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Claims for Patent: 8,859,504

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Claims for Patent: 8,859,504

Title:Boronate ester compounds and pharmaceutical compositions thereof
Abstract: The present invention provides novel compounds useful as proteasome inhibitors. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases.
Inventor(s): Elliott; Eric L. (Watertown, MA), Ferdous; Abu J. (Nottingham, MD), Kaufman; Michael J. (Lexington, MA), Komar Lay; Sonja A. (Belmont, MA), Mazaik; Debra L. (Holliston, MA), McCubbin; Quentin J. (Belmont, MA), Nguyen; Phuong M. (Cambridge, MA), Palaniappan; Vaithianathan (Andover, MA), Skwierczynski; Raymond D. (Andover, MA), Truong; Nobel T. (Milford, MA), Varga; Csanad M. (Newton, MA), Zawaneh; Peter N. (Brookline, MA)
Assignee: Millennium Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:13/667,164
Patent Claims: 1. A compound of formula (II): ##STR00018## or a pharmaceutically acceptable salt thereof, wherein: A is 0; P is R.sup.c--C(O)--; R.sup.c is R.sup.D; R.sup.D is 2,5-dichlorophenyl; R.sup.a is isobutyl; R.sup.a1 is hydrogen: each R.sup.b1 and R.sup.b2 independently is hydrogen; each R.sup.b3 and R.sup.b4 independently is --(CH.sub.2).sub.p--CO.sub.2H; p is 0 or 1; and n is 0 or 1.

2. 2,2'-{2-[(1R)-1-({[(2,5-Dichlorobenzoyl)-amino]acetyl}amino)-3-methylb- utyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid, characterized by formula (III): ##STR00019## or a pharmaceutically acceptable salt thereof, wherein: A is 0; P is R.sup.c--C(O)--; R.sup.c is --R.sup.D; R.sup.D is 2,5-dichlorophenyl; R.sup.a is isobutyl; and R.sup.a1 is hydrogen.

3. 4-(R,S)-(Carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-- 3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid, characterized by formula (IV): ##STR00020## or a pharmaceutically acceptable salt thereof, wherein: A is 0; P is RE-C(O)--; R.sup.x is --R.sup.D; R.sup.D is 2,5-dichlorophenyl; R.sup.a is isobutyl; and R.sup.a1 is hydrogen.

4. A compound of formula (IIIa): ##STR00021## or a pharmaceutically acceptable salt thereof wherein: A is 0; P is R.sup.c--C(O)--; R.sup.c is --R.sup.D; R.sup.D is 2,5-dichlorophenyl: R.sup.a is isobutyl; and R.sup.a1 is hydrogen.

5. A compound of formula (IVa): ##STR00022## or a pharmaceutically acceptable salt thereof, wherein: A is 0; P is R.sup.c--C(O)--; R.sup.c is --R.sup.D; R.sup.D is 2,5-dichlorophenyl; R.sup.a is isobutyl; and R.sup.a1 is hydrogen.

6. A crystalline form of 2,2'-{2-[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methyl butyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid, comprising an x-ray powder diffraction pattern having characteristic peaks expressed in degrees two-theta at approximately 6.4, 8.3, 15.1, 16.4, and 19.1.

7. The crystalline form of claim 6, comprising an x-ray powder diffraction pattern having characteristic peaks expressed in degrees two-theta at: TABLE-US-00032 Angle Intensity 2.theta. .degree. % 6.441 100 8.304 29.5 10.35 19 11.619 5.1 12.695 13.6 15.077 28.2 16.352 28.7 17.504 16.3 18.231 6 19.086 21.4 20.40 11.7 21.231 7.6 21.916 7.6 25.371 15.2 27.588 6.2.

8. The crystalline form of claim 6 or 7, characterized by an endothermic transition with an onset melting temperature of approximately between 191.8.degree. C. and 225.degree. C.

9. A crystalline form of 2,2'-{2-[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl- ]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid, comprising an x-ray powder diffraction pattern having characteristic peaks expressed in degrees two-theta at approximately 5.8, 7.6, 11.6, 11.9, 16.7, 18.2, 19.6, 20.0, and 22.4.

10. The crystalline form of claim 9, comprising an x-ray powder diffraction pattern having characteristic peaks expressed in degrees two-theta at: TABLE-US-00033 Angle Intensity 2-.theta. .degree. % 5.817 100 7.614 93.4 11.575 71.1 11.896 67.1 12.571 24.3 14.43 32.2 16.689 65.8 17.362 17.8 18.232 53.9 19.596 77.6 19.959 63.8 20.376 36.2 20.998 32.2 21.5 40.1 21.764 43.4 22.407 77.6 23.12 33.6 23.901 26.3 24.402 20.4 24.882 19.7 25.764 19.1 26.464 39.5 27.347 21.7 27.65 17.1 27.979 16.4 29.41 20.4.

11. The crystalline form of the compound of claim 9 or 10, characterized by an endothermic transition with an onset melting temperature of approximately between 206.5.degree. C. and 225.degree. C.

12. A crystalline form of 4-(R,S)-(carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-m- ethylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid, comprising an x-ray powder diffraction pattern having characteristic peaks expressed in degrees two-theta at approximately 5.7, 7.6, 11.4, 11.8, 16.5, 18.1, 19.4, 19.8, and 22.2.

13. The crystalline form of claim 12, comprising an x-ray powder diffraction pattern having characteristic peaks expressed in degrees two-theta at: TABLE-US-00034 Angle Intensity 2-.theta. .degree. % 5.69 100 7.64 66 9.66 4 11.22 23 11.42 51 11.79 37 12.41 15 14.23 15 15.60 6 16.53 32 17.15 4 18.07 31 19.39 55 19.79 41 20.24 21 20.79 15 21.36 20 21.61 22 22.23 63 22.55 14 22.97 20 23.22 7 23.67 10 23.90 7 24.19 10 24.74 7 24.97 3 25.64 8 26.31 24 26.64 10 27.21 7 27.40 7 27.88 5 28.25 4 29.27 11 29.72 10.

14. The crystalline form of the compound of claim 12 or 13, characterized by an endothermic transition with a onset melting temperature of approximately between 231.3.degree. C. and 239.9.degree. C.

15. A pharmaceutical composition, the pharmaceutical composition comprising a compound as in any one of claim 1-5, and a pharmaceutically acceptable carrier.
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