Estrogenic compounds as anti-mitotic agents

A method for treating a mammalian disease characterized by abnormal cell mitosis, said method comprising administering to a mammal a cell-mitosis-inhibiting compound of the formula below, said compound being administered in an amount sufficient to inhibit cell mitosis:

• 7
• wherein:
• I. Ra-Rk are defined as follows:
• A) each Ra, Rb, Rc, Rd, Rg, Rh, Ri, Rk independently is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, or —I;
• and Ra is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, —I or —C≡CH;
• or
• B) each Ra, Rb, Rc, Rd, Rk, independently is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, or —I;
• and each Reg, Rh, Ri, independently is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —Br, or —I;
• and Re is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —Br, —I or —C≡CH;
• and
• II. Z′ is defined as follows:
• A) Z′ is X, where X is >COR1,
• 8
• or
• B) Z′ is
• 9
• where Rn is —R1, —OR1, —SR1, —F, —NHR2, —Br or —I, and X′ is X, as defined above;
• or X′ is also >C═O;
• and
• III. Z″ is defined as follows:
• A) Z″ is Y, where Y is —O—,
• 10
• CHR1,
• 11
• or
• B) Z″ is
• 12
• where Rp is —R1, —OR1, —SR1, —F, —NHR2, —Br or —I;
• where, in each formula set forth above, each R1 and R2 independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkynl group of 1-6 carbons.

A method for treating a mammalian disease characterized by abnormal cell mitosis, said method comprising administering to a mammal a cell-mitosis-inhibiting compound of the formula below, said compound being administered in an amount sufficient to inhibit cell mitosis:

• 13
• wherein:
• I. Ra-Ro are defined as follows:
• A) each Ra, Rb, Rc, Rd, Re, Rf, Ri, Rj, Rk, Rl, Rm, Ro independently is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, or —I;
• and Rg is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, —I or —C≡CH;
• or
• B) each Ra, Rb, Rc, Rf, Rk, Rl, independently is —R1, —OR1, —OCORl, —SR1, —F, —NHR2, —Br, or —I;
• and each Rd, Re, Ri, Rj, Rm, Ro independently is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, or —I;
• and Rg is ═O, —Rl, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, —I or —C≡CH;
• and
• II. Z is defined as follows:
• A) Z is Y, where Y is —O—,
• 14
• >CHR1,
• 15
• or
• B) Z is
• 16
• where Rn is —R1, —ORl, —SR1, —F, —NHR2, —Br or —I;
• where, in each formula set forth above, each R1 and R2 independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkynl group of 1-6 carbons.

A method for treating a mammalian disease characterized by abnormal cell mitosis, said method comprising administering to a mammal a cell-mitosis-inhibiting compound of the formula below, said compound being administered in an amount sufficient to inhibit cell mitosis:

• 17
• wherein:
• I. Ra-Rk are defined as follows:
• A) each Ra, Rb, Rc, Rd, Rg, Rh, Ri, Rk independently is —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br, or —I;
• and Re is —R1, —ORl, —OCOR1, —SR1, —F, —NHR1, —Br, —I or —C≡CH;
• or
• B) each Ra, Rb, Rc, Rd, independently is —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br, or —I and each Rg, Rh, Ri, Rk independently is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br or —I;
• and Re is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br, —I or —C≡CH;
• and
• II. Z is defined as follows:
• A) Z is Y, where Y is —O—,
• 18
• >CHR1,
• 19
• or
• B) Z is
• 20
• where Rn is —R1, —OR1, —SR1, —F, —NHR2, —Br or —I;
• where, in each formula set forth above, each R1 and R2 independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkynl group of 1-6 carbons.

A method for treating a mammalian disease characterized by abnormal cell mitosis, said method comprising administering to a mammal a cell-mitosis-inhibiting compound of the formula below, said compound being administered in an amount sufficient to inhibit cell mitosis:

• 21
• wherein:
• I. Ra-Ro are defined as follows:
• A) each Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Rj, Rk, Rl, Rm, Rn, Ro independently is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, or —I;
• and Ri is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, —I or —C≡CH;
• or
• B) each Ra, Rd, Rf, Rj, Rm, Rn, Ro independently is —R1, —OR1, —OCR1, —SR1, —F, —NHR2, —Br, or —I;
• and each Rb, Rc, Re, Rg, Rh, Rk, Rl, independently is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br or —I;
• and Ri is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —Br, —I or —C≡CH;
• or
• C) each Ra, Rb, Rc, Rd, Rf, Rj, Rm, Rn, Ro independently is —R1, —OR1, OCR1, —SR1, —F, —NHR2, —Br, —I and each Re, Rg, Rh, Rk, Rl independently is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br or —I;
• and Ri is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —Br, —I or —C≡CH;
• II. Z is defined as follows:
• A) Z is X, where X is >COR1,
• 22
• or
• B) Z is
• 23
• where Rp is —R1, —OR1, —SR1, —F, —NHR2, —Br or —I;
• and X′ is X, as defined above;
• or X′ is >C═O;
• where, in each formula set forth above, each R1 and R2 independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkynl group of 1-6 carbons;
• and the bond indicated by C . . . C is absent or, in combination with the C—C bond, is the unit HC═CH.

A method for treating a mammalian disease characterized by abnormal cell mitosis, said method comprising administering to a mammal a cell-mitosis-inhibiting compound of the formula below, said compound being administered in an amount sufficient to inhibit cell mitosis:

• 24
• wherein:
• I. Ra-Ro are defined as follows:
• A) each Ra, Rb, Rc, Re, Rg, Rh, Rk, Rl, Rm, Rn, Ro independently is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, or —I;
• and Ri is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, —I or —C≡CH;
• or
• B) each Ra, Re, Rl, Rm, Rn, Ro independently is —R1, —OR1, —OCOR1, —SR1, —F, NHR2, —Br, or —I;
• and each Rb, Rc, Rg, Rh is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br or —I;
• and Ri is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br, —I or —C≡CH;
• or
• C) each Ra, Rb, Rc, Re, Rm, Rn, Ro independently is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, —I, and each Rh, Ri independently is ═O, —R1,—OR1, —OCOR1, —SR1, —F, —NHR1, —Br or —I;
• and Ri is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br, —I or —C≡CH;
• and
• I. Z is defined as follows:
• A) Z is X, where X is >COR1,
• 25
• or
• B) Z is
• 26
• where Rp is —R1, —OR1, —SR1, —F, —NHR2, —Br or —I, and X′ is X, as defined above;
• or X′ is ═O;
• where, in each formula set forth above, each R1 and R2 independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkynl group of 1-6 carbons;
• and the bond indicated by C . . . C is absent or, in combination with the C—C bond is the unit HC═CH.

A compound of the general formula below, said compound being a cell-mitosis-inhibiting compound:

• 27
• wherein:
• I. Ra-Ro are defined as follows:
• (A) each Ra, Rb, Rc, Rd, Re, Rf, Ri, Rj, Rk, Rl, Rm, Ro, independently is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2,—Br, or —I;
• and Rg is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, —I or —C≡CH;
• or
• (B) each Ra, Rb, Rc, Rf, Rk, Rl, Ro, is —R1, —OR1, —OCOR1 —SR1, —F, —NHR2, —Br, or —I;
• and each Rd, Re, Ri, Rj, Rm, independently is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br or .I;
• and Rg is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, —I or —C≡CH;
• and
• II. Z′ is defined as follows:
• A) Z′ is X, where X is >COR1,
• 28
• or
• B) Z′ is
• 29
• where Rn is —R1, —OR1, —SR1, —F, —NHR2, —Br or —I;
• or X′ is X, as defined above;
• or X′ is >C═O;
• and
• III. Z″ is defined as follows:
• A) Z″ is Y, where Y is —O—,
• 30
• >CHR1,
• 31
• or
• B) Z″ is
• 32
• where Rp is —R1,—OR1, —SR1, —F, —NHR2, —Br or —I;
• provided that when:
• 3) each Rb, Rc, Rd, Re, Rj, Rk, Rl, Rm, is —H;
• Rf is —CH3;
• Rg is —OH,
• 33
• Ri is —H, —OH, or ═O;
• Ro is —H or —Br;
• Z′ is >COH;
• and Z″ is >CH2 or —OH;
• then Ra is not —F, —Br, —OH or —H;
• and
• 4) each Rb, Rc, Rd, Re, Ri, Rj, Rk, Rl, Rm, is —H;
• Rf is —CH3;
• Rg is —OH;
• and Z″ is >CH2;
• then Z′ is not >COCH3 or
• 34
• and each Ra, Ro independently or together are not —OCH3 or —H;
• and
• 5) each Rc, Re, Rj, Rk, Rl, Rm, Ro is —H;
• Ra is —H or —OCH3;
• Rb is —H or —CH3;
• Rd is —OH;
• Rf is —CH3;
• Rg is ═O;
• Ri is —OH, ═O or —C≡CH;
• and Z″ is >CH2;
• then Z′ is not >COH;
• 35
• or —H;
• where, in each formula set forth above, each R1 and R2 independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkynl group of 1-6 carbons.

A compound of the general formula below, said compound being a cell-mitosis-inhibiting compound:

• 36
• wherein:
• I. Ra-Rk are defined as follows:
• A) each Ra, Rb, Rc, Rd, Rg, Rh, Ri, Rk independently is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, or —I;
• and Re is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, —I or —C≡CH;
• or
• B) each Ra, Rb, Rc, Rd, Rk, is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, or —I;
• and each Rg, Rh, Ri, independently is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —Br, or —I;
• and Re is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —Br, —I or —C≡CH;
• and
• I. Z′ is defined as follows:
• A) Z′ is X, where X is >COR1,
• 37
• or
• B) Z′ is
• 38
• where Rn is —R1, —OR1, —SR1, —F, —NHR2, —Br or —I, and X′ is X, as defined above;
• or X′ is also >C═O;
• and
• II. Z″ is defined as follows:
• A) Z″ is Y, where Y is —O—,
• 39
• >CHR1,
• 40
• or
• B) Z″ is
• 41
• where Rp is —R1, —OR1, —SR1, —F, —NHR2, —Br or —I;
• where, in each formula set forth above, each R1 and R2 independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkynl group of 1-6 carbons.

A compound of the general formula below, said compound being a cell-mitosis-inhibiting compound:

• 42
• wherein:
• I. Ra-Ro are defined as follows:
• A) each Ra, Rb, Rc, Rd, Re, Rf, Ri, Rj, Rk, Rl, Rm, Ro independently is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, or —I;
• and Rg is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, —I or —C≡CH;
• or
• B) each Ra, Rb, Rc, Rf, Rk, Rl, independently is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, or —I;
• and each Rd, Re, Ri, Rj, Rm, Ro independently is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, —I;
• and Rg is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, —I or —C≡CH;
• and
• II. Z is defined as follows:
• A) Z is Y, where Y is —O—,
• 43
• >CHR1, >C═O,
• 44
• 45
• or
• B) Z is
• 46
• where Rn is —R1, —OR1, —SR1, —F, —NHR2, —Br or —I;
• where, in each formula set forth above, each R1 and R2 independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkynl group of 1-6 carbons.

A compound of the general formula below, said compound being a cell-mitosis-inhibiting compound:

• 47
• wherein:
• I. Ra-Rk are defined as follows:
• A) each Ra, Rb, Rc, Rd, Rg, Rh, Ri, Rk independently is —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br, or —I;
• and Re is —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br, —I or —C≡CH;
• or
• B) each Ra, Rb, Rc, Rd, independently is —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br, or —I;
• and each Rg, Rh, Ri, Rk independently is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br or —I;
• and Re is —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br, —I or —C≡CH;
• II. Z is defined as follows:
• 1) Z is Y, where Y is —O—,
• 48
• >CHR1,
• 49
• or
• Z is
• 50
• where Rn is —R1, —OR1, —SR1, —F, —NHR2, —Br or —I;
• where, in each formula set forth above, each R1 and R2 independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkynl group of 1-6 carbons.

A compound of the general formula below, said compound being a cell-mitosis-inhibiting compound:

• 51
• wherein:
• I. Ra-Ro are defined as follows:
• A) each Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Rj, Rk, Rl, Rm, Rn, Ro independently is —R1,—OR1, —OCOR1 , —SR1 , —F , NHR2, —Br, or —I;
• and Ri is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, —I or —C≡CH;
• or
• B) each Ra, Rd, Rf, Rj, Rm, Rn, Ro independently is —R1, —OR1, —OCR1, —SR1, —F, —NHR2, —Br, —I;
• and each Rb, Rc, Re, Rg, Rh, Rk, Rl independently is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br or —I;
• and Ri is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br, —I or —C≡CH;
• or
• C) each Ra, Rb, Rc, Rd, Rf, Rj, Rm, Rn, Ro independently is —R1, —OR1, OCR1, —SR1, —F, —NHR2, —Br, —I;
• and each Re, Rg, Rh, Rk, Rl independently is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br or —I;
• and Ri is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br, —I or —C≡CH;
• and
• I. Z is defined as follows:
• ) Z is X, where X is >COR1,
• 52
• Z is
• 53
• where Rp is —R1, —OR1, —SR1, —F, —NHR2, —Br or —I;
• and X′ is X, as defined above;
• or X′ is >C═O;
• where, in each formula set forth above, each R1 and R2 independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkynl group of 1-6 carbons;
• and the bond indicated by C . . . C is absent or, in combination with the C—C bond is the unit HC═CH.

A compound of the general formula below, said compound being a cell-mitosis-inhibiting compound:

• 54
• wherein:
• I. Ra-Ro are defined as follows:
• A) each Ra, Rb, Rc, Re, Rg, Rh, Rk, Rl, Rm, Rn, Ro independently is —R1, —OR1, OCOR1, —SR1, —F, —NHR2, —Br, or —I;
• and Ri is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, —I or —C≡CH;
• or
• B) each Ra, Re, Rl, Rm, Rn, Ro independently is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, —I;
• and each Rb, Rc, Rg, Rh is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br or —I;
• and Ri is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br, —I or —C≡CH;
• or
• C) each Ra, Rb, Rc, Re, Rk, Rm, Rn, Ro independently is —R1, —OR1, OCOR1, —SR1, —F, —NHR2, —Br, —I;
• and each Rg, Rh independently is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br or —I;
• and Ri is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br, —I or —C≡CH;
• and
• II. Z is defined as follows:
• A) Z is X, where X is >COR1,
• 55
• or
• B) Z is
• 56
• where Rp is —R1, —OR1, —SR1, —F, —NHR2, —Br or —I, and X′ is X, as defined above;
• or X′ is ═O;
• where, in each formula set forth above, each R1 and R2 independently is —H, or substituted or unsubstituted alkyl, alkenyl or alkynl group of 1-6 carbons;
• and the bond indicated by C . . . C is absent or, in combination with the C—C bond is the unit HC═CH.