US2009325903A1PendingUtilityA1
Boronate ester compounds and pharmaceutical compositions thereof
Est. expiryJun 17, 2028(~1.9 yrs left)· nominal 20-yr term from priority
Inventors:Eric L. ElliottAbu J. FerdousMichael J. KaufmanSonja A. KomarDebra L. MazaikQuentin J. MccubbinPhuong M. NguyenVaithianathan PalaniappanRaymond D. SkwierczynskiNobel T. TruongCsanad M. VargaPeter N. Zawaneh
A61P 37/06A61P 43/00A61P 9/00A61P 7/06A61P 9/10A61P 37/02A61P 35/04A61P 25/14A61P 25/28A61P 25/00A61P 31/00A61P 27/02A61P 25/04A61P 25/16A61P 29/00A61P 31/18A61P 35/00A61P 35/02A61P 1/16A61P 19/02A61P 1/04A61P 11/00A61P 1/00A61P 17/00A61P 11/06A61P 17/02A61P 17/06C07F 5/025A61K 31/454A61K 31/69C07K 5/06139C07F 5/04A61K 31/198A61K 47/183A61K 9/19A61K 9/0019C07C 233/83C07F 5/05A61K 38/00C07K 5/06191C07F 5/02
70
PatentIndex Score
0
Cited by
0
References
0
Claims
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.
Claims
exact text as granted — not AI-modified1 . 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;
R a is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 4 )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ;
R a1 is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ;
each R a2 independently is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic, —(CH 2 ) m —CH 2 —R 3 , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ;
each R B independently is a substituted or unsubstituted mono- or bicyclic ring system;
each R 4 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4 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 R 5 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R 5a independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R 5b independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R 6 independently is a substituted or unsubstituted aliphatic, aryl, or heteroaryl group;
Y is hydrogen, —CN, or —NO 2 ;
m is 0, 1, or 2; and
Z 1 and Z 2 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 Z 1 and Z 2 together form a moiety derived from a beta-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom.
2 . The compound of claim 1 , characterized by formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
each of R b1 and R b2 independently is hydrogen, —CO 2 H, —OH or a substituted or unsubstituted aliphatic, aryl, heteroaryl or heterocyclyl group;
each of R b3 and R b4 independently is hydrogen, —CO 2 H, or a substituted or unsubstituted aliphatic, aryl, heteroaryl or heterocyclyl group;
or R b2 and R b4 are each independently hydrogen, and R b1 and R b3 , 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 R b2 and R b4 are absent, and R b1 and R b3 , 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.
3 . The compound of claim 2 , wherein each of R b3 and R b4 independently is hydrogen, C 1-6 aliphatic, or —(CH 2 ) p —CO 2 H;
and p is 0, 1, or 2.
4 . The compound of claim 3 wherein P is R c —C(O)—, R c —O—C(O)—, R c —N(R 4c )—C(O)—, R c —S(O) 2 —, or R c —N(R 4c )—S(O) 2 —;
R c is selected from the group consisting of C 1-6 aliphatic, C 1-6 fluoroaliphatic, R D , T 1 -R D , and -T 1 —R 2c ; T 1 is a C 1-6 alkylene chain substituted with 0-2 independently selected R 3a or R 3b , wherein the alkylene chain optionally is interrupted by C(R 5 )—C(R 5 )—, —C≡C—, or —O—; R D is a substituted or unsubstituted mono- or bicyclic ring system; R 2c is halo, —OR 5 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , —N(R 4 ) 2 , —NR 4 C(O)R 5 , —NR 4 C(O)—N(R 4 ) 2 , —NR 4 CO 2 R 6 , —N(R 4 )SO 2 R 6 , —N(R 4 )SO 2 N(R 4 ) 2 , —O—C(O)R 5 , —OC(O)N(R 4 ) 2 , —C(O)—R 5 , —CO 2 R 5 , or —C(O)N(R 4 ) 2 ; each R 3a independently is selected from the group consisting of —F, —OH, —O(C 1-4 alkyl), —CN, —N(R 4 ) 2 , —C(O)(C 1-4 alkyl), —CO 2 H, —CO 2 (C 1-4 alkyl), —C(O)NH 2 , and —C(O)—NH(C 1-4 alkyl); each R 3b independently is a C 1-3 aliphatic substituted or unsubstituted with R 3a or R 7 ; or two substituents R 3b 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 R 7 is a substituted or unsubstituted aromatic group; and R 4c is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or C 6-10 ar(C 1-4 )alkyl, the aryl portion of which is substituted or unsubstituted.
5 . The compound of claim 3 , wherein A is 0;
R a1 is hydrogen, —(CH 2 ) m —CH 2 —R B , or —(CH 2 ) m —CH(R 5a )—OR 5b ; and m is 0.
6 . The compound of claim 3 , wherein P is R c —C(O)— or R c —S(O) 2 — and R c is —R D .
7 . The compound of claim 6 , wherein R D 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.
8 . The compound of claim 7 , wherein R D is substituted on substitutable carbon atoms with 0-1 R d and 0-2 R 8d ;
each R d independently is C 1-6 aliphatic, C 1-6 fluoroaliphatic or halo; and each R 8d independently is C 1-4 aliphatic, C 1-4 fluoroaliphatic or halo.
9 . The compound of claim 4 , wherein A is 0;
R a is C 1-6 aliphatic, or —(CH 2 ) m —C 1-2 —R B ; R a1 is hydrogen, —(CH 2 ) m —CH 2 —R B , or —(CH 2 ) m —CH(R 5a )—OR 5b ; P is R c —C(O)— or R c —S(O) 2 —; R c is R D ; and m is 0 or 1.
10 . The compound of claim 9 , wherein R a is C 1-6 aliphatic.
11 . The compound of claim 10 , wherein R 8 is CH 2 —R B ;
R B is phenyl; and R D is 2-pyrazinyl.
12 . The compound of claim 10 , wherein R a1 is —CH(R 5a )—OR 5b ;
R 5a is C 1-6 aliphatic; R 5b is hydrogen; and R D is 6-phenyl-2-pyridinyl-.
13 . The compound of claim 10 , wherein R a1 is hydrogen, and R D is 2,5-dichlorophenyl.
14 . The compound of claim 3 , wherein Z 1 and Z 2 together form a moiety derived from citric acid.
15 . The compound of claim 14 , in a substantially crystalline form.
16 . The compound of claim 14 , characterized by formula (III), (IIIa), (IV), (IVa):
or a mixture thereof.
17 . The compound of claim 16 , wherein R a is C 1-6 aliphatic.
18 . The compound of claim 16 , wherein A is 0; R a1 is hydrogen, —(CH 2 ) m —CH 2 —R B , or —(CH 2 ) m —CH(R 5 )—OR 5b ; P is R c —C(O)—; and R c is —R D .
19 . The compound of claim 18 , wherein R D 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.
20 . The compound of claim 18 , wherein R a is isobutyl.
21 . The compound of claim 20 , wherein R a1 is —CH 2 —R B ;
R B is phenyl; and R D is 2-pyrazinyl.
22 . The compound of claim 20 , wherein R a1 is hydrogen, and
R D is 2,5-dichlorophenyl.
23 . The compound of claim 20 , wherein R a1 is —CH(R 5a )—OR 5b ;
R 5a is C 1-6 aliphatic; R 5b is hydrogen; and R D is 6-phenyl-2-pyridinyl-.
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;
R a is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ;
R a1 is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ;
each R a2 independently is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ;
each R B independently is a substituted or unsubstituted mono- or bicyclic ring system;
each R 4 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4 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 R 5 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R 5a independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R 5b independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R 6 independently is a substituted or unsubstituted aliphatic, aryl, or heteroaryl group;
Y is hydrogen, —CN, or —NO 2 ;
m is 0, 1, or 2; and
Z 1 and Z 2 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 Z 1 and Z 2 together form a moiety derived from a beta-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom.
25 . The pharmaceutical composition of claim 24 , wherein the pharmaceutical composition optionally further comprises a flow-aid, and optionally further comprises a buffer.
26 . The pharmaceutical composition of claim 25 , wherein the pharmaceutical composition comprises about 0.2% to about 3% of the compound of formula (I), or a crystalline form thereof, about 86.5% to about 99.8% of a filler, optionally up to about 1.5% of a lubricant, optionally up to about 5% of a flow-aid, and optionally up to about 5% of a buffer, by weight as a percentage of total weight.
27 . The pharmaceutical composition of claim 25 , wherein the pharmaceutical composition comprises about 0.2% to about 3% of the compound of formula (I), or a crystalline form thereof; about 97% to about 99.8% of a filler; and optionally up to about 1.5% of a lubricant, by weight as a percentage of total weight.
28 . The pharmaceutical composition of claim 25 , wherein the pharmaceutical composition comprises about 0.25% to about 2% of the compound of formula (I), or a crystalline form thereof; and about 98% to about 99.75% of a filler, by weight as a percentage of total weight.
29 . The pharmaceutical composition of claim 25 , wherein the pharmaceutical composition is an oral pharmaceutical dosage form.
30 . The pharmaceutical composition of claim 29 , wherein the oral pharmaceutical dosage form is a capsule.
31 . The pharmaceutical composition of claim 25 , wherein the compound of formula (I), or a crystalline form thereof, is present in an amount of about 0.2% to about 3%, by weight as a percentage of total weight.
32 . The pharmaceutical composition of claim 25 , wherein the compound of formula (I), or a crystalline form thereof, is present in an amount of about 0.25% to about 2%, by weight as a percentage of total weight.
33 . The pharmaceutical composition of claim 25 , wherein the filler is present in an amount of about 97% to about 99.8%, by weight as a percentage of total weight.
34 . The pharmaceutical composition of claim 25 , wherein the filler is present in an amount of about 98% to about 99.75%, by weight as a percentage of total weight.
35 . The pharmaceutical composition of claim 25 , wherein the filler is present in an amount of about 86.5% to about 99.8%, by weight as a percentage of total weight.
36 . The pharmaceutical composition of claim 25 , wherein the filler is selected from the group consisting of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, low-moisture microcrystalline cellulose, sodium starch glycolate, pregelatinized starch, and mixtures thereof.
37 . The pharmaceutical composition of claim 25 , wherein the filler is selected from the group consisting of low-moisture microcrystalline cellulose, sodium starch glycolate, pregelatinized starch, and mixtures thereof.
38 . The pharmaceutical composition of claim 25 , wherein the lubricant, when present, is present in an amount of up to about 1.5%, by weight as a percentage of total weight.
39 . The pharmaceutical composition of claim 25 , wherein the lubricant, when present, is present in an amount of about 1%, by weight as a percentage of total weight.
40 . The pharmaceutical composition of claim 25 , wherein the lubricant, when present, is selected from the group consisting of magnesium stearate, glyceryl bebenate, hydrogenated vegetable oil, talc, zinc stearate, calcium stearate, sucrose stearate, sodium stearyl fumarate, and mixtures thereof.
41 . The pharmaceutical composition of claim 25 , wherein the lubricant is magnesium stearate.
42 . The pharmaceutical composition of claim 25 , wherein the flow-aid, when present, is present in an amount of up to about 5%, by weight as a percentage of total weight.
43 . The pharmaceutical composition of claim 25 , wherein the flow-aid, when present is present in an amount of about 1%, by weight as a percentage of total weight.
44 . The pharmaceutical composition of claim 25 , wherein the flow-aid, when present, is talc.
45 . The pharmaceutical composition of claim 25 , wherein the buffer, when present, is present in an amount of up to about 5%, by weight as a percentage of total weight.
46 . The pharmaceutical composition of claim 25 , wherein the buffer, when present, is present in an amount of about 2%, by weight as a percentage of total weight.
47 . The pharmaceutical composition of claim 25 , wherein the buffer, when present, is sodium citrate.
48 . The pharmaceutical composition of claim 25 , wherein:
the alpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acid is citric acid; A is 0; R a is isobutyl; R a1 is hydrogen, C 1-6 aliphatic, —(CH 2 ) m —CH 2 —R B , or —(CH 2 ) m —CH(R 5a )—OR 5b ; P is R c —C(O)—; R c is —R D ; 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; and the lubricant, when present, is magnesium stearate.
49 . 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; and
the lubricant, when present, is magnesium stearate.
50 . The pharmaceutical composition of claim 25 , wherein:
the alpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acid is citric acid; A is 0; R a is isobutyl; R a1 is hydrogen, C 1-6 aliphatic, —(CH 2 ) m —CH 2 —R B , or —(CH 2 ) m —CH(R 5a )—OR 5b ; P is R c —C(O)—; R c is —R D ; 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.
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.
52 . A pharmaceutical composition comprising the compound of formula (I-1):
or a crystalline form thereof, a filler, and optionally a lubricant.
53 . The pharmaceutical composition of claim 52 , wherein:
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.
54 . The pharmaceutical composition of claim 52 , wherein the crystalline form is Form 2.
55 . The pharmaceutical composition of claim 52 , wherein the pharmaceutical composition optionally further comprises a flow-aid, and optionally further comprises a buffer.
56 . The pharmaceutical composition of claim 55 , wherein:
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.
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).
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.
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;
R a is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 —(CH 2 ) m —CH(R 5a )—OR b , or —(CH 2 ) m —CH(R 5 )—SR 5 ;
R a1 is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ;
each R a2 independently is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ;
each R B independently is a substituted or unsubstituted mono- or bicyclic ring system;
each R 4 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4 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 R 5 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R 5a independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R 5b independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R 6 independently is a substituted or unsubstituted aliphatic, aryl, or heteroaryl group;
Y is hydrogen, —CN, or —NO 2 ;
m is 0, 1, or 2; and
Z 1 and Z 2 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 Z 1 and Z 2 together form a moiety derived from a beta-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom.
60 . The pharmaceutical composition of claim 59 , wherein the bulking agent is present in an amount of about 1% w/v to about 5% w/v.
61 . The pharmaceutical composition of claim 59 , wherein the bulking agent is present in an amount of about 3% w/v.
62 . The pharmaceutical composition of claim 59 , wherein the bulking agent is glycine.
63 . The pharmaceutical composition of claim 59 , wherein the buffer is sodium citrate, and citric acid.
64 . The pharmaceutical composition of claim 59 , wherein
the alpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acid is citric acid; A is 0; R a is isobutyl; R a1 is hydrogen, C 1-6 aliphatic, —(CH 2 ) m —CH 2 —R B , or —(CH 2 ) m —CH(R 5a )—OR 5b ; P is R c —C(O)—); R c is —R D ; m is 0 or 1; the bulking agent is glycine; and the buffer is sodium citrate, and citric acid.
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.
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;
R a is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ;
R a1 is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ;
each R a2 independently is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic, —(CH 2 ) m —-CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ;
each R B independently is a substituted or unsubstituted mono- or bicyclic ring system;
each R 4 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4 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 R 5 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R 5a independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R 5b independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R 6 independently is a substituted or unsubstituted aliphatic, aryl, or heteroaryl group;
Y is hydrogen, —CN, or —NO 2 ;
m is 0, 1, or 2; and
Z 1 and Z 2 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 Z 1 and Z 2 together form a moiety derived from a beta-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom.
67 . The pharmaceutical composition of claim 66 , further comprising a bulking agent) and a buffer.
68 . The pharmaceutical composition of claim 67 , wherein the bulking agent is glycine.
69 . The pharmaceutical composition of claim 67 , wherein the buffer is sodium citrate and citric acid.
70 . The pharmaceutical composition of claim 67 , wherein the alpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acid is citric acid;
A is 0; R a is isobutyl; R a1 is hydrogen, C 1-6 aliphatic, —(CH 2 ) m —CH 2 —R B , or —(CH 2 ) m —CH(R 5a )—OR 5b ; P is R c —C(O)—; R c is —R D ; m is 0 or 1; the bulking agent is glycine; and the buffer is sodium citrate, and citric acid.
71 . The pharmaceutical composition of claim 67 , wherein
the compound of formula (I) is represented by compounds (I-1), (I-15) or (I-18):
the bulking agent is glycine; and
the buffer is sodium citrate, and citric acid.
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).
73 . The unit dose pharmaceutical composition of claim 72 , wherein the compound of formula (I-1) is present in an amount equivalent on a molar weight basis of about 3.5 mg of the compound of formula (VIII-1).
74 . The unit dose pharmaceutical composition of claim 72 , wherein the pharmaceutical composition further comprises glycine, sodium citrate and citric acid.
75 . The unit dose pharmaceutical composition of claim 74 , wherein the amount of glycine present is about 0.01 g to about 0.50 g.
76 . The unit dose pharmaceutical composition of claim 74 , wherein the sodium citrate and citric acid is present in an amount equivalent to about 0.005 g to about 0.250 g of citrate ion.
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).
78 . The unit dose pharmaceutical composition of claim 77 , wherein the compound of formula (I-15) is present in an amount equivalent on a molar weight basis of about 3.5 mg of the compound of formula (VIII-15).
79 . The unit dose pharmaceutical composition of claim 78 , wherein the pharmaceutical composition further comprises glycine, sodium citrate and citric acid.
80 . The unit dose pharmaceutical composition of claim 78 , wherein the amount of glycine present is about 0.01 g to about 0.50 g.
81 . The unit dose pharmaceutical composition of claim 78 , wherein the sodium citrate and citric acid is present in an amount equivalent to about 0.005 g to about 0.250 g of citrate ion.
82 . A method for preparation of a pharmaceutical composition of the compound (I-1) as a lyophilized powder, the method comprising the steps:
(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.
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.
84 . The method of claim 83 , wherein the tert-butyl alcohol in the aqueous solvent mixture is present in an amount of about 3% v/v to about 6% v/v tert-butyl alcohol.
85 . A method for the preparation of a pharmaceutical composition of the compound (I-1) as a liquid pharmaceutical dosage form, said process comprising the step of reconstituting a lyophilized powder of the compound (I-1) according to claim 72 with water for injection.
86 . A method for the preparation of s pharmaceutical composition of the compound (I-15) as a liquid pharmaceutical dosage form, said method comprising the step of reconstituting a lyophilized powder of the compound (I-15) according to claim 77 with water for injection.
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;
R a is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic, —(CH 2 ) m —CH 2 —R 8 , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 —(CH 2 ) m —CH(R a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ;
R a1 is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CONR 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , —(CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ;
each R a2 independently is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic, —(CH 2 ) m —CH 2 —R B , —(CH 2 ) m —CH 2 —NHC(═NR 4 )NH—Y, —(CH 2 ) m —CH 2 —CON(R 4 ) 2 , —(CH 2 ) m —CH 2 —N(R 4 )CON(R 4 ) 2 , —(CH 2 ) m —CH(R 6 )N(R 4 ) 2 , (CH 2 ) m —CH(R 5a )—OR 5b , or —(CH 2 ) m —CH(R 5 )—SR 5 ;
each R B independently is a substituted or unsubstituted mono- or bicyclic ring system;
each R 4 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4 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 R 5 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R 5a independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R 5b independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R 6 independently is a substituted or unsubstituted aliphatic, aryl, or heteroaryl group;
Y is hydrogen, —CN, or —NO 2 ;
m is 0, 1, or 2; and
Z 1 and Z 2 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 Z 1 and Z 2 together form a moiety derived from a beta-hydroxy carboxylic acid, wherein the atom attached to boron in each case is an oxygen atom.
88 . The liquid pharmaceutical composition of claim 87 , wherein the tonicity modifier, when present, is sodium chloride.
89 . The liquid pharmaceutical composition of claim 87 , wherein the buffer is sodium citrate, and citric acid.
90 . The liquid pharmaceutical composition of claim 87 wherein:
the alpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acid is citric acid; A is 0; R a is isobutyl; R a1 is hydrogen, C 1-6 aliphatic, —(CH 2 ) m —CH 2 —R B , or —(CH 2 ) m —CH(R 5a )—OR 5b ; P is R c —C(O)—; R c is —R; m is 0 or 1; the buffer is sodium citrate and citric acid; and the tonicity modifier, when present, is sodium chloride.
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).
92 . The unit dose liquid pharmaceutical composition of claim 91 , further comprising sodium citrate, citric acid and sodium chloride.
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 .Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.