Claims for Patent: 8,188,094

Summary for Patent: 8,188,094

Title:	Inhibitors of glutaminyl cyclase
Abstract:	Compounds of formula (I), combinations and uses thereof for disease therapy, ##STR00001## or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof wherein: A represents ##STR00002## and B, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, Y and Z are as defined throughout the description and the claims.
Inventor(s):	Buchholz; Mirko (Halle/Saale, DE), Heiser; Ulrich (Halle/Saale, DE), Sommer; Robert (Halle/Saale, DE)
Assignee:	Probiodrug AG (Halle (Saale), DE)
Application Number:	12/105,832
Patent Claims:	1. A compound of formula (I), ##STR00067## or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof wherein: R.sup.1 represents alkyl; alkenyl; carbocyclyl; heterocyclyl; optionally substituted aryl or optionally substituted heteroaryl; wherein any of the aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl and oxo; and wherein any of the aforesaid aryl and heteroaryl groups may optionally be substituted by one or more substituents selected from C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl, --C.sub.1-6thioalkyl, --SO.sub.2C.sub.1-4alkyl, C.sub.1-6alkoxy-, --O--C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl, --SO.sub.2C.sub.3-8cycloalkyl, C.sub.3-6alkenyloxy-, C.sub.3-6alkynyloxy-, --C(O)C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl-, nitro, halogen, cyano, hydroxyl, --C(O)OH, --NH.sub.2, --NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl)(C.sub.1-4alkyl), --C(O)N(C.sub.1-4alkyl)(C.sub.1-4alkyl), --C(O)NH.sub.2, --C(O)NH(C.sub.1-4alkyl), --C(O)OC.sub.1-6alkyl, SOC.sub.1-4alkyl and --SOC.sub.3-6cycloalkyl; or R.sup.1 represents -carbocyclyl-phenyl; -carbocyclyl-(monocyclic heteroaryl); -heterocyclyl-phenyl; -carbocyclyl fused to phenyl; carbocyclyl fused to monocyclic heteroaryl or heterocyclyl fused to phenyl; wherein any of the aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl and oxo; and wherein any of the aforesaid phenyl and heteroaryl groups may optionally be substituted by one or more substituents selected from C.sub.1-6alkyl, C.sub.1-6haloalkyl, --C.sub.1-6thioalkyl, --SO.sub.2C.sub.1-4alkyl, C.sub.1-6alkoxy-, --C(O)C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl-, nitro, halogen, cyano, hydroxyl, --C(O)OH, --NH.sub.2, --NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl)(C.sub.1-4alkyl), --C(O)N(C.sub.1-4 alkyl)(C.sub.1-4alkyl), --C(O)NH.sub.2, --C(O)NH(C.sub.1-4alkyl) and --SOC.sub.1-4alkyl; and R.sup.2 represents alkyl; alkenyl; carbocyclyl; heterocyclyl; optionally substituted aryl or optionally substituted heteroaryl; wherein any of the aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl and oxo; and wherein any of the aforesaid aryl and heteroaryl groups may optionally be substituted by one or more substituents selected from C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl, --C.sub.1-6thioalkyl, --SO.sub.2C.sub.1-4alkyl, C.sub.1-6alkoxy-, --O--C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl, --SO.sub.2C.sub.3-8cycloalkyl, C.sub.3-6alkenyloxy-, C.sub.3-6alkynyloxy-, --C(O)C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl-, nitro, halogen, cyano, hydroxyl, --C(O)OH, --NH.sub.2, --NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl)(C.sub.1-4alkyl), --C(O)N(C.sub.1-4alkyl)(C.sub.1-4alkyl), --C(O)NH.sub.2, --C(O)NH(C.sub.1-4alkyl), --C(O)OC.sub.1-6alkyl, SOC.sub.1-4alkyl and --SOC.sub.3-6cycloalkyl; and A represents ##STR00068## wherein Y represents a C.sub.2-5 alkylene chain, which may optionally be substituted by one or two methyl groups or may optionally be substituted by two alkylene substituents at the same position wherein the two alkylene substituents are joined to each other to form a C.sub.3-5spiro-cycloalkyl group; and R.sup.3, R.sup.4 and R.sup.5 independently represent H or C.sub.1-2alkyl; or A represents ##STR00069## wherein Z represents a bond, --CH.sub.2--, --CH.sub.2--CH.sub.2--, --CH(Me)-, --CH(Me)-CH.sub.2--or --CH.sub.2--CH(Me)- and R.sup.6 and R.sup.7 independently represent H or C.sub.1-2alkyl; B represents H or methyl; and wherein the compound is not one selected from the group consisting of: N-[3-(1H-imidazol-1-yl)propyl]-6-phenyl-2-(3-pyridinyl)-4-pyrimidinamine; 6-(5-bromo-3-pyridinyl)-N-[3-(1H-imidazol-1-yl)propyl]-2-phenyl-4-pyrimid- inamine; N-[3-(1H-imidazol-1-yl)propyl]-2-phenyl-6-(4-pyridinyl)-4-pyrimid- inamine; N-[3-(1H-imidazol-1-yl)propyl]-6-(1H-pyrazol-1-yl)-2-(2-thienyl)-- 4-pyrimidinamine; 2-(2-furanyl)-N-[3-(1H-imidazol-1-yl)propyl]-6-(1H-pyrazol-1-yl)-4-pyrimi- dinamine; 2-(3-chloro-4-fluorophenyl)-6-ethyl-N-[3-(1H-imidazol-1-yl)propy- l]-4-pyrimidinamine; 2-(4-bromophenyl)-N-[3-(1H-imidazol-1-yl)propyl]-6-methyl-4-pyrimidinamin- e; 2-(4-chlorophenyl)-N-[3-(1H-imidazol-1-yl)propyl]-6-phenyl-4-pyrimidina- mine; 2-(4-bromophenyl)-6-ethyl-N-[3-(1H-imidazol-1-yl)propyl]-4-pyrimidin- amine; 6-(4-fluorophenyl)-N-[3-(1H-imidazol-1-yl)propyl]-2-methyl-4-pyrimi- dinamine; N-[3-(1H-imidazol-1-yl)propyl]-2,6-di-4-pyridinyl-4-pyrimidinami- ne, N-[3-(1H-imidazol-1-yl)propyI]-2-(3-pyridinyl)-6-(4-pyridinyl)-4-pyrim- idinamine; N-[3-(1H-imidazol-1-yl)propyl]-2-(2-pyridinyl)-6-(4-pyridinyl)-- 4-pyrimidinamine; N-[3-(1H-imidazol-1-yl)propyl]-2-methyl-6-(4-pyridinyl)-4-pyrimidinamine; N-[3-(1H-imidazol-1-yl)propyl]-6-(3-pyridinyl)-2-(4-pyridinyl)-4-pyrimidi- namine; N-[3-(1H-imidazol-1-yl)propyl]-2,6-di-3-pyridinyl-4-pyrimidinamine- ; N-[3-(1H-imidazol-1-yl)propyl]-2-(2-pyridinyl)-6-(3-pyridinyl)-4-pyrimid- inamine; N-[3-(1H-imidazol-1-yl)propyl]-2-phenyl-6-(2-pyridinyl)-4-pyrimid- inamine; N-[3-(1H-imidazol-1-yl)propyl]-2-phenyl-6-(3-pyridinyl)-4-pyrimid- inamine; N-[3-(1H-imidazol-1-yl)propyl]-2-methyl-6-(2-pyridinyl)-4-pyrimid- inamine; N-[3-(1H-imidazol-1-yl)propyl]-2-methyl-6-(3-pyridinyl)-4-pyrimid- inamine; N-[3-(1H-imidazol-1-yl)propyl]-6-phenyl-2-(4-pyridinyl)-4-pyrimid- inamine; N-[3-(1H-imidazol-1-yl)propyl]-2-(4-pyridinyl)-6-[3-(trifluoromet- hyl)phenyl]-4-pyrimidinamine; N-[3-(1H-imidazol-1-yl)propyl]-6-(2-pyridinyl)-2-(4-pyridinyl)-4-pyrimidi- namine; N-[3-(1H-imidazol-1-yl)propyl]-2-(3-pyridinyl)-6[3-(trifluoromethy- l)phenyl]-4-pyrimidinamine; N-[3-(1H-imidazol-1-yl)propyl]-6-(2-pyridinyl)-2-(3-pyridinyl)-4-pyrimidi- namine; N-[3-(1H-imidazol-1-yl)propyl]-6-phenyl-2-(2-pyridinyl)-4-pyrimidi- namine N-[3-(1H-imidazol-1-yl)propyl]-2-(2-pyridinyl)-6-[3-(trifluoromethy- l)phenyl]-4-pyrimidinamine; N-[3-(1H-imidazol-1-yl)propyl]-2,6-di-2-pyridinyl-4-pyrimidinamine; N-[3-(1H-imidazol-1-yl)propyl]-2-phenyl-6-[3-(trifluoromethyl)phenyl]-4-p- yrimidinamine; N-[3-(1H-imidazol-1-yl)propyl]-2-methyl-6-[3-(trifluoromethyl)phenyl]-4-p- yrimidinamine; 6-(2-fluorophenyl)-N-[3-(1H-imidazol-1-yl)propyl]-2-(4-pyridinyl)-4-pyrim- idinamine; 6-(2-fluorophenyl)-N-[3-(1H-imidazol-1-yl)propyl]-2-(3-pyridiny- l)-4-pyrimidinamine; 6-(2-fluorophenyl)-N-[3-(1H-imidazol-1-yl)]-2-(2-pyridinyl)-4-pyrimidinam- ine; 6-(2-fluorophenyl)-N-[3-(1H-imidazol-1-yl)]-2-phenyl-4-pyrimidinamine- ; 6-(2-fluorophenyl)-N-[3-(1H-imidazol-1-yl)]-2-methyl-4-pyrimidinamine; 6-(4-fluorophenyl)-N-[3-(1H-imidazol-1-yl)]-2-(4-pyridinyl)-4-pyrimidinam- ine; 6-(4-fluorophenyl)-N-[3-(1H-imidazol-1-yl)]-2-(3-pyridinyl)-4-pyrimid- inamine; 6-(5-bromo-3-pyridinyl)-N-[3-(1H-imidazol-1-yl)propyl]-2-methyl-4- -pyrimidinamine; 6-(4-fluorophenyl)-N-[3-(1H-imidazol-1-yl)propyl]-2-(2-pyridinyl)-4-pyrim- idinamine; 6-(4-fluorophenyl)-N-[3-(1H-imidazol-1-yl)propyl]-2-phenyl-4-py- rimidinamine; and N-[3-(1H-imidazol-1-yl)propyl]-6-(methoxymethyl)-2-(2-thienyl)-4-pyrimidi- namine. 2. A compound according to claim 1 wherein: R.sup.1 represents alkyl; alkenyl; carbocyclyl; heterocyclyl; optionally substituted aryl or optionally substituted heteroaryl; wherein any of the aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl and oxo; and wherein any of the aforesaid aryl and heteroaryl groups may optionally be substituted by one or more substituents selected from C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl, --C.sub.1-6thioalkyl, --SO.sub.2C.sub.1-4alkyl, C.sub.1-6alkoxy-, --O--C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl, --SO.sub.2C.sub.3-8cycloalkyl, C.sub.3-6alkenyloxy-, C.sub.3-6alkynyloxy-, --C(O)C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl-, nitro, halogen, cyano, hydroxyl, --C(O)OH, --NH.sub.2, --NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl)(C.sub.1-4alkyl), --C(O)N(C.sub.1-4alkyl)(C.sub.1-4alkyl), --C(O)NH.sub.2 and --C(O)NH(C.sub.1-4alkyl); and R.sup.2 represents alkyl; alkenyl; carbocyclyl; heterocyclyl; optionally substituted aryl or optionally substituted heteroaryl; wherein any of the aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl and oxo; and wherein any of the aforesaid aryl and heteroaryl groups may optionally be substituted by one or more substituents selected from C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl, --C.sub.1-6thioalkyl, --SO.sub.2C.sub.1-4alkyl, C.sub.1-6alkoxy-, --O--C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl, --SO.sub.2C.sub.3-8cycloalkyl, C.sub.3-6alkenyloxy-, C.sub.3-6alkynyloxy-, --C(O)C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl-, nitro, halogen, cyano, hydroxyl, --C(O)OH, --NH.sub.2, --NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl)(C.sub.1-4alkyl), --C(O)N(C.sub.1-4alkyl)(C.sub.1-4alkyl), --C(O)NH.sub.2 and --C(O)NH(C.sub.1-4alkyl); and A represents ##STR00070## wherein Y represents a C.sub.2-5 alkylene chain, which may optionally be substituted by one or two methyl groups or may optionally be substituted by two alkylene substituents at the same position wherein the two alkylene substituents are joined to each other to form a C.sub.3-5spiro-cycloalkyl group and R.sup.3, R.sup.4 and R.sup.5 independently represent H or C.sub.1-2alkyl; or A represents ##STR00071## wherein Z represents a bond, --CH.sub.2--, --CH.sub.2--CH.sub.2--, --CH(Me)-, --CH(Me)-CH.sub.2--or --CH.sub.2-CH(Me)- and R.sup.6 and R.sup.7 independently represent H or C.sub.1-2alkyl; and B represents H or methyl. 3. A compound according to claim 1 wherein R.sup.2 represents alkyl. 4. A compound according to claim 1 wherein R.sup.2 represents optionally substituted aryl. 5. A compound according to claim 1 wherein R.sup.2 represents optionally substituted heteroaryl. 6. A compound according to claim 1 wherein R.sup.1 represents alkyl, optionally substituted aryl; carbocyclyl; haloalkyl or optionally substituted heteroaryl. 7. A compound according to claim 6 wherein R.sup.1 represents optionally substituted aryl. 8. A compound according to claim 1 wherein A represents ##STR00072## 9. A compound according to claim 8 wherein R.sup.3, R.sup.4 and R.sup.5 do not all represent H. 10. A compound according to claim 8 wherein R.sup.3 represents H, R.sup.4 represents H and R.sup.5 represents methyl. 11. A compound according to claim 8 wherein Y represents an unsubstituted C.sub.2-5 alkylene chain. 12. A compound according to claim 8 wherein Y does not represent --(CH.sub.2).sub.3--. 13. A compound according to claim 11 wherein Y represents --(CH.sub.2).sub.4--. 14. A compound according to claim 8 wherein A represents ##STR00073## 15. A compound according to claim 8 wherein A represents ##STR00074## 16. A compound according to claim 1 wherein A represents ##STR00075## 17. A compound according to claim 16 wherein Z represents a bond, --CH.sub.2--or --CH.sub.2CH.sub.2--. 18. A compound according to claim 1 wherein B represents H. 19. A compound according to claim 1 wherein compound (I) is selected from the group consisting of: N-(3-(1H-imidazol-1-yl)propyl)-6-methyl-2-phenylpyrimidin-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-2,6-diphenylpyrimidin-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-2-methyl-6-phenylpyrimidin-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-2,6-dimethylpyrimidin-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-2-methyl-6-p-tolylpyrimidin-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(3,5-bis(trifluoromethyl)phenyl)-2-methy- lpyrimidin-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(3,5-bis(trifluoromethyl)phenyl)-2-pheny- lpyrimidin-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(3,4,5-trimethoxyphenyl)-2-phenylpyrimid- in-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-2-phenyl-6-p-tolylpyrimidin-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(4-nitrophenyl)-2-phenylpyrimidin-4-amin- e; N-(3-(1H-imidazol-1-yl)propyl)-6-(2-methoxyphenyl)-2-phenylpyrimidin-4-- amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(3-methoxyphenyl)-2-phenylpyrimidi- n-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(furan-3-yl)-2-phenylpyrimidin- -4-amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(adamant-1 yl)-2-phenylpyrimidin-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(trifluoromethyl)-2-phenylpyrimidin-4-am- ine; N-(3-(1H-imidazol-1-yl)propyl)-6-(3,4,5-trimethoxyphenyl)-2-(pyridin-- 4-yl)pyrimidin-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(furan-3-yl)-2-(pyridin-4-yl)pyrimidin-4- -amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(trifluoromethyl)-2-(pyridin-4-yl- )pyrimidin-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(3-methoxyphenyl)-2-methylpyrimidin-4-am- ine; N-(3-(1H-imidazol-1-yl)propyl)-6-(3,4,5-trimethoxy-phenyl)-2-methylpy- rimidin-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(4-methoxyphenyl)-2-methylpyrimidin-4-am- ine; N-(3-(1H-imidazol-1-yl)propyl)-6-(2-methoxyphenyl)-2-methylpyrimidin-- 4-amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(3,5-bis(trifluoromethyl)phenyl)- -2-(pyridin-4-yl)pyrimidin-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(4-nitrophenyl)-2-(pyridin-4-yl)pyrimidi- n-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-2-(pyridin-4-yl)-6-p-tolylpyrimi- din-4-amine N-(3-(1H-imidazol-1-yl)propyl)-6-(2-methoxyphenyl)-2-(pyridin-4-yl)pyrimi- din-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(3-methoxyphenyl)-2-(pyridin-4-yl)pyrimi- din-4-amine; 6-(2-methoxyphenyl)-N-(3-(5-methyl-1H-imidazol-1-yl)propyl)-2-(pyridin-4-- yl)pyrimidin-4-amine; 6-(3,4,5-trimethoxyphenyl)-2-methyl-N-(3-(5-methyl-1H-imidazol-1-yl)propy- l)pyrimidin-4-amine; N-(2-phenyl-6-(quinolin-6-yl)pyrimidin-4-yl)-3H-benzo[d]imidazol-5-amine; N-(3-(1H-imidazol-1-yl)propyl)-2-methyl-6-(quinolin-6-yl) pyrimidin-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-2-phenyl-6-(2-phenylcyclopropyl)pyrimidin-- 4-amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(2-phenylcyclopropyl)-2-(pyridin- -4-yl)pyrimidin-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(2,3-dihydro-1H-inden-2-yl)-2-methylpyri- midin-4-amine; N-(3-(1H-imidazol-1-yl)propyl)-6-(2,3-dihydro-1H-inden-2-yl)-2-phenylpyri- midin-4-amine; and N-(3-(1H-imidazol-1-yl)propyl)-6-(2,3-dihydro-1H-inden-2-yl)-2-(pyridin-4- -yl)pyrimidin-4-amine; or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof. 20. A pharmaceutical composition comprising a compound according to claim 1 optionally in combination with one or more therapeutically acceptable diluents or carriers. 21. The pharmaceutical composition of claim 20 which comprises additionally at least one compound, selected from the group consisting of neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs. 22. The pharmaceutical composition according to claim 21, which comprises additionally at least one compound, selected from the group consisting of PEP-inhibitors, LiCl, inhibitors of inhibitors of DP IV or DP IV-like enzymes, acetylcholinesterase (ACE) inhibitors, PIMT enhancers, inhibitors of beta secretases, inhibitors of gamma secretases, inhibitors of neutral endopeptidase, inhibitors of Phosphodiesterase-4 (PDE-4), TNFalpha inhibitors, muscarinic M1 receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulatory agents, immunosuppressive agents or an agent selected from the group consisting of antegren (natalizumab), Neurelan (fampridine-SR), campath (alemtuzumab), IR 208, NBI 5788/MSP 771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD 271, adapalene), BAY 361677 (interleukin-4), matrix-metalloproteinase-inhibitors, interferon-tau (trophoblastin) and SAIK-MS. 23. A method of treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, and neurodegeneration in Down Syndrome, which comprises administering to a subject an effective amount of a compound of formula (I) according to claim 1. 24. A process for preparation of a compound of formula (I) according to claim 1 which comprises reacting a compound of formula (II) ##STR00076## wherein X represents a leaving group, with a compound of formula (III) ##STR00077## wherein R.sup.1, X, A and B are defined as in claim 1.

Details for Patent 8,188,094

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Jubilant Hollisterstier Llc	N/A	positive skin test control-histamine	Injection	103891	03/13/1924		2027-04-20
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	05/07/2001		2027-04-20
Genzyme Corporation	LEMTRADA	alemtuzumab	Injection	103948	11/14/2014		2027-04-20
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	10/12/2004		2027-04-20
Biogen Inc.	TYSABRI	natalizumab	Injection	125104	11/23/2004		2027-04-20