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The addition of organometallic reagents to the 13b-position of the indolo[2′,3′:3,4]pyrido[1,2-b]isoquinoline imminium salt 4 is described. Reaction of 4 with tetraallyl tin in 2-methoxyethanol gave the allyl adduct 7 in moderate yield. Further elaboration of 7 yielded the pentacyclic benzylidene alcohols 13 and 14. Structure elucidation of the compounds prepared was achieved by a combination of 1H nmr spec troscopy and X-ray crystallography.

The preparation of several novel 5-hydroxyindole-2-carboxamides is described. A 5-benzyloxyindole ester was elaborated to the 3-bromo, 3-hydroxy, and 3-alkoxy ester intermediates followed by conversion to the amide and debenzylation. A related 5-acetyloxy indole ester was converted to 3-sulfinyl and 3-alkylthio intermediates before simultaneous amidation and removal of the 5-hydroxy protecting group.

The preparation of pyrimidine analogs of the 2,6-di-tert-butylphenol antiinflammatory agents Prifelone (R-830), Tebufelone (NE-11740) and Ym-13,162 is described. Grignard addition to the N-methoxy-N-methylamide derived from 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinecarboxylic acid yielded a series of 2-pyrimidinyl ketones. Further elaboration of an ethyl ketone and cyclization with sodium cyanate gave a pyrimidinylimidazole.

The preparation of a series of analogs of 2,6-di-tert-butylphenol linked to a 1,3,4-oxadiazole or 1,3,4-thiadiazole via an ethylene or methyleneoxy spacer is discussed.

A series of styrylpyrazoles, styrylisoxazoles, and styrylisothiazoles were prepared and found to be dual inhibitors of 5-lipoxygenase and cyclooxygenase in rat basophilic leukemia cells. Compounds from this series also were found to inhibit the in vivo production of LTB4 when dosed orally in rats. Among these compounds, di-tert-butylphenols 19 and 33 exhibit oral activity in various models of inflammation and, most importantly, are devoid of ulcerogenic potential.

The synthesis and antiallergic activity of a series of novel thiophene-, pyrrole-, furan-, and benzenecarboxamidotetrazoles are described. A number of compounds inhibit the release of histamine from anti-IgE-stimulated human basophils. Optimal inhibition is exhibited in compounds with a 3-alkoxy, a 4-halo, and a 5-methyl, 5-methoxy, or 5-bromo on a thiophene-2-carboxamidotetrazole.

(Thiazolylethenyl)phenols were prepared as potential antiinflammatories by reaction of thiazole 4- and 5-acetic acid derivatives with 3,5-di-tert-butyl-4-hydroxybenzaldehyde. Alternatively, an arylethenyl methyl ketone was brominated and the bromoketone product reacted with methyl dithiocarbamate, ammonium dithiocarbamate, or thiourea.

The preparation of 1,2,4-thiadiazoles with a di-tert-butylphenol substituent at the thiadiazole 3-position is described. A thermally generated nitrile sulfide was reacted with tosyl cyanide in a 1,3-dipolar cyclization reaction to provide a thiadiazole intermediate containing a labile 5-tosyl substituent.

A series of 1,2,4-oxadiazoles and 1,2,4-thiadiazoles containing a 2,6-di-tert-butylphenol substituent were prepared and evaluated as dual inhibitors of 5-lipoxygenase and cyclooxygenase in rat basophilic leukemia (RBL-1) cells. Several of these compounds show oral efficacy in the rat carrageenan footpad edema (CFE) and mycobacterium footpad edema (MFE) antiinflammatory models, without concomitant gastric ulceration. Structure-activity relationships are discussed. The best compounds (ID40 values in MFE of 3-8 mg/kg po) contain guanidine-derived substituents on the heterocyclic ring.

A variety of benzylideneoxazoles, -thiazoles, and -imidazoles derived from 2,6-di-tert-butylphenol were prepared and evaluated as dual inhibitors of 5-lipoxygenase and cyclooxygenase in rat basophilic leukemia (RBL-1) cells. The target compounds exhibit varying degrees of selectivity toward the two enzymes. Several compounds are orally active in the rat carageenan footpad edema (CFE) and mycobacterium footpad edema (MFE) antiinflammatory models. Structure-activity relationships are discussed. From this work, (Z)-5-[[3,5-bis(1,1-dimethylethyl)-4- hydroxyphenyl]-methylene]-2-imino-4-thiazolidinone methanesulfonate salt (CI-1004) was identified as a potent dual inhibitor of 5-lipoxygenase (IC50 = 0.77 microM) and cyclooxygenase (IC50 = 0.39 microM), with oral activity (ID40 = 0.6 mg/kg) in the rat MFE model of inflammation.

The preparation of a series of analogs of 2,6-di-tert-butylphenol linked to a 1,3,4-oxadiazole or 1,3,4-thiadiazole via an ethylene or methyleneoxy spacer is discussed.

The preparation of several novel 5-hydroxyindole-2-carboxamides is described. A 5-benzyloxyindole ester was elaborated to the 3-bromo, 3-hydroxy, and 3-alkoxy ester intermediates followed by conversion to the amide and debenzylation. A related 5-acetyloxy indole ester was converted to 3-sulfinyl and 3-alkylthio intermediates before simultaneous amidation and removal of the 5-hydroxy protecting group.

(Thiazolylethenyl)phenols were prepared as potential antiinflammatories by reaction of thiazole 4- and 5-acetic acid derivatives with 3,5-di-tert-butyl-4-hydroxybenzaldehyde. Alternatively, an arylethenyl methyl ketone was brominated and the bromoketone product reacted with methyl dithiocarbamate, ammonium dithiocarbamate, or thiourea.

A new synthetic protocol has been developed to provide entry into a series of novel tricyclic aryltriazole‐3‐thiones analogs. The classical reaction conditions of subjecting an arylhydrazide with thiophosgene to form the thioisocyanate intermediate and ultimately the corresponding aryltriazole‐3‐thione framework were not successful. However, using a combination of carbon disulfide and 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) to form the thioisocyanate intermediate was found to produce the novel tricyclic aryltriazole‐3‐thiones (5, 8a–c) in good yield.

The preparation of 1,2,4-thiadiazoles with a di-tert-butylphenol substituent at the thiadiazole 3-position is described. A thermally generated nitrile sulfide was reacted with tosyl cyanide in a 1,3-dipolar cyclization reaction to provide a thiadiazole intermediate containing a labile 5-tosyl substituent.

The addition of organometallic reagents to the 13b-position of the indolo[2′,3′:3,4]pyrido[1,2-b]isoquinoline imminium salt 4 is described. Reaction of 4 with tetraallyl tin in 2-methoxyethanol gave the allyl adduct 7 in moderate yield. Further elaboration of 7 yielded the pentacyclic benzylidene alcohols 13 and 14. Structure elucidation of the compounds prepared was achieved by a combination of 1H nmr spec troscopy and X-ray crystallography.

The synthesis of pyridine N-oxide substituted chromones, chromanones, coumarins, quinolines, dihydroquinolines and cinnolines from l-(2-hydroxyphenyl)-2-(2-pyridinyl)ethanone N-oxide, 1-(2-aminophenyl)-2-(2-pyridinyl)ethanone N-oxide and 1-[2-(methylamino)phenyl]-2-(2-pyri-dinyl)ethanone N-oxide is described.

Methods for the synthesis of 3-[2-aminoethyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-ones and 3-[2-aminopropyl]-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-ones are described. The scope and limitations of the various methods are discussed.

3-Aminochromone and 3-aminocoumarin were condensed with diethyl ethoxymethylenemalonate and with dimethyl acetylenedicarboxylate to give intermediates, which were thermally cyclized to give 4,10-dihydro-4,10-dioxo-lH-[1]-benzopyrano[3,2-b]pyridinecarboxylates and 1,5-dihydro-1,5-dioxo-4H-[1]-benzopyrano-[3,4-b]pyridinecarboxylates. 2-Aminochromone was converted to 4,5-dihydro-4,5-dioxo-1H-[1]-benzopyrano-[2,3-b]pyridinecarboxylate via an intermediate condensation product with diethyl ethoxymethylenemalonate. These esters were hydrolyzed to the corresponding carboxylic acids (21, 30, 36, 50, and 60). Attempts to prepare 4,5-dihydro-4,5-dioxo-1H-[1]-benzopyrano[4,3-b]pyridinecarboxylates from 4-aminocoumarin were unsuccessful.

The synthesis of novel indole-2-carboxylic acids with amino- and sulfur-containing substituents in the indole 3-position is described. An Ullmann reaction with bromobenzene converted 1H-indoles with 3-(acetylamino)- and 3-(diethylamino)-substituents into 1-phenyl-1H-indoles. Reaction of 3-unsubstituted indoles with thionyl chloride provided indole 3-sulfinyl chlorides, which reacted with alkyl and aryl Grignard reagents to form the corresponding sulfoxides. The indole sulfoxides thus obtained were reduced to sulfides or oxidized to sulfones.

A general synthesis of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]-thieno[3,2-d]pyrimidines is described. Methyl tetrahydro-4-oxo-3-thiophenecarboxylate (13) was condensed with 6-aminonicotinic acid (18) to give 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (19). Treatment of 19 successively with chlorotrimethylsilane, N-chlorosuccinimide and water gave 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid (17). Methyl tetrahydro-3-oxo-2-thiophenecarboxylate (21) was converted to 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid (25) by an analogous route.

Methods for the synthesis of novel 3-hydroxy, 3-alkoxy, and 3-alkyl indole-2-carboxylic acids and esters are described. Dieckmann cyclization of various 2-[(carboxymethyl)amino]benzoic acid diesters yielded 1-unsubstituted-, 1-methyl-, and 1-phenyl-3-hydroxy-1H-indole-2-carboxylic acid esters. An Ullmann reaction with bromobenzene converted 1H-indoles to 1-phenylindoles.

The treatment of ketosulfoxide 1 with phosgene in pyridine gave a mixture of 1-(4-hydroxy-8-methoxy-2-oxo-2H-1-benzopyran-3-yl)pyridinium hydroxide inner salt (4) and 7-methoxy-2-(methylthio)-3-(2H)benzofuranone (7). Ketosulfoxides 8 and 11 behaved similarly. The inner salt structure assigned to compounds 4, 10, and 13 was confirmed by the unambiguous synthesis of 10 and 13 from hydroxycoumarins 15 and 18.

A series of 2,3,4,6-tetrahydro-8,9-dimethoxybenzo[c][2,7]naphthyridin-5(1H)-ones was prepared as potential anticholinergic bronchodilators. The naphthyridine ring system was constructed by cyclization of a 3-amido-4-piperidone. Alkylation with alkylaminoethyl chlorides or reductive amination of an intermediate methyl ketone yielded the final target compounds.

The reaction of 2-picoline N-Oxide anion with o-substituted henzoates and isatoic anhydrides to give synthetically useful l-(2-methoxyphenyl)-2-(2-pyridinyl)ethanone N-oxides, I-(2-hydroxy-phenyJ)-2-(2-pyridinyl)ethanone N-oxides and I -(2-arninopheny])-2-(2-pyridinyl)ethanone N-oxides is described.

Synthesis of 1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-ones via a Pechmann condensation of 3-carbethoxy-1-methyl-4-piperidone with various phenols is described. The limitations of this method are discussed. Synthesis of the parent ring system 3a via reduction of 1,2,3,4-tetrahydro-3-(phenylmethyl)-8-[(1-phenyl-1H-tetrazol-5-yl)oxy]-5H-[1]benzopyrano[3,4-c]pyridin-5-one (5) is also described.

The reaction of 1-methyl-3-(methylsulfinyl)-4(1H)quinolinone (1) with acetic anhydride and thionyl chloride gave 3-[[(acetyloxy)methyl]thio]]-1-methyl-4(1H)quinolinone (2) and 3-[(chloromethyl)thio]-1-methyl-4(1H)quinolinone (3) respectively. 3-(Methylsulfinyl)-4(1H)cinnolinone (4) gave the corresponding products when treated under similar conditions. Treatment of 8-methoxy-3-(methylsulfinyl)-4H-1-benzopyran-4-one (11) with acetic anhydride and thionyl chloride gave bis addition vinyl Pummerer products 2,3-bis(acetyloxy)-2,3-dihydro-8-methoxy-3-(methylthio)-4H-1-benzopyran-4-one (12) and 2,3-dichloro-2,3-dihydro-8-methoxy-3-(methylthio)-4H-1-benzopyran-4-one (13), respectively.

Synthesis and antiallergy activity of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines (2 and 3) and 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines (4 and 5) are described. The activity, shown by these compounds in the rat passive cutaneous anaphylaxis (PCA) test, is compared to the PCA data previously reported for a series of 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidines. 10-Oxo-N-1H-tetrazol-5-yl-10H-pyrido[1,2-a]thieno[3,4-d]pyri midine (2b), 10-oxo-7-(1H-tetrazol-5-yl)-10H-pyrido[1,2-a]thieno[3,4-d]py rimidine (4e), and 3,10-dihydro-10-oxo-7-(1H-tetrazol-5-yl)-1H-pyrido[1,2-a]thieno[3, 4-d] pyrimidine (7e) gave a 100% inhibition in the rat PCA test at a dose of 5 mg/kg. The activity displayed by these compounds is comparable to that of the most active compounds in the 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine series.

A series of 2,3,4,6-tetrahydro-8,9-dimethoxybenzo[c][2,7]naphthyridin-5(1H)-ones was prepared as potential anticholinergic bronchodilators. The naphthyridine ring system was constructed by cyclization of a 3-amido-4-piperidone. Alkylation with alkylaminoethyl chlorides or reductive amination of an intermediate methyl ketone yielded the final target compounds.

Ambruticin (I) wird auf den im Formelschema skizzierten Wegen in Analoga (II)-(XII) umgewandelt.

A series of 3-(aminoalkyl)benzopyrano[3,4-c]pyridin-5-ones was prepared and tested as potential orally active anticholinergic bronchodilators. Inhibition of methacholine-induced collapse in guinea pigs and inhibition of pilocarpine-induced bronchoconstriction in dogs served as in vivo models. Simultaneous measurement of salivary inhibition in the dog model allowed determination of a pulmonary selectivity ratio. The benzopyrano[3,4-c]pyridin-5-one parent ring system was prepared by Pechman condensation of phenols with a piperidine beta-keto ester. Alkylation with aminoalkyl halides, or with 1-chloro-2-propanone followed by reductive amination, yielded the 3-substituted target compounds. Bronchodilator potency was related to the extent of steric crowding surrounding the side-chain terminal amine function. Addition of a methyl substituent on the carbon alpha to the terminal amine often increased potency or pulmonary selectivity. After secondary pharmacological evaluation, compound 7a, designated CI-923, was selected for clinical trial as a bronchodilator.

The synthesis and antiallergic potential of a series of novel indolecarboxamidotetrazoles are described. A number of compounds inhibit the release of histamine from anti-IgE-stimulated basophilic leukocytes obtained from allergic donors. Optimal inhibition is exhibited by compounds with 3-alkoxy, 5-methoxy, and 1-phenyl substituents on the indole core structure. Compound 8d (5-methoxy-3-(1-methylethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H -indole-2-carboxamide; designated CI-949) is a potent inhibitor of histamine release from human basophils and from guinea pig and human chopped lung.

Aus dem 2-Hydroxy-1-methylsulfinylacetyl-benzol (I) erhalt man unter Ruckflus in Gegenwart von Trifluoressigsaure unter Annahme der Zwischenstufe (II),das Benzofuranon (III).

Die Kondensation des Amino-thiophenesters (I) mit den Nicotinsaurederivaten (II) fuhrt zu den 4-Oxo-pyrido[1,2-a]thieno[2,3-d]pyrimidinen (IIIa)-(IIIC), die in die Derivate (IIId)-(IIIf) und (V) ubergefuhrt werden.

Sulfoxides (1 and 10) gave oxidation-reduction products when treated with 5N hydrochloric acid. 8-Methoxy-3-(methylsulfinyl)-4H-benzopyran-4-one (1) gave 8-methoxy-3-(methylthio)-4H-1-benisopyran-4-one (4) and 8-methoxy-3-(methylsulfonyl)-4H-1-benzopyran-4-one (5), whereas 1-melhyl-3-(methylsulfinyl)-4(1H)quinolinone (10) gave 1-methyl-3-(methylthio)-4(1H)-quinolinone (12) and 1-methyl-4(1H)-quinolinone (13).