Lilly Industries, Inc.

Eli Lilly and Company

Lilly, Sa

Lilly House

Terrence M Hotten

David Edward Tupper

Jiban Kumar Chakrabarti

Charles M Beasley, Jr

Charles A Bunnell

Samuel Dean Larsen

Maria I Fernandez

David J Steggles

Maria Isabel Fernandez Fernandez

David T Wong

John Fairhurst

Graham H Timms

Reba Chakrabarti

2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5]benzodiazepine, or an acid salt thereof, has pharmaceutical properties, and is of particular use in the treatment of disorders of the central nervous system. The compound has the following structure:

Process for preparing 2-methyl-thieno-benzodiazepine

Pharmaceutical compounds of the formula ##STR1## in which R.sup.1 is hydrogen or halo, and R.sup.2 is C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-6 cycloalkyl optionally substituted by 1 to 3 C.sub.1-4 alkyl groups, C.sub.3-6 cycloalkyl-C.sub.1-4 alkyl in which the cycloalkyl group is optionally substituted by 1 to 3 C.sub.1-4 alkyl groups, or optionally substituted phenyl-C.sub.1-4 alkyl; or a salt thereof. Such compounds are useful for treating a disorder of the central nervous system which is associated with the modulation of a 5-HT.sub.3 receptor.

Thienobenzodiazepine compounds

2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5]benzodiazepine, or an acid salt thereof, has pharmaceutical properties, and is of particular use in the treatment of disorders of the central nervous system. The compound has the following structure: ##STR1##

2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-�2,3-b!�1,5!benzodiazepine, or an acid salt thereof, has pharmaceutical properties, and is of particular use in the treatment of mental disorders. The compound has the following structure: ##STR1##

Mental disorders

2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno -�2,3-b!�1,5!benzodiazepine, or an acid salt thereof, has pharmaceutical properties, and is of particular use in the treatment of disorders of the central nervous system. The compound has the following structure: ##STR1##

Methods of treatment using a thieno-benzodiazepine

2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-�2,3-b!�1,5!benzodiazepine, or an acid salt thereof, has pharmaceutical properties, and is of particular use in the treatment of disorders relating to the use of psychoactive substances. The compound has the following structure: ##STR1##

Psychoactive substance disorders

The invention provides lower alcohol solvates of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno�2,3-b!�1,5!benzodiazepine (olanzapine) and a process for making such lower alcohol solvates of olanzapine. The invention provides a method for using such solvates of olanzapine to prepare substantially pure anhydrous Form I 2-methyl-thieno-benzodiazepine.

Process and solvate of 2-methyl-thieno-benzodiazepine

The invention provides lower alcohol solvates of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (olanzapine) and a process for making such lower alcohol solyates of olanzapine. The invention provides a method for using such solyates of olanzapine to prepare substantially pure anhydrous Form I 2-methyl-thieno-benzodiazepine.

2-methyl-thieno-benzodiazepine

Olanzapine, or an acid salt thereof, has pharmaceutical properties, and is of particular use in the treatment of disorders of the central nervous system. The compound has the following structure: ##STR1##

2-Methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b][1,5]benzodiazepine, or an acid salt thereof, has pharmaceutical properties, and is of particular use in the treatment of disorders of the central nervous system. The compound has the following structure: ##STR1##

Pharmaceutical thiazolo-[1,5]benzodiazepines of the formula ##STR1## in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently hydrogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, halogen, C.sub.1-4 haloalkyl, nitro, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, C.sub.1-4 alkylthio or phenylsulphonyl; in which R.sup.5 is a group of the formula formula ##STR2## where R.sup.7 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl C.sub.1-4 alkyl, benzyl or ZO--C.sub.2-6 alkyl where Z is hydrogen or an acyl group, R.sup.8 is hydrogen or C.sub.1-4 alkyl and n is 0 or 1, provided that when R.sup.7 is hydrogen n is 0; in which R.sup.6 is hydrogen, C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy or C.sub.1-4 alkylthio; and in which ##STR3## represents a thiazole ring selected from ##STR4## and acid addition salts thereof. The compounds have central nervous system activity.

Benzodiazepine compounds and their use as pharmaceuticals

A pharmaceutically-active compound of the formula ##STR1## in which R.sup.1 is C.sub.1-4 alkythio, C.sub.1-4 alkylsulphinyl or C.sub.1-4 alkylsulphonyl, R.sup.2 is C.sub.1-4 alkyl, R.sup.3 is C.sub.1-4 alkyl or C.sub.2-4 alkenyl, and X is (i) --(CH.sub.2).sub.n N(R.sup.4).sub.2 where each R.sup.4 independently is C.sub.1-4 alkyl, C.sub.2-4 alkenyl or optionally substituted C.sub.6 H.sub.5 CH.sub.2 --, and n is 1, 2 or 3, or (ii) a 5- to 8-membered alicyclic group containing one or two nitrogen atoms and directly attached to the amido nitrogen or attached by a C.sub.1-3 alkylene chain; and salts thereof.

Organic compounds and their use as pharmaceuticals

A pharmaceutical compound of the formula ##STR1## in which R.sup.1 is --CHO, CH.sub.2 OH, --CH.sub.2 OC.sub.1-4 alkyl, --COC.sub.1-3 alkyl, --CH(OH)C.sub.1-3 alkyl or --COOH, R.sup.2 is C.sub.1-4 alkyl, --CHO, --CH.sub.2 OH, --CH.sub.2 OC.sub.1-4 alkyl, --COC.sub.1-3 alkyl, --CH(OH)C.sub.1-3 alkyl or --COOH, R.sup.3 is C.sub.1-4 alkyl and X is pyrrolidinyl or pyrrolidinylmethyl; and salts and esters thereof.

A pharmaceutical compound of the formula ##STR1## in which R.sup.1, R.sup.2 and R.sup.3 independently are hydrogen, hydroxy, halo, nitro, amino, C.sub.2-5 acylamino, C.sub.1-4 alkyl, --CHO, --CH.sub.2 OH, --CH.sub.2 OC.sub.1-4 alkyl, --COOH, --COC.sub.1-3 alkyl, --CH(OH)C.sub.1-3 alkyl, C.sub.1-4 alkoxy, C.sub.2-4 alkenyloxy, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulphinyl, C.sub.1-4 alkylsulphonyl, N-substituted heterocyclyl, optionally substituted phenyl, optionally substituted phenylthio, optionally substituted phenylsulphinyl, optionally substituted phenylsulphonyl or optionally substituted phenylsulphonamido, or R.sup.1 and R.sup.2 together form a C.sub.3-5 alkylene bridge; provided that at least one of R.sup.2 and R.sup.3 is C.sub.1-4 alkoxy or C.sub.2-4 alkenyloxy; and X is (i) --(CH.sub.2).sub.n N(R.sup.4).sub.2 where each R.sup.4 independently is C.sub.1-4 alkyl, C.sub.2-4 alkenyl or optionally substituted C.sub.6 H.sub.5 CH.sub.2 --, and n is 1, 2 or 3, or (ii) a 5- to 8-membered alicyclic group containing one or two nitrogen atoms and directly attached to the amido nitrogen or attached by a C.sub.1-3 alkylene chain; and salts and esters thereof.

Growing community of inventors

Farnborough, United Kingdom

Terrence M Hotten