Vitamin D derivatives with cyclic substructures in the side...

Details Vitamin D derivatives with cyclic substructures in the side... Vitamin D derivatives with cyclic substructures in the side...

2000-07-24

2003-08-05

Qazi, Sabiha (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

9,10-seco-cyclopentanohydrophenanthrene ring system or...

C514S167000

Reexamination Certificate

active

06603031

ABSTRACT:

This application claims priority of German 199,3.5771.4 filed on Jul. 23, 1999.
The invention relates to new vitamin D derivatives of general formula I
process for their production, intermediate products of the process as well as the use for the production of pharmaceutical agents.
PRIOR ART
Natural vitamins D
2
and D
3
are inherently biologically inactive and are converted into biologically active metabolites [1&agr;, 25-dihydroxy vitamin D
3
(calcitriol) or -D
2
] only after hydroxylation at C-atom 25 in the liver and at C-atom 1 in the kidney. The action of the active metabolites involves the regulation of the calcium and phosphate concentration in the serum; they counteract a dropping of the calcium concentration in the serum by increasing the calcium absorption in the intestine and under certain circumstances promoting calcium mobilization from the bones. Table 1 shows the structure of some known vitamin D derivatives:
TABLE 1

Ergocalciferol:
R
a
═R
b
═H, R
c
═CH
3,
Double bond C-22/23
Vitamin D
2
Cholecalciferol:
R
a
═R
b
═R
c
═H,
Vitamin D
3
25-Hydroxycholecalciferol:
R
a
═R
c
═H, R
b
═OH,
1a-Hydroxycholecalciferol:
R
a
═OH, R
b
═R
c
═H
1a,25-Diydroxycholecalciferol:
R
a
═R
b
═OH, R
c
═H
In addition to their pronounced effect on the calcium and phosphate metabolism, the active metabolites of vitamin D
2
and vitamin D
3
and their synthetic derivatives have a proliferation-inhibiting and differentiation-stimulating action on tumor cells and normal cells, such as, for example, skin cells. In addition, a pronounced effect on cells of the immune system (inhibiting of proliferation and interleukin-2-synthesis of lymphocytes, increase of cytotoxicity and phagocytosis in vitro of monocytes) has been found, which manifests itself in an immunomodulatory action. Finally, because of a stimulating action on bone-forming cells, an increased formation of bone in normal and osteoporotic rats is found [R. Bouillon et al. “Short Term Course of 1,25(OH)
2
D
3
Stimulates Osteoblasts But Not Osteoclasts,” Calc. Tissue Int. 49, 168 (1991)]. All actions are mediated by binding to the vitamin D receptor. Because of the binding, the activity of specific genes is regulated.
When using biologically active metabolites of vitamins D
2
and D
3
, a toxic effect on the calcium metabolism is produced (hypercalcemia).
By structural manipulations of the side chain, therapeutically usable effectiveness can be separated from undesirable hypercalcemic activity. A suitable structural variant is the introduction of a 24-hydroxy group.
1&agr;-Cholecalciferols that are hydroxylated in 24-position are already described in DE 25 26 981. They have a lower toxicity than the corresponding non-hydroxylated 1&agr;-cholecalciferol. Further, 24-hydroxy derivatives are described in the following patent applications: DE 39 33 034, DE 40 03 854, DE 40 34 730 (?), EP 0 421 561, EP 0 441 467, WO 87/00834, and WO 91/12238.
Finally, 25-carboxylic acid derivatives of calcitriol that are hydroxylated at C-24 are described in WO 94/07853, and said derivatives exhibit a more advantageous spectrum of action than calcitriol. The equivalent is also true for new vitamin D derivatives with other substituents at C-25 (WO 97/00242). While the ability to trigger a hypercalcemia is considerably weakened, proliferation-inhibiting and differentiation-stimulating actions are maintained. Generally, however, the introduction of the 24-hydroxyl group results in metabolic destabilization of the derivatives. For this reason, these compounds are only conditionally suitable for systemic administration.
There is therefore a need for new vitamin D derivatives that have as advantageous or improved a spectrum of action as the compounds that are described in the prior art (especially WO 94/07853 and WO 97/00242), but that are better suited for systemic administration owing to their higher metabolic stability.
The object of this patent application is therefore to make available such vitamin D derivatives. This object is achieved by the compounds that are disclosed in the claims.
This invention therefore relates to vitamin D derivatives of general formula I,
in which
Y
1
and Y
2
, independently of one another, each mean a hydrogen atom or a group —C(O)R
5
,
and Y
3
means a hydrogen atom or a hydroxy group, a halogen atom, a group —OC(O)R
5
or an —OR
5
group, whereby
R
5
stands for an aromatic radical with 5 to 12 C atoms or for an aliphatic, straight-chain or branched, saturated or unsaturated C
1
-C
12
alkyl radical, which optionally is interrupted by 1-2 oxygen atoms, 1-2 sulfur atoms and/or 1-2 NH groups and/or optionally is substituted by 1-2 hydroxy groups, 1-2 amino groups, 1-2 SH groups, 1-2 COOH groups and/or 1-2 phenyl groups,
and the group Y
3
can be present both in the 2&agr;-situation and the epimeric 2&bgr;-situation,
R
1
and R
2
each mean a hydrogen atom or together an exocyclic methylene group,
R
3
and R
4
, independently of one another, mean a hydrogen atom, a fluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms, together a methylene group or together with quaternary carbon atom 20 a 3- to 7-membered, saturated or unsaturated carbocyclic ring,
Q means a straight-chain alkylene group with 1 to 5 carbon atoms,
X
1
and X
2
together mean a double-bound keto-oxygen atom or, independently of one another, a hydrogen atom, a hydroxy group, an —OC(O)R
5
group, a fluorine, chlorine or bromine atom, whereby X
1
and X
2
, not at the same time, each should be a hydroxy group or each an —OC(O)R
5
group,
Z means a carbocyclic or heterocyclic, optionally aromatic or heteroaromatic ring with 5 or 6 ring members or a condensed ring system that consists of a 5- and a 6-membered ring or two 6-membered rings, which can be substituted by one or more fluorine, chlorine, bromine or iodine atoms, one or more hydroxy groups, one or more COOR
6
groups, one or more C
1
-C
5
alkyl groups, which in turn can be substituted by one or more fluorine, chlorine, bromine or iodine atoms, C
1
-C
6
alkoxy groups and/or COOR
6
groups, whereby
R
6
stands for a C
1
-C
6
alkyl group, a benzyl group or a phenyl group,
and all possible epimers or diastereomers and mixtures thereof.
The invention also relates to a process for the production of the compounds according to the invention, intermediate products in the production process as well as the use of the compounds according to the invention for the production of pharmaceutical agents.
Especially advantageous embodiments of the invention are the subject of the subclaims.
The group —C(O)R
5
, which is defined for Y
1
and Y
2
, can carry 1 to 13 carbon atoms and is derived especially from saturated carboxylic acids. The radicals can be cyclic, acyclic, straight-chain or branched, saturated or unsaturated, carbocyclic or heterocyclic. The radicals are preferably derived from C
1
-C
9
carboxylic acids. For example, formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid and pivalic acid can be mentioned. The groups Y
1
and Y
2
, independently of one another, especially preferably can each mean a hydrogen atom or an acetyl, propionyl or pivaloyl group.
This explanation is also used for the group —OC(O)R
5
, which is defined for the radicals Y
3
, X
1
and X
2
.
The group Y
3
can mean a hydrogen atom, a fluorine, chlorine or bromine atom or a hydroxy group, an OR
5
group or an —OC(O)R
5
group.
The alkoxy group Y
3
can mean straight-chain or branched, preferably unsubstituted and without interruption of heteroatoms, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy. The preferred chain length is C
1
-C
9
.
Groups R
3
and R
4
, independently of one another, can each mean a fluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms (methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl), together a methylene group or together with quaternary carbon atom 20 a 3- to 7-membered, saturated or unsaturated carbocyclic ring.
F

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