Estrogenic compounds as anti-mitotic agents

• US 5,661,143 A
• Filed: 12/12/1995
• Issued: 08/26/1997
• Est. Priority Date: 08/06/1993
• Status: Expired due to Term

• Current Assignee: Children's Medical Center Corporation
• Original Assignee: Children's Medical Center Corporation
• Inventors: D'Amato, Robert John, Folkman, Moses Judah
• Primary Examiner(s): Cook, Rebecca
• Application Number:
  US08/571,265
• Time in Patent Office: 623 Days
• Field of Search: 514/182, 514/178
• US Class Current: 514/182
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/566 having an oxo group in position 17, e.g. estrone
• CPC Class Codes: A61K 31/567 substituted in position 17 alpha, e.g. mestranol, norethandrolone
• CPC Class Codes: A61K 31/59 Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/30 Oestrogens
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07J 1/00 : Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
• CPC Class Codes: C07J 1/0059 : substituted in position 17 by a keto group
• CPC Class Codes: C07J 1/007 : the substituent being an OH group free esterified or etherified
• CPC Class Codes: C07J 1/0096 : Alkynyl derivatives
• CPC Class Codes: C07J 13/00 : Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 for carbonyl groups C07J1/00
• CPC Class Codes: C07J 31/00 : Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
• CPC Class Codes: C07J 41/00 : Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
• CPC Class Codes: 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
• CPC Class Codes: C07J 63/00 : Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
• CPC Class Codes: 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
• CPC Class Codes: 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

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.

Claims

1. A method for treating a mammalian disease characterized by undesirable cell mitosis, said method comprising administering to a mammal a compound of the formula below, said compound being administered in an amount sufficient to inhibit tubulin polymerization or depolymerization:

##STR4## wherein;

I. R_a -R_o are defined as follows;

A) each R_a, R_b, R_c, R_d, R_e, R_f, R_i, R_j, R_k, R_L, R_m, R_o, independently is --R₁, --OR₁, --OCOR₁, --SR₁, --F, --NHR₂, --Br, or --I; and

R_g is --R₁, --OR₁, --OCOR₁, --SR₁, --F, --NHR₂, --Br, --I, or --C.tbd.CH;

or

B) each R_a, R_b, R_c, R_f, R_k, R_L R_o, independently is --R₁, --OR₁, --OCOR₁, --SR₁, --F, --NHR₂, --Br, or --I; and

each R_d, R_e, R_i, R_j, R_m, independently is ═

O, --R₁, --OR₁, --OCOR₁, --SR₁, --F, NHR₂, --Br or --I; and

R_g is ═

O, --R₁, --OR₁, --OCOR₁, --SR₁, --F, --NHR₂, --Br, --I, or --C.tbd.CH; and

II. Z'"'"' is defined as follows;

##STR5## and III. Z" is defined as follows;

Z" is Y, where Y is ##STR6## where n is 0-6;

IV. provided that when each R_b, R_c, R_d, R_e, R_i, R_j, R_k, R_L, R_m and R_o is H;

R_f is --CH₃ ;

R_g is --OH;

Z'"'"' is >

CHOH; and

Z" is >

CH₂ ;

then R_a is not --H; and

V. provided that when each R_b, R_c, R_d, R_e, R_i, R_j, R_k, R_L, R_m and R_o is H;

R_f is --CH₃ ;

R_g is OH;

Z'"'"' is >

COH; and

Z" is >

CH₂ ;

then R_a is not OCH₃ ;

where, in each formula set forth above, each R₁ and R₂ independently is --H, or an alkyl, alkenyl or alkynl group of up to 6 carbons.

2. The method of claim 1, wherein the compound is 2-fluoroestradiol.

3. The method of claim 1, wherein the compound is 2-bromoestradiol.

4. The method of claim 1, wherein the compound is 2-methoxyestrone.

5. The method of claim 1, wherein the compound is 17-ethynylestradiol.

6. The method of claim 1, wherein the compound is 2-ethoxyestradiol.

7. The method of claim 1, wherein the compound is 2-propenylestradiol.

8. The method of claim 1, wherein at least one of the group consisting of R_a -R_p is --OCH₃.