Claims for Patent: 10,233,171

Summary for Patent: 10,233,171

Title:	Compounds, compositions, and methods for modulating ferroptosis and treating excitotoxic disorders
Abstract:	The present invention provides, inter alia, a compound having the structure: ##STR00001## Also provided are compositions containing a pharmaceutically acceptable carrier and a compound according to the present invention. Further provided are methods for treating or ameliorating the effects of an excitotoxic disorder in a subject, methods of modulating ferroptosis in a subject, methods of reducing reactive oxygen species (ROS) in a cell, and methods for treating or ameliorating the effects of a neurodegenerative disease.
Inventor(s):	Stockwell; Brent R. (New York, NY), Dixon; Scott J. (New York, NY), Skouta; Rachid (New York, NY)
Assignee:
Application Number:	15/442,475
Patent Claims:	1. A compound having the structure of formula (I): ##STR00273## wherein X is N; Y is H, halo, or C.sub.1-4alkyl; R.sub.1 is NR.sub.4R.sub.5, and at least one of R.sub.4 and R.sub.5 has a ring structure as defined below; R.sub.2 is NR.sub.6R.sub.7; R.sub.3 is selected from the group consisting of H, ##STR00274## R.sub.4 and R.sub.5 are independently selected from the group consisting of H, C.sub.1-12alkyl, C.sub.3-12cycloalkyl, 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.sub.10R.sub.11, Boc, COOR.sub.12, and C.sub.1-8alkyl; R.sub.6 and R.sub.7 are independently selected from the group consisting of H, C.sub.1-6alkyl, Boc, O, COOR.sub.12, ##STR00275## and C.sub.1-3alkyl-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.sub.2, C.sub.1-4 ether, C.sub.1-4 ester, OCOOR.sub.12, and C.sub.1-8alkyl, which C.sub.1-8alkyl is optionally further substituted with one or more halo; R.sub.8 and R.sub.9 are independently selected from the group consisting of no atom, O, N, NHR.sub.12, C.sub.1-10 alkyl, and C.sub.1-10 ether, wherein the alkyl and the ether are optionally substituted with NH.sub.2, NHBoc, or C.sub.3-12cycloalkyl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms; R.sub.10 and R.sub.11 are independently selected from H and Boc; and R.sub.12 is a C.sub.1-4alkyl optionally substituted with aryl, with the proviso that: ##STR00276## when R.sub.1 is ##STR00277## and R.sub.2 is NH.sub.2, R.sub.3 cannot be ##STR00278## when R.sub.1 is ##STR00279## R.sub.3 cannot be ##STR00280## when R.sub.1 is ##STR00281## R.sub.3 cannot be ##STR00282## 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: ##STR00283## or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof. 3. A compound according to claim 1 having the structure of: ##STR00284## 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): ##STR00285## wherein X is N; Y is H, halo, or C.sub.1-4alkyl; R.sub.1 is NR.sub.4R.sub.5, and at least one of R.sub.4 and R.sub.5 has a ring structure as defined below; R.sub.2 is NR.sub.6R.sub.7; R.sub.3 is selected from the group consisting of H, ##STR00286## R.sub.4 and R.sub.5 are independently selected from the group consisting of H, C.sub.1-12alkyl, C.sub.3-12cycloalkyl, 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.sub.10R.sub.11, Boc, COOR.sub.12, and C.sub.1-8alkyl; R.sub.6 and R.sub.7 are independently selected from the group consisting of H, C.sub.1-6alkyl, Boc, O, COOR.sub.12, ##STR00287## and C.sub.1-3alkyl-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.sub.2, C.sub.1-4 ether, C.sub.1-4 ester, OCOOR.sub.12, and C.sub.1-8alkyl, which C.sub.1-8alkyl is optionally further substituted with one or more halo; R.sub.8 and R.sub.9 are independently selected from the group consisting of no atom, O, N, NHR.sub.12, C.sub.1-10 alkyl, and C.sub.1-10 ether, wherein the alkyl and the ether are optionally substituted with NH.sub.2, NHBoc, or C.sub.3-12cycloalkyl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms; R.sub.10 and R.sub.11 are independently selected from H and Boc; and R.sub.12 is a C.sub.1-4alkyl optionally substituted with aryl, with the proviso that: when R.sub.1 is ##STR00288## and R.sub.2 is NH.sub.2, R.sub.3 cannot be ##STR00289## when R.sub.1 is ##STR00290## R.sub.3 cannot be ##STR00291## when R.sub.1 is ##STR00292## R.sub.3 cannot be ##STR00293## 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: ##STR00294## 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: ##STR00295## 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): ##STR00296## wherein X is N; Y is H, halo, or C.sub.1-4alkyl; R.sub.1 is NR.sub.4R.sub.5, and at least one of R.sub.4 and R.sub.5 has a ring structure as defined below; R.sub.2 is NR.sub.6R.sub.7 ; R.sub.3 is selected from the group consisting of H, ##STR00297## R.sub.4 and R.sub.5 are independently selected from the group consisting of H, C.sub.1-12alkyl, C.sub.3-12cycloalkyl, 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.sub.10R.sub.11, Boc, COOR.sub.12, and C.sub.1-8alkyl; R.sub.6 and R.sub.7 are independently selected from the group consisting of H, C.sub.1-6alkyl, Boc, O, COOR.sub.12, ##STR00298## and C.sub.1-3alkyl-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.sub.2, C.sub.1-4 ether, C.sub.1-4 ester, OCOOR.sub.12, and C.sub.1-8alkyl, which C.sub.1-8alkyl is optionally further substituted with one or more halo; R.sub.8 and R.sub.9 are independently selected from the group consisting of no atom, O, N, NHR.sub.12, C.sub.1-10 alkyl, and C.sub.1-10 ether, wherein the alkyl and the ether are optionally substituted with NH.sub.2, NHBoc, or C.sub.3-12cycloalkyl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms; R.sub.10 and R.sub.11 are independently selected from H and Boc; and R.sub.12 is a C.sub.1-4alkyl optionally substituted with aryl, with the proviso that: when R.sub.1 is ##STR00299## and R.sub.2 is NH.sub.2, R.sub.3 cannot be ##STR00300## when R.sub.1 is ##STR00301## R.sub.3 cannot be ##STR00302## when R.sub.1 is ##STR00303## R.sub.3 cannot be ##STR00304## 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: ##STR00305## 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: ##STR00306## 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): ##STR00307## wherein X is N; Y is H, halo, or C.sub.1-4alkyl; R.sub.1 is NR.sub.4R.sub.5, and at least one of R.sub.4 and R.sub.5 has a ring structure as defined below; R.sub.2 is NR.sub.6R.sub.7; R.sub.3 is selected from the group consisting of H, ##STR00308## R.sub.4 and R.sub.5 are independently selected from the group consisting of H, C.sub.1-12alkyl, C.sub.3-12cycloalkyl, 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.sub.10R.sub.11, Boc, COOR.sub.12, and C.sub.1-8alkyl; R.sub.6 and R.sub.7 are independently selected from the group consisting of H, C.sub.1-6alkyl, Boc, O, COOR.sub.12, ##STR00309## and C.sub.1-3alkyl-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.sub.2, C.sub.1-4 ether, C.sub.1-4 ester, OCOOR.sub.12, and C.sub.1-8alkyl, which C.sub.1-8alkyl is optionally further substituted with one or more halo; R.sub.8 and R.sub.9 are independently selected from the group consisting of no atom, O, N, NHR.sub.12, C.sub.1-10 alkyl, and C.sub.1-10 ether, wherein the alkyl and the ether are optionally substituted with NH.sub.2, NHBoc, or C.sub.3-12cycloalkyl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms; R.sub.10 and R.sub.11 are independently selected from H and Boc; and R.sub.12 is a C.sub.1-4alkyl optionally substituted with aryl, with the proviso that: when R.sub.1 is ##STR00310## and R.sub.2 is NH.sub.2, R.sub.3 cannot be ##STR00311## when R.sub.1 is ##STR00312## R.sub.3 cannot be ##STR00313## when R.sub.1 is ##STR00314## R.sub.3 cannot be ##STR00315## 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): ##STR00316## wherein X is N; Y is H, halo, or C.sub.1-4alkyl; R.sub.1 is NR.sub.4R.sub.5, and at least one of R.sub.4 and R.sub.5 has a ring structure as defined below; R.sub.2 is NR.sub.6R.sub.7; R.sub.3 is selected from the group consisting of H, ##STR00317## R.sub.4 and R.sub.5 are independently selected from the group consisting of H, C.sub.1-12alkyl, C.sub.3-12cycloalkyl, 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.sub.10R.sub.11, Boc, COOR.sub.12, and C.sub.1-8alkyl; R.sub.6 and R.sub.7 are independently selected from the group consisting of H, C.sub.1-6alkyl, Boc, O, COOR.sub.12, ##STR00318## and C.sub.1-3alkyl-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.sub.2, C.sub.1-4 ether, C.sub.1-4 ester, OCOOR.sub.12, and C.sub.1-8alkyl, which C.sub.1-8alkyl is optionally further substituted with one or more halo; R.sub.8 and R.sub.9 are independently selected from the group consisting of no atom, O, N, NHR.sub.12, C.sub.1-10 alkyl, and C.sub.1-10 ether, wherein the alkyl and the ether are optionally substituted with NH.sub.2, NHBoc, or C.sub.3-12cycloalkyl, wherein one or more of the ring carbons of the cycloalkyl are optionally substituted with one or more heteroatoms; R.sub.10 and R.sub.11 are independently selected from H and Boc; and R.sub.12 is a C.sub.1-4alkyl optionally substituted with aryl, with the proviso that: when R.sub.1 is ##STR00319## and R.sub.2 is NH.sub.2, R.sub.3 cannot be ##STR00320## when R.sub.1 is ##STR00321## R.sub.3 cannot be ##STR00322## when R.sub.1 is ##STR00323## R.sub.3 cannot be ##STR00324## or pharmaceutically acceptable salts thereof, or individual enantiomers or diastereomers thereof.

Details for Patent 10,233,171

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	January 15, 1974		2032-04-02
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	December 27, 1984		2032-04-02
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	February 15, 1985		2032-04-02
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	February 16, 1990		2032-04-02
Bel-mar Laboratories, Inc.	CHORIONIC GONADOTROPIN	chorionic gonadotropin	Injection	017054	March 26, 1974		2032-04-02
Fresenius Kabi Usa, Llc	CHORIONIC GONADOTROPIN	chorionic gonadotropin	For Injection	017067	March 05, 1973		2032-04-02
Genentech, Inc.	ACTIVASE	alteplase	For Injection	103172	November 13, 1987		2032-04-02