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WO2025184294A1 - Méthodes pour améliorer la récupération suite à un accident vasculaire cérébral - Google Patents

Méthodes pour améliorer la récupération suite à un accident vasculaire cérébral

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Publication number
WO2025184294A1
WO2025184294A1 PCT/US2025/017521 US2025017521W WO2025184294A1 WO 2025184294 A1 WO2025184294 A1 WO 2025184294A1 US 2025017521 W US2025017521 W US 2025017521W WO 2025184294 A1 WO2025184294 A1 WO 2025184294A1
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WO
WIPO (PCT)
Prior art keywords
compound
stroke
subject
administered
alkyl
Prior art date
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Pending
Application number
PCT/US2025/017521
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English (en)
Inventor
Dongwook WI
Barbara Jagodzinska
Xiaofei WEI
Jesus CAMPAGNA
Stanley CARMICHAEL
Istvan Mody
Naohiko OKABE
Varghese John
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of California Berkeley
University of California San Diego UCSD
Original Assignee
University of California Berkeley
University of California San Diego UCSD
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Application filed by University of California Berkeley, University of California San Diego UCSD filed Critical University of California Berkeley
Publication of WO2025184294A1 publication Critical patent/WO2025184294A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/4465—Non condensed piperidines, e.g. piperocaine only substituted in position 4
    • 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
    • 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
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • Rehabilitation is an effective therapy for post-stroke recovery, yet its effects remain limited, its mechanisms unknown.
  • structural and functional neuronal network changes that mediate rehabilitation-induced recovery are shown.
  • Rehabilitation induces selective synapses between stroke-projecting neurons and parvalbumin interneurons, concomitant with improved motor performance and neuronal connectivity.
  • Parvalbumin interneurons regulate this neuronal connectivity, and their activation is necessary for recovery.
  • gamma oscillation a parv albumin-regulated rhythm, is associated with rehabilitation-induced recovery in animals after stroke and stroke patients.
  • Pharmacological enhancement of parvalbumin interneuron function improves motor recovery after stroke, reproducing rehabilitation recovery. In view of the foregoing, there is an unmet need to identify new therapeutics for stroke treatment and post-stroke recovery.
  • A is heterocyclyl
  • X 1 is alkylene, carbonyl, N(R 2 ), or O;
  • X 2 is aryl or heteroaryl; R 1 is alkyl, hydroxyl, or alkyloxy; and
  • R 2 is H, alkyl, or aralkyl.
  • a neurodegenerative disease or disorder in a subject in need thereof comprising administering to the subject a compound of Formula II, or a pharmaceutically acceptable salt thereof: wherein
  • R 3 is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, thiol, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, and sulfonamide.
  • R 3 is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, thiol, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, and sulfonamide.
  • FIGS. 1A-1 L show gamma oscillation in stroke and PVIN targeting drug therapy.
  • FIG. 1A shows electrode placement and timeline for the EEG recording.
  • FIG. IB shows representative LFP traces in stroke animals.
  • FIG. 1C shows normalized power spectra of network oscillation in ipsilesional premotor cortex in awake period mice. The orange rectangle indicates the lower gamma frequency band.
  • FIG. ID shows normalized spectrum power change in low gamma frequency.
  • Mixed-effects model *P ⁇ 0.05, **P ⁇ 0.01, ****P ⁇ 0.0001: Naive vs Stroke ipsi, ++ P ⁇ 0.01: Stroke ipsi vs Stroke contra, Tukey’s multiple comparisons test.
  • FIG. IE shows illustration of human EEG.
  • FIG. IF shows arm motor Fugl-Meyer (FM) score after stroke.
  • FIG. 1G shows correlation matrix of the FM score and the relative gamma power during the recovery period (V3-5) in the ipsi (i) and contralesional (c) motor related areas.
  • Ml primary motor area
  • PMD dorsal premotor area
  • SMA supplementary motor area in moderate to severe stroke patients (VI FM ⁇ 46).
  • FIG. II shows timeline and procedure for the drug administration of AUT00201 (‘AUT’, 20mg/kg p.o.) or DEE-920 (‘DDE’, lOmg/kg p.o.) and behavioral test.
  • FIG. 1J shows ratio of Zif268 positive PV interneurons (Left) and density of Zif268 positive cells (right).
  • FIG. IK shows normalized motor performance in the pasta matrix test.
  • FIG. IL shows Functional recovery from day 3 to day 14. Paired t-test, ****p ⁇ 0.0001: day 3 vs day 14, Unpaired t-test, ****P ⁇ 0.01: Stroke + vehicle vs Stroke + DDL-920
  • FIGS. 2A-2B show effects of the PV interneuron-activating drugs in the grid walk test.
  • FIG. 2A shows Foot faults in the grid walk test. Two-way repeated measure ANOVA, *P ⁇ 0.05, **P ⁇ 0.01, ****P ⁇ 0.0001: Sham + vehicle vs Stroke + Vehicle, ####P ⁇ 0.0001: Sham + vehicle vs Stroke + AUT, ++++P ⁇ 0.0001 : Sham + vehicle vs Stroke + DDL, &P ⁇ 0.05: Stroke + vehicle vs Stroke + AUT / Stroke + DDL, Sidak’s multiple comparison test.
  • FIG. 2B shows functional recovery from day 3 to day 14. Paired t-test, *P ⁇ 0.05: day 3 vs day 14.
  • FIGS. 3A-3B show pharmacokinetic studies of DDL-920 in mice following subcutaneous, oral gavage, or oral pipette administration.
  • FIG. 3A shows brain concentrations and levels of DDL-920 after subcutaneous administration at 1, 5, and 10 mg/kg.
  • FIG. 3B shows brain concentrations and levels of DDL-920 after oral gavage at 5 and 10 mg/kg, or by oral pipette administration at 10 mg/kg.
  • FIG. 4 shows that DDL-930 produces gamma oscillations approximately ten-fold more powerful than an equivalent dose of DDL-920.
  • FIGs. 5A-5B show the pharmacokinetics of DDL-930 (10 mg/kg).
  • FIG. 5A shows the concentration of DDL-930 in plasma (top) and brain (bottom) following subcutaneous administration.
  • FIG. 5B shows the concentration of DDL-930 in plasma (top) and brain (bottom) following oral (pipette) administration.
  • FIGs. 6A-6B show a comparison of DDL-920 (50 mg/kg) and DDL-930 (10 mg/kg) plasma and brain levels 1 hour after the fourth subcutaneous dose following three previous daily doses.
  • FIG. 6A shows a comparison of the plasma levels.
  • FIG. 6B shows a comparison of the brain levels. No adverse behavioral effects were noted after the repeated administration of the drugs.
  • A is heterocyclyl
  • X 1 is alkylene, carbonyl, N(R 2 ), or O;
  • X 2 is aryl or heteroaryl
  • R 1 is alkyl, hydroxyl, or alkyloxy
  • R 2 is H, alkyl, or aralkyl.
  • A is a 4-8 membered nitrogen containing heterocyclyl, e.g., azetidinyl, pyrrolidinyl, piperidinyl (e.g., piperidinyl, N-methylpiperidinyl, N-ethylpiperidinyl, or N-propylpiperidinyl), azepanyl, or azocanyl.
  • A is piperidinyl.
  • R 1 is hydroxyl.
  • X 1 is alkylene (e.g., methylenyl).
  • X 2 is substituted with alkyl (e.g., methyl, ethyl, isopropyl, difluoromethyl, or trifluoromethyl). In some such embodiments, X 2 is substituted with methyl. In other such embodiments, X 2 is substituted with ethyl. In alternative such embodiments, X 2 is substituted with isopropyl. In yet other such embodiments, X 2 is substituted with difluoromethyl. In still further such embodiments, X 2 is substituted with trifluoromethyl.
  • alkyl e.g., methyl, ethyl, isopropyl, difluoromethyl, or trifluoromethyl.
  • the compound has a structure represented by Formula (la), or a pharmaceutically acceptable salt thereof:
  • X 2 is aryl (e.g., phenyl, naphthyl, dihydrobenzodioxinyl, or benzodioxolyl). In further embodiments, X 2 is naphthyl. In yet further embodiments, X 2 is heteroaryl (e.g., quinolinyl or isoquinolinyl).
  • X 2 is substituted with alkyl, alkenyl, alkynyl, halo, hydroxyl, thiol, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, and sulfonamide.
  • the compound is selected from:
  • the methods comprise administering to the subject a compound of Formula (II), or a pharmaceutically acceptable salt thereof: wherein
  • R 3 is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, thiol, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, and sulfonamide.
  • a neurodegenerative disease or disorder in a subject in need thereof comprising administering to the subject a compound of Formula II, or a pharmaceutically acceptable salt thereof: wherein R 3 is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, thiol, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, and sulfonamide.
  • R 3 is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, thiol, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfony
  • the compound has a structure represented by Formula (Ila), or a pharmaceutically acceptable salt thereof:
  • R 3 is alkyl (e.g., methyl, ethyl, isopropyl, difluoromethyl, or trifluoromethyl). In some such embodiments, R 3 is methyl. In other such embodiments, R 3 is ethyl. In alternative such embodiments, R 3 is isopropyl. In yet other such embodiments, R 3 is difluoromethyl. In still further such embodiments, R 3 is trifluoromethyl.
  • R 3 is alkoxy (e.g., methoxy, ethoxy, or n-propyloxy). In some such embodiments, R 3 is methoxy. In certain such embodiments, R 3 is ethoxy. In yet other such embodiments, R 3 is n-propyloxy.
  • R 3 is halo (e.g., chloro or bromo). In some such embodiments, R 3 is chloro. In other such embodiments, R 3 is bromo. In certain embodiments, R 3 is cyano. In some embodiments, R 3 is hydroxyl.
  • R 3 is selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, thiol, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azido, alkylthio, cycloalkyl, alkylsulfonyl, and sulfonamide.
  • the compound has a structure represented by Formula (Ila), or a pharmaceutically acceptable salt thereof:
  • R 3 is alkoxy (e.g., methoxy, ethoxy, or n-propyloxy). In some such embodiments, R 3 is methoxy. In other such embodiments, R 3 is ethoxy. In further such embodiments, R 3 is n-propyloxy.
  • R 3 is halo (e.g., chloro or bromo). In certain such embodiments, R 3 is chloro. In other such embodiments, R 3 is bromo. In alternative embodiments, R 3 is cyano. In yet other embodiments, R 3 is hydroxyl.
  • the neurodegenerative disease or disorder is selected from Autism Spectrum Disorder (ASD), Rett syndrome, intellectual disability arising from Fragile X syndrome, intellectual disability arising from variants of Fragile X syndrome, schizophrenia, depression, major depressive disorder, or post-traumatic stress disorder (PTSD).
  • ASD Autism Spectrum Disorder
  • Rett syndrome intellectual disability arising from Fragile X syndrome
  • intellectual disability arising from variants of Fragile X syndrome schizophrenia, depression, major depressive disorder, or post-traumatic stress disorder (PTSD).
  • the neurodegenerative disease or disorder is Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis, multiple sclerosis, progressive supranuclear palsy, or age-related cognitive decline.
  • the neurodegenerative disease or disorder is age-related mild cognitive impairment (MCI).
  • MCI age-related mild cognitive impairment
  • the neurodegenerative disease or disorder is Alzheimer’s disease.
  • the stroke is an ischemic stroke.
  • the ischemic stroke occurs in the anterior circulation of the brain.
  • the method improves motor control in the subject.
  • the method reduces tonic neural inhibition in the subject.
  • the method increases excitability of parvalbumin neurons in the subject.
  • the method increases the frequency of gamma wave oscillations in the subject.
  • the method increases the amplitude of gamma wave oscillations in the subject.
  • the method induces synapse formation between parvalbumin neurons and stroke-projecting neurons.
  • the compound is administered about 0-30 days after the stroke occurs. In further embodiments, the compound is administered about 0-15 days after the stroke occurs. In yet further embodiments, the compound is administered about 0-12 hours after the stroke occurs. In still further embodiments, the compound is administered over 3 hours after the stroke occurs. In certain embodiments, the compound is administered over 6 hours after the stroke occurs. In further embodiments, the compound is administered over 9 hours after the stroke occurs. In yet further embodiments, the compound is administered at least 1 day after the stroke occurs. In still further embodiments, the compound is administered at least 5 days after the stroke occurs. In certain embodiments, the compound is administered at least 10 days after the stroke occurs. In further embodiments, the compound is administered at least 15 days after the stroke occurs.
  • the subject has improved motor function.
  • motor function may be assessed in a subject with one or more of several diagnostic tests, illustrative examples including the Fugl-Meyer test, the ARAT (action research arm) test, or the 10-minute walk test.
  • the subject has reduced tonic neural inhibition.
  • the subject has increased excitability of parvalbumin neurons.
  • the subject has gammaoscillations with an increased frequency.
  • the subject has gamma-oscillations with an increased amplitude.
  • the compound is administered orally. In certain embodiments, the compound is administered intravenously.
  • Rehabilitation is an effective therapy for post-stroke recovery, yet its effects remain limited, its mechanisms unknown.
  • structural and functional neuronal network changes that mediate rehabilitation-induced recovery are shown.
  • Rehabilitation induces selective synapses between stroke-projecting neurons and parvalbumin interneurons, concomitant with improved motor performance and neuronal connectivity.
  • Parvalbumin interneurons regulate this neuronal connectivity, and their activation is necessary for recovery.
  • gamma oscillation, a parv albumin-regulated rhythm is associated with rehabilitation-induced recovery in animals after stroke and stroke patients.
  • Pharmacological enhancement of parvalbumin interneuron function improves motor recovery after stroke, reproducing rehabilitation recovery. In view of the foregoing, there is an unmet need to identify new therapeutics for stroke treatment and post-stroke recovery.
  • PV interneurons may also be involved in neuronal plasticity to reorganize neuronal circuits. PV interneurons behave in a manner analogous to their regulation of a developmental critical period in postnatal brain, with similar alterations in peri-neuronal nets after rehabilitation. This cellular platform for post-stroke rehabilitation led to the identification of a drug that reproduces the beneficial effects on rehabilitation on behavioral recovery after stroke. A rehabilitation drug could provide substantial benefits in clinical stroke recovery.
  • DDL-930 which comprises a methyl group at the naphthyl 7-position.
  • DDL-930 demonstrates excellent properties in comparison with DDL-920.
  • DDL-930 induces gamma oscillations approximately ten-fold more powerful than an equivalent dosage of DDL-920, and is more effective than DDL-920 at permeating the brain following an oral dose.
  • the naphthyl 7-position is surprisingly privileged for both improving the power of gamma-oscillations as well as improving oral brain permeability.
  • compositions and methods of the present invention may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a selfmicroemulsifying drug delivery system.
  • the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin).
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
  • an active compound such as a compound of the invention
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • Compositions or compounds may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents,
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfaceactive or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the active compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as poly lactide-poly glycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • biodegradable polymers such as poly lactide-poly glycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.
  • a variety of biocompatible polymers including hydrogels, including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • therapeutically effective amount is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention.
  • a larger total dose can be delivered by multiple administrations of the agent.
  • Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
  • compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.
  • contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
  • contemplated salts of the invention include, but are not limited to, L-arginine, benethamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, IH-imidazole, lithium, L- lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2- hydroxycthy I) pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.
  • contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
  • contemplated salts of the invention include, but are not limited to, l-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2- hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4- acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1-ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+) -camphor- 10- sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid
  • the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • agent is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues.
  • Agents include, for example, agents whose structure is known, and those whose structure is not known.
  • a “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).
  • Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • preventing is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
  • a condition such as a local recurrence (e.g., pain)
  • a disease such as cancer
  • a syndrome complex such as heart failure or any other medical condition
  • administering or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
  • a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct).
  • a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • a compound or an agent is administered orally, e.g., to a subject by ingestion.
  • the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.
  • the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents).
  • the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially.
  • an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.
  • a “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect.
  • the full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a therapeutically effective amount may be administered in one or more administrations.
  • the precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation .
  • the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not.
  • “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.
  • substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O- alkyl, -OP(O)(O-alkyl)2 or -CH2-OP(O)(O-alkyl)2.
  • “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.
  • alkyl refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups or C1-C10 branched-chain alkyl groups.
  • the “alkyl” group refers to Ci-Ce straight-chain alkyl groups or Ci-Ce branched- chain alkyl groups.
  • the “alkyl” group refers to C1-C4 straight-chain alkyl groups or C1-C4 branched-chain alkyl groups.
  • alkyl examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec -butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1 -hexyl, 2-hexyl, 3-hexyl, 1 -heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1 -octyl, 2-octyl, 3-octyl or 4-octyl and the like.
  • the “alkyl” group may be optionally substituted.
  • acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
  • acylamino is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.
  • acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.
  • alkoxy refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • alkyl as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2- trifluoroethyl, etc.
  • C x.y or “C x -C y ”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • Coalkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • a C 1 -ealkyl group for example, contains from one to six carbon atoms in the chain.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • R 9 and R 10 each independently represent a hydrogen or hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by Rio ’ wherein R 9 , R 10 , and R 10 ’ each independently represent a hydrogen or a hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • aryl as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7-membered ring, more preferably a 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • carboxylate is art-recognized and refers to a group wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl group.
  • Carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • Carbocycle includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • fused carbocycle refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
  • Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct- 3-ene, naphthalene and adamantane.
  • Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-lH- indene and bicyclo[4.1.0]hept-3-ene.
  • “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.
  • Carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • carbonate is art-recognized and refers to a group -OCO2-.
  • cycloalkyl includes substituted or unsubstituted non-aromatic single ring structures, preferably 4- to 8-membered rings, more preferably 4- to 6-membered rings.
  • cycloalkyl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is cycloalkyl and the substituent (e.g., R 100 ) is attached to the cycloalkyl ring, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, denzodioxane, tetrahydroquinoline, and the like.
  • esters refers to a group -C(O)OR 9 wherein R 9 represents a hydrocarbyl group.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
  • halo and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
  • heteroalkyl and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • heteroaryl and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocycle group.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer.
  • acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
  • polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”.
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • sulfate is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.
  • sulfoxide is art-recognized and refers to the group-S(O)-.
  • sulfonate is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic mo
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thioester refers to a group -C(O)SR 9 or -SC(O)R 9 wherein R 9 represents a hydrocarbyl.
  • thioether is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
  • urea is art-recognized and may be represented by the general formula wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl.
  • modulate includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.
  • compositions, excipients, adjuvants, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.
  • pharmaceutically acceptable acid addition salt means any non-toxic organic or inorganic salt of any base compounds represented by Formula I.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
  • mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sul
  • the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection of the appropriate salt will be known to one skilled in the art.
  • Other non- pharmaceutically acceptable salts e.g., oxalates, may be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable basic addition salt means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or any of their intermediates.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.
  • Prodrug or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of formula I).
  • Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound.
  • prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference.
  • the prodrugs of this disclosure are metabolized to produce a compound of Formula I.
  • the present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.
  • Log of solubility is used in the art to quantify the aqueous solubility of a compound.
  • the aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption.
  • LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol/liter.
  • ischemic stroke refers to a stroke resulting from the occlusion or failure of a blood vessel, which may occur due to such illustrative causes as plaque buildup, rupture, or dislodging of a previously formed blood clot.
  • tonic neural inhibition refers to the inhibition of neural activity which is mediated through molecular means, e.g., by a neurotransmitter or other smallmolecule.
  • the term “excitability” refers to the ability of a nerve cell to generate a rapid and large change in membrane voltage in response to a stimulus, and the degree to which this change occurs.
  • parvalbumin neuron(s) refers to a neuron which expresses parv albumin.
  • gamma wave oscillation(s) refers to concerted oscillations in neural membrane potential or concerted patterns of action potentials with a frequency between about 25 Hz and 140 Hz, and particularly about 40 Hz.
  • stroke-projecting neuron(s) refers to brain cells (e.g., neurons) that project (i.e. , have one or more prolongations or processes which extend from the cell, such as axons or dendrites) to the stroke locus.
  • mice All procedures were performed under an NIH approved animal protocol and the University of California Los Angeles Chancellor’s Animal Research Committee. 2-4 month- old adult C57BL/6 (Charles River and Jackson Lab) or B6 PV-Cre (B6;129P2- Pvalbtml(cre)Arbr/J, The Jackson Laboratory) male mice were maintained on a 12 h light/dark cycle with free access to food and water except for the periods during behavior tests and rehabilitation for chronic DREADDs experiments. All procedures were conducted by the blinded experimenters, except for rehabilitation treatment.
  • Easer illumination was made centered at 1.5mm lateral and 0.25mm rostral to the bregma for CFA stroke.
  • laser illumination was made 1mm lateral and 2mm rostral to the bregma for RFA stroke based on the forelimb representation of the C57BL/6 mouse motor cortex.
  • Post-stroke rehabilitation was carried out with a plexiglass reaching box consisting of a chamber with a central table for the mouse to climb onto and millet seed containers on either side (FIG. 6).
  • mice with the same dominant hand for the skilled reaching test were paired in a cage.
  • Two reaching boxes per cage were set, and 4 g of millet seeds were filled in the container on the dominant limb side every day, five days a week, for 3 weeks, starting day 10 after stroke.
  • mice were given the reaching box without millet seed.
  • mice The skilled reaching test was carried out as previously described with slight modifications.
  • mice After shaping the reaching behavior, mice received 25 trials of training per day for 2 weeks, and prestroke motor performance was calculated by averaging the results of the last 2 days prior to stroke.
  • We examined motor performance in a testing session of 25 trials with a maximum time of 5 min. Mice were allowed to reach up to 3 reaches in each trial. The motor performance score was calculated in the following way: success rate (%) (number of trials in which the pellet was retrieved / number of trials) x 100. Testing sessions were performed as 25 trials with a maximum time of 5 minutes. We used only animals with a 30% or higher success rate at baseline for the study.
  • Post-stroke motor performance was evaluated for 1 and 4 weeks after stroke. The animals with motor deficits of less than 10% related to the baseline value were omitted from the study.
  • the grid walking device consisted of an elevated metal grid (height 32 cm, length 20 cm, width 26 cm) with a square 13.5 x 13.5 mm mesh (diameter of rungs 1 mm). A mirror was fixed at a 60° angle below the grid, allowing recording from the side and below. Mice were placed onto the grid and were allowed to move for 2 min freely. Mice were trained 1 day before pre-stroke testing and tested 1 day before the stroke and 7 and 28 days after the stroke. Testing trials were video recorded and analyzed frame by frame. The number of foot faults of the contralesional (affected) forelimb in the first 50 steps was counted, and the probability of foot fault was calculated.
  • mice were trained for 4 weeks (5 days/week) prior to photothrombotic stroke administration. Diet was mildly restricted to maintain approximately 90% of normal body weight.
  • mice were placed in the plexiglass chamber with a narrow open slit window (14 x 1/2 inch), and 3.2 cm long pasta pieces were placed in a 5x5 orientation (pasta matrix).
  • mice were trained for 30 min/day with the pasta matrix set in front of the slit and tilted toward the chamber.
  • mice were trained in an upright pasta matrix for 30 min/day.
  • AUT00201 (Autifony Therapeutics Ltd) was dissolved in PEG400 at 60 °C, and the resulting solution was added to condensed milk (AUT00201: 10 mg, PEG400: 100 mg, condensed milk: 400 mg, resulting in a final concentration of 2%).
  • DDL-920 was dissolved in I-fcO at 60 °C, and the solution was added to condensed milk ( DDL-920: 10 mg, H2O: 600 mg, condensed milk: 400 mg, resulting in a final concentration of 1%).
  • Animals were orally administered the drag-containing condensed milk at a dosage of 1 mg/g body weight (equivalent to 20 mgZkg body weight for AUT00201 and 10 mg/kg body weight for DDL-920).
  • Oral doses of AUT00201 have previously been shown to be active in a mouse model of progressive myoclonic epilepsy on a similar C57/BL6 background and pharmacokinetic studies have demonstrated at 20mg/kg steady state, after one week of daily dosing, mean peak blood concentrations of approx. lOOOng/ml are achieved using the formulation employed in this study (corresponding to approx.
  • the reaction mixture was reconstituted using 15 mL of ethyl acetate and quenched with saturated ammonium chloride (15 mL), and the product was extracted with ethyl acetate (15 mL x 2).
  • the resultant crude compound was purified by using a 4 g silica flash column, eluted with Hexane: Ethyl acetate (time /% Ethyl acetate: 0/0, 5/0, 30/100), The desired fractions were eluted at 50% ethyl acetate to afford DDL 930 intermediate 1 (81.2 mg, 37%, colorless powder).
  • DDL930 3- ((7 -methylnaphthalen-2-yl)methyl) -4- (piperidin-4-yl) - 1H- pyrazol- 1 - ol, (step 3)
  • the recrystallized product was triturated with diethyl ether and dried in the desiccator overnight to yield DDL-930 with impurity. Further purification of DDL-930 was done under reflux at 130 °C in concentrated HC1 (3 mL) for 55 hours, and the reaction was monitored by flow injection analysis. After the reaction was completed, the excess HC1 was evaporated and recrystallized from MeOH/diethyl ether (1:1), filtered and the solid was dried under a high-speed vacuum to yield DDL-930 (19.39 mg, 85.2 %) as a light brown solid with >95% purity.
  • (+esi)[M+H]+ 322.42; 1H NMR (400 MHz, d6- DMSO ) 5 12.10 (Br s, HC1, 1H), 7.84 - 7.65 (m, 3H), 7.55 (s, 1H), 7.32 (s, 1H), 7.27-7.23 (m, 2H), 3.95 (s, 2H), 3.56 - 3.36 (m, 2H), 2.83-2.66 (m, 3H), 2.40 (s, 3H), 1.76-1.67 (m, 2H), 1.64 - 1.54 (m, 2H).
  • the resultant crude compound was purified by using a 4 g silica flash column, eluted with Hexane: Ethyl acetate (time /% Ethyl acetate: 0/0, 5/0, 30/100), and the desired fractions were eluted at 50% ethyl acetate to afford DDL931 (180.5mg, 29.1% colorless powder).
  • the purity of Ethyl 4-(l-(benzyloxy)-3-((7-bromonaphthalen-2-yl)(hydroxy)methyl)-lH-pyrazol-4- yl)piperidine-l -carboxylate was determined via LC/MS.
  • DDL 931 3-((7-bromonaphthalen-2-yl)methyl)-4-(piperidin-4-yl)-lH-pyrazol-l- ol
  • Desired ADME properties include kinetic solubility > 5 pM, microsomal stability ti/2 > 1 hr, brain tissue binding ⁇ 80%, and plasma binding ⁇ 90%.
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • Example 10 Acute Toxicokinetics and Toxicodynamics of DDL-920 and DDL-930
  • mice were administered DDL-920 via SQ at a dose of 50 mg/kg for 3 days (Only in the morning). On day 4, 1 hour after dosing, mice were euthanized, followed by perfusion, plasma and brain collection. No notable changes in mice behavior or induced toxicity due to higher drug exposure in brain & plasma were observed.
  • a targeted LC-MS/MS assay was developed for each compound using the multiple reaction monitoring (MRM) acquisition method on a 6460 triple quadrupole mass spectrometer (Agilent Technologies) coupled to a 1290 Infinity HPLC system (Agilent Technologies) with a Phenomenex analytical column (Kinetex 3.0 pm C18 100 A 100 x 2.1 mm).
  • the HPLC method utilized a mixture of solvent A (99.9/1 Water/Formic Acid) and solvent B (99.9/1 Acetonitrile/Formic Acid) and a gradient was used for the elution of the compounds (min/%B: 0/20, 3/20, 19/99, 20/99, 21/20, 30/20).
  • IS internal standard
  • Standards were made in drug naive brain lysates with increasing amounts of DDL-920 (SI, S2: 0.1 pmol/ S3, S4: 1 pmol/ S5, S6: 10 pmol/ S7, S8: 100 pmol, S9, S10: 1000 pmol).
  • the standard curve was made by plotting the amount of compound (pmol) per standard vs. the ratio of measured chromatographic peak areas corresponding to that of each analyte over that of the IS (analyte/IS). The trendline equation was then used to calculate the absolute concentrations of each compound in brain tissue.
  • mice were administered DDL-930 via SQ at a dose of 10 mg/kg for 3 days (Only in the morning). On day 4, 1 hour after dosing, mice were euthanized, followed by perfusion, plasma and brain collection. No notable changes in mice behavior or induced toxicity due to higher drug exposure in brain & plasma were observed.
  • a targeted LC-MS/MS assay was developed for each compound using the multiple reaction monitoring (MRM) acquisition method on a 6460 triple quadrupole mass spectrometer (Agilent Technologies) coupled to a 1290 Infinity HPLC system (Agilent Technologies) with a Phenomenex analytical column (Kinetex 3.0 pm C18 100 A 100 x 2.1 mm).
  • the HPLC method utilized a mixture of solvent A (99.9/1 Water/Formic Acid) and solvent B (99.9/1 Acetonitrile/Formic Acid) and a gradient was used for the elution of the compounds (min/%B: 0/20, 3/20, 19/99, 20/99, 21/20, 30/20).
  • Example 11 Power Measurement of Gamma Oscillations Induced by DDL-920 and DDL-930
  • mice were at least 3-months-old when the ex vivo experiments were undertaken. They were anesthetized with isoflurane and decapitated following UCLA Chancellor's Animal Research Committee protocol. Horizontal 350 pm thick slices were cut on a Leica VT1200S vibratome in ice-cold N-Methyl-D-Glutamine (NMDG)-based HEPES -buffered solution, containing (in mM): 135 NMDG, 10 D-glucose, 4 MgCh, 0.5 CaCh, 1 KC1, 1.2 KH2PO4, 20 HEPES, 27 sucrose (bubbled with 100% O2, pH 7.4, 290-300 mOsm/L).
  • NMDG N-Methyl-D-Glutamine
  • Kainic acid (KA, Tocris) was used to generate gamma y-oscillations in slices. To get a stable level of y-oscillations after the slice cutting and recovery incubation period, as previously described (1,2) the slices were incubated for at least 30 min in ACSF containing 50 nM KA before transferring them to the recording chamber. Recordings were done in an interface chamber at 34°C perfused with normal ACSF also containing 50 nM KA at a speed of 5 ml/min.
  • Oscillatory network activity was recorded in CA3 stratum pyramidale with the use of a patch pipette (3-5 MQ resistance) filled with KA-containing ACSF connected to the headstage of an amplifier (A-M Systems Inc., model 3000).
  • the signal was band-pass filtered between 0.1 and 1000 Hz and fed through an instrumentation amplifier (Brownlee BP Precision, model 210A) and sampled at 4096 s' 1 with a National Instruments A/D board.
  • Field potentials were recorded using a custom LabView software (EVAN) and analyzed with a custom written procedure (Wavemetrics, IGOR Pro 8).
  • Peak frequencies, power at peak frequency and total power were obtained from the corresponding root-mean-square of the signals (RMS), averaged from 60 s recording periods.
  • the effects of 20 min perfusions of 1 or 100 nM DDL-920, or 1 nM DDL- 930, or vehicle (aCSE) were compared on the power (RMS) averaged during 60 s epochs of in vitro y-oscillations (n’s represent the number of slices).
  • the changes in RMS (A Power) are expressed relative to the power measured during the baseline recording period (Baseline; 10 min). Results of these experiments are depicted in FIG. 4.

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Abstract

L'invention concerne des compositions et des méthodes pour traiter un accident vasculaire cérébral et des maladies neurodégénératives.
PCT/US2025/017521 2024-02-28 2025-02-27 Méthodes pour améliorer la récupération suite à un accident vasculaire cérébral Pending WO2025184294A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
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US20150322063A1 (en) * 2013-01-11 2015-11-12 Fujifilm Corporation Nitrogen-containing heterocyclic compound or salt thereof
WO2022226172A1 (fr) * 2021-04-21 2022-10-27 The Regents Of The University Of California Compositions et méthodes de traitement de maladies neurodégénératives
CN115772170A (zh) * 2021-12-03 2023-03-10 徐诺药业(南京)有限公司 一种吡唑并[1,5-a]吡啶衍生物及其制备方法和应用

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Publication number Priority date Publication date Assignee Title
US20150322063A1 (en) * 2013-01-11 2015-11-12 Fujifilm Corporation Nitrogen-containing heterocyclic compound or salt thereof
WO2022226172A1 (fr) * 2021-04-21 2022-10-27 The Regents Of The University Of California Compositions et méthodes de traitement de maladies neurodégénératives
CN115772170A (zh) * 2021-12-03 2023-03-10 徐诺药业(南京)有限公司 一种吡唑并[1,5-a]吡啶衍生物及其制备方法和应用

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MØLLER HENRIETTE A., SANDER TOMMY, KRISTENSEN JESPER L., NIELSEN BIRGITTE, KRALL JACOB, BERGMANN MARIANNE L., CHRISTIANSEN BOLETTE: "Novel 4-(Piperidin-4-yl)-1-hydroxypyrazoles as γ-Aminobutyric Acid A Receptor Ligands: Synthesis, Pharmacology, and Structure−Activity Relationships", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 53, no. 8, 22 April 2010 (2010-04-22), US , pages 3417 - 3421, XP055979059, ISSN: 0022-2623, DOI: 10.1021/jm100106r *
SANDER TOMMY, FRØLUND BENTE, BRUUN ANNE TECHAU, IVANOV IVAYLO, MCCAMMON JAMES ANDREW, BALLE THOMAS: "New insights into the GABA A receptor structure and orthosteric ligand binding: Receptor modeling guided by experimental data", PROTEINS: STRUCTURE, FUNCTION, AND BIOINFORMATICS, JOHN WILEY & SONS, INC., US, vol. 79, no. 5, 1 March 2011 (2011-03-01), US , pages 1458 - 1477, XP055979053, ISSN: 0887-3585, DOI: 10.1002/prot.22975 *

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