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Details for Patent: 8,252,923

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Details for Patent: 8,252,923

Title:Peptidomimetic protease inhibitors
Abstract: The present invention relates to peptidomimetic compounds useful as protease inhibitors, particularly as serine protease inhibitors and more particularly as hepatitis C NS3 protease inhibitors; intermediates thereto; their preparation including novel steroselective processes to intermediates. The invention is also directed to pharmaceutical compositions and to methods for using the compounds for inhibiting HCV protease or treating a patient suffering from an HCV infection or physiological condition related to the infection. Also provided are pharmaceutical combinations comprising, in addition to one or more HCV serine protease inhibitors, one or more interferons exhibiting anti-HCV activity and/or one or more compounds having anti HCV activity and a pharmaceutically acceptable carrier, and methods for treating or preventing a HCV infection in a patient using the compositions. The present invention is also directed to a kit or pharmaceutical pack for treating or preventing HCV infection in a patient.
Inventor(s): Babine; Robert Edward (Franklin, MA), Chen; Shu-Hui (Carmel, IN), Lamar; Jason Eric (Indianapolis, IN), Snyder; Nancy June (Lizton, IN), Sun; Xicheng (Superior, CO), Tebbe; Mark Joseph (Hamburg, DE), Victor; Frantz (Indianapolis, IN), Wang; Q. May (Indianapolis, IN), Yip; Yvonne Yee Mai (Indianapolis, IN), Collado; Ivan (Madrid, ES), Garcia-Paredes; Cristina (Madrid, ES), Parker, III; Raymond Samuel (Doylestown, PA), Jin; Ling (Carmel, IN), Guo; Deqi (Carmel, IN), Glass; John Irvin (Indianapolis, IN)
Assignee: Vertex Pharmaceuticals Incorporated (Cambridge, MA)
Filing Date:Sep 08, 2008
Application Number:12/231,982
Claims:1. A compound of formula 24 ##STR00457## wherein: ##STR00458## is optionally substituted C.sub.5-C.sub.6 cycloalkyl or optionally substituted C.sub.6-C.sub.10 aryl fused with C.sub.5-C.sub.6 cycloalkyl; R.sup.11 is --CO.sub.2R.sup.13; R.sup.12 is a moiety selected from the group consisting of ##STR00459## M* is a transition metal; R.sup.13 is acid protecting group or optionally substituted aliphatic group; R.sup.14 is --CONR.sup.15R.sup.15, --CN, ##STR00460## or --CO.sub.2R.sup.16; MOM is methoxymethyl; R.sup.15 is optionally substituted aliphatic group; R.sup.16 is acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group; R.sup.17 is optionally substituted aryl, optionally substituted aliphatic group, ##STR00461## R.sup.18 is hydrogen, alkyl, alkylthio, or optionally substituted aryl; or R.sup.17 and R.sup.18 taken together with the carbon to which R.sup.17 and R.sup.18 are attached form ##STR00462## and is a solid phase.

2. A compound of claim 1 wherein: optionally substituted C.sub.5-C.sub.6 cycloalkyl is a non-aromatic mono- or multicyclic ring system of 5 to 6 carbon atoms optionally substituted with one or more ring group substituents; optionally substituted C.sub.6-C.sub.10 fused arylcycloalkyl is a fused arylcycloalkyl of 6 to 10 carbon atoms optionally substituted with one or more ring group substituents; optionally substituted aliphatic group are alkyl, alkenyl, or alkynyl optionally substituted with an aliphatic group substituent; wherein; ring group substituents are substituents attached to aromatic or non-aromatic ring systems inclusive of aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), --C(O)--NHOH, --C(O)--CH.sub.2OH, --C(O)--CH.sub.2SH, --C(O)--NH--CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydroxy-1-methylpyrazoly, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, Y.sup.1Y.sup.2N--, Y.sup.1Y.sup.2NC(O)--, Y.sup.1Y.sup.2NC(O)O, Y.sup.1Y.sup.2NC(O)NY.sup.3-- or Y.sup.1Y.sup.2NSO.sub.2--, wherein Y.sup.1, Y.sup.2 and Y.sup.3 are independently hydrogen, alkyl, aryl or heteroaryl, or for where the substituent is Y.sup.1Y.sup.2N--, then one of Y.sup.1 and Y.sup.2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y.sup.1 and Y.sup.2 is as defined previously, or for where the substituent is Y.sup.1Y.sup.2NC(O)--, Y.sup.1Y.sup.2NC(O)O--, Y.sup.1Y.sup.2NC(O)NY.sup.3-- or Y'Y.sup.2NSO.sub.2--, Y.sup.1 and Y.sup.2 may also be taken together with the N atom through which Y.sup.1 and Y.sup.2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl or when the ring system is saturated or partially saturated, the ring group substituents further include, methylene (H.sub.2C.dbd.), oxo (O.dbd.) and thioxo (S.dbd.); and aliphatic group substituents is aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), --C(O)--NHOH, --C(O)--CH.sub.2OH, --C(O)--CH.sub.2SH, --C(O)--NH--CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydroxy-1-methylpyrazolyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, methylene (H.sub.2C.dbd.), oxo (O.dbd.), thioxo (S.dbd.), Y.sup.1Y.sup.2N--, Y.sup.1Y.sup.2NC(O)--, Y.sup.1Y.sup.2NC(O)O--, Y.sup.1Y.sup.2NC(O)NY.sup.3--, Y.sup.1Y.sup.2NSO.sub.2--, or Y.sup.3SO.sub.2NY.sup.1-- wherein R.sup.2 is as defined herein, Y.sup.1 and Y.sup.2 are independently hydrogen, alkyl, aryl or heteroaryl, and Y.sup.3 is alkyl, cycloalkyl aryl or heteroaryl, or for where the substituent is Y.sup.1Y.sup.2N--, then one of Y.sup.1 and Y.sup.2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y.sup.1 and Y.sup.2 is as defined previously, or for where the substituent is Y.sup.1Y.sup.2NC(O)--, Y.sup.1Y.sup.2NC(O)O--, Y.sup.1Y.sup.2NC(O)NY.sup.3-- or Y.sup.1Y.sup.2NSO.sub.2--, Y.sup.1 and Y.sup.2 may also be taken together with the N atom through which Y.sup.1 and Y.sup.2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl; and aryl is an aromatic monocyclic or multicyclic ring system of 6 to 14 carbon atoms.

3. A compound according to claim 1 where ##STR00463## is ##STR00464##

4. A compound according to claim 3 where ##STR00465## is ##STR00466##

5. A compound according to claim 3 where R.sup.13 is an optionally substituted aliphatic group.

6. A compound according to claim 5 where R.sup.13 is an alkyl group.

7. A compound according to claim 6 where R.sup.13 is lower alkyl.

8. A compound according to claim 7 where R.sup.13 is methyl.

9. A compound according to claim 1 where R.sup.12 is ##STR00467## wherein: R.sup.14 is --CONR.sup.15R.sup.15, --CN, ##STR00468## or --CO.sub.2R.sup.16; R.sup.15 is optionally substituted aliphatic group; R.sup.16 is acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group; R.sup.17 is optionally substituted aryl, optionally substituted aliphatic group, ##STR00469## R.sup.18 is hydrogen, alkyl, alkylthio, or optionally substituted aryl; or R.sup.17 and R.sup.18 taken together with the carbon to which R.sup.17 and R.sup.18 are attached form ##STR00470## and is a solid phase.

10. A compound according to claim 9 where R.sup.14 is --CO.sub.2R.sup.16.

11. A compound according to claim 10 where R.sup.16 is optionally substituted aliphatic.

12. A compound according to claim 11 where R.sup.16 is alkyl.

13. A compound according to claim 12 where R.sup.16 is lower alkyl.

14. A compound according to claim 13 where R.sup.16 is t-Bu.

15. A compound according to claim 9 where R.sup.17 is optionally substituted aryl.

16. A compound according to claim 15 where R.sup.17 is phenyl.

17. A compound according to claim 9 where R.sup.18 is optionally substituted aryl.

18. A compound according to claim 17 where R.sup.18 is phenyl.

19. A compound according to claim 1 wherein R.sup.17 and R.sup.18 taken together with the carbon to which R.sup.17 and R.sup.18 are attached form ##STR00471##
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