The United States of America, as Represented by the Secretary, Department of Health and Human Services

The United States of America as Represented by the Department of Health

Carmie Kirk Acosta

Hyun K Kim

Pemmaraju Narasimha Rao

Richard P Blye

James W Cessac

Anne Marie Simmons

James E Burdett, Jr

Pemmaraju Narasinha Rao

Pemmaraju N Rao

James W Cessas

The present invention relates, inter alia, to compounds having the general formula: in which R, R, R, Rand X are as defined by the present specification. In addition to providing the compounds of Formula I, the present invention provides methods wherein the compounds of Formula I are advantageously used, inter alia, to antagonize endogenous progesterone; to induce menses; to treat endometriosis; to treat dysmenorrhea; to treat endocrine hormone-dependent tumors; to treat meningiomas; to treat uterine leiomyomas; to treat uterine fibroids; to inhibit uterine endometrial proliferation; to induce cervical ripening; to induce labor; and for contraception.

Structural modification of 19-norprogesterone I: 17-&#x3b1;-substituted-11-&#x3b2;-substituted-4-aryl and 21-substituted 19-norpregnadienedione as new antiprogestational agents

A compound having the general formula: in which: Ris a member selected from the group consisting of &#x2014;OCH, &#x2014;SCH, &#x2014;N(CH), &#x2014;NHCH, &#x2014;CHO, &#x2014;COCHand &#x2014;CHOHCH; Ris a member selected from the group consisting of halogen, alkyl, acyl, hydroxy, alkoxy, acyloxy, alkyl carbonate, cypionyloxy, S-alkyl and S-acyl; Ris a member selected from the group consisting of alkyl, hydroxy, alkoxy and acyloxy; Ris a member selected from the group consisting of hydrogen and alkyl; and X is a member selected from the group consisting of &#x2550;O and &#x2550;N&#x2014;OR, wherein Ris a member selected from the group consisting of hydrogen and alkyl. In addition to providing the compounds of Formula I, the present invention provides methods wherein the compounds of Formula I are advantageously used, inter alia, to antagonize endogenous progesterone; to induce menses; to treat endometriosis; to treat dysmenorrhea; to treat endocrine hormone-dependent tumors; to treat uterine fibroids; to inhibit uterine endometrial proliferation; to induce labor; and for contraception.

21-substituted progesterone derivatives as new antiprogestational agents

Methods of using 7&#x3b1;,11&#x3b2;-dimethyl-17&#x3b2;-hydroxyestra-4,14-dien-3-one (III) and 17 esters thereof for various hormonal therapies, oral and parenteral dosage forms comprising these actives, and processes for their preparation.

Methods of making, using and pharmaceutical formulations comprising 7&#x3b1;, 11&#x3b2;-dimethyl-17&#x3b2;-hydroxyestra-4, 14-dien-3-one and 17 esters thereof

The present invention relates, inter alia, to compounds having the general formula:in which: Ris a member selected from the group consisting of &#x2014;OCH, &#x2014;SCH, &#x2014;N(CH), &#x2014;NHCH, &#x2014;NCH, &#x2014;NCH, &#x2014;NCHO, &#x2014;CHO, &#x2014;CH(OH)CH, &#x2014;C(O)CH, &#x2014;O(CH)N(CH), and &#x2014;O(CH)NCH; Ris a member selected from the group consisting of hydrogen, halogen, alkyl, acyl, hydroxy, alkoxy (e.g., methoxy, ethoxy, vinyloxy, ethynyloxy, cyclopropyloxy, etc.), acyloxy (e.g., acetoxy, glycinate, etc.), alkylcarbonate, cypionyloxy, S-alkyl, &#x2014;SCN, S-acyl and &#x2014;OC(O)R, wherein Ris a functional group including, but not limited to, alkyl (e.g., methyl, ethyl, etc.), alkoxy ester (e.g., &#x2014;CHOCH) and alkoxy (&#x2014;OCH); Ris a member selected from the group consisting of alkyl, hydroxy, alkoxy and acyloxy; Ris a member selected from the group consisting of hydrogen and alkyl; and X is a member selected from the group consisting of &#x2550;O and &#x2550;N&#x2014;OR, wherein Ris a member selected from the group consisting of hydrogen and alkyl. In addition to providing the compounds of Formula I, the present invention provides methods wherein the compounds of Formula I are advantageously used, inter alia, to antagonize endogenous progesterone; to induce menses; to treat endometriosis; to treat dysmenorrhea; to treat endocrine hormone-dependent tumors; to treat meningiomas; to treat uterine leiomyomas; to treat uterine fibroids; to inhibit uterine endometrial proliferation; to induce cervical ripening; to induce labor; and for contraception.

A compound having the general formula:in which: Ris a member selected from the group consisting of &#x2014;OCH, &#x2014;SCH, &#x2014;N(CH), &#x2014;NHCH, &#x2014;CHO, &#x2014;COCHand &#x2014;CHOHCH; Ris a member selected from the group consisting of halogen, alkyl, acyl, hydroxy, alkoxy, acyloxy, alkyl carbonate, cypionyloxy, S-alkyl and S-acyl; Ris a member selected from the group consisting of alkyl, hydroxy, alkoxy and acyloxy; Ris a member selected from the group consisting of hydrogen and alkyl; and X is a member selected from the group consisting of &#x2550;O and &#x2550;N&#x2014;OR, wherein Ris a member selected from the group consisting of hydrogen and alkyl. In addition to providing the compounds of Formula I, the present invention provides methods wherein the compounds of Formula I are advantageously used, inter alia, to antagonize endogenous progesterone; to induce menses; to treat endometriosis; to treat dysmenorrhea; to treat endocrine hormone-dependent tumors; to treat uterine fibroids; to inhibit uterine endometrial proliferation; to induce labor; and for contraception.

Methods for the preparation of the 19-norprogesterone of formula I ##STR1## and its intermediates, in crystalline and amorphous forms are disclosed. The process is performed by (1) protecting the hydroxyl group of a compound of formula II ##STR2## (2) reacting the protected compound with an alkali or alkaline earth metal anion radical, (3) hydrolyzing the resulting compound, (4) ketalizing the carbonyl groups, (5) epoxidizing the compound, (6) opening the epoxide ring and introducing an N,N,dimethylamino-phenyl functional group into the axial position of C.sub.11, (7) deketalizing and dehydrating the resulting compound, and (8) acetylating to provide 17.alpha.-acetoxy-11.beta.-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-di ene-3,20-dione (I).

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San Antonio, TX, United States of America

Carmie Kirk Acosta