Claims for Patent: 9,034,907

Summary for Patent: 9,034,907

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: R.sup.1 represents ##STR00002## and R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, X.sub.1, X.sub.2, X.sub.3, X.sub.4, Y and Z are as defined throughout the description and the claims.
Inventor(s):	Buchholz; Mirko (Halle/Saale, DE), Heiser; Ulrich (Halle/Saale, DE)
Assignee:	Probiodrug AG (Halle (Saale), DE)
Application Number:	12/105,849
Patent Claims:	1. A compound of formula (I): ##STR00086## or a pharmaceutically acceptable salt thereof, including all tautomers and stereoisomers thereof, wherein: (a) R.sup.1 represents ##STR00087## with Y representing 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.2, R.sup.3,and R.sup.4 independently representing H or C.sub.1-2alkyl, or ##STR00088## with Z representing 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.5 and R.sup.6 independently representing H or C.sub.1-2alkyl; (b) X.sub.1 represents C; (c) X.sub.2 represents C; (d) X.sub.3 represents sulfur; (e) X.sub.4 represents a bond; (f) the heteroaryl ring formed by X.sub.1, X.sub.2, X.sub.3, and X.sub.4 may optionally be substituted by one or more substituents selected from C.sub.1-6alkyl, halogen, C.sub.1-6alkoxy, carbocyclyl, phenyl, monocyclic heteroaryl, --C.sub.1-4alkyl-phenyl, --C.sub.1-4alkyl-(monocyclic heteroaryl) or one or more substituents selected from C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl, --C.sub.1-6thioalkyl, --SO.sub.2C.sub.1-4alkyl, --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(O)O C.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl-, nitro, 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), --SOC.sub.1-4alkyl, and --SOC.sub.3-6cycloalkyl; wherein, the phenyl or heteroaryl rings may optionally be substituted by one or more substituents selected from C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, C.sub.1-4haloalkoxy, and halogen; and the carbocyclyl may optionally be substituted by methyl or oxo; and, optionally, (g) two neighbouring atoms selected from X.sub.1 and X.sub.2 may be linked by a C.sub.3-6alkylene chain wherein the alkylene chain may optionally be substituted by methyl or oxo. 2. A compound according to claim 1 wherein: the heteroaryl ring formed by X.sub.1, X.sub.2, X.sub.3, and X.sub.4 may optionally be substituted by one or more substituents selected from C.sub.1-6alkyl, halogen, C.sub.1-6alkoxy, carbocyclyl, phenyl, monocyclic heteroaryl, --C.sub.1-4alkyl-phenyl, --C.sub.1-4alkyl-(monocyclic heteroaryl), wherein, (a) the phenyl or heteroaryl rings may optionally be substituted by one or more substituents selected from C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, C.sub.1-4haloalkoxy, and halogen; (b) the carbocyclyl may optionally be substituted by methyl; and (c) two neighbouring atoms selected from X.sub.1 and X.sub.2 may be linked by a C.sub.3-6alkylene chain wherein the alkylene chain may optionally be substituted by methyl or oxo. 3. A compound according to claim 1 wherein: R.sup.1 represents ##STR00089## and, Y, R.sup.2, R.sup.3 and R.sup.4 are as defined in claim 1. 4. A compound according to claim 3 wherein R.sup.2, R.sup.3, and R.sup.4 do not all represent H. 5. A compound according to claim 4 wherein: R.sup.2 represents H, R.sup.3 represents H, and R.sup.4 represents methyl. 6. A compound according to claim 4 wherein: R.sup.2 represents H, R.sup.3 represents methyl, and R.sup.4 represents H. 7. A compound according to claim 3, wherein Y represents an unsubstituted C.sub.2-5 alkylene chain. 8. A compound according to claim 7, wherein Y represents --(CH.sub.2).sub.3-- or --(CH.sub.2).sub.4--. 9. A compound according to claim 1 wherein: R.sup.1 represents ##STR00090## and Z, R.sup.5, and R.sup.6 are as defined in claim 1. 10. A compound according to claim 9 wherein: R.sup.5 represents H, and R.sup.6 represents H. 11. A compound according claim 9 wherein Z represents a bond, --CH.sub.2--, or --CH.sub.2--CH.sub.2--. 12. A compound according to claim 11, wherein Z represents a bond. 13. A compound according to claim 11, wherein Z represents --CH.sub.2--. 14. A compound according to claim 1 wherein: X.sub.1 is carbon, X.sub.2 is carbon, X.sub.3 is sulfur, X.sub.4 is a bond; and X.sub.1, X.sub.2, X.sub.3, and X.sub.4, together, form an unsubstituted thiophene. 15. A compound according to claim 1 wherein: X.sub.1 is carbon, X.sub.2 is carbon, X.sub.3 is sulfur, X.sub.4 is a bond; and X.sub.1, X.sub.2, X.sub.3, and X.sub.4, together, form a substituted thiophene. 16. A compound according to claim 15 wherein X.sub.1 and X.sub.2 represent C, X.sub.3 represents S, and X.sub.4 represents a bond such that the heteroaryl ring represents ##STR00091## wherein: (i) R.sup.15 and R.sup.16 are selected from H, C.sub.1-6alkyl, halogen, C.sub.1-6alkoxy, carbocyclyl, phenyl, monocyclic heteroaryl, --C.sub.1-4alkyl-phenyl, --C.sub.1-4alkyl-(monocyclic heteroaryl) or one or more substituents selected from C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl, --C.sub.1-6thioalkyl, --SO.sub.2C.sub.1-4alkyl, --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(O)OC.sub.1-6alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl-, nitro, cyano, hydroxyl, --C(O)OH, --NH.sub.2, --NHC.sub.1-4alkyl, -N(C.sub.i-4alkyl)(C.sub.i-4alkyl), --C(O)N(C.sub.i-4alkyl)(C.sub.i-4alkyl), --C(O)NH.sub.2, --C(O)NH(C.sub.1-4alkyl), --SOC.sub.1-4alkyl, and --SOC.sub.3-6cycloalkyl, wherein (a) the phenyl or heteroaryl rings may optionally be substituted by one or more substituents selected from C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, C.sub.1-4haloalkoxy, and halogen; and (b) the carbocyclyl may optionally be substituted by methyl or oxo; or (ii) R.sup.15 and R.sup.16 together represent propylene, butylene, (methyl)butylene, pentylene, or hexylene. 17. A compound according to claim 16 wherein: R.sup.15 represents H, methyl, ethyl, unsubstituted phenyl or benzyl; or R.sup.15 and R.sup.16 together represent propylene, butylene, (methyl)butylene, pentylene, or hexylene. 18. A compound according to claim 16, wherein: R.sup.16 K represents H, methyl, ethyl, unsubstituted phenyl or benzyl; or R.sup.15 and R.sup.16 together represent propylene, butylene, (methyl)butylene, pentylene, or hexylene. 19. A compound according to claim 1 selected from the group consisting of: 3-[3-(5-methyl-1H-imidazol-1-yl)propyl]-2-thioxo-2,3,6,7,8,9-hexahydr- o[1]benzothieno[2,3-d]pyrimidin-4(1H)-one; 6-ethyl-3-[3-(5-methyl-1 H-imidazol-1-yl)propyl]-2-thioxo-2,3-dihydrothieno[2,3-d]pyrimidin-4(1 H)-one; 2,3-dihydro-5,6-dimethyl-3-(3-(5-methyl-1 H-imidazol-1-yl)propyl)-2-thioxothieno[2,3-d]pyrimidin-4(1 H)-one; 5-ethyl-2,3-di hydro-6-methyl-3-(3-(5-methyl-1 H-imidazol-1-yl)propyl)-2-thioxothieno[2,3-d]pyrimidin-4(1 H)-one; 2,3-dihydro-3-(3-(5-methyl-1 H-imidazol-1-yl)propyl)-6-phenyl-2-thioxothieno[2,3-d]pyrimidin-4(1 H)-one; 3-[3-(5-methyl-1 H-imidazol-1-yl)propyl]-2-thioxo-1,2,3,5,6,7-hexahydro-4H-cyclopenta[4,5]- thieno[2,3-d]pyrimidin-4-one; 7-methyl-3-[3-(5-methyl-1 H-imidazol-1-yl)propyl]-2-thioxo-2,3,5,6,7,8-hexahydro[1]benzothieno[2,3-- d]pyrimidin-4(1H)-one; 3-[3-(5-methyl-1 H-imidazol-1-yl)propyl]-2-thioxo-1,2,3,5,6,7,8,9-octahydro-4H-cyclohepta[- 4,5]thieno[2,3-d]pyrimidin-4-one; 3-[3-(5-methyl-1 H-imidazol-1 -yl)propyl]-2-thioxo-2,3,5,6,7,8,9,10-octahydrocycloocta[4,5]thieno[2,3-d- ]pyrimidin-4(1 H)-one; 2,3-dihydro-6-methyl-3-(3-(5-methyl-1 H-imidazol-1-yl)propyl)-5-phenyl-2-thioxothieno[2,3-d]pyrimidin-4(1 H)-one; 6-benzyl-2,3-dihydro-3-(3-(5-methyl-1 H-imidazol-1-yl)propyl)-2-thioxothieno[2,3-d]pyrimidin-4(1 H)-one; 3-[3-(4-methyl-1 H-imidazol-1-yl)propyl]-2-thioxo-2,3,6,7,8,9-hexahydro[1]benzothieno[2,3-- d]pyrimidin-4(1H)-one; 6-ethyl-3-[3-(4-methyl-1 H-imidazol-1-yl)propyl]-2-thioxo-2,3-dihydrothieno[2,3-d]pyrimidin-4(1 H)-one; 2,3-dihydro-5,6-dimethyl-3-(3-(4-methyl-1 H-imidazol-1-yl)propyl)-2-thioxothieno[2,3-d]pyrimidin-4(1 H)-one; 5-ethyl-2,3-di hydro-6-methyl-3-(3-(4-methyl-1 H-imidazol-1-yl)propyl)-2-thioxothieno[2,3-d]pyrimidin-4(1 H)-one; 2,3-dihydro-3-(3-(4-methyl-1 H-imidazol-1-yl)propyl)-6-phenyl-2-thioxothieno[2,3-d]pyrimidin-4(1 H)-one; 3-[3-(4-methyl-1H-imidazol-1-yl)propyl]-2-thioxo-1,2,3,5,6,7-hexa- hydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-one; 7-methyl-3-[3-(4-(4-methyl-1H-imidazol-1-yl)propyl]-2-thioxo-2,3,5,6,7,8-- hexahydro[1]benzothieno[2,3-d]pyrimidin-4(1H)-one; 3-[3-(4-methyl-1H-imidazol-1-yl)propyl]-2-thioxo-1,2,3,5,6,7,8,9-octahydr- o-4H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-one; 3-[3-(4-methyl-1H-imidazol-1-yl)propyl]-2-thioxo-2,3,5,6,7,8,9,10-octahyd- rocycloocta[4,5]thieno[2,3-d]pyrimidin-4(1H)-one; 2,3-dihydro-6-methyl-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)-5-phenyl-2-t- hioxothieno[2,3-d]pyrimidin-4(1H)-one; 6-benzyl-2,3-dihydro-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)-2-thioxothie- no[2,3-d]pyrimidin-4(1 H)-one; 2,3-dihydro-3-(3-(4-methyl-1H-imidazol-1-yl)propyl)-2-thioxothieno[3,2-d]- -pyrimidin-4(1 H)-one; 2,3-dihydro-7-methyl-3-(3-(1H-imidazol-1-yl)propyl)-2-thioxothieno[3,2-d]- pyrimidin-4(1 H)-one; 3-[3-(1H-imidazol-1-yl)propyl]-2-thioxo-2,3,6,7,8,9-hexahydro[1]benzothie- no[2,3-d]pyrimidin-4(1 H)-one; 6-ethyl-3-[3-(1H-imidazol-1-yl)propyl]-2-thioxo-2,3-dihydrothieno[2,3-d]p- yrimidin-4(1H)-one; 2,3-dihydro-5,6-dimethyl-3-(3-(1H-imidazol-1-yl)propyl)-2-thioxothieno[2,- 3-d]pyrimidin-4(1 H)-one; 5-ethyl-2,3-dihydro-6-methyl-3-(3-(1H-imidazol-1-yl)propyl)-2-thioxothien- o[2,3-d]pyrimidin-4(1 H)-one; 2,3-dihydro-3-(3-(1H-imidazol-1-yl)propyl)-6-phenyl-2-thioxothieno[2,3-d]- pyrimidin-4(1H)-one; 3-[3-(1H-imidazol-1-yl)propyl]-2-thioxo-1,2,3,5,6,7-hexahydro-4H-cyclopen- ta[4,5]thieno[2,3-d]pyrimidin-4-one; 7-methyl-3-[3-(1 H-imidazol-1-yl)propyl]-2-thioxo-2,3,5,6,7,8-hexahydro[1]benzothieno[2,3-- d]pyrimidin-4(1 H)-one; 3-[3-(1 H-imidazol-1-yl)propyl]-2-thioxo-1,2,3,5,6,7,8,9-octahydro-4H-cyclohepta[- 4,5]thieno[2,3-d]pyrimidin-4-one; 3-[3-(1 H-imidazol-1-yl)propyl]-2-thioxo-2,3,5,6,7,8,9,10-octahydrocycloocta[4,5]- thieno[2,3-d]pyrimidin-4(1H)-one; 2,3-dihydro-6-methyl-3-(3-(1 H-imidazol-1-yl)propyl)-5-phenyl-2-thioxothieno[2,3-d]pyrimidin-4(1 H)-one; 6-benzyl-2,3-dihydro-3-(3-(1 H-imidazol-1-yl)propyl)-2-thioxothieno[2,3-d]pyrimidin-4(1 H)-one; 2,3-dihydro-3-(3-(5-methyl-1 H-imidazol-1-yl)propyl)-2-thioxothieno[3,2-d]pyrimidin-4(1 H)-one; and 3-(1 H-benzo[d]imidazol-5-yl)methanamine-2-thioxo-2,3,6,7,8,9-hexahydro[1- ]-benzothieno[2,3-d]-pyrimidin-4(1 H)-one; or a pharmaceutically acceptable salt 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 of claim 21, which comprises additionally at least one compound, selected from the group consisting of prolyl endopeptidase (PEP)-inhibitors, LiCI, inhibitors of dipeptidyl peptidase (DP) IV or an enzyme having DP IV activity, acetylcholinesterase (ACE) inhibitors, Protein L-isoaspartyl methyltransferase (PIMT) enhancers, inhibitors of beta secretases, inhibitors of gamma secretases, inhibitors of neutral endopeptidase, inhibitors of Phosphodiesterase-4 (PDE-4), tumor necrosis factor (TNF)-alpha inhibitors, muscarinic M1 receptor antagonists, N-Methyl-D-aspartic acid (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 sodium 5-chloro-3-[ethyl(phenyl)carbamoyl]-1-methyl-2-oxoquinolin-4-olate (SAIK-MS). 23. (currently amended; withdrawn) A process for preparation of a compound of formula (I) according to claim 1, which comprises reaction of a compound of formula (II) ##STR00092## wherein X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are defined as in claim 1 and E represents a leaving group with a compound of formula (III), R.sup.1--NH.sub.2 (III) wherein R.sup.1 is defined as in claim 1. 24. The process of claim 23, wherein E is an alkoxy group.

Details for Patent 9,034,907

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		2027-04-18
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	05/07/2001		2027-04-18
Genzyme Corporation	LEMTRADA	alemtuzumab	Injection	103948	11/14/2014		2027-04-18
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	10/12/2004		2027-04-18