U.S. patent application number 10/515647 was filed with the patent office on 2006-01-12 for novel physiologically active substances.
This patent application is currently assigned to MERCIAN CORPORATION. Invention is credited to Yoshio Fukuda, Regina Mikie Kanada, Yoshihiko Kotake, Mitsuo Nagai, Takashi Nakashima, Jun Niijima, Toshio Tsuchida, Masahi Yoshida.
Application Number | 20060009439 10/515647 |
Document ID | / |
Family ID | 29587471 |
Filed Date | 2006-01-12 |
United States Patent
Application |
20060009439 |
Kind Code |
A1 |
Kotake; Yoshihiko ; et
al. |
January 12, 2006 |
Novel physiologically active substances
Abstract
The present invention relates to a compound represented by the
formula (I): ##STR1## (wherein, R.sup.3, R.sup.6, R.sup.7 and
R.sup.21 are the same as or different from one another and each
represents a hydroxyl group etc.), a pharmacologically acceptable
salt thereof or a hydrate of them. The compound (I) of the present
invention suppresses angiogenesis, in particular, suppresses VEGF
production in a hypoxic condition and is useful as a therapeutic
agent for treating solid cancer.
Inventors: |
Kotake; Yoshihiko; (Ibaraki,
JP) ; Niijima; Jun; (Ibaraki, JP) ; Fukuda;
Yoshio; (Ibaraki, JP) ; Nagai; Mitsuo;
(Ibaraki, JP) ; Kanada; Regina Mikie; (Ibaraki,
JP) ; Nakashima; Takashi; (Shizuoka, JP) ;
Yoshida; Masahi; (Shizuoka, JP) ; Tsuchida;
Toshio; (Shizuoka, JP) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
MERCIAN CORPORATION
5-8, Kyobashi 1-chome, Chou-ku
Tokyo
JP
Eisai Co., Ltd.
6-10, Koishikawa 4-chome, Bunkyo-ku
Tokyo
JP
|
Family ID: |
29587471 |
Appl. No.: |
10/515647 |
Filed: |
May 29, 2003 |
PCT Filed: |
May 29, 2003 |
PCT NO: |
PCT/JP03/06779 |
371 Date: |
July 20, 2005 |
Current U.S.
Class: |
514/183 |
Current CPC
Class: |
A61P 35/04 20180101;
A61P 27/02 20180101; A61P 35/02 20180101; A61K 31/4523 20130101;
A61K 31/366 20130101; A61P 19/02 20180101; A61K 31/4427 20130101;
A61K 31/4025 20130101; C07D 407/06 20130101; A61P 43/00 20180101;
A61K 31/336 20130101; A61K 31/5377 20130101; A61P 9/10 20180101;
A61P 9/00 20180101; A61P 35/00 20180101; A61K 31/454 20130101; A61P
17/06 20180101; A61K 31/551 20130101; A61K 31/4545 20130101; A61K
31/496 20130101; A61P 29/00 20180101 |
Class at
Publication: |
514/183 |
International
Class: |
A61K 31/33 20060101
A61K031/33 |
Foreign Application Data
Date |
Code |
Application Number |
May 29, 2002 |
JP |
2002-155853 |
Jul 31, 2002 |
JP |
2002-223355 |
Mar 10, 2003 |
JP |
2003-63176 |
Claims
1. A compound represented by the formula (I): ##STR241## (in the
formula, R.sup.3, R.sup.6, R.sup.7 and R.sup.21 are the same as or
different from one another and each represents 1) a hydroxyl group
or an oxo group formed together with the carbon atom to which each
of R.sup.3, R.sup.6, R.sup.7 and R.sup.21 is bound, provided that
R.sup.6 is limited to hydroxyl group, 2) an optionally substituted
C.sub.1-22 alkoxy group, 3) an optionally substituted unsaturated
C.sub.2-22 alkoxy group, 4) an optionally substituted C.sub.7-22
aralkyloxy group, 5) an optionally substituted 5 to 14-membered
heteroaralkyloxy group, 6) RCO--O-- (wherein R represents a) a
hydrogen atom, b) an optionally substituted C.sub.1-22 alkyl group,
c) an optionally substituted unsaturated C.sub.2-22 alkyl group, d)
an optionally substituted C.sub.6-14 aryl group, e) an optionally
substituted 5 to 14-membered heteroaryl group, f) an optionally
substituted C.sub.7-22 aralkyl group, g) an optionally substituted
5 to 14-membered heteroaralkyl group, h) an optionally substituted
C.sub.1-22 alkoxy group, i) an optionally substituted unsaturated
C.sub.2-22 alkoxy group, j) an optionally substituted C.sub.6-14
aryloxy group or k) an optionally substituted 5 to 14-membered
heteroaryloxy group), 7) R.sup.S1R.sup.S2R.sup.S3SiO-- (wherein
R.sup.S1, R.sup.S2 and R.sup.S3 are the same as or different from
one another and each represents a) a C.sub.1-6 alkyl group or b) a
C.sub.6-14 aryl group), 8) a halogen atom, 9)
R.sup.N1R.sup.N2N--R.sup.M-- (wherein R.sup.M represents a) a
single bond, b) --CO--O--, c) --SO.sub.2--O--, d) --CS--O-- or e)
--CO--NR.sup.N3-- (wherein R.sup.N3 represents a hydrogen atom or
an optionally substituted C.sub.1-6 alkyl group), provided that
each of the leftmost bond in b) to e) is bound to the nitrogen
atom; and R.sup.N1 and R.sup.12 are the same as or different from
each other and each represents a) a hydrogen atom, b) an optionally
substituted C.sub.1-22 alkyl group, c) an optionally substituted
unsaturated C.sub.2-22 alkyl group, d) an optionally substituted
aliphatic C.sub.2-22 acyl group, e) an optionally substituted
aromatic C.sub.7-15 acyl group, f) an optionally substituted
C.sub.6-14 aryl group, g) an optionally substituted 5 to
14-membered heteroaryl group, h) an optionally substituted
C.sub.7-22 aralkyl group, i) an optionally substituted C.sub.1-22
alkylsulfonyl group, j) an optionally substituted C.sub.6-14
arylsulfonyl group, k) an optionally substituted 3 to 14-membered
non-aromatic heterocyclic group formed by R.sup.N1 and R.sup.N2
together with the nitrogen atom to which R.sup.N1 and R.sup.N2 are
bound, and the non-aromatic heterocyclic group may have
substituents, l) an optionally substituted 5 to 14-membered
heteroaralkyl group, m) an optionally substituted C.sub.3-14
cycloalkyl group or n) an optionally substituted 3 to 14-membered
non-aromatic heterocyclic group), 10) R.sup.N4 SO.sub.2--O--
(wherein R.sup.N4 represents a) an optionally substituted
C.sub.1-22 alkyl group, b) an optionally substituted C.sub.6-14
aryl group, c) an optionally substituted C.sub.1-22 alkoxy group,
d) an optionally substituted unsaturated C.sub.2-22 alkoxy group,
e) an optionally substituted C.sub.6-14 aryloxy group, f) an
optionally substituted 5 to 14-membered heteroaryloxy group, g) an
optionally substituted C.sub.7-22 aralkyloxy group or h) an
optionally substituted 5 to 14-membered heteroaralkyloxy group),
11) (R.sup.N5O).sub.2PO--(wherein R.sup.N5 represents a) an
optionally substituted C.sub.1-22 alkyl group, b) an optionally
substituted unsaturated C.sub.2-22 alkyl group, c) an optionally
substituted C.sub.6-14 aryl group, d) an optionally substituted 5
to 14-membered heteroaryl group, e) an optionally substituted
C.sub.7-22 aralkyl group or f) an optionally substituted 5 to
14-membered heteroaralkyl group), 12)
(R.sup.N1R.sup.N2N).sub.2PO--O-- (wherein R.sup.N1 and R.sup.N2
have the same meanings as defined above) or 13)
(R.sup.N1R.sup.N2N)(R.sup.N5O)PO--O-- (wherein R.sup.N1, R.sup.N2
and R.sup.N5 have the same meanings as defined above), provided
that a compound in which R.sup.3, R.sup.6, R.sup.7 and R.sup.21 are
all hydroxyl groups, and a compound in which R.sup.3, R.sup.6 and
R.sup.21 are all hydroxyl groups and R.sup.7 is an acetoxy group
are excluded), a pharmacologically acceptable salt thereof or a
hydrate of them.
2. The compound according to claim 1 represented by the formula
(I-a): ##STR242## (in the formula, R.sup.3a, R.sup.6a, R.sup.7a and
R.sup.21a are the same as or different from one another and each
represents 1) a hydroxyl group or an oxo group formed together with
the carbon atom to which each of R.sup.3a, R.sup.6a, R.sup.7a and
R.sup.21a is bound, provided that R.sup.6a is limited to a hydroxyl
group, 2) an optionally substituted C.sub.1-22 alkoxy group, 3)
R.sup.aCO--O-- (wherein R.sup.a represents a) a hydrogen atom, b)
an optionally substituted C.sub.1-22 alkyl group, c) an optionally
substituted unsaturated C.sub.2-22 alkyl group, d) an optionally
substituted C.sub.6-14 aryl group, e) an optionally substituted 5
to 14-membered heteroaryl group, f) an optionally substituted
C.sub.7-22 aralkyl group, g) an optionally substituted 5 to
14-membered heteroaralkyl group, h) an optionally substituted
C.sub.1-22 alkoxy group, i) an optionally substituted unsaturated
C.sub.2-22 alkoxy group, j) an optionally substituted C.sub.6-14
aryloxy group or k) an optionally substituted 5 to 14-membered
heteroaryloxy group), 4) R.sup.aS1R.sup.aS2R.sup.aS3SiO-- (wherein
R.sup.aS1, R.sup.aS2 and R.sup.aS3 are the same as or different
from one another and each represents a) a C.sub.1-6 alkyl group or
b) a C.sub.6-14 aryl group), 5) a halogen atom or 6)
R.sup.aN1R.sup.aN2N--R.sup.aM-- (wherein R.sup.aM represents a) a
single bond, b) --CO--O--, c) --SO.sub.2--O--, d) --CS--O-- or e)
--CO--NR.sup.aN3-- (wherein R.sup.aN3 represents a hydrogen atom or
an optionally substituted C.sub.1-6 alkyl group, provided that each
of the leftmost bond in b) to e) is bound to the nitrogen atom);
and R.sup.aN1 and R.sup.aN2 are the same as or different from each
other and each represents a) a hydrogen atom, b) an optionally
substituted C.sub.1-22 alkyl group, c) an optionally substituted
unsaturated C.sub.2-22 alkyl group, d) an optionally substituted
aliphatic C.sub.2-22 acyl group, e) an optionally substituted
aromatic C.sub.7-15 acyl group, f) an optionally substituted
C.sub.6-14 aryl group, g) an optionally substituted 5 to
14-membered heteroaryl group, h) an optionally substituted
C.sub.7-22 aralkyl group, i) an optionally substituted C.sup.1-22
alkylsulfonyl group, j) an optionally substituted C.sub.6-14
arylsulfonyl group, k) an optionally substituted 3 to 14-membered
non-aromatic heterocyclic group formed by R.sup.aN1 and R.sup.aN2
together with the nitrogen atom to which R.sup.aN1 and R.sup.aN2
are bound, and the non-aromatic heterocyclic group may have
substituents, l) an optionally substituted 5 to 14-membered
heteroaralkyl group, m) an optionally substituted C.sub.3-1.sub.4
cycloalkyl group or n) an optionally substituted 3 to 14-membered
non-aromatic heterocyclic group)), a pharmacologically acceptable
salt thereof or a hydrate of them.
3. The compound according to claim 1 represented by the formula
(I-b): ##STR243## (in the formula, R.sup.3b, R.sup.6b, R.sup.7b and
R.sup.21b are the same as or different from one another and each
represents 1) a hydroxyl group or an oxo group formed together with
the carbon atom to which each of R.sup.3b, R.sup.6b, R.sub.7b and
R.sup.21b is bound, provided that R.sup.6b is limited to a hydroxyl
group, 2) an optionally substituted C.sub.1-22 alkoxy group, 3)
R.sup.bCO--O-- (wherein R.sup.b represents a) a hydrogen atom, b)
an optionally substituted C.sub.1-22 alkyl group, c) an optionally
substituted unsaturated C.sub.2-22 alkyl group, d) an optionally
substituted C.sub.6-14 aryl group, e) an optionally substituted 5
to 14-membered heteroaryl group, f) an optionally substituted
C.sub.7-22 aralkyl group, g) an optionally substituted 5 to
14-membered heteroaralkyl group, h) an optionally substituted
C.sub.1-22 alkoxy group, i) an optionally substituted unsaturated
C.sub.2-22 alkoxy group, j) an optionally substituted C.sub.6-14
aryloxy group or k) an optionally substituted 5 to 14-membered
heteroaryloxy group), 4) R.sup.bS1R.sup.bS2R.sup.bS3SiO-- (wherein
R.sup.bS1, R.sup.bS2 and R.sup.bS3 are the same as or different
from one another and each represents a) a C.sub.1-6 alkyl group or
b) a C.sub.6-14 aryl group) or 5) R.sup.bN1R.sup.bN2N--R.sup.bM--
(wherein R.sup.bM represents a) --CO--O-- or b) --CS--O--, provided
that each of the leftmost bond in a) and b) is bound to the
nitrogen atom; and R.sup.bN1 and R.sup.bN2 are the same as or
different from each other and each represents a) a hydrogen atom,
b) an optionally substituted C.sub.1-22 alkyl group, c) an
optionally substituted unsaturated C.sub.2-22 alkyl group, d) an
optionally substituted aliphatic C.sub.2-22 acyl group, e) an
optionally substituted aromatic C.sub.7-15 acyl group, f) an
optionally substituted C.sub.6-14 aryl group, g) an optionally
substituted 5 to 14-membered heteroaryl group, h) an optionally
substituted C.sub.7-22 aralkyl group, i) an optionally substituted
C.sub.1-22 alkylsulfonyl group, j) an optionally substituted
C.sub.6-14 arylsulfonyl group, k) an optionally substituted 3 to
14-membered non-aromatic heterocyclic group formed by R.sup.bN1 and
R.sup.bN2 together with the nitrogen atom to which R.sup.bN1 and
R.sup.bN2 are bound, and the non-aromatic heterocyclic group may
have substituents, l) an optionally substituted 5 to 14-membered
heteroaralkyl group, m) an optionally substituted C.sub.3-14
cycloalkyl group or n) an optionally substituted 3 to 14-membered
non-aromatic heterocyclic group)), a pharmacologically acceptable
salt thereof or a hydrate of them.
4. The compound according to claim 1 represented by the formula
(I-c): ##STR244## (in the formula, R.sup.3c, R.sup.6c, R.sup.7c and
R.sup.21c are the same as or different from one another and each
represents 1) a hydroxyl group or an oxo group formed together with
the carbon atom to which each of R.sup.3c, R.sup.6c, R.sup.7c and
R.sup.21c is bound, provided that R.sup.6c is limited to a hydroxyl
group, 2) an optionally substituted C.sub.1-22 alkoxy group, 3)
R.sup.cCO--O-- (wherein R.sup.c represents a) an optionally
substituted C.sub.1-22 alkyl group, b) an optionally substituted
C.sub.6-14 aryl group, c) an optionally substituted C.sub.7-22
aralkyl group or d) an optionally substituted C.sub.6-14 aryloxy
group), 4) R.sup.cS1R.sup.cS2R.sup.cS3SiO-- (wherein R.sup.cS1,
R.sup.cS2 and R.sup.cS3 are the same as or different from one
another and each represents a) a C.sub.1-6 alkyl group or b) a
C.sub.6-14 aryl group) or 5) R.sup.cN1R.sup.cN2N--R.sup.cM--
(wherein R.sup.cM represents a) --CO--O-- or b) --CS--O--, provided
that each of the leftmost bond in a) and b) is bound to the
nitrogen atom; and R.sup.cN and R.sup.cN2 are the same as or
different from each other and each represents a) a hydrogen atom,
b) an optionally substituted C.sub.1-22 alkyl group, c) an
optionally substituted 3 to 14-membered non-aromatic heterocyclic
group formed by R.sup.cN1 and R.sup.cN2 together with the nitrogen
atom to which R.sup.cN1 and R.sup.cN2 are bound, and the
non-aromatic heterocyclic group may have substituents, d) an
optionally substituted 5 to 14-membered heteroaralkyl group, e) an
optionally substituted C.sub.3-14 cycloalkyl group or f) an
optionally substituted 3 to 14-membered non-aromatic heterocyclic
group)), a pharmacologically acceptable salt thereof or a hydrate
of them.
5. The compound according to claim 1 represented by the formula
(I-d): ##STR245## (in the formula, R.sup.3d represents 1) a
hydroxyl group or an oxo group formed together with the carbon atom
to which R.sup.3d is bound, 2) an optionally substituted C.sub.1-22
alkoxy group, 3) an optionally substituted unsaturated C.sub.2-22
alkoxy group, 4) an optionally substituted C.sub.7-22 aralkyloxy
group, 5) R.sup.dCO--O-- (wherein R.sup.d represents a) a hydrogen
atom, b) an optionally substituted C.sub.1-22 alkyl group, c) an
optionally substituted unsaturated C.sub.2-22 alkyl group, d) an
optionally substituted C.sub.6-14 aryl group, e) an optionally
substituted 5 to 14-membered heteroaryl group, f) an optionally
substituted C.sub.7-22 aralkyl group, g) an optionally substituted
5 to 14-membered heteroaralkyl group, h) an optionally substituted
C.sub.1-22 alkoxy group, i) an optionally substituted unsaturated
C.sub.2-22 alkoxy group, j) an optionally substituted C.sub.6-14
aryloxy group or k) an optionally substituted 5 to 14-membered
heteroaryloxy group) or 6) R.sup.dN1R.sup.dN2N--CO--O-- (wherein
R.sup.dN1 and R.sup.dN2 are the same as or different from each
other and each represents a) a hydrogen atom, b) an optionally
substituted C.sub.1-22 alkyl group, c) an optionally substituted
unsaturated C.sub.2-22 alkyl group, d) an optionally substituted
C.sub.6-14 aryl group, e) an optionally substituted 5 to
14-membered heteroaryl group, f) an optionally substituted
C.sub.7-22 aralkyl group, g) an optionally substituted 5 to
14-membered heteroaralkyl group, h) an optionally substituted
C.sub.3-14 cycloalkyl group, i) an optionally substituted 3 to
14-membered non-aromatic heterocyclic group or j) an optionally
substituted 3 to 14-membered non-aromatic heterocyclic group formed
by R.sup.dN1 and R.sup.dN2 together with the nitrogen atom to which
R.sup.dN1 and R.sup.dN2 are bound, and the non-aromatic
heterocyclic group may have substituents); and R.sup.6d, R.sup.7d
and R.sup.21d are the same as or different from one another and
each represents 1) a hydroxyl group or an oxo group formed together
with the carbon atom to which each of R.sup.6d, R.sup.7d and
R.sup.21d is bound, provided that R.sup.6d is limited to a hydroxyl
group, 2) an optionally substituted C.sub.1-22 alkoxy group, 3) an
optionally substituted unsaturated C.sub.2-22 alkoxy group, 4) an
optionally substituted C.sub.7-22 aralkyloxy group, 5)
R.sup.dCO--O-- (wherein Rd has the same meaning as defined above),
6) R.sup.dN1R.sup.dN2N--CO--O-- (wherein R.sup.dN1 and R.sup.dN2
have the same meanings as defined above), 7)
R.sup.dN1R.sup.dN2N--SO.sub.2--O-- (wherein R.sup.dN1 and R.sup.dN2
have the same meanings as defined above), 8)
R.sup.dN1R.sup.dN2N--CS--O-- (wherein R.sup.dN1 and R.sup.dN2 have
the same meanings as defined above), 9) R.sup.dN3SO.sub.2--O--
(wherein R.sup.dN3 represents a) an optionally substituted
C.sub.1-22 alkyl group, b) an optionally substituted C.sub.1-22
alkoxy group, c) an optionally substituted unsaturated C.sub.2-22
alkoxy group, d) an optionally substituted C.sub.6-14 aryl group,
e) an optionally substituted C.sub.6-14 aryloxy group, f) an
optionally substituted 5 to 14-membered heteroaryloxy group, g) an
optionally substituted C.sub.7-22 aralkyloxy group or h) an
optionally substituted 5 to 14-membered heteroaralkyloxy group),
10) (R.sup.dN5O).sub.2PO-- (wherein R.sup.dN5 represents a) an
optionally substituted C.sub.1-22 alkyl group, b) an optionally
substituted unsaturated C.sub.2-22 alkyl group, c) an optionally
substituted C.sub.6-14 aryl group, d) an optionally substituted 5
to 14-membered heteroaryl group, e) an optionally substituted
C.sub.7-22 aralkyl group or f) an optionally substituted 5 to
14-membered heteroaralkyl group), 11)
(R.sup.dN1R.sup.dN2N).sub.2PO-- (wherein R.sup.dN1 and R.sup.dN2
have the same meanings as defined above) or 12)
(R.sup.dN1R.sup.dN2N)(R.sup.dN5O)PO-- (wherein R.sup.dN1, R.sup.dN2
and R.sup.dN1 have the same meanings as defined above), provided
that a compound in which R.sup.3d, R.sup.6d, R.sup.7d and R.sup.21d
are all hydroxyl groups, and a compound in which R.sup.3d, R.sup.6d
and R.sup.21d are hydroxyl groups and R.sup.7d is an acetoxy group
are excluded), a pharmacologically acceptable salt thereof or a
hydrate of them.
6. The compound according to claim 1, wherein R.sup.6 and/or
R.sup.7 represents R.sup.N1R.sup.N2N--R.sup.M-- (wherein R.sup.M
represents a) --CO--O-- or b) --CS--O--; and R.sup.N1 and R.sup.N2
have the same meanings as defined above, provided that each of the
leftmost bond in a) and b) is bound to the nitrogen atom), a
pharmacologically acceptable salt thereof or a hydrate of them.
7. The compound according to claim 1, a pharmacologically
acceptable salt thereof or a hydrate of them, wherein R.sup.21 is
an oxo group formed together with the carbon atom to which R.sup.21
is bound.
8. The compound according to claim 5 represented by the formula
(I-e): ##STR246## (in the formula, R.sup.3e and R.sup.21e are the
same as or different from each other and each represents 1) a
hydroxyl group or an oxo group formed together with the carbon atom
to which each of R.sup.3e and R.sup.21e is bound, 2) an optionally
substituted C.sub.1-6 alkoxy group, 3) an optionally substituted
unsaturated C.sub.2-10 alkoxy group, 4) an optionally substituted
C.sub.7-10 aralkyloxy group, 5) an optionally substituted aliphatic
C.sub.2-6 acyloxy group or 6) R.sup.eN1R.sup.eN2N--CO--O-- (wherein
R.sup.eN1 and R.sup.eN2 are the same as or different from each
other and each represents A) a hydrogen atom or B) an optionally
substituted C.sub.1-6 alkyl group); and R.sup.6e and R.sup.7e are
the same as or different from each other and each represents 1) a
hydroxyl group or an oxo group formed together with the carbon atom
to which each of R.sup.6e and R.sup.7e is bound, provided that
R.sup.6e is limited to a hydroxyl group, 2) an optionally
substituted C.sub.1-6 alkoxy group, 3) an optionally substituted
unsaturated C.sub.2-10 alkoxy group, 4) an optionally substituted
C.sub.7-10 aralkyloxy group, 5) an optionally substituted aliphatic
C.sub.2-6 acyloxy group or 6) R.sup.eC(.dbd.Y.sup.e)--O-- (wherein
Y.sup.e represents an oxygen atom or a sulfur atom; and R.sup.e
represents a) a hydrogen atom, b) an optionally substituted
C.sub.1-6 alkyl group, c) an optionally substituted C.sub.7-10
aralkyl group, d) an optionally substituted 5 to 14-membered
heteroaralkyl group, e) the formula (III): ##STR247## (in the
formula, A) n represents an integer of 0 to 4; X.sub.e represents
i) --CHR.sup.eN4--, ii) --NR.sup.eN5--, iii) --O--, iv) --S--, v)
--SO-- or vi) --SO.sub.2--; R.sup.eN1 represents i) a hydrogen atom
or ii) a C.sub.1-6 alkyl group; R.sup.eN2 represents i) a hydrogen
atom or ii) a C.sub.1-6 alkyl group; R.sup.eN3 and R.sup.eN4 are
the same as or different from each other and each represents i) a
hydrogen atom, ii) an optionally substituted C.sub.1-6 alkyl group,
iii) an optionally substituted unsaturated C.sub.2-10 alkyl group,
iv) an optionally substituted C.sub.6-14 aryl group, v) an
optionally substituted 5 to 14-membered heteroaryl group, vi) an
optionally substituted C.sub.7-10 aralkyl group, vii) an optionally
substituted C.sub.3-8 cycloalkyl group, viii) an optionally
substituted C.sub.4-9 cycloalkyl alkyl group, ix) an optionally
substituted 5 to 14-membered heteroaralkyl group, x) an optionally
substituted 5 to 14-membered non-aromatic heterocyclic group, xi)
--NR.sup.eN6R.sup.eN7 (wherein R.sup.eN6 and R.sup.eN7 are the same
as or different from each other and each represents a hydrogen atom
or an optionally substituted C.sub.1-6 alkyl group) or xii) an
optionally substituted 5 to 14-membered non-aromatic heterocyclic
group formed by R.sup.eN3 and R.sup.eN4 together with the carbon
atom to which R.sup.eN3 and R.sup.eN4 are bound, and the
non-aromatic heterocyclic group may have substituents; and
R.sup.eN5 represents i) a hydrogen atom, ii) an optionally
substituted C.sub.1-6 alkyl group, iii) an optionally substituted
unsaturated C.sub.2-10 alkyl group, iv) an optionally substituted
C.sub.6-14 aryl group, v) an optionally substituted 5 to
14-membered heteroaryl group, vi) an optionally substituted
C.sub.7-10 aralkyl group, vii) an optionally substituted C.sub.3-8
cycloalkyl group, viii) an optionally substituted C.sub.4-9
cycloalkyl alkyl group, ix) an optionally substituted 5 to
14-membered heteroaralkyl group, x) an optionally substituted 5 to
14-membered non-aromatic heterocyclic group or xi) an optionally
substituted 5 to 14-membered non-aromatic heterocyclic group formed
by R.sup.eN3 and R.sup.eN5 together with the nitrogen atom to which
R.sup.eN3 and R.sup.eN5 are bound, and the non-aromatic
heterocyclic group may have substituents, B) X.sub.e, n, R.sup.eN3,
R.sup.eN4 and R.sup.eN5 each represents the group as defined above;
and R.sup.eN1 and R.sup.eN2 together form an optionally substituted
5 to 14-membered non-aromatic heterocyclic group, C) X.sub.e, n,
R.sup.eN2, R.sup.eN4 and R.sup.eNn5 each represents the group as
defined above; and R.sup.eN1 and R.sup.eN3 together form an
optionally substituted 5 to 14-membered non-aromatic heterocyclic
group or D) X.sub.e, n, R.sup.eN1, R.sup.eN4 and R.sup.eN5 each
represents the group as defined above; and R.sup.eN2 and R.sup.eN3
together form an optionally substituted 5 to 14-membered
non-aromatic heterocyclic group) or f) the formula (IV): ##STR248##
(in the formula, R.sup.eN8 and R.sup.eN9 are the same as or
different from each other and each represents i) a hydrogen atom,
ii) an optionally substituted C.sub.1-6 alkyl group, iii) an
optionally substituted C.sub.6-14 aryl group, iv) an optionally
substituted 5 to 14-membered heteroaryl group, v) an optionally
substituted C.sub.7-10 aralkyl group or vi) an optionally
substituted 5 to 14-membered heteroaralkyl group))), a
pharmacologically acceptable salt thereof or a hydrate of them.
9. The compound according to claim 5, wherein R.sup.6d and/or
R.sup.7d represents R.sup.d1C(.dbd.Y.sup.d1)--O-- (wherein Y.sup.d1
represents an oxygen atom or a sulfur atom; and R.sup.d1 represents
1) a hydrogen atom, 2) an optionally substituted C.sub.1-6 alkyl
group, 3) an optionally substituted C.sub.7-10 aralkyl group or 4)
an optionally substituted 5 to 14-membered heteroaralkyl group), a
pharmacologically acceptable salt thereof or a hydrate of them.
10. The compound according to claim 5, wherein R.sup.6d and/or
R.sup.7d represents R.sup.d2C(.dbd.Y.sup.d2)--O-- (wherein Y.sup.d2
represents an oxygen atom or sulfur atom; and R.sup.d2 represents
the formula (III'): ##STR249## (in the formula, n represents an
integer of 0 to 4; X.sub.1 represents 1) --CHR.sup.dN7--, 2)
NR.sup.dN8--, 3) --O--, 4) --S--, 5) --SO-- or 6) --SO.sub.2--;
R.sup.dN4 and R.sup.dN5 are the same as or different from each
other and each represents 1) a hydrogen atom or 2) a C.sub.1-6
alkyl group; R.sup.dN6 and R.sup.dN7 are the same as or different
from each other and each represents 1) a hydrogen atom, 2) an
optionally substituted C.sub.1-6 alkyl group, 3) an optionally
substituted unsaturated C.sub.2-10 alkyl group, 4) an optionally
substituted C.sub.6-14 aryl group, 5) an optionally substituted 5
to 14-membered heteroaryl group, 6) an optionally substituted
C.sub.7-10 aralkyl group, 7) an optionally substituted C.sub.3-8
cycloalkyl group, 8) an optionally substituted C.sub.4-9 cycloalkyl
alkyl group, 9) an optionally substituted 5 to 14-membered
heteroaralkyl group, 10) an optionally substituted 5 to 14-membered
non-aromatic heterocyclic group, 11) --NR.sup.dN9R.sup.dN10
(wherein R.sup.dN9 and R.sup.dN10 are the same as or different from
each other and each represents a hydrogen atom or an optionally
substituted C.sub.1-6 alkyl group) or 12) an optionally substituted
5 to 14-membered non-aromatic heterocyclic group formed together by
R.sup.dN6 and R.sup.dN7, and the non-aromatic heterocyclic group
may have substituents; and R.sup.dN8 represents 1) a hydrogen atom,
2) an optionally substituted C.sub.1-6 alkyl group, 3) an
optionally substituted unsaturated C.sub.2-10 alkyl group, 4) an
optionally substituted C.sub.6-14 aryl group, 5) an optionally
substituted 5 to 14-membered heteroaryl group, 6) an optionally
substituted C.sub.7-10 aralkyl group, 7) an optionally substituted
C.sub.3-8 cycloalkyl group, 8) an optionally substituted C.sub.4-9
cycloalkyl alkyl group, 9) an optionally substituted 5 to
14-membered heteroaralkyl group, 10) an optionally substituted 5 to
14-membered non-aromatic heterocyclic group, 11) an optionally
substituted 5 to 14-membered non-aromatic heterocyclic group formed
by R.sup.dN4, d.sup.dN5 or R.sup.dN6 together with the nitrogen
atom to which each of R.sup.dN4, R.sup.dN5 and R.sup.dN5 is bound,
and the non-aromatic heterocyclic group may have substituents or
12) an optionally substituted 5 to 14-membered non-aromatic
heterocyclic group formed by two substituents selected from the
group consisting of R.sup.dN4, R.sup.dN5 and R.sup.dN6 together
with the nitrogen atom to which it is bound, and the non-aromatic
heterocyclic group may have substituents)), a pharmacologically
acceptable salt thereof or a hydrate of them.
11. The compound according to claim 10, a pharmacologically
acceptable salt thereof or a hydrate of them, wherein X.sub.1
represents --NR.sup.dN8-- (wherein NR.sup.dN8 has the same meanings
as defined above).
12. The compound according to claim 5 represented by the formula
(I-f): ##STR250## (in the formula, R.sup.7f represents
R.sup.fC(.dbd.Y.sup.f)--O-- (wherein Y.sup.f represents an oxygen
atom or a sulfur atom; and R.sup.f represents the formula (V):
##STR251## (wherein n represents an integer of 0 to 4; R.sup.fN1
represents 1) a hydrogen atom, 2) a methyl group or 3) an ethyl
group; and R.sup.fN2 represents 1) a hydrogen atom, 2) a
methylamino group, 3) a dimethylamino group, 4) an ethylamino
group, 5) a diethylamino group, 6) an ethylmethylamino group, 7) a
pyridinyl group, 8) a pyrrolidin-1-yl group, 9) a piperidin-1-yl
group, 10) a morpholin-4-yl group or 11) a 4-methylpiperazin-1-yl
group))), a pharmacologically acceptable salt thereof or a hydrate
of them.
13. The compound according to claim 5, wherein R.sup.6d and/or
R.sup.7d represents R.sup.d3CO--O-- (wherein R.sup.d3 represents
the formula (VI): ##STR252## (wherein n.sub.1 and n.sub.2 are the
same as or different from each other and each represents an integer
of 0 to 4; X.sub.2 represents 1) --CHR.sup.dN13--, 2)
--NR.sup.dN14--, 3) --O--, 4) --S--, 5) --SO-- or 6) --SO.sub.2--;
R.sup.dN11 represents 1) a hydrogen atom or 2) an optionally
substituted C.sub.1-6 alkyl group; R.sup.dN12 represents 1) a
hydrogen atom, 2) an optionally substituted C.sub.1-6 alkyl group,
3) an optionally substituted C.sub.6-14 aryl group or 4) an
optionally substituted C.sub.7-10 aralkyl group; R.sup.dN13
represents 1) a hydrogen atom, 2) an optionally substituted
C.sub.1-6 alkyl group, 3) an optionally substituted unsaturated
C.sub.2-10 alkyl group, 4) an optionally substituted C.sub.6-14
aryl group, 5) an optionally substituted 5 to 14-membered
heteroaryl group, 6) an optionally substituted C.sub.7-10 aralkyl
group, 7) an optionally substituted C.sub.3-8 cycloalkyl group, 8)
an optionally substituted C.sub.4-9 cycloalkyl alkyl group, 9) an
optionally substituted 5 to 14-membered heteroaralkyl group, 10)
--NR.sup.dN15R.sup.dN16 (wherein R.sup.dN15 and R.sup.dN16 are the
same as or different from each other and each represents a hydrogen
atom or an optionally substituted C.sub.1-6 alkyl group) or 11) an
optionally substituted 5 to 14-membered non-aromatic heterocyclic
group; and R.sup.dN14 represents 1) a hydrogen atom, 2) an
optionally substituted C.sub.1-6 alkyl group, 3) an optionally
substituted unsaturated C.sub.2-10 alkyl group, 4) an optionally
substituted C.sub.6-14 aryl group, 5) an optionally substituted 5
to 14-membered heteroaryl group, 6) an optionally substituted
C.sub.7-10 aralkyl group, 7) an optionally substituted C.sub.3-8
cycloalkyl group, 8) an optionally substituted C.sub.4-9 cycloalkyl
alkyl group, 9) an optionally substituted 5 to 14-membered
heteroaralkyl group or 10) an optionally substituted 5 to
14-membered non-aromatic heterocyclic group)), a pharmacologically
acceptable salt thereof or a hydrate of them.
14. The compound according to claim 5 represented by the formula
(I-g): ##STR253## (in the formula, R.sup.7g represents
R.sup.gCO--O-- (wherein R.sup.g represents the formula (VII):
##STR254## (wherein n.sub.3 represents 1 or 2; R.sup.dN17
represents 1) a hydrogen atom, 2) a methyl group or 3) an ethyl
group; and R.sup.dN18 represents 1) a hydrogen atom, 2) a methyl
group or 3) an ethyl group))), a pharmacologically acceptable salt
thereof or a hydrate of them.
15. The compound according to claim 5, wherein R.sup.6d and/or
R.sup.7d represents R.sup.d4CO--O-- (wherein R.sup.d4 represents
the formula (VIII): ##STR255## (wherein n.sub.1 and n.sub.2 are the
same as or different from each other and each represents an integer
of 0 to 4; X.sub.3 represents 1) --CHR.sup.dN21, 2) NR.sup.dN22--,
3) --O--, 4) --S--, 5) --SO-- or 6) --SO.sub.2--; R.sup.dN19
represents 1) a hydrogen atom or 2) a C.sub.1-6 alkyl group;
R.sup.dN20 represents 1) a hydrogen atom, 2) an optionally
substituted C.sub.1-6 alkyl group, 3) an optionally substituted
C.sub.6-14 aryl group or 4) an optionally substituted C.sub.7-10
aralkyl group; R.sup.dN21 represents 1) a hydrogen atom, 2) an
optionally substituted C.sub.1-6 alkyl group, 3) an optionally
substituted unsaturated C.sub.2-10 alkyl group, 4) an optionally
substituted C.sub.1-6 alkoxy group, 5) an optionally substituted
C.sub.6-14 aryl group, 6) an optionally substituted 5 to
14-membered heteroaryl group, 7) an optionally substituted
C.sub.7-10 aralkyl group, 8) an optionally substituted C.sub.3-8
cycloalkyl group, 9) an optionally substituted C.sub.4-9 cycloalkyl
alkyl group, 10) an optionally substituted 5 to 14-membered
heteroaralkyl group, 11) --NR.sup.dN23R.sup.dN24 (wherein
R.sup.dN23 and R.sup.dN24 are the same as or different from each
other and each represents a hydrogen atom or an optionally
substituted C.sub.1-6 alkyl group) or 12) an optionally substituted
5 to 14-membered non-aromatic heterocyclic group; and R.sup.dN22
represents 1) a hydrogen atom, 2) an optionally substituted
C.sub.1-6 alkyl group, 3) an optionally substituted unsaturated
C.sub.2-10 alkyl group, 4) an optionally substituted C.sub.6-14
aryl group, 5) an optionally substituted 5 to 14-membered
heteroaryl group, 6) an optionally substituted C.sub.7-10 aralkyl
group, 7) an optionally substituted C.sub.3-8 cycloalkyl group, 8)
an optionally substituted C.sub.4-9 cycloalkyl alkyl group, 9) an
optionally substituted 5 to 14-membered heteroaralkyl group or 10)
an optionally substituted 5 to 14-membered non-aromatic
heterocyclic group)), a pharmacologically acceptable salt thereof
or a hydrate of them.
16. The compound according to claim 5 represented by the formula
(I-h): ##STR256## (in the formula, R.sup.7h represents
R.sup.hCO--O-- (wherein R.sup.h represents the formula (IX):
##STR257## (wherein n.sub.4 represents an integer of 1 to 3; and
R.sup.dN25 represents 1) an amino group, 2) a methylamino group, 3)
a dimethylamino group, 4) a pyrrolidin-1-yl group, 5) a
piperidin-1-yl group or 6) a morpholin-4-yl group))), a
pharmacologically acceptable salt thereof or a hydrate of them.
17. The compound according to claim 5 represented by the formula
(I-i): ##STR258## (in the formula, R.sup.7i represents
R.sup.iCO--O-- (wherein R.sup.i represents the formula (X):
##STR259## (wherein n.sub.4 represents an integer of 1 to 3;
R.sup.dN26 represents 1) a hydrogen atom, 2) an optionally
substituted C.sub.1-6 alkyl group, 3) an optionally substituted
C.sub.6-14 aryl group or 4) an optionally substituted C.sub.7-10
aralkyl group; and R.sup.dN27 represents 1) a hydrogen atom, 2) an
optionally substituted C.sub.1-6 alkyl group, 3) an optionally
substituted C.sub.3-8 cycloalkyl group, 4) an optionally
substituted 3 to 8-membered non-aromatic heterocyclic group, 5) an
optionally substituted C.sub.6-14 aryl group, 6) an optionally
substituted 5 to 14-membered heteroaryl group, 7) an optionally
substituted C.sub.7-10 aralkyl group, 8) an optionally substituted
5 to 14-membered heteroaralkyl group or 9) an optionally
substituted C.sub.4-9 cycloalkyl alkyl group))), a
pharmacologically acceptable salt thereof or a hydrate of them.
18. The compound according to claim 5 represented by the formula
(I-j): ##STR260## (in the formula, R.sup.7j represents
R.sup.jCO--O-- (wherein R.sup.j represents the formula (XI):
##STR261## (wherein n.sub.4 represents an integer of 1 to 3; and
R.sup.dN28 represents 1) a hydrogen atom, 2) an optionally
substituted C.sub.1-6 alkyl group, 3) a C.sub.3-8 cycloalkyl group,
4) a C.sub.4-9 cycloalkyl alkyl group, 5) a C.sub.7-10 aralkyl
group, 6) a pyridinyl group or 7) a tetrahydropyranyl group))), a
pharmacologically acceptable salt thereof or a hydrate of them.
19. The compound according to claim 5 represented by the formula
(I-k): ##STR262## (in the formula, R.sup.7k represents
R.sup.kCO--O-- (wherein R.sup.k represents the formula (XII):
##STR263## (wherein m.sub.1, m.sub.2, m.sub.3 and m.sub.4 are the
same as or different from one another and each represents 0 or 1;
n.sub.4 represents an integer of 1 to 3; and R.sup.dN29 represents
1) a hydrogen atom, 2) an optionally substituted C.sub.1-6 alkyl
group, 3) an optionally substituted unsaturated C.sub.2-10 alkyl
group, 4) an optionally substituted C.sub.6-14 aryl group, 5) an
optionally substituted 5 to 14-membered heteroaryl group, 6) an
optionally substituted C.sub.7-10 aralkyl group, 7) an optionally
substituted C.sub.3-8 cycloalkyl group, 8) an optionally
substituted C.sub.4-9 cycloalkyl alkyl group, 9) an optionally
substituted 5 to 14-membered heteroaralkyl group or 10) an
optionally substituted 5 to 14-membered non-aromatic heterocyclic
group))), a pharmacologically acceptable salt thereof or a hydrate
of them.
20. The compound according to claim 5 represented by the formula
(I-m): ##STR264## (in the formula, R.sup.7m represents
R.sup.mCO--O-- (wherein R.sup.m represents the formula (XIII):
##STR265## (wherein m.sub.5 represents an integer of 1 to 3; and
n.sub.5 represents 2 or 3))), a pharmacologically acceptable salt
thereof or a hydrate of them.
21. The compound according to claim 5 represented by the formula
(I-n): ##STR266## (in the formula, R.sup.7n represents
R.sup.nCO--O-- (wherein R.sup.n is a group represented by the
formula (XIV): ##STR267## a pharmacologically acceptable salt
thereof or a hydrate of them.
22. The compound according to claim 1, which is selected from:
(8E,12E,14E)-7-(N-(2-(N',N'-Dimethylamino)ethyl)-N-methylcarbamoyloxy)-3,-
6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14--
trien-11-olide;
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methy-
lhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide-
;
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-meth-
ylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide;
(8E,12E,14E)-7-((4-Butylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydrox-
y-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;
(8E,12E,14E)-7-((4-Ethylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydrox-
y-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propy-
lpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide;
(8E,12E,14E)-7-((4-Cyclohexylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrah-
ydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide-
;
(8E,12E,14E)-7-((4-(Cyclopropylmethyl)piperazin-1-yl)carbonyl)oxy-3,6,16-
,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trie-
n-11-olide;
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propy-
lhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide-
;
(8E,12E,14E)-7-((4-(Cyclopropylmethyl)homopiperazin-1-yl)carbonyl)oxy-3,-
6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14--
trien-11-olide;
(8E,12E,14E)-7-((4-Cyclopentylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetra-
hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olid-
e;
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isopropylpiperazin-1-yl)carbo-
nyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olid-
e;
(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tet-
rahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-ol-
ide;
(8E,12E,14E)-7-(N-(2-(N',N'-Diethylamino)ethyl)-N-methylcarbamoyloxy)-
-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,-
14-trien-11-olide;
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isobutylhomopiperazin-1-yl)carb-
onyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-oli-
de;
(8E,12E,14E)-7-((4-Ethylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetr-
ahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-oli-
de;
(8E,12E,14E)-7-((4-Butylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetr-
ahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-oli-
de;
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7--
((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11--
olide;
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-
-7-((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12-
,14-trien-11-olide;
(8E,12E,14E)-7-((4-(2,2-Dimethylpropyl)homopiperazin-1-yl)carbonyl)oxy-3,-
6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14--
trien-11-olide; and
(8E,12E,14E)-3,6,16-Trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7-((4-
-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-oli-
de.
23. The compound according to claim 1, which is selected from:
(8E,12E,14E)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methy-
lhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide-
;
(8E,12E,14E)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-(4-methy-
lhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide-
;
(8E,12E,14E)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-meth-
ylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide;
(8E,12E,14E)-7-((4-cyclohexylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrah-
ydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide-
;
(8E,12E,14E)-3,6,16,21-tetrahydroxy-7-((4-isopropylpiperazin-1-yl)carbon-
yl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide-
;
(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetr-
ahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-oli-
de; and
(8E,12E,14E)-7-(N-(2-(N',N'-Diethylamino)ethyl)-N-methylcarbamoylo-
xy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,-
12,14-trien-11-olide.
24. A medicament comprising the compound according to claim 1, a
pharmacologically acceptable salt thereof or a hydrate of them as
an active ingredient.
25. A pharmaceutical composition comprising the compound according
to claim 1, a pharmacologically acceptable salt thereof or a
hydrate of them as an active ingredient.
26. The medicament according to claim 24, which is an agent for
preventing or treating a disease against which a regulation of gene
expression is efficacious.
27. The medicament according to claim 24, which is an agent for
preventing or treating a diseases against which suppression of VEGF
production is efficacious.
28. The medicament according to claim 24, which is an agent for
preventing or treating a disease against which an antiangiogenic
effect is efficacious.
29. The medicament according to claim 24, which is an angiogenesis
inhibitor.
30. The medicament according to claim 24, which is an antitumor
agent.
31. The medicament according to claim 24, as a therapeutic agent
for treating angioma.
32. The medicament according to claim 24, which is cancer
metastasis inhibitor.
33. The medicament according to claim 24, which is a therapeutic
agent for treating retinal neovascularization or diabetic
retinopathy.
34. The medicament according to claim 24, which is a therapeutic
agent for treating inflammatory disease.
35. The medicament according to claim 24, which is a therapeutic
agent for treating inflammatory diseases consisting of deformans
arthritis, rheumatoid arthritis, psoriasis and delayed
hypersensitivity reaction.
36. The medicament according to claim 24, which is a therapeutic
agent for treating atherosclerosis.
37. The medicament according to claim 24, which is a therapeutic
agent for treating solid cancer.
38. The medicament according to claim 37, wherein the solid cancer
is lung cancer, brain tumor, breast cancer, prostate cancer,
ovarian cancer, colon cancer or melanoma.
39. The medicament according to claim 24, which is a therapeutic
agent for treating leukemia.
40. The medicament according to claim 24, which is an antitumor
agent based on a regulation of gene expression.
41. The medicament according to claim 24, which is an antitumor
agent based on suppression of VEGF production.
42. The medicament according to claim 24, which is an antitumor
agent based on an effect of angiogenesis inhibition.
43. A method for preventing or treating a disease against which a
regulation of gene expression is efficacious, which comprises
administering a pharmacologically effective dose of the medicament
according to claim 24 to a patient.
44. A method for preventing or treating a disease against which
suppression of VEGF production is efficacious, which comprises
administering a pharmacologically effective dose of the medicament
according to claim 24 to a patient.
45. A method for preventing or treating a disease against which an
angiogenesis inhibition is efficacious, which comprises
administering a pharmacologically effective dose of the medicament
according to claim 24 to a patient.
46. Use of the compound according to claim 1, a pharmacologically
acceptable salt thereof or a hydrate of them, for manufacturing an
agent for preventing or treating a disease against which a
regulation of gene expression is efficacious.
47. Use of the compound according to claim 1, a pharmacologically
acceptable salt thereof or a hydrate of them, for manufacturing an
agent for preventing or treating a disease against which
suppression of VEGF production is efficacious.
48. Use of the compound according to claim 1, a pharmacologically
acceptable salt thereof or a hydrate of them, for manufacturing an
agent for preventing or treating a disease against which an
angiogenesis inhibition is efficacious.
49. Use of the compound according to claim 1, a pharmacologically
acceptable salt thereof or a hydrate of them, for manufacturing an
agent for preventing or treating solid cancers.
Description
TECHNICAL FIELD
[0001] The present invention relates to a 12-membered ring
macrolide compound useful as a medicament, preparation thereof and
use thereof.
BACKGROUND OF THE INVENTION
[0002] Compounds having cytotoxicity have been used as antitumor
agents, and many screenings have been carried out using
cytotoxicity as an index. As a result, most of pre-existing
antitumor agents give affection to cancer cells and simultaneously
to normal tissues in which a proliferation of cell is active, for
example, to bone marrow, intestine epithelium and the like. Thus,
the improvement of QOL of patients has not been sufficiently
accomplished yet.
[0003] Further, although it can be expected that treatments by the
antitumor agents are rather effective for leukemia, it cannot be
always said that they are effective for solid cancer. Therefore
strong demands have been made to provide antitumor agents that are
effective for solid cancer and are highly safe.
[0004] Screenings for fermentation products of microorganism have
been carried out using the cytotoxicity in vitro as an index,
expecting that they might also be used as antitumor agents. Many
compounds having cytotoxicity have been found, however, most of
them show cytotoxic activities only in vitro, and few compounds of
them show antitumor activities in vivo, and very few compounds
exhibit effectiveness for solid cancer.
DISCLOSURE OF THE INVENTION
[0005] It is the object of the present invention to find out
compounds which show antitumor activity not only in vitro but also
in vivo and have antitumor activities for solid cancer from
fermentation products of microorganism or derivatives thereof.
[0006] It is considered that tumorgenesis of a normal cell is
caused by mutation of a gene in the cell occurs and an abnormal
gene is expressed. Accordingly, the present inventors have made
intensive investigations based on the inference that the growth of
a tumor cell can be suppressed by changing the gene expression of
the tumor cell, namely, the growth of the tumor cell can be
controlled by changing the gene expression of oncogene or tumor
suppressor gene, or by changing the gene expression involved in
cell cycle. The present inventors have considered that a compound
changing of the gene expression, in particular, a compound
suppressing VEGF (vascular endothelial growth factor) production at
a hypoxic condition could suppress angiogenesis by a tumor and has
an antitumor activities for solid cancer. Then, they carried out
screening for fermentation products of microorganism and
derivatives thereof using the VEGF production by U251 cell under
hypoxic stimulation as an index. As the results, the inventors have
found out novel physiologically active compounds, 12-membered ring
macrolide compounds, named 11107 and analogues thereof which
suppress the VEGF production at a hypoxic condition in vitro, and
further suppress the growth of solid tumor cells in vivo.
[0007] The present inventors have further found that 11107D among
the 11107 analogues is stable even in an aqueous solution, and that
compounds obtained by chemical modifications of 11107D
(hereinafter, these are referred to as 11107D derivatives) inherit
the property of stability in an aqueous solution from 11107D and
inhibit the growth of solid tumor cells in vivo experiments in much
more degree. The present invention has been accomplished based on
these findings.
[0008] As a related art of a 12-membered ring macrolide compound
which is most structurally similar to the compounds of the present
invention, a 12-membered ring macrolide compound FD-895 (JP-A
4-352783) represented by the formula (XIV): ##STR2## is mentioned.
The publication discloses that FD-895 has in vitro cell growth
inhibitory activities against P388 mouse leukemia cell, L-1210
mouse leukemia cell and HL-60 human leukemia cell in RPM-1640
medium (column 6, Table 2). However, it has been reported that
FD-895 did not show antitumor activities in an in vivo experiment
using P388 mouse leukemia cell (Seki-Asano M. et al, J.
Antibiotics, 47, 1395-1401, 1994).
[0009] In addition, FD-895 is unstable in an aqueous solution as
described later and is expected to be inappropriate to mix with an
infusion solution upon administration. Thus, it cannot be said that
FD-895 has sufficient qualities as an antitumor agent.
[0010] That is, the present invention relates to: [0011] (1) a
compound represented by the formula (I): ##STR3## (in the formula,
R.sup.3, R.sup.6, R.sup.7 and R.sup.21 are the same as or different
from one another and each represents [0012] 1) a hydroxyl group or
an oxo group formed together with the carbon atom to which each of
R.sup.3, R.sup.6, R.sup.7 and R.sup.21 is bound, provided that
R.sup.6 is limited to a hydroxyl group, [0013] 2) an optionally
substituted C.sub.1-22 alkoxy group, [0014] 3) an optionally
substituted unsaturated C.sub.2-22 alkoxy group, [0015] 4) an
optionally substituted C.sub.7-22 aralkyloxy group, [0016] 5) an
optionally substituted 5 to 14-membered heteroaralkyloxy group,
[0017] 6) RCO--O-- (wherein R represents [0018] a) a hydrogen atom,
[0019] b) an optionally substituted C.sub.1-22 alkyl group, [0020]
c) an optionally substituted unsaturated C.sub.2-22 alkyl group,
[0021] d) an optionally substituted C.sub.6-14 aryl group, [0022]
e) an optionally substituted 5 to 14-membered heteroaryl group,
[0023] f) an optionally substituted C.sub.7-22 aralkyl group,
[0024] g) an optionally substituted 5 to 14-membered heteroaralkyl
group, [0025] h) an optionally substituted C.sub.1-22 alkoxy group,
[0026] i) an optionally substituted unsaturated C.sub.2-22 alkoxy
group, [0027] j) an optionally substituted C.sub.6-14 aryloxy group
or [0028] k) an optionally substituted 5 to 14-membered
heteroaryloxy group), [0029] 7) R.sup.S1R.sup.S2R.sup.S3SiO--
(wherein R.sup.S1, R.sup.S2 and R.sup.S3 are the same as or
different from one another and each represents [0030] a) a
C.sub.1-6 alkyl group or [0031] b) a C.sub.6-14 aryl group), [0032]
8) a halogen atom, [0033] 9) R.sup.N1R.sup.N2N--R.sup.M-- (wherein
R.sup.M represents [0034] a) a single bond, [0035] b) --CO--O--,
[0036] c) --SO.sub.2--O--, [0037] d) --CS--O-- or [0038] e)
--CO--NR.sup.N3-- (wherein R.sup.N3 represents a hydrogen atom or
an optionally substituted C.sub.1-6 alkyl group), provided that
each of the leftmost bond in b) to e) is bound to the nitrogen
atom; and [0039] R.sup.N1 and R.sup.N2 are the same as or different
from each other and each represents [0040] a) a hydrogen atom,
[0041] b) an optionally substituted C.sub.2-22 alkyl group, [0042]
c) an optionally substituted unsaturated C.sub.2-22 alkyl group,
[0043] d) an optionally substituted aliphatic C.sub.2-22 acyl
group, [0044] e) an optionally substituted aromatic C.sub.7-15 acyl
group, [0045] f) an optionally substituted C.sub.6-14 aryl group,
[0046] g) an optionally substituted 5 to 14-membered heteroaryl
group, [0047] h) an optionally substituted C.sub.7-22 aralkyl
group, [0048] i) an optionally substituted C.sub.1-22 alkylsulfonyl
group, [0049] j) an optionally substituted C.sub.6-14 arylsulfonyl
group, [0050] k) an optionally substituted 3 to 14-membered
non-aromatic heterocyclic group formed by R.sup.N1 and R.sup.N2
together with the nitrogen atom to which R.sup.N1 and R.sup.N2 are
bound, and the non-aromatic heterocyclic group may have
substituents, [0051] l) an optionally substituted 5 to 14-membered
heteroaralkyl group, [0052] m) an optionally substituted C.sub.3-14
cycloalkyl group or [0053] n) an optionally substituted 3 to
14-membered non-aromatic heterocyclic group), [0054] 10) R.sup.N4
SO.sub.2--O-- (wherein R.sup.N4 represents [0055] a) an optionally
substituted C.sub.1-22 alkyl group, [0056] b) an optionally
substituted C.sub.6-14 aryl group, [0057] c) an optionally
substituted C.sub.1-22 alkoxy group, [0058] d) an optionally
substituted unsaturated C.sub.2-22 alkoxy group, [0059] e) an
optionally substituted C.sub.6-14 aryloxy group, [0060] f) an
optionally substituted 5 to 14-membered heteroaryloxy group, [0061]
g) an optionally substituted C.sub.7-22 aralkyloxy group or [0062]
h) an optionally substituted 5 to 14-membered heteroaralkyloxy
group), [0063] 11) (R.sup.N5O).sub.2PO--O-- (wherein R.sup.N5
represents [0064] a) an optionally substituted C.sub.1-22 alkyl
group, [0065] b) an optionally substituted unsaturated C.sub.2-22
alkyl group, [0066] c) an optionally substituted C.sub.6-14 aryl
group, [0067] d) an optionally substituted 5 to 14-membered
heteroaryl group, [0068] e) an optionally substituted C.sub.7-22
aralkyl group or [0069] f) an optionally substituted 5 to
14-membered heteroaralkyl group), [0070] 12)
(R.sup.N1R.sup.N2N).sub.2PO--O-- (wherein R.sup.N1 and R.sup.N2
have the same meanings as defined above) or [0071] 13)
(R.sup.N1R.sup.N2 N)(R.sup.N5O)PO--O-- (wherein R.sup.N1, R.sup.N2
and R.sup.N5 have the same meanings as defined above), provided
that a compound in which R.sup.3, R.sup.6, R.sup.7 and R.sup.21 are
all hydroxyl groups, and a compound in which R.sup.3, R.sup.6 and
R.sup.21 are all hydroxyl groups and R.sup.7 is an acetoxy group
are excluded), a pharmacologically acceptable salt thereof or a
hydrate of them; [0072] (2) the compound described in (1)
represented by the formula (I-a): ##STR4## (in the formula,
R.sup.3a, R.sup.6a, R.sup.7a and R.sup.2a are the same as or
different from one another and each represents [0073] 1) a hydroxyl
group or an oxo group formed together with the carbon atom to which
each of R.sup.3a, R.sup.6a, R.sup.7a and R.sup.21a is bound,
provided that R.sup.6a is limited to a hydroxyl group, [0074] 2) an
optionally substituted C.sub.1-22 alkoxy group, [0075] 3)
R.sup.aCO--O-- (wherein R.sup.a represents [0076] a) a hydrogen
atom, [0077] b) an optionally substituted C.sub.1-22 alkyl group,
[0078] c) an optionally substituted unsaturated C.sub.2-22 alkyl
group, [0079] d) an optionally substituted C.sub.6-14 aryl group,
[0080] e) an optionally substituted 5 to 14-membered heteroaryl
group, [0081] f) an optionally substituted C.sub.7-22 aralkyl
group, [0082] g) an optionally substituted 5 to 14-membered
heteroaralkyl group, [0083] h) an optionally substituted C.sub.1-22
alkoxy group, [0084] i) an optionally substituted unsaturated
C.sub.2-22 alkoxy group, [0085] j) an optionally substituted
C.sub.6-14 aryloxy group or [0086] k) an optionally substituted 5
to 14-membered heteroaryloxy group), [0087] 4)
R.sup.aS1R.sup.aS2R.sup.aS3SiO-- (wherein R.sup.aS1, R.sup.aS2 and
R.sup.aS3 are the same as or different from one another and each
represents [0088] a) a C.sub.1-6 alkyl group or [0089] b) a
C.sub.6-14 aryl group), [0090] 5) a halogen atom or [0091] 6)
R.sup.aN1R.sup.aN2N--R.sup.aM-- (wherein R.sup.aM represents [0092]
a) a single bond, [0093] b) --CO--O--, [0094] c)--SO.sub.2--O--,
[0095] d) --CS--O-- or [0096] e) --CO--NR.sup.aN3-- (wherein
R.sup.aN3 represents a hydrogen atom or an optionally substituted
C.sub.1-6 alkyl group, provided that each of the leftmost bond in
b) to e) is bound to the nitrogen atom); and [0097] R.sup.aN1 and
R.sup.aN2 are the same as or different from each other and each
represents [0098] a) a hydrogen atom, [0099] b) an optionally
substituted C.sub.1-22 alkyl group, [0100] c) an optionally
substituted unsaturated C.sub.2-22 alkyl group, [0101] d) an
optionally substituted aliphatic C.sub.2-22 acyl group, [0102] e)
an optionally substituted aromatic C.sub.7-15 acyl group, [0103] f)
an optionally substituted C.sub.6-14 aryl group, [0104] g) an
optionally substituted 5 to 14-membered heteroaryl group, [0105] h)
an optionally substituted C.sub.7-22 aralkyl group, [0106] i) an
optionally substituted C.sub.1-22 alkylsulfonyl group, [0107] j) an
optionally substituted C.sub.6-14 arylsulfonyl group, [0108] k) an
optionally substituted 3 to 14-membered non-aromatic heterocyclic
group formed by R.sup.aN1 and R.sup.aN2 together with the nitrogen
atom to which R.sup.aN1 and R.sup.aN2 are bound, and the
non-aromatic heterocyclic group may have substituents, [0109] l) an
optionally substituted 5 to 14-membered heteroaralkyl group, [0110]
m) an optionally substituted C.sub.3-14 cycloalkyl group or [0111]
n) an optionally substituted 3 to 14-membered non-aromatic
heterocyclic group)), a pharmacologically acceptable salt thereof
or a hydrate of them; [0112] (3) the compound described in (1)
represented by the formula (I-b): ##STR5## (in the formula,
R.sup.3b, R.sup.6b, R.sup.7b and R.sup.21b are the same as or
different from one another and each represents [0113] 1) a hydroxyl
group or an oxo group formed together with the carbon atom to which
each of R.sup.3b, R.sup.6b, R.sup.7b and R.sup.21b is bound,
provided that R.sup.6b is limited to a hydroxyl group, [0114] 2) an
optionally substituted C.sub.1-22 alkoxy group, [0115] 3)
R.sup.bCO--O-- (wherein R.sup.b represents [0116] a) a hydrogen
atom, [0117] b) an optionally substituted C.sub.1-22 alkyl group,
[0118] c) an optionally substituted unsaturated C.sub.2-22 alkyl
group, [0119] d) an optionally substituted C.sub.6-14 aryl group,
[0120] e) an optionally substituted 5 to 14-membered heteroaryl
group, [0121] f) an optionally substituted C.sub.7-22 aralkyl
group, [0122] g) an optionally substituted 5 to 14-membered
heteroaralkyl group, [0123] h) an optionally substituted C.sub.1-22
alkoxy group, [0124] i) an optionally substituted unsaturated
C.sub.2-22 alkoxy group, [0125] j) an optionally substituted
C.sub.6-14 aryloxy group or [0126] k) an optionally substituted 5
to 14-membered heteroaryloxy group), [0127] 4)
R.sup.bS1R.sup.bS2R.sup.bS3SiO-- (wherein R.sup.bS1, R.sup.bS2 and
R.sup.bS3 are the same as or different from one another and each
represents [0128] a) a C.sub.1-6 alkyl group or [0129] b) a
C.sub.6-14 aryl group) or [0130] 5) R.sup.bN1R.sup.bN2N--R.sup.bM--
(wherein R.sup.bM represents [0131] a) --CO--O-- or [0132] b)
--CS--O--, provided that each of the leftmost bond in a) and b) is
bound to the nitrogen atom; and [0133] R.sup.bN1 and R.sup.bN2 are
the same as or different from each other and each represents [0134]
a) a hydrogen atom, [0135] b) an optionally substituted C.sub.1-22
alkyl group, [0136] c) an optionally substituted unsaturated
C.sub.2-22 alkyl group, [0137] d) an optionally substituted
aliphatic C.sub.2-22 acyl group, [0138] e) an optionally
substituted aromatic C.sub.7-15 acyl group, [0139] f) an optionally
substituted C.sub.6-14 aryl group, [0140] g) an optionally
substituted 5 to 14-membered heteroaryl group, [0141] h) an
optionally substituted C.sub.7-22 aralkyl group, [0142] i) an
optionally substituted C.sub.1-22 alkylsulfonyl group, [0143] j) an
optionally substituted C.sub.6-14 arylsulfonyl group, [0144] k) an
optionally substituted 3 to 14-membered non-aromatic heterocyclic
group formed by R.sup.bN1 and R.sup.bN2 together with the nitrogen
atom to which R.sup.bN1 and R.sup.bN2 are bound, and the
non-aromatic heterocyclic group may have substituents, [0145] l) an
optionally substituted 5 to 14-membered heteroaralkyl group, [0146]
m) an optionally substituted C.sub.3-14 cycloalkyl group or [0147]
n) an optionally substituted 3 to 14-membered non-aromatic
heterocyclic group)), a pharmacologically acceptable salt thereof
or a hydrate of them; [0148] (4) the compound described in (1)
represented by the formula (I-c): ##STR6## (in the formula,
R.sup.3c, R.sup.6c, R.sup.7c and R.sup.21c are the same as or
different from one another and each represents [0149] 1) a hydroxyl
group or an oxo group formed together with the carbon atom to which
each of R.sup.3c, R.sup.6c, R.sup.7c and R.sup.21c is bound,
provided that R.sup.6c is limited to a hydroxyl group, [0150] 2) an
optionally substituted C.sub.1-22 alkoxy group, [0151] 3)
R.sup.cCO--O-- (wherein R.sup.c represents [0152] a) an optionally
substituted C.sub.1-22 alkyl group, [0153] b) an optionally
substituted C.sub.6-14 aryl group, [0154] c) an optionally
substituted C.sub.7-22 aralkyl group or [0155] d) an optionally
substituted C.sub.6-14 aryloxy group), [0156] 4)
R.sup.cS1R.sup.cS2R.sup.cS3SiO-- (wherein R.sup.cS1, R.sup.cS2 and
R.sup.cS3 are the same as or different from one another and each
represents [0157] a) a C.sub.1-6 alkyl group or [0158] b) a
C.sub.6-14 aryl group) or [0159] 5) R.sup.cN1R.sup.cN2N--R.sup.cM--
(wherein R.sup.cM represents [0160] a) --CO--O-- or [0161] b)
--CS--O--, provided that each of the leftmost bond in a) and b) is
bound to the nitrogen atom; and [0162] R.sup.cN1 and R.sup.cN2 are
the same as or different from each other and each represents [0163]
a) a hydrogen atom, [0164] b) an optionally substituted C.sub.1-22
alkyl group, [0165] c) an optionally substituted 3 to 14-membered
non-aromatic heterocyclic group formed by R.sup.cN1 and R.sup.cN2
together with the nitrogen atom to which R.sup.cN1 and R.sup.cN2
are bound, and the non-aromatic heterocyclic group may have
substituents, [0166] d) an optionally substituted 5 to 14-membered
heteroaralkyl group, [0167] e) an optionally substituted C.sub.3-14
cycloalkyl group or [0168] f) an optionally substituted 3 to
14-membered non-aromatic heterocyclic group, and the non-aromatic
heterocyclic group may have substituents)), a pharmacologically
acceptable salt thereof or a hydrate of them; [0169] (5) the
compound described in (1) represented by the formula (I-d):
##STR7## (in the formula, R.sup.3d represents [0170] 1) a hydroxyl
group or an oxo group formed together with the carbon atom to which
R.sup.3d is bound, [0171] 2) an optionally substituted C.sub.1-22
alkoxy group, [0172] 3) an optionally substituted unsaturated
C.sub.2-22 alkoxy group, [0173] 4) an optionally substituted
C.sub.7-22 aralkyloxy group, [0174] 5) R.sup.dCO--O-- (wherein
R.sup.d represents [0175] a) a hydrogen atom, [0176] b) an
optionally substituted C.sub.1-22 alkyl group, [0177] c) an
optionally substituted unsaturated C.sub.2-22 alkyl group, [0178]
d) an optionally substituted C.sub.6-14 aryl group, [0179] e) an
optionally substituted 5 to 14-membered heteroaryl group, [0180] f)
an optionally substituted C.sub.7-22 aralkyl group, [0181] g) an
optionally substituted 5 to 14-membered heteroaralkyl group, [0182]
h) an optionally substituted C.sub.1-22 alkoxy group, [0183] i) an
optionally substituted unsaturated C.sub.2-22 alkoxy group, [0184]
j) an optionally substituted C.sub.6-14 aryloxy group or [0185] k)
an optionally substituted 5 to 14-membered heteroaryloxy group) or
[0186] 6) R.sup.dN1R.sup.dN2N--CO--C-- (wherein R.sup.dN1 and
R.sup.dN2 are the same as or different from each other and each
represents [0187] a) a hydrogen atom, [0188] b) an optionally
substituted C.sub.1-22 alkyl group, [0189] c) an optionally
substituted unsaturated C.sub.2-22 alkyl group, [0190] d) an
optionally substituted C.sub.6-14 aryl group, [0191] e) an
optionally substituted 5 to 14-membered heteroaryl group,
[0192] f) an optionally substituted C.sub.7-22 aralkyl group,
[0193] g) an optionally substituted 5 to 14-membered heteroaralkyl
group, [0194] h) an optionally substituted C.sub.3-14 cycloalkyl
group, [0195] i) an optionally substituted 3 to 14-membered
non-aromatic heterocyclic group or [0196] j) an optionally
substituted 3 to 14-membered non-aromatic heterocyclic group formed
by R.sup.dN1 and R.sup.dN2 together with the nitrogen atom to which
R.sup.dN1 and R.sup.dN2 are bound, and the non-aromatic
heterocyclic group may have substituents); and [0197] R.sup.6d,
R.sup.7d and R.sup.21d are the same as or different from one
another and each represents [0198] 1) a hydroxyl group or an oxo
group formed together with the carbon atom to which each of
R.sup.6d, R.sup.7d and R.sup.21d is bound, provided that R.sup.6d
is limited to a hydroxyl group, [0199] 2) an optionally substituted
C.sub.1-22 alkoxy group, [0200] 3) an optionally substituted
unsaturated C.sub.2-22 alkoxy group, [0201] 4) an optionally
substituted C.sub.7-22 aralkyloxy group, [0202] 5) R.sup.dCO--O--
(wherein R.sup.d has the same meaning as defined above), [0203] 6)
R.sup.dN1R.sup.dN2N--CO--O-- (wherein R.sup.dN1 and R.sup.dN2 have
the same meanings as defined above), [0204] 7)
R.sup.dN1R.sup.dN2N--SO.sub.2--O-- (wherein R.sup.dN1 and R.sup.dN2
have the same meanings as defined above), [0205] 8)
R.sup.dN1R.sup.dN2N--CS--C-- (wherein R.sup.dN1 and R.sup.dN2 have
the same meanings as defined above), [0206] 9)
R.sup.dN3SO.sub.2--O-- (wherein R.sup.dN3 represents [0207] a) an
optionally substituted C.sub.1-22 alkyl group, [0208] b) an
optionally substituted C.sub.1-22 alkoxy group, [0209] c) an
optionally substituted unsaturated C.sub.2-22 alkoxy group, [0210]
d) an optionally substituted C.sub.6-14 aryl group, [0211] e) an
optionally substituted C.sub.6-14 aryloxy group, [0212] f) an
optionally substituted 5 to 14-membered heteroaryloxy group, [0213]
g) an optionally substituted C.sub.7-22 aralkyloxy group or [0214]
h) an optionally substituted 5 to 14-membered heteroaralkyloxy
group), [0215] 10) (R.sup.dN5O).sub.2PO-- (wherein R.sup.dN5
represents [0216] a) an optionally substituted C.sub.1-22 alkyl
group, [0217] b) an optionally substituted unsaturated C.sub.2-22
alkyl group, [0218] c) an optionally substituted C.sub.6-14 aryl
group, [0219] d) an optionally substituted 5 to 14-membered
heteroaryl group, [0220] e) an optionally substituted C.sub.7-22
aralkyl group or [0221] f) an optionally substituted 5 to
14-membered heteroaralkyl group), [0222] 11)
(R.sup.dN1R.sup.dN2N).sub.2PO-- (wherein R.sup.dN1 and R.sup.dN2
have the same meanings as defined above) or [0223] 12)
(R.sup.dN1R.sup.dN2N)(R.sup.dN5O)PO-- (wherein R.sup.dN1, R.sup.dN2
and R.sup.dN5 have the same meanings as defined above), provided
that a compound in which R.sup.3d, R.sup.6d, R.sup.7d and R.sup.21d
are all hydroxyl groups, and a compound in which R.sup.3d, R.sup.6d
and R.sup.21d are hydroxyl groups and R.sup.7d is an acetoxy group
are excluded), a pharmacologically acceptable salt thereof or a
hydrate of them; [0224] (6) the compound described in (1), wherein
R.sup.6 and/or R.sup.7 represents R.sup.N1R.sup.N2N--R.sup.M--
(wherein R.sup.M represents [0225] a) --CO--O-- or [0226] b)
--CS--O--; and [0227] R.sup.N1 and R.sup.N2 have the same meanings
as defined above, provided that each of the leftmost bond in a) and
b) is bound to the nitrogen atom), a pharmacologically acceptable
salt thereof or a hydrate of them; [0228] (7) the compound
described in (1), a pharmacologically acceptable salt thereof or a
hydrate of them, wherein R.sup.21 is an oxo group formed together
with the carbon atom to which R.sup.21 is bound; [0229] (8) the
compound described in (5) represented by the formula (I-e):
##STR8## (in the formula, R.sup.3e and R.sup.21e are the same as or
different from each other and each represents [0230] 1) a hydroxyl
group or an oxo group formed together with the carbon atom to which
each of R.sup.3e and R.sup.21e is bound, [0231] 2) an optionally
substituted C.sub.1-6 alkoxy group, [0232] 3) an optionally
substituted unsaturated C.sub.2-10 alkoxy group, [0233] 4) an
optionally substituted C.sub.7-10 aralkyloxy group, [0234] 5) an
optionally substituted aliphatic C.sub.2-6 acyloxy group or [0235]
6) R.sup.eN1R.sup.eN2N--CO--O-- (wherein R.sup.eN1 and R.sup.eN2
are the same as or different from each other and each represents
[0236] A) a hydrogen atom or [0237] B) an optionally substituted
C.sub.1-6 alkyl group); and [0238] R.sup.6e and R.sup.7e are the
same as or different from each other and each represents [0239] 1)
a hydroxyl group or an oxo group formed together with the carbon
atom to which each of R.sup.6e and R.sup.7e is bound, provided that
R.sup.6e is limited to a hydroxyl group, [0240] 2) an optionally
substituted C.sub.1-6 alkoxy group, [0241] 3) an optionally
substituted unsaturated C.sub.2-10 alkoxy group, [0242] 4) an
optionally substituted C.sub.7-10 aralkyloxy group, [0243] 5) an
optionally substituted aliphatic C.sub.2-6 acyloxy group or [0244]
6) R.sup.eC(.dbd.Y.sup.e)--O-- (wherein Y.sup.e represents an
oxygen atom or a sulfur atom; and R.sup.e represents [0245] a) a
hydrogen atom, [0246] b) an optionally substituted C.sub.1-6 alkyl
group, [0247] c) an optionally substituted C.sub.7-10 aralkyl
group, [0248] d) an optionally substituted 5 to 14-membered
heteroaralkyl group, [0249] e) the formula (III): ##STR9## [0250]
(in the formula, [0251] A) n represents an integer of 0 to 4;
[0252] X.sub.e represents [0253] i) --CHR.sup.eN4, [0254] ii)
--NR.sup.eN5--, [0255] iii) --O--, [0256] iv) --S--, [0257] v)
--SO-- or [0258] vi) --SO.sub.2--; [0259] R.sup.eN1 represents
[0260] i) a hydrogen atom or [0261] ii) a C.sub.1-6 alkyl group;
[0262] R.sup.eN2 represents [0263] i) hydrogen atom or [0264] ii) a
C.sub.1-6 alkyl group; [0265] R.sup.eN3 and R.sup.eN4 are the same
as or different from each other and each represents [0266] i) a
hydrogen atom, [0267] ii) an optionally substituted C.sub.1-6 alkyl
group, [0268] iii) an optionally substituted unsaturated C.sub.2-10
alkyl group, [0269] iv) an optionally substituted C.sub.6-14 aryl
group, [0270] v) an optionally substituted 5 to 14-membered
heteroaryl group, [0271] vi) an optionally substituted C.sub.7-10
aralkyl group, [0272] vii) an optionally substituted C.sub.3-8
cycloalkyl group, [0273] viii) an optionally substituted C.sub.4-9
cycloalkyl alkyl group, [0274] ix) an optionally substituted 5 to
14-membered heteroaralkyl group, [0275] x) an optionally
substituted 5 to 14-membered non-aromatic heterocyclic group,
[0276] xi) --NR.sup.eN6R.sup.eN7 (wherein R.sup.eN6 and R.sup.eN7
are the same as or different from each other and each represents a
hydrogen atom or an optionally substituted C.sub.1-6 alkyl group)
or [0277] xii) an optionally substituted 5 to 14-membered
non-aromatic heterocyclic group formed by R.sup.eN3 and R.sup.eN4
together with the carbon atom to which R.sup.eN3 and R.sup.eN4 are
bound, and the non-aromatic heterocyclic group may have
substituents; and [0278] R.sup.eN5 represents [0279] i) a hydrogen
atom, [0280] ii) an optionally substituted C.sub.1-6 alkyl group,
[0281] iii) an optionally substituted unsaturated C.sub.2-10 alkyl
group, [0282] iv) an optionally substituted C.sub.6-14 aryl group,
[0283] v) an optionally substituted 5 to 14-membered heteroaryl
group, [0284] vi) an optionally substituted C.sub.7-10 aralkyl
group, [0285] vii) an optionally substituted C.sub.3-8 cycloalkyl
group, [0286] viii) an optionally substituted C.sub.4-9 cycloalkyl
alkyl group, [0287] ix) an optionally substituted 5 to 14-membered
heteroaralkyl group, [0288] x) an optionally substituted 5 to
14-membered non-aromatic heterocyclic group or [0289] xi) an
optionally substituted 5 to 14-membered non-aromatic heterocyclic
group formed by R.sup.eN3 and R.sup.eN5 together with the nitrogen
atom to which R.sup.eN3 and R.sup.eN5 are bound, and the
non-aromatic heterocyclic group may have substituents, [0290] B)
X.sub.e, n, R.sup.eN3, R.sup.eN4 and R.sup.eN5 each represents the
group as defined above; and R.sup.eN1 and R.sup.eN2 together form
an optionally substituted 5 to 14-membered non-aromatic
heterocyclic group, [0291] C) X.sub.e, n, R.sup.eN2, R.sup.eN4 and
R.sup.eNn5 each represents the group as defined above; and
R.sup.eN1 and R.sup.eN3 together form an optionally substituted 5
to 14-membered non-aromatic heterocyclic group or [0292] D)
X.sub.e, n, R.sup.eN1, R.sup.eN4 and R.sup.eN5 each represents the
group as defined above; and R.sup.eN2 and R.sup.eN3 together form
an optionally substituted 5 to 14-membered non-aromatic
heterocyclic group) or [0293] f) the formula (IV): ##STR10## [0294]
(in the formula, R.sup.eN8 and R.sup.eN9 are the same as or
different from each other and each represents [0295] i) a hydrogen
atom, [0296] ii) an optionally substituted C.sub.1-6 alkyl group,
[0297] iii) an optionally substituted C.sub.6-14 aryl group, [0298]
iv) an optionally substituted 5 to 14-membered heteroaryl group,
[0299] v) an optionally substituted C.sub.7-10 aralkyl group or
[0300] vi) an optionally substituted 5 to 14-membered heteroaralkyl
group))), a pharmacologically acceptable salt thereof or a hydrate
of them; [0301] (9) the compound described in (5), wherein R.sup.6d
and/or R.sup.7d represents R.sup.d1C(.dbd.Y.sup.d1)--O-- (wherein
Y.sup.d1 represents an oxygen atom or a sulfur atom; and R.sup.d1
represents [0302] 1) a hydrogen atom, [0303] 2) an optionally
substituted C.sub.1-6 alkyl group, [0304] 3) an optionally
substituted C.sub.7-10 aralkyl group or [0305] 4) an optionally
substituted 5 to 14-membered heteroaralkyl group), a
pharmacologically acceptable salt thereof or a hydrate of them;
[0306] (10) the compound described in (5), wherein R.sup.6d and/or
R.sup.7d represents R.sup.d2C(.dbd.Y.sup.d2)--O-- (wherein Y.sup.d2
represents an oxygen atom or a sulfur atom; and R.sup.d2 represents
the formula (III'): ##STR11## (in the formula, n represents an
integer of 0 to 4; X.sub.1 represents [0307] 1) CHR.sup.dN7--,
[0308] 2) --NR.sup.dN8--, [0309] 3) --O--, [0310] 4) --S--, [0311]
5) --SO-- or [0312] 6) --SO.sub.2--; [0313] R.sup.dN4 and R.sup.dN5
are the same as or different from each other and each represents
[0314] 1) a hydrogen atom or [0315] 2) a C.sub.1-6 alkyl group;
[0316] R.sup.dN6 and R.sup.dN7 are the same as or different from
each other and each represents [0317] 1) a hydrogen atom, [0318] 2)
an optionally substituted C.sub.1-6 alkyl group, [0319] 3) an
optionally substituted unsaturated C.sub.2-10 alkyl group, [0320]
4) an optionally substituted C.sub.6-14 aryl group, [0321] 5) an
optionally substituted 5 to 14-membered heteroaryl group, [0322] 6)
an optionally substituted C.sub.7-10 aralkyl group, [0323] 7) an
optionally substituted C.sub.3-8 cycloalkyl group, [0324] 8) an
optionally substituted C.sub.4-9 cycloalkyl alkyl group, [0325] 9)
an optionally substituted 5 to 14-membered heteroaralkyl group,
[0326] 10) an optionally substituted 5 to 14-membered non-aromatic
heterocyclic group, [0327] 11) --NR.sup.dN9R.sup.dN10 (wherein
R.sup.dN9 and R.sup.dN10 are the same as or different from each
other and each represents a hydrogen atom or an optionally
substituted C.sub.1-6 alkyl group) or [0328] 12) an optionally
substituted 5 to 14-membered non-aromatic heterocyclic group formed
together by R.sup.dN6 and R.sup.dN7, and the non-aromatic
heterocyclic group may have substituents; and [0329] R.sup.dN8
represents [0330] 1) a hydrogen atom, [0331] 2) an optionally
substituted C.sub.1-6 alkyl group, [0332] 3) an optionally
substituted unsaturated C.sub.2-10 alkyl group, [0333] 4) an
optionally substituted C.sub.6-14 aryl group, [0334] 5) an
optionally substituted 5 to 14-membered heteroaryl group, [0335] 6)
an optionally substituted C.sub.7-10 aralkyl group, [0336] 7) an
optionally substituted C.sub.3-8 cycloalkyl group, [0337] 8) an
optionally substituted C.sub.4-9 cycloalkyl alkyl group, [0338] 9)
an optionally substituted 5 to 14-membered heteroaralkyl group,
[0339] 10) an optionally substituted 5 to 14-membered non-aromatic
heterocyclic group, [0340] 11) an optionally substituted 5 to
14-membered non-aromatic heterocyclic group formed by R.sup.dN4,
R.sup.dN5 or R.sup.dN6 together with the nitrogen atom to which
each of R.sup.dN4, R.sup.dN5 and R.sup.dN6 is bound, and the
non-aromatic heterocyclic group may have substituents or [0341] 12)
an optionally substituted 5 to 14-membered non-aromatic
heterocyclic group formed by two substituents selected from the
group consisting of R.sup.dN4, R.sup.dN5 and R.sup.dN6 together
with the nitrogen atom to which it is bound, and the non-aromatic
heterocyclic group may have substituents)), a pharmacologically
acceptable salt thereof or a hydrate of them; [0342] (11) the
compound described in (10), a pharmacologically acceptable salt
thereof or a hydrate of them, wherein X.sub.1 represents
--NR.sup.dN8-- (wherein NR.sup.dN8 has the same meanings as defined
above); [0343] (12) the compound described in (5) represented by
the formula (I-f): ##STR12## (in the formula, R.sup.7f represents
R.sup.fC(.dbd.Y.sup.f)--O-- (wherein Y.sup.f represents an oxygen
atom or a sulfur atom; and R.sup.f represents the formula (V):
##STR13## (wherein n represents an integer of 0 to 4; [0344]
R.sup.fN1 represents [0345] 1) a hydrogen atom, [0346] 2) a methyl
group or [0347] 3) an ethyl group; and [0348] R.sup.fN2 represents
[0349] 1) a hydrogen atom, [0350] 2) a methylamino group, [0351] 3)
a dimethylamino group, [0352] 4) an ethylamino group, [0353] 5) a
diethylamino group, [0354] 6) an ethylmethylamino group, [0355] 7)
a pyridinyl group, [0356] 8) a pyrrolidin-1-yl group, [0357] 9) a
piperidin-1-yl group, [0358] 10) a morpholin-4-yl group or [0359]
11) a 4-methylpiperazin-1-yl group))), a pharmacologically
acceptable salt thereof or a hydrate of them; [0360] (13) the
compound described in (5), wherein R.sup.6d and/or R.sup.7d
represents R.sup.d3CO--O-- (wherein R.sup.d3 represents the formula
(VI): ##STR14## (wherein n.sub.1 and n.sub.2 are the same as or
different from each other and each represents an integer of 0 to 4;
[0361] X.sub.2 represents [0362] 1) --CHR.sup.dN13--, [0363] 2)
--NR.sup.dN14--, [0364] 3) --O--, [0365] 4) --S--, [0366] 5) --SO--
or [0367] 6) --SO.sub.2--; [0368] R.sup.dN11 represents [0369] 1) a
hydrogen atom or [0370] 2) an optionally substituted C.sub.1-6
alkyl group; [0371] R.sup.dN12 represents [0372] 1) a hydrogen
atom,
[0373] 2) an optionally substituted C.sub.1-6 alkyl group, [0374]
3) an optionally substituted C.sub.6-14 aryl group or [0375] 4) an
optionally substituted C.sub.7-10 aralkyl group; [0376] R.sup.dN13
represents [0377] 1) a hydrogen atom, [0378] 2) an optionally
substituted C.sub.1-6 alkyl group, [0379] 3) an optionally
substituted unsaturated C.sub.2-10 alkyl group, [0380] 4) an
optionally substituted C.sub.6-14 aryl group, [0381] 5) an
optionally substituted 5 to 14-membered heteroaryl group, [0382] 6)
an optionally substituted C.sub.7-10 aralkyl group, [0383] 7) an
optionally substituted C.sub.3-8 cycloalkyl group, [0384] 8) an
optionally substituted C.sub.4-9 cycloalkyl alkyl group, [0385] 9)
an optionally substituted 5 to 14-membered heteroaralkyl group,
[0386] 10) --NR.sup.dN15R.sup.dN16 (wherein R.sup.dN15 and
R.sup.dN16 are the same as or different from each other and each
represents a hydrogen atom or an optionally substituted C.sub.1-6
alkyl group) or [0387] 11) an optionally substituted 5 to
14-membered non-aromatic heterocyclic group; and [0388] R.sup.dN14
represents [0389] 1) a hydrogen atom, [0390] 2) an optionally
substituted C.sub.1-6 alkyl group, [0391] 3) an optionally
substituted unsaturated C.sub.2-10 alkyl group, [0392] 4) an
optionally substituted C.sub.6-14 aryl group, [0393] 5) an
optionally substituted 5 to 14-membered heteroaryl group, [0394] 6)
an optionally substituted C.sub.7-10 aralkyl group, [0395] 7) an
optionally substituted C.sub.3-8 cycloalkyl group, [0396] 8) an
optionally substituted C.sub.4-9 cycloalkyl alkyl group, [0397] 9)
an optionally substituted 5 to 14-membered heteroaralkyl group or
[0398] 10) an optionally substituted 5 to 14-membered non-aromatic
heterocyclic group)), a pharmacologically acceptable salt thereof
or a hydrate of them; [0399] (14) the compound described in (5)
represented by the formula (I-g): ##STR15## (in the formula,
R.sup.7g represents R.sup.gCO--O-- (wherein R.sup.g represents the
formula (VII): ##STR16## (wherein n.sub.3 represents 1 or 2; [0400]
R.sup.dN17 represents [0401] 1) a hydrogen atom, [0402] 2) a methyl
group or [0403] 3) an ethyl group; and [0404] R.sup.dN18 represents
[0405] 1) a hydrogen atom, [0406] 2) a methyl group or [0407] 3) an
ethyl group))), a pharmacologically acceptable salt thereof or a
hydrate of them; [0408] (15) the compound described in (5), wherein
R.sup.6d and/or R.sup.7d represents R.sup.d4CO--O-- (wherein
R.sup.d4 represents the formula (VIII): ##STR17## (wherein n.sub.1
and n.sub.2 are the same as or different from each other and each
represents an integer of 0 to 4; [0409] X.sub.3 represents [0410]
1) --CHR.sup.dN21--, [0411] 2) --NR.sup.dN222--, [0412] 3) --O--,
[0413] 4) --S--, [0414] 5) --SO-- or [0415] 6) --SO.sub.2--; [0416]
R.sup.dN19 represents [0417] 1) a hydrogen atom or [0418] 2) a
C.sub.1-6 alkyl group; [0419] R.sup.dN20 represents [0420] 1) a
hydrogen atom, [0421] 2) an optionally substituted C.sub.1-6 alkyl
group, [0422] 3) an optionally substituted C.sub.6-14 aryl group or
[0423] 4) an optionally substituted C.sub.7-10 aralkyl group;
[0424] R.sup.dN21 represents [0425] 1) a hydrogen atom, [0426] 2)
an optionally substituted C.sub.1-6 alkyl group, [0427] 3) an
optionally substituted unsaturated C.sub.2-10 alkyl group, [0428]
4) an optionally substituted C.sub.1-6 alkoxy group, [0429] 5) an
optionally substituted C.sub.6-14 aryl group, [0430] 6) an
optionally substituted 5 to 14-membered heteroaryl group, [0431] 7)
an optionally substituted C.sub.7-10 aralkyl group, [0432] 8) an
optionally substituted C.sub.3-8 cycloalkyl group, [0433] 9) an
optionally substituted C.sub.4-9 cycloalkyl alkyl group, [0434] 10)
an optionally substituted 5 to 14-membered heteroaralkyl group,
[0435] 11) --NR.sup.dN23R.sup.dN24 (wherein R.sup.dN23 and
R.sup.dN24 are the same as or different from each other and each
represents a hydrogen atom or an optionally substituted C.sub.1-6
alkyl group) or [0436] 12) an optionally substituted 5 to
14-membered non-aromatic heterocyclic group; and [0437] R.sup.dN22
represents [0438] 1) a hydrogen atom, [0439] 2) an optionally
substituted C.sub.1-6 alkyl group, [0440] 3) an optionally
substituted unsaturated C.sub.2-10 alkyl group, [0441] 4) an
optionally substituted C.sub.6-14 aryl group, [0442] 5) an
optionally substituted 5 to 14-membered heteroaryl group, [0443] 6)
an optionally substituted C.sub.7-10 aralkyl group, [0444] 7) an
optionally substituted C.sub.3-8 cycloalkyl group, [0445] 8) an
optionally substituted C.sub.4-9 cycloalkyl alkyl group, [0446] 9)
an optionally substituted 5 to 14-membered heteroaralkyl group or
[0447] 10) an optionally substituted 5 to 14-membered non-aromatic
heterocyclic group)), a pharmacologically acceptable salt thereof
or a hydrate of them; [0448] (16) the compound described in (5)
represented by the formula (I-h): ##STR18## (in the formula,
R.sub.7h represents R.sup.hCO--O-- (wherein R.sup.h represents the
formula (IX): ##STR19## (wherein n.sub.4 represents an integer of 1
to 3; and [0449] R.sup.dN25 represents [0450] 1) an amino group,
[0451] 2) a methylamino group, [0452] 3) a dimethylamino group,
[0453] 4) a pyrrolidin-1-yl group, [0454] 5) a piperidin-1-yl group
or [0455] 6) a morpholin-4-yl group))), a pharmacologically
acceptable salt thereof or a hydrate of them; [0456] (17) the
compound described in (5) represented by the formula (I-i):
##STR20## (in the formula, R.sup.7i represents R.sup.iCO--O--
(wherein R.sup.i represents the formula (X): ##STR21## (wherein
n.sub.4 represents an integer of 1 to 3; [0457] R.sup.dN26
represents [0458] 1) a hydrogen atom, [0459] 2) an optionally
substituted C.sub.1-6 alkyl group, [0460] 3) an optionally
substituted C.sub.6-14 aryl group or [0461] 4) an optionally
substituted C.sub.7-10 aralkyl group; and [0462] R.sup.dN27
represents [0463] 1) a hydrogen atom, [0464] 2) an optionally
substituted C.sub.1-6 alkyl group, [0465] 3) an optionally
substituted C.sub.3-8 cycloalkyl group, [0466] 4) an optionally
substituted 3 to 8-membered non-aromatic heterocyclic group, [0467]
5) an optionally substituted C.sub.6-14 aryl group, [0468] 6) an
optionally substituted 5 to 14-membered heteroaryl group, [0469] 7)
an optionally substituted C.sub.7-10 aralkyl group, [0470] 8) an
optionally substituted 5 to 14-membered heteroaralkyl group or
[0471] 9) an optionally substituted C.sub.4-9 cycloalkyl alkyl
group))), a pharmacologically acceptable salt thereof or a hydrate
of them; [0472] (18) the compound described in (5) represented by
the formula (I-j): ##STR22## (in the formula, R.sup.7j represents
R.sup.jCO--O-- (wherein R.sup.j represents the formula (XI):
##STR23## (wherein n.sub.4 represents an integer of 1 to 3; and
[0473] R.sup.dN28 represents [0474] 1) a hydrogen atom, [0475] 2)
an optionally substituted C.sub.1-6 alkyl group, [0476] 3) a
C.sub.3-8 cycloalkyl group, [0477] 4) a C.sub.4-9 cycloalkyl alkyl
group, [0478] 5) a C.sub.7-10 aralkyl group, [0479] 6) a pyridinyl
group or [0480] 7) a tetrahydropyranyl group))), a
pharmacologically acceptable salt thereof or a hydrate of them;
[0481] (19) the compound described in (5) represented by the
formula (I-k): ##STR24## (in the formula, R.sup.7k represents
R.sup.kCO--O-- (wherein R.sup.k represents the formula (XII):
##STR25## (wherein m.sub.1, m.sub.2, m.sub.3 and m.sub.4 are the
same as or different from one another and each represents 0 or 1;
[0482] n.sub.4 represents an integer of 1 to 3; and [0483]
R.sup.dN29 represents [0484] 1) a hydrogen atom, [0485] 2) an
optionally substituted C.sub.1-6 alkyl group, [0486] 3) an
optionally substituted unsaturated C.sub.2-10 alkyl group, [0487]
4) an optionally substituted C.sub.6-14 aryl group, [0488] 5) an
optionally substituted 5 to 14-membered heteroaryl group, [0489] 6)
an optionally substituted C.sub.7-10 aralkyl group, [0490] 7) an
optionally substituted C.sub.3-8 cycloalkyl group, [0491] 8) an
optionally substituted C.sub.4-9 cycloalkyl alkyl group, [0492] 9)
an optionally substituted 5 to 14-membered heteroaralkyl group or
[0493] 10) an optionally substituted 5 to 14-membered non-aromatic
heterocyclic group))), a pharmacologically acceptable salt thereof
or a hydrate of them; [0494] (20) the compound described in (5)
represented by the formula (I-m): ##STR26## (in the formula,
R.sup.7m represents R.sup.mCO--O-- (wherein R.sup.m represents the
formula (XIII): ##STR27## (wherein m.sub.5 represents an integer of
1 to 3; and n.sub.5 represents 2 or 3))), a pharmacologically
acceptable salt thereof or a hydrate of them; [0495] (21) the
compound described in (5) represented by the formula (I-n)
##STR28## (in the formula, R.sup.7n represents R.sup.nCO--O--
(wherein R.sup.n is a group represented by the formula (XIV):
##STR29## a pharmacologically acceptable salt thereof or a hydrate
of them; [0496] (22) the compound described in (1), which is
selected from:
(8E,12E,14E)-7-(N-(2-(N',N'-Dimethylamino)ethyl)-N-methylcarbamoyloxy)-3,-
6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14--
trien-11-olide (Compound 6);
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methy-
lhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 9);
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methy-
lpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 12);
(8E,12E,14E)-7-((4-Butylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydrox-
y-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 16);
(8E,12E,14E)-7-((4-Ethylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydrox-
y-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 21);
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propy-
lpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 25);
(8E,12E,14E)-7-((4-Cyclohexylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrah-
ydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 26);
(8E,12E,14E)-7-((4-(Cyclopropylmethyl)piperazin-1-yl)carbonyl)oxy-3,6,16,-
21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-
-11-olide (Compound 27);
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propy-
lhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 31);
(8E,12E,14E)-7-((4-(Cyclopropylmethyl)homopiperazin-1-yl)carbonyl)oxy-3,6-
,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-t-
rien-11-olide (Compound 36);
(8E,12E,14E)-7-((4-Cyclopentylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetra-
hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olid-
e (Compound 38);
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isopropylpiperazin-1-yl)carbony-
l)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 44);
(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetra-
hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olid-
e (Compound 45);
(8E,12E,14E)-7-(N-(2-(N',N'-Diethylamino)ethyl)-N-methylcarbamoyloxy)-3,6-
,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-t-
rien-11-olide (Compound 75);
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isobutylhomopiperazin-1-yl)carb-
onyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-oli-
de (Compound 54);
(8E,12E,14E)-7-((4-Ethylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahy-
droxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 63);
(8E,12E,14E)-7-((4-Butylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahy-
droxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 64);
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-
-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-oli-
de (Compound 85);
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-
-(piperidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-tr-
ien-11-olide (Compound 109);
(8E,12E,14E)-7-((4-(2,2-Dimethylpropyl)homopiperazin-1-yl)carbonyl)oxy-3,-
6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14--
trien-11-olide (Compound 69); and
(8E,12E,14E)-3,6,16-Trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7-((4-
-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-oli-
de (Compound 131); [0497] (23) the compound described in (1), which
is selected from:
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methy-
lhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 9);
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methy-
lpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 12);
(8E,12E,14E)-7-((4-Cyclohexylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrah-
ydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 26);
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isopropylpiperazin-1-yl)carbony-
l)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 44);
(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetra-
hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olid-
e (Compound 45); and
(8E,12E,14E)-7-(N-(2-(N',N'-Diethylamino)ethyl)-N-methylcarbamoyloxy)-3,6-
,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-t-
rien-11-olide (Compound 75); [0498] (24) a medicament comprising
the compound described in any one of (1) to (23), a
pharmacologically acceptable salt thereof or a hydrate of them as
an active ingredient; [0499] (25) a pharmaceutical composition
comprising the compound described in any one of (1) to (23), a
pharmacologically acceptable salt thereof or a hydrate of them as
an active ingredient; [0500] (26) the medicament described in (24),
which is an agent for preventing or treating a disease against
which a regulation of gene expression is efficacious; [0501] (27)
the medicament described in (22), which is an agent for preventing
or treating a diseases against which suppression of VEGF production
is efficacious; [0502] (28) the medicament described in (22), which
is an agent for preventing or treating a disease against which an
antiangiogenic effect is efficacious; [0503] (29) the medicament
described in (24), which is an angiogenesis inhibitor; [0504] (30)
the medicament described in (24), which is an antitumor agent;
[0505] (31) the medicament described in (24), as a therapeutic
agent for treating angioma; [0506] (32) the medicament described in
(24), which is a cancer metastasis inhibitor;
[0507] (33) the medicament described in (22), which is a
therapeutic agent for treating retinal neovascularization or
diabetic retinopathy; [0508] (34) the medicament described in (24),
which is a therapeutic agent for treating inflammatory disease;
[0509] (35) the medicament described in (24), which is a
therapeutic agent for treating inflammatory diseases consisting of
deformans arthritis, rheumatoid arthritis, psoriasis and delayed
hypersensitivity reaction; [0510] (36) the medicament described in
(24), which is a therapeutic agent for treating atherosclerosis;
[0511] (37) the medicament described in (24), which is a
therapeutic agent for treating solid cancer; [0512] (38) the
medicament described in (37), wherein the solid cancer is lung
cancer, brain tumor, breast cancer, prostate cancer, ovarian
cancer, colon cancer or melanoma; [0513] (39) the medicament
described in (24), which is a therapeutic agent for treating
leukemia; [0514] (40) the medicament described in (24), which is an
antitumor agent based on a regulation of gene expression; [0515]
(41) the medicament described in (24), which is an antitumor agent
based on suppression of VEGF production; [0516] (42) the medicament
described in (24), which is an antitumor agent based on an effect
of angiogenesis inhibition; [0517] (43) a method for preventing or
treating a disease against which a regulation of gene expression is
efficacious, which comprises administering a pharmacologically
effective dose of the medicament described in (24) to a patient;
[0518] (44) a method for preventing or treating a disease against
which suppression of VEGF production is efficacious, which
comprises administering a pharmacologically effective dose of the
medicament described in (24) to a patient; [0519] (45) a method for
preventing or treating a disease against which an angiogenesis
inhibition is efficacious, which comprises administering a
pharmacologically effective dose of the medicament described in
(24) to a patient; [0520] (46) use of the compound described in any
one of (1) to (23), a pharmacologically acceptable salt thereof or
a hydrate of them, for manufacturing an agent for preventing or
treating a disease against which a regulation of gene expression is
efficacious; [0521] (47) use of the compound described in any one
of (1) to (23), a pharmacologically acceptable salt thereof or a
hydrate of them, for manufacturing an agent for preventing or
treating a disease against which suppression of VEGF production is
efficacious; [0522] (48) use of the compound described in any one
of (1) to (23), a pharmacologically acceptable salt thereof or a
hydrate of them, for manufacturing an agent for preventing or
treating a disease against which an angiogenesis inhibition is
efficacious; and [0523] (49) use of the compound described in any
one of (1) to (23), a pharmacologically acceptable salt thereof or
a hydrate of them, for producing an agent for preventing or
treating solid cancers.
[0524] The terms, symbols and the like used in the present
specification will be illustrated below.
[0525] In the present specification, the chemical formula of the
compound according to the present invention is illustrated as a
planimetric chemical formula for convenience but the compound can
include certain isomers drawn from the chemical formula. The
present invention can include all isomers and mixtures of the
isomers such as a geometric isomer which is generated from the
configuration of the compound, an optical isomer based on an
asymmetric carbon, a rotamer, a stereoisomer and a tautomer. The
present invention is not limited to the expediential description of
the chemical formula, and can include either of isomers or a
mixture thereof. Accordingly, when the compound of the present
invention has an asymmetric carbon in the molecule, and its
optically active substance and racemate exist, any one is included.
Further, when polymorphic crystals exist, the crystal form of the
present invention is not specifically limited to one form, and any
one of the crystal forms may be single or a mixture of the crystal
forms. The compound represented by the formula (I) according to the
present invention or a salt thereof may be an anhydrate or a
hydrate, and both are included in the present invention. The
metabolite which is generated in vivo by decomposition of the
compound of the formula (I) according to the present invention and
the prodrug of the compound of the formula (I) according to the
present invention or a salt thereof are also included in the
present invention.
[0526] The "halogen atom" used in the specification of the present
application means a fluorine atom, a chlorine atom, a bromine atom
and an iodine atom. Among them, for example, a fluorine atom, a
chlorine atom or a bromine atom is preferred, of which a fluorine
atom or a chlorine atom is typically preferred.
[0527] The "C.sub.1-22 alkyl group" used in the specification of
the present application indicates a linear or branched alkyl group
having 1 to 22 carbon atoms, such as methyl group, ethyl group,
n-propyl group, iso-propyl group, n-butyl group, iso-butyl group,
sec-butyl group, tert-butyl group, n-pentyl group,
1,1-dimethylpropyl group, 1,2-dimethylpropyl group,
2,2-dimethylpropyl group, 1-ethylpropyl group, n-hexyl group,
1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group,
1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group,
1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl
group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group,
2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group,
n-heptyl group, n-octyl group, n-nonyl group or n-decyl group;
preferably a linear or branched alkyl group having 1 to 6 carbon
atoms, such as methyl group, ethyl group, n-propyl group,
iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group,
tert-butyl group or n-pentyl group; and more preferably, for
example, methyl group, ethyl group, propyl group, iso-propyl group,
n-butyl group, iso-butyl group or tert-butyl group.
[0528] The "unsaturated C.sub.2-22 alkyl group" used in the
specification of the present application indicates a linear or
branched alkenyl group having 2 to 22 carbon atoms or a linear or
branched alkynyl group having 2 to 22 carbon atoms, such as vinyl
group, allyl group, 1-propenyl group, isopropenyl group,
2-methyl-1-propenyl group, 2-methyl-2-propenyl group, 1-butenyl
group, 2-butenyl group, 3-butenyl group, 1-pentenyl group,
1-hexenyl group, 1,3-hexadienyl group, 1,5-hexadienyl group,
ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group,
2-butynyl group, 3-butynyl group, 1-ethynyl-2-propynyl group,
2-methyl-3-butynyl group, 1-pentynyl group, 1-hexynyl group,
1,3-hexanediynyl group or 1,5-hexanediynyl group. It preferably
indicates a linear or branched alkenyl group having 2 to 10 carbon
atoms or a linear or branched alkynyl group having 2 to 10 carbon
atoms, such as vinyl group, allyl group, 1-propenyl group,
2-propenyl group, isopropenyl group, 3-methyl-2-butenyl group,
3,7-dimethyl-2,6-octadienyl group, ethynyl group, 1-propynyl group,
2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group
or 3-methyl-1-propynyl group.
[0529] The "C.sub.6-14 aryl group" used in the specification of the
present application means an aromatic cyclic hydrocarbon group
having 6 to 14 carbon atoms, and a monocyclic group and condensed
rings such as a bicyclic group and a tricyclic group are included.
Examples thereof are phenyl group, indenyl group, 1-naphthyl group,
2-naphthyl group, azulenyl group, heptalenyl group, indacenyl
group, acenaphthyl group, fluorenyl group, phenalenyl group,
phenanthrenyl group and anthracenyl group; of which a preferred
example is phenyl group, 1-naphthyl group or 2-naphthyl group.
[0530] The "5 to 14-membered heteroaryl group" used in the
specification of the present application means a monocyclic,
bicyclic or tricyclic 5 to 14-membered aromatic heterocyclic group
which contains one or more of hetero atoms selected from the group
consisting of nitrogen atom, sulfur atom and oxygen atom. Preferred
examples thereof are a nitrogen-containing aromatic heterocyclic
group such as pyrrolyl group, pyridinyl group, pyridazinyl group,
pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl
group, benzotriazolyl group, pyrazolyl group, imidazolyl group,
benzimidazolyl group, indolyl group, isoindolyl group, indolizinyl
group, purinyl group, indazolyl group, quinolinyl group,
isoquinolinyl group, quinolizinyl group, phthalazinyl group,
naphthyridinyl group, quinoxalinyl group, quinazolinyl group,
cinnolinyl group, pteridinyl group, imidazotriazinyl group,
pyrazinopyridazinyl group, acridinyl group, phenanthridinyl group,
carbazolyl group, carbazolinyl group, perimidinyl group,
phenanthrolinyl group, phenazinyl group, imidazopyridinyl group,
imidazopyrimidinyl group, pyrazolopyridinyl group or
pyrazolopyridinyl group; a sulfur-containing aromatic heterocyclic
group such as thienyl group or benzothienyl group; and an
oxygen-containing aromatic heterocyclic group such as furyl group,
pyranyl group, cyclopentapyranyl group, benzofuryl group or
isobenzofuryl group; an aromatic heterocyclic group containing two
or more different hetero atoms, such as thiazolyl group,
isothiazolyl group, benzothiazolyl group, benzthiadiazolyl group,
phenothiazinyl group, isoxazolyl group, furazanyl group,
phenoxazinyl group, oxazolyl group, isoxazoyl group, benzoxazolyl
group, oxadiazolyl group, pyrazolooxazolyl group, imidazothiazolyl
group, thienofuranyl group, furopyrrolyl group or pyridoxazinyl
group, of which a preferred example is thienyl group, furyl group,
pyridinyl group, pyridazinyl group, pyrimidinyl group or pyrazinyl
group.
[0531] The "3 to 14-membered non-aromatic heterocyclic group" used
in the specification of the present application indicates a
monocyclic, bicyclic or tricyclic 3 to 14-membered non-aromatic
heterocyclic group which may contain one or more hetero atoms
selected from the group consisting of nitrogen atom, sulfur atom
and oxygen atom. Preferred examples thereof are aziridinyl group,
azetidinyl group, pyrrolidinyl group, pyrrolyl group, piperidinyl
group, piperazinyl group, homopiperidinyl group, homopiperazinyl
group, imidazolyl group, pyrazolidinyl group, imidazolidinyl group,
morpholinyl group, thiomorpholinyl group, imidazolinyl group,
oxazolinyl group, 2,5-diazabicyclo[2.2.1]heptyl group,
2,5-diazabicyclo[2.2.2]octyl group, 3,8-diazabicyclo[3.2.1]octyl
group, 1,4-diazabicyclo[4.3.0]nonyl group, quinuclidinyl group,
tetrahydrofuranyl group and tetrahydrothiophenyl group. The
non-aromatic heterocyclic group also includes a group derived from
a pyridone ring, and a non-aromatic fused ring (e.g., a group
derived from, for example, phthalimide ring or succinimide
ring).
[0532] The "C.sub.7-22 aralkyl group" used in the specification of
the present application means a group corresponding to the
above-defined "C.sub.1-22 alkyl group" of which substitutable
moiety is replaced by the above-defined "C.sub.6-14 aryl group".
Specific examples thereof are benzyl group, phenethyl group,
3-phenylpropyl group, 4-phenylbutyl group, 1-naphthylmethyl group
and 2-naphthylmethyl group, of which an aralkyl group having 7 to
10 carbon atoms such as benzyl group or phenethyl group is
preferred.
[0533] The "5 to 14-membered heteroaralkyl group" used in the
specification of the present application means a group
corresponding to the above-defined "C.sub.1-22 alkyl group" of
which substitutable moiety is replaced by the above-defined "5 to
14-membered heteroaryl group". Specific examples thereof are
thienylmethyl group, furylmethyl group, pyridinylmethyl group,
pyridazinylmethyl group, pyrimidinylmethyl group and
pyrazinylmethyl group, of which a preferred example is
thienylmethyl group, furylmethyl group or pyridinylmethyl
group.
[0534] The "C.sub.3-14 cycloalkyl group" used in the specification
of the present application indicates a cycloalkyl group having 3 to
14 carbon atoms, and suitable examples thereof are cyclopropyl
group, cyclobutyl group, cyclopentyl group, cyclohexyl group,
cycloheptyl group and cyclooctyl group, of which a preferred
example is cyclopentyl group, cyclohexyl group, cycloheptyl group
or cyclooctyl group.
[0535] The "C.sub.4-9 cycloalkyl alkyl group" used in the
specification of the present application means a group
corresponding to the above-defined "C.sub.1-22 alkyl group" of
which substitutable moiety is replaced by the above-defined
"C.sub.3-14 cycloalkyl group". Specific examples thereof are
cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl
group, cyclohexylmethyl group, cycloheptylmethyl group and
cyclooctylmethyl group, of which a preferred example is
cyclopropylmethyl group, cyclobutylmethyl group or
cyclopentylmethyl group.
[0536] The "C.sub.1-22 alkoxy group" used in the specification of
the present application means a group corresponding to the
above-defined "C.sub.1-22 alkyl group" to which end an oxygen atom
is bonded. Suitable examples thereof are methoxy group, ethoxy
group, n-propoxy group, iso-propoxy group, n-butoxy group,
iso-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy
group, iso-pentyloxy group, sec-pentyloxy group, n-hexyloxy group,
iso-hexyloxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy
group, 2,2-dimethylpropoxy group, 1-methyl-2-ethylpropoxy group,
1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group,
1,2,2-trimethylpropoxy group, 1,1-dimethylbutoxy group,
1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group,
2,3-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2-ethylbutoxy
group, 2-methylpentyloxy group, 3-methylpentyloxy group and
hexyloxy group, of which a preferred example is methoxy group,
ethoxy group, n-propoxy group, iso-propoxy group, iso-butoxy group
or 2,2-dimethylpropoxy group.
[0537] The "unsaturated C.sub.2-22 alkoxy group" used in the
specification of the present application means a group
corresponding to the above-defined "unsaturated C.sub.2-22 alkyl
group" to which end an oxygen atom is bonded. Suitable examples
thereof are vinyloxy group, allyloxy group, 1-propenyloxy group,
2-propenyloxy group, isopropenyloxy group, 2-methyl-1-propenyloxy
group, 2-methyl-2-propenyloxy group, 1-butenyloxy group,
2-butenyloxy group, 3-butenyloxy group, 1-pentenyloxy group,
1-hexenyloxy group, 1,3-hexadienyloxy group, 1,5-hexadienyloxy
group, propargyloxy group and 2-butynyloxy group, of which a
preferred example is allyloxy group, propargyloxy group or
2-butynyloxy group.
[0538] The "C.sub.6-14 aryloxy group" used in the specification of
the present application means a group corresponding to the
above-defined "C.sub.6-14 aryl group" to which end an oxygen atom
is bonded. Specific examples thereof are phenyloxy group,
indenyloxy group, 1-naphthyloxy group, 2-naphthyloxy group,
azulenyloxy group, heptalenyloxy group, indacenyloxy group,
acenaphthyloxy group, fluorenyloxy group, phenalenyloxy group,
phenanthrenyloxy group and anthracenyloxy group, of which a
preferred example is phenyloxy group, 1-naphthyloxy group or
2-naphthyloxy group.
[0539] The "C.sub.7-22 aralkyloxy group" used in the specification
of the present application means a group corresponding to the
above-defined "C.sub.7-22 aralkyl group" to which end an oxygen
atom is bonded. Specific examples thereof are benzyloxy group,
phenethyloxy group, 3-phenylpropyloxy group, 4-phenylbutyloxy
group, 1-naphthylmethyloxy group and 2-naphthylmethyloxy group, of
which a preferred example is benzyloxy group.
[0540] The "5 to 14-membered heteroaralkyloxy group" used in the
specification of the present application means a group
corresponding to the above-defined "5 to 14-membered heteroaralkyl
group" to which end an oxygen atom is bonded. Specific examples
thereof are thienylmethyloxy group, furylmethyloxy group,
pyridinylmethyloxy group, pyridazinylmethyloxy group,
pyrimidinylmethyloxy group and pyrazinylmethyloxy group, of which a
preferred example is thienylmethyloxy group, furylmethyloxy group
or pyridinylmethyloxy group.
[0541] The "5 to 14-membered heteroaryloxy group" used in the
specification of the present application means a group
corresponding to the above-defined "5 to 14-membered heteroaryl
group" to which end an oxygen atom is bonded. Specific examples
thereof are pyrrolyloxy group, pyridinyloxy group, pyridazinyloxy
group, pyrimidinyloxy group, pyrazinyloxy group, triazolyloxy
group, tetrazolyloxy group, benzotriazolyloxy group, pyrazolyloxy
group, imidazolyloxy group, benzimidazolyloxy group, indolyloxy
group, isoindolyloxy group, indolizinyloxy group, purinyloxy group,
indazolyloxy group, quinolinyloxy group, isoquinolinyloxy group,
quinolizinyloxy group, phthalazinyloxy group, naphthyridinyloxy
group, quinoxalinyloxy group, quinazolinyloxy group, cinnolinyloxy
group, pteridinyloxy group, imidazotriazinyloxy group,
pyrazinopyridazinyloxy group, acridinyloxy group,
phenanthridinyloxy group, carbazolyloxy group, carbazolinyloxy
group, perimidinyloxy group, phenanthrolinyloxy group,
phenazinyloxy group, imidazopyridinyloxy group,
imidazopyrimidinyloxy group, pyrazolopyridinyloxy group,
pyrazolopyridinyloxy group, thienyloxy group, benzothienyloxy
group, furyloxy group, pyranyloxy group, cyclopentapyranyloxy
group, benzofuryloxy group, isobenzofuryloxy group, thiazolyloxy
group, isothiazolyloxy group, benzothiazolyloxy group,
benzothiadiazolyloxy group, phenothiazinyloxy group, isoxazolyloxy
group, furazanyloxy group, phenoxazinyloxy group, oxazolyloxy
group, isoxazolyloxy group, benzoxazolyloxy group, oxadiazolyloxy
group, pyrazolooxazolyloxy group, imidazothiazolyloxy group,
thienofuranyloxy group, furopyrrolyloxy group and pyridoxazinyloxy
group, of which a preferred example is thienyloxy group,
pyridinyloxy group, pyrimidinyloxy group or pyrazinyloxy group.
[0542] The "aliphatic C.sub.2-22 acyl group" used in the
specification of the present application means a group
corresponding to the above-defined "C.sub.1-22 alkyl group" or
"unsaturated C.sub.2-22 alkyl group" to which end a carbonyl group
is bonded. Examples thereof are acetyl group, propionyl group,
butyryl group, iso-butyryl group, valeryl group, iso-valeryl group,
pivaloyl group, caproyl group, decanoyl group, lauroyl group,
myristoyl group, palmitoyl group, stearoyl group, arachidoyl group,
acryloyl group, propioloyl group, crotonoyl group, iso-crotonoyl
group, olenoyl group and linolenoyl group, of which a preferred
example is an acyl group having 2 to 6 carbon atoms, such as acetyl
group, propionyl group, butyryl group, iso-butyryl group or
acryloyl group.
[0543] The "aromatic C.sub.7-15 acyl group" used in the
specification of the present application means a group
corresponding to the above-defined "C.sub.6-14 aryl group" or "5 to
14-membered heteroaryl group" to which end a carbonyl group is
bonded. Examples thereof are benzoyl group, 1-naphthoyl group,
2-naphthoyl group, picolinoyl group, nicotinoyl group,
isonicotinoyl group, furoyl group and thiophenecarbonyl group, of
which a preferred example is benzoyl group, picolinoyl group,
nicotinoyl group or isonicotinoyl group.
[0544] The "C.sub.1-22 alkylsulfonyl group" used in the
specification of the present application means a sulfonyl group to
which the above-defined "C.sub.1-22 alkyl group" is bound. Specific
examples thereof are methanesulfonyl group, ethanesulfonyl group,
n-propanesulfonyl group and iso-propanesulfonyl group, of which a
preferred example is methanesulfonyl group.
[0545] The "C.sub.6-14 arylsulfonyl group" used in the
specification of the present application means a sulfonyl group to
which the above-defined "C.sub.6-14 aryl group" is bound. Specific
examples thereof are benzenesulfonyl group, 1-naphthalenesulfonyl
group and 2-naphthalenesulfonyl group, of which a preferred example
is benzenesulfonyl group.
[0546] The "aliphatic C.sub.2-22 acyloxy group" used in the
specification of the present application means a group
corresponding to the above-defined "aliphatic C.sub.2-22 acyl
group" to which end an oxygen atom is bonded. Specific examples
thereof are acetoxy group, propionyloxy group and acryloxy group,
of which a preferred example is acetoxy group or propionyloxy
group.
[0547] The "C.sub.2-22 alkoxycarbonyl group" used in the
specification of the present application means a group
corresponding to the above-defined "C.sub.1-22 alkoxy group" to
which end a carbonyl group is bonded. Examples thereof are
methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl
group, iso-propoxycarbonyl group, n-butoxycarbonyl group,
iso-butoxycarbonyl group, sec-butoxycarbonyl group and
tert-butoxycarbonyl group, of which a preferred example is
ethoxycarbonyl group, iso-propoxycarbonyl group or
tert-butoxycarbonyl group.
[0548] The "unsaturated C.sub.3-22 alkoxycarbonyl group" used in
the specification of the present application means a group
corresponding to the above-defined "unsaturated C.sub.2-22 alkoxy
group" to which end a carbonyl group is bonded. Examples thereof
are vinyloxycarbonyl group, allyloxycarbonyl group,
1-propenyloxycarbonyl group, isopropenyloxycarbonyl group,
propargyloxycarbonyl group and 2-butynyloxycarbonyl group, of which
a preferred example is allyloxycarbonyl group.
[0549] The "C.sub.1-22 alkylthio group" used in the specification
of the present application means a group corresponding to the
above-defined "C.sub.1-22 alkyl group" to which end a sulfur atom
is bonded. Examples thereof are methylthio group, ethylthio group,
n-propylthio group and iso-propylthio group, of which a preferred
example is methylthio group or ethylthio group.
[0550] The "C.sub.1-22 alkylsulfinyl group" used in the
specification of the present application means a group
corresponding to the above-defined "C.sub.1-22 alkyl group" to
which end a sulfinyl group is bonded. Examples thereof are
methanesulfinyl group, ethanesulfinyl group, n-propanesulfinyl
group and iso-propanesulfinyl group, of which a preferred example
is methanesulfinyl group or ethanesulfinyl group.
[0551] The "C.sub.1-22 alkylsulfonyloxy group" used in the
specification of the present application means a group
corresponding to the above-defined "C.sub.1-22 alkylsulfonyl group"
to which end an oxygen atom is bonded. Examples thereof are
methanesulfonyloxy group, ethanesulfonyloxy group,
n-propanesulfonyloxy group and iso-propanesulfonyloxy group, of
which a preferred example is methanesulfonyloxy group.
[0552] The substituent of the phrase "an optionally substituted"
used in the specification of the present application may be one or
more groups selected from: [0553] (1) a halogen atom, [0554] (2) a
hydroxyl group, [0555] (3) a thiol group, [0556] (4) a nitro group,
[0557] (5) a nitroso group, [0558] (6) a cyano group, [0559] (7) a
carboxyl group, [0560] (8) a hydroxysulfonyl group, [0561] (9) a
amino group, [0562] (10) a C.sub.1-22 alkyl group (for example,
methyl group, ethyl group, n-propyl group, iso-propyl group,
n-butyl group, iso-butyl group, sec-butyl group and tert-butyl
group), [0563] (11) an unsaturated C.sub.2-22 alkyl group (for
example, vinyl group, allyl group, 1-propenyl group, 2-propenyl
group, isopropenyl group, ethynyl group, 1-propynyl group,
2-propynyl group, 1-butynyl group, 2-butynyl group and 3-butynyl
group), [0564] (12) a C.sub.6-14 aryl group (for example, phenyl
group, 1-naphthyl group and 2-naphthyl group), [0565] (13) a 5 to
14-membered heteroaryl group (for example, thienyl group, furyl
group, pyridinyl group, pyridazinyl group, pyrimidinyl group and
pyrazinyl group), [0566] (14) a 3 to 14-membered non-aromatic
heterocyclic group (for example, aziridinyl group, azetidyl group,
pyrrolidinyl group, pyrrolyl group, piperidinyl group, piperazinyl
group, homopiperidinyl group, homopiperazinyl group, imidazolyl
group, pyrazolidinyl group, imidazolidinyl group, morpholinyl
group, thiomorpholinyl group, imidazolinyl group, oxazolinyl group
and quinuclidinyl group), [0567] (15) a C.sub.3-14 cycloalkyl group
(for example, cyclopropyl group, cyclobutyl group, cyclopentyl
group, cyclohexyl group, cycloheptyl group and cyclooctyl group),
[0568] (16) a C.sub.1-22 alkoxy group (for example, methoxy group,
ethoxy group, n-propoxy group, iso-propoxy group, sec-propoxy
group, n-butoxy group, iso-butoxy group and tert-butoxy group),
[0569] (17) an unsaturated C.sub.2-22 alkoxy group (for example,
vinyloxy group, allyloxy group, 1-propenyloxy group, 2-propenyloxy
group, isopropenyloxy group, ethynyloxy group, 1-propynyloxy group,
2-propynyloxy group, 1-butynyloxy group and 2-butynyloxy group),
[0570] (18) a C.sub.6-14 aryloxy group (for example, phenyloxy
group, 1-naphthyloxy group and 2-naphthyloxy group), [0571] (19) a
C.sub.7-22 aralkyloxy group (for example, benzyloxy group,
phenethyloxy group, 3-phenylpropyloxy group, 4-phenylbutyloxy
group, 1-naphthylmethyloxy group and 2-naphthylmethyloxy group),
[0572] (20) a 5 to 14-membered heteroaralkyloxy group (for example,
thienylmethyloxy group, furylmethyloxy group, pyridinylmethyloxy
group, pyridazinylmethyloxy group, pyrimidinylmethyloxy group and
pyrazinylmethyloxy group), [0573] (21) a 5 to 14-membered
heteroaryloxy group (for example, thienyloxy group, furyloxy group,
pyridinyloxy group, pyridazinyloxy group, pyrimidinyloxy group and
pyrazinyloxy group), [0574] (22) an aliphatic C.sub.2-22 acyl group
(for example, acetyl group, propionyl group, butyryl group,
iso-butyryl group, valeryl group, iso-valeryl group, pivaloyl
group, caproyl group, decanoyl group, lauroyl group, myristoyl
group, palmitoyl group, stearoyl group, arachidoyl group, acryloyl
group, propioloyl group, crotonoyl group, iso-crotonoyl group,
olenoyl group and linolenoyl group), [0575] (23) an aromatic
C.sub.71-5 acyl group (for example, benzoyl group, 1-naphthoyl
group and 2-naphthoyl group), [0576] (24) an aliphatic C.sub.2-22
acyloxy group (for example, acetoxy group, propionyloxy group and
acryloxy group), [0577] (25) a C.sub.2-22 alkoxycarbonyl group (for
example, methoxycarbonyl group, ethoxycarbonyl group,
n-propoxycarbonyl group, iso-propoxycarbonyl group,
n-butoxycarbonyl group, iso-butoxycarbonyl group,
sec-butoxycarbonyl group and tert-butoxycarbonyl group), [0578]
(26) an unsaturated C.sub.3-22 alkoxycarbonyl group (for example,
vinyloxycarbonyl group, allyloxycarbonyl group,
1-propenyloxycarbonyl group, 2-propenyloxycarbonyl group,
isopropenyloxycarbonyl group, propargyloxycarbonyl group and
2-butynyloxycarbonyl group), [0579] (27) a C.sub.1-22 alkylthio
group (for example, methylthio group, ethylthio group, n-propylthio
group and iso-propylthio group), [0580] (28) a C.sub.1-22
alkylsulfinyl group (for example, methanesulfinyl group,
ethanesulfinyl group, n-propanesulfinyl group and
iso-propanesulfinyl group), [0581] (29) a C.sub.1-22 alkylsulfonyl
group (for example, methanesulfonyl group, ethanesulfonyl group,
n-propanesulfonyl group and iso-propanesulfonyl group), [0582] (30)
a C.sub.6-14 arylsulfonyl group (for example, benzenesulfonyl
group, 1-naphthalenesulfonyl group and 2-naphthalenesulfonyl
group), [0583] (31) a C.sub.1-22 alkylsulfonyloxy group (for
example, methanesulfonyloxy group, ethanesulfonyloxy group,
n-propanesulfonyloxy group and iso-propanesulfonyloxy group),
[0584] (32) carbamoyl group, and [0585] (33) formyl group. Among
them, a preferred example is an amino group, a C.sub.1-22 alkyl
group, an unsaturated C.sub.2-22 alkyl group, a C.sub.6-14 aryl
group, a 5 to 14-membered heteroaryl group, a 3 to 14-membered
non-aromatic heterocyclic group and a C.sub.3-14 cycloalkyl group,
and a more preferred example is an amino group, a C.sub.1-22 alkyl
group, a 3 to 14-membered non-aromatic heterocyclic group and a
C.sub.3-14 cycloalkyl group. The above-mentioned (9) an amino group
and (31) a carbamoyl group as the substituent in "an optionally
substituted" may each be further substituted with one or two of a
C.sub.1-22 alkyl group, an unsaturated C.sub.2-22 alkyl group or a
C.sub.6-14 aryl group.
[0586] The compounds of the formula (I) according to the present
invention will be elucidated below.
[0587] The compounds of the formula (I) suppress VEGF production
under a hypoxic condition and possess a growth inhibitory
activities to solid tumor cells in in vivo. Among them, the
compounds of the formula (I-a) are preferred, of which the
compounds of the formula (I-b) are more preferred and the compounds
of the formula (I-c) are typically advantageous.
[0588] The compounds of the formula (I) are structurally
characterized by the 6-position side chain and/or 7-position side
chain, and the group of more preferred compounds can be defined as
the compounds of the formula (I-d). In addition to the compounds of
the formula (I-d), the compounds of the formula (I), in which
R.sup.21 forms an oxo group together with the carbon atom to which
R.sup.21 is bound, belong to the group of compounds having good
activities. As detailed embodiments of more preferred compounds
among the compounds of the formula (I-d), the compounds of the
above-mentioned "5." to "19." of the present invention may be
exemplified.
[0589] Preferred examples of the compounds of the formula (I) will
be illustrated below. The group of the preferred compounds
inclusive of compounds described later in Examples include, for
example, Compound 6, Compound 9, Compound 12, Compound 15, Compound
16, Compound 20, Compound 21, Compound 22, Compound 25, Compound
26, Compound 27, Compound 31, Compound 34, Compound 36, Compound
38, Compound 39, Compound 40, Compound 41, Compound 43, Compound
44, Compound 45, Compound 48, Compound 51, Compound 53, Compound
54, Compound 55, Compound 57, Compound 58, Compound 62, Compound
63, Compound 64, Compound 65, Compound 69, Compound 70, Compound
72, Compound 74, Compound 75, Compound 77, Compound 79, Compound
85, Compound 88, Compound 105, Compound 106, Compound 108, Compound
109 and Compound 131. Among them, examples of more preferred
compounds are Compound 6, Compound 9, Compound 12, Compound 16,
Compound 21, Compound 25, Compound 26, Compound 27, Compound 31,
Compound 36, Compound 38, Compound 44, Compound 45, Compound 54,
Compound 63, Compound 64, Compound 69, Compound 75, Compound 85,
Compound 109 and Compound 131, of which, for example, Compound 9,
Compound 12, Compound 26, Compound 44, Compound 45 and Compound 75
are typically preferred.
[0590] Next, the preparation of the compound of the formula (I)
according to the present invention will be illustrated.
[0591] The compound of the formula (I) can be prepared by culturing
a strain belonging to the genus Streptomyces which has an ability
of producing the bioactive substance 11107D [the compound of the
formula (I), in which R.sup.3, R.sup.6 and R.sup.21 are hydroxyl
groups, and R.sup.7 is an acetoxy group] under aerobic conditions,
collecting the compound from the microorganism cell and culture,
and chemically modifying the obtained compound as a key compound
according to a conventional procedure.
[0592] Initially, the process for preparation of 11107D will be
elucidated below.
[0593] The following deposit microorganism strain can be used for
the microorganism for producing 11107D. The strain was
internationally deposited to International Patent Organism
Depositary (IPOD) National Institute of Advanced Industrial Science
and Technology (Tsukuba Central 6, 1-1, Higashi 1-Chome
Tsukuba-shi, Ibaraki-ken 305-8566 Japan). Specifically,
Streptomyces sp. Mer-11107 was deposited as FERM P-18144 at the
National Institute of Bioscience and Human-Technology Agency of
Industrial Science and Technology (1-3, Higashi 1-chome
Tsukuba-shi, Ibaraki-ken 305-8566 Japan). Further, this was
transferred to International Deposit FERM BP-7812 at International
Patent Organism Depositary (IPOD) National Institute of Advanced
Industrial Science and Technology (Tsukuba Central 6, 1-1, Higashi
1-Chome Tsukuba-shi, Ibaraki-ken 305-8566 Japan).
[0594] The strain for producing 11107D is not specifically limited
and also includes variants of such strains, as long as the strain
is belonging to the genus Streptomyces and has an ability of
producing 11107D. Examples of the strain are Streptomyces sp.
A-1532, Streptomyces sp. A-1533 and Streptomyces sp. A-1534, in
addition to the above-mentioned strain. These strains were also
internationally deposited to International Patent Organism
Depositary (IPOD) National Institute of Advanced Industrial Science
and Technology (Tsukuba Central 6, 1-1, Higashi 1-Chome
Tsukuba-shi, Ibaraki-ken 305-8566 Japan) as FERM BP-7849, FERM
BP-7850 and FERM BP-7851, respectively.
[0595] Detailed description of 1. the property of separated
microorganism, 2. the fermentation method of the microorganism and
3. the purification method of an active substance in the
preparation of 11107D will be made below.
1. The Property of Separated Microorganism
[0596] As the strain for use in the present invention, it is
expected that any one of strains belonging to the genus
Streptomyces and having an ability of producing 11107D can be used.
However, as a typical strain used in the present invention, a
strain which was named as "Mer-11107 strain" by the inventors is
exemplified. The taxonomical properties of this strain are as
follows.
(1) Morphological Characteristics
[0597] Aerial hyphae that bore spirales is extended from vegetative
hypha in this strain. Spore chain consisting of about 10 to 20 of
columnar spores are formed at the edge of the ripened aerial
hyphae. The size of the spores is about 0.7.times.1.0 .mu.m, the
surface of the spores is smooth, and specific organs such as
sporangium, sclerotium and flagellum are not observed.
(2) Cultural Characteristics on Various Media
[0598] Cultural characteristics of the strain after incubation at
28.degree. C. for two weeks on various media are shown below. The
color tone is described by the color name and codes which are shown
in the parenthesis of the Color Harmony Manual (Container
Corporation of America).
[0599] 1) Yeast Extract-Malt Extract Agar Medium
[0600] The strain grew well, the aerial hyphae grew up on the
surface, and light gray spores (Light gray; d) were observed. The
reverse side of colony was Light melon yellow (3ea). Soluble
pigment was not produced.
[0601] 2) Oatmeal Agar Medium
[0602] The strain grew in the middle level, the aerial hyphae grew
slightly on the surface, and gray spores (Gray; g) were observed.
The reverse side of colony was Nude tan (4gc) or Putty (11/2 ec).
Soluble pigment was not produced.
[0603] 3) Inorganic Salt-Starch Agar Medium
[0604] The strain grew well, the aerial hyphae grew up on the
surface, and gray spores (Gray; e) were observed. The reverse side
of colony was Fawn (4ig) or Gray (g). Soluble pigment was not
produced.
[0605] 4) Glycerol-Asparagine Agar Medium
[0606] The strain grew well, the aerial hyphae grew up on the
surface, and white spores (White; a) were observed. The reverse
side of colony was Pearl pink (3ca). Soluble pigment was not
produced.
[0607] 5) Peptone-Yeast Extract-Iron Agar Medium
[0608] The strain growth was bad, and the aerial hyphae did not
grow on the surface. The reverse side of colony was Light melon
yellow (3ea). Soluble pigment was not produced.
[0609] 6) Tyrosine Agar Medium
[0610] The strain grew well, the aerial hyphae grew up on the
surface, and white spores (White; a) were observed. The reverse
side of colony was Pearl pink (3ca). Soluble pigment was not
produced.
(3) Utilization of Various Carbon Sources
[0611] Various carbon sources are added in Pridham-Gottlieb agar
medium, growth of the strain after incubation at 28.degree. C. for
two weeks are shown below. [0612] 1) L-arabinose.+-. [0613] 2)
D-xylose.+-. [0614] 3) D-glucose+ [0615] 4) D-fructose+ [0616] 5)
sucrose+ [0617] 6) inositol+ [0618] 7) L-rhamnose- [0619] 8)
D-mannitol+ [0620] 9) D-raffinose+ (+: positive, .+-.: slightly
positive, -: negative) (4) Physiological Properties
[0621] The physiological properties of the strain are as shown
below. [0622] (a) Range of growth temperature (yeast extract-malt
extract agar medium, incubation for 2 weeks) 12.degree. C. to
37.degree. C. [0623] (b) Range of optimum temperature (yeast
extract-malt extract agar medium, incubation for 2 weeks)
21.degree. C. to 33.degree. C. [0624] (c) Liquefaction of gelatin
(glucose-peptone-gelatin agar medium) negative [0625] (d)
Coagulation of milk (skim milk agar medium) negative [0626] (e)
Peptonization of milk (skim milk agar medium) negative [0627] (f)
Hydrolysis of starch (inorganic salt-starch agar medium) positive.
[0628] (g) Formation of melanoid pigment (peptone-yeast
extract-iron agar medium) negative (tyrosine medium) negative
[0629] (h) Production of hydrogen sulfide (peptone-yeast
extract-iron agar medium) negative [0630] (i) Reduction of nitrate
(broth containing 0.1% potassium nitrate) negative [0631] (j)
Sodium chloride tolerance (yeast extract-malt extract agar medium,
incubation for 2 weeks) grown at a salt content of 4% or less (5)
Chemotaxonomy
[0632] LL-diaminopimelic acid and glycine were detected from the
cell wall of the present strain.
[0633] It is considered that the present strain is a strain of the
genus Streptomyces from the above-mentioned microbial
characteristics. Accordingly, the present inventors have named the
present microbial strain as Streptomyces sp. Mer-11107 and have
deposited the strain as FERM P-18144 at the National Institute of
Bioscience and Human-Technology Agency of Industrial Science and
Technology.
2. Fermentation Method of Producing Microorganism
[0634] The physiologically active substance 11107D according to the
present invention can be produced by inoculating the strain on a
nutrition source medium and carrying out aerobic fermentation. The
strain for producing the physiologically active substance 11107D is
not limited to the above-mentioned strain, and any strain belonging
to the genus Streptomyces and having an ability of producing 11107D
can be used in the present invention.
[0635] The fermentation method of the above-mentioned microorganism
is according to the general fermentation method of microorganism,
but it is preferably carried out under aerobic conditions such as
shaking culture or aeration-agitation fermentation using liquid
medium. The medium used for culture may be a medium containing a
nutrition source which can be utilized by microorganism belonging
the genus Streptomyces, therefore all of various synthetic, a
semi-synthetic medium, an organic medium and the like can be
utilized. As the carbon source in the medium composition, there can
be used a single or a combination of glucose, sucrose, fructose,
glycerin, dextrin, starch, molasses, soybean oil and the like. As
the nitrogen source, there can be used a single or a combination of
organic nitrogen sources such as pharma media, peptone, meat
extract, soybean powder, casein, amino acid, yeast extract and
urea, and inorganic nitrogen sources such as sodium nitrate and
ammonium sulfate. Additionally, for example, there can be added and
used salts such as sodium chloride, potassium chloride, calcium
carbonate, magnesium sulfate, sodium phosphate, potassium phosphate
and cobalt chloride; heavy metal salts, vitamins such as vitamin B
or biotin, if necessary. Further, when foaming is remarkable during
culture, various defoaming agents can be appropriately added in the
medium as necessary. When the defoaming agent is added, it is
required to set at a concentration for not adversely affecting the
production of an objective substance, and for example, the use
concentration is desirably 0.05% or less.
[0636] The culture condition can be appropriately selected within
the range at which the microbial strain grows well and can produce
the above-mentioned substance. For example, the pH of a medium is
about 5 to 9, and preferably nearby neutral in general. The
temperature of fermentation is usually kept at 20.degree. C. to
40.degree. C. and preferably 28.degree. C. to 35.degree. C. The
fermentation period is about 2 to 8 days, and usually about 3 to 5
days. The above-mentioned fermentation conditions can be suitably
changed in accordance with the kind and property of microorganism
used, external conditions and the like, and it is needless to say
that an optimum condition can be selected. The physiologically
active substance 11107D of the present invention which was
accumulated in the cultured broth can be collected by usual
separation procedures utilizing its property such as a solvent
extraction method and an absorbing resin method.
[0637] The physiologically active substance 11107D can also be
prepared, for example, by using a microorganism belonging to the
genus Streptomyces (for example, Streptomyces sp. AB-1704 strain
(FERM P-18999)) and using 11107B substance (the compound described
in Example A4 of WO 02/060890, as shown in Referential Examples 6
to 10.
3. Purification Method for the Bioactive Substance
[0638] General methods for separation and purification which are
used for isolation of microbial metabolites from the cultured broth
can be employed in order to collect 11107D from the cultured medium
after the fermentation. For example, there can be corresponded all
methods such as extraction by an organic solvent typically using
methanol, ethanol, butanol, ethyl acetate or chloroform; various
kinds of ion-exchange chromatography; gel filtration chromatography
using Sephadex LH-20; the treatment of adsorption and desorption by
absorption chromatography typically using active carbon or silica
gel or by thin layer chromatography; or high performance liquid
chromatography typically using a reverse phase column, to this.
Further, the purification methods for 11107D are not specifically
limited to the methods shown here.
[0639] The compound 11107D can be isolated and purified by using
these methods alone or in combination or repeatedly using them.
[0640] Next, the preparation for the compounds of the formula (I)
other than 11107D will be elucidated.
[0641] The compounds of the formula (I) can be synthesized from
11107D isolated and purified as a starting compound by converting
the hydroxyl group and/or acetoxy group of the compound according
to general organic synthetic procedures. Typical examples of the
synthesis methods are A. a preparation for an urethane derivative,
B. a preparation for a thiourethane derivative, C. a preparation
for an ether derivative, D. a preparation for an ester derivative,
E. a preparation for a phosphoric ester or amidophosphoric ester
derivative, F. a preparation for a sulfuric ester or amidosulfuric
ester derivative, G. a preparation for a halogen derivative, H. a
preparation for a sulfonic ester derivative, I. a preparation for
an amine derivative, and J. a preparation for an oxo-derivative by
oxidation of a hydroxyl group. The introduction and removal of a
protecting group for a hydroxyl group can be carried out according
to need by the method described in document (Protective Groups in
Organic Synthesis, T. W. Greene, John Wiley & Sons, Inc. 3rd
Edition) or a method analogous thereto, while depending on the type
of the protecting group and the stability of the compound relating
to the preparation. The compounds of the formula (I) can be
prepared by using the introduction and removal reactions for the
hydroxyl-protecting group and the preparation described above in a
suitable combination. More specifically, the compounds of the
formula (I) in which R.sup.3, R.sup.6, R.sup.7 and R.sup.21 are the
substituents listed in above-mentioned 9) can be prepared by using
the preparation for a urethane derivative, a thiourethane
derivative, an amidosulfuric ester or an amine derivative; those in
which R.sup.3, R.sup.6, R.sup.7 and R.sup.22 are the substituents
listed in above-mentioned 2) to 5) can be prepared by using the
preparation for an ether derivative; those in which R.sup.3,
R.sup.6, R.sup.7 and R.sup.21 are the substituents listed in
above-mentioned 6) can be prepared by using the preparation for an
ester derivative; those in which R.sup.3, R.sup.6, R.sup.7 and
R.sup.21 are the substituents listed in above-mentioned 11) to 13)
can be prepared by using the preparation for a phosphoric ester or
amidophosphoric ester derivative; those in which R.sup.3, R.sup.6,
R.sup.7 and R.sup.21 are the substituents listed in above-mentioned
10) can be prepared by using the preparation for a sulfuric ester
or sulfonic ester derivative; those in which R.sup.3, R.sup.6,
R.sup.7 and R.sup.21 are the substituents listed in above-mentioned
8) can be prepared by using the preparation for a halogen
derivative; those in which R.sup.3, R.sup.6, R.sup.7 and R.sup.21
are the substituents listed in above-mentioned 7) can be prepared
by using the introduction and removal reactions of a
hydroxyl-protecting group; and the oxo-derivative in which R.sup.3,
R.sup.6, R.sup.7 and R.sup.21 are the substituents listed in
above-mentioned 1) can be prepared by using the preparation for an
oxo-derivative by oxidation of a hydroxyl group.
[0642] Next, synthetic methods for preparing the compounds of the
formula (I) will be elucidated. A. A Preparation for a Urethane
Derivative ##STR30## ##STR31## In the formula, R.sup.3A, R.sup.6A,
R.sup.16A and R.sup.21A each represents a hydrogen atom or a
protecting group, provided that R.sup.3A, R.sup.6A, R.sup.16A and
R.sup.21A do not concurrently represent hydrogen atoms; R.sup.3B,
R.sup.6B, R.sup.16B and R.sup.21B each represents a hydrogen atom,
a protecting group or a group represented by the formula
R.sup.FO--CO-- (wherein R.sup.F represents an optionally
substituted C.sub.6-14 aryl group), provided that R.sup.3B,
R.sup.6B, R.sup.16B and R.sup.21B do not concurrently represent
hydrogen atoms; R.sup.3C, R.sup.6C, R.sup.16C and R.sup.21C each
represents a hydrogen atom, a protecting group or a group
represented by the formula R.sup.N1R.sup.N2N--CO-- (wherein
R.sup.N1 and R.sup.N2 each represents the group as defined above);
and R.sup.3D, R.sup.6D, R.sup.16D and R.sup.21D each represents a
hydrogen atom or a group represented by the formula
R.sup.N1R.sup.N2N--CO-- (wherein R.sup.N1 and R.sup.N2 each
represents the group as defined above).
[0643] The step A1 is a step for preparing the compound of the
formula (IA). This step is carried out by protecting the hydroxyl
group(s) of 11107D.
[0644] The reaction for protecting the hydroxyl group(s) is carried
out according to a procedure well known in organic synthetic
chemistry, while being selected depending on the type of the
protecting group.
[0645] Examples of the protecting group are 1-ethoxyethyl,
tetrahydropyranyl, 1-methyl-1-methoxyethyl,
1-(2-chloroethoxy)ethyl, 1-methoxycyclohexyl,
4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl,
4-methoxytetrahydrothiopyranyl S,S-dioxide, methoxymethyl,
methylthiomethyl, methoxyethoxymethyl, trichloroethoxymethyl,
trimethylsilylethyl, trimethylsilylethoxymethyl,
tert-butyldimethylsilyl, triethylsilyl, diethylisopropylsilyl,
trimethylsilyl, triisopropylsilyl, methyl-di-tert-butylsilyl,
diphenylmethylsilyl, benzyl, p-methoxybenzyl, p-methylbenzyl,
p-nitrobenzyl, p-chlorobenzyl and triphenylmethyl. All or part of
the hydroxyl groups can be appropriately protected by these
protecting groups.
[0646] For example, hydroxyl-protected derivatives protected by
1-ethoxyethyl, tetrahydropyranyl, 1-methoxycyclohexyl,
4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl or
4-methoxytetrahydrothiopyranyl-S,S-dioxide can be synthesized by
treating 11107D with a corresponding vinyl ether such as ethylvinyl
ether or dihydropyran in the presence of an acid. Examples of the
acid are general acids including organic acids such as pyridinium
p-toluenesulfonate (PPTS), p-toluenesulfonic acid, camphorsulfonic
acid, acetic acid, trifluoroacetic acid or methanesulfonic acid;
and inorganic acids such as hydrogen chloride, nitric acid,
hydrochloric acid or sulfuric acid. Among them, a preferred example
is pyridinium p-toluenesulfonate (PPTS), p-toluenesulfonic acid or
camphorsulfonic acid. The solvent used in the reaction is not
specifically limited, but an inert solvent which cannot easily
react with a starting material is desirable. Examples of such
solvents are ethers such as tetrahydrofuran, diethyl ether,
diisopropyl ether, dioxane and dimethoxyethane; halogenated
hydrocarbons such as dichloromethane, chloroform, carbon
tetrachloride and 1,2-dichloroethane; hydrocarbons such as hexane,
benzene and toluene; ketones such as acetone and methyl ethyl
ketone; nitrites such as acetonitrile; amides such as
N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyridone
and hexamethylphosphoramide; and sulfoxides such as dimethyl
sulfoxide, of which a preferred example is dichloromethane,
chloroform or tetrahydrofuran. The reaction time is 10 minutes to 5
days and is preferably 1 day to 2 days. The reaction temperature is
a temperature of -78.degree. C. to heating under reflux and is
preferably room temperature. The amounts of the vinyl ether and
acid used in the reaction are 1 to 200 equivalents and 0.05 to 2
equivalents, and preferably 30 to 50 equivalents and 0.1 to 0.3
equivalent, respectively, to 11107D.
[0647] Examples of other protecting groups are methoxymethyl,
methylthiomethyl, methoxyethoxymethyl, trichloroethoxymethyl,
trimethylsilylethyl, trimethylsilylethoxymethyl,
tert-butyldimethylsilyl, triethylsilyl, trimethylsilyl,
diethylisopropylsilyl, triisopropylsilyl, di-tert-butylmethylsilyl,
diphenylmethylsilyl, benzyl, p-methoxybenzyl, p-methylbenzyl,
p-nitrobenzyl, p-chlorobenzyl and triphenylmethyl. Such
hydroxyl-protected derivatives can be synthesized by reacting a
starting material with a chloride, bromide or
trifluoromethanesulfonate of the respective protecting groups in
the presence of a base. The base is a general organic base or
inorganic base. Examples of the organic base are an aromatic base
such as imidazole, 4-(N,N-dimethylamino)pyridine (the
4-dimethylaminopyridine, N,N-dimethylaminopyridine and
dimethylaminopyridine used in the present specification have the
same meaning), pyridine, 2,6-lutidine or collidine; a tertiary
amine such as N-methylpiperidine, N-methylpyrrolidine,
triethylamine, trimethylamine, di-iso-propylethylamine,
cyclohexyldimethylamine, N-methylmorpholine or
1,8-bis(dimethylamino)naphthalene; a secondary amine such as
di-iso-butylamine or dicyclohexylamine; an alkyllithium such as
methyllithium or butyllithium; a metal alkoxide such as sodium
methoxide or sodium ethoxide. Examples of the inorganic base are an
alkali metal hydride such as sodium hydride or potassium hydride;
an alkaline earth metal hydride such as calcium hydride; an alkali
metal hydroxide such as sodium hydroxide or potassium hydroxide; an
alkali metal carbonate such as sodium carbonate, potassium
carbonate or cesium carbonate; and an alkali metal hydrogen
carbonate such as sodium bicarbonate. Preferred examples of the
base for the protection of the hydroxyl group by a silyl protecting
group are an aromatic base such as imidazole or
4-dimethylaminopyridine; and a tertiary amine such as
triethylamine. The solvent used in the reaction is not specifically
limited, but one which does not easily react with a starting
material is desirable. Examples of such solvents are the
above-mentioned inert solvents, of which a preferred example is
tetrahydrofuran, dichloromethane or N,N-dimethylformamide. The
reaction time is 10 minutes to 3 days and is preferably 1 day to 2
days. The reaction temperature is a temperature of -78.degree. C.
to heating under reflux and is preferably -10.degree. C. to
50.degree. C. The amounts of the chloride, bromide or
trifluoromethanesulfate and the base used in the reaction are 1 to
20 equivalents and 0.5 to 30 equivalents, preferably 1 to 15
equivalents and 0.5 to 20 equivalents, respectively, to 11107D.
[0648] The hydroxyl groups of 11107D can be selectively protected
by selecting the reagent and equivalence thereof for use in the
protection of the hydroxyl groups. For example, a compound in which
the hydroxyl groups at the 3-position and 21-position are
selectively protected can be obtained by carrying out the reaction
at room temperature using chlorotriethylsilane, triethylamine and
4-dimethylaminopyridine in dichloromethane or using
tert-butylchlorodimethylsilane and imidazole in
N,N-dimethylformamide. In this procedure, for example, the hydroxyl
group at the 3-position can be selectively protected by controlling
the equivalence of chlorotriethylsilane or
tert-butylchlorodimethylsilane. Further, it is possible that two or
three of the four hydroxyl groups are protected by a silyl group,
and then the other two or one hydroxyl group is protected by the
above-mentioned ethoxyethyl or the like.
[0649] The step A2 is a step for preparing the compound of the
formula (IIA). This step is carried out by converting the acetoxy
group of the compound of the formula (IA) into the hydroxyl group
by the treatment of a base in an inert solvent.
[0650] Examples of the base used herein are inorganic bases
including an alkali metal hydride such as sodium hydride or
potassium hydride; an alkaline earth metal hydride such as calcium
hydride; an alkali metal hydroxide such as lithium hydroxide,
sodium hydroxide or potassium hydroxide; an alkali metal carbonate
such as lithium carbonate, sodium carbonate or potassium carbonate;
an alkali metal hydrogen carbonate such as sodium bicarbonate; and
a metal alkoxide such as lithium methoxide, sodium methoxide,
sodium ethoxide or potassium tert-butoxide, as well as bases such
as guanidine or ammonia. Preferred examples of the base are
potassium carbonate and guanidine.
[0651] Examples of the inert solvent used herein include, in
addition to the above-mentioned inert solvents, an alcohol solvent
such as methanol, ethanol, isopropanol or tert-butanol, and water.
These solvents can be used in combination as a mixture. A preferred
solvent is an alcohol solvent or a mixture of an alcohol and a
halogen solvent. The reaction time is 10 minutes to 5 days and is
preferably 30 minutes to 1 day. The reaction temperature is a
temperature of -78.degree. C. to heating under reflux and is
preferably room temperature. The amount of the base used in the
reaction is 1 to 10 equivalents and preferably 2 to 5 equivalents
to the compound of the formula (IA).
[0652] The step A3 is a step for preparing the compound of the
formula (IIIA). This step is carried out by treating the hydroxyl
group of the compound of the formula (IIA) with a chloroformate
derivative or carbonyldiimidazole in the presence of a base.
Examples of the chloroformate derivative are 4-nitrophenyl
chloroformate, phenyl chloroformate, 4-chlorophenyl chloroformate,
4-bromophenyl chloroformate and 2,4-dinitrophenyl chloroformate.
Examples of the base are the above-mentioned organic bases and
inorganic bases, of which, for example, diisopropylethylamine,
4-dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or
sodium hydride is preferably used. The solvent used in the reaction
is not specifically limited, but a solvent that does not easily
react with a starting material is desirable. Examples of such
solvents are the above-mentioned inert solvents, of which, for
example, tetrahydrofuran, dichloromethane or N,N-dimethylformamide
is preferably used. The amounts of the chloroformate derivative and
base for use in the reaction are 1 to 10 equivalents and 1 to 20
equivalents, and preferably 1 to 5 equivalents and 1 to 10
equivalents, respectively, to the compound of the formula (IIA).
The reaction time is 10 minutes to 30 hours and is preferably 1 to
4 hours. The reaction temperature is a temperature of -78.degree.
C. to heating under reflux and is preferably -10.degree. C. to
50.degree. C.
[0653] For the hydroxyl compound (IA) in which one to three of
OR.sup.3A, OR.sup.6A, OR.sup.16A and OR.sup.21A have not been
protected in the step A1, the hydroxyl groups can be converted into
carbonic ester groups by the step A3. More specifically, the
hydroxyl groups of the compound (IA) other than the hydroxyl group
at the 7-position can be converted into carbonic ester groups by
the same way as the hydroxyl group at the 7-position by treatment
with a base and a chloroformate derivative in equivalents
corresponding to the number of hydroxyl groups to be converted into
carbonic ester groups.
[0654] The step A4 is a step for preparing the compound of the
formula (IVA). This step is carried out by treating the carbonic
ester of the formula (IIIA) with an amine (R.sup.N1R.sup.N2H) that
can form a desired compound of the formula (I) in an inert solvent
in the presence of a base or with the amine alone.
[0655] Examples of the amine used herein are methylamine,
ethylamine, propylamine, butylamine, octylamine, decylamine,
cyclopropylamine, cyclopentylamine, cyclohexylamine, dimethylamine,
diethylamine, ethylmethylamine, ethylenediamine,
1,3-propanediamine, 1,4-butanediamine, N,N-dimethylethylenediamine,
N,N-dimethyl-1,3-propanediamine, N,N-dimethyl-1,4-butanediamine,
N,N-diethylethylenediamine, N,N-diethyl-1,3-propanediamine,
N,N-diethyl-1,4-butanediamine, N,N,N'-trimethylethylenediamine,
N,N,N'-trimethyl-1,3-propanediamine,
N,N,N'-trimethyl-1,4-butanediamine,
N-ethyl-N',N'-dimethylethylenediamine,
N-ethyl-N',N'-dimethyl-1,3-propanediamine,
N-ethyl-N',N'-dimethyl-1,4-butanediamine,
N,N,N'-triethylethylenediamine, N,N,N'-triethyl-1,3-propanediamine,
N,N,N'-triethyl-1,4-butanediamine,
N,N-diethyl-N'-methylethylenediamine,
N,N-diethyl-N'-methyl-1,3-propanediamine,
N,N-diethyl-N'-methyl-1,4-butanediamine,
N,N'-dimethyl-N-phenylethylenediamine,
N,N'-dimethyl-N-phenyl-1,3-propanediamine,
N-benzyl-N,N'-dimethylethylenediamine,
N-benzyl-N,N'-dimethyl-1,3-propanediamine, morpholine,
thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide,
pyrrolidine, piperidine, piperazine, homopiperazine,
4-hydroxypiperidine, 4-methoxypiperidine, 1-methylpiperazine,
1-ethylpiperazine, 1-propylpiperazine, 1-butylpiperazine,
1-isopropylpiperazine, 1-cyclobutylpiperazine,
1-cyclopentylpiperazine, 1-cyclohexylpiperazine,
1-cycloheptylpiperazine, 1-cyclooctylpiperazine,
1-(cyclopropylmethyl)piperazine, 1-benzylpiperazine,
1-methylhomopiperazine, 1-ethylhomopiperazine,
1-(2-aminoethyl)pyrrolidine,
1-(2-(N-methylamino)ethyl)pyrrolidine),
1-(3-aminopropyl)pyrrolidine,
1-(3-(N-methylamino)propyl)pyrrolidine),
1-(2-aminoethyl)piperidine, 1-(2-(N-methylamino)ethyl)piperidine),
1-(3-aminopropyl)piperidine,
1-(3-(N-methylamino)propyl)piperidine), 4-(2-aminoethyl)morpholine,
4-(2-(methylamino)ethyl)morpholine), 4-(3-aminopropyl)morpholine,
4-(3-(N-methylamino)propyl)morpholine),
1-(2-aminoethyl)-4-methylpiperazine,
1-(3-aminopropyl)-4-methylpiperazine,
1-(3-(N-methylamino)propyl)-4-methylpiperazine,
1-amino-4-methylpiperidine, 1-methylamino-4-methylpiperidine,
1-ethyl-4-(N-methylamino)piperidine,
1-methylamino-4-propylpiperidine,
1-butyl-4-(N-methylamino)piperidine,
1-(N,N-dimethylamino)piperidine, 1-(N,N-diethylamino)piperidine,
4-(pyrrolidin-1-yl)piperidine, 4-(piperidin-1-yl)piperidine,
3-aminoquinuclidine, 3-(N-methylamino)quinuclidine, aniline,
N-methylaniline, N,N-dimethyl-p-phenylenediamine,
N,N-dimethyl-m-phenylenediamine,
N,N,N'-trimethyl-p-phenylenediamine,
N,N,N'-trimethyl-m-phenylenediamine, 1-naphthylamine,
2-naphthylamine, benzylamine, N-methylbenzylamine, phenethylamine,
N-methylphenethylamine, 2-picolylamine, 3-picolylamine,
4-picolylamine, N-methyl-2-picolylamine, N-methyl-3-picolylamine,
N-methyl-4-picolylamine, 2,5-diazabicyclo[2.2.1]heptane,
2-methyl-2,5-diazabicyclo[2.2.1]heptane,
3,8-diazabicyclo[3.2.1]octane and
1,4-diazabicyclo[4.3.0]nonane.
[0656] Examples of the base are the above-mentioned organic bases
and inorganic bases, of which, for example, diisopropylethylamine,
dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or
sodium hydride is preferably used. The solvent used in the reaction
is not specifically limited, but a solvent that does not easily
react with a starting material is desirable. Examples of such
solvents are the above-mentioned inert solvents, of which, for
example, tetrahydrofuran, dichloromethane or N,N-dimethylformamide
is preferably used. The amounts of the amine and base used in the
reaction are 1 to 10 equivalents and 2 to 20 equivalents, and
preferably 1.5 to 5 equivalents and 2 to 10 equivalents,
respectively, to the compound of the formula (IIIA). The reaction
time is 10 minutes to 30 hours and is preferably 1 to 2 hours. The
reaction temperature is a temperature of -78.degree. C. to heating
under reflux and is preferably -10.degree. C. to 50.degree. C.
[0657] The compound of the formula (IVA) can also be prepared by
treating the compound of the formula (IIA) with an isocyanate in an
inert solvent in the presence of a base and/or cuprous chloride.
The isocyanate is not specifically limited and includes, for
example, ethyl isocyanate, methyl isocyanate and phenyl isocyanate.
Examples of the base are the above-mentioned organic bases and
inorganic bases, of which, for example, diisopropylethylamine,
dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or
sodium hydride is preferably used. The solvent used in the reaction
is not specifically limited, but a solvent that does not easily
react with a starting material is desirable. Examples of such
solvents are the above-mentioned inert solvents, of which, for
example, tetrahydrofuran, dichloromethane or N,N-dimethylformamide
is preferably used. The amounts of the base and isocyanate used in
the reaction are 3 to 100 equivalents and 1 to 20 equivalents,
preferably 5 to 20 equivalents and 3 to 10 equivalents,
respectively, to the compound of the formula (IIIA). In the case
where cuprous chloride is used, the amount thereof is 1 to 10
equivalents and preferably 2 to 6 equivalents. The reaction time is
10 minutes to 30 hours and is preferably 1 to 2 hours. The reaction
temperature is a temperature of -78.degree. C. to heating under
reflux and is preferably -10.degree. C. to 50.degree. C.
[0658] The hydroxyl compound in which one to three of OR.sup.3A,
OR.sup.6A, OR.sup.6A and OR.sup.21A have not been protected in the
step A1 can be converted into a derivative having a plurality of
urethane structures by converting those hydroxyl groups into
carbonic ester groups in the step A3 and further converting them
into carbamoyloxy groups in the step A4.
[0659] The step A5 is a step for producing the compound of the
formula (VA). This step is carried out by subjecting the urethane
derivative of the formula (IVA) to a deprotection treatment
mentioned below in an inert solvent. The deprotection reaction for
the protecting groups of the hydroxyl groups varies depending on
the type of the protecting group but is carried out by a method
well known in organic synthetic chemistry.
[0660] For the respective hydroxyl group protected by, for example,
1-ethoxyethyl, tetrahydropyranyl, 1-methoxycyclohexyl,
4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl or
4-methoxytetrahydrothiopyranyl-S,S-dioxide, the deprotection
reaction can be easily carried out by treatment with an acid in an
inert solvent. Examples of the acid are the above-mentioned organic
acids and inorganic acid, of which, for example, pyridinium
p-toluenesulfonate, p-toluenesulfonic acid or camphorsulfonic acid
is preferred. The solvent used in the reaction is not specifically
limited, but a solvent that does not easily react with a starting
material is desirable. Preferred examples thereof are an alcohol
solvent such as methanol, ethanol, isopropanol or tert-butanol, or
a mixture of the alcohol and the above-mentioned inert solvent. The
amount of the acid used in the reaction is 0.5 to 5 equivalents and
is preferably 1 to 3 equivalents to the compound of the formula
(IVA). The reaction time is 10 minutes to 10 days and is preferably
1 day to 4 days. The reaction temperature is a temperature of
-78.degree. C. to heating under reflux and is preferably
-10.degree. C. to 50.degree. C.
[0661] When the hydroxyl group is protected by the other protecting
group such as tert-butyldimethylsilyl, triethylsilyl,
diethylisopropylsilyl, trimethylsilyl, triisopropylsilyl,
di-tert-butylmethylsilyl or diphenylmethylsilyl, it can be
deprotected by the treatment of a fluoride anion or an acid.
Examples of the fluoride anion are tetrabutylammonium fluoride,
hydrogen fluoride, potassium fluoride and hydrogen
fluoride-pyridine. Examples of the acid are the above-mentioned
organic acids and inorganic acids, of which a preferred example is
acetic acid, formic acid, trifluoroacetic acid, pyridinium
p-toluenesulfonate or camphorsulfonic acid. The solvent used in the
reaction is not specifically limited, but a solvent that does not
easily react with a starting material is desirable. Examples
thereof are the above-mentioned inert solvents, of which, for
example, tetrahydrofuran, diethyl ether or water is preferably
used. The amounts of the fluoride anion and acid used in the
reaction are 1 to 5 equivalents and 0.5 to 5 equivalents,
preferably 1 to 4 equivalents and 0.5 to 3 equivalents,
respectively, to the compound of the formula (IVA). The reaction
time is 10 minutes to 30 hours and is preferably 1 to 2 hours. The
reaction temperature is a temperature of -78.degree. C. to heating
under reflux and is preferably -10.degree. C. to 50.degree. C.
[0662] By a combination of the various protection methods for
hydroxyl groups described in the step A1 and the various
deprotection methods described in the step A5, the respective
hydroxyl groups at the 3-position, 6-position and 21-position can
be converted into urethane derivatives selectively. For example, a
urethane derivative having a hydroxyl group at the 6-position can
be synthesized by subjecting the hydroxyl group at the 6-position
of the compound (IA) in which R.sup.3A, R.sup.16A and R.sup.21A are
triethylsilyl groups to the step A3, the step A4 and the step A5
sequentially.
[0663] The selective modification of the hydroxyl group at the
3-position, 6-position or 21-position which is carried out by a
combination of the protection and the deprotection procedures can
also be applied to the other modification methods described below.
B. A Preparation for a Thiourethane Derivative ##STR32## In the
formula, R.sup.3A, R.sup.6A, R.sup.16A and R.sup.21A each
represents the same group as defined above; R.sup.3E, R.sup.6E,
R.sup.16E and R.sup.21E each represents a hydrogen atom, a
protecting group or a group represented by the formula
R.sup.N1R.sup.N2 N--CS-- (wherein R.sup.N1 and R.sup.N2 each
represents the same group as defined above), provided that
R.sup.3E, R.sup.6E, R.sup.16E and R.sup.21E do not concurrently
represent hydrogen atoms; and R.sup.3F, R.sup.6F, R.sup.16F and
R.sup.21F each represents hydrogen atom or a group represented by
the formula R.sup.N1R.sup.N2N--CS-- (wherein R.sup.N1 and R.sup.N2
each represents the same group as defined above).
[0664] The step B1 is a step for preparing the compound of the
formula (IB) by using a thioisocyanate or a thiocarbamoyl chloride
instead of the isocyanate. This step is carried out by treating the
compound of the formula (IIA) with an isothiocyanate or a
thiocarbamoyl chloride in an inert solvent in the presence of a
base or bis(tributyltin)oxide. The isothiocyanate used herein is
not specifically limited and includes, for example, ethyl
isothiocyanate, methyl isothiocyanate, phenyl isothiocyanate,
benzyl isothiocyanate, allyl isothiocyanate,
2-(N,N-dimethylamino)ethyl isothiocyanate,
2-(N,N-diethylamino)ethyl isothiocyanate,
3-(N,N-dimethylamino)propyl isothiocyanate,
3-(N,N-diethylamino)propyl isothiocyanate, 2-(morpholin-4-yl)ethyl
isothiocyanate, 2-(piperidin-1-yl)ethyl isothiocyanate and
2-(pyrrolidin-1-yl)ethyl isothiocyanate. The thiocarbamoyl chloride
used herein is not specifically limited and includes, for example,
N,N-dimethylthiocarbamoyl chloride, N-phenyl-N-methylthiocarbamoyl
chloride, (morpholin-4-yl)thiocarbamoyl chloride,
(4-methylpiperazin-1-yl)thiocarbamoyl chloride and
(4-methylhomopiperazin-1-yl)thiocarbamoyl chloride. Examples of the
base are the above-mentioned organic bases and inorganic bases, of
which, for example, diisopropylethylamine, 4-dimethylaminopyridine,
triethylamine, pyridine, 2,6-lutidine or sodium hydride is
preferably used. The solvent used in the reaction is not
specifically limited, but a solvent that does not easily react with
a starting material is desirable. Examples of such solvents are the
above-mentioned inert solvents, of which, for example,
tetrahydrofuran, dichloromethane, N,N-dimethylformamide or toluene
is preferably used. The amounts of the base or
bis(tributyltin)oxide, and isothiocyanate or thiocarbamoyl chloride
are 1 to 5 equivalents and 1 to 10 equivalents, preferably 1 to 3
equivalents and 2 to 5 equivalents, respectively, to the compound
of the formula (IIA). The reaction time is 10 minutes to 72 hours
and is preferably 1 to 24 hours. The reaction temperature is a
temperature of -78.degree. C. to heating under reflux and is
preferably -10.degree. C. to 70.degree. C.
[0665] A compound of the formula (IB) having a plurality of
thiocarbamoyl groups can be synthesized by converting the hydroxyl
group(s) of the compound represented by the formula (IIA), in which
one to three of OR.sup.3A, OR.sup.6A, OR.sup.16A and OR.sup.21A are
not protected, into thiocarbamoyloxy group(s) in the step B1.
[0666] The thiourethane derivative of the formula (IIB) can be
synthesized by deprotecting the protecting group of the hydroxyl
group by the step A5. C. A Preparation for an Ether Derivative
##STR33## In the formula, R.sup.3G, R.sup.6G, R.sup.16G and
R.sup.21G each represents a hydrogen atom or a protecting group,
provided that R.sup.3G, R.sup.6G, R.sup.16G and R.sup.21G do not
concurrently represent hydrogen atoms and at least one of them
represents a hydrogen atom; and R.sup.3H, R.sup.6H, R.sup.16H and
R.sup.21H each represents a protecting group or an optionally
substituted C.sub.1-22 alkyl group.
[0667] The step C1 is a step for synthesizing the compound of the
formula (IC). This step is carried out by the same way as in the
reaction corresponding to the step A1 of the preparation A, except
that one to three hydroxyl groups are to be protected.
[0668] On this step, alternatively, a compound in which one at the
3-position, 6-position or 21-position is a hydroxyl group and the
other hydroxyl groups are protected can be synthesized by using a
combination of the various protection methods for the hydroxyl
group corresponding to the step A1 and deprotection methods for a
protected hydroxyl group corresponding to the step A5 in the
preparation.
[0669] The step C2 is a step for synthesizing the compound of the
formula (IIC). This step is carried out by alkylating the
unprotected hydroxyl group(s) of the compound (IC).
[0670] The alkylation can be carried out by the treatment of an
alkylating agent of the formula R.sup.m--X in the presence of a
base. The substituent R.sup.m represents a C.sub.1-22 alkyl group
which may have substituents and includes, for example, methyl
group, ethyl group and benzyl group. X represents a leaving group.
Examples of the leaving group are chloro group, bromo group, iodo
group and trifluoromethanesulfonyl group. Examples of the base are
the above-mentioned organic bases and inorganic bases, of which
preferred examples are sodium hydride, lithium
bis(trimethylsilyl)amide, lithium diisopropylamide, lithium
dicyclohexylamide, potassium carbonate, cesium carbonate and
1,8-bis(N,N-dimethylamino)naphthalene. The solvent used in the
reaction is not specifically limited, but a solvent that does not
easily react with a starting material is desirable. Examples
thereof are the above-mentioned inert solvents, of which, for
example, diethyl ether, tetrahydrofuran, dimethoxyethane or toluene
is preferably used. The amounts of the alkylating agent and base
used in the reaction are 3 to 20 equivalents and 5 to 30
equivalents, preferably 3 to 5 equivalents and 5 to 10 equivalents,
respectively, to the compound of the formula (IC). The reaction
time is 10 minutes to 48 hours and is preferably 1 to 24 hours. The
reaction temperature is a temperature of -78.degree. C. to heating
under reflux and is preferably -10.degree. C. to -70.degree. C.
##STR34## In the formula, R.sup.3J, R.sup.6J, R.sup.16J and
R.sup.21J each represents an alkyl group or a protecting group;
R.sup.3K, R.sup.6K, R.sup.16K and R.sup.21K each represents an
alkyl group or a hydrogen atom; and R.sup.7K represents a carbamoyl
group or a thiocarbamoyl group, and each may have substituents on
the nitrogen atom.
[0671] If desired, a derivative having a carbamoyl group introduced
into the hydroxyl group at the 7-position and an alkyl group
introduced into one or two of the hydroxyl groups at the
3-position, 6-position and 21-position can be obtained by further
subjecting the compound of the formula (IIC) to the steps A2, A3,
A4 and A5.
[0672] Alternatively, a derivative having a thiocarbamoyl group
introduced into the hydroxyl group at the 7-position and an alkyl
group introduced into one or two of the hydroxyl groups at the
3-position, 6-position and 21-position can be obtained by
subjecting the compound of the formula (IIIC) to the step B1 and
then to the step A5. ##STR35## In the formula, R.sup.3A, R.sup.6A,
R.sup.16A and R.sup.21A each represents the same group as defined
above; and R.sup.3L, R.sup.6L, R.sup.7L, R.sup.16L and R.sup.21L
each represents a hydrogen atom or an alkyl group.
[0673] The ether derivative represented by the formula (IIC'), in
which the hydroxyl group at the 7-position is alkylated can be
prepared by subjecting the compound of the formula (IIA) to the
step C2 and then to the step A5 in a similar way as described
above.
[0674] Further, a corresponding ether derivative can be prepared by
using, instead of the alkylating agent, an unsaturated-alkylating
agent, aralkylating agent or heteroaralkylating agent that can
parepare a desired compound of the formula (I). D. A Preparation
for an Ester Derivative ##STR36## In the formula, R.sup.3G,
R.sup.6G, R.sup.16G and R.sup.21G each represents the same group as
defined above; and R.sup.3M, R.sup.6M, R.sup.16M and R.sup.21M each
represents a hydrogen atom, a protecting group or a group
represented by the formula R.sup.coCO-- (wherein R.sup.co
represents a hydrogen atom, an optionally substituted C.sub.1-22
alkyl group, an optionally substituted unsaturated C.sub.2-C.sub.22
alkyl group, an optionally substituted C.sub.6-14 aryl group, an
optionally substituted 5 to 14-membered heteroaryl group, an
optionally substituted C.sub.7-22 aralkyl group or an optionally
substituted 5 to 14-membered heteroaralkyl group), provided that
R.sup.3M, R.sup.6M, R.sup.16M and R.sup.21M do not concurrently
represent hydrogen atoms.
[0675] The step D1 is a step for converting the unprotected
hydroxyl group into an ester group by using the compound of the
formula (IC) synthesized in the step C1 as a starting material.
[0676] The esterification is carried out, for example, by using an
acid anhydride with a base, an acid halide with a base, a
carboxylic acid with a condensing agent or by carrying out
Mitsunobu reaction. As the acid anhydride, a variety of anhydrides
of carboxylic acids are used. Examples thereof are a mixed
anhydride comprising, for example, acetic acid, propionic acid,
butyric acid, valeric acid and benzoic acid; a symmetrical
anhydride; a cyclic anhydride such as succinic anhydride, glutaric
anhydride or adipic anhydride. Preferred examples are acetic
anhydride, propionic anhydride, butyric anhydride and benzoic
anhydride. As the acid halide, for example, various acid chlorides
and bromides are used, of which a preferred example is acetyl
chloride, propionyl chloride, benzoyl chloride or benzoyl bromide.
Examples of the base are the above-mentioned organic bases and
inorganic bases, of which a preferred example is imidazole,
4-dimethylaminopyridine, pyridine or sodium hydride. As the
carboxylic acid, various carboxylic acids are used, of which a
preferred example is acetic acid or propionic acid. Preferred
examples of the condensing agent are, for example,
dicyclohexylcarbodiimide, trifluoroacetic anhydride,
carbonyldiimidazole, N,N-diisopropylcarbodiimide and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. In the Mitsunobu
reaction, a variety of carboxylic acids can be substituted in the
presence of triphenylphosphine and diethyl azodicarboxylate or
diisopropyl azodicarboxylate. The solvent used in each of the
reactions is not specifically limited, but a solvent that does not
easily react with a starting material is desirable. Examples
thereof are the above-mentioned inert solvents, of which, for
example, dichloromethane, chloroform or tetrahydrofuran is
preferably used. The amounts of the acid anhydride with the base,
the acid halide with the base, and the carboxylic acid with the
condensing agent are 1 to 10 equivalents with 3 to 20 equivalents,
1 to 10 equivalents with 3 to 20 equivalents, and 1 to 20
equivalents with 1 to 20 equivalents, preferably 1 to 5 equivalents
with 2 to 10 equivalents, 1 to 5 equivalents with 2 to 10
equivalents, and 1 to 5 equivalents with 1 to 5 equivalents,
respectively, to the compound of the formula (IC). The reaction can
be accelerated by adding 0.2 to 2 equivalents of
4-dimethylaminopyridine as the case requires. The reaction time is
10 minutes to 30 hours and is preferably 1 to 2 hours. The reaction
temperature is a temperature of -78.degree. C. to heating under
reflux and is preferably -10.degree. C. to 50.degree. C.
[0677] The compound of the formula (ID) can be produced by
subjecting the thus-synthesized ester derivative to a reaction
similar to the step A5 to thereby deprotect the protecting group of
a hydroxyl group.
[0678] It is also possible to esterify one to four hydroxyl groups
by carrying out an esterification similar to the step D1 using
11107D as a starting material. ##STR37## In the formula, R.sup.3A,
R.sup.6A, R.sup.16A and R.sup.21A each represents the same group as
defined above; and R.sup.3N, R.sup.6N, R.sup.7N, R.sup.16N or
R.sup.21N represents a hydrogen atom or a group represented by the
formula R.sup.coCO-- (wherein R.sup.co represents the same group as
defined above).
[0679] The derivative represented by the formula (ID') in which the
hydroxyl group at the 7-position is esterified can be synthesized
by subjecting the compound of the formula (IIA) to the step D1 and
then to the step A5 in a similar way as described above. E. A
Preparation for a Phosphoric Ester or Amidophosphoric Ester
Derivative ##STR38##
[0680] In the formula, R.sup.3A, R.sup.6A, R.sup.16A and R.sup.21A
each represents the same group as defined above; R.sup.3P,
R.sup.6P, R.sup.7P, R.sup.16P and R.sup.21P each represents a
hydrogen atom, a group represented by the formula
(R.sup.N3O).sub.2PO--, the formula (R.sup.N1R.sup.N2N).sub.2PO-- or
the formula (R.sup.N1R.sup.N2N)(R.sup.N3O)PO-- (wherein R.sup.N1,
R.sup.N2 and R.sup.N3 each represents the same group as defined
above).
[0681] The step E1 is a step for converting the hydroxyl group of
the compound of the formula (IIA) as a starting material into a
phosphoric ester or an amidophosphoric ester.
[0682] The phosphoric-esterification is carried out, for example,
by using a phosphoryl halide and a base. Various phosphoryl halides
can be used herein, and examples thereof are a dialkoxyphosphoryl
chloride, a diphenyloxyphosphoryl chloride, an
alkoxy(N,N-disubstituted amino)phosphoryl chloride, an
allyloxy(N,N-disubstituted amino)phosphoryl chloride, an
alkoxy(N-substituted amino)phosphoryl chloride and an
allyloxy(N-substituted amino)phosphoryl chloride. Examples of the
base are the above-mentioned organic bases and inorganic bases, of
which a preferred example is pyridine, 4-dimethylaminopyridine,
triethylamine, ethyldiisopropylamine, sodium hydride,
n-butyllithium, potassium carbonate or sodium carbonate. The
solvent used in each of the reactions is not specifically limited,
but a solvent that does not easily react with a starting material
is desirable. Examples thereof are the above-mentioned inert
solvents, of which, for example, dichloromethane, chloroform,
tetrahydrofuran or N,N-dimethylformamide is preferably used. The
reaction time is 10 minutes to 72 hours and is preferably 1 to 24
hours. The amounts of the phosphoryl halide and base used in the
reaction are 1 to 10 equivalents and 2 to 20 equivalents,
preferably 1 to 5 equivalents and 2 to 10 equivalents,
respectively, to the compound of the formula (IIA). The reaction
temperature is a temperature of -78.degree. C. to heating under
reflux and is preferably -10.degree. C. to 50.degree. C.
[0683] The compound of the formula (IE) can be prepared by
subjecting the thus-synthesized phosphoric ester derivative to a
similar reaction as the step A5 to thereby deprotect the protecting
group of a hydroxyl group.
[0684] It is also possible to convert one to four hydroxyl groups
into phosphoric esters by carrying out phosphoric-esterification of
11107D as a starting material by a similar way as described for the
step E1. F. A Preparation for a Sulfuric Ester or Amidosulfuric
Ester Derivative ##STR39## In the formula, R.sup.3A, R.sup.6A,
R.sup.16A and R.sup.21A each represents the same group as defined
above; and R.sup.3Q, R.sup.6Q, R.sup.7Q, R.sup.16Q and R.sup.21Q
each represents a hydrogen atom or a group represented by
R.sup.N1R.sup.N2N--SO.sub.2-- or R.sup.N3O--SO.sub.2-- (wherein
R.sup.N1, R.sup.N2 and R.sup.N3 each represents the same group as
defined above).
[0685] The step F1 is a step for converting the hydroxyl group of
the compound of the formula (IIA) as a starting material into a
sulfuric ester.
[0686] The sulfuric-esterification is carried out, for example, by
using a sulfonyl halide and a base. Various sulfonyl halides can be
used herein, and examples thereof are an alkoxysulfonyl chloride
and an N,N-disubstituted sulfamoyl chloride. Examples of the base
are the above-mentioned organic bases and inorganic bases, of which
a preferred example is pyridine, 4-dimethylaminopyridine,
triethylamine, ethyldiisopropylamine, sodium hydride,
n-butyllithium, potassium carbonate or sodium carbonate. The
solvent used in each of the reactions is not specifically limited,
but a solvent that does not easily react with a starting material
is desirable. Examples thereof are the above-mentioned inert
solvents, of which, for example, dichloromethane, chloroform,
tetrahydrofuran or N,N-dimethylformamide is preferably used. The
amounts of the sulfonyl halide and base used in the reaction are 1
to 10 equivalents and 2 to 20 equivalents, preferably 1 to 5
equivalents and 2 to 10 equivalents, respectively, to the compounds
of the formula (IIA). The reaction time is 10 minutes to 72 hours
and is preferably 1 to 24 hours. The reaction temperature is a
temperature of -78.degree. C. to heating under reflux and is
preferably -10.degree. C. to 50.degree. C.
[0687] The compound of the formula (IF) can be synthesized by
subjecting the those synthesized sulfuric ester derivative to a
similar reaction as the step A5 to thereby deprotect the
hydroxyl-protecting group.
[0688] It is also possible to convert one to four of the hydroxyl
groups into sulfuric acid esters by subjecting 11107D as a starting
material to sulfuric-esterification by a similar way as the step
F1. G. A Preparation for a Halogen Derivative ##STR40## In the
formula, R.sup.3A, R.sup.6A, R.sup.16A and R.sup.21A each
represents the same group as defined above; R.sup.3R, R.sup.6R,
R.sup.16R and R.sup.21R each represents a hydroxyl group or a
halogen atom.
[0689] The step G1 is a step for converting the hydroxyl group of
the compound of the formula (IA) as a starting material into a
halogen.
[0690] The halogenation is carried out, for example, by treating
diethylaminosulfur trifluoride (DAST) or triphenylphosphine with
carbon tetrabromide, bromine, phosphorus tribromide, iodine or
carbon tetrachloride in the presence of a base. The base used
herein includes, for example, general organic bases and inorganic
bases such as diisopropylethylamine, dimethylaminopyridine,
triethylamine, pyridine, 2,6-lutidine and sodium hydride. The
solvent used in the reaction is not specifically limited, but a
solvent that does not easily react with a starting material is
desirable. Examples thereof are tetrahydrofuran, dichloromethane
and N,N-dimethylformamide. Among them, fluorination with
diethylaminosulfur trifluoride is preferred. The amount of
diethylaminosulfur trifluoride (DAST) is 1 to 5 equivalents, and
preferably 1 to 3 equivalents to the compound of the formula (IIA).
The reaction time is 10 minutes to 10 hours. The reaction
temperature is a temperature of -78.degree. C. to room
temperature.
[0691] The compound of the formula (IG) can be synthesized by
subjecting the those synthesized halogen derivative to the
procedure of the step A5 to thereby remove the protecting group of
a hydroxyl group. H. A Preparation for a Sulfonic Ester Derivative
##STR41##
[0692] In the formula, R.sup.3A, R.sup.6A, R.sup.16A and R.sup.21A
each represents the same group as defined above; and R.sup.3S,
R.sup.6S, R.sup.7S, R.sup.16S and R.sup.21S each represents a
hydrogen atom or a group represented by R.sup.N3SO.sub.2-- (wherein
R.sup.N3 represents the same group as defined above).
[0693] The step H1 is a step for sulfonylating the hydroxyl group
of the compound of the formula (IIA) as a starting material.
[0694] The sulfonylation can be carried out, for example, by the
treatment of a sulfonyl chloride such as p-toluenesulfonyl
chloride, methanesulfonyl chloride or benzenesulfonyl chloride in
the presence of a base. Examples of the base are general organic
bases and inorganic bases such as diisopropylethylamine,
dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine and
sodium hydride. The solvent used in the reaction is not
specifically limited, but a solvent that does not easily react with
a starting material is desirable. Examples thereof are
tetrahydrofuran, dichloromethane and N,N-dimethylformamide. The
amounts of the sulfonyl chloride and base used in the reaction are
1 to 5 equivalents and 2 to 10 equivalents, preferably 1 to 3
equivalents and 2 to 6 equivalents, respectively, to the compound
of the formula (IIA). The reaction time is 10 minutes to 30 hours.
The reaction temperature is a temperature of -78.degree. C. to
heating under reflux.
[0695] The derivative represented by the formula (1H) in which the
hydroxyl group at the 7-position is sulfonylated can be synthesized
by subjecting the those synthesized sulfonic ester derivative to
the step A5 to deprotect the protecting group of a hydroxyl
group.
[0696] It is also possible that 11107D as a starting material is
subjected to sulfonylation by a similar procedure as the step H1 to
thereby sulfonylate one to four of the hydroxyl groups. I. A
Preparation for an Amine Derivative ##STR42## In the formula,
R.sup.3A, R.sup.6A, R.sup.16A and R.sup.21A each represents the
same group as defined above; and R.sup.3T, R.sup.6T, R.sup.7T,
R.sup.16T and R.sup.21T each represents a hydroxyl group or the
formula R.sup.N1R.sup.N2 N-- (wherein R.sup.N1 and R.sup.N2 each
represents the same group as defined above).
[0697] The step I1 is a step for converting the hydroxyl group of
the compound of (IIA) directly into an amine or into a good leaving
group, then into an azide and then into an amine by reduction.
[0698] In the case where the hydroxyl group is converted into an
azide, examples of reagents used in the reaction are 1)
diphenylphosphoryl azide (DPPA), diethyl azodicarboxylate and
triphenylphosphine, 2) DPPA and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), 3) hydrogen azide, diethyl azodicarboxylate and
triphenylphosphine, 4) DPPA, tetramethylazodicarboxamide (TMAD) and
tributylphosphine, and 5) sodium azide in the presence of a base.
Examples of the base are the above-mentioned organic bases and
inorganic bases, of which, for example, diisopropylethylamine,
dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or
sodium hydride is preferably used. It is also possible to convert
into an azide by the treatment of sodium azide in the presence of a
palladium catalyst. An example of the palladium catalyst is
Pd(PPh.sub.3).sub.4. The solvent used in the reaction is not
specifically limited, but a solvent that does not easily react with
a starting material is desirable. Examples thereof are
tetrahydrofuran, dichloromethane, N,N-dimethylformamide, toluene
and benzene. The reaction time is 10 minutes to 30 hours. The
reaction temperature is a temperature of -78.degree. C. to heating
under reflux.
[0699] The reduction from the azide to the amine can be carried out
by using, for example, triphenylphosphine or lithium aluminum
hydride. The azide can be also reduced into the amine, for example,
by using a catalyst such as palladium-carbon or Lindlar catalyst
under hydrogen atmosphere. The solvent used in the reaction is not
specifically limited, but a solvent that does not easily react with
a starting material is desirable. Examples thereof are
tetrahydrofuran, diethyl ether and ethanol. The reaction time is 10
minutes to 30 hours. The reaction temperature is a temperature of
-78.degree. C. to heating under reflux.
[0700] The conversion of a hydroxyl group into a good leaving group
can be carried out by the similar procedure of the step G1
(halogenation) or the step H1 (sulfonylation). Examples of the good
leaving group are chloro group, bromo group, iodo group,
methanesulfonyl group and p-toluenesulfonyl group. Next, by
treating the converted compound having a leaving group with an
amine in an inert solvent in the presence of a base, the compound
in which the hydroxyl group is converted into an amino group or
substituted amino group can be synthesized.
[0701] Examples of the amine used herein are methylamine,
ethylamine, dimethylamine and diethylamine. Examples of the base
are the above-mentioned organic bases and inorganic bases, of
which, for example, diisopropylethylamine, dimethylaminopyridine,
triethylamine, pyridine, 2,6-lutidine or sodium hydride is
preferably used. The solvent used in the reaction is not
specifically limited, but a solvent that does not easily react with
a starting material is desirable. Examples thereof are the
above-mentioned inert solvents, of which, for example,
tetrahydrofuran, dichloromethane or N,N-dimethylformamide is
preferably used. The reaction time is 10 minutes to 30 hours and is
preferably 1 to 2 hours. The reaction temperature is a temperature
of -78.degree. C. to heating under reflux and is preferably
-10.degree. C. to 50.degree. C.
[0702] The compound of the formula (II) can be prepared by
subjecting the those synthesized amine derivative to deprotect the
protecting group of a hydroxyl group the by a similar way as the
step A5. It is also possible to convert one or two of the hydroxyl
groups of 11107D as a starting material into amino groups by
amination by a similar way as the step I1.
[0703] The compound of the formula (I) can be also prepared by
alkylating, acylating, carbamoylating or sulfonylating the amino
group of the compound of the formula (II) by methods well known in
organic synthetic chemistry and the above-mentioned methods. J. A
Preparation for an Oxo-Compound (Oxidation of a Hydroxyl Group)
##STR43## In the formula, either one of R.sup.3Ja and R.sup.3Ja
represents a hydroxyl group and the other represents a hydrogen
atom, or R.sup.3Ja and R.sup.3Ja together with the carbon atom to
which R.sup.3Ja and R.sup.3Ja are bound represent an oxo group,
either one of R.sup.21Ja and R.sup.21Ja represents a hydroxyl group
and the other represents a hydrogen atom, or R.sup.21Ja and
R.sup.21Ja together with the carbon atom to which R.sup.21Ja and
R.sup.21Ja are bound represent an oxo group.
[0704] The step J1 is a step for synthesizing the oxo-compound
represented by the formula (IIJ) by oxidizing the hydroxyl group of
11107D as a starting material.
[0705] Examples of the oxidizing agent used in this step are
manganese dioxide, pyridinium chlorochromate, pyridinium
dichromate, Dess-Martin reagent and reagents used in Swern
oxidation. The solvent used in the reaction is not specifically
limited, but a solvent that does not easily react with a starting
material is desirable. Examples thereof are tetrahydrofuran,
dichloromethane, chloroform and toluene. The reaction temperature
is a temperature of -78.degree. C. to heating under reflux. The
reaction time is 10 minutes to 78 hours. Among these reactions, for
example, the reaction using Dess-Martin reagent, manganese dioxide
or reagents used in Swern oxidation is preferred, of which the
reaction using a Dess-Martin reagent is typically preferred. As the
solvent for use in the oxidation using Dess-Martin reagent,
dichloromethane or chloroform is typically preferred. The amount of
the oxidizing agent used herein is 1 to 20 equivalents and is
preferably 1 to 5 equivalents to the compound (11107D). The
reaction temperature is preferably 0.degree. C. to room
temperature. The reaction time is 30 minutes to 24 hours and is
preferably 1 to 8 hours.
[0706] A compound in which the hydroxyl group at the 3-position or
21-position of these derivatives has been converted into an oxo
moiety can be synthesized by subjecting, for example, an urethane
derivative, thiourethane derivative, ester derivative or alkyl
derivative, which is precedently prepared by the above-mentioned
methods to the step J1 instead of 11107D. Further, a 7-oxo compound
can be obtained by oxidizing the hydroxyl group at the 7-position
of the compound represented by the formula (IIA).
[0707] Further, the hydroxyl group at the 3-position, 7-position
and/or 21-position can be selectively converted into an oxo moiety
by a various combination of the protection and deprotection
conditions of the step A1 and the step A5 with the step J1. In
addition, a compound which has both an oxo moiety and a urethane,
thiourethane, ester or alkyl moiety can be respectively synthesized
by subjecting a compound, which is precedently converted into an
oxo moiety, to the above-mentioned methods for a urethane
derivative, thiourethane derivative, ester derivative or alkyl
derivative.
[0708] The compounds represented by the formula (I) can be
synthesized by an appropriate combination of the reactions A to J
and protection and deprotection procedures of the hydroxyl
group.
[0709] After termination of the reaction, the target product in the
respective reaction is isolated from a reaction mixture according
to a conventional procedure. For example, the target compound can
be obtained by filtration, if insoluble matter is present, and
evaporation of the solvent, or by diluting the reaction mixture
with an organic solvent such as ethyl acetate, washing the organic
layer with water, drying over anhydrous magnesium sulfate and
evaporating the solvent. The compound can be further purified by a
conventional procedure such as column chromatography, thin layer
chromatography or high performance liquid chromatography as the
case requires.
[0710] To illustrate the usefulness of the present invention
specifically, the VEGF transcription-suppressing activity, growth
inhibitory activity on WiDr human colon cancer cell, growth
inhibitory activity on solid cancer, body weight loss (acute
toxicity) and stability in an aqueous solution of representative
compounds of the compounds of the formula (I) according to the
present invention were determined.
TEST EXAMPLE 1
Construction of Reporter System for Screening Compound which
Suppresses the Transcription of VEGF
[0711] In order to prepare reporter system reflecting transcription
from VEGF promoter, VEGF promoter sequence was cloned, and inserted
in secretory alkaline phosphatase (PLAP) vector to construct
reporter vector.
[0712] In order to obtain the promoter region of human VEGF, VEGF
genomic DNA was cloned from phage library. PCR primers having the
sequences described in Sequence Numbers 1 and 2 were designed based
on VEGF cDNA (GenBank accession number: X62568) and a fragment
having about 340 bp was obtained by carrying out PCR. Human genomic
phage library (Human genomic library, Clontech Co.) was screened
using this as a probe to obtain VEGF genomic DNA. The DNA was
digested by EcoRI, and the resultant fragments were inserted in the
EcoRI site of pUC18. Finally, pUC18-VEGFA containing about 5.4 kb
of VEGF 5' flanking region was obtained. The pUC18-VEGFA was
digested by KpnI/NheI, VEGF promoter region of about 2.3 kb
obtained was inserted in the multi cloning site KpnI/NheI of
secretory alkaline phosphatase (PLAP) vector (Goto et al, Mol.
Pharmacol., 49, 860-873, 1996), and thus, VEGF-PLAP vector was
constructed.
[0713] The above-mentioned VEGF-PLAP vector was transfected in the
U251 cell cultured in the DULBECCO-modified eagle medium (DMEM;
manufactured by SIGMA Co., Ltd.) containing 10% fetal calf serum,
and the cells were cultured in the presence of 1 mg/mL G418 (Merck
Co.) to establish G418 resistant stable clone (U251/1-8 cell).
[0714] It was confirmed that U251/1-8 cell secreted PLAP under
hypoxic condition (2% O.sub.2 incubator) in the same manner as in
the report (Cell. Mol. Biol. Res. 40, 35-39, 1994) and was a
reporter system reflecting the transcription from VEGF promoter.
The screening of the compound suppressing VEGF production which was
induced by hypoxic stimulation was carried out below using the
clone.
TEST EXAMPLE 2
VEGF transcription-suppressing activities of various 11107
analogues and derivatives
[0715] In order to remove the influence of alkaline phosphates in
serum, U251/1-8 cells were rinsed twice with the adequate amount of
PBS (Phosphate buffered saline), diluted in the DMEM medium
containing 10% of serum in which alkaline phosphates was
inactivated by the treatment of 65.degree. C. for 20 min., and
dispensed in 96-well plates by 4.times.10.sup.4 cells/180
.mu.L.
[0716] After culturing at 37.degree. C. overnight in a CO.sub.2
incubator (5% CO.sub.2), 20 .mu.L of the above-mentioned incubation
solution containing the test compound diluted with 3-fold
succession was added, and then they were incubated in a hypoxic (2%
CO.sub.2) incubator for 18 hours. With respect to the PLAP activity
in the culture supernatants, 10 .mu.L of the supernatants was added
to 50 .mu.L of 0.28 M Na.sub.2CO.sub.3--NaHCO3 buffer solution (pH
10.0, 8.0 mM MgSO.sub.4), and finally 50 .mu.L of alkaline
phosphatase substrate (LUMISTEIN, Genomescience Co.) was added.
After reacting for one hour, the alkaline phosphatase activity of
the PLAP was measured by detecting the chemical luminescence by a
micro plate reader (Perkin-Elmer Co.). The PLAP activity under
normoxia was set as 0%, the PLAP activity of cell which was treated
under hypoxia was set as 100%, and the concentration suppressing
the PLAP activity by 50% was set as the IC.sub.50 value of PLAP.
The IC.sub.50 values of 11107D derivatives shown in Examples were
measured, and the IC.sub.50 values of representative 11107D
derivatives are shown in Table 1. The 11107D derivatives showed
strong VEGF transcription-suppressing activities. TABLE-US-00001
TABLE 1 VEGF transcription-suppressing activities Compound
(IC.sub.50: nM) 6 32.0 9 12.9 12 10.2 16 3.1 17 3.9 21 6.1 22 25.6
24 5.5 25 2.9 26 2.8 27 3.7 44 3.9 45 1.9 75 9.1 95 1.2 109 3.3 122
4.4 127 2.4 131 1.7 136 1.2 142 11.2
TEST EXAMPLE 3
Growth Inhibitory Activities on WiDr Human Colon Cancer Cells
[0717] WiDr human colon cancer cells cultured in DULBECCO-modified
eagle medium (DMEM; manufactured by SIGMA Co., Ltd.) containing 10%
fetal calf serum, penicillin (100 unit/mL) and streptomycin (100
.mu.g/mL) were dispensed in 96-well plates by 2.times.10.sup.3
cells/well. After culturing overnight in a CO.sub.2 incubator, 20
.mu.L of the above-mentioned incubation solution containing the
test compound diluted with 3-fold succession was added, followed by
incubation. After three days, 5 .mu.L of 3.3 mg/mL MTT solution was
added, followed by culturing for further one hour. Then, formazan
formed by the reduction by the action of living cells was extracted
with 100 .mu.L of DMSO, the absorbance (A540/A660) was determined
and was set as the index of the number of living cells.
[0718] The concentrations of the compounds of the formula (I) at
which the growth of WiDr human colon cancer cells are inhibited 50%
were determined. The IC.sub.50 values of representative compounds
are shown in Table 2. The compounds of the formula (I) showed
strong growth inhibitory activities on WiDr human colon cancer
cells. TABLE-US-00002 TABLE 2 Growth inhibitory activities on WiDr
human colon cancer cells Compound (IC.sub.50: nM) 6 12.5 9 5.5 16
2.0 17 2.6 21 3.2 22 14.6 24 5.3 25 1.2 26 1.6 27 1.2 44 2.1 45 0.7
75 4.1 95 0.5 109 1.5 122 1.1 127 0.7 131 0.7 136 0.8 142 4.9
TEST EXAMPLE 4
Solid Tumor Growth Inhibitory Activities
[0719] In order to study solid tumor growth inhibitory activities
of the compounds of the formula (I) in vivo, WiDr human colon
cancer cells were implanted subcutaneously into the flanks of nude
mice. transplanted to the subcutaneous body sides of mice. The
animals were grouped so that the average of the volumes of the
respective groups became uniform, when it reached about 100
mm.sup.3. Control group was made up of 10 mice and
11107D-administering groups were made up of 5 mice. The derivatives
were administered for the administering groups for 5 consecutive
days by intravenous injection so as to be any of 0.625 mg, 1.25 mg,
2.5 mg, 5 mg and 10 mg/kg/day, and a vehicle was administered to
the control group. The tumor volumes on Day 15 were measured, and
relative tumor volume ratios (T/C %) were determined setting the
tumor volume of the control group as 100%. The T/C % of
representative compounds of the formula (I) are shown in Table 3.
The body weights on Day 1, Day 5, Day 8, Day 12 and Day 15 (or 16)
were measured, and relative body weight variations were determined
setting the body weight on Day 1 as 100%. The relative body weight
ratios on the day where the body weight reached the minimum were
defined as the minimum relative weight ratios and are shown in
Table 3. TABLE-US-00003 TABLE 3 Growth inhibitory activities in the
WiDr human solid tumor the minimum Dose model relative Compound
(mg/kg) (T/C %) weight ratios 6 1.25 35 0.81 9 5.0 10 0.86 12 2.5
21 0.85 15 2.5 36 0.82 16 2.5 28 0.90 21 2.5 28 0.80 22 5.0 39 0.74
26 2.5 42 0.93 44 5.0 19 0.89 45 5.0 20 0.90 75 5.0 17 0.82 109
0.625 36 0.89 131 2.5 28 0.83
[0720] The compounds of the formula (I) showed growth inhibitory
activities in the WiDr human colon tumor model even in a dose
without remarkable weight loss also in vivo.
TEST EXAMPLE 5
Stability in an Aqueous Solution
[0721] The compounds of the formula (I) were dissolved in DMSO in
concentrations of 10 to 20 mM, and these were diluted about 500
folds with Britton-Robinson's buffer solution of pH 7. Each of the
solutions as sample solutions was incubated at 25.degree. C. for 24
hours.
[0722] The sample solutions were analyzed by high performance
liquid chromatography before and after incubation, and the residual
ratios of the tested substances in the sample solutions after
incubation were determined from the peak areas of the obtained
chromatograms. TABLE-US-00004 Peak area (mAU .times. sec) The
residual ratios Example initial after 24 hours (%) FD895 1197 993
83.0 11107D 3994 3817 95.6 Compound 9 5690 5476 96.2 Compound 12
5450 5169 94.9 Compound 22 4713 4514 95.8 Compound 44 4031 3820
94.8 Compound 45 5291 5024 95.0 Compound 75 2594 2478 95.5 Compound
109 2224 2111 94.9 Compound 122 4872 4620 94.8 Compound 130 4819
4583 95.1 Compound 131 168 157 93.2 Compound 136 3750 3579 95.4
Compound 142 3916 3705 94.6
[0723] The results show that the content of FD895 decreased to 83%
after 24 hours, but that the contents of Compounds 9, 12 and 22 as
representative compounds of the compounds of the formula (I)
remained 95 to 96%, indicating that the 11107D derivatives are
stable in an aqueous solution.
[0724] As is evident from the above Pharmacological Test Examples,
the compounds of the formula (I) according to the present invention
especially suppress VEGF production by varying the gene expression
and are expected to use as an antitumor agent, in particular, as a
treating agent for solid cancer, a carcinoma metastasis suppressor,
as well as an agent for treating diabetic retinopathy, rheumatoid
arthritis and anginoma. Further, as is evident from the toxicity
test of Test Example 4, the compounds of the formula (I) show
growth inhibitory activities in the WiDr human colon tumor modle in
such a dose as to not cause remarkable weight loss of the tested
mice and are safe compounds. Accordingly, they are efficacious as
an agent for preventing or treating a disease against which gene
expression control is efficacious, a disease against which VEGF
production suppressing activity is efficacious and a disease
against which angiogenesis inhibiting activity is efficacious. The
"preventing or treating" indicates either of preventing or
treating, or both of them. More specifically, the compounds of the
formula (I) of the present invention are effective as an antitumor
agent, and in particular, as an antitumor agent and a carcinoma
metastasis suppressor for solid cancer. As the solid cancer, for
example, pancreatic cancer, gastric cancer, colon cancer, breast
cancer, prostate cancer, lung cancer, kidney cancer, brain tumor,
head and neck cancer, esophageal cancer, skin cancer, liver cancer,
uterus cancer, cervix uteri cancer, urinary bladder cancer, thyroid
cancer, testicular cancer, chorionic carcinoma, osteosarcoma, soft
tissue sarcoma, and ovarian cancer may be proposed, of which a
cancer such as colon cancer, breast cancer, prostate cancer, lung
cancer, head and neck cancer or ovarian cancer is preferred.
Further, they are also effective as an antitumor agent for
leukemia. Further, they are also effective as an agent for treating
hematoma. Furthermore, they are also effective as an agent for
treating diabetic retinopathy, rheumatoid arthritis and hematoma,
which is based on VEGF production suppressing action. In addition,
they are also effective as an agent for treating inflammatory
diseases consisting of osteoarthritis, psoriasis and prolonged
hypersensitivity reaction, and atherosclerosis.
[0725] When the compounds are prepared as an injection, a pH
regulator, a buffer, a stabilizer, a solubilizer and the like are
added to the main drug, if necessary, to prepare an subcutaneous,
intramuscular, intra-articular or intravenous injection according
to a conventional procedure.
[0726] When the compound is administered as a preventive or
therapeutic agent for various diseases, it may be orally
administered as tablets, powders, granules, capsules, syrups and
the like, and may be parenterally or parenterally administered as a
spray, a suppository, an injection, an external preparation or a
drip. The dose remarkably varies according to the severity of
symptom, age, the kind of liver disease etc., and approximately 1
mg to 100 mg per day for an adult is administered in general at one
time or several times.
[0727] Conventional excipients are used at production of
pharmaceuticals, and the pharmaceutical products are prepared by a
conventional method. Namely, when a solid formulation for oral use
is prepared, a filler is added to the main drug, and if necessary,
a binder, a disintegrant, a lubricant, a colorant, a flavoring
agent and the like are added thereto, and then tablets, coated
tablets, granules, powders, capsules and the like are prepared. It
is needless to say that sugar coating, gelatin coating or suitable
coating may conducted on the tablet and granule, if necessary.
[0728] According to the present invention, the compounds of the
formula (I) of the present invention suppress, in particular, VEGF
production by varying the gene expression and show excellent
antitumor activities in in vivo solid tumor models. Further, the
compounds of the formula (I) of the present invention are stable in
an aqueous solution and can provide, for example, an agent for
treating cancer, in particular, an agent for treating solid cancer,
a carcinoma metastasis suppressor, an agent for treating diabetic
retinopathy, rheumatoid arthritis and angioma.
EXAMPLES
[0729] The present invention will be illustrated in further detail
with reference to Examples and Referential Examples below, which
are not intended to limit the scope of the present invention.
[0730] The symbols used in the chemical structural formulae in
Examples will be illustrated below. [0731] DEIPS:
diethylisopropylsilyl group [0732] Et: ethyl group [0733] EE:
1-ethoxyethyl group [0734] Me: methyl group [0735] TES:
triethylsilyl group
Example 1
Fermentation of Mer-11107 Strain and Purification of 11107D
[0736] One loopful of the slant culture (ISP-2) of Mer-11107 strain
was inoculated into a 500 ml Erlenmeyer flask containing 50 mL of
seed medium (2% of glycerin, 2% of glucose, 2% of soybean meal
(ESUSAN-MEAT manufactured by Ajinomoto Co. Ltd.), 0.5% of yeast
extract, 0.25% of sodium chloride, 0.32% of calcium carbonate,
0.0005% of copper sulfate, 0.0005% of manganese chloride, 0.0005%
of zinc sulfate, pH 7.4), and it was cultured at 28.degree. C. for
three days on a shaker to give the first seed culture. The seed
culture (0.6 mL) was inoculated into a 500 mL Erlenmeyer flask
containing 60 mL of the producing medium (5% of soluble starch,
0.5% of corn steep liquor, 0.5% of dry yeast, 0.5% of gluten meal,
0.1% of calcium carbonate) and it was fermented at 28.degree. C.
for four days on a rotary shaker to give a fermentation cultured
broth.
[0737] The cultured broth (10 L) was extracted with 1-butanol (10
L), then thus acquired butanol layer was evaporated to dryness to
give 100 g of crude active fraction. The crude active fraction was
applied on Sephadex LH-20 (1500 mL; manufactured by Pharmacia Co.
Ltd.), and eluted with tetrahydrofuran-methanol (1:1) as a solvent.
An eluted fraction from 540 mL to 660 mL was concentrated to
dryness, to give a residue (660 mg). The resulting residue was
dissolved in a mixture of ethyl acetate and methanol (9:1; v/v) and
subjected to silica gel column chromatography (WAKO GEL C-200, 50
g). The column was eluted with a mixture (2 L) consisting of
n-hexane and ethyl acetate (1:9, v/v), the fractions eluted from
1440 mL to 1566 mL were collected, evaporated to give 15 mg of a
crude active fraction.
[0738] The obtained crude active fraction was subjected to
preparative high performance liquid chromatography (HPLC) under the
following preparative HPLC condition (A), and the fractions eluted
at the retention time of 17 minutes were collected. After removing
acetonitrile, the respective fractions were desalted by HPLC under
the following preparative HPLC condition (B) to give 11107D
(Retention time: 36 minutes, 1.8 mg).
Preparative HPLC Conditions A:
[0739] Column: YMC-PACK ODS-AM F20 mm.times.250 mm (manufactured by
YMC Co.) [0740] Flow rate: 10 ml/min. [0741] Detection: 240 nm
[0742] Eluent: acetonitrile/0.15% aqueous potassium
dihydrogenphosphate (pH 3.5) (2:8 to 8:2, v/v, 0 to 50 min., linear
gradient) Preparative HPLC Conditions B: [0743] Column: YMC-PACK
ODS-AM F20 mm.times.250 mm (manufactured by YMC Co.) [0744] Flow
rate: 10 mL/min. [0745] Detection: 240 nm [0746] Eluent:
methanol/water (2:8 to 10:0, v/v, 0 to 40 min., linear
gradient)
Example 2
Physico-Chemical Properties of 11107D
[0747] The physico-chemical properties of 11107D are shown below.
The structure of 11107D was determined as shown below. [0748] 1.
Appearance: Colorless Powder [0749] 2. Molecular weight: 552,
ESI-MS m/z 551 (M-H).sup.-, 575 (M+Na).sup.+ [0750] 3. Molecular
formula: C.sub.30H.sub.48O.sub.9 [0751] 4. Solubility: soluble in
dimethyl sulfoxide, pyridine, methanol and acetone, and slightly
soluble in water [0752] 5. Color reaction: positive for iodine and
sulfuric acid [0753] 6. Ultraviolet absorption spectrum (methanol,
maximum value) nm: 239 (.epsilon. 33100) [0754] 7. Infrared
absorption spectrum (KBr) cm.sup.-1: 3417, 2967, 1732, 1714, 1455,
1372, 1248, 1176 [0755] 8. .sup.1H-NMR spectrum (CD.sub.3OD, 500
MHz): .delta. ppm (integral, multiplicity, coupling constant J
(Hz)): [0756] 0.93(3H,d,J=7.0 Hz), 0.95(3H,d,J=6.8 Hz),
0.98(3H,t,J=8.0 Hz), 1.23(3H,s), 1.30(1H,m), 1.36-1.66(9H,m),
1.70(1H,dd,J=6.4,14.2 Hz), 1.82(3H,d,J=1.0 Hz),
1.90(1H,dd,J=6.4,14.2 Hz), 2.10(3H,s), 2.52(2H,m), 2.62(1H,m),
2.72(1H,dd,J=2.4,8.3 Hz), 2.94(1H,dt,J=2.4,5.7 Hz),
3.55(1H,dt,J=8.3,4.4 Hz), 3.82(1H,m), 5.10(1H,d,J=9.8 Hz),
5.11(1H,d,J=10.8 Hz), 5.60(1H,dd,J=9.8,15.2 Hz),
5.74(1H,dd,J=8.3,15.2 Hz), 5.92(1H,d,J=15.2 Hz), 6.18(1H,d,J=10.8
Hz), 6.57(1H,dd,J=10.8,15.2 Hz) [0757] 9. .sup.13C-NMR Spectrum
(CD.sub.3OD, 125 MHz):.delta. ppm (multiplicity): [0758]
10.52(q),10.82(q),11.98(q),16.84(q),21.07(q),24.21(q),
28.62(t),28.79(q),30.46(t),37.53(t),40.10(t),41.80(d),
42.58(d),45.97(t),55.99(d),62.53(d),70.42(d),73.09(s),
74.11(s),75.30(d),80.31(d),84.19(d),123.64(d),127.10(d),
131.76(d),133.81(s),141.61(d),143.22(d),171.75(s),172.18(s)
##STR44##
Example 3
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(pyrro-
lidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-
-olide (Compound 3)
[0759] ##STR45##
Example 3-1
(8E,12E,14E)-7-Acetoxy-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pe-
ntamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (Formula XV)
and
(8E,12E,14E)-7-acetoxy-3,16,21-tris(1-ethoxyethoxy)-6-hydroxy-6,10,12,16,-
20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (Formula
XVI)
[0760] ##STR46##
[0761] To a solution of
(8E,12E,14E)-7-acetoxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-1-
8,19-epoxytricosa-8,12,14-trien-11-olide (50 mg, 0.09 mmol) in
dichloromethane (2.5 mL) were added ethyl vinyl ether (326 mg, 4.5
mmol) and pyridinium p-toluenesulfonate (6.8 mg, 27 .mu.mol) at
room temperature, followed by stirring at the same temperature for
19 hours. The reaction mixture was diluted with ethyl acetate and
washed with a saturated aqueous solution of sodium bicarbonate and
brine. The organic layer was dried over anhydrous magnesium
sulfate, filtrated and evaporated. The resulting residue was
purified by silica gel column chromatography (Kanto silica gel 60N,
40 to 100 .mu.m; ethyl acetate:hexane=30:70) to give
(8E,12E,14E)-7-acetoxy-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-p-
entamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (60 mg, 79%)
as a colorless oil (Formula XV).
[0762] ESI-MS m/z 863 (M+Na).sup.+.
[0763] Next,
(8E,12E,14E)-7-acetoxy-3,16,21-tris(1-ethoxyethoxy)-6-hydroxy-6,10,12,16,-
20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (6 mg, 9%)
was obtained as a colorless oil (Formula XVI) from an eluted
fraction of ethyl acetate:hexane=50:50.
[0764] ESI-MS m/z 791 (M+Na).sup.+.
Example 3-2
(8E,12E,14E)-3,6,16,21-Tetrakis(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pe-
ntamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
[0765] ##STR47##
[0766] To a solution of
(8E,12E,14E)-7-acetoxy-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-p-
entamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (145 mg, 0.17
mmol) in methanol (2.5 mL) was added potassium carbonate (95 mg,
0.69 mmol) at room temperature, followed by stirring at the same
temperature for two hours and 30 minutes. The reaction mixture was
diluted with ethyl acetate and then washed with brine. The organic
layer was dried over anhydrous magnesium sulfate, filtrated and
evaporated. The resulting residue was purified by silica gel column
chromatography (Kanto silica gel 60N, 40 to 100 .mu.m; ethyl
acetate:hexane=40:60) to give the title compound (128 mg, 93%) as a
colorless oil.
[0767] ESI-MS m/z 821 (M+Na).sup.+.
Example 3-3
(8E,12E,14E)-3,6,16,21-Tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl--
7-(4-nitrophenoxy)carboxy-18,19-epoxytricosa-8,12,14-trien-11-olide
[0768] ##STR48##
[0769] To a solution of
(8E,12E,14E)-3,6,16,21-tetrakis(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-p-
entamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (139 mg, 0.17
mmol) in dichloromethane (2.5 mL) were added triethylamine (88 mg,
0.87 mmol), N,N-dimethylaminopyridine (64 mg, 0.52 mmol) and
4-nitrophenyl chloroformate (105 mg, 0.52 mmol) under ice cooling,
followed by stirring at room temperature under nitrogen atmosphere
for one hour. The reaction mixture was diluted with ethyl acetate,
and then washed with a saturated aqueous solution of sodium
bicarbonate and brine. The organic layer was dried over anhydrous
magnesium sulfate, filtrated and evaporated. The resulting residue
was purified by silica gel column chromatography (Kanto silica gel
60N, 40 to 100 .mu.m; ethyl acetate:hexane=20:80) to give the title
compound (134 mg, 80%) as a colorless oil.
[0770] ESI-MS m/z 986 (M+Na).sup.+.
Example 3-4
(8E,12E,14E)-3,6,16,21-Tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl--
7-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12-
,14-trien-11-olide
[0771] ##STR49##
[0772] To
(8E,12E,14E)-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-p-
entamethyl-7-(4-nitrophenoxy)carboxy-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (11.4 mg, 12 .mu.mol) was added a solution of
4-(pyrrolidin-1-yl)piperidine (2.4 mg, 16 .mu.mol) in
tetrahydrofuran (0.5 mL) at room temperature. To the mixture was
added triethylamine (2.3 mg, 24 .mu.mol) at room temperature,
followed by stirring at the same temperature for three hours. The
reaction mixture was evaporated to give the compound (11 mg) as a
crude product (a pale yellow oil).
Example 3-5
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(pyrro-
lidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-
-olide (Compound 3)
[0773] ##STR50##
[0774] To the crude product of
(8E,12E,14E)-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-
-7-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,1-
2,14-trien-11-olide (11 mg, 11 .mu.mol) was added a solution of
pyridinium p-toluenesulfonate (11.4 mg, 45 .mu.mol) in a mixture of
tetrahydrofuran:2-methyl-2-propanol=1:1 (1 mL) at room temperature.
To the mixture was added molecular sieves 4 .ANG. (10 mg), followed
by stirring at room temperature for 18.5 hours. Additional
pyridinium p-toluenesulfonate (11.4 mg, 45 .mu.mol) was added,
followed by stirring at room temperature for 72 hours. The reaction
mixture was evaporated, and the resulting residue was diluted with
ethyl acetate, and then washed with a saturated aqueous solution of
sodium bicarbonate and brine. The organic layer was dried over
anhydrous sodium sulfate, filtrated and evaporated. The resulting
residue was purified by thin layer chromatography (Fuji Silysia, NH
Silica gel Plate, methanol:dichloromethane=1:19) to give the title
compound (2.88 mg, 35%, two steps) as a colorless oil.
[0775] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.92(3H,t,J=7.2
Hz),1.21(3H,s),1.22-1.68
(8H,m),1.34(3H,s),1.77(3H,s),1.78-2.00(9H,m),2.48-2.62
(3H,m),2.67(1H,dd,J=2.4,8.0 Hz),2.68-2.92(9H,m),3.46-3.54
(1H,m),3.72-3.82(1H,m),4.24-4.40(1H,m),4.92(1H,d,J=10.8 Hz),
5.06(1H,d,J=10.8 Hz),5.57(1H,dd,J=9.6,14.8 Hz),5.72(1H,dd,
J=9.2,14.8 Hz),5.86(1H,d,J=14.8 Hz),6.13(1H,d,J=10.8 Hz),6.53
(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 691 (M+H).sup.+.
Example 4
(8E,12E,14E)-7-(N-Ethylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20--
pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound
4)
[0776] ##STR51##
[0777] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0778] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.10(3H,t,J=7.6 Hz), 1.20(3H,s),1.22-1.62(7H,m),1.34(3H,s),
1.65 (1H,dd,J=6.6,13.7 Hz), 1.77(3H,s),1.86(1H,dd,J=5.7,13.7 Hz),
2.50-2.53(2H,m),2.53-2.60(1H,m),2.67(1H,dd,J=2.4,7.6 Hz),
2.89(1H,dt,J=2.0,6.0 Hz),3.12(2H,q,J=7.2 Hz),3.49-3.54(1H,m),
3.74-3.81(1H,m),4.82-4.98(1H,covered with H.sub.2O), 5.06
(1H,d,J=10.8 Hz), 5.55(1H,dd,J=9.6,15.2 Hz),5.69 (1H,dd,J=9.2,15.2
Hz), 5.87(1H,d,J=15.2 Hz),6.13 (1H,d,J=11.2 Hz),
6.52(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 604 (M+Na).sup.+.
Example 5
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-(3-(mor-
pholin-4-yl)propyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 5)
[0779] ##STR52##
[0780] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0781] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.4 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.20(3H,s),1.26-1.73
(10H,m),1.34(3H,s),1.77(3H,s),1.86(1H,dd,J=5.4,14.1 Hz),
2.35-2.60(9H,m),2.67(1H,dd,J=2.4,7.6 Hz),2.89 (1H,dt,J=2.4,6.0
Hz),3.15(2H,t,J=7.2 Hz),3.48-3;54 (1H,m), 3.68(4H,t,J=4.8
Hz),3.74-3.82(1H,m),4.82-4.98 (1H,covered with
H.sub.2O),5.06(1H,d,J=10.8 Hz),5.55(1H,dd,J=10.0,15.2 Hz),
5.69(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13 (1H,d,J=10.4
Hz),6.52(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 681 (M+H).sup.+.
Example 6
(8E,12E,14E)-7-(N-(2-(N',N'-Dimethylamino)ethyl)-N-methylcarbamoyloxy)-3,6-
,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-t-
rien-11-olide (Compound 6)
[0782] ##STR53##
[0783] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0784] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.22(3H,s),1.24-1.68
(8H,m),1.34(3H,s),1.77(3H,s),1.86(1H,dd,J=5.2,14.0 Hz), 2.28
(6H,s),2.45-2.62(7H,m),2.67(1H,dd,J=2.4,8.0 Hz),2.86-2.99 (4H,m),
3.49-3.56(1H,m),3.75-3.82(1H,m),4.92(1H,d,J=10.0 Hz),
5.06(1H,d,J=10.8 Hz),5.57(1H,dd,J=10.0,15.6 Hz),5.72
(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=14.8 Hz),6.14 (1H,d,J=10.8 Hz),
6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 639 (M+H).sup.+.
Example 7
(8E,12E,14E)-(7-N-(3-(N',N'-Dimethylamino)propyl)-N-methylcarbamoyloxy)-3,-
6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14--
trien-11-olide (Compound 7)
[0785] ##STR54##
[0786] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0787] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.21(3H,s),1.24-1.75
(10H,m),1.34(3H,s),1.77(3H,s),1.86(1H,dd,J=5.9,13.7 Hz),
2.28(6H,s),2.37(2H,t,J=7.6 Hz),2.48-2.62(5H,m), 2.67
(1H,dd,J=2.4,7.6
Hz),2.86-2.99(4H,m),3.48-3.58(1H,m),3.74-3.82(1H,m),4.93(1H,d,J=10.4
Hz),5.06(1H,d,J=10.8 Hz),5.57 (1H,dd,J=9.6,15.2
Hz),5.73(1H,dd,J=9.6,15.2 Hz),5.87 (1H,d,J=15.6
Hz),6.13(1H,d,J=11.2 Hz),6.52 (1H,dd,J=11.2,15.2 Hz); ESI-MS m/z
653 (M+H).sup.+.
Example 8
(8E,12E,14E)-7-(N-(2-(N',N'-Dimethylamino)ethyl)carbamoyloxy)-3,6,16,21-te-
trahydroxy-6,10,12,16,20-pentamethyl18,19-epoxytricosa-8,12,14-trien-11-ol-
ide (Compound 8)
[0788] ##STR55##
[0789] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0790] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.21(3H,s),1.22-1.68
(8H,m),1.34(3H,s),1.77(3H,s),1.86(1H,dd,J=5.7,14.3 Hz),2.29
(6H,s),2.44-2.62(7H,m),2.67(1H,dd,J=2.4,8.0 Hz),2.89
(1H,dt,J=2.0,6.0 Hz),3.49-3.56(1H,m),3.74-3.82(1H,m),
4.82-4.98(1H,covered with H.sub.2O peak),5.06(1H,d,J=10.8 Hz),5.55
(1H,dd,J=10.4,15.2 Hz),5.69(1H,dd,J=9.6,15.2 Hz),5.87 (1H,d,J=15.2
Hz),6.13(1H,d,J=10.8 Hz),6.52 (1H,dd,J=11.2,15.2 Hz);ESI-MS m/z 625
(M+H).sup.+.
Example 9
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methyl-
homopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 9)
[0791] ##STR56##
[0792] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0793] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.887(3H,d,J=6.6 Hz), 0.894(3H,d,J=7.0 Hz), 0.93(3H,t,J=7.3 Hz),
1.23-1.27(4H,m), 1.33(3H,s),1.33-1.68(7H,m),1.77(3H,d,J=0.7
Hz),1.82-1.91
(3H,m),2.35(3H,s),2.50-2.66(7H,m),2.66(1H,dd,J=2.2,7.7 Hz),
2.89(1H,dt,J=2.2,5.5 Hz),3.49-3.56(3H,m),3.58-3.67(2H,m),
3.75-3.81(1H,m),4.94(1H,d,J=9.5 Hz),5.06(1H,d,J=10.6 Hz),
5.57(1H,dd,J=9.9,15.0 Hz),5.72(1H,dd,J=9.5,15.0 Hz),5.86
(1H,d,J=15.0 Hz),6.13(1H,d,J=9.9 Hz),6.52 (1H,dd,J=11.0,15.0
Hz);ESI-MS m/z 651 (M+H).sup.+.
Example 10
(8E,12E,14E)-7-(N-(3-(N',N'-Dimethylamino)propyl)carbamoyloxy)-3,6,16,21-t-
etrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11--
olide (Compound 10)
[0794] ##STR57##
[0795] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0796] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.6 Hz), 0.89(3H,d,J=7.0 Hz),0.93(3H,t,J=7.3
Hz),1.20(3H,s),1.20-1.26
(1H,m),1.33(3H,s),1.33-1.71(9H,m),1.77(3H,s),1.86 (1H,dd,J=5.5,14.3
Hz),2.25(6H,s),2.36(2H,t,J=7.3
Hz),2.49-2.61(3H,m),2.66(1H,dd,J=2.2,8.1 Hz),2.89(1H,dt,J=2.2,5.5
Hz), 3.13(2H,t,J=6.6 Hz),3.52(1H,dt,J=4.4,8.1 Hz),3.75-3.81(1H,m),
4.89(1H,d,J=9.5 Hz),5.05(1H,d,J=10.6 Hz),5.55(1H,dd,J=9.5, 15.4
Hz),5.69(1H,dd,J=9.5,15.4 Hz),5.86(1H,d,J=15.4 Hz),
6.13(1H,d,J=10.6 Hz),6.52(1H,dd,J=10.6,15.4 Hz); ESI-MS m/z 639
(M+H).sup.+.
Example 11
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-((pyrid-
in-4-yl)methyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 11)
[0797] ##STR58##
[0798] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0799] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=5.1 Hz), 0.89(3H,d,J=7.0 Hz),0.94(3H,t,J=7.3
Hz),1.23(3H,s),1.23-1.27
(1H,m),1.33(3H,s),1.33-1.62(6H,m),1.65(1H,dd,J=6.2,14.3 Hz),
1.77(3H,s),1.86(1H,dd,J=6.2,14.3 Hz),2.48-2.65(3H,m),2.66
(1H,dd,J=2.2,8.1 Hz),2.89(1H,dt,J=2.2,6.2 Hz),3.52 (1H,dt,J=4.4,8.1
Hz),3.74-3.80(1H,m),4.35(2H,s),4.93 (1H,d,J=9.5
Hz),5.06(1H,d,J=10.6 Hz),5.56(1H,dd,J=9.5,15.4 Hz),
5.73(1H,dd,J=9.5,15.4 Hz),5.86(1H,d,J=15.0 Hz),6.13 (1H,d,J=11.0
Hz),6.52(1H,d,J=11.0,15.0 Hz),7.33(2H,d,J=5.9 Hz),
8.45(2H,dd,J=1.5,4.4 Hz); ESI-MS m/z 645 (M+H).sup.+.
Example 12
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methyl-
piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 12)
[0800] ##STR59## First Step
(8E,12E,14E)-6-(1-Ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-((4-methylpipe-
razin-1-yl)carbonyl)oxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,-
12,14-trien-11-olide (Compound 12-1)
[0801] ##STR60##
[0802] A solution of Compound 46-4
(8E,12E,14E)-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitropheno-
xy)carboxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-1-
1-olide (628 mg, 0.575 mmol) obtained in the fourth step of Example
46 in tetrahydrofuran (7 mL) was cooled to 5.degree. C., and a
solution of 1-methylpiperazine (118 mg, 1.152 mmol) in
tetrahydrofuran (1.5 mL) and a solution of triethylamine (236 mg,
2.305 mmol) in tetrahydrofuran (1.5 mL) were added dropwise
thereto. The reaction mixture was stirred at room temperature for
1.5 hours. The reaction mixture was diluted with ethyl acetate, and
washed with an aqueous solution of sodium bicarbonate and brine.
The organic layer was dried over anhydrous magnesium sulfate,
filtrated and evaporated. The resulting residue was purified by
silica gel column chromatography (Kanto silica gel 60N, 40 to 50
.mu.m; ethyl acetate-hexane-methanol, 1:1:0 to 4:1:0 to 9:1:0 to
1:0:0 to 39:0:1 to 19:0:1) to give the title compound (514 mg, 85%)
as a colorless oil.
Second Step
(8E,12E,14E)-6-(1-Ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentameth-
yl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trie-
n-11-olide (Compound 12-2)
[0803] ##STR61##
[0804] A solution of Compound 12-1
(8E,12E,14E)-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-((4-methylpip-
erazin-1-yl)carbonyl)oxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8-
,12,14-trien-11-olide (514 mg, 0.489 mmol) obtained in the first
step in tetrahydrofuran (10 mL) was cooled to 5.degree. C., and
tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 1.62
mL, 1.62 mmol) was added dropwise thereto. The reaction mixture was
stirred at room temperature for two hours. Additional
tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.3
mL, 0.3 mmol) was added dropwise, and the reaction mixture was
stirred at room temperature for one hour. The reaction mixture was
diluted with ethyl acetate and washed with an aqueous solution of
sodium bicarbonate. The organic layer was dried over anhydrous
magnesium sulfate, filtrated and evaporated. The resulting residue
was purified by silica gel column chromatography (Fuji Silysia, NH
Silica gel, 200 to 350 mesh; ethyl acetate-hexane-methanol, 1:1:0
to 4:1:0 to 1:0:0 to 49:0:1 to 19:0:1) to give the title compound
(364 mg, 99%) as a colorless oil.
[0805] ESI-MS m/z 709 (M+H).sup.+
Third Step
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methyl-
piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 12)
[0806] ##STR62##
[0807] To a solution of Compound 12-2
(8E,12E,14E)-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamet-
hyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-tri-
en-11-olide (364 mg, 0.489 mmol) obtained in the second step in a
mixture of tetrahydrofuran:2-methyl-2-propanol=1:1 (10 mL) was
added pyridinium p-toluenesulfonate (184 mg, 0.734 mmol), and the
reaction mixture was stirred at room temperature for 19 hours.
After triethylamine (75 mg, 0.734 mmol) was added dropwise to the
reaction mixture, the mixture was evaporated. The resulting residue
was dissolved in ethyl acetate and washed with a saturated aqueous
solution of sodium bicarbonate. The organic layer was dried over
anhydrous magnesium sulfate, filtrated and evaporated. The
resulting residue was purified by silica gel column chromatography
(Fuji Silysia, NH Silica gel, 200 to 350 mesh; ethyl
acetate-hexane-methanol, 1:1:0 to 2:1:0 to 4:1:0 to 1:0:0 to 39:0:1
to 29:0:1 to 19:0:1). The crude purified fraction was evaporated,
and the residue was purified by thin layer chromatography (Fuji
Silysia, NH Silica gel Plate; methanol-dichloromethane, 1:29) to
give the title compound (286 mg, 92%) as a colorless oil.
[0808] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.28(4H,m),1.32-1.68 (10H,m),1.77(3H,d,J=0.8
Hz),1.86(1H,dd,J=5.6,14.4 Hz),
2.30(3H,s),2.36-2.44(4H,m),2.50-2.64(3H,m),2.66(1H,dd,J=2.4,8.0
Hz),2.89(1H,dt,J=2.4,6.0
Hz),3.38-3.70(5H,m),3.75-3.81(1H,m),4.93(1H,d,J=10.0
Hz),5.06(1H,d,J=10.8 Hz),5.57(1H, dd,J=10.0,15.2
Hz),5.71(1H,dd,J=9.6,15.2 Hz),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 637
(M+H).sup.+.
Example 13
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((piperazi-
n-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 13)
[0809] ##STR63##
[0810] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0811] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=7.2 Hz), 0.94(3H,t,J=7.6 Hz),
1.20-1.30(4H,m), 1.32-1.68 (10H,m),1.77(3H,d,J=0.8
Hz),1.86(1H,dd,J=5.6, 14.4 Hz),2.50-2.64(3H,m),2.67
(1H,dd,J=2.4,8.0 Hz),2.76 (4H,t,J=5.2 Hz),2.89(1H,dt,J=2.4,5.6
Hz),3.34-3.68(5H,m), 3.75-3.81(1H,m),4.94(1H,d,J=9.6
Hz),5.06(1H,d,J=10.8 Hz), 5.57(1H,dd,J=9.6,15.2
Hz),5.72(1H,dd,J=9.6,15.2 Hz), 5.87(1H,d,J=15.2
Hz),6.13(1H,d,J=11.2 Hz),6.53 (1H,dd,J=11.2,15.2 Hz);ESI-MS m/z 623
(M+H).sup.+.
Example 14
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(pyrid-
in-4-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-ol-
ide (Compound 14)
[0812] ##STR64##
[0813] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0814] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.20-1.30(4H,m), 1.32-1.69 (10H,m),1.77(3H,d,J=0.8
Hz),1.86(1H,dd,J=5.6, 14.4 Hz),2.50-2.64(3H,m),2.66(1H,dd,J=2.4,8.0
Hz),2.89(1H,dt, J=2.4,6.0
Hz),3.38-3.46(4H,m),3.49-3.84(6H,m),4.97(1H,d, J=10.0
Hz),5.06(1H,d,J=10.8 Hz),5.59(1H,dd,J=10.0,15.2 Hz),
5.74(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d, J=10.8
Hz),6.53(1H,dd,J=11.2,15.2 Hz),6.86(2H,d,J=6.8 Hz), 8.13(2H,d,J=6.8
Hz);ESI-MS m/z 700 (M+H).sup.+.
Example 15
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl--
N-(1-methylpiperidin-4-yl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-1-
1-olide (Compound 15)
[0815] ##STR65##
[0816] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0817] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.30(4H,m),1.32-1.69
(12H,m),1.72-1.90(6H,m),2.06-2.22(2H,m),2.28(3H,s),
2.50-2.64(3H,m),2.66(1H,dd,J=2.4,8.0 Hz),2.76-2.98(6H,m),
3.52(1H,dt,J=4.4,8.4 Hz),3.75-3.82(1H,m),3.85-4.14(1H,m),
4.95(1H,d,J=10.0 Hz),5.06(1H,d,J=10.8 Hz),5.57(1H,dd,J=10.0, 15.2
Hz),5.73(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13
(1H,d,J=10.8 Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 665
(M+H).sup.+.
Example 16
(8E,12E,14E)-7-((4-Butylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-
-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 16)
[0818] ##STR66##
[0819] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0820] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),0.94(3H,t,J=7.6 Hz), 1.19-1.69(18H,m),1.77(3H,d,J=1.2
Hz),1.86(1H,dd,J=5.6,14.0 Hz),2.34-2.64(9H,m),2.67(1H,dd,J=2.4,8.0
Hz),2.89(1H,dt, J=2.4,6.4
Hz),3.38-3.72(5H,m),3.75-3.82(1H,m),4.93(1H,d, J=9.6
Hz),5.06(1H,d,J=10.8 Hz),5.57(1H,dd,J=9.6,15.2 Hz),5.71
(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d, J=10.8
Hz),6.53(1H,dd,J=11.2,15.2 Hz);ESI-MS m/z 679 (M+H).sup.+.
Example 17
(8E,12E,14E)-7-((4-Benzylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahy-
droxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 17)
[0821] ##STR67##
[0822] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0823] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.85-0.92(6H,m), 0.94(3H,t,J=7.6 Hz),1.19-1.30(4H,m),1.32-1.69
(10H,m),1.78
(3H,s),1.79-1.90(3H,m),2.50-2.72(8H,m),2.89(1H,dt,J=2.4, 6.0
Hz),3.42-3.68(7H,m),3.75-3.82(1H,m),4.91-4.97(1H,m),5.06
(1H,d,J=10.8 Hz),5.53-5.62(1H,m),5.67-5.77(1H,m),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=11.2,15.2 Hz),
7.21-7.35(5H,m); ESI-MS m/z 727 (M+H).sup.+.
Example 18
(8E,12E,14E)-7-((4-(3-Chloropropyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,-
21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-
-11-olide (Compound 18)
[0824] ##STR68##
[0825] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0826] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.30(4H,m),1.32-1.69 (10H,m),1.77(3H,d,J=0.8
Hz),1.80-1.96(5H,m),2.49-2.74 (10H,m),2.89(1H,dt,J=2.4,6.4
Hz),3.41-3.69(7H,m),3.75-3.81
(1H,m),4.92-4.97(1H,m),5.07(1H,d,J=10.4 Hz),5.57(1H,dd, J=9.6,15.2
Hz),5.73(1H,dd,J=10.0,15.2 Hz),5.87(1H,d,J=15.2 Hz),
6.13(1H,d,J=11.2 Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z
713(M).sup.+.
Example 19
(8E,12E,14E)-7-((4-(N,N-Dimethylamino)piperidin-1-yl)carbonyl)oxy-3,6,16,2-
1-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien--
11-olide (Compound 19)
[0827] ##STR69##
[0828] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0829] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.68 (16H,m),1.77 (3H,d,J=0.8
Hz),1.83-1.93(3H,m),2.28(6H,s),2.38(1H,tt, J=3.6, 11.6
Hz),2.49-2.62(3H,m),2.67(1H,dd,J=2.4,8.0 Hz),2.71-2.88
(2H,m),2.89(1H,dt,J=2.4,6.0 Hz),3.52(1H,dt,J=4.4,8.4 Hz),
3.75-3.82(1H,m),4.08-4.45(2H,m),4.92(1H,d,J=10.0 Hz),5.06
(1H,d,J=10.8 Hz),5.57(1H,dd,J=10.0,15.2 Hz),5.72(1H,dd,J=9.6, 15.2
Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,
J=11.2,15.2 Hz); ESI-MS m/z 665 (M+H).sup.+.
Example 20
(8E,12E,14E)-7-((1,4-Diazabicyclo[4,3,0]nonane-4-yl)carbonyl)oxy-3,6,16,21-
-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-1-
1-olide (Compound 20)
[0830] ##STR70##
[0831] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0832] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.30(4H,m),1.32-1.69
(10H,m),1.73-2.02(6H,m),2.09-2.22(2H,m),2.49-2.71(6H,m),
2.87-3.12(6H,m),3.52(1H,dt,J=4.4,8.0 Hz),3.75-3.82(1H,m),
4.01-4.51(2H,m),4.88-4.99(1H,m),5.06(1H,d,J=10.8 Hz),5.57
(1H,dd,J=9.6,14.8 Hz),5.72(1H,dd,J=9.6,15.2 Hz),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 663
(M+H).sup.+.
Example 21
(8E,12E,14E)-7-((4-Ethylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-
-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 21)
[0833] ##STR71##
[0834] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0835] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.11(3H,t,J=7.6 Hz),
1.21(3H,s),1.22-1.64(7H,m),1.34(3H,s),1.65(1H,dd,J=6.2, 14.2 Hz),
1.77(3H,s),1.86(1H,dd,J=5.2,14.0 Hz),2.39-2.49
(6H,m),2.50-2.53(2H,m),2.53-2.62(1H,m),2.66(1H,dd,J=2.4, 7.6
Hz),2.89(1H,dt,J=2.0,6.0 Hz),3.34-3.72(5H,m),3.74-3.82
(1H,m),4.93(1H,d,J=9.6 Hz),5.05(1H,d,J=10.4 Hz),5.56(1H,dd,
J=10.0,15.2 Hz),5.71(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),
6.13(1H,d,J=10.8 Hz),6.52(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 651
(M+H).sup.+.
Example 22
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(piper-
idin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11--
olide (Compound 22)
[0836] ##STR72##
[0837] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0838] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.4 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.21(3H,s),1.20-1.69
(16H,m),1.34(3H,s),1.77(3H,s),1.83-1.93(3H,m),2.45-2.65
(8H,m),2.66(1H,dd,J=2.4,7.6 Hz),2,70-2.85(2H,m),2.89(1H,dt,
J=2.4,6.0 Hz),3.51(1H,td,J=4.4,8.0
Hz),3.74-3.82(1H,m),4.12-4.25(1H,m),4.30-4.45(1H,m),4.92(1H,d,J=9.6
Hz),5.06(1H,d, J=10.4 Hz),5.56(1H,dd,J=10.0,15.2
Hz),5.71(1H,dd,J=10.0, 15.6 Hz),5.87(1H,d,J=15.2
Hz),6.13(1H,d,J=11.2 Hz),6.52(1H,dd, J=11.2,15.2 Hz);ESI-MS m/z 705
(M+H).sup.+.
Example 23
(8E,12E,14E)-7-((Homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,-
10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 23)
[0839] ##STR73##
[0840] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0841] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.4
Hz),1.23(3H,s),1.24-1.69
(8H,m),1.34(3H,s),1.77(3H,s),1.78-1.90(3H,m),2.48-2.62
(3H,m),2.66(1H,dd,J=2.4,8.0 Hz),2.72-2.93(5H,m),3.43-3.67
(5H,m),3.74-3.82(1H,m),4.94(1H,d,J=9.6 Hz),5.06(1H,d, J=10.4
Hz),5.57(1H,dd,J=10.4,15.2 Hz),5.72(1H,dd,J=9.8, 15.4
Hz),5.86(1H,d,J=15.2 Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,
J=11.0,15.4 Hz); EI-MS m/z 637 (M+H).sup.+.
Example 24
(8E,12E,14E)-7-((4-Benzylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydrox-
y-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 24)
[0842] ##STR74##
[0843] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0844] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.89(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.20(3H,s),1.22-1.65 (7H,m),1.34(3H,s),1.65(1H,dd,J=6.2,14.2
Hz),1.77(3H,s),1.87 (1H,dd,J=5.4,14.2
Hz),2.39-2.49(4H,m),2.50-2.64(3H,m),2.67 (1H,dd,J=2.4,8.0
Hz),2.89(1H,dt,J=2.0,5.6 Hz),3.36-3.72(7H,m),
3.74-3.83(1H,m),4.92(1H,d,J=9.6 Hz),5.06(1H,d,J=10.8 Hz),5.56
(1H,dd,J=10.0,15.2 Hz),5.71(1H,dd,J=9.6,15.2 Hz),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=11.2 Hz),6.53(1H,dd,J=11.2,15.2 Hz),
7.22-7.37(5H,m); ESI-MS m/z 713 (M+H).sup.+.
Example 25
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propyl-
piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 25)
[0845] ##STR75##
[0846] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0847] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.86-0.97 (12H,m), 1.21(3H,s),1.21-1.68
(10H,m),1.34(3H,s),1.77(3H,s), 1.87 (1H,dd,J=5.2,14.0
Hz),2.30-2.36(2H,m),2.38-2.47(4H,m),2.49-2.63(3H,m),2.66(1H,dd,J=2.4,7.6
Hz),2.89(1H,dt,J=2.0,6.0 Hz),
3.35-3.72(5H,m),3.74-3.83(1H,m),4.93(1H,d,J=9.6 Hz),5.06
(1H,d,J=10.8 Hz),5.57(1H,dd,J=10.0,15.2 Hz),5.71(1H,dd,J=1.0, 15.2
Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=10.0 Hz),6.52(1H,dd,
J=10.8,15.2 Hz); ESI-MS m/z 665 (M+H).sup.+.
Example 26
(8E,12E,14E)-7-((4-Cyclohexylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahy-
droxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 26).
[0848] ##STR76##
[0849] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0850] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.10-1.69 (15H,m),1.21
(3H,s),1.34(3H,s),1.78(3H,s),1.78-1.93(4H,m),2.26-2.35
(1H,m),2.47-2.64(7H,m),2.67(1H,dd,J=2.0,8.0 Hz),2.89
(1H,dt,J=2.0,6.0 Hz),3.36-3.70(5H,m),3.75-3.82(1H,m),4.93
(1H,d,J=9.6 Hz),5.06(1H,d,J=10.8 Hz),5.57(1H,dd,J=10.0, 15.2
Hz),5.71(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13
(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 705
(M+H).sup.+.
Example 27
(8E,12E,14E)-7-((4-(Cyclopropylmethyl)piperazin-1-yl)carbonyl)oxy-3,6,16,2-
1-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien--
11-olide (Compound 27)
[0851] ##STR77##
[0852] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0853] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.12-0.17(2H,m), 0.52-0.58(2H,m),0.89(3H,d,J=6.8
Hz),0.90(3H,d,J=6.8
Hz),0.90-0.97(4H,m),1.21(3H,s),1.21-1.69(8H,m),1.34(3H,s),1.78(3H,s),
1.86(1H,dd,J=5.2,14.0 Hz),2.29(2H,d,J=6.8 Hz),2.47-2.64(7H,m),
2.67(1H,dd,J=2.0,8.0 Hz),2.89(1H,dt,J=2.0,6.0 Hz),3.40-3.72
(5H,m),3.74-3.82(1H,m),4.93(1H,d,J=9.6 Hz), 5.06(1H,d, J=10.8
Hz),5.57(1H,dd,J=10.0,15.2 Hz),5.71(1H,dd,J=9.6, 15.2
Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,
J=10.8,15.2 Hz); ESI-MS m/z 677 (M+H).sup.+.
Example 28
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(morph-
olin-4-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11--
olide (Compound 28)
[0854] ##STR78##
[0855] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0856] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.30(4H,m),1.31-1.68 (12H,m),1.77(3H,d,J=1.2
Hz),1.83-1.95(3H,m),2.34-2.43
(1H,m),2.50-2.64(7H,m),2.67(1H,dd,J=2.4,8.0 Hz),2.73-2.89
(2H,m),2.89(1H,dt,J=2.4,6.0 Hz),3.52(1H,td,J=4.4,8.0 Hz),
3.66-3.72(4H,m),3.75-3.81(1H,m),4.07-4.44(2H,m),4.92(1H,d, J=9.6
Hz),5.06(1H,d,J=10.4 Hz),5.57(1H,dd,J=10.0,15.2 Hz),5.72
(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d, J=11.2
Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 707 (M+H).sup.+.
Example 29
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(3,3,3-
-trifluoropropyl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-tr-
ien-11-olide (Compound 29)
[0857] ##STR79##
[0858] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0859] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.30(4H,m),1.31-1.69 (10H,m),1.77(3H,d,J=1.2
Hz),1.86(1H,dd,J=5.6,14.0 Hz), 2.35-2.66
(11H,m),2.67(1H,dd,J=2.4,8.0 Hz),2.89(1H,dt, J=2.0,6.0
Hz),3.38-3.71(5H,m),3.75-3.82(1H,m),4.93(1H,d, J=10.0
Hz),5.06(1H,d,J=10.8 Hz),5.57(1H,dd,J=10.0,15.2 Hz),
5.71(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d, J=11.2
Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 719 (M+H).sup.+, 741
(M+Na).sup.+.
Example 30
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(4,4,4-
-trifluorobutyl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-tri-
en-11-olide (Compound 30)
[0860] ##STR80##
[0861] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0862] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.30(4H,m),1.32-1.69
(10H,m),1.70-1.81(5H,m),1.86(1H,dd,J=5.6,14.0
Hz),2.14-2.28(2H,m),2.38-2.49(6H,m),2.50-2.64(3H,m),2.67(1H,dd,
J=2.4,8.0 Hz),2.89(1H,dt,J=2.4,6.0
Hz),3.39-3.72(5H,m),3.75-3.82(1H,m),4.93(1H,d,J=10.0
Hz),5.06(1H,d,J=10.4 Hz),5.57(1H, dd,J=10.0,15.2
Hz),5.72(1H,dd,J=10.0,15.2 Hz),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=11.2 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 733
(M+H).sup.+, 755 (M+Na).sup.+.
Example 31
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propyl-
homopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 31)
[0863] ##STR81##
[0864] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0865] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.87-0.92(9H,m),0.94 (3H,t,J=7.6 Hz),1.20-1.30(4H,m),1.32-1.69
(12H,m),1.77(3H,d, J=0.8
Hz),1.82-1.91(3H,m),2.41-2.49(2H,m),2.50-2.77(8H,m),
2.89(1H,dt,J=2.4,6.0 Hz),3.42-3.67(5H,m),3.75-3.82(1H,m),
4.94(1H,d,J=9.6 Hz),5.07(1H,d,J=10.8 Hz),5.57(1H,dd,J=10.0, 15.2
Hz),5.73(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13
(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 679
(M+H).sup.+.
Example 32
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-(2-methoxyethyl)piperazin-1-yl)c-
arbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11--
olide (Compound 32)
[0866] ##STR82##
[0867] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0868] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.30(4H,m),1.31-1.69 (10H,m),1.77(3H,d,J=1.2
Hz),1.86(1H,dd,J=5.6,14.0 Hz), 2.44-2.64(9H,m),2.67(1H,dd,J=2.4,8.0
Hz),2.89(1H,dt,J=2.4, 6.0
Hz),3.33(3H,s),3.39-3.71(7H,m),3.75-3.82(1H,m),4.93(1H,d, J=9.6
Hz),5.06(1H,d,J=10.8 Hz),5.57(1H,dd,J=10.0,15.2 Hz),5.71
(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d, J=10.8
Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 681 (M+H).sup.+.
Example 33
(8E,12E,14E)-7-((4-Cyclobutylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahy-
droxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 33)
[0869] ##STR83##
[0870] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0871] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.30(4H,m),1.32-1.69
(10H,m),1.70-1.81(5H,m),1.83-1.95(3H,m),2.02-2.11(2H,m),
2.27-2.37(4H,m),2.49-2.64(3H,m),2.67(1H,dd,J=2.4,8.0 Hz),
2.72-2.81(1H,m),2.89(1H,dt,J=2.4,6.0 Hz),3.37-3.71(5H,m),
3.75-3.82(1H,m),4.93(1H,d,J=9.6 Hz),5.06(1H,d,J=10.8 Hz),
5.57(1H,dd,J=9.6,15.2 Hz),5.71(1H,dd,J=9.6,15.2 Hz),5.87
(1H,d,J=15.2 Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=11.2, 15.2 Hz);
ESI-MS m/z 677 (M+H).sup.+.
Example 34
(8E,12E,14E)-7-((4-(1-Ethylpropyl)piperazin-1-yl)carbonyl)oxy-3,6,16,21-te-
trahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (Compound 34)
[0872] ##STR84##
[0873] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0874] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.87-0.97 (15H,m), 1.19-1.69 (18H,m),1.77(3H,d,J=0.8
Hz),1.86(1H,dd,J=5.2, 14.0
Hz),2.15-2.23(1H,m),2.45-2.64(7H,m),2.67(1H,dd,J=2.4, 8.0
Hz),2.89(1H,dt,J=2.4,6.0 Hz),3.34-3.65(5H,m),3.75-3.82
(1H,m),4.93(1H,d,J=10.0 Hz),5.06(1H,d,J=10.8 Hz),5.57(1H,dd,
J=9.6,15.2 Hz),5.72(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),
6.13(1H,d,J=11.2 Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 693
(M+H).sup.+.
Example 35
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(tetra-
hydropyran-4-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-tri-
en-11-olide (Compound 35)
[0875] ##STR85##
[0876] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0877] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.21(3H,s),1.21-1.69
(10H,m),1.34(3H,s),1.77(3H,s),1.77-1.90(3H,m),2.42-2.62
(8H,m),2.66(1H,dd,J=2.0,7.6 Hz),2.89(1H,dt,J=2.0,6.0 Hz),
3.34-3.71(7H,m),3.74-3.82(1H,m),3.94-4.02(2H,m),4.93(1H,d, J=9.6
Hz),5.05(1H,d,J=10.4 Hz),5.57(1H,dd,J=10.0,15.2 Hz),5.71
(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d, J=10.4
Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 707 (M+H).sup.+.
Example 36
(8E,12E,14E)-7-((4-(Cyclopropylmethyl)homopiperazin-1-yl)carbonyl)oxy-3,6,-
16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-tr-
ien-11-olide (Compound 36)
[0878] ##STR86##
[0879] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0880] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.08-0.14(2H,m), 0.48-0.54(2H,m),0.83(3H,d,J=6.8
Hz),0.88(3H,d,J=7.2
Hz),0.89-0.94(4H,m),1.20-1.67(8H,m),1.21(3H,s),1.31(3H,s),1.75(3H,s),
1.80-1.90(3H,m),2.37(2H,d,J=6.4),2.47-2.61(3H,m),2.62-2.82
(5H,m),2.87(1H,dt,J=2.4,6.0 Hz),3.43-3.69(5H,m),3.73-3.80
(1H,m),4.92(1H,d,J=9.6 Hz),5.04(1H,d,J=10.8 Hz),5.55(1H,dd,
J=10.0,15.2 Hz),5.70(1H,dd,J=9.6,15.2 Hz),5.84(1H,d,J=15.2 Hz),
6.11(1H,d,J=11.2 Hz),6.50(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 691
(M+H).sup.+.
Example 37
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(2,2,2-
-trifluoroethyl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-tri-
en-11-olide (Compound 37)
[0881] ##STR87##
[0882] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0883] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.21(3H,s),1.20-1.69
(8H,m),1.34(3H,s),1.77(3H,s),1.86(1H,dd,J=5.2,14.4
Hz),2.50-2.69(8H,m),2.86-2.92(1H,m),3.38-3.72(2H,m),3.04-3.14(5H,m),
3.74-3.82(1H,m),4.93(1H,d,J=10.0 Hz),5.05(1H,d,J=10.8 Hz),
5.57(1H,dd,J=10.0,15.2 Hz),5.71(1H,dd,J=10.0,15.2 Hz),5.87
(1H,d,J=15.6 Hz),6.13(1H,d,J=11.2 Hz),6.52(1H,dd,J=11.2, 15.2 Hz);
ESI-MS m/z 727 (M+Na).sup.+.
Example 38
(8E,12E,14E)-7-((4-Cyclopentylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrah-
ydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 38)
[0884] ##STR88##
[0885] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0886] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.21(3H,s),1.21-1.76
(14H,m),1.34(3H,s),1.77(3H,s),1.83-1.95(3H,m),2.46-2.62
(8H,m),2.66(1H,dd,J=2.4,7.6 Hz),2.88(1H,dt,J=2.4,6.4 Hz),
3.34-3.72(5H,m),3.74-3.82(1H,m),4.93(1H,d,J=10.0 Hz),5.05
(1H,d,J=10.4 Hz),5.57(1H,dd,J=10.0,15.2 Hz),5.71(1H,dd, J=10.0,15.2
Hz),5.87(1H,d,J=15.6 Hz),6.13(1H,d,J=11.2 Hz),6.52
(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 691 (M+H).sup.+.
Example 39
(8E,12E,14E)-7-((4-Isobutylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydr-
oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 39)
[0887] ##STR89##
[0888] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0889] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.87-0.97 (15H,m),
1.21(3H,s),1.21-1.69(8H,m),1.34(3H,s),1.77(3H,s),1.78-1.90
(2H,m),2.11(2H,d,J=7.2 Hz),2.32-2.41(4H,m),2.50-2.63(3H,m),
2.67(1H,dd,J=2.4,8.0 Hz),2.89(1H,dt,J=2.0,6.0 Hz),3.38-3.70
(5H,m),3.74-3.82(1H,m),4.93(1H,d,J=9.6 Hz),5.05(1H,d, J=10.4
Hz),5.57(1H,dd,J=9.6,15.2 Hz),5.71(1H,dd,J=10.0, 15.2
Hz),5.87(1H,d,J=15.6 Hz),6.13(1H,d,J=11.2 Hz),6.52(1H,dd,
J=11.2,15.2 Hz); ESI-MS m/z 679 (M+H).sup.+.
Example 40
(8E,12E,14E)-7-(((1S,4S)-5-Benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbo-
nyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricos-
a-8,12,14-trien-11-olide (Compound 40)
[0890] ##STR90##
[0891] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0892] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.84(3H,d,J=7.0 Hz), 0.85(3H,d,J=7.0 Hz),0.89(3H,t,J=7.3
Hz),1.14-1.27(4H,m),1.27-1.65(7H,m),1.30(3H,s),1.65-1.92(6H,m),2.44-2.66(-
5H,m),2.79-2.88(2H,m),3.16(0.6H, dd,J=1.8,10.3
Hz),3.25-3.31(0.4H,m), 3.45-3.78(6H,m),4.29(0.4H, brs),4.52(0.6H,
brs),4.89(1H,d, J=9.9 Hz),5.02(1H,d,J=10.6
Hz),5.54(1H,dd,J=9.9,15.0 Hz),5.68 (0.6H, dd,J=9.9,15.0
Hz),5.73(0.4H, dd,J=9.9,15.0 Hz),5.82(1H,d, J=15.4
Hz),6.09(1H,d,J=11.0 Hz),6.48(1H,d,J=11.0,15.4 Hz),
7.16-7.32(5H,m); ESI-MS m/z 725 (M+H).sup.+.
Example 41
(8E,12E,14E)-7-(N-(2-(N',N'-Dimethylamino)ethyl)-N-ethylcarbamoyloxy)-3,6,-
16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-tr-
ien-11-olide (Compound 41)
[0893] ##STR91##
[0894] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3. .sup.1H-NMR Spectrum
(CD.sub.3OD,400 MHz) .delta.(ppm): 0.88(3H,d,J=7.0 Hz),
0.89(3H,d,J=7.0 Hz),0.93(3H,t,J=7.3
Hz),1.08-1.14(3H,m),1.20-1.29(1H,m),1.22(3H,s),1.31-1.68(7H,m),1.33(3H,s)-
,1.77(3H,d, J=0.7 Hz),1.86(1H,dd,J=5.5,14.3
Hz),2.28(6H,s),2.43-2.62 (5H,m),2.66(1H,dd,J=2.2,8.1
Hz),2.89(1H,dt,J=2.2,5.5 Hz), 3.23-3.52(4H,m),3.52(1H,dt,J=4.4,8.4
Hz),3.74-3.82(1H,m),4.92(1H,d,J=9.9 Hz),5.06(1H,d,J=10.6 Hz),5.56
(1H,dd,J=9.9,15.0 Hz),5.73(1H,dd,J=9.9,15.0 Hz),5.86(1H,d, J=15.0
Hz),6.13(1H,dd,J=1.1,11.0 Hz),6.52(1H,dd,J=11.0, 15.0 Hz); ESI-MS
m/z 653 (M+H).sup.+.
Example 42
(8E,12E,14E)-7-(N-(2-(N',N'-Diethylamino)ethyl)-N-ethylcarbamoyloxy)-3,6,1-
6,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-tri-
en-11-olide (Compound 42)
[0895] ##STR92##
[0896] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0897] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.6 Hz), 0.89(3H,d,J=7.0 Hz),0.93(3H,t,J=7.3
Hz),1.06(6H,t,J=7.0 Hz),
1.06-1.15(3H,m),1.20-1.29(1H,m),1.22(3H,s),1.31-1.68(7H,m),
1.33(3H,s),1.77(3H,d,J=1.1 Hz),1.86(1H,dd,J=5.5,14.3 Hz),
2.48-2.66(5H,m),2.59(4H,q,J=7.0 Hz),2.66(1H,dd,J=2.2,8.1 Hz),
2.89(1H,dt,J=2.2,5.5 Hz),3.21-3.60(4H,m),3.52(1H,dt,J=4.4, 8.4
Hz),3.74-3.81(1H,m),4.93(1H,d,J=9.9 Hz),5.06(1H,d,J=10.6
Hz),5.57(1H,dd,J=9.9,15.0 Hz),5.73(1H,dd,J=9.9,15.0 Hz),
5.86(1H,d,J=15.4 Hz),6.13(1H,d,J=11.0 Hz),6.52(1H,dd,J=11.0, 15.4
Hz); ESI-MS m/z 681 (M+H).sup.+.
Example 43
(8E,12E,14E)-7-Acetoxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamet-
hyl-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound 43)
[0898] ##STR93##
[0899]
(8E,12E,14E)-7-Acetoxy-3,16,21-tris(1-ethoxyethoxy)-6-hydroxy-6,10-
,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (34
mg, 44 .mu.mol) obtained in Example 3 and
1,8-bis(N,N-dimethylamino)naphthalene (57 mg, 266 .mu.mol) were
dissolved in toluene (2 mL). Methyl trifluoromethanesulfonate (22
mg, 133 mmol) was added to this solution, and the reaction mixture
was stirred at 65.degree. C. for 11 hours. After removing the
precipitate by filtration, the reaction mixture was diluted with
ethyl acetate, and an aqueous solution of ammonium chloride was
added, followed by vigorous stirring for 5 minutes. The organic
layer was washed with a saturated aqueous solution of sodium
bicarbonate and brine, dried over anhydrous magnesium sulfate, and
concentrated. The resulting residue was purified by silica gel
column chromatography (Kanto silica gel 60N spherical, neutral, 40
to 100 .mu.m; hexane:ethyl acetate=1:1) to give
(8E,12E,14E)-7-acetoxy-3,16,21-tris(1-ethoxyethoxy)-6-methoxy-6,10,1-
2,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (14
mg) as a colorless oil.
[0900] The obtained compound was subjected to deprotection of
ethoxyethyl group by a similar method as described for Example 3,
to give the title compound (5.7 mg, 22.9%, two steps) as a
colorless oil.
[0901] .sup.1H-NMR Spectrum (CD.sub.3OD,500 MHz) .delta.(ppm):
0.88(3H,d,J=6.5 Hz), 0.91(3H,d,J=7.5 Hz),0.94(3H,t,J=7.5
Hz),1.21(3H,s),1.22-1.32
(1H,m),1.34(3H,s),1.40-1.70(7H,m),1.78(3H,s),1.86(1H,dd, J=5.5,14.0
Hz),2.06(3H,s),2.46-2.63(3H,m),2.67(1H,d,J=8.5 Hz),
2.99(1H,brs),3.33(3H,s),3.50-3.56(1H,m),3.78-3.86(1H,m),
5.06(1H,d,J=10.5 Hz),5.12(1H,d,J=10.0 Hz),5.56(1H,dd,J=10.0, 15.5
Hz),5.72(1H,dd,J=10.5,15.5 Hz),5.87(1H,d,J=15.5 Hz),6.14
(1H,d,J=10.5 Hz),6.53(1H,dd,J=10.5,15.5 Hz); ESI-MS m/z 589
(M+Na).sup.+.
Example 44
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl-
)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 44)
[0902] ##STR94## First Step
(8E,12E,14E)-6-(1-Ethoxyethoxy)-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-
-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-
-8,12,14-trien-11-olide (Compound 44-1)
[0903] ##STR95##
[0904] To a solution of Compound 46-4
(8E,12E,14E)-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitropheno-
xy)carboxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-1-
1-olide (1.27 g, 1.16 mmol) obtained in the fourth step of Example
46 in tetrahydrofuran (25 mL) were added triethylamine (470 mg,
4.64 mmol) and isopropylpiperazine (298 mg, 2.32 mmol) at room
temperature, and the reaction mixture was stirred at the same
temperature for 1.5 hours. The reaction mixture was diluted with
ethyl acetate and then washed with a saturated aqueous solution of
sodium bicarbonate and brine. The organic layer was dried over
anhydrous magnesium sulfate, filtrated and concentrated. The
resulting residue was purified by silica gel column chromatography
(Kanto silica gel 60N, 40 to 100 .mu.m; hexane:ethyl acetate=1:1 to
ethyl acetate to ethyl acetate:methanol=97:3) to give the title
compound (1.12 g, 89%) as a colorless oil.
[0905] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.58-0.70 (27H,m), 0.80-1.72
(53H,m),1.76(3H,s),1.88-1.98(1H,m),2.33-2.64(8H,m),
2.64-2.76(1H,m),2.80-2.90(1H,m),3.38-3.66(6H,m),3.68-3.78
(1H,m),3.85-3.98(1H,m),4.88-4.99(2H,m),5.05(0.4H,q,J=5.2 Hz),
5.13(0.6H,q,J=5.2 Hz),5.57(1H,dd,J=10.0,15.2 Hz),5.72-5.80
(1H,m),5.82(1H,d,J=14.8 Hz),6.13(1H,d,J=10.8 Hz),6.50(1H,dd,
J=10.8,15.2 Hz).
Second Step
(8E,12E,14E)-6-(1-Ethoxyethoxy)-3,16,21-trihydroxy-7-((4-isopropylpiperazi-
n-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-t-
rien-11-olide (Compound 44-2)
[0906] ##STR96##
[0907] To a solution of Compound 44-1
(8E,12E,14E)-6-(1-ethoxyethoxy)-7-((4-isopropylpiperazin-1-yl)carbonyl)ox-
y-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricos-
a-8,12,14-trien-11-olide (1.12 g, 1.03 mmol) obtained in the first
step in tetrahydrofuran (20 mL) was added tetrabutylammonium
fluoride (4.1 mL, 1.0 M tetrahydrofuran solution) at room
temperature, and the reaction mixture was stirred at the same
temperature for 4 hours. The reaction mixture was diluted with
ethyl acetate and then washed with a saturated aqueous solution of
sodium bicarbonate and brine. The organic layer was dried over
anhydrous magnesium sulfate, filtrated and evaporated. The
resulting residue was purified by silica gel column chromatography
(Fuji Silysia, NH Silica gel, 200-350 mesh; ethyl acetate to ethyl
acetate:methanol=95:5) to give the title compound (0.76 g, 99%) as
a colorless oil.
[0908] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.06(6H,d,J=6.4 Hz), 1.12-1.70
(20H,m),1.78(3H,s),1.86(1H,dd,J=2.4,7.6
Hz),2.42-2.62(7H,m),2.64-2.76(2H,m),2.89(1H,dt,J=2.0,6.0
Hz),3.38-3.66(7H,m),3.75-3.84(1H,m),4.98(1H,d,J=9.6 Hz),5.02-5.16
(2H,m),5.56(1H,dd,J=10.0,15.6 Hz),5.72-5.80(1H,m),5.87(1H,d, J=15.6
Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 737
(M+H).sup.+.
Third Step
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl-
)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 44)
[0909] ##STR97##
[0910] To a solution of Compound 44-2
(8E,12E,14E)-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-7-((4-isopropylpiperaz-
in-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14--
trien-11-olide (0.76 g, 1.03 mmol) obtained in the second step in a
mixture of tetrahydrofuran:2-methyl-2-propanol=1:1 (20 mL) was
added pyridinium p-toluenesulfonate (0.39 g, 1.55 mmol) at room
temperature, and the reaction mixture was stirred at the same
temperature for 16 hours. Triethylamine (0.25 g, 3.10 mmol) was
added to the reaction mixture at room temperature, and the organic
solvent was evaporated. The resulting residue was diluted with
ethyl acetate and washed with a saturated aqueous solution of
sodium bicarbonate and brine. The organic layer was dried over
anhydrous sodium sulfate, filtrated and evaporated. The resulting
residue was purified by silica gel column chromatography (Fuji
Silysia, NH Silica gel, 200-350 mesh; ethyl acetate to ethyl
acetate:methanol=95:5) to give the title compound (0.76 g, 85%) as
a colorless oil.
[0911] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.6 Hz), 0.90(3H,d,J=6.9 Hz),0.94(3H,t,J=7.4
Hz),1.07(6H,d,J=6.4 Hz), 1.14-1.67
(14H,m),1.77(3H,brs),1.86(1H,dd,J=5.4,14.2 Hz),
2.46-2.63(7H,m),2.66(1H,dd,J=2.4,8.0 Hz),2.64-2.79(1H,m),
2.89(1H,dt,J=2.4,6.0Hz),3.36-3.67(5H,m),3.72-3.81(1H,m),
4.93(1H,d,J=9.7 Hz),5.06(1H,d,J=10.8 Hz),5.57(1H,dd,J=9.7, 15.1
Hz),5.71(1H,dd,J=9.7,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13
(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 665
(M+H).sup.+.
Example 45
(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrah-
ydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 45)
[0912] ##STR98## First Step
(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethox-
y)-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytrico-
sa-8,12,14-trien-11-olide (Compound 45-1)
[0913] ##STR99##
[0914] To a solution of Compound 46-4
(8E,12E,14E)-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitropheno-
xy)carboxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-1-
1-olide (1.368 g, 1.254 mmol) obtained in the fourth step of
Example 46 in tetrahydrofuran (20 mL) were sequentially added
dropwise 1-cycloheptylpiperazine (462 mg, 2.51 mmol) and
triethylamine (513 mg, 5.02 mmol). Then, tetrahydrofuran (8 mL) was
added thereto, and the reaction mixture was stirred at room
temperature for 1.5 hours. The reaction mixture was diluted with
ethyl acetate and washed with an aqueous solution of sodium
bicarbonate and brine. The organic layer was dried over anhydrous
magnesium sulfate, filtrated and concentrated. The resulting
residue was purified by silica gel column chromatography (Kanto
silica gel 60N, 40-50 .mu.m; ethyl acetate-hexane, 1:9 to 1:4 to
1:3) to give the title compound (1.455 g, 99%) as a colorless
oil.
Second Step
(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethox-
y)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-
-trien-11-olide (Compound 45-2)
[0915] ##STR100##
[0916] A solution of Compound 45-1
(8E,12E,14E)-7-((4-cycloheptylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyetho-
xy)-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytric-
osa-8,12,14-trien-11-olide (1.454 g, 1.254 mmol) obtained in the
first step in tetrahydrofuran (30 mL) was cooled to 5.degree. C.,
tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 4.5
mL, 4.5 mmol) was added dropwise thereto, and the reaction mixture
was stirred at room temperature for 1.5 hours. Tetrabutylammonium
fluoride (1.0 M tetrahydrofuran solution, 0.52 mL, 0.52 mmol) was
further added dropwise, and the reaction mixture was stirred at
room temperature for two hours. The reaction mixture was diluted
with ethyl acetate and washed with an aqueous solution of sodium
bicarbonate and brine. The organic layer was dried over anhydrous
magnesium sulfate, filtrated and concentrated. The resulting
residue was purified by silica gel column chromatography (Fuji
Silysia, NH Silica gel, 200-350 mesh; ethyl acetate-hexane, 1:1 to
4:1 to 9:1 to 1:0) to give the title compound (965 mg, 97%) as a
colorless oil.
[0917] ESI-MS m/z 791 (M+H)+
Third Step
(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrah-
ydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 45)
[0918] ##STR101##
[0919] To a solution of Compound 45-2
(8E,12E,14E)-7-((4-cycloheptylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyetho-
xy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,1-
4-trien-11-olide (964 mg, 1.218 mmol) obtained in the second step
in a mixture of tetrahydrofuran:2-methyl-2-propanol=1:1 (22 mL) was
added pyridinium p-toluenesulfonate (459 mg, 1.827 mmol), and the
reaction mixture was stirred at room temperature for 16 hours. The
reaction mixture was diluted with ethyl acetate and washed with an
aqueous solution of sodium bicarbonate and brine. The organic layer
was dried over anhydrous magnesium sulfate, filtrated and
concentrated. The resulting residue was purified by silica gel
column chromatography (Fuji Silysia, NH Silica gel, 200 to 350
mesh; ethyl acetate-hexane-methanol, 2:1:0 to 4:1:0 to 99:0:1 to
98:0:1 to 97:0:1), and the crude fraction was concentrated. The
resulting residue was purified by silica gel column chromatography
(Kanto silica gel 60N, 40-50 .mu.n; methanol-dichloromethane, 1:29
to 1:19 to 1:17 to 1:14 to 1:9) to give the title compound (866 mg,
99%) as a colorless oil.
[0920] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.10-1.77 (24H,m),1.77
(3H,brs),1.79-1.90(3H,m),2.42-2.74(9H,m),2.85-2.92(1H,m),
3.36-3.70(5H,m),3.72-3.84(1H,m),4.92(1H,d,J=10.0 Hz),5.06
(1H,d,J=10.8 Hz),5.57(1H,dd,J=9.6,15.2 Hz),5.71(1H,dd,J=10.0, 15.2
Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=11.2 Hz),6.52(1H,dd,
J=11.2,15.2 Hz); ESI-MS m/z 719 (M+H).sup.+.
Example 46
(8E,12E,14E)-7-((4-Allylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-3,1-
6,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-
-11-olide (Compound 46)
[0921] ##STR102## First Step
(8E,12E,14E)-7-Acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris(tr-
iethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound
46-1)
[0922] ##STR103##
[0923] To a solution of
(8E,12E,14E)-7-acetoxy-6,3,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-1-
8,19-epoxytricosa-8,12,14-trien-11-olide (100 mg, 0.18 mmol) in
dichloromethane (6 mL) were added N,N-dimethylaminopyridine (221
mg, 1.8 mmol) and chlorotriethylsilane (272 mg, 1.8 mmol) at room
temperature, and the reaction mixture was stirred at the same
temperature for 18 hours. The reaction mixture was diluted with
ethyl acetate and washed with saturated aqueous solution of
ammonium chloride and brine. The organic layer was dried over
anhydrous magnesium sulfate, filtrated and concentrated. The
resulting residue was purified by silica gel column chromatography
(Kanto silica gel 60N, 40-100 .mu.m; ethyl acetate:hexane=20:80) to
give the title compound (159 mg, 98%) as a colorless oil. ESI-MS
m/z 918 (M+Na).sup.+.
Second Step
(8E,12E,14E)-7-Acetoxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,16,2-
1-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 46-2)
[0924] ##STR104##
[0925] To a solution of Compound 46-1
(8E,12E,14E)-7-acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris(t-
riethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide (1.6 g,
1.8 mmol) obtained in the first step in dichloromethane (35 mL)
were added ethyl vinyl ether (2.6 g, 36 mmol) and pyridinium
p-toluenesulfonate (22 mg, 89 .mu.mol) at room temperature, and the
resulting mixture was stirred at the same temperature for 19 hours.
The reaction mixture was washed with a saturated aqueous solution
of sodium bicarbonate and brine. The organic layer was dried over
anhydrous magnesium sulfate, filtrated and concentrated. The
resulting residue was purified by silica gel column chromatography
(Kanto silica gel 60N, 40-100 .mu.m; ethyl acetate:hexane=10:90) to
give the title compound (1.6 g, 93%) as a colorless oil.
[0926] ESI-MS m/z 990 (M+Na).sup.+.
Third Step
(8E,12E,14E)-6-(1-Ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-3,16,2-
1-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 46-3)
[0927] ##STR105##
[0928] To Compound 46-2
(8E,12E,14E)-7-acetoxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,16,-
21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide
(1.6 g, 1.7 mmol) obtained in the second step was added
guanidine/guanidine nitrate (41 mL, 0.2M
dichloromethane:methanol=10:90 solution) at room temperature,
followed by stirring at the same temperature for three hours. The
reaction mixture was diluted with ethyl acetate and washed with a
saturated aqueous solution of ammonium chloride and brine. The
organic layer was dried over anhydrous magnesium sulfate, filtrated
and concentrated. The resulting residue was purified by silica gel
column chromatography (Kanto silica gel 60N, 40-100 .mu.m; ethyl
acetate:hexane=20:80) to give the title compound (1.3 g, 84%) as a
colorless oil.
[0929] ESI-MS m/z 948 (M+Na).sup.+.
Fourth Step
(8E,12E,14E)-6-(1-Ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenox-
y)carboxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-
-olide (Compound 46-4)
[0930] ##STR106##
[0931] To a solution of Compound 46-3
(8E,12E,14E)-6-(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-3,16,-
21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide
(1.3 g, 1.4 mmol) obtained in the third step in dichloromethane (30
mL) were added triethylamine (826 mg, 8.2 mmol),
N,N-dimethylaminopyridine (831 mg, 6.8 mmol) and 4-nitrophenyl
chloroformate (823 mg, 4.1 mmol) at room temperature, and the
resulting mixture was stirred at the same temperature for 1.5
hours. The reaction mixture was diluted with dichloromethane and
washed with a saturated aqueous solution of ammonium chloride, a
saturated aqueous solution of sodium bicarbonate and brine. The
organic layer was dried over anhydrous magnesium sulfate, filtrated
and concentrated. The resulting residue was purified by silica gel
column chromatography (Kanto silica gel 60N, 40-100 .mu.m; ethyl
acetate:hexane=10:90) to give the title compound (1.4 g, 97%) as a
colorless oil.
[0932] ESI-MS m/z 1114 (M+Na).sup.+.
Fifth Step
(8E,12E,14E)-7-((4-Allylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-6,1-
0,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,1-
2,14-trien-11-olide (Compound 46-5)
[0933] ##STR107##
[0934] To a solution of Compound 46-4
(8E,12E,14E)-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitropheno-
xy)carboxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-1-
1-olide (37 mg, 34 .mu.mol) obtained in the fourth step in
tetrahydrofuran (2 mL) were added triethylamine (14 mg, 0.14 mmol)
and allylpiperazine (8.5 mg, 68 .mu.mol) at room temperature, and
the resulting mixture was stirred at the same temperature for 1.5
hours. The reaction mixture was diluted with ethyl acetate and
washed with a saturated aqueous solution of sodium bicarbonate and
brine. The organic layer was dried over anhydrous magnesium
sulfate, filtrated and concentrated. The resulting residue was
purified by silica gel column chromatography (Kanto silica gel 60N,
40-100 .mu.m; ethyl acetate:hexane=30:70) to give the title
compound (28 mg, 77%) as a colorless oil.
[0935] ESI-MS m/z 1078 (M+H).sup.+.
Sixth Step
(8E,12E,14E)-7-((4-Allylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-3,1-
6,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-
-11-olide (Compound 46)
[0936] ##STR108##
[0937] To a solution of Compound 46-5
(8E,12E,14E)-7-((4-allylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-6,-
10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,-
12,14-trien-11-olide (26 mg, 24 .mu.mol) obtained in the fifth step
in tetrahydrofuran (2.5 mL) was added tetrabutylammonium fluoride
(79 .mu.L, 1.0 M tetrahydrofuran solution) at room temperature, and
this mixture was stirred at the same temperature for three hours.
The reaction mixture was diluted with ethyl acetate and washed with
a saturated aqueous solution of sodium bicarbonate and brine. The
organic layer was dried over anhydrous magnesium sulfate, filtrated
and concentrated. The resulting residue was purified by thin layer
chromatography (Fuji Silysia, NH Silica gel Plate;
methanol:dichloromethane=5:95) to give the title compound (13 mg,
72%) as a colorless oil.
[0938] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.85-0.90(6H,m),0.94 (3H,t,J=7.6 Hz),1.12-1.68
(20H,m),1.78(3H,s),1.86(1H,dd,J=2.4, 7.6
Hz),2.38-2.62(7H,m),2.67(1H,dd,J=2.4,8.0 Hz),2.89(1H,dt, J=2.0,6.0
Hz),3.03(2H,d,J=6.4 Hz),3.44-3.62(7H,m),3.76-3.84
(1H,m),4.94-5.14(3H,m),5.16-5.26(2H,m),5.56(1H,dd,J=10.0, 15.6
Hz),5.70-5.82(3H,m),6.13(1H,d,J=10.8 Hz),6.53(1H,dd, J=10.8,15.2
Hz); ESI-MS m/z 735 (M+H).sup.+.
Example 47
(8E,12E,14E)-7-((4-Allylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-
-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 47)
[0939] ##STR109##
[0940] To Compound 46
(8E,12E,14E)-7-((4-allylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-3,-
16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trie-
n-11-olide (8.7 mg, 12 .mu.mol) obtained in Example 46 was added a
solution of pyridinium p-toluenesulfonate (3.3 mg, 13 .mu.mol) in a
mixture of tetrahydrofuran:2-methyl-2-propanol=1:1 (1 mL) at room
temperature, and the reaction mixture was stirred at the same
temperature for 17 hours. The reaction mixture was concentrated.
The resulting residue was purified by thin layer chromatography
(Fuji Silysia, NH Silica gel Plate; methanol:dichloromethane=5:95)
to give the title compound (5.5 mg, 70%) as a colorless oil.
[0941] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.21(3H,s),1.34(3H,s),
1.22-1.68(8H,m),1.78(3H,s),1.86(1H,dd,J=2.4,7.6
Hz),2.38-2.46(4H,m),2.48-2.60(3H,m),2.67(1H,dd,J=2.0,8.0 Hz),2.89
(1H,dt,J=2.0,5.6 Hz),3.04(2H,d,J=6.8 Hz),3.42-3.64(5H,m),
3.74-3.82(1H,m),4.92(1H,d,J=9.6 Hz),5.06(1H,d,J=10.8 Hz),
5.16-5.26(2H,m),5.57(1H,dd,J=10.0,15.6 Hz),5.71(1H,dd,J=9.6, 15.2
Hz),5.82-5.92(2H,m),6.13(1H,d,J=11.2 Hz),6.53 (1H,dd,J=11.2,15.2
Hz); ESI-MS m/z 663 (M+H).sup.+.
Example 48
(8E,12E,14E)-7-((4-(3,7-Dimethyl-2,6-octadien-1-yl)piperazin-1'-yl)carbony-
l)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa--
8,12,14-trien-11-olide (Compound 48)
[0942] ##STR110##
[0943] The title compound (a colorless oil) was synthesized by a
similar method as described for Examples 46 and 47.
[0944] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.21(3H,s),1.34(3H,s),
1.24-1.68(8H,m),1.60(3H,s),1.66(6H,s),1.77(3H,s),1.86(1H,dd,
J=5.6,14.0 Hz),2.04-2.16(4H,m),2.40-2.46(4H,m),2.48-2.62
(3H,m),2.67(1H,dd,J=2.4,8.0 Hz),2.89(1H,dt,J=2.0,5.2 Hz),3.02
(2H,d,J=6.8 Hz),3.42-3.64(5H,m),3.75-3.82(1H,m),4.93(1H,d, J=10.0
Hz),5.02-5.12(2H,m),5.24(1H,t,J=7.2 Hz),5.57(1H,dd, J=10.0,15.2
Hz),5.72(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),
6.14(1H,d,J=11.2 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 760
(M+H).sup.+.
Example 49
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-pentyl-
piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 49)
[0945] ##STR111##
[0946] The title compound (a colorless oil) was synthesized by a
similar method as described for Examples 46 and 47.
[0947] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=7.2 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.21(3H,s),1.22-1.68 (20H,m),1.77(3H,s),1.86(1H,dd,J=5.6,13.7
Hz),2.32-2.60(9H,m), 2.67(1H,dd,J=2.4,8.0 Hz),2.89(1H,dt,J=1.6,5.6
Hz),3.40-3.70 (5H,m),3.74-3.82(1H,m),4.93(1H,d,J=9.6
Hz),5.06(1H,d,J=10.8 Hz),5.57(1H,dd,J=10.8,15.2
Hz),5.72(1H,dd,J=10.8,15.2 Hz), 5.87(1H,d,J=15.2
Hz),6.13(1H,d,J=9.2 Hz),6.53(1H,dd,J=10.8, 15.2 Hz); ESI-MS m/z 693
(M+H).sup.+.
Example 50
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-(((1S,4S)-5-isopropyl-2,5-diazabicyc-
lo[2.2.1]heptan-2-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytri-
cosa-8,12,14-trien-11-olide (Compound 50)
[0948] ##STR112##
[0949] The title compound (a colorless oil) was synthesized by a
similar method as described for Examples 46 and 47.
[0950] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.06-1.12(6H,m),1.18-1.68
(16H,m),1.78(3H,s),1.86(1H,dd,J=5.7,13.7 Hz),2.47-2.62
(7H,m),2.67(1H,dd,J=2.4,8.0 Hz),2.89(1H,dt,J=2.4,6.4 Hz),3.05
(1H,t,J=10.0 Hz),3.19(1H,dd,J=2.4,10.8 Hz),3.48-3.68(2H,m),
3.78(1H,brs),4.92(1H,d,J=9.6 Hz),5.06(1H,d,J=10.4 Hz),5.58
(1H,dd,J=9.6,15.2 Hz),5.68-5.78(1H,m),5.87(1H,d,J=15.2 Hz),
6.13(1H,d,J=11.2 Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 677
(M+H).sup.+.
Example 51
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(3-met-
hyl-2-buten-1-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-tr-
ien-11-olide (Compound 51)
[0951] ##STR113##
[0952] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0953] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.21(3H,s),1.34(3H,s),
1.24-1.64(8H,m),1.67(3H,s),1.75(3H,s),1.77(3H,s),1.86(1H,dd,
J=5.6,14.0 Hz),2.38-2.48(4H,m),2.50-2.53(2H,m),2.54-2.62
(1H,m),2.67(1H,dd,J=2.4,8.0 Hz),2.89(1H,dt,J=2.0,6.0 Hz),3.00
(2H,d,J=6.8 Hz),3.42-3.66(5H,m),3.74-3.82(1H,m),4.93(1H,d, J=9.6
Hz),5.06(1H,d,J=10.4 Hz),5.25(1H,t,J=6.8 Hz),5.57(1H,dd,
J=10.0,15.2 Hz),5.71(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),
6.13(1H,d,J=10.4 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 691
(M+H).sup.+.
Example 52
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((morpholi-
n-4-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 52)
[0954] ##STR114##
[0955] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0956] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=7.2 Hz),0.93(3H,t,J=7.2
Hz),1.21(3H,s),1.34(3H,s),
1.24-1.70(8H,m),1.78(3H,s),1.86(1H,dd,J=5.6,14.0
Hz),2.50-2.62(3H,m),2.67(1H,dd,J=2.4,8.0
Hz),2.86-2.92(1H,m),3.42-3.56(5H,m),3.58-3.68(4H,m),3.76-3.82(1H,m),4.95(-
1H,d, J=9.6 Hz),5.06(1H,d,J=10.4 Hz),5.58(1H,dd,J=10.0,15.2
Hz),5.72 (1H,dd,J=9.6,15.6 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,
J=10.8 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 646
(M+Na).sup.+.
Example 53
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isopropylhomopiperazin-1-yl)carb-
onyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-oli-
de (Compound 53)
[0957] ##STR115##
[0958] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0959] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.04(6H,d,J=6.4 Hz),
1.23(3H,s),1.23-1.69(9H,m),1.34(3H,s),1.77(3H,s),1.77-1.90
(2H,m),2.47-2.76(8H,m),2.84-2.98(2H,m),3.42-3.68(5H,m),
3.74-3.82(1H,m),4.94(1H,d,J=9.6 Hz),5.05(1H,d,J=10.8 Hz),5.57
(1H,dd,J=9.6,15.6 Hz),5.73(1H,dd,J=9.6,15.6 Hz),5.87(1H,d, J=15.6
Hz),6.13(1H,d,J=11.2 Hz),6.52(1H,dd,J=11.2,15.6 Hz); ESI-MS m/z 679
(M+H).sup.+.
Example 54
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isobutylhomopiperazin-1-yl)carbo-
nyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olid-
e (Compound 54)
[0960] ##STR116##
[0961] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0962] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.87-0.97 (15H,m),
1.23(3H,s),1.23-1.69(10H,m),1.34(3H,s),1.77(3H,s),1.69-1.90(2H,m-
),2.23(2H,d,J=6.8 Hz),2.50-2.70(8H,m),2.89(1H,dt, J=2.0,6.0
Hz),3.43-3.66(5H,m),3.74-3.82(1H,m),4.94(1H,d,J=10.0
Hz),5.06(1H,d,J=10.8 Hz),5.57(1H,dd,J=9.6,15.6 Hz),5.73
(1H,dd,J=9.6,15.6 Hz),5.87(1H,d,J=15.6 Hz),6.13(1H,d,J=11.2
Hz),6.52(1H,dd,J=11.2,15.6 Hz); ESI-MS m/z 693 (M+H).sup.+.
Example 55
(8E,12E,14E)-7-((4-(Cyclopentylmethyl)homopiperazin-1-yl)carbonyl)oxy-3,6,-
16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-tr-
ien-11-olide (Compound 55)
[0963] ##STR117##
[0964] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0965] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.15-2.20 (20H,m),1.23
(3H,s),1.34(3H,s),1.77(3H,s),2.42(2H,d,J=7.2 Hz),2.46-2.74
(8H,m),2.86-2.92(1H,m),3.40-3.68(5H,m),3.75-3.82(1H,m),4.94
(1H,d,J=9.6 Hz),5.07(1H,d,J=10.8 Hz),5.57(1H,dd,J=9.6,15.2 Hz),
5.73(1H,dd,J=9.6,15.6 Hz),5.87(1H,d,J=15.6 Hz),6.13(1H,d, J=10.8
Hz),6.52(1H,dd,J=10.8,15.6 Hz); ESI-MS m/z 719 (M+H).sup.+.
Example 56
(8E,12E,14E)-7-(N-((3S)-1-Ethylpyrrolidin-3-yl)-N-methylcarbamoyloxy)-3,6,-
16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-tr-
ien-11-olide (Compound 56)
[0966] ##STR118##
[0967] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0968] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.12(3H,t,J=7.6 Hz),
1.23(3H,s),1.23-1.70(9H,m),1.34(3H,s),1.77(3H,s),1.86
(1H,dd,J=5.2,14.0 Hz),2.08-2.22(1H,m),2.38-2.90 (11H,m),2.90
(3H,s),3.28-3.33(1H,covered with CD.sub.3OD),3.49-3.56(1H,m),
3.75-3.82(1H,m),4.87-4.93(1H,covered with H.sub.2O),5.06(1H,d,
J=10.4 Hz),5.58(1H,dd,J=9.6,15.2 Hz),5.71(1H,dd,J=9.6,15.6 Hz),
5.87(1H,d,J=15.6 Hz),6.13(1H,d,J=11.2 Hz),6.52(1H,dd,J=11.2, 15.6
Hz); ESI-MS m/z 665 (M+H).sup.+.
Example 57
(8E,12E,14E)-7-((4-(Cyclobutylmethyl)homopiperazin-1-yl)carbonyl)oxy-3,6,1-
6,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-tri-
en-11-olide (Compound 57)
[0969] ##STR119##
[0970] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0971] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(6H,d,J=6.8 Hz), 0.94(3H,t,J=7.2 Hz),1.23(3H,s),1.23-1.96
(16H,m),1.34(3H,s),
1.77(3H,s),2.02-2.12(2H,m),2.50-2.64(8H,m),2.64-2.70(2H,m),
2.86-2.92(1H,m),3.40-3.68(5H,m),3.75-3.82(1H,m),4.94(1H,d, J=9.6
Hz),5.07(1H,d,J=10.8 Hz),5.57(1H,dd,J=9.6,15.2 Hz),5.72
(1H,dd,J=9.6,15.6 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d, J=10.8
Hz),6.52(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 705 (M+H).sup.+.
Example 58
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(((2S)-2-(-
(pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,-
12,14-trien-11-olide (Compound 58)
[0972] ##STR120##
[0973] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0974] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.2
Hz),1.20-2.03 (17H,m),1.23 (3H,s),1.34(3H,s),1.77(3H,s),2.38-2.70
(10H,m),2.85-2.92
(1H,m),3.33-3.44(1H,m),3.49-3.56(1H,m),3.75-3.82(1H,m),
3.93-4.08(2H,m),4.93(1H,d,J=9.6 Hz),5.06(1H,d,J=10.4 Hz),5.57
(1H,dd,J=9.6,15.2 Hz),5.73(1H,dd,J=9.6,15.6 Hz),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 691
(M+H).sup.+.
Example 59
(8E,12E,14E)-7-(((3S)-3,4-Dimethylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-te-
trahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (Compound 59)
[0975] ##STR121##
[0976] The title compound (a colorless oil) was synthesized by a
similar method as described for Examples 46 and 47.
[0977] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.08(3H,d,J=6.4 Hz),
1.21(3H,s),1.221-1.69(8H,m),1.34(3H,s),1.77(3H,s),1.86
(1H,dd,J=5,2,14.0
Hz),2.02-2.23(2H,m),2.30(3H,s),2.46-2.84(6H,m),2.89(1H,dt,J=2.0,5.6
Hz),2.94-3.12(1H,m),3.48-3.55(1H,m),3.75-3.82(1H,m),3.82-4.20(2H,m),4.93
(1H,d,J=9.6 Hz),5.06(1H,d,J=10.8 Hz),5.57(1H,dd,J=10.0, 15.2
Hz),5.71(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13
(1H,d,J=10.8 Hz),6.52(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 651
(M+H).sup.+.
Example 60
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(prop--
2-yn-1-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11--
olide (Compound 60)
[0978] ##STR122##
[0979] The title compound (a colorless oil) was synthesized by a
similar method as described for Examples 46 and 47.
[0980] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=7.2 Hz), 0.94(3H,t,J=7.6 Hz),
1.22(3H,s),
1.22-1.69(8H,m),1.34(3H,s),1.77(3H,s),1.86(1H,dd,J=5,6,14.0 Hz),
2.50-2.64(7H,m),2.64-2.70(2H,m),2.89(1H,dt,J=2.0,5.6 Hz),
3.30(2H,d,J=2.4 Hz),3.40-3.74(5H,m),3.75-3.82(1H,m),4.93
(1H,d,J=9.6 Hz),5.06(1H,d,J=10.8 Hz),5.58(1H,dd,J=9.6,15.2 Hz),
5.71(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d, J=10.8
Hz),6.52(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 661 (M+H).sup.+.
Example 61
(8E,12E,14E)-7-((4-(But-2-yn-1-yl)piperazin-1-yl)carbonyl)oxy-3,6,16,21-te-
trahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (Compound 61)
[0981] ##STR123##
[0982] The title compound (a colorless oil) was synthesized by a
similar method as described for Examples 46 and 47.
[0983] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.22(3H,s),1.22-1.69
(8H,m),1.34(3H,s),1.77(3H,s),1.80(3H,t,J=2.4 Hz),1.86(1H,dd,
J=14.0,5,6 Hz),2.45-2.64(7H,m),2.66(1H, dd,J=2.0,8.0 Hz),2.89
(1H,dt,J=2.0,6.0 Hz),3.25(2H,q,J=2.4
Hz)3.40-3.72(5H,m),3.74-3.82(1H,m),4.93(1H,d,J=9.6
Hz),5.06(1H,d,J=10.4 Hz),5.57 (1H,dd,J=10.0,15.2
Hz),5.73(1H,dd,J=10.6,15.2 Hz),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=11.2 Hz),6.52(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 675
(M+H).sup.+.
Example 62
(8E,12E,14E)-7-((4-Cyclobutylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tet-
rahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-ol-
ide (Compound 62)
[0984] ##STR124##
[0985] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0986] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.23(3H,s),1.25-1.29
(1H,m),1.34(3H,s),1.34-1.71(9H,m),1.77(3H,brs),1.80-1.90
(5H,m),2.01-2.12(2H,m),2.38-2.62(7H,m),2.66(1H,dd,J=2.0, 7.6
Hz),2.86-2.97(2H,m),3.42-3.67(5H,m),3.75-3.82(1H,m),
4.94(1H,d,J=9.6 Hz),5.06(1H,d,J=10.8 Hz),5.57(1H,dd,J=9.6, 15.2
Hz),5.72(1H,dd,J=10.0,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13
(1H,d,J=10.8 Hz),6.52(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 691
(M+H).sup.+.
Example 63
(8E,12E,14E)-7-((4-Ethylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahyd-
roxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 63)
[0987] ##STR125##
[0988] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0989] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.2
Hz),1.09(3H,t,J=7.2 Hz),
1.23(3H,s),1.23-1.30(1H,m),1.34(3H,s),1.34-1.69(7H,m),1.77
(3H,s),1.83-1.92(3H,m),2.47-2.78 (10H,m),2.89(1H,dt,J=2.4, 6.4
Hz),3.44-3.68(5H,m),3.75-3.83(1H,m),4.94(1H,d,J=9.6 Hz),
5.06(1H,d,J=10.8 Hz),5.58(1H,dd,J=9.6,15.2 Hz),5.73(1H,dd,
J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=10.8 Hz),6.52
(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 665 (M+H).sup.+.
Example 64
(8E,12E,14E)-7-((4-Butylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahyd-
roxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 64)
[0990] ##STR126##
[0991] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0992] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.4 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),0.95(3H,t,J=7.2 Hz),
1.23(3H,s),1.23-1.30(1H,m),1.34(3H,s),1.30-1.69 (11H,m),
1.77(3H,s), 1.86(1H,dd,J=5.6,14.0 Hz),1.90-1.98(2H,m),2.47-2.62
(3H,m), 2.62-2.73(3H,m),2.78-2.98(5H,m),3.44-3.73
(5H,m),3.76-3.82(1H,m),4.95(1H,d,J=10.4 Hz),5.06(1H,d, J=10.4
Hz),5.58(1H,dd,J=9.6,15.2 Hz),5.73(1H,dd,J=9.6,15.2 Hz),
5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=10.8 Hz),6.52(1H,dd,J=10.8, 15.2
Hz); ESI-MS m/z 693 (M+H).sup.+.
Example 65
(8E,12E,14E)-7-((4-Cyclohexylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tet-
rahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-ol-
ide (Compound 65)
[0993] ##STR127##
[0994] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0995] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.06-1.69 (20H,m), 1.74-1.90
(10H,m),2.44-2.85(9H,m),2.89(1H,dt,J=2.0,5.6 Hz),
3.40-3.67(5H,m),3.74-3.83(1H,m),4.94(1H,d,J=10.0 Hz),5.06
(1H,d,J=10.8 Hz),5.57(1H,dd,J=9.6,15.2 Hz),5.72(1H,dd,J=9.6, 15.2
Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,
J=10.8,15.2 Hz);ESI-MS m/z 719 (M+H).sup.+.
Example 66
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(3-met-
hyl-2-buten-1-yl)homopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,1-
4-trien-11-olide (Compound 66)
[0996] ##STR128##
[0997] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[0998] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.16-1.67 (14H,m),1.67
(3H,s),1.76(3H,s),1.77(3H,s),1.82-1.93(3H,m),2.44-2.80
(8H,m),2.89(1H,dd,J=2.4,5.6 Hz),3.17(2H,d,J=7.2 Hz),3.43-3.70
(5H,m),3.72-3.83(1H,m),4.95(1H,d,J=10.0 Hz),5.06(1H,d, J=10.4
Hz),5.20-5.30(1H,m),5.57(1H,dd,J=10.0,15.2 Hz),5.72
(1H,dd,J=10.0,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d, J=11.2
Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 705 (M+H).sup.+.
Example 67
(8E,12E,14E)-7-((4-(2-(N,N-Dimethylamino)ethyl)piperazin-1-yl)carbonyl)oxy-
-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,-
14-trien-11-olide (Compound 67)
[0999] ##STR129##
[1000] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[1001] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.98-1.69 (14H,m),1.77 (3H,s),1.86(1H,dd,J=6.0,15.2
Hz),2.33(6H,s),2.40-2.62 (11H,m), 2.66(1H,dd,J=2.4,8.0
Hz),2.89(1H,dt,J=2.4,6.4 Hz),3.38-3.70
(5H,m),3.74-3.82(1H,m),4.93(1H,d,J=10.0 Hz),5.06(1H,d, J=10.4
Hz),5.57(1H,dd,J=10.0,15.2 Hz),5.71(1H,dd,J=10.0, 15.2
Hz),5.86(1H,d,J=15.2 Hz),6.13(1H,d,J=10.8 Hz),6.52(1H,dd,
J=10.8,15.2 Hz); ESI-MS m/z 694 (M+H).sup.+.
Example 68
(8E,12E,14E)-7-((4-(2-(N,N-Diethylamino)ethyl)piperazin-1-yl)carbonyl)oxy--
3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,1-
4-trien-11-olide (Compound 68)
[1002] ##STR130##
[1003] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[1004] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.08(6H,t,J=7.2 Hz),
1.21(3H,s),1,22-1.30(1H,m),1.34(3H,s),1.34-1.68(7H,m),1.77
(3H,s),1.86(1H,dd,J=5.2,14.0 Hz),2.40-2.72 (16H,m),2.89(1H,dt,
J=2.0,6.0 Hz),3.38-3.70(5H,m),3.74-3.82(1H,m),4.93(1H,d, J=9.6
Hz),5.06(1H,d,J=10.8 Hz),5.57(1H,dd,J=9.6,15.2 Hz),5.71
(1H,dd,J=9.6,15.2 Hz),5.86(1H,d,J=15.2 Hz),6.13(1H,d, J=10.8
Hz),6.52(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 722 (M+H).sup.+.
Example 69
(8E,12E,14E)-7-((4-(2,2-Dimethylpropyl)homopiperazin-1-yl)carbonyl)oxy-3,6-
,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-t-
rien-11-olide (Compound 69)
[1005] ##STR131##
[1006] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[1007] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.85(6H,s), 0.86 (3H,s),0.89(3H,d,J=6.8 Hz),0.90(3H,d,J=6.8
Hz),0.94(3H,t, J=7.2 Hz),1.18-1.68
(14H,m),1.72-1.82(5H,m),1.86(1H,dd,J=5.6, 14.0
Hz),2.28(2H,s),2.46-2.62(3H,m),2.66(1H,dd,J=2.4,8.0 Hz),
2.68-2.75(2H,m),2.81(2H,dd,J=5.2,10.4 Hz),2.89(1H,dt,J=2.0, 6.0
Hz),3.36-3.68(5H,m),3.72-3.82(1H,m),4.94(1H,d,J=9.6 Hz),
5.06(1H,d,J=10.8 Hz),5.57(1H,dd,J=9.6,14.8 Hz),5.73(1H,dd,
J=9.6,14.8 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=10.8 Hz),6.53
(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 707 (M+H).sup.+.
Example 70
(8E,12E,14E)-7-((4-Cyclopentylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-te-
trahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (Compound 70)
[1008] ##STR132##
[1009] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[1010] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.2
Hz),1.18-1.68 (18H,m),
1.70-1.77(2H,m),1.77(3H,s),1.86(1H,dd,J=5.6,14.0
Hz),1.88-2.02(4H,m), 2.46-2.62(3H,m),2.66(1H,dd,J=2.0,8.0
Hz),2.82-3.02(5H,m),3.08-3.22(1H,m),3.42-3.73(5H,m),3.73-3.84(1H,m),
4.95(1H,d,J=9.6 Hz),5.06(1H,d,J=10.4 Hz),5.58(1H,dd,J=9.6, 15.2
Hz),5.73(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13
(1H,d,J=11.2 Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 705
(M+H).sup.+.
Example 71
(8E,12E,14E)-7-((4-Cyclopropylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrah-
ydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 71)
[1011] ##STR133##
[1012] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[1013] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.34-0.52(4H,m),0.89 (3H,d,J=6.8 Hz),0.90(3H,d,J=6.8
Hz),0.94(3H,t,J=7.6 Hz),1.13-1.70
(15H,m),1.77(3H,s),1.86(1H,dd,J=5.2,14.0 Hz),2.35-2.72
(8H,m),2.80-2.92(1H,m),3.30-3.68(5H,m),3.70-3.82(1H,m),
4.92(1H,d,J=10.0 Hz),5.05(1H,d,J=10.4 Hz),5.57(1H,dd,J=9.6, 15.2
Hz),5.70(1H,dd,J=9.6,15.2 Hz),5.86(1H,d,J=15.2 Hz),6.13
(1H,d,J=11.2 Hz),6.52(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 663
(M+H).sup.+, 685 (M+Na).sup.+.
Example 72
(8E,12E,14E)-7-((4-(1,1-Dimethylethyl)piperazin-1-yl)carbonyl)oxy-3,6,16,2-
1-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien--
11-olide (Compound 72)
[1014] ##STR134##
[1015] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[1016] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.10(9H,s),1.22(3H,s),
1.22-1.30(1H,m),1.34(3H,s),1.35-1.69(7H,m),1.77(3H,s),1.86
(1H,dd,J=5.2,14.0 Hz),2.50-2.64(7H,m),2.67(1H,dd,J=2.4, 8.0 Hz),
2.89(1H,dt,J=2.0,6.0 Hz),3.38-3.68(5H,m),3.74-3.82
(1H,m),4.93(1H,d,J=10.0 Hz),5.06(1H,d,J=10.4 Hz),5.57(1H,dd,
J=9.6,15.2 Hz),5.71(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),
6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 679
(M+H).sup.+.
Example 73
(8E,12E,14E)-7-((4-Cyclopropylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-te-
trahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (Compound 73)
[1017] ##STR135##
[1018] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[1019] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.32-0.54(4H,m),0.89 (3H,d,J=6.8 Hz),0.90(3H,d,J=6.8
Hz),0.94(3H,t,J=7.2 Hz),1.14-1.68
(15H,m),1.69-1.93(6H,m),2.42-2.62(3H,m),2.66(1H,dd, J=2.4,8.0
Hz),2.70-2.92(5H,m),3.38-3.68(5H,m),3.68-3.82
(1H,m),4.94(1H,d,J=10.4 Hz),5.06(1H,d,J=10.4 Hz),5.57(1H,dd,
J=10.0,15.2 Hz),5.72(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),
6.13(1H,d,J=11.2 Hz),6.52(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 677
(M+H).sup.+.
Example 74
(8E,12E,14E)-7-((4-(2,2-Dimethylpropyl)piperazin-1-yl)carbonyl)oxy-3,6,16,-
21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-
-11-olide (Compound 74)
[1020] ##STR136##
[1021] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[1022] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.87-0.92 (15H,m), 0.94(3H,t,J=7.6 Hz),1.20-1.29(4H,m),1.31-1.69
(10H,m),1.77 (3H,d,J=1.2 Hz),1.86(1H,dd,J=5.2,14.0
Hz),2.09(2H,s),2.45-2.64(7H,m),2.67(1H,dd,J=2.4,8.0
Hz),2.89(1H,dt,J=2.4,6.0 Hz),
3.36-3.67(5H,m),3.75-3.83(1H,m),4.92(1H,d,J=9.6 Hz),5.06
(1H,d,J=10.8 Hz),5.57(1H,dd,J=10.0,15.2 Hz),5.71(1H,dd,J=9.6, 15.2
Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,dd,J=1.6,10.8 Hz),6.53
(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 693 (M+H).sup.+.
Example 75
(8E,12E,14E)-7-(N-(2-(N',N'-Diethylamino)ethyl)-N-methylcarbamoyloxy)-3,6,-
16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-tr-
ien-11-olide (Compound 75)
[1023] ##STR137##
[1024] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[1025] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.6 Hz), 0.89(3H,d,J=7.0 Hz),0.93(3H,t,J=7.3
Hz),1.06(6H,brt,J=7.0 Hz),
1.15-1.65(7H,m),1.22(3H,brs),1.33(3H,s),1.65(1H,dd,J=6.2,
14.3H),1.77(3H,s),1.86(1H,dd,J=6.2,14.3 Hz),2.46-2.65(5H,m),
2.59(4H,q,J=7.0 Hz),2.66(1H,dd,J=2.2,8.1 Hz),2.89(1H,dt,J=2.2, 6.2
Hz),2.92(1.6H, s),2.99(1.4H, s),3.28-3.40(1H,m),3.52(1H,dt,
J=4.0,8.4 Hz),3.52-3.62(1H,m),3.74-3.81(1H,m),4.92(1H,d, J=9.5
Hz),5.06(1H,d,J=10.6 Hz),5.56(1H,dd,J=9.9,15.0 Hz),5.72
(1H,dd,J=9.5,15.0 Hz),5.86(1H,d,J=15.4 Hz),6.13(1H,d, J=11.0
Hz),6.52(1H,dd,J=11.0,15.4 Hz); ESI-MS m/z 667 (M+H).sup.+.
Example 76
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl--
N-(2-(morpholin-4-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien--
11-olide (Compound 76)
[1026] ##STR138##
[1027] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[1028] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.888(3H,d,J=6.6 Hz), 0.894(3H,d,J=7.0 Hz),0.93(3H,t,J=7.3
Hz),1.19-1.65(7H,m),1.22 (3H,s),1.33(3H,s),1.65(1H,dd,J=6.6,13.9
Hz),1.77(3H,d, J=0.7 Hz),1.86(1H,dd,J=6.2,13.9
Hz),2.45-2.61(9H,m),2.66 (1H,dd,J=2.6,7.7 Hz),2.89(1H,dt,J=2.6,6.2
Hz),2.91(1.6H, s), 2.98(1.4H,
s),3.30-3.45(1H,m),3.52(1H,dt,J=4.4,8.1
Hz),3.60-3.71(5H,m),3.74-3.81(1H,m),4.92(1H,d,J=9.9 Hz),5.06(1H,d,
J=10.6 Hz),5.51-5.60(1H,m),5.67-5.77(1H,m),5.86(1H,d, J=15.0
Hz),6.13(1H,d,J=11.0 Hz),6.52(1H,dd,J=11.0,15.0 Hz); ESI-MS m/z 681
(M+H).sup.+.
Example 77
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl--
N-(2-(piperidin-1-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien--
11-olide (Compound 77)
[1029] ##STR139##
[1030] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[1031] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=7.0 Hz), 0.89(3H,d,J=7.0 Hz),0.93(3H,t,J=7.3
Hz),1.19-1.68 (17H,m),1.33 (3H,s),1.77(3H,d,J=0.7
Hz),1.86(1H,dd,J=5.5,13.9 Hz),2.41-2.62(9H,m),2.66(1H,dd,J=2.6,7.7
Hz),2.87-2.92(1H,m),2.90 (1.6H, s),2.98(1.4H,
s),3.36-3.45(1H,m),3.52(1H,dt,J=4.4, 8.4
Hz),3.55-3.62(1H,m),3.74-3.81(1H,m),4.86-4.93(1H,m),5.05
(1H,d,J=10.6 Hz),5.56(1H,dd,J=9.9,15.0 Hz),5.71(1H,dd,J=10.6, 15.0
Hz),5.86(1H,d,J=15.4 Hz),6.13(1H,d,J=11.0 Hz),6.52(1H,dd,
J=11.0,15.4 Hz); ESI-MS m/z 679 (M+H).sup.+.
Example 78
(8E,12E,14E)-7-(N-Ethyl-N-(2-(morpholin-4-yl)ethyl)carbamoyloxy)-3,6,16,21-
-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-1-
1-olide (Compound 78)
[1032] ##STR140##
[1033] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[1034] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.886(3H,d,J=6.6 Hz), 0.893(3H,d,J=7.0 Hz), 0.93(3H,t,J=7.3 Hz),
1.08-1.17(3H,m),
1.18-1.65(7H,m),1.22(3H,s),1.33(3H,s),1.65(1H,dd,J=5.5, 13.9
Hz),1.77(3H,d,J=1.1 Hz),1.86 (1H,dd,J=5.5,13.9
Hz),2.44-2.62(9H,m),2.66(1H,dd,J=2.2,8.1 Hz),2.89(1H,dt,J=2.2,5.5
Hz), 3.30-3.54(3H,m),3.52(1H,dt,J=4.4,8.4 Hz),3.54-3.71(5H,m),
3.73-3.81(1H,m),4.92(1H,brd,J=9.5 Hz),5.06(1H,d,J=10.6 Hz),
5.57(1H,dd,J=9.9,15.0 Hz),5.67-5.78(1H,m),5.86(1H,d, J=15.0
Hz),6.13(1H,d,J=11.0 Hz),6.52(1H,dd,J=11.0,15.0 Hz); ESI-MS m/z 695
(M+H).sup.+.
Example 79
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl--
N-(2-(pyrrolidin-1-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-
-11-olide (Compound 79)
[1035] ##STR141##
[1036] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[1037] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.6 Hz), 0.89(3H,d,J=7.0 Hz),0.93(3H,t,J=7.3
Hz),1.19-1.65 (10H,m),1.33 (3H,s),1.65(1H,dd,J=5.5,14.3
Hz),1.74-1.85(4H,m),1.77(3H,s), 1.86(1H,dd,J=5.5,14.3 Hz),2.49-2.68
(10H,m),2.86-2.92(1H,m), 2.91(1.6H, s),2.99(1.4H,
s),3.39-3.60(2H,m),3.52(1H,dt,J=4.4, 8.4
Hz),3.73-3.81(1H,m),4.91(1H,d,J=9.5 Hz),5.05(1H,d, J=10.6
Hz),5.56(1H,dd,J=9.9,15.4 Hz),5.72(1H,dd,J=9.5,15.4 Hz),
5.86(1H,d,J=15.4 Hz),6.13(1H,d,J=11.0 Hz),6.52(1H,dd,J=11.0, 15.4
Hz); ESI-MS m/z 665 (M+H).sup.+.
Example 80
(8E,12E,14E)-7-(N-(3-(N',N'-Diethylamino)propyl)-N-methylcarbamoyloxy)-3,6-
,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-t-
rien-11-olide (Compound 80)
[1038] ##STR142##
[1039] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[1040] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.6 Hz), 0.89(3H,d,J=7.0 Hz),0.93(3H,t,J=7.3
Hz),1.05(6H,t,J=7.3 Hz), 1.21-1.81 (10H,m),1.21
(3H,s),1.33(3H,s),1.77(3H,s),1.86(1H, dd,J=5.5,13.6
Hz),2.46-2.62(5H,m),2.58(4H,q,J=7.3 Hz),2.66 (1H,dd,J=2.2,8.1
Hz),2.87-2.95(1H,m),2.89(1.6H, s),2.97 (1.4H,
s),3.20-3.32(1H,m),3.50-3.59(1H,m),3.52(1H,dt,J=4.4, 8.4
Hz),3.74-3.82(1H,m),4.93(1H,d,J=9.9 Hz),5.06(1H,d, J=10.6
Hz),5.56(1H,dd,J=9.9,15.0 Hz),5.73(1H,dd,J=9.9,15.0 Hz),
5.86(1H,d,J=15.4 Hz),6.13(1H,d,J=11.0 Hz),6.52(1H,dd,J=11.0, 15.4
Hz); ESI-MS m/z 681 (M+H).sup.+.
Example 81
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(((1S,4S)--
5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-18,19-epoxytricos-
a-8,12,14-trien-11-olide (Compound 81)
[1041] ##STR143##
[1042] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 3.
[1043] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.6 Hz), 0.89(3H,d,J=7.0 Hz),0.93(3H,t,J=7.3
Hz),1.19-1.70(7H,m),1.20 (1.2H, s),1.22(1.8H,
s),1.33(3H,s),1.65(1H,dd,J=6.2,14.3 Hz),
1.72-1.77(1H,m),1.77(3H,d,J=0.7 Hz),1.86(1H,dd,J=6.2,14.3 Hz),
1.86-1.92(1H,m),2.38(1.2H, s),2.40(1.8H, s),2.50-2.62(3H,m),
2.63-2.70(2H,m),2.74-2.83(1H,m),2.89(1H,dt,J=2.2,6.2 Hz),
3.21(0.6H, dd,J=1.8,10.6 Hz),3.36(0.4H, dd,J=1.8,10.6
Hz),3.47-3.59(3H,m),3.75-3.82(1H,m),4.32(0.4H, s),4.55(0.6H,
s),4.91 (1H,d,J=9.9 Hz),5.06(1H,d,J=10.6
Hz),5.68-5.77(1H,m),5.51-5.61(1H,m),5.86(1H,d,J=15.0
Hz),6.13(1H,d,J=11.0 Hz),6.52 (1H,dd,J=11.0,15.0 Hz); ESI-MS m/z
649 (M+H).sup.+.
Example 82
(8E,12E,14E)-7-(((1S,4S)-5-Ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbon-
yl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-
-8,12,14-trien-11-olide (Compound 82)
[1044] ##STR144##
[1045] The title compound (a colorless oil) was synthesized by a
similar method as described for Examples 46 and 47.
[1046] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.93(3H,d,J=6.8 Hz), 0.94(3H,d,J=6.8 Hz),0.98(3H,t,J=7.2
Hz),1.10-1.18(3H,m),1.22-1.74
(14H,m),1.80(1H,brs),1.82(3H,s)1.87-1.95(2H,m),2.51-2.77(7H,m),2.87-2.97(-
2H,m),3.23-3.29(0.5H,m),3.37-3.43
(0.5H,m),3.51-3.63(2H,m),3.63-3.69(1H,m),3.79-3.87(1H,m),
4.37(0.5H,brs),4.60(0.5H,brs),4.96(1H,d,J=9.6 Hz),5.11(1H,d, J=10.4
Hz),5.57-5.67(1H,m),5.72-5.67(1H,m),5.91(1H,d, J=15.2
Hz),6.18(1H,d,J=11.2 Hz),6.57(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 663
(M+H).sup.+.
Example 83
(8E,12E,14E)-7-((4-Cyclooctylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahy-
droxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 83)
[1047] ##STR145##
[1048] The title compound (a colorless oil) was synthesized by a
similar method as described for Examples 46 and 47.
[1049] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.94(3H,d,J=6.8 Hz), 0.94(3H,d,J=6.8 Hz),0.98(3H,t,J=7.2
Hz),1.25(3H,s),1.25-1.87 (28H,m),1.91(1H,dd,J=5.6,14.4
Hz),2.50-2.76(9H,m),2.93 (1H,dt,J=2.0,6.0
Hz),3.42-3.74(5H,m),3.78-3.88(1H,m),4.97 (1H,d,J=9.6
Hz),5.11(1H,d,J=10.4 Hz),5.61(1H,dd,J=9.6,15.2 Hz),
5.76(1H,dd,J=9.6,15.2 Hz),5.91(1H,d,J=15.2 Hz),6.18(1H,d, J=11.2
Hz),6.57(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 733 (M+H).sup.+.
Example 84
(8E,12E,14E)-7-((4-(Ethoxycarbonylmethyl)piperazin-1-yl)carbonyl)oxy-3,6,1-
6,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-tri-
en-11-olide (Compound 84)
[1050] ##STR146##
[1051] The title compound (a colorless oil) was synthesized by a
similar method as described for Examples 46 and 47.
[1052] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.20-1.42(3H,m),1.21 (3H,s),1.26(3H,t,J=7.2
Hz),1.34(3H,s),1.44-1.54(2H,m),1.56-1.64(2H,m),1.65(1H,dd,J=6.5,14.4
Hz),1.78(3H,s),1.86(1H,dd, J=5.0,14.4
Hz),2.50-2.62(7H,m),2.67(1H,dd,J=2.4,8.0
Hz),2.87-2.91(1H,m),3.26(2H,s),3.40-3.70(4H,m),3.50-3.55(1H,m),3.75-3.81(-
1H,m),4.17(2H,q,J=7.2 Hz),4.93(1H,d,J=10.0 Hz),5.06(1H,d, J=10.4
Hz),5.57(1H,dd,J=10.0,15.2 Hz),5.71(1H,dd,J=9.8, 15.2
Hz)5.87(1H,d,J=15.6 Hz),6.13(1H,d,J=10.0 Hz),6.53(1H,dd,
J=10.8,15.2 Hz); ESI-MS m/z 731 (M+Na).sup.+.
Example 85
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4--
methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olid-
e (Compound 85)
[1053] ##STR147## First Step
(8E,12E,14E)-7-Acetoxy-6-methoxy-6,10,12,16,20-pentamethyl-3,16,21-tris(tr-
iethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound
85-1)
[1054] ##STR148##
[1055] To a solution of Compound 46-1
(8E,12E,14E)-7-acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris(t-
riethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide (171 mg,
0.19 mmol) obtained in the first step of Example 46 in toluene (6
mL) were added methyl trifluoromethanesulfonate (188 mg, 1.14 mmol)
and 1,8-bis(N,N-dimethylamino)naphthalene (368 mg, 1.71 mmol) at
room temperature, and the reaction mixture was stirred at
65.degree. C. for 14 hours. Further, methyl
trifluoromethanesulfonate (304 mg, 1.9 mmol) and
1,8-bis(N,N-dimethylamino)naphthalene (400 mg, 1.9 mmol) were added
to this mixture at room temperature, and the reaction mixture was
stirred at 65.degree. C. for 6 hours. The reaction mixture was
diluted with diethyl ether and was filtrated through a glass
filter. The filtrate was mixed with 28% aqueous ammonia (1 mL), and
the reaction mixture was stirred at room temperature for one hour
and sequentially washed with brine, a 0.1M aqueous solution of
citric acid, a saturated aqueous solution of sodium bicarbonate and
brine. The organic layer was dried over anhydrous magnesium
sulfate, filtrated and concentrated. The resulting residue was
purified by silica gel column chromatography (Kanto silica gel 60N,
40-100 .mu.m; ethyl acetate:hexane=10:90) to give the title
compound (141 mg, 84%) as a colorless oil.
[1056] ESI-MS m/z 932 (M+Na).sup.+.
Second Step
(8E,12E,14E)-7-Hydroxy-6-methoxy-6,10,12,16,20-pentamethyl-3,16,21-tris(tr-
iethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound
85-2)
[1057] ##STR149##
[1058] To a solution of Compound 85-1
(8E,12E,14E)-7-acetoxy-6-methoxy-6,10,12,16,20-pentamethyl-3,16,21-tris(t-
riethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide (158 mg,
0.17 mmol) obtained in the first step in methanol (5 mL) was added
potassium carbonate (120 mg, 0.87 mmol) at room temperature, then
the reaction mixture was stirred at the same temperature for three
hours. The reaction mixture was diluted with ethyl acetate and
washed with brine. The organic layer was dried over anhydrous
magnesium sulfate and concentrated. The crude product was purified
by silica gel column chromatography (Kanto silica gel 60N, 40-100
.mu.m; ethyl acetate:hexane=10:90) to give the title compound (91
mg, 61%) as a colorless oil.
[1059] ESI-MS m/z 890 (M+Na).sup.+.
Third Step
(8E,12E,14E)-6-Methoxy-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-
-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 85-3)
[1060] ##STR150##
[1061] To a solution of Compound 85-2
(8E,12E,14E)-7-hydroxy-6-methoxy-6,10,12,16,20-pentamethyl-3,16,21-tris(t-
riethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide (91 mg,
0.11 mmol) obtained in the second step in dichloromethane (4 mL)
were added triethylamine (64 mg, 0.52 mmol),
N,N-dimethylaminopyridine (64 mg, 0.52 mmol) and 4-nitrophenyl
chloroformate (63 mg, 0.31 mmol) at room temperature, and the
reaction mixture was stirred at the same temperature for 2.5 hours.
The reaction mixture was diluted with ethyl acetate and washed with
a saturated aqueous solution of sodium bicarbonate and brine. The
organic layer was dried over anhydrous magnesium sulfate and
concentrated. The resulting residue was purified by silica gel
column chromatography (Kanto silica gel 60N, 40-100 .mu.m; ethyl
acetate:hexane=10:90) to give the title compound (97 mg, 89%) as a
colorless oil.
[1062] ESI-MS m/z 1055 (M+Na).sup.+.
Fourth Step
(8E,12E,14E)-6-Methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-y-
l)carbonyl)oxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-tri-
en-11-olide (Compound 85-4)
[1063] ##STR151##
[1064] To a solution of Compound 85-3
(8E,12E,14E)-6-methoxy-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carbox-
y-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide
(30 mg, 29 .mu.mol) obtained in the third step in tetrahydrofuran
(2 mL) were added triethylamine (11 mg, 0.12 mmol) and
1-methylpiperazine (5.8 mg, 58 .mu.mol) at room temperature, and
the reaction mixture was stirred at the same temperature for one
hour. The reaction mixture was diluted with ethyl acetate and
washed with a saturated aqueous solution of sodium bicarbonate and
brine. The organic layer was dried over anhydrous magnesium
sulfate, filtrated and concentrated. The resulting residue was
purified by silica gel column chromatography (Kanto silica gel 60N,
40-100 .mu.m; methanol:dichloromethane=3:97) to give the title
compound (26 mg, 89%) as a colorless oil. ESI-MS m/z 994
(M+H).sup.+. .mu.Fifth Step
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4--
methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olid-
e (Compound 85)
[1065] ##STR152##
[1066] To a solution of Compound 85-4
(8E,12E,14E)-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1--
yl)carbonyl)oxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-tr-
ien-11-olide (25 mg, 25 .mu.mol) obtained in the fourth step in
tetrahydrofuran (3 mL) was added tetrabutylammonium fluoride (83
.mu.l, 1.0 M tetrahydrofuran solution) at room temperature, then
the reaction mixture was stirred at the same temperature for 1.5
hours. The reaction mixture was diluted with ethyl acetate and
washed with a saturated aqueous solution of sodium bicarbonate and
brine. The organic layer was dried over anhydrous magnesium
sulfate, filtrated and concentrated. The resulting residue was
purified by thin layer chromatography (Fuji Silysia, NH Silica gel
Plate; methanol:dichloromethane=5:95) to give the title compound
(11 mg, 67%) as a colorless oil.
[1067] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.21(3H,s),1.34(3H,s),
1.22-1.69(8H,m),1.78(3H,s),1.86(1H,dd,J=5.6,14.0 Hz),2.29
(3H,s),2.36-2.44(4H,m),2.45-2.60(3H,m),2.67(1H,dd,J=2.4, 8.0 Hz),
2.86-2.92(1H,m),3.34(3H,s),3.44-3.58(5H,m),3.78-3.86(1H,m),5.01(1H,d,J=9.-
6 Hz),5.06(1H,d,J=11.2 Hz),5.56 (1H,dd,J=9.6,15.2
Hz),5.73(1H,dd,J=10.0,15.2 Hz),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=9.2 Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 651
(M+H).sup.+.
Example 86
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((pi-
perazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 86)
[1068] ##STR153##
[1069] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1070] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.22(3H,s),1.22-1.82
(8H,m),1.34(3H,s),1.77(3H,s),1.86(1H,dd,J=6.0,14.0
Hz),2.44-2.62(3H,m),2.66(1H,dd,J=2.0,8.0
Hz),2.70-2.82(4H,m),2.89(1H, dt,J=2.4,5.6 Hz)3.25-3.36(3H,covered
with CD.sub.3OD),3.38-3.55 (5H,m),3.78-3.86(1H,m),5.02(1H,d,J=9.6
Hz),5.06(1H,d, J=10.8 Hz),5.57(1H,dd,J=9.6,15.6
Hz),5.73(1H,dd,J=9.6,15.6 Hz), 5.86(1H,d,J=15.6
Hz),6.13(1H,d,J=11.2 Hz),6.52(1H,dd,J=11.2, 15.6 Hz); ESI-MS m/z
637 (M+H).sup.+.
Example 87
(8E,12E,14E)-7-(N-(2-(N',N'-Diethylamino)ethyl)carbamoyloxy)-3,16,21-trihy-
droxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-
-11-olide (Compound 87)
[1071] ##STR154##
[1072] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1073] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.0 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.06(6H,t,J=7.2 Hz),
1.22(3H,s),1.22-1.70(8H,m),1.34(3H,s),1.78(3H,s),1.86(1H,dd,
J=5.2,14.0 Hz),2.44-2.64(9H,m),2.66(1H,dd,J=2.0,8.0 Hz),2.89
(1H,dt,J=2.4,6.0 Hz),3.21(2H,t,J=7.2 Hz)3.25-3.36(3H,covered with
CD.sub.3OD),3.48-3.56(1H,m),3.77-3.85(1H,m),4.97(1H,d, J=9.6
Hz),5.06(1H,d,J=10.8 Hz),5.54(1H,dd,J=10.0,15.2 Hz),5.71
(1H,dd,J=9.6,15.6 Hz),5.86(1H,d,J=15.6 Hz),6.13(1H,d, J=10.8
Hz),6.52(1H,dd,J=11.2,15.6 Hz); ESI-MS m/z 667 (M+H).sup.+.
Example 88
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-(N-m-
ethyl-N-(1-methylpiperidin-4-yl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-t-
rien-11-olide (Compound 88)
[1074] ##STR155##
[1075] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1076] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.4 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.2
Hz),1.17-1.69 (16H,m),
1.72-1.90(6H,m),2.10-2.26(2H,m),2.33(3H,s),2.44-2.62(3H,m),
2.66(1H,dd,J=2.4,8.0 Hz),2.82(3H,s),2.89(1H,dt,J=2.4,6.0 Hz),
2.95-3.03(2H,m),3.35(3H,s),3.52(1H,dt,J=4.4,8.0
Hz),3.78-3.85(1H,m),3.92-4.04(1H,m),5.03(1H,d,J=10.0 Hz),5.06(1H,d,
J=10.4 Hz),5.56(1H,dd,J=10.0,15.2 Hz),5.73(1H,dd,J=9.6, 15.2
Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,
J=10.8,15.2 Hz); ESI-MS m/z 679 (M+H).sup.+.
Example 89
(8E,12E,14E)-7-((4-(N,N-Dimethylamino)piperidin-1-yl)carbonyl)oxy-3,16,21--
trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14--
trien-11-olide (Compound 89)
[1077] ##STR156##
[1078] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1079] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.0 Hz), 0.89(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.17-1.68 (16H,m),1.78
(3H,s),1.81-1.94(3H,m),2.29(6H,s),2.34-2.63(4H,m),2.67
(1H,dd,J=2.4,8.0 Hz),2.73-2.89(2H,m),2.89(1H,dt,J=2.4,6.0 Hz),
3.33(3H,s),3.52(1H,dt,J=4.4,7.6
Hz),3.78-3.85(1H,m),4.10-4.30(2H,m),5.01(1H,d,J=9.2
Hz),5.06(1H,d,J=10.8 Hz),5.56 (1H,dd,J=10.0,15.2
Hz),5.73(1H,dd,J=9.6,15.2 Hz),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 679
(M+H).sup.+.
Example 90
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4--
propylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11--
olide (Compound 90)
[1080] ##STR157##
[1081] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1082] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.84-0.92(9H,m),0.94 (3H,t,J=7.2
Hz),1.24(3H,s),1.34(3H,s),1.22-1.69 (10H,m),1.78 (3H,d,J=0.8
Hz),1.82-1.90(3H,m),2.40-2.72 (10H,m),2.89(1H,dt, J=2.0,6.0
Hz),3.24-3.36(3H,covered with CD.sub.3OD),3.44-3.60
(5H,m),3.78-3.86(1H,m),5.03(1H,d,J=9.6 Hz),5.07(1H,d, J=10.8
Hz),5.56(1H,dd,J=9.6,15.2 Hz),5.74(1H,dd,J=9.6,15.2 Hz),
5.87(1H,d,J=15.6 Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8, 15.6
Hz);ESI-MS m/z 693 (M+H).sup.+.
Example 91
(8E,12E,14E)-7-((4-Butylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-
-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (Compound 91)
[1083] ##STR158##
[1084] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1085] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.86-0.98 (12H,m), 1.23(3H,brs),1.34(3H,s),1.22-1.70
(12H,m),1.78(3H,d,J=0.8 Hz), 1.82-1.89(3H,m),2.44-2.74
(10H,m),2.89(1H,dt,J=2.0,6.0 Hz),
3.30(3H,s),3.42-3.58(5H,m),3.79-3.85(1H,m),5.03(1H,d, J=9.2
Hz),5.07(1H,d,J=10.4 Hz),5.56(1H,dd,J=10.0,15.2 Hz),5.74
(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d, J=11.2
Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 707 (M+H).sup.+.
Example 92
(8E,12E,14E)-7-((4-Cyclopropylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trih-
ydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trie-
n-11-olide (Compound 92)
[1086] ##STR159##
[1087] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1088] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.38-0.42(2H,m), 0.47-0.52(2H,m),0.88(3H,d,J=6.4
Hz),0.90(3H,d,J=7.2 Hz), 0.94(3H,t,J=7.2
Hz),1.23(3H,s),1.34(3H,s),1.22-1.68(9H,m), 1.78(3H,d,J=0.8
Hz),1.80-1.92(3H,m),2.44-2.60(3H,m),2.66 (1H,dd,J=2.0,7.6
Hz),2.74-2.87(4H,m),2.89(1H,dt,J=1.6, 5.6
Hz),3.33(3H,s),3.44-3.60(5H,m),3.78-3.86(1H,m),5.03(1H,d, J=9.6
Hz),5.06(1H,d,J=10.4 Hz),5.56(1H,dd,J=10.0,15.6 Hz),5.74
(1H,dd,J=10.0,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d, J=11.2
Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 691 (M+H).sup.+.
Example 93
(8E,12E,14E)-7-((4-Cyclobutylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihy-
droxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-
-11-olide (Compound 93)
[1089] ##STR160##
[1090] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1091] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.23(3H,s),1.34(3H,s), 1.22-1.72
(10H,m),1.78(3H,s),1.80-1.90(5H,m),2.02-2.10(2H,m),
2.41-2.60(7H,m),2.67(1H,dd,J=2.4,8.0 Hz),2.86-2.94(2H,m),
3.24-3.36(3H,covered with CD.sub.3OD),3.44-3.60(5H,m),3.78-3.86
(1H,m),5.03(1H,dd,J=2.0,9.6 Hz),5.07(1H,d,J=10.8 Hz),5.56(1H,
dd,J=10.0,15.2 Hz),5.74(1H,dd,J=9.6,15.6 Hz),5.87(1H,d, J=15.2
Hz),6.14(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 705
(M+H).sup.+.
Example 94
(8E,12E,14E)-7-((4-Cyclopentylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trih-
ydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trie-
n-11-olide (Compound 94)
[1092] ##STR161##
[1093] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1094] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.23(3H,s),1.34(3H,s), 1.36-1.72 (16H,m),1.78(3H,d,J=0.8
Hz),1.82-1.90(3H,m),2.44-2.60(3H,m),2.64-2.70(3H,m),2.73-2.82(2H,m),2.84--
2.94(2H,m), 3.24-3.36(3H,covered with
CD.sub.3OD),3.44-3.60(5H,m),3.78-3.86 (1H,m),5.04(1H,d,J=11.6
Hz),5.07(1H,d,J=10.8 Hz),5.56(1H,dd, J=9.6,15.6
Hz),5.74(1H,dd,J=10.0,15.2 Hz),5.87(1H,d,J=15.2 Hz),
6.13(1H,d,J=11.2 Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 719
(M+H).sup.+.
Example 95
(8E,12E,14E)-7-((4-Cyclohexylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihy-
droxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-
-11-olide (Compound 95)
[1095] ##STR162##
[1096] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1097] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.0 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.23(3H,s),1.34(3H,s), 1.12-1.68(18H,m),1.78(3H,d,J=0.8
Hz),1.75-1.89(3H,m),2.42-2.60(4H,m),2.64-2.72(3H,m),2.75-2.82(2H,m),2.89(-
1H,dt,J=1.2, 5.2 Hz),3.26-3.36(3H,covered with
CD.sub.3OD),3.42-3.56(5H,m), 3.78-3.86(1H,m),5.03(1H,dd,J=3.2,9.6
Hz),5.07(1H,d,J=10.8 Hz), 5.56(1H,dd,J=10.0,15.2
Hz),5.74(1H,dd,J=10.0,14.8 Hz),5.87 (1H,d,J=15.2
Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=11.2, 15.2 Hz); ESI-MS m/z
733 (M+H).sup.+.
Example 96
(8E,12E,14E)-3,16,21-Trihydroxy-7-((4-isopropylhomopiperazin-1-yl)carbonyl-
)oxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien--
11-olide (Compound 96)
[1098] ##STR163##
[1099] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1100] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.0 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.03(6H,d,J=6.4 Hz),
1.24(3H,s),1.34(3H,s),1.22-1.69(8H,m),1.78(3H,s),1.76-1.90
(3H,m),2.44-2.74(8H,m),2.86-2.94(2H,m),3.33(3H,s),3.44-3.60
(5H,m),3.79-3.86(1H,m),5.03(1H,dd,J=4.4,9.6 Hz),5.07(1H,d, J=10.8
Hz),5.56(1H,dd,J=10.8,16.0 Hz),5.74(1H,dd,J=9.6, 15.6
Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=11.6 Hz),6.53(1H,dd,
J=10.8,15.2 Hz); ESI-MS m/z 693 (M+H).sup.+.
Example 97
(8E,12E,14E)-3,16,21-Trihydroxy-7-((4-isobutylhomopiperazin-1-yl)carbonyl)-
oxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-1-
1-olide (Compound 97)
[1101] ##STR164##
[1102] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1103] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.84-0.95 (15H,m),
1.26(3H,s),1.34(3H,s),1.22-1.76(9H,m),1.78(3H,s),1.78-1.90
(3H,m),2.23(2H,d,J=6.8 Hz),2.44-2.72(8H,m),2.89(1H,dt,J=2.0, 5.2
Hz),3.24-3.38(3H,covered with CD.sub.3OD),3.42-3.58(5H,m),
3.78-3.86(1H,m),5.03(1H,d,J=9.6 Hz),5.07(1H,d,J=10.4 Hz),5.56
(1H,dd,J=9.6,15.2 Hz),5.74(1H,dd,J=9.2,14.8 Hz),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 707
(M+H).sup.+.
Example 98
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4--
(morpholin-4-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-tri-
en-11-olide (Compound 98)
[1104] ##STR165##
[1105] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1106] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=5.2 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.21(3H,s),1.34(3H,s), 1.24-1.68 (10H,m),1.78(3H,d,J=1.2
Hz),1.82-1.96(3H,m),2.32-2.43(1H,m),2.44-2.62(7H,m),2.67(1H,dd,J=2.4,8.0
Hz),2.74-2.92(3H,m),3.32(3H,s),3.52(1H,dt,J=3.6,8.0 Hz),3.64-3.74
(4H,m),3.78-3.86(1H,m),4.08-4.28(2H,m),5.01(1H,d,J=9.6 Hz),
5.06(1H,d,J=10.8 Hz),5.54(1H,dd,J=9.6,15.2 Hz),5.73(1H,dd,
J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=11.2 Hz),6.53
(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 721 (M+H).sup.+.
Example 99
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4--
(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-tr-
ien-11-olide (Compound 99)
[1107] ##STR166##
[1108] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1109] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=5.6 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.22(3H,s),1.34(3H,s), 1.23-1.70
(10H,m),1.78(3H,s),1.79-1.90(5H,m),1.92-2.00(2H,m),
2.20-2.30(1H,m),2.44-2.68(8H,m),2.76-2.92(3H,m),3.24-3.36 (3H,
covered with CD.sub.3OD),3.52(1H,dt,J=4.8,8.0 Hz),3.77-3.86
(1H,m),4.04-4.24(2H,m),5.01(1H,d,J=10.0 Hz),5.06(1H,d, J=10.4
Hz),5.56(1H,dd,J=9.6,15.2 Hz),5.73(1H,dd,J=9.6,15.2 Hz),
5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8, 15.2
Hz); ESI-MS m/z 705 (M+H).sup.+.
Example 100
(8E,12E,14E)-3,16,21-Trihydroxy-7-((4-(4-hydroxypiperidin-1-yl)piperidin-1-
-yl)carbonyl)oxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,-
12,14-trien-11-olide (Compound 100)
[1110] ##STR167##
[1111] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1112] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.0 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.21(3H,s),1.34(3H,s), 1.22-1.69
(12H,m),1.78(3H,s),1.82-1.93(5H,m),2.28-2.38(2H,m),
2.43-2.58(4H,m),2.67(1H,dd,J=2.0,7.6 Hz),2.72-2.83(5H,m),
3.24-3.39(3H, covered with CD.sub.3OD),3.52(1H,dt,J=4.8,8.0 Hz),
3.56-3.64(1H,m),3.78-3.86(1H,m),4.10-4.30(2H,m),5.00(1H,d, J=9.6
Hz),5.06(1H,d,J=10.8 Hz),5.55(1H,dd,J=10.4,15.2 Hz),
5.73(1H,dd,J=10.0,15.6 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d, J=10.8
Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 735 (M+H).sup.+.
Example 101
(8E,12E,14E)-7-(N-(3-(N',N'-Dimethylamino)propyl)-N-methylcarbamoyloxy)-3,-
16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,-
12,14-trien-11-olide (Compound 101)
[1113] ##STR168##
[1114] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1115] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.0 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.22(3H,s),1.34(3H,s), 1.20-1.78
(10H,m),1.78(3H,s),1.86(1H,dd,J=6.3,14.5 Hz),2.24
(6H,s),2.31(2H,t,J=8.8 Hz),2.44-2.60(3H,m),2.66(1H,dd,J=2.4, 8.0
Hz),2.85-2.96(4H,m),3.22-3.38(5H,covered with CD.sub.3OD),
3.52(1H,dd,J=3.6,8.0 Hz),3.78-3.85(1H,m),5.01(1H,d,J=10.0 Hz),
5.06(1H,d,J=10.4 Hz),5.55(1H,dd,J=9.6,15.2 Hz),5.74(1H,dd,
J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=10.8 Hz),6.53
(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 667 (M+H).sup.+.
Example 102
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-(N-m-
ethyl-N-(2-(morpholin-4-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14--
trien-11-olide (Compound 102)
[1116] ##STR169##
[1117] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1118] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.22(3H,s),1.34(3H,s),
1.23-1.69(8H,m),1.78(3H,s),1.86(1H,dd,J=4.6,12.7
Hz),2.44-2.56(9H,m),2.66(1H,dd,J=2.4,7.6
Hz),2.86-2.96(4H,m),3.22-3.38(2H,covered with
CD.sub.3OD),3.34(3H,s),3.52(1H,dt,J=4.0, 8.0
Hz),3.62-3.72(4H,m),3.78-3.84(1H,m),5.01(1H,d,J=10.0 Hz),
5.06(1H,d,J=10.8 Hz),5.55(1H,dd,J=10.0,15.2 Hz),5.68-5.79
(1H,m),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=10.4 Hz),6.53(1H,dd,
J=10.8,15.2 Hz);ESI-MS m/z 695 (M+H).sup.+.
Example 103
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-(N-m-
ethyl-N-(2-(pyrrolidin-1-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-
-trien-11-olide (Compound 103)
[1119] ##STR170##
[1120] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1121] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.22(3H,s),1.34(3H,s), 1.23-1.68(8H,m),1.78(3H,d,J=0.8
Hz),1.78-1.83(4H,m),1.86 (1H,dd,J=5.4,13.1 Hz),2.44-2.68
(10H,m),2.86-2.97(4H,m),3.34
(3H,s),3.40-3.48(2H,m),3.52(1H,dt,J=4.0,7.6 Hz),3.78-3.86
(1H,m),5.00(1H,d,J=9.6 Hz),5.06(1H,d,J=10.4 Hz),5.55(1H,dd,
J=10.0,14.8 Hz),5.74(1H,dd,J=9.6,14.8 Hz),5.87(1H,d,J=15.2 Hz),
6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 679
(M+H).sup.+.
Example 104
(8E,12E,14E)-7-(N-(3-(N',N'-Eiethylamino)propyl)-N-methylcarbamoyloxy)-3,1-
6,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,1-
2,14-trien-11-olide (Compound 104)
[1122] ##STR171##
[1123] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1124] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.4 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.05(6H,t,J=7.2 Hz), 1.22(3H,s),1.34(3H,s),1.20-1.82
(10H,m),1.78(3H,s),1.86 (1H,dd,J=5.6,14.4
Hz),2.42-2.60(9H,m),2.66(1H,dd,J=2.4, 8.0 Hz),
2.84-2.96(4H,m),3.22-3.40(5H,covered with CD.sub.3OD),
3.52(1H,dt,J=3.6,8.0 Hz),3.78-3.86(1H,m),5.01(1H,d,J=9.6 Hz),
5.06(1H,d,J=10.4 Hz),5.55(1H,dd,J=10.0,15.6 Hz),5.74(1H,dd,
J=9.6,15.6 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=10.0 Hz),6.53
(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 695 (M+H).sup.+.
Example 105
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4--
methylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11--
olide (Compound 105)
[1125] ##STR172##
[1126] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1127] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.29(4H,m),1.34 (3H,s),1.38-1.69(7H,m),1.78(3H,d,J=0.8
Hz),1.83-1.93(3H,m),
2.35(3H,s),2.45-2.65(7H,m),2.67(1H,dd,J=2.4,8.0 Hz),2.89
(1H,dt,J=2.4,6.0 Hz),3.32(1.5H, s),3.33(1.5H, s),3.46-3.62
(5H,m),3.79-3.86(1H,m),5.01-5.06(1H,m),5.07(1H,d,J=10.4 Hz),
5.56(1H,dd,J=9.6,15.2 Hz),5.74(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,
J=15.2 Hz),6.13(1H,dd,J=1.2,11.2 Hz),6.53(1H,dd,J=10.8, 15.2 Hz);
ESI-MS m/z 665 (M+H).sup.+.
Example 106
(8E,12E,14E)-7-((4-Ethylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-m-
ethoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 106)
[1128] ##STR173##
[1129] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1130] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.11(3H,t,J=7.6 Hz),
1.20-1.29(4H,m),1.34(3H,s),1.37-1.69(7H,m),1.78(3H,d, J=0.8
Hz),1.86(1H,dd,J=5.2,14.0 Hz),2.41-2.63(9H,m),2.67 (1H,dd,J=2.4,8.0
Hz),2.89(1H,dt,J=2.4,6.0 Hz),3.32(3H,s),
3.43-3.59(5H,m),3.79-3.86(1H,m),5.01(1H,d,J=9.6 Hz),5.06
(1H,d,J=10.8 Hz),5.56(1H,dd,J=9.6,15.2 Hz),5.73(1H,dd,J=9.6, 15.2
Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,dd,J=1.2,10.8 Hz),6.53
(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 665 (M+H).sup.+.
Example 107
(8E,12E,14E)-7-((4-Ethylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-
-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (Compound 107)
[1131] ##STR174##
[1132] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1133] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.08(3H,t,J=7.2 Hz),
1.19-1.29(4H,m),1.34(3H,s),1.38-1.70(7H,m),1.78(3H,d, J=0.8
Hz),1.82-1.90(3H,m),2.45-2.73 (10H,m),2.89(1H,dt,J=2.4, 6.0
Hz),3.33(1.5H, s),3.33(1.5Hs),3.46-3.62(5H,m),3.79-3.85
(1H,m),5.00-5.06(1H,m),5.07(1H,d,J=10.8 Hz),5.56(1H,dd, J=10.0,15.2
Hz),5.74(1H,dd,J=10.0,15.2 Hz),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 679
(M+H).sup.+.
Example 108
(8E,12E,14E)-7-(N-(2-(N',N'-Dimethylamino)ethyl)-N-methylcarbamoyloxy)-3,1-
6,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,1-
2,14-trien-11-olide (Compound 108)
[1134] ##STR175##
[1135] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1136] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz), 0.94(3H,t,J=7.6 Hz),
1.19-1.29(4H,m), 1.34(3H,s), 1.38-1.70(7H,m), 1.78(3H,d,J=0.8 Hz),
1.86(1H,dd,J=5.2,14.0 Hz), 2.27(6H,s), 2.45-2.63(5H,m),
2.67(1H,dd,J=2.4,8.0 Hz), 2.87-2.97(4H,m), 3.30-3.36(3H,m),
3.37-3.46(2H,m), 3.52(1H,td,J=4.4,8.0 Hz), 3.78-3.85(1H,m),
5.00(1H,d,J=9.6 Hz), 5.06(1H,d,J=10.4 Hz), 5.55(1H,dd,J=9.6, 15.2
Hz),5.69-5.79(1H,m),5.87(1H,d,J=15.2 Hz),6.13(1H,d, J=10.8
Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 653 (M+H).sup.+.
Example 109
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4--
(piperidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-tri-
en-11-olide (Compound 109)
[1137] ##STR176##
[1138] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1139] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.29(4H,m),1.31-1.69(18H,m),1.78(3H,s),1.83-1.93(3H,m),2.41-2.61-
(8H,m),2.67 (1H,dd,J=2.4,8.0
Hz),2.70-2.88(2H,m),2.89(1H,dt,J=2.0,6.0 Hz),
3.33(3H,s),3.52(1H,td,J=4.4,8.0
Hz),3.78-3.85(1H,m),4.11-4.29(2H,m),5.00(1H,d,J=9.6
Hz),5.06(1H,d,J=10.4 Hz),5.56 (1H,dd,J=9.6,15.2
Hz),5.73(1H,dd,J=9.6,15.2 Hz),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 719
(M+H).sup.+.
Example 110
(8E,12E,14E)-3,16,21-Trihydroxy-7-(4-(isopropylpiperazin-1-yl)carbonyl)oxy-
-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (Compound 110)
[1140] ##STR177##
[1141] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1142] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.07(6H,d,J=6.8 Hz), 1.20-1.29(4H,m),1.32-1.76
(10H,m),1.78(3H,d,J=0.8 Hz),1.86 (1H,dd,J=5.6,14.0
Hz),2.45-2.63(7H,m),2.64-2.75(2H,m),2.89 (1H,dt,J=2.4,6.0
Hz),3.32(3H,s),3.42-3.59(5H,m),3.78-3.86 (1H,m),5.01(1H,d,J=9.6
Hz),5.06(1H,d,J=10.4 Hz),5.56(1H,dd, J=9.6,15.2
Hz),5.73(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),
6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 679
(M+H).sup.+.
Example 111
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4--
propylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olid-
e (Compound 111)
[1143] ##STR178##
[1144] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1145] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=7.2 Hz),0.93(3H,t,J=7.2
Hz),0.94(3H,t,J=7.2 Hz),
1.20-1.30(4H,m),1.34(3H,s),1.39-1.69(9H,m),1.78(3H,d, J=1.2
Hz),1.87(1H,dd,J=5.2,14.0
Hz),2.31-2.37(2H,m),2.40-2.63(7H,m),2.67(1H,dd,J=2.4,8.0
Hz),2.90(1H,dt,J=2.0,6.0 Hz),
3.32(3H,s),3.42-3.60(5H,m),3.79-3.86(1H,m),5.02(1H,d, J=9.6
Hz),5.07(1H,d,J=10.4 Hz),5.57(1H,dd,J=10.0,15.2 Hz),5.74
(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.14(1H,d, J=11.2
Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 679 (M+H).sup.+.
Example 112
(8E,12E,14E)-7-((4-Butylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-m-
ethoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 112)
[1146] ##STR179##
[1147] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1148] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),0.94(3H,t,J=7.2 Hz), 1.19-1.29(4H,m),1.29-1.69
(14H,m),1.78(3H,d,J=0.8 Hz),1.86 (1H,dd,J=5.2,14.0
Hz),2.34-2.39(2H,m),2.40-2.63(7H,m),2.67 (1H,dd,J=2.4,8.0
Hz),2.89(1H,dt,J=2.0,6.0 Hz),3.32(3H,s),
3.41-3.60(5H,m),3.79-3.85(1H,m),5.01(1H,d,J=10.0 Hz),5.06
(1H,d,J=10.8 Hz),5.56(1H,dd,J=10.0,15.2 Hz),5.73(1H,dd, J=9.6,15.2
Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=11.2 Hz),6.53
(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 693 (M+H).sup.+.
Example 113
(8E,12E,14E)-3,16,21-Trihydroxy-7-((4-isobutylpiperazin-1-yl)carbonyl)oxy--
6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-ol-
ide (Compound 113)
[1149] ##STR180##
[1150] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1151] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.91(6H,d,J=6.4
Hz),0.94(3H,t,J=7.6 Hz),
1.19-1.29(4H,m),1.34(3H,s),1.39-1.69(7H,m),1.76-1.90(5H,m),
2.11(2H,d,J=7.2 Hz),2.33-2.41(4H,m),2.45-2.63(3H,m),2.67
(1H,dd,J=2.4,8.0 Hz),2.89(1H,dt,J=2.4,6.0 Hz),3.32(3H,s),
3.40-3.58(5H,m),3.79-3.86(1H,m),5.01(1H,d,J=9.6 Hz),5.06
(1H,d,J=10.8 Hz),5.56(1H,dd,J=10.0,15.2 Hz),5.73(1H,dd, J=9.6,15.2
Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=10.8 Hz),6.53
(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 693 (M+H).sup.+.
Example 114
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-7-((4-(2-methoxyethyl)piperazin--
1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-tri-
en-11-olide (Compound 114)
[1152] ##STR181##
[1153] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1154] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.29(4H,m),1.34 (3H,s),1.38-1.69(7H,m),1.78(3H,d,J=0.8
Hz),1.86(1H,dd,J=5.6, 14.0 Hz),2.44-2.63(9H,m),2.67(1H,dd,J=2.4,8.0
Hz),2.89(1H,dt, J=2.0,6.0
Hz),3.32(3H,s),3.33(3H,s),3.41-3.59(7H,m),3.78-3.85(1H,m),5.01(1H,d,J=9.6
Hz),5.06(1H,d,J=10.8 Hz),5.56 (1H,dd,J=10.0,15.2
Hz),5.73(1H,dd,J=9.6,15.2 Hz),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 695
(M+H).sup.+.
Example 115
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4--
(tetrahydropyran-4-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,-
14-trien-11-olide (Compound 115)
[1155] ##STR182##
[1156] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1157] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.29(4H,m),1.34
(3H,s),1.38-1.69(9H,m),1.77-1.85(5H,m),1.86(1H,dd,J=5.2, 14.0
Hz),2.43-2.63(8H,m),2.67(1H,dd,J=2.4,8.0 Hz),2.89(1H,dt, J=2.4,6.0
Hz),3.32(3H,s),3.35-3.43(2H,m),3.43-3.59(5H,m),
3.78-3.85(1H,m),3.98(2H,dd,J=4.4,11.2 Hz),5.01(1H,d,J=10.0
Hz),5.06(1H,d,J=10.4 Hz),5.56(1H,dd,J=10.0,15.2 Hz),5.73
(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,dd,J=1.2, 11.2
Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 721 (M+H).sup.+.
Example 116
(8E,12E,14E)-7-((4-Cyclopropylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydro-
xy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-
-olide (Compound 116)
[1158] ##STR183##
[1159] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1160] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.40-0.46(2H,m), 0.46-0.53(2H,m),0.89(3H,d,J=6.4
Hz),0.90(3H,d,J=6.8 Hz), 0.94(3H,t,J=7.6
Hz),1.19-1.29(4H,m),1.34(3H,s),1.38-1.70 (8H,m),1.78(3H,d,J=0.8
Hz),1.86(1H,dd,J=5.2,14.0 Hz),2.45-2.63(7H,m),2.67(1H,dd,J=2.4,8.0
Hz),2.89(1H,dt,J=2.4,6.0 Hz),
3.32(3H,s),3.37-3.56(5H,m),3.78-3.85(1H,m),5.01(1H,d, J=9.6
Hz),5.06(1H,d,J=10.8 Hz),5.56(1H,dd,J=9.6,15.2 Hz),5.73
(1H,dd,J=10.0,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,dd,J=1.2, 10.8
Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 677 (M+H).sup.+.
Example 117
(8E,12E,14E)-7-((4-Cyclobutylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydrox-
y-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11--
olide (Compound 117)
[1161] ##STR184##
[1162] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1163] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.29(4H,m),1.34 (3H,s),1.39-1.78(9H,m),1.78(3H,d,J=0.8
Hz),1.83-1.95(3H,m), 2.02-2.10(2H,m),2.31(4H,t,J=4.8
Hz),2.45-2.63(3H,m),2.67 (1H,dd,J=2.4,8.0
Hz),2.72-2.81(1H,m),2.89(1H,dt,J=2.0,6.0 Hz),
3.31(3H,s),3.40-3.58(5H,m),3.78-3.85(1H,m),5.01(1H,d, J=9.6
Hz),5.06(1H,d,J=10.8 Hz),5.56(1H,dd,J=10.0,15.2 Hz),5.73
(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d, J=11.2
Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 691 (M+H).sup.+.
Example 118
(8E,12E,14E)-7-((4-Cyclopentylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydro-
xy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-
-olide (Compound 118)
[1164] ##STR185##
[1165] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1166] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.19-1.29(4H,m),1.34 (3H,s),1.36-1.77 (13H,m),1.78(3H,d,J=0.8
Hz),1.86(1H,dd,J=5.2, 14.0
Hz),1.86-1.95(2H,m),2.44-2.63(8H,m),2.67(1H,dd,J=2.4, 8.0
Hz),2.89(1H,dt,J=2.0,6.0 Hz),3.32(3H,s),3.42-3.59(5H,m),
3.78-3.85(1H,m),5.01(1H,d,J=10.0 Hz),5.06(1H,d,J=10.4 Hz),
5.56(1H,dd,J=9.6,15.2 Hz),5.73(1H,dd,J=9.6,15.2 Hz),5.87(1H,d,
J=15.2 Hz),6.13(1H,dd,J=1.2,10.8 Hz),6.53(1H,dd,J=11.2, 15.2 Hz);
ESI-MS m/z 705 (M+H).sup.+.
Example 119
(8E,12E,14E)-7-((4-Cyclohexylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydrox-
y-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11--
olide (Compound 119)
[1167] ##STR186##
[1168] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1169] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.09-1.33 (10H,m),1.34 (3H,s),1.39-1.69(7H,m),1.78(3H,d,J=0.8
Hz)1.78-1.93(5H,m),
2.27-2.35(1H,m),2.45-2.65(7H,m),2.67(1H,dd,J=2.4,8.0 Hz),
2.89(1H,dt,J=2.4,6.0
Hz),3.32(3H,s),3.39-3.58(5H,m),3.79-3.86(1H,m),5.01(1H,d,J=9.6
Hz),5.07(1H,d,J=10.8 Hz),5.57 (1H,dd,J=10.0,15.2
Hz),5.74(1H,dd,J=9.6,15.2 Hz),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 719
(M+H).sup.+.
Example 120
(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydro-
xy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-
-olide (Compound 120)
[1170] ##STR187##
[1171] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1172] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.30(4H,m),1.34 (3H,s),1.38-1.75 (17H,m),1.78(3H,d,J=0.8
Hz),1.79-1.86(2H,m), 1.86(1H,dd,J=5.2,14.0
Hz),2.45-2.64(8H,m),2.67(1H,dd,J=2.4, 8.0 Hz),2.89(1H,dt,J=2.4,6.0
Hz),3.32(3H,s),3.39-3.57(5H,m), 3.78-3.85(1H,m),5.01(1H,d,J=9.6
Hz),5.06(1H,d,J=10.8 Hz),5.56 (1H,dd,J=9.6,15.2
Hz),5.73(1H,dd,J=9.6,15.2 Hz),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 733
(M+H).sup.+.
Example 121
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-(((1-
S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-18,19-epoxy-
tricosa-8,12,14-trien-1-olide (Compound 121)
[1173] ##STR188##
[1174] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1175] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.20-1.29(4H,m),1.34
(3H,s),1.40-1.69(7H,m),1.74-1.82(4H,m),1.83-1.93(2H,m),2.38 (1.2H,
s),2.41(1.8H,
s),2.44-2.63(3H,m),2.65-2.71(2H,m),2.75-2.85(1H,m),2.89(1H,dt,J=2.0,6.0
Hz),3.20-3.30(1H,m),3.33 (1.8H, s), 3.34(1.2H,
s),3.46-3.59(3H,m),3.79-3.85(1H,m),4.32 (0.4H, s),4.42(0.6H,
s),4.98-5.04(1H,m),5.06(1H,d,J=10.4 Hz), 5.56(1H,dd,J=9.6,15.2
Hz),5.74(1H,dd,J=9.6,15.2 Hz),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 663
(M+H).sup.+.
Example 122
(8E,12E,14E)-7-(((1S,4S)-5-Ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbon-
yl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxyt-
ricosa-8,12,14-trien-11-olide (Compound 122)
[1176] ##STR189##
[1177] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1178] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.05-1.13(3H,m),1.20-1.30(4H,m),1.34(3H,s),1.38-1.69(7H,m),1.78(3H,d,-
J=0.8 Hz),
1.83-1.91(2H,m),2.45-2.72(8H,m),2.82-2.93(2H,m),3.20-3.31
(1H,m),3.33(1.5H, s),3.34(1.5H, s),3.50-3.64(3H,m),3.79-3.85
(1H,m),4.32(0.5H, s),4.42(0.5H, s),4.98-5.04(1H,m),5.06(1H,d,
J=10.8 Hz),5.56(1H,dd,J=10.0,15.2 Hz),5.74(1H,dd,J=10.0, 15.2
Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,dd,J=1.2,10.8 Hz),6.53
(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 677 (M+H).sup.+.
Example 123
(8E,12E,14E)-3,16,21-Trihydroxy-7-(((1S,4S)-5-isopropyl-2,5-diazabicyclo[2-
.2.1]heptan-2-yl)carbonyl)oxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-ep-
oxytricosa-8,12,14-trien-11-olide (Compound 123)
[1179] ##STR190##
[1180] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1181] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.05-1.11(6H,m),1.19-1.30(4H,m),1.34(3H,s),1.37-1.69(7H,m),1.73-1.90(-
5H,m),2.45-2.65(6H,m),2.67(1H,dd,J=2.4,8.0),2.89(1H,dt,J=2.0,6.0
Hz), 3.01-3.20(1H,m),3.18-3.29(1H,m),3.32-3.35(3H,m),3.52 (1H,td,
J=4.4,8.4 Hz),3.54-3.65(1H,m),3.76-3.86(2H,m),4.30(0.5H, s), 4.40
(0.5H, s),4.98-5.09(2H,m),5.57(1H,dd,J=9.6,15.2
Hz),5.70-5.79(1H,m),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=10.8 Hz),6.53
(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 691 (M+H).sup.+.
Example 124
(8E,12E,14E)-7-((4-(2-(N,N-Dimethylamino)ethyl)piperazin-1-yl)carbonyl)oxy-
-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-
-8,12,14-trien-11-olide (Compound 124)
[1182] ##STR191##
[1183] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1184] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.30(4H,m),1.34 (3H,s),1.37-1.69(7H,m),1.78(3H,d,J=0.8
Hz),1.86(1H,dd,J=5.2, 14.0
Hz),2.27(6H,s),2.43-2.48(4H,m),2.48-2.62(7H,m),2.67
(1H,dd,J=2.4,8.0 Hz),2.89(1H,dt,J=2.0,6.0 Hz),3.32(3H,s),
3.41-3.59(5H,m),3.78-3.85(1H,m),5.01(1H,d,J=9.6 Hz),5.06
(1H,d,J=10.8 Hz),5.56(1H,dd,J=10.0,15.2 Hz),5.73(1H,dd,J=10.0, 15.2
Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=10.8 Hz),6.53
(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 708 (M+H).sup.+.
Example 125
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4--
(1-methylpiperidin-4-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,1-
2,14-trien-11-olide (Compound 125)
[1185] ##STR192##
[1186] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1187] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.30(4H,m),1.34 (3H,s),1.39-1.69(9H,m),1.78(3H,d,J=1.2
Hz),1.83-1.90(3H,m),
1.98-2.07(2H,m),2.24-2.33(1H,m),2.25(3H,s),2.45-2.62(7H,m),
2.67(1H,dd,J=2.4,8.0
Hz),2.87-2.96(3H,m),3.32(3H,s),3.41-3.58(5H,m),3.79-3.86(1H,m),5.01(1H,d,-
J=9.6 Hz),5.06(1H,d,J=10.8 Hz),5.56(1H,dd,J=10.0,15.2
Hz),5.73(1H,dd,J=10.0,15.2 Hz), 5.87(1H,d,J=15.2
Hz),6.13(1H,dd,J=1.2,10.8 Hz),6.53(1H,dd, J=10.8,15.2 Hz); ESI-MS
m/z 734 (M+H).sup.+.
Example 126
(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4--
(pyridin-4-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-
-11-olide (Compound 126)
[1188] ##STR193##
[1189] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85.
[1190] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.19-1.29(4H,m),1.34 (3H,s),1.38-1.69(7H,m),1.78(3H,d,J=1.2
Hz),1.86(1H,dd,J=5.2, 14.0 Hz),2.45-2.63(3H,m),2.66(1H,dd,J=2.4,8.0
Hz),2.89(1H,dt, J=2.0,6.0
Hz),3.34(3H,s),3.40-3.47(4H,m),3.52(1H,td,J=4.4, 8.4
Hz),3.56-3.72(4H,m),3.80-3.87(1H,m),5.05(1H,d,J=9.2 Hz),
5.07(1H,d,J=10.4 Hz),5.58(1H,dd,J=10.0,15.2 Hz),5.76(1H,dd,
J=10.0,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,dd,J=1.2,11.2 Hz),
6.53(1H,dd,J=11.2,15.2 Hz),6.86(2H,d,J=6.4 Hz),8.02-8.04 (2H,m);
ESI-MS m/z 714 (M+H).sup.+.
Example 127
(8E,12E,14E)-6-Ethoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-m-
ethylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 127)
[1191] ##STR194##
[1192] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 85 except for using ethyl
trifluoromethanesulfonate in the first step. .sup.1H-NMR Spectrum
(CD.sub.3OD,400 MHz) .delta.(ppm): 0.88(3H,d,J=6.8 Hz),
0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6 Hz),1.16(3H,t,J=7.2 Hz),
1.22(3H,s),1.22-1.60(7H,m),1.34(3H,s),1.65(1H,dd,J=6.4, 14.0
Hz),1.78(3H,s),1.86(1H,dd,J=5.6,13.6 Hz),2.30(3H,s),
2.36-2.43(4H,m),2.43-2.69(4H,m),2.89(1H,dt,J=2.4,5.6 Hz),
3.43-3.61(7H,m),3.77-3.84(1H,m),4.98(1H,d,J=9.6 Hz),5.06
(1H,d,J=10.8 Hz),5.55(1H,dd,J=10.0,15.2 Hz),5.76(1H,dd,J=9.6, 15.2
Hz),5.86(1H,d,J=15.2 Hz),6.13(1H,d,J=11.2 Hz),6.52(1H,dd,
J=11.2,15.2 Hz); ESI-MS m/z 665 (M+H).sup.+.
Example 128
(8E,12E,14E)-6-Ethoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-(-
piperidin-1-yl)piperidin-1yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-
-11-olide (Compound 128)
[1193] ##STR195##
[1194] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 127.
[1195] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.0 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.17(3H,t,J=6.8 Hz), 1.22(3H,s),1.22-1.69
(16H,m),1.34(3H,s),1.78(3H,s),1.83-1.93
(3H,m),2.42-2.63(8H,m),2.67(1H,dd,J=2.4,7.6 Hz),2.70-2.92
(3H,m),3.49-3.62(3H,m),3.77-3.84(1H,m),4.13-4.27(2H,m),4.98
(1H,d,J=9.6 Hz),5.06(1H,d,J=10.4 Hz),5.54(1H,dd,J=10.0, 15.2
Hz),5.76(1H,dd,J=9.6,15.6 Hz),5.86(1H,d,J=15.2 Hz),6.13
(1H,d,J=10.0 Hz),6.52(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 733
(M+H).sup.+.
Example 129
(8E,12E,14E)-7-Acetoxy-6,16-dihydroxy-6,10,12,16,20-pentamethyl-3,21-bis(t-
riethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound
129)
[1196] ##STR196##
[1197] A solution of
(8E,12E,14E)-7-acetoxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-1-
8,19-epoxytricosa-8,12,14-trien-11-olide (221 mg, 0.4 mmol),
N,N-dimethylaminopyridine (25 mg, 0.2 mmol) and triethylamine (613
mg, 6 mmol) in dichloromethane (7 mL) was cooled to 5.degree. C., a
solution of chlorotriethylsilane (609 mg, 4 mmol) in
dichloromethane (3 mL) was added dropwise thereto, and the reaction
mixture was stirred at room temperature for one hour. The reaction
mixture was diluted with ethyl acetate, washed with water and a
saturated aqueous solution of sodium bicarbonate, dried over
anhydrous magnesium sulfate and evaporated. The resulting residue
was purified by silica gel column chromatography (Kanto silica gel
60N, 40 to 50 .mu.m; ethyl acetate-hexane, 1:9 to 1:4 to 1:3) to
give the title compound (320 mg, quantitative) as a colorless
oil.
[1198] ESI-MS m/z 803 (M+Na).sup.+.
Example 130
(8E,12E,14E)-3,6,16-Trihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy--
21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (Compound 130)
[1199] ##STR197## First Step
(8E,12E,14E)-7-Acetoxy-6,16-bis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl--
3,21-bis(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 130-1)
[1200] ##STR198##
[1201] To a solution of Compound 129
(8E,12E,14E)-7-acetoxy-6,16-dihydroxy-6,10,12,16,20-pentamethyl-3,21-bis(-
triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide (320 mg,
0.41 mmol) obtained in Example 129 and ethylvinyl ether (589 mg, 8
mmol) in dichloromethane (6 mL) was added a solution of pyridinium
p-toluenesulfonate (5 mg, 20 .mu.mol) in dichloromethane (1 mL) at
room temperature, and the reaction mixture was stirred at the same
temperature overnight. The reaction mixture was diluted with ethyl
acetate, washed with water and a saturated aqueous solution of
sodium bicarbonate, dried over anhydrous magnesium sulfate and
evaporated. The resulting residue was purified by silica gel column
chromatography (Kanto silica gel 60N, 40 to 50 .mu.m; ethyl
acetate-hexane, 1:9 to 1:7) to give the title compound (252 mg,
67%) as a colorless oil.
[1202] ESI-MS m/z 947 (M+Na).sup.+.
Second Step
(8E,12E,14E)-7-Acetoxy-6,16-bis(1-ethoxyethoxy)-3,21-dihydroxy-6,10,12,16,-
20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound
130-2)
[1203] ##STR199##
[1204] A solution of Compound 130-1
(8E,12E,14E)-7-acetoxy-6,16-bis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-
-3,21-bis(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide
(107 mg, 0.1156 mmol) obtained in the first step in tetrahydrofuran
(6 mL) was cooled to 5.degree. C., tetrabutylammonium fluoride (1.0
M tetrahydrofuran solution, 0.25 mL, 0.25 mmol) was added dropwise
thereto, and the reaction mixture was stirred at room temperature
for 1.5 hours. The reaction mixture was diluted with ethyl acetate
and then washed with water and a saturated aqueous solution of
sodium bicarbonate, dried over anhydrous magnesium sulfate and
evaporated. The resulting residue was purified by silica gel column
chromatography (Kanto silica gel 60N, 40 to 50 .mu.m; ethyl
acetate-hexane, 1:1 to 2:1) to give the title compound (81 mg,
100%) as a colorless oil.
[1205] ESI-MS m/z 719 (M+Na).sup.+.
Third Step
(8E,12E,14E)-7-Acetoxy-3-diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-2-
1-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-ol-
ide (Compound 130-3)
[1206] ##STR200##
[1207] A solution of Compound 130-2
(8E,12E,14E)-7-acetoxy-6,16-bis(1-ethoxyethoxy)-3,21-dihydroxy-6,10,12,16-
,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (33.2 mg,
47.6 mmol) obtained in the second step, N,N-dimethylaminopyridine
(3 mg, 23.8 .mu.mol) and triethylamine (49 mg, 0.476 mmol) in
dichloromethane (1 mL) was cooled to -20.degree. C.,
diethylisopropylsilyl chloride (10.3 mg, 59.5 .mu.mol) was added
dropwise thereto, and the reaction mixture was stirred at
-20.degree. C. to 5.degree. C. for 1.2 hours. Next,
diethylisopropylsilyl chloride (31 mg, 179 .mu.mol) was added
dropwise to the reaction mixture at the same temperature, followed
by stirring for 4.5 hours. Further, diethylisopropylsilyl chloride
(41.2 mg, 238 .mu.mol) was added dropwise to the reaction mixture
at the same temperature, followed by stirring for 1.3 hours, and
then stirring at room temperature for one hour. The reaction
mixture was diluted with ethyl acetate, washed with water and a
saturated aqueous solution of sodium bicarbonate, dried over
anhydrous magnesium sulfate and evaporated. The resulting residue
was purified by thin layer chromatography (Merck Art 1.05628; ethyl
acetate-hexane, 1:2) to give the title compound (19.1 mg, 49%) as a
colorless oil.
[1208] ESI-MS m/z 847 (M+Na).sup.+.
Fourth Step
(8E,12E,14E)-7-Acetoxy-3-diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-2-
1-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-ol-
ide (Compound 130-4)
[1209] ##STR201##
[1210] A solution of Compound 130-3
(8E,12E,14E)-7-acetoxy-3-diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)--
21-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (33.2 mg, 40 .mu.mol) obtained in the third step and
1,8-bis(N,N-dimethylamino)naphthalene (51.4 mg, 0.24 mmol) in
toluene (0.7 mL) was cooled to 5.degree. C., and methyl
trifluoromethanesulfonate (20 mg, 0.12 mmol) was added dropwise to
the reaction mixture, followed by addition of 0.5 mL of toluene.
The reaction mixture was stirred at 50.degree. C. for 12.5 hours.
The reaction mixture was cooled to room temperature, diluted with
toluene, and 0.06 N aqueous ammonia (5 mL) was added at 5.degree.
C., followed by stirring at room temperature for about 20 minutes.
Ethyl acetate, water and a saturated aqueous solution of ammonium
chloride were added thereto, the mixture was stirred for a while,
and the organic layer was separated. The organic layer was washed
with a 0.05 M aqueous solution of citric acid and an aqueous
solution of sodium bicarbonate successively, dried over anhydrous
magnesium sulfate and evaporated. The resulting residue was
purified by silica gel column chromatography (Kanto silica gel 60N,
40 to 50 .mu.m; ethyl acetate-hexane, 1:9 to 1:7 to 1:4 to 1:3) to
give the title compound (15.8 mg, 47%) as a colorless oil.
[1211] ESI-MS m/z 861 (M+Na).sup.+.
<Fifth Step>
(8E,12E,14E)-3-Diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-7-hydroxy-2-
1-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-ol-
ide (Compound 130-5)
[1212] ##STR202##
[1213] To Compound 130-4
(8E,12E,14E)-7-acetoxy-3-diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)--
21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (21.5 mg, 25.6 .mu.mol) obtained in the fourth step was added
a 0.2M solution of guanidine/guanidine nitrate
(methanol-dichloromethane, 9:1) (0.26 mL, 52 .mu.mol), followed by
stirring at room temperature for 12.5 hours. The reaction mixture
was diluted with ethyl acetate, washed with water and a saturated
aqueous solution of ammonium chloride, dried over anhydrous
magnesium sulfate and evaporated. The resulting residue was
purified by silica gel column chromatography (Kanto silica gel 60N,
40 to 50 .mu.m; ethyl acetate-hexane, 1:7 to 1:5 to 1:4) to give
the title compound (19.3 mg, 95%) as a colorless oil.
[1214] ESI-MS m/z 819 (M+Na).sup.+.
Sixth Step
(8E,12E,14E)-3-Diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-21-methoxy--
6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-18,19-epoxytricosa-8,1-
2,14-trien-11-olide (Compound 130-6)
[1215] ##STR203##
[1216] A solution of Compound 130-5
(8E,12E,14E)-3-diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-7-hydroxy--
21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (19.3 mg, 24.2 .mu.mol) obtained in the fifth step,
N,N-dimethylaminopyridine (3 mg, 24.2 .mu.mol) and triethylamine
(25 mg, 0.242 mmol) in dichloromethane (1.2 mL) was cooled to
5.degree. C., a solution of 4-nitrophenyl chloroformate (25 mg, 121
.mu.mol) in dichloromethane (0.3 mL) was added dropwise thereto,
followed by stirring at room temperature for three hours. The
reaction mixture was diluted with ethyl acetate and then washed
with an aqueous solution of sodium bicarbonate. Further the organic
layer was sequentially washed with an aqueous solution of ammonium
chloride, an aqueous solution of sodium bicarbonate and water in
this order. The organic layer was dried over anhydrous magnesium
sulfate and evaporated to give a residue of the title compound
(40.7 mg) as a pale yellow solid.
[1217] This solid was subjected to the subsequent reaction without
purification.
Seventh Step
(8E,12E,14E)-3-Diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-7-((4-isopr-
opylpiperazin-1-yl)carbonyl)oxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-
-epoxytricosa-8,12,14-trien-11-olide (Compound 130-7)
[1218] ##STR204##
[1219] A solution of the crude product of Compound 130-6
(8E,12E,14E)-3-diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-21-methoxy-
-7-(4-nitrophenoxy)carboxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,-
12,14-trien-11-olide (20.4 mg, 12.1 .mu.mol) obtained in the sixth
step in tetrahydrofuran (0.9 mL) was cooled to 5.degree. C., and a
solution of 1-isopropylpiperazine (2.4 mg, 18.2 .mu.mol) in
tetrahydrofuran (0.1 mL) and triethylamine (3.7 mg, 36.3 .mu.mol)
were added dropwise thereto, followed by stirring at room
temperature for 6.5 hours. The reaction mixture was diluted with
ethyl acetate, washed with water and a saturated aqueous solution
of sodium bicarbonate, dried over anhydrous magnesium sulfate and
evaporated. The resulting residue was purified by thin layer
chromatography (Fuji Silysia NH Silica gel plate; ethyl
acetate-hexane, 1:3) to give the title compound (10.0 mg, 87%, two
steps) as a colorless oil.
[1220] ESI-MS m/z 951 (M+H).sup.+.
Eighth Step
(8E,12E,14E)-6,16-Bis(1-ethoxyethoxy)-3-hydroxy-7-((4-isopropylpiperazin-1-
-yl)carbonyl)oxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8-
,12,14-trien-11-olide (Compound 130-8)
[1221] ##STR205##
[1222] A solution of Compound 130-7
(8E,12E,14E)-3-diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-7-((4-isop-
ropylpiperazin-1-yl)carbonyl)oxy-21-methoxy-6,10,12,16,20-pentamethyl-18,1-
9-epoxytricosa-8,12,14-trien-11-olide (10 mg, 10.5 .mu.mol)
obtained in the seventh step in tetrahydrofuran (1.0 mL) was cooled
to 5.degree. C., and tetrabutylammonium fluoride (1.0 M
tetrahydrofuran solution, 11.6 .mu.l, 11.6 .mu.mol) was added
dropwise thereto, followed by stirring at room temperature for 1.5
hours. The reaction mixture was diluted with ethyl acetate, washed
with water and a saturated aqueous solution of sodium bicarbonate,
dried over anhydrous magnesium sulfate and evaporated. The
resulting residue was purified by thin layer chromatography (Merck
Art 1.05628; methanol-dichloromethane, 1:29) to give the title
compound (7.4 mg, 86%) as a colorless oil.
[1223] ESI-MS m/z 823 (M+H).sup.+.
Ninth Step
(8E,12E,14E)-3,6,16-Trihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy--
21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (Compound 130)
[1224] ##STR206##
[1225] To a solution of Compound 130-8
(8E,12E,14E)-6,16-bis(1-ethoxyethoxyy-3-hydroxy-7-((4-isopropylpiperazin--
1-yl)carbonyl)oxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa--
8,12,14-trien-11-olide (7.4 mg, 9 .mu.mol) obtained in the eighth
step in a mixture of tetrahydrofuran:2-methyl-2-propanol=1:1 (0.7
mL) was added pyridinium p-toluenesulfonate (6.8 mg, 27 .mu.mol),
followed by stirring at room temperature for 24 hours. The reaction
mixture was diluted with ethyl acetate, washed with water and a
saturated aqueous solution of sodium bicarbonate, dried over
anhydrous magnesium sulfate and evaporated. The resulting residue
was purified by thin layer chromatography (Fuji Silysia NH Silica
gel plate; methanol-dichloromethane, 1:39) to give the title
compound (4.2 mg, 69%) as a colorless oil. .sup.1H-NMR Spectrum
(CD.sub.3OD,400 MHz) .delta.(ppm): 0.88(3H,d,J=7.2 Hz),
0.88(3H,t,J=7.6 Hz),0.89(3H,d,J=6.8 Hz),1.07(6H,d,J=6.4 Hz),
1.21(3H,s),1.28-1.70 (11H,m),1.77(3H,d,J=1.2 Hz),1.85(1H,dd,
J=5.2,14.0 Hz),2.47-2.62(7H,m),2.64(1H,dd,J=2.4,8.0
Hz),2.67-2.74(1H,m),2.88(1H,dt,J=2.4,6.0 Hz),3.14-3.19(1H,m),3.38
(3H,s),3.42-3.70(4H,m),3.75-3.82(1H,m),4.93(1H,d,J=10.0 Hz),
5.06(1H,d,J=10.8 Hz),5.57(1H,dd,J=10.0,15.2 Hz),5.72(1H,dd,
J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=10.8 Hz),6.53
(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 679 (M+H).sup.+.
Example 131
(8E,12E,14E)-3,6,16-Trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7-((4--
methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olid-
e (Compound 131)
[1226] ##STR207##
[1227] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 130.
[1228] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=7.2 Hz), 0.88(3H,t,J=7.6 Hz),0.89(3H,d,J=6.8
Hz),1.21(3H,s),1.29-1.70 (11H,m),1.77(3H,d,J=1.2
Hz),1.85(1H,dd,J=5.2,14.0 Hz),
2.30(3H,s),2.35-2.63(7H,m),2.64(1H,dd,J=2.4,8.0 Hz),2.88
(1H,dt,J=2.4,6.0 Hz),3.14-3.20(1H,m),3.38(3H,s),3.39-3.71
(4H,m),3.75-3.82(1H,m),4.93(1H,d,J=10.0 Hz),5.06(1H,d, J=10.8
Hz),5.57(1H,dd,J=9.6,15.2 Hz),5.72(1H,dd,J=9.6,15.2 Hz),
5.87(1H,d,J=15.2 Hz),6.13(1H,dd,J=1.2,10.8 Hz),6.53(1H,dd,
J=10.8,15.2 Hz); ESI-MS m/z 651 (M+H).sup.+.
Example 132
(8E,12E,14E)-3,6,16-Trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7-((4--
methylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11--
olide (Compound 132)
[1229] ##STR208##
[1230] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 130.
[1231] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=7.2 Hz), 0.88(3H,t,J=7.6 Hz),0.89(3H,d,J=6.8
Hz),1.22(1.2H, s),1.23 (1.8H, s),1.28-1.71 (11H,m),1.77(3H,d,J=0.8
Hz),1.81-1.93 (3H,m),2.34(1.2H, s),2.35(1.8H,
s),2.50-2.67(8H,m),2.88 (1H,dt,J=2.0,6.0
Hz),3.14-3.20(1H,m),3.38(3H,s),3.47-3.56
(2H,m),3.58-3.67(2H,m),3.75-3.82(1H,m),4.95(1H,d,J=10.0 Hz),
5.07(1H,d,J=10.8 Hz),5.57(1H,dd,J=9.6,15.2 Hz),5.73(1H,dd,
J=9.6,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.13(1H,d,J=11.2 Hz),6.53
(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 665 (M+H).sup.+.
Example 133
(8E,12E,14E)-7-((4-Ethylhomopiperazin-1-yl)carbonyl)oxy-3,6,16-trihydroxy--
21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (Compound 133)
[1232] ##STR209##
[1233] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 130.
[1234] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=7.2 Hz), 0.88(3H,t,J=7.6 Hz),0.89(3H,d,J=6.8
Hz),1.08(1.5H, t,J=7.2 Hz), 1.09(1.5H, t,J=7.2 Hz),1.22(1.5H,
s),1.23(1.5H, s),1.28-1.70 (11H,m),1.77(3H,d,J=1.2
Hz),1.82-1.91(3H,m),2.47-2.76 (10H,m), 2.88(1H,dt,J=2.4,6.0
Hz),3.14-3.1.9(1H,m),3.38(3H,s),3.45-3.67(4H,m),3.75-3.82(1H,m),4.95(1H,d-
,J=9.6 Hz),5.07(1H,d, J=10.8 Hz),5.57(1H,dd,J=9.6,15.2
Hz),5.73(1H,dd,J=9.6,15.2 Hz), 5.87(1H,d,J=15.2
Hz),6.13(1H,d,J=11.2 Hz),6.53(1H,dd,J=10.8, 15.2 Hz); ESI-MS m/z
679 (M+H).sup.+.
Example 134
(8E,12E,14E)-7-Acetoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-6-((4--
methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olid-
e (Compound 134)
[1235] ##STR210## First Step
(8E,12E,14E)-7-Acetoxy-6,10,12,16,20-pentamethyl-6-(4-nitrophenoxy)carboxy-
-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 134-1)
[1236] ##STR211##
[1237] To a solution of Compound 46-1
(8E,12E,14E)-7-acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris(t-
riethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide (44 mg, 49
.mu.mol) obtained in the first step of Example 46 in
dichloromethane (2.0 mL) were added triethylamine (30 mg, 0.29
mmol), N,N-dimethylaminopyridine (90 mg, 0.73 mmol) and
4-nitrophenyl chloroformate (90 mg, 0.44 mmol) under ice-cooling,
and the reaction mixture was stirred at room temperature under
nitrogen atmosphere for three days. The reaction mixture was
diluted with ethyl acetate and washed with a saturated aqueous
solution of sodium bicarbonate and brine. The organic layer was
dried over anhydrous magnesium sulfate, filtrated and evaporated.
The resulting residue was purified by silica gel column
chromatography (Kanto silica gel 60N, 40 to 100 .mu.m; ethyl
acetate:hexane=10:90) to give the title compound (19 mg, 36%) as a
colorless oil.
[1238] ESI-MS m/z 1082 (M+Na).sup.+.
Second Step
(8E,12E,14E)-7-Acetoxy-6,10,12,16,20-pentamethyl-6-((4-methylpiperazin-1-y-
l)carbonyl)oxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-tri-
en-11-olide (Compound 134-2)
[1239] ##STR212##
[1240] To a solution of Compound 134-1
(8E,12E,14E)-7-acetoxy-6,10,12,16,20-pentamethyl-6-(4-nitrophenyl)carboxy-
-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide
(9 mg, 8.5 .mu.mol) obtained in the first step in tetrahydrofuran
(1 mL) were added triethylamine (8 mg, 85 .mu.mol) and
1-methylpiperazine (1.7 mg, 17 .mu.mol) at room temperature,
followed by stirring at the same temperature under nitrogen
atmosphere for 4 hours. The reaction mixture was diluted with ethyl
acetate and then washed with brine. The organic layer was dried
over anhydrous sodium sulfate, filtrated and evaporated. The
resulting residue was purified by silica gel column chromatography
(Kanto silica gel 60N, 40 to 100 .mu.m; ethyl acetate:hexane=50:50)
to give the title compound (8.6 mg, 100%) as a colorless oil.
[1241] ESI-MS m/z 1021 (M+H).sup.+.
Third Step
(8E,12E,14E)-7-Acetoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-6-((4--
methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olid-
e (Compound 134)
[1242] ##STR213##
[1243] To a solution of Compound 134-2
(8E,12E,14E)-7-acetoxy-6,10,12,16,20-pentamethyl-6-((4-methylpiperazin-1--
yl)carbonyl)oxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-tr-
ien-11-olide (9 mg, 8.5 .mu.mol) obtained in the second step in
tetrahydrofuran (1 mL) was added tetrabutylammonium fluoride (1.0 M
tetrahydrofuran solution, 48 .mu.L, 48 .mu.mol) at room
temperature, and the reaction mixture was stirred at the same
temperature under nitrogen atmosphere for 5 hours. The reaction
mixture was diluted with ethyl acetate and washed with brine. The
organic layer was dried over anhydrous sodium sulfate, filtrated
and evaporated. The resulting residue was purified by silica gel
column chromatography (Kanto silica gel 60N, 40 to 100 .mu.m;
methanol:dichloromethane=5:95) to give the title compound (4.4 mg,
77%) as a colorless oil. .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz)
.delta.(ppm): 0.89(6H,d,J=6.8 Hz), 0.94(3H,t,J=7.2
Hz),1.20-1.28(1H,m),1.34(3H,s),1.38-1.70
(10H,m),1.78(3H,s),1.86(1H,dd,J=5.2,14.0 Hz),2.04(3H,s),2.31
(3H,s),2.38-2.48(4H,m),2.48-2.52(2H,m),2.56-2.65(1H,m),2.66
(1H,dd,J=2.0,7.6 Hz),2.89(1H,dt,J=2.0,6.4 Hz),3.42-3.62(5H,m),
3.76-3.84(1H,m),5.01(1H,d,J=9.6 Hz),5.06(1H,d,J=10.8 Hz),5.63
(1H,dd,J=9.6,15.2 Hz),5.75(1H,dd,J=9.2,15.2 Hz),5.87(1H,d, J=15.2
Hz),6.14(1H,d,J=10.8 Hz),6.52(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 679
(M+H).sup.+.
Example 135
(8E,12E,14E)7-Acetoxy-6-((4-cycloheptylpiperazin-1-yl)carbonyl)oxy-3,16,21-
-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11--
olide (Compound 135)
[1244] ##STR214##
[1245] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 134.
[1246] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.22-1.32(1H,m),1.34 (3H,m),1.40-1.78
(20H,m),1.79(3H,s),1.82-1.93(3H,m),2.05
(3H,s),2.39-2.47(1H,m),2.50(2H,d,J=3.6 Hz),2.54-2.66(6H,m),
2.89(1H,dt,J=2.0,6.4 Hz),3.37-3.64(5H,m),3.76-3.83(1H,m),
5.07(1H,d,J=10.8 Hz),5.15(1H,d,J=9.2 Hz),5.63(1H,dd,J=9.2, 15.2
Hz),5.71(1H,dd,J=9.2,15.2 Hz),5.87(1H,d,J=15.2 Hz),6.14
(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 761
(M+H).sup.+.
Example 136
(8E,12E,14E)-7-Acetoxy-6-((4-ethylhomopiperazin-1-yl)carbonyl)oxy-3,16,21--
trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (Compound 136)
[1247] ##STR215##
[1248] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 134.
[1249] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(6H,d,J=7.2 Hz), 0.94(3H,t,J=7.2 HZ),1.08(3H,t,J=7.2
Hz),1.20-1.28(1H,m),1.34 (3H,s),1.38-1.70
(10H,m),1.78(3%,s),1.83-1.91(3H,m),2.03
(3H,s),2.33-2.42(1H,m),2.50(2H,d,J=3.9 Hz),2.58-2.80(7H,m),
2.89(1H,dt,J=2.4,6.4 Hz),3.45-3.65(5H,m),3.75-3.84(1H,m),
5.02(1H,d,J=9.6 Hz),5.07(1H,d,J=10.4 Hz),5.63(1H,dd,J=9.6, 15.2
Hz),5.76(1H,dd,J=9.6,15.6 Hz),5.87(1H,d,J=15.6 Hz),6.14
(1H,d,J=11.2 Hz),6.53(1H,dd,J=11.2,15.6 Hz); ESI-MS m/z 707
(M+H).sup.+.
Example 137
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-(N-isopropylthiocarbamoyloxy)-6,10,1-
2,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 137)
[1250] ##STR216## First Step
(8E,12E,14E)-3,6,16,21-Tetrakis(1-ethoxyethoxy)-7-(N-isopropylthiocarbamoy-
loxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 137-1)
[1251] ##STR217##
[1252] To a suspension of sodium hydride (60% oil dispersion, 2 mg,
0.052 mmol) in tetrahydrofuran (0.5 mL) was added dropwise a
solution of
(8E,12E,14E)-3,6,16,21-tetra(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pent-
amethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (19 mg, 0.019
mmol) obtained in Example 3-(2) in tetrahydrofuran (0.5 mL) under
ice-cooling and stirring, and the reaction mixture was stirred at
room temperature for 10 minutes. Then, isopropyl isothiocyanate
(6.6 mg, 0.066 mmol) was added dropwise thereto, and the reaction
mixture was stirred at room temperature for three hours. Water was
added to the reaction mixture under ice-cooling to terminate the
reaction, followed by diluting with ethyl acetate and washing with
brine. The organic layer was dried over anhydrous sodium sulfate
and evaporated. The resulting residue was purified by silica gel
column chromatography (Kanto silica gel 60N, 40 to 100 .mu.m; ethyl
acetate:hexane=25:75) to give the title compound (10 mg, 60%) as a
colorless oil.
[1253] ESI-MS m/z 922 (M+Na).sup.+.
Second Step
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-(N-isopropylthiocarbamoyloxy)-6,10,1-
2,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Compound 137)
[1254] ##STR218##
[1255] The title compound (a colorless oil) was obtained by a
similar method as described for Example 3-5.
[1256] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.89(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.14-1.69 (20H,m),1.77 (3H,s),1.86(1H,dd,J=5.2,14.0
Hz),2.48-2.60(3H,m),2.66(1H,dd, J=2.0,8.0 Hz),2.89(1H,dt,J=2.0,6.0
Hz),3.49-4,08 (1H,m),3.73-3.83(1H,m),4.23-4.34(1H,m)4.95(1H,d,J=9.6
Hz),5.07(1H,d,J=10.4 Hz),5.60-5.92(3H,m),6.13(1H,d,J=10.8
Hz),6.52(1H,dd, J=10.8,15.2 Hz); ESI-MS m/z 634 (M+Na).sup.+.
Example 138
(8E,12E,14E)-7-(N-Butylthiocarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16-
,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound
138)
[1257] ##STR219##
[1258] The title compound (a colorless oil) was obtained by a
similar method as described for Example 137.
[1259] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.4 Hz), 0.90(3H,d,J=7.2 Hz),0.937(3H,t,J=7.2
Hz),0.942(3H,t,J=7.2 Hz), 1.19(3H,s),1.19-1.69
(15H,m),1.77(3H,s),1.86(1H,dd,J=5.6, 14.0
Hz),2.49-2.62(3H,m),2.66(1H,dd,J=2.0,8.0 Hz),2.89(1H,dt, J=2.0,6.0
Hz),3.42-3.57(3H,m),3.73-3.83(1H,m),4.95(1H,d, J=9.6
Hz),5.07(1H,d,J=10.4 Hz),5.62-5.92(3H,m),6.14(1H,d, J=10.8
Hz),6.52(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 648 (M+Na).sup.+.
Example 139
(8E,12E,14E)-7-(N-(3-(N',N'-Diethylamino)propyl)thiocarbamoyloxy)-3,6,16,2-
1-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien--
11-olide (Compound 139)
[1260] ##STR220##
[1261] The title compound (a colorless oil) was obtained by a
similar method as described for Example 137.
[1262] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.4 Hz), 0.90(3H,d,J=7.2 Hz),0.94(3H,t,J=7.2
Hz),1.14(6H,t,J=6.8 Hz), 1.19(3H,s),1.21-1.69 (13H,m),1.77(3H,s),
1.86(1H,dd,J=5.2, 14.0 Hz),2.48-2.61(3H,m),2.66(1H,dd,J=2.4,8.0
Hz),3.70-3.86 (6H,m),2.89(1H,dt,J=2.4,5.6
Hz),3.44-3.58(3H,m),3.75-3.83 (1H,m),4.96(1H,d,J=8.4
Hz),5.07(1H,d,J=10.4 Hz),5.64-5.92 (3H,m),6.14(1H,d,J=10.8
Hz),6.52(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 683 (M+H).sup.+.
Example 140
(8E,12E,14E)-7-Benzoyloxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-
-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound 140)
[1263] ##STR221## First Step
(8E,12E,14E)-7-Benzoyloxy-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-
-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound
140-1)
[1264] ##STR222##
[1265] To a solution of
(8E,12E,14E)-3,6,16,21-tetrakis(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-p-
entamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (10 mg, 12.5
.mu.mol) obtained in Example 3-2 in pyridine (0.5 mL) were added
N,N-dimethylaminopyridine (8 mg, 62.5 mol) and benzyl chloride
(17.6 mg, 125 .mu.mol) at room temperature, and the reaction
mixture was stirred at the same temperature under nitrogen
atmosphere for 12 hours. The reaction mixture was diluted with
ethyl acetate and washed with a saturated aqueous solution of
ammonium chloride and brine. The organic layer was dried over
anhydrous magnesium sulfate and evaporated. The resulting residue
was purified by silica gel column chromatography (Kanto silica gel
60N, 40 to 100 .mu.m; ethyl acetate:hexane=25:75) to give the title
compound (6 mg, 55%) as a colorless oil.
[1266] ESI-MS m/z 925 (M+Na).sup.+.
Second Step
(8E,12E,14E)-7-Benzoyloxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-
-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound 140)
[1267] ##STR223##
[1268] The title compound (a colorless oil) was obtained by a
similar method as described for Example 3-5.
[1269] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.89(3H,d,J=7.2 Hz),0.93(3H,t,J=7.2
Hz),1.20-1.76 (14H,m),1.78 (3H,s),1.86(1H,dd,J=5.6,14.0
Hz),2.53-2.64(3H,m),2.66(1H,dd, J=2.4,8.0 Hz),2.89(1H,dt,J=2.4,5.6
Hz),3.52(1H,dt,J=4.8, 8.0 Hz), 3.78-3.85(1H,m),5.09(1H,d,J=10.8
Hz),5.29(1H,d, J=9.6 Hz),5.69(1H,dd,J=9.6,15.2
Hz),5.83(1H,dd,J=9.6,15.2 Hz), 5.87(1H,d,J=15.2
Hz),6.14(1H,d,J=10.4 Hz),6.53(1H,dd,J=10.8, 15.2
Hz),7.47(2H,dd,J=7.6,7.6 Hz),7.60(1H,dd,J=7.6,7.6 Hz),
8.12(2H,d,J=7.6 Hz); ESI-MS m/z 637 (M+Na).sup.+.
Example 141
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-propanoylo-
xy-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound 141)
[1270] ##STR224##
[1271] The title compound (a colorless oil) was obtained by a
similar method as described for Example 140.
[1272] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 0.89(3H,d,J=7.2 Hz),0.94(3H,t,J=7.2
Hz),1.11(3H,t,J=8.0 Hz), 1.18(3H,s),1.22-1.68
(11H,m),1.77(3H,s),1.86(1H,dd,J=5.2, 14.0
Hz),2.28-2.45(2H,m),2.50-2.61(3H,m),2.66(1H,dd,J=2.4, 8.0
Hz),2.89(1H,dt,J=2.0,6.0 Hz),3.52(1H,dt,J=4.8,8.0 Hz),
3.75-3.82(1H,m),4.95(1H,d,J=9.6 Hz),5.05(1H,d,J=9.6 Hz),5.57
(1H,dd,J=10.0,15.2 Hz),5.70(1H,dd,J=9.6,15.2 Hz),5.87(1H,d, J=15.2
Hz),6.13(1H,d,J=10.8 Hz),6.52(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 589
(M+Na).sup.+.
Example 142
(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(3-phenylp-
ropanoyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound
142)
[1273] ##STR225##
[1274] The title compound (a colorless oil) was obtained by a
similar method as described for Example 140.
[1275] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.86(3H,d,J=6.8 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.2
Hz),1.09(3H,s),1.20-1.69 (11H,m),1.77(3H,s),1.86(1H,dd,J=5.2,14.0
Hz),2.46-2.59(3H,m),
2.62-2.70(3H,m),2.85-2.96(3H,m),3.48-3.56(1H,m),3.72-3.80
(1H,m),5.03(1H,d,J=9.2 Hz),5.05(1H,d,J=10.8 Hz),5.54(1H,dd,
J=9.6,15.2 Hz),5.66(1H,dd,J=9.2,15.2 Hz),5.87(1H,d,J=14.8 Hz),
6.13(1H,d,J=10.8 Hz),6.53(1H,dd,J=10.8,14.8 Hz),7.12-7.28 (5H,m);
ESI-MS m/z 665 (M+Na).sup.+.
Example 143
(8E,12E,14E)-7-(Hexanoyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamet-
hyl-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound 143)
[1276] ##STR226##
[1277] The title compound (a colorless oil) was obtained by a
similar method as described for Example 140.
[1278] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.76-0.83(9H,m),0.98 (3H,t,J=7.2 Hz),1.23(3H,s),1.24-1.74
(17H,m),1.82(3H,brs), 1.91(1H,dd,J=5.6,14.4
Hz),2.32-2.44(2H,m),2.52-2.69(3H,m), 2.71(1H,dd,J=2.4,8.0
Hz),2.94(1H,dt,J=2.4,6.0 Hz),3.53-3.60
(1H,m),3.78-3.86(1H,m),5.10(1H,d,J=9.6 Hz),5.11(1H,d, J=9.6
Hz),5.61(1H,dd,J=9.6,15.2 Hz),5.74(1H,dd,J=9.6,15.2 Hz),
5.91(1H,d,J=15.2 Hz),6.18(1H,d,J=11.2 Hz),6.57(1H,dd,J=11.2, 15.2
Hz); ESI-MS m/z 631 (M+Na).sup.+.
Example 144
(8E,12E,14E)-7,21-Diacetoxy-3,6,16-trihydroxy-6,10,12,16,20-pentamethyl-18-
,19-epoxytricosa-8,12,14-trien-11-olide (Compound 144-1) and
(8E,12E,14E)-3,7,21-triacetoxy-6,16-dihydroxy-6,10,12,16,20-pentamethyl-1-
8,19-epoxytricosa-8,12,14-trien-11-olide (Compound 144-2)
[1279] Compound 144-1 ##STR227## Compound 144-2 ##STR228##
[1280] A solution of
(8E,12E,14E)-7-acetoxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-1-
8,19-epoxytricosa-8,12,14-trien-11-olide (276 mg, 0.5 mmol),
N,N-dimethylaminopyridine (31 mg, 0.25 mmol) and triethylamine (256
mg, 2.5 mmol) in dichloromethane (15 mL) was cooled to -20.degree.
C., a solution of acetic anhydride (53 mg, 0.5 mmol) in
dichloromethane (2 mL) was added dropwise thereto over 30 minutes,
and the reaction mixture was stirred at the same temperature for 30
minutes. A solution of acetic anhydride (10.5 mg, 0.1 mmol) in
dichloromethane (1 mL) was added dropwise to the reaction mixture
over 30 minutes, followed by stirring at the same temperature for
2.5 hours. Further, a solution of acetic anhydride (10.5 mg, 0.1
mmol) in dichloromethane (1 mL) was added dropwise to the reaction
mixture over 5 minutes, followed by stirring at the same
temperature for 30 minutes. Furthermore, a solution of acetic
anhydride (21 mg, 0.2 mmol) in dichloromethane (1 mL) was added
dropwise to the reaction mixture over 5 minutes, followed by
stirring at the same temperature for 30 minutes. The reaction
mixture was diluted with ethyl acetate, washed with water and a
saturated aqueous solution of sodium bicarbonate, dried over
anhydrous magnesium sulfate and evaporated. The resulting residue
was purified by silica gel column chromatography (Kanto silica gel
60N, 40 to 50 .mu.m; ethyl acetate-hexane, 2:1 to 3:1 to 4:1 to
9:1) to give the residue of Compound 144-1 as a colorless oil, and
Compound 144-2 (67.7 mg, 21%) as colorless crystals. The residue of
Compound 144-1 was then purified by thin layer chromatography
(Merck Art 1.13792; ethyl acetate-hexane, 8:1 to 9:1) to give
Compound 144-1 (214.3 mg, 72%) as a colorless oil. Compound
144-1
[1281] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.87(3H,t,J=7.6 Hz), 0.88(3H,d,J=7.2 Hz),0.92(3H,d,J=6.8
Hz),1.18(3H,s),1.31-1.68 (11H,m),1.77(3H,d,J=0.8
Hz),1.82(1H,dd,J=5.2,14.0 Hz),2.05
(3H,s),2.06(3H,s),2.46-2.63(4H,m),2.88(1H,dt,J=2.0,6.0 Hz),
3.75-3.81(1H,m),4.84-4.92(1H,covered with H.sub.2O),5.04(1H,d,
J=9.6 Hz),5.05(1H,d,J=10.8 Hz),5.56(1H,dd,J=9.6,15.2 Hz),5.70
(1H,dd,J=9.6,15.2 Hz),5.86(1H,d,J=15.2 Hz),6.13(1H,d, J=11.2 Hz),
6.52(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 617 (M+Na).sup.+.
Compound 144-2
[1282] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.87(3H,t,J=7.6 Hz), 0.89(3H,d,J=6.8 Hz),0.91(3H,d,J=6.8
Hz),1.18(3H,s),1.33(3H,s), 1.34-1.73(8H,m),1.77(3H,d,J=0.8
Hz),1.83(1H,dd,J=5.6,14.0 Hz),
2.04(3H,s),2.05(3H,s),2.06(3H,s),2.53-2.68(4H,m),2.88(1H,dt,
J=2.0,6.0 Hz),4.78-4.96(2H,covered with H.sub.2O),4.99(1H,d,J=10.4
Hz),5.02(1H,d,J=9.6 Hz),5.57(1H,dd,J=9.6,15.2 Hz),5.72
(1H,dd,J=9.6,15.2 Hz),5.86(1H,d,J=15.2 Hz),6.14(1H,dd,J=1.2, 10.8
Hz),6.52(1H,dd,J=11.2,15.2 Hz); ESI-MS m/z 659 (M+Na).sup.+.
Example 145
(8E,12E,14E)-21-Acetoxy-3,6,16-trihydroxy-7-((4-isopropylpiperazin-1-yl)ca-
rbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-o-
lide (Compound 145-1) and
(8E,12E,14E)-3,21-diacetoxy-6,16-dihydroxy-7-((4-isopropylpiperazin-1-yl)-
carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-
-olide (Compound 145-2)
[1283] Compound 145-1 ##STR229## Compound 145-2 ##STR230##
[1284] The title compounds (each a colorless oil) were synthesized
by a similar method as described for Example 144 except for using
Compound 44 obtained in Example 44.
Compound 145-1
[1285] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHZ) .delta.(ppm):
0.91(3H,t,J=7.2 Hz), 0.93(3H,d,J=6.8 Hz),0.96(3H,d,J=7.2
Hz),1.12(6H,d,J=6.4 Hz),
1.26(3H,s),1.30-1.56(6H,m),1.58-1.76(5H,m),1.82(3H,s),1.87
(1H,dd,J=5.6,14.0 Hz),2.10(3H,s),2.48-2.70(8H,m),2.70-2.82
(1H,m)2.93(1H,dt,J=2.0,5.6 Hz),3.44-3.76(4H,m),3.78-3.88
(1H,m),4.86-4.98(1H,covered with H.sub.2O),4.97(1H,d,J=9.6 Hz),
5.10(1H,d,J=10.8 Hz),5.62(1H,dd,J=10.0,15.2 Hz),5.76(1H,dd,
J=9.6,15.2 Hz),5.90(1H,d,J=15.2 Hz),6.18(1H,d,J=10.8 Hz),6.57
(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 707 (M+H).sup.+.
Compound 145-2
[1286] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.91(3H,t,J=7.6 Hz), 0.93(3H,d,J=6.8 Hz),0.96(3H,d,J=7.2
Hz),1.12(6H,d,J=6.4 Hz), 1.25(3H,s),1.30-1.92
(15H,m),2.088(3H,s),2.094(3H,s),2.50-2.80(9H,m),2.93(1H,dt,J=2.0,6.0
Hz),3.40-3.76(4H,m),4.80-4.96(2H,covered with
H.sub.2O),4.96(1H,d,J=9.6 Hz),5.04(1H,d,J=10.8
Hz),5.63(1H,dd,J=10.0,15.2 Hz),5.78(1H,dd,J=9.6,15.2 Hz),
5.91(1H,d,J=15.2 Hz),6.18(1H,d,J=10.8 Hz),6.56(1H,dd,J=10.8, 15.2
Hz); ESI-MS m/z 749 M+.
Example 146
(8E,12E,14E)-6,16-Dihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,1-
0,12,16,20-pentamethyl-3,21-dioxo-18,19-epoxytricosa-8,12,14-trien-11-olid-
e (Compound 146-1) and
(8E,12E,14E)-3,6,16-trihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-
-6,10,12,16,20-pentamethyl-21-oxo-18,19-epoxytricosa-8,12,14-trien-11-olid-
e (Compound 146-2)
[1287] Compound 146-1 ##STR231## Compound 146-2 ##STR232##
[1288] To a solution of Compound 44 (20 mg, 30 .mu.mol) obtained in
Example 44 in dichloromethane (2.0 mL) was added Dess-Martin
reagent (43 mg, 0.101 mmol) under ice-cooling and stirring, and the
reaction mixture was stirred at room temperature under nitrogen
atmosphere for six hours. The reaction mixture was diluted with
ethyl acetate and then washed with a saturated aqueous solution of
sodium bicarbonate and brine. The organic layer was dried over
anhydrous sodium sulfate and evaporated. The resulting residue was
purified by silica gel column chromatography (Kanto silica gel 60N,
40 to 100 .mu.m; dichloromethane:methanol=95:5 to 90:10) to give
the title compounds, Compound 146-1 (9.6 mg, 48%) and Compound
146-2 (8.9 mg, 45%), each as a colorless oil.
Compound 146-1
[1289] H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.91(3H,d,J=6.8 Hz), 1.00(3H,t,J=7.2 Hz),1.07(3H,d,J=7.2
Hz),1.10(6H,d,J=6.4 Hz),
1.30(3H,s),1.33(3H,s),1.63(1H,dd,J=6.8,14.4 Hz),1.74-1.80
(1H,m),1.80(3H,s),1.89(1H,dd,J=5.6,14.4 Hz),2.00-2.08(1H,m),
2.28-2.37(1H,m),2.46(2H,d,J=12.4
Hz),2.52-2.70(7H,m),2.72-2.84(3H,m),2.92(1H,dt,J=2.0,6.4
Hz),3.31-3.33(1H,m),3.42-3.64(4H,m),4.94(1H,d,J=8.0
Hz),4.96(1H,d,J=10.8 Hz),5.23 (1H,dd,J=8.8,15.6
Hz),5.50(1H,dd,J=8.4,15.6 Hz),5.86(1H,d, J=15.2
Hz),6.10(1H,d,J=10.8 Hz),6.54(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 661
(M+H).sup.+,683 (M+Na).sup.+.
Compound 146-2
[1290] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.88(3H,d,J=6.8 Hz), 1.00(3H,t,J=7.2 Hz),1.07(3H,d,J=6.8
Hz),1.10(6H,d,J=7.2 Hz),
1.21(3H,s),1.38-1.42(5H,m),1.54-1.68(3H,m)1.77(3H,s),1.89
(1H,dd,J=4.8,14.0 Hz),2.28-2.36(1H,m),2.50-2.64(8H,m),2.75
(1H,dd,J=2.0,8.4 Hz),2.76-2.84(1H,m),2.91(1H,dt,J=2.4,7.6 Hz),
3.31-3.33(1H,m),3.42-3.64(4H,m),3.75-3.82(1H,m),4.93(1H,d, J=9.6
Hz),5.06(1H,d,J=10.4 Hz),5.57(1H,dd,J=10.0,15.2 Hz),5.72
(1H,dd,J=10.0,15.2 Hz),5.86(1H,d,J=15.2 Hz),6.14(1H,d, J=10.8
Hz),6.53(1H,dd,J=10.8,15.2 Hz); ESI-MS m/z 663 (M+H).sup.+, 685
(M+Na).sup.+.
Example 147
(8E,12E,14E)-7-Acetoxy-6-ethoxy-3,16,21-trihydroxy-6,10,12,16,20-pentameth-
yl-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound 147)
[1291] ##STR233##
[1292] The title compound (a colorless oil) was synthesized by a
similar method as described for Example 43 except for using ethyl
trifluoromethanesulfonate.
[1293] .sup.1H-NMR Spectrum (CD.sub.3OD,400 MHz) .delta.(ppm):
0.87(3H,d,J=6.4 Hz), 0.90(3H,d,J=6.8 Hz),0.94(3H,t,J=7.6
Hz),1.17(3H,t,J=7.2 Hz),
1.20(3H,s),1.22-1.60(7H,m),1.34(3H,s),1.65(1H,dd,J=6.4, 14.0
Hz),1.78(3H,s),1.86(1H,dd,J=5.2,14.0 Hz),2.04(3H,s),
2.44-2.68(4H,m),2.89(1H,dt,J=2.4,5.2 Hz),3.49-3.66(3H,m),
3.77-3.84(1H,m),5.06(1H,d,J=10.4 Hz),5.10(1H,d,J=9.6 Hz),5.55
(1H,dd,J=9.6,15.6 Hz),5.75(1H,dd,J=10.0,15.6 Hz),5.86(1H,d, J=15.2
Hz),6.13(1H,d,J=11.2 Hz),6.52(1H,dd,J=11.2,15.6 Hz); ESI-MS m/z 603
(M+Na).sup.+.
FORMULATION EXAMPLE
[1294] Formulation Examples of the compounds of the present
invention will be illustrated below, but the formulation of the
compounds of the present invention is not limited to these
Formulation Examples.
Formulation Example 1
[1295] Compound of Example 4445 (part) [1296] Heavy magnesium oxide
15 [1297] Lactose 75 were mixed homogeneously and formulated into a
powdered medicine in the form of a powder or fine granules having a
size of 350 .mu.m or less. The powdered medicine was charged into
capsules to give capsule form.
Formulation Example 2
[1297] [1298] Compound of Example 7545 (part) [1299] Starch 15
[1300] Lactose 16 [1301] Crystalline cellulose 21 [1302] Poly(vinyl
alcohol) 3 [1303] Distilled water 30 were mixed homogeneously,
pulverized, granulated, dried and then sieved to give granules
having a size of 1410 to 177 .mu.m.
Formulation Example 3
[1304] Granules were produced by a similar method as described for
Formulation Example 2, 4 parts of calcium stearate was added to 96
parts of the granules, compressed and molded to give tablets having
a diameter of 10 mm.
Formulation Example 4
[1305] To 90 parts of granules obtained by the method of
Formulation Example 2 were added 10 parts of crystalline cellulose
and 3 parts of calcium stearate, compressed and molded to give
tables having a diameter of 8 mm. Then, a mixed suspension of
syrup, gelatin and precipitated calcium carbonate was added thereto
to give sugar-coated tablets.
Formulation Example 5
[1306] Compound of Example 450.6 (part) [1307] Nonionic surfactant
2.4 [1308] Isotonic sodium chloride solution 97 were heated, mixed
and charged into an ampoule, the ampoule was sterilized to produce
an injection.
REFERENTIAL EXAMPLES
[1309] Referential Example 1
1-(Cyclopropylmethyl)piperazine
[1310] The compound was synthesized by the following three
steps.
Referential Example 1-1
Benzyl 4-(cyclopropylcarbonyl)piperazin-1-carboxylate
[1311] ##STR234##
[1312] In 35 mL of N,N-dimethylformamide were dissolved benzyl
1-piperazinecarboxylate (5.00 g, 22.7 mmol) and
cyclopropanecarboxylic acid (2.54 g, 29.5 mmol), and
1-ethyl-3-(3-(N,N-dimethylamino)propyl)-carbodiimide hydrochloride
(6.53 g, 34.1 mmol), 1-hydroxybenzotriazole (4.52 g, 29.5 mmol) and
triethylamine (3.60 g, 35.9 mmol) were added thereto at room
temperature, followed by stirring at the same temperature for three
hours. The reaction mixture was mixed with water, and extracted
twice with ethyl acetate. The organic layer was sequentially washed
with water twice, with a saturated aqueous solution of sodium
bicarbonate once and with brine once, and then dried over anhydrous
sodium sulfate. The organic layer was passed through a silica gel
column (Fuji Silysia, NH Silica gel) and evaporated to give the
title compound (6.10 g, 93.1%) as a white amorphous. .sup.1H-NMR
Spectrum (CDCl.sub.3,400 MHz) .delta.(ppm): 0.75-0.83(2H,m),
0.95-1.03(2H,m),1.65-1.75(1H,m),3.40-3.80(8H,m),5.16(2H,s),
7.30-7.40(5H,m).
Referential Example 1-2
1-(Cyclopropylcarbonyl)piperazine
[1313] ##STR235##
[1314] In 100 mL of ethanol was dissolved benzyl
4-(cyclopropylcarbonyl)piperazine-1-carboxylate (3.00 g, 10.4
mmol), and 1.5 g of 10% palladium-carbon was added thereto,
followed by stirring at room temperature under hydrogen atmosphere
overnight. The palladium-carbon was removed by filtration, and the
filtrate was evaporated to give the title compound (1.50 g, 97.3%)
as a colorless oil.
[1315] .sup.1H-NMR Spectrum (CDCl.sub.3,400 MHz) .delta.(ppm):
0.73-0.80(2H,m),
0.96-1.03(2H,m),1.67-1.77(1H,m),2.82-2.97(4H,m),3.60-3.71
(4H,m).
Referential Example 1-3
1-(Cyclopropylmethyl)piperazine
[1316] ##STR236##
[1317] Lithium aluminium hydride (770 mg, 20.3 mmol) was suspended
in tetrahydrofuran (150 mL), 1-(cyclopropylcarbonyl)piperazine
(1.56 g, 10.1 mmol) was gradually added thereto, and the reaction
mixture was heated under reflux for 30 minutes. The reaction
mixture was cooled to room temperature, and 0.8 mL of water, 0.8 mL
of a 15% aqueous solution of sodium hydroxide and 2.3 mL of water
were sequentially gradually added thereto. The precipitated
insoluble matter was removed by filtration through Celite, and the
filtrate was evaporated to give the title compound (1.40 g) as a
colorless oil. The product was used for the synthesis of
(8E,12E,14E)-7-((4-cyclopropylmethylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-
-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-1-
1-olide (the compound of Example 27) without further
purification.
[1318] .sup.1H-NMR Spectrum (CDCl.sub.3,400 MHz) .delta.(ppm):
0.09-0.15(2H,m), 0.48-0.56(2H,m),0.82-0.93(1H,m),2.25(2H,d,J=7.2
Hz) 2.48-2.65(4H,m),2.90-2.99(4H,m).
Referential Example 2
1-Isobutylpiperazine
[1319] ##STR237##
[1320] Benzyl 1-piperazinecarboxylate (1.1 g, 5.00 mmol) and
isobutylaldehyde (0.91 mL, 10.0 mmol) were dissolved in 30 mL of
tetrahydrofuran, and acetic acid (0.57 mL, 10.0 mmol) and sodium
triacetoxyborohydride (2.11 g, 10.0 mmol) were added thereto, and
the reaction mixture was stirred at room temperature for two hours.
The reaction mixture was mixed with a 1N aqueous solution of sodium
hydroxide, extracted with ethyl acetate twice, and the combined
organic layers were washed with brine once. The mixture was dried
over anhydrous sodium sulfate and evaporated. The resulting residue
was purified by silica gel column chromatography (Fuji Silysia, NH
Silica gel; ethyl acetate:hexane=50:50) to give benzyl
4-isobutylpiperazin-1-carboxylate (1.05 g) as a colorless oil.
[1321] The resulting benzyl 4-isobutylpiperazin-1-carboxylate (1.05
g) was dissolved in 35 mL of ethanol, 10% palladium-carbon (750 mg)
was added thereto, and the reaction mixture was stirred at room
temperature under hydrogen atmosphere (1 atm) for 12 hours. The
palladium-carbon was removed by filtration, and the filtrate was
evaporated to give the title compound (610 mg) as a colorless
oil.
[1322] .sup.1H-NMR Spectrum (CDCl.sub.3,400 MHz) .delta.(ppm):
0.90(6H,d,J=6.8 Hz), 1.71-1.86(1H,m),2.07(2H,d,J=7.6
Hz),2.33-2.43(4H,m),2.86-2.93(4H,m).
Referential Example 3
1-(Tetrahydropyran-4-yl)piperazine
[1323] ##STR238##
[1324] The title compound was synthesized by a similar method as
described for the compound of Referential Example 2
(1-isobutylpiperazine).
[1325] .sup.1H-NMR Spectrum (CDCl.sub.3,400 MHz) .delta.(ppm):
1.50-1.64(2H,m),
1.72-1.80(2H,m),2.36-2.46(1H,m),2.54-2.64(4H,m),2.91-2.97
(4H,m),3.37(2H,dt,J=2.0,11,6,Hz),4.03(2H,dd,J=4.4,11.6 Hz).
Referential Example 4
1-(Cyclopropylmethyl)homopiperazine
[1326] ##STR239##
[1327] Benzyl 1-homopiperazinecarboxylate (1.95 g, 8.32 mmol) and
cyclopropanecarboxyaldehyde (700 mg, 10.0 mmol) were dissolved in
40 mL of tetrahydrofuran. Acetic acid (600 mg, 10.0 mmol) and
sodium triacetoxyborohydride (2.11 g, 10.0 mmol) were added
thereto, and the reaction mixture was stirred at room temperature
for two hours. The reaction mixture was mixed with 1 N aqueous
solution of sodium hydroxide, extracted with ethyl acetate twice,
and the combined organic layers were washed with brine once. The
mixture was dried over anhydrous sodium sulfate and evaporated. The
resulting residue was purified by silica gel column chromatography
(Fuji Silysia, NH Silica gel; ethyl acetate:hexane=50:50) to give
benzyl 4-(cyclopropylmethyl)homopiperazin-1-carboxylate (2.5 g) as
a colorless oil.
[1328] The resulting benzyl
4-(cyclopropylmethyl)homopiperazin-1-carboxylate (2.5 g) was
dissolved in 50 mL of ethanol, 10% palladium-carbon (500 mg) was
added, and the reaction mixture was stirred at room temperature
under hydrogen atmosphere (1 atm) for 12 hours. The
palladium-carbon was removed by filtration, and the filtrate was
evaporated to give the title compound (1.4 g) as a colorless
oil.
[1329] .sup.1H-NMR Spectrum (CDCl.sub.3,400 MHz) .delta.(ppm):
0.08-0.15(2H,m),
0.47-0.56(2H,m),0.82-0.95(1H,m),1.80-1.89(2H,m),2.44 (2H,d,J=6.4
Hz) 2.75-2.85(4H,m),2.94-3.03(4H,m).
Referential Example 5
1-(2,2,2-Trifluoroethyl)piperazine
[1330] ##STR240##
[1331] Benzyl 1-piperazinecarboxylate (2.0 g, 9.08 mmol),
2,2,2-trifluoroethyl trifluoromethanesulfonate (2.5 g, 10.8 mmol)
and triethylamine (1.9 mL, 13.8 mmol) were dissolved in 50 mL of
tetrahydrofuran, and the reaction mixture was stirred at 60.degree.
C. for two hours. After cooling to room temperature, the reaction
mixture was mixed with a saturated aqueous solution of sodium
bicarbonate and extracted with ethyl acetate twice. The combined
organic layers were sequentially washed with water and brine in
this order. The mixture was dried over anhydrous sodium sulfate and
evaporated. The resulting residue was purified by silica gel column
chromatography (Fuji Silysia, NH Silica gel; ethyl
acetate:hexane=50:50) to give
4-(2,2,2-trifluoroethyl)piperazin-1-carboxylic acid benzyl ester
(3.1 g) as a colorless oil.
[1332] Resulting benzyl
4-(2,2,2-trifluoroethyl)piperazin-1-carboxylate (3.1 g) was
dissolved in 50 mL of ethanol, and 10% palladium-carbon (900 mg)
was added, followed by stirring at room temperature under hydrogen
atmosphere (1 atm) overnight. The palladium-carbon was removed by
filtration, and the filtrate was evaporated to give the title
compound (1.4 g) as a colorless oil.
[1333] .sup.1H-NMR Spectrum (CDCl.sub.3,400 MHz) .delta.(ppm):
2.64-2.77(4H,m), 2.90-3.01(6H,m).
Referential Example 6
[1334] One loopful of the slant culture [0.5% of soluble starch,
0.5% of glucose, 0.1% of fish meat extract (manufactured by Wako
Pure Chemical Industries, Ltd.), 0.1% of yeast extract
(manufactured by Oriental Yeast Co., Ltd.), 0.2% of NZ-case
(manufactured by Humko Sheffield Chemical Co.), 0.2% of sodium
chloride, 0.1% of calcium carbonate, and 1.6% of agar (manufactured
by Wako Pure Chemical Industries, Ltd.)] of Streptomyces sp.
AB-1704 strain (FERM P-18999) isolated from the soil was inoculated
into a 65 mL test tube containing 7 mL of a seed medium [2.0% of
soluble starch, 1.0% of glucose, 0.5% of polypeptone (manufactured
by Nihon Pharmaceutical Co., Ltd.), 0.5% of yeast extract
(manufactured by Oriental Yeast Co., Ltd.), and 0.1% of calcium
carbonate], and it was cultured at 28.degree. C. for three days in
a shaking incubator to give a seed culture.
[1335] Further, 0.5 mL of the seed culture was inoculated into a 65
mL test tube containing 7 mL of a production medium [2.0% of
soluble starch, 1.0% of glucose, 0.5% of polypeptone (manufactured
by Nihon Pharmaceutical Co., Ltd.), 0.5% of yeast extract
(manufactured by Oriental Yeast Co., Ltd.), and 0.1% of calcium
carbonate], and it was cultured at 28.degree. C. for three days in
a shaking incubator.
[1336] Next, a 25 mg/mL solution of the substrate 11107B substance
(the compound of Example A4 of WO 02/060890) in ethanol was
prepared, and 0.2 mL of the solution was added to the culture.
After addition, it was shaken at 28.degree. C. for 48 hours to
carry out conversion reaction.
[1337] After the reaction, the reaction mixture was analyzed by
HPLC under the following analytic HPLC condition (a) to verify that
11107D substance was formed in the reaction mixture.
Analytic HPLC Condition (a)
[1338] Column: CAPCELL PAK C18 SG120 .phi.4.6 mm.times.250 mm
(manufactured by SHISEIDO Co.) [1339] Temperature: 40.degree. C.
[1340] Flow rate: 1 mL/min. [1341] Detection: 240 nm [1342] Eluent:
acetonitrile/0.15% potassium dihydrogenphosphate (pH 3.5) (3:7 to
5:5, v/v, 0 to 18 minutes, linear gradient), acetonitrile/0.15%
potassium dihydrogenphosphate (pH 3.5) (5:5 to 85:15, v/v, 18 to 22
minutes, linear gradient) [1343] Retention time: 11107D substance
9.9 min., 11107B substance 19.4 min.
Referential Example 7
[1344] One loopful of the slant culture (yeast-malt agar medium) of
A-1545 strain (FERM P-18944) isolated from the soil was inoculated
into a 250 mL Erlenmeyer flask containing 20 mL of a seed medium
[2.4% of soluble starch, 0.1% of glucose, 0.5% of soybean meal
(ESUSAN-MEAT manufactured by Ajinomoto Co., Ltd.), 0.3% of beef
extract (manufactured by Difco), 0.5% of yeast extract
(manufactured by Difco), 0.5% of triptone-peptone (manufactured by
Difco), and 0.4% of calcium carbonate], and it was cultured at
28.degree. C. for three days in a shaking incubator to give a seed
culture.
[1345] Further, 0.6 mL of the seed culture was inoculated into a
500 mL Erlenmeyer flask containing 60 mL of a production medium [2%
of soluble starch, 2% of glucose, 2% of soybean meal (ESUSAN-MEAT
manufactured by Ajinomoto Co., Ltd.), 0.5% of yeast extract
(manufactured by Oriental Yeast Co., Ltd.), 0.25% of sodium
chloride, 0.32% of calcium carbonate, 0.0005% of copper sulfate,
0.0005% of manganese chloride, 0.0005% of zinc sulfate, pH 7.4
before sterilization], and it was cultured at 28.degree. C. for
four days in a shaking incubator. Each 2 mL of the resulting
culture was dispensed into 15 mL test tubes. Next, a 20 mg/mL
solution of the substrate 11107B substance in dimethyl sulfoxide
was prepared, and 0.05 mL of the solution was added. After the
addition, it was shaken at 28.degree. C. for 23 hours to carry out
conversion. After the reaction, the reaction mixture was analyzed
by HPLC under the following analytic HPLC condition (b) to verify
that the 11107D substance was formed in the reaction mixture.
Analytic HPLC Condition (b)
[1346] Column: CAPCELL PAK C18 SG120 .phi.4.6 mm.times.250 mm
(manufactured by SHISEIDO Co.) [1347] Temperature: 40.degree. C.
[1348] Flow rate: 1 mL/min. [1349] Detection: 240 nm [1350] Eluent:
acetonitrile/water (50:50, v/v) isocratic [1351] Retention time:
11107B substance 7.2 min., 11107D substance 3.6 min.
Referential Example 8
[1352] One loopful of the slant culture [0.5% of soluble starch,
0.5% of glucose, 0.1% of fish meat extract (manufactured by Wako
Pure Chemical Industries, Ltd.), 0.1% of yeast extract
(manufactured by Oriental Yeast Co., Ltd.), 0.2% of NZ-case
(manufactured by Humko Sheffield Chemical Co.), 0.2% of sodium
chloride, 0.1% of calcium carbonate, and 1.6% of agar (manufactured
by Wako Pure Chemical Industries, Ltd.)] of Streptomyces sp.
AB-1704 strain (FERM P-18999) isolated from the soil was inoculated
into a 500-mL Erlenmeyer flask containing 100 mL of a seed medium
[2.0% of soluble starch, 1.0% of glucose, 0.5% of polypeptone
(manufactured by Nihon Pharmaceutical Co., Ltd.), 0.5% of yeast
extract (manufactured by Oriental Yeast Co., Ltd.), and 0.1% of
calcium carbonate], and it was cultured at 28.degree. C. for three
days in a shaking incubator to give a seed culture. Further, each 2
mL of the seed culture was inoculated into 500 mL Erlenmeyer flasks
(150 flasks) each containing 100 mL of a production medium [2.0% of
soluble starch, 1.0% of glucose, 0.5% of polypeptone (manufactured
by Nihon Pharmaceutical Co., Ltd.), 0.5% of yeast extract
(manufactured by Oriental Yeast Co., Ltd.), and 0.1% of calcium
carbonate], and it was cultured at 28.degree. C. for two days in a
shaking incubator.
[1353] A 20 mg/mL solution of the substrate 11107B substance in
ethanol was prepared, and each 0.44 mL of the solution was added to
the culture (100 mL/500 mL Erlenmeyer flask, 150 flasks). After the
addition, it was shaken at 28.degree. C. for 9 hours to carry out
conversion. After the completion of reaction, the cultures were
collected and separated into the culture supernatant and the
mycelium cake by centrifugation at 2700 rpm for 10 minutes. The
mycelium cake was extracted with 5 L of methanol and filtrated to
give the methanol extract. This methanol extract was evaporated to
remove methanol, combined with the culture supernatant and
extracted with 10 L of ethyl acetate. The resulting ethyl acetate
solution was evaporated to give 2090 mg of a crude active fraction.
The crude active fraction was dissolved in 4 mL of a mixture of
tetrahydrofuran-methanol (1:1, v/v) and 6 mL of a 50% aqueous
solution of acetonitrile, subjected to ODS column chromatography
(manufactured by YMC Co., ODS-AM 120-S50 .phi.3.6 cm.times.43 cm)
and eluted with a 40% aqueous solution of acetonitrile. An eluted
fraction from 336 mL to 408 mL was concentrated to dryness under
reduced pressure to give 560 mg of a residue. Further, the residue
was dissolved in 10 mL of a 50% aqueous solution of methanol,
subjected to ODS column chromatography (manufactured by YMC Co.,
ODS-AM 120-S50 .phi.3.6 cm.times.40 cm) and eluted with a 50%
aqueous solution of methanol. An eluted fraction from 1344 mL to
1824 mL was concentrated to dryness under reduced pressure to give
252 mg of 11107D substance.
Referential Example 9
[1354] One loopful of the slant culture (yeast-malt agar medium) of
A-1544 strain (FERM P-18943) was inoculated into a 250 mL
Erlenmeyer flask containing 25 mL of a seed medium [2% of soluble
starch, 2% of glucose, 2% of soybean meal (ESUSAN-MEAT manufactured
by Ajinomoto Co., Ltd.), 0.5% of yeast extract (manufactured by
Difco), 0.25% of sodium chloride, and 0.32% of calcium carbonate,
pH 7.4 before sterilization], and it was cultured at 28.degree. C.
for two days in a shaking incubator to give a seed culture. Each
0.75 mL of the culture was dispensed into 2 mL serum tubes
(manufactured by Sumitomo Bakelite Co., Ltd.), and an equal amount
of a 40% aqueous solution of glycerol was added. After stirring, it
was frozen at -70.degree. C. to give a frozen seed culture. The
frozen seed culture was melted, 0.25 mL thereof was inoculated into
a 250 mL Erlenmeyer flask containing 25 mL of a seed medium [2% of
soluble starch, 2% of glucose, 2% of soybean meal (ESUSAN-MEAT
manufactured by Ajinomoto Co., Ltd.), 0.5% of yeast extract
(manufactured by Oriental Yeast Co., Ltd.), 0.25% of sodium
chloride, and 0.32% of calcium carbonate, pH 7.4 before
sterilization], and it was cultured at 28.degree. C. for two days
in a shaking incubator to give a seed culture. Further, the seed
culture (0.5 mL) was inoculated into a 500 mL Erlenmeyer flask
containing 100 mL of production medium [2% of soluble starch, 2% of
glucose, 2% of soybean meal (ESUSAN-MEAT manufactured by Ajinomoto
Co., Ltd.), 0.5% of yeast extract (manufactured by Oriental Yeast
Co., Ltd.), 0.25% of sodium chloride, and 0.32% of calcium
carbonate, pH 7.4 before sterilization], and it was cultured at
28.degree. C. for three days in a shaking incubator.
[1355] Each of the resulting cultures (100 mL/500 mL Erlenmeyer
flask, 10 flasks) was subjected to centrifugation at 3000 rpm for
10 minutes to collect cells, and the cells were suspended into 100
mL of a 50 mM phosphate buffer solution (pH 6.0). Next, a 100 mg/mL
solution of the substrate 11107B substance in dimethyl sulfoxide
was prepared, and each 0.5 mL of the solution was added. After the
addition, it was shaken at 28.degree. C. for 24 hours to carry out
conversion. After the completion of the reaction, the reaction
mixtures were collected and separated into the supernatant and
mycelium cake by centrifugation at 5000 rpm for 20 minutes. The
supernatant was extracted with 1 L of ethyl acetate. The mycelium
cake was extracted with 500 mL of methanol and then filtrated to
give a methanol extract. The methanol extract was evaporated to
remove methanol and extracted with 1 L of ethyl acetate. Each of
the ethyl acetate layers was washed with water, dried over
anhydrous sodium sulfate, and the combined layers were evaporated
to give 937 mg of a crude active fraction. The crude active
fraction was subjected to silica gel column chromatography (Kiesel
gel 60, 50 g) and eluted with 1200 mL of a mixture of ethyl acetate
and n-hexane (90:10; v/v) to give 234 mg of an active fraction. The
resulting active fraction was subjected to preparative high
performance liquid chromatography (HPLC) under the following
preparative HPLC condition (C), and the resulting eluate was
analyzed by HPLC under the following analytic HPLC condition (c).
The solvent was removed from the fraction containing the 11107D
substance thus obtained, to give 80 mg of the 11107D substance.
Preparative HPLC Condition (C)
[1356] Column: CAPCELL PAK C18 UG120 .phi.30.times.250 mm
(manufactured by SHISEIDO Co.) [1357] Flow rate: 20 mL/min. [1358]
Detection: 240 nm [1359] Eluent: acetonitrile/water (30:70, v/v)
isocratic Analytic HPLC Condition (c) [1360] Column: CAPCELL PAK
C18 SG120 .phi.4.6 mm.times.250 mm (manufactured by SHISEIDO Co.)
[1361] Temperature: 40.degree. C. [1362] Flow rate: 1 mL/min.
[1363] Detection: 240 nm [1364] Eluent: acetonitrile/water (35:65,
v/v) isocratic [1365] Retention time: 11107D substance 7.8 min.
Referential Example 10
[1366] Each of cultures of A-1545 strain (FERM P-18944) (100 mL/500
mL Erlenmeyer flask, 10 flasks) obtained by a similar method as
described for Referential Example 9 was subjected to centrifugation
at 3000 rpm for 10 minutes to collect cells, and the cells were
suspended into 100 mL of a 50 mM phosphate buffer solution (pH
6.0). Next, a 100 mg/mL solution of the substrate 11107B in
dimethyl sulfoxide was prepared, and each 1 mL of the solution was
added. After the addition, it was shaken at 28.degree. C. for 24
hours to carry out conversion. After the completion of the
reaction, the reaction mixtures were collected and separated into
the supernatant and mycelium cake by centrifugation at 5000 rpm for
20 minutes. The supernatant was extracted with 1 L of ethyl
acetate. The mycelium cake was extracted with 500 mL of acetone,
and then filtrated to give an acetone extract. The acetone extract
was evaporated to remove acetone, and extracted with 1 L of ethyl
acetate. Each of the ethyl acetate layers was washed with water,
dried and dehydrated over anhydrous sodium sulfate, and the
combined layers were evaporated to give 945 mg of a crude active
fraction. The crude active fraction was subjected to silica gel
column chromatography (Kiesel gel 60, 50 g), eluted with 100 mL of
a mixture of ethyl acetate and n-hexane (50:50; v/v), 200 mL of a
mixture of ethyl acetate and n-hexane (75:25; v/v), and 600 mL of a
mixture of ethyl acetate and n-hexane (90:10; v/v), to give 463 mg
of an active fraction. The obtained active fraction was subjected
to preparative high performance liquid chromatography (HPLC) under
the preparative HPLC condition (C) described in Example 4, the
resulting eluate was analyzed by HPLC under the analytic HPLC
condition described in Example 4. The solvent was removed from the
fraction containing 11107D substance thus obtained, to give 304 mg
of 11107D substance.
* * * * *