US20110015179A1 - Compositions for treating cognitive disorders - Google Patents

Compositions for treating cognitive disorders Download PDF

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US20110015179A1
US20110015179A1 US12/838,019 US83801910A US2011015179A1 US 20110015179 A1 US20110015179 A1 US 20110015179A1 US 83801910 A US83801910 A US 83801910A US 2011015179 A1 US2011015179 A1 US 2011015179A1
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galantamine
physostigmine
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Ursula V. Staubli
John E. Donello
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Allergan Inc
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Allergan Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/407—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 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
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    • 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
    • A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
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    • 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
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
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    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
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    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • composition comprising a cholinesterase inhibitor and a compound represented by Formula I:
  • X is CH 2 or CH 2 —CH 2
  • A is aryl or heteroaryl having 0, 1, 2, or 3 heteroatoms selected from the group consisting of N, S, and O, wherein A has 0, 1, 2, or 3 substituents independently selected from the group consisting of 0 to 8 carbon atoms, from 0 to 3 oxygen atoms, from 0 to 3 halogen atoms, from 0 to 2 nitrogen atoms, from 0 to 2 sulfur atoms, and from 0 to 24 hydrogen atoms.
  • composition is effective for treating cognitive disorders, and methods of treating such disorders using the composition are also disclosed.
  • Cholinesterase inhibitors have many undesirable side effects, such as nausea, diarrhea, insomnia, muscle cramps, sweating, and trembling.
  • the inventors have discovered that administering the compounds of Formula I with a cholinesterase inhibitor allows one to treat cognitive disorders using significantly lower doses of cholinesterase inhibitors—in some embodiments, as low as one-tenth the usual dose or even lower—thereby providing an effective treatment with fewer side effects.
  • FIG. 1 shows the effect of Compound X on hippocampal fEPSP amplitude recorded in the freely moving rat compared to physostigmine alone and to physostigmine combined with Compound X.
  • Statistical results for each treatment using within group comparisons are indicated by stars (for exact values see Table 1). Comparisons between treatments involved unpaired t-tests, the results of which are illustrated next to the respective connector lines (using unpaired t-tests across groups).
  • BL baseline before vehicle injection.
  • FIG. 2 shows the effect of Compound X on cortical fEPSP amplitude recorded in the freely moving rat compared to physostigmine alone and to physostigmine combined with Compound X.
  • Statistical results for each of the three treatments using within group comparisons are indicated by stars (for exact values see Table 2). Comparisons between treatments involved unpaired t-tests, the results of which are illustrated next to the respective connector lines (using unpaired t-tests across groups).
  • FIG. 3 shows the effect of Compound X on cortical fEPSP amplitude recorded in the freely moving rat compared to galantamine alone and to galantamine combined with Compound X.
  • Statistical results for each of the three treatments using within group comparisons are indicated by stars (for exact values see Table 3). Comparisons between treatments involved unpaired t-tests, the results of which are illustrated next to the respective connector lines (using unpaired t-tests across groups).
  • cholinesterase inhibitor means a compound that inhibits the enzymatic degradation of the neurotransmitter acetylcholine, thereby increasing the duration of action of acetylcholine and its levels in the synaptic cleft.
  • Two enzymes are principally responsible for the degradation of acetylcholine, acetylcholinesterase and butyrylcholinesterase.
  • Choolinesterase inhibitor includes compounds that inhibit or otherwise reduce the action of one or both of those enzymes.
  • compositions and methods of the invention contemplate that the cholinesterase inhibitors be pharmaceutically effective.
  • “Pharmaceutically effective,” as used here, means that the cholinesterase inhibitor is therapeutically useful in humans. The term therefore excludes those cholinesterase inhibitors used as pesticides, such as aldicarb (2-methyl-2-(methylthio)propionaldehyde O-methylcarbamoyloxime), carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate), and carbaryl (1-naphthyl methylcarbamate), and those cholinesterase inhibitors that are so toxic to humans that they are used as chemical weapons, such as sarin (2-(fluoro-methylphosphoryl)oxypropane), VX (S-[2-(diisopropylamino)ethyl]-O-ethyl methylphosphonothioate), and soman (3-(fluoro-methyl-phosphoryl)
  • cholinesterase inhibitors include 7-methoxytacrine, alvameline, ambenonium, anseculin, arecoline, cevimeline, citicoline, demacarium, donepizil, edrophonium, eptastigmine, fasciculin, heptyl-physostigmine, huperzine A and its analogs, icopezil, ipidacrine, linopiridine, metrifonate, milameline, neostigmine, nomeostigmine, norpyridostigmine, tacrine, physostigmine, rivastigmine, subcomeline, suronacrine, tacrine analogs, tacrine, talsaclidine, velnacrine, x
  • At least three pharmaceutically effective cholinesterase inhibitors have been used in humans to treat dementia. These include donepezil, galantamine, and rivastigmine.
  • Donepezil is a reversible inhibitor of acetylcholinesterase. It has the following structure
  • the hydrochloride salt of donepezil is sold in the United States under the brand name Aricept®.
  • Donepezil is indicated for the treatment of dementia of the Alzheimer's type. It is administered at an adult dose of 5 mg or 10 mg once per day. Because of the possibility of adverse events, the 10 mg dose is not administered until patients have been on a dose of 5 mg/day for 4 to 6 weeks.
  • the most common adverse events defined as those occurring in at least 5% in patients receiving 10 mg/day and twice the placebo rate, include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue and anorexia.
  • Galantamine is a reversible inhibitor of acetylcholinesterase. It has the following structure:
  • the hydrobromide salt of galantamine is sold in the United States under the brand name Razadyne®.
  • Galantamine is indicated for the treatment of mild to moderate dementia of the Alzheimer's type. It is administered at an adult dose of between 16-24 mg/day given as twice-daily dosing. The starting dose is 4 mg twice a day (8 mg/day), increased after 4 weeks to 8 mg twice a day (16 mg/day), and then increased after another 4 weeks to 12 mg twice a day (24 mg/day).
  • the most frequent adverse events defined as those occurring at a frequency of at least 5% and at least twice the placebo rate, include nausea, vomiting, diarrhea, anorexia, and weight decrease.
  • Rivastigmine is a reversible cholinesterase inhibitor having the following structure:
  • Rivastigmine tartrate is sold in the United States under the brand name Exelon®. Rivastigmine is indicated for the treatment of mild to moderate dementia of the Alzheimer's type, and for the treatment of mild to moderate dementia associated with Parkinson's disease. Rivastigmine is administered at an adult dose of 6-12 mg/day, given as twice-a-day dosing (daily doses of 3 to 6 mg BID). The starting dose is 1.5 mg twice a day, and, if well tolerated, is increased after a minimum of 2 weeks of treatment to 3 mg twice a day. After an additional 2 weeks of treatment the dose is further increased to 4.5 mg twice a day, and, 2 weeks later, to 6 mg twice a day, unless adverse events occur requiring lower doses. The most frequent adverse events, defined as those occurring at a frequency of at least 5% and at least twice the placebo rate, include nausea, vomiting, anorexia, dyspepsia, and asthenia.
  • cholinesterase inhibitors that have been widely used to treat conditions in humans include physostigmine, pyridostigmine, and neostigmine.
  • compositions and methods of the invention include, in addition to a cholinesterase inhibit, the compounds of Formula I:
  • X is CH 2 or CH 2 —CH 2
  • A is aryl, or is heteroaryl having 0, 1, 2, or 3 heteroatoms selected from the group consisting of N, S, and O, wherein A has 0, 1, 2, or 3 substituents each comprising 0 to 8 carbon atoms, from 0 to 3 oxygen atoms, from 0 to 3 halogen atoms, from 0 to 2 nitrogen atoms, from 0 to 2 sulfur atoms, and from 0 to 24 hydrogen atoms.
  • Aryl as used here, means any ring or ring system that contains at least one aromatic ring.
  • Heteroaryl as used here, means an aromatic ring in which 0, 1, 2, or 3 of the atoms in the ring are N, S, or O; this includes, for example, pyridinyl, thienyl, and furyl.
  • substituents may be the same or different. Examples of substituents having the constraints defined here include, but are not limited to, the following:
  • hydrocarbyl meaning a moiety consisting of carbon and hydrogen only, including, but not limited to,
  • alkyl-CN such as —CH 2 —CN, —(CH 2 ) 2 —CN; —(CH 2 ) 3 —CN, and the like;
  • hydroxyalkyl i.e., alkyl-OH, such as hydroxymethyl, hydroxyethyl, and the like;
  • ether substituents including —O-alkyl, alkyl-O-alkyl, and the like;
  • hydroxy alkyl ether such as —COON
  • thioalkyl and thioether substituents including —S-alkyl, alkyl-5-alkyl, and the like;
  • amine substituents including —NH 2 , —NH-alkyl, —N-alkyl 1 alkyl 2 (i.e., alkyl 1 and alkyl 2 are the same or different, and both are attached to N), alkyl-NH 2 , alkyl-NH-alkyl, alkyl-N-alkyl 1 alkyl 2 , and the like;
  • aminoalkyl meaning alkyl-amine, such as aminomethyl (—CH 2 -amine), aminoethyl, and the like;
  • ester substituents including —CO 2 -alkyl, —CO 2- phenyl, etc.;
  • phenyl and substituted phenyl may itself be optionally fused with another phenyl or cycloalkyl substituent;
  • fluorocarbons and hydrofluorocarbons such as —CF 3 , - CH 2 CF 3 , etc.;
  • a substituent is a salt, for example of a carboxylic acid or an amine
  • the counter-ion of said salt i.e. the ion that is not covalently bonded to the remainder of the molecule is not counted for the purposes of the number of heavy atoms in a substituent.
  • the salt —CO 2 Na + is a stable substituent consisting of 3 heavy atoms, i.e. sodium is not counted.
  • the salt —NH(Me) 2 + Cl ⁇ is a stable substituent consisting of 3 heavy atoms, i.e. chlorine is not counted.
  • A is pyridinyl, meaning that compounds of structures such as those shown below are contemplated.
  • R1, R2, and R3 are substituents as defined herein:
  • A is thienyl, meaning that compounds of structures such as those shown below are contemplated.
  • R1 and R2 are substituents as defined herein:
  • A is furyl, meaning that compounds of structures such as those shown below are contemplated.
  • R1, R2, and R3 are substituents as defined herein:
  • each substituent is independently alkyl having from 1 to 8 carbon atoms.
  • A is unsubstituted or has an isopropyl substituent.
  • each substituent of B is —F, —Cl, —CH 3 , or —CF 3 .
  • A is pyridyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyrimidinyl, quinolinyl, or pyrazinyl having 0, 1, 2, or 3 substituents.
  • reference to a compound includes pharmaceutically acceptable salts, tautomers, alternate solid forms, and non-covalent complexes of a chemical entity of the depicted structure or chemical name.
  • a pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to an animal or human.
  • a salt comprises one or more ionic forms of the compound, such as a conjugate acid or base, associated with one or more corresponding counter-ions. Salts can form from or incorporate one or more deprotonated acidic groups (e.g. carboxylic acids), one or more protonated basic groups (e.g. amines), or both (e.g. zwitterions).
  • Pharmaceutically acceptable salts of acidic functional groups may be derived from organic or inorganic bases.
  • the salt may comprise a mono or polyvalent ion.
  • the inorganic ions lithium, sodium, potassium, calcium, and magnesium.
  • Organic salts may be made with amines, particularly ammonium salts such as mono, di and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules.
  • Hydrochloric acid or some other pharmaceutically acceptable acid may form a salt with a compound that includes a basic group, such as an amine or a pyridine ring.
  • Tautomers are isomers that are in rapid equilibrium with one another. They often, but do not necessarily, include a transfer of a proton, hydrogen atom, or hydride ion.
  • the structures herein are intended to include, but are not limited to, the tautomeric forms shown below:
  • a structure includes every possible stereoisomer, both pure or in any possible mixture.
  • Alternate solid forms are different solid forms than ones that may result from practicing the procedures described herein.
  • alternate solid forms may be polymorphs, different kinds of amorphous solid forms, glasses, and the like.
  • Non-covalent complexes are complexes that may form between the Compound and one or more additional chemical species that do not involve a covalent bonding interaction between the Compound and the additional chemical species. They may or may not have a specific ratio between the Compound and the additional chemical species. Examples might include solvates, hydrates, charge transfer complexes, and the like.
  • compositions useful in the method of the invention may further include an excipient.
  • an excipient may be a carrier or a diluent; this is usually mixed with the active compound, or permitted to dilute or enclose the active compound.
  • the carrier may be solid, semi-solid, or liquid material that acts as an excipient or vehicle for the active compound.
  • the formulations may also include wetting agents, emulsifying agents, preserving agents, sweetening agents, and/or flavoring agents.
  • cognitive disorder means any condition characterized by a deficit in mental activities associated with thinking, learning, or memory. Examples of such disorders include agnosias, amnesias, aphasias, apraxias, deliriums, dementias, and learning disorders.
  • the cause of a cognitive disorder may be unknown or uncertain.
  • the cognitive disorder may be associated with (that is, be caused by or occur in the presence of) other conditions characterized by damage to or loss of neurons or other structures involved in the transmission of signals between neurons.
  • cognitive disorders may be associated with neurodegenerative diseases such as Alzheimer's disease, corticobasal degeneration, Creutzfeldt-Jacob disease, frontotemporal lobar degeneration, Huntington's disease, multiple sclerosis, normal pressure hydrocephalus, organic chronic brain syndrome, Parkinson's disease, Pick disease, progressive supranuclear palsy, or senile dementia (Alzheimer type); it may be associated with trauma to the brain, such as that caused by chronic subdural hematoma, concussion, intracerebral hemorrhage, or with other injury to the brain, such as that caused by infection (e.g., encephalitis, meningitis, septicemia) or drug intoxication or abuse; and may be associated with Down syndrome and Fragile X syndrome.
  • neurodegenerative diseases such as Alzheimer's disease, corticobasal degeneration, Creutzfeldt-Jacob disease, frontotemporal lobar degeneration, Huntington's disease, multiple sclerosis, normal pressure hydroce
  • Cognitive disorders may also be associated with other conditions which impair normal functioning of the central nervous system, including psychiatric disorders such as anxiety disorders, dissociative disorders, mood disorders, schizophrenia, and somatoform and factitious disorders; it may also be associated with conditions of the peripheral nervous system, such as chronic pain.
  • the compounds described here may be used to treat agnosias, amnesias, aphasias, apraxias, deliriums, dementias, learning disorders and other cognitive disorders regardless of whether their cause is known or not.
  • dementias which may be treated with the methods of the invention include AIDS dementia complex, Binswanger's disease, dementia with Lewy Bodies, frontotemporal dementia, multi-infarct dementia, Pick's disease, semantic dementia, senile dementia, and vascular dementia.
  • Examples of learning disorders which may be treated with the methods of the invention include Asperger's syndrome, attention deficit disorder, attention deficit hyperactivity disorder, autism, childhood disintegrative disorder, and Rett syndrome.
  • Examples of aphasia which may be treated with the methods of the invention include progressive non-fluent aphasia.
  • the compounds described here may also be used to treat patient having deficits in mental activities that are mild or that otherwise do not significantly interfere with daily life.
  • Mild cognitive impairment is an example of such a condition: a patient with mild cognitive impairment displays symptoms of dementia (e.g., difficulties with language or memory) but the severity of these symptoms is such that a diagnosis of dementia may not be appropriate.
  • the compounds described here may be used to treat mild cognitive impairment and other, similarly less severe forms of cognitive disorders.
  • compositions of the invention comprise one or more pharmaceutically effective cholinesterase inhibitors and one or more compounds of Formula I.
  • compositions of the invention may be formulated such that a patient receives a dose of a cholinesterase inhibitor that is usually effective, when administered separately, to treat the cognitive disorder for which the cholinesterase inhibitor is indicated, and a dose of a compound of Formula I that is usually effective, when administered separately, to treat the cognitive disorder.
  • the pharmaceutical compositions of the invention may also be formulated such that doses of each compound may be those that are ineffective or minimally effective when the compounds are administered alone. This allows one to administer to a patient a formulation of the invention that is as effective as larger doses of cholinesterase inhibitors and compounds of Formula I administered alone, but that is less likely to lead to side effects.
  • formulations of the invention comprise cholinesterase inhibitors and compounds of Formula I in only such doses which are, when administered alone, minimally effective: a patient administered a composition comprising the usual dose of such compounds is likely to experience an improvement that is greater than the improvement the patient would experience when administered the compounds alone.
  • dose and frequency of administration depends on the severity and nature of the patient's condition, on the manner of administration, on the potency and pharmacodynamics of the particular compound employed, and on the judgment of the prescribing physician. Determining dose is a routine matter that is well within the capability of someone of ordinary skill in the art. Doses of pain-relieving anticonvulsants for treating convulsions, discussed in previous sections, may moreover be used as a guide.
  • a dose of the cholinesterase inhibitor and the compound of Formula I that is ineffective or minimally effective when the compounds are administered alone. Determining such a dose is a routine matter. Typical such doses are set forth below:
  • cholinesterase inhibitors and compounds of Formula I can be admixed with pharmaceutically acceptable excipient which are well known in the art.
  • a pharmaceutical composition to be administered systemically may be confected as a powder, pill, tablet or the like, or as a solution, emulsion, suspension, aerosol, syrup or elixir suitable for oral or parenteral administration or inhalation.
  • non-toxic solid carriers include, but are not limited to, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, the polyalkylene glycols, talcum, cellulose, glucose, sucrose and magnesium carbonate.
  • the solid dosage forms may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in U.S. Pat. No. 4,256,108, No. 4,166,452, and No.
  • Liquid pharmaceutically administrable dosage forms can, for example, comprise a solution or suspension of one or more of the presently useful compounds and optional pharmaceutical adjutants in a carrier, such as for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
  • a carrier such as for example, water, saline, aqueous dextrose, glycerol, ethanol and the like
  • the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like. Typical examples of such auxiliary agents are sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, etc.
  • composition of the formulation to be administered contains a quantity of one or more of the presently useful compounds in an amount effective to provide the desired therapeutic effect.
  • Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and the like.
  • the injectable pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like.
  • compositions and methods of the invention are useful for treating cognitive disorders.
  • treat means to deal with medically. It includes, for example, administering a compound of the invention to prevent the onset of a cognitive disorder as well as to alleviate its severity.
  • Compound X by itself significantly enhanced hippocampal excitatory synaptic transmission, and was similarly effective at enhancing transmission in the olfactory cortex.
  • Physostigmine and galantamine had marginal effects on synaptic transmission in hippocampus and cortex at the doses tested.
  • Physostigmine and galantamine when co-applied with Compound X, facilitated synaptic transmission to a degree that was significantly larger than the increase obtained with Compound X alone for both hippocampus and cortex.
  • This synergism between two structurally and functionally very different classes of compounds suggests that the pro-cognitive effects of Compound X can be magnified with cholinergic compounds already approved for Alzheimer's disease.
  • fEPSPs Field excitatory post-synaptic responses evoked by electrical stimulation were recorded in freely moving animals with depth electrodes permanently implanted in the hippocampus and olfactory cortex.
  • Experiment 1 compared the effect of one dose level (6 mg/kg ip) of Compound X on hippocampal and cortical fEPSPs with vehicle control data.
  • Experiment 2 compared the effect of Compound X (6 mg/kg ip) combined with either physostigmine (0.1 mg/kg ip) or galantamine (1 mg/kg ip) on hippocampal and cortical fEPSPs with vehicle control data.
  • mice Male Sprague Dawley rats, 3 months of age at the time of surgery, were used. The animals were housed individually and kept in a 12:12 light/dark cycle with food and water available ad libitum.
  • Hippocampal animals (subjects with electrodes implanted into hippocampus) were randomly assigned to one of 3 groups, i.e., Compound X alone, Compound X plus physostigmine, physostigmine alone.
  • Cortical animals (subjects with electrodes implanted into olfactory cortex) were randomly assigned to 5 groups, i.e., Compound X alone, Compound X plus physostigmine, physostigmine alone, Compound X plus galantamine, galantamine alone.
  • baseline responses were recorded for at least 15 minutes to establish stability, followed by injection of vehicle solution (ddw) and recording for another 20 min to verify that the injection procedure or the vehicle did not affect baseline responses.
  • Compound X was kept frozen at approximately ⁇ 20° C. in a freezer as a powder. Immediately prior the powder was dissolved in double distilled water (ddw) to make a 12 mg/ml stock and then diluted by 50% for injection at 6 mg/kg at a final volume of 1 ml/kg.
  • ddw double distilled water
  • the 12 mg/ml stock solution of Compound X and the 1 mg/ml stock of physostigmine were diluted by 50% and 10%, respectively, and injected at a final volume of 1 ml/kg.
  • the 12 mg/ml stock solution of Compound X and the 2 mg/ml stock of galantamine were each diluted by 50% and injected at a final volume of 1 ml/kg.
  • Table 1 shows the effect physostigmine, Compound X, and Compound X combined with physostigmine on hippocampal excitatory synaptic transmission in the freely moving rat.
  • Drug effects were assessed by measuring changes in amplitude of the fEPSP in presence of drug relative to changes occurring following vehicle injection that immediately preceded drug administration.
  • Both Compound X by itself, and co-applied with physostigmine significantly enhanced hippocampal fEPSPs, in contrast to physostigmine which caused no significant alterations in basal transmission.
  • the facilitation produced by coapplication of Compound X with physostigmine was significantly larger than that observed with Compound X alone or physostigmine alone (see FIG. 1 ).
  • VEHICLE FEPSP DRUG FEPSP AMPLITUDE [% OF AMPLITUDE [% OF P-VALUE PRE-VEHICLE PRE-VEHICLE (DRUG DOSE BASELINE ⁇ BASELINE ⁇ VS. TREATMENT (MG/KG) S.E.M.] S.E.M.] VEHICLE) Physostigmine 0.1 0.86 + 0.49 2.33 + 2.91 0.62 Compound X 6.0 ⁇ 1.24 + 0.43 7.86 + 2.98 0.05* Compound X 6.0 plus ⁇ 1.0 + 0.44 18.1 + 2.04 0.02* plus 0.1 Physostigmine
  • Table 2 shows the effect physostigmine, Compound X, and Compound X combined with physostigmine on excitatory synaptic transmission in the olfactory cortex.
  • Drug effects were assessed by measuring changes in amplitude of the fEPSP in presence of drug relative to changes occurring following vehicle injection that immediately preceded drug administration.
  • Physostigmine also caused a significant increase in basal transmission, but this effect was significantly smaller than that observed with Compound X alone or Compound X co-applied with physostigmine (see FIG. 2 ).
  • the facilitation produced by co-application of Compound X plus physostigmine was significantly larger than that observed with Compound X alone (see FIG. 2 ).
  • Table 3 shows the effect galantamine, Compound X, and Compound X combined with galantamine on excitatory synaptic transmission in the olfactory cortex.
  • Drug effects were assessed by measuring changes in amplitude of the fEPSP in presence of drug relative to changes occurring following vehicle injection preceding drug administration.
  • Both Compound X by itself, and Compound X co-applied with galantamine significantly enhanced hippocampal fEPSPs, in contrast to galantamine which caused no significant alterations in basal transmission.
  • compositions of the invention are exemplified further in the table below.
  • X is CH 2 or CH 2 —CH 2
  • A is aryl, or is heteroaryl having 0, 1, 2, or 3 heteroatoms selected from the group consisting of N, S, and O, wherein A has 0, 1, 2, or 3 substituents each comprising 0 to 8 carbon atoms, 0 to 3 oxygen atoms, 0 to 3 halogen atoms, 0 to 2 nitrogen atoms, 0 to 2 sulfur atoms, and 0 to 24 hydrogen atoms.
  • A is selected from the group consisting of pyridinyl, thienyl, furyl, quinolinyl, methylphenyl, and biphenyl.
  • the pharmaceutical composition of 1, wherein the compound of Formula I is selected from the group consisting of
  • cholinesterase inhibitor is selected from the group consisting of donepezil, galantamine, and rivastigmine.
  • a method of treating a cognitive disorder comprising administering to a human in need of such a treatment a pharmaceutical composition comprising a pharmaceutically effective cholinesterase inhibitor and a compound of Formula I:
  • X is CH 2 or CH 2 —CH 2
  • A is aryl, or is heteroaryl having 0, 1, 2, or 3 heteroatoms selected from the group consisting of N, S, and O, wherein A has 0, 1, 2, or 3 substituents each comprising 0 to 8 carbon atoms, 0 to 3 oxygen atoms, 0 to 3 halogen atoms, 0 to 2 nitrogen atoms, 0 to 2 sulfur atoms, and 0 to 24 hydrogen atoms.
  • A is selected from the group consisting of pyridinyl, thienyl, furyl, quinolinyl, methylphenyl, and biphenyl. 8. The method of 7, wherein A is unsubstituted.
  • the compound of Formula I is selected from the group consisting of
  • cholinesterase inhibitor is selected from the group consisting of donepezil, galantamine, and rivastigmine.
  • the cognitive disorder is selected from the group consisting of an agnosia, an amnesias, an aphasias, an apraxias, a delirium, a dementia, and a learning disorder. 12. A method of treating a cognitive disorder, the method comprising administering to a patient in need of such a treatment a first composition comprising a pharmaceutically effective cholinesterase inhibitor and a second composition comprising compound of Formula I:
  • X is CH 2 or CH 2 —CH 2
  • A is aryl, or is heteroaryl having 0, 1, 2, or 3 heteroatoms selected from the group consisting of N, S, and O, wherein A has 0, 1, 2, or 3 substituents each comprising 0 to 8 carbon atoms, 0 to 3 oxygen atoms, 0 to 3 halogen atoms, 0 to 2 nitrogen atoms, 0 to 2 sulfur atoms, and 0 to 24 hydrogen atoms.
  • A is selected from the group consisting of pyridinyl, thienyl, furyl, quinolinyl, methylphenyl, and biphenyl. 14. The method of 13, wherein A is unsubstituted.
  • the compound of Formula I is selected from the group consisting of
  • cholinesterase inhibitor is selected from the group consisting of donepezil, galantamine, and rivastigmine.
  • the cognitive disorder is selected from the group consisting of an agnosia, an amnesia, an aphasia, an apraxia, a delirium, a dementia, and a learning disorder. 18.
  • a method of treating dementia comprising administering to a patient in need of such treatment a pharmaceutical composition comprising
  • a pharmaceutically effective cholinesterase inhibitor selected from the group consisting of donepezil, galantamine, and rivastigmine;

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