US2005049246A1PendingUtilityA1
Inhibitors of Src and Lck protein kinases
Priority: Jul 3, 2001Filed: Dec 4, 2003Published: Mar 3, 2005
Est. expiryJul 3, 2021(expired)· nominal 20-yr term from priority
A61P 37/00A61P 5/14A61P 37/06A61P 37/08A61P 9/10A61P 35/04A61P 37/02A61P 43/00A61P 7/00A61P 9/00A61P 3/14A61P 25/16A61P 35/02A61P 35/00A61P 25/28A61P 29/00A61P 27/16A61P 25/00A61P 11/06C07D 413/04A61P 19/10A61P 17/02A61P 17/06A61P 1/16A61P 1/04A61P 11/00A61P 19/02
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Claims
Abstract
The present invention provides compounds of formula I: or a pharmaceutically acceptable derivative thereof, wherein A-B is N—O or O—N and G, R 1 , R 2 , R 3 , and R 4 are as described in the specification. These compounds are inhibitors of protein kinase, particularly inhibitors of Src and Lck kinase. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.
Claims
exact text as granted — not AI-modified1 . A compound of formula I:
or a pharmaceutically acceptable derivative thereof, wherein:
A-B is N—O or O—N;
R 1 is selected from halogen, NO 2 , TYR, or TCN;
each T is independently selected from an optionally substituted C 1 -C 6 alkylidene chain, wherein:
one methylene unit of T is optionally replaced by O, NR, NRC(O), C(O)NR, NRC(O)NR, C(O), C(O)CH 2 C(O), C(O)C(O), C(O)O, OC(O), NRSO 2 , S, SO, SO 2 NR, or SO 2 ;
y is zero or one;
each R is independently selected from hydrogen or an optionally substituted C 1 -C 6 aliphatic group, or:
two R on the same nitrogen are taken together with the nitrogen to form a 3-7 membered saturated, partially unsaturated, or fully unsaturated ring having 1-2 heteroatoms, in addition to the nitrogen bound thereto, independently selected from nitrogen, oxygen, or sulfur;
R 2 is R or Ar 1 ;
G is selected from X m R or X m Ar 1 ;
each m is independently selected from zero or one;
X is selected from O, S, SO, SO 2 , NH, C(O), C(O)NH, NHC(O), NHC(O)NH, SO 2 NH, NHSO 2 , or NHSO 2 NH;
each Ar 1 is independently selected from an optionally substituted ring selected from a 5-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 3 is selected from ZQ n R 5 or ZQ n R 7 , wherein ZQ n R 7 is not hydrogen;
Q is an optionally substituted C 1 -C 6 alkylidene chain wherein:
one or two non-adjacent methylene units of Q are optionally and independently replaced by O, NR, NRC(O), C(O)NR, C(O), S, SO, SO 2 , or SO 2 NR;
provided that said optionally replaced methylene unit of Q is a methylene unit non-adjacent to R 7 ;
each n is independently selected from zero or one;
Z is selected from a valence bond, O, S, SO, SO 2 , NH, C(O), C(O)NH, NHC(O), SO 2 NH, or NHSO 2 ;
R 4 is selected from R, halogen, NO 2 , CN, OR, SR, N(R) 2 , NRC(O)R, NRC(O)N(R) 2 , NRCO 2 R, C(O)R, CO 2 R, OC(O)R, C(O)N(R) 2 , OC(O)N(R) 2 , SOR, SO 2 R, SO 2 N(R) 2 , NRSO 2 R, NRSO 2 N(R) 2 , C(O)C(O)R, or C(O)CH 2 C(O)R, or:
two R 4 on adjacent positions of the phenyl ring are taken together to form a saturated, partially unsaturated, or fully unsaturated 5-7 membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 5 is Ar 1 , wherein R 5 is optionally substituted with up to three R 6 ;
each R 6 is independently selected from R, halogen, NO 2 , CN, OR, SR, N(R) 2 , NRC(O)R, NRC(O)N(R) 2 , NRCO 2 R, C(O)R, CO 2 R, C(O)N(R) 2 , OC(O)N(R) 2 , SOR, SO 2 R, SO 2 N(R) 2 , NRSO 2 R, NRSO 2 N(R) 2 , C(O)C(O)R, or C(O)CH 2 C(O)R, or:
two R 6 on adjacent positions of R 5 are taken together to form a saturated, partially unsaturated, or fully unsaturated 5-7 membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
R 7 is selected from R, halogen, NO 2 , CN, OR, SR, N(R) 2 , NRC(O)R, NRC(O)N(R) 2 , NRCO 2 R, C(O)R, CO 2 R, OC(O)R, C(O)N(R) 2 , OC(O)N(R) 2 , SOR, SO 2 R, SO 2 N(R) 2 , NRSO 2 R, NRSO 2 N(R) 2 , C(O)C(O)R, or C(O)CH 2 C(O)R;
provided that:
(a) when R 3 is ZQR 7 , R 1 is other than hydrogen, and
(b) when R 1 is hydrogen, R 5 is other than phenyl.
2 . The compound according to claim 1 , wherein said compound has the formula Ia or Ib:
or a pharmaceutically acceptable derivative thereof.
3 . The compound according to claim 2 , wherein said compound has the formula II:
or a pharmaceutically acceptable derivative thereof.
4 . The compound according to claim 3 wherein:
R 3 is ZQ n R 5 ; Z is a valence bond, O, NH, or NHC(O); and R 5 is a 5-6 membered saturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally substituted with up to two R 6 groups.
5 . The compound according to claim 3 , wherein:
R 3 is ZQ n R 7 ; Z is a valence bond, O, NH, or NHC(O); and R 7 is selected from OR, N(R) 2 , OC(O)R, CO 2 R, C(O)N(R) 2 , NRC(O)OR, or NRC(O)R.
6 . The compound according to claim 2 , wherein said compound has the formula IIIa:
or a pharmaceutically acceptable derivative thereof.
7 . The compound according to claim 6 , wherein:
n is one; Q is a C 1-6 alkylidene chain wherein one or two non-adjacent methylene units of Q are optionally and independently replaced by O, NR, S, or C(O); and R 5 is a 5-6 membered saturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally substituted with up to two R 6 groups.
8 . The compound according to claim 2 , wherein said compound has the formula IIIb:
or a pharmaceutically acceptable derivative thereof.
9 . The compound according to claim 8 , wherein:
n is one; Q is a C 1-6 alkylidene chain wherein one or two non-adjacent methylene units of Q are optionally and independently replaced by O, NR, S, or C(O); and R 7 is selected from OR, N(R) 2 , OC(O)R, CO 2 R, C(O)N(R) 2 , NRC(O)OR, or NRC(O)R.
10 . The compound according to claim 2 , wherein said compound has the formula IVa:
or a pharmaceutically acceptable derivative thereof.
11 . The compound according to claim 10 , wherein:
n is one; Q is a C 1-6 alkylidene chain wherein one or two non-adjacent methylene units of Q are optionally and independently replaced by O, NR, S, or C(O); and R 5 is a 5-6 membered saturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally substituted with up to two R 6 groups.
12 . The compound according to claim 1 , wherein said compound has the formula IVb:
or a pharmaceutically acceptable derivative-thereof.
13 . The compound according to claim 12 , wherein:
n is one; Q is a C 1-6 alkylidene chain wherein one or two non-adjacent methylene units of Q are optionally and independently replaced by O, NR, S, or C(O); and R 7 is selected from OR, N(R) 2 , OC(O)R, CO 2 R, C(O)N(R) 2 , NRC(O)OR, or NRC(O)R.
14 . The compound according to claim 2 , wherein said compound has the formula Va:
or a pharmaceutically acceptable derivative thereof.
15 . The compound according to claim 14 , wherein:
n is one; Q is a C 1-6 alkylidene chain wherein one or two non-adjacent methylene units of Q are optionally and independently replaced by O, NR, S, or C(O); and R 5 is a 5-6 membered saturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally substituted with up to two R 6 groups.
16 . The compound according to claim 2 , wherein said compound has the formula Vb:
or a pharmaceutically acceptable derivative thereof.
17 . The compound according to claim 16 , wherein:
n is one; Q is a C 1-6 alkylidene chain wherein one or two non-adjacent methylene units of Q are optionally and independently replaced by O, NR, S, or C(O); and R 7 is selected from OR, N(R) 2 , OC(O)R, CO 2 R, C(O)N(R) 2 , NRC(O)OR, or NRC(O)R.
18 . The compound according to any of claims 4 , 5 , 7 , 9 , 11 , 13 , 15 , or 17, wherein:
G is X m R or X m Ar 1 ; each m is independently zero or one; each X is independently selected from O, S, or NH; R is C 1-4 aliphatic; and Ar 1 is an optionally substituted 5-6 membered saturated or aryl ring having 0-2 heteroaroms independently selected from nitrogen, oxygen, or sulfur.
19 . The compound according to claim 1 , wherein said compound is selected from the following Table 1 compounds:
TABLE 1
Compounds of Formula II
II
No.
R 1
II-1
CH 3
II-2
CH 3
II-3
CH 3
II-4
CH 3
II-5
CH 3
II-6
CH 2 CN
II-7
COOH
II-8
H
II-9
CH 2 CH 3
II-10
C(O)NH 2
20 . The compound according to claim 1 , wherein said compound is selected from the following Table 2 compounds:
TABLE 2
Compounds of Formula IIIa
IIIa
No.
R 1
IIIa-1
H
IIIa-2
H
IIIa-3
H
IIIa-4
H
IIIa-5
H
IIIa-6
H
IIIa-7
H
IIIa-8
H
IIIa-9
H
IIIa-10
H
IIIa-11
H
IIIa-12
H
IIIa-13
H
IIIa-14
H
IIIa-15
H
IIIa-16
H
IIIa-17
H
IIIa-18
H
IIIa-19
H
IIIa-20
H
IIIa-21
H
IIIa-22
H
IIIa-23
H
IIIa-24
H
IIIa-25
H
IIIa-26
H
IIIa-27
H
IIIa-28
H
IIIa-29
H
IIIa-30
H
IIIa-31
H
IIIa-32
CH 3
IIIa-33
CN
IIIa-34
H
IIIa-35
H
IIIa-36
CH 3
IIIa-37
CH 3
IIIa-38
CH 3
IIIa-39
CH 3
IIIa-40
IIIa-41
OH
IIIa-42
CH 3
IIIa-43
H
IIIa-44
H
IIIa-45
H
IIIa-46
H
21 . The compound according to claim 1 , wherein said compound is selected from the following Table 3 compounds:
TABLE 3
Compounds of Formula IIIb
IIIb
No.
R 1
IIIb-1
CH 3
IIIb-2
CH 3
IIIb-3
CH 2 CH 3
IIIb-4
CH 2 OH
IIIb-5
CH 3
IIIb-6
CH 2 CN
IIIb-7
CH 2 OH
IIIb-8
CH 3
IIIb-9
CH 3
IIIb-10
CH 2 OH
IIIb-11
CH 3
IIIb-12
CH 2 CH 3
IIIb-13
CH 3
IIIb-14
CH 3
IIIb-15
CH 3
IIIb-16
CH 3
IIIb-17
CH 3
IIIb-18
CH 2 OH
IIIb-19
CH 2 OH
IIIb-20
CH 2 OH
IIIb-21
CH 2 OH
IIIb-22
CH 3
IIIb-23
CO 2 CH 3
IIIb-24
CO 2 H
IIIb-25
CH 2 OH
IIIb-26
C(O)NH 2
IIIb-27
CN
IIIb-28
CH 3
IIIb-29
CH 2 OCH 2 CH 2 CH 3
22 . The compound according to claim 1 , wherein said compound is selected from the following Table 4 compounds:
TABLE 4
Compounds of Formula IVa
IVa
No.
R 1
IVa-1
H
IVa-2
H
IVa-3
H
IVa-4
H
IVa-5
CH 3
IVa-6
CH 3
IVa-7
CH 3
IVa-8
CH 3
IVa-9
H
IVa-10
H
IVa-11
H
IVa-12
H
IVa-13
CH 3
IVa-14
CH 3
IVa-15
CH 3
IVa-16
CH 3
23 . The compounds according to claim 1 , wherein said compound is selected from the following Table 5 compounds:
TABLE 5
Compounds of Formula IVb
IVb
No.
R 1
IVb-1
CH 3
IVb-2
CH 2 CH 3
IVb-3
CH 3
IVb-4
CH 2 OH
IVb-5
OH
IVb-6
CH 2 CH 3
IVb-7
CH 2 CN
IVb-8
IVb-9
NH 2
24 . The compound according to claim 1 , wherein said compound is selected from the following Table 6 compounds:
TABLE 6
Compounds of Formula Va
Va
No.
R 1
Va-1
H
Va-2
H
Va-3
H
Va-4
CH 3
Va-5
H
Va-6
H
Va-7
CH 2 CH 3
Va-8
CH 2 CN
Va-9
CH 2 OH
Va-10
H
Va-11
H
Va-12
H
Va-13
CH 3
Va-14
OH
Va-15
H
Va-16
NH 2
Va-17
H
25 . The compound according to claim 1 , wherein said compound is selected from the following Table 7 compounds:
TABLE 7
Compounds of Formula Vb
Vb
No.
R 1
Vb-1
CH 3
Vb-2
CH 2 CH 3
Vb-3
CH 3
Vb-4
CH 2 OH
Vb-5
OH
Vb-6
CH 2 CH 3
Vb-7
CH 2 CN
Vb-8
CH 2 OH
Vb-9
NH 2
Vb-10
CH 2 CN
Vb-11
CH 2 OH
Vb-12
NH 2
Vb-13
CH 2 OH
Vb-14
CH 3
Vb-15
CH 2 CH 3
Vb-16
CH 3
Vb-17
CH 2 OH
Vb-18
OCH 3
Vb-19
CH 2 OCH 3
Vb-20
CH 3
Vb-21
CH 2 CH 3
Vb-22
CH 2 OH
26 . A composition comprising a compound according to claim 1 , in an amount to detectably inhibit Src or Lck protein kinase activity, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
27 . The composition according to claim 26 , additionally comprising an additional therapeutic agent selected from an a chemotherapeutic or anti-proliferative agent, a treatment for Alzheimer's Disease, a treatment for Parkinson's Disease, an agent for treating Multiple Sclerosis (MS), a treatment for asthma, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an agent for treating a blood disorder, or an agent for treating an immunodeficiency disorder.
28 . A method of inhibiting Src or Lck kinase activity in a biological sample, comprising the step of contacting said biological sample with:
a) a composition according to claim 26; or b) a compound according to claim 1 .
29 . A method of treating or lessening the severity of a Src- or Lck-mediated disease or condition in a patient, comprising the step of administering to said patient:
a) a composition according to claim 26; or b) a compound according to claim 1 .
30 . The method according to claim 29 , wherein said Src-mediated disease is selected from hypercalcemia, restenosis, osteoporosis, osteoarthritis, symptomatic treatment of bone metastasis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, lupus, graft vs. host disease, T-cell mediated hypersensitivity disease, Hashimoto's thyroiditis, Guillain-Barre syndrome, chronic obtructive pulmonary disorder, contact dermatitis, cancer, Paget's disease, asthma, ischemic or reperfusion injury, allergic disease, atopic dermatitis, or allergic rhinitis.
31 . The method according to claim 29 , wherein said Lck-mediated disease is selected from an autoimmune disease, allergies, rheumatoid arthritis, or leukemia.
32 . The method according to claim 29 , comprising the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, a treatment for Alzheimer's Disease, a treatment for Parkinson's Disease, an agent for treating Multiple Sclerosis (MS), a treatment for asthma, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an agent for treating a blood disorder, or an agent for treating an immunodeficiency disorder, wherein:
said additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.
33 . A composition for coating an implantable device comprising a compound according to claim 1 and a carrier suitable for coating said implantable device.
34 . An implantable device coated with a composition according to claim 33.Join the waitlist — get patent alerts
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