American Home Products Corporation

Michael W Winkley

Ronald J McCaully

Gerhard R Wendt

James L Diebold

George C Buzby, Jr

John W Ellingboe

Jehan F Bagli

Scott J Childress

Robert D Mitchell

The solvate 3.beta.,5.alpha.,6.beta.-trihydroxy-6.alpha.,17.alpha.-dimethylpregnan-20- one monomethanolate, a crystalline intermediate in the manufacture of medrogestone, and a method for its production by displacing the solvent in a solution of 3.beta.,5.alpha.,6.beta.-trihydroxy-6.alpha.,17.alpha.-dimethylpregnan-20- one with methanol are disclosed.

Medrogestone production

A process for the production of 6,17.alpha.-dimethylpregna-4,6-diene-3,20-dione which comprises isolating 3.beta.,5.alpha., 6.beta.-trihydroxy- 6.alpha.,17.alpha.- dimethylpregnan-20-one monomethanolate from the solution of a Grignard reaction product of 3.beta.,5.alpha.-dihydroxy -17.alpha.-methyl-17.beta.-carbomethoxyandrostane-6-one and a methylmagnesium halide by solvent displacement with methanol; oxidizing the monomethanolate to the 3,20-dione; dehydrating the said 3,20-dione to the 4-ene-3,20-dione; dehydrating the 4-ene-3,20 dione; removing a 6-methylene-4-ene-3,20-dione byproduct and isolating the desired product.

A process for the production of medrogestone, in which, in an intermediate step, the solvate 3.beta.,5.alpha.,6.beta.-trihydroxy-6.alpha.,17.alpha.-dimethylpregnan-20- one monomethanolate is obtained as a solid, stable compound by displacing the organic solvent from a solution of of 3.beta.,5.alpha.,6.beta.-trihydroxy-6.alpha.,17.alpha.-dimethylpregnan-20- one with a lower alkanol, and a Diels-Alder adduct of 6-methylene-17.alpha.-methylpregn-4-ene-3,20-dione with maleic anhydride is used as an intermediate for production of the corresponding dicarboxylic acid salt for removal of 6-methylene-17.alpha.-methylpregn-4-ene-3,20-dione contamination of the desired product. Another intermediate, 6.beta.-hydroxy-6.alpha.,17.alpha.-dimethylpregn-4-ene-3,20-dione, has been found to prevent smooth muscle proliferation and is useful in the treatment of atherosclerosis and restinosis.

Medrogestrone production

This invention relates to substituted arylsulfonamides and benzamides possessing aniarrhythmic activity, to pharmaceutical compositions and to methods for production thereof.

Substituted arylsulfonamides and benzamides

Disclosed herein are novel 1,2,3,4,5,6-hexahydro[1,3,6]triazocino[1,2-a]benzimidazole of Formulas I and II: ##STR1## wherein R.sup.1 may be phenyl, m- or p-nitrophenyl, m- or p-methylsulfonylaminophenyl, napthtyl, naphthyl mono-substituted by nitro or methylsulfonylamino, benzofurazanyl, 2-pyrimidinyl, 2- or 4-pyridinyl, 2- or 4-naphthyridinyl, pyrazinyl, isoquinolinyl, or quinolinyl;

2,3,4,5-tetrahyd

Disclosed herein are novel 1,4-substituted-2,3,5,6-tetrahydro[1,3,6]triazocino[1,2-a]benzimidazole of Formulas I and II: ##STR1## wherein R.sup.1 may be phenyl, m- or p-nitrophenyl, m- or p-methylsulfonylaminophenyl, naphthyl, naphthyl mono-substituted by nitro or methylsulfonylamino, benzofurazanyl, 2-pyrimidinyl, 2- or 4-pyridinyl, 2- or 4-naphthyridinyl, pyrazinyl, isoquinolinyl, or quinolinyl; R.sup.2 may be hydrogen; C.sub.1 -C.sub.8 alkyl; C.sub.1 -C.sub.4 alkylphenyl or C.sub.1 -C.sub.4 alkyl-substituted-phenyl, in which phenyl may have one to three substituents selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, fluorine, chlorine or bromine; phenyl or substituted-phenyl in which the phenyl substituents are the same as for c.sub.1 -C.sub.4 alkyl-substituted-phenyl; 2- or 4-pyrimidinyl; pyrazinyl; imidazolyl; C.sub.1 -C.sub.4 alkanoyl; halo or dihalo-(C.sub.1 -C.sub.4)alkanoyl, in which halo is fluoro or chloro; benzoyl or benzoyl substituted on the phenyl ring by one or two C.sub.1 -C.sub.4 alkyl groups; C.sub.1 -C.sub.4 alkanoyloxy; C.sub.1 -C.sub.4 alkylamino(C.sub.1 -C.sub.4)alkanoyl; C.sub.1 -C.sub.4 alkyloxycarbonyl; C.sub.1 -C.sub.4 alkylaminocarbonyl; phenylaminocarbonyl in which phenyl may have one to three C.sub.1 -C.sub.4 alkyl groups; phenyloxy or naphthyloxy(C.sub.1 -C.sub.4)alkyl in which the phenyl or naphthyl ring may be substituted by one to three C.sub.1 - C.sub.4 alkyl groups; C.sub.1 -C.sub.4 alkylsulfonyl; N-(C.sub.1 -C.sub.4) alkyl- or N-(C.sub.1 -C.sub.4) dialkylcarboxamido(C.sub.1 -C.sub.4)alkyl; N-phenyl or substituted phenyl-carboxamido(C.sub.1 -C.sub.4)alkyl in which phenyl may be substituted as above for C.sub.1 -C.sub.4 alkyl-substituted phenyl; cyano; amidino in which each N atom is substituted by a C.sub.1 -C.sub.4 alkyl group; and C.sub.1 -C.sub.4 alkylguanidino; and R.sup.3 and R.sup.4 are, independently, selected from hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, fluorine and chlorine, or acid addition salts thereof. Compounds of formulas I and II having certain values of R.sup.2 are antiarrhythmic or antiischaemic agents. The remaining values of R.sup.2 provide intermediate compounds of formulas I and II. Also disclosed herein a novel tetrahydro-3-substituted-7-substituted-1H-[1,2,5]triazepino[1,2-a][1,2,4]b enzotriazines, wherein the 7 substituent may be --SMe, .dbd.S, .dbd.O, Cl or Br and the 3 substituent is the same as R.sup.2 in formulas I and II above. These componds also serve as intermediates for the production of the antiarrhythmic agents of formula II above.

1,2,3,4,5,6-hexahydro[1,3,6]triazocino[1,1-a]benzimidazoles

Disclosed herein are N-substituted-hexahydro-1,2,5-triazepines of formula I, which is ##STR1## or a pharmaceutically acceptable acid addition salt thereof, wherein R.sup.4 and R.sup.5 are independently hydrogen or C.sub.1 -C.sub.4 alkyl;

N-substituted-hexahydro-1,2,5-triazepines

Disclosed herein is a process for obtaining indoline-2-carboxylic acid (or derivatives thereof) comprising the following steps: (a) reducing .alpha.-oxo-2-nitrobenzenepropanoic acid to .alpha.-hydroxy-2-nitrobenzenepropanoic acid, (b) replacing the hydroxyl group of the latter with a chlorine atom utilizing a selected Vilsmeier chlorinating reagent at temperatures of at least 20.degree. C., (c) reducing the nitro group of the resulting .alpha.-chloro-2-nitrobenzenepropanoic acid to obtain .alpha.-chloro-2-aminobenzenepropanoic acid, and (d) cyclizing the latter in aqueous base to form the desired indoline-2-carboxylic acid. Alternately, steps (c) and (d) may be combined in a one pot step by using, for example, a Raney nickel-hydrazine reducing medium.

Process for preparing indoline-2-carboxylic acids via

Disclosed herein are new 4-aryl-benzazocine-2,6-diones of Formula I ##STR1## in which R.sup.1 is phenyl, naphthyl or phenyl or naphthyl substituted by one to three moieties selected from fluoro, chloro, bromo, and alkyl or alkoxy of 1 to 4 carbon atoms;

1-[2-(dialkyl

Disclosed herein is a process for producing an asymmetric indoline-2-carboxylic acid of the structural Formula: ##STR1## wherein X is hydrogen, bromine, chlorine, C.sub.1-4 alkyl or C.sub.1-4 alkoxy, which comprises:

Process for the asymmetric synthesis of chiral

Disclosed herein is a process for obtaining indoline-2-carboxylic acid (or derivaties thereof) comprising the following step: (a) reducing .alpha.-oxo-2-nitrobenzenepropanoic acid to .alpha.-hydroxy-2-nitrobenzenepropanoic acid, (b) replacing the hydroxyl group of the latter with a chlorine atom utilizing a selected Vilsmeier chlorinating reagent at temperatures of at least 20.degree. C., (c) reducing the nitro group of the resulting .alpha.-chloro-2-nitrobenzenepropanoic acid to obtain .alpha.-chloro-2-aminobenzenepropanoic acid, and (d) cyclizing the latter in aqueous base to form the desired indoline-2-carboxylic acid. Alternately, steps (c) and (d) may be combined in a one pot step by using, for example, a Raney nickel-hydrazine reducing medium.

Process for the asymmetric synthesis of chiral indoline-2-carboxylic

Disclosed herein are (lower)alkylsulfonyl derivatives of various proline amides, thiazolidine carboxylic acid amides and indoline-2-carboxylic acid amides, among others, which inhibit angiotensin converting enzyme and are antihypertensive agents.

Growing community of inventors

Malvern, PA, United States of America

Michael W Winkley