USRE42890EExpiredUtilityPatentIndex 60
Furazanobenzimidazoles
Est. expiryMay 23, 2023(expired)· nominal 20-yr term from priority
A61P 37/06A61P 9/00A61P 35/00A61P 3/10A61P 37/02A61P 37/00A61P 43/00A61P 9/10A61P 29/00A61P 25/28A61P 25/00A61P 15/00A61P 17/00A61P 19/02C07D 413/14C07D 413/04
60
PatentIndex Score
4
Cited by
16
References
39
Claims
Abstract
The invention relates to compounds of formula (I) wherein R represents aryl or heteroaryl, X is oxygen, a carbonyl group, an oxime derivative of a carbonyl group or an α,β-unsaturated carbonyl group, and the substituents R 1 to R 6 have the meanings given in the specification, for use as medicaments, to novel compounds of formula (I), to methods of synthesis of such compounds, to pharmaceutical compositions containing compounds of formula (I), to the use of a compounds of formula (I) for the preparation of a pharmaceutical composition for the treatment of neoplastic and autoimmune diseases, and to methods of treatment of neoplastic and autoimmune diseases using such compounds of formula (I) or of pharmaceutical compositions containing same
Claims
exact text as granted — not AI-modified1. A compound of the formula
wherein
R represents phenyl, naphthyl, thienyl, pyridinyl or pyridazinyl ring, said phenyl ring being optionally substituted by one or two substituents independently selected from alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy lower alkoxy, phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, lower alkoxycarbonylamino, lower alkycarbonylamino, substituted amino wherein the two substituents on nitrogen form together with the nitrogen a heterocyclcyl, lower alkylcarbonyl, formyl, carboxy, lower alkoxycarbonyl, cyano, halogen, and nitro;
and wherein two adjacent substituents are methylenedioxy;
and said pyridinyl or pyridazinyl being optionally substituted in one or two positions with lower alkoxy, amino, or halogen;
X is —O— or >C═Y, wherein Y is oxygen;
R 1 represents hydrogen, hydroxy-lower alkyl, cyano-lower alkyl or lower alkyl-carbonyl, and
R 2 , R 3 , R 4 , R 5 and R 6 is hydrogen;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 where X is >C═Y, wherein Y is oxygen, or it's pharmaceutically acceptable salts.
3. The compound of claim 2 , which compounds are selected from the group consisting of the compounds 1, 5, 6, 11, 14, 15, 16, 19, 23, 29, 35, 41, 42, 44, 45, 46, 47, 48, 50, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 64, 65, 66, 67, 68, 69, 70, 72, 74, 76, 77, 78 and 79, which compounds are set forth according to the following table:
Compound
R
R 1
1
H
5
(CO)CH 3
6
CH 2 CH 2 CN
11
CH 2 CH 2 CH 2 OH
14
H
15
H
16
H
19
H
23
H
29
H
35
H
41
H
42
H
44
H
45
H
46
CH 2 CH 2 CN
47
CH 2 CH 2 CN
48
CH 2 CH 2 CN
50
H
52
CH 2 CH 2 CH 2 OH
53
H
54
CH 2 CH 2 CN
55
H
56
CH 2 CH 2 CN
57
CH 2 CH 2 CN
58
CH 2 CH 2 CN
59
H
61
CH 2 CH 2 CN
62
H
64
H
65
H
66
H
67
H
68
H
69
CH 2 CH 2 CN
70
H
72
H
74
H
76
H
77
H
78
H
79
CH 2 CH 2 CN
or their pharmaceutically acceptable salts.
4. The compound of claim 2 wherein R 1 represents hydrogen or cyano-lower alkyl.
5. The compound of claim 4 wherein the compounds are selected from the group consisting of the compounds 6, 15, 29, 42, 44, 45, 46, 47, 48, 50, 54, 56, 58, 61, 64, 65, 70, 78 and 79, which compounds are set forth according to the following table:
Compound
R
R 1
6
CH 2 CH 2 CN
15
H
29
H
42
H
44
H
45
H
46
CH 2 CH 2 CN
47
CH 2 CH 2 CN
48
CH 2 CH 2 CN
50
H
54
CH 2 CH 2 CN
56
CH 2 CH 2 CN
58
CH 2 CH 2 CN
61
CH 2 CH 2 CN
64
H
65
H
70
H
78
H
79
CH 2 CH 2 CN
or their pharmaceutically acceptable salts.
6. The compound of claim 2 , wherein R is optionally substituted phenyl.
7. The compound of claim 6 wherein said compound is 4-[1-(4-aminophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine or pharmaceutically acceptable salts thereof.
8. The compound of claim 4 where the compound has the formula
wherein
R is pyridinyl optionally substituted in one or two positions by lower alkoxy, amino, or halogen;
X is —C═Y; Y is oxygen;
R 1 is cyano-lower alkyl or hydrogen and;
R 2 , R 3 , R 4 , R 5 , R 6 is hydrogen;
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 wherein R 1 is cyano-lower alkyl.
10. The compound of claim 9 wherein said compound is 4-[1-(6-amino-3-pyridylcarbonylmethyl)-1H-benzimidazol-2-yl]-furazan-3-yl]-N-(2-cyanoethyl)-amine or its pharmaceutical acceptable salts.
11. The compound of claim 8 wherein R 1 is hydrogen.
12. The compound of claim 11 wherein said compound is 4-[1-(6-amino-3-pyridylcarbonylmethyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine; or pharmaceutical acceptable salts thereof.
13. The compound of claim 6 where said compound has the formula
which compound is selected from the group consisting of the compounds 7, 10, 88, 89, 92, 93, 94, 95, 96, 97, 101 and 103, which compounds are set forth according to the following table:
Compound
R
R 1
7
H
10
CH 2 CH 2 CN
88
H
89
H
92
H
93
CH 2 CH 2 CN
94
CH 2 CH 2 CN
95
CH 2 CH 2 CN
96
H
97
H
101
H
103
H
or pharmaceutically acceptable salts thereof.
14. The compound of claim 13 , which compound is selected from the group consisting of the compounds 89, 92, 94 and 101, which compound are set forth according to the following table:
Compound
R
R 1
89
H
92
H
94
CH 2 CH 2 CN
101
H
or their pharmaceutically acceptable salts.
15. A compound of the formula (I)
wherein
R represents phenyl or pyridinyl wherein phenyl is optionally substituted by one or two substituents independently selected from alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy lower alkoxy, phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, lower alkoxycarbonylamino, lower alkylcarbonylamino, substituted amino wherein the two substituents on nitrogen form together with the nitrogen a heterocyclyl, lower alkylcarbonyl, carboxy, lower alkoxycarbonyl, formyl, cyano, halogen, and nitro; and wherein two adjacent substituents are methylenedioxy; and wherein pyridinyl is optionally substituted by lower alkoxy, amino or halogen;
X is —C═Y and Y is nitrogen substituted by an alkoxy;
R 1 represents hydrogen, lower alkylcarbonyl, hydroxy-lower alkyl or cyano-lower alkyl;
R 2 , R 3 and R 6 represent hydrogen;
R 4 and R 5 , independently of each other, represent hydrogen, lower alkyl or lower alkoxy;
or R 4 and R 5 together represent methylenedioxy; or
pharmaceutically acceptable salts thereof.
16. The compound of claim 15 , which compound is selected from the group consisting of the compounds 18 and 22, which compounds are set forth according to the following table:
Compound
R
R 1
18
H
22
H
or their pharmaceutically acceptable salts.
17. A compound selected from the group consisting of Compound 9 and 13, which compounds are as represented by the following formula and are set forth according to the following table:
wherein Y is oxygen
Compound
R
R 1
9
CH 2 CH 2 (CO)OCH 3
13
CH 2 CH 2 (CO)OH
or their pharmaceutically acceptable salts.
18. A pro-drug of a compound selected from the group consisting of a furazanobenzimidazole of the formula (I)
and a pharmaceutically acceptable salt thereof,
wherein
R represents a phenyl, naphthyl, thienyl, pyridinyl or pyridazinyl ring,
said phenyl ring being optionally substituted by one or two substituents independently selected from the group consisting of alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy lower alkoxy, phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, lower alkoxycarhonylamino, lower alkycarhonylamino, substituted amino wherein the two substituents on nitrogen form together with the nitrogen hetercyclcyl, lower alkylcarbonyl, formyl, carboxy, lower alkoxycarbonyl, cyano, halogen, and nitro; and
said pyridinyl or pyridazinyl being optionally substituted in one or two positions with lower lower alkoxy, amino, or halogen;
X is —O— or >C═Y, wherein Y is oxygen;
R 1 represents hydrogen, hydroxy-lower alkyl, cyano-lower alkyl or lower alkyl-carbonyl, and
R 2 , R 3 , R 4 , R 5 and R 6 is hydrogen; and
said furazanobenzimidazole of formula (I) comprises a substituent selected from the group consisting of hydroxyl, carboxy and amino
and said pro-drug is selected from the group consisting of
an ester or an amide of said compound with a natural occurring amino acid and
an ester or amide of said compound with a small peptide consisting of up to 5 amino acids, where
said esters are formed by reaction of an acid function of the said natural occurring amino acid or the C terminal of said small peptide with a hydroxyl substituent of said compound and said amides are formed by reaction of an amino function of said natural occurring amino acid or the N terminal of said small peptide with a carboxy group of said compound or by reaction of an acid function of said natural occurring amino acid or the C terminal of said small peptide with an amino group of said compound.
19. A pro-drug of a compound selected from the group consisting of a furazanobenzimidazole of the formula (I)
and a pharmaceutically acceptable salt thereof,
wherein
R represents phenyl or pyridinyl wherein
phenyl is optionally substituted by one or two substituents independently selected from the group consisting of alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy lower alkoxy, phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, lower alkoxycarbonylamino, lower alkylcarbonylamino substituted amino wherein the two substituents on nitrogen form together with the nitrogen a heterocyclyl, lower alkylcarhonyl, carboxy, lower alkoxycarbonyl, formyl, cyano, halogen, and nitro; and wherein
pyridinyl is optionally substituted by lower alkoxy, amino or halogen;
X is —C═Y and Y is nitrogen substituted by a alkoxy;
R 1 represents hydrogen, lower alkylcarbonyl, hydroxy-lower alkyl or cyano-lower alkyl;
R 2 , R 3 and R 6 represent hydrogen;
R 4 and R 5 , independently of each other, represent hydrogen, lower alkyl or lower alkoxy; or R 4 and R 5 together represent methylenedioxy; and
said furazanobenzimidazole of formula (I) comprises a substituent selected from hydroxyl, carboxy and amino;
and said pro-drug is selected from the group consisting of
an ester or an amide of said compound with a natural occurring amino acid and
an ester or amide of said compound with a small peptide consisting of up to 5 amino acids, where
said esters are formed by reaction of an acid function of the said natural occurring amino acid or the C terminal of said small peptide with a hydroxyl substituent of said compound and
said amides are formed by reaction of an amino function of said natural occurring amino acid or the N terminal of said small peptide with a carboxy group of said compound of formula (I) by reaction of an acid function of said natural occurring amino acid or the C terminal of said small peptide with an amino group of said compound of formula (I).
20. The pro-drug according to claim 18, wherein
X in formula (I) is >C═Y and Y is oxygen.
21. The pro-drug according to claim 20, wherein said furazanobenzimidazole of formula (I) is selected from the group consisting of 1, 11, 14, 15, 16, 19, 23, 29, 35, 41, 42, 44, 45, 50, 52, 53, 55, 58, 59, 62, 64, 65, 66, 67, 68, 69, 70, 72, 74, 76, 77, 78 and 79 according to the following table:
R
R1
1
H
11
CH 2 CH 2 CH 2 OH
14
H
15
H
16
H
19
H
23
H
29
H
35
H
41
H
42
H
44
H
45
H
50
H
52
CH 2 CH 2 CH 2 OH
53
H
55
H
58
CH 2 CH 2 CN
59
H
62
H
64
H
65
H
66
H
67
H
68
H
69
CH 2 CH 2 CN
70
H
72
H
74
H
76
H
77
H
78
H
79
CH 2 CH 2 CN.
22. The pro-drug according to claim 20, wherein
R 1 in formula (I) represents hydrogen or cyano-lower alkyl.
23. The pro-drug according to claim 22, wherein said furazanobenzimidazole is selected from the group consisting of 15, 29, 42, 44, 45, 50, 58, 64, 65, 70, 78 and 79 according to the following table:
R
R1
15
H
29
H
42
H
44
H
45
H
50
H
58
CH 2 CH 2 CN
64
H
65
H
70
H
78
H
79
CH 2 CH 2 CN.
24. The pro-drug according to claim 20, wherein
R in formula (I) is optionally substituted phenyl.
25. A pro-drug of an amino compound selected from the group consisting of 4-[1-(4-aminophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine and a pharmaceutically acceptable salt thereof with a naturally occurring amino acid, wherein said pro-drug is an amide formed by the reaction of an acid group of said naturally occurring amino acid with the amino group of said compound.
26. A pro-drug of an amino compound selected from the group consisting of 4-[1-(4-aminophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine and a pharmaceutically acceptable salt thereof with a small peptide having up to 5 amino acids, wherein said pro-drug is an amide formed by reaction of said C terminal of said small peptide with the amino group of said compound.
27. The pro-drug according to claim 18, wherein said pro-drug is an amide of said compound with a natural occurring amino acid, wherein said amide is formed by reaction of an acid function of said natural occurring amino acid with an amino group of said compound.
28. The pro-drug according to claim 27, wherein in formula (I)
R is pyridinyl optionally substituted in one or two positions by lower alkoxy, amino, or halogen; X is —C═Y; Y is oxygen; R 1 is cyano-lower alkyl or hydrogen and; R 2 , R 3 , R 4 , R 5 , R 6 is hydrogen.
29. The pro-drug according to claim 28, wherein in formula (I)
R is pyridinyl substituted in one or two positions by amino and R 1 in formula (I) is cyano-lower alkyl.
30. A pro-drug of an amino compound selected from the group consisting of 4-[1-(6-amino-3-pyridylcarbonylmethyl)-1H-benzimidazol-2-yl]-furazan-3-yl]-N-(2-cyanoethyl)-amine and a pharmaceutically acceptable salt thereof with a naturally occurring amino acid, wherein said pro-drug is an amide formed by the reaction of an acid function of said naturally occurring amino acid with the amino group of said compound.
31. A pro-drug of an amino compound selected from the group consisting of 4-[1-(6-amino-3-pyridylcarbonylmethyl)-1H-benzimidazol-2-yl]-furazan-3-yl]-N-(2-cyanoethyl)-amine and a pharmaceutically acceptable salt thereof with a small peptide having up to 5 amino acids, wherein said pro-drug is an amide formed by reaction of said C terminal of said small peptide with the amino group of said compound.
32. The pro-drug according to claim 28, wherein
R 1 in formula (I) is hydrogen.
33. A pro-drug of an amino compound selected from the group consisting of 4-[1-(6-amino-3-pyridylcarbonylmethyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine and a pharmaceutically acceptable salt thereof with a naturally occurring amino acid, wherein said pro-drug is an amide formed by the reaction of an acid function of said naturally occurring amino acid with an amino group of said compound.
34. A pro-drug of an amino compound selected from the group consisting of 4-[1-(6-amino-3-pyridylcarbonylmethyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine or of said pharmaceutically acceptable salt thereof with a small peptide having up to 5 amino acids, wherein said pro-drug is an amide formed by reaction of said C terminal of said small peptide with an amino group of said compound.
35. A pro-drug of a compound selected from the group consisting of a furazanobenzimidazole of formula (IB)
and a pharmaceutically acceptable salt thereof, wherein the furazanobenzimidazole is selected from the group consisting of furazanobenzimidazoles 7, 88, 89, 92, 96, 97, 101 and 103, which are set forth according to the following table:
R
R1
7
H
88
H
89
H
92
H
96
H
97
H
101
H
103
H
wherein said pro-drug is selected from the group consisting of an amide of said compound with a natural occurring amino acid and an amide of said compound with a small peptide consisting of up to 5 amino acids, wherein said amide is formed by reaction of an acid function of said natural occurring amino acid or the C terminal of said small peptide with an amino group of said compound.
36. The pro-drug according to claim 35, wherein the furazanobenzimidazole of formula (IB) is selected from the group consisting of furazanobenzimidazoles 89, 92, and 101, which are set forth according to the following table:
R
R1
89
H
92
H
101
H.
37. The pro-drug according to claim 19, wherein the furazanobenzimidazole of formula (I) is selected from the group consisting of furazanobenzimidazoles 18 and 22 which are set forth according to the following table:
R
R1
18
H
22
H.
38. A pro-drug of a furazanobenzimidazole of the formula (I)
wherein
R represents a phenyl, naphthyl, thienyl, pyridinyl or pyridazinyl ring,
said phenyl ring being optionally substituted by one or two substituents independently selected from the group consisting of alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy lower alkoxy, phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, lower alkoxycarbonylamino, lower alkycarbonylamino, substituted amino wherein the two substituents on nitrogen form together with the nitrogen hetercyclcyl, lower alkylcarbonyl, formyl, carboxy, lower alkoxycarbonyl, cyano, halogen, and nitro; and
said pyridinyl or pyridazinyl being optionally substituted in one or two positions with lower lower alkoxy, amino, or halogen;
X is —O— or >C═Y, wherein Y is oxygen;
R 1 represents hydrogen, hydroxy-lower alkyl, cyano-lower alkyl or lower alkyl-carbonyl, and
R 2 , R 3 , R 4 , R 5 and R 6 is hydrogen; and
said furazanobenzimidazole of formula (I) comprises a substituent selected from the group consisting of hydroxyl, carboxy and amino
and said pro-drug is selected from the group consisting of
an ester or an amide of said compound of formula (I) with a natural occurring amino acid, and an ester or amide of said furazanobenzimidazole of formula (I) with a small peptide consisting of up to 5 amino acids, where
said esters are formed by reaction of an acid function of the said natural occurring amino acid or the C terminal of said small peptide with a hydroxyl substituent of said compound of formula (I) and
said amides are formed by reaction of an amino function of said natural occurring amino acid or the N terminal of said small peptide with a carboxy group of said furazanobenzimidazole of formula (I) or by reaction of an acid function of said natural occurring amino acid or the C terminal of said small peptide with an amino group of said furazanobenzimidazole of formula (I).
39. A pro-drug according to claim 38 which is a pro-drug of 4-[1-(4-aminophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine with a naturally occurring amino acid, wherein said pro-drug is an amide formed by the reaction of an acid group of said naturally occurring amino acid with an amino group of said compound.Cited by (0)
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