The Upjohn Co.

Martin Gall

Jackson B Hester, Jr

John R Palmer

Donald J Cram

Michael F Lipton

Robert I Higuchi

Amino-9,10-secosteroids useful for treating head injury, spinal cord

The present invention provides certain aminoalkyl and aminoalkenyl triazoles which are useful as anti-psychotics. Certain of these aminoalkyl triazoles were previously known as anti-allergy agents.

Aminoalkyl and aminoalkenyl triazoles as anti-psychotic agents

The present invention provides novel 4-phenyl-triazol-3-yl- and 3-phenyl-triazol-4-yl-piperidines which are useful as analgesics.

4H-1,2,4-Triazol-3-yl compounds

An improved process for preparing a 1-aminomethyl-6-substituted-4H-s-triazolo[4,3-a][1,4]benzodiazepine product, e.g., adinazolam, directly from the corresponding 1-hydrogen-6-substituted-4H-s-triazolo[4,3-a][1,4]benzodiazepine starting material, e.g., from estazolam, by conducting the reaction between the estazolam-type compound and the dimethylaminomethylene salt in the selected solvent in the presence of an alkali metal carbonate, and thereafter extracting the 1-aminomethyl-6-substituted-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine from an aqueous organic solvent mixture thereof into a halogenated C.sub.1 to C.sub.3 -alkane solvent while maintaining the pH of the aqueous phase between pH 3.0 and 4.0, and thereafter recovering the product from the halogenated alkane solvent.

Preparing

The present invention provides certain substituted-piperazinyl-1,2,4-triazoles which are useful for the treatment of sensitized humans for allergies and anaphylactic reactions.

Substituted piperazinyl-1,2,4-triazoles

Aminoalkyl-substituted imidazoles

The present invention provides certain piperazinyl-substituted imidazoles which are useful for the treatment of sensitized humans for allergies and anaphylactic reactions.

Piperazinyl-substituted imidazoles

Novel aminoalkyl triazoles are provided which are useful for the treatment of sensitized humans and animals for allergies and anaphylactic reactions. Additionally, a number of the compounds are useful in the treatment of hypertension. These compounds are of the formula ##STR1## wherein R.sub.4 is hydrogen, alkyl, alkoxy, aryl, sulfonyl, or sulfinyl, R.sub.5 is aryl, R.sub.6 is hydrogen, hydroxy, alkyl, alkoxy, or alkanoyloxy, and R.sub.1 is piperidinyl or amino.

Aminoalkyl-1,2,4-triazoles

3-Substituted 4-(.alpha.-amino-.alpha.-phenyl-o-tolyl)-4H-1,2,4-triazoles, 2-substituted 1-(.alpha.amino-.alpha.-phenyl-o-tolyl)imidazoles, pharmacologically acceptable acid addition salts thereof and processes for their production. The compounds of this invention and the pharmacologically acceptable acid addition salts thereof are useful as sedatives, hypnotics, anticonvulsants, tranquilizers, and muscle relaxants. They are also useful as feed additives for increasing growth rate and feed efficiency of livestock and poultry.

1-(.alpha.-Amino-.alpha.-phenyl-o-tolyl)imidazoles

Compounds of the formula I: ##STR1## wherein R.sub.1 is hydroxymethyl, or -CH.sub.2 NR.sub.6 R.sub.7, in which R.sub.6 is -CH.sub.2 -C.tbd.CH, -CH.sub.2 -CH=CH.sub.2, ##STR2## or alkyl of 1 to 3 carbon atoms, inclusive; R.sub.7 is hydrogen or alkyl of 1 to 3 carbon atoms, or together ##STR3## is pyrrolidino, piperidino or morpholino; wherein R.sub.2 is hydrogen, chlorine or fluorine; wherein R.sub.3 is hydrogen, or fluorine if R.sub.2 is fluorine; wherein R.sub.4 is hydrogen, fluorine, chlorine, bromine, nitro, or trifluoromethyl; and wherein R.sub.5 is hydrogen, methyl or ethyl. These compounds, except those in which R.sub.7 is hydrogen, are produced by heating a compound of formula II: ##STR4## wherein R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are defined as hereinabove, and wherein R'.sub.1 is the same as R.sub.1 except that in defining R'.sub.1,R.sub.7 may not be hydrogen, with aqueous formaldehyde in formic acid solution at reflux temperature (about 100.degree. C.). Compounds in which R.sub.7 are hydrogen require steps further shown in the specification. The compounds of formula I and their pharmacologically acceptable acid addition salts thereof have tranquilizing, anti-anxiety and anti-convulsant activity useful for the treatment of animals and man.

[3-Substituted-5-[(di-methylamino)methyl]-4H-1,2,4-triazol-

Compounds of the formula III ##STR1## wherein R.sub.1 is hydrogen or methyl; wherein R.sub.2 is hydrogen, fluoro, chloro, bromo, trifluoromethyl, or nitro; and wherein Ar is phenyl, o-chlorophenyl, o-fluorophenyl, o,o-difluorophenyl, or 2-pyridyl, are produced by a two-step process. The compounds of formula III as well as their pharmacologically acceptable acid addition salts thereof are antidepressant agents possessing additionally antianxiety activity. Thus these compounds III are useful in the treatment of anxieties in mammals and birds, and also as anti-depressants in man.

1-[(Dimethylamino)-methyl]-6-aryl-4H-imidazo[1,5-a][1,4]benzodiazepines

A process for the preparation of 1-[(dimethylamino)-methyl]-6-substituted-4H-imidazo[1,2-a][1,4]benzodiazep ine which comprises the reaction of a 6-phenyl-4H-imidazo-[1,2-a][1,4]benzodiazepine with the reagent ##STR1## wherein X.sup.- signifies the anion of a monovalent acid.

Process for the production of

A process for the preparation of 1-[(dimethylamino)methyl]-6-substituted-4H-s-triazolo[4,3-a][1,4]benzodiaz epine which comprises the reaction of a 4H-s-triazolo[4,3-a][1,4]benzodiazepine with the reagent ##STR1## wherein X.sup.- signifies the anion of a monovalent acid.

Compounds of the formulae IV and V: ##SPC1## wherein R.sub.0 and R.sub.1 are hydrogen or alkyl of 1 to 3 carbon atoms, inclusive; wherein R.sub.2 is hydrogen, fluoro, chloro, or trifluoromethyl; wherein R.sub.3 is hydrogen or fluoro with the proviso that R.sub.3 cannot be fluoro, if R.sub.2 is chloro or trifluoromethyl; and wherein R.sub.4 is hydrogen, fluoro, chloro, bromo, trifluoromethyl, or nitro, are obtained by a multi-step reaction from the corresponding .alpha.-(phenyl)-o-toluidine of the formula I: ##SPC2## wherein R.sub.2, R.sub.3, and R.sub.4 are defined as above, by treating I in sequence with an alkyl ester of orthoformic acid the resulting product with 2-alkyl-2-(aminoalkyl)-1,3-dioxolane or a 2-amino-alkanone dialkyl ketal and finally with titanium tetrachloride to obtain compound IV, and oxidizing compound IV to obtain the corresponding compound V.

1-(.alpha.-Phenyl-o-tolyl)imidazoles

8-Bromo-1-[(dimethylamino)methyl]-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzo diazepine of the formula: ##SPC1## Is prepared, which compound has anti-depressant, anti-convulsant, and anti-anxiety activities and is particularly useful in mammals to combat depression and anxieties.

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Kalamazoo, MI, United States of America

Martin Gall