# US 8,569,276 B2 · Structural modification of 19-norprogesterone I: 17-α-substituted-11-β-substituted-4-aryl and 21-substituted 19-norpregnadienedione as new antiprogestational agents

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- Number: US 8,569,276 B2
- Document ID: US8569276B2
- Status: Granted
- Kind: B2
- Application number: 11/069,817
- Filed: 2005-02-28
- Published: 2005-06-30
- Granted: 2013-10-29
- Earliest claimed: 1996-05-01
- Assignees: The United States of America, as represented by the Secretary, Department of Health and Human Services
- Applicants: Hyun K. Kim; Richard P. Blye; Pemmaraju N. Rao; James W. Cessac; Carmie K. Acosta
- Inventors: Hyun K. Kim; Richard P. Blye; Pemmaraju N. Rao; James W. Cessac; Carmie K. Acosta
- Web page: https://patentgrep.com/patent/US8569276B2

## CPC

- C07J 41/0083: {substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings}
- C07J 5/00: Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, {i.e. only one oxygen bound to position 21 by a single bond}
- C07J 5/0053: {not substituted in position 16}
- C07J 7/00: Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms (C07J5/00 takes precedence)
- C07J 7/0045: {not substituted in position 16}
- C07J 7/0085: {by an halogen atom}
- C07J 9/00: Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J 21/006: {at position 3}
- C07J 31/006: {not covered by C07J31/003}
- C07J 41/00: Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J 41/0016: {Oximes}
- C07J 41/0094: {containing nitrile radicals, including thiocyanide radicals}
- C07J 43/003: {not condensed}
- C07J 51/00: Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
- C07J 71/001: {Oxiranes}
- C07J: STEROIDS (seco-steroids C07C)

## Abstract

The present invention relates, inter alia, to compounds having the general formula: in which R1, R2, R3, R4 and 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.

## Claims

### Claim 1

A compound of the general formula:
wherein:
R1 is a member selected from the group consisting of —CHO, —CH(OH)CH3, and —C(O)CH3;
R2 is a member selected from the group consisting of —SAc, alkoxy, vinyloxy, —SCN, and —OC(O)R6, wherein R6 is a member selected from the group consisting of alkyl, substituted alkyl, alkoxyalkyl, alkoxy, vinyloxy and ethynyloxy;
R3 is a member selected from the group consisting of alkyl, substituted alkyl, alkoxy and acyloxy;
R4 is a member selected from the group consisting of hydrogen and alkyl; and
X is a member selected from the group consisting of ═O and ═N—OR5, wherein R5 is a member selected from the group consisting of hydrogen and alkyl;
wherein the term “alkyl” refers to a saturated monovalent hydrocarbon radical of 1-12 carbon atoms; and
with the proviso that if R2 is —OC(O)R6, wherein R6 is alkyl, and R1 is —CHO or —C(O)CH3, then R3 is other than C1-4 alkyl or —OC(O)C1-6 alkyl.

### Claim 2 (depends on 1)

The compound in accordance with claim 1, wherein R1 is —C(O)CH3.

### Claim 3 (depends on 1)

The compound in accordance with claim 1, wherein R2 is a member selected from the group consisting of —SCN and —OC(O)R6, wherein R6 is a member selected from the group consisting of alkyl, substituted alkyl, alkoxyalkyl, and alkoxy.

### Claim 4

A compound of general formula I:
wherein:
R1 is a member selected from the group consisting of —CHO, —CH(OH)CH3, and —C(O)CH3;
R2 is —OC(O)R6 and R6 is a member selected from the group consisting of —CH2CH3, —CH2OCH3 and —OCH3;
R3 is a member selected from the group consisting of alkyl, substituted alkyl, alkoxy and acyloxy;
R4 is a member selected from the group consisting of hydrogen and alkyl;
X is a member selected from the group consisting of ═O and ═N—OR5, wherein R5 is a member selected from the group consisting of hydrogen and alkyl;
wherein the term “alkyl” refers to a saturated monovalent hydrocarbon radical of 1-12 carbon atoms; and
with the proviso that if R6 is —CH2CH3 and R1 is —CHO or —C(O)CH3, then R3 is other than C1-4 alkyl or —OC(O)C1-6 alkyl.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 1 and a pharmaceutically acceptable excipient.

### Claim 6

A compound of the general formula I:
wherein:
R1 is a member selected from the group consisting of —CHO, —CH(OH)CH3, and —C(O)CH3;
R2 is —OC(O)R6 wherein R6 is alkyl or alkoxyalkyl;
R3 is a member selected from the group consisting of alkyl, substituted alkyl, alkoxy and acyloxy;
R4 is a member selected from the group consisting of hydrogen and alkyl;
X is a member selected from the group consisting of ═O and ═N—OR5, wherein R5 is a member selected from the group consisting of hydrogen and alkyl;
wherein the term “alkyl” refers to a saturated monovalent hydrocarbon radical of 1-12 carbon atoms; and
with the proviso that if R6 is alkyl and R1 is —CHO or —C(O)CH3, then R3 is other than C1-4 alkyl or —OC(O)C1-6 alkyl.

### Claim 7 (depends on 6)

The compound of claim 6, wherein R3 is alkoxy or acyloxy.

### Claim 8 (depends on 6)

The compound of claim 6, wherein R4 is alkyl.

### Claim 9 (depends on 6)

The compound of claim 6, wherein X is ═O.

### Claim 10 (depends on 2)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 2 and a pharmaceutically acceptable excipient.

### Claim 11 (depends on 3)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 3 and a pharmaceutically acceptable excipient.

### Claim 12 (depends on 4)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 4 and a pharmaceutically acceptable excipient.

### Claim 13 (depends on 6)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 6 and a pharmaceutically acceptable excipient.

### Claim 14 (depends on 7)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 7 and a pharmaceutically acceptable excipient.

### Claim 15 (depends on 8)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 8 and a pharmaceutically acceptable excipient.

### Claim 16 (depends on 9)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 9 and a pharmaceutically acceptable excipient.

### Claim 17

A compound of the general formula:
wherein:
R1 is a member selected from the group consisting of —OCH3, —SCH3, —CHO, —CH(OH)CH3 and —C(O)CH3;
R2 is a member selected from the group consisting of alkoxy, SAc, vinyloxy, —SCN, and —OC(O)R6, wherein R6 is a member selected from the group consisting of alkyl, substituted alkyl, alkoxyalkyl, alkoxy, vinyloxy and ethynyloxy;
R3 is selected from the group consisting of methoxymethoxy, methoxyethoxy, aryloxy, arylalkoxy, and acyloxy;
R4 is a member selected from the group consisting of hydrogen and alkyl; and
X is a member selected from the group consisting of ═O and ═N—OR5, wherein R5 is a member selected from the group consisting of hydrogen and alkyl;
wherein the term “alkyl” refers to a saturated monovalent hydrocarbon radical of 1-12 carbon atoms; and
with the proviso that if R2 is —OC(O)R6, wherein R6 is alkyl, and R1 is —CHO or —C(O)CH3, then R3 is other than —OC(O)C1-6 alkyl.

### Claim 18

A compound of the general formula:
wherein:
R1 is —C(O)CH3:
R2 is a member selected from the group consisting of —SAc, alkoxy, vinyloxy, —SCN, and —OC(O)R6, wherein R6 is a member selected from the group consisting of alkyl, substituted alkyl, alkoxyalkyl, alkoxy, vinyloxy and ethynyloxy;
R3 is a member selected from the group consisting of alkyl, substituted alkyl, alkoxy and acyloxy;
R4 is a member selected from the group consisting of hydrogen and alkyl; and
X is a member selected from the group consisting of ═O and ═N—OR5, wherein R5 is a member selected from the group consisting of hydrogen and alkyl;
wherein the term “alkyl” refers to a saturated monovalent hydrocarbon radical of 1-12 carbon atoms; and
with the proviso that if R2 is —OC(O)R6. wherein R6 is alkyl, then R3 is other than C1-4 alkyl or —OC(O)C1-6 alkyl.

### Claim 19 (depends on 18)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 18 and a pharmaceutically acceptable excipient.

### Claim 20

A compound of the general formula:
wherein:
R1 is a member selected from the group consisting of —OCH3, —SCH3, —CHO, —CH(OH)CH3, and —C(O)CH3;
R2 is —OC(O)R6, wherein R6 is a member selected from the group consisting of alkyl and alkoxyalkyl;
R3 is a member selected from the group consisting of alkyl, substituted alkyl, alkoxy and acyloxy;
R4 is a member selected from the group consisting of hydrogen and alkyl; and
X is a member selected from the group consisting of ═O and ═N—OR5, wherein R5 is a member selected from the group consisting of hydrogen and alkyl;
wherein the term “alkyl” refers to a saturated monovalent hydrocarbon radical of 1-12 carbon atoms; and
with the proviso that if R2 is —OC(O)R6, wherein R6 is alkyl, and R1 is —CHO or —C(O)CH3, then R3 is other than C1-4 alkyl or —OC(O)C1-6 alkyl.

### Claim 21 (depends on 20)

The compound of claim 20, wherein:
R2 is —OC(O)R6, wherein R6 is a member selected from the group consisting of —CH2CH3, —CH2OCH3 and —OCH3.

### Claim 22 (depends on 17)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 17 and a pharmaceutically acceptable excipient.

### Claim 23 (depends on 21)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 21 and a pharmaceutically acceptable excipient.

### Claim 24 (depends on 1)

A method of treating a patient in need thereof, comprising administering an effective amount of a compound of claim 1 to the patient, wherein the treatment is selected from the group consisting of: inducing menses, treating endometriosis, treating dysmenorrhea, treating breast cancer, treating uterine leiomyoma, treating meningiomas, treating uterine fibroids, treating uterine endometrial proliferation, inducing labor, producing contraception, and producing postcoital contraception.

### Claim 25 (depends on 17)

A method of treating a patient in need thereof, comprising administering an effective amount of a compound of claim 17 to the patient, wherein the treatment is selected from the group consisting of: inducing menses, treating endometriosis, treating dysmenorrhea, treating breast cancer, treating uterine leiomyoma, treating meningiomas, treating uterine fibroids, treating uterine endometrial proliferation, inducing labor, producing contraception, and producing postcoital contraception.

### Claim 26 (depends on 18)

A method of treating a patient in need thereof comprising administering an effective amount of a compound of claim 18 to the patient, wherein the treatment is selected from the group consisting of: inducing menses, treating, endometriosis, treating dysmenorrhea, treating breast cancer, treating uterine leiomyoma, treating meningiomas, treating uterine fibroids, treating uterine endometrial proliferation, inducing labor, producing contraception, and producing postcoital contraception.

### Claim 27 (depends on 20)

A method of treating a patient in need thereof, comprising administering an effective amount of a compound of claim 20 to the patient, wherein the treatment is selected from the group consisting of: inducing menses, treating endometriosis, treating dysmenorrhea, treating breast cancer, treating uterine leiomyoma, treating meningiomas, treating uterine fibroids, treating uterine endometrial proliferation, inducing labor, producing contraception, and producing postcoital contraception.

### Claim 28 (depends on 20)

The compound of claim 20, wherein R4 is alkyl.

### Claim 29 (depends on 20)

The compound of claim 20, wherein X is ═O.

### Claim 30 (depends on 20)

The compound of claim 20, wherein R1 is CHO.

### Claim 31 (depends on 20)

The compound of claim 20, wherein R1 is —CH(OH)CH3.

### Claim 32 (depends on 20)

The compound of claim 20, wherein R1 is —SCH3.

### Claim 33 (depends on 20)

The compound of claim 20, wherein R1 is —C(O)CH3.

### Claim 34 (depends on 20)

The compound of claim 20, wherein R3 is alkoxy.

### Claim 35 (depends on 20)

The compound of claim 20, wherein R6 is alkoxyalkyl.

### Claim 36 (depends on 28)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 28 and a pharmaceutically acceptable excipient.

### Claim 37 (depends on 29)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 29 and a pharmaceutically acceptable excipient.

### Claim 38 (depends on 30)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 30 and a pharmaceutically acceptable excipient.

### Claim 39 (depends on 31)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 31 and a pharmaceutically acceptable excipient.

### Claim 40 (depends on 32)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 32 and a pharmaceutically acceptable excipient.

### Claim 41 (depends on 1)

The compound of claim 1, wherein R2 is alkoxy.

### Claim 42 (depends on 41)

The compound of claim 41, wherein R1 is —C(O)CH3, R2 is methoxy, R3 is acetoxy, R4 is methyl, and X is ═O.

### Claim 43 (depends on 41)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 41 and a pharmaceutically acceptable excipient.

### Claim 44 (depends on 42)

A pharmaceutical composition comprising an effective amount of the compound in accordance with claim 42 and a pharmaceutically acceptable excipient.

### Claim 45 (depends on 41)

A method of treating a patient in need thereof, comprising administering an effective amount of a compound of claim 41 to the patient, wherein the treatment is selected from the group consisting of: inducing menses, treating endometriosis, treating dysmenorrhea, treating breast cancer, treating uterine leiomyoma, treating meningiomas, treating uterine fibroids, treating uterine endometrial proliferation, inducing labor, producing contraception, and producing postcoital contraception.

### Claim 46 (depends on 42)

A method of treating a patient in need thereof, comprising administering an effective amount of a compound of claim 42 to the patient, wherein the treatment is selected from the group consisting of: inducing menses, treating endometriosis, treating dysmenorrhea, treating breast cancer, treating uterine leiomyoma, treating meningiomas, treating uterine fibroids, treating uterine endometrial proliferation, inducing labor, producing contraception, and producing postcoital contraception.

### Claim 47 (depends on 1)

The compound of claim 1, wherein R2 is —SAc.

### Claim 48 (depends on 47)

The compound of claim 47, wherein R1 is —C(O)CH3, R2 is —SAc, R3 is acetoxy, R4 is methyl, and X is ═O.

### Claim 49 (depends on 47)

A pharmaceutical composition comprising an effective amount of a compound in accordance with claim 47 and a pharmaceutically acceptable excipient.

### Claim 50 (depends on 48)

A pharmaceutical composition comprising an effective amount of the compound in accordance with claim 48 and a pharmaceutically acceptable excipient.

### Claim 51 (depends on 47)

A method of treating a patient in need thereof, comprising administering an effective amount of a compound of claim 47 to the patient, wherein the treatment is selected from the group consisting of: inducing menses, treating endometriosis, treating dysmenorrhea, treating breast cancer, treating uterine leiomyoma, treating meningiomas, treating uterine fibroids, treating uterine endometrial proliferation, inducing labor, producing contraception, and producing postcoital contraception.

### Claim 52 (depends on 48)

A method of treating a patient in need thereof, comprising administering an effective amount of a compound of claim 48 to the patient, wherein the treatment is selected from the group consisting of: inducing menses, treating endometriosis, treating dysmenorrhea, treating breast cancer, treating uterine leiomyoma, treating meningiomas, treating uterine fibroids, treating uterine endometrial proliferation, inducing labor, producing contraception, and producing postcoital contraception.