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Inhibitors of type 5 and type 3 17beta-hydroxysteroid dehydrogenase and methods for their use

a technology of 17beta-hydroxysteroid and dehydrogenase, which is applied in the field of androgen-sensitive inhibitors, can solve the problems of benign prostatic hyperplasia responding unfavorably, unfavorable benign prostatic hyperplasia, and undesirable initial upward spike of androgenic production and secretion by the testes

Inactive Publication Date: 2004-04-29
ENDORES & DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009] It is accordingly an object of the present invention to more selectively and effectively inhibit type 3 and / or type 5 17.beta.-hydroxysteroid dehydrogenase while preferably avoiding inhibition of other 17.beta.-hydroxysteroid dehydrogenases, type 1 or 2 3.alpha.-hydroxysteroid dehydrogenases, or other androgen degradation enzymes.

Problems solved by technology

They may, for example, respond favorably, unfavorably or not at all to androgens.
An undesirable initial upward spike of androgenic production and secretion by the testes occurs during the very early portion of treatment with LHRH agonist, prior to the beginning of the beneficial effect of androgen reduction caused by LHRH agonist.
Strategies which suppress formation of certain androgens may increase levels of precursors thereto which are also estrogen precursors thus undesirably increasing estrogen formation.
On the other hand, benign prostatic hyperplasia responds unfavorably to activation of either the estrogen or androgen receptor.
However, these combinations may be supplemented using one or more of the six strategies listed above, limited only by whether a particular disease responds favorably or adversely to estrogenic activity or to androgenic activity.

Method used

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  • Inhibitors of type 5 and type 3 17beta-hydroxysteroid dehydrogenase and methods for their use
  • Inhibitors of type 5 and type 3 17beta-hydroxysteroid dehydrogenase and methods for their use
  • Inhibitors of type 5 and type 3 17beta-hydroxysteroid dehydrogenase and methods for their use

Examples

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Effect test

example 1

Synthesis of 6-methyl 4,6-pregnadien / 1,4,6-pregnatrien-17-ol-3,20-dione Alkanoates / Benzoates

[0556] These syntheses are described in Schemes 1 and 2. 71 72

example 1a

[0557] 6-methyl-1,4,6-Pregnatrien-17.alpha.-ol-3,20-dione acetate (2; EM-910):

[0558] Megestrol acetate (2.5 g; 6.7 mmol) and DDQ (5.07 g; 22 mmol) in dioxane (30 mL) were refluxed for 2 h. Solvent was removed and the mixture in EtOAc was washed with saturated NaHCO.sub.3 solution (3 times). Solvent was dried (MgSO.sub.4) and evaporated to give the product. Purification on silica gel column (hexanes / acetone) gave the trienone (2.1 g) in 90% yield; IR (KBr, cm.sup.-1) 2953, 2895, 1729, 1709, 1658, 1646, 1610, 1365, 1264, 1247, 887. .sup.1H NMR (CDCl.sub.3) .delta. 0.69 (s, 3H, H-C18), 1.13 (s, 3H, H-C19), 1.87 (s, 3H, 6-CH3), 2.0 (s, 3H) 2.02 (s, 3H), 2.89-2.98 (m, 1H), 5.79 (s, 1H), 6.22 (s, 1H), 6.20-6.24 (m, 1H, 2-H), 7.04 (d, 1H, 1-H, J=10 Hz); .sup.13C NMR (CDCl.sub.3) .delta. 203.7, 186.4, 170.6, 163.2, 153.4, 134.5, 131.8, 127.7, 121.6, 96.2, 49.1, 47.9, 47.1, 41.1, 37.7, 31.1 30.3, 26.4, 23.2, 21.5, 20.5 19.2, 14.4.

example 1b

[0559] 6-methyl-4,6-Pregnadien-17.alpha.-ol-3,20-dione (3): Megestrol acetate (11.2 g) was dissolved in 200 mL of boiling MeOH and to this, was added 2N NaOH (20 mL). The mixture was refluxed for 5 h. Approx. 100 mL of MeOH was removed, and water (50 mL) was added and the suspension was cooled to 0.degree. C. to give a solid, which was filtered and washed with water (9.6 g, 96%); IR (KBr, cm.sup.-1) 3493, 2942, 2767, 1702, 1658, 1646, 1623, 1575. .sup.1H NMR (CDCl.sub.3) .delta. 0.75 (s, 3H, H-C18), 1.06 (s, 3H, H-C19), 1.81 (s, 3H, 6-CH.sub.3), 2.25 (s, 3H), 2.96 (s, 1H), 5.83 (s, 1H), 5.95 (s, 1H); .sup.13C NMR (CDCl.sub.3) .delta. 211.3, 200.0, 164.4, 138.5, 131.1, 121.0, 89.5, 50.3, 48.7, 47.9, 36.9, 36.1, 34.0 33.5, 30.2, 27.7, 23.3, 20.1, 19.8 16.3, 15.2.

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Abstract

Novel methods of medical treatment and / or inhibition of development of diseases are disclosed for diseases that are sensitive to androgenic or estrogenic activity. The treatments utilize inhibitors of type 5 and / or type 3 17beta-hydroxysteroid dehydrogenase. Novel inhibitors of type 5 17beta-hydroxysteroid dehydrogenase are also disclosed, as are novel inhibitors of type 3 17beta-hydroxysteroid dehydrogenase.

Description

[0001] This patent application is a regular, non-provisional application claiming priority of provisional application Serial No. 60 / 077,510, filed Mar. 11, 1998, the entire specification of which is incorporated by reference as though fully set forth herein. This application also claims priority of U.S. Provisional Application Serial No. 60 / 095,623, filed Aug. 7, 1998, the entire disclosure of which is incorporated by reference as though fully set forth herein.[0002] The present invention relates to inhibitors of enzymes involved in the biosynthesis of sex steroids from natural precursors and to their use in the treatment of sex steroid dependent diseases. In particular, inhibitors are disclosed which suppress the activity of type 3 and type 5 17.beta.-hydroxysteroid dehydrogenase, thus diminishing the production of androgens catalyzed by these two enzymes. Pharmaceutical use of the inhibitors may reduce the natural production of androgens such as testosterone and dihydrotestosteron...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/56A61K31/566A61K31/5685A61K31/57A61K31/575A61K31/585A61K45/06A61P5/28A61P13/08A61P15/00A61P17/08A61P17/10A61P17/14A61P35/00A61P43/00C07J1/00C07J5/00C07J9/00C07J21/00C07J41/00C07J63/00
CPCA61K31/566A61K31/5685A61K31/585A61K45/06C07J21/00A61K2300/00A61P13/08A61P15/00A61P17/00A61P17/08A61P17/10A61P17/14A61P35/00A61P43/00A61P5/24A61P5/28
Inventor LABRIE, FERNANDBELANGER, ALAINGAUTHIER, SYLVAINLUU-THE, VANMERAND, YVESPOIRIER, DONALDPROVENCHER, LOUISSINGH, SHANKAR M.
Owner ENDORES & DEV
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