Vitamin D derivatives with phosphorus atoms in the side chains

Details Vitamin D derivatives with phosphorus atoms in the side chains Vitamin D derivatives with phosphorus atoms in the side chains

2000-08-04

2003-03-11

Badio, Barbara P. (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

9,10-seco- cyclopentanohydrophenanthrene ring system doai

C552S653000

Reexamination Certificate

active

06531459

ABSTRACT:

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.
FIG. 1
shows the structure of some known vitamin D derivatives.
In addition to their pronounced effect on the calcium and phosphate metabolism, the active metabolites of vitamins D
2
and 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, and 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 bonding to the vitamin D receptor. Because of the bonding, the activity of specific genes is regulated.
When biologically active metabolites of vitamins D
2
and D
3
are used, 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, especially if a cyclopropyl ring is in the neighboring position. 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
means a hydrogen atom, a hydroxyl group, a fluorine, chlorine or bromine atom or a group —O(CO)R
5
, in which
R
5
is an aliphatic or aromatic radical with 1 to 12 C atoms,
Y
2
means a hydrogen atom or a group —(CO)R
6
, in which
R
6
is an aliphatic or aromatic radical with 1 to 12 C atoms,
and group Y
2
O can be present both in naturally occurring situation (3&bgr;) and in epimeric situation (3&agr;),
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 chlorine or fluorine 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,
V and W together mean an E-double bond or V means a hydroxyl group and W means a hydrogen atom, or V and W each mean hydrogen atoms,
X
1
and X
2
, independently of one another, mean a hydrogen atom, a hydroxyl group, a group —OR
7
or O(CO)R
7
, in which
R
7
is an aliphatic or aromatic radical with 1 to 12 C atoms,
 or a group PO(OR
8
)
2
, a group PO(N(R
8
)
2
)
2
or a group PO(R
8
)
2
, a group OPO(OR
8
)
2
, a group OPO(N(R
8
)
2
)
2
or a group OPO(R
8
)
2
or a group CH
2
—PO(OR
8
)
2
, a group CH
2
—PO(N(R
8
)
2
)
2
or a group CH
2
—PO(R
8
)
2
, in which
R
8
, independently of one another, are a hydrogen atom or an aliphatic or aromatic radical with 1 to 12 C atoms,
 or
X
1
and X
2
together stand for a carbonyl group,
p means the number 1 or 0,
E
1
means a group PO(OR
9
)
2
, a group PO(N(R
9
)
2
)
2
, a group PO(R
9
)
2
or a group CO
2
R
9
in which
R
9
, independently of one another, are a hydrogen atom or an aliphatic or aromatic radical with 1 to 12 C atoms,
E
2
means a group PO(OR
9
)
2
, a group PO(N(R
9
)
2
)
2
, a group PO(R
9
)
2
, a halogen atom (fluorine, chlorine, bromine), an aliphatic or aromatic radical with 1 to 12 C atoms or a hydrogen atom,
Q means a hydrogen atom, an aliphatic or aromatic radical with 1 to 12 C atoms, a hydroxyl group, a group —O(CO)R
10
, a fluorine, chlorine or bromine atom, an amino group or an NHR
10
or N(R
10
)
2
group, in which
R
10
is an aliphatic or aromatic radical with 1 to 12 C atoms,
 or
X
1
and E
2
together mean a double bond and at the same time X
2
means a hydrogen atom or a group O—Z, in which
Z means an aliphatic or aromatic radical with 1 to 12 C atoms, an aliphatic or aromatic acyl group with 1 to 12 C atoms or a group E
2
,
 or
X
1
, X
2
, E
2
and Q together mean a triple bond.
The invention also relates to a process for the production of the compounds according to the invention, intermediate products of 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.
Groups E
1
and E
2
, i.a., stand for phosphonic acid derivatives or carboxylic acid derivatives or for phosphine oxide derivatives. The term phosphonic acid derivatives or carboxylic acid derivatives comprises the free phosphonic acids or carboxylic acids (—PO
3
H
2
, —CO
2
H), phosphonic- or carboxylic acid esters (—PO
3
(R
9
)
2
, —CO
2
R
9
), phosphonic- or carboxylic acid amides (e. g., —PO(N(R
9
)
2
)
2
, —CO(NR
9
)
2
, —PO(NHR
9
)
2
, —CO
2
NHR
9
), but also phosphonic acid monoesters or -amides, such as, e.g., PO(OH)OR
9
, PO(OH)N(R
9
)
2
.
Groups X
1
and X
2
, i.a., stand for hydrogen atoms, hydroxyl groups, etherified or esterified hydroxyl groups. They can also stand for (E
1
and E
2
) already defined above under phosphoric acid derivatives (—PO
3
H
2
, —PO
3
(R
8
)
2
, —PO(N(R
8
)
2
)
2
, —PO(NHR
8
)
2
, but also phosphonic acid monoesters or amides). This conformation and its synthesis is described in, for example, Example 29. Groups X
1
and X
2
together can also stand for a carbonyl group, however (see, e.g., Example 10).
It is common in all compounds according to the invention that at least one phosphorus-containing group is contained that is bonded to the vitamin D skeleton by a phosphorus-carbon bonding. Especially preferred are compounds in which both groups (E
1
and E

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