US2008312228A1PendingUtilityA1
Pyrimidine compound and medical use thereof
Est. expiryJun 11, 2024(expired)· nominal 20-yr term from priority
Inventors:Hisashi KawasakiHiroyuki AbeKazuhide HayakawaTetsuya IidaShinichi KikuchiTakayuki YamaguchiToyomichi NanayamaHironori KurachiMasahiro TamaruYoshikazu HoriMitsuru TakahashiTakayuki YoshidaToshiyuki Sakai
A61P 35/00C07C 2601/16C07D 239/545C07D 487/04C07D 239/62C07D 471/04A61K 31/519C07D 471/16C07C 275/30A61P 29/00C07D 239/553C07F 9/53C07C 275/50
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Claims
Abstract
The present invention relates to a pyrimidine compound or a pharmaceutically acceptable salt thereof represented by the following formula [I] wherein each symbol is as defined in the specification and a method of therapeutically or prophylactically treating an undesirable cell proliferation, comprising administering such a compound. The compound of the present invention has superior activity in suppressing undesirable cell proliferation, particularly, an antitumor activity, and is useful as an antitumor agent for the prophylaxis or treatment of cancer, rheumatism, and the like. In addition, the compound of the present invention can be a more effective antitumor agent when used in combination with other antitumor agents such as an alkylating agent or metabolism antagonist.
Claims
exact text as granted — not AI-modified1 . A method of therapeutically or prophylactically treating an undesirable cell proliferation in a mammal comprising administering to the mammal a therapeutic or prophylactic amount of a compound represented by the following formula [I] or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
wherein
X 1 and X 2 are the same or different and each is a carbon atom or a nitrogen atom, a
moiety is
R 1 , R 2 , and R 6 are the same or different and each is
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, or
wherein m is 0 or an integer of 1 to 4,
ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B,
R 3 , R 4 , and R 5 are the same or different and each is
a hydrogen atom,
a hydroxyl group,
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A,
a C 3-12 carbon ring group or
a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B, or
R 2 and R 3 are optionally linked to form a C 1-4 alkylene group, or R 4 and R 5 are optionally linked to form a C 1-4 alkylene group,
wherein group A is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-4 alkyl group,
5) —OR A1 wherein R A1 is a hydrogen atom or a C 1-4 alkyl group,
6) —SR A2 wherein R A2 is a hydrogen atom or a C 1-4 alkyl group,
7) —NR A3 R A4 wherein R A3 and R A4 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
8) —COOR A5 wherein R A5 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR A6 COR A7 wherein R A6 is a hydrogen atom or a C 1-4 alkyl group, R A7 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
10) —NR A8 COOR A9 wherein R A8 and R A9 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
11) a C 3-12 carbon ring group and
12) a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
each of the C 1-4 alkyl groups of the above-mentioned 4), R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 and R A9 is optionally substituted by the same or different 1 to 3 substituents selected from the following group C, and
each of the C 3-12 carbon ring groups of the above-mentioned 11) and R A7 , and the heterocyclic groups of 12) and R A7 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C
group B is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-8 alkyl group,
5) a C 2-4 alkenyl group,
6) a C 2-4 alkynyl group,
7) —OR B1 wherein R B1 is a hydrogen atom or a C 1-4 alkyl group,
8) —SR B2 wherein R B2 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR B3 R B4 wherein R B3 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group, and R B4 is a hydrogen atom or a C 1-4 alkyl group,
10) —NR B5 COR B6 wherein R B5 is a hydrogen atom or a C 1-4 alkyl group, and R B6 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
11) —NR B7 COOR B8 wherein R B7 and R B8 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
12) —NR B9 CONR B10 R B11 wherein R B9 , R B10 and R B11 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
13) —NR B12 CONR B13 OR B14 wherein R B12 , R B13 and R B14 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
14) —NR B15 SO 2 R B16 wherein R B15 is a hydrogen atom or a C 1-4 alkyl group, and R B16 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
15) —SO 2 —R B17 wherein R B17 is a C 1-4 alkyl group or a heterocyclic group,
16) —SO 2 NR B18 R B19 wherein R B18 and R B19 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
17) —P(═O)(R B20 )(R B21 ) wherein R B20 and R B21 are the same or different and each is a C 1-4 alkyl group,
18) —COOR B22 wherein R B22 is a hydrogen atom or a C 1-4 alkyl group,
19) —CONR B23 R B24 wherein R B23 and R B24 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
20) —NR B25 SO 2 NR B26 R B27 wherein R B25 , R B26 and R B27 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
21) —NR B28 SO 2 NR B29 CONR B30 R B31 wherein R B28 , R B29 , R B30 and R B31 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
22) a C 3-12 carbon ring group and
23) a heterocyclic group
wherein each of the “C 1-8 alkyl group” of the above-mentioned 4), and the C 1-4 alkyl groups for R B1 to R B31 is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
each of the C 2-4 alkenyl group of 5) and the C 2-4 alkynyl group of 6) is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and
each of the C 3-12 carbon ring group of the above-mentioned 22), R B3 , R B6 and R B16 , and the heterocyclic group of the above-mentioned 23), R B3 , R B6 , R B16 and R B17 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and
group C is a group consisting of
1) a halogen atom,
2) a cyano group,
3) a C 1-4 alkyl group,
4) —OR C1 wherein R C1 is a hydrogen atom or a C 1-4 alkyl group,
5) —NR C2 R C3 wherein R C2 and R C3 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
6) —COOR C4 wherein R C4 is a hydrogen atom or a C 1-4 alkyl group and
7) an oxo group,
whereupon the undesirable cell proliferation is treated.
2 . The method of claim 1 , wherein the compound is represented by the following formula [I-1]:
wherein each symbol in the formula is as defined in claim 1 .
3 . The method of claim 1 , wherein the compound is represented by the following formula [I-2]:
wherein each symbol in the formula is as defined in claim 1 .
4 . The method of claim 1 , wherein the compound is represented by the following formula [I-3]:
wherein each symbol in the formula is as defined in claim 1 .
5 . The method of claim 1 , wherein R 1 is a C 1-6 alkyl group.
6 . The method of claim 1 , wherein R 1 is
wherein m is 0, and ring Cy is a C 3-12 carbon ring group,
wherein the C 3-12 carbon ring group is optionally substituted by 1 to 5 substituents selected from group B of claim 1 .
7 . The method of claim 1 , wherein R 1 is a C 3-8 cycloalkyl group.
8 . The method of claim 7 , wherein R 1 is a cyclopropyl group.
9 . The method of claim 1 , wherein R 2 is
wherein m is 0, and ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B of claim 1 .
10 . The method of claim 1 , wherein R 3 is a C 1-6 alkyl group.
11 . The method of claim 1 , wherein R 4 is a hydrogen atom.
12 . The method of claim 1 , wherein R 5 is a hydrogen atom.
13 . The method of claim 1 , wherein R 6 is
wherein m is 0, and ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B of claim 1 .
14 . The method of claim 1 , wherein the undesirable cell proliferation causes rheumatism.
15 . The method of claim 1 , wherein the undesirable cell proliferation causes a tumor.
16 . A compound represented by the following formula [I′] or a pharmaceutically acceptable salt thereof:
wherein
X 1 and X 2 are the same or different and each is a carbon atom or a nitrogen atom, a
moiety is
R 1′ , R 2′ and R 6 are the same or different and each is
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, or
m is an integer of 0 or 1 to 4,
ring Cy is a C 3-12 carbon ring group or a heterocyclic group
wherein the heterocyclic group is a saturated or unsaturated ring having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B,
R 3 , R 4 , and R 5 are the same or different and each is
a hydrogen atom,
a hydroxyl group,
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A,
a C 3-12 carbon ring group or
a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B, or
R 4 and R 5 are optionally linked to form a C 1-4 alkylene group,
wherein group A is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-4 alkyl group,
5) —OR A1 wherein R A1 is a hydrogen atom or a C 1-4 alkyl group,
6) —SR A2 wherein R A2 is a hydrogen atom or a C 1-4 alkyl group,
7) —NR A3 R A4 wherein R A3 and R A4 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
8) —COOR A5 wherein R A5 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR A6 COR A7 wherein R A6 is a hydrogen atom or a C 1-4 alkyl group, R A7 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
10) —NR A8 COOR A9 wherein R A8 and R A9 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
11) a C 3-12 carbon ring group and
12) a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
each of the C 1-4 alkyl groups of the above-mentioned 4), R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 and R A9 is optionally substituted by the same or different 1 to 3 substituents selected from the following group C, and
each of the C 3-12 carbon ring groups of the above-mentioned 11) and R A7 , and the heterocyclic groups of 12) and R A7 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C
group B is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-8 alkyl group,
5) a C 2-4 alkenyl group,
6) a C 2-4 alkynyl group,
7) —OR B1 wherein R B1 is a hydrogen atom or a C 1-4 alkyl group,
8) —SR B2 wherein R B2 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR B3 R B4 wherein R B3 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group, and R B4 is a hydrogen atom or a C 1-4 alkyl group,
10) —NR B5 COR B6 wherein R B5 is a hydrogen atom or a C 1-4 alkyl group, and R B6 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
11) —NR B7 COOR B8 wherein R B7 and R B8 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
12) —NR B9 CONR B10 R B11 wherein R B9 , R B10 and R B11 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
13) —NR B12 CONR B13 OR B14 wherein R B12 , R B13 and R B14 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
14) —NR B15 SO 2 R B16 wherein R B15 is a hydrogen atom or a C 1-4 alkyl group, and R B16 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
15) —SO 2 —R B17 wherein R B17 is a C 1-4 alkyl group or a heterocyclic group,
16) —SO 2 NR B18 R B19 wherein R B18 and R B19 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
17) —P(═O)(R B20 )(R B21 ) wherein R B20 and R B21 are the same or different and each is a C 1-4 alkyl group,
18) —COOR B22 wherein R B22 is a hydrogen atom or a C 1-4 alkyl group,
19) —CONR B23 R B24 wherein R B23 and R B24 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
20) —NR B25 SO 2 NR B26 R B27 wherein R B25 , R B26 and R B27 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
21) —NR B28 SO 2 NR B29 CONR B30 R B31 wherein R B28 , R B29 , R B30 and R B31 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
22) a C 3-12 carbon ring group and
23) a heterocyclic group
wherein each of the “C 1-8 alkyl group” of the above-mentioned 4), and the C 1-4 alkyl groups for R B1 to R B31 is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
each of the C 2-4 alkenyl group of 5) and the C 2-4 alkynyl group of 6) is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and
each of the C 3-12 carbon ring group of the above-mentioned 22), R B3 , R B6 and R B16 , and the heterocyclic group of the above-mentioned 23), R B3 , R B6 , R B16 and R B17 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and
group C is a group consisting of
1) a halogen atom,
2) a cyano group,
3) a C 1-4 alkyl group,
4) —OR C1 wherein R C1 is a hydrogen atom or a C 1-4 alkyl group,
5) —NR C2 R C3 wherein R C2 and R C3 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
6) —COOR C4 wherein R C4 is a hydrogen atom or a C 1-4 alkyl group and
7) an oxo group,
provided that, when the
moiety is
then R 2′ is not a methyl group, and
when R 2′ is a phenyl group, then R 1′ is not a phenyl group.
17 . A pharmaceutical composition which comprises
(a) a compound of claim 16 or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier.
18 . A commercial package comprising
(i) a pharmaceutical composition comprising (a) a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier and (ii) a written matter associated therewith, wherein the written matter states that the pharmaceutical composition can or should be used for treating a disease caused by an undesirable cell proliferation.
19 . The commercial package of claim 18 , wherein the disease is a tumor or rheumatism.
20 . A pharmaceutical composition comprising
(a) a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof, (b) at least one antitumor compound that is not a compound of the formula [I], and (c) a pharmaceutically acceptable carrier.
21 . A kit comprising
(i) a pharmaceutical composition comprising (a) a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier; and (ii) a pharmaceutical composition comprising (a) at least one antitumor agent that is not a compound of the formula [I], and (b) a pharmaceutically acceptable carrier.
22 . A method of inhibiting MEK in a mammal comprising administering to the mammal an MEK inhibiting amount of a compound represented by the following formula [I] or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
wherein
X 1 and X 2 are the same or different and each is a carbon atom or a nitrogen atom, a
moiety is
R 1 , R 2 , and R 6 are the same or different and each is
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, or
wherein m is 0 or an integer of 1 to 4,
ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B,
R 3 , R 4 , and R 5 are the same or different and each is
a hydrogen atom,
a hydroxyl group,
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A,
a C 3-12 carbon ring group or
a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B, or
R 2 and R 3 are optionally linked to form a C 1-4 alkylene group, or R 4 and R 5 are optionally linked to form a C 1-4 alkylene group,
wherein group A is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-4 alkyl group,
5) —OR A1 wherein R A1 is a hydrogen atom or a C 1-4 alkyl group,
6) —SR A2 wherein R A2 is a hydrogen atom or a C 1-4 alkyl group,
7) —NR A3 R A4 wherein R A3 and R A4 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
8) —COOR A5 wherein R A5 is a hydrogen atom or a C 1-4 alkyl group.
9) —NR A6 COR A7 wherein R A6 is a hydrogen atom or a C 1-4 alkyl group, R A7 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
10) —NR A8 COOR A9 wherein R A8 and R A9 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
11) a C 3-12 carbon ring group and
12) a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
each of the C 1-4 alkyl groups of the above-mentioned 4), R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 and R A9 is optionally substituted by the same or different 1 to 3 substituents selected from the following group C, and
each of the C 3-12 carbon ring groups of the above-mentioned 11) and R A7 , and the heterocyclic groups of 12) and R A7 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C
group B is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-8 alkyl group,
5) a C 2-4 alkenyl group,
6) a C 2-4 alkynyl group,
7) —OR B1 wherein R B1 is a hydrogen atom or a C 1-4 alkyl group,
8) —SR B2 wherein R B2 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR B3 R B4 wherein R B3 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group, and R B4 is a hydrogen atom or a C 1-4 alkyl group,
10) —NR B5 COR B6 wherein R B5 is a hydrogen atom or a C 1-4 alkyl group, and R B6 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
11) —NR B7 COOR B8 wherein R B7 and R B8 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
12) —NR B9 CONR B10 R B11 wherein R B9 , R B10 and R B11 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
13) —NR B12 CONR B13 R B14 wherein R B12 , R B13 and R B14 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
14) —NR B15 SO 2 R B16 wherein R B15 is a hydrogen atom or a C 1-4 alkyl group, and R B16 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
15) —SO 2 —R B17 wherein R B17 is a C 1-4 alkyl group or a heterocyclic group,
16) —SO 2 NR B18 R B19 wherein R B18 and R B19 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
17) —P(═O)(R B20 )(R B21 ) wherein R B20 and R B21 are the same or different and each is a C 1-4 alkyl group,
18) —COOR B22 wherein R B22 is a hydrogen atom or a C 1-4 alkyl group,
19) —CONR B23 R B24 wherein R B23 and R B24 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
20) —NR B25 SO 2 NR B26 R B27 wherein R B25 , R B26 and R B27 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
21) —NR B28 SO 2 NR B29 CONR B30 R B31 wherein R B28 , R B29 , R B30 and R B31 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
22) a C 3-12 carbon ring group and
23) a heterocyclic group
wherein each of the “C 1-8 alkyl group” of the above-mentioned 4), and the C 1-4 alkyl groups for R B1 to R B31 is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
each of the C 2-4 alkenyl group of 5) and the C 2-4 alkynyl group of 6) is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and
each of the C 3-12 carbon ring group of the above-mentioned 22), R B3 , R B6 and R B16 , and the heterocyclic group of the above-mentioned 23), R B3 , R B6 , R B16 and R B17 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and
group C is a group consisting of
1) a halogen atom,
2) a cyano group,
3) a C 1-4 alkyl group,
4) —OR C1 wherein R C1 is a hydrogen atom or a C 1-4 alkyl group,
5) —NR C2 R C3 wherein R C2 and R C3 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
6) —COOR C4 wherein R C4 is a hydrogen atom or a C 1-4 alkyl group and
7) an oxo group,
whereupon MEK is inhibited.
23 . A method of inducing p15 protein in a mammal comprising administering to the mammal a p15 protein inducing amount of a compound represented by the following formula [I] or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
wherein
X 1 and X 2 are the same or different and each is a carbon atom or a nitrogen atom, a
moiety is
R 1 , R 2 , and R 6 are the same or different and each is
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group, are optionally substituted by 1 to 3 substituents selected from the following group A, or
wherein m is 0 or an integer of 1 to 4,
ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B,
R 3 , R 4 , and R 5 are the same or different and each is
a hydrogen atom,
a hydroxyl group,
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A,
a C 3-12 carbon ring group or
a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B, or
R 2 and R 3 are optionally linked to form a C 1-4 alkylene group, or R 4 and R 5 are optionally linked to form a C 1-4 alkylene group,
wherein group A is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-4 alkyl group,
5) —OR A1 wherein R A1 is a hydrogen atom or a C 1-4 alkyl group,
6) —SR A2 wherein R A2 is a hydrogen atom or a C 1-4 alkyl group,
7) —NR A3 R A4 wherein R A3 and R A4 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
8) —COOR A5 wherein R A5 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR A6 COR A7 wherein R A6 is a hydrogen atom or a C 1-4 alkyl group, R A7 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
10) —NR A8 COOR A9 wherein R A8 and R A9 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
11) a C 3-12 carbon ring group and
12) a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
each of the C 1-4 alkyl groups of the above-mentioned 4), R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 and R A9 is optionally substituted by the same or different 1 to 3 substituents selected from the following group C, and
each of the C 3-12 carbon ring groups of the above-mentioned 11) and R A7 , and the heterocyclic groups of 12) and R A7 is optionally substituted by the same or different 1 to substituents selected from the following group C
group B is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-8 alkyl group,
5) a C 2-4 alkenyl group,
6) a C 2-4 alkynyl group,
7) —OR B1 wherein R B1 is a hydrogen atom or a C 1-4 alkyl group,
8) —SR B2 wherein R B2 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR B5 R B4 wherein R B3 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group, and R B4 is a hydrogen atom or a C 1-4 alkyl group,
10) —NR B5 COR B6 wherein R B5 is a hydrogen atom or a C 1-4 alkyl group, and R B6 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
11) —NR B7 COOR B8 wherein R B7 and R B8 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
12)-NR B9 CONR B10 R B11 wherein R B9 , R B10 and R B11 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
13) —NR B12 CONR B13 OR B14 wherein R B12 , R B13 and R B14 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
14) —NR B15 SO 2 R B16 wherein R B15 is a hydrogen atom or a C 1-4 alkyl group, and R B16 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
15) —SO 2 R B17 wherein R B17 is a C 1-4 alkyl group or a heterocyclic group,
16) —SO 2 NR B18 R B19 wherein R B18 and R B19 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
17) —P(═O)(R 20 )(R B21 ) wherein R B20 and R B21 are the same or different and each is a C 1-4 alkyl group,
18) —COOR B22 wherein R B22 is a hydrogen atom or a C 1-4 alkyl group,
19) —CONR B23 R B24 wherein R B23 and R B24 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
20) —NR B25 SO 2 NR B26 R B27 wherein R B25 , R B26 and R B27 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
21) —NR B28 SO 2 NR B29 CONR B30 R B31 wherein R B28 , R B29 , R B30 and R B31 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
22) a C 3-12 carbon ring group and
23) a heterocyclic group
wherein each of the “C 1-8 alkyl group” of the above-mentioned 4), and the C 1-4 alkyl groups for R B1 to R B31 is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
each of the C 2-4 alkenyl group of 5) and the C 2-4 alkynyl group of 6) is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and
each of the C 3-12 carbon ring group of the above-mentioned 22), R B3 , R B6 and R B16 , and the heterocyclic group of the above-mentioned 23), R B3 , R B6 , R B16 and R B17 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and
group C is a group consisting of
1) a halogen atom,
2) a cyano group,
3) a C 1-4 alkyl group,
4) —OR C1 wherein R C1 is a hydrogen atom or a C 1-4 alkyl group,
5) —NR C2 R C3 wherein R C2 and R C3 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
6) —COOR C4 wherein R C4 is a hydrogen atom or a C 1-4 alkyl group and
7) an oxo group,
whereupon p15 protein is induced.
24 . A method of regulating cell cycle in a mammal comprising administering to the mammal a cell cycle regulating amount of a compound of the represented by the following formula [I] or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
wherein
X 1 and X 2 are the same or different and each is a carbon atom or a nitrogen atom, a
moiety is
R 1 , R 2 , and R 6 are the same or different and each is
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, or
wherein m is 0 or an integer of 1 to 4,
ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B,
R 3 , R 4 , and R 5 are the same or different and each is
a hydrogen atom,
a hydroxyl group,
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A,
a C 3-12 carbon ring group or
a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B, or
R 2 and R 3 are optionally linked to form a C 1-4 alkylene group, or R 4 and R 5 are optionally linked to form a C 1-4 alkylene group,
wherein group A is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-4 alkyl group,
5) —OR A1 wherein R A1 is a hydrogen atom or a C 1-4 alkyl group,
6) —SR A2 wherein R A2 is a hydrogen atom or a C 1-4 alkyl group,
7) —NR A3 R A4 wherein R A3 and R A4 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
8) —COOR A5 wherein R A5 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR A6 COR A7 wherein R A6 is a hydrogen atom or a C 1-4 alkyl group, R A7 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
10) —NR A8 COOR A9 wherein R A8 and R A9 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
11) a C 3-12 carbon ring group and
12) a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
each of the C 1-4 alkyl groups of the above-mentioned 4), R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 and R A9 is optionally substituted by the same or different 1 to 3 substituents selected from the following group C, and
each of the C 3-12 carbon ring groups of the above-mentioned 11) and R A7 , and the heterocyclic groups of 12) and R A7 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C
group B is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-8 alkyl group,
5) a C 2-4 alkenyl group,
6) a C 2-4 alkynyl group,
7) —OR B1 wherein R B1 is a hydrogen atom or a C 1-4 alkyl group,
8) —SR B2 wherein R B2 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR B3 R B4 wherein R B3 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group, and R B4 is a hydrogen atom or a C 1-4 alkyl group,
10) —NR B5 COR B6 wherein R B5 is a hydrogen atom or a C 1-4 alkyl group, and R B6 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
11) —NR B7 COOR B8 wherein R B7 and R B8 are the same or different and each is a hydrogen atom or a CA alkyl group,
12) —NR B9 CONR B10 R B11 wherein R B9 , R B10 and R B11 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
13) —NR 12 CONR B13 OR B14 wherein R B12 , R B13 and R B14 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
14) —NR B15 SO 2 R B16 wherein R B15 is a hydrogen atom or a C 1-4 alkyl group, and R B16 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
15) —SO 2 —R B17 wherein R B17 is a C 1-4 alkyl group or a heterocyclic group,
16) —SO 2 NR B18 R B19 wherein R B18 and R B19 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
17) —P(═O)(R B20 )(R B21 ) wherein R B20 and R B21 are the same or different and each is a C 1-4 alkyl group,
18) —COOR B22 wherein R B22 is a hydrogen atom or a C 1-4 alkyl group,
19) —CONR B23 R B24 wherein R B23 and R B24 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
20) —NR B25 SO 2 NR B26 R B27 wherein R B25 , R B26 and R B27 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
21) —NR B28 SO 2 NR B29 CONR B30 R B31 wherein R B28 , R B29 , R B30 and R B31 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
22) a C 3-12 carbon ring group and
23) a heterocyclic group
wherein each of the “C 1-8 alkyl group” of the above-mentioned 4), and the C 1-4 alkyl groups for R B1 to R B31 is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned grout A,
each of the C 2-4 alkenyl group of 5) and the C 2-4 alkynyl group of 6) is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and
each of the C 3-12 carbon ring group of the above-mentioned 22), R B3 , R B6 and R B16 , and the heterocyclic group of the above-mentioned 23), R B3 , R B6 , R B16 and R B17 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and
group C is a group consisting of
1) a halogen atom,
2) a cyano group,
3) a C 1-4 alkyl group,
4) —OR C1 wherein R C1 is a hydrogen atom or a C 1-4 alkyl group,
5) —NR C2 R C3 wherein R C2 and R C3 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group
6) —COOR C4 wherein R C4 is a hydrogen atom or a C 1-4 alkyl group and
7) an oxo group,
whereupon the cell cycle is regulated.
25 . A compound represented by the following formula or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
wherein
X 1 and X 2 are the same or different and each is a carbon atom or a nitrogen atom, a
moiety is
R 1 and R 6 are the same or different and each is
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, or
wherein m is 0 or an integer of 1 to 4,
ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B,
R 2 is
a C 2-6 alkenyl group,
wherein the C 2-6 alkenyl group is optionally substituted by 1 to 3 substituents selected from the following group A, or
wherein m is 0 or an integer of 1 to 4,
ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B,
R 3 , R 4 , and R 5 are the same or different and each is
a hydrogen atom,
a hydroxyl group,
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A,
a C 3-12 carbon ring group or
a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B, or
R 2 and R 3 are optionally linked to form a C 1-4 alkylene group, or R 4 and R 5 are optionally linked to form a C 1-4 alkylene group,
wherein group A is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-4 alkyl group,
5) —OR A1 wherein R A1 is a hydrogen atom or a C 1-4 alkyl group,
6) —SR A2 wherein R A2 is a hydrogen atom or a C 1-4 alkyl group,
7) —NR A3 R A4 wherein R A3 and R A4 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
8) —COOR A5 wherein R A5 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR A6 COR A7 wherein R A6 is a hydrogen atom or a C 1-4 alkyl group, R A7 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
10) —NR A8 COOR A9 wherein R A8 and R A9 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
11) a C 3-12 carbon ring group and
12) a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
each of the C 1-4 alkyl groups of the above-mentioned 4), R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 and R A9 is optionally substituted by the same or different 1 to 3 substituents selected from the following group C, and
each of the C 3-12 carbon ring groups of the above-mentioned 11) and R A7 , and the heterocyclic groups of 12) and R A7 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C
group B is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-8 alkyl group,
5) a C 2-4 alkenyl group,
6) a C 2-4 alkynyl group,
7) —OR B1 wherein R B1 is a hydrogen atom or a C 1-4 alkyl group,
8) —SR B2 wherein R B2 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR B3 R B4 wherein R B3 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group, and R B4 is a hydrogen atom or a C 1-4 alkyl group,
10) —NR B5 COR B6 wherein R B5 is a hydrogen atom or a C 1-4 alkyl group, and R B6 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
11) —NR B7 COOR B8 wherein R B7 and R B8 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
12) —NR B9 CONR B10 R B11 wherein R B9 , R B10 and R B11 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
13) —NR B12 CONR B13 OR B14 wherein R B12 , R B13 and R B14 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
14) —NR B15 SO 2 R B16 wherein R B15 is a hydrogen atom or a C 1-4 alkyl group, and R B16 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
15) —SO 2 —R B17 wherein R B17 is a C 1-4 alkyl group or a heterocyclic group,
16) —SO 2 NR B18 R B19 wherein R B18 and R B19 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
17) —P(═O)(R B20 )(R B21 ) wherein R B20 and R B21 are the same or different and each is a C 1-4 alkyl group,
18) —COOR B22 wherein R B22 is a hydrogen atom or a C 1-4 alkyl group,
19) —CONR B23 R B24 wherein R B23 and R B24 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
20) —NR B25 SO 2 NR B26 R B27 wherein R B25 , R B26 and R B27 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
21) —NR B28 SO 2 NR B29 CONR B30 R B31 wherein R B28 , R B29 , R B30 and R B31 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
22) a C 3-12 carbon ring group and
23) a heterocyclic group
wherein each of the “C 1-8 alkyl group” of the above-mentioned 4), and the C 1-4 alkyl groups for R B1 to R B31 is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
each of the C 2-4 alkenyl group of 5) and the C 2-4 alkynyl group of 6) is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and
each of the C 3-12 carbon ring group of the above-mentioned 22), R B3 , R B6 and R B16 , and the heterocyclic group of the above-mentioned 23), R B3 , R B6 , R B16 and R B17 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and
group C is a group consisting of
1) a halogen atom,
2) a cyano group,
3) a C 1-4 alkyl group,
4) —OR C1 wherein R C1 is a hydrogen atom or a C 1-4 alkyl group,
5) —NR C2 R C3 wherein R C2 and R C3 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
6) —COOR C4 wherein R C4 is a hydrogen atom or a C 1-4 alkyl group and
7) an oxo group,
provided that when R 2 is a phenyl group, then R 1 is not a phenyl group, and
wherein the compound has at least one hydroxyl group that is substituted by a moiety selected from the group consisting of —CO-alkyl, —CO 2 -alkyl, —CONH-alkyl, —CO-alkenyl, —CO 2 -alkenyl, —CONH-alkenyl, —CO-aryl, —CO 2 -aryl, —CONH-aryl, —CO-heterocycle, —CO 2 -heterocycle, —CONH-heterocycle, and —PO 3 H 2 , wherein the alkyl, alkenyl, aryl, and heterocycle groups are optionally substituted by a halogen atom, alkyl group, hydroxyl group, alkoxy group, carboxy group, amino group, amino acid residue, —PO 3 H 2 , —SO 3 H, —OPO 3 H 2 , or —OSO 3 H.
26 . The compound of claim 25 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is represented by the following formula:
27 . The compound of claim 25 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 is
wherein m is 0, and ring Cy is a C 3-12 carbon ring group,
wherein the C 3-12 carbon ring group is optionally substituted by 1 to 5 substituents selected from group B.
28 . The compound of claim 26 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 is
wherein m is 0, and ring Cy is a C 3-12 carbon ring group,
wherein the C 3-12 carbon ring group is optionally substituted by 1 to 5 substituents selected from group B.
29 . The compound of claim 27 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 is a C 3-8 cycloalkyl group.
30 . The compound of claim 28 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 is a C 3-8 cycloalkyl group.
31 . The compound of claim 29 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 is a cyclopropyl group.
32 . The compound of claim 30 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 is a cyclopropyl group.
33 . The compound of claim 25 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2 is
wherein m is 0, and ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B.
34 . The compound of claim 26 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2 is
wherein m is 0, and ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B.
35 . The compound of claim 25 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 3 is a C 1-6 alkyl group.
36 . The compound of claim 26 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 3 is a C 1-6 alkyl group.
37 . The compound of claim 25 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 5 is a hydrogen atom.
38 . The compound of claim 26 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 5 is a hydrogen atom.
39 . The compound of claim 25 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 6 is
wherein m is 0, and ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B.
40 . The compound of claim 26 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 6 is
wherein m is 0, and ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B.
41 . The compound of claim 25 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R A1 is a hydrogen atom.
42 . The compound of claim 41 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is
43 . The compound of claim 41 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is
44 . The compound of claim 41 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is
45 . The compound of claim 41 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is
46 . The compound of any of claims 25 - 45 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the at least one hydroxyl group of the compound is substituted by a group selected from the group consisting of acetyl, propionyl, isobutyryl, pivaloyl, palmitoyl, benzoyl, 4-methylbenzoyl, dimethylcarbamoyl, dimethylaminomethylcarbonyl, sulfo, alanyl, and fumaryl.
47 . The compound of any one of claims 25 - 45 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the at least one hydroxyl group of the compound is substituted by sodium salt of 3-carboxybenzoyl or sodium salt of 2-carboxyethylcarbonyl group.
48 . A compound represented by the following formula or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
wherein
X 1 and X 2 are the same or different and each is a carbon atom or a nitrogen atom, a
moiety is
R 1 and R 6 are the same or different and each is
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, or
wherein m is 0 or an integer of 1 to 4,
ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B,
R 2 is
a C 2-6 alkenyl group,
wherein the C 2-6 alkenyl group is optionally substituted by 1 to 3 substituents selected from the following group A, or
wherein m is 0 or an integer of 1 to 4,
ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B,
R 3 , R 4 , and R 5 are the same or different and each is
a hydrogen atom,
a hydroxyl group,
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A,
a C 3-12 carbon ring group or
a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B, or
R 2 and R 3 are optionally linked to form a C 1-4 alkylene group, or R 4 and R 5 are optionally linked to form a C 1-4 alkylene group,
wherein group A is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-4 alkyl group,
5) —OR A1 wherein R A1 is a hydrogen atom or a C 1-4 alkyl group,
6) —SR A2 wherein R A2 is a hydrogen atom or a C 1-4 alkyl group,
7) —NR A3 R A4 wherein R A3 and R A4 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
8) —COOR A5 wherein R A5 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR A6 COR A7 wherein R A6 is a hydrogen atom or a C 1-4 alkyl group, R A7 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
10) —NR A8 COOR A9 wherein R A8 and R A9 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
11) a C 3-12 carbon ring group and
12) a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
each of the C 1-4 alkyl groups of the above-mentioned 4), R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 and R A9 is optionally substituted by the same or different 1 to 3 substituents selected from the following group C, and
each of the C 3-12 carbon ring groups of the above-mentioned 11) and R A7 , and the heterocyclic groups of 12) and R A7 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C
group B is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-8 alkyl group,
5) a C 2-4 alkenyl group,
6) a C 2-4 alkynyl group,
7) —OR B1 wherein R B1 is a hydrogen atom or a C 1-4 alkyl group,
8) —SR B2 wherein R B2 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR B3 R B4 wherein R B3 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group, and R B4 is a hydrogen atom or a C 1-4 alkyl group,
10) —NR B5 COR B6 wherein R B5 is a hydrogen atom or a C 1-4 alkyl group, and R B6 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
11) —NR B7 COOR B8 wherein R B7 and R B8 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
12) —NR B9 CONR B10 R B11 wherein R B9 , R B10 and R B11 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
13) —NR B12 CONR B13 R B14 wherein R B12 , R B13 and R B14 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
14) —NR B15 SO 2 R B16 wherein R B15 is a hydrogen atom or a C 1-4 alkyl group, and R B16 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
15) —SO 2 —R B17 wherein R B17 is a C 1-4 alkyl group or a heterocyclic group,
16) —SO 2 NR B18 R B19 wherein R B18 and R B19 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
17) —P(═O)(R B20 )(R B21 ) wherein R B20 and R B21 are the same or different and each is a C 1-4 alkyl group,
18) —COOR B22 wherein R B22 is a hydrogen atom or a C 1-4 alkyl group,
19) —CONR B23 R B24 wherein R B23 and R B24 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
20) —NR B25 SO 2 NR B26 R B27 wherein R B25 , R B26 and R B27 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
21) —NR B28 SO 2 NR B29 CONR B30 R B31 wherein R B28 , R B29 , R B30 and R B31 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
22) a C 3-12 carbon ring group and
23) a heterocyclic group
wherein each of the “C 1-8 alkyl group” of the above-mentioned 4), and the C 1-4 alkyl groups for R B1 to R B31 is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
each of the C 2-4 alkenyl group of 5) and the C 2-4 alkynyl group of 6) is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and
each of the C 3-12 carbon ring group of the above-mentioned 22), R B3 , R B6 and R B16 , and the heterocyclic group of the above-mentioned 23), R B3 , R B6 , R B16 and R B17 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and
group C is a group consisting of
1) a halogen atom,
2) a cyano group,
3) a C 1-4 alkyl group,
4) —OR C1 wherein R C1 is a hydrogen atom or a C 1-4 alkyl group,
5) —NR C2 R C3 wherein R C2 and R C3 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
6) —COOR C4 wherein R C4 is a hydrogen atom or a C 1-4 alkyl group and
7) an oxo group,
provided that when R 2 is a phenyl group, then R 1 is not a phenyl group, and
wherein the compound has at least one —NH 2 group that is substituted by a moiety selected from the group consisting of —CO-alkyl, —CO 2 -alkyl, —CO-alkenyl, —CO 2 -alkenyl, —CO 2 -aryl, —CO-aryl, —CO-heterocycle, —CO 2 -heterocycle, and —PO 3 H 2 , wherein the alkyl, alkenyl, aryl, and heterocycle groups are optionally substituted by a halogen atom, alkyl group, hydroxyl group, alkoxy group, carboxy group, amino group, amino acid residue, —PO 3 H 2 , —SO 3 H, —OPO 3 H 2 , or —OSO 3 H.
49 . The compound of claim 48 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is represented by the following formula:
50 . The compound of claim 48 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 is a C 1-6 alkyl group.
51 . The compound of claim 49 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 is a C 1-6 alkyl group.
52 . The compound of claim 48 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 is
wherein m is 0, and ring Cy is a C 3-12 carbon ring group,
wherein the C 3-12 carbon ring group is optionally substituted by 1 to 5 substituents selected from group B.
53 . The compound of claim 49 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 is
wherein m is 0, and ring Cy is a C 3-12 carbon ring group,
wherein the C 3-12 carbon ring group is optionally substituted by 1 to 5 substituents selected from group B.
54 . The compound of claim 52 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 is a C 3-8 cycloalkyl group.
55 . The compound of claim 53 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 is a C 3-8 cycloalkyl group.
56 . The compound of claim 54 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 is a cyclopropyl group.
57 . The compound of claim 55 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 1 is a cyclopropyl group.
58 . The compound of claim 48 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2 is
wherein m is 0, and ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B.
59 . The compound of claim 49 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2 is
wherein m is 0, and ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B.
60 . The compound of claim 48 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 3 is a C 1-6 alkyl group.
61 . The compound of claim 49 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 3 is a C 1-6 alkyl group.
62 . The compound of claim 48 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 5 is a hydrogen atom.
63 . The compound of claim 49 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 5 is a hydrogen atom.
64 . The compound of claim 48 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 6 is
wherein m is 0, and ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B.
65 . The compound of claim 49 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 6 is
wherein m is 0, and ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B.
66 . The compound of claim 48 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R B18 and R B19 are hydrogen.
67 . The compound of claim 66 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is
68 . The compound of claim 66 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is
69 . The compound of claim 66 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound is
70 . The compound of any one of claims 48 - 69 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the at least one —NH 2 group of the compound is substituted by a moiety selected from the group consisting of tert-butyl, docosanoyl, pivaloylmethyloxy, alanyl, hexylcarbamoyl, pentylcarbamoyl, 3-methylthio-1-(acetylamino)propylcarbonyl, 1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl, tetrahydrofuranyl, and pyrrolidylmethyl.
71 . A pharmaceutical composition comprising
(a) a compound of claim 25 or 48 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and (b) a pharmaceutically acceptable carrier.
72 . A method of therapeutically or prophylactically treating an undesirable cell proliferation in a mammal comprising administering to the mammal a therapeutic or prophylactic amount of a compound of claim 25 or 48 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, whereupon the undesirable cell proliferation is treated.
73 . A method of inhibiting MEK in a mammal comprising administering to the mammal an MEK inhibiting amount of a compound of claim 25 or 48 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, whereupon MEK is inhibited.
74 . A method of inducing p15 protein in a mammal comprising administering to the mammal a p15 protein inducing amount of a compound of claim 25 or 48 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, whereupon p15 protein is induced.
75 . A method of regulating cell cycle in a mammal comprising administering to the mammal a cell cycle regulating amount of a compound of claim 25 or 48 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, whereupon the cell cycle is regulated.
76 . A compound which is N-{3-[3-cyclopropyl-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
77 . The compound of claim 76 , wherein the compound is an acetic acid solvate thereof.
78 . A compound which is N-{3-[5-(2-fluoro-4-iodophenylamino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
79 . The compound of claim 78 , wherein the compound is a sodium salt thereof.
80 . A compound which is N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
81 . A compound having the structural formula
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
82 . A compound having the structural formula
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
83 . A compound having the structural formula
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
84 . A compound having the structural formula
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
85 . A compound having the structural formula
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
86 . A compound having the structural formula
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
87 . A compound having the structural formula
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
88 . A compound having the structural formula
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
89 . A compound having the structural formula
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
90 . A compound having the structural formula
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
91 . A pharmaceutical composition comprising
(a) a compound of any one of claims 76 , 78 , and 80 - 90 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and (b) a pharmaceutically acceptable carrier.Join the waitlist — get patent alerts
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