WO2006060186A2 - Pyrazole derivatives for the treatment of dementia and related disorders - Google Patents

Pyrazole derivatives for the treatment of dementia and related disorders Download PDF

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Publication number
WO2006060186A2
WO2006060186A2 PCT/US2005/041834 US2005041834W WO2006060186A2 WO 2006060186 A2 WO2006060186 A2 WO 2006060186A2 US 2005041834 W US2005041834 W US 2005041834W WO 2006060186 A2 WO2006060186 A2 WO 2006060186A2
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Prior art keywords
chlorophenyl
phenyl
dihydro
pyrazole
sulfonyl
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PCT/US2005/041834
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French (fr)
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WO2006060186A3 (en
Inventor
Zahra Fathi
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Bayer Pharmaceuticals Corporation
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Publication of WO2006060186A3 publication Critical patent/WO2006060186A3/en

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    • 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
    • A61K31/415—1,2-Diazoles

Definitions

  • This invention relates to pyrazole derivatives which are useful in the treatment of treating dementia and related disorders.
  • Dementia is a disease characterized by the progressive deterioration in cognitive and social adaptive functions that can eventually interfere with the patient's ability to live independently (Strub, South Med. J. 96: 363-366, 2003). Dementia also constitutes of impairment in short- and long-term memory plus additional symptoms, such as problems with abstract thinking, judgment, or personality. An estimated 18 million patients suffer from dementia worldwide. The most common forms of dementia include Alzheimer's disease and vascular dementia. Other forms are frontotemporal dementia and Pick's disease.
  • AD Alzheimer's disease
  • AD the most common and important form of dementia
  • cognitive functions such as abstract reasoning and memory.
  • AD is a neurodegenerative disorder that is characterized by progressive impairment of cognitive functions, such as abstract reasoning and memory.
  • AD is one of the most prevalent illnesses in the elderly (Fratiglioni, et al., Drugs Aging 15: 365-375, 1999).
  • the majority of AD patients are in their sixties or older. More than 5% of all persons over the age of 70 have significant memory loss due to AD.
  • AD is mainly characterized through a gradual development of forgetfulness. In further advanced disease stages, other failures in cerebral function become increasingly apparent. This includes impairment of speech, writing, and arithmetic skills. Visiospacial orientation, such as parking the car, dressing properly, and giving and understanding directions to a location, can become defective or impaired. In late stage disease, patients forget how to use common objects and tools while retaining necessary motor power and co-ordination for these activities (Victor and Ropper, Adams and Victor's Principles of Neurology, 7th Ed., New York: McGraw-Hill Professional, 2001).
  • AD neurofibrillary tangles
  • senile plaques are spherical accumulations consisting mainly of amyloid beta-peptide. Abundance of amyloid beta-peptide has been proposed to be central to the pathogenesis of AD.
  • Amyloid beta-peptide is generated from a larger amyloid precursor protein (APP) through proteolytic cleavage, catalyzed by specific enzymes such as beta and gamma secretases.
  • APP amyloid precursor protein
  • the abundance of NFTs also correlates with the severity of cognitive impairment.
  • NFTs and intraneuronal aggregates have been linked with hyperphosphorylation of the neuronal microtubule-associated protein tau by multiple protein kinases, including GSK3beta, cdk5, MAPK, and PKA (Morishima-Kawashima, J Neurosci. Res. 70: 392-401, 2002.
  • Tau deposition is associated with neuronal loss, and is also observed in various other neurodegenerative diseases.
  • AD Alzheimer brain shows a loss of cholinergic neurons, monoaminergic neurons, and diminution of noradrenergic, GABAergic, and serotoninergic functions in the affected neocortex.
  • decreased concentrations of several neuropeptide transmitters, such as substance P, somatostatin, and cholecystokinin in the brain cortex has been described.
  • AD can also be associated with pathologically elevated glutamate levels in the CNS. Pathologic activation of the glutamate receptor produces high levels of intracellular calcium and ultimately leads to cell death. This can result in several acute and chronic neurological diseases, including AD (Lipton, et al., N. Engl. J. Med. 330: 613-622, 1994).
  • AD Alzheimer's disease
  • acetylcholine esterase inhibitors such as donepezil, galantamine, rivastigmine, and tacrine.
  • Memantine a blocker of N- methyl-D-aspartate (NMDA) receptors in the brain is undergoing clinical trials.
  • Estrogen replacement therapy has been described to protect against AD development in women.
  • antioxidants, cerebral vasodilators, extracts from Ginko biloba, L-dopa, vitamins, lecithin, choline, and other stimulants are used to treat AD.
  • NMDA N- methyl-D-aspartate
  • Vascular dementia is considered to be the second most common dementia of late life, affecting approximately 10-15% of all cases. AD and vascular dementia can exist in isolation or together (mixed dementia). In vascular dementia, atherosclerotic changes in cerebral vessels can lead to reduced local blood flow that results in multiple small strokes (multi-infarct dementia) (Braunwald, et al., Harrison's Principles of Internal Medicine, 15th Ed., New York: McGraw-Hill Professional, 2001). Vascular dementia is pharmacologically treated by stroke prophylaxis, and by treatment of the cognitive deficit. These include treatment with aspirin, warfarin, other antithrombotic therapies, and cognitive enhancers.
  • the present invention relates to compounds which are useful in the treatment of for dementia and related disorders, and in particular, Alzheimer's disease and vascular dementia.
  • the invention relates to pyrazole derivatives that have utility in the treatment of dementia and related disorders, said derivatives of the Formula (I), prodrugs thereof, tautomers thereof and salts thereof
  • R and R 1 are the same or different and represent phenyl, thienyl or pyridyl which groups may be substituted with 1, 2, or 3 substituents Y, which can be the same or different, from the group (C r C 3 )-alkyl, (Ci-C 3 )-alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono (C 1 - C 2 )-amino, dialkyl (Ci-C 2 )-amino, mono (C 1 -C 2 )-amido, dialkyl (C 1 -C 2 )-amido, (Ci-C 3 )-alkyl sulfonyl, dimethylsulfamido, (Ci ⁇ C 3 )-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulf
  • R and/or R 1 represent naphtyl
  • R 2 represents hydrogen, hydroxy, (C r C 3 )-alkoxy, acetyloxy, or propionyloxy;
  • Aa represents one of the groups (i), (ii), (iii), (iv), or (v)
  • R 4 and R 5 independently of each other represent hydrogen or (Ci-C 8 ) branched or unbranched alkyl or (C 3 -C 8 )cycloalkyl,
  • R 4 represents acetamido, dimethylamino, 2,2,2-trifluoroethyl, phenyl, or pyridyl with the proviso that R 5 represents hydrogen;
  • R 6 represents hydrogen or (Ci-C 3 ) unbranched alkyl
  • Bb represents sulfonyl or carbonyl
  • R 3 represents benzyl, phenyl, thienyl, or pyridyl which may be substituted with 1, 2, or 3 substituents Y, which can be the same or different,
  • R 3 represents (Ci-C 8 ) branched or unbranched alkyl or (C 3 - C 8 )cycloalkyl
  • R 3 represents naphtyl
  • Examples of compounds of Formula (I) include, but are not limited to: 3-(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4-phenyl-lH-pyrazole; 3-(4-chlorophenyl)-4,5-dihydro-N-((4-fluorophenyl)sulfonyl)-4-phenyl- IH pyrazole- 1 - carboxamidine;
  • the invention also relates to enantiomers of pyrazole derivatives having an S configuration at the 4 position of the 4,5-dihydropyrazole ring, said derivatives of the Formula (II), prodrugs thereof, tautomers thereof and salts thereof
  • R and Ri are the same or different and represent 3-pyridyl, 4-pyridyl, or phenyl which may be substituted with halogen or methoxy;
  • R 2 and R 3 are the same or different and represent hydrogen, (Ci-C 3 )-alkyl, or dimethylamino;
  • R 4 represents phenyl which may be substituted with 1, 2, or 3 substituents selected from the group halogen, trifluoromethyl, methoxy, and (C r C 3 )-alkyl
  • Examples of compounds of Formula (II) include, but are not limited to:
  • any moiety when any moiety is described as being substituted, it can have one or more of the indicated substituents that can be located at any available position on the moiety. When there are two or more substituents on any moiety, each term shall be defined independently of any other in each occurrence.
  • Representative salts of the compounds of the present invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanes
  • Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine.
  • basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
  • diamyl sulfates long chain halides such as decyl, lauryl
  • the compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers. Any isomer may be present in the (R)-, (S)-, or (R 1 S) configuration, preferably in the (R)- or (S)- configuration, whichever is most active.
  • prodrug forms of the compounds of this invention will prove useful in certain circumstances, and such compounds are also intended to fall within the scope of the invention.
  • Prodrug forms may have advantages over the parent compounds exemplified herein, in that they are better absorbed, better distributed, more readily penetrate the central nervous system, are more slowly metabolized or cleared, etc.
  • Prodrug forms may also have formulation advantages in terms of crystallinity or water solubility.
  • compounds of the invention having one or more hydroxyl groups may be converted to esters or carbonates bearing one or more carboxyl, hydroxyl or amino groups, which are hydrolyzed at physiological pH values or are cleaved by endogenous esterases or lipases in vivo. See for example U.S. Patent Nos.4,942,184; 4,960,790; 5,817,840; and 5,824,701 (all of which are incorporated herein by reference in their entirety), and references therein.
  • subject includes mammals (e.g., humans and animals).
  • treatment includes any process, action, application, therapy, or the like, wherein a subject, including a human being, is provided medical aid with the object of improving the subject's condition, directly or indirectly, or slowing the progression of a condition or disorder in the subject.
  • combination therapy means the administration of two or more therapeutic agents to treat a disease condition and/or disorder.
  • administration encompasses co-administration of two or more therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each inhibitor agent.
  • administration encompasses use of each type of therapeutic agent in a sequential manner.
  • terapéuticaally effective means the amount of each agent administered that will achieve the goal of improvement in a disease condition or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment.
  • pharmaceutically acceptable means that the subject item is appropriate for use in a pharmaceutical product.
  • the compounds of the present invention are useful in treating dementia and related disorders including Alzheimer's disease and vascular dementia.
  • the compounds of the present invention may be used alone or in combination with additional therapies and/or compounds known to those skilled in the art in the treatment of dementia. Alternatively, the methods and compounds described herein may be used, partially or completely, in combination therapy.
  • Such co-therapies may be administered in any combination of two or more drugs (e.g., a compound of the invention in combination with a drug to treat dementia). Such co-therapies may be administered in the form of pharmaceutical compositions, as described above.
  • the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient (e.g., compounds) to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered may generally range from about 0.0001 mg/kg to about 200 mg/kg, and preferably from about 0.01 mg/kg to about 200 mg/kg body weight per day.
  • a unit dosage may contain from about 0.05 mg to about 1500 mg of active ingredient, and may be administered one or more times per day.
  • the daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injections, and use of infusion techniques may be from about 0.01 to about 200 mg/kg.
  • the daily rectal dosage regimen may be from 0.01 to 200 mg/kg of total body weight.
  • the transdermal concentration may be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age of the patient, the diet of the patient, time of administration, route of administration, rate of excretion of the drag, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention may be ascertained by those skilled in the art using conventional treatment tests.
  • the compounds of this invention may be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound.
  • a pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • a therapeutically effective amount of a compound is that amount which produces a result or exerts an influence on the particular condition being treated.
  • the compounds described herein may be administered with a pharmaceutically- acceptable carrier using any effective conventional dosage unit forms, including, for example, immediate and timed release preparations, orally, parenterally, topically, or the like.
  • the compounds may be formulated into solid or liquid preparations such as, for example, capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • the solid unit dosage forms may be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers.
  • the compounds of this invention may be tableted with conventional tablet bases in combination with binders, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, dyes, coloring agents, and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • Suitable excipients for use in oral liquid dosage forms include diluents either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, those sweetening, flavoring and coloring agents described above, may also be present.
  • compositions of this invention may also be in the form of oil-in-water emulsions.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents.
  • sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose.
  • Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents.
  • the compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid or mixture of liquids with or without the addition of a pharmaceutically acceptable surfactant or emulsifying agent and other pharmaceutical adjuvants.
  • a pharmaceutical carrier which may be a sterile liquid or mixture of liquids with or without the addition of a pharmaceutically acceptable surfactant or emulsifying agent and other pharmaceutical adjuvants.
  • compositions of this invention may typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant.
  • compositions may be in the form of sterile injectable aqueous suspensions.
  • Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono or diglycerides.
  • fatty acids such as oleic acid may be used in the preparation of injectables.
  • a composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions may be prepared by mixing the drug (e.g., compound) with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches")- Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art ⁇ see, e.g., U.S. Patent No. 5,023,252, incorporated herein by ⁇ reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Another formulation employs the use of biodegradable microspheres that allow controlled, sustained release.
  • Such formulations can be comprised of synthetic polymers or copolymers.
  • Such formulations allow for injection, inhalation, nasal or oral administration.
  • the construction and use of biodegradable microspheres for the delivery of pharmaceutical agents is well known in the art (e.g., U.S. Patent No. 6, 706,289, incorporated herein by reference).
  • compositions of the invention may also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Any of the compositions of this invention may be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.
  • Formulations suitable for subcutaneous, intravenous, intramuscular, and the like; suitable pharmaceutical carriers; and techniques for formulation and administration may be prepared by any of the methods well known in the art ⁇ see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20 th edition, 2000).
  • Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to demonstrate the efficacy of a pharmaceutical agent for the treatment of a dementia, the following assays may be used.
  • the Morris water maze is a behavioral in vivo test to measure spatial orientation learning and memory through a complex learning task. It is highly suitable for testing compounds that enhance learning and memory.
  • a circular water tank or pool (diameter 2 m, height 0.7 m) is filled with water, and a 10 cm 2 platform is placed 1-1.5 cm below the water surface at a defined location within the pool. The escape platform is not visible for an animal swimming in the water tank. For the experiment, a rat or mouse is placed into the pool to swim freely.
  • the animals have the task to localize the submerged platform, and the time and distance required for successful retrieval is measured.
  • Multiple extra-maze cues are provided by the furniture in the room, including desks, computer equipment, a second water tank, the presence of the experimenter, and by a radio on a shelf that is playing softly.
  • test compounds are administered orally or intraperitoneally on the day of the experiment at a defined time (e.g., 30 minutes before the first swim test). Control animals are dosed with the corresponding vehicle not containing test compound. Active compounds yield shorter times and distances to localize the platform (i.e., the better the animal remembers the location of the platform, the shorter the distance covered and the faster the platform is reached).
  • the test can also be carried out using transgenic or cognitively impaired animals.
  • Cognitive impairment is induced either by old age or experimentally through brain lesions, such as bilateral lesions of the entorhinal cortex in rats. Such lesions can be induced by intracerebral injections of the excitotoxin ibotenic acid.
  • the object recognition task is used to assess the effects of compounds on the cognitive performance of rodents.
  • a rat is placed in an open field, in which two identical objects are located. The rats inspects both objects during the initial trial of the test. After a certain retention interval (e.g., 24 hours), a second trial is carried out.
  • a certain retention interval e.g. 24 hours
  • a second trial is carried out.
  • one of the two objects used in the first trial (the 'familiar' object) and a novel object are placed in the open field, and the inspection time at each of the objects is measured. Good retention is reflected by higher exploration times towards the novel compared with the 'familiar' object.
  • Administration of the putative cognition enhancer prior to the first trial predominantly allows assessment of the effects on acquisition, and on the consolidation processes.
  • Administration of the test compound after the first trial allows to assess the effects on consolidation processes, whereas administration before the second trial allows to measure effects on retrieval processes.
  • the passive avoidance task assesses memory performance in rats and mice.
  • the inhibitory avoidance uses an apparatus consisting of a box with two compartments separated by a guillotine door that can be operated by the experimenter. One compartment is illuminated with bright light, and the other compartment is dark. A threshold of 2 cm separates the two compartments when the guillotine door is 15 raised. When the door is open, the illumination in the dark compartment is about 2 lux. The light intensity is about 500 lux at the center of the floor of the light compartment.
  • the guillotine door between the compartments is lowered as soon as the rat has entered the dark compartment with all paws, and a scrambled 1 mA footshock is administered for 2 seconds. Then the rat is removed from the apparatus and returned into its home cage. The procedure during the retention session is identical to that of the habituation sessions.
  • the step-through latency that is, the first latency of entering the dark compartment (in seconds) during the retention session is an index of the memory performance of the animal: a better retention is assumed if the latency to enter the dark compartment is longer.
  • a test compound is given 30 minutes before the shock session, together with 1 mg/kg scopolamine. Scopolamine impairs the memory performance during the retention session 24 hours later. If the test compound increases the enter latency compared with the scopolamine-treated controls, it is considered to possess cognition enhancing activity.
  • T-maze spontaneous alternation task assesses the spatial memory performance in mice.
  • the start arm and the two goal arms of the T-maze are provided with guillotine doors that can be operated manually by the experimenter.
  • a mouse is put into the start arm at the beginning of training.
  • either the left or right goal arm is blocked by lowering the respective guillotine door (forced trial).
  • the mouse After the mouse has been released from the start arm, it will explore the maze, eventually entering the open goal arm, and return to the start position, where it will be confined for 5 seconds, by lowering the guillotine door. Then, the animal can choose freely between the left and right goal arm (all guillotine-doors opened) during 14 additional trials (free choice trials). As soon as a mouse has entered one goal arm, the other arm is closed. The mouse eventually returns to the start arm and is free to visit whichever arm it wants after having been confined to the start arm for 5 seconds. After completion of 14 free choice trials in one session, the animal is removed from the maze.

Abstract

This invention relates to pyrazole derivatives which are useful in treating dementia and related disorders.

Description

PYRAZOLE DERIVATIVES FOR THE TREATMENT OF DEMENTIA AND RELATED DISORDERS
[001] This application claims benefit of U.S. Provisional Application Serial No. 60/632,0024; filed on November 30, 2004, the contents of which are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[002] This invention relates to pyrazole derivatives which are useful in the treatment of treating dementia and related disorders.
BACKGROUND OF THE INVENTION
[003] Dementia is a disease characterized by the progressive deterioration in cognitive and social adaptive functions that can eventually interfere with the patient's ability to live independently (Strub, South Med. J. 96: 363-366, 2003). Dementia also constitutes of impairment in short- and long-term memory plus additional symptoms, such as problems with abstract thinking, judgment, or personality. An estimated 18 million patients suffer from dementia worldwide. The most common forms of dementia include Alzheimer's disease and vascular dementia. Other forms are frontotemporal dementia and Pick's disease.
[004] Alzheimer's disease (AD), the most common and important form of dementia, is a neurodegenerative disorder that is characterized by progressive impairment of cognitive functions, such as abstract reasoning and memory. Currently, an estimated 2 million people in the United States and 12 million worldwide are afflicted by this disease. Due to increasing life expectancy, it is predicted that there will be over 100 million AD patients worldwide by the year 2050 (Scorer, Drag Discov. Today 6: 1207-1219, 2001; Victor and Ropper, Adams and Victor's Principles of Neurology, 7th Ed., New York: McGraw-Hill Professional, 2001). AD is one of the most prevalent illnesses in the elderly (Fratiglioni, et al., Drugs Aging 15: 365-375, 1999). The majority of AD patients are in their sixties or older. More than 5% of all persons over the age of 70 have significant memory loss due to AD.
[005] AD is mainly characterized through a gradual development of forgetfulness. In further advanced disease stages, other failures in cerebral function become increasingly apparent. This includes impairment of speech, writing, and arithmetic skills. Visiospacial orientation, such as parking the car, dressing properly, and giving and understanding directions to a location, can become defective or impaired. In late stage disease, patients forget how to use common objects and tools while retaining necessary motor power and co-ordination for these activities (Victor and Ropper, Adams and Victor's Principles of Neurology, 7th Ed., New York: McGraw-Hill Professional, 2001).
[006] Pathologically, AD is characterized by neurofibrillary tangles (NFTs), senile plaques, and the death of neurons in neocortical and limbic brain regions. Senile plaques are spherical accumulations consisting mainly of amyloid beta-peptide. Abundance of amyloid beta-peptide has been proposed to be central to the pathogenesis of AD. Amyloid beta-peptide is generated from a larger amyloid precursor protein (APP) through proteolytic cleavage, catalyzed by specific enzymes such as beta and gamma secretases. The abundance of NFTs also correlates with the severity of cognitive impairment.
[007] NFTs and intraneuronal aggregates have been linked with hyperphosphorylation of the neuronal microtubule-associated protein tau by multiple protein kinases, including GSK3beta, cdk5, MAPK, and PKA (Morishima-Kawashima, J Neurosci. Res. 70: 392-401, 2002. Tau deposition is associated with neuronal loss, and is also observed in various other neurodegenerative diseases.
[008] Moreover, the Alzheimer brain shows a loss of cholinergic neurons, monoaminergic neurons, and diminution of noradrenergic, GABAergic, and serotoninergic functions in the affected neocortex. In addition, decreased concentrations of several neuropeptide transmitters, such as substance P, somatostatin, and cholecystokinin in the brain cortex has been described. AD can also be associated with pathologically elevated glutamate levels in the CNS. Pathologic activation of the glutamate receptor produces high levels of intracellular calcium and ultimately leads to cell death. This can result in several acute and chronic neurological diseases, including AD (Lipton, et al., N. Engl. J. Med. 330: 613-622, 1994).
[009] Current treatments of AD are mostly symptomatic, and include acetylcholine esterase inhibitors such as donepezil, galantamine, rivastigmine, and tacrine. Memantine, a blocker of N- methyl-D-aspartate (NMDA) receptors in the brain is undergoing clinical trials. Estrogen replacement therapy has been described to protect against AD development in women. Furthermore, antioxidants, cerebral vasodilators, extracts from Ginko biloba, L-dopa, vitamins, lecithin, choline, and other stimulants are used to treat AD. Overall, there is a high medical need for 'disease modifying' agents that either delay disease onset, or slow disease progression.
[010] Dementia can also be of vascular origin. Vascular dementia (atherosclerotic cerebrovascular disease) is considered to be the second most common dementia of late life, affecting approximately 10-15% of all cases. AD and vascular dementia can exist in isolation or together (mixed dementia). In vascular dementia, atherosclerotic changes in cerebral vessels can lead to reduced local blood flow that results in multiple small strokes (multi-infarct dementia) (Braunwald, et al., Harrison's Principles of Internal Medicine, 15th Ed., New York: McGraw-Hill Professional, 2001). Vascular dementia is pharmacologically treated by stroke prophylaxis, and by treatment of the cognitive deficit. These include treatment with aspirin, warfarin, other antithrombotic therapies, and cognitive enhancers.
[011] Accordingly, despite the presence of some pharmaceuticals that are used to treat these diseases, there remains a need for new pharmaceuticals that are both safe and effective agents for the treatment of disease, and for useful methods to prepare them.
[012] The present invention relates to compounds which are useful in the treatment of for dementia and related disorders, and in particular, Alzheimer's disease and vascular dementia.
DETAILED DESCRIPTION OF THE INVENTION
[013] The invention relates to pyrazole derivatives that have utility in the treatment of dementia and related disorders, said derivatives of the Formula (I), prodrugs thereof, tautomers thereof and salts thereof
Figure imgf000004_0001
wherein R and R1 are the same or different and represent phenyl, thienyl or pyridyl which groups may be substituted with 1, 2, or 3 substituents Y, which can be the same or different, from the group (CrC3)-alkyl, (Ci-C3)-alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono (C1- C2)-amino, dialkyl (Ci-C2)-amino, mono (C1-C2)-amido, dialkyl (C1-C2)-amido, (Ci-C3)-alkyl sulfonyl, dimethylsulfamido, (Ci~C3)-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl, and acetyl,
or
R and/or R1 represent naphtyl;
R2 represents hydrogen, hydroxy, (CrC3)-alkoxy, acetyloxy, or propionyloxy; Aa represents one of the groups (i), (ii), (iii), (iv), or (v)
Figure imgf000005_0001
(i) (ϋ) (ϋi) (iv) (v)
wherein
R4 and R5 independently of each other represent hydrogen or (Ci-C8) branched or unbranched alkyl or (C3-C8)cycloalkyl,
or
R4 represents acetamido, dimethylamino, 2,2,2-trifluoroethyl, phenyl, or pyridyl with the proviso that R5 represents hydrogen;
R6 represents hydrogen or (Ci-C3) unbranched alkyl;
Bb represents sulfonyl or carbonyl;
R3 represents benzyl, phenyl, thienyl, or pyridyl which may be substituted with 1, 2, or 3 substituents Y, which can be the same or different,
or
R3 represents (Ci-C8) branched or unbranched alkyl or (C3- C8)cycloalkyl,
or
R3 represents naphtyl.
[014] Methods of synthesizing compounds of Formula (T) are described in WO 01/70700 (PCT/EP01/03247), which is incorporated herein in its entirety.
[015] Examples of compounds of Formula (I) include, but are not limited to: 3-(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4-phenyl-lH-pyrazole; 3-(4-chlorophenyl)-4,5-dihydro-N-((4-fluorophenyl)sulfonyl)-4-phenyl- IH pyrazole- 1 - carboxamidine;
3-(4-chlorophenyl)-4,5-dihydro-N-(l-naphtoyl)-4-phenyl-lH-pyrazole-l-carboxamidine;
N1,N1-dimethyl-N2-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro- 4-phenyl-lH- pyrazole- 1 -carboxamidine ;
N-methyl-N' -((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-(3 pyridyl)-l H- pyrazole- 1 -carboxamidine;
N-methyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-(4 pyridyl)-l H- pyrazole-1-carboxamidine;
N1 ,N1 -dimethyl- N2-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4- phenyl-lH-pyrazole-1-carboxamidine;
N-ethyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4-phenyl-lH- pyrazole- 1 -carboxamidine ;
N-methyl-N' -(3-(trifluoromethyl)benzoyl)-3-(4-chlorophenyl)- 4,5-dihydro-4-phenyl-lH- pyrazole- 1 -carboxamidine;
N-methyl-N' -((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH-pyrazole-l- carboxamidine;
N-methyl-N' -((3-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)- 4,5-dihydro-4-phenyl-lH-pyrazole-
1-carboxamidine;
N-methyl-N' -((4-chlorophenyl)sulfonyl)-3-(5-chloro-2-thienyl)-4,5-dihydro-4-phenyl-lH- pyrazole- 1 -carboxamidine ;
N-propyl-N'-((4-rluorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH-pyrazole-l- carboxamidine;
N-(2-propyl)-N'-((4-fluorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole-1-carboxamidine;
N-methyl-N' -((2-propyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH-pyrazole-l- carboxamidine;
N-(2-propyl)-N'-((4-chlorophenyl)sulfonyl)-3-(4-pyridyl)-4,5-dihydro-4-phenyl-lH-pyrazole-l- carboxamidine;
N1-ethyl-N1-methyl-N2-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole-1-carboxamidine;
N1-ethyl-N1-methyl-N2-((4-fluorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole- 1 -carboxamidine ;
N1, N1-dimethyl-N2-((4-(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-lH-pyrazole-1-carboxamidine; N1, N1-dimethyl-N2-((3-methylphenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4phenyl-lH- pyrazole-1-carboxamidine;
N1, N1-dimethyl-N2-((3-methoxyphenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole- 1 -carboxamidine;
N-ethyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH-pyrazole-l- carboxamidine;
N-dimethylamino-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole-1-carboxamidine;
N-methyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole-1-carboxamidine;
N1, N1-dimethyl- N2-((2-methylphenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole-1-carboxamidine;
N-methyl-N'-((2,4-difluorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4 phenyl-lH- pyrazole-1-carboxamidine;
N-acetamido-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole- 1 -carboxamidine;
N-(2,2,2-trifluoroethyl)-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)- 4,5-dihydro-4-phenyl- lH-pyrazole- 1-carboxamidine;
N-(2-pyridyl)-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole- 1 -carboxamidine;
N-(4-pyridyl)-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole- 1 -carboxamidine;
N-phenyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH-pyrazole-l- carboxamidine;
3-(4-chlorophenyl)-l -[3-((4-chlorophenyl)sulfonyl)butanoyl]-4,5-dihydro- 4-phenyl-lH-pyrazole;
3-(4-chlorophenyl)-l-[3-(phenylsulfonyl)propanoyl]-4,5-dihydro-4-phenyl-lH-pyrazole;
3-(4-chlorophenyl)-l-[3-((4-chlorophenyl)sulfonyl)propanoyl]-4,5-dihydro- 4-phenyl-lH- pyrazole;
3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-l-[2-((3-(trifluoromethyl)phenyl)-sulfonyl)ethyl]-lH- pyrazole;
3-(4-chlorophenyl)-l-[2-(benzylsulfonyl)ethyl]-4,5-dihydro-4-phenyl-lH- pyrazole;
3-(4-chlorophenyl)-l-[2-((4-chlorophenyl)sulfonyl)ethyl]-4,5-dihydro-4-phenyl-lH pyrazole;
3-(4-chlorophenyl)-l -[2-((4-chlorophenyl)sulfonyl)ethyl]-4,5-dihydro-4-hydroxy-4-phenyl-lH- pyrazole; and
N-[2-(3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH-pyrazol-l-yl)ethyl]-3(trifluoromethyl) benzenesulfonamide. [016] The invention also relates to enantiomers of pyrazole derivatives having an S configuration at the 4 position of the 4,5-dihydropyrazole ring, said derivatives of the Formula (II), prodrugs thereof, tautomers thereof and salts thereof
Figure imgf000008_0001
wherein
R and Ri are the same or different and represent 3-pyridyl, 4-pyridyl, or phenyl which may be substituted with halogen or methoxy;
R2 and R3 are the same or different and represent hydrogen, (Ci-C3)-alkyl, or dimethylamino;
R4 represents phenyl which may be substituted with 1, 2, or 3 substituents selected from the group halogen, trifluoromethyl, methoxy, and (CrC3)-alkyl
[017] Methods of synthesizing compounds of Formula (II) are described in WO 02/076949 (PCT/EP02/03079), which is incorporated herein in its entirety.
[018] Examples of compounds of Formula (II) include, but are not limited to:
(-)-(4S)-N-methyl-N'-((4-chlorophenyl)surfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole-1-carboxamidine; '
(-)-(4S)-N-ethyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole- 1-carboxamidine;
(-)-(4S)-N-dimethylarnino-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-lH-pyrazole-1-carboxamidine;
(-)-(4S)-N-methyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-lH-pyrazole-1-carboxamidine; and
(-)-(4S)-N1, N1-dimethyl-N2-((2-methylphenyl)sulfonyl)-3-(4-chlorophenyl)- 4,5-dihydro-4- phenyl- 1 H-pyrazole- 1 -carboxamidine.
[019] When any moiety is described as being substituted, it can have one or more of the indicated substituents that can be located at any available position on the moiety. When there are two or more substituents on any moiety, each term shall be defined independently of any other in each occurrence.
[020] Representative salts of the compounds of the present invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate.
[021] Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
[022] It will be appreciated that diastereomers and enantiomers of the exemplified structures will often be possible, and that pure isomers represent preferred embodiments. It is intended that pure stereoisomers, and mixtures thereof, are within the scope of the invention.
[023] The compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers. Any isomer may be present in the (R)-, (S)-, or (R1S) configuration, preferably in the (R)- or (S)- configuration, whichever is most active.
[024] All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this invention are encompassed within the scope of this invention. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art.
[025] Geometric isomers by nature of substituents about a double bond or a ring may be present in cis (= Z-) or trans (= E-) form, and both isomeric forms are encompassed within the scope of this invention.
[026] The particular process to be utilized in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as the selection of the specific moieties and the specific substituents on the various moieties, all play a role in the path to be followed in the preparation of the specific compounds of this invention. These factors are readily recognized by one of ordinary skill in the art.
[027] For synthesis of any particular compound, one skilled in the art will recognize that the use of protecting groups may be required for the synthesis of compounds containing certain substituents. A description of suitable protecting groups and appropriate methods of adding and removing such groups may be found in: Protective Groups in Organic Synthesis, Second Edition, T. W. Greene, John Wiley and Sons, New York, 1991.
[028] It is anticipated that prodrug forms of the compounds of this invention will prove useful in certain circumstances, and such compounds are also intended to fall within the scope of the invention. Prodrug forms may have advantages over the parent compounds exemplified herein, in that they are better absorbed, better distributed, more readily penetrate the central nervous system, are more slowly metabolized or cleared, etc. Prodrug forms may also have formulation advantages in terms of crystallinity or water solubility. For example, compounds of the invention having one or more hydroxyl groups may be converted to esters or carbonates bearing one or more carboxyl, hydroxyl or amino groups, which are hydrolyzed at physiological pH values or are cleaved by endogenous esterases or lipases in vivo. See for example U.S. Patent Nos.4,942,184; 4,960,790; 5,817,840; and 5,824,701 (all of which are incorporated herein by reference in their entirety), and references therein.
Methods of Use
[029] As used herein, various terms are defined below.
[030] When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.
[031] The term "subject" as used herein includes mammals (e.g., humans and animals).
[032] The term "treatment" includes any process, action, application, therapy, or the like, wherein a subject, including a human being, is provided medical aid with the object of improving the subject's condition, directly or indirectly, or slowing the progression of a condition or disorder in the subject.
[033] The term "combination therapy" or "co-therapy" means the administration of two or more therapeutic agents to treat a disease condition and/or disorder. Such administration encompasses co-administration of two or more therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each inhibitor agent. In addition, such administration encompasses use of each type of therapeutic agent in a sequential manner.
[034] The phrase "therapeutically effective" means the amount of each agent administered that will achieve the goal of improvement in a disease condition or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment.
[035] The term "pharmaceutically acceptable" means that the subject item is appropriate for use in a pharmaceutical product.
[036] The compounds of the present invention are useful in treating dementia and related disorders including Alzheimer's disease and vascular dementia.
[037] The compounds of the present invention may be used alone or in combination with additional therapies and/or compounds known to those skilled in the art in the treatment of dementia. Alternatively, the methods and compounds described herein may be used, partially or completely, in combination therapy.
[038] Such co-therapies may be administered in any combination of two or more drugs (e.g., a compound of the invention in combination with a drug to treat dementia). Such co-therapies may be administered in the form of pharmaceutical compositions, as described above.
[039] Based on well known assays used to determine the efficacy for treatment of conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient (e.g., compounds) to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
[040] The total amount of the active ingredient to be administered may generally range from about 0.0001 mg/kg to about 200 mg/kg, and preferably from about 0.01 mg/kg to about 200 mg/kg body weight per day. A unit dosage may contain from about 0.05 mg to about 1500 mg of active ingredient, and may be administered one or more times per day. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injections, and use of infusion techniques may be from about 0.01 to about 200 mg/kg. The daily rectal dosage regimen may be from 0.01 to 200 mg/kg of total body weight. The transdermal concentration may be that required to maintain a daily dose of from 0.01 to 200 mg/kg. [041] Of course, the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age of the patient, the diet of the patient, time of administration, route of administration, rate of excretion of the drag, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention may be ascertained by those skilled in the art using conventional treatment tests.
[042] The compounds of this invention may be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound. A pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A therapeutically effective amount of a compound is that amount which produces a result or exerts an influence on the particular condition being treated. The compounds described herein may be administered with a pharmaceutically- acceptable carrier using any effective conventional dosage unit forms, including, for example, immediate and timed release preparations, orally, parenterally, topically, or the like.
[043] For oral administration, the compounds may be formulated into solid or liquid preparations such as, for example, capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms may be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers.
[044] In another embodiment, the compounds of this invention may be tableted with conventional tablet bases in combination with binders, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, dyes, coloring agents, and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include diluents either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit.
For instance tablets, pills or capsules may be coated with shellac, sugar or both. [045] Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, those sweetening, flavoring and coloring agents described above, may also be present.
[046] The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The emulsions may also contain sweetening and flavoring agents.
[047] Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents.
[048] The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid or mixture of liquids with or without the addition of a pharmaceutically acceptable surfactant or emulsifying agent and other pharmaceutical adjuvants.
[049] The parenteral compositions of this invention may typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant.
[050] The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
[051] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.
[052] A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the drug (e.g., compound) with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. [053] Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches")- Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art {see, e.g., U.S. Patent No. 5,023,252, incorporated herein by ■reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
[054] Another formulation employs the use of biodegradable microspheres that allow controlled, sustained release. Such formulations can be comprised of synthetic polymers or copolymers. Such formulations allow for injection, inhalation, nasal or oral administration. The construction and use of biodegradable microspheres for the delivery of pharmaceutical agents is well known in the art (e.g., U.S. Patent No. 6, 706,289, incorporated herein by reference).
[055] It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. For example, direct techniques for administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in U.S. Patent No. 5,011,472, incorporated herein by reference.
[056] The compositions of the invention may also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Any of the compositions of this invention may be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.
[057] Formulations suitable for subcutaneous, intravenous, intramuscular, and the like; suitable pharmaceutical carriers; and techniques for formulation and administration may be prepared by any of the methods well known in the art {see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20th edition, 2000).
[058] It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without departing from the spirit or scope of the invention as it is set forth herein. Evaluation of Biological Activity
[059] In order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any manner. All publications mentioned herein are incorporated by reference in their entirety.
[060] Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to demonstrate the efficacy of a pharmaceutical agent for the treatment of a dementia, the following assays may be used.
Morris Water Maze Task
[061] The Morris water maze is a behavioral in vivo test to measure spatial orientation learning and memory through a complex learning task. It is highly suitable for testing compounds that enhance learning and memory. A circular water tank or pool (diameter 2 m, height 0.7 m) is filled with water, and a 10 cm2 platform is placed 1-1.5 cm below the water surface at a defined location within the pool. The escape platform is not visible for an animal swimming in the water tank. For the experiment, a rat or mouse is placed into the pool to swim freely.
[062] The animals have the task to localize the submerged platform, and the time and distance required for successful retrieval is measured. Multiple extra-maze cues are provided by the furniture in the room, including desks, computer equipment, a second water tank, the presence of the experimenter, and by a radio on a shelf that is playing softly.
[063] Before administration of the test compound, animals are usually trained in the task 4 times a day for 5 days. Test compounds are administered orally or intraperitoneally on the day of the experiment at a defined time (e.g., 30 minutes before the first swim test). Control animals are dosed with the corresponding vehicle not containing test compound. Active compounds yield shorter times and distances to localize the platform (i.e., the better the animal remembers the location of the platform, the shorter the distance covered and the faster the platform is reached).
[064] The test can also be carried out using transgenic or cognitively impaired animals. Cognitive impairment is induced either by old age or experimentally through brain lesions, such as bilateral lesions of the entorhinal cortex in rats. Such lesions can be induced by intracerebral injections of the excitotoxin ibotenic acid.
Object Recognition Task
[065] The object recognition task is used to assess the effects of compounds on the cognitive performance of rodents. A rat is placed in an open field, in which two identical objects are located. The rats inspects both objects during the initial trial of the test. After a certain retention interval (e.g., 24 hours), a second trial is carried out. Here, one of the two objects used in the first trial (the 'familiar' object) and a novel object are placed in the open field, and the inspection time at each of the objects is measured. Good retention is reflected by higher exploration times towards the novel compared with the 'familiar' object.
[066] Administration of the putative cognition enhancer prior to the first trial predominantly allows assessment of the effects on acquisition, and on the consolidation processes. Administration of the test compound after the first trial allows to assess the effects on consolidation processes, whereas administration before the second trial allows to measure effects on retrieval processes.
Passive Avoidance Task
[067] The passive avoidance task assesses memory performance in rats and mice. The inhibitory avoidance uses an apparatus consisting of a box with two compartments separated by a guillotine door that can be operated by the experimenter. One compartment is illuminated with bright light, and the other compartment is dark. A threshold of 2 cm separates the two compartments when the guillotine door is 15 raised. When the door is open, the illumination in the dark compartment is about 2 lux. The light intensity is about 500 lux at the center of the floor of the light compartment.
[068] Two habituation sessions, one shock session, and a retention session are given, separated by inter-session intervals of 24 hours. During the habituation sessions and the retention session, the rat is allowed to explore the apparatus for 300 seconds. The rat is placed in the light compartment, facing the wall opposite to the guillotine door. After an accommodation period of 15 seconds, the guillotine door is opened so that all parts of the apparatus can be visited freely. Rats normally avoid brightly lit areas and will enter the dark compartment within a few seconds.
[069] In the shock session, the guillotine door between the compartments is lowered as soon as the rat has entered the dark compartment with all paws, and a scrambled 1 mA footshock is administered for 2 seconds. Then the rat is removed from the apparatus and returned into its home cage. The procedure during the retention session is identical to that of the habituation sessions.
[070] The step-through latency, that is, the first latency of entering the dark compartment (in seconds) during the retention session is an index of the memory performance of the animal: a better retention is assumed if the latency to enter the dark compartment is longer. A test compound is given 30 minutes before the shock session, together with 1 mg/kg scopolamine. Scopolamine impairs the memory performance during the retention session 24 hours later. If the test compound increases the enter latency compared with the scopolamine-treated controls, it is considered to possess cognition enhancing activity. T-maze Spontaneous Alternation Task
[071] The T-maze spontaneous alternation task (TeMCAT) assesses the spatial memory performance in mice. The start arm and the two goal arms of the T-maze are provided with guillotine doors that can be operated manually by the experimenter. A mouse is put into the start arm at the beginning of training. In the first trial, either the left or right goal arm is blocked by lowering the respective guillotine door (forced trial).
[072] After the mouse has been released from the start arm, it will explore the maze, eventually entering the open goal arm, and return to the start position, where it will be confined for 5 seconds, by lowering the guillotine door. Then, the animal can choose freely between the left and right goal arm (all guillotine-doors opened) during 14 additional trials (free choice trials). As soon as a mouse has entered one goal arm, the other arm is closed. The mouse eventually returns to the start arm and is free to visit whichever arm it wants after having been confined to the start arm for 5 seconds. After completion of 14 free choice trials in one session, the animal is removed from the maze.
[073] Out of the 14 trials the alternations in percent are calculated. This percentage and the total time needed to complete the first forced trial and the subsequent 14 free choice trials (in seconds) is analyzed. In addition, cognitive deficits can be induced by injection of scopolamine 30 minutes before the start of the training session. A cognition enhancer, administered before the training session, will at least partially, antagonize the scopolamine-induced reduction in the spontaneous alternation rate.
[074] The structures, materials, compositions, and methods described herein are intended to be representative examples of the invention, and it will be understood that the scope of the invention is not limited by the scope of the examples. Those skilled in the art will recognize that the invention may be practiced with variations on the disclosed structures, materials, compositions and methods, and such variations are regarded as within the ambit of the invention.

Claims

ClaimsWhat is claimed:
1. A method for treating dementia comprising administering to a subject in need thereof an effective amount of a compound of Formula (I)
Figure imgf000018_0001
wherein
R and Ri are the same or different and represent phenyl, thienyl or pyridyl which groups may be substituted with 1, 2, or 3 substituents Y, which can be the same or different, from the group (Ci-C3)-alkyl, (Q-C^-alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono (Q- C2)-amino, dialkyl (CrC2)-amino, mono (Ci-C2)-amido, dialkyl (Ci-C2)-amido, (Ci-C3)-alkyl sulfonyl, dimethylsulfamido, (Ci-C3)-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl, and acetyl,
or
R and/or R1 represent naphtyl;
R2 represents hydrogen, hydroxy, (Ci-C3)-alkoxy, acetyloxy, or propionyloxy;
Aa represents one of the groups (i), (ii), (iii), (iv), or (v)
Figure imgf000018_0002
(I) (H) (iϋ) (iv) (v)
wherein R4 and R5 independently of each other represent hydrogen or (C1-C8) branched or unbranched alkyl or (C3-C8)cycloalkyl,
or
R4 represents acetamido, dimethylamino, 2,2,2-trifluoroethyl, phenyl, or pyridyl with the proviso that R5 represents hydrogen;
Re represents hydrogen or (Ci-C3) unbranched alkyl;
Bb represents sulfonyl or carbonyl;
R3 represents benzyl, phenyl, thienyl, or pyridyl which may be substituted with 1, 2, or 3 substituents Y, which can be the same or different,
or
R3 represents (Ci-C8) branched or unbranched alkyl or (C3- C8)cycloalkyl,
or
R3 represents naphtyl.
2. The method of claim 1, wherein said compound of Formula (I) is selected from
3-(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4-phenyl-lH-pyrazole;
3-(4-chlorophenyl)-4,5-dihydro-N-((4-fluorophenyl)sulfonyl)-4-phenyl- IH pyrazole- 1 - carboxamidine;
3-(4-chlorophenyl)-4,5-dihydro-N-(l-naphtoyl)-4-phenyl-lH-pyrazole-l-carboxamidine;
N1,N1-dimethyl-N2-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro- 4-phenyl- lH-pyrazole-1-carboxamidine;
N-methyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-(3 pyridyl)-l
H-pyrazole-1-carboxamidine;
N-methyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-(4 pyridyl)-l
H-pyrazole-1-carboxamidine;
N^N1 -dimethyl- N2-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- hydroxy-4-phenyl-lH-pyrazole-l-carboxamidine;
N-ethyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4- phenyl-lH-pyrazole-1-carboxamidine; N-methyl-N' -(3-(trifluoromethyl)benzoyl)-3-(4-chlorophenyl)- 4,5-dihydro-4-phenyl- IH- pyrazole-1-carboxamidine;
N-methyl-N' -((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- py razole- 1 -carboxamidine ;
N-methyl-N' -((3-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)- 4,5-dihydro-4-phenyl-lH- pyrazole-1-carboxamidine;
N-methyl-N' -((4-chloroρhenyl)suhconyl)-3-(5-chloro-2-thienyl)-4,5-dihydro-4-phenyl-lH- pyrazole-1-carboxamidine;
N-propyl-N'-((4-fluorophenyl)suhconyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole-1-carboxamidine;
N-(2-propyl)-N'-((4-fluorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole-1-carboxamidine;
N-methyl-N' -((2-propyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH-pyrazole-
1-carboxamidine;
N-(2-propyl)-N'-((4-chlorophenyl)sulfonyl)-3-(4-pyridyl)-4,5-dihydro-4-phenyl-lH- pyrazole-1- carboxamidine;
N1-ethyl-N1-methyl-N2-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-lH- pyrazole-1-carboxamidine;
N1-ethyl-N1-methyl-N2-((4-fluorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-lH- pyrazole-1-carboxamidine;
N1, N1-dimethyl-N2-((4-(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-
4- phenyl-lH-pyrazole-l-carboxamidine;
N1, N1-dimethyl-N2-((3-methylphenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4phenyl- lH-pyrazole-1-carboxamidine;
N1, N1-dimethyl-N2-((3-methoxyphenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl- lH-pyrazole- 1 -carboxamidine;
N-ethyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole- 1 -carboxamidine;
N-dimethylamino-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl- IH- pyrazole- 1 -carboxamidine;
N-methyl-N' -((4-(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl- lH-pyrazole- 1 -carboxamidine;
N1, N1-dimethyl- N2-((2-methylphenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-lH-pyrazole-1-carboxamidine;
N-methyl-N' -((2,4-difluorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4 phenyl-lH- pyrazole- 1 -carboxamidine; N-acetamido-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole-1-carboxamidine;
N-(2,2,2-trifluoroethyl)-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)- 4,5-dihydro-4- phenyl- 1 H-pyrazole- 1 -carboxamidine;
N-(2-pyridyl)-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl- lH-pyrazole-1-carboxamidine;
N-(4-pyridyl)-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl- lH-pyrazole-1-carboxamidine;
N-phenyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH- pyrazole- 1 -carboxamidine;
3-(4-chlorophenyl)-l -[3-((4-chlorophenyl)sulfonyl)butanoyl]-4,5-dihydro- 4-phenyl- IH- pyrazole;
3-(4-chlorophenyl)-l-[3-(phenylsulfonyl)propanoyl]-4,5-dihydro-4-phenyl-lH-pyrazole;
3-(4-chlorophenyl)-l-[3-((4-chlorophenyl)sulfonyl)propanoyl]-4,5-dihydro- 4-phenyl-lH- pyrazole;
3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-l-[2-((3-(trifluoromethyl)phenyl)- sulfonyl)ethyl]- lH-pyrazole;
3-(4-chlorophenyl)-l-[2-(benzylsulfonyl)ethyl]-4,5-dihydro-4-phenyl-lH- pyrazole;
3-(4-chlorophenyl)-l-[2-((4-chlorophenyl)sulfonyl)ethyl]-4,5-dihydro-4-phenyl-lH pyrazole;
3-(4-chlorophenyl)-l -[2-((4-chlorophenyl)sulfonyl)ethyl]-4,5-dihydro-4-hydroxy-4- phenyl-lH-pyrazole; and
N-[2-(3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH-pyrazol-l-yl)ethyl]-3(trifluoromethyl) benzenesulfonamide.
3. A method for treating dementia comprising administering to a subject in need thereof an effective amount of a compound of Formula (II)
Figure imgf000021_0001
(H)
wherein R and R1 are the same or different and represent 3-pyridyl, 4-pyridyl, or phenyl which may be substituted with halogen or methoxy;
R2 and R3 are the same or different and represent hydrogen, (Ci-C3)-aIkyl, or dimethylamino;
R4 represents phenyl which may be substituted with 1, 2, or 3 substituents selected from the group halogen, trifluoromethyl, methoxy, and (Ci-C3)-alkyl.
4. The method of claim 3, wherein said compound of Formula (II) is selected from (-)-(4S)-N-methyl-N'-((4-chlorophenyl)surfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4- phenyl-lH-pyrazole-1-carboxamidine;
(-)-(4S)-N-ethyl-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl- IH- pyrazole-1-carboxamidine;
(-)-(4S)-N-dimethylamino-N'-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro- 4-phenyl-lH-pyrazole-l-carboxamidine;
(-)-(4S)-N-methyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5- dihydro-4-phenyl-lH-pyrazole-l-carboxamidine; and
(-)-(4S)-N1, N1-dimethyl-N2-((2-methylphenyl)sulfonyl)-3-(4-chlorophenyl)- 4,5-dihydro- 4-phenyl-lH-pyrazole-l-carboxamidine.
5. The method of any of claims 1, 2, 3, or 4, wherein said dementia is selected from Alzheimer's disease, vascular dementia, frontotemporal dementia, and Pick's disease.
6. The method of claim 5, further comprising administering a pharmaceutical agent for dementia in combination with said compound of Formula (I) or compound of Formula (Tl).
7. The method of claim 6, wherein said dementia is Alzheimer' s disease.
8. The method of claim 7, wherein said pharmaceutical agent is selected from donepezil, galantamine, rivastigmine, tacrine, memantine, and estrogen replacement therapy.
9. The method of claim 6, wherein said dementia is vascular dementia.
10. The method of claim 9, wherein said pharmaceutical agent is selected from aspirin, warfarin, antithrombotic therapies, and cognitive enhancers.
11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as defined in claim 1 or 2 or compound of Formula (IT) as defined in claim 3 or 4, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents for dementia.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as defined in claim 1 or 2 or compound of Formula (II) as defined in claim 3 or 4, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents for Alzheimer's disease.
13. The pharmaceutical composition of claim 12, wherein said pharmaceutical agent is selected from donepezil, galantamine, rivastigmine, tacrine, memantine, and estrogen replacement therapy.
14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as defined in claim 1 or 2 or compound of Formula (H) as defined in claim 3 or 4, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents for vascular dementia.
15. The pharmaceutical composition of claim 14, wherein said pharmaceutical agent is selected from aspirin, warfarin, antithrombotic therapies, and cognitive enhancers.
PCT/US2005/041834 2004-11-30 2005-11-18 Pyrazole derivatives for the treatment of dementia and related disorders WO2006060186A2 (en)

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WO2002076949A1 (en) * 2001-03-22 2002-10-03 Solvay Pharmaceuticals B.V. 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity
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Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
US6036973A (en) * 1994-06-27 2000-03-14 Alza Corporation Therapy for neurological diseases
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US6476060B2 (en) * 2000-03-23 2002-11-05 Solvay Pharmaceuticals, B.V. 4,5-dihydro-1H-pyrazole derivatives having CB1-antagonistic activity
WO2002076949A1 (en) * 2001-03-22 2002-10-03 Solvay Pharmaceuticals B.V. 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity

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