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Last Updated: March 28, 2024

Claims for Patent: 8,772,508


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Summary for Patent: 8,772,508
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, stereoisomers and polymorphs thereof, wherein A, B and R.sup.1 are as defined throughout the description and the claims.
Inventor(s): Buchholz; Mirko (Halle/Saale, DE), Heiser; Ulrich (Halle/Saale, DE), Hamann; Antje (Dieskau, DE)
Assignee: Probiodrug AG (Halle (Saale), DE)
Application Number:12/105,730
Patent Claims:1. A compound of formula (I), ##STR00054## or a pharmaceutically acceptable salt, including all tautomers and stereoisomers thereof wherein: R.sup.1 represents alkenyl, wherein the double bond is not adjacent to the nitrogen; carbocyclyl; --C.sub.1-6alkyl-carbocyclyl; heterocyclyl; --C.sub.1-6alkyl-heterocyclyl; aryl; heteroaryl; --C.sub.1-6alkylaryl; --C.sub.1-6alkylheteroaryl; -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.1-4-alkyl, 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.1-6-alkyl, C.sub.1-6alkoxy-C.sub.1-6alkyl-, nitro, halogen, cyano, hydroxyl, --C(O)OH, --NH.sub.2, --NHC.sub.1-4-alkyl, --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.1-4alkoxy; or R.sup.1 represents phenyl substituted by benzyloxy- in which any of the aforesaid phenyl or benzyloxy groups may optionally be substituted on the ring by one or more groups selected from C.sub.1-4alkyl, halogen and C.sub.1-4alkoxy; and A represents ##STR00055## 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.3-5-spiro-cycloalkyl group and R.sup.2, R.sup.3 and R.sup.4 independently represent H or C.sub.1-2alkyl, provided that R.sup.2 and R.sup.3 and R.sup.4 do not all represent H; or A represents ##STR00056## 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.5 and R.sup.6 independently represent H or C.sub.1-2alkyl and B represents H or methyl.

2. A compound according to claim 1 wherein R.sup.1 represents alkenyl, wherein the double bond is not adjacent to the nitrogen; carbocyclyl; --C.sub.1-6alkyl-carbocyclyl; heterocyclyl; --C.sub.1-6alkyl-heterocyclyl; aryl; heteroaryl; --C.sub.1-6alkylaryl; --C.sub.1-6alkylheteroaryl; -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.1-6thioalkyl, --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.1-4alkoxy.

3. A compound according to claim 1 wherein R.sup.1 represents optionally substituted aryl.

4. A compound according to claim 1 wherein R.sup.1 is aryl, optionally substituted by one or more substituents selected from C.sub.1-6alkyl, C.sub.1-6alkoxy-, C.sub.1-6haloalkyl and halogen.

5. A compound according to claim 1 wherein R.sup.1 represents optionally substituted carbocyclyl.

6. A compound according to claim 1 wherein R.sup.1 represents optionally substituted phenyl fused to optionally substituted heterocyclyl.

7. A compound according to claim 1 wherein A represents ##STR00057## wherein R.sup.2, R.sup.3, R.sup.4 and Y are as defined in claim 1.

8. A compound according to claim 7 wherein R.sup.2 represents H, R.sup.3 represents H and R.sup.4 represents methyl.

9. A compound according to claim 7 wherein Y represents an unsubstituted C.sub.2-5 alkylene chain.

10. A compound according to claim 9 wherein Y represents --(CH.sub.2).sub.3-- or --(CH.sub.2).sub.4--.

11. A compound according to claim 7 wherein A represents ##STR00058##

12. A compound according to claim 1 wherein A represents ##STR00059## wherein R.sup.5, R.sup.6 and Z are as defined in claim 1.

13. A compound according to claim 12 wherein R.sup.5 represents H and R.sup.6 represents H.

14. A compound according to claim 12 wherein Z represents a bond, --CH.sub.2-- or --CH.sub.2--CH.sub.2--.

15. A compound according to claim 1 wherein B represents H.

16. A compound according to claim 1 as defined in any one of examples 1 to 18 selected from: (1) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)cyclohexanam- ine, (2) N-(1-(3-(5-methyl-1H-imidazol-1-yl)-propylamino)-2-nitrovinyl)-2,- 4-dimethoxybenzenamine, (3) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-3,4,5-trime- thoxybenzenamine, (4) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-3,4-dimetho- xybenzenamine, (5) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-2,3-dihydro- benzo[b][1,4]dioxin-6-amine, (6) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-4-(trifluor- omethyl)benzenamine, (7) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-4-chloroben- zenamine, (8) N-(1-(4-(5-methyl-1H-imidazol-1-yl)butylamino)-2-nitrovinyl)cyclohexanami- ne, (9) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)benzo- [d][1,3]dioxol-5-amine, (10) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)naphthalen-1- -amine, (8) N-(1-(4-(5-methyl-1H-imidazol-1-yl)butylamino)-2-nitrovinyl)cyclohexanami- ne (9) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)benzo[- d][1,3]dioxol-5-amine (10) N-(1-(3-(5-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)naphthalen-1- -amine (11) N-(1-(3-(4-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-4-chloroben- zenamine (12) N-(1-(3-(4-methyl-1H-imidazol-1-yl)-propylamino)-2-nitrovinyl)-4-(trifluo- romethyl)benzenamine (13) N-(1-(3-(4-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-2,3-dihydro- benzo[b][1,4]dioxin-6-amine (14) N-(1-(3-(4-methyl-1H-imidazol-1-yl)-propylamino)-2-nitrovinyl)-3,4-dimeth- oxybenzen-amine (15) N-(1-(3-(4-methyl-1H-imidazol-1-yl)-propylamino)-2-nitrovinyl)-3,4,5-tri-- methoxybenzen-amine (16) N-(1-(3-(4-methyl-1H-imidazol-1-yl)propylamino)-2-nitrovinyl)-2,4-dimetho- xybenzen-amine (17) N-(1-(3-(4-methyl-1H-imidazol-1-yl)-propylamino)-2-nitrovinyl)benzo[d]-[1- ,3]dioxol-5-amine and (18) N-(1-(3-(4-methyl-1H-imidazol-1-yl)-propylamino)-2-nitrovinyl)-naphthalen- -1-amine or a pharmaceutically acceptable salt of any one thereof.

17. A compound according to claim 1 as defined in example 8: N-(1-(4-(5-methyl-1H-imidazol-1-yl)butylamino)-2-nitrovinyl)cyclohexanami- ne, or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound according to claim 1 optionally in combination with one or more therapeutically acceptable diluents or carriers.

19. The pharmaceutical composition of claim 18, 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.

20. The pharmaceutical composition of claim 18, 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.

21. A process for preparation of a compound of formula (I) according to claim 1, which comprises reaction of a compound of formula (II) ##STR00060## wherein R.sup.7 represents C.sub.1-6alkyl and R.sup.1 is as defined in claim 1, with a compound of formula (III) ##STR00061## wherein A and B are as defined in claim 1.

Details for Patent 8,772,508

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 ⤷  Try a Trial 2039-02-26
Genzyme Corporation CAMPATH alemtuzumab Injection 103948 05/07/2001 ⤷  Try a Trial 2039-02-26
Genzyme Corporation LEMTRADA alemtuzumab Injection 103948 11/14/2014 ⤷  Try a Trial 2039-02-26
Genzyme Corporation CAMPATH alemtuzumab Injection 103948 10/12/2004 ⤷  Try a Trial 2039-02-26
Biogen Inc. TYSABRI natalizumab Injection 125104 11/23/2004 ⤷  Try a Trial 2039-02-26
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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