BORONATE ESTER COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF
First Claim
Patent Images
1. A compound of formula (I):
- or a pharmaceutically acceptable salt thereof, wherein;
A is 0, 1, or 2;
P is hydrogen or an amino-group-blocking moiety;
Ra is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
RB, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2, —
(CH2)m—
CH(R4)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;
Ra1 is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
RB, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2, —
(CH2)m—
CH(R5a)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;
each Ra2 independently is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
R3, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2, —
(CH2)m—
CH(R5a)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;
each RB independently is a substituted or unsubstituted mono- or bicyclic ring system;
each R4 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
or two R4 on the same nitrogen atom, taken together with the nitrogen atom, form a substituted or unsubstituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;
each R5 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R5a independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R5b independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R6 independently is a substituted or unsubstituted aliphatic, aryl, or heteroaryl group;
Y is hydrogen, —
CN, or —
NO2;
m is 0, 1, or 2; and
Z1 and Z2 together form a moiety derived from an alpha-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom;
or Z1 and Z2 together form a moiety derived from a beta-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom.
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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.
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Citations
93 Claims
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1. A compound of formula (I):
-
or a pharmaceutically acceptable salt thereof, wherein; A is 0, 1, or 2; P is hydrogen or an amino-group-blocking moiety; Ra is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
RB, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2, —
(CH2)m—
CH(R4)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;Ra1 is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
RB, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2, —
(CH2)m—
CH(R5a)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;each Ra2 independently is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
R3, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2, —
(CH2)m—
CH(R5a)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;each RB independently is a substituted or unsubstituted mono- or bicyclic ring system; each R4 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
or two R4 on the same nitrogen atom, taken together with the nitrogen atom, form a substituted or unsubstituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;each R5 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; each R5a independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; each R5b independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; each R6 independently is a substituted or unsubstituted aliphatic, aryl, or heteroaryl group; Y is hydrogen, —
CN, or —
NO2;m is 0, 1, or 2; and Z1 and Z2 together form a moiety derived from an alpha-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom;
or Z1 and Z2 together form a moiety derived from a beta-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23)
or a pharmaceutically acceptable salt thereof, wherein; each of Rb1 and Rb2 independently is hydrogen, —
CO2H, —
OH or a substituted or unsubstituted aliphatic, aryl, heteroaryl or heterocyclyl group;each of Rb3 and Rb4 independently is hydrogen, —
CO2H, or a substituted or unsubstituted aliphatic, aryl, heteroaryl or heterocyclyl group;or Rb2 and Rb4 are each independently hydrogen, and Rb1 and Rb3, taken together with the carbon atoms to which they are attached, form an unsubstituted or substituted fused 4- to 8-membered non-aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S, wherein said ring may be optionally fused to an unsubstituted or substituted 4- to 8-membered non-aromatic ring, or 5- to 6-membered aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S; or Rb2 and Rb4 are absent, and Rb1 and Rb3, taken together with the carbon atoms to which they are attached, form an unsubstituted or substituted fused 5- to 6-membered aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S, wherein said ring may be optionally fused to an unsubstituted or substituted 4- to 8-membered non-aromatic ring, or 5- to 6-membered aromatic ring having 0-3 ring heteroatoms selected from the group consisting of O, N, and S; and n is 0 or 1.
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3. The compound of claim 2, wherein each of Rb3 and Rb4 independently is hydrogen, C1-6 aliphatic, or —
- (CH2)p—
CO2H;and p is 0, 1, or 2.
- (CH2)p—
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4. The compound of claim 3 wherein P is Rc—
- C(O)—
, Rc—
O—
C(O)—
, Rc—
N(R4c)—
C(O)—
, Rc—
S(O)2—
, or Rc—
N(R4c)—
S(O)2—
;Rc is selected from the group consisting of C1-6 aliphatic, C1-6 fluoroaliphatic, RD, T1-RD, and -T1—
R2c;T1 is a C1-6 alkylene chain substituted with 0-2 independently selected R3a or R3b, wherein the alkylene chain optionally is interrupted by C(R5)—
C(R5)—
, —
C≡
C—
, or —
O—
;RD is a substituted or unsubstituted mono- or bicyclic ring system; R2c is halo, —
OR5, —
SR6, —
S(O)R6, —
SO2R6, —
SO2N(R4)2, —
N(R4)2, —
NR4C(O)R5, —
NR4C(O)—
N(R4)2, —
NR4CO2R6, —
N(R4)SO2R6, —
N(R4)SO2N(R4)2, —
O—
C(O)R5, —
OC(O)N(R4)2, —
C(O)—
R5, —
CO2R5, or —
C(O)N(R4)2;each R3a independently is selected from the group consisting of —
F, —
OH, —
O(C1-4 alkyl), —
CN, —
N(R4)2, —
C(O)(C1-4 alkyl), —
CO2H, —
CO2(C1-4 alkyl), —
C(O)NH2, and —
C(O)—
NH(C1-4 alkyl);each R3b independently is a C1-3 aliphatic substituted or unsubstituted with R3a or R7;
or two substituents R3b on the same carbon atom, taken together with the carbon atom to which they are attached, form a 3- to 6-membered cycloaliphatic ring;each R7 is a substituted or unsubstituted aromatic group; and R4c is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or C6-10 ar(C1-4)alkyl, the aryl portion of which is substituted or unsubstituted.
- C(O)—
-
5. The compound of claim 3, wherein A is 0;
-
Ra1 is hydrogen, —
(CH2)m—
CH2—
RB, or —
(CH2)m—
CH(R5a)—
OR5b; andm is 0.
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6. The compound of claim 3, wherein P is Rc—
- C(O)—
or Rc—
S(O)2— and
Rc is —
RD.
- C(O)—
-
7. The compound of claim 6, wherein RD is a substituted or unsubstituted mono- or bicyclic ring system selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, naphthyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and dihydrodrobenzoxazinyl.
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8. The compound of claim 7, wherein RD is substituted on substitutable carbon atoms with 0-1 Rd and 0-2 R8d;
-
each Rd independently is C1-6 aliphatic, C1-6 fluoroaliphatic or halo; and each R8d independently is C1-4 aliphatic, C1-4 fluoroaliphatic or halo.
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9. The compound of claim 4, wherein A is 0;
-
Ra is C1-6 aliphatic, or —
(CH2)m—
C1-2—
RB;Ra1 is hydrogen, —
(CH2)m—
CH2—
RB, or —
(CH2)m—
CH(R5a)—
OR5b;P is Rc—
C(O)—
or Rc—
S(O)2—
;Rc is RD; and m is 0 or 1.
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10. The compound of claim 9, wherein Ra is C1-6 aliphatic.
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11. The compound of claim 10, wherein R8 is CH2—
- RB;
RB is phenyl; and RD is 2-pyrazinyl.
- RB;
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12. The compound of claim 10, wherein Ra1 is —
- CH(R5a)—
OR5b;R5a is C1-6 aliphatic; R5b is hydrogen; and RD is 6-phenyl-2-pyridinyl-.
- CH(R5a)—
-
13. The compound of claim 10, wherein Ra1 is hydrogen, and RD is 2,5-dichlorophenyl.
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14. The compound of claim 3, wherein Z1 and Z2 together form a moiety derived from citric acid.
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15. The compound of claim 14, in a substantially crystalline form.
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16. The compound of claim 14, characterized by formula (III), (IIIa), (IV), (IVa):
or a mixture thereof.
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17. The compound of claim 16, wherein Ra is C1-6 aliphatic.
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18. The compound of claim 16, wherein A is 0;
- Ra1 is hydrogen, —
(CH2)m—
CH2—
RB, or —
(CH2)m—
CH(R5)—
OR5b;
P is Rc—
C(O)—
; and
Rc is —
RD.
- Ra1 is hydrogen, —
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19. The compound of claim 18, wherein RD is a substituted or unsubstituted mono- or bicyclic ring system selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, naphthyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and dihydrobenzoxazinyl.
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20. The compound of claim 18, wherein Ra is isobutyl.
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21. The compound of claim 20, wherein Ra1 is —
- CH2—
RB;RB is phenyl; and RD is 2-pyrazinyl.
- CH2—
-
22. The compound of claim 20, wherein Ra1 is hydrogen, and
RD is 2,5-dichlorophenyl. -
23. The compound of claim 20, wherein Ra1 is —
- CH(R5a)—
OR5b;R5a is C1-6 aliphatic; R5b is hydrogen; and RD is 6-phenyl-2-pyridinyl-.
- CH(R5a)—
-
24. A pharmaceutical composition comprising the compound of formula (I):
-
or a crystalline form thereof, a filler, and optionally a lubricant; wherein; A is 0, 1, or 2; P is hydrogen or an amino-group-blocking moiety; Ra is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
RB, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2, —
(CH2)m—
CH(R5a)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;Ra1 is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
RB, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2, —
(CH2)m—
CH(R5a)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;each Ra2 independently is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
RB, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2, —
(CH2)m—
CH(R5a)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;each RB independently is a substituted or unsubstituted mono- or bicyclic ring system; each R4 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
or two R4 on the same nitrogen atom, taken together with the nitrogen atom, form a substituted or unsubstituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;each R5 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; each R5a independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; each R5b independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; each R6 independently is a substituted or unsubstituted aliphatic, aryl, or heteroaryl group; Y is hydrogen, —
CN, or —
NO2;m is 0, 1, or 2; and Z1 and Z2 together form a moiety derived from an alpha-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom;
or Z1 and Z2 together form a moiety derived from a beta-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom.- View Dependent Claims (25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 93)
the filler is selected from the group consisting of low-moisture microcrystalline cellulose, sodium starch glycolate, pregeletanized starch, and mixtures thereof; and the lubricant, when present, is magnesium stearate.
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50. The pharmaceutical composition of claim 25, wherein:
-
the alpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acid is citric acid; A is 0; Ra is isobutyl; Ra1 is hydrogen, C1-6 aliphatic, —
(CH2)m—
CH2—
RB, or —
(CH2)m—
CH(R5a)—
OR5b;P is Rc—
C(O)—
;Rc is —
RD;m is 0 or 1; the filler is selected from the group consisting of low-moisture microcrystalline cellulose, sodium starch glycolate, pregeletanized starch, and mixtures thereof; the lubricant, when present, is magnesium stearate; the flow-aid, when present, is talc; and the buffer, when present, is sodium citrate.
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51. The pharmaceutical composition of claim 25, wherein
the compound of formula (I) is represented by compounds (I-1), (I-15) or (I-18): the filler is selected from the group consisting of low-moisture microcrystalline cellulose, sodium starch glycolate, pregeletanized starch, and mixtures thereof; the lubricant, when present, is magnesium stearate; the flow-aid, when present, is talc; and the buffer, when present, is sodium citrate.
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93. A method for treating cancer, comprising the administration of a therapeutically effective amount of the pharmaceutical composition of any one of claims 24, 52, 57, 58, 59, 72, 77, and 87.
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52. A pharmaceutical composition comprising the compound of formula (I-1):
-
or a crystalline form thereof, a filler, and optionally a lubricant. - View Dependent Claims (53, 54, 55, 56)
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57. A unit dose pharmaceutical composition comprising the compound of formula (I-1), or a crystalline form thereof, wherein the compound of formula (I-1) is present in an amount equivalent on a molar weight basis of about 0.1 mg to about 3.0 mg of the compound of formula (VIII-1).
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58. A unit dose pharmaceutical composition comprising about 0.143 mg to about 4.3 mg of the compound of formula (I-1), or a crystalline form thereof, measured as about 0.1 mg to about 3.0 mg of the compound of formula (VIII-1), on a weight for weight basis.
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59. A pharmaceutical composition comprising the compound of formula (I):
-
or a crystalline form thereof, a bulking agent; and
a buffer;wherein; A is 0, 1, or 2; P is hydrogen or an amino-group-blocking moiety; Ra is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
RB, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2—
(CH2)m—
CH(R5a)—
ORb, or —
(CH2)m—
CH(R5)—
SR5;Ra1 is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
RB, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2, —
(CH2)m—
CH(R5a)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;each Ra2 independently is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
RB, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2, —
(CH2)m—
CH(R5a)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;each RB independently is a substituted or unsubstituted mono- or bicyclic ring system; each R4 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
or two R4 on the same nitrogen atom, taken together with the nitrogen atom, form a substituted or unsubstituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;each R5 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; each R5a independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; each R5b independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; each R6 independently is a substituted or unsubstituted aliphatic, aryl, or heteroaryl group; Y is hydrogen, —
CN, or —
NO2;m is 0, 1, or 2; and Z1 and Z2 together form a moiety derived from an alpha-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom;
or Z1 and Z2 together form a moiety derived from a beta-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom.- View Dependent Claims (60, 61, 62, 63, 64, 65)
A is 0; Ra is isobutyl; Ra1 is hydrogen, C1-6 aliphatic, —
(CH2)m—
CH2—
RB, or —
(CH2)m—
CH(R5a)—
OR5b;P is Rc—
C(O)—
);Rc is —
RD;m is 0 or 1; the bulking agent is glycine; and the buffer is sodium citrate, and citric acid.
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65. The pharmaceutical composition of claim 59 wherein
the compound of formula (I) is represented by compounds (I-1), (I-15) or (I-1× - );
the bulking agent is glycine; and the buffer is sodium citrate, and citric acid.
- );
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66. A pharmaceutical composition comprising the compound of formula (I) in a lyophilized powder:
-
wherein; A is 0, 1, or 2; P is hydrogen or an amino-group-blocking moiety; Ra is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
RB, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2, —
(CH2)m—
CH(R5a)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;Ra1 is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
RB, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2, —
(CH2)m—
CH(R5a)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;each Ra2 independently is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
-CH2—
RB, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2, —
(CH2)m—
CH(R5a)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;each RB independently is a substituted or unsubstituted mono- or bicyclic ring system; each R4 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
or two R4 on the same nitrogen atom, taken together with the nitrogen atom, form a substituted or unsubstituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;each R5 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; each R5a independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; each R5b independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; each R6 independently is a substituted or unsubstituted aliphatic, aryl, or heteroaryl group; Y is hydrogen, —
CN, or —
NO2;m is 0, 1, or 2; and Z1 and Z2 together form a moiety derived from an alpha-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom;
or Z1 and Z2 together form a moiety derived from a beta-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom.- View Dependent Claims (67, 68, 69, 70, 71)
the bulking agent is glycine; and the buffer is sodium citrate, and citric acid.
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72. A unit dose pharmaceutical composition comprising the compound of formula (I-1), in a lyophilized powder:
wherein; the compound of formula (I-1) is present in an amount equivalent on a molar weight basis of about 1 mg to about 5 mg of the compound of formula (VIII-1). - View Dependent Claims (73, 74, 75, 76, 85)
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77. A unit dose pharmaceutical composition comprising the compound of formula (I-15), in a lyophilized powder:
wherein; the compound of formula (I-15) is present in an amount equivalent on a molar weight basis of about 1 mg to about 5 mg of the compound of formula (VIII-15). - View Dependent Claims (78, 79, 80, 81, 86)
-
82. A method for preparation of a pharmaceutical composition of the compound (I-1) as a lyophilized powder, the method comprising the steps:
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(f-1) combining; i. water; ii. the compound (I-1); iii. glycine; iv. sodium citrate; and v. citric acid;
to form a mixture; and(f-2) lyophilizing the mixture.
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83. A method for the preparation of a pharmaceutical composition of the compound (I-15) as a lyophilized powder, the method comprising the steps
(g-1) combining: -
i. an aqueous solvent mixture comprising water and tert-butyl alcohol; ii. the compound (VIII-15); iii. glycine; iv. sodium citrate; and v. citric acid;
to form a mixture; and(g-2) lyophilizing the mixture. - View Dependent Claims (84)
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87. A liquid pharmaceutical composition comprising the compound of formula (I):
a buffer, and optionally a tonicity modifier; wherein; A is 0, 1, or 2; P is hydrogen or an amino-group-blocking moiety; Ra is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
R8, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2—
(CH2)m—
CH(Ra)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;Ra1 is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
RB, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CONR4)2, —
(CH2)m—
CH(R6)N(R4)2, —
(CH2)m—
CH(R5a)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;each Ra2 independently is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —
(CH2)m—
CH2—
RB, —
(CH2)m—
CH2—
NHC(═
NR4)NH—
Y, —
(CH2)m—
CH2—
CON(R4)2, —
(CH2)m—
CH2—
N(R4)CON(R4)2, —
(CH2)m—
CH(R6)N(R4)2, (CH2)m—
CH(R5a)—
OR5b, or —
(CH2)m—
CH(R5)—
SR5;each RB independently is a substituted or unsubstituted mono- or bicyclic ring system; each R4 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
or two R4 on the same nitrogen atom, taken together with the nitrogen atom, form a substituted or unsubstituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;each R5 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; each R5a independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; each R5b independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; each R6 independently is a substituted or unsubstituted aliphatic, aryl, or heteroaryl group; Y is hydrogen, —
CN, or —
NO2;m is 0, 1, or 2; and Z1 and Z2 together form a moiety derived from an alpha-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom;
or Z1 and Z2 together form a moiety derived from a beta-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom.- View Dependent Claims (88, 89, 90)
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91. A unit dose liquid pharmaceutical composition comprising the compound of formula (I-1):
wherein; the compound of formula (I-1) is present at a concentration of about 0.5 mg/ml to about 3 mg/ml of the compound of formula (VIII-1). - View Dependent Claims (92)
Specification