U.S. patent application number 09/747578 was filed with the patent office on 2002-09-12 for 14-membered macrolides derived from leucomycins.
Invention is credited to Binet, Sophie, Lazarova, Tsvetelina, Or, Yat Sun, Wang, Jianchao.
Application Number | 20020128212 09/747578 |
Document ID | / |
Family ID | 25005701 |
Filed Date | 2002-09-12 |
United States Patent
Application |
20020128212 |
Kind Code |
A1 |
Or, Yat Sun ; et
al. |
September 12, 2002 |
14-membered macrolides derived from leucomycins
Abstract
There is described a novel class of ring contracted 14-membered
macrolides, and pharmaceutically acceptable salts, esters and
prodrugs thereof, having antibacterial activity, compositions
comprising a therapeutically effective amount of a compound of the
invention in combination with a pharmaceutically acceptable carrier
as well as a method for treating bacterial infections by
administering to a mammal a pharmaceutical composition containing a
therapeutically effective amount of a compound of the invention.
There are also described synthetic processes for preparing the
compounds of the invention
Inventors: |
Or, Yat Sun; (Cambridge,
MA) ; Lazarova, Tsvetelina; (Brookline, MA) ;
Binet, Sophie; (Roslindale, MA) ; Wang, Jianchao;
(Castro Valley, CA) |
Correspondence
Address: |
Sandhya L Kalkunte
Enanta Pharmaceuticals Inc
500 Arsenal Street
Watertown
MA
02472
US
|
Family ID: |
25005701 |
Appl. No.: |
09/747578 |
Filed: |
December 22, 2000 |
Current U.S.
Class: |
514/29 ; 536/7.2;
536/7.4 |
Current CPC
Class: |
C07H 17/08 20130101;
A61P 31/04 20180101 |
Class at
Publication: |
514/29 ; 536/7.2;
536/7.4 |
International
Class: |
A61K 031/7048; C07H
017/08 |
Claims
What is claimed is:
1. A compound represented by the Formula: 6or a pharmaceutically
acceptable salt, ester and prodrug thereof, wherein A is: (1) CHO;
(2) CH2-X, where X is selected from the group consisting of a.
hydroxy or protected hydroxy, b. halogen, c. NR7R8 wherein R7 and
R8 are each independently selected from hydrogen and C1-C6-alkyl
optionally substituted with aryl, or heterocyclic groups; or R7 and
R8 taken together with the nitrogen atom to which they are
connected form a 3- to 7-membered ring which, may optionally
contain a hetero function selected from the group consisting
of--O--, --NH--, --N(C1-C6-alkyl)--, --N(aryl)--,
--N(heteroaryl)--, --S--, --S(O)-- and --S(O)2--, d. NR7C(O)--R9,
where R7 is as previously defined and R9 is selected from the group
consisting of i. C1-C6-alkyl optionally substituted with aryl,
substituted aryl, heterocyclic or substituted heterocyclic, ii.
aryl, iii. substituted aryl, iv. heterocyclic, and v. substituted
heterocyclic, e. S(O).sub.n--(C1-C6-alkyl) optionally substituted
with aryl or a heterocyclic group where n=0, 1 or 2, f.
S(O).sub.n--( aryl or heterocyclic group) where n=0, 1 or 2, and g.
O--( aryl or heterocyclic group); (3) an aldehyde protecting group
(4) substituted or unsubstituted imidazole, arylimidazole or
heteroarylimidazole (5) substituted or unsubstituted oxazole,
aryloxazole or heteroaryloxazole (6) substituted or unsubstituted
thioxazole, arylthioxazole or heteroarylthioxazole (7) substituted
or unsubstituted imidazoline, arylimidazoline or
heteroarylimidazoline (8) substituted or unsubstituted oxazoline,
aryloxazoline or heteroaryloxazoline (9) substituted or
unsubstituted thioxazoline, arylthioxazoline or
heteroarylthioxazoline. R1 and R2 are each independently selected
from the group consisting of (1) hydrogen, (2) hydroxy, (3)
protected hydroxy, (4) OC(O)--C1-C12 alkyl, optionally substituted
with aryl, substituted aryl, heterocyclic, substituted
heterocyclic, (5) O--R7 where R7 is as previously defined, (6)
halogen, and (7) R1 and R2 taken together are oxo; R3, R4 and R5
are each independently selected from the group consisting of (1)
hydrogen, (2) a hydroxy protecting group, and (3) C(O)--C1-C12
alkyl, optionally substituted with aryl, substituted aryl,
heterocyclic, substituted heterocyclic, O--R7 or NR7R8 where R7 and
NR7R8 are as previously defined; and R.sup.p is hydrogen or a
hydroxy protecting group.
2. A compound according to claim 1 which is represented by Formula
II.
3. A compound according to claim 1 which is represented by Formula
III.
4. A compound according to claim 1 which is selected from the group
consisting of: Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H;
Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH, R2.dbd.H,
R3.dbd.H, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of
Formula II wherein A.dbd.CHO, R1.dbd.OH, R2.dbd.H, R3.dbd.H,
R4.dbd.C(O)CH2CH2CH3, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CHO, R1.dbd.OH, R2.dbd.H, R3.dbd.H,
R4.dbd.C(O)CH2CH3, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula II
wherein A.dbd.CHO, R1.dbd.OH, R2.dbd.H, R3.dbd.H, R4.dbd.C(O)CH3,
R5.dbd.H, R.sup.p.dbd.H; Compound of Formula II wherein A.dbd.CHO,
R1.dbd.OH, R2.dbd.H, R3.dbd.H, R4.dbd.H, R5.dbd.H, R.sup.p.dbd.H;
Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH, R2.dbd.H,
R3.dbd.C(O)CH3, R4.dbd.C(O)CH2CH2CH3, R5.dbd.H, R.sup.p.dbd.H;
Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH, R2.dbd.H,
R3.dbd.C(O)CH3, R4.dbd.C(O)CH2CH3, R5.dbd.H, R.sup.p.dbd.H;
Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH, R2.dbd.H,
R3.dbd.C(O)CH3, R4.dbd.C(O)CH3, R5.dbd.H, R.sup.p.dbd.H; Compound
of Formula II wherein A.dbd.CHO, R1.dbd.OH, R2.dbd.H,
R3.dbd.C(O)CH3, R4.dbd.H, R5.dbd.H, R.sup.p.dbd.H; Compound of
Formula II wherein A.dbd.CHO, R1.dbd.OAc, R2.dbd.H,
R3.dbd.C(O)CH2CH3 R4.dbd.C(O)CH2CH2CH3, R5.dbd.Ac, R.sup.p.dbd.H;
Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH, R2.dbd.H,
R3.dbd.H, R4.dbd.C(O)CH2CH3, R5.dbd.C(O)CH2CH3, R.sup.p.dbd.H;
Compound of Formula II wherein A.dbd.CH2Br, R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound
of Formula II wherein A.dbd.CH2F, R1.dbd.OH, R2.dbd.H, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CH2NMe(Bn), R1.dbd.OH, R2.dbd.H, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CH(OMe)2, R1.dbd.OH, R2.dbd.H, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CH2OH, R1.dbd.OBn, R2.dbd.H, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CHNOPh, R1.dbd.OH, R2.dbd.H, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CHNOCH2CH3, R1.dbd.OH, R2.dbd.H, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CHNOCH3, R1.dbd.OH, R2.dbd.H, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CHNOH, R1.dbd.OH, R2.dbd.H, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CH2OH, R1.dbd.OH, R2.dbd.H, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
III wherein A.dbd.CHO, R1.dbd.OH, R2.dbd.H, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
III wherein R1.dbd.CH2OH, R1.dbd.OH, R2.dbd.H, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CHO, R1.dbd.OAc, R2.dbd.H, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CHO, R1.dbd.OC(O)CH2CH2C(O)OH, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound
of Formula II wherein A.dbd.CHO, R1.dbd.OC(O)Ph, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound
of Formula II wherein A.dbd.CH2[(4-methyl)-1-piperazinyl],
R1.dbd.OH, R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H; Compound of Formula II wherein
A.dbd.CH2[(4-phenyl)-1-piperazinyl], R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound
of Formula II wherein A.dbd.CH2NMe2, R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound
of Formula II wherein A.dbd.CHO, R1 and R2.dbd.O, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CHNNH2, R1.dbd.OH, R2.dbd.H, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CHNNMe2, R1.dbd.OH, R2.dbd.H, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CH.dbd.N--(N-morpholine), R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound
of Formula II wherein A.dbd.CH(OMe)2, R1.dbd.H, R2.dbd.OH,
R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of
Formula III wherein A.dbd.CH(OMe)2, R1.dbd.H, R2.dbd.OH, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CH(OMe)2, R1.dbd.Cl, R2.dbd.H, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CHO, R1.dbd.H, R2.dbd.OH, R3.dbd.Ac
R4C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula III
wherein A.dbd.CH(OMe)2, R1.dbd.H, R2.dbd.OH, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
III wherein A.dbd.CHO, R1.dbd.H, R2.dbd.OH, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; Compound of Formula
II wherein A.dbd.CH(OMe)2, R1.dbd.OAc, R2.dbd.H, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H; and Compound of
Formula III wherein A.dbd.CHO, R1 and R2.dbd.O, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H;
5. A compound according to claim 2 wherein A.dbd.CHO, R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H and
R.sup.p.dbd.H.
6. A compound according to claim 2 wherein A.dbd.CHO, R1.dbd.H,
R2.dbd.OH, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H and
R.sup.p.dbd.H.
7. A compound according to claim 2 wherein A.dbd.CHO, R1.dbd.OH,
R2.dbd.H, R3.dbd.H, R4.dbd.C(O)CH2CH2CH3, R5.dbd.H,
R.sup.p.dbd.H.
8. A pharmaceutical composition for treating bacterial infections
comprising a therapeutically effective amount of a compound of
claim 1 or a pharmaceutically acceptable salt, ester or prodrug
thereof in combination with a pharmaceutically acceptable
carrier.
9. A method for treating bacterial infections comprising
administering to a mammal in need of such treatment a
pharmaceutical composition containing a pharmaceutically effective
amount of a compound of claim 1 or a pharmaceutically acceptable
salt, ester or prodrug thereof.
10. A process for preparing a compound represented by Formula II as
defined in claim 1 comprising: (a) reacting a compound represented
by the Formula 7wherein A, R1, R2, R3, R4, and R.sup.p are as
defined in claim 1 with a ruthenium or molybdenum catalyst,
optionally in the presence of an additive selected from the group
consisting of ethylene, 1-hexene, isobutylene, titanium (IV)
isopropoxide and aluminum (III) propoxide in an organic solvent to
provide a compound of Formula II.
11. A process for the preparation of a compound represented by
Formula III as defined in claim 1 comprising hydrogenating a
compound represented by Formula II as defined in claim 1 with a
palladium catalyst in the presence of hydrogen in an organic
solvent to provide a compound of Formula III.
Description
TECHNICAL FIELD
[0001] The present invention relates to novel macrolides having
antibacterial activity and useful in the treatment and prevention
of bacterial infections. More particularly, the invention relates
to ring contracted Leucomycin analogs, compositions containing such
compounds and methods for using the same, as well as processes for
making such compounds.
BACKGROUND OF THE INVENTION
[0002] Macrolide antibiotics play a therapeutically important role,
particularly with the emergence of new pathogens. Structural
differences are related to the size of the lactone ring and to the
number and nature (neutral or basic) of the sugars. Natural
macrolides are classified according to the size of the lactone ring
(12, 14, 15 or 16 atoms). The macrolide antibiotic family (14-, 15-
and 16-membered ring derivatives) shows a wide range of
characteristics (antibacterial spectrum, side-effects and
bioavailability). The most commonly used macrolides are
erythromycin and josamycin.
[0003] The 16-membered ring macrolide antibiotics constitute an
important clinically useful series of naturally occurring compounds
within the macrolide class of antibiotics, as they show some
advantages over 14-membered ring compounds (gastrointestinal
tolerance and activity against strains expressing resistance of the
inducible type). Sixteen membered macrolides usually contain an
amino disaccharide (4-O-(L-mycarosyl)-D-mycaminose and/or
D-desosamine). One class has only neutral sugars. The sixteen
membered macrolides can be classified into two major groups--the
leucomycins and the tylosin series.
[0004] The leucomycins, represented by Formulae Ia and Ib, are
further divided, as follows, into five groups according to the
chromophores: 1
[0005] 1. Leucomycin group containing platenomycin A1, A0 and C2,
josamycin (leucomycin A3) and midecamycin A1 and A2.
[0006] 2. Maridomycin group containing platenomycin C1.
[0007] 3. Carbomycin B group containing platenomycin W1,
midecamycin A4 and A3 and niddamycin
[0008] 4. Carbomycin A group containing the deltamycin complex
[0009] 5. Spiramycin complex.
[0010] The leucomycins, carbomycins, maridomycins, platenomycins,
midecamycins and spiramycins are members of the magnamycin group of
16-membered macrolides, having D-mycaminose and L-mycarose as sugar
moieties and an aglycone with an identical carbon skeleton. The
antibiotics differ from each other in terms of the acyl group on
positions O-3 and O-4" and the C12, 13 epoxy group. Platenolide I
(or II) is the earliest lactonic intermediate in their
biosynthesis.
[0011] The deoxy sugars and amino sugars in the macrolide
antibiotics are biosynthesized from D-glucose with retention of
carbon skeletons. The L-sugar is attached at C-3 , while the
D-sugar attaches at C-5.
[0012] The acyl moieties attached at positions O-3 and O-4" are
derived from amino acids. Within a given chromophoric group, it is
possible to differentiate the various compounds by the substituent
at C-3.
1 2 Leucomycin R3 R4 A1 H C(O)CH2CHMe2 A5 H C(O)CH2CH2CH3 A7 H
C(O)CH2CH3 A9 H C(O)CH3 V(A11) H H (Josamycin) A3 C(O)CH3
C(O)CH2CHMe2 A4 C(O)CH3 C(O)CH2CH2CH3 A6 C(O)CH3 C(O)CH2CH3 A8
C(O)CH3 C(O)CH3 U C(O)CH3 H Miokamycin.sup.1 C(O)CH2CH3
C(O)CH2CH2CH3 Rokitamycin.sup.2 H C(O)CH2CH2CH3 1: 9-OAc; 3"-OAc 2:
3"-OC(O)CH2CH3; 4"-OC(O)CH2CH2CH3
[0013] Josamycin is produced by Streptomyces narbonensis var.
josamyceticus. Josamycin was found to be identical to leucomycin
A3. Josamycin belongs to the leucomycin Ac group and differs from
the other members by the 4"-O-substituent. Josamycin has a
4"-O-isovaleryl side-chain. In acidic aqueous solution, josamycin
is transformed into isojosamycin (isoleucomycin A3) in which the
hydroxyl group at C-13 is transferred from C-9. Four metabolites
have been isolated from the urine and plasma of adults given oral
josamycin. Two show poor antimicrobial activity
[(5-hydroxyjosamycin (O.sub.1) and .beta.-hydroxyisovaleryl
josamycin (O.sub.2)] and two are inactive (desisovaleryl josamycin
and demycarosyl josamycin or josambose). The pediatric formulation
is josamycin propionate.
[0014] Leucomycin A5 is one of the components of the leucomycin
complex named kitasamycin, and is produced from the fermentation
broth of a strain of Streptomyces kitasatoensis. It was obtained as
a single component by controlling the culture conditions.
[0015] Leucomycin A5 belongs to the Fr group, because it has a
hydroxyl group at C-3, C-9 and C-2' and a tertiary hydroxyl group
at C-3". It also has a 4"-butyryl moiety ( L-mycarose) instead of a
4"-isovaleryl (A1), 4"-butyryl (A7), 4"-acetate (A9) or 4"--OH (V).
Leucomycin A5 shows good antibacterial activity in vitro.
[0016] Rokitamycin is a semisynthetic 16-membered-ring macrolide
obtained by attaching a propionate to the 3" position of leucomycin
A5. 3"-O-propionyl leucomycin A5 is the most active derivative of
4"-O-butyryl derivatives and shows the highest serum levels in dogs
and monkeys. The 3"-O-acetyl and 3"-O-butyryl derivatives were less
active than 3"-O-propionyl leucomycin A5.
[0017] The in vitro activity of rokitamycin against against
Gram-negative bacteria is twice as high as that of leucomycin A5,
josamycin, and midecamycin. Rokitamycin is highly metabolized into
four metabolites (10"-hydroxyrokitamycin, leucomycin A7, leucomycin
V and 14-hydroxyleucomycin V. Leucomycin A7 and Lecomycin V
(4"-debutyryl leucomycin A5) are the main metabolites). Their in
vitro potency is respectively one-half and one-tenth that of the
parent compound.
[0018] Midecamycins are fermentation products of Streptomyces
mycarofaciens and include four components--A1, A2, A3, and A4.
Midecamycin A1 and A2 belong to chromophoric group I, and
midecamycin A3 and A4 to chromophoric group III.
[0019] Midecamycin A2, A3 and A4 are minor components of the
mixture produced by Streptomyces mycarofaciens; the major
component, A1, has been marketed.
[0020] Miokamycin is a semisynthetic 16-membered-ring macrolide
derived from midecamycin A1 by introducing two acetyl groups at
C-3" and C-9. A large number of acyl derivatives has been prepared
by modifying the hydroxyl groups at C-9, C-2' and C-3" of
midecamycin A1, in order to improve the biological activities and
pharmaceutical properties.
[0021] Platenomycins were isolated from the fermentation broth of
Streptomyces platensis MCRL 0388. Platenomycin complex is composed
of nine components--A.sub.o (YL-7.sub.04), A1 (turimycin P5), B1,
C1, C2 (espinomycin A3), C4 (maridomycin II), W1,W2 and W3. The
chemical structure of the different compounds has been elucidated.
Platenomycin C1 was found to be identical to maridomycin III, and
platenomycin B 1 to midecamycin III, and platenomycin B1 to
midecamycin and espinomycin A1.
[0022] Platenomycin has a 16-membered-ring lactone, one aminosugar
(D-mycaminose) and one neutral sugar (L-mycarose).
[0023] The members of platenomycin complex can be differentiated by
the aglycone moiety: platenolide I has a 9-hydroxyl (platenomycins
W1, W2).
[0024] Carbomycin was isolated from the fermentation broth of
Streptomyces halstedii. The carbomycin complex has two
components--carbomycin A and carbomycin B.
[0025] Carbomycin A is identical to deltamycin A4. Carbomycin B
(magnamycin B) is used in veterinary medicine.
[0026] Niddamycin was isolated from the fermentation broth of a
strain of Streptomyces djaktensis. It is a substituted 16-membered
lactone with an amino sugar (D-mycaminose) and a neutral sugar
(L-mycarose). The D-mycaminose is bound to C-5 of the aglycone
nucleus, while the L-mycarose (substituted at C-4" with an
isovaleryl) binds to the C-4' hydroxyl of D-mycaminose. The lactone
ring has a C-6 formylmethyl group. It has no acetyl group at
C-3.
[0027] Niddamycin shows good antibacterial activity in vitro
against Gram-positive bacteria and Mycoplasma spp.
[0028] Spiramycin complex consists of three major (I, II, III) and
three minor components (IV, V, VI). They were derived from the
fermentation broth of Streptomyces ambofaciens, a soil organism
isolated in the north of France.
[0029] Spiramycins consist of four structural components--a
16-membered lactone (platenolide), two amino sugars (D-mycaminose
and D-forosamine) and one neutral sugar (L-mycarose). Of the
16-membered-ring macrolide antibiotics, only the spiramycins bear
D-forosamine. This amino-sugar is attached to position 9 of the
platenolide ring. The three major components differ by the
substituent at position 3, as follows: spiramycin I (3--OH),
spiramycin II (3-O-acetyl) and spiramycin III (3-O-propionyl).
Spiramycin IV and spiramycin VI have a secondary alcohol at C-6
instead of a formylmethyl group. Spiramycin V differs from
spiramycin I by the presence of an L-mycarose instead of a
D-forosamine. Spiramycin IV bears a D-forosamine and spiramycin VI
an L-mycarose.
[0030] The antibacterial spectrum of the spiramycins is similar to
that of other macrolide antibiotics. They are less active than
erythromycin A and show antiprotozoal activity. After oral intake,
a certain proportion of spiramycin is demycarsolated into
neospiramycin in the stomach.
[0031] The search for macrolides active against MLS-resistant
strains (MLS=Macrolides-Lincosamides-Streptogramines) has become a
major goal, together with retaining the overall profile of the
macrolides in terms of stability, tolerance and pharmacokinetics.
Semisynthetic molecules have recently been developed from
erythromycin A; new compounds containing a 14-membered lactone ring
with chemical modifications to enhance acid stability and prevent
anhydro formation include roxithromycin and clarithromycin.
[0032] However, less research has been done to improve the sixteen
membered macrolides to overcome bacterial resistance.
SUMMARY OF THE INVENTION
[0033] The present invention provides a novel class of ring
contracted 14-membered macrolides derived from the leucomycins
possessing increased antibacterial activity toward Gram positive
and Gram negative bacteria as well as macrolide resistant Gram
positives.
[0034] In one embodiment, the present invention provides compounds
represented by Formulae II or III, or a pharmaceutically acceptable
salt, ester or prodrug thereof. 3
[0035] wherein,
[0036] A is:
[0037] (1) CHO;
[0038] (2) CH2-X, where X is selected from the group consisting
of
[0039] a. hydroxy or protected hydroxy,
[0040] b. halogen,
[0041] c. NR7R8 wherein R7 and R8 are each independently selected
from hydrogen and C1 -C6-alkyl, optionally substituted with aryl or
heterocyclic groups; or R7 and R8 taken together with the nitrogen
atom to which they are connected form a 3- to 7-membered ring
which, may optionally contain a hetero function selected from the
group consisting of--O--, --NH--, --N(C1-C6-alkyl)--, --N(aryl)--,
--N(heteroaryl)--, --S--, --S(O)-- and --S(O)2--,
[0042] d. NR7C(O)--R9, where R7 is as previously defined and R9 is
selected from the group consisting of
[0043] i. C1-C6-alkyl, optionally substituted with aryl,
substituted aryl, heterocyclic or substituted heterocyclic,
[0044] ii. aryl,
[0045] iii. substituted aryl,
[0046] iv. heterocyclic, and
[0047] v. substituted heterocyclic
[0048] e. S(O).sub.n--(C1-C6-alkyl), optionally substituted with
aryl or a heterocyclic group where n=0, 1 or 2,
[0049] f. S(O).sub.n--( aryl or heterocyclic group) where n=0, 1 or
2, and
[0050] g. O--( aryl or heterocyclic group);
[0051] (3) an aldehyde protecting group,
[0052] (4) substituted or unsubstituted imidazole, arylimidazole or
heteroarylimidazole,
[0053] (5) substituted or unsubstituted oxazole, aryloxazole or
heteroaryloxazole,
[0054] (6) substituted or unsubstituted thioxazole, arylthioxazole
or heteroarylthioxazole,
[0055] (7) substituted or unsubstituted imidazoline,
arylimidazoline or heteroarylimidazoline,
[0056] (8) substituted or unsubstituted oxazoline, aryloxazoline or
heteroaryloxazoline, or
[0057] (9) substituted or unsubstituted thioxazoline,
arylthioxazoline or heteroarylthioxazoline.
[0058] R1 and R2 are each independently selected from the group
consisting of
[0059] (1) hydrogen,
[0060] (2) hydroxy,
[0061] (3) protected hydroxy,
[0062] (4) OC(O)--C1-C12 alkyl, optionally substituted with aryl,
substituted aryl, heterocyclic, substituted heterocyclic,
[0063] (5) O-R7 where R7 is as previously defined,
[0064] (6) halogen, and
[0065] (7) R1 and R2 taken together are oxo;
[0066] R3, R4 and R5 are each independently selected from the group
consisting of
[0067] (1) hydrogen,
[0068] (2) a hydroxy protecting group, and
[0069] (3) C(O)--C1-C12- alkyl, optionally substituted with aryl,
substituted aryl, heterocyclic, substituted heterocyclic, O--R7 or
NR7R8 where R7 and NR7R8 are as previously defined; and
[0070] R.sup.P is hydrogen or a hydroxy protecting group.
DETAILED DESCRIPTION OF THE INVENTION
[0071] A first embodiment of the invention is a compound
represented by the Formula II as described above.
[0072] A second embodiment of the invention is a compound
represented by the Formula III as described above.
[0073] Representative compounds of the invention are those selected
from the group consisting of:
[0074] Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0075] Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH,
R2.dbd.H, R3.dbd.H, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0076] Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH,
R2.dbd.H, R3.dbd.H, R4.dbd.C(O)CH2CH2CH3, R5.dbd.H,
R.sup.p.dbd.H;
[0077] Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH,
R2.dbd.H, R3.dbd.H, R4.dbd.C(O)CH2CH3, R5.dbd.H, R.sup.p.dbd.H;
[0078] Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH,
R2.dbd.H, R3.dbd.H, R4.dbd.C(O)CH3, R5.dbd.H, R.sup.p.dbd.H;
[0079] Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH,
R2.dbd.H, R3.dbd.H, R4.dbd.H, R5.dbd.H, R.sup.p.dbd.H;
[0080] Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH,
R2.dbd.H, R3.dbd.C(O)CH3, R4.dbd.C(O)CH2CH2CH3, R5.dbd.H,
R.sup.p.dbd.H;
[0081] Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH,
R2.dbd.H, R3.dbd.C(O)CH3, R4.dbd.C(O)CH2CH3, R5.dbd.H,
R.sup.p.dbd.H;
[0082] Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH,
R2.dbd.H, R3.dbd.C(O)CH3, R4.dbd.C(O)CH3, R5.dbd.H,
R.sup.p.dbd.H;
[0083] Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH,
R2.dbd.H, R3.dbd.C(O)CH3, R4.dbd.H, R5.dbd.H, R.sup.p.dbd.H;
[0084] Compound of Formula II wherein A.dbd.CHO, R1.dbd.OAc,
R2.dbd.H, R3.dbd.C(O)CH2CH3 R4.dbd.C(O)CH2CH2CH3, R5.dbd.Ac,
R.sup.p.dbd.H;
[0085] Compound of Formula II wherein A.dbd.CHO, R1.dbd.OH,
R2.dbd.H, R3.dbd.H, R4.dbd.C(O)CH2CH3, R5.dbd.C(O)CH2CH3,
R.sup.p.dbd.H;
[0086] Compound of Formula II wherein A.dbd.CH2Br, R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0087] Compound of Formula II wherein A.dbd.CH2F, R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0088] Compound of Formula II wherein A.dbd.CH2NMe(Bn), R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0089] Compound of Formula II wherein A.dbd.CH(OMe)2, R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0090] Compound of Formula II wherein A.dbd.CH2OH, R1.dbd.OBn,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0091] Compound of Formula II wherein A.dbd.CHNOPh, R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0092] Compound of Formula II wherein A.dbd.CHNOCH2CH3, R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0093] Compound of Formula II wherein A.dbd.CHNOCH3, R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0094] Compound of Formula II wherein A.dbd.CHNOH, R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0095] Compound of Formula II wherein A.dbd.CH2OH, R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0096] Compound of Formula III wherein A.dbd.CHO, R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0097] Compound of Formula III wherein R1.dbd.CH2OH, R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0098] Compound of Formula II wherein A.dbd.CHO, R1.dbd.OAc,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0099] Compound of Formula II wherein A.dbd.CHO,
R1.dbd.OC(O)CH2CH2C(O)OH, R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2,
R5.dbd.H, R.sup.p.dbd.H;
[0100] Compound of Formula II wherein A.dbd.CHO, R1.dbd.OC(O)Ph,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0101] Compound of Formula II wherein
A.dbd.CH2[(4-methyl)-1-piperazinyl], R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H;
[0102] Compound of Formula II wherein
A.dbd.CH2[(4-phenyl)-1-piperazinyl], R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H;
[0103] Compound of Formula II wherein A.dbd.CH2NMe2, R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0104] Compound of Formula II wherein A.dbd.CHO, R1 and R2.dbd.O,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H;
[0105] Compound of Formula II wherein A.dbd.CHNNH2, R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0106] Compound of Formula II wherein A.dbd.CHNNMe2, R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0107] Compound of Formula II wherein
A.dbd.CH.dbd.N--(N-morpholine), R1.dbd.OH, R2.dbd.H, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H;
[0108] Compound of Formula II wherein A.dbd.CH(OMe)2, R1.dbd.H,
R2.dbd.OH, R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0109] Compound of Formula III wherein A.dbd.CH(OMe)2, R1.dbd.H,
R2.dbd.OH, R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0110] Compound of Formula II wherein A.dbd.CH(OMe)2, R1.dbd.C1,
R2.dbd.H, R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0111] Compound of Formula II wherein A.dbd.CHO, R1.dbd.H,
R2.dbd.OH, R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0112] Compound of Formula III wherein A.dbd.CH(OMe)2, R1.dbd.H,
R2.dbd.OH, R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0113] Compound of Formula III wherein A.dbd.CHO, R1.dbd.H,
R2.dbd.OH, R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H;
[0114] Compound of Formula II wherein A.dbd.CH(OMe)2, R1.dbd.H,
R2.dbd.OAc, R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H;
and
[0115] Compound of Formula III wherein A.dbd.CHO, R1 and R2.dbd.O,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H;
Definitions
[0116] The terms "C.sub.1-C.sub.3-alkyl" or "C.sub.1-C.sub.6-alkyl"
as used herein refer to saturated, straight- or branched-chain
hydrocarbon radicals containing between one and three or one and
six carbon atoms, respectively. Examples of C.sub.1-C.sub.3 alkyl
radicals include methyl, ethyl, propyl and isopropyl, and examples
of C.sub.1-C.sub.6-alkyl radicals include, but are not limited to,
methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl
and n-hexyl.
[0117] The term "C.sub.1-C.sub.6-alkoxy" as used herein refers to a
C.sub.1-C.sub.6-alkyl group, as previously defined, attached to the
parent molecular moiety through an oxygen atom. Examples of
C.sub.1-C.sub.6-alkoxy include, but are not limited to, methoxy,
ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and
n-hexoxy.
[0118] The term "C.sub.1-C.sub.3-alkyl-amino" as used herein refers
to one or two C.sub.1-C.sub.3-alkyl groups, as previously defined,
attached to the parent molecular moiety through a nitrogen atom.
Examples of C.sub.1-C.sub.3-alkyl-amino include, but are not
limited to methylamino, dimethylamino, ethylamino, diethylamino and
propylamino.
[0119] The term "aprotic solvent" as used herein refers to a
solvent that is relatively inert to proton activity, i.e., not
acting as a proton-donor. Examples include, but are not limited to,
hydrocarbons, such as hexane and toluene, for example, halogenated
hydrocarbons, such as, for example, methylene chloride, ethylene
chloride, chloroform, and the like, heterocyclic compounds, such
as, for example, tetrahydrofuran and N-methylpyrrolidinone, and
ethers such as diethyl ether, bis-methoxymethyl ether. Such
compounds are well known to those skilled in the art, and it will
be apparent to those skilled in the art that individual solvents or
mixtures thereof may be preferred for specific compounds and
reaction conditions, depending upon such factors as the solubility
of reagents, reactivity of reagents and preferred temperature
ranges, for example. Further discussions of aprotic solvents may be
found in organic chemistry textbooks or in specialized monographs,
for example: Organic Solvents Physical Properties and Methods of
Purification, 4th ed., edited by John A. Riddick et al., Vol. II,
in the Techniques of Chemistry Series, John Wiley & Sons, NY,
1986.
[0120] The term "aryl" as used herein refers to unsubstituted
carbocyclic aromatic groups including, but not limited to, phenyl,
1- or 2-naphthyl and the like.
[0121] The term "C.sub.3-C.sub.5-cycloalkyl- and
C.sub.3-C.sub.7-cycloalky- l" as used herein refers to carbocyclic
groups of 3 to 5 or 3 to 7 carbons, respectively, for example,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and
cycloheptyl.
[0122] The term "C.sub.1-C.sub.3-alkyl-C.sub.3-C.sub.5-cycloalkyl",
as used herein refers to a C.sub.3-C.sub.5-cycloalkyl radical, as
defined above, attached to a C.sub.1-C.sub.3-alkyl radical by
replacement of a hydrogen atom on the latter.
[0123] The terms "halo" and "halogen" as used herein refer to an
atom selected from fluorine, chlorine, bromine and iodine.
[0124] The term "heteroaryl", as used herein, refers to a cyclic
aromatic radical having from five to ten ring atoms of which one
ring atom is selected from S, O and N; zero, one or two ring atoms
are additional heteroatoms independently selected from S, O and N;
and the remaining ring atoms are carbon, the radical being joined
to the rest of the molecule via any of the ring atoms, such as, for
example, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,
imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,
oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and
the like.
[0125] The term "heterocycloalkyl" as used herein, refers to a
non-aromatic 5-, 6- or 7-membered ring or a bi- or tri-cyclic group
comprising fused six-membered rings having between one and three
heteroatoms independently selected from oxygen, sulfur and
nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds
and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen
and sulfur heteroatoms may optionally be oxidized, (iii) the
nitrogen heteroatom may optionally be quaternized, and (iv) any of
the above heterocyclic rings may be fused to a benzene ring.
Representative heterocycles include, but are not limited to,
pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,
imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,
isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and
tetrahydrofuryl.
[0126] The term "heterocyclic" as used herein, refers to
heterocycloalkyl and heteroaryl. The term "substituted
heterocyclic" as used herein, refers to substituted
heterocycloalkyl and substituted heteroaryl.
[0127] "Hydroxy-protecting group", as used herein, refers to an
easily removable group which is known in the art to protect a
hydroxy group against undesirable reaction during synthetic
procedures and to be selectively removable. The use of
hydroxy-protecting groups is well known in the art for protecting
groups against undesirable reactions during a synthetic procedure
and many such protecting groups are known, cf, for example, T. H.
Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,
2nd edition, John Wiley & Sons, New York (1991). Examples of
hydroxy-protecting groups include, but are not limited to,
methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, acyl
substituted with an aromatic group and the like.
[0128] The term "protected-hydroxy" refers to a hydroxy group
protected with a hydroxy protecting group, as defined above,
including benzoyl, acetyl, trimethylsilyl, triethylsilyl,
methoxymethyl groups, for example.
[0129] The term "protogenic organic solvent" as used herein refers
to a solvent that tends to provide protons, such as an alcohol, for
example, methanol, ethanol, propanol, isopropanol, butanol,
t-butanol, and the like. Such solvents are well known to those
skilled in the art, and it will be apparent to those skilled in the
art that individual solvents or mixtures thereof may be preferred
for specific compounds and reaction conditions, depending upon such
factors as the solubility of reagents, reactivity of reagents and
preferred temperature ranges, for example. Further discussions of
protogenic solvents may be found in organic chemistry textbooks or
in specialized monographs, for example: Organic Solvents Physical
Properties and Methods of Purification, 4th ed., edited by John A.
Riddick et al., Vol. II, in the Techniques of Chemistry Series,
John Wiley & Sons, NY, 1986.
[0130] The term "substituted aryl" as used herein refers to an aryl
group as defined herein substituted by independent replacement of
one, two or three of the hydrogen atoms thereon with F, Cl, Br, I,
OH, NO.sub.2, CN, C(O)-C.sub.1-C.sub.6-alkyl, C(O)-aryl,
C(O)-heteroaryl, CO.sub.2-alkyl, CO.sub.2-aryl,
CO.sub.2-heteroaryl, CONH.sub.2, CONH-C.sub.1-C.sub.6-alky- l,
CONH-aryl, CONH-heteroaryl, OC(O)-C.sub.1-C.sub.6-alkyl,
OC(O)-aryl, OC(O)-heteroaryl, OCO.sub.2-alkyl, OCO.sub.2-aryl,
OCO.sub.2-heteroaryl OCONH.sub.2, OCONH-C.sub.1-C.sub.6-alkyl,
OCONH-aryl, OCONH-heteroaryl, NHC(O)-C.sub.1-C.sub.6-alkyl,
NHC(O)-aryl, NHC(O)-heteroaryl, NHCO.sub.2-alkyl, NHCO.sub.2-aryl,
NHCO.sub.2-heteroaryl, NHCONH.sub.2, NHCONH-C.sub.1-C.sub.6-alkyl,
NHCONH-aryl, NHCONH-heteroaryl, SO.sub.2-C.sub.1-C.sub.6-alkyl,
SO.sub.2-aryl, SO.sub.2-heteroaryl, SO.sub.2NH.sub.2,
SO.sub.2NH-C.sub.1-C.sub.6-alkyl, SO.sub.2NH-aryl,
SO.sub.2NH-heteroaryl, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-cycloalkyl, CF.sub.3, CH.sub.2CF.sub.3, CHCl.sub.2,
CH.sub.2OH, CH.sub.2CH.sub.2OH, CH.sub.2NH.sub.2,
CH.sub.2SO.sub.2CH.sub.3, aryl, heteroaryl, benzyl, benzyloxy,
aryloxy, heteroaryloxy, C.sub.1-C.sub.6-alkoxy, methoxymethoxy,
methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino,
C.sub.1-C.sub.3-alkyl-amino, thio, aryl-thio, heteroarylthio,
benzyl-thio, C.sub.1-C.sub.6-alkyl-thio, or methylthiomethyl.
[0131] The term "substituted heteroaryl" as used herein refers to a
heteroaryl group as defined herein substituted by independent
replacement of one, two or three of the hydrogen atoms thereon with
F, Cl, Br, I, OH, NO.sub.2, CN, C(O)-C.sub.1-C.sub.6-alkyl,
C(O)-aryl, C(O)-heteroaryl, CO.sub.2-alkyl, CO.sub.2-aryl,
CO.sub.2-heteroaryl, CONH.sub.2, CONH-C.sub.1-C.sub.6-alkyl,
CONH-aryl, CONH-heteroaryl, OC(O)-C.sub.1-C.sub.6-alkyl,
OC(O)-aryl, OC(O)-heteroaryl, OCO.sub.2-alkyl, OCO.sub.2-aryl,
OCO.sub.2-heteroaryl, OCONH.sub.2, OCONH-C.sub.1-C.sub.6-alkyl,
OCONH-aryl, OCONH-heteroaryl, NHC(O)-C.sub.1-C.sub.6-alkyl,
NHC(O)-aryl, NHC(O)-heteroaryl, NHCO.sub.2-alkyl, NHCO.sub.2-aryl,
NHCO.sub.2-heteroaryl, NHCONH.sub.2, NHCONH-C.sub.1-C.sub.6-alkyl,
NHCONH-aryl, NHCONH-heteroaryl, SO.sub.2-C.sub.1-C.sub.6-alkyl,
SO.sub.2-aryl, SO.sub.2-heteroaryl, SO.sub.2NH.sub.2,
SO.sub.2NH-C.sub.1-C.sub.6-alkyl, SO.sub.2NH-aryl,
SO.sub.2NH-heteroaryl, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-cycloalkyl, CF.sub.3, CH.sub.2CF.sub.3, CHCl.sub.2,
CH.sub.2OH, CH.sub.2CH.sub.2OH, CH.sub.2NH.sub.2,
CH.sub.2SO.sub.2CH.sub.3, aryl, heteroaryl, benzyl, benzyloxy,
aryloxy, heteroaryloxy, C.sub.1-C.sub.6-alkoxy, methoxymethoxy,
methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino,
C.sub.1-C.sub.3-alkyl-amino, thio, aryl-thio, heteroarylthio,
benzyl-thio, C.sub.1-C.sub.6-alkyl-thio, or methylthiomethyl.
[0132] The term "substituted heterocycloalkyl" as used herein,
refers to a heterocycloalkyl group, as defined above, substituted
by independent replacement of one, two or three of the hydrogen
atoms thereon with F, Cl, Br, I, OH, NO.sub.2, CN,
C(O)-C.sub.1-C.sub.6-alkyl, C(O)-aryl, C(O)-heteroaryl,
CO.sub.2-alkyl, CO.sub.2-aryl, CO.sub.2-heteroaryl, CONH.sub.2,
CONH-C.sub.1-C.sub.6-alkyl, CONH-aryl, CONH-heteroaryl,
OC(O)-C.sub.1-C.sub.6-alkyl, OC(O)-aryl, OC(O)-heteroaryl,
OCO.sub.2-alkyl, OCO.sub.2-aryl, OCO.sub.2-heteroaryl, OCONH.sub.2,
OCONH-C.sub.1-C.sub.6-alkyl, OCONH-aryl, OCONH-heteroaryl,
NHC(O)-C.sub.1-C.sub.6-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl,
NHCO.sub.2-alkyl, NHCO.sub.2-aryl, NHCO.sub.2-heteroaryl,
NHCONH.sub.2, NHCONH-C.sub.1-C.sub.6-alkyl, NHCONH-aryl,
NHCONH-heteroaryl, SO.sub.2-C.sub.1-C.sub.6-alkyl, SO.sub.2-aryl,
SO.sub.2-heteroaryl, SO.sub.2NH.sub.2,
SO.sub.2NH-C.sub.1-C.sub.6-alkyl, SO.sub.2NH-aryl,
SO.sub.2NH-heteroaryl, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-cycloalkyl, CF.sub.3, CH.sub.2CF.sub.3, CHCl.sub.2,
CH.sub.2OH, CH.sub.2CH.sub.2OH, CH.sub.2NH.sub.2,
CH.sub.2SO.sub.2CH.sub.3, aryl, heteroaryl, benzyl, benzyloxy,
aryloxy, heteroaryloxy, C.sub.1-C.sub.6-alkoxy, methoxymethoxy,
methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino,
C.sub.1-C.sub.3-alkyl-amino, thio, aryl-thio, heteroarylthio,
benzyl-thio, C.sub.1-C.sub.6-alkyl-thio, or methylthiomethyl.
[0133] Numerous asymmetric centers may exist in the compounds of
the present invention. Except where otherwise noted, the present
invention contemplates the various stereoisomers and mixtures
thereof. Accordingly, whenever a bond is represented by a wavy
line, it is intended that a mixture of stereo-orientations or an
individual isomer of assigned or unassigned orientation may be
present. Further, in those cases where a bond between carbon atoms
of the macrolide is a double bond both the cis and trans forms are
within the scope of the invention described in this application
[0134] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgement, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. Pharmaceutically acceptable salts are well
known in the art. For example, S. M. Berge, et al. describe
pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences, 66: 1-19 (1977), incorporated herein by reference. The
salts can be prepared in situ during the final isolation and
purification of the compounds of the invention, or separately by
reacting the free base function with a suitable organic acid.
Examples of pharmaceutically acceptable, nontoxic acid addition
salts are salts of an amino group formed with inorganic acids such
as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric
acid and perchloric acid or with organic acids such as acetic acid,
oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid
or malonic acid or by using other methods used in the art such as
ion exchange. Other pharmaceutically acceptable salts include
adipate, alginate, ascorbate, aspartate, benzenesulfonate,
benzoate, bisulfate, borate, butyrate, camphorate,
camphorsulfonate, citrate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts include, when appropriate,
nontoxic ammonium, quaternary ammonium, and amine cations formed
using counterions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
[0135] As used herein, the term "pharmaceutically acceptable ester"
refers to esters which hydrolyze in vivo and include those that
break down readily in the human body to leave the parent compound
or a salt thereof. Suitable ester groups include, for example,
those derived from pharmaceutically acceptable aliphatic carboxylic
acids, particularly alkanoic, alkenoic, cycloalkanoic and
alkanedioic acids, in which each alkyl or alkenyl moiety
advantageously has not more than 6 carbon atoms. Examples of
particular esters include formates, acetates, propionates,
butyates, acrylates and ethylsuccinates.
[0136] The term "pharmaceutically acceptable prodrugs", as used
herein refers to those prodrugs of the compounds of the present
invention which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, commensurate with a reasonable risk/reward ratio, and
effective for their intended use, as well as the zwitterionic
forms, where possible, of the compounds of the invention. The term
"prodrug" refers to compounds that are rapidly transformed in vivo
to yield the parent compound of the above formulae, for example, by
hydrolysis in blood. A thorough discussion is provided in T.
Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14
of the A.C.S. Symposium Series and in Edward B. Roche, ed.,
Bioreversible Carriers in Drug Design, American Pharmaceutical
Association and Pergamon Press, 1987, both of which are
incorporated by reference herein.
Antibacterial Activity
[0137] Susceptibility tests can be used to quantitatively measure
the in vitro activity of an antimicrobial agent against a given
bacterial isolate. Compounds were tested for in vitro antibacterial
activity by a microdilution method. Minimal Inhibitory
Concentration (MIC) was determined in 96 well microtiter plates
utilizing the appropriate Mueller Hinton Broth medium (CAMHB) for
the observed bacterial isolate. Antimicrobial agents were serial
diluted (2-fold) in DMSO to produce a concentration range of 32
ug/ml to 0.0625 ug/ml. The diluted compounds (2 ul/well) were then
transferred into sterile, uninoculated CAMHB (0.2 mL) by use of a
96-fixed tip pipetting station. The inoculum for each bacterial
strain was standardized to 5.times.10.sup.5 CFU/mL by optical
comparison to a 0.5 McFarland turbidity standard. The plates were
inoculated with 1 ul/well of adjusted bacterial inoculum. The 96
well plates were covered and incubated at 35+/-2.degree. C. for
20-24 hours in an ambient air environment. Following incubation,
plate wells were visually examined by Optical Density measurement
for the presence of growth (turbidity). The lowest concentration of
an antimicrobial agent at which no visible growth occurs was
defined as the MIC.
[0138] Antibiotic control standards were included in alternate
wells of the same 96 well plate as the antimicrobial agent of
interest for testing. The selected control agent was chosen as a
compound belonging to the same antibiotic class as the test
compound and having known susceptibility patterns for the bacterial
organism being tested.
[0139] All in vitro testing followed the guidelines described in
the Approved Standards M7-A4 protocol published by the National
Committee for Clinical Laboratory Standards (NCCLS).
Pharmaceutical Compositions
[0140] The pharmaceutical compositions of the present invention
comprise a therapeutically effective amount of a compound of the
present invention formulated together with one or more
pharmaceutically acceptable carriers. As used herein, the term
"pharmaceutically acceptable carrier" means a non-toxic, inert
solid, semi-solid or liquid filler, diluent, encapsulating material
or formulation auxiliary of any type. Some examples of materials
which can serve as pharmaceutically acceptable carriers are sugars
such as lactose, glucose and sucrose; starches such as corn starch
and potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols; such a propylene glycol; esters such as ethyl oleate
and ethyl laurate; agar; buffering agents such as magnesium
hydroxide and aluminun hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol, and phosphate
buffer solutions, as well as other non-toxic compatible lubricants
such as sodium lauryl sulfate and magnesium stearate, as well as
coloring agents, releasing agents, coating agents, sweetening,
flavoring and perfuming agents, preservatives and antioxidants can
also be present in the composition, according to the judgement of
the formulator. The pharmaceutical compositions of this invention
can be administered to humans and other animals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments, or drops), bucally, or as an
oral or nasal spray.
[0141] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof. Besides inert diluents,
the oral compositions can also include adjuvants such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring,
and perfuming agents.
[0142] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0143] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0144] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This may be accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution which, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the drug
in biodegradable polymers such as polylactide-polyglycolide.
Depending upon the ratio of drug to polymer and the nature of the
particular polymer employed, the rate of drug release can be
controlled. Examples of other biodegradable polymers include
poly(orthoesters) and poly(anhydrides) Depot injectable
formulations are also prepared by entrapping the drug in liposomes
or microemulsions which are compatible with body tissues.
[0145] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0146] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0147] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
[0148] The solid dosage forms of tablets, powders, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and can also be of a composition whereby they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions which can be used
include polymeric substances and waxes.
[0149] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polethylene glycols and the like.
[0150] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. In such solid dosage
forms, the active compound may be admixed with at least one inert
diluent such as sucrose, lactose or starch. Such dosage forms may
also comprise, as is normal practice, additional substances other
than inert diluents, e.g., tableting lubricants and other tableting
aids such as magnesium stearate and microcrystalline cellulose. In
the case of capsules, tablets and pills, the dosage forms may also
comprise buffering agents.
[0151] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, eye
ointments, powders and solutions are also contemplated as being
within the scope of this invention.
[0152] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0153] Powders and sprays can contain, in addition to the compounds
of this invention, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants such as chlorofluorohydrocarbons.
[0154] Transdermal patches have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0155] According to the methods of treatment of the present
invention, bacterial infections are treated or prevented in a
patient such as a human or lower mammal by administering to the
patient a therapeutically effective amount of a compound of the
invention, in such amounts and for such time as is necessary to
achieve the desired result. By a "therapeutically effective amount"
of a compound of the invention is meant a sufficient amount of the
compound to treat bacterial infections, at a reasonable
benefit/risk ratio applicable to any medical treatment. It will be
understood, however, that the total daily usage of the compounds
and compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgement.
The specific therapeutically effective dose level for any
particular patient will depend upon a variety of factors including
the disorder being treated and the severity of the disorder; the
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed; and like
factors well known in the medical arts.
[0156] The total daily dose of the compounds of this invention
administered to a human or other mammal in single or in divided
doses can be in amounts, for example, from 0.01 to 50 mg/kg body
weight or more usually from 0.1 to 25 mg/kg body weight. Single
dose compositions may contain such amounts or submultiples thereof
to make up the daily dose. In general, treatment regimens according
to the present invention comprise administration to a patient in
need of such treatment of from about 10 mg to about 1000 mg of the
compound(s) of this invention per day in single or multiple
doses.
Abbreviations
[0157] Abbreviations which have been used in the descriptions of
the scheme and the examples that follow are: AIBN for
azobisisobutyronitrile; Bu3SnH for tributyltin hydride; CDI for
carbonyldiimidazole; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene;
DEAD for diethylazodicarboxylate; DMF for dimethyl formamide; DPPA
for diphenylphosphoryl azide; EtOAc for ethyl acetate; MeOH for
methanol; NaN(TMS).sub.2 for sodium bis(trimethylsilyl)amide; NMO
for N-methylmorpholine N-oxide; TEA for triethylamine; THF for
tetrahydrofuran; TPP for triphenylphosphine; DMAP for
4-N,N-dimethylamino-purine; and TFA for trifluoroacetic acid.
Synthetic Methods
[0158] The compounds and processes of the present invention will be
better understood in connection with the following synthetic
schemes which illustrate the methods by which the compounds of the
invention may be prepared. The groups A, R1, R2, R3, R4, and
R.sup.p are as defined above unless otherwise noted below. 4
Process I
[0159] The process of the invention for the preparation of the
compounds of Formula II comprises reacting a compound of Formula IV
with Grubbs' ruthenium alkylidene or benzylidene catalysts (see (a)
U.S. Pat. No. 6,111,121. (b) Reviews: Synlett.1999, 2, 267 (c)
Reviews: Ivin, K. J.; Mol, J. C. Olefin Metathesis and Metathesis
Polymerization, 2.sup.nd ed.; Academic Press: New York, 1997. (d)
J. Org. Chem. 1999, 64, 4798-4816. (e) Angew. Chem., Int. Ed. Engl.
1997, 36, 2036-2056. (f) Tetrahedron 1998, 54, 4413-4450) or
Nolan's ruthenium catalyst (see (a) International Patent
Application No. PCT/US99/20629; International Publication No. WO
00/15339; (b) Org. Lett. 2000, 2, 1517-1519. (c) J. Org. Chem.
2000, 65, 2204-2207.) or molybdenum catalysts (see (a) J. Am. Chem.
Soc. 1990, 112, 3875. (b) J. Am. Chem. Soc. 1996, 118,
10926-10927.) optionally in the presence of additives such as
ethylene, 1-hexene, isobutylene, titanium (IV) isopropoxide or
aluminum (III) isopropoxide in an organic solvent such as
dichlomethane, chloroform, toluene, benzene, THF, DMF and the like
at from room temperature to 100.degree. C. for 1-7 days to provide
a 14-membered ring contracted product of Formula II (such as
Formula V). The preferred ruthenium catalysts are Nolan's catalyst
(tricyclohexylphosphine [1,3-bis
(2,4,6-trimethylphenyl)-imidazol-2-ylide- ne] benzylidene Ruthenium
(IV) dichloride) or tricyclohexylphosphine [1,3-bis
(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene] benzylidene
Ruthenium (IV) dichloride and the preferred solvent is
dichlomethane or toluene.
Process II
[0160] Compounds of Formula II where A is CHO can be further
derivatized to amino derivatives via reductive amination methods by
treating with an amine compound in the presence of sodium
borohydride or sodium cyanoborohydide and the like in an alcoholic
solvent such as methanol, ethanol, or isopropanol at a pH of 2-6.
Compounds of Formula II (such as Formula V) where A is CHO can be
further reduced to a corresponding alcohol where A is --CH.sub.2OH
with various hydride reducing agents such as sodium borohydrides,
lithium borohydrides, and the like. Compounds of Formula II (such a
Formula V) can be further converted to compounds of Formula III
(such as Formula VI) via hydrogenolysis methods such as treating
compounds of Formula II with palladium catalysts (palladium black,
palladium on carbon, RhCl(PPh.sub.3).sub.3 and the like) in the
presence of 1-4 atmospheres of hydrogen gas in an organic solvent
such as methanol, ethanol, isopropanol, ethylacetate, DMF, and the
like at from room temperature to about 60.degree. C. for 1 hour to
2 days.
EXAMPLES
[0161] The procedures described above for preparing the compounds
of the present invention will be better understood in connection
with the following examples, which are intended to be illustrative
only and not limiting of the scope of the invention. Various
changes and modifications to the disclosed embodiments will be
apparent to those skilled in the art. Such changes and
modifications, including without limitation, those relating to the
chemical structures, substituents, derivatives, intermediates,
syntheses, formulations and/or methods of the invention may be made
without departing from the spirit of the invention and the scope of
the appended claims.
Example 1
Compound of Formula II: A.dbd.CHO, R1.dbd.OH, R2.dbd.H, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0162] To a solution of Josamycin (5 g, 6.1 mmol) in
dichloromethane (40 ml) there were added Nolan catalyst (see
International Patent Application Publication No. WO 00/15339) (1.05
g, 1.21 mmol) and 1-hexene (1.53 ml, 12.2 mmol) and the reaction
mixture was heated at reflux for 30 h. Afterwards, the crude
mixture was concentrated in vacuo and combined with 2 g crude
product from another run. The crude product was dissolved in a
minimum amount of ethyl ether and was precipitated by a slow
addition of hexane (6001). The orange solid was collected by
filtration, dissolved in ethyl acetate and extracted with 10%
NaHSO3. The aqueous extracts were basified with 1N NaOH to pH 8 and
re-extracted with ethyl acetate. The combined organic extracts were
dried over MgSO4 and concentrated in vacuo to give an off-white
solid. The solid was dissolved in dichloromethane and stirred for
30 min with activated charcoal. After filtration and concentration
in vacuo, the pure product was obtained as a white solid (3 g, 44%
yield) MS (ESI) m/z: 802 (M+H).sup.+.
[0163] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 201.4, 173.1,
171.2, 170.1, 130.8, 123.1, 103.7, 97.7, 85.2, 76.0, 73.1, 71.6,
71.1, 70.8, 69.5, 68.9, 63.7, 62.3, 43.4, 42.1, 41.8, 39.0, 34.9,
25.7, 25.5, 22.6, 22.5, 21.2, 19.9, 18.9, 18.0. 5
[0164] Partial proton and carbon NMR assignments in D2O/DMSO
(20/80):
2 Site H C 2a 2.96 38.6 2b 3.35 3 5.73 71.8 4 4.06 84.3 4-OMe 4.04
5 4.26 77.6 6 2.53 30.3 7a 1.72 29.6 7b 1.81 8 2.25 35.5 8-Me 1.52
16.4 9 4.46 72.8 10 6.11 131.6 11 6.41 130.8 14a 2.84 38.8 14b 3.08
15 5.37 71.4 16-Me 1.87 19.9 18a 3.45 43.2 18b 3.09 19 10.2 20 2.47
41.5 21 2.62 25.6 21-Me 1.53 1' 4.94 103.8 2' 3.88 4" 4.01 5" 4.94
5"-Me 1.66
Example 2
Compound of Formula II: A.dbd.CHO, R1.dbd.OH, R2.dbd.H, R3.dbd.H,
R4.dbd.C (O) CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0165] The title compound of Example 2 was made by treating the
compound of Example 1 with potassium carbonate in methanol at room
temperature for 20 minutes.
[0166] MS m/z 761 (M+H).sup.+, .sup.13C NMR (100 MHz, CDCl.sub.3),
.delta. 203.0, 173.1, 17.03, 132.8, 129.9, 97.1, 75.7, 73.3, 71.3,
70.3, 69.5, 68.8, 63.6, 61.6, 60.5, 44.9, 43.4, 42.1, 41.8, 41.6,
39.3, 35.6, 32.4, 31.1, 30.6, 25.7, 25.5, 22.6, 22.5, 20.6, 19.2,
18.0, 16.6.
[0167] The title compound of Example 2 can also be prepared from
leucomycin A1 (6.1 mmol), Nolan's catalyst (1.21 mmol) and 1-hexene
in methylene chloride according to the procedures described in
Example 1.
Example 3
Compound of Formula II: A.dbd.CHO, R1.dbd.OH, R2.dbd.H, R3.dbd.H,
R4.dbd.C (O) CH2CH2CH3, R5.dbd.H, R.sup.p.dbd.H
[0168] The title compound of Example 3 was prepared by adding
1-hexene (82 .mu.L, 0.65 mmol) and Nolan's catalyst (169 mg, 0.19
mmol) to a solution of kitasamycin (Leucomycin A5) (500 mg, 0.65
mmol in 30 ml of dichloromethane. The reaction mixture was brought
to reflux and stirred for 3 days. The reaction mixture was
monitored by mass spectroscopy and NMR spectroscopy. An additional
15% of catalyst (85 mg, 0.09 mmol) was added followed by the
addition of 1-hexene (41 mL, 32 mmol) and the reaction mixture was
stirred for one more day.
[0169] The solvent was evaporated in vacuo and the resulting foam
was purified by column chromatography to provide the title
compound. A gradient of solvent was used for purification: 1.
hexane 2. methylene chloride 3.5% methanol, methylene chloride.
[0170] MS (ESI) m/z: 746.8 (M+H).sup.+, .sup.13C NMR (100 MHz,
CDCl.sub.3), .delta. 203.1, 173.7, 170.4, 133.0, 129.34, 105.7,
97.0, 75.6, 73.2, 71.8, 71.3, 71.2, 70.3, 69.7, 69.5, 69.5, 68.8,
63.5, 61.9, 61.6, 44.8, 421, 41.8, 39.3, 36.3, 35.7, 31.9, 31.1,
30.6, 27.7, 27.1, 27.0, 26.4, 26.2, 25.4, 20.5, 19.4, 19.2, 19.1,
19.0, 17.9, 16.6, 14.0, 13.8.
Example 4
Compound of Formula II: A.dbd.CHO, R1.dbd.OH, R2.dbd.H, R3.dbd.H,
R4.dbd.C (O) CH2CH3, R5.dbd.H R.sup.p.dbd.H
[0171] The title compound of Example 4 is prepared from leucomycin
A7 (6.1 mmol), Nolan's catalyst (1.21 mmol) and 1-hexene in
methylene chloride according to the procedures described in Example
1.
Example 5
Compound of Formula II: A.dbd.CHO, R1.dbd.OH, R2.dbd.H, R3.dbd.H,
R4.dbd.C (O) CH3, R5.dbd.H, R.sup.p.dbd.H
[0172] The title compound of Example 5 is prepared from leucomycin
A9 (6.1 mmol), Nolan's catalyst (1.21 mmol) and 1-hexene in
methylene chloride according to the procedures described in Example
1.
Example 6
Compound of Formula II: A.dbd.CHO, R1.dbd.OH, R2.dbd.H, R3.dbd.H,
R4.dbd.H, R5.dbd.H, R.sup.p.dbd.H
[0173] The title compound of Example 6 is prepared from leucomycin
V (A11) (6.1 mmol), Nolan's catalyst (1.21 mmol) and 1-hexene in
methylene chloride according to the procedures described in Example
1.
[0174] Alternatively, the title compound was obtained by treating
the compound of Example 1 with potassium carbonate in ethylene
glycol at 100.degree. C.
[0175] MS (ESI) m/z: 676 (M+H).sup.+
Example 7
Compound of Formula II: A.dbd.CHO, R1.dbd.OH, R2.dbd.H, R3.dbd.C
(O) CH3, R4.dbd.C (O) CH2CH2CH3, R5.dbd.H, R.sup.p.dbd.H
[0176] The title compound of Example 7 is prepared from leucomycin
A4 (6.1 mmol), Nolan's catalyst (1.21 mmol) and 1-hexene in
methylene chloride according to the procedures described in Example
1.
Example 8
Compound of Formula II: A.dbd.CHO, R1.dbd.OH, R2.dbd.H, R3.dbd.C
(O) CH3, R4.dbd.C (O) CH2CH3, R5.dbd.H, R.sup.p.dbd.H
[0177] The title compound of Example 8 is prepared from leucomycin
A6 (6.1 mmol), Nolan's catalyst (1.21 mmol) and 1-hexene in
methylene chloride according to the procedures described in Example
1.
Example 9
Compound of Formula II: A.dbd.CHO, R1.dbd.OH, R2.dbd.H, R3.dbd.C
(O) CH3, R4.dbd.C (O) CH3, R5.dbd.H, R.sup.p.dbd.H
[0178] The title compound of Example 9 is prepared from leucomycin
A8 (6.1 mmol), Nolan's catalyst (1.21 mmol) and 1-hexene in
methylene chloride according to the procedures described in Example
1.
Example 10
Compound of Formula II: A.dbd.CHO, R1.dbd.OH, R2.dbd.H, R3.dbd.C
(O) CH3, R4.dbd.H, R5.dbd.H, R.sup.p.dbd.H
[0179] The title compound of Example 10 is prepared from leucomycin
U (6.1 mmol), Nolan's catalyst (1.21 mmol) and 1-hexene in
methylene chloride according to the procedures described in Example
1.
Example 11
Compound of Formula II: A.dbd.CHO, R1.dbd.OAc, R2.dbd.H, R3.dbd.C
(O) CH2CH3, R4.dbd.C (O) CH2CH2CH3, R5.dbd.Ac. R.sup.p.dbd.H
[0180] The title compound of Example 11 is prepared from leucomycin
Miokamycin.sup.1 (6.1 mmol), Nolan's catalyst (1.21 mmol) and
1-hexene in methylene chloride according to the procedures
described in Example 1.
Example 12
Compound of Formula II: A.dbd.CHO, R1.dbd.OH, R2.dbd.H, R3.dbd.H,
R4.dbd.C (O) CH2CH2CH3, R5.dbd.C (O) CH2CH3, R.sup.p.dbd.H
[0181] The title compound of Example 12 is prepared from leucomycin
Rokitamycin.sup.2 (6.1 mmol), Nolan's catalyst (1.21 mmol) and
1-hexene in methylene chloride according to the procedures
described in Example 1.
Example 13
Compound of Formula II: A.dbd.CH2Br, R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H. R.sup.p.dbd.H
[0182] The title compound of Example 13 is prepared from the
compound of Formula Ia where A .dbd.CH2Br, R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, Nolan's catalyst and 1-hexene in
methylene chloride according to the procedures described in Example
1.
Example 14
Compound of Formula II: A.dbd.CH2F, R1.dbd.OH, R2.dbd.H, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0183] The title compound of Example 14 is prepared from the
compound of Formula Ia where A .dbd.CH2F, R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, Nolan's catalyst and 1-hexene in
methylene chloride according to the procedures described in Example
1.
Example 15
Compound of Formula II: A.dbd.CH2NMe(Bn), R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0184] The title compound of Example 15 is prepared from the
compound of Formula Ia where A .dbd.CH2NMe(Bn), R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, Nolan's catalyst and
1-hexene in methylene chloride according to the procedures
described in Example 1.
Example 16
Compound of Formula II: A.dbd.CH(OMe)2, R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0185] The title compound of Example 16 is prepared from the
compound of Formula Ia where A .dbd.CH(OMe)2, R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, Nolan's catalyst and 1-hexene in
methylene chloride according to the procedures described in Example
1.
Example 17
Compound of Formula II: A.dbd.CH2OH, R1.dbd.OBn, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0186] The title compound of Example 17 is prepared from the
compound of Formula Ia where A .dbd.CH2OH, R1.dbd.OBn, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, Nolan's catalyst and 1-hexene in
methylene chloride according to the procedures described in Example
1.
Example 18
Compound of Formula II. A.dbd.CHNOPh, R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0187] To a solution of the compound of Example 1 (200 mg, 0.24
mmol) in methanol (5 mL) there were added phenylhydroxylamine
hydrochloride (35 mg, 0.24 mmol) and sodium acetate (20 mg, 0.24
mmol). The reaction mixture was heated to reflux for two hours and
afterwards was concentrated to dryness. The crude mixture was
diluted with ethyl acetate and washed with brine. Purification by
flash chromatography (silica gel, 30/1 methylene
choloride/methanol) afforded the pure product as a white solid( 70
mg, 33% yield).
[0188] MS (ESI) m/z 893 (M+H).sup.+
Example 19
Compound of Formula II. A.dbd.CHNOCH2CH3, R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0189] To a solution of the compound of Example 1 (100 mg, 0.12
mmol) in methanol (5 mL) there were added ethylhydroxylamine
hydrochloride (11 mg, 0.12 mmol) and sodium acetate (10 mg, 0.12
mmol). The reaction mixture was heated to reflux for two hours and
afterwards was concentrated to dryness. The crude mixture was
diluted with ethyl acetate and washed with brine. Purification by
flash chromatography (silica gel, 30/1 methylene
choloride/methanol) afforded the pure product as a white solid (50
mg, 49% yield).
[0190] MS (ESI) m/z: 845 (M+H).sup.+
Example 20
Compound of Formula II: A.dbd.CHNOCH3, R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0191] To a solution of the compound of Example 1 (300 mg, 0.36
mmol) in methanol (5 mL) there were added methylhydroxylamine
hydrochloride (33 mg, 0.36 mmol) and sodium acetate (30 mg, 0.36
mmol). The reaction mixture was heated to reflux for two hours and
afterwards was concentrated to dryness. The crude mixture was
diluted with ethyl acetate and washed with brine. Purification by
flash chromatography (silica gel, 30/1 methylene
choloride/methanol) afforded the pure product as a white solid (150
mg, 50% yield).
[0192] MS (ESI) m/z: 831 (M+H).sup.+
Example 21
Compound of Formula II: A.dbd.CHNOH, R1.dbd.OH, R2.dbd.H, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0193] To a solution of the compound of Example 1 (100 mg, 0.12
mmol) in methanol (5 mL) there were added hydroxylamine
hydrochloride (8.7 mg, 0.12 mmol) and sodium acetate (10 mg, 0.12
mmol). The reaction mixture was heated to reflux for two hours and
afterwards was concentrated to dryness. The crude mixture was
diluted with ethyl acetate and washed with brine. Purification by
flash chromatography (silica gel, 30/1 methylene
choloride/methanol) afforded the pure product as a white solid (8
mg 8% yield).
[0194] MS (ESI) m/z: 817 (M+H).sup.+
Example 22
Compound of Formula II: A.dbd.CH2OH, R1.dbd.OH, R2.dbd.H, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0195] To a solution of the compound of Example 1 (250 mg, 0.3
mmol) in isopropanol and water (10 ml, 1/1) there was added sodium
borohydride (3 mg, 0.07 mmol) and the reaction was stirred for four
hours at ambient temperature. The reaction mixture was quenched
with saturated sodium bicarbonate and the crude was extracted with
methylene chloride. Purification by flash chromatography (silica
gel, 30/1 methylene chloride/methanol) afforded the pure product as
a white solid (75 mg, 31% yield).
[0196] MS (ESI) m/z: 804 (M+H).sup.+
Example 23
Compound of Formula III A.dbd.CHO, R1.dbd.OH, R2.dbd.H, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0197] A solution of the compound of Example 1, (100 mg, 0.12 mmol)
and 10% mol platinum oxide in ethanol (3 ml) was placed under a
hydrogen balloon and stirred at ambient temperature for 18 hours.
Afterwards, the reaction was filtered, rinsed with ethanol and
concentrated to dryness to afford the product as a white solid (76
mg, 79% yield).
[0198] MS (ESI) m/z: 804 (M+H).sup.+
Example 24
Compound of Formula III: A.dbd.CH2OH, R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0199] A solution of the compound of Example 22 (30 mg, 0.035
mmol)) and 10% mol platinum oxide in ethanol (3 ml) was placed
under a hydrogen balloon and stirred at ambient temperature for 18
hours. Afterwards, the reaction was filtered, rinsed with ethanol
and concentrated to dryness to afford the product as a white solid
(20 mg, 71% yield).
[0200] MS (ESI) m/z: 806 (M+H).sup.+
Example 25
Compound of Formula II: A.dbd.CHO, R1.dbd.OAc, R2.dbd.H, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0201] To a solution of the compound of Example 1 (100 mg, 0.12
mmol) in methylene chloride (3 ml) there were added acetic
anhydride (0.015 ml, 0.13 mmol), 4-methylmorpholine (0.012 ml, 0.13
mmol), and DMAP (1.4 mg, 0.013 mmol) and the reaction was stirred
at ambient temperature for 18 hours. Afterwards, the mixture was
diluted with ethyl acetate, washed with saturated sodium
bicarbonate, brine, dried over magnesium sulfate, and concentrated.
Purification by flash chromatography (silica gel, 30/1 methylene
chloride/methanol) afforded the pure product as a clear oil (75 mg,
74% yield).
[0202] MS (ESI) m/z: 844 (M+H).sup.+
Example 26
Compound of Formula II: A.dbd.CHO, R1.dbd.OC(O)CH2CH2C(O)OH,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H
[0203] To a solution of the compound of Example 1 (100 mg, 0.12
mmol) in methylene chloride (3 ml) there were added succinic
anhydride (13 mg, 0.13 mmol), 4-methylmorpholine (0.012 ml, 0.13
mmol), and DMAP (1.4 mg, 0.013 mmol) and the reaction was stirred
at ambient temperature for 18 hours. Afterwards, the mixture was
diluted with ethyl acetate, washed with saturated sodium
bicarbonate, brine, dried over magnesium sulfate, and concentrated.
Purification by flash chromatography (silica gel, 30/1 methylene
chloride/methanol) afforded the pure product as a clear oil (73 mg,
67% yield).
[0204] MS (ESI) m/z: 902 (M+H).sup.+
Example 27
Compound of Formula II: A.dbd.CHO, R1.dbd.OC(O)Ph, R2.dbd.H,
R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0205] To a solution of the compound of Example 1 (200 mg, 0.25
mmol) in methylene chloride (3 ml) there were added benzoic
anhydride (62 mg, 0.28 mmol), 4-methylmorpholine (0.038 ml, 0.28
mmol), and DMAP (3.1 mg, 0.025 mmol) and the reaction was stirred
at ambient temperature for 18 hours. Afterwards, the mixture was
diluted with ethyl acetate, washed with saturated sodium
bicarbonate, brine, dried over magnesium sulfate, and concentrated.
Purification by flash chromatography (silica gel, 30/1 methylene
chloride/methanol) afforded the pure product as a clear oil (49 mg,
23% yield).
[0206] MS (ESI) m/z: 906 (M+H).sup.+
Example 28
Compound of Formula II: A.dbd.CH2[(4-methyl)-1-piperazinyl],
R1.dbd.OH, R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H
[0207] To a solution of the compound of Example 1 (75 mg, 0.094
mmol) in methanol (3 mL) there were added 4A molecular sieves and
1-methylpiperazine (0.027 ml, 0.188 mmol) and the reaction mixture
was stirred for 30 min at ambient temperature. Afterwards sodium
cyanoborohydride (23.6 mg, 0.376 mmol) was added and the reaction
was stirred for an additional 1 hour. The reaction was then
quenched with saturated sodium bicarbonate and extracted with
methylene chloride. The organic extracts were washed with brine,
dried over magnesium sulfate and concentrated to dryness.
Purification by flash chromatography (silica gel, 9/1 methylene
chloride/methanol, 2% Et3N) afforded the pure product as a white
solid (11 mg, 13% yield).
[0208] MS (ESI) m/z: 886 (M+H).sup.+
Example 29
Compound of Formula II: A.dbd.CH2[(4-phenyl)-1-piperazinyl],
R1.dbd.OH, R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H
[0209] To a solution of the compound of Example 1 (95 mg, 0.118
mmol) in methanol (3 mL) there were added 4A molecular sieves and
1-phenylpiperazine (0.036 ml, 0.236 mmol) and the reaction mixture
was stirred for 30 min at ambient temperature. Afterwards sodium
cyanoborohydride (30.0 mg, 0.472 mmol) was added and the reaction
was stirred for an additional 1 hour. The reaction was then
quenched with saturated sodium bicarbonate and extracted with
methylene chloride. The organic extracts were washed with brine,
dried over magnesium sulfate and concentrated to dryness.
Purification by flash chromatography (silica gel, 9/1 methylene
chloride/methanol, 2% Et3N) afforded the pure product as a white
solid (7 mg, 6% yield).
[0210] MS (ESI) m/z: 948 (M+H).sup.+
Example 30
Compound of Formula II: A.dbd.CH2NMe2, R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0211] To a solution of the compound of Example 1(95 mg, 0.118
mmol) in methanol (3 mL) there were added 4A molecular sieves and
dimethylamine (2M in methanol, 0.118 ml, 0.234 mmol)) and the
reaction mixture was stirred for 30 min at ambient temperature.
Afterwards sodium cyanoborohydride (30.0 mg, 0.472 mmol) was added
and the reaction was stirred for an additional 1 hour. The reaction
was then quenched with saturated sodium bicarbonate and extracted
with methylene chloride. The organic extracts were washed with
brine, dried over magnesium sulfate and concentrated to dryness.
Purification by flash chromatography (silica gel, 9/1 methylene
chloride/methanol, 2% Et3N) afforded the pure product as a white
solid (9 mg, 6% yield).
[0212] MS (ESI) m/z: 831 (M+H).sup.+
Example 31
Compound of Formula II: A.dbd.CHO, R1 and R2.dbd.O, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0213] To a solution of the compound of Example 1 (130 mg, 0.162
mmol) in methylene chloride (5 ml) there were added pyridinium
chlorochromate (105 mg, 0.486 mmol) and sodium acetate (12.2 mg,
0.149 mmol) and the reaction mixture was stirred at ambient
temperature for 18 hours. Afterwards the crude mixture was filtered
and purified by flash chromatography (silica gel, 16/1 methylene
chloride/methanol) to afford the pure product as a white solid (9
mg, 7% yield).
[0214] MS (ESI) m/z: 800 (M+H).sup.+
Example 32
Compound of Formula II: A.dbd.CHNNH2, R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0215] To a solution of the compound of Example 1 (100 mg, 0.125
mmol) in methanol (3 ml) there was added hydrazine (1M in THF,
0.0125 ml, 0.125 mmol) and the reaction was stirred at ambient
temperature overnight. Afterwards the crude mixture was
concentrated and purified by flash chromatography (silica gel, 9/1
methylene chloride/methanol, 1% Et3N) to afford the pure product as
a white solid (8.7 mg, 9% yield).
[0216] MS (ESI) m/z: 816 (M+H).sup.+
Example 33
Compound of Formula II: A.dbd.CHNNMe2, R1.dbd.OH, R2.dbd.H,
R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0217] To a solution of the compound of Example 1 (200 mg, 0.249
mmol) in methanol (3 ml) there were added 3A molecular sieves and
dimethylhydrazine (15 mg, 0.249 mmol) and the reaction was heated
at reflux for 24 hours. Afterwards the crude mixture was diluted
with ethyl acetate, washed with brine and dried over magnesium
sulfate. After concentration to dryness and purification by flash
chromatography (silica gel, 15/1 methylene chloride/methanol), the
pure product was isolated as a white solid (19.1 mg, 19%
yield).
[0218] MS (ESI) m/z: 844 (M+H).sup.+
Example 34
Compound of Formula II: A.dbd.CH.dbd.N--(N-morpholine), R1.dbd.OH,
R2.dbd.H, R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H,
R.sup.p.dbd.H
[0219] To a solution of the compound of Example 1 (200 mg, 0.249
mmol) in methanol (3 ml) there were added 3A molecular sieves and
4-aminomorpholine (25.4 mg, 0.249 mmol) and the reaction was heated
at reflux for 24 hours. Afterwards the crude mixture was diluted
with ethyl acetate, washed with brine and dried over magnesium
sulfate. After concentration to dryness and purification by flash
chromatography (silica gel, 20/1 methylene chloride/methanol), the
pure product was isolated as a white solid (21.2 mg, 11%
yield).
[0220] MS (ESI) m/z: 886 (M+H).sup.+
Example 35
Compound of Formula II: A.dbd.CH(OMe)2, R1.dbd.H, R2.dbd.OH,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
Step 35a
Compound of Formula IV: A.dbd.CHO, R1 and R2.dbd.O, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R.sup.p.dbd.H
[0221] A solution of CrO.sub.3 (7.0 g, 70 mmol) in water (7 mL) was
added dropwise over 10 minutes to pyridine (30 mL) at 0.degree. C.
To the CrO.sub.3 mixture, a solution of josamycin (6.6 g, 7.98
mmol) in pyridine (15 mL) was added, and stirred for 2 hours at
room temperature. The mixture was diluted with water and extracted
with dichloromethane. The organic solution was dried over anhydrous
sodium sulfate, and concentrated under vacuum. The residue was
purified by chromatography on silica gel (eluting with 1:5
hexanes:ethyl acetate) to give the desired compound (2.87 g, 44%)
as a white solid.
[0222] MS (ESI) m/z: 826 (M+H).sup.+
[0223] .sup.13C-NMR(100 MHz, CDCl.sub.3): .delta. 203.03,
201.00,149.74, 144.35, 140.55, 136.33, 132.67, 129.14, 128.34,
125.42, 123.98, 122.35, 103.73, 97.13, 84.94, 77.80, 77.57, 77.12,
76.02, 72.99, 71.66, 69.47, 69.21, 68.82, 68.55, 63.58, 62.63,
44.34, 43.40, 43.03, 42.05, 41.77, 40.82, 36.85, 32.26, 30.88,
25.65, 25.47, 22.58, 22.52, 21.32, 20.61, 18.90, 17.97, 17.57.
Step 35b
Compound of Formula IV: A.dbd.CH(OMe)2, R1 and R2.dbd.O, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R.sup.p.dbd.Bz
[0224] A solution of the compound from step 35a (1.37 g, 1.66
mmol), Bz.sub.2O (1.0 g, 4.42 mmol) in pyridine (20 mL) was stirred
overnight at room temperature. The solution was concentrated under
vacuum, diluted with dichloromethane (80 mL), washed with aqueous
sodium bicarbonate solution, and dried over anhydrous sodium
sulfate. The solvent was evaporated, and the residue was dissolved
in methanol (60 mL). The pH of the methanol solution was adjusted
to 3 by adding acetic chloride at 0.degree. C. The solution was
stirred overnight, neutralized with sodium bicarbonate, and
concentrated. Purification on silica gel chromatography (eluting
with 5:1 toluene:acetone) gave compound 3 (1.52 g, 94%) as a light
yellow solid.
[0225] MS (ESI) m/z: 976 (M+H).sup.+
[0226] .sup.13C-NMR(100 MHz, CDCl.sub.3): .delta. 203.94, 173.02,
170.10, 169.86, 164.41, 143.57, 139.65, 133.38, 132.99, 130.22,
129.85, 129.18, 128.76, 128.37, 125.45, 122.84, 100.61, 100.55,
97.15, 85.61, 77.52, 77.15, 75.84, 75.20, 72.94, 71.61, 69.55,
69.35, 68.95, 68.10, 63.60, 62.16, 54.16, 47.12, 44.32, 43.41,
41.94, 41.80, 40.45, 36.81, 33.10, 32.11, 29.73, 25.67, 25.46,
22.59, 22.54, 21.17, 20.61, 19.04, 18.11, 17.94.
Step 35c
Compound of Formula IV: A.dbd.CH(OMe)2, R1.dbd.H, R2.dbd.OH,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R.sup.p.dbd.Bz
[0227] To a mixture of the compound from step 35b (1.39 g, 1.43
mmol), CeCl.sub.37H.sub.2O (531 mg, 1.43 mmol) in methanol (4 mL)
there was added NaBH.sub.4 (107.8 mg, 2.85 mmol) at -60.degree. C.
The mixture was stirred for 5 minutes, quenched with aqueous
ammonium chloride solution, and extracted with dichloromethane. The
organic solution was washed with aqueous sodium bicarbonate
solution, dried over anhydrous sodium sulfate, and concentrated
under vacuum. Purification with silica gel chromatography (eluting
with 5:1 toluene:acetone) gave the desired compound (1.13 g, 82%)
as a white solid.
[0228] MS (ESI) m/z: 978 (M+H).sup.+
[0229] .sup.13C-NMR(100 MHz, CDCl.sub.3): .delta. 173.01, 170.21,
170.12, 164.41, 133.30, 132.92, 131.36, 130.30, 130.01, 129.82,
129.38, 129.15, 128.71, 128.35, 125.44, 102.32, 100.46, 97.10,
85.50, 77.56, 77.13, 76.41, 75.94, 75.22, 72.95, 71.59, 69.60,
69.54, 69.19, 68.13, 63.58, 62.03, 52.56, 51.37, 43.40, 41.97,
41.78, 40.69, 36.75, 35.70, 32.45, 30.89, 30.15, 25.64, 25.44,
22.57, 22.52, 21.59, 21.32, 20.87, 20.40, 19.10, 18.10.
Step 35d
Compound of Formula II: A.dbd.CH(OMe)2, R1.dbd.H, R2.dbd.OH,
R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.Bz
[0230] To a solution of the compound from step 35c (1.0 g, 1.02
mmol) in dichloromethane (50 mL) there was added
Ti(O.sup.iPr).sub.4 (0.120 mL, 0.40 mmol) and refluxed for 20
minutes. The solution was cooled down to room temperature, degassed
with nitrogen, and then Nolan catalyst (86 mg, 0.10 mmol) was
added. The solution was stirred for 3 days at 50.degree. C. under
nitrogen, and concentrated under vacuum. Purification with silica
gel chromatography (eluting with ethyl acetate) gave the desired
compound (0.90 g, 92%) as a white solid.
[0231] MS (ESI) m/z: 952 (M+H).sup.+
[0232] .sup.13C-NMR(100 MHz, CDCl.sub.3): .delta. 173.03, 170.49,
168.88, 164.45, 135.60, 133.32, 130.27, 129.74, 129.15, 128.68,
128.35, 127.28, 125.43, 101.52, 100.69, 97.12, 78.44, 77.55, 77.13,
75.88, 72.94, 71.53, 70.24, 69.55, 68.10, 63.59, 61.78, 53.83,
43.40, 41.96, 41.78, 38.08, 37.66, 36.77, 35.26, 31.44, 25.64,
25.44, 22.57, 22.52, 21.11, 19.06, 18.41, 18.09.
Step 35e
Compound of Formula II: A.dbd.CH(OMe)2, R1.dbd.H, R2.dbd.OH,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0233] The compound from step 35d is treated with methanol at
reflux for 24 hours to give the title compound.
Example 36
Compound of Formula III: A.dbd.CH(OMe)2, R1.dbd.H, R2.dbd.OH,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
Step 36 a
Compound of Formula VI: A.dbd.CH(OMe)2, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R.sup.p.dbd.Bz
[0234] A mixture of the compound from step 35d (0.54 g, 0.568 mmol)
and Pd(OH).sub.2/C (50 mg) in methanol (30 mL) was stirred under
H.sub.2 (attached with a balloon) overnight. The catalyst was
filtered off. The solvent was evaporated to give the desired
compound (0.53 g, 98%) as white solid.
[0235] MS (ESI) m/z: 954 (M+H).sup.+
[0236] .sup.13C-NMR(100 MHz, CDCl.sub.3): .delta. 173.11, 170.50,
169.02, 164.54, 133.42, 130.27, 129.87, 128.80, 101.54, 100.72,
97.18, 77.43, 75.93, 75.37, 73.59, 72.96, 71.72, 70.01, 69.60,
68.03, 63.64, 61.94, 54.11, 48.79, 43.45, 42.02, 41.82, 37.01,
34.30, 34.09, 33.57, 32.88, 32.74, 25.70, 25.47, 22.61, 22.55,
21.11, 21.02, 19.94, 19.07, 18.13, 15.83.
Step 36b
Compound of Formula III: A.dbd.CH(OMe)2, R1.dbd.H, R2.dbd.OH,
R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0237] The compound from step 36a is treated with methanol at
reflux for 24 hours to give the title compound.
Example 37
Compound of Formula II: A.dbd.CH(OMe)2, R1.dbd.Cl, R2.dbd.H,
R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
Step 37a
Compound of Formula II: A.dbd.CH(OMe), R1.dbd.Cl, R2.dbd.H, R350 Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.Bz
[0238] To a solution of the compound from step 35d (0.115 g, 0.121
mmol) in dichloromethane (10 mL) containing triethylamine (0.05 mL,
0.36 mmol) there was added MsCl (0.011 mL, 0.145 mmol) at 0.degree.
C. The solution was stirred overnight, washed with aqueous sodium
bicarbonate, and dried over anhydrous sodium sulfate. The solvent
was evaporated. Purification with silica gel chromatography
(eluting with 3:1 ethyl acetate:hexane) gave the title compound (51
mg, 44%) as a white solid.
[0239] MS (ESI) m/z: 970 (M+H).sup.+
[0240] .sup.13C-NMR(100 MHz, CDCl.sub.3): .delta. 171.91, 169.48,
168.43, 163.31, 136.40, 132.22, 129.49, 129.02, 128.58, 127.54,
99.97, 99.67, 96.02, 85.37, 76.24, 75.49, 74.70, 71.73, 70.30,
69.43, 68.40, 67.02, 62.46, 60.96, 60.87, 59.62, 52.75, 47.43,
42.25, 40.75, 40.64, 30.62, 30.51, 24.50, 24.28, 21.41, 21.36,
19.85, 19.75, 19.56, 18.79, 17.84, 16.94.
Step 37b
Compound of Formula II: A.dbd.CH(OMe)2, R1.dbd.Cl, R2.dbd.H,
R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0241] The compound from step 37a is treated with methanol at
reflux for 24 hours to give the title compound
Example 38
Compound of Formula II: A.dbd.CHO, R1.dbd.H, R2.dbd.OH, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
Step 38a
Compound of Formula II A.dbd.CHO, R1.dbd.H, R2.dbd.OH, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.Bz
[0242] To a solution of the compound from step 35d (0.20 g, 0.21
mmol) in acetonitrile ( 3 mL) there were added water (15 mL) and
TFA (0.048 mL, 0.63 mmol). The mixture was stirred overnight at
room temperature, diluted with aqueous sodium bicarbonate and
extracted with dichloromethane. The organic solution was dried over
anhydrous sodium sulfate and concentrated under vacuum.
Purification with silica gel chromatography (eluting with ethyl
acetate) gave the desired compound (0.151 g, 80%) as a white
solid.
[0243] MS (ESI) m/z: 906 (M+H).sup.+
Step 38b
Compound of Formula II: A.dbd.CHO, R1.dbd.H, R2.dbd.OH, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0244] A solution of the compound from step 38a (0.15 g, 0.166
mmol) in methanol (30 mL) was refluxed for 3 days. The solvent was
evaporated under vacuum. Purification with silica gel
chromatography (eluting with ethyl acetate) gave the title compound
(85.6 mg, 64%) as a white solid.
[0245] MS (ESI) m/z: 802 (M+H).sup.+
[0246] .sup.13C-NMR(100 MHz, CDCl.sub.3): .delta. 201.79, 173.11,
171.45, 169.47, 133.96, 127.95, 103.99, 97.20, 92.03, 84.25, 78.63,
77.96, 77.44, 77.16, 76.07, 73.11, 71.68, 70.69, 70.34, 69.53,
68.88, 63.67, 62.16, 44.07, 43.46, 42.10, 41.83, 38.52, 37.88,
36.59, 32.89, 29.85, 25.70, 25.51, 22.61, 22.55, 21.30, 19.77,
19.29, 18.98, 18.00, 14.34, 14.28.
Example 39
Compound of Formula III: A.dbd.CH(OMe)2, R1.dbd.H, R2.dbd.OH,
R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0247] A solution of the compound from step 36a (0.20 g, 0.21 mmol)
in methanol (30 mL) was refluxed for 3 days. The solvent was
evaporated under vacuum to give the crude title compound.
[0248] MS (ESI) m/z: 850 (M+H).sup.+
Example 40
Compound of Formula III: A.dbd.CHO, R1.dbd.H, R2.dbd.OH, R3.dbd.Ac
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0249] To a solution of the crude compound from Example 39 in
acetonitrile ( 3 mL) there were added water (15 mL) and TFA (0.048
mL, 0.63 mmol). The mixture was stirred overnight at room
temperature, diluted with aqueous sodium bicarbonate and extracted
with dichloromethane. The organic solution was dried over anhydrous
sodium sulfate and concentrated under vacuum. Purification with
silica gel chromatography (eluting with ethyl acetate) gave the
title compound (70 mg, 42% yield from the starting compound) as a
white solid.
[0250] MS (ESI) m/z: 804 (M+H).sup.+
[0251] .sup.13C-NMR(100 MHz, CDCl.sub.3): .delta. 201.70, 173.13,
171.61, 169.69, 97.23, 79.00, 77.44, 77.17, 76.10, 75.74, 74.68,
73.09, 71.71, 69.88, 69.54, 68.87, 63.69, 62.21, 45.42, 43.47,
42.12, 41.85, 38.46, 34.34, 32.71, 31.74, 29.86, 25.72, 25.52,
22.62, 22.57, 21.27, 20.45, 19.00, 18.01.
Example 41
Compound of Formula II: A.dbd.CH(OMe)2, R1.dbd.H, R2.dbd.OAc,
R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.Ac
Step 41a
Compound of Formula II: A.dbd.CH(OMe)2, R1.dbd.H, R2.dbd.OH,
R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.Ac
[0252] To a degassed solution of a compound of Formula IV:
A.dbd.CH(OMe)2, R1.dbd.H, R2.dbd.OH, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R.sup.p.dbd.Ac (2.57 g, 2.81 mmol) in
dichloromethane (100 mL) there was added Nolan catalyst (0.50 g,
0.59 mmol) followed by 1-hexene (0.70 mL, 5.62 mmol). The solution
was stirred for 1 day at 50.degree. C. under nitrogen, and
concentrated under vacuum. Purification with silica gel
chromatography (eluting with ethyl acetate) gave the titlecompound
(1.06 g, 43%) as white solid.
[0253] MS (ESI) m/z: 890 (M+H).sup.+
[0254] .sup.13C-NMR(100 MHz, CDCl.sub.3): .delta. 173.04, 170.57,
169.13, 168.85, 100.56, 97.15, 78.45, 77.52, 77.13, 75.85, 72.81,
71.09, 70.45, 69.55, 68.08, 63.58, 61.63, 43.41, 41.80, 25.66,
25.41, 22.57, 22.52, 21.77, 21.13, 19.00, 18.78, 18.09.
Step 41b
Compound of Formula II: A.dbd.CH(OMe)2, R1.dbd.H, R2.dbd.OAc,
R3.dbd.Ac, R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.Ac
[0255] A solution of the compound from step 41a (0.23 g, 0.259
mmol), Ac.sub.2O (1.5 mL) in pyridine (20 mL) was stirred overnight
at room temperature. The solution was concentrated under vacuum,
diluted with dichloromethane (80 mL), washed with aqueous sodium
bicarbonate solution, and dried over anhydrous sodium sulfate.
Purification with silica gel chromatography (eluting with ethyl
acetate) gave the title compound (0.23 g, 96%).
[0256] MS (ESI) m/z: 932 (M+H).sup.+
[0257] .sup.13C-NMR(100 MHz, CDCl.sub.3): .delta. 172.94, 170.60,
170.22, 168.96, 168.85, 100.59, 97.00, 79.39, 77.61, 76.97, 75.80,
72.78, 71.01, 70.31, 69.69, 67.86, 63.53, 61.52, 43.29, 41.70,
41.59, 25.56 25.28, 22.48, 22.43, 21.62, 21.22, 21.10, 21.06,
18.94, 18.61, 17.98.
Step 41c
Compound of Formula II: A.dbd.CH(OMe)2, R1.dbd.H, R2.dbd.OAc,
R3.dbd.Ac R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0258] The compound from step 41b is treated with methanol at
reflux for 24 hours to give the title compound.
Example 42
Compound of Formula III: A.dbd.CHO, R1 and R2.dbd.O, R3.dbd.Ac,
R4.dbd.C(O)CH2CHMe2, R5.dbd.H, R.sup.p.dbd.H
[0259] The compound of Example 40 was converted to the title
compound according to the procedure described in Example 31.
[0260] MS (ESI) m/z: 803 (M+H).sup.+
[0261] Although the invention has been described with respect to
various preferred embodiments, it is not intended to be limited
thereto, but rather those skilled in the art will recognize that
variations and modifications may be made therein which are within
the spirit of the invention and the scope of the appended
claims.
* * * * *