U.S. patent application number 10/343972 was filed with the patent office on 2004-05-06 for avermectin derivatives.
Invention is credited to Nagai, Kenichiro, Omura, Satoshi, Sunazuka, Toshiaki.
Application Number | 20040087519 10/343972 |
Document ID | / |
Family ID | 18732258 |
Filed Date | 2004-05-06 |
United States Patent
Application |
20040087519 |
Kind Code |
A1 |
Omura, Satoshi ; et
al. |
May 6, 2004 |
Avermectin derivatives
Abstract
A compound represented by the general formula (I) or a salt
thereof: 1 wherein, --XY-- represents --CH.dbd.CH--,
--CH.sub.2--CH.sub.2-- or the like, between R.sup.1 and the carbon
atom at 4'-position represents a single bond or a double bond,
between R.sup.2 and the carbon atom at 5-position represents a
single bond or a double bond, and for example, 1) when --XY--
represents --CH.dbd.CH-- or --CH.sub.2--CH.sub.2--, and between
R.sup.1 and the carbon atom at 4'-position represents a double
bond, R.sup.1 represents .dbd.C(R.sup.11)(R.sup.12) (wherein
R.sup.11 represents a lower alkyl group or the like and R.sup.12
represents a hydrogen atom or the like) or the like, and R.sup.2
represents a hydroxyl group or the like, or R.sup.2 may be combined
together with the carbon atom at 5-position to form a carbonyl
group, and 2) when --XY-- represents --CH.dbd.CH-- or
--CH.sub.2--CH.sub.2--, and between R.sup.1 and the carbon atom at
4'-position represents a single bond, R.sup.1 represents
--OCH(R.sup.1a)(R.sup.1b) (wherein R.sup.1a represents a lower
alkyl or the like and R.sup.1b represents a hydrogen atom or the
like) or the like, and R.sup.2 represents a hydroxyl group or the
like.
Inventors: |
Omura, Satoshi; (Tokyo,
JP) ; Nagai, Kenichiro; (Tokyo, JP) ;
Sunazuka, Toshiaki; (Chiba, JP) |
Correspondence
Address: |
GREENBLUM & BERNSTEIN, P.L.C.
1950 ROLAND CLARKE PLACE
RESTON
VA
20191
US
|
Family ID: |
18732258 |
Appl. No.: |
10/343972 |
Filed: |
September 8, 2003 |
PCT Filed: |
August 8, 2001 |
PCT NO: |
PCT/JP01/06803 |
Current U.S.
Class: |
514/28 ;
536/7.1 |
Current CPC
Class: |
A61P 33/10 20180101;
A61K 31/365 20130101; A61P 33/00 20180101; C07H 17/08 20130101;
A61K 31/7048 20130101 |
Class at
Publication: |
514/028 ;
536/007.1 |
International
Class: |
A61K 031/7048; C07H
017/08 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 9, 2000 |
JP |
2000-240988 |
Claims
What is claimed is:
1. A compound represented by the general formula (I) or a salt
thereof: 34wherein, --XY-- represents --CH.dbd.CH--,
--CH.sub.2--C(.dbd.O)--, --CH.sub.2--CH.sub.2--, or
--CH.sub.2--CH(R.sup.13S)-- (wherein R.sup.13 represents a hydroxyl
group or a lower alkylcarbonyloxy group, between R.sup.1 and the
carbon atom at 4'-position represents a single bond or a double
bond, between R.sup.2 and the carbon atom at 5-position represents
a single bond or a double bond, and 1) when --XY-- represents
--CH.dbd.CH-- or --CH.sub.2--CH.sub.2, and between R.sup.1 and the
carbon atom at 4'-position represents a double bond, R.sup.1
represents .dbd.C(R.sup.11)(R.sup.12) <wherein R.sup.11
represents a substituted or unsubstituted lower alkyl group, a
formyl group, a lower alkoxycarbonyl group (wherein a lower alkyl
moiety of said lower alkoxycarbonyl group may be substituted with a
heterocyclic group), --CH.dbd.N--OR.sup.2 (wherein R.sup.3
represents a hydrogen atom or a lower alkyl group), a lower
alkenylcarbonyl group, --CH.dbd.N--NH--CONH.sub.2, a cyano group,
--COR.sup.4 (wherein R.sup.4 represents a hydroxyl group, a lower
alkenyloxy group ,or --N(R.sup.5)(R.sup.6) (wherein R.sup.5 and
R.sup.6 are combined together with the adjacent nitrogen atom to
form a nitrogen-containing heterocyclic group)), a vinyl group
substituted with a lower alkenyloxycarbonyl group,
--CO--S--CH.sub.2--CH.sub.2--NH CO--R.sup.x (wherein R.sup.x
represents a lower alkyl group), or --CH.dbd.CH--COOH, and R.sup.12
represents a hydrogen atom, provided that when R.sup.11 represents
a cyano group, R.sup.12 represents a hydrogen atom or a lower alkyl
group>, or is combined together with the carbon atom at
4'-position to form a carbonyl group, and when between R.sup.2 and
the carbon atom at 5-position represents a single bond, R.sup.2
represents a hydroxyl group, a lower alkoxyl group, or a lower
alkenyloxycarbonyloxy group, and when between R.sup.2 and the
carbon atom at 5-position represents a double bond, R.sup.2 is
combined together with the carbon atom at 5-position to form a
carbonyl group or a hydroxime group (--C(.dbd.NOH)--); 2) when
--XY-- represents --CH.dbd.CH-- or --CH.sub.2--CH.sub.2--, and
between R.sup.1 and the carbon atom at 4'-position represents a
single bond, R.sup.1 represents a hydroxyl group,
--OCH(R.sup.1a)(R.sup.1b) <wherein R.sup.1a represents a
substituted or unsubstituted lower alkyl group, a formyl group, a
carboxyl group, a lower alkoxycarbonyl group (wherein a lower alkyl
moiety of said lower alkoxycarbonyl group may be substituted with a
heterocyclic group), --CH.dbd.N--OR.sup.7 (wherein R.sup.7
represents a hydrogen atom or a lower alkyl group), a lower
alkenyloxycarbonyl group, --CH.dbd.N--NH--CONH.sub.2, a cyano
group, --COR.sup.8 {(wherein R.sup.8 represents an arylalkyloxy
group (wherein the aryl group may contain one or more heteroatoms
as ring-constituting atoms) or --N(R.sup.9)(R.sup.10) (wherein
R.sup.9 and R.sup.10 are combined together with the adjacent
nitrogen atom to form a nitrogen-containing heterocyclic group)}, a
vinyl group substituted with a lower alkenyloxycarbonyl group,
--CO--S--CH.sub.2--CH.sub.2--NH--CO--R.sup.Y (wherein R.sup.Y
represents a lower alkyl group), --CH.dbd.CH--COOH, or a
substituted or unsubstituted aryl group, and R.sup.1b represents a
hydrogen atom, provided that when R.sup.1a represents a carboxyl
group or a lower alkoxycarbonyl group (wherein a lower alkyl moiety
of said lower alkoxycarbonyl group may be substituted with a
heterocyclic group), R.sup.1b may further represents a lower
alkoxycarbonyl group (wherein a lower alkyl moiety of said lower
alkoxycarbonyl group may be substituted with a heterocyclic group),
a carboxyl group, a cyano group, or an aryl group>, a
carboxymethyl group, or a cyanomethyl group, and when between
R.sup.2 and the carbon atom at 5-position represents a single bond,
R.sup.2 represents a hydroxyl group, a lower alkoxyl group, or a
lower alkenyloxycarbonyloxy group, and when between R.sup.2 and the
carbon atom at 5-position represents a double bond, R.sup.2 is
combined together with the carbon atom at 5-position to form a
carbonyl group or a hydroxime group (--C(.dbd.NOH)--); 3) when
--XY-- represents --CH.sub.2--C(.dbd.O)--, and between R.sup.1 and
the carbon atom at 4'-position represents a double bond, R.sup.1
represents .dbd.C(R.sup.11a)(R.sup.12a) (wherein R.sup.11a
represents a lower alkoxycarbonyl group (wherein a lower alkyl
moiety of said lower alkoxycarbonyl group may be substituted with a
heterocyclic group) or --COOCH.sub.2CH.dbd.CH.sub.2, and R.sup.12a
represents a hydrogen atom), or is combined together with the
carbon atom at 4'-position to form carbonyl group, between R.sup.2
and the carbon atom at 5-position represents a single bond, and
R.sup.2 represents a hydroxyl group, a lower alkoxyl group, or a
lower alkenyloxycarbonyloxy group; 4) when --XY-- represents
--CH.sub.2--C(.dbd.O)--, and between R.sup.1 and the carbon atom at
4'-position represents a single bond, R.sup.1 represents
--OCH(R.sup.1aa)(R.sup.1ba) <wherein R.sup.1aa represents a
substituted or unsubstituted lower alkyl group, a formyl group, a
carboxyl group, a lower alkoxycarbonyl group (wherein a lower alkyl
moiety of said lower alkoxycarbonyl group may be substituted with a
heterocyclic group), --CH.dbd.N--OR.sup.7a (wherein R.sup.7a
represents a hydrogen atom or a lower alkyl group), a lower
alkenyloxycarbonyl group, --CH.dbd.N--NH--CONH.sub.2, a cyano
group, --COR.sup.6a {wherein R.sup.6a represents an arylalkyloxy
group (wherein the aryl group may contain one or more heteroatoms
as ring-constituting atoms), or --N(R.sup.9a)(R.sup.10a) (wherein
R.sup.9a and R.sup.10a are combined together with the adjacent
nitrogen atom to form a nitrogen-containing heterocyclic group)}, a
vinyl group substituted with a lower alkenyloxycarbonyl group,
--CO--S--CH.sub.2--CH.sub.2--NH--CO--R.sup.Ya (wherein R.sup.Ya
represents a lower alkyl group), --CH.dbd.CH--COOH, or a
substituted or unsubstituted aryl group, and R.sup.1ba represents a
hydrogen atom, provided that when R.sup.1aa represents a carboxyl
group or a lower alkoxycarbonyl group (wherein a lower alkyl moiety
of said lower alkoxycarbonyl group may be substituted with a
heterocyclic group), R.sup.1ba may further represents a lower
alkoxycarbonyl group (wherein a lower alkyl moiety of said lower
alkoxycarbonyl group may be substituted with a heterocyclic group),
a carboxyl group, a cyano group, or an aryl group>, and when
between R.sup.2 and the carbon atom at 5-position represents a
single bond, R.sup.2 represents a hydroxyl group, a lower alkoxyl
group, or a lower alkenyloxycarbonyloxy group, and when between
R.sup.2 and the carbon atom at 5-position represents a double bond,
R.sup.2 is combined together with the carbon atom at 5-position to
form a carbonyl group or a hydroxime group (--C(.dbd.NOH)--); 5)
when --XY-- represents --CH.sub.2--CH(R.sup.13)-- (wherein R.sup.18
has the same meaning as that defined above), and between R.sup.1
and the carbon atom at 4'-position represents a double bond,
R.sup.1 represents .dbd.C(R.sup.11b)(R.sup.12b) (wherein R.sup.11b
represents a cyano group, a carboxyl group, a lower alkoxycarbonyl
group, or a lower alkenyloxycarbonyl group, or is combined
togethrer with the carbon atom at 4'-position to form a carbonyl
group, and R.sup.12b represents a hydrogen atom), between R.sup.2
and the carbon atom at 5-position represents a single bond, and
R.sup.2 represents a hydroxyl group, a lower alkoxyl group, or a
lower alkenyloxycarbonyloxy group; and 6) when --XY-- represents
--CH.sub.2--CH(R.sup.13)-- (wherein R.sup.13 has the same meaning
as that defined above), and between R.sup.1 and the carbon atom at
4'-position represents a single bond, R.sup.1 represents
--OCH(R.sup.1ab)(R.sup.1bb) <wherein R.sup.1ab represents a
substituted or unsubstituted lower alkyl group, a formyl group, a
carboxyl group, a lower alkoxycarbonyl group (wherein a lower alkyl
moiety of said lower alkoxycarbonyl group may be substituted with a
heterocyclic group), --CH.dbd.N--OR.sup.7b (wherein R.sup.7b
represents a hydrogen atom or a lower alkyl group), a lower
alkenyloxycarbonyl group, --CH.dbd.N--NH--CONH.sub.2, a cyano
group, --COR.sup.8b }wherein R.sup.8b represents an arylalkyloxy
group (wherein the aryl group may contain one or more heteroatoms
as ring-constituting atoms), or --N(R.sup.9b)(R.sup.10b) (wherein
R.sup.9b and R.sup.10b are combined together with the adjacent
nitrogen atom to form a nitrogen-containing heterocyclic group)}, a
vinyl group substituted with a low r alkenyloxycarbonyl group,
--CO--S--CH.sub.2--CH.sub.2--NH--CO--R.sup.Yb (wherein R.sup.Yb
represents a lower alkyl group), --CH.dbd.CH--COOH, or a
substituted or unsubstituted aryl group, and R.sup.1bb represents a
hydrogen atom, provided that when R.sup.1ab represents a carboxyl
group or a lower alkoxycarbonyl group (wherein a lower alkyl moiety
of said lower alkoxycarbonyl group may be substituted with a
heterocyclic group), R.sup.1bb may further represents a lower
alkoxycarbonyl group (wherein a lower alkyl moiety of said lower
alkoxycarbonyl group may be substituted with a heterocyclic group),
a carboxyl group, a cyano group, or an aryl group>, and when
between R.sup.2 and the carbon atom at 5-position represents a
single bond, R.sup.2 represents a hydroxyl group, a lower alkoxyl
group, or a lower alkenyloxycarbonyloxy group, and when between
R.sup.2 and the carbon atom at 5-position represents a double bond,
R.sup.2 is combined together with the carbon atom at 6-position to
form a carbonyl group or a hydroxime group (--C(.dbd.NOH)--)
2. The compound or the salt according to claim 1, wherein --XY-- is
--CH.dbd.CH--.
3. The compound or the salt according to claim 1, wherein --XY-- is
--CH.sub.2--CH.sub.2--.
4. The compound or the salt according to any one of claims 1 to 3,
wherein R.sup.11 is a substituted or unsubstituted lower alkyl
group, a formyl group, a lower alkoxycarbonyl group, a lower
alknenylcarbonyl group, a cyano group, or --COR.sup.4 (wherein
R.sup.4 has the same meaning as that defined above).
5. The compound or the salt according to any one of claims 1 to 3,
wherein R.sup.1 is a hydroxyl group or --OCH.sub.2R.sup.1ac
{wherein R.sup.1ac represents a substituted or unsubstituted lower
alkyl group, a carboxyl group, or a lower alkoxycarbonyl group
(wherein a lower alkyl moiety of said lower alkoxycarbonyl group
may be substituted with a heterocyclic group)}.
6. The compound or the salt according to any one of claims 1 to 5,
wherein R.sup.2 is a hydroxyl group or a lower
alkenyloxycarbonyloxy group.
7. A medicament which comprises the compound according to any one
of claims 1 to 6 or a physiologically acceptable salt thereof as an
active ingredient.
8. A method for therapeutic treatment of parasitosis which
comprises the step of administering to a mammal including a human a
therapeutically effective amount of the compound according to any
one of claims 1 to 6 or a physiologically acceptable salt
thereof.
9. A medicament for therapeutic treatment of parasitosis which
comprises the compound according to any one of claims 1 to 6 or a
physiologically acceptable salt thereof as an active
ingredient.
10. Use of the compound according to any one of claims 1 to 6 or a
physiologically acceptable salt thereof for manufacture of an
antiparasitic agent.
Description
TECHNICAL FIELD
[0001] The present invention relates to avermectin derivatives
having antiparasitic activity.
BACKGROUND ART
[0002] Avermectins are antiparasitic antibiotics produced by
Streptomyces avermitilis. Four main ingredients (A1a, A2a, B1a and
B2a) have been known, and among them, avermectin B1a is known to
have potent activity (Japanese Patent Unexamined Publication
(KOKAI) No. (Hei) 3-254678/1991).
[0003] Various derivatives have been synthesized so far to provide
avermectin derivatives having higher activity. However, these
derivatives fail to have fully satisfactory antiparasitic activity.
For example, a monosaccharide derivative as avermectin derivatives
are known. However, these derivatives are known to have two to four
fold weaker activity than corresponding disaccharide compounds (J.
Med. Chem., 23, 1134-1136, 1980).
DISCLOSURE OF THE INVENTION
[0004] An object of the present invention is to provide avermectin
derivatives having antiparasitic activity.
[0005] In order to find avermectin derivatives having higher
antiparasitic activity, the inventors of the present invention
synthesized various derivatives using avermectins B1a, B2a and
ivermectin as starting materials. As a result, we succeeded in
obtaining derivatives represented by the following general formula
(I) which have high antiparasitic activity. The present invention
was achieved on the basis of the findings.
[0006] The present invention thus provides compounds represented by
th general formula (I) or salts thereof; 2
[0007] wherein, --XY-- represents --CH.dbd.CH--,
--CH.sub.2--C(.dbd.O)--, --CH.sub.2--CH.sub.2--, or
--CH.sub.2--CH(R.sup.13)-- (wherein R.sup.13 represents a hydroxyl
group or a lower alkylcarbonyloxy group),
[0008] between R.sup.1 and the carbon atom at 4'-position
represents a single bond or a double bond,
[0009] between R.sup.2 and the carbon atom at 5-position represents
a single bond or a double bond, and
[0010] 1) when --XY-- represents --CH.dbd.CH-- or
--CH.sub.2--CH.sub.2--, and between R.sup.1 and the carbon atom at
4'-position represents a double bond,
[0011] R.sup.1 represents .dbd.C(R.sup.11)(R.sup.12) <wherein
R.sup.11 represents a substituted or unsubstituted lower alkyl
group, a formyl group, a lower alkoxycarbonyl group (wherein a
lower alkyl moiety of said lower alkoxycarbonyl group may be
substituted with a heterocyclic group), --CH.dbd.N--OR.sup.3
(wherein R.sup.3 represents a hydrogen atom or a lower alkyl
group), a lower alkenylcarbonyl group, --CH.dbd.N--NH--CONH.sub.2,
a cyano group, --COR.sup.4 (wherein R.sup.4 represents a hydroxyl
group, a lower alkenyloxy group ,or --N(R.sup.5)(R.sup.6) (wherein
R.sup.5 and R.sup.6 are combined together with the adjacent
nitrogen atom to form a nitrogen-containing heterocyclic group)}, a
vinyl group substituted with a lower alkenyloxycarbonyl group,
--CO--S--CH.sub.2--CH.sub.2--NH--CO--R.sup.x (wherein R.sup.x
represents a lower alkyl group), or --CH.dbd.CH--COOH, and R.sup.12
represents a hydrogen atom, provided that when R.sup.11 represents
a cyano group, R.sup.12 repres nts a hydrogen atom or a lower alkyl
group>, or is combined together with the carbon atom at
4'-position to form a carbonyl group, and
[0012] when between R.sup.2 and the carbon atom at 5-position
represents a single bond, R.sup.2 represents a hydroxyl group, a
lower alkoxyl group, or a lower alkenyloxycarbonyloxy group,
and
[0013] when between R.sup.2 and the carbon atom at 5-position
represents a double bond, R.sup.2 is combined together with the
carbon atom at 5-position to form a carbonyl group or a hydroxime
group (--C(.dbd.NOH)--);
[0014] 2) when --XY-- represents --CH.dbd.CH-- or
--CH.sub.2--CH.sub.2--, and between R.sup.1 and the carbon atom at
4'-position represents a single bond,
[0015] R.sup.1 represents a hydroxyl group,
--OCH(R.sup.1a)(R.sup.1b) <wherein R.sup.1a represents a
substituted or unsubstituted lower alkyl group, a formyl group, a
carboxyl group, a lower alkoxycarbonyl group (wherein a lower alkyl
moiety of said lower alkoxycarbonyl group may be substituted with a
heterocyclic group), --CH.dbd.N--OR.sup.7 (wherein R.sup.7
represents a hydrogen atom or a lower alkyl group), a lower
alkenyloxyearbonyl group, --CH.dbd.N--NH--CONH.sub.2, a cyano
group, --COR.sup.8 {wherein R.sup.8 represents an arylalkyloxy
group (wherein the aryl group may contain one or more heteroatoms
as ring-constituting atoms) or --N(R.sup.9)(R.sup.10) (wherein
R.sup.9 and R.sup.10 are combined together with the adjacent
nitrogen atom to form a nitrogen-containing heterocyclic group)], a
vinyl group substituted with a lower alkenyloxycarbonyl group,
--CO--S--CH.sub.2--CH.sub.2--NH--CO--R.- sup.Y (wherein R.sup.Y
represents a lower alkyl group), --CH.dbd.CH--COOH, or a
substituted or unsubstituted aryl group, and R.sup.1b represents a
hydrogen atom, provided that when R.sup.1a represents a carboxyl
group or a lower alkoxycarbonyl group (wherein a lower alkyl moiety
of said lower alkoxycarbonyl group may be substituted with a
heterocyclic group), R.sup.1b may further represents a lower
alkoxycarbonyl group (wherein a lower alkyl moiety of said lower
alkoxycarbonyl group may be substituted with a heterocyclic group),
a carboxyl group, a cyano group, or an aryl group>, a
carboxymethyl group, or a cyanomethyl group, and
[0016] when between R.sup.2 and the carbon atom at 5-position
represents a single bond, R.sup.2 represents a hydroxyl group, a
lower alkoxyl group, or a lower alkenyloxycarbonyloxy group,
and
[0017] when between R.sup.2 and the carbon atom at 5-position
represents a double bond, R.sup.2 is combined together with the
carbon atom at 5-position to form a carbonyl group or a hydroxime
group (--C(.dbd.NOH)--);
[0018] 3) when --XY-- represents --CH.sub.2--C(.dbd.O)--, and
between R.sup.1 and the carbon atom at 4'-position represents a
double bond,
[0019] R.sup.1 represents .dbd.C(R.sup.11a)(R.sup.12a) (wherein
R.sup.11a represents a lower alkoxycarbonyl group (wherein a lower
alkyl moiety of said lower alkoxycarbonyl group may be substituted
with a heterocyclic group) or --COOCH.sub.2CH.dbd.CH.sub.2, and
R.sup.12a represents a hydrogen atom), or is combined together with
the carbon atom at 4'-position to form carbonyl group,
[0020] between R.sup.2 and the carbon atom at 5-position represents
a single bond, and
[0021] R.sup.2 represents a hydroxyl group, a lower alkoxyl group,
or a lower alkenyloxycarbonyloxy group;
[0022] 4) when --XY-- represents --CH.sub.2--C(.dbd.O)--, and
between R.sup.1 and the carbon atom at 4'-position represents a
single bond,
[0023] R.sup.1 represents --OCH(R.sup.1aa)(R.sup.1ba) <wherein
R.sup.1aa represents a substituted or unsubstituted lower alkyl
group, a formyl group, a carboxyl group, a lower alkoxycarbonyl
group (wherein a lower alkyl moiety of said lower alkoxycarbonyl
group may be substituted with a heterocyclic group),
--CH.dbd.N--OR.sup.7a (wherein R.sup.7a represents a hydrogen atom
or a lower alkyl group), a lower alkenyloxycarbonyl group,
--CH.dbd.N--NH--CONH.sub.2, a cyano group, --COR.sup.8a (wherein
R.sup.8a represents an arylalkyloxy group (wherein the aryl group
may contain one or more heteroatoms as ring-constituting atoms), or
--N(R.sup.9a)(R.sup.10a) (wherein R.sup.9a and R.sup.10a are
combined together with the adjacent nitrogen atom to form a
nitrogen-containing heterocyclic group)}, a vinyl group substituted
with a lower alkenyloxycarbonyl group,
--CO--S--CH.sub.2--CH.sub.2--NH--CO--R.- sup.Ya (wherein R.sup.Ya
represents a lower alkyl group), --CH.dbd.CH--COOH, or a
substituted or unsubstituted aryl group, and R.sup.1ba represents a
hydrogen atom, provided that when R.sup.1aa represents a carboxyl
group or a lower alkoxycarbonyl group (wherein a lower alkyl moiety
of said lower alkoxycarbonyl group may be substituted with a
heterocyclic group), R.sup.1ba may further represents a lower
alkoxycarbonyl group (wherein a lower alkyl moiety of said lower
alkoxycarbonyl group may be substituted with a heterocyclic group),
a carboxyl group, a cyano group, or an aryl group>, and
[0024] when between R.sup.2 and the carbon atom at 5-position
represents a single bond, R.sup.2 represents a hydroxyl group, a
lower alkoxyl group, or a lower alkenyloxycarbonyloxy group,
and
[0025] when between R.sup.2 and the carbon atom at 5-position
represents a double bond, R.sup.2 is combined together with the
carbon atom at 5-position to form a carbonyl group or a hydroxime
group (--C(.dbd.NOH)--);
[0026] 5) when --XY-- represents --CH.sub.2--CH(R.sup.13)--
(wherein R.sup.13 has the same meaning as that defined above), and
between R.sup.1 and the carbon atom at 4'-position represents a
double bond,
[0027] R.sup.1 represents .dbd.C(R.sup.11b)(R.sup.12b) (wherein
R.sup.11b represents a cyano group, a carboxyl group, a lower
alkoxycarbonyl group, or a lower alkenyloxycarbonyl group, or is
combined togethrer with the carbon atom at 4'-position to form a
carbonyl group, and R.sup.12b represents a hydrogen atom),
[0028] between R.sup.2 and the carbon atom at 5-position represents
a single bond, and R.sup.2 represents a hydroxyl group, a lower
alkoxyl group, or a lower alkenyloxycarbonyloxy group; and
[0029] 6) when --XY-- represents --CH.sub.2--CH(R.sup.13)--
(wherein R.sup.13 has the same meaning as that defined above), and
between R.sup.1 and the carbon atom at 4'-position represents a
single bond,
[0030] R.sup.1 represents --OCH(R.sup.1ab)(R.sup.1bb) <wherein
R.sup.1ab represents a substituted or unsubstituted lower alkyl
group, a formyl group, a carboxyl group, a lower alkoxycarbonyl
group (wherein a lower alkyl moiety of said lower alkoxycarbonyl
group may be substituted with a heterocyclic group),
--CH.dbd.N--OR.sup.7b (wherein R.sup.7b represents a hydrogen atom
or a lower alkyl group), a lower alkenyloxycarbonyl group,
--CH.dbd.N--NH--CONH.sub.2, a cyano group, --COR.sup.8b {wherein
R.sup.8b represents an arylalkyloxy group (wherein the aryl group
may contain one or more heteroatoms as ring-constituting atoms), or
--N(R.sup.9b)(R.sup.10b) (wherein R.sup.9b and R.sup.10b are
combined together with the adjacent nitrogen atom to form a
nitrogen-containing heterocyclic group)}, a vinyl group substituted
with a lower alkenyloxycarbonyl group,
--CO--S--CH.sub.2--CH.sub.2--NH--CO--R.- sup.Yb (wherein R.sup.Yb
represents a lower alkyl group), --CH.dbd.CH--COOH, or a
substituted or unsubstituted aryl group, and R.sup.1bb represents a
hydrogen atom, provided that when R.sup.1ab represents a carboxyl
group or a lower alkoxycarbonyl group (wherein a lower alkyl moiety
of said lower alkoxycarbonyl group may be substituted with a
heterocyclic group), R.sup.1bb may further represents a lower
alkoxycarbonyl group (wherein a lower alkyl moiety of said lower
alkoxycarbonyl group may be substituted with a heterocyclic group),
a carboxyl group, a cyano group, or an aryl group>, and
[0031] when between R.sup.2 and the carbon atom at 5-position
represents a single bond, R.sup.2 represents a hydroxyl group, a
lower alkoxyl group, or a lower alkenyloxycarbonyloxy group,
and
[0032] when between R.sup.2 and the carbon atom at 5-position
represents a double bond, R.sup.2 is combined together with the
carbon atom at 5-position to form a carbonyl group or a hydroxime
group (--C(.dbd.NOH)--).
[0033] According to the general formula (I) of the present
invention, the compound or a salt thereof wherein --XY-- is
--CH.dbd.CH-- is preferred. Among them, the compound wherein
R.sup.11 is a substituted or unsubstituted lower alkyl group, a
formyl group, a lower alkoxycarbonyl group, a lower alkenylcarbonyl
group, cyano group, or --COR.sup.4 (wherein R.sup.4 has the same
meaning as that defined above), the compound {wherein R.sup.1 is
hydroxyl group or --OCH.sub.2R.sup.1ac wherein R.sup.1ac represents
a substituted or unsubstituted lower alkyl group, carboxyl group,
or a lower alkoxycarbonyl group (the lower alkyl moiety of the
lower alkoxycarbonyl group may be substituted with a heterocyclic
group)} or the salts thereof are preferred.
[0034] According to the general formula (I) of the present
invention, the compound or a salt thereof wherein --XY-- is
--CH.sub.2--CH.sub.2-- is also preferred. Among them, the compound
wherein R.sup.11 is a substituted or unsubstituted lower alkyl
group, a formyl group, a lower alkoxycarbonyl group, a lower
alkenylcarbonyl group, cyano group, or --COR.sup.4 (wherein R.sup.4
has the same meaning as that defined above), the compound wherein
R.sup.1 is hydroxyl group or --OCH.sub.2R.sup.1ac (wherein
R.sup.1ac represents a substituted or unsubstituted lower alkyl
group, carboxyl group, or a lower alkoxycarbonyl group (the lower
alkyl moiety of the lower alkoxycarbonyl group may be substituted
with a heterocyclic group)) or the salts thereof are preferred.
[0035] Also according to the general formula (I) of the present
invention, the compound or a salt thereof wherein R.sup.2 is
hydroxyl group or a lower alkenyloxycarbonyloxy group is
preferred.
[0036] According to another aspect of the present invention, ther
are provided medicaments which comprise as an active ingredient the
compound represented by the aforementioned general formula (I) or
the physiologically acceptable salt thereof. The medicaments can be
administered as agents for therapeutic treatment of parasitosis to
a mammal including a human.
[0037] According to further aspects of the present invention, there
are provided a use of the compound represented by the
aforementioned general formula (I) or the physiologically
acceptable salt thereof for the manufacture of the aforementioned
medicament; and a method for therapeutic treatment of parasitosis
which comprises the step of administering a therapeutically
effective amount of the compound represented by the aforementioned
general formula (I) or the physiologically acceptable salt thereof
to a mammal including a human.
BEST MODE FOR CARRYING OUT THE INVENTION
[0038] Hereinafter the compounds represented by the general formula
(I) are referred to as the compounds (1). The compounds of other
formula numbers are abbreviated in a similar manner.
[0039] In the compounds (I) of the present invention, --XY--
represents --CH.dbd.CH--, --CH.sub.2--C(.dbd.O)--,
--CH.sub.2--CH.sub.2--, or --CH.sub.2--CH(R.sup.13)-- (wherein
R.sup.13 has the same meaning as that defined above, and in each
formula, the carbon atom on the left side corresponds to X.).
[0040] In the compounds (I) of the present invention, the compounds
wherein --XY-- is --CH.dbd.CH-- and between R.sup.1 and a carbon
atom at the 4'-position is a double bond are referred to as the
compounds (Ia), and the compounds wherein --XY-- is --CH.dbd.CH--
and between R.sup.1 and a carbon atom at the 4'-position is a
single bond are referred to as the compounds (Ic).
[0041] In the compounds (I) of the present invention, the compounds
wherein --X Y-- is --CH.sub.2--CH.sub.2--, and between R.sup.1 and
a carbon atom at the 4'-position is a double bond is referred to as
the compounds (Ib), the compounds wherein --XY-- is
--CH.sub.2--CH.sub.2--, and between R.sup.1 and a carbon atom at
the 4'-position is a single bond is referred to as the compounds
(Id).
[0042] In the compounds (I) of the present invention, the compounds
wherein --XY-- is --CH.sub.2--C(.dbd.O)-- are referred to as the
compounds (Ie), and the compounds wherein --XY-- is
--CH.sub.2--CH(R.sup.13) (wher in R.sup.13 has th same meaning as
that defined above) are referred to as the compounds (If).
[0043] In the definition of each group in the compounds (I), the
lower alkyl group may be any of C.sub.1-C.sub.8 linear, branched,
and cyclic alkyl groups or a combination thereof, preferably a
C.sub.1-C.sub.8 linear or branched alkyl group. The lower alkyl
group includes, for example, a methyl group, ethyl group, propyl
group, isopropyl group, cyclopropyl group, butyl group, isobutyl
group, sec-butyl group, tert-butyl group, cyclopropylmethyl group,
cyclobutyl group, pentyl group, hexyl group, heptyl group, octyl
group, and the like. A lower alkyl moiety in functional groups
having the lower alkyl moiety, such as the lower alkoxycarbonyl
group, lower alkoxyl group, and lower alkylcarbonyloxy group, has
the same meaning as that defined in the aforementioned lower alkyl
group, unless otherwise specifically mentioned.
[0044] The alkyl moiety of the arylalkyloxy group is a group
wherein one of hydrogen atom is removed from an a lower alkyl
group.
[0045] Examples of a lower alkenyl moiety in the lower
alkenylcarbonyl group, the lower alkenyloxycarbonyl group, the
lower alkenyloxy group, and the lower alkenyloxycarbonyloxy group
include C.sub.2-C.sub.6 straight and branched alkenyl groups, for
example, a vinyl group, allyl group, methacryl group, butenyl
group, pentenyl group, hexenyl group and the like. Allyl group is
particularly preferred. The number of double bonds present in the
alkenyl group is not particularly limited, and preferably one.
[0046] Example of the aryl group and the aryl moiety of the
arylalkyloxy group include phenyl group, and naphthyl group.
[0047] The heterocyclic group may be either an aromatic or
aliphatic heterocyclic group. Examples of the aromatic heterocyclic
group include, for example, a 5- or 6-membered monocyclic aromatic
heterocyclic group which contains at least one heteroatom selected
from the group consisting of nitrogen, oxygen, and sulfur atoms.
More specifically, examples include a pyridyl group, pyrrolyl
group, furyl group, thienyl group, thiazolyl group, pyrazinyl
group, imidazolyl group, pyrazolyl group, triazolyl group,
tetrazolyl group, and oxazolyl group. Examples of the aliphatic
heterocyclic group include, for example, a 5- or 6-membered
monocyclic aliphatic het rocyclic gr up which contains at least one
heteroatom selected from the group consisting of nitrogen, oxygen,
and sulfur atoms. More specifically, examples include a
pyrrolidinyl group, tetrahydrofuryl group, and tetrahydropyranyl
group.
[0048] The nitrogen containing heterocyclic group formed together
with the adjacent nitrogen atom includes a morpholino group,
thiomorpholino group, piperidino group, 1-piperazinyl group, and
1-pyrrolidinyl group.
[0049] The type and number of the substituent of the substituted
lower alkyl group are not particularly limited. Preferably, the
number of the substituent is from 1 to 3, and examples include a
hydroxyl group, a halogen atom ("a halogen atom" used herein may be
any of fluorine, chlorine, bromine, and iodine atoms), an amino
group, a hydroxyamino group, a mono(lower alkyl)amino group, a
mono(lower alkoxy)amino group, a lower alkanoylamino group, an
azide group, a heterocyclic group (examples of the heterocyclic
group include the groups exemplified for the aforementioned
heterocyclic group and the nitrogen containing heterocyclic group
formed together with the adjacent nitrogen atom), a lower
alkanoyloxy group, a heterocyclic carbonyloxy group(i.e.,
heterocycle-C(.dbd.O)--O-- wherein the heterocyclic moiety has the
same meaning as that defined in the aforementioned heterocyclic
group and the heterocyclic moiety may be substituted with a halogen
atom or a lower alkoxycarbonyl group), a heterocyclic-oxy group
such as tetrahydropyranyloxy group, an aryl group, a substituted or
unsubstituted arylcarbonyloxy group (the type and number of the
substituent on the aryl group of the substituted arylcarbonyloxy
group is not particularly limited, and examples preferably include
one to five substituents such as a halogen atom, an amino group, a
hydroxyl group, and a nitro group), a substituted or unsubstituted
arylsulfonyloxy group (the substituent of the substituted
arylsulfonyloxy group may be the alkyl group having the same
meaning as that defined above), a lower alkylsulfonyloxy group, a
carboxyl group, a lower alkoxycarbonyl group, and a cyano
group.
[0050] In the definition of the substituent of the substituted
lower alkyl group, a lower alkyl moiety of the mono(lower
alkyl)amino group, mono(lower alkoxy)amino group, lower
alkanoylamino group, lower alkanoyloxy group, lower alkoxycarbonyl
group, and lower alkylsulfonyloxy group has the same meaning as
that defined in the aforementioned lower alkyl group.
[0051] In the definition of the substituents of the substituted
lower alkyl group, the aryl group and an aryl moiety of the
arylcarbonyloxy group and arylsulfonyloxy group has the same
meaning as that defin d in the aforementioned aryl group.
[0052] The type and number of the substituent of the substituted
aryl group are not particularly limited. Preferably, examples
include one to five substituents such as a nitro group, an amino
group, a hydroxyl group, and a halogen atom.
[0053] Examples of the salt of the compounds (I) include
acid-addition salts, metal salts, ammonium salts, and organic
amine-addition salts. Examples of the acid-addition salts include
inorganic acid salts such as hydrochlorides, sulfates, nitrates and
phosphates, and organic acid salts such as acetates, maleates,
fumarates and citrates. Examples of the metal salts include alkali
metal salts such as sodium salts and potassium salts,
alkaline-earth metal salts such as magnesium salts and calcium
salts, aluminium salts, and zinc salts. Examples of the ammonium
salts include ammonium salts and tetramethylammonium salts, and
examples of the organic amine-addition salts include salts with
morpholine and piperidine. When a salt of the compound (I) is used
as an active ingredient of the medicament of the present invention,
a physiologically acceptable salt is preferably used.
[0054] Preparations of the compounds (I) will be explained
below.
[0055] Avermectin B1a monosaccharide, avermectin B2a
monosaccharide, and ivermectin monosaccharide
(22,23-dihydroavermectin B1a monosaccharide), which are used as
intermediates for the compound (I) disclosed by the present
invention, were prepared respectively from avermectin B1a and
avermectin B2a according to the method described in the publication
(J. Med. Chem., 23, 1134-1136, 1980).
[0056] Avermectins B1and B2a, which are used as starting materials,
are isolated from the culture of Streptomyces avermitilis, and they
are known compounds (Japanese Patent Unexamined Publication (KOKAI)
Nos. (Hei) 3-74397/1991 and 3-254678/1991, and U.S. Pat. No.
5,206,166 and the like).
[0057] Among the compound (I) of the present invention, the
compound wherein --XY-- is --CH.dbd.CH-- (the compound (Ia) and the
compound (Ic)) can be prepared from the aforementioned intermediate
avermectin B1a monosaccyaride, and the compound wherein --XY-- is
CH.sub.2--CH.sub.2-- (the compound (Ib) and th compound (Id)) can
be prepared from the aforementioned intermediat ivermectin
monosaccyaride.
[0058] Among the compound (I) of the present invention, the
compound (Ie) wherein --XY-- is --CH.sub.2--C(.dbd.O) can be
prepared from the compound obtained by oxidation of the hydroxyl
group at the 23-position of the aforementioned intermediate
avermectin B2a monosaccyaride, and the compound (If) wherein --XY--
is --CH.sub.2--CH(R.sup.13)-- (wherein R.sup.13 has the same
meaning as that defined above) can be prepared from the
aforementioned intermediate avermectin B2a monosaccyaride.
[0059] In the following preparations, when a defined group is
changed under conditions for a method to be applied, or the group
is unsuitable for carrying out the method, desired compound can be
obtained by employing introduction and elimination of a protective
group conventionally used in synthetic organic chemistry (see, for
example, Protective Groups in Organic Synthesis, T. W. Greene, John
Wiley & Sons Inc. (1981)].
[0060] Preparation 1
[0061] Among the compound (I), the compound wherein --XY-- is
--CH.dbd.CH--, --CH.sub.2--CH.sub.2--, or --CH.sub.2--C(.dbd.O)--,
R.sup.1 is a lower alkoxycarbonylmethylidene group optionally
substituted with a heterocyclic group, a lower
alkenylozycarbonylmethylidene group, or
.dbd.CH--COOCH.sub.2CH.dbd.CH.sub.2, or a cyanomethylidene group,
and R.sup.2 is a lower alkenyloxycarbonyloxy group (the compound
(Ia2), the compound (Ib2), and the compound (Ie2)) can be prepared
by the process set out below: 3
[0062] (In the scheme, R.sup.11A represents a lower alkoxycarbonyl
group optionally substituted with a heterocyclic group, a lower
alkenyloxycarbonyl group or --COOCH.sub.2CH.dbd.CH.sub.2, or a
cyano group among the definition of R.sup.11 or R.sup.11a; R.sup.2a
represents a lower alkenyloxycarbonyloxy group among the definition
of R.sup.2; and --X.sup.1Y.sup.1-- represents --CH.dbd.CH--,
--CH.sub.2--CH.sub.2--, or --CH.sub.2--C(.dbd.O)--.)
[0063] The compound (Ia2), (Ib2), or (Ie2) can be obtained by
reacting the compound (Ia1), (Ib1), or (Ie1) with 1 to 10
equivalents of the compound (II) represented by the formula:
(RO).sub.2P(O)CH.sub.2R.sup.11A wherein R represents a lower alkyl
group having the same meaning as that defined above and R.sup.11A
has the same meaning as that defined above, in the presence of 1 to
10 equivalents of a base in an inert solvent at a temperature
ranging from -78.degree. C. to a boiling point of a solvent used
for 1 minute to 24 hours.
[0064] As the inert solvent, tetrahydrofuran, ether, benzene,
toluene and the like can be used alone or as a mixture thereof.
Examples of the base include potassium tert-butoxide, sodium
hydride, potassium hydride, lithium hexamethyldisilazane, and
lithium diisopropylamide.
[0065] And also the compound (Ia2-1) or (Ib2-1) wherein --XY-- is
--CH.dbd.CH-- or --CH.sub.2--CH.sub.2--, R.sup.11 is a lower
alkoxycarbonyl group optionally substituted with a heterocyclic
group and R.sup.2 is a lower alkenyloxycarbonyloxy group can also
be obtained using as a starting material the compound wherein
--XY-- is --CH.dbd.CH-- or --CH.sub.2--CH.sub.2--, R.sup.11 is a
carboxyl group, and R.sup.2 is a lower alkenyloxycarbonyloxy group
(the compound (Ia5) or (Ib5)) which is obtained in Preparation 4
explained below.
[0066] The reaction can be carried out by reacting the compound
(Ia5) or (Ib5) with a corresponding lower alcohol optionally
substituted with a heterocyclic group or an ester of a
corresponding lower alcohol optionally substituted with a
heterocyclic group in the presence or absence of a base in an inert
solvent at a temperature ranging from 0.degree. C. to a boiling
point of a solvent used for one minute to 3 days.
[0067] As the inert solvent, lower alcohols such as methanol,
ethanol, propanol and tert-butanol, tetrahydrofuran, ether,
chloroform, methylene chloride, 1,2-dichloroethane, and the like
may be used. The corresponding lower alcohol optionally substituted
with a heterocyclic group or the ester of the corresponding lower
alcohol optionally substituted with a heterocyclic group may be
used as a solvent instead of the aforementioned inert solvent.
[0068] As the base, diisopropylethylamine, triethylamine, pyridine,
4-dimethylaminopyridine and the like may be used.
[0069] Furthermore, the compound wherein R.sup.1 is a cyanomethyl
group or a carboxymethyl group, R.sup.2 is a lower
alkenyloxycarbonyloxy group, and --XY-- is --CH.sub.2--CH.sub.2--
can be obtained by catalytic hydrogenation of the compound wherein
--XY-- is --CH.dbd.CH-- and R.sup.11 is a cyano group which is
obtained by Preparation 1, or the compound wherein --XY-- is
--CH.dbd.CH-- and R.sup.11 is a carboxyl group which is obtained by
Preparation 4 mentioned below in a solvent such as benzene in the
pr senc of a catalyst such as triphenylphosphine rhodium chloride
in the presence of a hydrogen sourc such as hydrogen gas, ammonium
formate at a temperature ranging from 0.degree. C. to a boiling
point of a solvent used for 1 minute to 100 hours.
[0070] Preparation 2
[0071] Among the compound (I), the compound wherein --XY-- is
--CH.dbd.CH-- or --CH.sub.2--CH.sub.2--, R.sup.11 is a
hydroxymethyl group, and R.sup.2 is a lower alkenyloxycarbonyloxy
group (the compound (Ia3) or (Ib3)) can be obtained according to
the process set out below: 4
[0072] (In the scheme, R.sup.11A1 represents a lower alkoxycarbonyl
group optionally, substituted with a heterocyclic group, or a lower
alkenyloxycarbonyl group among the definition of R.sup.11A;
--X.sup.2Y.sup.2-- represents --CH.dbd.CH-- or
--CH.sub.2--CH.sub.2--, and R.sup.2a has the same meaning as that
defined above.)
[0073] The compound (Ia3) or (Ib3) can be obtained by treating the
compound, among the compound obtained in Preparation 1, wherein
R.sup.11A is a lower alkoxycarbonyl group optionally substituted
with a heterocyclic group, or a lower alkenyloxycarbonyl group, and
--X.sup.1Y.sup.1-- is --CH.dbd.CH-- or --CH.sub.2--CH.sub.2--
(compound (Ia2-2) or (Ib2-2)) with an equivalent to an excess
amount of a reducing agent in an inert solvent at a temperature
ranging from -78.degree. C. to a boiling point of a solvent used
for 1 minute to 24 hours.
[0074] As the inert solvent, methanol, ethanol, water,
tetrahydrofuran, ether, benzene, toluene, pyridine, hexane,
methylene chloride, chloroform, 1,2-dichloroethane, and the like
may be used alone or as a mixture thereof. Examples of the reducing
agent include sodium borohydride, lithium aluminium hydride, and
diisobutylaluminium hydride.
[0075] Furthermore, the compound wherein R.sup.11 is a halomethyl
group can be obtained by treating the compound (Ia3) or (Ib3)
obtained above wherein R.sup.11 is a hydroxymethyl group with a
halogenating agent in the presence or absence of a base in an inert
solvent at a temperature ranging from -78.degree. C. to a boiling
point of a solvent used for 1 minute to 24 hours.
[0076] As the inert solvent, methylene chloride, chloroform,
1,2-dichloroethane, benzene, ether, tetrahydrofuran, and the like
may be used alone or as a mixture thereof As the halogenating
agent, p-toluenesulfonyl chloride, thionyl chloride, thionyl
bromide, and the like may be used.
[0077] As the base, diisopropylethylamine, triethylamine, pyridine,
4-dimethylaminopyridine, and the like may be used.
[0078] Furthermore, the compound wherein R.sup.11 is an aminomethyl
group can be obtained by reacting the compound wherein R.sup.11 is
a halomethyl group with an azide-formation agent in an inert
solvent at a temperature ranging from -78.degree. C. to a boiling
point of a solvent used for 1 minute to 24 hours and then carrying
out reduction in a conventional manner.
[0079] As the azide-formation agent, sodium azide, potassium azide,
and the like may be used.
[0080] As the inert solvent, ether, tetrahydrofuran, and the like
may be used alone or as a mixture thereof.
[0081] Preparation 3
[0082] Among the compound (I), the compound wherein --XY-- is
--CH.dbd.CH-- or --CH.sub.2--CH.sub.2--, R.sup.11 is a formyl
group, and R.sup.2 is a lower alkenyloxycarbonyloxy group (the
compound (Ia4) or (Ib4)) can be obtained by the process set out
below: 5
[0083] (In the scheme, R.sup.2a and --X.sup.2Y.sup.2-- have the
same meanings as those defined above, respectively.)
[0084] The compound (Ia4) or (Ib4) can b obtain d by treating the
compound (Ia3) or (Ib3) obtained in Preparation 2 with an
equivalent to an excess amount of an oxidizing agent in an inert
solvent at a temperature ranging from -78.degree. C. to a boiling
point of a solvent used for 1 minute to 24 hours.
[0085] As the inert solvent, water, tetrahydrofuran, ether,
benzene, hexane, methylene chloride, chloroform,
1,2-dichloroethane, tert-butanol, and the like may be used alone or
as a mixture thereof. Examples of the oxidizing agent include
pyridinium chlorochromate, pyridinium dichromate, manganese
dioxide, and potassium permanganate.
[0086] And also, the compound (Ia4) or (Ib4) can also be obtained
from the compound (Ia2-2) or (Ib2-2), which is used as a starting
material in Preparation 2, by controlling reaction conditions for
reduction described in Preparation 2. Examples of the reaction
solvent, the reducing agent, equivalents of the reducing agent, the
reaction time, and the reaction temperature for the reduction of
the compound (Ia2-2) or (Ib2-2) to obtain the compound (Ia4) or
(Ib4) include those exemplified in Preparation 2.
[0087] Furthermore, the compound wherein R.sup.11 is a vinyl group
or a substituted vinyl group (for example, the compound wherein
R.sup.11 is --CH.dbd.CH--COOH) can be obtained by subjecting the
compound (Ia4) or (Ib4), which is obtained above wherein R.sup.11
is a formyl group, to the Wittig reaction.
[0088] Examples of the solvent, the reaction temperature,
equivalents of the reagent, and the reaction time for the Wittig
reaction are similar to those described in Preparation 1.
[0089] Preparation 4
[0090] Among the compound (I), the compound wherein --XY-- is
--CH.dbd.CH-- or --CH.sub.2--CH.sub.2--, R.sup.11 is a carboxyl
group, and R.sup.2 is a lower alkenyloxycarbonyloxy group (the
compound (Ia5) or (Ib5)) can be obtained by the process set out
below: 6
[0091] (In the scheme, R.sup.2a and --X.sup.2Y.sup.2-- have the
same meanings as those defined above, respectively.)
[0092] The compound (Ia5) or (Ib5) can be obtained by treating the
compound (Ia3) or (Ib3) obtained in Preparation 2 with an
equivalent to an excess amount of an oxidizing agent in an inert
solvent at a temperature ranging from -78.degree. C. to a boiling
point of a solvent used for 1 minute to 24 hours.
[0093] As the inert solvent, water, tetrahydrofuran, ether,
benzene, hexane, chloroform, methylene chloride,
1,2-dichloroethane, tert-butanol, and the like may be used alone or
as a mixture thereof. Examples of the oxidizing agent include
pyridinium dichromate, pyridinium chlorochromate, Jones reagent,
chromium trioxide, and potassium permanganate.
[0094] The compound (Ia5) or (Ib6) can also be obtained, according
to the aforementioned method for preparing the compound (Ia5) or
(Ib5) from the compound (Ia3) or (Ib3), by oxidizing the formyl
group of the compound (Ia4) or (Ib4) obtained in Preparation 8.
[0095] The compound (Ia5) or (Ib5) can also be obtained by
hydrolyzing the compound (Ia2) or (Ib2) obtained in Preparation 1
in the presence of an equivalent to an excess amount of an acid or
a base in an inert solvent.
[0096] Examples of the inert solvent includ methanol, ethanol,
water, tetrahydrofuran, ether, and acetonitrile. Examples of the
acid include hydrochloric acid, sulfuric acid, and nitric acid, and
examples of the base include sodium hydroxide, potassium hydroxide,
and lithium hydroxide.
[0097] The compound (Ia5) or (Ib6) can also be obtained by treating
the compound, wherein R.sup.11A is a lower alkenyloxycarbonyl group
among the compound (Ia2) or (Ib2) obtained in Preparation 1, with
an equivalent to an excess amount of a reducing agent in the
presence of a palladium catalyst in an inert solvent at a
temperature ranging from -78.degree. C. to a boiling point of a
solvent used for 1 minute to 24 hours.
[0098] Examples of the inert solvent include methanol and ethanol,
and examples of the reducing agent include sodium borohydride,
formic acid, and hydrazine. Examples of the palladium catalyst
include tetrakis(triphenylphosphono)palladium.
[0099] The compound wherein R.sup.11 is
--CO--S--CH.sub.2--CH.sub.2--NH--C- O--R.sup.x (R.sup.x has the
same meaning as that defined above) can be obtained by further
reacting the compound (Ia5) or (Ib5) obtained above wherein
R.sup.11 is a carboxyl group with HS--CH.sub.2--CH.sub.2--NH--CO--
-R.sup.x (R.sup.x has the same meaning as that defined above).
[0100] For the preparation of the compound wherein R.sup.11 is
--CO--S--CH.sub.2--CH.sub.2--NH--CO--R.sup.x (R.sup.x has the same
meaning as that defined above) from the compound (Ia5) or (Ib5),
reaction is generally carried out in the presence of a condensing
agent and a base
[0101] Examples of the solvent and the base used in the preparation
of the compound wherein R.sup.11 is
--CO--S--CH.sub.2--CH.sub.2--NH--CO--R.sup.x (R.sup.x has the same
meaning as that defined above) from the compound (Ia5) or (Ib5)
include the inert solvents and the bases used in the reaction of
the compound (Ia5) or (Ib5) with the compound (V) in Preparation 9
explained below.
[0102] As the condensing agent,
benzotriazol-1-yloxytripyrrolidinophosphon- ium hexafluorophosphate
and the like may be used, as well as the condensing agents used in
the reaction of the compound (Ia5) or (Ib5) and compound (V) in
Preparation 9 explained below.
[0103] Examples of the reaction time, the reaction temperature,
equivalents of the reagent and the like for the preparation of the
compound wherein R.sup.11 is
--CO--S--CH.sub.2--CH.sub.2--NH--CO--R.sup.x (R.sup.x has th same
meaning as that defined above) from the compound (Ia5) or (Ib5) are
similar to those ex mplified in the reaction of the compound (Ia5)
or (Ib5) with the compound (V) in Preparation 9 explained
below.
[0104] Preparation 5
[0105] Among the compound (I), the compound wherein --XY-- is
--CH.dbd.CH-- or --CH.sub.2--CH.sub.2--, R.sup.11 is a lower
alkanoyloxymethyl group, a substituted or unsubstituted
arylcarbonyloxymethyl group, or a heterocyclic carbonyloxymethyl
group, and R.sup.2 is a lower alkenyloxycarbonyloxy group (the
compound (Ia6) or (Ib6)) can be obtained by the following method.
7
[0106] [In the scheme, R.sup.7X represents a lower alkyl group, a
substituted or unsubstituted aryl group (the type and number of the
substituent of the substituted aryl group are not particularly
limited, and preferably, examples include from 1 to 5 substituents
such as a halogen atom, an amino group, a hydroxyl group, and a
nitro group), or a heterocyclic group (wherein the heterocyclic
group may be substituted with a halogen atom or a lower
alkoxycarbonyl group); R.sup.2a and --X.sup.2Y.sup.2-- hav the sam
meanings as those defined above, respectively. The lower alkyl
group, aryl group, heterocyclic group, halogen atom, and lower
alkoxycarbonyl group in the definition of R.sup.7X have the same
meanings as those defined above, respectively.]
[0107] The compound (Ia6) or (Ib6) can be obtained by reacting the
compound (Ia3) or (Ib3) obtained in Preparation 2 with an
equivalent to an excess amount of the compound (IIIa) represented
by the formula: R.sup.7XCOCl wherein R.sup.7X has the same meaning
as that defined above, in the presence or absence of an equivalent
to an excess amount of a base in an inert solvent at a temperature
ranging from -78.degree. C. to a boiling point of a solvent used
for 1 minute to 24 hours.
[0108] Examples of the inert solvent include chloroform, methylene
chloride, 1,2-dichloroethane and pyridine, and examples of the base
include triethylamine, diisopropylethylamine, pyridine, and
dimethylaminopyridine.
[0109] The desired compound (Ia6) or (Ib6) can also be obtained by
reacting the compound (Ia3) or (Ib3) with an equivalent to an
excess amount of the compound (IIIb) represented by the formula:
(R.sup.7XCO).sub.2O wherein R.sup.7X has the same meaning as that
defined above, in the presence or absence of an equivalent to an
excess amount of a base in an inert solvent at a temperature
ranging from -78.degree. C. to a boiling point of a solvent used
for 1 minute to 24 hours.
[0110] Examples of the inert solvent and the base used include
those used in the reaction of the compound (Ia3) or (Ib3) and
compound (IIIa).
[0111] The desired compound (Ia6) or (Ib6) can alternatively be
obtained by reacting the compound (Ia3) or (Ib3) with an equivalent
to an excess amount of the compound (IIIc) represented by the
formula: R.sup.7XCOOH wherein R.sup.7X has the same meaning as that
defined above, for 1 minute to 24 hours in the presence or absence
of an equivalent to an excess amount of a base and in the presence
of an equivalent to an excess amount of a condensing agent in an
inert solvent at a temperature ranging from -78.degree. C. to a
boiling point of a solvent used.
[0112] Examples of the inert solvent and the base used include
those used in the reaction of the c mpound (Ia3) or (Ib3) with the
compound (IIIa). Examples of the condensing agent include
1-ethyl-3-(3-dimethylaminopropyl- )carbodiimide (WSCI)
hydrochloride and 1,3-dicyclohexylcarbodiimide.
[0113] Preparation 6
[0114] Among the compound (I), the compound wherein --XY-- is
--CH.dbd.CH-- or --CH.sub.2--CH.sub.2--, R.sup.11 is
--CH.dbd.N--OR.sup.3 wherein R.sup.8 has the same meaning as that
defined above, or --CH.dbd.N--NH--CONH.sub.2, and R.sup.2 is a
lower alkenyloxycarbonyloxy group (the compound (Ia7) or (Ib7)) can
be obtained by using the compound (Ia4) or (Ib4) obtained in
Preparation 3 as a starting material by the following method. 8
[0115] [In the scheme, R.sup.9X represents OR.sup.3 wherein R.sup.3
has the same meaning as that defined above, r --NH--CONH.sub.2, and
R.sup.2a and --X.sup.2Y.sup.2-- have the same meanings as those
defined above, respectively.]
[0116] The compound (Ia7) or (Ib7) can be obtained by reacting the
compound (Ia4) or (Ib4) with an equivalent to an excess amount of
the compound (IV) represented by the formula: H.sub.2N--OR.sup.8
wherein R.sup.8 has the same meaning as that defined above or a
salt thereof (examples of the salt include acid addition salts
having the same meaning as that defined above), or an equivalent to
an excess amount of a semicarbazide or a salt thereof (examples of
the salt include acid addition salts having the same meaning as
that defined above) for 1 minute to 24 hours in the presence or
absence of an equivalent to an excess amount of a base in an inert
solvent at a temperature ranging from -78.degree. C. to a boiling
point of a solvent used.
[0117] Examples of the inert solvent include methanol and ethanol.
Examples of the base include pyridine, triethylamine, and
dimethylaminopyridine.
[0118] The compound wherein R.sup.11 is CH.sub.2--NH--OR.sup.3 can
be obtained by reducing the compound obtained above wherein
R.sup.11 is --CH.dbd.N--OR.sup.3.
[0119] The reduction can be carried out, for example, using a
reducing reagent such as diisobutylaluminium hydride in an inert
solvent such as methylene chloride, chloroform, and
tetrahydrofuran.
[0120] Preparation 7
[0121] Among the compound (I), the compound wherein --XY-- is
--CH.dbd.CH-- or --CH.sub.2--CH.sub.2--, R.sup.11 is a
tetrahydropyranyloxymethyl group, and R.sup.2 is a lower
alkenyloxycarbonyloxy group (the compound (Ia8) or (Ib8)) can be
obtained by using the compound (Ia3) or (Ib9) obtained in
Preparation 2 by the following method. 9
[0122] (In the scheme, R.sup.2a and --X.sup.2Y.sup.2-- have the
same meanings as those defined above, respectively.)
[0123] The compound (Ia8) or (Ib8) can be obtained by reacting the
compound (Ia3) or (Ib3) obtained in Preparation 2 with an
equivalent to an excess amount of dihydropyran in the presence of
an acid catalyst in an inert solvent.
[0124] Examples of the acid catalyst include hydrochloric acid,
p-toluenesulfonic acid, and pyridinium p-toluenesulfonate. Examples
of the inert solvent include chloroform and methylene chloride.
[0125] Preparation 8
[0126] Among the compound (I), the compound wherein --XY-- is
--CH.dbd.CH-- or --CH.sub.2--CH.sub.2--, R.sup.11 is an aminomethyl
group or a methylaminomethyl group, and R.sup.2 is a lower
alkenyloxycarbonyloxy group (the compound (Ia9) or (Ib9)) can be
obtained by using the compound (Ia4) or (Ib4) obtained in
Preparation 3 as a starting material by the following method.
10
[0127] (In the scheme, R.sup.10X represents a hydrogen atom or a
methyl group, and R.sup.2a and --X.sup.2Y.sup.2-- have the same
meanings as those defined above, respectively.) Among the compound
(Ia9) or (Ib9), the compound wherein R.sup.10X is a hydrogen atom
can be obtained by reacting the compound (Ia4) or (Ib4) with an
equivalent to an excess amount of hexamethyldisilazane in the
presence of a catalytic amount to an excess amount of a metal salt
in an inert solvent at a temperature ranging from -78.degree. C. to
a boiling point of a solvent used for 1 minute to 24 hours, and
then adding an equivalent to an excess amount of a reducing
agent.
[0128] Examples of the inert solvent include methyl acetate, ethyl
acetate, propyl acetate, isopropyl acetate, methanol, and
ethanol.
[0129] Examples of the metal salt include zinc chloride, and
examples of the reducing agent include sodium borohydride, formic
acid, hydrogen gas, and lithium aluminium hydride.
[0130] Among the compound (Ia9) or (Ib9), the compound wherein
R.sup.10X is a methyl group can be obtained by using
heptamethyldisilazane instead of hexamethyldisilazane described
above.
[0131] Preparation 9
[0132] Among the compound (I), the compound wherein --XY-- is
--CH.dbd.CH-- or --CH.sub.2--CH.sub.2--, R.sup.11 is
CON(R.sup.5)(R.sup.6) wherein R.sup.5 and R.sup.6 have the same
meanings as those defined above, respectively, and R.sup.2 is a
lower alkenyloxycarbonyloxy group (the compound (Ia10) or (Ib10))
can be obtained by using the compound (Ia5) or (Ib5) obtained in
Preparation 4 as a starting material by the following method.
11
[0133] (In the schem, R.sup.81 represents --N(R.sup.5)(R.sup.6)
wherein R.sup.5 and R.sup.6 have the same meanings as those defined
above, respectively, and R.sup.2a and --X.sup.2Y.sup.2-- have the
same meanings as those defined above, respectively.]
[0134] The compound (Ia10) or (Ib10) can be obtained by reacting
the compound (Ia5) or (Ib5) with an equivalent to an excess amount
of the compound (V) represented by the formula: R.sup.81H wherein
R.sup.81 has the same meaning as that defined above, for 1 minute
to 24 hours in the presence of a base and a condensing agent in an
inert solvent at a temperature ranging from -78.degree. C. to a
boiling point of a solvent used.
[0135] Examples of the inert solvent include chloroform, methylene
chloride, methyl acetate, ethyl acetate, propyl acetate, isopropyl
acetate, methanol, and ethanol.
[0136] Examples of the condensing agent include
1-ethyl-3-(3-dimethylamino- propyl)-carbodiimide (WSCI)
hydrochloride, and 1,3-dicyclohexylcarbodiimid- e. Examples of the
base include triethylamine, diisopropylethylamine,
dimethylaminopyridine, and pyridine.
[0137] The compound (Ia10) or (Ib10) can also be obtained by
treating the compound (Ia5) or (Ib5) with a chlorinating agent in
an inert solvent or in the absence of a solvent at a temperature
ranging from an ice-cooling temperature to a boiling point of a
solvent used (at a boiling temperature of the chlorinating agent
when no solvent is used) to convert the compound into a
corresponding acid chloride, and reacting the resulting product
with the compound (V) represented by the formula: R.sup.31H wherein
R.sup.31 has the same meaning as that defined above, in an inert
solvent in the presence of a base at a temperature ranging from an
ice-cooling temperature to a boiling point of a solvent used.
[0138] Examples of the chlorinating agent include phosphorus
oxychloride, phosphorus pentachloride, phosphorus trichloride,
thionyl chloride, and thionyl bromide.
[0139] Examples of the inert solvent for the chlorination include
chloroform, methylene chloride, 1,2-dichloroethane, toluene, and
benzene.
[0140] Examples of the inert solvent for the condensation reaction
include chloroform, methylene chloride, methyl acetate, ethyl
acetate, propyl acetate, isopropyl acetate, tetrahydrofuran,
methanol, and ethanol.
[0141] Examples of the base include triethylamine,
diisopropylethylamine, dimethylaminopyridine, and pyridine.
[0142] Preparation 10
[0143] Among the compound (I), the compound wherein R.sup.2 is a 1
wer alkenyloxycarbonyloxy group, or the compound as a synthetic
intermediate for the compound (I) wherein the position
corresponding to 5-position of the compound (I) is a tri(lower
alkyl)silyloxy group such as tert-butyldimethylsilyloxy group
(wherein the lower alkyl moiety of the tri(lower alkyl)silyloxy
group has the same meaning as that defined in the aforementioned
lower alkyl group and each of the lower alkyl group moiety may be
the same or different) can be prepared by the method described in
the Japanese Patent Publication (KOKOKU) No. (Hei)6-33273/1994, the
Japanese Patent Unexamined Publication (KOKAI) No.
(Hei)3-74397/1991 and the like, or a similar method thereto by
using avermectin B1a monosaccharide, avermectin B2a monosaccharide,
ivermectin monosaccharide and the like.
[0144] The compound wherein R.sup.1 and the carbon atom at
4'-position combine to each other to form a carbonyl group in the
compound (I) can be prepared by oxidizing the hydroxyl group at
4'-position of the compound (I) wherein 4'-position is a hydroxyl
group by the method described in the Japanese Patent Publication
(KOKOKU) No. (Hei)6-33273/1994, the Japanese Patent Unexamined
Publication (KOKAI) No. (Hei)3-74397/1991, or a similar method
thereto.
[0145] Examples of oxidizing methods described in the Japanese
Patent Publication (KOKOKU) No. (Hei)6-33273/1994, the Japanese
Patent Unexamined Publication (KOKAI) No. (Hei)3-74397/1991 or the
like include oxidation using phenyldichlorophosphate
(C.sub.6H.sub.5OPOCl.sub.2)/triet- hylamine (TEA)/dimethyl
sulfoxide (DMSO), oxidation using tetrapropylammonium perruthenate
(C.sub.3H.sub.7).sub.4NRuO.sub.4)/4-meth- ylmorpholine-N-oxide
(NMO) in methylene chloride in the presence of molecular sieves 4A
(MS4A), oxidation using sulfur trioxide pyridine complex in
dimethyl sulfoxide (DMSO) and the like.
[0146] Preparation 11
[0147] Among the compound (I), the compound wherein --XY-- is
--CH.dbd.CH--, --CH.sub.2--CH.sub.2--, or --CH.sub.2--C(.dbd.O)--,
the bond between R.sup.1 and the carbon atom at 4'-position is a
double bond, and R.sup.2 is a hydroxyl group (the compound (Ia11),
the compound (Ib11), or the compound (Ie11)) can be prepared by
deprotection at 5-position of the compound (the compound (A)),
which is obtained by Preparations 1 to 10 and the like from the
compound wherein the hydroxyl group at 6-position of the compound
(Ia), the compound (Ib), or the compound (Ie) wherein 5-position is
a hydroxyl group is protected with a tri(lower alkyl)silyl group
such as tert-butyldimethylsilyl group (in which the lower alkyl
moiety of the tri(lower alkyl)silyl group has the same meaning as
that defined in the aforementioned lower alkyl group and each of
the lower alkyl group moiety may be the same or different), or the
compound (the compound (IA)) wherein R.sup.2 is a lower
alkenyloxycarbonyl group obtained by Preparations 1 to 10 and the
like. 12
[0148] [In the scheme, R.sup.1 and --X.sup.1Y.sup.1-- have the same
meanings as those defined above, respectively, R.sup.2A represents
a lower alkenyloxycarbonyloxy group wherein the lower alkyl moiety
of the lower alkenyloxycarbonyloxy group has the same meaning as
that defined in the aforementioned lower alkyl group, or a
tri(lower alkyl)silyloxy group wherein the lower alkyl moiety of th
tri(lower alkyl)silyloxy group has the same meaning as that defined
in the aforementioned lower alkyl group and each of the lower alkyl
group moiety may be the same or different.]
[0149] The lower alkenyloxycarbonyl group can be eliminated by
reducing the compound (IA) obtained by Preparations 1 to 10 or the
like in an inert solvent in the presence of a palladium compound
such as tetrakis(triphenylphosphine)palladium by using sodium
borohydride and the like as a hydrogen source.
[0150] The reaction is generally completed for 1 minute to 24 hours
at a temperature ranging from -78.degree. C. to a boiling point of
a solvent used.
[0151] As the inert solvent, an etheric solvent such as
tetrahydrofuran and ether, an alcoholic solvent such as ethanol,
and the like may be used alone or as a mixture thereof.
[0152] The lower alkenyloxycarbonyloxy group at 5-position may
sometimes be converted to a hydroxyl group depending on a reaction
condition for carrying out a conversion of a functional group in
other position.
[0153] And also the tri(lower alkyl)silyl group can be eliminated
by treating the compound (A) obtained by the method according to
Preparations 1 to 10 or the like in an inert solvent for 1 minute
to 24 hours with a catalytic amount to an amount serving as a
solvent of a desilylating agent at a temperature ranging from
-78.degree. C. to a boiling point of a solvent used.
[0154] As the inert solvent, tetrahydrofuran, ether, benzene,
toluene, pyridine, isopropyl acetate, and the like may be used
alone or as a mixture thereof. Examples of the desilylating agent
include hydrogen fluoride, hydrochloric acid, hydrogen bromide,
sulfuric acid, and hydrogen fluoride/pyridine complex.
[0155] The tri(lower alkyl)silyloxy group at 5-position may
sometimes be converted to a hydroxyl group depending on a reaction
condition for carrying out a conversion of a functional group in
other position.
[0156] Preparation 12
[0157] The compound (IC) wherein R.sup.2 and the carbon atom at
5-position are combined to form a carbonyl group can be prepared by
oxidizing the compound (IB) wherein R.sup.2 is a hydroxyl group
among the compound (I) obtain d by Preparation 11 or Preparations
13 to 15.
[0158] The compound (IC) can be obtained by tr ating the compound
(IB) in an inert solvent with one equivalent to excess amount of an
oxidizing agent at a temperature ranging from -78.degree. C. to a
boiling point of a solvent used. The reaction is generally
completed for one minutes to two days.
[0159] Examples of the inert solvent include chloroform, methylene
chloride, and 1,2-dichloromethane, and examples of the oxidizing
agent include manganese dioxide, pyridinium chlorochromate,
chromium trioxide, and pyridinium dichromate.
[0160] Furthermore, the compound wherein R.sup.2 and the carbon
atom at 5-position are combined to form a hydroxime group can be
obtained by reacting the compound (IC) with hydroxylamine or a salt
thereof (examples of the salt include acid addition salts having
the same meaning as those defined above).
[0161] The reaction between the compound (IC) and hydroxyl amine or
a salt thereof can be carried out in an inert solvent in the
presence of absence of a base at a temperature ranging from
-78.degree. C. to a boiling point of a solvent used. The hydroxyl
amine or a salt thereof and the base can be used in an equivalent
to an excess amount. The reaction is generally completed in 1
minute to 2 days.
[0162] Examples of the inert solvent include lower alcohols such as
methanol, ethanol and propanol, ethers such as ether and
tetrahydrofuran, and halogenated hydrocarbons such as chloroform,
methylene chloride and 1,2-dichloroethane.
[0163] Examples of the base include pyridine, 2,6-dimethylpyridine,
dimethylaminopyridine, triethylamine, and diisopropylamine.
[0164] Preparation 13
[0165] The compound (If1) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group, --XY-- is --CH.sub.2--CH(OH)--, and
R.sup.11b is a cyano group, a carboxyl group, a lower
alkoxycarbonyl group, or a lower alkenyloxycarbonyl group can be
obtained by treating, in the same manner as Preparation 1 or 4, the
compound among the compound obtained in the above Preparation 10 wh
rein R.sup.2 is a lower alkenyloxycarbonyloxy group, --XY-- is
--CH.sub.2--CH(OH)--, and R.sup.1 and the carbon atom at
4'-position are combined to form a carbonyl group.
[0166] The compound (If2) wherein R.sup.2 is a hydroxyl group,
--XY-- is --CH.sub.2--CH(OH)--, and R.sup.11b is a cyano group, a
carboxyl group, a lower alkoxycarbonyl group, or a lower
alkenyloxycarbonyl group can be obtained from the compound (If1)
according to the method described in Preparation 11.
[0167] Preparation 14
[0168] Among the compound (I), the compound (If3) wherein --XY-- is
--CH.sub.2--CH(R.sup.13a)-- (wherein R.sup.13a represents a lower
alkylcarbonyloxy group and wherein the lower alkylcarbonyloxy group
has the same meaning as that defined above), R.sup.2 is a lower
alkenyloxycarbonyloxy group, and R.sup.11b is a cyano group, a
lower alkoxycarbonyl group, or a lower alkenyloxycarbonyl group can
be prepared by the method similar to Preparation 5 by using, as a
raw material, the compound wherein R.sup.11b is a cyano group, a
lower alkoxycarbonyl group, or a lower alkenyloxycarbonyl group
among the compound (Ifl) obtained in Preparation 13.
[0169] Furthermore, the compound (If4) wherein R.sup.2 is a
hydroxyl group, --XY-- is --CH.sub.2--CH(R.sup.13a)-- (wherein
R.sup.13a has the same meaning as that defined above), and
R.sup.11b is a cyano group, a lower alkoxycarbonyl group, or a
lower alkenyloxycarbonyl group can be obtained from the compound
(If3) according to the method described in Preparation 11.
[0170] Preparation 15
[0171] Among the compound (I), the compound (If5) wherein --XY-- is
--CH.sub.2--CH(R.sup.13)-- (wherein R.sup.13 has the same meaning
as that defined above), R.sup.2 is a hydroxyl group or a lower
alkenyloxycarbonyloxy group, and R.sup.11b is a carboxyl group can
be obtained by hydrolyzing, in an ordinary manner, the compound
wherein --XY-- is --CH.sub.2--CH(R.sup.13)-- (wherein R.sup.13 has
the same meaning as that defined above), and R.sup.11b is a cyano
group, a lower alkoxycarbonyl group, or a lower alkenyloxycarbonyl
group among the compound (I) obtained in Preparation 13 or 14.
[0172] Furthermore, the compound (If5-i) wherein R.sup.2 is a lower
alkenyloxycarbonyl group among the compound (If5) can be converted,
according to the method described in Preparation 11, to the
compound (If5-ii) wherein R.sup.2 is a hydroxyl group among the
compound (If5).
[0173] Preparations of the compound wherein between R.sup.1 and the
carbon atom at 4'-position is a single bond (compound (ID)) among
the compound (I) will be explained below.
[0174] Preparation 16
[0175] Compound (ID2) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with a lower alkoxycarbonyl group (wherein the lower
alkyl moiety of the lower alkoxycarbonyl group may be substituted
with a heterocyclic group) can be obtained by reacting the compound
(ID1) wherein R.sup.2 is a lower alkenyloxycarbonyloxy group and
R.sup.1 is a hydroxyl group among the compound (I) with a lower
alkyl diazoacetate derivative such as ethyl diazoacetate and
diethyl diazomalonate.
[0176] Furthermore, the compound (ID3) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with a carboxyl group can be obtained by treating the
resulting compound (ID2) with a base such as alcoholic potassium
hydroxide.
[0177] And also the compound (ID4) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with a cyano group and a lower alkoxycarbonyl group
(wherein the lower alkyl moiety of the lower alkoxycarbonyl group
may be substituted with a heterocyclic group) can be obtained by
reacting the compound (ID1) with a lower alkyl diazocianoacetate
derivative such as ethyl diazocianoacetate.
[0178] And also, the compound (ID4) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with an aryl group and a lower alkoxycarbonyl group
(wherein the lower alkyl moiety of the lower alkoxycarbonyl group
may be substituted with a heterocyclic group) can be obtained by
reacting the compound (ID1) with a lower alkyl diazoarylacetate
derivative such as ethyl diazophenylacetate.
[0179] Furthermore, the compound wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with a cyano group and a carboxyl group or with an aryl
group and a carboxyl group can b obtained by reacting the compound
(ID4) or the compound (ID5) with a base such as alcoholic potassium
hydroxide.
[0180] Preparation 17
[0181] The compound (ID6) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with --CON(R.sup.9X)(R.sup.10X) (wherein R.sup.9X and
R.sup.10X have the same meaning as those of the aforementioned
R.sup.9 and R.sup.10, respectively) can be obtained by reacting the
compound (ID3) obtained in Preparation 16, wherein R.sup.2 is a
lower alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with a carboxyl group, with a cyclic amine compound
such as piperazine or morpholine in the presence of a condensing
agent.
[0182] Examples of the condensing agent include
1-ethyl-3-(3-dimethylamino- propyl)-carbodiimide (WSCI)
hydrochloride and 1,3-dicyclohexylcarbodiimide- .
[0183] And also the compound (ID7) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with --COR.sup.8d (wherein R.sup.8d represents an
arylalkyloxy group wherein said aryl group may contain one or more
hetero atoms as ring-constituting atoms) can be obtained by
reacting the compound (ID3) with an arylalkylalcohol (wherein said
aryl group may contain one or more hetero atoms as
ring-constituting atoms) in the presence of a condensing agent
[0184] Preparation 18
[0185] The compound (ID8) wherein R.sup.2 is a lower
alkenyloxycarboyloxy group and R.sup.1 is a methoxy group
substituted with a formyl group can be obtained by reducing the
compound (ID3) wherein R.sup.2 is a lower alkenyloxycarbonyloxy
group and R.sup.1 is a methoxy group substituted with a carboxyl
group, or the compound (ID2) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with a lower alkoxycarbonyl group, which is obtained in
Preparation 16.
[0186] Examples of a reducing agent include sodium borohydride,
lithium aluminium hydride, and diisobutylaluminium hydride.
[0187] Furthermore, the compound (ID8) can be converted to the
oxime compound wherein R.sup.2 is a lower alkenyloxycarbonyloxy
group (a hydroxime compound or an alkoxime compound) by reaction
with a compound represented by H.sub.2N--OR.sup.7X wherein R.sup.7X
has the same meaning as that of the aforementioned R.sup.7.
[0188] And also the compound (ID9) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with hydroxymethyl group can be obtained by treating
the compound (ID3) or the compound (ID2) with a stronger reducing
agent.
[0189] As the reducing agent, lithium triethylborohydride may be
used.
[0190] Preparation 19
[0191] The compound (ID10) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with a p-nitrophenyl group can be obtained by reacting
the compound (ID1) with p-nitrobenzyl bromide.
[0192] The compound (ID11) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with a p-aminophenyl group can be obtained by reducing
the compound (ID10).
[0193] The reduction can be carried out, for example, by catalytic
hydrogenation in the presence of palladium carbon catalyst.
[0194] Preparation 20
[0195] Another compound (ID) can be obtained by using the compound
(ID9), as a starting material, wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with a hydroxymethyl group, which is obtained in
[0196] Preparation 18.
[0197] The compound (ID11) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with a substituted or unsubstituted
arylsulfonyloxymethyl group can be obtained by reacting the
compound (ID9) with a substituted or unsubstituted arylsulfonyl
chloride or the like in the presence of a base.
[0198] And also the compound (ID12) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with a halogenated methyl group can be obtained by
halogenating the moiety of a hydroxyl group of the methoxy group at
4'-position of the compound (ID9) which is substituted with the
hydroxymethyl group.
[0199] Examples of conditions for the halogenation include a
reaction with triphenylphosphine/carbon tetrabromide in the
presence of a base, and triph nylphosphine/iodine in the presenc of
a base.
[0200] Furthermore, by reacting the compound (ID12) with
HNR.sup.9YR.sup.10Y (wherein R.sup.9Y and R.sup.10Y have the same
meanings as those of the aforementioned R.sup.9 and R.sup.10,
respectively) optionally in the presence of a base, the compound
(ID13) can be obtained wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with CH.sub.2NR.sup.9YR.sup.10- Y (wherein R.sup.9Y and
R.sup.10Y have the same meaning as those defined above).
[0201] And also the compound wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with an azide methyl group can be obtained by azide
formation of the compound (ID12) which is obtained in Preparation
20.
[0202] Examples of conditions for the azide formation include
reactions with an alkali azide such as sodium azide, potassium
azide in a polar solvent.
[0203] Furthermore, the compound (ID15) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with an aminomethyl group can be obtained by reducing
the compound (ID14).
[0204] Examples of conditions for the reduction include reduction
by catalytic hydrogenation in the presence of a hydrogen source
such as hydrogen gas or hydrazine or reduction using
triphenylphosphine, which are ordinarily used.
[0205] Furthermore, the compound (ID16) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with a lower alkanoylaminomethyl group can be obtained
by lower-alkanoylation of the compound (ID15).
[0206] Examples of the method for the lower-alkanoylation include
reaction of the compound (ID15) with a halogenated lower alkanoyl
compound or a method comprising reaction with an acid
anhydride.
[0207] Preparation 21
[0208] The compound (ID17) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group, and R.sup.1 is a methoxy group
substituted with a lower alkenyloxycarbonyl group, and the compound
(ID18) wherein R.sup.2 is a lower alkenyloxycarbonyloxy group, and
R.sup.1 is a a methoxy group substituted with a cyano group can be
obtained according to the method d scribed in Preparation 16, which
is for preparation of the compound (ID2) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with a lower alkoxycarbonyl group (wherein the lower
alkyl moiety of the lower alkoxycarbonyl group may be substituted
with a heterocyclic group).
[0209] The compound (ID19) wherein R.sup.2 is a lower alk
nyloxycarbonyloxy group and R.sup.1 is substituted with
--CH.dbd.N--NH--CONH.sub.2 can be obtained by the compound (ID8)
obtained by Preparation 18 wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with a formyl group, and H.sub.2N--NH--CONH.sub.2 or a
salt thereof such as an acid addition salt.
[0210] And also the compound (ID20) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with a vinyl group substituted with a lower
alkenyloxycarbonyl group can be obtained by reacting the compound
(ID8) with an appropriate Wittig reagent such as that prepared from
allyldiethylphosphonoacetate.
[0211] Furthermore, the compound (ID21) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with --CH.dbd.CH--COOH can be prepared by treating the
compound (ID20) under an appropriate deprotection condition such as
deprotection by an acid, or deprotection by a hydrogen source such
as sodium borohydride, hydrogen gas, and hydrazine in the presence
of a metal catalyst such as
tetrakis(triphenylphosphono)palladium.
[0212] And also the compound (ID22) wherein R.sup.2 is a lower
alkenyloxycarbonyloxy group and R.sup.1 is a methoxy group
substituted with --CO--S--CH.sub.2--CH.sub.2--NH--CO--R.sup.Y
(wherein Y has the same meaning as that defined above) can be
obtained by reacting the compound (ID3) obtained by Preparation 16,
wherein R.sup.2 is a lower alkenyloxycarbonyloxy group and R.sup.1
is a methoxy group substituted with a carboxyl group, with
HS--CH.sub.2--CH.sub.2--NH--CO--R.sup.Y (wherein R.sup.Y has the
same meaning as that defined above).
[0213] Preparation 22
[0214] The compound (ID23) wherein R.sup.1 is
--OCHR.sup.1aR.sup.1b, --OCHR.sup.1aaR.sup.1ba, or
--OCHR.sup.1abR.sup.1bb, and R.sup.2 is a hydroxyl group can be
obtained can be obtained by deprotection at 5-position of the
compound according to Preparation 11 from the compound obtained
according to Preparations 16 to 21 from the compound wherein
R.sup.1 is --OCHR.sup.1aR.sup.1b, --OCHR.sup.1aaR.sup.1ba, or
--OCHR.sup.1abR.sup.1bb, and the position corresponding to R.sup.2
is tri(lower alkyl)silyloxy group such as
tert-butyldimethylsilyloxy group (wherein the moiety of the lower
alkyl group hydroxyl group of the tri(lower alkyl)silyloxy group
has the same meaning as that defined above and each of the lower
alkyl group may be the same or different), or of the compound
obtained by Preparations 16 to 21.
[0215] Preparation 23
[0216] The compound (ID24) wherein R.sup.1 is
--OCHR.sup.1aR.sup.1b, --OCHR.sup.1aaR.sup.1ba, or
--OCHR.sup.1abR.sup.1bb, and R.sup.2 and the carbon atom at
6-position are combined to form a carbonyl group can be obtained by
oxidation of a hydroxyl group as R.sup.2 of the compound (ID23)
obtained by the aforementioned Preparation 22, in an ordinary
manner.
[0217] Furthermore, the compound (ID26) wherein R.sup.2 and the
carbon atom at 5-position are combined to form a hydroxime group
can be obtained by reacting the resulting compound (ID24) wherein
R.sup.2 and the carbon atom at 6-position are combined to form a
carbonyl group with hydroxylamine or a salt thereof (examples of
the salt include acid addition salts such as hydrochloride), in an
ordinary manner.
[0218] The aforementioned methods are typical examples of the
preparations of the compound (I), and the preparations of the
compound (I) are not limited to those explained above. It can be
easily understood by a person skilled in the art that the compound
of the present invention can be obtained by other methods and the
compound (I) can also be obtained by carrying out the above methods
in an appropriate combination or with an appropriate modification
or alteration, if necessary.
[0219] In addition, the compound (I) can also be obtained by an
appropriate combination of the methods for converting a functional
group which are usually used in the field of synthetic organic
chemistry. For example, the compound (I) wherein R.sup.2 is a
methoxy group can be obtained by a conventional methylation of the
hydroxyl group of the corresponding compound wherein R.sup.2 is a
hydroxyl group. Similarly, the compound (I) wherein R.sup.2 is a
lower alkoxyl group can be obtained by a conventional alkylation of
the hydroxyl group of the corresponding compound wherein R.sup.2 is
a hydroxyl group.
[0220] For converting functional groups, desired conversions of
functional groups can efficiently be made by protecting appropriate
functional groups by meth ds for protection conventionally used in
the field of synthetic organic chemistry [e.g., s e Protective
Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons
Inc. (1981)] and the like, if necessary.
[0221] Specific examples of the aforementioned preparation and
other preparations are described in Examples, and accordingly, a
person skilled in the art can prepare any compounds falling within
the compound (I) by referring to the above general explanations and
specific explanations in Examples, and by appropriately choosing
starting materials, reagents and reaction conditions and adding an
appropriate alteration or modification, if necessary.
[0222] Purification of the desired compounds in the aforementioned
preparations can be made by an appropriate combination of methods
ordinarily used in the filed of synthetic organic chemistry, for
example, filtration, extraction, washing, drying, concentration,
crystallization, and various chromatography and the like. Synthetic
intermediates may be subjected to a next reaction without
purification.
[0223] Isomers such as regio isomers, geometrical isomers,
tautomers and optical isomers may exist as the compounds (I). Any
possible isomers and mixtures thereof in any proportion fall within
the scope of the present invention. When a bond of a functional
group that substitutes on a carbon atom forming a double bond is
represented by a waved line in the specification, it means that the
compound is an E- or Z-compound, or a mixture thereof.
[0224] For the preparation of a salt of the compound (I), a
resulting salt, per se, may be purified when the compound (I) is
obtained in the form of a salt. When a product is obtained in a
free form, a salt may be isolated and purified after dissolving or
suspending the product in a suitable solvent, and adding an acid or
a base thereto to form a salt. The compounds (I) and salts thereof
may exist in the forms of adducts with water or various solvents
(i.e., hydrates or solvates), and these adducts also fall into the
scope of the present invention. Moreover, any forms of crystal also
fall into the scope of the present invention.
[0225] Specific examples of the compounds (I) obtained according to
the present invention are shown in Tables 1 to 5. However, the
compounds of the present invention ar not limited to these
examples.
1TABLE 1 13 Compound No. Z 4' 1 OH Single bond 2 O Double bond 3
CHCO.sub.2CH.sub.2CH.dbd.CH.sub.2 Double bond 4 CHCN Double bond 5
OCH.sub.2CO.sub.2CH.sub.2CH.sub.3 Single bond
[0226]
2TABLE 2 14 Compound No. R.sup.11 6 CO.sub.2H 7 CN 8
CO.sub.2CH.sub.2CH.dbd.CH.sub.2 9 CO.sub.2CH.sub.2CH.sub.3 10
CH.sub.2OH 11 CH.sub.2Cl 12 CO.sub.2C(CH.sub.3).sub.3 13 15 14 16
15 CHO 16 17 17 18 18 19
[0227]
3TABLE 3 20 Compound No. R.sup.11 19 CO.sub.2H 20
CO.sub.2CH.sub.2CH.dbd.- CH.sub.2 21 CO.sub.2CH.sub.2CH.sub.3 22 CN
23 CO.sub.2C(CH.sub.3).sub.3 24 21 25 CH.sub.2OH 26 CHO 27
CH.sub.2Cl 28 22 29 23 30 24 31 25 32 26 33 27
[0228]
4TABLE 4 28 Compound No. R.sup.1a 34 CO.sub.2CH.sub.2CH.sub.3 35
CO.sub.2H 36 CH.sub.2OH 37 CH.sub.2Br
[0229]
5TABLE 5 29 Compound No. R.sup.1a 38 CO.sub.2CH.sub.2CH.sub.3 39
CO.sub.2H 40 CH.sub.2OH 41 CH.sub.2Br
[0230] As active ingredient of the medicament of the present
invention, one or more substances selected from the group
consisting of the compounds represented by the general formula (I)
in the free form and physiologically acceptable salts thereof, and
hydrates thereof and solvates thereof can be used. Any mixture of
isomers or an isomer in a pure form may be used. The medicament of
the present invention is generally provided in the form of a
pharmaceutical composition which comprises one or more
pharmaceutical additives and the aforementioned substance as an
active ingredient. The route of administration is not particularly
limited, and the medicament can be orally administered using
preparations such as tablets, granules, capsules, syrups and
powders, or parenterally administered by means of injection,
intrarectal administration, transdermal administration or the like.
Pharmaceutical formulations suitable for oral or parenteral
administration are well-known to persons skilled in the art, and
they can appropriately choose pharmaceutical additives suitable for
the manufacture of the pharmaceutical formulations.
[0231] The medicament of the present invention may be applied to
various parasitic diseases, and the kinds of the parasitic disease
are not particularly limited. The medicament of the present
invention may be applied to a human or a mammal other than a human.
When the medicament is applied to a mammal other than a human, the
medicament may be administered as a pharmaceutical composition, or
alternatively, a pharmaceutical composition or the aforementioned
active ingredient per se may be added to a feed. The compound of
the present invention may be applied as pesticides such as an agent
for controlling injurious insects such as blowflies, cockroaches,
fleas and the Like.
EXAMPLES
[0232] The present invention will be explained more specifically
with reference to the following examples. However, the present
invention is not limited to these examples. Analytical data of the
compounds described in the examples were measured by using the
following apparatuses. The number and structure of the compounds
are the same as those described in Table 1 to 5 set out above.
[0233] IR: Horiba FT-210 NMR: JEOL (Nippon Denshi) JMN-EX270 MS:
JEOL (Nippon Denshi) JMS-AX505
Example 1
[0234] Compound 1
[0235] Under nitrogen atmosphere, Intermediate 1 (1.0 g) obtained
in Reference Example 1 was dissolved in tetrahydrofuran (6.9 mL),
and tetramethylethylenediamine (0.50 mL) and allyl chloroformate
(0.17 mL) were successively added to the solution. The mixture was
stirred for 30 minutes at -20.degree. C. After purified water was
added to the mixture, the mixture was extracted with ethyl acetate
The organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. The solvent was evaporated under reduced
pressure to give a crude product. The resulting crude product was
purified by silica gel column chromatography with eluting solvents
of hexane/ethyl acetate=4/1, 3/1, and 2/1 to give Compound 1 (0.80
g, 72%).
[0236] HRFABMS: Calcd. for C.sub.45H.sub.64O.sub.13 [M+Na].sup.+
835.4245. Found 835.4250.
[0237] IR(KBr) .lambda..sub.max(cm.sup.-1): 3473, 2966, 2933, 1747,
1716, 1454, 1379,1344, 1308, 1254, 1184, 1161, 1116, 1080, 1051,
993
[0238] .sup.1H NMR (270 MHz, CDCl.sub.3, partial data) .delta.
(ppm): 5.86 (5H, m), 5.57 (1H, m), 5.55 (1H, dd, J=9.9, 2.3 Hz),
5.38 (3H, m), 5.26 (1H, d, J=10.6 Hz), 4.98 (1H, m), 4.81 (1H, d,
J=3.3 Hz), 4.64 (4H, m), 4.12 (1H, d, J=6.2 Hz), 3.95 (1H, br),
3.86 (2H, m), 3.52 (2H, m), 3.48 (3H, s), 3.37 (1H, d, J=2.3 Hz),
3.16 (1H, d, J=9.0 Hz), 2.51 (1H, m), 2.29 (4H, m), 2.02 (1H, dd,
J=12.3, 3.6 Hz), 1.81 (3H, s), 1.49 (3H, s), 1.27 (3H, d, J=6.3
Hz), 1.15 (3H, d, J=6.9 Hz)
[0239] .sup.13C NMR (67.8 MHz, CDCl.sub.8) .delta. (ppm): 173.4,
154.8, 139.2, 138.0, 136.2, 135.1, 133.0, 131.4, 127.7, 124.7,
121.5, 120.4, 118.7, 118.2, 95.7, 95.0, 81.7, 80.8 (.times.2),
78.3, 76.0, 74.8, 73.5, 68.7, 68.5, 68.4, 68.3, 68.1, 56.6, 45.7,
40.4, 39.7, 36.5, 35.1, 34.2, 33.8, 80.5, 27.5, 20.1, 19.6, 17.7,
16.3, 15.1, 12.9, 12.0
Example 2
[0240] Compound 2
[0241] Under nitrogen atmosphere, Compound 1 (0.10 g) obtained in
Example 1 was dissolved in dimethyl sulfoxide (1.2 mL) After
triethylamine (54 .mu.L) was added to the solution, a solution of
sulfur trioxide/pyridine complex (97 mg) in dimethyl sulfoxide (1.2
mL) was slowly added dropwise to the mixture, and the mixture was
stirred at 0.degree. C. for 1 hour. After purified water was added
to the reaction mixture, the reaction mixture was extracted with
ethyl acetate. The organic layer was washed successively with
purified water and saturated brine and dried over anhydrous sodium
sulfate. The solvent was evaporated under reduced pressure to give
a crude product. The resulting crude product was purified by silica
gel column chromatography with eluting solvents of hexane/ethyl
acetate=5/1 and 2/1 to give Compound 2 (0.67 g, 68%).
[0242] HRFABMS: Calcd. for C.sub.45H.sub.62O.sub.13 [M+Na].sup.+
833.4088. Found 833.4087.
[0243] IR(KBr) .lambda..sub.max(cm.sup.31 1): 3471, 2966, 2933,
1743, 1456, 1379, 1344, 1308, 1254, 1182, 1161, 1118, 1076, 1051,
997
[0244] .sup.1H NMR (270 MHz, CDCl, partial data) .delta. (ppm):
5.89 (5H, m), 5.57 (1H, m), 5.55 (1H, dd, J=9.9, 2.3 Hz), 5.37 (3H,
m), 5.27 (1H, d, J=10.5 Hz), 5.05 (1H, m), 4.96 (1H, d, J=2.3 Hz),
4.65 (4H, m), 4.50 (1H, dd, J=12.8, 6.6 Hz), 4.25 (1H, dd, J=12.5,
6.3 Hz), 4.12 (1H, d, J=5.9 Hz), 4.07 (1H, br), 3.89 (1H, m), 3.56
(3H, s), 3.48 (1H, d, J=9.9 Hz), 3.37 (1H, d, J=2.0 Hz), 2.58 (1H,
m), 2.50 (1H, dd, J=12.2, 6.2 Hz), 2.31 (3H, m), 2.09 (2H, m), 1.82
(3H, s), 1.53 (3H, s), 1.27 (3H, d, J=6.6 Hz), 1.17 (3H, d, J=6.9
Hz)
[0245] .sup.13C NMR (67.8 MHz, CDCl.sub.3) .delta. (ppm): 205.6,
173.3, 154.7, 139.6, 137.3, 136.3, 134.8, 133.0, 131.4, 127.7,
125.1, 121.5, 120.2, 118.7, 118.6, 95.7, 94.6, 82.2, 80.8
(.times.2), 78.1, 77.4, 74.8, 73.5, 70.7, 68.7, 68.4, 68.2, 58.5,
45.6, 40.4, 39.6, 39.0, 36.6, 35.1, 34.2, 30.5, 27.4, 20.1, 19.6,
16.3, 15.1, 13.9, 13.0, 12.0
Example 3
[0246] Compound 3
[0247] Under nitrogen atmosphere, allyl diethylphosphonoacetate (54
.mu.L) was added to a 1.0 mol/L solution of lithium
hexamethyldisilazane in tetrahydrofuran (0.17 mL) at 0.degree. C.,
and the mixture was stirred at 0.degree. C. for 1 hour. Then, a
solution of Compound 2 (67 mg) obtained in Example 2 in
tetrahydrofuran (1.0 mL) was slowly added dropwise to the mixture,
and the mixture was further stirred at 0.degree. C. for 1 hour.
After a saturated aqueous ammonium chloride solution was added to
the reaction mixture, the reaction mixture was extracted with ethyl
acetate. The organic layer was washed successively with a saturated
aqueous sodium hydrogencarbonate solution and saturated brine and
dried over anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure to give a crude product. The resulting crude
product was purified by silica gel column chromatography with
eluting solvents of hexane/ethyl acetate=5/1 and 2/1 to give
Compound 3 (0.43 g, 58%).
[0248] .sup.1H NMR (270 MHz, CDCl.sub.3, partial data) .delta.
(ppm): 5.95 (2H, m), 5.88 (1H, s), 5.75 (4H, m), 5.56 (1H, m), 5.54
(1H, dd, J=9.6, 2.3 Hz), 5.35 (4H, m), 5.26 (2H, d, J=10.2 Hz),
5.16 (1H, brs), 5.03 (1H, m), 4.90 (1H, t, J=6.4 Hz), 4.63 (7H, m),
4.10 (1H, dd, J=5.3 Hz), 4.03 (1H, br), 3.84 (1H, m), 3.48 (2H, m),
3.36 (3H, s), 2.51 (1H, m), 2.33 (4H, m), 2.01 (1H, m), 1.80 (3H,
s), 1.47 (3H, s), 1.39 (3H, d, J=6.3 Hz), 1.11 (3H, d, J=6.6
Hz)
Example 4
[0249] Compound 4
[0250] Under nitrogen atmosphere, diethylphosphonocyanomethyl (80
.mu.L) was added to a 1.0 mol/L solution of lithium
hexamethyldisilazane in tetrahydrofuran (0.49 mL) at 0.degree. C.,
and the mixture was stirred at 0.degree. C. for 1 hour. Then, a
solution of Compound 2 (0.20 g) obtained in Example 2 in
tetrahydrofuran (2.5 mL) was slowly added dropwise to the mixtur,
and the mixture was further stirred at 0.degree. C. for 1 hour.
After a saturated aqueous ammonium chloride solution was added to
the reaction mixture, the reaction mixture was extracted with ethyl
acetate. The organic layer was washed successively with a saturated
aqueous sodium hydrogencarbonate solution and saturated brine and
dried over anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure to give a crude product of Compound 4. The
resulting crude product was purified by short silica gel column
chromatography and used for the reaction in Example 7.
Example 5
[0251] Compound 5
[0252] Under nitrogen atmosphere, Compound 1 (0.30 g) obtained in
Example 1 was dissolved in methylene chloride (0.60 mL), and
diacetyl rhodium dimer (1.0 mg) was added to the solution. The
mixture was stirred for 10 minutes at room temperature. Then, a
solution of ethyl diazoacetate (43 .mu.L) in methylene chloride
(0.60 mL) was slowly added dropwise to the mixture, and the mixture
was stirred at room temperature for 6 hours. After a saturated
aqueous sodium hydrogencarbonate solution was added to the mixture,
the mixture was extracted with methylene chloride. The organic
layer was washed with saturated brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated under reduced
pressure to give a crude product. The resulting crude product was
purified by silica gel column chromatography with eluting solvents
of hexane/ethyl acetate=6/1, 5/1, 4/1, and 2/1 to give Compound 5
(91 mg, 27%).
[0253] .sup.1H NMR (270 MHz, CDCl.sub.3, partial data) .delta.
(ppm): 5.95 (5H, m), 5.55 (1H, dcd, J=9.9, 2.3 Hz), 5.39 (3H, m),
5.27 (1H, d, J=10.5 Hz), 4.99 (1H, m), 4.76 (1H, d, J=3.0 Hz), 4.65
(4H, m), 4.40 (2H, d, J=2.0 Hz), 4.21 (2H, m), 4.12 (1H, d, J=6.3
Hz), 3.99 (3H, m), 3.78 (1H, m), 3.48 (1H, d, J 9.9 Hz), 3.44 (3H,
s), 3.37 (1H, d, J=2.3 Hz), 2.97 (1H, t, J=9.1 Hz), 2.51 (1H, m),
2.24 (4H, m), 2.02 (1H, m), 1.82 (3H, s), 1.49 (3H, s), 1.30 (6H,
m), 1.12 (3H, d, J=6.9 Hz)
Example 6
[0254] Compound 6
[0255] Compound 3 (42 mg) obtained in Example 3 was dissolved in
ethanol (500 .mu.L), tetrakis(triphenylphosphine)palladium (1.0 mg)
was added to the solution, and the mixture was stirred at 0.degree.
C. for 10 minutes. Then, sodium borohydride (5.0 mg) was added to
the mixture, and then the mixture was stirred for 1 hour. After a
saturated aqueous ammonium chloride solution was added to the
reaction mixture, the reaction mixture was extracted with ethyl
acetate. The organic layer was washed successively with a saturated
aqueous sodium hydrogencarbonate solution and saturated brine and
dried over anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure to give a crude product. The resulting crude
product was purified by plate silica gel column chromatography with
eluting solvents of chloroform/methanol=10/1 to give the desired
compound (43 mg, 68%).
[0256] .sup.1H NMR (270 MHz, CDCl.sub.3, partial data) .delta.
(ppm): 5.89 (1H, s), 5.84 (1H, m), 5.76 (1H, d, J=9.9 Hz), 5.70
(1H, m), 5.55 (1H, dd, J=9.9, 2.3 Hz), 5.41 (1H, brs), 5.37 (1H,
m), 5.08 (1H, brs), 5.04 (1H, m), 4.91 (1H, t, J=6.1 Hz), 4.67 (2H,
brs), 4.59 (1H, m), 4.29 (1H, d, J=6.0 Hz), 4.04 (1H, brs), 3.96
(1H, d, J=6.3 Hz), 3.85 (1H, m), 3.49 (1H, d, J=9.9 Hz), 3.40 (3H,
s), 3.28 (1H, d, J=2.0 Hz), 2.52 (1H, m), 2.31 (4H, m), 2.01 (1H,
dd, J=11.9, 4.0 Hz), 1.86 (3H, s), 1.48 (3H, s), 1.40 (3H, d, J=6.2
Hz), 1.12 (3H, d, J=6.9 Hz)
[0257] .sup.13C NMR (67.8 MHz, CDCl.sub.3) .delta. (ppm): 173.6,
169.5, 158.4, 139.4, 138.2, 137.8, 136.3, 135.3, 127.7, 124.6,
120.4, 118.1, 117.9, 116.4, 95.7, 93.5, 81.2, 80.3, 79.1, 74.8,
70.6, 68.4 (.times.3), 67.7, 67.2, 66.6, 45.7, 40.5, 39.7, 36.5,
35.1, 34.3, 33.0, 30.5, 27.5, 19.9, 19.5, 19.1, 16.3, 14.9, 13.0,
12.0
Example 7
[0258] Compound 7
[0259] Compound 4 obtained in Example 4 (0.15 g) was dissolved in
ethanol (1.8 mL), and tetrakis(triphenylphosphine)palladium (1.0
mg) was added to the solution. The mixture was stirred for 10
minutes at 0.degree. C. Then, sodium borohydride (7.0 mg) was added
to the mixture, and the mixture was stirred for 5 minutes. After a
saturated aqueous ammonium chloride solution was added to the
reaction mixture, the reaction mixture was extracted with ethyl
acetate. The organic layer was washed successively with a saturated
aqueous sodium hydrogencarbonate solution and saturated brine and
dried over anhydrous sodium sulfate. The solvent was evaporated
under reduced pr ssure to give a crude product. The resulting crude
product was purified by silica gel column chromatography with
eluting solvents of hexane/ethyl acetate=5/1 and 1/1 to give
Compound 7 (0.13 g, 100%).
[0260] .sup.1H NMR (270 MHz, CDCl.sub.3, partial data) .delta.
(ppm): 5.86 (1H, m), 5.75 (3H, m), 5.55 (1H, dd, J=9.9, 2.3 Hz),
5.45 (1H, s), 5.40 (1H, m), 5.37 (1H, s), 5.01 (1H, m), 4.88 (1H,
t, J=4.2 Hz), 4.67 (2H, s), 4.56 (1H, m), 4.36 (1H, t, J=6.3 Hz),
4.29 (1H, d, J=6.0 Hz), 4.00 (1H, s), 3.96 (1H, d, J=6.3 Hz), 3.96
(1H, m), 3.53 (3H, s), 3.48 (1H, d, J=10.2 Hz), 3.29 (1H, d, J=2.3
Hz), 2.53 (1H, m), 2.29 (4H, m), 1.87 (3H, s), 1.49 (3H, s), 1.34
(6H,d, J=6.6 Hz), 1.13 (3H, d, J=6.9 Hz)
Example 8
[0261] Compound 8
[0262] Intermediate 7 (49 mg, 53.0 .mu.mol) obtained in Reference
Example 7 was dissolved in tetrahydrofuran (1.6 mL). Hydrogen
fluoride/pyridine complex (60 .mu.L) was added to the solution, and
the mixture was stirred at room temperature for 12 hours. After the
reaction mixture was cooled to 0.degree. C., a saturated aqueous
sodium hydrogencarbonate solution (10 mL) was added for
neutralization, and the mixture was extracted with ethyl acetate
(10 mL.times.3). The organic layer was washed successively with a
saturated aqueous sodium hydrogencarbonate solution (10 mL) and
saturated brine (10 mL) and dried over anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure to give a crude
product. The resulting crude product was purified on a silica gel
plate with development solvents of chloroform/methanol=15/1 to give
Compound 8 (41.0 mg, 84%).
[0263] HRFABMS: Calcd. for C.sub.46H.sub.64O.sub.12 [M+Na].sup.+
831.4295. Found 831.4296.
[0264] IR (KBr) .lambda..sub.max(cm.sup.-1): 3475, 2966, 2933,
1722, 1658, 1466, 1377, 1340, 1242, 1186, 1159, 1117, 1082, 1036,
995
[0265] .sup.1H NMR (270 MHz, CDCl.sub.3, partial data) .delta.
(ppm): 5.94 (ddt, J=17.2, 10.2, 5.6 Hz, 1H), 5.88 (s, 1H), 5.83 (m,
1H), 5.75 (dd, J 9.9, 1.7 Hz, 1H), 5.72 (m, 2H), 5.54 (dd, J=9.9,
2.8 Hz, 1H), 5.40 (s, 1H), 5.35 (m, 1H), 5.33 (dd, J=17.2, 1.7 Hz,
1H), 5.25 (dd, J=10.2, 1.7 Hz, 2H), 5.16 (t, J=3.1 Hz, 1H), 5.03
(m, 1H), 4.89 (t, J=6.3 Hz, 1H), 4.69 (dd, J=14.5, 2,3 Hz, 1H),
4.63 (dd, J=14.5, 2.3 Hz, 1H), 4.62 (d, J=5.6 Hz, 2H), 4.58 (dq,
J=6.6, 1.3 Hz, 1H), 4.27 (d, J=6.3 Hz, 1H), 4.03 (brs, 1H), 3.94
(d, J=6.3 Hz, 1H), 3.84 (m, 1H), 3.48 (d, J=9.6 Hz, 1H), 3.36 (s,
3H), 2.27 (q, J=2.3 Hz, 1H), 1.85 (s, 3H), 1.47 (s, 3H), 1.38 (d,
J=6.6 Hz, 3H), 1.11 (d, J 6.6 Hz, 3H)
[0266] .sup.13C NMR (67.8 MHz, CDCl.sub.3) .delta. (ppm):
178.6,165.4, 157.3, 139.5, 138.3, 137.8, 136.2, 135.3, 132.0,
127.8, 124.5, 120.4, 118.5, 118.0, 117.9, 116.5, 95.7, 93.5, 81.2,
80.3, 79.1, 74.8, 70.0, 68.4. 68.3 (X2), 67.7, 67.2, 65.0, 56.3,
45.7, 40.5, 39.7, 36.5, 35.1, 34.3, 32.8, 30.5, 27.5, 19.9, 19.4,
19.3, 16.4, 14.8, 13.0, 12.0
Example 9
[0267] Compound 9
[0268] In the manner similar to that of Example 8, Compound 9 (61.2
mg, 100%) was obtained from Intermediate 8 (70.0 mg, 76.8 .mu.mol)
obtained in Reference Example 8.
[0269] HRFABMS: Calcd. for C.sub.45H.sub.64O.sub.12 [M+Na].sup.+
819.4295. Found 819.4297.
[0270] IR (KBr) .lambda..sub.max(cm.sup.-1): 3448, 2966, 2933,
1720, 1655, 1460, 1379, 1340, 1244, 1186, 1159, 1116, 1082, 1084,
989
Example 10
[0271] Compound 10
[0272] In the manner similar to that of Example 8, Compound 10
(63.7 mg, 100%) was obtained from Intermediate 9 (70.0 mg, 80.5
.mu.mol) obtained in Reference Example 9.
[0273] HRFABMS: Calcd. for C.sub.43H.sub.77O.sub.11 [M+Na].sup.+
777.4190. Found 777.4180.
[0274] IR (KBr) .lambda..sub.max(cm.sup.-1):3453, 2966, 2931, 1735,
1714, 1456, 1376, 1340, 1244, 1184, 1160, 1117, 1080, 1038, 996
Example 11
[0275] Compound 11
[0276] In the manner similar to that of Example 8, Compound 11
(77.4 mg, 92%) was obtained from Intermediate 14 (97.0 mg, 80.5
.mu.mol) obtained in Reference Example 14.
[0277] HRFABMS: Calcd. for C.sub.43H.sub.61ClO.sub.10 [M+Na].sup.+
795.8851. Found 795.3833.
[0278] IR (KBr) .lambda..sub.max(cm.sup.-1): 3455, 2966, 2933,
1712, 1456, 1376, 1340, 1255, 1184, 1159, 1116, 1080, 1088, 997
Example 12
[0279] Compound 12
[0280] Intermediate 10 (70.0 mg, 79.2 .mu.mol) obtained in
Reference Example 10 was dissolved in tert-butanol (0.8 mL).
4-Dimethylaminopyridine (3 mg, 23.7 .mu.mol) and di-tert-butyl
carbonate (25 mg, 118 .mu.mol) were successively added, and the
mixture was stirred at room temperature for 2 hours. After a
saturated aqueous ammonium chloride solution (0.5 mL) was added to
the reaction mixtur, the reaction mixture was extracted with ethyl
acetate (3 mL.times.3). The organic layer was washed with saturated
brine (5 mL) and dried over anhydrous sodium sulfate. The solvent
was evaporated under reduced pressure to give a crude product.
Then, from the resulting crude product, Compound 12 (46.4 mg, 53%
for the two steps) was obtained in the manner similar to that of
Example 8.
[0281] HRFABMS: Calcd. for C.sub.47H.sub.68O.sub.12 [M+Na].sup.+
847.4608. Found 847.4599.
[0282] IR (KBr) .lambda..sub.max(cm.sup.-1): 3475, 2964, 2929,
1716, 1456, 1396, 1340, 1307, 1248, 1159, 1117, 1080, 1038, 997
Example 13
[0283] Compound 13
[0284] Intermediate 10 (70.0 mg, 79.2 .mu.mol) obtained in
Reference Example 10 was dissolved in methylene chloride (0.8 mL).
Morpholine (10 .mu.L, 103 .mu.mol), anhydrous 1-hydroxybenzotriazol
(20 mg, 103 .mu.mol) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (20 mg,
103 .mu.mol) were successively added to the solution, and the
mixture was stirred at room temperature for 12 hours. After
purified water (0.5 mL) was added to the reaction mixture, the
reaction mixture was extracted with methylene chloride (5
mL.times.3). The organic layer was washed with saturated brine (3
mL) and dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure to give a crude product. Then,
from the resulting crude product, Compound 13 (66.3 mg, 100%, for
the two steps) was obtained in the manner similar to that of
Example 8.
[0285] HRFABMS: Calcd. for C.sub.47H.sub.67NO.sub.12 [M+Na].sup.+
860.4561. Found 860.4512.
[0286] IR (KBr) .lambda..sub.max(cm.sup.-1): 3456, 2964, 2927,
1735, 1735, 1648, 1460, 1379, 1338, 1244, 1182, 1161, 1117, 1074,
1045, 999
Example 14
[0287] Compound 14
[0288] Intermediate 14 (70.0 mg, 79.8 .mu.mol) obtained in
Reference Example 14 was dissolved in ethanol (1 mL). Morpholine
(10 .mu.L, 103 .mu.mol) was added to the solution, and th mixture
was stirred at 40.degree. C. for 12 hours. After a saturated
aqueous ammonium chloride solution (0.5 mL) was added to the
reaction mixture, the reaction mixture was extracted with ethyl
acetate (5 mL.times.3). The organic layer was washed with saturated
brine (3 mL) and dried over anhydrous sodium sulfate. The solvent
was evaporated under reduced pressure to give a crude product.
Then, from the resulting crude product, Compound 14 (60.0 mg, 77%,
for the two steps) was obtained in the manner similar to that of
Example 8.
[0289] HRFABMS: Calcd. for C.sub.47H.sub.70NO.sub.11 [M+Na].sup.+
824.4949. Found 824.4938.
[0290] IR (KBr) .lambda..sub.max(cm.sup.-1): 3458, 2964, 2929,
1731, 1718, 1456, 1377, 1338, 1311, 1270, 1182, 1161, 1117, 1080,
1038, 995
Example 15
[0291] Compound 15
[0292] Intermediate 9 (70.0 mg, 80.5 .mu.mol) obtained in Reference
Example 9 was dissolved in methylene chloride (1 mL). Manganese
dioxide (70.0 mg) was added to the solution, and the mixture was
stirred at room temperature for 10 hours. After the reaction
mixture was filtered by using Cerite.RTM., the solvent was
evaporated under reduced pressure to give a crude product. Then,
from the resulting crude product, Compound 15 (86.2 mg, 65%, for
the two steps) was obtained in the manner similar to that of
Example 8.
Example 16
[0293] Compound 16
[0294] Intermediate 9 (50.0 mg, 57.6 .mu.mol) obtained in Reference
Example 9 was dissolved in methylene chloride (0.6 mL). Nicotinoyl
chloride hydrochloride (15.0 mg, 86.2 .mu.mol),
diisopropylethylamine (15 .mu.L, 86.2 .mu.moL),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17.0
mg, 86.2 .mu.mol) and 4-dimethylaminopyridine (3 mg, 23.7 .mu.mol)
were successively added to the solution, and the mixture was
stirred at room temperature for 4 hours. After a saturated aqueous
ammonium chloride solution (0.5 mL) was added to the reaction
mixture, the reaction mixture was extracted with methylene chloride
(3 mL.times.3). The organic layer was washed with saturated brine
(5 mL) and dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure to give a crude product.
[0295] Then, from the resulting crude product, Compound 16 (40.0
mg, 66%, for the two steps) was obtained in the manner similar to
that of Example 8.
[0296] HRFABMS: Calcd. for C.sub.49H.sub.65NO.sub.12 [M+Na].sup.+
882.4404. Found 882.4399.
[0297] IR (KBr) .lambda..sub.max(cm.sup.-1): 3464, 2962, 2929,
1735, 1456, 1377, 1344, 1244, 1196, 1171, 1119, 1074, 1038, 993
Example 17
[0298] Compound 17
[0299] Intermediate 9 (70.0 mg, 80.5 .mu.mol) obtained in Reference
Example 9 was dissolved in methylene chloride (0.8 mL).
Isonicotinoyl chloride hydrochloride (22.0 mg, 120 .mu.mol),
diisopropylethylamine (21 .mu.L, 120 .mu.moL),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.0
mg, 120 .mu.mol) and 4-dimethylaminopyridine (5.00 mg, 40.0
.mu.mol) were successively added to the solution, and the mixture
was stirred at room temperature for 4 hours. After a saturated
aqueous ammonium chloride solution (0.5 mL) was added to the
reaction mixture, the reaction mixture was extracted with methylene
chloride (3 mL.times.3). The organic layer was washed with
saturated brine (5 mL) and dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure to give a crude
product. Then, from the resulting crude product, Compound 17 (60.0
mg, 87%, for the two steps) was obtained in the manner similar to
that of Example 8.
[0300] HRFABMS: Calcd. for C.sub.49H.sub.65NO.sub.12 [M+Na].sup.+
882.4404. Found 882.4438.
[0301] IR (KBr) .lambda..sub.max(cm.sup.-1): 3458, 2964, 2931,
1732, 1456, 1377, 1326, 1279, 1182, 1159, 1119, 1084, 1039, 997
Example 18
[0302] Compound 18
[0303] Intermediate 9 (70.0 mg, 80.5 .mu.mol) obtained in Reference
Example 9 was dissolved in methylene chloride (0.8 mL).
4-Nitrobenzoyl chloride hydrochloride (22.0 mg, 120 .mu.mol),
diisopropylethylamine (21 .mu.L, 120 .mu.moL),
1-ethyl3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.0
mg, 120 .mu.mol) and 4-dimethylaminopyridine (5.00 mg, 40.0
.mu.mol) were successively added to the solution, and the mixture
was stirred at room temperature for 4 hours. After a saturated
aqueous ammonium chloride solution (0.5 mL) was added to the
reaction mixture, the reaction mixture was extracted with methylene
chloride (3 mL.times.3). The organic layer was washed with
saturated brine (5 mL) and dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pr ssure to give a crude
product. Then, from the resulting crude product, Compound 18 (70.5
mg, 97%, for the two steps) was obtained in the manner similar to
that of Example 8.
[0304] HRFABMS: Calcd. for C.sub.50H.sub.65NO.sub.14 [M+Na].sup.+
926.4303. Found 926.4338.
[0305] IR (KBr) .lambda..sub.max(cm.sup.-1): 3482, 2966, 2931,
1726, 1529, 1458, 1348, 1271, 1182, 1161, 1117, 1086, 1039, 997
Example 19
[0306] Compound 19
[0307] In the manner similar to that of Example 8, Compound 19
(48.8 mg, 80%) was obtained from Intermediate 16 (70.0 mg, 79.1
.mu.mol) obtained in Reference Example 16.
[0308] HRFABMS: Calcd. for C.sub.43H.sub.62O.sub.12 [M+Na].sup.+
793.4139. Found 793.4185.
[0309] IR (KBr) .lambda..sub.max(cm.sup.-1): 3455, 2962, 2931,
1712, 1655, 1458, 1377, 1340, 1243, 1198, 1171, 1119, 1082, 1036,
993
Example 20
[0310] Compound 20
[0311] In the manner similar to that of Example 8, Compound 20
(61.1 mg, 100%) was obtained from Intermediate 11 (70.0 mg, 75.6
.mu.mol) obtained in Reference Example 11.
[0312] HRFABMS: Calcd. for C.sub.46H.sub.66O.sub.12 [M+Na].sup.+
833.4452. Found 833.4457.
[0313] IR (KBr) .lambda..sub.max(cm.sup.-1): 3456, 2962, 2929,
1722, 1456, 1379, 1340, 1243, 1196, 1165, 1119, 1080, 1037, 993
Example 21
[0314] Compound 21
[0315] In the manner similar to that of Example 8, Compound 21
(61.1 mg, 100%) was obtained from Intermediate 12 (70.0 mg, 75.6
.mu.mol) obtained in Reference Example 12.
[0316] HRFABMS: Calcd. for C.sub.48H.sub.66O.sub.12 [M+Na].sup.+
833.4452. Found 833.4457.
[0317] IR (KBr) .lambda..sub.max(cm.sup.-1): 3456, 2962, 2929,
1722, 1456, 1379, 1340, 1243, 1196, 1165, 1119, 1080, 1037, 993
Example 22
[0318] Compound 22
[0319] In the manner similar to that of Example 8, Compound 22 (123
mg, 92%) was obtained from Intermediate 13 (154 mg, 177 .mu.mol)
obtained in Reference Example 13.
[0320] HRFABMS: Calcd. for C.sub.43H.sub.61NO.sub.10 [M+Na].sup.+
774.4193. Found 774.4222.
[0321] IR (KBr) .lambda..sub.max(cm.sup.-1): 3483, 2960, 2931,
2221, 1712, 1458, 1877, 1340, 1243, 1196, 1174, 1119, 1086, 1027,
993
Example 23
[0322] Compound 23
[0323] In the manner similar to that of Example 12, Compound 23
(53.0 mg, 81%, for the two steps) was obtained from Intermediate 16
(70.0 mg, 79.1 .mu.mol) obtained in Reference Example 16.
[0324] HRFABMS: Calcd. for C.sub.47H.sub.70O.sub.12 [M+Na].sup.+
849.4765. Found 849.4727.
[0325] IR (KBr) .lambda..sub.max(cm.sup.-1): 3479, 2964, 2931,
1716, 1456, 1377, 1339, 1248, 1171, 1119, 1035, 993
Example 24
[0326] Compound 24
[0327] In the manner similar to that of Example 13, Compound 24
(66.4 mg, 100%, for the two steps) was obtained from Intermediate
16 (70.0 mg, 79.1 .mu.mol) obtained in Reference Example 16.
[0328] HRFABMS: Calcd. for C.sub.47H.sub.69NO.sub.12 [M+Na].sup.+
862.4717. Found 862.4731.
[0329] IR (KBr) .lambda..sub.max(cm.sup.-1): 8461, 2962, 2929,
1731, 1713, 1633, 1456, 1377, 1338, 1244, 1172, 1117, 1072, 1043,
996
Example 25
[0330] Compound 25
[0331] In the manner similar to that of Example 8, Compound 25
(34.0 mg, 65%) was obtained from Intermediate 15 (60.0 mg, 68.8
.mu.mol) obtained in Reference Example
[0332] HRFABMS: Calcd. for C.sub.43H.sub.64O.sub.11 [M+Na].sup.+
779.4346. Found 779.4361.
[0333] IR (KBr) .lambda..sub.max(cm.sup.-1): 3455, 2962, 2929,
1722, 1456, 1379, 1340, 1306, 1244, 1196, 1165, 1119, 1072, 1036,
993
Example 26
[0334] Compound 26
[0335] In the manner similar to that of Example 15, Compound 26
(48.0 mg, 79%, for the two steps) was obtained from Intermediate 15
(70.0 mg, 80.3 .mu.mol) obtained in Reference Example 15.
[0336] HRFABMS: Calcd. for C.sub.43H.sub.62O.sub.11 [M+Na].sup.+
777.4190. Found 777.4179.
[0337] IR (KBr) .lambda..sub.max(cm.sup.-1): 3473, 2962, 2931,
1713, 1674, 1456, 1377, 1338, 1244, 1174, 1119, 1074, 1041,
995.
Example 27
[0338] Compound 27
[0339] In the manner similar to that of Example 8, Compound 27
(42.0 mg, 80%) was obtained from Intermediate 19 (60.0 mg, 67.4
.mu.mol) obtained in Reference Example 19.
[0340] HRFABMS: Calcd. for C.sub.48H.sub.62ClO.sub.10 [M+Na].sup.+
797.4007. Found 797.3985.
[0341] IR (KBr) .lambda..sub.max(cm.sup.-1): 3471, 2962, 2929,
1713, 1456, 1377, 1338, 1243, 1195, 1172, 1119, 1074, 1038, 997
Example 28
[0342] Compound 28
[0343] In the manner similar to that of Example 14, Compound 28
(53.0 mg, 80%, for the two steps) was obtained from Intermediate 19
(70.0 mg, 80.5 .mu.mol) obtained in Reference Example 19.
[0344] HRFABMS: Calcd. for C.sub.47H.sub.71NO.sub.11 [M+Na].sup.+
848.4925. Found 848.4913.
[0345] IR (KBr) .lambda..sub.max(cm.sup.-1): 3440, 2962, 2929,
1734, 1713, 1456, 1377, 1346, 1243, 1172, 1119, 1074, 1038, 993
Example 29
[0346] Compound 29
[0347] In the manner similar to that of Example 16, Compound 29
(41.0 mg, 38%, for the two steps) was obtained from Intermediate 15
(70.0 mg, 80.5 .mu.mol) obtained in Reference Example 15.
[0348] HRFABMS: Calcd. for C.sub.49H.sub.67NO.sub.12 [M+Na].sup.+
844.4561. Found 844.4595.
[0349] IR (KBr) .lambda..sub.max(cm.sup.-1): 3457, 2962, 2929,
1728, 1456, 1376, 1336, 1279, 1173, 1119, 1087, 1038, 995
Example 30
[0350] Compound 30
[0351] In the manner similar to that of Example 17, Compound 30
(58.0 mg, 84%, for the two st ps) was obtained from Intermediate 15
(60.0 mg, 69.0 .mu.mol) obtained in Reference Example 15.
[0352] HRFABMS: Calcd. for C.sub.49H.sub.67NO.sub.12 [M+Na].sup.+
844.4561. Found 844.4561.
[0353] IR (KBr) .lambda..sub.max(cm.sup.-1): 3454, 2962, 2929,
1731, 1456, 1375, 1327, 1279, 1173, 1119, 1087, 1039, 993
Example 31
[0354] Compound 31
[0355] In the manner similar to that of Example 18, Compound 31
(58.0 mg, 93%, for the two steps) was obtained from Intermediate 15
(60.0 mg, 69.0 .mu.mol) obtained in Reference Example 15.
[0356] HRFABMS: Calcd. for C.sub.50H.sub.67NO.sub.14 [M+Na].sup.+
928.4459. Found 928.4433.
[0357] IR (KBr) .lambda..sub.max(cm.sup.-1): 3444, 2962, 2931,
1726, 1531, 1456, 1375, 1348, 1270, 1173, 1119, 1087, 1039, 995
Example 32
[0358] Compound 32
[0359] Intermediate 16 (70.0 mg, 79.1 .mu.mol) obtained in
Reference Example 16 was dissolved in methylene chloride (0.8 mL).
Piperidine (10 .mu.L, 158 .mu.mol), anhydrous 1-hydroxybenzotriazol
(13.0 mg, 103 .mu.mol) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18.0
mg, 103 .mu.mol) were added to the solution, and the mixture was
stirred at room temperature for 23 hours. After purified water (0.5
mL) was added to the reaction mixture, the reaction mixture was
extracted with methylene chloride (5 mL.times.3). The organic layer
was washed with saturated brine (5 mL) and dried over anhydrous
sodium sulfate. The solvent was evaporated under reduced pressure
to give a crude product. Then, from the resulting crude product,
Compound 32 (59.0 mg, 89%, for the two steps) was obtained in the
manner similar to that of Example 8.
[0360] HRFABMS: Calcd. for C.sub.48H.sub.71NO.sub.11 [M+Na].sup.+
860.4925. Found 860.4951.
[0361] IR (KBr) .lambda..sub.max(cm.sup.-1):3454, 2960, 2931, 1735,
1712, 1628, 1446, 1375, 1340, 1265, 1173, 1119, 1036, 997
Example 33
[0362] Compound 33
[0363] Intermediate 16 (70.0 mg, 79.1 .mu.mol) obtained in
Reference Example 16 was dissolved in methylene chloride (0.8 mL).
Piperazine (14 mg, 158 .mu.mol), anhydrous 1-hydroxybenzotriazol
(13.0 mg, 103 .mu.mol) and
1-ethyl-3-(3-dimethylaminopropyl)-carbodiimid hydrochloride (18.0
mg, 103 .mu.mol) were added to the solution, and the mixture was
stirred at room temperature for 23 hours. After purified water (0.5
mL) was added to the reaction mixture, the reaction mixture was
extracted with methylene chloride (5 mL.times.3). The organic layer
was washed with saturated brine (5 mL) and dried over anhydrous
sodium sulfate. The solvent was evaporated under reduced pressure
to give a crude product. Then, from the resulting crude product,
Compound 33 (28.0 mg, 42%, for the two steps) was obtained in the
manner similar to that of Example 8.
[0364] HRFABMS: Calcd. for C.sub.47H.sub.70N.sub.2O.sub.11
[M+Na].sup.+ 861.4877. Found 861.4888.
[0365] IR (KBr) .lambda..sub.max(cm.sup.-1): 3448, 2960, 2929,
1735, 1716, 1628, 1466, 1377, 1338, 1244, 1173, 1119, 1039, 997
Example 34
[0366] Compound 34
[0367] Compound 5 (91 mg) obtained in Example 5 was dissolved in
ethanol (1.0 ml), tetrakistriphenylphosphine palladium (1.2 mg) was
added to the solution, and the mixture was stirred for 10 minutes
at 0.degree. C. Then, sodium borohydride (3.8 mg) was added to the
mixture, and the mixture was stirred for 5 minutes. After a
saturated aqueous ammonium chloride solution was added to the
reaction mixture, the reaction mixture was extracted with ethyl
acetate. The organic layer was washed successively with a saturated
aqueous sodium hydrogencarbonate solution and saturated brine and
dried over anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure to give a crude product. The resulting crude
product was purified by silica gel column chromatography with
eluting solvents of hexane/ethyl acetate=5/1, 2/1, and 1/1 to give
Compound 34 (67 mg, 82%).
[0368] .sup.1H NMR (270 MHz, CDCl.sub.3, partial data) .delta.
(ppm): 5.84 (1H, m), 5.72 (3H, m), 5.53 (1H, dd, J=9.9, 2.3 Hz),
5.40 (1H, s), 5.37 (1H, m), 4.96 (1H, m), 4.74 (1H, d, J=3.3 Hz),
4.65 (2H, brs), 4.37 (2H, d, J=2.0 Hz), 4.27 (1H, m), 4.20 (2H, q,
J=7.3 Hz), 3.94 (1H, d, J=6.3 Hz), 3.91 (1H, brs), 3.87 (2H, m),
3.70 (1H, m), 3.46 (1H, d, J=8.9 Hz), 3.41 (3H, s), 3.27 (1H, d,
J=2.0 Hz), 2.94 (1H, t, J=9.1 Hz), 2.47 (2H, m), 2.24 (4H, m), 2.00
(1H, dd, J=12.2, 4.3 Hz), 1.85 (3H, s), 1.47 (3H, s), 1.30 (6H, m),
1.12 (3H, d, J=6.9 Hz)
[0369] .sup.13C NMR (67.8 MHz, CDCl.sub.3) .delta. (ppm): 173.3,
170.5, 139.5, 138.0, 137.9, 136.2, 135.1, 127.7, 124.7, 120.4,
118.3, 118.0, 95.7, 94.8, 84.7, 82.0, 80.3, 79.1, 78.7, 74.8, 70.0,
68.4, 68.3 (.times.2), 67.6, 67.2, 60.6, 56.4, 45.6, 40.4, 39.7,
36.5, 35.1, 34.5, 34.2, 30.6, 27.4, 20.1, 19.9, 17.9, 16.3, 15.0,
14.2, 12.9, 12.0
Example 35
[0370] Compound 35
[0371] Intermediate 20 (100 mg, 99.9 .mu.mol) obtained in Reference
Example 20 was dissolved in tetrahydrofuran (2.0 mL), a 1 mol/L
aqueous potassium hydroxide solution (50 .mu.L) was added to the
solution, and the mixture was stirred at room temperature for 5
hours. The reaction mixture was neutralized with a saturated
aqueous ammonium chloride solution (5 mL) and extracted with ethyl
acetate (5 mL.times.3). The organic layer was washed with a
saturated aqueous ammonium chloride solution (5 mL) and saturated
brine (5 mL) and dried over anhydrous sodium sulfate. The solvent
was evaporated under reduced pressure to give a crude product.
Then, from the resulting crude product, Compound 35 (55.8 mg, 71%,
for the two steps) was obtained from the resulting crude product in
the manner similar to that of Example 8.
[0372] HRFABMS: Calcd. for C.sub.43H.sub.61O.sub.13 [M+2Na].sup.+
831.3908. Found 831.3970.
[0373] IR (KBr) .lambda..sub.max(cm.sup.-1):3470, 2968, 2933, 1760,
1737, 1713, 1452, 1381, 1342, 1308, 1273, 1192, 1161, 1124, 1070,
1038, 993
Example 36
[0374] Compound 36
[0375] In the manner similar to that of Example 8, Compound 36
(49.0 mg, 76%) was obtained from Intermediate 21 (80.0 mg, 83.3
.mu.mol) obtained in Reference Example 21.
[0376] HRFABMS: Calcd. for C.sub.43G.sub.64O.sub.12 [M+Na]+
795.4295. Found 795.4298.
[0377] IR (KBr) .lambda..sub.max(cm.sup.-1): 3450, 2966, 2933,
1738, 1716, 1456, 1381, 1340, 1309, 1272, 1193, 1161, 1124, 1066,
989
Example 37
[0378] Compound 37
[0379] In the mann r similar to that of Example 8, Compound 37
(35.9 mg, 88%) was obtained from Intermediate 22 (50.2 mg, 49.1
.mu.mol) obtained in Referenc Example 22.
[0380] HRFABMS: Calcd. for C.sub.43H.sub.63BrO.sub.11 [M+Na].sup.+
857.3451. Found 857.3463.
[0381] IR (KBr) .lambda..sub.max(cm.sup.-1): 3465,2964, 2931, 1737,
1718, 1456, 1377, 1340, 1309, 1273, 1184, 1161, 1122, 1072, 995
Example 38
[0382] Compound 38
[0383] In the manner similar to that of Example 8, Compound 38
(57.1 mg, 70%) was obtained from Intermediate 24 (100 mg, 99.7
.mu.mol) obtained in Reference Example 24.
[0384] HRFABMS: Calcd. for C.sub.45H.sub.68O.sub.8 [M+Na].sup.+
839.4558. Found 839.4563.
[0385] IR (KBr) .lambda..sub.max(cm.sup.-1): 3473, 2962, 2931,
1759, 1736, 1716, 1456, 1379, 1340, 1306, 1275, 1244, 1198, 1173,
1120, 1066, 1036, 991
Example 39
[0386] Compound 39
[0387] In the manner similar to that of Example 35, Compound 39
(38.6 mg, 51%, for the two steps) was obtained from Intermediate 24
(83.2 mg, 82.9 .mu.mol) obtained in Reference Example 24.
[0388] HRFABMS: Calcd. for C.sub.43H.sub.63O.sub.13 [M-H].sup.+
787.4269. Found 787.4231.
[0389] IR (KBr) .lambda..sub.max(cm.sup.-1): 3456, 2962, 2931,
1763, 1736, 1716, 1456, 1379, 1342, 1308, 1273, 1244, 1198, 1173,
1120, 1070, 1036, 991
Example 40
[0390] Compound 40
[0391] In the manner similar to that of Example 8, Compound 40
(46.2 mg, 75%) was obtained from Intermediate 25 (76.8 mg, 79.8
.mu.mol) obtained in Reference Example 25.
[0392] HRFABMS: Calcd. for C.sub.43H.sub.66O.sub.12 [M+Na].sup.+
797.4452. Found 797.4448.
[0393] IR (KBr) .lambda..sub.max(cm.sup.-1): 3450, 2962, 2931,
1732, 1718, 1456, 1379, 1340, 1308, 1273, 1244, 1196, 1171, 1120,
1066, 1010, 989
Example 41
[0394] Compound 41
[0395] In the manner similar to that of Example 8, Compound 41
(61.7 mg, 80%) was obtained from Intermediate 26 (93.9 mg, 91.6
.mu.mol) obtained in Reference Example 26.
[0396] HRFABMS: Calcd. for C.sub.43H.sub.65BrO.sub.11 [M+Na]+
859.3698. Found 859.3586.
[0397] IR (KBr) .lambda..sub.max(cm.sup.-1):3482, 2962, 2931, 1716,
1458, 1379, 1340, 1308, 1275, 1244, 1196, 1171, 1120, 1072, 1086,
989
Reference Example 1
[0398] Intermediate 1 (Avermectin B1a Monosaccharide)
[0399] Intermediate 1 (15.5 g, 93%) was obtained from avermectin
B1a (20.0 g, 22.9 mmol) according to the method given in literature
(J. Med. Chem., 23, 1134-1136 (1980)).
[0400] HRFABMS: Calcd. for C.sub.41H.sub.60O.sub.11 [M+Na].sup.+
751.4033. Found 751.4052.
[0401] IR (KBr) .lambda..sub.max(cm.sup.-1): 3467, 2967, 2931,
1741, 1633, 1456, 1378, 1338, 1308, 1193, 1161, 1120, 1078, 1053,
989
[0402] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. (ppm): 5.86 (m,
1H), 5.75 (m, 3H), 5.54 (dd, J=9.9, 2.7 Hz, 1H), 5.42 (s, 1H), 5.39
(m, 1H), 4.98 (m, 1H), 4.81 (d, J=3.3 Hz, 1H), 4.67 (brs, 2H), 4.29
(d, J=6.6 Hz, 1H), 4.01 (s, 1H), 3.96 (d, J=6.6 Hz, 1H), 3.95 (brs,
1H), 3.85 (m, 2H), 3.55 (ddd, J=11.5, 8.9, 4.6 Hz, 1H), 3.48 (d,
J=10.3 Hz, 1H), 3.47 (s, 3H), 3.29 (q, J=2.3 Hz, 1H), 3.15 (t,
J=9.2 Hz, 1H), 2.65 (brs, 1H), 2.58 (m, 1H), 2.43 (brs, 1H), 2.26
(m, 4H), 2.01 (dd, J=11.9, 3.3 Hz, 1H), 1.86 (s, 3H), 1.78 (dd,
J=12.5, 2.3 Hz, 1H), 1.48 (s, 3H), 1.45 (m, 5H), 1.26 (d, J=6.3 Hz,
3H), 1.14 (d, J 6.9 Hz, 3H), 0.93 (m, 9H), 0.84 (m, 1H)
[0403] .sup.13C NMR (67.8 MHz, CDCl.sub.3) .delta. (ppm): 173.7,
139.6, 138.0, 137.9, 136.3, 135.1, 127.7, 124.7, 120.4, 118.3,
118.0, 95.8, 95.1, 81.8, 80.4, 79.1, 78.3, 76.1, 74.9, 68.4, 68.3
(.times.2), 68.1, 67.7, 66.6, 45.7, 40.5, 39.7, 36.6, 35.1, 34.2,
33.9, 30.5, 27.5, 20.2, 19.9, 17.7, 16.4, 15.1, 12.9, 12.0
Reference Example 2
[0404] Intermediate 2
[0405] Under nitrogen atmosphere, Intermediate 1 (3.50 g, 4.80
mmol) obtained in Reference Example 1 was dissolved in
N,N-dimethylformamide (9.6 mL). Imidazole (0.78 g, 5.76 mmol) and
tert-butyldimethylsilyl chloride (0.78 g, 11.5 mmol) were
successively added to the solution, and the mixture was stirred at
room temperature for 2 hours. After purified water (20 mL) was
added to the reaction mixture, the reaction mixture was extracted
with ethyl acetate (20 mL.times.3). The organic layer was washed
with purified water (20 mL.times.3) and saturated brine (20 mL) and
dried over anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure to give a crude product. The crude product
was purified by silica gel column chromatography with eluting
solvents of hexane/ethyl acetate=5/1 to give Intermediate 2 (2.50
g, 62%).
[0406] HRFABMS: Calcd. for C.sub.47H.sub.74O.sub.11Si [M+Na].sup.+
865-4898. Found 865.4901.
[0407] IR (KBr) .lambda..sub.max(cm.sup.-1): 3467, 2962, 2931,
1716, 1628, 1463, 1379, 1336, 1251, 1194, 1160, 1124, 1082, 1051,
989
[0408] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. (ppm): 5.82 (m,
1H), 5.73 (m, 2H), 5.71 (dd, J=9.9, 2.6 Hz, 1H), 5.54 (dd, J=9.9,
2.3 Hz, 1H), 5.35 (m, 1H), 5.32 (m, 1H), 4.98 (m, 1H), 4.80 (d,
J=3.3 Hz, 1H), 4.68 (dd, J=14.5, 2.0 Hz, 1H), 4.57 (dd, J=14.5, 2.0
Hz, 1H), 4.41 (d, J=5.6 Hz, 1H), 4.08 (brs, 1H), 3.94 (brs, 1H),
3.87 (m, 2H), 3.81 (d, J=5.6 Hz, 1H), 3.55 (ddd, J=11.5, 8.6, 4.2
Hz, 1H), 3.48 (s, 3H), 3.46 (m, 1H), 3.38 (q, J=2.2 Hz, 1H), 3.15
(t, J=9.1 Hz, 1H), 2.50 (m, 1H), 2.43 (brs, 1H), 2.26 (m, 4H), 2.03
(dd, J=12.2, 4.3 Hz, 1H), 1.78 (s, 3H), 1.78 (m, 1H), 1.49 (s, 3H),
1.46 (m, 5H), 1.26 (d, J=6.3 Hz, 3H), 1.13 (d, J=6.9 Hz, 3H), 0.92
(m, 9H), 0.91 (s, 9H), 0.87 (m, 1H), 0.12 (s, 6H)
[0409] .sup.13C NMR (67.8 MHz, CDCl.sub.3) .delta. (ppm): 174.0,
140.1, 137.5 (.times.2), 136.2,135.1, 127.8, 124.8, 119.4, 118.3,
117.2, 95.7, 96.1, 81.9, 80.2, 80.1, 78.3, 76.1, 74.8, 69.4, 68.4,
68.3, 68.1, 67.9, 57.0, 45.8, 40.4, 39.6, 36.5, 35.1, 34.3, 33.9,
30.5, 27.5, 25.8 (.times.3), 20.2, 20.0, 18.4. 17.7, 16.3, 15.1,
12.9, 12.0, -4.6, -4.9
Reference Example 3
[0410] Intermediate 3 (Ivermectin Monosaccharide)
[0411] In the manner similar to that of Reference Example 1,
Intermediate 3 (7.83 g, 93%) was obtained from ivermectin (10.0 g,
11.4 mmol).
[0412] HRFABMS: Calcd. for C.sub.41H.sub.62O.sub.11 [M+Na].sup.+
753.4190. Found 751.4186.
[0413] IR (KBr) .lambda..sub.max(cm.sup.-1): 3450, 2962, 2931,
1714, 1456, 1379, 1838, 1308, 1196, 1173, 1118, 1080, 1058, 989
[0414] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. (ppm): 5.87 (m,
1H), 5.72 (m, 2H), 5.43 (s, 1H), 5.39 (m, 1H), 4.98 (m, 1H), 4.82
(d, J=3.3 Hz, 1H), 4.71 (dd, J=14.2, 2.0 Hz, 1H), 4.64 (dd, J=14.2,
2.0 Hz, 1H), 4.29 (t, J=6.6 Hz, 1H), 4.09 (s, 1H), 3.97 (d, J=6.6
Hz, 1H), 3.96 (brs, 1H), 3.86 (dd, J=9.2, 6.3 Hz, 1H), 3.67 (m,
1H), 3.56 (ddd, J=11.6, 8.9, 4.3 Hz, 1H), 3.47 (s, 3H), 3.28 (q,
J=2.3 Hz, 1H), 3.22 (d, J=8.3 Hz, 1H), 3.16 (t, J=9.2 Hz, 1H), 2.54
(m, 1H), 2.36 (m, 3H), 1.98 (m, 1H), 1.87 (s, 3H), 1.77 (m, 1H),
1.68-1.40 (m, 8H), 1.50 (s, 3H), 1.35 (m, 1H), 1.27 (d, J=6.3 Hz,
3H), 1.15 (d, J=6.9 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H), 0.85 (d, J=6.6
Hz, 3H), 0.82 (m, 1H), 0.78 (d, J=5.2 Hz, 3H)
[0415] .sup.13C NMR (67.8 MHz, CDCl.sub.3) .delta. (ppm) 173.7,
139.6, 138.0, 137.9, 134.9, 124.7, 120.4, 118.3, 118.1, 97.5, 94.5,
81.6, 80.4, 79.1, 78.3, 76.6, 76.0, 68.6, 68.4, 68.1, 67.7, 67.2,
56.6, 45.7, 41.2, 39.7, 36.9, 35.7, 35.4, 34.1, 33.9, 31.2, 28.0,
27.4, 20.2, 19.9, 17.7, 17.4, 15.1, 12.4, 12.1
Reference Example 4
[0416] Intermediate 4
[0417] In the manner similar to that of Reference Example 2,
Intermediate 4 (5.09 g, 74%) was obtained from Intermediate 3 (6.00
g, 8.20 mmol) obtained in Reference Example 3.
[0418] HRFABMS: Calcd. for C.sub.47H.sub.76O.sub.11Si [M+Na].sup.+
867.5055. Found 867.5044.
[0419] IR (KBr) .lambda..sub.max(cm.sup.-1): 3477, 2960, 2931,
1712, 1462, 1379, 1338, 1250, 1196, 1173, 1120, 1082, 1051, 989
[0420] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. (ppm): 5.82 (m,
1H), 5.72 (m, 2H), 5.33 (brs, 1H), 5.32 (m, 1H), 4.98 (m, 1H), 4.82
(d, J=3.3 Hz, 1H), 4.68 (dd, J=14.5, 2.3 Hz, 11), 4.57 (dd, J=14.5,
2.3 Hz, 1H), 4.43 (d, J 5.6 Hz, 1H), 4.17 (s, 1H), 3.95 (brs, 1H),
3.87 (m, 1H), 3.82 (d, J=5.6 Hz, 1H), 3.64 (m, 1H1), 3.56 (ddd,
J=11.5, 9.2, 4.6 Hz, 1H), 3.48 (s, 3H), 3.39 (q, J=2.3 Hz, 1H),
3.21 (m, 1H), 3.16 (t, J 9.2 Hz, 1H), 2.51 (m, 1H), 2.27 (m, 3H),
1.99 (dd, J=12.1, 4.0 Hz, 1H), 1.79 (s, 3H), 1.75 (m, 1H),
1.67-1.31 (m, 9H), 1.51 (s, 3H), 1.27 (d, J=6.3 Hz, 3H), 1.14 (d,
J=6.9 Hz, 3H), 0.93 (s, 9H), 0.93 (t, J=7.5 Hz, 3H), 0.85 (d, J=6.6
Hz, 1H), 0.78 (d, J=5.3 Hz, 3H), 0.13 (s, 6H)
[0421] .sup.13C NMR (67.8 MHz, CDCl.sub.3) .delta. (ppm): 174.0,
140.1, 137.5, 137.4, 134.9,124.7, 119.4, 118.3, 117.3, 97.4, 94.9,
81.7, 80.2, 80.1, 78.3, 76.5, 76.0, 69.4, 68.7, 68.0, 67.9, 67.2,
56.5, 45.7, 41.2, 39.6, 36.8, 35.7, 35.4, 34.1, 33.9, 31.2, 28.0,
27.2, 25.8 (.times.3), 20.2, 20.0, 18.4, 17.7, 17.4, 15.1, 12.4,
12.1, -4.6, -4.9
Reference Example 5
[0422] Intermediate 5
[0423] Under nitrogen atmosphere, Intermediate 2 (5.00 g, 5.93
mmol) obtained in Reference Example 2 was dissolved in dimethyl
sulfoxide (30 mL). Triethylamine (8.2 mL, 59.3 mmol) was added to
the solution, then a solution of sulfur trioxide/pyridine c mplex
(7.6 g, 29.6 mmol) in dimethyl sulfoxide (20 mL) was slowly added
dropwise to the mixture, and the mixture was stirred at room
temperature for 2 hours. After purified water(100 mL) was added to
the reaction mixture, the reaction mixture was extracted with ethyl
acetat (60 mL.times.3). The organic layer was washed successively
with purified water (20 mL.times.3) and saturated brine (20 mL) and
dried over anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure to give a crude product. The resulting crude
product was purified by silica gel column chromatography with
eluting solvents of hexane/ethyl acetate=5/1 to give Intermediate 5
(4.46 g, 89%).
[0424] HRFABMS: Calcd. for C.sub.47H.sub.72O.sub.11Si [M+Na].sup.+
863.4742. Found 863.4736.
[0425] IR (KBr) .lambda..sub.max(cm.sup.-1): 3473, 2962, 2931,
1741, 1712, 1628, 1461, 1379, 1338, 1251, 1184, 1160, 1124, 1079,
1051, 999
[0426] .sup.1H NMR (270 MHz, CDCl.sub.3) .delta. (ppm): 5.83 (m,
1H), 5.80 (m, 2H), 5.75 (dd, J=9.6, 2.0 Hz, 1H), 5.54 (dd, J=9.9,
2.3 Hz, 1H), 5.36 (m, 1H), 5.32 (d, J=1.4 Hz, 1H), 5.06 (m, 1H),
4.96 (d, J=2.0 Hz, 1H), 4.69 (dd, J=14.5, 2.0 Hz, 1H), 4.58 (dd,
J=14.5, 2.0 Hz, 1H), 4.50 (q, J=6.6 Hz, 1H), 4.43 (brd, J=5.3 Hz,
1H), 4.25 (dd, J 12.0, 6.4 Hz, 1H), 4.12 (brs, 1H), 4.06 (brs, 1H),
3.87 (m, 1H), 3.82 (d, J=5.3 Hz, 1H), 3.55 (s, 3H), 3.48 (d, J=9.9
Hz, 1H), 3.39 (q, J=2.3 Hz, 1H), 2.54 (m, 1H), 2.49 (m, 1H), 2.28
(m, 3H), 2.13 (dt, J=12.0, 4.0 Hz, 1H), 2.02 (dd, J=11.6, 5.0 Hz,
1H), 1.78 (s, 3H), 1.77 (m, 1H), 1.64 (m, 2H), 1.53 (s, 3H), 1.47
(m, 2H), 1.27 (d, J=6.6 Hz, 3H), 1.16 (d, J=6.9 Hz, 3H), 0.93 (m,
10H), 0.92 (s, 9H), 0.12 (s, 6H)
[0427] .sup.13C NMR (67.8 MHz, CDCl.sub.3) .delta. (ppm):
206.7,174.0, 140.6, 137.6, 136.8, 136.2, 134.8, 127.7, 125.2,
119.2, 118.7, 117.2, 95.8, 94.5, 82.3, 80.2, 80.1, 78.1, 74.8,
70.7, 69.4, 68.4, 68.2, 67.9, 58.5, 45.7, 40.4, 39.6, 39.0, 36.6,
35.1, 34.3, 30.5, 27.5, 25.8 (.times.3), 20.3, 20.0, 18.4, 16.4,
15.2, 13.9, 13.0, 12.0, -4.6, -4.9
Reference Example 6
[0428] Intermediate 6
[0429] In the manner similar to that of Reference Example 5,
Intermediate 6 (4.11 g, 98%) was obtained from Intermediate 4 (4.21
g, 4.96 mmol) obtained in Reference Example 4.
[0430] HRFABMS: Calcd. for C.sub.47H.sub.74O.sub.11Si [M+Na].sup.+
865.4989. Found 865.4888.
[0431] IR (KBr) .lambda..sub.max(cm.sup.-1): 3473, 2960, 2931,
1740, 1713, 1461, 1379, 1336, 1250, 1182, 1120, 1078, 1053, 1012,
991
[0432] .sup.1H NMR (270 MHz, CDCl.sub.3, partial data) .delta.
(ppm): 5.84 (m, 1H), 5.75 (m, 2H), 5.32 (s, 1H), 5.30 (m, 1H), 5.05
(m, 1H), 4.96 (d, J=2.3 Hz, 1H), 4.68 (dd, J=14.5, 2.0 Hz, 1H),
4.57 (dd, J=14.5, 2.0 Hz, 1H), 4.50 (q, J 6.6 Hz, 1H), 4.43 (brd,
J=5.3 Hz, 1H), 4.25 (dd, J=12.0, 6.4 Hz, 1H), 4.21 (brs, 1H), 4.06
(brs, 1H), 3.82 (d, J=5.3 Hz, 1H), 3.68 (m, 1H), 3.56 (s, 3H), 3.38
(q, J=2.3 Hz, 1H), 3.21 (d, J=7.3Hz, 1H), 2.60 (m, 1H), 2.50 (m,
1H), 2.33 (m, 2H), 2.11 (m, 1H), 1.99 (dd, J=12.4, 4.5 Hz, 1H),
1.79 (s, 3H), 1.54 (s, 3H), 1.28 (d, J=6.6 Hz, 3H), 1.17 (d, J=6.9
Hz, 3H), 0.94 (t, J=7.3 Hz, 3H), 0.92 (s, 9H), 0.85 (d, J=6.9 Hz,
3H), 0.78 (d, J=4.6Hz, 3H), 0.13 (s, 6H)
[0433] .sup.13C NMR (67.8 MHz, CDCl.sub.3) .delta. (ppm): 205.7,
174.1, 140.7, 137.5, 136.8, 134.6, 125.2, 119.2, 118.7, 117.2,
97.5, 94.4, 82.3, 80.2, 80.0, 78.1, 76.7, 70.7, 69.5, 68.7, 67.9,
67.1, 58.5, 45.7, 41.2, 39.6, 39.1, 36.9, 35.7, 35.5, 34.1, 31.2,
28.1, 27.3, 25.9 (.times.3), 20.3, 20.0, 18.4, 17.5, 15.2, 13.9,
12.5, 12.1, -4.6, -4.9
Reference Example 7
[0434] Intermediate 7
[0435] Under nitrogen atmosphere, a 1.0 mol/L solution of lithium
hexamethyldisilazane in tetrahydrofuran (2.4 mL, 2.36 mmol) was
added to tetrahydrofuran (3 mL) at 0.degree. C. Then, allyl
diethylphosphonoacetate (0.50 mL, 2.36 mmol) was added to the
mixture, and the mixture was stirred for 30 minutes at 0.degree. C.
Then, a solution of Intermediate 5 (1.00 g, 1.18 mmol) obtained in
Reference Example 5 in tetrahydrofuran (9.0 mL) was slowly added
dropwise to the mixture, and the mixture was further stirred at
0.degree. C. for 1 hour. After purified water was added to the
reaction mixture (20 mL), the reaction mixture was extracted with
ethyl acetate (20 mL.times.3). The organic layer was washed
successively with a saturated aqueous ammonium chloride solution
(20 mL) and saturated brine (20 mL) and dried over anhydrous sodium
sulfate. The solvent was evaporated under reduced pressure to give
a crude product. The resulting crude product was purified by silica
gel column chromatography with eluting solvents of hexane/ethyl
acetate=10/1 to give Intermediate 7 (1.08 g, 100%).
[0436] HRFABMS: Calcd. for C.sub.52H.sub.78O.sub.12Si [M+Na].sup.+
945.5160. Found 945.5157.
[0437] IR (KBr) .lambda..sub.max(cm.sup.-1); 3500, 2962, 2931,
1724, 1655, 1459, 1377, 1336, 1250, 1186, 1159, 1124, 1084, 1035,
997
[0438] .sup.1H NMR (270 MHz, CDCl.sub.3, partial data) .delta.
(ppm): 5.94 (ddt, J=17.2, 10.2, 5.6 Hz, 1H), 5.87 (s, 1H), 5.76
(dd, J=9.9, 1.7 Hz, 1H), 5.74 (m, 3H), 5.54 (dd, J=9.9, 2.3 Hz,
1H), 5.34 (dd, J=17.2, 1.3 Hz, 1H), 5.33 (m, 1H), 5.31 (s, 1H),
5.26 (dd, J=10.2, 1.3 Hz, 1H), 5.16 (t, J=3.1 Hz, 1H), 5.03 (mn,
1H), 4.90 (t, J=6.3 Hz, 1H), 4.67 (dd, J=14.2, 2.3 Hz, 1H), 4.63
(d, J=5.6 Hz, 2H), 4.52 (m, 1H), 4.42 (d, J=5.6 Hz, 1H), 4.03 (brs,
1H), 3.84 (m, 1H), 3.80 (d, J=5.6 Hz, 1H), 3.48 (d, J=9.6 Hz, 1H),
3.36 (s, 3H), 1.78 (s, 3H), 1.48 (s, 3H), 1.39 (d, J=6.6 Hz, 3H),
1.10 (d, J=6.9 Hz, 3H), 0.92 (s, 9H), 0.12 (s, 6H)
[0439] .sup.1C NMR (67.8 MHz, CDCl.sub.3) .delta. (ppm): 1713.9,
165.4, 157.4, 140.1, 137.8, 137.4, 136.2, 135.3, 132.0, 127.8,
124.6, 119.4, 118.5, 117.9, 117.3, 116.5, 95.7, 93.5, 81.3, 80.1
(.times.2), 74.7, 70.0, 69.5, 68.4, 68.3, 67.9, 67.1, 65.0, 56.5,
45.7, 40.5, 39.6, 36.4, 35.1, 34.3, 32.8, 30.5, 27.5, 25.8
(.times.3), 20.0, 19.5, 19.3, 18.4, 16.4, 14.9, 13.0, 12.0, -4.6,
-4.9
Reference Example 8
[0440] Intermediate 8
[0441] Under nitrogen atmosphere, a 1.0 mol/L solution of lithium
hexamethyldisilazane (9.5 mL, 9.50 mmol) in tetrahydrofuran was
added to tetrahydrofuran (12 mL) at 0.degree. C. Then,
triethylphosphonoacetic acid (1.8 mL, 9.50 mmol) was added to the
mixture, and the mixture was stirred for 30 minutes at 0.degree. C.
Then, a solution of Intermediate 5 (4.00 g, 4.75 mmol) obtained in
Reference Example 5 in tetrahydrofuran (30 mL) was slowly added
dropwise to the mixture, and the mixture was further stirred at
0.degree. C. for 1 hour. After purified water (50 mL) was added to
the reaction mixture, the reaction mixture was extracted with ethyl
acetate (50 mL.times.3). The organic layer was washed successively
with a saturated aqueous ammonium chloride solution (50 mL) and
saturated brine (50 mL) and dried over anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure to give a crude
product. The resulting crude product was purified by silica gel
column chromatography with eluting solvents of hexane/ethyl
acetate=15/1 to give Intermediate 8 (3.82 g, 86%).
[0442] HRFABMS: Calcd. for C.sub.51H.sub.78O.sub.12Si [M+Na].sup.+
933.6160. Found 933.5152.
[0443] IR (KBr) .lambda..sub.max(cm.sup.-1): 3482, 2962, 2931,
1720, 1655, 1462, 1379, 1340, 1250, 1186, 1159, 1126, 1083, 1033,
997
Reference Example 9
[0444] Intermediate 9
[0445] Under nitrogen atmosphere, Intermediate 8 (2.80 g, 3.07
mmol) obtained in Reference Example 8 was dissolved in methylene
chloride (30 mL). To this solution, a 0.95 mol/L solution of
diisobutylaluminum hydride in n-hexane (15 mL, 15.3 mmol) was added
dropwise at -78.degree. C., and the mixture was stirred at
-78.degree. C. for 1 hour. The reaction mixture was diluted with
methylene chloride (100 mL), and then methanol was added to the
reaction mixture to terminate the reaction. Furthermore, sodium
sulfate decahydrate (20 g) and Cerite.RTM. (20 g) were added to the
reaction mixture, and the reaction mixture was stirred vigorously.
After 1 hour, the reaction mixture was filtered, and the solvent
was evaporated under reduced pressure to give a crude product. The
resulting crude product was purified by silica gel column
chromatography with eluting solvents of hexane/ethyl acetate=3/1 to
give Intermediate 9 (1.83 g, 69%).
[0446] HRFABMS: Calcd. for C.sub.49H.sub.76O.sub.11Si [M+Na].sup.+
891.5055. Found 891.5087.
[0447] IR (KBr) .lambda..sub.max(cm.sup.-1): 3448, 2966, 2933,
1720, 1655, 1460, 1379, 1340, 1244, 1186, 1159, 1116, 1082, 1034,
989
Reference Example 10
[0448] Intermediate 10
[0449] Sodium borohydride (36.0 mg, 967 .mu.mol) was added to a
solution of Intermediate 7 (596 mg, 645 .mu.mol) obtained in
Reference Example 7 in ethanol (6.5 mL) containing
tetrakistriphenylphosphine palladium (1 mg, 6.45 .mu.mol), and the
mixture was stirred for 2 hours. After a saturated aqueous ammonium
chloride solution (5 mL) was added to the reaction mixture, the
reaction mixture was extracted with ethyl acetate (10 mL.times.3).
The organic layer was washed with saturated brine (10 mL) and dried
over anhydrous sodium sulfate. The solvent was evaporated under
reduced pressure to give a crude product. The resulting crude
product was purified by silica gel column chromatography with
eluting solvents of hexane/ethyl acetate=5/1 to give Intermediate
10 (567 mg, 100%).
[0450] HRFABMS: Calcd. for C.sub.49H.sub.74O.sub.12Si [M+Na].sup.+
905.4817. Found 906.4892.
[0451] IR (KBr) .lambda..sub.max(cm.sup.-1): 3448, 2962, 2931,
1716, 1460, 1379, 1342, 1251, 1186, 1161, 1124, 1084, 1038, 999
Referenc Example 11
[0452] Intermediate 11
[0453] In the manner similar to that of Reference Example 7,
Intermediate 11 (1.27 g, 97%) was obtained from Intermediate 6
(1.20 g, 1.42 mmol) obtained in Reference Example 6.
[0454] HRFABMS: Calcd. for C.sub.42H.sub.80O.sub.12Si
[M+Ma].sup.+947.5317. Found 947.5336.
[0455] IR (KBr) .lambda..sub.max(cm.sup.-1): 3473, 2960, 2931,
1724, 1649, 1460, 1379, 1338, 1248, 1197, 1163, 1120, 1088, 1037,
1012, 991
Reference Example 12
[0456] Intermediate 12
[0457] In the manner similar to that of Reference Example 8,
Intermediate 12 (1.60 g, 70%) was obtained from Intermediate 6
(2.10 g, 2.49 mmol) obtained in Reference Example 6.
[0458] HRFABMS: Calcd. for C.sub.51H.sub.80O.sub.12Si [M+Na].sup.+
936.6317. Found 935.5298.
[0459] IR (KBr) .lambda..sub.max(cm.sup.-1): 3448, 2960, 2931,
1720, 1462, 1379, 1338, 1248, 1198, 1163, 1120, 1090, 1036, 991
Reference Example 13
[0460] Intermediate 13
[0461] Under nitrogen atmosphere, a 1.0 mol/L solution of lithium
hexamethyldisilazane in tetrahydrofuran (523 .mu.L, 523 .mu.mol)
was added to tetrahydrofuran (1 mL) at 0.degree. C. Then,
diethylphosphonocyanomethyl (84 .mu.L, 523 .mu.mol) was added to
the mixture, and the mixture was stirred for 30 minutes at
0.degree. C. A solution of Intermediate 6 (210 mg, 249 .mu.mol)
obtained in Reference Example 6 in tetrahydrofuran (1.4 mL) was
slowly added dropwise to the reaction mixture, and the reaction
mixture was further stirred at 0.degree. C. for 1 hour. After
purified water (5 mL) was added to the reaction mixture, the
reaction mixture was extracted with ethyl acetate (5 mL.times.3).
The organic layer was washed successively with a saturated aqueous
ammonium chloride solution (10 mL) and saturated brine (10 mL) and
dried over anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure to give a crude product. The resulting crude
product was purified by silica gel column chromatography with
eluting solvents of hexane/ethyl acetate=15/1 to give Interm diate
13 (206 mg,. 96%).
Reference Example 14
[0462] Intermediate 14
[0463] Intermediate 9 (100 mg, 112 .mu.mol) obtained in Reference
Example 9 was dissolved in methylene chloride (1.1 mL).
Diisopropylethylamine (77 .mu.L, 448 .mu.mol),
4-dimethylaminopyridine (20 mg, 168 .mu.mol) and p-toluenesulfonyl
chloride (85 mg, 448 .mu.mol) were successively added to the
solution, and the mixture was stirred at room temperature for 16
hours. After a saturated aqueous ammonium chloride solution (2 mL)
was added to the reaction mixture, the reaction mixture was
extracted with m ethylene chloride (5 mL.times.3). The organic
layer was washed with saturated brine (5 mL) and dried over
anhydrous sodium sulfate. The solvent was evaporated under reduced
pressure to give a crude product. The resulting crude product was
purified by silica gel column chromatography with eluting solvents
of hexane/ethyl acetate=5/1 to give Intermediate 14 (97.8 mg,
96%).
[0464] HRFABMS: Calcd. for C.sub.49H.sub.76ClO.sub.10 [M+Na].sup.+
909.4716. Found 909.4748.
[0465] IR (KBr) .lambda..sub.max(cm.sup.-1): 3480, 2962, 2931,
1733, 1462, 1379, 1338, 1255, 1186, 1161, 1122, 1084, 1038, 997
Reference Example 15
[0466] Intermediate 15
[0467] In the manner similar to that of Reference Example 9,
Intermediate 15 (862 mg, 65%) was obtained from Intermediate 12
(1.40 g, 1.35 mmol) obtained in Reference Example 12.
[0468] HRFABMS: Calcd for C.sub.49H.sub.78O.sub.11Si [M+Na].sup.+
893.5211. Found 893.5220.
[0469] IR (KBr) .lambda..sub.max(cm.sup.-1): 3477, 2960, 2931,
1735, 1712, 1678, 1458, 1379, 1338, 1252, 1196, 1174, 1119, 1086,
1038, 993
Reference Example 16
[0470] Intermediate 16
[0471] In the manner similar to that of Reference Example 10,
Intermediate 16 (760 mg, 86%) was obtained from Intermediate 11
(924 mg, 999 s mol) obtained in Reference Example 11.
[0472] HRFABMS: Calcd. for C.sub.49H.sub.76O.sub.12Si [M+Na].sup.+
907.5004. Found 907.5019.
[0473] IR (KBr) .lambda..sub.max(cm.sup.-1): 3464, 2960, 2931,
1714, 1460, 1377, 1340, 1250, 1184, 1172, 1120, 1088, 1036, 993
Reference Example 17
[0474] Intermediate 17
[0475] Under nitrogen atmosphere, Intermediate 2 (820 mg, 972
.mu.mol) obtained in Reference Example 2 was dissolved in
N,N-dimethylformamide (9 mL). Imidazole (463 mg, 6.80 mmol) and
trimethylsilyl chloride (0.42 mL, 3.40 mmol) were successively
added to the solution, and the mixture was stirred at room
temperature for 20 hours. After purified water (50 mL) was added to
the reaction mixture, the reaction mixture was extracted with ethyl
acetate (50 mL.times.8). The organic layer was washed successively
with purified water (100 mL.times.3) and saturated brine (50 mL)
and dried over anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure to give a crude product. The crude product
was purified by silica gel column chromatography with eluting
solvents of hexane/ethyl acetate=5/1 to give Intermediate 17 (1-01
g, 100%).
[0476] HRFABMS: Calcd. for C.sub.58H.sub.90O.sub.11Si.sub.3
[M+Na].sup.+ 1009.5689. Found 1009.5690.
[0477] IR (KBr) .lambda..sub.max(cm.sup.-1): 2960, 2933, 1745,
1462, 1385, 1836, 1311, 1252, 1205, 1161, 1128, 1105, 1086, 991
Reference Example 18
[0478] Intermediate 18
[0479] Intermediate 17 (940 mg, 951 .mu.mol) obtained in Reference
Example 17 was dissolved in tetrahydrofuran (25 mL). A mixture of
acetic acid (5 mL) and purified water (5 mL) was added to the
solution, and the mixture was stirred at room temperature for 10
hours. The reaction mixture was poured into a saturated aqueous
sodium hydrogencarbonate solution (100 mL), and then the mixture
was extracted with ethyl acetate (50 mL.times.3). The organic layer
was washed with saturated brine (50 mL) and dried over anhydrous
sodium sulfate. The solvent was evaporated under reduced pressure
to give a crude product. The crude product was purified by silica
gel column chromatography with eluting solvents of hexane/ethyl
acetate=511 to give Intermediate 18 (831 mg, 96%).
[0480] HRFABMS: Calcd. for C.sub.50H.sub.82O.sub.11Si.sub.2
[M+Na].sup.+ 937.5293. Found 937.5276.
[0481] IR (KBr) .lambda..sub.max(cm.sup.-1): 3450, 2960, 2933,
1743, 1458, 1381, 1336, 1251, 1160, 1130, 1086, 995
Reference Example 19
[0482] Intermediate 19
[0483] In the manner similar to that of Reference Exampl 14, Interm
diate 19 (407 mg, 99%) was obtained from Intermediate 15 (400 mg,
459 .mu.mol) obtained in Reference Example 15.
[0484] HRFABMS: Calcd. for C.sub.49H.sub.71ClO.sub.10Si
[M+Na].sup.+ 888.4975. Found 888.6025.
[0485] IR (KBr) .lambda..sub.max(cm.sup.-1): 3483, 2960, 2931,
1712, 1460, 1377, 1338, 1250, 1172, 1120, 1087, 1038, 995
Reference Example 20
[0486] Intermediate 20
[0487] Under nitrogen atmosphere, Intermediate 18 (50.0 mg, 64.6 4
mol) obtained in Reference Example 18 was dissolved in methylene
chloride (1 mL), and rhodium acetate direr (1 mg, 2.73 .mu.mol) was
added to the solution. To this solution, a solution of ethyl
diazoacetate (12 .mu.L, 109 .mu.mol) in methylene chloride (1 mL)
was added dropwise at room temperature. After the mixture was
stirred at room temperature for 2 hours, the solvent was evaporated
under reduced pressure to give a crude product. The resulting crude
product was purified by silica gel column chromatography with
eluting solvents of hexane/ethyl acetate=6/1 to give Intermediate
20 (20.4 mg. 87%).
[0488] HRFABMS: Calcd. for C.sub.54H.sub.68O.sub.13Si.sub.2
[M+Na].sup.+ 1023.5661. Found 1023.5696.
[0489] IR (KBr) .lambda..sub.max(cm.sup.-1): 3450, 2960, 2933,
1743, 1458, 1381, 1336, 1252, 1159, 1130, 1086.997
Reference Example 21
[0490] Intermediate 21
[0491] Under nitrogen atmosphere, a 1.0 mol/L solution of super
hydride in tetrahydrofuran (1.5 mL, 1.50 mmol) was added dropwise
to a solution of Intermediate 20 (300 mg, 300 .mu.mol) obtained in
Reference Example 20 in tetrahydrofuran (21 mL) at -78.degree. C.,
and the mixture was stirred for 30 minutes. After a 30% aqueous
hydrogen peroxide solution (200 ;i L) was added to the mixture, the
mixture was stirred at -78.degree. C. for 30 minutes. Sodium
sulfite (100 mg) was added to the reaction mixture, and the
reaction mixture was extracted with ethyl acetate (10 mL.times.3).
The organic layer was washed with saturated brine (10 mL) and dried
over anhydrous sodium sulfate. The solvent was evaporated under
reduced pressure to give a crude product. The crude product was
purified by silica gel column chromatography (15 g) with eluting
solvents of hexane/ethyl acetate=3/1 to give Intermediate 21 (90.7
mg, 32%).
[0492] HRFABMS: Calcd. for C.sub.52H.sub.86O.sub.12Si.sub.2
[M+Na].sup.+ 981.5556. Found 981.5597.
[0493] IR (KBr) .lambda..sub.max(cm.sup.-1): 3475, 2960, 2933,
1743, 1462, 1385, 1336, 1309, 1262, 1205, 1161, 1128, 1085, 989
Reference Example 22
[0494] Intermediate 22
[0495] Under nitrogen atmosphere, Intermediate 21 (84.5 mg, 82.7
.mu.mol) obtained in Reference Example 21 was dissolved in
methylene chloride (1.7 mL). Triphenylphosphine (54.2 mg, 0.207
mmol) and imidazole (68.5 mg, 0.207 mmol) were added to the
solution, and the mixture was stirred at room temperature for 3
hours. A saturated ammonium chloride solution (3 mL) was added to
the reaction mixture, and the reaction mixture was extracted with
methylene chloride (10 mL.times.3). The organic layer was washed
with saturated brine (10 mL) and dried over anhydrous sodium
sulfate. The solvent was evaporated under reduced pressure to give
a crude product. The resulting crude product was purified by silica
gel column chromatography (15 g) with eluting solvents of
hexane/ethyl acetate=5/1 to give Intermediate 22 (50.2 mg,
59%).
[0496] HRFABMS: Calcd. for C.sub.52H.sub.85BrO.sub.11Si.sub.2
[M+Na].sup.+ 1043.47,12. Found 1043.4658.
[0497] IR (KBr) .lambda..sub.max(cm.sup.-1): 3465, 2960, 2933,
1743, 1462, 1381, 1336, 1309, 1252, 1205, 1161, 1128, 1095, 993
Reference Example 23
[0498] Intermediate 23
[0499] Under nitrogen atmosphere, Intermediate 4 (2.12 g, 2.51
mmol) obtained in Reference Example 4 was dissolved in
N,N-dimethylformamide (25 mL). Imidazole (1.19 g, 17.5 mmol) and
trimethylsilyl chloride (1.1 mL, 8.78 mmol) were successively added
to the solution, and the mixture was stirred at room temperature
for 20 hours.
[0500] After purified water (200 mL) was added to the reaction
mixture, the reaction mixture was extracted with ethyl acetate (100
mL.times.3). The organic layer was washed successively with
purified water (200 mL.times.3) and saturated brine (100 mL) and
dried over anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure to give a crude product. Then, from the
resulting crude product, Intermediate 23 (1.89 g, 82%, for th two
steps) was obtained in the manner similar to that of Reference
Example 18.
[0501] HRFABMS: Calcd. for C.sub.50H.sub.84O.sub.11Si.sub.2
[M+Na].sup.+ 939.5460. Found 939.5452.
[0502] IR (KBr) .lambda..sub.max(cm.sup.-1): 3489, 2960, 2933,
1743, 1462, 1389, 1336, 1309, 1252, 1203, 1168, 1120, 1084, 1051,
1009, 989
Reference Example 24
[0503] Intermediate 24
[0504] In the manner similar to that of Reference Example 20,
Intermediate 24 (443 mg, 21%) was obtained from Intermediate 23
(1.89 g, 2.07 mmol) obtained in Reference Example 23.
[0505] HRFABMS: Calcd. for C.sub.54H.sub.90O.sub.13Si.sub.2
[M+Na].sup.+ 1025.5818. Found 1025.5837.
[0506] IR (KBr) .lambda..sub.max(cm.sup.-1): 3455, 2960, 2931,
1759, 1741, 1462, 1379, 1336, 1308, 1252, 1203, 1169, 1132, 1088,
1035, 991
Reference Example 25
[0507] Intermediate 26
[0508] In the manner similar to that of Reference Example 21,
Intermediate 25 (271 mg, 87%) was obtained from Intermediate 24
(326 mg, 324 .mu.mol) obtained in Reference Example 24.
[0509] HRFABMS: Calcd. for C.sub.52H.sub.88O.sub.12Si.sub.2
[M+Na].sup.+ 983.5712. Found 983.6719.
[0510] IR (KBr) .lambda..sub.max(cm.sup.-1): 3456, 2958, 2931,
1743, 1458, 1380, 1336, 1309, 1251, 1205, 1169, 1128, 1088, 1010,
989
Reference Example 26
[0511] Intermediate 26
[0512] In the manner similar to that of Reference Example 22,
Intermediate 26 (94.3 mg, 74%) was obtained from Intermediate 25
(76.8 mg, 79.8 .mu.mol) obtained in Reference Example 25.
[0513] HRFABMS; Calcd. for C.sub.52H.sub.87BrO.sub.11Si.sub.2
[M+Na].sup.+ 1045.4868. Found 1045.4890
[0514] IR (KBr) .lambda..sub.max(cm.sup.-1): 3488, 2960, 2981,
1743, 1462, 1379, 1336, 1309, 1252, 1205, 1169, 1128, 1088, 1009,
989
[0515] The intermediates obtained in the above reference xamples
and the starting materials are shown in Table 6.
6TABLE 6 30 Intermediate No. Z.sup.A 4' R.sup.2A R.sup.7A
Avermectin B1a 31 Single bond OH OH 1 OH Single bond OH OH 2 OH
Single bond OTBDMS OH 5 O Double bond OTBDMS OH 7
CHCO.sub.2CH.sub.2CH.dbd.CH.sub.2 Double bond OTBDMS OH 8
CHCO.sub.2CH.sub.2CH.sub.3 Double bond OTBDMS OH 9 CHCH.sub.2OH
Double bond OTBDMS OH 10 CHCO.sub.2H Double bond OTBDMS OH 14
CHCH.sub.2Cl Double bond OTBDMS OH 17 OSi(CH.sub.3).sub.3 Single
bond OTBDMS OSi(CH.sub.3).sub.3 18 OH Single bond OTBDMS
OSi(CH.sub.3).sub.3 20 OCH.sub.2CO.sub.2CH.sub.2CH.sub.3 Single
bond OTBDMS OSi(CH.sub.3).sub.3 21 OCH.sub.2CH.sub.2OH Single bond
OTBDMS OSi(CH.sub.3).sub.3 22 OCH.sub.2CH.sub.2Br Single bond
OTBDMS OSi(CH.sub.3).sub.3 32 Ivermectin 33 Single bond OH OH 3 OH
Single bond OH OH 4 OH Single bond OTBDMS OH 6 O Double bond OTBDMS
OH 11 CHCO.sub.2CH.sub.2CH.dbd.CH.sub.2 Double bond OTBDMS OH 12
CHCO.sub.2CH.sub.2CH.sub.3 Double bond OTBDMS OH 13 CHCN Double
bond OTBDMS OH 15 CHCH.sub.2OH Double bond OTBDMS OH 16 CHCO.sub.2H
Double bond OTBDMS OH 19 CHCH.sub.2Cl Single bond OTBDMS OH 23 OH
Single bond OTBDMS OSi(CH.sub.3).sub.3 24
OCH.sub.2CO.sub.2CH.sub.2CH.sub.3 Single bond OTBDMS
OSi(CH.sub.3).sub.3 25 OCH.sub.2CH.sub.2OH Single bond OTBDMS
OSi(CH.sub.3).sub.3 26 OCH.sub.2CH.sub.2Br Single bond OTBDMS
OSi(CH.sub.3).sub.3 *OTBDMS: O-tert-Butyldimethylsilyl
Test Example 1
[0516] Methods for determining antiparasitic effects of the
compounds disclosed according to the present invention are
explained below.
[0517] As model insects for simple determination of antiparasitic
and insecticidal activities, those insects are desired which can be
easily obtained and bred in laboratories, and have no pathogenicity
to a human. Caenorhabditis elegans, an unparasitic eelworm widely
used in experiments of genetics, was used as a typical steam worm,
and artemia salina used as feed for tropical fish and named Brine
shrimp, was used instead of insects.
[0518] <Preparation of Caenorhabditis elegans Used for
Evaluation>
[0519] Escherichia. coli for the feed of caenorhabditis elegans
(mutant having uracil requirement) was inoculated in a seed medium
for E. coli to which a small amount of uracil was added, and
cultured with shaking at 27.degree. C. for 1 day. A petri dish of 6
cm diameter was filled with 10 mL of an agar medium for eelworm
proliferation, and the medium was solidified. Then 0.5 mL of the
culture of E. coli was spread over the medium in the dish, and the
dish was incubated at 37.degree. C. to proliferate E. coli A piece
of the agar was collected with a platinum loop from a petri dish in
which caenorhabditis elegans successfully proliferated, and
inoculated in petri dishes in which E. coli was proliferated. The
petri dishes were incubated at 20.degree. C. to proliferate
caenorhabditis elegans. Since the life of eelworm is about 2 weeks,
subculture was carried out every once a week. The eelworms grown
with spread on the surface of the petri dish after 3 to 5 days from
subculture were used for the experiments.
[0520] <Preparation of Artemia salina Used for
Evaluation>
[0521] To a buffer for artemia salina (obtained by dissolving 0.24%
of Tris, 2.57% of sodium chloride, 0.47% of magnesium chloride,
0.07% of potassium chloride, 0.02% of sodium carbonate, 0.64% of
magnesium sulfate and 0.11% of calcium chloride in distilled water
and adjusting the pH to 7.1 with hydrochloric acid), dried eggs of
artemia salina [Tetra Brine Shrimp Eggs, Warner Lambert Co.] were
added. The noprius larvae 1 or 2 days after hatching were used for
the experiments.
[0522] <Preparation of Agar Medium for Eelworm
Proliferation>
[0523] Solution A was obtained by dissolving 0.3% of sodium
chloride, 1.7% of bact-agar (DIFCO Co.), 0.5% of bact-p ptone
(DIFCO Co.) and 1.0% of yeast extract (DIFCO Co.) in distilled
water.
[0524] Solution B was obtained by dissolving 0.5% of cholesterol in
ethanol.
[0525] Solution C was obtained by dissolving 13.9% of calcium
chloride in distilled water.
[0526] Solution D was obtained by dissolving 30.8% of magnesium
sulfate heptahydrate in distilled water.
[0527] Solution E was obtained by dissolving 13.54% of
KH.sub.2PO.sub.4 and 4.45% of K.sub.2HPO.sub.4 in distilled
water.
[0528] The aforementioned Solutions A, C and D were sterilized in
an autoclave at 121.degree. C. for 20 minutes, and each solution
was stored at 4.degree. C.
[0529] The agar medium for eelworm proliferation was prepared by
mixing the solutions in the following proportion: Solution A: 100
mL, Solution B: 0.1 mL, Solution C: 0.05 mL, Solution D: 0.1 mL and
Solution E: 2.5 mL (without pH adjustment), and dispensing each 10
mL portion into petri dishes of 60.times.15 mm.
[0530] <Preparation of E. coli Seed Medium>
[0531] In distilled water, 2.0% of bact-trypton (DIFCO Co.), 0.55%
of sodium chloride and 0.001% of uracil (SIGMA Co., pH 7.4) were
dissolved, and the solution was sterilized in an autoclave at
121.degree. C. for 20 minutes.
[0532] <Experimental Procedure>
[0533] Each well of a 96 well microplate was filled with the
solution of the test compound (methanol as a solvent), and the
solvent was removed using a vacuum pump, then 250 .mu.l of the
assay medium was added to each wells (the assay medium was prepared
by dissolving 7.5 mM sodium hydrogencarbonate, 7.5 mM potassium
chloride, 7.5 mM calcium chloride dihydrate and 7.5 mM magnesium
sulfate heptahydrate in distilled water and adding 0.01% of
lecithin to the solution), and then the microplate was shaken using
a microplate mixer for 16 minutes. To each well, a few individuals
of caenorhabditis elegans were added by softly rubbing the surface
of the agar using a toothpick, or a few individuals of artemia
salina were added together with 60 u I of the buffer. The
microplate was incubated at 20.degree. C., and then the insects
were observed after 24 and 48 hours under a microscope
(magnification of 40.times.). The results were compared to those
obtained without addition of the test compound, and evaluated by 4
grades.
[0534] The evaluation results were shown by indications of 4 grades
from 0 to 3.
[0535] 3: No movement
[0536] 2: Between 1 and 3
[0537] 1: A little week movements
[0538] 0: Active movements
[0539] Of the 4 grades, Indications 3 and 2 were judged as
effective, and Indications 1 and 0 as ineffective. The results are
shown in Table 7. In Table 7, the values for each compound are
minimum inhibitory concentrations (MIC) which were required to give
Indication 2 (or 3) for caenorhabditis elegans or artemia salina In
Table 7, caenorhabditis elegans and.sub.--artemia salina are
abbreviated as C. E. and A. S., respectively.
7TABLE 7 Compound No. C.E. (ng/mL) A.S. (ng/mL) Avermectin B1a 2
0.5 Ivermectin 2 2 Avermectin B1a 2 2 monosaccharide Ivermectin 2 2
monosaccharide 6 2 2 22 2 2 28 2 2 34 2 0.5 35 1 2 36 2 2 38 2 0.5
41 2 0.5
Industrial Applicability
[0540] according to the present invention, avermectin derivatives
having antiparasitic activity and salts thereof are provided. The
aforementioned derivatives and salts thereof are useful as active
ingredients of antiparasitic agents.
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