Compounds, compositions, and methods for modulating ferroptosis and treating excitotoxic disorders

1. A compound having the structure of formula (I):

wherein

X is N;

Y is H, halo, or C 1-4 alkyl;

R 1 is NR 4 R 5 , and at least one of R 4 and R 5 has a ring structure as defined below;

R 2 is NR 6 R 7 ;

R 3 is selected from the group consisting of H,

R 4 and R 5 are independently selected from the group consisting of H, C 1-12 alkyl, C 3-12 cycloalkyl, and aryl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms, and the cycloalkyl optionally comprises one or more pendant groups selected from the group consisting of H, F, NR 10 R 11 , Boc, COOR 12 , and C 1-8 alkyl;

R 6 and R 7 are independently selected from the group consisting of H, C 1-6 alkyl, Boc, O, COOR 12 ,

 and C 1-3 alkyl-aryl, wherein one or more of the ring carbons of the alkyl-aryl are optionally substituted with one or more nitrogen atoms, and the alkyl-aryl optionally comprises one or more pendant groups selected from the group consisting of H, halo, CN, NO 2 , C 1-4 ether, C 1-4 ester, OCOOR 12 , and C 1-8 alkyl, which C 1-8 alkyl is optionally further substituted with one or more halo;

R 8 and R 9 are independently selected from the group consisting of no atom, O, N, NHR 12 , C 1-10 alkyl, and C 1-10 ether, wherein the alkyl and the ether are optionally substituted with NH 2 , NHBoc, or C 3-12 cycloalkyl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms;

R 10 and R 11 are independently selected from H and Boc; and

R 12 is a C 1-4 alkyl optionally substituted with aryl,

with the proviso that:

when R 1 is

 and R 2 is NH 2 , R 3 cannot be

when R 1 is

 R 3 cannot be

when R 1 is

 R 3 cannot be

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

2. A compound according to claim 1 having the structure selected from the group consisting of:

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

3. A compound according to claim 1 having the structure of:

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

4. A composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 .

5. A method for treating or ameliorating the effects of an excitotoxic disorder in a subject in need thereof comprising administering to the subject an effective amount of a compound having the structure of formula (I):

wherein

X is N;

Y is H, halo, or C 1-4 alkyl;

R 1 is NR 4 R 5 , and at least one of R 4 and R 5 has a ring structure as defined below;

R 2 is NR 6 R 7 ;

R 3 is selected from the group consisting of H,

R 4 and R 5 are independently selected from the group consisting of H, C 1-12 alkyl, C 3-12 cycloalkyl, and aryl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms, and the cycloalkyl optionally comprises one or more pendant groups selected from the group consisting of H, F, NR 10 R 11 , Boc, COOR 12 , and C 1-8 alkyl;

R 6 and R 7 are independently selected from the group consisting of H, C 1-6 alkyl, Boc, O, COOR 12 ,

 and C 1-3 alkyl-aryl, wherein one or more of the ring carbons of the alkyl-aryl are optionally substituted with one or more nitrogen atoms, and the alkyl-aryl optionally comprises one or more pendant groups selected from the group consisting of H, halo, CN, NO 2 , C 1-4 ether, C 1-4 ester, OCOOR 12 , and C 1-8 alkyl, which C 1-8 alkyl is optionally further substituted with one or more halo;

R 8 and R 9 are independently selected from the group consisting of no atom, O, N, NHR 12 , C 1-10 alkyl, and C 1-10 ether, wherein the alkyl and the ether are optionally substituted with NH 2 , NHBoc, or C 3-12 cycloalkyl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms;

R 10 and R 11 are independently selected from H and Boc; and

R 12 is a C 1-4 alkyl optionally substituted with aryl,

with the proviso that:

when R 1 is

 and R 2 is NH 2 , R 3 cannot be

when R 1 is

 R 3 cannot be

when R 1 is

 R 3 cannot be

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

6. The method according to claim 5 , wherein the compound is selected from the group consisting of:

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

7. The method according to claim 5 , wherein the compound has the structure of:

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

8. The method according to claim 5 , wherein the excitotoxic disorder is a disease involving oxidative cell death.

9. The method according to claim 5 , wherein the excitotoxic disorder is selected from the group consisting of epilepsy, stroke, myocardial infarction, type I diabetes, and neurodegenerative disease.

10. The method according to claim 9 , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, Friedreich's ataxia, Multiple sclerosis, Huntington's Disease, Transmissible spongiform encephalopathy, Charcot-Marie-Tooth disease, Dementia with Lewy bodies, Corticobasal degeneration, Progressive supranuclear palsy, and Hereditary spastic paraparesis.

11. The method according to claim 5 further comprising co-administering to the subject an effective amount of one or more compositions selected from the group consisting of: 5-hydroxytryptophan, Activase, AFQ056 (Novartis), Aggrastat, Albendazole, alpha-lipoic acid/L-acetyl carnitine, Alteplase, Amantadine (Symmetrel), amlodipine, Ancrod, Apomorphine (Apokyn), Arimoclomol, Arixtra, Armodafinil, Ascorbic acid, Ascriptin, Aspirin, atenolol, Avonex, baclofen (Lioresal), Banzel, Benztropine (Cogentin), Betaseron, BGG492 (Novartis Corp.), Botulinum toxin, Bufferin, Carbidopa/levodopa immediate-release (Sinemet), Carbidopa/levodopa oral disintegrating (Parcopa), Carbidopa/levodopa/Entacapone (Stalevo), CERE-110: Adeno-Associated Virus Delivery of NGF (Ceregene), cerebrolysin, CinnoVex, citalopram, citicoline, Clobazam, Clonazepam, Clopidogrel, clozapine (Clozaril), Coenzyme Q, Creatine, dabigatran, dalteparin, Dapsone, Davunetide, Deferiprone, Desmoteplase, Diastat, Diazepam, Digoxin, Dimebon, dipyridamole, divalproex (Depakote), Donepezil (Aricept), EGb 761, Eldepryl, ELND002 (Elan Pharmaceuticals), Enalapril, enoxaparin, Entacapone (Comtan), epoetin alfa, Eptifibatide, Erythropoietin, Escitalopram, Eslicarbazepine acetate, Esmolol, Ethosuximide, Ethyl-EPA, Exenatide, Extavia, Ezogabine, Felbamate, Fingolimod (Gilenya), fluoxetine (Prozac), fondaparinux, Fragmin, Frisium, Gabapentin, Galantamine, Glatiramer (Copaxone), haloperidol (Haldol), Heparin, human chorionic gonadotropin (hCG), Idebenone, insulin, Interferon beta 1a, Interferon beta 1b, ioflupane 123I, IPX066 (Impax Laboratories Inc.), JNJ-26489112 (Johnson and Johnson), Klonopin, Lacosamide, L-Alpha glycerylphosphorylcholine, Lamotrigine, Levetiracetam, liraglutide, Lisinopril, Lithium carbonate, Lopressor, Lorazepam, losartan, Lovenox, Lu AA24493, Luminal, LY450139 (Eli Lilly), Lyrica, Masitinib, Mecobalamin, Memantine, methylprednisolone, metoprolol tartrate, Minitran, Minocycline, mirtazapine, Mitoxantrone (Novantrone), Natalizumab (Tysabri), Niacinamide, Nitro-Bid, Nitro-Dur, nitroglycerin, Nitrolingual, Nitromist, Nitrostat, Nitro-Time, Norepinephrine (NOR), Carbamazepine, octreotide, Oxcarbazepine, Oxybutinin chloride, PF-04360365 (Pfizer), Phenobarbital, Phenytoin, piclozotan, Pioglitazone, Plavix, Potiga, Pramipexole (Mirapex), pramlintide, Prednisone, Primidone, Prinivil, probenecid, Propranolol, PRX-00023 (EPIX Pharmaceuticals Inc.), PXT3003, Quinacrine, Ramelteon, Rasagiline (Azilect), Rebif, ReciGen, remacemide, Resveratrol, Retavase, reteplase, riluzole (Rilutek), Rivastigmine (Exelon), Ropinirole (Requip), Rotigotine (Neupro), Rufinamide, Sabril, safinamide (EMD Serono), Salagen, Sarafem, Selegiline (I-deprenyl, Eldepryl), SEN0014196 (Siena Biotech), sertraline (Zoloft), Simvastatin, Sodium Nitroprussiate (NPS), sodium phenylbutyrate, Stanback Headache Powder, Tacrine (Cognex), Tamoxifen, tauroursodeoxycholic acid (TUDCA), Tenecteplase, Tenormin, Tetrabenazine (Xenazine), THR-18 (Thrombotech Ltd.), Tiagabine, Tideglusib, tirofiban, tissue plasminogen activator (tPA), tizanidine (Zanaflex), TNKase, Tolcapone (Tasmar), Tolterodine, Topiramate, Trihexyphenidyl (formerly Artane), ursodiol, Valproic Acid, valsartan, Varenicline (Pfizer), Vimpat, Vitamin E, Warfarin, Zestril, Zonisamide, Zydis selegiline HCL Oral disintegrating (Zelapar), and combinations thereof.

12. The method according to claim 5 , wherein the subject is a mammal.

13. The method according to claim 12 , wherein the mammal is selected from the group consisting of humans, veterinary animals, and agricultural animals.

14. The method according to claim 5 , wherein the subject is a human.

15. A method for treating or ameliorating the effects of an excitotoxic disorder in a subject in need thereof comprising administering to the subject an effective amount of a composition comprising a pharmaceutically acceptable carrier and a compound having the structure (I):

wherein

X is N;

Y is H, halo, or C 1-4 alkyl;

R 1 is NR 4 R 5 , and at least one of R 4 and R 5 has a ring structure as defined below;

R 2 is NR 6 R 7 ;

R 3 is selected from the group consisting of H,

R 4 and R 5 are independently selected from the group consisting of H, C 1-12 alkyl, C 3-12 cycloalkyl, and aryl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms, and the cycloalkyl optionally comprises one or more pendant groups selected from the group consisting of H, F, NR 10 R 11 , Boc, COOR 12 , and C 1-8 alkyl;

R 6 and R 7 are independently selected from the group consisting of H, C 1-6 alkyl, Boc, O, COOR 12 ,

 and C 1-3 alkyl-aryl, wherein one or more of the ring carbons of the alkyl-aryl are optionally substituted with one or more nitrogen atoms, and the alkyl-aryl optionally comprises one or more pendant groups selected from the group consisting of H, halo, CN, NO 2 , C 1-4 ether, C 1-4 ester, OCOOR 12 , and C 1-8 alkyl, which C 1-8 alkyl is optionally further substituted with one or more halo;

R 8 and R 9 are independently selected from the group consisting of no atom, O, N, NHR 12 , C 1-10 alkyl, and C 1-10 ether, wherein the alkyl and the ether are optionally substituted with NH 2 , NHBoc, or C 3-12 cycloalkyl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms;

R 10 and R 11 are independently selected from H and Boc; and

R 12 is a C 1-4 alkyl optionally substituted with aryl,

with the proviso that:

when R 1 is

 and R 2 is NH 2 , R 3 cannot be

when R 1 is

 R 3 cannot be

when R 1 is

 R 3 cannot be

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

16. The method according to claim 15 , wherein the subject is a mammal.

17. The method according to claim 16 , wherein the mammal is selected from the group consisting of humans, veterinary animals, and agricultural animals.

18. The method according to claim 15 , wherein the subject is a human.

19. The method according to claim 15 , wherein the compound is selected from the group consisting of:

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

20. The method according to claim 15 , wherein the compound has the structure of:

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

21. The method according to claim 15 , wherein the excitotoxic disorder is a disease involving oxidative cell death.

22. The method according to claim 21 , wherein the excitotoxic disorder is selected from the group consisting of epilepsy, stroke, myocardial infarction, type I diabetes, and neurodegenerative disease.

23. The method according to claim 22 , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, Friedreich's ataxia, Multiple sclerosis, Huntington's Disease, Transmissible spongiform encephalopathy, Charcot-Marie-Tooth disease, Dementia with Lewy bodies, Corticobasal degeneration, Progressive supranuclear palsy, and Hereditary spastic paraparesis.

24. The method according to claim 5 further comprising co-administering to the subject an effective amount of one or more compositions selected from the group consisting of: 5-hydroxytryptophan, Activase, AFQ056 (Novartis), Aggrastat, Albendazole, alpha-lipoic acid/L-acetyl carnitine, Alteplase, Amantadine (Symmetrel), amlodipine, Ancrod, Apomorphine (Apokyn), Arimoclomol, Arixtra, Armodafinil, Ascorbic acid, Ascriptin, Aspirin, atenolol, Avonex, baclofen (Lioresal), Banzel, Benztropine (Cogentin), Betaseron, BGG492 (Novartis Corp.), Botulinum toxin, Bufferin, Carbidopa/levodopa immediate-release (Sinemet), Carbidopa/levodopa oral disintegrating (Parcopa), Carbidopa/levodopa/Entacapone (Stalevo), CERE-110: Adeno-Associated Virus Delivery of NGF (Ceregene), cerebrolysin, CinnoVex, citalopram, citicoline, Clobazam, Clonazepam, Clopidogrel, clozapine (Clozaril), Coenzyme Q, Creatine, dabigatran, dalteparin, Dapsone, Davunetide, Deferiprone, Desmoteplase, Diastat, Diazepam, Digoxin, Dimebon, dipyridamole, divalproex (Depakote), Donepezil (Aricept), EGb 761, Eldepryl, ELND002 (Elan Pharmaceuticals), Enalapril, enoxaparin, Entacapone (Comtan), epoetin alfa, Eptifibatide, Erythropoietin, Escitalopram, Eslicarbazepine acetate, Esmolol, Ethosuximide, Ethyl-EPA, Exenatide, Extavia, Ezogabine, Felbamate, Fingolimod (Gilenya), fluoxetine (Prozac), fondaparinux, Fragmin, Frisium, Gabapentin, Galantamine, Glatiramer (Copaxone), haloperidol (Haldol), Heparin, human chorionic gonadotropin (hCG), Idebenone, insulin, Interferon beta 1a, Interferon beta 1b, ioflupane 123I, IPX066 (Impax Laboratories Inc.), JNJ-26489112 (Johnson and Johnson), Klonopin, Lacosamide, L-Alpha glycerylphosphorylcholine, Lamotrigine, Levetiracetam, liraglutide, Lisinopril, Lithium carbonate, Lopressor, Lorazepam, losartan, Lovenox, Lu AA24493, Luminal, LY450139 (Eli Lilly), Lyrica, Masitinib, Mecobalamin, Memantine, methylprednisolone, metoprolol tartrate, Minitran, Minocycline, mirtazapine, Mitoxantrone (Novantrone), Natalizumab (Tysabri), Niacinamide, Nitro-Bid, Nitro-Dur, nitroglycerin, Nitrolingual, Nitromist, Nitrostat, Nitro-Time, Norepinephrine (NOR), Carbamazepine, octreotide, Oxcarbazepine, Oxybutinin chloride, PF-04360365 (Pfizer), Phenobarbital, Phenytoin, piclozotan, Pioglitazone, Plavix, Potiga, Pram ipexole (Mirapex), pramlintide, Prednisone, Primidone, Prinivil, probenecid, Propranolol, PRX-00023 (EPIX Pharmaceuticals Inc.), PXT3003, Quinacrine, Ramelteon, Rasagiline (Azilect), Rebif, ReciGen, remacemide, Resveratrol, Retavase, reteplase, riluzole (Rilutek), Rivastigmine (Exelon), Ropinirole (Requip), Rotigotine (Neupro), Rufinamide, Sabril, safinamide (EMD Serono), Salagen, Sarafem, Selegiline (I-deprenyl, Eldepryl), SEN0014196 (Siena Biotech), sertraline (Zoloft), Simvastatin, Sodium Nitroprussiate (NPS), sodium phenylbutyrate, Stanback Headache Powder, Tacrine (Cognex), Tamoxifen, tauroursodeoxycholic acid (TUDCA), Tenecteplase, Tenormin, Tetrabenazine (Xenazine), THR-18 (Thrombotech Ltd.), Tiagabine, Tideglusib, tirofiban, tissue plasminogen activator (tPA), tizanidine (Zanaflex), TNKase, Tolcapone (Tasmar), Tolterodine, Topiramate, Trihexyphenidyl (formerly Artane), ursodiol, Valproic Acid, valsartan, Varenicline (Pfizer), Vimpat, Vitamin E, Warfarin, Zestril, Zonisamide, Zydis selegiline HCL Oral disintegrating (Zelapar), and combinations thereof.

25. A method of modulating ferroptosis in a subject in need thereof comprising administering to the subject an effective amount of a ferroptosis inhibitor, wherein the ferroptosis inhibitor comprises a compound having the structure of formula (I):

wherein

X is N;

Y is H, halo, or C 1-4 alkyl;

R 1 is NR 4 R 5 , and at least one of R 4 and R 5 has a ring structure as defined below;

R 2 is NR 6 R 7 ;

R 3 is selected from the group consisting of H,

R 4 and R 5 are independently selected from the group consisting of H, C 1-12 alkyl, C 3-12 cycloalkyl, and aryl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms, and the cycloalkyl optionally comprises one or more pendant groups selected from the group consisting of H, F, NR 10 R 11 , Boc, COOR 12 , and C 1-8 alkyl;

R 6 and R 7 are independently selected from the group consisting of H, C 1-6 alkyl, Boc, O, COOR 12 ,

 and C 1-3 alkyl-aryl, wherein one or more of the ring carbons of the alkyl-aryl are optionally substituted with one or more nitrogen atoms, and the alkyl-aryl optionally comprises one or more pendant groups selected from the group consisting of H, halo, CN, NO 2 , C 1-4 ether, C 1-4 ester, OCOOR 12 , and C 1-8 alkyl, which C 1-8 alkyl is optionally further substituted with one or more halo;

R 8 and R 9 are independently selected from the group consisting of no atom, O, N, NHR 12 , C 1-10 alkyl, and C 1-10 ether, wherein the alkyl and the ether are optionally substituted with NH 2 , NHBoc, or C 3-12 cycloalkyl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms;

R 10 and R 11 are independently selected from H and Boc; and

R 12 is a C 1-4 alkyl optionally substituted with aryl,

with the proviso that:

when R 1 is

 and R 2 is NH 2 , R 3 cannot be

when R 1 is

 R 3 cannot be

when R 1 is

 R 3 cannot be

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

26. A method of reducing reactive oxygen species (ROS) in a cell comprising contacting a cell with a ferroptosis modulator wherein the ferroptosis modulator is a ferroptosis inhibitor, which comprises a compound having the structure of formula (I):

wherein

X is N;

Y is H, halo, or C 1-4 alkyl;

R 1 is NR 4 R 5 , and at least one of R 4 and R 5 has a ring structure as defined below;

R 2 is NR 6 R 7 ;

R 3 is selected from the group consisting of H,

R 4 and R 5 are independently selected from the group consisting of H, C 1-12 alkyl, C 3-12 cycloalkyl, and aryl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms, and the cycloalkyl optionally comprises one or more pendant groups selected from the group consisting of H, F, NR 10 R 11 , Boc, COOR 12 , and C 1-8 alkyl;

R 6 and R 7 are independently selected from the group consisting of H, C 1-6 alkyl, Boc, O, COOR 12 ,

 and C 1-3 alkyl-aryl, wherein one or more of the ring carbons of the alkyl-aryl are optionally substituted with one or more nitrogen atoms, and the alkyl-aryl optionally comprises one or more pendant groups selected from the group consisting of H, halo, CN, NO 2 , C 1-4 ether, C 1-4 ester, OCOOR 12 , and C 1-8 alkyl, which C 1-8 alkyl is optionally further substituted with one or more halo;

R 8 and R 9 are independently selected from the group consisting of no atom, O, N, NHR 12 , C 1-10 alkyl, and C 1-10 ether, wherein the alkyl and the ether are optionally substituted with NH 2 , NHBoc, or C 3-12 cycloalkyl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms;

R 10 and R 11 are independently selected from H and Boc; and

R 12 is a C 1-4 alkyl optionally substituted with aryl,

with the proviso that:

when R 1 is

 and R 2 is NH 2 , R 3 cannot be

when R 1 is

 R 3 cannot be

when R 1 is

 R 3 cannot be

or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.