Claims for Patent: 8,202,897

Summary for Patent: 8,202,897

Title:	Inhibitors of glutaminyl cyclases
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 R.sup.1, B and Y are as described throughout the description and the claims.
Inventor(s):	Buchholz; Mirko (Halle/Saale, DE), Heiser; Ulrich (Halle/Saale, DE), Harmann; Antje (Dieskau, DE)
Assignee:	Probiodrug AG (Halle (Saale), DE)
Application Number:	12/105,808
Patent Claims:	1. A compound of formula (I), ##STR00035## or a pharmaceutically acceptable salt thereof, including all tautomers and stereoisomers thereof wherein: R.sup.1 represents C.sub.3-8alkyl, carbocyclyl; aryl; heteroaryl; phenyl fused to carbocyclyl or phenyl fused to heterocyclyl; in which any of the aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl and oxo; and in which any of the aforesaid phenyl, 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 phenyl substituted by phenyl or phenyl substituted by an optionally substituted monocyclic heteroaryl group in which any of the aforesaid phenyl and monocyclic heteroaryl groups may optionally be substituted by one or more groups selected from C.sub.1-4alkyl, halogen and C.sub.1-4 alkoxy; A represents ##STR00036## 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 B represents H or methyl. 2. A compound according to claim 1 wherein R.sup.1 represents C.sub.3-8alkyl, carbocyclyl; aryl; heteroaryl; phenyl fused to carbocyclyl or phenyl fused to heterocyclyl; in which any of the aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl and oxo; and in which any of the aforesaid phenyl, 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); or R.sup.1 represents phenyl substituted by phenyl or phenyl substituted by an optionally substituted monocyclic heteroaryl group in which any of the aforesaid phenyl and monocyclic heteroaryl groups may optionally be substituted by one or more groups selected from C.sub.1-4alkyl, halogen and C.sub.1-4 alkoxy. 3. A compound according to claim 1 wherein R.sup.1 represents carbocyclyl; aryl; heteroaryl; phenyl fused to carbocyclyl or phenyl fused to heterocyclyl; in which any of the aforesaid carbocyclyl and heterocyclyl groups may optionally be substituted by one or more groups selected from methyl and oxo; and in which any of the aforesaid phenyl, 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); or R.sup.1 represents phenyl substituted by phenyl or phenyl substituted by an optionally substituted monocyclic heteroaryl group in which any of the aforesaid phenyl and monocyclic heteroaryl groups may optionally be substituted by one or more groups selected from C.sub.1-4alkyl, halogen and C.sub.1-4 alkoxy. 4. A compound according to claim 3 wherein R.sup.1 represents optionally substituted carbocyclyl. 5. A compound according to claim 3 wherein R.sup.1 represents optionally substituted aryl. 6. A compound according to claim 3 wherein R.sup.1 represents phenyl fused to optionally substituted heterocyclyl. 7. A compound according to claim 1 wherein Y represents --(CH.sub.2).sub.3--. 8. A compound according to claim 1 wherein Y represents --(CH.sub.2).sub.4--. 9. A compound according claim 1 wherein B represents H. 10. A compound according to claim 1 as defined in any one of examples 1 to 12: (1) N-(3-(1H-imidazol-1-yl)propyl)-N-butyl-2-nitroethene-1,1-diamine, (2) N-(1-(3-(1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-cyclohexanamine, (3) N-(1-(3-(1H-imidazol-1-yl)-propylamino)-2-nitrovinyl)benzenamine, (4) N-(1-(3-(1H-imidazol-1-yl)-propylamino)-2-nitrovinyl)naphthalen-1-amine, (5) N-(1-(3-(1H-imidazol-1-yl)-propylamino)-2-nitrovinyl)-4-chlorobenzena- mine, (6) N-(1-(3-(1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-4-(trifluor- omethyl)benzenamine, (7) N-(1-(3-(1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-4-methoxybenzenamine- , (8) N-(1-(3-(1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-2,3-dihydrobenz- o[b][1,4]dioxin-6-amine, (9) N-(1-(3-(1H-imidazol-1-yl)propylamino)-2-nitrovinyl)benzo[d][1,3]dioxol-5- -amine, (10) N-(1-(3-(1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-2,4-dimethoxybenzena- mine, (11) N-(1-(3-(1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-3,4,5-trim- ethoxybenzenamine, (12) N-(1-(3-(1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-3,4-dimethoxybenzena- mine, or a pharmaceutically acceptable salt of any one thereof. 11. A pharmaceutical composition comprising a compound of claim 1 optionally in combination with one or more therapeutically acceptable diluents or carriers. 12. A pharmaceutical composition comprising a compound of claim 10 optionally in combination with one or more therapeutically acceptable diluents or carriers. 13. The pharmaceutical composition of claim 11, 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. 14. The pharmaceutical composition of claim 12, 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. 15. The pharmaceutical composition of claim 11, 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. 16. The pharmaceutical composition of claim 12, 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. 17. A method of treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, and Familial Danish Dementia, which comprises administering to a subject a therapeutically effective amount of a compound of claim 1. 18. A method of treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, and Familial Danish Dementia, which comprises administering to a subject a therapeutically effective amount of a pharmaceutical composition of claim 13. 19. A method of treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, and Familial Danish Dementia, which comprises administering to a subject a therapeutically effective amount of a pharmaceutical composition of claim 14. 20. A method of treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, and Familial Danish Dementia, which comprises administering to a subject a therapeutically effective amount of a pharmaceutical composition of claim 15. 21. A method of treatment of a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, neurodegeneration in Down Syndrome, Familial British Dementia, and Familial Danish Dementia, which comprises administering to a subject a therapeutically effective amount of a pharmaceutical composition of claim 16. 22. A process for preparation of a compound of formula (I) according to claim 1, which comprises reaction of a compound of formula (II) ##STR00037## wherein R.sup.7 represents C.sub.1-6alkyl e.g. methyl and R.sup.1 is as defined in any one of claims 1 and 6 to 10 with a compound of formula (III) ##STR00038## wherein A and B are as defined in claim 1.

Details for Patent 8,202,897

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