Syntex (u.s.a.) Inc.

Syntex LLC

Francisco S Alvarez

Albert R Van Horn

John A Edwards

Certain 3-oxoandrost-4-ene and 3-oxoandrosta-1,4-diene 17.beta.-carboxylic acids (and esters thereof) substituted at the 4-position with a fluoro or chloro, optionally substituted at the 6- position with fluoro or chloro and at 16.beta. with methyl are useful as anti-inflammatory steroids. These compounds are optionally substituted at the 9.alpha. position with fluoro, chloro or bromo; substituted at the 11 with a keto, a beta-hydroxy or a beta-chloro (the latter only when there is a 9.alpha.-chloro); when there is a 17.alpha.-hydroxy (or an ester).

3-Oxo-4-halo-16.beta.-methylandrost-4-ene 17.beta.-carboxylic acids and

Certain pregn-4-ene-3,20-diones or pregn-1,4-diene-3,20-diones 4-substituted with a fluoro or chloro are useful as topical anti-inflammatory steroids. These compounds are substituted at 9.alpha. with hydrogen, fluoro, chloro or bromo; at 6.alpha. with hydrogen, fluoro or chloro; at the 11 position with a keto, a .beta.-hydroxy or a .beta.-chloro (the latter only when there is a 9.alpha.-chloro); at 16.alpha., 17.alpha.-positions with isopropylidenedioxy or at 16.alpha.- (or 16.beta.) with methyl when 17.alpha. is hydroxy (or an ester); and at the 21-position with mono-fluoro, chloro, bromo, hydroxy or alkanoyloxy of 2-6 carbons or difluoro, dichloro, dihydroxy or dimethoxy.

4-Halo steroids

Certain 3-oxoandrost-4-ene and 3-oxoandrosta-1,4-diene 17.beta.-thiocarboxylic acid esters substituted at the 4-position with a fluoro or chloro, optionally substituted at the 6- position with fluoro or chloro and at 16.beta. with methyl are useful as anti-inflammatory steroids. These compounds are optionally substituted at the 9.alpha. position with fluoro, chloro or bromo; substituted at the 11 with a keto, a beta-hydroxy or a beta-chloro (the latter only when there is a 9.alpha.-chloro); when there is a 17.alpha.-hydroxy (or an ester).

17.beta.-thiocarboxylic acid esters of

Certain 3-oxoandrost-4-ene and 3-oxoandrosta-1,4-diene 17.beta.-carboxylic acids and esters substituted at the 4-position with a fluoro or chloro and optionally substituted at the six position with fluoro or chloro are useful as anti-inflammatory steroids. These compounds are optionally substituted at the 9.alpha.-position with fluoro, chloro or bromo; substituted at the 11 with a keto, a .beta.-hydroxy or a .beta.-chloro (the latter only when there is a 9.alpha.-chloro); substituted at 16.alpha. (or 16.beta.) with methyl or hydrogen, and at 17.alpha. with hydroxy or an ester.

4-Halo etianic acids and derivatives thereof

Certain 3-oxoandrost-4-ene and 3-oxoandrosta-1,4-diene 17 beta-thiocarboxylic acid esters substituted at the 4-position with a fluoro, chloro or bromo and optionally substituted at the six position with fluoro or chloro are useful as anti-inflammatory steroids. These compounds are optionally substituted at the 9 alpha position with fluoro, chloro or bromo; substituted at the 11 with a keto, a beta-hydroxy or a beta-chloro (the latter only when there is a 9 alpha-chloro); substituted at 16 alpha,-17 alpha-positions with isopropylidenedioxy; and substituted at 16 alpha (or 16 beta) with methyl or hydrogen when there is a 17 alpha-hydroxy (or an ester).

17 Beta-thiocarboxylic acid esters of 4-halo-3-oxoandrost-4-enes

Certain 3-ketoandrost-4-ene and 3-ketoandrosta-1,4-diene 17 beta-carboxylic acids and esters substituted at the 6 alpha and 6 beta positions with fluorine substituents are useful as anti-inflammatory steroids. These compounds are optionally substituted at the 9 alpha position with fluoro, chloro or bromo; substituted at the 11 with a keto, a beta-hydroxy or a beta-chloro (the latter only when there is a 9 alpha-chloro); substituted at 16 alpha (or 16 beta) with methyl or hydrogen when there is a 17 alpha-hydroxy (or an ester).

6 Alpha, 6 beta-difluoro-etianic acid derivatives

This invention is a process for preparing 3-keto-androst-4-ene 17.alpha.-carboxylic acids, androsta-1,4-diene 17.alpha.-carboxylic acids and their 17.alpha.-esters by reacting a corresponding 21-hydroxypregn-4-ene-3,20-dione, 21-hydroxypregna-1,4-diene-3, 20-dione, or their 21-esters with an alkali metal carbonate base in a lower alkanol in the presence of oxygen. The 17.alpha.-esters are formed by reacting the 17.alpha.-carboxylic acid with a suitable alkylating agent.

Chemical process for preparing androsta-4-ene 17.alpha.-carboxylic acids

Novel prostaglandin intermediates and process for the production thereof. Compounds, and process for the production thereof, useful in the production of (dl)-[1.alpha.-hydroxy-3.beta.-(3S-tetrahydropyranyloxy-trans-1-octenyl)-4 .alpha.-tetrahydropyranyloxy-cyclopent-1.alpha.-yl] acetaldehyde hemiacetal and [1.alpha.-hydroxy-3.beta.-(3S-tetrahydropyranyloxy-trans-1-octenyl)-4.alph a.-tetrahydropyranyloxycyclopent-1.alpha.-yl] acetaldehyde hemiacetal.

Novel prostaglandin intermediates and process for the production thereof

Novel prostaglandin intermediates and process for the production thereof. Compounds, and process for the production thereof, useful in the production of (dl)-[1.alpha.-hydroxy-3.beta.-(3S-tetrahydropyranyloxy-trans-1-octenyl)-4 .alpha.-tetrahydropyranyloxycyclopent-1.alpha.-yl] acetaldehyde hemiacetal and [1.alpha.-hydroxy-3.beta.-(3S-tetrahydropyranyloxy-trans-1-octenyl)-4.alph a.-tetrahydropyranyloxycyclopent-1.alpha.-yl] acetaldehyde hemiacetal.

New compounds, 2-(6'-methoxynaphth-2'-yl)-propylene oxide, 2-(6'-methoxynaphth-2'-yl)proppionaldoxime, 2-hydroxy-2-(6'-methoxynaphth-2'-yl)-propionitrile, 2-(6'-methoxynaphth-2'-yl)acrylonitrile, 2-(6'-methoxynaphth-2'-yl)acrylic acid, the corresponding 5'-halo compounds and 2-(5'-halo-6'-methoxynaphth-2'-yl)propionaldehyde are useful intermediates in producing 2-(6'-methoxynaphth-2'-yl)propionic acid and the corresponding 5'-halo acids from 6-methoxy-2-acetylnaphthalene and the corresponding 5-halo compounds. The 2-propionic acids are anti-inflammatory, analgesic, anti-pyretic and anti-pruritic agents. The 2-propionaldehydes, obtained from the 2-acetyl compounds by way of the 2-propylene oxide, can be converted directly to the 2-propionic acids by way of the 2-propionaldoximes and the 2-priopionitriles or more directly by Jones oxidation. Alternatively the 2-acrylonitriles, obtained from the 2-acetyl compounds by way of the 2-hydroxy-2-propionitrile, can be converted to the 2-propionic acid by way of the 2-acrylic acid or 2-propionitrile.

2-(5'-Halo-6'-methoxynaphth-2'-yl)-acrylic acid

2-(6-Methoxy-2-naphthyl)propionic acid is prepared by reacting di(6-methoxy-2-naphthyl)-zinc or 6-methoxy-2-naphthylzinc halide with a lower alkyl 2-halopropionate in a suitable solvent to form a lower alkyl 2-(6-methoxy-2-naphthyl)propionate and hydrolyzing the ester group thereof. The product has anti-inflammatory, analgesic and anti-pyretic activities.

Process for preparing 2-(6-methoxy-2-naphthyl)propionic acid

New compounds, 2-(6'-methoxynaphth-2'-yl)propylene oxide, 2-(6'-methoxynaphth-2'-yl)propionaldoxime, 2-hydroxy-2-(6'-methoxynaphth-2'-yl)-propionitrile, 2-(6'methoxynaphth-2'-yl)acrylonitrile, 2-(6'-methoxynaphth-2'-yl)acrylic acid, the corresponding 5'-halo compounds and 2-(5'-halo-6'-methoxynaphth-2'-yl)propionaldehyde are useful intermediates in producing 2-(6'-methoxynaphth-2'-yl)propionic acid and the corresponding 5'-halo acids from 6-methoxy-2-acetylnaphthalene and the corresponding 5-halo compounds. The 2-propionic acids are anti-inflammatory, analgesic, anti-pyretic and anti-pruritic agents. The 2-propionaldehydes, obtained from the 2-acetyl compounds by way of the 2-propylene oxide, can be converted directly to the 2-propionic acids by way of the 2-propionaldoximes and the 2-propionitriles or more directly by Jones oxidation. Alternatively the 2-acrylonitriles, obtained from the 2-acetyl compounds by way of the 2-hydroxy-2-propionitrile, can be converted to the 2-propionic acid by way of the 2-acrylic acid or 2-propionitrile.

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Sunnyvale, CA, United States of America

Francisco S Alvarez