Non-steroidal sulfatase inhibitor compounds and their method of use

• US 5,567,831 A
• Filed: 08/16/1995
• Issued: 10/22/1996
• Est. Priority Date: 08/16/1995
• Status: Expired due to Term

• Current Assignee: Duquesne University of The Holy Ghost
• Original Assignee: Duquesne University of the Holy Spirit
• Inventors: Li, Pui-Kai
• Primary Examiner(s): O'Sullivan, Peter
• Application Number:
  US08/516,021
• Time in Patent Office: 433 Days
• Field of Search: 554/43, 558/50, 514/579, 514/601, 514/600, 514/608, 514/625, 514/630
• US Class Current: 554/43
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/32 Antioestrogens
• CPC Class Codes: C07C 307/02 Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids

Abstract

This invention discloses compounds useful as non-steroidal sulfatase inhibitors. The compounds comprise the formula (1) ##STR1## wherein (a) R₁ is selected from the group consisting of hydrogen and a lower alkyl group, (b) R₂ is selected from the group consisting of H and a lower alkyl group, (c) m is an integer from 0 to 4, and (d) n is an integer from 5 to 14. R₁ is selected from the group consisting of H and C₁ -C₆ alkyl and R₂ is selected from the group consisting of H and C₁ -C₆ alkyl. The invention also discloses methods of treating a patient prophylactically to provide protection as an estrogen depleting agent for estrogen dependent illnesses and treating a patient therapeutically for estrogen dependent diseases. A method of making the non-steroidal sulfatase inhibitors is also disclosed.

Claims

1. A compound comprising the formula (1) ##STR8## wherein (a) R₁ is selected from the group consisting of hydrogen and a lower alkyl group, (b) R₂ is selected from the group consisting of H and a lower alkyl group, (c) m is an integer from 0 to 4, and (d) n is an integer from 5 to 14.

2. The compound of claim 1, wherein

said lower alkyl group has 1 to 6 carbon atoms branched and unbranched.

3. The compound of claim 2, wherein

R₁ is H, R₂ is H, m is 2 and n is 11.

4. The compound of claim 2, wherein

R₁ is H, R₂ is H, m is 2 and n is 10.

5. The compound of claim 2, wherein

R₁ is H, R₂ is H, m is 0 and n is 13.

6. A method of therapeutically treating a patient for estrogen dependent diseases comprising employing a compound having the formula (1) ##STR9## wherein (a) R₁ is selected from the group consisting of hydrogen and a lower alkyl group, (b) R₂ is selected from the group consisting of H and a lower alkyl group, (c) m is an integer from 0 to 4, and (d) n is an integer from 5 to 14;

incorporating said compound in a suitable pharmaceutical carrier;

administering a therapeutically effective dosage of said compound incorporated in said carrier to said patient; and

employing said method in therapeutically treating a patient for estrogen dependent diseases selected from the group consisting of breast cancer, ovarian cancer, vaginal cancer, endometrial cancer and endometriosis.

7. The method of claim 6, including

employing as said carrier a solution selected from the group consisting of physiologic saline and 5% dextrose.

8. The method of claim 7, including administering said compound incorporated in said carrier to a patient by the parenteral route.

9. The method of claim 7, including

administering said compound incorporated in said carrier to a patient by injection.

10. The method of claim 7, including

administering said compound incorporated in said carrier to a patient by the oral route.

11. A method of prophylactically administering to a patient to provide protection as an estrogen depleting agent a compound having the formula (1) ##STR10## wherein (a) R₁ is selected from the group consisting of hydrogen and a lower alkyl group, (b) R₂ is selected from the group consisting of hydrogen and a lower alkyl group, (c) m is an integer from 0 to 4, and (d) n is an integer from 5 to 11;

incorporating said compound in a suitable pharmaceutical carrier;

administering a prophylactically effective dosage of said compound incorporated in said carrier to a patient;

employing said method in prophylactically administering to a patient to provide protection as an estrogen depleting agent against an estrogen dependent illness selected from the group consisting of breast cancer, ovarian cancer, vaginal cancer, endometrial cancer and endometriosis.

12. The method of claim 11, including

employing as said carrier a solution selected from the group consisting of physiologic saline and 5% dextrose in water.

13. The method of claim 12, including

administering said compound incorporated in said carrier to a patient by the parenteral route.

14. The method of claim 12, including

administering said compound incorporated in said carrier to a patient by the oral route.

15. The method of claim 12, including

administering said compound incorporated in said carrier by injection.

16. A method for preparing the compound comprising the formula (1) ##STR11## wherein R₁ is selected from the group consisting of hydrogen and a lower alkyl group, R₂ is selected from the group consisting of H and a lower alkyl group, m is an integer from 0 to 4 and n is an integer from 5 to 14, the method comprising:

adding alkanoyl chloride dropwise into a cooled solution of p-hydroxyphenylamine and triethylamine to form a first mixture;

extracting said first mixture to give a first product N-alkanoyl-p-hydroxyphenylamine;

adding a hydride and a sulfamide to said first product to form a second mixture;

extracting said second mixture to give a second product (p-o-sulfamoyl)-N-alkanoyl p-hydroxyphenylamine.

17. The method of claim 16, further including

stirring said first mixture at room temperature and pouring into acidic solution;

separating, drying, and concentrating under reduced pressure said first mixture to give said first product;

stirring said second mixture at room temperature and pouring into basic solution;

separating, drying and concentrating said second mixture under reduced pressure to give said second product.

18. The method of claim 17, including

employing HCl in said first mixture and extracting said first product with ethylacetate.

19. The method of claim 18, including

employing sodium bicarbonate in said second mixture and extracting said second product with methylene chloride.

20. The method of claim 19, wherein

the alkanoyl chloride has the formula (2) ##STR12## wherein n is an integer from 5 to 14.