EP0934040A1

EP0934040A1 - Method for treating dementia due to aids

Info

Publication number: EP0934040A1
Application number: EP97912879A
Authority: EP
Inventors: Franklin P. Bymaster; Harlan E. Shannon
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1996-10-23
Filing date: 1997-10-23
Publication date: 1999-08-11
Also published as: CA2269506A1; AU4995797A; WO1998017214A1; JP2001502696A

Abstract

The present invention provides a method for treating Dementia Due to HIV Disease using a compound of the Formula (I).

Description

METHOD FOR TREATING DEMENTIA DUE TO AIDS

This invention provides a method for treating or alleviating the symptoms of dementia due to AIDS, comprising administering an effective amount of 3- (4-hexyloxy-l, 2, 5- thiadiazol-3-yl) -1,2,5, 6-tetrahydro-l-methylpyridine .

Human immunodeficiency virus (HIV) disease may often result in the patient being further incapacitated due to the serious psychological disorder, Dementia Due to HIV Disease (characterized in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (American Psychiatric Association, 1994) DSM-IV as catagory 294.9). Such Dementia can result in hospitalization of the patient, stress for caretakers, and increased medical expense.

Sauerberg et al . in U.S. Patent 5,043,345 ('345) disclose the 3- (4-hexyloxy-l, 2, 5-thiadiazol-3-yl) -1, 2, 5, 6- tetrahydro-1-methylpyridine compound which Applicants have discovered is useful for treating Dementia due to HIV Disease. The compounds in the '345 patent are taught to be useful in treating Alzheimer's disease, severe painful conditions, and glaucoma. There is no disclosure in the patent of using the compounds to treat Dementia due to HIV Disease.

Surprisingly, we have discovered that 3- (4- hexyloxy-1, 2, 5-thiadiazol-3-yl) -1, 2, 5, 6-tetrahydro-l- methylpyridine, thought to be a muscarinic agonist, can be useful for treating Dementia Due to HIV Disease. The present invention relates to a method of treating Dementia Due to HIV Disease. More specifically, the invention provides a method of treating Dementia Due to HIV Disease in humans using 3- (4-hexyloxy-l, 2, 5-thiadiazol-3-yl) -1, 2, 5, 6- tetrahydro-1-methylpyridine . As noted hereinbefore, the compounds employed in the method of the present invention are known. Methods of preparing the compounds, as well as pharmaceutical formulations containing the compounds, are taught by Sauerberg in U.S. Pat. No. 5,043,345 herein incorporated by reference .

The present invention provides a method for treating Dementia Due to HIV Disease in humans comprising administering to a human in need thereof, an effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof.

It is to be understood that the invention extends to the use of each of the stereoisomeric forms of the compound of the present invention as well as any pure diastereomeric, pure enantiomeric, and racemic forms of the named compounds .

The term "effective amount", as used herein, represents an amount of compound necessary to prevent or treat a human susceptible to or suffering from Dementia due to HIV Disease following administration to such human. The active compound is effective over a wide dosage range. For example, dosages per day will normally fall within the range of about 0.005 to about 500 mg/kg of body weight. In the treatment of adult humans, the range of about 0.05 to about 100 mg/kg, in single or divided doses, is preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. While the present compound may be administered orally to humans susceptible to or suffering from Dementia Due to HIV Disease, the compound is particularly well suited to be administered transdermally. When the compound is delivered transdermally, it is preferred that the effective amount is from about 50mg to about lOOmg per day delivery of base compound. It is especially preferred that such patch delivers an effective amount for about three to seven days. The compound may further be delivered by a variety of other pharmaceutically accepted routes including, but in no way limited to parenterally, subcutaneous, intranasal, intramuscular and intravenous routes. Such formulations may be designed to provide delayed or controlled release using formulation techniques which are known in the art.

As used herein the term "treating" includes prophylaxis of a physical and/or mental condition or amelioration or elimination of the developed physical and/or mental condition once it has been established or alleviation of the characteristic symptoms of such condition.

As used herein the term "Dementia Due to HIV Disease" refers to a disorder that upon neuropathological examination may commonly involve diffuse multifocal destruction of the white matter and subcortical structures. The spinal fluid may show normal or slightly elevated protein and a mild lymphocytosis, and HIV can usually be isolated directly from the cerebrospinal fluid. Dementia associated with HIV is typically characterized by slowness, poor concentration, difficulties with problem solving, and forgetfulness . Behavioral manifestations most commonly include apathy and social withdrawal, and occasionally these may be accompanied by delirium, delusions, or hallucinations . Tremor, impaired rapid repetitive movements, imbalance, ataxia, hypertonia, generalized hyperreflexia, positive frontal release signs, and impaired pursuit and saccadic eye movements may be presented on physical examination.

Dementia Due to HIV Disease has been characterized in the DSM-IV-R. Diagnostic and Statistical Manual of Mental Disorders, Revised, 4th Ed. (1994) . The DSM-IV-R was prepared by the Task Force on Nomenclature and Statistics of the American Psychiatric Association, and provides clear descriptions of diagnostic catagories. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for pathologic psychological conditions and that these systems evolve with medical scientific progress.

The compounds employed in the invention are not believed to act via the GABA/benzodiazepine, 5HT1A, or Dl receptor systems in humans. Rather, the activity of the present compound as a treatment for Dementia Due to HIV Disease is believed to be based upon modulation of muscarinic cholinergic receptors. However, the mechanism by which the present compounds function is not necessarily the mechanism stated supra . , and the present invention is not limited by any mode of operation. The following Examples are studies to establish the usefulness of the named compounds for treating Dementia Due to HIV Disease.

Example 1 Human Clinical Trials

Finally, the activity of 3- (4-hexyloxy-l, 2, 5- thiadiazol-3-yl) -1,2,5, 6-tetrahydro-l-methylpyridine for treating or alleviating Dementia Due to HIV Disease can be demonstrated by human clinical trials. The study was designed as a double-blind, parallel, placebo-controlled multicenter trial. The patients were randomized into four groups, placebo and 25, 50, and 75 mg tid of test compound. The dosages were administered orally with food. Patients were observed at four visits to provide baseline measurements. Visits 5-33 served as the treatment phase for the study. During the visits, patients and their caregivers are questioned and observed for signs of agitation, mood swings, tremor, delirium, social withdrawal, and concentration abilities. Each of these behaviors are indicative of the effect of the test compound on Dementia Due to HIV Disease. Additionally, patients are asked a series of questions designed to assess ability to solve problems and slowness.

Treatment groups are compared with respect to the number and percent of patients who ever had the symptom during the double-blind portion of the study (visits 5 through 33) , at a severity that was worse than during the baseline visits (1 through 4) .

Claims

1. A method for treating Dementia Due to HIV

Disease in humans comprising administering to a human in need thereof, an effective amount of a compound of Formula

I:

a pharmaceutically acceptable salt thereof.

2. A method of Claim 1 wherein the effective amount is from 1 mg/kg to about 100 mg/kg per day.

3. A method of Claim 2 wherein the effective amount is from about 50 mg/kg to about 100 mg/kg per day,

4. A method of Claim 1 wherein the effective amount is delivered using a transdermal patch.

5. A method of Claim 4 wherein the transdermal patch delivers from about 50 to about 100 mg of base compound per day.

6. A method of Claim 5 wherein the transdermal patch delivers an effective amount for three (3) to seven (7) days.

7. A compound of Formula I:

I

CH_{3 j} or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of Dementia Due to HIV Disease.

8.A compound of Claim 7 wherein the compound is administered using a transdermal delivery formulation.

9. A compound of Claim 7 wherein the compound is administered using a transdermal delivery system that delivers and effective amount of compound from about three (3) to about seven (7) days.