Claims for Patent: 9,512,115

Summary for Patent: 9,512,115

Title:	Inhibitors
Abstract:	The invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined herein, as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (5-oxo-prolyl, pGlu*) under liberation of ammonia and the intramolecular cyclization of N-terminal glutamate residues into pyroglutamic acid under liberation of water. ##STR00001##
Inventor(s):	Heiser; Ulrich (Halle/Saale, DE), Buchholz; Mirko (Halle/Saale, DE), Sommer; Robert (Magdeburg, DE), Meyer; Antje (Halle/Saale, DE), Demuth; Hans-Ulrich (Halle/Saale, DE)
Assignee:	PROBIODRUG AG (Halle (Saale), DE)
Application Number:	14/775,785
Patent Claims:	1. A compound of formula (I), ##STR00083## or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, wherein R.sup.1 represents alkyl, --O-alkyl, heterocyclyl, or cycloalkyl; R.sup.2 and R.sup.3 independently represent hydrogen, halogen, or CN; R.sup.4 and R.sup.5 independently represent hydrogen or halogen; wherein at least one of R.sup.2, R.sup.3, R.sup.4, and R.sup.5 is halogen or CN; and wherein the above alkyl, --O-alkyl, heterocyclyl, or cycloalkyl groups are substituted by one or more halogen. 2. The compound according to claim 1 wherein: R.sup.1 represents alkyl, --O-alkyl, heterocyclyl, or cycloalkyl; R.sup.2 and R.sup.3 independently represent hydrogen, fluorine, or CN; R.sup.4 and R.sup.5 independently represent hydrogen or fluorine; wherein at least one of R.sup.2, R.sup.3, R.sup.4, and R.sup.5 is fluorine or CN; and wherein the above alkyl, --O-alkyl, heterocyclyl, or cycloalkyl groups are substituted by one or more fluorine. 3. The compound according to claim 1, wherein R.sup.1 is selected from the group consisting of: --O--C.sub.2-6alkyl substituted by one or more halogen; and --O--C.sub.3-4alkyl substituted by one or more halogen. 4. The compound according to claim 1, wherein R.sup.1 is selected from the group consisting of: --O--C.sub.2-6alkyl substituted by one or more fluorine; and --O--C.sub.3-4alkyl substituted by one or more fluorine. 5. The compound according to claim 1, wherein R.sup.1 is selected from the group consisting of: difluoropropoxy; difluorobutoxy; difluoropyrrolidinyl; difluorocyclohexyl; and difluorobutyl. 6. The compound according to claim 1, wherein R.sup.1 is selected from the group consisting of: pyrrolidinyl substituted by one or more halogen; cyclohexyl substituted by one or more halogen; --C.sub.2-6alkyl substituted by one or more halogen; and --C.sub.3-4alkyl substituted by one or more halogen. 7. The compound according to claim 1, wherein R.sup.1 is selected from the group consisting of: 3,3-difluoropyrrolidin-1-yl; 4,4-difluorocyclohexyl; 2,2-difluoropropoxy; 3, 3-difluoropropoxy; 3,3-difluorobutoxy; and 3,3-difluorobutyl. 8. The compound to claim 1, wherein R.sup.1 is selected from the group consisting of: cyclohexyl substituted by one or more fluorine; --C.sub.2-6alkyl substituted by one or more fluorine; and --C.sub.3-4alkyl substituted by one or more fluorine. 9. The compound according to claim 1, wherein R.sup.2 and R.sup.5 are halogen and R.sup.3 and R.sup.4 are hydrogen; R.sup.2 is halogen and R.sup.3, R.sup.4, and R.sup.5 are hydrogen; R.sup.3 and R.sup.4 are halogen, and R.sup.2 and R.sup.5 are hydrogen; R.sup.3 is halogen, and R.sup.2, R.sup.4, and R.sup.5 are hydrogen; R.sup.2 and R.sup.3 are halogen, and R.sup.4 and R.sup.5 are hydrogen; R.sup.2 is CN and R.sup.3, R.sup.4, and R.sup.5 are hydrogen; or R.sup.3 is CN and R.sup.2, R.sup.4, and R.sup.5 are hydrogen. 10. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers, wherein the compound is selected from the group consisting of: (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluorobutoxy)-2,3-difluo- rophenyl)-oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropropoxy)-2-fluoropheny- l)oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluorobutoxy)-2-fluorophenyl- )oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(2,2-difluoropropoxy)-3-fluoropheny- l)oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(2,2-difluoropropoxy)-2,3-difluorop- henyl)oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(2,2-difluoropropoxy)-2-fluoropheny- l)oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(2,2-difluoropropoxy)-3,5-difluorop- henyl)oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluorobutoxy)-3-fluorophenyl- )oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropropoxy)-2,3-difluorop- henyl)oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropropoxy)-3-fluoropheny- l)oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-6-yl)-4-(4-(3,3-difluoropropoxy)-3,5-difluorop- henyl)oxazolidin-2-one; (S)-5-(3-(1H-benzo[d]imidazol-5-yl)-2-oxooxazolidin-4-yl)-2-(2,2-difluoro- propoxy) benzonitrile; (S)-2-(3-(1H-benzo[d]imidazol-5-yl)-2-oxooxazolidin-4-yl)-5-(2,2-difluoro- propoxy) benzonitrile; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(2,2-difluoropropoxy)-2,6-difluorop- henyl)oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropyrrolidin-1-yl)-2-flu- orophenyl)-oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropyrrolidin-1-yl)-2,3-d- ifluorophenyl)-oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropyrrolidin-1-yl)-2,6-d- ifluorophenyl) oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropyrrolidin-1-yl)-3-flu- orophenyl) oxazolidin-2-one; (S)-2-(3-(1H-benzo[d]imidazol-5-yl)-2-oxooxazolidin-4-yl)-5-(3,3-difluoro- pyrrolidin-1-yl)benzonitrile; (S)-5-(3-(1H-benzo[d]imidazol-5-yl)-2-oxooxazolidin-4-yl)-2-(3,3-difluoro- pyrrolidin-1-yl)benzonitrile; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(4,4-difluorocyclohexyl)-2-fluoroph- enyl)oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(4,4-difluorocyclohexyl)-3-fluoroph- enyl)oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluorobutyl)-2,3-difluorophe- nyl)oxazolidin-2-one; (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluorobutyl)-3-fluorophenyl)- oxazolidin-2-one; and (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluorobutyl)-2-fluorophenyl)- oxazolidin-2-one. 11. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers, wherein the compound is (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(2,2-difluoropropoxy)-2-fluoropheny- l)oxazolidin-2-one. 12. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, or polymorph thereof, including all tautomers and stereoisomers, wherein the compound is (S)-3-(1H-benzo[d]imidazol-5-yl)-4-(4-(3,3-difluoropropoxy)-2, 3-difluorophenyl)oxazolidin-2-one. 13. A method of treatment of a disease associated with glutaminyl cyclase, which comprises administering to a subject an effective amount of a compound according to claim 1. 14. A pharmaceutical composition comprising a compound according to claim 1 in combination with one or more therapeutically acceptable diluents or carriers. 15. The pharmaceutical composition of claim 14, 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. 16. The pharmaceutical composition of claim 14, 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. The method according to claim 13, wherein the disease is selected from the group consisting of Kennedy's disease, duodenal cancer with or without Helicobacter pylori infections, colorectal cancer, Zolliger-Ellison syndrome, gastric cancer with or without Helicobacter pylori infections, pathogenic psychotic conditions, schizophrenia, infertility, neoplasia, inflammatory host responses, cancer, malign metastasis, melanoma, psoriasis, impaired humoral and cell-mediated immune responses, leukocyte adhesion and migration processes in the endothelium, impaired food intake, impaired sleep-wakefulness, impaired homeostatic regulation of energy metabolism, impaired autonomic function, impaired hormonal balance or impaired regulation of body fluids, multiple sclerosis, Guillain-Barre syndrome, and chronic inflammatory demyelinizing polyradiculoneuropathy. 18. The method according to claim 13, wherein the disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, neurodegeneration in Down Syndrome, and Huntington's disease. 19. The method according to claim 13, wherein the disease selected from the group consisting of rheumatoid arthritis, atherosclerosis, pancreatitis, and restenosis. 20. A process for the preparation of a compound of formula (I) according to claim 1, which comprises: (a) preparing a compound of formula (I) from a compound of formula (II): ##STR00084## by reacting a compound of formula (II) with formamidine acetate in the presence of a suitable solvent, wherein R.sup.2, R.sup.3, R.sup.4, and R.sup.5 and are as defined above for compounds of formula (I); R.sup.6 is alkyl and R.sup.7 and R.sup.8 are halogen; or (b) preparing a compound of formula (I) from a compound of formula (III): ##STR00085## by reacting a compound of formula (III) with formamidine acetate in the presence of a suitable solvent, wherein R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are as defined above for compounds of formula (I) and R.sup.9 is cycloalkyl or heterocyclyl and R.sup.10 and R.sup.11 are halogen; or (c) preparing a compound of formula (I) from a compound of formula (IV): ##STR00086## by reacting a compound of formula (IV) with diethylaminosulfur trifluoride employed in the presence of a suitable solvent; wherein R.sup.12 is cycloalkyl; or (d) preparing a compound of formula (I) from a compound of formula (V): ##STR00087## by reacting a compound of formula (V) with formamidine acetate in the presence a suitable solvent; wherein R.sup.1, R.sup.2, and R.sup.4 are as defined above for compounds of formula (I), R.sup.13 is alkyl and R.sup.14 and R.sup.15 are halogen. 21. The compound according to claim 1, wherein R.sup.1 is selected from the group consisting of: pyrrolidinyl substituted by one or more fluorine; cyclohexyl substituted by one or more fluorine; and C.sub.2-6alkyl substituted by one or more fluorine; R.sup.2 is fluorine; R.sup.3 is fluorine R.sup.4 is fluorine; or R.sup.5 fluorine. 22. The process according to claim 20, wherein R.sup.7 is fluorine; R.sup.8 is fluorine; R.sup.10 is fluorine; R.sup.11 is fluorine; R.sup.14 is fluorine; R.sup.15 is fluorine; the solvent is acetonitrile or dichloromethane; or the agent is diethylaminosulfur trifluoride.

Details for Patent 9,512,115

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		2039-02-26
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	05/07/2001		2039-02-26
Genzyme Corporation	LEMTRADA	alemtuzumab	Injection	103948	11/14/2014		2039-02-26