CA2235942C - Tricyclic erythromycin derivatives - Google Patents

Abstract

Compounds, or pharmaceutically acceptable salts and esters thereof, of formulae (I); (II); (III) or (IV) wherein A, B, D and E, R1, R2 and Z are specificall y defined, having antibacterial activity, pharmaceutical compositions containing said compounds, treatment of antibacterial infections with such compositions, and processes for the preparation of the compounds.

Description

WO~ 97/17356 PCT/US96116585 TRICYCLIC ERYTHROMYCIN DERIVATIVES
- Technical Field The present invention relates to novel semisynthetic macrolides having antibacterial activity and useful in the treatment and prevention of bacterial infections.
More particularly, the invention relates to tricyclic erythromycin derivatives, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
Background of the Invention Erythromycins A through D, represented by formula (E), NMez O
HO,,~

g 2' CH3.,~ OH ~
CH
~

~ Erythromycin Ra Rb Ho,""
s ,",.
o o"
cH3 , H B -H -CH3 HsC H

' ~,"~s~"
C -OH -H

4"
H
cH3 , D -H -H
~

OH
O
''~' ORb are well-known and potent antibacterial agents, used widely to treat and prevent bacterial infection. As with other antibacterials, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds which possess improved antibacterial activity, which have less potential for developing resistance, which possess the desired Gram-negative activity, or which possess unexpected selectivity against target microorganisms. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity.
Ka.shimura et al. have disclosed 6-O-methylerythromycin derivatives having a tricyclic basic nuclear structure in European Application 559896, published November 11, 1991. Also, Asaka et al. have disclosed 5-O-desoaminylerythronolide derivatives containing a tricyclic carbamate structure in PCT Application WO 93/21200, published April 22, 1992.

~ummarv of the Invention The present invention provides a novel class of antibacterial tricyclic erythromycin compounds which possess antibacterial activity.
In one aspect of the present invention are disclosed novel tricyclic erythromycin compounds selected from the group having the formulas:
CH3 R2 NMe2 'a A ~ 0., H3C''~. CH3 ..
,~~ R~
O~ Nn.. s ....a O CH3 O
HsCv.,, CHa ~0,,,. O CH3 O

O .~~~ OH
(I) H3C '~OCH3 CH3 RZ NMe2 ~, 1 A N
H 9 . CH3 O''~.
gm..
6 .~eRi ~
O~ Nm.. ~~~n O O_ ' CH3 O
HsC~~'. H~~~ CH

(B) O
p CH3 R2 NMe2 .:
N
A
gi ~.. ' ~ O'', H3C~~,. 9 CH3 .~.R~
O~Nn..
""~ O O CH3 O
H3Cv.,. CHs _O
O

C > and p CH3 RZ NMe2 E, 0...
gm.. H3C~~, 9 CH3 ~~~ R~
O~ Nm. s ...n O Cl-13 O
HaCv,. H~.. CHs 'H
O
CH3 ~ CH3 (n') ° ;
as well as the pharmaceutically acceptable salts and esters thereof. 1n formulas (1) - (IV) above, A, B, D and E are independently selected from the group consisting of:
(a) hydrogen;
(b) C1-C6-alkyl, as defined below, optionally substituted with one or more substituents selected from the group consisting of:
(i) aryl, as defined below;
(ii) substituted-aryl, as defined below;
(iii) heteroaryl, as defined below;
(iv) substituted-heteroaryl, as defined below;
(v) heterocycloalkyl, as defined below;
(vi) hydroxy;
(vii) C1-C6-alkoxy, as defined below;
(viii) halogen consisting of Br, Cl, F or I; and (ix) NR3R4, where R3 and R4 are independently selected from hydrogen and C1-C6-alkyl, or R3 and R4 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring optionally containing a hetero function consisting of -O-, -NH-, -N(C1-C6-alkyl-)-, -N(aryl-C1-Cs-alkyl-)-, -N(substituted-aryl-C1-C6-alkyl-)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl-)-, -S-or -S(O)S-, wherein n is 1 or 2;
(c) C3-C7-cycloalkyl;
(d) aryl;
(e) substituted-aryl;
(fj heteroaryl;
(g) substituted-heteroaryl;
(h) heterocycloalkyl;
~ and (i) a group selected from option (b) above further substituted with -M-R5, wherein M is selected from the group consisting of (aa) -C(O)-NH-;
(bb) W-C(O)-;
(cc) -NH-(dd) -N(CH3)-(ee) -O-(ff) -S(O)S-, wherein n is 0, 1 or 2; and (gg) -C(=NH)-NH-;
and RS is selected from the group consisting of:
(aaa) Ci-C6-alkyl, optionally substituted with a substituent selected i0 from the group consisting of:
(i) aryl;
(ii) substituted-aryl;
(iii) heteroaryl; and (iv) substituted-heteroaryl;
(bbb) aryl;
(ccc) substituted-aryl;
(ddd) heteroaryl;
(eee) substituted-heteroaryl; and (fff) heterocycloalkyl;
or any one pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7-membered ring optionally containing a hetero function consisting of:
-O-, -NH-, -N(C i-C6-alkyl-)-, _N(aryl_C i _C6_~Yl-)_~
-N(substituted-aryl-C i-C6-allcyl-)-, -N(heteroaryl-Ci-C6-alkyl-)-, -N(substituted-heteroar 1-C
Y i-C6-aikYl-)-, -S- or -S(O)S-, wherein n is 1 or 2;
-C(~)-NH-;
-C(O)-NR5-, wherein R5 is as described above;
W-C(O)-;
-NR5-C(O)-, wherein R5 is as described above; and , -C(=NH)-NH-;
Ri is selected from the group consisting of:
(a) hydrogen;

(b) hydroxy;
(c) _O_Cl_C3_alkyl;
(d) -O-C3-C5-cycloalkyl;

(e) -O-Cl-C3-alkyl-C3-CS-cycloalkyl;

(f) -O-C(O)-Cl-C3-alkyl;

(g) -O-C(O)-O-Cl-C3-alkyl;
and (h) _O_C(O)_NH_C1_C3_~'l;

R2 is hydrogen or a hydroxy-protecting group, as defined below; and Z is hydroxy or protected-hydroxy;
with the provisos that when the compound is of Formulas (I) or (IIII) then A, B, D, and E
may not all be hydrogen, D and E may not be C1-C3-alkyl when A and B are hydrogen, nor may one of D and E be hydrogen and the other be C1-C3-alkyl when A and B are hydrogen.
In another aspect of the present invention are disclosed pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier and treatment of antibacterial infections with such compositions. Suitable carriers and methods of formulation are also disclosed.
The compounds and compositions of the present invention have antibacterial activity.
In a further aspect of the present invention are provided processes for the preparation of tricyclic macrolide derivatives of Formulas (I), (II), (IIn and (IV) above.
~et~iled Description of the Invention In one embodiment of the present invention are compounds selected from the group having formula (1) above, wherein A, B, D, E, and R1-RS are as described above.
In a second embodiment of the present invention are compounds selected from the group having formula (II) above, wherein A, B, D, E, R1-RS and Z are as described above.
In another embodiment of the present invention are compounds selected from the group having formula (III) above, wherein A, B, D, E, and R 1-RS are as described above.
In yet another embodiment of the present invention are compounds selected from the group having formula (IV) above, wherein A, B, D, E, and Ri-RS are as described above.
In one preferred embodiment of the present invention are compounds of formula (III) above wherein R1 is hydrogen, hydroxy or methoxy, R2 is hydrogen, and A, B, D, E and R1-RS are as described above.
In another preferred embodiment of the present invention are compounds of formula (III) above wherein R1 is hydrogen or methoxy, R2 is hydrogen, and any three of the A, B, D and E groups are hydrogen and the other group is selected from a singly substituted Ci-C6-alkyl group comprised of -(CH2)mR6 where m=l, 2, 3 or 4 and R6 is:
(a) aryl;
(b) substituted-aryl;

(c) heteroaryl;
(d) substituted-heteroaryl;
(e) heterocycloalkyl;
(f) hydroxy;
(g) C1-C6-alkoxy (h) NR3R4, where R3 and R4 are independently selected from hydrogen and Cl-C6-alkyl, or R3 and R4 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring optionally containing a hetero function consisting of -O-, -NH-, -N(Cl-C6-alkyl-)-, -N(aryl-C1-C6-alkyl-)-, -N(substituted-aryl-C1-C6-alkyl-)-, l0 -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-Ci-C6-alkyl-)-, -S-or -S(O)S-, wherein n is 1 or 2;
(i) halogen consisting of Br, Cl, F or I;
Ci-C3 alkyl; or (k) -(CH2)r-M-(CH2)S-R~ wherein r=0,1 or 2; s=0,1 or 2 and M is (aa) -C(O)-NH-;
(bb) (cc) -NH-(dd) -N(CH3)-(ee) _O_ (ff) -S(O)S-, wherein n is 0, 1 or 2; and (gg) -C(=NH)-NH-;
and R~ is selected from the group consisting of:
(aaa) Ci-C3-alkyl, (bbb) aryl;
(ccc) substituted-aryl;
(ddd) heteroaryl; and (eee) substituted-heteroaryl.
In yet another preferred embodiment of the present invention are compounds of formula (IIn above wherein R1 is hydrogen or methoxy, R2 is hydrogen, B=E=H, and A
and D taken together is selected from the group consisting of:
(a) -CH2-Z-CH2-, wherein Z is (aa) -C(O)-NH_;
(bb) -C(O)-NR5-, wherein R5 is selected from the group consisting of:
(aaa) Ci-C6-alkyl, optionally substituted with a substituent selected from the group consisting of:
(i) aryl;
(ll) substituted-aryl;

(iii) heteroaryl; and (iv) substituted-heteroaryl;
(bbb) aryl;
(ccc) substituted-aryl;
(ddd) heteroaryl;
(eee) substituted-heteroaryl; and (fff) heterocycloalkyl;
(cc) -NH-C(O)-;
(dd) -NR5-C(O)-, wherein R5 is as defined .above;
(ee) -NH-(ff) -N(CH3}-(gg) -(hh) -S(O)n-, wherein n is 0, 1 or 2; and (ii) -C(=NH)-NH-;
(b) -CH2-N(-(CH2)S-R')-CH2-, wherein s=0,1 or 2, and R~ is selected from the group consisting of:
(aaa) C1_C3_alkYl, (bbb) aryl;
(ccc) substituted-aryl;
(ddd) heteroaryl; and (eee) substituted-heteroaryl;
(c) -CH2-N(-(CH2)r-M-(CH2)S-R')-CH2-, wherein r=0,1 or 2; s=0,1 or 2, and M and R~ are as defined above; and (d) -CH2-(CH2)r-CH2-, wherein r=0,1 or 2.
Representative of the compounds of the invention include:
Compound of Formula (IV); Ri=methoxy; R2=hydrogen; A=B=D=E=hydrogen;
Compound of Formula (III), A=B=E=H, D=benzyl, R1=methoxy, R2=hydrogen;
Compound of Formula (III), A=B=D=H, E=benzyl, R 1=methoxy, R2=hydrogen;
Compound of Formula (III); A=benzyl, B=D=E=H, Rl=metlloxy;
Compound of Formula (III); B=benzyl, A=D=E=H, R1=methoxy, R2=hydrogen;
Compound of Formula (III); A=E=phenyl, B=D=H, R1=methoxy, R2=hydrogen;
Compound of Formula (III); A=methyl, B=D=E=H, Rl=methoxy, R2=hydrogen;
Compound of Formula (III); B=methyl, A=D=E=H, R1=methoxy, R2=hydrogen;
Compound of Formula (III); A=D=methyl; B=E=H, R i=methoxy, R2=hydrogen;
Compound of Formula (III); A=E=methyl; B=D=H, R1=methoxy, R2=hydrogen ;
Compound of Formula (III); B=D=H; A and E taken together is -CH2CH2CH2-, Ri=methoxy, R2=hydrogen;

Compound of Formula (III); B=E=H; A and D taken together is -CH2CH2CH2CH2-, Ri=methoxy, R2=hydrogen ;
Compound of Formula (I); A=B=D=E=hydrogen; R i=hydrogen, R2=hydrogen;
Compound of Formula (III): R'=OCH3, RZ=H; A=B=D=H; E=-CH2NH2;
Compound of Formula (III): R1=OCH3, RZ=H; A=B=E=H; D=-CH2NH2;
Compound of Formula (III): RI=OCH3, RZ=H; B=E=H; A and D taken together is -CH2CH2CH2-;
Compound of Formula (III): R1=OCH3, R2=H; B=E=H; A and D taken together is -CH20CHz-;
Compound of Formula (III): R1=OCH3, RZ=H; B=E=H; A and D taken together is -CH2-NH-CH2-;
Compound of Formula (DI): R1=OCH3, R2=H; B=E=H; A and D taken together is -CH2-N(Cbz)-CH2-;
Compound of Formula (III): R I=OCH3, Rz=H; B=E=H; A and D taken together is -CH2-N(benzyl)-CH2-;
Compound of Formula (III): R1=OCH3, R2=H; B=E=H; A and D taken together is -CH2-N(benzoyl)-CH2-;
Compound of Formula (llI): R1=OCH3, RZ=H; B=E=H; A and D taken together is -CH2-N(phenyl-CH2-CH2-)-CHZ-;
Compound of Formula (III): R1=OCH3, RZ=H; B=E=H; A and D taken together is -CH2-N(4-Cl-phenyl-CH2-)-CH2_;
Compound of Formula (la): R1=OCH3, R2=H; B=E=H; A and D taken together is -CH2-N(4-pyridyl-CH2-)-CH2-;
Compound of Formula (DI): R1=OCH3, R2=H; B=E=H; A and D taken together is -CH2-N(2-pyridyl-CH2-)-CH2-;
Compound of Formula (III): RI=OCH3, RZ=H; B=E=H; A and D taken together is -CH2-N(3-pyridyl-CH2-)-CH2-;
Compound of Formula (DI): RI=OCH3, R'=H; B=E=H; A and D taken together is -CH2-N(4-quinolyl-CH2-)-CH2-;
Compound of Formula (III): R1=OCH3, R2=H; B=E=H; A=D=-CH2-O-CH2-phenyl;
Compound of Formula (III): R 1=OCH3, R2=H; B=E=H; A=D=-CH2-OH;
Compound of Formula (III): R'=OCH3, R2=H; B=E=H; A=D=-CH2-O-phenyl;
Compound of Formula (lII): RI=OCH3, RZ=H; A=B=H; D and E taken together is -CH2-CH2-CH2-CH2-;
Compound of Formula (III): R1=OCH3, RZ=H; A and B taken together is -CH2-CH2-CH2-CH2-; D=E=H;
_g_ W~ 97/17356 PCT/US96/16585 Compound of Formula (III): R1=OCH3, R2=H; A=B=H; D and E taken together is -CH2-O-CH2-;
Compound of Formula (III): R1=OCH~, R2=H; A=D=E=H; B=-CH2-CH2-phenyl ;
Compound of Formula (III): R1=OCH3, R2=H; A=D=E=H; B=-CH2-CH2-CH2-phenyl ;
Compound of Formula (III): R1=OCH3, R2=H; A=D=E=H; B=-CH2-O-CH2-phenyl ;
Compound of Formula (III): R'=OCH3, R~=H; A=D=E=H; B=-CH2-CH2-(4-OCH3-phenyl );
Compound of Formula (III): R'=OCH3, R2=H; A=-CH2-CH2-phenyl; B=D=E=H ;
Compound of Formula (III): R1=OCH3, R2=H; A=-CH2-CH2-CH2-phenyl;
B=D=E=H ;
Compound of Formula (III): R1=OCH3, RZ=H; A=-CH2-O-CH2-phenyl ;
B=D=E=H ;
i5 Compound of Formula (III): Rl=OCH3, R2=H; B=D=E=H; A=-CH2-CH2-(4-OCH3-phenyl);
Compound of Formula (III): R'=OCH3, RZ=H; A=B=D=H; E=-CH2-CH2-Ph;
Compound of Formula (III): RI=OCH3, R2=H; A=B=E=H; D=-CH2-CH2-Ph;
Compound of Formula (III): RI=OCH3, R2=H; A=B=D=H; E=-2o CH2-CH2-CH2-Ph;
Compound of Formula (III): Ri=OCH3, R2=H; A=B=E=H; D=-CH2-CH2-CH2-Ph;
Compound of Formula (III): R1=OCH3, RZ=H; A=- CH2-CH2-OPh; B=D=E=H;
Compound of Formula (III): R1=OCH3, R2=H; A=- CH2-CH2-NHCbz;
25 B=D=E=H;
Compound of Formula (III) R1=OCH3, R2=H; A=-CH2-CH2-NH2; B=D=E=H;
Compound of Formula (III): R~=OCH3, R2=H; A=- CH2-CO2Benzyl; B=D=E=H;
Compound of Formula (III) Rl=OCH3, R2=H; A=-CH2-COOH; B=D=E=H;
Compound of Formula (III) R1=OCH3, R2=H; A=-CH2-CHz-OH; B=D=E=H;
30 Compound of Formula (III): R1=OCH3, R2=H; A=- CH2-CH2-NH(4-Pyridyl-);
B=D=E=H
Compound of Formula (III): R'=OCH3, RZ=H; A=B=D=H; E=-CH2-OH;
Compound of Formula (III): R1=OCH~, R2=H; A=B=E=H; D=-CH2-OH;
Compound of Formula (III): RI=OCH3, R2=H; A=B=E=H; D=-CH2-NHBenzoyl;
35 Compound of Formula (III): R'=OCH3, R2=H; A=B=E=H; D=-CH2-NHBenzyl;
Compound of Formula (III): Rl=OCH~, R2=H; A=B=D=H; E=-CH2-NHBenzoyl;
Compound of Formula (III): R'=OCH3, RZ=H; A=B=D=H; E=-CH2-NHBenzyl;

Compound of Formula (IIT): R1=OCH3, RZ=H; B=D=H; A=E=-CH20CH2(4-Cl-phenyl);
Compound of Formula (III): R1=OCH3, R'=H; A=B=E=H; D=-CH2-N(CH3)-Benzyl;
Compound of Formula (III): R1=OCH3, R2=H; A=B=D=H; E=-CH2-N(CH3)-Benzyl;
Compound of Formula (III): Ri=OCH3, R2=H; A=B=D=H; E=-CH2-NH-phenyl;
and Compound of Formula (III): R1=OCH3, R'=H; A=B=E=H; D=-CH2-NH-phenyl.
A selected group of representative compounds includes:
Compound of Formula (IV); Ri=methoxy; R2=hydrogen; A=B=D=E=hydrogen;
Compound of Formula (lII), A=B=E=H, D=benzyl, R i=methoxy, R2=hydrogen;
Compound of Formula (III), A=B=D=H, E=benzyl, R i=methoxy, R2=hydrogen;
i5 Compound of Formula (III); A=benzyl, B=D=E=H, Ri=methoxy, R2=hydrogen;
Compound of Formula (III); B=benzyl, A=D=E=H, Ri=methoxy, R2=hydrogen;
Compound of Formula (III); A=E=phenyl, B=D=H, R 1=methoxy, R2=hydrogen;
Compound of Formula (BI); A=methyl, B=D=E=H, R1=methoxy, R2=hydrogen;
Compound of Formula (III); B=methyl, A=D=E=H, Ri=methoxy, R2=hydrogen;
Compound of Formula (lII); A=D=methyl; B=E=H, R i=methoxy, R2=hydrogen;
Compound of Formula (III); A=E=methyl; B=D=H, R i=methoxy, R2=hydrogen ;
Compound of Formula (III); B=D=H; A and E taken together is -CH2CH2CH2-, R i=methoxy, RZ=hydrogen;
Compound of Formula (III); B=E=H; A and D taken together is -CH2CH2CH2CH2-, R i=methoxy, R2=hydrogen ; and Compound of Formula (I); A=B=D=E=hydrogen; R i=hydrogen, R2=hydrogen.
One object of the present invention is to provide a process for the preparation of tricyclic macrolide derivatives having the Formulas:
CH3 R2 NMe2 .:
0., gn.. H3C~~, 9 .~~ Ri N~~..
.. O CH3 O .~~~ OH
H3C .'~OCH3 ~ (I), CH3 CH3.

W(3 97/17356 PCT/CTS96/16585 CHs R2 NMe2 p ~' ~ 0...
CHs gn.. H3C,~,.
s ... R ~
O~ Nm ..
CHs O
HaC~~,. H~.. CHs 'Z
O
CHs CHs O , (~), p CHs R2 NMe2 E~. I
A N~ 0...
H3C,~,. 9 CHs ~ ... R
O~Nm.. ...u O O CHs O
H3C~~~~ ~ CHs 'O

CHs CHs (III) or CHs R2 NMe2 p ~' ~ 0.,.
gm.. H3C,~, 9 CHs .
~~~R
O~ N~ ~.. s ...» O CHs O
H3Cv,. H~.. CHs 'H
O
CHs CHs O ~ (IV)~
wherein A, B, D and E are independently selected from the group consisting of:
(a) hydrogen;
(b) C1-C6-alkyl, as defined below, optionally substituted with one or more substituents selected from the group consisting of:
(i) aryl, as defined below;
' (ii) substituted-aryl, as defined below;
(iii) heteroaryl, as defined below;
' (iv) substituted-heteroaryl, as defined below;
(v) heterocycloalkyl, as defined below;
(vi) hydroxy;
-il-(vii) C1-C6-alkoxy, as defined below;
(viii) halogen consisting of Br, Cl, F or I; and (ix) NR3R4, where R3 and R4 are independently selected from hydrogen and C1-C6-alkyl, or R3 and R4 are taken with the nitrogen atom to which they are connected to 3- to 7-membered ring optionally containing a hetero form a function consisting of -O-, -NH-, -N(C1-C6-alkyl-)-, -N(aryl-Ci-C6-alkyl-)-, -N(substituted-aryl-C1-C6-alkyl-)-, -N(heteroaryl-Ci-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl-)-, -S- or -S(O)n-, wherein n is 1 or 2;

(c) C3-C~-cycloalkyl;

l0 (d) aryl;

(e) substituted-aryl;

(f7 heteroaryl;

(g) substituted-heteroaryl;

(h) heterocycloalkyl;

~d (i) a group selected from option (b) above further substituted with -M-R5, wherein M is selected from the group consisting of:

(aa) -C(O)-NH-;

(bb) -~-C(O)-;

(cc) -NH-(dd) -N(CH3)-(ee) -O-(rr) -S(O)S-, wherein n is 0, 1 or 2; and (gg) -C(=NH)-NH-;

and R5 is selected from the group consisting of:

C1-C6-~yl, optionally substituted with a substituent selected from the group consisting of:

(i) aryl;

(ii) substituted-aryl;

(iii) heteroaryl; and (iv) substituted-heteroaryl;

(bbb) aryl;

(ccc) substituted-aryl; , (ddd) heteroaryl;

(eee) substituted-heteroaryl; and , (fffj heterocycloalkyl;

or any one pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3-to 7-membered ring optionally containing a hetero function consisting of -O-, -NH-, -N(C 1-C6-a~Yl-)->
-N(~.3'1-C1-C6-a~Yl-)->
-N(substituted-aryl-C1-C6-alkyl-)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C 1-C6-alkyl-)-, -S- or -S(O)S-, wherein n is 1 or 2;
-C(O)-NH-;
-C(O)-NRS-, wherein RS is as described above;
-NH-C(O)-;
-NRS-C(O)-, wherein RS is as described above; and -C(-NH)_NH_;
Rl is selected from the group consisting of:
(a) hydrogen;
(b) hydroxy;
(c) -O-C1-C3-alkyl;
(d) -O-C3-CS-cycloalkyl;
(e) -O-C1-C3-alkyl-C3-Cg-cycloallcyl;
(f) -O-C(O)-C1-C3-alkyl;
(g) -O-C(O)-O-Ci-C3-alkyl; and (h) -O-C(O)-NH-C1-C3-alkyl;
R2 is hydrogen or a hydroxy-protecting group, as defined below; and Z is hydroxy or protected-hydroxy;
except when the compound is of Formulas (I) or (III) then A, B, D, and E may not all be hydrogen, D and E may not be C1-C3-alkyl when A and B are hydrogen, nor may one of D and E be hydrogen and the other be Cl-C3-alkyl when A and B
are hydrogen;
the method comprising:
(a) treating a compound having the formula CHa NMez O zRO,, HaCi.. RC Ha ~
HOm.. ....r O' _CHa HO
H3C~~ CHa Or... CHa CHa CHa O .rOR2 Hac ~''ocHa , (compound (2) from Scheme 1), CHa RZ NMe2 O
O,, H°C~~~ 'RCHa HO r...
""r O O CHa HO
HsC.: CHa p O-Cbz CHa CHa (compound (6) from Scheme 2), CHa RZ NMe2 O
O,, i HaC''~ 'RCHa HO r...
-"'r O O CHa HO
H3C'~ O CHa O
CHa CHa O
(compound (7) from Scheme 3), or CHa RZ NMe2 O
0,,, HaCa .~RCHa HO r...
".v O O CHa HO
HaC.: CHa O
CHa CHa O
respectively, wherein R1 is as described above and R2 is a hydroxy-protecting group, with a base, such as sodium hydride, lithium hydride, potassium carbonate, for example, and followed by reaction with carbonyldiimidazole, in an aprotic solvent, as defined below, which does not adversely affect the reaction, preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof, with cooling or heating, depending on the conditions used, at a reaction temperature from -20°C to 70°C, WO~ 97/17356 PCTNS96/16585 preferably from 0°C to reaction temperature, for a period from 0.5 haurs to 10 days, preferably 1-5 days, to prepare first intermediate compounds having the formulas:
CH3 NMez O zRO,, HaC ~'RCH

/ "'m O O CH3 N~ N~ O
II HaC.: CHs O ~0,,,. O CH3 O ..,~ ORz H3c ~~'ocH, , (compound (3) from Scheme 1), CH3 Rz NMez O I
a,, H3C ~ RCHa ~
N N O / ...u O~ CH3 U
HsCr:
OCb H' CH3~ CH3 (compound (6) from Scheme 2), CHs Rz NMez O I

~---~ 3 ~
N~N O / ....r O' _ CHy U
HsC~, CHI
'O
CH~~ CH3 (compound (8) from Scheme 3), or CH3 Rz NMez I
0,,, N N 1 O~ CH3 O ~Ha ,(compound ( tt7) from scheme 4), respectively; wherein Ri and R2 are as described above;
(b) reacting said first intermediate compounds (3), (6), (8), or (10) with a compound having the formula:
D
NHz E r...
A
g' NHz wherein A, B, D, and E are as described above, preferably in a solvent such as aqueous acetonitrile, DMF or aqueous DMF, to give the bicyclic second intermediate compounds having the formulas:
NHZ CH3 NMe2 E rr..
O ZRO,, A
H3C ' CH

O~ Nn..' ~...r p O CH3 O
H3C~~ CH3 O -O,~ O CHs .~° OFD
H3c ~~'ocH, (compound (11), from Scheme 5), p NHZ CH3 NMei E r''Y O
ZRO
H C RCH ~~~.
O Nr...
O ~"" O O CH3 HsCo.~ CHs O OCbz (compound ( 15), from Scheme 7), p NHZ CH3 NMe2 E , A O RO',,.
B,. HaC 'RCH3 N a..
O O ...n O O CH3 H3C~, O CH3 O

O
(compound ( 19) from Scheme 9), p NHZ CH3 NMe2 E r'Y O
'' IAA
B'~~ H3C ~RCH3 O~ Nn.. ~.." O O CH3 O
HsC.: CHa O

O
(compound (23), from Scheme 11 ), respectively; , wherein R1 and RZ are as described above;
(c) deprotecting said second intermediate compounds ( 11 ), ( 15), ( 19) or (23) by , treatment with methanol or ethanol when OR2 is an ester or with fluoride in THF or acetonitrile when R2 is a trialkylsilyl group, for from 1 to 24 hours, to give the third intermediate compounds Wd~ 97/17356 PCT/US96/16585 CHa NMeZ
NHZ
E i... O
p R~ HOn..
' g~.,. H3C . CHa O? N i...
"'m0 O CHa O
HaC~~ ~CHa O ' O,, O CHa CHa CHa O ~~ ~ OH
Hac ~~'ocHa (compound ( 12), from Scheme 5), D NH2 CHa NMe2 Ey p W..
A
HaC ~'RCHa O~Nn.. ...np O CHa \O
HaC~ ~CHa O OCbz CHa CHa (compound ( 16), from Scheme 7), D NHZ CHs NMe2 E n. O
q R' Ha ~~ CHa O~N a..
""' O O CHa O
HaC~ 'CHa O
O
CHa CHa (compound (20) from Scheme 9), D NHZ CHa NMe2 E,~ O HO
A~ , B" HaC .RCHa O~N~... .....0 O CHa O
1-IsG~ ~CHa O
CHa CHa ° (compound (24) from Scheme 11), respectively; and (d) cyclizing said third intermediate compounds ( 12), ( 16), (20) or (24) by treatment with dilute acid, such as acetic acid or HCl, for example, in an organic solvent, preferably ethanol or propanol, for a period of from 4 hours to 10 days to give the desired compounds (~, (II), (III) or (IV) above.
Another object of the present invention is to provide an alternate process for the preparation of tricyclic macrolide derivatives having the Formulas:

D CHs R2 NMe2 E
A ~ 0., gn.. H3C~~.. s CHs ... R i O~ Nn.. s O CHs O
HsC~.,. CHs ~0,,~. O CHs O
CHs CHs O .~~~ OH
H3C ~~~OCH3 > (I)>
E p CHs R2 NMe2 ':
A ~ 0., g~... H3C~~, s CHs O~ Ni ~..
CHs O
H3C~~,. H~~~' CH

CHs CHs O
CHs R2 NMe2 .:
A NW 0....
gi... s CH3 HsC'~~.
O~N~...
O CHs O
HaCv.,. CHs 'O

CHs CHs O
> (III) or CHs R2 NMep .:
A ~ 0.,.
gn.. H3C~~I s CHs ..e R 1 O~ Ni... s ....~ O
O CHs . . H~..
H3C~ . CHs 'H

CHs CHs O
wherein ' ~N)>
A, B, D and E are independently selected from the group consisting of:
- i8 -(a) hydrogen;
(b) C1-C6-alkyl, as defined below, optionally substituted with one or more substituents selected from the group consisting of:
(i) aryl, as defined below;
(ii) substituted-aryl, as defined below;
(iii) heteroaryl, as defined below;
(iv) substituted-heteroaryl, as defined below;
(v) heterocycloalkyl, as defined below;
(vi) hydroxy;
(vii) C1-Cf,-alkoxy, as defined below;
(viii) halogen consisting of Br, Cl, F or I; and (ix) NR3R4, where R3 and R4 are independently selected from hydrogen and C1-C6-alkyl, or R3 and R4 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring optionally containing a hetero function consisting of -O-, -NH-, -N(C1-C6-alkyl-)-, -N(aryl-C1-C6-alkyl-)-, -N(substituted-aryl-C1-C6-alkyl-)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-allcyl-)-, -S- or -S(O)S-, wherein n is 1 or 2;
(c) C3-C~-cycloallcyl;
(d) aryl;
(e) substituted-aryl;
(f) heteroaryl;
(g) substituted-heteroaryl;
(h) heterocycloalkyl;
and (i) a group selected from option (b) above further substituted with -M-R5, wherein M is selected from the group consisting of:
(aa) -C(O)-NH_;
(bb) -NH-C(O)-;
(cc) -NH-(dd) -N(CH3)-(ee) -O-(rr) -S(O)n-, wherein n is 0, 1 or 2; and (gg) -C(=NH)-~-;
and R5 is selected from the group consisting of:
(aaa) C1-Ct,-alkyl, optionally substituted with a substituent selected from the group consisting of:
(i) aryl;
(ii) substituted-aryl;

(iii) heteroaryl; and (iv) substituted-heteroaryl;
(bbb) aryl;
(ccc) substituted-aryl;
(ddd) heteroaryl;
(eee) substituted-heteroaryl; and (fff) heterocycloalkyl;
or any one pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken l0 together with the atom or atoms to which they are attached to form a 3- to 7-membered ring optionally containing a hetero function consisting of:
-O-, -NH-, -N(C1-C6-a~Yl-)->
15 -N(aryl-C1-C6-alkyl-)--N(substituted-aryl-C1-C6-alkyl-)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C 1-C6-alkyl-)-, -S- or -S(O)n-, wherein n is 1 or 2;
20 -C(O)-NH-;
-C(O)-NR$-, wherein RS is as described above;
-C(O)-;
-NRS-C(O)-, wherein RS is as described above; and -C(=NH)-NH-;
25 R1 is selected from the group consisting of:
(a) hydrogen;
(b) hydroxy;
(c) -O-C1-C3-alkyl;
(d) -O-C3-Cg-cycloalkyl;
30 (e) -O-C1-C3-alkyl-C3-Cg-cycloalkyl;
-O-C(O)-Cl-C3-alkyl;
(g) -O-C(O)-O-Cl-C3-alkyl; a.nd (h) -O-C(O)-NH-C1-C3-alkyl;
R2 is hydrogen or a hydroxy-protecting group, as defined below; and 35 Z is hydroxy or protected-hydroxy;
except when the compound is of Formulas (I) or (1Tl) then A, B, D, and E may not all be hydrogen, D and E may not be C1-C3-alkyl when A and B are hydrogen, nor may one of D
and E be hydrogen and the other be Cl-C3-alkyl when A and B are hydrogen;

W~ 97/17356 PCT/US96/16585 the method comprising:
(a) treating a compound having the formula:
' CH3 NMe2 O 2R0~~
HaCi,,, .RCH3 HO n.~ ..." O CH3 HO
HaCr ~ CHa O,, CH3 CH3 CH3 ~~
O ~~~ ORZ
H,c ~~°ocH, , (compound (2) from Scheme 1), CHs RZ NMe2 O
O,, HaC~. ~'RCHa HO i...
....,0 O CH3 HO
H ~; CH
O O-Cbz (compound (6) from scheme 2), CHs RZ NMe2 O
0,,, HsCi.. ~'RCH~
F~ a..
""~O O CH3 HO
HaCr O CHa O
CHs CH3 O
(compound (7) from Scheme 3), or CHs RZ NMez O
O,, i H3C~~ ~RCH3 HO,...
""~O O CHI
HO
HaCo; CHa O

O
(compound (9) from Scheme 4), respectively, wherein R1 is as described above and RZ is a hydroxy-protecting group, with a base, such as sodium hydride, lithium hydride, potassium carbonate, for example, and followed by reaction with carbonyldiimidazole, in an aprotic solvent, as defined above, which does not adversely affect the reaction, preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof, with cooling or WO 97/17356 PCT/iJS96/16585 heating, depending on the conditions used, at a reaction temperature from -20°C to 70°C, preferably from 0°C to reaction temperature, for a period from 0.5 to 24 hours, preferably 1-8 hours, to prepare first intermediate compounds having the formulas:
CH3 NMaz O zRO,, H3C Ri '~ C H3 / "~~~O O CH3 N~ N O
H3C~ CH3 p ' O,, O CH3 CHa CH3 O ~~ ~ ORz H3c ~~~'ocH3 , (compound (3) from Scheme 1), CH3 RZ NMep 0,,.
R' H3C ~ CHs N~ N O / .~.n O CH3 HsC~' OC ZHa CHs x ' CH3 (compound (6) from Scheme 2) CH3 RZ NMe2 ' I
O,, N~ N\ _ O CH3 'OIL =Hs (compound (8) from Scheme 3), or CHa RZ NMe2 N~ N\ _ O CH3 'O'~ %Ha (compound ( 10) from Scheme 4), respectively; wherein R 1 and R2 are as described above;
(b) reacting said first intermediate compounds (3), (6), (8), or ( 10) with a compound having the formula:

D
OH
E ~...
A
g NHz wherein A, B, D, and E are as described above, preferably in a solvent such as aqueous acetonitrile, DMF or aqueous DMF, to give the bicyclic second intermediate compounds:
D OH CHs NMez E,..
A O zRO,,.
Bv H3C ~ RCH3 O? N ,.... ....~ p O CH3 \O
HsC. ~CH3 ' 0,,,_ O CH3 CHa CH3 O ...~ ORz H3c '''ocH3 , (compound ( 14), from Scheme 6, Y=OH), D ~ CHs NMez E,...
A~ O ~ 2R0...

O~ Ni... ...n O O CHa O
HsC~ CHs O OCbz (compound ( 18), from Scheme 8, Y=OH), CHa NMez Ei~ R
O zRO,, A
B,. Hs '' CH5 O?Nn.~ ~~.uO O CHa \O _ HaC~ ~CHa O
O
CH3 CHs (compound (22) from Scheme 10, Y=OH), or D OH CH3 NMez Ey O zRO,,, ~A
B» H3C ~RCH~
O~ N~... °.u O O CH3 O~

(compound (26), from Scheme 12, Y=OH), respectively;
(c) reacting the hydroxy group of the said bicyclic second intermediate compounds ( 14), ( 18), (22) and (26) by treatment triphenylphosphine and diphenyl-phosphoryl azide-DEAD in tetrahydrofuran, under Mitsunobu reaction conditions, to prepare the third intermediate compounds:
N3 CHs NMe2 E r~.. O
A
g~"~ H3C ' CH
a O~ N~.... ~~.~r p O CH3 O
HsC~~ CH3 O o,,..~oYcH, ~~ ~ OH
(compound ( 14), from Scheme 6, Y=N3), p N3 CHa NMe2 E r~.. O
A

.~RCHs O Nn..
O ~...r O O CH3 H3C~. CHa OCbz CHa CH3 (compound ( 18), from Scheme 8, Y=N3), p Na CHa NMe2 Ey O
A
g" HaC 'RCH

O? Nr...
\O ""'O O CH3 HaCS: CHa O
O
CHy CH3 , (compound (22) from Scheme 10, Y=N3), or p Na CH3 NMe2 E r~.. O
A
gy HaC 'RCH3 O N~...
""'O O CHs HaC.: CHa O
CHs CH3 (compound (26), from Scheme 12, Y=N3), respectively;
(d) reducing the third intermediate compounds having an azido group, with suitable reducing reagents such as triphenylphosphine-water, hydrogen with a catalyst, sodium borohydride, or dialkylaluminum hydride, to prepare the fourth intermediate compounds having the formulas:

Way 97/17356 PCT/US96/16585 p NHZ CHa NMez E r.. O
A ~~..
gy HaC ~~ CHa o~Nr...
"'~ O O CHa O
H3C'~ ~CHa p -0,,,. O CHa CHa CHa ~~ ~ OH
Hac ~~'ocHa , (compound (12), from Scheme 6), NHZ CHa NMe2 ErY O
p B" HaC JRCHa OaNr... ...'~O O CHa \O
HaC.: CHa O OCbz CHa CHa (compound (16), from Scheme 8), NHZ CHa NMe2 Ey O
A
B" HaC RCH

p NI~..
"'rr O O CHa H3C' ~CHa O
O
CHa CHa (compound (20) from Scheme 10), or NHZ CHa NMe2 E r., O
A HO...
~ R' B"'-\ HsC , CHa O~N ' O O CH
O .~ n a HaC' ~CHa O
CHa CHa , (compound (24), from Scheme 12), respectively; and (e) cyclizing said fourth intermediate compounds ( 12), ( 16), (20) or (24), wherein Y is an amino group, by treatment with dilute acid, such as acetic acid or HCI, for example, in an organic solvent, preferably ethanol or propanol, for a period of from 4 hours to 10 days to give the desired compounds of Formulas (I), (II), (III) or (IV).
In an alternate embodiment of the alternate process above, the third intermediate compounds may be prepared by a two-step sequence (replacing step (c) thereof) which comprises ( 1 ) reacting the hydroxy group of the bicyclic second intermediate compounds with an alkyl or aryl sulfonyl chloride, an alkyl or aryl sulfonic anhydride or trifluoromethanesulfonic anhydride in an aprotic solvent at -78°C to reaction temperature to give the corresponding sulfonate, and (2) reacting the said sulfonate with lithium azide or sodium azide in an aprotic solvent at 0°C to 100°C to give the third intermediate compound.
peflnitions The terms "C1-C3-alkyl" or "C1-C6-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 C1-C3 alkyl radicals include methyl, ethyl, propyl and isopropyl, and examples of C1-C6-alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl.
The term "Cl-C6-alkoxy" as used herein refers to an C1-C6-alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.
Examples of Ci-C6-alkoxy, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, ~a-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
The term "C1-C3-alkyl-amino" as used herein refers to one or two Cl-C3-alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. Examples of C1-C3-alkyl-amino include, but are not limited to methylamino, dimethylamino, ethylamino, diethylamino, and propylamino.
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 obvious 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:
(.~reanic 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.
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.
The term "C3-CS-cycloalkyl- and C3-C7-cycloalkyl" 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.

The term "C1-C3-alkyl-C3-C5-cycloalkyl", as used herein refers to a C3-C5-cycloallcyl radical, as defined above, attached to a Cl-C3-alkyl radical by replacement of a hydrogen atom on the Latter.
The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.
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.
The term "heterocycloallcyl" 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.
"Hydroxy-protecting group", as used herein, refers to an easily removable group to which are known in the art to protect a hydroxyl 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 Group in Or anic 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.
A 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.
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 obvious 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 P~~sical Pro erties aid 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.
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 Cl, Br, l~, I, OH, Ct-C3-alkyl, Ct-C6-alkoxy, methoxymethoxy, amino, or alkyl-amino.
The teml "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 Cl, Br, F, I, OH, Ct-C3-alkyl, Ct-C6-alkoxy, methoxymethoxy, amino, or Ci-C3-alkyl-amino.
The term "substituted heterocycloalkyl'' as used herein, refers to a heterocycloallcyl group, as defined above, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, Ct-C3-alkyl, Ct-C6-alkoxy, methoxymethoxy, amino, or C1-C3-alkyl-amino.
Numerous asymmetric centers may exist in the compounds of the present invention.
Exceptwhere 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.
As used herein, the term "pharmaceutically acceptable salt" refers to those salts 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, 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), 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, malefic acid, tartaric acid, citric acid, succinic acid or maloruc acid or by using other methods used in the art such as ion exchange. Other pham~aeeutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyelopentanepropionate, W~ 97/17356 PCT/US96/16585 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. p'urther 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.
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 a.lkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters includes formates, acetates, propionates, butyates, acrylates and ethylsuccinates.
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 Garners. 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 aluminum 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 judgment 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.

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, tetrahydrofiufuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants 0 such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
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 5 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 20 synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
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 25 medium prior to use.
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, 30 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. Injecta.ble 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 35 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.

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.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mused with at least one inert, pharmaceutically acceptable excipient or earner such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, i0 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 15 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.
Solid compositions of a similar type may also be employed as fillers in soft and hard-20 filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, 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 25 also be of a composition that they release the active ingredients) 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.
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 30 molecular weight polethylene glycols and the like.
The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating a.rt. In 35 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 a magnesium stearate and microcrystalline cellulose. In the case of WO 97/17356 PC'T/US96/16585 capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredients) 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.
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.
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.
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.
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.
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 judgment. 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 speck compound employed; and like factors well known in the medical arts.
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 from about 10 mg to about 1000 mg of the compounds) of this invention per day in single or multiple doses.
Abbreviations 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]under-7-ene; DEAD
for diethylazodicarboxylate; DMF for dimethyl formamide; DPPA for diphenylphosphoryl azide;
EtOAc for ethyl acetate; MeOH for methanol; NaN(TMS)2 for sodium bis(trimethylsilyl)amide; NMMO for N-methylmorpholine N-oxide; TEA for triethylamine;
THF for tetrahydrofuran; TPP for triphenylphosphine.
Synthetic Methods 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, B, D, E, R1 and R2 are as defined above unless otherwise noted below.

Scheme 1 Preparation of Starting Materials, 12-imidazolylcarbonyloxy macrolide (3) for Compounds of Formula (I) CH3 NMe2 CH3 NMe2 O ~ ~~.. O 2R0 HaCi. R ~ i..
CH3 2 ~"~3C~~ CH3 HOd.. ~ ...., O O CH HOn..
HO 3 protect HO ""'O O CH3 HaC.; CHa -----~ HaC'.. CHa O O,, O CHa CHs CH3 - CH O C03 ~. O CH3 O 4" . O
OH .~' ORZ
HsC ~~OCHa HaC ~~OCH3 ('1 ) (2) R' is as described for formula I R2 is a hydroxy-protecting group NaH-CDI
CH3 NMe2 O ZROi.

""~O O CH3 N~ N O
H3C~ CH3 O O,, O CHI
CH' CH3..
O ~~ ~ ORZ
H3C ~OCH3 (3) R ~ is as described for formula I
R2 is a hydroxy-protecting group Scheme 1 illustrates a general procedure for preparing the starting material, imidazolylcarbonyloxy macrolide (3), for compounds of Formula (I). The 2'- and 4"-hydroxyl groups of compound ( 1 ) are protected by reacting ( 1 ) with suitable hydroxy group protecting reagents (cf. T. W. Greene and P. G. M. Wuts, protective nouns in Org nic Synth, 2nd ed., John Wiley & Son, Inc., 1991) such as acetic anhydride, benzoic anhydride, benzyl chloroformate or a trialkylsilyl chloride in an aprotic solvent, as defined above, which does not adversely affect the reaction, preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof.

W~ 97/17356 PCT/LTS96/16585 The protected macrolide (2) is reacted under anhydrous conditions with base such as sodium hydride, lithium hydride, potassium carbonate and followed by carbonyldiimidazole to form compound (3) in an aprotic solvent, as defined above, which does not adversely affect the reaction, preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof. The reaction may require cooling or heating, depending on the conditions used. The reaction temperature may be from -20°C to 70°C, and preferably from 0°C to reaction temperature. The reaction may require 0.5 hours to 10 days, and preferably 1-5 days, to complete.
Scherrle 2 Preparation of Starting Materials, 12-imidazolylcarbonyloxy macrolide (6). for Compounds of Formula (II) CH3 NMe2 ~Ha RZ NMe2 O HO~.
~R~
iaCi.. . CHa r.. ~..rr0 O CH3 H+ CHI

0 0,,..~oYCH3 r 'OH
HaC~~OCH~ (4a) R2 = li R1 is as described for formula II (4) R2 = hydroxy- protecting group CH3 RZ NMe2 CHI RZ NMe2 O ~ O
0,,, O,r H3C 'RCH Ri H3C,,. v CH3 / ...rr0 O CHI O~Om.. ~rn0 O CH3 N~N~H3C~' CHs NaH-CDI ~.' cH, O ~O-Cbz O 'O-Cbz CH3 CHI CHa CHs O
(g) ( R1 is as described for formula II R2 is a hydroxy-protecting group R2 is a hydroxy-protecting group Scheme 2 illustrates a general procedure for preparing the starting materials, imidazolylcarbonyloxy macrolide (6), for the preparations of compounds of formula (II).
The cladinose moiety of macrolides of formula (1) is removed either by mild aqueous acid hydrolysis of by enzymatic hydrolysis. In accordance with Scheme 2, a suspension of (1) in WO 97/17356 PCT/fJS96/16585 a solution of protogenic organic solvent (for example methanol, ethanol, isopropanol or butanol) and water is treated with dilute hydrochloric acid, chloroacetic acid, dichloroacetic acid or trifluoroacetic acid for 0.5 to 24 hours. The reaction temperature is preferably -10 to 35 °C to give the des-cladinose compounds (4a). The 2'-hydroxy group of (4a) is protected and converted to (4a) by treatment with a suitable hydroxy protecting reagent (cf. T. W.
Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley &
Son, Inc., 1991 ) such as acetic anhydride, benzoyl anhydride, benzyl chloroformate or trialkylsilyl chloride in an aprotic solvent, as defined above, preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof.
The protected macrolide (4) is reacted under anhydrous conditions with base such as sodium hydride, lithium hydride, potassium carbonate or dimethylaminopyridine and followed by phosgene, diphosgene, triphosgene or benzyl chloroformate in an aprotic solvent, as defined above. The reactive intermediate is then trapped with benzyl alcohol to give compound (5).
Compound (5) is reacted under anhydrous conditions with NaH and CDI in an aprotic solvent, preferably THF, DMF or a mixture thereof. The reaction may require cooling of heating, depending upon the conditions used. The reaction temperature may be from -20°C
to 70°C, and preferably from 0°C to reaction temperature. The reaction may require 0.5 hours to 10 days, and preferably 1-5 days, to complete.

Scheme 3 Preparation of Starting Materials, 12-imidazolylcarbonyloxy xnacrolides, for Compounds of Formula (III) CHa R2 NMeZ CHs Rz NMez o I
O~~ O
i H3C~~~ RCH3 H3Cir~ ~CH3 HOr... .~~~r0 O CHs ~m~. ...rr0 O CH3 HO Hp H3C~'~ 3 CHs ~~ H3Cv' 3 CHI
O OOH O O
CHs CH3 CH3 CH3 O O
(4) NaH-CDI
CHs RZ NMep CH3 RZ NMea I I
O 0,,, O Oi~.
iC .R~ HaC RCHs / ....r p ~ O CHs O~ / ...rr O O CH3 NaH-CDI
CHa ---w. HaC~: O CHs O O

O O
~a) R' is as described for formula III
R2 is a hydroxy-protecting group Scheme 3 illustrates two general procedures for the synthesis of 12-imidazolylcarbonyloxy macrolide (8), starting materials for the preparation of compounds of formula (III). In accordance with scheme 3, the 3-hydroxy group of a 2'-protected des-cladinose macrolide (4) is oxidized to the corresponding 3-oxo compound (7) using a modified Swern oxidation procedure. In scheme 3, suitable oxidizing agents are N-chlorosuccinimide-dimethyl sulfide or carbodiimide-dimethylsulfoxide. In a typical example, (4) is added into a pre-formed N-chlorosuccinimide and dimethyl sulfide complex in a chlorinated solvent such as methylene chloride at -10 to 25 °C.
After being stirred for 0.5-4 hours, a tertiary amine such as triethylamine or Hunig's base is added to produce the oxidized compound (7).
In the first approach in scheme 3, (7) is reacted with sodium hydride or lithium hydride and CDI under anhydrous conditions in an aprotic solvent, as defined above, which does not adversely affect the reaction, preferably dichloromethane, chloroform, DMF, _ -37-tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof. The resulting allcoxide is then reacted with excess carbonyldiimidazole for 0.5 hours to 10 days in the same reaction mixture to produce (8). The preferred temperature is from -10 °C to reaction temperature.
In the second approach in Scheme 3, (7) is converted to (7a) with sodium hydride or lithium hydride and phosgene, diphosgene or triphosgene under anhydrous conditions followed by aqueous work up. Alternatively, (7) is converted to its corresponding 11-mesylate by reacting (7) with methanesulfonic anhydride in pyridine. The 11-mesylate is then converted to (7a) with an amino base such as DBU or dimethylaminopyridine in acetone or acetonitrile. (7a) is then reacted with sodium hydride or lithium hydride under anhydrous 1o conditions in an aprotic solvent, as defined above, which does not adversely affect the reaction, preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof. The reactive alkoxide is then reacted with carbonyldiimidazole for 0.5 hours to 10 days in the same reaction mixture to produce (8).
The preferred temperature is from -10 °C to reaction temperature.

W~ 97/17356 PCT/US96/16585 Scheme 4 Preparation of 12-imidazolylcarbonyloxy macrolides (10). for Compounds of Formula IIVI
CH3 Rz NMe2 CH3 R2 NMe2 O R~ O'.,. O R ~ O'.,.
H3C~'~ ° CH3 H3C~~.~ ~ CH3 Ho",. '...,o o cH3 1. NaH CS eo~,..
' O O CH3 H° 2. Bu3SnH, AIBN Ho H3C~ ~CH3 H3C~ CH3 p 'OH O
CHa CH3 CH3 CH3 O O
(5) (9) NaH-CDI
N CHI RZ NMe2 I
o,,, HaC RCH3 O~ / ~~~u O O CH3 O
H..C~' CH3 CH3 ~ ~ CH3 R' is as described for formula III
R2 is a hydroxy-protecting group In accordance with Scheme 4, a protected descladinose compound of formula (5) is dissolved in an aprotic solvent such as THF, then reacted with an excess of NaH at from 0°C
to -30°C under an inert atmosphere, followed by reaction of the intermediate anion with CS2, then CH3I at -5 to 10°C, to form a 3-O-xanthyl compound. This xanthate intermediate is then reacted with 1.1-1.3 equivalents of Bu3SnI-I under an inert atmosphere in the presence of a catalytic amount of AIBN in a solvent suitable for a free radical reaction, such as benzene or toluene, for example, at reflux conditions to afford the desired compound (9).
Compounds (9) are then reacted with carbonyldiimidazole and NaH under anhydrous conditions in an aprotic solvent, as defined above, which does not adversely affect the reaction, preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof, at a temperature from 0°C to reaction temperature for 0.5 hours to 10 days to provide the compounds of formula ( 10).

Scheme 5 Preparation of Compound of Formula (I) CHs NMez O Z p NH2 CEb NMei FiOr.. p Err..
Ri O x H3C ~ CH3 E rr.. NHZ A~ R~ ROr'~~
/ A B~,~.~/ I-6C ~~ CHs \ N O ~~~np O CI~ '~ O~Nr... ...rr O CH
g' NHz a w H3C~ C~ It,C~~ CH
O ~0~, O CH3 CHa CHs .

CH3 CH3 ~~
O
I~rORz O
(11) .,.oRz (3) HsC .'FOCI-~
R 1 is as described for formula I
R2 is a hydroxy-protecting group deprotect E~~~ NMex D NHz ~3 NMe2 Err.. p HO
''/ ..
B~ r'' A I-bC R
CHa O
CH3 ~
O
~Nn.. ~~,rr O CHa O
g O' - CH3 O
Nrr~. ~~,rr CyCIIZe H3C~~ CH3 w _ F~,C~~ _ CH3 p ~1,,. CH3 Or., CH3 CHa CH3 CI-h .
O ~~~ ~ O .,~ OH
(13) H,c ~~'ocH, (12) Et,c ~°ocH, Compound of Formula (I).
In accordance with Scheme 5, a starting material compound of formula (3) is reacted with a diamine compound having substituents A, B, D and E as defined above but with C2 or Cs symmetry or A=B=H, in a suitable solvent, such as for example, aqueous acetonitrile, DMF or aqueous DMF, to give the bicyclic compound of formula ( 11 ). The 2' and 4"
hydroxy protecting group of compound ( 11 ) are then removed by standard methods (cf. T.
W. Greene and P. G. M. Wuts, Protective C~roun~ in rganic Svnthe~ie, 2nd ed., John Wiley & Son, Inc., 1991 ) to give ( 12). When OR2 is an ester, for example, such as acetate or benzoate, the compound may be deprotected by treatment with methanol or ethanol.
When R2 is a trialkylsilyl group, the compound may be deprotected by treatment with fluoride in THF or acetonitrile, for example. Compound ( 12) is then cyclized by treatment with dilute acid, such as acetic acid or HCI, for example, in a suitable organic solvent, such as methanol, ethanol or propanol, for example, for a period of from 4 hours to 10 days, from reaction temperature to reflux, in order to prepare the compound of formula (13).

a~t~ ~ f ~~~ ~}

Scheme 6 Alternate Preparation of Compounds of Formula (n NMe~ p y C!-la NMez O ~p~y D ~ O 'RCL..
EI,C ~~ E~... ~ A, H~ R.
. A 8 "'~ O O C rY... , Fi, ~ .. "O O CF[, NHx O
':
H~ CH, O O i'.. O ~' Y=~H O ~.. O CH, OR O ..' OR:
H,c ~ocH, (14 H,c ocEh R' is as described for formula I
RZ is a hydroxy-protecting group En. D Oli, NMei p'' NHi ~' NMe, E ~..
A ~ HCy.. p~ O H~~.
R' I-hCi, ~ ~ g~. HOC ~ CH
' p Nr...
p Nr.... - ~~ ? ~ O O
O O CHI Cy0111e H,Oa ~ ~ H,O' OH, O, ~ CFL, D On,, O CH, O
O O ~~~~ OH
OH
(13~ 1-t~C OCH, (12~ H,C ~~OCH~
Compound of Formula (I).
Scheme 6 illustrates an alternative preparation of compounds of formula (I).
Starting material (3) is reacted with a beta-aminoalcohol (Y=OH) having substituents A, B, D and E, as defined above, in a suitable solvent system such as aqueous acetonitrile, DMF or aqueous DMF at 0 - 70 °C to give compound (14) where Y=OH. The azido intermediate, compound ( 14) Y=N3, is prepared by Mitsunobu reaction by reacting compound ( 14) Y=OH
with triphenylphosphine and diphenylphosphoryl azide-DEAD in tetrahydrofuran.
Compound (14) is then deprotected by standard methods (cf. T. W. Greene and P. G. M.
Wuts, Protective Groups in OrfJanic Synthesis, 2nd ed., John Wiley & Son, Inc., 1991). When OR2 is an ester, for example, such as acetate or benzoate, the compound may be deprotected by treatment with methanol or ethanol. When R2 is a trialkylsilyl group, the compound may be deprotected by treatment with fluoride in THF or acetonitrile, for example.
The azido intermediate, compound (14) Y=N3, is then reduced to the amino compound (12).
Suitable reducing reagents are triphenylphosphine-water, hydrogen with a catalyst, sodium borohydride, or dialkylaluminum hydride. Compound (12) is then cyclized by treatment with dilute acid, such as acetic acid or HCl, for example, in a suitable organic solvent, such as methanol, ethanol or propanol, for example, for a period of from 4 hours to 10 days, in order to prepare the compound of formula ( 13).
Alternatively in scheme 6, the hydroxy group (Y=OH) in ( 14) is activated by treatment with sulfonyl chloride, alkyl or aryl sulfonic anhydride or trifluoromethanesufonic anhydride in an aprotic solvent (e.g., diethyl ether, dichloromethane, tetrahydrofuran, chloroform, pyridine or a mixture thereof). The reaction requires cooling or heating, depending on the conditions used. The reaction temperature is preferably -100 to 10 °C.
The reaction may require 20 minutes to 24 hours to complete. The activated hydroxy group in (14) (e.g., Y=-OS02CF3) is then converted to the corresponding azide (Y=N3, 14) by reacting with lithium azide or sodium azide in the same solvent described above. The reaction temperature is preferably 0-100 °C. The azido compound is then converted to (I3) according to the procedures described above.

Scheme 7 Preparation of Compounds of Formula (II) aa, NMe, p N~ G-la NMe.
'RO, p Eu... zR~, R' tdii A ~ Rn a ~ En...
/ ..." A
O O CHI p? N....
~N B' ~.. \O ...np ~/ O H'O ~ ~'bC'° ci-L.
~ O~x C
o (6) O (iCJ) R~ is as described for formula I
Rz is a hydroxy-protecting group deprotect E~ p ~' . NMe1 p NHi ~' NMei En..
A \ HCy.. A HO~.
B~ ~cm. 'Rq.b g,. H~
Nr... , Q Nr...
.. o o ~ cyclize ~ ...,.o a~, ~c'~~ ~ °H~ H,c'' oceZ ocbz cr6 cH, a-6 cH, (17) (16) Compound of Formula (11) In accordance with Scheme 7, a starting material compound (6) is reacted with a diamine compound having substituents A, B, D and E as defined above but with C2 or Cs symmetry or A=B=H, in a suitable solvent, such as for example, aqueous acetonitrile, DMF
S or aqueous DMF, to give the bicyclic compound of formula (15). Compound (15) is then deprotected to prepare the compound of formula ( 16). The deprotection is accomplished by standard methods described (cf. T. W. Greene and P. G. M. Wuts, Protective Groups in Glr a~ic Synthesis, 2nd ed., John Wiley & Son, Inc., 1991). When OR2 is an ester, for example, such as acetate or benzoate, the compound may be deprotected by treatment with methanol or ethanol. When R2 is a trialkylsilyl group, the compound may be deprotected by treatment with fluoride in THF or acetonitrile, for example. Compound (16) is then cyclized by treatment with dilute acid, such as acetic acid or HCl, for example, in a suitable organic solvent, such as ethanol or propanol, for example, for a period of from 4 hours to 10 days, from reaction temperature to reflux, in order to prepare the compound of formula ( 17).

SUBSTITUTE SHEET (RULE 26) WO 97/17356 PC"T/US96/16585 Scheme 8 Alternate Preparation of Compounds of Formula (IIl H NMh ~~NH; CH, HMS
O ,per E n.~~'.
O
' 'AO,, Ha A
'' CH, Em. NH' H R.
B' "'NO O CH, A~ O W,.. n H~N~O B~' NH. ~ ~~~ O O GH, C H, O
O H'C~~ CH, O OCbx H,C
CH, CH, O OCbx CH, CH, O
(6) o (15) R~ is as described for formula I
R2 is a hydroxy-protecting group deprotect CH, NM~, NHr CH, NM~, A N HO,I Em O
A H O,, Bn~G... ' CH B H' '' CH
O~ N,... . O? N".. ....,0 ~ C H
° ~~"o o cH, cycllze o ' HaCV: CH, H,C4: CH, O OCbx O OCbx CH, CH, CN, CH, O O
(17) (16) Compound of Formula (II) Scheme 8 illustrates an alternative preparation of compounds of formula (II).
Starting material (6) is reacted with a beta-aminoalcohol (Y=OH) having substituents A, B, D and E, as defined above, in a suitable solvent system such as aqueous acetonitrile, DMF
or aqueous DMF at 0 - 70 °C to give compound ( 18) where Y=OH. The azido intermediate, compound (18) Y=N3, is prepared by Mitsunobu reaction by reacting compound (18) Y=OH with triphenylphosphine and diphenylphosphoryl azide-DEAD in tetrahydrofuran.
Compound ( 18) is then deprotected to prepare the compound of formula ( 16) wherein R2 is H. The deprotection is accomplished by standard methods (cf. T. W. Greene and P. G. M.
Wuts, Protective Groups in Or. anic Synthesis, 2nd ed., John Wiley & Son, Inc., 1991).
When OR2 is an ester, for example, such as acetate or benzoate, the compound may be deprotected by treatment with methanol or ethanol. When R2 is a trialkylsilyl group, the compound may be deprotected by treatment with fluoride in THF or acetonitrile, for example. The azido intermediate, compound ( 18) Y=N3, is then reduced to the amino compound (16). Suitable reducing reagents are triphenylphosphine-water, hydrogen with a SUBSTITUTE SHEET (RULE 26) WO~ 97/17356 PCT/iJS96/16585 catalyst, sodium borohydride, or dialkylaluminum hydride. Compound ( 16) is then cyclized by treatment with dilute acid, such as acetic acid or HCI, for example, in a suitable organic solvent, such as methanol, ethanol or propanol, for example, for a period of from 4 hours to days, from reaction temperature to reflux, in order to prepare the compound of formula . s (17).
Alternatively in scheme 8, the hydroxy group (Y=OH) in (18) is activated by treatment with sulfonyl chloride, alkyl or aryl sulfonic anhydride or trifluoromethanesufonic anhydride in an aprotic solvent (e.g., diethyl ether, dichloromethane, tetrahydrofuran, chloroform, pyridine or a mixture thereof. The reaction requires cooling or heating, 1o depending on the conditions used. The reaction temperature is preferably -100 to 10 °C.
The reaction may require 20 minutes to 24 hours to complete. The activated hydroxy group in (18) (e.g., Y=-OS02CF3) is then converted to the corresponding azide (Y=N3, 18) by reacting with lithium azide or sodium azide in the same solvent described above. The reaction temperature is preferably 0-100 °C.- The azido compound is then converted to (13) according to the procedures described above.

Scheme 9 Preparation of Comt~ounds of Formula IIII) C_H, NMv, C ~RO,, p Em. NH CH NMV, H~ R' NHr ~ ~O rROrr '' CH Er.., R.
...., A 6~~ H' '' CHI
O O CH, O Nr", O B' NH, ~ .~'~r0 O CH, CH, O
O HrC: O O HrCa; O CHr CH, CH, O
CH, CH, O
(8) o (19) R~ is as described for formula I
RZ is a hydroxy-protecting group deprotect ~pro~~
cyclize CHr NMv, NH CH' NM~, A HOp Eh~. r0 HO,.
aC R~ A~_ [/ R.
r'' ' CHr 9"' \ Ha '' CH, o w.... ~ w....
"'~~O O CH, O~ "'.r0 O CH, O~ CYCIIZA p H C~ I ~ o CHa ~ H~~' CH, O O
CH, CH, CH, CH, O O
(21 ) (2~) Compound of Forrnula (III) In accordance with Scheme 9, a starting material compound(8) is reacted with a diamine compound having substituents A, B, D and E as defined above but with C2 or Cs S symmetry or A=B=H, in a suitable solvent, such as for example, aqueous acetonitrile, DMF
or aqueous DMF, to give the bicyclic compound of formula ( 19). Compound ( 19) is then deprotected prepare the compound of formula (20). The deprotection is accomplished by standard methods (cf. T. W. Greene and P. G. M. Wuts, Protective Groups in Or anic nthe is, 2nd ed., John Wiley & Son, Inc., 1991). When OR2 is an ester, for example, such as acetate or benzoate, the compound may be deprotected by treatment with methanol or ethanol. When R2 is a trialkylsilyl group, the compound may be deprotected by treatment with fluoride in THF or acetonitrile, for example. Compound (20) is then cyclized by treatment with dilute acid, such as acetic acid or HCI, for example, in a suitable organic solvent, such as ethanol or propanol, for example, for a period of from 4 hours to 10 days, from reaction temperature to reflux, in order to prepare the compound of formula (21 ).

SUBSTITUTE SHEET (RULE 26) WQ~ 97/17356 PCT/US96/16585 Alternately, as is readily apparent to those skilled in the art it is possible to cychze compound (19) first, then deprotect, to obtain the compound (21).
Scheme 10 Alternate Preparation of Compounds of Formula (l~l NMei p ,, CI-Lr NMer O r ZRO~. p E u. O TROT
E6C E rr.. Y A R.
~'r ~ A g ~ ~p ° CH, " O O CH, O N ... ..nr ~ N~ ~ O O CH, O H~ O CHr H~C~. CHI
~O
Y=OH ~o G-I, CFh o ($) o (22) R' is as described for formula I
RZ is a hydroxy-protecting group p ~ NMei p NHz ~' NMar E...LL Err.
A- / ~ Rr. HO, A O Rr. HQ~
B' ~ FhC~.. ~ CHa g H,C '~ CH
a ~Nr... ~ ..rrO O ~ ~N.o' ~.nO O CH
p CYCItZe H,C O CH' ~ HoC~~' ~ CE6 O O
CJ-la CH, CH, Ch6 O O
(21 ) (2~) Compound of Formula (III) Scheme 10 illustrates an alternative preparation of compounds of formula (III).
Starting material (8) is reacted with a beta-aminoalcohol (Y=OH) having substituents A, B, D and E in a suitable solvent system such as aqueous acetonitrile, DMF or aqueous DMF at 0 - 70 °C to give compound (22) where Y=OH. the azido intermediate, compound (22) Y=N3, is prepared by Mitsunobu reaction by reacting compound (22) Y=OH with triphenyl-phosphine and diphenylphosphoryl azide-DEAD in tetrahydrofuran. Compound (22) is then deprotected by standard methods (cf. T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Son, Inc., 1991 ). When OR2 is an ester, for example, such as acetate or benzoate, the compound may be deprotected by treatment with methanol or ethanol. When R2 is a trialkylsilyl group, the compound may be deprotected by treatment with fluoride in THF or acetonitrile, for example. The deprotected azido SUBSTITUTE SHEET (RULE 2fi) intermediate, compound (22) Y=N3, is then reduced to the amino compound (20).
Suitable reducing reagents are triphenylphosphine-water, hydrogen with a catalyst, sodium borohydride, or dialkylaluminum hydride. Compound (20) is then cyclized by treatment with dilute acid, such as acetic acid or HCl, for example, in a suitable organic solvent, such as methanol, ethanol or propanol, for example, for a period of from 4 hours to 10 days, from reaction temperature to reflux, in order to prepare the compound of formula (21 ).
Alternatively in scheme 10, the hydroxy group (Y=OH) in (22) is activated by treatment with sulfonyl chloride, alkyl or aryl sulfonic anhydride or trifluoromethanesufonic anhydride in an aprotic solvent (e.g., diethyl ether, dichloromethane, tetrahydrofuran, chloroform, pyridine or a mixture thereof. The reaction requires cooling or heating, depending on the conditions used. The reaction temperature is preferably -100 to 10 °C.
The reaction may require 20 minutes to 24 hours to complete. The activated hydroxy group in (22) (e.g., Y=-OS02CF3) is then converted to the corresponding azide (Y=N3, 14) by reacting with lithium azide or sodium azide in the same solvent described above. The reaction temperature is preferably 0-100 °C. The azido compound is then converted to (13) according to the procedures described above.

Scheme 11 Preparation of Compounds of Formula (N7 NMei D ~s CHa NMei O 'ROy p Er.. O a RO.,, F[,C .R~~ Er... N~ A C Rn a ~ H~ ' ~b .....0 O O~~ A O Nr... ...., O g~ N~ ~ O O CH, O H~ ~ wCH~ H~C~,. CH, O O
CI-l, CH, p (10) p (23) R~ is as described for formula I
RZ is a hydroxy-protecting group d~rotect D CHI NMe, D NHs U~~ NMer W R. A R.
A~N HC1.. Er "\ O H4~~
B E6Cr... ' CHI ~ g.r HOC ~ CH
O~t~l... ....e0 O Cfi~ p~Nr... ..rr0 O CFir p CYCIIZe ~Cv: C~ ~-~C~: wCH, O
CHI CH, C~"6 CF6 O O
(24) Compound of Formula (IV) In accordance with Scheme 11, a starting material compound ( 10) is reacted with a diamine compound having substituents A, B, D and E as defined above but with C2 or Cs symmetry or A=B=H, in a suitable solvent, such as for example, aqueous acetonitrile, DMF
or aqueous DMF, to give the bicyclic compound of formula (23). Compound (23) is then deprotected to prepare the compound of formula (24) by standard methods (cf.
T. W.
Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Son, Inc., 1991 ). When OR2 is an ester, for example, such as acetate or benzoate, the compound may be deprotected by treatment with methanol or ethanol. When R2 is a trialkylsilyl group, the compound may be deprotected by treatment with fluoride in THF or acetonitrile, for example. Compound (24) is then cyclized by treatment with dilute acid, such as acetic acid or HCI, for example, in a suitable organic solvent, such as ethanol or propanol, for example, for a period of from 4 hours to 10 days, from reaction temperature to reflux, in order to prepare the compound of formula (25).

SUBSTtTUTE SKEET (RULE 26) Scheme 12 Alternate Prena_ration of Compounds of Formula fIV) NMei D E D~~ y'Y ~' NMei E r~ Y q~ O R~' Z RO,,, B HOC
r0 O CI-h g ~2 O~Nr... '~~~.r0 O Cfir O
H~O~~' OHM
Y=OH
~h G-6 (10) ~ (26) R~ is as described for formula I
RZ is a hydroxy-protecting group c E r.. H, ~°~ D NHx ~' NMs, q HO~, E O
q HO., B"". Hero.. ~ CFir g HOC
Nr... ~
"' O O q.h Nr... ...r p~
CyCIiZB
E60 Clip H~'f CH, O
CHI ~ CF{, CI-[, D O
(25) (24) Compound of Formula (IV) Scheme 12 illustrates an alternative preparation of compounds of formula (IV).
Starting material ( 10) is reacted with an beta-aminoalcohol (Y=OH) having substituents A, B, D and E, as defined above, in a suitable solvent system such as aqueous acetonitrile, S DMF or aqueous DMF at 0 - 70 °C to give compound (26) where Y=OH.
The azido intermediate, compound (26) Y=N3, is prepared by Mitsunobu reaction by reacting compound (26) Y=OH with diphenylphosphoryl azide-DEAD in tetrahydrofuran.
Compound (26) is then deprotected by standard methods (cf. T. W. Greene and P.
G. M.
Wuts, Protective Groups in Oreanic Synthesis, 2nd ed., John Wiley & Son, Inc., 1991).
When OR2 is an ester, for example, such as acetate or benzoate, the compound may be deprotected by treatment with methanol or ethanol. When R2 is a trialkylsilyl group, the compound may be deprotected by treatment with fluoride in THF or acetonitrile, for example. The deprotected azido intermediate, compound (26) Y=N3, is then reduced to the amino compound (24). Suitable reducing reagents are triphenylphosphine-water, hydrogen with a catalyst, sodium borohydride, or dialkylaluminum hydride. Compound (24) is then SUBSTITUTE SHEET (RULE 26) W~ 97/17356 PCT/US96/16585 cyclized by treatment with dilute acid, such as acetic acid or HCl, for example, in a suitable organic solvent, such as methanol, ethanol or propanol, for example, for a period of from 4 hours to 10 days, in order to prepare the compound of formula (25).
Alternatively in Scheme 12, the hydroxy group (Y=OH) in (26) is activated by treatment with sulfonyl chloride, alkyl or aryl sulfonic anhydride or trifluoromethanesufonic anhydride in a solvent does not adversely affect the reaction (e.g., diethyl ether, dichloromethane, tetrahydrofuran, chloroform, pyridine or a mixture thereof.
The reaction requires cooling or heating, depending on the conditions used. The reaction temperature is preferably -100 to 10 °C. The reaction may require 20 minutes to 24 hours to complete. The activated hydroxy group in (26) (e.g., Y=-OS02CF3) is then converted to the corresponding azide (Y=N3, 26) by reacting with lithium azide in the same solvent described above. The reaction temperature is preferably 0-70 °C. The azido compound may be deprotected and converted to (25) according to the procedures described above.
The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.
Exaunple 1 Compound (IV): R~--methoxy: R~hydro~en: A=B=D=E=hydrogen la. 5-O-desosaminyl-6-O-methylerythronolide A
A sample of clarithromycin (3-O-cladinosyl-5-O-desosaminyl-6-O-methyl-erythronolide A, Abbott Labs> 142.38 g, 190.35 mmol) was suspended in an ethanol-water solution (1700/600 mL), and 341 mL of 1N HCl was added. The reaction mixture was stirred for 24 hours, and 2 M NaOH (170 mL) and an additional 250 mL of water were added with vigorous stirring. The precipitate was collected by filtration, washed with water, and dried to afford the title compound (95.00 g, 84%). MS m/z: 590 (M+H)+.
lb. 3-O-xanth~ 1-5-O-desosaminyl-6-O-methylerythronolideA
To a solution of 5-O-desosaminyl-6-O-methylerythronolide A (11.79 g, 20 mmoL, from step 1 a above) in THF (100 mL) at -20°C under an inert atmosphere NaH ( 1.80 g, 60 mmoL, 60% dispersion) was added slowly over a 5 minute period. Several minutes later CS2 (1.2 mL, 20 mmoL) was added. After 5 minutes of stirring CH3I (1.24 mL, 20 mmol) was added, the reaction mixture was allowed to gradually warm to -5 -0°C, and the mixture was stirred for 1 hour. The reaction mixture was diluted with EtOAc (400 mL), and the mixture was washed with saturated aqueous NaHC03 and brine, dried (MgS04), and concentrated to afford the crude product. The residue was purified by chromatography on silica gel, eluting with CHCl3 and CHC13-MeOH (95:5), to afford the title compound (7.68 g; 56%). MS m/z: 680 (M+H)+. Anal. Calcd. for C32H5~NO1pS2: C, 56.52; H, 8.45;
N, 2.06; Found: C, 56.95; H, 8.65; N, 1.92.
~1 c. 3-deoxv-5-O-desosaminyl-6-O-methyler5rthronolide A
A solution of 3-O-xanthyl-5-O-desosaminyl-6-O-methyl erythronolide A (20.00 g;
29.41 mmoL, from step lb), Bu3SnH (9.49 mL, 35.29 mmol) and AIBN (~50 mg, catalytic) in benzene (200 mL) was heated at reflux (adding 25 mg portions of AIBN
periodically) for 8 hours. The organic layer was separated and washed with 10%
aqueous KF and brine, dried (MgS04), and concentrated to afford the crude product as an oil. The residue was purified by chromatography on silica gel, eluting with CHCl3 and MeOH (97.5:2.5). The material was recrystallizated from hexane to afford the title compound (5.48 g; 32%). MS m/z: 574 (M+H)+. Anal. Calcd. for C3pH55NO9: C, 62.80; H, 9.66; N, 2.44; Found: C, 63.02; H, 9.74; N, 2.30.
ld 2'-O-acetyl-3-deox~-5-O desosaminyl 6 O methylerythronolide A
Samples of 3-deoxy-5-O-desosaminyl-6-O-methylerythronolide A (573 mg, 1.0 mmol, from Example lc above), acetic anhydride (0.188 mL) and TEA (0.278 mL) were dissolved in 10 mL of methylene chloride, and the reaction mixture was stirred at reaction temperature for 20 hours. The reaction mixture was diluted with 40 mL of methylene chloride, and the organic solution was washed with saturated aqueous NaHC03 and brine, dried and concentrated to obtain the title compound (600 mg). MS m/z: 616 (M+H)+.
le. Compound 1101 from Scheme 4- R.1--methoxy: R2=ace 1 A sample of 2'-O-acetyl-3-deoxy-5-O-desosaminyl-6-O-methylerythronolide A
(0.63 g, 1.023 mmol, from Example ld above) was dissolved in 10 mL of THF, and the solution was cooled to -60°C. To this stirred solution was added sodium bis(trimethylsilyl) amide (1.22 mL, 1.0 M in THF). After 4 hours l, l-carbonyldiimidazole (0.66 g, 4.09 mmol) was added as a solution in 6 mL of 2:3 DMF:THF, and the reaction mixture was slowly warmed to reaction temperature and stirred for 16 hours. The reaction was quenched by addition of 5% aqueous NaH2P04, and the resulting mixture was extracted with chloroform.
The organic layer was washed with water, dried over MgS04 and concentrated to give the title compound. MS m/z: 692 (M+H)+.
lf. Compound 1231 from Scheme 11' Ri-methoxv: R2=acetyl: A=B=D=E=hvdro en A sample of the compound from step le above (0.25 g, 0.36 mmol) was dissolved in 3 mL of acetonitrile, ethylenediamine (0.24 mL, 3.6 mmol) was added, and the reaction mixture was stirred at reaction temperature for 3 hours. The solvent was removed under vacuum, and the residue was dissolved in ethyl acetate. This solution was washed with saturated aqueous NaHC03 solution, dried over Na2S04 and concentrated. The residue was twice purified by flash chromatography on silica gel, eluting with 2-20'%
ethanol in chloroform containing 0.5-2% NHq.OH to give the title compound. MS m/z: 684 (M+H)+.
1~,;- Compound 1241 from Scheme 11: R.1=methoxv: A=B=D=E=h5rdrog_en A sample of the compound from step if was dissolved in methanol and stirred at reaction temperature for 64 hours. The title compound (170 mg) was obtained after filtration and removal of the solvent.
lh. Compound (IVl : R1-methoxy: R2=hydr~en: A=B=D=E=hydrogen A sample of the compound from step 6b ( 170 mg, 0.265 mmol) was dissolved in 2 mL of ethanol to which was added 0.03 mL of acetic acid, and the reaction mixture was stirred at reaction temperature for 16 hours. The solvent was removed, and the residue was suspended in water. The solution was adjusted to approximately pH 10-11 with 2M NaOH, and the mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2S04 and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 10% ethanol in chloroform containing 0.1 %
NH40H. The product was re-chromatographed, eluting with 0-15% ethanol in chloroform to give the title compound (55 mg). MS m/z: 624 (M+H)+, 646 (M+NHq.)+. Anal.
Calcd.
for C33Hg7N3Og: C, 63.53; H, 9.20; N, 6.73; Found: C, 64.68; H, 9.27; N, 7.01.
13CNMR: C=O (16) 156.3, NCH2 (17) 42.4, NCH2 (18) 49.1 ExaBnple 2 Preparation of Intermediate Starting Material:
Compound (8) from Scheme 3: R~--methoxv-R~benzovl 2a. 5-O-desosaminvl-6-O-meth~crvthronolide A
A sample of clarithromycin (3-O-cladinosyl-5-O-desosaminyl-6-O-methylerythronolide A, Abbott Labs, 900 g, 1.2 mole) was suspended in water ( 10.8 L) and ethanol (4.0 L), and the resulting slurry was stirred at reaction temperature until homogeneous (about 20 minutes). HCl (1.00 M, 2.16 L) was added over 15 minutes, and the reaction mixture was stirred for 20 hours. NaOH solution (2.00 M, 1.20 L) was added over 30 minutes until pH 10.5-11.0 was reached, and the reaction mixture was stirred for 2 hours. The precipitate was collected and washed with cold water, which was dried under vacuum at 50°C to afford 601 g of the title compound. MS m/z (M+H)+:
590.
2b. 2'-O-benzovl-5-O-desosaminyl-6-O-methylerythronolide A
To a solution of 5-O-desosaminyl-6-O-methylerythronolide A, (600 g, 1.01 mol from step 2a above) in methylene chloride (2.0 L) was added 90% technical grade benzoic anhydride (380 g, 1.59 mol). Triethylamine (222 mL, 1.59 mol) was added over minutes, and the thick solution was stirred for 48 hours. Sodium bicarbonate solution (10%, 1.5 L) was added, and the mixture was stirred for 30 minutes. The layers were separated, and the organic fraction was washed with water (3 x 600 mL) and brine (600 mL). The organic layer was dried (Na2S04) and filtered, and the volatiles were removed on a rotary evaporator to leave a syrup. Trituration with a warm solution of hexane (2.0 L) and ethyl acetate (100 mL) converted the product to white crystals. The product was filtered, washed with hexane and dried in a vacuum oven overnight at ambient temperature to give the title compound (691 g). MS m/z (M+H)+: 694.
2c. 2'-O-benzovl-5-O-desosaminvl-3-deoxv 3 oxo 6 O methylervthronolide A
A sample of N-chlorosuccinimide (57.0 g, 0.42 mol) was slurried in anhydrous methylene chloride (600 mL), and dimethyl sulfide (36.0 mL, 0.49 mol) wa.s added dropwise over 30 minutes. A sample of the compound from step 2b (200.0 g, 0.29 mol) was dissolved in methylene chloride ( 1.20 L), and this solution was added to the reaction mixture over 45 minutes. After stirring for 30 minutes a solution of triethylamine (40.0 mL) in methylene chloride (200 mL) was added dropwise over 30 minutes at 0°C under nitrogen.
The resulting solution was washed with sodium bicarbonate ( 10%, 3 x 600 mL) and brine (600 mL). The organic fraction was dried (Na2S04) and filtered, and the volatiles were removed on a rotary evaporator to give a thick syrup, which became a solid upon standing.
The solid was crushed and dried overnight at ambient temperature in a vacuum oven to give 2o the title compound ( 196 g). MS m/z (M+H)+: 692.
2d. 2'-O-benzoyl-5-O-desosaminyl-3-deoxy-3-oxo-6-O-methvl-11-O-methanesulfonyl-6-O-methylervthronolide A
To a solution of 2'-O-benzoyl-5-O-desosaminyl-3-deoxy-3-oxo-6-O-methyl-erythronolide A from step 2c above (20.00 g, 28.9 mmole) in pyridine (40 mL) cooled to 0°
and held under N2 was added methanesulfonic anhydride ( 14.6 g, 83.81 mmole), and the reaction was allowed to stir at reaction temperature for 17 hours. The pyridine was removed under vacuum, and the residue was dissolved in EtOAc (400 mL). This solution was washed with saturated aqueous NaHC03, H20 and brine, dried (MgS04), decolorized with charcoal, and filtered through a diatomaceous earth filter aid. The solvent was removed under vacuum to afford the crude product (24.46 g). This material was taken directly to the next step without further purification.
2e. 10,11-anhydro-2'-O-benzoyl-5-O-desosaminyl-3-deoxy-3-oxo-6-O-methylerythronolid~A
The mesylate from step 2d above was dissolved in acetone (70 mL), and DBU
(5.22 mL, 34.9 mmole) added. After stirring at reaction temperature for 22 hours the acetone was removed under vacuum, EtOAc (250 mL) was added, and the organic layer was washed with 100-mL portions of sat. aq. NaHC03 (2x), H20 (lx), and brine (lx). The solution was dried (MgS04), decolorized with charcoal and filtered through a diatomaceous earth falter aid. The solvent was removed under vacuum to afford the crude product ( 18.54 g).
This material was purified by chromatography on silica gel, eluting wittu 40%
ethyl acetate/hexanes containing 0.25 % concentrated NH40H. The appropriate fractions were combined and concentrated to give the product. MS m/z (M+H)+: 674.
~f. Compound (8) from Scheme 3: R1-methoxy: R~=benzovl A 500 mL flask was charged with 60% NaH (1.05 g, 26.3 mmole). The NaH was ransed with 3 portions of hexanes, and dried under a N2 stream. Freshly distilled THF (90 mL) was added, and the solution was cooled to 0 °C under N2. The 10,11-anhydro compound from step 2d above (8.40 g, 12.5 mmol) was then added over a one minute period. After stirring for 15 minutes, a solution of carbonyl diimidazole (5.98 g, 36.9 mmole) in 60 mL of THF was added to the reaction mixture via cannula over a period of 15 minutes. After stirring for 5 hours, the reaction mixture was quenched with 5%

solution, and the mixture was stirred at 0 °C for 20 minutes. The mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SOq.
and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with 25% -40% acetone/hexanes. The appropriate fractions were combined and concentrated to give the product. MS m/z (M+H)+: 768. 1H NMR
(CDC13):
0.90(t, 3H), 0.95(d, 3H), 1.21(d, 3H), 1.27(d, 3H), 1.32(s, 3H), 2.25(s, 6H), 2.78(s, 3H), 2.97(m, 1H), 3.58(m, 1H), 2.63(q, 1H), 4.14(d, 1H), 4.50(d, 1H), 5.00(dd, 1H), 5.65(dd, 1H), 6.75(s, 1H), 7.05(m, 1H), 7.35(m, 1H), 7.43(dd, 2H), 7.54(t, 1H), 8.02(d, 2H), 8.07(s, 1H); 13C NMR (CDC13): 204.8, 168.8, 165.0, 145.9, 138.4, 138.1, 137.0, 132.7, 130.8, 130.5, 129.7, 128.2, 117.0, 102.1, 84.5, 81.0, 78.5, 76.9, 72.0, 69.2, 63.7, 50.9, 50.2, 47.2, 40.7, 40.3, 38.8, 31.1, 30.8, 22.5, 20.9, 20.7, 20.0, 18.8, 14.8, 14.2, 13.2, 10.4.
Example 3 Compound of Formula IIII). A. B & E=hydrogen, D=benzvl-R~=methoxy: R.~-hydr~o.~en 3a. 2-lR)-BOC-amino)-3-phenyl-1-propanol To a 5.2 g (23.8 mmole) sample of di-t-butyl dicarbonate in 20 mL of methylene chloride held at 0°C was added (R)-2-amino-3-phenyl-1-propanol (3.0 g, 19.8 mmole, Aldrich), and the reaction mixture was stirred 1.5 hours at reaction temperature. The solvent was removed, and the residue was dried under high vacuum and taken directly to the next Step.
3b. 2-(R)-(BOC-amino)-1-O-methanesulfon~lox~phen ly_nropane The material from step 3a was dissolved in 20 mL of methylene chloride and 5 mL of THF, and the solution was cooled to 0°C. Triethylamine (4.1 mL, 29.4 mmole) was added, then methanesulfonyl chloride (1.9 mL, 24.5 mmole) was added slowly. The mixture was stirred 45 minutes at reaction temperature, then the solvent was removed under vacuum. The residue was dissolved in ethyl acetate, and the solution was washed with water and brine, dried (Na2SOq.) and filtered. The solvent was removed under vacuum to afford 6.38 g of the title compound. MS m/z (M+H)+: 330, MS m/z (M+NH4)+: 347.
3c. 1-azido-2-(Rl-(BOC-aminol-3-phenylpropane The compound from step 3b above (6.36 g, 193 mmole) was dissolved in 25 mL of DMF, and 2.5 g (38 mmole) of NaN3 was added. The reaction mixture was stirred for 24 l0 hours at 62°C. The solution was cooled to reaction temperature, then extracted with ethyl acetate. The organic extract was washed with water and brine, dried (Na2S04) and filtered.
The solvent was removed under vacuum to afford 4.34 g of the title compound.
MS m/z (M+H)+: 277, MS m/z (M+NH4)+: 294.
3d. 1-azido-2-(Rl-amino-3-phenylpropane The compound from step 3c (4.3 g,15.6 mmole) was dissolved in 30 mL of 4 N HCl in ethanol, and the reaction mixture was stirred for 1.5 hours at reaction temperature. The solvent was stripped and chased with ether. The residue was dissolved in water, NaCI was added, and the mixture was extracted with ethyl ether, which was discarded.
The aqueous layer was adjusted to pH 12 with K2C03, saturated with NaCI, then extracted with CHCl3.
The organic extract was washed with brine, dried (Na2SOq.) and filtered. The solvent was removed under vacuum to afford 2.17 g of the title compound. MS m/z (M+H)+:
177, MS
m/z (M+NH4)+: 194.
3e. 1 2-fR)-diamino-3- henylpro ane A sample of the compound from step 3d (1.2 g, 6.8 mmole) was hydrogenated (4 atm) in ethanol over 1.2 g of 10% Pd/C for 21.5 hours at reaction temperature.
The mixture was filtered to remove the catalyst, and the solvent was removed to afford the title compound (1.055 g). MS m/z (M+H)+: 151, MS m/z (M+NH4)+: 168.
mnound ( 19) from Scheme 9 A=B=E=H D-benzyl R~--methoxy-R.~= enz 1 Samples of the compound of formula (8) (Scheme 3; R1=methoxy; R2=benzoyl;
from Example 2, 750 mg, 0.98 mmole) and l, 2-(R)-diamino-3-phenylpropane (from step 3e above, 1.04 g, 6.92 mmole) were dissolved in 4 mL of acetonitrile and 0.5 mL of water.
The reaction mixture was stirred for 24 hours at reaction temperature. The solvent was removed, and the residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried (Na2SOq.), filtered, and the solvent was removed. The residue was purified by chromatography on silica gel, eluting with hexane to 30% acetone in hexane to give 236 mg of the title compound. MS m/z (M+H)+: 850.

3g. Compound (20) from Scheme 9, A=B=E=H, D=bend. R.1=methoxy, R2=hydrogen A sample (217 mg, 0.26 mmole) of the compound from step 3f above in 6 mL of methanol was stirred at reflux for 4 hours. The solvent was removed, and the residue was purified by column chromatography on silica gei, eluting with 1.5% methanol in chloroform containing 1 % NH40H to afford 176 mg of the title compound. MS rn/z (M+H)+:
746.
3h. Compound of Formula lIlP, A=B=E=H, D=benzyl. RI=methoxy. R~h,~gen A sample of the compound from step 3g (148 mg, 0.20 mmole) was dissolved in 2.6 l0 mL of ethanol, and of acetic acid (0.026 mL, 0.45 mmole) was added. The reaction mixture was stirred for 24 hours at reflux, then the solvent was removed. The residue was dissolved in ethyl acetate, which was washed with aqueous K2C03, water and brine. The solution was dried (Na2SO4), filtered, and the solvent was removed under vacuum to afford 150 mg of product. This material was purified by column chromatography on silica gel, eluting with 0.5% to 0.6% methanol in chloroform containing 0.5% NH40H to afford 134 mg of the title compound. MS m/z (M+H)+: 728. 1H NMR (CDC13): 0.82(t, 3H), 1.02(d, 3H), 1.18(d, 3H), 1.32(s, 3H), 1.35(d> 3H), 1.43(s, 3H), 1.50(m, 1H)> 1.87(m, 1H), 2.27(s, 6H)>
2.32(s, 3H), 2.56(dd, 1H), 2.66(m, 2H), 3.03(m, 1H), 3.19(dd, 1H), 3.63(s, 1H), 3.75(q, 1H), 3.94(dd, 1H), 4.04(m, 1H), 4.13(d, 1H), 4.28(d, 1H), 4.85(dd, 1H), 7.10-7.35(m, 5H); 13C NMR (CDC13): 204.0, 177.8, 169.4, 156.0, 138.3, 130.1, 127.9, 126.1, 103.9, 81.4, 79.4, 78.5, 76.4, 70.3, 69.5, 65.9, 59.5, 57.9, 51.2, 48.7, 48.3, 46.5, 42.8, 40.2, 38.5, 36.0, 31.6, 28.2, 22.0, 21.2, 19.6, 19.0, 16.7, 14.4, 14.1, 12.7, 11.0, 10.4;
Example 4 Compound of Formula (III). A=B=D=H, E=benzyl, R~--methoxy~R2=hydrogen 4a. 1-azido-2-fS)-amino-3-phenyl-propane Following the procedure of Example 3a, except substituting (S)-2-amino-3-phenyl-1-propanol (Aldrich) for the (R)-2-amino-3-phenyl-1-propanol thereof, and carrying the product forward as in Example 3, steps a-d, the title compound was prepared (1.74 g). MS
m/z (M+H)+: 177, MS m/z (M+NHq.)+: 194.
4b 12-(S)-diamino-3-phen~~luropane A sample of the compound from step 4a (790 mg, 4.48 mmole) was dissolved in 30 mL of THF and 6 mL of water, triphenylphosphine (5.0 g, 19.1 mmole) was added, and the reaction mixture was stirred for 24 hours at reflux. The solvent was removed, and the residue was dissolved in 2 N HCl. NaCI was added, and the solution was extracted with ethyl ether. The aqueous layer was adjusted to pH 12 with K2C03, saturated with NaCI, then extracted with CHCl3 and CHC13 containing 15% isopropanol. The solvent was removed under vacuum to afford 439 mg of the title compound. MS m/z (M+H)+:
151, MS
m/z (M+NH4)+: 168.
4c. Comuound (191 Scheme 9. A=B=D=H E=benzyl R1-methoxy. R~benzovl Samples of the compound of formula (8) (Scheme 3; R1=methoxy; R2=benzoyl;
from Example 2, 450 mg, 0.59 mmole) and 1,2-(S)-diamino-3-phenylpropane (from step 4b above, 435 mg, 2.90 mmole) were dissolved in 2 mL of acetonitrile and 0.25 mL
of water.
The reaction mixture was stirred for 24 hours at reaction temperature. The solvent was removed, and the residue was dissolved in ethyl acetate. The solution was washed with brine, dried (Na2S04), filtered, and the solvent was removed. The residue was purified by chromatography on silica gel, eluting with hexane to 25% acetone in hexane to give 405 mg of the title compound. MS m/z (M+H)+: 850.
4d. Compound (20). A=B=D=H E=benzyl R.1=methoxy. R~hydrogen A sample (386 mg, 0.45 mmole) of the compound from step 4c above in 7 mL of methanol was stirred at reflux for 4 hours. The solvent was removed, and the residue was purified by column chromatography on silica gel, eluting with 1.5 % methanol in chloroform containing 1 % NH40H to afford 315 mg of the title compound. MS m/z (M+H)+:
746.
4e. Compound of Formula IIIII A=B=D=H E=phenyl R.~methox3r: R~hvdro en Following the procedure of Example 3h, except substituting the (S)-compound (150 mg, 0.20 mmole) from step 4d for the (R)-isomer of 3h, the title compound (136 mg) was prepared. MS m/z (M+H)+: 728. 1H NMR (CDCl3): 0.86(t, 3H), 1.08(d, 3H), 1.19(d, 3H), 1.33(x, 3H), 1.39(d, 3H), 1.47(s, 3H), I.54(m, 1H), 1.92(m, 1H), 2.28(s, 6H), 2.58(s, 3H), 3.19(dd, 1H), 3.52(m, IH), 3.67(s, 1H), 3.77(q, 1H), 4.12(d, 1H), 4.27(d, 1H), 4.92(dd, 1H), 7.10-7.40(m, 5H); 13C NMR (CDC13): 203.7, 176.0, 169.4, 156.5, 139.2, 130.0, 129.7, 128.3, 127.9, 126.3, 126.1, 104.1, 80.9, 80.5, 78.6, 78.1, 70.3, 69.5, 65.9, 62.0, 61.1, 51.2, 49.5, 48.8, 48.6, 45.9, 43.3, 42.9, 41.4, 40.2, 40.0, 35.2, 28.2, 22.2, 21.1, 19.7, 19.4, 17.1, 16.8, 15.3, 14.5, 14.1, 10.4;
Example 5 Compound of Formula lIlI1 A=benzyl B=D=E=H R1-methoxy. R~hvdro~en 5a. Compound (22) (Scheme 10), A=benzyl;
B=D=E=H. R1-methoxy-R~=benzoyl: Y=OH
Compound (8) (Scheme 3; R1=methoxy; R2=benzoyl; from Example 2, 450 mg, 0.59 mmole) and (S)-2-amino-3-phenyl-1-propanol (1.97 g, 13.0 mmole, Aldrich) were dissolved in 4.5 mL of acetonitrile and 0.5 mL of water. The reaction mixture was stirred for 7 days at reaction temperature. The solvent was removed, and the residue was dissolved in ethyl acetate. The solution was washed with 20% aqueous KH2P04, water and brine, then dried (Na2S04) and filtered. The solvent was removed, and the residue dried under high vacuum to afford I.09 g of product. This material was purified by chromatography on silica gel, eluting with hexane to 20% acetone in hexane to give 644 mg of the tide compound. MS m/z (M+H)+: 851.
Sb. Compound (22) (Scheme 10), A=benzyl;
B=D=E=H. RI=methoxy. R~=benzoyl: Y=azido A sample of the compound from step Sa above (617 mg, 0.72 mmole) was dissolved i0 in l2mL of THF, and triphenylphosphine (610 mg, 2.33 mmole) was added. This solution was cooled to 0°C, DEAD (0.375 mL, 2.38 mmole) was added dropwise over 3 minutes, and the mixture was stirred for 10 minutes. Next was added DPPA (0.515 mL, 2.37 rnmole) dropwise over 3 minutes, and the mixture was stirred for 2 hours at 0°C and 48 hours at reaction temperature. The volatiles were removed under vacuum to leave an oily residue. The residue was purified by chromatography on silica gel, eluting with hexane to 30% ethyl acetate in hexane followed by 20% acetone in hexane to afford 321 mg of the title compound. MS m/z (M+H)+: 876.
Sc. Compound (22) (Scheme 10), A=benzyl;
B=D=E=H. R.1=methoxyiR~=hydrogen: Y=azido A sample of the compound from step Sb above (317 mg, 0.36 mmole) was dissolved in 5 mL of methanol, and the mixture was stirred at reflex for 4.5 hour. s.
The solvent was removed, the residue was purified by chromatography on silica gel, eluting with 1:1 acetone in hexane , and the residue was dried under high vacuum to afford 218 mg of the title compound. MS m/z (M+H)+: 772.
~d. Compound 120) (Scheme 10), A=benzvl: B=D=E=H, R-1=methoxy, R.~~,1 ydro~en A sample of the compound from step Sc above (208 mg, 0.27 mmole) was dissolved in 3 mL of THF and 0.5 mL of water, triphenylphosphine (425 mg, 1.62 mmole) was added, and the reaction was stirred for 24 hours at reflex. The solvent was removed under vacuum, chased with toluene, and the residue dried under high vacuum. The residue was purified by chromatography on silica gel, eluting with chloroform containing 1.5% methanol and 1 % NH40H to afford I 96 mg of the rifle compound. MS m/z (M+H)~: 746.
Se. Compound of Formula (IIII: A=benzvl, B=D=E=H. R1-methoxy-R~hvdroEen A sample of the compound from step Sd above ( 128 mg, 0.17 mmole) was dissolved in 2.3 mL of ethanol and 0.023 mL (0.40 mmole) of acetic acid was added. The reaction mixture was stirred at reflex for 48 hours, and the solvent was removed. The residue was dissolved in ethyl acetate, and the solution was washed with aqueous K2C03, water and brine. The solution was dried (Na2S04), filtered, and the solvent was removed under vacuum to afford 100 mg of a tan compound. The residue was purified by chromatography on silica gel, eluting with chloroform containing 0.6°lo methanol and 0.5% NHq.OH
progressing to chloroform containing 0.7% methanol and 0.5% NH40H to afford 52 mg of the title compound. MS m/z (M+H)+: 728. 1H NMR (CDCl3): 0.86(t, 3H), 1.08(d, 3I-~, 1.34(d, 3H), 1.37(d, 3H), 1.44(s, 3H), 1.52(s, 3H), 1.93(m, 1H), 2.29(s, 6H), 2.48(m, 1H), 2.67(dd, 1H), 2.86(s, 3H), 3.06(dd, 1H), 3.57(m, 1H), 3.74(q, 1H), 3.86(s, 1H), 4.33(d, 1H), 4.39(d, 1H), 4.95(dd, 1H), 7.18-7.40(m, 5H); 13C NMR (CDCl3):
204.4, 169.6, 155.8, 138.0, 129.5, 129.3, 128.6, 128.5, 126.5, 103.8, 81.4, 78.8, 77.3, 70.3, 69.6, 65.9, 57.3, 53.7, 51.2, 50.8, 49.8, 47.4, 42.7, 40.3, 38.5, 35.6, 31.6, 28.2, 22.6, 22.2, 21.2, 20.6, 20.3, 15.4, 14.9, 14.1, 13.4, 11.1, 10.4;
Example 6 Compound of Formula fIII): B=benzvl A=D=E=H R.l--methoxy, R~hydrogen Following the procedures of Example 5, except replacing the (S)-2-amino-3-phenyl-1-propanol of step 5a with (R)-2-amino-3-phenyl-1-propanol (1.97 g, 13.0 mmole, Aldrich), and carrying the product forward according to the procedures of steps 5b-5e, the title compound (83 mg) was prepared. MS m/z (M+H)+: 728. iH NMR (CDC13):
0.73(t, 3H), 1.05(d, 3H), 1.24(d, 3H), 1.29(d, 3H), 1.33(s, 3H), 1.37(d, 3H), 1.41(s, 3H), 2.26(s, 6H), 2.44(m, 1H), 2.68(m, 1H), 2.79(s, 3H), 3.18(dd, 1H), 3.46(m, 1H), 3.60(s, 1H), 3.71(dd, 1H), 3.81(q, 1H), 3.94(dd, 1H), 4.30(dd, 1H), 4.72(dd, 1H), 7.10-7.38(m, 5H); 13C NMR (CDCl3): 204.4, 180.7, 169.3, 154.5, 138.4, 128.9, 128.8, 128.6, 128.3, 126.8, 126.2, 125.1, 104.2, 103.7, 81.1, 78.5, 78.3, 78.1, 77.2, 76.2, 70.3, 69.5, 65.8, 65.7, 62.4, 58.1, 53.6, 51.2, 51.0, 49.4, 47.6, 42.9, 40.2, 38.5, 36.7, 36.0, 31.5, 28.2, 25.2, 22.6, 21.6, 21.1, 19.7, 19.3, 16.2, 15.6, 14.6, 14.3, 14.0, 12.6, 11.1, 10.4, 10.2;
Example 7 Compound of Formula (lII)~ A=E=phenyl B-D-H R.~-methoxy, R~=hydro en Comuound (19) from Scheme 9~ A=E=phenyl B-D-H R.1--=methoxy-R~benzovl Compound (8) (Scheme 3; R1=methoxy; R2=benzoyl; from Example 2, 400 mg, 0.52 mmole) and (1S,2S)-1,2-diphenyl-1,2-ethylenediamine (500 mg, 2.36 mmole, Aldrich) were dissolved in 2 mL of acetonitrile and 0.25 mL of water. The reaction mixture was stirred for 10 days at reaction temperature. The mixture was diluted with methylene chloride, the solution was dried over NaCl and Na2S04, filtered, and the solvent was removed. The residue (958 mg) was taken directly to the next step . MS (m/z) :

(M+H)+.

7b. Compound (19) from Scheme 9;
A=E=phenyl. B=D=H. R1=methoxy. R~h~g_en The compound from step 7a (958 mg) was dissolved in 15 mL of methanol, and the solution was heated at reflux for 24 hours. The solvent was removed, and the residue was purified by column chromatography on silica gel, eluting with 0 to S% methanol in methylene chloride to afford 340 mg of the title product as the C10-epi-isomer. MS (m/z) 808 (M+H)+. 1H NMR (300 MHz, CDCl3) : 8 6.90-7.20 (m, lOH), 5.48 (dd, 1H), 5.04 {d, 1 H), 4.27 (d, 1H), 4.23 (d, 2H), 3.93 (q, 1 T-i), 3.76 (d, 1 H), 3.62 (d, 1 H, H 11 ), 3.52 {m, ZH)3.12-3.22 (m, 4H), 3.07 (s, 3H, OMe), 2.75 (dd, 1H), 2.75 (m, 1H), 2.2-2.5 (m), l0 2.24 (s, 6H, NMe2), 1.94 (dq, 2H), 1.59 (s, 3H), 1.46 (d, 3H), 1.29 (d, 3H), 1.22 (d, 3H), 0.90 (t, 3H), 0.84 (d, 3H), 0.73 (d, 3H). 13C NMR (75 MHz, CDC13) : 8 214.2, 205.5, 171.0, 156.3, 143.5, 140.5, 128.0, 128.0, 127.9, 127.2, 126.9, 126.8, 104.1, 83.5, 78.8, 78.7, 78.2, 77.4, 77.0, 76.6, 70.2, 69.9, 69.3, 67.6, 65.6, 57.9, 51.7, 50.7, 49.0,48.5, 41.1, 41.0, 40.1, 28.2, 21.2, 21.1, 21.0, 19.3, 18.0, 16.0, 14.4, 10.5, 9.9.
7c. Compound of Formula IIII): A=E=phenyl. B=D=H. Ri-methoxy-R~hydrogen Following the procedure of Example Se, except replacing the compound from Sd with the compound from 7b, the title compound was prepared. MS (m/z) : 790 (M+H)+.
13C NMR {125 MHz, CDC13): selected signals: 8 203.3, 175.7, 169.5, 156.5, 104.1.
Example 8 Compound of Formula (nI): A=methyl. B=D=E=hydro eg n R.1--methoxy. R~hydrogen 8a. Compound (22) from Scheme 10;
A=methyl. B=D=E=H. R~methoxy. R~benzoyl. Y=OH
Compound (8) (Scheme 3; R1=methoxy; R2=benzoyl; from Example 2, 400 mg, 0.52 mmole) and (S)-2-amino-1-propanol (0.200 mL, 2.6 mmole, Aldrich) were dissolved im 0.9 mL of acetonitrile, 0.1 mL of water was added, and the reaction was stirred for 40 hours at reaction temperature. The solvent was removed, and the residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried (Na2SOq.), filtered, and the solvent was removed. The residue was purified by chromatography on silica gel, eluting with 20% to 30% acetone in hexane to give 135 mg of the title compound. MS m/z (M+H)+:
'775.
8b_ Compound (22) from Scheme 10; A=methyl, B=D=E=H. R-1--methoxy. R~benzoyl. Y=azido A sample of the compound from step 8a above (277 mg, 0.362 mmole) was dissolved in 6 mL of THF, and triphenylphosphine (302 mg, 1.15 mmole) was added. This solution was cooled to 0°C, DEAD (0.190 mL, 1.21 mmole) was added dropwise over 3 minutes, and the mixture was stirred for 10 minutes. Next was added DPPA
(0.260 mL, 1.21 mmole) dropwise over 3 minutes, and the mixture was stirred for 3 hours at 0°C and 24 hours at reaction temperature. The volatiles were removed under vacuum. The residue was purified by chromatography on silica gel, eluting with 15% to 20% acetone in hexane, then rechromatographed on silica gel> eluting with 40% ethyl acetate in hexane to 25% acetone in hexane, to afford 140 mg of the title compound. MS m/z (M+K)~-: 838.
8c. Compound (22) from Scheme 10; A=methyl, B=D=E=H. R 1=methoxv, R2=hydrogen. Y=azido A sample of the compound from step 8b ( 133mg, 0.17 mmole) was dissolved in 2 mL of methanol, and the solution was stirred for 4 hours at reflux. The solvent was removed under vacuum, and the residue was dried under high vacuum to give a glassy residue. The residue was purified by chromatography on silica gel, eluting with 1:1 acetone in hexane to 100% acetone to afford the title compound (98 mg). MS m/z (M+H)+:
696.
8d. Compound (20) from Scheme 10;
A=methyl. B=D=E=H R 1=methoxv-R~hydro~en A sample of the compound from step 8c above (185 mg, 0.27 mmole) was dissolved in 4 mL of THF, and 2 mL of H20 and triphenylphosphine (425 mg, 1.62 mmole) was added. This solution was stirred at reaction temperature for 40 hours and at reflux for 24 hours. The volatiles were removed under vacuum. The residue was purified by chromatography on silica gel, eluting with 3% methanol and 1% NH40H in chloroform to afford the title compound ( 128 mg). MS m/z (M+H)+: 670.
Vie. Comr~nd of Formula fIIIO A=methyl B-D-E-H Ri=methoxy-R~hydrogen A sample of the compound from step 8d above ( 123 mg, 0.18 mmole) was dissolved in 2.6 mL of ethanol and 0.24 mL of acetic acid, the reaction was heated at reflux for 24 hours, then stirred at reaction temperature for 48 hours. The solvent was removed under vacuum, and the residue was dissolved in ethyl acetate. The solution was washed with 10%
aqueous K2C03, water and brine, then dried (Na2S04) and filtered. The solvent was removed, and residue was dried under high vacuum. The residue was purified by chromatography on silica gel, eluting with 0.5% NH40H and 2% to 3% methanol in chloroform to afford the title compound (38 mg). MS m/z (M+H)+: 652. 1H NMR
(CDC13): 0.86 (t, 3H), 1.04 (d, 3H), 1.21 (d, 3H), 1.24 (d, 3H), 1.50 (s, 3H), 1.87-1.98 (m, 2H), 2.26 (s, 6H), 2.41-2.50 (m, 1 H), 2.78 (s, 3H), 3.11-3.23 (m, 3H), 3.51-3.59 (m, 1 H), 3.76 (dd, 1 H), 3.76 (s, 1 H), 3.85 (q, 1 H), 3.92 (dd, 1 H), 4.31 (d, 1 H), 4.37 (d, 1H), 4.90 (dd, 1H); 13C NMR (CDCl3): 204.3, 181.5, 169.6, 155.6, 103.7, 81.3, 78.6, 77.9, 76.6, 70.3, 69.5, 65.8, 56.5, 53.4, 51.1, 50.6, 47.4, 47.2, 42.6, 40.2, 38.4, 35.5, 28.1, 22.0, 21.2, 20.5, 20.1, 15.8, 15.2, 14.8, 13.2, 10.6, 10.3; High resolution mass spectrum: calculated (M+H)+ m/z for C34HSgN3O9=652.4173; observed (M+H)+
m/z=652.4175.
Example 9 C~~ound of Formula fIIIh B=methyl A=D=E=hydrogen Rl.--methox~, R~hydro~en Following the procedures of Example 8, except with a larger amount of the starting compound from Example 2 (1.23 g, 1.6 mmole) and replacing the (S)-2-amino-1-propanol of step 8a with an appropriately larger amount of (R)-2-amino-1-propanol (1.23 mL, 16.2 l0 mmole, Aldrich), carrying the product forward as in steps 8b-8e, the tide compound was prepared (71 mg). 1H NMR (CDCl3): 0.87 (t, 3H), 1.45 (s, 3H), 1.82-2.01 (dd, 2H), 2.26 (s, 6H), 2.37-2.51 (m, 1H), 2.72 (s, 3H), 3.07 (dd, 1H), 3.18 (dd, 1H), 3.22-3.36 (m, 1H), 3.47-3.59 (m, 1H), 3.61 (s> 1H), 3.77-3.91 (m, 2H), 4.25 (d, 1H), 4.29 (d, 1H), 5.01 (dd, 1H); 13C NMR '(CDC13): 204.1, 180.7, 169.7, 154.7, 103.8, 80.6, 78.9, 78.5, 76.4, 70.3, 69.6, 65.9, 62.3, 56.6, 53.1, 51.1, 49.3, 47.8, 42.8, 40.2, 38.6, 36.5, 34.6, 31.5, 28.2, 25.3> 22.6, 21.9, 21.2, 20.7, 19.6, 19.3, 17.1, 15.8> 14.4, 14.1, 12.9, 11.0, 10.3; MS (M+H)+ m/z=652. High resolution mass spectrum: calculated (M+H)+ m1z for C34HggN3O9=652.4173; observed (M+H)+ m/z=652.4188.
2o Example 10 Compound of Formula (lm: A=D=methyl: B=E=H, Ri-methoxy, R2=hydrogen lsla. meso-2.3-bis(methanesulfon~ylbutane Samples of meso-2,3-butanediol (10 g, 111 mmole, Aldrich) and triethylamine (92.8 mL, 666 mmole) were dissolved in methylene chloride. The solution was cooled to -78°C, and methanesulfonyl chloride (25.8 mL, 333 mmole) was added dropwise. A
precipitate formed. The mixture was diluted with additional methylene chloride, and the mixture was stirred for 20 minutes at -78°C and at 0°C for 2 hours. The reaction mixture was warmed to reaction temperature, diluted with additional solvent, and washed with H20, aqueous 3o NaHC03 and aqueous NaCI. The organic solution was dried over MgS04, and the solvent was removed to afford the title compound (25.01 g). IH NMR (300 MHz, CDCl3) :
8 4.91 (q, 2H), 3.10 (s, 6H), 1.45 (d, 6H).
lOb. meso-2.3-diazidobutane A sample of the compound from step l0a (25 g) was dissolved in 250 mL of DMF, and NaN3 (40 g) was added. The mixture was stirred vigorously at 85°C
for 24 hours, then cooled to reaction temperature. The mixture was diluted with 800 mL of ether, washed with H20, aqueous NaHC03 and aqueous NaCI, then dried over MgS04. The solution was filtered and concentrated to afford the title compound ( 13.00 g). 1H NMR (300 MHz, CDC13) : 8 3.50 (m, 2H), 1.30 (d, 6H).

lOc. meso-2 3-butanedia_minP
A sample of the compound from step l Ob ( 13.0 g, 125 mmole) was dissolved in ethanol and hydrogenated at 4 atm over 10% Pd/C for 20 hours at reaction temperature. The catalyst was removed by filtration, and the solvent was removed under vacuum to afford the title compound. 1H NMR (300 MHz, CDC13) : 8 2.70 (m, 2H), 1.45 (br, 4H), 1.05 (d, 6H). MS (m/z) : 89 (M+H)+.
l Od. Compound ( 19) from Scheme 9' A-D-methyl B-E-H R.1--methoxy. R~benzoyl to A sample of 10,11-anhydro-2'-O-benzoyl-5-O-desosaminyl-6-O-methyl-3-oxo-erythronolide A 12-O-imidazolyl carbamate (from Example 2, 500 mg, 0.651 mmole) and meso-2,3-butanediamine (500 mg, from step lOd above) were dissolved in 3 mL of acetonitrile and 0.3 mL of water, and the reaction was stirred for 72 hours at reaction temperature and 17 hours at reflux. The solution was diluted with methylene chloride, dried IS over NaCI and MgS04, and filtered. The solvent was removed, and the residue was taken directly to the next step.
~Oe. Compound (201 from Scheme 9~ A-D-methvl~ B-E-H R1=methoxv The compound from step lOd above was dissolved in methanol, and the solution was 20 heated at reflux for 12 hours. The solvent was removed, and the residue was taken directly to the next step. MS (m/z) : 684 (M+H)+.
l Of. Comvound of Formula (IIW A-D-methyl- B-E-H R 1-methoxv, R~hydro en To the material from the previous step, dissolved in methanol, acetic acid was added, 25 and the reaction mixture was heated at reflux for 24 hours. A solution of NH3 in methanol was added, and the solution was concentrated. The residue was dissolved in ethyl acetate, and the solution was washed with 1 N NaOH, H20 and brine, then dried over Na2S04. The solvent was removed, and the residue was purified on silica gel, eluting with 10% methanol in methylene chloride to 10% methanol (containing NH3) in methylene chloride to afford the 3o title compound. This material was rechromatographed on pH 8 silica gel, eluting with 4:1 ethyl acetate:hexane to 100% ethyl acetate to afford 116 mg of the title compound. The NMR analysis confirmed the product to be the A=D=methyl isomer. MS (m/z) : 666 (M+H)+. HRMS Calc. for C35H~N309: 666.4330; Observed: 666.4326. 'H NMR (300 MHz, CDCl3) : 8 4.81 (dd, 1H), 4.27 (d, 1H), 4.22 (d, 2H), 4.05 (m, 1H), 3.96 (m, 1H), 35 3.78 (q, 1H), 3.65 (s, 1H, H11), 3.48 (m, 1H), 3.10 (dd, 1H), 3.06 (m, 1H), 2.75 (q, 1H), 2.67 (s, 3H), 2.65 (m, 1H), 2.37 (m, 2H), 2.19 (s, 6H), 1.85, 1.49 (m, 2H), 1.59, 1.15 (m, 2H), 1.55 (m, 2H), 1.42 (s, 3H), 1.27 (d, 3H), 1.27 (s, 3H), 1.25 (d, 2H), 1.24 (d, 3H), 1.17 (d, 3H), 1.16 (d, 3H), 1.04 (d, 3H), 0.96 (d, 3H), 0.78 (t, 3H).
'3C NMR
(75 MHz, CDC13) : 8 204.2, 179.0, 169.5, 155.6, 118.8, 103.7, 81.3, 78.6, 77.7, 76.8, WO~ 97/17356 PCT/US96/16585 70.2, 69.4, 65.8, 56.1, 55.5, 51.9, 51.0, 50.4, 47.0, 42.5, 40.1, 38.4, 35.2, 28.1, 22.3, 22.0, 21.1, 20.7, 20.1, 15.0, 14.8, 13.1, 11.5, 10.6, 12_2. IR (film) : 3460 (w), 2972, 1.750, 1718 (w), 1647, 1456, 1423, 1372, 1305, 1246, 1163, 1107, 1051, 989, 757 cm 1.
Example 11 ompound of Formula IIIII: A=E=me~yl: B=D=H. R1=methoxv-R~hvdro~en Following the procedures of Example 10 steps a-c, except substituting (R,R)-2,3-butanediol (1 g, 11.1 mmole, Aldrich) for the meso-isomer thereof of step 10a, and carrying the product forward as in steps lOb and l Oc, the title compound (494 mg) was prepared.
MS (m/z) : 89 (M+H)+. 1H NMR (300 MHz, CDC13) : 8 2.62 (m, 2Id], 1.45 (br s, 4H), 1.08 (d, 6H).
11 b. Compound ( 191 from Scheme 9: A=E=methyl: B=D=H. RI-methox3r, R~benzovl A sample of 10,11-anhydro-2'-O-benzoyl-5-O-desosaminyl-6-O-methyl-3-oxo-erythronolide A 12-O-imidazolyl carbamate (from Example 2, 1.56 g, 2.03 mmole) and 2S, 3S-butanediamine (400 mg, 4.54 mmole, from step 11 a above) were dissolved in 16 mL of 20% aqueous acetonitrile, and the reaction mixture was stirred at reaction temperature for 7 days. The solution was diluted with methylene chloride, dried over NaCI and MgS04, and filtered. The solvent was removed, and the residue was taken directly to the next step.
l~jc. Compound f201 from Scheme 9: A=E=methyl: B=D=H. R1-methoxv The compound from step 1 lb above was dissolved in methanol, and the solution was heated at reflux for 12 hours. The solvent was removed, and the residue was taken directly to the next step.
l ld. Compound of Formula 1I11): A=E=methyl: B=D=H. R1-methoxy-R~h~rdrogen The material from the previous step was dissolved in 20 mL of ethanol, acetic acid (0.80 mL) was added, and the reaction mixture was heated at reflux for 3 days.

methanol was added, and the solvent was removed. The residue was dissolved in ethyl acetate, and the solution was washed with 1 N NaOH, H20 and brine, then dried over IVa2S04. The solvent was removed, and the residue was purled on neutral silica gel, eluting with 4:1 ethyl acetate:hexane to 5% methanol in ethyl acetate to afford 682 mg of the title compound. MS (m/z) : 666 (M+H)+. HRMS Calc. for C35H~N3O9: 666.4330;
Observed: 666.4333. 1H NMR (300 MHz, CDC13): 8 4.85 (dd, 1H), 4.35 (d, 1H), 4.30 (d, 1H), 4.12 (q, 2H), 3.65 (s to d, 1H, J=1.2 Hz), 3.56 (m, 1H), 3.46 (br s, 1H), 3.21 (dd, 1H), 3.13 (t, 1H), 2.86 (q, 1H), 2.78 (s, 3H), 2.68 (m, 2H), 2.46 (dt, 1H), 2.28 (s, 6H), 1.95 (m, 1H), 1.68 (m, 3H), 1.52 (s, 3H), 1.38 (d, 3H), 1.36 (d, 3H0, 1.33 (s, 3H), 4.0 1.32 (d, 3H), 1.31 (d, 3H), 1.26 (d, 3H), 1.21 (d, 3H), 1.05 (d, 3H); 0.87 (t, 3H). 13C

NMR (75 MHz, CDCl3) : 8 203.9, 177.9, 169.5, 156.4, 103.8, 81.1, 78.5, 78.4, 77.6, 70.3, 69.5, 65.8, 60.4, 56.9, 52.3, 50.9, 50.6, 47.6, 43.9, 40.2, 39.5, 35.0, 28.1, 21.7, 21.1, 20.8, 20.2, 19.9, 18.3, 16.3, 15.6, 14.7, 14.1, 13.6, 10.1.
IR (KBr) : 3441, 2972, 2938, 1755, 1117 (w), 1653, 1457, 1425, 1376, 1306, 1248, 1167, 1109, 1053 crri 1.
Example 12 Compound of Formula (III); B=D=H;
A and E taken together is -CH~CH~CH2- Rl--methoxy. R~hy ro~en to 12a. racemic-tra r-1 2-cYclonen anP~iiamine Following the procedures of Example 10 steps a-c, except substituting (DL)-1,2-cyclopentanediol (5.0 g, 49.0 mmole, Aldrich) for the diol of step 10a, and carrying the product forward as in steps lOb and lOc, the title compound (2.76 g) was prepared. MS
(m/z) : 101 (M+H)+. 1H NMR (300 MHz, CDCl3) : 8 2.75 (m, 2H), 2.00 (m, 2H), 1.65 (m, 2H), 1.50 (s, 4H), 1.30 (m, 2H).
12b. Compound (19) from Scheme 9; B=D=H;
A and E taken together is -CH~CH~~=, R1-methoxv-R~=benzovl Samples of 10,11-anhydro-2'-O-benzoyl-5-O-desosaminyl-6-O-methyl-3-oxo-erythronolide A 12-O-imidazolyl carbamate (from Example 2, 200 mg, 0.26 mmole) and racemic-tram-1,2-cyclopentanediamine (104 mg, 1.04 mmole, from step 12a) were dissolved in 20% aqueous acetonitrile, and the reaction mixture was stirred at reaction temperature for 4 days and at reflux for 8 hours. The solution was diluted with 100 mL of ethyl acetate, dried over NaCl and MgS04, and filtered. The solvent was removed, and the residue was purified by chromatography on silica gel, eluting with 5% to 10%
methanol in methylene chloride to afford the title compound (88 mg). MS (m/z) : 800 (M+H)+.
12c. Compound (20) from Scheme 9; B=D=H;
A and E taken together is -C''H2~H~~H2- RL=methoxY
The compound from step 12b above (88 mg) was dissolved in methanol, and the solution was heated at reflux for 10 hours. The solvent was removed, and the residue was purified by chromatography on silica gel, eluting with 5% methanol in methylene chloride to afford the title compound. MS (m/z) : 696 (M+H)+.
12d. Compound of Formula (ITI); B=D=H;
A and E taken to~~ether is -CH~CH~~H2 RL=methoxv. R~hvdro, en Following the procedure of Example 1 ld the title compound was prepared. MS
(m/z) : 678 (M+H)+.

Example 13 Compound of Formula (IQ); B=E=H;
A and D taken together is -CHZCH2CH~CH2-. R~=methoxv. R.~h~droaen 13a. Compound (19) from Scheme 9; B=E=H;
A and D taken together is -CH2CH2CH2CH~yR.I--methoxy. R2= nz Following the procedure of Example 1 l, step l lb, except substituting cis-1,2-cyclohexanediamine (800 mg, 1.04 mmole, Aldrich) for the diamine thereof, the title compound was prepared.
13b. Compound of Formula (Iln; B=E=H;
A and D taken together is -CH~CH~CH~CH~-. RI=methox~. R~=hvdro~en Following the procedures of Example 11 steps c and d, substituting the compound of step 13a for the compound of l lb thereof, the title compound was prepared.
'H NMR (300 MHz, CDCl3): 8 4.87 (dd, 1H), 4.34 (d, 1H), 4.31 (d, 1H), 4.10 (br s, 1 H), 4.07 (br m, 1 H), 3.84 (q, 1 H), 3.70 (s, 1 H, H 11 ), 3.56 (m, 1 H), 3.22 (dd, 1H), 3.14 (pent, 1H), 2.78 (s, 3H, OMe), 2.49 (m, 1H), 2.30 (s, 6H), 1.30-2.00 (m), 1.49 (s, 1H), 1.39 (s, 3H), 1.37 (d, 3H), 1.32 (d, 3H), 1.26 (d, 3H), 1.22 (d, 3H), 1.06 (d, 3H), 0.85 (t, 3H).
13C NMR (75 MHz, CDCl3) : 8 203.8, 178.1, 169.3, 155.6, 103.7, 81.1, 78.6, 78.1, 76.64, 70.2, 69.3, 65.7, 56.3, 55.9, 55.8, 51.0, 50.4, 47.4, 42.6, 40.1, 38.2, 35.4, 34.4, 28.1, 25.2, 25.1, 25.0, 21.9, 21.0, 20.2, 20.1, 19.2, 15.6, 14.7, 12_9, 10.6, 10.2.
MS (m/z) : 692 (M+H)+.
Example 14 Compound of Formula (IIII: A=B=D=E=H. Rl.=h,~g_en. R~hydrogen 14a. 2'-O-acetyl-6-deoxy-erythromycin A
A sample of 6-deoxyerythromycin A (4.34 g, 6.04 mmole, Abbott Labs) was dissolved in 250 mL of methylene chloride, and acetic anhydride ( 1.54 g, 15 mmole) and triethylamine ( 1.22 g, 12 mmole) were added. The reaction mixture was stirred at reaction temperature for 16 hours, then poured into 5% aqueous NaHC03. The mixture was extracted with methylene chloride, and the organic layer was dried, filtered and concentrated.
The residue was chased with toluene, ethylene dichloride, chloroform and methylene chloride. The residue then dried under high vacuum to afford 4.46 g of the title product, which was taken to the next step without further purification. MS m/z (M+H)+:
760.
14b. 2'-O-acetyl-6-deoxy-4"-triethylsilyl-erythromycin A
A sample of the compound from step 14.a (4.44 g, 5.84 mmole) was dissolved in 100 mL of dry methylene chloride, and imidazole ( 1.59 g, 23.3 mmole) was added. The mixture was cooled to 0°C, and a solution of tziethylsilyl chloride ( 1.76 g, 117 mmole) in 25 mL of methylene chloride dropwise. The reaction mixture was stirred for 1 hour at 0°C and at reaction temperature for 16 hours. The reaction mixture was poured into 5%
aqueous NaHC03, and the mixture was extracted with CHC13. The organic extract was washed with saturated brine, dried over MgSOq, filtered and concentrated. The residue was dried under high vacuum for 48 hours to afford 5.38 g of the title product, which was taken to the next step without further purification. . MS m/z (M+H)+: 874.
14c. 2'-O-acetyl-10,11-anhydro-6-deoxy-4"-triethylsilyl-erythromycin A
12-O-imdazolyl carbamate (Compound (3) from Scheme 5, RI=hydI'Ogen. 2'-R~acetyl: 4"-R2=trieth~yl) A sample of the compound from step 14b (5.36 g, 6.13 mmole) was dissolved in mL of dry DMF, and carbonyldiimidazole (4.98 g, 30 mmole) was added. After the reagent had dissolved, the solution was diluted with 15 mL of THF, and the solution was cooled to 0°C. To this solution was added NaH (807 mg, 60% dispersion, 20.2 mmole) in portions.
The reaction mixture was stirred for 30 minutes, and 10 mL of H20 was added.
The reaction mixture was poured into saturated brine, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried over MgS04, filtered and concentrated. The residue was co-distilled with ethylene dichloride, chloroform and methylene chloride. The residue was dried under high vacuum for 16 hours to afford 6.95 g of the title product, which was taken to the next step without further purification. MS
m/z (M+H)+: 986.
14d. Compound (11) from Scheme 5;
A=B=D=E=H: R1-_hydrogen. 2'-R~acetvl: 4"- R~triet yl ilvl A sample of the compound from step 14c (6.93 g, 6.13 mmole) was dissolved in rnL of acetonitrile, ethylene diamine was added (4.31 g, 7.19 mmole), and the solution was stirred for 17 hours at reaction temperature. The reaction mixture was poured into saturated brine containing NHq.OH. This mixture was extracted with chloroform, and the organic extracts were combined, filtered and concentrated. The residue was co-distilled with ethylene dichloride, chloroform and methylene chloride. The residue was dried under high vacuum for 72 hours to afford 5.77 g of the title product which was taken to the next step without further purification. MS m/z (M+H)+: 924.
14e. Compound (12) from Scheme 5;
A=B=D=E=H' R~hydrogen. 2'-R~4"-R~=hvdro en A sample of the compound from step 14d (5.75 g) was dissolved in THF ( 120 mL) and 14.3 mL of tetrabutylammonium fluoride ( 1 M in THF) was added in one portion. The reaction mixture was stirred at reaction temperature for 4 hours, diluted with 400 mL of methanol, and stirred at reaction temperature for 64 hours. The solution was concentrated W~ 97/17356 PCT/US96/16585 and then poured into 5% aqueous NaHC03 containing 0.5% NH40H. The mixture was extracted with CHCl3, the extract was washed with brine, and dried over MgSOq.. The solvent was removed, and the residue was co-distilled with ethylene chloride and methylene chloride. The residue was further dried under vacuum for 16 hours to afford the title compound (5.59 g).
14f. Compound of Formula CI): A=B=D=E=H: R1=h~ e~ n-R~hydroaen A sample of the compound from step 14e (5.56 g, 7.07 mmole) was dissolved in mL of ethanol, and acetic acid (637 mg, 106 mmole) was added. The solution was heated at reflux for 3.5 hours, cooled to reaction temperature, then poured into 5%
aqueous NaHC03.
This mixture was extracted with CHCl3, and the organic extracts were combined, dried over MgS04, filtered and concentrated. The residue was co-distilled with ethylene dichloride, chloroform and methylene chloride, then dried under high vacuum for 72 hours to afford 4.12 g of the product. This material was purified by chromatography on silica gel, eluting with 1:6 TEA:ethyl acetate, to afford the title compound (1_29 g). MS m/z (M+H)+: 768.
1H NMR (CDCl3) 8: 0.88 (m), 2.28 (s), 3.28 (s), 4.23 (m), 4.85 (m), 4.92 (m).

NMR (CDCI3) b: 40.3 (N(CH3)2), 42.8 (NCH2), 49.4 (OCH~), 49.9 (NCH2), 155.8 (O-CO-N). IR (CDC13): 1755 cm-1.
Example 15 Compound of Formula 1I111: Rl=OCH~ R~=H: A=B=D=H: E~CH2NH2 15a. 1.2-diazido-3-IBOC-aminolpropane A sample of 3-(BOC-amino)propene (Aldrich, 15.72 g, 0.1 mole), manganese triacetate (80.43 g, 0.3 mole) and NaN3 (65.01 g, 1.0 mmole) were suspended in 400 mL of acetic acid, and the mixture was heated at 100°C for 10 minutes. The mixture was cooled in an ice bath and diluted with 400 mL of 1N NaOH. The mixture was extracted with ethyl acetate, which was washed wrath 1 N cold NaOH, H20, NaHC03, brine and dried over Na2S04. The solvent was removed, and the residue was chromatographed on silica gel, eluting with 4:1 hexane:ether to give 7.18 g of the title compound. MS m/z (M+NH4)+:
259.
15b. 1.2-diamino-3-BOC-aminolpropane The compound of the previous step was dissolved in ethanol and hydrogenated (4 atm H2) over Pd/C for 22 hours at reaction temperature. The solvent was removed, and the product was taken to the next step. MS m/z (M+H)+: 190.
15c. Compound of Formula (III): Rl-= OCH~ R~=H: A=B=D=H: E=-CH2NH2 Following the procedures of Example 3 steps f h, samples of the compound of formula (8) (Scheme 3; R1=methoxy; R2=benzoyl; from Example 2, 400 mg, 0.52 mmole) and the compound from step 15b ( 1.478 g, 7.81 mmol) were reacted and the title product was obtained. Chromatographic separation of the isomers of the N-BOC compound, followed by deprotection with HCl in ethanol at reaction temperature gives the title compound. MS m/z (M+H)+: 889.
Example 16 compound of Formula (IIT1~ Rl--~ R~=H: A=B=E=H: D=-CH2NH2 The compound is obtained by deprotection with HCl in ethanol at reaction temperature of the isomer separated by chromatography from the mixture obtained in Example 15c.
Example 17 Compound of Formula (III): R1=OCH3, R~=H; B=E=H: A and D taken together is -CH2CH2CH2 17a. cvclopentane cis-1 2-diamine Following the procedures of Example 10 steps a-c, except substituting cis-1,2-cyclopentanediol for the diol of step 10a, and carrying the product forward as in steps lOb and l Oc, the title compound is prepared.
17b. Compound of Formula (III): R1=OCH3, R~=H~ B=E=H~ A and D taken togeth r;s -CH2CH2CH2-Following the procedures of Example 10 steps d-f, except substituting cis-1,2-cyclopentanediamine, from the previous step, for the meso-2,3-butanediamine thereof, the title compound is prepared.
Example 18 Compound of Formula (III): RI=OCH3, R~=H: B=E=H~ A and D taken together is -CH20CH2 18a. tetrahydrofuran cis-3 4-diamine Following the procedures of Example 10 steps a-c, except substituting 1,4-anhydroerythritol for the diol of step 10a, and carrying the product forward as in steps lOb and lOc, the title compound is prepared.
18b. Compound of Formula (III):
Rl--OCH~ R~=H: B=E=H: A and D taken to ether is -CH OCH2 Following the procedures of Example 10 steps d-f, except substituting tetrahydrofuran cis-3,4-diamine, from the previous step, for the meso-2,3-butanediamine of step lOd, the title compound is prepared.

Example 19 Compound of Formula (Iln: R1=OCH3, RAH: B=E=H: A and D taken together is -CH2-NH-CH2-19a cis-3 4-diamino-pyrrolidine Pyrolline (Aldrich) is N-protected by treatment with benzyloxycarbonyloxysuccinimide in ethyl acetate at reaction temperature. The N-Cbz-pyrroline is oxidized with catalytic Os04 and excess N-methylinorpholine N-oxide. (NNMO) in THF and t-butanol according to the procedure of Tetrahedron Lett., 1976:
1973 to give to the N-Cbz-pyrroline-3,4-diol. Following the procedures of Example 10 steps a-c, except substituting N-Cbz-pyrroline-3,4-diol for the diol of step 10a, and carrying the product forward as in steps lOb and lOc, the title compound is prepared.
19b. Compound of Formula (III):
i5 Rl=OCH,~ R~=H: B=E=H: A and D taken to~~ether is -CH2-NH-CH2-Following the procedures of Example 10 steps d-f, except substituting cis-3,4-diamino-( 1-Cbz-pyrrolidine), from the previous step, for the meso-2,3-butanediamine of step lOd, the title compound is prepared.
20 Example 20 Compound of Formula (111): RI=OCH3, ,~~=H: B=E=H' A and D taken together is -CH2-NlCbz)-CH2-Starting with the Compound of Formula (III): Rl=QCH~, R2=H; B=E=H; A and D
taken together is -CH2-NH-CH2-, from Example 19 above, adding the Cbz group by 25 treatment with benzyloxycarbonyloxysuccinimide in ethyl acetate at reaction temperature, the title compound is prepared.
Example 21 Compound of Formula (lII): RI=OCH3, 30 $~=H: B=E=H' A and D taken together is -CH2-N(benzyl)-CH2-Starting with the Compound of Formula (IQ): Rl=OCH3, R2=H; B=E=H; A and D
taken together is -CH2-NH-CH2-, from Example 19 above, reacting the amine of the -CH2-NH-CH2- group with benzyl chloride in the presence of triethylamine, the title compound is prepared.
Example 22 Compound of Formula (III): Rl=OCH3, $~_--H: B=E=H: A a_n_d D taken together is -CH2-Nlben~o~n -CH2-Starting with the Compound of Formula (111): R'=OCH3, R2=H; B=E=H; A and D
taken together is -CH2-NH-CH2-, from Example 19 above, reacting the amine of the -CH2-NH-CH2- group with benzoyl chloride in the presence of triethylamine, the title compound is prepared.
Example 23 Compound of Formula (III): R'=OCH3, $~=H: B=E=H; A and D taken tether is -CH2-N(nhenyl-CH2-CH2-1-CH2-Starting with the Compound of Formula (III): R'=OCH3, R~=H; B=E=H; A and D
taken together is -CH2-NH-CH2-, from Example 19 above, reacting the amine of the -CH2-NH-CH2- group with 2-phenylethyl bromide in the presence of triethylamine, the title compound is prepared.
Example 24 Compound of Formula (III): Rl=OCH3, $2=H: B=E=H: A and D taken toeether i - H2-N(4-Cl-yahenvl-CH2-1-CH2-Starting with the Compound of Formula (III): R'=OCH3, RZ=H; B=E=H; A and D
taken together is -CH2-NH-CH2-, from Example 19 above, reacting the amine of the -CH2-NH-CH2- group with 4-chlorobenzyl chloride in the presence of triethylamine, the title compound is prepared.
Example 25 Compound of Formula (III): R'=OCH3, R~=H. B=E=H: A and D taken together is -CH2-Nl4-pyridyl-CH2-)-CH2-Starting with the Compound of Formula (III): R1=OCH3, R2=H; B=E=H; A and D
taken together is -CH2-NH-CH2-, from Example 19 above, reacting the amine of the -CH2-NH-CH2- group with 4-picolyl chloride in the presence of triethylamine, the title compound is prepared.
Example 26 Compound of Formula (111): R'=OCH3, $~=H: B=E=H~ A and D taken together is -CH2-Ni2-p~ridyl-CH2-)-CH2-Starting with the Compound of Formula (III): RI=OCH3, R2=H; B=E=H; A and D
taken together is -CH2-NH-CH2-, from Example 19 above, reacting the amine of the -CH2-NH-CH2- group with 2-picolyl chloride in the presence of triethylamine, the title compound is prepared.
Example 27 Compound of Formula (IIn: R'=OCH3, $~=H: B=E=H: A and D taken togethPT;s -CH2-NH(3-wridyl-CH2-)-CH2-Starring with the Compound of Formula (III): R'=OCH3, RZ=H; B=E=H; A and D
taken together is -CH2-NH-CH2-, from Example 19 above, reacting the amine of the -CH2-WO 97/17356 PCT/US9b/16585 NH-CH2- group with 3-picolyl chloride in the presence of triethylamine, the title compound is prepared.
Example 28 Compound of Formula (111): Rl=OCH3, $~=H: B=E=H: A and D taken together is -CH2-N(4-quinolxl-CH2-)-CH2-Stardng with the Compound of Formula (III): R1=OCH3, R2=I-i; B=E=H; A and D
taken together is -CH2-NH-CH2-, from Example 19 above, reacting the amine of the -CH2-NH-GH2- group with 4-chloromethylquinoline in the presence of triethylamine, the title compound is prepared.
Example 29 Compound of Formula (III): Rl-~ R~=H: B=E=H: A=D=-CH2-O-CH2=phenyl 29a. PhCH20CH2CH(NH2) H(NH2)CH20CH2Ph Meso-erythritol (Aldrich) is 1,4-dibenzylated by reaction with NaH and benzyl bromide in DMF according to the procedure of El Amin et al., J. Org. Chem.
44:3442, (1979). Following the procedures of Example 10 steps a-c, except substituting 1,4-dibenzyl-meso-erythritol for the diol of step 10a, and carrying the product forward as in steps lOb and lOc, the title compound is prepared.
29b. Compound of Formula (III):
Rl-OCH~,,~~=H: B=E=H: A=D=-CH2-O- H2-~n3r1 Following the procedures of Example 10 steps d-f, except substituting IPhCH20CH2CH(NH2)CH(NH2)CH20CH2Ph, from the previous step, for the meso-2,3-butanediamine of step lOd, the title compound is prepared.
Example 30 Compound of Formula /TTT1~ R1R~=H: B=E=H: A=D=-CH2-OH
Starting with the Compound of Formula (III): RI=OCH3, R2=H; B=E=H; A=D=-CH2-O-CH2-phenyl, from Example 29 above, removing the benzyl groups by hydrogenation over Pd/C, the title compound is prepared.
Example 31 Compound of Formula fIIII- Rl-- .~H R~=H~ B=E=H~ A=D=-CH2-O-p_h~~~l Starting with the Compound of Formula (III): R1=OCH3, R2=I-i; B=E=H; A=D=-CH2-OH, from Example 30 above, reacting the -CH2-OH groups (of substituents A
and D) with phenol, triphenylphosphine and DEAD under Mitsunobu conditions the title compound is prepared.

Example 32 Compound of Formula (III): Ri=OCH3, R~=H: A=B=H: D and E taken together is -CH2-CH2-CH2-CH2-Following the procedures of Example 3 except substituting 1-amino-1-cyclo-pentanemethanol (Aldrich) for the 2-(R)-amino-3-phenyl-1-propanol thereof, the title compound is obtained.
Example 33 Compound of Formula (111): R1=OCH3, ~~=H: A and B taken together is -CH2-CH2-CH2-CHI-~ D-E-H
Following the procedures of Example 5, except replacing the (S)-2-amino-3-phenyl-1-propanol of step Sa with 1-amino-1-cyclopentanemethanol (Aldrich), the title compound is obtained.
Example 34 Compound of Formula (III): RI=OCH3, Rz'=H; A=B=H: D and E taken together is -CH2-O-CH2-34a. 3-amino-3-aminomethyloxetane A sample of tris(hydroxymethyl)methylamine (Aldrich) is reacted with di-t-butyldicarbonate and triethylamine to give N-BOC-tris(hydroxymethyl)methylamine. This compound is reacted with 1 equivalent of methanesulfonyl chloride and triethylamine to give 3-(BOC-amino)-3-hydroxymethyloxetane. This compound is converted to the title compound according to the procedures of Example 3 steps b-e.
34b. Compound of Formula (III): R1=OCH3, R~=H: A=B=H: D and E taken together is -CH2-O-CH2-Following the procedures of Example 3 steps f h except substituting the compound from step 34a for the (R)-3-phenyl-1,2-propanediamine thereof, the title compound is obtained.
Example 35 Compound of Formula IIIII: Rl--OCH~ RAH: A=D=E=H~ B=-CH2-CH2-phen~
Following the procedures of Example 5, except replacing the (S)-2-amino-3-phenyl-1-propanol of step Sa with D-homophenylalaninol (prepared by LiAlH4 reduction of the D-homophenylalanine available from Aldrich), the title compound is obtained.

Example 36 Coa~r~nound of Formula (IIII: Rl-~ R2=I-I: A=D=E=H: B=-CH2-CH2-CH2=phenyl-36a. 2-(R)-amino-5-phen~nentanoic acid (t)-2-Amino-5-phenylpentanoic acid (35 g, from Example 40a) was suspended in water (3 L) and solubilized by adjusting the pH to 12 with 7 N NaOH solution.
The pH was readjusted to pH 8 with 1 M phosphoric acid while stirring at 45°C. The solution was cooled to 40°C, and L-amino acid oxidase (Sigma, 0.7 unit/mg) was added. The reaction was stirred with good aeration for 2 weeks. The reaction mixture was concentrated to 500 mL
under vacuum, the pH was adjusted to 5, and the precipitate was collected. The material was recrystallized from ethanol-water to afford 17.32 g of the title compound).
36b. 2-(R)-amino-5-phenylpentanol The compound from step 36a is reduced with LiAIHq. under standard conditions to give the title compound.
36c. Compound of Formula (BI):
RI=O H R' =H: A=D=E=H' B=-CH2-CH2-CH2=phenyl Following the procedures of Example 5, except replacing the (S)-2-amino-3-phenyl-1-propanol of step Sa with the 2-(R)-amino-5-phenylpentanol from step 36b, the title compound is obtained.
Example 37 Compound of Formula (III): Rl--OCHx R~=H: A=D=E=H: B=-CH2-O-CH2=phenyl 37a. 1-N-(CBZ)-2-IS)-diamino-3-O-ben~lpropane N-BOC-O-benzyl-D-serine (Bachem) is reduced under the reaction conditions described by Kotokos, Synthesis, 299-301 (1990) to give the N-BOC-O-benzyl-D-serinol.
This compound is treated according to the procedures of Example l0a-c to give the corresponding amine. The amine is converted to the benzyloxycarbonyl (CBZ) derivative, and the BOC group is removed to give the title compound.
37b. Compound of Formula (III):
~1--~H R~=Ii: A=D=E=H: B=- H2-O- H2~heB,y1 Following the procedures of Example 10 steps d-f, except substituting the material from the previous step, for the meso-2,3-butanediamine of step lOd, the title compound is prepared.

Example 38 Compound of Formula (IIII): R'=OGH3, R"=H. A=D=E=H~ B=-CH2-CH2-(4-OCH~- hen 1 38a D-homo-O-methvl osinnl D-Homo-O-methyltyrosine (prepared according to the procedure of Melillo et al., J.
Org. Chem., x:5149-5150 (1987)) is reduced with LiAIHq under standard conditions to give the title compound.
38b. Cimpound o~Formula (III):
~ .,~3. =H: A=D=E=H' B=- H2- -H~-tq.-OCH~- n 1 Following the procedures of Example 5, except replacing the (S)-2-amino-3-phenyl-1-propanol of step Sa with the compound of step 38a, the title compound is obtained.
Example 39 Compound of Formula (IIII: Rl---I R~=H' A=-CH2-CH2-ph~nvl- B=D=E=H
Following the procedures of Example S, except substituting L-homophenylalaninol (prepared by LiAIHq. reduction of the L-homophenylalanine (Aldrich) compound) for the (S)-2-amino-3-phenyl-1-propanol of step Sa , the title compound is obtained.
Example 40 Compound of Formula ,(IIII: Rl---I ,~~=H: A=-CH2-CH2-CH2-~henvl~ B=D=E=H
40a. (~)-2-Amino-5-~rhenvlnentann;c a~-;rt Diethyl acetamidomalonate (220 g) in 1 L of absolute ethanol was added to a stirred solution of sodium ethoxide in ethanol, prepared by dissolving sodium (24 g) in absolute ethanol (500 mL), under nitrogen. The reaction mixture was refluxed under nitrogen for 30 minutes, then 1-bromo-3-phenylpropane (200g) was added. The reaction mixture was refluxed overnight, cooled to ambient temperature, filtered, and the solvent was removed under vacuum. Concentrated HCl (800 mL) was added to the residue, and the reaction mixture was refluxed for 14 hours. The cooled aqueous solution was washed with ether, and the residual ether in the aqueous phase was removed by bubbling nitrogen through the solution. The pH of the aqueous phase was adjusted to pH 7-8 by the addition of ammonium hydroxide. The title compound was collected by filtration, air dried and recrystallized from ethanol-water (150 g) m.p. 255-257°C. MS m/z: 194 (M+H)+.
49b l+1- 2-amino-5-phenvlpen annl The compound from step 40a is reduced with LiAlH4 under standard conditions to give the title compound.

WO 97/17356 PC'1'/US96/16585 40c. Compound of Formula (af):
Rl-,-~ R~=H: A=-CHz-CHz-CHz-phenyl: B=D=E=H
Following the procedures of Example 5, except replacing the (S)-2-amino-3-phenyl 1-propanol of step Sa with the (~)- 2-amino-5-phenylpentanol from step 40b, and separating the isomers by chromatography the title compound is obtained.
Example 41 Compound of Formula IIIi): Rl-=OCH~ R~=H: A=-CH2-O-CH2-phenyl ~ B=D=E=H
Following the procedures of Example 37, except substituting the N-BOC-O-benzyl-L-serine (Sigma) for the N-BOC-O-benzyl-D-serine thereof the title compound is prepared.
Example 42 Compound of Formula (111): R1=OCH3, $~-_-H: B=D=E=H: A=- H2-CH2-l4-OCH~-_ henvll 42a. L-homo-O-methyltvros~n_ol L-Homo-O-methyltyrosine (prepared according to the procedure of Melillo et al., J.
drg. Chem., ,x:5149-5150 (1987)) is reduced with LiAlHø under standard conditions to give the title compound.
42b. Compound of Formula (III):
Rl=OCH~ R~=H: B=D=E=H: A=-CH2-CH2-(4-OCH~- hen 1 Following the procedures of Example 5, except replacing the (S)-2-amino-3-phenyl-1-propanol of step Sa with the compound of step 42a, the title compound is obtained.
Example 43 Compound of Formula lIln: Rl=OCH~. R~=H: A=B=D=H: E=-CH2CH2Ph Following the procedures of Example 3 except replacing the 2-(R)-amino-3-phenyl-1-propanol of step 3a thereof with L-homo-phenylalaninol (prepared by LiAIHq.
reduction under standard conditions of the L-homo-phenylalanine compound available from Aldrich) the title compound is prepared.
Example 44 Compound of Formula (IIIO Rl-OCH~ R~=H. A=B=E=H: D=-CH2~H2Ph Following the procedures of Example 3 except replacing the 2-(R)-amino-3-phenyl-1-propanol of step 3a thereof with D-homo-phenylalaninol (prepared by LiAIHq.
reduction under standard conditions of the D-homo-phenylalanine compound available from Aldrich) the title compound is prepared.
_77_ Example 45 Compound of Formula (IIII: Rl----OCH~ R2=H: A=B=D=H: E=~HzCH2CHzPh Following the procedures of Example 3 except replacing the 2-(R)-amino-3-phenyl-1-propanol of step 3a thereof with (~)- 2-amino-5-phenylpentanol (prepared in Example 40b) and separating the desired isomer by chromatography the title compound is prepared.
Example 46 Compound of Formula (III): Rte--OCH~ R~=H: A=B=E=H: D=-CH2CH2CH2Ph Following the procedures of Example 3 except replacing the 2-(R)-amino-3-phenyl-l0 1-propanol of step 3a thereof with 2-(R)-amino-5-phenylpentanol (prepared in Example 36b) the title compound is prepared.
Example 47 Compound of Formula (IIII R 1=OCH~,R2=H: A=-CH2CH20Ph~ B=D=E=H
47a. N-a-Boc-L-homo-serine benz~rl ester The title compound is prepared from N-a-Boc-L-aspartic acid a-benzyl ester, ethyl chloroformate, N-methylinorpholine and sodium borohydride in tetrahydrofuran and methanol according to the procedures described by Kokotos, Synthesis, (1990):
299-301.
47b. 4-Phenoxy-2-(S)-Boc-aminobutyric acid benzyl ester A solution of N-a-Boc-L-homo-serine benzyl ester, phenol and triphenylphosphine in THF is treated with diethylazodicarboxylate (DEAD) at 0 °C. After being stirred at reaction temperature for 2 hours, the reaction is worked up and product purled by silica gel chromatography. (c~ Organic Reactions, Vol. 42, John Wiley & Son, Inc, 1992).
47c. 4-phenoxy-2-(S 1-Boc-aminobutane-1-0l Lithium aluminum hydride is added into a stirred solution of 4-phenoxy-2-(S)-Boc-aminobutyric acid benzyl ester, from step 47b, in THF at 0 °C. The reaction mixture is heated to reflux for 0.5 hour and cooled to ice-cold temperature. Water, equal weight to the lithium aluminum hydride used, is added and stirred at reaction temperature overnight. The reaction is diluted with ethyl acetate and dried over sodium sulfate. After filtration and removal of solvent in vacuo, the product is purified by silica gel chromatography.
47d. 4-nhenoxv-2-(S)-aminobutane-1-of The amino protecting group of 4-phenoxy-2-(S)-Boc-aminobutane-1-of from step 47c is removed by treatment of the protected compound with hydrogen chloride in dioxane.
(cf. T. W. Greene and P. G. M. Wuts: Protective Groups in Organic Synthesis.
2nd ed., John Wiley and Son, 1991, pp 309-315.) _7g_ 47e. Compound (22) Scheme 10:
R~-OCH~~ R~'=Bz: A~CH2CH2-OPh: B=D=E=H: Y=OH
The title compound is prepared from 4-phenoxy-2-(S)-aminobutane-1-of and compound (8) in aqueous acetonitrile according to the procedures described in Example 5.
47f. Compound l207 Scheme 10: Rl=_ OCHY: A=-CH2CH2-OPh: B=D=E=H
The title compound is prepared from the compound of step 47d. according to the procedures described in Example 5.
47 g. Compound of Formula (III) R 1=OCH~, R2=H: A=-CH2CH20Ph: B=D=E=H
The title compound of Example 47 is prepared from the compound of 47f according to the procedures described in Example 5.
Example 48 i5 Compound of Formula~III) R1=OCH~, R2=H: A=-CH2CH2NHCbz: B=D=E=H
48a. N-a-!S)-Boc -N-y Cbz-2.4-diaminobutvric acid benzyl ester Diphenylphosphoryl azide is added into a solution of N-a-(S)-Boc-L-glutamic acid a -benzyl ester in THF and the resulting solution is refluxed for 2 hours.
Benzyl alcohol is added and the reaction mixture is refluxed for an additional hour. The product is purified by silica gel chromatography.
4$b. N-a-!S)-Boc -N-'y Cbz-2.4-diamino-butane-1-of Lithium aluminum hydride is added into a stirred solution of N-oc-(S)-Boc -N-y Cbz-diaminobutyric acid benzyl ester, from step 48a, in THF at 0 °C. The reaction mixture is heated to reflux for 0.5 hour and cooled to ice-cold temperature. Water, equal weight to the lithium aluminum hydride used, is added and stirred at reaction temperature overnight. The reaction is diluted with ethyl acetate and dried over sodium sulfate. After filtration and removal of solvent in vacuo, the product is purified by silica gel chromatography.
48c. 2-!S 1-4-N-Cbz-diamino-1-butanol The amino protecting group of N-a-(S)-Boc -N-'y Cbz-2,4-diamino-butane-1-of from step 48b is removed by treatment of the protected compound with hydrogen chloride in dioxane according to literature method. (cf. T. W. Greene and P. G. IVI. Wuts:
Protective Groups in Organic Synthesis. 2nd ed., John Wiley and Son, 1991, pp 309-315.) 48d. Compound (22) Scheme 10:
$1--OC ~H ;~~=Bz~ A=-CH2CH2-NHCbz~ B=D-E-H~ Y-OH
The title compound is prepared from 2-(S)-amino-4-N-y Cbz-diamino-butane-1-ol, from step 48c, and compound (8) from Scheme 3 in aqueous acetonitrile according to the procedures described in Example 5.

48e. Compound (201 Scheme 10' Rl=~; A=-CH2CH2-NHCbz; B=D=E=H
The title compound is prepared from the compound of step 48d according to the procedures described in Example 5.
48f. Compound of Formula (IIII R1=OCH~ R2=H: A=-CH2CH2NHCbz~ B=D=E=H
The title compound is prepared from the compound of step 48e according to the procedures described in Example 5.
1o Example 48-A
Compound of Formula (Im Rl=OCH~, R2=H: A=-CH2CH2NH2~ B=D=E=H
The title compound is prepared from the compound of Example 48 and hydrogen in the presence of Pd-C in ethanol.
Example 49 Compound of Formula (III1 R 1=OCH~ R2=H: A=-CH2C02Bzl: B=D=E=H
49a. 4-hvdroxy-3-N-(S)-Boc-aminobutvric acid benzyl ester The title compound is prepared from N-a-Boc-L-aspartic acid y benzyl ester, ethyl chloroformate, N-methylinorpholine and sodium borohydride in tetrahydrofuran and methanol according to the procedures described by Kokotos, Synthesis, (1990):
299-301.
49b. 4-hydroxy-3-(S)-aminobutyric acid Benz ly ester The amino protecting group of 4-hydroxy-3-N-(S)-Boc-aminobutyric acid benzyl ester, from step 49a, is removed by treatment of the protected compound with hydrogen chloride in dioxane according to literature method.(cf. T. W. Greene and P. G.
M. Wuts:
Protective Groups in Organic Synthesis. 2nd ed., John Wiley and Son, 1991, pp 309-315.) 49c. Compound (22) Scheme 10:
R~-OCH~- R~=Bz: A~CH2C02Bz1~ B=D=E=H' Y=OH
The title compound is prepared from 4-hydroxy-3-(S)-aminobutyric acid benzyl ester, from step 49b and compound (8) of Scheme 3 in aqueous acetonitrile according to the procedures described in Example 5.
49d. Compound (20) Scheme 10- Rl=y A=-CH2C02Bzl: B=D=E=H
The title compound is prepared from the compound of step 49c according to the procedures described in Example 5.

49e. Compound of Formula (III) R1=OCH~, R2=H; A=-CH2C02Bzl: B=D=E=H
The title compound is prepared from compound from the compound of step 49d according to the procedures described in Example 5.
Example 49-A
Compound of Formula (IIP Rl=OCH~, R2=H, A=-CH2COOl~i~ B=D=E=H
The title compound is prepared from the compound of Example 49 and hydrogen in the presence of Pd-C in ethanol.
to Example 49-B
Formula (IIII R1=OCH~ R2=H: A=-CH2CH20H~ B=D=E=H
The title compound is prepared from the title compound of Example 49-A, ethyl chloroformate, N-methyhnorpholine and sodium borohydride in tetrahydrofuran and methanol according to the procedures described by Kokotos, Synthesis, (1990):
299-301.
Example 50 Compound of Formula (IIII R1=OCHY R2=H; A=-CH2CH2NH(4'-fyridyll B=D=E=H
The title compound is prepared from the compound of Example 48-A, 4-chloropyridine, and Cu0 or CuBr-K2C03 heated at 70-90 °C overnight. The reaction mixture is partitioned between ethyl acetate and water. The organic phase is washed once with dilute hydrochloric acid followed by saturated sodium bicarbonate. The product is purified by silica gel chromatography.
Example 51 Compound of Formula (IIIO Rl--OCH~ R~1~; A=B=D=H; E=-CH20H
~ 1 a. 1 2-diamino-3-nropanol Allyl acetate (Aldrich) is reacted with manganese triacetate, sodium azide and acetic acid. The resulting compound is treated with NaHC03 and methanol followed by hydrogenation to give the title compound.
~ 1 b. Compound of Formula IIII~ ~ Rl=O~ R~=H: A=B=D=H: E=-CH20H
Following the procedures of Example 3 steps f h, except substituting 1,2-diamino-3 propanol from the previous step, for the l, 2-(R)-diamino-3-phenylpropane thereof, the title compound is prepared, and the diastereomers are separated by chromatography.
Example 52 Compound of Formula (III)' Rl-~ RAH; A=B=E=H: D=-CH20H
The compound is separated from the diastereomeric mixture of Example 51b by chromatography.

Example 53 Compound of Formula (III): R~-~ R~=H: A=B=E=H: D=-CH2NHBenzo~l The compound is prepared from the compound of Example 16 by treatment with benzoyl chloride and TEA.
Example 54 Compound of Formula (III): Rl=OCHY R~=H: A=B=E=H: D=-CH2NHBenzvl The compound is prepared from the compound of Example 16 by treatment with benzaidehyde, NaCNBH3 and acetic acid in methanol at reaction temperature.
Example 55 Compound of Formula IIII): Rl-~ R~=H: A=B=D=H: E=-CH2NHBenzovl The compound is prepared from the compound of Example 15 by treatment with benzoyl chloride and TEA.
Example 56 Compound of Formula (III): Rl-~ R~=H: A=B=D=H: E=-CH2NHBenzyl_ The compound is prepared from the compound of Example 15 by treatment with benzaldehyde, NaCNBH3 and acetic acid in methanol at reaction temperature.
Example 57 Compound of Formula (III): Rl-~ R~=H: B=D=H: A=E=-CH20CH2(4-Cl-phenyl-) ~7a. (R.R)-(+)-1.4- bis-O-(4-chlorobenzvl)-2.3-butanediamine Following the procedure of Example 10 steps a-c, replacing the meso-2,3-butanediol thereof with (R,R)-(+)-1,4- bis-O-(4-chlorobenzyl)-D-threitol (Aldrich) the title compound is obtained.
57b. Compound of Formula (III):
Rl--I R2=H: B=D=H: A=E=-CH20CH2(4-Cl-phenyl-1 Following the procedures of Example 10 steps d-f, replacing the meso-2,3-butanediamine of step d thereof with the diamine from step 57a, the title compound is prepared.
Example 58 Compound of Formula (III): Rl=OCH3. R~=H: A=B=E=H: D=-CH2-N(CH~)-Benzx_1 The title compound is prepared by treating the compound of Example 54 with HCHO, NaCNBH3 and acetic acid in methanol at reaction temperature.

Example 59 Compound of Formula (IIIZ: Rl=OCH3. R~=H; A=B=D=H: E=-CH2-N(CH~ -Benz 1 The title compound is prepared by treating the compound of Example 56 with I~CHO, NaCNBH3 and acetic acid in methanol at reaction temperature.
Example 60 Compound of Formula (III): Rl=OCH3. R~=H; A=B=D=H: E=-CH2-NH-phenvl The title compound is prepared by treating the compound of Example 51 with l0 triphenyl phosphine, DEAD and aniline under Mitsunobu conditions.
Example 61 Compound of Formula fIII): Rl=OCH3. R~=H: A=B=E=H: D=-CH2-NH- hn envl The title compound is prepared by treating the compound of Example 52 with triphenyl phosphine, DEAD and aniline under Mitsunobu conditions.
Example 62 In Vitro Assay of Antibacterial Activity Representative compounds of the present invention were assayed in vitro for antibacterial activity as follows: Twelve petri dishes containing successive aqueous dilutions of the test compound mixed with 10 mL of sterilized Brain Heart Infusion (BHn agar (Difco 0418-O1-5) were prepared. Each plate was inoculated with 1:100 (or I:10 for slow-growing strains, such as Micrococcus and Streptococcus) dilutions of up to 32 different microorganisms, using a Steers replicator block. The inoculated plates were incubated at 35-37 °C for 20 to 24 hours. In addition, a control plate, using BHI agar containing no test compound, was prepared and incubated at the beginning and end of each test.
An additional plate containing a compound having known susceptibility patterns for the organisms being tested and belonging to the same antibiotic class as the test compound was also prepared and incubated as a further control, as well as to provide test-to-test comparability. Erythromycin A was used for this purpose.
After incubation, each plate was visually inspected. The minimum inhibitory concentration (MIC) was defined as the lowest concentration of drug yielding no growth, a slight haze, or sparsely isolated colonies on the inoculum spot as compared to the growth control. The results of this assay, shown below in Table 2 demonstrate the antibacterial activity of the compounds of the invention.

Table 2 Atltibacterial Activity (MIC's) of Selected Compounds Ery A Cmpd of Cmpd of MICROORGANISM (Ref. Ex 1 Ex 3 std) STAPHYLOCOCCUS AUREUS ATCC 0.2 6.2 0.39 STAPHYLOCOCCUS AUREUS A5177 6.2 6.2 0.39 STAPHYLOCOCCUS AUREUS A-5278 > 100 > 100 > 100 STAPHYLOCOCCUS AUREUS CMX 642A0.39 6.2 0.39 STAPHYLOCOCCUS AUREUS NCTC10649M0.2 6.2 0.39 STAPHYLOCOCCUS AUREUS CMX 553 0.2 6.2 0.39 STAPHYLOCOCCUS AUREUS 1775 > 100 > 100 > 100 STAPHYLOCOCCUS EPIDERMIDIS 0.39 12.5 0.39 ENTEROCOCCUS FAECIC1M ATCC 0.05 0.78 0.05 STREPTOCOCCUS BOVIS A-5169 0.05 0.39 0.02 STREPTOCOCCUS AGALACTIAE CMX 0.05 0.39 0.01 STREPTOCOCCUS PYOGENES EES61 0.05 0.39 0.01 STREPTOCOCCUS PYOGENES 930 >100 >100 100 STREPTOCOCCUS PYOGENES PIU 6.2 0.78 na MICROCOCCUS LUTEUS ATCC 9341 0.02 0.39 0.1 MICROCOCCUS LUTEUS ATCC 4698 0.2 0.39 0.39 ESCHERICHIA COLI JUHI. 100 na >100 ESCHERICHIA COLI SS 0.2 na na ESCHERICHIA COLI DC-2 >100 0.78 >100 ESCHERICHIA COLI H560 25 50 >100 ESCHERICHIA COLI KNK 437 50 25 >100 ENTEROBACTER AEROGENES ATCC 100 >100 >100 KLEBSIELLA PNEUMOMAE ATCC 8045100 >100 >100 PROVIDENCIA STUARTII CMX 640 >100 100 >100 PSEUDOMONAS AERUGINOSA BMH10 >100 >100 >100 PSEUDOMONAS AERUGINOSA 5007 > 100 > 100 > 100 PSEUDOMONAS AERUGINOSA K799/WT50 >100 >100 PSEUDOMONAS AERUGINOSA K799/610.78 >100 3.1 PSEUDOMONAS CEPACIA 296I > 100 12.5 > 100 ACINETOBACTERCALCOACETICUSCMX6696.2 >100 >100 PSEUDOMONAS AERUGINOSA DPHD-5263>100 50 >100 PSEUDOMONAS AERUGINOSA DPHD-2862>100 >100 >100 CANDll~A ALBICANS CCH442 >100 >100 >100 MYCOBACTERIUM SMEGMATIS ATCC 0.02 3.1 >100 W(y 97/17356 PCT/US96/16585 Table 2 Antibacterial Activit3r (MIC's) of Selected Compounds Cmpd of Cmpd of Cmpd of MICROORGANISM Ex 4 Ex 6 Ex 8 STAPHYLOCOCCUS AUREUS ATCC 6538P 0.2 0.1 0.78 STAPHYLOCOCCUS AUREUS A5177 0.2 0.05 0.78 STAPHYLOCOCCUS AUREUS A-5278 >100 >100 >100 STAPHYLOCOCCUS ALTREUS CMX 642A 0.78 0.1 0.78 STAPHYLOCOCCUS AUREUS NCTC10649M 0.78 0.1 0.78 STAPHYLOCOCCUS AUREUS CMX 553 0.78 0.2 0.78 STAPHYLOCOCCUS AUREUS 1775 > 100 > 100 > 100 STAPHYLOCOCCUS EPIDERMIDIS 3519 0.78 . 0.1 0.78 LNTEROCOCCUS FAECIUM ATCC 8043 0.1 0.1 0.78 STREPTOCOCCUS BOVIS A-5169 0.02 0.01 0.1 STREPTOCOCCUS AGALACTTAF CMX 508 0.005 0.02 0.1 STREPTOCOCCUS PYOGENES EES61 0.05 0.02 0.1 STREPTOCOCCUS PYOGENES 930 > 100 > 100 > 100 STREPTOCOCCUS PYOGENES PICT 2548 na 0.39 0.78 1VIICROCOCCUS LUTEUS ATCC 9341 0.1 0.02 1.56 MICROCOCCUS LUTEUS ATCC 4698 0.39 0.1 1.56 ESCHERICHIA COLI JCTHI. >100 12.5 100 ESCHERICHIA COLI SS na 0.02 0.78 LSCHERICHIA COLI DC-2 100 12.5 50 LSCHERICHIA COLI H560 25 3.1 25 ESCHERICHIA COLI KNK 437 >100 6.2 100 ENTEROBACTER AEROGENES ATCC 13048 100 12.5 100 KLEBSIELLA PNEUMONIAE ATCC 8045 >100 12.5 100 PROVIDENCIA STUARTII CMX 640 >100 100 >100 PSEUDOMONAS AERUGINOSA BMH10 >100 50 100 PSEUDOMONAS AERUGINOSA 5007 > 100 100 > 100 1'SEUDOMONAS AERUGINOSA K799/WT >100 25 100 PSEUDOMONAS AERUGINOSA K799/61 1.56 0.39 na.

1'SEUDOMONAS CEPACIA 296I >100 50 >100 ACINETOBACTER CALCOACETICUS CMX 669 25 12.5 25 1'SEUDOMONAS AERUGINOSA DPHD-5263 >100 12.5 >100 1'SEUDOMONAS AERUGINOSA DPHD-2862 >100 100 >100 CANDIDA ALBICANS CCH 442 100 > 100 > 100 MYCOBACTERIUM SMEGMATIS ATCC 114 na na 6.2 WO 97/17356 PCT/(TS96/16585 Tabte 2 Antibacterial Activity (MIC'sl of Selected Com -hounds Cmpd of Cmpd of Cmpd of MICROORGANISM Ex 9 Ex 10 Ex 11 STAPHYLOCOCCUS AUREUS ATCC 0.39 0.39 0.39 STAPHYLOCOCCUS AUREUS A5177 0.39 na 0.39 STAPHYLOCOCCUS AUREUS A-5278 > 100 > 100 > 100 STAPHYLOCOCCUS AUREUS CMX 642A0.39 0.39 0.39 STAPHYLOCOCCUS AUREUS NCTC10649M0.2 0.39 0.39 STAPHYLOCOCCUS AUREUS CMX 553 0.39 0.39 0.39 STAPHYLOCOCCUS AUREUS 1775 >100 >100 >100 STAPHYLOCOCCUS EPIDERMIDIS 0.39 0.39 0.39 ENTEROCOCCUS FAECIiJM ATCC 0.05 na 0.1 STREPTOCOCCUS BOVIS A-5169 na 0.05 0.01 STREPTOCOCCUS AGALACTIAE CMX 0.01 na 0.05 STREPTOCOCCUS PYOGENES EES61 0.01 na 0.005 STREPTOCOCCUS PYOGENES 930 > 100 > 100 > 100 STREPTOCOCCUS PYOGENES PIU 0.39 0.39 0.39 MICROCOCCUS LUTEUS ATCC 9341 0.1 0.1 0.2 MICROCOCCUS LUTEUS ATCC 4698 0.39 0.2 0.39 ESCHERICHIA COLI JUHI. na 25 25 ESCHERICHIA COLI SS na 0.2 0.39 ESCHERICHIA COLI DC-2 25 ~5 ~5 ESCHERICHIA COLI H560 25 25 6.2 ESCHERICHIA COLI KNK 437 100 na 25 KLEBSIELLA PNEUMONIAE ATCC 25 na 12.5 PROVIDENCIA STUARTII CMX 640 > 100 > 100 > 100 PSEUDOMONAS AERUGINOSA BMH10 100 >100 >100 PSEUDOMONAS AERUGINOSA 5007 > 100 > 100 > 100 PSEUDOMONAS AERUGINOSA K799/WT100 na >100 PSEUDOMONAS AERUGINOSA K799/616.2 na na PSEUDOMONAS CEPACIA 296I >100 100 >100 ACINETOBACTER CALCOACETICUS 12.5 25 6.2 PSEUDOMONAS AERUGINOSA DPHD-5263>100 >100 >100 PSEUDOMONAS AERUGINOSA DPHD-2862> 100 > 100 > 100 CANDIDA ALBICANS CCH 442 >100 >100 >100 MYCOBACTERIUM SMEGMATIS ATCC 3.1 6.2 6.2

Claims (17)

WHAT IS CLAIMED IS:

1. A compound selected from the group having the formulas:
or a pharmaceutically acceptable salt or ester thereof wherein:
A, B, D and E are independently selected from the group consisting of:
(a) hydrogen;
(b) C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of:
(i) aryl;
(ii) substituted-aryl;
(iii) heteroaryl;
(iv) substituted-heteroaryl;
(v) heterocycloalkyl;
(vi) hydroxy;
(vii) C1-C6-alkoxy;
(viii) halogen consisting of Br, Cl, F or I; and (ix) NR3R4, where R3 and R4 are independently selected from hydrogen and C1-C6-alkyl, or R3 and R4 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring optionally containing a hetero function consisting of -O-, -NH-, -N(C1-C6-alkyl-)-, -N(aryl-C1-C6-alkyl-)-, -N(substituted-aryl-C1-C6-alkyl-)-J(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl-)-, -S- or -S(O)n-, wherein n is 1 or 2;
(c) C3-C7-cycloalkyl;
(d) aryl;
(e) substituted-aryl;
(f) heteroaryl;
(g) substituted-heteroaryl;
(h) heterocycloalkyl;
(i) a group selected from option (b) above further substituted with -M-R5, wherein M is selected from the group consisting of:
(aa) -C(O)-NH-;

(bb) -NH-C(O)-;

(cc) -NH-(dd) -N(CH3)-(ee) -O-(ff) -S(O)n-, wherein n is 0, 1 or 2; and (gg) -C(=NH)-NH-;

and R5 is selected from the group consisting of:

(aaa) C1-C6-alkyl, optionally substituted with a substituent selected from the group consisting of:
(i) aryl;

(ii) substituted-aryl;

(iii) heteroaryl; and (iv) substituted-heteroaryl;

(bbb)aryl;

(ccc)substituted-aryl;

(ddd)heteroaryl;

(eee)substituted-heteroaryl; and (fff)heterocycloalkyl;

or any one pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7-membered ring optionally containing a hetero function consisting of -O-, -NH-, -N(C1-C6-alkyl-)-, -N(aryl-C1-C6-alkyl-)-, -N(substituted-aryl-C1-C6-alkyl-)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl-)-, -S- or -S(O)n-, wherein n is 1 or 2;
-C(O)-NH-;
-C(O)-NR5-, wherein R5 is as described above;
-NH-C(O)-;
-NR5-C(O)-, wherein R5 is as described above; and -C(=NH)-NH-;
R1 is selected from the group consisting of:
(a) hydrogen;
(b) hydroxy;

(c) -O-C1-C3-alkyl;
(d) -O-C3-C5-cycloalkyl;
(e) -O-C1-C3-alkyl-C3-C5-cycloalkyl;
(f) -O-C(O)-C1-C3-alkyl;
(g) -O-C(O)-O-C1-C3-alkyl; and (h) -O-C(O)-NH-C1-C3-alkyl;

R2 is hydrogen or a hydroxy-protecting group; and Z is hydroxy or protected-hydroxy;
wherein aryl hereinbefore is phenyl or naphthyl;
heteroaryl hereinbefore is a cyclo aromatic radical of 5 to 10 ring atoms having 1 to 3 ring atoms selected from S, O and N, and the remaining ring atoms being C
atoms;
heterocycloalkyl hereinbefore is a non-aromatic 5-, 6- or 7-membered ring or a bi-or tri-cyclic group comprising fused six-membered rings, having 1 to 3 heteroatoms independently selected from O, S and N; and wherein:
i) each 5-membered ring has 0 or 1 double bonds and each 6-membered ring has 0, 1 or 2 double bonds;
ii) N and S heteroatoms are unoxidized or oxidized;
iii) N heteroatoms are unquaternized or quaternized; and iv) heterocyclic rings are unfused or fused to a benzene ring;
with the provisos that when the compound is of Formulas (I) or (III) then A, B, D, and E
may not all be hydrogen, D and E may not be C1-C3-alkyl when A and B are hydrogen, nor may one of D and E be hydrogen and the other be C1-C3-alkyl when A and B are hydrogen.

2. A compound according to Claim 1 having the formula:

wherein A, B, D, E, and R1-R5 are as defined in claim 1.

3. A compound according to Claim 1 having the formula:
wherein A, B, D, E, R1-R5 and Z are as defined in claim 1.

4. A compound according to Claim 1 having the formula:
wherein A, B, D, E, and R1-R5 are as defined in claim 1.

5. A compound according to Claim 1 having the formula:
wherein A, B, D, E, and R1-R5 are as defined in claim 1.

6. A compound according to Claim 4 wherein R1 is hydrogen, hydroxy or methoxy, R2 is hydrogen, and A, B, D, E and R1-R5 are as described therein.

7. A compound according to Claim 6 wherein R1 is hydrogen or methoxy, R2 is hydrogen, and any three of the A, B, D and E groups are hydrogen and the other group is selected from a singly substituted C1-C6-alkyl group which is -(CH2)m R6 where m=1, 2, 3 or 4 and R6 is:
(a)aryl;
(b)substituted-aryl;
(c)heteroaryl;
(d)substituted-heteroaryl;
(e)heterocycloalkyl;
(f)hydroxy;
(g)C1-C6-alkoxy (h) NR3R4, where R3 and R4 are independently selected from hydrogen and C1-C6-alkyl, or R3 and R4 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring optionally containing a hetero function consisting of -O-, -NH-, -N(C1-C6-alkyl-)-, -N(aryl-C1-C6-alkyl-)-, -N(substituted-aryl-C1-C6-alkyl-)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl-)-, -S- or -S(O)n-, wherein n is 1 or 2;
(i) halogen consisting of Br, Cl, F or I;
(j) C1-C3 alkyl; or (k) -(CH2)r-M-(CH2)s-R7 wherein r=0,1 or 2; s=0;1 or 2 and M is (aa) -C(O)-NH-;
(bb) -NH-C(O)-;
(cc) -NH-(dd) -N(CH3)-(ee) -O-(rr) -S(O)n-, wherein n is 0, 1 or 2; and (gg) -C(=NH)-NH-;
and R7 is selected from the group consisting of:
(aaa) C1-C3-alkyl, (bbb) aryl;
(ccc) substituted-aryl;
(ddd) heteroaryl; and (eee) substituted-heteroaryl.

8. A compound according to Claim 7 wherein R1 is hydrogen or methoxy, R2 is hydrogen, B=E=H, and A and D taken together is selected from the group consisting of:
(a) -CH2-Z-CH2-, wherein Z is (aa) -C(O)-NH-;
(bb) -C(O)-NR5-, wherein R5 is selected from the group consisting of:
(aaa) C1-C6-alkyl, optionally substituted with a substituent selected from the group consisting of:
(i) aryl;
(ii) substituted-aryl;
(iii) heteroaryl; and (iv) substituted-heteroaryl;
(bbb) aryl;
(ccc) substituted-aryl;

(ddd) heteroaryl;
(eee) substituted-heteroaryl; and (fff) heterocycloalkyl;
(cc) -NH-C(O)-;
(dd) -NR5-C(O)-, wherein R5 is as defined above;
(ee) -NH-(ff) -N(CH3)-(gg) -O-(hh) -S(O)n-, wherein n is 0, 1 or 2; and (ii) -C(=NH)-NH-;
(b) -CH2-N(-(CH2)s-R7)-CH2-, wherein s=0,1 or 2, and R7 is selected from the group consisting of:
(aaa) C1-C3-alkyl, (bbb) aryl;
(ccc) substituted-aryl;
(ddd) heteroaryl; and (eee) substituted-heteroaryl;
(c) -CH2-N(-(CH2)r-M-(CH2)s-R7)-CH2-, wherein r=0,1 or 2; s=0,1 or 2, and M and R7 are as defined above; and (d) -CH2-(CH2)r-CH2-, wherein r=0, 1 or 2.

9. A compound according to Claim 1 which is:
Compound of Formula (IV); R1=methoxy; R2=hydrogen; A=B=D=E=hydrogen;
Compound of Formula (III), A=B=E=H, D=benzyl, R1=methoxy, R2=hydrogen;
Compound of Formula (III), A=B=D=H, E=benzyl, R1=methoxy, R2=hydrogen;
Compound of Formula (III); A=benzyl, B=D=E=H, R1=methoxy, R2=hydrogen;
Compound of Formula (III); B=benzyl, A=D=E=H, R1=methoxy, R2=hydrogen;
Compound of Formula (III); A=E=phenyl, B=D=H, R1=methoxy, R2=hydrogen;
Compound of Formula (III); A=methyl, B=D=E=H, R1=methoxy, R2=hydrogen;
Compound of Formula (III); B=methyl, A=D=E=H, R1=methoxy, R2=hydrogen;
Compound of Formula (III); A=D=methyl; B=E=H, R1=methoxy, R2=hydrogen;
Compound of Formula (III); A=E=methyl; B=D=H, R1=methoxy, R2=hydrogen;
Compound of Formula (III); B=D=H; A and E taken together is -CH2CH2CH2-, R1=methoxy, R2=hydrogen;
Compound of Formula (III); B=E=H; A and D taken together is -CH2CH2CH2CH2-, R1=methoxy, R2=hydrogen;
Compound of Formula (I); A=B=D=E=hydrogen; R1=hydrogen, R2=hydrogen;
Compound of Formula (III): R1=OCH3, R2=H; A=B=D=H; E=-CH2NH2;

Compound of Formula (III): R1=OCH3, R2=H; A=B=E=H; D=-CH2NH2;
Compound of Formula (III): R1=OCH3, R2=H; B=E=H; A and D taken together is -CH2CH2CH2-;
Compound of Formula (III): R1=OCH3, R2=H; B=E=H; A and D taken together is -CH2OCH2-;
Compound of Formula (III): R1=OCH3, R2=H; B=E=H; A and D taken together is -CH2-NH-CH2-;
Compound of Formula (III): R1=OCH3, R2=H; B=E=H; A and D taken together is -CH2-N(Cbz)-CH2-;
Compound of Formula (III): R1=OCH3, R2=H; B=E=H; A and D taken together is -CH2-N(benzyl)-CH2-;
Compound of Formula (III): R1=OCH3, R2=H; B=E=H; A and D taken together is -CH2-N(benzoyl)-CH2-;
Compound of Formula (III): R1=OCH3, R2=H; B=E=H; A and D taken together is -CH2-N(phenyl-CH2-CH2-)-CH2-;
Compound of Formula (III) R1=OCH3, R2=H; B=E=H; A and D taken together is -CH2-N(4-Cl-phenyl-CH2-)-CH2-;
Compound of Formula (III) R1=OCH3, R2=H; B=E=H; A and D taken together is -CH2-N(4-pyridyl-CH2-)-CH2-;
Compound of Formula (III) R1=OCH3, R2=H; B=E=H; A and D taken together is -CH2-N(2-pyridyl-CH2-)-CH2-;
Compound of Formula (III) R1=OCH3, R2=H; B=E=H; A and D taken together is -CH2-N(3-pyridyl-CH2-)-CH2-;
Compound of Formula (III) R1=OCH3, R2=H; B=E=H; A and D taken together is -CH2-N(4-quinolyl-CH2-)-CH2-;
Compound of Formula (III): R1=OCH3, R2=H; B=E=H; A=D=-CH2-O-CH2-phenyl;
Compound of Formula (III): R1=OCH3, R2=H; B=E=H; A=D=-CH2-OH;
Compound of Formula (III): R1=OCH3, R2=H; B=E=H; A=D=-CH2-O-phenyl;
Compound of Formula (III): R1=OCH3, R2=H; A=B=H; D and E taken together is -CH2-CH2-CH2-CH2-;
Compound of Formula (III): R1=OCH3, R2=H; A and B taken together is -CH2-CH2-CH2-CH2-; D=E=H;
Compound of Formula (III): R1=OCH3, R2=H; A=B=H; D and E taken together is -CH2-O-CH2-;
Compound of Formula (III): R1=OCH3, R2=H; A=D=E=H; B=-CH2-CH2-phenyl;
Compound of Formula (III): R1=OCH3, R2=H; A=D=E=H; B=-CH2-CH2-CH2-phenyl;

Compound of Formula (III): R1=OCH3, R2=H; A=D=E=H; B=-CH2-O-CH2-phenyl;
Compound of Formula (III): R1=OCH3, R2=H; A=D=E=H; B=-CH2-CH2-(4-OCH3-phenyl);
Compound of Formula (III): R1=OCH3, R2=H; A=-CH2-CH2-phenyl; B=D=E=H;
Compound of Formula (III): R1=OCH3, R2=H; A=-CH2-CH2-CH2-phenyl;
B=D=E=H;
Compound of Formula (III): R1=OCH3, R2=H; A=-CH2-O-CH2-phenyl;
B=D=E=H;
Compound of Formula (III): R1=OCH3, R2=H; B=D=E=H; A=-CH2-CH2-(4-OCH3-phenyl);
Compound of Formula (III): R1=OCH3, R2=H; A=B=D=H; E=-CH2-CH2-Ph;
Compound of Formula (III): R1=OCH3, R2=H; A=B=E=H; D=-CH2-CH2-Ph;
Compound of Formula (III): R1=OCH3, R2=H; A=B=D=H; E=-CH2-CH2-CH2-Ph;
Compound of Formula (III): R1=OCH3, R2=H; A=B=E=H; D=-CH2-CH2-CH2-Ph;
Compound of Formula (III): R1=OCH3, R2=H; A=- CH2-CH2-OPh; B=D=E=H;
Compound of Formula (III): R1=OCH3, R2=H; A=- CH2-CH2-NHCbz;
B=D=E=H;
Compound of Formula (III) R1=OCH3, R2=H; A=-CH2-CH2-NH2; B=D=E=H;
Compound of Formula (III): R1=OCH3, R2=H; A=- CH2-CO2Benzyl; B=D=E=H;
Compound of Formula (III) R1=OCH3, R2=H; A=-CH2-COOH; B=D=E=H;
Compound of Formula (III) R1=OCH3, R2=H; A=-CH2-CH2-OH; B=D=E=H;
Compound of Formula (III):R1=OCH3, R2=H; A=- CH2-CH2-NH(4-Pyridyl-);
B=D=E=H
Compound of Formula (III): R1=OCH3, R2=H; A=B=D=H; E=-CH2-OH;
Compound of Formula (III): R1=OCH3, R2=H; A=B=E=H; D=-CH2-OH;
Compound of Formula (III): R1=OCH3, R2=H; A=B=E=H; D=-CH2-NHBenzoyl;
Compound of Formula (III): R1=OCH3, R2=H; A=B=E=H; D=-CH2-NHBenzyl;
Compound of Formula (III): R1=OCH3, R2=H; A=B=D=H; E=-CH2-NHBenzoyl;
Compound of Formula (III): R1=OCH3, R2=H; A=B=D=H; E=-CH2-NHBenzyl;
Compound of Formula (III): R1=OCH3, R2=H; B=D=H; A=E=-CH2OCH2(4-Cl-phenyl);
Compound of Formula (III): R1=OCH3, R2=H; A=B=E=H; D=-CH2-N(CH3)-Benzyl;
Compound of Formula (III): R1=OCH3, R2=H; A=B=D=H; E=-CH2-N(CH3)-Benzyl;

Compound of Formula (III): R1=OCH3, R2=H; A=B=D=H; E=-CH2-NH-phenyl;
or Compound of Formula (III): R1=OCH3, R2=H; A=B=E=H; D=-CH2-NH-phenyl.

10. A compound according to Claim 1 which is:
Compound of Formula (IV); R1=methoxy; R2=hydrogen; A=B=D=E=hydrogen;

Compound of Formula (III), A=B=E=H, D=benzyl, R1=methoxy, R2=hydrogen;

Compound of Formula (III), A=B=D=H, E=benzyl, R1=methoxy, R2=hydrogen;
Compound of Formula (III); A=benzyl, B=D=E=H, R1=methoxy, R2=hydrogen;
Compound of Formula (III); B=benzyl, A=D=E=H, R1=methoxy, R2=hydrogen;
Compound of Formula (III); A=E=phenyl, B=D=H, R1=methoxy, R2=hydrogen;

Compound of Formula (III); A=methyl, B=D=E=H, R1=methoxy, R2=hydrogen;

Compound of Formula (III); B=methyl, A=D=E=H, R1=methoxy, R2=hydrogen;

Compound of Formula (III); A=D=methyl; B=E=H, R1=methoxy, R2=hydrogen;

Compound of Formula (III); A=E=methyl; B=D=H, R1=methoxy, R2=hydrogen;

Compound of Formula (III); B=D=H; A and E taken together is -CH2CH2CH2-, R1=methoxy, R2=hydrogen;
Compound of Formula (III); B=E=H; A and D taken together is -CH2CH2CH2CH2-, R1=methoxy, R2=hydrogen; or Compound of Formula (I); A=B=D=E=hydrogen; R1=hydrogen, R2=hydrogen.

11. A pharmaceutical composition comprising an antibacterially effective amount of a compound as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable carrier.

12. Use of a compound as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for controlling a bacterial infection in a mammal.

13. A process for the preparation of tricyclic macrolide compounds having the Formulas:
wherein A, B, D and E are independently selected from the goup consisting of:
(a) hydrogen;
(b) C1-C6-alkyl, as defined below, optionally substituted with one or more substituents selected from the group consisting of:
(i) aryl, as defined below;
(ii) substituted-aryl, as defined below;
(iii) heteroaryl, as defined below;
(iv) substituted-heteroaryl, as defined below;
(v) heterocycloalkyl, as defined below;
(vi) hydroxy;
(vii) C1-C6-alkoxy, as defined below;
(viii) halogen consisting of Br, Cl, F or I; and (ix) NR3R4, where R3 and R4 are independently selected from hydrogen and C1-C6-alkyl, or R3 and R4 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring optionally containing a hetero function consisting of -O-, -NH-, -N(C1-C6-alkyl-)-, -N(aryl-C1-C6-alkyl-)-, -N(substituted-aryl-C1-C6-alkyl-)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl-)-, -S-or -S(O)n-, wherein n is 1 or 2;
(c) C3-C7-cycloalkyl;
(d) aryl;
(e) substituted-aryl;
(f) heteroaryl;
(g) substituted-heteroaryl;
(h) heterocycloalkyl;
and (i) a goup selected from option (b) above further substituted with -M-R5, wherein M is selected from the group consisting of (aa) -C(O)-NH-;

(bb) -NH-C(O)-;
(cc) -NH-(dd) -N(CH3)-(ee) -O-(rr) -S(O)n-, wherein n is 0, 1 or 2; and (gg) -C(=NH)-NH-:
and R5 is selected from the group consisting of:
(aaa) C1-C6-alkyl, optionally substituted with a substituent selected from the group consisting of:
(i) aryl;
(ii) substituted-aryl;
(iii) heteroaryl; and (iv) substituted-heteroaryl;
(bbb) aryl;
(ccc) substituted-aryl;
(ddd) heteroaryl;
(eee) substituted-heteroaryl; and (fff) heterocycloalkyl;
or any one pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7-membered ring optionally containing a hetero function consisting of -O-, -NH-, -N(C1-C6-alkyl-)-, -N(aryl-C1-C6-alkyl-)-, -N(substituted-aryl-C1-C6-alkyl-)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl-)-, -S- or -S(O)n-, wherein n is 1 or 2;
-C(O)-NH-;
-C(O)-NR5-, wherein R5 is as described above;
-NH-C(O)-;
-NR5-C(O)-, wherein R5 is as described above; and -C(=NH)-NH-;
R1 is selected from the group consisting of:
(a) hydrogen;
(b) hydroxy;

(c) -O-C1-C3-alkyl;
(d) -O-C3-C5-cycloalkyl;
(e) -O-C1-C3-alkyl-C3-C5-cycloalkyl;
(f) -O-C(O)-C1-C3-alkyl;
(g) -O-C(O)-O-C1-C3-alkyl; and (h) -O-C(O)-NH-C1-C3-alkyl;

R2 is hydrogen or a hydroxy-protecting group, as defined below; and Z is hydroxy or protected-hydroxy;

wherein aryl hereinbefore is phenyl or naphthyl;
heteroaryl hereinbefore is a cyclo aromatic radical of 5 to 10 ring atoms having 1 to 3 ring atoms selected from S, O and N, and the remaining ring atoms being C
atoms;
heterocycloalkyl hereinbefore is a non-aromatic 5-, 6- or 7-membered ring or a bi-or tri-cyclic group comprising fused six-membered rings, having 1 to 3 heteroatoms independently selected from O, S and N; and wherein:
i) each 5-membered ring has 0 or 1 double bonds and each 6-membered ring has 0, 1 or 2 double bonds;
ii) N and S heteroatoms are unoxidized or oxidized;
iii) N heteroatoms are unquaternized or quaternized; and iv) heterocyclic rings are unfused or fused to a benzene ring;

except when the compound is of Formulas (I) or (III) then A, B, D, and E may not all be hydrogen, D and E may not be C1-C3-alkyl when A and B are hydrogen, nor may one of D
and E be hydrogen and the other be C1-C3-alkyl when A and B are hydrogen;
the method comprising:
(a) treating a compound having the formula:

respectively, wherein R1 is as described above and R2 is a hydroxy-protecting group, with a base, and followed by reaction with carbonyldiimidazole, in an aprotic solvent, at a reaction temperature from -20°C to 70°C, for a period from 0.5 hours to 10 days, to prepare first intermediate compounds having the formulas:

respectively;
wherein R1 and R2 are as described above;
(b) reacting said first intermediate compounds with a compound having the formula:

wherein A, B, D, and E are as described above, to give the bicyclic second intermediate compounds having the formulas:

respectively;
wherein R1 and R2 are as described above;
(c) deprotecting said second intermediate compounds by treatment with methanol or ethanol when OR2 is an ester or with fluoride. in THF or acetonitrile when R2 is a trialkylsilyl group, for from 1 to 24 hours, to give the third intermediate compounds:

respectively; and (d) cyclizing said third intermediate compounds by treatment with dilute acid, in an organic solvent, for a period of from 4 hours to 10 days to give the desired compounds (I), (II), (III) or (IV) above.

14. A process according to Claim 13 wherein:
in step (a) the aprotic solvent is selected from the group consisting of dichloro-methane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof, the reaction temperature is from 0°C to reaction temperature, and the period of reaction is 1-8 hours;
in step (b) the reaction is run in aqueous acetonitrile, DMF ar aqueous DMF;
in step (c) deprotecting said second intermediate compounds by treatment with methanol or ethanol when OR2 is an ester or with fluoride in THF or acetonitrile when R2 is a trialkylsilyl group, for from 1 to 24 hours; and in step (d) cyclizing said third intermediate compounds by treatment with dilute acetic acid or HCl in ethanol or propanol for a period of from 4 hours to 10 days to give the desired compounds.

15. A process for the preparation of tricyclic macrolide derivatives having the Formulas:

wherein A, B, D and E are independently selected from the group consisting of:
(a) hydrogen;
(b) C1-C6-alkyl, as defined below, optionally substituted with one or more substituents selected from the group consisting of:
(i) aryl, as defined below;
(ii) substituted-aryl, as defined below;
(iii heteroaryl, as defined below;
(iv substituted-heteroaryl, as defined below;
(v) heterocycloalkyl, as defined below;
(vi) hydroxy;
(vii) C1-C6-alkoxy, as defined below;
(viii) halogen consisting of Br, Cl, F or I; and (ix) NR3R4, where R3 and R4 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring optionally containing a hetero function consisting of -O-, -NH-, -N(C1-C6-alkyl-)-, -N(aryl-C1-C6-alkyl-)-, -N(substituted-aryl-C1-C6-alkyl-)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl-)-, -S- or -S(O)n-, wherein n is 1 or 2;
(c) C3-C7-cycloalkyl;
(d) aryl;
(e) substituted-aryl;
(f) hereroaryl;
(g) substituted-heteroaryl;
(h) heterocycloalkyl;
and (i) a group selected from option (b) above further substituted with -M-R5, wherein M is selected from the group consisting of (aa) -C(O)-NH-;
(bb) -NH-C(O)-;

(cc) -NH-(dd) -N(CH3)-(ee) -O-(rr) -S(O)n-, wherein n is 0, 1 or 2; and (gg) -C(=NH)-NH-;
and R5 is selected from the group consisting of:
(aaa) C1-C6-alkyl, optionally substituted with a substituent selected from the group consisting of:
(i) aryl;
(ii) substituted-aryl;
(iii) heteroaryl; and (iv) substituted-heteroaryl;
(bbb) aryl;
(ccc) substituted-aryl;
(ddd) heteroaryl;
(eee) substituted-heteroaryl; and (fff) heterocycloalkyl;
or any one pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7-membered ring optionally containing a hetero function consisting of:
-O-.
-NH-, -N(C1-C6-alkyl-)-, -N(aryl-C1-C6-alkyl-)-, -N(substituted-aryl-C1-C6-alkyl-)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl-)-, -S- or -S(O)n-, wherein n is 1 or 2;
-C(O)-NH-;
-C(O)-NR5-, wherein R5 is as described above;
-NH-C(O)-;
-NR5-C(O)-, wherein R5 is as described above; and -C(=NH)-NH-;
R1 is selected from the group consisting of:
(a) hydrogen;
(b) hydroxy;
(c) -O-C1-C3-alkyl;

(d) -O-C3-C5-cycloalkyl;
(e) -O-C1-C3-alkyl-C3-C5-cycloalkyl;
(f) -O-C(O)-C1-C3-alkyl;
(g) -O-C(O)-O-Cl-C3-alkyl; and (h) -O-C(O)-NH-C1-C3-alkyl;
R2 is hydrogen or a hydroxy-protecting group, as defined below; and Z is hydroxy or protected-hydroxy;
wherein aryl hereinbefore is phenyl or naphthyl;
heteroaryl hereinbefore is a cyclo aromatic radical of 5 to 10 ring atoms having 1 to 3 ring atoms selected from S, O and N, and the remaining ring atoms being C
atoms;
heterocycloalkyl hereinbefore is a non-aromatic 5-, 6- or 7-membered ring or a bi-or tri-cyclic group comprising fused six-membered rings, having 1 to 3 heteroatoms independently selected from O, S and N; and wherein:
i) each 5-membered ring has 0 or 1 double bonds and each 6-membered ring has 0, 1 or 2 double bonds;
ii) N and S heteroatoms are unoxidized or oxidized;
iii) N heteroatoms are unquaternized or quaternized; and iv) heterocyclic rings are unfused or fused to a benzene ring;

except when the compound is of Formulas (I) or (III) then A, B, D, and E may not all be hydrogen, D and E may not be C1-C3-alkyl when A and B are hydrogen, nor may one of D
and E be hydrogen and the other be C1-C3-alkyl when A and B are hydrogen;
the method comprising:
(a) treating a compound having the formula:
respectively, wherein R1 is as described above and R2 is a hydroxy-protecting group, with a base, and followed by reaction with carbonyldiimidazole, in an aprotic solvent, at a reaction temperature from -20°C to 70°C, for a period from 0.5 to 24 hours, to prepare first intermediate compounds having the formulas:
respectively;
wherein R1 and R2 are as described above;
(b) reacting said first intermediate compounds with a compound having the having the formula:
wherein A, B, D, and E are as described above to give the bicyclic second intermediate compounds:
respectively;
(c) reacting the hydroxy group of the said bicyclic second intermediate compounds by treatment with triphenylphosphine and diphenylphosphoryl azide in tetrahydrofuran, under Mitsunobu reaction conditions, to prepare the third intermediate compounds:
respectively;
(d) reducing the third intermediate compounds having an azido group, with reducing reagents to prepare the fourth intermediate compounds having the formulas:
respectively; and (e) cyclizing said fourth intermediate compounds by treatment with a dilute acid, in an organic solvent, for a period of from 4 hours to 10 days to give the desired compounds of Formulas (I), (II), (III) or (IV).

16. The process as in Claim 15 wherein:
in step (a) the base is sodium hydride, lithium hydride, or potassium carbonate, the aprotic solvent is dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof, the reaction temperature is from 0°C to reaction temperature, and the reaction period is from 1-8 hours;
in step (b) the solvent is aqueous acetonitrile, DMF or aqueous DMF;
in step (c) the reagents are triphenylphosphine and diphenylphosphoryl azide-DEAD
in tetrahydrofuran, under Mitsunobu reaction conditions;
in step (d) the reducing reagent is triphenylphosphine-water, hydrogen with a catalyst, sodium borohydride, or dialkylaluminum hydride;
in step (e) cyclizing said third intermediate compounds by treatment with dilute acetic acid or HCl in ethanol or propanol for a period of from 4 hours to 10 days to give the desired compounds.

17. The process as in Claim 15 wherein:
step (c) is replaced with a two-step sequence which comprises (1) reacting the hydroxy group of the bicyclic second intermediate compounds thereof with an alkyl or aryl sulfonyl chloride, an alkyl or aryl sulfonic anhydride or trifluoromethanesulfonic anhydride in an aprotic solvent at -78°C to reaction temperature to give the corresponding sulfonate, and (2) reacting the said sulfonate with lithium azide or sodium azide in an aprotic solvent at 0°C
to 100°C to give the third intermediate compound.