166777 B1
Forsøg med saliduretiske forbindelser i rotterExperiments with saliduretic compounds in rats
Man foretager screeningforsøg med hanrotter tilhørende LATI CFY-stammen med en gennemsnitsvægt på 240 g. Dyrene får standardrotteernæring. 16 timer før eksperimentet frata-5 ges dyrene ernæringen, men væskeindtagelsen begrænses ikke.Screening experiments are performed with male rats belonging to the LATI CFY strain with an average weight of 240 g. The animals are fed standard rat nutrition. About 16 hours before the experiment, the animals are deprived of nutrition, but fluid intake is not restricted.
For at vise diuretisk aktivitet anvendes fremgangsmåden af Lipschitznek, modificeret af Kagawa og Kalm (Arch. Pharma-codyn. 137. side 241-9 (1962)). Dyrene placeres i et metabolismebur. Urinopsamlingen foretages i perioder på 0-6 og 0-10 24 timer. Kontroldyrene indgives 25 cm3/kg fysiologisk salt opløsning gennem en mavesonde. Forsøgssubstansen indgives til dyrene gennem en mavesonde i en dosis af 5 mg/kg i en fysiologisk saltopløsning i en mængde svarende til den mængde fysiologisk saltopløsning, der gives til kontroldyrene.To show diuretic activity, the method of Lipschitznek, modified by Kagawa and Kalm (Arch. Pharma Code 137, pp. 241-9 (1962)) is used. The animals are placed in a metabolism cage. Urine collection is performed for periods of 0-6 and 0-10 24 hours. The control animals are administered 25 cc / kg of physiological saline solution through a gastric tube. The test substance is administered to the animals through a gastric tube at a dose of 5 mg / kg in a physiological saline solution in an amount equal to the amount of physiological saline solution administered to the control animals.
15 Efter 6 timers forløb indgives dyrene gennem en mavesonde samme mængde fysiologisk saltopløsning som det indenfor 0-6 timer udskilte volumen.After 6 hours, the animals are administered through a stomach probe the same amount of physiological saline solution as the volume separated within 0-6 hours.
Mængden af udskilt urin mellem 0-6 og 0-24 timer måles og beregnes sammen med koncentrationen af natrium og 20 kalium, og Na/K-forholdet i den udskilte urin inden for en given periode.The amount of urine excreted between 0-6 and 0-24 hours is measured and calculated together with the sodium and potassium concentration and the Na / K ratio of the excreted urine within a given period.
Samtidigt med hvert enkelt forsøg behandles kontrolgrupper med en fysiologisk saltopløsning og hypothiazid.At the same time with each trial, control groups were treated with a physiological saline solution and hypothiazide.
25 Virkningen af en enkelt oral dosis på 5 mg/kg af forbindelserne på udskillelsen af vand, natrium og kalium inden for 0-6 og 0-24 timer i % af de samtidigt målte kontrolværdier og på det udskilte Na/K.The effect of a single oral dose of 5 mg / kg of the compounds on the excretion of water, sodium and potassium within 0-6 and 0-24 hours in% of the simultaneously measured control values and on the separated Na / K.
iflg. Vand Na K Na/Kacc. Water Na K Na / K
30 eksempel 0-6 0-24 0-6 0-24 0-6 0-24 0-6 0-24 nr. timer timer timer timer30 Example 0-6 0-24 0-6 0-24 0-6 0-24 0-6 0-24 No. hours hours hours hours
Kontrol 100 100 100 100 100 100 1,81 2,45 35 1. 216 148 260 152 145 82 9,09 5,94 2. 233 154 279 151 170 100 7,56 5,38 3. 147 112 186 121 104 84 4,74 3,99Control 100 100 100 100 100 100 1.81 2.45 35 1. 216 148 260 152 145 82 9.09 5.94 2. 233 154 279 151 170 100 7.56 5.38 3. 147 112 186 121 104 84 4.74 3.99
Hypothiazid 159 119 187 123 117 109 3,90 3,50Hypothiazide 159 119 187 123 117 109 3.90 3.50
Claims (3)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU876123A HU199925B (en) | 1987-12-30 | 1987-12-30 | Multiple-purpose spatial lattice system |
| HU612387 | 1987-12-30 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK727388D0 DK727388D0 (en) | 1988-12-29 |
| DK727388A DK727388A (en) | 1989-07-01 |
| DK166777B1 true DK166777B1 (en) | 1993-07-12 |
Family
ID=10971237
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK727388A DK166777B1 (en) | 1987-12-30 | 1988-12-29 | 2- (SUBSTITUTED BENZOYL) -AMINO-1,2,3,4-TETRAHYDROISOQUINOLINE DERIVATIVES, PROCEDURES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATION CONTAINING THEM. |
Country Status (2)
| Country | Link |
|---|---|
| DK (1) | DK166777B1 (en) |
| HU (1) | HU199925B (en) |
-
1987
- 1987-12-30 HU HU876123A patent/HU199925B/en not_active IP Right Cessation
-
1988
- 1988-12-29 DK DK727388A patent/DK166777B1/en active
Also Published As
| Publication number | Publication date |
|---|---|
| DK727388D0 (en) | 1988-12-29 |
| DK727388A (en) | 1989-07-01 |
| HUT48812A (en) | 1989-07-28 |
| HU199925B (en) | 1990-03-28 |
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