Estrogenic compounds as anti-mitotic agents
AssigneeChildren's Medical Center Corporation
InventorsRobert John D'Amato, Moses Judah Folkman
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Abstract
The application discloses methods of treating mammalian diseases characterized by abnormal cell mitosis by administering estradiol derivatives including those comprising colchicine or combretastatin A-4 structural motifs of the general formulae found below in a dosage sufficient to inhibit cell mitosis. The application discloses novel compounds used in the methods.
Claims25
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:
- 1
- wherein:
- I. Ra-Roare 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, independently 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:
- 2
- and
- III. Z″ is defined as follows:
- 3
- Rg is —OH;
- Z′ is >COH;
- and
- Z″ is >CH2;
- then Ra is not —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 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:
- 4
- wherein:
- I. Ra-Rkare 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, 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:
- 5
- and
- III. Z″ is defined as follows:
- 6
- 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:
- 7
- 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, R1, 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, or —I;
- and Rg is ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, —I or —C≡CH;
- and
- II. Z is defined as follows:
- 8
- 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:
- 9
- 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 ═O, —R1, —OR1, —OCOR1, —SR1, —F, —NHR1, —Br, —I or —C≡CH;
- and
- II. Z is defined as follows:
- 10
- 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:
- 11
- 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:
- 12
- 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:
- 13
- 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 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:
- 14
- or
- 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:
- 15
- 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:
- 16
- 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:
- 17
- provided that when:
- 3) each Rb, Rc, Rd, Re, Rj, Rk, Rl, Rm, is —H;
- Rf is —CH3;
- 18
- 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
- 19
- 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
- 20
- 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:
- 21
- 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:
- 22
- and
- II. Z″ is defined as follows:
- 23
- 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:
- 24
- 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:
- 25
- 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:
- 26
- wherein:
- I. Ra-Rk are defined as follows:
- A) each Ra, Rb, RcI Rd, Rg, Rh, Ri, Rk independently is —R1, —OR1, —OCOR1, —SR1, —F, —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:
- 27
- 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:
- 28
- wherein:
- I. Ra-Ro are defined as follows:
- A) each Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Rj, Rk, Rj, Rm, Rn, Ro independently is —R1, —OR1, —OCOR1, —SR1, —F, —NHR2, —Br, or —I;
- and Rj 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, R, Rn, Ro independently is —R1, —OR1, —OCR1, —SR1, —F, —NHR2, —Br, —I;
- and each Re. Rg, Rh, Rk, R, 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:
- 29
- 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:
- 30
- wherein:
- I. Ra-Roare 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:
- 31
- 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.
Dependencies are inferred from the claim text.