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WO1995006470A1 - Prevention et traitement de la maladie d'alzheimer - Google Patents

Prevention et traitement de la maladie d'alzheimer Download PDF

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Publication number
WO1995006470A1
WO1995006470A1 PCT/US1994/007518 US9407518W WO9506470A1 WO 1995006470 A1 WO1995006470 A1 WO 1995006470A1 US 9407518 W US9407518 W US 9407518W WO 9506470 A1 WO9506470 A1 WO 9506470A1
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WO
WIPO (PCT)
Prior art keywords
hmg
coa reductase
reductase inhibitor
alkyl
patient
Prior art date
Application number
PCT/US1994/007518
Other languages
English (en)
Inventor
Edward M. Scolnick
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU73970/94A priority Critical patent/AU7397094A/en
Publication of WO1995006470A1 publication Critical patent/WO1995006470A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole

Definitions

  • 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.
  • 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
  • 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.
  • the first class consists of compounds that augment acetylcholine neurotransmitter function.
  • cholinergic agonists such as the antichohnesterase drugs are being used in the treatment of Alzheimer's disease.
  • physostigmine eserine
  • 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
  • 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.
  • calcium channel blocking drugs including Nimodipine which is a selective calcium channel blocker that affects primarily brain vasculature.
  • 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.
  • Apolipoprotein E type 4 allele was 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 ⁇ -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.
  • 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.
  • 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.
  • 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
  • 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):
  • Z is selected from:
  • R2 is selected from:
  • Ci-3 alkyl substituted with hydroxy; R3 is selected from:
  • X is NCH(CH 3 ) 2 or C(CH 2 ) 4 .
  • R4 and R ⁇ are each independently selected from hydrogen, halogen, Ci-4 alkyl, Ci-4 alkoxy and trifluoromethyl, and
  • R5, R6, R7 5 and R8 are each independently selected from hydrogen, halogen, C ⁇ _4 alkyl, and Cl-4 alkoxy; the corresponding open-ring dihydroxy acid forms thereof and pharmaceutically acceptable salts and esters thereof.
  • 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:
  • RlO is selected from:
  • 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.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)amin
  • One class of compounds of the present invention are those wherein Z is:
  • 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • HF high fat
  • LF low fat
  • P placebo
  • L lovastatin
  • ApoE unit is mg/dl.
  • HMG-CoA reductase inhibitors 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.)
  • LDL low density lipoprotein
  • 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/mm ⁇ F), 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.

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Abstract

L'invention se rapporte à l'administration d'un inhibiteur de la réductase HMG-CoA comprenant de la lovastatine (MEVACOR®) et de la sinvastatine (ZOCOR®), des formes acide dishydroxy à cycle ouvert ainsi que les sels et esters de ces dernières et de la pravastatine (PRAVACHOL®) ainsi que de la fluvastatine (LESCOL®), des formes lactone à cycle fermé et des sels et esters de ces dernières, à des sujets humains de manière à réduire les taux d'isoforme 4 d'apoliprotéine E(isoforme 4 ApoE) dans le système nerveux central de manière à traiter, à stopper le développement et à prévenir le commencement de la maladie d'Alzheimer.
PCT/US1994/007518 1993-08-30 1994-07-05 Prevention et traitement de la maladie d'alzheimer WO1995006470A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU73970/94A AU7397094A (en) 1993-08-30 1994-07-05 Prevention and treatment of alzheimer's disease

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US11388093A 1993-08-30 1993-08-30
US11427093A 1993-08-30 1993-08-30
US113,880 1993-08-30
US114,270 1993-08-30

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WO1999038498A1 (fr) * 1998-01-28 1999-08-05 Warner-Lambert Company Procede pour le traitement de la maladie d'alzheimer
US5955472A (en) * 1995-11-02 1999-09-21 Warner-Lambert Company Naphthylazo inhibition of amyloidosis
US6017913A (en) * 1999-05-03 2000-01-25 Warner-Lambert Company Naphthylazo inhibition of amyloidosis
WO1999015159A3 (fr) * 1997-09-24 2000-02-17 Nova Molecular Inc Methodes permettant d'augmenter les taux d'apolipoproteine dans le traitement de maladies neurodegeneratives
US6046381A (en) * 1998-04-30 2000-04-04 The Regents Of The University Of California Apolipoprotein E transgenic mice and assay methods
WO1999048488A3 (fr) * 1998-03-23 2000-06-22 Childrens Medical Center ABAISSEMENT DE LA TENEUR EN PROTEINE β-AMYLOÏDE
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Cited By (56)

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US5955472A (en) * 1995-11-02 1999-09-21 Warner-Lambert Company Naphthylazo inhibition of amyloidosis
WO1998047518A1 (fr) * 1997-04-17 1998-10-29 Europäisches Laboratorium für Molekularbiologie (EMBL) Utilisation d'agents hypo-cholesterolemiants pour influer sur les processus de transduction de signaux au niveau de la membrane cellulaire, dans le cadre de la prophylaxie ou du traitement de maladies associees aux prions ou de la maladie d'alzheimer
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US7396659B2 (en) 1997-11-25 2008-07-08 Musc Foundation For Research Development Inhibitors of nitric oxide synthase to treat type 1 diabetes
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US8507219B2 (en) 1997-11-25 2013-08-13 Musc Foundation For Research Development Method of treating inflammation with statins
US8679534B2 (en) 1997-12-12 2014-03-25 Andrx Labs, Llc HMG-CoA reductase inhibitor extended release formulation
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WO1999038498A1 (fr) * 1998-01-28 1999-08-05 Warner-Lambert Company Procede pour le traitement de la maladie d'alzheimer
WO1999048488A3 (fr) * 1998-03-23 2000-06-22 Childrens Medical Center ABAISSEMENT DE LA TENEUR EN PROTEINE β-AMYLOÏDE
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