Claims for Patent: 8,541,596

Summary for Patent: 8,541,596

Title:	Inhibitors
Abstract:	Novel heterocyclic derivatives 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.
Inventor(s):	Heiser; Ulrich (Halle/Saale, DE), Ramsbeck; Daniel (Halle/Saale, DE), Hoffmann; Torsten (Halle/Saale, DE), Boehme; Livia (Halle/Saale, DE)
Assignee:	Probiodrug AG (Halle/Saale, DE)
Application Number:	13/091,276
Patent Claims:	1. A compound of formula (I): ##STR00119## or a pharmaceutically acceptable salt, tautomer, or stereoisomers thereof wherein: X represents a bond or a --(CH.sub.2).sub.m-group; m represents an integer selected from 1 to 3; R.sup.1 represents -aryl, --C.sub.1-6alkylaryl, -cycloalkyl, --C.sub.1-6alkylcycloalkyl, --C.sub.1-6alkyl-Het, -aryl fused to heterocyclyl, --C.sub.1-6alkylaryl fused to heterocyclyl, -aryl substituted by heteroaryl, --C.sub.1-6alkylaryl substituted by heteroaryl, -aryl substituted by phenyl, --C.sub.1-6alkylaryl substituted by phenyl, -aryl substituted by phenoxy or --C.sub.1-6alkylaryl substituted by phenoxy; and in which any of aforesaid aryl, heterocyclyl, heteroaryl, phenyl or phenoxy groups may optionally be substituted by one or more groups selected from C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl, --C.sub.1-6thioalkyl, --SOC.sub.1-4alkyl, --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, --SOC.sub.3-6cycloalkyl, 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, 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) and --C(O)NH(C.sub.3-10cycloalkyl); R.sup.2 represents -aryl, --C.sub.1-6alkylaryl, -cycloalkyl, --C.sub.1-6alkylcycloalkyl, --C.sub.1-6alkyl- Het, -aryl fused to heterocyclyl, --C.sub.1-6alkylaryl fused to heterocyclyl, -aryl substituted by heteroaryl, --C.sub.1-6alkylaryl substituted by heteroaryl, -aryl substituted by phenyl, --C.sub.1-6alkylaryl substituted by phenyl, -aryl substituted by phenoxy or --C.sub.1-6alkylaryl substituted by phenoxy; and in which any of aforesaid aryl, heterocyclyl, heteroaryl, phenyl or phenoxy groups may optionally be substituted by one or more groups selected from C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl, --C.sub.1-6thioalkyl, --SOC.sub.1-4alkyl, --S0.sub.2C.sub.1-4alkyl, C.sub.1-6alkoxy-, --O--C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl, --SO.sub.2C.sub.3-8cycloalkyl, --SOC.sub.3-6cycloalkyl, 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, 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) and --C(O)NH(C.sub.3-10cycloalkyl); Het represents a bicyclic heteroaryl group; in which said bicyclic heteroaryl group may be optionally substituted by one or more groups selected from C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6haloalkyl, --C.sub.1-6thioalkyl, --SOC.sub.1-4alkyl, --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, --SOC.sub.3-6cycloalkyl, C.sub.3-6alkenyloxy-, C.sub.3-6alkynyloxy-, --C(O)OC.sub.1-6alkyl, --C(O)OC.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) and --C(O)NH(C.sub.3-10cycloalkyl). 2. A compound as defined in claim 1, wherein R.sup.1 represents C.sub.1-6alkylaryl, --C.sub.1-6alkyl-Het, --C.sub.1-6alkylaryl fused to heterocyclyl or --C.sub.1-6alkylaryl substituted by heteroaryl. 3. A compound as defined in claim 1, wherein R.sup.2 represents -aryl, --C.sub.1-6alkylaryl, --C.sub.1-6alkylcycloalkyl, --C.sub.1-6alkyl-Het, --C.sub.1-6alkylaryl fused to heterocyclyl or --C.sub.1-6alkylaryl substituted by heteroaryl. 4. A compound as defined in claim 1, wherein R.sup.1 represents --C.sub.1-6alkylaryl and R.sup.2 represents --C.sub.1-6alkylaryl or --C.sub.1-6alkylcycloalkyl; wherein said aryl groups are optionally substituted by one or more halogen, cyano, C.sub.1-6alkyl, C.sub.1-6alkoxy, --C.sub.1-6thioalkyl or --N(C.sub.1-4alkyl)(C.sub.1-4alkyl) groups. 5. A compound as defined in claim 1, wherein R.sup.1 and R.sup.2 both represent --C.sub.1-6alkylaryl; wherein said phenyl groups are optionally substituted by one or more halogen, cyano, C.sub.1-6alkyl, C.sub.1-6alkoxy, --C.sub.1-6thioalkyl or --N(C.sub.1-4alkyl)(C.sub.1-4alkyl) groups. 6. A compound as defined in claim 1, wherein R.sup.1 and R.sup.2 both represent --C.sub.1-6alkylaryl substituted by to heteroaryl. 7. A compound as defined in claim 1, wherein R.sup.1 and R.sup.2 both represent --C.sub.1-6alkylaryl substituted by heteroaryl. 8. A compound as defined in claim 1, wherein R.sup.1 represents --C.sub.1-6alkyl-Het and R.sup.2 represents --C.sub.1-6alkyl-Het, C.sub.1-6alkylaryl, or --C.sub.1-.sub.6alkyl cycloalkyl; wherein said Het groups are optionally substituted by one or more halogen or C.sub.1-6alkyl groups; and wherein said aryl group is optionally substituted by one or more --C.sub.1-6thioalkyl, C.sub.1-6alkyl, C.sub.1-6alkoxy, halogen or --N(C.sub.1-4alkyl)(C.sub.1-4alkyl) groups. 9. A compound as defined in claim 1, wherein R.sup.1 and R.sup.2 bothrepresent --C.sub.1-6alkyl-Het; wherein said Het groups are optionally substituted by one ormore halogen or C.sub.1-6alky groups. 10. A compound as defined in claim 1, wherein R.sup.1 represents aryl and R.sup.2 represents --C.sub.1-6alkylaryl. 11. A compound as defined in claim 1, wherein X represents a bondor a --CH.sub.2-group. 12. A compound as defined in claim 11, wherein X representsa bond. 13. A compound according to claim 1, wherein saidcompound is selected from the group consisting of TABLE-US-00006 ##STR00120## N,N-Dibenzyl-1H- benzo[d]imidazol-5-amine; ##STR00121## N,N-Bis(2,4,5- trifluorobenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00122## N,N-Bis(4-cyanobenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00123## N,N-Bis((4-methylbenzyl)- 1H-benzo[d]imidazol-5- amine; ##STR00124## N,N-Bis(4-isopropylbenzyl)- 1H-benzo[d]imidazol-5- amine; ##STR00125## N,N-Bis(4-tert-butylbenzyl)- 1H-benzo[d]imidazol-5- amine; ##STR00126## N,N-Bis(4-methoxybenzyl)- 1H-benzo[d]imidazol-5- amine; ##STR00127## N,N-Bis(2-fluoro-3- methylbenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00128## N,N-Bis(4-(thiophen-2- yl)benzyl)-1H- benzo[d]imidazol-5-amine; ##STR00129## N,N-Bis((naphthalen-2- yl)methyl))-1H- benzo[d]imidazol-5-amine; ##STR00130## N,N-Bis((benzo[d]thiazol-2- yl)methyl)-1H- benzo[d]imidazol-5-amine; ##STR00131## N,N-Bis- ((benzo[c][1,2,5]thiadiazol-5- yl)methyl)-1H- benzo[d]imidazol-5-amine; ##STR00132## N,N-Bis((5- chlorobenzo[b]thiophen-3- yl)methyl)-1H- benzo[d]imidazol-5-amine; ##STR00133## N,N-Bis((2-methylquinolin-6- yl)methyl)-1H- benzo[d]imidazol-5-amine; ##STR00134## N-(4-(Methylthio)benzyl)-N- benzyl-1H-benzo[d]imidazol- 5-amine; ##STR00135## N,N-Bis(3-methoxybenzyl)- 1H-benzo[d]imidazol-5- amine; ##STR00136## N,N-Bis((3,4-dihydro-2H- benzo[b][1,4]dioxepin-9- yl)methyl)-1H- benzo[d]imidazol-5-amine; ##STR00137## N,N-Bis(4- (methylthio)benzyl)-1H- benzo[d]imidazol-5-amine; ##STR00138## N,N-Bis(4-bromobenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00139## N,N-Bis(3-bromobenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00140## N,N-Bis(2-fluorobenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00141## N,N-Bis(3,5-difluorobenzyl)- 1H-benzo[d]imidazol-5- amine; ##STR00142## N-(4-(Methylthio)benzyl)-N- (4-methylbenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00143## N-(4-(Methylthio)benzyl)-N- (4-isopropylbenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00144## N-(4-(Methylthio)benzyl)-N- (4-methoxybenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00145## N-(3-Methoxybenzyl)-N-(4- (methylthio)benzyl)-1H- benzo[d]imidazol-5-amine; ##STR00146## N-(3,5-Dimethoxybenzyl)-N- (4-(methylthio)benzyl)-1H- benzo[d]imidazol-5-amine; ##STR00147## N-(2-Fluoro-4,5- dimethoxybenzyl)-N-(4- (methylthio)benzyl)-1H- benzo[d]imidazol-5-amine; ##STR00148## N-(2-Fluoro-3-methylbenzyl)- N-(4-(methylthio)benzyl)-1H- benzo[d]imidazol-5-amine; ##STR00149## N-(3,5-Difluorobenzyl)-N-(4- (methylthio)benzyl)-1H- benzo[d]imidazol-5-amine; ##STR00150## N-(3,4,5-Trifluorobenzyl)-N- (4-(methylthio)benzyl)-1H- benzo[d]imidazol-5-amine; ##STR00151## N-(2,4,5-Trifluorobenzyl)-N- (4-(methylthio)benzyl)-1H- benzo[d]imidazol-5-amine; ##STR00152## N-(2,3,5,6-Tetrafluoro-4- methylbenzyl)-N-(4- (methylthio)benzyl)-1H- benzo[d]imidazol-5-amine; ##STR00153## N-(2,5-Dichlorobenzyl)-N-(4- (methylthio)benzyl)-1H- benzo[d]imidazol-5-amine; ##STR00154## N-(4-(Methylthio)benzyl)-N- (4-bromobenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00155## N-(4-(Methylthio)benzyl)-N- ((5-chlorobenzo[b]thiophen- 3-yl)methyl)-1H- benzo[d]imidazol-5-amine; ##STR00156## N-(4-(Methylthio)benzyl)-N- ((benzo[d]thiazol-2- yl)methyl)-1H- benzo[d]imidazol-5-amine; ##STR00157## N-(4-(Methylthio)benzyl)-N- ((benzo[c][1,2,5]thiadiazol-6- yl)methyl)-1H- benzo[d]imidazol-5-amine; ##STR00158## N-(4-Ethylbenzyl)-N-(4- methylbenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00159## N-(4-(Methylthio)benzyl)-N- (4-ethylbenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00160## N-(2,3,5,6-Tetrafluoro-4- methylbenzyl)-N-(4- ethylbenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00161## N-(3,4,5-Trifluorobenzyl)-N- (4-ethylbenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00162## N-(4-Cyanobenzyl)-N-(4- ethylbenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00163## N-(4-Ethylbenzyl)-N-((5- chlorobenzo[b]thiophen-3- yl)methyl)-1H- benzo[d]imidazol-5-amine; ##STR00164## N-(4-Ethylbenzyl)-N- ((benzo[d]thiazol-2- yl)methyl)-1H- benzo[d]imidazol-5-amine; ##STR00165## N-(4-Ethylbenzyl)-N- ((benzo[c][1,2,5]thiadiazol-6- yl)methyl)-1H- benzo[d]imidazol-5-amine; ##STR00166## N-(4-Methoxybenzyl)-N- ((benzo[c][1,2,5]thiadiazol-6- yl)methyl)-1H- benzo[d]imidazol-5-amine; ##STR00167## N-(4-Chlorobenzyl)-N- ((benzo[c][1,2,5]thiadiazol-6- yl)methyl)-1H- benzo[d]imidazol-5-amine; ##STR00168## N-(4- (Dimethylamino)benzyl)-N- (4-methylbenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00169## N-(4- (Dimethylamino)benzyl)-N- (4-methoxybenzyl)-1H- benzo[d]imidazol-5-amine; ##STR00170## N-(4- (Dimethylamino)benzyl)-N- (4-(methylthio)benzyl)-1H- benzo[d]imidazol-5-amine; ##STR00171## N-(4- (Dimethylamino)benzyl)-N- ((benzo[c][1,2,5]thiadiazol-5- yl)methyl)-1H- benzo[d]imidazol-5-amine; ##STR00172## N-(4-(Methylthio)benzyl)-N- (cyclohexylmethyl)-1H- benzo[d]imidazol-5-amine; ##STR00173## N-(4-Methoxybenzyl)-N- benzyl-3H-benzo[d]imidazol- 5-amine; ##STR00174## N-(4-Methoxybenzyl)-N- ((naphthalen-2-yl)methyl)- 3H-benzo[d]imidazol-5- amine; ##STR00175## N-(4-Methoxybenzyl)-N- phenethyl-1H- benzo[d]imidazol-5-amine; ##STR00176## N-(4-Methoxybenzyl)-N-(3- phenylpropyl)-3H- benzo[d]imidazol-5-amine; and ##STR00177## N-Benzyl-N-phenyl-1H- benzo[d]imidazol-5-amine; or a pharmaceutically accepted salt thereof, including all tautomers and stereoisomers. 14. A pharmaceutical composition comprising acompound according to claim 1, optionally in combination with one or moretherapeutically acceptable diluents or carriers. 15. The pharmaceutical composition of claim 14, which comprisesadditionally at least one compound, selected from the group consisting ofneuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, betaamyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs andanti-multiple sclerosis drugs. 16. The pharmaceutical composition of claim 14, which comprisesadditionally 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 ofPhosphodiesterase-4 (PDE-4), TNFalpha inhibitors, muscarinic M1 receptorantagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulatory agents, immunosuppressive agents or an agentselected 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 process for preparation of a compound of formula(I) according to claim 1, which comprises: (a) preparing a compound of formula (I) wherein X represents a bond by reacting a compound of formula (II) ##STR00178## with a compound of formula NHR.sup.1R.sup.2, wherein l.sup.1 represents a suitable leaving group and R.sup.1 and R.sup.2 are as defined in claim 1; (b) preparing a compound of formula (I) wherein X represents a bond, R.sup.1 is as defined in claim 1 and R.sup.2 represents --C.sub.1-6alkylaryl, --C.sub.1-6alkyl-Het, --C.sub.1-6alkylaryl fused to heterocyclyl, --C.sub.1-6alkylaryl substituted by heteroaryl,--C.sub.1-6alkylaryl substituted by phenyl or --C.sub.1-6alkylaryl substituted by phenoxy, by alkylatinga compound of formula (III): ##STR00179## wherein Cy.sup.1 represents the aryl or Het group of R.sup.2; (c) preparing a compound of formula (I) wherein X represents a bond, R.sup.1 is as defined in claim 1 and R.sup.2 represents --C.sub.1-6alkyl, --C.sub.1-6alkylaryl, --C.sub.1-6alkylcycloalkyl, --C.sub.1-6alkyl-Het, --C.sub.1-6alkylaryl fused to heterocyclyl, --C.sub.1-6alkylaryl substituted by heteroaryl, --C.sub.1-6alkylaryl substituted by phenyl or --C.sub.1-6alkyaryl substituted by phenoxy, by reacting a compound of formula (IV): ##STR00180## with a compound of formula H--CO--R.sup.2, wherein R.sup.2 is as defined in claim 1; (d) preparing a compound of formula (I) wherein: X represents a bond, R.sup.1 is as defined in claim 1 and R.sup.2 is as defined in claim 1; or X represents a bond and R.sup.1 and R.sup.2 represent identical groups, by reacting a compound offormula (IV): ##STR00181## or an optionally protecting derivative thereof with a compound of formula L.sup.2-R.sup.2, whereinL.sup.2 represents a suitable leaving group and R.sup.2 is as defined in claim 1; (e) preparing a compound of formula (I) wherein X represents a --(CH.sub.2).sub.m-group,by reacting a compound of formula (VI): ##STR00182## with a compound of formula HNR.sup.1R.sup.2, wherein R.sup.1 and R.sup.2 are as defined in claim 1; (f) interconversion of compounds of formula (I), such as preparing acompound of formula (I) wherein R.sup.1 is as defined in claim 1 by reacting a compound of formula (V): ##STR00183## with a compound of formula L.sup.4--R.sup.1a, wherein R.sup.2 is as defined in claim1, L.sup.4 represents a suitable leaving group such as bromine and R.sup.1a represents an R.sup.1 group as defined in claim1; and/or (g) deprotecting a compound of formula (I) which is protected. 18. The process of claim 17, wherein L.sup.1 is bromine, L.sup.2 is bromine, or L.sup.4 bromine.

Details for Patent 8,541,596

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		2030-04-21
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	05/07/2001		2030-04-21
Genzyme Corporation	LEMTRADA	alemtuzumab	Injection	103948	11/14/2014		2030-04-21
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	10/12/2004		2030-04-21
Biogen Inc.	TYSABRI	natalizumab	Injection	125104	11/23/2004		2030-04-21