Schering Corporation

Richard W Draper

Donald Hou

Gary M Lee

Janet L Mas

Eugene John Vater

Charles J Casmer

Michael J Green

Ingrid Mergelsberg

Elliot L Shapiro

Radha V Iyer

Thomas L Popper

Arthur S Watnick

In its several embodiments, this invention discloses a novel process to prepare the compounds of Formula 3: wherein Ris lower alkyl, and Rand Rcan be the same or different, each being independently selected from the group consisting of alkyl, aryl and aralkyl; said process being carried out in a suitable solvent with at least one tert-amine carboxylate salt catalyst. The compounds of formula 3 are chemical intermediates useful for the synthesis of various heterocyclic compounds. These heterocyclic compounds are in turn useful precursors for diverse pharmaceutical, herbicidal and insecticidal agents. In particular, these intermediates are useful precursors to a variety of CCR5 inhibitors.

Process for the preparation and purification of 2-(alkoxyalkylidene)-3-ketoalkanoic acid esters from 3-ketoalkanoic acid esters

4-Cyclohexyl-1,3,2-oxazaborolidine chiral accessories

A short practical commercial process for the efficient enantioselective synthesis of the non-steroidal antiestrogen of formula I or XIV

Enantioselective synthesis

Disclosed is a process for producing a compound of the formula: ##STR1## by reacting a compound of the formula: ##STR2## with: (1) a chlorinating reagent selected from an N-chloroimide or an N-chloroamide; (2) an anhydrous strong acid selected from orthophosphoric acid, alkylsulfonic acids, fluoroalkylsulfonic acids or arylsulfonic acids; and (3) anhydrous dimethylformamide; at a temperature within the range of about -78.degree. to about 0.degree. C.

Process for preparation of 9.alpha. -chloro-11.beta.

Disclosed are a process and intermediates of the formulae ##STR1## wherein X.sup.- is halide, BF.sub.4.sup.-, R.sup.3 SO.sub.3.sup.-, wherein R.sup.3 is C.sub.1 -C.sub.6 alkyl, CF.sub.3, C.sub.1 -C.sub.6 alkylphenyl or phenyl, and Q is a group of the formula ##STR2## wherein R is C.sub.1 -C.sub.6 alkyl; useful for preparing benzazepine intermediates of the formula ##STR3## These benzazepine intermediates are useful for preparing benzazepines having activity as selective D1 receptor antagonists.

Process for preparing intermediates for the synthesis of D1 antagonists

Disclosed is a process for producing a compound of the formula: ##STR1## by reacting a compound of the formula: ##STR2## with: (1) a chlorinating reagent selected from an N-chloroimide or an N-chloroamide; (2) an anhydrous strong acid selected from orthophosphoric acid, alkylsulfonic acids, fluoroalkylsulfonic acids or arylsulfonic acids; and (3) anhydrous dimethyl formamide; at a temperature within the range of about -78.degree. to about 0.degree. C., under anhydrous conditions under an inert atmosphere.

Process for preparation of

Disclosed are a process and intermediates of the formula ##STR1## wherein R is --CH.sub.3 or --C(O)--OR.sup.1, and R.sup.1 is C.sub.1 -C.sub.6 alkyl or --CH.sub.2 C.sub.6 H.sub.5 ; or the formula ##STR2## wherein: R.sup.2 is H or OH, R is --C(O)OR.sup.1 and R.sup.1 is C.sub.1 -C.sub.6 alkyl or --CH.sub.2 C.sub.6 H.sub.5, or where R.sup.2 is H, R can also be CH.sub.3 ; for preparing benzazepine intermediates of the formula ##STR3## The benzazepine intermediates are useful for preparing benzazepines having activity as selective D1 receptor antagonists.

Process for preparing benzazepine intermediates for the synthesis of D1

Described is the use of 6.beta.-fluoro-7.alpha.-halogeno-1,4-pregnadiene-17.alpha.,21-diol-3,20-di ones and their esters as topical anti-inflammatory agents, and pharmaceutical formulations thereof useful therefor. Preferred compounds are 6.beta.,9.alpha.-difluoro-7.alpha.-chloro (or bromo)-16.beta.-methyl-1,4-pregnadiene-11.beta.,17.alpha.,21-triol-3,20-di one 17-mono- and 17,21-di-lower alkanoates.

Use of 6.beta.-fluoro-7.alpha.-halogenocorticoids as topical

Novel 6-acyloxy-3,20-dioxo-1,4,6-pregnatrienes and 6-acyloxy-3,20-dioxo-4,6-pregnadienes, useful anti-inflammatory agents, are prepared by reaction of the corresponding 3,6,20-trioxo-1,4-pregnadiene or 3,6,20-trioxo-4-pregnene with an acyl halide or an acid anhydride in pyridine. Preferred anti-inflammatory agents are 6-alkanoyloxy-9.alpha.-halogeno-16-methyl-1,4,6-pregnatriene-3,20-diones. Also described are novel 6-oxo-9.alpha.-halogeno-16-substituted-1,4-pregnadienes, useful as intermediates in preparing the corresponding 6-acyloxy-1,4,6-pregnatrienes and which also exhibit anti-inflammatory activity per se.

6-Acyloxy-1,4,6-pregnatrienes, their use as anti-inflammatory agents,

1,3,5(10),6,8-19-Nor-pregnapentaene-20-ones exhibit anti-mitotic activity with minimal or no hormonal activity. They are particularly useful in the treatment and control of psoriasis when applied topically, preferred anti-psoriatic compounds being 1,3,5(10),6,8-19-nor-pregnapentaene-3,17.alpha.,21-triol-20-one 21-acetate and the 16.alpha.-methyl and 16.beta.-methyl analogs thereof. The 1,3,5(10),6,8-19-nor-pregnapentaene-20-ones are also useful as intermediates in the preparation of the corresponding 14-dehydro compounds which also exhibit anti-mitotic activity as described and claimed in copending application Ser. No. 819,182 filed July 26, 1977 of Richard W. Draper and Charles J. Casmer of common assignee as this application, and now abandoned.

1,3,5(10),6,8-19-Nor-pregnapentaenes, their use as anti-psoriatic

1,3,5(10),6,8,14-19 Nor-pregnahexaene-20-ones exhibit anti-mitotic activity with minimal or no hormonal activity. They are particularly useful in the treatment and control of psoriasis when applied topically, a preferred anti-psoriatic compound being 16.alpha.-methyl-1,3,5(10),6,8,14-19-nor-pregnahexaene-3,17.alpha.,21-trio l-20-one 21-acetate.

1,3,5(10),6,8,14-19-Nor-pregnahexaenes, their use as anti-psoriatic

Novel retinoic acid esters of anti-inflammatory steroids of the pregnane series are described and their use in the treatment and control of acne vulgaris via the topical or intralesional route. A preferred mode of the invention comprises treating acne by applying topically to the affected area hydrocortisone 21-all-trans-retinoate in concentrations of from about 0.05 to about 0.15 percent. Pharmaceutical formulations and methods for the manufacture of the novel steroidal retinoates are also described.

Retinoic acid esters of steroids of the pregnane series, their use in

Steroidal 6-azido-4,6-pregnadieno[3,2-c]pyrazoles having glucocorticoid activity are prepared by treating a 6-unsubstituted-4,6-pregnadieno[3,2-c]pyrazole with a halogen azide followed by treatment of the thereby formed 6-azido-7-halogeno-6,7-dihydro-4-pregnene[3,2-c]pyrazole with a dehydrohalogenating agent. Other methods of preparing these compounds are described, including the process of treating a 6-azido-17.alpha.,20; 20,21-bismethylenedioxy-4,6-pregnadiene-3-one with an alkyl formate in the presence of base followed by treatment of the resulting 2-hydroxymethylene derivative with a hydrazine or, alternatively, by converting said 2-hydroxymethylene to a 2-alkoxymethylene derivative followed by treatment thereof with a hydrazine. Preferred compounds include 6-azido-11.beta.,17.alpha.,21-trihydroxy-20-keto-4,6-pregnadieno[3,2-c]pyr azoles, particularly 2'-phenyl-9.alpha.-fluoro(and 9.alpha.-chloro)-16-methyl-derivatives thereof which possess potent anti-inflammatory activity. Of interest is 2'-phenyl-6-azido-9.alpha.-fluoro-11.beta.,17.alpha.,21-trihydroxy-16.alph a.-methyl-20-keto-4,6-pregnadieno[3,2-c]pyrazole.

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North Caldwell, NJ, United States of America

Richard W Draper