Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-16
2002-07-23
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S008100, C514S012200, C514S015800, C514S264110, C514S265100, C514S922000
Reexamination Certificate
active
06423719
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a method of treating benign prostate hyperplasia in a subject suffering therefrom with an effective amount of dyphylline or an analog thereof.
BACKGROUND
Xanthine is a dioxypurine that is structurally related to uric acid. Xanthine can be represented by the following structure:
Caffeine, theophylline and theobromine are methylated xanthines. Methylated xanthines such as caffeine and theophylline are typically used for their bronchodilating action in the management of obstructive airways diseases such as asthma. The bronchodilator effects of methylxanthines are thought to be mediated by relaxation of airway smooth muscle. Generally, methylxanthines function by inhibiting cyclic nucleotide phosphodiesterases and antagonizing receptor-mediated actions of adenosine.
Theophylline can be represented by the following structure:
However, when administered intravenously or orally, theophylline has numerous undesired or adverse effects that are generally systemic in nature. It has a number of adverse side effects, particularly gastrointestinal disturbances and CNS stimulation. Nausea and vomiting are the most common symptoms of theophylline toxicity. Moderate toxicity is due to relative epinephrine excess, and includes tachycardia, arrhythmias, tremors, and agitation. Severe toxicity results in hallucinations, seizures, dysrhythmias and hypotension. The spectrum of theophylline toxicity can also include death.
Furthermore, theophylline has a narrow therapeutic range of serum concentrations above which serious side effects can occur. The pharmacokinetic profile of theophylline is dependent on liver metabolism, which can be affected by various factors including smoking, age, disease, diet, and drug interactions.
Generally, the solubility of methylxanthines is low and is enhanced by the formation of complexes, such as that between theophylline and ethylenediamine (to form aminophylline). The formation of complex double salts (such as caffeine and sodium benzoate) or true salts (such as choline theophyllinate) also enhances aqueous solubility. These salts or complexes dissociate to yield the parent methylxanthine when dissolved in aqueous solution. Although salts such as aminophylline have improved solubility over theophylline, they dissociate in solution to form theophylline and hence have similar toxicities.
Dyphylline is a covalently modified derivative of xanthine (1,3, -dimethyl-7-(2,3-dihydroxypropl)xanthine. Because it is covalently modified, dyphylline is not converted to free theophylline in vivo. Instead, it is absorbed rapidly in therapeutically active form. Dyphylline has a lower toxicity than theophylline. Dyphylline can be represented by the following structure:
Dyphylline is an effective bronchodilator that is available in oral and intramuscular preparations. Generally, dyphylline possesses less of the toxic side effects associated with theophylline.
U.S. Pat. No. 4,031,218 (E1-Antably) discloses the use of 7-(2,3-dihydroxypropyl)-1,3-di-n-propylxanthine, a derivative of theophylline, as a bronchodilator. U.S. Pat. No. 4,341,783 (Scheindlin) discloses the use of dyphylline in the treatment of psoriasis and other diseases of the skin by topical administration of dyphylline. U.S. Pat. No. 4,581,359 (Ayres) discloses methods for the management of bronchopulmonary insufficiency by administering an N-7-substituted derivative of theophylline, including dyphylline, etophylline, and proxyphylline.
Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate that is due to excessive cellular growth of both glandular and stromal elements of the prostate. The condition is very common in men over 40 years of age. BPH has two components: a static component that is related to the enlargement of the prostate and a dynamic component that reflects the tone or degree of contraction of smooth muscle within the prostate. The smooth muscle tone depends on extra-and intracellular Ca
2+
stores and is regulated by various second messenger pathways, including cyclic 3′-5′adenosine monophosphate (cAMP).
Transurethral resection of the prostate is a common form of treatment. However, complications of transurethral resection include retrograde ejaculation, impotence, postoperative urinary tract infection and some urinary incontinence. Therefore, medical and/or minimally invasive treatments for benign prostatic hyperplasia are more desirable.
Minimally invasive treatments for BPH include transurethral incision of the prostate, balloon dilation of the prostate, prostatic stents, microwave therapy, laser prostatectomy, transrectal high-intensity focused ultrasound therapy and transurethral needle ablation of the prostate.
Known medical treatments for BPH include androgen deprivation therapy, the use of 5&agr;-reductase inhibitors and &agr;-adrenergic-antagonist drugs. Androgen deprivation therapy includes administering agents which diminish androgen secretion or action, such as gonadotrophin-releasing hormone (GnRH) analogues, antiandrogens. 5&agr;-reductase inhibitors inhibit the action of type 2 5&agr;-reductase, an enzyme that catalyzes the conversion of testosterone to dihydrotestosterone in most androgen sensitive tissues. Finasteride [N-(2-methyl-2-propyl)3-oxo-4-aza-5&agr;-androst-1-ene-17&bgr;-carboxamide] is a known 5&agr;-reductase inhibitor. &agr;-Adrenergic antagonist drugs block adrenergic receptors in hyperplastic prostatic tissue, the prostatic capsule, and the bladder neck, to decrease smooth muscle tone of these structures. &agr;-Adrenergic receptors in the trigone muscle of the bladder and urethra contribute to the resistance of outflow of urine. When smooth muscle tone is decreased, resistance to urinary flow through the bladder neck and the prostatic urethra decreases and urinary flow increases. A variety of &agr;-adrenergic antagonists are used in the treatment of BPH. Nonselective drugs include phenoxybenzamine and thymoxamine. Short acting selective drugs include alfuzosin, indoramin and prazosin. Long acting selective drugs including doxazosin, terazosin and tamsulosin.
U.S. Pat. No. 5,753,641 (Gormley et al.) discloses a method for treating benign prostatic hyperplasia (BPH) involving combination therapy of a 5&agr;-reductase inhibitor in combination with an &agr;
1
-adrenergic receptor blocker.
SUMMARY
The invention provides a method of treating benign prostatic hyperplasia or reducing the symptoms of benign prostatic hyperplasia by administering a therapeutic or prophylactic effective amount of dyphylline or a dyphylline analog, or a pharmaceutically acceptable salt thereof to the patient. According to the invention, the compound can be of the formula:
wherein R
1
and R
2
, independently, are hydrogen or a C
1
-C
6
linear or branched alkyl optionally interrupted by a carbonyl group. R
3
is a C
1
-C
8
alkyl substituted by one or more moieties selected from the group consisting of a hydroxyl, amino, mercapto, dioxolan, carbonyl, and mixtures thereof. R
4
is hydrogen; a substituted or unsubstituted aromatic member selected from the group consisting of phenyl, biphenyl, benzyl, or furyl, in which the substituent is selected from the group consisting of C
1-
C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, halo and nitro; or cyclohexyl and cyclopentyl. Preferably, R
1
and R
2
, are methyl; R
3
is dihydroxypropyl; and R
4
is hydrogen or a substituted or unsubstituted aromatic member selected from the group consisting of phenyl, biphenyl, benzyl, or furyl, in which the substituent is selected from the group consisting of C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkylthio, halo and nitro. Most preferred is dyphylline, wherein R
1
and R
2
are methyl; R
3
is 2,3-dihydroxypropyl; and R
4
is hydrogen.
A second aspect of the present invention is a method of treating benign prostatic hyperplasia, or reducing the symptoms thereof, by administering a dyphylline-type compound, described above, with a combination of an &agr;-adrenergic
Krass Frederick
Upsher-Smith Laboratories, Inc.
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