Claims for Patent: 7,977,336

Summary for Patent: 7,977,336

Title:	Aminopyrimidine derivatives as PLK1 inhibitors
Abstract:	The present invention relates to a compound represented by Formula [I]: ##STR00001## or a pharmaceutically acceptable salt or ester thereof, wherein R.sub.1 and R.sub.2, which may be the same or different, are each a hydrogen atom, a lower alkyl group, a cycloalkyl group, or the like; R.sub.3 and R.sub.4, which may be the same or different, are each a hydrogen atom, a lower alkyl group, NR.sub.aR.sub.b, a phenyl group, a lower alkyl group substituted with a phenyl group, a 4-to 7-membered aliphatic heterocyclic group, a lower alkyl group substituted with a 4- to 7-membered aliphatic heterocyclic group, a 5-or 6-membered aromatic heterocyclic group, a lower alkyl group substituted with a 5-or 6-membered aromatic heterocyclic group, or the like; and R.sub.5 is a hydrogen atom, a cyano group, a halogen atom, or a lower alkyl group.
Inventor(s):	Hashihayata; Takashi (Tsukuba, JP), Kawamura; Mikako (Tsukuba, JP), Mitsuya; Morihiro (Tsukuba, JP), Sato; Yoshiyuki (Hanamigawa-ku, JP)
Assignee:	Banyu Pharmaceutical Co. Ltd (Tokyo, JP)
Application Number:	12/002,546
Patent Claims:	1. A compound of Formula [I]: ##STR00138## or a pharmaceutically acceptable salt or ester thereof wherein: R.sub.1 is a substituent selected from <Substituent Group .alpha.>; a lower alkyl group which may be substituted with one or more substituents selected from <Substituent Group .alpha.>; or a cyclopropyl group, where the <Substituent Group .alpha.> is a halogen atom; and R.sub.2 is a hydrogen atom; one of R.sub.3 and R.sub.4 is a hydrogen atom, while the other one of R.sub.3 and R.sub.4 is: a) a lower alkyl group substituted with NR.sub.aR.sub.b, where R.sub.a and R.sub.b, which may be the same or different, are each a hydrogen atom, a lower alkyl group, a benzyl group, or a cycloalkyl group having three to six carbon atoms, wherein the cycloalkyl group may be substituted with one or more substituents, which may be the same or different, selected from the following 1) to 3): 1) a lower alkyl group; 2) a substituent selected from <Substituent Group .beta.>; and 3) a lower alkyl group substituted with one or more substituents selected from <Substituent Group .beta.>; and the cycloalkyl group may include an unsaturated bond; b) a 4 -to 6-membered aliphatic heterocyclic group selected from an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, and a piperazinyl group; or c) a lower alkyl group substituted with a 4- to 6-membered aliphatic heterocyclic group selected from an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, and a piperazinyl group, wherein the aliphatic heterocyclic group may be substituted with one or more substituents, which may be the same or different, selected from the following 1) to 4): 1) a lower alkyl group; 2) a substituent selected from the <Substituent Group .beta.>; 3) a lower alkyl group substituted with one or more substituents selected from the <Substituent Group .beta.>; and 4) a cycloalkyl group having 3 to 6 carbon atoms, which may be substituted with one or more substituents selected from the <Substituent Group .beta.>; R.sub.5 is a hydrogen atom, a cyano group, a halogen atom, or a methyl group; and <Substituent Group .alpha.> and <Substituent Group .beta.> are defined as below: <Substituent Group .alpha.>: a halogen atom, a hydroxy group, a nitro group, a cyano group, an amino group, a carbamoyl group, an aminosulfonyl group, an imino group, a lower alkylamino group, a di-lower alkylamino group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkoxycarbonylamino group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkylthio group, and a carboxyl group; and <Substituent Group .beta.>: a halogen atom, a hydroxy group, a nitro group, a cyano group, an amino group, a carbamoyl group, an aminosulfonyl group, an imino group, a lower alkylsulfonyl group, a lower alkylsulfonylamino group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkoxycarbonylamino group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkylthio group, a carboxyl group, and a benzyl group. 2. The compound according to claim 1 or a pharmaceutically acceptable salt or ester thereof, wherein R.sub.1 is a lower alkyl group having 1 or 2 carbon atom(s), which may be substituted with 1 to 3 fluorine atoms; a cyclopropyl group; or a chlorine atom. 3. The compound according to claim 2 or a pharmaceutically acceptable salt or ester thereof, wherein the <Substituent Group .beta.> is a halogen atom, a hydroxyl group, an amino group, a lower alkylsulfonyl group, and a lower alkoxy group. 4. The compound according to claim 3 or a pharmaceutically acceptable salt or ester thereof, wherein: one of R.sub.3 and R.sub.4 is a hydrogen atom, while the other one of R.sub.3 and R.sub.4 is: a) a lower alkyl group substituted with NR.sub.aR.sub.b, where R.sub.a and R.sub.b, which may be the same or different, are each a hydrogen atom, a lower alkyl group, or a cycloalkyl group having five to six carbon atoms, wherein the cycloalkyl group may be substituted with one or more substituents, which may be the same or different, selected from the following 1) to 3): 1) a lower alkyl group; 2) a substituent selected from <Substituent Group .beta.>; and 3) a lower alkyl group substituted with one or more substituents selected from <Substituent Group .beta.>; or b) a 4- or 6-membered aliphatic heterocyclic group selected from an azetidinyl group, a pyrrolidinyl group and a piperidinyl group, wherein the aliphatic heterocyclic group may be substituted with one or more substituents, which may be the same or different, selected from the following 1) to 3): 1) a lower alkyl group; 2) a substituent selected from the <Substituent Group .beta.>; and 3) a lower alkyl group substituted with one or more substituents selected from the <Substituent Group .beta.>. 5. The compound according to claim 1 or a pharmaceutically acceptable salt or ester thereof, wherein: R.sub.1 is a lower alkyl group having 1 or 2 carbon atom(s), which may be substituted with 1 to 3 fluorine atoms; a cyclopropyl group; or a halogen atom; R.sub.2 is a hydrogen atom; one of R.sub.3 and R.sub.4 is a hydrogen atom, while the other one of R.sub.3 and R.sub.4 is an amino lower alkyl group (wherein said lower alkyl is a linear or branched alkyl group having 1 to 3 carbon atom(s)) which is N-substituted or N,N-di-substituted with a linear or branched alkyl group having 1 to 5 carbon atom(s); a piperidinyl group which is N-substituted with a linear or branched alkyl group having 1 to 5 carbon atom(s); a pyrrolidinyl group which is N-substituted with a linear or branched alkyl group having 1 to 5 carbon atom(s); an azetidinyl group which is N-substituted with a linear or branched alkyl group having 1 to 5 carbon atom(s); or a cycloalkyl group having five to six carbon atoms, wherein the piperidinyl group, the pyrrolidinyl group, and the azetidinyl group each independently may be further substituted with a linear or branched alkyl group having 1 to 3 carbon atom(s), and the cycloalkyl group may be substituted with a linear or branched alkyl group having 1 to 3 carbon atom(s) optionally having a hydroxy group; and R.sub.5 is a cyano group, a halogen atom, or a methyl group. 6. The compound according to claim 5 or a pharmaceutically acceptable salt or ester thereof, wherein: R.sub.1 is a methyl group, an ethyl group, a difluoromethyl group, a trifluoromethyl group, a cyclopropyl group, or a chlorine atom; R.sub.2 is a hydrogen atom; one of R.sub.3 and R.sub.4 is a hydrogen atom, while the other one of R.sub.3 and R.sub.4 is a linear or branched alkyl group having 1 to 3 carbon atom(s) which is substituted with a dimethylamino group, an isopropylamino group, 1,1-dimethylpropylamino group, or t-butylamino group; a piperidinyl group which is N-substituted with a linear or branched alkyl group having 1 to 5 carbon atom(s); a pyrrolidinyl group which is N-substituted with a linear or branched alkyl group having 1 to 5 carbon atom(s); an azetidinyl group which is N-substituted with a linear or branched alkyl group having 1 to 5 carbon atom(s); or a cyclopentyl group which may be substituted with a methyl group or a hydroxymethyl group, wherein the piperidinyl group, the pyrrolidinyl group, and the azetidinyl group each independently may be further substituted with a linear or branched alkyl group having 1 to 3 carbon atom(s); and R.sub.5 is a cyano group, a fluorine atom, or a methyl group. 7. The compound which is: (a) 2-[((1S)-1-{4-[2-(tert-butylamino) -1-hydroxyethyl]phenyl}ethyl)amino]-4-(8-ethylimidazo[1,2-a]pyridin-3-yl)- pyrimidine-5-carbonitrile; (b) (1R)-1-[4-((1S)-1-{[5-bromo-4-(8-ethylimidazo[1,2-a]pyridin-3-yl)pyrimidi- n-2-yl]amino}ethyl)phenyl]-2-(tert-butylamino)ethanol; (c) 2-[((1S)-1-{4-[hydroxy(pyridin-2-yl)methyl]phenyl}ethyl)amino]-4-(8-methy- limidazo[1,2-a]pyridin-3-yl)pyrimidine-5-carbonitrile; (d) 4-(8-ethylimidazo[1,2-a]pyridin-3-yl)-2-({(1S)-1-[4-(4-hydroxy-1-methylpi- peridin-4-yl)phenyl]ethyl}amino)pyrimidine-5-carbonitrile; (e) 4-(8-ethylimidazo[1,2-a]pyridin-3-yl)-2-[((1S)-1-{4-[hydroxy(1-isopropylp- iperidin-4-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile; (f) 4-(8-cyclopropylimidazo[1,2-a]pyridin-3-yl)-2-[((1S)-1-{4-[hydroxy(1-meth- ylpiperidin-4-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile; (g) 4-(8-chloroimidazo[1,2-a]pyridin-3-yl)-2-[((1S)-1-{4-[(1-cyclopropylpiper- idin-4-yl)(hydroxy)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile; (h) 4-(8-ethylimidazo[1,2-a]pyridin-3-yl)-2-[((1S)-1-{4-[hydroxy(1-methyl- piperidin-3-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile; (i) 2-{[(1S)-1 -(4-{hydroxy[1 -methylpyrrolidin-2-yl]methyl}phenyl)ethyl]amino}-4-(8-methylimidazo[1,2-- a]pyridin-3-yl)pyrimidine-5-carbonitrile; (j) 2-[((1S)-1-{4-[2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-(- 8-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidine-5-carbonitrile; (k) 2-[((1S)-1-{4-[2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-[- 8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine-5-carbonitrile, (l) 4-(8-cyclopropylimidazo[1,2-a]pyridin-3-yl)-2-[((1S)-1-{4-[(1,2-dimet- hylpyrrolidin-2-yl)(hydroxy)methyl]phenyl}ethyl)amino]pyrimidine-5-carboni- trile; (m) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-- a]pyridin-3-yl)-5-fluoropyrimidin-2-yl]amino}ethyl)phenyl]ethanol; (n) (1S)-1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridin-3-yl)-5-fluoropyrimi- din-2-yl]amino}ethyl)phenyl]-2-[(1,1-dimethylpropyl)amino]ethanol; (o) (1S)-1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridin-3-yl)-5-fluoropyrimi- din-2-yl]amino}ethyl)phenyl]-2-[(1-methylcyclopentyl)amino]ethanol; (p) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-cyclopropylimidazo[1,2-a]pyr- idin-3-yl)-5-methylpyrimidin-2-yl]amino}ethyl)phenyl]ethanol; (q) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridin-- 3-yl)-5-methylpyrimidin-2-yl]amino}ethyl)phenyl]ethanol; (r) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-cyclopropylimidazo[1,2-a]pyr- idin-3-yl)-5-fluoropyrimidin-2-yl]amino}ethyl)phenyl]ethanol; (s) (1S)-2-(tert-butylamino)-1-{4-[(1S)-1-({5 -fluoro-4-[8-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl}a- mino)ethyl]phenyl}ethanol; (t) [4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridin-3-yl)-5-fluoropyrimidin-2-y- l]amino}ethyl)phenyl](1,2-dimethylpyrrolidin-2-yl)methanol; (u) 1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridin-3-yl)-5-fluoropyrimidin-2- -yl]amino}ethyl)phenyl]-2-(dimethylamino)-2-methylpropan-1-ol; (v) [4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridin-3-yl)-5-fluoropyrimidin-2-y- l]amino}ethyl)phenyl](1-isopropylazetidin-3-yl)methanol; (w) [4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridin-3-yl)-5-fluoropyrimidin-2-y- l]amino}ethyl)phenyl](1-isopropylpiperidin-4-yl)methanol; or (x) (1S)-2-(tert-butylamino)-1-{4-[(1S)-1-({4-[8-(difluoromethyl)imidazo[1,2-- a]pyridin-3-yl]-5-fluoropyrimidin-2-yl}amino)ethyl]phenyl}ethanol, or a pharmaceutically acceptable salt or ester thereof 8. A pharmaceutical composition comprising, together with a pharmaceutically acceptable carrier or diluent, at least one compound according to claim 1 as an active ingredient. 9. A combined preparation for simultaneous, separate, or sequential administration, comprising two separate preparations: a preparation including, together with a pharmaceutically acceptable carrier or diluent, the compound of claim 1 which is represented by the Formula [I]or a pharmaceutically acceptable salt or ester thereof; and a preparation including, together with a pharmaceutically acceptable carrier or diluent, an antitumor agent selected from the group consisting of antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum complex compounds, antitumor camptothecin derivatives, antitumor tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, and other antitumor agents, or a pharmaceutically acceptable salt or ester thereof, wherein: the antitumor alkylating agents are nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, and carmustine; the antitumor antimetabolites are methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, gemcitabine, fludarabine, and pemetrexed disodium; the antitumor antibiotics are actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin stimalamer, idarubicin, sirolimus, and valrubicin; the plant-derived antitumor agents are vincristine, vinblastin, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel, and vinorelbine; the antitumor platinum complex compounds are cisplatin, carboplatin, nedaplatin, and oxaliplatin; the antitumor camptothecin derivatives are irinotecan, topotecan, and camptothecin; the antitumor tyrosine kinase inhibitors are gefitinib, imatinib, and erlotinib; the monoclonal antibodies are cetuximab, bevacizumab, rituximab, bevacizumab, alemtuzumab, and trastuzumab; the interferons are interferon .alpha., interferon .alpha.-2a, interferon .alpha.-2b, interferon .beta., interferon .gamma.-1a, and interferon .gamma.-nl; the biological response modifiers are krestin, lentinan, sizofiran, picibanil, and ubenimex; and the other antitumor agents are mitoxantrone, L-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin, alefacept, darbepoetin alfa, anastrozole, exemestane, bicalutamide, leuproreline, flutamide, fulvestrant, pegaptanib octasodium, denileukin diftitox, aldesleukin, thyrotropin alpha, arsenic trioxide, bortezomib, capecitabine, and goserelin. 10. The preparation according to claim 9 wherein one of or both of the two separate preparations is/are oral preparation(s) or parental preparation(s). 11. The preparation according to claim 9 which is further combined with at least one preparation comprising, together with a pharmaceutically acceptable carrier or diluent: an antitumor agent selected from the group consisting of antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum complex compounds, antitumor camptothecin derivatives, antitumor tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, and other antitumor agents, wherein the definition of each antitumor agent is the same as defined in claim 9; or a pharmaceutically acceptable salt or ester thereof. 12. The preparation according to claim 9 wherein: among the combined preparations, one preparation comprises, together with a pharmaceutically acceptable carrier or diluent, (a) 2-[((1S)-1-{4-[2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-(- 8-ethylimidazo[1,2-a]pyridin-3-yl)pyrimidine-5-carbonitrile; (b) (1R)-1-[4-((1S)-1-{[5-bromo-4-(8-ethylimidazo[1,2-a]pyridin-3-yl)pyrimidi- n-2-yl]amino}ethyl)phenyl]-2-(tert-butylamino)ethanol; (c) 2-[((1S)-1-{4-[hydroxy(pyridin-2-yl)methyl]phenyl}ethyl)amino]-4-(8-methy- limidazo[1,2-a]pyridin-3-yl)pyrimidine-5-carbonitrile; (d) 4-(8-ethylimidazo[1,2-a]pyridin-3-yl)-2-({(1S)-1-[4-(4-hydroxy-1-methylpi- peridin-4-yl)phenyl]ethyl}amino)pyrimidine-5-carbonitrile; (e) 4-(8-ethylimidazo[1,2-a]pyridin-3-yl)-2-[((1S)-1-{4-[hydroxy(1-isopropylp- iperidin-4-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile; (f) 4-(8-cyclopropylimidazo[1,2-a]pyridin-3-yl)-2-[((1S)-1-{4-[hydroxy(1-meth- ylpiperidin-4-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile; (g) 4-(8-chloroimidazo[1,2-a]pyridin-3-yl)-2-[((1S)-1-{4-[(1-cyclopropylpiper- idin-4-yl)(hydroxy)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile; (h) 4-(8-ethylimidazo[1,2-a]pyridin-3-yl)-2-[((1S)-1-{4-[hydroxy(1-methyl- piperidin-3-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile; (i) 2-{[(1S)-1-(4-{hydroxy[1-methylpyrrolidin-2-yl]methyl}phenyl)ethyl]amino}- -4-(8-methylimidazo[1,2-a]pyridin-3-yl)pyrimidine-5-carbonitrile; (j) 2-[((1S)-1-{4-[2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-(- 8-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidine-5-carbonitrile; or (k) 2-[((1S)-1-{4-[2-(tert-butylamino)-1-hydroxyethyl]phenyl}ethyl)amino]-4-[- 8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine-5-carbonitrile, (l) 4-(8-cyclopropylimidazo[1,2-a]pyridin-3-yl)-2-[((1 S)-1-{4(1,2-dimethylpyrrolidin-2-yl)(hydroxy)methyl]phenyl}ethyl)amino]py- rimidine-5-carbonitrile; (m) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridin-- 3-yl)-5-fluoropyrimidin-2-yl]amino}ethyl)phenyl]ethanol; (n) (1S)-1-[4-((1S)-1-{[4-(8-chloroimidazo [1,2-a]pyridin-3-yl)-5-fluoropyrimidin-2-yl]amino}ethyl)phenyl]-2-[(1,1-d- imethylpropyl)amino]ethanol; (o) (1S)-1-[4-((1S)-1-{[4-(8-chloroimidazo [1,2-a]pyridin-3-yl)-5-fluoropyrimidin-2-yl]amino}ethyl)phenyl]-2-[(1-met- hylcyclopentyl)amino]ethanol; (p) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-cyclopropylimidazo[1,2-a]pyr- idin-3-yl)-5-methylpyrimidin-2-yl]amino}ethyl)phenyl]ethanol; (q) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridin-- 3-yl)-5-methylpyrimidin-2-yl]amino}ethyl)phenyl]ethanol; (r) (1S)-2-(tert-butylamino)-1-[4-((1S)-1-{[4-(8-cyclopropylimidazo[1,2-a]pyr- idin-3-yl)-5-fluoropyrimidin-2-yl]amino}ethyl)phenyl]ethanol; (s) (1S)-2-(tert-butylamino)-1-{4-[(1S)-1-({5 -fluoro-4-[8-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl}a- mino)ethyl]phenyl}ethanol; (t) [4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridin-3-yl)-5-fluoropyrimidin-2-y- l]amino}ethyl)phenyl](1,2-dimethylpyrrolidin-2-yl)methanol; (u) 1-[4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridin-3-yl)-5-fluoropyrimidin-2- -yl]amino}ethyl)phenyl]-2-(dimethylamino)-2-methylpropan-1-ol; (v) [4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridin-3-yl)-5-fluoropyrimidin-2-y- l]amino}ethyl)phenyl](1-isopropylazetidin-3-yl)methanol; (w) [4-((1S)-1-{[4-(8-chloroimidazo[1,2-a]pyridin-3-yl)-5-fluoropyrimidin-2-y- l]amino}ethyl)phenyl](1-isopropylpiperidin-4-yl)methanol; or (x) (1S)-2-(tert-butylamino)-1-{4-[(1S)-1-({4-[8-(difluoromethyl)imidazo[1,2-- a]pyridin-3-yl]-5-fluoropyrimidin-2-yl}amino)ethyl]phenyl}ethanol, or a pharmaceutically acceptable salt or ester thereof.

Details for Patent 7,977,336

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2026-12-28
Clinigen, Inc.	PROLEUKIN	aldesleukin	For Injection	103293	05/05/1992		2026-12-28
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2026-12-28