Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-07-12
2001-06-05
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
C514S725000
Reexamination Certificate
active
06242435
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions comprising certain retinoids and vitamin D analogs useful in inducing differentiation and inhibiting undesirable proliferation of cells, such as cancer cells and skin cells. The present invention also relates to methods of using the above compositions in the treatment of diseases and conditions characterized by abnormal cell differentiation and/or cell proliferation.
DESCRIPTION OF THE RELATED ART
Abnormal cell differentiation and/or cell differentiation is associated with many conditions and diseases. For instance, hyperproliferation of epithelial cells is associated with psoriasis causes the skin to shed itself too rapidly, every three to four days. The goal in treating psoriasis is to reduce inflammation and to slow down rapid skin cell division.
U.S. Pat. No. 4,866,048 discloses that certain vitamin D derivatives, in particular calcitriol (1 alpha,25-dihydroxy-vitamin D
3
or) and calcipotriol are able to stimulate the differentiation of cells and inhibit excessive cell proliferation, and it has been suggested that these compounds are useful in the treatment of diseases characterized by abnormal cell differentiation and/or cell differentiation such as leukemia, myelofibrosis, psoriasis and acne.
Certain retinoids are also known for their antiproliferative and differentiation activity. For instance, retinol (vitamin A) is an endogenous compound which occurs naturally in the human body and is essential for normal cell differentiation of certain cell types such as epithelial cells. Retinoic acid is believed to be an active derivative of retinol. Thus, retinoic acid is believed to be more effective than retinol and retinyl esters at providing skin benefits.
Natural and synthetic vitamin A derivatives (including retinoic acid) have been used extensively in the treatment of a variety of skin and hyperproliferation disorders. For example, retinoic acid has been employed to treat certain types of leukemia like acute apromyelocytic leukemia as well as a variety of skin conditions such as acne, wrinkles, psoriasis, age spots and discoloration (Vahlquist, A. et al.,
J. Invest. Dermatol.,
Vol. 94, Holland D. B. and Cunliffe, W. J. (1990), pp. 496-498; Ellis C. N. et al., “Pharmacology of Retinols in Skin”, Vasel, Karger, Vol. 3, (1989), pp.249-252; Lowe, N. J. et al., Vol. 3, (1989), pp. 240-248; PCT Patent Application No. WO 93/19743). Although retinoids have been viewed classically as cancer prevention agents, considerable laboratory evidence supports their testing as antitumor drugs as well (Cancer Treat Rep 1987; 71: 493-515 May, 1987).
It is important to note that while clinical experience with either retinoids or vitamin D derivatives against conditions associated with abnormal cell differentiation and/or cell differentiation has met with certain amount of success in some instances, these compounds have frequently been unable to provide the desired clinical results.
For instance, the synthetic Vitamin D, calcipotriol, or retinoic acid which are available in prescription form are somewhat useful for individuals with localized psoriasis. However, these compound are not very effective on most patients.
Therapeutic regimens for acne involve local and systemic therapies, although the former is indicated in the vast majority of cases. Topical application of a variety of chemical application which include mainly sulfur, resorcinol, salicylic acid, benzoyl peroxide, and retinoic acid are frequently used to treat acne. All the foregoing agents are known as “peeling” or “drying” agents which are believed to exert their therapeutical effect by causing erythema, irritation, and desquamination of the skin to expel comedones. The therapeutic efficacy of these agents, however, is rather variable, and their utility is limited partially because of the irritation caused by their application (see U.S. Pat. No. 3,932,665). Oral formulations of retinoic acid are also used but serious side effects are associated with the oral use of this compound including severe fetal malformation in pregnant women.
SUMMARY OF THE INVENTION
The present invention provides compositions comprising certain vitamin D and retinoid compounds which are useful for the treatment of disorders characterized by abnormal cell-proliferation and/or cell-differentiation.
Specifically, the present invention provides a composition comprising a vitamin D analog and a retinoid, wherein:
(a) the vitamin D analog is capable of binding a vitamin D receptor or being converted in vivo into a compound capable of binding a vitamin D receptor; and
(b) the retinoid is selected from the group consisting of retinol in a concentration of at least about 1.0% by weight, a compound in a concentration of at least about 1.0% by weight capable of being converted in vivo into retinol, retinoid D with an alcohol CH
2
OH terminal side chain, retinoid D with an ester at the terminal side chain, retinoid D with an ether at the terminal side chain, retinoid D with an aldehyde at the terminal side chain, and retinoid D with a carboxylic acid at the terminal side chain, wherein retinoid D with the alcohol CH
2
OH terminal side chain has the structure:
wherein the configuration at the 7-, 9-, 11- and 13-position double bonds is independently Z or E and wherein R
1
is selected from the group consisting of
wherein the keto group at the 4-position is free or protected, or is replaced by a thioketone group which is free or protected or is replaced by C
1-6
-alkylidene group;
wherein X is selected from the group consisting of hydrogen and C
1-6
-alkyl and Y is selected from the group consisting of C
1-6
-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C
1-6
-alkyl substituted amino and wherein the absolute configuration at the 4-position is independently R or S;
wherein X
1
, Y
1
are independently selected from the group consisting of hydrogen, C
1-6
-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C
1-6
-alkyl substituted amino and Z
1
is selected from the group consisting of C
1-6
-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C
1-6
-alkyl substituted amino;
wherein X
2
is selected from the group consisting of hydrogen, C
1-6
-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C
1-6
-alkyl substituted amino and Z
2
is selected from the group consisting of C
1-6
-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C
1-6
-alkyl substituted amino;
wherein X
3
and Y
3
are independently selected from the group consisting of hydrogens, C
1-6
-alkyl, hydroxyl, alkoxyl, acyloxyl, halide, azide, sulfhydryl, amine and C
1-6
-alkyl substituted amino so long as X
3
and Y
3
are not both hydrogens.
The present inventions also provides methods for treating various conditions associated with abnormal cell proliferation and/or abnormal cell differentiation.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the invention, It has been surprisingly discovered that a composition comprising a vitamin D analog and a certain retinoid is useful in treating a subject suffering from a disorder characterized by abnormal cell-proliferation and/or cell-differentiation more effectively than either a composition comprising a vitamin D or the above retinoid or a composition comprising a vitamin D analog with other types of retinoids.
The retinoid used in the composition of the present invention is selected from the group consisting of retinol in a concentration of at least about 1.0% by weight, a compound in a concentration of at least about 1.0% by weight capable of being converted in vivo into retinol, retinoid D with an alcohol CH
2
OH terminal side chain, retinoid D with an ester at the terminal side chain, retinoid D with an ether at the terminal side chain, retinoid D with an aldehyde at the terminal side chain, and retinoid D with a carboxylic acid at the terminal side chain, wherein retinoid D with the alcohol CH
2
OH terminal side chain has the structure:
wherein the configurati
Gentrix LLC
Spivack Phyllis G.
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