[Benzo[c][2,7]naphthyridine-5-yl-arylamines-phenol Mannich bases of the amodiaquine-, cycloquine- and pyronaridine-type]. / Benzo[c][2,7]naphthyridin-5-yl-arylamine-Phenol-Mannich-Basen vom Amodiaquin-, Cycloquin- und Pyronaridin-Typ.

2,5-Dichloro-4-methyl-benzo[c][2,7]naphthyridine (1) reacted with aromatic amines selectively by substitution at the 5-position to yield the amidines 2. The 4-aminophenol 2c could also be synthesized by cleavage of the ether 2b. The structure of 2c was proved by X-ray crystal analysis. Aminomethylation of 2c yielded the amodiaquine analogue 3. The mono- and bisaminomethylated derivatives 4 and 5 were obtained by reaction of compound 1 with phenol Mannich base hydrochlorides. Compounds 3-5 were tested in vitro for antimalarial activity using chloroquine-sensitive and resistant Plasmodium-falciparum strains. The highest activities were shown by the pyronaridine-type compounds 5a and 5b with IC50 values of approximately 200 nM.

[Benzo[c][2,7]naphthyridine-5-yl-amines and benzo[h][1,6]naphthyridine-5-yl-amines--potential antimalarials]. / Benzo[c][2,7]naphthyridin-5-yl-amine und Benzo[h][1,6]naphthyridin-5-yl-amine--Potenzielle Antimalariamittel.

The chloroimine 1a reacted with the novaldiamine-base to yield the 5-(2-methylpyrrolidinyl)-derivative 3. The 5-chloro-benzonaphthyridines 1 and 9 reacted with secondary aliphatic amines to give the amidines 5-8 and 10, while the aromatic amidines 11-14 were obtained with primary aromatic amines. Mixtures of the phenol Mannich bases 15 and 16 of the isoquine type were isolated from the aminomethylation of 13b. The amodiaquine analogues 19 and 20 were obtained from the reaction of 1b and 9a with 4-amino-2-piperidinomethyl-phenol dihydrochloride. The structure of the compounds 5a (potassium salt), 6b, 10a, 11e and 18 was proven by X-ray crystal analysis. Compounds 3, 6a-e, 7, 10a, 11a, 16, 19 and 20 were tested for in vitro antimalarial activity using a chloroquine-sensitive and -resistant Plasmodium falciparum strain. The highest activity against the sensitive strain was shown by the amodiaquine analogoue 20 with an IC50 value of 160 nM. The mixture of the isoquine derivatives 15a and 16a possessed the highest activity against the resistant strain with an IC50 value of 1100 nM.

[Thieno[3,4-c]quinoline-4-yl-amines--synthesis and investigation of activity against malaria]. / Thieno[3,4-c]chinolin-4-yl-amine--Synthese und Prüfung auf Wirksamkeit gegen Malaria.

The 4-aryl derivative 3, obtained by Suzuki cross coupling of the methyl 4-bromothiophene-3-carboxylate (2) with 2-nitrophenylboronic acid cyclizes under reductive conditions pH-dependant to yield the tricyclic hydroxamic acid 4 or the lactam 5. The chlorothieno[3,4-c]quinoline 6 was formed by reaction of the lactam 5 with P,P-dichlorophenylphosphinoxide. The amines 7-14 were synthesized from the chloroimine 6. Compounds 7a,b, 8, 9, 10b, 11, 12 and 14a, b were tested for in vitro antimalarial activity using the chloroquine sensitive 3D7 and the chloroquine resistant Plasmodium falciparum strain Dd2. The highest activity were shown by 10b with IC50 values of 130 nM and 50 nM, respectively and by 11 with IC50 values of 190 nM and 44 nM, respectively.

[Derivatives of exemestane--synthesis and evaluation of aromatase inhibition]. / Exemestan-derivate--Synthese und Prüfung auf Aromatase-Hemmung.

The irreversible aromatase inhibitor exemestane (6) reacts with nitromethane and sodium ethanolate to yield the Michael adduct 9. The aldehyde 10 is obtained by Nef reaction of the nitro compound 9 and affords the 1,4-dihydropyridine (DHP) 11 by Hantzsch reaction using methyl beta-aminocrotonate in acetic acid. The new compounds showed a reduced inhibitory potency towards aromatase (IC50 values: 9, 0.91 microM; 10, 2.5 microM; 11, 10 microM) compared to 6 (IC50 = 0.23 microM). The 1,4-DHP 11 was dehydrogenated with CAN or electrochemically (E1/2 =1.18 V) to yield the corresponding pyridine 12.

[Thieno[3,2-c]quinoline-4-yl-amines--synthesis and investigation of activity against malaria]. / Thieno[3,2-c]chinolin-4-yl-amine--Synthese und Prufung auf Wirksamkeit gegen Malaria.

Thieno[3,2-c]quinoline-4-yl-amines - synthesis and investigation of activity against malaria pH-Dependant reduction of the methyl 2-(2-nitrophenyl)thiophene-3-carboxylate 3, formed by Suzuki coupling of methyl 2-iodothiophene-3-carboxylate (2) with 2-nitrophenylboronic acid, yielded the cyclic hydroxamic acid 4 and the lactam 5, respectively. The 4-chlorothieno[3,2-c]quinoline 6 was formed from the lactam 5 by heating with POCI3/PCI5s. Melting of 6 with the novaldiamine base in phenol gave the chloroquine analogue 7, whereas the amodiaquine and the pyronaridine analogues 8 and 9 were obtained using phenol Mannich bases. The reaction of 6 with putrescine and N,N'-bis(3-aminopropyl)piperazine as spacer formed the bisquinoline derivatives 10 and 11 as well as the monosubstituted quinoline 12. In the same manner the isomeric 4-chlorothieno[2,3-c]quinoline 13 reacted to yield the quinoline-4-yl-amines 14-16. The compounds 7-12 and 14-16 were tested for in vitro growth inhibition of the malaria parasite Plasmodium falciparum. As most active compound the pyronaridine derivative 9 displayed an IC50 value of 210 nM with the chloroquine sensitive P. falciparum strain 3D7 and 750 nM with the chloroquine resistant P. falciparum strain Dd2. The N,N'-bis(3-aminopropyl)piperazine derivative 11 displayed in vivo activity in Plasmodium vinckei infected mice with an ED50 value of 30 mg/kg after i.p. administration.

[Contribution to the erythroquine and thalleioquine reaction]. / Zur Erythrochin- und Thalleiochin-Reaktion.

The 8,8'-biquinoline-5,5'-diones 2A are formed by the erythroquine and thalleioquine reaction from the 6-methoxyquinolines 1 as model compounds. The red substances 2A react with hydrochloric acid to yield the yellow biquinolinedihydrochlorides 3. The structure of 3b dihydrate is determined by X-ray crystal analysis. The redox properties of 2A are investigated by voltammetric methods.

[Annulated heterocycles from methyl 6-chloro-5-formyl-2-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3-carboxylate]. / Anellierte Heterocyclen aus 6-chlor-5-formyl-2-methyl-4-(2-nitrophenyl)-1,4- dihydropyridin-3-carbonsäuremethylester.

The pyridone 1a reacts with POCl3/DMF to yield the title compound 2a. After irradiation of 2a the enolether 3 is isolated, as shown by an X-ray structure determination. The pyridine 4 obtained by dehydrogenation of 2a leads under reductive conditions to the benzo[c][2,7]naphthyridines 5-7. The reaction of 4 with o-phenylenediamine gives the benzimidazole 8, while using 2-aminophenol or 2-aminothiophene respectively the pyrido[2,3-b[1,5]benzoxazepine 11 and the corresponding benzothiazepine 12 are obtained.

[Benzo[c][2,7]naphthyridine-2-yl-, 5-yl- and 2,5-diyl novaldiamines--synthesis and investigation of anti-malarial activity]. / Benzo[c][2,7]naphthyridin-2-yl-, 5-yl- und 2,5-diyl-novaldiamine--synthese und prüfung auf wirksamkeit gegen Malaria.

The 2,5-dichlorobenzo[c][2,7]naphthyridine 6 was synthesized starting from the 2-pyridone 1 in four or five steps, respectively. The 5-yl amine 7 and the 2,5-diyl amines 8 and 9 were isolated by the reaction of compound 6 with the novaldiamine base. Starting with the reaction of the 6-chloropyridine 3 with the novaldiamine base to yield the 6-aminopyridine 11, the 2-yl amine 13, isomeric to 7, was obtained. Compounds 7-13 were tested for in vitro antimalarial activity using a chloroquine sensitive and resistant Plasmodium falciparum strain. The highest activity was shown by 8 with IC50 values of 90 nM and 190 nM, respectively.

[Biphenyl derivatives as by-products from the synthesis of 4-aryl-4H-pyrans]. / Biphenyl-derivate als nebenprodukte der synthese von 4-aryl-4H-pyranen.

The reaction of the 1,5-diketones 1 with acetic anhydride/acetic acid in the presence of zinc chloride yields the 4-aryl-4H-pyrans 2 as main products. The annulated lactone 3 and the cyclohexene derivatives 5 are isolated as by-products. The configuration of the cyclohexanone 4a and the cyclohexenes 5 are deduced from nmr spectroscopic methods. The structure of 5b is confirmed by X-ray crystal analysis.

[Dimers from o-nitrobenzylidene acetoacetic esters]. / Dimere aus o-Nitrobenzylidenacetessigestern.

The o-nitrobenzylidene acetoacetic esters 1 dimerize in the presence of BuLi or LDA to give the cyclohexenes 2 in poor yield. Two diastereomer of 2b were isolated, whose configuration is deduced by nmr-spectroscopic methods.

[12-acyl-6,1 2-dihydro-6-phenyl-[1 ]benzofuro[2,3-c]- and -[1,5]benzothieno[2,3-c]-[1 ,5]-benzothiazepines--tetracyclic diltiazem derivatives]. / 12-Acyl-6,12-dihydro-6-phenyl-[1]benzofuro[2,3-c]- und -[1]benzothieno-[2,3-c]-[1,5]benzothiazepine--tetracyclische Diltiazem-Derivate.

The reaction of the tetracycles 1 with chloroacetylchloride yields the amides 2. The structure of 2a was proven by X-ray analysis. The amides 2 exist as diastereomers in solution because of planar chirality. From the N-chloroacetyl compounds only 2a, b could be substituted with diethylamine to give 3a, b. Reduction experiments of 3a, b with DIBAH do not afford diltiazem analogues; instead, the starting compounds la, b are formed by hydrolysis.

[Color reaction of chlorhexidine and proguanil with hypobromite]. / Zur Farbreaktion von Chlorhexidin und Proguanil mit Hypobromit.

Colour reaction of chlorhexidine and proguanil with hypobromite The antimalarial agent proguanil reacts with hypobromite to yield the red coloured (E)-3-[(4-chlorophenyl)imino]-N-isopropyl-3H-1,2,4-triazol-5-amine (6B). The structure of 6B was proven by X-ray. The red colour obtained by the test for the disinfectant chlorhexidinedihydrochloride Ph. Eur. with hypobromite is probably attributable to a corresponding chromophore.

[Benzo[h][1 ,6]naphthyridines from dimethyl 1,2-dihydro-2-(2-nitrophenyl)-pyridine-3,5-dicarboxylate]. / Benzo[h][1,6]naphthyridine aus 1,2-dihydro-2-(2-nitrophenyl)-pyridin-3,5-di-carbonsäuredimethylester.

The reaction of 2-nitrobenzaldehyde with methyl propiolate and ammonium acetate in acetic acid yields 2,6-dinor-nifedipine (1a) and as a by-product not the dimethyl 2,5-dicarboxylate isomer, but the rac. 1,2-dihydropyridine (DHP) 1b, as proven by X-ray analysis. The benzo[h][1,6]naphthyridines 4-6 are synthesized from the oxidation product 2b and the photo-product 3b. The compounds 6 represent starting materials for potential anti-malarial agents.

[Medium sized rings from alprenolol and oxprenolol]. / Mittlere Ringe aus Alprenolol und Oxprenolol.

The N-allyl derivatives 2 formed from the beta-blockers 1, were acetylated to give the esters 5. The 1,5-benzoxazacycloundecine 6a and the 1,10,5-benzodioxazacyclododecine 7a were isolated by ring closing metathesis (RCM) of 5a and 5b, respectively, using Grubbs catalyst in the presence of titanium tetraisopropanolate. Alkaline hydrolysis yielded the alcohols 6b and 7b.

[Bisbenzothieno[3,2-b: 2',3'-e]pyridines]. / Bisbenzothieno[3,2-b: 2',3'-e]pyridine.

Heating potassium 3-aminobenzo[b]thiophene-2-carboxylate (1) with ethyl propiolate or ethyl 3-ethoxyacrylate in acetic acid yielded the ethyl 2-(6,12-Dihydro-bis[1]benzothieno[3,2-b:2',3'-e]pyridin-6-yl)acetate (3) as main product and 1,4-dihydro-[1]benzothieno[3,2-b]-4-pyridone (2) as by-product. The dihydropyridine (DHP) 3 was dehydrogenated with ammonium cerium nitrate (CAN) to give the pyridine (Py) 4. The half wave potential E(1/2) = 1.64 V showed that 3 was much more stable against oxidizing agents than the reference compound nifedipine with E(1/2) = 1.15 V. Alkaline saponification of the acetic acid ester 4 did not yield the corresponding acetic acid, because decarboxylation took place to form the methylpyridine 5.

[Bromometric assay of alprenolol and oxprenolol]. / Zur bromometrischen Bestimmung von Alprenolol und Oxprenolol.

Alprenolol (1a) reacts with an excess of bromine to yield the tribromo derivative 3a by addition and monosubstitution, while applying oxprenolol (1b) the disubstituted tetrabromo derivative 2b is obtained. The N-dealkylated substance 3c was isolated as a by-product. Heating the compounds 2b and 3a with potassium hydroxide in acetone gives the 2-bromoallyl derivatives 5. Using potassium tert-butanolate the 2-propyne 7 is formed from 3a. The different colours, obtained from 1a, 1b, pindolol and propranolol with perchloric acid in acetic acid or conc. sulfuric acid, are suitable for the identification test in the European Pharmacopoeia.

[Bisbenzofuro[3,2-b: 2',3'-e]pyridines]. / Bisbenzofuro[3,2-b: 2',3'-e]pyridine.

Heating the potassium 3-enaminobenzo[b]furan-2-carboxylate 3 in acetic acid on 110 degrees C yielded the pentacyclic acetate 6. The acetic acid 7, formed by hydrolysis of the ester 6, decarboxylated easily giving 6-methyl-bis[1]benzofuro[3,2-b: 2',3'-e]pyridine (8).

[[1]Benzothieno[3,2-b]pyridin-4-yl-amine--synthesis and investigation of activity against malaria]. / [1]Benzothieno[3,2-b]pyridin-4-yl-amine--synthese und prüfung auf wirksamkeit gegen Malaria.

The ethyl 4-chlorobenzothieno[3,2-b]pyridine-3-carboxylate (2) reacted with the hydrochlorides of the mono- and bis-phenol Mannich bases 6 to yield the amodiaquine and pyronaridine analogues 9. The chloroquine analogue 10 was formed by melting 2 with the novaldiamine base (7) in phenol. The stability of the 4-aminophenols 9 was investigated by anodic oxidation using the rotating platinum electrode by means of difference pulse voltammetry. The half wave potentials were measured giving E(1/2) approximately 1.05 V. Compound 9g displayed the highest activity against the growth of the malaria parasite Plasmodium falciparum. Testing against the chloroquine sensitive 3D7 and the chloroquine resistant Dd2 strain resulted in IC50 values of 150 nM and 210 nM, respectively. Surprisingly, the 3-carbinol 4 and the 3-chloromethyl derivative 5, synthesized from the 3-carboxylic acid ester 2, reacted with the phenol Mannich base 6a and the novaldiamine base (7), respectively, to yield the 4-pyridone 8.

[Thieno[2,3-c]quinolines - synthesis and biological investigation]. / Thieno[2,3-c]chinoline - Synthese und biologische Prüfung.

pH-Dependant reduction of the methyl 3-(2-nitrophenyl)thiophene-2-carboxylate (3), obtained by Suzuki cross-coupling of the methyl 3-iodothiophene-2-carboxylate with 2-nitrophenyl boronic acid yields the cyclic hydroxamic acid 4 and the lactam 5, respectively. The lactam 5 is also formed by reacting the compound 2 with pinacolato 2-aminophenylboronate. The 4-chlorothieno[2,3-c]quinoline 6 is formed from the lactam 5 by heating with POCl3/PCl5. Melting of 6 with the novaldiamine base in phenol gives the chloroquine analogue 7, whereas the amodiaquine and the cycloquine analogues 8 and 9 are obtained using phenol Mannich bases. The hydroxamic acid 4 has a moderate effect on eicosanoid biosynthesis in human whole blood. The growth of the chloroquine resistent Plasmodium falciparum strain Dd2 is inhibited by the pyronaridine derivative 9 with an IC50 value of 650 nM.

[[1]Benzofuro[3,2-b]pyridin-4-yl-amines - synthesis and investigation of activity against malaria]. / [1]Benzofuro[3,2-b]pyridin-4-yl-amine - Synthese und Prüfung auf Wirksamkeit gegen Malaria.

The ethyl 4-chlorobenzofuro[3,2-b]pyridine-3-carboxylate (2) reacted with the hydrochlorides of the mono- and bis-phenol Mannich bases 3 to yield the amodiaquine and pyronaridine analogues 4. The chloroquine analogue 6 was formed by melting 2 with the novaldiamine base (5) in phenol. The most active compound 4c inhibited the growth of the malaria parasite Plasmodium falciparum with an IC50 of 500 nM.