WO1995006470A1

WO1995006470A1 - Prevention and treatment of alzheimer's disease

Info

Publication number: WO1995006470A1
Application number: PCT/US1994/007518
Authority: WO
Inventors: Edward M. Scolnick
Original assignee: Merck & Co., Inc.
Priority date: 1993-08-30
Filing date: 1994-07-05
Publication date: 1995-03-09
Also published as: AU7397094A

Abstract

The present invention relates to the administration of an HMG-CoA reductase inhibitor, including lovastatin (MEVACOR®) and simvastatin (ZOCOR®), the open-ring dihydroxy acid forms thereof, and salts and esters thereof, and pravastatin (PRAVACHOL®) and fluvastatin (LESCOL®), the closed ring lactone forms and salts and esters thereof, to humans to lower Apolipoprotein E isoform 4 (ApoE isoform 4) levels in the central nervous system to treat, arrest the development of and prevent the onset of Alzheimer's disease.

Description

TITLE OF THE INVENTION

PREVENTION AND TREATMENT OF ALZHEIMER'S DISEASE

SUMMARY OF THE INVENTION

The present invention relates to the administration of an HMG-CoA reductase inhibitor, including lovastatin (MEVACOR®) and simvastatin (ZOCOR®), the open-ring dihydroxy acid forms thereof, and salts and esters thereof, and pravastatin (PRAVACHOL®) and fluvastatin (LESCOL®), the closed ring lactone forms and salts and esters thereof, to humans to lower ApoUpoprotein E isoform 4 (ApoE isoform 4) levels in the central nervous system to treat, arrest the development of and prevent the onset of Alzheimer's disease.

BACKGROUND OF THE INVENTION

Alzheimer's disease is a neurodegenerative disease of the brain leading to severely impaired cognition and functionality. This disease leads to progressive regression of memory and learned functions. Alzheimer's disease is a complex disease that affects cholinergic neurons, as well as serotonergic, noradrenergic and other central neurotransmitter systems. Manifestations of Alzheimer's disease extend beyond memory loss and include personality changes, neuromuscular changes, seizures, and occasionally psychotic features.

Alzheimer's disease is the most common type of dementia in the United States. Some estimates suggest that up to 47% of those older than 85 years have Alzheimer's disease. Since the average age of the population is on the increase, the frequency of Alzheimer's disease is increasing and requires urgent attention. Alzheimer's is a difficult medical problem because there are presently no adequate methods available for its prevention or treatment.

Three classes of drugs are being investigated for the treatment of Alzheimer's disease. The first class consists of compounds that augment acetylcholine neurotransmitter function. Currently, cholinergic agonists such as the antichohnesterase drugs are being used in the treatment of Alzheimer's disease. In particular, physostigmine (eserine), an inhibitor of acetylcholinesterase, has been used in its treatment. The administration of physostigmine has the drawback of being considerably limited by its short half-life of effect, poor oral bioavailabihty, and severe dose-limiting side-effects, particularly towards the digestive system. Tacrine (tetrahydroaminocridine) is another cholinesterase inhibitor that has been employed; however, this compound may cause hepatotoxicity.

A second class of drugs that are being investigated for the treatment of Alzheimer's disease is neurotropics that affect neuron metabolism with little effect elsewhere. These drugs improve nerve cell function by increasing neuron metabolic activity. Piracetam is a neurotropic that may be useful in combination with acetylcholine precursors and may benefit Alzheimer's patients who retain some quantity of functional acetylcholine neurons. Oxiracetam is another related drug that has been investigated for Alzheimer treatment.

A third class of drugs include those drugs that affect brain vasculature. A mixture of ergoloid mesylates is used for the treatment of dementia. Ergoloid mesylates decrease vascular resistance and thereby increase cerebral blood flow. Also employed are calcium channel blocking drugs including Nimodipine which is a selective calcium channel blocker that affects primarily brain vasculature.

Other miscellaneous drugs are targeted to modify other defects found in Alzheimer's disease. Selegiline, a monoamine oxidase B inhibitor which increases brain dopamine and norepinephrine has reportedly caused mild improvement in some Alzheimer's patients. Aluminum chelating agents have been of interest to those who believe Alzheimer's disease is due to aluminum toxicity. Drugs that affect behavior, including neuroleptics, and anxiolytics have been employed. Side effects of neuroleptics range from drowsiness and anti cholinergic effects to extrapyramidal side effects; other side effects of these drugs include seizures, inappropriate secretion of antidiuretic hormone, jaundice, weight gain and increased confusion. Anxiolytics, which are mild tranquilizers, are less effective than neuroleptics, but also have milder side effects. Use of these behavior-affecting drugs, however, remains controversial.

None of the drugs discussed above are targeted to prevent the onset of Alzheimer's disease. These drugs are employed as treatments for the disease. At best one or more of these drugs may slow down the course of the disease, but there is currently no evidence for this.

Recently, it has been reported in Corder et al_.., "Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer's Disease in Late Onset Families," Science 261:921-23 (13 August 1993), that the Apolipoprotein E type 4 allele ("APOE-ε4") is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease. Specifically, it was found that the risk of Alzheimer's disease increased by a factor of 2.84 for each additional Apolipoprotein E type 4 allele the patient had. Hence, individuals with two copies of the Apoliprotein E type 4 allele were more than eight times as likely to be affected with Alzheimer's disease than individuals who did not possess any copies of the Apolipoprotein E type 4 allele. The protein encoded by Apolipoprotein E type 4 allele, ApoE isoform 4, has a higher avidity in vitro for β-amyloid than ApoE isoform 3. Apolipoprotein E is the major apolipoprotein in the central nervous system, where it appears to be involved in nerve regeneration following injury. Apolipoprotein E is synthesized in several extra hepatic tissues, including brain, and is catabolized predominantly by the liver.

The present invention provides for a method of treating, arresting the development of and preventing Alzheimer's disease by regulating the amount of ApoE isoform 4 circulating in the bloodstream and in the brain, most particularly in the brain of a patient with or at risk of developing Alzheimer's disease employing an HMG-CoA reductase inhibitor selected from lovastatin and simvastatin, including the corresponding open-ring dihydroxy acid forms and the salts and esters thereof.

Lovastatin (MEVACOR®), simvastatin (ZOCOR®) pravastatin (PRAVACHOL®), and fluvastatin (LESCOL®) are known cholesterol lowering agents.

LOVASTATIN

PRAVASTATIN FLUVASTATIN

These compounds are inhibitors of HMG-CoA reductase, which is the rate-limiting step in the biosynthesis of cholesterol.

Lovastatin and related compounds are disclosed in U.S. Patent No. 4,231 ,938; simvastatin and related comounds are disclosed in U.S. Patent No. 4,450,171 and U.S. Patent No. 4,346,227; pravastatin and related compounds are disclosed in U.S. Patent No. 4,346,227 and fluvastatin and related compounds such as disclosed in PCT Publication WO 84/02131.

The present invention provides for a method of preventing and treating Alzheimer's disease by treating a patient in need of such treatment with an HMG-CoA reductase inhibitor, including lovastatin (MEVACOR®) and simvastatin (ZOCOR®), the open-ring dihydroxy acid forms thereof, and salts and esters thereof, and pravastatin (PRAVACHOL®) and fluvastatin (LESCOL®), the closed ring lactone forms and salts and esters thereof, to lower Apolipoprotein E isoform 4 (ApoE isoform 4) levels in the central nervous system.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to administration of an HMG- CoA reductase inhibitor to humans at risk for developing Alzheimer's disease for the purpose of preventing the onset of Alzheimer's disease. The HMG-Co A reductase inhibitors which are used in the method of this invention include the compounds represented by the following structural formula (I):

(I) wherein:

Z is selected from:

wherein:

R*is Cl-10alkyl,

R2 is selected from:

(a) hydrogen, (b) Ci-3 alkyl,

(c) hydroxy, and

(d) Ci-3 alkyl substituted with hydroxy; R3 is selected from:

(a) Cl-3 alkyl,

(b) hydroxy,

(c) oxo, and

(d) Cl-3 alkyl substituted with hydroxy; n is 0,1, or 2; a, b, c and d are all single bonds or a and c are double bonds or b and d are double bonds or one of a, b, c or d is a double bond;

wherein X is NCH(CH₃)₂ or C(CH₂)₄.

wherein R4 and R^ are each independently selected from hydrogen, halogen, Ci-4 alkyl, Ci-4 alkoxy and trifluoromethyl, and

R5, R6, R7₅ and R8 _are each independently selected from hydrogen, halogen, Cι_4 alkyl, and Cl-4 alkoxy; the corresponding open-ring dihydroxy acid forms thereof and pharmaceutically acceptable salts and esters thereof.

The terms "halo" and "halogen" each refer to -F, -CI, -Br and The term "open-ring dihydroxy acid form and pharmaceutically acceptable salts and esters" of the compound of formula (I) refers to the corresponding compound of formula (II) below:

(ii) wherein RlO is selected from:

(a) hydrogen,

(b) Cι_5alkyl,

(c) substituted C 1-5 alkyl in which the substituent is selected from the group consisting of:

(1) phenyl,

(2) dimethylamino, and

(3) acetylamino, and

(d) 2,3-dihydroxypropyl; and pharmaceutically acceptable salts thereof.

The pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethyl ammonium hydroxide. These salts are prepared by standard procedures.

One class of compounds of the present invention are those wherein Z is:

and n is 1. One subclass of these compounds is where R3 is 5-OH, and a, b, c, and d are each single bonds. Another subclass of compounds is characterized by R3 being 3-oxo and a and c being a double bond, or c being a double bond. Yet a third subclass of these compounds is where R3 is 7-(l-hydroxyethyl), b and d are double bonds; provided that when R2 is OH, b and d are double bonds or c is a double bond or a, b, c, and d are single bonds.

Another class of compounds of the present invention are those wherein Z is:

As used herein the term "preventing" includes not only preventing of the onset of the disease in disease-free patients, but also arresting the development of the disease in patients already manifesting symptoms of the disease, and ameliorating symptoms in patients afflicted with the disease.

Specifically, the method of this invention is useful for treating individuals who possess one or two copies of the apolipoprotein E type 4 allele. These individuals are more likely to develop late onset and sporadic Alzheimer's disease. The method of this invention is also useful in halting the progression of Alzheimer's disease in a patient who already exhibits symptoms of dementia, and ameliorating the degenerative effects of Alzheimer's disease.

The present invention provides for a means of lowering the levels of Apolipoprotein E isoform 4 circulating in the bloodstream and in the brain by employing an HMG-CoA reductase inhibitor of structural formula (I) the open ring dihydroxy acid forms thereof and salts and esters thereof. Particularly, this invention relates to the lowering of Apolipoprotein E isoform 4 circulating through the central nervous system and present in the cerebrospinal fluid.

Apolipoprotein E isoform 4 ("ApoE isoform 4") is an apolipoprotein which is the gene product of the apolipoprotein E type 4 allele. Possession of one or two copies of the apolipoprotein E type 4 allele has been linked to a greatly increased risk of developing Alzheimer's disease. The present invention provides for a method of decreasing circulating blood levels of ApoE isoform 4 throughout the body, including the brain. In the liver, low density lipoprotein receptors (LDL receptors) are responsible for absorbing and taking up from the bloodstream various lipoproteins including some of those containing ApoE isoform 4. LDL receptors are regulated by gene repressors derived from cholesterol which suppress the transcription of the LDL-receptor. Inhibition of cholesterol biosynthesis reduces the presence of these cholesterol-derived LDL gene repressors. This relieves the suppression of the production of the LDL receptor, leading to production of additional LDL receptors in the liver, which, in turn, remove additional ApoE containing lipoproteins from the bloodstream. Reduced levels of ApoE isoform 4 in the bloodstream promotes an increase in the flux of ApoE isoform 4 from the CNS to the plasma, thus reducing the risk of, halting the development of and/or ameliorating the symptoms of Alzheimer's disease. It is also possible that these agents could work directly on the CNS to reduce ApoE levels in the brain.

For the prevention, treatment or amelioration of the symptoms of Alzheimer's disease, the HMG-CoA reductase inhibitor of structural formula (I), the open-ring dihydroxy acid forms thereof, and salts and esters thereof, may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is usually desirable to use the oral route. The compounds of structural formula (I), the open-ring dihydroxy acid forms thereof, and salts and esters thereof, may be administered orally in the form of a capsule, a tablet or the like. The orally administered medicament may be administered in the form of a time-controlled release vehicle, including diffusion controlled systems, osmotic devices, dissolution controlled matrices and erodible/degradable matrices. Doses may be varied, depending on the age, severity, body weight and other conditions of human patients, but daily dosage for adults is within a range of from about 1 mg to 1000 mg (preferably 5 to 100 mg,) which may be given in a single dose or in two to four divided doses. Higher doses may be favorably employed as required.

The following example is given for the purpose of illustrating the present invention and shall not be construed as being limitations on the scope or spirit of the invention.

EXAMPLE 1

Apolipoprotein E Polymorphism On ApoE Response To an HMG-CoA

Reductase Inhibitor

Method: One hundred eleven outpatients with moderate hypercholesterolemia were treated at five lipid clinics with the National Cholesterol Education Program Step 2 diet (which is low in fat and cholesterol) and lovastatin (20 mg once a day), both alone and together. A diet high in fat and cholesterol and a placebo identical n appearance to the lovastatin were used as the respective controls. Each of the 97 patients completing the study (58 men and 39 women) underwent four consecutive nine- week periods of treatment according to a randomized, balanced design: a high fat diet-placebo period, a low-fat diet— placebo period, a high-fat diet— lovastatin period, and a low-fat diet— lovastatin period. Mean ApoE levels at the End of Each Intervention

Apo E HF/P LF/P HF/L LF/L p(dief) p(drug pheno- tvpe (n

3/3(52) 7.5 7.4 6.9 6.5 0.07 <0.001

3/4(26) 6.9 6.2 5.4 5.4 0.17 <0.001

4/4(5) 8.9 8.0 4.0 5.8 n too n too small small

HF=high fat; LF= low fat; P=placebo; L=lovastatin; ApoE unit is mg/dl. There is considerable variation of ApoE within and between patients. (This is true of other components of VLDL, including VLDL cholesterol and triglycerides.) Also, the sample sizes for the 4/4 and 3/4 phenotypes are relatively small. For these reasons, % change in the mean, (rather than mean or median % change is shown below:

% Change in Mean ApoE

phenotvpe (ή) due to diet due to drug

3/3 (52 -5 -1 1

3/4 (26) -7 -21

4/4 +7 -42

These data suggest that the serum level of ApoE isoform 4 falls more during treatment with lovastatin, an HMG-CoA reductase inhibitor, than does the level of ApoE isoform 3. EXAMPLE 2

Effect of HMG-CoA Reductase Inhibitor on Cerebrospinal

Fluid Levels of ApoE in Alzheimer's Patients Homozygous for

ApoE Type 4 Allele

The following protocol is used to determine the effect of HMG-CoA reductase inhibitors on cerebrospinal fluid levels of ApoE in Alzheimer's patients homozygous for ApoE type 4 allele. Other HMG- CoA reductase inhibitors may be substituted for simvastatin.

A randomized, double-blind placebo controlled, parallel- design, multicenter six week study is conducted. Approximately 30 men and women (to provide 20 patients with baseline and follow-up lumbar punctures) between the ages of 50 and 85 years with a diagnosis of sporadic or late-onset familial AD, homozygous for the ApoE4 isoform, and with a low density lipoprotein (LDL) cholesterol level greater than 100 mg/dl are recruited for participation in the study and informed consent is obtained. (Patients incapable of giving informed consent have written consent from their guardian or representative.)

Patients qualifying for entry after screening are randomized to simvastatin, 40 mg/day or placebo for six weeks. A lumbar puncture will be performed prior to randomization and at Week 6 to determine cerebrospinal fluid levels of ApoE and other apolipoproteins. If the lumber puncture is judged traumatic (greater than grossly hemorrhage and greater than 50,000 RBC/mmβF), it is repeated in one week. Plasma is obtained at these time points for plasma total, LDL, HDL cholesterol and apolipoproteins including ApoE. For those patients in whom the six week lumbar puncture follow-up cannot be performed on time, a two week window is allowed (Week 4 to 8 of active treatment). The primary endpoint is a comparison between simvastatin and placebo groups in the mean cerebrospinal ApoE levels. While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the casual variations, adaptations, modifications, deletions, or additions of procedures and protocols described herein, as come within the scope of the following claims and its equivalents.

Claims

WHAT IS CLAIMED IS:

1. A method for preventing, treating, or ameliorating the symptoms of Alzheimer's disease in a human patient comprising administration to the patient of an HMG-CoA reductase inhibitor.

2. The method for preventing, treating, or ameliorating the symptoms of Alzheimer's disease in a human patient of Claim 1 comprising administration to the patient of an HMG-CoA reductase inhibitor of structural formula (I),

(I)

wherein:

Z is selected from:

wherein:

R is Cl-lθalkyl,

R2 is selected from:

(a) hydrogen,

(b) Cl-3 alkyl,

(c) hydroxy, and

(d) Cl-3 alkyl substituted with hydroxy; R3 is selected from:

(a) Cl-3 alkyl,

(b) hydroxy,

(c) oxo, and

(d) Cl-3 alkyl substituted with hydroxy; n is 0,1, or 2; a, b, c and d are all single bonds or a and c are double bonds or b and d are double bonds or one of a, b, c. or d is a double bond;

wherein X is NCH(CH₃)₂ or C(CH₂)₄.

wherein R4 and R are each independently selected from hydrogen, halogen, Cl-4 alkyl, Cl-4 alkoxy and trifluoromethyl, and

R5, R6, R7₅ and R^ are each independently selected from hydrogen, halogen, Cl-4 alkyl, and Cl-4 alkoxy; the corresponding open-ring dihydroxy acid forms thereof and pharmaceutically acceptable salts and esters thereof.

3. The method of Claim 1 wherein the HMG-CoA reductase inhibitor is selected from lovastatin, simvastatin, pravastatin and fluvastatin.

4. The method of Claim 3 wherein the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin.

5. The method of Claim 1 wherein the patient has at least one copy of the Apolipoprotein E type 4 allele.

6. The method of Claim 1 wherein the patient has Alzheimer's disease.

7. The method of Claim 1 wherein 1 to 1000 mg of the HMG-CoA reductase inhibitor is administered daily.

8. The method of Claim 7 wherein 5 to 100 mg of the HMG-CoA reductase inhibitor is administered daily.

9. The method of Claim 1 wherein the HMG-CoA reductase inhibitor is administered orally.

10. The method of Claim 7 wherein the HMG-CoA reductase inhibitor is administered by a controlled release dosage form.

11. The method of Claim 2 wherein the HMG-CoA reductase inhibitor is in the open ring dihydroxy acid form of formula (II):

(II) wherein R 10 i_s selected from: (a) hydrogen, (b) Cl-5alkyl,

(c) substituted Cl_5 alkyl in which the substituent is selected from the group consisting of:

(1) phenyl,

(2) dimethylamino, and

(3) acetylamino, and

(d) 2,3-dihydroxypropyl; and pharmaceutically acceptable salts thereof.

12. The method of Claim 2 wherein Z is:

wherein: n is 1 and

(1) R3 is 5-OH, and a, b, c, and d are each single bonds, (2) R3 is 3-oxo and a and c are each double bonds, or c is a double bond, or

(3) R3 is 7-(l-hydroxyethyl), and b and d are double bonds; provided that when R2 is OH, b and d are double bonds or c is a double bond or a, b, c, and d are single bonds.

13. A method of lowering ApoE isoform 4 levels in the cerebrospinal fluid of a patient in need of such treatment comprising the administration to the patient of an HMG-CoA reductase inhibitor.

14. The method of lowering ApoE isoform 4 levels in the cerebrospinal fluid of the patient according to Claim 13 comprising administration to the patient of an HMG-CoA reductase inhibitor of structural formula (I),

(I)

wherein:

Z is selected from:

wherein: Rlis Ci-ioalkyl, R2 is selected from:

(a) hydrogen,

(b) Cl-3 alkyl,

(c) hydroxy, and (d) Cl-3 alkyl substituted with hydroxy; R3 is selected from:

(a) Cl-3 alkyl,

(b) hydroxy,

(c) oxo, and

(d) Cl-3 alkyl substituted with hydroxy; n is 0,1, or 2; a, b, c and d are all single bonds or a and c are double bonds or b and d are double bonds or one of a, b, (^ or d is a double bond;

wherein X is NCH(CH₃)₂ or C(CH₂)₄.

wherein R4 and R9 are each independently selected from hydrogen, halogen, Cl-4 alkyl, Cl-4 alkoxy and trifluoromethyl, and

R5, R6, R J_ and R8 are each independently selected from hydrogen, halogen, Cl_4 alkyl, and Cl-4 alkoxy; the corresponding open-ring dihydroxy acid forms thereof and pharmaceutically acceptable salts and esters thereof.

15. The method of Claim 13 wherein the HMG-CoA reductase inhibitor is selected from lovastatin, simvastatin, pravastatin and fluvastatin.

16. The method of Claim 15 wherein the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin.

17. The method of Claim 13 wherein the patient has at least one copy of the Apolipoprotein E type 4 allele.

18. The method of Claim 13 wherein the patient has Alzheimer's disease.

19. The method of Claim 13 wherein 1 to 1000 mg of the HMG-CoA reductase inhibitor is administered daily.

20. The method of Claim 19 wherein 5 to 100 mg of the HMG-CoA reductase inhibitor is administered daily.

21. The method of Claim 13 wherein the HMG-CoA reductase inhibitor is administered orally.

22. The method of Claim 13 wherein the HMG-CoA reductase inhibitor is administered by a controlled release dosage form.

23. The method of Claim 13 wherein the HMG-CoA reductase inhibitor is in the open ring dihydroxy acid form of formula (II):

CO wherein RlO is selected from: (a) hydrogen, (b) Cl-5alkyl,

(1) phenyl,

(2) dimethylamino, and

(3) acetylamino, and

(d) 2,3-dihydroxypropyl; and pharmaceutically acceptable salts thereof.

24. The method of Claim 2 wherein Z is:

wherein: n is 1 and

25. A method of lowering ApoE isoform 4 levels in a patient in need of such treatment comprising the administration to the patient of an HMG-CoA reductase inhibitor of structural formula (I),

(I)

wherein:

Z is selected from:

wherein:

Rlis Ci-ioalkyl,

R2 is selected from:

(a) hydrogen,

(b) Cl-3 alkyl,

(c) hydroxy, and

(d) Cl-3 alkyl substituted with hydroxy; R3 is selected from:

(a) Cl-3 alkyl,

(b) hydroxy,

(c) oxo, and (d) Cl-3 alkyl substituted with hydroxy; n is 0,1, or 2; a, b, c and d are all single bonds or a and c are double bonds or b and d are double bonds or one of a, b, c or d is a double bond;

wherein X is NCH(CH₃)₂ or C(CH₂)₄.

wherein R4 and R are each independently selected from hydrogen, halogen, Cl-4 alkyl, Cl-4 alkoxy and trifluoromethyl, and R5, R6, R7_? a d R^ are each independently selected from hydrogen, halogen, Cl-4 alkyl, and Cl-4 alkoxy; the corresponding open-ring dihydroxy acid forms thereof and pharmaceutically acceptable salts and esters thereof; provided that when Rl is 1 -methyl propyl or 1,1-dimethylpropyl, R^ is hydrogen and b and d represent double bonds, R2 is not methyl.