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Details for Patent: 4,349,475

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Details for Patent: 4,349,475

Title: Process for producing imidazodiazepines
Abstract:This invention is directed toward pharmacologically active compound of the formula ##STR1## wherein A is ##STR2## R.sub.1 is selected from the group consisting of hydrogen, lower alkyl, hydroxy lower alkyl, acyloxy lower alkyl, phenyl, alkoxy lower alkyl, halo lower alkyl, amino lower alkyl, substituted amino lower alkyl, substituted phenyl, pyridyl, aralkyl and the groups ##STR3## wherein R is hydrogen or lower alkyl and ROOC where R is lower alkyl; R.sub.2 is selected from the group consisting of hydrogen, lower alkyl, hydroxy lower alkyl, acyloxy lower alkyl, alkoxy lower alkyl, halo lower alkyl, amino or substituted amino lower alkyl, amino, cyano, cyano lower alkyl, substituted amino, chloro, bromo and iodo, the group --COOR where R is hydrogen or lower alkyl, the group ##STR4## where R is hydrogen or lower alkyl, or derivatives thereof, e.g., the group R--C.dbd.N--R' wherein R' is hydrogen, lower alkyl, hydroxy, phenyl, alkoxy, amino, mono or di-alkylamino and arylamino and R is hydrogen or lower alkyl, the group ##STR5## (where R and R' are individually hydrogen, lower alkyl, hydroxy lower alkyl, lower alkenyl, aryl or together R and R' form a part of a heterocyclic ring and the group (CH.sub.2).sub.n NRR' where R and R' are hydrogen, lower alkyl, hydroxy lower alkyl, lower alkenyl or together R and R' form a part of a heterocyclic ring and n is 1 to 4); the group ##STR6## where R.sup.10, R.sup.11, R.sup.12 are hydrogen or lower alkyl and the group (CH.sub.2).sub.n NR.sup.13 R.sup.14 where n is 1 to 4 and R.sup.13, R.sup.14 are hydrogen, lower alkyl, hydroxy lower alkyl, lower alkenyl or R.sup.13 and R.sup.14 together form part of a heterocyclic ring, with the limitation that where R.sup.10, R.sup.11 or R.sup.12 is a basic side chain, then the remaining substituents are hydrogen or lower alkyl; R.sub.3 is selected from the group consisting of hydrogen and lower alkyl; R.sub.5 is selected from the group consisting of hydrogen, lower alkanoyloxy and hydroxy; R.sub.4 is selected from the group consisting of hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, hydroxy lower alkyl and lower alkanoyl; R.sub.6 is selected from the group consisting of phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl and mono-substituted pyridyl; and ##STR7## is selected from the group consisting of ##STR8## and the pharmaceutically acceptable salts thereof. Also provided are methods for the preparation of these compounds as well as pharmaceutical formulations which contain the active compounds of this invention. The compounds of the formulas illustrated above and their analogs are useful as anticonvulsants, muscle relaxants, anxiolytic and sedative agents.
Inventor(s): Walser; Armin (West Caldwell, NJ), Fryer; Rodney I. (North Caldwell, NJ)
Assignee: Hoffmann-La Roche Inc. (Nutley, NJ)
Filing Date:Mar 12, 1981
Application Number:06/242,945
Claims:1. A process to produce a compound of the formula ##STR95## wherein A is ##STR96## R.sub.1 is selected from the group consisting of hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, pyridyl, and tolyl; R.sub.2 is selected from the group consisting of hydrogen or lower alkyl; R.sub.3 is selected from the group consisting of hydrogen or lower alkyl; R.sub.4 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, lower alkyl, mono- or di- C.sub.1 to C.sub.7 alkyl or phenyl, chlorophenyl or tolyl substituted amino, amino, hydroxy lower alkyl and lower alkanoyl; R.sub.6 is selected from the group consisting of phenyl, mono-halo substituted phenyl, di-halo substituted phenyl, pyridyl and mono-halo substituted pyridyl; and ##STR97## is selected from the group consisting of ##STR98## which comprises the following steps in combination (a) reacting a compound of the formula ##STR99## wherein A is selected from the group consisting of ##STR100## wherein R.sub.3, R.sub.4, R.sub.6 and ##STR101## are as above; with a compound selected from the group consisting of alkali metal nitrites, alkyl nitrites or a nitrosyl chloride gaseous solution;

(b) condensing either the product from (a) or a compound of the formula ##STR102## wherein A, ##STR103## R.sub.4, R.sub.3, R.sub.6 are as above with a nitroalkane anion of the formula R.sub.2 --CH--NO.sub.2 wherein R.sub.2 is selected from the group consisting of hydrogen or lower alkyl;

(c) catalytically hydrogenating the product from (b) with H.sub.2 /Raney nickel or lithium aluminum hydride with limitation that A is not N-oxide;

(d) acylating the product from (c) with an acid halide or an acid anhydride of the formulas R.sub.1 COX or (R.sub.1 CO).sub.2) respectively wherein R.sub.1 is as above;

(e) cyclizing the product from (d) with a dehydrating agent selected from phosphorus pentoxide, polyphosphoric acid or an organic or inorganic acid;

(f) dehydrogenating with manganese dioxide, palladium on carbon or potassium permanganate the cyclized product of (e) to produce the final product.

2. A process for producing a compound of the formula ##STR104## wherein A is ##STR105## R.sub.1 is selected from the group consisting of hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, mono- or di-C.sub.1 to C.sub.7 alkyl or phenyl, chlorophenyl or tolyl substituted amino lower alkyl, pyridyl, and tolyl; R.sub.2 and R.sub.3 are selected from the group consisting of hydrogen, lower alkyl; R.sub.4 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, lower alkyl, mono- or di-C.sub.1 to C.sub.7 alkyl or phenyl, chlorophenyl or tolyl substituted amino, amino, hydroxy lower alkyl and lower alkanoyl; R.sub.6 is selected from the group consisting of phenyl, mono-halo substituted phenyl, di-halo substituted phenyl, pyridyl and mono-halo substituted pyridyl; and ##STR106## is selected from the group consisting of ##STR107## which comprises the following steps in combination (a) reacting a compound of the formula ##STR108## wherein ##STR109## R.sub.3, R.sub.4 and Rhd 6 are as above and A is ##STR110## with a compound selected from the group consisting of alkali metal nitrites, alkyl nitrites or a nitrosyl chloride gaseous solution;

(b) condensing the product from (a) with a nitroalkane of the formula R.sub.2 --CH.sub.2 NO.sub.2 wherein R.sub.2 is selected from the group consisting of hydrogen and lower alkyl;

(c) catalytically hydrogenating the product from (b) with H.sub.2 /Raney nickel or lithuim aluminum hydride with limitation that A is not N-oxide;

(d) acylating and spontaneously cyclizing the product from (c) with an acylating agent selected from the group consisting of orthoesters, esters, amidines, nitriles, orthoamides, ester imidates or a compound of the formula ##STR111## (e) dehydrogenating with manganese dioxide, palladium on carbon or potassium permanganate the cyclized product of (d) to produce the final product.
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Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

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