6,011,024 Jan. 4, 2000

Transcription

1 United States Patent [19] Reed et al. US A [11] Patent Number: [45] Date of Patent: 6,011,024 Jan. 4, 2000 [54] STEROID SULPHATASE INHIBITORS [75] Inventors: Michael John Reed, London; Barry Victor Lloyd Potter, Avon, both of United Kingdom [73] Assignee: Imperial College of Science Technology & Medicine, London, United Kingdom [21] Appl. No.2 09/111,927 [22] Filed: Jul. 8, 1998 Related US. Application Data [62] Continuation-in-part of application No. 08/458,352, Jun. 2, 1995, Pat. No. 5,830,886, application No. PCT/GB97/ 00600, Mar. 4, 1997, application No. PCT/GB97/00444, Feb. 17, 1997, and application No. PCT/GB97/03352, Dec. 4, 1997, said application No. 08/458,352, is a division of application No. 08/196,192,?led as application No. PCT/ GB92/01587, Aug. 28, 1992, Pat. No. 5,616,574. [30] Foreign Application Priority Data Aug. 28, 1991 [GB] United Kingdom [51] Int. Cl A61K 31/165 [52] US. Cl /171; 514/178; 514/601; 514/603; 514/604 [58] Field of Search /178, 171, 514/603, 604 [56] References Cited U.S. PATENT DOCUMENTS 4,937,237 6/1990 Holtetal.. 5,281,587 1/1994 Reed. 5,344,827 9/1994 Reed. 5,604,215 2/1997 Reed et al.. 5,616,574 4/1997 Reed etal.. 5,677,292 10/1997 Li et al.. WPI AN , Y. Lo et al, Tierexperimenteller Beitrag Zur EntWicklung Estrogener Wirkstoffe, Dissertation sur Erlangung des akademischen Grades eines Doktors der Wissenschaften an der Mathema tisch NaturWissenschaftlich Technischen Fakultat des Wis senschaftlichen Rates der Friedrich Schiller Universitat Jena, Wolfgang StolZner, Jena, Germany, Aug ErythroZyten als ArZneimitteltrager Untersuchungen mit ausgewahlten Estrogenen Zur Beladung nach oraler Gabe, Dissertation B sur Erlangung des akademischen Grades eines Doktors der Wissenschaften, Der Fakultat fiir Natur Wissenschaftlichen Rates der Martin Luther Universitat Halle Wittenberg, Claus Claussen, Jena, Germany, Aug SchWarZ et al., PharmaZie, vol. 30 (1975), pp HoWarth et al., J. Med. Chem., vol. 37 (1994), pp ToWnsley et al., Research Steroids, vol. 5 (1973), pp Zeitschrift Fur Chemie, vol. 14, No. 1, 1974, pp Primary Examiner Rebecca Cook Attorney, Agent, or Firm Frommer Lawrence & Haug LLp; Thomas J. KoWalski [57] ABSTRACT A method of inhibiting steroid sulphatase activity in a subject in need of same is described. The method comprises administering to said subject a steroid sulphatase inhibiting amount of a ring system compound; Which ring system compound comprises a ring to Which is attached a sulpha mate group of the formula FOREIGN PATENT DOCUMENTS /1990 European Pat. Off /1972 France /1975 United Kingdom. OTHER PUBLICATIONS Animal Experimental Contribution to the Development of Estrogenic Substances (hereinafter the StolZer Disserta tion ), Dissertation for award of Doctor of Science degree at the Mathematic NaturWissenschaftlichh Technischen Fac ulty of Friedrich Schiller University Jena, Jul Erythrocytes as a drug carrier Investigations With selected estrogens for loading following oral administration, Natural Science Faculty, Science Council, Martin Luther Universi tat Halle Wittenberg, Germany, Aug. 1989, Claussen. Wherein each of R1 and R2 is independently selected from H, alkyl, alkenyl, cycloalkyl and aryl, or together represent alkylene optionally containing one or more hetero atoms or groups in the alkylene chain; and Wherein said compound is an inhibitor of an enzyme having steroid sulphatase activity (E.C ); and if the sulphamate group of said compound is replaced With a sulphate group to form a sulphate com pound and incubated With a steroid sulphatase enzyme (E.C ) at a ph 7.4 and 37 C. it Would provide a Km value of less than 50 pm. 6 Claims, 26 Drawing Sheets

2 U.S. Patent Jan. 4,2000 Sheet 1 0f 26 6,011,024 mbwiaiw mzommpwomqz<emomq>imq l mzommhwomazinmomatlmo [x4 F GE

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7 U.S. Patent Jan. 4,2000 Sheet 6 0f 26 6,011,024 FIG. 6

8 U.S. Patent Jan. 4,2000 Sheet 7 0f 26 6,011,024 IO QI N

9 U.S. Patent Jan. 4,2000 Sheet 8 0f 26 6,011,024 Oil (12) (14) Me 0 FIG. 8 Me 0 HO

10 U.S. Patent Jan. 4,2000 Sheet 9 0f 26 6,011, a: 288 iv Q: GE m m2

11 U.S. Patent Jan. 4, 2000 Sheet 10 0f 26 6,011,024 (16) P///// ////////////////~ FIG (15) 10 (14) (0M) INHIBITORS 0.1 (13) \\\\\\\\\\\\\\ (X) co 5? NOIilElHNI % N O

12 U.S. Patent Jan. 4,2000 Sheet 11 0f 26 6,011, on a 2 o m 2% m2: zoimgozmml cm Ail/\LLOV IVNIEDIHO % SO I

13 U.S. Patent Jan. 4,2000 Sheet 12 0f 26 6,011,024 0 M u axaaiéov M2238 O3 NOIiISIHNI %

14 U.S. Patent Jan. 4, 2000 Sheet 13 0f 26 6,011,024 R4 R2 R5 R6 X 0 R1 (A) R3 R4 R2 R 5 R 1 \ R6 0 0 (B) R3 R4 R5 (CH2)n \ R6 X 0 (C)

15 U.S. Patent Jan. 4, 2000 Sheet 14 0f 26 6,011,024 FIG.14 (D) R4 R5 \ R6 0 O R4 (F) \ 0 0 (G) R4 R3 R4 (H) R5 \ R5 \ R6 0 0 R6 0 O

16 U.S. Patent Jan. 4,2000 Sheet 15 0f 26 6,011,024 GI m 5

17 U.S. Patent Jan. 4,2000 Sheet 16 0f 26 6,011,024 FIG. 16a X E Y A B C D I FIG. 16b 0 H F J G Y H FIG. 16C III

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