Method of locking 1.alpha.-OH of vitamin D compounds in axial or

Details Method of locking 1.alpha.-OH of vitamin D compounds in axial or Method of locking 1.alpha.-OH of vitamin D compounds in axial or

1998-05-21

2000-09-05

Dees, Jose' G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

9,10-seco- cyclopentanohydrophenanthrene ring system doai

552653, A01N 4500, C07C40100

Patent

active

061143170

ABSTRACT:
A method of modifying or altering the structure of a 1.alpha.-hydroxylated vitamin D compound to increase its biological activity by altering the conformational equilibrium of the A-ring to favor a chair conformation that presents the 1.alpha.-hydroxyl in the axial orientation. This is accomplished by either locking the A-ring chair conformation in a geometry having an axially orientated 1.alpha.-hydroxyl, or by the addition of one or more substituents to the A-ring which interact with other substituents in the molecule or on the A-ring to provide a driving force to the A-ring to adopt a chair conformation which presents the 1.alpha.-hydroxyl in the axial orientation.

REFERENCES:
patent: 4666634 (1987-05-01), Miyamoto et al.
patent: 5536713 (1996-07-01), DeLuca et al.
patent: 5877168 (1999-03-01), Miyamoto et al.
patent: 5945410 (1999-08-01), DeLuca et al.
Scheddin et al, 2 beta -chloro, -fluoro, -methoxy, 1 -alpha, 25-dihydroxy vitamin D3, Steroids, 63, 633-43, 1998.
Sato et al, 1 -alpha -hydroxyl derivatives of vitamin D3, Chem. Pharm. Bull., 26, 2933-40, 1978.
Tohira et al, 1 -alpha -[2-3H]-hydroxyvitamin D3, Anal. Biochem., 77, 495-502, 1977.
Posner et al, "2-Fluoroalkyl A-Ring Analogs of 1,25-Dihydroxyvitamin D.sub.3. Stereocontrolled Total Synthesis Via Intramolecular and Intermolecular Diels-Alder Cycloadditions. Preliminary Biological Testing", Journal of Organic Chemistry, vol. 60, No. 14, pp. 4617-4623, Jul. 14, 1995.
Konno et al, "A Novel and Practical Route to A-Ring Enyne Synthon for 1.alpha.,25-Dihydroxyvitamin D.sub.3 Analogs: Synthesis of A-Ring Diastereomers of 1.alpha.,25-Dihydroxyvitamin D.sub.3 and 2-Methyl-1,25-Dihydroxyvitamin D.sub.3 ", Bioorganic & Medicinal Chemistry Letters, vol. 8, No. 2, pp. 151-156, Jan. 20, 1998.
Sincinski et al, "Synthesis, Conformational Analysis and Biological Activity of the 1.alpha., 25-Dihydroxy-10,19-Dihydrovitamin D.sub.3 Isomers", Bioorganic Chemistry, vol. 22, pp. 150-171, 1994.
Fujishima et al, "Synthesis and Biological Activity of 2-Methyl-20-EPI Analogues of 1.alpha.,25-Dihydroxyvitamin D.sub.3 ", Bioorganic & Medicinal Chemistry Letters, vol. 8, No. 16, pp. 2145-2148, Aug. 18, 1998.
Sincinski et al, "New 1.alpha.-25-Dihydroxy-19-Norvitamin D.sub.3 Compounds of High Biological Activity: Synthesis and Biological Evaluation of 2-Hydroxymethyl, 2-Methyl, and 2-Methylene Analogues", Journal or Medicinal Chemistry, vol. 41, pp. 4662-4674, Oct. 22, 1998.
Trinh et al, "Solid-State Conformations of Vitamin D.sub.3 ", J. Org. Chem., vol. 41, No. 21, 1976, pp. 3476-3478.
Trinh et al, "Crystal Structure of 25-Hydroxy-Vitamin D.sub.3 Monohydrate: A Stereo-chemical Analysis of Vitamin D Molecules", J. Org. Chem., 1977, pp. 393-401.
Okamura et al, "Vitamin D: Concerning the Relationship Between Molecular Topology and Biological Function", Proc. Nat. Acada, Sci., U.S.A., Oct. 1974, vol. 71, No. 10, pp. 4194-4197.
Wing et al, "Vitamin D in Solution: Conformations of Vitamin D.sub.3, 1.alpha.,25-Dihydroxyvitamin D.sub.3, and Dihydrotachysterol.sub.3 ", Science 186, 939, 1974, pp. 939-941.
Posner et al, "Stereocontrolled Synthesis of a Trihydroxylated A Ring as an Immediate Precursor to 1.alpha.,2.alpha.,25-Trihydroxyvitamin D.sub.3 ", J. Org. Chem. 56, pp. 4339-4341, Apr. 15, 1991.
Okano et al, "Regulatory Activities of 2.beta.-(3-Hydroxypropoxy)-1.alpha.,25-Dihydroxyvitamin D.sub.3. A Novel Synthetic Vitamin D.sub.3 Derivative on Calcium Metabolism", Biochemical and Biophysical Research Communications, vol. 163, No. 3, pp. 1444-1449, Sep. 29, 1989.

Affiliated with

Also associated with

Rating

Method of locking 1.alpha.-OH of vitamin D compounds in axial or does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Method of locking 1.alpha.-OH of vitamin D compounds in axial or, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method of locking 1.alpha.-OH of vitamin D compounds in axial or will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2212271