Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-09-21
2001-12-18
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C562S455000
Reexamination Certificate
active
06331570
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
The present invention relates to preparation of the (+) or (R)-enantiomer of an RAR&ggr;-specific agonist previously described in the prior art and the discovery that all of the retinoid activity of such agonist resided in such enantiomer.
The (R)-enantiomer of the present invention may be used in a wide variety of dermatological conditions, e.g. acne, psoriasis, eczema and photoaging of the skin, in treatment of corneopathies in opthamology, in treatment of degenerative diseases of connective tissue, e.g. arthritis, and in the treatment of malignancies.
2. Description of the Prior Art
U.S. Pat. No. 5,624,957 discloses the racemic compound, 3-fluoro-4(2′(5″,6″,7″,8″-tetrahydro-5″,5″,8″,8″-tetramethyl-2″-naphthyl)-2′-hydroxy)acetamidobenzoic acid (see Example 1) as an RAR&ggr;-specific retinoid with the highly useful property of lacking the liver toxicity of non-elective retinoids. The compound is also disclosed by B. P. Klaholz, et al.,
Nature Structural Biology
, 5(3), pp. 199-202 (1998), as a complex with the RAR&ggr; receptor protein. However, the compound indicated as binding to the receptor is the (S)-enantiomer, which is the inactive form.
Although the above-described patent reference indicates that the disclosed RAR&ggr;-specific retinoids exist in the form of the individual enantiomers as well as racemic mixtures, there is no disclosure of the (R)-enantiomer or the fact that, unexpectedly, all of the retinoid activity of the compound of Example 1 resides in this enantiomer.
SUMMARY OF THE INVENTION
The present invention provides the compound of the formula
or a pharmaceutically acceptable salt thereof. Enantiomer IA has retinoid-like activity and is thus useful in the treatment of skin disorders such as acne, Darier's disease, psoriasis, icthyosis, eczema, atopic dermatitis and epithelial cancers. It is also useful in the treatment of arthritic diseases and other immunological disorders (e.g. lupus erythematosus), in promoting wound healing, in treating dry eye syndrome and in treatment of the effects of sun damage to skin, i.e. photoaging. It is also useful in the treatment of various malignant tumors and premalignant skin lesions, e.g. actinic keratoses.
Also included in the invention is a process for preparing enantiomer IA via chiral synthesis or separation, and pharmaceutical compositions containing the enantiomer IA in combination with a pharmaceutically acceptable carrier or diluent.
In another aspect of the invention there is provided a method for treating a mammalian host for dermatological, rheumatic, antitumor, respiratory or opthamological conditions known to be affected by retinoid derivatives which comprises administering a therapeutically effective amount of a compound of formula IA or a pharmaceutically acceptable salt thereof.
In yet another aspect of the invention, there is provided a method for the prevention of spontaneous squamous cell carcinoma in immunocompromised human transplant patients which comprises systemically administering a therapeutically effective amount of a compound of formula IA.
DETAILED DESCRIPTION OF THE INVENTION
As noted above the racemic compound of the formula
is disclosed in U.S. Pat. No. 5,624,957 along with its method of preparation and therapeutic uses. Compound I is an RAR&ggr;-specific agonist which has the advantage of lacking the liver toxicity characteristic of non-specific retinoids.
The present inventors have discovered, surprisingly and unexpectedly, that all of the retinoid activity of compound I resides in the (+) or (R)-enantiomer IA, i.e.
The individual enantiomers of compound I may be isolated by subjecting the allyl ester of compound I (6, below) to chiral chromatography to isolate the allyl esters of the enantiomeric acids, followed by cleavage under mild conditions to preserve the enantiomeric purity of the products. The synthesis of 6 generally follows the synthesis disclosed in U.S. Pat. No. 5,624,957:
Known acid 1 (U.S. Pat. No. 5,624,957) can be reduced to the amino acid, 2, using either catalytic hydrogenation or a chemical reducing agent, such as stannous chloride. Acid 2 can be converted to amino ester 3 using, for example, allyl bromide. Known acid 4 is then converted to its acid chloride and condensed with 3 to give 5, which may be reduced using sodium borohydride to give 6.
Intermediate 6 is then subjected to chromatography on a Chiralpak AD column to give 7a and 7b, which are cleaved under mild conditions (for example, morpholine and palladium catalyst) to give the individual (R) and (S) enantiomers.
Optical purity analysis was carried out by chiral analytical HPLC, following derivatization of the free acid to the corresponding methyl ester under non-racemizing conditions. The determination of absolute configuration was carried out by X-ray crystal analysis of 8, the (R)-Mosher ester of 7a:
The active (R) I may be enantioselectively synthesized by the following pathway, using as a key step, the enantioselective reduction of ketoester 10 with known chiral reducing agent (R)-Alpine borane:
Known ethyl ester 9 (U.S. Pat. No. 5,624,957) is converted to allyl ester 10 using base hydrolysis followed by allyl bromide alkylation. 10 is then enantioselectively reduced to 11 using (R)-Alpine borane. The crude 11 (~94% ee) is hydrolyzed to crude 12 (94% ee), then 12 is purified to>9 % ee via crystallization. Activation of 12 with diphosgene and condensation with amino ester 3 gives 7a, whose ester group is cleaved to give the final product, (R) I (ee>99%).
Compound IA may be converted with bases to pharmaceutically acceptable salts thereof by methods known in the art. Examples of suitable salts are ammonium and alkali metal salts, especially of sodium, potassium and lithium, and alkaline earth metal salts, especially calcium and magnesium, as well as salts with suitable bases such as with lower alkylamines, e.g. methylamine, ethylamine or cyclohexylamine, or with substituted lower alkylamines such as diethanolamine or triethanolamine and with piperidine or morpholine.
As noted above, the compound of the present invention has retinoid-like activity and can, therefore, be used for the treatment of dermatological, rheumatic, antitumor, respiratory and opthalmological conditions know to be affected by retinoid derivatives. For example, the compound may be used for the treatment of:
dermatological conditions linked to a disorder of keratinisation involving differentiation and proliferation, e.g. in treating acne vulgaris, comedonic or polymorphic acne, nodulocystic acne, acne conglobata, senile acne and secondary acnes such as solar, drug and occupational acne;
for treating other types of keratinisation disorders such as ichthyoses, ichthyosiform states, Darier's disease, palmoplantar keratoderma, leucoplakia and leucoplakiform states, and lichenplanus;
for treating dermatolgical conditions linked to a keratinisation disorder with an inflammatory and/or immunoallergic component, e.g. all forms of psoriasis, whether cutaneous, mucosal and ungual, and psoriatic rheumatism, or alternatively, cutaneous atopy, such as eczema, or repiratory atopy;
for treating dermal or epidermal proliferations, whether benign or malignant, including those of vital origin, such as common warts, flat warts and epidermodysplasia verruciformis;
for treatment of other dermatological disorders such as vesicular dematoses and collagen diseases;
for treatment of certain opthalmological disorders: in particular corneopathies;
for prophylaxis or treatment of skin aging, both light induced (photoaging) and that occurring with the passage of time;
for preventing or treating the stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy;
for treatment of malignant tumors;
for treatment of premalignant skin lesions such as actinic keratosis;
for rheumatic illnesses, especially those of an inflammatory or degenerative kind which
Belema Makonen
Tramposch Kenneth M.
Zusi Fred C.
Bristol--Myers Squibb Company
Maier Leigh C.
Morse David M.
Wilson James O.
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