# US 8,785,422 B2 · A-ring modified 19-nor-vitamin D analogs and their uses

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- Number: US 8,785,422 B2
- Document ID: US8785422B2
- Status: Granted
- Kind: B2
- Application number: 13/828,168
- Filed: 2013-03-14
- Published: 2013-12-12
- Granted: 2014-07-22
- Earliest claimed: 2012-06-06
- Assignees: Wisconsin Alumni Research Foundation
- Applicants: Wisconsin Alumni Research Foundation
- Inventors: Hector F. DeLuca; Margaret Clagett-Dame; Lori A. Plum; Agnieszka Glebocka
- Web page: https://patentgrep.com/patent/US8785422B2

## CPC

- C07C 401/00: Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
- C07C 2602/24: the ring system containing nine carbon atoms, e.g. perhydroindane
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

Disclosed are 19-nor-vitamin D compounds, and specifically seco-A-2,19-dinor-1,25-dihydroxyvitamin D3 as well as pharmaceutical uses therefor. These compounds exhibit relatively high activity in vivo, specifically in intestinal tissues, but relatively low VDR binding activity, cell differentiation activity and gene transcription activity. There is thus potential for these compounds to have strong cell selectivity for use as therapeutic agents against some cancers, such as colon cancer or polyps, as well as hyperplastic intestinal disorders, such as Crohn's disease, ulcerative colitis and celiac disease. These compounds also have relatively high intestinal calcium transport activity evidencing potential in the treatment of bone diseases.

## Claims

### Claim 1

A compound having the formula:
where X is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where R may be an alkyl, hydrogen, hydroxyalkyl or fluoroalkyl group, or R may represent a side chain of the formula:
where the stereochemical center at carbon 20 may have the R or S configuration, and where Z in the above side chain structure is selected from Y, —OY, —CH2OY, —C≡CY and —CH═CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —COR5 and a radical of the structure:
where m and n, independently, represent the integers from 0 to 5, where R1 is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C1-5-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R2, R3, and R4, independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R1 and R2, taken together, represent an oxo group, or an alkylidene group having a general formula CkH2k— where k is an integer, the group ═CR2R3, or the group —(CH2)p—, where p is an integer from 2 to 5, and where R3 and R4, taken together, represent an oxo group, or the group —(CH2)q—, where q is an integer from 2 to 5, and where R5 represents hydrogen, hydroxy, protected hydroxy, or C1-5 alkyl and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —CH(CH3)—, —(CH2)m—, —CR1R2— or —(CH2)n— at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.

### Claim 2 (depends on 1)

The compound of claim 1 wherein X is hydrogen.

### Claim 3 (depends on 1)

The compound of claim 1 wherein R is selected from:

### Claim 4 (depends on 3)

The compound of claim 3 wherein X is hydrogen.

### Claim 5 (depends on 1)

A pharmaceutical composition containing an effective amount of at least one compound as claimed in claim 1 together with a pharmaceutically acceptable excipient.

### Claim 6 (depends on 5)

The pharmaceutical composition of claim 5 wherein said effective amount composes from about 0.01 μg to about 1000 μg per gram of composition.

### Claim 7 (depends on 5)

The pharmaceutical composition of claim 5 wherein said effective amount comprises from about 0.1 μg to about 500 μg per gram of composition.

### Claim 8

A compound having the formula:
and named seco-A-2,19-dinor-1,25-dihydroxyvitamin D3.

### Claim 9

A pharmaceutical composition containing an effective amount of seco-A-2,19-dinor-1,25-dihydroxyvitamin D3 together with a pharmaceutically acceptable excipient.

### Claim 10 (depends on 9)

The pharmaceutical composition of claim 9 wherein said effective amount comprises from about 0.01 μg to about 1000 μg per gram of composition.

### Claim 11 (depends on 9)

The pharmaceutical composition of claim 9 wherein said effective amount comprises from about 0.1 μg to about 500 μg per gram of composition.

### Claim 12

A method of treating a disease selected from the group consisting of colon cancer, Crohn's disease, ulcerative colitis, and celiac disease comprising administering to a subject with said disease an effective amount of a 19-nor-vitamin D having the formula:
where X is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where R may be an alkyl, hydrogen, hydroxyalkyl or fluoroalkyl group, or R may represent a side chain of the formula:
where the stereochemical center at carbon 20 may have the R or S configuration, and where Z in the above side chain structure is selected from Y, —OY, —CH2OY, —C≡CY and —CH═CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —COR5 and a radical of the structure:
where m and n, independently, represent the integers from 0 to 5, where R1 is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C1-5-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R2, R3, and R4, independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R1 and R2, taken together, represent an oxo group, or an alkylidene group having a general formula CkH2k— where k is an integer, the group ═CR2R3, or the group —(CH2)p—, where p is an integer from 2 to 5, and where R3 and R4, taken together, represent an oxo group, or the group —(CH2)q—, where q is an integer from 2 to 5, and where R5 represents hydrogen, hydroxy, protected hydroxy, or C1-5 alkyl and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —CH(CH3)—, —(CH2)m—, —CR1R2— or —(CH2)n— at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.

### Claim 13 (depends on 12)

The method of claim 12 wherein the vitamin D is administered orally.

### Claim 14 (depends on 12)

The method of claim 12 wherein the vitamin D is administered parenterally.

### Claim 15 (depends on 12)

The method of claim 12 wherein the vitamin D is administered transdermally.

### Claim 16 (depends on 12)

The method of claim 12 wherein the vitamin D is administered rectally.

### Claim 17 (depends on 12)

The method of claim 12 wherein the vitamin D is administered nasally.

### Claim 18 (depends on 12)

The method of claim 12 wherein the vitamin D is administered sublingually.

### Claim 19 (depends on 12)

The method of claim 12 wherein the vitamin D is administered in a dosage of from about 0.01 μg/day to about 1000 μg/day.

### Claim 20 (depends on 12)

The method of claim 12 wherein the vitamin D has the formula:
and is named seco-A-2,19-dinor-1,25-dihydroxyvitamin D3.

### Claim 21

A method of treating metabolic bone disease where it is desired to maintain or increase bone mass comprising administering to a patient with said disease an effective amount of a compound having the formula:
where X is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where R may be an alkyl, hydrogen, hydroxyalkyl or fluoroalkyl group, or R may represent a side chain of the formula:
where the stereochemical center at carbon 20 may have the R or S configuration, and where Z in the above side chain structure is selected from Y, —OY, —CH2OY, —C═CY and —CH═CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —COR5 and a radical of the structure;
where m and n, independently, represent the integers from 0 to 5, where R1 is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C1-5-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R2, R3, and R4, independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R1 and R2, taken together, represent an oxo group, or an alkylidene group having a general formula CkH2k— where k is an integer, the group ═CR2R3, or the group —(CH2)p—, where p is an integer from 2 to 5, and where R3 and R4, taken together, represent an oxo group, or the group —(CH2)q—, where q is an integer from 2 to 5, and where R5 represents hydrogen, hydroxy, protected hydroxy, or C1-5 alkyl and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —CH(CH3)—, —(CH2)m—, —CR1R2— or —(CH2)n— at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.

### Claim 22 (depends on 21)

The method of claim 21 wherein the compound is administered orally.

### Claim 23 (depends on 21)

The method of claim 21 wherein the compound is administered parenterally.

### Claim 24 (depends on 21)

The method of claim 21 wherein the compound is administered transdermally.

### Claim 25 (depends on 21)

The method of claim 21 wherein the compound is administered rectally.

### Claim 26 (depends on 21)

The method of claim 21 wherein the compound is administered nasally.

### Claim 27 (depends on 21)

The method of claim 21 wherein the compound is administered sublingually.

### Claim 28 (depends on 21)

The method of claim 21 wherein the compound is administered in a dosage of from about 0.01 μg/day to about 1000 μg/day.

### Claim 29 (depends on 21)

The method of claim 21 where the disease is senile osteoporosis.

### Claim 30 (depends on 21)

The method of claim 21 where the disease is postmenopausal osteoporosis.

### Claim 31 (depends on 21)

The method of claim 21 where the disease is steroid-induced osteoporosis.

### Claim 32 (depends on 21)

The method of claim 21 where the disease is low bone turnover osteoporosis.

### Claim 33 (depends on 21)

The method of claim 21 where the disease is osteomalacia.

### Claim 34 (depends on 21)

The method of claim 21 where the disease is renal osteodystrophy.

### Claim 35 (depends on 21)

The method of claim 21 wherein the compound has the formula:
and is named seco-A-2,19-dinor-1,25-dihydroxyvitamin D3.