U.S. patent application number 09/901264 was filed with the patent office on 2002-04-18 for nonacyclic nodulisporic acid derivatives.
Invention is credited to Colletti, Steven L., Fisher, Michael H., Meinke, Peter T., Wyvratt, Matthew J..
Application Number | 20020045598 09/901264 |
Document ID | / |
Family ID | 26912648 |
Filed Date | 2002-04-18 |
United States Patent
Application |
20020045598 |
Kind Code |
A1 |
Colletti, Steven L. ; et
al. |
April 18, 2002 |
Nonacyclic nodulisporic acid derivatives
Abstract
The present invention relates to novel nodulosporic acid
derivatives, which are acaricidal, antiparasitic, insecticidal and
anthelmintic agents.
Inventors: |
Colletti, Steven L.;
(Princeton Junction, NJ) ; Fisher, Michael H.;
(Ringoes, NJ) ; Meinke, Peter T.; (Plainfield,
NJ) ; Wyvratt, Matthew J.; (Mountainside,
NJ) |
Correspondence
Address: |
MERCK AND CO INC
P O BOX 2000
RAHWAY
NJ
070650907
|
Family ID: |
26912648 |
Appl. No.: |
09/901264 |
Filed: |
July 9, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60218183 |
Jul 14, 2000 |
|
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Current U.S.
Class: |
514/79 ; 514/365;
514/397; 514/410; 548/181; 548/311.7; 548/413; 548/417 |
Current CPC
Class: |
C07D 491/16 20130101;
A61P 33/10 20180101; A01N 43/90 20130101; C07D 491/22 20130101 |
Class at
Publication: |
514/79 ; 514/410;
548/413; 548/417; 548/311.7; 548/181; 514/397; 514/365 |
International
Class: |
A61K 031/675; A61K
031/4178; A61K 031/427; A61K 031/407; C07D 491/16 |
Claims
What is claimed is:
1. A compound having the formula I: 49wherein R.sub.1 is (1)
hydrogen, (2) C(O)H, (3) optionally substituted
(C.dbd.O).sub.p--R.sub.x, wherein the substituent is one to ten
groups independently selected from R.sup.z, OR.sup.a, OC(O)R.sup.b,
CO.sub.2R.sup.b, NR.sup.cCOR.sup.d, CONR.sup.cR.sup.d, and
NR.sup.cR.sup.d, (4) C.sub.1-C.sub.10alkoxy, (5)
C.sub.1-C.sub.10alkylthio, (6) CO.sub.2R.sup.b, (7)
CONR.sup.cR.sup.d, (8) CONR.sup.cSO.sub.2R.sup.d, (9) CN, R.sub.2
is (1) hydrogen, (2) OR.sup.a, (3) SR.sup.a; or R.sub.1+R.sub.2
represent .dbd.O; or R.sub.1 and R.sub.2 together with the carbon
atom to which they are attached form a 5- to 7-membered ring
containing 0 to 2 heteroatoms selected from O, S(O).sub.m and N,
optionally substituted with 1 to 4 groups independently selected
from R.sup.a; R.sub.3 is (1) hydrogen, (2) OR.sup.a, (3)
NR.sup.cR.sup.d, (4) NR.sup.cCOR.sup.d, (5)
NR.sup.cSO.sub.2R.sup.d, (6) NR.sup.eCONR.sup.cR.sup.d, (7)
NR.sup.cCO.sub.2R.sup.d; or R.sub.2+R.sub.3 represent a bridging
oxygen atom; R.sub.4 is hydrogen, or R.sub.2 and R.sub.4 together
represents a bond between the carbon atoms to which they are
attached; R.sup.a is (1) H, (2) optionally substituted R.sup.y, (3)
optionally substituted C(O)R.sup.x, (4) PO(OR.sup.b).sub.2, (5)
SO.sub.2R.sup.b, (6) a natural or unnatural mono-, di- or
tri-saccharide composed of any furanose or pyranose, or combination
thereof; wherein said substituent for R.sup.x and R.sup.y are 1 to
10 groups independently selected from R.sup.z, hydroxy,
C.sub.1-C.sub.6alkoxy, OC(O)R.sup.b, CO.sub.2R.sup.b,
NR.sup.cCOR.sup.d, CONR.sup.cR.sup.d, and NR.sup.cR.sup.d, R.sup.b
is (1) hydrogen (2) optionally substituted R.sup.y, wherein said
substituents are 1 to 10 groups independently selected from
R.sup.z, hydroxy, C.sub.1-C.sub.6 alkoxy,
OC(O)C.sub.1-C.sub.6alkyl, carboxy, CO.sub.2C.sub.1-C.sub.6alkyl,
NR.sup.cCOR.sup.d, CONR.sup.cR.sup.d, and NR.sup.cR.sup.d, (3) a
natural or unnatural mono-, di- or tri-saccharide composed of any
furanose or pyranose, or combination thereof; R.sup.c is (1)
hydrogen, (2) optionally substituted R.sup.y, wherein said
substituents are 1 to 10 groups independently selected from
R.sup.z, hydroxy, C.sub.1-C.sub.6alkoxy, OC(O)C.sub.1-C.sub.6alkyl,
carboxy, CO.sub.2C.sub.1-C.sub.6alkyl, NHCOC.sub.1-C.sub.6alkyl,
CONH(C.sub.1-C.sub.6alkyl), NH.sub.2, NH(C.sub.1-C.sub.6alkyl),
N(C.sub.1-C.sub.6alkyl).sub.2, R.sup.d is independently selected
from R.sup.c; or R.sup.c and R.sup.d together with the N to which
they are attached form a 3- to 10-membered ring containing 0 to 2
additional heteroatoms selected from O, S(O).sub.m and N,
optionally substituted with 1 to 4 groups independently selected
from R.sup.e; R.sup.e is halogen, cyano, oxo or optionally
substituted R.sup.x wherein said substituents are 1 to 10 groups
independently selected from R.sup.z, hydroxy,
C.sub.1-C.sub.6alkoxy, OC(O)C.sub.1-C.sub.6alkyl, carboxy,
CO.sub.2C.sub.1-C.sub.6alkyl, NHCOC.sub.1-C.sub.6alkyl,
CONH(C.sub.1-C.sub.6alkyl), NH.sub.2, NH(C.sub.1-C.sub.6alkyl),
N(C.sub.1-C.sub.6alkyl).sub.2, R.sup.x is (1) C.sub.1-C.sub.10
alkyl, (2) C.sub.2-C.sub.10 alkenyl, (3) C.sub.2-C.sub.10 alkynyl,
(4) C.sub.3-C.sub.8 cycloalkyl, (5) C.sub.5-C.sub.8 cycloalkenyl,
(6) aryl, (7) a 5- or 6-membered heterocycle containing from 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen; R.sup.y is
(1) C.sub.1-C.sub.10 alkyl, (2) C.sub.3-C.sub.10 alkenyl, (3)
C.sub.3-C.sub.10 alkynyl, (4) C.sub.3-C.sub.8 cycloalkyl, (5)
C.sub.5-C.sub.8 cycloalkenyl, (6) aryl, (7) a 5- or 6-membered
heterocycle containing from 1 to 4 heteroatoms selected from
oxygen, sulfur and nitrogen; R.sup.z is (1) C.sub.1-C.sub.5 alkyl,
(2) C.sub.2-C.sub.5 alkenyl, (3) C.sub.3-C.sub.8 cycloalkyl, (4)
aryl, optionally substituted by 1 to 4 groups selected from
C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.5 alkenyl, C.sub.1-C.sub.5
alkoxy, hydroxy, amino, cyano, halogen, OC(O)C.sub.1-C.sub.6alkyl,
carboxy, CO.sub.2C.sub.1-C.sub.6alkyl, NHCOC.sub.1-C.sub.6alkyl,
CONH(C.sub.1-C.sub.6alkyl), NH(C.sub.1-C.sub.6alkyl),
N(C.sub.1-C.sub.6alkyl).sub.2, (5) halogen, (6) cyano, (7) oxo, (8)
a 5- or 6-membered heterocycle containing from 1 to 4 heteroatoms
selected from oxygen, sulfur and nitrogen optionally substituted by
1 to 4 groups selected from C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.5
alkenyl, C.sub.1-C.sub.5 alkoxy, hydroxy, oxo, amino, cyano,
halogen, OC(O)C.sub.1-C.sub.6alkyl, carboxy,
CO.sub.2C.sub.1-C.sub.6alkyl, NHCOC.sub.1-C.sub.6alkyl,
CONH(C.sub.1-C.sub.6alkyl), NH(C.sub.1-C.sub.6alkyl),
N(C.sub.1-C.sub.6alkyl).sub.2, m is 0 to 2; n is 0 or 1; p is 0 or
1; or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 wherein n is 0.
3. A compound of claim 1 wherein n is 1.
4. A compound of claim 1 wherein R.sub.1 is H, and R.sub.2 is H,
OR.sup.a or SR.sup.a.
5. A compound of claim 5 wherein R.sub.2 is OR.sup.a or SR.sup.a,
wherein R.sup.a is H, optionally substituted C.sub.1-C.sub.6alkyl,
optionally substituted C.sub.3-C.sub.6alkenyl, or optionally
substituted aryl, wherein the substituent is 1 to 4 groups
independently selected from R.sup.z, hydroxy,
C.sub.1-C.sub.6alkoxy, OC(O)R.sup.b, CO.sub.2R.sup.b,
NR.sup.cCOR.sup.d, CONR.sup.cR.sup.d, and NR.sup.cR.sup.d.
6. A compound of claim 1 wherein R.sub.2 is H, and R.sub.1is
R.sup.x, optionally substituted with one to ten groups
independently selected from R.sup.z, OR.sup.a, OC(O)R.sup.b,
CO.sub.2R.sup.b, NR.sup.cCOR.sup.d, CONR.sup.cR.sup.d, and
NR.sup.cR.sup.d.
7. A compound of claim 6 wherein R.sub.1 is selected from
C.sub.1-6alkyl, C.sub.3-6alkenyl, thienyl and furanyl.
8. A compound of claim 1 having the formula: 50
9. A compound of claim 8 wherein n is 1, R.sub.1, R.sub.3 and
R.sub.4 are each hydrogen, and R.sub.2 is selected from OR.sup.a
and SR.sup.a, wherein R.sup.a is H, optionally substituted
C.sub.1-C.sub.6alkyl, optionally substituted
C.sub.3-C.sub.6alkenyl, or optionally substituted aryl, wherein the
substituent is 1 to 4 groups independently selected from R.sup.z,
hydroxy, C.sub.1-C.sub.6alkoxy, OC(O)R.sup.b, CO.sub.2R.sup.b,
NR.sup.cCOR.sup.d, CONR.sup.cR.sup.d, and NR.sup.cR.sup.d.
10. A compound of claim 8 wherein n is 1, R.sub.2, R.sub.3 and
R.sub.4 are each hydrogen, and R.sub.1 is selected from R.sup.x,
optionally substituted with one to ten groups independently
selected from R.sup.z, OR.sup.a, OC(O)R.sup.b, CO.sub.2R.sup.b,
NR.sup.cCOR.sup.d, CONR.sup.cR.sup.d, and NR.sup.cR.sup.d.
12. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
13. A composition of claim 12 further comprising an anthelmintic
agent.
14. A composition of claim 13 wherein said anthelmintic agent is
selected from the group consisting of: ivermectin, avermectin
5-oxime, abamectin, emamectin, eprinamectin, doramectin, doramectin
monosaccharide 5-oximes, fulladectin, milbemycin, milbamycin
5-oxime, moxidectin, Interceptor.TM., nemadectin, imidacloprid,
fipronil, lufenuron, thiabendazole, cambendazole, parbendazole,
oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole,
albendazole, cyclobendazole, febantel, thiophanate,
tetramisole-levamisole, butamisole, pyrantel, pamoate, oxantel and
morantel.
15. A composition of claim 12 further comprising fipronil,
imidacloprid, lufenuron or an ecdysone agonist.
16. A method for the treatment or prevention of a parasitic disease
in a mammal which comprises administering to said mammal an
antiparasitic effective amount of a compound of claim 1.
17. A method of claim 16 further comprising administering an
anthelmintic agent.
18. A method of claim 16 further comprising administering fipronil,
imidacloprid or lufenuron.
Description
BACKGROUND OF THE INVENTION
[0001] Nodulisporic acid is an antiparasitic agent and
ectoparasiticidal agent isolated from the fermentation culture of
Nodulisporium sp. MF-5954 (ATCC 74245), and having the following
structure: 1
[0002] Nodulisporic acid is disclosed as "Compound 1" in U.S. Pat.
No. 5,399,582. Also disclosed therein are "Compound 2" and
"Compound 3": 2 3
[0003] Derivatives of nodulisporic acid are disclosed in U.S. Pat.
No. 5,962,499.
SUMMARY OF THE INVENTION
[0004] This invention relates to new acaricidal, antiparasitic,
insecticidal and anthelmintic agents related to the nodulisporic
acids, to processes for their preparation, compositions thereof,
their use in the treatment of parasitic infections, including
helminthiasis, in human and animals, and their use in the treatment
of parasitic infections in plants or plant products.
DETAILED DESCRIPTION OF THE INVENTION
[0005] The present invention provides compounds having the formula
I: 4
[0006] wherein
[0007] R.sup.1 is (1) hydrogen,
[0008] (2) C(O)H,
[0009] (3) optionally substituted (C.dbd.O).sub.p--R.sup.x, wherein
the substituent is one to ten groups independently selected from
R.sup.z, OR.sup.a, OC(O)R.sup.b, CO.sub.2R.sup.b,
NR.sup.cCOR.sup.d, CONR.sup.cR.sup.d, and NR.sup.cR.sup.d,
[0010] (4) C.sub.1-C.sub.10alkoxy,
[0011] (5) C.sub.1-C.sub.10alkylthio,
[0012] (6) CO.sub.2R.sup.b,
[0013] (7) CONR.sup.cR.sup.d,
[0014] (8) CONR.sup.cSO.sub.2R.sup.d,
[0015] (9) CN,
[0016] R.sub.2 is (1) hydrogen,
[0017] (2) OR.sup.a,
[0018] (3) SR.sup.a; or
[0019] R.sub.1+R.sub.2 represent .dbd.O; or
[0020] R.sub.1 and R.sub.2 together with the carbon atom to which
they are attached form a 5- to 7-membered ring containing 0 to 2
heteroatoms selected from O, S(O).sub.m and N, optionally
substituted with 1 to 4 groups independently selected from
R.sup.a;
[0021] R.sub.3 is (1) hydrogen,
[0022] (2) OR.sup.a,
[0023] (3) NR.sup.cR.sup.d,
[0024] (4) NR.sup.cCOR.sup.d,
[0025] (5) NR.sup.cSO.sub.2R.sup.d,
[0026] (6) NR.sup.eCONR.sup.cR.sup.d,
[0027] (7) NR.sup.cCO.sub.2R.sup.d; or
[0028] R.sub.2+R.sub.3 represent a bridging oxygen atom;
[0029] R.sub.4 is hydrogen, or
[0030] R.sub.2 and R.sub.4 together represents a bond between the
carbon atoms to which they are attached;
[0031] R.sup.a is (1) H,
[0032] (2) optionally substituted R.sup.y,
[0033] (3) optionally substituted C(O)R.sup.x,
[0034] (4) PO(OR.sup.b).sub.2,
[0035] (5) SO.sub.2R.sup.b,
[0036] (6) a natural or unnatural mono-, di- or tri-saccharide
composed of any furanose or pyranose, or combination thereof;
[0037] wherein said substituent for R.sup.x and R.sup.y are 1 to 10
groups independently selected from R.sup.z, hydroxy,
C.sub.1-C.sub.6alkoxy, OC(O)R.sup.b, CO.sub.2R.sup.b,
NR.sup.cCOR.sup.d, CONR.sup.cR.sup.d, and NR.sup.cR.sup.d,
[0038] R.sup.b is (1) hydrogen
[0039] (2) optionally substituted R.sup.y, wherein said
substituents are 1 to 10 groups independently selected from
R.sup.z, hydroxy, C.sub.1-C.sub.6alkoxy, OC(O)C.sub.1-C.sub.6alkyl,
carboxy, CO.sub.2C.sub.1-C.sub.6alkyl, NR.sup.cCOR.sup.d,
CONR.sup.cR.sup.d, and NR.sup.cR.sup.d,
[0040] (3) a natural or unnatural mono-, di- or tri-saccharide
composed of any furanose or pyranose, or combination thereof;
[0041] R.sup.c is (1) hydrogen,
[0042] (2) optionally substituted R.sup.y, wherein said
substituents are 1 to 10 groups independently selected from
R.sup.z, hydroxy, C.sub.1-C.sub.6alkoxy, OC(O)C.sub.1-C.sub.6alkyl,
carboxy, CO.sub.2C.sub.1-C.sub.6alkyl, NHCOC.sub.1-C.sub.6alkyl,
CONH(C.sub.1-C.sub.6alkyl), NH.sub.2, NH(C.sub.1-C.sub.6alkyl),
N(C.sub.1-C.sub.6alkyl).sub.2,
[0043] R.sup.d is independently selected from R.sup.c; or
[0044] R.sup.c and R.sup.d together with the N to which they are
attached form a 3- to 10-membered ring containing 0 to 2 additional
heteroatoms selected from O, S(O).sub.m and N, optionally
substituted with 1 to 4 groups independently selected from
R.sup.e;
[0045] R.sup.e is halogen, cyano, oxo or optionally substituted
R.sup.x wherein said substituents are 1 to 10 groups independently
selected from R.sup.z, hydroxy, C.sub.1-C.sub.6alkoxy,
OC(O)C.sub.1-C.sub.6alkyl, carboxy, CO.sub.2C.sub.1-C.sub.6alkyl,
NHCOC.sub.1-C.sub.6alkyl, CONH(C.sub.1-C.sub.6alkyl), NH.sub.2,
NH(C.sub.1-C.sub.6alkyl), N(C.sub.1-C.sub.6alkyl).sub.2,
[0046] R.sup.x is (1) C.sub.1-C.sub.10 alkyl,
[0047] (2) C.sub.2-C.sub.10 alkenyl,
[0048] (3) C.sub.2-C.sub.10 alkynyl,
[0049] (4) C.sub.3-C.sub.8 cycloalkyl,
[0050] (5) C.sub.5-C.sub.8 cycloalkenyl,
[0051] (6) aryl,
[0052] (7) a 5- or 6-membered heterocycle containing from 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen;
[0053] R.sup.y is (1) C.sub.1-C.sub.10 alkyl,
[0054] (2) C.sub.3-C.sub.10 alkenyl,
[0055] (3) C.sub.3-C.sub.10 alkynyl,
[0056] (4) C.sub.3-C.sub.8 cycloalkyl,
[0057] (5) C.sub.5-C.sub.8 cycloalkenyl,
[0058] (6) aryl,
[0059] (7) a 5- or 6-membered heterocycle containing from 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen;
[0060] R.sup.z is (1) C.sub.1-C.sub.5 alkyl,
[0061] (2) C.sub.2-C.sub.5 alkenyl,
[0062] (3) C.sub.3-C.sub.8 cycloalkyl,
[0063] (4) aryl, optionally substituted by 1 to 4 groups selected
from C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.5 alkenyl,
C.sub.1-C.sub.5 alkoxy, hydroxy, amino, cyano, halogen,
OC(O)C.sub.1-C.sub.6alkyl, carboxy, CO.sub.2C.sub.1-C.sub.6alkyl,
NHCOC.sub.1-C.sub.6alkyl, CONH(C.sub.1-C.sub.6alkyl),
NH(C.sub.1-C.sub.6alkyl), N(C.sub.1-C.sub.6alkyl).sub.2,
[0064] (5) halogen,
[0065] (6) cyano,
[0066] (7) oxo,
[0067] (8) a 5- or 6-membered heterocycle containing from 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen optionally
substituted by 1 to 4 groups selected from C.sub.1-C.sub.5 alkyl,
C.sub.2-C.sub.5 alkenyl, C.sub.1-C.sub.5 alkoxy, hydroxy, oxo,
amino, cyano, halogen, OC(O)C.sub.1-C.sub.6alkyl, carboxy,
CO.sub.2C.sub.1-C.sub.6alkyl, NHCOC.sub.1-C.sub.6alkyl,
CONH(C.sub.1-C.sub.6alkyl), NH(C.sub.1-C.sub.6alkyl),
N(C.sub.1-C.sub.6alkyl).sub.2,
[0068] m is 0 to 2;
[0069] n is 1 or 1;
[0070] p is 0 or 1; or
[0071] a pharmaceutically acceptable salt thereof.
[0072] The present invention provides in another aspect
pharmaceutical compositions comprising a compound of Formula I and
a pharmaceutically acceptable carrier. Such compositions may
further comprise one or more other active ingredients such as
anthelmintic agents, insect regulators, ecdosyne agonists and
fipronil.
[0073] The present invention provides in another aspect a method
for treating parasitic diseases in a mammal which comprises
administering an antiparasitic amount of a compound of Formula I.
The treatment may further comprise co-administering one or more
other active ingredients such as anthelmintic agents, insect
regulators, ecdosyne agonists and fipronil.
[0074] In one subset of compounds of formula I, n is 0.
[0075] In another subset of compounds of formula I, n is 1.
[0076] In another subset of compounds of formula I, R.sub.1 is H,
and R.sub.2 is H, OR.sup.a or SR.sup.a. Preferably, R.sub.2 is
OR.sup.a or SR.sup.a wherein R.sup.a is H, optionally substituted
C.sub.1-C.sub.6alkyl, optionally substituted
C.sub.3-C.sub.6alkenyl, or optionally substituted aryl, wherein the
substituent is 1 to 4 groups independently selected from R.sup.z,
hydroxy, C.sub.1-C.sub.6alkoxy, OC(O)R.sup.b, CO.sub.2R.sup.b,
NR.sup.cCOR.sup.d, CONR.sup.cR.sup.d, and NR.sup.cR.sup.d. Examples
of R.sub.2 include, but are not limited to, hydrogen, hydroxy,
methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, allyloxy,
6-methoxycarbonyl-n-hexyloxy, benzyloxy,
2-oxo-5-pyrrolidinylmethoxy, 2-acetamidoethoxy,
2-methyl-2-acetylethoxy, 2-(2-oxo-1-pyrrolidinyl)ethoxy,
2-(2,5-dioxo-1-pyrrolidinyl)ethoxy, 2-cyanoethoxy,
3-furanyl-methoxy, 4-imidazolylmethoxy,
2-(4-methyl-5-thiazolyl)ethoxy, methylthio, ethylthio, phenylthio,
2-methoxyphenylthio.
[0077] In another subset of compounds of formula I, R.sub.2 is H,
and R.sub.1 is R.sup.x, optionally substituted with one to ten
groups independently selected from R.sup.z, OR.sup.a, OC(O)R.sup.b,
CO.sub.2R.sup.b, NR.sup.cCOR.sup.d, CONR.sup.cR.sup.d, and
NR.sup.cR.sup.d. In one embodiment R.sub.1 is selected from
C.sub.1-6alkyl, C.sub.3-6alkenyl and aryl. Examples of R.sub.1
include, but are not limited to, methyl, allyl, 2-thienyl,
2-furanyl.
[0078] In another subset of compounds of formula I, R.sub.1 and
R.sub.2 together is an oxo group.
[0079] In another subset of compounds of formula I, R.sub.2 and
R.sub.4 together form a bond across the carbon atoms to which they
are attached.
[0080] In a preferred embodiment, compounds of formula I have the
stereoconfiguratioin is shown: 5
[0081] "Alkyl" as well as other groups having the prefix "alk",
such as alkoxy, alkanoyl, alkenyl, alkynyl and the like, means
carbon chains which may be linear or branched or combinations
thereof. Examples of alkyl groups include methyl, ethyl, propyl,
isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and
the like. "Alkenyl", "alkynyl" and other like terms include carbon
chains containing at least one unsaturated C-C bond. Examples of
alkenyl groups include allyl, homoallyl and the like. Examples of
alkynyl groups include propargyl, homopropargyl and the like.
[0082] Alkanoyl means alkylcarbonyl in which alkyl is as defined
above.
[0083] Alkenoyl means alkenylcarbonyl in which alkenyl is as
defined above.
[0084] The term "cycloalkyl" means carbocycles containing no
heteroatoms, and includes mono-, bi- and tricyclic saturated
carbocycles, as well as benzofused carbocycles. Examples of
cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, decahydronaphthalene, adamantane, indanyl, fluorenyl,
1,2,3,4-tetrahydronaphalene and the like. Similarly, "cycloalkenyl"
means carbocycles containing no heteroatoms and at least one
non-aromatic C-C double bond, and include mono-, bi- and tricyclic
partially saturated carbocycles, as well as benzofused
cycloalkenes. Examples of cycloalkenyl include cyclohexenyl,
indenyl, and the like.
[0085] The term "halogen" is intended to include the halogen atoms
fluorine, chlorine, bromine and iodine.
[0086] The term "heterocycle", unless otherwise specified, means
mono- or bicyclic compounds that are saturated or partly
unsaturated, as well as benzo- or heteroaromatic ring fused
saturated heterocycles or partly unsaturated heterocycles, and
containing from 1 to 4 heteroatoms independently selected from
oxygen, sulfur and nitrogen. Examples of saturated heterocycles
include lactams, cyclic imides, morpholine, thiomorpholine,
piperidine, piperazine, tetrahydropyran, tetrahydrofuran, dioxane,
tetrahydrothiophene, oxazolidine, pyrrolidine; examples of partly
unsaturated heterocycles include dihydropyran, dihydropyridazine,
dihydrofuran, dihydrooxazole, dihydropyrazole, dihydropyridine,
dihydropyridazine and the like. Examples of benzo- or
heteroaromatic ring fused heterocycles include
2,3-dihydrobenzofuranyl, benzopyranyl, tetrahydroquinoline,
tetrahydroisoquinoline, benzomorpholinyl, 1,4-benzodioxanyl,
2,3-dihydrofuro(2,3-b)pyridyl and the like.
[0087] The term "aryl" is intended to include mono- and bicyclic
aromatic and heteroaromatic rings containing from 0 to 5
heteroatoms independently selected from nitrogen, oxygen and
sulfur. The term "aryl" is also meant to include benzofused
cycloalkyl, benzofused cycloalkenyl, and benzofused heterocyclic
groups. Examples of "aryl" groups include phenyl, pyrrolyl,
isoxazolyl, pyrazinyl, pyridinyl, oxazolyl, thiazolyl, imidazolyl,
triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl,
pyridazinyl, pyrazinyl, naphthyl, benzoxazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, furo(2,3-b)pyridyl,
2,3-dihydrofuro(2,3-b)p- yridyl, benzoxazinyl, benzothiophenyl,
quinolinyl, indolyl, 2,3-dihydrobenzofuranyl, benzopyranyl,
1,4-benzodioxanyl, indanyl, indenyl, fluorenyl,
1,2,3,4-tetrahydronaphthalene and the like.
[0088] Aroyl means arylcarbonyl in which aryl is as defined
above.
[0089] Examples of NR.sup.cR.sup.d forming a 3- to 10- membered
ring containing 0 to 2 additional heteroatoms selected from O,
S(O).sub.m and N are aziridine, azetidine, pyrrolidine, piperidine,
thiomorpholine, morpholine, piperazine, octahydroindole,
tetrahydroisoquinoline and the like.
[0090] The term "optionally substituted" is intended to include
both substituted and unsubstituted; thus, for example, optionally
substituted aryl could represent a pentafluorophenyl or a phenyl
ring.
[0091] The term "composition", as in pharmaceutical composition, is
intended to encompass a product comprising the active
ingredient(s), and the inert ingredient(s) that make up the
carrier, as well as any product which results, directly or
indirectly, from combination, complexation or aggregation of any
two or more of the ingredients, or from dissociation of one or more
of the ingredients, or from other types of reactions or
interactions of one or more of the ingredients. Accordingly, the
pharmaceutical compositions of the present invention encompass any
composition made by admixing a compound of the present invention
and a pharmaceutically acceptable carrier.
[0092] Certain of the above defined terms may occur more than once
in the above formula and upon such occurrence each term shall be
defined independently of the other; thus, for example, OR.sup.a at
R.sub.2 may represent OCH.sub.3 and at R.sub.3 represent OH.
[0093] Compounds described herein contain one or more asymmetric
centers and may thus give rise to diastereomers and optical
isomers. The present invention is intended to include all possible
diastereomers as well as their racemic and resolved,
enantiomerically pure forms and all possible geometric isomers. In
addition, the present invention includes all pharmaceutically
acceptable salts thereof. The term "pharmaceutically acceptable
salts" refers to salts prepared from pharmaceutically acceptable
non-toxic bases including inorganic bases and organic bases. Salts
derived from inorganic bases include aluminum, ammonium, calcium,
copper, ferric, ferrous, lithium, magnesium, manganic salts,
manganous, potassium, sodium, zinc, and the like. Particularly
preferred are the ammonium, calcium, magnesium, potassium, and
sodium salts. Salts derived from pharmaceutically acceptable
organic non-toxic bases include salts of primary, secondary, and
tertiary amines, substituted amines including naturally occurring
substituted amines, cyclic amines, and basic ion exchange resins,
such as arginine, betaine, caffeine, choline,
N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,
2-dimethylaminoethanol, ethanolamine, ethylenediamine,
N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,
histidine, hydrabamine, isopropylamine, lysine, methylglucamine,
morpholine, piperazine, piperidine, polyamine resins, procaine,
purines, theobromine, triethylamine, trimethylamine,
tripropylamine, tromethamine, and the like.
[0094] When the compound of the present invention is basic, salts
may be prepared from pharmaceutically acceptable non-toxic acids,
including inorganic and organic acids. Such acids include acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid, and the like. Particularly preferred are
citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric,
and tartaric acids.
[0095] Compounds of the present invention are prepared from
nodulisporic acid, which in turn is obtained from the fermentation
culture of Nodulisporium sp. MF-5954 (ATCC 74245). The descriptions
of the producing microorganism, the fermentation process, and the
isolation and purification of nodulisporic acid are disclosed in
U.S. Pat. No. 5,399,582, issued Mar. 21, 1995, which is hereby
incorporated by reference in its entirety.
[0096] The above structural formula I is shown without a definitive
stereochemistry at certain positions. However, during the course of
the synthetic procedures used to prepare such compounds, or using
racemization or epimerization procedures known to those skilled in
the art, the products of such procedures can be a mixture of
stereoisomers. In particular, the stereoisomers at C4, C20, C26,
C29, C30 and C31 may be oriented in either the alpha- or
beta-position, representing such groups oriented below or above the
plane of the molecule, respectively. In each such case, and at
other positions in the molecule, both the alpha- and
beta-configurations are intended to be included within the ambit of
this invention.
[0097] The carbon atoms within the compounds of the present
invention are numbered as indicated in Formulas IIa and IIb, and
are directly related to the numbering system of the parent
compound, nodulisporic acid. 6 7
1 Abbreviation: DAST (diethylamino)sulfur trifluoride DBU
1,8-diazabicyclo[5.4.0]undec- -7-ene DMF dimethylformamide DMSO
dimethylsulfoxide DPPA diphenyl phosphoryl azide Et ethyl EtOAc
ethyl acetate EtOH ethanol HMDS hexamethyldisilazane iPr isopropyl
MCPBA meta-chloroperbenzoic acid Me methyl MeOH methanol NBS
N-bromosuccinimide NMO N-methylmorpholine-N-oxide PCC pyridinium
chlorochromate PPTS pyridinium para-toluenesulfonic acid TBHP
t-butyl hydroperoxide TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy,
free radical TES triethylsilyl Tf trifluoromethanesulfonyl THF
tetrahydrofuran TMS trimethylsilyl TPAP tetrapropylammonium
perruthenate TsOH para-toluenesulfonic acid
[0098] Compounds of formula I wherein the propenyl group at
position C26 is in the epi configuration, relative to the
nodulisporic acid starting material, may be obtained by treatment
of the appropriate precursor with a base such as hydroxide,
methoxide, imidazole, triethylamine, potassium hydride, lithium
diisopropylamide and the like in protic or aprotic solvents (as
appropriate) such as water, methanol, ethanol, methylene chloride,
chloroform, tetrahydrofuran, dimethylformamide and the like. The
reaction is complete at temperatures from -78.degree. C. to the
reflux temperature of the solution in from 15 minutes to 12
hours.
[0099] The stereoconfiguration at C4 of compounds of formula I may
be inverted from that of the nodulisporic acid starting material
using protocols known to those skilled in the art. For example, the
hydroxy group at C4 may be reacted under Mitsunobu conditions with
a carboxylic acid (formic acid, propionic acid, 2-chloro-acetic
acid, benzoic acid, para-nitrobenzoic acid and the like), a
tri-substituted phosphine (triphenylphosphine, tri-n-butylphoshine,
tripropylphosphine and the like) and a dialkyl diazodicarboxylate
(diethyl diazodicarboxylate, dimethyl diazodicarboxylate,
diisopropyl diazodicarboxylate and the like) in an aprotic solvent
such as methylene chloride, tetrahydrofuran, chloroform, benzene
and the like. The Mitsunobu reactions are complete in from 1 to 24
hours at temperatures from 0.degree. C. to the reflux temperature
of the solution. The resultant esters may be hydrolyzed by
treatment with hydroxide or ammonium hydroxide in a protic solvent
such as methanol, ethanol, water, tetrahydrofuran/water or
dimethylformamide/water and the like at from 0.degree. C. to the
reflux temperature of the solution. Alternatively, the resultant
esters may be hydrolyzed by treatment with a Lewis acid, such as
magnesium chloride, aluminum chloride, titanium tetra-isopropoxide
and the like in a protic solvent such as methanol, ethanol,
isopropanol and the like and the reactions are complete in from 1
to 24 hours at 0.degree. C. to the reflux temperature of the
solution.
[0100] During certain reactions described below, it may be
necessary to protect the hydroxyl groups at C4 and C20 of
nodulisporic acid-derived synthetic intermediates, and the hydroxyl
group at C4 of formula I. With these positions protected, the
reactions may be carried out at other positions without affecting
the remainder of the molecule. Subsequent to any of the described
reactions (vida infra), the protecting group(s) may be removed and
the unprotected product isolated. The protecting groups employed at
C4 and C20 are those which may be readily synthesized, not
significantly affected by the reactions at the other positions, and
may be removed without significantly affecting any other
functionality of the molecule. One preferred type of protecting
group is the tri-substituted silyl group, preferably the
tri-loweralkyl silyl group or di-loweralkyl-aryl silyl group.
Especially preferred examples are the trimethylsilyl (TMS),
triethylsilyl (TES), triisopropylsilyl, tert-butyldimethylsilyl and
dimethylphenylsilyl groups.
[0101] The protected compound may be prepared with
hexamethyldisilazane (HMDS) or the appropriately substituted silyl
trifluoromethanesulfonate or silyl chloride. The reaction is
carried out in an aprotic solvent such as methylene chloride,
benzene, toluene, ethyl acetate, isopropyl acetate,
tetrahydrofuran, acetonitrile, dimethylformamide and the like. In
order to minimize side reactions, there can be included in the
reaction mixture a base to react with the acid released during the
course of the reaction. Preferred bases are amines such as
imidazole, pyridine, triethylamine or diisopropylethylamine and the
like. The base is required in amounts equimolar to the amount of
hydrogen halide liberated, however, generally several equivalents
of the amine are employed. The reaction is stirred at from
0.degree. C. to the reflux temperature of the reaction mixture and
is complete from 1 to 24 hours.
[0102] The silyl group is removed by treatment of the silyl
compound with anhydrous pyridine-hydrogen fluoride in
tetrahydrofuran or dimethylsulfoxide or with tetraalkylammonium
fluoride in tetrahydrofuran. The reaction is complete in from 1 to
24 hours at from 0.degree. C. to 50.degree. C. Alternatively, the
silyl group may be removed by stirring the silylated compound in an
aprotic solvent such as tetrahydrofuran (THF), or lower protic
solvents such as methanol, ethanol, isopropanol and the like
catalyzed by an acid, preferably a sulfonic acid monohydrate such
as pyridinium para-toluenesulfonic acid (PPTS),
para-toluenesulfonic acid (TsOH), benzenesulfonic acid or
carboxylic acids such as acetic acid, propionic acid,
monochloroacetic acid, dichloroacetic acid, trichloroacetic acid
and the like. The reaction is complete in 1 to 24 hours at from
0.degree. C. to 50.degree. C.
[0103] Protecting groups that may also be suitably used in the
preparation of compounds of the present invention may be found in
standard textbooks such as Greene and Wutz, Protective Groups in
Organic Synthesis, 1991, John Wiley & Sons, Inc.
[0104] Compounds of formula I wherein n is 1, R.sub.2 is a
hydroxyl, R.sub.1, R.sub.3 and R.sub.4 are hydrogen, may be
prepared according to the procedure shown in Scheme la. Thus,
Compound III, prepared by oxidative cleavage of nodulisporic acid
using potassium permanganate or a nodulisporamide using osmium
tetroxide, is hydrogenated using conventional procedures known to
those skilled in the art to provide hemiacetal VI. The enal double
bond may be reduced with any of a variety of standard precious
metal hydrogenation catalysts such as Wilkinson'vs catalyst,
Pearlman's catalyst, 1-25% palladium on carbon (Pd--C), 1-25%
platinum on carbon and the like. The reaction is generally carried
out in non-reducible solvents (either protic or aprotic) such as
methanol, ethanol, isopropanol, tetrahydrofuran, isopropyl acetate,
benzene, toluene, dimethylformamide and the like. The hydrogen
source may be hydrogen gas from 1 to 50 atmospheres of pressure or
other hydrogen sources such as ammonium formate, cyclohexene,
cyclohexadiene and the like. The reduction also may be carried out
using sodium dithionite and sodium bicarbonate in the presence of a
phase transfer catalyst, in particular a tetraalkylammonium phase
transfer catalyst, and the like. The reactions may be run from
0.degree. C. to 100.degree. C. and are complete in from 5 min to 24
hours. Alternatively, Compound IV, from compound III using HMDS, is
hydrogenated under similar conditions described above to provide V.
Preferred hydrogenation conditions of III and IV are 1 atmosphere
of hydrogen with catalytic 10% palladium on carbon in ethyl acetate
solvent. Compound V is treated with PPTS in THF to also afford
hemiacetal VI. 8
[0105] Compounds of formula I wherein n is 0, R.sub.2 is a
hydroxyl, R.sub.1, R.sub.3 and R.sub.4 are hydrogen, may be
prepared according to the procedure shown in Scheme lb. Thus,
Compound XVII is treated with diphenylphosphoryl azide and heated
in an aprotic solvent such as, but not restricted to, toluene,
resulting in a rearrangement yielding vinyl isocyanate XVIII.
Compound XVIII is then converted to hemiacetal XX via treatment
with an acid or acid mixture in an aqueous or partially aqueous
solvent system. Typical acids used independently or in mixtures
with each other for this transformation are sulfonic acid
monohydrates such as benzenesulfonic acid, camphor sulfonic acid or
carboxylic acids such as acetic acid, propionic acid,
monochloroacetic acid, dichloroacetic acid, trichloroacetic acid,
trifluoroacetic acid or inorganic acids such as hydrochloric acid,
sulfuric acid, polyphosphoric acid and the like. The preferred acid
mixture is a combination of pyridinium para-toluenesulfonic acid
(PPTS) with a lesser amount of para-toluenesulfonic acid (TsOH).
The solvent system used is either water or a mixture of water with
organic solvents such as, but not restricted to, tetrahydrofuran,
dimethoxyethane, diethyl ether, benzene, toluene, acetonitrile,
nitromethane, methylene chloride, chloroform, dimethylformamide,
dimethylacetamide, N-methylpyrrolidinone and the like. The
preferred solvent system is a mixture of dioxane and water. These
hemiacetal-forming reactions may be performed from -20.degree. C.
to 100.degree. C. and are complete in 5 minutes to 48 hours. 9
[0106] As shown in Scheme 2, the hemiacetal VIa is treated with an
organic acid in an alcohol solvent under conditions known to those
skilled in the art to yield the acetal VII. Typical organic acids
used for this transformation are sulfonic acid monohydrates such as
para-toluenesulfonic acid (TsOH), benzenesulfonic acid,
camphorsulfonic acid or carboxylic acids such as acetic acid,
propionic acid, monochloroacetic acid, dichloroacetic acid,
trichloroacetic acid and the like. The preferred organic acid is
pyridinium para-toluenesulfonic acid (PPTS). The reaction is
complete in 1 to 24 hours at from 0.degree. C. to 50.degree. C.
[0107] Similarly, thioacetal VIII are prepared from thiol under
conditions analogous to those described for the preparation of
acetal VII. Additionally, an aprotic solvent is used such as
dimethylformamide, dimethylacetamide, N-methylpyrrolidinone,
tetrahydrofuran, dioxane, benzene, toluene, chloroform,
1,2-dichloroethane and the like. The preferred solvent is methylene
chloride. 10
[0108] Compounds of formula I wherein R.sub.1and R.sub.2 together
represent a oxo, (.dbd.O), and R.sub.3 and R.sub.4 are each
hydrogen may be prepared by treating the appropriate hemiacetal
with an oxidant under conditions known to those skilled in the art
to produce the corresponding lactone. For example, hemiacetal VI is
oxidized to IX as shown in Scheme 3. Lactone formation may be
accomplished by using reagents including, but not restricted to,
Dess-Martin periodinane, SO.sub.3-pyridine/DMSO,
4-acetamido-TEMPO/para-toluenesulfonic acid, PCC and the like.
Unreactive solvents that may be used in the oxidation are
chloroform, 1,2-dichloroethane, benzene and the like. The preferred
reaction conditions are catalytic tetrapropylammonium perruthenate
(TPAP) with the addition of excess co-oxidant, N-methylmorpholine
N-oxide, in methylene chloride solvent. The reaction is complete in
1 to 24 hours at from -20.degree. C. to 50.degree. C. 11
[0109] Compounds of formula I wherein R.sub.1 and R.sub.3 are
hydrogen, and R.sub.2 and R.sub.4 together form a bond across the
carbon atoms to which they are attached, may be prepared by
treatment of the appropriate hemiacetal with dehydrating reagents
known to those skilled in the art such as para-toluenesulfonyl
chloride, methanesulfonyl chloride, dinitrobenzenesulfonyl
chloride, acetyl chloride, thionyl chloride, Burgess reagent,
Martin sulfurane, Ph.sub.3P-CBr.sub.4-DBU,
4-hydroxymethyleneimidazole-PPTS and the like. The reaction is
conducted in a solvent such as chloroform, tetrahydrofuran,
dioxane, benzene, toluene and the like, and the reactions are
complete in from 1 to 48 hours at -20.degree. C. to the reflux
temperature of the solution. For example, the preferred conditions
for the dehydration of hemiacetal VI employ thiocarbonyl
diimidazole (TCDI) with diisopropylethylamine (Hunig's base) in
methylene chloride as shown in Scheme 3 to prepare Compound X.
Compound X may be converted to compound XI by conventional
hydrogenation procedures known to those skilled in the art, for
example under conditions analogous to the reductions of III and IV
above. The preferred conditions utilize 1 atmosphere of hydrogen
with catalytic 10% palladium on carbon in ethyl acetate
solvent.
[0110] Compounds of formula I wherein R.sub.1 is a methyl, R.sub.3
is hydrogen, and R.sub.2 and R.sub.4 together form a bond across
the carbon atoms to which they are attached, may be prepared
according to the procedure shown in Scheme 4 using conditions known
to those skilled in the art. For example, the lactone XII is
treated with olefination reagents including, but not restricted to,
Tebbe, Wittig, Peterson and the like to yield the methyl glycal
XIII. Typical media used for this transformation are aprotic
organic solvents such as benzene, mesitylene, diethyl ether,
dioxane and the like. The preferred conditions utilize dimethyl
titanocene in a solvent mixture of THF and toluene. The reactions
are complete in from 1 to 48 hours at -78.degree. C. to the reflux
temperature of the solution.
[0111] Compounds of formula I wherein R.sub.1 is a methyl, R.sub.2,
R.sub.3 and R.sub.4 are hydrogen, may be prepared in an analogous
fashion to the synthesis of compound XI above. The preferred
conditions utilize 1 atmosphere of hydrogen with catalytic 10%
palladium on carbon in ethyl acetate solvent as shown in Scheme 4
for the synthesis of IXV, subsequent to silyl group removal using
conditions described above, preferably with PPTS in ethanol. 12
[0112] Compounds of formula I wherein R.sub.1 is a phosphate
(OP(O)(OR.sup.b)2) or sulfonate (OSO.sub.2R.sup.b), R.sub.3 is
hydrogen, and R.sub.2 and R.sub.4 together form a bond across the
carbon atoms to which they are attached, may be prepared according
to the procedure shown in Scheme 5 using conditions known to those
skilled in the art. The lactone XII is treated with a strong base
including, but not restricted to, lithium diisopropylamide, lithium
bis(trimethylsilyl)amide, potassium hydride, lithium
tetramethylpiperidine and the like. The resulting anion is quenched
with an electrophile such as (R.sup.bO).sub.2POCl, trifluoromethane
sulfonylchloride, trifluoromethane sulfonic anhydride,
N-phenyltriflimide, N-(choropyridyl)triflimide and the like.
Typical media used for this transformation are aprotic organic
solvents such as benzene, diethyl ether, dioxane, HMPA and the
like. The reactions are complete in from 1 to 24 hours at
-78.degree. C. to the room temperature. The preferred conditions
are potassium bis(trimethylsilyl)amide and (PhO).sub.2POCl in a
solvent mixture of THF and toluene to prepare ketene acetal
phosphate XV. 13
[0113] Compounds of formula I wherein R.sub.1 is alkenyl,
cycloalkenyl, alkynyl, alkanoyl, alkenoyl, carboxy, carboxamido,
aryl or aroyl, R.sub.3 is hydrogen, and R.sub.2 and R.sub.4
together represent a bond across the carbon atoms to which they are
attached, may be prepared from the appropriate ketene acetal
phosphate or sulfonate using conditions known to those skilled in
the art. For example, reaction of ketene acetal phosphate XV with
the appropriate stannane, boronic acid, silane, zinc reagent,
carbon monoxide gas and the like, can be catalyzed by, but not
restricted to, ligated palladium (0) or (II), ligated nickel (0) or
(II) and the like. Other additives include, but are not restricted
to, copper salts, various chloride ions, primary or secondary or
tertiary amines, carbonate bases and the like. Solvents can be
DMSO, dimethoxyethane, dioxane, diethyl ether, water, alcohols
including, but not restricted to, methanol, also toluene, benzene,
mesitylene and the like. The reactions are complete in from 1 to 72
hours at from 23.degree. C. to the reflux temperature of the
solution. The preferred conditions to prepare vinyl XVI from XV
employ tributylvinylstannane, lithium chloride, palladium(0)
tetrakis(triphenylphosphine) and THF solvent as shown in Scheme 5.
Alternatively, XV may be converted directly to a stannane using
hexamethylditin, and the like, under analogous palladium coupling
conditions described above. The resultant stannane of XV can then
react with acid chlorides, alkenyl halides, cycloalkenyl halides,
alkynyl halides, and the like, also under analogous palladium
coupling conditions described above.
[0114] Compounds of formula I wherein n is 0, R.sub.1is optionally
substituted alkyl, R.sub.2, R.sub.3 and R.sub.4 are hydrogen, may
be prepared according to the procedure shown in Scheme 6. Thus, the
aldehyde (Compound IXX) is homologated to an
.alpha.,.beta.,-unsaturated carbonyl such as, but not restricted
to, enone XXII. Compound XXII is then converted to tetrahydrofuran
XXIII under conditions analogous to, but not restricted to, silyl
group removal as described above. The preferred conditions utilize
pyridinium para-toluenesulfonic acid (PPTS) in ethanol solvent for
the synthesis of 14
[0115] Compounds of formula I wherein R.sub.1, R.sub.3 and R.sub.4
are hydrogen, and R.sub.2 is a glycosidic linkage to a natural or
unnatural mono-, di- or tri-saccharide moiety, may be prepared from
hemiacetals VI and XX, or other appropriate glycosyl donors, using
protocols known to those skilled in the art. For example, Compounds
VI, VIII or XX may be reacted with a protected or partially
protected natural or unnatural mono-, di- or tri-saccharide
glycosyl acceptor under conditions that utilize reagents such as,
but not restricted to, methyl triflate, trimethylsilyl triflate,
DAST/SnCI.sub.2, potassium
bis(trimethylsilyl)amide/(PhO).sub.2P(O)Cl/trimethylsilyl triflate,
Cl.sub.3CCN/DBU or NaH or K.sub.2CO.sub.3/silver triflate, tin
triflate/trimethylsilyl chloride/lithium perchlorate and the like
in an aprotic solvent such as methylene chloride,
1,2-dichloroethane, diethyl ether, tetrahydrofuran, benzene,
toluene and the like. The glycosidation reactions are complete in
from 5 minutes to 24 hours at temperatures from -78.degree. C. to
50.degree. C.
[0116] Compounds of formula I wherein R.sub.1 and R.sub.4 are each
hydrogen, and R.sub.2 together with R.sub.3 share a bridging oxygen
atom represented as an epoxide ring, may be prepared from glycal X,
or other appropriate glycals, using protocols known to those
skilled in the art. For example, Compound X may be epoxidized with
dimethyl dioxirane, substituted oxaziridines, NBS/water/DBU, MCPBA,
TBHP, peracetic acid, oxone and the like in water or an aprotic
solvent such as acetone, methylene chloride, tetrahydrofuran,
chloroform, benzene, toluene, acetonitrile and the like. The
epoxidation reactions are complete in from 1 to 24 hours at
temperatures from -78.degree. C. to the reflux temperature of the
solution.
[0117] Compounds of formula I wherein R.sub.1 and R.sub.4 are
hydrogen, R.sub.2 is hydroxy or optionally substituted oxygen or
sulfur, and R.sub.3 is hydroxy or optionally substituted oxygen may
be prepared using various protocols known to those skilled in the
art. For example, the above epoxide intermediate may be treated
with neat acetic acid or acetic anhydride and pyridine with or
without DMAP and with or without an added glycosyl acceptor.
Alternatively, the above epoxide intermediate may be treated with
any alcohol or glycosyl acceptor with the addition of, but not
restricted to, ZnCl.sub.2, ZrCl.sub.4, Ti(Oi--Pr).sub.4,
MgBr.sub.2--OEt.sub.2 and the like. The above reactions may be run
in an aprotic solvent such as tetrahydrofuran, diethyl ether,
dioxane, methylene chloride, chloroform, benzene and the like. The
oxonium ion-assisted epoxide opening reactions are complete in from
5 minutes to 24 hours at temperatures from -78.degree. C. to
23.degree. C. Alternatively, glycal donors of formula I such as
Compound X may be treated with a mixture of diphenyl sulfoxide with
triflic anhydride and 2,6-di-tert-butyl-4-methylpyridine followed
by triethylamine with methanol and subsequent addition of
ZnCl.sub.2 or Sc(OTf).sub.3 with any alcohol or glycosyl acceptor
in a solvent such as methylene chloride at temperatures from
-78.degree. C. to 23.degree. C. in from 30 minutes to 24 hours.
Alternatively, glycals of formula I such as Compound X also may be
dihydroxylated by treatment with, but not restricted to, osmium
tetraoxide with or without the addition of co-oxidents such as, but
not restricted to, N-methylmorpholine N-oxide, trimethylamine
N-oxide and the like in solvents such as acetone, water, methylene
chloride, tetrahydrofuran and the like. The reactions are complete
in from 30 minutes to 24 hours at temperatures from -20.degree. C.
to 23.degree. C. The vicinal diol products may be treated under
anhydrous conditions with, but not restricted to, dibutyltin oxide
in methanol followed by cesium fluoride in toluene and an alkyl
triflate in DMF to provide glycosylation products in from 15
minutes to 24 hours at from -10.degree. C. to 70.degree. C.
[0118] Compounds of formula I wherein R.sub.1 and R.sub.4 are
hydrogen, R.sub.2 is hydrogen or hydroxy or optionally substituted
oxygen or sulfur, and R.sub.3 is amino or optionally substituted
nitrogen may be prepared using various protocols known to those
skilled in the art. For example, an appropriate glycal donor such
as Compound X may be treated with, but not resticted to, sodium
azide with ceric ammonium nitrate or PhI(OAc).sub.2 and the like,
followed by acetic anhydride/sodium acetate, diphenyl diselenide,
sodium nitrite, lithium bromide/silver triflate/tetramethyl
urea/methanol and the like, in acetonitrile, methylene chloride and
the like, in from 1 to 48 hours at from -20.degree. C. to
60.degree. C. The resultant azides of these reactions may be
reduced to the amines under a variety of conditions known to those
skilled in the art such as, but not restricted to,
triphenylphosphine/THF/water, hydrogenolysis with Lindlar catalyst
or other hydrogenation conditions described above, H.sub.2S in an
alcohol solvent and the like. The reactions are complete in from 1
to 48 hours at temperatures from 23.degree. C. to the reflux
temperature of the solution. The subsequent amines can be
functionalized to include, but not restricted to, amides, ureas,
carbamates, sulfonamides and the like. Alternatively, a glycal
donor such as Compound X may be treated with, but not restricted
to, Br.sub.2NSO.sub.2Ph in a solvent such as methylene chloride,
followed by ammonium iodide in an alcohol solvent and treatment
with potassium bis(trimethylsilyl)amide and the like, with a
glycosyl acceptor in a solvent such as DMF and the like.
Alternatively, a glycal donor such as Compound X also may be
treated with, but not restricted to, H.sub.2NSO.sub.2Ph with
I(sym-collidine).sub.2CIO.sub.4 in a solvent such as methylene
chloride, followed by treatment with lithium
bis(trimethylsilyl)amide and the like, with a glycosyl acceptor in
a solvent such as DMF and the like. These benzenesulfonamide
forming reactions described above are complete at from -78.degree.
C. to 40.degree. C. in from 5 minutes to 24 hours. The resultant
benzenesulfonamides may be transformed into their respective amines
and subsequent amides, ureas, carbamates, sulfonamides and the
like, under conditions known to those skilled in the art.
Alternatively, a glycal donor such as Compound X also may be
treated with, but not restricted to, (saltmen)Mn(N) with
trifluoroacetic anhydride in a solvent such as methylene chloride,
followed by treatment with a glycosyl acceptor and borontrifluoride
etherate or treatment with silica gel, H.sub.3O+ and the like, in
from 5 minutes to 24 hours at from -78.degree. C. to 40.degree. C.
The resultant trifluoroacetamides may be transformed into their
respective amines and subsequent amides, ureas, carbamates,
sulfonamides and the like, under conditions known to those skilled
in the art. Lactol and phenylselenide acetal products from the
above procedures may be reduced under conditions known to those
skilled in the art thus converting the substituted anomeric carbons
into unsubstituted methylenes.
[0119] Compounds of formula I wherein R.sub.3 and R.sub.4 are
hydrogen, R.sub.1 and R.sub.2 each are oxygen and together with the
carbon atom to which they are attached (anomeric carbon), form a
heterocycle, more specifically referred to as a spirocyclic
orthoester, may be prepared using protocols known to those skilled
in the art. All possible combinations of 5- to 7-membered
spirocyclic orthoesters may be ultimately prepared from hemiacetals
VI and XX, or other appropriate hemiacetals, upon conversion to
their respective glycals and subsequent dihydroxylation to their
respective diols using protocols described above. The appropriate
diol may then be mono-protected under conditions known to those
skilled in the art, the lactol activated for use as a glycosyl
donor under conditions described above, and converted to the
anomeric phenyl selenide using, but not restricted to, PhSeH and
borontrifluoride etherate. In turn the protected vicinal hydroxyl
moiety may be deprotected under conditions known to those skilled
in the art, and the anomeric selenide treated with, but not
restricted to, DAST in methylene chloride to induce the 1,2-seleno
migration providing the anomeric fluoro glycosyl donor vicinally
substituted with a phenylselenide moiety. This intermediate, in
turn, may be glycosylated with an appropriate mono-protected diol
glycosyl acceptor under conditions described above, and the pendent
hydroxyl deprotected under conditions known to those skilled in the
art. The vicinal selenide may then be oxidized with, but not
restricted to, sodium periodate with sodium hydrogen carbonate,
MCPBA, hydrogen peroxide, ozone and the like in methylene
chloride/methanol/water, THF/water, toluene and the like. The
selenoxide intermediate is then exposed to conditions including,
but not restricted to, dissolution into vinyl acetate/toluene with
diisopropylethylamine and heated at 140.degree. C. to affect
spirocyclic orthoester formation.
[0120] Compounds of formula I wherein R.sub.3 and R.sub.4 are
hydrogen, R.sub.2 is alkoxy and R.sub.1 is a carboxylic ester, may
be prepared using protocols known to those skilled in the art. For
example, an appropriate lactone, such as Compound IX, may be
treated with, but not resticted to,
bis(2,2,2-trifluoroethyl)-2-(1,3-dithiane)phosphonate with
potassium bis(trimethylsilyl)amide in toluene/THF followed by NBS
and an alcohol in methylene chloride at temperatures from
-78.degree. C. to 23.degree. C. in from 5 minutes to 12 hours.
[0121] The instant compounds are potent endo- and
ecto-antiparasitic agents, particularly against helminths,
ectoparasites, insects, and acarids, infecting man, animals and
plants, thus having utility in human and animal health, agriculture
and pest control in household and commercial areas.
[0122] The disease or group of diseases described generally as
helminthiasis is due to infection of an animal host with parasitic
worms known as helminths. Helminthiasis is a prevalent and serious
economic problem in domesticated animals such as swine, sheep,
horses, cattle, goats, dogs, cats, fish, buffalo, camels, llamas,
reindeer, laboratory animals, furbearing animals, zoo animals and
exotic species and poultry. Among the helminths, the group of worms
described as nematodes causes widespread and often times serious
infection in various species of animals. The most common genera of
nematodes infecting the animals referred to above are Haemonchus,
Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris,
Bunostomum, Oesophagostomum, Chabertia, Trichuris, Strongylus,
Trichonema, Dictyocaulus, Capillaria, Habronema, Druschia,
Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria,
Toxascaris and Parascaris. Certain of these, such as Nematodirus,
Cooperia, and Oesophagostomum attack primarily the intestinal tract
while others, such as Haemonchus and Ostertagia, are more prevalent
in the stomach while still others such as Dictyocaulus are found in
the lungs. Still other parasites may be located in other tissues
and organs of the body such as the heart and blood vessels,
subcutaneous and lymphatic tissue and the like. The parasitic
infections known as helminthiases lead to anemia, malnutrition,
weakness, weight loss, severe damage to the walls of the intestinal
tract and other tissues and organs and, if left untreated, may
result in death of the infected host. The compounds of this
invention have activity against these parasites, and in addition
are also active against Dirofilaria in dogs and cats,
Nematospiroides, Syphacia, Aspiculuris in rodents, arthropod
ectoparasites of animals and birds such as ticks, mites such as
scabies lice, fleas, blowflies, and other biting insects in
domesticated animals and poultry, such as Tenophalides, Ixodes,
Psoroptes, and Hemotobia, in sheep Lucilia sp., biting insects and
such migrating dipterous larvae as Hypoderma sp. in cattle,
Gastrophilus in horses, and Cuterebra sp. in rodents and nuisance
flies including blood feeding flies and filth flies.
[0123] The instant compounds are also useful against parasites
which infect humans. The most common genera of parasites of the
gastro-intestinal tract of man are Ancylostoma, Necator, Ascaris,
Strongyloides, Trichinella, Capillaria, Trichuris, and Enterobius.
Other medically important genera of parasites which are found in
the blood or other tissues and organs outside the gastrointestinal
tract are the filiarial worms such as Wuchereria, Brugia,
Onchocerca and Loa, Dracunuculus and extra intestinal stages of the
intestinal worms Strongyloides and Trichinella. The compounds are
also of value against arthropods parasitizing man, biting insects
and other dipterous pests causing annoyance to man.
[0124] The compounds are also active against household pests such
as the cockroach, Blatella sp., clothes moth, Tineola sp., carpet
beetle, Attagenus sp., the housefly Musca domestica as well as
fleas, house dust mites, termites and ants.
[0125] The compounds of this invention are also useful in
combatting agricultural pests that inflict damage upon crops while
they are growing or while in storage. The compounds are applied
using known techniques as sprays, dusts, emulsions and the like, to
the growing or stored crops to effect protection from such
agricultural pests.
[0126] The compounds are also useful against insect pests of stored
grains such as Tribolium sp., Tenebrio sp. and of agricultural
plants such as aphids, (Acyrthiosiphon sp.); against migratory
orthopterans such as locusts and immature stages of insects living
on plant tissue. The compounds are useful as a nematocide for the
control of soil nematodes and plant parasites such as Meloidogyne
sp. which may be of importance in agriculture. The compounds are
also highly useful in treating acreage infested with fire ant
nests. The compounds are scattered above the infested area in low
levels in bait formulations which are brought back to the nest. In
addition to a direct-but-slow onset toxic effect on the fire ants,
the compound has a long-term effect on the nest by sterilizing the
queen which effectively destroys the nest.
[0127] The compounds of this invention may be administered in
formulations wherein the active compound is intimately admixed with
one or more inert ingredients and optionally including one or more
additional active ingredients. The compounds may be used in any
composition known to those skilled in the art for administration to
humans and animals, for application to plants and for premise and
area application to control household pests in either a residential
or commercial setting. For application to humans and animals to
control internal and external parasites, oral formulations, in
solid or liquid or parenteral liquid, implant or depot injection
forms may be used. For topical application dip, spray, powder,
dust, pour-on, spot-on, jetting fluid, shampoos, collar, tag or
harness, may be used. For agricultural premise or area application,
liquid spray, powders, dust, or bait forms may be used. In addition
"feed-through" forms may be used to control nuisance flies that
feed or breed in animal waste. The compounds are formulated, such
as by encapsulation, to lease a residue of active agent in the
animal waste which controls filth flies or other arthropod
pests.
[0128] Accordingly, the present invention provides a method for the
treatment or prevention of diseases caused by parasites which
comprises administering to a host in need of such treatment or
prevention an antiparasitic effective amount of a compound of
Formula I. The parasites may be, for example, arthropod parasites
such as ticks, lice, fleas, mites and other biting arthropods in
domesticated animals and poultry. The parasites also include
helminths such as those mentioned above.
[0129] Compounds of formula I are effective in treatment of
parasitic diseases that occur in other animals including humans.
The optimum amount to be employed for best results will, of course,
depend upon the particular compound employed, the species of animal
to be treated and the type and severity of parasitic infection or
infestation. Generally good results are obtained with our novel
compounds by the oral administration of from about 0.001 to 500 mg
per kg of animal body weight, such total dose being given at one
time or in divided doses over a relatively short period of time
such as 1-5 days. With the preferred compounds of the invention,
excellent control of such parasites is obtained in animals by
administering from about 0.025 to 100 mg per kg of body weight in a
single dose. Repeat treatments are given as required to combat
re-infections and are dependent upon the species of parasite and
the husbandry techniques being employed. Repeat treatments may be
given daily, weekly, biweekly, monthly, or longer for example up to
six months, or any combination thereof, as required. The techniques
for administering these materials to animals are known to those
skilled in the veterinary field.
[0130] Compounds of formula I may be co-administered or used in
combination with one or more other agents to the host.
Co-administration or combination use includes administering all
active ingredients in one formulation, for example a tablet,
capsule, feed stuff, or liquid containing a compound of formula I
and one or more said other agents; administering each ingredient in
a separate formulation; and combinations thereof. When one or more
of a compound of formula I or said other agent(s) is contained in a
separate formulation, any order of administration as well as any
interval between the administration of the active ingredients are
within the meaning of co-administration or combination use.
[0131] Agents that may be co-administered or used in combination
with compounds of formula I include any that are used in the
treatment or prevention of human or animal diseases or conditions,
or used in agricultural applications, or for pest control. In a
preferred embodiment, the co-administered agents are used in
veterinary medicine, particularly those used in domesticated
animals such as dogs and cats or other companion animals. Examples
of other agents that may be co-administered with compounds of
formula I are provided below. It is to be understood that the
specific agents enumerated are illustrative only, and are not meant
to be restrictive in any manner.
[0132] Accordingly, compounds of the present invention may be co-
administered or used in combination with anthelmintic agents. These
anthelmintic agents are meant to include, but not be restricted to,
compounds selected from the avermectin and milbemycin class of
compounds such as ivermectin, avermectin, abamectin, emamectin,
eprinamectin, doramectin, milbemycin derivatives described in EPO
357460, EPO 444964 and EPO 594291, moxidectin, Interceptor.TM. and
nemadectin. Additional anthelmintic agents include the
benzimidazoles such as thiabendazole, cambendazole, parbendazole,
oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole,
albendazole, cyclobendazole, febantel, thiophanate and the like.
Additional anthelmintic agents include imidazothiazoles and
tetrahydropyrimidines such as tetramisole-levamisole, butamisole,
pyrantel, pamoate, oxantel or morantel.
[0133] Compounds of this invention may be co-administered or used
in combination with fipronil (FRONTLINE.TM.); or with an insect
growth regulator with molt inhibiting activity such as lufenuron
(PROGRAM.TM.) and the like; or with ecdysone agonists such as
tebufenozide and the like, which induces premature molt and causes
feeding to cease; or with imidacloprid (ADVANTAGE.TM.).
[0134] Compounds of this invention may be co-administered or used
in combination with avermectin or milbemycin or doramectin
derivatives such as those described in U.S. Pat. No. 5,015,630, WO
94/15944, WO 95/22552.
[0135] Compounds of this invention may be co-administered or used
in combination with cyclic depsipeptides that exhibit anthelmintic
efficacy such as those described in WO96/11945, WO93/19053, WO
93/25543, EP 626375, EP 382173, WO 94/19334, EP 382173 and EP
503538.
[0136] Compounds of this invention may be used in combination or be
co-administered with derivatives and analogs of the general class
of dioxomorpholine antiparasitic and anthelmintic agents as
illustrated by WO 9615121; or with pyrethroids or organophosphates
or insecticidal carbamates, such as those described in
"Chemotherapy of Parasitic Diseases", Campbell, W. C. and Rew, R.
S, Eds., 1986; or with derivatives and analogs of the general class
of paraherquamide and macfortine anthelmintic agents.
[0137] The co-administered compounds are given via routes, and in
doses, that are customarily used for those compounds.
[0138] Compounds of formula I may be administered orally in a unit
dosage form such as a capsule, bolus or tablet including chewable
tablet, or as a liquid drench where used as an anthelmintic in
mammals. The drench is normally a solution, suspension or
dispersion of the active ingredient usually in water together with
a suspending agent such as bentonite and a wetting agent or like
excipient. Generally, the drenches also contain an antifoaming
agent. Drench formulations generally contain from about 0.001 to
0.5% by weight of the active compound. Preferred drench
formulations may contain from 0.01 to 0.1% by weight. The capsules
and boluses comprise the active ingredient admixed with a carrier
vehicle such as starch, talc, magnesium stearate, or di-calcium
phosphate.
[0139] Where it is desired to administer the instant compounds in a
dry, solid unit dosage form, capsules, boluses or tablets
containing the desired amount of active compound usually are
employed. These dosage forms are prepared by intimately and
uniformly mixing the active ingredient with suitable finely divided
diluents, fillers, disintegrating agents, and/or binders such as
starch, lactose, talc, magnesium stearate, vegetable gums and the
like. Such unit dosage formulations may be varied widely with
respect to their total weight and content of the antiparasitic
agent depending upon factors such as the type of host animal to be
treated, the severity and type of infection and the weight of the
host.
[0140] When the active compound is to be administered via an animal
feedstuff, it is intimately dispersed in the feed or used as a top
dressing or in the form of pellets or liquid which may then be
added to the finished feed or optionally fed separately.
Alternatively, feed based individual dosage forms may be used such
as a chewable treat. Alternatively, the antiparasitic compounds of
this invention may be administered to animals parenterally, for
example, by intraruminal, intramuscular, intravascular,
intratracheal, or subcutaneous injection in which the active
ingredient is dissolved or dispersed in a liquid carrier vehicle.
For parenteral administration, the active material is suitably
admixed with an acceptable vehicle, preferably of the vegetable oil
variety such as peanut oil, cotton seed oil and the like. Other
parenteral vehicles such as organic preparation using solketal,
glycerol formal, propylene glycol, and aqueous parenteral
formulations are also used. The active compound or compounds are
dissolved or suspended in the parenteral formulation for
administration; such formulations generally contain from 0.0005 to
5% by weight of the active compound.
[0141] When the compounds described herein are administered as a
component of the feed of the animals, or dissolved or suspended in
the drinking water, compositions are provided in which the active
compound or compounds are intimately dispersed in an inert carrier
or diluent. By inert carrier is meant one that will not react with
the antiparasitic agent and one that may be administered safely to
animals. Preferably, a carrier for feed administration is one that
is, or may be, an ingredient of the animal ration.
[0142] Suitable compositions include feed premixes or supplements
in which the active ingredient is present in relatively large
amounts and which are suitable for direct feeding to the animal or
for addition to the feed either directly or after an intermediate
dilution or blending step. Typical carriers or diluents suitable
for such compositions include, for example, distillers' dried
grains, corn meal, citrus meal, fermentation residues, ground
oyster shells, wheat shorts, molasses solubles, corn cob meal,
edible bean mill feed, soya grits, crushed limestone and the like.
The active compounds are intimately dispersed throughout the
carrier by methods such as grinding, stirring, milling or tumbling.
Compositions containing from about 0.005 to 50% weight of the
active compound are particularly suitable as feed premixes. Feed
supplements, which are fed directly to the animal, contain from
about 0.0002 to 0.3% by weight of the active compounds.
[0143] Such supplements are added to the animal feed in an amount
to give the finished feed the concentration of active compound
desired for the treatment and control of parasitic diseases.
Although the desired concentration of active compound will vary
depending upon the factors previously mentioned as well as upon the
particular compound employed, the compounds of this invention are
usually fed at concentrations of between 0.00001 to 10% in the feed
in order to achieve the desired anti-parasitic result.
[0144] In using the compounds of this invention, the individual
compounds may be prepared and used in that form. Alternatively,
mixtures of the individual compounds may be used, or they may be
combined with other active compounds not related to the compounds
of this invention.
[0145] Also included in the present invention are pharmaceutical
compositions comprising a compound of formula I and a
pharmaceutically acceptable carrier. The pharmaceutical
compositions of the present invention may further comprise a second
active ingredient such as those described above for
co-administration. Preferred second ingredient is selected from an
anthelmintic agent, fipronil, imidocloprid, an insect growth
regulator, or a ecdysone agonist. Said second ingredient is
preferably selected from the group consisting of: ivermectin,
avermectin 5-oxime, abamectin, emamectin, eprinamectin, doramectin,
doramectin monosaccharide 5-oximes, fulladectin, milbemycin,
milbemycin 5-oxime, moxidectin, Interceptor.TM., nemadectin,
imidacloprid, fipronil, lufenuron, thiabendazole, cambendazole,
parbendazole, oxibendazole, mebendazole, flubendazole,
fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel,
thiophanate, tetramisole-levamisole, butamisole, pyrantel, pamoate,
oxantel and morantel.
[0146] The following examples are provided to more fully illustrate
the present invention, and shall not be construed as limiting the
scope in any manner.
REFERENCE EXAMPLE 1
[0147] 15
[0148] (a) Synthesis from nodulisporic acid:
[0149] To KMnO.sub.4 (3 g) at 25.degree. C. was added water (5 mL).
The KMnO.sub.4 solution was cooled to 0.degree. C. and
Al.sub.2O.sub.3 (weakly acidic, 10.8 g) was added and stirred for 5
min until thoroughly mixed. A solution of nodulisporic acid (3 g)
in CH.sub.2Cl.sub.2 (300 mL) was added dropwise via an addition
funnel over 20 min. The solution was aged for an additional 20 min
at 0.degree. C. then at 25.degree. C. for 90 min. The solution was
filtered through a 3 inch pad of Celite using CH.sub.2Cl.sub.2 as
eluant followed by EtOAc. The solvents were removed under reduced
pressure at ambient temperature to yield pure title compound (2.234
g, 82%) without any additional purification.
[0150] (b) Synthesis from t-butyl nodulisporamide
[0151] To N-tert-butyl nodulisporamide (50 mg) in CH.sub.2Cl.sub.2
(2 mL) at 25.degree. C. was added N-methylmorpholine N-oxide (50
mg) followed by 0.024 M OSO.sub.4 in water (0.31 mL). After aging
the solution for 16 hr, TLC showed the presence of the desired
compound and the R,R- and S,S- 31,32-diols of N-tert-butyl
nodulisporamide A. The title compound (10.5 mg) and the diols (36
mg) were isolated in pure form by PTLC on silica gel using 2:1
EtOAc:hexanes as eluant. The R,R- and S,S-diols were combined. To a
mixture of diols (10 mg) in acetone (0.9 mL) at 25.degree. C. was
added NaIO.sub.4 (25 mg) and the solution was allowed to age for 12
h. The solution was poured into saturated aqueous NaHCO.sub.3,
extracted with EtOAc and dried (Na.sub.2SO.sub.4). Pure title
compound (7 mg) was obtained following PTLC on silica gel using 1/1
hexanes/EtOAc as eluant.
REFERENCE EXAMPLE 2
[0152] 16
[0153] To the compound of Reference Example 1 (560 mg) in
acetonitrile (10 mL) at 25.degree. C. was added
(Me.sub.3Si).sub.2NH (1.8 mL) and the the solution was aged for 12
h. Additional (Me.sub.3Si).sub.2NH (1.5 mL) and acetonitrile (3 mL)
were then added. After 3 h, the solvent was removed under reduced
pressure and the residue dried in vacuo for 1 h to yield pure title
compound (870 mg, 100%) which required no purification. The product
was characterized by proton NMR.
REFERENCE EXAMPLE 3
[0154] 17
[0155] The compound of Reference Example 2 (10 mg, 0.013 mmol) was
dissolved in EtOAc (1 mL), treated with a catalytic amount of 10%
Pd--C and the system vacuum-purged with hydrogen. The mixture was
stirred vigorously under one atmosphere of hydrogen at 23.degree.
C. for 4 h. The mixture was then filtered through a bed of celite,
washed with EtOAc and the filtrate concentrated in vacuo. The
product was purified (PTLC, 500 micron SiO.sub.2, 20.times.20 cm,
20% acetone-hexane) to provide the title compound V (4 mg, 40%)
characterized by .sup.1H NMR.
REFERENCE EXAMPLE 4
[0156] 18
[0157] Step 1. To the compound of Reference Example 1 (750 mg) in
pyridine/DMF (30 mL, 1/1) at room temperature was added
Et.sub.3SiOSO.sub.2CF.sub.3 (3.2 g) and aged for 20 min. The
solution was diluted with ethyl acetate, washed with saturated
CuSO.sub.4(aq) (4.times.), water (1.times.), brine (1.times.), and
dried (Na.sub.2SO.sub.4). The solution was filtered, concentrated
under reduced pressure and pure product was obtained following
flash chromatography on silica gel using 7/93 acetone/hexanes as
eluant to provide the bis-triethylsilyl protected compound of
Reference Example 1.
[0158] Step 2. Method A
[0159] To the product of Step 1 (1 g) in tBuOH (25 mL) at
25.degree. C. was added 2-methyl-2-butene (6 mL) and stirred for 5
min. A solution of NaClO.sub.2 (954 mg) and
NaH.sub.2PO.sub.4.multidot.2H.sub.2O (1.28 g) in water (10 mL) was
then added. After 4 h, the solution was poured into saturated
NH.sub.4Cl(aq), extracted with CH.sub.2Cl.sub.2 (3.times.) and
dried (Na.sub.2SO.sub.4). The solution was filtered and
concentrated to dryness under reduced pressure. Pure title compound
(725 mg) was obtained following flash chromatography on silica gel
using gradient elution (5%.fwdarw.25% EtOAc in hexanes).
[0160] Method B
[0161] A solution of KMnO.sub.4 (1.3 g) in acetone (64 mL) and pH 7
phosphate buffer (21 mL) was prepared. To the product of Step 1
(3.63 g) in acetone (64 mL) was added the KMnO.sub.4/buffer
solution (.about.20 mL) and the solution was aged for 30 min.
Additional KMnO.sub.4 solution (.about.20 mL) was added every 30
min for 2 h. The solution was then cooled to 0.degree. C. and 1M
Na.sub.2SO.sub.3 was added until all of the KMnO.sub.4 was reacted.
The mixture was filtered and washed with 15/85 MeOH/acetone
(2.times.). The filtrate was concentrated under reduced pressure to
dryness and redissolved in water. The aqueous solution was
extracted with 3/7 iPrOH/CHCl.sub.3 (3.times.) and the organic
layers were dried (Na.sub.2SO.sub.4). The solids were removed by
filtration and the solution was evaporated to drynesss under
reduced pressure. Pure title product (1.29 g) along with recovered
starting aldehyde (.about.1.3 g) was obtained following flash
chromatography on silica gel using 2/8 EtOAc/hexanes as eluant.
REFERENCE EXAMPLE 5
[0162] 19
[0163] The compound of Reference Example 4 (150 mg, 0.173 mmol) was
dissolved in dry CH.sub.2Cl.sub.2 (3.5 mL) and treated with
triethylamine (0.075 mL, 0.519 mmol) followed by DPPA (0.057 mL,
0.260 mmol). The reaction mixture was maintained at 23.degree. C.
for 14 h, concentrated in vacuo and purified (PTLC, 1500 micron
SiO.sub.2, 20.times.20 cm, 2 plates, 10% acetone-hexane) to provide
the intermediate acyl azide (150 mg, 97%). This material (150 mg,
0.168 mmol) was immediately dissolved in dry toluene (3.4 mL) under
nitrogen and heated at 80.degree. C. for 2 h. The mixture was
cooled, concentrated in vacuo and vacuum pumped to dryness to
provide the title compound XVIII (140 mg, 96%) characterized by
.sup.1H NMR.
REFERENCE EXAMPLE 6
[0164] 20
[0165] The compound of Reference Example 5 (140 mg, 0.162 mmol) was
dissolved in 9:1 dioxane:H.sub.2O (8 mL) and treated with 50% PPTS
(20 mg, 0.081 mmol). The reaction mixture was aged at 23.degree. C.
for 4 h, partitioned between saturated NaHCO3(aq) and
CH.sub.2Cl.sub.2, the organic phase dried over sodium sulfate and
concentrated in vacuo. The product was purified by centrifugal thin
layer chromatography (chromatotron, 2 mm SiO.sub.2, hexane to 20%
EtOAc-hexane gradient elution) to provide the title compound (70
mg, 52%) characterized by .sup.1H NMR.
REFERENCE EXAMPLE 7
[0166] 21
[0167] The compound of Reference Example 6 (6 mg, 0.007 mmol) was
dissolved in dry toluene (0.4 mL) and treated with the stabilized
ylide Ph.sub.3PCHCOCH.sub.3 (9 mg, 0.028 mmol). The reaction
mixture was maintained at 80.degree. C. for 20 h, concentrated in
vacuo and purified (PTLC, 250 micron SiO.sub.2, 20.times.20 cm, 10%
EtOAc-hexane) to provide the title compound (3 mg, 50%)
characterized by .sup.1H NMR.
EXAMPLE 1
[0168] 22
[0169] Method A
[0170] The compound of Reference Example 1 (1.2 g, 1.93 mmol) was
dissolved in EtOAc (100 mL), treated with a catalytic amount of 10%
Pd--C, and the system vacuum-purged with hydrogen. The mixture was
stirred vigorously under one atmosphere of hydrogen at 23.degree.
C. for 5 h. The mixture was then filtered through a bed of celite,
washed with EtOAc, and the filtrate concentrated in vacuo. The
product was purified by flash chromatography (Biotage 40M,
SiO.sub.2, hexane to 30% EtOAc-hexane gradient elution) to provide
the title compound (890 mg, 74%) characterized by .sup.1H NMR, HPLC
and mass spectrometry (m/z: 626 (M.sup.++1)).
[0171] Method B
[0172] Compound of Reference Example 3 (4 mg, 0.005 mmol) was
suspended in THF (0.5 mL), treated with PPTS (2.5 mg, 0.0104 mmol)
and the turbid mixture stirred vigorously at 23.degree. C. for 14 h
to provide after purification (PTLC, 500 micron SiO.sub.2,
20.times.10 cm, 30% acetone-hexane) the title compound
characterized by .sup.1H NMR.
EXAMPLE 2
[0173] 23
[0174] The compound of Example 1 (400 mg, 0.640 mmol) was dissolved
in anhydrous MeOH (64 mL), treated with PPTS (321 mg, 1.28 mmol),
and the reaction mixture was aged at 23.degree. C. for 3 h. The
mixture was then concentrated in vacuo and purified by flash
chromatography (Biotage 40M, SiO.sub.2, hexane to 50% EtOAc-hexane
gradient elution) to provide the title compound (325 mg, 80%)
characterized by 1H NMR, HPLC and mass spectrometry (m/z: 640
(M.sup.++1)).
EXAMPLES 3-24
[0175] The following acetals were prepared under conditions similar
to those described in Example 2 using 50 molar equivalents of a
given alcohol in either anhydrous THF or DMF solvent at a
concentration of 0.01 M. The ethyl acetal in Example 3 was obtained
from a reaction mixture conducted in neat ethanol. The following
acetals were characterized by .sup.1H NMR, HPLC and mass
spectrometry.
2 24 Mass Spectrum EXAMPLE R Group Stereochemistry (m/z) 3
--CH.sub.2CH.sub.3 .alpha. 654 (M.sup.+ + 1) 4
--CH.sub.2CH.sub.2CH.sub.3 .alpha. 668 (M.sup.+ + 1) 5
--CH.sub.2CH.sub.2CH.sub.3 .beta. 668 (M.sup.+ + 1) 6
--CH(CH.sub.3).sub.2 .alpha. 668 (M.sup.+ + 1) 7
--CH(CH.sub.3).sub.2 .beta. 668 (M.sup.+ + 1) 8 --C(CH.sub.3).sub.3
.alpha. 682 (M.sup.+ + 1) 9 --CH.sub.2CH.dbd.CH.sub.2 .alpha. 666
(M.sup.+ + 1) 10 --CH.sub.2CH.dbd.CH.sub.2 .beta. 666 (M.sup.+ + 1)
11 --(CH.sub.2).sub.6CO.sub.2CH.sub.3 .alpha. 768 (M.sup.+ + 1) 12
--CH.sub.2Ph .alpha. 716 (M.sup.+ + 1) 13 25 .alpha.*(S) 723
(M.sup.+ + 1) 14 26 .alpha.*(R) 723 (M.sup.+ + 1) 15
--(CH.sub.2).sub.2N(H)COCH.sub.3 .alpha. 711 (M.sup.+ + 1) 16
--(CH.sub.2)CH(CH.sub.3)*COCH.sub.3 .alpha.*(R/S) 710 (M.sup.+ + 1)
17 27 .alpha. 737 (M.sup.+ + 1) 18 28 .alpha. 751 (M.sup.+ + 1) 19
29 .beta. 768 (M.sup.+ + NH.sub.4) 20 --(CH.sub.2).sub.2CN .alpha.
679 (M.sup.+ + 1) 21 30 .alpha. 706 (M.sup.+ + 1) 22 31 .alpha. 706
(M.sup.+ + 1) 23 32 .alpha. 751 (M.sup.+ + 1) 24
--(CH.sub.2).sub.2OCOC(CH.sub.3).dbd.CH.sub.2 .alpha. 738 (M.sup.+
+ 1) EXAMPLE 25 33
[0176] In a three-neck round bottom flask, the compound of Example
1 (20 mg, 0.032 mmol) was dissolved in anhydrous CH.sub.2Cl.sub.2
(0.5 ML), then treated with ethanethiol (0.5 mL), followed by PPTS
(32 mg, 0.128 mmol) and the reaction mixture was aged at 23.degree.
C. for 12 h. One of the flask necks was fitted with a nitrogen
inlet tube, and another neck was fitted with an outlet tube that
was submerged in aqueous bleach. After the volatiles were removed
via nitrogen purging, the remaining residue was purified (PTLC, 500
micron SiO.sub.2, 20.times.20 cm, 20% acetone-hexane) to provide
the title compound (15 mg, 70%) characterized by .sup.1H NMR, HPLC
and mass spectrometry (m/z: 670 (M.sup.++1)).
EXAMPLES 26-28
[0177] Using reaction conditions similar to those described in
Example 25, the following thioacetals were prepared employing a
modified work-up procedure. The crude reaction mixtures were first
eluted through a short plug of SiO.sub.2 and washed with hexane to
remove excess thiol. Following product elution with acetone, the
eluent was concentrated, and the residue was purified as described
in Example 25.
3 34 EXAMPLE R Group MS (m/z) 26 --(CH.sub.2).sub.2N(H)COCH.sub.3
727 (M.sup.+ + 1) 27 --Ph 718 (M.sup.+ + 1) 28 --Ph(2-OMe) 748
(M.sup.+ + 1)
[0178] 35
[0179] The compound of Example 1 (500 mg, 0.800 mmol) and NMO (281
mg, 2.40 mmol) were dissolved in anhydrous CH.sub.2Cl.sub.2 (40 mL)
and treated with activated powdered molecular sieves. Under an
atmosphere of nitrogen, the reaction mixture was cooled to
0.degree. C. and treated with TPAP (28 mg, 0.080 mmol). The
reaction mixture was stirred at 0.degree. C. for 2.5 h and then
quenched with 20 mL of 10% NaHSO.sub.3(aq). The mixture was then
filtered through celite, partitioned between CH.sub.2Cl.sub.2 and
brine, the organic phase dried over sodium sulfate and concentrated
in vacuo to provide the title compound (500 mg, 100%) characterized
by .sup.1H NMR, HPLC and mass spectrometry (m/z: 624 (M.sup.++1)).
36
[0180] The compound of Example 1 (430 mg, 0.688 mmol) was dissolved
in anhydrous CH.sub.2Cl.sub.2 (7 mL) and treated with
diisopropylethylamine (0.38 mL, 2.06 mmol) and thiocarbonyl
diimidazole (184 mg, 1.03 mmol) at 0.degree. C. under an atmosphere
of nitrogen. The reaction mixture was stirred at 0.degree. C. for
14 h and then concentrated in vacuo to provide a residue which was
purified by centrifugal thin layer chromatography (chromatotron, 4
mm SiO.sub.2, hexane to EtOAc gradient elution). The title compound
(111 mg, 27%) was characterized by .sup.1H NMR, HPLC and mass
spectrometry (m/z: 590 (M.sup.++1-H.sub.2O)). 37
[0181] The compound of Example 30 (9 mg, 0.015 mmol) was dissolved
in EtOAc (1 mL), treated with a catalytic amount of 10% Pd--C and
the system vacuum-purged with hydrogen. The mixture was stirred
vigorously under one atmosphere of hydrogen at 23.degree. C. for 25
min. The mixture was then filtered through a bed of celite, washed
with EtOAc and the filtrate concentrated in vacuo. The product was
purified (PTLC, 250 micron SiO.sub.2, 20.times.20 cm, 40%
EtOAc-hexane) to provide the title compound (9 mg, 100%)
characterized by .sup.1H NMR, HPLC and mass spectrometry (m/z: 610
(M.sup.++1)).
EXAMPLE 32
[0182] 38
[0183] Step 1. The compound of Example 29 (500 mg, 0.800) was
dissolved in anhydrous CH.sub.3CN (15 mL) and treated with HMDS
(0.85 mL, 4.00 mmol) under nitrogen at 23.degree. C. The reaction
mixture was maintained for 1 h, concentrated in vacuo and purified
by centrifugal thin layer chromatography (chromatotron, 4 mm
SiO.sub.2, hexane to 60% EtOAc-hexane gradient elution) to provide
the intermediate 4-O-TMS of the compound of Example 29 (420 mg,
76%) characterized by .sup.1H NMR.
[0184] Step 2. The product of Step 1 (30 mg, 0.0432 mmol) was
dissolved in anhydrous THF (0.87 mL) and treated with
dimethyltitanocene (0.26 mL, 1M in toluene). The reaction mixture
was bubbled with nitrogen to remove residual oxygen, and the
mixture was then heated at 70.degree. C. for 4 h. The mixture was
cooled and concentrated in vacuo to a residue which was
subsequently purified (PTLC, 500 micron SiO.sub.2, 20.times.20 cm,
20% acetone-hexane) to provide intermediate (4-O-TMS
30,31-unsaturated title compound, 10 mg, 40%) characterized by
.sup.1H NMR.
[0185] Step 3. The product of step 2 (10 mg, 0.014 mmol) was
dissolved in EtOAc (1.4 mL), treated with a catalytic amount of 10%
Pd--C and the system vacuum-purged with hydrogen. The mixture was
stirred vigorously under one atmosphere of hydrogen at 23.degree.
C. for 5.5 h. The mixture was then filtered through a bed of
celite, washed with CH.sub.2Cl.sub.2 and the filtrate concentrated
in vacuo. The residue was purified (PTLC, 250 micron SiO.sub.2,
20.times.20 cm, 20% acetone-hexane) to provide one isomeric product
(5 mg, 50%) which was dissolved in EtOH (1 mL) and treated with
excess PPTS at 23.degree. C. for 10 min. The reaction mixture was
concentrated in vacuo and purified (PTLC, 250 micron SiO.sub.2,
20.times.10 cm, 15% ethyl acetate-hexane, developed 4.times.) to
provide the title compound (2 mg, 50%) which was characterized by
.sup.1H NMR, HPLC and mass spectrometry (m/z: 624 (M.sup.++1)).
EXAMPLE 33
[0186] 39
[0187] Step 1. The product of Step 1, Example 32 (90 mg, 0.130
mmol) was dissolved in dry THF (0.4 mL), cooled to -78.degree. C.
under nitrogen and treated with KHMDS (0.44 mL, 0.5 M toluene). The
mixture was aged for 20 min and then treated with a solution of
(PhO).sub.2POCl (0.21 mL, 1.04 mmol) in THF (0.4 mL). The mixture
was aged at -78.degree. C. for 1 h with monitoring by TLC
(Et.sub.3N vapor pre-treated SiO.sub.2, 20% EtOAc-hexane eluent).
The mixture was reverse quenched from -78.degree. C. into a
0.degree. C. solution of 1:10 NH.sub.4OH:H.sub.2O (1.5 mL) and
maintained 10 min. This solution was then partitioned at 23.degree.
C. between 1% Et.sub.3N-CH.sub.2Cl.sub.2 and brine. The organic
phase was separated, dried over sodium sulfate and concentrated to
a turbid solution. This solution was treated with excess Et.sub.2O,
filtered through celite to remove the precipitate, and the filtrate
was concentrated to an oily solid. The residue was purified by
dilution into a slurry with 1% Et.sub.3N-hexane followed by flash
column chromatography of this slurry using hexane as eluent
(3.times.12 cm, SiO.sub.2 pre-treated with 1% Et.sub.3N-hexane) to
provide the intermediate shown below (80 mg, 67%) characterized by
.sup.1H NMR. 40
[0188] Step 2. The product of Step 1 (25 mg, 0.027 mmol) was then
tared with LiCl (5 mg, 0.119 mmol), diluted under nitrogen with dry
THF (0.5 mL), and then treated sequentially with vinyltributyltin
(0.05 mL, 0.158 mmol) and (Ph.sub.3P).sub.4Pd (10 mg, 0.009 mmol).
The mixture was heated at 65.degree. C. for 12 h under TLC control
(SiO.sub.2, 30% EtOAc-hexane), cooled to 23.degree. C., partitioned
between saturated NaHCO.sub.3(aq) and CH.sub.2Cl.sub.2, and the
organic phase dried over sodium sulfate and concentrated in vacuo.
The product was purified (PTLC, SiO.sub.2, 1000 micron, 20.times.20
cm, 20% EtOAc-hexane) to give trimethylsilyl-protected title
compound (4.5 mg, 25%) characterized by .sup.1H NMR.
[0189] Step 3. The product of Step 2 (2 mg, 0.003 mmol) was
desilylated by treatment with PPTS (1 mg, 0.004 mmol) in EtOH (0.5
mL), and the reaction mixture was aged at 23.degree. C. for 15 min
after which the mixture was concentrated in vacuo and purified
(PTLC, SiO.sub.2, 250 micron, 20.times.10 cm, 20% acetone-hexane)
to give the product alcohol shown above (1 mg, 55%) characterized
by .sup.1H NMR, HPLC and mass spectrometry (m/z: 616
(M.sup.++1-H.sub.2O)).
EXAMPLES 34
[0190] 41
[0191] The title compound was obtained using identical reaction
conditions to those described in Example 33, using 5 molar
equivalents of tributyltin-2-thiophene in the palladium coupling
reaction. The product was characterized by 1H NMR, HPLC and mass
spectrometry (m/z: 690 (M.sup.++1)).
EXAMPLE 35
[0192] 42
[0193] The title compound was prepared using identical reaction
conditions to those described in Example 33 using 5 molar
equivalents of tributyltin-2-furan in the palladium coupling
reaction, with the exception that prior to the final desilylation,
the product of step 2 was hydrogenated under conditions similar to
those described in Example 32, step 3. The final product was
purified (PTLC, 250 micron SiO.sub.2, 20.times.10 cm, 20%
acetone-hexane) to provide the title compound characterized by
.sup.1H NMR. 43 44
[0194] The product of Step 2, Example 33 (4 mg, 0.006 mmol) was
dissolved in EtOAc (1 mL), treated with a catalytic amount of 10%
Pd--C and the system vacuum-purged with hydrogen. The mixture was
stirred vigorously under 1 atmosphere of hydrogen at 23.degree. C.
for 6 h. The mixture was then filtered through a bed of celite,
washed with EtOAc and the filtrate concentrated in vacuo. The
residue was dissolved in EtOH (0.5 mL) and treated with excess PPTS
at 23.degree. C. for 15 min. The reaction mixture was concentrated
in vacuo and purified (PTLC, 250 micron SiO.sub.2, 20.times.10 cm,
20% acetone-hexane) to provide Example 36 shown above as the less
polar product (2 mg, 52%) and Example 37 shown above as the more
polar product (1 mg, 25%). Both compounds were characterized by
.sup.1H NMR, HPLC and mass spectrometry (Example 36 m/z: 636
(M.sup.++1)) and (Example 37 m/z: 654 (M.sup.++1)).
EXAMPLE 38
[0195] 45
[0196] The compound of Reference Example 5 (17 mg, 0.020 mmol) was
dissolved in 9:1 dioxane:H.sub.2O (1 mL) to which was added PPTS
(25 mg, 0.098 mmol) followed by TsOH (4 mg, 0. 020 mmol). The
reaction mixture was maintained at 23.degree. C. for 14 h,
concentrated in vacuo and purified immediately (PTLC, 500 micron
SiO.sub.2, 20.times.20 cm, 30% acetone-hexane) to provide the title
compound (7 mg, 60%) characterized by .sup.1H NMR, HPLC and mass
spectrometry (m/z: 612 (M.sup.++1)).
EXAMPLE 39
[0197] 46
[0198] The title compound was prepared from the compound of Example
38 using similar reaction conditions to those described in Example
2. The product was purified (PTLC, 250 micron SiO.sub.2,
20.times.10 cm, 30% acetone-hexane) to provide the title compound
(5 mg, 70%) which was characterized by 1H NMR, HPLC and mass
spectrometry (m/z: 626 (M.sup.++1)).
EXAMPLE 40
[0199] 47
[0200] The compound of Example 38 (7 mg, 0.012 mmol) was dissolved
in dry THF (0.4 mL) and treated with racemic
3-methyl-4-hydroxy-2-butanone (0.2 mL) and PPTS (15 mg, 0.057
mmol). The reaction mixture was aged at 23.degree. C. for 1 h and
then 0.degree. C. for 48 h. The reaction mixture was concentrated
to an oil and subjected to reverse phase flash column
chromatography (C-18 SiO.sub.2, 1.5.times.4 cm, H.sub.2O to
acetonitrile gradient elution) to provide semi-pure product. This
material was then further purified (PTLC, 250 micron SiO.sub.2,
20.times.20 cm, 20% acetone-hexane) to provide the title compound
(5 mg, 63%) characterized by .sup.1H NMR, HPLC and mass
spectrometry (m/z: 696 (M.sup.++1)).
EXAMPLE 41
[0201] 48
[0202] The compound of Reference Example 7 (3 mg, 0.003 mmol) was
dissolved in EtOH (0.3 mL) and treated with PPTS (1 mg, 0.004
mmol). The reaction mixture was aged at 23.degree. C. for 16 h,
concentrated in vacuo and purified (PTLC, 250 micron SiO.sub.2,
20.times.10 cm, 40% acetone-hexane) to provide the title compound
(1 mg, 51%) characterized by .sup.1H NMR, HPLC and mass
spectrometry (m/z: 652 (M.sup.++1)).
* * * * *