Physiologically active substances
View Patent ↗The present invention relates to a compound represented by the formula (I): (wherein, R 3 , R 6 , R 7 and R 21 are the same as or different from one another and each represents a hydroxyl group etc.), a pharmacologically acceptable salt thereof or a hydrate of them. The compound (I) of the present invention suppresses angiogenesis, in particular, suppresses VEGF production in a hypoxic condition and is useful as a therapeutic agent for treating solid cancer.
1. A method for treating a disease against which suppression of VEGF production is efficacious, which comprises administering a compound represented by the formula (I):
(in the formula, R 3 , R 6 , R 7 and R 21 are the same as or different from one another and each represents
1) a hydroxyl group or an oxo group formed together with the carbon atom to which each of R 3 , R 6 , R 7 and R 21 is bound, provided that R 6 is limited to hydroxyl group,
2) an optionally substituted C 1-22 alkoxy group,
3) an optionally substituted unsaturated C 2-22 alkoxy group,
4) an optionally substituted C 7-22 aralkyloxy group,
5) an optionally substituted 5 to 14-membered heteroaralkyloxy group,
6) RCO—O— (wherein R represents
a) a hydrogen atom,
b) an optionally substituted C 1-22 alkyl group,
c) an optionally substituted unsaturated C 2-22 alkyl group,
d) an optionally substituted C 6-14 aryl group,
e) an optionally substituted 5 to 14-membered heteroaryl group,
f) an optionally substituted C 7-22 aralkyl group,
g) an optionally substituted 5 to 14-membered heteroaralkyl group,
h) an optionally substituted C 1-22 alkoxy group,
i) an optionally substituted unsaturated C 2-22 alkoxy group,
j) an optionally substituted C 6-14 aryloxy group or
k) an optionally substituted 5 to 14-membered heteroaryloxy group),
7) a halogen atom,
8)R N1 R N2 N—R M — (wherein R M represents
a) a single bond,
b) —CO—O—,
c) —SO 2 —O—,
d) —CS—O— or
e) —CO—NR N3 — (wherein R N3 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group), provided that each of the leftmost bond in b) to e) is bound to the nitrogen atom; and
R N1 and R N2 are the same as or different from each other and each represents
a) a hydrogen atom,
b) an optionally substituted C 1-22 alkyl group,
c) an optionally substituted unsaturated C 2-22 , alkyl group,
d) an optionally substituted aliphatic C 2-22 acyl group,
e) an optionally substituted aromatic C 7-15 acyl group,
f) an optionally substituted C 6-14 aryl group,
g) an optionally substituted 5 to 14-membered heteroaryl group,
h) an optionally substituted C 7-22 aralkyl group,
i) an optionally substituted C 1-22 alkylsulfonyl group,
j) an optionally substituted C 6-14 arylsulfonyl group,
k) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed by R N1 and R N2 together with the nitrogen atom to which R N1 and R N2 are bound, and the non-aromatic heterocyclic group may have substituents,
l) an optionally substituted 5 to 14-membered heteroaralkyl group,
m) an optionally substituted C 3-14 cycloalkyl group or
n) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group),
9) R N4 SO 2 —O— (wherein R N4 represents
a) an optionally substituted C 1-22 alkyl group,
b) an optionally substituted C 6-14 aryl group,
c) an optionally substituted C 1-22 alkoxy group,
d) an optionally substituted C 2-22 alkoxy group,
e) an optionally substituted C 6-14 aryloxy group,
f) an optionally substituted 5 to 14-membered heteroaryloxy group,
g) an optionally substituted C 7-22 aralkyloxy group or
h) an optionally substituted 5 to 14-membered heteroaralkyloxy group),
10) (R N5 O) 2 PO—O— (wherein R N5 represents
a) an optionally substituted C 1-22 alkyl group,
b) an optionally substituted unsaturated C 2-22 alkyl group,
c) an optionally substituted C 6-14 aryl group,
d) an optionally substituted 5 to 14-membered heteroaryl group,
e) an optionally substituted C 7-22 aralkyl group or
f) an optionally substituted 5 to 14-membered heteroaralkyl group),
11) (R N1 R N2 N) 2 PO—O— (wherein R N1 and R N2 have the same meanings as defined above) or
12) (R N1 R N2 N)(R N5 O)PO—O— (wherein R N1 , R N2 and R N5 have the same meanings as defined above), provided that a compound in which R 3 , R 6 , R 7 and R 21 are all hydroxyl groups, and a compound in which R 3 , R 6 and R 21 are all hydroxyl groups and R 7 is an acetoxy group and a compound in which R 3 and R 6 are hydroxyl groups, R 7 is an acetoxy group and R 21 is an oxo group formed together with the carbon atom to which R 21 is bound are excluded), or a pharmacologically acceptable salt thereof as an active ingredient to a patient in need thereof.
2. A method for treating a disease against which an angiogenesis inhibition is efficacious, which comprises administering a compound represented by the formula (I):
(in the formula, R 3 , R 6 , R 7 and R 21 are the same as or different from one another and each represents
1) a hydroxyl group or an oxo group formed together with the carbon atom to which each of R 3 , R 6 , R 7 and R 21 is bound, provided that R 6 is limited to hydroxyl group,
2) an optionally substituted C 1-22 alkoxy group,
3) an optionally substituted unsaturated C 2-22 alkoxy group,
4) an optionally substituted C 7-22 aralkyloxy group,
5) an optionally substituted 5 to 14-membered heteroaralkyloxy group,
6) RCO—O— (wherein R represents
a) a hydrogen atom,
b) an optionally substituted C 1-22 alkyl group,
c) an optionally substituted unsaturated C 2-22 alkyl group,
d) an optionally substituted C 6-14 aryl group,
e) an optionally substituted 5 to 14-membered heteroaryl group,
f) an optionally substituted C 7-22 aralkyl group,
g) an optionally substituted 5 to 14-membered heteroaralkyl group,
h) an optionally substituted C 1-22 alkoxy group,
i) an optionally substituted unsaturated C 2-22 alkoxy group,
j) an optionally substituted C 6-14 aryloxy group or
k) an optionally substituted 5 to 14-membered heteroaryloxy group),
7) a halogen atom,
8) R N1 R N2 N—R M (wherein R M represents
a) a single bond,
b) —CO—O—,
c) —SO 2 —O—,
d) —CS—O— or
e) —CO—NR N3 — (wherein R N3 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group), provided that each of the leftmost bond in b) to e) is bound to the nitrogen atom; and R N1 and R N2 are the same as or different from each other and each represents
a) a hydrogen atom,
b) an optionally substituted C 1-22 alkyl group,
c) an optionally substituted unsaturated C 2-22 alkyl group,
d) an optionally substituted aliphatic C 2-22 acyl group,
e) an optionally substituted aromatic C 7-15 acyl group,
f) an optionally substituted C 6-14 aryl group,
g) an optionally substituted 5 to 14-membered heteroaryl group,
h) an optionally substituted C 7-22 aralkyl group,
i) an optionally substituted C 1-22 alkylsulfonyl group,
j) an optionally substituted C 6-14 arylsulfonyl group,
k) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed by R N1 and R N2 together with the nitrogen atom to which R N1 and R N2 are bound, and the non-aromatic heterocyclic group may have substituents,
l) an optionally substituted 5 to 14-membered heteroaralkyl group,
m) an optionally substituted C 3-4 cycloalkyl group or
n) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group),
9) R N4 SO 2 —O— (wherein R N4 represents
a) an optionally substituted C 1-22 alkyl group,
b) an optionally substituted C 6-14 aryl group,
c) an optionally substituted C 1-22 alkoxy group,
d) an optionally substituted unsaturated C 2-22 alkoxy group,
e) an optionally substituted C 6-14 aryloxy group,
f) an optionally substituted 5 to 14-membered heteroaryloxy group,
g) an optionally substituted C 7-22 aralkyloxy group or
h) an optionally substituted 5 to 14-membered heteroaralkyloxy group),
10) (R N5 O) 2 PO—O— (wherein R N5 represents
a) an optionally substituted C 1-22 alkyl group,
b) an optionally substituted unsaturated C 2-22 alkyl group,
c) an optionally substituted C 6-14 aryl group,
d) an optionally substituted 5 to 14-membered heteroaryl group,
e) an optionally substituted C 7-22 aralkyl group or
f) an optionally substituted 5 to 14-membered heteroaralkyl group),
11) (R N1 R N2 N) 2 PO—O— (wherein R N1 and R N2 have the same meanings as defined above) or
12) (R N1 R N2 N)(R N5 O)PO—O— (wherein R N1 , R N2 and R N5 have the same meanings as defined above), provided that a compound in which R 3 , R 6 , R 7 and R 21 are all hydroxyl groups, and a compound in which R 3 , R 6 and R 21 are all hydroxyl groups and R 7 is an acetoxy group and in which R 3 and R 6 are hydroxyl groups, R 7 is an acetoxy group and R 21 is an oxo group formed together with the carbon atom to which R 21 is bound are excluded), or a pharmacologically acceptable salt thereof as an active ingredient to a patient in need thereof.
3. The method according to claim 1 , wherein the disease is retinal neovascularization or diabetic retinopathy.
4. The method according to claim 2 , wherein the disease is retinal neovascularization or diabetic retinopathy.
5. The method according to claim 1 , wherein the inflammatory disease is selected from the group consisting of deformans arthritis, rheumatoid arthritis, psoriasis, and delayed hypersensitivity reaction.
6. The method according to claim 1 , wherein the disease is retinal neovascularization, diabetic retinopathy, inflammatory disease or atherosclerosis.
7. The method according to claim 6 , wherein the inflammatory disease is selected from the group consisting of deformans arthritis, rheumatoid arthritis, psoriasis, and delayed hypersensitivity reaction.
8. The method according to claim 2 , wherein the disease is retinal neovascularization, diabetic retinopathy, inflammatory disease or atherosclerosis.
9. The method according to claim 8 , wherein the inflammatory disease is selected from the group consisting of deformans arthritis, rheumatoid arthritis, psoriasis, and delayed hypersensitivity reaction.