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

Becton Dickinson and Company Limited

American Home Products Corporation

Southwest Foundation for Biomedical Research

Southwest Research Institute

Evestra, Inc.

Pemmaraju Narasimha Rao

James W Cessac

Hyun K Kim

Richard P Blye

Carmie Kirk Acosta

Susan L Mooberry

Anne Marie Simmons

Tina L Tinley

Klaus Nickisch

Kesavaram Narkunan

Robert H Purdy

Perry H Moore, Jr

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

Described herein are 3-(6,6-ethylene-17&#x3b2;-hydroxy-3-oxo-17&#x3b1;-pregna-4-ene-17&#x3b1;-yl)propionic acid &#x3b3;-lactone derivatives having progestational and aldosterone antagonistic activity. Also described herein are methods of preparing and using these novel compounds.

Progestational 3-(6,6-ethylene-17B-hydroxy-3-oxo-17A-pregna-4-ene-17A-yl)propionic acid G-lactones

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.

The application discloses novel 2-alkoxyestradiol analogs which exhibit anti-proliferative properties, and methods of making and using such compounds to inhibit undesired cell proliferation and tumor growth. Additionally, methods are disclosed of treating diseases associated with undesired angiogenesis and undesired proliferation, and methods of treating infectious disease wherein the infectious agent is particularly susceptible to inhibition by agents that disrupt microtubule organization and function.

2-alkoxyestradiol analogs with antiproliferative and antimitotic activity

A compound having general formula (I) in which R is a member selected from the group consisting of &mdash;OCH , &mdash;SCH , &mdash;N(CH ) , &mdash;NHCH , &mdash;CHO, &mdash;COCH and &mdash;CHOHCH ; R is a member selected from the group consisting of halogen, alkyl, acyl, hydroxy, alkoxy, acyloxy, alkyl carbonate, cypionyloxy, S-alkyl and S-acyl; R is a member selected from the group consisting of alkyl, hydroxy, alkoxy and acyloxy; R is a member selected from the group consisting of hydrogen and alkyl; and X is a member selected from the group consisting of &mdash;O and &mdash;N&mdash;OR , wherein R is 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.

PROCESS FOR PREPARING 17&agr;-ACETOXY-11&bgr;-&lsqb;4-N,N(DIMETHYLAMINO)PHENYL&rsqb;-21-METHOXY-19-NORPREGNA-4,9-DIENE-3,20-DIONE, INTERMEDIATES USEFUL IN THE PROCESS , AND PROCESSES FOR PREPARING SUCH INTERMEDIATES

A hapten is obtained by replacing the 3-hydroxy group of 17 .alpha.-dihydroequilin with HO--CO--A--O-- wherein A is an alkylene of one to six carbon atoms. The hapten is conjugated with an immunological carrier to provide an immunogen, which in turn produces a specific antiserum to 17 .alpha.-dihydroequilin. The antiserum is used in a radioimmunoassay for 17 .alpha.-dihydroequilin.

17 .alpha.-Dihydroequilin hapten and assay method

A hapten is obtained by replacing the 3-hydroxy group of equilin with HO--CO--A--O-- wherein A is an alkylene of one to six carbon atoms. The hapten is conjugated with an immunological carrier to provide an immunogen, which in turn produces a specific antiserum to equilin. The antiserum is used in a radioimmunoassay for equilin.

Equilin hapten and assay method

An anti-testosterone serum is provided which is highly selective to the measurement of testosterone using radioimmunossay techniques in both male and female plasma without resorting to chromatography even though the plasma may have a high 5.alpha.-dihydrotestosterone content. In addition, the high progesterone concentration normally present in female plasma has no effect on the assay of this plasma. The preferred hapten for producing the serum is 17.beta., 19-dihydroxyandrost-4-en-3-one 19-carboxymethyl ether although related compounds as disclosed herein are also useful.

Testosterone derivatives and assay method

Testosterone-15.alpha. or .beta.-carboxyethyl thioether, 5.alpha.-, dihydrotestosterone-15.alpha. or .beta.-carboxyethyl thioether related compounds and intermediates for preparation thereof. The compounds are conjugated to an immunological protein and employed to elicit an antibody highly specific to testosterone and 5.alpha.-dihydrotestosterone respectively. The elicited antibody can be employed for determination of testosterone and 5.alpha.-dihydrotestosterone respectively, in samples, by radioimmunoassay.

Growing community of inventors

San Antonio, TX, United States of America

Pemmaraju Narasimha Rao