U.S. patent application number 11/603688 was filed with the patent office on 2007-06-28 for fumagillol derivative and the medical use thereof.
Invention is credited to Byung-Ha Chang, Cheol-Kyu Han, Nam-Doo Kim, Seung-Moak Kim, Jee-Young Lee, Tae-Bo Sim, Jeong-Hyeok Yoon.
Application Number | 20070149613 11/603688 |
Document ID | / |
Family ID | 26639368 |
Filed Date | 2007-06-28 |
United States Patent
Application |
20070149613 |
Kind Code |
A1 |
Han; Cheol-Kyu ; et
al. |
June 28, 2007 |
Fumagillol derivative and the medical use thereof
Abstract
The disclosure relates to a fumagillol compound which can be
usefully used not only as an angiogenesis inhibiting agent showing
a superior angiogenesis inhibitory effect with less toxicity, but
also as a cancer metastasis inhibitor and a therapeutic agent
against cancer and other various inflammatory diseases such as
rheumatic disease, psoriasis, etc., and diabetic retinopathy
related to angiogenesis, and also a method for preparing the
same.
Inventors: |
Han; Cheol-Kyu; (Seoul,
KR) ; Yoon; Jeong-Hyeok; (Yongin-si, KR) ;
Kim; Seung-Moak; (Daejeon-si, KR) ; Kim; Nam-Doo;
(Incheon-si, KR) ; Chang; Byung-Ha; (Suwon-si,
KR) ; Lee; Jee-Young; (Ahnyang-si, KR) ; Sim;
Tae-Bo; (Seoul, KR) |
Correspondence
Address: |
BACHMAN & LAPOINTE, P.C.
900 CHAPEL STREET
SUITE 1201
NEW HAVEN
CT
06510
US
|
Family ID: |
26639368 |
Appl. No.: |
11/603688 |
Filed: |
November 21, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11494026 |
Jul 26, 2006 |
|
|
|
11603688 |
Nov 21, 2006 |
|
|
|
10490588 |
Mar 23, 2004 |
7087768 |
|
|
11494026 |
Jul 26, 2006 |
|
|
|
Current U.S.
Class: |
514/475 |
Current CPC
Class: |
C07D 405/12 20130101;
A61P 35/00 20180101; C07D 407/12 20130101; C07D 303/22
20130101 |
Class at
Publication: |
514/475 |
International
Class: |
A61K 31/336 20060101
A61K031/336 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 27, 2001 |
KR |
2001-60017 |
May 29, 2002 |
KR |
2002-29915 |
Claims
1. A method for inhibiting angiogenesis comprising administering to
a subject in need of treatment, a fumagillol derivative represented
by the following formula I or a pharmaceutically acceptable salt
thereof. ##STR96## wherein, X is --OH and Y is halogen, or X and Y
are linked together to form an oxirane ring, B represents
--(C.dbd.O)-- or --CH.sub.2--, R.sub.1 represents hydrogen;
hydroxy; --CN; --NO.sub.2; --CF.sub.3; formyl; C.sub.1-C.sub.4
thioalkyl; acetamido; acetoxy; C.sub.1-C.sub.6 alkyl;
C.sub.1-C.sub.4 aminoalkyl; C.sub.1-C.sub.4 alkylaminoalkyl;
C.sub.1-C.sub.4 dialkylaminoalkyl; C.sub.1-C.sub.6 alkoxy;
C.sub.1-C.sub.6 aminoalkoxy; C.sub.1-C.sub.4 alkylaminoalkoxy;
C.sub.1-C.sub.4 dialkylaminoalkoxy; amino; C.sub.1-C.sub.6
alkylamino; C.sub.1-C.sub.4 dialkylamino; C.sub.1-C.sub.4
hydroxyalkyl; C.sub.1-C.sub.4 alkyloxycarboxylic acid, or ##STR97##
in which R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6, which are
the same or different, each represents hydrogen; hydroxy; --CN;
--NO.sub.2; --CF.sub.3; formyl; C.sub.1-C.sub.4 thioalkyl;
acetamido; acetoxy; C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.4
aminoalkyl; C.sub.1-C.sub.4 alkylaminoalkyl; C.sub.1-C.sub.4
dialkylaminoalkyl; C.sub.1-C.sub.6 alkoxy; C.sub.1-C.sub.6
aminoalkoxy; C.sub.1-C.sub.4 alkylaminoalkoxy; C.sub.1-C.sub.4
dialkylaminoalkoxy; amino; C.sub.1-C.sub.6 alkylamino;
C.sub.1-C.sub.4 dialkylamino; C.sub.1-C.sub.4 hydroxyalkyl; or
C.sub.1-C.sub.4 alkyloxycarboxylic acid; or, R.sub.2 and R.sub.3,
R.sub.3 and R.sub.4, R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6,
are linked together to form a C.sub.1-C.sub.3 alkylene dioxy ring,
and Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 each represent
carbon or nitrogen.
2. The method according to claim 1, wherein X and Y of the
fumagillol derivative are linked together to form the oxirane ring,
and B of the fumagillol derivative is --(C.dbd.O)--.
3. The method according to claim 1, wherein X and Y of the
fumagillol derivative are linked together to form the oxirane ring,
B of the fumagillol derivative is --(C.dbd.O)--, R.sub.1 of the
fumagillol derivative is hydrogen; hydroxy; --CN; --NO.sub.2;
--CF.sub.3; formyl; acetamido; acetoxy; C.sub.1-C.sub.6 alkyl;
C.sub.1-C.sub.4 aminoalkyl; C.sub.1-C.sub.4 alkylaminoalkyl;
C.sub.1-C.sub.4 dialkylaminoalkyl; C.sub.1-C.sub.6 alkoxy;
C.sub.1-C.sub.6 aminoalkoxy; C.sub.1-C.sub.4 alkylaminoalkoxy;
C.sub.1-C.sub.4 dialkylaminoalkoxy; amino; C.sub.1-C.sub.6
alkylamino; C.sub.1-C.sub.4 dialkylamino; C.sub.1-C.sub.4
hydroxyalkyl; C.sub.1-C.sub.4 alkyloxycarboxylic acid; or R.sub.2,
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 of the fumagillol derivative,
which are the same or different, each represents hydrogen; hydroxy;
--CN; --NO.sub.2; --CF.sub.3; formyl; acetamido; acetoxy;
C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.4 aminoalkyl; C.sub.1-C.sub.4
alkylaminoalkyl; C.sub.1-C.sub.4 dialkylaminoalkyl; C.sub.1-C.sub.6
alkoxy; C.sub.1-C.sub.6 aminoalkoxy; C.sub.1-C.sub.4
alkylaminoalkoxy; C.sub.1-C.sub.4 dialkylaminoalkoxy; amino;
C.sub.1-C.sub.6 alkylamino; C.sub.1-C.sub.4 dialkylamino;
C.sub.1-C.sub.4 hydroxyalkyl; or C.sub.1-C.sub.4 alkyloxycarboxylic
acid; or R.sub.2 and R.sub.3, R.sub.3 and R.sub.4, R.sub.4 and
R.sub.5, or R.sub.5 and R.sub.6 of the fumagillol derivative are
linked together to form the C.sub.1-C.sub.3 alkylene dioxy ring;
and Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 each represent
carbon or nitrogen.
4. The method according to claim 1, wherein X and Y of the
fumagillol derivative are linked together to form the oxirane ring,
B of the fumagillol derivative is --(C.dbd.O)-- R.sub.1 of the
fumagillol derivative is selected from the group consisting of
hydrogen; hydroxy; methyl; chlorine; methoxy; methylpropoxy;
isopropoxy; allyloxy; propyloxy; acetoxy cyano; amino;
dimethylaminomethyl; methylpropoxy; dimethylethoxy;
3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy;
isopropyl-4-ethoxy; dimethylamino; ethylamino; methylenedioxy;
nitro; acetoxy; trifluoromethyl; and hydroxyethoxy; R.sub.2,
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 of the fumagillol derivative
is independently selected from the group consisting of hydrogen;
hydroxy; methyl; chlorine; methoxy; methylpropoxy; isopropoxy;
allyloxy; propyloxy; acetoxy cyano; amino; dimethylaminomethyl;
methylpropoxy; dimethylethoxy; 3,5-diisopropyl-4-methoxy;
3,5-dimethyl-4-methoxy; isopropyl-4-ethoxy; dimethylamino;
ethylamino; methylenedioxy; nitro; acetoxy; trifluoromethyl; and
hydroxyethoxy; and Z.sub.1, Z.sub.2, Z.sub.3 Z.sub.4 and Z.sub.5
each represent carbon or nitrogen.
5. The method according to claim 1, wherein the fumagillol
derivative is selected from the group consisting of: 1)
6-O-(4-methoxyaniline)acetyl fumagillol; 2)
6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol; 3)
6-O-(2,4-dimethoxyaniline)acetyl fumagillol; 4)
6-O-(3,4-dimethoxyaniline)acetyl fumagillol; 5)
6-O-(3,4-dimethoxy-6-nitroaniline)acetyl fumagillol; 6)
6-O-(3,4-dimethoxy-6-cyanoaniline)acetyl fumagillol; 7)
6-O-(4-allyloxyaniline)acetyl fumagillol; 8)
6-O-(4-(2-acetoxyethoxy)aniline)acetyl fumagillol; 9)
6-O-(3-cyano-4-methoxyaniline)acetyl fumagillol; 10)
6-O-(3-(dimethylaminomethyl)-4-methoxyaniline) acetyl fumagillol;
11) 6-O-(4-(2-methylpropoxyaniline)acetyl fumagillol; 12)
6-O-(3-isopropoxy-4-methoxyaniline)acetyl fumagillol; 13)
6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol; 14)
6-O-(3,5-diisopropyl-4-methoxyaniline)acetyl fumagillol; 15)
6-O-(3,5-dimethyl-4-methoxyaniline)acetyl fumagillol; 16)
6-O-(3-isopropyl-4-ethoxy-6-methylaniline)acetyl fumagillol; 17)
6-O-(4-propyloxyaniline)acetyl fumagillol; 18) 6-O-(aniline)acetyl
fumagillol; 19) 6-O-(4-chloroaniline)acetyl fumagillol; 20)
6-O-(4-dimethylaminoaniline)acetyl fumagillol; 21)
6-O-(4-hydroxyaniline)acetyl fumagillol; 22)
6-O-(4-aminoaniline)acetyl fumagillol; 23)
6-O-(3,4-methylenedioxyaniline)acetyl fumagillol; 24)
6-O-(4-nitroaniline)acetyl fumagillol; 25)
6-O-(2,3,4-trimethoxy-6-aminoaniline)acetyl fumagillol; 26)
6-O-(4-acetoxy-3,5-dimethoxyaniline)acetyl fumagillol; 27)
6-O-(3,4-dimethoxy-5-hydroxyaniline)acetyl fumagillol; 28)
6-O-(4-dimethylaminoethoxyaniline)acetyl fumagillol; 29)
6-O-(4-ethylaminoaniline)acetyl fumagillol; 30)
6-O-(4-ethylaminoethoxyaniline)acetyl fumagillol; 31)
6-O-(3-dimethylaminomethyl-4-methoxyaniline)acetyl fumagillol; 32)
6-O-(4-trifluoromethylaniline)acetyl fumagillol; 33) 6-O-(4-acetoxy
aniline)acetyl fumagillol; 34) 6-O-(4-cyanoaniline)acetyl
fumagillol; 35) 6-O-(4-hydroxyethoxyaniline)acetyl fumagillol; 36)
6-O-(5-amino-2-methoxypyridine)acetyl fumagillol; 37)
6-O-(5-methoxypyrimidine-2-amino)acetyl fumagillol; 38)
6-O-(3-methoxy-6-aminopyridazine)acetyl fumagillol; 39)
4-((4-methoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-me-
thoxy-1-chloromethyl-1-cyclohexanol; 40)
4-((3,4,5-trimethoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexeny-
l)-3-methoxy-1-chloromethyl-1-cyclohexanol; 41)
6-O-(ethylamino)acetyl fumagillol; 42) 6-O-(isopropyl amino)acetyl
fumagillol; 43) 6-O-(1-propyl amino)acetyl fumagillol; 44)
6-O-(1-butyl amino)acetyl fumagillol; 45) 6-O-(sec-butyl
amino)acetyl fumagillol; 46) 6-O-(2-methyl-butylamino)acetyl
fumagillol; 47) 6-O-(t-butyl amino)acetyl fumagillol; 48)
6-O-(pentyl amino)acetyl fumagillol; 49) 6-O-(1-methyl-butyl
amino)acetyl fumagillol; 50) 6-O-(1-ethyl-propyl amino)acetyl
fumagillol; 51) 6-O-(1-methyl-pentylamino)acetyl fumagillol; 52)
6-O-(1,2-dimethyl-butylamino)acetyl fumagillol; 53)
6-O-(1,2,2-trimethyl-propylamino)acetyl fumagillol; 54)
6-O-(1-isopropyl-2-methylpropylamino)acetyl fumagillol; 55)
6-O-(3-methylbutylamino)acetyl fumagillol; 56)
6-O-(2-methylallylamino)acetyl fumagillol; 57)
6-O-(4-methyl-hepta-2,4-dienylamino)acetyl fumagillol; 58)
6-O-(1,5-dimethyl-4-hexenylamino)acetyl fumagillol; 59)
6-O-(1,1-dimethyl-2-propynylamino)acetyl fumagillol; 60)
6-O-(prop-2-enylamino)acetyl fumagillol; 61)
6-O-(2-bromo-ethylamino)acetyl fumagillol; 62)
6-O-(chloroethynylamino)acetyl fumagillol; 63)
6-O-(cyclopropylamino)acetyl fumagillol; 64)
6-O-(cyclobutylamino)acetyl fumagillol; 65)
6-O-(cyclopentylamino)acetyl fumagillol; 66)
6-O-(cyclohexylamino)acetyl fumagillol; 67)
6-O-(4-tert-butylcyclohexylamino)acetyl fumagillol; 68)
6-O-(2-dimethylamino-1-methylethylamino)acetyl fumagillol; 69)
6-O-(2-dimethylamino-propylamino)acetyl fumagillol; 70)
6-O-(2-methoxy-2-methyl-propylamino)acetyl fumagillol; 71)
6-O-(2-oxo-propylamine)acetyl fumagillol; 72)
6-O-(1,1-dimethyl-3-oxobutylamino)acetyl fumagillol; 73)
6-O-(ethyl-2-aminoacetate)acetyl fumagillol; 74)
6-O-(alanine-methylesteramino)acetyl fumagillol; 75)
6-O-(methyl-2-amino-3,3-dimethylbutanoate)acetyl fumagillol; 76)
6-O-(allylglycine-methylester)acetyl fumagillol; 77)
6-O-(2,2-dimethoxy-ehtylamino)acetyl fumagillol; 78)
4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-me-
thoxy-1-chloromethyl-1-cyclohexanol; and 79)
4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-met-
hoxy-1-chloromethyl-1-cyclohexanol.
6. A method for treating cancer, rheumatoid arthritis, psoriasis or
diabetic retinopathy, or for inhibiting cancer metastasis,
comprising administering to a subject in need of treatment, a
fumagillol derivative represented by the following formula I or a
pharmaceutically acceptable salt thereof. ##STR98## wherein, X is
--OH and Y is halogen, or X and Y are linked together to form an
oxirane ring, B represents --(C.dbd.O)-- or --CH.sub.2--, R.sub.1
represents hydrogen; hydroxy; --CN; --NO.sub.2; --CF.sub.3; formyl;
C.sub.1-C.sub.4 thioalkyl; acetamido; acetoxy; C.sub.1-C.sub.6
alkyl; C.sub.1-C.sub.4 aminoalkyl; C.sub.1-C.sub.4 alkylaminoalkyl;
C.sub.1-C.sub.4 dialkylaminoalkyl; C.sub.1-C.sub.6 alkoxy;
C.sub.1-C.sub.6 aminoalkoxy; c.sub.1-C.sub.4 alkylaminoalkoxy;
C.sub.1-C.sub.4 dialkylaminoalkoxy; amino; C.sub.1-C.sub.6
alkylamino; C.sub.1-C.sub.4 dialkylamino; C.sub.1-C.sub.4
hydroxyalkyl; C.sub.1-C.sub.4 alkyloxycarboxylic acid, or ##STR99##
in which R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6, which are
the same or different, each represents hydrogen; hydroxy; --CN;
--NO.sub.2; --CF.sub.3; formyl; C.sub.1-C.sub.4 thioalkyl;
acetamido; acetoxy; C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.4
aminoalkyl; C.sub.1-C.sub.4 alkylaminoalkyl; C.sub.1-C.sub.4
dialkylaminoalkyl; C.sub.1-C.sub.6 alkoxy; C.sub.1-C.sub.6
aminoalkoxy; C.sub.1-C.sub.4 alkylaminoalkoxy; C.sub.1-C.sub.4
dialkylaminoalkoxy; amino; C.sub.1-C.sub.6 alkylamino;
C.sub.1-C.sub.4 dialkylamino; C.sub.1-C.sub.4 hydroxyalkyl; or
C.sub.1-C.sub.4 alkyloxycarboxylic acid; or, R.sub.2 and R.sub.3,
R.sub.3 and R.sub.4, R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6,
are linked together to form a C.sub.1-C.sub.3 alkylene dioxy ring,
and Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 each represent
carbon or nitrogen.
7. The method according to claim 6, wherein X and Y of the
fumagillol derivative are linked together to form the oxirane ring,
and B of the fumagillol derivative is --(C.dbd.O)--.
8. The method according to claim 6, wherein X and Y of the
fumagillol derivative are linked together to form the oxirane ring,
B of the fumagillol derivative is --(C.dbd.O)--, R.sub.1 of the
fumagillol derivative is hydrogen; hydroxy; --CN; --NO.sub.2;
--CF.sub.3; formyl; acetamido; acetoxy; C.sub.1-C.sub.6 alkyl;
C.sub.1-C.sub.4 aminoalkyl; C.sub.1-C.sub.4 alkylaminoalkyl;
C.sub.1-C.sub.4 dialkylaminoalkyl; C.sub.1-C.sub.6 alkoxy;
C.sub.1-C.sub.6 aminoalkoxy; C.sub.1-C.sub.4 alkylaminoalkoxy;
C.sub.1-C.sub.4 dialkylaminoalkoxy; amino; C.sub.1-C.sub.6
alkylamino; C.sub.1-C.sub.4 dialkylamino; C.sub.1-C.sub.4
hydroxyalkyl; C.sub.1-C.sub.4 alkyloxycarboxylic acid; or R.sub.2,
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 of the fumagillol derivative,
which are the same or different, each represents hydrogen; hydroxy;
--CN; --NO.sub.2; --CF.sub.3; formyl; acetamido; acetoxy;
C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.4 aminoalkyl; C.sub.1-C.sub.4
alkylaminoalkyl; C.sub.1-C.sub.4 dialkylaminoalkyl; C.sub.1-C.sub.6
alkoxy; C.sub.1-C.sub.6 aminoalkoxy; C.sub.1-C.sub.4
alkylaminoalkoxy; C.sub.1-C.sub.4 dialkylaminoalkoxy; amino;
C.sub.1-C.sub.6 alkylamino; C.sub.1-C.sub.4 dialkylamino;
C.sub.1-C.sub.4 hydroxyalkyl; or C.sub.1-C.sub.4 alkyloxycarboxylic
acid; or R.sub.2 and R.sub.3, R.sub.3 and R.sub.4, R.sub.4 and
R.sub.5, or R.sub.5 and R.sub.6 of the fumagillol derivative are
linked together to form the C.sub.1-C.sub.3 alkylene dioxy ring;
and Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 each represent
carbon or nitrogen.
9. The method according to claim 6, wherein X and Y of the
fumagillol derivative are linked together to form the oxirane ring,
B of the fumagillol derivative is --(C.dbd.O)-- R.sub.1 of the
fumagillol derivative is selected from the group consisting of
hydrogen; hydroxy; methyl; chlorine; methoxy; methylpropoxy;
isopropoxy; allyloxy; propyloxy; acetoxy cyano; amino;
dimethylaminomethyl; methylpropoxy; dimethylethoxy;
3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy;
isopropyl-4-ethoxy; dimethylamino; ethylamino; methylenedioxy;
nitro; acetoxy; trifluoromethyl; and hydroxyethoxy; R.sub.2,
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 of the fumagillol derivative
is independently selected from the group consisting of hydrogen;
hydroxy; methyl; chlorine; methoxy; ethylpropoxy; isopropoxy;
allyloxy; propyloxy; acetoxy cyano; amino; dimethylaminomethyl;
methylpropoxy; dimethylethoxy; 3,5-diisopropyl-4-methoxy;
3,5-dimethyl-4-methoxy; isopropyl-4-ethoxy; dimethylamino;
ethylamino; methylenedioxy; nitro; acetoxy; trifluoromethyl; and
hydroxyethoxy; and Z.sub.1, Z.sub.2, Z.sub.3 Z.sub.4 and Z.sub.5
each represent carbon or nitrogen.
10. The method according to claim 6, wherein the fumagillol
derivative is selected from the group consisting of: 1)
6-O-(4-methoxyaniline)acetyl fumagillol; 2)
6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol; 3)
6-O-(2,4-dimethoxyaniline)acetyl fumagillol; 4)
6-O-(3,4-dimethoxyaniline)acetyl fumagillol; 5)
6-O-(3,4-dimethoxy-6-nitroaniline)acetyl fumagillol; 6)
6-O-(3,4-dimethoxy-6-cyanoaniline)acetyl fumagillol; 7)
6-O-(4-allyloxyaniline)acetyl fumagillol; 8)
6-O-(4-(2-acetoxyethoxy)aniline)acetyl fumagillol; 9)
6-O-(3-cyano-4-methoxyaniline)acetyl fumagillol; 10)
6-O-(3-(dimethylaminomethyl)-4-methoxyaniline) acetyl fumagillol;
11) 6-O-(4-(2-methylpropoxyaniline)acetyl fumagillol; 12)
6-O-(3-isopropoxy-4-methoxyaniline)acetyl fumagillol; 13)
6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol; 14)
6-O-(3,5-diisopropyl-4-methoxyaniline)acetyl fumagillol; 15)
6-O-(3,5-dimethyl-4-methoxyaniline)acetyl fumagillol; 16)
6-O-(3-isopropyl-4-ethoxy-6-methylaniline)acetyl fumagillol; 17)
6-O-(4-propyloxyaniline)acetyl fumagillol; 18) 6-O-(aniline)acetyl
fumagillol; 19) 6-O-(4-chloroaniline)acetyl fumagillol; 20)
6-O-(4-dimethylaminoaniline)acetyl fumagillol; 21)
6-O-(4-hydroxyaniline)acetyl fumagillol; 22)
6-O-(4-aminoaniline)acetyl fumagillol; 23)
6-O-(3,4-methylenedioxyaniline)acetyl fumagillol; 24)
6-O-(4-nitroaniline)acetyl fumagillol; 25)
6-O-(2,3,4-trimethoxy-6-aminoaniline)acetyl fumagillol; 26)
6-O-(4-acetoxy-3,5-dimethoxyaniline)acetyl fumagillol; 27)
6-O-(3,4-dimethoxy-5-hydroxyaniline)acetyl fumagillol; 28)
6-O-(4-dimethylaminoethoxyaniline)acetyl fumagillol; 29)
6-O-(4-ethylaminoaniline)acetyl fumagillol; 30)
6-O-(4-ethylaminoethoxyaniline)acetyl fumagillol; 31)
6-O-(3-dimethylaminomethyl-4-methoxyaniline)acetyl fumagillol; 32)
6-O-(4-trifluoromethylaniline)acetyl fumagillol; 33) 6-O-(4-acetoxy
aniline)acetyl fumagillol; 34) 6-O-(4-cyanoaniline)acetyl
fumagillol; 35) 6-O-(4-hydroxyethoxyaniline)acetyl fumagillol; 36)
6-O-(5-amino-2-methoxypyridine)acetyl fumagillol; 37)
6-O-(5-methoxypyrimidine-2-amino)acetyl fumagillol; 38)
6-O-(3-methoxy-6-aminopyridazine)acetyl fumagillol; 39)
4-((4-methoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-me-
thoxy-1-chloromethyl-1-cyclohexanol; 40)
4-((3,4,5-trimethoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexeny-
l)-3-methoxy-1-chloromethyl-1-cyclohexanol; 41)
6-O-(ethylamino)acetyl fumagillol; 42) 6-O-(isopropyl amino)acetyl
fumagillol; 43) 6-O-(1-propyl amino)acetyl fumagillol; 44)
6-O-(1-butyl amino)acetyl fumagillol; 45) 6-O-(sec-butyl
amino)acetyl fumagillol; 46) 6-O-(2-methyl-butylamino)acetyl
fumagillol; 47) 6-O-(t-butyl amino)acetyl fumagillol; 48)
6-O-(pentyl amino)acetyl fumagillol; 49) 6-O-(1-methyl-butyl
amino)acetyl fumagillol; 50) 6-O-(1-ethyl-propyl amino)acetyl
fumagillol; 51) 6-O-(1-methyl-pentylamino)acetyl fumagillol; 52)
6-O-(1,2-dimethyl-butylamino)acetyl fumagillol; 53)
6-O-(1,2,2-trimethyl-propylamino)acetyl fumagillol; 54)
6-O-(1-isopropyl-2-methylpropylamino)acetyl fumagillol; 55)
6-O-(3-methylbutylamino)acetyl fumagillol; 56)
6-O-(2-methylallylamino)acetyl fumagillol; 57)
6-O-(4-methyl-hepta-2,4-dienylamino)acetyl fumagillol; 58)
6-O-(1,5-dimethyl-4-hexenylamino)acetyl fumagillol; 59)
6-O-(1,1-dimethyl-2-propynylamino)acetyl fumagillol; 60)
6-O-(prop-2-enylamino)acetyl fumagillol; 61)
6-O-(2-bromo-ethylamino)acetyl fumagillol; 62)
6-O-(chloroethynylamino)acetyl fumagillol; 63)
6-O-(cyclopropylamino)acetyl fumagillol; 64)
6-O-(cyclobutylamino)acetyl fumagillol; 65)
6-O-(cyclopentylamino)acetyl fumagillol; 66)
6-O-(cyclohexylamino)acetyl fumagillol; 67)
6-O-(4-tert-butylcyclohexylamino)acetyl fumagillol; 68)
6-O-(2-dimethylamino-1-methylethylamino)acetyl fumagillol; 69)
6-O-(2-dimethylamino-propylamino)acetyl fumagillol; 70)
6-O-(2-methoxy-2-methyl-propylamino)acetyl fumagillol; 71)
6-O-(2-oxo-propylamine)acetyl fumagillol; 72)
6-O-(1,1-dimethyl-3-oxobutylamino)acetyl fumagillol; 73)
6-O-(ethyl-2-aminoacetate)acetyl fumagillol; 74)
6-O-(alanine-methylesteramino)acetyl fumagillol; 75)
6-O-(methyl-2-amino-3,3-dimethylbutanoate)acetyl fumagillol; 76)
6-O-(allylglycine-methylester)acetyl fumagillol; 77)
6-O-(2,2-dimethoxy-ehtylamino)acetyl fumagillol; 78)
4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-me-
thoxy-1-chloromethyl-1-cyclohexanol; and 79)
4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-met-
hoxy-1-chloromethyl-1-cyclohexanol.
11. Use of a compound of formula I in the preparation of a
medicament for inhibiting development of a hepatoma in a patient,
wherein said compound of formula I is as represented by the claim
1.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of prior
application Ser. No. 11/494,026 filed on Jul. 26, 2006 and
incorporated herein by reference in its entirety, which is a
divisional of U.S. Pat. No. 7,087,768 issued on Aug. 8, 2006 and
incorporated herein by reference in its entirety, which claimed
priority of Korean Application No. 2001-60017 filed on Sep. 27,
2001 and Korean Application No. 2002-29915 filed on May 29,
2002.
TECHNICAL FIELD
[0002] The present invention is directed to a fumagillol derivative
or a pharmaceutically acceptable salt thereof, showing excellent
angiogenesis inhibitory effect, with low toxicity; a preparation
method thereof; and a medical use thereof.
PRIOR ART
[0003] Angiogenesis is a phenomenon of forming new vessels at the
capillary level by a series of processes, such as proliferation,
infiltration and transfer, and interactions of vein endothelial
cells. This phenomenon is considered to be not only a normal
physiological process but also a pathological process of various
diseases. Angiogenesis, properly controlled by various
physiological substances, is an important physiological process,
which is seen upon healing of wounded parts or formation of uterine
endothelia after birth or menstruation.
[0004] However, in the uncontrolled state, angiogenesis that
excessively generates novel capillary vessels is regarded as a
pathological condition. Such angiogenesis is known to be closely
associated with growth and metastasis of solid cancers, diabetic
retinopathy, rheumatic arthritis and psoriasis [Billington, D. C.
Drug Design and Discovery, (1991), 8, 3.].
[0005] Much research on inhibition of such angiogenesis regarded as
a pathological condition has been performed. Judah Folkman of the
Medical College of Harvard University suggested a new concept of
treating solid cancer by inhibiting angiogenesis in 1971 [J.
Folkman, New Engl. Med., 185 (1971), 1182-1185]. In other words, an
angiogenesis inhibitory agent is responsible for decrease or
inhibition of growth of solid cancers, resulting in blocking
metastasis of solid cancer. Such an angiogenesis inhibitory agent
has a useful therapeutic effect for other inflammatory diseases,
such as diabetic retinopathy, rheumatoid arthritis, psoriasis, etc,
in addition to solid cancers.
[0006] Compounds inhibiting angiogenesis have been developed
through many efforts up to the present, and so various compounds
are known as novel angiogenesis inhibitory agents.
[0007] In this regard, European Pat. Nos. 0 354 787, 0 357 061 and
0 415 294, and Japanese Pat. No. JP-AO1-233275 disclose fumagillol
derivatives.
[0008] Further, it has been reported that 6-amino-6-deoxyfumagillol
[Chem. Pharm. Bull., 40, 575-579 (1992)], 6-O-acyl, 6-O-sulfonyl,
6-O-alkyl, 6-O-(N-substituted carbamoyl)fumagillol [Chem. Pharm.
Bull., 40, 96-101 (1992)] have angiogenesis inhibitory
functions.
[0009] However, there is required a continuous development of
angiogenesis inhibitory agents exhibiting excellent angiogenesis
inhibitory effect with less toxicity, and having novel chemical
structure.
DISCLOSURE OF THE INVENTION
[0010] Leading to the present invention, the intensive and thorough
research into novel compounds having high inhibitory effect on
angiogenesis, carried out by the present inventors, resulted in the
finding that an aniline derivative having various substituents can
be introduced to a known fumagillol, whereby a compound of the
formula I, which has angiogenesis inhibitory effect and low
toxicity, can be prepared.
[0011] It is therefore an object of the present invention to
provide a fumagillol derivative or a pharmaceutically acceptable
salt thereof, exhibiting excellent angiogenesis inhibitory
effect.
[0012] It is another object of the present invention to provide a
method of preparing such a fumagillol derivative.
[0013] It is a further object of the present invention to provide a
pharmaceutical composition for angiogenesis inhibition, usable as
an angiogenesis inhibitor, comprising a fumagillol derivative or a
pharmaceutically acceptable salt thereof as a useful
ingredient.
[0014] The above objects are achieved by providing the fumagillol
derivative or the pharmaceutically acceptable salt thereof of the
present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is a view showing the decrease of the tumor size of
mice treated with the compounds of Ex. 1, Ex. 11, Ex. 63 and Ex. 64
according to the present invention compared with that of mice
treated with vehicle alone.
[0016] FIG. 2 is a series of photographs showing the size of tumor
cells in xenografted nude mice treated with buffer alone or treated
with Ex. 1 and Ex. 64 according to the present invention.
BEST MODES FOR CARRYING OUT THE INVENTION
[0017] The present invention provides a fumagillol derivative
represented by the following general formula I, or a
pharmaceutically acceptable salt thereof: ##STR1##
[0018] (wherein,
[0019] X is --OH and Y is halogen, or X and Y are linked together
to form an oxirane ring,
[0020] B represents --(C.dbd.O)-- or --CH.sub.2--,
[0021] R.sub.1 represents hydrogen; hydroxy; --CN; --NO.sub.2;
--CF.sub.3; formyl; C.sub.1-C.sub.4 thioalkyl; acetamido; acetoxy;
C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.4 aminoalkyl; C.sub.1-C.sub.4
alkylaminoalkyl; C.sub.1-C.sub.4 dialkylaminoalkyl; C.sub.1-C.sub.6
alkoxy; C.sub.1-C.sub.6 aminoalkoxy; C.sub.1-C.sub.4
alkylaminoalkoxy; C.sub.1-C.sub.4 dialkylaminoalkoxy; amino;
C.sub.1-C.sub.6 alkylamino; C.sub.1-C.sub.4 dialkylamino;
C.sub.1-C.sub.4 hydroxyalkyl; C.sub.1-C.sub.4 alkyloxycarboxylic
acid, or ##STR2##
[0022] in which R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6,
which are the same or different, each represents hydrogen; hydroxy;
--CN; --NO.sub.2; --CF.sub.3; formyl; C.sub.1-C.sub.4 thioalkyl;
acetamido; acetoxy; C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.4
aminoalkyl; C.sub.1-C.sub.4 alkylaminoalkyl; C.sub.1-C.sub.4
dialkylaminoalkyl; C.sub.1-C.sub.6 alkoxy; C.sub.1-C.sub.6
aminoalkoxy; C.sub.1-C.sub.4 alkylaminoalkoxy; C.sub.1-C.sub.4
dialkylaminoalkoxy; amino; C.sub.1-C.sub.6 alkylamino;
C.sub.1-C.sub.4 dialkylamino; C.sub.1-C.sub.4 hydroxyalkyl; or
C.sub.1-C.sub.4 alkyloxycarboxylic acid; or, R.sub.2 and R.sub.3,
R.sub.3 and R.sub.4, R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6,
are linked together to form a C.sub.1-C.sub.3 alkylene dioxy ring,
and
[0023] Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 each
represent carbon or nitrogen).
[0024] Preferably, X and Y are linked together to form the oxyran
ring, and B is --(C.dbd.O)--,
[0025] R.sub.1 is hydrogen; hydroxy; --CN; --NO.sub.2; --CF.sub.3;
formyl; acetamido; acetoxy; C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.4
aminoalkyl; C.sub.1-C.sub.4 alkylaminoalkyl; C.sub.1-C.sub.4
dialkylaminoalkyl; C.sub.1-C.sub.6 alkoxy; C.sub.1-C.sub.6
aminoalkoxy; C.sub.1-C.sub.4 alkylaminoalkoxy; C.sub.1-C.sub.4
dialkylaminoalkoxy; amino; C.sub.1-C.sub.6 alkylamino;
C.sub.1-C.sub.4 dialkylamino; C.sub.1-C.sub.4 hydroxyalkyl;
C.sub.1-C.sub.4 alkyloxycarboxylic acid, or
[0026] R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6, which are
the same or different, each represents hydrogen; hydroxy; --CN;
--NO.sub.2; --CF.sub.3; formyl; acetamido; acetoxy; C.sub.1-C.sub.6
alkyl; C.sub.1-C.sub.4 aminoalkyl; C.sub.1-C.sub.4 alkylaminoalkyl;
C.sub.1-C.sub.4 dialkylaminoalkyl; C.sub.1-C.sub.6 alkoxy;
C.sub.1-C.sub.6 aminoalkoxy; C.sub.1-C.sub.4 alkylaminoalkoxy;
C.sub.1-C.sub.4 dialkylaminoalkoxy; amino; C.sub.1-C.sub.6
alkylamino; C.sub.1-C.sub.4 dialkylamino; C.sub.1-C.sub.4
hydroxyalkyl; or C.sub.1-C.sub.4 alkyloxycarboxylic acid, or
[0027] R.sub.2 and R.sub.3, R.sub.3 and R.sub.4, R.sub.4 and
R.sub.5, or R.sub.5 and R.sub.6 are linked together to form the
C.sub.1-C.sub.3 alkylene dioxy ring, and
[0028] Z.sub.1, Z.sub.2, Z.sub.3, Z.sub.4 and Z.sub.5 each
represent carbon or nitrogen.
[0029] More preferably, R.sub.1 is selected from the group
consisting of hydrogen; hydroxy; methyl; chlorine; methoxy;
methylpropoxy; isopropoxy; allyloxy; propyloxy; acetoxy cyano;
amino; dimethylaminomethyl; methylpropoxy; dimethylethoxy;
3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy;
isopropyl-4-ethoxy; dimethylamino; ethylamino; methylenedioxy;
nitro; acetoxy; trifluoromethyl; and hydroxyethoxy,
[0030] R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 is
independently selected from the group consisting of hydrogen;
hydroxy; methyl; chlorine; methoxy; methylpropoxy; isopropoxy;
allyloxy; propyloxy; acetoxy cyano; amino; dimethylaminomethyl;
methylpropoxy; dimethylethoxy; 3,5-diisopropyl-4-methoxy;
3,5-dimethyl-4-methoxy; isopropyl-4-ethoxy; dimethylamino;
ethylamino; methylenedioxy; nitro; acetoxy; trifluoromethyl; and
hydroxyethoxy, and
[0031] Z.sub.1, Z.sub.2, Z.sub.3 Z.sub.4 and Z.sub.5 each represent
carbon or nitrogen.
[0032] The fumagillol derivative of the above formula I has at
least 6 chiral centers, as represented by the following formula,
and in the scope of the present invention, each optical isomer or
mixtures thereof is included: ##STR3##
[0033] In addition, the present invention further comprises
6-O-(chloro)acetyl fumagillol as an intermediate represented by the
formula II, for use in preparation of the fumagillol derivative of
the formula I: ##STR4##
[0034] Among the compounds of the formula I, preferred are: [0035]
1) 6-O-(4-methoxyaniline)acetyl fumagillol; [0036] 2)
6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol; [0037] 3)
6-O-(2,4-dimethoxyaniline)acetyl fumagillol; [0038] 4)
6-O-(3,4-dimethoxyaniline)acetyl fumagillol; [0039] 5)
6-O-(3,4-dimethoxy-6-nitroaniline)acetyl fumagillol; [0040] 6)
6-O-(3,4-dimethoxy-6-cyanoaniline)acetyl fumagillol; [0041] 7)
6-O-(4-allyloxyaniline)acetyl fumagillol; [0042] 8)
6-O-(4-(2-acetoxyethoxy)aniline)acetyl fumagillol; [0043] 9)
6-O-(3-cyano-4-methoxyaniline)acetyl fumagillol; [0044] 10)
6-O-(3-(dimethylaminomethyl)-4-methoxyaniline) acetyl fumagillol;
[0045] 11) 6-O-(4-(2-methylpropoxyaniline)acetyl fumagillol; [0046]
12) 6-O-(3-isopropoxy-4-methoxyaniline)acetyl fumagillol; [0047]
13) 6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol; [0048]
14) 6-O-(3,5-diisopropyl-4-methoxyaniline)acetyl fumagillol; [0049]
15) 6-O-(3,5-dimethyl-4-methoxyaniline)acetyl fumagillol; [0050]
16) 6-O-(3-isopropyl-4-ethoxy-6-methylaniline)acetyl fumagillol;
[0051] 17) 6-O-(4-propyloxyaniline)acetyl fumagillol; [0052] 18)
6-O-(aniline)acetyl fumagillol; [0053] 19)
6-O-(4-chloroaniline)acetyl fumagillol; [0054] 20)
6-O-(4-dimethylaminoaniline)acetyl fumagillol; [0055] 21)
6-O-(4-hydroxyaniline)acetyl fumagillol; [0056] 22)
6-O-(4-aminoaniline)acetyl fumagillol; [0057] 23)
6-O-(3,4-methylenedioxyaniline)acetyl fumagillol; [0058] 24)
6-O-(4-nitroaniline)acetyl fumagillol; [0059] 25)
6-O-(2,3,4-trimethoxy-6-aminoaniline)acetyl fumagillol; [0060] 26)
6-O-(4-acetoxy-3,5-dimethoxyaniline)acetyl fumagillol; [0061] 27)
6-O-(3,4-dimethoxy-5-hydroxyaniline)acetyl fumagillol; [0062] 28)
6-O-(4-dimethylaminoethoxyaniline)acetyl fumagillol; [0063] 29)
6-O-(4-ethylaminoaniline)acetyl fumagillol; [0064] 30)
6-O-(4-ethylaminoethoxyaniline)acetyl fumagillol; [0065] 31)
6-O-(3-dimethylaminomethyl-4-methoxyaniline)acetyl fumagillol;
[0066] 32) 6-O-(4-trifluoromethylaniline)acetyl fumagillol; [0067]
33) 6-O-(4-acetoxy aniline)acetyl fumagillol; [0068] 34)
6-O-(4-cyanoaniline)acetyl fumagillol; [0069] 35)
6-O-(4-hydroxyethoxyaniline)acetyl fumagillol; [0070] 36)
6-O-(5-amino-2-methoxypyridine)acetyl fumagillol; [0071] 37)
6-O-(5-methoxypyrimidine-2-amino)acetyl fumagillol; [0072] 38)
6-O-(3-methoxy-6-aminopyridazine)acetyl fumagillol; [0073] 39)
4-((4-methoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-me-
thoxy-1-chloromethyl-1-cyclohexanol; [0074] 40)
4-((3,4,5-trimethoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexeny-
l)-3-methoxy-1-chloromethyl-1-cyclohexanol; [0075] 41)
6-O-(ethylamino)acetyl fumagillol; [0076] 42) 6-O-(isopropyl
amino)acetyl fumagillol; [0077] 43) 6-O-(1-propyl amino)acetyl
fumagillol; [0078] 44) 6-O-(1-butyl amino)acetyl fumagillol; [0079]
45) 6-O-(sec-butyl amino)acetyl fumagillol; [0080] 46)
6-O-(2-methyl-butylamino)acetyl fumagillol; [0081] 47) 6-O-(t-butyl
amino)acetyl fumagillol; [0082] 48) 6-O-(pentyl amino)acetyl
fumagillol; [0083] 49) 6-O-(1-methyl-butyl amino)acetyl fumagillol;
[0084] 50) 6-O-(1-ethyl-propyl amino)acetyl fumagillol; [0085] 51)
6-O-(1-methyl-pentylamino)acetyl fumagillol; [0086] 52)
6-O-(1,2-dimethyl-butylamino)acetyl fumagillol; [0087] 53)
6-O-(1,2,2-trimethyl-propylamino)acetyl fumagillol; [0088] 54)
6-O-(1-isopropyl-2-methylpropylamino)acetyl fumagillol; [0089] 55)
6-O-(3-methylbutylamino)acetyl fumagillol; [0090] 56)
6-O-(2-methylallylamino)acetyl fumagillol; [0091] 57)
6-O-(4-methyl-hepta-2,4-dienylamino)acetyl fumagillol; [0092] 58)
6-O-(1,5-dimethyl-4-hexenylamino)acetyl fumagillol; [0093] 59)
6-O-(1,1-dimethyl-2-propynylamino)acetyl fumagillol; [0094] 60)
6-O-(prop-2-enylamino)acetyl fumagillol; [0095] 61)
6-O-(2-bromo-ethylamino)acetyl fumagillol; [0096] 62)
6-O-(chloroethynylamino)acetyl fumagillol; [0097] 63)
6-O-(cyclopropylamino)acetyl fumagillol; [0098] 64)
6-O-(cyclobutylamino)acetyl fumagillol; [0099] 65)
6-O-(cyclopentylamino)acetyl fumagillol; [0100] 66)
6-O-(cyclohexylamino)acetyl fumagillol; [0101] 67)
6-O-(4-tert-butylcyclohexylamino)acetyl fumagillol; [0102] 68)
6-O-(2-dimethylamino-1-methylethylamino)acetyl fumagillol; [0103]
69) 6-O-(2-dimethylamino-propylamino)acetyl fumagillol; [0104] 70)
6-O-(2-methoxy-2-methyl-propylamino)acetyl fumagillol; [0105] 71)
6-O-(2-oxo-propylamine)acetyl fumagillol; [0106] 72)
6-O-(1,1-dimethyl-3-oxobutylamino)acetyl fumagillol; [0107] 73)
6-O-(ethyl-2-aminoacetate)acetyl fumagillol; [0108] 74)
6-O-(alanine-methylesteramino)acetyl fumagillol; [0109] 75)
6-O-(methyl-2-amino-3,3-dimethylbutanoate)acetyl fumagillol; [0110]
76) 6-O-(allylglycine-methylester)acetyl fumagillol; [0111] 77)
6-O-(2,2-dimethoxy-ehtylamino)acetyl fumagillol; [0112] 78)
4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-me-
thoxy-1-chloromethyl-1-cyclohexanol; [0113] 79)
4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-met-
hoxy-1-chloromethyl-1-cyclohexanol; and [0114] 80)
6-O-(chloro)acetyl fumagillol.
[0115] Among the compounds of the formula I, most preferred are:
[0116] 1) 6-O-(4-methoxyaniline)acetyl fumagillol; [0117] 2)
6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol; [0118] 3)
6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol; [0119] 4)
6-O-(cyclopropylamino)acetyl fumagillol; [0120] 5)
6-O-(cyclobutylamino)acetyl fumagillol; [0121] 6)
4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-me-
thoxy-1-chloromethyl-1-cyclohexanol; and [0122] 7)
4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-met-
hoxy-1-chloromethyl-1-cyclohexanol.
[0123] Structural formulas of the above compounds are shown in
Tables 1a to 1d, below. TABLE-US-00001 TABLE 1a ##STR5## Ex. 1
##STR6## Ex. 2 ##STR7## Ex. 3 ##STR8## Ex. 4 ##STR9## Ex. 5
##STR10## Ex. 6 ##STR11## Ex. 7 ##STR12## Ex. 8 ##STR13## Ex. 9
##STR14## Ex. 10 ##STR15## Ex. 11 ##STR16## Ex. 12 ##STR17## Ex. 13
##STR18## Ex. 14 ##STR19## Ex. 15 ##STR20## Ex. 16 ##STR21## Ex. 17
##STR22## Ex. 18 ##STR23## Ex. 19 ##STR24## Ex. 20 ##STR25##
[0124] TABLE-US-00002 TABLE 1b ##STR26## Ex. 21 ##STR27## Ex. 22
##STR28## Ex. 23 ##STR29## Ex. 24 ##STR30## Ex. 25 ##STR31## Ex. 26
##STR32## Ex. 27 ##STR33## Ex. 28 ##STR34## Ex. 29 ##STR35## Ex. 30
##STR36## Ex. 31 ##STR37## Ex. 32 ##STR38## Ex. 33 ##STR39## Ex. 34
##STR40## Ex. 35 ##STR41## Ex. 36 ##STR42## Ex. 37 ##STR43## Ex. 38
##STR44## Ex. 39 ##STR45## Ex. 40 ##STR46##
[0125] TABLE-US-00003 TABLE 1c ##STR47## Ex. 41 ##STR48## Ex. 42
##STR49## Ex. 43 ##STR50## Ex. 44 ##STR51## Ex. 45 ##STR52## Ex. 46
##STR53## Ex. 47 ##STR54## Ex. 48 ##STR55## Ex. 49 ##STR56## Ex. 50
##STR57## Ex. 51 ##STR58## Ex. 52 ##STR59## Ex. 53 ##STR60## Ex. 54
##STR61## Ex. 55 ##STR62## Ex. 56 ##STR63## Ex. 57 ##STR64## Ex. 58
##STR65## Ex. 59 ##STR66## Ex. 60 ##STR67##
[0126] TABLE-US-00004 TABLE 1d ##STR68## Ex. 61 ##STR69## Ex. 62
##STR70## Ex. 63 ##STR71## Ex. 64 ##STR72## Ex. 65 ##STR73## Ex. 66
##STR74## Ex. 67 ##STR75## Ex. 68 ##STR76## Ex. 69 ##STR77## Ex. 70
##STR78## Ex. 71 ##STR79## Ex. 72 ##STR80## Ex. 73 ##STR81## Ex. 74
##STR82## Ex. 75 ##STR83## Ex. 76 ##STR84## Ex. 77 ##STR85## Ex. 78
##STR86## Ex. 79 ##STR87## Inter- medi- ate ##STR88##
[0127] The fumagillol derivative of the present invention,
represented by the formula I, may be used in a form of a
pharmaceutically acceptable salt. In particular, an acid addition
salt formed by a pharmaceutically acceptable free acid is usefully
used. As the free acid, an inorganic acid and an organic acid may
be used. Examples of the inorganic acid include hydrochloric acid,
bromic acid, sulfuric acid and phosphoric acid. The organic acid is
exemplified by citric acid, acetic acid, lactic acid, tartaric
acid, maleic acid, umaric acid, gluconic acid, methansulfonic acid,
glyconic acid, succinic acid, 4-toluenesulfonic acid, galacturonic
acid, embonic acid, glutamic acid or aspartic acid.
[0128] Additionally, the present invention provides a method of
preparing an acetyl fumagillol derivative and a pharmaceutically
acceptable salt thereof, as represented by the following Reaction
Scheme 1.
[0129] Specifically, the preparation method of the fumagillol
derivative compound in which B is --(C.dbd.O)--, comprises the
steps of:
[0130] (a) acylating a compound of the formula 2 with
.alpha.-halocarboxylic acid derivative in the presence of a base,
to give a compound of the formula 3; and
[0131] (b) reacting the compound of the formula 3 with an amine
compound of the formula 4, to prepare the fumagillol derivative
represented by the formula 1a via substitution. ##STR89##
[0132] (wherein, R.sub.1 is as defined above)
[0133] In the present invention, the prepared compound of the
formula 1a is treated with an acid, or reacted with a salt in the
presence of an acid catalyst, to perform an oxirane ring-opening
reaction, thereby yielding the fumagillol derivative represented by
the formula 1b, as shown in the following Reaction Scheme 2:
##STR90##
[0134] (wherein, R.sub.1, X and Y are as defined above)
[0135] Below, a description will be given of each step.
[0136] (1) Acylation Step
[0137] The compound of the formula 2 as a starting material is
acylated with .alpha.-halocarboxylic acid derivative having high
reactivity, in the presence of the base, to give the compound of
the formula 3, as seen in the following Reaction Scheme 3.
##STR91##
[0138] Specifically, the compound of the formula III is a
fumagillol, which is a hydrolyzed product of fumagillin produced by
microbial fermentation [Tarbell, D, S. et. al., J. Am. Chem, Soc.,
83, 3096 (1961)]81). ##STR92##
[0139] The above .alpha.-halocarboxylic acid derivative is selected
from among chloroacetyl chloride, chloroacetyl bromide,
chloroacetyl iodide, and chloroacetyl fluoride, and used in the
amount of 1-5 equivalents, preferably in 1-1.5 equivalents, based
on the compound of the formula 2.
[0140] As for the base, an acid anhydride, a mixed anhydride or an
acid chloride may be commonly used, and preferably, tertiary
amines, such as triethylamine, diisopropylethyl amine, pyridine,
dimethylamino pyridine, etc., are used in the amount of 1-10
equivalents. More preferably, 1-3 equivalents of triethylamine, or
dimethylaminopyridine is used.
[0141] The solvent used for acylation is selected from the group
consisting of dimethylformamide, dichloromethane, chloroform,
diethylether, tetrahydrofuran, dioxane, acetonitrile, benzene and
toluene. Preferably, dimethylformamide, dichloromethane or
tetrahydrofuran is used.
[0142] As such, acylation is carried out at 0-50.degree. C.,
preferably at 20-50.degree. C.
[0143] 2) Halogen-Amine Substitution Step
[0144] The compound of the formula 0.3, obtained from the previous
acylation step, is reacted with the compound of the formula 4 as
the amine derivative, to yield the compound of the formula 1a
having a substituted amine compound, as seen in the following
Reaction Scheme 4. ##STR93##
[0145] (wherein, R.sub.1 is as defined above)
[0146] The aromatic compound of the formula 4, used in the above
substitution reaction, is used in the amount of 1-10 equivalents,
preferably 1-3 equivalents, based on the compound of the formula
3.
[0147] As for the amine compound, aliphatic or aromatic amine
compound can be used. Such derivatives are specifically stated in
the examples of the present invention.
[0148] The solvent used in this substitution reaction is selected
from the group consisting of dimethylformamide, dichloromethane,
chloroform, diethylether, tetrahydrofuran, dioxane, acetonitrile,
benzene and toluene. It is preferred that dimethylformamide,
dichloromethane or tetrahydrofuran is used.
[0149] The substitution reaction is performed at 0-100.degree. C.,
preferably at 20-50.degree. C.
[0150] 3) Oxirane Ring-Opening Step
[0151] The compound of the formula 1a, resulting from the above
step, is treated with the acid, or reacted with the salt in the
presence of the acid catalyst, to perform the oxirane ring-opening
reaction, thereby yielding the fumagillol derivative represented by
the formula 1b, as in the following Reaction Scheme 5.
##STR94##
[0152] (wherein, R.sub.1, X and Y.sub.4 are as defined above)
[0153] Examples of the acid used in the ring-opening reaction
include hydrochloric acid, bromic acid or iodic acid. The acid
usable as the catalyst comprises acetic acid, sulfuric acid,
para-toluene sulfonic acid, hydrochloric acid, phosphoric acid or
nitric acid. Of the acid catalysts, acetic acid or hydrochloric
acid is preferably used.
[0154] The salt used in this reaction is selected from the group
consisting of bromolithium, chlorolithium, sodium chloride,
potassium chloride, potassium bromide, sodium bromide, potassium
iodide, sodium iodide and lithium iodide. Preferably,
chlorolithium, bromolithium, lithium iodide or sodium hydrogen
carbonate.
[0155] Meanwhile, the preparation method of the compound in which B
is --CH.sub.2-- is specifically shown in the following Reaction
Scheme 6. ##STR95##
[0156] Further, the present invention provides a pharmaceutical
composition for angiogenesis inhibition, comprising the fumagillol
derivative of the formula I or a pharmaceutically acceptable salt
thereof as an effective ingredient.
[0157] In order to investigate activity of the fumagillol
derivative on cell growth, proliferation inhibition activity was
measured using HUVECs (human umbilical vein endothelial cells). As
the result, it was found that the inventive fumagillol derivative
has superior growth inhibition effect, up to 2000 times greater
than TNP-470, a conventional angiogenesis inhibitory agent.
[0158] Therefore, it is expected that the fumagillol derivative of
the formula I can strongly inhibit proliferation of vein
endothelial cells, thus having excellent angiogenesis inhibitory
effect. Such a fumagillol derivative can be usefully used for
decreasing and inhibiting growth and metastasis of cancer as well
as treating other various inflammatory diseases, including diabetic
retinopathy, rheumatic arthritis and psoriasis. Hence, the
fumagillol derivative is usable as a cancer metastasis inhibitor,
or a therapeutic agent against cancer, rheumatic arthritis,
psoriasis and diabetic retinopathy.
[0159] With a view to evaluating general toxicity of the compound
of the formula I according to the present invention, experiments on
acute toxicity were carried out using mice. As a result, it was
found that the half lethal dose (LD.sub.50) of each compound upon
single oral administration was not less than 2 g/kg, whereby the
compound was evaluated as a very safe compound.
[0160] The compound of the formula I according to the present
invention may be formulated, upon clinical administration, as a
pharmaceutical solid, semi-solid or liquid type formulation which
is suitable for oral or parenteral administration by blending this
compound with a pharmaceutically acceptable inert carrier.
[0161] The pharmaceutical composition of the present invention is
formulated into dosage form for oral administration, for instance,
tablet, troches, lozenge, water- or oil-soluble suspension,
prepared powder or grain, emulsion, hard or soft capsule, syrup or
elixir. For formulation of the tablet and capsule form, used are
binders such as lactose, sacharose, sorbitol, mannitol, starch,
amylopectin, cellulose or gelatin; vehicles such as dicalcium
phosphate; disintegrating agents, such as corn starch or
sweet-potato starch; and lubricants, such as magnesium stearate,
calcium stearate, sodium stearylfumaric acid or polyethyleneglycol
wax. In the case of capsule formulation, liquid carriers including
fatty oil may be further included, in addition to the above
materials.
[0162] Pharmaceutical preparations for parenteral administration
comprise sterile aqueous solution, water-insoluble solvent,
suspension, emulsion, and lyophilized agent. As the water-insoluble
solvent and suspension, use may be made of vegetable oil such as
propylene glycol, polyethylene glycol, olive oil, and injection
ester, such as ethyl oleate.
[0163] In typical medical substances, effective doses of the
compound of the formula I according to the present invention may
range from 0.2 to 2.0 mg/kg, and they can be administered in a
single dose or in divided daily doses. However, it should be
understood by anyone skilled in the art that the amount of the
active ingredient actually administered ought to be determined in
light of various relevant factors including constitutional
peculiarity and body weight of the individual subject, kinds and
severity of diseases, properties of dosage form, properties of
medicinal administration, and administration period or
interval.
[0164] A better understanding of the present invention may be
obtained in light of the following examples which are set forth to
illustrate, but are not to be construed to limit the present
invention.
EXAMPLE 1
Preparation of 6-O-(4-methoxyaniline)acetyl Fumagillol
Step 1: (Acylation) Preparation of 6-O-chloroacetyl Fumagillol
[0165] Fumagillol (500 mg) in dichloromethane (10 ml) was added
with dimethylaminopyridine (432 mg) and chloroacetyl chloride (199
mg), and stirred at room temperature for 1 hour. The reaction was
vacuum concentrated, to give the residue, which was then purified
by silica gel column chromatography (ethyl acetate:n-hexane=1:4),
yielding 270 mg of the title compound as a light yellow oil.
[0166] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.76-5.74 (m, 1H), 5.22
(br t, 1H, J=7.3 Hz), 4.19 (s, 2H), 3.71 (dd, 1H, J=2.8, 11.1 Hz),
3.47 (s, 3H), 3.01 (d, 1H, J=4.3 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.56
(d, 1H, J=4.3 Hz), 2.41-1.81 (m, 9H), 1.75 (s, 3H), 1.66 (s, 3H),
1.24 (s, 3H), 1.18-1.06 (m, 1H).
Step 2: (Substitution) Preparation of 6-O-(4-methoxyaniline)acetyl
Fumagillol
[0167] 6-O-chloroacetyl fumagillol (160 mg), obtained from the
above step 1, was dissolved in dimethylformamide (1 ml), to which
4-methoxyaniline (0.055 mg) was added. The mixture was further with
K.sub.2CO.sub.3 (61.48 mg) and KI (73.84 mg) and stirred at
70.degree. C. for 6 hours.
[0168] Thereafter, the resultant reaction was diluted with ethyl
acetate (20 ml), and washed with saturated aqueous sodium hydrogen
carbonate (5 ml) and saturated brine (5 ml). The organic layer was
separated, dried over anhydrous magnesium sulfate and filtered. The
obtained filtrate was vacuum concentrated to give the residue,
which was purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 112 mg of the title
compound as a white solid.
[0169] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.57 (s, 2H), 5.70-5.73
(m, 1H), 5.19 (br t, 1H, J=7.3 Hz), 4.21 (s, 2H), 3.86 (s, 3H),
3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.45 (s, 3H), 3.01 (d, 1H, J=4.2
Hz), 2.56 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.2 Hz), 2.43-1.83 (m,
6H), 1.78 (s, 3H) 1.63 (s, 3H) 1.25 (s, 3H) 1.19-1.03 (m, 1H).
EXAMPLE 2
Preparation of 6-O-(3,4,5-trimethoxyaniline)acetyl Fumagillol
[0170] 6-O-chloroacetyl fumagillol (166 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which 3,4,5-trimethoxyaniline (0.079
mg) was added. Then, this mixture was further added with
K.sub.2CO.sub.3 (63.78 mg) and KI (76.61 mg), and stirred at
70.degree. C. for 6 hours.
[0171] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The organic layer was separated,
and dried over anhydrous magnesium sulfate and filtered. The
obtained filtrate was vacuum concentrated to give the residue,
which was purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 136 mg of the title
compound as a white solid.
[0172] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.54 (s, 2H), 5.73-5.73
(m, 1H), 5.21 (br t, 1H, J=7.3 Hz), 4.21 (s, 2H), 3.89 (s, 9H),
3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.44 (s, 3H), 3.01 (d, 1H, J=4.2
Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.2 Hz), 2.43-1.83 (m,
6H), 1.75 (s, 3H) 1.67 (s, 3H) 1.23 (s, 3H) 1.15-1.04 (m, 1H).
EXAMPLE 3
Preparation of 6-O-(2,4-dimethoxyaniline)acetyl Fumagillol
[0173] 6-O-chloroacetyl fumagillol (168 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which 2,4-dimethoxyaniline (0.072 mg)
was added. Then, the mixture was further added with K.sub.2CO.sub.3
(64.54 mg) and KI (77.52 mg) and stirred at 70.degree. C. for 6
hours.
[0174] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The organic layer was separated,
dried over anhydrous magnesium sulfate and filtered. The obtained
filtrate was vacuum concentrated to give the residue, which was
purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 140 mg of the title
compound as a white solid.
[0175] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.57-6.48 (m, 3H),
5.73-5.71 (m, 1H), 5.24 (br t, 1H, J=7.2 Hz), 4.23 (s, 2H), 3.91
(s, 6H), 3.72 (dd, 1H, J=2.9, 11.0 Hz), 3.49 (s, 3H), 3.01 (d, 1H,
J=4.3 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.3 Hz),
2.43-1.83 (m, 6H), 1.77 (s, 3H) 1.66 (s, 3H) 1.24 (s, 3H) 1.15-1.01
(m, 1H).
EXAMPLE 4
Preparation of 6-O-(3,4-dimethoxyaniline)acetyl Fumagillol
[0176] 6-O-chloroacetyl fumagillol (164 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which 3,4-dimethoxyaniline (0.07 mg)
was added. Then, the mixture was added with K.sub.2CO.sub.3 (63.01
mg) and KI (75.68 mg), and stirred at 70.degree. C. for 6
hours.
[0177] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The separated organic layer was
dried over anhydrous magnesium sulfate and filtered. The obtained
filtrate was vacuum concentrated to give the residue, which was
purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 132 mg of the title
compound as a colorless oil.
[0178] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.54-6.47 (m, 3H),
5.73-5.69 (m, 1H), 5.21 (br t, 1H, J=7.2 Hz), 4.25 (s, 2H), 3.86
(s, 6H), 3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.51 (s, 3H), 3.03 (d, 1H,
J=4.2 Hz), 2.56 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.2 Hz),
2.41-1.81 (m, 6H), 1.75 (s, 3H) 1.67 (s, 3H) 1.26 (s, 3H) 1.18-1.02
(m, 1H).
EXAMPLE 5
Preparation of 6-O-(3,4-dimethoxy-6-nitroaniline)acetyl
Fumagillol
[0179] 6-O-chloroacetyl fumagillol (154 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which 3,4-dimethoxy-6-nitroaniline
(0.085 mg). Then, the mixture was added with K.sub.2CO.sub.3 (59.18
mg) and KI (71.08 mg) and stirred at 70.degree. C. for 6 hours.
[0180] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The separated organic layer was
dried over anhydrous magnesium sulfate and filtered. The obtained
filtrate was vacuum concentrated to give the residue, which was
purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 161 mg of the title
compound as a white solid.
[0181] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.73-6.66 (m, 2H),
5.75-5.71 (m, 1H), 5.23 (br t, 1H, J=7.2 Hz), 4.27 (s, 2H), 3.93
(s, 6H), 3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.49 (s, 3H), 3.01 (d, 1H,
J=4.2 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.2 Hz),
2.43-1.83 (m, 6H), 1.75 (s, 3H) 1.64 (s, 3H) 1.25 (s, 3H) 1.18-1.03
(m, 1H).
EXAMPLE 6
Preparation of 6-O-(3,4-dimethoxy-6-cyanoaniline)acetyl
Fumagillol
[0182] 6-O-chloroacetyl fumagillol (160 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which 3,4-dimethoxy-6-cyanoaniline
(0.079 mg) was added. The mixture was further added with
K.sub.2CO.sub.3 (61.48 mg) and KI (73.84 mg), and stirred at
70.degree. C. for 6 hours.
[0183] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The organic layer was dried over
anhydrous magnesium sulfate and filtered. The filtrate was vacuum
concentrated to give the residue, which was purified by silica gel
column chromatography (methanol:dichloromethane=1:10), yielding 128
mg of the title compound as a white solid.
[0184] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.77-6.64 (m, 2H),
5.73-5.70 (m, 1H), 5.21 (br t, 1H, J=7.2 Hz), 4.26 (s, 2H), 3.90
(s, 6H), 3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.51 (s, 3H), 3.03 (d, 1H,
J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.1 Hz),
2.46-1.80 (m, 6H), 1.76 (s, 3H) 1.66 (s, 3H) 1.23 (s, 3H) 1.19-1.04
(m, 1H).
EXAMPLE 7
Preparation of 6-O-(4-allyloxyaniline)acetyl Fumagillol
[0185] 6-O-chloroacetyl fumagillol (165 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which 4-allyloxyaniline (0.085 mg) was
added. The mixture was further added with K.sub.2CO.sub.3 (63.40
mg) and KI (76.14 mg) and stirred at 70.degree. C. for 7 hours.
[0186] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The separated organic layer was
dried over anhydrous magnesium sulfate and filtered. The filtrate
was vacuum concentrated to give the residue, which was purified by
silica gel column chromatography (methanol:dichloromethane=1:10),
yielding 151 mg of the title compound as a colorless oil.
[0187] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.58-6.54 (m, 2H),
6.32-6.29 (m, 2H), 5.87-5.85 (m, 1H), 5.73-5.70 (m, 1H), 5.41-5.35
(m, 2H), 5.21 (br t, 1H, J=7.2 Hz), 4.61 (d, 2H, J=7.4 Hz), 4.26
(s, 2H), 3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.51 (s, 3H), 3.03 (d, 1H,
J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.1 Hz),
2.46-1.80 (m, 6H), 1.76 (s, 3H) 1.66 (s, 3H) 1.23 (s, 3H) 1.19-1.04
(m, 1H).
EXAMPLE 8
Preparation of 6-O-(4-(2-acetoxyethoxy)aniline)acetyl
Fumagillol
[0188] 6-O-chloroacetyl fumagillol (160 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which 4-(2-acetoxyethoxy)aniline (0.08
mg) was added. Then, the mixture was further added with
K.sub.2CO.sub.3 (61.48 mg) and KI (73.84 mg) and stirred at
70.degree. C. for 6 hours.
[0189] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The separated organic layer was
dried over anhydrous magnesium sulfate and filtered. The filtrate
was vacuum concentrated to give the residue, which was purified by
silica gel column chromatography (methanol:dichloromethane=1:10),
yielding 153 mg of the title compound as a colorless oil.
[0190] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.54-6.52 (m, 2H),
6.38-6.34 (m, 2H), 5.73-5.70 (m, 1H), 5.21 (br t, 1H, J=7.2 Hz),
4.52 (t, 2H, J=7.0 Hz), 4.29 (t, 2H, J=7.0 Hz), 4.24 (s, 2H), 3.73
(dd, 1H, J=2.9, 11.1 Hz), 3.53 (s, 3H), 3.01 (d, 1H, J=4.3 Hz),
2.58 (t, 1H, J=6.4 Hz), 2.52 (d, 1H, J=4.3 Hz), 2.45-1.82 (m, 6H),
2.02 (s, 3H), 1.79 (s, 3H) 1.65 (s, 3H) 1.24 (s, 3H) 1.17-1.02 (m,
1H).
EXAMPLE 9
Preparation of 6-O-(3-cyano-4-methoxyaniline)acetyl Fumagillol
[0191] 6-O-chloroacetyl fumagillol (150 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which 3-cyano-4-methoxyaniline (0.062
mg) was added. Then, the mixture was further added with
K.sub.2CO.sub.3 (57.64 mg) and KI (69.22 mg) and stirred at
70.degree. C. for 6 hours.
[0192] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The organic layer was dried over
anhydrous magnesium sulfate and filtered. The filtrate was vacuum
concentrated to give the residue, which was purified by silica gel
column chromatography (methanol:dichloromethane=1:10), yielding 124
mg of the title compound as a white solid.
[0193] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.77-6.64 (m, 3H),
5.73-5.70 (m, 1H), 5.21 (br t, 1H, J=7.2 Hz), 4.25 (s, 2H), 3.92
(s, 3H), 3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.54 (s, 3H), 3.03 (d, 1H,
J=4.1 Hz), 2.60 (t, 1H, J=6.4 Hz), 2.53 (d, 1H, J=4.1 Hz),
2.46-1.80 (m, 6H), 1.79 (s, 3H) 1.69 (s, 3H) 1.24 (s, 3H) 1.18-1.02
(m, 1H).
EXAMPLE 10
Preparation of 6-O-(3-(dimethylaminomethyl)-4-methoxyaniline)acetyl
Fumagillol
[0194] 6-O-chloroacetyl fumagillol (153 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which
3-(dimethylaminomethyl)-4-methoxyaniline (0.092 mg) was added.
Then, the mixture was further added with K.sub.2CO.sub.3 (58.79 mg)
and KI (70.61 mg), and stirred at 70.degree. C. for 6 hours.
[0195] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The separated organic layer was
dried over anhydrous magnesium sulfate and filtered. The filtrate
was vacuum concentrated to give the residue, which was purified by
silica gel column chromatography (methanol:dichloromethane=1:10),
yielding 161 mg of the title compound as a white solid.
[0196] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.43-6.19 (m, 3H),
5.73-5.70 (m, 1H), 5.23 (br t, 1H, J=7.2 Hz), 4.23 (s, 2H), 3.93
(s, 3H), 3.74 (dd, 1H, J=2.9, 11.1 Hz), 3.66 (s, 2H), 3.52 (s, 3H),
3.00 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.52 (d, 1H, J=4.1
Hz), 2.46-1.80 (m, 6H), 2.26 (s, 6H), 1.78 (s, 3H) 1.66 (s, 3H)
1.25 (s, 3H) 1.16-1.04 (m, 1H)
EXAMPLE 11
Preparation of 6-O-(4-(2-methylpropoxyaniline)acetyl Fumagillol
[0197] 6-O-chloroacetyl fumagillol (152 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which 4-(2-methylpropoxy)aniline (0.07
mg) was added. This mixture was further added with K.sub.2CO.sub.3
(58.41 mg) and KI (70.15 mg), and stirred at 70.degree. C. for 6
hours.
[0198] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The separated organic layer was
dried over anhydrous magnesium sulfate and filtered. The filtrate
was vacuum concentrated to give the residue, which was purified by
silica gel column chromatography (methanol:dichloromethane=1:10),
yielding 123 mg of the title compound as a white solid.
[0199] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.59-6.55 (m, 2H),
6.37-6.33 (m, 2H), 5.74-5.71 (m, 1H), 5.25 (br t, 1H, J=7.2 Hz),
4.23 (s, 2H), 3.91 (d, 2H, J=6.5 Hz), 3.74 (dd, 1H, J=2.9, 11.1
Hz), 3.52 (s, 3H), 3.03 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz),
2.52 (d, 1H, J=4.1 Hz), 2.45-1.80 (m, 7H), 1.78 (s, 3H) 1.66 (s,
3H) 1.25 (s, 3H), 1.19 (d, 6H, J=6.1 Hz), 1.15-1.01 (m, 1H)
EXAMPLE 12
Preparation of 6-O-(3-isopropoxy-4-methoxyaniline)acetyl
Fumagillol
[0200] 6-O-chloroacetyl fumagillol (161 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which 3-(isopropoxy)-4-methoxyaniline
(0.081 mg) was added. This mixture was added with K.sub.2CO.sub.3
(61.87 mg) and KI (74.3 mg), and stirred at 70.degree. C. for 6
hours.
[0201] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The separated organic layer was
dried over anhydrous magnesium sulfate and filtered. The filtrate
was vacuum concentrated to give the residue, which was purified by
silica gel column chromatography (methanol:dichloromethane=1:10),
yielding 151 mg of the title compound as a white solid.
[0202] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.43-6.11 (m, 3H),
5.73-5.70 (m, 1H), 5.23 (br t, 1H, J=7.2 Hz), 4.23 (s, 2H), 4.11
(q, 1H, J=6.7 Hz), 3.93 (s, 3H), 3.74 (dd, 1H, J=2.9, 11.1 Hz),
3.52 (s, 3H), 3.00 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.52
(d, 1H, J=4.1 Hz), 2.46-1.80 (m, 6H), 1.78 (s, 3H) 1.66 (s, 3H),
1.40 (d, 6H, J=6.7 Hz), 1.25 (s, 3H) 1.16-1.04 (m, 1H).
EXAMPLE 13
Preparation of 6-O-(4-(N,N-dimethylethoxy)aniline)acetyl
Fumagillol
[0203] 6-O-chloroacetyl fumagillol (154 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which 4-(N,N-dimethylethoxy)aniline
(0.077 mg) was added. This mixture was further added with
K.sub.2CO.sub.3 (59.18 mg) and KI (71.08 mg), and stirred at
70.degree. C. for 6 hours.
[0204] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The separated organic layer was
dried over anhydrous magnesium sulfate and filtered. The filtrate
was vacuum concentrated to give the residue, which was purified by
silica gel column chromatography (methanol:dichloromethane=1:10),
yielding 158 mg of the title compound as a white solid.
[0205] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.61-6.57 (m, 2H),
6.39-6.35 (m, 2H), 5.74-5.70 (m, 1H), 5.26 (br t, 1H, J=7.2 Hz),
4.23 (s, 2H), 4.03 (t, 2H, J=6.8 Hz), 3.75 (dd, 1H, J=2.9, 11.1
Hz), 3.52 (s, 3H), 3.05 (d, 1H, J=4.1 Hz), 2.57 (t, 1H, J=6.4 Hz),
2.79 (t, 2H, J=6.8 Hz), 2.59 (s, 6H), 2.50 (d, 1H, J=4.1 Hz),
2.45-1.80 (m, 6H), 1.77 (s, 3H) 1.65 (s, 3H) 1.26 (s, 3H),
1.17-1.02 (m, 1H).
EXAMPLE 14
Preparation of 6-O-(3,5-diisopropyl-4-methoxyaniline)acetyl
Fumagillol
[0206] 6-O-chloroacetyl fumagillol (160 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which 3,5-diisopropyl-4-methoxyaniline
(0.092 mg) was added. This mixture was further added with
K.sub.2CO.sub.3 (61.48 mg) and KI (73.84 mg), and stirred at
70.degree. C. for 6 hours.
[0207] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The separated organic layer was
dried over anhydrous magnesium sulfate and filtered. The obtained
filtrate was vacuum concentrated to give the residue, which was
purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 171 mg of the title
compound as a white solid.
[0208] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.58-6.54 (m, 2H),
5.74-5.71 (m, 1H), 5.25 (br t, 1H, J=7.2 Hz), 4.23 (s, 2H), 3.91
(s, 3H), 3.74 (dd, 1H, J=2.9, 11.1 Hz), 3.52 (s, 3H), 3.19 (q, 2H,
J=6.3 Hz), 3.03 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.52 (d,
1H, J=4.1 Hz), 2.45-1.80 (m, 6H), 1.78 (s, 3H) 1.69 (s, 3H), 1.32
(d, 12H, J=6.3 Hz), 1.25 (s, 3H), 1.18-1.00 (m, 1H).
EXAMPLE 15
Preparation of 6-O-(3,5-dimethyl-4-methoxyaniline)acetyl
Fumagillol
[0209] 6-O-chloroacetyl fumagillol (155 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which 3,5-dimethyl-4-methoxyaniline
(0.065 mg) was added. This mixture was further added with
K.sub.2CO.sub.3 (59.56 mg) and KI (71.53 mg), and stirred at
70.degree. C. for 6 hours.
[0210] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The separated organic layer was
dried over anhydrous magnesium sulfate and filtered. The filtrate
was vacuum concentrated to give the residue, which was purified by
silica gel column chromatography (methanol:dichloromethane=1:10),
yielding 145 mg of the title compound as a white solid.
[0211] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.56-6.51 (m, 2H),
5.75-5.72 (m, 1H), 5.27 (br t, 1H, J=7.2 Hz), 4.25 (s, 2H), 3.93
(s, 3H), 3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.55 (s, 3H), 3.04 (d, 1H,
J=4.1 Hz), 2.56 (t, 1H, J=6.4 Hz), 2.50 (d, 1H, J=4.1 Hz),
2.45-1.80 (m, 12H), 1.78 (s, 3H) 1.69 (s, 3H), 1.25 (s, 3H),
1.18-1.00 (m, 1H).
EXAMPLE 16
Preparation of 6-O-(3-isopropyl-4-ethoxy-6-methylaniline)acetyl
Fumagillol
[0212] 6-O-chloroacetyl fumagillol (158 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which
3-isopropyl-4-ethoxy-6-methylaniline (0.101 mg) was added. This
mixture was added with K.sub.2CO.sub.3 (60.71 mg) and KI (72.91
mg), and stirred at 70.degree. C. for 6 hours.
[0213] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The separated organic layer was
dried over anhydrous magnesium sulfate and filtered. The filtrate
was vacuum concentrated to give the residue, which was purified by
silica gel column chromatography (methanol:dichloromethane=1:10),
yielding 166 mg of the title compound as a white solid.
[0214] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.54-6.51 (m, 2H),
5.75-5.72 (m, 1H), 5.27 (br t, 1H, J=7.2 Hz), 4.21 (s, 2H), 3.97
(q, 2H, J=6.2 Hz), 3.74 (dd, 1H, J=2.9, 11.1 Hz), 3.52 (s, 3H),
3.14 (q, 1H, J=6.5 Hz), 3.03 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4
Hz), 2.52 (d, 1H, J=4.1 Hz), 2.45-1.80 (m, 9H), 1.78 (s, 3H) 1.69
(s, 3H), 1.35 (t, 3H, J=6.2 Hz), 1.28 (d, 6H, J=6.5 Hz), 1.25 (s,
3H), 1.18-1.00 (m, 1H).
EXAMPLE 17
Preparation of 6-O-(4-propyloxyaniline)acetyl Fumagillol
[0215] 6-O-chloroacetyl fumagillol (160 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which 4-propyloxyaniline (0.084 mg)
was added. This mixture was added with K.sub.2CO.sub.3 (61.48 mg)
and KI (73.84 mg), and stirred at 70.degree. C. for 6 hours.
[0216] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The separated organic layer was
dried over anhydrous magnesium sulfate and filtered. The filtrate
was vacuum concentrated to give the residue, which was purified by
silica gel column chromatography (methanol:dichloromethane=1:10),
yielding 105 mg of the title compound as a white solid.
[0217] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.63-6.58 (m, 2H),
6.40-6.36 (m, 2H), 5.74-5.71 (m, 1H), 5.25 (br t, 1H, J=7.2 Hz),
4.23 (s, 2H), 3.95 (t, 2H, J=6.8 Hz), 3.74 (dd, 1H, J=2.9, 11.1
Hz), 3.55 (s, 3H), 3.01 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz),
2.52 (d, 1H, J=4.1 Hz), 2.45-1.82 (m, 6H), 1.77-1.74 (m, 5H) 1.68
(s, 3H) 1.26 (s, 3H), 1.15-1.01 (m, 4H).
EXAMPLE 18
Preparation of 6-O-(aniline)acetyl Fumagillol
[0218] 6-O-chloroacetyl fumagillol (157 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), to which aniline (0.04 mg) was added.
This mixture was added with K.sub.2CO.sub.3 (60.33 mg) and KI
(72.46 mg), and stirred at 70.degree. C. for 6 hours.
[0219] The resultant reaction was diluted with ethyl acetate (20
ml), and washed with saturated aqueous sodium hydrogen carbonate (5
ml) and saturated brine (5 ml). The organic layer was dried over
anhydrous magnesium sulfate and filtered. The obtained filtrate was
vacuum concentrated to give the residue, which was purified by
silica gel column chromatography (methanol:dichloromethane=1:10),
yielding 118 mg of the title compound as a white solid.
[0220] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.66-7.14 (m, 5H),
5.75-5.71 (m, 1H), 5.20 (br t, 1H, J=7.3 Hz), 4.18 (s, 2H), 3.72
(dd, 1H, J=2.8, 11.1 Hz), 3.45 (s, 3H), 3.00 (d, 1H, J=4.3 Hz),
2.59 (t, 1H, J=6.4 Hz), 2.58 (d, 1H, J=4.3 Hz), 2.41-1.81 (m, 6H),
1.78 (s, 3H) 1.66 (s, 3H), 1.26 (s, 3H), 1.17-1.04 (m, 1H).
EXAMPLES 19-38
[0221] The fumagillol derivatives represented by the formula I were
prepared in the same manner as in the above example 1, except that
aromatic compounds were changed. The results are given in Table 2,
below. TABLE-US-00005 TABLE 2 Ex. No. Fumagillol Derivative
Aromatic Compound 19 6-O-(4-chloroaniline)acetyl fumagillol
4-chloroaniline 20 6-O-(4-dimethylaminoaniline)acetyl fumagillol
4-dimethylaminoaniline 21 6-O-(4-hydroxyaniline)acetyl fumagillol
4-hydroxyaniline 22 6-O-(4-aminoaniline)acetyl fumagillol
4-aminoaniline 23 6-O-(3,4-methylenedioxyaniline)acetyl
3,4-methylenedioxyaniline fumagillol 24 6-O-(4-nitroaniline)acetyl
fumagillol 4-nitroaniline 25 6-0-(2,3,4-trimethoxyaniline)acetyl
2,3,4-trimethoxyaniline fumagillol 26
6-0-(4-acetoxy-3,5-dimethoxyaniline)acetyl
4-acetoxy-3,5-dimethoxyaniline fumagillol 27
6-0-(3,4-dimethoxy-4-hydroxyaniline)acetyl
3,4-dimethoxy-4-hydroxyaniline fumagillol 28
6-O-(4-dimethylaminoethoxyaniline)acetyl
4-dimethylaminoethoxyaniline fumagillol 29 6-0-(4-ethylamino)acetyl
fumagillol 4-ethylamino 30 6-0-(4-ethylaminoaniline)acetyl
fumagillol 4-ethylaminoaniline 31 6-O-(3-dimethylaminomethyl-4-
3-dimethylaminomethyl-4- methoxyaniline)acetyl fumagillol
methoxyaniline 32 6-O-(4-trifluoromethylaniline)acetyl
4-trifluoromethylaniline fumagillol 33 6-O-(4-acetoxyaniline)acetyl
fumagillol 4-acetoxyaniline 34 6-O-(4-cyanoaniline)acetyl
fumagillol 4-cyanoaniline 35 6-O-(4-hydroxyethoxyaniline)acetyl
fumagillol 4-hydroxyethoxyaniline 36
6-O-(5-amino-2-methoxypyridine)acetyl 5-amino-2-methoxypyridine
fumagillol 37 6-O-(5-methoxypyrimidine-2-amino)acetyl
5-methoxypyrimidine-2-amino fumagillol 38
6-O-(3-methoxy-6-aminopyridazine)acetyl 3-methoxy-6-aminopyridazine
fumagillol
[0222] Each of the fumagillol derivatives, obtained from the above
examples 1 and 2, was treated with an acid, or reacted with a salt
in the presence of an acid catalyst, to perform an oxirane
ring-opening reaction.
EXAMPLE 39
Preparation of
4-((4-methoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-me-
thoxy-1-chloromethyl-1-cyclohexanol
[0223] 6-O-(4-methoxyaniline)acetyl fumagillol (100 mg), obtained
from the above example 1, was dissolved in tetrahydrofuran (10 ml),
to which chlorolithium (48 mg) and acetic acid (0.12 ml) were
added. This mixture was stirred at 30.degree. C. for 36 hours. The
resultant reaction was added with water (10 ml) and ethyl acetate
(100 ml). The organic layer was separated, washed with saturated
brine (10 ml), dried over anhydrous magnesium sulfate and filtered,
followed by distilling off the solvent under reduced pressure.
Then, thusly obtained residue was purified by silica gel column
chromatography (ethyl acetate:n-hexane=1:2), to give 85 mg of the
title compound as a white solid.
[0224] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.57 (s, 2H), 5.70-5.73
(m, 1H), 5.19 (br t, 1H, J=7.3 Hz), 4.21 (s, 2H), 3.86 (3s, 9H),
3.72 (dd, 1H, J=2.6, 11.1 Hz), 3.45 (s, 3H), 3.01 (d, 1H, J=4.2
Hz), 2.56 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.2 Hz), 2.43-1.83 (m,
6H), 1.78 (s, 3H) 1.63 (s, 3H) 1.25 (s, 3H) 1.19-1.03 (m, 1H)
EXAMPLE 40
Preparation of
4-((3,4,5-trimethoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexeny-
l)-3-methoxy-1-chloromethyl-1-cyclohexanol
[0225] 6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol (100 mg),
obtained from the above example 2, in tetrahydrofuran (10 ml), was
added with hydrochloric acid (0.14 ml) and stirred for 32 hours.
This mixture was added with water (10 ml) and ethyl acetate (100
ml). The organic layer was separated, washed with saturated brine
(10 ml), dried over anhydrous magnesium sulfate and filtered. Then,
the solvent was distilled off under reduced pressure, to give the
residue, which was purified by silica gel column chromatography
(ethyl acetate:n-hexane=1:2), yielding 72 mg of the title compound
as a white solid.
[0226] .sup.1H-NMR (CDCl.sub.3) .delta.: 6.54 (s, 2H), 5.73-5.73
(m, 1H), 5.21 (br t, 1H, J=7.3 Hz), 4.21 (s, 2H), 3.89 (3s, 9H),
3.72 (dd, 1H, J=2.6, 11.1 Hz), 3.44 (s, 3H), 3.01 (d, 1H, J=4.2
Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.2 Hz), 2.43-1.83 (m,
6H), 1.75 (s, 3H) 1.67 (s, 3H) 1.23 (s, 3H) 1.15-1.04 (m, 1H).
EXAMPLE 41
Preparation of 6-O-(ethylamino)acetyl Fumagillol
[0227] 6-O-chloroacetyl fumagillol (130 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with ethylamine (16 mg) and stirred
at room temperature for 5 hours. The reaction was diluted with
ethyl acetate (20 ml) and washed with saturated aqueous sodium
hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic
layer was dried over anhydrous magnesium sulfate and filtered. The
filtrate was vacuum concentrated to give the residue, which was
purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 84 mg of the title
compound as a colorless oil.
[0228] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.72-5.70 (m, 1H), 5.21
(br t, 1H, J=7.2 Hz), 3.67 (dd, 1H, J=2.8, 11.1 Hz), 3.58-3.39 (m,
5H), 3.48 (s, 3H), 3.00 (d, 1H, J=4.3 Hz), 2.58 (t, 1H, J=6.4 Hz),
2.54 (d, 1H, J=4.3 Hz), 2.50 (q, 2H, J=11.0 Hz), 2.41-1.81 (m, 9H),
1.73 (s, 3H), 1.66 (s, 3H), 1.25 (s, 3H), 1.18-1.05 (m, 4H), 1.00
(t, 3H, J=11.0 Hz).
EXAMPLE 42
Preparation of 6-O-(isopropylamino)acetyl Fumagillol
[0229] 6-O-chloroacetyl fumagillol (134 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with isopropylamine (22 mg) and
stirred at room temperature for 5 hours. The reaction was diluted
with ethyl acetate (20 ml) and washed with saturated aqueous sodium
hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic
layer was dried over anhydrous magnesium sulfate and filtered. The
filtrate was vacuum concentrated to give the residue, which was
purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 93 mg of the title
compound as a colorless oil.
[0230] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.73-5.71 (m, 1H), 5.19
(br t, 1H, J=7.2 Hz), 3.65 (dd, 1H, J=2.8, 11.1 Hz), 3.56-3.37 (m,
5H), 3.47 (s, 3H), 3.02 (d, 1H, J=4.2 Hz), 2.59 (t, 1H, J=6.4 Hz),
2.55 (d, 1H, J=4.2 Hz), 2.50 (q, 1H, J=11.2 Hz), 2.44-1.82 (m, 9H),
1.72 (s, 3H), 1.64 (s, 3H), 1.23 (s, 3H), 1.13-1.05 (m, 7H), 1.01
(d, 1H, J=11.2 Hz).
EXAMPLE 43
Preparation of 6-O-(propylamino)acetyl Fumagillol
[0231] 6-O-chloroacetyl fumagillol (131 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with propylamine (22 mg) and
stirred at room temperature for 8 hours. The reaction was diluted
with ethyl acetate (20 ml) and washed with saturated aqueous sodium
hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic
layer was dried over anhydrous magnesium sulfate and filtered. The
filtrate was vacuum concentrated to give the residue, which was
purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 98 mg of the title
compound as a colorless oil.
[0232] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.72-5.70 (m, 1H), 5.22
(br t, 1H, J=7.2 Hz), 3.65 (dd, 1H, J=2.8, 11.1 Hz), 3.59-3.40 (m,
5H), 3.46 (s, 3H), 3.00 (d, 1H, J=4.4 Hz), 2.56 (t, 1H, J=6.4 Hz),
2.55 (d, 1H, J=4.4 Hz), 2.51 (t, 2H, J=11.0 Hz), 2.40-1.79 (m, 9H),
1.75 (s, 3H), 1.67 (s, 3H), 1.24 (s, 3H), 1.20-1.05 (m, 6H).
EXAMPLE 44
Preparation of 6-O-(1-butylamino)acetyl Fumagillol
[0233] 6-O-chloroacetyl fumagillol (128 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with 1-butylamine (26 mg) and
stirred at room temperature for 5 hours. The reaction was diluted
with ethyl acetate (20 ml) and washed with saturated aqueous sodium
hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic
layer was dried over anhydrous magnesium sulfate and filtered. The
filtrate was vacuum concentrated to give the residue, which was
purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 102 mg of the title
compound as a colorless oil.
[0234] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.73-5.71 (m, 1H), 5.21
(br t, 1H, J=7.2 Hz), 3.66 (dd, 1H, J=2.8, 11.1 Hz), 3.59-3.40 (m,
5H), 3.46 (s, 3H), 3.00 (d, 1H, J=4.3 Hz), 2.57 (t, 1H, J=6.3 Hz),
2.54 (d, 1H, J=4.3 Hz), 2.51 (t, 2H, J=11.0 Hz), 2.40-1.79 (m, 9H),
1.76 (s, 3H), 1.69 (s, 3H), 1.25 (s, 3H), 1.21-1.00 (m, 8H).
EXAMPLE 46
Preparation of 6-O-(2-methyl-butylamino)acetyl Fumagillol
[0235] 6-O-chloroacetyl fumagillol (130 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with 2-methyl-butylamine (32 mg)
and stirred at room temperature for 7 hours. The reaction was
diluted with ethyl acetate (20 ml) and washed with saturated
aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5
ml). The organic layer was dried over anhydrous magnesium sulfate
and filtered. The filtrate was vacuum concentrated to give the
residue, which was purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 114 mg of the title
compound as a colorless oil.
[0236] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.74-5.72 (m, 1H), 5.20
(br t, 1H, J=7.1 Hz), 3.67 (dd, 1H, J=2.8, 11.1 Hz), 3.60-3.40 (m,
5H), 3.47 (s, 3H), 3.01 (d, 1H, J=4.3 Hz), 2.56 (t, 1H, J=6.3 Hz),
2.53 (d, 1H, J=4.3 Hz), 2.50 (t, 2H, J=11.2 Hz), 2.40-1.77 (m, 9H),
1.75 (s, 3H), 1.69 (s, 3H), 1.26 (s, 3H), 1.21-0.95 (m, 10H).
EXAMPLE 47
Preparation of 6-O-(2,2-dimethyl-propylamino)acetyl Fumagillol
[0237] 6-O-chloroacetyl fumagillol (130 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with 2,2-dimethyl-propylamine (32
mg) and stirred at room temperature for 10 hours. The reaction was
diluted with ethyl acetate (20 ml) and washed with saturated
aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5
ml). The organic layer was dried over anhydrous magnesium sulfate
and filtered. The filtrate was vacuum concentrated to give the
residue, which was purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 103 mg of the title
compound as a colorless oil.
[0238] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.73-5.70 (m, 1H), 5.20
(br t, 1H, J=7.2 Hz), 3.67 (dd, 1H, J=2.9, 11.1 Hz), 3.57-3.36 (m,
5H), 3.46 (s, 3H), 3.00 (d, 1H, J=4.1 Hz), 2.60 (t, 1H, J=6.4 Hz),
2.55 (d, 1H, J=4.1 Hz), 2.45-1.80 (m, 10H), 1.71 (s, 3H), 1.66 (s,
3H), 1.23 (s, 3H), 1.01 (s, 9H).
EXAMPLE 50
Preparation of 6-O-(1-ethyl-propylamino)acetyl Fumagillol
[0239] 6-O-chloroacetyl fumagillol (130 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with 1-ethyl-propylamine (32 mg)
and stirred at room temperature for 6 hours. The reaction was
diluted with ethyl acetate (20 ml) and washed with saturated
aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5
ml). The organic layer was dried over anhydrous magnesium sulfate
and filtered. The filtrate was vacuum concentrated to give the
residue, which was purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 99 mg of the title
compound as a colorless oil.
[0240] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.73-5.71 (m, 1H), 5.19
(br t, 1H, J=7.1 Hz), 3.68 (dd, 1H, J=2.7, 11.1 Hz), 3.57-3.35 (m,
5H), 3.46 (s, 3H), 3.01 (d, 1H, J=4.2 Hz), 2.58 (t, 1H, J=6.4 Hz),
2.54 (d, 1H, J=4.2 Hz), 2.52 (t, 1H, J=11.0 Hz), 2.46-1.80 (m, 9H),
1.74 (s, 3H), 1.65 (s, 3H), 1.31-1.00 (m, 14H), 1.21 (s, 3H).
EXAMPLE 54
Preparation of 6-O-(1-isopropyl-2-methyl-propylamino)acetyl
Fumagillol
[0241] 6-O-chloroacetyl fumagillol (135 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with
1-isopropyl-2-methyl-propylamine (43 mg) and stirred at room
temperature for 10 hours. The reaction was diluted with ethyl
acetate (20 ml) and washed with saturated aqueous sodium hydrogen
carbonate (5 ml) and saturated brine (5 ml). The organic layer was
dried over anhydrous magnesium sulfate and filtered. The filtrate
was vacuum concentrated to give the residue, which was purified by
silica gel column chromatography (methanol:dichloromethane=1:10),
yielding 97 mg of the title compound as a colorless oil.
[0242] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.73-5.70 (m, 1H), 5.19
(br t, 1H, J=7.0 Hz), 3.65 (dd, 1H, J=2.6, 11.1 Hz), 3.56-3.37 (m,
5H), 3.47 (s, 3H), 3.01 (d, 1H, J=4.3 Hz), 2.60 (t, 1H, J=6.4 Hz),
2.57 (d, 1H, J=4.3 Hz), 2.52 (d, 1H, J=11.2 Hz), 2.47-1.81 (m,
12H), 1.73 (s, 3H), 1.67 (s, 3H), 1.25 (s, 3H), 0.99 (d, 12H,
J=10.8 Hz).
EXAMPLE 55
Preparation of 6-O-(3-methylbutylamino)acetyl Fumagillol
[0243] 6-O-chloroacetyl fumagillol (134 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with 3-methylbutylamine (48 mg) and
stirred at room temperature for 5 hours. The reaction was diluted
with ethyl acetate (20 ml) and washed with saturated aqueous sodium
hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic
layer was dried over anhydrous magnesium sulfate and filtered. The
filtrate was vacuum concentrated to give the residue, which was
purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 111 mg of the title
compound as a colorless oil.
[0244] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.73-5.71 (m, 1H), 5.17
(br t, 1H, J=7.0 Hz), 3.66 (dd, 1H, J=2.8, 11.1 Hz), 3.57-3.36 (m,
5H), 3.49 (s, 3H), 3.01 (d, 1H, J=4.2 Hz), 2.60 (t, 1H, J=6.4 Hz),
2.57 (d, 1H, J=4.2 Hz), 2.54-2.52 (m, 1H), 2.46-1.79 (m, 13H), 1.74
(s, 3H), 1.65 (s, 3H), 1.23 (s, 3H), 1.03-0.98 (m, 13H).
EXAMPLE 56
Preparation of 6-O-(2-methyl-allylamino)acetyl Fumagillol
[0245] 6-O-chloroacetyl fumagillol (129 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with 2-methyl-allylamine (26 mg),
and stirred at room temperature for 5 hours. The reaction was
diluted with ethyl acetate (20 ml) and washed with saturated
aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5
ml). The organic layer was dried over anhydrous magnesium sulfate
and filtered. The filtrate was vacuum concentrated to give the
residue, which was purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 105 mg of the title
compound as a colorless oil.
[0246] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.74-5.71 (m, 1H),
5.52-5.48 (m, 2H), 5.21 (br t, 1H, J=7.2 Hz), 3.67 (dd, 1H, J=2.8,
11.1 Hz), 3.59-3.41 (m, 5H), 3.48 (s, 3H), 3.11 (br s, 2H), 3.03
(d, 1H, J=4.3 Hz), 2.57 (t, 1H, J=6.3 Hz), 2.55 (d, 1H, J=4.3 Hz),
2.40-1.77 (m, 13H), 1.79 (s, 3H), 1.74 (s, 3H), 1.65 (s, 3H), 1.22
(s, 3H)
EXAMPLE 63
Preparation of 6-O-(cyclopropylamino)acetyl fumagillol
[0247] 6-O-chloroacetyl fumagillol (51.4 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with cyclopropylamine (8 mg) and
stirred at room temperature for 8 hours. The reaction was diluted
with ethyl acetate (10 ml) and washed with saturated aqueous sodium
hydrogen carbonate (3 ml) and saturated brine (3 ml). The organic
layer was dried over anhydrous magnesium sulfate and filtered. The
filtrate was vacuum concentrated to give the residue, which was
purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 38 mg of the title
compound as a colorless oil.
[0248] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.74-5.71 (m, 1H), 5.21
(br t, 1H, J=7.0 Hz), 3.64 (dd, 1H, J=2.7, 11.1 Hz), 3.57-3.39 (m,
5H), 3.48 (s, 3H), 3.00 (d, 1H, J=4.3 Hz), 2.62 (t, 1H, J=6.4 Hz),
2.56 (d, 1H, J=4.3 Hz), 2.47-1.81 (m, 7H), 1.71 (s, 3H), 1.66 (s,
3H), 1.31-1.01 (m, 5H), 1.21 (s, 3H), 0.98-0.87 (m, 1H), 0.55-0.41
(m, 2H).
EXAMPLE 64
Preparation of 6-O-(cyclobutylamino)acetyl Fumagillol
[0249] 6-O-chloroacetyl fumagillol (50.3 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with cyclobutylamine (10 mg) and
stirred at room temperature for 6 hours. The reaction was diluted
with ethyl acetate (10 ml) and washed with saturated aqueous sodium
hydrogen carbonate (3 ml) and saturated brine (3 ml). The organic
layer was dried over anhydrous magnesium sulfate and filtered. The
filtrate was vacuum concentrated to give the residue, which was
purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 40 mg of the title
compound as a colorless oil.
[0250] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.77-5.70 (m, 1H), 5.20
(br t, 1H, J=7.1 Hz), 3.64 (dd, 1H, J=2.8, 11.1 Hz), 3.56-3.34 (m,
6H), 3.46 (s, 3H), 3.02 (d, 1H, J=4.4 Hz), 2.61 (t, 1H, J=6.4 Hz),
2.56 (d, 1H, J=4.4 Hz), 2.48-2.37 (m, 1H), 2.21-1.60 (m, 17H), 1.74
(s, 3H), 1.64 (s, 3H), 2.22-1.01 (m, 4H), 1.19 (s, 3H).
EXAMPLE 65
Preparation of 6-O-(cyclopentylamino)acetyl Fumagillol
[0251] 6-O-chloroacetyl fumagillol (51.0 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with cyclopentylamine (12 mg) and
stirred at room temperature for 6 hours. The reaction was diluted
with ethyl acetate (10 ml) and washed with saturated aqueous sodium
hydrogen carbonate (3 ml) and saturated brine (3 ml). The organic
layer was dried over anhydrous magnesium sulfate and filtered. The
filtrate was vacuum concentrated to give the residue, which was
purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 36 mg of the title
compound as colorless oil.
[0252] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.73-5.67 (m, 1H), 5.22
(br t, 1H, J=7.1 Hz), 3.62 (dd, 1H, J=2.8, 11.1 Hz), 3.57-3.36 (m,
5H), 3.44 (s, 3H), 3.21-3.10 (m, 1H), 2.99 (d, 1H, J=4.2 Hz), 2.60
(t, 1H, J=6.7 Hz), 2.55 (d, 1H, J=4.2 Hz), 2.44-2.35 (m, 1H),
2.21-1.60 (m, 15H), 1.74 (s, 3H), 1.64 (s, 3H), 1.56-1.43 (m, 2H),
1.39-1.31 (m, 2H), 1.22-1.01 (m, 4H), 1.20 (s, 3H).
EXAMPLE 66
Preparation of 6-O-(cyclohexylamino)acetyl Fumagillol
[0253] 6-O-chloroacetyl fumagillol (53.5 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with cyclohexylamine (15 mg) and
stirred at room temperature for 6 hours. The reaction was diluted
with ethyl acetate (10 ml) and washed with saturated aqueous sodium
hydrogen carbonate (3 ml) and saturated brine (3 ml). The organic
layer was dried over anhydrous magnesium sulfate and filtered. The
filtrate was vacuum concentrated to give the residue, which was
purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 42 mg of the title
compound as a colorless oil.
[0254] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.75-5.68 (m, 1H), 5.19
(br t, 1H, J=7.3 Hz), 3.64 (dd, 1H, J=2.8, 11.0 Hz), 3.57-3.34 (m,
6H), 3.45 (s, 3H), 3.00 (d, 1H, J=4.3 Hz), 2.61 (t, 1H, J=6.7 Hz),
2.55 (d, 1H, J=4.3 Hz), 2.46-2.33 (m, 2H), 2.23-1.57 (m, 14H), 1.76
(s, 3H), 1.63 (s, 3H), 1.36-1.02 (m, 10H), 1.20 (s, 3H).
EXAMPLE 67
Preparation of 6-O-(4-tert-butyl-cyclohexylamino)acetyl
Fumagillol
[0255] 6-O-chloroacetyl fumagillol (128 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with 4-tert-butyl-cyclohexylamine
(55 mg) and stirred at room temperature for 6 hours. The reaction
was diluted with ethyl acetate (20 ml) and washed with saturated
aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5
ml). The organic layer was dried over anhydrous magnesium sulfate
and filtered. The filtrate was vacuum concentrated to give the
residue, which was purified by silica gel column chromatography
(methanol:dichloromethane=1:10), yielding 104 mg of the title
compound as a colorless oil.
[0256] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.75-5.68 (m, 1H), 5.19
(br t, 1H, J=7.4 Hz), 3.65 (dd, 1H, J=2.7, 11.3 Hz), 3.56-3.35 (m,
6H), 3.46 (s, 3H), 3.03 (d, 1H, J=4.4 Hz), 2.61 (t, 1H, J=6.7 Hz),
2.56 (d, 1H, J=4.4 Hz), 2.46-2.33 (m, 2H), 2.23-1.72 (m, 10H), 1.78
(s, 3H), 1.65 (s, 3H), 1.36-1.19 (m, 4H), 1.21 (s, 3H), 1.16-0.94
(m, 6H), 0.82 (s, 9H)
EXAMPLE 68
Preparation of 6-O-(2-dimethylamino-1-methylethylamino)acetyl
Fumagillol
[0257] 6-O-chloroacetyl fumagillol (132 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with
2-dimethylamino-1-methylethylamine (38 mg) and stirred at room
temperature for 6 hours. The reaction was diluted with ethyl
acetate (20 ml) and washed with saturated aqueous sodium hydrogen
carbonate (5 ml) and saturated brine (5 ml). The organic layer was
dried over anhydrous magnesium sulfate and filtered. The filtrate
was vacuum concentrated to give the residue, which was purified by
silica gel column chromatography (methanol:dichloromethane=1:5),
yielding 104 mg of the title compound as a colorless oil.
[0258] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.74-5.71 (m, 1H), 5.19
(br t, 1H, J=7.0 Hz), 3.68 (dd, 1H, J=2.7, 11.1 Hz), 3.56-3.37 (m,
5H), 3.49 (s, 3H), 3.03 (d, 1H, J=4.4 Hz), 2.91-2.88 (m, 1H), 2.65
(d, 2H, J=7.8 Hz), 2.61 (t, 1H, J=6.4 Hz), 2.56 (d, 1H, J=4.4 Hz),
2.50 (s, 6H), 2.45-1.76 (m, 10H), 1.74 (s, 3H), 1.66 (s, 3H), 1.25
(s, 3H), 1.04 (d, 3H, J=8.1 Hz)
EXAMPLE 69
Preparation of 6-O-(2-dimethylamino-propylamino)acetyl
Fumagillol
[0259] 6-O-chloroacetyl fumagillol (126 mg), obtained from the
above step 1 of the above example 1, was dissolved in
dimethylformamide (1 ml), added with 2-dimethyl-propylamine (36 mg)
and stirred at room temperature for 7 hours. The reaction was
diluted with ethyl acetate (20 ml) and washed with saturated
aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5
ml). The organic layer was dried over anhydrous magnesium sulfate
and filtered. The filtrate was vacuum concentrated to give the
residue, which was purified by silica gel column chromatography
(methanol:dichloromethane=1:5), yielding 118 mg of the title
compound as a colorless oil.
[0260] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.75-5.72 (m, 1H), 5.20
(br t, 1H, J=7.0 Hz), 3.66 (dd, 1H, J=2.8, 11.1 Hz), 3.57-3.38 (m,
5H), 3.45 (s, 3H), 3.17-3.14 (m, 1H), 3.01 (d, 1H, J=4.2 Hz), 2.81
(d, 2H, J=8.4 Hz), 2.62 (t, 1H, J=6.4 Hz), 2.57 (d, 1H, J=4.2 Hz),
2.47 (s, 6H), 2.44-1.78 (m, 10H), 1.73 (s, 3H), 1.64 (s, 3H), 1.24
(s, 3H), 1.02 (d, 3H, J=8.6 Hz).
EXAMPLES 45, 48, 49, 51-53, 57-62 and 70-77
[0261] The fumagillol derivatives, as represented by the formula I,
were prepared in the same manner as in the above example 1, except
that amine compounds were changed. The results are presented in the
following Table 3. TABLE-US-00006 TABLE 3 Ex. No. Fumagillol
Derivative Amine Compound 45 6-O-(sec-butylamino)acetyl fumagillol
sec-butylamine 48 6-O-(pentylamino)acetyl fumagillol Pentylamine 49
6-O-(1-methyl-butylamino)acetyl 1-methyl-butylamine fumagillol 51
6-O-(1-methyl-pentylamino)acetyl 1-methyl-pentylamine fumagillol 52
6-0-(1,2-dimethylbutylamino)acetyl fumagillol
1,2-dimethylbutylamine 53 6-O-(1,2,2-trimethylpropylamino)acetyl
fumagillol 1,2,2-trimethylpropylamine 57 6-O-(4-methyl-hepta-2,4-
4-methyl-hepta-2,4- dienylamino)acetyl fumagillol dienylamine 58
6-O-(1,5-dimethyl-4-hexenylamino)acetyl 1,5-dimethyl-4- fumagillol
hexenylamine 59 6-O-(1,1-dimethyl-2-propinylamino)acetyl
1,1-dimethyl-2- fumagillol propinylamine 60
6-O-(prop-2-enylamino)acetyl fumagillol prop-2-enylamine 61
6-O-(2-bromoethylamino)acetyl fumagillol 2-bromoethylamine 62
6-O-(chloroethynylamino)acetyl chloroethynylamine fumagillol 70
6-0-(2-methoxy-2-methyl- 2-methoxy-2-methyl- propylamino)acetyl
fumagillol propylamine 71 6-O-(2-oxo-propylamino)acetyl fumagillol
2-oxo-propylamine 72 6-O-(1,1-dimethyl-3-oxobutylamino)acetyl
1,1-dimethyl-3- fumagillol oxobutylamino 73
6-O-(ethyl-2-aminoacetate)acetyl ethyl-2-aminoacetate fumagillol 74
6-O-(alaninemethylesteramino)acetyl Alaninemethylesteramine
fumagillol 75 6-O-(methyl-2-amino-3,3- methyl-2-amino-3,3-
dimethylbutanoate)acetyl fumagillol dimethylbutanoate 76
6-O-(allylglycinemethylester)acetyl Allylglycinemethylester
fumagillol 77 6-O-(2,2-dimethoxyethylamino)acetyl
2,2-dimethoxyethylamine fumagillol
[0262] Each of the fumagillol derivatives obtained from the above
examples 63 and 64 was treated with the acid, or reacted with the
salt in the presence of the acid catalyst, to perform the oxirane
ring-opening reaction.
EXAMPLE 78
Preparation of
4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-me-
thoxy-1-chloromethyl-1-cyclohexanol
[0263] 6-O-(cyclopropylamino)acetyl fumagillol (100 mg), obtained
from the above example 63, in tetrahydrofuran (10 ml), was added
with hydrochloric acid (0.14 ml) and stirred for 32 hours. The
reaction was added with water (10 ml) and ethyl acetate (100 ml).
The organic layer was separated, washed with saturated brine (10
ml), dried over anhydrous magnesium sulfate and filtered. Then, the
solvent was distilled off under reduced pressure to give the
residue, which was purified by silica gel column chromatography
(ethyl acetate:n-hexane=1:2), yielding 54 mg of the title compound
as a white solid.
[0264] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.77-5.70 (m, 1H), 5.20
(br t, 1H, J=7.1 Hz), 3.64 (dd, 1H, J=2.8, 11.1 Hz), 3.56-3.34 (m,
6H), 3.49 (s, 3H), 3.02 (d, 1H, J=4.4 Hz), 2.61 (t, 1H, J=6.4 Hz),
2.56 (d, 1H, J=4.4 Hz), 2.48-2.37 (m, 1H), 2.21-1.60 (m, 17H), 1.74
(s, 3H), 1.64 (s, 3H), 2.22-1.01 (m, 4H), 1.19 (s, 3H)
EXAMPLE 79
Preparation of
4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-met-
hoxy-1-chloromethyl-1-cyclohexanol
[0265] 6-O-(cyclobutylamino)acetyl fumagillol (100 mg), obtained
from the above example 64, in tetrahydrofuran (10 ml) was added
with chlorolithium (48 mg) and acetic acid (0.12 ml), and stirred
at 30.degree. C. for 36 hours. The reaction was added with water
(10 ml) and ethyl acetate (100 ml). The organic layer was
separated, washed with saturated brine (10 ml), dried over
anhydrous magnesium sulfate and filtered. Then, the solvent was
distilled off under reduced pressure to give the residue, which was
purified by silica gel column chromatography (ethyl
acetate:n-hexane=1:2), yielding 49 mg of the title compound as a
white solid.
[0266] .sup.1H-NMR (CDCl.sub.3) .delta.: 5.77-5.70 (m, 1H), 5.20
(br t, 1H, J=7.1 Hz), 3.64 (dd, 1H, J=2.8, 11.1 Hz), 3.56-3.34 (m,
6H), 3.46 (s, 3H), 3.02 (d, 1H, J=4.4 Hz), 2.61 (t, 1H, J=6.4 Hz),
2.56 (d, 1H, J=4.4 Hz), 2.48-2.37 (m, 1H), 2.21-1.60 (m, 17H), 1.74
(s, 3H), 1.64 (s, 3H), 2.22-1.01 (m, 4H), 1.19 (s, 3H)
PREPARATION EXAMPLE 1
Preparation of Tablet
[0267] A tablet containing the fumagillol compound of the present
invention as an effective ingredient was prepared according to the
following processes.
[0268] The compound of the above example 1 was sieved, mixed with
lactose, starch and pregelatinized corn starch. To the mixture,
purified water was added in a suitable volume. The paste was
granulated, dried, mixed with magnesium stearate, and then
compressed, to obtain the tablet.
[0269] Such a tablet comprises the following components:
TABLE-US-00007 Compound of example 1 5.0 mg Lactose BP 150.0 mg
Starch BP 30.0 mg Pregelatinized corn starch BP 15.0 mg Magnesium
stearate 1.0 mg
PREPARATION EXAMPLE 2
Preparation of Capsule
[0270] A capsule containing the fumagillol compound of the present
invention as the effective ingredient was prepared as follows.
[0271] The compound of the example 1 was mixed with a predetermined
amount of a vehicle and magnesium state. Thusly obtained mixture
was filled in a gelatin capsule.
[0272] Such a capsule comprises the following components:
TABLE-US-00008 Compound of the example 1 5.0 mg Starch 1500 100.0
mg Magnesium sterate BP 1.0 mg
PREPARATION EXAMPLE 3
Preparation of Injection
[0273] An injection containing the fumagillol compound of the
present invention as the effective ingredient was prepared as
follows.
[0274] The compound of the example 1 was dissolved in a suitable
volume of saline for injection BP. The pH of the resultant solution
was controlled with dilute hydrochloric acid BP to be 3.5, and then
the solution volume was controlled with saline for injection BP.
The solution was filled in 5 ml type 1 ampule made of transparent
glass, and the top of ampule was fused for sealing. The solution
contained in the ampule was autoclaved at 120.degree. C. for at
least 15 minutes to be sterilized, giving the injection.
[0275] Such an injection comprises the following components:
TABLE-US-00009 Compound of example 1 100 .mu.g/ml Dilute
hydrochloric acid BP to be pH 3.5 Saline for injection BP maximal 1
ml
EXPERIMENTAL EXAMPLE 1
Inhibitory Effect of Fumagillol Derivative on Cell Growth
[0276] Using the HUVECs (human umbilical vein endothelial), the
effect of the fumagillol derivative of the present invention on
cell growth was evaluated.
[0277] The HUVECs were added to M199 medium supplemented with 20%
FBS (fetal bovine serum), 100 U/ml penicillin, 100 .mu.g/ml
streptomycin, 1.5 g/L sodium bicarbonate, 0.1 mg/ml endothelial
cell growth supplement (Sigma) and 0.1 mg/ml heparin (Sigma), after
which the cells were incubated in an incubator at 37.degree. C.
under 5% CO.sub.2. Cells were subcultured a maximum of 8 times
before being discarded.
[0278] In order to evaluate inhibitory activity of the fumagillin
derivative on growth of HUVECs, the inventive compound was
dissolved in DMSO and its concentration was adjusted from 10 mM to
1 mM. Cells were aliquotted to 96 well plates at a density of
2.times.10.sup.3 cells per well and incubated for about 12-24 hours
to be properly attached to the plate. Thereafter, the medium was
replaced with new medium. The cells were treated with the compound
obtained from each of the above examples at various concentration
ranges of from 10 .mu.M to 0.001 .mu.M, and cultured for 2-3 days,
followed by removing 100 .mu.l of the medium from each well.
[0279] Colorimetry was performed to determine the extent of cell
growth. The cells on each plate was added with 20 .mu.l of aqueous
one solution and then incubated at 37.degree. C. under 5% CO.sub.2
for 2 hours. Using a 96-well plate reader, absorption was measured
at 490 nm. The results are given in Table 4, below.
[0280] As such, a conventional TNP-470 having angiogenesis
inhibitory effect was used as a control. TABLE-US-00010 TABLE 4
Compound IC.sub.50 (.eta. g/ml) TNP-470 29 Ex. 1 0.0071 Ex. 2 0.15
Ex. 3 0.09 Ex. 4 0.08 Ex. 5 142 Ex. 6 19 Ex. 7 21 Ex. 8 42 Ex. 9
0.63 Ex. 10 0.06 Ex. 11 0.08 Ex. 12 0.07 Ex. 13 0.016 Ex. 14 14 Ex.
15 0.06 Ex. 16 0.17 Ex. 17 0.61 Ex. 18 17 Ex. 19 174 Ex. 20 162 Ex.
21 185 Ex. 22 179 Ex. 23 0.24 Ex. 24 181 Ex. 25 0.31 Ex. 26 179 Ex.
27 88 Ex. 28 102 Ex. 29 178 Ex. 30 0.09 Ex. 31 0.06 Ex. 32 128 Ex.
33 109 Ex. 34 98 Ex. 35 116 Ex. 36 0.021 Ex. 37 0.017 Ex. 38 0.019
Ex. 39 0.019 Ex. 40 0.18 Ex. 41 20 Ex. 42 12 Ex. 43 2400 Ex. 44
3200 Ex. 45 370 Ex. 46 2600 Ex. 47 16 Ex. 48 3000 Ex. 49 44 Ex. 50
24 Ex. 51 32000 Ex. 52 290 Ex. 53 162 Ex. 54 11 Ex. 55 17 Ex. 56 28
Ex. 57 420 Ex. 58 415 Ex. 59 174 Ex. 60 185 Ex. 61 2800 Ex. 62 340
Ex. 63 0.008 Ex. 64 0.07 Ex. 65 250 Ex. 66 0.6 Ex. 67 0.06 Ex. 68
240 Ex. 69 260 Ex. 70 178 Ex. 71 260 Ex. 72 330 Ex. 73 1200 Ex. 74
800 Ex. 75 2400 Ex. 76 1490 Ex. 77 330 Ex. 78 0.014 Ex. 79 0.037
Intermediate 2000
[0281] From the above Table 4, it can be seen that the inventive
compound exhibits superior inhibitory effect on cell proliferation,
compared to conventionally known fumagillin. In particular, the
compound in which R.sub.1 is aromatic is superior in angiogenesis
inhibitory effect to the compound in which R.sub.1 is aliphatic.
For instance, in the case where R.sub.1 is aromatic,
6-O-(4-methoxyaniline)acetyl fumagillol of the above example 1 has
excellent inhibitory effect, 2000 times greater than known TNP-470.
In the case where R.sub.1 is aliphatic,
6-O-(cyclopropylamino)acetyl fumagillol and
6-O-(4-(cyclobutylamino)acetyl fumagillol of the above examples 63
and 64, respectively, are 100-1000 times higher in inhibitory
effect on HUVEC, compared to TNP-470.
EXPERIMENTAL EXAMPLE 2
Acute Toxicity Test for Oral Administration of Fumagillol
Derivative Using Rats
[0282] To investigate acute toxicity of the compound of the formula
I, the following experiment was performed.
[0283] Using 6-week-old specific pathogen-free (SPF) Sprague-Dawley
rats, acute toxicity was tested. Each of the compounds obtained
from the above examples was suspended in 0.5% methylcelluose
solution, and orally administered once to every two rats
constituting each group in the dose of 1 g/kg/15 ml. After
administration, mortality, clinical symptoms and body weight of the
tested animals were observed. Hematological and blood-biochemical
tests were carried out. The animals were dissected and abnormal
conditions of pleural cavity and abdominal cavity were observed
with the naked eye. As the test result, there were no specifically
abnormal symptoms in any of the tested animals and no mortality. In
addition, toxicity indicators were not observed in the body weight,
hematological and blood-biochemical tests, or by dissection.
[0284] The present compounds did not show toxicity up to the
amounts of 2 g/kg for all rats, and the minimal lethal dose
(LD.sub.50) of each compound in case of oral administration was 2
g/kg or more, thus the present compound was evaluated as a safe
compound.
EXPERIMENTAL EXAMPLE 3
[0285] Eight-week-old athymic Nu/Nu mice (Charles River
Laboratories, Wilmington, Mass.) were inoculated with SNU-398 human
hepatoma cells. The cells were reconstituted at 6.times.10.sup.6
cells/ml in 20% saline and 80% phenol red-free Matrigel. Cells
(0.25 ml; 1.5 million cells) were injected subcutaneously in the
left upper abdominal quadrant. After postimmunization day 9, nude
mice bearing a tumor of approximately 180 mm.sup.2 were
subcutaneously administered MetAP2 inhibitors (50 mg/kg; n=5 per
each inhibitor) twice daily and an equivalent volume of vehicle was
administered to control mice (n=5). Tumor measurements were made
using Vernier calipers and tumor volumes were calculated using the
ellipsoid formula: length.times.width.times.height.times.0.52.
[0286] The present compounds showed that significant suppression of
tumor growth was observed compared with that of mice treated with
vehicle alone (FIG. 1). The size of tumor cells was significantly
different in xenografted nude mice treated with buffer alone or
treated with Ex. 1 and Ex. 64 (See series of photographs of FIG.
2). Furthermore, the tumor suppressive efficacies of Ex. 1, Ex. 11,
Ex. 63 and Ex. 64 were superior to that of TNP-470. This group of
MetAP2 inhibitors may therefore provide a novel hepatoma
therapeutic regime (FIG. 1).
INDUSTRIAL APPLICABILITY
[0287] As described hereinbefore, the compound of the formula I of
the present invention is advantageous in light of excellent
angiogenesis inhibitory effect and low toxicity, and is usefully
applicable as an angiogenesis inhibitory agent. As well, the
inventive compound can inhibit cancer metastasis and treat cancer,
rheumatic arthritis, psoriasis and diabetic retinopathy, which are
associated with angiogenesis regarded as a pathogenic
phenomenon.
[0288] The present invention has been described in an illustrative
manner, and it is to be understood that the terminology used is
intended to be in the nature of description rather than of
limitation. Many modifications and variations of the present
invention are possible in light of the above teachings. Therefore,
it is to be understood that within the scope of the appended
claims, the invention may be practiced otherwise than as
specifically described.
* * * * *