Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-08-20
2001-01-23
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06177471
ABSTRACT:
BACKGROUND OF THE INVENTION
Acne is a skin disease that often scars those afflicted, and can afflict patients at young ages—typically teen years—when their self-images are the most sensitive. The scarring is commonly permanent even if the condition is treated with medications. Some patients experience symptoms well into their adult years.
Acne is believed to be caused typically when the sebaceous glands become clogged due to skin cell debris and an excess of a specific type of skin bacteria. Sebaceous glands are located within the dermis layer of the skin along the hair shaft. Keratin and other chemicals associated with the skin can clog the hair shaft and the sebaceous gland. The bacteria,
Propionibacterium acnes
(
P. acnes
), which is always present, multiplies to a much greater degree when the sebaceous glands are clogged because the bacteria prefer an anaerobic environment, which is present when the glands become clogged.
P. acnes
produces a lipase enzyme that hydrolyzes triglycerides of the sebaceous gland into free fatty acids. The fatty acids along with bacterial proteins and keratin can irritate the skin tissues. This may lead to an inflammatory response and the formation of an acne lesion.
Although the exact cause of acne is unknown, hormones, genetics, and environmental factors all seem to play a role. Androgens, such as testosterone, play an important role in the development of acne lesions. This is evidenced by the correlation between the onset of puberty and the development of acne, and the fact that acne is generally more severe in males than in females.
The type of acne treatments currently recommended depend on the type and the severity of the acne. A few over-the-counter medications (e.g., benzoyl peroxide and salicylic acid) can be used for mild forms of acne, but are ineffective for the moderate and severe cases of acne.
Tretinoin (Retin-A) is often used in combination with or as a replacement for treatment with benzoyl peroxide. Tretinoin is a derivative of vitamin A and is available for topical use. It acts to prevent comedone formation through its anti-keratinization effect. The side effects of tretinoin include heightened sensitivity to exposure to sunlight and local irritation.
Topical antibiotics are sometimes used for treatment of patients with mild to moderate inflammatory acne, but are ineffective against more severe inflammatory acne. To the extent antibiotics have effects against more severe (i.e. inflammatory) forms of acne, the antibiotics must be systemically administered, usually at high doses (e.g., 500 to 2,000 mg/day) initially followed by maintenance doses (e.g., 250-500 mg/day). The most commonly prescribed antibiotic is tetracycline, but erythromycin and minocycline are also used. Such antibiotics, particularly at high doses can lead to side effects including gastrointestinal symptoms such as nausea, vomiting, abdominal pain, diarrhea, rashes, and other allergic reactions. Tetracyclines also can cause fetal harm if used during pregnancy.
Hormone therapy is another approach to treatment of acne based on the involvement of androgens in the development of acne. Estrogen therapy can be effective, but its usefulness is particularly limited in males by side effects such as gynecomastia, suppression of the testes, and uncertain effects on skeletal growth.
Isotretinoin (ACCUTANE) has been used in the treatment of severe nodulocystic acne. ACCUTANE therapy can lead to improvement in acne and can, in some cases exhibit the potential to prevent most permanent scarring from inflammatory acne. The severe side effects of ACCUTANE, however, are often prohibitive. Dry skin, dry eyes, headache, hair thinning, musculoskeltal pain, and other complications may result from treatment with ACCUTANE. Due to its teratogenicity, ACCUTANE should not be used by women who are pregnant or might become pregnant.
Thus, to date, there is typically a trade-off between efficacy and side effects, particularly in the treatment of more severe forms of acne. Accordingly, an effective treatment of acne, particularly its more severe forms, with clinically insignificant side effects is desired.
BRIEF SUMMARY OF THE INVENTION
This invention relates to a method for treating acne by administering to an afflicted patient a therapeutically effective amount of a cGMP-specific phosphodiesterase (“PDE”) inhibitor. With such an inhibitor, acne can be treated with minimal side effects associated with conventional acne medications.
DETAILED DESCRIPTION OF THE INVENTION
An example of a cGMP-specific PDE inhibitor is a compound of Formula
wherein R
1
is independently selected in each instance from the group consisting of hydrogen, halogen, lower alkoxy, hydroxy, lower alkyl, lower alkyl mercapto, lower alkylsulfonyl, lower alkylamino, di-lower alkyl amino, amino, nitro, nitrile, lower alkyl carboxyl ate, —CO
2
H, and sulfonamido;
R
2
is selected from the group consisting of hydrogen and lower alkyl;
R
3
is selected from the group consisting of hydrogen, lower alkyl, hydroxy, and amino;
R
4
is selected from the group consisting of -COM and CH
2
OH wherein M is selected from the group consisting of hydroxy, substituted lower alkoxy, amino, alkylamino, dialkylamino, N-morpholino, hydroxyalkylamino, polyhydroxyamino, dialkylaminoalkylamino, aminoalklyamino, and the group OMe, wherein Me is a cation;
R
5
is an alkyl sulfonyl; and n is an integer from 0 to four; or a pharmaceutically acceptable salt thereof.
Preferred compounds within the scope of Formula I include those wherein R
1
is halogen; n is 1; R
2
is lower alkyl; M is hydroxy; and R
3
is hydrogen or lower alkyl. More preferred compounds useful in the therapeutic method of this invention include those wherein R
1
is 5-fluoro; n is 1; R
2
is methyl; M is hydroxy; and R
3
is hydrogen.
The most preferred compound of Formula I for treating acne is exisulind. The chemical formula of exisulind is (Z)-5-fluoro-2-methyl-1-[[4-(methylsulfonyl)phenyl]methylene]indene-3-yl acetic acid. The cGMP-specific PDE inhibitory characteristics of exisulind are reported in U.S. Pat. No. 5,858,694. Clinical studies have demonstrated that exisulind is generally well tolerated by patients, has no reported clinically relevant side effects, and can be used safely by humans.
As used herein, the term “acne” includes the various known types of acne and related skin disorders, including acne vulgaris, acne conglobata, acne fulminans, pyoderma facaile, acne keloidalis, chloracne, and steroid acne. The most common form of acne is acne vulgaris, which is characterized by two types of lesions, inflammatory and noninflammatory. Noninflammatory lesions include open comedones (blackheads) and closed comedones (whiteheads) and are characterized by a lymphocytic infiltrate. Inflammatory lesions can be superficial or deep. Superficial inflammatory lesions include papules and pustules, and deep inflammatory lesions consist of cysts and nodules. Inflammatory lesions include those characterized by rupture of the follicular wall and aggregation of neutrophils and mononuclear cells. Acne vulgaris and the other forms of acne which may be treated by administering a therapeutically effective amount of a compound of Formula I are described in more detail in
Principles and Practice of Dermatology
, Chapter 70: Acne and Related Disorders, W. Mitchell Sams, Jr. and Peter J. Lynch eds., 1990, which is incorporated herein by reference.
As used herein, the term “alkyl” refers to straight, branched or cyclic alkyl groups and to substituted aryl alkyl groups. The term “lower alkyl” refers to C
1
to C
8
alkyl groups.
The term “lower alkoxy” refers to alkoxy groups having from 1 to 8 carbons, including straight, branched or cyclic arrangements.
The term “lower alkylmercapto” refers to a sulfide group that is substituted with a lower alkyl group; and the term “lower alkyl sulfonyl” refers to a sulfone group that is substituted with a lower alkyl group.
The term “lower alkyl carboxylate” refers to a carboxylate group that is substituted with a lower alkyl group.
Mayle Mark Jeffrey
Menander Kerstin B.
Brinks Hofer Gilson & Lione
Cell Pathways Inc.
Henley III Raymond
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