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WO2009082039A1 - Ampa receptor antagonists for epilepsy, mental disorders or deficits in sensory organ - Google Patents

Ampa receptor antagonists for epilepsy, mental disorders or deficits in sensory organ Download PDF

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Publication number
WO2009082039A1
WO2009082039A1 PCT/JP2008/073978 JP2008073978W WO2009082039A1 WO 2009082039 A1 WO2009082039 A1 WO 2009082039A1 JP 2008073978 W JP2008073978 W JP 2008073978W WO 2009082039 A1 WO2009082039 A1 WO 2009082039A1
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WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
hydrate
acceptable salt
disorders
dronabinol
Prior art date
Application number
PCT/JP2008/073978
Other languages
French (fr)
Inventor
Takahisa Hanada
Shigeki Hibi
Kazuki Miyazaki
Original Assignee
Eisai R & D Management Co., Ltd.
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Filing date
Publication date
Application filed by Eisai R & D Management Co., Ltd. filed Critical Eisai R & D Management Co., Ltd.
Priority to JP2010520362A priority Critical patent/JP2011507800A/en
Priority to US12/744,454 priority patent/US20100297181A1/en
Priority to EP08863731A priority patent/EP2254577A1/en
Publication of WO2009082039A1 publication Critical patent/WO2009082039A1/en

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    • 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
    • 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
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • 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
    • 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

  • the invention provides pharmaceutical compositions, combinations, and kits comprising AMPA receptor antagonists and methods using AMPA receptor antagonists for treating Epilepsy, Mental disorders or Deficits in sensory organ.
  • Epilepsy is common neurological disease showing repetitive seizures. Incidence of this disease is around 1 % of the total population. They are treated with antiepileptics which mainly modulate voltage sensitive ion channels, GABA receptor or GABA metabolism. Large part of patients respond to the antiepileptic drugs but about 20 % of epilepsy patients is refractory to the treatments. Therefore it is anticipated that antiepileptic drug which shows good efficacy with good pharmacodynamic interaction with other antiepileptic drugs.
  • AMPA receptor is distributed throughout brain and has a role in fast synaptic neurotransmission. It is believed that AMPA receptor play a role in abnormal excitation of neuron and neuronal cell death. Broad spectrum anti-seizure effect of AMPA antagonist is confirmed from the studies with various experimental models.
  • antiepileptics are utilized for the treatment for seizures.
  • sodium or calcium channel inhibitors like carbamazepine, phenytoin and lamotario, calcium channel modulator like gabapentin and pregabalin, and modulators of GABA are used for partial onset seizures.
  • Generalized seizure is treated with limited antiepileptics.
  • valproate is frequently used as first-line drug for generalized seizure and ethosuximide is specifically used for absence seizures.
  • antiepileptics for partial seizure worsen the generalized seizure.
  • These preferences in seizure subtypes causes difficulty in combination therapy.
  • antiepileptics are also utilized as adjunctive drug for treatment refractory seizures. It is recommended that adjunctive drug should be selected among antiepileptics having different mode of action from prescribed drug.
  • Mental disorder is sometimes refractory to the therapy.
  • Antiepileptics often utilized as adjunctive therapy or sometimes utilized as monotherapy.
  • glutamate is a neurotransmitter in sensory organs.
  • Tinnitus or hearing loss is caused by various reasons. Experimental tinnitus or hearing loss is caused by exposure to the loud noise, intoxication of drugs like antibiotics or injection of glutamate agonist into cochlea. It is described that glutamate antagonists worked in these models. Therefore inhibitor of glutamate system could be a treatment option but there is no scientific evaluation has been made. Treatment for these diseases is not established. Antiepileptics or vitamins are sometimes used. Glaucoma and diabetic retinopathy are major reason of blindness. Several treatment options are utilized but there is no drug aimed for neuronal protection. It is well described glutamate is a causal factor of retinal neuronal degeneration in experimental models and it is also estimated in human case.
  • AMPA receptor antagonists include 1,2-dihydropyridine compounds.
  • An exemplary 1,2- dihydropyridine compound is perampanel [i.e., 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2- dihydropyridin-2-one], and is described in US Patent No. 6,949,571.
  • Methods for treating diseases and administering these compounds in conjunction with a cholinesterase inhibitor are described in WO 2006/107859 and WO 2006/107860.
  • Methods for treating diseases and administering these compounds in conjunction with a NMDA receptor antagonist are described in WO 2008/111590.
  • Methods for treating diseases and administering these compounds in conjunction with a cinnamide compound are described in WO 2008/139984.
  • the invention provides methods for treatment and/or prophylaxis of epilepsy including partial seizure and generalized seizure in a patient in need thereof by administering a therapeutically effective amount of at least one AMPA receptor antagonist (e.g., 1,2- dihydropyridine compound), optionally in combination with one or more other active ingredients that are useful for treating epilepsy, hi one embodiment, the AMPA receptor antagonist is 3-(2- cyanophenyl)-5-(2-pyridyl)-l -phenyl- 1 ,2-dihydropyridin-2-one.
  • the methods for the treatment and/or prophylaxis of Epilepsy include the treatment and/or prophylaxis of epilepsy.
  • the invention provides methods for treatment and/or prophylaxis of mental disorders in a patient in need thereof by administering a therapeutically effective amount of at least one AMPA receptor antagonist (e.g., 1,2-dihydropyridine compound).
  • the AMPA receptor antagonist is 3 -(2-cyanophenyl)-5 -(2-pyridyl)- 1 -phenyl- 1 ,2-dihydropyridin-2-one.
  • the AMPA receptor antagonist can optionally be administered with one or more other active ingredients that are useful for treating mental disorders.
  • the methods for the treatment and/or prophylaxis of mental disorders include the treatment and/or prophylaxis of one or more symptoms of the mental disorders.
  • the invention provides methods for treatment and/or prophylaxis of deficits in sensory organ in a patient in need thereof by administering a therapeutically effective amount of at least one AMPA receptor antagonist (e.g., 1,2-dihydropyridine compound).
  • the AMPA receptor antagonist is 3-(2-cyanophenyl)-5-(2-pyridyl)-l -phenyl-1 ,2-dihydropyridin-2- one.
  • the AMPA receptor antagonist can optionally be administered with one or more other active ingredients that are useful for treating mental disorders.
  • the methods for the treatment and/or prophylaxis of deficit in sensory organ include the treatment and/or prophylaxis of one or more symptoms of the deficit in sensory organ.
  • the invention provides pharmaceutical compositions, combinations, and kits comprising a therapeutically effective amount of at least one AMPA receptor antagonist (e.g., 3-(2- cyanophenyl)-5 -(2-pyridyl)-l -phenyl- 1 ,2-dihy dropyridin-2-one).
  • the pharmaceutical compositions, combinations, and kits can optionally comprise one or more other active ingredients that are useful for treating epilepsy, mental disorders and deficits in sensory organ.
  • the invention relates to the following:
  • a pharmaceutical composition comprising:
  • composition of (1) wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or the hydrate of the pharmaceutically acceptable salt thereof is a compound of Formula (HI), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; wherein the compound of Formula (ID) is:
  • X 1 , X 2 and X 3 are each independently a single bond, an optionally substituted Ci-6 alkylene, an optionally substituted C2-6 alkenylene, an optionally substituted C2-6 alkynylene, -O-, -S-, -CO-, -SO-, -SO 2 -, -N(R 6 )-, -N(R 7 )-CO-, -CO-N(R 8 )-, -N(R 9 )-CH 2 -, -CH 2 -N(R 10 )-, -CH 2 -CO-, -CO-CH 2 -, -N(R 11 VS(O) 1n -, -S(O) n -N(R 12 )-, -CH 2 -S(O) P -, -S(O) q -CH 2 -, -CH 2 -O-, -O-CH 2 -, -N(R 13
  • composition of (1) wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or hydrate of a pharmaceutically acceptable salt thereof is 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
  • composition of (1) wherein the composition is used for treating epilepsy or one or more symptoms of epilepsy.
  • composition of (1) wherein the composition is used for treating generalized seizure or one or more symptoms of generalized seizure.
  • composition of (1) wherein the composition is used for treating mental disorders or one or more symptoms of a mental disorder.
  • Glaucoma or Diabetic retinopathy Glaucoma or Diabetic retinopathy.
  • composition of (1) wherein the composition is adapted to be associated with a treatment regimen.
  • a combination comprising:
  • X 1 , X 2 and X 3 are each independently a single bond, an optionally substituted C 1 ⁇ alkylene, an optionally substituted C 2- ⁇ alkenylene, an optionally substituted C 2- 6 alkynylene, -O-, -S-, -CO-, -SO-, -SO 2 -, -N(R 6 )-, -N(R 7 )-CO-, -CO-N(R 8 )-, -N(R 9 )-CH 2 -, -CH 2 -N(R 10 )-, -CH 2 -CO-, -CO-CH 2 -, -N(R ⁇ )-S(O) ffl -, -S(O) n -N(R 12 )-, -CH 2 -S(O) 1 ,-, -S(O) q -CH 2 -, -CH 2 -O-, -0-CH 2 -
  • IR and R and R are each independently hydrogen, halogen, or C 1-6 alkyl.
  • the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or hydrate of a pharmaceutically acceptable salt thereof is 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
  • Gabapentin Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodaf ⁇ nil, Naproxen sodium/metoclopramide, Stiripentol,
  • Dihydroergotamine inhalation DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfmamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583 , Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940,
  • AZD 9272 BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
  • (40) Use of compounds (A) and (B) for producing a pharmaceutical composition in the treatment of deficits in sensory organ or one or more symptoms of a deficits in sensory organ, wherein (A) and (B) are: (A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
  • X 1 , X 2 and X 3 are each independently a single bond, an optionally substituted Ci- ⁇ alkylene, an optionally substituted C 2 - ⁇ alkenylene, an optionally substituted C 2 - ⁇ alkynylene, -O-, -S-, -CO-, -SO-, -SO 2 -, -N(R 6 )-, -N(R 7 )-C0-, -CO-N(R 8 )-, -N(R 9 )-CH 2 -, -CH 2 -N(R 10 )-, -CH 2 -CO-, -CO-CH 2 -, -N(R u )-S(O) m -, -S(O) n -N(R 12 )-, -CH 2 -S(O) 1 ,-, -S(O) q -CH 2 -, -CH 2 -O-, -0-CH 2 -
  • Gabapentin Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol,
  • (50) Compounds (A) and (B) for use in the treatment of generalized seizure or one or more symptoms of generalized seizure, wherein (A) and (B) are: (A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
  • Dihydroergotamine inhalation DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583 , Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940,
  • AZD 9272 BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
  • the compound of (50), wherein the generalized seizure is an absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures or atonic seizures.
  • Gabapentin Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR. 104, Naratriptan, Neurotropic Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol,
  • Gabapentin Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol,
  • Diabetic retinopathy Diabetic retinopathy.
  • kits comprising the pharmaceutical composition of any one of (1) to (15) or the combination of any one of (16) to (31).
  • a method for treating epilepsy or one or more symptoms of epilepsy comprising administering to a patient in need thereof a therapeutically effective amount of:
  • a method for treating partial seizure or one or more symptoms of partial seizure comprising administering to a patient in need thereof a therapeutically effective amount of:
  • a method for treating generalized seizure or one or more symptoms of generalized seizure comprising administering to a patient in need thereof a therapeutically effective amount of:
  • a method for treating mental disorders or one or more symptoms of a mental disorder comprising administering to a patient in need thereof a therapeutically effective amount of:
  • Gabapentin Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextrometho ⁇ han/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butor
  • Dihydroergotamine inhalation DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralf ⁇ namide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940,
  • AZD 9272 BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
  • a method for treating deficits in sensory organ or one or more symptoms of a deficits in sensory organ comprising administering to a patient in need thereof a therapeutically effective amount of:
  • Dihydroergotamine inhalation DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940,
  • AZD 9272 BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
  • Diabetic retinopathy (72) The method of any one of (61) to (71), wherein the treatment is part of a treatment regimen and the administration involves a series of administrations.
  • a pharmaceutical composition for treating mental disorders or one or more symptoms of a mental disorder comprising: an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers.
  • a pharmaceutical composition for treating deficits in sensory organ or one or more symptoms of a deficits in sensory organ comprising: an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers.
  • composition of any one of (73) to (78), wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or the hydrate of the pharmaceutically acceptable salt thereof is a compound of Formula (IE), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; wherein the compound of Formula (JK) is:
  • X 1 , X 2 and X 3 are each independently a single bond, an optionally substituted Ci-6 alkylene, an optionally substituted C 2- 6 alkenylene, an optionally substituted C 2- 6 alkynylene, -O-, -S-, -CO-, -SO-, -SO 2 -, -N(R 6 )-, -N(R 7 )-C0-, -CO-N(R 8 )-, -N(R 9 )-CH 2 -, -CH 2 -N(R 10 )-, -CH 2 -CO-, -CO-CH 2 -, -N(R ⁇ )-S(O) m -, -S(O) n -N(R 12 )-, -CH 2 -S(O) P -, -S(O) q -CH 2 -, -CH 2 -O-, -0-CH 2 -, -
  • composition of any one of (73) to (78), wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or hydrate of a pharmaceutically acceptable salt thereof is 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2- dihydropyridin-2-one, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
  • X 1 , X 2 and X 3 are each independently a single bond, an optionally substituted C 1 ⁇ alkylene, an optionally substituted C 2-6 alkenylene, an optionally substituted C 2- 6 alkynylene, -O-, -S-, -CO-, -SO-, -SO 2 -, -N(R 6 )-, -N(R 7 )-C0-, -CO-N(R 8 )-, -N(R 9 )-CH 2 -, -CH 2 -N(R 10 )-, -CH 2 -CO-, -CO-CH 2 -, -N(R ⁇ )-S(O) m -, -S(O) n -N(R 12 )-, -CH 2 -S(O) 1 ,-, -S(O) 4 -CH 2 -, -CH 2 -O-, -0-CH 2 -, -N-
  • Compound (A) for use in the treatment of mental disorders or one or more symptoms of a mental disorder wherein (A) is: (A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
  • kits for treating mental disorders or one or more symptoms of a mental disorder comprising the pharmaceutical composition of any one of (73) to (75) and (79) to (81).
  • kits of (99), wherein the mood disorders is depression or bipolar disorder (100) The kit of (99), wherein the mood disorders is depression or bipolar disorder. (101) A kit for treating deficits in sensory organ or one or more symptoms of a deficits in sensory organ comprising the pharmaceutical composition of any one of (76) to (81).
  • kits of any one of (98) to (103), wherein the kit is adapted to be associated with a treatment regimen.
  • a method for treating mental disorders or one or more symptoms of a mental disorder comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of (73) to (75) and (79) to (81).
  • a method for treating deficits in sensory organ or one or more symptoms of a deficits in sensory organ comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of (76) to (81).
  • Patient refers to animals, preferably mammals, more preferably humans.
  • patient includes men and women; and includes adults, children and neonates.
  • patient can be an animal companion, such as a dog or a cat.
  • Active ingredient refers to the AMPA receptor antagonists and other compounds described herein that are responsible for treatment and/or prophylaxis of a disease or disorder.
  • the active ingredients may have mechanisms of action that are known or unknown, and the active ingredients may have one or more mechanisms of action.
  • the active ingredient may have an asymmetric carbon depending on the type of substituent and may have a stereoisomer (e.g., a geometric isomer, an enantiomer, a diastereomer or the like).
  • the active ingredient or a stereoisomer thereof may form a pharmaceutically acceptable salt.
  • the active ingredient, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a pharmaceutically acceptable salt of a stereoisomer thereof may be an anhydride, and may form a solvate.
  • the active ingredient, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof or a solvate thereof may be crystalline or amorphous. Crystalline polymorphs may exist in the active ingredient, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof or a solvate thereof, although not limited thereto and any form of crystal may exist alone or in combination, which are within the scope of the present invention.
  • Treatment and “treating” refer to the acquisition of a desired pharmacological effect and/or physiologic effect. These effects are prophylactic in terms of completely or partially preventing a disease and/or one or more symptom(s) of the disease, and therapeutic in terms of partially or completely curing a disease and/or one or more symptoms caused by a disease.
  • Treatment and “treating” include any treatment of a disease (e.g., epilepsy, mental disorders, or deficits in sensory organ) in a patient including, for example: (a) to prevent a disease or one or more symptom(s) of the disease in a patient who is suspected of being predisposed to the disease but not yet been diagnosed as having the disease or who has previously been diagnosed as having the disease but is not currently diagnosed as having the disease; (b) to inhibit one or more symptom(s) of a disease, i.e., to inhibit or delay the progression of one or more of the symptom(s) of the disease; (c) to alleviate one or more symptom(s) of a disease, i.e., to reverse or eliminate one or more symptom(s) of the disease; (d) to reverse the progress of one or more symptom(s) of the disease; or (e) to stabilize one or more symptom(s) of a disease, such that one or more symptom(s) of the disease do not worsen or improve.
  • a particular treatment regimen for a patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the condition treated.
  • administering separately with reference to the administration of two or more compounds to treat and/or prevent the diseases and/or the onset of the diseases and disorders described herein includes, for example, the sequential administration of the compounds in any order or the simultaneous administration of the compounds.
  • Simultaneous administration of the compounds means that the compounds are administered to the patient at substantially the same time or at exactly the same time, depending on the mode of administration.
  • the sequential administration of the compounds may occur in any order and may occur with any amount of time elapsing between administrations of the compounds. Sequential administration may be based on factors that would influence which of the compounds should be administered first and which should be administered second, and how much time should elapse between administrations of the compounds.
  • factors that effect when the compounds are administered to the patient include, for example, (a) the time(s) that provides the best efficacy for the compound being administered, (b) the time(s) that provides the fewest side effects for the compound being administered, (c) the dosage of the compound, (d) the route of administration of the compound, (e) the disease or disorder being treated, (f) the patient being treated, (g) the in vivo relationship of the compounds being administered, and other such factors known in the art.
  • the time intervals for sequential administration are chosen so that the effect on the disease or disorder being treated in the combined use of the active ingredients is greater than additive when compared to the effect which would be obtained by use of only one of the active ingredients.
  • “Combination” refers to the AMPA receptor antagonist and the second active ingredient
  • “Monotherapy” is a therapy which uses only one active ingredient (e.g., an AMPA receptor antagonist) for treatment and/or prophylaxis of a disease or disorder.
  • active ingredient e.g., an AMPA receptor antagonist
  • Combination therapy is a therapy where two or more active ingredients are administered separately or are administered in the form of a pharmaceutical composition for the treatment and/or prophylaxis of a disease.
  • “Therapeutically effective amount” refers to the amount of the active ingredient that is necessary for the treatment and/or prophylaxis of a disease.
  • the term "therapeutically effective amount” refers to the amount of active ingredients that are necessary for treatment and/or prophylaxis of a disease and includes, for example: (a) a therapeutically effective amount of a first active ingredient and a therapeutically effective amount of a second active ingredient (i.e., the amount of each active ingredient that would be used for monotherapy for the treatment and/or prophylaxis of a disease is used for the combination therapy); (b) a therapeutically effective amount of a first active ingredient and a sub-therapeutic amount of a second active ingredient, which in combination effectively provide for treatment and/or prophylaxis of a disease (e.g., the sub-therapeutic amount of the second active ingredient can be used in combination therapy to achieve a result that would be equal to or greater than the result that the second active ingredient would achieve if it was used for monotherapy); (c) a sub-therapeutic amount of a first active ingredient and a therapeutically effective amount of a second active ingredient, which in
  • the same therapeutic/sub-therapeutic amounts can be used when there are three or more active ingredients used in combination therapy.
  • active ingredients used in combination therapy.
  • “Kits,” also known as commercial packages, can include a combination of (i) a first pharmaceutical composition or formulation comprising the AMPA receptor antagonist; (ii) an optional second pharmaceutical composition or formulation comprising the second active ingredient; (iii) instructions for using the pharmaceutical compositions or formulations for treating or preventing the diseases, or delaying the onset of the disease; and (iv) optionally other materials to administer the pharmaceutical compositions or formulations (e.g., syringes, diluents, medical gloves, hand sanitizers, and the like); to monitor drug levels in the body; to support patient compliance with medication dosing; or to monitor the status of the disease.
  • the kit can supply enough medication and materials for days, weeks or months.
  • kits can include (i) pharmaceutical composition or formulation comprising an AMPA receptor antagonist and optionally a second active ingredient; (ii) instructions for using the pharmaceutical composition or formulation for treating or preventing the diseases, or delaying the onset of the disease; and (iii) optionally other materials to administer the pharmaceutical compositions or formulations (e.g., syringes, diluents, medical gloves, hand sanitizers, and the like); to monitor drug levels in the body; to support patient compliance with medication dosing; or to monitor the status of the disease.
  • the kit can supply enough medication and materials for days, weeks or months. Additionally, the kit can supply enough medication and materials to complete all or a portion of a treatment regimen.
  • the solvate is well known in the art.
  • the solvate is preferably a pharmaceutically acceptable solvate.
  • the pharmaceutically acceptable solvate may be either a hydrate or a nonhydrate, but preferably a hydrate.
  • the solvent such as water, alcohol (e.g., methanol, ethanol, n-propanol), dimethylformamide, dimethyl sulfoxide (DMSO) or the like may be used.
  • “Hydrate” refers to a compound containing a molecule of water of crystallization.
  • the molecule of water of crystallization can be an integer of 1 or more, such as 1 to 10; or can be any fraction greater than 0 or a fraction of an integer from 1 to 10.
  • the hydrate may be represented as compound ⁇ l /4H 2 O; compound»2H 2 O; compound»5M>H 2 O; compound»6H2 ⁇ ; and the like.
  • the “compound” can be any described herein, such as 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one.
  • “Pharmaceutically acceptable salts” are well known in the art and include those of inorganic acids, such as hydrochloride, sulfate, hydrobromide and phosphate; and those of organic acids, such as formate, tartrate, acetate, trifluoroacetate, methanesulfonate, benzenesulfonate and toluenesulfonate.
  • the compounds of the invention can form, for example, alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic amine salts, such as a salt with trimethyl-amine, triethylamine, pyridine, picoline, dicyclohexylamine or N,N'- dibenzylethylenediamine.
  • alkali metal salts such as sodium or potassium salts
  • alkaline earth metal salts such as calcium or magnesium salts
  • organic amine salts such as a salt with trimethyl-amine, triethylamine, pyridine, picoline, dicyclohexylamine or N,N'- dibenzylethylenediamine.
  • the invention provides methods for the treatment and/or prophylaxis of epilepsy, mental disorders and deficits in sensory organ using at least one AMPA receptor antagonist and, optionally, a second active ingredient useful for treating these diseases and disorders.
  • seizures For the purposes of clinical assessment, patients are classified according to the type of seizure. There are two classes of seizures: partial seizures and generalized seizures. Partial seizures are further classified as simple partial seizures, complex partial seizures and partial seizures secondarily generalized. Generalized seizures are classified as convulsive and nonconvulsive seizures. They are further classified as absence (previously referred to as 'petit mal') seizures, atypical absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and atonic seizures.
  • Partial seizure can be classified into the following three fundamental groups.
  • Absence seizures i) Absence seizure ii) Atypical absence seizures
  • Unclassified epileptic seizures include all seizures that can not be classified into the above listed seizures (1) and (2) because of inadequate or incomplete clinical data, and because of some causes that were not defined hitherto into the described categories. Examples of the unclassified epileptic seizures include some of neonatal seizures, e.g. rhythmic eye movements, chewing, and swimming.
  • Epilepsy refers to a brain disorder in which clusters of nerve cells, or neurons, in the brain sometimes signal abnormally. In epilepsy, thenormal pattern of neuronal activity becomes disturbed, causing strange sensations, emotions and behavior, or sometimes convulsions, muscle spasms, and loss of consciousness. Only when a person has had two or more seizures is she or he considered to have epilepsy.
  • Epilepsy can be classified as partial seizure generalized seizure or unclassified epileptic seizures (adapted from Epilepsia (1981) 22; 489-501).
  • Epilepsy syndrome refers to disorders characterized by a specific set of symptoms that include epilepsy. Epilepsy syndromes are described by their symptoms or by where in the brain they originate.
  • Partial seizure refers to focal seizures that occur in just one part of the brain.
  • Simple partial seizure refers to focal seizures that occur in just one part of the brain where the person experiencing the focal seizure remains conscious but may experience unusual feelings or sensations.
  • Complex partial seizure refers to to a focal seizures where the person suffers a change in or loss of consciousness.
  • Partial seizures secondarily generalized refer to seizures which start as a partial seizure, i.e., they start in one limited area of the brain and then spread throughout the brain, becoming “generalized.”
  • Absence seizure refers to a epilepsy disorder where there are repeated instances of seizures where there are momentary losses of consciousness. These seizures almost always start in childhood or adolescence.
  • Myoclonic seizures refer to seizures that cause sudden jerks or twitches, especially in the upper body, arms or legs.
  • Chronic seizures refer to seizures that cause repeated jerking movements of muscles on both sides of the body.
  • Tonic seizures refer to seizures that cause stiffening of muscles of the body, generally those in the back, legs and arms.
  • Tonic-clonic seizures (“grand mal seizures”) refer to seizures that cause a mixture of symptoms, including loss of consciousness, stiffening of the body, and repeated jerks of the arms and legs.
  • Atonic seizures (“drop attacks”) refer to seizures that cause a sudden loss of muscle tone.
  • Mood disorders including major depression and bipolar diseases
  • Mood disorders refer to various conditions involving cyclic changes in mood. Mood disorders include “Mania” (characterized by symptoms of euphoria, increased psychomotor activity, rapid speech, flight of ideas, decreased need for sleep, distractibility, irritability, increased sexual desire, increased energy, grandiosity, and/or poor judgment); “Hypomania” (a mild form of mania); “Depression” (major depression, dysthymia and bipolar disorder); and "Apathy”.
  • Major depression is characterized by a persistent sad, anxious and/or empty mood; feelings of hopelessness, pessimism, guilt, worthlessness, and/or helplessness; a loss of interest or pleasure in hobbies and activities, including sex; decreased energy or fatigue; difficulty concentrating, remembering and/or making decisions; insomnia, early-morning awakening or oversleeping; increased or decreased appetite; thoughts of suicide or death; suicide attempts; restlessness and/or irritability; and/or persistent physical symptoms that do not respond to treatment, such as headaches, digestive disorders and/or chronic pain.
  • Major depression can be characterized by a few or many symptoms which can vary over time. Dysthymia refers to a less severe (sometimes chronic) form of major depression.
  • Bipolar disorder also called manic-depressive illness, is characterized by cycling mood changes from highs (e.g., mania) to lows (e.g., major depression or dysthymia).
  • Apathy is characterized by a slowing of cognitive processes and/or a lack of motivation as manifested by one or more of the following: lack of productivity, lack of initiative, lack of perseverance, diminished socialization or recreation, lack of interest in learning new things, lack of interest in new experiences, lack of emotional responsivity to positive or negative events, unchanging or flat affect, and/or absence of excitement or emotional intensity.
  • Anxiety disorders refer to disorders which often come when people hold in their fears until they begin to feel anxiety.
  • the signs of an anxiety disorder can include: endless checking or rechecking actions, a constant and unrealistic worry about everyday occurrences and activities and fear and anxiety that appear for no apparent reason.
  • Anxiety disorders can include: Panic
  • Personality disorders refer to long-term patterns of thoughts and behaviors that cause serious problems with relationships and work. People with personality disorders have difficulty dealing with everyday stresses and problems. They often have stormy relationships with other people. The exact cause of personality disorders is unknown. However, genes and childhood experiences may play a role.
  • Schizophrenia refers to reactive and process schizophrenias, including, for example, chronic schizophrenia, ambulatory schizophrenia, catatonic schizophrenia, disorganized schizophrenia, latent schizophrenia, paranoid schizophrenia, pseudoneurotic schizophrenia, residual schizophrenia, and simple schizophrenia.
  • Substance-related disorders refer to disorders related to the taking of a drug of abuse, to side effects of a medication, and to toxin exposure. Substance related disorders are divided into two groups: substance use disorders and substance-induced disorders.
  • Tinitus head noise refers to a symptom associated with many forms of hearing loss. It is commonly a ringing, roaring or hissing sound in an affected person's ears. Persons with severe cases of tinnitus may find it difficult to hear, work or even sleep.
  • Sound induced hearing deficit refers to hearing loss by too much exposure to loud noise.
  • Subject induced hearing deficit refers to hearing loss caused by chemical compounds.
  • Some medicines can cause can cause tinnitus.
  • Other health problems can also cause tinnitus, e.g. allergies, tumors, problems in the heart and blood vessels, jaw and neck.
  • Glaucoma refers to a group of disorders that lead to damage of the optic nerve, the nerve that carries visual information from the eye to the brain. Damage to the optic nerve causes vision loss, which may progress to blindness. Most people with glaucoma have increased fluid pressure to the eye, a condition known as increased ocular pressure. There are four major types of glaucoma: open angle (chronic) glaucoma, angle closure (acute) glaucoma, congenital glaucoma and secondary glaucoma.
  • Diabetic retinopathy refers to the most common diabetic eye disease and a leading cause of blindness in American adults. It is caused by changes in the blood vessels of the retina. Diabetic retinopathy, over time, cause vision loss. Diabetic retinopathy has four stages: mild nonproliferative, moderate nonproliferative, severe non proliferative and proliferative retinopathy.
  • the AMPA receptor antagonist used in the methods and compositions described herein may be any known in the art.
  • Exemplary AMPA receptor antagonists, all of which are active ingredients, include 1,2-dihydropyridine compounds, quinoxalinedione aminoalkylphosphonates, and the like.
  • the AMPA receptor antagonist may be becampanel, EGIS 8332 (7- acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-l,3-dioxolo[4,5-h][2,3]benzodiazepine-8- carbonitrile); GYKI 47261 (4-(7-chloro-2-methyl-4H-3,10,10a-triaza-benzo[f]azulen-9- yl)phenylamine)); irampanel (N,N-dimethyl-2-[2-(3 -phenyl- 1, 2,4-oxadiazol-5 - yl)phenoxy]ethanamine); KRP 199 ((7-[4-[[[[4-carboxyphenyl)-amino]carbonyl]oxy]methyl]- lH-imidazol-l-yl]-3,4-dihydro-3-oxo-6-(trifluoromethyl)
  • the AMPA receptor antagonist is a 1,2-dihydropyridine compound.
  • the 1,2-dihydropyridine compound used in the methods and compositions described herein may be any known in the art.
  • the term "1,2-dihydropyridine compound” includes 1,2- dihydropyridine compounds, pharmaceutically acceptable salts of 1,2-dihydropyridine compounds, stereoisomers of 1 ,2-dihydropyridine compounds, pharmaceutically acceptable salts of stereoisomers of 1,2-dihydropyridine compounds, hydrates of 1,2-dihydropyridine compounds, hydrates of pharmaceutically acceptable salts of 1 ,2-dihydropyridine compounds, stereoisomers of hydrates of 1,2-dihydropyridine compounds, and stereoisomer of hydrates of pharmaceutically acceptable salts of 1 ,2-dihydropyridine compounds.
  • the 1,2-dihydropyridine compound used in the methods and compositions described herein may be a compound of Formula (I):
  • Q is NH, O or S
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, halogen, C 1-6 alkyl, or -X-A;
  • X is a single bond, an optionally substituted C 1-6 alkylene, an optionally substituted C 2-6 alkenylene, an optionally substituted C 2- 6 alkynylene, -O-, -S-, -CO-, -SO-, -SO 2 -, -N(R 6 )-, -N(R 7 )-C0-, -CO-N(R 8 )-, -N(R 9 )-CH 2 -, -CH 2 -N(R 10 )-, -CH 2 -CO-, -CO-CH 2 -, -N(R ⁇ )-S(O) m -, -S(O) n -N(R 12 )-, -CH 2 -S(OV, -S(O) q -CH 2 -, -CH 2 -O-, -0-CH 2 -, -N(R 13 )-CO-N(R 14 )- or -
  • R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently hydrogen, C 1-6 alkyl, or C 1-6 alkoxy; m, n, p and q are each independently an integer of 0, 1 or 2;
  • A is an optionally substituted Ci-$ cycloalkyl, an optionally substituted C3-8 cycloalkenyl, an optionally substituted 5- to 14-membered non-aromatic heterocyclic ring, an optionally substituted C 6-14 aromatic hydrocarbocyclic ring, or an optionally substituted 5- to 14-membered aromatic heterocyclic ring; provided that 3 groups among R 1 , R 2 , R 3 , R 4 and R 5 are -X-A; and that the residual 2 groups among R 1 , R 2 , R 3 , R 4 and R 5 are independently hydrogen, halogen, or C 1-6 alkyl.
  • the following compounds are excluded from the scope of the compound of Formula (I): (1) when Q is O; R 1 and R 5 are hydrogen; and R 2 , R 3 and R 4 are phenyl; (2) when Q is O; R 1 and R 4 are hydrogen; and R 2 , R 3 and R 5 are phenyl; and (3) when Q is O; R 1 and R 2 are hydrogen; and R 3 , R 4 and R 5 are phenyl.
  • the 1 ,2-dihydropyridine compound used in the methods and compositions described herein is a compound of Formula (H):
  • X 1 , X 2 and X 3 are each independently a single bond, an optionally substituted C 1 ⁇ alkylene, an optionally substituted C 2- 6 alkenylene, an optionally substituted C 2- 6 alkynylene, -O-, -S-, -CO-, -SO-, -SO 2 -, -N(R 6 )-, -N(R 7 )-C0-, -CO-N(R 8 )-, -N(R 9 )-CH 2 -, -CH 2 -N(R 10 )-, -CH 2 -CO-, -CO-CH 2 -, -N(R u )-S(O) m -, -S(O) n -N(R 12 )-, -CH 2 -S(O) 1 ,-, -S(O) q -CH 2 -, -CH 2 -O-,
  • Q-6 alkyl, or Ci-6 alkoxy are each independently an integer of O, 1 or 2;
  • a 1 , A 2 and A 3 are each independently an optionally substituted C3-8 cycloalkyl, an optionally substituted C 3 -g cycloalkenyl, an optionally substituted 5- to 14-membered non- aromatic heterocyclic ring, an optionally substituted C ⁇ -u aromatic hydrocarbocyclic ring, or an optionally substituted 5 to 14-membered aromatic heterocyclic ring;
  • R 17 and R 18 are each independently hydrogen, halogen, or Ci-6 alkyl.
  • the invention provides the compound of Formula (II) wherein X 1 , X 2 and X 3 are each independently a single bond, an optionally substituted C 1-6 alkylene, an optionally substituted C 2- ⁇ alkenylene, or an optionally substituted C2-6 alkynylene.
  • the substituents may be one or more of -0-, -S-, -CO-, -SO-, -SO 2 -, -N(R 6 )-, -N(R 7 )-C0-, -CO-N(R 8 )-, -N(R 9 VCH 2 -, -CH 2 -N(R 10 )-, -CH 2 -CO-, -CO-CH 2 -, -N(R n )-S(O) m -, -S(O) n -N(R 12 )-, -CH 2 -S(OV, -S(OVCH 2 -, -CH 2 -O-, -0-CH 2 -, -N(R 13 )-CO-N(R 14 )- and -N(R 15 )-CS-N(R 16 )-;
  • R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently hydrogen, Ci -6 alkyl, or Ci -6 alkoxy; m, n, p and q are each independently an integer of 0, 1 or 2;
  • a 1 , A 2 and A 3 are each independently an optionally substituted C 3-8 cycloalkyl, an optionally substituted C3.8 cycloalkenyl, an optionally substituted 5- to 14-membered non- aromatic heterocyclic ring, an optionally substituted C 6-H aromatic hydrocarbocyclic ring, or an optionally substituted 5- to 14-membered aromatic heterocyclic ring.
  • the substituents for the 1 ,2-dihydropyridine compounds of the invention may be one or more of hydroxy; halogen; nitrile; nitro; Q -6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl [wherein the alkyl, alkenyl, and alkynyl can independently and optionally be substituted with one or more groups selected from hydroxy, nitrile, halogen, Ci -6 alkylamino, di(Ci-6 alkyl) amino, C 2-6 alkenylamino, di(C 2-6 alkenyl)amino, C 2-6 alkynylamino, di(C 2-6 alkynyl)amino, N-Ci -6 alkyl-N-C 2-6 alkenylamino, N-Ci -6 alkyl-N-C 2- 6 alkynylamino, N-C 2-6 alkenyl-N-C 2-6 alkynylamino, aralkyloxy
  • the invention provides compounds of Formula (II) wherein A 1 , A and A are each independently an optionally substituted C 3-8 cycloalkyl, an optionally substituted C 3-8 cycloalkenyl or an optionally substituted 5- to 14-membered non-aromatic hetero ring.
  • the invention provides the compound of Formula (II) wherein A 1 , A 2 and A 3 are each independently an optionally substituted Q ⁇ -u aromatic hydrocarbon ring or an optionally substituted 5- to 14-membered aromatic hetero ring.
  • the invention provides the compound of Formula (II) wherein A 1 , A 2 and A 3 are each independently phenyl, pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, furyl, naphthyl, quinolyl, iso-quinolyl, indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, imidazopyridyl, carbazolyl, cyclopentyl, cyclohexyl, cyclohexenyl, dioxinyl, adamantyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholyl; any of which may optionally have substituents.
  • the invention provides the compound of Formula (II) wherein A 1 , A 2 and A 3 are each independently selected from:
  • the invention provides the compound of Formula (II) wherein A 1 , A 2 and A 3 are each independently substituted with hydroxyl, halogen, amino, or nitrile.
  • the invention provides the compound of Formula (H) wherein A 1 , A 2 and A 3 are each independently hydroxyl, halogen, amino, nitrile, or nitro.
  • the invention provides the compound of Formula (It) wherein Q is oxygen.
  • the invention provides the compounds of Formula (I) or (II) wherein X 1 , X 2 and X 3 are each a single bond.
  • the invention provides the compounds of Formula (I) or (It) wherein R 17 and R 18 are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, or iso- propyl. In another embodiment, the invention provides the compounds of Formula (I) or (H) wherein R 17 and R 18 are each hydrogen.
  • the halogen atom indicates fluorine, chlorine, bromine, iodine and the like, and the preferable atoms include fluorine, chlorine and bromine.
  • the C 1 ⁇ alkyl indicates an alkyl having 1 to 6 carbons, and examples include linear chain or branched chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1 -ethylpropyl, 2- ethylpropyl, n-hexyl, l-methyl-2-ethylpropyl, l-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1- propylpropyl, 1-methylbutyl, 2-methylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2- dimethylbutyl,
  • the C 2- ⁇ alkenyl indicates an alkenyl group having 2 to 6 carbons, and examples include vinyl, allyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-l-propenyl, 3 -methyl- 1-propenyl, 2-methyl-2-propenyl, 3- methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 1-hexenyl, 1,3-hexadienyl, 1,6- hexadienyl, and the like.
  • the C 2- 6 alkynyl indicates an alkynyl group having 2 to 6 carbons, and examples include ethynyl, 1 -propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 3 -methyl- 1 -propynyl, 1 -ethynyl-2-propynyl, 2- methyl-3 -propynyl, 1-pentynyl, 1-hexynyl, 1,3-hexadiynyl, 1 ,6-hexadiynyl, and the like.
  • the Ci- 6 alkoxy indicates an alkoxy group having 1 to 6 carbons, and examples include methoxy, ethoxy, n- propoxy, iso-propoxy, sec-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, iso-pentyloxy, sec-pentyloxy, n-hexoxy, iso-hexoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 2-ethylpropoxy, 1 -methyl-2-ethylpropoxy, 1 -ethyl-2-methylpropoxy, 1,1,2-trimethylpropoxy, 1,1,2-trimethylpropoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 2,2- dimethylbutoxy, 2,3-dimethylbutoxy, 1,3-dimethylbutoxy, 2-ethylbutoxy,
  • the C 2- ⁇ alkynyloxy indicates an alkynyloxy group having 2 to 6 carbon atoms, and examples include ethynyloxy, 1- propynyloxy, 2-propynyloxy, 1 -butynyloxy, 2-butynyloxy, 3-butynyloxy, l-methyl-2- propynyloxy, l-ethyl-2-propynyloxy, l-ethynyl-2 -propynyl oxy, 1-pentynyloxy, 1 -hexynyloxy, 1,3-hexadiynyloxy, 1,6-hexadiynyloxy, and the like.
  • the C 2- 6 alkenyloxy indicates an alkenyloxy group having 2 to 6 carbons, and examples include vinyloxy, 2- propenyloxy, 1-propenyl oxy, 2-propenyloxy, iso-propenyloxy, 2-methyl-l-propenyloxy, 3- methyl-1-propenyloxy, 2-methyl-2-propenyloxy, 3-methyl-2-propenyloxy, 1-butenyl oxy, 2- butenyloxy, 3-butenyloxy, 1-pentenyloxy, 1-hexenyloxy, 1,3-hexadienyloxy, 1,6-hexadienyloxy, and the like.
  • the C3-8 cycloalkyl indicates a cycloalkyl group composed of 3 to 8 carbon atoms, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • the C 3-8 cycloalkenyl indicates a cycloalkenyl group composed of 3 to 8 carbon atoms, and examples include cyclopropen-1-yl, cyclopropen-3-yl, cyclobuten-1-yl, cyclobuten-3-yl, 1,3- cyclobutadien-1-yl, cyclopenten-1-yl, cyclopenten-3-yl, cyclopenten-4-yl, 1,3-cyclopentadien-l- yl, l,3-cyclopentadien-2-yl, l,3-cyclopentadien-5-yl, cyclohexen-1-yl, cyclohexen-3-yl, cyclohexen-4-yl, 1,3-cyclohexadien-l-yl, l,3-cyclohexadien-2-yl, l,3-cycloooodien-5-yl, cyclohexen
  • the 5- to 14- membered non-aromatic heterocyclic ring means a mono-cyclic, di-cyclic, or tri-cyclic 5- to 14- membered non-aromatic heterocyclic ring which contains one or more hetero atoms selected from nitrogen, sulfur, and oxygen.
  • Specific examples include pyrrolidinyl, pyrrolyl, piperidinyl, piperazinyl, imidazolyl, pyrazolidyl, imidazolidyl, morpholyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolinyl, dihydrofuryl, dihydropyranyl, imidazolinyl, oxazolinyl, and the like.
  • a group derived from a pyridone ring and a non-aromatic condensed ring are also included in the non-aromatic heterocyclic ring.
  • the Ce -14 aromatic hydrocarbocyclic ring and the aryl mean an aromatic hydrocarbocyclic ring which is composed of 6 to 14 carbon atoms, a mono-cyclic ring, and a condensed di-cyclic, tri-cyclic and the like.
  • phenyl indenyl, 1-naphthyl, 2-naphthyl, azulenyl, heptalenyl, biphenyl, indathenyl, acenaphthyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, cyclopentacyclooctenyl, benzocyclooctenyl and the like.
  • the 5- to 14- membered aromatic heterocyclic ring and the heteroaryl ring mean mono-cyclic, di-cyclic, or tricyclic 5- to 14-membered aromatic heterocyclic ring which contain one or more hetero atoms selected from nitrogen, sulfur, and oxygen.
  • aromatic heterocyclic rings containing nitrogen such as pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, benzotriazolyl, pyrazolyl, imidazolyl, benzimidazolyl, indolyl, iso-indolyl, indolizinyl, prenyl, indazolyl, quinolyl, iso-quinolyl, quinoliziyl, phthalazyl, naphthylidinyl, quinoxalyl, quinazolinyl, cynnolinyl, pteridinyl, imidazotriazinyl, pyrazinopyridazinyl, acridinyl, phenanthridinyl, carbazolyl, carbazolinyl, perimidinyl, phenanthrolinyl, phen
  • the invention provides the compounds of Formula (HI) wherein A 1 , A 2 and A 3 are each independently an optionally substituted C ⁇ -u aromatic hydrocarbon ring or 5- to 14-membered aromatic hetero ring.
  • the invention provides the compounds of Formula (DI) wherein A 1 , A 2 and A 3 are each independently phenyl, pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, furyl, naphthyl, quinolyl, iso- quinolyl, indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, imidazopyridyl, carbazolyl, cyclopentyl, cyclohexyl, cyclohexenyl, dioxinyl, adamantyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholyl; wherein each may optionally be substituted.
  • the invention provides the compounds of Formula (HI) wherein A 1 , A 2 and A 3 are each independently selected from:
  • the invention provides the compounds of Formula (IH) wherein the bonding site of the substituent at A 1 , A 2 and A 3 are in the ⁇ -position of the carbon atom bonding to the group X 1 , X 2 and X 3 , respectively.
  • the invention provides the compounds of Formula (HI) wherein X 1 , X 2 and X 3 are single bonds.
  • the invention provides the compounds of Formula (IH) wherein R 7 and R 18 are hydrogen.
  • the 1 ,2-dihydropyridine compound used in the methods and compositions described herein is Compound A:
  • the IUPAC name for Compound A is 2-(2-oxo-l-phenyl-5-pyridin-2-yl-l,2-dihydropyridin-3- yl)benzonitrile.
  • Compound A may also be referred to as 3-(2-cyanophenyl)-5-(2-pyridyl)-l- phenyl-l,2-dihydropyridin-2-one.
  • Compound A is also known as perampanel.
  • Compound A "2-(2-oxo-l-phenyl-5-pyridin-2- yl- 1 ,2-dihydropyridin-3 -yl)benzonitrile, " "3 -(2-cyanophenyl)-5-(2-pyridyl)- 1 -phenyl- 1 ,2- dihydropyridin-2-one,” and “perampanel” are intended to include pharmaceutically acceptable salts thereof, stereoisomers thereof, pharmaceutically acceptable salts of stereoisomers thereof, hydrates thereof, hydrates of pharmaceutically acceptable salts thereof, stereoisomers of hydrates thereof, and stereoisomer of hydrates of pharmaceutically acceptable salts thereof.
  • the terms "Compound A, " "2-(2-oxo- 1 -phenyl-S-pyridin ⁇ -yl- 1 ,2-dihydropyridin- 3 -yl)benzonitrile, " "3 -(2-cyanophenyl)-5-(2-pyridyl)- 1 -phenyl- 1 ,2-dihydropyridin-2-one, " and "perampanel” are intended to include pharmaceutically acceptable salts thereof, hydrates thereof, and hydrates of pharmaceutically acceptable salts thereof.
  • the 1,2-dihydropyridine compounds that are useful in the methods and compositions of the invention are 3-(2-cyanophenyl)-5-(2-methylsulfonylaminophenyl)-l- phenyl- 1 ,2-dihydropyridin-2-one; 3 -(2-chloro-3 -pyridyl)-5-(2-pyridyl)- 1 -phenyl- 1 ,2- dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l -phenyl-1 ,2-dihydropyridin-2-one; 3- (2-cyanophenyl)-5-(2-pyridyl)-l -(3-nitrophenyl)-l ,2-dihydropyridin-2-one; 3-(2-cyanophenyl)- 5-(2-pyridyl)-l-(3-aminophenyl)-l ,2-dihydro
  • the 1,2-dihydropyridine compounds and methods for making the 1,2-dihydropyridine compounds are described in US Patent No. 6,949,571 , US Publication No. 2004/0023973 , and PCT Publication No. WO 03/047577, WO 04/009553, WO 06/004100, WO 06/004107, WO 07/072868, WO 07/072869, WO 07/126060, and WO 08/093392, the disclosures of which are incorporated by reference herein in their entirety.
  • AMPA receptor antagonists such as quinoxalinedione aminoalkylphosphonates are described, for example, in WO 2005/094797 and WO 98/17672.
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist, (ii) at least one other active ingredient that can be used to treat epilepsy, mental disorders or deficits in sensory organ, and (iii) at least one pharmaceutically acceptable excipient.
  • the invention also provides combinations comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist and (ii) at least one other active ingredient that can be used to treat epilepsy, mental disorders or deficits in sensory organ; wherein the compounds may be administered separately (e.g., simultaneously, sequentially) to a patient to treat the diseases or disorders described.
  • kits comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist, (ii) at least one other active ingredient that can be used to treat epilepsy, mental disorders or deficits in sensory organ; and (iii) instructions for the simultaneous, separate or sequential use of (i) and (ii) in the treatment of the diseases and disorders described herein.
  • the AMPA receptor antagonist can be any described herein.
  • the 1,2-dihydropyridine compound can be a compound of Formula (I), a compound of Formula (II), a compound of Formula (IH), or Compound A.
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of: (i) 3-(2- cyanophenyl)-5-(2-pyridyl)-l -phenyl- l,2-dihydropyridin-2-one; (ii) at least one other active ingredient that can be used to treat epilepsy, mental disorders or deficits in sensory organ; and (iii) at least one pharmaceutically acceptable excipient.
  • One or more other active ingredients can be used in conjunction with the AMPA receptor antagonists of the invention for the treatment or prophylaxis of epilepsy, mental disorders or deficits in sensory organ.
  • Exemplary active ingredients useful to treat epilepsy, mental disorders or deficits in sensory organ include Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan,
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist, (ii) optionally one or more other active ingredients useful to treat epilepsy, mental disorders or deficits in sensory organ, and (iii) at least one pharmaceutically acceptable excipient.
  • the invention also provides combinations comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist and (ii) optionally one or more other active ingredients useful to treat epilepsy, mental disorders or deficits in sensory organ; wherein the compounds may be administered separately (e.g., simultaneously, sequentially) to a patient to treat the diseases or disorders described.
  • kits comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist, (ii) optionally one or more other active ingredients useful to treat epilepsy, mental disorders or deficits in sensory organ; and (iii) instructions for the simultaneous, separate or sequential use of (i) and (ii) in the treatment of the diseases and disorders described herein.
  • the AMPA receptor antagonist can be any described herein.
  • the 1,2-dihydropyridine compound can be a compound of Formula (I), a compound of Formula (II), a compound of Formula (IE), or Compound A.
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of: (i) 3 -(2-cyanophenyl)-5 -(2-pyridyl)- 1 -phenyl- 1 ,2-dihydropyridin-2-one; (ii) optionally one or more other active ingredients useful to treat epilepsy, mental disorders or deficits in sensory organ; and (iii) at least one pharmaceutically acceptable excipient.
  • the invention provides methods for the treatment and/or prophylaxis of epilepsy, mental disorders or deficits in sensory organ and one or more symptoms of epilepsy, mental disorders or deficits in sensory organ in a patient in need thereof by administering a therapeutically effective amount of: (a) at least one AMPA receptor antagonist, and (b) optionally one or more other active ingredients useful to treat epilepsy, mental disorders or deficits in sensory organ.
  • the methods for the treatment of epilepsy, mental disorders or deficits in sensory organ and one or more symptoms of epilepsy, mental disorders or deficits in sensory organ include (i) methods for reducing the frequency of epilepsy, mental disorders or deficits in sensory organ, or one or more symptoms of epilepsy, mental disorders or deficits in sensory organ, (ii) methods for reducing the severity of epilepsy, mental disorders or deficits in sensory organ, or one or more symptoms of epilepsy, mental disorders or deficits in sensory organ, (iii) methods for reducing the duration of epilepsy, mental disorders or deficits in sensory organ, or one or more symptoms of epilepsy, mental disorders or deficits in sensory organ, (iv) methods for reducing the frequency and severity of epilepsy, mental disorders or deficits in sensory organ, or one or more symptoms of epilepsy, mental disorders or deficits in sensory organ, (v) methods for reducing the frequency and duration of epilepsy, mental disorders or deficits in sensory organ, or one or more symptoms of epilepsy, mental disorders or deficits in sensory organ
  • the AMPA receptor antagonist and, optionally, one or more other active ingredients, can be administered separately to the patient or may be administered in the form of a pharmaceutical composition.
  • the dosage form of the formulation included in the combination, kit and/or pharmaceutical composition of the invention is not particularly limited.
  • the combination, kit and/or pharmaceutical composition of the invention is useful as a combination, kit and/or a pharmaceutical composition for treating neuropathic pain; for the prophylaxis of neuropathic pain; and for delaying the onset of neuropathic pain.
  • the combination, kit and/or pharmaceutical composition of the invention may be used as a drug for treating neuropathic pain; for the prophylaxis of neuropathic pain; and for delaying the onset of neuropathic pain.
  • the pharmaceutical composition of the invention may be made into various forms, for example, into solid oral formulations, injectable solution or the like.
  • the AMPA receptor antagonists and one or more other active ingredients of the invention can be administered orally, topically, parenterally, by inhalation (nasal or oral), or rectally in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • parenteral includes subcutaneous, intravenous, intramuscular, intrathecal, intrasternal injection, or infusion techniques.
  • the daily dose of the AMPA receptor antagonists of the invention is usually 30 ⁇ g to 10 g/day; 100 ⁇ g to 5 g/day; or 100 ⁇ g to 100 mg/day, in the case of oral administration.
  • the daily dose is usually 30 ⁇ g to 1 g/day; 100 ⁇ g to 500 mg/day; or 100 ⁇ g to 30 mg/day.
  • the compounds are administered once daily or in several portions a day.
  • the numerical weight refers to the weight of the 1,2-dihydropyridine, exclusive of any salt, counterion, hydrate, and the like. Therefore to obtain the equivalent of 500 mg of 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one, it would be necessary to use more than 500 mg of a pharmaceutically acceptable salt and/or hydrate of the compound, due to the additional weight of the pharmaceutically acceptable salt and/or hydrate.
  • the daily dose of the other active ingredients that are useful for treating epilepsy, mental disorders or deficits in sensory organ e.g., Valproate semisodium, Phenytoin, Carbamazepine, Oxcarbazepine, Licarbazepine, Lamotrigine, Gabapentin, Topiramate, Levetiracetam,
  • Ruf ⁇ namide, Phenobarbital and Clobazam are usually 400 mg/day to 1200 mg/day for Valproate semisodium; 200 mg/day to 300 mg/day for Phenytoin; 200 mg/day to 300 mg/day for Fosphenytoin; 200 mg/day to 1200 mg/day for Carbamazepine; 600 mg/day to 1200 mg/day for Oxcarbazepine; 750 mg/day to 2000 mg/day for Licarbazepine; 25 mg/day to 200 mg/day for Lamotrigine; 600 mg/day to 2400 mg/day for Gabapentin; 50 mg/day to 600 mg/day for
  • Topiramate 1000 mg/day to 3000 mg/day for Levetiracetam; 100 mg/day to 3200 mg/day for Rufinamide; 30 mg/day to 200 mg/day for Phenobarbital; 250 mg/day to 2000 mg/day for Primidone; or 10 mg/day to 40 mg/day for Clobazam.
  • the compounds are administered once daily, in several portions a day or continuously.
  • the numerical weight refers to the weight of the other active ingredients that are useful for treating epilepsy, mental disorders or deficits in sensory organ, exclusive of any salt, counterion, and the like.
  • the equivalent of the other active ingredients that are useful for treating epilepsy, mental disorders or deficits in sensory organ it would be necessary to use more than above noted amount of drugs, due to the additional weight of the salts.
  • the dose When administered to a child, the dose may possibly be lower than that for an adult.
  • the actual method for administration may fluctuate widely and may depart from the preferred method described herein.
  • Any other compounds described herein may be administered in doses well known in the art by reference, for example, to package inserts of commercially available compounds, The Physician's Desk Reference, to patents describing dosing for the compounds, and to journal articles describing dosing for the compounds.
  • the mode of administration is by injection, such as subcutaneous injection, intramuscular injection, intravenous injection, or intra-arterial injection.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the art using suitable dispersing or wetting agents, suspending agents (e.g., methylcellulose, Polysorbate 80, hydroxyethylcellulose, acacia, powdered tragacanth, sodium carboxymethylcellulose, polyoxytehylene sorbitan monolaurate and the like), pH modifiers, buffers, solubilizing agents (e.g., polyoxyethylene hydrogenated castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol, an ethyl ester of castor oil fatty acid, and the like), stabilizers (e.g., sodium sulfite and sodium metasulfite; examples of the preservative include methyl parahydroxybenzol,
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • a nontoxic parenterally acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally used as a solvent or suspending medium.
  • any bland fixed oil can be used including synthetic mono- or diglycerides, in addition, fatty acids, such as oleic acid, can be used in the preparation of injectables.
  • the preparations can be lyophilized by methods known in the art.
  • an excipient In order to prepare a solid oral formulation, an excipient, and if necessary, a binder, disintegrant, lubricant, colorant, a flavoring agent and the like are added to the principal agent, and then made into a tablet, a coated tablet, granule, fine granule, dispersant, a capsule or the like according to a conventional method.
  • lactose, cornstarch, sucrose, glucose, sorbit, crystalline cellulose, silicon dioxide or the like may be used as the excipient; for example, polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropylmethyl cellulose or the like may be used as the binder; for example, magnesium stearate, talc, silica or the like may be used as the lubricant; those that are allowed to be added to drags may be used as the colorant; and for example, cocoa powder, menthol, aromatic acid, peppermint oil, camphor, cinnamon powder or the like may be used as the flavoring agent.
  • Solid dosage forms for oral administration can include chewing gum, capsules, tablets, sublingual tablets, powders, granules, and gels.
  • the active compound can be admixed with one or more inert diluents such as lactose or starch.
  • such dosage forms can also comprise other substances including lubricating agents such as magnesium stearate.
  • the dosage forms can also comprise buffering agents.
  • the tablets can be prepared with enteric or film coatings, preferably film coatings.
  • the compounds can be admixed with pharmaceutically acceptable carriers known in the art such as, for example, vehicles (e.g., lactose, white sugar, mannitol, glucose, starches, calcium carbonate, crystalline cellulose, silicic acid, and the like), binders (e.g., water, ethanol, myranol, glucose solution, starch solution, gelatin solution, polyvinylpyrrolidone, and the like), disintegrators (e.g., dry starch, sodium, alginate, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride, starches, lactose, and the like), absorption promoters (e.g., quaternary ammonium base, sodium laurylsulfate, and the like), wetting agents (e.g.
  • vehicles e.g., lactose, white sugar, mannitol, glucose, starches, calcium
  • the tablets can be in the form of a conventional tablet, a molded tablet, a wafer and the like.
  • Sublingual administration refers to the administration in the mouth (e.g., under the tongue, between the cheek and gum, between the tongue and roof of the mouth).
  • the highly vascular mucosal lining in the mouth is a convenient location for the compounds to be administered into the body.
  • the solid dosage form can be packaged as granules or a powder in a pharmaceutically acceptable carrier, where the granules or powder are removed from the packaging and sprinkled on food or mixed with a liquid, such as water or juice, or where the granules are inserted into capsules.
  • a liquid such as water or juice
  • the compounds described herein can be mixed with flavoring or sweetening agents.
  • the packaging material can be plastic, coated paper, or any material that prevents water or moisture from reaching the granules and/or powder.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, sublingual solutions, suspensions, and syrups containing inert diluents commonly used in the art, such as water.
  • Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • the compounds can be admixed with various carriers, excipients, pH adjusters, and the like (e.g., water, sugar, lactic acid, acetic acid, fructose, glucose, saccharin, polyethylene glycol, propylene glycol, alcohol, bentonite, tragacanth, gelatin, alginates, aspartame, sorbitol, methylparaben, propylparaben, sodium benzoate, artificial flavoring and coloring agents).
  • carriers e.g., water, sugar, lactic acid, acetic acid, fructose, glucose, saccharin, polyethylene glycol, propylene glycol, alcohol, bentonite, tragacanth, gelatin, alginates, aspartame, sorbitol, methylparaben, propylparaben, sodium benzoate, artificial flavoring and coloring agents).

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Abstract

The invention provides methods for treating epilepsy, mental disorders and/or deficits in sensory organ by administering to patients therapeutically effective amounts of AMPA receptor antagonists in combination with one or more other active ingredients useful for treating epilepsy, mental disorders and/or deficits in sensory organ. The invention also provides pharmaceutical combinations, kits, and pharmaceutical compositions comprising therapeutically effective amounts of AMPA receptor antagonists, and optionally, one or more other active ingredients that are useful for treating epilepsy, mental disorders and/or deficits in sensory organ.

Description

Description
AMPA Receptor Antagonists for Epilepsy, Mental disorders or Deficits in sensory organ
Related Application
This application claims priority under 35 U.S. C. § 119 to US Provisional Application No. 61/006,134 filed on December 26, 2007, the disclosures of which are incorporated by reference herein in their entirety.
Field of the Invention
The invention provides pharmaceutical compositions, combinations, and kits comprising AMPA receptor antagonists and methods using AMPA receptor antagonists for treating Epilepsy, Mental disorders or Deficits in sensory organ.
Background of the Invention
Epilepsy is common neurological disease showing repetitive seizures. Incidence of this disease is around 1 % of the total population. They are treated with antiepileptics which mainly modulate voltage sensitive ion channels, GABA receptor or GABA metabolism. Large part of patients respond to the antiepileptic drugs but about 20 % of epilepsy patients is refractory to the treatments. Therefore it is anticipated that antiepileptic drug which shows good efficacy with good pharmacodynamic interaction with other antiepileptic drugs.
AMPA receptor is distributed throughout brain and has a role in fast synaptic neurotransmission. It is believed that AMPA receptor play a role in abnormal excitation of neuron and neuronal cell death. Broad spectrum anti-seizure effect of AMPA antagonist is confirmed from the studies with various experimental models.
There are a lot of antiepileptics are utilized for the treatment for seizures. For example sodium or calcium channel inhibitors like carbamazepine, phenytoin and lamotorigine, calcium channel modulator like gabapentin and pregabalin, and modulators of GABA are used for partial onset seizures.
Generalized seizure is treated with limited antiepileptics. For example, valproate is frequently used as first-line drug for generalized seizure and ethosuximide is specifically used for absence seizures. It is known that some of antiepileptics for partial seizure worsen the generalized seizure. These preferences in seizure subtypes causes difficulty in combination therapy. Above mentioned antiepileptics are also utilized as adjunctive drug for treatment refractory seizures. It is recommended that adjunctive drug should be selected among antiepileptics having different mode of action from prescribed drug. Mental disorder is sometimes refractory to the therapy. Antiepileptics often utilized as adjunctive therapy or sometimes utilized as monotherapy.
Deficit in sensory system is caused by various factors. It is known glutamate is a neurotransmitter in sensory organs.
Tinnitus or hearing loss is caused by various reasons. Experimental tinnitus or hearing loss is caused by exposure to the loud noise, intoxication of drugs like antibiotics or injection of glutamate agonist into cochlea. It is described that glutamate antagonists worked in these models. Therefore inhibitor of glutamate system could be a treatment option but there is no scientific evaluation has been made. Treatment for these diseases is not established. Antiepileptics or vitamins are sometimes used. Glaucoma and diabetic retinopathy are major reason of blindness. Several treatment options are utilized but there is no drug aimed for neuronal protection. It is well described glutamate is a causal factor of retinal neuronal degeneration in experimental models and it is also estimated in human case. Glutamate antagonists worked in animal models but those compounds have not been developed for the treatment of neurodegeneration in retina. AMPA receptor antagonists include 1,2-dihydropyridine compounds. An exemplary 1,2- dihydropyridine compound is perampanel [i.e., 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2- dihydropyridin-2-one], and is described in US Patent No. 6,949,571. Methods for treating diseases and administering these compounds in conjunction with a cholinesterase inhibitor are described in WO 2006/107859 and WO 2006/107860. Methods for treating diseases and administering these compounds in conjunction with a NMDA receptor antagonist are described in WO 2008/111590. Methods for treating diseases and administering these compounds in conjunction with a cinnamide compound are described in WO 2008/139984.
There is a need in the art for treating epilepsy, mental disorders and deficits in sensory organ using novel pharmaceutical compositions or combinations. The invention is directed to these, as well as other, important goals.
Summary of the Invention
The invention provides methods for treatment and/or prophylaxis of epilepsy including partial seizure and generalized seizure in a patient in need thereof by administering a therapeutically effective amount of at least one AMPA receptor antagonist (e.g., 1,2- dihydropyridine compound), optionally in combination with one or more other active ingredients that are useful for treating epilepsy, hi one embodiment, the AMPA receptor antagonist is 3-(2- cyanophenyl)-5-(2-pyridyl)-l -phenyl- 1 ,2-dihydropyridin-2-one. The methods for the treatment and/or prophylaxis of Epilepsy include the treatment and/or prophylaxis of epilepsy.
The invention provides methods for treatment and/or prophylaxis of mental disorders in a patient in need thereof by administering a therapeutically effective amount of at least one AMPA receptor antagonist (e.g., 1,2-dihydropyridine compound). Li one embodiment, the AMPA receptor antagonist is 3 -(2-cyanophenyl)-5 -(2-pyridyl)- 1 -phenyl- 1 ,2-dihydropyridin-2-one. The AMPA receptor antagonist can optionally be administered with one or more other active ingredients that are useful for treating mental disorders. The methods for the treatment and/or prophylaxis of mental disorders include the treatment and/or prophylaxis of one or more symptoms of the mental disorders.
The invention provides methods for treatment and/or prophylaxis of deficits in sensory organ in a patient in need thereof by administering a therapeutically effective amount of at least one AMPA receptor antagonist (e.g., 1,2-dihydropyridine compound). In one embodiment, the AMPA receptor antagonist is 3-(2-cyanophenyl)-5-(2-pyridyl)-l -phenyl-1 ,2-dihydropyridin-2- one. The AMPA receptor antagonist can optionally be administered with one or more other active ingredients that are useful for treating mental disorders. The methods for the treatment and/or prophylaxis of deficit in sensory organ include the treatment and/or prophylaxis of one or more symptoms of the deficit in sensory organ. The invention provides pharmaceutical compositions, combinations, and kits comprising a therapeutically effective amount of at least one AMPA receptor antagonist (e.g., 3-(2- cyanophenyl)-5 -(2-pyridyl)-l -phenyl- 1 ,2-dihy dropyridin-2-one). The pharmaceutical compositions, combinations, and kits can optionally comprise one or more other active ingredients that are useful for treating epilepsy, mental disorders and deficits in sensory organ.
The invention relates to the following:
(1) A pharmaceutical composition comprising:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof;
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine,
Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafmil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-ρeptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof; and
(C) one or more pharmaceutically acceptable carriers.
(2) The pharmaceutical composition of (1), wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or the hydrate of the pharmaceutically acceptable salt thereof is a compound of Formula (HI), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; wherein the compound of Formula (ID) is:
Figure imgf000006_0001
wherein X1, X2 and X3 are each independently a single bond, an optionally substituted Ci-6 alkylene, an optionally substituted C2-6 alkenylene, an optionally substituted C2-6 alkynylene, -O-, -S-, -CO-, -SO-, -SO2-, -N(R6)-, -N(R7)-CO-, -CO-N(R8)-, -N(R9)-CH2-, -CH2-N(R10)-, -CH2-CO-, -CO-CH2-, -N(R11VS(O)1n-, -S(O)n-N(R12)-, -CH2-S(O)P-, -S(O)q-CH2-, -CH2-O-, -O-CH2-, -N(R13)-CO-N(R14)- or -N(R15)-CS-N(R16); R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently hydrogen, C1^ alkyl, or C1^ alkoxy; m, n, p and q are each independently an integer of O, 1 or 2; A1, A2 and A3 are each independently an optionally substituted Ci-g cycloalkyl, an optionally substituted C3..8 cycloalkenyl, an optionally substituted 5- to 14-membered non-aromatic heterocyclic ring, an optionally substituted Cβ-u aromatic hydrocarbocyclic ring, or an optionally substituted 5 to 14-membered aromatic heterocyclic ring; and R17 and R18 are each independently hydrogen, halogen, or Ci-6 alkyl.
(3) The pharmaceutical composition of (1), wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or hydrate of a pharmaceutically acceptable salt thereof is 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
(4) The pharmaceutical composition of (1), wherein the composition is used for treating epilepsy or one or more symptoms of epilepsy.
(5) The pharmaceutical composition of (1), wherein the composition is used for treating partial seizure or one or more symptoms of partial seizure.
(6) The pharmaceutical composition of (5), wherein the partial seizure is a simple partial seizure, complex partial seizure, or a partial seizure secondarily generalized.
(7) The pharmaceutical composition of (1), wherein the composition is used for treating generalized seizure or one or more symptoms of generalized seizure.
(8) The pharmaceutical composition of (7), wherein the generalized seizure is an absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures or atonic seizures.
(9) The pharmaceutical composition of (1), wherein the composition is used for treating mental disorders or one or more symptoms of a mental disorder.
(10) The pharmaceutical composition of (9), wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance-related disorders.
(11) The pharmaceutical composition of (10), wherein the mood disorders is depression or bipolar disorder.
(12) The pharmaceutical composition of (1), wherein the composition is used for treating deficits in sensory organ or one or more symptoms of a deficits in sensory organ. (13) The pharmaceutical composition of (12), wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
(14) The pharmaceutical composition of (12), wherein the deficits in sensory organ is
Glaucoma or Diabetic retinopathy.
(15) The pharmaceutical composition of (1), wherein the composition is adapted to be associated with a treatment regimen.
(16) A combination comprising:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1 , ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
(17) The combination of (16), wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or the hydrate of the pharmaceutically acceptable salt thereof is a compound of Formula (DI), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; wherein the compound of Formula (IH) is:
Figure imgf000009_0001
wherein X1, X2 and X3 are each independently a single bond, an optionally substituted C1^ alkylene, an optionally substituted C2-β alkenylene, an optionally substituted C2-6 alkynylene, -O-, -S-, -CO-, -SO-, -SO2-, -N(R6)-, -N(R7)-CO-, -CO-N(R8)-, -N(R9)-CH2-, -CH2-N(R10)-, -CH2-CO-, -CO-CH2-, -N(Rπ)-S(O)ffl-, -S(O)n-N(R12)-, -CH2-S(O)1,-, -S(O)q-CH2-, -CH2-O-, -0-CH2-, -N(R13)-CO-N(R14)- or -N(R15)-CS-N(R16); R6, R7, R8, R9, R10, R11, R12 5 R13, R14, R15 and R16 are each independently hydrogen, Ci_6 alkyl, or C1-6 alkoxy; m, n, p and q are each independently an integer of 0, 1 or 2; A1, A2 and A3 are each independently an optionally substituted C3-8 cycloalkyl, an optionally substituted C3-8 cycloalkenyl, an optionally substituted 5- to 14-membered non-aromatic heterocyclic ring, an optionally substituted Cβ-u aromatic hydrocarbocyclic ring, or an optionally substituted 5 to 14-membered aromatic heterocyclic ring;
11 IR and R and R are each independently hydrogen, halogen, or C1-6 alkyl. (18) The combination of (16), wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or hydrate of a pharmaceutically acceptable salt thereof is 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
(19) The combination of (16), wherein (A) and (B) are administered separately to a patient or are administered to a patient in the form of a pharmaceutical composition.
(20) The combination of (16), wherein the combination is used for treating epilepsy or one or more symptoms of epilepsy.
(21) The combination of (16), wherein the combination is used for treating partial seizure or one or more symptoms of partial seizure.
(22) The combination of (21 ), wherein the partial seizure is a simple partial seizure, complex partial seizure, or a partial seizure secondarily generalized.
(23) The combination of (16), wherein the combination is used for treating generalized seizure or one or more symptoms of generalized seizure.
(24) The combination of (23), wherein the generalized seizure is an absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures or atonic seizures.
(25) The combination of (16), wherein the combination is used for treating mental disorders or one or more symptoms of a mental disorder.
(26) The combination of (25), wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance- related disorders. (27) The combination of (26), wherein the mood disorders is depression or bipolar disorder.
(28) The combination of (16), wherein the combination is used for treating deficits in sensory organ or one or more symptoms of a deficits in sensory organ.
(29) The combination of (28), wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
(30) The combination of (28), wherein the deficits in sensory organ is Glaucoma or Diabetic retinopathy.
(31) The combination of (16), wherein the combination is adapted to be associated with a treatment regimen.
(32) Use of compounds (A) and (B) for producing a pharmaceutical composition in the treatment of epilepsy or one or more symptoms of epilepsy, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
(33) Use of compounds (A) and (B) for producing a pharmaceutical composition in the treatment of partial seizure or one or more symptoms of partial seizure, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine,
Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA5 Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1 , Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
(34) The use of (33), wherein the partial seizure is a simple partial seizure, complex partial seizure, or a partial seizure secondarily generalized.
(35) Use of compounds (A) and (B) for producing a pharmaceutical composition in the treatment of generalized seizure or one or more symptoms of generalized seizure, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
(36) The use of (35), wherein the generalized seizure is an absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures or atonic seizures.
(37) Use of compounds (A) and (B) for producing a pharmaceutical composition in the treatment of mental disorders or one or more symptoms of a mental disorder, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan,
Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafϊnil, Naproxen sodium/metoclopramide, Stiripentol,
Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide,
Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfmamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583 , Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940,
AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
(38) The use of (37), wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance-related disorders.
(39) The use of (38), wherein the mood disorders is depression or bipolar disorder.
(40) Use of compounds (A) and (B) for producing a pharmaceutical composition in the treatment of deficits in sensory organ or one or more symptoms of a deficits in sensory organ, wherein (A) and (B) are: (A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butoφhanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211 , GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
(41) The use of (40), wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
(42) The use of (40), wherein the deficits in sensory organ is Glaucoma or Diabetic retinopathy.
(43) The use of any one of (32) to (42), wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or the hydrate of the pharmaceutically acceptable salt thereof is a compound of Formula (EH), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; wherein the compound of Formula (DI) is:
Figure imgf000017_0001
wherein X1, X2 and X3 are each independently a single bond, an optionally substituted Ci-β alkylene, an optionally substituted C2-β alkenylene, an optionally substituted C2-β alkynylene, -O-, -S-, -CO-, -SO-, -SO2-, -N(R6)-, -N(R7)-C0-, -CO-N(R8)-, -N(R9)-CH2-, -CH2-N(R10)-, -CH2-CO-, -CO-CH2-, -N(Ru)-S(O)m-, -S(O)n-N(R12)-, -CH2-S(O)1,-, -S(O)q-CH2-, -CH2-O-, -0-CH2-, -N(R13)-CO-N(R14)- or -N(R15)-CS-N(R16); R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently hydrogen, C1^ alkyl, or C1^ alkoxy; m, n, p and q are each independently an integer of 0, 1 or 2; A1, A2 and A3 are each independently an optionally substituted C3-8 cycloalkyl, an optionally substituted C3-S cycloalkenyl, an optionally substituted 5- to 14-membered non-aromatic heterocyclic ring, an optionally substituted Cβ-u aromatic hydrocarbocyclic ring, or an optionally substituted 5 to 14-membered aromatic heterocyclic ring; and R17 and R18 are each independently hydrogen, halogen, or C1-O alkyl.
(44) The use of any one of (32) to (42), wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or hydrate of a pharmaceutically acceptable salt thereof is 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
(45) The use of any one of (32) to (42), wherein (A) and (B) are administered separately to a patient or are administered to a patient in the form of a pharmaceutical composition. (46) The use of any one of (32) to (42), wherein the treatment is part of a treatment regimen.
(47) Compounds (A) and (B) for use in the treatment of epilepsy or one or more symptoms of epilepsy, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan,
Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol,
Bifeprunox, Desvenlafaxine, Dextromethorplian/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfϊnamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN OOl, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof. (48) Compounds (A) and (B) for use in the treatment of partial seizure or one or more symptoms of partial seizure, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufϊnamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethoφhan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211 , GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1 , Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01 , GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
(49) The compound of (48), wherein the partial seizure is a simple partial seizure, complex partial seizure, or a partial seizure secondarily generalized.
(50) Compounds (A) and (B) for use in the treatment of generalized seizure or one or more symptoms of generalized seizure, wherein (A) and (B) are: (A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide,
Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583 , Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940,
AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof. (51) The compound of (50), wherein the generalized seizure is an absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures or atonic seizures.
(52) Compounds (A) and (B) for use in the treatment of mental disorders or one or more symptoms of a mental disorder, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan,
Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR. 104, Naratriptan, Neurotropic Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol,
Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof. (53) The compound of (52), wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance- related disorders.
(54) The compound of (53), wherein the mood disorders is depression or bipolar disorder.
(55) Compounds (A) and (B) for use in the treatment of deficits in sensory organ or one or more symptoms of a deficits in sensory organ, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan,
Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol,
Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BBBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
(56) The compound of (55), wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
(57) The compound of (55), wherein the deficits in sensory organ is Glaucoma or
Diabetic retinopathy.
(58) The compound of any one of (47) to (57), wherein the treatment is part of a treatment regimen.
(59) A kit comprising the pharmaceutical composition of any one of (1) to (15) or the combination of any one of (16) to (31).
(60) The kit of (59), wherein the kit is adapted to be associated with a treatment regimen.
(61) A method for treating epilepsy or one or more symptoms of epilepsy, comprising administering to a patient in need thereof a therapeutically effective amount of:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafmil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
(62) A method for treating partial seizure or one or more symptoms of partial seizure, comprising administering to a patient in need thereof a therapeutically effective amount of:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine,
Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butoφhanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG2417, SB 509, Seletracetam, SLV 313, SRN OOl, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
(63) The method of (62), wherein the partial seizure is a simple partial seizure, complex partial seizure, or a partial seizure secondarily generalized.
(64) A method for treating generalized seizure or one or more symptoms of generalized seizure, comprising administering to a patient in need thereof a therapeutically effective amount of:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafmil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
(65) The method of (64), wherein the generalized seizure is an absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures or atonic seizures.
(66) A method for treating mental disorders or one or more symptoms of a mental disorder, comprising administering to a patient in need thereof a therapeutically effective amount of:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan,
Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethoφhan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide,
Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfϊnamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940,
AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
(67) The method of (66), wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance- related disorders.
(68) The method of (67), wherein the mood disorders is depression or bipolar disorder.
(69) A method for treating deficits in sensory organ or one or more symptoms of a deficits in sensory organ, comprising administering to a patient in need thereof a therapeutically effective amount of:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide,
Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940,
AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
(70) The method of (69), wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
(71) The method of (69), wherein the deficits in sensory organ is Glaucoma or
Diabetic retinopathy. (72) The method of any one of (61) to (71), wherein the treatment is part of a treatment regimen and the administration involves a series of administrations.
(73) A pharmaceutical composition for treating mental disorders or one or more symptoms of a mental disorder comprising: an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers.
(74) The pharmaceutical composition of (73), wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance-related disorders.
(75) The pharmaceutical composition of (74), wherein the mood disorders is depression or bipolar disorder.
(76) A pharmaceutical composition for treating deficits in sensory organ or one or more symptoms of a deficits in sensory organ comprising: an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers.
(77) The pharmaceutical composition of (76), wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
(78) The pharmaceutical composition of (76), wherein the deficits in sensory organ is Glaucoma or Diabetic retinopathy.
(79) The pharmaceutical composition of any one of (73) to (78), wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or the hydrate of the pharmaceutically acceptable salt thereof is a compound of Formula (IE), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; wherein the compound of Formula (JK) is:
Figure imgf000030_0001
(m) wherein X1, X2 and X3 are each independently a single bond, an optionally substituted Ci-6 alkylene, an optionally substituted C2-6 alkenylene, an optionally substituted C2-6 alkynylene, -O-, -S-, -CO-, -SO-, -SO2-, -N(R6)-, -N(R7)-C0-, -CO-N(R8)-, -N(R9)-CH2-, -CH2-N(R10)-, -CH2-CO-, -CO-CH2-, -N(Rπ)-S(O)m-, -S(O)n-N(R12)-, -CH2-S(O)P-, -S(O)q-CH2-, -CH2-O-, -0-CH2-, -N(R13)-CO-N(R14)- or -N(R15)-CS-N(R16); R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently hydrogen, Ci-6 alkyl, or Ci-6 alkoxy; m, n, p and q are each independently an integer of 0, 1 or 2; A1, A2 and A3 are each independently an optionally substituted CB-8 cycloalkyl, an optionally substituted C3_s cycloalkenyl, an optionally substituted 5- to 14-membered non-aromatic heterocyclic ring, an optionally substituted Cβ-u aromatic hydrocarbocyclic ring, or an optionally substituted 5 to 14-membered aromatic heterocyclic ring; and R17 and R18 are each independently hydrogen, halogen, or Ci-6 alkyl.
(80) The pharmaceutical composition of any one of (73) to (78), wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or hydrate of a pharmaceutically acceptable salt thereof is 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2- dihydropyridin-2-one, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
(81) The pharmaceutical composition of any one of (73) to (78), wherein the composition is adapted to be associated with a treatment regimen. (82) Use of compound (A) for producing a pharmaceutical composition in the treatment of mental disorders or one or more symptoms of a mental disorder, wherein (A) is:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
(83) The use of (82), wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance-related disorders.
(84) The use of (83), wherein the mood disorders is depression or bipolar disorder.
(85) Use of compound (A) for producing a pharmaceutical composition in the treatment of deficits in sensory organ or one or more symptoms of a deficits in sensory organ, wherein (A) is: (A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
(86) The use of (85), wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
(87) The use of (85), wherein the deficits in sensory organ is Glaucoma or Diabetic retinopathy.
(88) The use of any one of (82) to (87), wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or the hydrate of the pharmaceutically acceptable salt thereof is a compound of Formula (EH), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; wherein the compound of Formula (IH) is:
Figure imgf000032_0001
wherein X1, X2 and X3 are each independently a single bond, an optionally substituted C1^ alkylene, an optionally substituted C2-6 alkenylene, an optionally substituted C2-6 alkynylene, -O-, -S-, -CO-, -SO-, -SO2-, -N(R6)-, -N(R7)-C0-, -CO-N(R8)-, -N(R9)-CH2-, -CH2-N(R10)-, -CH2-CO-, -CO-CH2-, -N(Rπ)-S(O)m-, -S(O)n-N(R12)-, -CH2-S(O)1,-, -S(O)4-CH2-, -CH2-O-, -0-CH2-, -N(R13)-CO-N(R14)- or -N(R1^-CS-N(R16); R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently hydrogen, C1-6 alkyl, or Ci-6 alkoxy; m, n, p and q are each independently an integer of 0, 1 or 2; A1, A2 and A3 are each independently an optionally substituted C3-s cycloalkyl, an optionally substituted C3-8 cycloalkenyl, an optionally substituted 5- to 14-membered non -aromatic heterocyclic ring, an optionally substituted Ce-I4 aromatic hydrocarbocyclic ring, or an optionally substituted 5 to 14-membered aromatic heterocyclic ring; and R17 and R18 are each independently hydrogen, halogen, or Ci-6 alkyl.
(89) The use of any one of (82) to (87), wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or hydrate of a pharmaceutically acceptable salt thereof is 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
(90) The use of any one of (82) to (87), wherein the treatment is part of a treatment regimen.
(91) Compound (A) for use in the treatment of mental disorders or one or more symptoms of a mental disorder, wherein (A) is: (A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
(92) The compound of (91), wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance- related disorders.
(93) The compound of (92), wherein the mood disorders is depression or bipolar disorder.
(94) Compound (A) for use in the treatment of deficits in sensory organ or one or more symptoms of a deficits in sensory organ, wherein (A) is:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
(95) The compound of (94), wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
(96) The compound of (94), wherein the deficits in sensory organ is Glaucoma or Diabetic retinopathy.
(97) The compound of any one of (91 ) to (96), wherein the treatment is part of a treatment regimen.
(98) A kit for treating mental disorders or one or more symptoms of a mental disorder comprising the pharmaceutical composition of any one of (73) to (75) and (79) to (81).
(99) The kit of (98), wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance-related disorders.
(100) The kit of (99), wherein the mood disorders is depression or bipolar disorder. (101) A kit for treating deficits in sensory organ or one or more symptoms of a deficits in sensory organ comprising the pharmaceutical composition of any one of (76) to (81).
(102) The kit of (101), wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
(103) The kit of (101), wherein the deficits in sensory organ is Glaucoma or Diabetic retinopathy.
(104) The kit of any one of (98) to (103), wherein the kit is adapted to be associated with a treatment regimen.
(105) A method for treating mental disorders or one or more symptoms of a mental disorder comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of (73) to (75) and (79) to (81).
(106) The method of (105), wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance- related disorders.
(107) The method of (106), wherein the mood disorders is depression or bipolar disorder.
(108) A method for treating deficits in sensory organ or one or more symptoms of a deficits in sensory organ comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of (76) to (81).
(109) The method of (108), wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit. (110) The method of (108), wherein the deficits in sensory organ is Glaucoma or Diabetic retinopathy.
(111) The method of any one of (105) to (110), wherein the treatment is part of a treatment regimen and the administration involves a series of administrations.
These and other aspects of the invention are described in more detail herein.
Detailed Description of the Invention "Patient" refers to animals, preferably mammals, more preferably humans. The term
"patient" includes men and women; and includes adults, children and neonates. In one embodiment, the patient can be an animal companion, such as a dog or a cat.
"Active ingredient" refers to the AMPA receptor antagonists and other compounds described herein that are responsible for treatment and/or prophylaxis of a disease or disorder. The active ingredients may have mechanisms of action that are known or unknown, and the active ingredients may have one or more mechanisms of action. The active ingredient may have an asymmetric carbon depending on the type of substituent and may have a stereoisomer (e.g., a geometric isomer, an enantiomer, a diastereomer or the like). The active ingredient or a stereoisomer thereof may form a pharmaceutically acceptable salt. The active ingredient, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a pharmaceutically acceptable salt of a stereoisomer thereof may be an anhydride, and may form a solvate. The active ingredient, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof or a solvate thereof may be crystalline or amorphous. Crystalline polymorphs may exist in the active ingredient, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of a stereoisomer thereof or a solvate thereof, although not limited thereto and any form of crystal may exist alone or in combination, which are within the scope of the present invention.
"Treatment" and "treating" refer to the acquisition of a desired pharmacological effect and/or physiologic effect. These effects are prophylactic in terms of completely or partially preventing a disease and/or one or more symptom(s) of the disease, and therapeutic in terms of partially or completely curing a disease and/or one or more symptoms caused by a disease. "Treatment" and "treating" include any treatment of a disease (e.g., epilepsy, mental disorders, or deficits in sensory organ) in a patient including, for example: (a) to prevent a disease or one or more symptom(s) of the disease in a patient who is suspected of being predisposed to the disease but not yet been diagnosed as having the disease or who has previously been diagnosed as having the disease but is not currently diagnosed as having the disease; (b) to inhibit one or more symptom(s) of a disease, i.e., to inhibit or delay the progression of one or more of the symptom(s) of the disease; (c) to alleviate one or more symptom(s) of a disease, i.e., to reverse or eliminate one or more symptom(s) of the disease; (d) to reverse the progress of one or more symptom(s) of the disease; or (e) to stabilize one or more symptom(s) of a disease, such that one or more symptom(s) of the disease do not worsen or improve. A particular treatment regimen for a patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the condition treated.
"Administered separately" with reference to the administration of two or more compounds to treat and/or prevent the diseases and/or the onset of the diseases and disorders described herein includes, for example, the sequential administration of the compounds in any order or the simultaneous administration of the compounds. Simultaneous administration of the compounds means that the compounds are administered to the patient at substantially the same time or at exactly the same time, depending on the mode of administration. The sequential administration of the compounds may occur in any order and may occur with any amount of time elapsing between administrations of the compounds. Sequential administration may be based on factors that would influence which of the compounds should be administered first and which should be administered second, and how much time should elapse between administrations of the compounds. For example, when two or more compounds are administered separately and sequentially, factors that effect when the compounds are administered to the patient include, for example, (a) the time(s) that provides the best efficacy for the compound being administered, (b) the time(s) that provides the fewest side effects for the compound being administered, (c) the dosage of the compound, (d) the route of administration of the compound, (e) the disease or disorder being treated, (f) the patient being treated, (g) the in vivo relationship of the compounds being administered, and other such factors known in the art. Preferably, the time intervals for sequential administration are chosen so that the effect on the disease or disorder being treated in the combined use of the active ingredients is greater than additive when compared to the effect which would be obtained by use of only one of the active ingredients. "Combination" refers to the AMPA receptor antagonist and the second active ingredient
(e.g., antiepilepsy agents, anti-mental disorder agents or anti-deficits in sensory organ agents) being administered separately as distinct pharmaceutical compositions or formulations. The pharmaceutical compositions or formulations can have the same or different modes of administration. "Monotherapy" is a therapy which uses only one active ingredient (e.g., an AMPA receptor antagonist) for treatment and/or prophylaxis of a disease or disorder.
"Combination therapy" is a therapy where two or more active ingredients are administered separately or are administered in the form of a pharmaceutical composition for the treatment and/or prophylaxis of a disease. "Therapeutically effective amount" refers to the amount of the active ingredient that is necessary for the treatment and/or prophylaxis of a disease. When two or more active ingredients are administered for combination therapy, the term "therapeutically effective amount" refers to the amount of active ingredients that are necessary for treatment and/or prophylaxis of a disease and includes, for example: (a) a therapeutically effective amount of a first active ingredient and a therapeutically effective amount of a second active ingredient (i.e., the amount of each active ingredient that would be used for monotherapy for the treatment and/or prophylaxis of a disease is used for the combination therapy); (b) a therapeutically effective amount of a first active ingredient and a sub-therapeutic amount of a second active ingredient, which in combination effectively provide for treatment and/or prophylaxis of a disease (e.g., the sub-therapeutic amount of the second active ingredient can be used in combination therapy to achieve a result that would be equal to or greater than the result that the second active ingredient would achieve if it was used for monotherapy); (c) a sub-therapeutic amount of a first active ingredient and a therapeutically effective amount of a second active ingredient, which in combination effectively provide for treatment and/or prophylaxis of a disease (e.g., the sub-therapeutic amount of the first active ingredient can be used in combination therapy to achieve a result that would be equal to or greater than the result that the first active ingredient would achieve if it was used for monotherapy); and (d) a sub-therapeutic amount of a first active ingredient and a sub-therapeutic amount of a second active ingredient, which in combination therapy provide for treatment and/or prophylaxis of a disease or disorder (e.g., the sub-therapeutic amount of the first active ingredient can be used in combination therapy to achieve a result that would be equal to or greater than the result that the first active ingredient would achieve if it was used for monotherapy; and the sub-therapeutic amount of the second active ingredient can be used in combination therapy to achieve a result that would be equal to or greater than the result that the second active ingredient would achieve if it was used for monotherapy). The same therapeutic/sub-therapeutic amounts can be used when there are three or more active ingredients used in combination therapy. For example, (a) there may be therapeutically effective amounts of all three active ingredients; (b) there may be therapeutically effective amounts of two active ingredients and a sub-therapeutic amount of a third active ingredient; (c) there may be a therapeutically effective amount of one active ingredient and subtherapeutic amounts of two other active ingredients; or (d) there may be sub-therapeutic amounts of all three active ingredients .
"Kits," also known as commercial packages, can include a combination of (i) a first pharmaceutical composition or formulation comprising the AMPA receptor antagonist; (ii) an optional second pharmaceutical composition or formulation comprising the second active ingredient; (iii) instructions for using the pharmaceutical compositions or formulations for treating or preventing the diseases, or delaying the onset of the disease; and (iv) optionally other materials to administer the pharmaceutical compositions or formulations (e.g., syringes, diluents, medical gloves, hand sanitizers, and the like); to monitor drug levels in the body; to support patient compliance with medication dosing; or to monitor the status of the disease. The kit can supply enough medication and materials for days, weeks or months. In another embodiment, "kits" can include (i) pharmaceutical composition or formulation comprising an AMPA receptor antagonist and optionally a second active ingredient; (ii) instructions for using the pharmaceutical composition or formulation for treating or preventing the diseases, or delaying the onset of the disease; and (iii) optionally other materials to administer the pharmaceutical compositions or formulations (e.g., syringes, diluents, medical gloves, hand sanitizers, and the like); to monitor drug levels in the body; to support patient compliance with medication dosing; or to monitor the status of the disease. The kit can supply enough medication and materials for days, weeks or months. Additionally, the kit can supply enough medication and materials to complete all or a portion of a treatment regimen.
"Solvate" is well known in the art. The solvate is preferably a pharmaceutically acceptable solvate. The pharmaceutically acceptable solvate may be either a hydrate or a nonhydrate, but preferably a hydrate. The solvent such as water, alcohol (e.g., methanol, ethanol, n-propanol), dimethylformamide, dimethyl sulfoxide (DMSO) or the like may be used.
"Hydrate" refers to a compound containing a molecule of water of crystallization. The molecule of water of crystallization can be an integer of 1 or more, such as 1 to 10; or can be any fraction greater than 0 or a fraction of an integer from 1 to 10. For example, the hydrate may be represented as compoundφl/4H2O;
Figure imgf000039_0001
compound»2H2O; compound»5M>H2O; compound»6H2θ; and the like. The "compound" can be any described herein, such as 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one.
"Pharmaceutically acceptable salts" are well known in the art and include those of inorganic acids, such as hydrochloride, sulfate, hydrobromide and phosphate; and those of organic acids, such as formate, tartrate, acetate, trifluoroacetate, methanesulfonate, benzenesulfonate and toluenesulfonate. When certain substituents are selected, the compounds of the invention can form, for example, alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic amine salts, such as a salt with trimethyl-amine, triethylamine, pyridine, picoline, dicyclohexylamine or N,N'- dibenzylethylenediamine. One skilled in the art will recognize that the compounds of the invention can be made in the form of any other pharmaceutically acceptable salt.
The invention provides methods for the treatment and/or prophylaxis of epilepsy, mental disorders and deficits in sensory organ using at least one AMPA receptor antagonist and, optionally, a second active ingredient useful for treating these diseases and disorders.
I. Epilepsy
For the purposes of clinical assessment, patients are classified according to the type of seizure. There are two classes of seizures: partial seizures and generalized seizures. Partial seizures are further classified as simple partial seizures, complex partial seizures and partial seizures secondarily generalized. Generalized seizures are classified as convulsive and nonconvulsive seizures. They are further classified as absence (previously referred to as 'petit mal') seizures, atypical absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and atonic seizures.
(1) Partial seizure can be classified into the following three fundamental groups. A. Simple partial seizure
B. Complex partial seizure
C. Partial seizures secondarily generalized
(2) Generalized seizures involve bilateral hemispheres in the first clinical change. Following types of seizures are included in the generalized seizures.
A. Absence seizures i) Absence seizure ii) Atypical absence seizures
B. Myoclonic seizures C. Clonic seizures
D. Tonic seizures
E. Tonic-clonic seizures
F. Atonic seizures.
(3) Unclassified epileptic seizures
Unclassified epileptic seizures include all seizures that can not be classified into the above listed seizures (1) and (2) because of inadequate or incomplete clinical data, and because of some causes that were not defined hitherto into the described categories. Examples of the unclassified epileptic seizures include some of neonatal seizures, e.g. rhythmic eye movements, chewing, and swimming.
Detail of classification of epilepsy or epileptic syndrome is described in the art (Epilepsia (1989) 30;389-399) which is incorporated herein in their entirety for reference.
Following diseases (1) to (3) are diagnosed in accordance with the combination of the above classified or unclassified seizures. (1) Idiopathic epilepsies
A. Idiopathic epilepsies with partial seizures
B. Idiopathic epilepsies with generalized seizures
(2) Symptomatic epilepsies A. Symptomatic epilepsies with partial seizures
B. Symptomatic epilepsies with generalized seizures
(3) Epilepsies that are difficult to categorize
A. West's syndrome
B. Lennox-Gastaut syndrome C. Acquired epileptic aphasia (the Landau-Kleffner syndrome)
D. Epilepsy with continuous spike-wave during slow wave sleep
"Epilepsy" refers to a brain disorder in which clusters of nerve cells, or neurons, in the brain sometimes signal abnormally. In epilepsy, thenormal pattern of neuronal activity becomes disturbed, causing strange sensations, emotions and behavior, or sometimes convulsions, muscle spasms, and loss of consciousness. Only when a person has had two or more seizures is she or he considered to have epilepsy.
"Epilepsy" can be classified as partial seizure generalized seizure or unclassified epileptic seizures (adapted from Epilepsia (1981) 22; 489-501).
"Epilepsy syndrome," refers to disorders characterized by a specific set of symptoms that include epilepsy. Epilepsy syndromes are described by their symptoms or by where in the brain they originate.
"Partial seizure" refers to focal seizures that occur in just one part of the brain. "Simple partial seizure" refers to focal seizures that occur in just one part of the brain where the person experiencing the focal seizure remains conscious but may experience unusual feelings or sensations.
"Complex partial seizure" refers to to a focal seizures where the person suffers a change in or loss of consciousness. "Partial seizures secondarily generalized" refer to seizures which start as a partial seizure, i.e., they start in one limited area of the brain and then spread throughout the brain, becoming "generalized."
"Absence seizure" refers to a epilepsy disorder where there are repeated instances of seizures where there are momentary losses of consciousness. These seizures almost always start in childhood or adolescence.
"Atypical absence" seizures refer to absence seizures with atypic features, e.g. bizarre motor activity.
"Myoclonic seizures" refer to seizures that cause sudden jerks or twitches, especially in the upper body, arms or legs.
"Clonic seizures" refer to seizures that cause repeated jerking movements of muscles on both sides of the body.
"Tonic seizures" refer to seizures that cause stiffening of muscles of the body, generally those in the back, legs and arms.
"Tonic-clonic seizures" ("grand mal seizures") refer to seizures that cause a mixture of symptoms, including loss of consciousness, stiffening of the body, and repeated jerks of the arms and legs.
"Atonic seizures" ("drop attacks") refer to seizures that cause a sudden loss of muscle tone.
II. Mental disorders
(1) Mood disorders including major depression and bipolar diseases
"Mood disorders" refer to various conditions involving cyclic changes in mood. Mood disorders include "Mania" (characterized by symptoms of euphoria, increased psychomotor activity, rapid speech, flight of ideas, decreased need for sleep, distractibility, irritability, increased sexual desire, increased energy, grandiosity, and/or poor judgment); "Hypomania" (a mild form of mania); "Depression" (major depression, dysthymia and bipolar disorder); and "Apathy".
Major depression is characterized by a persistent sad, anxious and/or empty mood; feelings of hopelessness, pessimism, guilt, worthlessness, and/or helplessness; a loss of interest or pleasure in hobbies and activities, including sex; decreased energy or fatigue; difficulty concentrating, remembering and/or making decisions; insomnia, early-morning awakening or oversleeping; increased or decreased appetite; thoughts of suicide or death; suicide attempts; restlessness and/or irritability; and/or persistent physical symptoms that do not respond to treatment, such as headaches, digestive disorders and/or chronic pain. Major depression can be characterized by a few or many symptoms which can vary over time. Dysthymia refers to a less severe (sometimes chronic) form of major depression. Bipolar disorder, also called manic-depressive illness, is characterized by cycling mood changes from highs (e.g., mania) to lows (e.g., major depression or dysthymia). Apathy is characterized by a slowing of cognitive processes and/or a lack of motivation as manifested by one or more of the following: lack of productivity, lack of initiative, lack of perseverance, diminished socialization or recreation, lack of interest in learning new things, lack of interest in new experiences, lack of emotional responsivity to positive or negative events, unchanging or flat affect, and/or absence of excitement or emotional intensity.
(2) Anxiety disorders
"Anxiety disorders" refer to disorders which often come when people hold in their fears until they begin to feel anxiety. The signs of an anxiety disorder can include: endless checking or rechecking actions, a constant and unrealistic worry about everyday occurrences and activities and fear and anxiety that appear for no apparent reason. Anxiety disorders can include: Panic
Disorder (a sudden, uncontrollable attack of terror that can manifest itself with heart palpitations, dizziness, shortness of breath, and an out of control or terribly frightening feeling); Generalized Anxiety Disorder (excessive anxiety and worry that last for at least six months accompanied by other physical and behavioral problems); Social Phobia (a persistent fear of one or more situations in which the person is exposed to possible scrutiny of others); Obsessive Compulsive Disorder (repeated, intrusive and unwanted thoughts that cause anxiety, often accompanied by ritualized behavior that relieve this anxiety); and Post-traumatic Stress Disorder (caused when someone experiences a severely distressing or traumatic event; recurring nightmares and/or flashbacks and unprovoked anger are common symptoms).
(3) Personality disorders refer to long-term patterns of thoughts and behaviors that cause serious problems with relationships and work. People with personality disorders have difficulty dealing with everyday stresses and problems. They often have stormy relationships with other people. The exact cause of personality disorders is unknown. However, genes and childhood experiences may play a role. The personality disorders that have shared characteristics into one of three clusters: Cluster A (personality disorders marked by odd, eccentric behavior, including paranoid, schizoid and schizotypal personality disorders); Cluster B (personality disorders are those defined by dramatic, emotional behavior, including histrionic, narcissistic, antisocial and borderline personality disorders) and Cluster C (personality disorders are characterized by anxious, fearful behavior and include obsessive-compulsive, avoidant and dependent personality disorders).
(4) Schizophrenia and other psychotic disorders
"Schizophrenia and other psychotic disorders" refer to "Schizophrenia" is a psychosis characterized by a disorder in the thinking processes, such as delusions and hallucinations, and extensive withdrawal of the patient's interest from other people and the outside world, and the investment of it in his own. Patients diagnosed with schizophrenia often have cognitive impairments and/or dementia caused by the underlying disease process and/or as a side-effect of the treatments with antipsychotic medications. As used herein, the term "schizophrenia" refers to reactive and process schizophrenias, including, for example, chronic schizophrenia, ambulatory schizophrenia, catatonic schizophrenia, disorganized schizophrenia, latent schizophrenia, paranoid schizophrenia, pseudoneurotic schizophrenia, residual schizophrenia, and simple schizophrenia.
(5) Substance-related disorders "Substance-related disorders" refer to disorders related to the taking of a drug of abuse, to side effects of a medication, and to toxin exposure. Substance related disorders are divided into two groups: substance use disorders and substance-induced disorders.
UI. Deficits in sensory organ
(1) Aural disorders:
A. Tinnitus
B. Sound induced hearing deficit
C. Substance induced hearing deficit
"Tinnitus" (head noise) refers to a symptom associated with many forms of hearing loss. It is commonly a ringing, roaring or hissing sound in an affected person's ears. Persons with severe cases of tinnitus may find it difficult to hear, work or even sleep.
"Sound induced hearing deficit" refers to hearing loss by too much exposure to loud noise. "Substance induced hearing deficit" refers to hearing loss caused by chemical compounds.
Some medicines can cause can cause tinnitus. Other health problems can also cause tinnitus, e.g. allergies, tumors, problems in the heart and blood vessels, jaw and neck.
(2) Ophthalmic disorders: A. Glaucoma B. Diabetic retinopathy
"Glaucoma" refers to a group of disorders that lead to damage of the optic nerve, the nerve that carries visual information from the eye to the brain. Damage to the optic nerve causes vision loss, which may progress to blindness. Most people with glaucoma have increased fluid pressure to the eye, a condition known as increased ocular pressure. There are four major types of glaucoma: open angle (chronic) glaucoma, angle closure (acute) glaucoma, congenital glaucoma and secondary glaucoma.
"Diabetic retinopathy" refers to the most common diabetic eye disease and a leading cause of blindness in American adults. It is caused by changes in the blood vessels of the retina. Diabetic retinopathy, over time, cause vision loss. Diabetic retinopathy has four stages: mild nonproliferative, moderate nonproliferative, severe non proliferative and proliferative retinopathy.
In one embodiment, the AMPA receptor antagonist used in the methods and compositions described herein may be any known in the art. Exemplary AMPA receptor antagonists, all of which are active ingredients, include 1,2-dihydropyridine compounds, quinoxalinedione aminoalkylphosphonates, and the like.
In one embodiment, the AMPA receptor antagonist may be becampanel, EGIS 8332 (7- acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-l,3-dioxolo[4,5-h][2,3]benzodiazepine-8- carbonitrile); GYKI 47261 (4-(7-chloro-2-methyl-4H-3,10,10a-triaza-benzo[f]azulen-9- yl)phenylamine)); irampanel (N,N-dimethyl-2-[2-(3 -phenyl- 1, 2,4-oxadiazol-5 - yl)phenoxy]ethanamine); KRP 199 ((7-[4-[[[[4-carboxyphenyl)-amino]carbonyl]oxy]methyl]- lH-imidazol-l-yl]-3,4-dihydro-3-oxo-6-(trifluoromethyl)-2-qumoxalinecarboxylic acid); NS 1209 (2-[[[5-[4-[(dimethylamino)-sulfonyl]phenyl]-l,2,6,7,8:9-hexahydro-8-methyl-2-oxo- 3H- pyrrolo[3,2-h]isoquinolin-3 -ylidene]amino]oxy]-4-hydroxybutanoic acid monosodium salt; topiramate (TOPAMAX®); talampanel (LY-300164, (R)-7-acetyl-5-(4-aminophenyl)-8,9- dibydro-8 methyl-7H-l,3-dioxolo[4,5-h][2,3]benzo-diazepine; YM90K (6-imidazol-l-yl-7- nitro-1 ,4-dibydro-quinoxaline-2,3-dione); S-34730 (7-chloro-6-sulfamoyl-2-(lH)-quinolinone-3- phosphonic acid); Zonampanel (YM-872; (7-imidazol-l-yl-6-nitro-2,3-dioxo-3,4-dihydro-2H- quinoxalin-l-yl)-acetic acid); GYKI 52466 (4-(8-methyl-9H-l,3-dioxa-6,7-diaza- cyclohepta[f]inden-5-yl)-phenylamine); ZK 200775 (MPQX, (7-morpholin-4-yl-2,3-dioxo-6- trifluoromethyl-3,4-dihydro-2H-quinoxalin-l-ylmethyl)-phosphonic acid); CP-465022 (3-(2- chlorophenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one); SYM-2189 (4-(4-amino-phenyl)-6-methoxy-l -methyl-lH-phthalazine-2-carboxylic acid propylamide); SYM-2206 (8-(4-amino-phenyl)-5-methyl-5H-[l,3]dioxolo[4,5-g]phthalazine-6- carboxylic acid propylamide); RPR-117824 ((4-oxo-2-phosphono-5,10-dihydro-4H-imidazo[l,2- a]indeno[l,2-e]pyrazin-9-yl)-acetic acid); or LY-293558 (6-[2-(lH-tetrazol-5-yl)-ethyl]- decahydro-isoquinoline-3 -carboxylic acid).
In another embodiment, the AMPA receptor antagonist is a 1,2-dihydropyridine compound. The 1,2-dihydropyridine compound used in the methods and compositions described herein may be any known in the art. The term "1,2-dihydropyridine compound" includes 1,2- dihydropyridine compounds, pharmaceutically acceptable salts of 1,2-dihydropyridine compounds, stereoisomers of 1 ,2-dihydropyridine compounds, pharmaceutically acceptable salts of stereoisomers of 1,2-dihydropyridine compounds, hydrates of 1,2-dihydropyridine compounds, hydrates of pharmaceutically acceptable salts of 1 ,2-dihydropyridine compounds, stereoisomers of hydrates of 1,2-dihydropyridine compounds, and stereoisomer of hydrates of pharmaceutically acceptable salts of 1 ,2-dihydropyridine compounds.
The 1,2-dihydropyridine compound used in the methods and compositions described herein may be a compound of Formula (I):
Figure imgf000047_0001
wherein
Q is NH, O or S;
R1, R2, R3, R4 and R5 are each independently hydrogen, halogen, C1-6 alkyl, or -X-A;
X is a single bond, an optionally substituted C1-6 alkylene, an optionally substituted C2-6 alkenylene, an optionally substituted C2-6 alkynylene, -O-, -S-, -CO-, -SO-, -SO2-, -N(R6)-, -N(R7)-C0-, -CO-N(R8)-, -N(R9)-CH2-, -CH2-N(R10)-, -CH2-CO-, -CO-CH2-, -N(Rπ)-S(O)m-, -S(O)n-N(R12)-, -CH2-S(OV, -S(O)q-CH2-, -CH2-O-, -0-CH2-, -N(R13)-CO-N(R14)- or -N(R15)-CS-N(R16)-;
R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently hydrogen, C1-6 alkyl, or C1-6 alkoxy; m, n, p and q are each independently an integer of 0, 1 or 2;
A is an optionally substituted Ci-$ cycloalkyl, an optionally substituted C3-8 cycloalkenyl, an optionally substituted 5- to 14-membered non-aromatic heterocyclic ring, an optionally substituted C6-14 aromatic hydrocarbocyclic ring, or an optionally substituted 5- to 14-membered aromatic heterocyclic ring; provided that 3 groups among R1, R2, R3, R4 and R5 are -X-A; and that the residual 2 groups among R1, R2, R3, R4 and R5 are independently hydrogen, halogen, or C1-6 alkyl. In one embodiment, the following compounds are excluded from the scope of the compound of Formula (I): (1) when Q is O; R1 and R5 are hydrogen; and R2, R3 and R4 are phenyl; (2) when Q is O; R1 and R4 are hydrogen; and R2, R3 and R5 are phenyl; and (3) when Q is O; R1 and R2 are hydrogen; and R3, R4 and R5 are phenyl.
In another embodiment, the 1 ,2-dihydropyridine compound used in the methods and compositions described herein is a compound of Formula (H):
Figure imgf000048_0001
wherein Q is NH, O or S; X1, X2 and X3 are each independently a single bond, an optionally substituted C1^ alkylene, an optionally substituted C2-6 alkenylene, an optionally substituted C2-6 alkynylene, -O-, -S-, -CO-, -SO-, -SO2-, -N(R6)-, -N(R7)-C0-, -CO-N(R8)-, -N(R9)-CH2-, -CH2-N(R10)-, -CH2-CO-, -CO-CH2-, -N(Ru)-S(O)m-, -S(O)n-N(R12)-, -CH2-S(O)1,-, -S(O)q-CH2-, -CH2-O-, -0-CH2-, -N(R13)-CO-N(R14)- or -N(R15)-CS-N(R16); R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently hydrogen,
Q-6 alkyl, or Ci-6 alkoxy; m, n, p and q are each independently an integer of O, 1 or 2; A1, A2 and A3 are each independently an optionally substituted C3-8 cycloalkyl, an optionally substituted C3-g cycloalkenyl, an optionally substituted 5- to 14-membered non- aromatic heterocyclic ring, an optionally substituted Cβ-u aromatic hydrocarbocyclic ring, or an optionally substituted 5 to 14-membered aromatic heterocyclic ring; and
R17 and R18 are each independently hydrogen, halogen, or Ci-6 alkyl. In another embodiment, the invention provides the compound of Formula (II) wherein X1, X2 and X3 are each independently a single bond, an optionally substituted C1-6 alkylene, an optionally substituted C2-β alkenylene, or an optionally substituted C2-6 alkynylene. The substituents may be one or more of -0-, -S-, -CO-, -SO-, -SO2-, -N(R6)-, -N(R7)-C0-, -CO-N(R8)-, -N(R9VCH2-, -CH2-N(R10)-, -CH2-CO-, -CO-CH2-, -N(Rn)-S(O)m-, -S(O)n-N(R12)-, -CH2-S(OV, -S(OVCH2-, -CH2-O-, -0-CH2-, -N(R13)-CO-N(R14)- and -N(R15)-CS-N(R16)-;
R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently hydrogen, Ci-6 alkyl, or Ci-6 alkoxy; m, n, p and q are each independently an integer of 0, 1 or 2;
A1, A2 and A3 are each independently an optionally substituted C3-8 cycloalkyl, an optionally substituted C3.8 cycloalkenyl, an optionally substituted 5- to 14-membered non- aromatic heterocyclic ring, an optionally substituted C6-H aromatic hydrocarbocyclic ring, or an optionally substituted 5- to 14-membered aromatic heterocyclic ring. The substituents for the 1 ,2-dihydropyridine compounds of the invention may be one or more of hydroxy; halogen; nitrile; nitro; Q-6 alkyl; C2-6 alkenyl; C2-6 alkynyl [wherein the alkyl, alkenyl, and alkynyl can independently and optionally be substituted with one or more groups selected from hydroxy, nitrile, halogen, Ci-6 alkylamino, di(Ci-6 alkyl) amino, C2-6 alkenylamino, di(C2-6 alkenyl)amino, C2-6 alkynylamino, di(C2-6 alkynyl)amino, N-Ci-6 alkyl-N-C2-6 alkenylamino, N-Ci-6 alkyl-N-C2-6 alkynylamino, N-C2-6 alkenyl-N-C2-6alkynylamino, aralkyloxy, TBDMS oxy, Ci-6 alkylsulfonylamino, Ci-6 alkylcarbonyloxy, C2-6 alkenylcarbonyloxy, C2-6 alkynylcarbonyloxy, N-Ci-6 alkylcarbamoyl, N-C2-6 alkenylcarbamoyl, and N-Ci-6 alkynylcarbamoyl]; Ci-6 alkoxy; C2-6 alkenyloxy; C2-6 alkynyloxy [wherein the alkoxy, alkenyloxy, and alkynyloxy may independently and optionally be substituted with one or more groups selected from Ci-6 alkylamino, aralkyloxy, and hydroxy]; Ci-6 alkylthio; C2-6 alkenylthio; C2-6 alkynylthio [wherein the alkylthio, alkenylthio, and alkynylthio may independently and optionally be substituted with one or more groups selected from hydroxy, nitrile, halogen, Ci-6 alkylamino, aralkyloxy, TBDMS oxy, Ci-6 alkylsulfonylamino, Ci-6 alkylcarbonyloxy, and Ci-6 alkyl carbamoyl]; optionally substituted carbonyl [which may be substituted with Ci-6 alkoxy, amino, Ci-6 alkylamino, di(Ci-6 alkyl)amino, C2-6 alkenylamino, di(C2-6 alkenyl)amino, C2-6 alkynylamino, di(C2-6 alkynyl)amino, N-Ci-6alkyl-N-C2-6 alkenylamino, N-Ci-6 alkyl-N-C2-6 alkynylamino and N-C2-6 alkenyl-N-C2-6 alkynylamino]; an optionally substituted amino [which may be substituted with one or two groups selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkylsulfonyl, C2-6 alkenylsulfonyl, C2-6 alkynylsulfonyl, Ci-6 alkylcarbonyl, C2-6 alkenylcarbonyl and C2-6 alkynylcarbonyl]; Ci-6 alkylsulfonyl; C2-6 alkenylsulfonyl; C2-6 alkynylsulfonyl; Ci-6alkylsulfinyl; C2-6 alkenylsulfinyl; C2-6 alkynylsulfinyl; formyl; optionally substituted C3-8 cycloalkyl; an optionally substituted C3-S cycloalkenyl [where the cycloalkyl group and/or the cycloalkenyl group may independently and optionally be substituted with one or more groups selected from hydroxy, halogen, nitrile, C1-6 alkyl, C1-6 alkyloxy, Ci-6 alkyloxy Ci-6 alkyl, and aralkyl]; a 5- to 14-membered non-aromatic heterocyclic ring [which may optionally be substituted with one or more groups selected from hydroxy, halogen, nitrile, Ci-6 alkyl, C1^ alkyloxy, C1-6 alkyloxy Ci-β alkyl, and aralkyl]; Ce-I4 aromatic hydrocarbocyclic ring [which may optionally be substituted with one or more groups selected from hydroxy, halogen, nitrile, C1-6 alkyl, C1^ alkyloxy, C1-6 alkyloxy C1-6 alkyl, and aralkyl]; and a 5- to 14-membered aromatic heterocyclic ring [which may optionally be substituted with one or more groups selected from hydroxy, halogen, nitrile, Ci-6 alkyl, C1-6 alkyloxy, C1-6 alkyloxy C1^ alkyl, and aralkyl].
In another embodiment, the invention provides compounds of Formula (II) wherein A1, A and A are each independently an optionally substituted C3-8 cycloalkyl, an optionally substituted C3-8 cycloalkenyl or an optionally substituted 5- to 14-membered non-aromatic hetero ring. In another embodiment, the invention provides the compound of Formula (II) wherein A1, A2 and A3 are each independently an optionally substituted Qβ-u aromatic hydrocarbon ring or an optionally substituted 5- to 14-membered aromatic hetero ring. In another embodiment, the invention provides the compound of Formula (II) wherein A1, A2 and A3 are each independently phenyl, pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, furyl, naphthyl, quinolyl, iso-quinolyl, indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, imidazopyridyl, carbazolyl, cyclopentyl, cyclohexyl, cyclohexenyl, dioxinyl, adamantyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholyl; any of which may optionally have substituents. In another embodiment, the invention provides the compound of Formula (II) wherein A1, A2 and A3 are each independently selected from:
Figure imgf000051_0001
each of which may optionally be substituted. In another embodiment, the invention provides the compound of Formula (II) wherein A1, A2 and A3 are each independently substituted with hydroxyl, halogen, amino, or nitrile. In another embodiment, the invention provides the compound of Formula (H) wherein A1, A2 and A3 are each independently hydroxyl, halogen, amino, nitrile, or nitro. In another embodiment, the invention provides the compound of Formula (It) wherein Q is oxygen.
In another embodiment, the invention provides the compounds of Formula (I) or (II) wherein X1, X2 and X3 are each independently a single bond, -CH2-, -CH(OH)-, -CH2-CH2-, -CH=CH-, -C≡C-, -O- or -CO-. In another embodiment, the invention provides the compounds of Formula (I) or (II) wherein X1, X2 and X3 are each a single bond. In another embodiment, the invention provides the compounds of Formula (I) or (It) wherein R17 and R18 are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, or iso- propyl. In another embodiment, the invention provides the compounds of Formula (I) or (H) wherein R17 and R18 are each hydrogen.
With respect to the 1,2-dihydropyridine compounds of the invention, the halogen atom indicates fluorine, chlorine, bromine, iodine and the like, and the preferable atoms include fluorine, chlorine and bromine.
With respect to the 1,2-dihydropyridine compounds of the invention, the C1^ alkyl indicates an alkyl having 1 to 6 carbons, and examples include linear chain or branched chain alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1 -ethylpropyl, 2- ethylpropyl, n-hexyl, l-methyl-2-ethylpropyl, l-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1- propylpropyl, 1-methylbutyl, 2-methylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2- dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3- methylpentyl, and the like.
With respect to the 1,2-dihydropyridine compounds of the invention, the C2-β alkenyl indicates an alkenyl group having 2 to 6 carbons, and examples include vinyl, allyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-l-propenyl, 3 -methyl- 1-propenyl, 2-methyl-2-propenyl, 3- methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 1-hexenyl, 1,3-hexadienyl, 1,6- hexadienyl, and the like.
With respect to the 1,2-dihydropyridine compounds of the invention, the C2-6 alkynyl indicates an alkynyl group having 2 to 6 carbons, and examples include ethynyl, 1 -propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 3 -methyl- 1 -propynyl, 1 -ethynyl-2-propynyl, 2- methyl-3 -propynyl, 1-pentynyl, 1-hexynyl, 1,3-hexadiynyl, 1 ,6-hexadiynyl, and the like.
With respect to the 1,2-dihydropyridine compounds of the invention, the Ci-6 alkoxy indicates an alkoxy group having 1 to 6 carbons, and examples include methoxy, ethoxy, n- propoxy, iso-propoxy, sec-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, iso-pentyloxy, sec-pentyloxy, n-hexoxy, iso-hexoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 2-ethylpropoxy, 1 -methyl-2-ethylpropoxy, 1 -ethyl-2-methylpropoxy, 1,1,2-trimethylpropoxy, 1,1,2-trimethylpropoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 2,2- dimethylbutoxy, 2,3-dimethylbutoxy, 1,3-dimethylbutoxy, 2-ethylbutoxy, 1,3-dimethylbutoxy, 2-methylpentoxy, 3-methylpentoxy, hexyloxy, and the like. With respect to the 1,2-dihydropyridine compounds of the invention, the C2-β alkynyloxy indicates an alkynyloxy group having 2 to 6 carbon atoms, and examples include ethynyloxy, 1- propynyloxy, 2-propynyloxy, 1 -butynyloxy, 2-butynyloxy, 3-butynyloxy, l-methyl-2- propynyloxy, l-ethyl-2-propynyloxy, l-ethynyl-2 -propynyl oxy, 1-pentynyloxy, 1 -hexynyloxy, 1,3-hexadiynyloxy, 1,6-hexadiynyloxy, and the like. With respect to the 1,2-dihydropyridine compounds of the invention, the C2-6 alkenyloxy indicates an alkenyloxy group having 2 to 6 carbons, and examples include vinyloxy, 2- propenyloxy, 1-propenyl oxy, 2-propenyloxy, iso-propenyloxy, 2-methyl-l-propenyloxy, 3- methyl-1-propenyloxy, 2-methyl-2-propenyloxy, 3-methyl-2-propenyloxy, 1-butenyl oxy, 2- butenyloxy, 3-butenyloxy, 1-pentenyloxy, 1-hexenyloxy, 1,3-hexadienyloxy, 1,6-hexadienyloxy, and the like.
With respect to the 1,2-dihydropyridine compounds of the invention, the C3-8 cycloalkyl indicates a cycloalkyl group composed of 3 to 8 carbon atoms, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
With respect to the 1,2-dihydropyridine compounds of the invention, the C3-8 cycloalkenyl indicates a cycloalkenyl group composed of 3 to 8 carbon atoms, and examples include cyclopropen-1-yl, cyclopropen-3-yl, cyclobuten-1-yl, cyclobuten-3-yl, 1,3- cyclobutadien-1-yl, cyclopenten-1-yl, cyclopenten-3-yl, cyclopenten-4-yl, 1,3-cyclopentadien-l- yl, l,3-cyclopentadien-2-yl, l,3-cyclopentadien-5-yl, cyclohexen-1-yl, cyclohexen-3-yl, cyclohexen-4-yl, 1,3-cyclohexadien-l-yl, l,3-cyclohexadien-2-yl, l,3-cyclohexadien~5-yl, 1,4- cyclohexadien-3-yl, 1,4-cyclohexadien-l-yl, cyclohepten-1-yl, cyclohepten-3-yl, cyclohepten-4- yl, cyclohepten-5-yl, l,3-cyclohepten-2-yl, 1,3-cyclohepten-l-yl, l,3-cycloheptadien-5-yl, 1,3- cycloheptadien-6-yl, l,4-cycloheptadien-3-yl, l,4-cycloheptadien-2-yl, 1,4-cycloheptadien-l-yl, 1 ,4-cycloheptadien-6-yl, l,3,5-cycloheptatrien-3-yl, l,3,5-cycloheptatrien-2-yl, 1,3,5- cycloheptatrien-1-yl, l,3,5-cycloheptatrien-7-yl, cycloocten-1-yl, cycloocten-3-yl, cycloocten-4- yl, cycloocten-5-yl, l,3-cyclooctadien-2-yl, 1,3-cyclooctadien-l-yl, l,3-cyclooctadien-5-yl, 1,3- cyclooctadien-6-yl, l,4-cyclooctadien-3-yl, l,4-cyclooctadien-2-yl, 1,4-cyclooctadien-l-yl, 1,4- cyclooctadien-6-yl, l,4-cyclooctadien-7-yl, l,5-cyclooctadien-3-yl, l,5-cyclooctadien-2-yl, l^S-cyclooctatrien-S-yl, l,3,5-cyclooctatrien-2-yl, 1,3,5-cyclooctatrien-l-yl, 1,3,5- cyclooctatrien-7-yl, l,3,6-cyclooctatrien-2-yl, 1,3,6-cyclooctatrien-l-yl, l,3,6-cyclooctatrien-5-yl, l,3,6-cyclooctatrien-6-yl group, and the like. With respect to the 1,2-dihydropyridine compounds of the invention, the 5- to 14- membered non-aromatic heterocyclic ring means a mono-cyclic, di-cyclic, or tri-cyclic 5- to 14- membered non-aromatic heterocyclic ring which contains one or more hetero atoms selected from nitrogen, sulfur, and oxygen. Specific examples include pyrrolidinyl, pyrrolyl, piperidinyl, piperazinyl, imidazolyl, pyrazolidyl, imidazolidyl, morpholyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolinyl, dihydrofuryl, dihydropyranyl, imidazolinyl, oxazolinyl, and the like. Further, a group derived from a pyridone ring and a non-aromatic condensed ring (for example, a group derived from a phthalimide ring, a succinimide ring, and the like) are also included in the non-aromatic heterocyclic ring.
With respect to the 1,2-dihydropyridine compounds of the invention, the Ce-14 aromatic hydrocarbocyclic ring and the aryl mean an aromatic hydrocarbocyclic ring which is composed of 6 to 14 carbon atoms, a mono-cyclic ring, and a condensed di-cyclic, tri-cyclic and the like. Specific examples include phenyl, indenyl, 1-naphthyl, 2-naphthyl, azulenyl, heptalenyl, biphenyl, indathenyl, acenaphthyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, cyclopentacyclooctenyl, benzocyclooctenyl and the like.
With respect to the 1,2-dihydropyridine compounds of the invention, the 5- to 14- membered aromatic heterocyclic ring and the heteroaryl ring mean mono-cyclic, di-cyclic, or tricyclic 5- to 14-membered aromatic heterocyclic ring which contain one or more hetero atoms selected from nitrogen, sulfur, and oxygen. Specific examples include (1) aromatic heterocyclic rings containing nitrogen such as pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, benzotriazolyl, pyrazolyl, imidazolyl, benzimidazolyl, indolyl, iso-indolyl, indolizinyl, prenyl, indazolyl, quinolyl, iso-quinolyl, quinoliziyl, phthalazyl, naphthylidinyl, quinoxalyl, quinazolinyl, cynnolinyl, pteridinyl, imidazotriazinyl, pyrazinopyridazinyl, acridinyl, phenanthridinyl, carbazolyl, carbazolinyl, perimidinyl, phenanthrolinyl, phenacinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, or pyrazolopyridinyl; (2) aromatic heterocyclic rings containing sulfur such as thienyl or benzothienyl; (3) aromatic heterocyclic rings containing oxygen such as furyl, pyranyl, cyclopentapyranyl, benzofuryl or iso-benzofuryl; and (4) aromatic heterocyclic rings containing 2 or more different hetero atoms such as thiazolyl, iso-thiazolyl, benzothiazolyl, benzthiadiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, oxazolyl, isoxazoyl, benzoxazolyl, oxadiazolyl, pyrazoloxadiazolyl, imidazothiazolyl, thienofuranyl, furopyrrolyl or pyridoxadinyl. In another embodiment, the 1 ,2-dihydropyridine compound used in the methods and compositions described herein is a compound of Formula (HI):
Figure imgf000054_0001
wherein X1, X2, X3, A1, A2, A3, R17 and R18 have the same meanings as defined in the above compound of Formula (II). In another embodiment, the invention provides the compounds of Formula (HI) wherein A1, A2 and A3 are each independently an optionally substituted Cβ-u aromatic hydrocarbon ring or 5- to 14-membered aromatic hetero ring. In another embodiment, the invention provides the compounds of Formula (DI) wherein A1, A2 and A3 are each independently phenyl, pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, furyl, naphthyl, quinolyl, iso- quinolyl, indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, imidazopyridyl, carbazolyl, cyclopentyl, cyclohexyl, cyclohexenyl, dioxinyl, adamantyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholyl; wherein each may optionally be substituted. In another embodiment, the invention provides the compounds of Formula (HI) wherein A1, A2 and A3 are each independently selected from:
Figure imgf000055_0001
each of which may optionally be substituted. In another embodiment, the invention provides the compounds of Formula (IH) wherein the bonding site of the substituent at A1, A2 and A3 are in the α-position of the carbon atom bonding to the group X1, X2 and X3, respectively. In another embodiment, the invention provides the compounds of Formula (HI) wherein X1, X2 and X3 are single bonds. In another embodiment, the invention provides the compounds of Formula (IH) wherein R7 and R18 are hydrogen.
In one embodiment, the 1 ,2-dihydropyridine compound used in the methods and compositions described herein is Compound A:
Figure imgf000055_0002
The IUPAC name for Compound A is 2-(2-oxo-l-phenyl-5-pyridin-2-yl-l,2-dihydropyridin-3- yl)benzonitrile. Compound A may also be referred to as 3-(2-cyanophenyl)-5-(2-pyridyl)-l- phenyl-l,2-dihydropyridin-2-one. Compound A is also known as perampanel.
Throughout the specification, the terms "Compound A," "2-(2-oxo-l-phenyl-5-pyridin-2- yl- 1 ,2-dihydropyridin-3 -yl)benzonitrile, " "3 -(2-cyanophenyl)-5-(2-pyridyl)- 1 -phenyl- 1 ,2- dihydropyridin-2-one," and "perampanel" are intended to include pharmaceutically acceptable salts thereof, stereoisomers thereof, pharmaceutically acceptable salts of stereoisomers thereof, hydrates thereof, hydrates of pharmaceutically acceptable salts thereof, stereoisomers of hydrates thereof, and stereoisomer of hydrates of pharmaceutically acceptable salts thereof. In another embodiment, the terms "Compound A, " "2-(2-oxo- 1 -phenyl-S-pyridin^-yl- 1 ,2-dihydropyridin- 3 -yl)benzonitrile, " "3 -(2-cyanophenyl)-5-(2-pyridyl)- 1 -phenyl- 1 ,2-dihydropyridin-2-one, " and "perampanel" are intended to include pharmaceutically acceptable salts thereof, hydrates thereof, and hydrates of pharmaceutically acceptable salts thereof.
In other embodiments, the 1,2-dihydropyridine compounds that are useful in the methods and compositions of the invention are 3-(2-cyanophenyl)-5-(2-methylsulfonylaminophenyl)-l- phenyl- 1 ,2-dihydropyridin-2-one; 3 -(2-chloro-3 -pyridyl)-5-(2-pyridyl)- 1 -phenyl- 1 ,2- dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l -phenyl-1 ,2-dihydropyridin-2-one; 3- (2-cyanophenyl)-5-(2-pyridyl)-l -(3-nitrophenyl)-l ,2-dihydropyridin-2-one; 3-(2-cyanophenyl)- 5-(2-pyridyl)-l-(3-aminophenyl)-l ,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l - (3 -methyls ulfonylaminophenyl)-l ,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l - (3-methylaminophenyl)-l ,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l -(3- dimethylaminophenyl)-l,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l-[3-(5- methoxymethyl-2-oxazolidinon-3-yl)-phenyl]-l,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5- (2-pyridyl)-l-(3-methoxycarbonylphenyl)-l,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2- pyridyl)-l-(3-methylaminocarbonylphenyl)-l,2-dihydropyridin-2-one; 3-(2-cyano-3-pyridyl)-5- (2-pyridyl)-l -phenyl-1 ,2-dihydropyridin-2-one; 3-(2-chlorophenyl)-5-(2-pyridyl)-l -(4- hydroxyphenyl)-l ,2-dihydropyridin-2-one; 3-(2-chlorophenyl)-5-(2-pyridyl)-l -(4- dimethylaminoethoxyphenyl)-l ,2-dihydropyridin-2-one; 3 -(2 -cyanophenyl)-5 -(2-pyridyl)- 1 -(3 - formylphenyl)-l ,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l -(3- hydroxymethylphenyl)-l,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l-(3- cyanomethylphenyl)-! ,2-dihydropyridine-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l -(3- acetylaminomethylphenyl)- 1 ,2-dihydropyridin-2-one; 3 -(2-cyanophenyl)-5 -(2-pyridyl)- 1 -(3 - methylsulfonylaminomethylphenyl)-l52-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)- 1 -(3-acetoxymethylphenyl)-l ,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l -(4- methylthiophenyl)-l,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l-(4- methylsulfonylpheny-l)-l ,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-formylthiophen-3- yl)-l -phenyl-1 ,2 -dihydropyridin-2-one; 3 -(2-cyanophenyl)-5-(2-diethylaminomethylthiophen-3 - yl)-l -phenyl- 1 ,2-dihydropyridin-2-one; 3 -(2-cyanophenyl)-5-(2-hy droxymethylthiophen-3 -yl)- 1 - phenyl- 1 ,2 -dihy dropyridine-2-one; 3 -(2-cyanophenyl)- 5 -(2 -pyridy 1) - 1 -b enzyl- 1 ,2- dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l-(3-pyridyl)-l,2-dihydropyridin-2-one; 3 -(2-cyanophenyl)-5-phenyl-(2-pyridyl)-l ,2-dihydropyridin-2-one; 3 -(2-cyanophenyl)- 1 ,5- diphenyl-l,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-methoxyphenyl)-l-phenyl-l,2- dihydropyridin-2-one; 3 -(2-cyanophenyl)-5 -(3 ,4-dimethoxyphenyl)- 1 -phenyl- 1 ,2- dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(thiophen-3-yl)-l -phenyl-1, 2-dihydropyridin-2 -one; 3-(2-cyanophenyl)-5-(2-fluorophenyl)-l -phenyl-1, 2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5- (thiophen-2-yl)-l -phenyl- l,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(3-furfuryl)-l-phenyl- 1 ,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-furfuryl)-l -phenyl-1 ,2-dihydropyridin-2 -one; 3 -(2-chlorophenyl)-5-(2-pyridyl)-l -phenyl-1 ,2-dihydropyridin-2-one; 3 -(2- methoxycarbonylphenyl)-5 -(2-pyridyl)-l -phenyl- 1 ,2-dihydropyridin-2-one; 3 -phenyl-5 -(2- pyridyl)-l -phenyl-1 ,2-dihydropyridin-2-one; 3-(2-fluorophenyl)-5-(2-pyridyl)-l -phenyl-1 ,2- dihydropyridin-2-one; 3 -(2-chlorophenyl)-5-(2-pyridyl)-l -(3 -methoxyphenyl)-l ,2- dihydropyridin-2-one; 3-(2-fluoro-3-pyridyl)-5-(2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one; 3-(4-methoxy-3-pyridyl)-5-(2-pyridyl)-l -phenyl-1, 2-dihydropyridin-2-one; 3-(2-fluoro-3- pyridyl)-5-(2-pyridyl)-l -(3-methoxyphenyl)-l ,2-dihydropyridin-2-one; 3-(2-fluoro-3-pyridyl)-5- (2-pyridyl)-l-(3-fluorophenyl)-l,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l-(4- fluorophenyl)-l,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l-(3-fluorophenyl)- 1 ,2 -dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l -(4-methoxyphenyl)-l ,2- dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l-(3-methoxy- phenyl)-l,2- dihydropyridin-2-one; 3-phenyl-5-(2-pyridyl)-l-(3-fluorophenyl- )-l,2-dihydropyridin-2-one; 3- (2-chlorophenyl)-5-(2-pyridyl)-l-(4-fluorophenyl)-l,2-dihydropyridin-2-one; 3-(2-cyanophenyl)- 5 -(2-pyridyl)- 1 -(4-formylphenyl)-l ,2-dihydropyridin-2-one; 3 -(2-cyanophenyl)-5 -(2-pyridyl)- 1 - (2-formylphenyl)-l ,2-dihydropyridin-2-one; 3 -(2-cyanophenyl)-5-(2-pyridyl)-l -(3- chlorophenyl)-l ,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l -(3-tolyl)-l ,2- dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l-(3-trifluoromethylphenyl)-l,2- dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l-(thiophen-3-yl)-l,2-dihydropyridin-2- one; 3 -(2-cyanophenyl)-5 -(2-pyridyl)- 1 -(3 -furfuryl)-l ,2-dihydropyridin-2-one; 3-(2- cyanophenyl)-5-(2-pyridyl)-l -(4-tolyl)-l ,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2- pyridyl)-l-(4-trifluoromethylphenyl)-l,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2- pyridyl)-l-(2-methoxypyridin-5-yl)-l,2-dihydropyri- din-2-one; 3-(2-cyanophenyl)-5-(2- pyridyl)-l-(pyrimidin-5-yl)-l,2-dihydrop- yridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l-(3- benzyloxymethylpyridin-5-yl)-l,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l-(2- ethylthiopyridin-5-yl)-l52-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl- )-l-(4- pyridyl)-l,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l-(3-methoxypyridin-5-yl)- 1 ,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l-(2-chloropyridin-5-yl)-l,2- dihydropyridin-2-one; 3 -(2-cyanophenyl)-5-(2-pyridyl)-l -(2-fluoropyridin-5-yl)-l ,2- dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l-(2-methoxyphenyl)-l,2- - dihydropyridin-2-one; 3-phenyl-5-(2-pyridyl)-l-(3-pyridyl)-l,2-dihydropyridin-2-one; 3-(2- chlorophenyl)-5 -(2-pyridyl)- 1 -(3 -pyridyl)- 1 ,2-dihydropyridin-2-one; 3 -(thiophen-3 -yl)-5-(2- pyridyl)-l -(3-pyridyl)-l ,2-dihydropyridin-2-one; 3-(2,6-dimethylphenyl)-5-(2-pyridyl)-l -(3- pyridyl)-l,2-dihydropyridin-2-one; 3-(2-cyanothiophen-3-yl)-5-(2-pyridyl)-l-(3-pyridyl)-l,2- dihydropyridin-2-one; 3-(2-fluoro-3-pyridyl)-5-(2-pyridyl)-l-(3-pyridyl)-l,2-dihydropyridin-2- one; 3-(2-chlorophenyl)-5-(2-pyridyl)-l-(3-hydroxyphenyl)-l- 52-dihydropyridin-2-one; 3-(2- chlorophenyl)-5 -(2-pyridyl)- 1 -(3 -dimethylaminoethoxyphenyl)-l ,2-dihydropyridin-2-one; 3 -(2- chlorophenyl)-5-(2-pyridyl)-l-(3-dimethylaminopropoxyphenyl)-l,2-dihydropyridin-2-one; 3-(2- cyanophenyl)-5-(2-pyridyl)-l-(2-hydroxymethylphenyl)-l:,2-dihydropyridin-2-one; 3-(2- cyanophenyl)-5-(2-pyridyl)-l -(4-cyanomethylphenyl)-l ,2-dihydropyridin-2-one; 3-(2- cyanophenyl)-5-(2-pyridyl)-l -(2-cyanomethylphenyl)-l ,2-dihydropyridin-2-one; 3 -(2- cyanophenyl)-5-(6-diethylaminomethyl-2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one; 3-(2- cyanophenyl)- 1 -phenyl-5 -(2-pyrimidinyl)- 1 ,2-dihydropyridin-2-one; 3 -(2-hydroxypyridin-6-yl)- l-phenyl-5-(2-pyridyl)-l,2-dihydropyridin-2-one; l-(2-aminobenzothiazol-6-yl)-3-(2- cyanophenyl)-5-(2-pyridyl)-l ,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l -(I - benzyl-1 ,2,3,6-tetrahydropyridin-5-yl)-l ,2-dihydropyridin-2-one; 3-[2-(5-methyl-l ,2,4- oxadiazol-3-yl)phenyl]-l -phenyl-5 -(2-pyridyl)- 1 ,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5- (6-methylpyridin-2-yl)-l-phenyl-l,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(5- methylpyridin-2-yl)-l-phenyl-l,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(3- hydroxypyridin-2-yl)-l-phenyl-l, 2 -dihydropyridin-2-one; 3-(2-cyanophenyl)-l-phenyl-5-(2- thiazolyl)-l ,2-dihydropyridin-2-one; 3 -(2-cyanophenyl)-5-(2-methoxypyridin-6-yl)-l -phenyl- 1 ,2-dihydropyridin-2-one; l-(4-aminophenyl)-3-(2-cyanophenyl)-5-(2-pyridyl)-l,2- dihydropyridin-2-one; 1 -(3-aminophenyl)-3-(2-cyanophenyl)-5-(2-pyrimidinyl)-l ,2- dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l -(2-aminotoluen-4-yl)-l- ,2- dihydropyridin-2-one; 3-(2-cyanophenyl)-l-[3-(dimethylaminoethoxy)phenyl]-5-(2-pyridyl)-l,2- dihydropyridin-2-one; 3 -(2-cyanophenyl)- 1 - [3 -(piperidinoethoxy)phenyl]-5-(2-pyridyl)- 1 ,2- dihydropyridin-2-one; 3 -(2-cyanophenyl)- 1 - [3 -(pyrrolidinoethoxy)phenyl]-5 -(2-pyridyl)- 1 ,2- dihydropyridin-2-one; 3 -(2-cyanophenyl)- 1 - [3 -(diisoproylaminoethoxy)phenyl]-5 -(- 2-pyridyl)- 1 ,2 -dihydropyridin-2-one; 3-(2-cyanophenyl)-l-[3-(4-piperidinobutyl-l-oxy)phenyl]-5-(2- pyridyl)-l ,2-dihydropyridin-2-one; 3 -(2-cyanophenyl)- 1 -(4-nitrophenyl)-5 -(2-pyridyl)- 1 ,2- dihydropyridin-2-one; l-phenyl-5-(2-pyridyl)-3-(2-thiazolyl)-l ,2-dihydropyridin-2-one; 3-(2- cyanophenyl)-l -(3-pyridyl)-5-(2-pyrimidinyl)-l ,2-dihydropyridin-2-one; 3-(2-fluoropyridin-3- yl)-l -phenyl-5-(2-pyrimidinyl)-l ,2-dihydropyridin-2-one; 3-(2-cyanopyridin-3-yl)-l -phenyl-5- (2-pyrimidinyl)- 1 ,2-dihydropyridin-2-one; 3 -(2-cyanophenyl)- 1 -(3 -nitrophenyl)-5 -(2- pyrimidinyl)-l ,2-dihydropyridin-2-one; 3-(2-nitrophenyl)-l -phenyl-5-(2-pyridyl)-l ,2- dihydropyridin-2-one; 3-(2-formylthiophen-3-yl)-5-(2-pyridyl)-l -phenyl- 1,2-dihydropyrid- in-2- one; 3-(2-cyanophenyl)-5-(2-pyridyl)-l-(2-naphthyl)-l52-dihydropyridin-2-one; 3-(2- cyanophenyl)-5-(2-pyridyl)-l-(l-naphthyl)-l,2-dihydropyridin-2-one; 5-(2-aminopyridin-6-yl)- 3 -(2-cyanophenyl)- 1 -phenyl- 1 ,2-dihydropyridin-2-one; 5-(2-bromopyridin-6-yl)-3-(2- cyanophenyl)-l-phenyl-l, 2 -dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-morphorinopyridin-6- yl)-l-phenyl-l,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-l-(3-hydoxyphenyl)-5-(2-pyridyl)- 1 ,2 -dihydropyridin-2-one; 3-(2-cyanophenyl)-l -[3-(4-piperidyloxy)]phenyl-5-(2-pyridyl)-l ,2- dihydropyridin-2-one; l-[3-(N-acetylpiperidin-4~yl-oxy)phenyl]-3-(2-cyanophenyl)-5-(2- pyridyl)- 1 ,2-dihydropyridin-2-one; 3 -(2-cyanophenyl)- 1 - {3 -[ 1 -(methanesufonyl)piperidin-4-yl- oxy]phenyl} -5 -(2-pyridyl)- 1 ,2-dihydropyridin-2~one; 1 -[3-(N-methylpiperidin-4-yl-oxy)pheny- l]-3-(2-cyanophenyl)-5-(2-pyridyl)-l,2-dihydropyridin-2-one; 3-(6-chloro-lH-benzimidazol-2- yl)-5 -(2-pyridyl)- 1 -phenyl- 1 ,2-dihydropyridin-2-one; 3 -(2-cyanophenyl)-5-(2-pyridyl)- 1 -(2- nitrotoluen-4-yl)-l ,2-dihydropyridin-2-one; 3-(2-cyanothiophen-3-yl)-5-(2-pyridyl)-l -phenyl- 1 ,2-dihydropyridin-2-one; 3-[2-(5-oxazolyl)phenyl]-l -phenyl-5-(2-pyridyl)-l,2-dihydropyridin- 2-one; 3-[2-(5-oxazolyl)thiophen-3-yl]-l-phenyl~5-(2-pyridyl)-l,2-dihydropyridin-2-one; and 3- (2-ethoxycarbonylvinylthiophen-3-yl)-5-(2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one.
The 1,2-dihydropyridine compounds and methods for making the 1,2-dihydropyridine compounds are described in US Patent No. 6,949,571 , US Publication No. 2004/0023973 , and PCT Publication No. WO 03/047577, WO 04/009553, WO 06/004100, WO 06/004107, WO 07/072868, WO 07/072869, WO 07/126060, and WO 08/093392, the disclosures of which are incorporated by reference herein in their entirety.
Methods for administering, dosing, and making other AMPA receptor antagonists such as quinoxalinedione aminoalkylphosphonates are described, for example, in WO 2005/094797 and WO 98/17672.
In other embodiments, the invention provides pharmaceutical compositions comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist, (ii) at least one other active ingredient that can be used to treat epilepsy, mental disorders or deficits in sensory organ, and (iii) at least one pharmaceutically acceptable excipient. The invention also provides combinations comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist and (ii) at least one other active ingredient that can be used to treat epilepsy, mental disorders or deficits in sensory organ; wherein the compounds may be administered separately (e.g., simultaneously, sequentially) to a patient to treat the diseases or disorders described. The invention provides kits (e.g., commercial packages) comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist, (ii) at least one other active ingredient that can be used to treat epilepsy, mental disorders or deficits in sensory organ; and (iii) instructions for the simultaneous, separate or sequential use of (i) and (ii) in the treatment of the diseases and disorders described herein. The AMPA receptor antagonist can be any described herein. For example, the 1,2-dihydropyridine compound can be a compound of Formula (I), a compound of Formula (II), a compound of Formula (IH), or Compound A. In one embodiment, the invention provides pharmaceutical compositions comprising a therapeutically effective amount of: (i) 3-(2- cyanophenyl)-5-(2-pyridyl)-l -phenyl- l,2-dihydropyridin-2-one; (ii) at least one other active ingredient that can be used to treat epilepsy, mental disorders or deficits in sensory organ; and (iii) at least one pharmaceutically acceptable excipient.
One or more other active ingredients can be used in conjunction with the AMPA receptor antagonists of the invention for the treatment or prophylaxis of epilepsy, mental disorders or deficits in sensory organ.
Exemplary active ingredients useful to treat epilepsy, mental disorders or deficits in sensory organ include Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1 , ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide, or two or more thereof. These active ingredients can be used in the form of a pharmaceutically acceptable salt, hydrate, or solvate (where appropriate).
In other embodiments, the invention provides pharmaceutical compositions comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist, (ii) optionally one or more other active ingredients useful to treat epilepsy, mental disorders or deficits in sensory organ, and (iii) at least one pharmaceutically acceptable excipient. The invention also provides combinations comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist and (ii) optionally one or more other active ingredients useful to treat epilepsy, mental disorders or deficits in sensory organ; wherein the compounds may be administered separately (e.g., simultaneously, sequentially) to a patient to treat the diseases or disorders described. The invention provides kits (e.g., commercial packages) comprising a therapeutically effective amount of: (i) at least one AMPA receptor antagonist, (ii) optionally one or more other active ingredients useful to treat epilepsy, mental disorders or deficits in sensory organ; and (iii) instructions for the simultaneous, separate or sequential use of (i) and (ii) in the treatment of the diseases and disorders described herein. The AMPA receptor antagonist can be any described herein. For example, the 1,2-dihydropyridine compound can be a compound of Formula (I), a compound of Formula (II), a compound of Formula (IE), or Compound A. In one embodiment, the invention provides pharmaceutical compositions comprising a therapeutically effective amount of: (i) 3 -(2-cyanophenyl)-5 -(2-pyridyl)- 1 -phenyl- 1 ,2-dihydropyridin-2-one; (ii) optionally one or more other active ingredients useful to treat epilepsy, mental disorders or deficits in sensory organ; and (iii) at least one pharmaceutically acceptable excipient.
The invention provides methods for the treatment and/or prophylaxis of epilepsy, mental disorders or deficits in sensory organ and one or more symptoms of epilepsy, mental disorders or deficits in sensory organ in a patient in need thereof by administering a therapeutically effective amount of: (a) at least one AMPA receptor antagonist, and (b) optionally one or more other active ingredients useful to treat epilepsy, mental disorders or deficits in sensory organ. The methods for the treatment of epilepsy, mental disorders or deficits in sensory organ and one or more symptoms of epilepsy, mental disorders or deficits in sensory organ include (i) methods for reducing the frequency of epilepsy, mental disorders or deficits in sensory organ, or one or more symptoms of epilepsy, mental disorders or deficits in sensory organ, (ii) methods for reducing the severity of epilepsy, mental disorders or deficits in sensory organ, or one or more symptoms of epilepsy, mental disorders or deficits in sensory organ, (iii) methods for reducing the duration of epilepsy, mental disorders or deficits in sensory organ, or one or more symptoms of epilepsy, mental disorders or deficits in sensory organ, (iv) methods for reducing the frequency and severity of epilepsy, mental disorders or deficits in sensory organ, or one or more symptoms of epilepsy, mental disorders or deficits in sensory organ, (v) methods for reducing the frequency and duration of epilepsy, mental disorders or deficits in sensory organ, or one or more symptoms of epilepsy, mental disorders or deficits in sensory organ, (vi) methods for reducing the severity and duration of epilepsy, mental disorders or deficits in sensory organ, or one or more symptoms of epilepsy, mental disorders or deficits in sensory organ, and (vii) methods for reducing the frequency, severity and duration of epilepsy, mental disorders or deficits in sensory organ, or one or more symptoms of epilepsy, mental disorders or deficits in sensory organ. The AMPA receptor antagonist and, optionally, one or more other active ingredients, can be administered separately to the patient or may be administered in the form of a pharmaceutical composition. The dosage form of the formulation included in the combination, kit and/or pharmaceutical composition of the invention is not particularly limited. The combination, kit and/or pharmaceutical composition of the invention is useful as a combination, kit and/or a pharmaceutical composition for treating neuropathic pain; for the prophylaxis of neuropathic pain; and for delaying the onset of neuropathic pain. The combination, kit and/or pharmaceutical composition of the invention may be used as a drug for treating neuropathic pain; for the prophylaxis of neuropathic pain; and for delaying the onset of neuropathic pain.
The combination, kit and/or pharmaceutical composition of the invention may be administered to a patient. The combination, kit and/or pharmaceutical composition of the invention may be used through oral or parenteral administration. When the combination, kit and/or pharmaceutical composition of the invention is used, the given dose of the compound of the invention differs depending on the degree of the symptom, age, sex, weight and sensitivity difference of the patient, administration mode, administration period, administration interval, nature, prescription and the type of the pharmaceutical formulation, and the type of the active element.
The pharmaceutical composition of the invention may be made into various forms, for example, into solid oral formulations, injectable solution or the like.
The AMPA receptor antagonists and one or more other active ingredients of the invention can be administered orally, topically, parenterally, by inhalation (nasal or oral), or rectally in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The term parenteral includes subcutaneous, intravenous, intramuscular, intrathecal, intrasternal injection, or infusion techniques.
The daily dose of the AMPA receptor antagonists of the invention (e.g., 3-(2- cyanopheny l)-5 -(2 -pyridyl)-l -phenyl- 1 ,2-dihydropyridin-2-one) is usually 30 μg to 10 g/day; 100 μg to 5 g/day; or 100 μg to 100 mg/day, in the case of oral administration. For administration by injection, the daily dose is usually 30 μg to 1 g/day; 100 μg to 500 mg/day; or 100 μg to 30 mg/day. The compounds are administered once daily or in several portions a day. When used in the context of a dosage amount, the numerical weight refers to the weight of the 1,2-dihydropyridine, exclusive of any salt, counterion, hydrate, and the like. Therefore to obtain the equivalent of 500 mg of 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one, it would be necessary to use more than 500 mg of a pharmaceutically acceptable salt and/or hydrate of the compound, due to the additional weight of the pharmaceutically acceptable salt and/or hydrate.
The daily dose of the other active ingredients that are useful for treating epilepsy, mental disorders or deficits in sensory organ (e.g., Valproate semisodium, Phenytoin, Carbamazepine, Oxcarbazepine, Licarbazepine, Lamotrigine, Gabapentin, Topiramate, Levetiracetam,
Rufϊnamide, Phenobarbital and Clobazam) are usually 400 mg/day to 1200 mg/day for Valproate semisodium; 200 mg/day to 300 mg/day for Phenytoin; 200 mg/day to 300 mg/day for Fosphenytoin; 200 mg/day to 1200 mg/day for Carbamazepine; 600 mg/day to 1200 mg/day for Oxcarbazepine; 750 mg/day to 2000 mg/day for Licarbazepine; 25 mg/day to 200 mg/day for Lamotrigine; 600 mg/day to 2400 mg/day for Gabapentin; 50 mg/day to 600 mg/day for
Topiramate; 1000 mg/day to 3000 mg/day for Levetiracetam; 100 mg/day to 3200 mg/day for Rufinamide; 30 mg/day to 200 mg/day for Phenobarbital; 250 mg/day to 2000 mg/day for Primidone; or 10 mg/day to 40 mg/day for Clobazam. The compounds are administered once daily, in several portions a day or continuously. When used in the context of a dosage amount, the numerical weight refers to the weight of the other active ingredients that are useful for treating epilepsy, mental disorders or deficits in sensory organ, exclusive of any salt, counterion, and the like. Therefore to obtain the equivalent of the other active ingredients that are useful for treating epilepsy, mental disorders or deficits in sensory organ, it would be necessary to use more than above noted amount of drugs, due to the additional weight of the salts. When administered to a child, the dose may possibly be lower than that for an adult. The actual method for administration may fluctuate widely and may depart from the preferred method described herein.
Any other compounds described herein may be administered in doses well known in the art by reference, for example, to package inserts of commercially available compounds, The Physician's Desk Reference, to patents describing dosing for the compounds, and to journal articles describing dosing for the compounds.
In one embodiment, the mode of administration is by injection, such as subcutaneous injection, intramuscular injection, intravenous injection, or intra-arterial injection. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the art using suitable dispersing or wetting agents, suspending agents (e.g., methylcellulose, Polysorbate 80, hydroxyethylcellulose, acacia, powdered tragacanth, sodium carboxymethylcellulose, polyoxytehylene sorbitan monolaurate and the like), pH modifiers, buffers, solubilizing agents (e.g., polyoxyethylene hydrogenated castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol, an ethyl ester of castor oil fatty acid, and the like), stabilizers (e.g., sodium sulfite and sodium metasulfite; examples of the preservative include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol, chlorocresol, and the like), tonicity agents and preservatives. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose any bland fixed oil can be used including synthetic mono- or diglycerides, in addition, fatty acids, such as oleic acid, can be used in the preparation of injectables. The preparations can be lyophilized by methods known in the art.
In order to prepare a solid oral formulation, an excipient, and if necessary, a binder, disintegrant, lubricant, colorant, a flavoring agent and the like are added to the principal agent, and then made into a tablet, a coated tablet, granule, fine granule, dispersant, a capsule or the like according to a conventional method.
For example, lactose, cornstarch, sucrose, glucose, sorbit, crystalline cellulose, silicon dioxide or the like may be used as the excipient; for example, polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropylmethyl cellulose or the like may be used as the binder; for example, magnesium stearate, talc, silica or the like may be used as the lubricant; those that are allowed to be added to drags may be used as the colorant; and for example, cocoa powder, menthol, aromatic acid, peppermint oil, camphor, cinnamon powder or the like may be used as the flavoring agent. Of course, if necessary, these tablets and granule may be coated appropriately with sugar coating, gelatin coating or else. Solid dosage forms for oral administration can include chewing gum, capsules, tablets, sublingual tablets, powders, granules, and gels. In such solid dosage forms, the active compound can be admixed with one or more inert diluents such as lactose or starch. As is normal practice, such dosage forms can also comprise other substances including lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents. The tablets can be prepared with enteric or film coatings, preferably film coatings.
To make tablets, the compounds can be admixed with pharmaceutically acceptable carriers known in the art such as, for example, vehicles (e.g., lactose, white sugar, mannitol, glucose, starches, calcium carbonate, crystalline cellulose, silicic acid, and the like), binders (e.g., water, ethanol, myranol, glucose solution, starch solution, gelatin solution, polyvinylpyrrolidone, and the like), disintegrators (e.g., dry starch, sodium, alginate, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride, starches, lactose, and the like), absorption promoters (e.g., quaternary ammonium base, sodium laurylsulfate, and the like), wetting agents (e.g. glycerin, starches, and the like), lubricants (e.g., stearates, polyethylene glycol, and the like), and flavoring agents (e.g., sweeteners). The tablets can be in the form of a conventional tablet, a molded tablet, a wafer and the like.
Sublingual administration refers to the administration in the mouth (e.g., under the tongue, between the cheek and gum, between the tongue and roof of the mouth). The highly vascular mucosal lining in the mouth is a convenient location for the compounds to be administered into the body.
In other embodiments, the solid dosage form can be packaged as granules or a powder in a pharmaceutically acceptable carrier, where the granules or powder are removed from the packaging and sprinkled on food or mixed with a liquid, such as water or juice, or where the granules are inserted into capsules. In this embodiment, the compounds described herein can be mixed with flavoring or sweetening agents. The packaging material can be plastic, coated paper, or any material that prevents water or moisture from reaching the granules and/or powder.
Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, sublingual solutions, suspensions, and syrups containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. To make sublingual solutions, the compounds can be admixed with various carriers, excipients, pH adjusters, and the like (e.g., water, sugar, lactic acid, acetic acid, fructose, glucose, saccharin, polyethylene glycol, propylene glycol, alcohol, bentonite, tragacanth, gelatin, alginates, aspartame, sorbitol, methylparaben, propylparaben, sodium benzoate, artificial flavoring and coloring agents).
Each of the patents, patent applications, and publications cited herein are incorporated by reference herein in their entirety.
It will be apparent to one skilled in the art that various modifications can be made to the invention without departing from the spirit or scope of the appended claims.

Claims

Claims
1. A pharmaceutical composition comprising: (A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof;
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide,
Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940,
AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof; and
(C) one or more pharmaceutically acceptable carriers.
2. The pharmaceutical composition of claim 1, wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or the hydrate of the pharmaceutically acceptable salt thereof is a compound of Formula (IEI), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; wherein the compound of Formula (HT) is:
Figure imgf000069_0001
wherein X1, X2 and X3 are each independently a single bond, an optionally substituted C^ alkylene, an optionally substituted C2-6 alkenylene, an optionally substituted C2-6 alkynylene, -O, -S-, -CO-, -SO-, -SO2-, -N(R6)-, -N(R7)-C0-, -CO-N(R8)-, -N(R9)-CH2-, -CH2-N(R10)-, -CH2-CO-, -CO-CH2-, -N(Rπ)-S(0)m-, -S(O)n-N(R12)-, -CH2-S(O)P-, -S(O)q-CH2-, -CH2-O-, -0-CH2-, -N(R13)-CO-N(R14)- or -N(R15)-CS-N(R16); R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently hydrogen, C1-O alkyl, or C1^ alkoxy; m, n, p and q are each independently an integer of 0, 1 or 2; A1, A2 and A3 are each independently an optionally substituted C3-s cycloalkyl, an optionally substituted C3-s cycloalkenyl, an optionally substituted 5- to 14-membered non-aromatic heterocyclic ring, an optionally substituted Cβ-14 aromatic hydrocarbocyclic ring, or an optionally substituted 5 to 14-membered aromatic heterocyclic ring; and R17 and R18 are each independently hydrogen, halogen, or C1^ alkyl.
3. The pharmaceutical composition of claim 1 , wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or hydrate of a pharmaceutically acceptable salt thereof is 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2- dihydropyridin-2-one, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
4. The pharmaceutical composition of claim 1, wherein the composition is used for treating epilepsy or one or more symptoms of epilepsy.
5. The pharmaceutical composition of claim 1, wherein the composition is used for treating partial seizure or one or more symptoms of partial seizure.
6. The pharmaceutical composition of claim 5, wherein the partial seizure is a simple partial seizure, complex partial seizure, or a partial seizure secondarily generalized.
7. The pharmaceutical composition of claim 1, wherein the composition is used for treating generalized seizure or one or more symptoms of generalized seizure.
8. The pharmaceutical composition of claim 7, wherein the generalized seizure is an absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures or atonic seizures.
9. The pharmaceutical composition of claim 1, wherein the composition is used for treating mental disorders or one or more symptoms of a mental disorder.
10. The pharmaceutical composition of claim 9, wherein the mental disorders is mood disorders, anxiely disorders, personality disorders, schizophrenia and other psychotic disorders, or substance-related disorders.
11. The pharmaceutical composition of claim 10, wherein the mood disorders is depression or bipolar disorder.
12. The pharmaceutical composition of claim 1, wherein the composition is used for treating deficits in sensory organ or one or more symptoms of a deficits in sensory organ.
13. The pharmaceutical composition of claim 12, wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
14. The pharmaceutical composition of claim 12, wherein the deficits in sensory organ is Glaucoma or Diabetic retinopathy.
15. The pharmaceutical composition of claim 1, wherein the composition is adapted to be associated with a treatment regimen.
16. A combination comprising:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan,
Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol,
Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfmamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
17. The combination of claim 16, wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or the hydrate of the pharmaceutically acceptable salt thereof is a compound of Formula (DI), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; wherein the compound of Formula (HI) is:
Figure imgf000072_0001
wherein X1, X2 and X3 are each independently a single bond, an optionally substituted Ci^ alkylene, an optionally substituted C2-6 alkenylene, an optionally substituted C2-6 alkynylene, -O-, -S-, -CO-, -SO-, -SO2-, -N(R6)-, -N(R7)-CO-, -CO-N(R8)-, -N(R9)-CH2-, -CH2-N(R10)-, -CH2-CO-, -CO-CH2-, -N(Rπ)-S(O)m-, -S(O)n-N(R12)-, -CH2-S(O)1,-, -S(O)q-CH2-, -CH2-O-, -0-CH2-, -N(R13)-CO-N(R14)- or -N(R15)-CS-N(R16); R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently hydrogen, Ci-6 alkyl, or Ci-6 alkoxy; m, n, p and q are each independently an integer of 0, 1 or 2; A1, A2 and A3 are each independently an optionally substituted C3-8 cycloalkyl, an optionally substituted C3-s cycloalkenyl, an optionally substituted 5- to 14-membered non -aromatic heterocyclic ring, an optionally substituted Cg-I4 aromatic hydrocarbocyclic ring, or an optionally substituted 5 to 14-membered aromatic heterocyclic ring; and R17 and R18 are each independently hydrogen, halogen, or Ci-6 alkyl.
18. The combination of claim 16, wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or hydrate of a pharmaceutically acceptable salt thereof is 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
19. The combination of claim 16, wherein (A) and (B) are administered separately to a patient or are administered to a patient in the form of a pharmaceutical composition.
20. The combination of claim 16, wherein the combination is used for treating epilepsy or one or more symptoms of epilepsy.
21. The combination of claim 16, wherein the combination is used for treating partial seizure or one or more symptoms of partial seizure.
22. The combination of claim 21, wherein the partial seizure is a simple partial seizure, complex partial seizure, or a partial seizure secondarily generalized.
23. The combination of claim 16, wherein the combination is used for treating generalized seizure or one or more symptoms of generalized seizure.
24. The combination of claim 23, wherein the generalized seizure is an absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures or atonic seizures.
25. The combination of claim 16, wherein the combination is used for treating mental disorders or one or more symptoms of a mental disorder.
26. The combination of claim 25, wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance-related disorders.
27. The combination of claim 26, wherein the mood disorders is depression or bipolar disorder.
28. The combination of claim 16, wherein the combination is used for treating deficits in sensory organ or one or more symptoms of a deficits in sensory organ.
29. The combination of claim 28, wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
30. The combination of claim 28, wherein the deficits in sensory organ is Glaucoma or Diabetic retinopathy.
31. The combination of claim 16, wherein the combination is adapted to be associated with a treatment regimen.
32. Use of compounds (A) and (B) for producing a pharmaceutical composition in the treatment of epilepsy or one or more symptoms of epilepsy, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN OOl, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
33. Use of compounds (A) and (B) for producing a pharmaceutical composition in the treatment of partial seizure or one or more symptoms of partial seizure, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine,
Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BlBN 4096, Bicifadine, BVT 115959, C-ρeρtide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A3 QR 3.33, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
34. The use of claim 33, wherein the partial seizure is a simple partial seizure, complex partial seizure, or a partial seizure secondarily generalized.
35. Use of compounds (A) and (B) for producing a pharmaceutical composition in the treatment of generalized seizure or one or more symptoms of generalized seizure, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufmamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
36. The use of claim 35, wherein the generalized seizure is an absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures or atonic seizures.
37. Use of compounds (A) and (B) for producing a pharmaceutical composition in the treatment of mental disorders or one or more symptoms of a mental disorder, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan,
Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol,
Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic add, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-ρeptide, Cariprazine, CNS 5161, CX 1010, Devazepide,
Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfmamide, RG2417, SB 509, Seletracetam, SLV 313, SRN OOl, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940,
AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
38. The use of claim 37, wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance- related disorders.
39. The use of claim 38, wherein the mood disorders is depression or bipolar disorder.
40. Use of compounds (A) and (B) for producing a pharmaceutical composition in the treatment of deficits in sensory organ or one or more symptoms of a deficits in sensory organ, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan,
Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethoφhan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide,
Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfϊnamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940,
AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
41. The use of claim 40, wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
42. The use of claim 40, wherein the deficits in sensory organ is Glaucoma or
Diabetic retinopathy.
43. The use of any one of claims 32 to 42, wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or the hydrate of the pharmaceutically acceptable salt thereof is a compound of Formula (HI), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; wherein the compound of Formula (HI) is:
Figure imgf000080_0001
wherein X1, X2 and X3 are each independently a single bond, an optionally substituted C1^ alkylene, an optionally substituted C2-6 alkenylene, an optionally substituted C2-6 alkynylene, -O-, -S-, -CO-, -SO-, -SO2-, -N(R6)-, -N(R7)-C0-, -CO-N(R8)-, -N(R9)-CH2-, -CH2-N(R10)-, -CH2-CO-, -CO-CH2-, -N(Ru)-S(0)m-, -S(O)n-N(R12)-, -CH2-S(O)P-, -S(O)q-CH2-, -CH2-O-, -0-CH2-, -N(R13)-CO-N(R14)- or -N(R15)-CS-N(R16); R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently hydrogen, Ci-β alkyl, or Ci-6 alkoxy; m, n, p and q are each independently an integer of 0, 1 or 2; A1, A2 and A3 are each independently an optionally substituted C3..8 cycloalkyl, an optionally substituted C3..8 cycloalkenyl, an optionally substituted 5- to 14-membered non-aromatic heterocyclic ring, an optionally substituted C6-i4 aromatic hydrocarbocyclic ring, or an optionally substituted 5 to 14-membered aromatic heterocyclic ring; and R17 and R18 are each independently hydrogen, halogen, or C1^ alkyl.
44. The use of any one of claims 32 to 42, wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or hydrate of a pharmaceutically acceptable salt thereof is 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
45. The use of any one of claims 32 to 42, wherein (A) and (B) are administered separately to a patient or are administered to a patient in the form of a pharmaceutical composition.
46. The use of any one of claims 32 to 42, wherein the treatment is part of a treatment regimen.
47. Compounds (A) and (B) for use in the treatment of epilepsy or one or more symptoms of epilepsy, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine,
Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodiuni/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1 , ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peρtide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfϊnamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
48. Compounds (A) and (B) for use in the treatment of partial seizure or one or more symptoms of partial seizure, wherein (A) and (B) are: (A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropic Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafϊnil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide,
Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940,
AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
49. The compound of claim 48, wherein the partial seizure is a simple partial seizure, complex partial seizure, or a partial seizure secondarily generalized.
50. Compounds (A) and (B) for use in the treatment of generalized seizure or one or more symptoms of generalized seizure, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan,
Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol,
Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
51. The compound of claim 50, wherein the generalized seizure is an absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures or atonic seizures.
52. Compounds (A) and (B) for use in the treatment of mental disorders or one or more symptoms of a mental disorder, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine,
Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV I3 ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
53. The compound of claim 52, wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance-related disorders.
54. The compound of claim 53, wherein the mood disorders is depression or bipolar disorder.
55. Compounds (A) and (B) for use in the treatment of deficits in sensory organ or one or more symptoms of a deficits in sensory organ, wherein (A) and (B) are:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A3 Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
56. The compound of claim 55, wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
57. The compound of claim 55, wherein the deficits in sensory organ is Glaucoma or Diabetic retinopathy.
*
58. The compound of any one of claims 47 to 57, wherein the treatment is part of a treatment regimen.
59. A kit comprising the pharmaceutical composition of any one of claims 1 to 15 or the combination of any one of claims 16 to 31.
60. The kit of claim 59, wherein the kit is adapted to be associated with a treatment regimen.
61. A method for treating epilepsy or one or more symptoms of epilepsy, comprising administering to a patient in need thereof a therapeutically effective amount of: (A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufϊnamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butoφhanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211 , GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
62. A method for treating partial seizure or one or more symptoms of partial seizure, comprising administering to a patient in need thereof a therapeutically effective amount of: (A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and (B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam,
Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butoφhanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfmamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
63. The method of claim 62, wherein the partial seizure is a simple partial seizure, complex partial seizure, or a partial seizure secondarily generalized.
64. A method for treating generalized seizure or one or more symptoms of generalized seizure, comprising administering to a patient in need thereof a therapeutically effective amount of: (A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butoφhanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211 , GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfmamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
65. The method of claim 64, wherein the generalized seizure is an absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures or atonic seizures.
66. A method for treating mental disorders or one or more symptoms of a mental disorder, comprising administering to a patient in need thereof a therapeutically effective amount of:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine,
Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lomoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropic Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethoφhan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butoφhanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1, ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633 F, Prochlorperazine, Prosaptide TXl 4 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
67. The method of claim 66, wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance- related disorders.
68. The method of claim 67, wherein the mood disorders is depression or bipolar disorder.
69. A method for treating deficits in sensory organ or one or more symptoms of a deficits in sensory organ, comprising administering to a patient in need thereof a therapeutically effective amount of:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and
(B) Almotriptan, Aripiprazole, Botulinum toxin A, Carbamazepine, Diazepam, Diclofenac, Dihydroergotamine mesylate, Dronabinol, Dronabinol/cannabidiol, Duloxetine, Eletriptan, Epalrestat, Ethosuximide, Felbamate, Fentanyl, Fosphenytoin, Frovatriptan, Gabapentin, Lamotrigine, Levacecarnine, Levetiracetam, Lomerizine, Lornoxicam, Meloxicam, Memantine, Mexiletine, MTR 104, Naratriptan, Neurotropin, Olanzapine, Olanzapine/fluoxetine, Oxcarbazepine, Paliperidone, Pregabalin, Quetiapine, Reboxetine, Risperidone, Rizatriptan, Rufinamide, Sumatriptan, Tiagabine, Topiramate, Valproate semisodium, Vigabatrin, Ziprasidone, Zolmitriptan, Armodafinil, Naproxen sodium/metoclopramide, Stiripentol, Bifeprunox, Desvenlafaxine, Dextromethorphan/quinidine, Lacosamide, MT 300, Naproxen sodium/sumatriptan, NGX 4010, Valproic acid, Asenapine, Brivaracetam, Butorphanol intranasal, Carisbamate, Eslicarbazepine acetate, Licarbazepine, LL 2011, MK 0974, Ranirestat, Retigabine, Tapentadol, XP 13512, Zenarestat, ABT 894, ACV 1 , ADX 10059, AGN 203818, AL 208, ALGRX 4975, Alprostadil, Amitriptyline/ketamine, Becampanel, BIBN 4096, Bicifadine, BVT 115959, C-peptide, Cariprazine, CNS 5161, CX 1010, Devazepide, Dihydroergotamine inhalation, DP-VPA, Galantamine, Ganaxolone, GRC 6211, GW 274150, Ibudilast, Indantadol, KRN 5500, Loxapine, MCC 257, MEM 1003, metabotropic glutamate receptor 3 antagonist, NS 1209, Perzinfotel, PNU 142633F, Prochlorperazine, Prosaptide TX14 A, QR 333, Ralfinamide, RG 2417, SB 509, Seletracetam, SLV 313, SRN 001, SRN 002, T 2000, TAK 428, TAK 583, Talampanel, Tezampanel, Tonabersat, ACR 325, AST 726, AZD 1940, AZD 9272, BF 1, Dihydroergotamine, Dronabinol sublingual, EVT 101, FHPC 01, GW 273629, HEPP, HF 0299, ICA 105665, KD 7040, Ketamine/butamben, LY 466195, NGX 426, NP 101, NXN 188, PF 4480682, SD 118, selective norepinephrine reuptake inhibitor, SLV 314, Tramadol, TRO 19622, Phenobarbital, Primidone, Clobazam, Clonazepam, Nitrazepam, Acetazolamide; or two or more thereof.
70. The method of claim 69, wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
71. The method of claim 69, wherein the deficits in sensory organ is Glaucoma or Diabetic retinopathy.
72. The method of any one of claims 61 to 71 , wherein the treatment is part of a treatment regimen and the administration involves a series of administrations.
73. A pharmaceutical composition for treating mental disorders or one or more symptoms of a mental disorder comprising: an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers.
74. The pharmaceutical composition of claim 73, wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance-related disorders.
75. The pharmaceutical composition of claim 74, wherein the mood disorders is depression or bipolar disorder.
76. A pharmaceutical composition for treating deficits in sensory organ or one or more symptoms of a deficits in sensory organ comprising: an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers.
77. The pharmaceutical composition of claim 76, wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
78. The pharmaceutical composition of claim 76, wherein the deficits in sensory organ is Glaucoma or Diabetic retinopathy.
79. The pharmaceutical composition of any one of claims 73 to 78, wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or the hydrate of the pharmaceutically acceptable salt thereof is a compound of Formula (DI), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; wherein the compound of Formula (JS) is:
Figure imgf000093_0001
wherein X1, X2 and X3 are each independently a single bond, an optionally substituted C^ alkylene, an optionally substituted C2-6 alkenylene, an optionally substituted C2-6 alkynylene, -O-, -S-, -CO-, -SO-, -SO2-, -N(R6)-, -N(R7)-C0-, -CO-N(R8)-, -N(R9)-CH2-, -CH2-N(R10)-, -CH2-CO-, -CO-CH2-, -N(R11VS(O)1n-, -S(O)n-N(R12)-, -CH2-S(O)p-, -S(O)q-CH2-, -CH2-O-, -0-CH2-, -N(R13)-CO-N(R14)- or -N(R15)-CS-N(R16); R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently hydrogen, C1-O alkyl, or C1^ alkoxy; m, n, p and q are each independently an integer of 0, 1 or 2; A1, A2 and A3 are each independently an optionally substituted C3-8 cycloalkyl, an optionally substituted C3-S cycloalkenyl, an optionally substituted 5- to 14-membered non-aromatic heterocyclic ring, an optionally substituted Cβ-u aromatic hydrocarbocyclic ring, or an optionally substituted 5 to 14-membered aromatic heterocyclic ring; and R17 and R18 are each independently hydrogen, halogen, or C1^ alkyl.
80. The pharmaceutical composition of any one of claims 73 to 78, wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or hydrate of a pharmaceutically acceptable salt thereof is 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2- dihydropyridin-2-one, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
81. The pharmaceutical composition of any one of claims 73 to 78, wherein the composition is adapted to be associated with a treatment regimen.
82. Use of compound (A) for producing a pharmaceutical composition in the treatment of mental disorders or one or more symptoms of a mental disorder, wherein (A) is:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
83. The use of claim 82, wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance- related disorders.
84. The use of claim 83, wherein the mood disorders is depression or bipolar disorder.
85. Use of compound (A) for producing a pharmaceutical composition in the treatment of deficits in sensory organ or one or more symptoms of a deficits in sensory organ, wherein (A) is:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
86. The use of claim 85, wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
87. The use of claim 85, wherein the deficits in sensory organ is Glaucoma or Diabetic retinopathy.
88. The use of any one of claims 82 to 87, wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or the hydrate of the pharmaceutically acceptable salt thereof is a compound of Formula (DI), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof; wherein the compound of Formula (HI) is:
Figure imgf000095_0001
wherein X1, X2 and X3 are each independently a single bond, an optionally substituted C1^ alkylene, an optionally substituted C2.6 alkenylene, an optionally substituted C2-6 alkynylene, -O-5 -S-, -CO-, -SO-, -SO2-, -N(R6)-, -N(R7)-C0-, -CO-N(R8)-, -N(R9)-CH2-, -CH2-N(R10)-, -CH2-CO-, -CO-CH2-, -N(Rπ)-S(O)in-, -S(O)n-N(R12)-, -CH2-S(O)P-, -S(O)q-CH2-, -CH2-O-, -0-CH2-, -N(R13)-CO-N(R14)- or -N(R15)-CS-N(R16); R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each independently hydrogen, Ci-β alkyl, or Ci-g alkoxy; m, n, p and q are each independently an integer of O, 1 or 2; A1, A2 and A3 are each independently an optionally substituted C3-8 cycloalkyl, an optionally substituted C3..8 cycloalkenyl, an optionally substituted 5- to 14-membered non-aromatic heterocyclic ring, an optionally substituted Cβ-u aromatic hydrocarbocyclic ring, or an optionally substituted 5 to 14-membered aromatic heterocyclic ring; and R17 and R18 are each independently hydrogen, halogen, or
Figure imgf000095_0002
alkyl.
89. The use of any one of claims 82 to 87, wherein the AMPA receptor antagonist, pharmaceutically acceptable salt thereof, hydrate thereof, or hydrate of a pharmaceutically acceptable salt thereof is 3-(2-cyanophenyl)-5-(2-pyridyl)-l-phenyl-l,2-dihydropyridin-2-one, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
90. The use of any one of claims 82 to 87, wherein the treatment is part of a treatment regimen.
91. Compound (A) for use in the treatment of mental disorders or one or more symptoms of a mental disorder, wherein (A) is: (A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
92. The compound of claim 91, wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance-related disorders.
93. The compound of claim 92, wherein the mood disorders is depression or bipolar disorder.
94. Compound (A) for use in the treatment of deficits in sensory organ or one or more symptoms of a deficits in sensory organ, wherein (A) is:
(A) an AMPA receptor antagonist, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of a pharmaceutically acceptable salt thereof.
95. The compound of claim 94, wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit. .
96. The compound of claim 94, wherein the deficits in sensory organ is Glaucoma or Diabetic retinopathy.
97. The compound of any one of claims 91 to 96, wherein the treatment is part of a treatment regimen.
98. A kit for treating mental disorders or one or more symptoms of a mental disorder comprising the pharmaceutical composition of any one of claims 73 to 75 and 79 to 81.
99. The kit of claim 98, wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance- related disorders.
100. The kit of claim 99, wherein the mood disorders is depression or bipolar disorder.
101. A kit for treating deficits in sensory organ or one or more symptoms of a deficits in sensory organ comprising the pharmaceutical composition of any one of claims 76 to 81.
102. The kit of claim 101, wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
103. The kit of claim 101, wherein the deficits in sensory organ is Glaucoma or Diabetic retinopathy.
104. The kit of any one of claims 98 to 103, wherein the kit is adapted to be associated with a treatment regimen.
105. A method for treating mental disorders or one or more symptoms of a mental disorder comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of claims 73 to 75 and 79 to 81.
106. The method of claim 105, wherein the mental disorders is mood disorders, anxiety disorders, personality disorders, schizophrenia and other psychotic disorders, or substance- related disorders.
107. The method of claim 106, wherein the mood disorders is depression or bipolar disorder.
108. A method for treating deficits in sensory organ or one or more symptoms of a deficits in sensory organ comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of claims 76 to 81.
109. The method of claim 108, wherein the deficits in sensory organ is Tinnitus, Sound induced hearing deficit, or Substance induced hearing deficit.
110. The method of claim 108, wherein the deficits in sensory organ is Glaucoma or Diabetic retinopathy.
111. The method ofany one of claims 105 to 110, wherein the treatment is part of a treatment regimen and the administration involves a series of administrations.
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